WO2014057498A2 - Procédé de préparation d'intermédiaires de cobicistate - Google Patents

Procédé de préparation d'intermédiaires de cobicistate Download PDF

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Publication number
WO2014057498A2
WO2014057498A2 PCT/IN2013/000608 IN2013000608W WO2014057498A2 WO 2014057498 A2 WO2014057498 A2 WO 2014057498A2 IN 2013000608 W IN2013000608 W IN 2013000608W WO 2014057498 A2 WO2014057498 A2 WO 2014057498A2
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WO
WIPO (PCT)
Prior art keywords
formula
ester
cobicistat
preparation
give
Prior art date
Application number
PCT/IN2013/000608
Other languages
English (en)
Other versions
WO2014057498A3 (fr
Inventor
Shankar Rama
Lakshmana Rao Vadali
Ramesh Babu Konda
Ravikanth Jaldu
Govardhana Phani Sharma VEMAVARAPU
Vijay Kumar Palla
Eswara Reddy YERVA
Original Assignee
Mylan Laboratories Ltd.
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Publication date
Application filed by Mylan Laboratories Ltd. filed Critical Mylan Laboratories Ltd.
Publication of WO2014057498A2 publication Critical patent/WO2014057498A2/fr
Publication of WO2014057498A3 publication Critical patent/WO2014057498A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C07D203/24—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/06—Compounds containing sulfur atoms only bound to two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present disclosure relates to cobicistat intermediates and processes for the conversion of intermediates to cobicistat with improved yield and quality.
  • Cobicistat is a component of a four-drug, fixed-dose combination for HIV treatment elvitegravir/cobicistat/emtricitabine/tenofovir (known as the "Quad Pill” or Stribild).
  • the Quad Pill/Stribild was approved by the FDA in August 2012 for use in the United States.
  • Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide fUmarate.
  • US 8148374 patent discloses cobicistat, its pharmaceutically acceptable salts and It ' s pharmaceutical composition.
  • WO2010115000 discloses a process for the preparation of cobicistat using novel intermediates. According to WO2010115000 publication, process for the preparation of Cobicistat and their novel intermediates are prepared as depicted below synthetic scheme- B.
  • a first aspect of the disclosure relates cobicistat intermediates of formula 9, 4a and further conversion of the intermediates to cobicistat.
  • Another aspect relates to a process for the preparation of (S)-2-benzyl-N,N-dimethylaziridine-1- sulfonamide (aziridine formula 8), comprising the steps of; protecting L-phenylalaninol with ⁇ , ⁇ -Dimethylsulfamoylchloride in the presence of a base to give amino protected alcohol of formula 9, and cyclising amino protected alcohol of formula 9 to give aziridine formula 8.
  • Still another aspect relates to a process for the preparation of morpholine thiazole ester formula 3a comprising the steps of: reacting L-thiazole amino lactone formula 5a with trimethylsilyl bromide in the presence of an alcohol solvent to give bromothiazole ester formula 4a, reacting the bromothiazole ester formula 4a with morpholine to give morpholine thiazole ester formula 3a, and
  • Yet another aspect is to provide a novel compound of formula 9.
  • Yet another aspect is to provide a novel compound of formula 4a.
  • Still another aspect relates to a process for the preparation of cobicistat as depicted in the following synthetic scheme (Scheme-C).
  • the present disclosure relates to an improved process for the preparation of cobicistat, wherein the process involves cost effective reagents and the process is feasible in large scale production.
  • the present disclosure encompasses an improved process for the preparation of cobicistat using intermediates of formula 9 and 4a.
  • Yet another embodiment relates to process for the preparation of aziridine intermediate formula 8 comprising the steps of: protecting the amine of L-phenylalaninol of formula 10 with N,N-dimethylsulfamoyl chloride in the presence of base to give amino protected alcohol of formula 9, and
  • Yet another embodiment relates to a process for the preparation of morpholine thiazole ester formula 3a comprising the steps: reacting L-thiazole amino lactone formula 5a with trimethylsilyl bromide in the presence of ROH to give bromothiazole ester formula 4a,
  • the quantity of the reagent ( ⁇ , ⁇ -dimethylsulfomyl chloride) range is between 0.9 to 1.1 molar equivalents with respect to L-phenylalaninol, preferably 1.0 molar equivalent.
  • the base used in this reaction may be, but is not limited to, triethylamine, diethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or combinations thereof.
  • the aziridine formula 8 may be prepared by reacting the compound of formula 9 with p- toluenesulfonyl chloride in the presence of base.
  • the base may be, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, or combinations thereof.
  • the reaction may be carried out, optionally, in the presence of a phase transfer catalyst.
  • the phase transfer catalyst may be, but is not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabubutylammonium iodide, or mixtures thereof.
  • the obtained compound of formula 8 may be crystallized in a solvent.
  • the solvent is selected from isopropyl alcohol, ethanol, methanol, acetone, heptanes, hexanes, and mixtures thereof.
  • the solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, and mixtures thereof, give a corresponding bromothiazole ester formula 4a.
  • the bromothiazole ester formula 4a may be reacted with morpholine in the presence of a solvent.
  • the solvent is selected from dichloromethane, toluene, methyl tert-butyl ether, acetone, acetonitrile, tetrahydrofuran, and mixtures thereof to give morpholine thiazole ester formula 3a.
  • the morpholine thiazole ester formula 3a may be optionally converted to a corresponding salt by treatment with an acid.
  • the acid is selected form oxalic acid, p-toluene sulfonic acid, salicylic acid, tartaric acid, formic acid, and citric acid.
  • solvent refers to an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a chlorinated solvent, dimethyl formamide, dimethy!sulfoxide, alkyl ester, an alcohol, water, ketone solvent, a nitrile solvent, or an ether.
  • Alcohol solvents include, but are not limited tomethanol, ethanol, propanol, isopropanol, n- butanol, sec-butanol, 2-butanol, t-butanol, pentanol, or mixtures thereof.
  • the ether solvents include, but are riot limited to tetrahydrofuran, 1 ,4-dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixtures thereof.
  • the chlorinated sol solvents include, but are not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixtures thereof.
  • the ketone solvents include, but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, or mixtures thereof.
  • the alkyl ester solvents include, but are not limited to ethyl acetate, ethyl acetoacetate, methyl acetate, or mixtures thereof.
  • the hydrocarbon solvents include, but are not limited to hexane, pentane, heptane, cyclohexane, xylene, toluene, or mixtures thereof.
  • the nitrile solvents include, but are not limited to acetonitrile.
  • the reaction may be carried out without isolating the bromo intermediate of compound of formula 4a and it is formed in-situ in the reaction.
  • the instant disclosed processes may be carried out with about one molare equivalents of N,N-dimethylsulfamoyl chloride.
  • the flammable reagent, sodium hydride, is' not used in the instant disclosed process step.
  • the instant disclosed process may utilize an optional phase transfer catalyst for faster
  • the instant disclosed process utilizes the trimethylsilyl bromide, a cheaper reagent than
  • Aqueous L-phenylalanine methyl ester hydrochloride formula 1 1 (100 gm, 0.463 mol) solution was added to a solution of sodium borohydride (53 gm, 1.4mol) in water at 0-5 °C over period of 3-4 hours.
  • the reaction mixture was stirred at about the same temperature for about 12 hours and then the pH was adjusted to about 5.0 with concentrated hydrochloric acid, followed by a basification with a sodium hydroxide solution (300 ml of 30% aqueous).
  • the reaction mixture was maintained at reflux for about 3 hours, and then the reaction mass was cooled to about 20-25 °C.
  • the aqueous solution thus obtained was extracted with dichloromethane.
  • Example-2 Preparation of ⁇ , ⁇ -dimethylsulfamoyl amino alcohol Formula 9: ⁇ , ⁇ -Dimethylsulfamoyl chloride (63 gm, 0.438 mol) was added to L-phenylalaninol (63 gm, 0.417 mol) in a solution of dichloromethane and triethylamine (51 gm, 0.504 mol) at reflux. The reaction mixture was stirred at about the same temp for 20-24 hours. The reaction mixture was then washed with a 1 N hydrochloric acid solution and water.
  • ⁇ , ⁇ -Dimethylsulfamoyl chloride 63 gm, 0.438 mol
  • L-phenylalaninol 63 gm, 0.417 mol
  • dichloromethane and triethylamine 51 gm, 0.504 mol
  • Tetrabutyl ammonium bromide (6 gm, 0.018 mol), potassium carbonate (217.3 gm, 1.575 mol) and p-toluenesulfonyl chloride (78.6 gm, 0.412 mol) were added to ⁇ , ⁇ -dimethylsulfamoyl amino alcohol (100 gm, 0.387 mol) in dichloromethane at 0-5 °C. The temperature of the reaction mass was raised to about 20-25 °C. The reaction mass was stirred at about same temperature for 12- 14 hours.
  • Aqueous L-phenylalanine methyl ester hydrochloride formula 1 1 (100 gm, 0.463 mol) solution was added to a solution of sodium borohydride (53 gm, 1.4 mol) in water at 0-5 °C for 3-4 hours. The reaction mixture was then stirred at about the same temperature for about 12 hours. Then the pH of the mixture was adjusted to 5.0 with concentrated hydrochloric acid followed by a basification with an aqueous sodium hydroxide solution (300ml of 30% aqueous). The reaction mixture was maintained at reflux for about 3 hours and then cooled to about 20-25 °C. The aqueous solution obtained was extracted with dichloromethane to give L-phenylalaninol formula 10 as a dichloromethane solution.
  • This dichloromethane layer was used without further purification by mixing with N,N-dimethylsulfamoyl amino alcohol, tetra butyl ammonium bromide (6 gm, 0.018 mol), potassium carbonate (217.3 gm, 1.575 mol) and p-toluenesulfonyl chloride (78.6 gm, 0.412 mol) at 0-5 °C.
  • the temperature of the reaction mass was raised to about 20-25 °C, then the reaction mass was stirred the reaction mass at about the same temperature for 12-14 hours.
  • a pre-cooled solution (about -20 °C of N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ((80 gm) in dichloromethane (about 800 ml)) was added to the reaction mixture while the reaction mass temperature was maintained at not more than about -20 °C.
  • the reaction mixture was then stirred at about the same temperature for 24 hours.
  • the reaction mass temperature was then adjusted to about 5 °C and the reaction was quenched with an aqueous citric acid solution.
  • the layers were separated and the organic layer was washed once with aqueous potassium bicarbonate solution and water.
  • the organic layer was concentrated under reduced pressure to give cobicistat (about 160 gm) as a residue.

Abstract

Cette invention concerne des intermédiaires de cobicistate, des procédés et la conversion ultérieure des intermédiaires en cobicistate avec un rendement et une qualité accrus.
PCT/IN2013/000608 2012-10-08 2013-10-07 Procédé de préparation d'intermédiaires de cobicistate WO2014057498A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4173/CHE/2012 2012-10-08
IN4173CH2012 2012-10-08

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WO2014057498A2 true WO2014057498A2 (fr) 2014-04-17
WO2014057498A3 WO2014057498A3 (fr) 2014-06-19

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103694196A (zh) * 2012-09-27 2014-04-02 上海迪赛诺化学制药有限公司 细胞色素p450单加氧酶抑制剂中间体及其制法和用途
WO2015083066A1 (fr) * 2013-12-03 2015-06-11 Mylan Laboratories Ltd. Préparation d'intermédiaires de cobicistat
CN105732538A (zh) * 2014-12-09 2016-07-06 杭州普晒医药科技有限公司 可比司他帕莫酸盐及其制备方法、药物组合物和用途
WO2016128885A1 (fr) * 2015-02-09 2016-08-18 Laurus Labs Private Limited Procédé de préparation de cobicistat
CN107513046A (zh) * 2016-06-15 2017-12-26 江苏福瑞生物医药有限公司 一种可比司他的合成方法
CN105884760B (zh) * 2016-06-13 2019-01-04 厦门市蔚嘉化学科技有限公司 一种可比司他中间体的制备方法
EP3259267A4 (fr) * 2015-02-18 2019-01-23 MSN Laboratories Private Limited Nouveau procédé de préparation de carbamate de 1,3-thiazol-5-ylméthyl[(2r,5r)-5-{[(2s)-2-[(méthyl{[2-(propan-2-yl)- 1,3-thiazol-4-yl]méthyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphénylhexan-2-yle]
CN110642721A (zh) * 2018-12-21 2020-01-03 安徽贝克生物制药有限公司 盐酸司来吉兰的制备方法
CN110668951A (zh) * 2018-12-21 2020-01-10 安徽贝克生物制药有限公司 一种盐酸司来吉兰的合成工艺
CN112110842A (zh) * 2020-09-08 2020-12-22 乐威医药（江苏）股份有限公司 一种手性磺酰基环丙胺衍生物的一锅法生产工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010115000A2 (fr) 2009-04-03 2010-10-07 Gilead Sciences, Inc. Procédés et intermédiaires pour la préparation d'agents pharmaceutiques
US8148374B2 (en) 2007-02-23 2012-04-03 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8148374B2 (en) 2007-02-23 2012-04-03 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
WO2010115000A2 (fr) 2009-04-03 2010-10-07 Gilead Sciences, Inc. Procédés et intermédiaires pour la préparation d'agents pharmaceutiques

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103694196A (zh) * 2012-09-27 2014-04-02 上海迪赛诺化学制药有限公司 细胞色素p450单加氧酶抑制剂中间体及其制法和用途
WO2015083066A1 (fr) * 2013-12-03 2015-06-11 Mylan Laboratories Ltd. Préparation d'intermédiaires de cobicistat
US9975864B2 (en) 2013-12-03 2018-05-22 Mylan Laboratories Limited Preparation of cobicistat intermediates
CN105732538A (zh) * 2014-12-09 2016-07-06 杭州普晒医药科技有限公司 可比司他帕莫酸盐及其制备方法、药物组合物和用途
WO2016128885A1 (fr) * 2015-02-09 2016-08-18 Laurus Labs Private Limited Procédé de préparation de cobicistat
EP3259267A4 (fr) * 2015-02-18 2019-01-23 MSN Laboratories Private Limited Nouveau procédé de préparation de carbamate de 1,3-thiazol-5-ylméthyl[(2r,5r)-5-{[(2s)-2-[(méthyl{[2-(propan-2-yl)- 1,3-thiazol-4-yl]méthyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphénylhexan-2-yle]
CN105884760B (zh) * 2016-06-13 2019-01-04 厦门市蔚嘉化学科技有限公司 一种可比司他中间体的制备方法
CN107513046A (zh) * 2016-06-15 2017-12-26 江苏福瑞生物医药有限公司 一种可比司他的合成方法
CN110642721A (zh) * 2018-12-21 2020-01-03 安徽贝克生物制药有限公司 盐酸司来吉兰的制备方法
CN110668951A (zh) * 2018-12-21 2020-01-10 安徽贝克生物制药有限公司 一种盐酸司来吉兰的合成工艺
CN110642721B (zh) * 2018-12-21 2022-09-30 安徽贝克生物制药有限公司 盐酸司来吉兰的制备方法
CN110668951B (zh) * 2018-12-21 2022-09-30 安徽贝克生物制药有限公司 一种盐酸司来吉兰的合成工艺
CN112110842A (zh) * 2020-09-08 2020-12-22 乐威医药（江苏）股份有限公司 一种手性磺酰基环丙胺衍生物的一锅法生产工艺

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