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ORGANIC SPECTROSCOPY

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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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

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GRAPIPRANT


Grapiprant.svg

Grapiprant.png

ChemSpider 2D Image | grapiprant | C26H29N5O3S

Structure of GRAPIPRANT

GRAPIPRANT

  • Molecular FormulaC26H29N5O3S
  • Average mass491.605 Da

CAS 415903-37-6

UNII-J9F5ZPH7NB, CJ 023423, CJ-023423,

Phase II, Arrys Therapeutics, CANCER,

PAIN, AskAt Phase II, 

N-{2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}-N’-[(4-methylphenyl)sulfonyl]urea
RQ-00000007, MR10A7
9763
AAT-007
Benzenesulfonamide, N-[[[2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methyl-
CJ-023,423
  • N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methylbenzenesulfonamide
  • 1-[2-[4-(2-Ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea
  • 2-Ethyl-4,6-dimethyl-1-[4-[2-[[[[(4-methylphenyl)sulfonyl]amino]carbonyl]amino]ethyl]phenyl]-1H-imidazo[4,5-c]pyridine
  • AAT 007
  • CJ 023423
  • Grapiprant
  • MR 10A7
  • RQ 00000007
  • RQ 7

Synonyms and Mappings

  • 415903-37-6
  • GRAPIPRANT [GREEN BOOK]
  • CJ-023
  • GRAPIPRANT [INN]
  • GRAPIPRANT [WHO-DD]
  • MR-10A7
  • AAT-007
  • MR10A7
  • RQ-00000007
  • RQ-7
  • GRAPIPRANT [USAN]
  • GRAPIPRANT
  • 2-ETHYL-4,6-DIMETHYL-1-(4-(2-(((((4-METHYLPHENYL)SULFONYL)AMINO)CARBONYL)AMINO)ETHYL)PHENYL)-1H-IMIDAZO(4,5-C)PYRIDINE
  • N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYLBENZENESULFONAMIDE
  • CJ 023423
  • BENZENESULFONAMIDE, N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-
  • CJ-023,423
  • N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-BENZENESULFONAMIDE
  • CJ-023423

SYN

Arrys Therapeutics (under license from AskAt ) and affiliate Ikena Oncology (formerly known as Kyn Therapeutics ) are developing ARY-007 , an oral formulation of grapiprant, for treating cancers; in December 2019, preliminary data were expected in 2020

Grapiprant (trade name Galliprant) is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA’s Center  for Veterinary  Medicine  and was  categorized  as a  non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.[1]

Preclinical studies also indicate that grapiprant is not only efficacious as a acute pain but also in chronic pain relief and inflammation drug. The effect of the drug is directly proportional to the dosage and its effects were comparable to human medication such as rofecoxib and piroxicam.[2]

Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).

Grapiprant  is also  used  in humans,  and  was researched  to be  used  as a pain  control  and inflammation associated with osteoarthritis. The effect of grapiprant could be explained through the function of prostaglandin E2, in which acts as a pro-inflammatory mediator of redness of the skin, edema and pain which are the typical signs of inflammation. The effect of PGE2 stems from its action through the four prostaglandin receptor subgroups EP1, EP2, EP3 and EP4, in which the prostaglandin EP4 receptor acts as the main intermediary of the prostaglandin-E2-driven inflammation. Grapiprant is widely accepted in veterinary medicine due to its specific and targeted approach to pain management in dogs. The serum concentration of grapiprant is increased when used in conjunction with other drugs such as acetaminophenalbendazole, and alitretinoin.

Common side effects are intestinal related effects such as mild diarrhea, appetite loss, and vomiting.[3] Additionally, it is found that it might lead to reduced tear production due to it being a sulfa-based medication and also reduced albumin levels.

Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).

Medical uses

Grapiprant is used once a day as an oral pain relief for dogs with inflammation-related osteoarthritis. It is a non-steroidal anti-inflammatory (NSAID) that functions as a targeted action to treat osteoarthritis pain and inflammation in dogs.

Mechanism of action

Grapiprant acts as a specific antagonist that binds and blocks the prostaglandin EP4 receptor, one out of the four prostaglandin E2 (PGE2) receptor subgroups. The EP4 receptor then mediates the prostaglandin-E2-elicited response to pain, and hence grapiprant was proven to be effective in the decrease of pain in several inflammatory pain models of rats. It was also proven to be effective in reducing osteoarthritis-related pain in humans, which serves as a proof for its mechanism of action. The approximate calculation for  canine efficacy  dose  is between the range of 1.3 and 1.7 mg/kg, in conjunction with a methylcellulose suspending agent. Based on the calculations from the comparisons of binding affinity of grapiprant to the EP4 receptors of  dogs, rats, and humans, the study of plasma and serum protein binding determinations, the effective doses determined in inflammation pain models of rats, and  human-related clinical  studies, it  is  evaluated that  Grapiprant should be administered just once a day. The approved dose of the commercial Grapiprant tablet by the FDA for the pain relief and inflammation associated with osteoarthritis to dogs is reported to be 2 mg/kg a day.[4]

Absorption

Studies in animals such as horses have shown the presence of Grapiprant in serum 72 hours with a concentration >0.005 ng/ml after the initial administration of a dose of 2 mg/kg. Grapiprant is expeditiously absorbed and the reported serum concentration was reported to be 31.9 ng/ml in an amount of time of 1.5 hours. The actual body exposure to grapiprant after administration of one dose was shown to be 2000 ng.hr/ml. The degree and rate at which grapiprant is absorbed into the body, presents a mean bioavailability of 39%. A significant reduction in the bioavailability, concentration time and maximal concentration were reported to have occurred after food intake.[1] And thus, grapiprant is usually not administered with food as it will not be as efficient.[5]

Distribution

The volume of distribution in cat studies was reported to be 918 ml/kg.[1]

Route of elimination

Following an oral administration, the majority of the dose was metabolized within the first 72 hours. Equine studies have shown that grapiprant is present in urine 96 hours after the first administration of a dose of 2 mg/kg and has a concentration >0.005 ng/ml. From the excreted dose conducted in horses, it is found that 55%, 15% and 19% of the orally-administered dose was excreted in bile, urine, and faeces respectively.[1]

Toxicity

Safety studies conducted on grapiprant have demonstrated that it generally possesses an exceptional safety profile and a wide safety margin in veterinary studies.[6] In animal studies, a research on 2.5-12 times overdose was conducted for grapiprant and the study resulted in soft-blobs and mucous-filled faeces, occasional bloody stools and emesis.

PATENT

WO-2020014465

Novel crystalline forms of grapiprant and their salts eg HCl (designated as Form A), useful for inhibiting prostaglandin EP4 receptor activity and treating cancers.

Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.

[0003] Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties exist. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production as well as PI3K and GSK3P signaling, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events. Various EP4 inhibitors have been described previously, for example, in WO 2002/032900, WO 2005/021508, EiS 6,710,054, and US 7,238,714, the contents of which are incorporated herein by reference in their entireties.

[0004] Accordingly, there is a need for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. The present invention addresses such a need.

It has now been found that compounds of the present invention, and compositions thereof, are useful for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. In general, salt forms and co-crystal forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of proliferative disorders associated with prostaglandin EP4 receptor activity, as described in detail herein. Such compounds are represented by the chemical structure below, denoted as compound A (also known as grapiprant):

A

or a pharmaceutically acceptable salt thereof.

United States Patent 7,960,407, filed March 1, 2006 and issued June 14, 2011 (“the ‘407 patent,” the entirety of which is hereby incorporated herein by reference), describes certain EP4 inhibitor compounds. Such compounds include compound A:

or a pharmaceutically acceptable salt thereof.

[0037] Compound A, N-[({2-[4-(2-Ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl) phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide, is described in detail in the ‘407

patent, including its synthetic route. The ‘407 patent also discloses a variety of physical forms of compound A.

[0038] It would be desirable to provide a solid form of compound A (e.g., as a co-crystal thereof or salt thereof) that imparts characteristics such as improved aqueous solubility, stability and ease of formulation. Accordingly, the present invention provides both co-crystal forms and salt forms of compound A:

A.

PATENT

WO 2002032900

PATENT

WO 2002032422

Family members of the product case ( WO0232422 ) of grapiprant have protection in most of the EU states until October 2021 and expire in the US in October 15, 2021.

PATENT

WO 2003086371

PATENT

WO2020014445 covering combinations of grapiprant and an immuno-oncology agent.

WO 2005102389

WO 2006095268

US 7960407

US 20190314390

References

  1. Jump up to:a b c d “Grapiprant”http://www.drugbank.ca. Retrieved 2019-05-15.
  2. ^ PubChem. “Grapiprant”pubchem.ncbi.nlm.nih.gov. Retrieved 2019-05-15.
  3. ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”VIN.com.
  4. ^ Nagahisa, A.; Okumura, T. (2017). “Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs”. Journal of Veterinary Pharmacology and Therapeutics40 (3): 285–292. doi:10.1111/jvp.12349ISSN 1365-2885PMID 27597397.
  5. ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”VIN.com.
  6. ^ Kirkby Shaw, Kristin; Rausch-Derra, Lesley C.; Rhodes, Linda (February 2016). “Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation”Veterinary Medicine and Science2 (1): 3–9. doi:10.1002/vms3.13ISSN 2053-1095PMC 5645826PMID 29067176.
Grapiprant
Grapiprant.svg
Clinical data
Trade names Galliprant
Routes of
administration
Oral
ATCvet code
Pharmacokinetic data
Bioavailability 6.6 L/kg, high volume of distribution
Elimination half-life 5.86 hours in horses
Excretion Urine
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H29N5O3S
Molar mass 491.61 g·mol−1
3D model (JSmol)

//////////////GRAPIPRANT, 415903-37-6, UNII-J9F5ZPH7NB, CJ 023423, CJ-023423, RQ-00000007, MR10A7, Galliprant, Phase II, Arrys Therapeutics, CANCER, PAIN, AskAt

CCC1=NC2=C(N1C3=CC=C(C=C3)CCNC(=O)NS(=O)(=O)C4=CC=C(C=C4)C)C=C(N=C2C)C

New TRPV1 Antagonist From Neurogen Corporation


SCHEMBL908261.png

MK ? NGD?

MK 2295; NGD 8243 may be???????

CAS 878811-00-8 FREE FORM

Molecular Formula: C27H31FN6O2
Molecular Weight: 490.572443 g/mol

6-[(3R)-4-[6-(4-fluorophenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]-3-methylpiperazin-1-yl]-5-methylpyridine-3-carboxylic acid

6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid

3-​Pyridinecarboxylic acid, 6-​[(3R)​-​4-​[6-​(4-​fluorophenyl)​-​2-​[(2R)​-​2-​methyl-​1-​pyrrolidinyl]​-​4-​pyrimidinyl]​-​3-​methyl-​1-​piperazinyl]​-​5-​methyl-

Neurogen Corp  INNOVATOR

MESYLATE

CAS 1855897-95-8

6-((R)-4-(6-(4-Fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-5-methylnicotinic acid methanesulfonic acid salt

white solid. 1H NMR (CD3OD, 400 MHz) δ 1.37 (d, 3H, J= 6.4 Hz), 1.48 (d, 3H, J = 6.7 Hz), 1.84 (m, 1H), 2.09 (m, 1H), 2.17–2.25 (m, 2H), 2.42 (s, 3H), 2.66 (s, 3H), 3.10 (dt, 1H, J = 12.3 and 3.3 Hz), 3.28 (dd, 1H, J = 13.1 and 3.7 Hz), 3.65–3.72 (m, 3H), 3.78 (m, 1H), 3.87 (m, 1H), 4.49 (m, 1H), 4.63 (m, 3H), 4.96 (br m, 1H), 6.61 (s, 1H), 7.32 (m, 2H), 7.82 (m, 2H), 8.05 (m, 1H), 8.69 (d, 1H, J = 1.9 Hz);

13C NMR (CD3OD, 125 MHz) δ 19.4, 24.5, 33.5, 39.6, 41.5, 48.6, 50.0, 50.9, 54.1, 56.9, 94.8, 117.3 (d, J = 22.5 Hz), 122.1, 125.0, 130.1 (d, J = 3.3 Hz), 131.8 (d, J = 8.9 Hz), 142.1, 148.7, 153.1, 153.3, 162.4, 165.4, 166.4, (d, J = 251.3 Hz), 168.8;

19F NMR (CD3OD, 470 MHz) δ −108.6.

