WO1999054297A1 - Process for preparing chloro alcohol derivatives and intermediates - Google Patents

Abstract

A process for preparing compounds represented by general formula (X), comprising the steps of: saponifying a (2S,3R)-4-hydroxy-2,3-epoxybutanoic acid derivative; regioselectively opening the epoxy ring of the resultant derivative to obtain an open-ring derivative; protecting the amino group of the derivative; lactonizing the protected derivative; reducing the lactone derivative; protecting the 1- and 2-hydroxy groups of the reduced derivative; thioetherifying the protected derivative; removing the protective groups of the thioetherified derivative; and selectively chlorinating the primary hydroxyl group of the diol derivative; and novel intermediate compounds obtained in the course of the production of the compounds (X). The compounds (X) are useful as a key intermediate of the compound (XI) useful as an HIV protease inhibitor.

Description

 TECHNICAL FIELD The present invention relates to a compound that inhibits the activity of a virus-derived protease and a method for producing an intermediate compound useful for synthesizing the same. More specifically, formulas [XI] useful as therapeutics for HIV-related diseases

 [xi]

[Here, Bu ^l is ί- butyl group, the P h is phenyl group]

And a novel method for producing an intermediate compound useful for the synthesis thereof. The present invention also relates to a novel compound useful for producing the above compound [XI]. These novel compounds can be used not only for producing the above compound [XI] but also for producing various compounds. BACKGROUND ART The above compound [XI] is known as an HIV protease inhibitor (W095Z09843). Conventionally, this compound has been produced through an extremely large number of steps including a carbohydrate reaction with serine as a starting material and a stereoselective carbonyl group reduction reaction. However, these conventional manufacturing methods are expensive In addition to the need for raw materials, it was extremely complicated and inefficient, requiring low-temperature reaction conditions.

 WO 97/1193 7 and WO 97/1193 38 use, 1, —2-butenediol as a raw material, and the key reaction is the epoxy ring-opening reaction with a chiral amine. A method for producing the above compound [XI] is disclosed. This manufacturing method requires a large number of steps.

 Dale L. Rieger (J. Org. Chem. 1997, 62, 8546-8548) discloses a method for producing the above compound [XI] using serine as a starting material and dithianyl alcohol as a key intermediate. ing. This manufacturing method requires a low-temperature reaction step. As described above, the conventional methods for synthesizing the above compound [XI] have many problems that must be solved in order to implement them industrially.

 An object of the present invention is to provide a method for efficiently producing the above compound [XI], which is useful as an HIV protease inhibitor. An object of the present invention is to provide a novel intermediate compound useful for producing the above compound and a method for producing the same. DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies in order to achieve the above object, and as a result, starting from a 5,3R) -4-hydroxy xy-2,3-epoxybutanoic acid derivative as a starting material, the following formula [X]

That the key intermediate of the compound [XI], which is useful as an HIV protease inhibitor, can be produced extremely efficiently, thereby completing the present invention. Reached.

 The production method of the present invention comprises a step of curing a (2S, -3R) -4-hydroxy-2,3-epoxybutanoic acid derivative, a step of regioselectively opening an epoxy ring of the obtained derivative, A step of protecting the amino group of the obtained ring-opened derivative, a step of lactonizing the protected ring-opened derivative, a step of reducing the obtained lactone derivative, a step of protecting the 1,2-diol group of the obtained reduced derivative, protection Thioetherifying the reduced derivative thus obtained,

 [

The method includes a step of removing a diol protecting group of the obtained thioether derivative and a step of selectively chlorinating a primary hydroxyl group of the obtained diol derivative. The outline of the reaction scheme is shown below.

Process (3)

 Oka.

[IV], [V]

Process (8)

 [VII] [VIII]

NHR NHR

RS-process (9)

 , OH 'S'

 OH OH

 [IX] [X]

(Wherein, R ¹ is [an alkyl group which may be substituted for S or an aryl group which may be substituted; R ² is an amino-protecting group of acyl or carbamate type; R ³ and R ⁴ May be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group, or a cycloalkyl in which R ³ and R 4 are taken together with an adjacent carbon atom to form a ring R 5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; And M 'is an alkali metal).

 One aspect of the present invention is a novel intermediate compound obtained during the process of producing the compound represented by the formula [X] and a method for producing the same. More specifically, the following 1 to

16 '.

1. 5, 3R) -4-hydroxy-2,3-epoxybutanoic acid derivative represented by the general formula [II]:

 [II]

 (Where M is an alkali metal).

2. A method for producing a (2S, 3R) -4-hydroxy-2,3-epoxybutanoic acid derivative represented by the general formula [II], comprising:

 [II]

 (Where M is Alkyri metal)

-General

 [I],

(Where R ¹ is an alkyl group or an aryl group which may be substituted) (including a step of curing a 2S, third-4-hydroxy-2,3-epoxybutanoic acid derivative, Method.

 3. 3S) -2-Amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [III]:

 OH

ΗΟ, ^ C0 ₂ M

NH ₂

 [III] (where M is an alkali metal).

4. A process for producing a (2R, 3S) -2-amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [III], comprising:

(Where M is Alkyri metal)

General formula [II]

[II]

 (Where Μ is Alkyri metal)

And reacting the ammonia with US, 3R) -4-hydroxy-2,3-epoxybutanoic acid derivative to open the epoxy ring of the derivative.

 5. 2R, 3S) -2-Amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [IV]:

 ΟΗ

.C0 ₂ H

NHR ²

 [IV]

(Where R ² is an acyl or carbamate amino protecting group).

 6. A process for producing a (2R '3S) -2-amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [IY], comprising:

 OH

HO, person 0 ₂ H

NHR ²

 [IV]

(Wherein R ² is an amino-protecting group of acyl or bamate type) [III]

(Where M is Alkyri metal)

2R, 3S) -2-Amino-3,4-dihydroxy-butanoic acid derivative represented by the following formula: a method comprising reacting a halide or an acid anhydride corresponding to R ² .

7. —R, 4S-Dihydro-3-amino-4-hydroxy-2 (3) -furanone derivative represented by general formula [V]:

 [V]

(Where R ² is an acyl or carbamate amino protecting group).

8. Method for producing (3R, 4S-dihydro-3-amino-3-hydroxy-2- (3;)-furanone derivative represented by general formula [V]

 [V]

(Where R ² is an acyl-based or carbamate-based amino-protecting group) [IV]

 OH

HO. ^ ^ .C0 ₂ H

NHR ²

[IV] (where R ² is an amino group of acyl or carbamate type) in the presence of an acid catalyst in the presence of a (2R, 3S) -2-amino-3,4-dihydroxy-butanoic acid derivative. A lactonization process. 9. 2S, -3-Amino-1,2,4-butanetriol derivative represented by the general formula [V:

(Where R ² is an acyl- or carbamate-based amino protecting group).

 1 0. —A process for producing a (2S, 3S) -3-amino-1,2,4-butanetriol derivative represented by the general formula [VI]:

(Where R ² is an acyl- or carbamate-based amino protecting group) General formula [V]

HO NHR ²

 .

 [V]

(Where R ² is an acyl- or carbamate-based amino-protecting group) represented by (3R, 4S ~) dihydro-3-amino-4-hydroxy-2 (3W-furanone derivative Including the method.

 1 1. (2S.3S) -3-Amino-1,2-0 "isopropylidene represented by the general formula [YII] and 2,4-butanetriol derivative:

[VII] (Where R ² is an amino- or amino-protected amino-protecting group, and R ³ and R ³ may be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or a cycloalkyl group wherein R ³ and R ⁴ are taken together with adjacent carbon atoms to form a ring).

 12. — Represented by the general formula [VII]-3-amino-1,2-isopropylidene-

A process for producing a 1,2,4-butanetriol derivative, comprising:

 [VII]

(Where R ² is an acyl-based or carbamate-based amino-protecting group, and R ³ and R ⁴ may be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or R ³ and R ⁴ are cycloalkyl groups formed together with adjacent carbon atoms to form a ring)

General formula [VI]

(Where R ² is an acyl-based or carbamate-based amino-protecting group), in the presence of an acid catalyst or an acid-catalyzed S, 3S-3-amino-1,2,4-butanetriol derivative. A method comprising reacting an acetalizing agent in the presence of a catalyst and a dehydrating agent to protect the 1,2-diol group of the derivative.

13. — (2S, 3R) -3-Amino-1,2 · ^ ί “isopropylidene-4-mercapto-1,2-butanediol derivative represented by the general formula [YIII]:

 [VIII]

(Where R ² is an acyl- or bamate-based amino-protecting group, and R ³ and R ⁴ may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or R ³ and R ⁴ are a cycloalkyl group which forms a ring together with adjacent carbon atoms, and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, or a substituted An alkenyl group which may be substituted, an aryl group which may be substituted or an aralkyl group which may be substituted).

 14. (25, -3-Amino-2- ^ isopropylidene represented by general formula [VIII]

A process for producing a 4--4-mercapto-i, 2-butanediol derivative, comprising:

 [VIII]

(Where R ² is an acyl-based or carbamate-based amino-protecting group, and R ³ and R ⁴ may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group. R ³ and R ⁴ are a cycloalkyl group which forms a ring together with adjacent carbon atoms, and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, An alkenyl group which may be substituted, an aryl group which may be substituted or an aralkyl group which may be substituted)

General formula [VII]

(Where R ² , R ³ and R ⁴ are the same as above)

Reacting a (2S, -3-amino-1,2-isopropylidene, 2,4-butanetriol derivative with a halogenating agent or a sulfonylating agent, and the resulting halogenated or sulfonylated derivative

R ⁵ SH

(Where R ⁵ is the same as above)

And thioetherification by reacting with mercaptan.

