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WO2012045007A1 - Procédé de préparation de l'ester thiazol-5-ylméthyl de l'acide (4-{4-acétylamino-2-[3-(2-isopropyl-thiazol-4-ylméthyl)-3-méthyl-uréido]-butyryl amino}-1-benzyl-5-phényl-pentyl) carbamique - Google Patents

Procédé de préparation de l'ester thiazol-5-ylméthyl de l'acide (4-{4-acétylamino-2-[3-(2-isopropyl-thiazol-4-ylméthyl)-3-méthyl-uréido]-butyryl amino}-1-benzyl-5-phényl-pentyl) carbamique Download PDF

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Publication number
WO2012045007A1
WO2012045007A1 PCT/US2011/054346 US2011054346W WO2012045007A1 WO 2012045007 A1 WO2012045007 A1 WO 2012045007A1 US 2011054346 W US2011054346 W US 2011054346W WO 2012045007 A1 WO2012045007 A1 WO 2012045007A1
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Prior art keywords
formula
compound
salt
preparing
xxvii
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Inventor
Douglas Edward Cordeau
Aaron J. Cullen
Benjamin R. Graetz
Katie Ann Keaton
Sean Timothy Neville
Steven Pfeiffer
Richard Polniaszek
Richard H. Yu
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Gilead Sciences Inc
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Gilead Sciences Inc
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Publication of WO2012045007A1 publication Critical patent/WO2012045007A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Definitions

  • the invention provides a method for preparing a compound of formula I:
  • Y is a suitable counter ion
  • the invention provides a compound of formula XIX, XXa, XXI, XXVI, XXVII, XXVIII, XL, XLI, XLII, or XLIII:
  • Y is a suitable counter ion
  • each R ⁇ is a protecting group, or a salt thereof is prepared and converted into the compound of formula I, characterized in that the compound of formula XX is prepared by dimerizing a corresponding compound of formula XIX:
  • each R ⁇ is a protecting group, or a salt thereof to provide the compound of formula XXI.
  • R 2 is (C 1 -C 8 )alkyl, or a salt thereof is prepared and converted into the compound of formula I, characterized in that the compound of formula XXVI is prepared by acylating a corresponding compound of formula XXX:
  • R 2 is (C 1 -C 8 )alkyl to provide the compound of formula XXVII.
  • XXVIII wherein Y is a suitable counter ion, or a salt thereof, is prepared and converted into the compound of formula I, characterized in that the compound of formula XXVIII or the salt thereof is prepared by converting an acid of formula XXVII: or a salt thereof to the compound of formula XXVIII or the salt thereof.
  • XL or a salt thereof is prepared and converted into the compound of formula I or the thereof, characterized in that the compound of formula XL or the salt thereof is prepared by reacting an amine formula XXI:
  • R 3 is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula XL.
  • R is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula I or the salt thereof.
  • each R 1 is a protecting group, or a salt thereof comprising dimerizing a corresponding compound of formula XIX:
  • each Ri is a protecting group, or a salt thereof comprising deprotecting a corresponding compound of formula XX:
  • each Ri is a protecting group, or a salt thereof, to provide the compound of formula XXI or the salt thereof.
  • R 2 is (C 1 -C 8 )alkyl, or a salt thereof comprising acylating a compound of formula XXX:
  • R 2 is (Ci-Cg)alkyl, or a salt thereof to provide the compound of formula XXVI or the salt thereof.
  • the invention provides a method for preparing a compound of formula XXVII:
  • Y is a suitable counter ion or a salt thereof comprising converting an acid of formula XXVII: or a salt thereof to the compound of formula XXVIII or the salt thereof.
  • the invention provides a method for preparing a compound of formula XLI: comprising coupling an amine of formula XXI:
  • R 3 is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula XLII.
  • the invention provides a method for preparing an amine formula ofXLIII:
  • the invention also provides novel synthetic intermediates described herein as well as methods for preparing such intermediates.
  • alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual group such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • (C 1 -C )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, or octyl.
  • R a and R b are independently (C]-C8)alkyl; or R a and R b together with the nitrogen to which they are attached form a 3 or 4 membered saturated ring or a 5, 6, or 7 membered saturated or partially unsaturated ring comprising 1 or 2 heteroatoms (e.g.
  • Rc is aryl, (C ⁇ - C 8 )alkyl, halo(C 1 -C 8 )alkyl (Ci-C8)alkoxy, or aryl-(C 1 -C 8 )alkoxy, wherein any aryl can optionally be substituted with one or more (C 1 -C 8 )alkyl.
  • Ri is not fert-butylsulfonyl.
  • heteroatoms e.g. an aziridine, azetidine, piperidine, morpholine, thiomorpholine, pyrrolidine, homopiperazine, homopiperidine, or piperazine ring.
  • a specific value for R] is an NN-disubstituted aminosulfonyl group.
  • R is an NN-dialkyl aminosulfonyl group.
  • R 1 Another specific value for R 1 is -S(0) 2 N(CH 3 ) 2 .
  • R 1 Another specific value for R 1 is benzyloxycarbonyl.
  • a specific value for R 2 is methyl.
  • the invention provides a compound of formula XIX, XX, XXI, XXVI, XXVII, or XXVIII; or a salt thereof.
  • the invention provides a compound of formula XL, XLI, XLII, or XLIII; or a salt thereof.
  • a compound of formula I or a salt thereof can be prepared as illustrated in
  • An intermediate compound of formula XXIII or a salt thereof can be prepared as illustrated in Scheme 6 below.
  • the compound of formula XXIII or the salt thereof can be carried on to a compound of formula I as described herein.
  • Ri is a protecting group, or a salt thereof.
  • R is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide a compound of formula XXIII:
  • Y is a suitable counter ion to provide the compound of formula I or the salt thereof.
  • the invention also provides the above method for preparing a compound of formula I which further comprises preparing the compound of formula XXVIII by:
  • the starting aziridine can be protected with any suitable protecting group (K ⁇ ) under standard conditions to provide the corresponding compound of formula XIX.
  • the reaction can be carried out in a suitable solvent in the presence of a base.
  • suitable solvents include aprotic solvents such as, dichloromethane, tetrahydrofuran, ethyl ether, tert-butyl methyl ether, tetrahydropyran, 1,4-dioxane, 1,2-dichloroethane, and mixtures thereof.
  • Suitable bases include trialkylamines such as: triethylamine, N- methyl morpholine, quinuclidine, N-methylpiperidine, N,N-diisopropylethylamine, and iV-methyl pyrrolidine; as well as other weak non-nucleophilic bases such as, potassium carbonate and sodium bicarbonate.
  • the reaction can conveniently be carried out at a temperature from about -10 °C to 40 °C.
  • the resulting compound of formula XIX can be purified by recrystallization from a suitable solvent or mixture of solvents.
  • suitable solvent or mixture of solvents for example, combinations of ethereal and non-polar solvents, such as ethyl ether, «-butyl ether, tetrahydrofuran, tetrahydropyran, 1,2-dimethoxyethane, hexanes, tert-butyl methyl ether, heptane, pentane, cyclohexane, toluene can be used.
  • the starting aziridine XIX can be dimerized by treatment with a suitable base in a suitable solvent to provide the corresponding compound of formula XX.
  • suitable solvents include ethyl ether, tert-butyl methyl ether, w-butyl ether, tetrahydropyran, hexanes, tetrahydrofuran, 1 ,2-dimethoxyethane, and mixtures thereof.
  • Suitable bases include 2,2,6,6-tetramethylpiperidine (TMP); w-butyllithium ( «-BuLi), as well as other hindered non-nucleophilic amine bases such as diisopropylamine,
  • dicyclohexylamine dicyclohexylamine; and other organolithium bases such as: rc-hexyllithium, s- butyllithium, and t-butyllithium.
  • the reaction can conveniently be carried out at a temperature from about -78 °C to 22 °C.
  • the resulting compound of formula XX can be purified by recrystallization from a suitable solvent or mixture of solvents.
  • suitable solvent or mixture of solvents for example, combinations of ethereal and non-polar solvents, such as ethyl ether, n-butyl ether, tetrahydrofuran, tetrahydropyran, 1,2-dimethoxyethane, and fert-butyl methyl ether can be used.
  • ethereal and non-polar solvents such as ethyl ether, n-butyl ether, tetrahydrofuran, tetrahydropyran, 1,2-dimethoxyethane, and fert-butyl methyl ether.
  • the starting compound of formula XX can be deprotected under standard conditions to provide the corresponding compound of formula XXI.
  • the reaction can be carried out in a solvent that comprises an amine; for example, a diamine such as 1,3-diaminopropane, ethylenediamine, 1,2-diaminocyclohexane, 1,2-phenylenediamine, putrescene, or cadaverine; also for example, an amino alcohol, such as 2-aminoehanol or 3-amino-l-propanol.
  • the solvent can also comprise toluene, anisole, or the like, or mixtures thereof.
  • the reaction can conveniently be carried out at a temperature from about 100 °C to about 140 °C.
  • the starting alkene XXI can be hydrogenated under standard conditions to provide the corresponding compound of formula XXII.
  • the starting alkene XXI can be hydrogenated under standard conditions to provide the corresponding compound of formula XXII.
  • hydrogenation can be carried out using a metal-containing catalyst in an alcoholic solvent.
  • Suitable solvents include methanol, ethanol, isopropanol, «-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof.
  • Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide The reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi.
  • the compound of formula XXII can be isolated by treatment with an acid in an organic solvent to provide a corresponding salt.
  • Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid.
  • Suitable solvents include dichloromethane, ethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, 1,2- dimethoxyethane, chloroform, 1 ,2-dichloroethane, toluene, and anisole, and mixtures thereof.
  • the conversion to the salt can conveniently be carried out at a temperature from about -10 °C to about 40 °C.
  • a compound of formula XXIII can be prepared from a compound of formula XXII by treatment with a carbonate of formula VIII wherein R 3 is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, in the presence of a suitable base in a suitable solvent.
  • Suitable bases include carbonate bases (e.g. potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine).
  • Suitable solvents include solvents such as dichloromethane, tetrahydrofuran, 1,2- dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof. Subsequent treatment with an acid source provides a salt of the compound of formula XXIII.
  • Suitable acid sources include 1) non-aqueous acid solutions such as hydrochloric acid in ether, hydrochloric acid in methanol, or hydrochloric acid in isopropanol; 2) other mineral acids such as: hydrobromic acid, hydroiodic acid, sulfuric acid, in similar solvents; and in situ generated acid sources such as TMSCl/methanol and acetyl chloride/methanol.
  • the mixed carbonate of formula VIII can be prepared by treating 5-hydroxy- methylthiazole with a suitable carbonate or carbonate equivalent having a leaving group adjacent to the carbonyl carbon, such as phosgene in the presence of a base.
  • suitable carbonates include bis-(4-nitrophenyl)carbonate and disuccinimidyl carbonate.
  • the reaction can conveniently be carried out in a suitable aprotic organic solvent, such as dichloromethane, tetrahydrofuran, 1 ,2-dichloro-ethane, or diethylether, or a mixture thereof.
  • suitable bases include trialkylamine bases, such as
  • the compound of formula XXV can be prepared by treating methyl
  • a salt of the compound of formula XXIV is used, the reaction can be carried out in the presence of a base.
  • the reaction can conveniently be carried out in a suitable aprotic organic solvent, such as dichloromethane, tetrahydrofuran, 1 ,2- dichloroethane, or diethylether, or a mixture thereof.
  • Suitable coupling agents include carbonyl diimidazole.
  • Suitable bases include trialkylamine bases, such as
  • Suitable protecting groups include carbamates such as a Boc group as well as acetates.
  • the compound of formula XXVI can be prepared by deprotecting a
  • Pg is a suitable protecting group other than acetate and R 2 is (CrC 8 )alkyl followed by treatment of the resulting primary amine with a acetic anhydride or acetyl chloride in the presence of a suitable base.
  • the deprotection reaction can conveniently be carried out under standard conditions for removing the group Pg.
  • Pg is a Boc group
  • the deprotection can be carried out in a suitable aprotic organic solvent, such as dichloromethane, tetrahydrofuran, 1,2- dichloroethane, or diethylether, or a mixture thereof, in the presence of an anhydrous acid source (e.g. methanesulfonic acid).
  • the acetylation reaction can conveniently be carried out at a temperature from about 0 °C to about 22 °C.
  • An acid of formula XXVII or a salt thereof can be prepared by hydrolyzing a corresponding ester of formula XXVI wherein R 2 is (C 1 -C 8 )alkyl or a salt thereof under standard conditions.
  • the hydrolysis can be carried out in an aqueous solvent (e.g. water and dichloromethane, 2-methyltetrahydrofuran, or tetrahydrofuran) in the presence of a base (e.g. potassium hydroxide or lithium hydroxide) at a temperature from about -10 °C to about -30 °C.
  • a base e.g. potassium hydroxide or lithium hydroxide
  • a salt of formula XXVIII wherein Y is counterion can be prepared by treating an acid of formula XXVII with a base.
  • the reaction can be carried out in a suitable solvent (e.g. acetone, 2-methyl tetrahydrofuran, tetrahydrofuran, methylethylketone, other keytones, methyl tert-butyl ether, and other ethers, and mixtures thereof) in the presence of a suitable base (e.g. an amine base such as dicyclohexylamine).
  • a suitable solvent e.g. acetone, 2-methyl tetrahydrofuran, tetrahydrofuran, methylethylketone, other keytones, methyl tert-butyl ether, and other ethers, and mixtures thereof
  • a suitable base e.g. an amine base such as dicyclohexylamine.
  • the reaction salt formation can conveniently be carried out at a
  • a compound of formula I or a salt thereof can be prepared by coupling an acid salt of formula XXVIII with an amine of formula XXIII to form the corresponding amide.
  • This amide forming reaction can be carried out under standard conditions. For example, it can be carried out in a suitable organic solyent (e.g. dichloromethane, tetrahydrofuran, diethylether, 1 ,2-dichloroethane, N,N-dimethylformamide, or a mixture thereof) in the presence of a suitable coupling agent, such as an onium salt reagent (e.g.
  • BOP, PyBOP, PyBroP, BOI, HBTU, HATU, or TBTU) or a carbodiimide reagent e.g. DCC or DICI
  • a suitable base e.g. a trialkylamine base such as diisopropylethylamine triethylamine or N-methyl morpholine.
  • a compound of formula XL can be prepared from a compound of formula XXI by treatment with a carbonate of formula VIII wherein R 3 is nitrophenyl (e.g. 4- nitrophenyl), succinimidyl, or thiazol-5-ylmethyl (in the presence of a suitable base in a suitable solvent.
  • Suitable bases include carbonate bases (e.g. potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine).
  • Suitable solvents include solvents such as dichloromethane, tetrahydrofuran, 1 ,2-dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof.
  • Suitable acid sources include 1) non-aqueous acid solutions such as hydrochloric acid in ether, hydrochloric acid in methanol, or hydrochloric acid in isopropanol; 2) other mineral acids such as: hydrobromic acid, hydroiodic acid, sulfuric acid, in similar solvents; and in situ generated acid sources such as TMSCl/methanol and acetyl chloride/methanol.
  • the starting alkene XL or a salt thereof can be hydrogenated under standard conditions.
  • the hydrogenation can be carried out using a metal containing catalyst in a suitable solvent.
  • suitable solvents include methanol, ethanol, isopropanol, w-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof.
  • Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide.
  • the reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi.
  • the compound of formula XXIII can be isolated by treatment with an acid in an organic solvent to provide a corresponding salt.
  • Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid.
  • Suitable solvents include dichloromethane, ethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, 1,2- dimethoxyethane, chloroform, 1,2-dichloroethane, toluene, and anisole, and mixtures thereof.
  • the conversion to the salt can conveniently be carried out at a temperature from about -10 °C to about 40 °C.
  • a compound of formula XLI or a salt thereof can be prepared by coupling a compound of formula XXVII (or a salt of formula XXVIII) with an amine of formula XXI to form the corresponding amide.
  • This amide forming reaction can be carried out under standard conditions. For example, it can be carried out in a suitable organic solvent (e.g. dichloromethane, tetrahydrofuran, diethylether, 1 ,2-dichloroethane, N,N- dimethylformamide, or a mixture thereof) in the presence of a suitable coupling agent, such as an onium salt reagent (e.g.
  • BOP, PyBOP, PyBroP, BOI, HBTU, HATU, or TBTU) or a carbodiimide reagent e.g. DCC or DICI
  • a suitable base e.g. a trialkylamine base such as diisopropylethylamine triethylamine or N-methyl morpholine.
  • a compound of formula XLII can be prepared from a compound of formula XLI by treatment with a carbonate of formula VIII (wherein R 3 is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl) in the presence of a suitable base in a suitable solvent.
  • Suitable bases include carbonate bases (e.g. potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine).
  • Suitable solvents include solvents such as dichloromethane, tetrahydrofuran, 1 ,2- dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof.
  • the starting alkene XLII can be hydrogenated under standard conditions.
  • the hydrogenation can be carried out using a metal containing catalyst in a suitable solvent.
  • suitable solvents include methanol, ethanol, isopropanol, «-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof.
  • Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide.
  • the reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi. Preparation of a compound of formula XLIII or a salt thereof
  • a compound of formula XLIII or a salt thereof can be prepared by
  • the hydrogenation can be carried out using a metal containing catalyst in an alcoholic solvent.
  • suitable solvents include methanol, ethanol, isopropanol, «-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof.
  • Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide The reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi.
  • the compound of formula XLIII can be isolated by treatment with an acid in an organic solvent to provide a corresponding salt.
  • Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid.
  • Suitable solvents include dichloromethane, ethyl ether, tetrahydrofuran, i-butyl methyl ether, 1,4-dioxane, 1,2- dimethoxyethane, chloroform, 1 ,2-dichloroethane, toluene, and anisole, and mixtures thereof.
  • the conversion to the salt can conveniently be carried out at a temperature from about -10 °C to about 40 °C.
  • the compound of formula XLIII or a salt thereof can be converted to a compound of formula I by treatment with a carbonate of formula VIII (wherein R 3 is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl) in the presence of a suitable base in a suitable solvent.
  • Suitable bases include carbonate bases (e.g.
  • Suitable solvents include solvents such as dichloromethane,
  • a compound of formula XLIII or a salt thereof can also be prepared by coupling a compound of formula XXVII or a salt thereof with an amine of
  • This amide forming reaction can be carried out under standard conditions. For example, it can be carried out in a suitable organic solvent (e.g. dichloromethane, tetrahydrofuran, diethylether, 1,2-dichloroethane, N,N-dimethylformamide, or a mixture thereof) in the presence of a suitable coupling agent, such as an onium salt reagent (e.g. BOP, PyBOP, PyBroP, BOI, HBTU, HATU, or TBTU) or a carbodiimide reagent (e.g. DCC or DICI) and in the presence of a suitable base (e.g. a trialkylamine base such as diisopropylethylamine triethylamine or N-methyl morpholine).
  • a suitable organic solvent e.g. dichloromethane, tetrahydrofuran, diethylether, 1,2-dichloroethane, N,N-dimethylformamide
  • Methanesulfonic acid (25.3 mL, 390.0 mmol) was added to a solution of XXVa (167.0 g, 390.0 mmol) in dichloromethane (1 L) at 22 °C and the resulting solution was allowed to stir for 1 hour. A second equivalent of MSA was added and the solution was stirred for 1 hour. A third equivalent of MSA was added and the solution was stirred for 1 hour. This was repeated until no starting material remained. The solution was cooled to 0 °C and diisopropylethylamine (340.0 mL, 1,950.0 mmol) was added slowly while keeping the temperature between 0-5 °C.
  • Acetamide XXVIa (117.0 g, 316.22 mmol) was dissolved in tetrahydrofuran (910 mL) and cooled to 0 °C. NaOH (347.8 mL, 347.8 mmol, 1M) was added to the solution such that the internal temperature did not exceed 5 °C. The reaction was allowed to stir for a total of 1 hour and then HC1 (205.5 mL, 411.0 mmol, 2M) was added to pH 3.2-3.5. The resulting solution was extracted with dichloromethane (1.8 L). The layers were separated and the aqueous layer was washed a second time with dichloromethane (440 mL).
  • reaction was seeded and cooled from 50 °C to 20 °C over 3 hours then held at 20 °C for 10 hours. The reaction was then cooled to 0 °C for at least 1 hour followed by filtration. The wet cake was rinsed with the mother liquor and the solids were dried in the vac oven at 35 °C to provide compound XXVIIIa (30.75 g, 81% yield).
  • the resulting golden-yellow solution was concentrated out of ethyl acetate (1 x 10 mL).
  • the crude mixture was diluted with ethyl acetate (15 mL), heated, seeded with previously formed I, and allowed to slowly cool to 22 °C. After stirring at 22 °C for 4 days the resulting thick slurry was filtered and the white, crystalline solids were washed with ethyl acetate.
  • a typical yield for this reaction is about 82%.
  • R f 0.24 (Si0 2 , 9:1 EtOAc:CH 3 OH, ⁇ 0 4 ).

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Abstract

Cette invention concerne des procédés et des intermédiaires utilisés pour préparer un composé de formule I et ses sels.
PCT/US2011/054346 2010-10-01 2011-09-30 Procédé de préparation de l'ester thiazol-5-ylméthyl de l'acide (4-{4-acétylamino-2-[3-(2-isopropyl-thiazol-4-ylméthyl)-3-méthyl-uréido]-butyryl amino}-1-benzyl-5-phényl-pentyl) carbamique Ceased WO2012045007A1 (fr)

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CN104447472A (zh) * 2014-11-06 2015-03-25 江苏森萱医药化工股份有限公司 D)-2-苄基-n,n-二甲基氮杂环丙烷基-1-磺酰胺合成方法
WO2016037588A3 (fr) * 2014-09-12 2016-05-26 宁波九胜创新医药科技有限公司 Nouvel intermédiaire pour la synthèse de cobicistat, un activateur de médicaments contre le sida
CN106749085A (zh) * 2016-12-23 2017-05-31 东北制药集团股份有限公司 一种制备利托那韦的方法
US9975864B2 (en) 2013-12-03 2018-05-22 Mylan Laboratories Limited Preparation of cobicistat intermediates
CN116239476A (zh) * 2022-11-28 2023-06-09 安徽贝克制药股份有限公司 一种盐酸司来吉兰异构体的制备方法

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CN106749085B (zh) * 2016-12-23 2019-05-24 东北制药集团股份有限公司 一种制备利托那韦的方法
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