It’s a receptor that binds glucose strongly and with the highest selectivity yet. Could help with #diabetes treatment: http://ow.ly/EPzn30mDYjf
Read all at
A new “flozin” seems to me appearing on the horizon in form of SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem, picked up a list from WO 2012160218, from TFChem…….see link , Sirona Biochem Announces SGLT2 Inhibitor and Skin Lightening Patent Granted, 29 Jun 2015, Patent entitled “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”
This led me to search, “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”
WO 2012160218 A1, IN 2013-DN10635, CN 103649033Tf化学公司
| Applicant | Tfchem |
List above as in http://www.google.com/patents/WO2012160218A1?cl=en
FROM THE ABOVE LIST, SBM-TFC-039 MAY BE PREDICTED/OR AS SHOWN BELOW
COMPD 16 as in/WO2012160218
COMPD 16, PREDICTED/LIKELY SBM-TFC-039 has CAS 1413373-30-4, name D-myo-Inositol, 1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1,2,3-trideoxy-2,2-difluoro-3-(hydroxymethyl)-
Just scrolling through the patent gave me more insight
MORE EVIDENCE….http://www.google.com/patents/WO2012160218A1?cl=en, this patent descibes compd 16 as follows
Compound 16 according to the invention has been compared to Dapaglifozin to underline the improvement of the duration of action, i.e. the longer duration of glucosuria, of the compound when the intracyclic oxygen atom of the glucose moiety is replaced by a CF2 moiety.
This assay has been carried out at a dose of 3 mg/ kg.
The results obtained are presented on Figure 5. It appears thus that 16 (3 mg/kg) triggered glucosuria that lasted beyond 24 hours compared to Dapagliflozin.
• Compound 16 according to the invention has been compared to the compound 9 of WO 2009/1076550 to underline the improvement of the duration of action of the compound when a mimic of glucose bearing a CH-OH moiety instead of the intracyclic oxygen atom is replaced by a mimic of glucose bearing a CF2 in place of the CH-OH moiet .
| Company | Sirona Biochem Corp. |
| Description | Sodium-glucose cotransporter 2 (SGLT2) inhibitor |
| Molecular Target | Sodium-glucose cotransporter 2 (SGLT2) |
| Mechanism of Action | Sodium-glucose cotransporter 2 (SGLT2) inhibitor |
| Therapeutic Modality | Small molecule |
| Latest Stage of Development | Preclinical |
| Standard Indication | Diabetes |
| Indication Details | Treat Type II diabetes |
| Regulatory Designation | |
| Partner | Shanghai Fosun Pharmaceutical Group Co. Ltd. |
SBM-TFC-039
PATENT
WO 2012160218
http://www.google.com/patents/WO2012160218A1?cl=en
Examples within this first subclass include but are not limited to:
Synthesis of compound 8
C35H34O5 M = 534.64 g.mol“
Mass: (ESI ): 535.00 (M + H); 552.00 (M + H20); 785.87; 1086.67 (2M + H20)
A.
Procedure A:
To a solution of 4 (10.5g, 15.89mmol, leq) in toluene (400mL) were added 18-crown-6 (168mg, 0.64mmol, 0.04eq) and potassium carbonate (6.69g, 48.5mmol, 3.05eq.). The mixture was stirred overnight at room temperature, and then the remising insoluble material was filtered off and washed with toluene. The filtrate and the washings were combined, washed with 2N hydrochloric acid aqueous solution followed by saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford cyclohexenone 8 (4.07g; 48% yield) as yellowish oil.
Procedure B:
A solution of 7 (3.27g, 5.92mmol, leq) in pyridine (14mL) was cooled to 0°C before POCl3 (2.75mL, 29.6mmol, 5eq) was added dropwise. The mixture was stirred at this temperature for 10 min before the cooling bath was removed. The reaction mixture was stirred overnight at room temperature before being re-cooled to 0°C. POCI3 (2.75mL, 29.6mmol, 5eq) was added once again trying to complete the reaction. The mixture was stirred for an additional 20h at room temperature before being diluted with Et20 (20mL) and poured onto crushed ice. 1M HC1 aqueous solution (lOOmL) was added, and the mixture was extracted with Et20 (200mL & l OOmL). The combined organic extracts were washed with brine (lOOmL), dried over sodium sulphate, filtered and concentrated before being purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 80:20) to afford compound 8 (1.46g, 46% yield) as an orange oil. Synthesis of compound 9
C15H12BrC102 M = 339.61 g.moF1
Mass: (GC-MS): 338-340
The synthesis of this product is described in J. Med. Chem. 2008, 51, 1 145—1149.Synthesis of compound 10
C15H14B1CIO M = 325.63 g.mof1
10 The synthesis of this product is described in J. Med. Chem. 2008, 51, 1145-1 149.
Synthesis of compound 11
C50H49CIO6 M = 781.37 g.moF1
Mass: ESI+): 798.20 (M + H20)
Under inert atmosphere, Mg powder (265mg, 10.9mmol, 2.4eq) was charged into a three necked flask, followed by addition of a portion of 1/3 of a solution of the 4- bromo-l-chloro-2-(4-ethylbenzyl)benzene (2.95g, 9.1mmol; 2eq) in dry THF (25mL) and 1 ,2-dibromoethane (10 mol % of Mg; 85mg; 0.45mmol). The mixture was heated to reflux. After the reaction was initiated (exothermic and consuming of Mg), the remaining solution of 2-(4-ethylbenzyl)-4-bromo-l-chlorobenzene in dry TFIF was added dropwise. The mixture was then allowed to react for another one hour under gentle reflux until most of the Mg was consumed.
The above Grignard reagent was added dropwise into the solution of cyclohexenone 8 (2.42g, 4.53mmol, leq) in dry THF (25mL) under inert atmosphere at room temperature (about 25°C), then allowed to react for 3h. A saturated aqueous solution of ammonium chloride was added into the mixture to quench the reaction. The mixture was extracted with Et20, washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound 11 as a yellow oil (3.01g, 86%).
Synthesis of compound 12
C5oH49C105 M = 765.37 g.mol“1
+): 782.13 (M + H20)
Triethylsilane (0.210mL, 1.30mmol, 3eq) and boron-trifluoride etherate (48% BF3, O. l lOmL, 0.866mmol, 2eq) were successively added into a solution of alcohol 1 1 (338mg, 0.433mmol, leq) in dichloromethane (5mL) under inert atmosphere at -20°C. After stirring for 2.5h, a saturated aqueous solution of sodium chloride was added to quench the reaction. The mixture was extracted with CH2C12 (10mLx3) and the organic layer was washed with brine, dried over Na2S04, filtrated and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound 12 as a white powder (278 mg, 0.363mmol, 84%).
Synthesis of compound 13
C5oH5tC106 M = 783.39g.moF1
Mass: (ESI+): 800 (M + H20); 1581 (2M + H20)
Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33mmol, 10.5eq) was added to a solution of 12 (2.41g; 3.15mmol, leq) in dry THF (lOOmL) cooled to 0°C. The reaction mixture was then refluxed for lh,cooled to 0°C and treated carefully with sodium hydroxide (3M in H20, 10.5mL, 31.5mmol, lOeq), followed by hydrogen peroxide (30% in H20, 3.2mL, 31.5mmol, l Oeq) at room temperature (above 30°C). The mixture was allowed to react overnight at room temperature (~25°C) before a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) to afford the desired compound 13 (1.05g; 43%) as a yellowish oil.
Synthesis of compound 14
C50H49CIO6 M = 781.37g.mol“1
Mass: (ESI+): 798 (M + H20); 1471; 1579 (2M + H20)
13 14
Dess-Martin periodinane (81mg; 1.91mmol; 1.5eq) was added portion wise to a solution of alcohol 13 (l .Og; 1.28mmol, leq) in anhydrous dichloromethane (20mL) at 0°C. The reaction was then stirred overnight at room temperature before being quenched with IN aqueous solution of sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 82: 18), to afford the target ketone 14 (783mg, 79% yield) as a colorless oil. Synthesis of compound 15
C5oH49ClF206 M = 803.37g.moF1
19 F NMR (CDCU, 282.5MHz): -100.3 (d, J=254Hz, IF, CFF); -1 13.3 (td, Jl=254Hz, J2=29Hz, IF, CFF).
Mass: (ESI+): 820.00 (M+H20)
14 15
A solution of ketone 14 (421mg, 0.539mmol, leq) in DAST (2mL, 16.3mmol, 30eq.) was stirred under inert atmosphere at 70°C for 12h. The mixture was then cooled to room temperature and dichloromethane was added. The solution was poured on a mixture of water, ice and solid NaHC03. Agitation was maintained for 30min while reaching room temperature. The aqueous layer was extracted with dichloromethane and the organic phase was dried over Na2S04, filtered and concentrated. The crude product was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound 15 as a yellowish oil ( 182mg, 42% yield).
Synthesis of compound 16
C22H25CIF2O5 M = 442.88g.mor1
19 F NMR (MeOD, 282.5MHz): -96.7 (d, J=254Hz, IF, CFF); 12.2 (td,
Jl=254Hz, J2=28Hz, IF, CFF).
Mass: (ESI+): 465.3 (M+Na)
o-Dichlorobenzene (0.320mL, 2.82mol, lOeq) followed by Pd/C 10% (0.342g, 0.32mol, l .leq) were added to a solution of 15 (228mg, 0.28mmol, leq) in a mixture of THF and MeOH (2: 1, v/v, 160mL). The reaction was placed under hydrogen atmosphere and stirred at room temperature for 2h. The reaction mixture was filtered and concentrated before being purified on silica gel chromatography (dichloromethane/methanol 100: 1 to 90: 10) to afford compound 16 (105mg, 83% yield).
Vancouver, British Columbia – December 7, 2012 – Sirona Biochem Corp. (TSX-V: SBM), announced its sodium glucose transporter (SGLT) inhibitor for Type 2 diabetes reduced blood glucose more effectively than Johnson and Johnson’s canagliflozin, an advanced SGLT inhibitor being considered for market approval in Europe and the U.S. Studies compared Sirona Biochem’s SGLT Inhibitor, SBM-TFC-039, with canagliflozin and were conducted on Zucker Diabetic Fatty (ZDF) rats.
In the study, SBM-TFC-039 significantly and rapidly reduced blood glucose levels at a dose of 1.0 mg/kg. Six (6) hours after administration, SBM-TFC-039 reduced blood glucose by 44% compared to canagliflozin at 26%. SBM-TFC-039 also had a longer duration of effect than canagliflozin. At 36 and 48 hours after treatment, SBM-TFC-039, at a dose of 1.0 mg/kg, was still effective at reducing blood glucose, whereas canagliflozin lost its effect after 36 hours. Studies were conducted at the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ) by Principal Investigator Dr. Denis Richard, Research Chair on Obesity and Professor, Faculty of Medicine, Department of Anatomy & Physiology at Laval University.
“SGLT Inhibitors are a ground-breaking new treatment for Type 2 diabetes and these results demonstrate that SBM-TFC-039 will be a significant competitor for other SGLT Inhibitors,” said Neil Belenkie, Chief Executive Officer of Sirona Biochem. “The first SGLT Inhibitor,Forxiga™, was approved last month by the European Commission. We believe there is tremendous market potential worldwide for SGLT Inhibitors in the treatment of diabetes.”
SBM-TFC-039 is a sodium glucose transporter (SGLT) inhibitor. SGLT inhibitors are a new class of drug candidates for the treatment of diabetes. In the kidneys, SGLT inhibitors reduce the reabsorption of glucose into the bloodstream by eliminating excess glucose into the urine.
About Sirona Biochem Corp.
Sirona Biochem is a biotechnology company developing diabetes therapeutics, skin depigmenting and anti-aging agents for cosmetic use, biological ingredients and cancer vaccine antigens. The company utilizes a proprietary chemistry technique to improve pharmaceutical properties of carbohydrate-based molecules. For more information visit www.sironabiochem.com.
Laboratory – France
TFChem
Voie de l’innovation
Pharma Parc II
Chaussée du Vexin
27100 Val de Reuil
France
Phone:+33(0)2.32.09.01.16
Fax:+33(0)2.32.25.07.64
……………………………………………………………………………….
Shanghai Fosun Pharmaceutical Group Co. Ltd.
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ALOGLIPTIN
Alogliptin is a potent, selective inhibitor of DPP-4 with IC50 of <10 nM, exhibits greater than 10,000-fold selectivity over DPP-8 and DPP-9.
