WO2002064553A1 - Process for preparation of halogenoalcohol derivatives - Google Patents

Process for preparation of halogenoalcohol derivatives Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
general formula
compound represented
formula
Prior art date
Application number
PCT/JP2002/001267
Other languages
French (fr)
Japanese (ja)
Inventor
Susumu Shimizu
Kazuhiko Sunagawa
Hideki Iwama
Koichi Niimura
Masataka Katohno
Shigeru Mizusawa
Original Assignee
Kureha Chemical Industry Company, 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 Kureha Chemical Industry Company, Limited filed Critical Kureha Chemical Industry Company, Limited
Priority to JP2002564486A priority Critical patent/JPWO2002064553A1/en
Publication of WO2002064553A1 publication Critical patent/WO2002064553A1/en

Links

Classifications

    • 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.

Landscapes

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

Abstract

A process for preparation of halogenoalcohol derivatives represented by the general formula (1) and novel useful intermediates are provided. Halogenoalcohols of the general formula (1), i.e., (2S,3R)-N-Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-olderivatives, can be efficiently prepared from a publicly known starting compound, i.e., N-Cbz-S-phenyl-L-cysteine, through novel active ester derivatives and novel ylide compounds of the general formulae (4) and (5) and halomethyl ketone intermediates of the general formula (6).

Description

明 細 書 ハロゲノアルコール誘導体の製造方法  Description Method for producing halogeno alcohol derivatives
技術分野 Technical field
本発明は、式 (1 )で表わされるハロゲノアルコール、（2S,3R) N-ベンジルォキシカ ルポニル 3 -ァミノ-卜ハロゲノ- 4-フエニルスルファニルブタン- 2-オール誘導体 (化合物番号 1、以下、/、ロゲノアルコールと記すことがある）の新規な製造方法 に関する。このハロゲノアルコールは、 HIVプロテア一ゼ阻害剤として極めて有用 な化合物である下記式 (7)で表される [3S - (3 ， 4a j8 ,8a )S )]-2 - [2' -ヒドロキシ- 3'- フエ二ルチオメチル -4'-ァザ- 5' -ォキソ- 5'- (2" -メチル- 3" -ヒドロキシフエ二 ル）ペンチル]デカヒドロイソキノリン - 3-N-t -プチルカルポキシアミドの製造のた めの中間体として有用である。本発明は、さらに、該ハロゲノアルコールを製造す るための新規な活性エステル化合物およびイリド化合物に関する。 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.
なお、化合物名の記載において、「ベンジルォキシカルボニル」を以下、 Γ Gbzj と略記することがある。  In the description of the compound name, “benzyloxycarbonyl” may be abbreviated as “Gbzj” below.
Figure imgf000003_0001
Figure imgf000003_0001
(1) (7) 背景技術  (1) (7) Background technology
上記式（7)で表される化合物の製造方法としては、例えば、次のような方法が 知られている。すなわち、  As a method for producing the compound represented by the above formula (7), for example, the following method is known. That is,
1〉セリンを出発原料としてアジド化合物を経て製造する方法（国際公開番号 WO 95/09843号公報）。  1> A method for producing via seride using azide compound as a starting material (International Publication No. WO 95/09843).
2) 2-ブテン - 1 ,4 -ジオールを出発原料としてキラルァミンを経て製造する方法 (国際公開番号 W097/1 1937、 W097/1 1938号公報）。 3) 1 ,3 -ォキサゾリジン- 2-オン誘導体からジァミノアルコールを経て製造する方 法（特開平 1 1 -2791 54号公報）。 2) A method in which 2-butene-1,4-diol is used as a starting material and produced via chiralamine (International Publication Nos. W097 / 1937 and W097 / 1938). 3) A method of producing from a 1,3-oxazolidin-2-one derivative via diamino alcohol (JP-A-11-279154).
上記の方法による上記式 (7)で表わされる化合物の製造においては、いずれの方 法も中間体として式 (1 )で表わされるハロゲノアルコール」を経て製造される。しか し、このハロゲノアルコール、すなわち（2S，3R) N- Cbz - 3-アミノ- 1—ハロゲノ- 4-フ- ェニルスルファニルブタン- 2 -オール誘導体を製造する場合に、 1 )の方法は、途 中の工程で、爆発性を有するジァゾメタンを使用したり、反応条件に一定の低温 条件を必要とする等、工程に非効率な点がある、 2)の方法は工業的に使用が規 制される塩化メチレンを大量に使用すること、 3)の方法は工程数が長いなど、従 来行われている製造方法はいずれも問題を内包している。したがって、 HIVプロ テアーゼ阻害剤として極めて有用な化合物である上記式（7)の化合物を安全に かつ安価に製造する方法が望まれている。 In the production of the compound represented by the above formula (7) by the above method, any of the methods is produced via a halogeno alcohol represented by the formula (1) as an intermediate. However, when producing this halogenoalcohol, that is, (2S, 3R) N-Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative, the method 1) is not applicable. In the middle process, 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.
本発明の目的は上記のような現状に鑑み、 HIVプロテア一ゼ阻害剤 [3S-(3 ， 4a β , 8a ;S )]-2- [2， -ヒドロキシ -3' -フエ二ルチオメチル - 4'-ァザ- 5'-ォキソ - 5'- (2" -メチル- 3〃 -ヒドロキシフエニル）ペンチノレ]デカヒドロイソキノリン- 3-N-t -ブ チルカルポキシアミド (上記式（7 ) )の製造中間体で、製造工程に種々問題のあつ た（2S， 3R) N- Cbz- 3-ァミノ-卜ハロゲノ- 4-フエニルスルファニルブタン- 2 -ォ一 ル誘導体（上記式（1 ) )の製造を改良された新規な方法により効率よく行う製造 方法を提供することである。  An object of the present invention is to provide an HIV protease inhibitor [3S- (3,4aβ, 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.
また、本発明の他の目的は、当該化合物を製造するために有用な新規中間体 化合物及びその製造方法を提供することである。 発明の開示  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
本発明者等は、上記目的に従って鋭意検討した結果、下記式 (2)で表わされる 公知の化合物 N-Cb S-フエニル -L-システィンを出発原料として、新規な活性 エステル誘導体（下記式 (4))及び新規なイリド化合物（下記式 (5))、ハロメチルケ トン中間体（下記式 (6))を経て、式（1 )で表されるハロゲノアルコール、すなわち、 (2S.3R) N-Cbz - 3-ァミノ-卜ハロゲノ- 4 -フエニルスルファニルブタン- 2 -オール誘 導体を効率よく製造する方法を見出し、本発明を完成した。 本発明方法によれば、従来の方法における問題点を解消し、温和な反応条件 で短い工程で目的の化合物を収率よく製造することができる。 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.
即ち、本発明の要旨は、  That is, the gist of the present invention is:
下記式 (2)で表される化合物 (2)を、  A compound (2) represented by the following formula (2):
Figure imgf000005_0001
Figure imgf000005_0001
一般式（3 )で表される化合物（化合物（3) )と縮合剤の存在下に反応させて、 Reacting a compound represented by the general formula (3) (compound (3)) with a condensing agent,
Z - R (3)  Z-R (3)
(式 (3)中、 Zは直鎖または分岐した 〜 アルコキシ基、 C^ GAアルキルチオ 基、フエノキシ基あるいは、ハロゲン原子、ニトロ基、アルキル基、アルコキシ基ま たは、ヒドロキシ基置換フエノキシ基、フエ二ルチオ基あるいは、ハロゲン原子、二 卜口基、アルキル基、アルコキシ基または、ヒドロキシ基置換フエ二ルチオ基、ベン ジルォキシ基あるいは、ハロゲン原子、 トロ基、アルキル基または、アルコキシ 基置換べンジルォキシ基、ベンジルチオ基あるいはハロゲン原子、ニトロ基、アル キル基またはアルコキシ基置換べンジルチオ基、ピリジルォキシ基、ピリ ルチオ 基、エトキシビニルォキシ基、直鎖または分岐した 〜 アルキルカルボニルォ キシ基、置換リン酸エステル基、置換硫酸エステル基、イミダゾリル基、アジド基、 アルコキシカルボニルォキシ基、シクロへキシルカルポジイミドキシ基、スクシンィ ミドキシ基、フタルイミドキシ基、ベンゾトリアゾリルォキシ基、ピペリジノォキシ基 及びハロゲン原子を表し、 Rは水素原子を表す。ただし、下記一般式 (4)におい て Zがハロゲン原子である場合には、 Z-Rは一緒になって、塩化チォニル、塩化 スルフリル、五塩化リン、三塩化リン、臭化チォニル、またはォキザルクロリドを表 す。） (In the formula (3), 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 -alkylcarbonyloxy group, substituted phosphate group , Substituted sulfate group, imidazolyl group, azide group, R represents a hydrogen atom, and represents a oxycarbonyloxy group, a cyclohexylcarbodiimidoxy group, a succinimidoxy group, a phthalimidoxy group, a benzotriazolyloxy group, a piperidinoxy group, or a halogen atom, provided that the following general formula: In (4), when Z is a halogen atom, ZR together represent thionyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl bromide, or oxal chloride.)
下記一般式 (4) 入 ュ The following general formula (4) Entry
o  o
(式 (4)中、 Zは前述のとおり。） (In equation (4), Z is as described above.)
で示される化合物 (4)に変換する工程、 A step of converting into a compound (4) represented by
得られた化合物 (4)をメチリド化合物と反応させて、下記式 (5)で表されるイリド 化合物（化合物 (5))を生成する工程、  Reacting the obtained compound (4) with a methylide compound to produce an ylide compound (compound (5)) represented by the following formula (5):
Figure imgf000006_0001
Figure imgf000006_0001
得られたイリド化合物をハロゲン化水素で処理して下記一般式 (6)で表されるハ ロメチルケトン（化合物 (6) )とし、 The obtained ylide compound is treated with hydrogen halide to give halomethylketone (compound (6)) represented by the following general formula (6).
Figure imgf000006_0002
(式中、 Xはハロゲン原子を表す）、
Figure imgf000006_0002
(Wherein X represents a halogen atom),
ついで、これを還元して一般式 (1 )で表されるハロゲノアルコール誘導体を製造 する方法である。  Next, this is a method for producing a halogeno alcohol derivative represented by the general formula (1) by reducing the same.
Figure imgf000007_0001
Figure imgf000007_0001
(式中、 Xはハロゲン原子を表す） (Wherein, X represents a halogen atom)
さらに、本発明は、前記一 IS式 (4)で表される新規な活性エステル化合物及び 前記式 (5)で表される新規なイリド化合物を提供する。 本発明方法は、公知の化合物である上記一般式 (2)で表される N-力ルポベン ゾキシ - S-フエニル- L-システィン（化合物 (2))を出発原料とし、この化合物の力 ルポキシル基をエステル化して上記一般式 (4)で表される活性エステル化合物 (化合物 (4) )に変換する工程、得られた活性エステル化合物をメチリド化合物と 反応させて、上記式 (5)で表されるイリド化合物（化合物 (5))を生成する工程、得 られたイリド化合物をハロゲン化水素で処理して下記一般式 (6)で表されるハロメ チルケトン（化合物 (6))とする工程、ついで、これを還元して一般式 (1 )で表され るハロゲノアルコール誘導体を製造する工程よりなる。  Further, 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) A step of producing an ylide compound (compound (5)), treating the obtained ylide compound with hydrogen halide to give a halomethyl ketone (compound (6)) represented by the following general formula (6), And reducing this to produce a halogeno alcohol derivative represented by the general formula (1).
(0活性エステル化合物生成工程 (0 active ester compound formation step
この工程では、出発化合物 N-ベンジルォキシ -S-フエニル -L-システィン（化 合物 (2))を適当な有機洚媒中で、エステルを形成するもう一方の一般式 (3) Z-R (式中 R，Zは前記と同じ） で表される化合物 (3)と反応させる。このような化合物 としては、好ましくはアルコール類、フエノール類、 N-ヒドロキシイミド類または N - ヒドロキシ複素環化合物等を用いることができ、これら化合物は種々の置換基を 有していてよく、前記化合物 (3)の定義中の Zとして定義した基を導入できるも のであればよい。特に好ましい Zとしては P-ニトロフエノキシ基、スクシンイミドキ シ基等を挙げることができる。 In this step, 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). As such a compound, 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.
反応は、例えば、 p -二卜口フエノールまたは N -ヒドロキシスクシンイミド等と、縮合 剤、例えば Ν，Ν'-ジシクロへキシルカルポイミド (DGG)、 または、塩化チォニル及 び塩基の存在下に、 - 20 °C〜150 °C、好ましくは- 10 °C〜80°Cの温度で反応させ ることによリー般式 (4)の活性エステル化合物を得ることができる。 The reaction is carried out, for example, in the presence of a condensing agent, for example, Ν, 等 ′ -dicyclohexylcarpimide (DGG), or thionyl chloride and a base, with p-nitrophenol or N-hydroxysuccinimide. The active ester compound of the general formula (4) can be obtained by reacting at a temperature of 20 ° C to 150 ° C, preferably -10 ° C to 80 ° C.
また、 P-ニトロフエノールや N -ヒドロキシスクシンイミド等を不活性溶媒中で、塩 化チォニルと 2倍量の塩基、例えばトリェチルアミン等を用いて 0°Cから 50°Cで 反応することにより、 p -二トロフエニル亜硫酸エステルあるいはスクシンイミド亜硫 酸エステルが得られる。このものは単離あるいは単離することなく、化合物 (2)と 反応させることにより、一般式 (4)の活性エステル化合物を得ることができる。 適当な有機溶媒としては、ジォキサン、ジェチルェ一テル、テトラヒドロフラン、 1 ,2 -ジェ卜キシェタン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳 香族溶媒が好ましぐ更に好ましくは、ジォキサン、トルエンが挙げられる。反応温 度は- 10°C〜60°C、好ましくは 0°C〜30°Cである。反応時間は 30分〜 2日間、好 ましくは 1時間〜 24時間である。  Also, by reacting P-nitrophenol, N-hydroxysuccinimide, etc. with thionyl chloride in an inert solvent with twice the amount of a base, for example, triethylamine at 0 ° C to 50 ° C, p- Ditrophenyl sulfite or succinimide sulfite is obtained. This is isolated or reacted without isolation with the compound (2) to obtain an active ester compound of the general formula (4). 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.
なお、一般式（4)の Zがハロゲン原子の化合物はそのままコーリー試薬と反応 させてイリド化合物 (5)とすることができるが、エステル化合物に変換させてから コ一リー試薬と反応させてもよし、。一般式（4)の Zがハロゲン原子の化合物を用 いてエステル化合物を得るには、不活性溶媒中、化合物（2)とハロゲン化剤、例 えば、塩化チォニル、塩化スルフリル、五塩化リン、三塩化リン、臭化チォニル、 オギザリルクロリド等と - 10°C〜80°C、好ましくは、 0°C~50°Cで、酸ハロゲン化物 とした後、アルコール類、チオール類、フエノール類等と反応することにより、活性 エステル化合物を得ることができる。  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. In order to obtain an ester compound by using a compound in which Z in the general formula (4) is a halogen atom, compound (2) and 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.
(ii)イリド化合物を生成させる工程（以下において、イリド化工程と記載する） この工程では、（i)で得られた活性エステル化合物とジメチルスルホキソメチリド (以下において、メチリド化合物と記載する。このメチリド化合物はコーリ一試薬と 称されることもある）とを反応させて、イリド化合物（化合物（5) )を生成させる。 このイリド化工程では、通常トリメチルスルホキソニゥ厶ハライドから生成させたメ チリド化合物を含有する混合物（以下において、メチリド含有混合物と記載する） とイリド化合物とを反応させる。 (ii) a step of producing an ylide compound (hereinafter referred to as an ylide-forming step) In this 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). To produce an ylide compound (compound (5)). In this ylidation step, 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.
メチリド含有混合物を調製する工程（以下において、メチリド調製工程と記載す る）は、卜リメチルスルホキソニゥムハライド（好ましいハライドは、 ロマイド、ョ一 ダイドであり、特に好ましくは、ブロマイドである）と塩基（好ましい塩基として、水 素化ナトリウム、カリウム tert—ブトキシド、ナトリウム tert—ブトキシドをあげ ることができる）とを反応させる。 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).
通常、メチリド調製工程とイリド化工程とを一連の工程で行う。 Usually, a methylide preparation step and an ylidation step are performed in a series of steps.
したがって、メチリド調製工程で使用する溶媒は、イリド化工程に悪影響を及ぼさ ない溶媒から選択して使用する。好ましい有機溶媒としては、 tert—ブタノール、 ジメチルスルホキシド、ジメチルホルムアミド、 2—メチルピロリドン、トルエン、テト ラヒドロフランをあげることができる。これらの溶媒の 1種または、 2種以上を混合 して使用する。 Therefore, 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.
2種類の溶媒混合物として、テトラヒドロフランとジメチルスルホキシド、テトラヒド 口フランと tert—ブタノール及び、 tert—ブタノールとトルエンとの組み合わせをあ げることができる。 メチリド調製工程の反応温度は、 5〜1 50°C、好ましくは、 20~ 1 00°C、特に好 ましくは、 40〜85°Cである。  As a mixture of two kinds of solvents, a combination of tetrahydrofuran and dimethyl sulfoxide, a combination of tetrahydrofuran and tert-butanol, and a combination of tert-butanol and toluene can be given. The 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.
メチリド調製工程の反応時間は、 1 0分〜 20時間、好ましくは、 30分〜 5時間で める。 The reaction time in the process for preparing methylide is 10 minutes to 20 hours, preferably 30 minutes to 5 hours.
イリドィ匕工程の反応温度は、一 70〜1 00。C、好ましくは、一 50〜70°C、特に好 ましくは、一 20〜40°Cである。 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.
イリド化工程の反応時間は、 1 0分〜 20時間、好ましくは、 30分〜 5時間である。 なお、上述の活性エステル化合物生成工程で得られるエステル化合物を分離精 製することなぐイリド化工程で使用することもできる。すなわち、エステル化反応 液中に析出した結晶を濾別した濾液を別途調製したメチリド含有混合物中に添加 することにより、イリド化合物を生成させることができる。反応溶媒としてはエステ ル化反応に適した溶媒とメチリド調製工程に適した溶媒の混合溶媒がよぐ適当 な混合溶媒としては、テトラヒドロフランとジメチルスルホキシド、テトラヒドロフラン と tert—ブタノールが好ましい。この場合は、エステル化合物を分離するためのェ ステル化反応溶媒の濃縮、エステル化合物の精製などの操作が省略できて有利 である。 The reaction time of the ylidation step is 10 minutes to 20 hours, preferably 30 minutes to 5 hours. It should be noted that 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. As 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.
(iii)ハロメチルケトンを生成する工程 (iii) Step of producing halomethyl ketone
イリド化合物（5)からハロメチルケトン（6)への変換は適当な有機溶媒中、ハロ ゲン化水素と - 50°C〜1 00°C、好ましくは、 - 20°C〜80°Cで反応を行うことにより、 化合物（6)のハロメチルケトンを得ることができる。  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.
適当な有機溶媒としては、酢酸ェチル、テトラヒドロフラン、ジクロロェタン、トル ェン等があげられ、反応時間は 1 0分〜 10時間、好ましくは 30分〜 5時間である ( ハロゲン化水素としては、塩化水素、臭化水素等があげられ、またこれらを有機 溶媒に溶解して使用してもよし、。特に好ましくは塩化水素を酢酸ェチル、テ卜ラヒ ドロフラン、ジェチルェ一テル、トルエン等に溶解して使用するのが良い。 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.
(iv) ノ、ロメチルケトンを還元する工程（以下において、ケ卜ン還元工程と記載す る） (iv) Step of reducing no and romethyl ketone (hereinafter referred to as ketone reduction step)
このケトン還元工程はメーャワイン一ポンドルフーバーリ一 (Meerwein- Ponndorf - VeHey)還元による方法もしくは、水素化ホウ素ナトリウムを用いる方法で有利に 行うこと力できる。 This ketone reduction step can be advantageously performed by a method based on Meerwein-Ponndorf-VeHey reduction or a method using sodium borohydride.
メーャワイン一ポンドルフーバーリー (Meerwein-Ponndorf-Verley)還元において は、一30〜1 00°C、好ましくは一 1 0〜70°Cで、イソプロパノール、 sec—ブタノ —ル等のアルコールを溶媒として、アルミニウムイソプロポキシド、アルミニウム s ec—ブトキシド等のアルミニウムアルコキシドを用いて還元を行う。 化合物（6)に対するアルミニウムアルコキシドの使用量は、反応条件によって適 宜に選ぶことが可能であり、通常、好ましくは、 0, 5〜3当量、より好ましくは、 1In the reduction of Meerwein-Ponndorf-Verley (Meerwein-Ponndorf-Verley), aluminum is used at a temperature of 130 to 100 ° C, preferably 110 to 70 ° C, using an alcohol such as isopropanol or sec-butanol as a solvent. Reduction is performed using an aluminum alkoxide such as isopropoxide or aluminum sec-butoxide. The amount of the aluminum alkoxide to be used for the compound (6) can be appropriately selected depending on the reaction conditions, and is usually preferably 0.5 to 3 equivalents, more preferably 1 to 5 equivalents.
〜1 . 5当量を使用する。反応に悪影響を及ぼさない溶媒を併用しても差し支えな く、例えば、トルエン、テトラヒドロフランをあげることができる。 Use ~ 1.5 equivalents. A solvent that does not adversely affect the reaction may be used in combination, and examples thereof include toluene and tetrahydrofuran.
また、水素化ホウ素ナトリウムを用いる方法においては、エーテル系溶媒または, エーテル系溶媒と水との混合溶媒中で行われる。好ましくは、テトラヒドロフラン、 テトラヒドロフランと水との混合溶媒があげられる。混合溶媒の比は、 1 000Z 1The 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
〜1 1 0、好ましくは、 1 00 "！〜 1 / 1、より好ましくは、 1 0 1〜5/ 1である ( 反応温度は一 20〜"！ 00°C、好ましくは一 1 0〜60°Cである。 ~ 110, preferably 100 "! ~ 1/1, more preferably 101-5 / 1 (reaction temperature is 120 ~"! 00 ° C, preferably 110-60 ° C.
化合物（6〉に対する水素化ホウ素ナトリウムの使用量は、好ましくは、 0. 5〜3 当量、より好ましくは、 "!〜 1 . 5当量を使用する。 The amount of sodium borohydride to be used for compound (6) is preferably 0.5 to 3 equivalents, more preferably "! To 1.5 equivalents.
なお、上記のようにして製造される化合物（1 )及び各種中間体化合物は、工程に 応じた分離'精製手段、例えば、濃縮、抽出、クロマトグラフィー、再結晶等の手段 を適宜施すことにより、任意の純度のものとして単離することができる。 発明を実施するための最良の形態 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. BEST MODE FOR CARRYING OUT THE INVENTION
以下、実施例により本発明を具体的に述べるが、本発明はこれらによって限定 されるものではない。  Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
実施例 Example
[実施例 1 ] [Example 1]
N-ベンジルォキシカルボニル- S-フエニル- L -システィン Ν'-ォキシスクシンィ ミドエステル（化合物 4 : Ζ=スクシンイミドキシ基:以下の実施例において「イミドエ ステル Jと記す）の合成  Synthesis of N-benzyloxycarbonyl-S-phenyl-L-cysteine Ν'-oxysuccinimide ester (compound 4: Ζ = succinimidoxy group: referred to as “imidoester J” in the following examples)
温度計、冷却器、撹拌装置を付した 100mlの四つ口フラスコに N-ベンジルォキ シカルボニル -S-フエニル -L-システィン（化合物 2 :光学純度 98.6% ee)  N-benzyloxycarbonyl-S-phenyl-L-cysteine (Compound 2: optical purity 98.6% ee) in a 100 ml four-necked flask equipped with a thermometer, condenser and stirrer
9.94g(0.03mol)を取り、ジォキサン 60mlに溶解した。 N-ヒドロキシコハク酸イミド 3.46g (0.031 mol)を加え、氷水で 4°Cまで冷却した後、 Ν,Ν'-ジシクロへキシルカ ルポジイミド (DGC) 6.4g(0.03mol)を添加した。 9.94 g (0.03 mol) was taken and dissolved in 60 ml of dioxane. After adding 3.46 g (0.031 mol) of N-hydroxysuccinimide and cooling to 4 ° C. with ice water, 6.4 g (0.03 mol) of Ν, Ν′-dicyclohexylcarbodiimide (DGC) was added.
結晶の析出と若干の発熱 (7°C)が見られた。 30分撹拌後、反応フラスコを冷蔵 庫に入れ、一夜放置した。析出結晶を濾別し、ジォキサンで洗浄した。 Crystal precipitation and slight exotherm (7 ° C) were observed. After stirring for 30 minutes, refrigerate the reaction flask It was put in the storage and left overnight. The precipitated crystals were separated by filtration and washed with dioxane.
濾液を減圧濃縮して半固体物 1 3,2gを得た。これを結晶化させた後、 n-へキサ ン /酢酸ェチル =5/1で再結晶して m.p 106-1 09°Cの白色結晶のイミドエステルを 1 2.65g(収率： 98.4%： HPLC； 97.1 %)得た。  The filtrate was concentrated under reduced pressure to obtain 13,2 g of a semi-solid substance. After this was crystallized, it was recrystallized with n-hexane / ethyl acetate = 5/1 to obtain 12.65 g of white crystalline imide ester having a mp of 106-109 ° C (yield: 98.4%: HPLC 97.1%).
'Η NMR(60 Hz;CDCI3, (5 ,ppm)： 2.70(4H,s)、 3.40(2H，d,J=5Hz)、 4.60-4.97 (1 H， m)、 5.02(2H，s)、 5.45(1 H，d，J=8Hz)、 7.03-7.43(10H,m). 'Η NMR (60 Hz; CDCI 3 , (5, ppm): 2.70 (4H, s), 3.40 (2H, d, J = 5 Hz), 4.60-4.97 (1 H, m), 5.02 (2H, s) , 5.45 (1 H, d, J = 8 Hz), 7.03-7.43 (10 H, m).
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.  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.
[実施例 2] [Example 2]
N-ベンジルォキシカルポニル- S-フエニル -L -システィン 4'-ニトロフエニルエス テル（化合物 4 : Z=4 -二 ロフエノキシ基:以下の実施例において Γρ-ニトロフエ二 ルエステル Jと記す）の合成  Synthesis of N-benzyloxycarbonyl-S-phenyl-L-cysteine 4'-nitrophenyl ester (compound 4: Z = 4-diphenyl group: referred to as -ρ-nitrophenyl ester J in the following examples)
実施例 2—1  Example 2-1
縮合剤 Ν,Ν'-ジシクロへキシルカルポジイミドを用いる Ρ-ニトロフエニルエステ ルの合成  Synthesis of ニ ト ロ -nitrophenylester using, Ν'-dicyclohexylcarposimide
温度計、撹拌装置、窒素導入管、滴下ロートを付した 100ml四ッロフラスコに、 N -べンジルォキシカルボニル- S -フエニル- L-システィン（化合物 2：光学純度 98.6% ee) 3.31 g(0.01 mol)、 p -二トロフエノール 1 .39g(0.01 mol)を取り、 1 ,4 -ジォキ サン 1 5mlで希釈した。  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.
次いで、 Ν,Ν'-ジシクロへキシルカルポジイミド (DGC) 2.1 7g(0.01 05mol)を 1 ,4-ジ ォキサン 5mlで希釈した溶液を滴下ロートより、窒素気流下、内温 6°C〜10°Cの 範囲で 10分間で滴下した。同温度で 5時間撹拌し、冷蔵庫中に一夜放韹した。 得られた黄色懸濁溶液を濾過して白色固体を除き、濾液を減圧濃縮した。黄色粘 調液体 5.24gを得た。 HPLC ; 96.4%  Then, a solution obtained by diluting 2.17 g (0.01 05 mol) of カ ル, Ν′-dicyclohexylcarposimide (DGC) with 5 ml of 1,4-dioxane was dropped from the dropping funnel under nitrogen gas flow at an internal temperature of 6 ° C. to 10 °. It was dropped in the range of C in 10 minutes. The mixture was stirred at the same temperature for 5 hours and released in a refrigerator overnight. The obtained yellow suspension was filtered to remove a white solid, and the filtrate was concentrated under reduced pressure. 5.24 g of a yellow viscous liquid was obtained. HPLC; 96.4%
これを n-へキサン/酢酸ェチル =5/1で固化させ、 m.p 93 - 95°Cの白色結晶の p -二トロフエニルエステルを 4.3g (収率： 95.1 %)得た。  This was solidified with n-hexane / ethyl acetate = 5/1 to obtain 4.3 g (yield: 95.1%) of white crystals of p-ditrophenyl ester having m.p 93-95 ° C.
1 H NMR(250 Hz;CDGI3, δ ,ppm)： 3.54(2H,d,J=5.0Hz)% 4.85— 4.89(1 H,m)、 5.1 1 (2H,s)、 5.63(1 H，d，J=7.0Hz)、 7.04(2H,d，J=9.0Hz)、 7.20- 7.50(1 0H，m)、 8.20(2H， d，J=9.0Hz). 1 H NMR (250 Hz; CDGI 3 , δ, ppm): 3.54 (2H, d, J = 5.0 Hz) % 4.85—4.99 (1 H, m), 5.1 1 (2H, s), 5.63 (1H, d, J = 7.0Hz), 7.04 (2H, d, J = 9.0Hz), 7.20-7.50 (10H, m), 8.20 (2H, d, J = 9.0Hz) Hz).
IR(KBr,cm-1 ) : 3356, 1 774,1 754,1682,1656,1624,1598,1560,1528,1490, 1458， 1442,1422,1 350,1 328,1 312,1 278,1 234,1206,1 1 70,1 144,1 1 1 2,1 090, 1042,1028, 101 6,990,974,928,910,888,864,850,782,758,742,714,694,658,632,61 8,600,582, 542,470,442,41 8. 実施例 2— 2  IR (KBr, cm-1): 3356,1 774,1 754,1682,1656,1624,1598,1560,1528,1490,1458,1442,1422,1 350,1 328,1 312,1 278,1 234,1206,1 1 70,1 144,1 1 1,2 090,1042,1028,101 6,990,974,928,910,888,864,850,782,758,742,714,694,658,632,61 8,600,582,542,470,442,41 8.Example 2-2
ビス- p-ニトロフエニル亜硫酸を用いる p -二トロフエニルエステルの合成 温度計、冷却器、撹拌装置を付した 1 00mlの四つ口フラスコに p -二トロフエノー ル 13.9g(0.1 mol)を取り、乾燥ジェチルエーテル 50mlに溶解し、塩化チォニル 6,0g(0.05mol)を加えた後、 0°Cに冷却した。撹拌下にトリェチルァミン 10.1 g (0.1 mol)を乾燥ジェチルエーテル 10mlに溶解した溶液を徐々に滴下した。滴下と同 時に、白煙、発熱を伴って結晶が析出してきた。滴下終了後、冷却下に 1時間、 室温で 1時間撹拌した。再度 5¾に冷却して反応液を濾別し、残渣を乾燥冷ジェ チルエーテルで洗浄した。この残渣を約 50mlの水に懸濁し、濾別して冷水で洗 浄した。  Synthesis of p-ditrophenyl ester using bis-p-nitrophenylsulfite Transfer 13.9 g (0.1 mol) of p-ditrophenol into a 100 ml four-necked flask equipped with a thermometer, condenser and stirrer, and dry. It was dissolved in 50 ml of getyl ether, added with 6.0 g (0.05 mol) of thionyl chloride, and cooled to 0 ° C. Under stirring, a solution of 10.1 g (0.1 mol) of triethylamine dissolved in 10 ml of dry getyl ether was gradually added dropwise. At the same time as the drop, crystals were precipitated with white smoke and heat. After completion of the dropwise addition, the mixture was stirred for 1 hour under cooling and for 1 hour at room temperature. After cooling again to 5¾, the reaction solution was separated by filtration, and the residue was washed with dry and cold ethyl ether. This residue was suspended in about 50 ml of water, filtered and washed with cold water.
更に、 50 mlの冷エタノールに懸濁し、濾別し、冷エタノール次いで冷ジェチルェ ールで洗浄して乾燥して m.p 105-106°Cの類白色結晶のビス - p -二トロフエニル 亜硫酸を 12.7g (収率： 78.3Wを得た。  Further, the suspension was suspended in 50 ml of cold ethanol, filtered, washed with cold ethanol and then with cold getyl gel, dried, and dried to obtain 12.7 g of bis-p-ditrophenyl sulfite, a white crystal of mp 105-106 ° C. (Yield: 78.3 W was obtained.
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.  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.
温度計、冷却器、撹拌装置を付した 50mlの三つ口フラスコに N-ベンジルォキ シカルボニル- S-フエニル- L -システィン（化合物 2 :光学純度 98.6% ee) 1 .0g (0.003 mol)をジメチルホルムアミド 5 mlとピリジン 5mlに溶解し、室温でビス - p - ニトロフエニル亜硫酸 2.9g(0.009mol)を添加した。その後、室温で 3.5時間反応し た後、 200mlの氷水中に投入し希塩酸で pH=2とした。酢酸ェチル 1 50mlで抽出 し、酢酸ェチル層を水洗した。更に、酢酸ェチル層を 10O/O水酸化ナトリウム水溶 液で洗浄、水洗後、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。酢酸 ェチル層を減圧濃縮して白色固体の P-ニトロフ: I：ニルエステルを 1.25g (収率： 91%)得た。 HPLC;96% 1.0 g (0.003 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) was added to a 50 ml three-necked flask equipped with a thermometer, a condenser and a stirrer. It was dissolved in 5 ml of formamide and 5 ml of pyridine, and 2.9 g (0.009 mol) of bis-p-nitrophenylsulfite was added at room temperature. Then, after reacting at room temperature for 3.5 hours, the mixture was poured into 200 ml of ice water and adjusted to pH = 2 with dilute hydrochloric acid. The mixture was extracted with 150 ml of ethyl acetate, and the ethyl acetate layer was washed with water. In addition, the ethyl acetate layer is The solution was washed with water, washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure to obtain 1.25 g (yield: 91%) of P-nitroph: I: nyl ester as a white solid. HPLC; 96%
1H NMR(60MHz;CDCI3, δ ,ppm)： 3.62(2H，d，J=5Hz)、 4.70 - 4.98(1 H,m)、 5.22 (2H，s)、 5.77(1 H，d,J=8Hz)、 7,22(2H，d，J=9Hz)、 7.28 - 7.73(10H,m)、 8.43 (2H，d， J=9Hz). 実施例 2— 3 1 H NMR (60 MHz; CDCI 3 , δ, ppm): 3.62 (2H, d, J = 5 Hz), 4.70-4.98 (1 H, m), 5.22 (2H, s), 5.77 (1 H, d, J = 8Hz), 7,22 (2H, d, J = 9Hz), 7.28-7.73 (10H, m), 8.43 (2H, d, J = 9Hz).
ビス一 P—ニトロ亜硫酸を単離しないで、 p-ニトロフエニルエステルを合成する 方法'  Method for synthesizing p-nitrophenyl ester without isolating bis-P-nitrosulfite
温度計、冷却器、攪拌機、窒素導入管を付した 1 OLのセパラブルフラスコに N 一べンジルォキシカルボニル一 S—フエ二ルー L一システィン（化合物 2:光学純 度98·6%ee)497·0g(1.5mol:1.0eq)、p—ニトロフェノーレ230.9g(1.65 mol;1.1eq)をトルエン 7.0Lに懸濁し、卜リエチルァミン 333.9g (3.3mol； 2.2e q)を加えた。添加後、懸濁溶液が溶解し黄色溶液となった。黄色溶液をドライア イス一アセトンバスで一 7°C前後に冷却し、塩化チォニル 196.3g(1.65mol;1.1 eq)をトルエン 0.5Lに溶解した液を、一5°Cで 0.5時間で滴下した。  In a 1 OL separable flask equipped with a thermometer, condenser, stirrer, and nitrogen inlet tube, 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. in a dry ice-acetone bath, and a solution of 196.3 g (1.65 mol; 1.1 eq) of thionyl chloride dissolved in 0.5 L of toluene was added dropwise at 15 ° C. for 0.5 hours.
滴下終了後、 0°Cで 3時間攪拌し、ドライアイス一アセトンパスをはずし、 50°C ±2°Cでさらに 3時間攪拌した。 HPLCで化合物 (2)が 0·2«½以下になったことを 確認し、反応を止めた、 2Lの水で 2回洗浄し、 5%炭酸水素ナトリウム水溶液 2L で 2回洗浄し、さらに 2しの水で 2回洗浄し ρ -二卜口フエニルエステルを含む卜ルェ ン溶液を得た。無水硫酸ナトリウムで乾燥した後、トルエンを減圧留去して残渣を 得た。この残渣を酢酸ェチル 2しで加熱溶解後、攪拌下に η—へキサン 1 OLを加 え、結晶を析出させた。 この結晶を濾過し、 η—へキサン 酢酸ェチル =5 1 2Lで洗浄後乾燥し、類白色結晶状の Ρ-ニトロフ: Lニルエステルを得た。  After completion of the dropwise addition, 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 ρ-nitro-2-phenyl ester was obtained. After drying over anhydrous sodium sulfate, toluene was distilled off under reduced pressure to obtain a residue. The residue was dissolved by heating in ethyl acetate, and η-hexane (1OL) was added with stirring to precipitate crystals. The crystals were filtered, washed with η-hexane ethyl acetate = 512 L, and dried to obtain a white crystalline Ρ-nitroph: L-nil ester.
収量： 650g (収率： 95.7%)  Yield: 650g (Yield: 95.7%)
m. p 91 -94°C% HPLC ;98.5% m.p 91 -94 ° C % HPLC; 98.5%
[実施例 3] 3-ベンジルォキシカルボニルアミノ- 1-(1'，1' -ジメチルォキシスルフラニル） -4- フエニルスルファニルブタン- 2-オン（化合物 5:以下の実施例において「イリド化 合物」と記す）の合成 [Example 3] 3-benzyloxycarbonylamino-1- (1 ′, 1′-dimethyloxysulfuranyl) -4-phenylsulfanylbutan-2-one (compound 5: “ylide compound” in the following examples) Described)
実施例 3—1  Example 3-1
水素化ナトリウムとトリメチルスルホキソニゥムョーダイドから生成させたコーリ 一試薬 (ジメチルスルホキソニゥムメチリド)とイミドエステルとを用いるイリド化合 物の合成  Synthesis of ylide compound using imide ester with sodium reagent (dimethylsulfoxonium methylide) formed from sodium hydride and trimethylsulfoxonium iodide
温度計、冷却器、撹拌機を付した 100ml四ッロフラスコに NaH(60%)0.186g (4.66mmol;2.0eq)を取り、 n-へキサン 5mlで 2回洗浄した後、乾燥 DMSOIOml に懸濁した。窒素気流下にトリメチルスルホキソニゥムョ一ダイド (TMSOI)1.03g (4.66m mol;2.0eq)を少量ずつ添加した。発泡、発熱を伴い NaHが溶解する。 添加終了後、 10分間撹拌した後、油浴中で 55°Cに 30分加熱撹拌し、コーリー 試薬を調製した。  0.186 g (4.66 mmol; 2.0 eq) of NaH (60%) was placed in a 100 ml four-neck flask equipped with a thermometer, a condenser, and a stirrer, washed twice with 5 ml of n-hexane, and suspended in dry DMSOIO ml. . Under a nitrogen stream, 1.03 g (4.66 mmol; 2.0 eq) of trimethylsulfoxonium moxide (TMSOI) was added little by little. NaH dissolves with foaming and heat generation. After the addition was completed, the mixture was stirred for 10 minutes and then heated and stirred at 55 ° C. for 30 minutes in an oil bath to prepare a Corey reagent.
その後、 THF 10mlを加えてドライアイス-アセトンバスで- 12°Cに冷却した。 - 12°Cでイミドエステル 1.0g(2.33mmol)を乾燥 THF 5mlに溶解してコーリー試薬中 に滴下し、 5mlの THFで洗浄した。滴下と同時に白濁し若干発熱した。滴下終了 後、同温度で 1.75時間反応した。  Thereafter, 10 ml of THF was added, and the mixture was cooled to -12 ° C in a dry ice-acetone bath. At −12 ° C., 1.0 g (2.33 mmol) of imide ester was dissolved in 5 ml of dry THF, added dropwise to the Cory reagent, and washed with 5 ml of THF. At the same time as the dropwise addition, the mixture became cloudy and slightly heated. After the completion of the dropwise addition, the mixture was reacted at the same temperature for 1.75 hours.
反応液を氷水中にあけ AcOEt 100mlで抽出した。水層を更に AcOEt 100mlで 抽出し、 AcOEt層を合わせ NaClaqで洗浄後、無水 Na2S04で乾燥後、濃縮して 微黄色油状物 1.0gを得た。 HPLC ;94%。これをシリカゲルカラムクロマトグラフィ —(ヮコーゲル C300:150 ml;ベンゼン/アセトン =2/1)にて分離精製し、微黄色 油状物のイリド化合物を 0.79g (収率： 83.6%： HPLC； 98.8%)得た。  The reaction solution was poured into ice water and extracted with 100 ml of AcOEt. The aqueous layer was further extracted with AcOEt (100 ml), and the AcOEt layers were combined, washed with NaClaq, dried over anhydrous Na2S04, and concentrated to obtain a pale yellow oil (1.0 g). HPLC; 94%. This was separated and purified by silica gel column chromatography (ヮ Kogel C300: 150 ml; benzene / acetone = 2/1) to obtain 0.79 g (yield: 83.6%: HPLC; 98.8%) of a slightly yellow oily ylide compound. Was.
NMR(60MHz;GDGI3,5，ppm):3.07(6H,s)、 3.13(2H,d,J=5Hz) NMR (60MHz; GDGI 3, 5 , ppm): 3.07 (6H, s), 3.13 (2H, d, J = 5Hz)
3.87 - 4.33(2H，m)、 4.87(2H，s)、 5.80(1 H,d,J=8Hz)、 6.77 - 7.18(誦, m).  3.87-4.33 (2H, m), 4.87 (2H, s), 5.80 (1H, d, J = 8Hz), 6.77-7.18 (citations, m).
IR(KBr,cm-1)： 3040,2932,1718,1640,1562,1544，1510,1482,1460,1442,1398, IR (KBr, cm-1): 3040,2932,1718,1640,1562,1544,1510,1482,1460,1442,1398,
1334,1248,1192,1138,1088,1026,942,898,856,742,682,420. 実施例 3— 2 1334,1248,1192,1138,1088,1026,942,898,856,742,682,420. Example 3-2
水素化ナトリウムとトリメチルスルホキソニゥムブロミドから生成させたコ一リー 試薬とイミドエステルとを用いるイリド化合物の合成 Collie formed from sodium hydride and trimethylsulfoxonium bromide Synthesis of ylide compounds using reagents and imidoesters
温度計、冷却器、窒素導入管、滴下ロート、撹拌機を付した 100ml四ッロフラス コに aH(60%) 0.747g(1 8.64mmol;2.0eq)を取り、 n-へキサン 10mlで 2回洗浄した 後、乾燥 DMSO 40mlに懸濁した。窒素気流下にトリメチルスルホキソニゥムブロ ミド (TMSOB) 3.23g(18.64mmol ; 2,0eq)を少量ずつ添加した。発泡、発熱を伴い NaHが溶解する。添加終了後、 10分間撹拌した後、油浴中で 55°Cに 60分加熱 撹拌し、コ-リ-試薬を調製した。  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.
調製したコーリー試薬を室温まで戻し、 THF 40mlを加えた後、ドライアイス -ァ セトンバスにより- 1 2°Cに冷却した。イミドエステル 4.0g(9.34mmol)を乾燥 THF 20mlに溶解した溶液を滴下口-卜に仕込み、内温が - 1 0°C以上にならないようにし て 1 0分間でコ一リー試薬中に滴下し、 5mlの THFで洗浄した。滴下終了後、同 温度で 1時間撹拌し、 2時間かけて 0°Cまで昇温させて反応を停止した。反応液 を氷水 200mlにあけ AcOEt 250mlで抽出した。水層を更に AcOEt 100ml X 2 で抽出して有機層を合わせ、飽和食塩水 200ml X 2で有機層を洗浄し、無水  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
Na2S04で乾燥後、濃縮して茶褐色油状物のイリド化合物を 3.89g得た。 HPLG ; 90% After drying over Na2S04, the mixture was concentrated to obtain 3.89 g of an ylide compound as a brown oil. HPLG; 90%
1H NMR(60MHz;CDCI3> δ ,ppm)： 3.07(6H，s)、 3.1 3(2H，d,J=5Hz)、 3.87-4.33 (2H,m)、 4.87(2H，s)、 5.80(1 H，d，J=8Hz)、 6.77-7.1 8(1 0H,m). 1 H NMR (60 MHz; CDCI 3> δ, ppm): 3.07 (6H, s), 3.13 (2H, d, J = 5 Hz), 3.87-4.33 (2H, m), 4.87 (2H, s), 5.80 (1 H, d, J = 8 Hz), 6.77-7.18 (10 H, m).
IR(KBr,cm-1 )： 3040,2932,1 71 8,1 640,1 562,1 544,1 51 0,1482,1460,1442,1 398, 1334,1248,1 192,1 138,1 088,1026,942,898,856,742,682,420. 実施例 3— 3  IR (KBr, cm-1): 3040,2932,1 71 8,1 640,1 562,1 544,1 51 0,1482,1460,1442,1 398,1334,1248,1 192,1 138,1 088,1026,942,898,856,742,682,420. Example 3-3
水素化ナトリウムとトリメチルスルホキソニゥムブロミドから生成させたコーリー 試薬と p -二卜口フエニルエステルとを用いるイリド化合物の合成  Synthesis of Ylide Compounds Using Corey Reagents Generated from Sodium Hydride and Trimethylsulfoxonium Bromide and p-Nitrotophenyl Esters
温度計、冷却器、窒素導入管、滴下ロート、撹拌機を付した 100ml四ッロフラス コに NaH(60%) 0.354g(8.84mmol;2.0eq)を取り、 n-へキサン 5mlで 2回洗浄した後, 乾燥 DMSO 20mlに懸濁した。  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.
窒素気流下にトリメチルスルホキソニゥムブロミド (TMSOB) 1 .53g(8.84mmol ; 2.0eq)を少量ずつ添加した。発泡、発熱を伴い NaHが溶解する。添加終了後、 10 分間撹拌した後、油浴中で 55°Cに 60分加熱撹拌し、コーリー試薬を調製した。 調製したコーリ一試薬を室温まで戻し、 THF 20mlを加えた後、ドライアイス-ァ セ卜ンバスにより- 12°Cに冷却した。 Under a nitrogen stream, 1.53 g (8.84 mmol; 2.0 eq) of trimethylsulfoxonium bromide (TMSOB) was added little by little. NaH dissolves with foaming and heat generation. After completion of addition, 10 After stirring for minutes, the mixture was heated and stirred at 55 ° C. for 60 minutes in an oil bath to prepare a Corey reagent. The prepared core reagent was returned to room temperature, 20 ml of THF was added, and the mixture was cooled to -12 ° C by a dry ice-aceton bath.
p -ニトロフエニルエステル 2.0g(4.42mmol)を乾燥 THF 20mlに溶解した溶液を 滴下ロ-トに仕込み、内温が - 10°C以上にならないようにして 1 0分間でコーリー試 薬中に滴下し、 5mlの THFで洗浄した。滴下終了後、同温度で 2時間撹拌した。 反応液を氷水 1 00mlにあけ AcOEt 1 50mlで抽出した。水層を更に AcOEt 50ml X 2で抽出して有機層を合わせ、飽和食塩水 50ml X 5で有機層を洗浄し、 無水 Na2S04で乾燥後、濃縮して茶褐色油状物のイリド化合物を 1 .58g (収率： 88.2% : HPLC ; 81 .2 %)得た。 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. The aqueous layer was further extracted with AcOEt 50 ml × 2, and the organic layers were combined, washed with saturated saline 50 ml × 5, washed with anhydrous Na2S04, dried over anhydrous Na2S04, and concentrated to give 1.58 g of a brown oily ylide compound ( Yield: 88.2%: HPLC; 81.2%).
H NMR(60MHz;CDCI3, δ ,ppm)： 3.07(6H,s), 3.1 3(2H，d，J=5Hz)、 3.87-4.33 (2H，m)、 4.87(2H,s)、 5.80(1 H,d,J=8Hz)、 6.77 - 7.1 8(10H，m). 1 H NMR (60 MHz; CDCI 3 , δ, ppm): 3.07 (6H, s), 3.13 (2H, d, J = 5 Hz), 3.87-4.33 (2H, m), 4.87 (2H, s), 5.80 ( 1 H, d, J = 8Hz), 6.77-7.1 8 (10H, m).
IR(KBr,cm-1 )： 3040,2932,1 71 8,1 640,1 562,1 544,1 510,1482,1460，1442,1 398， IR (KBr, cm-1): 3040,2932,1 71 8,1 640,1 562,1 544,1 510,1482,1460,1442,1 398,
1 334,1 248,1 1 92,1 1 38,1088,1026,942,898,856, 742,682,420. 実施例 3— 4 1 334,1 248,1 1 92,1 1 38,1088,1026,942,898,856,742,682,420. Example 3-4
イミドエステル合成反応液と、トリメチルスルホキソニゥムブロミドと水素化ナトリ ゥムとから生成させたコーリー試薬とを用いるイリド化合物の合成  Synthesis of ylide compounds using imide ester synthesis reaction solution and Corey reagent formed from trimethylsulfonium bromide and sodium hydride
温度計、冷却器、撹拌機を付した 100ml四ッロフラスコに N-ベンジルォキシカル ポニル -S-フエニル -L-システィン (化合物 2:光学純度 98.6%ee)3.31 g (0.01 mol)および N-ヒドロキシコハク酸イミド 1 .38g(0.01 2mol)を取り、テトラヒドロフラ ン 50mlに懸濁し、卜リエチルァミン 2.43g(0.024mol)を添加してドライアイス -ァ セトンバスで - 2°Cに冷却した。塩化チォニル 1 .43g(0.01 2mol)をテトラヒドロフラン 3mlと混合し、 -1 °Cでゆっくり滴下した。その後、 - 5°Cで 1時間、室温で 1時間攪 拌した。反応の終点は、 TLCHPLCで確認した。 3.31 g (0.01 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) and N-hydroxy were placed in a 100 ml four-neck flask equipped with a thermometer, condenser and stirrer. 1.38 g (0.01 2 mol) of succinimide was taken, suspended in 50 ml of tetrahydrofuran, added with 2.43 g (0.024 mol) of triethylamine, and cooled to −2 ° C. in a dry ice-acetone bath. 1.43 g (0.01 2 mol) of thionyl chloride was mixed with 3 ml of tetrahydrofuran, and slowly added dropwise at -1 ° C. Thereafter, the mixture was stirred at -5 ° C for 1 hour and at room temperature for 1 hour. The end point of the reaction was confirmed by TLCHPLC.
別に以下の方法でコーリー試薬（ジメチルスルホキソニゥ厶メチリド）を調製した c 温度計、冷却器、撹拌機を付した 1 00ml四ッロフラスコに窒素気流中、 Separately, 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,
NaH(60%)0.8g(0.02mol)を。乾燥 DMSO 30mlに懸濁し、トリメテルスルホキソニ ゥムブロミド (TMSOB)3.46g(0.02MOL)を少量ずつ添加した。発泡、発熱を伴い NaHが溶解する。添加終了後、 10分間攪拌した後、油浴中で 55°Cに 30分加熱 攪拌し、コ一リー試薬を調製した。この溶液にテトラヒドロフラン 10mlを加え、ドラ ィアイス-アセトンバスで - 5°Cに冷却した。 0.8 g (0.02 mol) of NaH (60%). The suspension was suspended in 30 ml of dry DMSO, and 3.46 g (0.02 MOL) of trimestersulfoxonium bromide (TMSOB) was added little by little. With foaming and fever NaH dissolves. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 55 ° C. for 30 minutes in an oil bath to prepare a coil reagent. 10 ml of tetrahydrofuran was added to this solution, and the mixture was cooled to −5 ° C. in a dry ice-acetone bath.
このコーリー試薬の溶液に、先に合成したイミドエステル反応液から析出した結 晶を濾別し、濾液を- 4°Cで滴下した。滴下終了後、 5 °C以下で 1 時間攪拌した後, 反応液を 300mlの氷水に投入した。 50mlの n -へキサンを加えて攪拌すると結晶 が析出した。この結晶を濾別しよく水洗乾燥して m.p.106- 1 1 2 °Cの微黄色結晶の イリド化合物を 2.85g (収率 :70.4%)得た。 実施例 3— 5  Crystals precipitated from the previously synthesized imide ester reaction solution were separated by filtration into the solution of the Cory reagent, and the filtrate was added dropwise at -4 ° C. After completion of the dropwise addition, the mixture was stirred at 5 ° C or lower for 1 hour, and the reaction solution was poured into 300 ml of ice water. After adding 50 ml of n-hexane and stirring, crystals were precipitated. The crystals were separated by filtration, washed well with water, and dried to obtain 2.85 g (yield: 70.4%) of slightly yellow crystalline ylide compound having a m.p. of 106-112 ° C. Example 3-5
p -二トロフエニルエステル合成反応液と、トリメチルスルホキソニゥ厶ブロミドと カリウム tert -ブトキシドとから生成させたコーリー試薬とを用いるイリド化合物 の合成  Synthesis of ylide compounds using p-ditrophenyl ester synthesis reaction solution and Corey reagent formed from trimethylsulfoxonium bromide and potassium tert-butoxide
温度計、冷却器、撹拌機を付した 100ml四ッロフラスコに N-ベンジルォキシカル ボニル -S-フエニル -L-システィン (化合物 2:光学純度 98.6%ee)3.31 g (0.01 mol)および p -二卜口フエノール 1 .67g(0.01 2mol)を取り、テトラヒドロフラン 30 ml に懸濁し、卜リエチルァミン 2.43g(0.024mol)を添加してドライアイス-アセトンバ スで- 5°Cに冷却した。塩化チォニル 1 .43g(0.01 2mol)をテトラヒドロフラン 3mlと 混合し、 - 5°Cでゆっくり滴下した。その後、 - 5°Cで 1.5時間、室温で 2昼夜攪拌し た。反応の終点は、 TLG.HPLGで確認した。 3.31 g (0.01 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) and p-diamine were added to a 100 ml four-neck flask equipped with a thermometer, condenser and stirrer. 1.67 g (0.01 2 mol) of Toguchi phenol was taken, suspended in 30 ml of tetrahydrofuran, added with 2.43 g (0.024 mol) of triethylamine, and cooled to -5 ° C with a dry ice-acetone bath. 1.43 g (0.01 2 mol) of thionyl chloride was mixed with 3 ml of tetrahydrofuran, and slowly added dropwise at -5 ° C. Thereafter, the mixture was stirred at -5 ° C for 1.5 hours and at room temperature for 2 days and nights. The end point of the reaction was confirmed by TLG.HPLG.
別に以下の方法でコ一リー試薬（ジメチルスルホキソニゥムメチリド）を調製した。 温度計、冷却器、撹拌機を付した 1 00ml四ッロフラスコに窒素気流中、力リウ ム- tert-ブトキシド 2.8g(0.025mol)を乾燥 t -ブタノール 60mlに懸濁し、トリメチル スルホキソニゥ厶ブロミド (TMSOB)4.33g(0,025mol)を少量ずつ添加した。添加終 了後、 10分間攪拌した後、油浴中で 65°C〜75°Cに 30分加熱攪拌し、コーリー 試薬を調製した。この溶液にテトラヒドロフラン 40mlを加え、ドライアイス-ァセト ンバスで- 5°Cに冷却した。 Separately, 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.
このコーリ一試薬の溶液に、先に合成した p -二トロフエニルエステル反応液から 析出した結晶を濾別し、濾液を - 4°Cで滴下した。滴下終了後、 5 °C以下で 3時間 攪拌した後、反応液を 300mlの氷水に投入した。酢酸ェチルで抽出し、酢酸ェチ ル層を 2%水酸化ナトリウム水溶液、次いで水洗、飽和食塩水でよく洗浄した。無 水硫酸ナトリウムで乾燥後、酢酸ェチルを濃縮して油状物のイリド化合物を 3.51 g (収率: 86.6%)得た。 実施例 3— 6 Crystals precipitated from the previously synthesized p-nitrophenyl ester reaction solution were separated by filtration into this solution of the core reagent, and the filtrate was added dropwise at -4 ° C. After dripping, 3 hours at 5 ° C or less After stirring, the reaction solution was poured into 300 ml of ice water. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed well with a 2% aqueous sodium hydroxide solution, then with water and a saturated saline solution. After drying over anhydrous sodium sulfate, ethyl acetate was concentrated to obtain 3.51 g (yield: 86.6%) of an ylide compound as an oil. Example 3-6
P-ニトロフエニルエステルと、卜リメチルスルホキソニゥムブロミドとカリウム tert- ブトキシドとから生成させたコ一リー試薬とを用いるイリド化合物の合成  Synthesis of Ylide Compounds Using P-Nitrophenyl Ester and a Coley Reagent Formed from Trimethylsulfoxonium Bromide and Potassium tert-Butoxide
温度計、冷却器、撹拌機を付した 200mlの四ッロフラスコに窒素気流中、乾燥 した t -ブタノール 50mlを取り、カリウム tert-ブトキシド 2.24g (0.02 mol;4.0eq) を加えた。室温（25°C)でトリメチルスルホキソニゥ厶ブロミド (TMSOB)3.46g (0.02 mol; 4.0eq)を少量づっ添加した。 TMSOB添加後、 70_75°Cに 30分間加熱攪拌 し、メチリドを調製した。  In a nitrogen stream, 50 ml of dried t-butanol was placed in a 200 ml four-neck flask equipped with a thermometer, a condenser, and a stirrer, and 2.24 g (0.02 mol; 4.0 eq) of potassium tert-butoxide was added. At room temperature (25 ° C.), 3.46 g (0.02 mol; 4.0 eq) of trimethylsulfoxonium bromide (TMSOB) was added little by little. After adding TMSOB, the mixture was heated and stirred at 70-75 ° C for 30 minutes to prepare methylide.
室温まで冷却し、 THF 50mlを加え、更にドライアイス一アセトンバスで - 12°Cに 冷却した。 - 12°Cで p-ニトロフエニルエステル (HPLC;99.6area%)2.26 g(0.005 mol)を固体のまま添加した。 0.5時間後に HPLCでモニターし、 1時間で反応を止 めて、反応液を 600mlの氷水中に投入した。一部結晶の析出が見られたが、酢 酸ェチルで抽出した。酢酸ェチル層は水洗、飽和食塩水で洗浄後、無水硫酸ナト リウムで乾燥後、濃縮して油状物 2.19gを得た。水層は 100mlの酢酸ェチル抽 出し、同様の処理をして油状物 0.19gを得た。 After cooling to room temperature, 50 ml of THF was added, and the mixture was further cooled to -12 ° C in a dry ice-acetone bath. At −12 ° C., 2.26 g (0.005 mol) of p-nitrophenyl ester (HPLC; 99.6 area%) was added as a solid. After 0.5 hour, the reaction was monitored by HPLC, the reaction was stopped after 1 hour, and the reaction solution was poured into 600 ml of ice water. Some crystals were precipitated, but extracted with ethyl acetate. 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.
両油状物を合わせ、シリカゲルクロマト（シリカゲル 60N,150mしベンゼン/ァセ トン = 1 /1展開）精製して微黄色結晶 1.91 gを得た。 m.p.89- 95°C  The two oils were combined and purified by silica gel chromatography (silica gel 60 N, 150 m, developed with benzene / acetone = 1/1) to obtain 1.91 g of pale yellow crystals. m.p.89- 95 ° C
これを HPLCで 4，4' -ジメチルベンゾフエノンを内部標準物質として内部標準法 で定量すると純度 95.8%を示すイリド化合物を 1.83g (収率 :90.3%)得た。 実施例 3— 7  When this was quantified by HPLC using 4,4'-dimethylbenzophenone as an internal standard substance by an internal standard method, 1.83 g (yield: 90.3%) of an ylide compound having a purity of 95.8% was obtained. Example 3-7
p—ニトロフエニルエステルとトリメチルスルホキソニゥムブロミドとナトリウム tert—ブトキシドから生成させたコーリー試薬とを用いたトルエン溶媒でのイリド 化合物の合成 温度計、冷却器、攪拌機、窒素導入管を付した 1 Lの四つ口フラスコにナトリウ 厶 tert—ブトキシド 22.1 g(0.23mol ; 2.3eq)、tert—ブタノ一ル 25ml、トルエン 225mlを仕込み、 45°Cで攪拌した。この混合物に、トリメチルスルホキソニゥ厶ブ ロミド 39,81 g (0.23mol ; 2.3eq)を加え、 1時間攪拌して、コ一リー試薬を調製した。 Synthesis of Ylide Compounds in Toluene Solvent Using p-Nitrophenyl Ester, Trimethylsulfoxonium Bromide and Corey Reagent Generated from Sodium tert-butoxide A 2 l g of sodium tert-butoxide (0.23 mol; 2.3 eq), 25 ml of tert-butanol, and 225 ml of toluene were charged into a 1 L four-necked flask equipped with a thermometer, a condenser, a stirrer, and a nitrogen inlet tube. Stirred at ° C. To this mixture, 39,81 g (0.23 mol; 2.3 eq) of trimethylsulfoxonium bromide was added, and the mixture was stirred for 1 hour to prepare a coiled reagent.
このコーリ一試薬を一 1 0°Cに冷却し、攪拌下、この中に P-ニトロフエニルエス テル [46.1 7g(0.1 mol； 1.Oeq) ]をトルエン 450mlに溶解した液を 20分かけて滴下 した。滴下後、同温度で 2.5時間攪拌を続けた。ついでこの反応混合物を 35°Cに 加温後、温水 250mlを加え 35°Cで 20分攪拌した。反応液を分液ロートに移し分 液し、得られたトルエン液を 2Lフラスコに移し、バス温 50°Cで共沸脱水し、さらに トルエン液を 1 Lフラスコに移し、減圧濃縮して液量を 200gとした。得られたトルェ ン液を温め、攪拌しながら n—へキサン 20 mlを加え攪拌下自然冷却し、結晶を 析出させた。この結晶を濾取し、トルエン 70mlで洗浄後、乾燥し、白色結晶状の イリド化合物を得た。  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. Was set to 200 g. 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.
収量： 38.52g (収率： 94.9%〉、 m. p 92— 96°C、 HPLC： 98.8 %  Yield: 38.52 g (Yield: 94.9%), m.p. 92—96 ° C, HPLC: 98.8%
[ α ] = - 22.7° (c 1 .0 ァセ卜ニ卜リノレ、 23.50C) [α] = -22.7 ° (c 1.0 acetonitrile, 23.5 0 C)
[実施例 4] [Example 4]
3 -べンジルォキシカルボニルアミノ- 1 -クロ口- 4-フエニルスルファニルブタン- 2- オン（化合物 6、以下の実施例において「クロロメチルケトン」と記す）の合成 実施例 4一 1  Synthesis of 3-benzyloxycarbonylamino-1-chloro-4--4-phenylsulfanylbutan-2-one (Compound 6, referred to as "chloromethyl ketone" in the following Examples) Example 4-1
HCIZ酢酸ェチル溶液を用いたクロロメチルケトンの合成  Synthesis of chloromethyl ketone using HCIZ ethyl acetate solution
イリド化合物 0.78g(1.92mmol)を温度計、冷却器、撹拌機を付した 100ml四ッ 口フラスコに取り、酢酸ェチル 30mlに溶解し、ドライアイス -アセトンバスで- 20°C に冷却した。- 20°Cで 2.18N HCI/AcOEt 1.06ml(1 ,2eq)を滴下した。反応液は白 濁した。その後、 1時間自然昇温で撹拌した。（_10°Cまで)。ドライアイス -アセトン バスをはずし、室温に戻した後、オイルバスで 78°Cで 20分加熱した。冷却後、反 応液に酢酸ェチル 100mlと水 100mlを加え抽出した。酢酸ェチル層を飽和食塩 水で洗浄後、無水硫酸ナトリウムで乾燥した。  0.78 g (1.92 mmol) of the ylide compound was placed in a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, dissolved in 30 ml of ethyl acetate, and cooled to -20 ° C in a dry ice-acetone bath. At −20 ° C., 1.06 ml (1.2 eq) of 2.18N HCI / AcOEt was added dropwise. The reaction solution became cloudy. Thereafter, the mixture was stirred for 1 hour at a natural temperature. (Up to _10 ° C). After removing the dry ice-acetone bath and returning to room temperature, it was heated in an oil bath at 78 ° C for 20 minutes. After cooling, 100 ml of ethyl acetate and 100 ml of water were added to the reaction solution for extraction. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate.
水層を 100mlの酢酸ェチルで抽出し、同様に乾燥した。酢酸ェチル層を合わせ 減圧濃縮して微黄色固体のクロロメチルケトンを 0.66g (収率： 92.8%： HPLC； 91 ,0%)得た。 The aqueous layer was extracted with 100 ml of ethyl acetate and dried similarly. Combine the ethyl acetate layers After concentration under reduced pressure, 0.66 g (yield: 92.8%: HPLC; 91,0%) of chloromethyl ketone as a pale yellow solid was obtained.
'H NMR(60MHz;CDCI3, δ ,ppm)： 3.1 3(2H，d,J=6Hz)、 3.94(2H,s)、 4.27—4.62 (1'H NMR (60 MHz; CDCI 3 , δ, ppm): 3.1 3 (2H, d, J = 6 Hz), 3.94 (2H, s), 4.27-4.62 (1
H，m)、 4.85(2H，s)、 5.40(1 H，d,J=8Hz)、 6.83 - 7.20(10H,m). H, m), 4.85 (2H, s), 5.40 (1H, d, J = 8Hz), 6.83-7.20 (10H, m).
IR(KBr,cm-1 ) : 3368,1 736,1 71 2,1 684,1 646,1 636,1 51 6,1486,1470,1458,1444, IR (KBr, cm-1): 3368,1 736,1 71 2,1 684,1 646,1 636,1 51 6,1486,1470,1458,1444,
1412,1 396,1 31 6,1 270,1 234,1 1 80,1 1 52,1084,1036,972,854,778,748,736,698,1412,1 396,1 31 6,1 270,1 234,1 1 80,1 1 52,1084,1036,972,854,778,748,736,698,
628,586,508,492,436. 628,586,508,492,436.
旋光度： [ Of ]一 87.0° (c 1 .0 in MeOH)  Optical rotation: [Of] one 87.0 ° (c 1.0 in MeOH)
実施例 4— 2 - HCI /テ卜ラヒドロフラン溶液を用いたクロロメチルケトンの合成 Example 4-2 Synthesis of chloromethyl ketone using 2-HCI / tetrahydrofuran solution
イリド化合物 2.03 g (5.0 mmol)を温度計、冷却器、撹拌機を付した 200 ml四つ 口フラスコに取り、トルエン 60 mlを加えて懸濁させ、 0°Cに冷却した。この白色懸 濁液に、塩化水素ガスをテ卜ラヒドロフランに吹き込んで調製した、 6.1 %塩化水 素 /テトラヒドロフラン溶液 3.0 g(5 mmol)を 5分で滴下し、同温度で 2時間撹袢 した。オイルバスにより、 65°Cに昇温し、 4時間反応させた。反応混合物は黄色透 明溶液になった。原料消失を確認後、冷却し、トルエン 100 mlを加え、飽和食塩 水 30 mlで 2回洗浄し、さらに水 30 mlで 2回洗浄した。このトルエン溶液を無 水硫酸ナトリウムで乾燥し、減圧濃縮し、茶白色結晶状のクロロメチルケトンを得 た。収量 1.69 g (収率 92.9%, HPし C 93.8 %, m.p. 87-91 °C)  2.03 g (5.0 mmol) of the ylide compound was placed in a 200 ml four-necked flask equipped with a thermometer, a condenser, and a stirrer, suspended in 60 ml of toluene, and cooled to 0 ° C. To this white suspension, 3.0 g (5 mmol) of a 6.1% hydrogen chloride / tetrahydrofuran solution prepared by blowing hydrogen chloride gas into tetrahydrofuran was added dropwise over 5 minutes, and the mixture was stirred at the same temperature for 2 hours. The temperature was raised to 65 ° C in an oil bath, and the reaction was performed for 4 hours. The reaction mixture became a clear yellow solution. After confirming the disappearance of the raw materials, the mixture was cooled, 100 ml of toluene was added, and the mixture was washed twice with 30 ml of saturated saline and twice with 30 ml of water. The toluene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain brown white crystalline chloromethyl ketone. Yield 1.69 g (Yield 92.9%, HP 93.8%, m.p. 87-91 ° C)
比旋光度： [ひ： 1= —76.9° (c 1 .0, 25.0°C, MeOH) 実施例 4— 3 Specific rotation: [H: 1 = -76.9 ° (c 1.0, 25.0 ° C, MeOH) Example 4-3
HCI/ジェチルエーテル溶液を用いたクロロメチルケトンの合成  Synthesis of chloromethyl ketone using HCI / getyl ether solution
イリド化合物 1 2.3 g (30.4 mmol)を温度計、冷却器、撹拌機を付した 1 しの四 つ口フラスコに取り、トルエン 498 mlを加えて懸濁させ、 0°Cに冷却した。この白 色懸濁液に、塩化水素ガスをジェチルエーテルに吹き込んで調製した、 1 M塩化 水素 /ジェチルエーテル溶液 31 ml (31 mmol)を 30分で滴下し、同温度で 1時 間撹拌した。オイルバスにより、 65°Cに昇温し、 3時間反応させた。この反応混合 物は黄色透明溶液になった。この反応混合物の原料消失を確認後、冷却して水 100 mlで 5回洗浄した。このトルエン液を無水硫酸ナトリウムで乾燥し、減圧濃 縮して、茶白色結晶状のクロロメチルケトンを得た。収量 10.4 g (収率 93.9%， HPLC 94.2 %, m.p.86_91°C)得られた。 12.3 g (30.4 mmol) of the ylide compound was placed in a four-necked flask equipped with a thermometer, a condenser and a stirrer, suspended in 498 ml of toluene, and cooled to 0 ° C. To this white suspension, 31 ml (31 mmol) of a 1 M hydrogen chloride / getyl ether solution prepared by blowing hydrogen chloride gas into getyl ether was added dropwise over 30 minutes, and stirred at the same temperature for 1 hour. did. The temperature was raised to 65 ° C in an oil bath and the reaction was performed for 3 hours. The reaction mixture became a clear yellow solution. After confirming the disappearance of the raw materials in the reaction mixture, Washed 5 times with 100 ml. The toluene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain chloromethyl ketone as brown white crystals. The yield was 10.4 g (93.9% yield, 94.2% HPLC, mp86_91 ° C).
比旋光度： [a]=—80.0° (c 1.0, 24.0°C, eOH) Specific rotation: [a] =-80.0 ° (c 1.0, 24.0 ° C, eOH)
[実施例 5] [Example 5]
(2S，3R) 3-ベンジルォキシカルボニルァミノ- 1-クロ口 _4 -フエニルスルファニル ブタン- 2 -オール（化合物 1:以下の実施例において「クロ口アルコール」と記す）の 合成  Synthesis of (2S, 3R) 3-Benzyloxycarbonylamino-1-chloro-4--4-phenylsulfanylbutan-2-ol (Compound 1: In the following examples, it is referred to as "chloroalcohol")
実施例 5— 1 Example 5-1
アルミニウムイソプロポキシドを用いたクロ口アルコールの合成 Synthesis of Alcohols Using Aluminum Isopropoxide
温度計、冷却器、撹拌機を付した 50ml三ッロフラスコに、クロロメチルケトン 0.4g(1.1 mmol)及びアルミニウムイソプロポキシド [AI(PrO - i)3] 0.225g (1 ·1 mmol)を 取り、イソプロパノール 10mlを加えた後、 60°C〜70°Cで加熱撹拌した。 TLC及び HPLCモニターで原料クロロメチルケトンの消失を確認し、 1.5時間で反応を停止 した。冷却後、反応液を氷水中に投入した後、希塩酸で pH=2-3とした。析出した 白色結晶を濾別、良く水洗し乾燥した。 0.4 g (1.1 mmol) of chloromethyl ketone and 0.225 g (1.1 mmol) of aluminum isopropoxide [AI (PrO-i) 3 ] were placed in a 50-ml flask equipped with a thermometer, a condenser, and a stirrer. After adding 10 ml of isopropanol, the mixture was heated and stirred at 60 ° C to 70 ° C. The disappearance of the raw material chloromethyl ketone was confirmed by TLC and HPLC monitor, and the reaction was stopped in 1.5 hours. After cooling, the reaction solution was poured into ice water, and the pH was adjusted to 2-3 with dilute hydrochloric acid. The precipitated white crystals were separated by filtration, washed well with water, and dried.
白色結晶、収量： 0.324g (収率： 81%) HPLC； 97.46%, syn/anti=90.44/7.02 これを n -へキサン/酢酸ェチル =6/2 mlより再結晶して、 m.p 115- 116°Cのクロ 口アルコールを 0.194g (収率： 48.5%)得た。  White crystals, yield: 0.324 g (yield: 81%) HPLC; 97.46%, syn / anti = 90.44 / 7.02 This was recrystallized from n-hexane / ethyl acetate = 6/2 ml to give mp 115-116 0.194 g (yield: 48.5%) of a mouth alcohol at ° C was obtained.
HPLC； 98.99%、 syri/anti=98.22/0.77  HPLC; 98.99%, syri / anti = 98.22 / 0.77
1H NMR(250 Hz;CDCl3, δ ,ppm)： 2.79(1 H.d,J=1.95Hz)、 3.29(2H,d'J=3.91 Hz) 、 3.59— 3.70(2H,m)、 3.92(2H,t,t,J=0.98Hz,3.42Hz) 5.07(2H,s)、 5.14(1H,d, J= 2.44Hz), 7.19-7.39(10H,m). 1 H NMR (250 Hz; CDCl 3, δ, ppm): 2.79 (1 Hd, J = 1.95Hz), 3.29 (2H, d'J = 3.91 Hz), 3.59- 3.70 (2H, m), 3.92 (2H , t, t, J = 0.98Hz, 3.42Hz) 5.07 (2H, s), 5.14 (1H, d, J = 2.44Hz), 7.19-7.39 (10H, m).
IR(KBr,cm-1): 3356,3072,2976,2952,1690,1646,1588,1536,1506,1484,1470, 1456,1440,1340,1294,1250,1226,1136,1110,1090,1068,1028,970,936,910,874, 836,778,742,730,694,658,614,580,476.  IR (KBr, cm-1): 3356,3072,2976,2952,1690,1646,1588,1536,1506,1484,1470,1456,1440,1340,1294,1250,1226,1136,1110,1090,1068 , 1028,970,936,910,874,836,778,742,730,694,658,614,580,476.
旋光度 [ ] -77.9°(c 1.0 in MeOH) 実施例 5— 2 Optical rotation [] -77.9 ° (c 1.0 in MeOH) Example 5-2
アルミニウム -sec-ブチレートを用いたクロ口アルコールの合成 Synthesis of Alcohol with Aluminum- sec -Butyrate
温度計、冷却器、攪拌機、シリカゲル乾燥管を付した 200mlの四つ口フラスコ にアルミニウム see—ブチレート [AI(OBu— s)3] 3.08g( 12.5mmol； 0.5eq)を 2— ブタノール 15ml及びトルエン 50mlをよく混合して溶液にした。次いで、室温（1 7°C)で攪拌しながら、この混合物に粉状のクロロメチルケトン 9.1 g (25mmol ; 1 . Oeq)を加え、さらにトルエン 25mlを加えた。室温で攪拌しながら HPLCモニター で原料クロロメチルケトンの消失を確認し、 4.5時間で攪拌を止めた。この反応物 を分液ロートに移し、酢酸ェチル 1 50mlを加え、 5%塩酸水溶液 75mlで 1回、つ いで 1 %塩酸水溶液 75mlで 1回、ついで水 75mlで 2回洗浄した後、有機層を取 リ出し、無水硫酸ナトリウムで乾燥した。洗浄に使用した 5%塩酸水溶液、 1 %塩 酸水溶液及び水層を合わせて酢酸ェチル液 30mlで再抽出し、酢酸ェチル液を 無水硫酸ナトリウムで乾燥した。 3Gグラスフィルターを使用して濾過、溶媒を留 去して白色結晶状のクロ口アルコールを得た。収量 8.85g (収率： 96.69。/0)。 In a 200 ml four-necked flask equipped with a thermometer, condenser, stirrer and silica gel drying tube, 3.08 g (12.5 mmol; 0.5 eq) of aluminum see-butyrate [AI (OBus) 3] was added to 15 ml of 2-butanol and toluene. 50 ml was mixed well to form a solution. Then, 9.1 g (25 mmol; 1. Oeq) of powdery chloromethyl ketone was added to the mixture while stirring at room temperature (17 ° C.), and further 25 ml of toluene was added. While stirring at room temperature, the disappearance of the raw material chloromethyl ketone was confirmed by an HPLC monitor, and the stirring was stopped in 4.5 hours. The reaction product was transferred to a separatory funnel, 150 ml of ethyl acetate was added, and the mixture was washed once with 75 ml of 5% aqueous hydrochloric acid, once with 75 ml of 1% aqueous hydrochloric acid, and twice with 75 ml of water. It was removed and dried over anhydrous sodium sulfate. The 5% aqueous hydrochloric acid solution, the 1% aqueous hydrochloric acid solution and the aqueous layer used for washing were combined and re-extracted with 30 ml of ethyl acetate solution, and the ethyl acetate solution was dried over anhydrous sodium sulfate. The mixture was filtered using a 3G glass filter, and the solvent was distilled off to obtain a white crystalline alcohol. Yield 8.85 g (yield: 96.69./ 0).
HPし C ; 98.67 % HP then C; 98.67%
syn/'anti = 95.1 2/3.50 syn / 'anti = 95.1 2 / 3.50
この白色結晶 8.85gにトルエン 88mlを加え、バス温 70— 75°Cで溶解後、 300ml のビーカ一に移し、攪拌下に n—へキサン 44mlを滴下して再度結晶させた。再結 晶物を濾取し、トルエンノ n—へキサン = 2/Ί 30mlで洗浄後、乾燥し白色結晶 状のクロ口アルコールを得た。白色結晶、 収量： 8.32g (収率： 92.1 1 %) m. p 1 1 6 - 1 1 7°C  To 8.85 g of the white crystals, 88 ml of toluene was added and dissolved at a bath temperature of 70 to 75 ° C., transferred to a 300 ml beaker, and 44 ml of n-hexane was added dropwise with stirring to recrystallize. The recrystallized product was collected by filtration, washed with toluene / n-hexane = 2/30 ml, and then dried to obtain a white crystalline alcohol. White crystals, yield: 8.32 g (yield: 92.1 1%) m.p 1 16-1 17 ° C
H PLC ; 99.72%、 syn/anti = 99.33X0.39 産業上の利用可能性  H PLC; 99.72%, syn / anti = 99.33X0.39 Industrial availability
本発明方法は、従来法におけるように危険な試薬の使用を必要とせず、またェ 程も短く、 3-ベンジルォキシカルボニルァミノ- 1 -ハロゲノ -4-フエ二ルチオブタ ン -2 -オールを有利に製造する方法を提供する。従って、これより誘導することが できる HIVプロテアーゼ阻害剤として有用な [3S- (3 or ,4a S，8a )8 )]- 2-[2' -ヒドロ キシ -3'-フエ二ルチオメチル- 4' -ァザ- 5' -ォキソ - 5'- (2" -メチル- 3" -ヒドロキシ フエニル）ペンチル]デカヒドロイソキノリン - 3 - Ν - 1 -プチルカルポキシアミドを工業 的に有利に製造し提供することができる。 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. Xy-3'-phenylthiomethyl-4'-aza-5'-oxo-5 '-(2 "-methyl-3" -hydroxyphenyl) pentyl] decahydroisoquinoline-3--3-Ν-1-butylbutyloxy Amides can be industrially advantageously produced and provided.

Claims

1 . 0下記式 (2)で表される化合物を、 1.0 A compound represented by the following formula (2):
請 の (2)
Figure imgf000025_0001
囲 一般式（3 )で表される化合物と縮合剤の存在下に反応させて、 (2)
Figure imgf000025_0001
A reaction with a compound represented by the general formula (3) in the presence of a condensing agent,
Z- R (3)  Z-R (3)
(式 (3)中、 Zは直鎖または分岐した G,〜G4アルコキシ基、 Ο, ΟΑアルキルチ ォ基、フヱノキシ基あるいは、ハロゲン原子、ニトロ基、アルキル基、アルコキシ基 または、ヒドロキシ基置換フ： Lノキシ基、フエ二ルチオ基あるいは、ハロゲン原子、 ニトロ基、アルキル基、アルコキシ基または、ヒドロキシ基置換フヱニルチオ基、ベ ンジルォキシ基あるいは、ハロゲン原子、ニトロ基、アルキル基または、アルコキ シ基置換べンジルォキシ基、ベンジルチオ基あるいはハロゲン原子、ニトロ基、ァ ルキル基またはアルコキシ基置換べンジルチオ基、ピリジルォキシ基、ピリジル チォ基、エトキシビニルォキシ基、直鎖または分岐した 〜 アルキルカルボ二 ルォキシ基、置換リン酸エステル基、置換硫酸エステル基、イミダゾリル基、アジ ド基、アルコキシカルポニルオギシ基、シクロへキシルカルポジイミドキシ基、スク シンイミドキシ基、フタルイミドキシ基、ベンゾトリアゾリルォキシ基、ピペリジノォ キシ基及びハロゲン原子を表し、 Rは水素原子を表す。ただし、下記一般式 (4) において Ζがハロゲン原子である場合には、 Ζ- Rは一緒になつて、塩化チォニル. 塩化スルフリル、五塩化リン、三塩化リン、臭化チォニル、またはォキザルクロリ ドを表す。 ) (In the formula (3), Z is a linear or branched G, ~G 4 alkoxy group, Omicron, Omikuron'arufa alkylthio O group, or Fuwenokishi group, a halogen atom, a nitro group, an alkyl group, an alkoxy group or a hydroxy group substituted off : L-noxy, phenylthio or halogen-, nitro-, alkyl-, alkoxy- or hydroxy-substituted phenylthio-, benzyloxy- or halogen-, nitro-, alkyl- or alkoxy-substituted Benzyloxy group, benzylthio group or halogen atom, nitro group, alkyl group or alkoxy group substituted benzylthio group, pyridyloxy group, pyridylthio group, ethoxyvinyloxy group, straight-chain or branched alkylcarboxy-substituted group, substituted phosphorus Acid ester group, substituted sulfate group, imidazolyl group, R, a hydrogen atom, a alkenyl group, an alkoxycarbonyloxy group, a cyclohexylcarbodiimidoxy group, a succinimidoxy group, a phthalimidoxy group, a benzotriazolyloxy group, a piperidinoxy group, and a halogen atom. In the general formula (4), when Ζ is a halogen atom, Ζ-R together form thionyl chloride. Sulfuryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl bromide, or oxal chloride.)
下記一般式 (4)
Figure imgf000026_0001
The following general formula (4)
Figure imgf000026_0001
(式 (4)中、 Zは前述のとおり。） (In equation (4), Z is as described above.)
で示される活性エステル化合物に変換する工程、 In the step of converting to an active ester compound represented by
ϋ)得られた一般式（4)で示される化合物をメチリド化合物と反応させて, 下記式 (5)で表されるイリド化合物を生成する工程、  ϋ) reacting the obtained compound represented by the general formula (4) with a methylide compound to produce an ylide compound represented by the following formula (5);
Figure imgf000026_0002
Figure imgf000026_0002
ίΠ)得られたイリド化合物をハロゲン化水素で処理して下記一般式 (6)で表され るハロメチルケトンとする工程、及び
Figure imgf000027_0001
ίΠ) treating the obtained ylide compound with hydrogen halide to give a halomethyl ketone represented by the following general formula (6); and
Figure imgf000027_0001
(式中、 Xはハロゲン原子を表す）、 (Wherein X represents a halogen atom),
iv)ついで、これを還元して一般式 (1 )で表されるハロゲノアルコール誘導体を製 造する方法。 iv) Next, a method for producing a halogenoalcohol derivative represented by the general formula (1) by reducing it.
Figure imgf000027_0002
Figure imgf000027_0002
(式中、 Xはハロゲン原子を表す） (Wherein, X represents a halogen atom)
2. 下記式（2)で表される化合物を、 2. A compound represented by the following formula (2):
Figure imgf000027_0003
—般式 Z— R (3)
Figure imgf000027_0003
—General formula Z— R (3)
で表される化合物と縮合剤の存在下に反応させて、下記式（4) Is reacted with a compound represented by the following formula (4)
Figure imgf000028_0001
Figure imgf000028_0001
(式中、 R,Zは前記と同じ）で表される活性エステル化合物の製造方法。 (Wherein, R and Z are the same as described above).
3. 下記一般式 (4) (式中、 Zは前記と同じ）で表される活性エステル化合物を、 塩基の存在下にトリメチルスルホキソニゥムハライドと反応させて、下記式 (5)で 表されるイリド化合物の製造方法。 3. The active ester compound represented by the following general formula (4) (wherein Z is the same as described above) is reacted with trimethylsulfoxonium halide in the presence of a base to obtain a compound represented by the following formula (5). A method for producing an ylide compound.
Figure imgf000028_0002
Figure imgf000028_0002
4. 下記式（5)で表されるイリド化合物を不活性溶媒中、ハロゲン化水素と反応 させて、下記式（6)で表される Qr义人 4. The ylide compound represented by the following formula (5) is reacted with hydrogen halide in an inert solvent to give the compound represented by the following formula (6). Qr 义 people
。
Figure imgf000029_0001
.
Figure imgf000029_0001
(5) (6)  (5) (6)
(式中、 Xは前記と同じ）のハロメチルケトン化合物の製造方法。 (Wherein X is the same as defined above).
5. 下記一般式（6)で表されるハロメチルケトン化合物（式中、 Xは前記と同じ） を還元して、下記一般式（1 )で表されるハロゲノアルコール誘導体の製造方法。  5. A method for producing a halogeno alcohol derivative represented by the following general formula (1) by reducing a halomethyl ketone compound represented by the following general formula (6) (where X is the same as described above).
Figure imgf000029_0002
Figure imgf000029_0002
6. 下記一般式（4) 6. The following general formula (4)
Figure imgf000029_0003
Figure imgf000029_0003
(式中、 zは前記と同じ、但し、 ζ-メトキシ基を除く）で示される新規な活性ェ ステル誘導体。 (Wherein z is as defined above, except for the ζ-methoxy group).
7. 下記式（5)で示されるイリド化合物。 83 7. An ylide compound represented by the following formula (5). 83
Figure imgf000030_0001
Figure imgf000030_0001
L9Zl0/Z0d£/∑Jd  L9Zl0 / Z0d £ / ∑Jd
PCT/JP2002/001267 2001-02-14 2002-02-14 Process for preparation of halogenoalcohol derivatives WO2002064553A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2002564486A JPWO2002064553A1 (en) 2001-02-14 2002-02-14 Method for producing halogeno alcohol derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001037325 2001-02-14
JP2001-37325 2001-02-14

Publications (1)

Publication Number Publication Date
WO2002064553A1 true WO2002064553A1 (en) 2002-08-22

Family

ID=18900468

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2002/001267 WO2002064553A1 (en) 2001-02-14 2002-02-14 Process for preparation of halogenoalcohol derivatives

Country Status (2)

Country Link
JP (1) JPWO2002064553A1 (en)
WO (1) WO2002064553A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1329373C (en) * 2003-12-11 2007-08-01 上海安基生物科技股份有限公司 Method for producing (2S.3R)-N-carbobenzoxy-3-amido-1-chlorine-4-benzenesulfenyl-2-butanol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604185A1 (en) * 1992-12-22 1994-06-29 Eli Lilly And Company Inhibitors of HIV protease useful for the treatment of aids
WO1995009843A1 (en) * 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
WO1998045271A1 (en) * 1997-04-10 1998-10-15 F. Hoffman-La Roche Ag Process for making a butylthio-isoquinoline and intermediates therefor
EP0897911A1 (en) * 1997-01-14 1999-02-24 Kaneka Corporation Process for producing cysteine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604185A1 (en) * 1992-12-22 1994-06-29 Eli Lilly And Company Inhibitors of HIV protease useful for the treatment of aids
WO1995009843A1 (en) * 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
EP0897911A1 (en) * 1997-01-14 1999-02-24 Kaneka Corporation Process for producing cysteine derivatives
WO1998045271A1 (en) * 1997-04-10 1998-10-15 F. Hoffman-La Roche Ag Process for making a butylthio-isoquinoline and intermediates therefor

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 (en) * 2003-12-11 2007-08-01 上海安基生物科技股份有限公司 Method for producing (2S.3R)-N-carbobenzoxy-3-amido-1-chlorine-4-benzenesulfenyl-2-butanol

Also Published As

Publication number Publication date
JPWO2002064553A1 (en) 2004-06-10

Similar Documents

Publication Publication Date Title
US5512565A (en) Cholesterol ester hydrolase inhibitors
US4920132A (en) Quinoline derivatives and use thereof as antagonists of leukotriene D4
US4920133A (en) Quinoline derivatives and use thereof as antagonists of leukotriene D4
JP2510839B2 (en) Novel process for the preparation of novel N- (acyloxy-alkoxy) carbonyl derivatives useful as biotransformable prodrug moieties for primary and secondary amine functional groups in drugs
EP0257882B1 (en) N-phenyl butenamides with pharmaceutical properties
JPH0253762A (en) Novel sulfonamide, and metabolic function disease and circulation disorder treatment drug containing the same
JP2601008B2 (en) Naphthyl oxazolidone derivatives, their preparation and their synthetic intermediates
JPS61207369A (en) Benzoic acid intermediate having three substituents
JP4344230B2 (en) Process for producing piperidine derivative fexofenadine
US4977162A (en) Quinolinyl-chromone derivatives and use for treatment of hypersensitive ailments
WO2002064553A1 (en) Process for preparation of halogenoalcohol derivatives
US5534533A (en) Carboxylate derivatives exhibiting phospholipase A2 inhibitory activity
CN111961083B (en) Montelukast sodium intermediate compound
JPH0213671B2 (en)
RU2184730C1 (en) Method of synthesis of 4-methyl-3-[2-(n-propyl- -amino)propionylamino]thiophene-2-carboxylic acid methyl ester hydrochloride
JP3193597B2 (en) Method for producing glycine derivative
JPS6355512B2 (en)
FR2758326A1 (en) PYRIDONE DERIVATIVES, THEIR PREPAPARATION AND THEIR USE AS SYNTHESIS INTERMEDIATES
JPH11269151A (en) Preparation of 3-(4(1-h-imidazol-1-yl-methyl)phenyl)-2-propenoic acid and its salt
EP0713865A1 (en) 2-Aminobenzenesulphonic acid and 2-aminobenzenesulphonyl chloride derivatives, their preparation and their use as synthetic intermediates
JP4507390B2 (en) 1-alkyl-1-substituted-3-organosulfonyloxyazetidinium salts and process for producing the same
SU952104A3 (en) Process for producing derivatives of interphenylene-9-thiaxo-12-azaprostanic acid
JPH0427977B2 (en)
JPH08333327A (en) Production of 1,4-cross-linked cyclohexane-based carboxylic acid derivative
JPH0657683B2 (en) Optically active amino acid derivative

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2002564486

Country of ref document: JP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase