PF 06650808

cancer, MONOCLONAL ANTIBODIES, Uncategorized Comments Off

Mar 252016

Picture credit….Bethany Halford

PF 06650808

	Phase 1

Phase 1

$PFE compound inspired by auristatins

https://clinicaltrials.gov/ct2/show/NCT02129205

http://www.pfizer.com/sites/default/files/product-pipeline/8_7_2014_Pipeline_Update.pdf

ALL DATA COMING………

Notch-3 receptor antagonists

Neoplasms
Breast

Pfizer

Cancer

PF-06650808, is currently being examined in a Ph1 clinical trial (Protocol B7501001).

Notch3
Researchers are also exploring the use of Notch3 targeting. “The Notch pathway plays an important role in the growth of several solid tumours, including breast and ovarian cancer and melanoma,” explained Joerger. “In particular, Notch3 alterations such as gene amplification and upregulation are associated with poor patient survival. Research using Notch3 targeting as an innovative approach to treat solid malignancies included 27 patients unselected for Notch3 who received increasing doses of the anti-Notch3 antibody-drug conjugate PF-06650808. Responses were seen in two breast cancer patients (LBA 30). While preliminary, targeting Notch3 may become a new treatment approach in patients with selected solid tumours.”

The anti-Notch3 antibody-drug conjugate PF-06650808 is being developed by Pfizer.

31 Jul 2014 Phase-I clinical trials in Solid tumours (Late-stage disease) in USA (Parenteral)
30 Apr 2014 Preclinical trials in Solid tumours in USA (Parenteral)
30 Apr 2014 Pfizer plans a phase I trial for Solid tumours (late-stage disease, second-line therapy or greater) in USA (NCT02129205)

251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 262

/////////PF 06650808, PF-06650808, PF-6650808, monoclonal antibody, pfizer, phase 1, Solid tumours , Notch-3 receptor antagonists

C1(C(N(C(C1)=O)CCCCCC(=O)NC([C@H](C)C)C(=O)NC(C(=O)Nc2ccc(cc2)COC(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)[N@](C)C(C(CC)C)[C@@H](OC)CC(=O)N3CCC[C@H]3C(OO)C(C)C(=O)N[C@H](c4nccs4)CC)CCCNC(=O)N)=O)SC

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BMS 986120

phase 1, Uncategorized Comments Off

Mar 252016

Picture credit….Bethany Halford

BMS 986120

Originator Bristol-Myers Squibb

Bristol-Myers Squibb Company, Université de Montréal

Molecular Formula:	C₂₃H₂₃N₅O₅S₂
Molecular Weight:	513.58922 g/mol

4-[4-[[6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-1-benzofuran-4-yl]oxymethyl]-5-methyl-1,3-thiazol-2-yl]morpholine

4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,l-b][l,3,4]thiadiazol-6-yl)benzofuran-4-yl) oxy)methyl)-5-methylthiazol-2-yl)morpholine

Imidazo[2,1-b]-1,3,4-thiadiazole, 2-methoxy-6-[6-methoxy-4-[[5-methyl-2-(4-morpholinyl)-4-thiazolyl]methoxy]-2-benzofuranyl]-

CAS 1478712-37-6

Phase I Thrombosis

02 Apr 2015 Bristol-Myers Squibb plans a phase I trial in Thrombosis (In volunteers) in United Kingdom (NCT02439190)
01 Aug 2014 Preclinical trials in Thrombosis in USA (PO)

https://clinicaltrials.gov/ct2/show/NCT02208882

https://clinicaltrials.gov/ct2/show/NCT02439190

Class Imidazoles; Small molecules; Thiadiazoles

$BMY antithrombic compound

PATENT

http://www.google.com/patents/WO2013163279A1?cl=en

Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®).

Current anti-platelet therapies have limitations including increased risk of bleeding as well as partial efficacy (relative cardiovascular risk reduction in the 20 to

30% range). Thus, discovering and developing safe and efficacious oral or parenteral antithrombotics for the prevention and treatment of a wide range of thromboembolic disorders remains an important goal.

Alpha-thrombin is the most potent known activator of platelet aggregation and degranulation. Activation of platelets is causally involved in atherothrombotic vascular occlusions. Thrombin activates platelets by cleaving G-protein coupled receptors termed protease activated receptors (PARs). PARs provide their own cryptic ligand present in the N-terminal extracellular domain that is unmasked by proteolytic cleavage, with subsequent intramolecular binding to the receptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic the sequence of the newly formed N-terminus upon proteolytic activation can induce signaling independent of receptor cleavage. Platelets are a key player in atherothrombotic events. Human platelets express at least two thrombin receptors, commonly referred to as PARI and PAR4. Inhibitors of PARI have been investigated extensively, and several compounds, including vorapaxar and atopaxar have advanced into late stage clinical trials. Recently, in the TRACER phase III trial in ACS patients, vorapaxar did not significantly reduce cardiovascular events, but significantly increased the risk of major bleeding (Tricoci, P. et al, N. Eng. J. Med., 366(l):20-33 (2012). Thus, there remains a need to discover new antiplatelet agents with increased efficacy and reduced bleeding side effects.

There are several early reports of preclinical studies of PAR4 inhibitors. Lee, F-Y. et al., “Synthesis of l-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as Novel Antiplatelet Agents”, J. Med. Chem., 44(22):3746-3749 (2001) discloses in the abstract that the compound

“was found to be a selective and potent inhibitor or protease-activated receptor type 4 (PAR4)-dependent platelet activation. ”

Compound 58 is also referred to as YD-3 in Wu, C-C. et al, “Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation by YD-3”, Thromb. Haemost., 87: 1026-1033 (2002). Also, see Chen, H.S. et al, “Synthesis and platelet activity”, J. Bioorg. Med. Chem., 16: 1262-1278 (2008).

EP1166785 Al and EP0667345 disclose various pyrazole derivatives which are useful as inhibitors of platelet aggregation.\

IB. 5-(Benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][l,3]dioxin-4-one

A solution of 5-hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][l,3]dioxin-4- one (30.00 g, 0.134 mol, see Kamisuki, S. et al, Tetrahedron, 60:5695-5700 (2004) for preparation) in N,N-dimethylformamide (400 mL) was treated with powdered anhydrous potassium carbonate (19.41 g, 0.14 mol) added all at once. The resulting mixture was stirred in vacuo for 10 min. and then flushed with nitrogen. The reaction flask was placed in a water bath (22 °C) and treated with benzyl bromide (24.03 g, 0.14 mol) added dropwise over 15 min. The resulting mixture was then stirred at 22 °C for 18 h (no starting material left by tic). The solid was filtered and washed with N,N- dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (500 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Crystallization form ethyl acetate (50 mL) and hexane (150 mL) gave 35.17 g of 5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H- benzo[d][l ,3]dioxin-4-one as large colorless prisms. Chromatography of the mother liquors on silica gel (4 x 13 cm, elution toluene – ethyl acetate 0-5%) gave 6.64 g of additional material to afford a total yield of 41.81 g (99%). HRMS(ESI) calcd for

Ci₈Hi₉0₅ [M+H]⁺ m/z 315.1227, found 315.1386. 1H NMR (CDC1₃, 600 MHz) δ 1.68 (s, 6H), 3.77 (s, 3H), 5.19 (s, 2H), 5.19 (s, 2H), 6.04 (d, J = 2.03 Hz, 1H), 6.15 (d, J = 2.03 Hz, 1H), 7.27 (broad t, 1H), 7.36 (broad t, 2H), 7.52 (broad d, 2H).

1 C. 2-(Benzyloxy)-6-hydroxy-4-methoxybenzaldehyde

A solution of 5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][l ,3]dioxin- 4-one (Example IB, 6.76 g, 21.5 mmol) in dichloromethane (120 mL) was cooled to -78 °C and treated with 43 mL (64.5 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene added dropwise over 20 min. The resulting mixture was then stirred at -78 °C for 3 h. The reaction mixture was quenched by the careful addition of methanol (5 mL) added dropwise over 15 min, followed by IN hydrochloric acid (50 mL) added dropwise over 15 min. The cooling bath was then removed and an additional 150 mL of IN hydrochloric acid was added over 20 min. The mixture was then stirred at 22 °C for 2 h and diluted with dichloromethane (400 mL). The organic phase was collected and the aqueous phase (pH ~1) was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil was diluted with tetrahydrofuran (70 mL), treated with 10 mL of 0.1N hydrochloric acid and stirred at 20 °C for 2 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with brine, dried over anhydrous magnesium sulfate, evaporated in vacuo to give a clear oil. Chromatography on silica gel (4 x 13 cm, elution toluene) gave 4.08 g (73% yield) of the title aldehyde as a clear oil which solidified on standing. LC (Method C): 2.237 min. HRMS(ESI) calcd for Ci₅Hi₅0₄ [M+H]⁺ m/z 259.0965, found 259.1153. 1H NMR (CDC1₃, 600 MHz) δ 3.80 (s, 3H), 5.07 (s, 2H), 5.97 (d, J= 2.1 Hz, 1H), 6.01 (d, J= 2.1 Hz, 1H), 7.3 – 7.4 (m, 5 H), 10.15 (s, 1H), 12.49 (s, 1H).

ID. 1 -(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)ethanone

A solution of 2-(benzyloxy)-6-hydroxy-4-methoxybenzaldehyde (Example 1C, 3.46 g, 13.4 mmol) in N,N-dimethylformamide (50 mL) was treated with powdered anhydrous cesium carbonate (4.58 g, 14.05 mmol) added all at once. The resulting mixture was stirred in vacuo for 10 min. and then flushed with nitrogen. The reaction flask was placed in a water bath (22 °C) and treated with chloroacetone (1.74 g, 18.7 mmol) added dropwise over 5 min. The resulting mixture was then stirred at 22 °C for 18 h (no starting aldehyde left by tic and formation of the intermediate alkylated aldehyde). The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (300 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. This syrup was diluted with tetrahydrofuran (50 mL) and ethyl acetate (50 mL), treated p- toluenesulfonic acid monohydrate (0.2 g) and stirred at 20 °C for 1 h (tic indicated complete cyclization of the intermediate alkylated aldehyde to the benzofuran). The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4 x 12 cm, elution toluene – ethyl acetate 2-4%) gave 3.51 g (88% yield) of the title benzofuran as a yellow solid. Recrystallization from ethyl acetate (10 mL) and hexane (20 mL) gave the title material as large yellow prisms (3.15 g). LC (Method D): 2.148 min. HRMS(ESI) calcd for Ci₈Hiv0₄ [M+H]⁺ m/z 297.1121, found 297.1092. 1H NMR (CDC1₃, 600 MHz) δ 2.51 (s, 3H), 3.82 (s, 3H), 5.13 (s, 2H), 6.37 (d, J= 1.77 Hz, 1H), 6.63 (broad s, 1H), 7.34 (broad t, 1H), 7.39 (broad t, 2H), 7.44 (broad d, 2H), 7.55 (d, J = 0.7 Ηζ,ΙΗ). IE. l-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone

A 250-mL, three-necked flask is equipped with a magnetic stirring bar and purged with a nitrogen atmosphere was charged with anhydrous tetrahydrofuran (25 mL) followed by 9.3 mL (9.3 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture was cooled to -78 °C and treated with a solution of l-(4- (benzyloxy)-6-methoxybenzofuran-2-yl)ethanone (Example ID, 2.40 g, 8.1 mmole) in tetrahydrofuran (20 mL) added dropwise over 10 min. The resulting mixture was then stirred at -78 °C for 45 min. Then chlorotrimethylsilane (1.18 mL, 9.31 mmol) was added dropwise over 5 min and the resulting solution was stirred at -78 °C for another 20 min. The cooling bath was then removed and the mixture is allowed to warm to room temperature over 30 min. The reaction mixture was then quenched by addition to a cold solution of ethyl acetate (200 mL), saturated sodium bicarbonate (30 mL) and ice. The organic phase was rapidly dried over anhydrous magnesium sulfate (magnetic stirring) and evaporated in vacuo to give the silyl enol ether as an oil which is co-evaporated with toluene (20 mL). The silyl enol ether was then dissolved in dry tetrahydrofuran (40 mL), cooled to -20 °C and treated with solid sodium bicarbonate (0.10 g) followed by N- bromosuccinimide (1.44 g, 8.1 mmol) added in small portions over 15 min. The reaction mixture was allowed to warm to 0 °C over 2h and then quenched by addition of ethyl acetate (300 mL) and saturated sodium bicarbonate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give an orange oil. Chromatography on silica gel (4 x 12 cm, elution toluene – ethyl acetate 0-5%) gave 2.62 g (86% yield) of the title bromomethylketone as a yellow solid. Recrystallization from ethyl acetate (10 mL) and hexane (20 mL) gave yellow prisms (2.30 g). LC (Method E): 1.977 min. HRMS(ESI) calcd for Ci₈Hi₆Br0₄ [M+H]⁺ m/z 375.0226, found 375.0277. 1H NMR (CDCls, 600 MHz) δ 3.84 (s, 3H), 4.33 (s, 2H), 5.14 (s, 2H), 6.38 (d, J = 1.76 Hz, 1H), 6.64 (broad s, 1H), 7.35 (broad t, 1H), 7.40 (broad t, 2H), 7.44 (broad d, 2H), 7.70 (s, 1H). 1 EE. 1 -(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-chloroethanone

Benzyltrimethylammonium dichloroiodate (117 g, 169 mmol) was added to a solution of l-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)ethanone (Example ID, 50 g, 170 mmol) in THF (500 mL) in a 1 L multineck round bottom flask under nitrogen atmosphere. The reaction mixture was stirred at RT for 6 h, cooled to 0 °C and quenched with 10% NaHCC”3 solution. The organic layer was washed with 1 M sodium thiosulphate solution, water, and brine, dried over Na₂S0₄, and concentrated in vacuo (bath temperature <45 °C). The residue was triturated with 5% EtOAc in pet. ether and dried to obtain the title chloromethylketone as a pale yellow solid (48 g, 130 mmol, 78%). 1H NMR (300 MHz, DMSO-d₆) δ 3.84-3.82 (d, J =4.5Hz, 3H) 4.98 (s, 2H), 5.27(s, 2H), 6.62 -6.61 (d, J = 1.8Hz, 1H), 6.92-6.93 (m, 1H), 7.54-7.36 (m, 5H), 8.10-8.09 (d, J = 3Hz, 1H); MS m/z: [M+H]⁺ 331.0. IF. 6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2, 1 – b] [ 1 ,3 ,4]thiadiazole

A mixture of l-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example IE, 3.00 g, 8.0 mmol) and 5-bromo-l,3,4-thiadiazol-2-amine (1.65 g, 9.16 mmol) in isopropanol (100 mL) was heated in a pressure flask equipped with a magnetic stirring bar at 78-80 °C for 18 h (homogeneous after 20 min and then formation of a precipitate after 2 h). The cooled mixture is then transferred into five 20 mL microwave vials and then heated in a microwave apparatus to 150 °C for 30 min. Each vial was then diluted with dichloromethane (250 mL) washed with saturated sodium bicarbonate (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate. The fractions were combined and concentrated in vacuo. Chromatography of the orange-brown residual solid on silica gel (4 x 10 cm, slow elution with dichloromethane due to poor solubility) gave 2.96 g of the title imidazothiadiazole contaminated with some l-(4-(benzyloxy)-6- methoxybenzofuran-2-yl)ethanone. The solid material was triturated with ethyl acetate (20 mL), filtered, washed with ethyl acetate (10 ml) and dried in vacuo to give 2.34 g (64% yield) of pure title imidazothiadiazole as an off white solid which is used as such for the next step. LC (Method E): 2.188 min. HRMS(ESI) calcd for C₂oHi₅BrN30₃S [M+H]⁺ m/z 456.00175, found 456.00397. 1H NMR (CDC1₃, 600 MHz) δ 3.82 (s, 3H), 5.16 (s, 2H), 6.38 (d, J= 1.67 Hz, 1H), 6.66 (broad s, 1H), 7.15 (s, 1H), 7.31 (broad t, 1H), 7.38 (broad t, 2H), 7.45 (broad d, 2H), 8.02 (s, 1H).

Alternatively, Example IF, 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2- bromoimidazo[2,l-b][l,3,4]thiadiazole, was prepared as follows:

A 1000-mL, three-necked flask equipped with a magnetic stirring bar and purged with a nitrogen atmosphere was charged with dry NMP (200 mL) followed by 1- (4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-chloroethanone (Example 1EE, 50 g, 150 mmol) and 5-bromo-l,3,4-thiadiazol-2-amine (27.2 g, 151 mmol). The resulting mixture was stirred at 80 °C for 8h. TLC (8:2 dichloromethane/pet. ether) and LC/MS showed intermediate uncyclized material (m/z 476) and the reaction mixture was stirred at 120 °C for 3h. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na₂S0₄, and concentrated in vacuo. The thick brown residue was purified by silica gel chromatography (0 to 100% dichloromethane in pet. ether) to give a brown solid. This material was triturated with EtOAc and dried to obtain the title imidazothiadiazole (24 g, 50 mmol, 33%>) as a light brown solid. (See the procedure set forth above for analytical data).

1 G. 6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2, 1 – b][l,3,4]thiadiazole

A solution of 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2- bromoimidazo[2,l-b][l,3,4]thiadiazole (Example IF, 2.30 g, 5.04 mmol) in a mixture of dichloromethane (180 mL) and methanol (45 mL) was treated at 22 °C with 4.2 mL of a 25 wt.% solution of sodium methoxide in methanol (0.2 mmol) added in one portion. More methanol (45 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched by the addition of 25 mL of IN hydrochloric acid followed by 20 ml of saturated sodium bicarbonate. The solvent was evaporated under reduced pressure and the residue was diluted with dichloromethane (400 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel (3 x 10 cm, elution with dichloromethane – ethyl acetate 0-4%) gave 1.70 g (83% yield) of the title compound as a white solid. This material was recrystallized from ethyl acetate (30 mL per gram, 80% recovery) to give white needles. LC (Method

D): 2.293 min. HRMS(ESI) calcd for C₂₁H₁₈N₃O₄S [M+H]⁺ m/z 408.1013, found 408.1024. 1H NMR (CDC1₃, 600 MHz) δ 3.81 (s, 3H), 4.18 (s, 3H), 5.16 (s, 2H), 6.37 (d, J = 1.75 Hz, 1H), 6.67 (broad s, 1H), 7.07 (s, 1H), 7.31 (broad t, 1H), 7.37 (broad t, 2H), 7.45 (broad d, 2H), 7.81 (s, 1H).

1H. 6-Methoxy-2-(2-methoxyimidazo[2,l-b][l,3,4]thiadiazol-6-yl)benzofuran-4-ol

A mixture of 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2- methoxyimidazo[2,l-b][l,3,4]thiadiazole (Example 1G, 1.250 g, 3.06 mmol) and pentamethylbenzene (3.17 g, 21.4 mmol) in dichloromethane (200 mL) was cooled to -78 °C under a nitrogen atmosphere and then treated immediately (to avoid crystallization) with 8 mL (8 mmol) of a 1 M solution of boron trichloride in dichloromethane added dropwise over 3 min. The resulting mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched by the addition of a solution of sodium bicarbonate (6 g) in water (100 mL) added in one portion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 h. The solid formed was filtered, washed successively with water (50 m) and dichloromethane (50 mL). The filter cake was allowed to soak with anhydrous ethanol (15 ml) and then sucked dry. The white solid obtained was then dried under vacuum for 24 h to give 0.788 g (80%> yield) of pure title material (> 95% by hplc). The combined filtrate and washings were diluted with dichloromethane (600 mL) and stirred in a warm water bath till the organic phase was clear with no apparent solid in suspension. The organic phase was collected, dried over anhydrous magnesium sulfate and rapidly filtered while still warm. The filtrate was evaporated and the residue (product and pentamethylbenzene) was triturated with toluene (20 mL), the solid collected and washed with toluene (20 mL) to give 0.186 g (19% yield, 99% combined yield) of title material as a tan solid (> 95% by hplc). LC (Method E): 1.444 min. HRMS(ESI) calcd for C₁₄H₁₂N₃O₄S [M+H]⁺ m/z 318.0543, found 318.0578. 1H NMR (DMSO-de, 600 MHz) 5 3.71 (s, 3H), 4.16 (s, 3H), 6.21 (d, J = 1.87 Hz, 1H), 6.61 (broad s, 1H), 6.95 (s, 1H), 8.29 (s, 1H), 9.96 (s, 1H).

Example 94

4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,l-b][l,3,4]thiadiazol-6-yl)benzofuran-4-yl) oxy)methyl)-5-methylthiazol-2-yl)morpholine

94 A. Methyl 5-methyl-2-morpholinothiazole-4-carboxylate [00258] A solution of methyl 2-bromo-5-methylthiazole-4-carboxylate (2.80 g, 11.86 mmol) and morpholine (4.5 mL, 51.7 mmol) in THF (10 mL) was heated at reflux under nitrogen for 18 h. The volatiles were then removed under reduced pressure and the crude product was purified on the ISCO using a REDISEP® 40 g column (0 to 40% EtOAc- DCM), to give the title compound (2.20 g, 77%) as a yellow solid. LCMS (APCI): calcd for CioHisNzOsS [M+H]⁺ m/z 243.07, found 243.1. 1H NMR (CDC1₃, 400 MHz) δ ppm: 3.89 (s, 3H), 3.77-3.83 (m, 4H), 3.41-3.47 (m, 4H), 2.64 (s, 3H). [00259] Alternatively, Example 94A, methyl 5-methyl-2-morpholinothiazole-4- carboxylate, was prepared as follows:

94AA. Methyl 3-bromo-2-oxobutanoate

A 5L 4-neck round bottom flask equipped with a mechanical stirrer, temperature thermocouple, condenser and a 1L addition funnel, was charged copper(II) bromide (962 g, 4310 mmol) and ethyl acetate (2 L). A solution of methyl 2-ketobutyrate (250 g, 2150 mmol) in CHC1₃ (828 mL) was added dropwise. A scrubber (400 mL 1 N NaOH) was connected and the reaction mixture was heated to reflux (75 °C). The reaction started as a dark green color and as heating progressed, it became a light green with a white precipitate forming. NMR after one hour at reflux indicated that the reaction was complete. The reaction was cooled to RT and filtered through a pad of CELITE®. The filtrate was concentrated to an oil, dissolved in methylene chloride (500 mL) and filtered again through CELITE®. The filtrate was then passed through a pad of silica gel and eluted with ethyl acetate. Concentration of the filtrate provided the title bromoketoester (399 g, 2040 mmol, 95%) as a yellow oil. 1H NMR (400MHz, CDC1₃) δ 5.18 (q, J = 6.7 Hz, 1H), 3.94 (s, 3H), 1.83 (d, J = 6.8 Hz, 3H). 94AAA. Morpholine-4-carbothioamide

To a solution of morpholine (199 g, 2280 mmol) in CHC1₃ (1 L) was added isothiocyanatotrimethylsilane (150 g, 1140 mmol) dropwise. A white precipitate formed almost immediately, and the reaction was stirred for 1 h at RT. The reaction was then filtered and the resulting solid was washed with additional CHC1₃ and dried in vacuo to give the title thiourea as a white solid. (137 g, 937 mmol, 82%). 1H NMR (400MHz, DMSO-de) δ 3.81 – 3.71 (m, 2H), 3.17 – 3.08 (m, 2H).

94 A. Methyl 5-methyl-2-morpholinothiazole-4-carboxylate

To a solution of morpholine-4-carbothioamide (Example 94 AAA, 175 g, 1200 mmol) in methanol (500 mL) was charged methyl 3-bromo-2-oxobutanoate (Example 94AA, 233 g, 1200 mmol). The reaction was then heated to reflux for 1 hour, cooled to RT, and filtered. The filtrate was concentrated and the crude product was purified on by silica gel chromatography. The title thiazole (206g, 850 mmol, 71%) was isolated as a yellow oil. (See the procedure set forth above for analytical data).

(5-Methyl-2-morpholinothiaz l-4-yl)methanol

The compound was prepared according to the protocol described for Example 92B. The crude product was purified on the ISCO using a REDISEP® Gold 24 g column (0 to 50% EtOAc-DCM) to give the title compound as a white solid (0.086 g, 51%). LCMS (APCI): calcd for C₉Hi₅N₂0₂S [M+H]⁺ m/z 215.08, found 215.1. 1H NMR (CDCI3, 400 MHz) δ ppm: 4.48 (d, J= 4.7 Hz, 2H), 3.77-3.83 (m, 4H), 3.37-3.43 (m, 4H), 2.30 (t, J= 4.7 Hz, 1H), 2.28 (s, 3H).

Example 94. 4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2, 1 -b] [ 1 ,3,4]thiadiazol-6-yl) benzofuran-4-yl)oxy)methyl)-5 -methylthiazol-2-yl)morpholine

The title compound was prepared according to the protocol described for Example 86. The crude product was purified on the ISCO using a REDISEP® 4 g column (0 to 40% EtOAc-DCM) and the obtained solid was suspended in MeOH, sonicated, filtered and dried to give the title compound as an off-white solid (0.094 g, 53%). LC (Method C): 2.314 min. HRMS(ESI): calcd for C₂₃H₂₄N₅0₅S₂ [M+H]⁺ m/z 514.122, found 514.126. 1H NMR (CDC1₃, 400 MHz) δ ppm: 7.83 (s, 1H), 7.06 (d, J = 0.8 Hz, 1H), 6.69 (d, J= 0.8 Hz, 1H), 6.50 (d, J= 2.0 Hz, 1H), 5.05 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.78- 3.84 (m, 4H), 3.39- 3.46 (m, 4H), 2.37 (s, 3H).

ABSTRACT

251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 263

Patent ID	Date	Patent Title
US2015094297	2015-04-02	IMIDAZOTHIADIAZOLE AND IMIDAZOPYRAZINE DERIVATIVES AS PROTEASE ACTIVATED RECEPTOR 4 (PAR4) INHIBITORS FOR TREATING PLATELET AGGREGATION

////////BMS 986120, phase 1, Bristol-Myers Squibb , Imidazoles, Small molecules, Thiadiazoles, 1478712-37-6

c1(sc2nc(cn2n1)c3cc4c(cc(cc4o3)OC)OCc5nc(sc5C)N6CCOCC6)OC

CC1=C(N=C(S1)N2CCOCC2)COC3=C4C=C(OC4=CC(=C3)OC)C5=CN6C(=N5)SC(=N6)OC

Tianagliflozin, IND filed by Tianjin Institute of Pharmaceutical research

phase 1 Comments Off

Mar 242016

Tianagliflozin,

taigeliejing, 6-deoxydapagliflozin

Molecular Formula:	C₂₁H₂₅ClO₅
Molecular Weight:	392.8732 g/mol

Tianjin Institute Of Pharmaceutical Research,

(3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methyloxane-3,4,5-triol

1-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-b-D-glucopyranose

D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-deoxy-, (1S)-

1–[4–Chloro–3–(4–ethoxybenzyl)phenyl]–1,6–dideoxy–β–d–glucopyranose

6-deoxydapagliflozin

https://pubchem.ncbi.nlm.nih.gov/compound/67891767#section=Top

A SGLT-2 inhibitor potentially for the treatment of type 2 diabetes.

CAS N. 1461750-27-5

The structures of dapagliflozin and 6-deoxydapagliflozin (1)

,deletion of the 6-OH in the sugar moiety of dapagliflozin led to the discovery of a more potent SGLT2 inhibitor, 6-deoxydapagliflozin (1, ). In an in vitro assay, 1 was a more active SGLT2 inhibitor, with IC ₅₀ = 0.67 nM against human SGLT2 (hSGLT2), as compared with 1.1 nM for dapagliflozin, leading to the identification of 1 as the most active SGLT2 inhibitor discovered so far in this field. Also in an in vivo assay, 1 also introduced more urinary glucose in a rat urinary glucose excretion test (UGE) and exhibited more potent blood glucose inhibitory activity in a rat oral glucose tolerance test (OGTT) than dapagliflozin.

Given the fact that 6-dexoydapagliflozin (1) is a very promising SGLT2 inhibitor that could be used to treat type 2 diabetes, led to preclinical trials

 Tianjin Institute Of Pharmaceutical Research,天津药物研究院

SPECTRAL DATA of Tianagliflozin

1 as a white solid (3.65 g, 93 %). R _f = 0.35 (EtOAc);

m.p.: 148–149 °C;

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.35 (d, 1H, J = 8.4 Hz), 7.25 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.4 Hz), 4.95 (d, 1H, J = 5.2 Hz, OH), 4.90 (d, 1H, J = 4.4 Hz, OH), 4.79 (d, 1H, J = 5.6 Hz, OH), 3.92–4.01 (m, 5H), 3.24–3.29 (m, 1H), 3.18–3.22 (m, 1H), 3.09–3.15 (m, 1H), 2.89–2.95 (m, 1H), 1.29 (t, 3H, J = 7.0 Hz, CH₂ CH ₃), 1.15 (d, 3H, J = 6.0 Hz, CHCH ₃) ppm;

¹³C NMR (100 MHz, DMSO-d ₆): δ = 156.85, 139.65, 137.82, 131.83, 131.16, 130.58, 129.52, 128.65, 127.14, 114.26, 80.71, 77.98, 75.77, 75.51, 74.81, 62.84, 37.55, 18.19, 14.62 ppm;

IR (KBr): v¯¯¯ = 3,564 (w), 3,385 (s), 2,981 (s), 2,899 (s), 2,861 (s), 1,613 (m), 1,512 (s), 1,477 (m), 1,247 (s), 1,102 (s), 1,045 (s), 1,012 (s) cm⁻¹;

HR–MS: calcd for C₂₁H₂₉ClNO₅ ([M + NH₄]⁺) 410.1729, found 410.1724.

PATENT

CN 103864737

http://www.google.com/patents/CN103864737A?cl=en

PATENT

WO 2014094544

http://www.google.com/patents/WO2014094544A1?cl=en

Figure imgf000032_0001

-27-

1 D1 -6 Optionally, the step (7 ‘) is the step (7’) in place:

LS l- [4 – D (I- Dl- 6)

(DMSO-d _6, 400 MHz), δ 7.35 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J ‘. 2.0 Hz), 7.17 (dd, IH, / = 2.0 Hz and 8.4 Hz), 7.05 (d, 2H, _J: 8.8 Hz), 6.79 (d, 2H, 8.8 Hz): 4.924,95 (m, 2H), 4,81 (d, IH, 6,0 Hz), 3.93- 3.99 (m, 5H), 3,85 (d, 1H, J = 10,4 Hz), 3,66 (dd, IH, 5,2 Hz and 11,6 Hz), 3.17-3,28 (m, 3H), 3.02-3.08 _(m: IH), 1.28 (t, 3H, J = 7,0 Hz), 0,80 (s, 9H), -0.05 (s, 3H), -0.09 (s, 3H) .

PATENT

CN 104045614

[0066] The added 100mL dried over anhydrous methanol 0. 5g of sodium metal, nitrogen at room temperature with stirring, until the sodium metal disappeared. Followed by addition of 5. 2g (10mmol) of compound 6, stirring was continued at room temperature for 3 hours. To the reaction system was added 5g strong acid cation exchange resin, stirred at room temperature overnight, the reaction mixture until pH = 7. The resin was removed by suction, and the filtrate evaporated to dryness on a rotary evaporator, the residue was further dried on a vacuum pump to give the product I-D1-6, as a white foamy solid.

PATENT

WO 2014139447

http://link.springer.com/article/10.1007%2Fs40242-014-4043-9#/page-1

Med Chem. 2015;11(4):317-28.

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

Cai W, Jiang L, Xie Y, Liu Y, Liu W, Zhao G¹.

Abstract

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

http://www.ncbi.nlm.nih.gov/pubmed/25557661

Paper

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Authors: Zhang, Lingyu; Wang, Yuli; Xu, Huaqiang; Shi, Yongheng; Liu, Bingni; Wei, Qunchao; Xu, Weiren; Tang, Lida; Wang, Jianwu; Zhao, Guilong

Source: Medicinal Chemistry, Volume 10, Number 3, May 2014, pp. 304-317(14)

http://www.ingentaconnect.com/content/ben/mc/2014/00000010/00000003/art00009?crawler=true

CLIP

A facile synthesis of 6-deoxydapagliflozin

Keywords. Carbohydrates Drug research Hydrogenolysis Dapagliflozin SGLT2 inhibitor

http://link.springer.com/article/10.1007/s00706-013-1053-0/fulltext.html

The synthetic route to the target compound 1 is shown in Scheme 3. The starting material methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-α–d-glucopyranoside (3) was prepared from commercially available methyl α–d-glucopyranoside (2) according to a known method [5, 6].

Iodide 3 was reductively deiodinated to give 4 in 91 % yield under hydrogenolytic conditions using 10 % Pd/C as catalyst in the presence of Et₃N as base in THF/MeOH at room temperature.

when the iodide 3 was treated with Barton–McCombie reagent (n-Bu₃SnH/AIBN) [7] in toluene at room temperature no reaction occurred; however, when the reaction was carried out at elevated temperatures, such as reflux, a complex mixture formed with only a trace amount (3 %, entry 1) of the desired product 4.

When the iodide 3 was treated with LiAlH₄ in THF at 0 °C to room temperature, another complex mixture was produced with only a trace amount (2 %, entry 2) of 4.

When Pd(OH)₂ was used as the hydrogenolysis catalyst instead of 10 % Pd/C, the desired 4 was indeed formed (14 %, entry 4), but most of the starting material was converted to a few more polar byproducts, which were believed to result from the cleavage of at least one of the benzyl groups.

pdf available

Monatshefte für Chemie – Chemical Monthly

December 2013, Volume 144, Issue 12, pp 1903-1910

http://download.springer.com/static/pdf/721/art%253A10.1007%252Fs00706-013-1053-0.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs00706-013-1053-0&token2=exp=1458808857~acl=%2Fstatic%2Fpdf%2F721%2Fart%25253A10.1007%25252Fs00706-013-1053-0.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs00706-013-1053-0*~hmac=bd1c3c2bdc3712f5540267c99f732b2f7588020a868aa23021792a2a2a58d65e

References

1.Washburn WN (2009) J Med Chem 52:1785
2.Hardman TC, Dubrey SW (2011) Diabetes Ther 2:133
3.Meng M, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JM, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN (2008) J Med Chem 51:1145
4.Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M (2010) J Med Chem 53:6355
5.Lee JC, Francis S, Georg GI, Dutta D, Gupta V, Tash JS, Yang Y, Zhu J-Y, Schoenbrunn E (2012) J Org Chem 77:3082
6.Bartoszewicz A, Kalek M, Stawinski J (2008) Tetrahedron 64:8843
7.Zhao GL, Lou YY, Zhang LS, Shao H, Xu WR, Tang LD, Zou MX (2012) Synth Commun 42:2885
8.Koto S, Morishima N, Miyata Y, Zen S (1976) Bull Chem Soc Jpn 49:2639
9.Kakinuma H, Oi T, Hashimoto-Tsuchiya Y, Arai M, Kawakita Y, Fukasawa Y, Iida I, Hagima N, Takeuchi H, Chino Y, Asami J, Okumura-Kitajima L, Io F, Yamamoto D, Miyata N, Takahashi T, Uchida S, Yamamoto K (2010) J Med Chem 53:3247
10.Xu J, Egger A, Bernet B, Vasella A (1996) Helv Chim Acta 79:2004
11.Lee SH, Song K-S, Kim JY, Kang M, Lee JS, Cho S-H, Park H-J, Kim J, Lee J (2011) Bioorg Med Chem 19:5813
12.Song K-S, Lee SH, Kim MJ, Seo HJ, Lee J, Lee S-H, Jung ME, Son E-J, Lee MW, Kim J, Lee J (2011) ACS Med Chem Lett 2:182
13.Lee J, Lee S-H, Seo HJ, Son E-J, Lee SH, Jung ME, Lee MW, Han HK, Kim J, Kang J, Lee J (2010) Bioorg Med Chem 18:2178
14.Kim MJ, Lee SH, Park SO, Kang H, Lee JS, Lee KN, Jung ME, Kim J, Lee J (2011) Bioorg Med Chem 19:5468
15.Skaanderup PR, Poulsen CS, Hyldtoft L, Jørgensen MR, Madsen R (2002) Synthesis 1721
Monatshefte fuer Chemie (2013), 144(12), 1903-1910
Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 10(3), 304-317
Chinese Journal of Structural Chemistry (2014), 33(1), 85-89
Xiandai Yaowu Yu Linchuang (2013), 28(6), 838-841
Chemical Research in Chinese Universities (2014), 30(5), 785-793

////////, SGLT-2 inhibitor, type 2 diabetes, Tianagliflozin, taigeliejing, 6-deoxydapagliflozin, 1461750-27-5

Clc1c(cc(cc1)C2[C@@H]([C@H]([C@@H]([C@H](O2)C)O)O)O)Cc3ccc(cc3)OCC

CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)C)O)O)O)Cl

c1(c(cc(cc1)C2OC(C(C(C2O)O)O)C)Cc3ccc(cc3)OCC)Cl

Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism

spectroscopy, SYNTHESIS Comments Off

Mar 242016

We present a series of oxadiazolothiazinones, selective inotropic agents on isolated cardiac tissues, devoid of chronotropy and vasorelaxant activity. Functional and binding data for the precursor of the series (compound 1) let us hypothesize LTCC blocking activity and the existence of a recognition site specific for this scaffold. We synthesized and tested 22 new derivatives: introducing a para-methoxyphenyl at C-8 led to compound 12 (EC₅₀ = 0.022 μM), twice as potent as its para-bromo analogue (1). For 10 analogues, we extended the characterization of the biological properties by including the assessment of metabolic stability in human liver microsomes and cytochrome P450 inhibition potential. We observed that the methoxy group led to active compounds with low metabolic stability and high CYP inhibition, whereas the protective effect of bromine resulted in enhanced metabolic stability and reduced CYP inhibition. Thus, we identified two para-bromo benzothiazino-analogues as candidates for further studies.

8-ethoxy-8-(4-methoxyphenyl)-5-methyl-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one

Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism

Emanuele Carosati ^*^†^‡, Barbara Cosimelli^§, Pierfranco Ioan^∥, Elda Severi^§, Kasiram Katneni^‡, Francis C. K. Chiu^‡, Simona Saponara^⊥, Fabio Fusi^⊥, Maria Frosini^⊥, Rosanna Matucci^#, Matteo Micucci^∥, Alberto Chiarini^∥, Domenico Spinelli^○, and Roberta Budriesi^∥

^† Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto 10, 06123 Perugia, Italy

^‡ Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, VIC 3052, Australia

^§ Dipartimento di Farmacia, Università di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy

^∥ Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy

^⊥ Dipartimento di Scienze della Vita, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy

^# Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino (NEUROFARBA), Viale Pieraccini 6, 50139 Firenze, Italy

^○ Dipartimento di Chimica ‘G. Ciamician’, Alma Mater Studiorum-Università di Bologna, Via Selmi 2, 40126 Bologna, Italy

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.6b00030

Publication Date (Web): March 10, 2016

*Phone: +39 75 5855550. Fax: +39 75 45646. E-mail: emanuele@chemiome.chm.unipg.it.

http://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b00030

/////////Cytochrome P450-Mediated Metabolism, Negative Inotropic Activity

CCOC2(c1ccc(OC)cc1)SC=C(C)n3c2noc3=O

EGF 816 , Nazartinib

Uncategorized Comments Off

Mar 232016

Full-size image (4 K)

EGF 816, Nazartinib

EGF-816; EGFRmut-TKI EGF816

Novartis Ag innovator

(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide

NCI-H1975 (L858R/T790M): 25 nM
H3255 (L858R): 9 nM
HCC827 (Del ex19): 11 nM

M.Wt	495.02
Formula	C26H31ClN6O2
CAS No	1508250-71-2

EGF816 is a novel covalent inhibitor of mutant-selective EGFR; overcomes T790M-mediated resistance in NSCLC.

Epidermal growth factor receptor antagonists; Protein tyrosine kinase inhibitors

Phase IINon-small cell lung cancer
Phase I/IISolid tumours
- 01 Feb 2015Phase-II clinical trials in Non-small cell lung cancer (Late-stage disease, Combination therapy) in Singapore (PO) (NCT02323126)
- 24 Nov 2014Phase-I/II clinical trials in Non-small cell lung cancer (Combination therapy, Late-stage disease) in Spain (PO) after November 2014 (EudraCT2014-000726-37)
- 24 Nov 2014Phase-I/II clinical trials in Non-small cell lung cancer (Combination therapy, Late-stage disease) in Germany (PO)

Determine MTD, or recommended phase II dose in patients with NSCLC harboring EGFR mutations, in combination with INC280

Recruiting
Phase I/II (NCT02335944)

Determine MTD, or recommended phase II dose in adult patients with EGFRm+ solid malignancies

Recruiting
Phase I/II (NCT02108964)

Determine efficacy and safety in patients with previously treated NSCLC, in combination with nivolumab

Recruiting
Phase II (NCT02323126)

In November 2015, FDA approved osimertinib (Tagrisso™) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR TKI therapy. Based on the clinical performance of the third generation EGFR drugs, more regulatory approvals can be expected.

Nazartinib, also known as EGF816, is an orally available, irreversible, third-generation, mutant-selective epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. EGF816 covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors

PATENT

WO 2016016822

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016016822

PATENT

WO 2015081463

http://www.google.co.in/patents/WO2015081463A1?cl=en

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015085482&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Intermediate 26

1055 (R)-tert-butyl 3-(2-amino-7-chloro- 1 H-benzo[dlimidazol- 1 -yOazepane- 1 -carboxylate

1060 (m, 2H), 4.31-4.03 (m, 1H), 3.84-2.98 (m, 4H), 1.98-1.60 (m, 5H), 1.46-1.39 (m, 10H); MS calculated for Ci₇H₂₅ClN₃0₄ (M+H⁺) 370.15, found 370.10.

Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH (22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na₂C0₃ solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined

1065 organic phase was washed with brine, dried with Na₂S0₄ and concentrated in vacuo to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l -carboxylate (I-26b). MS calculated for Ci₇H₂₇ClN₃0₂ (M+H⁺) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following

1070 procedures analogous to 1-15, Step C. 1H-NMR (400MHz, CDC1₃): d Ί .34-126 (m, 1H),

7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10-4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82-1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for C18H26CIN4O2 (M+H⁺) 365.17,

1075 found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzo[dlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

Intermediate 27

Step A

1080 Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza-lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH2CI2 (120 ml) was treated at room temperature with NEt₃ (4.1 mL, 29.4 mmol). The

reaction was stirred for 1 hour before it was slowly added into a CH₂CI₂ solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt₃ (4.1 mL, 29.4 mmol) was added and 1085 the mixture stirred for 2 h. The mixture was then diluted with CH₂CI₂ (240 mL), washed with H₂0 (2 x 80 mL), saturated aqueous NaHC0₃ solution (70 mL), and brine (70 mL). The organic phase was dried with Na₂SC>4, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford

(R)-tert-butyl

1090 3-(7-chloro-2-(2-methylisonicotinamido)-lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. 1H-NMR (400MHz, CDC1₃): d 12.81 (br s, 1H), 8.65-8.62 (m, 1H), 7.95-7.85 (m, 2H), 7.27-7.1 1 (m, 3H), 5.64 – 5.51 (m, 1H), 4.56-4.44 (m, 1H),

4.07-3.92 (m, 1H), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, 1H), 2.71-2.59 (m, 1H), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, 1H), 1.51-1.45 (m, 1H), 1.50 (s,

1095 3.5H), 1.41 (s, 5.5H); MS calculated for C₂5H₃iClN₅0₃ (M+H⁺) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HC1 in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound (Intermediate 27). The product was used in the next step without further purification. A sample was treated

1 100 with 1M NaOH, extracted with EtOAc, dried with Na₂SC>4 and concentrated under reduced pressure to afford 1-27 as a free base. 1H-NMR (400MHz, CD₃CN): d 8.49 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.50 (br d, J=7.52 Hz, 1H), 7.16 – 7.09 (m, 2H), 5.66-5.59 (m, 1H), 3.77 (dd, J = 6.54, 14.3 Hz, 1H), 3.18 (dd, J = 5.3, 14.3 Hz, 1H), 3.05 – 2.98 (m, 1H), 2.76-2.69 (m, 1H), 2.63-2.53 (m, 1H), 2.47 (s, 3H), 2.10-2.03 (m, 1H),

1 105 1.96-1.93 (m, 2H), 1.86 – 1.75 (m, 2H), 1.61 – 1.54 (m, 2H); MS calculated for

C₂oH₂₃ClN₅0 (M+H⁺) 384.15, found 384.20.

(i?.E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[dlimidazol-2

-yl)-2-methylisonicotinamide

1 1 10

reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na₂S0₄, and concentrated under reduced pressure. The crude was purified by

1 120 column chromatography (9: 1 :0.175N CH₂Cl₂/MeOH/NH₃ in CH₂C1₂, 0% to 100%) to afford the title compound. ^JH NM (400 MHz, DMSO-d₆) δ 8.59 (d, J= 4.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.30-7.22 (m, 2H), 6.71-6.65 (m, 1H), 6.57-6.54 (m, 1H), 5.54 (br. s, 1H), 4.54 (br. s, 1H), 4.20 (br s, 1H), 3.95 (br s, 1H), 3.48 (br s, 1H), 2.98 (br s, 2H), 2.72 (d, J = 12.0 Hz, 1H), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, J =

1 125 6.7 Hz, 3H), 1.88 (br s, 1H), 1.46 (d, J=l 1.3 Hz, 1H); MS calculated for C₂₆H₃₂C1N₆0₂

(M+H⁺) 495.22, found 495.10. Melting point (1 14.6 °C).

WO 2015083059

https://www.google.com/patents/WO2015083059A1?cl=en

Intermediate 26

(RVtert-butyl 3-(2-amino-7-chloro-lH-benzo[dlimidazol-l-vf)azepane-l-carboxylate

Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH

(22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na₂CC>3 solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined organic phase was washed with brine, dried with Na₂S0₄ and concentrated in vacuum to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l-carboxylate (I-26b). MS calculated for C17H27CIN3O2 (M+H⁺) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following procedures analogous to 1-15, Step C. ‘H-NMR (400MHZ, CDCI3): d 7.34-7.26 (m, 1H), 7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10-4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82-1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for Ci₈H₂₆ClN₄0₂(M+H⁺) 365.17, found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzo[dlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

5-26 step A l~27a intermediate 27

Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH₂C1₂ (120 ml) was treated at room temperature with NEt₃ (4.1 mL, 29.4 mmol). The reaction was stirred for 1 hour before it was slowly added into a CH₂C1₂solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt₃ (4.1 mL, 29.4 mmol) was added and the mixture stirred for 2 h. The mixture was then diluted with CH₂C1₂ (240 mL), washed with H₂0 (2 x 80 mL), saturated aqueous NaHCC solution (70 mL), and brine (70 mL). The organic phase was dried with Na₂S0₄, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford

(R)-tert-butyl

3-(7-chloro-2-(2-methylisonicotinamido)-lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. 1H-NMR (400MHz, CDCI3): d 12.81 (br s, 1H), 8.65-8.62 (m, 1H), 7.95-7.85 (m, 2H), 7.27-7.11 (m, 3H), 5.64 – 5.51 (m, 1H), 4.56-4.44 (m, 1H),

4.07-3.92 (m, 1H), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, 1H), 2.71-2.59 (m, 1H), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, 1H), 1.51-1.45 (m, 1H), 1.50 (s, 3.5H), 1.41 (s, 5.5H); MS calculated for C₂₅H₃iClN₅03 (M+H⁺) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HCI in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound (Intermediate 27). The product was used in the next step without further purification. A sample was treated with 1M NaOH, extracted with EtOAc, dried with Na₂S0₄ and concentrated under reduced pressure to afford 1-27 as a free base. ‘H-NMR (400MHZ, CD₃CN): d 8.49 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.50 (br d, J=7.52 Hz, 1H), 7.16 – 7.09 (m, 2H), 5.66-5.59 (m, 1H), 3.77 (dd, J = 6.54, 14.3 Hz, 1H), 3.18 (dd, J = 5.3, 14.3 Hz, 1H), 3.05 -2.98 (m, 1H), 2.76-2.69 (m, 1H), 2.63-2.53 (m, 1H), 2.47 (s, 3H), 2.10-2.03 (m, 1H), 1.96-1.93 (m, 2H), 1.86 – 1.75 (m, 2H), 1.61 – 1.54 (m, 2H); MS calculated for

C20H23CIN5O (M+H⁺) 384.15, found 384.20.

(i?,£^,)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[dlimidazol-2

-νΠ-2-methylisonicotinamide

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (58 mg, 0.35 mmol) and l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) in DMF (2 mL) was treated with hydroxybenzotriazole (54 mg, 0.35 mmol) and stirred at room temperature for 1 h. The resulting mixture was added to a solution of 1-27 (100 mg, 0.22 mmol) in DMF (2 mL). Triethylamine (199 mg, 1.97 mmol) was then added and the mixture was stirred for 5 days. Water (2 mL) was added and the mixture was concentrated under reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na₂S0₄, and concentrated under reduced pressure. The crude was purified by column chromatography (9: 1 :0.175N CH₂Cl₂/MeOH/NH₃ in CH₂C1₂, 0% to 100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.30-7.22 (m, 2H), 6.71-6.65 (m, 1H), 6.57-6.54 (m, 1H), 5.54 (br. s, 1H), 4.54 (br. s, 1H), 4.20 (br s, 1H), 3.95 (br s, 1H), 3.48 (br s, 1H), 2.98 (br s, 2H), 2.72 (d, J = 12.0 Hz, 1H), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, J = 6.7 Hz, 3H), 1.88 (br s, 1H), 1.46 (d, J=11.3 Hz, 1H); MS calculated for C₂₆H₃₂C1N₆0₂ (M+H⁺) 495.22, found 495.10. Melting point (114.6 °C).

PATENT

WO 2015112705

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015112705

PATENT

WO 2013184757

https://www.google.com/patents/WO2013184757A1?cl=en

Intermediate 26

(R)-tert-butyl 3 -(2-amino-7-chloro- 1 H-benzo Tdlimidazol- 1 – vDazepane- 1 – carboxylate

Intermediate 26

Step A: (R)-tert-butyl 3-((2-chloro-6-nitrophenyl)amino)azepane-l-carboxylate (I- 26a) was prepared following procedures analogous to 1-15, Step A, using the appropriate starting materials. ¹ H-NMR (400MHz, CDC1₃): d 8.00-7.91 (m, 1H), 7.58-7.49 (m, 1H), 7.02-6.51 (m, 2H), 4.31-4.03 (m, 1H), 3.84-2.98 (m, 4H), 1.98-1.60 (m, 5H), 1.46-1.39 (m, 10H); MS calculated for C17H25CIN₃O4 (M+H⁺) 370.15, found 370.10. Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH (22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na₂CC>3 solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined organic phase was washed with brine, dried with Na₂S0₄ and concentrated in vacuo to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l-carboxylate (I-26b). MS calculated for Ci7H₂₇ClN₃0₂ (M+H⁺) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following procedures analogous to 1-15, Step C. ^]H-NMR (400MHz, CDC1₃): d 7. ,34-7.26 (m, 1H), 7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10- 4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82- 1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for Ci₈H₂₆ClN₄0₂ (M+H⁺) 365.17, found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzordlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

l-27a Intermediate 27

Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza- 1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH₂C1₂ (120 ml) was treated at room temperature with NEt₃ (4.1 mL, 29.4 mmol). The reaction was stirred for 1 hour before it was slowly added into a CH₂C1₂ solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt₃ (4.1 mL, 29.4 mmol) was added and the mixture stirred for 2 h. The mixture was then diluted with CH₂C1₂ (240 mL), washed with H₂0 (2 x 80 mL), saturated aqueous NaHC0₃ solution (70 mL), and brine (70 mL). The organic phase was dried with Na₂S0₄, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford (R)-tert-butyl 3-(7-chloro-2-(2-methylisonicotinamido)- lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. ^]H- NMR (400MHz, CDC1₃): d 12.81 (br s, IH), 8.65-8.62 (m, IH), 7.95-7.85 (m, 2H), 7.27- 7.11 (m, 3H), 5.64 – 5.51 (m, IH), 4.56-4.44 (m, IH), 4.07-3.92 (m, IH), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, IH), 2.71-2.59 (m, IH), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, IH), 1.51-1.45 (m, IH), 1.50 (s, 3.5H), 1.41 (s, 5.5H); MS calculated for C25H₃1CIN5O₃ (M+H⁺) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HCl in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound

(Intermediate 27). The product was used in the next step without further purification. A sample was treated with 1M NaOH, extracted with EtOAc, dried with Na₂S0₄ and concentrated under reduced pressure to afford 1-27 as a free base. ^]H-NMR (400MHz, CD₃CN): d 8.49 (d, J=5.0 Hz, IH), 7.81 (s, IH), 7.72 (d, J=4.8 Hz, IH), 7.50 (br d, J=7.52 Hz, IH), 7.16 – 7.09 (m, 2H), 5.66-5.59 (m, IH), 3.77 (dd, J = 6.54, 14.3 Hz, IH), 3.18 (dd, J = 5.3, 14.3 Hz, IH), 3.05 – 2.98 (m, IH), 2.76-2.69 (m, IH), 2.63-2.53 (m, IH), 2.47 (s, 3H), 2.10-2.03 (m, IH), 1.96-1.93 (m, 2H), 1.86 – 1.75 (m, 2H), 1.61 – 1.54 (m, 2H); MS calculated for C2₀H2₃CIN5O (M+H⁺) 384.15, found 384.20.

Example 5

(/?,£^,)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)- lH- benzordlimidazol-2-yl)-2-methylisonicotinamide

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (58 mg, 0.35 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) in DMF (2 mL) was treated with hydroxybenzotriazole (54 mg, 0.35 mmol) and stirred at room temperature for 1 h. The resulting mixture was added to a solution of 1-27 (100 mg, 0.22 mmol) in DMF (2 mL). Triethylamine (199 mg, 1.97 mmol) was then added and the mixture was stirred for 5 days. Water (2 mL) was added and the mixture was concentrated under reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na2SC>4, and concentrated under reduced pressure. The crude was purified by column chromatography (9: 1 :0.175N CH₂Cl₂/MeOH/NH₃ in CH₂C1₂, 0% to 100%) to afford the title compound (Example 5). ^]H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J = 4.8 Hz, IH), 7.89 (s, IH), 7.79 (d, J = 4.8 Hz, IH), 7.60 (d, / = 7.5 Hz, IH), 7.30-7.22 (m, 2H), 6.71-6.65 (m, IH), 6.57-6.54 (m, IH), 5.54 (br. s, IH), 4.54 (br. s, IH), 4.20 (br s, IH), 3.95 (br s, IH), 3.48 (br s, IH), 2.98 (br s, 2H), 2.72 (d, / = 12.0 Hz, IH), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, / = 6.7 Hz, 3H), 1.88 (br s, IH), 1.46 (d, 7=11.3 Hz, IH); MS calculated for C26H₃2CIN6O2 (M+H⁺) 495.22, found 495.10. Melting point (114.6 °C).

(/?,E)-N-(7-chloro- l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH- benzo[d]imidazol-2-yl)-2-methylisonicotinamide (1.0 g) was dissolved in acetone (30 mL) by heating to 55°C to form a solution. Methanesulfonic acid (325 μί) was added to acetone (50 mL), and the methanesulfonic acid/acetone (22.2 mL) was added to the solution at 0.05ml/min. Following precipitation, the resulting suspension was cooled to room temperature at 0.5 °C/min, and crystals were collected by filtration, and dried for 4 hours at 40°C under vacuum. The collected crystals (300 mg) were suspended in acetone/H₂0 (6 mL; v/v=95/5) by heating to 50°C. The suspension was kept slurrying for 16 hours, and cooled to room temperature at 0.5 °C/min. The crystal was collected by filtration and dried for 4 hours at 40°C under vacuum.

The structure of (7?,£^‘)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)- lH-benzo[d]imidazol-2-yl)-2-methylisonicotinamide mesylate was confirmed by Differential Scanning Calorimetry, X-Ray Powder Diffraction, and Elemental Analyses. Melting point (170.1 °C). Theoretical calculated: C (54.8); H (5.9); N (14.2); 0 (13.5); %S (5.4); and C1 (6.0); C:N ratio: 3.86. Found: C (52.0); H (5.8); N (13.3); C1 (5.9); C:N ratio: 3.91. Stoichiometry: 1.01.

References

AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA.

nmr http://www.medchemexpress.com/product_pdf/HY-12872/EGF816-NMR-HY-12872-17795-2015.pdf

/////EGF 816, EGF816, EGFR, Covalent inhibitor, T790M, Oncogenic mutation, Lung cancer, NSCLC, SBDD, Drug resistance, EGF-816, EGFRmut-TKI EGF816, Nazartinib

O=C(NC1=NC2=CC=CC(Cl)=C2N1[C@H]3CN(C(/C=C/CN(C)C)=O)CCCC3)C4=CC=NC(C)=C4

罗西替尼 роцилетиниб روسيليتينيب Rociletinib, CO-1686. Third generation covalent EGFR inhibitors

Uncategorized Comments Off

Mar 232016

Full-size image (4 K)

Rociletinib (CO-1686)

AVL-301,CNX-419

Celgene (Originator) , Clovis Oncology

N-(3-{[2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5- (trifluoromethyl)pyrimidin-4-yl]amino}phenyl)prop-2-enamide

1374640-70-6 CAS

1446700-26-0 (Rociletinib Hydrobromide)

Tyrosine kinase inhibitor; EGFR inhibitorIndication：Non small cell lung cancer (NSCLC)

N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide

FREE FORM

Molecular FormulaC₂₇H₂₈F₃N₇O₃
Average mass555.552
HYDROBROMIDE 1446700-26-0

Molecular Weight 636.46

Formula C27H28F3N7O3 ● HBr

Cellular proliferation IC₅₀7–32 nM against EGFRm+ NSCLC cells
547 nM against A431 cell with WT EGFR

Ongoing, not currently recruiting
Phase I/II (NCT01526928)

Recruiting
Phase III (NCT02322281, TIGER-3)

SYNTHESIS COMING……….

Evaluate safety, PK and efficacy of previously treated NSCLC patients, Compare the efficacy of oral single agent versus single agent cytotoxic chemotherapy in patients with EGFRm+ NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet therapy. Compare the safety and efficacy of CO-1686 versus erlotinib as first line treatment of patients with EGFRm+ NSCLC

Rociletinib (CO-1686): Rociletinib is an orally administered irreversible inhibitor currently in several clinical trials targeting both the activating EGFR mutations and the acquired T790M resistance mutation while sparing WT EGFR. It is a potent inhibitor of EGFR T790M/L858R double mutant with a k_inact/K_i of 2.41 × 10⁵ M⁻¹ s⁻¹. It has a 22-fold selectivity over WT EGFR (k_inact/K_i of 1.12 × 10⁴ M⁻¹ s⁻¹). In NSCLC cell lines containing EGFR mutations, rociletinib demonstrates the following cellular pEGFR IC₅₀: 62 nM in NCI-1975 (L858R/T790M), 187 nM in HCC827 (exon 19 deletion), 211 nM in PC9 (exon 19 deletion). In cell lines expressing WT EGFR, cellular pEGFR IC₅₀ are: >4331 nM in A431, >2000 nM in NCI-H1299, and >2000 nM in NCI-H358.

Rociletinib displayed good oral bioavailability (65%) and long half-life when dosed at 20 mg/kg in female Nu/Nu mice. In tumor bearing mice when rociletinib was dosed orally once daily as a single agent, the compound showed dose-dependent tumor growth inhibition in various EGFR-mutant models. In NCI-H1975 as well as in patient-derived LUM 1868 lines expressing the EGFR T790M/L858R double mutation that are erlotinib-resistant models, rociletinib caused tumor regressions at 100 mg/kg/d. In the HCC827 xenograft model that expresses the del-19 activating EGFR mutation, rociletinib showed antitumor activity that was comparable with erlotinib and the second-generation EGFR TKI, afatinib. The wild-type sparing feature of rociletinib was further demonstrated through its minimal inhibition (36%) of tumor growth in the A431 xenograft model that is dependent on WT EGFR for proliferation.

In a Phase I/II study (TIGER-X), rociletinib was administered to patients with EGFR mutated NSCLC who had disease progression during treatment with a previous line of EGFR TKI therapy.The Phase I trial was a dose escalation study to assess safety, side-effect profile and pharmacokinetic properties of rociletinib, and the Phase II trial was an expansion arm to evaluate efficacy. T790M positivity was confirmed before enrollment in the Phase II portion. At the dose of 500 mg BID, the objective response rate in 243 centrally confirmed tissues from T790M positive patients was 60% and the disease control rate was 90%. The estimated overall median PFS at the time of the publication (May 2015) was 8.0 months among all centrally confirmed T790M positive patients. Rociletinib also showed activity in centrally confirmed T790M negative patients with the overall response rate being 37%. The common dose-limiting adverse event was grade 3 hyperglycemia occurring in 17% of patients at a dose of 500 mg BID. Grade 3 QTc prolongation was observed in 2.5% of the patients at the same dose. Treatment-related adverse events leading to drug discontinuation was seen in only 2.5% of patients at 500 mg BID.

Patent

WO2012061299A1

http://www.google.co.in/patents/WO2012061299A1?cl=en

EXAMPLE 1

Intermediate 1

Scheme 1

Step 1 :

In a 25 mL 3-neck RBF previously equipped with a magnetic stirrer, Thermo pocket and CaCl₂ guard tube, N-Boc-l,3-diaminobenzene (0.96 g) and n-butanol (9.00 mL) were charged. Reaction mixture was cooled to 0 °C. 2,4-Dichloro-5-trifluoromethylpyrimidine (1.0 g) was added dropwise to the above reaction mixture at 0 °C. The DIPEA (0.96 mL) was dropwise added to the above reaction mixture at 0 °C and the reaction mixture was stirred for 1 hr at 0 °C to 5 °C. Finally the reaction mixture was allowed to warm to room temperature. Reaction mixture was stirred for another 4 hrs at room temperature. Completion of reaction was monitored by TLC using hexane: ethyl acetate (7: 3). The solid precipitated out was filtered off and washed with 1-butanol (2 mL). Solid was dried under reduced pressure at 40 °C for 1 hr. ^-NMR (DMSO-d6, 400 MHz) δ 1.48 (S, 9 H), 7.02 (m, 1 H), 7.26 (m, 2 H), 7.58 (S, 1 H), 8.57 (S, 1 H), 9.48 (S, 1 H), 9.55 (S, 1 H).

Step 2:

To the above crude (3.1 g) in DCM (25 mL) was added TFA (12.4 mL) slowly at 0 °C. The reaction mixture was allowed to warm to room temperature. Reaction mixture was stirred for another 10 min at room temperature. The crude was concentrated under reduced pressure.

Step 3:

The concentrated crude was dissolved in DIPEA (2.0 mL) and DCM (25 mL), and then cooled to -30 °C. To the reaction mixture was slowly added acryloyl chloride (0.76 g) at -30 °C. The reaction mass was warmed to room temperature stirred at room temperature for 1.0 hr. The reaction was monitored on TLC using hexane: ethyl acetate (7:3) as mobile phase. Reaction got completed after 1 hr. 1H-NMR (DMSO-d6, 400 MHz) δ 5.76 (dd, J = 2.0, 10.0 Hz, 1 H), 6.24 (dd, J = 2.0, 17.2 Hz, 1 H), 6.48 (m, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.94 (S, 1 H), 8.59 (S, 1 H), 9.60 (S, 1 H), 10.26 (S, 1 H).

EXAMPLE 3

Compound 1-4 N- henylamino)-5-

(trifluor mide)

Using 2-methoxy-4-(4-acteylpiperazinyl)aniline and intermediate 1 in Example 1, the title compound 1-4 was prepared as described in Example 2. 1H-NMR (DMSO-d6, 400 MHz) δ 10.2 (S, 1 H), 8.2 (br, 1 H), 8.30 (S, 1 H), 7.73 (br, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.26 (J = 8.2 Hz, 1 H), 7.14 (be, 1 H), 6.60 (S, 1 H), 6.42 (dd, J = 11.4, 16.9 Hz, 1 H), 6.24 (d, J = 16.9 Hz, 1 H), 5.75 (d, J = 11.4 Hz, 1 H), 3.76 (S, 3 H), 3.04 (br, 4 H), 2.04 (S, 3 H); calculated mass for C27H28F3N7O3 : 555.2, found: 556.2 (M+H⁺).

Patent ID	Date	Patent Title
US2015344441	2015-12-03	SALTS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR
US2015246040	2015-09-03	HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015225422	2015-08-13	HETEROARYLS AND USES THEREOF
US8975249	2015-03-10	Heterocyclic compounds and uses thereof
US2013267531	2013-10-10	SALTS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR
US2013267530	2013-10-10	SOLID FORMS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR

References

A.O. Walter, R.T.T. Sjin, H.J. Haringsma, K. Ohashi, J. Sun, K. Lee, A. Dubrovskiy, M. Labenski, Z. Zhu, Z. Wang, M. Sheets, T. St. Martin, R. Karp, D. van Kalken, P. Chaturvedi, D. Niu, M. Nacht, R.C. Petter, W. Westlin, K. Lin, S. Jaw-Tsai, M. Raponi, T. Van Dyke, J. Etter, Z. Weaver, W. Pao, J. Singh, A.D. Simmons, T.C. Harding, A. Allen, Cancer Disc., 3 (2013), p. 1404

////Rociletinib, CO-1686, Clovis, Third generation, covalent EGFR inhibitors, AVL-301, CNX-419

CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)NC4=CC(=CC=C4)NC(=O)C=C)C(F)(F)F)OC

//////

Compound name AND SMILES string
Rociletinib COC(C=C(N1CCN(C(C)=O)CC1)C=C2)=C2NC3=NC=C(C(F)(F)F)C(NC4=CC=CC(NC(C=C)=O)=C4)=N3
Osimertinib CN(CCN(C)C)C(C(NC(C=C)=O)=C1)=CC(OC)=C1NC2=NC=CC(C3=CN(C)C4=C3C=CC=C4)=N2
EGF816 ClC1=C2C(N=C(NC(C3=CC(C)=NC=C3)=O)N2[C@H]4CN(C(/C=C/CN(C)C)=O)CCCC4)=CC=C1
PF-06747775 CN1C2=NC(N3C[C@@H](NC(C=C)=O)[C@H](F)C3)=NC(NC4=CN(C)N=C4OC)=C2N=C1
PF-06459988 CN(N=C1)C=C1NC2=NC3=C(C(Cl)=CN3)C(OC[C@H]4CN(C(C=C)=O)C[C@@H]4OC)=N2
WZ4002 ClC1=CN=C(NC2=C(OC)C=C(N3CCN(C)CC3)C=C2)N=C1OC4=CC=CC(NC(C=C)=O)=C4

PF-06747775 (Pfizer) Third generation covalent EGFR inhibitors

Uncategorized Comments Off

Mar 232016

Full-size image (4 K) PF-06747775 ≥98% (HPLC)

PF-06747775 (Pfizer)

PF06747775; PF06747775; PF 06747775; PF6747775; PF 6747775; PF6747775. PFE-X775

N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

CAS 1776112-90-3
Chemical Formula: C18H22FN9O2
Exact Mass: 415.188

Recruiting, Phase I/II (NTC02349633)

Epidermal growth factor receptor antagonists

Antineoplastics

Non-small cell lung cancer

Dose escalation study to evaluate safety, PK, PD and efficacy in advanced EGFRm+ NSCLC

02 May 2015Phase-I clinical trials in Non-small cell lung cancer (Metastatic disease, Second-line therapy or greater) in USA (PO) (NCT02349633)
05 Feb 2015Pfizer plans a phase I trial for Non-small cell lung cancer (Second-line therapy or greater) in USA (NCT02349633)
05 Jan 2015Preclinical trials in Non-small cell lung cancer in USA (PO)

SYNTHESIS COMING…………

PF-06747775 is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. EGFR T790M inhibitor PF-06747775 specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06747775 may have therapeutic benefits in tumors with T790M-mediated drug resistance.

for the oral treatment of patients with locally advanced or metastatic EGFR mutant (del19 or L858R) non-small cell lung cancer

Kinetic mechanism for two-step covalent inhibition of EGFR

PATENT

US 20150141402

Example 7

(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin -6-amine

(MOL) (CDX)

A suspension of 6-chloro-2-fluoro-9H-purine (5.49 g, 31.8 mmol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60 g, 40.34 mmol, 1.26 eq), and N,N-diisopropylethylamine (16.6 mL, 95.5 mmol, 3.00 eq) in DMSO (31.8 mL) was stirred at ambient temperature for 19 hr. The reaction mixture was then concentrated in vacuo at 50° C., poured into water (250 mL), and stirred vigorously at 0° C. for 1 hr. The resulting solids were filtered off, washed with ice cold water (20 mL), and dried for 16 hr at 50° C. to give the title compound (7.26 g, 87% yield, 96% purity) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3H). m/z (APCI+) for C₁₀H₁₁FN₇O 264.2 (M+H)⁺.

Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl -9H-purin-6-amine

(MOL) (CDX)

To a vigorously stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (7.25 g, 27.5 mmol, 1.00 eq) and potassium carbonate (7.61 g, 55.1 mmol, 2.00 eq) in 1,4-dioxane (92.0 mL), was added dimethyl sulfate (2.90 mL, 30.3 mmol, 1.10 eq) in a dropwise manner over 3 min. After 4 hr, additional portions of 1,4-dioxane (50.0 mL), potassium carbonate (3.80 g, 27.5 mmol, 1.00 eq), and dimethyl sulfate (1.00 mL, 10.4 mmol, 0.30 eq) were added to the reaction mixture. After a further 16 hr, the reaction mixture was concentrated in vacuo, diluted with water (120 mL), and stirred at ambient temperature for 1 hr. The resulting solids were filtered, washed with water (20 mL), and dried for 16 hr at 60° C. to give the title compound (6.42 g, 84% yield, >95% purity) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C₁₁H₁₃FN₇O 278.2 (M+H)⁺.

Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol -4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

To a stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (554 mg, 2.00 mmol, 1.00 eq) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (500 mg, 2.10 mmol, 1.05 eq) in DMSO (4.2 mL) was added N,N-diisopropylethylamine (0.83 mL, 5.00 mmol, 2.50 eq). The reaction mixture was then heated at 100° C. for 16 hr, cooled to ambient temperature, diluted with THF (4 mL), and treated with potassium tert-butoxide (4.00 mL, 1 M in THF, 2.00 eq). After 1 hr, an additional portion of potassium tert-butoxide (0.50 mL, 1 M in THF, 0.25 eq) was added to the reaction mixture. After a further 1 hr, the reaction mixture was poured into phosphate buffer (50 mL, pH=7) and water (50 mL), and extracted with ethyl acetate (5×40 mL). The combined organic layers were combined, dried (Na₂SO₄), and concentrated under reduced pressure. This crude product was then dissolved in ethyl acetate (40 mL) at 60° C. and then treated with heptanes (20 mL), at which point the solution became cloudy and was allowed to cool to ambient temperature and then to 0° C. After 16 hr at 0° C., the resulting solids were filtered and dried at ambient temperature to give the title compound (620.5 mg, 75% yield) as a white powder. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C₁₈H₂₃FN₉O₂416.3 (M+H)⁺.

Example 7A

(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

Preparation Step 1A: Preparation of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione

(MOL) (CDX)

A mixture of xylene, (1.2 L), benzylamine (120 g, 1.10 mol, 1.0 eq) and L-(+)-tartaric acid (173 g, 1.15 mol, 1.05 eq) were heated at 135° C. for 12 hr (flask jacket temperature). Upon reaction completion, the mixture was cooled to 65° C. and MeOH (120 mL, 1 vol) was added. The resulting mixture was stirred for 1 hr and the resulting suspension was cooled to 20° C. followed by the addition of EtOAc (480 mL). Stirring was continued at 10° C. for 2 hr. The crude product was isolated by filtration and washed with EtOAc (120 mL) and dried on the filter. The crude product was then taken up in MeOH (480 mL) and heated at a gentle reflux for 1 hr, then cooled to 20° C. and granulated for 1 hr. The suspension was filtered and the precipitate washed with MeOH (240 mL) and dried to give the title compound (191 g, 864 mmol, 79%) as a white granular solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.30 (m, 2H) 7.30-7.22 (m, 3 H) 6.32 (br. s., 1 H) 4.59 (d, J=14.8 Hz, 1 H) 4.53 (d, J=14.8 Hz, 1 H) 4.40 (br. D., J=4.3 Hz, 2 H). m/z (EI+) for C₁₁H₁₁NO₄221.0 (M)⁺.

Preparation Step 2A: Preparation of (3S,4S)-1-benzylpyrrolidine-3,4-diol

(MOL) (CDX)

To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C₁₁H₁₅NO₂194.2 (M+H)⁺.

Preparation Step 3A: Preparation of (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ⁶-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester

(MOL) (CDX)

To a 5 L jacketed reactor (Reactor 1) was added 1,4-dioxane (1.8 L), (3S,4S)-1-benzylpyrrolidine-3,4-diol (180 g, 0.932 mol, 1.0 eq) and TEA (792 mL, 5.68 mol, 6.1 eq) and the resulting mixture stirred at 10° C.

To a 2 L jacketed reactor (Reactor 2) was added 1,4-dioxane (1.6 L) and chlorosulfonyl isocyanate (596 g, 2.80 mol, 3.0 eq) and the resulting solution was cooled to 10° C. A solution of tert-butanol (211 g, 2.85 mol, 3.05 eq) in 1,4-dioxane (180 mL) was added over 45 min while maintaining the temperature between 10° C. and 20° C., and the resulting solution was then stirred for 15 min at 10° C.

The solution in Reactor 2 was transferred to Reactor 1 over 50 min while controlling the internal temperature of Reactor 1 from 10° C. to 20° C. Once the addition was complete, the jacket temperature was warmed at 20° C. and the resulting mixture was stirred for 16 hr. When UPLC analysis confirmed that the bis-alkylated intermediate was fully formed (target <3% mono-alkylated intermediate), the entire batch was filtered and the filtrate was sent into a clean reactor. The residual TEA-HCl cake was washed with dioxane (300 mL) and the wash was combined with the filtrate. The resulting dioxane solution was then heated to 80° C. and held for 3 hr. After sampling for reaction completion (<1% intermediate remaining), the batch was distilled (pot temp=80° C.) under partial vacuum (400 mbar) to less than half volume. The reaction mixture was diluted with EtOAc (2 L) and washed twice with water (2×2 L). The mixture was then washed with 0.5 N sodium bicarbonate (2 L) and then dried over sodium sulfate (360 g, 2 wt eq) and filtered into a clean dry reactor. The EtOAc solution was concentrated under partial vacuum to about 400 mL total volume resulting in the formation of a thick slurry. The mixture was cooled to 0° C. and stirred for 1 hr and then filtered and washed with cold EtOAc (200 mL) and then dried in a vacuum oven at 40° C. to give 173 g of the title compound. A second crop of product was isolated by concentrating the filtrate and then cooling, granulating and filtering to give an additional 28.4 g of the desired product. In total, the title compound was isolated in 61% yield (201 g, 568 mmol). ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 5.36 (dd, J=7.3, 3.8 Hz, 1 H) 4.79-4.73 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.70 (d, J=13.4 Hz, 1 H) 3.62 (d, J=13.4 Hz, 1 H) 3.13-2.99 (m, 2 H) 2.48-2.40 (m, 2 H) 1.46 (s, 9 H). m/z (EI+) for C₁₆H₂₂N₂O₅S 355.2 (M+H)⁺.

Preparation Step 4A: Preparation of (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate

(MOL) (CDX)

A solution of 1M tetrabutylammonium fluoride in THF (1.27 L, 1.27 mol, 2.5 eq) and (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ⁶-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester (180 g, 0.508 mol, 1.0 eq) were heated at 60° C. (jacket temperature) for 2 hr. Upon reaction completion, the mixture was partially distilled under vacuum to remove the THF. After concentration to a low stir volume, THF was displaced with EtOAc (2×500 mL). After again reducing to a low stir volume, EtOAc (3.6 L) and p-toluenesulfonic acid monohydrate (396 g, 2.10 mol, 4.1 eq) were charged and heated at 80° C. for 2 hr. The mixture was cooled to 10° C. over 1.5 hr and then granulated at 10° C. for 2 hr. The solid product was filtered and washed with EtOAc (2×900 mL) and dried at 50° C. in a vacuum oven for 12 hr. The title compound was isolated as an air stable crystalline solid in 83% yield (231 g, 419 mmol). ¹H NMR (400 MHz, D₂O) δ ppm 7.69-7.61 (m, 4 H) 7.56-7.42 (m, 5 H) 7.36-7.29 (m, 4 H) 5.65-5.49 (m, 1 H) 4.47 (br. s., 2H) 4.37-4.23 (m, H) 4.15 (ddd, J=12.8, 8.2, 1.4 Hz, 1 H) 3.88 (dd, J=19.1, 1.2 Hz, 1 H), 3.74 (ddd, J=33.2, 14.0, 5.5 Hz, 1 H) 3.44 (dd, J=12.8, 8.2 Hz, 1 H) 2.34 (s, 6 H). m/z (EI+) for C₁₁H₁₅FN₂194.8 (M+H)⁺.

Preparation Step 5A: N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

(MOL) (CDX)

A suspension of 1,1′-carbonyldiimidazole (73.0 g, 441 mmol, 1.1 eq) in acetonitrile (3.3 L) was stirred at 20° C. until a clear solution was obtained. 3-(methylsulfonyl)propanoic acid (67.0 g, 440 mmol, 1.1 eq) was then added and the mixture was stirred at 25° C. for 3 hr. (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate (220 g, 400 mmol, 1.0 eq) was added and the mixture was stirred at 25° C. for 16 hr resulting in a fine white slurry. The solids were filtered off and the byproduct cake washed with acetonitrile (600 mL). The acetonitrile solution was then concentrated to a low stir volume and then taken up in EtOAc (2.0 L) and washed with 1 N aqueous sodium bicarbonate (1.3 L). The aqueous layer was back extracted with EtOAc (500 mL) and the combined EtOAc layers were washed with water (1.0 L). The resulting EtOAc solution was distilled to remove about 2.0 L of distillate and then displaced with 2-propanol under atmospheric conditions until the internal temperature rose to 78° C. while maintaining a total volume of 2 L. The batch was then cooled to 20° C. and granulated at 20° C. for 12 hr resulting in product crystallization. The desired product was isolated by filtration and the cake washed with 2-propanol (600 mL), then dried in an oven at 40° C. under reduced pressure for 12 hr. The title compound (108 g, 308 mmol) was isolated in 77% yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br. d., J=7.0 Hz, 1 H) 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 4.90 (ddt, J=53.4, 5.3, 2×1.7 Hz, 1 H) 4.25 (dddd, J=26.4, 13.9, 7.0, 1.4 Hz, 1 H) 3.61 (d, J=13.2 Hz, 1 H) 3.57 (d, J=13.2 Hz, 1 H) 3.36-3.28 (m, 2 H) 3.03 (dd, J=9.3, 7.5 Hz, 1 H) 2.97 (s, 3 H) 2.80 (dd, J=24.0, 11.6 Hz, 1 H) 2.66 (ddd, J=30.6, 11.6, 5.3 Hz, 1 H) 2.57 (td, 2×7.7, 1.4 Hz, 2 H) 2.18 (dd, J=9.4, 6.7 Hz, 1 H). m/z (EI+) for C₁₅H₂₁FN₂O₃S 329.7 (M+H)⁺.

Preparation Step 6A: N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

(MOL) (CDX)

To a Parr reactor was added N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (86.5 g, 263 mmol, 1.0 eq), palladium hydroxide (20% on carbon, 2.59 g, 3.69 mmol, 3 wt/wt %) and MeOH (430 mL). The reactor was purged three times with nitrogen (50 psi) and then purged three times with hydrogen (20 psi). The reactor was heated at 50° C. and then pressurized to 50 psi while stirring at 1200 rpm. The material was hydrogenated for 7 hr and then cooled to 20° C. and purged with nitrogen. The mixture was filtered to remove the catalyst and the cake was washed with MeOH (173 mL). The combined filtrate and wash were concentrated to about 200 mL followed by addition of MTBE (200 mL) and then concentrated to a low stir volume. Additional MTBE (200 mL) was added and the resulting slurry granulated at 20° C. for 16 hr. The desired product was isolated by filtration, washed with MTBE (300 mL) and then dried in an oven at 40° C. for 12 hr. The title compound was isolated in 90% yield (53.3 g, 224 mmol) as a white crystalline solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (br. d., J=6.8 Hz, 1 H) 4.96-4.78 (m, 1 H) 4.14-4.01 (m, 1 H) 3.32 (dd, J=8.0, 7.3 Hz, 2 H) 3.13 (dd, J=11.8, 6.8 Hz, 1 H) 3.01-2.93 (m, 1 H) 2.98 (s, 3 H) 2.88 (d, J=3.0 Hz, 1 H) 2.60 (br. s., 1 H) 2.5 7-2.52 (m, 3 H). m/z (EI+) for C₈H₁₅FN₂O₃S 239.1 (M+H)⁺.

Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

(MOL) (CDX)

A suspension of 6-chloro-2-fluoro-9H-purine (88% potency, 5.90 kg, 30.20 mol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (98% potency, 5.55 kg, 33.22 mol, 1.10 eq), and sodium bicarbonate (10.1 kg, 120.81 mol, 4.00 eq) in EtOAc (106 L) was stirred at 50° C. for 12 hr. The reaction mixture was then cooled to 20° C., granulated for 1 hr, filtered, and the solids were washed with EtOAc (18 L) and dried on the filter. The crude product was charged back into the reactor and suspended in water (106 L) and stirred at 35° C. for 2 hr. The resulting slurry was cooled to 20° C. and the desired product was isolated by filtration and the cake was washed with water (30 L) and then with EtOAc (30 L) and dried for 16 hr at 50° C. to give the title compound (6.26 kg, 23.8 mol, 79% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3 H). m/z (APCI+) for C₁₀H₁₁FN₇O 264.2 (M+H)⁺.

Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine

(MOL) (CDX)

To a 100 L reactor fitted with a caustic scrubber was added 2-methyltetrahydrofuran (44.0 L), 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (2.20 kg, 8.36 mol, 1.00 eq) and potassium phosphate tribasic (7.10 kg, 33.43 mol mmol, 4.00 eq). The resulting mixture was stirred at 5° C. and dimethyl sulfate (1.42 kg, 11.28 mol, 1.35 eq) was added and the resulting mixture was stirred at 5° C. for 1 hr. The reaction was warmed from 5° C. to 15° C. over 2 hr and then held at 15° C. for 20 hr. The reaction mixture was cooled to 5° C. and quenched with water (44.0 L) while maintaining the internal temperature below 10° C. The mixture was then heated at 50° C. for 2 hr and then cooled to 10° C. and granulated for 2 hr. The product was isolated by filtration and washed with water (11.0 L) and then with 2-methyltetrahydrofuran (11.0 L). The cake was dried under vacuum at 40° C. for 8 hr to give the title compound (1.99 kg, 7.18 mol, 86% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H)3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C₁₁H₁₃FN₇O 278.2 (M+H)+.

Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

To a 200 L Hastelloy reactor heated to 40° C. was added sulfolane (22.4 L) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (4.03 kg, 16.9 mol, 1.05 eq) and stirred the resulting mixture until all solids were dissolved. To this solution was added 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (4.47 kg, 16.1 mol, 1.00 eq) and N,N-diisopropylethylamine (8.50 L, 48.7 mol, 3.0 eq) and the mixture heated at 115° C. for 16 hr. The reaction mixture was cooled to 30° C., and a solution of potassium hydroxide (2.26 kg, 40.3 mol, 2.5 eq) in water (44.7 L) was added. After stirring for 4 hr, the reaction mixture was cooled to 20° C., water (44.7 L) was added and the resulting mixture granulated for 12 hr. The crude product was isolated on a Nutsche filter and washed with water (27 L) and then dried under nitrogen on the filter. The reactor was cleaned and then charged with water (35.8 L) and acetone (53.6 L). The crude product cake was charged back into the reactor and heated to 60° C. until all of the solids had dissolved. The batch was then cooled to 40° C. and then transferred into a speck free 100 L reactor via an in-line 10 μm filter. The 200 L reactor, line and filter were rinsed with acetone (5 L) and sent into the 100 L reactor. The batch was concentrated with the jacket temperature set at 70° C. under partial vacuum until the acetone content reduced to 5 wt %, as determined by gas chromatography head space. The batch was then cooled to 20° C. and granulated for 4 hr. The product was filtered, washed with water (18 L) and dried in a vacuum oven at 55° C. for 8 hr. The title compound (3.942 kg, 9.49 mol, 59%) was isolated as a white crystalline solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C₁₈H₂₃FN₉O₂416.3 (M+H)⁺.

Summary of 1st generation and 2nd generation EGFR inhibitors

REFERENCES

Planken, S.; Murray, B. W.; Lafontaine, J.; Weinrich, S.; Hemkens, M.; Kath, J. C.; Nair, S. K.; Johnson, T. O.; Cheng, H.; Sutton, S. C.; Zientek, M.; Yin, M. -J.; Solowiej, J.; Nagata, A.; Gajiwala, K. Abstracts of Papers, 249th ACS National Meeting & Exposition, Denver, CO, United States, March 22–26, 2015; MEDI-248

//////Third generation, covalent EGFR inhibitors, PF-06747775, Pfizer, PFE-X775

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

PROCESS, SYNTHESIS Comments Off

Mar 232016

Herein, the first continuous cross-dehydrogenative homocoupling of an unactivated arene using oxygen as sole oxidant is reported. Employing microreactor technology which enables the use of elevated temperatures and pressures leads to a boost of the catalytic reaction. Hence, a major reduction in reaction time is achieved. Due to the significance as precursor for MOFs as well as high-tech and high-value polymers, the study focused on the production of 3,4,3′,4′-tetramethyl-biphenyl.

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

Nico Erdmann, Yuanhai Su, Benjamin Bosmans, Volker Hessel, and Timothy Noël^*

Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00044

Publication Date (Web): March 10, 2016

*E-mail: t.noel@tue.nl.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00044

Supporting Info SEEEEEEEEEEEEE

////Palladium-Catalyzed Aerobic Oxidative Coupling, o-Xylene, Flow, Safe and Scalable Protocol, Cross-Dehydrogenative Coupling

PICS

Cross-dehydrogenative coupling reactions. : The electron is a …

www.nature.com

Cross-dehydrogenative coupling reactions.

Enhancing the usefulness of cross dehydrogenative coupling …

pubs.rsc.org

Cross dehydrogenative coupling (CDC) reactions with different protecting group strategies.

Dipeptide-Based Metabolic Labeling of Bacterial Cells for Endogenous Antibody Recruitment

MONOCLONAL ANTIBODIES Comments Off

Mar 232016

The number of antibiotic-resistant bacterial infections has increased dramatically over the past decade. To combat these pathogens, novel antimicrobial strategies must be explored and developed. We previously reported a strategy based on hapten-modified cell wall analogues to induce recruitment of endogenous antibodies to bacterial cell surfaces. Cell surface remodeling using unnatural single d-amino acid cell wall analogues led to modification at the C-terminus of the peptidoglycan stem peptide. During peptidoglycan processing, installed hapten-displaying amino acids can be subsequently removed by cell wall enzymes. Herein, we disclose a two-step dipeptide peptidoglycan remodeling strategy aimed at introducing haptens at an alternative site within the stem peptide to improve retention and diminish removal by cell wall enzymes. Through this redesigned strategy, we determined size constraints of peptidoglycan remodeling and applied these constraints to attain hapten–linker conjugates that produced high levels of antibody recruitment to bacterial cell surfaces.

Dipeptide-Based Metabolic Labeling of Bacterial Cells for Endogenous Antibody Recruitment

Jonathan M. Fura, Sean E. Pidgeon, Morgan Birabaharan, and Marcos M. Pires^*

Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, United States

ACS Infect. Dis., Article ASAP

DOI: 10.1021/acsinfecdis.6b00007

Publication Date (Web): February 02, 2016

*(M.M.P.) E-mail: map311@lehigh.edu.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

http://pubs.acs.org/doi/full/10.1021/acsinfecdis.6b00007

SEE OTHER PUBLICATIONS

Illumination of growth, division and secretion by metabolic …

femsre.oxfordjournals.org

Figure 1.

A new metabolic cell-wall labelling method reveals peptidoglycan …

www.nature.com

Novel dipeptide PG labelling strategy.

Keywords:, antibiotics, bacterial, surface, remodeling, d-amino acids, Dipeptide-Based Metabolic Labeling, Bacterial Cells, Endogenous Antibody Recruitment

///

BRIVARACETAM

Uncategorized Comments Off

Mar 222016

BRIVARACETAM, UCB-34714

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide

1-Pyrrolidineacetamide, α-ethyl-2-oxo-4-propyl-, (αS,4R)-

CAS 357336-20-0

Molecular Formula:	C₁₁H₂₀N₂O₂
Molecular Weight:	212.2887 g/mol

UNII-U863JGG2IA

UCB; For the treatment of partial onset seizures related to epilepsy, Approved February 2016

Brivaracetam, the 4-n-propyl analog of levetiracetam, is a racetam derivative with anticonvulsant properties.^[1]^[2] Brivaracetam is believed to act by binding to the ubiquitous synaptic vesicle glycoprotein 2A (SV2A).^[3] Phase II clinical trials in adult patients with refractory partial seizures were promising. Positive preliminary results from stage III trials have been recorded,^[4]^[5] along with evidence that it is around 10 times more potent^[6] for the prevention of certain types of seizure in mouse models than levetiracetam, of which it is an analogue.

On 14 January 2016, the European Commission,^[7] and on 18 February 2016, the USFDA^[8] approved brivaracetam under the trade name Briviact (by UCB). The launch of this anti-epileptic is scheduled for the first quarter of that year. Currently, brivaracetam is still not approved in other countries like Australia, Canada and Switzerland.

Brivaracetam was approved by European Medicine Agency (EMA) on Jan 14, 2016 and approved by the U.S. Food and Drug Administration (FDA) on Feb 18, 2016. It was developed and marketed as Briviact^® by UCB in EU/US.

Brivaracetam is a selective high-affinity synaptic vesicle protein 2A ligand, as an adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adult and adolescent patients from 16 years of age with epilepsy.

Briviact^® is available in three formulations, including film-coated tablets, oral solution and solution for injection/infusion. And it will be available as 10 mg, 25 mg, 50 mg, 75 mg and 100 mg film-coated tablets, a 10 mg/ml oral solution, and a 10 mg/ml solution for injection/infusion. The recommended starting dose is either 25 mg twice a day or 50 mg twice a day, depending on the patient’s condition. The dose can then be adjusted according to the patient’s needs up to a maximum of 100 mg twice a day. Briviact can be given by injection or by infusion (drip) into a vein if it cannot be given by mouth.

European Patent No. 0 162 036 Bl discloses compound (S)-α-ethyl-2-oxo-l- pyrrolidine acetamide, which is known under the International Non-proprietary Name of Levetiracetam.

Levetiracetam

Levetiracetam is disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system in European patent EP 0 162 036 Bl. This compound is also effective in the treatment of epilepsy.

The preparation of Levetiracetam has been disclosed in European Patent No. 0 162 036 and in British Patent No. 2 225 322.

International patent application having publication number WO 01/62726 discloses 2-oxo-l -pyrrolidine derivatives and methods for their preparation. It particularly discloses compound (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-l-yl] butanamide known under the international non propriety name of brivaracetam.

Brivaracetam

International patent application having publication number WO 2005/121082 describes a process of preparation of 2-oxo-l -pyrrolidine derivatives and particularly discloses a process of preparation of (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxo-pyrrolidin-l- yl]butanamide known under the international non propriety name of seletracetam.

Seletracetam

Kenda et al., in J. Med. Chem. 2004, 47, 530-549, describe processes of preparation of 2-oxo-l -pyrrolidine derivatives and particularly discloses compound 1-((1S)-I- carbamoyl-propyl)-2-oxo-pyrrolidone-3-carboxylic acid as a synthetic intermediate.

WO2005028435

CLIPS

Find better ways to make old and new epilepsy drugs. J. Surtees and co-inventors disclose alternative processes for making active pharmaceutical ingredients (APIs) that are used to treat epilepsy and seizures. One compound that can be prepared by their processes is the established drug levetiracetam (1, Figure 1), marketed under the trade name Keppra. Because 1 is now off-patent, there is obvious interest in new drugs.

The inventors also claim that seletracetam (2) and brivaracetam (3) (Figure 2) can be prepared by their processes. These drugs are apparently much more active than 1.

All of the drugs are used as single isomers, so a stereoselective synthesis is desirable. The inventors describe two routes for preparing the molecules; the first, shown in Figure 1, is the synthesis of 1 by the reaction between pyrrolidone (4) and chiral bromo amide 5 in the presence of a base. GC analysis showed that the conversion is 40.3% and that the product contains 51% of the (S)-enantiomer and 49% of the (R)-isomer. No details of their separation are given, although the use of chiral HPLC is discussed.

The same reaction is used to prepare derivative 6 of 1. Compound 7 is prepared from the corresponding hydroxy ester and then condensed with 4 to give 6. Chiral HPLC showed that the product is a mixture of 89.3% (S)-enantiomer 6 and 10.7% of its (R)-isomer.

The inventors do not describe the detailed preparation of 2, but they report that acid 8 is prepared in 41% yield from pyrrolidone 9 and acid 10 in the presence of NaH (Figure 2). Ammonolysis of 8 produces 2; no reaction details are provided.

In a reaction similar to the preparation of 8, acid 11 is prepared from 10 and pyrrolidone 12. The product is isolated in 77% yield and can be converted to 3 by ammonolysis. Again, no details are provided for this reaction.

The second route for preparing the substituted pyrrolidones does not start with simple pyrrolidones and is the subject of additional claims. The route involves a cyclization reaction, shown in Figure 3. The preparation of enantiomer 13 begins with the reaction of racemic salt 14 and optically pure bromo ester 15. This step produces intermediate 16, isolated as a yellow oil. The crude material is treated with 2-hydroxypyridine (2-HP) to cyclize it to 17. This ester is hydrolyzed to give acid 18. Conversion to 13 is carried out by adding ClCO₂Et, followed by reaction with liquid NH₃ in the presence of K₂CO₃. The overall yield of 13 is 32%.

This route is also used to prepare levetiracetam (1) by treating 5 with the HCl salt of amino ester 19 to give 20, recovered as its HCl salt in 49% yield. The salt is basified with Et₃N and treated with 2-HP to cyclize it to 1, initially isolated as an oil. GC analysis showed 100% conversion, and chiral HPLC showed that the product contains 98.6% (S)-isomer and 1.4% (R)-isomer.

The inventors also prepared 1 and its (R)-enantiomer 21 by using a similar reaction scheme with alternative substrates to 5. Figure 4 outlines the route, which starts from protected hydroxy amide 22 and amino ester 23. When the reaction is carried out in the presence of Cs₂CO₃, the product is (R)-enantiomer24, which is used without purification to prepare 21 by treating it with 2-HP. Chiral HPLC showed that the product is 94% (R) and 6% (S).

When the reaction between 22 and 23 is run with K₂CO₃, the product is (S)-enantiomer 25. This is used to prepare 1, but the product contains only 79% (S)-isomer.

The inventors do not comment on the apparent stereoselectivity of the carbonate salts in the reaction of 22 with 23. This is an intriguing finding and worthy of investigation. (UCB S.A. [Brussels]. US Patent 8,338,621

SYNTHESIS

PATENT

WO2005028435

Example 1: Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide 1.1 Synthesis of (2S)-2-aminobutyramide free base

1800 ml of isopropanol are introduced in a 5L reactor. 1800 g of (2S)-2- aminobutyramide tartrate are added under stirring at room temperature. 700 ml of a 25% aqueous solution of ammonium hydroxide are slowly added while maintaining the temperature below 25°C. The mixture is stirred for an additional 3 hours and then the reaction is allowed to complete at 18°C for 1 hour. The ammonium tartrate is filtered. Yield : 86%.

1.2 Synthesis of 5-hydroxy-4-n-propyl-furan-2-one

Heptane (394 ml) and morpholine (127.5 ml) are introduced in a reactor. The mixture is cooled to 0°C and glyoxylic acid (195 g, 150 ml, 50w% in water) is added. The mixture is heated at 20°C during 1 hour, and then valeraldehyde (148.8 ml) is added . The reaction mixture is heated at 43°C during 20 hours. After cooling down to 20^CC, a 37 % aqueous solution of HCl (196.9 ml) is slowly added to the mixture, which is then stirred during 2 hours.

After removal of the heptane phase, the aqueous phase is washed three times with heptane. Diisopropyl ether is added to the aqueous phase. The organic phase is removed, and the aqueous phase further extracted with diisopropyl ether (2x). The diisopropyl ether phases are combined, washed with brine and then dried by azeotropic distillation. After filtration and evaporation of the solvent, 170g of 5- hydroxy-4-n-propyl-furan-2-one are obtained as a brown oil. Yield: 90.8 %

1.3 Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide and (2S)-2-((4S)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide

(S, R) (S, S) The (2S)-2-aιninobutyrarnide solution in isopropanol containing 250 g obtained as described here above is dried by azeotropic distillation under vacuum. To the dried (2S)-2-am obutyraιnide solution is added 5-hydroxy-4-n-propyl-furan-2-one (290 g) between 15°C and 25 °C; the mixture is heated to 30 °C and kept for at least 2 hours at that temperature. Acetic acid (1, 18 eq.), Pd/C catalyst (5 w/w%; Johnson Matthey 5% Pd on carbon – type 87L) are then added and hydrogen introduced into the system under pressure. The temperature is kept at 40 °C maximum and the H₂ pressure maintained between 0,2 bar and 0,5 bar followed by stirring for at least 20 hours following the initial reaction. The solution is then cooled to between 15 °C and 25 °C and filtered to remove the catalyst. The solution of product in isopropanol is solvent switched to a solution of product in isopropyl acetate by azeotropic distillation with isopropyl acetate. The organic solution is washed with aqueous sodium bicarbonate followed by a brine wash and then filtered. After recristallisation, 349 g of (2S)-2-((4R)-2- oxo-4-n-propyl-l-pyrrolidinyl)butanamide and (2S)-2-((4S)-2-oxo-4-n-propyl-l- pyιτolidinyl)butanamide are obtained (Yield: 82.5%).

1.4 Preparation of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide The chromatographic separation of the two diastereoisomers obtained in 1.3 is performed using of (CHIRALPAK AD 20 um) chiral stationary phase and a 45/55 (volume /volume) mixture of n-heptane and ethanol as eluent at a temperature of 25 + 2°C. The crude (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide thus obtained is recristallised in isopropylacetate, yielding pure (2S)-2-((4R)-2-oxo-4-n-propyl-l- pyrrolidinyl)butanamide (Overall yield: 80%) .

Example 2: Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide

Example 1 is repeated except that in step 1.1 a solution of (2S)-2- aminoburyramide.HCl in isopropanol is used (27.72 g, 1.2 equivalent), which is neutralised with a NHs/isopropanol solution (3,4-3,7 mol/L). The resulting ainmonium chloride is removed from this solution by filtration and the solution is directly used for reaction -with 5-hydroxy-4-n-propyl-furan-2-one (23.62 g, 1.0 equivalent) without intermediate drying of the (2S)-2-aminobutyramide solution. Yield after separation of the two diastereoisomers and recristallisation: approximately 84%.

Ref ROUTE1

1. WO0162726A2.

2. WO2005028435A1 / US2007100150A1.

3. J. Med. Chem. 1988, 31, 893-897.

4. J. Org. Chem. 1981, 46, 4889-4894.

PATENT

https://www.google.com/patents/WO2007031263A1?cl=en

Example 3-Synthesis of brivaracetam (I)

3.a. Synthesis of (S) and (R) 2-((R)-2-oxo-4-propyl-pyrrolidin-l-yl)-butyric acid methyl ester fVIaa^*) and (Wlab)

(VIaa) (VIab) A slurry of 60% sodium hydride suspension in mineral oil (0.94g, 23.4 mmol) in tetrahydrofuran (30 mL) is cooled at 0°C under a nitrogen atmosphere. A solution of substantially optically pure (R)-4-propyl-pyrrolidin-2-one (Ilia) (2g, 15.7 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred 10 min at 0°C then a solution of methyl-2-bromo-butyric acid methyl ester (V) (3.69g, 20.4 mmol) in tetrahydrofuran (2mL) was added over a 20 minutes period. The reaction mixture is stirred at O⁰C until maximum conversion of starting material and the reaction mixture is then allowed to warm to room temperature and diluted with water (20 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (20 ml + 10 mL). The combined organic layers are dried on anhydrous magnesium sulfate and evaporated to afford 3g (13.2 mmol, 86 %) of a mixture of epimers of compound (Via), as a mixture respectively of epimer (VIaa) and epimer (VIab). ¹H NMR(400 MHz, CDCI3) of the mixture of epimers (VIaa) and (VIab) : δ = 4.68

(dd, J= 10.8, J= 5.1, 2×1 H) ; 3.71 (s, 2x3H); 3.60 (t app, J= 8.2, IH); 3.42 (t app, J= 8.7, IH); 313 (dd, J= 9.2, J = 6.8, IH); 2.95 (dd, J= 9.2, J= 6.8, IH); 2.56 (dd, J= 16.6, J = 8.7, 2xlH); 2.37 (dm, 2xlH); 2.10 (m, 2xlH); 2.00 (m, 2xlH); 1.68 (m, 2xlH); 1.46 (m, 2x2H); 1.36 (m, 2x2H); 0.92 (m, 2x6H).

¹³C NMR (400 MHz, CDCl₃) of the mixture of epimers (VIaa) and (VIab) : δ =

175.9; 175.2; 171.9; 55.3; 52.4; 49.8; 49.5; 38.0; 37.8; 37.3; 36.9; 32.5; 32.2; 22.6; 22.4; 21.0; 14.4; 11.2; 11.1

HPLC (GRAD 90/10) of the mixture of epimers (VIaa) and (VIab): retention time= 9.84 minutes (100 %)

GC of the mixture of epimers (VIaa) and (VIab): retention time = 13.33 minutes (98.9 %)

MS of the mixture of epimers (VIaa) and (VIab) (ESI) : 228 MH+

3.b. Ammonolysis of compound of the mixture of (VIaa) and (VIab)

(VIaa) (VIab) (I) (VII)

A solution of (VIaa) and (VIab) obtained in previous reaction step (1.46g, 6.4 mmol) in aqueous ammonia 50 % w/w (18 mL) at 0⁰C is stirred at room temperature for 5.5hours. A white precipitate that appears during the reaction, is filtered off, is washed with water and is dried to give 0.77g (3.6 mmol, yield = 56 %) of white solid which is a mixture of brivaracetam (I) and of compound (VII) in a 1 :1 ratio.

¹H NMR of the mixture (I) and (VII) (400 MHz, CDCI3) : δ = 6.36 (s, broad, IH); 5.66 (s, broad, IH); 4.45 (m, IH); 3.53 (ddd, J= 28.8, J= 9.7, J= 8.1, IH); 3.02 (m, IH); 2.55 (m, IH); 2.35 (m, IH); 2.11 (m, IH); 1.96 (m, IH); 1.68 (m, IH); 1.38 (dm, 4H); 0.92 (m, 6H). 13c NMR of the mixture (I) and (VII) (400 MHz, CDCl₃) : δ = 176.0; 175.9; 172.8;

172.5; 56.4; 56.3; 50.0; 49.9; 38.3; 38.1; 37.3; 37.0; 32.3; 32.2; 21.4; 21.3; 21.0; 20.9; 14.4; 10.9; 10.8

HPLC (GRAD 90/10) of the mixture of (I) and (VII) retention time= 7.67 minutes (100 %)

Melting point of the mixture of (I) and (VII) = 104.9⁰C (heat from 40⁰C to 120⁰C at 10°C/min)

Compounds (I) and (VII) are separated according to conventional techniques known to the skilled person in the art. A typical preparative separation is performed on a 11.7g scale of a 1 :1 mixture of compounds (I) and (VII) : DAICEL CHIRALPAK® AD 20 μm, 100*500 mm column at 30⁰C with a 300 mL/minutes debit, 50 % EtOH – 50 % Heptane. The separation affords 5.28g (45 %) of compound (VII), retention time = 14 minutes and 5.2Og (44 %) of compounds (I), retention time = 23 minutes.

¹H NMR of compound (I) (400 MHz, CDCl₃): δ = 6.17 (s, broad, IH); 5.32 (s, broad, IH); 4.43 (dd, J= 8.6, J= 7.1, IH); 3.49 (dd, J= 9.8, J= 8.1, IH); 3.01 (dd, J= 9.8, J= 7.1, IH); 2.59 (dd, J= 16.8, J= 8.7, IH); 2.34 (m, IH); 2.08 (dd, J= 16.8, J= 7.9, IH); 1.95 (m, IH); 1.70 (m, IH); 1.47-1.28 (m, 4H); 0.91 (dt, J= 7.2, J= 2.1, 6H)

HPLC (GRAD 90/10) of compound (I) : retention time = 7.78 minutes

¹H NMR of compound (VII) (400 MHz, CDCl₃): δ = 6.14 (s, broad, IH); 5.27 (s, broad, IH); 4.43 (t app, J = 8.1, IH); 3.53 (t app, J = 9.1, IH); 3.01 (t app, J = 7.8, IH); 2.53 (dd, J = 16.5, J = 8.8, IH); 2.36 (m, IH); 2.14 (dd, J = 16.5, J = 8.1, IH); 1.97 (m, IH); 1.68 (m, IH); 1.43 (m, 2H); 1.34 (m, 2H); 0.92 (m, 6H)

3c. Epimerisation of compound of (2RV2-((R)-2-oxo-4-propyl-pyπOlidin-l-ylV butyramide (VID

Compound (VII) (200 mg, 0.94 mmol) is added to a solution of sodium tert- butoxide (20 mg, 10 % w/w) in isopropanol (2 mL) at room temperature. The reaction mixture is stirred at room temperature for 18h. The solvent is evaporated to afford 200 mg

(0.94 mmol, 100 %) of a white solid. Said white solid is a mixture of brivaracetam (I) and of (VII) in a ratio 49.3 / 50.7.

HPLC (ISO80): retention time= 7.45 min (49.3%) brivaracetam (I); retention time= 8.02 minutes (50.7%) compound (VII).

Route 2

Reference：ROUTE 2

1. WO2007031263A1 / US2009318708A1.

PATENT

http://www.google.com/patents/WO2007065634A1?cl=en

(scheme 3).

Scheme 3

scheme 4.

5h. Synthesis of brivaracetam and (V) A suspension of (Id) and (Ie) (0.6 g, 2.3 mmol) in MIBK (10 mL) is heated at

120°C for 6 hours. The resulting solution is concentrated and separated on chromatography column (Silicagel 600.068-0.200 mm, cyclohexane/EtOAc : 10/90) to give 0.13 g of brivaracetam (0.6 mmol, 26 %, ee = 94 %) and (V).

¹H NMR (400 MHz, CDCl₃): δ = 6.17 (s, broad, IH); 5.32 (s, broad, IH); 4.43 (dd, J= 8.6, J= 7.1, IH); 3.49 (dd, J= 9.8, J= 8.1, IH); 3.01 (dd, J= 9.8, J= 7.1, IH); 2.59 (dd, J= 16.8, J= 8.7, IH); 2.34 (m, IH); 2.08 (dd, J= 16.8, J= 7.9, IH); 1.95 (m, IH); 1.70 (m, IH); 1.47-1.28 (m, 4H); 0.91 (dt, J= 7.2,J= 2.1, 6H).

HPLC (method 90/10) : Retention time = 7.78 minutes Chiral HPLC : Retention time = 9.66 minutes (97%) MS (ESI): 213 MH⁺

Route 3

Reference：1. WO2007065634A1 / US2009012313A1.

References

von Rosenstiel P (Jan 2007). “Brivaracetam (UCB 34714)”. Neurotherapeutics 4 (1): 84–7. doi:10.1016/j.nurt.2006.11.004.PMID 17199019.
Malawska B, Kulig K (Jul 2005). “Brivaracetam UCB”. Current Opinion in Investigational Drugs 6 (7): 740–746. PMID 16044671.
Rogawski MA, Bazil CW (Jul 2008). “New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels”. Current Neurology and Neuroscience Reports 8 (4): 345–352. doi:10.1007/s11910-008-0053-7. PMC 2587091.PMID 18590620.
Clinical trial number NCT00464269 for “Double-blind, Randomized Study Evaluating the Efficacy and Safety of Brivaracetam in Adults With Partial Onset Seizures” at ClinicalTrials.gov
Rogawski MA (Aug 2008). “Brivaracetam: a rational drug discovery success story”. British Journal of Pharmacology 154 (8): 1555–7.doi:10.1038/bjp.2008.221. PMC 2518467. PMID 18552880.
Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H (Aug 2008). “Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A”. British Journal of Pharmacology 154 (8): 1662.doi:10.1038/bjp.2008.198. PMID 18500360.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003898/human_med_001945.jsp&mid=WC0b01ac058001d124
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486827.htm

Brivaracetam

Names

IUPAC name

(2S)-2-[(4R)-2-oxo- 4-propylpyrrolidin-1-yl] butanamide

Identifiers

Jmol interactive 3D

Properties

C₁₁H₂₀N₂O₂

212.15 g/mol

Pharmacology

ATC code

N03AX23

Legal status

Investigational

Routes of
administration

Oral

Nearly 100%

<20%

Hydrolysis, CYP2C8-mediated hydroxylation

Biological half-life

8 hrs

Excretion

>75% renal

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////BRIVARACETAM, UCB, 2016 FDA, UCB-34714

CCCC1CC(=O)N(C1)C(CC)C(=O)N

Older Entries Newer Entries

Molecular Weight	636.46
Formula	C27H28F3N7O3 ● HBr

AUTHOR OF THIS BLOG

amcrasto@gmail.com

1–[4–Chloro–3–(4–ethoxybenzyl)phenyl]–1,6–dideoxy–β–d–glucopyranose

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

Abstract

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism

SYNTHESIS COMING……….

N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

SYNTHESIS COMING…………

Example 7

(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin -6-amine

Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl -9H-purin-6-amine

Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol -4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

Example 7A

(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

Preparation Step 1A: Preparation of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione

Preparation Step 2A: Preparation of (3S,4S)-1-benzylpyrrolidine-3,4-diol

Preparation Step 3A: Preparation of (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ6-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester

Preparation Step 4A: Preparation of (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate

Preparation Step 5A: N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

Preparation Step 6A: N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine

Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

Summary of 1st generation and 2nd generation EGFR inhibitors

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

Dipeptide-Based Metabolic Labeling of Bacterial Cells for Endogenous Antibody Recruitment

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Keywords:, antibiotics, bacterial, surface, remodeling, d-amino acids, Dipeptide-Based Metabolic Labeling, Bacterial Cells, Endogenous Antibody Recruitment

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References

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Preparation Step 3A: Preparation of (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ⁶-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester