WO2002064553A1 - Procede de preparation de derives d'alcools halogenes - Google Patents

Procede de preparation de derives d'alcools halogenes Download PDF

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Publication number
WO2002064553A1
WO2002064553A1 PCT/JP2002/001267 JP0201267W WO02064553A1 WO 2002064553 A1 WO2002064553 A1 WO 2002064553A1 JP 0201267 W JP0201267 W JP 0201267W WO 02064553 A1 WO02064553 A1 WO 02064553A1
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group
compound
general formula
compound represented
formula
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PCT/JP2002/001267
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English (en)
Japanese (ja)
Inventor
Susumu Shimizu
Kazuhiko Sunagawa
Hideki Iwama
Koichi Niimura
Masataka Katohno
Shigeru Mizusawa
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Kureha Chemical Industry Company, Limited
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Priority to JP2002564486A priority Critical patent/JPWO2002064553A1/ja
Publication of WO2002064553A1 publication Critical patent/WO2002064553A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms

Definitions

  • the present invention relates to a halogeno alcohol represented by the formula (1), (2S, 3R) N-benzyloxycalponyl 3-amino-trihalogeno-4-phenylsulfanylbutan-2-ol derivative (compound number 1, hereinafter, /, Logeno alcohol).
  • This halogeno alcohol is a compound extremely useful as an HIV protease inhibitor and represented by the following formula (7) [3S- (3,4aj8,8a) S)]-2- [2'-hydroxy- 3'-phenylthiomethyl-4'-aza-5'-oxo-5 '-(2 "-methyl-3" -hydroxyphenyl) pentyl] decahydroisoquinoline-3-Nt-butylcarboxamide Useful as an intermediate for production.
  • the present invention further relates to a novel active ester compound and an ylide compound for producing the halogeno alcohol.
  • any of the methods is produced via a halogeno alcohol represented by the formula (1) as an intermediate.
  • this halogenoalcohol that is, (2S, 3R) N-Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative
  • the method 1) is not applicable.
  • explosive diazomethane is used, and the reaction condition requires certain low temperature conditions.There are inefficiencies in the process.
  • the use of method 2) is regulated industrially. All of the conventional manufacturing methods have problems, such as the use of a large amount of methylene chloride, and the method 3) requires a long number of steps. Therefore, a method for safely and inexpensively producing the compound of the above formula (7), which is a compound extremely useful as an HIV protease inhibitor, is desired.
  • An object of the present invention is to provide an HIV protease inhibitor [3S- (3,4a ⁇ , 8a; S)]-2- [2, -hydroxy-3′-phenylthiomethyl-4 Production of '-aza-5'-oxo-5'-(2 "-methyl-3 ⁇ -hydroxyphenyl) pentinole] decahydroisoquinoline-3-Nt-butylcarboxyamide (formula (7)) Preparation of (2S, 3R) N-Cbz-3-amino-halogeno-4-phenylsulfanylbutan-2-ol derivative (formula (1)) which is an intermediate and has various problems in the production process It is an object of the present invention to provide a manufacturing method for efficiently performing the above process by a novel improved method.
  • Another object of the present invention is to provide a novel intermediate compound useful for producing the compound and a method for producing the same. Disclosure of the invention
  • the present inventors have conducted intensive studies in accordance with the above object, and as a result, starting from a known compound N-CbS-phenyl-L-cysteine represented by the following formula (2) as a starting material, a novel active ester derivative (the following formula (4) )) And a new ylide compound (formula (5)) and a halomethylketone intermediate (formula (6)), and then a halogeno alcohol represented by formula (1), namely, (2S.3R) N-Cbz
  • the present inventors have found a method for efficiently producing a 3-amino-halogeno-4-phenylsulfanylbutan-2-ol derivative, and have completed the present invention.
  • ADVANTAGE OF THE INVENTION According to the method of this invention, the problem in the conventional method is solved and the target compound can be manufactured in a short process under mild reaction conditions with good yield.
  • the gist of the present invention is:
  • Z is a linear or branched alkoxy group, C ⁇ GA alkylthio group, phenoxy group, or a halogen atom, nitro group, alkyl group, alkoxy group, or hydroxy-substituted phenoxy group, phenoxy group, A dithio group, a halogen atom, a divalent group, an alkyl group, an alkoxy group, or a hydroxy-substituted phenylthio group, a benzyloxy group, or a halogen atom, a tro group, an alkyl group, or an alkoxy-substituted benzyloxy group; Benzylthio group or halogen atom, nitro group, alkyl group or alkoxy group substituted benzylthio group, pyridyloxy group, pyrylthio group, ethoxyvinyloxy group, straight-chain or branched -alkylcarbonyl
  • this is a method for producing a halogeno alcohol derivative represented by the general formula (1) by reducing the same.
  • the present invention provides a novel active ester compound represented by the above-mentioned formula (4) and a novel ylide compound represented by the above formula (5).
  • the method of the present invention starts from a known compound, N-potency oxybenzoxy-S-phenyl-L-cystine (compound (2)) represented by the above general formula (2) as a starting material, Is converted to an active ester compound (compound (4)) represented by the above general formula (4) by reacting the obtained active ester compound with a methylide compound to give a compound represented by the above formula (5)
  • the starting compound N-benzyloxy-S-phenyl-L-cysteine (compound (2)) is converted into an ester in a suitable organic solvent by the other general formula (3) ZR (wherein R and Z are the same as described above).
  • ZR preferably, an alcohol, a phenol, an N-hydroxyimide or an N-hydroxy heterocyclic compound can be used, and these compounds have various substituents. Any compound may be used as long as it can introduce the group defined as Z in the definition of compound (3).
  • Particularly preferred examples of Z include a P-nitrophenoxy group and a succinimide group.
  • the reaction is carried out, for example, in the presence of a condensing agent, for example, ⁇ , ⁇ ′ -dicyclohexylcarpimide (DGG), or thionyl chloride and a base, with p-nitrophenol or N-hydroxysuccinimide.
  • a condensing agent for example, ⁇ , ⁇ ′ -dicyclohexylcarpimide (DGG), or thionyl chloride and a base, with p-nitrophenol or N-hydroxysuccinimide.
  • Suitable organic solvents include dioxane, ethyl ether, tetrahydrofuran, ether solvents such as 1,2-dioxetane, and aromatic solvents such as benzene, toluene and xylene, and more preferably dioxane and toluene. Is mentioned.
  • the reaction temperature is ⁇ 10 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is 30 minutes to 2 days, preferably 1 hour to 24 hours.
  • the compound of the general formula (4) wherein Z is a halogen atom can be directly reacted with the Kohli reagent to give the ylide compound (5). However, it can be converted into an ester compound and then reacted with the Kohrie reagent. Alright.
  • a halogenating agent for example, thionyl chloride, sulfuryl chloride, phosphorus pentachloride, Phosphorus chloride, thionyl bromide, oxalyl chloride, etc. at ⁇ 10 ° C. to 80 ° C., preferably at 0 ° C. to 50 ° C., after being converted to an acid halide, with alcohols, thiols, phenols, etc. By reacting, an active ester compound can be obtained.
  • a step of producing an ylide compound (hereinafter referred to as an ylide-forming step)
  • the active ester compound obtained in (i) is reacted with dimethylsulfoxomethylide (hereinafter, referred to as a methylide compound; this methylide compound is sometimes referred to as Choli reagent).
  • a methylide compound dimethylsulfoxomethylide
  • Choli reagent dimethylsulfoxomethylide
  • a methylide compound this methylide compound is sometimes referred to as Choli reagent
  • a mixture containing a methylide compound usually produced from trimethylsulfoxonium halide (hereinafter referred to as a methylide-containing mixture) is reacted with the ylide compound.
  • the step of preparing the methylide-containing mixture (hereinafter, referred to as the methylide preparation step) is carried out in trimethylsulfoxonium halide (preferred halides are romide and chloride, particularly preferably bromide). And a base (preferable bases include sodium hydride, potassium tert-butoxide and sodium tert-butoxide).
  • a methylide preparation step and an ylidation step are performed in a series of steps.
  • the solvent used in the methide preparation step is selected from solvents that do not adversely affect the ylidation step.
  • Preferred organic solvents include tert-butanol, dimethylsulfoxide, dimethylformamide, 2-methylpyrrolidone, toluene and tetrahydrofuran. One or more of these solvents are used in combination.
  • reaction temperature in the step of preparing methylide is 5 to 150 ° C., preferably 20 to 100 ° C., and particularly preferably 40 to 85 ° C.
  • the reaction time in the process for preparing methylide is 10 minutes to 20 hours, preferably 30 minutes to 5 hours.
  • the reaction temperature of the iridido process is from 170 to 100. C, preferably from 50 to 70 ° C, particularly preferably from 20 to 40 ° C.
  • the reaction time of the ylidation step is 10 minutes to 20 hours, preferably 30 minutes to 5 hours.
  • the ester compound obtained in the above-mentioned active ester compound producing step can be used in an iridation step without separating and purifying. That is, the ylide compound can be produced by adding a filtrate obtained by filtering out crystals precipitated in the esterification reaction solution to a separately prepared methylide-containing mixture.
  • a reaction solvent a mixed solvent of a solvent suitable for an esterification reaction and a solvent suitable for a methylide preparation step is preferred.
  • Suitable mixed solvents are preferably tetrahydrofuran and dimethyl sulfoxide, and tetrahydrofuran and tert-butanol. In this case, operations such as concentration of the esterification reaction solvent for separating the ester compound and purification of the ester compound can be advantageously omitted.
  • the conversion of the ylide compound (5) to the halomethyl ketone (6) is performed by reacting with hydrogen halide in an appropriate organic solvent at -50 ° C to 100 ° C, preferably at -20 ° C to 80 ° C. By carrying out, the halomethyl ketone of the compound (6) can be obtained.
  • Suitable organic solvents include ethyl acetate, tetrahydrofuran, dichloroethane, toluene, and the like, and the reaction time is 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
  • the hydrogen halide is hydrogen chloride. And hydrogen bromide, etc., and these may be used by dissolving them in an organic solvent, particularly preferably by dissolving hydrogen chloride in ethyl acetate, tetrahydrofuran, getyl ether, toluene and the like. Good to do.
  • Step of reducing no and romethyl ketone (hereinafter referred to as ketone reduction step)
  • This ketone reduction step can be advantageously performed by a method based on Meerwein-Ponndorf-VeHey reduction or a method using sodium borohydride.
  • a solvent that does not adversely affect the reaction may be used in combination, and examples thereof include toluene and tetrahydrofuran.
  • the method using sodium borohydride is carried out in an ether solvent or a mixed solvent of an ether solvent and water.
  • Preferred are tetrahydrofuran and a mixed solvent of tetrahydrofuran and water.
  • the mixed solvent ratio is 1 000Z 1
  • reaction temperature is 120 ⁇ "! 00 ° C, preferably 110-60 ° C.
  • the amount of sodium borohydride to be used for compound (6) is preferably 0.5 to 3 equivalents, more preferably "! To 1.5 equivalents.
  • the compound (1) and various intermediate compounds produced as described above can be appropriately subjected to separation and purification means according to the process, for example, means such as concentration, extraction, chromatography, and recrystallization. It can be isolated as of any purity.
  • separation and purification means for example, means such as concentration, extraction, chromatography, and recrystallization. It can be isolated as of any purity.
  • IR (KBr, cm-1): 348,3044,2952,1 818,1 790,1 746,1 696,1 636,1 578,1 538,1472,1458,1442,1430,1418,1 368,1 308,1 280,1 210,1 1 60,1094,1066, 1042,1024,1 004,994,922,848,814,776,750,698,660,642,61 8,584,500,480,424.
  • N-benzyloxycarbonyl-S-phenyl-L-cystine (compound 2: optical purity 98.6% ee) 3.31 g (0.01 mol) in a 100 ml four-neck flask equipped with a thermometer, a stirrer, a nitrogen inlet tube, and a dropping funnel. ), 1.39 g (0.01 mol) of p-ditrophenol was taken and diluted with 15 ml of 1,4-dioxane.
  • IR (KBr, cm-1): 3472,31 28,3092,1 61 8,1592,1 51 8,1488,1460,1 352,1 324,1 296,1 238,1 1 98,1 1 80, 1 1 64,1 1 54,1 1 1 2,1 102,101 0,862,832,824,758,71 8,700,650,626,5 32,480,418.
  • N-benzyloxycarbonyl-S-phenyl-L-cysteine (Compound 2: optical purity 98.6% ee) 497.0 g (1.5 mol: 1.0 eq) and 230.9 g (1.65 mol; 1.1 eq) of p-nitrophenol were suspended in 7.0 L of toluene, and 333.9 g (3.3 mol; 2.2 eq) of triethylamine was added. After the addition, the suspension dissolved and became a yellow solution. The yellow solution was cooled to about 17 ° C.
  • the mixture was stirred at 0 ° C for 3 hours, the dry ice / acetone pass was removed, and the mixture was further stirred at 50 ° C ⁇ 2 ° C for 3 hours.
  • the compound (2) was confirmed to be less than 0.2 0% by HPLC, the reaction was stopped, and the mixture was washed twice with 2 L of water, washed twice with 2 L of 5% aqueous sodium hydrogen carbonate solution, and further washed with 2 L After washing twice with water, a toluene solution containing ⁇ -nitro-2-phenyl ester was obtained. After drying over anhydrous sodium sulfate, toluene was distilled off under reduced pressure to obtain a residue.
  • 0.747 g (1 8.64 mmol; 2.0 eq) of aH (60%) is taken in a 100 ml square flask equipped with a thermometer, condenser, nitrogen inlet tube, dropping funnel and stirrer, and washed twice with 10 ml of n-hexane. After that, the resultant was suspended in 40 ml of dry DMSO. Under a nitrogen stream, 3.23 g (18.64 mmol; 2.0 eq) of trimethylsulfoxonium bromide (TMSOB) was added little by little. NaH dissolves with foaming and heat generation. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 55 ° C. for 60 minutes in an oil bath to prepare a core reagent.
  • TMSOB trimethylsulfoxonium bromide
  • the prepared Corey reagent was returned to room temperature, added with THF (40 ml), and cooled to ⁇ 12 ° C. with a dry ice-acetone bath.
  • a solution prepared by dissolving 4.0 g (9.34 mmol) of imide ester in 20 ml of dry THF was charged into the dropping port, and the solution was added dropwise to the Coley reagent over 10 minutes while keeping the internal temperature not lower than -10 ° C. Washed with 5 ml of THF. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and heated to 0 ° C over 2 hours to stop the reaction.
  • the reaction solution was poured into 200 ml of ice water and extracted with 250 ml of AcOEt.
  • the aqueous layer was further extracted with AcOEt 100 ml ⁇ 2, and the organic layers were combined.
  • the organic layer was washed with saturated saline 200 ml ⁇ 2, and dried over anhydrous
  • 0.354 g (8.84 mmol; 2.0 eq) of NaH (60%) was placed in a 100 ml square flask equipped with a thermometer, condenser, nitrogen inlet tube, dropping funnel and stirrer, and washed twice with 5 ml of n-hexane. Thereafter, the cells were suspended in 20 ml of dry DMSO.
  • TMSOB trimethylsulfoxonium bromide
  • a solution prepared by dissolving 2.0 g (4.42 mmol) of p-nitrophenyl ester in 20 ml of dry THF was charged into a dropping funnel, and the internal temperature was kept at -10 ° C or higher. It was added dropwise and washed with 5 ml of THF. After the addition, the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into 100 ml of ice water and extracted with 50 ml of AcOEt.
  • a Corey reagent (dimethylsulfoxonium methylide) was prepared by the following method. C In a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer,
  • a Coley reagent (dimethylsulfoxonium methylide) was prepared by the following method. 2.8 g (0.025 mol) of potassium tert-butoxide was suspended in 60 ml of dry t-butanol in a 100 ml four-neck flask equipped with a thermometer, a cooler, and a stirrer in a nitrogen stream, and trimethyl sulfoxonium bromide (TMSOB) was added. 4.33 g (0.025 mol) was added in small portions. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 65 ° C to 75 ° C in an oil bath for 30 minutes to prepare a Corey reagent. To this solution was added 40 ml of tetrahydrofuran, and the mixture was cooled to ⁇ 5 ° C. in a dry ice-aceton bath.
  • TMSOB trimethyl sulfoxonium bromide
  • TMSOB trimethylsulfoxonium bromide
  • the ethyl acetate layer was washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 2.19 g of an oil.
  • the aqueous layer was extracted with 100 ml of ethyl acetate and subjected to the same treatment to obtain 0.19 g of an oily substance.
  • the core reagent was cooled to 110 ° C, and a solution prepared by dissolving P-nitrophenyl ester [46.17 g (0.1 mol; 1.Oeq)] in 450 ml of toluene was stirred for 20 minutes under stirring. Was dropped. After the dropwise addition, stirring was continued at the same temperature for 2.5 hours. Then, the reaction mixture was heated to 35 ° C, 250 ml of warm water was added, and the mixture was stirred at 35 ° C for 20 minutes.
  • the reaction solution was transferred to a separatory funnel to separate the solution, the obtained toluene solution was transferred to a 2 L flask, azeotropically dehydrated at a bath temperature of 50 ° C, and the toluene solution was transferred to a 1 L flask and concentrated under reduced pressure to obtain a liquid volume.
  • the resulting toluene solution was warmed, 20 ml of n-hexane was added with stirring, and the mixture was allowed to cool under stirring to precipitate crystals. The crystals were collected by filtration, washed with 70 ml of toluene, and dried to obtain a white crystalline ylide compound.
  • the method of the present invention does not require the use of hazardous reagents as in the conventional method, is short in length, and allows the use of 3-benzyloxycarbonylamino-1-halogeno-4-phenylthiobutan-2-ol.
  • An advantageous method of manufacture is provided. Therefore, [3S- (3 or, 4aS, 8a) 8)]-2- [2'-hydrogen is useful as an HIV protease inhibitor that can be derived therefrom.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de préparation d'alcools halogénés correspondant à la formule générale (1) et de nouveaux intermédiaires utiles. Les alcools halogénés correspondant à la formule générale (1), à savoir les dérivés (2S, 3R)-n-Cbz-3-amino-1-halogéno-4-phénylsulfanylbutan-2-ol, peuvent être efficacement préparés à partir d'un composant initiateur largement connu tel que N-Cbz-S-phényl-L-cystéine, au moyen de nouveaux dérivés d'esters et de nouveaux composés d'ylide correspondant à la formule générale (4) et (5) des intermédiaires d'halométhyl cétone correspondant à la formule générale (6).
PCT/JP2002/001267 2001-02-14 2002-02-14 Procede de preparation de derives d'alcools halogenes WO2002064553A1 (fr)

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JP2002564486A JPWO2002064553A1 (ja) 2001-02-14 2002-02-14 ハロゲノアルコール誘導体の製造方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1329373C (zh) * 2003-12-11 2007-08-01 上海安基生物科技股份有限公司 （2s.3r）－n－苄氧羰基－3－氨基－1－氯－4－苯硫基－2－丁醇的生产方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604185A1 (fr) * 1992-12-22 1994-06-29 Eli Lilly And Company Inhibiteurs de la HIV protéase pour le traitement du SIDA
WO1995009843A1 (fr) * 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Inhibiteurs de la protease du vih
WO1998045271A1 (fr) * 1997-04-10 1998-10-15 F. Hoffman-La Roche Ag Procede servant a preparer une butylthio-isoquinoleine et ses intermediaires
EP0897911A1 (fr) * 1997-01-14 1999-02-24 Kaneka Corporation Procede servant a preparer des derives de cysteine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604185A1 (fr) * 1992-12-22 1994-06-29 Eli Lilly And Company Inhibiteurs de la HIV protéase pour le traitement du SIDA
WO1995009843A1 (fr) * 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Inhibiteurs de la protease du vih
EP0897911A1 (fr) * 1997-01-14 1999-02-24 Kaneka Corporation Procede servant a preparer des derives de cysteine
WO1998045271A1 (fr) * 1997-04-10 1998-10-15 F. Hoffman-La Roche Ag Procede servant a preparer une butylthio-isoquinoleine et ses intermediaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DALE L. RIEGER: "A concise formal synthesis of the potent HIV protease inhibitor nelfinavir mesylate", J. ORG. CHEM., vol. 62, no. 24, 1997, pages 8546 - 8548, XP002952506 *
NAKAJIMA KEIICHIRO ET AL.: "Studies on 2-aziridinecarboxylic acid. IX. Convenient synthesis of optically active S-alkylcysteine, threo-S-alkyl-beta-methylcysteine and lanthionine derivatives via the ring-opening reaction of aziridine by several thiols", BULL. CHEM. SOC. JPN., vol. 56, no. 2, 1983, pages 520 - 522, XP002952507 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1329373C (zh) * 2003-12-11 2007-08-01 上海安基生物科技股份有限公司 （2s.3r）－n－苄氧羰基－3－氨基－1－氯－4－苯硫基－2－丁醇的生产方法

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