Anal. Calcd For C28H35FN6O5S: C, 57.32; H, 6.01; N, 14.32. Found: C, 57.34; H, 6.13; N, 14.29.

 

Activated by a wide range of stimuli such as capsaicin, acid, or heat, the transient receptor potential vanilloid-1 (TRPV1) has been identified as a potential treatment for chronic pain.TRPV1 is a highly characterized member of the TRP cation channel family believed to be involved in a number of important biological roles and plays a role in the transmission of pain.TRPV1 activation inhibits the transition of pain signals from the periphery to the central nervous system (CNS), leading to the possible development of analgesic and anti-inflammatory agents. TRPV1 antagonists have also been evaluated in multiple clinical trials where hyperthermic effects seen preclinically are also observed in humans

 

TRPV1

TRPV1

 

 

 

PATENT

http://www.google.com.na/patents/US20110003813

6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid 1. 1-(5-Bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine

  • Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc., Waterford, Conn.) (2.0 g, 7.97 mmol), (R)-2-methyl-piperazine (ChemPacific Corp., Baltimore, Md.; 3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine as a solid.

2. 2,4-dichloro-6-(4-fluorophenyl)pyrimidine

  • Dissolve 4-fluorobromobenzene (8.75 g, 0.05 moles) in anhydrous ether (80 mL) under nitrogen atmosphere and cool to −78° C. Add dropwise 1.6 M n-BuLi (34 mL, 0.055 moles) and stir at −78° C. for 45 min. Dissolve 2,4-dichloropyrimidine (7.45 g, 0.05 moles) in Et2O (100 mL) and add dropwise to the reaction mixture. Warm the reaction mixture to −30° C. and stir at this temperature for 30 min followed by 0° C. for 30 min. Quench the reaction mixture with AcOH (3.15 mL, 0.055 moles) and water (0.5 mL, 0.027 moles) dissolved in THF (5.0 mL). Add dropwise a THF (40 mL) solution of DDQ (11.9 g, 0.053 moles) to the reaction mixture. Bring the reaction mixture to room temperature and stir at room temperature for 30 min. Cool the reaction mixture to 0° C., add 3.0 N aq. NaOH (35 mL) and stir for 30 min. Decant the organic layer from the reaction mixture and wash the brown solid with Et2O (3×100 mL). Combine the organic layers, wash several times with saturated NaCl solution and dry with MgSO4. Filter and evaporate under vacuum to afford a brown colored solid. Purify by flash column chromatography using 5% EtOAc/hexane to afford the title product as a white solid.

3. 4-[4-(5-Bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine

  • Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (6.0 g, 24.7 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (7.0 g, 25.9 mmol) and K2CO3 (6.8 g, 49.4 mmol) in DMA at 60° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 15% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.

4. 4-[4-(5-Bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine

  • Heat a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine (7.7 g, 16.2 mmol), (R)-2-methylpyrrolidine hydrobromide [prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54(1):209] (3.5 g, 21.1 mmol) and K2CO3 (5.1 g, 37.3 mmol) in DMA at 110° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
  • 5. 6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinonitrile
  • To a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg, 1.33 mmol) and Zn(CN)2 (94 mg, 0.799 mmol) in DMF, add Pd(PPh3)4 (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N2. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
  • 6. 6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid
  • Heat a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinonitrile (100 mg, 0.212 mmol) in 12 M HCl for 3 hours at 90° C. Concentrate the mixture under reduced pressure. Add a small amount of water, adjust the pH to 6-7, and collect the resulting white precipitate to afford the title compound as a off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 1.24 (m, 6H, 2×CH3)); 1.61 (m, 1H,); 1.84 (m, 1H); 1.98 (m, 2H); 2.34 (s, 3H, Ar—CH3); 2.91 (m, 1H); 3.08 (m, 1H); 3.26 (m, 2H); 3.56 (m, 2H); 3.74 (m, 1H); 4.21 (m, 1H); 4.35 (m, 1H); 4.74 (m, 1H); 6.57 (s, 1H); 7.26 (m, 2H); 7.91 (d, 1H, J=3 Hz); 8.15 (m, 2H); 8.60 (d, 1H, J=3 Hz).

 

END…………………

MESYLATE NMR

STR1

1H NMR (CD3OD, 400 MHz) δ 1.37 (d, 3H, J= 6.4 Hz), 1.48 (d, 3H, J = 6.7 Hz), 1.84 (m, 1H), 2.09 (m, 1H), 2.17–2.25 (m, 2H), 2.42 (s, 3H), 2.66 (s, 3H), 3.10 (dt, 1H, J = 12.3 and 3.3 Hz), 3.28 (dd, 1H, J = 13.1 and 3.7 Hz), 3.65–3.72 (m, 3H), 3.78 (m, 1H), 3.87 (m, 1H), 4.49 (m, 1H), 4.63 (m, 3H), 4.96 (br m, 1H), 6.61 (s, 1H), 7.32 (m, 2H), 7.82 (m, 2H), 8.05 (m, 1H), 8.69 (d, 1H, J = 1.9 Hz);

 

STR1

13C NMR (CD3OD, 125 MHz) δ 19.4, 24.5, 33.5, 39.6, 41.5, 48.6, 50.0, 50.9, 54.1, 56.9, 94.8, 117.3 (d, J = 22.5 Hz), 122.1, 125.0, 130.1 (d, J = 3.3 Hz), 131.8 (d, J = 8.9 Hz), 142.1, 148.7, 153.1, 153.3, 162.4, 165.4, 166.4, (d, J = 251.3 Hz), 168.8;

STR1

19F NMR (CD3OD, 470 MHz) δ −108.6.

PATENT

http://www.google.ga/patents/WO2006026135

Scheme 1

Figure imgf000040_0001

Scheme 3

Figure imgf000041_0001

Scheme 4

Figure imgf000041_0002

Scheme 5

Figure imgf000041_0003

Scheme 6

Figure imgf000042_0002

Scheme 7

Figure imgf000042_0001

Scheme 8

Figure imgf000043_0001

Scheme 9

Figure imgf000043_0002

Scheme 10

Figure imgf000043_0003
Figure imgf000044_0001

Scheme 14

Figure imgf000045_0001

Scheme 15

Figure imgf000046_0001

Scheme 16

Figure imgf000047_0001

Scheme 17

Figure imgf000048_0001

Scheme 18

Figure imgf000048_0002

Scheme 19

Figure imgf000049_0001

Scheme 20

Figure imgf000049_0002

In

6-{4-[6~(4-Fluoro-phenyl)-2-(2~methyl-pyrrolidin-l-yl)-pyrimidin-4-yl]-3-(R)-met}τyl- piperazin-l-yl}-5-methyl-nicotinic acid

Figure imgf000100_0002

Heat a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-l-yl)-pyrimidin-4-yl]- 3-(R)-methyl-piperazin-l-yl}-5-methyl-nicotinonitrile (100 mg, 0.212 mmol) in 12 M HCl for 3 hours at 9O0C. Concentrate the mixture under reduced pressure. Add a small amount of water, adjust the pH to 6-7, and collect the resulting white precipitate to afford the title compound as a off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 1.24 (m, 6H, 2xCH3)); 1.61 (m, 1Η,); 1.84 (m, 1Η); 1.98 (m, 2Η); 2.34 (s, 3H, Ar-CH3); 2.91 (m, 1Η); 3.08 (m, 1Η); 3.26 (m, 2Η); 3.56 (m, 2H); 3.74 (m, IH); 4.21 (m, IH); 4.35 (m, IH); 4.74 (m, IH); 6.57 (s, IH); 7.26 (m, 2H); 7.91 (d, IH, J = 3Hz); 8.15 (m, 2H); 8.60 (d, IH, J = 3Hz).

PAPER

Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

Department of Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00388
Publication Date (Web): January 13, 2016
Copyright © 2016 American Chemical Society

Abstract

Abstract Image

A highly efficient, regioselective five-step synthesis of the TRPV1 antagonist 1 is described. The coupling of piperazine 7 with dichloropyrimidine 8 proceeded via a regioselective Pd-mediated amination affording product 11 in excellent yield. Conversion of the penultimate product 14 afforded 1 through formation of a magnesium ate complex and trapping with CO2.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00388

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00388/suppl_file/op5b00388_si_001.pdf

 

 

TRPV1

Patent Submitted Granted
Substituted biaryl piperazinyl-pyridine analogues [US7662830] 2006-06-08 2010-02-16
SUBSTITUTED BIARYL PIPERAZINYL-PYRIDINE ANALOGUES [US2011003813] 2011-01-06

 

Blum, C. A.; Brielmann, H.; Chenard, B. L.; Zheng, X. Preparation of substituted biaryl piperazinyl-pyridine analogues as capsaicin modulators. PCT Int. Appl. WO 2006026135 A2 20060309, 2006.

Neurogen Corporation, a Subsidiary of Ligand Pharmaceuticals Inc., 11119 North Torrey Pines Road, Suite 200, La Jolla, CA 92037, U.S.A.

Neurogen and Merck Agreement for Next-Generation Pain Drugs Consummated

Source Press Release
Company NeurogenMerck & Co
Tags Central Nervous System, Research Collaboration
Date January 16, 2004

Branford, CT — January 16, 2004 — Neurogen  Corporation (Nasdaq: NRGN) today announced that it has consummated its previously announced alliance with  Merck & Co ., Inc. (NYSE: MRK) to discover and develop next-generation drugs for the treatment of pain. The deal received clearance from the Federal Trade Commission under the Hart-Scott-Rodino Act and the companies have now commenced the collaboration. The alliance, announced December 1, 2003, enables Merck , through a subsidiary, and Neurogen  to pool drug candidates targeting the  vanilloid  receptor (VR1 ), a key integrator of pain signals in the nervous system, and combine their ongoing VR1  programs to form a global research and development collaboration.

With consummation of the deal, Neurogen  has received $30 million from  Merck , including a $15 million up-front license fee payment and a $15 million equity investment in Neurogen  common stock. Under the agreement,  Merck  has purchased 1,783,252 shares of newly issued  Neurogen  common stock at $8.41 per share, the average market price per share for the 25 trading days preceding regulatory clearance.  Merck ‘s new shareholder position represents approximately 9% of Neurogen ‘s 19,873,464 total shares outstanding.

About Neurogen

Neurogen  Corporation targets new small molecule drugs to improve the lives of patients suffering from disorders with significant unmet medical need.  Neurogen  has generated a portfolio of compelling new drug candidates through its Accelerated Intelligent Drug Discovery (AIDD(TM)) system, its expertise in cellular functional assays, and its depth in medicinal chemistry.  Neurogen conducts its research and development independently and, when advantageous, collaborates with world-class pharmaceutical companies to obtain additional resources and to access complementary expertise.

////////

n1c(nc(cc1c2ccc(cc2)F)N3CCN(C[C@H]3C)c4ncc(cc4C)C(=O)O)N5CCC[C@H]5C

Mavatrep, JNJ 39439335,


Mavatrep.png

Mavatrep; UNII-F197218T99; Mavatrep (USAN); JNJ-39439335; 956274-94-5;

2-(2-(2-(2-(4-trifluoromethylphenyl)vinyl)-1H-benzimidazol-5-yl)phenyl)propan-2-ol

(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

(E)-2-(2-(2-(4-(Trifluoromethyl)styryl)-1H-benzo[d]imidazol-5-yl)phenyl)-propan-2-ol Hydrochloride

Phase I Musculoskeletal pain; Pain

  • 01 Mar 2013 Janssen Research and Development completes a phase I trial in Japanese and Caucasian adult male volunteers in the US (NCT01631487)
  • 01 Mar 2013 Janssen completes enrolment in its phase I trial for Pain (in volunteers) in the USA (NCT01631487)
  • 05 Feb 2013 Janssen Research and Development initiates enrolment in a phase I trial for Pain (Japanese and Caucasian volunteers) in USA (NCT01631487)
  • Originator Johnson & Johnson Pharmaceutical Research & Development
  • Developer Janssen Research & Development
  • Class Analgesics; Benzimidazoles; Small molecules
  • Mechanism of Action TRPV1 receptor antagonists

ChemSpider 2D Image | Mavatrep | C25H21F3N2O

PHASE 1
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Public title: A Clinical Study to Investigate the Effect on Pain Relief of a Single Dose of JNJ-39439335 in Patients With Chronic Osteoarthritis Pain of the Knee

http://clinicaltrials.gov/ct2/show/NCT01006304
http://apps.who.int/trialsearch/trial.aspx?trialid=NCT00933582

WP_000113.jpg

http://www.ama-assn.org/resources/doc/usan/mavatrep.pdf  SEE STRUCTURE IN THIS FILE

MAVATREP IS JNJ-39439335

WP_000112.jpg

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol hydrochloride

956282-89-6 CAS NO OF HCl SALT

Org. Process Res. Dev., Article ASAP
Figure
The process development of Mavatrep (1), a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, is described. The two key synthetic transformations are the synthesis of (E)-6-bromo-2-(4-(trifluoromethyl)styryl)1H-benzo[d]imidazole (4) and the Suzuki coupling of 4 with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (5). Compound 1a was prepared in four chemical steps in 63% overall yield.
HCl SALT
 1a as an off-white solid. 1H NMR (DMSO-d6, 500 MHz) δ 8.35 (d, J = 16.6 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.80 (dd, J = 8.1, 1.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 6.6 Hz, 1H), 7.43 (dd,J = 8.4, 1.5 Hz, 1H), 7.39 (ddd, J = 8.1, 7.4, 1.5 Hz, 1H), 7.27 (ddd, J = 7.4, 7.4, 1.3 Hz, 1H), 7.04 (dd, J = 7.5, 1.5, 1H), 1.29 (s, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 147.7 (C), 147.4 (C), 142.3 (C), 140.3 (CH), 139.0 (C), 138.0 (C), 131.7 (CH), 131.1 (C), 130.5 (C), 130.2 (C), 128.7 (2CH), 128.3 (CH), 127.4 (CH), 126.2 (CH), 126.2 (CH), 125.8 (2CH), 124.0 (CF3), 114.3 (CH), 113.2 (CH), 112.4 (CH), 71.6 (C), 32.4 (2CH3); Anal. Calcd for C25H22F3ClN2O·1.2H2O: C, 62.49; H, 5.12; Cl, 7.38; F, 11.86; N, 5.83. Found: C, 62.34; H, 4.93; Cl, 7.24; F, 11.61; N, 5.78. Water wt % calcd, 4.50%; found, 4.52% (determined by KF analysis).
Patent
 p1

CLICK ON IMAGE FOR CLEAR VIEW

Example 10 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol(Cpd 18)

Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

  • [0278]
    A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 μL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70° C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). 1HNMR (400 MHz, DMSO-d6) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.70 (d, 1H, J=16.0 Hz).
  • [0000]

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

  • [0279]
    A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and “3 drops” of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step.
  • [0280]
    To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7 mmol) in acetic acid (100 mL) was added dropwise a solution of Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and a mixture of ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was triturated at room temperature for 3 h to give a precipitate. The solid was filtered, and dried in vacuo to give the title Compound 10c (23.2 g, 73%). 1H NMR (400 MHz, DMSO-d6/CDCl3) δ (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d, 2H, J=8.3
  • [0281]
    Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H, 16.7 Hz).
  • [0000]

Step C. 2-(2-bromo-phenyl)-propan-2-ol

  • [0282]
    To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
  • [0000]

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

  • [0283]
    To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL of THF at −78° C. under argon was slowly added a solution of Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the internal temperature remained below −70° C. The mixture was stirred at −75° C. for 2 h. To the reaction mixture was then added triisopropylborate (59 mL, 255 mmol) in three portions. The mixture was allowed to warm slowly to room temperature overnight. The mixture was then cooled to 0° C., and was carefully quenched with dilute hydrochloric acid (250 mL, 2N). The mixture was then stirred at room temperature for 1 h. The pH of the mixture was checked and adjusted to acidic using additional 2N HCl if prophetic. The two layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, and dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a pale yellow oil. The residue was then diluted with ethyl acetate (400 mL) and, washed with 1N sodium hydroxide solution (150 mL×3). The basic aqueous layers were combined and acidified with 2N HCl. The clear solution turned cloudy when the acid was added. The mixture was extracted with ether (150 mL×3). The organic layers were combined and dried with magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield the title Compound 10e as a colorless oil (26.2 g, 82%) which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (s, 1H), 7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm, 1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
  • [0000]

Step E. (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

  • [0284]
    To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c (19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and PdCl2(dppf).CH2Cl2 (8.9 g, 11 mmol) in a 1 L round bottom flask equipped with water condenser was added 400 mL of anhydrous DME and 200 mL of water. The mixture was evacuated and filled with Argon three times. The mixture was heated to 100° C. for 20 h. The mixture was then cooled to room temperature. The biphasic system was transferred to a 1 L separatory funnel and the two layers were separated. The organic layer was washed with brine (2×300 mL). The aqueous layers were combined and extracted with ethyl acetate once (about 300 mL). The organic layers were combined, dried with sodium sulfate, and filtered. The volume of the filtrate was reduced to about 170 mL under reduced pressure. The mixture was then filtered through a pad of silica gel and the pad was washed with ethyl acetate until the filtrate did not contain any product. After concentration, a light pink/beige solid was obtained. The solid was triturated with 50 mL ethyl acetate, and the mixture was heated to 85° C. for 5 min. The mixture was slowly cooled to r.t., then cooled at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with cold ethyl acetate twice, and dried under vacuum at 40° C. to yield the title Compound 18 as a light beige solid (7.58 g, 33%). RP-HPLC 95% pure.
  • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2 Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d, 1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H), 7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz), 4.85 (s, 1H), 1.21 (s, 6H).
  • Mass Spectrum (LCMS, APCI pos.) Calcd. For C25H21F3N2O: 423.2 (M+H). Found 423.3.
  • m.p. (uncorr.) 250-251° C.

Example 10.1 Scale Up Preparation of (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Cpd 18) Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

  • [0286]
    A 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40° C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (Tmax about 42° C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60° C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40° C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60° C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

  • [0287]
    To a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b (>100%) as a yellow oily solid.
  • [0288]
    A 5-L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, air condenser with argon inlet, and a stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27 mol) and acetic acid (2.13 L). To this solution was added a solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL). After this addition, the temperature spiked to 45° C. in about 30 seconds and then subsided. The reaction was then heated to 90° C. for 16 h (overnight). The reaction was cooled to 40° C., and poured into a mixed solution of EtOAc and heptane (about 1:3, 5.75 L) and a precipitate occurred. The resulting slurry was stirred for 3 h, and the solid was collected by filtration, washed with EtOAc:heptane (1:3, 3 L), and then dried in a vacuum oven (60° C.) to give 324.3 g (65%) of the title Compound 10c as a partial acetate salt.

Step C. 2-(2-bromo-phenyl)-propan-2-ol

  • [0289]
    A 12-Liter 4-neck flask equipped with a thermocouple, condenser, septum, addition funnel and overhead mechanical stirrer under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05 mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a temperature between 2 and 5° C. with stirring and held for 30 min. To the solution was slowly added methyl magnesium bromide in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at a rate to maintain the reaction temperature below 15° C. An exotherm was observed during the addition, the reaction temperature warmed from 3 to 15° C. The addition of 1.05 L Grignard was complete in 4 h (approximate feed rate was 4.17 mL/min). The reaction mixture appeared to be off-white/yellow slurry. The reaction was allowed to warm to room temperature and stirred overnight (15 h). The reaction was sampled by HPLC/TLC and showed no starting material present. The ice bath was again applied to the reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was slowly added over a period of 2 h. The temperature increased dramatically from 0 to 15° C. After the quench was complete, the reaction was stirred at room temperature for 30 min. Additional 2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less than 6. MTBE (1 L) was added to help with the phase split. The reaction was stirred at room temperature for 1 to 2 h to dissolve the solid material into the aqueous phase (most likely Mg(OH)2 which is very basic). The pH must be checked and adjusted with additional acid when necessary. The phases were separated and the aqueous layer was washed with an additional 1 L MTBE (2×500 mL). The organic phases were combined, washed with NaHCO3 solution (2×300 mL), dried over MgSO4, filtered and the filtrate was concentrated under vacuum to yield the title Compound 10d (220.83 g, 97.48% yield) as a clear yellow oil.

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

  • [0290]
    A 12-Liter 4-neck round bottom flask equipped with a thermocouple, condenser, addition funnel and overhead mechanical stirrer under dry Argon was charged with anhydrous THF, (3 L) and chilled to −70 to −78° C. via a dry ice/acetone bath. n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly added via addition funnel. An exotherm was observed as the temperature rose from −78 to −70° C. To the addition funnel was added a solution of Compound 10d (220 g, 979.97 mmol) in anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was slowly added to the n-BuLi solution. The addition took 90 min in order to maintain a reaction temperature below −70° C. After the addition was complete, the reaction mixture was stirred at −70 to −75° C. for 30 min. The triethylborate (230 mL, 1.35 mol) was quickly added in 3 portions at −70° C. An exotherm was observed, the batch temperature rose from −70 to −64° C. The reaction was stirred at −70° C. and slowly warmed to room temperature over night. After the reaction was cooled to 0-5° C., the reaction was slowly quenched with 2 M HCl (1 L, 2.00 mol) added via the addition funnel while maintaining the batch temperature 0-5° C. The reaction mixture was stirred for 1 h. The aqueous phase pH was 9-10. The pH was then adjusted to acidic (4-5) with 2 M HCl (200 mL). The two phases were separated and the aqueous layer was extracted with MTBE (2×500 mL). The combined organic phases were dried with anhydrous magnesium sulfate. The solution was filtered and concentrated to yield a yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed with 1M NaOH (3×500 mL). The product containing basic aqueous phases were combined and acidified with 2 M HCl (800 mL) (the clear solution turns turbid with the addition of acid). After stirring the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted with MTBE (2×500 mL). The organic phases were combined and dried over MgSO4. The solution was filtered and the filtrate was concentrated to yield the title Compound 10e as a clear yellow oil (121.78 grams, 77% yield).

Step E. (E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

  • A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone Valve® and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N2 three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N2 three times. PdCl2(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N2 three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L separatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated to an oil. Two separate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to −5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C25H21N2OF3.0.04% H2O.0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

Example 10.2 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt (Cpd 18)

  • A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, and a nitrogen inlet/outlet was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25 L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3 mol) was added. The reaction was heated to 65° C. for 30 min and all solids dissolved. The solution was cooled and evaporated to dryness. The foam was collected by scraping it out of the flask. The solids were placed in vacuum oven for 24 h at 40° C. to afford 139 g (about 100% isolated yield) of the title Compound 18 monosodium salt as a yellowish solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz), 7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H), 7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For C25H21F3N2O: 423.2 (M+H). Found 423.3. m.p. (uncorr.) 258-259° C.

Example 10.3 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol hydrochloride salt (Cpd 18)

  • A 250-mL separatory funnel was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL). Aqueous HCl (1M, 20 mL) was added to the white slurry, and the separatory funnel was shaken. The solid product quickly dissolved, and a white precipitate started to form. The organic layer was transferred to a 100 mL round bottom flask equipped with a magnetic stir bar, and was stirred for 2 h. The thick slurry was filtered, rinsed with EtOAc (2×5 mL), and put into a vacuum oven at 40° C. for 36 h to afford 0.95 g (87.5%) of the title Compound 18 hydrochloride salt.
Patent Submitted Granted
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190344] 2011-08-04
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190364] 2011-08-04
Benzimidazole Modulators of VR1 [US7951829] 2007-11-08 2011-05-31
////////////Phase I,  Musculoskeletal pain,  Pain, Mavatrep, JNJ 39439335,

New pain relief targets discovered


Lyra Nara Blog

New pain relief targets discovered

The immune cell enters the nerve. Credit: Dr. Marzia Malcangio, King’s College London

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King’s College London made the discovery when researching how pain occurs in nerves in the periphery of the body.

Dr Marzia Malcangio said: “We have been investigating and identifying mechanisms underlying pain generation and our findings could help chemotherapy patients who suffer pain related side effects.”

One potential side effect of some chemotherapy drugs (such as vincristine) is damage to nerves. This is particularly prominent in hands and feet as the drugs affect nerves in the periphery of the body. This causes pain which doctors treat with painkillers. However, some people find that the pain persists.

Dr Malcangio’s team investigated why the chemotherapy drugs were causing pain in hope to solve the problem. The used mice in…

View original post 257 more words

Janssen Research Development, LLC , JNJ 39439335, Mavatrep


Mavatrep.png

Mavatrep; UNII-F197218T99; Mavatrep (USAN); JNJ-39439335; 956274-94-5;

2-(2-(2-(2-(4-trifluoromethylphenyl)vinyl)-1H-benzimidazol-5-yl)phenyl)propan-2-ol

(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

Phase I Musculoskeletal pain; Pain

  • 01 Mar 2013 Janssen Research and Development completes a phase I trial in Japanese and Caucasian adult male volunteers in the US (NCT01631487)
  • 01 Mar 2013 Janssen completes enrolment in its phase I trial for Pain (in volunteers) in the USA (NCT01631487)
  • 05 Feb 2013 Janssen Research and Development initiates enrolment in a phase I trial for Pain (Japanese and Caucasian volunteers) in USA (NCT01631487)
  • Originator Johnson & Johnson Pharmaceutical Research & Development
  • Developer Janssen Research & Development
  • Class Analgesics; Benzimidazoles; Small molecules
  • Mechanism of Action TRPV1 receptor antagonists

ChemSpider 2D Image | Mavatrep | C25H21F3N2O

PHASE 1
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Public title: A Clinical Study to Investigate the Effect on Pain Relief of a Single Dose of JNJ-39439335 in Patients With Chronic Osteoarthritis Pain of the Knee

http://clinicaltrials.gov/ct2/show/NCT01006304
http://apps.who.int/trialsearch/trial.aspx?trialid=NCT00933582

WP_000113.jpg

http://www.ama-assn.org/resources/doc/usan/mavatrep.pdf  SEE STRUCTURE IN THIS FILE

MAVATREP IS JNJ-39439335

WP_000112.jpg

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol hydrochloride

956282-89-6 CAS NO OF HCl SALT

Org. Process Res. Dev., Article ASAP
Figure
The process development of Mavatrep (1), a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, is described. The two key synthetic transformations are the synthesis of (E)-6-bromo-2-(4-(trifluoromethyl)styryl)1H-benzo[d]imidazole (4) and the Suzuki coupling of 4 with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (5). Compound 1a was prepared in four chemical steps in 63% overall yield.
 p1

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Example 10 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol(Cpd 18)

Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

  • [0278]
    A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 μL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70° C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). 1HNMR (400 MHz, DMSO-d6) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.70 (d, 1H, J=16.0 Hz).
  • [0000]

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

  • [0279]
    A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and “3 drops” of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step.
  • [0280]
    To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7 mmol) in acetic acid (100 mL) was added dropwise a solution of Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and a mixture of ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was triturated at room temperature for 3 h to give a precipitate. The solid was filtered, and dried in vacuo to give the title Compound 10c (23.2 g, 73%). 1H NMR (400 MHz, DMSO-d6/CDCl3) δ (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d, 2H, J=8.3
  • [0281]
    Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H, 16.7 Hz).
  • [0000]

Step C. 2-(2-bromo-phenyl)-propan-2-ol

  • [0282]
    To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
  • [0000]

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

  • [0283]
    To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL of THF at −78° C. under argon was slowly added a solution of Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the internal temperature remained below −70° C. The mixture was stirred at −75° C. for 2 h. To the reaction mixture was then added triisopropylborate (59 mL, 255 mmol) in three portions. The mixture was allowed to warm slowly to room temperature overnight. The mixture was then cooled to 0° C., and was carefully quenched with dilute hydrochloric acid (250 mL, 2N). The mixture was then stirred at room temperature for 1 h. The pH of the mixture was checked and adjusted to acidic using additional 2N HCl if prophetic. The two layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, and dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a pale yellow oil. The residue was then diluted with ethyl acetate (400 mL) and, washed with 1N sodium hydroxide solution (150 mL×3). The basic aqueous layers were combined and acidified with 2N HCl. The clear solution turned cloudy when the acid was added. The mixture was extracted with ether (150 mL×3). The organic layers were combined and dried with magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield the title Compound 10e as a colorless oil (26.2 g, 82%) which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (s, 1H), 7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm, 1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
  • [0000]

Step E. (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

  • [0284]
    To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c (19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and PdCl2(dppf).CH2Cl2 (8.9 g, 11 mmol) in a 1 L round bottom flask equipped with water condenser was added 400 mL of anhydrous DME and 200 mL of water. The mixture was evacuated and filled with Argon three times. The mixture was heated to 100° C. for 20 h. The mixture was then cooled to room temperature. The biphasic system was transferred to a 1 L separatory funnel and the two layers were separated. The organic layer was washed with brine (2×300 mL). The aqueous layers were combined and extracted with ethyl acetate once (about 300 mL). The organic layers were combined, dried with sodium sulfate, and filtered. The volume of the filtrate was reduced to about 170 mL under reduced pressure. The mixture was then filtered through a pad of silica gel and the pad was washed with ethyl acetate until the filtrate did not contain any product. After concentration, a light pink/beige solid was obtained. The solid was triturated with 50 mL ethyl acetate, and the mixture was heated to 85° C. for 5 min. The mixture was slowly cooled to r.t., then cooled at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with cold ethyl acetate twice, and dried under vacuum at 40° C. to yield the title Compound 18 as a light beige solid (7.58 g, 33%). RP-HPLC 95% pure.
  • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2 Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d, 1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H), 7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz), 4.85 (s, 1H), 1.21 (s, 6H).
  • Mass Spectrum (LCMS, APCI pos.) Calcd. For C25H21F3N2O: 423.2 (M+H). Found 423.3.
  • m.p. (uncorr.) 250-251° C.

Example 10.1 Scale Up Preparation of (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Cpd 18) Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

  • [0286]
    A 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40° C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (Tmax about 42° C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60° C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40° C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60° C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

  • [0287]
    To a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b (>100%) as a yellow oily solid.
  • [0288]
    A 5-L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, air condenser with argon inlet, and a stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27 mol) and acetic acid (2.13 L). To this solution was added a solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL). After this addition, the temperature spiked to 45° C. in about 30 seconds and then subsided. The reaction was then heated to 90° C. for 16 h (overnight). The reaction was cooled to 40° C., and poured into a mixed solution of EtOAc and heptane (about 1:3, 5.75 L) and a precipitate occurred. The resulting slurry was stirred for 3 h, and the solid was collected by filtration, washed with EtOAc:heptane (1:3, 3 L), and then dried in a vacuum oven (60° C.) to give 324.3 g (65%) of the title Compound 10c as a partial acetate salt.

Step C. 2-(2-bromo-phenyl)-propan-2-ol

  • [0289]
    A 12-Liter 4-neck flask equipped with a thermocouple, condenser, septum, addition funnel and overhead mechanical stirrer under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05 mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a temperature between 2 and 5° C. with stirring and held for 30 min. To the solution was slowly added methyl magnesium bromide in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at a rate to maintain the reaction temperature below 15° C. An exotherm was observed during the addition, the reaction temperature warmed from 3 to 15° C. The addition of 1.05 L Grignard was complete in 4 h (approximate feed rate was 4.17 mL/min). The reaction mixture appeared to be off-white/yellow slurry. The reaction was allowed to warm to room temperature and stirred overnight (15 h). The reaction was sampled by HPLC/TLC and showed no starting material present. The ice bath was again applied to the reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was slowly added over a period of 2 h. The temperature increased dramatically from 0 to 15° C. After the quench was complete, the reaction was stirred at room temperature for 30 min. Additional 2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less than 6. MTBE (1 L) was added to help with the phase split. The reaction was stirred at room temperature for 1 to 2 h to dissolve the solid material into the aqueous phase (most likely Mg(OH)2 which is very basic). The pH must be checked and adjusted with additional acid when necessary. The phases were separated and the aqueous layer was washed with an additional 1 L MTBE (2×500 mL). The organic phases were combined, washed with NaHCO3 solution (2×300 mL), dried over MgSO4, filtered and the filtrate was concentrated under vacuum to yield the title Compound 10d (220.83 g, 97.48% yield) as a clear yellow oil.

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

  • [0290]
    A 12-Liter 4-neck round bottom flask equipped with a thermocouple, condenser, addition funnel and overhead mechanical stirrer under dry Argon was charged with anhydrous THF, (3 L) and chilled to −70 to −78° C. via a dry ice/acetone bath. n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly added via addition funnel. An exotherm was observed as the temperature rose from −78 to −70° C. To the addition funnel was added a solution of Compound 10d (220 g, 979.97 mmol) in anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was slowly added to the n-BuLi solution. The addition took 90 min in order to maintain a reaction temperature below −70° C. After the addition was complete, the reaction mixture was stirred at −70 to −75° C. for 30 min. The triethylborate (230 mL, 1.35 mol) was quickly added in 3 portions at −70° C. An exotherm was observed, the batch temperature rose from −70 to −64° C. The reaction was stirred at −70° C. and slowly warmed to room temperature over night. After the reaction was cooled to 0-5° C., the reaction was slowly quenched with 2 M HCl (1 L, 2.00 mol) added via the addition funnel while maintaining the batch temperature 0-5° C. The reaction mixture was stirred for 1 h. The aqueous phase pH was 9-10. The pH was then adjusted to acidic (4-5) with 2 M HCl (200 mL). The two phases were separated and the aqueous layer was extracted with MTBE (2×500 mL). The combined organic phases were dried with anhydrous magnesium sulfate. The solution was filtered and concentrated to yield a yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed with 1M NaOH (3×500 mL). The product containing basic aqueous phases were combined and acidified with 2 M HCl (800 mL) (the clear solution turns turbid with the addition of acid). After stirring the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted with MTBE (2×500 mL). The organic phases were combined and dried over MgSO4. The solution was filtered and the filtrate was concentrated to yield the title Compound 10e as a clear yellow oil (121.78 grams, 77% yield).

Step E. (E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

  • A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone Valve® and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N2 three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N2 three times. PdCl2(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N2 three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L separatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated to an oil. Two separate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to −5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C25H21N2OF3.0.04% H2O.0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

Example 10.2 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt (Cpd 18)

  • A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, and a nitrogen inlet/outlet was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25 L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3 mol) was added. The reaction was heated to 65° C. for 30 min and all solids dissolved. The solution was cooled and evaporated to dryness. The foam was collected by scraping it out of the flask. The solids were placed in vacuum oven for 24 h at 40° C. to afford 139 g (about 100% isolated yield) of the title Compound 18 monosodium salt as a yellowish solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz), 7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H), 7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For C25H21F3N2O: 423.2 (M+H). Found 423.3. m.p. (uncorr.) 258-259° C.

Example 10.3 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol hydrochloride salt (Cpd 18)

  • A 250-mL separatory funnel was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL). Aqueous HCl (1M, 20 mL) was added to the white slurry, and the separatory funnel was shaken. The solid product quickly dissolved, and a white precipitate started to form. The organic layer was transferred to a 100 mL round bottom flask equipped with a magnetic stir bar, and was stirred for 2 h. The thick slurry was filtered, rinsed with EtOAc (2×5 mL), and put into a vacuum oven at 40° C. for 36 h to afford 0.95 g (87.5%) of the title Compound 18 hydrochloride salt.
Patent Submitted Granted
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190344] 2011-08-04
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190364] 2011-08-04
Benzimidazole Modulators of VR1 [US7951829] 2007-11-08 2011-05-31
////////////Phase I,  Musculoskeletal pain,  Pain, Mavatrep, JNJ 39439335,
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