 1 5. —Method for producing (2S, 3-3-amino-3-mercapto-1,2-butanediol derivative represented by general formula [IX]:

(Where R ² is an acyl-based or carbamate-based amino-protecting group; R ^s is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group Or an aralkyl group which may be substituted)

General formula [VI II]

 [VIII]

(Where R ² and R ⁵ are the same as above, and R ³ and R ⁴ may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group, Or R ³ and R ⁴ are a cycloalkyl group which forms a ring together with adjacent carbon atoms)

(2S, third-3-amino-1,2-0 to isopropylidene-4-mercapto- and 2-butanediol derivative, which is hydrolyzed in the presence of an acid catalyst.

 16. A process for preparing a 3-cyclohex-2-hydroxy-3-amino-4-mercaptobutane derivative represented by the general formula [X]:

(Where R ² is an acyl-based or carbamate-based amino-protecting group, and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group Or an aralkyl group which may be substituted)

General formula [IX]

(Where R ² and R ⁵ are the same as above)

(S, 3R) -3-Amino-3-mercapto- and 2-butanediol derivatives A method of selectively chlorinating only the primary hydroxyl group of the butanediol derivative by reacting it with rufonyl chloride.

 As used herein, the term "alkali metal" includes sodium, potassium, lithium, rubidium, cesium and francium, preferably sodium, potassium or lithium.

 The term “alkyl group” embraces both straight-chain and branched-chain alkyl groups, preferably having 1 to 6 carbons. Preferable alkyl groups in the present invention include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, and di-pentyl group. Group, hexyl group, isohexyl group, neohexyl group and the like. Preferred alkyl groups are "lower alkyl groups" having 1 to 4 carbon atoms, and specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, f-butyl and the like. It is.

 The term “optionally substituted 'alkyl group” refers to an alkyl group substituted with one or more substituents that does not affect the reaction. This substituent may be a hydroxyl group; a halogen atom such as fluorine, chlorine, bromine, or iodine; an amino group; a nitro group; a mono- to mono-carbon group having 1 to 6 carbon atoms, such as Or a dialkylamino group; a cyano group; a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group; a methoxy group, an ethoxy group, a propoxy group, or a butoxy group Alkoxy group having 1 to 6 carbon atoms such as a pentoxy group, a pentoxy group, a pentoxy group, a pentoxy group, a methoxycarbonyl group, a ethoxycarbonyl group, a pentoxycarbonyl group, a pentoxy group; And alkoxyalkenyl groups having 2 to 6 carbon atoms. Preferred substituents are a halogen atom, an amino group and the like.

The substitution position and number of the above substituents with respect to the alkyl group are not particularly limited. The term "aryl group" includes aromatic groups such as phenyl, naphthyl, biphenyl and the like, and is preferably phenyl '.

 The term "optionally substituted aryl group" means an aryl group substituted with one or more substituents that do not affect the reaction. This substituent includes the substituents described in the above “optionally substituted alkyl group”, and further includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and an s-butyl group. An alkyl group having 1 to 6 carbon atoms, such as a monobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a dipentyl group, a hexyl group, an isohexyl group, a neohexyl group; a vinyl group, an aryl group, An alkenyl group having 2 to 6 carbon atoms such as a butenyl group, a pentenyl group, and a hexenyl group; Include. Preferred substituents are an alkyl group, a hydroxyl group, a halogen atom, an amino group, a nitro group, an alkoxy group, and an acyloxy group, and more preferred are an alkyl group, a hydroxyl group, a halogen atom, an alkoxide group, and an acyloxy group.

 The substitution position and number of the above substituents on the aryl group are not particularly limited,

1 to 3 substituents, more preferably 1 to 2 substituents are preferred.

The term “acyl- or carbamate-based amino-protecting group” refers to rumyl, acetyl, propionyl, butyryl, bivaloyl, 2-crocoacetyl, 2-bromoacetyl, 2-bromoacetyl, 2,2. —Dichloroacetyl group, 2,2,2-Trichloroacetyl group, 2,2,2-Trifluoroacetyl group, Phenylacetyl group, Benzoyl group, 4-Methoxybenzoyl group, 3-Hydroxy-2-Methylbenzoyl group , 3-acetoxy 2-methylbenzoyl group, 412-trobenzoyl group, optionally substituted acyl group such as naphthylcarbonyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl Group, pentyloxycarbonyl group, isopentyl Oxycarbonyl group, cyclohexyloxycarbonyl group, 2-chloroethoxycarbonyl, 2-odoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzhydryloxycarbonyl, bis (4-methoxyphenyl) methoxycarbonyl, Optionally substituted alkoxycarbonyl groups such as phenacyloxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group and 2- (triphenylsilyl) ethoxycarbonyl group; vinyloxycarbonyl group, 2-propidinylo Xycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarboxy-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butyl Optionally substituted alkenyl such as tenyloxycarbonyl, cinnamyloxycarbonyl, etc. Optionally substituted aryloxycarbonyl groups such as phenoxycarbonyl group; benzyloxycarbonyl group, 4-bromobenzyloxycarbonyl group, 2-hydroxybenzyloxycarbonyl group Group, 3-chlorobenzyloxycarbonyl group, 3,5-dimethylbenzylcarbonyl group, 4-methoxybenzylcarbonyl group, 2-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, Optionally substituted aralkyloxycarbonyl groups such as 2,2-troth 4,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, phenethyloxycarbonyl group A methylthiocarbonyl group, an ethylthiocarbonyl group, a butylthiocarbonyl group, a t-butylthioca Including and base Nji thiocarbonyl optionally substituted § Lal key Lucio carbonylation Le groups such as; Boniru optionally substituted have good alkylthiocarbonyl group such. In some cases, it may be a phthaloyl group or the like. A preferred "amino group of an acyl or carbamate type" is an aralkyloxycarbonyl group, more preferably a benzyloxycarbonyl group.

The term "alkenyl group" embraces straight-chain and branched alkenyl groups, preferably having 2 to 6 carbons. Arke preferred in the present invention: Examples of ± groups include A vinyl group, an aryl group, a crotyl group, a 2-pentenyl group, a 3-pentenyl group, a 2-hexenyl group, a 3-hexenyl group and the like. More preferred alkenyl groups are alkenyl groups having 2 to 4 carbon atoms, and are a vinyl group, an aryl group and a crotyl group. The term “optionally substituted alkenyl group” means an alkenyl group substituted with one or more substituents that do not affect the reaction. This substituent includes the substituents described above for the “optionally substituted alkyl group”. The substitution position and the number of substituents on the alkenyl group are not particularly limited.

 The term “aralkyl group” is composed of the above aryl group (phenyl group, naphthyl group, biphenyl group, etc.) and the above alkyl group (alkyl group having 1 to 6 carbon atoms), such as benzyl group, phenethyl group, phenylpropyl group. Group, phenylbutyl group, phenylhexyl group and the like. A preferred aralkyl group comprises a phenyl group and an alkyl group having 1 to 4 carbon atoms.

The term "optionally substituted aralkyl group" means an aralkyl group substituted with one or more substituents that does not affect the reaction. This substituent includes the substituents described in the above “optionally substituted alkyl group”, and further includes a haloalkyl group having 1 to 6 carbon atoms such as a chloromethyl group, a chloroethyl group and a chlorobutyl group. I do. Preferred are a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a nitro group, an acyloxy group, an amino group, a cyano group and the like, and more preferred are a halogen atom, an alkyl group, an alkoxy group and an acyloxy group. The “optionally substituted aralkyl group” includes a benzyl group, a halogen-substituted benzyl group, an alkyl-substituted benzyl group, an alkoxy-substituted benzyl group, a phenethyl group, a halogen-substituted phenyl group, an alkyl-substituted phenyl group, and an alkoxy-substituted group. It includes a phenyl group, a phenylpropyl group, a halogen-substituted phenylpropyl group, an alkyl-substituted phenylpropyl group, an alkoxy-substituted phenylpropyl group and the like, and is preferably a benzyl group or a phenethyl group. The substitution position and the number of the above substituents with respect to the aralkyl group are not particularly limited, but 1 to 3 substituents are preferable. The term [cycloalkyl group] preferably includes a cycloalkyl group having 3 to 7 carbon atoms, and includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. More preferably, it is a cycloalkyl group having 4 to 6 carbon atoms, including a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. BEST MODE FOR CARRYING OUT THE INVENTION Next, a method for producing the above compound (X) will be described together with the above reaction scheme, step (3)

Process (6)

Process (8)

 [VII] [VIII]

 [IX] [X]

(Where RR ² , R ³ , RR ⁵ and M are the same as above) Step (1): Esterification of ester-Compound (I) can be prepared, for example, by 1) Dunigan, J .; Weigel, L. 0. J. Org. Chew. 1991, 56, 6225, 2) Weigel, manufactured according to the method described in USP 5, 097, 04.

 In this step, compound (II) is obtained by dissolving compound (I) in a suitable alcoholic solvent at a predetermined temperature and reacting with a predetermined amount of a suitable base. As a suitable base, sodium hydroxide, potassium hydroxide, lithium hydroxide can be used, preferably sodium hydroxide.

Suitable alcoholic solvents include, for example, methanol, ethanol, pucopropyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, s_butyl alcohol;; -butyl alcohol, etc., preferably methanol, Ethanol, isopropyl alcohol and more preferably methanol are used. The amount of the salt group to be used is 1 equivalent to 2 equivalents, preferably 1.0 equivalent to 1.2 equivalents, relative to compound (I).

