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WO2006100552A1 - Procedes pour preparer du lopinavir et son produit intermediaire, l'acide acetique -(s)-tetrahydro-$g(a)-(1-methylethyl)-2-oxo-1(2h)-pyrimidine - Google Patents

Procedes pour preparer du lopinavir et son produit intermediaire, l'acide acetique -(s)-tetrahydro-$g(a)-(1-methylethyl)-2-oxo-1(2h)-pyrimidine Download PDF

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Publication number
WO2006100552A1
WO2006100552A1 PCT/IB2006/000413 IB2006000413W WO2006100552A1 WO 2006100552 A1 WO2006100552 A1 WO 2006100552A1 IB 2006000413 W IB2006000413 W IB 2006000413W WO 2006100552 A1 WO2006100552 A1 WO 2006100552A1
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WO
WIPO (PCT)
Prior art keywords
process according
formula
lopinavir
tetrahydro
methylethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2006/000413
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English (en)
Inventor
Prosenjit Bose
Sujoy Biswas
Ramendra Singh Rathore
Yatendra Kumar
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2006100552A1 publication Critical patent/WO2006100552A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the field of the invention relates to processes for the preparation of (S)-tetrahydro- ⁇ -(l-methylethyl)-2-oxo-l(2H)-pyrimidineacetic acid or a salt thereof, and to use of this compound as an intermediate for the preparation of compounds with antiviral activity.
  • the invention also relates to a process for the preparation of lopinavir, and pharmaceutical compositions that include the lopinavir.
  • lopinavir is [lS-[lR*,(R*),3R*,4R*]]-N-[4-[[(2,6-dimethyl- phenoxy)acetyl]amino]-3-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]tetrahydro-Q!-(l- methylethyl)-2-oxo-l(2H)-pyrimidineacetamide having the structural Formula I. It is indicated in combination with other antiretroviral agents for the treatment of HIV- infection.
  • U.S. Patent No. 5,914,332 discloses a process for the preparation of (S)-tetrahydro- ⁇ -(l-methylethyl)-2-oxo-l(2H)-pyrimidine acetic acid by reacting L- valine with acrylonitrile and methyl chloroformate, followed by isolating the N-(2-cyanoethyl)-N- (methoxycarbonyl)-L-valine intermediate which is then hydrogenated over Raney-nickel in the presence of alkaline earth metal hydroxide to get the required intermediate.
  • the overall yield obtained is about 25%.
  • the process includes: a) reacting L-valine with acrylonitrile and alkyl chloroformate to form N-(2- cyanoethyl)-N-(2-alkoxycarbonyl)-L-valine; b) hydrogenating the product of step a) in the presence of a hydrogenating catalyst and a base; and c) cyclizing the product of step b) to get the (S)-tetrahydro-o(l -methylethyl)- 2-oxo-l (2H)-pyrimidineacetic acid of Formula II, or a salt thereof, wherein all the process steps are carried out in situ.
  • the process may include further drying of the product obtained.
  • the process may include further converting the product obtained into lopinavir.
  • the lopinavir may be made into a finished dosage form with one or more pharmaceutically acceptable excipients and administered to a patient in need of an anti-viral therapy.
  • the process includes: a) reacting L-valine with acrylonitrile and alkyl chloroformate to form N-(2- cyanoethyl)-N-(2-alkoxycarbonyl)-L-valine; b) hydrogenating the product of step a) in the presence of a hydrogenating catalyst and a base; c) cyclizing the product of step b) to get (S)-tetrahydro- ⁇ -(l-methylethyl)-2- oxo-l(2H)-pyrimidineacetic acid of Formula II or salt thereof; and d) reacting the compound of Formula II with a compound of Formula III,
  • a pharmaceutical composition that includes a therapeutically effective amount of lopinavir; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the resulting pharmaceutical composition or dosage form may be administered to a patient in need of an anti-viral therapy.
  • the inventors have developed an efficient process for the preparation of (S)- tetrahydro- ⁇ -(l-methylethyl)-2-oxo-l(2H)-pyrimidineacetic acid of Formula II.
  • the process involves reacting L-valine with acrylonitrile and alkyl chloroformate to form N- (2-cyanoethyl)-N-(2-alkoxycarbonyl)-L-valine; hydrogenating in the presence of a hydrogenating catalyst and a base; and cyclizing to get the (S)-tetrahydro- ⁇ -(l- methylethyl)-2-oxo-l(2H)-pyrimidineacetic acid of Formula II or salt thereof, wherein all the process steps are carried out in situ.
  • L-valine may be added to water or an organic solvent and an alkali metal salt or an alkaline earth metal salt, or a mixture thereof, at a temperature of from about O 0 C to about 6O 0 C for about 0 to 1.5 hours.
  • the reaction mixture may be stirred at a temperature from about O 0 C to about 6O 0 C to get a clear solution.
  • Acrylonitrile may be added to the clear solution at a temperature of from about O 0 C to about 1O 0 C for about 0 to 1.5 hours.
  • the resulting reaction mixture may be stirred at a temperature of from about O 0 C to about 10 0 C for about 2 to 10 hours and water may be added at the same temperature.
  • the organic solvent, alkali metal salt, or alkaline earth metal salts which can be used in the reaction are known to a person of ordinary skill in the art. Any organic solvents can be used which are inert and do not change under the reaction conditions.
