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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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FDA approves new antibacterial drug Vabomere (meropenem, vaborbactam)


Image result for meropenem

Meropenem

Beta-lactamase inhibitor vaborbactam
08/29/2017
The U.S. Food and Drug Administration today approved Vabomere for adults with complicated urinary tract infections (cUTI), including a type of kidney infection, pyelonephritis, caused by specific bacteria. Vabomere is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

The U.S. Food and Drug Administration today approved Vabomere for adults with complicated urinary tract infections (cUTI), including a type of kidney infection, pyelonephritis, caused by specific bacteria. Vabomere is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

“The FDA is committed to making new safe and effective antibacterial drugs available,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This approval provides an additional treatment option for patients with cUTI, a type of serious bacterial infection.”

The safety and efficacy of Vabomere were evaluated in a clinical trial with 545 adults with cUTI, including those with pyelonephritis. At the end of intravenous treatment with Vabomere, approximately 98 percent of patients treated with Vabomere compared with approximately 94 percent of patients treated with piperacillin/tazobactam, another antibacterial drug, had cure/improvement in symptoms and a negative urine culture test. Approximately seven days after completing treatment, approximately 77 percent of patients treated with Vabomere compared with approximately 73 percent of patients treated with piperacillin/tazobactam had resolved symptoms and a negative urine culture.

The most common adverse reactions in patients taking Vabomere were headache, infusion site reactions and diarrhea. Vabomere is associated with serious risks including allergic reactions and seizures. Vabomere should not be used in patients with a history of anaphylaxis, a type of severe allergic reaction to products in the class of drugs called beta-lactams.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of antibacterial drugs, Vabomere should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Vabomere was designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of its QIDP designation, Vabomere received a priority review.

The FDA granted approval of Vabomere to Rempex Pharmaceuticals.

//////////////FDA,  antibacterial drug,  Vabomere, meropenem, vaborbactam, fda 2017, Rempex Pharmaceuticals, qualified infectious disease product, QIDP, Generating Antibiotic Incentives Now, GAIN, priority review
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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

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

MK 7655, RELEBACTAM, a β-Lactamase inhibitor


MK 7655, RELEBACTAM

(1R,2S,5R)-7-Oxo-N-(4-piperidinyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

(1R,2S,5R)-7-oxo-2-((piperidin-4-yl)carbamoyl)-1,6-diazabicyclo(3.2.1)octan-6-yl hydrogen sulfate monohydrate

Sulfuric acid, mono((1R,2S,5R)-7-oxo-2-((4-piperidinylamino)carbonyl)-1,6-diazabicyclo(3.2.1)oct-6-yl) ester, hydrate (1:1)

MF C12H22N4O7S
MW 366.39068 g/mol

CAS 1174020-13-3

β-Lactamase inhibitor

MK-7655 is a beta-lactamase inhibitor in phase III clinical studies at Merck & Co for the treatment of serious bacterial infections…….See clinicaltrials.gov, trial identifier numbers NCT01505634 and NCT01506271.

In 2014, Qualified Infectious Disease Product (QIDP) and Fast Track designations were assigned by the FDA for the treatment of complicated urinary tract infections, complicated intra-abdominal infections and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia.

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PAPER

A concise synthesis of a beta-lactamase inhibitor
Org Lett 2011, 13(20): 5480

http://pubs.acs.org/doi/abs/10.1021/ol202195n

http://pubs.acs.org/doi/suppl/10.1021/ol202195n/suppl_file/ol202195n_si_001.pdf

 

Abstract Image

MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N–H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.

H NMR (400 MHz, DMSO-d6): δ 8.30 (br s, 2H), 8.20 (d, J = 7.8 Hz, 1H), 4.01 (s, 1H), 3.97-3.85 (m, 1H), 3.75 (d, J = 6.5 Hz, 1H), 3.28 (dd, J = 12.9, 2.5 Hz, 2H), 3.05-2.93 (m, 4H), 2.08-1.97 (m, 1H), 1.95-1.79 (m, 3H), 1.73-1.59 (m, 4H);

13C NMR (DMSO-d6, 100 MHz) δ 169.7, 166.9, 59.8, 58.3, 46.9, 44.3, 42.9, 28.5, 28.3, 20.8, 18.9;

HRMS calculated for C12H20N4O6S (M+H): 349.1182, found: 349.1183.

[α]D 25 = -23.3 (c = 1.0, CHCl3)

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sc2

PATENT

WO 2009091856

http://www.google.com/patents/WO2009091856A2?cl=en

EXAMPLE IA

(2S ,5 R)-7-Oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo [3.2.1 ]octane-2-carboxamide

Figure imgf000063_0001

Step 1 : tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yljcarbonyl } amino)piperidine- 1 -carboxylate : To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-l,6-diazabicyclot3.2.1]octane-

2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-l-methylpyridinium iodide (1.60 g, 6.26 mmol), and 4-amino-l- BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 500C for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compuond eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.

Step 2: tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-l ,6-diazabicyclo[3.2.1]oct-2- yl] carbonyl } amino)piρeridine- 1 -carboxylate:

Palladium on carbon (394 mg; 10% Pd/C) was added to a solution of the product of step 1 (1.81 g, 3.95 mmol) in methanol (50.6 mL) and the resulting mixture was stirred under hydrogen (balloon) overnight. LC/MS analysis indicated the reaction was not complete. Acetic acid (6 drops) and additional catalyst (159 mg of 10% Pd/C) were added to the reaction and the resulting mixture was stirred under hydrogen (balloon) for an additional 90 minutes. Additional catalyst (0.2085 g of 10% Pd/C) was added to the reaction and stirring under hydrogen was continued for an additional 2.5 hours at which time the reaction was judged complete by LC-MS analysis. The reaction was filtered through a celite pad and the collected solid was washed well wtih MeOH. The filtrate was concentrated under vacuum to afford the title compound as a colorless oil which was used without purification in the next step.

Step 3 : tert-butyl-4-({ [(2S,5R)-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]oct-2- yl] carbonyl } amino)ρiperidine- 1 -carboxylate:

To a solution of the product of step 2 (1.455 g, 3.95 mmol; theoretical yield of step 2) in dry pyridine (30 mL) was added sulfur trioxide pyridine complex (3.2 g, 20.11 mmol) at room temperature under nitrogen. The resulting thick mixture was stirred over the weekend.

The reaction was filtered and the white insoluble solids were washed well with dichloromethane. The filtrate was concentrated in vacuo. The residue was further azeotroped with toluene to remove excess pyridine to afford the title compound which was used without purification in the next step.

Step 4: (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide:

To a mixture of the product of step 3 (1.772 g, 3.95 mmol; theoretical yield of step 3) in dry dichloromethane (30 ml) at 00C under nitrogen was slowly added trifluoroacetic acid (6.1 ml, 79 mmol). Immediately the reaction became a solution. After 1 hour, additional trifluoroacetic acid (8 ml) was added to the reaction. The reaction was stirred at 00C until judged complete by LC-MS analysis then concentrated in vacuo. The residue was triturated with ether (3X) to remove excess TFA and organic impurities. The resulting white insoluble solid was collected via centrifugation, dried in vacuo, then purified by preparative HPLC (250X21.2 mm Phenomenex Synergi Polar-RP 80A column; 10 micron; 35 mL/min.; 210 nM; 0% to 30% methanol/water over 15 minutes; title compound eluted at 10% methanol/water). Fractions containing the title compound were combined and Iyophilized overnight to afford the title compound as a white solid. LC-MS (negative ionization mode) m/e 347 (M-H).

PAPER

Discovery of MK-7655, a beta-lactamase inhibitor for combination with Primaxin
Bioorg Med Chem Lett 2014, 24(3): 780

http://www.sciencedirect.com/science/article/pii/S0960894X13014856

Image for unlabelled figure

PATENT

WO 2014200786

http://www.google.dj/patents/WO2014200786A1?cl=en

 

 

 

Exemplary Scheme

– 50% isolated yield overall from 1 to 5

O via crystallization

XAMPLE 1

(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide

Preparation of (15′,45)-5-((2-nitrophenyl)sulfonyl)-2-oxa-5-azabicyclo[2.2.2]octan-3 one (2)

To a reactor (R-1) equipped with an additional funnel, nitrogen inlet and agitator was charged (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (77.3 wt%) (50.0 g, 344 mmol), and water (150 mL). Agitation was begun, the pH adjusted to 10-11 by addition of 10 N NaOH (~ 46.5 mL) and the reactor charged with acetone (50.0 mL).

In a separate reactor (R-2) equipped with an agitator and nitrogen inlet was charged 2-nitrobenzene-l-sulfonyl chloride (97%) (106.0 g, 478 mmol) and acetone (80 mL). The contents of R-2 were transferred to R-1 at 23-30 °C while the pH of the solution was maintained at 10-11 by simultaneously addition of 10 N NaOH. After 15 to 30 min, the pH was adjusted to about 6 by addition of 12 N HC1. The solution was charged with EtOAc (500 mL) and the pH adjusted to 3.0 by addition of 12 N HC1. The layers were separated and the aqueous back-extracted with EtOAc (150 mL x 2).

To a separate reactor (R-3) was charged product la in the combined organic layers, 2-nitrobenzene-l-sulfonyl chloride (73.0 g, 329 mmol), and triethylamine (130 mL). The batch in R-3 was agitated at 20-28°C for 30 min. The solution was charged with water (100 mL), the layers separated, and the aqueous back extracted with EtOAc (150 mL x 2). The combined EtOAc layer was washed with 10% NaHC03 (100 mL) and brine (100 mL). The organic phase was concentrated to 150 mL upon which a crystalline slurry was formed. The concentrated solution was agitated at 13-18°C for 2-3 hours followed by filtration of crystalline solids. The resulting wet cake was washed with EtOAc (60 mL) and then dried under vacuum oven at 25-30°C to afford 2 (65.6 g, 79% yield), m.p. 126.0-126.7 °C. 1H NMR (CDC13, 400 MHz) δ: 8.02 (m, 1 H), 7.80-7.71 (m, 2 H), 7.66 (m, 1 H), 4.88 (m, 1 H), 4.55 (dd, J= 3.8, 2.7 Hz, 1 H), 3.78 (dt, J= 11.2, 3.0 Hz, 1 H), 3.66 (dd, J = 11.2, 1.1 Hz, 1 H), 2.44 (m, 1 H), 2.11 (m, 2 H), 1.91 (m, 1 H); 13C NMR (CDC13, 100 MHz) δ: 168.4, 148.3, 134.4, 132.1, 131.0, 130.7, 124.2, 73.5, 51.4, 48.0, 25.1, 23.2

Preparation oftert-butyl 4-((25*,55)-l-((2-nitrophenyl)sulfonyl)-5-(((2- nitrophenyl)sulfony l)oxy)piperidine-2-carboxamido)piperidine- 1 -carboxylate (3)

To a reactor (R-l) was charged lactone 2 (65.5 g, 210 mmol), THF (131 mL) and tert-butyl 4-aminopiperidine-l -carboxylate (44.5 g, 222 mmol). The stirred solution was heated to reflux (typical temperature 72 °C) for ~18 hr. The reaction was cooled to 25-35 °C and then charged with THF (325 mL) and 4-dimethylaminopyridine (40.1 g, 328 mmol) followed by agitation for 30 minutes.

To a separate reactor (R-2) was charged 2-nitrobenzene-l-sulfonyl chloride (60.9 g,

275 mmol) and THF (200 mL). The contents of R-2 were added to R-l over the course of 45 to 75 minutes maintaining batch temperature of 20 to 30°C. The batch in R-l was agitated for 2 to 4 hours at a temperature of 20 to 30°C.

To a separate reactor (R-3) was charged water (600 mL) and methanol (600 mL). The contents of R-3 were charged to the main batch over the course of 45 to 75 minutes with agitation while maintaining temperature of 20 to 30°C. The batch was cooled to 5 to -5°C and then agitated at 5 to -5°C for at least 4 hours. The solids were filtered and then washed twice with methanol (130 mL x 2). The wet cake was dried in a vacuum oven at 40 to 50°C to afford 3 (144.0 g, 98% yield), m.p. 131.8-133.1 °C. 1H NMR (CDC13, 400 MHz) δ: 8.14 (m, 2 H), 7.83-7.74 (m, 6 H), 6.50 (d, J= 7.9 Hz, 1 H), 4.69 (m, 1 H), 4.43 (s, 1H), 4.11 (dd, , J= 13.7, 4.9 Hz, 1H), 3.95 (m, 2H), 3.83 (m, 1H), 3.47 (s, 1H), 3.10 (dd, J= 13.7, 11.0 Hz, 1H), 2.81 (m, 2H), 2.51 (m, 1H), 2.12 (m, 1H), 1.85-1.72 (m, 4H), 1.45 (s, 9H), 1.26 (m, 1H); 13C NMR (CDC13, 100 MHz) δ: 166.9, 154.6, 148.2, 147.6, 135.2, 134.8, 132.6, 132.5, 131.9, 131.6, 131.4, 129.7, 124.9, 124.7, 79.8, 76.5, 55.0, 47.1, 46.0, 31.8, 31.5, 28.4, 27.3, 24.4.

Preparation of N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine

To a reactor (R-l) was charged O-benzylhydroxylamine hydrochloride (61.0g, 382 mmol) and pyridine (400 mL). The solution cooled to 5 to -5°C.

To a separate reactor (R-2) was charged 4-nitrobenzenesulfonyl chloride (89.0 g, 402 mmol) and pyridine (200 mL). The contents of R-2 were transferred to R-l at a rate to maintain temperature range of -5 to -5°C. The batch in R-l was agitated at 5 to -5 °C for 15 to 45 minutes then warmed to 20 to 30°C for 45 to 75 minutes. Water (250 mL) was then added at a rate to maintain 20 to 30°C and agitated 5 to 15 minutes. The solids were filtered and the wet cake washed with water (100 mL x 3). The wet cake was dried in vacuum oven at 50°C to afford N-4-nitrobenzenesulfonyl-O-benzylhydroxylamine (113.3 g, 96% yield), m.p. 128.4-130.0 °C. 1H NMR (CDCls, 400 MHz) δ: 8.36 (d, J = 8.9 Hz, 2 H), 8.11 (d, J = 8.9 Hz, 2 H), 7.36 (m, 5H), 7.11 (s, 1H), 5.02 (s, 2H); 13C NMR (CDC13, 100 MHz) δ: 151.0, 142.5, 134.9, 130.2, 129.7, 129.3, 128.9, 124.5, 80.2.

Step C. Preparation of tert-butyl 4-((2S,5R)-5-((benzyloxy)amino)piperidine -2-carboxamido)piperidine- 1 -carboxylate (4)

Boc

To a reactor (R-l) was charged tert-butyl 4-((2R,5R)-l-((2-nitrophenyl)sulfonyl)-5-(((2-nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-l -carboxylate (3) (110 g, 158 mmol), N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine (58 g, 188 mmol), potassium carbonate (25.9 g, 187 mmol) and dimethylacetamide (440 mL). The stirred solution was heated to 60 to 70°C for 24 – 32 hours. The batch was cooled to 20 to 30°C and charged with toluene (660 mL). The batch was extracted with 1 N sodium hydroxide (3×220 mL) then washed with water (220 mL).

The toluene solution was azotropically distilled at ~50°C to about 1/3 volume. The solution was solvent-switched to MeOH at 45-55°C, adjusted to 237 mL.

The batch was cooled to 20-25°C, charged with thioglycolic acid (57.9 g, 629 mmol) at 10 °C, and then charged with K2CO3 anhydrous (172.0 g, 1225 mmol). The batch was agitated at 10-15°C for 0.5 h, warmed to 20-25°C, agitated at 20-25°C for 10-15 h, and heated at 48-53°C for 3-6 h.

The batch was charged with 10 wt% sodium chloride (1.10 L) and toluene (880 mL) at about 40°C. The layers were separated and the aq. layer back-extracted with toluene (3 x440 mL). The combined organic layer was washed with 10% NaHC03 (2 x220 mL). The batch was concentrated at 40-50°C to 165 mL, then cooled to 35-40°C. The batch was charged with seed (50 mg) and agitated for 1 h at 35-40°C. The batch was charged with heptanes (110 mL) at 35-40°C over 1 h, then slowly cooled to 15-20°C over 1 h. The batch was agitated for 3 h and the solids filtered. The wet cake was washed with toluene/heptanes (137.5 mL) then dried in vacuum oven at 30 °C for 3-8 h to affored 4. (47.3 g, 70% overall yield from 3), m.p. 117.5-118.0 °C. 1H NMR (CDC13, 500 MHz) δ: 7.37-7.29 (m, 5 H), 6.64 (d, J= 8.2 Hz, 1 H), 5.36 (brs, 1 H), 4.67 (s, 2 H), 4.00 (m, 2 H), 3.90 (m, 1 H), 3.28 (ddd, J= 11.8, 4.0, 1.7 Hz, 1 H), 3.12 (dd, J= 10.2, 3.2 Hz, 1 H), 2.95 (m, 1 H), 2.86 (m, 2 H), 2.46 (dd, J= 11.8, 9.5 Hz, 1 H), 2.10 (m, 1 H), 1.93-1.83 (m, 3 H), 1.58 (brs, 1 H), 1.45 (s, 9 H), 1.41 (m, 1 H), 1.35-1.23 (m, 3 H); 13C NMR (CDC13, 125 MHz) δ: 172.8, 154.7, 137.7, 128.4 (4 C), 127.9, 79.6, 76.9, 59.8, 57.0, 49.2, 46.1, 42.8 (br, 2 C), 32.0 (2 C), 28.4 (3 C), 28.3, 27.2.

Step D: Preparation of tert-butyl 4-((lR,2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 ]octane-2-carboxamido)piperidine- 1 -carboxylate (5)

To a reactor (R-l) was charged tert-butyl 4-((2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxamido)piperidine-l-carboxylate (4) (46.3 g, 107 mmol), dichloromethane (463 mL), and Hunig’s base (58.0 mL). The batch was cooled to -18°C and then charged with triphosgene in four portions (25.1 g total; 85 mmol) at <-8°C. The batch was agitated at -5 to 0°C for 0.5 h then charged with 11.4 wt% aqueous H3P04 at -5 to 0 °C (347 g, 3541 mmol). The batch was agitated at 20-25°C for 15-20 h then phase cut. The aqueous layer was back-extracted with dichloromethane (138 mL). The combined organic layer was washed with 10% NaHC03 (115 mL), then water (115 mL). The organic solution was concentrated at atmospheric pressure to ~80

mL, then charged with MTBE (347 mL) at 35-45 °C over 0.5 h, then concentrated at 35-45 °C to 231 mL two times to form a slurry.

The slurry was charged with heptanes (139 mL) at 35-45 °C over 2 h, then slowly cooled to 15-20°C over 1 h. The batch was agitated at 15-20°C for 6-8 h. Solids were filtered and the wet cake washed with MTBE/heptanes (1.4 : 1 , 185 mL) then dried under vacuum at 25-30°C for 5-10 hours to afford 5 (43.7 g, 92% yield), m.p. 161.3-161.8 °C. 1H NMR (CDC13, 500 MHz) δ: 7.45-7.32 (m, 5 H), 6.55 (d, J= 8.2 Hz, 1 H), 5.05 (d, J= 11.6 Hz, 1 H), 4.90 (d, J= 11.6 Hz, 1 H), 4.02 (m, 2 H), 3.90 (m, 2 H), 3.30 (m, 1 H), 2.99 (dt, J= 11.7, 1.1 Hz, 1 H), 2.86 (m, 2 H), 2.64 (d, J = 11.7 Hz, 1 H), 2.37 (dd, J= 14.6, 6.9 Hz, 1 H), 2.04-1.82 (m, 4 H), 1.58 (m, 1 H), 1.45 (s, 9 H), 1.30 (m, 2 H); 13C NMR (CDC13, 125 MHz) δ: 168.3, 167.5, 154.7, 135.6, 129.2 (2 C), 128.8, 128.6 (2 C), 79.7, 78.3, 60.4, 57.8, 47.5, 46.8, 42.5 (br, 2 C), 32.0, 31.7, 28.4 (3 C), 20.8, 17.2.

Step E: Preparation of tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1|octane- 2-carboxamido) iperidine- 1 -carboxylate

tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-l -carboxylate (9.2 g, 20.1 mmol) was charged to a glass bottle, and the solids were dissolved in THF (150 mL). The solution was then charged to a hydrogenation reactor along with Pd/Al203 (10 wt%, 1.5 g). The reaction was purged three times with hydrogen and then set to a hydrogen pressure of 50 psi. The reaction temperature was adjusted to 25°C and the reaction was allowed to agitate for 22 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through SOLKA-FLOC® (Interational Fiber Corporation, North Tonawanda, NY) to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to iPrOAc to a final volume of 40 mL. The resulting iPrOAc slurry was aged at room temperature for 1 hour. The solids were then filtered and washed with iPrOAc (20 mL) and dried under vacuum and N2 at 40°C to afford the title product (6.62 g., 17.97 mmol, 90% isolated yield). Spectral data matched the reference compound.

Preparation of (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide

tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-l-carboxylate (20 g, 54.3 mmol), THF (200 mL), 2-picoline (10.9 mL, 309 mmol) and pyridine-S03 complex (30.2 g, 190 mmol) were charged to a flask under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 h). The reaction mixture was cooled to -10°C then DCM (200 mL) was added. 0.5 M K2HP04 (168 mL, 84 mmol) was added over 10 minutes. Bu4NHS04 (19.4 g, 57 mmol) was then added over 10 minutes. The biphasic mixture was stirred for 30 minutes, phase cut and the water layer was back extracted with 40 ml of DCM. The combined DCM solution was washed with water (120 ml), phase cut and the organic solution was solvent-switched to MeCN (320 ml) by vacuum distillation with 3 bed volumes of MeCN (total 1.0 L) and used as is in the next step. The solution of Bu4N+ OSO3 salt 7 in MeCN solution was used with an assumed yield of 100% (37.5 g, 54.3 mmol). The reaction mixture was cooled in an ice bath, and TMSI (10.26 ml, 70.7 mmol) was added via addition funnel over 30 minutes between 0°C and 5°C. The resulting mixture was agitated for 1-2 h and then quenched with H20:MeCN (1 :1, 6 ml) to afford a slurry. The slurry was warmed to room temperature and agitated for 12 h and after this time the pH of the supernatant was about 3.0. Tetrabutylammonium acetate (13.6 ml, 13.59 mmol) was slowly added over 30 min. The slurry was agitated for 1 h and pH of the supernatant was about 4.0. Solids were collected by filtration. The solid was washed with 60 mL of aqueous MeCN to afford 19.5 g of the crude product 8 in a 93% isolated yield from compound 6 .

At this stage, all byproducts (including hydro lyzation products of TMS-carbonate) and impurities were soluble in the organic phase.

The product was dissolved back into 140 ml of MeCN:H20 (1 :2) at room temperature. 1-Butanol (390 ml) as antisolvent was slowly added into the solution to afford a slurry. The slurry was agitated overnight. The white crystalline solid was filtered and washed with 3:1 IPA: water (40 ml) and dried under vacuum and nitrogen at room temperature to afford the title product in the form of a crystalline hydrate. (Yield = 16.3 g, 82%). Spectral data matched reference compound.

Preparation of (2S,5R)-7-oxo-2-(piperidin- 1 -ium-4-ylcarbamoyl)- 1 ,6-diazabicyclo[3.2.1 ]octan-6-yl sulfate (1).

tert-Butyl 4-( {[(25*,5i?)-6-hydroxy-7-oxo- 1 ,6-diazabicyclo[3.2.1 ]oct-2-yl]carbonyl}amino)piperidine-l-carboxylate 16 (0.54 g, 1.5 mmol), THF (5.4 mL), 2-picoline (0.29 mL, 2.9 mmol) and pyridine-S03 complex (0.70 g, 4.4 mmol) were charged to a vial under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 hr). The reaction mixture was cooled to -10°C then dichloromethane (5.4 mL) was added. 0.5 M K2HPO4 (4.5 mL, 2.3 mmol) was added over 10 minutes. BU4NHSO4 (0.53 g, 1.54 mmol) was then added over 10 min. The biphasic mixture was stirred for 30 min, phase cut and the water layer was back extracted with 1 ml of DCM. The combined DCM solution was washed with water (2.0 mL), phase cut and the organic solution was solvent-switched to MeCN (3.2 mL) by vacuum distillation with 3 bed volumes of MeCN. The product was used as is in the next step (water content less than 1000 ppm).

The solution of Bu4N+S04~~ salt 8 in MeCN solution was used with an assumed yield of 100% (1.0 g, 1.47 mmol). The reaction mixture was cooled in an ice bath, and Ν,Ο-bis(trimethylsilyl)trifluoroacetamide (BSTFA) (0.4 lg, 1.59 mmol) was added into the reaction and was allowed to stir for 10 min. TMSI (0.06g, 0.27 mmol) was added between 0°C and 5°C. The resulting mixture was allowed to agitate for 2 hr and then quenched with H2O (0.07g, 4.1 mmol) and acetic acid (0.08g, 1.5 mmol) to afford a slurry. The slurry was warmed to room temperature and agitated for 12 hr. Filter to collect the solid. The solid was washed with MeCN/water (94:6, 1 mL X 4) to afford the crystalline product 1 (0.38 g) in a 75% yield.

If NO-bis(trimethylsilyl)acetamide (BSA) (0.32g, 1.59 mmol) was applied, the reaction needed 24 hr to achieve full conversion.

Patent

WO2015033191

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015033191&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Scheme 1.

Formula (V)

Formula (VI)

Formula (I)

Scheme – 1

Example -1

Preparation of (2S, 5R)-Sulfuric acid mono-{2-[N’-(4-aminopiperidinyl)-carbonyl]-7-oxo- l,6-diaza-bicyclo[3.2.1]oct-6-yl} ester (I).

Step-1: Preparation of (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (IV):

To a 250 ml round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-sodium 6-benzyloxy-7-oxo-l,6-diaza-bicyclo [3.2.1] octane-2-carboxylate (11.1 gm, 0.037 mol, prepared using a method disclosed in Indian Patent Application No 699/MUM/2013) in water (180 ml) followed by l-tert-butoxycarbonyl-4-amino-piperidine (7.8 gm, 0.039 mol), EDC hydrochloride (11 gm, 0.055 mol) and 1 -hydro ybenzotriazole (4.8 gm, 0.037 mol) at 30°C successively under stirring. The reaction mixture was stirred for 24 hours at 30°C to provide a suspension. The suspension was filtered under suction and washed with 45°C warm water (40 ml) to provide (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 12.7 gm quantity in 74% yield after drying under vacuum.

Analysis

NMR: (CDC13,) = 7.36-7.44 (m, 5H), 6.56 (d,lH), 5.06 (d,lH), 4.91 (d, 1H), 4.03 (br s, 1H), 3.88-3.97 (m, 2H), 3.29 (s, 1H), 3.00 (d, 1H), 2.86 (t, 2H), 2.64 (d, 1H), 2.37 (dd, 1H), 1.85-2.01 (m, 4H), 1.54-1.62 (m, 2H), 1.45 (s, 9H), 1.25-1.36 (m, 2H).

MS (ES+) C24H34N405 = 459.5 (M+l).

Step-2: Preparation of (2S, 5R)-tert-butyl { (6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (V):

To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (9 g, 19.5 mmol) in methanol (90 ml) followed by 10% palladium on carbon (2.7 g) at 35°C. The reaction mixture was stirred under 1 atm hydrogen pressure at 35°C for 2 hours. The catalyst was removed by filtering the reaction mixture under suction over a celite bed. The celite bed was washed with dichloromethane (50 ml). The combined filtrate was evaporated under vacuum below 35°C to provide (2S, 5R)-tert-butyl {(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 8.45 g quantity; it was used as such for the next reaction.

Analysis

NMR: (CDC13,) = 6.60 (d, 1H), 3.88-4.10 (m, 4H), 3.78 (s, 1H), 3.20 (d, 1H), 3.90 (t, 2H), 2.80 (d, 1H), 2.46 (dd, 1H), 2.1-2.2 (m, 1H), 2.85-2.20 (m, 4H), 1.70-1.80 (m, 1H), 2.47 (s, 9H), 1.30-1.41 (m, 3H).

MS (ES+) C17H28N405 = 369.4 (M+l).

Step-3: Preparation of Tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (VI):

To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-tert-butyl {(6-hydroxy-7-oxo-l,6-diaza-bicyclo [3.2.1 ]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (6.40 g, 7.6 mmol) in dichloromethane (90 ml), triethyl amine (9.3 ml), followed by pyridine – sulfur trioxide complex (5.4 g, 34.2 mmol) at 35°C under stirring. The reaction mixture was stirred for additional 4 hours at 35°C. The solvent was evaporated under vacuum below 40°C to provide a residue. The residue was stirred with 0.5N aqueous potassium dihydrogen phosphate solution (90 ml) for 1 hour. The resulting solution was extracted with dichloromethane (2 x 100 ml) to remove impurities. To the aqueous layer was added tetrabutyl ammonium hydrogen sulfate (6.9 g, 20.52 mmol) and the reaction mixture was stirred for 14 hours at 35°C. It was extracted with dichloromethane (3 x 30 ml). Combined organic layer was dried over sodium sulfate and evaporated under vacuum to provide tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 8.0 g quantity in 62% yield.

Analysis

NMR: (CDC13,) – 6.64 (d, 1H), 4.36 (br s, 1H), 4.05(br s, 2H), 3.90-4.00 (m, 1H), 3.87 (d, 1H), 2.28-3.34 (m, 10H), 3.80-3.95 (m, 2H), 3.74 (d, 1H), 2.42 (dd, 1H), 2.15-2.24 (m, 1H), 1.82-1.97 (m, 4H), 1.61-1.74 (m, 14 H), 1.41-1.52 (m, 10 H), 1.02 (t, 12H).

MS (ES-) C17H27N408S. N(C4H9)4 = 447.4 (M-l) as a free sulfonic acid.

Step-4: Synthesis of (2S, 5R)- Sulfuric acid mono-{ [(4-aminopiperidin-4-yl) carbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1]-oct-6-yl} ester (I):

To a 100 ml round bottom flask equipped with magnetic stirrer was charged a solution of tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (6.0 g) in dichloromethane (15 ml). The solution was cooled to -10°C under stirring and to it was added trifluoro acetic acid (15 ml) drop wise. The reaction mixture was stirred at -10°C for 1 hour. Solvents were evaporated under vacuum below 30°C to its 1/3 volume to provide a thick residue. The thick residue was stirred twice with diethyl ether (60 ml each time) to provide a precipitation. The solid obtained was filtered at suction and suspended in acetone (90 ml). To the suspension was added 10% solution of sodium-2-ethyl-hexanoate in acetone to adjust pH between 4.5 to 5.5. The suspension was stirred for 10 minutes and filtered under suction. The wet cake was washed with acetone and dried under vacuum below 40°C to provide 3 gm crude compound. The crude compound was stirred with aqueous isopropanol (3ml water: 21 ml iospropanol) for overnight to purify further. The resulting suspension was filtered under suction and washed with aqueous isopropanol (1 ml water: 7 ml IPA mixture). Finally the cake was dried under vacuum below 40°C to provide the title compound as a off-white solid in 1.8 g quantity in 65% yield.

Analysis

H1NMR (DMSO-d6, D20 exchange) = 8.19 (d, exchanges with D20), 3.99 (s, 1H), 3.82-3.92 (m, 1H), 3.72 (d, 1H), 2.24 (br d, 3H), 2.90-3.04 (m, 5H), 1.96-2.06 (m, 1H), 1.80-1.94 (m, 3H), 1.58-1.72 (m, 4H).

MS (ES+) C12H20N4O6S = 349.2 (M+l) as a free sulfonic acid;

Purity by HPLC: 99.2%

Specific rotation: [a] D -45.25 °, (c 0.3%, water)

SEE BACTAM SERIES…………..http://apisynthesisint.blogspot.in/p/bactam-series.html

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C1CC(N2CC1N(C2=O)OS(=O)(=O)O)C(=O)NC3CCNCC3.O

WCK 5222, Wockhardt receives QIDP status for its new drug WCK 5222 from USFDA


 

WCK 5222

Watch this post as I get to the structure…………..

DEC2015

Wockhardt has received Qualified Infectious Disease Product (QIDP) status for its new drug WCK 5222,  a product from its breakthrough New Drug Discovery program in Anti Infectives from the US Food and Drug Administration (FDA).
This is the fourth product from the company to receive this coveted status. During last year, the company has received approval for WCK 771 & WCK 2349 and in early this year approval was received for WCK 4873. The only company globally to receive QIDP status for 4 drugs from US FDA.
Wockhardt is one of the few companies with end to end integrated capabilities for its products, starting with the manufacture of the oral and sterile API’s, the dose forms and marketing through wholly owned subsidiary in the US, enabling the company to capture maximum value.

 

Ten compounds generally represented by a general Formula (I) were used and are as follows:

(a) Sodium salt of ir ns-7-oxo-6-sulphooxy-l ,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (Compound A);

(b) trans-sulphuric acid mono-[2-(5-carboxamido)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound B);

(c) trans-sulphuric acid mono-[2-(5-(piperidin-4-yl)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound C);

(d) trans-sulphuric acid mono-[2-(5-azetidin-3-ylmethyl-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound D);

(e) (25,5i?)-7-Oxo-6-sulphooxy-2-[N’-((i?)-piperidine-3-carbonyl)-hydrazinocarbonyl] -1,6-diaza-bicyclo[3.2.1]octane (Compound E);

(f) (25, 5i?)-7-Oxo-N-[(25)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-l,6-diaza bicyclo [3.2.1] octane-2-carboxamide (Compound F);

(g) (25,5i?)-7-Oxo-6-sulphooxy-2-[N’-((i?)-pyrrolidine-3-carbonyl)-hydrazinocarbonyl]-l ,6-diaza -bicyclo[3.2.1]octane (Compound G);

(h) (25,5i?)-7-Oxo-N-[(25)-piperidine-2-ylmethyloxy]-6-(sulfooxy)-l ,6-diazabicyclo

octane-2-carboxamide (Compound H);

(i) trans-sulphuric acid mono-[2-(5-((5)-l-amino-ethyl)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound I); and

j) trans-sulphuric acid mono-[2-(5-((5)-pyrrolidin-2-yl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound J).

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WCK 2349 in phase II trials by Wockhardt


Figure imgf000002_0001. CH3SO3H
WCK 2349
Cas 948895-94-1  methane sulfonate
Base..706809-20-3
527.563., C22 H26 F N3 O5 . C H4 O3 S
8-[4-(L-Alanyloxy)piperidin-1-yl]-9-fluoro-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid methanesulfonate
S-​(-​)​-​9-​fluoro-​6,​7-​dihydro-​8-​(4-​L-​alaninyloxypiperidin-​1-​yl)​-​5-​methyl-​1-​oxo-​1H,​5H-​benzo[i,​j]​quinolizine-​2-​carboxylic acid methanesulfonate
(2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-L-alaninyl-oxy-piperidin-l-yl)-5-methyl- l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid methanesulfonic acid salt
Oral broad-spectrum antibiotic
WO 2000068229, WO 2002009758, WO 2007102061, WO 2008053295, Indian (2015), IN 267210 , IN 2008MU00864,
Shetty, N.M.; Nandanwar, M.B.; Kamalavenkatesh, P.; et al.
WCK 2349: A novel fluoroquinolone (FQ) prodrug-13 week oral (PO) safety profile in cynomolgus monkeys
47th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 17-20, Chicago) 2007, Abst F1-2133a

8-{4-[2(S)-Amino-propionyloxy] piperidine-l-yl}-9-fluoro-5 (S)-methyl-ό, 7-dihydro-l- oxo-lH, 5H-benzo[i,j]quinolizine-2-carboxylic acid of structural Formula I can be used to treat bacterial Gram-positive, Gram-negative and anaerobic infections; especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections.

Figure imgf000002_0001

Formula I

U.S. Patent Nos. 6,750,224 and 7,247,642 describes optically pure S-(-)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, their processes of preparation and their pharmaceutical compositions.

PATENT

 

WO 2007102061

http://www.google.co.in/patents/WO2007102061A2?cl=en

Figure imgf000008_0001
Figure imgf000008_0002

Scheme 1

Experimental:

(S)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[ij] quinolizine-2-carboxylic acid was prepared as per procedure described in Chem. Pharm. Bull. 1996, 44(4), 642-645.

Example-l

Preparation of (2’S,5S)-9-fluoro-6,7-dihydro-8-(4-(N-tert-butoxycarbonyI-L-aIaninyl- oxy)-piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid:

Method-1 : To a mixture of N-tert-butoxycarbonyl-L-alanine (473 g) in dichloromethane (2 L), dicyclohexylcarbodiimide (515 g) dissolved in dichloromethane (2 L) was charged at -10 to 0 0C to provide a turbid suspension. To the turbid suspension, 300 g of (S)-9-fluoro-6,7- dihydro-8-(4-hydroxy-piperidin- 1 -yl)-5-methyl- 1-oxo- lH,5H-benzo[i,j]quinolizine-2- carboxylic acid was added followed by 4-N,N-dimethylamino pyridine (58 g) and the reaction mixture was stirred at -10 to 5 °C temperature over a period of 2 h. Suspension was filtered and solid was washed with 500 ml of dichloromethane. The filtrate was washed with water. Filtrate was dried over anhydrous sodium sulfate. Dried organic layer was then concentrated to its half volume where upon solid was precipitated. The solid was filtered and washed with 300 ml of dichloromethane. Clear organic filtrate was concentrated to dryness to provided an oily mass. Oily mass was triturated with diethyl ether (4 L) to provide white solid. The solid was filtered under suction and washed with diethyl ether (1 L) to provide title compound in 415 g (94%) quantity.

Method-2: To a mixture of triethylamine (98.0 ml) and N-tert-butoxycarbonyl-L-alanine (110 g) in tetrahydrofuran (1050 ml) and N,N-dimethyl formamide (350 ml) mixture, was added 2,4,6-trichlorobenzoyl chloride (100 ml). The resultant mixture was stirred at a temperature -5 to 0 °C for 5 h. To the > reaction mixture 4-N,N-dimethylamino pyridine (24g) and (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid (70 g) was added. The reaction mixture was stirred for additional 7 h at -5 to 0 0C temperature. The suspension was filtered at room temperature and the filtrate was extracted with ethyl acetate after addition of water. The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 85 g quantity.

Method-3: To a solution N-tert-butoxycarbonyl-L-alanine (7.9 g) in tetrahydrofuran (75 ml) and N,N-dimethyl formamide (25 ml) mixture at -10 to 0°C was added methanesulfonyl chloride (2.42 ml) dropwise. To the above solution triethylamine (8.7 ml) was added dropwise over 5 min. the reaction was stirred for 1.5 h maintaining the temperature between at -10 to 0 0C. To the reaction mixture (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l- yl)-5-methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (5.01 g) and 4-N5N- dimethylamino pyridine (1.70 g) was added. The reaction mixture was stirred for additional 1 h at -5 to 0 °C temperature. The suspension was filtered at room temperature and the filtrate was diluted with water (300 ml) and extracted with ethyl acetate (150 ml x 2). The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 6.38 g (86%) quantity.

Example-2

Preparation of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-L-alaninyl-oxy-piperidin-l-yl)-5-methyl- l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid methanesulfonic acid salt:

To a mixture of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-N-tert-butoxycarbonyl-L-alaninyloxy- piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid (415 g) in acetone (4.5 L) was charged methanesulfonic acid (66 ml). Reaction mixture was stirred at 65-67 °C temperature for overnight. The suspension was filtered at 40-45 0C. Solid was washed with acetone (1.5 L) followed by diethyl ether (1.5 L). Off white solid was dried under 40 to 45 mm vacuum at 55-60 °C temperature over the period of 3-4 h. Title compound was obtained as a free flowing off white material 383.0 g (93%).

For MF: C23H30FN3O8S, MS (ES+) m/z 432 (obtained as free base for MF: C22H26FN3O5);

M.P. 278.50 0C by DSC

PATENT

WO 2000068229
A S-(-)-optically pure benzoquinolizine carboxylic acid, its derivatives, its pharmaceutically acceptable salts, derivatives, pseudopolymorphs, polymorphs or hydrates thereof of formula I,
Figure imgf000066_0001
Formula I

Patent

WO 2011101710

PATENT

The tablets may optionally be coated with film forming agents and/or pharmaceutically acceptable excipients. Particularly suitable for use are commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® and Eudragit®. The coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 :

Table 1 provides the composition of batches of the present invention.

Table 1

Figure imgf000007_0001

Procedure: The compound of Formula I or pharmaceutically acceptable salts, esters or products thereof, lactose and croscannellose sodium were sifted and dry mixed in a rapid mixer granulator. The above mass was granulated by spraying aqueous solution of povidone. The granules were dried in a fluidized bed drier, sifted and oversize granules were milled in a Quadra mill. The resultant granules were mixed with talc, croscarmellose sodium, microcrystalline cellulose and sodium stearyl fumarate in a double cone blender. The lubricated granules were compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of opadry.

Table 2 provides the dissolution data for the compound of formula I or pharmaceutically acceptable salts, esters or products thereof tablets prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 0.1 N hydrochloric acid (900 ml) was used as a medium. Table 2: Dissolution data

Figure imgf000008_0001
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aChemical name: S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate. bChemical name: S-(–)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3, 3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate. cChemical name: R-(+)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate.
31 Aug, 2014,
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.
Levonadifloxacin arginine salt, WCK 771
RN: 306748-89-0
  • C19-H21-F-N2-O4.C6-H14-N4-O2
  • MW: 534.5855
  • L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)
 WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate
(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate
 L-arginine salt of (S)-nadifloxacin
A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232
CN 102532131, WO 2005023805, WO 2002009758, WO 2001085095, WO 2000068229
WO1991012815A1 * Feb 25, 1991 Sep 5, 1991 Squibb Bristol Myers Co COMPOSITIONS AND METHODS FOR TREATING INFECTIONS CAUSED BY ORGANISMS SENSITIVE TO β-LACTAM ANTIBIOTICS
WO2000068229A2 * May 8, 2000 Nov 16, 2000 S K Agarwal (s)-benzoquinolizine carboxylic acids and their use as antibacterial agents
WO2001085095A2 * May 3, 2001 Nov 15, 2001 Shiv Kumar Agarwal Chiral fluoroquinolizinone arginine salt forms
WO2002009758A2 * Jul 31, 2001 Feb 7, 2002 Satish B Bhawsar Inhibitors of cellular efflux pumps of microbes
EP2062582A1 * Aug 14, 2007 May 27, 2009 Tianjin Hemey Bio-Tech Co., Ltd. The antibiotics composition comprising beta-lactam antibiotics and buffers
US4524073 * Jul 20, 1983 Jun 18, 1985 Beecham Group P.1.C. β-Lactam compounds
US6465428 * Aug 25, 2000 Oct 15, 2002 Aventis Pharma S.A. Pharmaceutical combinations based on dalfopristine and quinupristine, and on cefepime
US20040254381 * Aug 15, 2003 Dec 16, 2004 Day Richard A. Antibiotic compositions and methods of using the same
US20050148571 * Nov 29, 2002 Jul 7, 2005 Nancy Niconovich Method of treating bacterial infections using gemifloxacin or a salt thereof and a betha-Lactam antibiotic
US20090148512 * Apr 17, 2008 Jun 11, 2009 Lannett Co Inc Novel uses of chloramphenicol and analogous thereof
US20090232744 * Feb 26, 2009 Sep 17, 2009 Pari Pharma Gmbh Macrolide compositions having improved taste and stability
WO2002009758A2 * 31 Jul 2001 7 Feb 2002 Satish B Bhawsar Inhibitors of cellular efflux pumps of microbes
US6750224 17 Aug 2000 15 Jun 2004 Wockhardt Limited Antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment

 

Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.

 

///////////keywords  USFDA, Qualified Infectious Disease Product status, Wockhardt,  drugs,  WCK 2349, QIDP

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Levonadifloxacin arginine salt, WCK 771


Figure imgf000005_0001
 STEREOCENTERS SHOWN
Levonadifloxacin arginine salt, WCK 771
S-()-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic Acid l-Arginine Salt Tetrahydrate
 QIDP STATUS BY USFDA
RN: 306748-89-0
  • C19-H21-F-N2-O4.C6-H14-N4-O2
  • MW: 534.5855
  • L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)
 WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate
(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate
 L-arginine salt of (S)-nadifloxacin
S-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[ij]qumorizine-2-carboxylic acid L-arginine salt is a broad-spectrum antibiotic, medically grouped together with the fluoroquinolone class of antibiotics, which is disclosed and claimed in  U.S. patent 6,514,986 B2 as being isolated in a less crystalline anhydrate form and a more crystalline hydrate form.
U.S. patent 6,664,267 describes a crystalline monohydrate form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt that is disclosed as having advantages over the anhydrate and hydrate forms described in US 6,514,986 B2.
SYNTHESIS
A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232………..http://pubs.acs.org/doi/abs/10.1021/jm050035f
Abstract Image

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known “floxacin”. The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(−)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

S-()-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic Acid l-Arginine Salt Tetrahydrate (Crystalline Form) (21). To a three-necked round-bottom flask fitted on an oil bath and equipped with a mechanical stirrer, a thermometer pocket, and a reflux condenser was charged 1 (100 g, 0.278 mol) followed by acetone (300 mL). Stirring was started and to the stirred suspension was charged powderedl-arginine (48.4 g, 0.278 mol) followed by distilled water (250 mL). The reaction mixture was stirred at a temperature between 50 and 60 °C for 1 h to obtain a clear solution. Activated charcoal (3 g) was added to the solution and the solution was filtered hot. To the filtrate was then added acetone (700 mL) and the reaction mixture was allowed to cool to 30−35 °C. The reaction mixture was stirred for an additional 2 h at this temperature. The crystalline solid was filtered under reduced pressure and the wet cake was washed with acetone (100 mL). The resulting solid was dried under vacuum at 65−70 °C to furnish 21 (137 g, 92% yield):
mp 236−240 °C;
1H NMR (DMSO-d6) δ 1.4 (d, 3H, J = 7.0 Hz), 1.5−2.2 (m, 8H), 2.8−4.2 (m, 16H), 4.8 (m, 1H), 7.8 (d, 1H, J = 13.0 Hz), 8.8 (s, 1H). MS (ES+) m/z 535 (M + H).
Anal. (C25H35FN6O6·4H2O) C, H, N. HPLC assay of free base (theoretical free base content) 67.41%, found 67.16%. Estimated l-arginine by HPLC (theoretical l-arginine content) 32.59%, found 32.14%.

S-(−)-Nadifloxacin is S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid (1). Prodrugs and aqueous soluble salts of 1were synthesized and explored for possible use in parenteral or oral formulations………….De Souza, N. J.; Agarwal, S. K.; Patel, M. V.; Bhawsar, S. B.; Beri, R. K.; Yeole, R. D.; Shetty, N.; Khorakiwala, H. F. Chiral Fluoroquinolone Arginine Salt Form. US patent 6,514,986, 2003.

(b) De Souza, N. J.; Deshpande, P. K.; Shukla, M. C.; Mukarram S. M. J.; Kulkarni, D. G.; Rahman, A.; Yeole, R. D.; Patel, M. V.; Gupte, S. V. Crystalline Fluoroquinolone Arginine Salt Form. US patent 6,664,267, 2003.
………………………………………………………….
CN 102532131,

quinolones has now grown to four generations, the first generation to nalidixic acid is represented as the representative of the second generation to PPA, only the Gram-negative bacteria effectively, the third generation is the development of these drugs the peak period, there has been a lot of drugs, and is a broad-spectrum antibiotic, which to norfloxacin, ciprofloxacin and other representatives. The fourth-generation quinolone antibiotics is in the third generation on the basis of a broad spectrum of antibacterial spectrum further expanded to make it available against mycoplasma and chlamydia infections.

[0003] R & D has been relatively popular domestic antibiotics, the most widely used on the market today is the third generation fluoroquinolones. Nadifloxacin developed by the Japanese company Otsuka, belongs to the third-generation quinolone antibacterial drugs, topical treatment of acne and folliculitis. 1993 for the first time in Japan (trade name: Acuatim), 2004 in the German market (trade name: Nadixa), 2005 in China listed (trade name: By Union, ointment).

[0004] nadifloxacin irritation due to its absorption and vascular problems, only made of topical formulations for in vitro Propionibacterium acnes (propionibacterium acnes) caused by acne. Wherein the S-(-) – that is the main role difloxacin isomer, the antibacterial activity of the R-isomer of 64 to 256 times that of racemic 2 times.

[0005] fine that gatifloxacin is S-(-) _ nadifloxacin salt on the basis of the system.Significantly improved solubility nadifloxacin well absorbed by the body, so it retains nadifloxacin broad spectrum antimicrobial, antibacterial activity, especially methicillin-sensitive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus Effective characteristics (Antimicrobial Agents and Chemotherapy, 2004,3188 ~ 31920; J. Med. Chem. 2005 (48), 5232 ~ 5242). Pre-clinical tests prove that the product on the market anti-methicillin-resistant Staphylococcus aureus Antibiotic better compare the efficacy, including vancomycin, trovafloxacin, quinupristin + dalfopristin, linezolid amine.

[0006] fine molecular structure that gatifloxacin following formula:

[0007]

Figure CN102532131AD00031

[0008] S-(-) _ nadifloxacin (C19H21FN2O4) with L-arginine salt, the further improve the play a major role in antibacterial s-(-) – nadifloxacin isomer content, and improved oral bioavailability, so that it can develop an oral or injectable preparations.

[0009] the literature (J. Med. Chem. 2005 (48), 5232 ~ 5242) discloses the synthesis of S_ (_) _ Nadifloxacin-L-arginine salt, S-(-) _ that fluoride gatifloxacin and L-arginine salt in the reaction solvent system, which solvent system is mainly methanol – water system, according to the paper reported in S-(-) – Nadifloxacin-L-arginine salt, yields were and related substances are not high enough.

Example 1

[0026] In equipped with oil bath, magnetic stirrer, thermometer, reflux condenser flask at 25 ° C was added (S) – (-) – nadifloxacin (100. 0g, 278mmol), dioxane ring (300ml), and the reaction solution was added dropwise to the L-arginine 4g, 278mmol) in distilled water (250ml) was added. Then heated to 50_60 ° C stirred 1.5 hours, and then adding activated carbon (3. Og) for 5 minutes, filtered hot, and then added dropwise at 55-60 ° C dioxane (700ml), and the natural cooling to 30 -35 ° C for 2 hours crystallization. The solid was collected by filtration and acetone (IOOml) wash. Dried at room temperature M hours. To give a white solid 137g, yield: 92%.

……………………………………
WO 2005023805,

Example 1

Preparation of the single crystal of S-(- -9-fluoro-6,7-dihvdro-8-(4-hvdroxypiperidin-l-ylV5- methyl-l-oxo-lH,5H-benzo[i,ιlquinolizine-2-carboxylic acid L-arginine salt terahvdrate.

S-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt (1.0 g) was dissolved in a mixture of acetone (40 ml) and water (10 ml) by heating the suspension at 70 °C for 15 minutes. The clear solution thus obtained was left for slow evaporation at room temperature in a beaker covered with a perforated aluminum foil. The crystal formation started after 2 days. Finally the single crystal was selected for X-ray crystal analysis from a cluster left after complete evaporation of the solvent. The ORTEP diagrams are described in Figures 1 and 2.

………………………………………………………………
WO 2002009758,
…………………………………………………
WO 2001085095,

EXAMPLE 1

S-(-)-9-Fluoro-6,7-dihvdro-8-(4-hvdroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo Ti l quinolizine-2-carboxylic acid arginine salt Synthesis of SubstantiaUy CrystaUine product A solution of L-(+)-arginine (48.372 g, 0.278 mole) in distilled water (600 ml) was added dropwise over a period of 30 min to the stirred solution/suspension of finely powdered S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylic acid (100 g, 0.278 mole) in acetone (1250 ml). The obtained clear solution was stirred for 30 min and concentrated on a water bath in vacuum (175 mbar) at 80°C. When product started solidifying, the concentration was carried out in vacuum (50 mbar) at 80°C up to dryness. Hexane (1 liter) was added, the reaction mixture was stirred for 4 hr, the solid thus separated was filtered and dried in vacuum (0.7 mbar) for 12 hrs at 70 °C. Yield 145 g (96.9%), m.p. 238-242 °C, and solubility 6 mg/ml (pH 9.5 buffer solution).

The substantially crystalline S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5- methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt prepared according to Example 1 possesses the following properties: a) Crystalline form, with a degree of crystallinity as determined by X-ray powder diffraction and as shown in Fig. 1. , b) A thermogram as determined by Differential scanning calorimetry and as shown in Fig. 3. c) Particle size measured as mean mass diameter (MMD) of 83.92 μm, as determined by laser diffraction technique. d) Density of 0.51 g/cm3 (untapped) and 0.7 g/cm3 (tapped). e) Hygroscopicity of 0% increase of weight upon storage for 14 days up to 22% relative atmospheric humidity as determined gravimetricaUy. f) A content of moisture water of 0.1 % by weight as determined by titration according to Karl Fischer. g) A content of acetone of 0.014 % by weight as determined by gas chromatography

……………………………………………………..
WO 2000068229

Example 1

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyI-l-oxo-lH,5H-benzo [ij] quinolizine-2-car boxy lie acid anhydrate

Method A

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yI)-5-methyl-l-oxo-lH,5H-benzo [ij] quinoIizine-2-carboxylic acid (3.0 g) obtained according to the process described in literature [K Hashimoto et al., Chem.Pharm.Bull.44, 642-5(1996)] was dissolved in acetonitrile (250 ml) at 85 °C. The resulting clear solution was filtered (to remove if any fibrous material is in suspension). The filtrate was concentrated to 125 ml and left at room temperature for crystallization. The crystals thus separated were filtered and dried in a drying cabinet at 40 °C for 2 hr in vacuum at 50 mm of Hg to obtain constant weight. Yield 2.6 g (86%).

Method B:

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyI-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxyIic acid (2.0 g) obtained according to the process described in literature [K.Hashimoto etal., Chem.Pharm.Bull.44, 642-5(1996)] was dissolved in ethyl alcohol (95 %; 200 ml) at 80 °C. The obtained clear solution was filtered (to remove if any fibrous material is in suspension), concentrated to 100 ml and left for crystallization. The separated solid was Altered and dried in a drying cabinet at 40 °C for 3 hr in vacuum at 50 mm of Hg to obtain constant weight. Yield 1.7 g (85 %).

M.p.258-62 °C, moisture content 0 % (by Karl Fisher method) [CXJD 26 -299°, HPLC purity 99.8%

Example 8

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyI-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylic acid, L-arginine salt 0.75 hydrate

L-(+)-Arginine (0.958 g., 5.5 mmoles) was added in portions to a suspension solution of S- (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinoIizine-2-carboxyIic acid 0.2 hydrate (2.0 g., 5.5 mmole) in methanol (400 ml). The obtained solution was concentrated in vacuum to give the desired product as a yellow solid, which was dried at 50 °C at 50 mm/Hg for 5 hours. Yield 3.0 g. (100%), m.p. 220- 223 °C (dec), m/z 535 (M+H), moisture content 2.3% (by Karl Fisher, required 2.46%), [CIJD 25 -144 ° (1% methanol c=l), solubility 93 mg/ml.

……………………………..

Chemical and Pharmaceutical Bulletin
Vol. 44 (1996) No. 4 P 642-645

https://www.jstage.jst.go.jp/article/cpb1958/44/4/44_4_642/_article

A Practical Synthesis of (S)-(-)-Nadifloxacin : Novel Acid-Catalyzed Racemization of Tetrahydroquinaldine Derivative

(S)-(-)-Nadifloxacin [(S)-(-)-9-fluoro-6, 7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H, 5H-benzo[i, j]quinolizine-2-carboxylic acid, (S)-(-)-OPC-7251], an antibacterial agent, was synthesized from (S)-(-)-5, 6-difluoro-2-methyl-1, 2, 3, 4-tetrahydroquinoline (DFTQ), which was prepared by the optical resolution of recemic DFTQ with 2, 3-di-O-benzoxyl-L-tartaric acid. Racemization of the undesired enantiomer [(R)-(+)-DFTQ] was studied in the presence of various acids and the best result was obtained in the case of methanesulfonic acid. The absolute configuration of (-)-nadifloxacin was determined as S by X-ray crystallographic analysis.

https://www.jstage.jst.go.jp/article/cpb1958/44/4/44_4_642/_pdf   ………..FREE PDF

31 Aug, 2014,
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.
Figure
  1.  Ishikawa, H.; Tabusa, F.; Miyamoto, H.; Kano, M.; Ueda, H.; Tamaoka, H.; Nakagawa, K. Studies on antibacterial agents. I. Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acids. Chem. Pharm. Bull198937, 2103-2108.

    (b) Kurokawa, I.; Akamatsu, H.; Nishigima, S.; Asada, Y.; Kawabata, S. Clinical and Bacteriologic Evaluation of OPC-7251 in Patients with Acne:  A Double Blind Group Comparison Study vs Cream Base. J. M. Acad. Dermatol. 199125, 674−81.

    (c) Morita, S.; Otsubo, K.; Matsubara, J.; Ohtnai, T.; Uchida, M. An Efficient Synthesis of a Key Intermediate towards (S)-(−)-Nadifloxacin. Tetrahedron:  Asymmetry 19956 (1), 245−254.

  2. (7) (a) Patel, M. V.; Gupte, S. V.; Sreenivas, K.; Chugh, Y.; Agarwal, S. K.; De Souza, N. J. S-(−)-Nadifloxacin:  Oral Bioavailbility and Bioefficacy in Mouse Model of Staphylococcal Septicemia. Abstract of Papers40th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 2000; American Society for Microbiology:  Washington, DC, 2000; Poster F-558.

  3. (8) A preliminary version of this work was described in a poster. Deshpande, P. K.; Desai, V. N.; Bhavsar, S. V.; Chaturvedi, N. C.; Ghalsasi, S. A.; Aher, S.; Yeole, R. D.; Pawar, D.; Shukla, M. C.; Patel, M. V.; Gupte, S. V.; De Souza, N. J.; Khorakiwala, H. F. WCK 771A Chiral Benzoquinolizine-2-carboxylic acid Arginine Salt Active against Vancomycin Intermediate Staphylococcus aureus (VISA). Abstract of Papers43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, ChicagoSeptember 2003;American Society for Microbiology:  Washington, DC, 2003; Poster F-430

 Some quinolones introduced for clinical use.

KEY  Levonadifloxacin arginine salt, WCK 771, QIDP

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USFDA grants Qualified Infectious Disease Product status to two Wockhardt drugs WCK 771, WCK 2349.


 
31 Aug, 2014,
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.
Levonadifloxacin arginine salt, WCK 771
RN: 306748-89-0
  • C19-H21-F-N2-O4.C6-H14-N4-O2
  • MW: 534.5855
  • L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)
 WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate
(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate
 L-arginine salt of (S)-nadifloxacin
A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232
CN 102532131, WO 2005023805, WO 2002009758, WO 2001085095, WO 2000068229
WCK 2349
cas 948895-94-1  methane sulfonate
base..706809-20-3
8-[4-(L-Alanyloxy)piperidin-1-yl]-9-fluoro-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid methanesulfonate
WO 2000068229, WO 2002009758, WO 2007102061, WO 2008053295
Shetty, N.M.; Nandanwar, M.B.; Kamalavenkatesh, P.; et al.
WCK 2349: A novel fluoroquinolone (FQ) prodrug-13 week oral (PO) safety profile in cynomolgus monkeys
47th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 17-20, Chicago) 2007, Abst F1-2133a
keywords  USFDA, Qualified Infectious Disease Product status, Wockhardt,  drugs, WCK 771,  WCK 2349, QIDP
aChemical name: S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate. bChemical name: S-(–)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3, 3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate. cChemical name: R-(+)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate.

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Radezolid in phase 2, Rib-X Pharmaceuticals


Antibiotics 02 00500 i017

Radezolid

869884-78-6 cas no

http://www.ama-assn.org/resources/doc/usan/radezolid.pdf

869884-78-6, RX-103, RX-1741, RX-O1_667, Radezolid (USAN/INN),  UNII-53PC6LO35W
Molecular Formula: C22H23FN6O3
Molecular Weight: 438.454823

Rib-X Pharmaceuticals

Phase II completed

N-{[(5S)-3-(2-fluoro-4′-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide

(5S)-N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide

Rib-X Pharmaceuticals has completed two Phase II clinical trials of radezolid for the treatment of pneumonia and uncomplicated skin infections. The trial completion dates were in 2008 and 2009, but to date the Phase III trials have not been initiated [1-6].

 

Radezolid (INN, codenamed RX-1741) is a novel oxazolidinone antibiotic being developed by Rib-X Pharmaceuticals, Inc. for the treatment of serious multi-drug–resistant infections. Radezolid has completed two phase-II clinical trials. One of these clinical trials was for uncomplicated skin and skin-structure infections (uSSSI) and the other clinical trial was for community acquired pneumonia (CAP).

Oxazolidinone antibiotics are a relatively new class of antibacterial agents with activity against a broad spectrum of gram-positive pathogens. The first member of this new class to be commercialized, linezolid, was approved in 2000. Since that time the development of linezolid resistant organisms has prompted efforts to discover more effective members of the oxazolidinone class.

A new family of biaryl oxazolidinone antibacterials with activity against both linezolid-susceptible and -resistant Gram-positive bacteria, as well as certain Gram-negative bacteria has been reported (see Bioorganic & Medicinal Chemistry Letters, 2008, 18, 6175-6178, and PCT Patent Publication WO 2005/019211).

Among the known biaryloxazolidinones is N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-bipheny- l-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, more commonly known as radezolid (RX-1741), currently being developed for multi-drug-resistant infections.

Although a monohydrochloride salt of radezolid was disclosed in PCT Patent Publication WO 2006/133397, there is a continuing need for new salts and polymorphs thereof having improved properties such as solubility to optimize bioavailability on therapeutic administration.

 

Radezolid

Synthesis 1

http://www.google.co.il/patents/WO2005019211A2?hl=iw&cl=en

Scheme A

 

Figure imgf000025_0002

Scheme B illustrates the synthesis of intermediates 7 and 8 of the present invention using Suzuki coupling chemistry between boronic acids and aryl triflates. Boronic ester 6 is treated with an appropriate aryl triflate to yield the BOC-protected biaryl 7. The BOC group of 7 is removed to provide amine 8, an intermediate useful in the synthesis of certain compounds of the present invention.

Scheme B

 

Figure imgf000026_0001

8, R = NH2-HCI Scheme C depicts the synthesis of intermediates 9-13, which are useful in producing certain methoxy-substituted biaryl derivatives of the present invention. Suzuki coupling of boronic ester 6 produces biaryl aldehyde 9, which can be reduced to alcohol 10. Mesylation of 10 yields 11 that can be converted to azide 12. Reduction of azide 12 yields amine 13.

Scheme C

 

Figure imgf000027_0001

Scheme D depicts the synthesis of pyridyl intermediates, which are useful for the synthesis of compounds of the present invention, via similar chemistry to that shown in Scheme C. Coupling of boronic ester 6 to a halopyridine aldehyde produces biaryl aldehyde 14. Aldehyde 14 serves as the precursor to intermediates 15-18 via chemistry described above.

Scheme D

 

Figure imgf000028_0001

Biaryl aldehyde 19 (Scheme E) can be synthesized from a Suzuki coupling of iodide 1 and 4-formylphenylboronic acid. Scheme E illustrates how intermediate aldehydes of type 19, 9, and 14 can be converted via reductive amination chemistry to other amines, such as amines 20-22, which are useful as intermediates for the synthesis of certain compounds of the invention.

Scheme E

 

Figure imgf000028_0002

Scheme F depicts the general synthesis of compounds of type la and lb from amines of type 5, 13, 18, and 20-22. Compounds of type la and lb are synthesized via acylation of amines 5, 13 and 18 and 20-22 with the appropriate acids using, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as the coupling agent. Compounds 4001-4007 were specifically synthesized from amine 5 and the appropriate carboxylic acids. Scheme F

 

Figure imgf000029_0001

Scheme G highlights the synthesis of compounds of general structure II from amines of type 5 and 18. The amine can be acylated with carboxylic acids using EDCI (or other commonly employed peptide coupling reagents known in the art) to afford amides II.

Acid chlorides can be purchased or synthesized and allowed to react with amines 5 and 18, in the presence of bases such as triethylamine, to also produce amides II.

Alternatively, carboxylic acids can be pre-loaded onto a solid polymeric support, such as a tetrafluorophenol containing resin (TFP resin), and reacted with amines to yield amide products of general structure II (such as compounds 4008-4015).

Scheme G

 

Figure imgf000029_0002

Scheme H illustrates the synthesis of compounds of general structure Ilia from amines of type 5, 13, and 18 using reductive amination chemistry. For example, biaryl amine compounds 4016-4028 are synthesized in this manner. Scheme H

 

Figure imgf000030_0001

Scheme I depicts the synthesis of general structure Illb of the present invention from amine intermediate 8. For example, compounds 4029-4031 are synthesized using this reductive amination chemistry.

Scheme I

 

Figure imgf000030_0002

Scheme J shows the synthesis of compounds of general structure IVa and IVb. Amines 20, 21, and 22 can be converted to tertiary amines IVa, such as compounds 4032-4034 and 4036, using standard reductive amination chemistry employed earlier for other derivatives.

This reductive amination chemistry can be employed on biaryl aldehyde intermediates such as 19, 9, and 14 to yield optionally substituted amines of general structure IVb, illustrated by compound 4037.

Scheme J

 

Figure imgf000030_0003

producing compounds of the present invention. Known iodoaryl oxazolidinone intermediate 50 (see U.S. Patent Nos. 5,523,403 and 5,565,571) is coupled to a substituted aryl boronic acid (the Suzuki reaction) to produce biaryl alcohol 51. Mesylate 52, azide 53, and amine 54 are then synthesized using chemistry well known to those skilled in the art. Scheme 1

 

Figure imgf000154_0001

NaN3, DMF, 70 °C

 

Figure imgf000154_0002

 

Figure imgf000154_0003

http://www.google.co.il/patents/WO2005019211A2?hl=iw&cl=en

……………….

NO 2

http://www.google.com/patents/US20100234615

TABLE 1
Compound
Number Structure
1
Figure US20100234615A1-20100916-C00053

Example 1 Synthesis of Compound 1

Compound 1 and its hydrochloride salt are synthesized according to the following Scheme:

 

Figure US20100234615A1-20100916-C00176
Figure US20100234615A1-20100916-C00177

 

4-Methoxybenzyl Azide

1001.

A solution of 4-methoxybenzyl chloride 1000 (51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solid sodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and the resulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature.

The two layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic extracts were washed with H2O (2×200 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2 g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil, which by HPLC and 1H NMR was found to be essentially pure and was directly used in the subsequent reaction without further purifications. For 4-methoxybenzyl azide 1001:

1H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H, ArOCH3), 4.29 (s, 2H, Ar—CH2), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H, J=7.8 Hz).

C-[1-(4-Methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-Methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine

(1003 and 1004).

A solution of 4-methoxybenzyl azide 1001 (61.2 g, 375.5 mmol) in toluene (188 mL) was heated with propargylamine 1002 (commercially available, 30.97 g, 38.6 mL, 563.0 mmol, 1.5 equiv) at 25° C., and the resulting reaction mixture was warmed up to gentle reflux at 100-110° C. for 21 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being concentrated in vacuo to remove the excess amount of propargylamine and solvent.

