WO2009136365A1 - Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof - Google Patents

Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof Download PDF

Info

Publication number
WO2009136365A1
WO2009136365A1 PCT/IB2009/051843 IB2009051843W WO2009136365A1 WO 2009136365 A1 WO2009136365 A1 WO 2009136365A1 IB 2009051843 W IB2009051843 W IB 2009051843W WO 2009136365 A1 WO2009136365 A1 WO 2009136365A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
amino
represented
compound
acid
Prior art date
Application number
PCT/IB2009/051843
Other languages
French (fr)
Inventor
Rakesh Sinh
Prasad Yeragorla
Mahavir Singh Khanna
Mohan Prasad
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to US12/991,635 priority Critical patent/US20110178305A1/en
Priority to EP09742538A priority patent/EP2288593A1/en
Publication of WO2009136365A1 publication Critical patent/WO2009136365A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals

Definitions

  • the present invention relates to production method of threo-3,4-epoxy-2-amino-l- substituted butane derivatives represented by general Formula I:
  • R 1 is phenyl
  • R is hydrogen or amino protecting groups
  • R 3 is secondary or tertiary lower alkyl and configurations at 2 and 3 positions are either (2S,3R) or (2R,3S).
  • the carbon atom bonded to the radical R 3 in Formula I may be in (R)-, (S)- or
  • the compounds of Formula I are useful intermediates for the production of various HIV protease compounds.
  • (2S,3R)-3,4-epoxy-2-amino-l-substituted butane derivatives represented by general Formula Ia are useful pharmaceutical intermediates of atazanavir- an inhibitor of retroviral aspartate protease.
  • Atazanavir and its bisulfate salt (1:1) are disclosed in U.S. Patent Nos. 5,849,911 and 6,087,383 respectively.
  • Atazanavir bisulfate is chemically known as (35,85,95,125)- 3,12-bis(l,l-dimethylethyl)-8-hydroxy-4,l l-dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1) and represented by following chemical structure -
  • Atazanavir bisulfate is inhibitor of retroviral aspartate protease and also known to have high degree of inhibitory activity against the HIV virus.
  • U.S. Patent No. 5,847,169 describes process for preparing 3,4-epoxy-2-amino-l- substituted butane derivatives comprising the steps of activating an aminodiol, acylating the aminodiol and reacting the acylated aminodiol with a base to form an epoxy compound.
  • the methods disclosed in U.S. Patent No. 6,127,556 for the preparation of epoxy compounds or 3,4-epoxy-2-amino-l -substituted butane derivatives make use of halomethyl organometallic reagent and aminoaldehyde compound whereas U.S. Patent No.
  • 6,278,002 describes the preparation of similar type of compounds by making use of quaternary ammonium salt or carboxylic acid metal salt.
  • U.S. Patent No. 6,693,205 makes use of Mitsunobu reaction during preparation of 3,4-epoxy-2-amino-l-substituted butane derivatives.
  • U.S. Patent Nos. 5,693,847; 6,344,572; 6,764,545; 6,765,100; 6,867,311; 6,605,732 and 7,122,696 mention preparation of various 3,4-epoxy-2-amino-l -substituted butane derivatives and are incorporated herein by reference.
  • the present invention overcomes the disadvantages associated with the prior art by providing a process for the preparation of compounds of the Formula I using reagents and conditions which are convenient to operate on commercial scale and operationally safe.
  • the threo-4-halo-3-hydroxy-2-amino-l-substituted butane derivative represented by general Formula II serves as substrate in the preparation method of 3,4-epoxy-2-amino- 1 -substituted butane derivatives (Formula-I) of present invention.
  • R 1 , R 2 , R 3 in Formula-II are same as mentioned hereinabove for the compounds of Formula I and X represents halogen atom, such as a chlorine, bromine, fluorine or iodine.
  • the carbon atom bonded to the radical R 3 in Formula II may be in the (R)-, (S)- or (R,S)-configuration.
  • the configurations at positions 2 and 3 in the above Formula II are either (2S,3R) or (2R,3S).
  • the preferred configuration is (2S,3R) as represented by Formula Ha Formula Ha
  • the above threo-4-halo-3-hydroxy-2-amino-l- substituted butane derivative should have the (2S,3R) configuration (Formula-IIa).
  • the substrate should be of (2R,3S) configuration.
  • the present invention provides efficient process for the preparation of compounds of the Formulae I and II. Detailed Description of the Invention
  • Tower alkyl' is meant for 'C 1 -C 4 alkyl'.
  • the Tower alkyl' is selected from the group comprising of tert-butyl, sec-butyl, isobutyl, n-butyl, isopropyl, n- propyl, ethyl and methyl.
  • amino protecting groups' can be any protecting group known to a person skilled in the art. Some non-limiting examples are lower alkoxycarbonyl (such as tert- butoxycarbonyl, methoxycarbonyl etc.), aryl-lower alkoxycarbonyl (such as benzyloxycarbonyl) or acyl protecting group (such as CH3CO, trifluoroacetyl).
  • lower alkoxycarbonyl such as tert- butoxycarbonyl, methoxycarbonyl etc.
  • aryl-lower alkoxycarbonyl such as benzyloxycarbonyl
  • acyl protecting group such as CH3CO, trifluoroacetyl
  • 'Atazanavir bisulfate' refers to Atazanavir bisulfate as well as Atazanavir sulfate.
  • a first aspect of the present invention provides process for the preparation of 4- halo-3-hydroxy-2-amino-l -substituted butane derivative represented by Formula II
  • R is hydrogen or amino protecting groups
  • R 3 is secondary or tertiary lower alkyl
  • X is chlorine, bromine, fluorine or iodine.
  • the compounds of Formula II and III are either in (2S.3R) or (2R.3S) configuration.
  • the carbon atom bonded to the radical R 3 in Formula II and IV can be in (R)-, (S)- or (R,S)-configuration.
  • the reaction can be performed in presence of base and organic solvent.
  • the 'base' as used herein can be selected from the group comprising of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate and alkaline earth metal phosphate.
  • the base can be an organic base.
  • Some non-limiting examples of base are NaOH, KOH, Mg(OH) 2 , K 2 HPO 4 , MgC ⁇ 3 , Na 2 COs, K 2 CO 3 , triethylamine, diisopropylethylamine and/or N-methyl morpholine.
  • the Organic solvent' as used herein can be selected from the group comprising methylene chloride, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile and N,N-dimethylformamide or mixture(s) thereof.
  • the acid of Formula IV can be converted into its active ester by reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l- pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l- pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • the active ester of an acid of Formula IV can be represented by following compound of Formula V
  • reaction of compound of Formula III with active ester of acid of Formula IV can be performed at temperature selected from about 5°C to about 40 0 C.
  • the compound of Formula III in its hydrochloride salt form can be reacted with active ester of compound of Formula IV.
  • the compound of Formula III in its salt form is reacted with active ester of acid of Formula IV in presence of base and organic solvent at temperature selected from about 5°C to about 40 0 C.
  • the reaction is performed at pH range of 5 to 7.
  • the so produced compound of Formula II is then isolated from the reaction mixture.
  • the obtained 4-halo-3-hydroxy-2-amino-l- substituted butane derivative of Formula II has (2S,3R) configuration and can be represented by Formula-IIa.
  • the compounds of Formula II and Ha can be further used as intermediates in the preparation of Atazanavir or salt thereof.
  • a second aspect of the present invention provides process for preparation of threo- 3,4-epoxy-2-amino-l -substituted butane derivative represented by Formula I:
  • R 1 is phenyl
  • R 2 is hydrogen or amino protecting groups
  • R 3 is secondary or tertiary lower alkyl and X is chlorine, bromine, fluorine or iodine.
  • the compounds of Formula I, II and III can be in (2S,3R) or (2R,3S) configuration.
  • the carbon atom bonded to the radical R 3 in Formula I, II and IV can be in (R)-, (S)- or (R,S)-configuration.
  • the step a) can be performed in presence of base and organic solvent.
  • the 'base' as used herein in steps a) and b) can be selected from the group comprising alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate and alkaline earth metal phosphate.
  • the base can be an organic base.
  • Some non-limiting examples of base are NaOH, KOH, Mg(OH) 2 , K 2 HPO 4 , MgCO 3 , Na 2 CO 3 , K 2 CO 3 , triethylamine, diisopropylethylamine and/or N-methyl morpholine.
  • the Organic solvent' as used herein in step a) can be selected from the group comprising methylene chloride, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile and/or N,N-dimethylformamide.
  • the acid of Formula IV can be converted into its active ester by the reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l- pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l- pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • the active ester of an acid of Formula IV can be represented by following compound of Formula V