  • alkali metal salts include salts of lithium, sodium, or potassium.
  • alkaline earth metal salts include those of magnesium, calcium or barium.
  • alkyl groups of alkylchloroformate include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and the like.
  • the alkylchloroformate may be added at a temperature from about O 0 C to about 6O 0 C, for example from about 2O 0 C to about 4O 0 C.
  • the pH of the mixture may be maintained at about 8 to 12 with an addition of an alkali metal salt or an alkaline earth metal salt over a period of 0.5 to 2 hours.
  • the reaction mixture may be stirred at a temperature from about O 0 C to about 6O 0 C for about 2 to 30 hours at pH 8 to 12.
  • a suitable organic solvent may be added to the reaction mixture and it may be cooled to about O 0 C to about 4O 0 C.
  • the pH of the mixture may be adjusted to about 0 to 4 by addition of a mineral acid.
  • the organic layer may be separated and concentrated under reduced pressure to give N-(2-cyanoethyl)-N-(2-alkoxycarbonyl)-L-valine as oil.
  • suitable solvent includes any solvent which is immiscible or partially miscible with water.
  • solvents include chlorinated hydrocarbons such as methylene dichloride, chloroform, and dichloroethane; esters such as ethyl acetate and isopropyl acetate; ketones such as methylisobutylketone; hydrocarbons such as benzene, toluene and hexane; and mixtures thereof.
  • mineral acid includes, but is not limited to, hydrochloric acid, sulphuric acid, nitric acid, perchloric acid, hydroiodic acid, and hydrobromic acid.
  • N-(2-cyanoethyl)-N-(2-alkoxycarbonyl)-L- valine may be dissolved in an organic solvent followed by the addition of a hydrogenating catalyst and a base.
  • the hydrogenation catalysts are the customary hydrogenation catalysts known in organic chemistry, such as transition metal compounds.
  • transition metal compounds include palladium compounds such as palladium/carbon and palladium hydroxide, platinum compounds such as platinum oxide and platinum/carbon, ruthenium compounds such as ruthenium oxide, rhodium compounds such as rhodium/carbon and nickel compounds such as Raney nickel.
  • bases which can be used in the hydrogenation reaction include, but are not limited to, pyridine, ammonia, hydroxylamine, methylamine, and the like.
  • the hydrogenation reaction may be carried out at normal pressure, or at elevated pressure depending on the choice of a catalyst. In general, it may be carried out at a hydrogen pressure in the range from about 1 kg/cm 2 to about 10 kg/cm 2 , for example at a hydrogen pressure in the range from about 2 kg/cm 2 to about 6 kg/cm 2 .
  • the hydrogenation temperature may be varied depending on the choice of a catalyst and/or pressure employed.
  • the hydrogenation may be carried out at a temperature range from about 2O 0 C to about 120 0 C, or at a temperature range from about 3O 0 C to about 8O 0 C. In particular, it may be carried out at a temperature range from about 35°C to about 65°C.
  • the catalyst may be filtered off and washed with a solvent.
  • the filtrate may be concentrated under vacuum.
  • the volume may be reduced to between about half of the original volume and about one-fourth of volume.
  • Water may be added to the reduced filtrate residue and hydroxide of an alkali metal or an alkaline earth metal may be added at a temperature of from about O 0 C to about 6O 0 C.
  • the mixture may be heated up to a reflux temperature for about 5 hours to about 12 hours till the reaction is complete.
  • the reaction mixture may be cooled to a temperature of from about O 0 C to about 40 0 C. It may be acidified with a'mineral acid to a pH of less than 2.
  • Sodium chloride may be added to the above mixture followed by the addition of a suitable organic solvent.
  • the mixture may be stirred at a temperature of from about O 0 C to about 6O 0 C for about 1 to 60 minutes.
  • the organic layer may be separated and the aqueous layer may be extracted with organic solvent.
  • the organic layers may be combined and evaporated under reduced pressure to get a solid.
  • the solid may be suspended in organic solvent and the suspension stirred at a temperature of from about 1O 0 C to about 100 0 C.
  • the reaction mixture may be partially concentrated under reduced pressure.
  • a further quantity of the same or a different organic solvent may be added into the above mixture and the suspended mixture may be stirred at a temperature of from about 1O 0 C to about 100 0 C. It may be cooled down to about 5 0 C, stirred at the temperature of about 5 to 15 0 C for 5 to 18 hours and then at about O 0 C for about 1 to 5 hours.
  • the white solid then should be filtered, washed and dried
  • the mineral acid which may be used includes hydrochloric acid, sulphuric acid, nitric acid, perchloric acid, hydroiodic acid, hydrobromic acid.
  • the organic solvents which can be used in these reactions are known to a person of ordinary skills in art. Suitable solvents are inert organic solvents which do not react under the reaction conditions.
  • solvents examples include alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; esters such as ethylacetate and isopropylacetate; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; nitriles such as acetonitrile and benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; alkyl ethers such as diethylether, diisopropylether and dimethoxye thane; cyclic ethers such as dioxane and tetrahydrofuran, and mixtures thereof.
  • alcohols such as methanol, ethanol, isopropanol and butanol
  • ketones such as acetone and methyl isobutyl ketone
  • esters such as ethylacetate and isopropy
  • the inventors also have developed a process for the preparation of lopinavir of Formula I or a pharmaceutically acceptable salt, ester or a prodrug thereof.
  • the process involves reacting L-valine with acrylonitrile and alkyl chloroformate to form N-(2- cyanoethyl)-N-(2-alkoxycarbonyl)-L-valine; hydrogenating in presence of hydrogenating catalyst and a base; cyclizing to get the (S)-tetrahydro-O!-(l-methylethyl)-2-oxo-l(2H)- pyrimidineacetic acid of Formula II or salt thereof; and reacting the compound of Formula II with a compound of Formula III to get lopinavir of Formula I or a pharmaceutically acceptable salt, ester or a prodrug thereof, wherein all the process steps for the preparation of the compound of Formula II are carried out in situ.
  • the (S)-tetrahydro-O!-(l-methylethyl)-2-oxo-l(2H) - pyrimidineacetic acid may be obtained in an overall yield of about 65%, i.e., in a yield higher than that obtained by working according to the process described in U.S. Patent No. 5,914,332 and PCT application WO 03/101971.
  • Methylchloroformate (79.5 g) was added slowly to the resultant mass at 20-25 0 C while maintaining the pH of the mixture from about 9.5 to 10.5 by addition of 30% sodium hydroxide over a period of 1 hour. The mixture was stirred at 20-25 0 C for 15 hours at pH 9.5-10.5. Methylene chloride (120 ml) was added into the mixture and it was cooled to 10 0 C. Concentrated hydrochloric acid (100 ml) was added to adjust its pH to 1.0-1.5. The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 X 120 ml). The combined organic layer was concentrated under reduced pressure to provide the title compound as a thick oil.
  • Example 2 (S)-Tetrahvdro-o:-(l-methylethyl)-2-oxo-l(2h)-pyrimidineacetic acid N-(2-cyanoethyl)-N-(2-methoxycarbonyl)-L- valine (20.5 g) was dissolved in methanol (70 ml) followed by addition of Raney-Nickel (50% wet, 16 g) and aqueous ammonia (70 ml). The mixture was hydrogenated under pressure 4 kg/cm at 50 0 C for about 4-5 hours till completion of reaction. After cooling the reaction mixture to room temperature, the catalyst was filtered and washed with methanol (80 ml).
  • the combined filtrate was concentrated under vacuum to l/4th of initial volume at a temperature not exceeding 50 0 C to obtain a residue.
  • Water (100 ml) was added to the residue followed by addition of sodium hydroxide (6.6 g) at 20-25 0 C.
  • the mixture was refluxed for 7-8 hours till reaction completion.
  • the reaction mixture was cooled to 10-15 0 C and then acidified with concentrated hydrochloric acid (about 17 ml) to pH less than 1.5.
  • Sodium chloride (40 g) was added into the above mixture followed by addition of methylene chloride (80 ml). The mixture was stirred at 20-25 0 C for 10-15 minutes.
  • the organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 80 ml).
  • Step 1 Preparation of 2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride.
  • Step 2 (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyI)amino-3-hydroxy-5-[2s-(l- tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-l,6-diphenylhexane
  • reaction mixture was stirred at 0 to 5 0 C for next 30 minutes, and then warmed to room temperature (20-25 0 C) and stirred at room temperature (20-25 0 C) for 12 hours.
  • the reaction mixture was again cooled to 1O 0 C and quenched with aqueous hydrochloric acid (100 ml, 0.2N) at 10-15°C.
  • Ethyl acetate (50 ml) was added into the mixture and stirred at room temperature (20 to 25°C) for 30 minutes.
  • the layers were separated and the organic layer was washed with aqueous sodium bicarbonate (50 ml, 5% w/v) followed by washing with water (2 X 50 ml).
  • the solvent was evaporated under reduced pressure to get crude material as an off- white solid.
  • the compounds described herein can be formulated into dosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial.
  • the lopinavir made according to the above processes can be formulated into a tablet, capsule, injectable solution, etc. along with one or more pharmaceutically acceptable excipients and administered to a patient in need of an anti-viral treatment.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • AIDS & HIV (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés pour préparer de l'acide acétique (S)-tétrahydro-α-(1-méthyléthyl)-2-oxo-1(2H)-pyrimidine ou un sel de celui-ci, ainsi que l'utilisation de ce composé comme produit intermédiaire dans la préparation de composés présentant une activité antivirale. Cette invention concerne également un procédé pour préparer du lopinavir, ainsi que des compositions pharmaceutiques comprenant du lopinavir.
PCT/IB2006/000413 2005-02-28 2006-02-28 Procedes pour preparer du lopinavir et son produit intermediaire, l'acide acetique -(s)-tetrahydro-$g(a)-(1-methylethyl)-2-oxo-1(2h)-pyrimidine Ceased WO2006100552A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN429DE2005 2005-02-28
IN429/DEL/2005 2005-02-28

Publications (1)

Publication Number Publication Date
WO2006100552A1 true WO2006100552A1 (fr) 2006-09-28

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PCT/IB2006/000413 Ceased WO2006100552A1 (fr) 2005-02-28 2006-02-28 Procedes pour preparer du lopinavir et son produit intermediaire, l'acide acetique -(s)-tetrahydro-$g(a)-(1-methylethyl)-2-oxo-1(2h)-pyrimidine

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010089753A3 (fr) * 2009-02-06 2012-01-05 Hetero Research Foundation Nouveaux polymorphes du lopinavir
CN103936679A (zh) * 2014-03-03 2014-07-23 厦门市亨瑞生化有限公司 一种2s—（1—四氢嘧啶—2—酮）—3—甲基丁酸的制备方法
CN113512569A (zh) * 2021-03-12 2021-10-19 江苏阿尔法药业股份有限公司 一种洛匹那韦中间体的酶催化合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5914332A (en) * 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
WO2003101971A1 (fr) * 2002-05-30 2003-12-11 Clariant Life Science Molecules (Italia) S.P.A. Procede de preparation d'acide acetique (s)-tetrahydro-a-(1-methylethyl)-2-oxo-1(2h)-pyrimidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5914332A (en) * 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
WO2003101971A1 (fr) * 2002-05-30 2003-12-11 Clariant Life Science Molecules (Italia) S.P.A. Procede de preparation d'acide acetique (s)-tetrahydro-a-(1-methylethyl)-2-oxo-1(2h)-pyrimidine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010089753A3 (fr) * 2009-02-06 2012-01-05 Hetero Research Foundation Nouveaux polymorphes du lopinavir
US8445506B2 (en) 2009-02-06 2013-05-21 Hetero Research Foundation Polymorphs of lopinavir
CN103936679A (zh) * 2014-03-03 2014-07-23 厦门市亨瑞生化有限公司 一种2s—（1—四氢嘧啶—2—酮）—3—甲基丁酸的制备方法
CN103936679B (zh) * 2014-03-03 2016-05-11 厦门市亨瑞生化有限公司 一种2s—(1—四氢嘧啶—2—酮)—3—甲基丁酸的制备方法
CN113512569A (zh) * 2021-03-12 2021-10-19 江苏阿尔法药业股份有限公司 一种洛匹那韦中间体的酶催化合成方法
CN113512569B (zh) * 2021-03-12 2023-04-18 江苏阿尔法药业股份有限公司 一种洛匹那韦中间体的酶催化合成方法

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