New Drug Approvals

Home » Posts tagged 'neuropathic pain'

Tag Archives: neuropathic pain

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 3,993,098 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,735 other followers
Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,735 other followers
DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

TRK 700


1-[4-(Dimethylamino)piperidin-1-yl]-3-(1-methylimidazol-2-yl)propan-1-one.png

TRK-700

CAS 1463432-16-7C14 H24 N4 O264.371-Propanone, 1-[4-(dimethylamino)-1-piperidinyl]-3-(1-methyl-1H-imidazol-2-yl)-

1-[4-(dimethylamino)piperidin-1-yl]-3-(1-methylimidazol-2-yl)propan-1-one

  • 1-[4-(Dimethylamino)-1-piperidinyl]-3-(1-methyl-1H-imidazol-2-yl)-1-propanone
  • OriginatorToray Industries
  • ClassAnalgesics
  • Mechanism of ActionUndefined mechanism
  • Phase IIPostherpetic neuralgia
  • PreclinicalPeripheral nervous system diseases
  • 12 Sep 2018Pharmacodynamics data from a preclinical trial in Peripheral neuropathy presented at the 17th World Congress on Pain (WCP-2018)
  • 01 Jul 2017Toray Industries completes a phase II trial for Postherpetic neuralgia (In adults, In the elderly) in Japan (PO) (NCT02701374)
  • 21 May 2017Toray Industries completes a phase I drug-drug interaction trial in Healthy volunteers in Japan (PO) (NCT03043248)

developed by Toray for treating neuropathic pain and investigating for fibromyalgia. In August 2021, this drug was reported to be in phase 1 clinical development.

PATENT

WO 2016136944

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016136944

(Reference Example 22) Synthesis of (E) -methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate:
[Chemical 56]


 1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, Methyl (triphenylphosphoranylidene) acetate (33.4 g, 99.9 mmol) was added to a solution of 90.8 mmol) in dichloromethane (240 mL) at room temperature, and the mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane / dichloromethane = 19/1, and the washing liquid was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (E) -methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate as a white solid (11.9 g, 71. 6 mmol, 79%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.76 (3H, s), 3.81 (3H, s), 6.82 (1H, d, J = 15.6 Hz), 6.98 (1H, brs), 7.16 (1H, brs), 7.53 (1H, d, J = 15.6Hz).
ESI-MS: m / z = 167 (M + H) + .

(Reference Example 27) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one:
[Chemical 61]


 (E) )-Methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium-carbon (10% wet, 15 mg) at room temperature In a hydrogen atmosphere, the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) was added to the obtained residue at room temperature to dissolve it, and the mixture was cooled to 0 ° C. An aqueous sodium hydroxide solution (1.0 N, 1.19 mL, 1.19 mmol) was added to the reaction solution at 0 ° C., the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Chloroform (10.0 mL) was added to the obtained residue at room temperature to dissolve it. Add diisopropylethylamine (0.568 mL, 3.25 mmol), HBTU (0.616 g, 1.63 mmol) and 4- (dimethylamino) piperidine (0.125 g, 0.975 mmol) to the reaction solution at room temperature, and add the reaction solution. The mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propane. -1-one (0.179 g, 0.68 mmol, 63%) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .

(Comparative Example 1) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one hydrochloride:
[Chemical 66]


 1- (4- (Dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one (1.50 g, 5.67 mmol) diethyl ether (60) A dioxane solution of hydrogen chloride (4.0 M, 3.69 mL, 14.8 mmol) was added to the (0.0 mL) solution at 0 ° C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 30 minutes. The precipitated white solid was collected by filtration, washed with diethyl ether (100 mL), dried at room temperature for 36 hours, and then 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-). Imidazole-2-yl) propan-1-one hydrochloride (1.41 g, 4.18 mmol, 74%) (hereinafter, the compound of Comparative Example 1) was obtained as a white solid.
1 1 H-NMR (400 MHz, D 2 O) δ: 1.53-1.80 (2H, m), 2.12-2.23 (2H, m), 2.68-2.80 (1H, m), 2.88 (6H, s), 3.01- 3.08 (2H, m), 3.15-3.26 (3H, m), 3.47-3.58 (1H, m), 3.84 (3H, s), 4.08-4.16 (1H, m), 4.50-4.59 (1H, m), 7.29-7.33 (2H, m).
ESI-MS; 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) as propan-1-one : m / z = 265 (M + H) + .

(Comparative Example 2) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one sulfate monohydrate:
[Chemical 67]


 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one (6.72 g, 25.4 mmol) Concentrated sulfuric acid (2.49 g, 25.4 mmol), water (1.83 g, 102 mmol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl) in a DMSO (100 mL) solution. Seed crystals (50 mg, 0.13 mmol) of -1H-imidazol-2-yl) propan-1-one sulfate monohydrate were added at 80 ° C. The reaction was stirred at the same temperature for 2.5 hours, at 50 ° C. for 2.5 hours and at room temperature for 15 hours. The precipitated white solid was collected by filtration, washed successively with DMSO (20 mL) and methyl ethyl ketone (40 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl). -1H-imidazol-2-yl) propan-1-one sulfate monohydrate (8.42 g, 22.1 mmol, 87%) (hereinafter, the compound of Comparative Example 2) was obtained as white crystals.
1 1 H-NMR (400 MHz, DMSO-d 6)) δ: 1.36 (1H, m), 1.58 (1H, m), 1.95 (2H, br), 2.44-2.57 (1H, m), 2.65 (6H, s), 2.74-2.88 (4H, m), 3.00 (1H, t, J = 12.0 Hz), 3.22 (1H, m), 3.61 (3H, s), 4.02 (1H, d, J = 14.0 Hz), 4.47 (1H, d, J = 12.8 Hz), 6.87 (1H, d, J = 1.2 Hz), 7.11 (1H, d, J = 1.2 Hz).
ESI-MS; 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-) As 1H-imidazol-2-yl) propan-1-one: m / z = 265 (M + H) + .

NEW DRUG APPROVALS

ONE TIME

$10.00

PATENT

WO-2021153744

PATENT

WO-2021153743

Novel crystalline polymorphic form of 1-(4-(dimethylamino) piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propan-1-one, useful as an analgesic in treating neuropathic pain and/or fibromyalgia.Pain is an experience with unpleasant sensations and emotions that occurs when or may cause tissue damage. Pain is mainly classified into nociceptive pain, neuropathic pain or psychogenic pain according to its cause. In addition, fibromyalgia is known as pain of unknown cause. 
 Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, and is caused by direct damage or compression of nervous tissue even though nociceptors are not stimulated. It refers to the pain that occurs. As a therapeutic agent for neuropathic pain, an anticonvulsant, an antidepressant, anxiolytic, or an antiepileptic drug such as gabapentin or pregabalin is used. 
 Fibromyalgia is a disease in which systemic pain is the main symptom and neuropsychiatric symptoms and autonomic nervous system symptoms are secondary symptoms. Pregabalin approved in the United States and Japan, duloxetine and milnacipran approved in the United States are mainly used as therapeutic agents for fibromyalgia, and non-approved agents for fibromyalgia are not approved. It has also been used for steroidal anti-inflammatory agents, opioid compounds, antidepressants, anticonvulsants and antiepileptic drugs. However, the therapeutic effects of non-steroidal anti-inflammatory drugs and opioid compounds are generally considered to be low (Non-Patent Document 1). 
 On the other hand, Patent Document 1 discloses that certain substituted piperidins have cardiotonic activity, and Patent Document 2 discloses that an imidazole derivative exhibits an FXa inhibitory effect. Patent Document 3 suggests that the substituted piperidins may have a medicinal effect on overweight or obesity, and Patent Documents 4 to 6 and Non-Patent Document 2 indicate that the imidazole derivative has an analgesic effect. It is disclosed. 
 In addition, the quality of pharmaceutical products needs to be maintained over a long period of time such as distribution and storage, and the compound as an active ingredient is required to have high chemical and physical stability. Therefore, as the active ingredient of a pharmaceutical product, a crystal that can be expected to have higher stability than an amorphous substance is generally adopted. Further, if crystals are obtained, a purification effect due to recrystallization during production can be expected. Further, it is preferable to have low hygroscopicity from the viewpoint of maintaining stability and handling during manufacturing, storage, formulation and analysis of the drug substance. In addition, since a drug needs to be dissolved in the digestive tract in order to exhibit its medicinal effect, it is preferable that the drug has excellent solubility, which is a physical property contrary to stability. 
 In order to obtain crystals of a compound that is an active ingredient of a pharmaceutical product, it is necessary to study various conditions for precipitating crystals from the solution. It is common to carry out crystallization under the condition of being dissolved in.

Patent documents

Patent Document 1: French Patent Invention No. 2567885
Patent Document 2: Japanese Patent Application Laid-Open No. 2006-0083664
Patent Document 3: International Publication No. 2003/031432
Patent Document 4: International Publication No. 2013/147160
Patent Document 5: International Publication No. 2015/046403
Patent Document 6: International Publication No. 2016/136944

Non-patent literature

Non-Patent Document 1: Okifuji et al., Pain and Therapy, 2013, Volume 2, p. 87-104
Non-Patent Document 2: Takahashi et al., Toxicological Pathology, 2019, Vol. 47. p. 494-503

Compound (I) was synthesized by the method described in the following reference example. For the compounds used in the synthesis of the reference example compounds for which the synthesis method is not described, commercially available compounds were used. 
(Reference Example 4) Synthesis of amorphous compound (I):
[Chemical formula 2] 2 of

crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanol (5.00 g, 27.4 mmol) Aqueous sodium hydroxide solution (1.0N, 30.2 mL, 30.2 mmol) was added to a solution of -propanol (55 mL) at 0 ° C., and the mixture was stirred at room temperature for 12 hours. 2-Propanol (220 mL) was added to the reaction solution at room temperature, and crude 4- (dimethylamino) piperidine (3.17 g, 24.7 mmol) and DMT-MM (8.35 g, 30.2 mmol) were added at room temperature to react. The liquid was stirred at the same temperature for 3 hours. A 10% aqueous sodium chloride solution and a 1.0N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound (I) (6.98 g) as an amorphous substance.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 (5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz) ), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .
(Reference Example 5) Synthesis of crude 4- (dimethylamino) piperidine:
[Chemical

formula 3] 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (20.1 g, 77.0 mmol) in methanol (154.0 mL) Palladium-carbon (10% wet, 2.01 g) was added thereto, and the mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a crude product of 4- (dimethylamino) piperidine (9.86 g).
(Reference Example 6) Synthesis of crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate:
[Chemical

formula 4] Sodium hydride (55%, 4.36 g, 100 mmol) aqueous solution and tetrahydrofuran (150 mL) To the mixture was added triethylphosphonoacetate (19.1 mL, 95.0 mmol) at 0 ° C. After stirring the reaction solution for 20 minutes, a solution of 1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, 91.0 mmol) in tetrahydrofuran (150 mL) was added at 0 ° C., and then ethanol (30 mL) was added in the same manner. The mixture was added at temperature and stirred at room temperature for 2 hours. A 10% aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform / methanol). After adding methanol (310 mL) to the residue, palladium-carbon (10% wet, 1.40 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (14.2 g) of ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate.
(Reference Example 7) Synthesis of 1-benzyloxycarbonyl-4- (dimethylamino) piperidine:
[Chemical

formula 5] dichloromethane (55.7 mL) of 1-benzyloxycarbonyl-4-oxopiperidine (13.0 g, 55.7 mmol) ) Solution of dimethylamine in tetrahydrofuran (2.0 M, 34.8 mL, 69.7 mmol), acetic acid (0.32 mL, 5.6 mmol) and sodium triacetoxyborohydride (4.8 g, 22.6 mmol). Added at ° C. After stirring the reaction solution at the same temperature for 30 minutes, sodium triacetoxyborohydride (4.8 g, 22.6 mmol) was added at 0 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (8.1 g, 38.2 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The reaction solution was cooled to 0 ° C. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) and then again by flash chromatography (silica gel, chloroform / methanol) to obtain 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (dimethylamino) piperidine. 13.6 g, 51.8 mmol, 93%) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3) δ: 1.34-1.46 (2H, m), 1.78-1.86 (2H, m), 2.28 (6H, s), 2.29-2.34 (1H, m), 2.75-2.85 (2H, m), 4.14-4.28 ( 2H, m), 5.12 (2H, s), 7.29-7.36 (5H, m).
ESI-MS: m / z = 263 (M + H) + .
(Reference Example 8) Synthesis of 1-benzyloxycarbonyl-4-oxopiperidine:
[Chemical

formula 6] Hydrochloride (130 mL) and water (130 mL) of 4-piperidinone hydrochloride monohydrate (10.0 g, 65.1 mmol) Sodium carbonate (13.8 g, 130.2 mmol) and benzyl chloroformate (8.79 mL, 61.8 mmol) were added to the mixed solution with and at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) to give 1-benzyloxycarbonyl-4-oxopiperidine (13.1 g, 56.2 mmol, 86%) as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.42-2.50 (4H, m), 3.78-3.82 (4H, m), 5.18 (2H, s), 7.32-7.38 (5H, m).
(Example 1) Production of A-type crystal of
compound (I): Amorphous compound (6.98 g) of compound (I) prepared in Reference Example 4 is purified and concentrated with chloroform / methanol by silica gel column chromatography. After that, the wall surface of the flask was rubbed with a spartel and mechanical stimulation was applied to obtain A-type crystals of compound (I) as a powder. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT ultima + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) Was done. The results of these measurements are shown in FIGS. 1 and 2.
Diffraction angle 2θ: 5.9, 16.5, 17.7, 20.8, 26.7 °
Endothermic peak: 55 ° C

PATENT

WO2013147160

Example 1 Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one:
[Chemical 27]

(E) )-Methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium-carbon (10% wet, 15 mg) at room temperature In a hydrogen atmosphere, the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) was added to the obtained residue at room temperature to dissolve it, and the mixture was cooled to 0 ° C. An aqueous sodium hydroxide solution (1.0 N, 1.19 mL, 1.19 mmol) was added to the reaction solution at 0 ° C., the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Chloroform (10.0 mL) was added to the obtained residue at room temperature to dissolve it. Add diisopropylethylamine (0.568 mL, 3.25 mmol), HBTU (0.616 g, 1.63 mmol) and 4- (dimethylamino) piperidine (0.125 g, 0.975 mmol) to the reaction solution at room temperature, and add the reaction solution. The mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan- 1-one (0.179 g, 0.68 mmol, 63%) (hereinafter, the compound of Example 1) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .

Publication Number TitlePriority Date Grant Date
WO-2016136944-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
JP-WO2013147160-A1Cyclic amine derivatives and their pharmaceutical use2012-03-29 
TW-201350119-ACyclic amine derivatives and their medical uses2012-03-29 
WO-2013147160-A1Cyclic amine derivative and use thereof for medical purposes2012-03-29 
Publication Number TitlePriority Date Grant Date
RU-2667062-C1Dynamic cyclic amine and pharmaceutical application thereof2015-02-272018-09-14
TW-201639826-ACyclic amine derivatives and their medical uses2015-02-27 
TW-I682927-BCyclic amine derivatives and their medical uses2015-02-272020-01-21
US-10173999-B2Cyclic amine derivative and pharmaceutical use thereof2015-02-272019-01-08
US-2018065950-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
Publication Number TitlePriority Date Grant Date
EP-3263565-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
EP-3263565-B1Cyclic amine derivative and pharmaceutical use thereof2015-02-272019-06-26
ES-2744785-T3Cyclic amine derivative and pharmaceutical use thereof2015-02-272020-02-26
JP-6569671-B2Cyclic amine derivatives and their pharmaceutical use2015-02-272019-09-04
JP-WO2016136944-A1Cyclic amine derivatives and their pharmaceutical use2015-02-27 
Publication Number TitlePriority Date Grant Date
WO-2019189781-A1Agent for inhibiting rise in intraneuronal calcium concentration2018-03-30 
AU-2016224420-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
AU-2016224420-B2Cyclic amine derivative and pharmaceutical use thereof2015-02-272019-08-22
CA-2977614-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
CN-107250128-BCyclic amine derivatives and its medical usage2015-02-272019-07-26

//////////TRK-700, phase 1, neuropathic pain, fibromyalgia, toray

O=C(CCc1nccn1C)N1CCC(CC1)N(C)C

BMS-741672


str1

Figure

SCHEMBL2786493.png

BMS-741672

N-((1R,2S,5R)-5-(Isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide BMS-741672

N-((lR,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6- (trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-l-yl)cyclohexyl)acetamide

N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide;

C25 H33 F3 N6 O2, 506.56
Acetamide, N-[(1R,2S,5R)-5-[methyl(1-methylethyl)amino]-2-[(3S)-2-oxo-3-[[6-(trifluoromethyl)-4-quinazolinyl]amino]-1-pyrrolidinyl]cyclohexyl]-

CAS 1004757-96-3

PHASE 2, , Treatment of Type 2 Diabetes, Agents for Neuropathic Pain

Chemokine CCR2 (MCP-1 Receptor) Antagonists

Image result for Bristol-Myers Squibb

Molecular Formula: C25H33F3N6O2
Molecular Weight: 506.574 g/mol

Image result for bristol myers squibb headquarters

Michael G. Yang, Robert J. Cherney
Original Assignee Bristol-Myers Squibb Company
Michael G. Yang, Robert J. Cherney, Martin G. Eastgate, Jale Muslehiddinoglu, Siva Josyula Prasad, Zili Xiao
Bristol-Myers Squibb Company
  • Originator Bristol-Myers Squibb
  • Class Analgesics; Antihyperglycaemics
  • Mechanism of Action CCR2 receptor antagonists
  • Discontinued Diabetic neuropathies; Type 2 diabetes mellitus

Most Recent Events

  • 10 Apr 2007 Preclinical trials in Inflammation in USA (unspecified route)

BMS-741672, 1 , is a highly selective CCR2 antagonist (IC50 = 1.4 nM) featuring a complex array of four stereocenters. The key synthetic challenge was efficient assembly of the densely functionalized 1,2,4-triaminocyclohexane (TACH) core in a minimum number of linear steps.

Figure

N-((1R,2S,5R)-5-(Isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide BMS-741672

Mp 161.3 °C.

1H NMR (400 MHz, CDCl3) δ 9.50–9.20 (1H), 9.04 (s, 1H), 8.68 (s, 1H), 8.41 (d, J = 7.1 Hz, 1H), 7.87 (s, 1H), 5.04 (dt, J = 1.3, 7.3 Hz, 1H), 4.9 (m, 1H), 4.07 (dt, J = 3.7, 12.9 Hz, 1H), 3.53 (dt, J = 1.4, 9.9 Hz, 1H), 3.44–3.30 (m, 2H), 2.39 (dq, J = 13.6, 8.4 Hz, 1H), 2.26 (m, 1H), 2.21 (s, 3H), 2.17 (q, J = 2.9 Hz, 1H), 2.03–1.91 (m, 5H), 1.71–1.54 (m, 5H), 1.04 (s, br., 6H).

13C NMR (100 MHz, d6-DMSO) δ 171.46, 169.49, 159.62, 156.92, 151.22, 129.28, 128.27 (q, 4JCF = 3 Hz), 125.78 (q, 2JCF = 32 Hz), 124.11 (q, 1JCF = 272 Hz), 121.57 (q, 3JCF = 4 Hz), 114.33, 54.83, 53.54, 52.36, 47.34, 46.94, 43.13, 30.76, 30.24, 26.94, 26.38, 23.28, 20.87, 17.65 (br.), 16.73 (br.).

13C NMR (100 MHz, CDCl3) δ 172.17. 170.73, 159.89, 156.91, 151.16, 128.68, 128.06 (q,4JCF = 3.0 Hz), 127.25 (q, 2JCF = 32 Hz), 123.98 (q, 1JCF = 272 Hz), 121.78 (q, 3JCF = 4 Hz), 115.11, 54.89, 53.21, 52.40, 47.40, 46.98, 43.72, 30.84, 30.70, 29.96, 27.80, 23.55, 19.96, 17.70 (2C).

LCMS (ESI, pos.): 508 (16.8), 507 (66.2), 254 (5.0). HR-ESI(pos)-MS: calcd for C25H34F3N6O2 507.2690 [M + H]+, found 507.2694.

IR (KBr): ν = 3428 (m, br.), 2966 (w), 1686 (s), 1635 (m), 1584 (s), 1540 (m), 1334 (m), 1307 (s), 1164 (m), 1121 (m), 870 (w), 845 (w).

[α]20D−187.9 (c 1.0, CHCl3).

Anal. Calcd for C25H33F3N6O2: C, 59.28; H, 6.57; F, 11.25; N, 16.59. Found: C, 59.21; H, 6.43; F, 11.07; N, 16.53.

Image result for Bristol-Myers Squibb

PATENT

WO 2008014381

http://www.google.ch/patents/WO2008014381A2?cl=en&hl=de

EXAMPLE 1

N-((lR,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6- (trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-l-yl)cyclohexyl)acetamide

Figure imgf000072_0001

[00212] Example 1, Step 1: (IR, 2S, 5R)-tert-Butyl 2-benzyloxycarbonylamino- 7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (89.6 g, 0.24 mol, see: P. H. Carter, et al. PCT application WO 2005/021500) was dissolved in ethyl acetate (1.5 L) and the resulting solution was washed with sat. NaHCCh (2 x 0.45 L) and sat. NaCl (I x 0.45 L). The solution was dried (Na2SO4) and then filtered directly into a 3 -necked 3 L round-bottom flask. The solution was purged with direct nitrogen injection before being charged with 10% Pd/C (13.65 g) under nitrogen atmosphere. The flask was evacuated and back-filled with hydrogen; this was repeated twice more. Hydrogen was bubbled through the solution for 30 min and then the reaction was stirred under 1 atm H2 for 18 h. The flask was evacuated, back-filled with nitrogen, and charged with fresh catalyst (6 g of 10% Pd/C). Hydrogen was bubbled through the solution for 30 min and then the reaction was stirred under 1 atm H2 for 18 h. The flask was evacuated and back-filled with nitrogen. The mixture was filtered through Celite; the filter pad was then washed with ethyl acetate. The filtrate (-1.6 L EtOAc volume) was diluted with acetonitrile (0.3 L) and charged sequentially with Z-N-Cbz- methionine (68 g, 0.24 mol), TBTU (77 g, 0.24 mol), and Ν,Ν-diisopropylethylamine (42 mL, 0.24 mol). The reaction was stirred at room temperature for 4 h, during which time it changed from a suspension to a clear solution. The reaction was quenched with the addition of sat. NH4Cl (0.75 L) and water (0.15 L); the mixture was diluted further with EtOAc (0.75 L). The phases were mixed and separated and the organic phase was washed with sat. Na2Cθ3 (2 x 0.9 L) and sat. NaCl (1 x 0.75 L). The solution was dried (Na2SO4), filtered, and concentrated in vacuo to give (IR,2S,5R)- tert-butyl 2-((5)-2-(benzyloxycarbonylamino)-4-

(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate as an oil, which was taken into the next step without further purification. LC/MS for primary peak: [M-Boc+H]+ = 406.3; [M+Naf = 528.3. 1H-NMR (400 MHz, d4-Me0H): δ 7.36 (m, 5H), 5.11 (s, 2H), 4.32 (m, IH), 4.2 (m, IH), 4.0 (m, IH), 2.5 – 2.7 (m, 3H), 2.25 (m, IH), 2.11 (s, 3H), 2.05 (m, 4H), 1.9 (m, IH), 1.7 (m, 2H), 1.54 (s, 9H). Also present are EtOAc [1.26 (t), 2.03 (s), 4.12 (q)] and N,N,N,N-tetramethylurea [2.83

(S)].

[00213] Example 1, Step 2: A sample of (1^,25,5^)- tert-butyl 2-((5)-2- (benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza- bicyclo[3.2. l]octane-6-carboxylate (0.24 mol assumed; see previous procedure) was dissolved in iodomethane (1,250 g) and stirred for 48 h at room temperature. The reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated in vacuo. This was repeated twice more. The resultant sludge was dissolved in dichloromethane (0.4 L) and poured into a rapidly stirring solution of MTBE (4.0 L). The resultant yellow solids were collected via suction filtration and dried under high vacuum to afford the sulfonium salt (179 g). This material was taken into the next step without further purification. LC/MS for primary peak: [M- Me2S+H]+ = 458.4; [M]+ = 520.4. 1H-NMR (400 MHz, d4-Me0H): δ 7.35 (m, 5H), 5.09 (s, 2H), 4.33 (m, IH), 4.28 (m, IH), 3.98 (m, IH), 3.3 – 3.45 (m, 2H), 2.97 (s, 3H), 2.94 (s, 3H), 2.78 (m, IH), 2.0 – 2.3 (m, 4H), 1.7 (m, 2H), 1.52 (s, 9H). Also present are MTBE [1.18 (s), 3.2 (s)] and traces of N,N,N,N-tetramethylurea [2.81 (s)]. [00214] Example 1, Step 3: All of the sulfonium salt from the previous step (0.24 mol assumed) was dissolved in DMSO (2.0 L). The resultant solution was stirred under nitrogen at room temperature and charged with cesium carbonate (216 g) portionwise. The suspension was stirred at room temperature for 3 h and then filtered to remove the solids. The solution was divided into -0.22 L portions and worked up as follows: the reaction mixture (-0.22 L) was diluted with ethyl acetate (1.5 L) and washed successively with water (3 x 0.5 L) and brine (1 x 0.3 L). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The desired (\R,2S,5R)- tert-bvXyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-l-yl)-7-oxo-6- azabicyclo[3.2.1]octane-6-carboxylate (90.8 g, 83%) was obtained as a microcrystalline foam, free from tetramethyl urea impurity. LC/MS for primary peak: [M-Boc+H]+ = 358.4; [M+Na]+ = 480.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.12 (s, 2H), 4.35 (m, 2H), 4.2 (m, IH), 3.6 (m, IH), 3.3 (m, IH), 2.64 (m, IH), 2.28 – 2.42 (m, 2H), 2.15 (m, IH), 1.7 – 2.0 (m, 5H), 1.55 (s, 9H). If desired, this material can be isolated as a solid by dissolving in MTBE (1 volume), adding to heptane (3.3 volumes), and collecting the resultant precipitate.

[00215] Example 1, Step 4: A stirring solution of (\R,2S,5R)- tert-butyl 2-((S>3- (benzyloxycarbonylamino)-2-oxopyrrolidin-l-yl)-7-oxo-6-azabicyclo[3.2.1]octane-6- carboxylate (108 g, 0.236 mol) in THF (1 L) was charged with lithium hydroxide monohydrate (21.74 g, 0.519 mol). Water (0.3 L) was added slowly, such that the temperature did not exceed 20 0C. The reaction was stirred at room temperature overnight and the volatiles were removed in vacuo. The pH was adjusted to -4 through the addition of IN HCl (450 mL) and NaH2PO4. The resultant white precipitates were collected by filtration and washed with water (2 x 1 L). The solid was dissolved in dichloromethane (1.5 L) and water (~ 1 L). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (0.7 L) and the resultant solution was heated at reflux for 1 h. Solids separated after cooling to RT, and were collected via filtration. These solids were purified by recrystallization in isopropanol to afford the desired (\R,2S,5R)-2-((S)-3- (benzyloxycarbonylamino)-2-oxopyrrolidin-l-yl)-5-(tert- butoxycarbonylamino)cyclohexanecarboxylic acid as a white solid (104.5 g, 93% yield). LC/MS for primary peak: [M-tBu+H]+ = 420.2; [M-Boc+H]+ = 376.2; [M+H]+ = 476.2. 1H-NMR (400 MHz, d4-Me0H): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.35 (m, 2H), 3.71 (m, IH), 3.45 – 3.6 (m, 2H), 2.99 (m, IH), 2.41 (m, IH), 2.15 (m, IH), 2.0 (m, 2H), 1.6 – 1.9 (m, 4H), 1.46 (s, 9H).

[00216] Example 1, Step 5: A 3 L round bottom flask was charged with (lR,25′,5R)-2-((5)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-l-yl)-5-(tert- butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDOHCl (33.5 g, 0.175 mol), 1 -hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCθ3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (lR,2S,5R)-2-((5)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-l-yl)-5-(tert- butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, -100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+ = 375.3; [M+H]+ = 475.4; [M-tBu+H]+ = 419.3. 1H-NMR (400 MHz, Cl4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, IH), 3.6 (m, IH), 3.45 (m, IH), 2.91 (m, IH), 2.38 (m, IH), 2.12 (m, IH), 1.9 – 2.05 (m, 2H), 1.65 – 1.9 (m, 4H), 1.46 (s, 9H).