The oily residue was then treated with 30% ethyl acetate-hexane (v/v, 260 mL), and the resulting mixture was warmed up to reflux and stirred at reflux for 30 min before being cooled down to room temperature for 1 h. The pale-yellow solids were then collected by filtration, washed with 30% ethyl acetate-hexane (v/v, 2×100 mL), and dried in vacuo at 40° C. for overnight to afford the crude, cycloaddition product (78.8 g, 81.75 g theoretical, 96.4%) as a mixture of two regioisomers, C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004), in a ratio of 1.2 to 1 by 1H NMR.

The crude cycloaddition product was found to be essentially pure and the two regioisomers were not separated before being used directly in the subsequent reaction without further purification. For 1003 and 1004:

1H NMR (300 MHz, DMSO-d6) δ 1.82 (br. s, 2H, NH2), 3.72 and 3.73 (two s, 3H, Ar—OCH3), 5.47 and 5.53 (two s, 2H, ArCH2), 6.89 and 6.94 (two d, 2H, J=8.7 Hz, Ar—H), 7.17 and 7.29 (two d, 2H, J=8.7 Hz, Ar—H), 7.58 and 7.87 (two br. s, 1H, triazole-CH); C11H14N4O, LCMS (EI) m/e 219 (M++H) and 241 (M++Na).

4-({tert-Butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-Butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009).

Method A. A solution of the regioisomeric C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004, 20.0 g, 91.74 mmol) in 1,2-dichloroethane (DCE, 280 mL) was treated with 4-formylphenylboronic acid 1005 (commercially available, 12.39 g, 82.57 mmol, 0.9 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)3H, 29.2 g, 137.6 mmol, 1.5 equiv) was then added to the reaction mixture in three portions over the period of 1.5 h at room temperature, and the resulting reaction mixture was stirred at room temperature for an additional 3.5 h.

When TLC and HPLC/MS showed that the reductive animation reaction was complete, the reaction mixture was concentrated in vacuo. The residue, which contained a regioisomeric mixture of 4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid as the reductive animation products (1006 and 1007), was then treated with tetrahydrofuran (THF, 100 mL) and water (H2O, 100 mL).

The resulting solution was subsequently treated with solid potassium carbonate (K2CO3, 37.98 g, 275.2 mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC2O, 20.02 g, 91.74 mmol, 1.0 equiv) at room temperature and the reaction mixture was stirred at room temperature for 2 h. When TLC and HPLC/MS showed that the N-BOC protection reaction was complete, the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) and water (H2O, 100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with H2O (50 mL), 1.5 N aqueous HCl solution (2×100 mL), H2O (100 mL), and saturated aqueous NaCl solution (100 mL), dried over MgSO4, and concentrated in vacuo.

The crude, regioisomeric 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 35.98 g, 37.32 g, 96.4%) was obtained as a pale-yellow oil, which solidified upon standing at room temperature in vacuo.

This crude material was directly used in the subsequent reaction without further purification. For 1008 and 1009:

1H NMR (300 MHz, DMSO-d6) δ 1.32 and 1.37 (two br. s, 9H, COOC(CH3)3), 3.70, 3.73 and 3.74 (three s, 3H, Ar—OCH3), 4.07-4.39 (m, 4H), 5.49 and 5.52 (two s, 2H), 6.70-8.04 (m, 9H, Ar—H and triazole-CH); C23H29BN4O5, LCMS (EI) m/e 453 (M++H) and 475 (M++Na).

Method B. A solution of the regioisomeric C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004, 20.06 g, 92.0 mmol) in tetrahydrofuran (THF, 300 mL) was treated with 4-formylphenylboronic acid (13.11 g, 87.4 mmol, 0.95 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)3H, 29.25 g, 138.0 mmol, 1.5 equiv) was then added to the reaction mixture in three portions over the period of 1.5 h at room temperature, and the resulting reaction mixture was stirred at room temperature for an additional 3.5 h.

When TLC and HPLC/MS showed that the reductive animation reaction was complete, the reaction mixture, which contained a regioisomeric mixture of 4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid as the reductive animation products (1006 and 1007), was then treated with water (H2O, 200 mL).

The resulting aqueous solution was subsequently heated with solid potassium carbonate (K2CO3, 38.0 g, 276 mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC2O, 20.08 g, 92 mmol, 1.0 equiv) at room temperature and the reaction mixture was stirred at room temperature for 2 h. When TLC and HPLC/MS showed that the N-BOC protection reaction was complete, the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) and water (H2O, 100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL).

The combined organic extracts were washed with H2O (50 mL), 1.5 N aqueous HCl solution (2×100 mL), H2O (100 mL), and saturated aqueous NaCl solution (100 mL), dried over MgSO4, and concentrated in vacuo. The crude, 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 38.45 g, 39.50 g, 97.3%) was obtained as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. This crude material was found to be essentially identical in every comparable aspect as the material obtained from Method A and was directly used in the subsequent reaction without further purification.

(5S)-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamic acid tert-butyl ester and (5S)-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamic acid tert-butyl ester

(1011 and 1012).

A suspension of the crude regioisomeric mixture of 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 37.62 g, 83.23 mmol) and N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1010, 28.32 g, 74.9 mmol, 0.90 equiv) in toluene (150 mL) was treated with powder K2CO(34.45 g, 249.7 mol, 3.0 equiv), EtOH (50 mL), and H2O (50 mL) at 25° C.,

and the resulting mixture was degassed three times under a steady stream of Argon at 25° C. Pd(PPh3)(866 mg, 0.749 mmol, 0.01 equiv) was subsequently added to the reaction mixture, and the resulting reaction mixture was degassed three times again under a stead stream of Argon at 25° C. before being warmed up to gentle reflux for 18 h. When TLC and HPLC/MS showed the coupling reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (100 mL) and ethyl acetate (100 mL). The two layers were then separated, and the aqueous layer was extracted with EtOAc (100 mL).

The combined organic extracts were washed with H2O (50 mL), 1.5 N aqueous HCl solution (2×150 mL), H2O (100 mL), and the saturated aqueous NaCl solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residual oil was solidified upon standing at room temperature in vacuo to afford the crude, (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-y]methyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamic acid tert-butyl ester (1011) and (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamic acid tert-butyl ester (1012) as a regioisomeric mixture.

This crude product (43.36 g, 49.28 g theoretical, 88%) was used directly in the subsequent reaction without further purification. For the mixture of 1011 and 10121H NMR (300 MHz, DMSO-d6) δ 1.35 and 1.38 (two br. s, 9H, COO(CH3)3), 1.85 (s, 3H, COCH3), 3.45 (t, 2H, J=5.4 Hz), 3.73 and 3.76 (two s, 3H, Ar—OCH3), 3.79 (dd, 1H, J=6.6, 9.1 Hz), 4.18 (t, 1H, J=9.1 Hz), 4.35-4.43 (m, 4H), 4.73-4.81 (m, 1H), 5.50 (br. s, 2H), 6.90 and 6.98 (two d, 2H, J=8.7 Hz), 7.28 and 7.32 (two d, 2H, J=8.7 Hz), 7.35 (dd, 2H, J=2.2, 8.6 Hz), 7.42 (dd, 1H, J=2.2, 8.6 Hz), 7.49-7.63 (m, 4H, aromatic-H), 7.90 and 7.99 (two br. s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH3); C35H39FN6O6, LCMS (EI) m/e 659 (M++H) and 681 (M++Na).

(5S)-N-{3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide Hydrochloride (1013)

and

(5S)-N-{3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H–[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide Hydrochloride (1014).

A solution of a regioisomeric mixture of (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamic acid tert-butyl ester and (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamic acid tert-butyl ester (1011 and 1012, 37.28 g, 56.65 mmol) in ethyl acetate (EtOAc, 150 mL) and methanol (MeOH, 30 mL) was treated with a solution of 4 N hydrogen chloride in 1,4-dioxane (113.3 mL, 453.2 mmol, 8.0 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 12 h. When TLC and HPLC/MS showed that the N-BOC deprotection reaction was complete,

the solvents were removed in vacuo. The residue was then suspended in 250 mL of 5% methanol (MeOH) in acetonitrile (CH3CN), and the resulting slurry was stirred at room temperature for 1 h. The solids were then collected by filtration, washed with toluene (2×100 mL) and 5% methanol in acetonitrile (2×50 mL), and dried in vacuo to afford a regioisomeric mixture of the crude, (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride and (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 30.0 g, 33.68 g theoretical, 89.1% yield) as off-white crystals in a ratio of 1.2 to 1.

This material was found by 1H NMR and HPLC/MS to be essentially pure and was directly used in the subsequent reactions without further purification. For the regioisomeric mixture of 1013 and 1014:

1H NMR (300 MHz, DMSO-d6) δ 1.84 (s, 3H, COCH3), 3.44 (t, 2H, J=5.4 Hz), 3.71 and 3.74 (two s, 3H, Ar—OCH3), 3.80 (dd, 1H, J=6.6, 9.1 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.23-4.30 (m, 4H), 4.73-4.80 (m, 1H), 5.58 and 5.70 (two s, 2H), 6.88 and 6.93 (two d, 2H, J=8.7 Hz), 7.15 and 7.32 (two d, 2H, J=8.7 Hz), 7.43 (dd, 2H, J=2.2, 8.6 Hz), 7.52-7.62 (m, 6H, aromatic-H), 8.28 (s, 1H, triazole-CH), 8.32 (t, 1H, J=5.8 Hz, NHCOCH3), 9.91 and 10.32 (two br. s, 2H, ArCH2N+H2); C30H31FN6O4, LCMS (EI) m/e 559 (M++H) and 581 (M++Na).

(5S)-N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide hydrochloride (1 hydrochloride salt).

A solution of the crude regioisomeric mixture of (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride and (5S)-1H-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 29.17 g, 49.07 mmol) in trifluoroacetic acid(TFA, 150 mL) was warmed up to 65-70° C., and the resulting reaction mixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotection reaction was complete, the solvents were removed in vacuo.

The residual solids were then treated with ethyl acetate (EtOAc, 100 mL) and H2O (150 mL) before being treated with a saturated aqueous solution of sodium carbonate (30 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 h before the solids were collected by filtration, washed with EtOAc (2×50 mL) and H2O (2×50 mL), and dried in vacuo at 40-45° C. to afford the crude, (5S)-N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl)-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1 as the free base, 18.9 g, 21.49 g theoretical, 87.9%) as off-white powders, which by HPLC/MS and 1H NMR was found to be one pure regioisomer and this regioisomer was found to be identical as the material obtained from deprotection of 1013 alone by the same method.

For 1 as the free base: 1H NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H, COCH3), 3.44 (t, 2H, J=5.4 Hz), 3.74 (s, 2H), 3.77 (s, 2H), 3.79 (dd, 1H, J=6.4, 9.2 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.72-4.81 (m, 1H), 7.39-7.62 (m, 7H, aromatic-H), 7.73 (s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH3), 9.72 (br. s, 2H, ArCH2N+H2), 15.20 (br. s, 1H, triazole-NH); C22H23FN6O3, LCMS (EI) m/e 439 (M++H) and 461 (M++Na).

A suspension of 1 free base (18.0 g, 41.1 mmol) in ethyl acetate (EtOAc, 80 mL), and methanol (MeOH, 20 mL) was treated with a solution of 4.0 N hydrogen chloride in 1,4-dioxane (41.1 mL, 164.4 mmol, 4.0 equiv) at room temperature, and the resulting mixture was stirred at room temperature for 8 h. The solvents were then removed in vacuo, and the residue was further dried in vacuo before being treated with a mixture of 10% methanol in acetonitrile (80 mL). The solids were collected by filtration, washed with 10% MeOH/acetonitrile (2×40 mL), and dried in vacuo to afford 1 hydrochloride salt (18.13 g, 19.50 g theoretical, 93% yield) as off-white crystals.

The crude 1 hydrochloride salt can be recrystallized from acetonitrile and water, if necessary, according to the following procedure: A suspension of the crude 1 hydrochloride salt (50.0 g) in acetonitrile (1250 mL) was warmed up to reflux before the distilled water (H2O, 280 mL) was gradually introduced to the mixture. The resulting clear yellow to light brown solution was then stirred at reflux for 10 min before being cooled down to 45-55° C. The solution was then filtered through a Celite bed at 45-55° C., and the filtrates were gradually cooled down to room temperature before being further cooled down to 0-5° C. in an ice bath for 1 h. The solids were then collected by filtration, washed with acetonitrile (2×50 mL), and dried in vacuo at 40° C. for 24 h to afford the recrystallized 1 hydrochloride salt (42.5 g, 50.0 g theoretical, 85% recovery) as off-white crystals.

For 1: 1H NMR (300 MHz, DMSO-d6) δ 1.86 (s, 3H, COCH3), 3.45 (t, 2H, J=5.4 Hz), 3.84 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=9.1 Hz), 4.24 (br. s, 2H), 4.31 (br. s, 2H), 4.74-4.79 (m, 1H), 7.44 (dd, 1H, J=2.2, 8.6 Hz), 7.57-7.66 (m, 6H, aromatic-H), 8.17 (s, 1H, triazole-CH), 8.30 (t, 1H, J=5.8 Hz, NHCOCH3), 9.72 (br. s, 2H, ArCH2N+H2), 15.20 (br. s, 1H, triazole-NH);

13C NMR (75 MHz, DMSO-d6) δ 22.57, 40.69, 41.50, 47.36, 49.23, 71.85, 105.70 (d, J=28.5 Hz), 114.14 (d, J=2.9 Hz), 122.29 (d, J=13.3 Hz), 128.82 (d, J=3.0 Hz), 130.70, 130.94, 131.0, 131.22, 135.30, 137.92 (br. s), 139.66 (d, J=11.2 Hz), 154.11, 159.13 (d, J=243.5 Hz), 170.19;

C22H23FN6O3—HCl, LCMS (EI) m/e 439 (M++H) and 461 (M++Na).

……………………………..

http://www.sciencedirect.com/science/article/pii/S0960894X0801192X

Full-size image (49 K)

 

 

 

References

  1. Sutcliffe, J.A. Antibiotics in development targeting protein synthesis. Ann. NY Acad. Sci. 20111241, 122–152, doi:10.1111/j.1749-6632.2011.06323.x.
  2. Rib-X. Radezolid. Available online: http://www.rib-x.com/pipeline/radezolid.php#development (accessed on 14 April 2013).
  3. Rib-X Pharmaceuticals, Inc. Safety and efficacy study of oxazolidinone to treat pneumonia. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00640926 (accessed on 14 April 2013).
  4. Rib-X Pharmaceuticals, Inc. Safety and efficacy study of oxazolidinones to treat uncomplicated skin infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00646958 (accessed on 14 April 2013).
  5. Shaw, K.J.; Barbachyn, M.R. The oxazolidinones: Past, present, and future. Ann. NY Acad. Sci. 20111241, 48–70, doi:10.1111/j.1749-6632.2011.06330.x.
  6. Skripkin, E.; McConnell, T.S.; DeVito, J.; Lawrence, L.; Ippolito, J.A.; Duffy, E.M.; Sutcliffe, J.; Franceschi, F. Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance.Antimicrob. Agents Chemother. 200852, 3550–3557, doi:10.1128/AAC.01193-07.

 

Cited Patent Filing date Publication date Applicant Title
US6969726 * Jun 2, 2004 Nov 29, 2005 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
US20050043317 * Jun 2, 2004 Feb 24, 2005 Jiacheng Zhou Biaryl heterocyclic compounds and methods of making and using the same
9-17-2010
BIARYL HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING THE SAME
9-17-2010
Process for the synthesis of triazoles
4-28-2010
BIARYL HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING THE SAME
11-26-2008
Biaryl heterocyclic compounds and methods of making and using the same
10-26-2007
Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
10-12-2007
Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
10-12-2007
Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
12-13-2006
Biaryl heterocyclic compounds and methods of making and using the same
11-30-2005
Biaryl heterocyclic compounds and methods of making and using the same

QIDP Designation for Radezolid for Acute Bacterial Skin and Skin Structure Infections, Community-acquired Bacterial Pneumonia

Rib-X Pharmaceuticals announced that the FDA designated radezolid as a Qualified Infectious Disease Product (QIDP) for the indications of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

The QIDP designation will enable Rib-X to benefit from certain incentives for the development of new antibiotics, including an additional five years of market exclusivity, priority review and eligibility for fast-track status, provided under the new Generating Antibiotic Incentives Now (GAIN) program. GAIN was included in the FDA Safety and Innovation Act (FDASIA), formerly known as PDUFA V, which received bipartisan Congressional support and was signed into law by President Obama in July 2012.

Radezolid has completed two Phase 2 clinical trials with an oral formulation in uncomplicated skin and skin structure infections (uSSSI) and in CABP. A Phase 1 study with an IV formulation was recently completed in healthy subjects. Rib-X recently announced data from a positive Phase 1 IV dosing study conducted in healthy subjects and an in vivo long-term safety study vs. linezolid (ZyvoxPfizer).

Radezolid is a next-generation oxazolidinone with a safety profile permitting long-term treatment of resistant infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

For more information call (203) 624-5606 or visit www.rib-x.com

 

 

 

FINAFLOXACIN IN PHASE II for the treatment of ear infections


FINAFLOXACIN

(S-cyano-1-cyclopropyl-ό-fluoro-T-^aS, 7aS)-hexahydropyrrolo [3,4- b]-1,4-oxazin-6(2H)-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid)

7-[(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]-8-cyano-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid |

BAY-35-3377
BY-377

CAS Registry Number: 209342-40-5

HYD SALT

(-)-(4aS,7aS)-8-Cyano-1-cyclopropyl-6-fluoro-4-oxo-7-(perhydropyrrolo[3,4-b]-1,4-oxazin-6-yl)-1,4-dihydroquinoline-3-carboxylic acid hydrochloride

209342-41-6,

C20 H19 F N4 O4 . Cl H
 MW 434.849

Synonyms: Finafloxacin, UNII-D26OSN9Q4R,

MerLion Pharmaceuticals (Singapore)…POSTER…….http://www.merlionpharma.com/sites/default/files/file/PPS/F1-2036_Wohlert.pdf

H. pylori, Broad-Spectrum

Finafloxacin is a novel fluoroquinolone being developed by MerLion Pharmaceuticals. Under neutral pH conditions (pH 7.2–7.4), the compound has shown in vitro activity equivalent to that of ciprofloxacin. However, under slightly acidic pH5.8 the compound shows enhanced potency.

Other marketed fluoroquinolones, such as ciprofloxacin, levofloxacin and moxifloxacin, exhibit reduced activity at slightly acidic pH 5.0–6.5. This feature of finafloxacin makes the compound suitable for use in the treatment of infections in acidic foci of infections such as urinary tract infections

Finafloxacin hydrochloride, a novel highly potent antibiotic, is in phase III clinical trials at Alcon for the treatment of ear infections. MerLion Pharmaceuticals is evaluating the product in phase II clinical trials at for the treatment of Helicobacter pylori infection and for the treatment of lower uncomplicated urinary tract infections in females.

A quinolone, finafloxacin holds potential for the treatment of Helicobacter pylori infection and urinary tract infection. Unlike existing antibiotics, finafloxacin demonstrates a unique acid activated activity whereby it becomes increasingly active under acidic conditions.

In 2009, a codevelopment agreement was signed between Chaperone Technologies and MerLion Pharmaceuticals. In 2011, finafloxacin hydrochloride was licensed to Alcon by MerLion Pharmaceuticals in North America for the treatment of ear infections.

MerLion Pharmaceuticals has announced that the FDA has granted a Qualified Infectious Disease Product Designation and Fast Track Status for finafloxacin. The company is currently recruiting patients for the Phase II clinical trial of the compound for the treatment of complicated urinary tract infections (cUTI) and/or acute pyelonephritis compared to ciprofloxacin

Finafloxacin and derivatives thereof can be synthesized according to the methods described in U.S. Patent No. 6,133,260 to Matzke et al., the contents of which are herein incorporated by reference in their entirety. The compositions of the invention are particularly directed toward treating mammalian and human subjects having or at risk of having a microbial tissue infection. Microbial tissue infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., “The Sanford Guide to Antimicrobial Therapy 2007” 37 Edition (Antimicrobial Therapy, Inc.). Particular microbial tissue infections that may be treatable by embodiments of the present invention include those infections caused by bacteria, protozoa, fungi, yeast, spores, and parasites.

 

SYNTHESIS

WO1998026779A1

http://www.google.sc/patents/WO1998026779A1   COPY PASTE ON BROWSER

 8-cyano-l-cyclopropyl-6-fluoro-7-((lS, 6S)-2-oxa-5 ,8-di-azabicyclo [4.3.0] non-8-yl)-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

The compounds, which are suitable for use in the invention are known already to some extent in EP-A-0350733, EP-A-0550903 as well as from DE-A-4329600 or can be prepared according to the processes described in .

If, for example 9,10-difluoro-3 ,8-dimethyl-7-oxo-2 ,3-dihydro-7H-pyrido [l ,2,3-d, e] [l, 3,4] benzoxadiazine-6 -carboxylic acid and 2-oxa-5 ,8-diazabicyclo [4.3.0] nonane, the reaction can be represented by the following equation:

Figure imgf000012_0001

The 7-halo-quinolonecarboxylic acid derivatives used for preparing the compounds of Fomel (I) of the invention are known or can be prepared by known methods. Thus, the 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid, or of the 7-chloro-8-cyano-l-cyclopropyl-6-fluoro- l been ,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester described in EP-A-0 276 700th The corresponding 7-fluoro derivatives can be, for example, via the following reaction sequence to build:

 

Figure imgf000012_0002

An alternative process for preparing the intermediate compound 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride as the starting material for the preparation of 7-chloro-

8-cyano-1-cyclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid is used (EP-A-0276700) and in the 3-cyano-2 ,4,5-trifluoro- benzoyl can be converted, is based on 5-fluoro-l ,3-xylene, 5-fluoro-l ,3-xylene, in the presence of a catalyst under ionic conditions in the nucleus disubstituted to 2,4-dichloro-5-fluoro-l ,3-dimethylbenzene, and this is subsequently chlorinated chlorinated under free radical conditions in the side chains of 2,4-dichloro-5-fluoro-3-dichloromethyl-l-trichloro-methylbenzene. This is the 2,4-dichloro-5-fluoro-3-dichloromethyl-benzoic acid to give 2,4-dichloro-5-fluoro-3-formyl-benzoic acid, and then hydrolyzed to 2,4-dichloro-5-fluoro-3 N-hydroxyiminomethyl acid implemented. By treatment with thionyl chloride, 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride is obtained, which can still be ,4,5-trifluoro-ben-zoylfluorid converted by a chlorine / fluorine exchange on-3-cyano-2 .

 

Figure imgf000013_0001

 

Figure imgf000013_0002

 

Figure imgf000013_0003

The amines used for the preparation of compounds of formula (I) according to the invention are known from EP-A-0550903, EP-A-0551653 as well as from DE-A-4 309 964th

An alternative to the synthesis of lS, 6S-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane-dihydro-drobromid or the free base 1 S, 6S-2-oxa-5 ,8-diazabicyclo [4.3.0 ] nonane and the corresponding IR, 6R enantiomer provides the following path represents:

Starting material for this synthesis is the cis-l ,4-dihydroxy-2-butene, which is converted to the bis-mesylate with mesylation tosylamide for 1-tosylpyrrolidine. This is converted into the epoxide m-chloroperbenzoic. The ring opening of the epoxide by heating in isopropanol with ethanolamine to trans-3-hydroxy-4 – (2-hydroxy-ethylamino)-l-(toluene-4-sulfonyl)-pyrrolidine in 80% yield. Tetrahydrofuran is then in pyridine / reacted with tosyl chloride, with cooling to Tris-tosylate, which as a crude product in a mixture with some tetra-tosyl derivative with basichen reaction conditions to give the racemic trans-5 ,8-bis-tosyl-2-oxa-5, 6 – diazabicyclo [4.3.0] nonane is cylisiert. At this stage occurs with high selectivity of a chromatographic resolution kieselgelgebundenem poly (N-methacryloyl-L-leucine-d menthylamide) as the stationary phase. The desired enantiomer, (lS, 6S) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] nonane, is of a purity of

> 99% ee. Cleavage of the p-tosyl protecting groups is carried out with HBr-acetic acid to the lS, 6S-2-Oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydrobromide, the one with a base such as sodium or potassium hydroxide or with the aid of ion exchanger can be converted into the free base. The analogous sequence may be used for the preparation of lR, 6R-2-Oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydrobromide.

 

Figure imgf000014_0001
Figure imgf000015_0001

HBr / AcOH

 

Figure imgf000015_0002

Synthesis of lS, 6S-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane

Examples of compounds of the invention are mentioned in addition to the compounds listed in the preparation examples, the compounds listed in Table 1 below, which can be used both in racemic form as well as enantiomerically pure or diastereomerically pure compounds. Table 1:

 

Figure imgf000016_0001

 

Figure imgf000016_0002

Example 1 Z

8-cyano-1-cyclopropyl-6 ,7-difluoro-1 ,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester

 

Figure imgf000020_0001

a 3-bromo-2 ,4,5-trifluoro-benzoate

To a mixture of 1460 ml of methanol and 340 g of triethylamine, 772 g of 3-bromo-2 ,4,5-trifluoro-benzoyl fluoride was added dropwise under ice cooling. There is one

Stirred for an hour at room temperature. The Reaktionsgemsich is concentrated, the residue dissolved in water and methylene chloride, and the aqueous phase was extracted with methylene chloride. After drying the organic phase over sodium sulfate, concentrated, and the residue was distilled in vacuum. This gives 752.4 g of 3-bromo-2 ,4,5-trifluoro-benzoic acid methyl ester of boiling point 122 ° C/20 mbar.

b. 3-Cyano-2 ,4,5-trifluoro-benzoic acid methyl ester:

269 ​​g of 3-bromo-2 ,4,5-trifluoro-benzoic acid methyl ester and 108 g of copper cyanide are heated to reflux in 400 ml of dimethylformamide for 5 hours. , All volatile components of the reaction mixture are then distilled off in vacuo. The distillate was then fractionated on a column. This gives 133 g of 3-cyano-2 ,4,5-trifluoro-benzoate of boiling point 88-89 ° C / 0.01 mbar.

c. 3-Cyano-2 ,4,5-trifluoro-benzoic acid

A solution of 156 g of 3-cyano-2 ,4,5-trifluoro-benzoate in 960 ml of glacial acetic acid, 140 ml of water and 69 ml concentrated sulfuric acid is heated for 8 hours under reflux. Then the acetic acid is distilled off under vacuum and the residue treated with water. Of failed-ne solid is filtered off, washed with water and dried. Obtained

118.6 g of 3-cyano-2 ,4,5-trifluoro-benzoic acid as a white solid, mp 187-190 ° C.

d 3-cyano-2 ,4,5-trifluoro-benzoyl chloride:

111 g of 3-cyano-2 ,4,5-trifluoro-benzoic acid and 84 g of oxalyl chloride are stirred in 930 ml of dry methylene chloride with the addition of a few drops of dimethylformamide for 5 hours at room temperature. The methylene chloride is evaporated and the residue distilled in vacuo. This gives 117.6 g of 3-cyano-2 ,4,5-trifluoro-benzoyl chloride as a yellow oil.

e 2 – (3-cyano-2 ,4,5-trifluoro-benzoyl)-3-dimethylamino-acrylic acid ethyl ester:

To a solution of 36.5 g of 3-dimethylamino-acrylate and 26.5 g of triethylamine in 140 ml toluene, a solution of 55 g 3-cyano-2, 4,5 – trifluoro-benzoyl chloride are added dropwise in 50 ml of toluene so that the temperature 50-55 ° C remains. Then stirred for 2 hours at 50 ° C.

The reaction mixture is concentrated in vacuo and used without further

Processing used in the next step. f 2 – (3-cyano-2 ,4,5-trifluoro-benzoyl)-3-cyclopropylamino-acrylic acid ethyl ester:

To the reaction product of step e 30 g of glacial acetic acid are added dropwise at 20 ° C. A solution of 15.75 g of cyclopropyl amine in 30 ml of toluene is added dropwise. The mixture is stirred at 30 ° C for 1 hour. Are then added 200 ml of water, stirred 15 minutes, the organic phase is separated off and shakes it again with 100 ml of water. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained is a set-without further purification in the next step.

g 8-cyano-l-cyclopropyl-6 ,7-difluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester:

The reaction product from stage f and 27.6 g of potassium carbonate are stirred in 80 ml dimethylformamide for 16 hours at room temperature. The reaction mixture is then poured into 750 ml ice water, the solid filtered off with suction and washed with 80 ml cold methanol. After drying, 47 g of 8 – cyano-l-cyclopropyl-6 ,7-difluoro-l ,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester, mp 209-211 ° C.

Example 2 Z

2,4-dichloro-5-fluoro-l ,3-dimethylbenzene

 

Figure imgf000023_0001

a solvent-free

In 124 g of 3,5-dimethyl-fluorobenzene 1 g of anhydrous iron (III) chloride are pre-loaded and launched with the speed of chlorine (about 4 h), with which the reaction. This is initially slightly exothermic (temperature increase from 24 to 32 ° C) and is maintained by cooling below 30 ° C. After addition of 120 g of chlorine, the mixture is determined. According to GC analysis are 33.4% monochloro compound, formed 58.4% desired product and 5%> overchlorinated connections. The hydrogen chloride is removed and the reaction mixture is then distilled in a column in a water jet vacuum:

In the run 49 g of 2-chloro-5-fluoro-l ,3-dimethylbenzene obtained at 72-74 ° C/22 mbar. After 5 g of an intermediate fraction proceed at 105 ° C/22 mbar 75 g of 2,4 – dichloro-5-fluoro-l ,3-dimethylbenzene via, Melting range: 64 – 65 ° C.

b in 1,2-dichloroethane

1 kg of 3,5-dimethyl-fluorobenzene and 15 g of anhydrous iron (III) chloride are placed in 1 1 1 ,2-dichloroethane and chlorine is introduced in the same extent as the reaction proceeds (about 4 h). The reaction is initially exothermic (temperature rise from 24 to 32 ° C) and is kept below 30 ° C by cooling. After the introduction of 1200 g of chlorine are according to GC analysis 4% monochloro compound, 81.1% and 13.3% desired product overchlorinated connections emerged. After distilling off the solvent and the hydrogen chloride is distilled in a column in a water jet vacuum:

In the run 40 g of 2-chloro-5-fluoro-l ,3-dimethylbenzene receive. After some intermediate run going at 127-128 ° C/50 mbar 1115 g of 2,4-dichloro-5-fTuor-l ,3-dimethyl-ethylbenzene over.

Example 3 Z

2,4-dichloro-5-fluoro-3-dichloromethyl-l-trichloromethylbenzene

 

Figure imgf000024_0001

In a photochlorination using chlorine inlet and outlet for the hydrogen chloride to a scrubber and a light source in the vicinity of the chlorine inlet tube, 1890 g of 2,4-dichloro-5-fluoro-l ,3-dimethylbenzene pre-loaded and at 140 to 150 ° C. Chlorine metered. Within 30 hours 3850 g of chlorine are introduced. The content of the desired product according to GC analysis is 71.1% and the proportion of connections minderchlorierten 27.7%. The DestiUaton a 60 cm column with Wilson spirals provides a flow of 1142 g, which can be reused in the chlorination. The main fraction at 160-168 ° C / 0.2 mbar gives 2200 g of 2,4-dichloro-5-fluoro-3-dichloromethyl-l-trichloro-methyl benzene having a melting range of 74-76 ° C. After one recrystallization

Sample from methanol, the melting point 81-82 ° C.

Example Z 4

2,4-dichloro-5-fluoro-3-formyl-benzoic acid

 

Figure imgf000025_0001

In a 2500 ml stirred apparatus with gas discharge are presented 95% sulfuric acid at 70 ° C. and under stirring, 500 g of molten added dropwise 2,4-dichloro-5-fluoro-3-dichloromethyl-1 trichloromethylbenzene. It is after a short while hydrochloric development. Is metered during a 2 h and stirred until the evolution of gas after. After cooling to 20 ° C., the mixture is discharged ice to 4 kg and the precipitated solid is filtered off with suction. The product is after-washed with water and dried.

Yield: 310 g, melting range: 172-174 ° C

Example Z 5

2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid

 

Figure imgf000026_0001

In a stirred reactor 80 g of hydroxylamine hydrochloride in 500 ml of ethanol are charged and added dropwise 200 ml of 45% strength sodium hydroxide solution and then with 40 – 200 g of 2,4-dichloro-5-fluoro-3-formyl-benzoic acid added 45.degree.The reaction is slightly exothermic and it is stirred for 5 h at 60 ° C. After cooling to

Room temperature is provided by the dropwise addition of hydrochloric acid to pH <3, the product taken up in tert-butyl methyl ether, the organic phase separated and the solvent distilled off. The residue obtained 185 g of 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl benzoic acid, melting range: 190 – 194 ° C.

Example No. 6

2,4-dichloro-3-cyano-5-benzoyl-fιuor

 

Figure imgf000026_0002

In a stirred vessel with metering and gas outlet via a reflux condenser to a scrubber 600 ml of thionyl chloride are introduced and registered at 20 ° C. 210 g of 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl benzoic acid in the proportion as hydrochloric developed and sulfur dioxide. After the addition the mixture is heated until the gas evolution under reflux. Mixture is then distilled, and boiling in the range of 142-145 ° C/10 mbar, 149 g of 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride (98.1% purity by GC) Melting range: 73-75 ° C.

Example No. 7

3-Cyano-2 ,4,5-trifluoro-benzoyl

 

Figure imgf000027_0001

50 g of potassium fluoride are suspended in 120 ml of tetramethylene sulfone and at 15 mbar for drying distilled (ca. 20 mL).Then, 50.4 g of 2,4 – dichloro-3-cyano-5-fluoro-benzoyl chloride was added and stirred at an internal temperature with exclusion of moisture for 12 hours at 180 ° C. Are removed by vacuum distillation to 32.9 g of 3-cyano-2 ,4,5-trifluoro-benzoyl fluoride in the boiling range of 98 –

Obtain 100 ° C/12 mbar.

Example No. 8

3-Cyano-2 ,4,5-trifluoro-benzoyl chloride

 

Figure imgf000027_0002

76.6 g of 3-cyano-2 ,4,5-trifluoro-benzoyl fluoride together with 1 g of anhydrous

Aluminum chloride introduced at 60-65 ° C and then added dropwise 25 g of silicon tetrachloride gas in the course of development. After the evolution of gas at 65 ° C is distilled in a vacuum. Boiling range 120-122 ° C/14 mbar, 73.2 g of 3 – cyano-2 ,4,5-trifluoro-benzoyl chloride over.

Example No. 9

1 – (toluene-4-sulfonyl-pyrroline

 

Figure imgf000028_0001

In a 20 1 HC4-HWS boilers are 2.016 kg (17.6 mol)

Submitted methanesulfonyl chloride in dichloromethane and 12 1 at -10 ° C internal temperature under strong cooling (-34 ° C) solution of 705 g (8.0 mol) of 2-butene-l ,4-diol in 1.944 kg (2.68 1 , 19.2 mol) of triethylamine was added dropwise over 30 minutes. A yellow suspension stirred for 1 hour at -10 ° C and then treated with 4 1 of water, the temperature rises to 0 ° C.The suspension is warmed to room temperature, stirred for 10 minutes at room temperature and then fed in a 30 1 separating funnel. The phases are stirred separately (good phase separation) and the aqueous phase extracted with 2 1 of dichloromethane. The combined dichloromethane phases are presented in a pre-cooled 20 1 HC4 vessel and kept at 0 ° C.

In another 20-1 HC4 boiler distillation 1.37 kg (8.0 mol) toluenesulfonamide be submitted in 6 1 toluene. It is mixed with 3.2 kg of 45% sodium hydroxide solution, 0.8 1 of water and 130.5 g Tetrabutylammomiimhydrogensulfat, heated to 40 ° C maximum temperature inside and creates a vacuum. Then, the previously obtained

Dichloromethane (15.2 1) was added dropwise over 1.5 hours while the dichloromethane was removed by distillation at 450 mbar (bath temperature: 60 ° C). During the distillation is foaming. In the end, a solution is available at an internal temperature of 33-40 ° C. After the addition of dichloromethane is distilled off, until barely distillate is (duration: about 85 minutes; internal temperature 40 ° C at 60 ° C bath temperature at the end). The vessel contents will be warm transferred to a separating funnel and rinsed the tank with water and 5 1 2 1 toluene at 50 ° C. Before phase separation, the solids are extracted in the intermediate phase and washed with 0.5 1 of toluene. The organic phase is extracted with 2.4 1 of water, separated and evaporated to dryness on a rotary evaporator. The solid residue (1758 g) is suspended in 50 ° C bath temperature in 1.6 1 of methanol, the suspension is transferred into a 10 1-flanged flask and the flask rinsed with diisopropyl 2,4 1. The mixture is heated to reflux temperature (59 ° C) and stirred for 30 minutes under reflux. The suspension is cooled to 0 ° C., stirred at 0 ° C for 1 hour and extracted with 0.8 1 of a cold mixture of ether Methanol/Diisopropyl-: washed (1 1.5). The crystals are dried under a nitrogen atmosphere at 50 ° C/400 mbar.

Yield: 1456 g (81.5% of theory)

Example Z 10

3 – (toluene-4-sulfonylV6-oxa-3-aza-bicvclo [3.1.0] hexane

o “|” h “CH3

334.5 g (1.5 mol) of l-(toluene-4-sulphonyl)-pyrroline are dissolved in 1.5 1 of dichloromethane at room temperature and over 15 minutes with a suspension of 408 g (approx. 1.65 to 1, 77 mol) of 70-75% m-chloroperbenzoic acid in 900 ml of dichloromethane (cools added in manufacturing from). The mixture is heated under reflux for 16 hr (test for

Peroxide with KI / starch paper shows yet to peroxide), the suspension was cooled to 5 ° C, sucks the precipitated m-chlorobenzoic acid and washed with 300 ml of dichloromethane (peroxide with Precipitation: negative; precipitate was discarded). The filtrate is to destroy excess peroxide with 300 ml of 10% sodium sulfite solution, washed twice (test for peroxide runs now negative), extracted with 300 ml of saturated sodium bicarbonate solution, washed with water, dried with sodium sulfate and about a quarter of the volume evaporated. Again on test peroxide: negative. The mixture is concentrated and the solid residue is stirred with ice cooling, 400 ml of isopropanol, the precipitate filtered off and dried at 70 ° C in vacuum.

Yield: 295 g (82.3%),

Mp: 136-139 ° C,

TLC (dichloromethane methanol 98:2): 1 HK (Jodkammer)

Example CLOSED

trans-3-Hydroxy-4-(2-hydroxy-ethylamino-l-(‘toluene-4-sulfonyl’) pyrrolidine

 

Figure imgf000030_0001

643.7 g (2.65 mol) 3 – (Toluoι-4-sulfonyl)-6-oxa-3-aza-bicyclo [3.1.0] hexane to 318.5 ml with ethanolamine in 4 1 of isopropanol at reflux for 16 hours cooked. After TLC monitoring, further 35.1 ml (total 5.86 mol) of ethanolamine added to the mixture and boiled again until the next morning. The mixture is filtered hot with suction and the filtrate concentrated on a rotary evaporator to 3.5 ltr. After seeding and stirring at room temperature for 3.5 1 diisopropyl ether are added, and stirred at 0 ° C for 6 hours. The precipitated crystals are filtered off, with 250 ml of a mixture of isopropanol / diisopropyl ether (1: 1) and washed 2 times with 300 ml of diisopropyl ether and dried overnight under high vacuum.

Yield: 663.7 g (83% of theory), content: 96.1% (area% by HPLC). Example Z 12

trans-toluene-4-sulfonic acid {2 – [[4-hydroxy-l-(toluene-4-sulfonyl)-pyrrolidin-3-yl] – ftoluol-4-sulfonyl)-amino]-ethyl ester)

 

Figure imgf000031_0001

552 g (1.837 mol) of trans-3-hydroxy-4-(2-hydroxy-ethylamino)-l-(toluene-4-sulfonyl) – pyrrolidine are dissolved under argon in 1.65 1 tetrahydrofuran and 0.8 1 of pyridine dissolved and at -10 ° C in portions 700 g (3.675 mol) p-toluenesulfonyl chloride are added thereto. The mixture is then stirred at this temperature for 16 hours. The work is done by adding 4.3 18.5 1% aqueous hydrochloric acid, extraction twice with dichloromethane (3 1, 2 1), washing the combined organic phases with saturated Natriurnhydrogencarbonatlösung (3 1, 2 1), drying over sodium sulfate, extracting and distilling off the solvent in vacuo. The residue is dried overnight at the oil pump and crude in the next reaction. There were 1093 g as a hard foam (content [area% by HPLC]: 80% Tris-tosyl-product and 13% tetra-tosyl-product, yield see next step). Example Z 13

rac. trans-5 ,8-bis-tosyl-2-oxa-5 .6-diazabicyclor4 .3.01 nonane

 

Figure imgf000032_0001

1092 g of crude trans-toluene-4-sulfonic acid {2 – [[4-hydroxy-l-(toluene-4-sulfonyl) – pyrrolidin-3-yl] – (toluene-4-sulfonyl)-amino]-ethyl} were dissolved in tetrahydrofuran and 9.4 1 at 0-3 ° C with 1.4 1 of a 1.43 molar solution of sodium hydroxide in

Methanol reacted. After half an hour at this temperature, 2.1 1 of water and 430 ml of diluted (2:1) was added to the mixture and acetic acid with previously isolated crystals of trans-toluene-4-sulfonic acid {2 – [[4-hydroxy-l – (toluene-4-sulfo-phenyl)-pyrrolidin-3-yl] – (toluene-4-sulfonyl)-amino] ethyl}-seeded. The suspension is stirred overnight at 0 to -4 ° C. The next morning, the crystals are filtered off, washed twice with 400 ml of cold mixture of tetrahydrofuran / water (4:1) and dried at 3 mbar at 50 ° C overnight.

Yield: 503 g of white crystals (62.7%> of theory over 2 steps), content: 99.7% (area% by HPLC). Example Z 14

Preparative chromatographic resolution of racemic rac. trans-5.8-bis-tosyl-2-oxa-5.6-diazabicyclor4.3.0] nonane

The chromatography of the racemate at room temperature in a column (inner diameter 75 mm), which with 870 g of a chiral stationary phase (kie-selgelgebundenes poly (N-methacryloyl-L-leucine-d menthylamide) based on the mer captomodifizierten silica Polygosil 100 , 10 microns; see EP-A 0 379 917) is filled (bed height: 38 cm). Detection is carried out using a UV detector at 254 nm

For the sample application using a solution of a concentration of 100 g of rac. trans-5 ,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] nonane in 3000 ml of tetrahydrofuran. A Trenncyclus is carried out under the following conditions: with the aid of a pump is required for 2 min at a flow of 50 ml / min, a part of the sample solution and the same time at a flow rate of 50 ml / min, pure n-heptane to the column.

Thereafter eluted at a flow rate of 100 ml / min 18 minutes with a mixture of n-Heptan/Tetrahydrofuran (3/2 vol / vol). This is followed for 3 minutes at a flow of 100 ml / min elution with pure tetrahydrofuran. Thereafter, further eluted with n-Heptan/Tetrahydro-furan (3/2 vol / vol). This cycle is repeated several times.

The first eluted enantiomer is the (lS, 6R) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo-[4.3.0] nonane, which is isolated by concentration. The eluate of the more retarding enantiomers is largely evaporated in vacuo, and the precipitated crystals are filtered off with suction and dried. From the separation of 179 g of racemate in this

As 86.1 g (96.2% of theory) of the enantiomer (lS, 6S) -5,8-bis-tosyl-2-oxa-5, 6 – diazabicyclo [4.3.0] nonane having a purity of> 99 % ee. Example Z 15

(LR, 6R-2-oxa-5.6-diazabicvclo [4.3.0] nonane dihydrobromide

 

Figure imgf000034_0001

38.3 g (87 mmol) of (lS, 6R) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] nonane in 500 ml of 33 -% HBr / glacial acetic acid 10 g added anisole and heated for 4 hours at 60 ° C (bath). After standing overnight, the suspension is cooled, the precipitate filtered, with

100 ml of abs. Ethanol and dried at 70 ° C under high vacuum.

Yield: 23.5 g (93%) of white solid product, mp 309-310 ° C (dec.), DC (dichloromethane/methanol/17% aq ammonia 30:8:1.): 1 HK

[Α] D: + 0.6 ° (c = 0.53, H 2 O) (fluctuating).