  • the step a) reaction can be performed at temperature selected from about 5°C to about 40 0 C.
  • the compound of Formula III can be reacted with compound of Formula IV in the form of its hydrochloride salt.
  • step a) 4-halo-3-hydroxy-2-amino-l -substituted butane derivative compound of Formula II obtained in step a) has (2S,3R) configuration.
  • step b) can be performed in presence of polar organic solvent.
  • the polar organic solvent with or without water can be used.
  • the 'polar organic solvent' is not particularly restricted but includes, among others, aprotic polar organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1, 2-dimethoxye thane, die thylene glycol dimethyl ether, trimethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, 1,2-diethoxyethane, diethylene glycol diethyl ether, Methylene glycol diethyl ether, tetraethylene glycol diethyl ether, polyethylene glycol diethyl ether, acetonitrile, dimethyl formamide and dimethyl sulfoxide or mixture(s) thereof; protic polar organic solvents such as alcohols, for example methanol, ethanol, n- propanol, isopropanol, n-butanol, sec-butan
  • compound of Formula I can be isolated from the reaction mixture by extracting it with ether solvent (e.g. diethyl ether). Accordingly, the compound of Formula III in its salt form is reacted with an active ester of acid of Formula IV in presence of base and organic solvent at a temperature from about 5°C to about 40 0 C. The reaction is performed at pH range of 5 to 7. The so produced compound of Formula II is then isolated from the reaction mixture.
  • ether solvent e.g. diethyl ether
  • the compound of Formula II is treated with base in polar organic solvent and water to produce the desired threo-3,4-epoxy-2-amino-l-substituted butane derivative of Formula I.
  • the so produced compound of Formula I is then isolated from the reaction mixture after neutralizing the reaction mixture by adding sodium dihydrogen orthophosphate solution into it.
  • Ether e.g. diethyl ether
  • the extracted compound of Formula I can be purified using hydrocarbon solvent (e.g. hexane).
  • the compound of Formula I can be further used as intermediates for the preparation of Atazanavir or salt thereof.
  • a third aspect of the present invention provides process for the preparation of methyl [(2S)- 1 - ⁇ [(2S ,3R)-4-chloro-3-hydroxy- 1 -phenylbutan-2-yl] amino ⁇ -3,3-dimethyl- l-oxobutan-2-yl] carbamate represented by Formula VI
  • reaction of compound of Formula VII or salt thereof with an active ester of acid of Formula VIII can be performed in presence of base and organic solvent.
  • the base and organic solvent used herein in this aspect are the same as mentioned in first aspect of the present invention.
  • the base and organic solvent used in first aspect for the preparation of compound of Formula II comprising reaction of compound of Formula III or salt thereof with active ester of acid of Formula IV can also be employed herein in this aspect of the invention but for the preparation of compound of Formula VI comprising reaction of compound of Formula VII or salt thereof with active ester of acid of Formula VIII.
  • the acid of Formula VIII can be converted into its active ester by the reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo- l-pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • the active ester of an acid of Formula VIII can be represented by following Formula IX
  • reaction of compound of Formula VII or salt thereof with active ester of acid of Formula VIII can be performed at temperature selected from about 5°C to about 40 0 C.
  • the compound of Formula VII in its hydrochloride salt form can be reacted with active ester of compound of Formula VIII.
  • the compound of Formula VII in its salt form is reacted with an active ester of acid of Formula VIII in presence of base and organic solvent at temperature selected from about 5°C to about 40 0 C.
  • the reaction is performed at pH range of 5 to 7.
  • the so produced compound of Formula VI is then isolated from the reaction mixture.
  • the compound of Formula VI can be used as an intermediate in the preparation of
  • Atazanavir or salt thereof Atazanavir or salt thereof.
  • a fourth aspect of the present invention provides process for the preparation of methyl [(2S)-3 ,3-dimethyl- 1 -( ⁇ ( 1 S)- 1 - [(2R)-oxiran-2-yl] -2-phenylethyl ⁇ amino)- 1 - oxobutan-2-yl] carbamate represented by Formula X:
  • Formula X which comprises a) reacting (2S,3R)-2-amino-4-chloro-l-phenylbutan-3-ol represented by Formula VII or salt thereof
  • the step a) can be performed in presence of base and organic solvent.
  • the 'base' as used herein in steps a) and b) can be selected from the group comprising alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate and alkaline earth metal phosphate.
  • the base can be an organic base.
  • Some non-limiting examples of base are NaOH, KOH, Mg(OH) 2 , K 2 HPO 4 , MgCO 3 , Na 2 CO 3 , K 2 CO 3 , triethylamine, diisopropylethylamine and/or N-methyl morpholine.
  • the Organic solvent' as used herein in step a) can be selected from the group comprising methylene chloride, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile and/or N,N-dimethylformamide.
  • the acid of Formula VIII can be converted into its active ester by the reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo- l-pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo- l-pyridyl)-N,N,N 1 ,N 1 -tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
  • the active ester of an acid of Formula VIII can be represented by following Formula IX
  • the step a) reaction can be performed at temperature selected from about 5°C to about 40 0 C.
  • the compound of Formula VII in its hydrochloride salt form can be reacted with active ester of compound of Formula VIII.
  • the step b) can be performed in presence of polar organic solvent.
  • the polar organic solvent with or without water can be used.
  • the 'polar organic solvent' is not particularly restricted but includes, among others, aprotic polar organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1 ,2-dimethoxye thane, diethylene glycol dimethyl ether, trimethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, 1,2-diethoxyethane, diethylene glycol diethyl ether, Methylene glycol diethyl ether, tetraethylene glycol diethyl ether, polyethylene glycol diethyl ether, acetonitrile, dimethyl formamide and dimethyl sulfoxide or mixture(s) thereof; protic polar organic solvents such as alcohols, for example methanol, ethanol, n- propanol, isopropanol, n-butanol, sec-butano
  • the step b) can be performed at temperature selected from O 0 C to 10 0 C.
  • compound of Formula X can be isolated from the reaction mixture by extracting it with ether solvent (e.g. diethyl ether). Accordingly, the compound of Formula VII in its salt form is reacted with an active ester of acid of Formula VIII in presence of base and organic solvent at temperature selected from about 5°C to about 40 0 C. The reaction is performed at pH range of 5 to 7. The so produced compound of Formula VI is then isolated from the reaction mixture.
  • ether solvent e.g. diethyl ether
  • the compound of Formula VI is treated with base in polar organic solvent and water to produce the desired methyl [(2S)-3,3-dimethyl-l-( ⁇ (lS)-l-[(2R)-oxiran-2-yl]-2- phenylethyl ⁇ amino)- l-oxobutan-2-yl] carbamate represented by Formula X.
  • the so produced compound of Formula X is then isolated from the reaction mixture after neutralizing the reaction mixture by adding sodium dihydrogen orthophosphate solution into it.
  • Ether e.g. diethyl ether
  • the extracted compound of Formula X can be purified using hydrocarbon solvent (e.g. hexane).
  • the compound of Formula X can be further used as an intermediate in the preparation of Atazanavir or salt thereof.
  • a fifth aspect of the present invention provides threo-4-halo-3-hydroxy-2-amino-l- substituted butane derivative represented by general Formula II
  • R 1 is phenyl
  • R is hydrogen or amino protecting groups
  • R 3 is secondary or tertiary lower alkyl
  • X is chlorine, bromine, fluorine or iodine.
  • the compound of Formula II can be in (2S, 3R) or
  • the carbon atom bonded to the radical R 3 in Formula II can be in (R)-, (S)- or (R,S)-configuration.
  • Another embodiment of this aspect provides methyl [(2S)-l- ⁇ [(2S,3R)-4-chloro-3- hydroxy- 1 -phenylbutan-2-yl] amino ⁇ -3 ,3-dimethyl- 1 -oxobutan-2-yl] carbamate represented by Formula VI
  • the compounds of Formula II and VI can be used as intermediates for Atazanavir or its salt preparation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to a process for the preparation of threo-3,4-epoxy-2- amino-1-substituted butane derivatives represented by general Formula I which comprises reacting compound of Formula III or salt thereof with an active ester of acid of Formula IV and treating the product thereof with base. The carbon atom bonded to the radical R3 in Formula I and IV is in the (R)-, (S)- or (R,S)-configuration. The compounds of Formula I and III, particularly in their (2S,3R) configuration are useful intermediates for the preparation of atazanavir bisulfate.

Description

PROCESS FOR THE PREPARATION OF 3,4-EPOXY-2-AMINO-l- SUBSTITUTED BUTANE DERIVATIVES AND INTERMEDIATE
COMPOUNDS THEREOF
Field of the Invention
The present invention relates to production method of threo-3,4-epoxy-2-amino-l- substituted butane derivatives represented by general Formula I:
Figure imgf000003_0001
Formula I wherein
R1 is phenyl,
R is hydrogen or amino protecting groups,
R3 is secondary or tertiary lower alkyl and configurations at 2 and 3 positions are either (2S,3R) or (2R,3S). The carbon atom bonded to the radical R3 in Formula I may be in (R)-, (S)- or
(R,S)-configuration.
The compounds of Formula I are useful intermediates for the production of various HIV protease compounds. Particularly, (2S,3R)-3,4-epoxy-2-amino-l-substituted butane derivatives represented by general Formula Ia are useful pharmaceutical intermediates of atazanavir- an inhibitor of retroviral aspartate protease.
Figure imgf000003_0002
Formula Ia
The R1, R2 and R3 in Formula Ia are same as described hereinabove for compound of Formula I. Background of the Invention
Atazanavir and its bisulfate salt (1:1) are disclosed in U.S. Patent Nos. 5,849,911 and 6,087,383 respectively. Atazanavir bisulfate is chemically known as (35,85,95,125)- 3,12-bis(l,l-dimethylethyl)-8-hydroxy-4,l l-dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1) and represented by following chemical structure -
Figure imgf000004_0001
Atazanavir bisulfate is inhibitor of retroviral aspartate protease and also known to have high degree of inhibitory activity against the HIV virus.
Several methods for preparing various 3,4-epoxy-2-amino-l -substituted butane derivatives are published. U.S. Patent Nos. 5,849,911; 6,300,519 and 6,110,946 describe preparation of 3,4-epoxy-2-amino-l-substituted butane derivatives starting from 2-amino- 3-substituted propanoic acid derivative. The acid is reduced to corresponding aldehyde which on further treatment with ylide compound (e.g. sulfur ylide compound) produces the desired 3,4-epoxy-2-amino-l -substituted butane derivative.
U.S. Patent No. 5,847,169 describes process for preparing 3,4-epoxy-2-amino-l- substituted butane derivatives comprising the steps of activating an aminodiol, acylating the aminodiol and reacting the acylated aminodiol with a base to form an epoxy compound. The methods disclosed in U.S. Patent No. 6,127,556 for the preparation of epoxy compounds or 3,4-epoxy-2-amino-l -substituted butane derivatives make use of halomethyl organometallic reagent and aminoaldehyde compound whereas U.S. Patent No. 6,278,002 describes the preparation of similar type of compounds by making use of quaternary ammonium salt or carboxylic acid metal salt. U.S. Patent No. 6,693,205 makes use of Mitsunobu reaction during preparation of 3,4-epoxy-2-amino-l-substituted butane derivatives. Several other publications, for example, U.S. Patent Nos. 5,693,847; 6,344,572; 6,764,545; 6,765,100; 6,867,311; 6,605,732 and 7,122,696 mention preparation of various 3,4-epoxy-2-amino-l -substituted butane derivatives and are incorporated herein by reference. Most of the prior-art processes for the preparation of 3,4-epoxy-2-amino-l- substituted butane derivatives suffer from one or more disadvantages such as use of expensive and inaccessible raw materials, commercially impractical and hazardous reaction conditions, time consuming multi-step reaction sequences employing unstable and/or dangerous intermediates and production of isomeric mixtures resulting in low yields of pure substance due to lengthy separation procedures that are impractical for larger scale production.
Summary of the Invention
The present invention overcomes the disadvantages associated with the prior art by providing a process for the preparation of compounds of the Formula I using reagents and conditions which are convenient to operate on commercial scale and operationally safe.
The threo-4-halo-3-hydroxy-2-amino-l-substituted butane derivative represented by general Formula II serves as substrate in the preparation method of 3,4-epoxy-2-amino- 1 -substituted butane derivatives (Formula-I) of present invention.
Figure imgf000005_0001
Formula II
The R1, R2, R3 in Formula-II are same as mentioned hereinabove for the compounds of Formula I and X represents halogen atom, such as a chlorine, bromine, fluorine or iodine.
The carbon atom bonded to the radical R3 in Formula II, may be in the (R)-, (S)- or (R,S)-configuration.
The configurations at positions 2 and 3 in the above Formula II are either (2S,3R) or (2R,3S). The preferred configuration is (2S,3R) as represented by Formula Ha
Figure imgf000006_0001
Formula Ha
To prepare threo-3,4-epoxy-2-amino-l -substituted butane derivatives having (2S,3R) configuration (Formula-la), the above threo-4-halo-3-hydroxy-2-amino-l- substituted butane derivative should have the (2S,3R) configuration (Formula-IIa). Similarly, for obtaining the (2R,3S) product, the substrate should be of (2R,3S) configuration.
Thus, the present invention provides efficient process for the preparation of compounds of the Formulae I and II. Detailed Description of the Invention
The term "about" as used herein (unless specified), when used along values assigned to certain measurements and parameters means a variation of 10% from such values, or in case of a range of values, means a 10% variation from both the lower and upper limits of such ranges. The term Tower alkyl' is meant for 'C1-C4 alkyl'. Preferably, the Tower alkyl' is selected from the group comprising of tert-butyl, sec-butyl, isobutyl, n-butyl, isopropyl, n- propyl, ethyl and methyl.
The term 'amino protecting groups' can be any protecting group known to a person skilled in the art. Some non-limiting examples are lower alkoxycarbonyl (such as tert- butoxycarbonyl, methoxycarbonyl etc.), aryl-lower alkoxycarbonyl (such as benzyloxycarbonyl) or acyl protecting group (such as CH3CO, trifluoroacetyl).
The term 'Atazanavir bisulfate' as employed herein refers to Atazanavir bisulfate as well as Atazanavir sulfate.
A first aspect of the present invention provides process for the preparation of 4- halo-3-hydroxy-2-amino-l -substituted butane derivative represented by Formula II
Figure imgf000007_0001
Formula II which comprises reacting compound of Formula III or salt thereof
Figure imgf000007_0002
Formula III with an active ester of acid of Formula IV
Figure imgf000007_0003
Formula IV wherein R1 is phenyl,
R is hydrogen or amino protecting groups, R3 is secondary or tertiary lower alkyl and X is chlorine, bromine, fluorine or iodine.
In an embodiment of this aspect, the compounds of Formula II and III are either in (2S.3R) or (2R.3S) configuration.
In another embodiment of this aspect, the carbon atom bonded to the radical R3 in Formula II and IV can be in (R)-, (S)- or (R,S)-configuration.
In another embodiment of this aspect, the reaction can be performed in presence of base and organic solvent. The 'base' as used herein can be selected from the group comprising of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate and alkaline earth metal phosphate. The base can be an organic base. Some non-limiting examples of base are NaOH, KOH, Mg(OH)2, K2HPO4, MgCθ3, Na2COs, K2CO3, triethylamine, diisopropylethylamine and/or N-methyl morpholine. The Organic solvent' as used herein can be selected from the group comprising methylene chloride, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile and N,N-dimethylformamide or mixture(s) thereof.
The acid of Formula IV can be converted into its active ester by reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l- pyridyl)-N,N,N1,N1-tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
In another embodiment of this aspect, the active ester of an acid of Formula IV can be represented by following compound of Formula V
Figure imgf000008_0001
Formula V
In another embodiment of this aspect, the reaction of compound of Formula III with active ester of acid of Formula IV can be performed at temperature selected from about 5°C to about 400C. In another embodiment of this aspect, the compound of Formula III in its hydrochloride salt form can be reacted with active ester of compound of Formula IV.
Accordingly, the compound of Formula III in its salt form is reacted with active ester of acid of Formula IV in presence of base and organic solvent at temperature selected from about 5°C to about 400C. The reaction is performed at pH range of 5 to 7. The so produced compound of Formula II is then isolated from the reaction mixture. In another embodiment of this aspect, the obtained 4-halo-3-hydroxy-2-amino-l- substituted butane derivative of Formula II has (2S,3R) configuration and can be represented by Formula-IIa.
The compounds of Formula II and Ha can be further used as intermediates in the preparation of Atazanavir or salt thereof.
A second aspect of the present invention provides process for preparation of threo- 3,4-epoxy-2-amino-l -substituted butane derivative represented by Formula I:
Figure imgf000009_0001
ormula I which comprises a) reacting compound of Formula III or salt thereof
Figure imgf000009_0002
Formula III with active ester of acid of Formula IV
Figure imgf000009_0003
Formula IV to produce 4-halo-3-hydroxy-2-amino-l -substituted butane derivative of Formula
II
Figure imgf000010_0001
Formula II b) treating compound of Formula II produced in step a) with base c) isolating threo-3,4-epoxy-2-amino-l -substituted butane derivative (I) from the reaction mixture of step b) wherein
R1 is phenyl,
R2 is hydrogen or amino protecting groups,
R3 is secondary or tertiary lower alkyl and X is chlorine, bromine, fluorine or iodine.
In an embodiment of this aspect, the compounds of Formula I, II and III can be in (2S,3R) or (2R,3S) configuration.
In another embodiment of this aspect, the carbon atom bonded to the radical R3 in Formula I, II and IV can be in (R)-, (S)- or (R,S)-configuration. In another embodiment of this aspect, the step a) can be performed in presence of base and organic solvent.
The 'base' as used herein in steps a) and b) can be selected from the group comprising alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate and alkaline earth metal phosphate. The base can be an organic base. Some non-limiting examples of base are NaOH, KOH, Mg(OH)2, K2HPO4, MgCO3, Na2CO3, K2CO3, triethylamine, diisopropylethylamine and/or N-methyl morpholine.
The Organic solvent' as used herein in step a) can be selected from the group comprising methylene chloride, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile and/or N,N-dimethylformamide.
The acid of Formula IV can be converted into its active ester by the reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l- pyridyl)-N,N,N1,N1-tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
In another embodiment of this aspect, the active ester of an acid of Formula IV can be represented by following compound of Formula V
Figure imgf000011_0001
Formula V
In another embodiment of this aspect, the step a) reaction can be performed at temperature selected from about 5°C to about 400C.
In another embodiment of this aspect, the compound of Formula III can be reacted with compound of Formula IV in the form of its hydrochloride salt.
In another embodiment of this aspect, 4-halo-3-hydroxy-2-amino-l -substituted butane derivative compound of Formula II obtained in step a) has (2S,3R) configuration. In another embodiment of this aspect, the step b) can be performed in presence of polar organic solvent. The polar organic solvent with or without water can be used. The 'polar organic solvent' is not particularly restricted but includes, among others, aprotic polar organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1, 2-dimethoxye thane, die thylene glycol dimethyl ether, trimethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, 1,2-diethoxyethane, diethylene glycol diethyl ether, Methylene glycol diethyl ether, tetraethylene glycol diethyl ether, polyethylene glycol diethyl ether, acetonitrile, dimethyl formamide and dimethyl sulfoxide or mixture(s) thereof; protic polar organic solvents such as alcohols, for example methanol, ethanol, n- propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol or mixture(s) thereof. In another embodiment of this aspect, the step b) can be performed at temperature selected from 00C to 100C.
In another embodiment of this aspect, compound of Formula I can be isolated from the reaction mixture by extracting it with ether solvent (e.g. diethyl ether). Accordingly, the compound of Formula III in its salt form is reacted with an active ester of acid of Formula IV in presence of base and organic solvent at a temperature from about 5°C to about 400C. The reaction is performed at pH range of 5 to 7. The so produced compound of Formula II is then isolated from the reaction mixture.
The compound of Formula II is treated with base in polar organic solvent and water to produce the desired threo-3,4-epoxy-2-amino-l-substituted butane derivative of Formula I.
The so produced compound of Formula I is then isolated from the reaction mixture after neutralizing the reaction mixture by adding sodium dihydrogen orthophosphate solution into it. Ether (e.g. diethyl ether) can be added to the reaction mixture to extract the compound of Formula I from the organic layer. The extracted compound of Formula I can be purified using hydrocarbon solvent (e.g. hexane).
The compound of Formula I can be further used as intermediates for the preparation of Atazanavir or salt thereof.
A third aspect of the present invention provides process for the preparation of methyl [(2S)- 1 - { [(2S ,3R)-4-chloro-3-hydroxy- 1 -phenylbutan-2-yl] amino } -3,3-dimethyl- l-oxobutan-2-yl] carbamate represented by Formula VI
Figure imgf000012_0001
Formula VI which comprises reacting (2S,3R)-2-amino-4-chloro-l-phenylbutan-3-ol represented by Formula VII or salt thereof
Figure imgf000012_0002
Formula VII with an active ester of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid represented by Formula VIII.
Figure imgf000013_0001
Formula VIII In an embodiment of this aspect, the reaction of compound of Formula VII or salt thereof with an active ester of acid of Formula VIII can be performed in presence of base and organic solvent.
The base and organic solvent used herein in this aspect are the same as mentioned in first aspect of the present invention. The base and organic solvent used in first aspect for the preparation of compound of Formula II comprising reaction of compound of Formula III or salt thereof with active ester of acid of Formula IV can also be employed herein in this aspect of the invention but for the preparation of compound of Formula VI comprising reaction of compound of Formula VII or salt thereof with active ester of acid of Formula VIII. The acid of Formula VIII can be converted into its active ester by the reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo- l-pyridyl)-N,N,N1,N1-tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC). In another embodiment of this aspect, the active ester of an acid of Formula VIII can be represented by following Formula IX
Figure imgf000013_0002
Formula IX In another embodiment of this aspect, the reaction of compound of Formula VII or salt thereof with active ester of acid of Formula VIII can be performed at temperature selected from about 5°C to about 400C.
In another embodiment of this aspect, the compound of Formula VII in its hydrochloride salt form can be reacted with active ester of compound of Formula VIII.
Accordingly, the compound of Formula VII in its salt form is reacted with an active ester of acid of Formula VIII in presence of base and organic solvent at temperature selected from about 5°C to about 400C. The reaction is performed at pH range of 5 to 7. The so produced compound of Formula VI is then isolated from the reaction mixture. The compound of Formula VI can be used as an intermediate in the preparation of
Atazanavir or salt thereof.
A fourth aspect of the present invention provides process for the preparation of methyl [(2S)-3 ,3-dimethyl- 1 -( { ( 1 S)- 1 - [(2R)-oxiran-2-yl] -2-phenylethyl } amino)- 1 - oxobutan-2-yl] carbamate represented by Formula X:
Figure imgf000014_0001
Formula X which comprises a) reacting (2S,3R)-2-amino-4-chloro-l-phenylbutan-3-ol represented by Formula VII or salt thereof
Figure imgf000014_0002
Formula VII with an active ester of (2S)-2-[(methoxycarbonyl)amino]-3,3- dimethylbutanoic acid represented by Formula VIII
Figure imgf000015_0001
Formula VIII to produce methyl [(2S)-l-{ [(2S,3R)-4-chloro-3-hydroxy-l-phenylbutan-2- yl]amino}-3,3-dimethyl-l-oxobutan-2-yl]carbamate represented by Formula VI
Figure imgf000015_0002
Formula VI b) treating compound of Formula VI produced in step a) with base c) isolating methyl [(2S)-3,3-dimethyl-l-({(lS)-l-[(2R)-oxiran-2-yl]- 2-phenylethyl}amino)-l-oxobutan-2-yl]carbamate represented by Formula X from the reaction mixture of step b).
In another embodiment of this aspect, the step a) can be performed in presence of base and organic solvent.
The 'base' as used herein in steps a) and b) can be selected from the group comprising alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate and alkaline earth metal phosphate. The base can be an organic base. Some non-limiting examples of base are NaOH, KOH, Mg(OH)2, K2HPO4, MgCO3, Na2CO3, K2CO3, triethylamine, diisopropylethylamine and/or N-methyl morpholine.
The Organic solvent' as used herein in step a) can be selected from the group comprising methylene chloride, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile and/or N,N-dimethylformamide.
The acid of Formula VIII can be converted into its active ester by the reaction of the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo- l-pyridyl)-N,N,N1,N1-tetramethyluronium-tetrafluoro-borate (TPTU), 1- hydroxybenzotriazole (HOBT) and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC).
In another embodiment of this aspect, the active ester of an acid of Formula VIII can be represented by following Formula IX
Figure imgf000016_0001
Formula IX
In another embodiment of this aspect, the step a) reaction can be performed at temperature selected from about 5°C to about 400C.
In another embodiment of this aspect, the compound of Formula VII in its hydrochloride salt form can be reacted with active ester of compound of Formula VIII.
In another embodiment of this aspect, the step b) can be performed in presence of polar organic solvent. The polar organic solvent with or without water can be used.
The 'polar organic solvent' is not particularly restricted but includes, among others, aprotic polar organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1 ,2-dimethoxye thane, diethylene glycol dimethyl ether, trimethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, 1,2-diethoxyethane, diethylene glycol diethyl ether, Methylene glycol diethyl ether, tetraethylene glycol diethyl ether, polyethylene glycol diethyl ether, acetonitrile, dimethyl formamide and dimethyl sulfoxide or mixture(s) thereof; protic polar organic solvents such as alcohols, for example methanol, ethanol, n- propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol or mixture(s) thereof.
In another embodiment of this aspect, the step b) can be performed at temperature selected from O0C to 100C. In another embodiment of this aspect, compound of Formula X can be isolated from the reaction mixture by extracting it with ether solvent (e.g. diethyl ether). Accordingly, the compound of Formula VII in its salt form is reacted with an active ester of acid of Formula VIII in presence of base and organic solvent at temperature selected from about 5°C to about 400C. The reaction is performed at pH range of 5 to 7. The so produced compound of Formula VI is then isolated from the reaction mixture.
The compound of Formula VI is treated with base in polar organic solvent and water to produce the desired methyl [(2S)-3,3-dimethyl-l-({(lS)-l-[(2R)-oxiran-2-yl]-2- phenylethyl} amino)- l-oxobutan-2-yl] carbamate represented by Formula X.
The so produced compound of Formula X is then isolated from the reaction mixture after neutralizing the reaction mixture by adding sodium dihydrogen orthophosphate solution into it. Ether (e.g. diethyl ether) can be added to the reaction mixture to extract the compound of Formula X from the organic layer. The extracted compound of Formula X can be purified using hydrocarbon solvent (e.g. hexane).
The compound of Formula X can be further used as an intermediate in the preparation of Atazanavir or salt thereof.
A fifth aspect of the present invention provides threo-4-halo-3-hydroxy-2-amino-l- substituted butane derivative represented by general Formula II
Figure imgf000017_0001
Formula II wherein
R1 is phenyl,
R is hydrogen or amino protecting groups, R3 is secondary or tertiary lower alkyl and X is chlorine, bromine, fluorine or iodine. In an embodiment of this aspect, the compound of Formula II can be in (2S, 3R) or
(2R, 3S) configuration.
In another embodiment of this aspect, the carbon atom bonded to the radical R3 in Formula II can be in (R)-, (S)- or (R,S)-configuration. Another embodiment of this aspect provides methyl [(2S)-l-{ [(2S,3R)-4-chloro-3- hydroxy- 1 -phenylbutan-2-yl] amino } -3 ,3-dimethyl- 1 -oxobutan-2-yl] carbamate represented by Formula VI
Figure imgf000018_0001
Formula VI
In another embodiment of this aspect, the compounds of Formula II and VI can be used as intermediates for Atazanavir or its salt preparation.
The preparation method of compounds of Formula II and VI are described hereinabove in first and third aspect, respectively, of the present invention. While the present invention has been described in terms of its specific aspects, 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.
In the following section aspects are described by way of examples to illustrate the processes of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Preparation of starting materials
(2S)-2-r(methoxycarbonyl)aminol-3,3-dimethylbutanoic acid
Figure imgf000018_0002
Formula VIII 23.5 ml of methyl chloroformate was added over a period of 20 minutes to a solution of 20 g of 2(S)-amino-3,3-dimethyl-butyric acid in a mixture of 252 ml of 2N aqueous sodium hydroxide solution and 80 ml of dioxane and the reaction solution was heated at 600C for 14 hours. It was cooled to room temperature and then washed 2 times with methylene chloride. The aqueous phase was acidified to pH 2 with 4N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic extracts were combined, dried (Na2S O4) and concentrated by evaporation, the product started to solidify. The solidified solid was digested with hexane yielded (2S)-2-[(methoxycarbonyl)amino]- 3,3-dimethylbutanoic acid in the form of a white powder. M.p. 106°-108°C
Active Ester of (2S)-2-r(methoxycarbonyl)amino1-3,3-dimethyrbutanoic acid
Figure imgf000019_0001
Formula IX To a 3000 mL, 3 -neck round bottom flask fitted with mechanical stirrer, addition funnel, nitrogen inlet, and temperature probe was added (2S)-2- [(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid (VIII; 77.2g), 1- hydroxybenzotriazole (HOBT) (60.8g), and N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC; 82.0 g) followed by CH2Cl2 (880 ml) and the mixture was stirred at ambient temperature (18-25°C) until formation of the active ester was completed, as judged by HPLC.
Example 1: Preparation of methyl [(2S)-I-? r(2S,3R)-4-chloro-3-hvdroxy-l-phenylbutan- 2-vHamino|-3,3-dimethyl-l-oxobutan-2-vHcarbamate ( Formula VI)
Figure imgf000020_0001
Formula VI
To (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid (VIII; 92.19 g), HOBT (72.13 g), EDC hydrochloride (98.289 g) and dichloromethane (800 ml) were added at 20-250C and the solution was stirred for 3 hours at 20-250C. A solution of K2HPO4 (120 g) in de-ionized water (800 ml) was added to the solution at 20-250C and then it was cooled to 10-150C.
Another prepared solution of (2S,3R)-2-amino-4-chloro-l-phenylbutan-3-ol (Formula- VII) (100 g) in de-ionized water (400 ml) was drop- wise added to the cooled (10-150C) solution over a period of 1-2 hours. The reaction mixture so prepared was stirred at ambient temperature for 13-14 hours maintaining pH of the mixture in the range of 5 to 7. Completion of the reaction was monitored by TLC (Thin layer chromatography). After completion of the reaction, organic layer was separated and aqueous sodium hydroxide solution (40 g of NaOH dissolved in 800 ml of de-ionized water) was added to it at 10-150C. The solution was then stirred for 30 minutes and again organic layer was separated. The organic layer was washed with 5% diluted hydrochloride solution (750 ml) at 10-150C and then with de-ionized water (800 ml). The solvent was completely removed from the organic layer under vacuum at not more then 450C to obtain the titled compound of Formula VI. Yield (w/w) = 1.45 Example 2: Preparation of methyl r(2S)-3,3-dimethyl-l-({(lS)-l-r(2R)-oxiran-2-yll-2- phenylethyl I amino)- l-oxobutan-2-vH carbamate (Formula X)
Figure imgf000021_0001
Formula X To methyl [(2S)-l-{ [(2S,3R)-4-chloro-3-hydroxy-l-phenylbutan-2-yl]amino}-3,3- dimethyl-l-oxobutan-2-yl] carbamate (VI; 100 g), tetrahydrofuran (450 ml), ethanol (260 ml) and de-ionized water (87 ml) were added at ambient temperature. The solution was cooled to 0-50C and then aqueous KOH solution (39 g of KOH dissolved in 39 ml de- ionized water) was added to it at 0-50C. The resultant reaction mixture was stirred at 0- 5°C for 2-3 hours. Completion of the reaction was monitored by TLC (Thin layer chromatography). After completion of the reaction, 6% sodium dihydrogen orthophosphate solution (725 ml) and diethyl ether (750 ml) were added to the reaction mixture at 0-50C and the solution was stirred for 10-15 minutes. The organic layer so formed was separated and de-ionized water (500 ml) was added to it at ambient temperature and stirred for 2 minutes. The organic layer was again separated and solvent was completely recovered under vacuum. To the residue, hexanes (300 ml) were added and it was stirred for 30 minutes at 5-100C. The solid, so obtained, was washed with hexanes (100 ml) and dried at 35-400C under vacuum to obtain the titled compound of Formula X. Yield (w/w) = 0.803

Claims

We Claim:
1. A process for the preparation of 4-halo-3-hydroxy-2-amino-l -substituted butane derivative represented by Formula II
Figure imgf000022_0001
Formula II which comprises reacting g compound of Formula III or salt thereof
Figure imgf000022_0002
Formula III with an active ester of acid of Formula IV
Figure imgf000022_0003
Formula IV wherein
R1 is phenyl,
R2 is hydrogen or amino protecting groups,
R3 is secondary or tertiary lower alkyl and
X is chlorine, bromine, fluorine or iodine.
2. The process according to claim 1 wherein the reaction is performed in presence of base and organic solvent. A process for preparation of threo-3,4-epoxy-2-amino-l -substituted butane derivative represented by Formula I:
Figure imgf000023_0001
Formula I which comprises a) reacting compound of Formula III or salt thereof
Figure imgf000023_0002
Formula III with active ester of acid of Formula IV
Figure imgf000023_0003
Formula IV to produce 4-halo-3-hydroxy-2-amino-l -substituted butane derivative of Formula II
Figure imgf000023_0004
Formula II b) treating compound of Formula II produced in step a) with base c) isolating threo-3,4-epoxy-2-amino-l -substituted butane derivative (I) from the reaction mixture of step b) wherein R is phenyl, R2 is hydrogen or amino protecting groups, R is secondary or tertiary lower alkyl and X is chlorine, bromine, fluorine or iodine. 4. The process according to claim 3 wherein the step a) reaction is performed in presence of base and organic solvent. 5. The process according to claim 1 or 3 wherein active ester of acid of Formula IV is prepared by reacting the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l-pyridyl)-N,N,N1,N1-tetramethyluronium- tetrafluoro-borate (TPTU), 1-hydroxybenzotriazole (HOBT) and N-ethyl-N'- dimethylaminopropyl carbodiimide (EDC). 6. The process according to claim 1 or 3 wherein the active ester is represented by general Formula V
Figure imgf000024_0001
Formula V 7. The process according to claim 3 wherein the step b) reaction is performed in presence of polar organic solvent optionally with water. 8. A process for the preparation of methyl [(2S)-l-{ [(2S,3R)-4-chloro-3-hydroxy-l- phenylbutan-2-yl]amino}-3,3-dimethyl-l-oxobutan-2-yl]carbamate represented by Formula VI
Figure imgf000024_0002
Formula VI which comprises reacting (2S,3R)-2-amino-4-chloro-l-phenylbutan-3-ol represented by Formula VII or salt thereof
Figure imgf000025_0001
Formula VII with an active ester of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid represented by Formula VIII.
Figure imgf000025_0002
Formula VIII 9. The process according to claim 8 wherein the reaction is performed in presence of base and organic solvent. 10. A process for the preparation of methyl [(2S)-3,3-dimethyl-l-({(lS)-l-[(2R)- oxiran-2-yl]-2-phenylethyl}amino)-l-oxobutan-2-yl]carbamate represented by Formula X:
Figure imgf000025_0003
Formula X which comprises a) reacting (2S,3R)-2-amino-4-chloro-l-phenylbutan-3-ol represented by Formula VII or salt thereof
Figure imgf000026_0001
Formula VII with an active ester of (2S)-2-[(methoxycarbonyl)amino]-3,3- dimethylbutanoic acid represented by Formula VIII
Figure imgf000026_0002
Formula VIII to produce methyl [(2S)-l-{ [(2S,3R)-4-chloro-3-hydroxy-l-phenylbutan-2- yl]amino}-3,3-dimethyl-l-oxobutan-2-yl]carbamate represented by Formula VI
Figure imgf000026_0003
Formula VI b) treating compound of Formula VI produced in step a) with base c) isolating methyl [(2S)-3,3-dimethyl-l-({(lS)-l-[(2R)-oxiran-2-yl]-2- phenylethyl} amino)- l-oxobutan-2-yl]carbamate represented by Formula X from the reaction mixture of step b).
11. The process according to claim 10 wherein the step a) reaction is performed in presence of base and organic solvent.
12. The process according to claim 8 or 10 wherein active ester of acid of Formula VIII is prepared by reacting the acid with coupling agent selected from the group comprising of O-(l,2-dihydro-2-oxo-l-pyridyl)-N,N,N τl ,N -tetramethyluronium- tetrafluoro-borate (TPTU), 1-hydroxybenzotriazole (HOBT) and N-ethyl-N'- dimethylaminopropyl carbodiimide (EDC). 13. The process according to claim 8 or 10 wherein the active ester is represented by Formula IX
Figure imgf000027_0001
Formula IX
14. The process according to claim 10 wherein the step b) reaction is performed in presence of polar organic solvent optionally with water.
15. A threo-4-halo-3-hydroxy-2-amino-l -substituted butane compound represented by general Formula II
Figure imgf000027_0002
Formula II wherein
R1 is phenyl,
R is hydrogen or amino protecting groups,
R3 is secondary or tertiary lower alkyl and
X is chlorine, bromine, fluorine or iodine.
16. The compound according to claim 15 wherein the compound is methyl [(2S)-I-
{ [(2S ,3R)-4-chloro-3-hydroxy- 1 -phenylbutan-2-yl] amino } -3 ,3-dimethyl- 1 - oxobutan-2-yl]carbamate represented by Formula VI
Figure imgf000028_0001
Formula VI
17. Use of compound of Formula II or VI for the preparation of atazanavir or salt thereof.
18. Use of compound of Formula I or X for the preparation of atazanavir or salt thereof.
PCT/IB2009/051843 2008-05-08 2009-05-05 Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof WO2009136365A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/991,635 US20110178305A1 (en) 2008-05-08 2009-05-05 Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof
EP09742538A EP2288593A1 (en) 2008-05-08 2009-05-05 Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1147/DEL/2008 2008-05-08
IN1147DE2008 2008-05-08

Publications (1)

Publication Number Publication Date
WO2009136365A1 true WO2009136365A1 (en) 2009-11-12

Family

ID=40910854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/051843 WO2009136365A1 (en) 2008-05-08 2009-05-05 Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof

Country Status (3)

Country Link
US (1) US20110178305A1 (en)
EP (1) EP2288593A1 (en)
WO (1) WO2009136365A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014633A1 (en) * 2011-07-27 2013-01-31 Ranbaxy Laboratories Limited Process for preparation of atazanavir or its bisulfate salt
US8461347B2 (en) 2011-08-05 2013-06-11 Scinopharm Taiwan, Ltd. Process for preparing form A of atazanavir sulfate
CN106905264A (en) * 2017-04-12 2017-06-30 连云港杰瑞药业有限公司 A kind of method of synthesis A Zhalawei intermediates
US10294234B2 (en) 2017-02-06 2019-05-21 Gilead Sciences, Inc. HIV inhibitor compounds
US11052087B2 (en) 2018-07-30 2021-07-06 Gilead Sciences, Inc. Anti-HIV compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5430151A (en) * 1991-08-10 1995-07-04 Bayer Aktiengesellschaft Trifluoromethyl-containing pseudopeptides active against retroviruses
US6110946A (en) * 1996-04-22 2000-08-29 Novartis Finance Corporation Antivirally active heterocyclic azahexane derivatives

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693847A (en) * 1995-04-19 1997-12-02 Vertex Pharmaceuticals Incorporated Heteroatom functionalized α-methyl ketones
JP2000509717A (en) * 1996-05-07 2000-08-02 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Preparation method of oxiranemethanamine derivatives
US6127556A (en) * 1996-12-31 2000-10-03 G. D. Searle & Co. Epoxide formation by continuous in-situ synthesis process
US6087383A (en) * 1998-01-20 2000-07-11 Bristol-Myers Squibb Company Bisulfate salt of HIV protease inhibitor
EP1029856B1 (en) * 1998-08-25 2004-06-16 Kaneka Corporation Process for the preparation of (2r, 3s)-3-amino-1,2-oxirane
ATE334121T1 (en) * 1999-01-29 2006-08-15 Kaneka Corp METHOD FOR PRODUCING THREO-1,2-EPOXY-3-AMINO-4-PHENYLBUTANE DERIVATIVES
US6605732B1 (en) * 1999-05-03 2003-08-12 Aerojet Fine Chemicals Llc Clean, high-yield preparation of S,S and R,S amino acid isosteres
KR100708221B1 (en) * 1999-08-31 2007-04-17 아지노모토 가부시키가이샤 Method for producing epoxide crystal
GB2369356B (en) * 2000-09-18 2004-02-04 Phoenix Chemicals Ltd Process
US7122696B2 (en) * 2000-11-30 2006-10-17 Ajinomoto Co., Inc. Processes for preparation of N-protected-β-amino alcohols and N-protected-β-amino epoxides
KR20020046948A (en) * 2000-12-12 2002-06-21 에가시라 구니오 Production method of epoxide crystal

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5430151A (en) * 1991-08-10 1995-07-04 Bayer Aktiengesellschaft Trifluoromethyl-containing pseudopeptides active against retroviruses
US6110946A (en) * 1996-04-22 2000-08-29 Novartis Finance Corporation Antivirally active heterocyclic azahexane derivatives
US6300519B1 (en) * 1996-04-22 2001-10-09 Novartis Finance Corporation Antivirally active heterocyclic azahexane derivatives

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BRAUN H A ET AL: "2-Iodoethanols from aldehydes, diiodomethane and isopropylmagnesium chloride", TETRAHEDRON LETTERS 20050411 GB, vol. 46, no. 15, 11 April 2005 (2005-04-11), pages 2551 - 2554, XP002540297, ISSN: 0040-4039 *
CHATTERJEE SANKAR ET AL: "Synthesis and biological activity of a series of potent fluoromethyl ketone inhibitors of recombinant human calpain I", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 23, 7 November 1997 (1997-11-07), pages 3820 - 3828, XP002540294, ISSN: 0022-2623 *
IMPERIALI B ET AL: "A VERSATILE SYNTHESIS OF PEPTIDYLFLUOROMETHYL KETONES", TETRAHEDRON LETTERS, vol. 27, no. 2, 1986, pages 135 - 138, XP002540295, ISSN: 0040-4039 *
REID ROBERT C ET AL: "Countering cooperative effects in protease inhibitors using constrained beta-strand-mimicking templates in focused combinatorial libraries.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, no. 7, 25 March 2004 (2004-03-25), pages 1641 - 1651, XP002540296, ISSN: 0022-2623 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014633A1 (en) * 2011-07-27 2013-01-31 Ranbaxy Laboratories Limited Process for preparation of atazanavir or its bisulfate salt
US8461347B2 (en) 2011-08-05 2013-06-11 Scinopharm Taiwan, Ltd. Process for preparing form A of atazanavir sulfate
US10294234B2 (en) 2017-02-06 2019-05-21 Gilead Sciences, Inc. HIV inhibitor compounds
US10752636B2 (en) 2017-02-06 2020-08-25 Gilead Sciences, Inc. HIV inhibitor compounds
US11078208B1 (en) 2017-02-06 2021-08-03 Gilead Sciences, Inc. HIV inhibitor compounds
CN106905264A (en) * 2017-04-12 2017-06-30 连云港杰瑞药业有限公司 A kind of method of synthesis A Zhalawei intermediates
CN106905264B (en) * 2017-04-12 2019-06-07 连云港杰瑞药业有限公司 A method of synthesis A Zhalawei intermediate
US11052087B2 (en) 2018-07-30 2021-07-06 Gilead Sciences, Inc. Anti-HIV compounds

Also Published As

Publication number Publication date
US20110178305A1 (en) 2011-07-21
EP2288593A1 (en) 2011-03-02

Similar Documents

Publication Publication Date Title
RU2664643C2 (en) Process for preparation of n-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepine-4-yl)-6-methyl-quinazoline-4-amine
WO2009136365A1 (en) Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof
US20110130576A1 (en) Process for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane
EP3280721B1 (en) Process for preparation of nitrogen mustard derivatives
EP0773932B1 (en) Benzenesulfonamide derivatives used as bradykinine antagonists
JP4299677B2 (en) Method for producing combretastatin
US20020042536A1 (en) Preparation of amino-protected lysine derivatives
US8431733B2 (en) Process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivatives
WO2011156355A1 (en) Production method of phenyl guanidine salts and their intermediates
WO2013014633A1 (en) Process for preparation of atazanavir or its bisulfate salt
US10329325B2 (en) Process for the preparation of (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxo-pentan-2-yl) amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido) pentanamide
US8143448B2 (en) Process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivatives
MXPA04011141A (en) A process for the preparation of modafinil.
US11498917B2 (en) Process for the preparation of lifitegrast
CN115461326A (en) Process for the preparation of N, N' -diacetyl-L-cystine disodium salt from cystine and acetyl chloride in methanol in the presence of sodium hydroxide
CA2361475A1 (en) Process for the preparation of .alpha.-aminoketones
EP1930324A1 (en) Process for the preparation of atazanavir
WO2014083575A2 (en) Improved process for the preparation of boceprevir intermediate
JPWO2004058681A1 (en) Method for producing benzylamine derivative
JP4407322B2 (en) Method for producing peptide
FI93730C (en) Process for the preparation of benzo (calcogeno) / 4,3,2-cd / indazoles
US4338259A (en) Alpha-halogeno-beta-aminopropionitriles or the mineral acid salts thereof, and processes for production thereof
CN115461325A (en) Process for preparing N, N' -diacetyl-L-cystine
JP2010510258A (en) Method for producing aminoglycol
US20190359553A1 (en) A process for the preparation of phenoxybenzamine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09742538

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009742538

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 12991635

Country of ref document: US