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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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Biafungin, CD 101, a Novel Echinocandin for Vulvovaginal candidiasis


STR1

str1

str1as  CH3COOH salt

UNII-W1U1TMN677.png

CD 101

Several structural representations above

Biafungin™; CD 101 IV; CD 101 Topical; CD101; SP 3025, Biafungin acetate, Echinocandin B

UNII-G013B5478J FRE FORM,

CAS 1396640-59-7 FREE FORM

MF, C63-H85-N8-O17, MW, 1226.4035

Echinocandin B,

1-((4R,5R)-4-hydroxy-N2-((4”-(pentyloxy)(1,1′:4′,1”-terphenyl)-4-yl)carbonyl)-5-(2-(trimethylammonio)ethoxy)-L-ornithine)-4-((4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine)-

Treat and prevent invasive fungal infections; Treat and prevent systemic Candida infections; Treat candidemia

2D chemical structure of 1631754-41-0

Biafungin acetate

CAS 1631754-41-0 ACETATE, Molecular Formula, C63-H85-N8-O17.C2-H3-O2, Molecular Weight, 1285.4472,

C63 H85 N8 O17 . C2 H3 O2
1-[(4R,5R)-4-hydroxy-N2-[[4”-(pentyloxy)[1,1′:4′,1”-terphenyl]-4-yl]carbonyl]-5-[2-(trimethylammonio)ethoxy]-L-ornithine]-4-[(4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine]-, acetate (1:1)

UNII: W1U1TMN677

CD101 – A novel echinocandin antifungal C. albicans (n=351) MIC90 = 0.06 µg/mL C. glabrata (n=200) MIC90 = 0.06 µg/mL  Echinocandins have potent fungicidal activity against Candida species

  • Originator Seachaid Pharmaceuticals
  • Developer Cidara Therapeutics
  • Class Antifungals; Echinocandins; Small molecules
  • Mechanism of Action Glucan synthase inhibitors

 

BIAFUNGIN, CD 101

Watch this space as I add more info…………….

U.S. – Fast Track (Treat candidemia);
U.S. – Fast Track (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat and prevent invasive fungal infections)

Fungal infections have emerged as major causes of human disease, especially among the immunocompromised patients and those hospitalized with serious underlying disease. As a consequence, the frequency of use of systemic antifungal agents has increased significantly and there is a growing concern about a shortage of effective antifungal agents. Although resistance rates to the clinically available antifungal agents remains low, reports of breakthrough infections and the increasing prevalence of uncommon fungal species that display elevated MIC values for existing agents is worrisome. Biafungin (CD101, previously SP 3025) is a novel echinocandin that displays chemical stability and long-acting pharmacokinetics that is being developed for once-weekly or other intermittent administration (see posters #A-693 and A- 694 for further information). In this study, we test biafungin and comparator agents against a collection of common Candida and Aspergillus species, including isolates resistant to azoles and echinocandins.

The echinocandins are an important class of antifungal agents, but are administered once daily by intravenous (IV) infusion. An echinocandin that could be administered once weekly could facilitate earlier hospital discharges and could expand usage to indications where daily infusions are impractical. Biafungin is a highly stable echinocandin for once-weekly IV administration. The compound was found to have a spectrum of activity and potency comparable to other echinocandins. In chimpanzees single dose pharmacokinetics of IV and orally administered biafungin were compared to IV anidulafungin, which has the longest half-life (T1/2 ) of the approved echinocandins.

Background  Vulvovaginal candidiasis (VVC) is a highly prevalent mucosal infection  VVC is caused by Candida albicans (~85%) and non-albicans (~15%)  5-8% of women have recurrent VVC (RVVC) which is associated with a negative impact on work/social life  Oral fluconazole prescribed despite relapse, potential DDIs and increased risk to pregnant women  No FDA-approved therapy for RVVC and no novel agent in >20 years

str1

Cidara Therapeutics 6310 Nancy Ridge Drive, Suite 101 San Diego, CA 92121

The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains ofCandida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents.

Echinocandins are a new class of antifungal drugs[1] that inhibit the synthesis of glucan in the cell wall, via noncompetitive inhibition of the enzyme 1,3-β glucan synthase[2][3] and are thus called “penicillin of antifungals”[4] (a property shared with papulacandins) as penicillin has a similar mechanism against bacteria but not fungi. Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components (The bacterial equivalent is peptidoglycan). Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.[5]

List of echinocandins:[17]

  • Pneumocandins (cyclic hexapeptides linked to a long-chain fatty acid)
  • Echinocandin B not clinically used, risk of hemolysis
  • Cilofungin withdrawn from trials due to solvent toxicity
  • Caspofungin (trade name Cancidas, by Merck)
  • Micafungin (FK463) (trade name Mycamine, by Astellas Pharma.)
  • Anidulafungin (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer)

History

Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma (Pers.), which were liposaccharide – i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase – and had action only on Candida spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity against Candida spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first approved of these newer echinocandins was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

CIDARA THERAPEUTICS DOSES FIRST PATIENT IN PHASE 2 TRIAL OF CD101 TOPICAL TO TREAT VULVOVAGINAL CANDIDIASIS

SAN DIEGO–(BUSINESS WIRE)–Jun. 9, 2016– Cidara Therapeutics, Inc. (Nasdaq:CDTX), a biotechnology company developing novel anti-infectives and immunotherapies to treat fungal and other infections, today announced that the first patient has been dosed in RADIANT, a Phase 2 clinical trial comparing the safety and tolerability of the novel echinocandin, CD101, to standard-of-care fluconazole for the treatment of acute vulvovaginal candidiasis (VVC). RADIANT will evaluate two topical formulations of CD101, which is Cidara’s lead antifungal drug candidate.

“There have been no novel VVC therapies introduced for more than two decades, so advancing CD101 topical into Phase 2 is a critical step for women with VVC and for Cidara,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “Because of their excellent safety record and potency against Candida, echinocandin antifungals are recommended as first line therapy to fight systemic Candida infections. CD101 topical will be the first echinocandin tested clinically in VVC and we expect to demonstrate safe and improved eradication of Candida with rapid symptom relief for women seeking a better option over the existing azole class of antifungals.”

RADIANT is a Phase 2, multicenter, randomized, open-label, active-controlled, dose-ranging trial designed to evaluate the safety and tolerability of CD101 in women with moderate to severe episodes of VVC. The study will enroll up to 125 patients who will be randomized into three treatment cohorts. The first cohort will involve the treatment of 50 patients with CD101 Ointment while a second cohort of 50 patients will receive CD101 Gel. The third cohort will include 25 patients who will be treated with oral fluconazole.

The primary endpoints of RADIANT will be the safety and tolerability of a single dose of CD101 Ointment and multiple doses of CD101 Gel in patients with acute VVC. Secondary endpoints include therapeutic efficacy in acute VVC patients treated with CD101. Treatment evaluations and assessments will occur on trial days 7, 14 and 28.

The RADIANT trial will be conducted at clinical trial centers across the United States. More information about the trial is available at www.clinicaltrials.gov, identifier NCT02733432.

About VVC and RVVC

Seventy-five percent of women worldwide suffer from VVC in their lifetime, and four to five million women in the United Statesalone have the recurrent form of the infection, which is caused by Candida. Many women will experience recurrence after the completion of treatment with existing therapies. Most VVC occurs in women of childbearing potential (the infection is common in pregnant women), but it affects women of all ages. In a recent safety communication, the U.S. Food and Drug Administration(FDA) advised caution in the prescribing of oral fluconazole for yeast infections during pregnancy based on a published study concluding there is an increased risk of miscarriage. The Centers for Disease Control and Prevention (CDC) guidelines recommend using only topical antifungal products to treat pregnant women with vulvovaginal yeast infections. Vaginal infections are associated with a substantial negative impact on day-to-day functioning and adverse pregnancy outcomes including preterm delivery, low birth weight, and increased infant mortality in addition to predisposition to HIV/AIDS. According to the CDC, certain species of Candida are becoming increasingly resistant to existing antifungal medications. This emerging resistance intensifies the need for new antifungal agents.

About CD101 Topical

CD101 topical is the first topical agent in the echinocandin class of antifungals and exhibits a broad spectrum of fungicidal activity against Candida species. In May 2016, the FDA granted Qualified Infectious Disease Product (QIDP) and Fast Track Designation to CD101 topical for the treatment of VVC and the prevention of RVVC.

About Cidara Therapeutics

Cidara is a clinical-stage biotechnology company focused on the discovery, development and commercialization of novel anti-infectives for the treatment of diseases that are inadequately addressed by current standard-of-care therapies. Cidara’s initial product portfolio comprises two formulations of the company’s novel echinocandin, CD101. CD101 IV is being developed as a once-weekly, high-exposure therapy for the treatment and prevention of serious, invasive fungal infections. CD101 topical is being developed for the treatment of vulvovaginal candidiasis (VVC) and the prevention of recurrent VVC (RVVC), a prevalent mucosal infection. In addition, Cidara has developed a proprietary immunotherapy platform, Cloudbreak™, designed to create compounds that direct a patient’s immune cells to attack and eliminate pathogens that cause infectious disease. Cidara is headquartered inSan Diego, California. For more information, please visit www.cidara.com.

REF http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474

CLIP

Cidara Therapeutics raises $42 million to develop once-weekly anti-fungal therapy

Cidara Therapeutics (formerly K2 Therapeutics) grabbed $42 million in a private Series B funding round Wednesday to continue developing its once-weekly anti-fungal therapy. Just in June 2014, the company completed a $32 million Series A financing led by 5AM Ventures, Aisling Capital, Frazier Healthcare and InterWest Partners, which was the fourth largest A round in 2014 for innovative startups[1]. FierceBiotech named the company as one of 2014 Fierce 15 biotech startups.

Cidara has an impressive executive team. The company was co-founded by Kevin Forrest, former CEO of Achaogen (NASDAQ: AKAO), and Shaw Warren. Jeffrey Stein, former CEO of Trius Therapeutics (NASDAQ: TSRX) and Dirk Thye, former president of Cerexa, have joined Cidara as CEO and CMO, respectively. Trius successfully developed antibiotic tedizolid and was acquired in 2013 by Cubist Pharmaceuticals (NASDAQ: CBST) for $818 million.

Cidara’s lead candidate, biafungin (SP3025), was acquired from Seachaid Pharmaceuticals for $6 million. Biafungin’s half-life is much longer than that of similar drugs known as echinocandins (e.g., caspofungin, micafungin, anidulafungin), which may allow it to be developed as a once-weekly therapy, instead of once daily. The company is also developing a topical formulation of biafungin, namely topifungin. Cidara intends to file an IND and initiate a Phase I clinical trial in the second half of 2015.

Merck’s Cancidas (caspofungin), launched in 2001, was the first of approved enchinocandins. The drug generated annual sales of $596 million in 2008. The approved echinocandins must be administered daily by intravenous infusion. Biafungin with improved pharmacokinetic characteristics has the potential to bring in hundreds of millions of dollars per year.

[1] Nat Biotechnol. 2015, 33(1), 18.

CLIP

Biafungin is a potent and broad-spectrum antifungal agent with excellent activity against wild-type and troublesome azole- and echinocandin-resistant strains of Candida spp. The activity of biafungin is comparable to anidulafungin. • Biafungin was active against both wild-type and itraconazole-resistant strains of Aspergillus spp. from four different species. • In vitro susceptibility testing of biafungin against isolates of Candida and Aspergillus may be accomplished by either CLSI or EUCAST broth microdilution methods each providing comparable results. • The use of long-acting intravenous antifungal agents that could safely be given once a week to select patients is desirable and might decrease costs with long-term hospitalizations. Background: A novel echinocandin, biafungin, displaying long-acting pharmacokinetics and chemical stability is being developed for once-weekly administration. The activities of biafungin and comparator agents were tested against 173 fungal isolates of the most clinically common species. Methods: 106 CAN and 67 ASP were tested using CLSI and EUCAST reference broth microdilution methods against biafungin (50% inhibition) and comparators. Isolates included 27 echinocandin-resistant CAN (4 species) with identified fks hotspot (HS) mutations and 20 azole nonsusceptible ASP (4 species). Results: Against C. albicans, C. glabrata and C. tropicalis, the activity of biafungin (MIC50, 0.06, 0.12 and 0.03 μg/ml, respectively by CLSI method) was comparable to anidulafungin (AND; MIC50, 0.03, 0.12 and 0.03 μg/ml, respectively) and caspofungin (CSP; MIC50, 0.12, 0.25 and 0.12 μg/ml, respectively; Table). C. krusei strains were very susceptible to biafungin, showing MIC90 values of 0.06 μg/ml by both methods. Biafungin (MIC50/90, 1/2 μg/ml) was comparable to AND and less potent than CSP against C. parapsilosis using CLSI methodology. CLSI and EUCAST methods displayed similar results for most species, but biafungin (MIC50, 0.06 μg/ml) was eight-fold more active than CSP (MIC50, 0.5 μg/ml) against C. glabrata using the EUCAST method. Overall, biafungin was two- to four-fold more active against fks HS mutants than CSP and results were comparable to AND. Biafungin was active against A. fumigatus (MEC50/90, ≤0.008/0.015 μg/ml), A. terreus (MEC50/90, 0.015/0.015 μg/ml), A. niger (MEC50/90, ≤0.008/0.03 μg/ml) and A. flavus (MEC50/90, ≤0.008/≤0.008 μg/ml) using CLSI method. EUCAST results for ASP were also low for all echinocandins and comparable to CLSI results. Conclusions: Biafungin displayed comparable in vitro activity with other echinocandins against common wild-type CAN and ASP and resistant subsets that in combination with the long-acting profile warrants further development of this compound. 1. Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope WW (2013). Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat 16: 81-95. 2. Castanheira M, Woosley LN, Messer SA, Diekema DJ, Jones RN, Pfaller MA (2014). Frequency of fks mutations among Candida glabrata isolates from a 10-year global collection of bloodstream infection isolates. Antimicrob Agents Chemother 58: 577-580. 3. Clinical and Laboratory Standards Institute (2008). M27-A3. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: third edition. Wayne, PA: CLSI. 4. Clinical and Laboratory Standards Institute (2008). M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Second Edition. Wayne, PA: CLSI. 5. Clinical and Laboratory Standards Institute (2012). M27-S4. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: 4th Informational Supplement. Wayne, PA: CLSI. 6. European Committee on Antimicrobial Susceptibility Testing (2014). Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January 2014. Available at: http://www.eucast.org/clinical_breakpoints/. Accessed January 1, 2014. 7. Pfaller MA, Diekema DJ (2010). Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1-53. 8. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS (2011). Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14: 164-176. ABSTRACT Activity of a Novel Echinocandin Biafungin (CD101) Tested against Most Common Candida and Aspergillus Species, Including Echinocandin- and Azole-resistant Strains M CASTANHEIRA, SA MESSER, PR RHOMBERG, RN JONES, MA PFALLER JMI Laboratories, North Liberty, Iowa, USA C

PATENT

https://www.google.com/patents/WO2015035102A2?cl=en

BIAFUNGIN ACETATE IS USED AS STARTING MATERIAL

Example 30b: Synthesis of Compound 31

Step a. Nitration of Biafungin Acetate

To a stirring solution of biafungin (1 00 mg, 0.078 mmol) in glacial acetic acid(1 .5 ml_) was added sodium nitrite (1 1 mg, 0.159 mmol) and the reaction was stirred at ambient temperature for 20 hours. The mixture was applied directly to reversed phase H PLC (Isco CombiFlash Rf; 50g RediSep C1 8 column, 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 85 mg of the desired product as a light yellow solid, formate salt. 1 H-NMR (300 M Hz, Methanol-d4) δ 8.58 (d, 1 H, J = 1 1 .7 Hz), 8.47 (t, 2H, J = 8.7Hz), 8.05 (d, 1 H, J = 2.1 Hz), 7.99 (d, 2H, J = 9.3 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.79-7.60 (m, 12H), 7.1 7 (d, 1 H, J = 8.7 Hz), 7.03 (d, 2H, J = 9 Hz), 5.48 (d, 1 H, J = 6 Hz), 5.08 (dd, 1 H, J = 1 .2, 5.7 Hz), 4.95-4.73 (m, 5H), 4.68-4.56 (m, 2H), 4.53 (d, 1 H, J = 5.7 Hz), 4.48-4.39 (m, 2H), 4.31 -3.79 (m, 6H), 4.04 (t, 2H, J = 5.7 Hz), 3.72-3.44 (m,3H), 3.1 8 (s, 9H), 2.60-1 .99 (m, 5H), 1 .83 (m, 2H, J = 8.7 Hz), 1 .56-1 .35 (m, 5H), 1 .28 (d, 6H, J = 4.2 Hz), 1 .09 (d, 3H, J = 1 0.2 Hz), 0.99 (t, 3H, J = 8.7 Hz) ; LC/MS, [M/2+H]+: 635.79, 635.80 calculated.

Step b. Reduction of Nitro-Biafungin To Amino-Biafungin

To a stirring solution of Nitro-Biafungin (1 00 mg, 0.075 mmol) in glacial acetic acid(1 .5 ml_) was added zinc powder (50 mg, 0.77 mmol) and the reaction was stirred at ambient temperature for 1 hour. The mixture was filtered and applied directly to reversed phase HPLC (Isco CombiFlash Rf, 50g Redisep C18 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 55 mg of the desired product as a white solid, formate salt. 1 H-NMR (300 MHz, Methanol-d4) 5 8.47 (bs, 1 H), 7.99 (d, 2H, J = 1 0.8Hz), 7.82 (d, 2H, J = 7.5 Hz), 7.80-7.67 (m, 6H), 7.62 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J = 7.5 Hz), 6.77 (d, 1 H, J = 1 .9 Hz), 6.68 (d, 1 H, J = 8.2 Hz), 6.55 (dd, 2H, J = 8.2, 1 .9 Hz), 5.43 (d, 1 H, J = 2.5 Hz), 5.05 (d, 1 H, J = 3 Hz), 4.83-4.73 (m, 2H), 4.64- 4.56 (m, 2H), 4.43-4.34 (m, 2H), 4.31 -4.15 (m, 4H), 4.03-4.08 (m, 1 H), 4.1 1 -3.89 (m, 8H), 3.83 (d, 1 H, J = 1 0.8 Hz), 3.68-3.47 (m, 3H), 3.1 7 (s, 9H), 2.57-2.42 (m, 2H), 2.35-2.27 (m, 1 H), 2.14-1 .98 (m, 2H), 1 .83 (m, 2H, J = 6 Hz), 1 .56-1 .38 (m, 4H), 1 .28 (dd, 6H, J = 6.5, 2 Hz), 1 .09 (d, 3H, J = 7 Hz), 0.986 (t, 3H, J = 7 Hz); High Res LC/MS: [M+H]+ 1241 .61 63; 1241 .6136 calculated.

Step c. Reaction of Amino-Biafungin with lnt-2 to Produce Compound 31

To a stirring solution of Amino-Biafungin (50 mg, 0.04 mmol) in DM F (1 ml_) was added formyl-Met-Leu-Phe- -Ala-OSu (lnt-2) (36 mg, 0.06 mmol) and DI PEA (7 uL, 0.04 mmol). The reaction was stirred at ambient temperature for 1 8 hours. The mixture was applied directly to reversed phase HPLC (Isco CombiFlash Rf; 50g Redisep C1 8 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 26 mg of a white solid as a formate salt. 1 H-NMR (300 M Hz, Methanol-d4) 5 8.55 (bs, 1 H), 8.44 (t, 1 H, J = 10 Hz), 8.1 8 (d, 1 H, J = 6 Hz), 8.1 1 (s, 1 H), 7.99 (d, 2H, J = 1 0 Hz), 7.84-7.70 (m, 6H), 7.63 (d, 2H, J = 7.8 Hz), 7.32-7.1 9 (m, 6H), 7.03 (d, 4H, J = 9 Hz), 6.87 (d, 1 H, J = 8.1 Hz), 5.44 (d, 1 H, J = 1 0.5 Hz), 5.05 (d, 1 H, J = 4.5 Hz), 4.83-4.74 (m, 2H), 4.66-4.50 (m, 6H), 4.45-4.29 (m, 10H), 4.1 9-3.82 (m, 1 0H), 3.67-3.57 (m, 6H), 3.1 7 (s, 9H), 2.64-2.46 (m, 6 H), 2.14-1 .92 (m, 6H), 1 .84 (m, 4H, J = 6 Hz), 1 .62-1 .40 (m, 8H), 1 .32-1 .22 (m, 6H), 1 .09 (d, 3H, J = 9 Hz), 0.99 (t, 3H, J = 7.5 Hz), 0.88 (m, 6H, J = 6.8 Hz) ; High Res LC/MS, [M/2+H]+ 865.4143, 865.4147 calculated.

REFERENCES

  1. Denning, DW (June 2002). “Echinocandins: a new class of antifungal.”. The Journal of antimicrobial chemotherapy 49 (6): 889–91. doi:10.1093/jac/dkf045. PMID 12039879.
  2.  Morris MI, Villmann M (September 2006). “Echinocandins in the management of invasive fungal infections, part 1”. Am J Health Syst Pharm 63 (18): 1693–703.doi:10.2146/ajhp050464.p1. PMID 16960253.
  3. Morris MI, Villmann M (October 2006). “Echinocandins in the management of invasive fungal infections, Part 2”. Am J Health Syst Pharm 63 (19): 1813–20.doi:10.2146/ajhp050464.p2. PMID 16990627.
  4. ^ Jump up to:a b “Pharmacotherapy Update – New Antifungal Agents: Additions to the Existing Armamentarium (Part 1)”.
  5.  Debono, M; Gordee, RS (1994). “Antibiotics that inhibit fungal cell wall development”.Annu Rev Microbiol 48: 471–497. doi:10.1146/annurev.mi.48.100194.002351.

17 Eschenauer, G; Depestel, DD; Carver, PL (March 2007). “Comparison of echinocandin antifungals.”. Therapeutics and clinical risk management 3 (1): 71–97. PMC 1936290.PMID 18360617.

///////////Biafungin™,  CD 101 IV,  CD 101 Topical,  CD101,  SP 3025, PHASE 2, CIDARA, Orphan Drug, Fast Track Designation, Seachaid Pharmaceuticals,  Qualified Infectious Disease Product, QIDP, UNII-G013B5478J, 1396640-59-7, 1631754-41-0, Vulvovaginal candidiasis, Echinocandin B, FUNGIN

FREE FORM

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)C(NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C

AND OF ACETATE

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)[C@@H](NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C.CC(=O)[O-]

Three antifungal drugs approved by the United States Food and Drug Administration, caspofungin, anidulafungin, and micafungin, are known to inhibit β-1 ,3-glucan synthase which have the structures shown below.

caspofungin

Anidulafungin

Other exemplary p-1 ,3-glucan synthase inhibitors include,

echinocandin B

cilofungin

pneumocandin A0

pneumocandin B0

L-705589

L-733560

A-174591

or a salt thereof,

Biafungin


or a salt thereof,

Amino-biafungin


or a salt thereof,

Amino-AF-053

ASP9726

Yet other exemplary p-1 ,3-glucan synthase inhibitors include, without limitation:

Papulacandin B

Ergokonin

//////////////

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VELPATASVIR (GS-5816), GILEAD SCIENCES, велпатасвир, فالباتاسفير , 维帕他韦 ,


img

VELPATASVIR (GS-5816), GILEAD SCIENCES

CAS 1377049-84-7

Molecular Formula: C49H54N8O8
Molecular Weight: 883.00186 g/mol

Hepatitis C virus NS 5 protein inhibitors

KEEP WATCHING AS I ADD MORE DATA, SYNTHESIS……………

Gilead Sciences, Inc. INNOVATOR

Elizabeth M. Bacon, Jeromy J. Cottell, Ashley Anne Katana, Darryl Kato, Evan S. Krygowski, John O. Link, James Taylor, Chinh Viet Tran, Martin Teresa Alejandra Trejo, Zheng-Yu Yang, Sheila Zipfel,

Elizabeth Bacon

Senior Research Associate II at Gilead Sciences

Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4′,3′:6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

methyl {(2S)-1 – [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate

str1

Research Scientist I at Gilead Sciences

{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(Méthoxycarbonyl)amino]-2-phénylacétyl}-4-(méthoxyméthyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-1,11-dihydroisochroméno[4′,3′:6,7]naphto[1,2-d]imidazol-2-yl)-5 -méthyl-1-pyrrolidinyl]-3-méthyl-1-oxo-2-butanyl}carbamate de méthyle
Carbamic acid, N-[(1R)-2-[(2S,4S)-2-[4-[1,11-dihydro-2-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-5-methyl-2-pyrrolidinyl][2]benzopyrano[4′,3′:6,7]naphth[1,2-d]imidazol-9-yl]-1H- imidazol-2-yl]-4-(methoxymethyl)-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-, methyl ester

Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}-1,11-dihydro[2]benzopyrano[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

str1

Velpatasvir.png

.

str1

Description Pan-genotypic HCV NS5A inhibitor
Molecular Target HCV NS5A protein
Mechanism of Action HCV non-structural protein 5A inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Hepatitis C virus (HCV)
Indication Details Treat HCV genotype 1 infection; Treat HCV infection
  • Gilead Sciences
  • Class Antivirals; Carbamates; Chromans; Imidazoles; Naphthols; Phenylacetates; Phosphoric acid esters; Pyrimidine nucleotides; Pyrrolidines; Small molecules
  • Mechanism of Action Hepatitis C virus NS 5 protein inhibitors
  • Registered Hepatitis C

Most Recent Events

  • 14 Jul 2016 Registered for Hepatitis C in Canada (PO)
  • 08 Jul 2016 Registered for Hepatitis C in Liechtenstein, Iceland, Norway, European Union (PO)
  • 30 Jun 2016 Gilead Sciences plans a phase III trial for Hepatitis C (Combination therapy, Treatment-experienced) in Japan (PO (NCT02822794)

 

Darryl Kato works on a hepatitis treatment at Gilead Sciences Inc.’s lab

Velpatasvir, also known as GS-5816, is a potent and selective Hepatitis C virus NS5A inhibitor. GS-5816 has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

WO 2013/075029. Compound I has the formula:


methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

.

PAPER

Patent Highlights: Recently Approved HCV NS5a Drugs

Cidara Therapeutics, 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States
Org. Process Res. Dev., Article ASAP

Abstract

Five inhibitors of the NS5a enzyme have been approved as part of oral regimens for the treatment of hepatitis C virus, including daclatasvir (Bristol-Myers Squibb), ledipasvir (Gilead Sciences), ombitasvir (AbbVie), elbasvir (Merck), and velpatasvir (Gilead Sciences). This article reviews worldwide patents and patent applications that have been published on synthetic routes and final forms for these five drugs.

 

PATENT

https://google.com/patents/WO2013075029A1?cl=en

Example NP

Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4′,3′:6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Methyl {(2S)-l-[(2S,5S)-2-(5-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-l,ll dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9- yl}-lH-imidazol-2-yl)-5-methylpyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate

The synthesis of this compound was prepared according to the procedure of example LR-1 with the following modification. During the Suzuki coupling, (2S)-l-[(2S,5S)-2-(5-iodo-lH-imidazol- 2-yl)-5-methylpyrrolidin-l-yl]-2-[(l-meth^ was used in lieu of

(2S)-l -[(2S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl]-2-[(l-methoxyethenyl)amino]-3- methylbutan-l-one. The crade material was purified by preparative HPLC to provide methyl {(2S)-1 – [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate as a white solid (17 mg, 0.019 mmol, 17%). lU NMR (400 MHz, cd3od) δ 8.63 (s, 1H), 8.19 (d, 1H), 8.04 (m, 1H), 7.87 (m, 2H), 7.66 (m, 2H), 7.52 – 7.39 (m, 6H), 5.50 (m, 2H), 5.32 (s, 2H), 5.16 (m, 1H), 4.12 (m, 1H), 3.80 (m, 4H), 3.66 (s, 6H), 3.43 (m, 4H), 3.23 (s, 3H), 2.72-1.99 (m, 9H), 1.56 (d, 3H), 1.29 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H).

PATENT

US 20150361073 A1

Scheme 1

Compound (J)

Compound (I) H CO- Com pound (G)

st alkylation: Conversion of Compound (I-a) to Compound (G-a)

Compound (I-a) (45 g, 1.0 equiv.), Compound (J-a) (26.7g, 1.03 equiv.) and potassium carbonate (20.7g, 1.5 equiv.) in dichloromethane (450 mL) were stirred at about 20 °C for approximately 3-4 hours. After the completion of the reaction, water (450 mL) was charged into the reactor and the mixture was stirred. Layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with 2 wt% NaH2PO4/10wt% NaCl solution (450 mL). The organic layer was then concentrated and the solvent was swapped from dichloromethane into tetrahydrofuran. A purified sample of Compound (G-a) has the following spectrum: ¾ NMR (400 MHz,

CDC13) δ 7.90-7.94 (m, 1H), 7.81-7.85 (m, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 5.19-5.56 (2dd, 2H), 5.17 (s, 2H), 4.73 (t, 1H), 4.39-4.48 (m, 1H), 3.70-3.77 (m, 1H), 3.37-3.45 (m, 2H), 3.33-3.35 (d, 3H), 3.28-3.32 (m, 1H), 3.20-3.25 (dd, 1H), 2.92-2.96 (dt, 1H), 2.44-2.59 (m, 4H), 1.97-2.09 (m, 1H), 1.44 (d, 9H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may be Compound (I) where X may be -CI, -Br, -OTs, -OS02Ph, -OS02Me, -OS02CF3, -OS02R, , and -OP(0)(OR)2 and Y may be -CI, -Br, -OTs, -OS02Ph, -OS02Me, -OS02CF3, -OS02R, and -OP(0)(OR)2. R may be alkyl, haloalkyl, or an optionally substituted aryl.

Various bases may also be employed, such as phosphate salts (including but not limited to KH2P04, K3P04, Na2HP04, and Na3P04) and carbonate salts (including but not limited to Na2C03,Cs2C03, and NaHC03). Where the starting material is Compound (J), KHC03 or preformed potassium, sodium, and cesium salts of Compound (J) may also be used.

Alternative solvents can include 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, dimethylformamide, acetone, MEK, and MIBK.

The reaction temperature may range from about 10 °C to about 60 °C.

” alkylation: Conversion of Compound (G-a) to Compound (B-a):

A solution of Compound (G-a) (prepared as described earlier starting from 45 g of Compound (I-a)) was mixed with Compound (H) (42.9g, 1.5 equiv.), and cesium carbonate (26. lg, 0.8 equiv.). The reaction mixture was stirred at about 40-45 °C until reaction was complete and then cooled to about 20 °C. Water (450 mL) and ethyl acetate (225 mL) were added and the mixture was agitated. Layers were separated, and the aqueous layer was extracted with ethyl acetate (150 mL). Combined organic phase was concentrated and solvent was swapped to toluene. A purified sample of Compound (B-a) has the following spectrum: ¾ NMR (400 MHz, CDC13) 57.90-7.93 (m, 1H), 7.81-7.83 (m, 1H), 7.73 (s, 1H), 7.63-7.64 (d, 1H), 7.59-7.60 (d, 1H), 5.52-5.63 (m, 1H), 5.30-5.43 (q, 1H), 5.13-5.23 (s+m, 3H), 4.56-4.64 (m, 2H), 4.39-4.48 (m, 1H), 4.20-4.27 (m, 1H), 3.62-3.79 (m, 2H), 3.66 (s, 2H), 3.36-3.45 (m, 2H), 3.34-3.35 (d, 3H), 3.07-3.25 (m, 3H), 2.59-2.37 (m, 5H), 1.97-2.16 (m, 3H), 1.60 (s, 3H), 1.38-1.45 (m, 12H), 0.91-1.03 (m, 6H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may include Compound (G) where Y may be -CI, -Br, -OTs, -OS02Ph, -OS02Me, -OS02CF3, -OS02R, , or -OP(0)(OR)2. where R is alkyl, aryl, or substituted aryl. In some embodiments, the substituted aryl may be an aryl having one or more substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, and others as discussed above.

Various bases may be employed. Non-limiting examples can include phosphate salts (including but not limited to KH2P04, K3P04, Na2HP04, and Na3P04) and carbonate salts (including but not limited to K2C03 or Na2C03). If Compound (H) is used as the starting material, Li2C03 or preformed potassium, sodium, and cesium salt of Compound (H) may be employed.

Alternative solvents may include 2-methyltetrahydrofuran, dichloromethane, toluene, mixtures of THF/Toluene, isopropyl acetate, ethyl acetate, l-methyl-2-pyrrolidinone, Ν,Ν-dimethylacetamide, acetone, MEK,and MIBK. An alternative additive may be

potassium iodide, and the reaction temperature may range from about 40 °C to about 60 °C or about 40 °C to about 50 °C.

A toluene solution of Compound (B-a) (604 g solution from 45 g of Compound (I-a)) was charged to a reaction vessel containing ammonium acetate (185.2 g) and isopropanol (91.0 g). The contents of the reactor were agitated at about 90 °C until the reaction was complete (about 16 to 24 hours). The reaction mixture was cooled to about 45 °C, and then allowed to settle for layer separation. Water (226 g) was added to the organic phase, and the resulting mixture was separated at about 30 °C. Methanol (274 g), Celite (26.9 g) and an aqueous solution of sodium hydroxide (67.5 g, 50%) and sodium chloride (54.0 g) in water (608 g) were added to the organic phase, and the resulting mixture was agitated for a minimum of 30 minutes. The mixture was then filtered through Celite and rinsed forward with a mixture of toluene (250 g) and isopropanol (1 1 g). The biphasic filtrate was separated and water (223 g) was added to the organic phase, and the resulting mixture was agitated at about 30 °C for at least 15 minutes. The mixture was filtered through Celite and rinsed forward with toluene (91 g). The organic layer was concentrated by vacuum distillation to 355 g and was added over 30 minutes to another reactor containing w-heptane (578 g). The resulting slurry is filtered, with the wetcake was washed with w-heptane (450 mL) and dried in a vacuum oven to afford Compound (C-a). A purified sample of Compound (C-a) has the following spectrum: *H NMR (400 MHz, CDC13) δ 12.27-11.60 (m, 1 H), 1 1.18-10.69 (m, 1 H), 7.83 – 7.44 (m, 4 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.28 – 7.05 (m, 1 H), 5.65 – 5.25 (m, 1H), 5.25 – 4.83 (m, 4 H), 4.34 – 4.03 (m, 2 H), 3.93 – 3.63 (m, 4 H), 3.52 (s, 1 H), 3.35 (d, J = 2.4 Hz, 4 H), 3.19 – 2.94 (m, 4 H), 2.88 (dd, J = 12.0, 7.9 Hz, 3 H), 2.66 – 1.85 (m, 5 H), 1.79 (s, 5 H), 1.37 – 1.12 (m, 6H), 1.04-0.98 (m, 6 H), 0.82 (t, J = 7.7 Hz, 2 H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative reagents, in lieu of ammonium acetate, can include hexamethyldisilazane, ammonia, ammonium formate, ammonium propionate, ammonium hexanoate, and ammonium octanoate. Various solvents, such as toluene, xylene, an alcohol

(including but not limited to isopropanol, 1-propanol, 1-butanol, 2-butanol, 2-methoxyethanol, and glycols, such as ethylene glycol and propylene glycol) may be employed. Alternative catalyst/additives may include magnesium stearate, acetic acid, propionic acid, and acetic anhydride. The reaction temperature may range from about 60 °C to about 110 °C or about 85 °C to about 95 °C.

D

Preparation of Compound (D-a) using DDQ as oxidant:

A solution of Compound (C-a) (255.84 g) in 2-methyltetrahydrofuran (1535 mL) was cooled to about 0 °C and acetic acid (0.92 mL) was added. To this mixture was added a solution of DDQ (76.98 g) in 2-methyltetrahydrofuran (385 mL) over about 30 minutes. Upon reaction completion, a 10 wt% aqueous potassium hydroxide solution (1275 mL) was added over about 30 minutes and the mixture was warmed to about 20 °C. Celite (101.5 g) was added and the slurry was filtered through Celite (50.0 g) and the filter cake was rinsed with 2-methyltetrahydrofuran (765 mL). The phases of the filtrate were separated. The organic phase was washed successively aqueous potassium hydroxide solution (1020 mL, 10 wt%), aqueous sodium bisulfite solution (1020 mL, 10 wt%), aqueous sodium bicarbonate solution (1020 mL, 5 wt%) and aqueous sodium chloride solution (1020 mL, 5 wt%). The organic phase was then concentrated to a volume of about 650 mL. Cyclopentyl methyl ether (1530 mL) was added and the resulting solution was concentrated to a volume of about 710 mL. The temperature was adjusted to about 40 °C and Compound (D-a) seed (1.0 g) was added. The mixture was agitated until a slurry forms, then methyl tert-butyl ether (2300 mL) was added over about 3 hours. The slurry was cooled to about 20 °C over about 2 hours and filtered. The filter cake was rinsed with methyl tert-butyl ether (1275 mL) and dried in a vacuum oven at about 40 °C to provide Compound (D-a). A purified sample of Compound (D-a) has the following spectrum: ¾ NMR (400 MHz, CDC13) δ 13.05-10.50 (comp m, 2H), 8.65-6.95 (comp m, 8H), 5.50-5.35 (m, 2H), 5.25^1.60 (comp m, 3H), 4.35-4.20 (m, 1H), 4.00-3.65 (comp m, 4H), 3.60-3.45 (m, 1H), 3.45-3.25 (comp m, 4H), 3.25-3.00 (comp m, 2H), 2.95-1.65 (comp m, 6H), 1.47 (br s, 9H), 1.40-1.25 (comp m, 2H), 1.20-0.70 (comp m, 9H).

Alternative Preparation of Compound (D-a) using Mn02 as oxidant:

A mixture of Compound (C-a) (50.0 g), manganese (IV) oxide (152.8 g) and dichloromethane (500 mL) is stirred at about 20 °C. Upon completion of the reaction, Celite (15 g) was added. The resulting slurry was filtered through Celite (20 g) and the filter cake was rinsed with dichloromethane (500 mL). The filtrate was concentrated and solvent exchanged into cyclopentyl methyl ether (250 mL). The resulting solution was warmed to about 60 °C and treated with an aqueous potassium hydroxide solution (250 mL, 10wt%). The biphasic mixture is stirred at about 45 °C for about 12 hours. The phases are then separated and the organic phase is concentrated to a volume of about 150 mL. The concentrate is filtered, seeded with Compound (D-a) seed and agitated at about 40 °C to obtain a slurry. Methyl tert-butyl ether (450 mL) was added to the slurry over 30 minutes and the resulting mixture was cooled to about 20 °C. The precipitated solid was filtered, rinsed with methyl tert-butyl ether (250 mL) and dried in a vacuum oven at about 40 °C to obtain Compound (D-a).

Alternative Preparation of Compound (D-a) through catalytic dehydrogenation

A mixture of Compound (C-a) (2.5 g, 2.7 mmol, 1 equiv), 5% Pd/Al203 (2.5 g) and 1-propanol (25 mL, degassed) was stirred at reflux under inert environment for about 5.5 hours. The reaction mixture was then cooled to ambient temperature and filtered through Celite, and the residue rinsed with 1-propanol (2 x 5 mL) to obtain a solution of Compound (D-a).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in a reaction scheme employing stoichiometric oxidants, alternative oxidants may include manganese(IV) oxide, copper(II) acetate, copper(II) trifluoroacetate, copper(II) chloride, copper(II) bromide, bromine (Br2), iodine (I2), N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1 ,4-benzoquinone, tetrachloro-l,4-benzoquinone (chloranil), eerie ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, άϊ-tert-butyl peroxide, benzoyl peroxide, oxygen ((¾), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, Oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene. Various additives may be employed, and non-limiting examples may be carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like), amines (e.g., triethylamine, diisopropylethylamine and the like), and acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid), sodium acetate, potassium acetate, and the like). The reaction temperature may range from about -10°C to 80 °C. The reaction may take place in solvents, such as halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), aromatic solvents (e.g., toluene, xylenes, etc.), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1 ,2-dimethoxyethane, diglyme, triglyme, etc.), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glycol, etc.), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, etc.), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, etc.), amine solvents (e.g., triethylamine, morpholine, etc.), acetic acid, and water.

In reaction schemes employing catalytic oxidants, alternative catalysts may include palladium catalysts (e.g., palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, palladium(II) benzoate, palladium(II) sulfate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-iert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride, bis(benzonitrile)palladium(II) chloride, palladium on carbon, palladium on alumina, palladium on hydroxyapatite, palladium on calcium carbonate, palladium on barium sulfate, palladium(II) hydroxide on carbon), platinum catalysts (e.g., platinum on carbon, platinum(IV) oxide, chloroplatinic acid, potassium chloroplatinate), rhodium catalysts (e.g., rhodium on carbon, rhodium on alumina,

bis(styrene)bis(triphenylphosphine)rhodium(0)), ruthenium catalysts (e.g., ruthenium(II) salen, dichloro(para-cymene)ruthenium(II) dimer), iridium catalysts (e.g., iridium(III) chloride, (l,5-cyclooctadiene)diiridium(I) dichloride, bis(l,5-cyclooctadiene)iridium(I) tetrafluoroborate, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) carbonyl chloride, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) tetrafluoroborate), copper catalysts (e.g., copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I) iodide, copper(II) iodide, copper(II) acetate, copper(II) trifluoroacetate, copper(I) trifluoromethanesulfonate, copper(II) trifluoromethanesulfonate, copper(II) sulfate), iron catalysts (e.g., iron(II) sulfate, iron(II) chloride, iron(III) chloride), vanadium catalysts (e.g., dichloro(ethoxy)oxovanadium, dichloro(isopropoxy)oxovanadium), manganese catalysts (e.g., manganese(rV) oxide, manganese(III) (salen) chloride), cobalt catalysts (e.g., cobalt(II) acetate, cobalt(II) chloride, cobalt(II) salen), indium(III) chloride, silver(I) oxide, sodium tungstate, quinone catalysts (e.g., 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, 1,4-benzoquinone, and tetrachloro-l,4-benzoquinone (chloranil)).

Alternative co-oxidants can include, but are not limited to, sodium nitrite, copper(II) acetate, sodium persulfate, potassium persulfate, ammonium persulfate, sodium perborate, nitrobenzenesulfonate, 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO), pyridine-N-oxide, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide, oxygen (02), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene.

Varoius hydrogen acceptors may be employed. Non-limiting examples can include unsaturated hydrocarbons (e.g., tert-butylethylene, tert-butyl acetylene, 2-hexyne, cyclohexene, and the like), acrylate esters (e.g., methyl acrylate, ethyl acrylate, isopropyl acrylate, tert-butyl acrylate, and the like), maleate esters (e.g., dimethyl maleate, diethyl maleate, diisopropyl maleate, dibutyl maleate, and the like), fumarate esters (e.g., dimethyl fumarate, diethyl fumarate, diisopropyl fumarate, dibutyl fumarate, and the like), and quinones (e.g. chloranil, 1 ,4-benzoquinone, etc.).

Alternative additives may be employed, such as carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc.), amine bases (e.g., triethylamine, diisopropylethylamine, etc.), phosphines (e.g., triphenylphosphine, tri(ort zotolyl)phosphine, tricyclohexylphosphine, tri-w-butylphosphine, tri-tert-butylphosphine, etc.), acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid, etc.), sodium acetate, N-hydroxyphthalimide, salen, 2,2 ‘-bipyri dine, 9,10-phenanthroline, and quinine.

The reaction can proceed at temperatures ranging from about 10 °C to about 120 °C. Various solvents can be employed, including but not limited to halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, and the like), aromatic solvents (e.g., toluene, xylenes, and the like), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme, triglyme, and the like), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, w-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glyco, and the like), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, and the like), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, and the like), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, and the like), amine solvents (e.g., triethylamine, morpholine, and the like), acetic acid, and water.

Acetyl chloride (135 mL, 5 equiv.) was added slowly to methanol (750 mL) under external cooling maintaining reaction temperature below 30 °C. The resulting methanolic hydrogen chloride solution was cooled to about 20 °C, and added slowly over about 1 hour to a solution of Compound (D-a) (300 g, 1 equiv.) in methanol (750 mL) held at about 60 °C, and rinsed forward with methanol (300 mL). The reaction mixture was agitated at about 60 °C until reaction was complete (about 1 hour), and then cooled to about 5 °C. The reaction mixture was adjusted to pH 7-8 by addition of sodium methoxide (25 wt. % solution in methanol, 370 mL) over about 20 minutes while maintaining reaction temperature below about 20 °C. Phosphoric acid (85 wt. %, 26 mL, 1 equiv.) and Celite (120 g) were added to the reaction mixture, which was then adjusted to about 20 °C, filtered, and the filter cake was rinsed with methanol (1050 mL). The combined filtrate was polish filtered and treated with phosphoric acid (85 wt. %, 104 mL, 4 equiv.). The mixture was was adjusted to about 60 °C, seeded with Compound (E-a) seed crystals (1.5 g), aged at about 60 °C for 4 hours and cooled slowly to about 20 °C over about 7.5 hours. The precipitated product was filtered, washed with methanol (2 x 600 mL), and dried in a vacuum oven at about 45 °C to provide

Compound (E-a). !H NMR (400 MHz, D20) δ 7.53-6.77 (comp m, 8H), 5.24-4.80 (comp m, 3H), 4.59-4.38 (comp m, 2H), 4.15-3.90 (m, 1H), 3.65-3.38 (comp m, 5H), 3.36-3.14 (comp m, 4H), 2.75 (s, 1H), 2.87-2.66 (m, 1H), 2.29-1.60 (comp m, 6H), 1.27 (d, 3H), 0.76 (m, 6H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. Various deprotection agents are well known to those skilled in the art and include those disclosed in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (4th edition) J. Wiley & Sons, 2007, hereby incorporated by reference in its entirety. For example, a wide range of acids may be used, including but not limited to phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, thionyl chloride,and trimethylsilyl chloride. A wide range of solvents may be employed, including but not limited to water, ethanol, acetonitrile, acetone, tetrahydrofuran, 1 ,4-dioxane, and toluene. Deprotection may proceed at temperatures ranging from about 20 °C to about 110 °C or from about 55 °C to about 65 °C.

A wide range of bases may be employed as a neutralization reagent. Non-limiting examples can include sodium phosphate dibasic, potassium phosphate dibasic, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, N, N-diisopropylethylamine, and 4-methylmorpholine. Various solvents may be used for neutralization, such as water, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, acetonitrile, 2-butanone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, and dichloroethane.

Neutralization may proceed at temperatures ranging from about -20 °C to about 60 °C or about 5 °C to about 15 °C.

Various crystallization reagents can be employed. Non-limiting examples may be hydrochloric acid, hydrobromic acid, sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid, oxalic acid, and glucuronic acid. Solvents for crystallization can include, but is not limited to, water, ethanol, 1-propanol, 2-propanol, and acetonitrile. Crystallization may proceed at temperatures ranging from about -20 °C to about 100 °C.

Free-Basing of Compound (E-a) to Prepare Compound (E)

ompound (E-a) OCH, H3CO- Compound (E)

Compound (E-a) (10.0 g, 10.1 mmol) was dissolved in water (100 g) and then dichloromethane (132 g) and 28% ammonium hydroxide (7.2 g) were added sequentially. The biphasic mixture was stirred for 45 minutes. Celite (2.2 g) was added, the mixture was filtered through a bed of additional Celite (5.1 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). ‘H NMR (400 MHz, CD3OD) δ 8.35-7.17 (m, 8H), 5.6^1.68 (m, 3H), 4.41-3.96 (m, 2H), 3.96-3.72 (br s, 1H), 3.74-3.48 (m, 2H), 3.42 (d, 2H), 3.33 (s, 3H), 3.28 (s, 1H), 3.19-3.01 (m, 1H), 3.00-2.79 (m, 1H), 2.69-1.82 (m, 6H), 1.80-1.45 (m, 3H), 1.21-0.73 (m, 8H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-hydrochloride salts of Compound (E) may be used. Various bases may be employed, such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Various solvents, such as 2-methyltetrahydrofuran and ethyl acetate, may be employed. The temperature may range from about 15 °C to about 25 °C.

Alternative Free-Basing of Compound (E-b) to Prepare Compound (E)

Compound (E-b) (15.2 g) was dissolved in water (100 g) and then dichloromethane

(132 g) and 28% ammonium hydroxide (7.4 g) were added sequentially. The biphasic mixture was stirred for about 45 minutes. Celite (2.1 g) was added, the mixture was filtered through a bed of additional Celite (5.2 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). *H NMR (400 MHz, CD3OD) δ 7.92-6.73 (m, 8H), 5.51-4.90 (m, 2H), 4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

Salt Conversion of Compound (E-a) to Compound (E-b)

A solution of Compound (E-a) (10.0 g, 10.1 mmol), a solution of 37% HCI (10 g) in water (20 g), and acetonitrile (30 g)was warmed to about 50 °C and agitated for about lh. The solution was cooled to about 20 °C and acetonitrile (58 g) was charged to the reactor during which time a slurry formed. The slurry was stirred for about 21 h and then additional acetonitrile (39 g) was added. The slurry was cooled to about 0 °C, held for about 60 min and the solids were then isolated by filtration, rinsed with 7% (w/w) water in acetonitrile (22 g) previously cooled to about 5 °C. The wet cake was partially deliquored to afford

Compound (E-b). *H NMR (400 MHz, D20) δ 7.92-6.73 (m, 8H), 5.51^1.90 (m, 2H),

4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

A flask was charged sequentially with 2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]-1,3,5-triazine (“CDMT”) (2.2 giv) and methanol (8.9 g) and the slurry was cooled to about 0 °C. To the mixture was added NMM (1.3 g) over about 5 minutes, maintaining an internal temperature of less than 20 °C. The solution was stirred for about 20 minutes to produce a solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol.

To a solution of Compound (E) (7.1 g) in dichloromethane (170 g) was added

Compound (Γ) (2.8 g). The solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol was added over 2 minutes followed by a rinse of methanol (1.1 g). After about 2.5 h, the completed reaction solution was washed sequentially with aqueous 10% potassium bicarbonate solution (40 mL), 3% hydrochloric acid (40 mL), and aqueous 10% potassium bicarbonate solution (40 mL). The lower organic phase was washed with water (40 mL), filtered, and then concentrated by rotary evaporation to produce Compound (A). ¾ NMR (400 MHz, CD3OD) δ 8.56-6.67 (m, 13H), 5.76^1.94 (m, 4H), 4.86-4.67 (m, 1H), 4.47-3.98 (m, 1H), 3.98-2.72 (m, 15H), 2.74-1.77 (m, 7H), 1.77-1.40 (m, 2H), 1.39-0.53 (m, 8H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-phosphate salts or tris-hydrochloride salts of Compound (G) may be used as alternative starting material. The reaction may take place at a temperature range of from about 10 °C to about 20 °C. Alternative coupling agents include, but are not limited to, EDC/HOBt, HATU, HBTU, TBTU, BOP, PyClOP, PyBOP, DCC/HOBt, COMU, EDCLOxyma, T3P, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate. An alternative bases that may be employed can be diisopropylethylamine. The reaction may proceed in DMF and at temperatures ranging from about -20 °C to about 30 °C.

Salt Formation and Crystallization of Compound (A)

Crystallization of Compound (A-a)

A flask was charged with Compound (A) (10 g) and ethanol (125 mL) and was then warmed to about 45 °C. Concentrated hydrochloric acid (2.3 mL) was added followed by Compound (A-a) seed crystals (5 mg). The mixture was cooled to about 20 °C over about 5 h and held for about an additional 1 1 h. The solids were isolated by filtration, washed with ethanol (2 x 20 mL), and deliquored to produce Compound (A-a). !H NMR (400 MHz, CD3OD) δ 8.94-7.22 (m, 14H), 5.78-5.1 1 (m, 5H), 4.53-4.04 (m, 1H), 3.99-3.57 (m, 10H), 3.57-3.41 (m, 2H), 2.99-2.24 (m, 5H), 2.24-1.85 (m, 3H), 1.80-1.50 (m, 2H), 1.39-0.73 (m, 8H).

Alternative Crystallization of Compound (A-b)

A reaction vessel was charged with Compound (A) (25.0 g) followed by ethanol (125 mL) and 10% H3PO4 (250 mL). The solution was seeded with Compound (A-b) (100 mg) and stirred for about 17.5 h. The solids were isolated by filtration, washed with ethanol (2 x 5 mL), deliquored, and dried in a vacuum oven to produce Compound (A-b). JH NMR (400 MHz, D20) δ 7.76-6.48 (m, 13H), 5.53^1.90 (m, 3H), 4.60-4.32 (m, 2H), 4.29-3.76 (m, 1H), 3.70-2.75 (m, 14H), 2.66-1.51 (m, 8H), 1.51-1.09 (m, 3H), 1.05-0.45 (m, 7H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative acids may be hydrochloric acid, hydrobromic acid, L-tartaric acid. Various solvents may be employed, such as methanol, ethanol, water, and isopropanol. The reaction may proceed at temperatures ranging from about 5 °C to about 60 °C.

Free-Basing of Compound (A)

Free-Basing of Compound (A-a) to Prepare Compound (A)

A reaction vessel was charged with Compound (A-a) (18.2 g) followed by ethyl acetate (188 g) and 10% potassium bicarbonate (188 g) and the mixture was stirred for about 25 minutes. The phases were separated and the upper organic phase was then washed with water (188 mL). The resulting organic solution was concentrated, ethanol (188 g) was added, and the solution was evaporated to produce a concentrate (75 g). The resulting concentrate added into water (376 g) to produce a slurry. The solids were isolated by filtration, washed with water (38 g), de liquored and dried in a vacuum oven at about 50 °C to produce

Compound (A).

Alternative Free-Basing of Compound (A-b) to Prepare Compound (A)

om poun –

A reaction vessel was charged with Compound (A-b) (3.0 g) followed by EtOAc (15 mL) and 10% KHCO3 (15 mL) and agitation was initiated. After about 5 h, the phases were separated and the organic phase was washed with water (15 mL) and then concentrated by rotary evaporation under vacuum. The residue was taken up in EtOH (4.5 mL) and then added to water (30 mL) to produce a slurry. After about 15 min, the solids were isolated by filtration rinsing forward water (3 x 3 mL). The solids were dried at about 50 to 60 °C vacuum oven for about 15 h to produce Compound (A).

CLIP AND ITS REFERENCES

Synthetic Route—Final Steps

The final steps to velpatasvir from backbone dibromide 62 (Scheme 14) are described and claimed in a process chemistry patent application.(43) The bond disconnections are the same as described in the composition of matter patents.(44)
The phenacyl bromide of 62 is selectively alkylated with the chiral methoxylmethyl proline 63 using K2CO3 in CH2Cl2 to provide intermediate64. After aqueous workup, the solvent is switched into THF for the alkylation of the secondary bromide with the 2-methylproline-Moc-l-valine dipeptide 65 using Cs2CO3 to afford bis-ester 66.
Formation of the bis-imidazole 67 is conducted using NH4OAc in toluene/i-PrOH, conditions similar to those originally described for daclatasvir  and also used for ledipasvir  except that i-PrOH is added as cosolvent, likely for increased solubility. Dehydrogenation to the aromatic core 68 is accomplished with DDQ and HOAc in 2-MeTHF solvent.
Deprotection of the Boc group with HCl/MeOH affords the bis-amine 69 which is crystallized as a triphosphate salt.
The final amide coupling with the chiral phenylglycine carbamate fragment 70 mediated by CDMT affords velpatasvir. No yields are provided in the experimental section of the patent and characterization is limited to generalized 1H NMR data, ie, the aromatic region of velpatasvir is reported as δ 8.56–6.67 (m, 13H).(43)
 STR1
STR1
Synthetic RouteEarly Steps. Multiple routes to intermediates 62, 63, and 65 are described in the process
patent application but are not claimed.43 The route to 2-methylproline-Moc-valine fragment 65 is outlined in Scheme 15.45
str1
N-Boc (S)-pyroglutamic acid ethyl ester is ring-opened with methylmagnesium bromide to form Boc-amine 71. Deprotection with TFA and reductive amination with NaBH(OAc)3 are conducted in a one-pot reaction. Hydride transfer to the intermediate imine occurs on the face opposite to the ethoxycarbonyl group to afford cis-pyrrolidine
72, which is isolated as the tosylate salt. Amide coupling with Moc-L-valine followed by hydrolysis affords the dipeptide 65.
Three routes are described for the synthesis of fragment 63. The first route, and the only chemistry in the patent that is
described on a multikilo scale, is outlined in Scheme 16.
str1
Dimethyl N-Boc-L-glutamate is formylated at low temperature with acetic formic anhydride, which is cyclized to the enamine 73 with TFA. The patent scheme shows both Boc groups present in structure 73, so it is not clear if this is an error or if the Boc groups remain intact upon TFA treatment and whether imine formation can occur with the Boc-protected amine.
Hydrogenation of the double bond is carried out with Pd/C;then the ester is reduced to the primary alcohol 74 with
NaBH4. Deprotection of both Boc groups is followed by reprotection of the nitrogen to afford 75. After methylation, the dicyclohexylamine salt of 63 is crystallized, presumably to remove the trans-diastereomer formed during the hydrogenation. After salt break, 63 free acid is crystallized from hexane/CH2Cl2.
The second approach to 63 starts with N-Boc-cis-4-cyano-Lproline methyl ester and converts the cyano group to the
methoxymethyl group in 4−5 steps (Scheme 17).
str1
The stereochemistry appears to be maintained at both chiral centers through the sequence. Methanolysis of the cyano group to the methyl ester occurs with concomitant deprotection of the Boc group, so reprotection is necessary. The ester at the 4-position is then selectively hydrolyzed with 1.4 equiv of NaOH in THF at −1 °C to afford ester-acid 76. No yield is provided so no information is available for the selectivity of hydrolysis at the 4-position vs the more hindered 2-position, except that hydrolysis later in the sequence requires a temperature of 20 °C.
Reduction of the carboxylic acid to the primary alcohol is accomplished with borane−dimethyl sulfide followed by
hydrolysis of the methyl ester, then alkylation of the primary alcohol with MeI to afford 63, which is purified by
crystallization from i-PrOH/water. Alternatively, hydrolysis of the ester and alkylation can be carried out in a single pot reaction with 63 crystallized from toluene/heptane.
A number of routes to backbone 62 are described, but all rely on an alkylation/C−H activation sequence as outlined in
Scheme 18.
str1
An alternate bond disconnection for the synthesis of velpatasvir is described in a Chinese patent application in which left (77) and right-hand (78) fragments are more fully elaborated and then the tetracyclic backbone is constructed at a stereochemistry appears to be maintained at both chiral centers through the sequence. Methanolysis of the cyano group to the methyl ester occurs with concomitant deprotection of the Bocgroup, so reprotection is necessary. The ester at the 4-position is then selectively hydrolyzed with 1.4 equiv of NaOH in THF
at −1 °C to afford ester-acid 76. No yield is provided so no information is available for the selectivity of hydrolysis at the 4-position vs the more hindered 2-position, except that hydrolysis later in the sequence requires a temperature of 20 °C.
Reduction of the carboxylic acid to the primary alcohol is accomplished with borane−dimethyl sulfide followed by
hydrolysis of the methyl ester, then alkylation of the primary alcohol with MeI to afford 63, which is purified by
crystallization from i-PrOH/water. Alternatively, hydrolysis of the ester and alkylation can be carried out in a single pot reaction with 63 crystallized from toluene/heptane.
A number of routes to backbone 62 are described, but all rely on an alkylation/C−H activation sequence as outlined in
Scheme 18. An alternate bond disconnection for the synthesis of velpatasvir is described in a Chinese patent application in which left (77) and right-hand (78) fragments are more fully elaborated and then the tetracyclic backbone is constructed at a late stage.46 This route is more convergent than the Gilead route but overall requires a similar number of steps (Scheme19).
str1
Final Form.
A patent application describes and claims 19 crystal forms of velpatasvir, including free base (1 form), bis-HCl salt (5 forms), phosphate salt (9 forms), bis-HBr salt (1form), L-tartrate salt (2 forms), and D-tartrate salt (1 form).47
Two patent applications describe solid dispersion formulations of velpitasvir alone and as a combination with sofosbuvir,48 suggesting that velpitasvir is rendered amorphous during the formulation process. According to the patent applications,several forms of velpitasvir API are suitable for use in the solid dispersion process although a specific claim is made for a spraydried process of free base in ethanol.48
(43) Allan, K. M.; Fujimori, S.; Heumann, L. V.; Huynh, G. M.;Keaton, K. A.; Levins, C. M.; Pamulapati, G. R.; Roberts, B. J.; Sarma,K.; Teresk, M. G.; Wang, X.; Wolckenhauer, S. A. Processes for Preparing Antiviral Compounds. U.S. Patent Application 2015/0361073 A1, December 17, 2015.
(44) (a) Bacon, E. M.; Cottrell, J. J.; Katana, A. A.; Kato, D.;Krygowski, E. S.; Link, J. O.; Taylor, J.; Tran, C. V.; Martin, T. A. T.;Yang, Z.-Y.; Zipfel, S. Antiviral Compounds. U.S. Patent 8,575,135 B2,November 5, 2013. (b) Bacon, E. M.; Cottrell, J. J.; Katana, A. A.;Kato, D.; Krygowski, E. S.; Link, J. O.; Taylor, J.; Tran, C. V.; Martin, T. A. T.; Yang, Z.-Y.; Zipfel, S. Antiviral Compounds. U.S. Patent 8,921,341 B2, December 30, 2014.
(45) The process patent43 appears to contain an error in structure Va,which should not contain a Boc group.
(46) Mu, X.; Liu, N. Velpatasvir Intermediate and PreparationMethod Thereof. Chinese Patent Application CN 105294713 A,February 3, 2016.
(47) Lapina, O. V.; Shi, B.; Wang, F.; Wolckenhauer, S. A. SolidForms of an Antiviral Compound. U.S. Patent Application 2015/0361085 A1, December 17, 2015.
(48) (a) Gorman, E.; Mogalian, E.; Oliyai, R.; Stefanidis, D.; Zia, V.Solid Dispersion Formulation of an Antiviral Compound. U.S. PatentApplication 2015/0064252 A1, March 5, 2015. (b) Gorman, E.;Mogalian, E.; Oliyai, R.; Stefanidis, D.; Wiser, L.; Zia, V. CombinationFormulation of Two Antiviral Compounds.

PATENT

US 2015/0361085

https://patentscope.wipo.int/search/en/detail.jsf?docId=US153621930&redirectedID=true

Compound I Form I
      An additional stable form screen was performed using the same procedure as described above but included a crystalline intermediate (Compound II shown below) as seeds.


      Compound II can be synthesized according to the methods described in WO 2013/075029 or U.S. Provisional Application No. 62/010,813. Needle-like particles were formed in butyronitrile, propionitrile, MEK/toluene, MEK/IPE and 2-pentanone/toluene. XRPD patterns of the wet solids were mostly consistent with each other with minor shifting in the peaks. The new form is named Compound I Form I, which is believed to be isostructural channel solvates with the respective solvents. After air drying all solids afforded amorphous XRPD patterns.
      Another stable form screen was performed using carbon (Darco G-60) treated Compound I, solvents, antisolvent (diisopropyl ether (IPE)), and seeds of Compound I Form I. This screen afforded crystalline solids from additional solvents as summarized in Table 1. The XRPD patterns of all of these solvates are consistent with Form I. The solvates were observed to convert to amorphous solids after drying. The XRPD patterns of Compound I were obtained in the experimental setting as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 2-40°, step size 0.0167°, counting time: 15.875 s.

[TABLE-US-00002]

TABLE 1
Stable form screen of carbon treated Compound I
Solvents PLM Comments
Water Amorphous Slurry
Water/EtOH Amorphous Sticky phase coating
ACN/IPE Birefringent Slurry of needles
MeOH/IPE Solution Seeds dissolved
EtOH/IPE Solution Seeds dissolved
Acetone/IPE Birefringent Thick slurry of
needles
IPA/IPE Amorphous Sticky coating
MEK/IPE Birefringent Thick slurry of
needles
MIBK/IPE Birefringent White paste
DCM/IPE Birefringent Thick slurry of small
needles
THF/IPE Solution Seeds dissolved
2-MeTHF/IPE Amorphous slurry
EtOAc/IPE Birefringent Thick slurry of
needles
IPAc/IPE Amorphous slurry
Toluene Amorphous Sticky coating
      The crystallinity of Compound I Form I can be improved by using a butyronitrile/butyl ether (BN/BE) mixture according to the following procedure.
      The crystallization experiment was started with 40 to 75 mg Compound I in 1.1 to 3.0 mL of a BN/BE in a ratio of 7:4 (anhydrous solvents). The sample was held at RT over P2O5 for 23 days without agitation, and crystals formed in the solution. Afterwards, the liquid phase was replaced with butyl ether and the solids were obtained by centrifuge. These solids, corresponding to Compound I Form I, were used for the subsequent step as seed.
      Purified Compound I (709.8 mg) was prepared from reflux of ethanol solution with Darco G-60 and was added to a new vial via a filter. While stirring, 7 mL of anhydrous butyronitrile (BN) was added. A clear orange solution was obtained. While stirring, 4 mL of anhydrous butyl ether (BE) was added slowly. To the solution was added 7.7 mg of Compound I Form I (from previous BN:BE crystallization experiment) as seed. The solution became cloudy and the seeds did not dissolve. The sample was stirred for ˜10 minutes before the agitation was stopped. The vial was capped and placed into a jar with some P2O5 solids at room temperature. After 6 days, a thin layer of bright yellow precipitate was observed on the wall and the bottom of the vial. The liquid phase was withdrawn and 3 mL of anhydrous butyl ether was added. Solids were scraped down with a spatula from the vial. The suspension was heated to about 30° C. for over half hour period and was held for ˜1 hour before cooling to 20° C. at about 0.1° C./min (without agitation). The sample was stored in ajar with P2O5 solids for 5 days. The sample was vacuum filtered using 0.22 μm nylon filter, washed with 2×200 μL of anhydrous butyl ether, and air dried under reduced pressure for about 5 minutes.
      XRPD analysis of the sample showed good very sharp peaks as shown in FIG. 1. The XRPD analysis setting was as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 1-40°, step size 0.0167°, counting time: 36.83 s. The characteristic peaks of crystalline Compound I Form I include: 2.9, 3.6, 4.8, 5.2, 6.0° 2θ (FIG. 1). The XRPD pattern of Form I was successfully indexed, indicating that Form I is composed primarily of a single crystalline phase. Extremely large unit cell volume containing up to ˜60 API molecules in the unit cell was observed. The amorphous halo observed in the XRPD pattern could be a result of the size of the unit cell. Butyl ether stoichiometry could not be estimated. Two alternative indexing solutions were found: monoclinic and orthorhombic.
      DSC and TGA data confirmed that Form I is a solvated form. DSC shows a broad endotherm with onset at 109° C. and small endotherm with onset at 177° C. (FIG. 2). TGA shows 22% weight loss below 150° C. (FIG. 3).

PATENT

CN 105294713

https://www.google.com/patents/CN105294713A?cl=en

https://patentimages.storage.googleapis.com/pdfs/2601c633c50937ffb780/CN105294713A.pdf

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Example 12

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Under nitrogen, was added l〇2g1 said, adding methylene burn 500 blood dissolved, 4mol / L fertilizer 1 1,4-dioxane SOOmL, football for 1 hour at room temperature, of the C (already burned: ethyl acetate 1: 1) point in the control board, the starting material spot disappeared, the reaction was stopped, the solvent was concentrated, was added (R & lt) -2- (methoxy several yl) -2-phenylacetic acid 29g, COMU60g, DMF blood 500, diisopropylethylamine 223M1,25 ° C reaction I h, ethyl acetate was added IL diluted, purified water is added IL painted twice, dried over anhydrous sulfate instrument, and concentrated, methanol was added SOOmL temperature 60 ° C dissolved, 250mL of purified water was slowly added dropwise, to precipitate a solid, the addition was completed, cooled to 50 ° C for 1 hour, cooled to room temperature, filtered, and concentrated to give Velpatasvir (GS-5816) product 90. 5g, 78. 2〇 yield / billion. H-NMR (400MHz, CDs isolated) 5 7. 94 – 7.67 (m, 4H), 7.59 of J = 9.1 Hz, 1H), 7. 52 (S, 1H), 7.48 – 7. 33 (m, 4H) , 7.11 of J = 18. 7Hz, 1H), 5.68 of J = 6.3Hz, 1H), 5.48 – 5.33 (m, 1H), 5.23 (dd, J = 24.1, 15.7Hz, 1H), 5.17 -5.03 (m, 3H), 4.22 (dd, J = 17.0, 9.6Hz, 1H), 4.16 – 4.01 (m, 1H), 3.91 (d, J = 24. 1 Hz, 1H), 3 83 -. 3. 68 (m, 1H), 3 68 -. 3. 59 (m, 3H), 3 59 -. 3. 49 (m, 3H), 3.38 (ddd, J = 15.9, 9.6, 5.7Hz, 2H), 3.28 – 3.14 (m, 5H), 3.10 (dd, J = 14.0, 8.2 Hz, 1H), 3.00 (dd, J = 17.8, 9.6Hz, 1H), 2.92 (dd, J = 14.5, 6.7 Hz, 1H), 2.73 – 2.41 (m, 2H), 2.40 – 2.11 (m, 2H), 2. 11 – 1.83 (m, 2H), 1.54 deduction J = 9. 7 Hz, 2H), 1.24 of J = 6.2Hz, 1H), 1.06 (t, J = 8.0 Hz, 1H), 0.99 of J = 6.8 Hz, 1H), 0. 94 (d, J = 6. 6Hz, 2H), 0. 85 (d, J = 6. 7Hz, 2H ).

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Clip and foot notes

Velpatasvir only got its name last year and was previously known as GS-5816. That compound was only announced back in 2013 when Gilead showed the initial in vitrostudies on a handful of posters. [1]  [2]  Very little information is available on this follow-up compound. The following was pretty much the summary of their poster presentation.

To understand the medical significance of this study, Sofosbuvir is the best-in-class NS5B inhibitor from Gilead (see link for more information). [3] These inhibitors work the fastest when paired with a NS5A inhibitor like Daclatasvir or Ledipasvir (making up the Sofosbuvir+Ledipasvir = Harvoni combination) or the Viekira Pak combo. Disclosure: I am an employee of Bristol-Myers Squibb which produces Daclatasvir. However, HCV comprises of 7 different genotypes. Harvoni and Viekira Pak are approved against genotypes 1a, 1b. Harvoni is indicated for genotypes 4, 5, and 6. For the treatment of genotypes 2 and 3, sofosbuvir is generally combined with ribavirin or interferon which has notable side effects. While 70% of patients have genotype 1, for the remainder of patients with the other variants, they are still stuck with the more risky (and more expensive and longer) therapy.