Example Z 16

(LS.6S-2-oxa-5.6-diazabicvclor4.3.01nonan-Dihvdrobromid

 

Figure imgf000034_0002

Z is analogous to Example 15 from (lS, 6S) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] no-nan (1S, 6S)-2-oxa-5, 6-diazabicyclo [4.3.0] nonane dihydrobromide receive. Example Z 17

(1 R.6R-2-oxa-5.8-diazabicvclo [4.3.Olnonan

 

Figure imgf000035_0001

1 Method: 5,8 g (20 mmol) of (lS, 6R)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydro-drobromid are suspended in 100 ml of isopropanol at room temperature with 2.4 g ( 42.9 mmol) and powdered potassium hydroxide while leaving about 1 hour in an ultrasonic bath. The suspension is cooled in an ice bath, filtered, washed with isopropanol and the undissolved salt, the filtrate was concentrated and distilled in a Kugelrohr oven at 150-230 ° C oven temperature and 0.7 mbar. Obtained 2.25 g (87.9% of theory) of a viscous oil which crystallizes. [Α] D -21.3 ° (c = 0.92, CHC1 3) Accordingly, this reaction can be carried out in ethanol.

2 Method: A homosexual genie catalyzed mixture of (lR, 6R)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydrobromide and 620 mg (11 mmol) of powdered potassium hydroxide is dry in a Kugelrohr apparatus at 0.2 mbar and increasing oven temperature to 250 ° C distilled. Obtained 490 mg (76.6% of theory) of (lR, 6R) -2 – oxa-5 ,8-diazabicyclo [4.3.0] nonane as a viscous oil which slowly crystallized.

3 Method: 100 g of moist, pretreated cation exchanger (Dowex 50WX, H + – form, 100-200 mesh, capacity: 5.1 meq / g of dry or 1.7 meq / mL) are charged into a column with about 200 ml 1 N HC1 activated and washed neutral with water 3 1. A solution of 2.9 g (10 mmol) of (lS, 6R)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane

Dihydrobromide in 15 ml of water is added to the ion exchanger, and then washed with 2 1 water, and eluted with approximately 1 1 1 N ammonia solution. The eluate is evaporated. concentrated. Yield: 1.3 g of a viscous oil (quantitative), DC (dichloromethane/methanol/17% NH 3 30:8:1): 1 HK, GC: 99.6% (area).

Example Z 18

(LS.6SV2-oxa-5.8-diazabicvclor4.3.01nonan

 

Figure imgf000036_0001

Z is analogous to Example 17 from (lS, 6S)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane-di-hydrobromide the free base (lS, 6S)-2-oxa-5 ,8-diazabicyclo [ 4.3.0] nonane made.

Example Z 19

2 – (2,4-dichloro-3-cyano-5-fluoro-benzoyl)-3-dimethylamino-acrylic acid ethyl ester

 

Figure imgf000036_0002

To a solution of 626 g (4.372 mol) of 3-dimethylamino-acrylate and 591 g (4.572 mol) of ethyl-diisopropyl-amine (Hunigs base) in 1060 ml of dichloromethane, a solution of 1075 g starting at room temperature 2,4-dichloro -3-cyano-5-fluoro-benzoyl chloride (94% pure, corresponding to 1010.5 g = 4.00 mol) was dropped in 850 ml of dichloromethane. The temperature rises to 50-55 ° C (dropwise addition about 90 minutes). Then stirred for 2 hours at 50 ° C and the reaction mixture was used without further purification in the next step.

Example Z 20

2 – (2,4-dichloro-3-Cyano-5-fluoro-benzoyl-3-cvclopropylamino-acrylate

 

Figure imgf000037_0001

To the reaction mixture from the above step 306 g (5.1 mol) of glacial acetic acid are added dropwise under cooling at about 15 ° C. Then, with further cooling at 10-15 ° C. 267.3 g (4.68 mol) of cyclopropyl amine is added dropwise. Immediately after which the reaction mixture is mixed with 1300 ml of water under ice-cooling and 15 minutes stirred well. The dichloromethane layer was separated and used in the next step.

Example 21 Z

7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1.4-dihydro-4-oxo-3-chinolincarbonsäureethyl ester

 

Figure imgf000038_0001

To a heated to 60-70 ° C suspension of 353 g (2.554 mol) of potassium carbonate in 850 ml of N-methylpyrrolidone, the dichloromethane phase is dropped from the precursor (about 90 minutes). During the addition of the dichloromethane at the same time

Reaction mixture was distilled off. Then the reaction mixture for 5 Vz hours at 60-70 ° C is well stirred. The mixture is cooled to about 50 ° C. and distilled under a vacuum of about 250 mbar residual dichloromethane from. At room temperature is added dropwise 107 ml 30% hydrochloric acid under ice cooling, then to obtain a pH of 5-6 is set. Then, 2,200 ml of water are added under ice cooling. The reaction mixture is thoroughly stirred for 15 minutes, the solid was then filtered off and washed on the filter twice with 1000 ml of water and extracted three times with 1000 ml of ethanol and then dried in a vacuum oven at 60 ° C.

Yield: 1200 g (89.6% of theory).

This product can be purified, if desired by, the solid is stirred in 2000 ml of ethanol for 30 minutes at reflux. You filtered hot with suction, washed with 500 ml of ethanol and dried at 60 ° C in vacuum. Melting point: 180-182 ° C.

Η-NMR (400 MHz, CDC1 3): d = 1.2 to 1.27 (m, 2H), 1.41 (t, 3H), 1.5-1.56 (m, 2H), 4, 1 to 4.8 (m, 1H), 4.40 (q, 2H), 8.44 (d, J = 8.2 Hz, H), 8.64 (s, 1H) ppm.

Example Z 22

7-chloro-8-cyano-1-cvclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid

 

Figure imgf000039_0001

33.8 g (0.1 mol) of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylate dissolved in a mixture of 100 ml of acetic acid, 20 ml water and 10 ml concentrated sulfuric acid was heated for 3 hours under reflux. After cooling, the mixture is poured onto 100 ml of ice water, the precipitate filtered off, washed with water and ethanol and dried at 60 ° C in vacuum.

Yield: 29.6 g (96% of theory),

Mp 216-21 C. (with decomposition)

Example 1

 

Figure imgf000040_0001

A 8-Cyano-l-cvclopropyl-6-fluoro-7-((lS.6S-2-oxa-5.8-diazabicvclo [4.3.0] non-8-yl – 1 ,4-dihydro-4-oxo-3 -quinoline carboxylic acid

1.00 g (3.26 mmol) of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated with 501 mg (3.91 mmol) of ( lS, 6S)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane and 0.9 ml of triethylamine in 30 ml of acetonitrile was stirred at 40-45 ° C under argon for 25 hours. All volatile components in vacuo. removed and the residue recrystallized from ethanol. Yield: 1.22 g (94%)

Melting point: 294 ° C. (with decomposition)

B) 8-Cyano-l-cyclopropyl-6-fluoro-7-(‘(lS.6S-2-oxa-5 ,8-diazabicvclo [4.3.01nonan-8-YLV 1.4-dihydro-4-oxo-3- quinoline carboxylic acid Hvdrochlorid

200 mg (0.63 mmol) of 8-cyano-l-cyclopropyl-6 ,7-difluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester to be 97 mg (0.75 mmol) of (lS, 6S)-2-oxa-5, 8 – diazabicyclo [4.3.0] nonane and 0.17 ml of triethylamine in 3 ml of acetonitrile was stirred at 40-45 ° C for 2 hours under argon. All volatile components in vacuo. removed, the residue treated with water, insolubles filtered off and the filtrate was extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. a. The resulting residue is dissolved in 6 ml of tetrahydrofuran and 2 ml of water and 30 mg (0.72 mmol) of lithium hydroxide monohydrate was added. After 16 hours of stirring at room temperature, acidified with dilute hydrochloric acid and the resulting precipitate was filtered off with suction and dried. Yield: 155 mg (57%) Melting point:> 300 ° C

C) 8-Cyano-l-cvclopropyl-6-fluoro-7-((lS, 6S-2-oxa-5.8-diazabicvclo [4.3.01non-8 yiyi.4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride

1 g (2.5 mmol) of 8-cyano-l-cyclopropyl-6-fluoro-7-((lS, 6S)-2-oxa-5 ,8-diazabicyclo [4.3.0] non-8-yl )-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid is suspended in 20 ml of water was added to the suspension, 10 ml hydrochloric acid and stirred for In at room temperature for 3 hours. The resulting precipitate is filtered off, washed with ethanol and dried at 80 ° C under high vacuum.

Yield: 987 mg (90.6% of theory), Melting point: 314-316 ° C. (with decomposition).

D) 8-Cyano-l-cvclopropyl-6-fluoro-7-(iS, 6S)-2-oxa-5.8-diazabicyclo [4.3.0] non-8-YLV 1 ,4-dihydro-4-oxo-3 -quinoline carboxylic acid hydrochloride

86.4 g (217 mmol) of 8-cyano-l-cyclopropyl-6-fluoro-7-((lS, 6S)-2-oxa-5, 8 – diazabicyclo [4.3.0] non-8-yl) – l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved at room temperature in 963 ml of water and 239 ml of 1 N aqueous sodium hydroxide solution. After filtration and washing with 200 ml of water is added to 477 ml in aqueous hydrochloric acid and the precipitated crystals placed at 95 ° C to 100 ° C in solution. The solution is cooled overnight, the precipitated crystals are filtered off with suction and washed three times with 500 ml of water and dried in vacuum.

Yield 90 g (94.7% of theory), content:> 99% (area% by HPLC) 99.6% ee. [] D 23: -112 ° (c = 0.29, N NaOH).

 

……………….

Tetrahedron Lett 2009, 50(21): 2525

A novel approach to Finafloxacin hydrochloride (BAY35-3377)

Pages 2525-2528
Jian Hong, Zonghua Zhang, Huoxing Lei, Haiying Cheng, Yufang Hu, Wanliang Yang, Yinglin Liang, Debasis Das, Shu-Hui Chen, Ge Li

 

Graphical abstract

 

image

Finafloxacin hydrochloride, an important clinical compound was synthesized by a novel synthetic approach. An active intermediate ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 19 was prepared by a new route. The chiral (S,S′)-N-Boc 10 was derived from protected pyrrolidine and the absolute stereochemistry was established by X-ray analysis.

http://www.sciencedirect.com/science/article/pii/S0040403909005875

……………….

 

 

 

  1. Durata Therapeutics, Inc. Finafloxacin for the treatment of cUTI and/or acute pyelonephritis. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01928433 (accessed on 28 September 2013).
  2. Merlion Pharma. A multi-dose, double-blind, double-dummy, active control, randomized clinical (Phase II) study of two dosing regimens of finafloxacin for the treatment of cUTI and/or acute pyelonephritis.Available online: http://www.clinicaltrialsregister.eu/ctr-search/trial/2011–006041–14/PL/ (accessed on 14 April 2013).
  3. Pharma, M. FDA Grants Qualified Infectious Disease Product Designation and Fast Track Status for MerLion Pharma’s Lead Antibacterial Candidate Finafloxacin; Merlion Pharma: Singapore, 2013; Volume 2013.
  4. Lemaire, S.; van Bambeke, F.; Tulkens, P.M. Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular Staphylococcus aureusListeria monocytogenes and Legionella pneumophilaInt. J. Antimicrob. Agents 201138, 52–59, doi:10.1016/j.ijantimicag.2011.03.002.
  5. Finafloxacin hydrochlorideDrugs Fut 2009, 34(6): 451
  6. A novel approach to finafloxacin hydrochloride (BAY35-3377)Tetrahedron Lett 2009, 50(21): 2525
  7. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (October 25-28, Washington DC) 2008, Abst F1-2036

 

WO2011003091A1 * 2 Jul 2010 6 Jan 2011 Alcon Research, Ltd. Compositions comprising finafloxacin and methods for treating ophthalmic, otic, or nasal infections
US7723524 29 Sep 2004 25 May 2010 Daiichi Pharmaceutical Co., Ltd. 8-cyanoquinolonecarboxylic acid derivative
US8536167 2 Jul 2010 17 Sep 2013 Alcon Research, Ltd. Methods for treating ophthalmic, otic, or nasal infections
DE4329600A1 * 2 Sep 1993 9 Mar 1995 Bayer Ag Pyrido [1,2,3-d,e] [1,3,4] benzoxadiazinderivate
EP0276700A1 * 15 Jan 1988 3 Aug 1988 Bayer Ag 8-Cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids, process for their preparation, and antibacterial agents containing them
EP0350733A2 * 30 Jun 1989 17 Jan 1990 Bayer Ag 7-(1-Pyrrolidinyl)-3-quinolone- and -naphthyridone-carboxylic-acid derivatives, method for their preparation and for substituted mono- and bi-cyclic pyrrolidine intermediates, and their antibacterial and feed additive compositions
EP0550903A1 * 28 Dec 1992 14 Jul 1993 Bayer Ag Quinolone- and naphthyridone carboxylic acid derivatives as antibacterial agents
EP0603887A2 * 23 Dec 1993 29 Jun 1994 Daiichi Pharmaceutical Co., Ltd. Bicyclic amine derivatives
EP0676199A1 * 23 Mar 1995 11 Oct 1995 Pfizer Inc. Use of trovafloxacin or derivatives thereof for the manufacture of a medicament for the treatment of H. pylori infections
GB2289674A * Title not available

Nemonoxacin….TaiGen’s pneumonia antibiotic Taigexyn 奈诺沙星 gets marketing approval in Taiwan


Nemonoxacin structure.svg

Nemonoxacin 奈诺沙星

378746-64-6 CAS

TG-873870

  • C20-H25-N3-O4
  • 371.4345

WARNER CHILCOTT ORIGINATOR

CLINICAL TRIALS    http://clinicaltrials.gov/search/intervention=Nemonoxacin

(3S,5S)-7-[3-amino-5-methyl-piperidinyl]-l-cyclopropyl-l,4- dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

7-[3(S)-Amino-5(S)-methylpiperidin-1-yl]-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Taigexyn has been approved in Taiwan IN 2014

“TAIPEI, MARCH 13, 2014 /PRNEWSWIRE/ — TAIGEN BIOTECHNOLOGY …”
13.03.14 |

TaiGen Biotechnology Receives Marketing Approval from the Taiwan Food and Drug Administration for Taigexyn in Taiwan

TAIPEI, March 13, 2014 /PRNewswire/ — TaiGen Biotechnology Company, Limited (“TaiGen”) today announced that the Taiwan Food and Drug Administration (TFDA) has approved the new drug application (NDA) of Taigexyn® (nemonoxacin) oral formulation (500 mg) for the treatment of community-acquired bacterial pneumonia (CAP). With this NDA approval, Taiwan is the first region to grant marketing approval to Taigexyn®. An NDA for Taigexyn®  was also submitted to China FDA (CFDA) in April 2013 and is currently under review.

Nemonoxacin is a novel non-fluorinated quinolone antibiotic undergoing clinical trials.

Taigexyn Granted QIDP and Fast Track Designations

TaiGen Biotechnology announced that the FDA has granted nemonoxacin (Taigexyn) Qualified Infectious Disease Product (QIDP) and Fast Track designations for community-acquired bacterial pneumonia (CAP) and acute bacterial skin and skin structure infections (ABSSSI).

Safety and clinical pharmacokinetics of nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and multiple oral doses

Nemonoxacin is a novel non-fluorinated quinolone broad spectrum antibiotic available in both oral and intravenous formulations. Nemonoxacin demonstrates activity against gram-positive and gram-negative bacteria and atypical pathogens. Nemonoxacin also possesses activities against methicillin-­resistant Staphylococcus aureus (MRSA) and vancomycin-resistant pathogens.

Nemonoxacin is a novel non-flourinated quinolone antibiotic registered in Taiwan for the oral treatment of community-acquired pneumonia. Clinical trials are in development at TaiGen Biotechnology for the treatment of diabetic foot infections and for the treatment of moderate to severe community-acquired pneumonia with an intravenous formulation. The drug is thought to accomplish its antibacterial action through topoisomerase inhibition.

Originally developed at Procter & Gamble, nemonoxacin was the subject of a strategic alliance formed in January 2005 between P&G and TaiGen to further the development and commercialization of nemonoxacin. In 2012, the product was licensed by TaiGen Biotechnology to Zhejiang Medicine in China for manufacturing, sales and marketing. In 2014, TaiGen out-licensed the exclusive rights of the product in Russian Federation, Commonwealth Independent States and Turkey to R-Pharm.

TaiGen has completed two Phase 2 clinical studies, one in CAP and the other in diabetic foot infections with demonstrated efficacy and safety. In the clinical trials conducted to date, nemonoxacin has shown activity against drug-resistant bacteria such as MRSA, quinolone-resistant MRSA, as well as quinolone-resistant Streptococcus pneumoniae.

Malate salt

Nemonoxacin malate anhydrous
951163-60-3 CAS NO, MW: 505.5209

Nemonoxacin malate hemihydrate
951313-26-1, MW: 1029.0566

Chemical structure of nemonoxacin as a malate salt (C20H25N3O4·C4H6O5·H2O). Nemonoxacin is the free base, and its molecular mass is 371.44 g/mol. The molecular mass of the salt, nemonoxacin malate, is 514.53 g/mol.

……………………..

isomeric compounds are:

Figure imgf000003_0002

(3S,5S)-7-[3-amino-5-methyl-piperidinyl]-l-cyclopropyl-l,4-dihydro-8- methoxy-4-oxo-3 -quinolinecarboxylic acid

COMPD1…….DESIRED

Figure imgf000003_0003

(3S,5R)-7-[3-amino-5-methyl-piperidinyl]-l-cyclopropyl-l,4-dihydro-8- methoxy-4-oxo-3 -quinolinecarboxylic acid

COMPD 1’….NOT DESIRED

EP2303271A1

Example 1

Malate salts of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-l-cyclopropyl-l,4- dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (Compound 1) and (3S,5R)-7- [3-ammo-5-methyl-piperidinyl]- 1 -cyclopropyl- 1 ,4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid (Compound 1′) were synthesized as follows:

(A) Synthesis of (3S,5S)-(5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (Compound 9) and (3S,5R)-(5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (Compound 9′): Compound 9′ was synthesized as shown in Scheme 1 below:

Scheme 1

Figure imgf000009_0001

3 4 Boc

Figure imgf000009_0002

A 50-L reactor was charged with Compound 2 (5.50 kg, 42.60 mol), methanol (27 L) and cooled to 10-150C. Thionyl chloride (10.11 kg, 2.0 equiv.) was added via an addition funnel over a period of 65 min, with external cooling to keep temperature below 30°. The resulting solution was stirred at 250C for 1.0 hour, after which methanol was removed under reduced pressure. The oily residue was azeotroped with ethyl acetate (3 x 2.5 L) to remove residual methanol, dissolved in ethyl acetate (27.4 L), charged into a 50 L reactor, and neutralized by slow addition of triethylamine (3.6 kg) below 3O0C. The resulting suspension was filtered to remove triethylamine hydrochloride.

The filtrate was charged to a 50 L reactor, along with DMAP (0.53 kg). Di- fert-butyl dicarbonate (8.43 kg) was added via hot water heated addition funnel, over a period of 30 min at a temperature of 20-300C. The reaction was complete after 1 hour as determined by TLC analysis. The organic phase was washed with ice cold IN HCl (2 x 7.5 L), saturated sodium bicarbonate solution (1 x 7.5 L), dried over magnesium sulfate, and filtered. After ethyl acetate was removed under reduced pressure, crystalline slurry was obtained, triturated with MTBE (10.0 L), and filtered to afford Compound 3 as a white solid (5.45 kg, 52.4%).

Anal. Calcd for CHHI7NO5 : C, 54.3; H, 7.04; N, 5.76. Found: C, 54.5; H, 6.96; N, 5.80. HRMS (ESI+) Expected for CHHI8NO5, [M+H] 244.1185. Found

244.1174; 1H NMR (CDCl3, 500 MHz):δ=4.54 (dd, J= 3.1, 9.5 Hz, IH), 3.7 (s, 3H), 2.58-2.50 (m, IH), 2.41 (ddd, IH, J= 17.6, 9.5, 3.7), 2.30-2.23 (m, IH), 1.98-1.93 (m, IH), 1.40 (s, 9H); 13C NMR (CDCl3, 125.70 MHz) δ 173.3, 171.9, 149.2, 83.5, 58.8, 52.5, 31.1, 27.9, 21.5. Mp 70.20C.

A 50-L reactor was charged with Compound 3 (7.25 kg, 28.8 mol), DME (6.31 kg), and Bredereck’s Reagent (7.7 kg, 44.2 mole). The solution was agitated and heated to 750C + 50C for three hours. The reaction was cooled to O0C over an hour, during which time a precipitate formed. The mixture was kept at O0C for an hour, filtered, and dried in a vacuum oven for at least 30 hours at 3O0C + 50C to give compound 4 as a white crystalline solid (6.93 kg, 77.9%).

Anal. Calcd for Ci4H22N2O5: C, 56.4; H, 7.43; N, 9.39. Found C, 56.4; H, 7.32; N, 9.48; HRMS (ESI+) Expected for Ci4H22N2O5, [M+H] 299.1607. Found 299.1613; 1H NMR (CDCl3, 499.8 MHz) δ = 7.11 (s, IH), 4.54 (dd, IH, J= 10.8, 3.6), 3.74 (s, 3H), 3.28-3.19 (m, IH), 3.00 (s, 6H), 2.97-2.85 (m,lH), 1.48 (s, 9H); 13C NMR (CDCl3, 125.7 MHz) δ = 172.6, 169.5, 150.5, 146.5, 90.8, 82.2, 56.0, 52.3, 42.0, 28.1, 26.3. MP 127.90C. A 10-gallon Pfaudler reactor was charged with ESCAT 142 (Engelhard Corp.

N.J, US) 5% palladium powder on carbon (50% wet, 0.58 kg wet wt), Compound 4 (1.89 kg, 6.33 mol), and isopropanol (22.4 Kg). After agitated under a 45-psi hydrogen atmosphere at 450C for 18 hrs, the reaction mixture was cooled to room temperature and filtered though a bed of Celite (0.51 kg). The filtrate was evaporated under reduced pressure to give a thick oil, which was solidified on standing to afford Compound 5 (1.69 kg, 100%) as a 93:7 diastereomeric mixture.

A sample of product mixture was purified by preparative HPLC to give material for analytical data. Anal. Calcd for Ci2Hi9NO5: C, 56.0; H, 7.44; N, 5.44. Found C, 55.8; H, 7.31; N, 5.44; MS (ESI+) Expected for Ci2Hi9NO5, [M+H] 258.1342. Found 258.1321; 1H NMR (CDCl3, 499.8 MHz) δ = 4.44 (m, IH), 3.72 (s, 3H), 2.60-2.48 (m, 2H), 1.59-1.54 (m, IH), 1.43 (s, 9H), 1.20 (d, j = 6.8 Hz,3H); 13C NMR (CDCl3, 125.7 MHz) δ = 175.7, 172.1, 149.5, 83.6, 57.4, 52.5, 37.5, 29.8, 27.9, 16.2. Mp 89.90C.

A 50-L reactor was charged with Compound 5 (3.02 kg, 11.7 mol), absolute ethanol (8.22 kg), and MTBE (14.81 kg). Sodium borohydride (1.36 kg, 35.9 mol) was added in small portions at 00C + 50C. A small amount of effervescence was observed. The reaction mixture was warmed to 1O0C + 50C and calcium chloride dihydrate (2.65 kg) was added in portions at 1O0C + 50C over an hour. The reaction was allowed to warm to 2O0C + 50C over one hour and agitated for an additional 12 hours at 200C + 50C. After the reaction was cooled to -50C + 50C, ice-cold 2N HCl (26.9 kg) was added slowly at of O0C + 50C. Agitation was stopped. The lower aqueous phase was removed. The reactor was charged with aqueous saturated sodium bicarbonate (15.6 kg) over five minutes under agitation. Agitation was stopped again and the lower aqueous phase was removed. The reactor was charged with magnesium sulfate (2.5 kg) and agitated for at leastlO minutes. The mixture was filtered though a nutsche filter, and concentrated under reduced pressure to afford Compound 6 (1.80 kg, 66%). Anal. Calcd for CnH23NO4: C, 56.6 H, 9.94; N, 6.00. Found C, 56.0; H, 9.68;

N, 5.96; HRMS (ESI+) Expected for CnH24NO4, [M+H] 234.1705. Found 234.1703; 1H NMR (CDCl3, 500 MHz) δ = 6.34 (d, J= 8.9 Hz, IH, NH), 4.51 (t, J= 5.8, 5.3 Hz, IH, NHCHCH2OH), 4.34 (t, J= 5.3, 5.3 Hz, IH, OBCHCH2OH), 3.46-3.45, (m, IH, NHCH), 3.28 (dd, J= 10.6, 5.3 Hz, NHCHCHHOH), 3.21 (dd, J= 10.2, 5.8 Hz , IH, CH3CHCHHOH), 3.16 (dd, J = 10.2, 6.2 Hz, IH, NHCHCHHOH), 3.12 (dd, J= 10.6, 7.1 Hz , IH, CH3CHCHHOH), 1.53-1.50 (m, IH, CH3CHCHHOH), 1.35 (s, 9H, 0(CHB)3, 1.30 (ddd, J = 13.9, 10.2, 3.7 Hz, IH, NHCHCHHCH), 1.14 (ddd, J= 13.6, 10.2, 3.4 Hz, IH, NHCHCHHCH), 0.80 (d, J= 6.6 Hz, 3H, CH3); 13C NMR (CDCl3, 125.7 MHz) δ 156.1, 77.9, 50.8, 65.1, 67.6, 65.1, 35.6, 32.8, 29.0, 17.1. Mp 92.10C. A 50 L reactor was charged with a solution of Compound 6 (5.1 kg) in isopropyl acetate (19.7 kg). The reaction was cooled to 150C + 5°C and triethylamine (7.8 kg) was added at that temperature. The reactor was further cooled to O0C + 50C and methanesulfonyl chloride (MsCl) (6.6 kg) was added. The reaction was stirred for a few hours and monitored for completion by HPLC or TLC. The reaction was quenched by saturated aqueous bicarbonate solution. The organic phase was isolated and washed successively with cold 10% aqueous triethylamine solution, cold aqueous HCl solution, cold saturated aqueous bicarbonate solution, and finally saturated aqueous brine solution. The organic phase was dried, filtered, and concentrated in vacuo below 550C + 50C to afford compound 7 as a solid/liquid slurry, which was used in the subsequent reaction without further purification.

After charged with 9.1 kg of neat benzylamine, a 50 L reactor was warmed to 550C, at which temperature, a solution of compound 7 (8.2 kg) in 1,2- dimethoxyethane (14.1 kg) was added. After the addition, the reaction was stirred at 6O0C + 50C for several hours and monitored for completion by TLC or HPLC. The reaction was cooled to ambient temperature and the solvent was removed under vacuum. The residue was diluted with 11.7 kg of 15% (v/v) ethyl acetate/hexanes solution and treated, while agitating, with 18.7 kg of 20% (wt) aqueous potassium carbonate solution. A triphasic mixture was obtained upon standing. The upper organic layer was collected. The isolated middle layer was extracted twice again with 11.7 kg portions of 15% (v/v) ethyl acetate/hexanes solution. The combined organic layers were concentrated under vacuum to give an oily residue. The residue was then purified by chromatography to afford Compound 8 as an oil. A 40 L pressure vessel was charged with 0.6 kg 50% wet, solid palladium on carbon (ElOl, 10 wt. %) under flow of nitrogen. A solution of Compound 8 (3.2 kg) in 13.7 kg of absolute ethanol was then added to the reactor under nitrogen. The reactor was purged with nitrogen and then pressurized with hydrogen at 45 psi. The reaction was then heated to 45°C. It was monitored by TLC or LC. Upon completion, the reaction was cooled to ambient temperature, vented, and purged with nitrogen. The mixture was filtered through a bed of Celite and the solid was washed with 2.8 kg of absolute ethanol. The filtrate was concentrated under vacuum to afford Compound 9 as a waxy solid.

TLC R/(Silica F254, 70:30 v/v ethyl acetate-hexanes, KMnO4 stain) = 0.12; 1H NMR (300 MHz, CDCl3) δ 5.31 (br s, IH), 3.80-3.68 (m, IH), 2.92 (d, J=I 1.4 Hz,

IH), 2.77 (AB quart, JAB=12.0 Hz, v=50.2 Hz, 2H), 2.19 (t, J=10.7 Hz, IH), 1.82-1.68 (m, 2H), 1.54 (br s, IH), 1.43 (s, 9H), 1.25-1.15 (m, IH), 0.83 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 155.3, 78.9, 54.3, 50.8, 45.3, 37.9, 28.4, 27.1, 19.2; MS (ESI+) m/z 215 (M+H), 429 (2M+H). Similarly, (3S,5R)-(5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester

(Compound 9′) was synthesized as shown in Scheme 2.

Scheme 2

Figure imgf000013_0001

HN Boc HN Boc

NaBH4,EtOH w –  MsCI1TEA . „ _. – – _. „ Benzyl Amine

THF EA1CoId

Figure imgf000013_0002

(B) Synthesis of l-Cyclopropyl-7-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid (Compound 10): Compound 10 was prepared according to the method described in U.S. Patent

6,329,391.

(C) Synthesis of borone ester chelate of l-Cyclopropyl-7-fluoro-8-methoxy-4-oxo- l,4-dihydro-quinoline-3-carboxylic acid (Compound 11):

Scheme 3

Figure imgf000013_0003

Toluene, tert-Butylmethyl ether 20-500C, filter

A reactor was charged with boron oxide (2.0 kg, 29 mol), glacial acetic acid (8.1 L, 142 mol), and acetic anhydride (16.2 L, 171 mol). The resulting mixture was refluxed at least 2 hours, and then cooled to 400C, at which temperature, 7- fluoroquinolone acid compound 10 (14.2 kg, 51 mol) was added. The mixture was refluxed for at least 6 hours, and then cooled to about 900C. Toluene (45 L) was added to the reaction. At 5O0C, terϊ-butylmethyl ether (19 L) was added to introduce precipitation. The mixture was then cooled to 200C and filtered to isolate the precipitation. The isolated solid was then washed with teτt-butylmethyl ether (26 L) prior to drying in a vacuum oven at 4O0C (50 torr) to afford Compound 11 in a yield of 86.4%. Raman (cm 1): 3084.7, 3022.3, 2930.8, 1709.2, 1620.8, 1548.5, 1468.0, 1397.7, 1368.3, 1338.5, 1201.5, 955.3, 653.9, 580.7, 552.8, 384.0, 305.8. NMR (CDCl3, 300 MHz) δ (ppm): 9.22 (s, IH), 8.38-8.33 (m, IH), 7.54 (t, J=9.8 Hz, IH), 4.38-4.35 (m, IH), 4.13 (s, 3H), 2.04 (s, 6H), 1.42-1.38 (m, 2H), 1.34-1.29 (m, 2H). TLC (Whatman MKC18F Silica, 6θA, 200 μm), Mobile Phase: 1 :1 (v/v) CH3CN : 0.5N NaCl (aq), UV (254/366 nm) visualization; R^O.4-0.5. (D) Synthesis of malate salt of (3S,5S)-7-[3-amino-5-methyl-piperidmyl]-l- cyclopropyl-l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (Compound 1) and malate salt of (3S,5R)-7-[3-amino-5-methyl-piperidmyl]-l-cyclopropyl-l,4- dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (Compound 1′)

Compound 1 was synthesized from compound 9 as shown in Scheme 4 below:

Scheme 4

Figure imgf000014_0001

5O0C 3 d

a 6 0 N HCI (aq) CH2CI2 35°40°C 12 h t> Extract pH ad]ust to ~7-8 50″-65″C filter

Figure imgf000014_0003
Figure imgf000014_0002
Figure imgf000014_0004

A reactor was charged with Compound 11 (4.4 kg, 10.9 mol), Compound 9 (2.1 kg, 9.8 mol), triethylamine (TEA) (2.1 L, 14.8 mol), and acetonitrile (33.5 L, 15.7 L/kg). The resulting mixture was stirred at approximately 500C till completion of the reaction, as monitored by HPLC or reverse phase TLC. It was cooled to approximately 35°C and the reaction volume was reduced to approximately half by distillation of acetonitrile under vacuum between 0-400 torr. After 28.2 kg of 3.0 N NaOH (aq) solution was added, the reaction mixture was warmed to approximately 4O0C, distilled under vacuum until no further distillates were observed, and hydro lyzed at room temperature. Upon completion of hydrolysis, which was monitored by HPLC or reverse phase TLC, 4-5 kg of glacial acetic acid was added to neutralize the reaction mixture.

The resulting solution was extracted 3 times with 12.7 kg (9.6 L) of dichloromethane. The organic layers were combined and transferred to another reactor. The reaction volume was reduced to approximately a half by evaporation at 400C. After 20.2 Kg 6.0N HCl (aq) solution was added, the reaction mixture was stirred for at least 12 hours at 35°C. After the reaction was completed as monitored by HPLC or reverse phase TLC, agitation was discontinued to allow phase separation. The organic phase was removed and the aqueous layer was extracted with 12.7 kg (9.6 L) of dichloromethane. The aqueous layer was diluted with 18.3 kg distilled water and warmed to approximately 500C. Dichloromethane was further removed by distillation under vacuum (100-400 torr).

The pH of the aqueous solution was then adjusted to 7.8-8.1 by adding about 9.42 kg of 3.0 N NaOH (aq) below 65°C. The reaction mixture was stirred at 500C for at least an hour and then cooled to room temperature. The precipitate was isolated by suction filtration, washed twice with 5.2 kg of distilled water, and dried with suction for at least 12 hours and then in a convection oven at 55°C for additional 12 hours. Compound 12 (3.2 kg, 79%) was obtained as a solid.

A reactor was charged with 3.2 kg of Compound 12 and 25.6 kg of 95% ethanol. To the reactor was added 1.1 kg of solid D,L-malic acid. The mixture was refluxed temperature (~80°C). Distilled water (-5.7 L) was added to dissolve the precipice and 0.2 kg of activated charcoal was added. The reaction mixture was passed through a filter. The clear filtrate was cooled to 45°C and allowed to sit for at least 2 hours to allow crystallization. After the reaction mixture was further cooled to 5°C, the precipitate was isolated by suction filtration, washed with 6.6 kg of 95% ethanol, and dried with suction for at least 4 hours. The solid was further dried in a convection oven at 450C for at least 12 hours to afford 3.1 kg of Compound 1 (yield: 70%). NEMONOXACIN

NMR (D2O, 300 MHz) δ (ppm): 8.54 (s, IH), 7.37 (d, J=9.0 Hz, IH), 7.05 (d, J=9.0 Hz, IH), 4.23-4.18 (m, IH), 4.10-3.89 (m, IH), 3.66 (br s, IH), 3.58 (s, 3H), 3.45 (d, J=9.0 Hz, IH), 3.34 (d, J=9.3 Hz, IH), 3.16 (d, J=12.9 Hz, IH), 2.65 (dd, J=16.1, 4.1 Hz, IH), 2.64-2.53 (m, IH), 2.46 (dd, J=16.1, 8.0 Hz, IH), 2.06 (br s, IH), 1.87 (d, J=14.4 Hz, IH), 1.58-1.45 (m, IH), 1.15-0.95 (m, 2H), 0.91 (d, J=6.3 Hz, 3H), 0.85-0.78 (m, 2H).

Similarly, Compound 1′ was synthesized from Compound 9′ as shown in Scheme 5 below:

Scheme 5

Figure imgf000016_0001
Figure imgf000003_0003

(3S,5R)-7-[3-amino-5-methyl-piperidinyl]-l-cyclopropyl-l,4-dihydro-8- methoxy-4-oxo-3 -quinolinecarboxylic acid

COMPD 1’….NOT DESIRED

…………………

US20070232650

US2007/232650 A1,

malate salts of

Figure US20070232650A1-20071004-C00001

(3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (hereinafter Compound I, see also intermediate (23) in Section D, of Detailed Description of the Invention).

EXAMPLES Example 1 Synthesis of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid and malate salt thereof A. Synthesis of (3S,5S)-(5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (8)

Figure US20070232650A1-20071004-C00002

(2S)-1-(1,1-Dimethylethyl)-5-oxo-1,2-pyrrolidinedicarboxylic acid-2-methyl ester, (2). A 50-L reactor is charged with compound (1) (5.50 Kg, 42.60 mol), methanol (27 L) and cooled to 10-15° C. Thionyl chloride (10.11 Kg, 2.0 equiv.) is added via addition funnel over a period of 65 min, with external cooling to maintain temperature at <30°. The resulting solution is stirred at 25° C.+5° C. for 1.0 hour, after which the methanol is distilled off under reduced pressure. The resulting thick oil is azeotroped with ethyl acetate (3×2.5 L) to remove residual methanol. The residue is dissolved in ethyl acetate (27.4 L), charged into a 50 L reactor, and neutralized by the addition of triethylamine (3.6 Kg) from an addition funnel over 30 minutes. The temperature of the neutralization is maintained below 30° C. via external cooling. The resulting suspension of triethylamine hydrochloride is removed by filtration, and the clarified mother liquor solution is charged to a 50 L reactor, along with DMAP (0.53 Kg). Di-tert-butyl dicarbonate (8.43 Kg) is added via hot water heated addition funnel, over a period of 30 min with external cooling to maintain temperature at about 20-30° C. The reaction is complete after 1 hour as determined by TLC analysis. The organic phase is washed with ice cold 1N HCl (2×7.5 L), saturated sodium bicarbonate solution (1×7.5 L), and dried over magnesium sulfate. The mixture is filtered through a nutsche filter and ethyl acetate is removed under reduced pressure to yield a crystalline slurry that is triturated with MTBE (10.0 L) and filtered to afford intermediate (2) as a white solid (5.45 Kg, 52.4%). Anal. Calcd for C11H17NO5: C, 54.3; H, 7.04; N, 5.76. Found: C, 54.5; H, 6.96; N, 5.80. HRMS (ESI+) Expected for C11H18NO5, [M+H] 244.1185. Found 244.1174; 1H NMR (CDCl3, 500 MHz): δ=4.54 (dd, J=3.1, 9.5 Hz, 1H), 3.7 (s, 3H), 2.58-2.50 (m, 1H), 2.41 (ddd, 1H, J=17.6, 9.5, 3.7), 2.30-2.23 (m, 1H), 1.98-1.93 (m, 1H), 1.40 (s, 9H); 13C NMR (CDCl3, 125.70 MHz) δ 173.3, 171.9, 149.2, 83.5, 58.8, 52.5, 31.1, 27.9, 21.5; Mp 70.2° C.

(2S,4E)-1-(1,1-Dimethylethyl)-4-[(dimethylamino)methylene]-5-oxo-1,2-pyrrolidinedicarboxylic acid-2-methyl ester (3). A 50-L reactor is charged with intermediate (2) (7.25 Kg, 28.8 mol), DME (6.31 Kg), and Bredereck’s Reagent (7.7 Kg, 44.2 mole). The solution is agitated and heated to 75° C.±5° C. for at least three hours. The progress of the reaction is monitored by HPLC. The reaction is cooled to 0° C.±5° C. over on hour during which time a precipitate forms. The mixture is held at 0° C.±5° C. for one hour and filtered though a nutsche filter and the product dried in a vacuum oven for at least 30 hours at 30° C.±5° C. to give intermediate (3) as a white crystalline solid (6.93 Kg, 77.9%). Anal. Calcd for C14H22N2O5: C, 56.4; H, 7.43; N, 9.39. Found C, 56.4; H, 7.32; N, 9.48; HRMS (ESI+) Expected for C14H22N2O5, [M+H] 299.1607. Found 299.1613; 1H NMR(CDCl3, 499.8 MHz)δ=7.11 (s, 1H), 4.54 (dd, 1H, J=10.8, 3.6), 3.74 (s, 3H), 3.28-3.19 (m, 1H), 3.00 (s, 6H), 2.97-2.85 (m, 1H), 1.48 (s, 9H); 13C NMR (CDCl3, 125.7 MHz) δ=172.6, 169.5, 150.5, 146.5, 90.8, 82.2, 56.0, 52.3, 42.0, 28.1, 26.3. Mp 127.9° C.

(2S,4S)-1-(1,1-Dimethylethyl)-4-methyl-5-oxo-1,2-pyrrolidinedicarboxylic acid-2-methyl ester (4). A 10-gallon Pfaudler reactor is inerted with nitrogen and charged with ESCAT 142 5% palladium powder on carbon (50% wet, 0.58 Kg wet wt.), intermediate (3) (1.89 Kg, 6.33 mol) and isopropanol (22.4 Kg). The reaction mixture is agitated under a 45-psi hydrogen atmosphere at 45° C. for 18 hrs. The reaction mixture is then cooled to room temperature and filtered though a bed of Celite (0.51 Kg) in a nutsche filter to remove catalyst. The mother liquor is evaporated under reduced pressure to give a thick oil that crystallizes on standing to afford 4 (1.69 Kg, 100%) as a 93:7 diastereomeric mixture. A sample of product mixture is purified by preparative HPLC to give material for analytical data. Anal. Calcd for C12H19NO5: C, 56.0; H, 7.44; N, 5.44. Found C, 55.8; H, 7.31; N, 5.44; MS (ESI+) Expected for C12H19NO5, [M+H] 258.1342. Found 258.1321; 1H NMR (CDCl3, 499.8 MHz) δ=4.44 (m, 1H), 3.72 (s, 3H), 2.60-2.48 (m, 2H), 1.59-1.54 (m, 1H), 1.43 (s, 9H), 1.20 (d, j=6.8 Hz,3H); 13C NMR (CDCl3, 125.7 MHz) δ=175.7, 172.1, 149.5, 83.6, 57.4, 52.5, 37.5, 29.8, 27.9, 16.2. Mp 89.9° C.

(1S,3S)-(4-Hydroxyl-1-hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (5). A 50-L reactor is charged with intermediate (4) (3.02 Kg, 11.7 mol), absolute ethanol (8.22 Kg), and MTBE (14.81 Kg). The solution is agitated and cooled to 0° C.±5° C. and sodium borohydride (1.36 Kg, 35.9 mol) is added in small portions so as to maintain reaction temperature at 0° C.±5° C. A small amount of effervescence is observed. The reaction mixture is warmed to 10° C.±5° C. and calcium chloride dihydrate (2.65 Kg) is added portion wise at a slow rate over an hour so as to maintain a reaction temperature of 10° C.±5° C. The reaction is allowed to warm to 20° C.±5° C. over one hour and agitated for an additional 12 hours at 20° C.±5° C. The reaction is cooled to −5° C.±5° C., ice-cold 2N HCl (26.9 Kg) is added at a rate to maintain a reaction temperature of 0° C.±5° C. Agitation is stopped to allow phases to separate. The lower aqueous phase (pH=1) is removed. The reactor is charged with aqueous saturated sodium bicarbonate (15.6 Kg) over five minutes. Agitation is stopped to allow phases to separate. The lower aqueous phase (pH=8) is removed. The reactor is charged with magnesium sulfate (2.5 Kg) and agitated for at least 10 minutes. The mixture is filtered though a nutsche filter, and condensed under reduced pressure to afford intermediate (5) (1.80 Kg, 66%). Anal. Calcd for C11H23NO4: C, 56.6; H, 9.94; N, 6.00. Found C, 56.0; H, 9.68; N, 5.96; HRMS (ESI+) Expected for C11H24NO4, [M+H] 234.1705. Found 234.1703; 1H NMR (CDCl3, 500 MHz)δ=6.34(d, J=8.9 Hz, 1H, NH), 4.51 (t, J=5.8, 5.3 Hz, 1H, NHCHCH2OH), 4.34 (t, J=5.3, 5.3 Hz, 1H, CH3CHCH2OH), 3.46-3.45, (m, 1H, NHCH), 3.28 (dd, J=10.6, 5.3 Hz, NHCHCHHOH), 3.21 (dd, J=10.2, 5.8 Hz, 1H, CH3CHCHHOH), 3.16 (dd, J=10.2, 6.2 Hz, 1H, NHCHCHHOH), 3.12 (dd, J=10.6, 7.1 Hz, 1H, CH3CHCHHOH), 1.53-1.50 (m, 1H, CH3CHCHHOH), 1.35 (s, 9H, O(CH 3)3, 1.30 (ddd, J=13.9, 10.2, 3.7 Hz, 1H, NHCHCHHCH), 1.14 (ddd, J=13.6, 10.2, 3.4 Hz, 1H, NHCHCHHCH), 0.80 (d, J=6.6 Hz, 3H, CH3); 13C NMR (CDCl3, 125.7 MHz) δ 156.1, 77.9, 50.8, 65.1, 67.6, 65.1, 35.6, 32.8, 29.0, 17.1. Mp 92.1° C.

(2S,4S)-Methanesulfonic acid 2-tert-butoxycarbonylamino-5-methanesulfonyloxy-4-methyl-pentyl ester (6). A 50 L reactor is charged with a solution of intermediate (5) (5.1 Kg) in isopropyl acetate (i-PrOAc) 11.8 Kg followed by a rinse with an additional 7.9 Kg i-PrOAc. The reaction is cooled to 15° C.±5° C. and triethylamine (TEA) (7.8 Kg) is added while maintaining the set temperature. The reactor is further cooled to 0° C.±5° C. and methanesulfonyl chloride (MsCl) (6.6 Kg) is added to the reaction solution while maintaining the set temperature. The reaction is stirred for a few hours and monitored for completion by HPLC or TLC. The reaction is quenched by the addition of a saturated aqueous bicarbonate solution and the resulting isolated organic phase is washed successively with cold 10% aqueous triethylamine solution, cold aqueous HCl solution, cold saturated aqueous bicarbonate solution, and finally saturated aqueous brine solution. The organic phase is dried, filtered, and concentrated in vacuo below 55° C.±5° C. until a solid/liquid slurry containing intermediate (6) is obtained. The slurry is used crude in subsequent reaction without further characterization.

(3S,5S)-(1-Benzyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (7). A 50 L reactor is charged with 9.1 Kg of neat benzylamine. The reactor is brought to 55° C. and a solution of intermediate (6) (8.2 Kg) in 1,2-dimethoxyethane (DME) (14.1 Kg) is added to the reactor while maintaining a temperature of 60° C.±5° C. After complete addition of this solution, the reaction is stirred at 60° C.±5° C. for several hours and monitored for completion by TLC or HPLC. The reaction is cooled to ambient temperature and volatiles (DME) are removed by rotary evaporation under vacuum. The residue is diluted with 11.7 Kg of 15% (v/v) ethyl acetate/hexanes solution and treated, while agitating, with 18.7 Kg of 20% (wt) aqueous potassium carbonate solution. A triphasic mixture is obtained upon settling. The bottom aqueous phase is removed and the middle phase is set aside. The upper organic phase is collected and held for combination with extracts from additional extractions. The isolated middle phase is extracted twice again with 11.7 Kg portions of 15% (v/v) ethyl acetate/hexanes solution, each time combining the extracts with original organic phase. The combined organic extracts are transferred into a rotary evaporator and solvent is removed under vacuum until an oily residue remains. The residue is then purified via large-scale preparative chromatography to afford purified intermediate (7) as an oil.

(3S,5S)-(5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (8). A 40 L pressure vessel is charged with 0.6 Kg 50% wet, solid palladium on carbon (E101, 10 wt. %) under flow of nitrogen. A solution of 3.2 Kg intermediate (7) in 13.7 Kg of absolute ethanol is then charged to the reactor under nitrogen. The reactor is purged with nitrogen and is then pressurized with hydrogen at 45 psi. The reaction is then heated to 45° C. while maintaining a hydrogen pressure of 45 psi. The reaction is monitored by TLC or LC until complete. The reaction is cooled to ambient temperature, vented, and purged with nitrogen. The reactor contents are filtered through a bed of Celite and the solids are washed with 2.8 Kg of absolute ethanol. The filtrate is concentrated by rotary evaporation under vacuum until a waxy solid is obtained to afford intermediate (8): TLC R(Silica F254, 70:30 v/v ethyl acetate-hexanes, KMnOstain)=0.12; 1H NMR (300 MHz, CDCl3) δ 5.31 (br s, 1H), 3.80-3.68 (m, 1H), 2.92 (d, J=11.4 Hz, 1H), 2.77 (AB quart, JAB=12.0 Hz, Δν=50.2 Hz, 2H), 2.19 (t, J=10.7 Hz, 1H), 1.82-1.68 (m, 2H), 1.54 (br s, 1H), 1.43 (s, 9H), 1.25-1.15 (m, 1H), 0.83 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 155.3, 78.9, 54.3, 50.8, 45.3, 37.9, 28.4, 27.1, 19.2; MS (ESI+) m/z 215 (M+H), 429 (2M+H).

B. Synthesis of 1-Cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (19)

Figure US20070232650A1-20071004-C00003
Figure US20070232650A1-20071004-C00004

Intermediate (12): A reactor is charged with a solution of intermediate (11) (1.2 Kg, 7.7 mol, 1.0 eq) in anhydrous toluene (12 L) followed by ethylene glycol (1.8 L, 15.7 mol, 4.2 eq) and solid p-toluenesulfonic acid (120 g, 10 wt. %). The reaction mixture is stirred at ambient temperature for at least 30 minutes and then heated to reflux, collecting the water/toluene azeotrope in a Dean Stark type trap apparatus until the reaction is complete as determined by TLC analysis (15% EtOAc/Hexanes v/v). Upon completion, the reaction is cooled to ambient temperature and poured into an aqueous solution of sodium bicarbonate (6 L). The organic toluene phase was removed and washed with saturated sodium bicarbonate solution (6 L), distilled water (2×6 L), and saturated aqueous brine (6 L). The organic phase was removed and dried over MgSO4, filtered, and evaporated under reduced pressure to afford intermediate (12) as an oil (1.3 Kg, 86%). The material is used without further purification in subsequent reaction steps.

Intermediate (13): A reactor is charged with a solution of intermediate (12) (1.2 Kg, 6.0 mol, 1.0 eq) in anhydrous tetrahydrofuran (12 L) and n-butyllithium (2.5M in hexanes, 2.6 L, 6.6 mol, 1.1 eq) is added at −40° C., while maintaining this temperature throughout the addition. The reaction is stirred for at least one hour at −40° C. and trimethylborate (0.9 L, 7.8 mol, 1.3 eq) is added to the mixture while maintaining the temperature at or below −40° C. The reaction mixture is stirred for at least one hour at −40° C. until complete as determined by TLC analysis (30% EtOAc/Hexanes v/v). The reaction is warmed slightly to −30° C. and acetic acid (3 L) is added slowly. Upon complete addition, water is added (0.5 L) to the reaction and the mixture is allowed to quickly warm to ambient temperature while stirring overnight. Organic solvent is removed from the reaction by distillation under reduced pressure at 45° C. To the reaction residue is added 3-4 volumes of water (6 L) and 30% hydrogen peroxide (0.7 L, 1.0 eq) slowly at ambient temperature with cooling provided to control the exotherm. The reaction is stirred for at least an hour at ambient temperature until complete as determined by TLC (15% EtOAc/Hexanes v/v). The reaction mixture is cooled to 0-5° C. and excess peroxide is quenched with the addition of 10% aqueous sodium bisulfite solution (2 L). The mixture is tested to ensure a negative peroxide result and the reaction is acidified by the addition of 6N HCl (aq) (1.2 L). The reaction is stirred until the hydrolysis reaction is complete as determined by TLC or NMR analysis. The resulting solids are collected by suction filtration to afford intermediate (13) as a yellow solid (1.0 Kg, 79%).

Intermediate (14): A reactor is charged with intermediate (13) (0.53 Kg, 3.0 mol, 1.0 eq) and dissolved in dry toluene (2.7 Kg, 3.1 L). To this solution is added dimethylsulfate (0.49 Kg, 3.9 mol, 1.30 eq) followed by solid potassium carbonate (0.58 Kg, 4.2 mol, 1.4 eq). The reaction mixture is heated to reflux and held for at least 1 hour until complete as determined by HPLC. During this time, vigorous gas evolution is observed. The reaction is then cooled to ambient temperature and diluted with distilled water (3.2 L) along with 30% NaOH (aq) (0.13 Kg, 0.33 eq). The aqueous phase is separated and the remaining toluene phase is extracted twice more with distilled water (3.2 L) combined with 30% NaOH (aq) (0.13 Kg, 0.33 eq), removing the aqueous phase each time. The organic upper phase is concentrated by distillation in vacuo (<100 mbar) at approximately 40° C. until a concentrated toluene solution is achieved. The resulting solution is cooled to ambient temperature, checked for quality and yield by HPLC, and carried forward to the next step in the synthesis without further purification (theoretical yield for intermediate (14) assumed, 0.56 Kg).

Intermediate (15a,b): A reactor is charged with 1.8 Kg (2.1 L) anhydrous toluene along with sodium hydride (0.26 Kg, 6.6 mol, 2.20 eq) as a 60 wt. % dispersion in mineral oil. To this mixture is added (0.85 Kg, 7.2 mol, 2.4 eq) diethylcarbonate as the reaction mixture is heated to 90° C. over 1 hour. A solution of intermediate (14) (˜1.0 eq) in toluene from the previous step is added to the reaction while maintaining a temperature of 90° C.±5° C. Gas evolution can be observed during this addition. After complete addition, the reaction is stirred for at least 30 minutes or until complete as determined by HPLC analysis. Upon completion, the mixture is cooled to ambient temperature and diluted with 10 wt. % aqueous sulfuric acid (3.8 Kg, 3.9 mol, 1.3 eq) with agitation. The phases are allowed to separate and the lower aqueous phase is removed. The remaining organic phase is concentrated in vacuo (<100 mbar) at approximately 40° C. until a concentrated toluene solution is achieved. The resulting solution is cooled to ambient temperature and carried forward to the next step in the synthesis without further purification (theoretical yield for intermediate (15a,b) assumed, 0.85 Kg).

Intermediate (16a,b; 17a,b): A reactor is charged with a solution of intermediate (15a,b) (0.85 Kg, ˜3.0 mol, ˜1.0 eq) in toluene from the previous step. To the reactor is then added dimethylformamide-dimethylacetal (0.54 Kg, 4.5 mol, 1.5 eq) and the resulting solution is heated to reflux temperature (˜95-105° C.). The lower boiling solvent (methanol from reaction) is allowed to distill off while the temperature is maintained at ≧90° C. Heating is continued for at least 1 hour or until complete as determined by HPLC analysis. Upon completion, the reaction containing the mixture of intermediate (16a,b), is cooled to ambient temperature and toluene (1.8 Kg, 2.1 L) along with cyclopropylamine (0.21 Kg, 3.6 mol, 1.2 eq) are added to the reaction. The reaction is stirred at ambient temperature for at least 30 minutes until complete as determined by HPLC. Upon completion, the reaction is diluted with 10 wt. % aqueous sulfuric acid (2.9 Kg, 3.0 mol, 1.0 eq) with agitation, and the phases are then allowed to separate. The aqueous phase is removed and the organic phase is concentrated under reduced pressure (<100 mbar) at approximately 40° C. by distillation. When the desired concentration is achieved, the solution is cooled to ambient temperature and the toluene solution containing the mixture of intermediate (17a,b) is carried forward to the next step in the synthesis without further purification (theoretical yield for intermediate (17a,b) assumed, ˜1.1 Kg).

Intermediate (18): A reactor is charged with a solution of the mixture of intermediate (17a,b) (˜4.7 Kg, ˜3.0 mol) at ambient temperature. To the reactor is added N,O-bis(trimethylsilyl)acetamide (0.61 Kg, 3.0 mol, 1.0 eq) and the reaction is heated to reflux temperature (˜105-115° C.) for at least 30 minutes or until complete as determined by HPLC analysis. If not complete, an additional amount of N,O-bis(trimethylsilyl)acetamide (0.18 Kg, 0.9 mol, 0.3 eq) is added to the reaction to achieve completion. Upon completion, the reaction is cooled to below 40° C. and organic solvent is removed under reduced pressure (<100 mbar) at approximately 40° C. by distillation until a precipitate is formed. The reaction is cooled to ambient temperature and the precipitated solids are isolated by suction filtration and washed with distilled water twice (1×1.8 L, 1×0.9 L). The solid is dried to afford intermediate (18) as a white solid (0.76 Kg, 82%). The material is used without further purification in the next reaction step.

Intermediate (19): A reactor is charged with solid intermediate (18) (0.76 Kg, ˜2.5 mol, ˜1.0 eq) at ambient temperature followed by ethanol (5.3 Kg, 6.8 L) and 32 wt. % aqueous hydrochloric acid (1.1 Kg, 10 mol). The reaction mixture is brought to reflux temperature (76-80° C.) during which time the mixture first becomes homogeneous and later becomes heterogeneous. The mixture is heated at reflux for at least 5 hours or until complete as determined by TLC analysis (15% EtOAc/Hexanes v/v). Upon completion, the reaction is cooled to 0° C.±5° C. and the precipitated solid is isolated by filtration and washed with distilled water (1.7 Kg) followed by ethanol (1.7 Kg). The isolated solid is dried to afford intermediate (19) as a white solid (0.65 Kg, ˜95%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 14.58 (s, 1H), 8.9 (s, 1H), 8.25 (m, 1H), 7.35 (m, 1H), 4.35 (m, 1H), 4.08 (s, 3H), 1.3 (m, 2H), 1.1 (m, 2H) 19F NMR (CDCl3+CFCl3, 292 MHz) δ (ppm): −119. HPLC: 99.5% by area.

C. Synthesis of borone ester chelate of 1-Cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (20)

Figure US20070232650A1-20071004-C00005

A reactor is charged with boron oxide (2.0 Kg, 29 mol) followed by dilution with glacial acetic acid (8.1 L, 142 mol) and acetic anhydride (16.2 L, 171 mol). The resulting mixture is heated to reflux temperature for at least 2 hours. The reaction contents are cooled to 40° C. and the solid 7-fluoroquinolone acid intermediate (19) (14.2 Kg, 51 mol) is added to the reaction mixture. The mixture is again heated to reflux temperature for at least 6 hours. Reaction progress is monitored by HPLC and NMR. The mixture is cooled to approximately 90° C. and toluene (45 L) is added to the reaction. The reaction is further cooled to 50° C. and tert-butylmethyl ether (19 L) is added to the reaction mixture to bring about precipitation of the product. The mixture is then cooled to 20° C. and the solid product 19 is isolated by filtration. The isolated solids are then washed with tert-butylmethyl ether (26 L) prior to drying in a vacuum oven at 40° C. (50 torr). The product yield obtained for intermediate (20) in this reaction is 86.4%. Raman (cm−1): 3084.7, 3022.3, 2930.8, 1709.2, 1620.8, 1548.5, 1468.0, 1397.7, 1368.3, 1338.5, 1201.5, 955.3, 653.9, 580.7, 552.8, 384.0, 305.8. NMR (CDCl3, 300 MHz) δ (ppm): 9.22 (s, 1H), 8.38-8.33 (m, 1H), 7.54 (t, J=9.8 Hz, 1H), 4.38-4.35 (m, 1H), 4.13 (s, 3H), 2.04 (s, 6H), 1.42-1.38 (m, 2H), 1.34-1.29 (m, 2H). TLC (Whatman MKC18F Silica, 60 Å, 200 μm), Mobile Phase: 1:1 (v/v) CH3CN:0.5N NaCl (aq), UV (254/366 nm) visualization; Rf=0.4-0.5.

D. Coupling of 1-Cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (20) to (3S,5S)-(5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (8), and synthesis of malate salt of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (25)

Figure US20070232650A1-20071004-C00006

A reactor is charged with solid intermediate (20) (4.4 Kg, 10.9 mol) followed by dilution with a solution of triethylamine (TEA) (2.1 L, 14.8 mol) and piperidine side chain intermediate (8) (2.1 Kg, 9.8 mol) in acetonitrile (33.5 L, 15.7 L/Kg) at room temperature. The resulting mixture is warmed to approximately 50° C. until reaction is judged complete. Reaction progress is monitored by HPLC or reverse phase TLC. When complete, the reaction is cooled to approximately 35° C. and reaction volume is reduced to approximately half by distillation of acetonitrile under vacuum between 0-400 torr. The reactor is then charged with 28.2 Kg of 3.0N NaOH (aq) solution and the temperature is raised to approximately 40° C. Distillation under vacuum is continued between 1-4 hours or until no further distillates are observed. The reaction is then cooled to room temperature and the hydrolysis reaction is monitored by HPLC or reverse phase TLC. Upon completion, the reaction mixture is neutralized to a pH of between 6-8 by adding ˜4-5 Kg of glacial acetic acid. The reactor is then charged with 12.7 Kg (9.6 L) of dichloromethane as an extraction solvent, the mixture is agitated, phases are allowed to separate, and the organic dichloromethane phase is removed. The extraction process is repeated two additional times using 12.7 Kg (9.6 L) of dichloromethane, collecting the lower, organic phase each time. The aqueous phase is discarded and the organic extracts are combined in a single reactor. The reactor contents are heated to 40° C. and the reaction volume is reduced to approximately one half by distillation. The reactor is then charged with 20.2 Kg 6.0N HCl (aq) solution, the temperature is adjusted to 35° C., and agitation is allowed for at least 12 hours to permit the Boc deprotection reaction to occur. The reaction is monitored by HPLC or reverse phase TLC. When complete, agitation is discontinued and the phases are allowed to separate. The lower, organic phase is removed and set aside. The reactor is then charged with 12.7 Kg (9.6 L) of dichloromethane as an extraction solvent, the mixture is agitated, phases are allowed to separate, and the organic dichloromethane phase is removed. The organic extracts are combined and discarded. The remaining aqueous phase is diluted with 18.3 Kg distilled water and the temperature is raised to approximately 50° C. Distillation under vacuum (100-400 torr) is performed to remove residual dichloromethane from the reaction. The pH of the reaction is then adjusted to between 7.8-8.1 using about 9.42 Kg of 3.0N NaOH (aq) solution while keeping the temperature of the reaction below 65° C. The reaction is cooled to 50° C. and the precipitated solids are aged for at least an hour prior to cooling the mixture to room temperature. The solids are isolated by suction filtration and washed twice with 5.2 Kg portions of distilled water. The solids are dried for at least 12 hours with suction and then for an additional 12 hours in a convection oven at 55° C. The yield achieved for intermediate (23) in this example is 3.2 Kg (79%). A reactor is charged with 3.2 Kg solid intermediate (23) and the solids are suspended in 25.6 Kg of 95% ethanol as solvent. To the reactor is then added 1.1 Kg of solid D,L-malic acid (24), and the mixture is heated to reflux temperature (˜80° C.). Distilled water (˜5.7 L) is added to the reaction until a complete solution is achieved and 0.2 Kg of activated charcoal is added. The reaction mixture is passed through a filter to achieve clarification, cooled to 45° C. and held for a period of at least 2 hours to allow crystallization to occur. The reaction mixture is further cooled to 5° C. and the suspended solids are isolated by suction filtration. The solids are then washed with 6.6 KG of 95% ethanol and dried for at least 4 hours with suction under vacuum. The solids are then further dried in a convection oven for at least 12 hours at 45° C. to afford 3.1 Kg of intermediate (24) (70%). NMR (D2O, 300 MHz) δ (ppm): 8.54 (s, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 1H), 4.10-3.89 (m, 1H), 3.66 (br s, 1H), 3.58 (s, 3H), 3.45 (d, J=9.0 Hz, 1H), 3.34 (d, J=9.3 Hz, 1H), 3.16 (d, J=12.9 Hz, 1H), 2.65 (dd, J=16.1, 4.1 Hz, 1H), 2.64-2.53 (m, 1H), 2.46 (dd, J=16.1, 8.0 Hz, 1H), 2.06 (br s, 1H), 1.87 (d, J=14.4 Hz, 1H), 1.58-1.45 (m, 1H), 1.15-0.95 (m, 2H), 0.91 (d, J=6.3 Hz, 3H); 0.85-0.78 (m, 2H). TLC (Whatman MKC18F Silica, 60 Å, 200 μm), Mobile Phase: 1:1 (v/v) CH3CN:0.5N NaCl (aq), UV (254/366 nm) visualization. HPLC: Mobile Phase H2O with 0.1% formic acid/Acetonitrile with 0.1% formic acid, gradient elution with 88% H2O/formic acid to 20% H2O/formic acid, Zorbax SB-C8 4.6 mm×150 mm column, Part No. 883975.906, 1.5 ml/min rate, 20 min run time, 292 nm, Detector Model G1314A, S/N JP72003849, Quat Pump Model G1311A, S/N US72102299, Auto Sampler Model G1313A, S/N DE14918139, Degasser Model G1322A, S/N JP73007229; approximate retention time for intermediate (19): 13.0 min; approximate retention time for intermediate (20): 11.6 min; approximate retention time for intermediate (21): 16.3 min; approximate retention time for intermediate (22): 18.2 min; approximate retention time for intermediate (23): 8.6 min; approximate retention time for compound (25): 8.6 min.

………………..

REF

A. ARJONA ET AL: “Nemonoxacin“, DRUGS OF THE FUTURE, vol. 34, no. 3, 1 January 2009 (2009-01-01), page 196, XP55014485, ISSN: 0377-8282, DOI: 10.1358/dof.2009.034.03.1350294

2 * ANONYMOUS: “TaiGen Announces Positive Data From the Phase II Study of Nemonoxacin (TG-873870) in Community-Acquired Pneumonia“, INTERNET CITATION, [Online] 7 April 2008 (2008-04-07), page 1, XP007919900, Retrieved from the Internet: URL:http://www.taigenbiotech.com/news.html#16&gt; [retrieved on 2011-12-12]
3 * ANONYMOUS: “TaiGen Biotechnology Initiates Phase II Trial Of Nemonoxacin For Treatment Of Adult Community Acquired Pneumonia (CAP)“, 20070108, [Online] 8 January 2007 (2007-01-08), page 1, XP007919910, Retrieved from the Internet: URL:http://www.taigenbiotech.com/news.html#11&gt; [retrieved on 2011-12-12]
4 * ANONYMOUS: “TaiGen Initiates Phase 1B Trial of a Novel Quinolone Antibiotic“, 20050618, 18 June 2005 (2005-06-18), pages 1-2, XP007919904,
5 * See also references of WO2010002415A1
WO2007110834A2 * Mar 26, 2007 Oct 4, 2007 Procter & Gamble Malate salts, and polymorphs of (3s,5s)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid
WO2009023473A2 * Aug 5, 2008 Feb 19, 2009 Chi-Hsin Richard King Antimicrobial parenteral formulation
WO2010009014A2 * Jul 10, 2009 Jan 21, 2010 Taigen Biotechnology Co., Ltd.
7-4-2012
TREATMENT OF ANTIBIOTIC-RESISTANT BACTERIA INFECTION
4-18-2012
Coupling Process For Preparing Quinolone Intermediates
10-19-2011
Malate salts, and polymorphs of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid
6-18-2010
STEREOSELECTIVE SYNTHESIS OF PIPERIDINE DERIVATIVES
2-19-2010
PNEUMONIA TREATMENT
5-6-2009
Hydride reduction process for preparing quinolone intermediates
2-13-2009
ANTIMICROBIAL PARENTERAL FORMULATION
11-26-2008
Coupling process for preparing quinolone intermediates
US8158798 Oct 27, 2008 Apr 17, 2012 Taigen Biotechnology Co., Ltd. Coupling process for preparing quinolone intermediates
US8211909 Sep 8, 2008 Jul 3, 2012 Taigen Biotechnology Co., Ltd. Treatment of antibiotic-resistant bacteria infection
WO2010002965A2 * Jul 1, 2009 Jan 7, 2010 Taigen Biotechnology Co., Ltd. Pneumonia treatmen

WO 2007110834

WO 2007110835

WO 2007110836

WO 1999014214

WO 2010077798

1, nemonoxacin; 2, delafloxacin; 3, finafloxacin; 4, zabofloxacin; 5, JNJ-Q2; 6, DS-8587; 7, KPI-10; 8, ozenoxacin; 9, chinfloxacin; 10, ACH-702.

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