Alogliptin (trade name Nesina in the US[1] and Vipidia in Europe[2]) is an orally administered anti-diabetic drug in the DPP-4 inhibitor class,[3] developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005. Like other medications for the treatment of Type 2 diabetes, alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of causing hypoglycemia, and exhibits relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in patients whose diabetes cannot adequately be controlled with metformin alone.[4]
Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) that is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). [5]
A randomized clinical trial reporting in 2011 aimed to determine the efficacy and safety of alogliptin versus placebo and vogliboseamong newly diagnosed Type 2 diabetes patients in Japan. The main outcome indicated that alogliptin was statistically superior to both comparitors.[6]
A randomized clinical trial reporting in 2012 aimed to demonstrate that alogliptin was “non-inferior” to a “very low fat/calorie traditional Japanese diet” among newly diagnosed Type 2 diabetes patients in Japan. The outcome indicated that both the drug and dietary treatments comparably impacted indicators of the diabetic condition, such as HbA1c levels and glycemic efficacy. The drug treatment had its impact without changing body mass index (BMI), but the dietary treatment was accompanied by a significant reduction in the BMI.[7]
A randomized clinical trial reporting in 2011 aimed to demonstrate the efficacy of alogliptin as an add-on agent in combination withmetformin and pioglitazone versus simply increasing the dosage of pioglitazone in combination with metformin; in other words, this was a study to look at a three-agent therapy versus a two-agent therapy. The outcome of this study suggested that the addition of alogliptin to metformin and pioglitazone provided superior impact on diabetes biomarkers (e.g. HbA1c) than increasing the dose of pioglitazone in a two agent therapy with metformin.[8]
Adverse events appear to be restricted to mild hypoglycemia based on clinical studies.[6][7][8]
Alogliptin is not associated with increased weight, increased risk of cardiovasular events, or heart failure.[9][10]
In December 2007, Takeda submitted a New Drug Application (NDA) for alogliptin to the United States Food and Drug Adminiistration (USFDA),[11] after positive results from Phase III clinical trials.[1] In September of 2008, the company also filed for approval in Japan,[12] winning approval in April 2010.[11] The company also filed a Marketing Authorization Application (MAA) elsewhere outside the United States, which was withdrawn in June 2009 needing more data.[12] The first USFDA NDA failed to gain approval and was followed by a pair of NDAs (one for alogliptin and a second for a combination of alogliptin and pioglitazone) in July 2011.[11] In 2012, Takeda received a negative response from the USFDA on both of these NDAs, citing a need for additional data.[11]
In 2013 the FDA approved the drug in three formulations: As a stand-alone with the brand-name Nesina. Combined with metforminusing the name Kazano, and when combined with pioglitazone as Oseni.
Diabetes affects millions of people worldwide and is considered one of the main threats to human health in the 21st century. In 2006, the World Health Organization (WHO) estimated that over 180 million people worldwide had diabetes, and the number is projected to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. According to the WHO, approximately 1.1 million people died from diabetes in 2005, and it is estimated that diabetes-related deaths will increase by more than 50% in the next decade. Globally, the socioeconomic burden of diabetes is substantial.
There are two main types of diabetes, designated type 1 and type 2, with type 2 diabetes accounting for over 90% of all diabetes cases globally. Type 1 diabetes is characterized by insulin deficiency, primarily caused by autoimmune-mediated destruction of pancreatic islet β-cells, and type 2 diabetes is characterized by abnormal insulin secretion and concomitant insulin resistance. To prevent the development of ketoacidosis, people with type 1 diabetes must take exogenous insulin for survival. Although those with type 2 diabetes are not dependent on exogenous insulin as much as subjects with type 1 diabetes, they may require exogenous insulin to control blood glucose levels.
As diabetes has become a global health concern, research interest in the condition has rapidly increased. In addition to studies on prevention, many studies with the aim of developing new interventions for the treatment of diabetes, especially type 2 diabetes, have been conducted. Currently available medications for the treatment and management of type 2 diabetes include metformin, sulfonylureas, thiazolidinediones and insulin. However, these therapies are commonly associated with secondary failure and may cause hypoglycemia. Insulin resistance and progressively worsening hyperglycemia caused by reduced β-cell function are major challenges in managing type 2 diabetes. Evidence suggests that patients with insulin resistance do not develop hyperglycemia until their β-cells are unable to produce enough insulin. New agents that can enhance insulin secretion from islet β-cells in a sustained glucose-dependent manner could therefore hold promise for the treatment of type 2 diabetes.
One promising approach is based on inhibition of the serine protease dipeptidyl- peptidase IV (DPP IV), a postproline dipeptidyl aminopeptidase that belongs to the S9b peptidase family of proteolytic enzymes. It is known that DPP IV plays a key role in maintaining glucose homeostasis by controlling the incretin activity of glucagon-like peptide 1 (GLP-I) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide). Inhibition of DPP IV is therefore recognized as a novel therapeutic approach for the treatment of type 2 diabetes.
Recently, a series of DPP IV inhibitors were developed. Among these highly potent compounds, alogliptin benzoate (SYR-322) and its analogs demonstrated encouraging antidiabetic efficacy (EP 1586571 (WO 2005/095381); WO 2008/067465; WO 2007/035379, and US 2004/097510).
Alogliptin benzoate can be prepared as described in EP 1586571 (WO 2005/095381) according to the process set forth in Scheme 1 :
Scheme 1
In accordance with this process, 6-Chlorouracil (1) is alkylated with 2- (bromomethyl)benzonitrile in the presence of NaH and LiBr in a mixture of DMF- DMSO to produce the TV-benzyluracil derivative (2) in 54% yield. Compound (2) is further alkylated with iodomethane and NaH in DMF/THF to give the 1 ,3 disubstituted uracil (3) in 72% yield. Subsequent displacement of chlorouracil (IV) with 3(R)- aminopiperidine dihydrochloride in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (4), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol. The overall yield of this three-stage process is -20-25%. One of the disadvantages of above described process is the difficulty to separate and purify mixtures of solvents with high boiling point (for example, DMF/DMSO) for recycling. Another disadvantage is the usage of hazardous materials such as sodium hydride, which requires anhydrous solvents as a reaction media.
Intermediate 2-((6-chloro-3-methyl-2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)methyl) benzonitrile (3) is alternatively obtained by alkylation of 6-chloro-3 methyluracil with 2-(bromomethyl)benzonitrile by means of diisopropylethylamine in hot NMP (WO 2007/035629). Although this process is more technological than the previously described process (EP 1586571), the overall yield is still moderate (50-55%). The problem of mixed solvents (toluene, NMP, diisopropylethylamine) separation persists for this process as well.
………….
http://www.google.com/patents/EP2410855A1?cl=en
EXAMPLE 1
Preparation of (R)-2-((6-(3 -aminopiperidin-l-yl)-3 -methyl-2,4-dioxo-3 ,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 3):
Scheme 3
Preparation of l-(2-isocyanobenzyl)-3-methylurea
2-cyanobenzylamine hydrochloride (90 g) and Dichloromethane (800 ml) were taken into a round bottomed (RB) flask. Methyl isocyanate (45.6 g) was added at 5°C. Triethylamine (81 g) in Dichloromethane (300 ml) was added at the same temperature and stirred at room temperature for 16h. Water (1 L) was added and stirred for 30 min. The obtained solid was collected by filtration and dried in oven at 50°C for 12h. The yield is 85% and the purity 99.8%.
Preparation of l-(2-isocyanobenzyl)-3-methyIpyrimidine-2,4,6(lH,3H,5H)-trione
a). To a stirred solution of 0.11 mol of sodium ethanolate in 80 ml of ethanol abs. was added 0.1 mol of l-(2-isocyanobenzyl)-3-methylurea and 0.1 mol diethyl malonate. The mixture was refluxed for 3-5 h. The cooled residue was acidified with 0.1 M hydrochloric acid (60 ml). The solid which separated was filtered off and recrystallized from ethanol or any suitable solvent. The yield is 78-85% and purity >95%.
b). In an alternate embodiment, l-(2-isocyanobenzyl)-3-methylurea (30 g), acetic acid (105 ml) and malonic acid (18 g) were mixed and heated to 60°C. Acetic anhydride (60 ml) was added at 60°C and heating was continued for two hours at 80°C. The reaction mixture was poured over ice water (300 ml) and the obtained solid was filtered, washed with water (1×500 ml) and methyl-tert-butylether (100 ml). The yield is 60% with 93.4% purity.
The compound thus prepared can be used for the next step without purification or purified by crystallization or column chromatography.
Preparation of 6-chloro-l-(2-isocyanobenzyl)-3-methylpyriinidine-2,4(lH,3H)- dione
a). l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4,6(lH,3H,5H)-trione (30 g) was mixed with phosphorus oxychloride (300 ml) and cooled to 0°C. Water (9 ml) was added slowly, stirred for 10 min. and heated to reflux at 110°C for 5h. Progress of the reaction was monitored by TLC (50% Ethyl acetate/Hexane). On completion of the reaction, phosphorus oxychloride was distilled off. The crude compound was dissolved in dichloromethane (500 ml) and poured into ice water (500 ml) by small portions. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. The mixture of two isomers (4-chloro and 6-chloro derivatives = 1:1) was isolated and separated by column chromatography using neutral alumina and eluent – 25-50% of ethylacetate and hexane). The off-white solid was obtained, yield – 37%, purity – 99.8%. 1H NMR corresponds to literature data (J. Med. Chem. 2007, 50, 2297-2300).
b). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (18 mmol), phosphorus oxychloride (85 ml), benzyltriethylammonium chloride (16.5 g, 72 mmol) and phosphorus pentachloride (3.8 g, 18 mol) in acetonitrile (80 ml) was refluxed for 4-5 h with stirring. After evaporation under reduced pressure, the resulting oily residue was mixed with methylene chloride (or chloroform) and the mixture was poured into water and ice (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Crude product was crystallized from THF-hexanes to give desired compound in 70.5% yield.
c). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (13.1 mmol) in POCl3 (30 ml) was refluxed for 1-3 h. The solvent was concentrated and then partitioned with CH2Cl2 (100 ml) and water (100 ml). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 6-chloro compound as a solid (-95%). Compound can be also precipitated from concentrated methylene chloride solution by hexanes and used as a crude for the next step or purified by reslurring in isopropanol, filtered off, washed with isopropanol, and dried under vacuum at 55-60° C.
Preparation of (R)-tert-butyl l-(3-(2-isocyanobenzyI)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate
a). 6-chloro- l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (13 g), Dimethylformamide (130 ml), Potassium carbonate (13 g) and tert-butyl (R)-piperidin- 3-ylcarbamate (10.4 g) were heated to 80°C for 7 hrs. The mixture was then allowed to come to room temperature and poured over ice water (500 ml). The obtained solid was filtered and washed with cold water (500 ml). The solid thus obtained was taken in Methyl-tert-butylether (50 ml) stirred for 10 min. filtered and washed with Hexane (50 ml), to give the N-tert-butyloxycarbonyl protected compound in -75% yield. b). In an alternate embodiment, a flask charged with a stir bar, 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (4.10 mmol), (Λ)-3- terrtnityloxycarbonylaminopiperidine (4.64 mmol), K2CO3 (1.15 g, 8.32 mmol) and DMF (12 mL) was stirred at 75 °C for 6 h. Then, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the N-ter/butyloxycarbonyl protected compound in -93-96% yield.
Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile salts
a). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile hydrochloride
The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from previous procedure was dissolved in THF and acidified with 6M hydrochloric acid while maintaining the temperature below 15° C. The resultant slurry was cooled to 0-5° C, stirred at this temperature for 3-5 h and then filtered. The filter cake was washed twice with isopropanol and dried in vacuum at 45-5O0C to provide hydrochloride as a white crystalline solid.
b). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile trifluoroacetate
TFA (ImL) was added into the methylene chloride solution of (R)-tert-butyl l-(3-(2- isocyanobenzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3,6-tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from the above-mentioned procedure. The solution was stirred at room temperature for 1 h and then the mixture was concentrated in vacuo. The residue was dissolved in a small amount of MeOH or isopropanol and the desired salt was precipitated by addition of diisopropyl ether. The solids were filtered off, washed with diisopropyl ether and dried in vacuum at 45-5O0C to provide trifluoroacetate as an off- white powder. c). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile benzoate (Alogliptin)
The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate was dissolved in ethanol. A solution of benzoic acid in ethanol was added and the mixture was slowly heated to 65-70°C. The solution was stirred at this temperature for Ih and was then crystallized by cooling to 0-5° C and stirring for 12 hrs. The solution was filtered, washed with alcohol. The wet cake was then conditioned under nitrogen for 2 hours. The cake was dried for 8 hrs at 40-50° C to provide the benzoic acid salt of alogliptin as a white crystalline solid.
EXAMPLE 2:
Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 4)
Scheme 4 Preparation of 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)- dione
a). l-(2-isocyanobenzyl)-3-methylurea (0.2 mol) and cyanoacetic acid (0.22 mol) were dissolved in acetic anhydride (400 ml), and the mixture was heated at 80°C for 2 hours. Acetic anhydride was distilled off under reduced pressure and water (200 ml) was added. The mixture was cooled to 0-5 0C and 2N NaOH solution (220 ml) was added and stirring was continued for 2 hours. The obtained solids were filtered off, washed with cold methanol and dried under vacuum. The yield of 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione was 72 %.
b). Under nitrogen atmosphere, l-(2-isocyanobenzyl)-3-methylurea (98.4 g) and cyanoacetic acid (80.0 g) was added to N,N-dimethylformamide (836 ml). The mixture was stirred at room temperature and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at this temperature. The mixture was stirred at room temperature for 4 hrs, cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added drop wise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 3-(2-cyano-acetyl)-3- methyl-l-(2-isocyanobenzyl)-urea with 68% yield.
To 3-(2-cyano-acetyl)-3-methyl-l-(2-isocyanobenzyl)-urea (120 g) were added water (962 ml) and 2N aqueous sodium hydroxide solution (24.9 ml), and the mixture was stirred with heating at 80° C for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give 6-amino-l-(2-isocyanobenzyl)-3- methylpyrimidine-2,4(lH,3H)-dione in 76% yield.
c). 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (0.1 mol) was mixed with (R)-piperidin-3-yl-carbamic acid tert.-butyl ester hydrochloride (0.1 mol) of the appropriate amine hydrochloride and (R)-piperidin-3-yl-carbamic acid tert.-butyl ester (0.1 mol). The mixture was heated at 100°C and bubbling continued for 3 hr. Water was added to the cooled mixture and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give N-tert-butyloxycarbonyl protected compound in ~93-96% yield.
d). Benzoate salt of alogliptin was prepared as described above. While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.
………………
Patent EP2410855A1
http://www.google.com/patents/EP2410855A1?cl=en
…………..
NMR
SOURCE APEXBT
References
| EP1083172A1 * | May 26, 1998 | Mar 14, 2001 | Rimma Iliinichna Ashkinazi | N-substituted derivatives of 5-oxyiminobarbituric acid |
| US2598936 * | Apr 13, 1950 | Jun 3, 1952 | Searle & Co | Disubstituted cyanoalkanoylureas and thioureas and methods for their production |
| US6066641 * | Dec 12, 1995 | May 23, 2000 | Euro-Celtique S.A. | Aryl thioxanthines |
| US6248746 * | Jan 7, 1999 | Jun 19, 2001 | Euro-Celtique S.A. | 3-(arylalkyl) xanthines |
| US20080194593 * | Jan 11, 2008 | Aug 14, 2008 | Rao Kalla | A2b adenosine receptor antagonists |
| WO1994003456A1 * | Aug 5, 1993 | Feb 17, 1994 | Boehringer Ingelheim Kg | Asymmetrically substituted xanthine with adenosine-antagonistic properties |
| WO2001029010A1 * | Oct 18, 2000 | Apr 26, 2001 | Amjad Ali | Gram-positive selective antibacterial compounds, compositions containing such compounds and methods of treatment |
| WO2007035629A2 * | Sep 15, 2006 | Mar 29, 2007 | Takeda Pharmaceutical | Process for the preparation of pyrimidinedione derivatives |
| WO2007150011A2 * | Jun 22, 2007 | Dec 27, 2007 | Smithkline Beecham Corp | Prolyl hydroxylase inhibitors |
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
|
|
| Clinical data | |
| Trade names | Nesina, Vipidia Kazano, Vipidomet (withmetformin) Oseni, Incresync (withpioglitazone) |
| Pregnancy category |
|
| Legal status |
|
| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | 100% |
| Protein binding | 20% |
| Metabolism | Limited, hepatic (CYP2D6– and3A4-mediated) |
| Biological half-life | 12–21 hours |
| Excretion | Renal (major) and fecal (minor) |
| Identifiers | |
| CAS Registry Number | 850649-62-6  BENZOATE850649-61-5 FREE BASE |
| ATC code | A10BH04 |
| PubChem | CID: 11450633 |
| IUPHAR/BPS | 6319 |
| ChemSpider | 9625485 |
| UNII | JHC049LO86 |
| KEGG | D06553 |
| ChEBI | CHEBI:72323  |
| ChEMBL | CHEMBL376359 |
| Synonyms | SYR-322 |
| Chemical data | |
| Formula | C18H21N5O2 |
| Molecular mass | 339.39 g/mol |
Alogliptin benzoate
| MF: | C18H21N5O2.C7H6O2 |
| MW: | 461.519 |
| Melting Point: | 185-188°C |
| Optical Rotation: | -56.3° (c=1, MeOH) |
Solubility:Soluble in MeOH; Insoluble in ACN
850649-62-6 CAS
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Kuaile Lina, Zhengyan Caia & Weicheng Zhoua*
pages 3281-3286
tga
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NMR
SEE AN ONLINE NMR BELOW
NMR…………http://file.selleckchem.com/downloads/nmr/S400205-Sitagliptin-phosphate-monohydrate-HNMR-Selleck.pdf
………………….
PAPER
http://pubs.rsc.org/en/content/articlelanding/2014/an/c4an01681e#!divAbstract
DOI:
10.1039/C4AN01681E
CHECK OUT PREDICTIONS
UNDERSTAND THE SIGNALS
PREDICTIONS 1H NMR
PREDICTIONS 13 C NMR
LOOK FOR DELTA VALUES OF GROUPS
COSY NMR PREDICTION
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BELOW PAPENT DESCIBES THIS DRUG WELL IS RANDOMLY CHOSEN
http://www.google.com/patents/EP2491040A2?cl=en
Further, WO 2005/097733 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine employing a rhodium-based catalyst, [Rh(cod)Cl]2 having a chiral diphosphine ligand, as shown in Reaction Scheme 4.
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For description see at synfacts
https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505
Contributor: Philip Kocienski
Philip Kocienski, Professor of Organic Chemistry.
https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505
Bao H, Bayeh L, Tambar UK * The University of Texas Southwestern Medical Center at Dallas, USA
Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.
Synlett 2013;
24: 2459-2463
P. J. Kocienski
School of Chemistry
University of Leeds
Leeds LS2 9JT, UK
p.kocienski@chem.leeds.ac.uk
http://www.chem.leeds.ac.uk
Philip J. Kocienski was born in Troy, New York, in 1946. His love for organic chemsitry, amply stimulated by Alfred Viola whilst an undergraduate at Northeastern University, was further developed at Brown University, where he obtained his PhD degree in 1971 under Joseph Ciabattoni. Postdoctoral study with George Büchi at MIT and later with Basil Lythgoe at Leeds University, England, confirmed his interest in the synthesis of natural products. He was appointed Brotherton Research lecturer at Leeds in 1979 and Professor of Chemistry at Southampton University in 1985. In 1990 he was appointed Glaxo Professor of Chemistry at Southampton University. He moved to the University of Glasgow in 1997, where he was Regius Professor of Chemistry and now he is a Professor of Chemistry at Leeds University.
In addition to Prof. Kocienski’s work as an author he is also a member of the SYNTHESIS Editorial Board and contributes greatly to the development of Thieme Chemistry’s journals
Furthermore, Prof. Kocienski has also contributed to the Science of Synthesis project where he was an author for Volume 4, Compounds of Group 15 (As, Sb, Bi) and Silicon Compounds.
Prof. Kocienski is also responsible for compiling a database called Synthesis Reviews. This resource is free and contains 16,257 English review articles (from journals and books) of interest to synthetic organic chemists. It covers literature from 1970 to 2002.
GREENING UP DRUGS Merck process chemists redesigned and significantly shortened the original synthesis of type 2 diabetes drug candidate sitagliptin (Januvia) to include an unprecedented efficient hydrogenation of an unprotected enamine.
MERCK was selected for the award in the greener synthetic pathways category for revising the synthesis for sitagliptin, a chiral β-amino acid derivative that is the active ingredient in Januvia, the company’s pending new treatment for type 2 diabetes. The breakthrough leading to the new synthesis was the discovery that the amino group of the key enamine intermediate doesn’t need to be protected prior to enantioselective catalytic hydrogenation of the double bond.
This development has solved a long-standing problem in the synthesis of β-amino acid derivatives, which are known for their pharmacological properties and are commonly used as chiral building blocks, noted Karl B. Hansen, a Merck process chemist involved with the synthetic effort. The outcome has been to slash the number of reaction steps in the sitagliptin synthesis from eight to three, leading to an equally dramatic reduction in the amount of chemicals and solvent needed and the amount of waste generated.
Merck’s first-generation synthesis of sitagliptin involved preparing a β-hydroxy carboxylic acid, which was converted to a protected β-lactam and then coupled to a triazole building block. Deprotecting the resulting intermediate provided the β-amino acid moiety, and sitagliptin was isolated as a phosphoric acid salt.
This synthesis involved a roundabout route involving four steps to introduce the pivotal chiral amino group of sitagliptin. The synthesis worked well to prepare more than 100 kg of the compound for clinical trials, and with modifications it was deemed to be a viable though not very green manufacturing process, Hansen pointed out. For example, the original synthesis required a number of distillations and aqueous extractions to isolate intermediates, leading to a large volume of waste to treat.
“Being environmentally friendly and economically savvy can, and does, go hand-in-hand.”
Merck process chemists recognized that a much more efficient process was possible by synthesizing the β-amino acid portion of the molecule directly from an enamine. But the protection-deprotection of the amine nitrogen with an acyl group during the hydrogenation is difficult on a large scale, and unprotected reactions generally result in lower yields and lower enantiomeric excesses, Hansen said.
Undaunted, the Merck scientists working on the revised synthesis discovered that the amino group could be efficiently introduced by an unprotected hydrogenation using a rhodium catalyst with a ferrocenyl phosphine ligand named Josiphos (C&EN, Sept. 5, 2005, page 40). Merck turned to Solvias, a Swiss company with experience in asymmetric hydrogenations that manufactures Josiphos, as a partner to help speed up the process development.
The new synthesis involves first coupling trifluorophenyl acetic acid and triazole building blocks to form a diketoamide, which in turn is converted to the enamine. This sequence is carried out without isolating intermediates. The enamine is then hydrogenated, sitagliptin is isolated and recrystallized as the phosphoric acid salt, and the rhodium Josiphos catalyst is recovered.
In sum, the revised synthesis increases the overall yield of sitagliptin by nearly 50% and reduces the amount of waste by more than 80%. A key difference is that the original synthesis produced more than 60 L of aqueous waste per kg of product, while the new synthesis completely eliminates aqueous waste. When tallied up, Merck expects these savings will prevent formation of 150,000 metric tons of solid and aqueous process waste over the lifetime of Januvia. Industry analysts speculate that regulatory approval of the drug will come by early next year and that it’s destined to become a top-selling drug.
The novel enamine hydrogenation “is arguably the most efficient means to prepare β-amino acid derivatives,” noted R. P. (Skip) Volante, Merck’s vice president of process research. The company currently is using the procedure to make several other exploratory drug candidates, he added. Overall, the redesigned synthesis of sitagliptin “is a green chemistry solution to the preparation of a challenging synthetic target and is an excellent example of a scientific innovation resulting in benefits to the environment,” Volante said.
First generation route to sitagliptin. BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; EDC = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride; DIAD = di-isopropyl azodicarboxylate; NMM = N-methylmorpholine……..http://www.technology.matthey.com/article/55/2/135-139/
http://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc11592h#!divAbstract
http://www.nature.com/nature/journal/v485/n7397/fig_tab/nature11117_F4.html
PAPER
A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.
The synthesis of 1 was completed using a four-step through-process (Scheme 4). Lactam 5 or ester 13 was hydrolyzed to amino acid 2bwith LiOH18 in THF/water by either stirring at room temperature or, in the case of 13, heating to 40 °C. While the benzyloxy group of 2b could be cleaved by hydrogenation and then protected with Boc2O to prevent side reactions during the coupling to triazole 3, the benzyloxy group of 2b was found to sufficiently protect the amino group to allow the desired amide to be formed. Thus, triazole 3 was coupled to2b at 0 °C using EDC−HCl and N-methylmorpholine (NMM) as base to afford 14in >99% assay yield. Following an aqueous workup, the organic extracts were distilled into ethanol and the solution was subjected to hydrogenation with 10% Pd on carbon. The presence of water in the hydrogenation was found to be crucial to the reaction success; anhydrous solutions of 14 hydrogenated with dry Pd on carbon proceeded only to low levels of conversion to 1, and addition of water to these reductions resulted in restored performance of the catalyst. Following hydrogenation, the catalyst was removed by filtration to provide an ethanol solution of 1. Sitagliptin was isolated in >99.5% purity as its anhydrous phosphoric acid salt by crystallizing from aqueous ethanol.
Scott D Edmondson, Michael H Fisher,Dooseop Kim, Malcolm Maccoss, Emma R Parmee, Ann E Weber, Jinyou Xu
MORE INFO………
Sitagliptin phosphate monohydrate, a dipeptidyl-peptidase IV inhibitor, is marketed by Merck & Co. for the once-daily oral treatment of type 2 diabetes. The product was first launched in Mexico followed by commercialization in the U.S. The compound has also been filed for approval in the U.S. as adjunct to diet and exercise and in combination with other therapies to improve glycemic control in the treatment of diabetes. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the U.K., Germany and Spain. In 2009, sitagliptin phosphate monohydrate was approved and launched in Japan. The product is also available in Japan for the treatment of type 2 diabetes in combination with alpha-glucosidase inhibitors and in combination therapy with insulin. In 2012, the company filed for approval in Japan for the treatment of type 2 diabetes in patients with severe renal dysfunction, and in 2013 obtained the approval.
Sitagliptin phosphate monohydrate boasts a much lower risk of hypoglycemia than currently available insulin-inducing products due to its novel mechanism of action. MSD KK (formed in 2010 following the merger of Banyu and Schering-Plough KK) and Ono are developing the drug candidate in Japan. In 2008, the compound was licensed to Almirall by Merck Sharp & Dohme for comarketing in Spain for the treatment of type 2 diabetes. In 2010, FAES obtained a comarketing and commercialization license from Merck Sharp & Dohme in Spain for the treatment of type 2 diabetes.
Januvia (sitagliptin phosphate) is an antihyperglycaemic drug containing an orally active inhibitor of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Developed by Merck Sharp & Dohme (MSD), a UK subsidiary of Merck & Co, sitagliptin is used for treating type 2 diabetes mellitus. The drug has proved effective in lowering blood sugar levels of diabetes patients when taken alone or in combination with other oral diabetes medications such as metformin and thiazolidinedione.
Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006 and is marketed under the brand name Januvia in the US. Sitagliptin in combination with metformin was approved by the FDA in March 2007 and is marketed as Janumet in the US. In the EU, Januvia was approved in April 2007 and Janumet was approved in July 2008.
Sitagliptin is a triazolopiperazine based inhibitor of DPP-IV, which was discovered by
Merck. It is a potent (IC50= 18 nM) and highly selective over DPP-8 (48000 nM), DPP-9
(>100000 nM) and other isozymes.[16] It enhances the pancreatic β-cell functions, fasting and
post-prandial glycemic control in type 2 diabetic patients. In the crystal structure with DPP-IV,
unlike other substrate-based DPP-IV inhibitors, the binding orientation of the amide carbonyl of
sitagliptin is reversed, i.e. the aromatic trifluorophenyl moiety occupies S1 pocket and the β-
amino amide moiety fits into S2 pockets. The amino group forms a salt bridge and hydrogen
bonding interactions with Glu205 and Glu206, and Tyr662, respectively.The triazolopiperazinemoiety occupies the S2 extended pocket and stacks against Phe357. The exhibited binding
interactions of the trifluoromethyl group with the Arg358 and Ser209 are responsible for its high
selectivity profile. The presence of the trifluoromethyl group in the triazole ring also improves
the oral bioavailability in animal models. Sitagliptin inhibited the plasma DPP-IV up to 80% and
47% at 2 and 24 h, respectively, after a single dose of 25.0 mg in a dose-dependent manner. In a
24-week study, sitagliptin significantly decreased fasting glucose levels and HbA1c levels
(0.8%) at doses of 100 mg q.d. Thus, sitagliptin is well tolerated and body weight neutral. It is
the first DPP-IV inhibitor in the class approved by USFDA in 2006 and is used as either a
monotherapy or in combination with metformin
In the first synthetic approach, the synthesis of sitagliptin was started with the reaction of a Schollkopf reagent 6 with 2,4,5-trifluorobenzyl bromide to afford the compound 7, which was converted to compound 9 via hydrolysis of ester 8. The resulting Boc-protected amino acid 9 was converted to diazoketone 11 through mix anhydride protocol by using diazomethane. The intermediate 11 was converted to desired β-amino acid 12 by sonication in the presence of silver benzoate.[21] The sitagliptin (14) was synthesized by coupling of β-amino acid 12 with triazolopiperazine intermediate 5 followed by Boc deprotection of amino group of 13, and its corresponding hemi fumarate salt was then prepared (Scheme 1).[16]
The second approach for synthesis of sitagliptinwas started from asymmetric reduction of β-ketoester 15 using the (S)-BinapRuCl2 complex with a catalytic amount of HBr in methanol followed by hydrolysis afforded the β-hydroxy acid 16. Lactam 17 was synthesized by coupling of 16 with BnONH2 •HCl using N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC), followed by cyclization reaction with diisopropyl azodicarboxylate (DIAD) and PPh3 . [22] Treatment of a catalytic amount of 0.1% NaOH with lactam 17 hydrolyzed and directly afforded the β-amino acid 18. This wascoupled withtriazolopiperazine 5 using EDC•HCl and N-methylmorpholine to provide the N-benzyloxy protected compound 19, which after hydrogenation using Pd/C and by consequent treatment with phosphoric acid provided the phosphate salt of sitagliptin (14) (Scheme 2).
The third approach towards the synthesis of sitagliptin is outlined in scheme 3. Meldrum adduct 22 (Hunig’s base salt) was synthesized from trifluorophenylacetic acid 20 by the formation of a mixed anhydride with pivaloyl chloride in the presence of Meldrum’s acid 21, DIPEA and catalytic amount of dimethylamino pyridine (DMAP) in acetonitrile. Treatment of 22 with TFA resulted compound 23. β-keto amide 24 was formed on reaction of 23 with triazolopiperazine 5. β-keto amide 24 on treatment with ammonium acetate in methanol formed a key intermediate, dehydrositagliptin 25 (enamine amide). This intermediate contains the entire structure of sitagliptin 14 except two hydrogen atoms. Thus, sitagliptin 14 was synthesized by enantioselective hydrogenation of dehydrositagliptin 25 in the presence of [Rh(COD)2 OTf] 12,13 and t Bu JOSIPHOS in excellent yield with 95% ee.[23,24]
http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
http://www.apiindia.org/medicine_update_2013/chap88.pdf
http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf
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Googleplus amcrasto@gmail.com1 TRELAGLIPTIN
2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2, 4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile; butanedioic acid
2-[6-[3(R)-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-4-fluorobenzonitrile
2- [ [6- [ (3R) -3-amino-l-piperidinyl] -3, 4-dihydro-3- methyl-2, 4-dioxo-l (2H) -pyrimidinyl]methyl] -4-fluorobenzonitrile
succinic acid salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile
Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals
Mechanism of action: DPP-4 inhibitor
865759-25-7 cas FREE BASE
1029877-94-8 succinate
Trelagliptin-succinate M. Wt: 475.47
Trelagliptin-succinate Formula: C22H26FN5O6
SYR-472 is an oral dipeptidyl peptidase IV inhibitor originated by Takeda. It is in phase III clinical trials for the treatment of type 2 diabetes.
TRELAGLIPTIN (SYR-472)
Trelagliptin is a novel DPP-4 inhibitor that is being developed by Takeda. In contrast to alogliplitin, which is once a day, trelagliptin is a once-weekly oral agent which should provide patients with a convenient therapeutic alternative and has the potential to improve compliance. Takeda has commenced Phase III trials of trelagliptin in Japan for the treatment of Type 2 diabetes.
Indication (Phase): Japan—Once-weekly oral treatment for type 2 diabetes (Phase III; study expected to be completed in second half of 2013)
Compound I, A, TRELAGLIPTIN which has the formula:
is a DPP-IV inhibitor that is described in U.S. patent application Ser. No. 11/080,992 filed Mar. 15, 2005 (see Compound 34). Its dosing, administration and biological activities are described in U.S. patent application Ser. No. 11/531,671 filed Sep. 13, 2006. U.S. patent application Ser. No. 11/080,992 and Ser. No. 11/531,671 are incorporated herein by reference in their entirety.
Dipeptidyl peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) (referred herein as “DPP-IV”) is a type II membrane protein and a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (e.g., intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of human disease states, including, but are not limit to, diabetes, particularly type II diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; AIDS; and cancers.
DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV.
Compound (A) or a salt thereof has been reported as an inhibitor of dipeptidyl peptidase (DPP-IV) , which is an enzyme that decomposes glucagon-like peptide-1 (GLP-1) , a hormone increasing insulin secretion (patent document 1) .
In addition, a method including administering 1 – 250 mg of compound (A) or a salt thereof to a patient once per week (patent documents 2, 3), crystal polymorphs of compound (A) (patent documents 4, 5) , and a preparation of compound (A)
(patent documents 6, 7) have also been reported. Compound (A) and a salt thereof are recommended for oral administration in view of the easiness of self-administration, and a tablet, particularly a tablet in the dosage form for administration once per week, is desired. [0006]
The dosage form of once per week is expected to improve drug compliance of patients, whereas it requires supply of compound (A) or a salt thereof to patients in a high dose as compared to, for example, the dosage form of once per day. Since a solid preparation containing compound (A) or a salt thereof in a high dose increases its size, it may conversely degrade the drug compliance for patients, particularly infants and elderly patients having difficulty in swallowing
……………………..
SYNTHESIS
Compound 34 IS TRELAGLIPTIN
4-Fluoro-2-methylbenzonitrile (31).
A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
2-Bromomethyl-4-fluorobenzonitrile (32).
A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
Alternatively, 32 was made as follows.
4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with AIBN (122 g) and heated to 75° C. A suspension of DBH (353 g) in DCE (500 mL) was added at 75° C. portionwise over 20 minutes. This operation was repeated 5 more times over 2.5 hours. The mixture was then stirred for one additional hour and optionally monitored for completion by, for example, measuring the amount of residual benzonitrile using HPLC. Additional AIBN (e.g., 12.5 g) was optionally added to move the reaction toward completion. Heating was stopped and the mixture was allowed to cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10° C. over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at <20° C. over 30 min). The mixture was then stirred for 30 minutes or until completion. The mixture was then washed with 1% sodium metabisulfite solution (5 L) and purified with water (5 L). The organic phase was concentrated under vacuum to afford 32 as a dark brown oil (3328 g), which was used without further purification (purity was 97% (AUC)).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (33).
A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.
Alternatively, 33 was made as follows.
To a solution of 6-chloro-3-methyluracil (750 g) and N,N-diisopropylethylamine (998 mL) in NMP (3 L) was added (at <30° C. over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 60° C. for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5° C. for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2×2.25 L). The material was then dried in a vacuum oven at 40±5° C. for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).
TFAsalt OF TRELAGLIPTIN
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (34).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
FREE BASE OF TRELAGLIPTIN
Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 60° C. until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 60° C. and the mixture was allowed to cool to <25° C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45° C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.
HCL salt OF TRELAGLIPTIN
The HCl salt of 34 was prepared from the TFA salt as follows. The TFA salt (34) was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0° C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH2Cl2 (12 L) was added (at <35° C. over 18 minutes) 2 M hydrochloric acid (3.1 L). The slurry was stirred for 1 hour and then filtered. The wet cake was washed with CH2Cl2 (3.6 L) and then THF (4.8 L). The wet cake was then slurried in THF (4.8 L) for one hour and then filtered. The filter cake was again washed with THF (4.8 L). The material was then dried in a vacuum oven at 50° C. (with a nitrogen bleed) until a constant weight (e.g., >26 hours) to afford 34 as the HCl salt as a white solid (1423 g, >85% yield).
Succinate salt OF TRELAGLIPTIN
The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH2Cl2 (7 L) and purified water (14 L) was added 50% NaOH solution (212 mL) until the pH of the mixture was >12. The biphasic mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (5.7 L) and the combined organic layers were washed with purified water (6 L). The organic layer was then passed through an in-line filter and concentrated under vacuum at 30° C. over three hours to afford the free base as an off-white solid. The free base was slurried in prefiltered THF (15 L) and prefiltered IPA (5.5 L). The mixture was then heated at 60° C. until complete dissolution of the free base was observed. A prefiltered solution of succinic acid (446 g) in THF (7 L) was added (over 23 min) while maintaining the mixture temperature at >57° C. After stirring at 60° C. for 15 min, the heat was turned off, the material was allowed to cool, and the slurry was stirred for 12 hours at 25±5° C. The material was filtered under vacuum and the wet cake was washed with prefiltered IPA (2×4.2 L). The material was then dried in a vacuum oven at 70±5° C. (with a nitrogen bleed) for >80 hours to afford the succinate salt of 34 as a white solid (1546 g, >90% yield).
The product was also converted to a variety of corresponding acid addition salts. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(−)-Mandelic and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.
Methanesulfonate salt
In addition, the methanesulfonate salt was prepared as follows. A 10.5 g aliquot of the benzonitrile product was mixed with 400 mL of isopropylacetate. The slurry was heated to 75° C. and filtered through #3 Whatman filter paper. The solution was heated back to 75° C. and a 1M solution of methanesulfonic acid (30.84 mL) was added slowly over 10 minutes while stirring. The suspension was cooled to room temperature at a rate of about 20° C./hr. After 1 hr at room temperature, the solid was filtered and dried in an oven overnight to obtain the methanesulfonate salt.
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FORMULATION
COMPD A IS TRELAGLIPTIN
Examples (Comparative Example IA)
Succinate of compound (A) (26.6 mg) was weighed in a glass bottle and used as Comparative Example IA. (Comparative Example 2A)
The succinate of compound (A) and microcrystalline cellulose were uniformly mixed in a mortar at a ratio of 1:10, and the mixture (226.6 mg) was weighed in a glass bottle and used as Comparative Example 2A. (Comparative Example 3A)
The succinate of compound (A) and corn starch were uniformly mixed in a mortar at a ratio of 1:5, and the mixture (126.6 mg) was weighed in a glass bottle and used as Comparative Example 3A. (Example IA) Succinate of compound (A) , mannitol and corn starch according to the formulation of Table IA were uniformly mixed in a fluid bed granulator (LAB-I, POWREX CORPORATION) , and the mixture was granulated by spraying an aqueous solution of dissolved hypromellose 2910, and dried therein. The obtained granules were passed through a sieve -(16M) to give milled granules. To the milled granules were added croscarmellose sodium, microcrystalline cellulose and magnesium stearate, and they were mixed in a bag to give granules for tableting. The granules were punched by a rotary tableting machine (Correct 19K, Kikusui Seisakusho, Ltd.) with a 6.5 mmφ punch to give a plain tablet weighting 121 mg. On the other hand, titanium oxide, yellow ferric oxide and talc were dispersed in a hypromellose 2910 aqueous solution to prepare a film coating liquid. The aforementioned coating liquid was sprayed onto the above-mentioned plain tablet in a film coating machine (Hicoater HCP-75, Freund Corporation), to give 2500 film- coated tablets containing 3.125 mg of compound (A) (free form) per tablet. Table IA
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POLYMORPHS AND SYNTHESIS
FORM A
Form A may be prepared by crystallization from the various solvents and under the various crystallization conditions used during the polymorph screen (e.g., fast and slow evaporation, cooling of saturated solutions, slurries, and solvent/antisolvent additions). Tables B and C of Example 3 summarize the procedures by which Form A was prepared. For example, Form A was obtained by room temperature slurry of an excess amount of Compound I in acetone, acetonitrile, dichloromethane, 1,4-dioxane, diethyl ether, hexane, methanol, isopropanol, water, ethylacetate, tetrahydrofuran, toluene, or other like solvents on a rotating wheel for approximately 5 or 7 days. The solids were collected by vacuum filtration, and air dried in the hood. Also, Form A was precipitated from a methanol solution of Compound I by slow evaporation (SE).
[0091] Form A was characterized by XRPD, TGA, hot stage microscopy, IR, Raman spectroscopy, solution 1H-NMR, and solid state 13C-NMR.
[0092] Figure 1 shows a characteristic XRPD spectrum (CuKa, λ=1.5418A) of Form A. The XRPD pattern confirmed that Form A was crystalline. Major X-Ray diffraction lines expressed in °2Θ and their relative intensities are summarized in Table 1.
Table 1. Characteristic XRPD Peaks (CuKa) of Form A
Characterization Data of Form A of Compound I
8. Amorphous Form
[0137] The Amorphous Form of Compound I was prepared by lyophilization of an aqueous solution of Compound I (Example 10). The residue material was characterized by XRPD and the resulting XRPD spectrum displayed in Figure 26. The XRPD spectrum shows a broad halo with no specific peaks present, which confirms that the material is amorphous. The material was further characterized by TGA, DSC, hot stage microscopy, and moisture sorption analysis.
Table A. Approximate Solubilities of Compound I
Compound I having the formula
POLYMORPH SCREEN
Crystallization Experiments of Compound I from Solvents
a) FE = fast evaporation; SE = slow evaporation; RT = room temperature; SC = slow cool;CC = crash cool, MB = moisture sorption/desorption analysis b) qty = quantity; PO = preferred orientation
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SYNTHESIS
EXAMPLES
1. Preparation of 2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro- 2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts
4-Fluoro-2-methylbenzonitrile (3)
[0166] A mixture of 2-bromo-5fluorotoluene ( 2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was re fluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 3 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H). 2-Bromomethyl-4-fluorobenzonitrile (4)
[0167] A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification.1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro- benzonitrile (6)
[0168] A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8 mmol), 2- Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO
(10 mL) was stirred at 60 C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, 1=12, 8.4Hz, IH), 7.26 (d, J- 4.0Hz, IH), 7.11-7.17 (m, IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for Ci3H9ClFN3O2, 293.68; found 293.68.
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, TFA salt (1) (TFA salt of Compound I)
[0169] 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4- fluoro-benzonitrile (5) (300 mg, 1.0 mmol), (i?)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 0C for 2 hrs. The final compound was obtained as a TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for Ci8H20FN5O2, 357.38; found, 357.38.
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, HCl salt
[0170] The TFA salt of Compound I was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0 C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for Ci8H20FN5O2, 357.38; found, 357.38.
General procedure for the preparation of salts of Compound I.
[0171] The benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to a corresponding acid addition salt. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of Compound I were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. [0172] The isolation and/or purification steps of the intermediate compounds in the above described process may optionally be avoided if the intermediates from the reaction mixture are obtained as relatively pure compounds and the by-products or impurities of the reaction mixture do not interfere with the subsequent reaction steps. Where feasible, one or more isolation steps may be eliminated to provide shorter processing times, and the elimination of further processing may also afford higher overall reaction yields.
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TABLET
2. Exemplary formulations comprising succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile
Provided are examples of tablet formulations that may be used to administer succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (Succinate salt of Compound I) according to the present invention. It is noted that the formulations provided herein may be varied as is known in the art.
The exemplary tablet formulations are as follows:
| 12.5 mg of Compound I (weight of free base form) per tablet | ||||
| Core Tablet Formulation | ||||
| (1) | 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- | 17.0 | mg | |
| dioxo-3,4-dihydro-2H-pyrimidin-1- | ||||
| ylmethyl]-4-fluoro-benzonitrile (succinate salt) | ||||
| (2) | Lactose Monohydrate, NF, Ph, Eur | 224.6 | mg | |
| (FOREMOST 316 FAST FLO) | ||||
| (3) | Microcrystalline Cellulose, NF, Ph, Eur | 120.1 | mg | |
| (AVICEL PH 102) | ||||
| (4) | Croscarmellose Sodium, NF, Ph, Eur | 32.0 | mg | |
| (AC-DO-SOL) | ||||
| (5) | Colloidal Silicon Dioxide, NF, Ph, Eur | 3.2 | mg | |
| (CAB-O-SIL M-5P) | ||||
| (6) | Magnesium Stearate, NF, Ph, Eur | 3.2 | mg | |
| (MALLINCKRODT, Non-bovine Hyqual) | ||||
| TOTAL | 400.0 | mg | ||
| (per tablet) | ||||
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POLYMORPHS AND SYNTHESIS
EXAMPLES Example 1 Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate (Compound I)
Compound I may be prepared by the follow synthetic route (Scheme 1)
A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)
Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product B (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)
Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl4 under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)
Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.
D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)
Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
E. Preparation of Compound I: the succinic acid salt of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile
The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent.
SUCCINATE SALT OF TRELAGLIPTIN
1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.
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patents
1. US 2013172377
2. WO 2011013639
3. WO 2009099172
4.WO 2009099171
5. WO 2008114807
6.WO 2008114800
7. WO 2008033851
8. WO 2007074884
9WO 2007035629
patent document 1: US2005/0261271
patent document 2: US2007/0060530
patent document 3: US2008/0287476
patent document 4: US2008/0227798
patent document 5: US2008/0280931
patent document 6: WO2008/114800
patent document 7: WO2011/013639
| US7906523 * | Oct 30, 2007 | Mar 15, 2011 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US8084605 * | Nov 29, 2007 | Dec 27, 2011 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| US8188275 * | Oct 30, 2007 | May 29, 2012 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US8222411 * | Sep 15, 2006 | Jul 17, 2012 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US20090275750 * | Sep 15, 2006 | Nov 5, 2009 | Jun Feng | Dipeptidyl peptidase inhibitors |
| WO2013183784A1 | Jun 4, 2013 | Dec 12, 2013 | Takeda Pharmaceutical Company Limited | Solid preparation |
| US20080227798 * | Nov 29, 2007 | Sep 18, 2008 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| US20120197018 * | Feb 15, 2012 | Aug 2, 2012 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| WO2007033265A1 * | Sep 13, 2006 | Mar 22, 2007 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetis |
| WO2007033266A2 * | Sep 13, 2006 | Mar 22, 2007 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetis |
| WO2007033350A1 * | Sep 13, 2006 | Mar 22, 2007 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetes |
| EP1586571A1 * | Dec 21, 2004 | Oct 19, 2005 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
GRC 8200; 868771-57-7, EMD-675992
4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile
4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile
GRC-8200, a dipeptidyl peptidase IV inhibitor (DPP-IV), is currently undergoing phase II clinical trials at Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. In 2006, the compound was licensed by Glenmark Pharmaceuticals to Merck KGaA in Europe, Japan and N. America for the treatment of type 2 diabetes, however, these rights were reaquired by Glenmark in 2008.
.
ALTERNATE……….
see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html
http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html
EVOGLIPTIN
CAS: 1222102-29-5 FREE
HCL……
Dong-A Pharmaceutical. Co., Ltd, 동아제약 주식회사
2-Piperazinone, 4-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-3-((1,1-dimethylethoxy)methyl)-, (3R)-
R)-4-((R)-3-Amino-4-(2,4,5-trifluorophenyl)-butanoyl)-3-(t-butoxymethyl)-piperazin-2-one
4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-3(R)-(tert-butoxymethyl)piperazin-2-one hydrochloride
DA-1229
DA-1229 is a dipeptidyl peptidase IV (CD26) inhibitor currently being developed in phase III clinical studies at Dong-A for the treatment of type 2 diabetes.
In 2014, Eurofarma aquired rights for product development and commercialization in Brazil.
86…………H. J. Kim, W. Y. Kwak, J. P. Min, J. Y. Lee, T. H. Yoon, H. D. Kim, C. Y. Shin, M. K.
Kim, S. H. Choi, H. S. Kim, E. K. Yang, Y. H. Cheong, Y. N. Chae, K. J. Park, J. M.
Jang, S. J. Choi, M. H. Son, S. H. Kim, M. Yoo and B. J. Lee, Bioorg. Med. Chem. Lett.,
2011, 21 (12), 3809-3812.
[87] …………K. S. Lim, J. Y. Cho, B. H. Kim, J. R. Kim, H. S. Kim, D. K. Kim, S. H. Kim, H. J. Yim,
S. H. Lee, S. G. Shin, I. J. Jang and K. S. Yu, Br. J. Clin. Pharmacol., 2009, 68 (6), 883-
890.
…………………………………..
WO 2010114291
http://www.google.co.in/patents/WO2010114291A2?cl=en
Formula 1
Korea Patent Publication No. 2008-0094604 the call to the scheme, as indicated by A Ⅰ) of formula (II) beta-compound of formula 3 is already substituted heterocyclic compound having 1-hydroxy-benzotriazole group (HOBT) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and reacting with a tertiary amine to prepare a compound of formula (4) connected by peptide bonds; Ⅱ) beta comprises the step of reacting under acidic conditions a compound of the formula (4) – a method of manufacturing the heterocyclic compounds of the formula I having an amino group is disclosed.
– Scheme A]
(Wherein, PG is a protecting group.)
In this case, the beta of the formula (2) of Scheme A – a compound having an amino group is prepared in addition to the DPP-IV inhibitor International Publication represented by Formula 1 WO03 / 000181, WO03 / 004498, WO03 / 082817, WO04 / 007468, WO04 / 032836, WO05 / 011581, WO06 / 097175, WO07 / 077508, WO07 / 063928, WO08 / 028662 WO08 / it may be used for the production of different DPP-IV inhibitors according 087,560 and can be prepared in a number of ways.
To, the compound of Formula 2 is an example as shown in Scheme J. Med.Chem. 2005; 141, and Synthesis 1997; it can be produced by the known method described in 873.
Specifically, (2S) – (+) – 2,5- dihydro-3,6-dimethoxy-2-isopropyl-pyrazine 2,4,5-trifluoro-react with benzyl bromide and acid treatment, and then the amine an ester compound obtained by the protection reaction. Ester compounds are hydrolyzed to re-3- (2,4,5-trifluoro-phenyl) -2-amino-propionic acid tert such as isobutyl chloroformate, triethylamine or diisopropylethylamine to give the amine, and then using diazomethane to form a diazo ketone, and then may be prepared by reaction with silver benzoate. However, the reaction can be performed at low temperature (-78 ℃) or high alpha-amino acid to purchase and use, and may have a risk of problems such as the need to use large diazomethane.
To a different process for preparing a compound of Formula 2 as shown in scheme Tetrahedron: Asymmetry 2006; It is known in 2622; 205 or similarly Bioorganic & Medicinal Chemistry Letters 2007.
That is, a 1,1′-carbonyl-2,4,5 which the phenyl trifluoroacetic acid activated using the following imidazole mono-methyl words potassium carbonate is reacted with the beta-keto ester compound is prepared. This produced an enamine ester using ammonium acetate and ammonium solution, the ester compound chloro (1,5-cyclooctadiene) rhodium (I) dimer using a chiral ferrocenyl ligands I the reaction of the high-pressure hydrogen with a chiral primary amine with a beta-amino ester compound after production and can lead to hydrolysis to prepare a compound of formula (2). However, use of expensive metal catalyst has a problem that must be performed in high pressure hydrogenation.
The method for preparing a compound of Formula 2 is disclosed in International Publication No. WO 04/87650.
Specifically, 2,4,5-fluorophenyl reagent is oxalyl chloride, the acid activated acid with 2,2-dimethyl-1,3-dioxane-4,6-dione, and after the reaction of methanol and the resulting material at reflux to prepare a corresponding compound. With a selective reducing reagents which enantiomers (S) -BINAP-RuCl 2 and hydrogen through a reaction (S) – producing a compound having coordinated to each other, it again after the decomposition, and the singer O- benzyl hydroxyl amine and the coupling reaction and the intermediate is prepared. To do this, the resulting intermediate tree azodicarboxylate and diisopropyl azodicarboxylate presence ring condensation reaction, treated with an aqueous solution of lithium hydroxide to (R) – while having the formula (II) coordinated to the amine group protected with a benzyl-O- the compound can be produced. However, the method has a problem as a whole to be prepared by the reaction yield to be low and a long processing time to perform the reaction.
Thus, the conventional known method for producing a compound of the general formula (2) has the disadvantage of using expensive reagents, or not suitable for commercial mass-production method by a long synthesis time yield is also low.
In addition, the compound represented by General Formula (3), as described in Korea Patent Publication No. 2008-0094604 call, can be prepared by way of reaction schemes.
Specifically, the starting material D- serine methyl ester is substituted by a hydroxy group when reflux again substituted by trityl chloride as methoxy groups converted to the aziridine compound.
[Scheme 3]
<Example 3> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) Preparation of the hydrochloride
Step 1: t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소 – 1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트(화학식 Preparation of 4)
2 L flask, prepared in Example 1 (R) -3-t- butoxycarbonyl-4- (2,4,5-trifluoro-phenyl) butanoate acid (Formula 2) 10.0 g of toluene was dissolved in 450 mL of bis (2,2′-benzothiazolyl) disulfide 13.0 g, was cooled and then 10.2 g triphenylphosphine was added to the reaction solution at 0 ℃. While stirring the reaction mixture was added to a solution of 0.8 mL of triethylamine in 20 mL of toluene was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 ℃ and prepared in Example 2 (R) -3- (t- butoxymethyl) piperazin-2-one (Formula 3) was dissolved in 5.6 g of toluene and 40 mL pyridine a 2.4 mL was added slowly. After 30 minutes the reaction mixture was heated to room temperature and stirred for 1 hour. Saturated sheet to be the aqueous acid solution to a pH of 2.5 and then diluted with ethyl acetate 400 mL. Washed twice with brine and the organic layer was dehydrated with magnesium sulfate and concentrated. The residue was purified by column chromatography to give the title compound 838 mg.
1 H NMR (400 MHz, CDCl 3) δ 7.03 (m, 1H), 6.88 (m, 1H), 5.97 (m, 1H), 5.48 (m, 1H), 4.16 ~ 4.07 (m, 1H), 4.02 ~ 3.91 (m, 1H), 3.74 (m, 2H) 3.37 (m, 2H), 3.24 (m, 1H), 2.92 (m, 2H), 2.80 (m, 1H), 2.59 (m, 2H), 1.34 ( d, 9H), 1.13 (s, 9H)
Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- on the production of (I) hydrochloride
Prepared in Step 1 t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소-1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트 97 mg was dissolved in methanol was added 3 mL 2N- hydrochloric acid / diethyl ether 2 mL was stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to give 64 mg of the title compound as a foaming solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.37 (m, 1H), 7.23 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H), 1.18 (s, 3H ), 1.11 (s, 6H)
Mass (M + 1): 402
<Example 4> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) tartaric acid salts
Step 1: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- Preparation of one (I)
Example 3 to give a compound of formula I in hydrochloride 60 mg 5% sodium hydrogen carbonate in dichloromethane was added to 10 mL of an aqueous solution / 2-propanol (4/1 (v / v)) was added to the mixed solution and extracted two times 10 mL The organic layer was dried under reduced pressure to give 55 mg of the title compound as a solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.27 (m, 1H), 7.14 (m, 1H), 4.56 ~ 4.39 (m, 1H), 3.96 ~ 3.81 (m, 3H), 3.70 (m, 1H) , 3.46 (m, 1H), 3.43 ~ 3.32 (m, 1H), 2.83 ~ 2.65 (m, 3H), 2.58 ~ 2.40 (m, 2H), 1.16 (s, 3H), 1.11 (s, 6H)
Mass (M + 1): 402
Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (t- butoxymethyl) piperazin-2- one (I) tartaric acid salt [
Was dissolved 55 mg of the compound of step 1 in 0.56 mL of acetone, L- tartrate 26 mg ethanol / water (9/1 (v / v)) was added slowly to a solution of 0.35 mL was stirred for 30 minutes. Here was added 0.56 mL of 2-propanol was stirred for 10 minutes and re-filtered to give 77 mg of the title compound as a solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.38 (m, 1H), 7.22 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 4.40 (s, 2H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H ), 1.15 (s, 3H), 1.11 (s, 6H)
Mass (M + 1): 402
………………………………
WO 2010114292
http://www.google.com/patents/WO2010114292A2?cl=en
…………………………………
Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
Bioorg Med Chem Lett 2011, 21(12): 3809
http://www.sciencedirect.com/science/article/pii/S0960894X11004859
A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.
http://www.luye.cn/en/uploads//2014-07/21/_1405936452_zr21xh.pdf
Dong-A ST has licensed its new diabetes drug Evogliptin to 17 Latin American countries including Mexico, Venezuela, Argentina, Chile, Colombia, Ecuador, Peru, the Dominican Republic, and Uruguay, Jung Jae-wook, Dong-A ST’s PR manager, told Business Korea.
Dong-A ST and Eurofarma, a Brazilian pharmaceutical company, concluded the licensing contract at Dong-A ST’s headquarters on April 13 in Seoul.
Eurofarma will be responsible for Evogliptin’s product development and sales in the 17 Latin American countries, Dong-A ST said. Dong-A ST will receive royalties from Eurofarma, and export the raw material of the medicine.
Dong-A ST has been developing Evogliptin with the support of the Ministry of Health & Welfare of South Korea as an innovative new medicine research project since May 2008. Evogliptin is a DPP-4 remedy based on the inhibition mechanism which is “excellent” at reducing blood sugar, whilst “less likely” to cause weight increases and hypoglycemia, the company said.
Park Chan-il, president of Dong-A ST, said that Dong-A ST will pursue further out-licensing “over the globe,” through continuous investment in research and development.
Maurizio Billi, Eurofarma’s president, wished to expand both companies’ partnership in the innovative new remedy development sector, according to Dong-A ST.
Last July, Dong-A ST and Eurofarma concluded a contract out-licensing Evogliptin to Brazil itself, the company said.
see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html
http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html
see gliptins at…..http://drugsynthesisint.blogspot.in/p/gliptin-series.html
see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html
http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html
Dong-A Pharm. Co., Ltd, Yongin-si, Gyeonggi-do, Republic of Korea.
GOSOGLIPTIN
CAS 869490-23-3 FREE BASE
DIHYDROCHLORIDE..869490-47-1
GOSOGLIPTIN; UNII-GI718UO477; PF-00734200; PF-734200;
(3,3-difluoropyrrolidin-1-yl)-[(2S,4S)-4-(4-pyrimidin-2-ylpiperazin-1-yl)pyrrolidin-2-yl]methanone
| Molecular Formula: | C17H24F2N6O |
|---|---|
| Molecular Weight: | 366.408866 g/mol |
| Company | Pfizer Inc. |
| Description | Dipeptidyl peptidase-4 (DPP-4) inhibitor |
| Molecular Target | Dipeptidyl peptidase-4 (DPP-4) (CD26) |
| Mechanism of Action | Dipeptidyl peptidase-4 (DPP-4) inhibitor |
| Latest Stage of Development | Phase II |
| Standard Indication | Diabetes |
| Indication Details | Treat Type II diabetes |
Type 2 diabetes mellitus is a chronic disorder characterized by hyperglycemia coupled with a gradual decline in insulin sensitivity and insulin secretion. The incretin hormone glucagon-like peptide-1 (GLP-1), which is released post-prandially from the L-cells of the intestine, stimulates the release of insulin from pancreatic β-cells. However, GLP-1 is rapidly degraded in vivo by peptidases, including dipeptidyl peptidase IV (DPP-4), which is a widely distributed serine protease that specifically cleaves N-terminal dipeptides from polypeptides with proline or alanine at the penultimate position.
In vivo administration of DPP-4 inhibitors to human subjects results in higher circulating concentrations of endogenous GLP-1 and subsequent decrease in plasma glucose. Long term treatment with a DPP-4 inhibitor leads to a reduction in circulating HbA1c (glycosylated hemoglobin). DPP-4 inhibition also offers the potential to improve the insulin producing function of the pancreas through either β-cell preservation or regeneration. Therefore, DPP-4 inhibition has emerged as a promising new treatment of Type 2 diabetes
PF-734200 is a potent, selective, orally active dipeptidyl peptidase IV inhibitor. It had been in phase II clinical development at Pfizer for the treatment of type 2 diabetes; however, in 2010 the company discontinued these trials. In 2012, the product was licensed to SatRx, a spin-off of the ChemRar High Tech Center, by Pfizer on an exclusive worldwide basis (with the exception of China) for the development and commercialization as monotherapy or in combination with other therapies for the treatment of type 2 diabetes. SatRx is conducting phase II clinical trials for the treatment of type 2 diabetes.
……………………….
PAPER
New synthetic route to a dipeptidyl peptidase-4 inhibitor
Org Process Res Dev 2012, 16(3): 409
http://pubs.acs.org/doi/abs/10.1021/op200309z
A new synthetic route to a dipeptidyl peptidase-4 (DPP4) inhibitor was developed and demonstrated on a multigram scale. This approach takes advantage of the cheap and readily available Boc-trans-4-hydroxy-l-proline methyl ester as starting material which was derivatized through an SN2 reaction. Several leaving groups were studied, and the nosylate group showed superiority over other derivatives. Formation of an amide using the most costly starting material, 3,3-difluoropyrrolidine, was performed late in the synthesis to minimize its economical impact on the overall cost of the API.
(3,3-Difluoropyrrolidin-1-yl)-(2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone.FREE BASE
Mp 149 °C (decomp).
[α]d = −31.1 (T = 24 °C, c = 1, CHCl3). Specific rotation of product 4 prepared using the initial route: [α]d = −31.5 (T = 24 °C, c = 1, CHCl3).
1H NMR (400 MHz; CDCl3) δ 8.30 (d, J = 4 Hz, 2H), 6.48 (t, J = 4 Hz, 1H), 3.95–3.6 (m, 9H), 3.25–2.85 (m, 4H), 2.6–2.25 (m, 7H), 1.75–1.6 (m, 1H).
13C NMR (100 MHz; CDCl3) δ 172.28; 161.55; 157.70; 127.22 (t, 1J C–F = 248 Hz), 126.22 (t, 1J C–F = 246 Hz), 109.95; 66.54; 58.87; 57.99; 52.71 (t, 2 J C–F = 32 Hz); 52.00; 50.41; 43.03; 34.46, 34.37, 34.25; 19F NMR (377 MHz, CDCl3) δ −102.1 (m, 2F).
IR (neat): 2951w, 2864w, 2799w, 2759w, 1630s, 1585vs, 1547m, 1449m, 1172m, 1254m, 1129m, 982w, 923m, 796m, 638w.
HRMS (ES, N2) Calcd for C17H24F2N6O: 367.20524, found: 367.20592.
……………………….
PAPER
(3,3-difluoro-pyrrolidin-1-yl)-((2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl)-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor
Bioorg Med Chem Lett 2009, 19(7): 1991
http://www.sciencedirect.com/science/article/pii/S0960894X09001966?np=y
A series of 4-substituted proline amides was evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC50 = 13 nM) and selective compound, with high oral bioavailability in preclinical species.
………………….
PATENT
WO 2005116014
http://www.google.co.in/patents/WO2005116014A1?cl=en
Example 113 (3.3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone
Step 1 – (S)-2-(3.3-Difluoro-pyrrolidine-1-carbonyl)-4-oxo-pyrrolidine-1 -carboxylic acid tert-butyl ester
(S)-4-Oxo-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (6.6 kg, 1.0 equivalent) was charged to a reactor, followed by addition of dichloromethane (15 volumes). The reaction mixture was cooled to 0°C. Triethylamine (4.82 liters, 1.2 equiv) was added over 30 minutes. The mixture turned from suspension to a clear solution at the end of triethylamine addition. The mixture was held at 0°C to 5°C for 10 minutes. Pivaloyl chloride (3.65 kg, 1.05 equivalents) was added slowly while keeping the reaction temperature at 0°C to 5°C. The reaction mixture turned back to aslurry. The reaction mixture was sampled for completion by HPLC (using diethylamine to derivatize) after held for 1 hour at 0°C to 5°C.
3,3-Difluoro- pyrrolidine hydrochloride (4.13 kg, 1.0 equivalent) was charged to the above mixture over 10 minutes at – 10°C to 0°C. Triethylamine (4.0 liters, 1.0 equiv) was introduced slowly over 70 minutes at -10°C to 0°C. Upon completion of triethylamine addition, the mixture was stirred for 1h at 0 to 5°C. The reaction was complete by HPLC assay (-1% starting material). The reaction was quenched with water (10 volumes) at 0°C to 5 °C. The mixture was heated to 20°C to 25 °C. The layers were separated, and the organic layer was washed with 0.5 M HCI (5 volumes). The organic layer was again washed with combined 5% NaHC03 (2 volumes) and half saturated brine solution (1.64 M, 3 volumes). The organic solution was concentrated atmospherically to a low stirrable volume (approximately 20 liters). Ethyl acetate (12.6 volumes, 82.8 liters) was added, the solution was concentrated atmospherically to -6 volumes. The mixture was held at 60°C to 65 °C for 2 hours and cooled to room temperature over 3 hours. The mixture was held at 20°C to 25 °C for 8 hours. Heptane (8 volumes) was added, and the mixture was granulated for a minimum of 2 hours. The solid was filtered, rinsed with 2:1 heptane/ethyl acetate (1 volume), and dried in a tray dryer at 25°C to 35°C for a minimum of 12 h. Yield: 7.26 kg, 79%. HPLC purity: 99.7%. The mother liquor (86 liters) was concentrated to 12 liters under partial vacuum at 65°C to 70°C. The mixture was cooled to 60°C to 65 °C. Ethyl acetate (4.0 liters) was added slowly over 15 minutes. The mixture was cooled to 20°C to 25 °C over 2 hours and was held at that temperature for at least 2 hours. The solid was filtered and rinsed with heptane/ethyl acetate (3:1 v/v, 1.7 liters). Drying in a tray dryer for 12 hours at 35°C to 45 °C yielded 435 grams of product. HPLC purity: 96.4%.
Step 2 – (2S.4S)-2-(3.3-Dif luoro-pyrrolidine-1 -carbonyl)-4-(4-pyrimidin-2-yl-piperazin-1 -yl)-pyrrolidine-1 – carboxylic acid tert-butyl ester A reactor was charged with THF (20 volumes), 2-piperazin-1-yl-pyrimidine (2.17 kg, 1.05 equivalents) and the product from Step 1 (4.00 kg, 1.0 equivalent). The mixture was held at 20°C to 25°C until all material was dissolved over 30 minutes. Acetic acid (0.792 kg, 1.05 equivalents) as added. The mixture was stirred for 1 hour during which the reaction mixture turned to cloudy. The reaction mixture was refluxed for 30 minutes and then concentrated at 60°C to 70°C until a steady temperature of 66.9°C was observed in the overheads indicating complete removal of water from the system. More THF was added as necessary. At the end, THF was added to bring the total volume in the reactor to 15 volumes of the limit reagent. The reaction mixture was cooled to -3°C to 7°C and sampled for complete formation of imine by HPLC (using sodium triacetoxyborohydride to reduce imine). Sodium triacetoxyborohydride (5.33 kg, 2.0 equivalents) was added portion-wise to the suspension at -5°C to 15°C. The reaction mixture was heated to 20°C to 25°C and held for 12 hours. HPLC results confirmed the reaction was complete by 99.8%. Sodium bicarbonate aqueous solution (10% w/w, 10 volumes) was added. The slurry was concentrated to remove 10 volumes of THF under partial vacuum at 30°C to 60°C. Ethyl acetate (10 volumes) was added to the suspension after it cooled to 20°C to 25CC. The organic phase was separated and the aqueous phase was checked by HPLC. It contained less than 2% of the product. The organic phase was washed with water (5 volumes), saturated brine solution (5 volumes) and concentrated to a small volume (2 volumes) under partial vacuum at 45°C to 50°C. To the slurry was added heptane (10 volumes) at 45°C to 50°C over 30 minutes. The mixture was cooled to 20°C to 25°C and granulated for 2 hours. Solid was collected by filtration, rinsed with heptane (2 volumes). Drying in a tray dryer for 12 hours at 35°C to 45°C yield 5.35 kg (91.3%) of the product. Step 3 – (3.3-Dif luoro-pyrrolidin-1 -yl)-f(2S.4S)-4-(4-pyrimidin-2-yl-piperazin-1 -yl)-pyrrolidin-2-yll- methanone Water (19 liters, 2 volumes) was charged to a reactor followed by the product from Step 2 (9.57 kg,
1.0 equivalent). To the slurry was added concentrated HCI (37 wt% in water, 19.1 liters, 2 volumes) slowly at 20°C to 30°C over 4 hours. The slurry went into solution after 12 liters of HCI was added. After the addition completion, the reaction was complete by HPLC assay. The reaction mixture was cooled to 5°C to 15°C. To the mixture was added 50% NaOH aqueous solution slowly with agitation to pH 10 to pH 11. The pH was monitored with a pH meter closely during the neutralization. The total volume of 50% NaOH added was 12.45 liters. The mixture was warmed to 20°C to 25°C and extracted with ethyl acetate twice (115 liters, 12 volumes and 57 liters, 6 volumes, respectively). The sample from aqueous layer after second extraction was analyzed by HPLC and showed only 1% of the product in that aqueous solution.
The organic layers were combined and treated with magnesium sulfate (5 kg) for 1 hour. The mixture was filtered. The filter cake was rinsed with ethyl acetate (10 liters). The filtrate was charged back to the reactor via a 0.2 micron in-line filter for speck free operation. (The following operations were performed under speck free conditions.) The solution was concentrated to 20 liters (2 volumes) under partial vacuum at 50°C to 60°C. The mixture was cooled to 20°C to 25°C over 30 minutes. Upon cooling to room temperature, crystallization occurred. The mixture was held for 30 minutes. Hexanes (20 liters, 2 volumes) was added slowly over 1 hour. The mixture was granulated for 2 hours. The solid product was collected by filtration and rinsed with hexanes/ethyl acetate (10 liters, 1 :1 v/v). The filter was blown dry with nitrogen for a minimum of 2 hours. The product was dried in a tray dryer at 44°C for 12 hours.
Yield: 5.7 kg, 75.9%.
m.p. 156°C. MS m/z 367 (MH+).
FREE BASE
1H NMR (400 MHz, D20): δ 8.15 (d, 2H, J = 5.0 Hz, CH of pyrimidine), 6.55 (t, 1 H, J = 4.8 Hz, CH of pyrimidine), 3.87-3.81 (dd, 1 H, H2b of proline, rotomeric), 3.78-3.50 (m, 4H, N-CH2 of pyrrolidide), 3.55-3.40 (m, 4H, N-CH2 of piperazine), 2.97 (dd, 1 H, J = 10.2, 6.6 Hz, H5a of proline), 2.85-2.75 (m, 1 H, H4b of proline), 2.69 (dd, 1 H, J = 10.0, 9.1 Hz, H5b of proline), 2.55-2.20 (m, 7H, overlapping N-CH2 of piperazine, CH2 of pyrrolidide and H3b of proline), 1.47-1.38 (m, 1 H, H3a of proline).
Alternatively, the dihydrochloride salt of the titled compound was prepared according to the method of Example 1.
………………
US 2005/0256310
http://www.google.com/patents/US20050256310
This approach begins with N–t-Boc-4-oxo-l-proline (1) that undergoes a mixed anhydride activation with pivaloyl chloride at 0 °C, followed by amidation with 3,3-difluoropyrrolidine to yield the intermediate 2. Reductive amination with 1-(2-pyrimidyl)piperazine using sodium triacetoxyborohydride in THF/AcOH provided the desired stereoisomer 3 in high yield and selectivity, the undesired diastereomer being completely removed by crystallization. Deprotection of 3 with 6 N HCl, followed by neutralization with 50% NaOH and extraction provided PF-734200 (4) in good yield.
EXAMPLE 113 (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone
Step 1—(S)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl
(S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6.6 kg, 1.0 equivalent) was charged to a reactor, followed by addition of dichloromethane (15 volumes). The reaction mixture was cooled to 0° C. Triethylamine (4.82 liters, 1.2 equiv) was added over 30 minutes. The mixture turned from suspension to a clear solution at the end of triethylamine addition. The mixture was held at 0° C. to 5° C. for 10 minutes. Pivaloyl chloride (3.65 kg, 1.05 equivalents) was added slowly while keeping the reaction temperature at 0° C. to 5° C. The reaction mixture turned back to a slurry. The reaction mixture was sampled for completion by HPLC (using diethylamine to derivatize) after held for 1 hour at 0° C. to 5° C. 3,3-Difluoro-pyrrolidine hydrochloride (4.13 kg, 1.0 equivalent) was charged to the above mixture over 10 minutes at −10° C. to 0° C. Triethylamine (4.0 liters, 1.0 equiv) was introduced slowly over 70 minutes at −10° C. to 0° C. Upon completion of triethylamine addition, the mixture was stirred for 1 h at 0 to 5° C. The reaction was complete by HPLC assay (˜1% starting material). The reaction was quenched with water (10 volumes) at 0° C. to 5 ° C. The mixture was heated to 20° C. to 25 ° C. The layers were separated, organic layer was washed with 0.5 M HCl (5 volumes). The organic layer was again washed with combined 5% NaHCO3 (2 volumes) and half saturated brine solution (1.64 M, 3 volumes). The organic solution was concentrated atmospherically to a low stirrable volume (approximately 20 liters). Ethyl acetate (12.6 volumes, 82.8 liters) was added, the solution was concentrated atmospherically to ˜6 volumes. The mixture was held at 60° C. to 65° C. for 2 hours and cooled to room temperature over 3 hours. The mixture was held at 20° C. to 25 ° C. for 8 hours. Heptane (8 volumes) was added, and the mixture was granulated for a minimum of 2 hours. The solid was filtered, rinsed with 2:1 heptane/ethyl acetate (1 volume), and dried in a tray dryer at 25° C. to 35° C. for a minimum of 12 h. Yield: 7.26 kg, 79%. HPLC purity: 99.7%. The mother liquor (86 liters) was concentrated to 12 liters under partial vacuum at 65° C. to 70° C. The mixture was cooled to 60° C. to 65° C. Ethyl acetate (4.0 liters) was added slowly over 15 minutes. The mixture was cooled to 20° C. to 25° C. over 2 hours and was held at that temperature for at least 2 hours. The solid was filtered and rinsed with heptane/ethyl acetate (3:1 v/v, 1.7 liters). Drying in a tray dryer for 12 hours at 35° C. to 45° C. yielded 435 grams of product. HPLC purity: 96.4%.
Step 2—(2S,4S)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester
A reactor was charged with THF (20 volumes), 2-piperazin-1-yl-pyrimidine (2.17 kg, 1.05 equivalents) and the product from Step 1 (4.00 kg, 1.0 equivalent). The mixture was held at 20° C. to 25° C. until all material was dissolved over 30 minutes. Acetic acid (0.792 kg, 1.05 equivalents) as added. The mixture was stirred for 1 hour during which the reaction mixture turned to cloudy. The reaction mixture was refluxed for 30 minutes and then concentrated at 60° C. to 70° C. until a steady temperature of 66.9° C. was observed in the overheads indicating complete removal of water from the system. More THF was added as necessary. At the end, THF was added to bring the total volume in the reactor to 15 volumes of the limit reagent. The reaction mixture was cooled to −3° C. to 7° C. and sampled for complete formation of imine by HPLC (using sodium triacetoxyborohydride to reduce imine). Sodium triacetoxyborohydride (5.33 kg, 2.0 equivalents) was added portion-wise to the suspension at −5° C. to 15° C. The reaction mixture was heated to 20° C. to 25° C. and held for 12 hours. HPLC results confirmed the reaction was complete by 99.8%. Sodium bicarbonate aqueous solution (10% w/w, 10 volumes) was added. The slurry was concentrated to remove 10 volumes of THF under partial vacuum at 30° C. to 60° C. Ethyl acetate (10 volumes) was added to the suspension after it cooled to 20° C. to 25° C. The organic phase was separated and the aqueous phase was checked by HPLC. It contained less than 2% of the product. The organic phase was washed with water (5 volumes), saturated brine solution (5 volumes) and concentrated to a small volume (2 volumes) under partial vacuum at 45° C. to 50° C. To the slurry was added heptane (10 volumes) at 45° C. to 50° C. over 30 minutes. The mixture was cooled to 20° C. to 25° C. and granulated for 2 hours. Solid was collected by filtration, rinsed with heptane (2 volumes). Drying in a tray dryer for 12 hours at 35° C. to 45° C. yield 5.35 kg (91.3%) of the product.
Step 3—(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone
Water (19 liters, 2 volumes) was charged to a reactor followed by the product from Step 2 (9.57 kg, 1.0 equivalent). To the slurry was added concentrated HCl (37 wt % in water, 19.1 liters, 2 volumes) slowly at 20° C. to 30° C. over 4 hours. The slurry went into solution after 12 liters of HCl was added. After the addition completion, the reaction was complete by HPLC assay. The reaction mixture was cooled to 5° C. to 15° C. To the mixture was added 50% NaOH aqueous solution slowly with agitation to pH 10 to pH 11. The pH was monitored with a pH meter closely during the neutralization. The total volume of 50% NaOH added was 12.45 liters. The mixture was warmed to 20° C. to 25° C. and extracted with ethyl acetate twice (115 liters, 12 volumes and 57 liters, 6 volumes, respectively). The sample from aqueous layer after second extraction was analyzed by HPLC and showed only 1% of the product in that aqueous solution. The organic layers were combined and treated with magnesium sulfate (5 kg) for 1 hour. The mixture was filtered. The filter cake was rinsed with ethyl acetate (10 liters). The filtrate was charged back to the reactor via a 0.2 micron in-line filter for speck free operation. (The following operations were performed under speck free conditions.) The solution was concentrated to 20 liters (2 volumes) under partial vacuum at 50° C. to 60° C. The mixture was cooled to 20° C. to 25° C. over 30 minutes. Upon cooling to room temperature, crystallization occurred. The mixture was held for 30 minutes. Hexanes (20 liters, 2 volumes) was added slowly over 1 hour. The mixture was granulated for 2 hours. The solid product was collected by filtration and rinsed with hexanes/ethyl acetate (10 liters, 1:1 v/v). The filter was blown dry with nitrogen for a minimum of 2 hours. The product was dried in a tray dryer at 44° C. for 12 hours.
Yield: 5.7 kg, 75.9%. m.p. 156° C. MS m/z 367 (MH+).
1H NMR (400 MHz, D2O): δ 8.15 (d, 2H, J=5.0 Hz, CH of pyrimidine), 6.55 (t, 1H, J=4.8 Hz, CH of pyrimidine), 3.87-3.81 (dd, 1H, H2b of proline, rotomeric), 3.78-3.50 (m, 4H, N—CH2 of pyrrolidide), 3.55-3.40 (m, 4H, N—CH2 of piperazine), 2.97 (dd, 1H, J=10.2, 6.6 Hz, H5a of proline), 2.85-2.75 (m, 1H, H4b of proline), 2.69 (dd, 1H, J=10.0, 9.1 Hz, H5b of proline), 2.55-2.20 (m, 7H, overlapping N—CH2 of piperazine, CH2 of pyrrolidide and H3b of proline), 1.47-1.38 (m, 1H, H3a of proline).
Alternatively, the dihydrochloride salt of the titled compound was prepared according to the method of Example 1.
……………..
PAPER
Scheme 1.
Reagents and conditions: (a) 3,3-difluoropyrrolidine hydrochloride, EDC, HOBt, TEA, DCM, rt; (b) NaBH4, MeOH, (c) (1) trifluoromethane-sulphonyl chloride, DIPEA, DCM; (2) 2-(1-piperazinyl)pyrimidine, DCM, −10 °C; (d) 4 N HCl in dioxane, rt; (e) 2-(1-piperazinyl)pyrimidine, NaBH(OAc)3, AcOH, DCE; (f) R1R2NH hydrochloride, EDC, HOBt TEA, DCM, 0–rt; (g) N-heterocyclic piperazine, NaBH(OAc)3, AcOH, DCE.
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| Patent | Submitted | Granted |
|---|---|---|
| Therapeutic compounds [US7291618] | 2005-11-17 | 2007-11-06 |
| (2S,4S)-4-(piperazin-1-yl)pyrrolidine-2-methanone derivatives [US7465732] | 2007-05-03 | 2008-12-16 |
| THERAPEUTIC COMPOUNDS [US2007161664] | 2007-07-12 | |
| Therapeutic compounds [US2006079498] | 2006-04-13 |
see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html
http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html
see gliptins at…………http://drugsynthesisint.blogspot.in/p/gliptin-series.html
TENELIGLIPTIN
| Teneligliptin; 760937-92-6; UNII-28ZHI4CF9C; Teneligliptin (INN); 28ZHI4CF9C | |
| MF | C22H30N6OS |
|---|---|
| MW | 426.5782 g/mol |
Teneligliptin (INN; trade name Tenelia) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It is approved for use in Japan.[1] It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or “gliptins”.[2] {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methanone
Teneligliptin was launched in Japan in 2012 by Mitsubishi Pharma and Daiichi Sankyo for the treatment of type 2 diabetes mellitus. In 2013, the indication was partially changed to include it as a combination therapy with existing oral hypoglycemic agents, such as biganides, alpha-glucosidaseinhibitors, rapid-acting insulin secretagogues, and insulin preparations, as well as sulfonylureas and thiazolidines that had been approved for the combination.
In 2014, the product was registered in KR for the treatment of type 2 diabetes mellitus.
In 2013, Mitsubishi Tanabe Pharma filed for approval in Japan for use of the compound as combination therapy for the treatment of diabetes type 2.
| CAS | 760937-92-6 |
|---|
3-{(2S,4S)-4-[4-(3-methyl-l -phenyl- 1 H- pyrazol-5-yl)- l-piperazinyl]-2-pyrrolidinylcarbonyl}-l , 3-thiazolidine is represented structurally by a compound of formula (I):
Teneligliptin (CAS 760937-92-6) is a novel, potent and long-lasting dipeptidyl peptidase-4 inhibitor in treatment of type 2 diabetes. Dipeptidyl-peptidase-4 (DPP- 4) inhibitor has been demonstrated to improve glycemic control, in particular postparandial hyperglycemic control.
Despite of their common mechanism of action, DPP-4 inhibitors show marked structural heterogeneity. DPP-4 inhibitors may be classified into peptidomimetic (i.e. sitagliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetic (i.e. alogliptin and linagliptin) subtypes.
Teneligliptin, is chemically known as a 3- {((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl 25 carbonyl}thiazolidine hemipentahydrobromide hydrate and is peptidomimetic with the molecular formula of C22H30N6OS.2½HBr.xH2O and molecular weight of 642.88 g/mol for hemipentahydrobromide. The hydrate can be from mono to dihydrate.
U.S. Patent No. 7,074,794 B2 (the US ‘794) discloses teneligliptin as L-proline derivative and its pharmaceutically acceptable salts which exhibits a Dipeptidyl 5 peptidase IV (DPP-IV) inhibitory activity, which is useful for the treatment or prophylaxis of diabetes, obesity, HIV infection, cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis, autoimmune diseases and the like.
The example-222 of the US ‘794 discloses the process for the preparation of teneligliptin as trihydrochloride salt U.S. Patent No. 8,003,790 B2 (the US ‘790) discloses salts of proline derivative, solvate thereof and production method thereof. In particular, the US ‘790 discloses 2.0 hydrochloride or 2.5 hydrochloride; 2.0 hydrobromide or 2.5 hydrobromide, and hydrates thereof teneligliptin.
The US ‘790 B2 further discloses different salts 15 of teneligliptin which are incorporated herein as reference in their entirety U.S. PG-Pub. No. 2011/0282058 A1 discloses salts of 3-{((2S,4S)-4-(4-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl}thiazolidine with mono-, di- and tri-basic acids or a solvate thereof. 20 International (PCT) publication No. WO 2012/165547 A1 discloses a process for preparation of teneligliptin and pharmaceutically acceptable salts thereof.
International (PCT) publication No. WO 2007/127635 A2 (the WO ‘635 A2) discloses a process for the preparation of diketo-piperazine and piperidine 25 derivatives. In particular, the WO ‘635 A2 discloses the process for preparation of 4-oxo-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (III)] by reacting piperazine with aryl halide.
International (PCT) publication No. WO 2012/099915 A1 (the WO ‘915 A1) 5 discloses the process for the preparation of deuterated thiazolidine derivatives. The WO ‘915 A1 also discloses the process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by condensation of 5- chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine.
Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by deprotection of Boc-protected 1-(3-methyl-1-phenyl-1Hpyrazol-5-yl)piperazine with triflouroacetic acid.
U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine by condensation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine in presence of n-BuLi in tetrahydrofuran. Bioorganic & Medicinal Chemistry, 14(11), 3662-3671 (2006),
Bioorganic & Medicinal Chemistry, 20(16), 5033-5041 (2012) and U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate by reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid with 25 thiazolidine in presence of HOBT and EDC.HCl in dimethylformamide solvent.
Bioorganic & Medicinal Chemistry, 15(2), 641-655 (2007) discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3- carbonyl)pyrrolidine-1-carboxylate by treating (2S,4S)-tert-butyl 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate with tetrabutylammonium fluoride in tetrahydrofuran.
Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the 5 process for the preparation of herein compound (II) after by reacting 1-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) with (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate in presence of sodium triacetoxyborohydride. There is provided different alternative processes for the preparation of teneligliptin and intermediates thereof.
Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) also discloses the process for the preparation of 4-[4-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-piperazin- 1-yl]-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (II)] after by reacting 1-(3-methyl-1-phenyl-1H-pyrazol-5- 15 yl)piperazine [herein compound (V)] with (2S,4S)-tert-butyl 4-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate in presence of trifluoromethylsulfonic anhydride and diisopropylethylamine. 3 – [[(2S, 4S) -4- [4- (3- methyl-1-phenyl–1H- pyrazol-5-yl) -1-piperazinyl ] -2-pyrrolidinyl] carbamoyl] thiazolidine, having the formula below, is a very novel DPP-4 inhibitor potential.
World Patent Application No. W02012099915 for Ge Lieting discloses a process for the preparation route is as follows:
Journal B10rganic & Medicinal Chemistry, 2012, 20, 5705-5719 also discloses a preparation method for Ge Lieting, the route is as follows:
[0009] 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine, was prepared for the Ge Lieting key intermediate. Journals B10rganic & Medicinal Chemistry, 2012,20,5705-5719 reported the preparation of the intermediates prepared route is as follows:
[0011] The preparative route after the N-Boc-N- acetoacetyl piperazine phenylhydrazine and methanesulfonic acid in an ethanol solution of the reaction at room temperature 14h, concentrated under reduced pressure after addition of pyridine.Was added phosphorus oxychloride in pyridine, 20h post treatment reaction at room temperature the reaction system. The compound obtained above was then added trifluoroacetic acid was dissolved in methylene chloride after, after treatment at room temperature for 1.5h to give 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine.
The reaction process requires mesylate mesylate flammable, easy-absorbent deliquescence, and has a strong corrosive and irritating, easy to cause the body burns; phosphorus oxychloride, a highly toxic substance, water violent hair in the air smoke, hydrolyzed into phosphoric acid and hydrogen chloride, is very unstable, to operate a lot of trouble; trifluoroacetic acid is highly corrosive and irritant, can cause the body burns; low yield of the reaction (10%). Seeking a simple operation, high reaction yield, low cost and suitable for industrial production production process 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine has a very important role in the field of medicine.
…………………………………….
since the capture is staggered, compd 165 is not clear in above pic see below
…………
…………………….
reaction scheme in http://www.google.com/patents/CN104177295A?cl=en
Description: LR as Lawesson reagent (Lawesson Reagent), is a sulfur oxygen exchange reagent. The present invention provides a method for preparing key intermediates Ge Lieting method, comprising the steps of: (I) N-Boc-N- acetoacetyl piperazine Lawesson’s reagent in the presence of an organic solvent, with a phenylhydrazine of the formula occurs ⑴ reaction shown:
(2) the step (1) The product was dissolved in an organic solvent, the following formula (II) in concentrated hydrochloric acid to deprotected shown:
Volume 20, Issue 19, 1 October 2012, Pages 5705–5719
………………………..
http://www.google.co.in/patents/WO2015019238A1?cl=en
Example 5: Preparation of {(2^,.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -vHpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)
Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was filtered through a Hyflo® bed. The filtrate was heated to a temperature of 70°C to 75°C. Hydrobromic acid (48%; 168 g) was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes. The reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes. The reaction mixture was filtered to obtain a solid. The solid obtained was washed with isopropyl alcohol (2 x 200 mL), and dried at 50°C under reduced pressure for 15 hours to obtain crude {(25*,45)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl} ( 1 ,3 -thiazolidin-3 -yl)methanone
hemipentahydrobromide hydrate.
Yield: 90%
Example 6: Purification of {(2^’.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)
A reaction mixture containing {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone
hemipentahydrobromide hydrate (100 g; prepared according to the process of Example 5) in ethanol (700 mL) was heated at 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to a temperature of 65 °C to 68°C, and deionized water (10 mL) was added at the same temperature. The solution was cooled to a temperature of 55°C to 60°C, and stirred at the same temperature for 2 hours. The solution was further cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, washed with ethanol (100 mL), and dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l- yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate .
Yield: 90%
HPLC Purity: 99.93%
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Vishva Shah, Royal Military College of Canada
see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html
http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html
see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html
http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html
SAXAGLIPTIN
| Saxagliptin | |
| CAS No.: | 361442-04-8 |
|---|---|
| Synonyms: |
|
| Formula: | C18H25N3O2 |
| Exact Mass: | 315.19500 |
| Molecular Weight: | 315.41000 |
is a dipeptidyl peptidase IV (DPP4) inhibitor. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.
13C NMR PREDICT
| ………………
http://www.google.com/patents/WO2012162507A1?cl=en two amino acid derivatives (A) and (B), described in further detail hereinbelow, coupled in the presence of a coupling reagent. The amide coupling of (S)-a[[(l,l-dimethyleethoxy)carbonyl]amino]-3- hydroxytricyclo [3.3.1.1]decane-l-acetic acid (A) and (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide (B), subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin (C).
 synthetic route is disclosed as follows:
  Scheme-IV
 Scheme-V
  ………………
……………..
………….
Savage, Scott A., et al., “Preparation of Saxagliptin, a Novel DPP-IV Inhibitor“, Organic Process Research & Development, 2009, vol. 13, pp. 1169-1176. |
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REFERENCES
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