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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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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Medicinal Chemistry International


Medicinal Chemistry International

World Drug Tracker: Degarelix …NICE backs Ferring’s Firmagon for prostate cancer subgroup


World Drug Tracker: Degarelix …NICE backs Ferring’s Firmagon for prostate cancer subgroup

TAVABOROLE, AN 2690, 他伐硼罗 Таваборол تافابورول


TAVABOROLE

  • AN 2690
  • AN-2690
  • AN2690
  • UNII-K124A4EUQ3

5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

5-Fluoro-2,1-benzoxaborol-1(3H)-ol;

1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole

MOLECULAR FORMULA C7H6BFO2

MOLECULAR WEIGHT 151.9

SPONSOR Anacor Pharmaceuticals, Inc.

CAS REGISTRY NUMBER 174671-46-6Fine

Mp 118-120° C…..US20070265226

1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H)

FDA APPROVED JULY 2 2014………..“FDA Approves Anacor Pharmaceuticals’ KERYDIN™ (Tavaborole) Topical Solution, 5% for the Treatment of Onychomycosis of the Toenails”. Market Watch. July 8, 2014.

Has antifungal activity.

The US Food and Drug Administration (FDA) 2014 JULY 8 ratified the Anacor’s Kerydin (5% Tavaborole solution) for the topical treatment of nail fungal infections. Tavaboroleindications of toenail fungus Trichophyton rubrum or Trichophyton rubrum infections.Instructions recommended once a day for toenail infections, treatment for 48 weeks, on the recommendation of Anacor, and do not need to nail debridement.

I tis an oxaborole antifungal used topically, as a 5% w/w solution, for the treatment of onychomycosis of the toenails due to Trichophyton rubrumor T. mentagrophytes. It is applied to the affected toenail once daily for 48 weeks.

Ingrowing toenails and application site reactions including exfoliation, erythema, and dermatitis have been reported during use.Stock market

1H NMR FROM NET

tavaborole nmr 1h

CLICK ON IMAGE FOR CLEAR VIEW

COSY NMR PREDICT

COSY NMR prediction (14)

Tavaborole (AN2690, trade name Kerydin) is a topical antifungal medication for the treatment of onychomycosis, a fungal infectionof the nail and nail bed. Tavaborole began its Phase 3 trials in December 2010[1] and was approved in July 2014.[2] Tavaborole inhibits an essential fungal enzyme, Leucyl-tRNA synthetase, or LeuRS, required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection. No treatment-related systemic side effects were observed in any of its clinical trials.Passing

Tavaborole is the first oxygen boron used to treat toenail infections dioxolane (oxaborole) antifungal agents, located in Palo Alto, Anacor focuses on boron-based drug development and production, according to the latest news, Tavaborole future also be used to infect fingernails. Wedbush Securities analyst predicts that next year the drug sales in the United States for $ 16 million, by 2021 will reach peak sales of $ 347 million.

Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism.Irrigation

Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the benzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue,  is active against Gram-negative bacteria, including Enterobacteriaceaebearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial,  has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

Anacor continued development on that drug, tavaborole, and filed for FDA approval in July. The FDA will review the phase 3 trial data and issue a decision on July 29, 2014.

If approved, Anacor hopes tavaborole’s ability to clear onychomycosis in 10% of treated patients will be enough to win market share away from generic Lamisil and generic topical Pentac. While Lamisil cleared the fungus in 38% of patients, it’s been associated with rare cases of liver failure. And Pentac requires frequent debridement of the nail and only clears the fungus in 5.5% to 8.5% of patients.

Tavaborole is a novel, topical antifungal medication being developed for the topical treatment of onychomycosis, a nail fungus infection, which affects seven to ten percent of the U.S. population. Early studies show AN-2690 penetrates the nail effectively and has robust activity against dermatophytes, which cause onychomycosis.Top

1H NMR PREDICTYou do not buy

Predict 1H proton NMR spectra (11)

Predict 1H proton NMR spectra VALUES

……………………………………………………………………………

13 C NMR PREDICTStock market

Predict 13C carbon NMR spectra (8)

Predict 13C proton NMR spectra VALUES

ARTICLEGrab spaces

July 18, 2013

Anacor Pharmaceuticals to Present Pivotal Phase 3 Data of Tavaborole for the Topical Treatment of Toenail Onychomycosis
Abstract Accepted for Oral Presentation at the 2013 American Podiatric Medical Association Annual Scientific Meeting

PALO ALTO, Calif.–(BUSINESS WIRE)– Anacor Pharmaceuticals (NASDAQ:ANAC) announced today that its abstract “Pivotal Phase 3 Safety and Efficacy Results of Tavaborole (Formerly AN2690), a Novel Boron-Based Molecule for the Topical Treatment of Toenail Onychomycosis” was accepted for oral presentation at the 2013 APMA Annual Scientific Meeting (The National) to be held in Las Vegas, Nevada. Max Weisfeld, DPM, will present the data from tavaborole’s Phase 3 studies on Monday, July 22, 2013 during the Evidence-Based Medicine and Oral Abstracts session.

As announced earlier this year, tavaborole achieved statistically significant and clinically meaningful results on all primary and secondary endpoints in two Phase 3 pivotal studies without concomitant debridement. Anacor is seeking approval for tavaborole from the Food and Drug Administration (FDA) and will file a New Drug Application imminently. Currently, there is only one FDA-approved topical treatment for onychomycosis, a fungal infection of the nail and nail bed, which affects approximately 35 million people in the United States.Mildew

“I’m impressed with tavaborole’s safety and efficacy data. There is no FDA-approved topical treatment for onychomycosis with tavaborole’s range of efficacy and ability to penetrate the nail to reach the site of the infection,” said Dr. Weisfeld. “Tavaborole’s Phase 3 results demonstrate its ability to clear the nail and eliminate the infection which is important to both patients and the physicians who treat them. In addition, tavaborole is easy to apply and dries quickly which makes it convenient for patients to use.”

“We are pleased to present these positive data at the APMA’s Annual Scientific Meeting, the leading annual meeting of podiatrists. As we seek FDAapproval for tavaborole, we look forward to developing relationships with podiatrists to potentially offer them a new treatment option for the large number of patients who seek treatment for onychomycosis,” said David Perry, Chief Executive Officer of Anacor Pharmaceuticals.

About the StudiesHappy

Anacor conducted two separate Phase 3 studies of tavaborole on patients with distal subungual onychomycosis affecting 20 to 60 percent of the target great toenail. Approximately 600 patients aged 18 years and older with no upper age limit (the oldest subject was 88 years old) were enrolled in each study and randomized two-to-one to receive either tavaborole or the vehicle control. Patients were instructed to apply tavaborole solution or the vehicle to the toenail once daily for 48 weeks.

A copy of the presentation will be available on Anacor’s website following the oral session.

About Anacor Pharmaceuticals

Anacor is a biopharmaceutical company focused on discovering, developing and commercializing novel small-molecule therapeutics derived from its boron chemistry platform. Anacor has discovered eight compounds that are currently in development. Its two lead product candidates are topically administered dermatologic compounds — tavaborole, a topical antifungal for the treatment of onychomycosis, and AN2728, a topical anti-inflammatory PDE-4 inhibitor for the treatment of atopic dermatitis and psoriasis. In addition to its two lead programs, Anacor has discovered three other wholly-owned clinical product candidates — AN2718 and AN2898, which are backup compounds to tavaborole and AN2728, respectively, and AN3365 an antibiotic for the treatment of infections caused by Gram-negative bacteria. We have discovered three other compounds that we have out-licensed for further development — two compounds for the treatment of animal health indications that are licensed to Eli Lilly and Company and AN5568, also referred to as SCYX-7158, for human African trypanosomiasis (HAT, or sleeping sickness), which is licensed to Drugs for Neglected Diseases initiative, or DNDi. We also have a pipeline of other internally discovered topical and systemic boron-based compounds in development. For more information, visit http://www.anacor.com.

 

Patents赞

WO 1995033754

WO 2004009578….

WO 2006089067

WO 2008025543

…………………………..

SYNTHESIS

APX1

 

APX1

APX1

 

 

 

Stock market

Reference:

ELI LILLY AND COMPANY Patent: WO2004/9578 A2, 2004 ; Location in patent: Page 36-37 ; WO 2004/009578 A2

 

APX1

 

PATENT

Anacor Pharmaceuticals Patent: US2007/265226 A1, 2007 ; Location in patent: Page/Page column 59 ;

http://www.google.com/patents/US20070265226

Figure US20070265226A1-20071115-C00072

1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (19b)

To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder:

mp 118-120° C.;

1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H);

ESI-MS m/z 151 (M−H);

HPLC purity 97.8%; Anal (C7H6BFO2) C, H.

Stock market

…………………

Gunasekera, Dinara S.; Gerold, Dennis J.; Aalderks, Nathan S.; Chandra, J. Subash; Maanu, Christiana A.; Kiprof, Paul; Zhdankin, Viktor V.; Reddy, M. Venkat Ram Tetrahedron, 2007 , vol. 63, # 38 p. 9401 – 9405

…………………….

Baker, Stephen J.; Zhang, Yong-Kang; Akama, Tsutomu; Lau, Agnes; Zhou, Huchen; Hernandez, Vincent; Mao, Weimin; Alley; Sanders, Virginia; Plattner, Jacob J. Journal of Medicinal Chemistry, 2006 , vol. 49, # 15 p. 4447 – 4450

………………..

Ding, Charles Z.; Zhang, Yong-Kang; Li, Xianfeng; Liu, Yang; Zhang, Suoming; Zhou, Yasheen; Plattner, Jacob J.; Baker, Stephen J.; Liu, Liang; Duan, Maosheng; Jarvest, Richard L.; Ji, Jingjing; Kazmierski, Wieslaw M.; Tallant, Matthew D.; Wright, Lois L.; Smith, Gary K.; Crosby, Renae M.; Wang, Amy A.; Ni, Zhi-Jie; Zou, Wuxin; Wright, Jon Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 24 p. 7317 – 7322

…………..

PATENT

US20050261277

PREPARATION 13 5-Fluoro-3H-benzo[c][1,2)oxaborol-1-ol

Figure US20050261277A1-20051124-C00027
Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene(5.4 g, 19.5 mmol) in dry THF (100 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at −78° C. Upon complete addition, stir the reaction at −78° C. for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into 1N HCl (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compoud as a white solid.

1H NMR (d6-DMSO)

9.18 (s, 1H),

7.70 (dd, J=8.2, 5.8 Hz, 1H),

7.20 (dd, J=9.5, 2.7 Hz, 1H),

7.11 (m, 1H), 4.92 (s, 1H).

…………………

SEE

http://jpet.aspetjournals.org/content/early/2012/11/28/jpet.112.200030.full.pdf

………………………………..

SEETop

Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis.

Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ.

J Med Chem. 2006 Jul 27;49(15):4447-50.

Boron-containing inhibitors of synthetases.

Baker SJ, Tomsho JW, Benkovic SJ.

Chem Soc Rev. 2011 Aug;40(8):4279-85. doi: 10.1039/c0cs00131g. Epub 2011 Feb 7. Review.

Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.

Zhang YK, Plattner JJ, Freund YR, Easom EE, Zhou Y, Ye L, Zhou H, Waterson D, Gamo FJ, Sanz LM, Ge M, Li Z, Li L, Wang H, Cui H.

Bioorg Med Chem Lett. 2012 Feb 1;22(3):1299-307. doi: 10.1016/j.bmcl.2011.12.096. Epub 2011 Dec 28.

Tavaborole Market Opportunity

Anacor is developing tavaborole specifically to address the current limitations of existing treatment options for onychomycosis. This includes designed leaps forward in both the potential safety and efficacy profile aimed to make the drug a best-in-class therapy. Additionally, management has used the company’s expertise in medicinal chemistry to improve delivery of the compound through the nail plate to the nail bed, the site of onychomycosis infection. For example, preclinical studies indicate that tavaborole is able to penetrate the nail plate 250 times more effectively than ciclopirox.

Tavaborole novel mechanism of action inhibits an essential fungal enzyme, leucyl transfer RNA synthetase, or LeuRS required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection.

Likewise, the topical dosing was designed to eliminate systemic absorption. Previous preclinical and clinical data shows topical treatment with tavaborole resulted in little or no detectable levels of drug in the blood or urine. No treatment related systemic side effects have been observed in any clinical trials to date. Safety data from the company’s studies to date was recently presented at the 100th National APMA meeting in Washington, DC.

Anacor’s topical solution currently in two phase III trials for onychomycosis. Phase II data with tavaborole suggests efficacy superior to ciclopirox with little to no systemic exposure.Top

Data from an open-label phase 2 program with tavaborole showed 50% patients using a 7.5% solution saw 2 mm clear nail growth and negative fungal cultures after six months. Roughly 25% of the patients saw 5 mm clear nail growth and negative fungal cultures after six months.

Anacor and partner Merck (NYSE:MRK) met with the U.S. FDA in 2009 to discuss the phase II data. Merck has since returned the rights to tavaborole to Anacor. The original deal was with Schering-Plough in 2007. Merck most likely felt as though tavaborole clashed with existing products or did not have peak sales potential large enough to continue the partnership with Anacor. We see tavaborole as a specialty promoted product, into podiatrists and dermatologists. For a company like Anacor, it’s an attractive first product.

Anacor’s first phase III trial completed enrollment in November 2011. The second phase III trial completed enrollment in December 2011. Data from these trials are expected around the middle of January 2013. Data from the second study is expected six weeks later. Given the positive phase II data noted above, we think odds favor a positive outcome. A benchmark for the trial is the efficacy of Lamisil, which is a complete cure rate of around 35% to 40%, and a mycological cure of around 70% after a typical course of treatment.

I note that on Anacor’s third quarter conference call management noted that they are pleased with the conduct of the trial to date. Specifically, the compliance rate appears to better than management had expected. The trial was designed with a 20% drop-out rate. It looks as though the drop-out rate is only around 13%, at a minimum suggestive of good safety and tolerability, but potentially also a sign that the drug is working.

I see onychomycosis as a significant market opportunity for Anacor. An estimated 35 million Americans have nail fungus, with about 95% of the infections in the toenail. With efficacy similar to Lamisil, we think Anacor can capture 20% of the market. With a price per course of treatment at around   $1,200, I think peak sales of tavaborole are $500 million.Fine

ChemSpider 2D Image | Tavaborole | C7H6BFO2

Conclusion

I’ll note two more important pieces of information for investors. Firstly, besides optimism for tavaborole, Anacor has apipeline of anti-infectant drugs. For this article I discussed only tavaborole. A second article can be dedicated entirely to AN2728 for the treatment of psoriasis and atopic dermatitis. Anacor also has an animal health collaboration with Eli Lilly (NYSE:LLY).

The second important thing to note is Anacor’s cash position. The company reported financial results on November 7, 2012. The company held $36.6 million in cash on the balance sheet as of September 30, 2012. However, in October 2012, the company completed an underwritten public offering of 4.0 million shares of common stock at $6.00 per share to raise net proceeds of $22.7 million. I view the current cash position as sufficient to report data from both phase 3 trials and, if positive, file the new drug application (NDA) around the middle of 2013.

With phase 3 data expected in less than two months, good prior evidence of both safety and efficacy, and a solid cash position, I think Anacor could be an attractive investment at today’s price. The stock is down meaningfully over the past month and investors can buy sizably below the October offering.

Fine赞顶顶顶路过顶灌水顶顶开心顶赞灌水路过

SYNTHESIS

ReferencesFine

Tavaborole
Tavaborole.svg
Tavaborole ball-and-stick model.png
Systematic (IUPAC) name
5-Fluoro-2,1-benzoxaborol-1(3H)-ol
Clinical data
Trade names Kerydin
Legal status
  • (Prescription only)
Routes of
administration
Topical use only
Identifiers
CAS Registry Number 174671-46-6
ATC code None
PubChem CID: 11499245
ChemSpider 9674047
Synonyms AN2690
Chemical data
Formula C7H6BFO2
Molecular mass 151.93 g/mol

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NMR PREDICT

H-NMR spectral analysis
5-fluoro-1-hydroxy-3H-2,1-benzoxaborole NMR spectra analysis, Chemical CAS NO. 174671-46-6 NMR spectral analysis, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole H-NMR spectrum
CAS NO. 174671-46-6, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole H-NMR spectral analysis
C-NMR spectral analysis
5-fluoro-1-hydroxy-3H-2,1-benzoxaborole NMR spectra analysis, Chemical CAS NO. 174671-46-6 NMR spectral analysis, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole C-NMR spectrum
CAS NO. 174671-46-6, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole C-NMR spectral analysis

more

GSK2251052

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.Anacor

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.

Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets………..https://pubs.acs.org/cen/coverstory/89/8912cover3.html

 UPDATED………….

Click to access NMR.pdf

mp 118-120….http://www.syninnova.com/catalog/product/SL-264

Click to access HPLC.pdf

antifugal AN2690 by Anacor

Tavaborole inhibits an essential fungal enzyme, Leucyl-tRNA synthetase, or LeuRS, required for protein synthesis.
Minimum Inhibitory Concentration: 1, 1, 0.5, 0.25, and 0.25 μg/mL for T.rubrum, T.mentagrophytes, C.albicans, C.neoformans, A.fumigatus, respectivley.

AN2690 is a new boron-containing antifungal agent for the potential treatment of onychomycosis. Onychomycosis is caused mainly by dermatophytes, a class of fungus that dwells on skin, hair, and nails and is the cause of other cutaneous fungal infections such as athlete’s foot.

In vitro: AN2690 showed the most active against fungi and especially against the dermatophytes T. rubrum and T. mentagrophytes, the primary fungal pathogens causing onychomycosis. In addition, AN2690 was identified as having a unique profile of in vitro antidermatophyte activity, maintenance of this activity in the presence of keratin, and exceedingly good penetration of human nails [1].

Ex vivo: AN2690 was found to have superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis [2].

Clinical trial: The efficacy of tavaborole as a topical treatment for onychomycosis has been evaluated in two identical randomised, double-blind phase III studies, NCT01270971 (301) and NCT01302119 (302), enrolling 593 and 601 patients, respectively. Completely or almost clear nail and negative mycology was achieved in 15.3 and 17.9 % of tavaborole recipients compared with 1.5 and 3.9 % of vehicle recipients [3]

References:
[1] Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem. 2006;49(15):4447-50.
[2] Hui X, Baker SJ, Wester RC, Barbadillo S, Cashmore AK, Sanders V, Hold KM, Akama T, Zhang YK, Plattner JJ, Maibach HI. In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007;96(10):2622-31.
[3] Markham A. Tavaborole: first global approval. Drugs. 2014;74(13):1555-8.

UPDATE

 

http://www.google.im/patents/EP1976536A2?cl=en

EXAMPLE 23

Alternative Preparation of 4 from 3

A 22.0 L 3-neck flask was equipped with a stir motor, N2 inlet, addition funnel, heating mantle, and condenser. The flask was charged with 3500 g (17.1 moi) of 2-bromo-5-fluorobenzyl alcohol followed by the addition of 3556 g of tetrahydrofuran and 16.4 g (0.17 mol) of methanesulfonic acid. Next, 400 g (4.7 mol) of 3,4-dihydro-2H-pyran was added at 100C. This step is exothermic so no additional charges should be made until exotherm subsides. The temperature was increased to 27°C, stirred for 15 min and then charged with 400 g (4.7 mol) of 3,4-dihydro-2H- pyran at 240C. Again the temperature increased (24°C to 380C). The mixture was stirred for 15 min. Once the exotherm subsided, the flask was again charged with 40Og (4.7 mol) of 3,4-dihydro-2H-pyran at 350C. The temperature again increased to 470C over a 20 min period. Once the exotherm subsided, the mixture was stirred for 15 min. Finally the remaining 400 g (4.7 mol) of 3,4-dihydro-2H-pyran was added at 440C. The temperature increased to 510C. After stirring for one hour, a sample was removed to check for removal of starting material. Upon reaction completion, contents were cooled to 20 ± 5 0C.

EXAMPLE 24

Figure imgf000215_0001

Alternative Preparation of 5 from 4

To a 22.0 L 3-neck flask equipped with a stir motor, N2 inlet, addition funnel, cooling bath, and condenser was charged 436 g (17.96 mol) of magnesium turnings. 5334 g of tetrahydrofuran was then added followed by 291 g (0.51 mol) of diisobutylaluminum hydride (DIBAL) (25%wt) in toluene. The mixture was stirred for 60 min at 20 ± 5 0C. Some gas evolution was seen. Next, 260-430 g -3-5% (by weight if solution of 4 was dropped to drums) of 4 in THF was added. The mixture was stirred for 15-30 min at which time a slight exotherm should be seen (ΔT = 10- 150C). Once the exotherm was observed, the reaction mixture was cooled to 5 ± 5 0C. To this mixture, the remaining 8.22-8.39 kg of 4 in THF was added at a rate such that the temperature was kept below 300C (t = 3h). The reaction was stirred at 20-25 0C for 30 min, at which time an aliquot was removed, quench with 3 N HCl (10 mL), and analyzed.

Upon completion, the contents were cooled to -25 ± 5°C. A solution of trimethylborate in THF was prepared by mixing 2665 g (25.7 mol) of trimethyl borate and 6666 g of tetrahydrofuran. This solution can be prepared in a drum with stirring. [0618] Next, the 9331 g of trimethyl borate in THF was added at a rate such that the temperature was kept between -35 and -20 °C (t = 2.5h). The mixture became very thick so THF was added. After stirring at -25 ± 5°C for 10 min, 50 mL aliquot was removed, quenched with 25 mL of 3N HCl, and submitted for CoR. Stirring continued at -25 ± 50C for Ih, and then the mixture was allowed to warm to ambient temperature, where it was stirred for at least 12h. Pull two samples (one at 6h and the other at 12h).

Results:

1H-NMR (300 MHz, DMSO-d6) δ (ppm) 1.45-1.75 (m, 6H), 3.53 (s, 6H), 3.45 (m, IH), 3.75 (m, IH), 4.69 (t, J=3 Hz, IH), 4.97 (d, J=14.1 Hz, IH), 5.14 (d, J=14.1 Hz, IH), 7.03 ((td, J=8.4, 2.7 Hz, IH), 7.24 (dd, J=10.8, 2.1 Hz, IH), 7.89 (t, J=7.8 Hz, IH), 8.76 (s, IH).

EXAMPLE 25

Alternative Preparation of I from 5

Figure imgf000216_0001

To the reaction mixture above was added 5.3 kg of USP water. After stirring for 30 min, the mixture was charged 5.3 kg of acetic acid. Gas evolution was seen. After stirring for 30 min, an aliquot was removed for analysis. Mixture was then heated to reflux for 36-48 hours. During the reflux period, 12-13 L of THF were removed.

When the reaction was complete, the contents were cooled by the reactor to <40°C by setting jacket and by charging 10.5 kg of USP water. THF was removed until distillate did not remain. Contents of the reactor were transferred to Rosenmund filter dryer and allowed to cool to 20 ± 5°C. Reactor was rinsed with water, filtered, and then washed again with 10.5 kg of USP water. The flask was charged with 10.5 kg of 10% ACN in water (v/v) and agitated for Ih. After filtering, the cake was washed with 10.5 kg of 10% ACN in water (v/v), and then charged with 10.5 kg 10% ACN in water (v/v). The contents were agitated for Ih. The contents were subsequently washed with 10.5 kg of USP water, charged with 7.0 L of 5% Methyl t- Butyl Ether (MTBE)/Heptane (v/v), agitated for Ih, filtered, charged with 7.0 L of 5% MTBE/Heptanes (v/v) and again agitated for Ih. After filtering, the contents were charged again with 7.0 L of heptane and filtered. Solids were dried at <45°C to constant weight. Solids were recrystallized from toluene :heptane 75:25.

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Medicinal Chemistry International


Medicinal Chemistry International

Vedroprevir


Vedroprevir

GS 9451, GS-9451, 1098189-15-1 USAN ZZ-81

VEDROPREVIR THERAPEUTIC CLAIM Treatment of hepatitis C

CHEMICAL NAMES 1. Cyclopropanecarboxylic acid, N-[[(1α,3β,5α)-bicyclo[3.1.0]hex-3- yloxy]carbonyl]-3-methyl-L-valyl-(4R)-4-[[8-chloro-2-[2-[(1-methylethyl)amino]- 4-thiazolyl]-7-[2-(4-morpholinyl)ethoxy]-4-quinolinyl]oxy]-L-prolyl-1-amino-2- ethyl-, (1R,2R)-

2. N-{[(1R,3r,5S)-bicyclo[3.1.0]hex-3-yloxy]carbonyl}-3-methyl-L-valyl-(4R)-4-[(8- chloro-2-{2-[(1-methylethyl)amino]thiazol-4-yl}-7-[2-(morpholin-4- yl)ethoxy]quinolin-4-yl)oxy]-L-prolyl-(1R,2R)-1-amino-2- ethylcyclopropanecarboxylic acid

MOLECULAR FORMULA C45H60ClN7O9S

MOLECULAR WEIGHT 910.5 daltons

SPONSOR Gilead Sciences, Inc.

CODE DESIGNATION GS-9451

CAS REGISTRY NUMBER1098189-15-1

WHO NUMBER9745

GS-9451 is a NS3 protease inhibitor in phase II clinical trials at Gilead for the oral treatment of hepatitis C.

…………………………………………………………………………

Discovery of GS-9451: An acid inhibitor of the hepatitis C virus NS3/4A protease Bioorg Med Chem Lett 2012, 22(7): 2629   ……………………………………………………………

PATENTS WO 2012087596 WO 2009005676 WO 2013106631 WO2013101550 ……………………….

WO2012087596A1 Compound 3 can be prepared using synthetic methods and intermediates like those described in USSN 12/215,605 (US 20090257978 A1). Compound 3 can also be prepared described in the following Example. Example 3: Preparation of Compound 3

Figure imgf000060_0001

Compound 315 (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11g, 260 mmol) in H20 (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 hours. Upon completion of the reaction, 4 N HCI in H20 was added to adjust pH to 7 at 0 °C. The mixture was extracted with EtOAc (2 x 400 ml). The combined organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo to give compound 3 as a yellow solid (11 g, 93%). LC/MS = 911.52(M++1 ). 1H NMR (300MHz, CD3OD)57.95 (d, 1H), 7.90 (s, 1H), 7.48 (s, 1H), 7.31 (d, 1H), 5.42 (s, 1H), 4.37 (dd, 1H), 4.20 (m, 2H), 3.83-3.56 (m, 7H), 3.50 (m, 2H), 3.39 (m, 2H), 2.45 (m, 1H), 2.27(m, 1H), 1.62 (m, 2H), 1.50 (m, 1H), 1.33 (m, 2H), 1.18 (m, 1H), 1.05 (m, 8H), 0.90 (m, 3H), 0.76 (m, 11H), 0.14-0.04 (m, 2H) The intermediate compound 315 was prepared as follows.

Figure imgf000060_0002

301 302 a. Preparation of compound 301. To a dry, argon purged three-neck round bottom flask (1000 mL) were added anhydrous dichloromethane (100 mL) and Et2Zn (28 mL, 273 mmol) at 0 °C. (CAUTION: Source of argon can not be from needle. Use appropriate glass adapter only. A second bubbler can also be attached to the flask to prevent excessive pressure build up.) Cyclopenten-3-ol (10.0 mL, 119 mmol) was then added dropwise (large quantity of ethane gas was produced) to the flask and the reaction mixture was allowed to stir until the evolution of gas had ceased. Diiodomethane (22 mL, 242 mmol) was then added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature and continued to stir overnight under a positive flow of argon, at which point TLC analysis had indicated complete disappearance of the starting alcohol. The reaction was then diluted with CH2CI2 and quenched with 2M HCI (white precipitate should be completely dissolved). The biphasic mixture was poured into a separatory funnel and the organic layer was collected. The solvent was removed under reduced pressure until 100 mL of material containing compound 301 remained. b. Preparation of compound 302. Anhydrous dichloromethane (525 mL) was added to the flask followed by the dropwise addition of triethylamine (34 mL, 245 mmol). The reaction continued to stir at room temperature under a positive flow of nitrogen at which point, disuccinimidylcarbonate (40.7 g, 159 mmol) was added to the flask portion wise. The reaction was allowed to stir until TLC analysis indicated complete disappearance of the starting material (2-3 days). Upon completion, the reaction mixture was quenched with 1 M HCI (200 mL x 2) and washed with H20 (200 mL x 2). The desired material was extracted using CH2CI2and the combined organic layers were dried using anhydrous MgS0 and passed through a silica plug. The solvent was removed under reduced pressure and the crude material was purified using flash chromatography (Rf = 0.33, 1 :1 Hex/EtOAc) to provide compound 302 (22 g, 75%): 1H NMR (300 MHz, CDCI3): δ 5. 24 (t, 1 H), 3.82 (s, 4H), 2.24 (m, 2H), 2.03 (d, 2H), 1.38 (m, 2H), 0.48 (m, 1 H), 0.40 (m, 1 H).

Figure imgf000061_0001
Figure imgf000062_0001

c. Preparation of compound 304. N-i-Boc-cis-4-Hydroxy-L-Proline methyl ester 303 (100.0 g, 407.7 mmol) and DABCO (1.5eq, 68.6g, 61 1.6 mmol) were dissolved in anhydrous toluene (200 mL) in a 2 L three necked round bottom flask with a mechanical stirrer and an addition funnel. After cooling the solution to 0 °C under N2, A solution of 4-Bromo-benzenesulfonyl chloride (1.3eq, 135.6g, 530.0 mmol) in 300 mL of toluene was added through addition funnel over 60 minutes. The reaction mixture was stirred and warmed to room temperature overnight (16 hours). The mixture was slowly poured into 2L 1 M Na2C03 (aq.), and the product was extracted with EtOAc (2L). After the organic phase was washed by 0.5 N HCI (2L), H20 (1 L), and brine (1 L), it was dried (MgS04), concentrated to give 195.45 g of a yellow oily brosylate product. To a solution of the above brosylate (407.7 mmol) in dichloromethane (300 mL) was slowly added 4.0 M HCI in dioxane (500 mL, 5eq) and the resulting solution was allowed to stir at room temperature for 2 hours. After ether (500mL) was added to the reaction mixture, the mixture was stirred for 15 minutes and the white precipitate was collected by filtration. The solid was washed with ether and hexane and then dried under vacuum overnight to obtain 153.0 g of the HCI amine salt of compound 304, 381.8 mmol, in 94% yield for two steps. d. Preparation of compound 305. To a solution of Boc-fert-butyl-glycine (97.0g, 420.0 mmol) in DMF (200mL) and DCM (200mL) were added HATU (217.76g, 572.7 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of the previous HCI salt (153.0 g, 381.8 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3h, with monitoring by LCMS. The reaction mixture was concentrated to remove dichloromethane under reduced pressure and the white solid that formed was filtered off. The remaining DMF solution was diluted with ethyl acetate (1 L), washed successively with 3% LiCI (aq) (3x650mL), sat’d NH4CI (2x500mL), 0.5N HCI (aq) (2x600ml_), brine (500ml_), sat’d NaHC03 (3x500mL), and brine (500mL). The resulting organic fraction was dried (MgS04) and concentrated to afford compound 305 (111g). e. Preparation of compound 306. To a solution of the methyl ester 305 (120 g, 207.8 mmol) in THF (300 ml_), MeOH (75 mL) was added a solution of LiOH (26.18 g, 623.4 mmol) in H20 (150 ml_). The solution was allowed to stir at room temperature for 4 hours. The mixture was cooled in an ice-bath while acidifying with 3N HCI to pH about 5.5, stirred for 10minut.es, and the resulting white solids were collected by filtration. The solids were washed with more water, ether and hexane. The solids were dried under vacuum at 40°C overnight to give 95.78g (82%) of the acid 306. f. Preparation of compound 307. To a solution of the carboxylic acid 306 (81.4 g, 144.27 mmol) in DMF (200ml_) and dichloromethane (200mL) was added HATU (82.3g, 216.4 mmol) and Hunig’s base (47.5 mL, 432.8 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of amine (158.7 mmol) and Hunig’s base (47.5 mL, 1145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3 hours and monitored by LCMS. After the mixture was concentrated under reduced pressure to remove dichloromethane, the white solids that formed were filtered off. The remaining DMF solution was diluted with ethyl acetate (600mL) and successively washed with 3% LiCI (aq) (2x550mL), sat’d NH4CI (500mL), 1 N HCI (aq) (500mL), sat’d NaHC03(500mL), and brine (300mL). The resulting organic fraction was dried (Na2S04) and concentrated to afford compound 307 (111 g). g. Preparation of compound 308. Compound 307 was dissolved in 4N HCI in dioxane (300 mL) at room temperature and stirred for 2 hours. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2 x 200mL) to dryness. The residue was dissolved in EtOAc (600mL) and sat’d aq. NaHC03 (1 L). It was stirred vigorously. After 10 minutes, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester 302 (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 minutes, the organic layer was collected and washed with brine (500mL), dried (Na2S04), and concentrated. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.44 g (92%) of compound 308.

Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003

h. Preparation of compound 310.1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 309 (70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110 °C for 72 hours. After the mixture was cooled to 0 °C with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHC03 solution (-350 mL), filtered, washed with water, and dried under vacuum to give – 40 g (61%) of crude 310 as a dark brown solid. LC/MS = 186 (M++1). i. Preparation of compound 311. 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 310 (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65 °C for 24 hours. Upon cooling to room temperature, EtOAc (1 L) and H20 (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1 x 400 ml). The combined organic layer was washed with aqueous 3% LiCI solution (2 x 1 L), brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 311 as a white solid (39 g, 67%). j. Preparation of compound 312. To a mixture of 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone 311 ( 13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (12.64 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at -40 °C. The mixture was then stirred at 0 °C for 4 hours. Upon completion of the reaction, H20 (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0 °C for another 15 minutes. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHC03 aqueous solution. The organic layer was dried (Na2S04) and concentrated in vacuo. The residue was dissolved in CH2CI2, hexanes were added slowly to the solution, and a yellow solid started to crash out. More hexanes were added until not much product was left in the mother liquid to provide compound 312 (18 g, 85%). k. Preparation of compound 313. 2-lsopropylamino-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)- phenyl]-amide 312 (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while monitoring H2evolution. The mixture became a clear solution during heating to reflux. The reaction was complete after refluxing for 3 hours. The mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H20 (3 vol) was added to the mixture. After vigorous agitation for 1 hour at 0 °C, the solids were collected by filtration, rinsed forward with H20. The wet cake was dried under high vacuum to a constant weight to provide compound 313 ( 5 g, 86%). I. Preparation of compound 314. To a mixture of brosylate intermediate 303 (15 g, 35 mmol) and compound 313 (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65 °C for 5 hours. The reaction was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCI (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCI (1 x 600 ml), brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired methyl ester as a yellow solid (23.6 g, 75%). LC/MS = 900. 1 3(M++ 1 ) . m. Preparation of compound 315. Methyl ester 314 (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml), 1.4 N HCI in H20 (75 ml) was added to the solution. The mixture was stirred at 60 °C for 1 hour. Upon completion of the reaction, the mixture was concentrated to remove the solvents, coevaporated with toluene (x 2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHC03 aqueous solution (enough to neutralize the mixture) while monitoring C02 evolution. The organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used as is for the next step. The crude was dissolved in CH2CI2 (360 ml), morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0 °C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 minutes at 0 °C. Sat. NaHC03 aqueous solution was added to quench the reaction. After stirring for another 20 minutes, the organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired amine product 315 as a yellow solid (12 g, 50%). LC/MS = 924.63(M++ 1 )

Preparation of 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylic acid 215. To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate 214 (36.5g, 0.145 mol) in a mixture of 1 :1 of MeOH: THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H20 (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCI. The resulted gummy residue was filtered and dried on the lyophilizer for 2 days to provide 34.4 g (99.6 %) of compound 215 as a white solid. El MS (mlz) 253.9 [M+H]. j. Preparation of 2-(2-diazo-l-oxo)-8-chloro-7-methoxyquinolin-4-yl isobutyl carbonate 216. To a solution of 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylic acid 215 (10.2 g, 0.04 mol) in THF (400 mL) was added triethyl amine (12.3 mL, 0.088 mol) and /-Butylchloroformate (11.6 mL, 0.088 mol) at 0°C under an argon atmosphere. The mixture was stirred at 0°C for 1 hour when LCMS analysis demonstrated completion of the reaction to provide the desired mixed anhydride. El MS (mlz) 454.0 [M+H]. To the reaction mixture of the anhydride was added a 1 M solution of diazomethane (121 mL, 0.121 mol) in diethyl ether via a plastic funnel at 0°C. This mixture was allowed to stir while warming up to room temperature for additional 2 hours. Analysis of the mixture by LCMS demonstrated completion of the reaction. The septum was removed and the reaction was stirred for additional 20 minutes before removal of the solvent. The residue was dried further under high vacuum to provide compound 216, which was carried on to the next step. El MS (m/z) 377.9 [M+H]. k. Preparation of 8-chloro-2-(2-(isopropylamino)thiazol-4-yl)-7-methoxyquinoiin-4-ol 207. To a cooled solution of 2-(2-diazo-l-oxo)-8-chloro-7-methoxyquinolin-4-yl isobutyl carbonate 216 (15.2 g, 0.040 mol) at 0°C in THF (268 mL) was added 48% HBr (23 mL, 0.201 mol) slowly over 15 minutes. The solution was stirred at 0°C for an additional 40 minutes when LCMS analysis demonstrated complete reaction. The reaction was worked up by addition of aqueous 1 N NaOH (180 mL) at 0° C to adjust the pH of the aqueous layer to 9. The layers were separated and the aqueous layer was washed with EtOAc (2 x 200 mL). Combined organic extracts were washed with brine and dried over MgS04. The solvent was removed in vacuo to provide 17.7 g of a yellow solid. El MS (m/z) 431.9 [M+H]. The solution of the bromoketone obtained from the previous reaction was suspended in i-propanol (270 mL) and isopropylisourea (9.4 g, 0.080 mol). The reaction mixture was heated at 72 °C for 32 hours. LCMS analysis of the reaction demonstrated complete conversion to the desired- product. The reaction was allowed to cool to room temperature to allow for the product to precipitate out of the solution. The reaction was further cooled to 0°C for 12 hours before filtration. The filtrate was washed with ether and dried on lyopholizer to provide 8.03 g of compound 207 as an orange solid. 1H NMR (500 MHz, CDCI3): δ 8.21 (d, J= 9 Hz, 1 H), 7.74 (s, 1 H), 7.44 (d, J= 10Hz), 1 H), 7.07 (s, 1 H), 4.05 (s, 3H), 3.92 (pentet, J=6 Hz, 1 H), 1.25 (d, J= 7 Hz, 6H): El MS (m/z) 350.0 [M+H].

Medicinal Chemistry International: NARLAPREVIR


Medicinal Chemistry International: NARLAPREVIR

TOLVAPTAN 的合成 …European Medicines Agency (EMA) Accepts Otsuka’s Marketing Authorisation Application (MAA) for Tolvaptan


TOLVAPTAN

的合成

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

Formula C26H25ClN2O3 
Mol. mass 448.941 g/mol

150683-30-0 CAS NO

OPC-41061

Otsuka…..innovator

European Medicines Agency (EMA) Accepts Otsuka’s Marketing Authorisation Application (MAA) for Tolvaptan, an Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD)

•Tolvaptan was discovered by Otsuka in Japan and, if approved by the EMA, would become the first pharmaceutical therapy in Europe for patients with ADPKD
•ADPKD is an inherited genetic disease that causes cyst growth in the kidneys, which gradually impairs their functioning. There is no current pharmaceutical treatment option
•Otsuka’s development of tolvaptan as a treatment for ADPKD illustrates the company’s commitment to address significant patient needs for diseases that traditionally have not been a priority for the pharmaceutical industry

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. announced today that the European Medicines Agency (EMA) has accepted the submission of a marketing authorisation application (MAA) for the potential approval of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine.

http://www.pharmalive.com/ema-accepts-otsukas-maa-for-tolvaptan

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP).

Tolvaptan is (±)-4′-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-otolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:

SAMSCA® (tolvaptan) Structural Formula Illustration

SAMSCA tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

ChemSpider 2D Image | Tolvaptan | C26H25ClN2O3

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

Chemical synthesis:[5] Tolvaptan.png

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Figure US20130190490A1-20130725-C00001

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. Pat. No. 5,258,510.

Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid. According to the journal, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation oftolvaptan can be prepared by the reduction of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

Biooganic and Medicinal Chemistry I (2007) 6455-6458, Biooganic andMedicinal Chemistry 14 (2000) 2493-2495 reported in the literature of the intermediate 2 – carboxylic acid -5 – (2 – methyl-benzoylamino) toluene synthesis method,

5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.

……………………………………….

PATENT

CN102382053AFigure CN102382053AD00031

……………………………………………..

PATENT

CN102060769

Figure CN102060769BC00021

Synthesis of Intermediate III: 1.

Example

  2-methyl-4-nitrobenzoic acid (available from Alfa Aesar Tianjin Chemical Co., purity> 99%, 25g,

0.14mol) was added to a 250ml reaction flask, is reacted with thionyl chloride under reflux conditions for 3h, thionyl chloride was distilled off under reduced pressure to give 2-methyl-4-nitrobenzoyl chloride (26.Sg, light yellow oily liquid), without purification, was used directly in the next step.

  Intermediate II (20g, 0.1moI) and 2_ methyl _4_ nitrobenzoylchloride (22.4g, 0.llmol) was added to a 250ml reaction flask. Dichloromethane (50ml), cooled to ice bath with stirring to dissolve O~5 ° C, was slowly added dropwise N- methylmorpholine (11.2g, 0.llmol), Bi dropwise with stirring while, at room temperature the reaction 4h. TLC [developing solvent: ethyl acetate – petroleum ether (I: I), hereinafter] is displayed after completion of the reaction, saturated aqueous sodium bicarbonate (20ml), stirred for lOmin, filtered, the filter cake with dichloromethane (15ml X 2 ) washing. The filtrate and washings were combined, washed with saturated sodium chloride solution (30ml X 3), dried over anhydrous sodium sulfate and filtered. The filtrate under reduced pressure to recover the solvent, the residue was recrystallized from anhydrous methanol to give a white powder 111 (27.5g, 75.2%), mp 154.8 ~155.6 ° C. Purity 97.9% (HPLC normalization method).

Synthesis of Intermediate IV:

Intermediate III (10g, 28mmol) was added to a 250ml reaction flask, concentrated hydrochloric acid (40ml) and ethanol (50ml), with stirring, was slowly added dropwise stannous chloride (20g, 88mmol) in ethanol (40ml) . Bi room temperature drops 5h. After TLC showed completion of the reaction, ethanol was distilled off under reduced pressure to about 70ml, the residue was -10 ° C -0 ° C allowed to stand overnight to cool. Filtered, and the filter cake was washed with water poured into water (40ml) in. Plus 20% sodium hydroxide solution (approximately 60ml) was adjusted to pH 9. Filtered, washed with ethanol and recrystallized to give a pale yellow powdered solid IV (6.3g, 68.7%), mp 190.4~191.1 ° C. Purity 97.2% (HPLC normalization method).

Synthesis of intermediate V:

  Intermediate IV (5g, 15mmol) and triethylamine (2.3g, 23mmol) was added followed by IOOml reaction flask was added dichloromethane (30ml), stir until dissolved. Solution of o-methylbenzoyl chloride (2.8g, 18mmol), dropwise at room temperature completion of the reaction Ih0 TLC showed the reaction was complete was poured into ice-water (about 40ml) in, (20ml X 3) and extracted with dichloromethane, the combined organic phases, and saturated sodium chloride solution successively (25ml X 3), dried over anhydrous sodium sulfate and filtered with 5% hydrochloric acid (25ml X 3). The filtrate under reduced pressure to recover the solvent (about 50ml), dried over anhydrous methanol residue – petroleum ether (2: 1) and recrystallized to give white crystals of Intermediate V (6.2g, 90.9%), mp 121.1 ~123.6 ° C. Purity 98.6% (HPLC normalization method).

Synthesis of tolvaptan: Example 4

Intermediate V (5g, Ilmmol) IOOml added to the reaction flask, was added anhydrous methanol (25ml), stirred and then added portionwise sodium borohydride (0.65g, 17mmol) to the reaction mixture, addition was complete the reaction at room temperature lh. After TLC showed the reaction was complete, the methanol recovered under reduced pressure (approximately 20ml), the residue was added methylene chloride (25ml), (25mlX3) and washed with saturated sodium chloride solution. Anhydrous sodium sulfate and filtered, and the filtrate under reduced pressure to recover the solvent, the residue with absolute methanol – petroleum ether (2: 1) and recrystallized tolvaptan white crystals (4.85g, 96.6%), mp 220.1~221.5 ° C. Purity 99.2% (HPLC normalization method). ES1-HRMS (C26H25C1N203, m / z) found (calc): 447.1476 (447.1481) [MH] – “

…………..

PATENT

http://www.google.com/patents/WO2012046244A1?cl=en

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxylH-l- benzazepin- 1 -yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. patent no. 5,258,510. Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5- one, 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine and 7-chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-lH-l- benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p- toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-l-p- toluenesulfonyl-lH-l-benzazepine, and then reacted with polyphospholic acid.

According to the journal, 7-chloro- 1 -(2 -methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro- l-[2-methyl-4-[(2- methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine can be prepared by reacting l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- lH-l-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation of tolvaptan can be prepared by the reduction of 7-chloro- l-[2-methyl-4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

 SYNTHESIS CONSTRUCTION

to1

TO0

to2

to3

to4

to5

Reference example 1 :

Preparation of methyl 5-chloro-2-nitrobenzoate

Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5- chloro-2-nitrobenzoate (534 gm). Reference example 2:

Preparation of methyl 2-amino-5-chlorobenzoate

A mixture of methyl 5-chloro-2-nitrobenzoate (534 gm) as obtained in reference example 1 and concentrated hydrochloric acid (2250 ml) was added to ethyl acetate (1120 ml). To the reaction mixture was added a solution of tin chloride (1680 gm) in ethyl acetate (2250 ml). The reaction mass was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with aqueous sodium hydroxide solution (2650 ml). The separated aqueous layer was extracted with ethyl acetate and then concentrated to obtain a residual solid of methyl 2- amino-5-chlorobenzoate (345 gm). Reference example 3:

Preparation of methyl 5-chIoro-2-(N-p-toluenesulfonyl)aminobenzoate

To a solution of methyl-2-amino-5-chloro benzoate (345 gm) as obtained in reference example 2 in pyridine (1725 ml) was added p-toluenesulfonyl chloride (425 gm). The reaction mixture was stirred for 2 hours at room temperature and poured to the ice water. The separated solid was filtered and dried to obtain 585 gm of methyl 5- chloro-2-(N-p-toluenesulfonyl)aminobenzoate.

Reference example 4:

Preparation of methyl 5-chloro-2-[N-(3-ethoxycarbonyI)propyI-N-p- toluenesulfonyl] aminobenzoate

Methyl 5-chloro-2-(N-p-toluenesulfonyl)aminobenzoate (585 gm) as obtained in reference example 3, ethyl-4-bromo butyrate (369.6 gm) and potassium carbonate (664 gm) in dimethylformamide (4400 ml) were added at room temperature. The contents were heated to 120°C and maintained for 2 hours. The reaction mass was poured into water and filtered. The solid obtained was dried to give 726 gm of methyl 5-chloro-2-[N- (3 -ethoxycarbonyl)propyl-N-p-toluenesulfonyl] aminobenzoate.

Reference example 5:

Preparation of 7-chloro-4-ethoxycarbonyI-5-oxo-N-p-toluenesufonyl-2,3,4,5- tetrahydro-lH-l-benzazepine

To a heated mixture of potassium tetrabutoxide (363 gm) in toluene (1000 ml) at 70°C was added portion wise methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p- toluenesulfonyl]aminobenzoate (726 gm) as obtained in reference example 4. The contents were heated to reflux and maintained for 30 minutes. The reaction mass was then cooled to room temperature and then poured to the ice water. The layers were separated and the aqueous layer was extracted with toluene. The solvent was distilled off under reduced pressure to obtain a residual solid of 7-chloro-4-ethoxycarbonyl-5-oxo-N- p-toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine (455 gm).

Example 1:

Preparation of 7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine

7-Chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (455 gm) as obtained in reference example 5 was added to aqueous sulfuric acid (80%, 2275 ml). The contents heated to 75°C and maintained for 2 hours. The reaction mass was then cooled to room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 7.5 to 8.0 with sodium hydroxide solution (2575 ml). The solid obtained was collected by filtration and dried to give 160 gm of 7- chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine.

Example 2:

Preparation of 7-chIoro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l- benzazepine

7-Chloro-5-oxo-2,3,4,5-tetrahydro-lH-l -benzazepine (160 gm) as obtained in example 1 was dissolved in methylene dichloride (480 ml) and then added aqueous sodium bicarbonate solution (20%, 68.75 gm). The reaction mixture was then cooled to 0 to 5°C and then added 2-methyl-4-nitrobenzoylchloride (180 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (170 ml). The layers were separated and the aqueous layer was extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual mass. To the residual mass was dissolved in isopropyl alcohol (7300 ml) and maintained for 2 hours at reflux temperature. The separated solid was filtered and dried to obtain 250 gm of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine. Example 3:

Preparation of l-(4-amino-2-methylbenzoyl)-7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH- 1-benzazepine

7-Chloro- 1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of l-(4- amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (185 gm).

Example 4:

Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine

1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5°C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm). Example 5:

Preparation of tolvaptan

7-Chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-1 -benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.

……………….

t1.

Process used to prepare Tolvaptan involves condensing 7-chloro-1, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one with 2-methyl, 4-nitro benzoyl chloride, followed by reduction using SnCl2/HCl catalyst resulting in amine which is then condensed with o-toluoyl chloride followed by reduction with sodium borohydride to give Tolvaptan

t2 t3 t4

 

Title: Tolvaptan
CAS Registry Number: 150683-30-0
CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide
Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine
Manufacturers’ Codes: OPC-41061
Molecular Formula: C26H25ClN2O3
Molecular Weight: 448.94
Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%
Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549; eidem, US 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).
Properties: Colorless prisms, mp 225.9°.
Melting point: mp 225.9°
Therap-Cat: In treatment of congestive heart failure.
Keywords: Vasopressin Receptor Antagonist.

  1. Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205.
  2.  Otsuka Maryland Research Institute, Inc.
  3. Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963PMID 15113814.
  4. (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
  5. Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
  6. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
  • Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

G. R. Belum, V. R. Belum, S. K. Chaitanya Arudra, and B. S. N. Reddy, “The Jarisch-Herxheimer reaction: revisited,” Travel Medicine and Infectious Disease, vol. 11, no. 4, pp. 231–237, 2013.
H. D. Zmily, S. Daifallah, and J. K. Ghali, “Tolvaptan, hyponatremia, and heart failure,” International Journal of Nephrology and Renovascular Disease, vol. 4, pp. 57–71, 2011.
M. N. Ferguson, “Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan,” Cardiology in Review, vol. 18, no. 6, pp. 313–321, 2010.
H. Ogawa, H. Miyamoto, K. Kondo, et al., US5258510, 1993.
K. Kondo, H. Ogawa, H. Yamashita et al., “7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist,” Bioorganic and Medicinal Chemistry, vol. 7, no. 8, pp. 1743–1754, 1999.

WO2012046244A1 * Aug 23, 2011 Apr 12, 2012 Hetero Research Foundation Process for preparing tolvaptan intermediates
CN102060769A * Dec 20, 2010 May 18, 2011 天津药物研究院 Preparation method of tolvaptan
CN102060769B Dec 20, 2010 Sep 18, 2013 天津药物研究院 Preparation method of tolvaptan
US9024015 Aug 23, 2011 May 5, 2015 Hetero Research Foundation Process for preparing tolvaptan intermediates
Cited Patent Filing date Publication date Applicant Title
CN101817783A May 12, 2010 Sep 1, 2010 天津泰普药品科技发展有限公司 Method for preparing tolvaptan intermediate
WO2007026971A2 Sep 1, 2006 Mar 8, 2007 Otsuka Pharma Co Ltd Process for preparing benzazepine compounds or salts thereof
Reference
1 Cordero-Vargas, Alejandro
2 Kondo, Kazumi et al.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist.《Bioorganic & Medicinal Chemistry》.1999,1743-1757.
3 Quiclet-Sire, Beatrice
4 Torisawa, Yasuhiro et al.Aminocarbonylation route to tolvaptan.《Bioorganic & Medicinal Chemistry Letters》.2007,6455-6458.
5 Zard, Samir Z.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan.《Bioorganic & Medicinal Chemistry》.2006,6165-6173.

Medicinal Chemistry International: DELDEPREVIR (NECEPREVIR)


Medicinal Chemistry International: DELDEPREVIR (NECEPREVIR)

WANT TO KNOW ABOUT VIR SERIES CLICK

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

DELDEPREVIR OR NECEPREVIR

Figure US20100152103A1-20100617-C00127
ACH-0142684, ACH-2684
HCV NS3 PR
USAN (YY-152) DELDEPREVIR
THERAPEUTIC CLAIM Treatment of Hepatitis C
CHEMICAL NAMES
1. Cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide, N-
(cyclopropylsulfonyl)-6-[2-(3,3-difluoro-1-piperidinyl)-2-oxoethyl]-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-
methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5,16-dioxo-, (2R,6R,12Z,13aS,14aR,16aS)-
2. (2R,6R,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-[2-(3,3-difluoropiperidin-1-yl)-
2-oxoethyl]-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-
5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16atetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-
carboxamide
MOLECULAR FORMULA C45H56F2N6O8S2
MOLECULAR WEIGHT 911.1
SPONSOR Achillion Pharmaceuticals, Inc.
CODE DESIGNATION ACH-0142684, ACH-2684
CAS REGISTRY NUMBER 1229626-28-1
WHO NUMBER 9600
NOTE: This adoption statement replaces adoption N12/17 and the name neceprevir is hereby rescinded.
……………………………………………………………………………………………………….
DELDEPREVIR SODIUM
USAN (yy-153) DELDEPREVIR SODIUM
THERAPEUTIC CLAIM Treatment of Hepatitis C
CHEMICAL NAMES
1. Cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide, N-
(cyclopropylsulfonyl)-6-[2-(3,3-difluoro-1-piperidinyl)-2-oxoethyl]-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-
methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5,16-dioxo-, sodium salt (1:1),
(2R,6R,12Z,13aS,14aR,16aS)-
2. Sodium (cyclopropylsulfonyl){[(2R,6R,12Z,13aS,14aR,16aS)-6-[2-(3,3-difluoropiperidin-
1-yl)-2-oxoethyl]-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-
yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-
tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-14a(5H)-
yl]formyl]azanide
MOLECULAR FORMULA C45H55F2N6NaO8S2
MOLECULAR WEIGHT 933.1
SPONSOR Achillion Pharmaceuticals, Inc.
CODE DESIGNATION ACH-0142684.Na, ACH-2684.Na
CAS REGISTRY NUMBER 1298053-61-8
NOTE: This adoption statement replaces adoption N12/18 and the name neceprevir sodium
is hereby rescinded.
ACH-2684 is a HCV NS3 protease inhibitor in phase I clinical development at Achillion for the oral treatment of chronic hepatitis C genotype 1 and 3.
WO 2010068761
US 2010152103
Figure US20100152103A1-20100617-C00127
COMPD 133
(2R,6R,14aR,16aS,Z)- N-(cyclopropylsulfonyl)- 6-(2-(3,3-difluoropiperidin- 1-yl)-2-oxoethyl)-2- (2-(2-isopropylthiazol- 4-yl)-7-methoxy-8- methylquinolin-4- yloxy)-5,16-dioxo- 1,2,3,5,6,7,8,9,10,11, 13a,14,14a,15,16,16a- hexadecahydrocyclopropa [e]pyrrolo[1,2- a][1,4] diazacyclopentadecine- 14a-carboxamide

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Deleobuvir » All About Drugs


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DELEOBUVIR

DELEOBUVIR
(2E)-3-(2-{1-[2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl}-1-methyl-1H-benzimidazol- 6-yl)prop-2-enoic acid
1221574-24-8 CAS  please check may be sodium salt??
cas no  as per below ref ……863884-77-9 (free acid)
PHASE 3
BI-207127NA
BI-207127 (free acid)
BI-207127 is a novel HCV RNA polymerase inhibitor in phase III clinical development at Boehringer Ingelheim for the treatment of hepatitis C.
Company Boehringer Ingelheim GmbH
Description Oral non-structural protein 5B (NS5B) RNA-dependent polymerase inhibitor
Molecular Target HCV NS5B polymerase 
Mechanism of Action Viral polymerase inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase III
Indication Hepatitis C virus (HCV)
Partner
Deleobuvir (formerly BI 207127) is an experimental drug for the treatment of hepatitis C. It is being developed by Boehringer-Ingelheimand is currently in Phase II trials. It is a non-nucleoside hepatitis C virus NS5B polymerase inhibitor. Deleobuvir is being tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including faldaprevir.
Data from the SOUND-C2 study, presented at the 2012 AASLD Liver Meeting, showed that a triple combination of deleobuvir, faldaprevir, and ribavirin performed well in HCV genotype 1b patients.[1] Efficacy fell below 50%, however, for dual regimens without ribavirin and for genotype 1a patients.Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days’ deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.
These results were confirmed in the SOUND-C3 study, presented at the 2013 APASL Liver Conference, which found that 16 week triple therapy with deleobuvir + faldaprevir + ribavirin gave 95% SVR12 in HCV genotype 1b patients but poor virological response in genotype 1a.[2]

  1.  Interferon-free hepatitis C treatment with faldaprevir proves safe and effective in people with cirrhosis. Alcorn, K. Aidsmap.com. 20 November 2012.
  2.  S Zeuzem, J-F Dufour, M Buti, V Soriano, R Buynak, P Mantry, J Taunk, JO Stern, R Vinisko, J-P Gallivan, WO Bocher and FJ Mensa.“Interferon-free treatment with faldaprevir, deleobuvir (BI 207127) and ribavirin in SOUND-C3: 95% SVR12 in HCV GT-1b”23rd Conference of the Asian Pacific Association for the Study of the Liver (APASL) 6–9 June 2013. Retrieved 12 Sep 2013.
PATENTS
WO 2013147750
 WO 2013147749
WO 2012041771
WO 2012044520
WO 2012016995
WO 2005080388
……………………………………………………
PATENT
Patent Filing date Publication date Applicant Title
WO2010059667A1 Nov 18, 2009 May 27, 2010 Boehringer Ingelheim International Gmbh Pharmaceutical composition of a potent hcv inhibitor for oral administration
WO2011005646A2 Jul 1, 2010 Jan 13, 2011 Boehringer Ingelheim International Gmbh Pharmaceutical composition for a hepatitis c viral protease inhibitor
WO2012041771A1 * Sep 23, 2011 Apr 5, 2012 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection
US4211771 Feb 13, 1978 Jul 8, 1980 Robins Ronald K Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
US6063772 Jun 15, 1998 May 16, 2000 Icn Pharmaceuticals, Inc. Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes
US6277830 Jul 7, 1999 Aug 21, 2001 Schering Corporation 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon
US6323180 Aug 5, 1999 Nov 27, 2001 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US6403564 Oct 14, 1999 Jun 11, 2002 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
US7141574 Jul 18, 2002 Nov 28, 2006 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US7514557 May 23, 2005 Apr 7, 2009 Boehringer Ingelheim International Gmbh Process for preparing acyclic HCV protease inhibitors
US7582770 Feb 18, 2005 Sep 1, 2009 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7585845 May 20, 2004 Sep 8, 2009 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US7642352 Feb 10, 2006 Jan 5, 2010 Boehringer Ingelheim International Gmbh Process for preparing 2,3-disubstituted indoles
US20090087409 Nov 26, 2008 Apr 2, 2009 Boehringer Ingelheim (Canada) Ltd. Viral Polymerase Inhibitors
US20100068182 Sep 16, 2009 Mar 18, 2010 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection
US20100093792 Sep 15, 2009 Apr 15, 2010 Boehringer Ingelheim International Gmbh Crystalline forms of a potent hcv inhibitor
* Cited by examiner

NON-PATENT CITATIONS
Ref
1 BALAGOPAL GASTROENTEROLOGY vol. 139, 2010, pages 1865 – 1876
2 BERG ET AL. HEPATOL vol. 52, no. S1, 2010,
3 * DOMINIQUE LARREY ET AL: “Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin“, JOURNAL OF HEPATOLOGY, vol. 57, no. 1, 7 March 2012 (2012-03-07), pages 39-46, XP55040240, ISSN: 0168-8278, DOI: 10.1016/j.jhep.2012.02.015
4 G. CAIRNS GENE VARIANT THAT HELPS HEPATITIS C TREATMENT MAY HINDER HIV TREATMENT, [Online] 2011, Retrieved from the Internet: <URL:http://www.bhiva.org/Ncws.aspx?NewsID=a7503829-94b9-4d2f-bd91-ld2fbaad6c8d&gt;
5 GE ET AL. NATURE vol. 461, 2009, pages 399 – 401
6 GHANY; MARC ET AL.: ‘An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases‘ HEPATOLOGY vol. 54, no. 4, 2011, pages 1433 – 44
7 * LIZ HIGHLEYMAN: “AASLD: All-Oral Combination of BI 201335, BI 207127 and Ribavirin Shows Good Efficacy at 12 Weeks“, INTERNET CITATION, [Online] 1 December 2011 (2011-12-01), pages 1-3, XP002684260, Retrieved from the Internet: URL:www.hivandhepatitis.com/hepatitis-c/he patitis-c-topics/hcv-treatment/3371-aasld- all-oral-combination-of-bi-201335-bi-20712 7-and-ribavirin-shows-good-efficacy-at-12- weeks> [retrieved on 2012-09-27]
8 * POL S ET AL: “SVR AND PHARMACOKINETICS OF THE HCV PROTEASE INHIBITOR BI201335 WITH PEGIFN/RBV IN HCV GENOTYPE-1 PATIENTS WITH COMPENSATED LIVER CIRRHOSIS AND NON-RESPONSE TO PREVIOUS PEGIFN/RBV“, JOURNAL OF HEPATOLOGY, vol. 54, no. Suppl. 1, March 2011 (2011-03), page S486, XP55038942, & 46TH ANNUAL MEETING OF THE EUROPEAN-ASSOCIATION-FOR-THE-STUDY-OF-THE- LIVER (EASL); BERLIN, GERMANY; MARCH 30 -APRIL 03, 2011 ISSN: 0168-8278
9 S. M. BIRGE ET AL. J. PHARM. SCI. vol. 66, 1977, pages 1 – 19
10 * STEFAN ZEUZEM ET AL: “Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV Infection“, GASTROENTEROLOGY, ELSEVIER, PHILADELPHIA, PA, vol. 141, no. 6, 1 December 2011 (2011-12-01), pages 2047-2055, XP002664706, ISSN: 0016-5085, DOI: 10.1053/J.GASTRO.2011.08.051
11 SULKOWSKI MS ET AL. HEPATOL vol. 50, 2009, page 2A
12 SULKOWSKI MS ET AL. J HEPATOL vol. 52, no. 1, 2010, pages S462 – S463
13 WHITE PW ET AL. ANTIMICROB AGENTS CHEMOTHER vol. 54, no. 11, 2010, pages 4611 – 4618
14 WHO COLLABORATIVE STUDY GROUP. VOX SANG vol. 76, 1999, pages 149 – 158
15 * ZEUZEM STEFAN ET AL: “STRONG ANTIVIRAL ACTIVITY AND SAFETY OF IFN-SPARING TREATMENT WITH THE PROTEASE INHIBITOR BI 201335, THE HCV POLYMERASE INHIBITOR BI 207127 AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C“, HEPATOLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 52, no. Suppl, 1 October 2010 (2010-10-01), pages 876A-877A, XP009154421, ISSN: 0270-9139
16 * ZEUZEM STEFAN ET AL: “VIROLOGIC RESPONSE TO AN INTERFERON-FREE REGIMEN OF BI201335 AND BI207127, WITH AND WITHOUT RIBAVIRIN, IN TREATMENT-NAIVE PATIENTS WITH CHRONIC GENOTYPE-1 HCV INFECTION: WEEK 12 INTERIM RESULTS OF THE SOUND-C2 STUDY“, HEPATOLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 54, no. Suppl. 1, 1 November 2011 (2011-11-01), page 1436A, XP009163087, ISSN: 0270-9139, DOI: 10.1002/HEP.24666 [retrieved on 2011-09-30]
…………………………………………………………
The following……
Figure imgf000004_0001
having the chemical name: (E)-3-[2-(l-{ [2-(5-Bromo-pyrimidin-2-yl)-3-cyclopentyl-l- methyl-lH-indole-6-carbonyl]-amino}-cyclobutyl)-3-methyl-3H-benzimidazol-5-yl]- acrylic acid, is known as a selective and potent inhibitor of the HCV NS5B RNA- dependent RNA polymerase and useful in the treatment of HCV infection. Compound (2) falls within the scope of HCV inhibitors disclosed in U.S. Patents 7,141,574 and
7,582,770, and US Application Publication 2009/0087409. Compound (2) is disclosed specifically as Compound # 3085 in U.S. Patent 7,582,770. Compound (2), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference in their entirety. Preferred forms of Compound (2) include the crystalline forms, in particular the crystalline sodium salt form which is prepared as herein described.
It is known in the art that particular HCV subtypes and patient subgenotypes may respond differently to HCV therapy. HCV Genotype la is traditionally more difficult to treat and are less responsive to antiviral therapy than Genotype lb. See, e.g., Ghany, Marc et al. “An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases”, Case No.: 09-0592-PCT
Hepatology, 54(4): 1433-44 (2011)). In addition, and particularly with interferon-based therapy, specific single nucleotide polymorphisms (SNPs) located on the long arm of chromosome 19 within the gene cluster of IL-28B (Interleukin (IL) 28B, (also called lambda interferon), of the patient undergoing therapy can directly effect the
responsiveness of that patient to the antiviral therapy. In particular, patients having a non- CC genotype of SNP rsl2979860 or a non-TT genotype of rs 8099917 are traditionally more difficult to treat and are less responsive in terms of a sustained virological response (SVR) than patients having the CC or TT genotype.. The SNP that was most strongly associated with SVR in the genome-wide analysis was rs 12979860 followed by rs 8099917. See, e.g., Ge et al., Nature, 461 :399-401 (2009) and Balagopal,
Gastroenterology, 139: 1865-1876 (2010). See G. Cairns, “Gene variant that helps hepatitis C treatment may hinder HIV treatment”, 2011, at:
http://www.bhiva.org^ Thus, there is a need in the art for therapies that are effective against even the more difficult-to-treat patient subpopulations, particularly those exhibiting HCV subtype la and the non-CC IL28B subgenotype, as well as those exhibiting compensated liver disease.
Examples
I. Methods for Preparing Compound (1)
Methods for preparing amorphous Compound (1) and a general description of
pharmaceutically acceptable salt forms can be found in US Patents 6,323,180, 7,514,557 and 7,585,845. Methods for preparing additional forms of Compound (1), in particular the crystalline sodium salt form, can be found in U.S. Patent Application Publication No. 2010/0093792.
II. Formulations of Compound (1) Case No. : 09-0592-PCT
One example of a pharmaceutical formulation of Compound (1) include an oral solution formulation as disclosed in WO 2010/059667. Additional examples include capsules containing a lipid-based liquid formulation, as disclosed in WO 201 1/005646. III. Methods for Preparing Compound (2)
Methods for preparing amorphous Compound (2) can be found in U.S. Patents 7, 141 ,574 and 7,582,770, and US Application Publication 2009/0087409.
The following Example provides the method for preparing an additional form of
Compound (2), the sodium salt form, that may be used in the present invention.
Example 1 – Preparation of Compound (2) Sodium Salt
Step 1. Synthesis of Isopropyl 3-Cyclopentyl-l-methyl-lH-indole-6-carboxylate
Figure imgf000024_0001
Because of the instability of brominated product, methyl 3 -cyclopentyl- 1 -methyl- 1Η- indole-6-carboxylate needed to be converted into the more stable isopropyl 3-cyclopentyl- l-methyl- lH-indole-6-carboxylate via a simple and high yielding operation. The conversion worked the best with stoichiometric amounts of solid lithium isopropoxide. Use of 0.1 eq lithium isopropoxide led to longer reaction times and as a result to more hydrolysis by-product, while lithium isopropoxide solution in THF caused a problematic isolation and required distillation of THF.
Procedure: Case No.: 09-0592-PCT
The mixture of methyl 3 -cyclopentyl- 1 -methyl- lH-indole-6-carboxylate (50.0 g, 0.194 mol) and lithium isopropoxide (16.2 g, 95%, 0.233 mol) in 2-propanol was stirred at 65+5 °C for at least 30 min for complete trans-esterification. The batch was cooled to 40+5 °C and water (600 g) was added at a rate to maintain the batch temperature at 40+5°C. After addition, the mixture was cooled to 20-25 °C over 2+0.5 h and held at 20-25 °C for at least 1 h. The batch was filtered and rinsed with 28 wt% 2-propanol in water (186 g), and water (500 g). The wet cake was dried in vacuo (< 200 Torr) at 40-45 °C until the water content was < 0.5% to give isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (52.7 g, 95% yield) in 99.2 A% (240 nm).
The starting material methyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate can be prepared as described in Example 12 of U.S. Patent 7,141,574, and in Example 12 of U.S. Patent 7,642,352, both herein incorporated by reference.
Step 2. Synthesis of Isopropyl 2-Bromo-3-cyclopentyl-l-methyl-lH-indole-6- carboxylate
Figure imgf000025_0001
This process identified the optimal conditions for the synthesis of 2-bromo-3-cyclopentyl- l-methyl-lH-indole-6-carboxylate via bromination of the corresponding 3 -cyclopentyl- 1- methyl-lH-indole-6-carboxylate with bromine. It’s very important to control the reaction temperature and to quench the reaction mixture with a mixture of aqueous sodium thiosulfate and 4-methylmorpholine to minimize the formation of the dibromo- and 2- indolone impurities. Further neutralization of the crude product with NaOH in isopropanol greatly increases the stability of the isolated product. Case No.: 09-0592-PCT
Procedure:
The mixture of isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (50.0 g, 0.175 mol) and acetonitrile (393 g) was cooled to -6+3 °C. Bromine (33.6 g, 0.210 mol) was added while the batch was maintained at -6+3°C. The resulting slurry was stirred at – 6+3°C for at least 30 min. When HPLC showed > 94 % conversion (the HPLC sample must be quenched immediately with aqueous 4-methylmorpholine/sodium thiosulfate solution), the mixture was quenched with a solution of sodium thiosulfate (15.3 g) and 28.4 g 4-methylmorpholine in water (440 g) while the temperature was maintained at -5+5 °C. After it was stirred at 0+5 °C for at least 2 h, the batch was filtered and rinsed with 85 wt methanol/water solution (415 g), followed by water (500 g), and dried until water content is < 30%. The wet cake was suspended in 2-propanol (675 g), and heated to 75+5 °C. The resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g) and then with 135.0 g water at a rate to maintain the batch at 75+5°C. The suspension was stirred at 75+5°C for at least 30 min, cooled to 15+2 °C over 30-40 min, and held at 15+2 °C for at least 1 h. The batch was filtered, rinsed with 75 wt% 2-propanol/water solution (161 g), and dried in vacuo (<200 Torr) at 50-60 °C until the water content was < 0.4% to give isopropyl 2-bromo-3-cyclopentyl-l -methyl- lH-indole-6-carboxylate as a solid (55.6 g, 87 % yield ) in 99.5 A% (240 nm) and 97.9 Wt%. Alternative Procedure:
The mixture of isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (84 g, 0.294 mol) and isopropyl acetate (1074 g) was cooled to between -10-0 °C. Bromine (50 g, 0.312 mol) was added while the batch was maintained at -10 – 0 °C. The resulting slurry was stirred at the same temperature for additional 30 min and quenched with a pre-cooled solution of sodium thiosulfate pentahydrate (13 g) and triethylamine (64.5 g) in water (240 g) while the temperature was maintained at 0-10 °C. The mixture was heated to 40 – 50 °C and charged with methanol (664 g). After it was stirred at the same temperature for at least 0.5 h, the batch was cooled to 0 – 10 °C and stirred for another 1 hr. The precipitate was filtered, rinsed with 56 wt% methanol/water solution (322 g), and dried in vacuo (<200 Case No. : 09-0592-PCT
Torr) at 50-60 °C until the water content was < 0.4% to give isopropyl 2-bromo-3- cyclopentyl-l -methyl- lH-indole-6-carboxylate as a beige solid (90-95 g, 80-85 % yield ).
Step 3a,b. Preparation of compound I by one-pot Pd-catalyzed borylation- Suzuki coupling reaction
Figure imgf000027_0001
To a clean and dry reactor containing 20.04 g of isopropyl 2-bromo-3-cyclopentyl- l- methyl- lH-indole-6-carboxylate, 1.06 g of Pd(TFP)2Cl2(3 mol%) and 0.76 g of tri(2- furyl)phosphine (6 mol%) was charged 8.35 g of triethylamine (1.5 equivalent), 39.38 g of CH3CN at 23+10 °C under nitrogen or argon and started agitation for 10 min. 9.24 g of 4,4,5, 5-tetramethyl-l ,3,2-dioxaborolane was charged into the reactor. The mixture was heated to reflux (ca. 81 -83 °C) and stirred for 6h until the reaction completed. The batch was cooled to 30+5 °C and quenched with a mixture of 0.99 g of water in 7.86 g of
CH3CN. 17.24 g of 5-bromo-2-iodopyrimidine and 166.7 g of degassed aqueous potassium phosphate solution (pre-prepared from 46.70 g of K3PO4 and 120 g of H20) was charged subsquently under argon or nitrogen. The content was heated to reflux (ca. 76-77 °C) for 2 h until the reaction completed. 4.5 g of 1-methylimidazole was charged into the reactor at 70 °C. The batch was cooled to 20+3 °C over 0.5h and hold at 20+3 °C for at least lh. The solid was collected by filtration. The wet cake was first rinsed with 62.8 g of 2-propanol, Case No. : 09-0592-PCT
followed by 200 g of H20. The solid was dried under vacuum at the temperature below 50 °C.
Into a dry and clean reactor was charged dried I, 10 wt Norit SX Ultra and 5 V of THF. The content was heated at 60+5 °C for at least 1 h. After the content was cooled to 35+5 °C, the carbon was filtered off and rinsed with 3 V of THF. The filtrate was charged into a clean reactor containing 1-methylimidazole (10 wt % relative to I). After removal of 5 V of THF by distillation, the content was then cooled to 31 ±2 °C. After the agitation rate was adjusted to over 120 rpm, 2.5 V of water was charged over a period of at least 40 minutes while maintaining the content temperature at 31 + 2 °C. After the content was agitated at 31 + 2 °C for additional 20 min, 9.5 V of water was charged into the reactor over a period of at least 30 minutes at 31 + 2 °C. The batch was then cooled to about 25 + 3 °C and stirred for additional 30 minutes. The solid was collected and rinsed with 3 V of water. The wet product I was dried under vacuum at the temperature below 50 °C (19.5 g, 95 wt , 76% yield).
Alternative Procedure:
To a clean and dry reactor containing 40 g of isopropyl 2-bromo-3-cyclopentyl- l-methyl- lH-indole-6-carboxylate (0.1 10 mol), 0.74 g of Pd(OAc)2 (3.30 mmol, 3 mol% equiv.) and 3.2 g of tri(2-furyl)phosphine (13.78 mmol, 12.5 mol% equiv.) was charged 16.8 g of triethylamine (1.5 equivalent), 100 mL of acetonitrile at 25 °C under nitrogen or argon. 20.8 g of 4,4,5, 5-tetramethyl- l ,3,2-dioxaborolane was charged into the reactor within 30 min. The mixture was heated to reflux (ca. 81 -83 °C) and stirred for over 5 hrs until the reaction completed. The batch was cooled to 20 °C and quenched with a mixture of 2.7 g of water in 50 mL of CH3CN. The batch was warmed to 30 °C, stirred for 1 hr and transferred to a second reactor containing 34.4 g of 5-bromo-2-iodopyrimidine in 100 mL of acetonitrile. The reactor was rinsed with 90 mL of acetonitrile. To the second reactor was charged with degassed aqueous potassium phosphate solution (pre-prepared from 93.2 g of K3PO4 and 100 g of H20) under argon or nitrogen. The content was heated to reflux (ca. 80 °C) for over 3 h until the reaction completed. 9.2 g of 1 -methylimidazole was charged into the reactor at 70 °C and the mixture was stirred for at least 10 min. The aqueous phase was removed after phase separation. 257 g of isopropanol was charged at 70 Case No.: 09-0592-PCT
°C. The batch was cooled slowly to 0 °C and hold for at least 1 h. The solid was collected by filtration. The wet cake was rinsed twice with 2-propanol (2 x 164 g) and dried under vacuum at the temperature below 50 °C to give I as a yellow to brown solid (26 g, 75% yield).
Step 4. Hydrolysis of I to II
Figure imgf000029_0001
I (20 g) and l-methyl-2-pyrrolidinone (NMP) (113 g) were charged into a clean reactor under nitrogen. After the batch was heated to 50-53 °C with agitation, premixed aq. NaOH (5.4 g of 50% aq. NaOH and 14.3 g of water) was introduced into the reactor. The resulting mixture was stirred at 50-53 °C for about 10 hrs until the reaction completed. A premixed aq. HOAc (60 g of water and 9.0 g of HOAc) was added over 0.5 h at 45 ±5 °C to reach pH 5.5- 7.5. The batch was cooled to 20+5 °C and then kept for at least 1.0 h. The solid product was collected and rinsed with 80 g of NMP/water (1 :3 volume ratio) and then 60 g of water. The product was dried under vacuum at the temperature below 50 °C to give II as a pale yellow powder (19 -20 g, purity > 99.0 A% and 88.4 wt%, containing 5.4 wt% NMP). The yield is about 93-98%.
Notes: The original procedure used for the hydrolysis of I was carried out with aq. NaOH (2.5 eq) in MeOH/THF at 60 °C. Although it has been applied to the preparation of II on several hundred grams scale, one disadvantage of this method is the formation of 5-MeO pyrimidine during hydrolysis (ca. 0.4 A%), which is extremely difficult to remove in the subsequent steps. In addition, careful control has to be exerted during crystallization. Case No.: 09-0592-PCT
Otherwise, a thick slurry might form during acidification with HO Ac. The use of NMP as solvent could overcome all aforementioned issues and give the product with desired purity.
Alternative Process
To a reactor was charged I (71 g), isopropanol (332 g), aqueous NaOH (22 g, 45 wt ) and water (140 g) at ambient temperature. The mixture was heated to reflux (80 °C) and stirred for at least 3 hrs until the reaction completed. The batch was cooled to 70 °C and charged a suspension of charcoal (3.7 g) in isopropanol (31 g). The mixture was stirred at the same temperature for over 10 min and filtered. The residue was rinsed with isopropanol (154 g). Water (40 g) was charged to the filtrate at 70 – 80 °C, followed by slow addition of 36% HC1 solution (20 g) to reach pH 5- 6. The batch was stirred for over 30 min at 70 °C, then cooled to 20 °C over 1 hr and kept for at least 1.0 h. The solid product was collected and rinsed with 407 g of isopropanol/water (229 g IPA, 178 g H20). The product was dried under vacuum at 80 °C for over 5 hrs to give II as a white powder (61 g, 95% yield).
Notes on Steps 5 to 8 below:
A concise and scalable 4-step process for the preparation of the benzimidazole
intermediate V was developed. The first step was the preparation of 4-chloro-2-(methyl)- aminonitrobenzene starting from 2,4-dichloronitrobenzene using aqueous methyl amine in DMSO at 65 °C. Then, a ligandless Heck reaction with n-butyl acrylate in the presence of Pd(OAc)2, ‘PrzNEt, LiCl, and DMAc at 110 °C was discovered.
Step 5: SNAr reaction of (5-chloro-2-nitrophenyl)-methylamine
Figure imgf000030_0001
To a solution of (5-chloro-2-nitrophenyl)-methylamine (40 g, 208.3 mmol, 1 equiv) in DMSO (160 mL) was added 40% MeNH2solution in water (100 mL, 1145. 6 mmol, 5.5 eq) slowly keeping the temperature below 35 °C. The reaction was stirred at r.t. until the Case No.: 09-0592-PCT
complete consumption of the starting material (>10 h). Water (400 mL) was added to the resulting orange slurry and stirred at r.t. for additional 2 h. The solid was filtered, rinsed with water (200 mL) and dried under reduced pressure at 40 °C. (5-chloro-2-nitrophenyl)- methylamine (36.2 g, 93% yield, 94 A% purity) was isolated as a solid.
Step 6: Heck Reaction of (5-chloro-2-nitrophenyl)-methylamine
Figure imgf000031_0001
DMAc (5 vol), 1 10 °C, 7-22 h To a mixture of 4-chloro-2-methylaminonitrobenzene (50.0 g, 268.0 mmol, 1.0 eq),
Pd(OAc)2 (0.30 g, 1.3 mmol, 0.005 eq) and LiCI (11.4 g 268.0 mmol, 1.0 eq) in DMAc (250 mL) was added ‘Pr2NEt (56 mL, 321.5 mmol, 1.2 eq) followed by n-butyl acrylate (40 mL, 281.4 mmol, 1.05 eq) under nitrogen. The reaction mixture was stirred at 110 °C for 12 h, then cooled to 50 °C. 1 -methylimidazole (10.6 mL, 134.0 mmol, 0.5 eq) was added and the mixture was stirred for 30 min before filtering and adding water (250 mL). The resulting mixture was cooled to r.t. over 1 h. The resulting solid was filtered and washed with water and dried to yield n-butyl 3-methylamino-4-nitrocinnamate (71.8 g, 96 %, 99.2 A% purity).
Step 7: Reduction of n-butyl (3-methylamino-4-nitro)-cinnamate
Figure imgf000031_0002
III Case No.: 09-0592-PCT
To a reactor was charged n-butyl 3-methylamino-4-nitrocinnamate (70.0 g, mmol, 1.0 eq) , Raney Ni (4.9 g, ~20wt% H20), charcoal “Norit SX Ultra” (3.5 g), toluene (476 mL) and MeOH (224 mL). The reactor was charged with hydrogen (4 bar) and the mixture was stirred at 20- 25 °C for about 2 hrs until the reaction was completed. The reaction mixture was filtered and rinsed the filter residue with toluene (70 mL). To the combined filtrates were added “Norit SX Ultra” charcoal (3.5 g). The mixture was stirred at 50 °C for 1.0 hr and filtered. The filtrate was concentrated under reduced pressure to remove solvents to 50% of the original volume. The remained content was heated to 70 °C and charged slowly methyl cyclohexane (335 mL) at the same temperature. The mixture was cooled to about 30 – 40 °C and seeded with III seed crystals, then slowly cooled the suspension to— 10 °C. The solid was filtered and rinsed with methyl cyclohexane in three portions (3 x 46 mL). The wet cake was dried in vacuo at 40 °C to give III (53.3 g, 215 mmol, 86%).
Step 8: Preparation of benzimidazole V
DCC
Figure imgf000032_0001
To reactor-1 was charged III (35 g, 140.95 mmol) in toluene (140 g). The mixture was heated to 50 °C to obtain a clear solution. To a second reactor was charged IV (36.4 g, 169.10 mmol) and toluene (300 g), followed by addition of a solution of dicyclohexyl carbodimide (11.6 g, in 50% toluene, 28.11 mmol) at 0 – 10 °C. The mixture was stirred at the same temperature for 15 min, then charged parallelly with the content of reactor-1 and the solution of dicyclohexyl carbodimide (52.4 g, in 50% toluene, 126.98 mmol) within 1 hr while maintaining the batch temperature at 0 – 10 °C. The mixture was agitated at the same temperature for 3 hrs, and warmed to 25 °C for another 1 hr. Once III was consumed, toluene (-300 mL) was distilled off under reduced pressure at 70 – 80 °C. n-Butanol (200 g) was added, followed by 3 M HCI solution in n-butanol (188 g) while maintaining the Case No.: 09-0592-PCT
temperature at 70 – 80 °C (Gas evolution, product precipitates). After stirring for over 30 min. at 70 – 80 °C, the mixture was cooled to 20 – 30 °C over 1 hr. The precipitate was filtered and washed with acetone (172 g) and toluene (88 g). The wet cake was dried in vacuo at -60 °C to give V toluene solvate as off white solid (60 – 72 g, 85 – 95% yield). Compound V could be used directly for the next step or basified prior to next step to obtain the free base compound VI used in the next step.
Step 9. Synthesis of (E)-Butyl 3-(2-(l-(2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-l- hydroxy-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[d]imidazol-6- yl)acrylate VII
Figure imgf000033_0001
5) MeOH/H20
Notes:
The conversion of the acid into acid chloride was achieved using inexpensive thionyl chloride in the presence of catalytic amount of NMP or DMF. An efficient crystallization was developed for the isolation of the desired product in high yield and purity.
Procedure (using free base VI):
To the suspension of 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl-lH-indole-6- carboxylic acid II (see Step 4) (33.36 g, 90.0 wt %, containing -0.2 equiv of NMP from previous step,75.00 mmol) in THF (133.4 g) was added thionyl chloride (10.71 g). The mixture was stirred at 25+5 °C for at least 1 h. After the conversion was completed as determined by HPLC (as derivative of diethylamine), the mixture was cooled to 10+5 °C and N,N-diisopropylethylamine (378.77 g, 300 mmol) below 25 °C. A solution of (E)-butyl 3-(2-(l-aminocyclobutyl)-l-methyl-lH-benzo[if|imidazol-6-yl)acrylate VI (25.86 g, 97.8 Wt%, 77.25 mmol) dissolved in THF (106.7 g) was added at a rate to maintain the Case No.: 09-0592-PCT
temperature of the content < 25 °C. The mixture was stirred at 25+5 °C for at least 30 min for completion of the amide formation. The mixture was distilled at normal pressure to remove ca. 197 mL (171.5 g) of volatiles (Note: the distillation can also be done under reduced pressure). The batch was adjusted to 40+5 °C, and MeOH (118.6 g) was added. Water (15.0 g) was added and the mixture was stirred at 40+5 °C until crystallization occurred (typically in 30 min), and held for another 1 h. Water (90 g) was charged at 40+5 °C over 1 h, and the batch was cooled to 25+5 °C in 0.5 h, and held for at least 1 h. The solid was filtered, rinsed with a mixture of MeOH (39.5 g), water (100 g), and dried in vacuo (< 200 Torr) at 50+5 °C to give (E)-butyl 3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3- cyclopentyl- 1 -methyl- lH-indole-6-carboxamido)cyclobutyl)- 1 -methyl- 1H- benzo[if|imidazol-6-yl)acrylate VII (51.82 g, 96.6 % yield) with a HPLC purity of 98.0 A% (240 nm) and 99.0 Wt%.
Alternative Process (using compound V from Step 8)
To reactor 1 was charged 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl-lH-indole-6- carboxylic acid II (33.6 g), toluene (214 g) and N-methylpyrrolidone (1.37 g). The mixture was heated to 40 °C, then added a solution of thionyl chloride (13 g) in toluene (17 g). The mixture was stirred at 40 °C for at least 0.5 h and cooled to 30 °C. To a second reactor was charged with compound V (the bis-HCl salt toluene solvate from Step 8) (39.4 g), toluene (206 g) and N,N-diisopropylethylamine (70.8 g) at 25 °C. The content of reactor 1 was transferred to reactor 2 at 30 °C and rinsed with toluene (50 g). The mixture was stirred at 30 °C for another 0.5 h, then charged with isopropanol (84 g) and water (108 g) while maintained the temperature at 25 °C. After stirring for 10 min, remove the aqueous phase after phase cutting. To the organic phase was charged isopropanol (43 g), water (54 g) and stirred for 10 min. The aqueous phase was removed after phase cutting. The mixture was distilled under reduced pressure to remove ca.250 mL of volatiles, followed by addition of methyl tert-butyl ether (MTBE, 238 g). The batch was stirred at 65 °C for over 1 hr, then cooled to 20 C over 1 hr and held for another 1 hr at the same temperature. The solid was filtered, rinsed with MTBE (95 g), and dried in vacuo at 80 °C to give (E)-butyl 3-(2-(l-(2- Case No.: 09-0592-PCT
(5-bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl-lH-indole-6-carboxamido)cyclobutyl) methyl- lH-benzo[if|imidazol-6-yl)acrylate VII as a beige solid (50 g, 90 % yield).
Step 10. Synthesis of (E)-3-(2-(l-(2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl- lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[</]imidazol-6-yl)acrylic acid (Compound (1))
Figure imgf000035_0001
Notes:
In this process, hydrolysis of (E)-butyl 3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl- l-methyl-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[d]imidazol-6- yl)acrylate was carried out in mixture of THF/MeOH and aq NaOH. Controlled acidification of the corresponding sodium salt with acetic acid is very critical to obtain easy-filtering crystalline product in high yield and purity.
Procedure:
To the suspension of (E)-butyl 3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l- methyl-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[(i]imidazol-6- yl)acrylate VII (489.0 g, 91.9 Wt%, 633.3 mmol) in THF (1298 g) and MeOH (387 g) was added 50% NaOH (82.7 g, 949.9 mmol), followed by rinse with water (978 g). The mixture was stirred between 65-68 C for about 1 h for complete hydrolysis. The resulting solution was cooled to 35 C, and filtered through an in-line filter (0.5 micron), and rinsed with a pre-mixed solution of water (978 g) and MeOH (387 g). The solution was heated to Case No.: 09-0592-PCT
60 +4 C, and acetic acid (41.4 g, 689 mmol) was added over 1 h while the mixture was well agitated. The resulting suspension was stirred at 60 ±4 C for 0.5 h. Another portion of acetic acid (41.4 g, 689 mmol) was charged in 0.5 h, and batch was stirred at 60 ±4 C for additional 0.5 h. The batch was cooled to 26 ±4 C over 1 h and held for 1 h. The batch was filtered, rinsed with a premixed solution of water (1956 g) and MeOH (773.6 g), dried at 50 C under vacuum to give (E)-3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l- methyl-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[(i]imidazol-6-yl)acrylic acid (1) (419.0 g, 95 % yield) with > 99.0 A% (240 nm) and 94.1 Wt% by HPLC. Step 11. Formation of Compound (1) Sodium Salt (Type A)
Figure imgf000036_0001
To a reactor were charged Compound (1) (150 g, mmol), THF (492 mL), H20 (51 mL) and 45% aqueous NaOH solution (20.4 g, mmol). The mixture was stirred for >1 hr at -25 °C to form a clear solution (pH = 9 -11). To the solution was charged a suspension of Charcoal (1.5 g) and H20 (27 mL). The mixture was stirred at -35 °C for >30 min and filtered. The filter was rinsed with THF (108 mL) and H20 (21 mL). The filtrate was heated to 50 °C and charged with methyl ethylketone (MEK) (300 mL). The mixture was seeded with Compound (1) sodium salt MEK solvate (Type A) seeds (0.5 g) and stirred for another 1 hr at 50 °C. To the mixture was charged additional MEK (600 mL). The resultant mixture was stirred for another 1 hr at 50 °C and then cooled to 25 °C. The precipitate was filtered and rinsed with MEK twice (2 x 300 mL). The wet cake was dried in vacuum at 80 °C to give Compound (1) sodium salt (Type A) (145.6 g, 94%). Case No.: 09-0592-PCT
The Compound (1) sodium salt (Type A) MEK solvate seeds used in the above process step can be manufactured by the above process except without using seeds and without drying of the solvate.

ANTHONY MELVIN CRASTO

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

GRAZOPREVIR, MK 5172


GRAZOPREVIR

  • Grazoprevir hydrate
  • UNII-4O2AB118LA
  • MK 5172
THERAPEUTIC CLAIM Antiviral
Note……..drug is k salt
MF C38H49N6O9SK
MW804.99
CHEMICAL NAMES
1. Cyclopropanecarboxamide, N-[[[(1R,2R)-2-[5-(3-hydroxy-6-methoxy-2-
quinoxalinyl)pentyl]cyclopropyl]oxy]carbonyl]-3-methyl-L-valyl-(4R)-4-hydroxy-L-prolyl-1-
amino-N-(cyclopropylsulfonyl)-2-ethenyl-, cyclic (1→2)-ether, hydrate (1 :1) (1R,2S)-
2. (1aR,5S,8S,10R,22aR)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-
ethenylcyclopropyl}-5-(1,1-dimethylethyl)-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-
methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-
carboxamide hydrate
MOLECULAR FORMULA C38H50N6O9S.H2O
MOLECULAR WEIGHT 784.92
SPONSOR Merck Sharp & Dohme Corp.
CAS REGISTRY NUMBER 1350462-55-3  HYDRATE, 1350514-68-9 (anhydrous)
WHO NUMBER
9857
GRAZOPREVIR
MERCK
MK-5172 is in phase II clinical development at Merck & Co. for the oral treatment of chronic hepatitis C in combination with peginterferon and ribavirin and in combination with MK-8742. Phase I clinical trials are ongoing for the treatment of hepatitis C in patients with genotype 1 and genotype 3. In 2013, breakthrough therapy designation was assigned to the compound.
 SYNTHESIS, THESIS PROCEDURES, NMR see………..http://www.allfordrugs.com/2015/07/31/mk-5172-grazoprevir/
Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor
ACS Med Chem Lett 2012, 3(4): 332DOI: 10.1021/ml300017p
Development of a practical, asymmetric synthesis of the hepatitis c virus protease inhibitor MK-5172
Org Lett 2013, 15(16): 4174
WO2013142159
WO 2013106631
WO 2013101550
WO 2013028470
WO 2013028471
WO2013028465
WO 2010011566
Description:
IC50 Value: 7.4nM and 7nM for genotype1b and 1a respectively, in replicon system [1]
MK-5172 is a novel P2-P4 quinoxaline macrocyclic HCV NS3/4a protease inhibitor currently in clinical development.
in vitro: In biochemical assays, MK-5172 was effective against a panel of major genotypes and variants engineered with common resistant mutations observed in clinical studies with other NS3/4a protease inhibitors. In the replicon assay, MK-5172 demonstrated subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a [2].
in vivo: In rats, MK-5172 showed a plasma clearance of 28 ml/min/kg and plasma half-life of 1.4 hr. When dosed p.o. at 5 mg/kg, the plasma exposure of MK-5172 was good with an AUC of 0.7 uM.hr. The liver exposure of the compound was quite good (23 uM at 4 hr), and MK-5172 remained in liver 24 hr after a single p.o. 5 mg/kg dose. At 24 hr, the liver concentration of MK-5172 was 0.2 uM, which was over 25-fold higher than the IC50 in the replicon assay with 50% NHS. When dosed to dogs, MK-5172 showed low clearance of 5 ml/min/kg and a 3 hr half-life after i.v. 2 mg/kg dosing and had good plasma exposure (AUC=0.4 uM.hr) after a p.o. 1 mg/kg dose [1].
Clinical trial: Evaluation of Hepatic Pharmacokinetics for MK-5172 in Participants With Chronic Hepatitis C . Phase1
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein. NS4A provide a cofactor for NS3 activity.
Potential treatments for HCV infection have been discussed in the different references including Balsano, Mini Rev. Med. Chem. 8(4):307-318, 2008, Rönn et al., Current Topics in Medicinal Chemistry 8:533-562, 2008, Sheldon et al., Expert Opin. Investig. Drugs 16(8):1171-1181, 2007, and De Francesco et al., Antiviral Research 58:1-16, 2003
Different HCV inhibitors are described in different publications. Macrocyclic compounds useful as inhibitors the HCV protease inhibitors are described in WO 06/119061, WO 7/015785, WO 7/016441, WO 07/148,135, WO 08/051,475, WO 08/051,477, WO 08/051,514, WO 08/057,209. Additional HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116, WO 02/48172, British Patent No. GB 2 337 262, and U.S. Pat. No. 6,323,180.
………………………
NMR
Figure US08080654-20111220-C00021
13C NMR (100 MHz, DMSO-d6) δ 172.32, 170.63, 169.04, 159.86, 156.95, 154.74, 148.10, 140.41, 133.55 (2 signals), 128.94, 118.21, 117.58, 105.89, 74.88, 59.75, 58.71, 55.68, 54.13, 54.01, 40.13, 34.49, 34.04, 33.76, 32.68, 30.71, 30.43, 28.55, 27.69, 27.28, 26.38, 21.98, 18.49, 10.67, 5.69, 5.46; MS (ES+) m/z 767 (M+H)+
(1aR,5S,8S,10R,22aR)-5-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide
index1
………………….
NMR OF GRAZOPREVIR K SALT
Potassium {[(1R,2S)-1-({[(1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-
methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-
yl]carbonyl}amino)-2-ethenylcyclopropyl]carbonyl}(cyclopropylsulfonyl)azanide (15 K-salt).
1H NMR (400 MHz, DMSO-d6) δ 7.91 (br s, 1 H), 7.75 (d, J =
8.3 Hz, 1 H), 7.15 (m, 1 H), 7.04 (m, 1 H), 5.97 (m, 1 H), 5.73 (br s, 1 H), 4.96 (m, 1 H), 4.79 (apparent q, J = 9.3 Hz, 1 H), 4.26 (dd, J = 9.7, 7.7 Hz, 1 H), 4.20 (d, J = 11.3 Hz, 1 H), 4.14 (d, J = 8.8 Hz, 1 H), 3.90 (dd, J = 11.1, 3.2 Hz, 1 H), 3.86 (s, 3 H), 3.62 (m, 1 H), 2.86-2.60 (m, 3 H), 2.38 (m, 1 H), 2.21 (m, 1 H), 1.80-1.48 (m, 6 H), 1.42 (m, 5 H), 1.14 (m, 1 H), 0.95 (m, 10 H), 0.81 (m, 2 H), 0.72-0.50 (m, 3 H), 0.41 (m, 1 H) ppm.http://pubs.acs.org/doi/suppl/10.1021/ml300017p/suppl_file/ml300017p_si_001.pdf
………………………………………………………
GRAZOPREVIR
(1aR,5S,8S,10R,22aR)-5-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino] carbonyl}-2-
vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-
7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-
carboxamide (MK-5172, 15).
1H NMR (400 MHz, CD3
OD) δ 7.79 (dd, J = 9.6, 1.8 Hz, 1 H), 7.23 (s, 1 H), 7.22 (m, 1 H), 7.10 (d, J = 9.6 Hz, 1 H), 6.01 (apparent t, J = 3.6 Hz, 1 H), 5.74 (m, 1 H), 5.24 (dd, J = 17.0 Hz, 1.6 Hz, 1 H), 5.11 (dd, J = 10.4 Hz, 1.6 Hz, 1 H), 4.49 (d, J = 11.2 Hz, 1 H), 4.40 (m, 2 H), 4.13 (dd, J = 12.0 Hz, 4.0 Hz, 1 H), 3.92 (s, 3 H), 3.76 (m, 1 H), 2.92 (m, 2 H), 2.85 (m, 1 H), 2.55 (dd, J = 13.6 Hz, 6.4 Hz, 1 H), 2.28 (m, 1 H), 2.18 (apparent q, J =8.8 Hz, 1 H), 1.85 (dd, J = 8.0 Hz, 5.6 Hz, 1 H), 1.73 (m, 2 H), 1.5 (m, 2 H), 1.40 (dd, J = 9.6 Hz, 5.6 Hz, 1 H), 1.3 (m, 2 H), 1.23 (m, 4 H), 1.08 (s, 9 H), 0.99 (m, 2 H), 0.89 (m, 3 H), 0.73 (m, 1 H), 0.49 (m, 1 H) ppm; HRMS (ESI) m/z 767.3411 [(M+H)+; calcd for C38H51N6O9S: 767.3433].http://pubs.acs.org/doi/suppl/10.1021/ml300017p/suppl_file/ml300017p_si_001.pdf
…………………………..
HPLC
……………………
SYNTHESIS OF INTERMEDIATES Intermediates A
Intermediate # Structure Name Lit. Reference
A1 Figure US08080654-20111220-C00003 (1R,2S)-1-Amino-N- (cyclopropylsulfonyl)-2- vinylcyclopropanecarboxamide hydrochloride Wang et al., U.S. Pat. No. 6,995,174
Intermediate B1 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine
Figure US08080654-20111220-C00004
Step 1: [(1E)-hepta-1,6-dien-1-yloxy](trimethyl)silane
Figure US08080654-20111220-C00005
A solution (0.5 M) of butenyl magnesium bromide in THF (1.4 eq) was treated at −78° C. with Cu(I) Br.SMe(0.05 eq) and HMPA (2.4 eq). The mixture was stirred for 10 min, then a solution (1 M) of acrolein (1 eq) and TMSCl (2 eq) in THF was added over 1 h such that the internal temperature remained below −68° C. The resulting mixture was stirred at −78° C. for 2 h, then treated with excess Et3N and diluted with hexane. After reaching room temperature, the mixture was treated with a small portion of H2O and filtered through CELITE. The filtrate was washed 10 times with H2O and then with brine. The organic layer was dried, and the volatiles were removed to give a residue that was distilled under reduced pressure (20 mbar). The fraction collected at 80-86° C. contained the title compound (58%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 6.19 (d, J=11.6 Hz, 1H), 5.85-5.75 (m, 1H), 5.02-4.92 (m, 3H), 2.08-2.02 (m, 2H), 1.94-1.88 (m, 2H), 1.46-1.38 (m, 2H), 0.18 (s, 9H).
Step 2: trans-2-pent-4-en-1-ylcyclopropanol
Figure US08080654-20111220-C00006
A solution (0.45 M) of the preceding compound in hexane was treated with a solution (15%) of Et2Zn (1.2 eq) in toluene, and the resulting solution was cooled in an ice bath. Diiodomethane (1.2 eq) was added dropwise, then the solution was stirred for 1 h before being warmed to 20° C. Pyridine (6 eq) was added, and the slurry was stirred for 15 min then poured onto petroleum ether. The mixture was filtered repeatedly through CELITE until a transparent solution was obtained. This mixture was concentrated at 100 mbar, and the solution that remained (that contained trimethyl{[(trans)-2-pent-4-en-1-ylcyclopropyl]oxy}silane, toluene and pyridine) was further diluted with THF. The mixture was cooled to 0° C. then treated dropwise with a solution (1 M) of TBAF (1.2 eq) in THF. After 10 min, the mixture was allowed to warm to 20° C., and after a further 1 h was poured into H2O. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine then dried. Removal of the volatiles afforded a residue that was purified by flash chromatography (eluent 0-66% Et2O/petroleum ether) to furnish the title compound (71%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1H), 5.00 (dd, J=17.1, 1.6 Hz, 1H), 4.94 (br d, J=10.4 Hz, 1H), 3.20 (apparent dt, J=6.4, 2.5 Hz, 1H), 2.10-2.04 (m, 2H), 1.52-1.44 (m, 2H), 1.29-1.19 (m, 1H), 1.15-1.07 (m, 1H), 0.95-0.87 (m, 1H), 0.71-0.66 (m, 1H), 0.31 (apparent q, J=6.0 Hz, 1H).
Step 3: methyl 3-methyl-N-(oxomethylene)-L-valinate
Figure US08080654-20111220-C00007
A solution (0.39 M) of methyl 3-methyl-L-valinate in a 2:1 mixture of saturated aqueous NaHCOand CH2Clwas cooled in an ice bath and stirred rapidly. The mixture was treated with triphosgene (0.45 eq) in one portion, and the resulting mixture was stirred for 0.5 h. The reaction was diluted with CH2Cl2, and the layers were separated. The aqueous phase was extracted with CH2Cl2, then the combined organics were washed with brine and dried. Removal of the solvent gave the title compound as clear oil that was kept for 12 h under vacuum (0.1 mbar) then used directly in the subsequent step. 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 3.75 (s, 1H), 1.00 (s, 9H).
Step 4: methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate and methyl 3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate
Figure US08080654-20111220-C00008
A solution (0.45 M) of trans-2-pent-4-en-1-ylcyclopropanol in toluene was treated with methyl 3-methyl-N-(oxomethylene)-L-valinate (1.1 eq) and then DMAP (1 eq). The resulting mixture was heated under reflux for 12 h then cooled to 20° C. H2O and EtOAc were added, and the organic layer was separated and washed with 1N HCl, brine and dried. Removal of the volatiles afforded a residue that was purified twice by flash chromatography (eluent 0-30% Et2O/petroleum ether). The first fractions contained methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate (38%) as an oil. MS (ES+) m/z 298 (M+H)+
The later fractions contained methyl 3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate (28%) as an oil. MS (ES+) m/z 298 (M+H)+
Step 5: 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine
Figure US08080654-20111220-C00009
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate in 2:1 mixture of MeOH/H2O was treated with LiOH.H2O (4 eq) and then heated at 60° C. for 4 h. The mixture was cooled and concentrated to half volume, then diluted with EtOAc and acidified with aqueous HCl (1 N). The organic layer was separated and washed with brine then dried. Removal of the volatiles afforded the title compound (98%) as an oil. MS (ES+) m/z 284 (M+H)+
Intermediates C Intermediate C1 methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride
Figure US08080654-20111220-C00010
Step 1: 6-methoxyquinoxaline-2,3-diol
Figure US08080654-20111220-C00011
A suspension of 4-methoxybenzene-1,2-diamine dihydrochloride in diethyl oxalate (8 eq) was treated with Et3N (2 eq) and then heated at 150° C. for 2 h. The mixture was cooled and filtered, and then the collected solid was washed with H2O and EtOH. The residue was dried to give the title compound (69%). MS (ES+) m/z 193 (M+H)+
Step 2: 3-chloro-6-methoxyquinoxalin-2-ol
Figure US08080654-20111220-C00012
A solution (1.53 M) of 6-methoxyquinoxaline-2,3-diol in DMF was treated with SOCl(1 eq) and heated at 110° C. After 1.5 h, the reaction mixture was cooled and poured into aqueous HCl (1 N). The resulting precipitate was filtered and washed with H2O and Et2O. The dried solid contained predominantly the title compound as a mixture with 6-methoxyquinoxaline-2,3-diol and 2,3-dichloro-6-methoxyquinoxaline. This material was used directly in the subsequent step. MS (ES+) m/z 211 (M+H)+
Step 3: 1-tert-butyl 2-methyl (2S,4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
Figure US08080654-20111220-C00013
A solution (0.35 M) of 3-chloro-6-methoxyquinoxalin-2-ol in NMP was treated with Cs2CO(1.5 eq) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.1 eq). The resulting mixture was stirred at 50° C. for 18 h, then a further portion (0.1 eq) of 1-tert-butyl 2-methyl (25,45)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate was added. After stirring for 2 h, the mixture was cooled and diluted with H2O and EtOAc. The organic phases were washed with aqueous HCl (1 N), saturated aqueous NaHCOand brine. The dried organic phase was concentrated to a residue that was purified by flash-chromatography (0-60% EtOAc/petroleum ether) to give the title compound (35% for two steps) as a solid. MS (ES+) m/z 438 (M+H)+
Step 4: methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride
Figure US08080654-20111220-C00014
A solution (0.62 M) of 1-tert-butyl 2-methyl (2S,4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate in CH2Clwas treated with a solution (4 M) of HCl in dioxane (5 eq). The mixture was stirred at 20° C. for 2 h, then treated with a solution (4 M) of HCl in dioxane (2 eq). After 5 h, the reaction was judged complete and the mixture was concentrated under reduced pressure. The residue was triturated with Et2O to give the title compound (95%) as a solid. MS (ES+) m/z 338 (M+H)+
Example 1 Potassium {[(1R,2S)-1-({[(1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-yl]carbonyl}amino)-2-vinylcyclopropyl]carbonyl}(cyclopropylsulfonyl)azanide
Figure US08080654-20111220-C00015
Step 1: methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate
Figure US08080654-20111220-C00016
A solution (0.2 M) of methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride in DMF was treated with 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine (1.1 eq), DIEA (5 eq) and HATU (1.2 eq). The resulting mixture was stirred at 20° C. for 5 h, then diluted with EtOAc. The organic layer was separated and washed with aqueous HCl (1 N), saturated aqueous NaHCOand brine. The dried organic phase was concentrated under reduced pressure to give a residue that was purified by flash chromatography (eluent 10-30% EtOAc/petroleum ether) to furnish the title compound (96%) as an oil. MS (ES+) m/z 604 (M+H)+
Step 2: methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(7-methoxy-3-vinylquinoxalin-2-yl)oxy]-L-prolinate
Figure US08080654-20111220-C00017
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate in EtOH was treated with potassium trifluoro(vinyl)borate (1.5 eq) and triethylamine (1.5 eq). The resulting mixture was degassed, then PdCl2(dppf)-CH2Cladduct (0.1 eq) was added. The mixture was heated under reflux for 1 h, then cooled to room temperature and diluted with H2O and EtOAc. The organic phase was separated, washed with H2O and brine then dried. Removal of the volatiles afforded a residue that was purified by flash chromatography (20-30% EtOAc/petroleum ether) to give the title compound as a yellow foam that was used directly in the subsequent step. MS (ES+) m/z 595 (M+H)+
Step 3: methyl (1aR,5S,8S,10R,18E,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate
Figure US08080654-20111220-C00018
A solution (0.02 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(7-methoxy-3-vinylquinoxalin-2-yl)oxy]-L-prolinate in DCE was heated to 80° C. then treated with Zhan 1 catalyst (0.15 eq). The resulting mixture was stirred at 80° C. for 1 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (20-50% EtOAc/petroleum ether) to give the title compound (25% for 2 steps) as a foam. MS (ES+) m/z 567 (M+H)+
Step 4: methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate
Figure US08080654-20111220-C00019
A solution (0.05 M) of methyl (1aR,5S,8S,10R,18E,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in MeOH/dioxane (1:1 ratio) was treated with Pd/C (8% in weight). The resulting mixture was stirred under atmosphere of hydrogen for 4 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (98%) as a solid. MS (ES+) m/z 569 (M+H)+
Step 5: (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid
Figure US08080654-20111220-C00020
A solution (0.1 M) of methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in a 1:1 mixture of H2O/THF was treated with LiOH.H2O (3 eq). The resulting mixture was stirred at 20° C. for 18 h, acidified with aqueous HCl (0.2 M) and diluted with EtOAc. The organic phase was separated, washed with aqueous HCl (0.2 M) and brine then dried. Removal of the volatiles afforded the title compound (98%) as a solid. MS (ES+) m/z 555 (M+H)+
Step 6: (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide
Figure US08080654-20111220-C00021
A solution (0.1 M) of (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid in CH2Clwas treated with (1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride (1.3 eq), DIEA (3 eq), DMAP (1.5 eq) and TBTU (1.45 eq). The resulting mixture was stirred at 20° C. for 18 h and then diluted with EtOAc. The solution was washed with aqueous HCl (0.2 M), saturated aqueous NaHCOand brine. The organic phases were dried and concentrated to give a residue that was purified by flash-chromatography (eluent 2.5% MeOH/CH2Cl2) to give the title compound (89%) as a solid. 13C NMR (100 MHz, DMSO-d6) δ 172.32, 170.63, 169.04, 159.86, 156.95, 154.74, 148.10, 140.41, 133.55 (2 signals), 128.94, 118.21, 117.58, 105.89, 74.88, 59.75, 58.71, 55.68, 54.13, 54.01, 40.13, 34.49, 34.04, 33.76, 32.68, 30.71, 30.43, 28.55, 27.69, 27.28, 26.38, 21.98, 18.49, 10.67, 5.69, 5.46; MS (ES+) m/z 767 (M+H)+
GRAZOPREVIR POTASSIUM
Step 7: potassium {[(1R,2S)-1-({[(1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-yl]carbonyl}amino)-2-vinylcyclopropyl]carbonyl}(cyclopropylsulfonyl)azanide
Figure US08080654-20111220-C00022
The preceding material was taken up in EtOH and the resulting solution (0.025 M) was cooled to 0° C. A solution (0.02 M) of tert-BuOK (1.5 eq) in EtOH was added leading to the formation of a precipitate. The mixture was stirred at 20° C. for 18 h, then the solid was collected by filtration. This material was washed with EtOH and dried to give the title compound (93%) as a white crystalline solid. MS (ES+) m/z 767 (M+H)+http://www.google.nl/patents/US8080654
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PATENT
WO 2015095437

Step 1: Quinoxaline Hydroxyproline Methyl Ester HCl Salt

A 250-ml RB, equipped with magnetic stirrer and N2 bubbler, was charged with chloroquinoxaline BOC hydroxyproline adduct in MeOH (100 ml), and the mixture was cooled in an ice bath. Acetyl chloride (17.9 g) was then added, and the mixture was stirred at RT for 2 h. The batch was diluted with IP Ac (80 ml). Solids were filtered off and washed with IPAc (20 ml). The washed solids were dried under vacuum for 3 d, to provide 48.9 g (100% yield ). Part of this material was used in the next step.

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WO2015057611

Example 17: Preparation of Compound A, Method A

Macrocyclic acid hemihydrate, the product of Example 15 (10.16 g, 18.03 mmol) was dissolved in THF (50 mL to 90 mL). The solution was azetropically dried at a final volume of 100 mL. Sulfonamide pTSA salt (7.98 g, 1.983 mmol) followed by DMAc (15 mL) was added at RT. The batch was cooled to 0°C to 10°C, and pyridine (10 mL) was added dropwise. Then, EDC HCl (4.49 g, 23.44 mmol) was added in portions or one portion at 0°C to 10°C. The reaction mixture was aged at 0°C to 10°C for 1 h, and then warmed to 15°C to 20°C for 2 h to 4 h. MeOAc (100 mL) followed by 15 wt% citric acid in 5% NaCl in water (50 mL) was added, while the internal temperature was maintained to < 25°C with external cooling. The separated organic phase was washed with 15 wt% citric acid in 5% NaCl in water (50 mL) followed by 5% NaCl (50 mL). The organic phase was solvent-switched to acetone at a final volume of ~80 mL. Water (10 mL) was added dropwise at 35°C to 40°C. The batch was seeded with Compound A monohydrate form III (~10 mg) and aged for 0.5 h tol h at 35°C to 40°C. Additional water (22 mL) was added dropwise over 2 h to 4 h at 35°C to 40°C. The slurry was aged at 20°C for 2 h to 4 h before filtration. The wet cake was displacement washed with 60% acetone in water (2x 40 mL). Suction drying at RT gave Compound A monohydrate form III as a white solid.

XH NMR (400 MHz, CDC13) δ 9.95 (s, br, 1 H), 7.81 (d, J = 9.1 Hz, 1 H), 7.18 (dd, J = 9.1, 2.7 Hz, 1 H), 7.16 (s, br, 1 H), 7.13 (d, J = 2.7 Hz, 1 H), 5.96 (t, J = 3.8 Hz, 1 H), 5.72 (m, 1 H), 5.68 (d, J = 10.1 Hz, 1 H), 5.19 (d, J = 17.1 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 9.8 Hz, 1 H), 4.36 (d, J = 10.5, 6.9 Hz, 1 H), 4.05 (dd, J = 11.5, 3.9 Hz, 1 H), 3.93 (s, 3 H), 3.78 (m, 1 H), 2.90 (m, 1 H), 2.82 (tt, J = 8.0, 4.8 Hz, 1 H), 2.74 (dt, J = 13.2, 4.8 Hz, 1 H), 2.59 (dd, J = 14.0, 6.7 Hz, 1 H), 2.40 (ddd, J = 14.0, 10.6, 4.0 Hz, 1 H), 2.10 (dd, J = 17.7, 8.7 Hz, 1 H), 1.98 (2 H, mono hydrate H20), 1.88 (dd, J 8.2, 5.9 Hz, 1 HO, 1.74 (m, 3 H), 1.61 (m, 1 H), 1.50 (m, 3 H), 1.42 (dd, J = 9.6, 5.8 Hz, 1 H), 1.22 (m, 2 H), 1.07 (s, 9 H), 0.95 (m, 4 H), 0.69 (m, 1 H), 0.47 (m, 1 H).

1 C NMR (100 MHz, CDC13) δ 173.5, 172.1, 169.1, 160.4, 157.7, 154.9, 148.4, 141.0, 134.3, 132.7, 129.1, 118.8, 118.7, 106.5, 74.4, 59.6, 59.4, 55.8, 55.5, 54.9, 41.8, 35.4, 35.3, 35.2, 34.3,. 31.2, 30.7, 29.5, 28.6, 28.2, 26.6, 22.6, 18.7, 11.2, 6.31, 6.17.

HPLC conditions: Ascentis Express Column, 10 cm x 4.6 mm, 2.7 μηι; Column temperature of 40°C; Flow rate of 1.8 mL/min; and Wavelength of 215 nm.

Gradiant: mm 0.1% ¾PO4

0 20 80

5 55 45

15 55 45

25 95 5

27 95 5

27.1 20 80

32 20 80

Retention time: mm.

Compound A 14.50

Example 18: Preparation of Compound A, Method B

To a 50-L flask equipped with overhead stirring was added macrocyclic acid (1.06 kg crude, 1.00 eq), amine-pTSA (862 g crude, 1.12 eq) and MeCN (7.42 L) at 19°C. The slurry was cooled in a water bath, pyridine (2.12 L, 13.8 eq) was added, aged 15 min, and then added EDC (586 g, 1.60 eq) in one portion, aged 1.5 h, while it turned into a clear homogeneous solution.

The solution cooled in a water bath, then quenched with 2 N HC1 (1.7 L), and seeded (9.2 g), aged 15 min, and the rest of the aqueous HC1 was added over 2.5 h. A yellow slurry was formed. The slurry was aged overnight at RT, filtered, washed with MeCN/water (1 : 1 v/v, 8 L), to obtain Compound A (Hydrate II).

Compound A was dissolved in acetone (4 L) at RT, filtered and transferred to a

12-L round-bottom flask with overhead stirring, rinsed with extra acetone (1 L), heated to 50°C, water (0.9 L) was added, seeded with Compound A monohydrate form III (-10 mg), and aged 15 min, and then added water (0.8 L) over 2.5 h, extra water 3.3 v over 2.5 h was added, stopped heating, cooled to RT, aged at RT overnight, filtered, washed with water/acetone (1 : 1 v/v, 4 L), and dried in air under vacuum. Compound A Hydrate III, 670 g, was obtained as an off-white solid.

Example 19: Preparation of Compound A, Method C

Macrocyclic acid hemihydrate from Example 15 (10.16 g, 18.03 mmol) was dissolved in THF (50 ml to 90 mL). The solution was azetropically dried at a final volume of 100 mL. Sulfonamide pTSA salt (7.98 g, 19.83 mmol) was added, followed by DMAc (15 mL), at RT. The batch was cooled to 0° to 10°C, and pyridine (10 mL) was added dropwise. Then, EDC HC1 (4.49 g, 23.44 mmol) was added (in portions or one portion) at 0°C to 10°C. The reaction mixture was aged at 0°C to 10°C for 1 h, and then warmed to 15°C to 20°C for 2 h to 4 h. THF (50 mL) was added, followed by 15 wt% citric acid in 15 wt% aq. NaCl (50 mL), while the internal temperature was maintained at < 25°C with external cooling. The separated organic phase was washed with 15 wt% citric acid in 1 % aq. NaCl (40 mL), followed by 15% NaCl (40 mL). The organic phase was solvent-switched to acetone at a final volume of ~75 mL Water (1 1 mL to 12 mL) was added dropwise at 35°C to 40°C. The batch was seeded with Compound A monohydrate form III (~20 mg) and aged for 0.5 h to 1 h at 35°C to 40°C.

Additional water (22 mL) was added dropwise over 2 h to 4 h at 35°C to 40°C. The slurry was aged at 20°C for 2 h to 4 h before filtration. The wet cake was displacement washed with 60% acetone in water (40 mL x 2). Suction drying at RT or vacuum-oven drying at 45°C gave Compound A monohydrate form III as a white solid.

Example 20: Preparation of Compound A, Method D

Macrocyclic acid hemihydrate from Example 12 (10 g, 98.4wt%, 17.74 mmol) was dissolved in THF (70 mL). The solution was azetropically dried at a final volume of ~60 mL. Sulfonamide pTSA salt (7.53 g, 18.7 mmol) was added at RT. The batch was cooled to 0°C to 5°C, and pyridine (1 1.4 mL) was added dropwise. Then, EDC HC1 (4.26 g, 22.2 mmol) was added in portions at 0°C to 15°C. The reaction mixture was aged at 10°C to 15°C for 2 h to 4 h. 35 wt% Citric acid in 10 wt% aq. NaCl (80 mL) was added, while the internal temperature was maintained at < 25°C with external cooling. The separated organic phase was solvent-switched to acetone at a final volume of ~75 mL. Water (12 mL) was added dropwise at 50°C. The batch was seeded with Compound A monohydrate form III (-300 mg) and aged for 0.5 h to 1 h at 50°C. Additional water (25 mL) was added dropwise over 6 h at 35°C to 40°C. The slurry was aged at 20°C for 2 h to 4 h before filtration. The wet cake was displacement washed with 65%) acetone in water (40 mL). Suction drying at RT or vacuum-oven drying at 45°C gave Compound A monohydrate form III as a white solid.

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WO2015095430

Example 24: Ring Closing Metathesis

To a 50 mL 2-neck RB flask with reflux condenser and needle for N2 bubbling was charged the product of Example 20 (1.034 g, 0.869 mmol, 1.0 eq), toluene (20.68 ml, 20X), and the resulting solution was degassed with N2. Hoveyda-Grubbs 2nd generation catalyst (10.90 mg, 0.017 mmol) was charged to the pot, and the system was heated to 80°C with constant sparge of N2, with color change from green to reddish. The reaction was sampled (5 h) and assay by HPLC to be approximately 80% converted. The system was removed from the heat and allowed to stir at RT overnight under N2. The reaction was again assayed and deemed complete by HPLC. Toluene was removed by concentration and the resulting red oil was purified by gradient silica gel chromatography (50 g BlOTAGE SNAP Si gel column; loaded with DCM; eluted with 0 to 10% EtOAc in DCM over 10 column volumes; then 10 to 20% EtOAc in DCM over 3 column volumes; then hold; detect by TLC-UV) to yield a yellow solid, which was further slurried in EtOAc (3 mL) and hexanes (6 mL). The resulting slurry was filtered and washed with 25% EtOAc in hexanes (6 mL) to yield the product (445 mg, 0.754 mmol, 87% yield) as a white solid.

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http://anewmerckreviewed.wordpress.com/2013/04/23/okay-trivial-pursuit-will-the-real-mk-5172-please-stand-up/

Synthesis of MK-5172_NS3 protease inhibitor_Hepatitis C_Merck 默沙东丙型肝炎药物MK-5172的的化学合成

Merck reported interim data from the Phase 2 C-WORTHY study in April 2014 at the International Liver Congress (ILC) in London that evaluated the efficacy and safety of its two-drug regimen based on NS3/4A protease inhibitor MK-5172 and NS5A replication complex inhibitor MK-8742, given with or without ribavirin, in GT1 HCV patients with cirrhosis. The once-daily single pill (without ribavirin) showed a 98% SVR12 (12-week sustained virologic response) in genotype-1, treatment-naive patients. Merck will start the phase III clinical trials (NCT02105688NCT02105662NCT02105467 andNCT02105701) for the combination in June 2014.

 

MK-5172 is a novel, competitive inhibitor of the HCV NS3/4a protease with selective, potent in vitro activity against a broad range of HCV genotypes (GTs) and known viral variants that are resistant to other protease inhibitors in development.
MK-5172 is a Next Generation HCV NS3/4a Protease Inhibitor with a Broad HCV Genotypic Activity Spectrum and Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients. MK-5172 exhibits excellent selectivity over other serine proteases such as elastase and trypsin (no measurable inhibition), and shows only modest inhibitory potency with chymotrypsin (IC50 = 1.5 µM; 75,000-fold selective). In the genotype 1b replicon assay, MK-5172 potently inhibits viral replication (IC50 = 2 nM) and demonstrates a modest shift in the presence of 50% NHS (EC50 = 9.5 nM). In vitro, MK-5172 inhibits the NS3/4A enzyme from genotypes 1b, 2a, 2b, and 3a with Ki values of <0.02, 0.15, 0.02, and 0.7 nM, respectively. The genotype 2a replicon is also potently inhibited by MK 5172 (EC50 = 5 nM).
Kuethe J, * Zhong Y.-L, * Yasuda N, * Beutner G, Linn K, Kim M, Marcune B, Dreher SD, Humphrey G, Pei T. Merck Research Laboratories, Rahway, USA
Development of a Practical, Asymmetric Synthesis of the Hepatitis C Virus Protease Inhibitor MK-5172.Org. Lett. 2013;
15: 4174-4177
SignificanceNotify Users About this Post

MK-5172 is a hepatitis C virus protease inhibitor. Key steps in the synthesis depicted are (1) the regioselective SNAr reaction of dichloroquinoxaline A with prolinol derivative B and (2) construction of the 18-membered macrocycle ­using a macrolactamization (F → G).

Comment

The medicinal chemistry route to MK-5172 is based on a ring-closing metathesis strategy (S. Harper et al.ACS Med. Chem. Lett. 2012, 3, 332). The best regioselectivity (20:1) and minimization of double substitution in the SNAr reaction of A with B was achieved using 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU) as the base in polar solvents such as DMSO, NMP, or DMAc.

 

SYNTHESIS, THESIS PROCEDURES, NMR see………..http://www.allfordrugs.com/2015/07/31/mk-5172-grazoprevir/

/////////////http://www.allfordrugs.com/2015/07/31/mk-5172-grazoprevir/

 

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