[00217] Example 1, Step 6: The reaction was run in three equal portions and combined for aqueous workup. A 5 L, 3-necked round bottom flask was charged with (lR,2S,5R)-2-((5)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-l-yl)-5-(tert- butoxycarbonylamino)cyclohexanecarboxamide (25.3 g, 53 mmol), acetonitrile (1.9 L), and 2.6 L of water/ice. The mixture was stirred and cooled to 0 0C. Iodobenzene diacetate (25.77 g, 80 mmol) was added and the reaction was stirred for 2 h; another 0.5 eq of iodobenzene diacetate was added. The reaction was stirred for 9 h (reaction temp < 10 0C). The mixture was charged with 8 eq N,N-diisopropylethylamine and 2 eq acetic anhydride. Over the next thirty minutes, 4 eq N,N-diisopropylethylamine and 2 eq acetic anhydride were added every ten minutes, until the reaction had proceeded to completion (HPLC). The acetonitrile was removed in vacuo; some solid separated from the residue, and this was collected by filtration. The remaining residue was extracted with dichloromethane (3 L, then 1 L). The organic phase was washed sequentially with water, sat. NaHCθ3, and brine. The collected solids were added to the organic phase, along with activated carbon (15 g). The mixture was stirred for 30 minutes at 40 0C before being filtered and concentrated in vacuo. The residue was dissolved in EtOAc (1 L), and the resultant solution was stirred at 75 0C for 1 h before being allowed to cool to room temperature. A solid separated and was collected by filtration. This solid was purified further by recrystallization: it was first dissolved in 0.5 L CH2CI2, then concentrated in vacuo, then re-crystallized from 1 L EtOAc; this was repeated three times. The solids obtained from the mother liquors of the above were recrystallized three times using the same method. The combined solids were recrystallized twice more from acetonitrile (0.7 L) to provide 66 g (84%) of tert-bυXyl (lR,3R,45)-3-acetamido-4-((5)-3-(benzyloxycarbonylamino)-2- oxopyrrolidin-l-yl)cyclohexylcarbamate (purity >99.5% by HPLC). LC/MS for primary peak: [M+H]+ = 489.4; [M-tBu+H]+ = 433.3. 1H-NMR (400 MHz, d4– MeOH): δ 7.3 – 7.4 (m, 5H), 5.11 (s, 2H), 4.35 (m, IH), 4.15 (m, IH), 4.04 (m, IH), 3.8 (m, IH), 3.6 (m, 2H), 2.44 (m, IH), 2.12 (m, IH), 1.87 – 2.05 (m, 4H), 1.87 (s, 3H), 1.55 – 1.7 (m, 2H), 1.46 (s, 9H). The stereochemical fidelity of the Hofmann rearrangement was confirmed through X-ray crystal structure analysis of this compound, as shown in Figure 1. [00218] Example 1, Step 7: A stirring solution of tert-butyl (\R,3R,4S)-3- acetamido-4-((5′)-3 -(benzyloxycarbonylamino)-2-oxopyrrolidin- 1 – yl)cyclohexylcarbamate (66 g, 0.135 mol) in dichloromethane (216 mL) was charged with trifluoroacetic acid (216 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in methanol and the resultant solution was concentrated in vacuo; this was repeated once. Benzyl («S)-l-((l«S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate was obtained as an oil and used directly in Step 8 below. LC/MS found [M + H]+ = 389.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.3 – 7.4 (m, 5H), 5.12 (s, 2H), 4.41 (br. s, IH), 4.15 (m, IH), 4.00 (t, J= 9.3 Hz, IH), 3.81 (t, J= 9.1 Hz, IH), 3.65 (q, J= 8.4 Hz, IH), 3.3 – 3.4 (m, IH), 2.45 (m, IH), 1.95 – 2.24 (m, 5H), 2.00 (s, 3H), 1.6 – 1.8 (m, 2H). [00219] Example 1, Step 8: A stirring solution of benzyl (S)- 1-(( \S,2R,4R)-2- acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (-0.135 mol) in methanol (675 mL) was charged sequentially with acetone (37.8 g, 4 eq), sodium acetate (33.2 g, 3 eq), and sodium cyanoborohydride (16.9 g, 2 eq). The mixture was stirred at room temperature for 6 h and filtered. The filtrate was dissolved in dichloromethane (1 L); this solution was washed with IN NaOH (1 L). The solids collected in the filtration were dissolved in IN NaOH (IL) at 0 0C and then extracted with dichloromethane (1 L). The organic extracts were combined and extracted with aqueous HCl (200 mL IN HCl + 800 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then IN NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-I- ((lS,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3- ylcarbamate as an oil. LC/MS found [M + H]+ = 431.45. 1H-NMR (400 MHz, d4– MeOH): δ 7.3 – 7.4 (m, 5H), 5.12 (s, 2H), 4.31 (m, IH), 4.24 (t, J= 9.4 Hz, IH), 4.11 (m, IH), 3.61 (t, J= 9.1 Hz, IH), 3.52 (q, J= 8.6 Hz, IH), 3.04 (br. s, IH), 2.96 (sep, J= 6.3 Hz, IH), 2.40 (m, IH), 2.15 (m, IH), 1.92 (s, 3H), 1.7 – 1.9 (m, 5H), 1.65 (m, IH), 1.12 (app. dd, J= 6.3, 1.1 Hz, 6H).

[00220] Example 1, Step 9 (See Alternative Step 9, below): A stirring solution of benzyl (S)-I -((lS’,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2- oxopyrrolidin-3-ylcarbamate (-115 mmol) in dichloromethane (600 mL) was cooled to 0 0C and charged sequentially with formaldehyde (18.6 g, 37 wt% solution), triethylamine (23 mL), and sodium triacetoxyborohydride (28.7 g). The mixture was stirred at room temperature for 30 minutes and diluted with dichloromethane (up to 1.2 L). This solution was washed thrice with 500 mL sat. NaHCθ3 + NaOH (sat. NaHCO3, pH to 11 w/ IN NaOH). The organic layer was extracted with aq. HCl (200 mL IN HCl + 600 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then IN NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (1.2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl {S)-\-{{\S,2R,AR)-2- acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil, which was used directly in Step 10 below. LC/MS found [M + H]+ = 445.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.3 – 7.4 (m, 5H), 5.12 (s, 2H), 4.33 (br s, IH), 4.25 (t, J= 9.2 Hz, IH), 4.11 (br s, IH), 3.5 – 3.6 (m, 2H), 2.77 (v br s, 2 H), 2.41 (m, IH), 2.26 (s, 3H), 2.0 – 2.1 (m, 2H), 1.92 (s, 3H), 1.7 – 1.9 (m, 5H), 1.10 (app. dd, J = 17, 6.4 Hz, 6H). [00221] Example 1, Step 10: To a solution of benzyl (S)- 1-(( 15″,2R,4R)-2- acetamido-4-(isopropyl(methyl)amino)-cyclohexyl)-2-oxopyrrolidin-3 -ylcarbamate (-0.115 mol) in methanol (600 mL) was added 10% Pd/C (6 g of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen. The mixture was stirred under 1 atm H2 for 2 h and the catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to provide N-((li?,25,5i?)-2-((S)-3-amino-2- oxopyrrolidin-l-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide as an oil, which was taken on to the next step without further purification. LC/MS found [M + H]+ = 311.47. 1H-NMR (400 MHz, (I4-MeOH): δ 4.39 (br s, IH), 4.00 (m, IH), 3.3 –

3.5 (m, 4H), 2.73 (m, IH), 2.38 (m, IH), 2.25 (s, 3H), 2.0 – 2.2 (m, 3H), 1.94 (s, 3H),

1.6 – 1.75 (m, 4H), 1.07 (app. dd, J= 21, 6.4 Hz, 6H). [00222] Example 1, Step 11: To a solution of N-((lR,25′,5R)-2-((S)-3-amino-2- oxopyrrolidin-l-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (~35 g, 0.115 mol) in isopropanol (600 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (32 g, 0.138 mol, 1.2 eq, see: P.H. Carter et al, PCT application WO 2005/021500). The mixture was stirred at room temperature overnight before being charged with triethylamine (46 g, 0.46 mol, 4 eq). The mixture was stirred at 60 0C for 10 h. The solvent was removed under reduced pressure to give an oil. Azeotropic distillation with isopropanol was performed twice. The residue was dissolved in dichloromethane (600 mL) and extracted with water (250 mL, containing 4 eq acetic acid). Dichloromethane (600 mL) was added to the combined aqueous washes, and the mixture was cooled to 0 0C. Aqueous NaOH (50% by weight) was added with stirring until the pH reached 11. The water layer was extracted with dichloromethane twice (2 x 600 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the amorphous free base of the title compound (99% purity by HPLC). LC/MS found [M+H]+ = 507.3. 1H-NMR (400 MHz, U4– MeOH): δ 8.82 (s, IH), 8.59 (s, IH), 8.05 (dd, J= 8.8, 1.8 Hz, IH), 7.9 (d, J= 8.7 Hz, IH), 5.28 (t, J= 8.6 Hz, IH), 4.58 (br s, IH), 4.06 (m, IH), 3.52 – 3.68 (m, 2H), 3.43 (m, IH), 2.76 (br s, IH), 2.55 (m, IH), 2.28 (s, 3H), 2.1 – 2.3 (m, 3H), 2.0 (s, 3H), 2.0 (m, IH), 1.65 – 1.8 (m, 3H), 1.09 (app. dd, J= 24, 6.4 Hz, 6 H).

Example 1, Alternative Step 9

Figure imgf000079_0001

[00223] Example 1, Alternative step 9a1: To a hydrogenator were charged ethyl (7R,SS)-S-((S)- l-phenyl-ethylamino)-l,4-dioxa-spiro[4.5]decane-7-carboxylate A- toluenesulfonate salt I A (1417 g, 2.8 moles, c.f : WO2004098516, prepared analogous to US Pat.6,835,841), ethanol (200 proof, 11.4 L), and 10% Pd/C catalyst (50% wet, 284 g). The mixture was inerted with nitrogen, then pressurized with hydrogen gas (45 psig) and agitated vigorously at approx. 40 0C until starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was removed by filtration while inerted. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated under vacuum to a volume of 2-3 L while maintaining the batch between 40°-60 0C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ~2 L until most ethanol was removed (<0.5%) and residual moisture content was <l,000 ppm. Batch volume was adjusted to -7.5 L by the addition of isopropyl acetate. The mixture was heated to 80 0C until clear, then cooled 65°-70 0C. Seed crystals of 1 (5 g) were added and the batch was cooled to 500C over 2 hours, then further cooled to 20 0C over 4 hours and held for ~10 hours. The resulting slurry was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vaccum at -35 0C until volatiles were recduced below -1% (LOD). Ethyl (7R,85′)-8-amino-l,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 was obtained as a white, crystalline solid (936 g, 83% yield; HPLC purity: 99.8%). 1H-NMR: (300MHz, CDCl3) 8.14-7.89 (brs, 3H), 7.75 (d, J 9.0Hz, 2H), 7.15 (d, J 8.0Hz, 2H), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, IH,), 3.20-3.13 (m, IH), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0Hz, 3H); HPLC: Waters Xterra MS C18 4.6 mm x 150 mm Ld., 3.5μm particle size, 0.05% NH40H (5% ACN, 95% H2O, solvent A), to 0.05% NH4OH (95% ACN, 5% H2O, solvent B), 5% B to 20% B in 10 minutes, changed to 95% B in 25 minutes, and then changed to 5% B in 1 minute; 11.1 minutes (aminoester 1).

Figure imgf000080_0001

Example 1, Alternative Step 9a”: Aminoester 1 (63g, 0.16M, leq.; the product of reductive deprotection of a known compound – (See e.g. R. J. Cherney, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993) was placed in a round bottom flask and MeCN (50OmL) was added. EDAC (33.1g, 0.17M, l. leq), HOBt-H2O (21.2g, 0.16M, l.Oeq) and N-Cbz-Z-methionine (46.7g, 0.17M, 1.05eq) were then added followed by TEA (48.OmL, 0.35M, 2.2eq). An exotherm to 38 0C was observed. The reaction mass was left to stir at RT. After 30mins, HPLC indicated complete conversion. The reaction mass was diluted with EtOAc (2.5L) and washed with KHCO3 (4x500mL, 20wt% aq. solution) and brine (50OmL). The organic phase was separated, dried over MgSO4 and concentrated. The residue was dissolved in TBME and reconcentrated to give ethyl (7R,85)-8- {(2S)-2-benzyloxycarbonylamino- 4-methylsulfanyl-butyr-yl-amino}-l,4-dioxa-spiro[4.5]decane-7-carboxylate 2 as a sticky semi-solid (76.2g, 98% yield, 93AP purity). 1H-NMR: (300MHz, CDCl3) δ 7.36-7.30 (m, 5H), 7.03 (d, J9.0Hz, IH), 5.66 (d, J 8.0Hz, IH), 5.10 (s, 2H), 4.35- 4.25 (m, 2H), 4.19-4.04 (m, 2H,), 3.98-3.86 (m, 4H), 2.87-2.80 (m, IH), 2.55-2.45 (m, 2H), 2.18 (dd, J 14.0Hz, 7.0Hz, IH), 2.08 (s, 3H), 2.05-1.67 (m, 6H), 1.26 (t, J 7.0Hz, 3H). HPLC: YMC-Pack Pro C18 5μm 4.6 x 150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% lOmin gradient. lO.Olmin (Compound 2, 93.1 AP). HRMS: m/z 495.2166 [CaIc: C24H35N2O7S 495.2165].

Figure imgf000081_0001

2 3 [00224] Example 1, Alternative Step 9b: Methionine amide 2 (75.Og, 0.15M) was dissolved in MeI (225mL, 3mL/g) – some off gassing was noted but no exotherm. The reaction mass was left to stir in the dark for 16.5h. After this time a thick light yellow precipitate had formed. The flask was then evacuated to 200mmHg and some of the MeI removed. The remaining material was slurried in TBME (50OmL), after a 30min stir-out the slurry was filtered, the cake washed with TBME (50OmL). NMR analysis of this material indicated a small amount of MeI remaining. The cake was re-slurried in TBME (50OmL), filtered, washed with TBME (50OmL) and dried under vacuum to give [(35)-3-benzyloxycarbonylamino-3-{(7R,85′)-7- ethoxycarbonyl-l,4-di-oxa-spiro[4.5]dec-8-ylcarbamoyl}-propyl]-dimethylsulfonium iodide 3 as a free flowing off-white solid (93.5g, 97%, 99 area% purity). 1H-NMR: (300MHz, CDCl3) δ 7.75 (d, J 9.0Hz, IH), 7.38-7.27 (m, 5H), 6.40 (d, J 7.0Hz, IH), 5.10 (s, 2H), 4.76-4.65 (m, IH), 4.48-4.39 (m, IH), 4.14-3.85 (m, 6H), 3.84-7.73 (m, IH), 3.68-3.55 (m, IH), 3.21 (s, 3H), 3.12 (s, 3H), 2.90-2.83 (s, IH), 2.52-1.55 (m, 8H), 1.24 (t, J7.0Hz, 3H). HPLC: YMC-Pack Pro C18 5μm 4.6 x 150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% lOmin gradient. 2.45min (I-), 8.14min (Compound 3, 43.6AP, I 54.6AP). HRMS: m/z 509.2341 [CaIc: C25H37N2O7S 509.2321].

Figure imgf000082_0001

[00225] Example 1, Alternative Step 9c: Cs2CO3 (61.5g, 0.19M, 1.5eq) was placed in an round bottom flask and anhydrous DMSO (2.4L) was added. Sulfonium salt 3 (80.Og, 0.13M, 1.Oeq) was then added portionwise. Once the addition was complete the reaction mass was left to stir in the dark for 2Oh. The reaction mass was then split in half and each half worked up separately: the reaction mass was diluted with EtOAc (2.0L) and washed with brine (2L), the organic phase was washed with brine (50OmL). The combined aq. layers were then washed EtOAc (50OmL). The combined organic phases were then washed with brine (3x750mL). The second half of the reaction mass was treated in an identical manner and the combined organics dried over MgSO4 and concentrated to give ethyl (7R,8S)-8-{(3S>3- Benzyloxycarbonylamino-2-oxo-pyrrolidin-l-yl}-l,4-dioxa-spiro[4.5]decane-7- carboxylate 4 as a light colored oil (56.5g, 0.13M, -100 area-% purity) pure by NMR analysis. 1H-NMR: (300MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.37 (br d, J4.0Hz, IH), 5.11 (s, 2H), 4.27-4.18 (m, IH), 4.17-3.82 (m, 8H), 3.32 (td, J 10.0Hz, 60.0Hz, IH), 3.23 (q, J5.0Hz, IH), 2.63-2.57 (m, IH), 2.42-2.25 (m, 2H), 1.94-1.68 (m, 5H), 1.25 (t, J 7.0Hz, 3H). HPLC: YMC-Pack Pro Cl 8 5μm 4.6 x 150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% lOmin gradient. 8.99min (Compound 5, produced on column, 4.2AP), 9.48 (Compound 4, 74.3AP). HRMS: m/z 447.2127 [CaIc: C23H31N2O7 447.2131].

Figure imgf000083_0001

4 5

[00226] Example 1, Alternative Step 9d: Pyrrolidinone 4 (50.Og, 0.1 IM) was dissolved in acetone (50OmL) and IN HCl (50OmL) was added. The reaction mass was then heated to 65°C. After 20mins HPLC indicated complete reaction. The reaction mass was allowed to cool to RT and the acetone was removed on a rotary evaporator. During this distillation the product precipitated from solution as a white solid. This was isolated by filtration and the cake washed with water. The cake was then dried azeotropically with toluene (3x3OOmL) to give ethyl (\R,2S)-2-((3S)-3- Benzyloxycarbonylamino-2-oxo-pyrrolidin-l-yl)-5-oxo-cyclohexanecarboxylate 5 as a white solid (39.8g, 88%, 97 area-% purity). 1H-NMR: (300MHz, CDCl3) δ 7.37- 7.32 (m, 5H), 6.65 (br d, J4.0Hz, IH), 5.12 (s, 2H), 4.54-4.47 (m, IH), 4.34-4.26 (m, IH), 4.18 (dq, J 11.0Hz, 7.0Hz, IH), 4.09 (dq, J 11.0Hz, , 7.0Hz, IH), 3.36-3.20 (m, 3H), 2.70-2.35 (m, 6H), 2.05-1.96 (m, IH), 1.81 (quin., J l l.OHz, IH), 1.24 (t, J 7.0Hz, 3H). HPLC: YMC-Pack Pro C18 5μm 4.6 x 150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% lOmin gradient. 8.95min (Compound 5). HRMS: m/z 403.1864 [CaIc: C2iH27N2O6403.1869].

Figure imgf000083_0002

[00227] Example 1, Alternative Step 9e: Cyclohexanone 5 (22.5g, 0.06M, leq), DMSO (3OmL) and Ti(O-ZPr)4 (33.7mL, 0.1 IM, 2.04eq) were placed in a round bottom flask. N-isopropyl-N-methylamine (11.6mL, 0.1 IM, 2.0eq) was then added in one portion. The mixture was left to stir for 30mins at room temperature before being cooled to <3°C in ice/water. MeOH (3OmL) was then added followed by the portionwise addition OfNaBH4 (4.33g, 0.1 IM, 2.04eq) – temperature kept <8°C. 30mins after the addition was completed the reaction mass was diluted with methylene chloride (30OmL) and then NaOH (IN, 4OmL). The resulting slurry was filtered through Celite, and the cake washed with methylene chloride (10OmL). The resulting liquor was concentrated under reduced pressure and the residue dissolved in EtOAc (50OmL). This solution was extracted with IN HCl (2x400mL), the combined aqueous layers were then basified with Na2CO3. Extraction with EtOAc (4x250mL) provided a clear and colorless organic phase which was dried over Na2SO4 and concentrated to give a white powder (24.6g, 96%, 7: 1 d.r.). This material was then slurried overnight in hexane (67OmL). The solid was isolated by filtration and dried under reduced pressure to give ethyl (lR,25′,5R)-2-((3S)-3-benzyloxycarbonylamino- 2-oxo-pyrrolidin-l-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate 6 as a while solid (20.9g, 81%, 24: 1 d.r.). 1H-NMR: (300MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.55 (d, J4.5, IH), 5.10 (s, 2H), 4.42 (q, J4.5, IH), 4.23-4.12 (m, IH), 4.08 (dq, J 10.5, 7.0, IH), 4.02 (dq, J 10.5, 7.0, IH), 3.84 (t, J9.0, IH), 3.46-3.36 (m, IH), 3.04 (septet, J6.5, IH), 2.86-2.80 (m, IH), 2.63-2.48 (m, 2H), 2.17 (s, 3H, Me), 2.10-1.63 (m, 7H), 1.22 (t, J 7.0, 3H), 1.00 (d, J 6.5, 3H), 0.97 (d, J 6.5, 3H). HPLC: YMC- Pack Pro C18 5μm 4.6 x 150 mm, 0.01M NH4OAc (MeOH:water 20:80) to 0.01M NH4OAc (MeOH:water:MeCN 20:5:75) 10 to 100% 15min gradient. 8.23 (Compound 6), 8.88 (5-e/«-Compound 6). HRMS: 460.2798 [CaIc: C25H38N3O5 460.2811].

Figure imgf000084_0001

[00228] Example 1, Alternative Step 9f: The aminoester 6 (9.76 g, 2.12 mmol) was dissolved in 2N HCl (80 mL), then heated to -55 0C under inert atmosphere. The reaction was stirred for 20 h, then cooled to room temperature. The reaction solution was washed twice with toluene (25 mL portions), neutralized to pH 6 – 7 by the addition of KOH pellets, then extracted eight times with methylene chloride (100 mL portions). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to 50 mL total volume. The concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring. The resulting white slurry was stirred at ambient temperature for Ih, then cooled to 0 0C and stirred for Ih. The product was filtered, and washed twice with methyl tert-butyl ether (25 mL portions). Water from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL). The product was dried under reduced pressure to provide (li?,25r,5R)-2-((35′)-3-Benzyloxycarbonylamino-2- oxo-pyrrolidin-l-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylic acid 7, (7.69 g, 84% yield) as a white foam. 1H-NMR: (400 MHz, 500C, CDCl3) δ 7.44-7.32 (m, 5H), 6.10 (broad s, IH), 5.19 (app s, 2H), 4.42 (dd, J= 15.6, 7.8 Hz, IH), 4.29-4.23 (m, IH), 3.68-3.60 (m, 2H), 3.33-3.27 (m, 2H), 3.20 (broad s, IH), 2.99 (broad s, IH), 2.51 (s, 3H), 2.49-2.45 (m, 3H), 2.33-2.31 (m, IH), 2.00 (ddd, J= 9.0, 8.6, 3.9 IH), 1.95-1.78 (m, 2H), 1.36-1.21 (m, 6H). LCMS: m/z 432.20 [CaIc: C23H34N3O5 432.25].

NHCbz

Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000085_0003

[00229] Example 1, Alternative Step 9g: Amino acid 7 (6.3g, 14.7mmol, l.Oeq) was dissolved in THF (8OmL) under N2 and NaH (584mg, 14.7mmol, l.Oeq, 60wt% dispersion in mineral oil) was added portionwise. When the addition was complete, and the evolution of gas had ceased, the reaction mass was concentrated under reduced pressure and the resulting solid azeotroped with toluene (50 mL) to give a white solid (KF 0.59wt%). This solid was slurried in toluene (100 mL) under N2and heated to 900C. DPPA (3.32 mL, 15.3 mmol, 1.05 eq) was added dropwise over ~2min. After ~5min all the solids had dissolved, after lOmins precipitation of a white solid was observed. After 30mins HPLC analysis indicated complete reaction. The reaction mass was allowed to cool to RT before being filtered, the cake was washed with toluene. The liquors where then slowly added into ACOH/AC2O (80/20, 168mL) solution at 900C. After 45mins HPLC still indicated some isocyanate. At 1.15h , the reaction mass was cooled to RT and diluted with toluene (10OmL) and water (10OmL). The organic layer was removed and the toluene washed with IN HCl

(10OmL). The combined aq. phases were then basified with K2Cθ3(s) and brought to pH 12 with NaOH (10N), keeping the temperature below 200C. The aq layer was then extracted with methylene chloride (4xl50mL), the combined organic layers dried over K2CO3 and concentrated to give benzyl (S)-l-((lS,2R,4R)-2-acetamido-4- (isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate 8 as a white foam (4.5g, 70%, 94AP purity). The 1H-NMR was identical to material obtained from the route described above (Example 1, Step 9). HPLC: YMC-Pack Pro Cl 8 5μm 4.6 x 150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% lOmin gradient. 7.20min (Compound 8), 7.85min (urea dimer). HRMS: 445.2809 [CaIc: C24H37N4O4 445.2815].

Alternative Preparation of Example 1

Figure imgf000086_0001

2 3

[00230] Example 1, Alternative Preparation, Step 1: Ethyl (7R,85)-8-amino- l,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 (450. Ig), was combined with l-ethyl-3-(3-dimethyl-amino-propyl)carbo-diimide hydrochloride (236.3g), 1-hydroxy benzotriazole hydrate (171.9g), N-carbobenzyloxy-Z -methionine (333.4g) and acetonitrile (3.1 L). To the stirred mixture was added triethylamine (249.5g) below 30 0C. Upon reaction completion (HPLC), the mixture was diluted with ethyl acetate (8.2 L) and washed with aqueous 25% potassium bicarbonate solution (2×4.5 L) followed by water (4.5 L). The organic phase was separated and concentrated under reduced pressure to obtain a solution of ethyl (7R,85)-8-((5)-2- benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-l,4-dioxa- spiro[4.5]decane-7-carboxylate 2 (1.4 L). Methyl iodide (2.39 kg) was added, the vessel was shielded from light and the mixture was held under slow agitation for approx. 24 h. To the thick yellow precipitate was added methyl tert-butyl ether (2.7 L) and the mixture was held for approx. 1 h. The product was isolated by filtration and the cake was washed with methyl tert-butyl ether (2×1.4 L), then dried under vacuum, yielding [(5)-3-benzyloxy-carbonylamino-3-((7R,8«S’)-7-ethoxycarbonyl-l,4- dioxa-spiro[4.5]dec-8-ylcarbamoyl)-propyl]-dimethylsulfonium iodide 3 (671.4 g, -94% yield) as an off-white solid (HPLC purity 99.9%).

Figure imgf000087_0001

[00231] Example 1, Alternative Preparation, Step 2: Sulfonium salt 3 (619.4 g), and cesium carbonate (416.8 g) and anhydrous dimethyl sulfoxide (6.2 L) were combined in a reactor equipped with a scrubber to neutralize volatile sulfides.

Vigorous agitation was maintained until complete conversion was obtained (HPLC). Ethyl acetate (12.4 L) was added, followed by 20 % brine (3 L). The organic phase was separated, washed twice with brine (2×3 L) and evaporated to obtain a solution of ethyl (7R,8«S)-8-((«S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-l-yl)-l,4-dioxa- spiro[4.5]decane-7-carboxylate 4 in ethyl acetate (~0.8 L). Acetone (2.55 L) was added, followed by aqueous 0.5 M hydrochloric acid solution (2.3 L). With good mixing, the solution was heated to 50 to 60 0C until conversion of 4 to ethyl (IR,2S)- 2-((5)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-l-yl)-5-oxo- cyclohexanecarboxylate 5 was complete (HPLC). The mixture was concentrated under reduced pressure while below 40 0C, cooled to -30 0C, and water (4.1 L) was added. The resulting slurry was cooled to 5 to 10 0C and agitated for ~1 hour. The product was filtered and the cake was washed with water (2×2.5 L). Upon deliquoring, the cake was dried to a constant weight below 40 0C in a vacuum oven. Cyclohexanone 5 (272g, 70% yield) was obtained (HPLC purity 98.7%).

Figure imgf000088_0001

[00232] Example 1, Alternative Preparation, Step 3: Cyclohexanone 5 (206 g) was dissolved in dichloromethane (1.1 L) and charged to a hydrogenator. Titanium tetraisopropoxide (218.2 g) and N-isopropyl N-methylamine (63.64 g) were added and the mixture was stirred at ambient temperature (23 to 25 0C) for at least 5 h. Platinum catalyst (5% Pt/S/C, 15 g, approx. 7.5 % relative to 5) was added and hydrogenation was performed at -30 psig for at least 6 h, yielding a mixture of ethyl (lR,25′,5R)-2-((5)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-l-yl)-5-(isopropyl- methyl-amino)-cyclohexanecarboxylate 6 and its 5-epz-isomer (-7%). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to approx. -600 mL. Wet ethyl acetate (-3% water, 2.0 L) was added with vigorous agitation over a period of at least 1.5 h. Stirring was continued for at least an additional 6 h. The slurry was filtered. Filter cake was washed with ethyl acetate (1.0 L) and discarded. The combined filtrate and washings were concentrated to -400 mL. Toluene (2.0 L) was added and the solution was washed with 2M aqueous hydrochloric acid (2 x 400 mL). The aqueous layer was warmed to 50° to 60 0C for approx. 20 h or hydrolysis of 6 was deemed complete (HPLC). Aqueous sodium hydroxide solution was added to adjust to pH -10, and mixture was extracted with toluene (3×600 mL). The organic phase was discarded and pH was readjusted to ~6 by addition of aqueous hydrochloric acid. The aqueous phase was concentrated to -600 mL under reduced pressure and extracted with methylene chloride (at least 3×2.0 L). The combined methylene chloride layers were evaporated under reduced pressure and continuously replaced with THF to obtain a solution of (\R,2S,5R)-2- ((5*)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-l-yl)-5-(isopropyl-methyl-amino)- cyclohexane carboxylic acid 7 (-148 g) in THF (-4 L). Seed crystals of 8 were added, followed by 25 % solution of sodium methoxide in methanol (81.24 g) below 25 0C. The slurry was held for at least additional 16h with agitation. The product was isolated by filtration and the cake was washed with THF (4×200 mL) and dried to a constant weight in vacuo below 30 0C. Dry (lR,25′,5R)-2-((5)-3-benzyloxycarbonyl- amino-2-oxo-pyrrolidin-l-yl)-5-(isopropyl-methyl-amino)-cyclohexane-carboxylate sodium salt 8 was obtained (139g, -60% yield from 5).

Figure imgf000089_0001

[00233] Example 1, Alternative Preparation, Step 4: Aminoester sodium salt 8 (10Og), diphenyl phosphate (3.86g), tert-BuOH (1275 mL) and toluene (225 mL) were combined and heated to reflux under reduced pressure. Approx. 500 mL of distillate were collected and discarded while being continuously replaced with a solution of toluene in tert-BuOH. Vacuum was removed and distillate was switched to percolate through a column filled with molecular sieves and allowed to return to the vessel. After drying was complete, DPPA (52.4mL; dissolved in 60 mL toluene) was added slowly to the slurry at 80 0C. Upon complete conversion (HPLC), tert- BuOH was removed by vacuum distillation and continuously replaced with toluene. The mixture was cooled to room temperature and washed twice with 10% aqueous K2HPO4 (lx800mL, 1×400 mL) and water (40OmL). The organic phase was heated and concentrated in vacuo to approx. 27OmL. Vacuum was removed and heptane (1.1 L) was added slowly at approx. 80 0C, followed by seeds of 9 (~lg). The slurry was slowly cooled to room temperature and benzyl {(S)-l-[(lS,2R,4R)-2- tert- butoxycarbonylamino-4-(isopropyl-methyl-amino)-cyclo-hexyl]-2-oxo-pyrrolidin-3- yl} -carbamate 9 was isolated by filtration as a white solid (86.76g, 78% yield).

Figure imgf000090_0001

[00234] Example 1, Alternative Preparation, Step 5: The tert-Butyl carbamate 9 (5Og) was dissolved in Toluene (50OmL) and /-PrOH (15OmL). The resulting solution was then heated to 6O0C. Methanesulfonic acid (19.6mL) was added below 65°C. Upon reaction completion (HPLC), the mixture was cooled to RT and triethylamine (69.4mL) added slowly below 25°C. Acetic anhydride was then added below 25°C. After Ih acetic acid (25OmL) was added below 25°C. The toluene phase was discarded and 2-methyl-THF (50OmL) was added to the aqueous phase. The mixture was stirred vigorously and basified with NaOH (25% aqueous solution) to pH 12. The aqueous phase was discarded and the organic layer was washed with brine (25OmL). The organic layer was concentrated under reduced pressure and continuously replaced with /-PrOH. The solution was cooled and filtered to provide benzyl {(5′)-l-[(15r,2R,4R)-2-acetylamino-4-(isopropyl-methyl-amino)-cyclohexyl]-2- oxo-pyrrolidin-3-yl} -carbamate 10 in /-PrOH solution which was used directly in the hydrogenation.

[00235] Example 1, Alternative Preparation, Step 6: To a solution containing acetamide 10 (~61g) in /-PrOH (-625 mL) was added 10% Pd/C wet catalyst (2.5 g) and the suspension was hydrogenated at 30 psig and approx. 25 0C for at least 2 h. Upon completion (HPLC), the catalyst was removed by filtration and the filtrate was concentrated to approx. 550 mL. Water (8.8 mL) was added, followed by 5.6 N hydrochloric acid in /-PrOH solution (69.5 mL). The resulting slurry was held at room temperature overnight. The product was isolated by filtration and the cake was rinsed with /-PrOH (2×100 mL) and dried in vacuo to constant weight at -50 0C to give N-[(li?,25r,5R)-2-((5′)-3-amino-2-oxo-pyrrolidin-l-yl)-5-(isopropyl-methyl- amino)-cyclohexyl]-acetamide 11 (55.6 g, 97% yield) as its hydrochloric acid salt (73.6% free base assay, HPLC).

NH,

CL,

Example 1

Figure imgf000091_0001

[00236] Example 1, Alternative Preparation, Step 7: To 6-trifluoromethyl- quinazolin-4-ol 12 (20.1 g) in MeCN (400 mL) was added 5.5 M solution of sodium methoxide in methanol (17.0 mL). The resulting suspension was distilled under reduced pressure and continuously replaced by MeCN to remove methanol. To the slurry was added DMF (1.4 g), followed by oxalyl chloride (13.0 mL) below 50 0C. Upon reaction completion (HPLC), excess reagent was removed under reduced pressure to give -400 mL of slurry. The mixture was cooled to room temperature and washed with 10 % aqueous K2HPO4 (lxl.O L, 1×0.5 L) to afford 4-chloro-6- trifluoromethyl-quinazoline 13 (-21.2 g) in approx. 450 mL of wet MeCN solution, which was used directly in the subsequent coupling reaction (HPLC purity 99.8 %). [00237] Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl- N-ethylamine (61 mL) at room temperature was added a solution of 13 (-21.2 g) in MeCN (-450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert- butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH >11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-bvAyl ether (-250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60 0C, followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((lR,25′,5R)-5- (isopropylamino)-2-((5′)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4- ylamino)pyrrolidin-l-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).

Crystallization Procedures for Example 1

[00238] Example 1, Production of bis-BSA salt and purification: The entirety of the amorphous free base from Example 1, Step 11 was dissolved in methanol (600 mL). The resultant solution was heated at 60 0C and charged with benzenesulfonic acid (2.5 eq). The mixture was cooled to room temperature and the resultant white solid was collected by filtration to yield the bis-benzene sulfonic acid salt of the title compound (95 g, 86%). This material was >99% pure by HPLC. This material was further purified by re-crystallization from 80/20 EtOH/H2θ, which provided the salt free from any residual methanol. HPLC purity = 99.8%. 1H ΝMR (500 MHz, D2O) δ ppm 8.75 (1 H, s), 8.66 (1 H, s), 8.25 (1 H, d, J=8.80 Hz), 7.90 (1 H, d, J=8.80 Hz), 7.75 (4 H, d, J=8.25 Hz), 7.43 – 7.57 (6 H, m), 5.42 (1 H, t), 4.33 – 4.44 (1 H, m), 4.09 – 4.19 (1 H, m), 3.83 – 3.91 (1 H, m), 3.74 – 3.83 (2 H, m), 3.61 (1 H, t, J=I 1.55 Hz), 2.75 (3 H, d, J=6.60 Hz), 2.61 – 2.70 (1 H, m), 2.31 – 2.44 (1 H, m), 2.20 – 2.27 (1 H, m), 2.17 (2 H, d, J=12.10 Hz), 1.94 – 2.04 (1 H, m, J=12.65 Hz), 1.90 – 1.95 (3 H, m), 1.72 – 1.91 (2 H, m), 1.37 (3 H, d, J=6.05 Hz), 1.29 (3 H, d, J=6.60 Hz). Differential scanning calorimetry utilized a heating rate of 10 °C/min and revealed a melting / decomposition endotherm with an onset temperature of 297.6 0C and a peak temperature at 299.1 0C. [00239] Example 1, Crystallization of the Free Base: A sample of the amorphous free base of N-((lR,25r,5R)-5-(isopropyl(methyl)amino)-2-((5′)-2-oxo-3- (6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin- 1 -yl)cyclohexyl)acetamide ( 1 g) was dissolved in dichloromethane (5 mL). The solution was charged with heptane (30 mL) and then warmed to distill the dichloromethane. The solution was cooled to 40 0C; a white solid precipitated. The suspension was heated to 90 0C and stirred for 2 h. The suspension was cooled to room temperature and filtered to provide the pure free base of the title compound. No residual solvent was apparent by 1H-NMR.

Image result for bristol myers squibb

PATENT

US 7671062

http://google.com/patents/US7671062

The present invention provides a novel antagonist or partial agonists/antagonists of MCP-1 receptor activity: N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide,
Figure US07671062-20100302-C00001

or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having an unexpected combination of desirable pharmacological characteristics. Crystalline forms of the present invention are also provided. Pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases is also an objective of this invention. The present disclosure also provides a process for preparing compounds of Formula (I), including N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide:

Figure US07671062-20100302-C00002

wherein R1, R8, R9, R10, and

Figure US07671062-20100302-C00003

are as described herein. Compounds that are useful intermediates of the process are also provided herein.

1st embodiment, the disclosure provides a process for preparing a compound of formula IV, or a salt thereof:

Figure US07671062-20100302-C00010

Example 1 N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide

Figure US07671062-20100302-C00060

Example 1, Step 1: (1R,2S,5R)-tert-Butyl 2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (89.6 g, 0.24 mol, see: P. H. Carter, et al. PCT application WO 2005/021500) was dissolved in ethyl acetate (1.5 L) and the resulting solution was washed with sat. NaHCO3 (2×0.45 L) and sat. NaCl (1×0.45 L). The solution was dried (Na2SO4) and then filtered directly into a 3-necked 3 L round-bottom flask. The solution was purged with direct nitrogen injection before being charged with 10% Pd/C (13.65 g) under nitrogen atmosphere. The flask was evacuated and back-filled with hydrogen; this was repeated twice more. Hydrogen was bubbled through the solution for 30 min and then the reaction was stirred under 1 atm H2 for 18 h. The flask was evacuated, back-filled with nitrogen, and charged with fresh catalyst (6 g of 10% Pd/C). Hydrogen was bubbled through the solution for 30 min and then the reaction was stirred under 1 atm H2 for 18 h. The flask was evacuated and back-filled with nitrogen. The mixture was filtered through Celite; the filter pad was then washed with ethyl acetate. The filtrate (˜1.6 L EtOAc volume) was diluted with acetonitrile (0.3 L) and charged sequentially with L-N-Cbz-methionine (68 g, 0.24 mol), TBTU (77 g, 0.24 mol), and N,N-diisopropylethylamine (42 mL, 0.24 mol). The reaction was stirred at room temperature for 4 h, during which time it changed from a suspension to a clear solution. The reaction was quenched with the addition of sat. NH4Cl (0.75 L) and water (0.15 L); the mixture was diluted further with EtOAc (0.75 L). The phases were mixed and separated and the organic phase was washed with sat. Na2CO3 (2×0.9 L) and sat. NaCl (1×0.75 L). The solution was dried (Na2SO4), filtered, and concentrated in vacuo to give (1R,2S,5R)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate as an oil, which was taken into the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=406.3; [M+Na]+=528.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.36 (m, 5H), 5.11 (s, 2H), 4.32 (m, 1H), 4.2 (m, 1H), 4.0 (m, 1H), 2.5-2.7 (m, 3H), 2.25 (m, 1H), 2.11 (s, 3H), 2.05 (m, 4H), 1.9 (m, 1H), 1.7 (m, 2H), 1.54 (s, 9H). Also present are EtOAc [1.26 (t), 2.03 (s), 4.12 (q)] and N,N,N,N-tetramethylurea [2.83 (s)].

Example 1, Step 2: A sample of (1R,2S,5R)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (0.24 mol assumed; see previous procedure) was dissolved in iodomethane (1,250 g) and stirred for 48 h at room temperature. The reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated in vacuo. This was repeated twice more. The resultant sludge was dissolved in dichloromethane (0.4 L) and poured into a rapidly stirring solution of MTBE (4.0 L). The resultant yellow solids were collected via suction filtration and dried under high vacuum to afford the sulfonium salt (179 g). This material was taken into the next step without further purification. LC/MS for primary peak: [M-Me2S+H]+=458.4; [M]+=520.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.09 (s, 2H), 4.33 (m, 1H), 4.28 (m, 1H), 3.98 (m, 1H), 3.3-3.45 (m, 2H), 2.97 (s, 3H), 2.94 (s, 3H), 2.78 (m, 1H), 2.0-2.3 (m, 4H), 1.7 (m, 2H), 1.52 (s, 9H). Also present are MTBE [1.18 (s), 3.2 (s)] and traces of N,N,N,N-tetramethylurea [2.81 (s)].

Example 1, Step 3: All of the sulfonium salt from the previous step (0.24 mol assumed) was dissolved in DMSO (2.0 L). The resultant solution was stirred under nitrogen at room temperature and charged with cesium carbonate (216 g) portionwise. The suspension was stirred at room temperature for 3 h and then filtered to remove the solids. The solution was divided into ˜0.22 L portions and worked up as follows: the reaction mixture (˜0.22 L) was diluted with ethyl acetate (1.5 L) and washed successively with water (3×0.5 L) and brine (1×0.3 L). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The desired (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (90.8 g, 83%) was obtained as a microcrystalline foam, free from tetramethyl urea impurity. LC/MS for primary peak: [M-Boc+H]+=358.4; [M+Na]+=480.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.12 (s, 2H), 4.35 (m, 2H), 4.2 (m, 1H), 3.6 (m, 1H), 3.3 (m, 1H), 2.64 (m, 1H), 2.28-2.42 (m, 2H), 2.15 (m, 1H), 1.7-2.0 (m, 5H), 1.55 (s, 9H). If desired, this material can be isolated as a solid by dissolving in MTBE (1 volume), adding to heptane (3.3 volumes), and collecting the resultant precipitate.

Example 1, Step 4: A stirring solution of (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (108 g, 0.236 mol) in THF (1 L) was charged with lithium hydroxide monohydrate (21.74 g, 0.519 mol). Water (0.3 L) was added slowly, such that the temperature did not exceed 20° C. The reaction was stirred at room temperature overnight and the volatiles were removed in vacuo. The pH was adjusted to ˜4 through the addition of 1N HCl (450 mL) and NaH2PO4. The resultant white precipitates were collected by filtration and washed with water (2×1 L). The solid was dissolved in dichloromethane (1.5 L) and water (˜1 L). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (0.7 L) and the resultant solution was heated at reflux for 1 h. Solids separated after cooling to RT, and were collected via filtration. These solids were purified by recrystallization in isopropanol to afford the desired (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as a white solid (104.5 g, 93% yield). LC/MS for primary peak: [M-tBu+H]+=420.2; [M-Boc+H]+=376.2; [M+H]+=476.2. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.35 (m, 2H), 3.71 (m, 1H), 3.45-3.6 (m, 2H), 2.99 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 2.0 (m, 2H), 1.6-1.9 (m, 4H), 1.46 (s, 9H).

Example 1, Step 5: A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC.HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M+H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).

Example 1, Step 6: The reaction was run in three equal portions and combined for aqueous workup. A 5 L, 3-necked round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide (25.3 g, 53 mmol), acetonitrile (1.9 L), and 2.6 L of water/ice. The mixture was stirred and cooled to 0° C. Iodobenzene diacetate (25.77 g, 80 mmol) was added and the reaction was stirred for 2 h; another 0.5 eq of iodobenzene diacetate was added. The reaction was stirred for 9 h (reaction temp<10° C.). The mixture was charged with 8 eq N,N-diisopropylethylamine and 2 eq acetic anhydride. Over the next thirty minutes, 4 eq N,N-diisopropylethylamine and 2 eq acetic anhydride were added every ten minutes, until the reaction had proceeded to completion (HPLC). The acetonitrile was removed in vacuo; some solid separated from the residue, and this was collected by filtration. The remaining residue was extracted with dichloromethane (3 L, then 1 L). The organic phase was washed sequentially with water, sat. NaHCO3, and brine. The collected solids were added to the organic phase, along with activated carbon (15 g). The mixture was stirred for 30 minutes at 40° C. before being filtered and concentrated in vacuo. The residue was dissolved in EtOAc (1 L), and the resultant solution was stirred at 75° C. for 1 h before being allowed to cool to room temperature. A solid separated and was collected by filtration. This solid was purified further by recrystallization: it was first dissolved in 0.5 L CH2Cl2, then concentrated in vacuo, then re-crystallized from 1 L EtOAc; this was repeated three times. The solids obtained from the mother liquors of the above were recrystallized three times using the same method. The combined solids were recrystallized twice more from acetonitrile (0.7 L) to provide 66 g (84%) of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (purity>99.5% by HPLC). LC/MS for primary peak: [M+H]+=489.4; [M-tBu+H]+=433.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.11 (s, 2H), 4.35 (m, 1H), 4.15 (m, 1H), 4.04 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 2.44 (m, 1H), 2.12 (m, 1H), 1.87-2.05 (m, 4H), 1.87 (s, 3H), 1.55-1.7 (m, 2H), 1.46 (s, 9H). The stereochemical fidelity of the Hofmann rearrangement was confirmed through X-ray crystal structure analysis of this compound, as shown in FIG. 1.

Example 1, Step 7: A stirring solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (66 g, 0.135 mol) in dichloromethane (216 mL) was charged with trifluoroacetic acid (216 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in methanol and the resultant solution was concentrated in vacuo; this was repeated once. Benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate was obtained as an oil and used directly in Step 8 below. LC/MS found [M+H]+=389.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.41 (br. s, 1H), 4.15 (m, 1H), 4.00 (t, J=9.3 Hz, 1H), 3.81 (t, J=9.1 Hz, 1H), 3.65 (q, J=8.4 Hz, 1H), 3.3-3.4 (m, 1H), 2.45 (m, 1H), 1.95-2.24 (m, 5H), 2.00 (s, 3H), 1.6-1.8 (m, 2H).

Example 1, Step 8: A stirring solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (˜0.135 mol) in methanol (675 mL) was charged sequentially with acetone (37.8 g, 4 eq), sodium acetate (33.2 g, 3 eq), and sodium cyanoborohydride (16.9 g, 2 eq). The mixture was stirred at room temperature for 6 h and filtered. The filtrate was dissolved in dichloromethane (1 L); this solution was washed with 1N NaOH (1 L). The solids collected in the filtration were dissolved in 1N NaOH (1 L) at 0° C. and then extracted with dichloromethane (1 L). The organic extracts were combined and extracted with aqueous HCl (200 mL 1N HCl+800 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then 1N NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil. LC/MS found [M+H]+=431.45. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.31 (m, 1H), 4.24 (t, J=9.4 Hz, 1H), 4.11 (m, 1H), 3.61 (t, J=9.1 Hz, 1H), 3.52 (q, J=8.6 Hz, 1H), 3.04 (br. s, 1H), 2.96 (sep, J=6.3 Hz, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.92 (s, 3H), 1.7-1.9 (m, 5H), 1.65 (m, 1H), 1.12 (app. dd, J=6.3, 1.1 Hz, 6H).

Example 1, Step 9 (See Alternative Step 9, below): A stirring solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (˜115 mmol) in dichloromethane (600 mL) was cooled to 0° C. and charged sequentially with formaldehyde (18.6 g, 37 wt % solution), triethylamine (23 mL), and sodium triacetoxyborohydride (28.7 g). The mixture was stirred at room temperature for 30 minutes and diluted with dichloromethane (up to 1.2 L). This solution was washed thrice with 500 mL sat. NaHCO3+NaOH (sat. NaHCO3, pH to 11 w/1N NaOH). The organic layer was extracted with aq. HCl (200 mL 1N HCl+600 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then 1N NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (1.2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil, which was used directly in Step 10 below. LC/MS found [M+H]+=445.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.33 (br s, 1H), 4.25 (t, J=9.2 Hz, 1H), 4.11 (br s, 1H), 3.5-3.6 (m, 2H), 2.77 (v br s, 2H), 2.41 (m, 1H), 2.26 (s, 3H), 2.0-2.1 (m, 2H), 1.92 (s, 3H), 1.7-1.9 (m, 5H), 1.10 (app. dd, J=17, 6.4 Hz, 6H).

Example 1, Step 10: To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)-cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.115 mol) in methanol (600 mL) was added 10% Pd/C (6 g of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen. The mixture was stirred under 1 atm H2 for 2 h and the catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to provide N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide as an oil, which was taken on to the next step without further purification. LC/MS found [M+H]+=311.47. 1H-NMR (400 MHz, d4-MeOH): δ 4.39 (br s, 1H), 4.00 (m, 1H), 3.3-3.5 (m, 4H), 2.73 (m, 1H), 2.38 (m, 1H), 2.25 (s, 3H), 2.0-2.2 (m, 3H), 1.94 (s, 3H), 1.6-1.75 (m, 4H), 1.07 (app. dd, J=21, 6.4 Hz, 6H).

Example 1, Step 11: To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (˜35 g, 0.115 mol) in isopropanol (600 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (32 g, 0.138 mol, 1.2 eq, see: P. H. Carter et al., PCT application WO 2005/021500). The mixture was stirred at room temperature overnight before being charged with triethylamine (46 g, 0.46 mol, 4 eq). The mixture was stirred at 60° C. for 10 h. The solvent was removed under reduced pressure to give an oil. Azeotropic distillation with isopropanol was performed twice. The residue was dissolved in dichloromethane (600 mL) and extracted with water (250 mL, containing 4 eq acetic acid). Dichloromethane (600 mL) was added to the combined aqueous washes, and the mixture was cooled to 0° C. Aqueous NaOH (50% by weight) was added with stirring until the pH reached 11. The water layer was extracted with dichloromethane twice (2×600 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the amorphous free base of the title compound (99% purity by HPLC). LC/MS found [M+H]+=507.3. 1H-NMR (400 MHz, d4-MeOH): δ 8.82 (s, 1H), 8.59 (s, 1H), 8.05 (dd, J=8.8, 1.8 Hz, 1H), 7.9 (d, J=8.7 Hz, 1H), 5.28 (t, J=8.6 Hz, 1H), 4.58 (br s, 1H), 4.06 (m, 1H), 3.52-3.68 (m, 2H), 3.43 (m, 1H), 2.76 (br s, 1H), 2.55 (m, 1H), 2.28 (s, 3H), 2.1-2.3 (m, 3H), 2.0 (s, 3H), 2.0 (m, 1H), 1.65-1.8 (m, 3H), 1.09 (app. dd, J=24, 6.4 Hz, 6 H).

Example 1 Alternative Step 9

Figure US07671062-20100302-C00061

Example 1, Alternative step 9ai: To a hydrogenator were charged ethyl (7R,8S)-8-((S)-1-phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1A (1417 g, 2.8 moles, c.f.: WO2004098516, prepared analogous to U.S. Pat. No. 6,835,841), ethanol (200 proof, 11.4 L), and 10% Pd/C catalyst (50% wet, 284 g). The mixture was inerted with nitrogen, then pressurized with hydrogen gas (45 psig) and agitated vigorously at approx. 40° C. until starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was removed by filtration while inerted. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated under vacuum to a volume of 2-3 L while maintaining the batch between 40°-60° C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ˜2 L until most ethanol was removed (<0.5%) and residual moisture content was <1,000 ppm. Batch volume was adjusted to ˜7.5 L by the addition of isopropyl acetate. The mixture was heated to 80° C. until clear, then cooled 65°-70° C. Seed crystals of 1 (5 g) were added and the batch was cooled to 50° C. over 2 hours, then further cooled to 20° C. over 4 hours and held for ˜10 hours. The resulting slurry was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vaccum at ˜35° C. until volatiles were reduced below ˜1% (LOD). Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 was obtained as a white, crystalline solid (936 g, 83% yield; HPLC purity: 99.8%). 1H-NMR: (300 MHz, CDCl3) 8.14-7.89 (brs, 3H), 7.75 (d, J 9.0 Hz, 2H), 7.15 (d, J 8.0 Hz, 2H), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, 1H,), 3.20-3.13 (m, 1H), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0 Hz, 3H); HPLC: Waters Xterra MS C18 4.6 mm×150 mm i.d., 3.5 μm particle size, 0.05% NH4OH (5% ACN, 95% H2O, solvent A), to 0.05% NH4OH (95% ACN, 5% H2O, solvent B), 5% B to 20% B in 10 minutes, changed to 95% B in 25 minutes, and then changed to 5% B in 1 minute; 11.1 minutes (aminoester 1).

Figure US07671062-20100302-C00062

Example 1, Alternative Step 9aii: Aminoester 1 (63 g, 0.16M, 1 eq.; the product of reductive deprotection of a known compound—(See e.g. R. J. Cherney, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993) was placed in a round bottom flask and MeCN (500 mL) was added. EDAC (33.1 g, 0.17M, 1.1 eq), HOBt.H2O (21.2 g, 0.16M, 1.0 eq) and N-Cbz-L-methionine (46.7 g, 0.17M, 1.05 eq) were then added followed by TEA (48.0 mL, 0.35M, 2.2 eq). An exotherm to 38° C. was observed. The reaction mass was left to stir at RT. After 30 mins, HPLC indicated complete conversion. The reaction mass was diluted with EtOAc (2.5 L) and washed with KHCO3 (4×500 mL, 20 wt % aq. solution) and brine (500 mL). The organic phase was separated, dried over MgSO4 and concentrated. The residue was dissolved in TBME and reconcentrated to give ethyl (7R,8S)-8-{(2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyr-yl-amino}-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 as a sticky semi-solid (76.2 g, 98% yield, 93 AP purity). 1H-NMR: (300 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 7.03 (d, J 9.0 Hz, 1H), 5.66 (d, J 8.0 Hz, 1H), 5.10 (s, 2H), 4.35-4.25 (m, 2H), 4.19-4.04 (m, 2H,), 3.98-3.86 (m, 4H), 2.87-2.80 (m, 1H), 2.55-2.45 (m, 2H), 2.18 (dd, J 14.0 Hz, 7.0 Hz, 1H), 2.08 (s, 3H), 2.05-1.67 (m, 6H), 1.26 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 10.01 min (Compound 2, 93.1 AP). HRMS: m/z 495.2166 [Calc: C24H35N2O7S 495.2165].

Figure US07671062-20100302-C00063

Example 1, Alternative Step 9b: Methionine amide 2 (75.0 g, 0.15M) was dissolved in MeI (225 mL, 3 mL/g)—some off gassing was noted but no exotherm. The reaction mass was left to stir in the dark for 16.5 h. After this time a thick light yellow precipitate had formed. The flask was then evacuated to 200 mmHg and some of the MeI removed. The remaining material was slurried in TBMF (500 mL), after a 30 min stir-out the slurry was filtered, the cake washed with TBMF (500 mL). NMR analysis of this material indicated a small amount of MeI remaining. The cake was re-slurried in TBMF (500 mL), filtered, washed with TBMF (500 mL) and dried under vacuum to give [(3S)-3-benzyloxycarbonylamino-3-{(7R,8S)-7-ethoxycarbonyl-1,4-di-oxa-spiro[4.5]dec-8-ylcarbamoyl}-propyl]-dimethylsulfonium iodide 3 as a free flowing off-white solid (93.5 g, 97%, 99 area % purity). 1H-NMR: (300 MHz, CDCl3) δ 7.75 (d, J 9.0 Hz, 1H), 7.38-7.27 (m, 5H), 6.40 (d, J 7.0 Hz, 1H), 5.10 (s, 2H), 4.76-4.65 (m, 1H), 4.48-4.39 (m, 1H), 4.14-3.85 (m, 6H), 3.84-7.73 (m, 1H), 3.68-3.55 (m, 1H), 3.21 (s, 3H), 3.12 (s, 3H), 2.90-2.83 (s, 1H), 2.52-1.55 (m, 8H), 1.24 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 2.45 min (I−), 8.14 min (Compound 3, 43.6 AP, I54.6 AP). HRMS: m/z 509.2341 [Calc: C25H37N2O7S 509.2321].

Figure US07671062-20100302-C00064

Example 1, Alternative Step 9c: Cs2CO3 (61.5 g, 0.19M, 1.5 eq) was placed in an round bottom flask and anhydrous DMSO (2.4 L) was added. Sulfonium salt 3 (80.0 g, 0.13M, 1.0 eq) was then added portionwise. Once the addition was complete the reaction mass was left to stir in the dark for 20 h. The reaction mass was then split in half and each half worked up separately: the reaction mass was diluted with EtOAc (2.0 L) and washed with brine (2 L), the organic phase was washed with brine (500 mL). The combined aq. layers were then washed EtOAc (500 mL). The combined organic phases were then washed with brine (3×750 mL). The second half of the reaction mass was treated in an identical manner and the combined organics dried over MgSO4 and concentrated to give ethyl (7R,8S)-8-{(3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl}-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4 as a light colored oil (56.5 g, 0.13M, ˜100 area-% purity) pure by NMR analysis. 1H-NMR: (300 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.37 (br d, J 4.0 Hz, 1H), 5.11 (s, 2H), 4.27-4.18 (m, 1H), 4.17-3.82 (m, 8H), 3.32 (td, J 10.0Hz, 60.0 Hz, 1H), 3.23 (q, J 5.0 Hz, 1H), 2.63-2.57 (m, 1H), 2.42-2.25 (m, 2H), 1.94-1.68 (m, 5H), 1.25 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 8.99 min (Compound 5, produced on column, 4.2 AP), 9.48 (Compound 4, 74.3 AP). HRMS: m/z 447.2127 [Calc: C23H31N2O7 447.2131].

Figure US07671062-20100302-C00065

Example 1, Alternative Step 9d: Pyrrolidinone 4 (50.0 g, 0.11M) was dissolved in acetone (500 mL) and 1N HCl (500 mL) was added. The reaction mass was then heated to 65° C. After 20 mins HPLC indicated complete reaction. The reaction mass was allowed to cool to RT and the acetone was removed on a rotary evaporator. During this distillation the product precipitated from solution as a white solid. This was isolated by filtration and the cake washed with water. The cake was then dried azeotropically with toluene (3×300 mL) to give ethyl (1R,2S)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-oxo-cyclohexanecarboxylate 5 as a white solid (39.8 g, 88%, 97 area-% purity). 1H-NMR: (300 MHz, CDCl3) δ 7.37-7.32 (m, 5H), 6.65 (br d, J 4.0 Hz, 1H), 5.12 (s, 2H), 4.54-4.47 (m, 1H), 4.34-4.26 (m, 1H), 4.18 (dq, J 11.0 Hz, 7.0 Hz, 1H), 4.09 (dq, J 11.0 Hz, 7.0 Hz, 1H), 3.36-3.20 (m, 3H), 2.70-2.35 (m, 6H), 2.05-1.96 (m, 1H), 1.81 (quin., J 11.0 Hz, 1H), 1.24 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 8.95 min (Compound 5). HRMS: m/z 403.1864 [Calc: C21H27N2O6403.1869].

Figure US07671062-20100302-C00066

Example 1, Alternative Step 9e: Cyclohexanone 5 (22.5 g, 0.06M, 1 eq), DMSO (30 mL) and Ti(O-iPr)4 (33.7 mL, 0.11M, 2.04 eq) were placed in a round bottom flask. N-isopropyl-N-methylamine (11.6 mL, 0.11M, 2.0 eq) was then added in one portion. The mixture was left to stir for 30 mins at room temperature before being cooled to <3° C. in ice/water. MeOH (30 mL) was then added followed by the portionwise addition of NaBH4 (4.33 g, 0.11M, 2.04 eq)—temperature kept <8° C. 30 mins after the addition was completed the reaction mass was diluted with methylene chloride (300 mL) and then NaOH (1N, 40 mL). The resulting slurry was filtered through Celite, and the cake washed with methylene chloride (100 mL). The resulting liquor was concentrated under reduced pressure and the residue dissolved in EtOAc (500 mL). This solution was extracted with 1N HCl (2×400 mL), the combined aqueous layers were then basified with Na2CO3. Extraction with EtOAc (4×250 mL) provided a clear and colorless organic phase which was dried over Na2SO4 and concentrated to give a white powder (24.6 g, 96%, 7:1 d.r.). This material was then slurried overnight in hexane (670 mL). The solid was isolated by filtration and dried under reduced pressure to give ethyl (1R,2S,5R)-2-((3S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate 6 as a while solid (20.9 g, 81%, 24:1 d.r.). 1H-NMR: (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.55 (d, J 4.5, 1H), 5.10 (s, 2H), 4.42 (q, J 4.5, 1H), 4.23-4.12 (m, 1H), 4.08 (dq, J 10.5, 7.0, 1H), 4.02 (dq, J 10.5, 7.0, 1H), 3.84 (t, J 9.0, 1H), 3.46-3.36 (m, 1H), 3.04 (septet, J 6.5, 1H), 2.86-2.80 (m, 1H), 2.63-2.48 (m, 2H), 2.17 (s, 3H, Me), 2.10-1.63 (m, 7H), 1.22 (t, J 7.0, 3H), 1.00 (d, J 6.5, 3H), 0.97 (d, J 6.5, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.01M NH4OAc (MeOH:water 20:80) to 0.01M NH4OAc (MeOH:water:MeCN 20:5:75) 10 to 100% 15 min gradient. 8.23 (Compound 6), 8.88 (5-epi-Compound 6). HRMS: 460.2798 [Calc: C25H38N3O5 460.2811].

Figure US07671062-20100302-C00067

Example 1, Alternative Step 9f: The aminoester 6 (9.76 g, 2.12 mmol) was dissolved in 2N HCl (80 mL), then heated to ˜55° C. under inert atmosphere. The reaction was stirred for 20 h, then cooled to room temperature. The reaction solution was washed twice with toluene (25 mL portions), neutralized to pH 6-7 by the addition of KOH pellets, then extracted eight times with methylene chloride (100 mL portions). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to 50 mL total volume. The concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring. The resulting white slurry was stirred at ambient temperature for Ih, then cooled to 0° C. and stirred for 1 h. The product was filtered, and washed twice with methyl tert-butyl ether (25 mL portions). Water from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL). The product was dried under reduced pressure to provide (1R,2S,5R)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylic acid 7, (7.69 g, 84% yield) as a white foam. 1H-NMR: (400 MHz, 50° C., CDCl3) δ 7.44-7.32 (m, 5H), 6.10 (broad s, 1H), 5.19 (app s, 2H), 4.42 (dd, J=15.6, 7.8 Hz, 1H), 4.29-4.23 (m, 1H), 3.68-3.60 (m, 2H), 3.33-3.27 (m, 2H), 3.20 (broad s, 1H), 2.99 (broad s, 1H), 2.51 (s, 3H), 2.49-2.45 (m, 3H), 2.33-2.31 (m, 1H), 2.00 (ddd, J=9.0, 8.6, 3.9 1H), 1.95-1.78 (m, 2H), 1.36-1.21 (m, 6H). LCMS: m/z 432.20 [Calc: C23H34N3O5 432.25].

Figure US07671062-20100302-C00068

Example 1, Alternative Step 9g: Amino acid 7 (6.3 g, 14.7 mmol, 1.0 eq) was dissolved in THF (80 mL) under N2 and NaH (584 mg, 14.7 mmol, 1.0 eq, 60 wt % dispersion in mineral oil) was added portionwise. When the addition was complete, and the evolution of gas had ceased, the reaction mass was concentrated under reduced pressure and the resulting solid azeotroped with toluene (50 mL) to give a white solid (KF 0.59 wt %). This solid was slurried in toluene (100 mL) under N2and heated to 90° C. DPPA (3.32 mL, 15.3 mmol, 1.05 eq) was added dropwise over ˜2 min. After ˜5 min all the solids had dissolved, after 10 mins precipitation of a white solid was observed. After 30 mins HPLC analysis indicated complete reaction. The reaction mass was allowed to cool to RT before being filtered, the cake was washed with toluene. The liquors where then slowly added into AcOH/Ac2O (80/20, 168 mL) solution at 90° C. After 45 mins HPLC still indicated some isocyanate. At 1.15 h, the reaction mass was cooled to RT and diluted with toluene (100 mL) and water (100 mL). The organic layer was removed and the toluene washed with 1N HCl (100 mL). The combined aq. phases were then basified with K2CO3(s) and brought to pH 12 with NaOH (10N), keeping the temperature below 20° C. The aq layer was then extracted with methylene chloride (4×150 mL), the combined organic layers dried over K2CO3 and concentrated to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate 8 as a white foam (4.5 g, 70%, 94AP purity). The 1H-NMR was identical to material obtained from the route described above (Example 1, Step 9). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 7.20 min (Compound 8), 7.85 min (urea dimer). HRMS: 445.2809 [Calc: C24H37N4O4445.2815].

Alternative Preparation of Example 1

Figure US07671062-20100302-C00069

Example 1, Alternative Preparation, Step 1: Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 (450.1 g), was combined with 1-ethyl-3-(3-dimethyl-amino-propyl)carbo-diimide hydrochloride (236.3 g), 1-hydroxy benzotriazole hydrate (171.9 g), N-carbobenzyloxy-L-methionine (333.4 g) and acetonitrile (3.1 L). To the stirred mixture was added triethylamine (249.5 g) below 30° C. Upon reaction completion (HPLC), the mixture was diluted with ethyl acetate (8.2 L) and washed with aqueous 25% potassium bicarbonate solution (2×4.5 L) followed by water (4.5 L). The organic phase was separated and concentrated under reduced pressure to obtain a solution of ethyl (7R,8S)-8-((S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 (1.4 L). Methyl iodide (2.39 kg) was added, the vessel was shielded from light and the mixture was held under slow agitation for approx. 24 h. To the thick yellow precipitate was added methyl tert-butyl ether (2.7 L) and the mixture was held for approx. 1 h. The product was isolated by filtration and the cake was washed with methyl tert-butyl ether (2×1.4 L), then dried under vacuum, yielding [(S)-3-benzyloxy-carbonylamino-3-((7R,8S)-7-ethoxycarbonyl-1,4-dioxa-spiro[4.5]dec-8-ylcarbamoyl)-propyl]-dimethylsulfonium iodide 3 (671.4 g, ˜94% yield) as an off-white solid (HPLC purity 99.9%).

Figure US07671062-20100302-C00070

Example 1, Alternative Preparation, Step 2: Sulfonium salt 3 (619.4 g), and cesium carbonate (416.8 g) and anhydrous dimethyl sulfoxide (6.2 L) were combined in a reactor equipped with a scrubber to neutralize volatile sulfides. Vigorous agitation was maintained until complete conversion was obtained (HPLC). Ethyl acetate (12.4 L) was added, followed by 20% brine (3 L). The organic phase was separated, washed twice with brine (2×3 L) and evaporated to obtain a solution of ethyl (7R,8S)-8-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4 in ethyl acetate (˜0.8 L). Acetone (2.55 L) was added, followed by aqueous 0.5 M hydrochloric acid solution (2.3 L). With good mixing, the solution was heated to 50 to 60° C. until conversion of 4 to ethyl (1R,2S)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-oxo-cyclohexanecarboxylate 5 was complete (HPLC). The mixture was concentrated under reduced pressure while below 40° C., cooled to ˜30° C., and water (4.1 L) was added. The resulting slurry was cooled to 5 to 10° C. and agitated for ˜1 hour. The product was filtered and the cake was washed with water (2×2.5 L). Upon deliquoring, the cake was dried to a constant weight below 40° C. in a vacuum oven. Cyclohexanone 5 (272 g, 70% yield) was obtained (HPLC purity 98.7%).

Figure US07671062-20100302-C00071

Example 1, Alternative Preparation, Step 3: Cyclohexanone 5 (206 g) was dissolved in dichloromethane (1.1 L) and charged to a hydrogenator. Titanium tetraisopropoxide (218.2 g) and N-isopropyl N-methylamine (63.64 g) were added and the mixture was stirred at ambient temperature (23 to 25° C.) for at least 5 h. Platinum catalyst (5% Pt/S/C, 15 g, approx. 7.5% relative to 5) was added and hydrogenation was performed at ˜30 psig for at least 6 h, yielding a mixture of ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate 6 and its 5-epi-isomer (˜7%). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to approx. ˜600 mL. Wet ethyl acetate (˜3% water, 2.0 L) was added with vigorous agitation over a period of at least 1.5 h. Stirring was continued for at least an additional 6 h. The slurry was filtered. Filter cake was washed with ethyl acetate (1.0 L) and discarded. The combined filtrate and washings were concentrated to ˜400 mL. Toluene (2.0 L) was added and the solution was washed with 2M aqueous hydrochloric acid (2×400 mL). The aqueous layer was warmed to 50° to 60° C. for approx. 20 h or hydrolysis of 6 was deemed complete (HPLC). Aqueous sodium hydroxide solution was added to adjust to pH ˜10, and mixture was extracted with toluene (3×600 mL). The organic phase was discarded and pH was readjusted to ˜6 by addition of aqueous hydrochloric acid. The aqueous phase was concentrated to ˜600 mL under reduced pressure and extracted with methylene chloride (at least 3×2.0 L). The combined methylene chloride layers were evaporated under reduced pressure and continuously replaced with THF to obtain a solution of (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexane carboxylic acid 7 (˜148 g) in THF (˜4 L). Seed crystals of 8 were added, followed by 25% solution of sodium methoxide in methanol (81.24 g) below 25° C. The slurry was held for at least additional 16 h with agitation. The product was isolated by filtration and the cake was washed with THF (4×200 mL) and dried to a constant weight in vacuo below 30° C. Dry (1R,2S,5R)-2-((S)-3-benzyloxycarbonyl-amino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexane-carboxylate sodium salt 8 was obtained (139 g, ˜60% yield from 5).

Figure US07671062-20100302-C00072

Example 1, Alternative Preparation, Step 4: Aminoester sodium salt 8 (100 g), diphenyl phosphate (3.86 g), tert-BuOH (1275 mL) and toluene (225 mL) were combined and heated to reflux under reduced pressure. Approx. 500 mL of distillate were collected and discarded while being continuously replaced with a solution of toluene in tert-BuOH. Vacuum was removed and distillate was switched to percolate through a column filled with molecular sieves and allowed to return to the vessel. After drying was complete, DPPA (52.4 mL; dissolved in 60 mL toluene) was added slowly to the slurry at 80° C. Upon complete conversion (HPLC), tert-BuOH was removed by vacuum distillation and continuously replaced with toluene. The mixture was cooled to room temperature and washed twice with 10% aqueous K2HPO4 (1×800 mL, 1×400 mL) and water (400 mL). The organic phase was heated and concentrated in vacuo to approx. 270 mL. Vacuum was removed and heptane (1.1 L) was added slowly at approx. 80° C., followed by seeds of 9 (˜1 g). The slurry was slowly cooled to room temperature and benzyl {(S)-1-[(1S,2R,4R)-2-tert-butoxycarbonylamino-4-(isopropyl-methyl-amino)-cyclo-hexyl]-2-oxo-pyrrolidin-3-yl}-carbamate 9 was isolated by filtration as a white solid (86.76 g, 78% yield).

Figure US07671062-20100302-C00073

Example 1, Alternative Preparation, Step 5: The tert-Butyl carbamate 9 (50 g) was dissolved in Toluene (500 mL) and i-PrOH (150 mL). The resulting solution was then heated to 60° C. Methanesulfonic acid (19.6 mL) was added below 65° C. Upon reaction completion (HPLC), the mixture was cooled to RT and triethylamine (69.4 mL) added slowly below 25° C. Acetic anhydride was then added below 25° C. After 1 h acetic acid (250 mL) was added below 25° C. The toluene phase was discarded and 2-methyl-THF (500 mL) was added to the aqueous phase. The mixture was stirred vigorously and basified with NaOH (25% aqueous solution) to pH 12. The aqueous phase was discarded and the organic layer was washed with brine (250 mL). The organic layer was concentrated under reduced pressure and continuously replaced with i-PrOH. The solution was cooled and filtered to provide benzyl {(S)-1-[(1S,2R,4R)-2-acetylamino-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamate 10 in i-PrOH solution which was used directly in the hydrogenation.

Example 1, Alternative Preparation, Step 6: To a solution containing acetamide 10 (˜61 g) in i-PrOH (˜625 mL) was added 10% Pd/C wet catalyst (2.5 g) and the suspension was hydrogenated at 30 psig and approx. 25° C. for at least 2 h. Upon completion (HPLC), the catalyst was removed by filtration and the filtrate was concentrated to approx. 550 mL. Water (8.8 mL) was added, followed by 5.6 N hydrochloric acid in i-PrOH solution (69.5 mL). The resulting slurry was held at room temperature overnight. The product was isolated by filtration and the cake was rinsed with i-PrOH (2×100 mL) and dried in vacuo to constant weight at ˜50° C. to give N-[(1R,2S,5R)-2-((S)-3-amino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexyl]-acetamide 11 (55.6 g, 97% yield) as its hydrochloric acid salt (73.6% free base assay, HPLC).

Figure US07671062-20100302-C00074

Example 1, Alternative Preparation, Step 7: To 6-trifluoromethyl-quinazolin-4-ol 12 (20.1 g) in MeCN (400 mL) was added 5.5 M solution of sodium methoxide in methanol (17.0 mL). The resulting suspension was distilled under reduced pressure and continuously replaced by MeCN to remove methanol. To the slurry was added DMF (1.4 g), followed by oxalyl chloride (13.0 mL) below 50° C. Upon reaction completion (HPLC), excess reagent was removed under reduced pressure to give ˜400 mL of slurry. The mixture was cooled to room temperature and washed with 10% aqueous K2HPO4 (1×1.0 L, 1×0.5 L) to afford 4-chloro-6-trifluoromethyl-quinazoline 13 (˜21.2 g) in approx. 450 mL of wet MeCN solution, which was used directly in the subsequent coupling reaction (HPLC purity 99.8%).

Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl-N-ethylamine (61 mL) at room temperature was added a solution of 13 (˜21.2 g) in MeCN (˜450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert-butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH>11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60° C., followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((1R,2S,5R)-5-(isopropylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).

Crystallization Procedures for Example 1Example 1, Production of bis-BSA salt and purification: The entirety of the amorphous free base from Example 1, Step 11 was dissolved in methanol (600 mL). The resultant solution was heated at 60° C. and charged with benzenesulfonic acid (2.5 eq). The mixture was cooled to room temperature and the resultant white solid was collected by filtration to yield the bis-benzene sulfonic acid salt of the title compound (95 g, 86%). This material was >99% pure by HPLC. This material was further purified by re-crystallization from 80/20 EtOH/H2O, which provided the salt free from any residual methanol. HPLC purity=99.8%. 1H NMR (500 MHz, D2O) δ ppm 8.75 (1H, s), 8.66 (1H, s), 8.25 (1H, d, J=8.80 Hz), 7.90 (1H, d, J=8.80 Hz), 7.75 (4H, d, J=8.25 Hz), 7.43-7.57 (6H, m), 5.42 (1H, t), 4.33-4.44 (1H, m), 4.09-4.19 (1H, m), 3.83-3.91 (1H, m), 3.74-3.83 (2H, m), 3.61 (1H, t, J=11.55 Hz), 2.75 (3H, d, J=6.60 Hz), 2.61-2.70 (1H, m), 2.31-2.44 (1H, m), 2.20-2.27 (1H, m), 2.17 (2H, d, J=12.10 Hz), 1.94-2.04 (1H, m, J=12.65 Hz), 1.90-1.95 (3H, m), 1.72-1.91 (2H, m), 1.37 (3H, d, J=6.05 Hz), 1.29 (3H, d, J=6.60 Hz). Differential scanning calorimetry utilized a heating rate of 10° C./min and revealed a melting/decomposition endotherm with an onset temperature of 297.6° C. and a peak temperature at 299.1° C.

Example 1, Crystallization of the Free Base: A sample of the amorphous free base of N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide (1 g) was dissolved in dichloromethane (5 mL). The solution was charged with heptane (30 mL) and then warmed to distill the dichloromethane. The solution was cooled to 40° C.; a white solid precipitated. The suspension was heated to 90° C. and stirred for 2 h. The suspension was cooled to room temperature and filtered to provide the pure free base of the title compound. No residual solvent was apparent by 1H-NMR.

Image result for Bristol-Myers Squibb

PAPER

Abstract Image

A concise bulk synthesis of stereochemically complex CCR2 antagonist BMS-741672 is reported. A distinct structural feature is the chiral all-cis 1,2,4-triaminocyclohexane (TACH) core, which was assembled through consecutive stereocontrolled heterogeneous hydrogenations: efficient Pt-catalyzed reduction of a β-enaminoester, directed by (S)-α-methylbenzylamine as a low-cost chiral template, and reductive amination of a 3,4-cis-disubstituted cyclohexanone over sulfided Pt/C introduced a tert-amine, setting the third stereocenter in the all-cis cyclohexane core. The heterogeneous catalysts were recycled. Ester hydrolysis produced a γ-amino acid, isolated as its Na salt. A challenging Curtius reaction to introduce the remaining C–N bond at C-2 was strongly influenced by the presence of the basic tert-amine, providing a stereoelectronically highly activated isocyanate. Detailed mechanistic and process knowledge was required to enable clean trapping with an alcohol (t-BuOH) while avoiding formation of side products, particularly an unusual carbamoyl phosphate. Deprotection, N-acetylation, and uncatalyzed SNAr coupling with known 4-chloroquinazoline provided the final product. The resulting 12-step synthesis was used to prepare 50 kg of the target compound in an average yield of 82% per step.

Stereoselective Bulk Synthesis of CCR2 Antagonist BMS-741672: Assembly of an All-cis (S,R,R)-1,2,4-Triaminocyclohexane (TACH) Core via Sequential Heterogeneous Asymmetric Hydrogenations

Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08901, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00282
*Phone: 732-227-6917. Fax: 732-227-3001. E-mail: joerg.deerberg@bms.com.

Patents

Patent ID Date Patent Title
US7687508 2010-03-30 CYCLIC DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
US7671062 2010-03-02 N-((IR, 2S, 5R)-5-(ISOPROPYL(METHYL)AMINO)-2-((S)-2-0XO-3-(6-TRIFLUOROMETHYL)QUINAZOLIN-4-YLAMINO)PYRROLIDIN-1-YL)CYCLOHEXYL)ACETAMIDE AND OTHER MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY, CRYSTALLINE FORMS AND PROCESS.

Image result for Bristol-Myers Squibb

Bristol-Myers Squibb, Paul Biondi Senior Vice President, Head of Business Development

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

//////////   ////////////////BMS-741672, BMS 741672, BRISTOL MEYER SQUIB, PHASE 2,  type 2 Diabetes, Neuropathic Pain, Bristol-Myers Squibb
CC(C)N(C)[C@H]1C[C@@H](NC(C)=O)[C@H](CC1)N4CC[C@H](Nc3ncnc2ccc(cc23)C(F)(F)F)C4=O

Glenmark’s TRPA1 antagonist ‘GRC 17536’ shows positive data in a proof of concept study


 

MUMBAI, India, Sep 17, 2014

- Glenmark's first in class TRPA1 antagonist, GRC 17536, has shown positive data in a Phase 2a proof of concept study in patients with painful diabetic neuropathy

Glenmark Pharmaceuticals today announced that its first in class Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist, GRC 17536 has shown positive data in a Phase 2a double blind, placebo controlled, multi-centre, proof of concept study conducted on 138 patients in Europe and India.

A statistically significant and clinically relevant response was seen in a prospectively-identified, substantial sub-group of patients with moderate to severe pain who had relatively intact sensory responses as detected by a standardized testing methodology. GRC 17536 was well-tolerated with no evidence of CNS or other drug related side effects.

Patrick Keohane, Chief Medical Officer, Glenmark stated “Diabetic neuropathy remains a difficult to manage chronic clinical condition with limited therapeutic options. These initial efficacy and safety data with GRC 17536, a peripherally acting novel therapeutic, are encouraging, and Glenmark intends to be ready to file for a Phase 2b dose range finding study in patients with neuropathic pain before the end of this financial year. This announcement also reaffirms our position globally in the development of novel pain therapies”.

Commenting on this result, Dr. Michael Buschle, Chief Scientific Officer & President – Biologics, Glenmark Pharmaceuticals mentioned, “This is very promising and GRC 17536 may be useful for several indications which we will pursue”.

The Glenmark TRPA1 program includes indications in pain as well as respiratory. Inhaled doses of GRC 17536 are also being tested in a Phase 2A proof of concept study in patients with Chronic Cough.

WORLD-CLASS CAPABILITIEIS: Glenn Saldanha (left), Managing Director and CEO, along with Dr. Michael Buschle, President Biologics, Glenmark Pharmaceuticals at a press conference in Mumbai on Monday. Photo: Paul Noronha
Glenn Saldanha (left), Managing Director and CEO, along with Dr. Michael Buschle, President Biologics,  Photo: Paul Noronha

 

 

http://www.marketwatch.com/story/glenmarks-trpa1-antagonist-grc-17536-shows-positive-data-in-a-proof-of-concept-study-2014-09-17-112031125

http://www.ptinews.com/pressrelease/11726_press-subGlenmark-s-TRPA1-Antagonist–GRC-17536–Shows-Positive-Data-in-a-Proof-of-Concept-Study

Note on TRPA1

TRPA1 is an ion channel expressed on peripheral and spinal sensory neurons and it mediates pain signal transmission. It functions as a cellular sensor for detecting painful mechanical, biochemical and thermal stimuli that cause sensory nerve hyperactivity during chronic pathologies including chronic pain, inflammation, itch and cough. TRPA1 receptor is shown to induce pain hypersensitivity in animal models of diabetic neuropathic pain and its blockade attenuates pain hypersensitivity as well as later loss of the nerve fibers and their function. GRC 17536 is a potent, selective and first in class antagonist of TRPA1 receptor. Preclinical studies have demonstrated its effectiveness in animal models of neuropathic and inflammatory pain including the peripheral diabetic neuropathic pain, osteoarthritic pain, postoperative pain and chemotherapy induced pain which supports potential utility of TRPA1 blockade in therapeutic pain management.

 

About Glenmark Pharmaceuticals Ltd

Glenmark Pharmaceuticals Ltd. (GPL) is a research-driven, global, integrated pharmaceutical company and ranked among the top 80 Pharma & Biotech companies of the world in terms of revenues as per SCRIP 100 Rankings. Glenmark is a leading player in the discovery of new molecules both NCEs and NBEs. Glenmark has several molecules in various stages of clinical development and primarily focused in the areas of Inflammation, Pain and Oncology. The company has significant presence in branded formulations across emerging economies including India. Its subsidiary, Glenmark Generics Limited services the requirements of the US and Western Europe markets.

 

Cebranopadol GRT 6005 セブラノパドール a Potent Analgesic NOP and Opioid Receptor Agonist


Cebranopadol
(GRT-6005; GRT 6005; GRT6005)
CAS: 863513-91-1
(1r,4r)-6′-Fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine
Spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-
Grünenthal GmbH  innovator
Cebranopadol(GRT-6005) is a novel first in class compounds with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor.
 Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several experimental model models of acute and chronic pain (tail–flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5–5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side–effect profile.
GRT-6005 is a centrally active analgesic in phase II clinical development for the oral treatment of neuropathic pain in patients with painful diabetic polyneuropathy and for the treatment of pain due to osteoarthritis of the knee. It is being developed by Grüenenthal and Forest. No recent development has been reported for research into the treatment of moderate to severe pain following bunionectomy. In 2010, GRT-6005 was licensed to Forest and Grünenthal in Canada and the U.S. for the treatment of moderate to severe chronic pain.
ChemSpider 2D Image | Cebranopadol | C24H27FN2O
Description: IC50 Value: N/A Cebranopadol and GRT 6006 are novel first-in-class compounds with unique pharmacological and pharmacokinetic profiles that may enhance their effect in certain pain conditions. The unique mode of action of these compounds builds on the ORL-1 receptor and, supported by the established mu opioid receptor, is particularly suitable for the treatment of moderate to severe chronic pain [1]. in vitro: N/A in vivo: N/A Clinical trial: Cebranopadol has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with further Phase II studies planned prior to initiation of Phase III studies.

Neuropathic pain

Neuropathic pain is caused when peripheral nerves are damaged by mechanical, metabolic or inflammatory way. The pain occurring images are mainly due to the occurrence of spontaneous pain, hyperalgesia and allodynia (pain is already triggered by non-noxious stimuli) in. As a result, the lesions to increased expression of Na + channels and thus to spontaneous activity in the damaged axons and their Nachbaraxonen (England et al., Neurology, 1996, 47, 272-276).The excitability of the neurons is increased and they react to incoming stimuli with an increased discharge frequency. This results in an increased sensitivity to pain, which contributes to the development of hyperalgesia and spontaneous pain (Baron, Clin J Pain 2000;. 16 (2 Suppl), 12-20). The causes and manifestations, and therefore the treatment needs of neuropathischerm pain are varied. They arise as a result of injury or disease of the brain, spinal cord or peripheral nerves.Causes may be operations, such as phantom pain after amputation, stroke, multiple sclerosis, spinal cord injury, alcohol or drug abuse or other toxins, cancers but also

Metabolic diseases such as diabetes, gout, kidney failure or liver cirrhosis, or infectious diseases such as mononucleosis, ehrlichiosis, typhoid, diphtheria, HIV, syphilis or Lyme disease. The pain experience is very different signs and symptoms that can change over time in number and intensity. Paradoxically, patients with neuropathic pain outline a slowdown or failure of acute pain perception and the simultaneous increase of neuropathic pain. The typical symptoms of neuropathic pain as tingling, burning, shooting or described, or radiating electrifying. Pharmacological basis for treatment of neuropathic pain include tricyclic antidepressants and anticonvulsants, which are used as monotherapy or in combination with opioids. These drugs usually provide only a certain pain relief during a pain-free but is often not achieved. The often-adjusting side effects are dose increases while the drug to achieve adequate pain relief often in the way. In fact, a higher dosage of a μ-opioid is often required as the treatment of acute pain, thereby reducing the side effects get even more important for satisfactory treatment of neuropathic pain. By the occurrence of typical μ-opioid tolerance development and the concomitant need for dose escalation of this problem is exacerbated. In summary it can be stated that neuropathic pain is difficult to treat and today is alleviated by high doses of μ-opioids only partially (Saudi Pharm J. 2002, 10 (3), 73-85). There is therefore an urgent need for medicines for the treatment of chronic pain, the dose should not be increased until the occurrence of intolerable side effects to ensure a satisfactory pain treatment.

……………

http://www.google.com/patents/US7547707

 

Example 24 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×60 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The solid contained in the suspension was filtered off with suction and dried. 955 mg of the more non-polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole were obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hot ethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2 mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 h. The solid formed was filtered off with suction. 640 mg of the hemicitrate were obtained as a white solid (m.p. 258-282° C.).

Example 25 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1 mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture was stirred at RT for 16 h. For working up, the mixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC (3×20 ml). The combined organic phases were dried with sodium sulfate and evaporated. The residue (364 mg of white solid) was suspended in hot ethanol (20 ml), and a similarly hot solution of citric acid (185 mg, 0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolved completely and no longer precipitated out even on cooling to approx. 5° C. Ethanol was removed on a rotary evaporator and the hemicitrate of the more polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained in this way in a yield of 548 mg as a white solid (m.p. 148-155° C.).

 

24
Figure US07547707-20090616-C00031
hemicitrate more non-polar diastereomer
25
Figure US07547707-20090616-C00032
hemicitrate more polar diastereomer

 

 

………………..
WO 2013113690

(1 r,4r)-6′-fluoro-N,N- dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1 ,1 ‘-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):

http://www.google.com/patents/WO2013113690A1?cl=en

Figure imgf000007_0001
…………………
Figure imgf000033_0001
see A4
…………………………

One particular drug that is of great interest for use in treating cancer pain (and other acute, visceral, neuropathic and chronic pain pain disorders) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine. This drug is depicted below as the compound of formula (I).

 

Figure US20130231381A1-20130905-C00001

 

The solid forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine that are known so far are not satisfactory in every respect and there is a demand for advantageous solid forms

A) Synthesis of Crystalline Form A100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by FT Raman, TG-FTIR and PXRD.
……………………
Abstract Image

In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

http://pubs.acs.org/doi/full/10.1021/ml500117c

ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/ml500117c
6′-Fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)
hemicitrate were obtained as a white solid (mp 258-282 °C).1H-NMR (300 MHz; DMSO-d6): 1.75-1.87 (m, 4 H); 2.14 (s, 6 H); 2.27 (t, 2 H); 2.61-
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).
13C-NMR (75.47 MHz; DMSO-d6): 22.1; 27.6; 30.2 (2 C); 38.0 (2 C); 43.1; 58.8 (2 C,
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);
112.0 (3JC,F = 10 Hz); 126.5; 126.6; 126.7 (2 C); 127.4 (2 C); 132.4; 138.7; 141.5;
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+
…………………………..
US20120034297 * Aug 4, 2011 Feb 9, 2012 Gruenenthal Gmbh Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 * Jul 6, 2012 Jan 10, 2013 Gruenenthal Gmbh Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
WO2004043967A1 Nov 5, 2003 May 27, 2004 Otto Aulenbacher Spirocyclic cyclohexane derivatives
WO2008040481A1 Sep 26, 2007 Apr 10, 2008 Gruenenthal Gmbh MIXED ORL 1/μ AGONISTS FOR TREATING PAIN
WO2004043967A1 * Nov 5, 2003 May 27, 2004 Otto Aulenbacher Spirocyclic cyclohexane derivatives
WO2005066183A1 * Dec 21, 2004 Jul 21, 2005 Gruenenthal Gmbh Spirocyclic cyclohexane derivatives with affinity for the orl1-receptor
US20050153998 * Aug 19, 2004 Jul 14, 2005 Fumitaka Ito Tetrahydroisoquinoline or isochroman compounds

 

 

Citing Patent Filing date Publication date Applicant Title
US7799931 * Feb 17, 2009 Sep 21, 2010 Gruenenthal Gmbh Spirocyclic cyclohexane compounds
US7951948 * Apr 19, 2010 May 31, 2011 Gruenenthal Gmbh Spirocyclic cyclohexane compounds
US7960404 Aug 21, 2009 Jun 14, 2011 Gruenenthal Gmbh Spirocyclic cyclohexane compounds
US8034936 Nov 4, 2010 Oct 11, 2011 Gruenenthal Gmbh Spirocyclic cyclohexane compounds useful to treat substance dependency
US8053576 Feb 17, 2009 Nov 8, 2011 Gruenenthal Gmbh Treating conditions associated with the nociceptin/ORL1 receptor system, e.g. pain, drug withdrawal, anxiety, muscle relaxants, anxiolytic agents; e.g. 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluorene
US8288406 Sep 22, 2010 Oct 16, 2012 Gruenenthal Gmbh Hydroxymethylcyclohexylamines
US8288430 Mar 25, 2009 Oct 16, 2012 Grunenthal Gmbh Spiro(5.5)undecane derivatives
US8293758 * Mar 25, 2009 Oct 23, 2012 Grunenthal Gmbh Substituted spirocyclic cyclohexane derivatives
US8357705 Mar 25, 2009 Jan 22, 2013 Gruenenthal Gmbh Substituted cyclohexyldiamines
US8404740 Aug 21, 2009 Mar 26, 2013 Gruenenthal Gmbh Spirocyclic cyclohexane compounds
US8614245 * Jan 8, 2013 Dec 24, 2013 Gruenenthal Gmbh Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US8618156 * Jul 6, 2012 Dec 31, 2013 Gruenenthal Gmbh Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 * Jul 6, 2012 Jan 10, 2013 Gruenenthal Gmbh Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463
GLENMARK SCIENTIST ,  INDIA
web link
http://anthonycrasto.jimdo.com/

Congratulations! Your presentation titled “Anthony Crasto Glenmark scientist, helping millions with websites” has just crossed MILLION views.
アンソニー     安东尼   Энтони    안토니     أنتوني
join my process development group on google
you can post articles and will be administered by me on the google group which is very popular across the world
LinkedIn group
 
blogs are
 
shark

========================

%d bloggers like this: