synthesis – Page 3 – All About Drugs

Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives……..WO 2013140419…CSIR INDIA PATENT

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Oct 012013

sumanirole

179386-43-7
179386-44-8 (maleate)

Sumanirole maleate, U-95666 (free base), U-95666E, PNU-95666E

	Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives
	Council Of Scientific & Industrial Research
	The present invention relates to novel and concise process for the construction of chiral 3-substituted tetrahydroquinoline derivatives based on proline catalyzed asymmetric α-functionalization of aldehyde, followed by in situ reductive cyclization of nitro group under catalytic hydrogenation condition with high optical purities. Further the invention relates to conversion of derived chiral 3-substituted tetrahydroquinoline derivatives into therapeutic agents namely (-)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone[(S)-903] (92% ee).
	Process,sumanirole
Indications	Restless legs syndrome; Parkinsons disease
Target-based Actions	Dopamine D2 receptor agonist
Other Actions	Anxiolytic; Antiparkinsonian

Inventors	Boopathi, Senthil, Kumar; Arumugam, Sudalai; Rawat, Varun
IPC Codes	C07D 215/20; C07D 471/06; C07D 215/38

DRUG	sumanirole
Publication Date	26-Sep-2013 WO-2013140419-A1

Sumanirole (PNU-95,666) is a highly selective D₂ receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson’s disease andrestless leg syndrome. While it has never been approved for medical use it is a highly valuable tool compound for basic research to identify neurobiological mechanisms that are based on a dopamine D2-linked (vs. D1, D3, D4, and D5-linked) mechanism of action

sumanirole

OTHER INFO

D-Phenylalanine (I) was protected as the methyl carbamate (II) by acylation with methyl chloroformate under Schotten-Baumann conditions. The N-methoxy amide (III) was then prepared by coupling of (II) with O-methyl hydroxylamine in the presence of EDC. Cyclization of (III) to the N-methoxy quinolinone (IV) was accomplished by treatment with bis(trifluoroacetoxy)iodobenzene in the presence of trifluoroacetic acid. Simultaneous reduction of the N-methoxy lactam and carbamate functions of (IV) by means of borane-methyl sulfide complex provided diamine (V). The aliphatic amino group of (V) was then selectively protected as the benzyl carbamate (VI) by using N-(benzyloxycarbonyloxy)succinimide at -40 C. Reaction of (VI) with phosgene, followed by treatment of the intermediate carbamoyl chloride with O-methyl hydroxylamine gave rise to the N-methoxy urea derivative (VII). This was cyclized with bis(trifluoroacetoxy)iodobenzene to the imidazoquinolinone (VIII). The N-methoxy and N-benzyloxycarbonyl groups of (VIII) were then removed by hydrogenolysis in the presence of Pearlman’s catalyst, and the title compound was finally converted to the corresponding maleate salt.

JOC 1997,62,(19):6582

SIMPONI® Receives European Commission Approval for Treatment of Moderately to Severely Active Ulcerative Colitis

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Sep 262013

SIMPONI® , golimumab

http://newdrugapprovals.wordpress.com/2013/07/20/simponi-aria-golimumabfor-infusion-receives-fda-approval-for-treatment-of-moderately-to-severely-active-rheumatoid-arthritis/

First and Only Subcutaneous Biologic Treatment Administered Every Four Weeks Approved for Ulcerative Colitis

LEIDEN, The Netherlands, Sept. 23, 2013 /PRNewswire/ — Janssen Biologics B.V. (“Janssen”) announced today that the European Commission has approved SIMPONI® (golimumab) for the treatment of moderately to severely active ulcerative colitis (UC) in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies. The European Commission approval follows a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in July 2013 recommending the use of SIMPONI.

read all at

http://www.pharmalive.com/eu-oks-simponi-for-ulcerative-colitis

Golimumab (Simponi; Centocor Ortho Biotech), a fully human antibody that is specific for tumour necrosis factor, was approved by the US FDA for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis in April 2009.

Golimumab

Golimumab is a human immunoglobulin G1 mAb that is specific for human TNF2, 3, 4, 5. It was created using genetically engineered mice that were immunized with human TNF, resulting in an antibody with human-derived variable and constant regions4, 5. Golimumab binds to both the soluble and transmembrane bioactive forms of human TNF, preventing the binding of TNF to its receptors and thereby inhibiting the biological activity of TNF

In the past decade, the introduction of biologics that inhibit the activity of the pro-inflammatory cytokine tumour necrosis factor (TNF) has revolutionized the treatment of a range of immuno-inflammatory disorders, such as rheumatoid arthritis, psoriasis and Crohn’s disease¹. The first two such biologics — infliximab (Remicade; Centocor/Schering-Plough), a chimeric monoclonal antibody (mAb) specific for TNF, and etanercept (Enbrel; Amgen/Wyeth), a fusion protein that contains the ligand-binding portion of the soluble TNF receptor — were approved for the treatment of rheumatoid arthritis in the late 1990s. Their use has since been expanded to other disorders, including psoriatic arthritis. In 2002, the fully human TNF-specific mAb adalimumab (Humira; Abbott) was approved for the treatment of rheumatoid arthritis and is now also approved for several other immuno-inflammatory disorders. A fourth TNF inhibitor, the PEGylated humanized TNF-specific antibody fragment certolizumab pegol (Cimzia; UCB), was approved for Crohn’s disease in 2008 and rheumatoid arthritis in May 2009.

Golimumab, in combination with MTX, is approved by the FDA for the treatment of adult patients with moderately to severely active rheumatoid arthritis. It is also approved for the treatment of adult patients with active psoriatic arthritis (alone or in combination with MTX) and for the treatment of adult patients with active ankylosing spondylitis

Takeda Gets Simultaneous EU OKs for Three Type 2 Diabetes Therapies

diabetes Comments Off

Sep 252013

Takeda Receives Simultaneous European Marketing Authorization for Three New Type 2 Diabetes Therapies, VipidiaTM (alogliptin) and Fixed-Dose Combinations VipdometTM (alogliptin and metformin) and IncresyncTM (alogliptin and pioglitazone)

Osaka, Japan, September 24, 2013 – Takeda Pharmaceutical Company Limited (Takeda) today announced that the European Commission has granted Marketing Authorization (MA) for VipidiaTM (alogliptin), a dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of type 2 diabetes patients who are uncontrolled on existing therapies1-3and for the fixed-dose combination (FDC) therapies VipdometTM (alogliptin with metformin) and IncresyncTM (alogliptin with pioglitazone). The Committee for Medicinal Products for Human Use (CHMP), of the European Medicines Agency (EMA), issued a positive opinion for these products on July 26, 2013.http://www.pharmalive.com/takeda-gets-simultaneous-eu-oks-for-three-new-type-2-diabetes-therapies

Synthetic drug Tramadol found in nature,pin cushion tree

Ayurveda, drugs Comments Off

Sep 182013

The bark of Nauclea latifolia contains tramadol at medicinal concentrations © imagebroker / Alamy

http://www.rsc.org/chemistryworld/2013/09/african-plant-natural-source-tramadol

In another example of nature beating chemists, the African plant Nauclea latifolia has been found to be a natural source of the synthetic opioid tramadol. First marketed in 1977, tramadol is frequently used to relive moderate to moderately-severe pain. While other synthetic drugs have later been found in nature, this is the first instance where the discovery involves clinically viable concentrations.

Colloquially known as the ‘African peach’ or ‘pin cushion tree’, N. latifolia is a flowering, sub-Saharan evergreen that grows widely across Central and West Africa and is used by local populations to treat a wide variety of ailments – including epilepsy, malaria, general pain and many infectious diseases………………………. READ ALL AT

http://www.rsc.org/chemistryworld/2013/09/african-plant-natural-source-tramadol

tramadol

tramadol hydrocloride

The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3methoxyphenyl) cyclohexanol hydrochloride

Tramadol (marketed as the hydrochloride salt by Janssen Pharmaceutica as Ultram in the United States, Ralivia by Biovail in Canada and many other companies throughout the world) is a centrally acting synthetic opioid analgesic used to treat moderate to moderately severe pain. The drug has a wide range of applications, including treatment of rheumatoid arthritis, restless legs syndrome, motor neurone disease and fibromyalgia.^{[citation needed]} It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977.

Tramadol is a weak μ-opioid receptor agonist, a serotonin releaser and a reuptake inhibitor of norepinephrine. Tramadol is metabolized to O-desmethyltramadol, a significantly more potent μ-opioid agonist. Tramadol and its major metabolite(s) are distinguished from other more potent opioid agonists by relative selectivity for μ-opioid receptors.

Chemistry

Characteristics

Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolized along the same hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the O-desmethyltramadol.

When administered through IV, patients notice very little clinical difference in subjective potency compared to morphine.

Comparison with related substances

Structurally, tapentadol is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety, attached directly to the aromatic, while tapentadol lacks this feature.

Synthesis and stereoisomerism

(1R,2R)-Tramadol (1S,2S)-Tramadol

(1R,2S)-Tramadol (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.^[62] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

(1R,2R)-isomer
(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described^[63] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects^[64] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals^[65] and in humans.^[66]

62…..Pharmaceutical Substances, Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert, 4. ed. (2000) 2 volumes, Thieme-Verlag Stuttgart (Germany), p. 2085 bis 2086, ISBN 978-1-58890-031-9; since 2003 online with biannual actualizations.
63………Zynovy, Zinovy; Meckler, Harold (2000). “A Practical Procedure for the Resolution of (+)- and (−)-Tramadol”. Organic Process Research & Development 4 (4): 291–294. doi:10.1021/op000281v.
64……..Burke D, Henderson DJ (April 2002). “Chirality: a blueprint for the future”. British Journal of Anaesthesia 88 (4): 563–76. doi:10.1093/bja/88.4.563. PMID 12066734.
65…Raffa, R. B.; Friderichs, E.; Reimann, W.; Shank, R. P.; Codd, E. E.; Vaught, J. L.; Jacoby, H. I.; Selve, N. (1993). “Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol”. The Journal of Pharmacology and Experimental Therapeutics 267 (1): 331–340. PMID 8229760.
66 ..Grond, S.; Meuser, T.; Zech, D.; Hennig, U.; Lehmann, K. A. (1995). “Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia”. Pain 62 (3): 313–320. doi:10.1016/0304-3959(94)00274-I. PMID 8657431.

tramadol hydrochloride, which is (RR, SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride (trans), from a mixture of its (RS, SR) (cis) and trans bases, and to an improved process for the preparation of tramadol (base) monohydrate, sometimes used as an intermediate in the preparation of tramadol hydrochloride.
Tramadol is a well-established drug disclosed in US patent specification no. 3 652 589, which is used in the form of its hydrochloride salt as a non-narcotic analgesic drug. Tramadol is the pharmacologically active trans isomer of 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, as opposed to the corresponding cis isomer, namely, (RS, SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol.
Various processes for the synthesis of tramadol hydrochloride have been described in the prior art. For example, US 3 652 589 and British patent specification no. 992 399 describe the preparation of tramadol hydrochloride. In this method, Grignard reaction of 2-dimethylaminomethyl cyclohexanone (Mannich base) with metabromo-anisole gives an oily mixture of tramadol and the corresponding cis isomer, along with Grignard impurities. This oily reaction mixture is subjected to high vacuum distillation at high temperature to give both the geometric isomers of the product base as an oil. This oil, on acidification with hydrogen chloride gas, furnishes insufficiently pure tramadol hydrochloride as a solid. This must then be purified, by using a halogenated solvent and 1,4-dioxane, to give sufficiently pure tramadol hydrochloride. The main drawback of this process is the use of large quantities of 1,4-dioxane and the need for multiple crystallizations to get sufficiently pure trans isomer hydrochloride (Scheme – 1).
The use of dioxane for the separation of tramadol hydrochloride from the corresponding cis isomer has many disadvantages, such as safety hazards by potentially forming explosive peroxides, and it is also a category 1 carcinogen (Kirk and Othmer, 3^rd edition, 17, 48). Toxicological studies of dioxane show side effects such as CNS depression, and necrosis of the liver and kidneys. Furthermore, the content of dioxane in the final tramadol hydrochloride has been strictly limited; for example, the German Drug Codex (Deutscher Arzneimittel Codex, DAC (1991)) restricts the level of dioxane in tramadol hydrochloride to 0.5 parts per million (ppm).
In another process, disclosed in US patent specification no. 5 414 129, the purification and separation of tramadol hydrochloride is undertaken from a reaction mixture containing the trans and cis isomers, and Grignard reaction side products, in which the reaction mixture is diluted in isopropyl alcohol and acidified with gaseous hydrogen chloride to yield (trans) tramadol hydrochloride (97.8%) and its cis isomer (2.2%), which is itself crystallized twice with isopropyl alcohol to give pure (trans) tramadol hydrochloride (Scheme – 2). This process relies on the use of multiple solvents to separate the isomers (ie butylacetate, 1-butanol, 1-pentanol, primary amyl alcohol mixture, 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol and anisole). The main drawback of this process is therefore in using high boiling solvents; furthermore, the yields of tramadol hydrochloride are still relatively low and the yield of the corresponding cis hydrochloride is relatively high in most cases.
PCT patent specification no. WO 99/03820 describes a method of preparation of tramadol (base) monohydrate, which involves the reaction of Mannich base with metabromo-anisole (Grignard reaction) to furnish a mixture of tramadol base with its corresponding cis isomer and Grignard impurities. This, on treatment with an equimolar quantity of water and cooling to 0 to -5°C, gives a mixture of tramadol (base) monohydrate with the corresponding cis isomer (crude). It is further purified with ethyl acetate to furnish pure (trans) tramadol (base) monohydrate, which is again treated with hydrochloric acid in the presence of a suitable solvent to give its hydrochloride salt (Scheme – 2). The drawback of this method is that, to get pure (trans) tramadol hydrochloride, first is prepared pure (trans) tramadol (base) monohydrate, involving a two-step process, and this is then converted to its hydrochloride salt. The overall yield is low because of the multiple steps and tedious process involved.
More recently, a process for the separation of tramadol hydrochloride from a mixture with its cis isomer, using an electrophilic reagent, has been described in US patent specification no. 5 874 620. The mixture of tramadol hydrochloride with the corresponding cis isomer is reacted with an electrophilic reagent, such as acetic anhydride, thionyl chloride or sodium azide, using an appropriate solvent (dimethylformamide or chlorobenzene) to furnish a mixture of tramadol hydrochloride (93.3 to 98.6%) with the corresponding cis isomer (1.4 to 6.66%), (Scheme – 3). The product thus obtained is further purified in isopropyl alcohol to give pure (trans) tramadol hydrochloride. However, the drawback of this process is that a mixture of tramadol base with its cis isomer is first converted into the hydrochloride salts, and this is further reacted with toxic, hazardous and expensive electrophilic reagents to get semi-pure (trans) tramadol hydrochloride. The content of the cis isomer is sufficiently high to require further purification, and this therefore results in a lower overall yield.

Synthesis and stereoisomerism

The chemical synthesis of tramadol is described in the literature. Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

(1R,2R)-isomer
(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described[62] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.

……………………………………………………

EP 1346978 A1

The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast

cancer Comments Off

Sep 172013

capecitabine

154361-50-9

R-340, Ro-09-1978, Xeloda

pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate

MONDAY Sept. 16, 2013 — The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast, the agency said Monday in a news release.

This year, an estimated 142,820 people will be diagnosed with cancer of the colon/rectum, and 50,830 are predicted to die from the disease, the FDA said, citing the U.S. National Cancer Institute. An estimated 232,340 women will be diagnosed with cancer of the breast this year, and some 39,620 will die from it.

The most common side effects of the drug are diarrhea, vomiting; pain, redness, swelling or sores in the mouth; fever and infection, the FDA said.

The agency stressed that approved generics have the same high quality and strength as their brand-name counterparts.

License to produce the generic drug was given to Israel-based Teva Pharmaceuticals. The brand name drug is produced by the Swiss pharma firm Roche.

Capecitabine (INN) /k eɪ p ˈ s aɪ t ə b iː n / (Xeloda, Roche) is an orally-administeredchemotherapeutic agent used in the treatment of metastatic breast andcolorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCR) and 5′-deoxy-5-fluorouridine (5′-DFUR), to form 5-fluorouracil

Indications

Capecitabine is FDA-approved for:

Adjuvant in colorectal cancer Stage III Dukes’ C – used as first-line monotherapy.
Metastatic colorectal cancer – used as first-line monotherapy, if appropriate.
Metastatic breast cancer – used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline).

In the UK, capecitabine is approved by the National Institute for Health and Clinical Excellence (NICE) for colon and colorectal cancer, and locally advanced or metastatic breast cancer.^[1] On March 29, 2007, the European Commission approved Capecitabine, in combination with platinum-based therapy (with or without epirubicin), for the first-line treatment of advanced stomach cancer.

Capecitabine is a cancer chemotherapeutic agent that interferes with the growth of cancer cells and slows their distribution in the body. Capecitabine is used to treat breast cancer and colon or rectum cancer that has spread to other parts of the body.

Formulation

Capecitabine (as brand-name Xeloda) is available in light peach 150 mg tablets and peach 500 mg tablets.

Lacy, Charles F; Armstrong, Lora L; Goldman, Morton P; Lance, Leonard L (2004). Lexi-Comp’s Drug Information Handbook (12th Edition). Lexi-Comp Inc. ISBN 1-59195-083-X
Fischer, David S; Knobf, M Tish; Durivage, Henry J; Beaulieu, Nancy J (2003). The Cancer Chemotherapy Handbook (6th Edition). Mosby. ISBN 0-323-01890-4
Thomson Centerwatch: Drugs Approved by the FDA (Xeloda) Retrieved 6/05
Mercier C, Ciccolini J (2007). “Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit?”. Trends in pharmacological sciences 28 (12): 597–598.doi:10.1016/j.tips.2007.09.009. PMID 18001850.

“Subtopics”. Nice.org.uk. Retrieved 2012-08-15.
Fingerprints May Vanish With Cancer Drug – US News and World Report
Cancer Drug Erases Man’s Fingerprints – CNN
“Stritch School of Medicine”. Stritch.luc.edu. Retrieved 2012-08-15.

Xeloda.com (patient information, tools, and resources)
OralChemo Advisor (patient information)

WO2009066892A1

Capecitabine is an orally-administered anticancer agent widely used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a ribofuranose-based nucleoside, and has the sterochemical structure of a ribofuranose having an β-oriented 5-fluorocytosine moiety at C-I position.

US Patent Nos. 5,472,949 and 5,453,497 disclose a method for preparing capecitabine by glycosylating tri-O-acetyl-5-deoxy-β-D-ribofuranose of formula I using 5-fluorocytosine to obtain cytidine of formula II; and carbamoylating and hydrolyzing the resulting compound, as shown in Reaction Scheme 1 :

Reaction Scheme 1

The compound of formula I employed as an intermediate in Reaction

Scheme 1 is the isomer having a β-oriented acetyl group at the 1 -position, for the reason that 5-fluorocytosine is more reactive toward the β-isomer than the α-isomer in the glycosylation reaction due to the occurrence of a significant neighboring group participation effect which takes place when the protecting group of the 2-hydroxy group is acyl.

Accordingly, β-oriented tri-O-acetyl-5-deoxy-β-D-ribofuranose (formula

I) has been regarded in the conventional art to the essential intermediate for the preparation of capecitabine. However, such a reaction gives a mixture of β- and α-isomers from which cytidine (formula II) must be isolated by an uneconomical step.

Meanwhile, US Patent No. 4,340,729 teaches a method for obtaining capecitabine by the procedure shown in Reaction Scheme 2, which comprises hydrolyzing 1-methyl-acetonide of formula III to obtain a triol of formula IV; acetylating the compound of formula IV using anhydrous acetic anhydride in pyridine to obtain a β-/α-anomeric mixture of tri-O-acetyl-5-deoxy-D-ribofuranose of formula V; conducting vacuum distillation to purify the β-/α-anomeric mixture; and isolating the β-anomer of formula I therefrom:

Reaction Scheme 2

III IV

However, the above method is also hampered by the requirement to perform an uneconomical and complicated recrystallization steps for isolating the β-anomer from the mixture of β-/α-anomers of formula V, which leads to a low yield of only about 35% to 40% (Guangyi Wang et al., J. Med. Chem., 2000, vol. 43, 2566-2574; Pothukuchi Sairam et al., Carbohydrate Research, 2003, vol. 338, 303-306; Xiangshu Fei et al., Nuclear Medicine and Biology, 2004, vol. 31, 1033-1041; and Henry M. Kissman et al., J. Am. Chem. Soc, 1957, vol. 79, 5534-5540).

Further, US Patent No. 5,476,932 discloses a method for preparing capecitabine by subjecting 5′-deoxy-5-fluorocytidine of formula VI to a reaction with pentylchloroformate to obtain the compound of formula VII having the amino group and the 2-,3-hydroxy groups protected with C₅Hi₁CO₂ groups; and removing the hydroxy-protecting groups from the resulting compound, as shown in Reaction Scheme 3 :

Reaction Scheme 3

Vl VII 1

However, this method suffers from a high manufacturing cost and also requires several complicated steps for preparing the 5′-deoxy-5-fluorocytidine of formula VI: protecting the 2-,3-hydroxy groups; conducting a reaction thereof with 5-fluorocytosine; and deprotecting the 2-,3-hydroxy groups.

Accordingly, the present inventors have endeavored to develop an efficient method for preparing capecitabine, and have unexpectedly found an efficient, novel method for preparing highly pure capecitabine using a trialkyl carbonate intermediate, which does not require the uneconomical β-anomer isolation steps.

synthesis

WO2010065586A2

more info and description

Aspects of the present invention relate to capecitabine and processes for the preparation thereof.

The drug compound having the adopted name “capecitabine” has a chemical name 5′-deoxy-5-fluoro-N-[(pentyloxy) carbonyl] cytidine and has structural formula I.

OH OH I

This compound is a fluoropyrimidine carbamate with antineoplastic activity. The commercial product XELODA™ tablets from Roche Pharmaceuticals contains either 150 or 500 mg of capecitabine as the active ingredient.

U.S. Patent No. 4,966,891 describes capecitabine generically and a process for the preparation thereof. It also describes pharmaceutical compositions, and methods of treating of sarcoma and fibrosarcoma. This patent also discloses the use of ethyl acetate for recrystallization of capecitabine. The overall process is summarized in Scheme I.

Scheme I

U.S. Patent No. 5,453,497 discloses a process for producing capecitabine that comprises: coupling of th-O-acetyl-5-deoxy-β-D-hbofuranose with 5- fluorocytosine to obtain 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine; acylating a 2′, 3′- di-O-acetyl-5′-deoxy-5-fluorocytidine with n-pentyl chloroformate to form 5′-deoxy- 2′,3′-di-O-alkylcarbonyl-5-fluoro-N-alkyloxycarbonyl cytidine, and deacylating the 2′ and 3′ positions of the carbohydrate moiety to form capecitabine. The overall process is summarized in Scheme II.

Capecitabine

Scheme Il

The preparation of capecitabine is also disclosed by N. Shimma et al., “The Design and Synthesis of a New Tumor-Selective Fluoropyrimidine Carbamate, Capecitabine,” Bioorganic & Medicinal Chemistry, Vol. 8, pp. 1697-1706 (2000). U.S. Patent No. 7,365,188 discloses a process for the production of capecitabine, comprising reacting 5-fluorocytosine with a first silylating agent in the presence of an acid catalyst under conditions sufficient to produce a first silylated compound; reacting the first silylated compound with 2,3-diprotected-5- deoxy-furanoside to produce a coupled product; reacting the coupled product with a second silylating agent to produce a second silylated product; acylating the second silylated product to produce an acylated product; and selectively removing the silyl moiety and hydroxyl protecting groups to produce capecitabine. The overall process is summarized in Scheme III. te

R: hydrocarbyl

Scheme III

Further, this patent discloses crystallization of capecitabine, using a solvent mixture of ethyl acetate and n-heptane. International Application Publication No. WO 2005/080351 A1 describes a process for the preparation of capecitabine that involves the refluxing N₄– pentyloxycarbonyl-5-fluorocytosine with trimethylsiloxane, hexamethyl disilazanyl, or sodium iodide with trimethyl chlorosilane in anhydrous acetonitrile, dichloromethane, or toluene, and 5-deoxy-1 ,2,3-tri-O-acetyl-D-ribofuranose, followed by hydrolysis using ammonia/methanol to give capecitabine. The overall process is summarized in Scheme IV.

Scheme IV

International Application Publication No. WO 2007/009303 A1 discloses a method of synthesis for capecitabine, comprising reacting 5′-deoxy-5- fluorocytidine using double (trichloromethyl) carbonate in an inert organic solvent and organic alkali to introduce a protective lactone ring to the hydroxyl of the saccharide moiety; reacting the obtained compound with chloroformate in organic alkali; followed by selective hydrolysis of the sugar component hydrolytic group using an inorganic base to give capecitabine. The overall process is summarized in Scheme V.

Scheme V

Even though all the above documents collectively disclose various processes for the preparation of capecitabine, removal of process-related impurities in the final product has not been adequately addressed. Impurities in any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient. Furthermore, the existence of undesired as well as unknown impurities reduces the bioavailability of the API in pharmaceutical products and often decreases the stability and shelf life of a pharmaceutical dosage form.

nmr

¹H NMR(CD₃OD) δ 0.91(3H₅ t), 1.36~1.40(4H, m), 1.41(3H, d), 1.68~1.73(2H, m), 3.72(1H, dd), 4.08(1H, dd), 4.13~4.21(3H, m), 5.7O(1H, s), 7.96(1H, d)

The acetylation of 5′-deoxy-5-fluorocytidine (I) with acetic anhydride in dry pyridine gives 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine (II), which is condensed with pentyl chloroformate (III) by means of pyridine in dichromethane yielding 2′,3′-di-O-acetyl-5′-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine (IV). Finally, this compound is deacetylated with NaOH in dichloromethane/water. The diacetylated cytidine (II) can also be obtained by condensation of 5-fluorocytosine (V) with 1,2,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose (VI) by means of trimethylchlorosilane in acetonitrile or HMDS and SnCl4 in dichloromethane..
- EP 602454, JP 94211891, US 5472949.
  - Capecitabine. Drugs Fut 1996, 21, 4, 358,
    - Bioorg Med Chem Lett2000,8,(7):1697,

Cyclic Dinucleotide Senses HIV

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Aug 302013

The enzyme cyclic GMP-AMP synthase stimulates the immune response during HIV infections

http://www.chemistryviews.org/details/news/5109171/Cyclic_Dinucleotide_Senses_HIV.html

Experimental Drug Shows Promise for Rare Genetic Disorder

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Aug 302013

Transthyretin, or TTR for amyloidosis

THURSDAY Aug. 29, 2013 — A new medication appears to be highly effective in combating a heredity-based form of the organ-damaging genetic disorder known as amyloidosis, according to researchers.

Amyloidosis refers to a family of more than a dozen diseases in which different types of abnormal proteins called amyloids lodge in major organs and nerves. These amyloids build up to the point that they cause damage and, ultimately, organ failure.

read all at

http://www.drugs.com/news/experimental-shows-promise-rare-genetic-disorder-47059.html

Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol. The liver secretes transthyretin into the blood, and the choroid plexus secretes TTR into thecerebrospinal fluid.

TTR was originally called prealbumin^[1] (or thyroxine-binding prealbumin) because it ran faster than albumin on electrophoresis gels.

Binding affinities

It functions in concert with two other thyroid hormone-binding proteins in the serum:

Protein	Binding strength	Plasma concentration
thyroxine-binding globulin (TBG)	highest	lowest
transthyretin (TTR)	lower	higher
albumin	poorest	much higher

In cerebrospinal fluid TTR is the primary carrier of T4. TTR also acts as a carrier ofretinol (vitamin A) through its association with retinol-binding protein (RBP) in the blood and the CSF. Less than 1% of TTR’s T4 binding sites are occupied in blood, which is taken advantage of below to prevent TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue.

Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as resveratrol), drugs (Tafamidis,^[2] or Vyndaqel, diflunisal,^[3]^[4]^[5] flufenamic acid),^[6] and toxins (PCB^[7]).

Structure

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the liver, choroid plexus and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. Each monomer is a 127-residue polypeptide rich in beta sheet structure. Association of two monomers via their edge beta-strands forms an extended beta sandwich. Further association of two of these dimers in a face-to-face fashion produces the homotetrameric structure and creates the two thyroxine binding sites per tetramer. This dimer-dimer interface, comprising the two T4 binding sites, is the weaker dimer-dimer interface and is the one the comes apart first in the process of tetramer dissociation.^[8]

Prealbumin at the US National Library of Medicine Medical Subject Headings (MeSH)
^ ^a ^b Razavi H, Palaninathan SK, Powers ET, Wiseman RL, Purkey HE, Mohamedmohaideen NN, Deechongkit S, Chiang KP, Dendle MT, Sacchettini JC, Kelly JW (June 2003). “Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action”. Angew. Chem. Int. Ed. Engl. 42 (24): 2758–61.doi:10.1002/anie.200351179. PMID 12820260.
^ Sekijima Y, Dendle MA, Kelly JW (December 2006). “Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis”. Amyloid 13 (4): 236–49. doi:10.1080/13506120600960882.PMID 17107884.
^ Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW (January 2004). “Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis”. J. Med. Chem. 47 (2): 355–74. doi:10.1021/jm030347n.PMID 14711308.
^ Vilaro M, Arsequell G, Valencia G, Ballesteros A, Barluenga J, Nieto J, Planas A, Almeida R, Saraiva MJ (2007). “Reengineering TTR amyloid inhibition properties of diflunisal”. In Seldin DC, Skinner M, Berk JL, Connors LH. XIth International Symposium on Amyloidosis. Boca Raton: CRC.doi:10.1201/9781420043358.ch69. ISBN 1-4200-4281-5.
^ Baures PW, Oza VB, Peterson SA, Kelly JW (July 1999). “Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid”. Bioorg. Med. Chem. 7 (7): 1339–47.doi:10.1016/S0968-0896(99)00066-8. PMID 10465408.
^ Purkey HE, Palaninathan SK, Kent KC, Smith C, Safe SH, Sacchettini JC, Kelly JW (December 2004). “Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity”.Chem. Biol. 11 (12): 1719–28.doi:10.1016/j.chembiol.2004.10.009. PMID 15610856.
^ Foss TR, Wiseman RL, Kelly JW (November 2005). “The pathway by which the tetrameric protein transthyretin dissociates”. Biochemistry 44 (47): 15525–33.doi:10.1021/bi051608t. PMID 16300401.

Single molecule fights heart disease on two fronts

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Aug 212013

1-Fe

Could antioxidant that also inhibits cholesterol biosynthesis be more effective than statins?

Researchers in Israel have identified an antioxidant that can lower cholesterol levels as well as eliminating free radicals. This compound could be a promising alternative to statins, the most prescribed cholesterol-lowering drugs in the world.

http://www.rsc.org/chemistryworld/2013/08/antioxidant-statin-alternative-cholesterol

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Brain Cancer Survival Improved Following FDA Approval of Bevacizumab, Mayo Study Finds

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Aug 202013

ROCHESTER, Minn. — A new population-based study has found that patients with glioblastoma who died in 2010, after the Food and Drug Administration (FDA) approval of bevacizumab, had lived significantly longer than patients who died of the disease in 2008, prior to the conditional approval of the drug for the treatment of the deadly brain cancer. Bevacizumab is used to treat patients with certain cancers whose cancer has spread. The study appears in the journal Cancer

http://www.pharmalive.com/study-brain-cancer-survival-improved-following-fda-approval-of-avastin

STR REF –http://www.kidneycancerinstitute.com/Bevacizumab.html

IN CASE U NEED TO CONTACT ME THEN MAIL ME. amcrasto@gmail.com

Bevacizumab (trade name Avastin, Genentech/Roche) is an angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is licensed to treat various cancers, including colorectal, lung, breast (outside the USA), glioblastoma (USA only), kidney and ovarian.

Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A). VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer. Bevacizumab was the first clinically availableangiogenesis inhibitor in the United States.

Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for certainmetastatic cancers. It received its first approval in 2004, for combination use with standardchemotherapy for metastatic colon cancer.It has since been approved for use in certain lung cancers, renal cancers, and glioblastoma multiforme of the brain.

At one point bevacizumab was approved for breast cancer by the FDA, but the approval was revoked on 18 November 2011. The approval for breast cancer was revoked because, although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging. In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDA’s advisory panel had recommended against approval. In July 2010, after new studies failed to show a significant benefit, the FDA’s advisory panel recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA ruled to withdraw the breast cancer indication in November 2011. FDA approval is required for Genentech to market a drug for that indication. Doctors may sometimes prescribe it for that indication, although insurance companies are less likely to pay for it. The drug remains approved for breast cancer use in other countries including Australia.

Clinical trials are underway for many other indications including ovarian cancer, pediatric osteosarcoma, and certain non-malignant eye diseases. In the curative setting (adjuvant therapy), clinical studies are underway in breast cancer and lung cancer.

Vibativ Back on the Market

companies Comments Off

Aug 162013

Theravance Inc. said Wednesday it is antibiotic Vibativ is now back on the market. Vibativ was approved as a treatment for complex skin infections in 2010, and it was approved for use against hospital-acquired pneumonia in June 2013. It is Theravance’s only approved drug.