 The reaction temperature is suitably from −20 to 50, preferably from 0 to 2 (TC. Usually, the reaction of the compound (I) is completed in a reaction time of 5 to 15 hours, and the compound (II) Step (2): Regioselective ring opening of the epoxy ring with ammonia

 In this step, the epoxy ring of the compound (II) is opened using a predetermined amount of ammonia in a suitable solvent at a predetermined temperature to obtain a compound (II).

 Suitable solvents include, for example, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol,] -butyl alcohol, isobutyl alcohol, s-butyl alcohol, and t-butyl alcohol; benzene, toluene, hexane, xylene, etc. Hydrocarbon solvents; ether solvents such as getyl ether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Or a polar solvent such as N, N-dimethylformamide, acetonitrile, acetone, or water; or a mixed solvent thereof, and preferably water.

 Ammonia is usually used in the form of an aqueous solution, and its use amount is 5 to 40 equivalents, preferably 10 to 25 equivalents, relative to compound (II).

 The reaction temperature is suitably from 0 to 100, preferably from 40 to 70. Usually, the epoxy ring of compound (II) is opened in a reaction time of 5 to 70 hours to obtain compound (III). Step (3): Protection of Amino Group

In this step, the compound (III) is added to a predetermined amount of an acid halide, a halogenated formate, an acid anhydride or a carbonate anhydride corresponding to a predetermined amount of R ² in a suitable solvent at a predetermined temperature. The amino group is protected with a protecting group (R ² ) to give a lig compound (IV).

Examples of the acyl-based or carbamate-based amino-protecting group (R ² ) include an acyl group, an imide group, a phenoxycarbonyl group, an aralkyloxycarbonyl group, an alkylthiocarbonyl group, an aralkylthiocarbonyl group and the like. Preferably, an aralkyloxycarbonyl group, more preferably a benzyloxycarbonyl group may be used.

Acid halide corresponding to R ^2, halogen formate ester is not particularly limited as long as it is a compound corresponding to R ^2, e.g., Asechirunikurori de, propionic sulfonyl = Kurori de, butyryl = Kurori de, Benzoiru == Kurori And 3-acetoxy-2-methylbenzoyl chloride, benzyloxycarbonyl chloride, ethoxycarbonyl chloride and the like. The acid anhydride corresponding to R ² or carbonitrides anhydride is not particularly limited as long as it is a compound corresponding to R ^2, e.g., acetic anhydride, di one f - butyl dicarbonate: di (2, 2, 2-trichloroethyl) dicarbonate or the like may be used.

 Suitable solvents include, for example, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, monobutyl alcohol, isobutyl alcohol, s-butyl alcohol, and butyl alcohol; and carbonized solvents such as benzene, toluene, hexane, and xylene. Hydrogen solvents; Ether solvents such as jet ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc .: Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc .; acetic acid Ester solvents such as ethyl, methyl acetate and butyl acetate; polar solvents such as Ν, Ν-methylformamide, acetonitrile, acetone, water and the like; or a mixed solvent thereof, preferably water or the above organic solvent. Mixture of solvent and water Can be used.

Of the above acid halides, halogenated formate esters, acid anhydrides or carbonate anhydrides The amount used is 1 g to 5 equivalents, preferably 1.0 equivalent to 1.2 equivalents, relative to the compound (Π).

 The reaction temperature is suitably from 0 to 10 °, preferably from 0 to 50 °. Usually, the amino group of compound (III) is protected in a reaction time of 5 to 15 hours to obtain compound (IV). Step (4): lactonization

 In this step, the compound (V) is obtained by lactonizing the compound (IV) at a predetermined temperature in a suitable solvent in the presence of a predetermined amount of a suitable acid or a reagent that generates an acid in the reaction system. ).

 For example, once the compound (IV) is esterified in a suitable alcoholic solvent, the resulting ester is closed to a lactone. As a suitable alcoholic solvent, for example, methanol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, S-butyl alcohol, polyvinyl alcohol and the like, preferably methanol can be used.

 As the acid, inorganic acids such as sulfuric acid and hydrochloric acid, and sulfonic acids such as methanesulfonic acid and ρ-toluenesulfonic acid can be used. In addition, chlorotrimethylsilane, ρ-toluenesulfonyl chloride, methanesulfonyl chloride, benzyloxycarbonyl chloride, Acetyl chloride and the like can be used, and preferably chlorotrimethylsilane can be used.

 The amount of the acid or the reagent that generates an acid in the reaction system to be used is 1 equivalent to 3 equivalents, preferably 1.0 equivalent to 1.5 equivalents, relative to compound (IV).

The reaction temperature is suitably from 110 to 50, preferably from 0 to 30. Usually, compound UV) is lactonized in a reaction time of 5 to 24 hours to obtain compound (V). Alternatively, compound (IV) is directly lactonized at a predetermined temperature in a suitable solvent in the presence of an acid catalyst to obtain compound (V).

 Suitable solvents include, for example, methanol, ethanol, propyl alcohol. Alcohol solvents such as isopropyl alcohol, J2-butyl alcohol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, etc .; -Ether solvents such as dimethoxyethane, tetrahydrofuran and diglyme; polar solvents such as N, N-dimethylformamide, acetonitrile, acetone and water; and mixed solvents thereof. Preferably, water is used. Suitable acid catalysts include, for example, inorganic acids such as sulfuric acid and hydrochloric acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and preferably p-toluenesulfonic acid.

 The amount of the acid or the reagent that generates an acid in the reaction system to be used is 0.1 equivalent to 1.0 equivalent, preferably 0.3 equivalent to 0.6 equivalent, relative to compound (IV).

 The reaction temperature is suitably 0.50, and preferably 2030. Usually, compound (IV) is lactonized in a reaction time of 524 hours to obtain compound (V). Step (5): Reduction

 In this step, compound (VI) is obtained by treating compound (V) with a predetermined amount of a suitable reducing agent in a suitable solvent at a predetermined temperature.

As reducing agents, sodium borohydride, calcium borohydride, lithium borohydride, lithium triethylborohydride, borane, lithium aluminum hydride, alane, diisobutylaluminum hydride, sodium bis (2-methoxhetoxy) Aluminum hydride or the like can be used, preferably sodium borohydride, calcium borohydride, lithium borohydride, and more preferably calcium borohydride. A suitable solvent is selected depending on the reducing agent used, and examples thereof include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, diglyme, and the like. Ether solvents such as dichloromethane, chloroform, carbon tetrachloride, and halogen solvents such as 1,2-dichlorobenzene; methanol, ethanol, propyl alcohol, isopropyl alcohol, π-butyl alcohol, isobutyl alcohol, Alcohol solvents such as s-butyl alcohol and ί-butyl alcohol can be used. When sodium borohydride, lithium borohydride, or calcium borohydride is used as the reducing agent, a preferable solvent is an alcohol solvent or an ether solvent, and more preferably methanol.

 The amount of the reducing agent to be used is 1 equivalent-3 equivalents, preferably 1.5 equivalents-2.0 equivalents, relative to compound (V).

 The reaction temperature is suitably from 0 to 100, preferably from 0 to 50. Usually, the compound (V) is reduced in a reaction time of 3 to 10 hours to obtain the compound (VI). Step (6): Protection of 1, 2-diol group

 In this step, the compound (VI) is reacted with a predetermined amount of an acetalizing agent in a suitable solvent at a predetermined temperature in the presence of a predetermined amount of an acid catalyst or in the presence of an acid catalyst and a dehydrating agent. The compound (VI I) is obtained by protecting the 1,2-diol group.

The solvent is appropriately selected depending on the kind of the acylating agent to be used, and suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, hexane and xylene; dimethyl ether, 1,2-dimethoxy Ether solvents such as ethane, tetrahydrofuran, and diglyme; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and ester solvents such as ethyl acetate, methyl acetate, and butyl acetate. : Ν, Ν-dimethylformamide, acetonitrile, acetone, dime W

A polar solvent such as tylsulfoxide: or a mixed solvent thereof can be used.

 Examples of the acetalizing agent include carbonyl compounds such as benzaldehyde, acetone, getyl ketone, methyl ethyl ketone, acetophenone, cyclopentynone, cyclohexanone; dimethoxymethane, 1,1-dimethoxyacetoaldehyde, benzaldehyde dimethyl Ge dialkoxy compounds such as acetal, 2,2-dimethoxypropane and cyclohexanone dimethyl acetate; or methyl vinyl ether, ethyl vinyl ether, 2-methoxypropene, 2-ethoxypropene, A vinyl ether compound such as 1-methoxycyclohexene or the like can be used, preferably a carbonyl compound or an e-dialkoxy compound, more preferably acetone or 2,2-dimethoxypropane.

 The amount of the acetalizing agent to be used is 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to compound (VI). However, in the case of acetone, a large excess is used as a solvent.

 The acid catalyst is appropriately selected depending on the type of acetalizing agent used. Suitable catalysts include, for example, inorganic acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; A salt of a sulfonic acid and an organic amine such as a pyridinium salt of toluenesulfonic acid may be used, and a salt of a sulfonic acid and an organic amine is preferably used, and a pyridinium salt of toluenesulfonic acid is more preferably used.

 The amount of the acid catalyst to be used is 0.01 equivalent to 0.5 equivalent, preferably 0.05 equivalent to 0.2 equivalent, relative to compound (VI).

 As a dehydrating agent, phosphorus oxychloride, molecular sieves, magnesium sulfate, etc. can be used, and molecular sieves are preferably used.

The amount of the dehydrating agent to be used is 0.1 to 30 times, preferably 1 to 5 times, by weight, relative to compound (VI). The reaction temperature is suitably from 0 to 100 ° C., preferably from 0 to 5 (TC. Usually, the reaction time of 10 to 24 hours allows the 1,2-diol group of the compound (V i) to be formed. Step (7): thioetherification of hydroxyl group to obtain compound (νπ)

In this step, the compound (VII) is reacted with a predetermined amount of a halogenating agent or a sulfonylating agent in a suitable solvent at a predetermined temperature and in the presence of a predetermined amount of a suitable base to form a hydroxyl group. Is replaced with a suitable leaving group, and after isolation or without isolation, in the presence of a predetermined amount of a suitable base, a predetermined amount of the desired R ⁵ SH (where R ⁵ is The compound (VI II) is obtained by reacting with a mercaptan represented by the formula:

 Suitable solvents for carrying out the halogenation or sulfonylation of hydroxyl groups include, for example, hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc .; ethyl ether, 1,2-dimethoxyquinone, tetrahydrofuran : Ether solvents such as diglyme; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; A polar solvent such as N-dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide; or a mixed solvent thereof can be used. Preferably, a hydrocarbon solvent, for example, toluene is used.

 Suitable leaving groups are, for example, halogens such as chlorine, bromine and iodine; methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, camphorsulfonyl And a sulfonyloxy group such as a oxy group, preferably a sulfonyloxy group, more preferably a methanesulfonyloxy group.

Examples of the halogenating agent include ordinary halogenating agents such as phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, thionyl chloride, phosphorus pentachloride, etc. Combinations of carbon and trirefenylphosphine may be used.

 Examples of the sulfonylating agent include sulfonyl chlorides such as methanesulfonyl dichloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, camphorsulfonyl-chloride and the like: methanesulfonic anhydride, p- Sulfonic anhydrides such as toluenesulfonic anhydride and trifluoromethanesulfonic anhydride can be used, preferably sulfonyl chloride, more preferably methanesulfonyl chloride.

 The amount of the dehalogenating agent or the sulfonylating agent to be used is 1 equivalent-2 equivalents, preferably 1.0 equivalent-1.2 equivalents, relative to compound (VII).

 Suitable bases include, for example, pyridine, lutidine, picoline, triethylamine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 1,8-diazabicyclo [5,4,0] -7-indenecene Organic bases such as (DBU), 1,5-diazabicyclo [4,3,0] -5-nonene (DBN), triethylenediamine (DAB C0), etc. may be used: preferably pyridine, trie Phenylamine, more preferably triethylamine.

 The amount of the base to be used is 1 equivalent-2 equivalents, preferably 1.2 equivalents-1.7 equivalents, relative to compound (VII).

 The reaction temperature of the halogenation or the sulfonylation is suitably from 0 to 100, preferably from 0 to 5 Ot :. Usually, the hydroxyl group of compound (VII) is substituted in a reaction time of 30 minutes to 6 hours.

Suitable solvents used for the reaction with the desired mercapnones include, for example, hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and ethers such as jetter ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme. Ether solvents; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; N, N-dimethylformamide, acetonitrile, acetone , Dimethyl sulfoxide, etc. Or a mixed solvent thereof, preferably a polar solvent, for example, dimethyl sulfoxide, acetone, methyl ethyl ketone, N,>:-dimethylformamide.

 The desired mercaptans may be any as long as they have a mercapto group, for example, optionally substituted aryl mercaptans such as thiophenol and toluene thiol; methyl mercaptan, ethyl mercaptan Alkyl mercaptans which may be substituted, such as propyl mercaptan, isopropyl mercaptan, butyl mercaptan, isobutyl mercaptan, s-butyl mercaptan, f-butyl mercaptan; benzyl mercaptan, phenethyl mercaptan, naphthyl Optionally substituted aralkyl mercaptans such as methyl mercaptan; substituted or unsubstituted aryl mercaptans such as vinyl mercaptan and aryl mercaptan may be used. Preferably, aryl mercaptans are used, more preferably thiophenol.

 The amount of the mercap compound to be used is 1 equivalent-2 equivalents, preferably 1. ◦ equivalent-1.2 equivalents, relative to compound (VII).

 Suitable bases used for the reaction with the desired mercapnones include, for example, pyridine, lutidine, picoline, triethylamine, diisopropylethylamine, dimethylaminopyridine, 1,8-diazabicyclo [5,4, Organic bases such as 0] — 7-indene (DBU), 1,5-diazabicyclo [4,3,0] —5-nonene (DBN) and triethylenediamine (DABCO): lithium hydroxide, sodium hydroxide, water Inorganic bases such as potassium oxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like can be used, and preferably, an inorganic base such as potassium carbonate is used.

 The amount of the above base to be used is 1 equivalent to 3 equivalents, preferably 1.5 equivalents to 2.5 equivalents, relative to compound (VII).

The reaction temperature with the desired mercapones is suitably 0 to 100 ° C, preferably 0 to 50. Usually, the compound 'III) is obtained in a reaction time of 5 to 20 hours. Step (8): Removal of diol protecting group

 In this step, the compound is prepared in a suitable solvent at a predetermined temperature in the presence of a predetermined amount of a suitable acid.

The acetal portion of (VIII) is hydrolyzed to obtain a diol (IX).

 Suitable solvents include, for example, alcoholic solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, s-butyl alcohol, and tert-butyl alcohol; or alcohol solvents and ether solvents. Mixed solvent with polar solvent (here, ether solvents include getyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc., and polar solvents include N, N-dimethylformamide, acetonitrile , Acetone, water, etc.), and preferably an alcoholic solvent, for example, methanol.

 Suitable acids include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; carboxylic acids such as acetic acid, chloroacetic acid, trichloroacetic acid, and trifluoroacetic acid; sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; Acids can be used, preferably inorganic acids, for example hydrochloric acid.

 The amount of the above acid to be used is 0.01 equivalent to 0.2 equivalent, preferably 0.05 equivalent to 0.1 equivalent, relative to compound (VIII).

 The reaction temperature is suitably from 0 to 100, preferably from 60 to 90. Usually, the compound (IX) is obtained in a reaction time of 30 minutes to 2 hours. Step (9): Chlorination with sulfonyl dichloride

In this step, the diol (IX) is reacted with a predetermined amount of sulfonyl chloride in a suitable solvent or without a solvent at a predetermined temperature in the presence of a predetermined amount of a suitable base. T / P 0175

Therefore, the primary hydroxyl group of the diol is converted into a sulfonic acid ester, and then the sulfonic acid ester is further substituted with a chlorine atom in the same reaction system to obtain a compound (X).

 The reaction can be carried out without a solvent, but it is preferable to carry out the reaction after diluting in an appropriate solvent.

 Suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, hexane and xylene; ether solvents such as getyl ether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; dichloromethane; Halogen solvents such as form, carbon tetrachloride and 1,2-dichloromethane; ester solvents such as ether acetate, methyl acetate and butyl acetate; N, N-dimethylformamide, acetonitrile, acetone, A polar solvent such as dimethyl sulfoxide; or a mixed solvent thereof can be used, and an ester solvent, for example, ethyl acetate can be used.

 In addition, among the bases described below, those that are liquid within the range of the temperature used can be used as the solvent. Examples of the sulfonyl chloride include, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, camphorsulfonyl chloride, and the like, and preferably p-toluenesulfonyl chloride. Use

 The amount of the sulfonyl ester and the mouth lid to be used is 1 equivalent-2 equivalents, preferably 1.0 equivalent-1.5 equivalents, relative to compound (IX).

 Suitable bases include, for example, pyridine, lutidine, picoline, triethylamine, diisopropylethylamine, dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene (DBU), 1 Organic bases such as, 5-diazabicyclo [4,3,0] -5-nonene (DBN) and triethylenediamine (DABCQ) can be used, preferably pyridine, triethylamine or DABCO, more preferably Use pyridine.

When the above base is used only as a base, the amount used is 1 equivalent to Compound '(IX). The amount is from 5 to 5, preferably from 1.5 to 2.5 equivalents.

 The reaction temperature is suitably from 0 to 100, preferably from 0 to 50 ° C. Usually, the compound (X) is obtained in a reaction time of 6 to 30 hours.

 From this compound (X), a compound of formula (XI) useful as a therapeutic agent for HIV-related diseases can be synthesized, for example, by the method described in WO95 / 09843. Examples Hereinafter, the present invention will be described in detail with reference to Examples. The following examples are illustrative of the invention and the invention is not limited thereto.

Process (e) OH

,,, C0 ₂ Na process ( ₂

HO., C〇, ヽ 'a process (3)

'OH NH

[4] [5] [6] Process ( ⁶⁾ O C0 ₂ H

NHCbz

 [7] [8] [9] Process (8)

Reference example 1

Synthesis of (3R, 4R) -dihydro-3,4-dihydroxy-2 {3H) -furanone i (3R, -dihydro-3,4-dihydroxy-2 furanone] compound [2]

[i] ² sodium erythorbate was cooled with sodium chloride one ice bath [sodium eryth orbate [1]; 100 g, O.ol mol] and _{Na 2 C0 3 (53.5 g,} 0.51 mol) pale yellow water containing a A 30% aqueous solution of H ₂ O ₂ (112 m and 0.99 mol) was added dropwise to the solution (1200 ml) with stirring, while maintaining the temperature of the solution in the range of 2 to 35. Stirring was continued under the same cooling conditions. When the solution temperature became 30 ° C or less, the sodium chloride / ice ice bath was removed. The colorless and transparent reaction solution was heated with stirring, and the solution temperature was raised to 40 ° C. The stirring was continued for 45 minutes while maintaining the solution temperature between 40 ^ and 45. After cooling, the solution was cooled again in a sodium chloride-ice bath, and a small amount of activated carbon (Darco; 20.4 g) was added little by little while maintaining the solution temperature in the range of 6 t: to 8. After completion of the addition, instead of sodium chloride one ice bath in warm water bath, and the temperature of the reaction mixture to decompose excess H ₂ 0 ₂ raised to at gradually 35. Stirring was continued at this temperature until gas evolution ceased. After confirming that no peroxide remained on the test paper using iodine-immobilized lime starch, the mixture was cooled to room temperature, and the mixture was filtered through Hyflo Super-Cel to remove activated carbon. The used laboratory equipment and residues were thoroughly washed with warm water (10Q mix 5). The filtrate and the washing solution were combined, and the pH was adjusted to 1 by adding a 5M HC1 aqueous solution (400 ml) while stirring at room temperature. At this time, since the foaming vigorously C0 _Z gas generated, were added carefully until the first 100 ml. The acidic solution was allowed to stand at room temperature, and then concentrated under reduced pressure at a bath temperature of 60 ° C. The obtained white solid residue was extracted with boiling ethyl acetate (400 mix 6). That is, the solid residue was suspended in hot acetate (400 ml) and heated until boiling, then the supernatant was decanted and filtered through filter paper. This operation was repeated six times. The absence of the desired product in the sixth extract was determined by thin layer chromatography (TLC; ck Kieseigel 60, thickness 0.25 ran; developing solvent: ethyl acetate). The combined ethyl acetate extract was concentrated under reduced pressure to give an almost white solid (86.3 g). This was dissolved in isopropyl alcohol (IPA; 50 m) under reflux with heating, and recrystallized by adding isopropyl ether (IPE; 250 ml) while stirring under water cooling. After continuing for 1 hour, the mixture was allowed to stand in a freezer (-12) for 4 hours, and the precipitated solid was collected by filtration, washed twice with mother liquor, air-dried, and dried under reduced pressure at 45 for 10 hours. (4,4R) -Dihydro-3,4-dihydroxy-2 (-furanone ([2]; 53.1, also 89.0¾) was obtained as white crystals. Reference Example 2

 (3R. 4R) -dihydro-4-hydroxy-3-tosicoxy-2 (3) -furanone [(3R, 4R) -dihydro-4-hydroxy-3-tosyloxy-2 (-iuranone) compound [3] Synthesis of

 [twenty three]

A solution of (3R, 4S) -3,4-dihydroxy-dihydro-2 (3H) -furanone ([2]; 24.0 g, 0.20 raoi) in pyridine (Py) (.O. Then, ρ-toluenesulfonyl chloride (Ts-CI; 10.0 g, 52.4 mmoi) was added. After 2 hours, 10.0 g (52.4 mmol) of Ts-, 4 hours later, 10.0 g (52.4 mmol), 5 hours 45 minutes, 10.0 g (52.4 mmol), 25 hours 15 minutes Later, 4.58 g (24.0 mmo 1) was added in portions. Under the same cooling conditions, the heterogeneous reaction mixture was stirred for an additional 44.5 hours. Ice water was added until the precipitate was almost dissolved, and the mixture was poured into an ice water mixture (500 ml). The solid matter adhering to the used laboratory equipment was washed into the above ice-water mixture with water. In addition, ice water was added to bring the volume of the mixture to 90 Q mi. Precipitated solid The body was collected by filtration, washed once with water, pressed to remove water, and air-dried at room temperature to give a solid with a wet weight of 91.3 g. This was dried 40 ^e C De晚風, (3R, 4R) - dihydro - 4-hydro carboxymethyl - 3-tosyloxy -2 (3H) - furanone; ho the ([3] 51.6 g, 93.4 %); or Obtained as a white, white solid. (Drying this under reduced pressure at 40 ° C for another 5 hours did not change its weight).

Ή-NMR (D S0-d ₆ , 400ΜΗζ) δ: 7.80 (d, J = 8Hz, 2H), 7.47 (d, J = 8Hz,

2H), 6.00 (br, 1H), 5.47 (d, J = 5Hz, 1H), 4.36 (m, 1H), 4.25 (m, 1H), 4.

10 (d, j =! 0Hz, 1H), 2.41 (s, 3H). Reference example 3

US, 3R) - _4: hydrin 5 ^ sheet - 2, 3 - Synthesis of methyl-epoxybutane acid [methyl (25, 3R) -4 -h ydroxy-2, 3-epoxybutanoate] Compound [4]

[3] [4] 3R, 4R) -4-Hydroxy-3-toxicoxy-dihydro-2 (3-phenone ([3]; 19.6 g, 72.1 mmol) in a suspension of tetrahydrofuran (THF) -methanol (MeOH) (1: 4; 300 ml), with stirring, a solution of NaOMe in MeOH [28% (w / w) NaOMe I MeOH: 15.3 g. 79.3 mmol; MeOH: 50 mi] was added dropwise over 30 minutes while maintaining the temperature of the suspension in the range of -1 Q to -9. The reaction mixture was heated at an internal temperature of -10 to -2 ° C. The mixture was stirred for 2.5 hours while keeping the temperature within the range, and acetic acid (AcOH; about 0.4 ml) was added to the reaction mixture, neutralized at 0 ° C or lower, and concentrated under reduced pressure. :-Extracted with hexane (1: 1; 80 ml x 1, 40 mix 8) No target product was present in the final extract Was confirmed by TLC [Merck Kieselgel 60, thickness 0.25 mm; developing solvent:? -Hexane: ethyl acetate (1: 1)]. Match 1 ^ 'was acetic Echiru: n - hexane (1: 1) The extract Drying (MgSO _4), and after treatment with activated carbon, vacuum; ffi reduced to the set made of the US, 3R) -4 hydro Methyl xy-2,3-epoxybutanoate ([4]; 8.66 g, 90.9¾) was obtained as a dark red oil. This was used for the next reaction without further purification.

_{'H- NMR (CDC1 3, 400MHz} ) δ: 4.03-3.98 (dd,] = 3, 14Hz, 1H), 3.80 (s, 3H), 3.75 (dd, J: 3, 14Hz, 1H), 3.57 (d , J = 2Hz, 1H), 3.41-3.39 (m, 1H),

2.10 (br, 1H). Reference example 4

 Synthesis of methyl (2S, 3R) -4-hydroxy-2,3-epoxybutanoate [methyl (2S, 3R) -4-hydroxy-2,3-epoxybutanoate] compound [4]

3R, 4R) -4-Hydroxy-3-toxicoxy-dihydro-2 (3-furanone (3); 13.6 g, 50.0 mmol) in methanol (140 ml) suspended in a sodium chloride-ice bath The suspension was added, with stirring, to a solution of NaOMe in MeOH [28% (w / w) NaOMe I MeOH: 10.6 g, 55.0 ml; MeOH: 30 ml], and the temperature of the suspension was increased from -10 ° C to -8 ° C. The reaction mixture was homogenized and turned dark red in the course of this process, keeping the temperature within the range of -8 to -1 while maintaining the temperature in the range of -8 to -1. The reaction mixture was stirred for 2 hours while adding neutral acid (AcOH; about 0.3 ml) to the reaction mixture, neutralized to 0 or less, and then concentrated under reduced pressure. 30 mix 4) The absence of the desired product in the final extract was determined by TLC [Merck Kieselgcl 60, 0.25 mm thick; developing solvent: hexane: acetic acid Le. (1: 1)] was confirmed by the combined acetate Echiru extracts were dried (GS0 _4), after treatment with active charcoal, 5 crude was concentrated under reduced pressure, 3R)-4-hydroxy - 2, 3 -Methyl epoxybutanoate ([4]; 6.22 g, 94.1%) was obtained as a dark red oil. This was used for the next reaction without further purification. Example 1.

Synthesis of (2S, 3-4-hydroxy-2,3-epoxybutanoic acid sodium [sodium (2S, 3R) -4-hydroxy-2, 3-epoxybutanoate] compound [5] 5—Λ, C ( ¾N _a

OH

 [Five]

 [Four]

Stir in a solution of the crude US, 3R) -4-hydroxy-2,3-epoxybutanoate methyl ([4]; 17.4 g, 132 mmol) in MeOH (20.0 ml) cooled in a sodium chloride mono-ice bath. Meanwhile, a solution of NaOH (5.80 g, 145 mmol) in MeOH (40.0 mi) was added dropwise over 45 minutes. A yellow-white solid precipitated as the mixture was dropped, and the reaction mixture became heterogeneous. After completion of the dropwise addition, the mixture was stirred under ice cooling for 6 hours, and IPE (240 ml) was added to the obtained yellow heterogeneous reaction mixture. After standing in a freezer (−12 ° C.), the precipitated solid was collected by filtration. The resulting solid was washed once with IPE, and the remaining solvent was pressed well to remove. The obtained solid was dried under reduced pressure at 40 for 4 hours to obtain sodium 5, -5-hydroxy-2,3-epoxybutanoate ([5]; 18.73 g, quantitative) as a pale yellow solid. Was.

_{'' H- NMR (D 2 0} , 400MHz) δ: 3.84-3.80 (m, 〗 H), 3.51-3.47 (m, 1H ), 3.2 4 (dd, J = 2, 4Hz, 1H), 3.12-3.08 (m, 1H); [a] _D ²⁵ 14.22 (c 0.900, 0).

Example 2

 (2R, 3S) -2-Amino-3,4-dihydroxy-butanoic acid sodium (sodium (2R, 3S

5) Synthesis of 2-ammo-3, 4-di ydroxybutanoate] compound [6]

A homogeneous mixture of sodium (2S, 3R) -4-hydroxy-23-epoxybutanoate ([5]; 18.73 g 133.7 mmol) and aqueous ammonia (210 ml) was heated at 55 for 61 hours with stirring. After cooling, the resulting dark red reaction mixture was concentrated under reduced pressure, McOH was added to the resulting viscous residue, and the mixture was concentrated under reduced pressure. The crude 2R> 3S) -2-amino-3,4-dihydroxy-butanoate sodium [6] was obtained as a dark red viscous oil. This was used for the next reaction without further purification as a target of 133.7 mmo [6]. Example 3

 _ 2R. 3S) -2- (Λbenzyloxycarbonyl) amino-3-4-dihydroxy-butanoic acid [(2R, 3S) -2- (iV-benzy 1 oxycarbony 1) amino-3, 4-d ihydroxybutanoic ac id] Synthesis of compound [7]

HO

(Cbz = α¾α¾Ρ1ι)

Ice-cooled (2R.3S) -2-amino-3,4-dihydroxy-sodium butanoate

Aqueous solution (110 ml) of; ([6] 129. lmmol) and NaHCO ₃ and (14.1 g 167.8 mmol), with stirring, base chloroformate Njiru; was added dropwise (Cbz-Cl 95% 26.6g 148.5 mmol) . The reaction mixture was stirred while slowly warming to room temperature. After further stirring at room temperature, water (100 ml) was added to the reaction mixture, and the precipitate was removed by filtration. Was. The residue was washed several times with water (50 ml in total), and the filtrate and the washing solution were combined. The combined filtrate and washings were washed with IPE (50 mix 3) and toluene-ethyl acetate (1: 1; 100 ml XI) to remove low polar reaction by-products. The water calendar was adjusted to PH2 with a 2.0M aqueous solution and concentrated under reduced pressure to obtain a dark brown syrup. Toluene (100 ml) was added to the syrup, the mixture was concentrated under reduced pressure, and the remaining water was distilled off by azeotropic dehydration. This procedure was repeated twice to obtain TLC pure (2,3S) -2-(//-benzyloxycarbonyl) amino-3,4-dihydroxy-butanoic acid [7]: R f 0.10; TLC [Merck ieselgel 60, thickness 0.25 mm; developing solvent: CHCl ₃ -MeOH (3: 1)]. It contained the inorganic salt NaC1, but was used in the next reaction without further purification as 129.1 bandol ol [7]. Example 4

(3R, 4S) -Dihydro-3--benzyloxycarbonyl) amino-4-hydroxy-2 (3H) -furanone [(3R, 45) -di'hydro-2- (A ^r -benzyloxycarbonyD ammo-4- hydrox y-2 (JH) -iuranone] Synthesis of compound [8]

Ice-cooled crude (2R, 3S) -2- (W-benzyloxycarbonyl) amino-3,4

A mixture of -dihydroxy-butanoic acid ([7]; 129.1 mmol) and MeOH was stirred and mixed with chlorotrimethylsilane (Me ₃ SiCl; TMS-C1; 16.6 m cf 0.856, 130 mmo).

1) was slowly added dropwise. After completion of the dropwise addition, the obtained reaction mixture was stirred at room temperature overnight. The insolubles were filtered off using Hyilo Super-Cel, and the insolubles were washed with MeOH (x 3). The filtrate and the washings were combined and concentrated under reduced pressure to obtain a dark red syrup. this is Crystallized upon standing at room temperature. The syrup containing the crystals was suspended in THF (200 cil), p- toluenesulfonic acid monohydrate _{(p- TsOH ■ H 2 0;} 0.24 g 1.26 mmol) was added at room temperature. The reaction mixture was stirred under reflux for 3 hours while heating. Furthermore; ^ TsOH · H _z 0 a (0.72 g 3.79 mmol) was added and stirring was continued 3 hours stirring under reflux. The solvent THF was distilled off under normal pressure to obtain a red syrup. This also crystallized when cooled to room temperature. The syrup containing the crystals was partitioned between acetic acid Echiru (350 ml) and saturated N'aHC0 ₃ solution (i0 0 mi). The separated aqueous layer was extracted with ethyl acetate (50 mix 3). Combining the acetic acid Eteru layer and extracts were washed with saturated aqueous NaCl (XI), dried (igS0 _4), to give an orange solid residue was concentrated under reduced pressure (34.8 g). This was dissolved in IPA (40 mi) under heating, allowed to cool while stirring for 1 minute, and IPE (200 ml) was added to precipitate crystals. After standing in a freezer (-12 V), the precipitated crystals were collected by filtration. After washing once with the mother liquor, it was dried under reduced pressure at 45 at 5.5 hours for,) -dihydro-3-(. 'Y-benzyloxycarbonyl) amino-4-hydroxy-2 (3B-furanone [8] Was obtained as almost white crystals [14.59 g; methyl (2S, 3R) -4- · hydroxy-2,3-epoxybutanoate as a total yield of 4 steps, 45.0%].

Ή-NMR (CDCh, 400ΜΗζ) δ: 7.40-7.20 (m, δΗ), 5.50 (m, ΊΗ), 5.14 (s, 2Η), 4.65 (m, 1Η), 4.50 (m, 1H), 4.35 (m , 2H), 2.88 (m, ΓΗ); _0- ° -40.79 (c 1.00, MeOH) ₀ Example 5

(3R, 4S) -Dihydro-3-(/ ^ benzyloxycarbonyl) -amino-4-hydroxy-2-fuhno [(3R, 4S) -d ihydr 0-2- (iY-benzy 1 oxycar bony 1) ami ηο-4-hydrox y-2 (J ^)-iur none] Separate synthesis of compound [8]

 [5] [8]

A homogeneous mixture of sodium (2S, 3R) -4-hydroxy-2,3-epoxybutanoate ([5]; 10.34 g. 73.8 mmol) and 28¾ aqueous ammonia (90 ml) was heated to 48-50 ° C. The mixture was stirred for 10 hours while heating. After cooling, the resulting dark red reaction mixture was concentrated under reduced pressure. _{D The} resulting viscous residue was added with water (50 ml) and concentrated under reduced pressure. Further, water (50 ml) was added thereto, and the mixture was concentrated under reduced pressure twice to obtain crude sodium (2R, 3S) -2-amino-3,4-dihydroxy-butanoate [6] as a dark red viscous oil. .

 The resulting aqueous solution of sodium (3S) -2-amino-3,4-dihydroxy-butanoate [6] and NazCOs (4.30 g, 51.1 mmol) was cooled on ice with stirring (100 mO). Benzyl acid (tbz-C1; 95¾, 13.2 g, 73.8 mmdl) was added dropwise, and the reaction mixture was stirred for 5 hours while maintaining the temperature in the range of 5 to 10. Then, IPE (20 mix 3) and toluene- After washing with ethyl acetate (1: 1; 20 mix 3) to remove low-polar reaction by-products, the organic solvent remaining in the aqueous layer was distilled off under reduced pressure, and the pH was adjusted to pH 3 with a 2.0 M HC1 aqueous solution. After adjustment, an aqueous solution of (2R, 3S) -2- (W-benzyloxycarbonyl) amino-3,4-dihydroxy-butanoic acid [7] was obtained.

This aqueous solution of [7] p-toluenesulfonic acid 'monohydrate _{(p ~ TsOH · H 2 0} ; 7.02 g, 36.9mmol) was added and stirred overnight. The resulting reaction mixture was extracted three times with ethyl acetate (100 ml, 30 ml, 30 ml). Acetate Echiru extract saturated ^N; neutralized with a ₂ C0 ₃ water, after washing with further saturated aqueous sodium chloride solution (20 mix 2), dried with MgSO _4, concentrated under reduced pressure to almost white crystals As 3R.4S) -dihydro-3- (W-benzyloxycarbonyl) amino-4-hydroxy-2 (3H) -furanone [8] [11.70 g; 5, 3R) -4-hydroxy

The total yield of three steps: 63.] was obtained from sodium -2,3-epoxybutanoate [5]. Example 6.

 (2S, 3S) -3- -benzyloxycarbonyl) amino-1,2,4-butantrio lille [(^ 5, J5) -3- (iV-benzyloxycarbonyl) amino-l, 2, 4-bu i ne trioi] The synthesis of 匕

(3R, 4S) -dihydro-3- (Λ'-benzyloxycarbonyl) amino-4-hydroxy-2 (3Η) -furanone [8] (7.00 g, 27.9 minol), sodium borohydride (2.00 g, A mixture of 55.8 mmol) and THF (112 ml) was heated with stirring to 50. MeOH (22.4 ml) was slowly added dropwise while maintaining the temperature of the mixture from 50 "C to 55. The first 10 The mixture was added dropwise in 100 minutes and the rest in 15 minutes, and then stirring was continued for 1 hour while maintaining the temperature of the mixture at 50. At this point, the raw material (3R, 4S-dihydro-3) was added. - (// - benzyl O butoxycarbonyl) Amino - 4-hydroxy - 2 (3W - loss TLC [Merck Kieselgel 60 of furanone [8], 0.25 thickness腦; developing _{solvent: CHC1 3 - Me OH (10} : After cooling, a 10¾ methanol solution of hydrochloric acid (Tokyo Kasei; 50 ml) was added to the reaction mixture to adjust the pH to 2. The mixture was concentrated under reduced pressure, and the residue was concentrated. Partitioned between ethyl acetate (300 ml) and water (15 ml) The ethyl acetate layer was washed with water (5 ml) The combined aqueous layer and wash water were extracted with ethyl acetate (4D ml) the. acetic E Chi le extracts combined with acetic Echiru layer, dried (MgSO ₄₎ and concentrated in vacuo to give a solid (7.10 g). of these 6.60 g of acetate Echiru (90 ml) and MeOH (10 ml 2/3 of the solvent was distilled off under reduced pressure to precipitate crystals, and the concentrated solution was diluted with ethyl acetate (30 ml), and the precipitated crystals were collected by filtration. ¾ | Washed with ethyl acetate (20 ml) and dried to obtain the first crystal (4.08 g) of 2S, -3- (W-benzyloxycarbonyl) amino-1,2,4-butanetriol [9]. Was. Ethyl acetate-I IPE (1: 1; 40 ml) was added to the concentrated mother liquor, followed by cooling. The precipitated crystals were collected by filtration, washed with ethyl acetate (2D ml), and dried to give the second crystal [9] (0.55 g); total yield of [9]: 4.63 g (70.0).

'H-N ^T MR (CDCi ₃ , 400MHz) δ 7.40-7.0 (m, 5H), 5.07-5.10 (m, 3H), 3.74-3.61 (m, 7H), 3.56-3.53 (m, 2H) [A] _D ^Z0 12.19 (C 1.00, C 0H).

Example 7

 (2S, 3S) -3- (Λ'-benzyloxycarbonyl) amino-1,2,4-butanetriol [(2S, 55) -3- (iY-benzyloxycarbonyl) amino-l, 2, 4- butane iol] compound

Separate synthesis of [9]

(3R, 4S) -dihydro-3- (iY-benzyloxycarbonyl) amino-4-hydroxy-2 (addition-furanone [8] (6.50 g, 25.9 mmol), sodium borohydride (3.91 g, 103 mmol) ) And ¹ MeOH (130 m]), calcium chloride (5.74 g, 51.7 mmol 1) was added under ice-cooling while maintaining the internal temperature at 30 C. After stirring at room temperature for 4 hours, the raw material [8] loss TLC [Merck Kieselgel 60> thickness 0.25 ram; developing _{solvent: CHC1 3 - MeOH (1 0} : 1)]. confirmed after cooling, 10¾ hydrochloric methanol solution to the reaction mixture (Tokyo Kasei; 80 ml) The resulting mixture was concentrated under reduced pressure, saturated brine (100 ml) was added to the concentrated solution, and the mixture was extracted three times with ethyl acetate (200 ml, 200 ml, 100 ml). washed with water (100 ml), dried (MgSO _4), and concentrated in vacuo to give a solid (5.85 g). this solid acid Echiru (24m addition,攪under reflux After stirring, IPE (24 ml) was added, and the mixture was gradually cooled and crystals were precipitated at 5 ° C. The crystals collected by filtration were washed with IPE (12 m), dried, and dried to obtain 4.78 g of [9]. 72.3¾) obtained. Example 8

 (2S, 3S) -3-(-(W-benzyloxydicarbonyl) amino-), 2- £> ~ isopropylidene-1,2, —4-butanetriol [5, J5) -3- (iY- bcnzy! oxycarbony 1) Synthesis of amino-l, 2-0 -isopropylidene-1, 2, 4-butantriol] compound [10]

A stirred solution of i2S, 3S) -3- (iV-benzyloxycarbonyl) amino-1,2,4-butanetriol [9] (11.85 g, 46.4 mmol) in acetone (178 ml) was added at room temperature. p-Pyridinium monotoluenesulfonate (PPTS; 1.17 g, 4.64 to 01) was added, and the mixture was stirred for 24 hours. After concentration under reduced pressure at 30 or less, the solvent acetone was distilled off, and the residue was dissolved in toluene (300 ml). This solution, saturated brine (10Q ml), 1%. HC1 aqueous solution (100 ml), 10¾ NaHC0 ₃ aqueous (100 ml), then with saturated brine (100 ml), dried (M gS0 _4), The mixture was concentrated under reduced pressure to obtain crude -3-(^ benzyloxycarbonyl) amino-1,2-0 "isopropylidene-2,4-butanetriol [10] (13.70 g, 99.9¾). This was used for the next reaction without further purification.

_{'H-NMR (CDC1 3 400MHz} ) δ: 7.36-7.2 6 (m, 5H), 5.38 (. Brd d, 1-4H z, 1H), 5.10 On, 2H), 4.3-4.2 (m, 1H), 4.1-4.0 On, 1H), 3.9-3.8 (m, 2H), 3.75-3.6 On, 2H), 2.42 (brd. S, 1H), 1.42 (s, 3H), 1.34 (s, 3H). Example 9

(2S.3R) -3- (W-benzyloxycarbonyl) amino-1,2-0-isopropylidene-4 -phenylthio-1,2-butanediol [(, Ji?)-3-(^ -benzyloxycarbonyl) am ino-1, 2- (9-isopropyl i dene-4-phenyl ihio-], 2-buiai] edioi] .Synthesis of compound [11]

hill

 Stirred (25,) -3-(//-benzyloxycarbonyl) amino-1,2- ^ isopropidylpyridene-1,2,4-butanetriol [10] (11.2 g, 37.9 recited 01) in toluene Triethylamine (7.92 ml, d = 0.728, 56.9 mmol) was added to the solution (80 ml), and the mixture was cooled to 4 ° C. Methanesulfonyl chloride (3.52 ml, d = 1.48, 45.δ mmol) was added dropwise to the mixture at 5 to 10 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. The mixture was diluted with toluene (50 ml) and ethyl acetate (100 ml), washed with water (50 ml), 0.5M aqueous solution of citric acid (50n), saturated aqueous NaHC03 (50 ml) and saturated saline (50 ml), and dried. (MgSO 4, followed by drying under reduced pressure to obtain white crystals (15.lg).

 The crystals were dissolved in DMF (100 ml), potassium carbonate (10.47 g, 75.8 inmol) was added, and the mixture was cooled (10 ° C) with stirring. PhSH (3.89 ml, d = 1.073, 37.9 mmol) was added to the heterogeneous mixture, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with toluene (200 ml), water (100 ml), saturated aqueous potassium carbonate solution (50 ml), saturated saline (50 ml), 0.5 M aqueous solution of citric acid (50ral), saturated aqueous NaHCOs (50 ml), and saturated sodium chloride water

(50 ml), and dried (MgSO 4, dried under reduced pressure) (2S, 3R) -3- (Λ'-benzyloxycarbonyl) amino-1,2-ί-isopropylidene-4-phenylthio- The 1,2-butanediol [11] was obtained as crude white crystals (13.90 g, 94.6 mg), which was used for the next reaction without further purification.

'H— NMR (CDCi ₃ , 400ΜΗζ) δ 7.40-7.10 On, 10H), 5.10 (m, 2H), 5.0

(m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 1H), 3.9-3.6 On, 2H), 3.30-3.18 (m, 2H), 1.39 (s, 3H), 1.28 ( [] _ΰ ^1α -70.69 (C 1.00, C 0H). Example 1 p

 (2S, 3R) -3-(W-benzyloxycarbonyl) amino-4 -phenylthio -1.2-butanediol [5, 3R) -3- (/ -benzy 1 oxycar ony 1) ami ηο- 4-pheny 1 th i ol, 2-butanediol] Synthesis of compound [12]

MeO of stirred US, 3-3- (W-benzyloxycarbonyl) amino-], 2- ^ isopropidopyridene-4-phenylthio-1,2-butanediol [11] (15.17 g, 39 mmol) 0.1 IN HCM (32 ml) was added to the H solution (120 ml), and the mixture was stirred with SO 2 for 1.5 hours. The disappearance of the raw material [11] was confirmed by TLC [Merck Kieselgel 60, thickness 0.25 mm; developing solution: CHCl ₃ -MeOH (10: 1)], and the mixture was concentrated under reduced pressure. 100 ml) and water (50 ml), and extracted with ethyl acetate (250 ml, 100 ml). The combined acetate Echiru extract was washed with saturated brine (50 ml), dried (MgSO ₄₎ after, and concentrated under reduced pressure, the crude (2S, 3 R) -3- ( W- benzyl O alkoxycarbonyl) Amino - 4-Phenyltheo-2-butanediol [12] (13.10 g) ′ was obtained. Ethyl acetate (55 ml) was added to this and dispersed under heating to reflux. The mixture was allowed to cool while stirring, and hexane (i30mi) was added to precipitate crystals. After cooling to 5 ° C, the precipitated crystals were collected by filtration. The crystals were washed with hexane (40m!), Dried by blowing air at 50, and dried with (2S, 3-3-benzyloxycarbonyl) amino-4-phenylthio-1,2-butanediol. White crystals of [Ni] (10.7 g, 78.7 78) were obtained.

_{• H-NMR (CDC1 3,} 400MHz) δ: 7.40-7.10 (m, 10H), 5.20 (m, 1H), 5.10 (m, 2H), 3.84 (in, 1H), 3.67-3.60 (m, 2H) , 3.49 (m. 1H), -3.39-3.22 (in, 2 H), 3.18-3.14 On, 1H) , 2.68 (d, J = 5Hz, 1H);. [] D 20 -81.41 (C 1.00, CH 3 0 H> Example 1 1

 ■ S,) -Trichloro-2-N-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylenediobutane [(2S, Ji?)-L-chloro-2-hyroxy-3--( benzyloxycar bony 1) Synthesis of mi no-4-pheny ί thiobut ane] compound [13]

 [12] [13] Ice-cooled (2S, 3rd-3- (Λ'-benzyloxycarbonyl) amino-4-phenylthio-1,2-butanediol [12] (l, 00g, 2.87MIO1) To a pyridine solution (5 ml) was added p-toluenesulfonyl chloride (0.690 g, 3.60 mmol) with stirring, and the mixture was stirred at room temperature for 24 hours.The reaction mixture was diluted with ethyl acetate (50 ml). , 2 N

HCl (30ml X 2), washed with brine (30iul), dried GMgS0 ₄₎ after, and concentrated under reduced pressure, the crude (2S, 3R) - 1-black port - 2-hydroxy - 3- N-(Benzyl Methoxycarbonyl) amino-4-phenylbutane ([13], 1.05 g) was obtained. This was dissolved in CH ₃ CI (5 ml) with heating under reflux, allowed to cool with stirring, and hexane (5 ml) was added to precipitate crystals. After cooling to 5T :, the precipitated crystals were collected by filtration. Hexane crystals

(13 ml), and dried by blowing air at 50 ° C for 10 minutes to obtain [13] as white crystals (0.44 g).

_{'H-NMR (CD 3 0D} , 400ΜΗζ) δ: 7.40-7.10 (m, 10H), 5.13, 1H), 5.00 (s, 2H), 3.98-3.88 (m, 2H), 3.70-3.54 (m, 2H ), 3.28 (d, J- 4Hz, 2H), 2.9 2 (m, 1H); [a] D 20 -64.6 (C 1.00, CH 3 0H); mp 103- 105 ".. - The mother liquor was condensed and purified by preparative TL C [Merck Kieselgel 60, thickness 2 Mar .; developing solvent: hexane-ethyl acetate (2: 1)] to give [13] as orange-white crystals. Total yield of [13] M: M.74 g (70.5 0.74 g of [13] (70.5) was obtained.

 (2S, 3 -trichloro-2-hydroxy-3- N- (benzyloxycarbonyl) amino-4 -phenylthiobutane i (2S, 5i?)-L-chloro-2-hyroxy-3-N Separate synthesis of-(benzyloxycarbonyl) ami ηο-4-pheny 1 thiobutane] compound [13]

Ice-cooled (2S, 3rd-3- (Λ'-benzyloxycarbonyl) amino-4-funinylthio-1,2-butanediol [12] (1.00 g, 2.87 mmol) in ethyl acetate (20 ml) To this mixture, triethylenediamine (DABCO: 0.64 g, 5.74 mmol) was added with stirring, and then toluenesulfonyl chloride (0.575 g, 3.01 mmoloL, 1.05 equivalent) was added to the mixture at 10. After 2 hours and 24 hours, toluene sulfonyl chloride was added at 0.1 l'09 g (0.574 mniol. 0.2 eq.) And 0.273 g (! .43 5 mmol 0.5 eq.), Respectively, for a total of 31 hours. stirring was continued. the reaction mixture was added acetic acid E Ji Le (30 mi) was added to the washed with 2 N HC1 (30 mix 2) and saturated brine (30MI), dried (MgSO _4), and concentrated in vacuo to crude [13] (1.70 g) was obtained by silica gel column chromatography (Daiso-gel IR-60, hexane). : Ethyl acetate 4: 1) to give [13] (0.76g, 72.4¾) Industrial applicability. The production method of the present invention is a very simple method compared to the conventional method. The compound (X) is effectively obtained in good yield, and is useful as an intermediate of a compound having HIV protease inhibitory activity (a compound (X)).

Claims

 The scope of the claims

1. (2S, 3R)-4-hydroxy 'Ζ, 3-epoxybutanoic acid derivative represented by the general formula [11]:

 [II]

 (Where M is an alkali metal).

2. A method for producing a (25, 3R) -4-hydroxy-2,3-epoxyphthalic acid derivative represented by the general formula [II], comprising:

 [II]

 (Where M is Alkyri metal)

 -General formula [I]

 [I]

Wherein R ¹ is an optionally substituted alkyl group or aryl group, and the step of curing a US, 3R) -4-hydroxy-2,3-epoxybutanoic acid derivative .

3. — (R, 3S) -2-Amino-3,4-dihydroxy-butanoic acid derivative represented by general formula [III]: HO C0 ₂ M

(Where M is Alkyri metal)

4. A process for producing a (2R, 3S) -2-amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [III]: 0 ₂ M

H ₂

 [ΠΙ]

 (Where M is Alkyri metal)

General formula [11]

 ["]

 (Where M is an alkali metal)

A step of reacting 2S, 3R) -4-hydroxy-2,3-epoxybutanoic acid derivative with ammonia to open the epoxy ring of the derivative.

5. UR, 3S) -2-Amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [IV]:

 OH

HO, JL ^ C0 ₂ H

NHR ²

 [IV]

(Where R ² is an acyl- or carbamate-based amino protecting group).

6. A method for producing a (2R '3S) -2-amino-3,4-dihydroxy-butanoic acid derivative represented by the general formula [IV]:

HR ²

 [IV]

(Where R ² is an acyl- or carbamate-based amino-protecting group) General formula [III]

 OH

HO ヽ people, C0 ₂ M

NH ₂

 [in]

 (Where M is Alkyri metal)

A step of reacting a 2R, 3S) -2-amino-3,4-dihydroxy-butanoic acid derivative represented by the formula (1) with a halide or an acid anhydride corresponding to R ² .

7. (3R, 4S) -dihydro-3-amino-4-hydroxy-2 (3H) -furanone derivative represented by general formula [V]

 [V]

(Where R ² is an acyl- or carbamate-based amino protecting group).

8. A process for the preparation of a (3R, -dihydro-3-amino-4-hydroxy-2 (3H) furanone derivative represented by the general formula [V]:

 [V]

(Where R ² is an amino-protecting group of acyl or carbamide type) [IV]

 0H

H0. People 0 ₂ H

NHR ²

 [IV]

(Where R ² is an acyl- or carbamate-based amino-protecting group) lactonizing (2R, 3S) -2-amino-3,4-dihydroxy-butanoic acid derivative in the presence of an acid catalyst A method comprising the steps of:

9. (2S'3S) -3-amino-1,2,4-butanetriol derivative represented by the general formula [VI]:

(Where R ² is an acyl or carbamate amino protecting group).

1 0. —A method for producing a 2S, 3S) -3-amino-1,1,4-butanetriol derivative represented by the general formula [VI]:

(Where R ² is an acyl or carbamate amino protecting group)

 [V]

Wherein R ² is an amino-protecting group of the acyl or carbamate type, including the step of reducing the derivative of 3R, 4S-dihydro-3-amino-4-hydroxy-2 (-furanone derivative , Method.

1 1. (2S, 3S) -3-Amino-1, 2-0 "isopropylidene-'ι, 2,4-butanetriol derivative represented by the general formula [VII]:

 [VII]

(Where R ² is an acyl-based or carbamate-based amino-protecting group, and R ³ and R ⁴ may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or a cycloalkyl group wherein R ³ and R ⁴ together with adjacent carbon atoms form a ring).

1 2. — (2S, 3S) -3-Amino-1,2_0 ~ isopropylidene-1, represented by the general formula [Y1I]

A process for producing a 2,4-butane.triol derivative, comprising:

 [VII]

(Where R ² is an acyl or carbamate amino protecting group; R ³ and And R ⁴ '4 may be the same or different and each represents a hydrogen atom, an optionally substituted alkyl group or an aryl group, or a ring in which R ³ and R ⁴ are taken together with adjacent carbon atoms. Is a cycloalkyl group)

General formula [VI]

NHR ²

(Where R ² is an acyl- or carbamate-based amino-protecting group) represented by (2S, 3S) -3-amino 1,2,4-butanetriol derivative in the presence of an acid catalyst or with an acid catalyst. A method comprising reacting an acetalizing agent in the presence of a dehydrating agent to protect the 1,2-diol group of the derivative.

1 3. —US, 3R)-3-amino-1,2-0> isopropylidene-4 represented by general formula [VIII]

-Mercapto-1,2-butanediol derivative:

 [VIII]

(Where R ² is an acyl-based or carbamate-based amino-protecting group, and R ³ and may be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group, Alternatively, R ³ and R ⁴ are a cycloalkyl group which forms a ring together with adjacent carbon atoms, and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl A substituted or unsubstituted aryl group or an optionally substituted aralkyl group).

4. A process for the preparation of a (2S, 3-3-amino-3-amino-2-isopropylidene-4-diol derivative of the formula [VI 11], comprising:

 [VIII]

(Where R ² is an acyl- or carbamate-based amino-protecting group, and R ³ and R ⁴ may be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or R ³ and R ⁴ are a cycloalkyl group formed together with adjacent carbon atoms to form 澴, and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted A good alkenyl group, an optionally substituted aryl group or an optionally substituted aralkyl group)

 General formula [VII]

(Where R ² , R ³ and R ⁴ are the same as above)

 Reacting a (2S, -3-amino-1,2-0 "isopropylidene-1,2,4-butanetriol derivative with a halogenizing agent or a sulfonylating agent, and the resulting halogen Derivatives or sulfonylation derivatives

R ⁵ SH

(Where R ⁵ is the same as above)

And thioetherification by reacting with mercaptan.

1 5. — ^ A process for producing a (2S, 3R) -3-amino-3-mercapto-1,2-butanediol derivative represented by the formula [IX]:

(Where R ² is an acyl- or carbamate-based amino-protecting group, and R ^s is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group Or an aralkyl group which may be substituted)

General formula [VI II]

 [VIII]

(Where R ² and R ^s are the same as above, and R ³ and R ⁴ may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group, Or R ³ and R ⁴ are a cycloalkyl group which forms a ring together with adjacent carbon atoms)

 A process comprising hydrolyzing a 2S, 3R) -3-amino-1,2- 1, λ-isopropylidene-4-mercapto-1,2-butanediol derivative represented by the formula (1) in the presence of an acid catalyst.

16. A method for producing a 5,)-cyclohex-2-hydroxy-3-amino-4-mercaptobutane derivative represented by the general formula [X]:

(Where R ² is an acyl-based or carbamate-based amino protecting group, and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group. Group or aralkyl group which may be substituted)

General formula [IX]

(Where R ² and R ⁵ are the same as above)

(2S.3R) -3-Amino-.3-mercapto-1,2-butanediol derivative is reacted with a sulfonylating agent to selectively chlorinate only the primary hydroxyl group of the butanediol derivative. A method comprising the steps of: