CN1753898A - Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof - Google Patents

Abstract

A process for efficiently producing compound (XIV) being useful as a drug intermediate on an industrial scale at low cost without the need to use ozonization and highly toxic agents; and an intermediate for use in the process. In particular, a process for producing a compound having the absolute configuration of the formula (XV) or an enantiometric isomer thereof without the need to use means such as optical resolution; and an intermediate for use in the process. (1) Compound (XIV) is produced by deriving compound (I) from compound (XIII) as a starting material and sequentially performing introduction of a protective group, reduction and cyclization. Particularly, compound (XIV) is produced by deriving compound (I) through compound (XX) from compound (XIII) as a starting material. Compound having the absolute configuration of the formula (XV) or the like is produced in high stereoselectivity from optically active compound (XIII) as a starting material. (2) Compound (XXVI) is produced by deriving compound (XXII) from compound (XXI) as a starting material through stereoselective reduction thereof and sequentially performing introduction of a protective group, reduction and cyclization. Compound (XV) is produced by inverting hydroxyl of the compound (XXVI). (1) (2) wherein symbols are as defined in the description.

Description

Preparation method of hexahydrofuranofuran alcohol derivatives, intermediates and preparation method thereof

technical field

The present invention relates to the following formula (XIV) as a drug intermediate, especially the preparation method of hexahydrofurofuran alcohol derivatives shown in the following formula (XV), and the following formula ( Compounds shown in A), (B) and (C) and their preparation methods.

Background technique

Formula (XIV):

In particular formula (XV):

The compounds shown are compounds useful as intermediates of anti-AIDS drugs (see International Publication No. 01/25240 pamphlet and International Publication No. 99/67254 pamphlet). Known methods for synthesizing compounds represented by formula (XIV) or (XV) include: International Publication No. 01/25240 pamphlet, European Patent Application Publication No. 539192 Specification, Tetrahedron Letters, Vol. 27, p3715 (1986) and The method described in Tetrahedron Letters, Volume 4, p505 (1995), in which ozone oxidation or highly toxic tributyltin hydride, etc. are used, cannot be said to be an industrially preferred method. In addition, among the above-mentioned documents, International Publication No. 01/25240 Handbook, European Patent Application Publication No. 539192 Specification and Tetrahedron Letters, Vol. 4, p505 (1995) describe that the obtained racemate is processed by enzymes or the like. Optical resolution is very inefficient to obtain an optically active compound represented by the formula (XV) in relative stereo configuration. Recently, Tetrahedron Letters, volume 42, p4653 (2001) published a method for directly synthesizing an optically active compound represented by formula (XV) in relative stereo configuration. This method also uses highly toxic organoselenium compounds, and it is difficult to say This is an industrial method.

Contents of the invention

The purpose of the present invention is to solve the problems of the existing preparation methods such as the use of ozone oxidation or toxic reagents, to provide efficient and industrial scale, low-cost preparation of the formula (XIV) useful as an intermediate of anti-AIDS drugs The method for showing the compound (hereinafter also referred to as compound (XIV)), and the intermediate used in the method and the preparation method thereof, especially provide the method for preparing the compound having the absolute stereostructure shown in formula (XV) without using methods such as optical resolution. A method for compound (XIV) and its enantiomers, intermediates used in the method and methods for their preparation.

The present inventors have carried out in-depth research to solve the above-mentioned problems, and as a result, have found a novel preparation method of compound (XIV) and an intermediate of the method-a novel compound shown in formulas (A) and (B), wherein the compound (XIV) ) is formula (XIII):

[In the formula, _PG represents a protecting group for a hydroxyl group, and _R represents a lower alkoxy group or a lower alkylthio group. ] shown compound as starting material, it is converted into formula (I):

[wherein, _PG represents the same meaning as above], and then introduce a protecting group into the compound, followed by reduction and cyclization to obtain compound (XIV). In addition, the present inventors have also discovered a novel preparation method of compound (XIV) and an intermediate of the method—the novel compound shown in the following formula (C), wherein, the novel preparation method of compound (XIV) is: ) shown compound is starting material, it is converted into formula (XIX):

[In the formula, _PG and _R2 represent the same meaning as above, and _R3 represents a protecting group of a hydroxyl group or a hydrogen atom. ] The compound shown in ] is hydrolyzed again, via formula (XX):

[wherein, _PG and R ₃ represent the same meaning as above. ], it is converted into the intermediate of the above method---compound shown in formula (I) or formula (III):

[wherein, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. ] The compound shown.

According to the method of the present invention, compound (XIV) can be efficiently produced on an industrial scale at low cost without using highly toxic reagents or ozonation, which is difficult to implement on an industrial scale. And, according to the use of BINAP catalyst or biocatalyst (USP5399722, Heterocycles, 26, 2841 (1987)), the fact that the compound shown in the formula (XIII) can be produced at low cost and on an industrial scale, the inventors have found that: In particular, the compound represented by the formula (XIII), which is an optically active body with high optical purity, is used as a starting material to implement the above method, without using methods such as optical resolution, and can be converted into a compound with high optical purity and absolute stereoselectivity with high stereoselectivity. Type by formula (VII):

[wherein, _PG represents the same meaning as above. ] represented by the compound or its enantiomer, and further the absolute stereoconfiguration of the compound represented by the formula (VII) or its enantiomer is highly stereoselectively converted into a good optical purity, the absolute stereoconfiguration by the formula The compound represented by (XV) or its enantiomer has completed the present invention.

In particular, it has been found that, in the process of the present invention via the carboxylic acid represented by the above formula (XX), purifying via the carboxylic acid can increase the diastereoisomeric purity and obtain optically pure Well, with formula (XVIII):

[wherein, _PG and R ₃ represent the same meaning as above. ] shown in the absolute stereoconfiguration compound or its enantiomer, and the compound with the absolute stereoconfiguration shown in the formula (XVIII) or its enantiomer high stereoselectivity is converted into optically good, absolute The compound represented by the formula (XV) or its enantiomer in stereo configuration has completed the present invention.

Since the present invention does not use ozone oxidation or highly toxic reagents, it is not only a useful preparation method for optically active bodies, but also superior to conventional methods as a racemate preparation method.

In order to solve the above-mentioned problems, the present inventors made further in-depth research, and found a new preparation method and intermediates of compounds with relative stereo configurations shown in formula (XV)-having relative stereo configurations shown in formulas (G) and (H) described later. The novel compound of configuration, wherein the preparation method of the novel compound with the relative stereo configuration shown in said formula (XV) is as follows: with formula (XXI):

[wherein, _PG2 represents a protecting group for a hydroxyl group. ] shown compound (hereinafter may be referred to as compound (XXI)) as starting material, through stereoselective reduction, it is converted to have formula (XXII):

[wherein, P _G2 represents the same meaning as above. ], the compound with the relative stereoconfiguration shown in ] is then introduced into a protecting group, reduced and cyclized to obtain formula (XXVI):

The compound having the relative stereoconfiguration shown in the formula (XV) can be obtained by inverting the hydroxyl group.

Also found: according to the method of the present invention, without using highly toxic reagents or ozone oxidation that is difficult to implement on an industrial scale, the compound having the relative stereoconfiguration shown in formula (XV) can be prepared efficiently and at low cost on an industrial scale, In particular, the compound having the relative stereo configuration represented by the formula (XV) and its enantiomer have completed the present invention.

That is, the present invention is as follows.

(1) Compound shown in formula (A):

[In the formula, R and _R are independently, identical or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing a group shown in the following formula:

(In the formula, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group.). Wherein, when R ₁ is a hydrogen atom, R is a protecting group of a hydroxyl group, and the relative stereo configuration of the compound shown in formula (A) is cis, R represents a protecting group of a hydroxyl group other than benzyl. ].

(2) Compound shown in formula (B):

[In the formula, R and _R are independently, identical or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing a group shown in the following formula:

(In the formula, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group.)].

(3) The compound of the above (1), wherein the relative stereo configuration is shown in formula (D):

[In the formula, R and _R1 have the same meaning as the above (1). ].

(4) The compound of the above (2), wherein the relative stereo configuration is shown in formula (E):

[In the formula, R and _R1 have the same meaning as the above-mentioned (2). ].

(5) The compound of (1) above, which is a compound represented by formula (D) in absolute stereo configuration or an enantiomer thereof.

(6) The compound of (2) above, which is a compound represented by the formula (E) in absolute stereoconfiguration or an enantiomer thereof.

(7) The compound of (1), (3) or (5) above, wherein R ₁ is a hydrogen atom and R is a tert-butyl group.

(8) The compound of any one of the above-mentioned (1)-(6), wherein R and _R together represent the formula:

The group shown, where R ₄ and R ₅ are methyl groups.

(9) The compound of any one of the above-mentioned (1)-(6), wherein R is benzyl or tert-butyl, and R is ₁ -ethoxyethyl or 3,4,5,6-tetrahydro- 2H-pyran-2-yl.

(10) The compound of (3) or (5) above, wherein R ₁ is a hydrogen atom and R is a benzyl group.

(11) Compounds or salts thereof represented by formula (C):

[In the formula, R, R ₁ and R ₃ are independently, the same or different, and represent a protecting group of a hydroxyl group or a hydrogen atom, and R ₆ represents a hydroxyl group, a lower alkoxy group or a lower alkylthio group. ]

(12) The compound of the above-mentioned (11), which is represented by the formula (F) in absolute stereo configuration:

[In the formula, R, R ₁ , R ₃ and R ₆ have the same meanings as in (11) above. ] or its enantiomer.

(13) The compound of (11) or (12) above, wherein R is benzyl, R ₁ is a hydrogen atom, R ₃ is benzyl or tert-butyl, and R ₆ is hydroxy or ethoxy.

(14) The relative stereo configuration is a compound represented by formula (G):

[In the formula, _R7 and _R8 are independently, the same or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or representing the following formula together:

(In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group.) The group shown. When R ₈ is a hydrogen atom and R ₇ is a protecting group for a hydroxy group, R ₇ represents a protecting group for a hydroxy group other than benzyl. ]

(15) Compounds represented by formula (H) in relative configuration:

[In the formula, R ₇ and R ₈ are independently, the same or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing the following formula

(In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group.) The group shown].

(16) The compound of the above-mentioned (14), which is a compound represented by the formula (G) in absolute stereo configuration or an enantiomer thereof.

(17) The compound of the above-mentioned (15), which is a compound represented by the formula (H) in absolute stereoconfiguration or an enantiomer thereof.

(18) A method for preparing the compound represented by formula (I), which comprises hydroxyethylating the compound represented by formula (XIII), followed by cyclization.

(19) The production method of the above (18), wherein the compound represented by the formula (I) is a compound having the relative configuration represented by the formula (VII).

(20) The production method of the above (18) or (19), wherein the compound represented by the formula (XIII) is an optically active form.

(21) The preparation method of the above (18), wherein the compound represented by the formula (XIII) is the formula (XVI):

[In the formula, each symbol has the same meaning as the above (18). ], the compound shown in formula (I) is a compound with absolute stereo configuration shown in formula (VII); or the compound shown in formula (XIII) is the following formula:

[In the formula, each symbol has the same meaning as the above (18). ], the compound shown in formula (I) is the enantiomer of the compound with the absolute stereo configuration shown in formula (VII).

(22) The preparation method of the above-mentioned (18), the method is to hydroxyethylate the compound represented by the formula (XIII) to obtain the compound represented by the formula (XIX), and hydrolyze the compound represented by the obtained formula (XIX) to obtain the compound represented by the formula The compound represented by (XX) is prepared by cyclizing the compound represented by the obtained formula (XX) to prepare the compound represented by the above formula (I).

(23) The preparation method of the above (22), wherein the compound represented by the formula (XIII) is the compound represented by the formula (XVI), and the compound represented by the formula (XIX) has the formula (XVII):

[In the formula, each symbol has the same meaning as the above (22). ], the compound with absolute stereoconfiguration shown in formula (XX), the compound shown in formula (XX) is a compound with absolute stereoconfiguration shown in formula (XVIII), and the compound shown in formula (I) is a compound with absolute stereoconfiguration shown in formula (VII) configuration; or the compound shown in formula (XIII) is an enantiomer of the compound shown in formula (XVI), and the compound shown in formula (XIX) is a pair of compounds with absolute stereo configuration shown in formula (XVII) Enantiomers, the compound shown in formula (XX) is the enantiomer of the compound shown in formula (XVIII), and the compound shown in formula (I) is the enantiomer of the compound shown in formula (VII). Enantiomers of compounds in stereo configuration.

(24) A method for preparing the compound represented by the formula (III), which uses the compound represented by the formula (I) as a raw material.

(25) The preparation method of the above (24), the method is to deprotect the compound shown in formula (I) to obtain formula (II):

Shown compound, the compound shown in gained formula (II) is converted into the compound shown in formula (III).

(26) The preparation method of the compound shown in formula (V):

[wherein, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. ], the method is to reduce the compound shown in formula (III).

(27) A method for preparing the compound represented by the formula (XIV), which comprises deprotecting and cyclizing the compound represented by the formula (V).

(28) The preparation method of the compound shown in formula (IV):

[wherein, _PG and _PG1 are independently, the same or different, and represent a protecting group for a hydroxyl group. ], the method is to protect the hydroxyl group of the compound shown in formula (I).

(29) The preparation method of the compound shown in formula (VI):

[wherein, _PG and _PG1 are independently, the same or different, and represent a protecting group for a hydroxyl group. ], the method is to reduce the compound shown in formula (IV).

(30) A method for preparing the compound represented by the formula (XIV), which comprises deprotecting and cyclizing the compound represented by the formula (VI).

(31) A method for preparing a compound represented by formula (XIV), the method comprising any of the following steps of (1A) or (1B):

(1A) using the compound shown in formula (I) as a raw material to obtain the compound shown in formula (III), the compound shown in the obtained formula (III) is reduced to obtain the compound shown in the formula (V), and the obtained formula (V ) deprotection and cyclization of the compound shown in ) to obtain the steps of the compound shown in formula (XIV);

(1B) protect the hydroxyl group of the compound shown in the formula (I), obtain the compound shown in the formula (IV), by reducing the compound shown in the formula (IV) obtained, obtain the compound shown in the formula (VI), the formula (VI obtained) ) deprotection and cyclization to obtain the compound shown in formula (XIV).

(32) The preparation method of the above (31), wherein in step (1A), the compound represented by the formula (I) as a raw material is deprotected to obtain the compound represented by the formula (II), and the obtained compound represented by the formula (II) is The compound is converted into a compound shown in formula (III).

(33) The preparation method of the above-mentioned (31) or (32), wherein the compound represented by formula (I) is a compound having a relative stereo configuration represented by formula (VII), and the compound represented by formula (XIV) is a compound having a formula (XV) ) The compound with the relative stereo configuration shown.

(34) The preparation method of the above-mentioned (31) or (32), wherein the compound represented by the formula (I) is a compound having the absolute relative stereo configuration represented by the formula (VII), and the compound represented by the formula (XIV) is a compound having the formula ( The compound of absolute stereoconfiguration shown in XV); Or the compound shown in formula (I) is the corresponding isomer of the compound with absolute relative stereoconfiguration shown in formula (VII), and the compound shown in formula (XIV) is having formula Enantiomers of the compound of the absolute stereoconfiguration shown in (XV).

(35) A method for preparing the compound represented by the formula (XIX), which uses the compound represented by the formula (XIII) as a raw material.

(36) A method for preparing the compound represented by the formula (XX), which comprises hydrolyzing the compound represented by the formula (XIX).

(37) The production method of the above-mentioned (36), wherein an organic amine is added after hydrolysis.

(38) The production method of the above (36), wherein the compound represented by the formula (XIX) is prepared from the compound represented by the formula (XIII) as a raw material.

(39) A method for preparing a compound represented by formula (III), which comprises deprotecting _PG and R ₃ of the compound represented by formula (XX), followed by acetalization or ketalization and lactonization.

(40) The production method of the above-mentioned (39), which is to use the compound represented by the formula (XIII) as a raw material to obtain the compound represented by the formula (XX).

(41) The preparation method of the compound shown in the formula (XIV), the method is to use the compound shown in the formula (XIII) as a raw material to obtain the compound shown in the formula (XIX), and the compound shown in the obtained formula (XIX) is hydrolyzed to obtain the formula The compound shown in (XX), then the _PG and _R of the compound shown in the gained formula (XX) Deprotection, then carry out acetalization or ketalization and lactonization, obtain the compound shown in the formula (III), the The compound represented by the obtained formula (III) is reduced to obtain the compound represented by the formula (V), and the compound represented by the obtained formula (V) is deprotected and cyclized.

(42) The production method of the above-mentioned (41), wherein the compound represented by formula (XIII) is a compound represented by formula (XVI), and the compound represented by formula (XIX) is a compound having an absolute stereo configuration represented by formula (XVII), The compound shown in formula (XX) is a compound with absolute stereo configuration shown in formula (XVIII), and the compound shown in formula (III) has formula (IX):

[wherein, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. ] shown in the absolute configuration of the compound, the compound shown in the formula (V) has the formula (XI):

[wherein, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. ], the compound with the absolute stereoconfiguration shown in the formula (XIV) is a compound with the absolute stereoconfiguration shown in the formula (XV); or the compound shown in the formula (XIII) is a pair of the compound shown in the formula (XVI) Enantiomers, the compound shown in formula (XIX) is the enantiomer of the compound shown in formula (XVII), the compound shown in formula (XX) has the absolute stereo configuration shown in formula (XVIII) The enantiomer of the compound of configuration, the compound shown in formula (III) is the enantiomer of the compound with the absolute stereo configuration shown in formula (IX), the compound shown in formula (V) has the formula ( The enantiomer of the compound having the absolute stereoconfiguration shown in XI), the compound shown in formula (XIV) is the enantiomer of the compound having the absolute stereoconfiguration shown in formula (XV).

(43) A method for preparing a compound having a relative stereoconfiguration represented by formula (XXII), the method comprising stereoselective reduction of the compound represented by formula (XXI).

(44) The production method of the above-mentioned (43), wherein the compound having the relative configuration represented by the formula (XXII) is a compound having the absolute configuration represented by the formula (XXII) or an enantiomer thereof.

(45) The preparation method of the compound having the relative stereo configuration shown in formula (XXIV):

[In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. ] Relative stereo configuration, the method comprises the steps of following (2A) or (2B):

(2A) using a compound having a relative stereoconfiguration shown in formula (XXII) as a raw material, simultaneously performing deprotection and introducing a protecting group to prepare a compound having a relative stereoconfiguration shown in formula (XXIV) above;

(2B) Deprotecting the compound having the relative configuration shown in formula (XXII) to obtain formula (XXIII):

The compound of the relative stereoconfiguration shown, the protective group is introduced into the obtained formula (XXIII)

The compound having the relative stereoconfiguration shown, the step of preparing the compound having the relative stereoconfiguration shown in the above formula (XXIV).

(46) A method for preparing a compound having a relative stereoconfiguration shown in formula (XXV), the method is to reduce a compound having a relative stereoconfiguration shown in formula (XXIV):

[In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. ] Relative stereo configuration Relative stereo configuration.

(47) A method for preparing a compound having a relative stereoconfiguration represented by formula (XXVI), the method comprising deprotecting and cyclizing a compound having a relative stereoconfiguration represented by formula (XXV).

(48) A method for preparing a compound having a relative stereoconfiguration shown in formula (XXVI), the method is to stereoselectively reduce a compound shown in formula (XXI) to obtain a compound having a relative stereoconfiguration shown in formula (XXII), Using the compound with the relative stereoconfiguration shown in the gained formula (XXII) as raw material, obtain the compound with the relative stereoconfiguration shown in the formula (XXIV), and reduce the compound with the relative stereoconfiguration shown in the gained formula (XXIV), The compound having the relative stereoconfiguration shown in formula (XXV) is obtained, and the obtained compound having the relative stereoconfiguration shown in formula (XXV) is deprotected and cyclized.

(49) The production method of the above-mentioned (48), wherein the compound having the relative stereoconfiguration represented by the formula (XXII) is a compound having the absolute stereoconfiguration represented by the formula (XXII), having the relative stereoconfiguration represented by the formula (XXIV) The compound of type is a compound having the absolute stereoconfiguration shown in formula (XXIV), the compound having the relative stereoconfiguration shown in formula (XXV) is the compound having the absolute stereoconfiguration shown in formula (XXV), and having the formula ( The compound of the relative stereoconfiguration shown in XXVI) is the compound with the absolute stereoconfiguration shown in formula (XXVI); or the compound with the relative stereoconfiguration shown in formula (XXII) is the absolute stereoconfiguration shown in formula (XXII). The enantiomer of the compound of formula (XXIV) is the enantiomer of the compound with the absolute stereoconfiguration shown in formula (XXIV), which has the formula (XXV) The compound showing the relative stereoconfiguration is the enantiomer of the compound having the absolute stereoconfiguration shown in formula (XXV), and the compound having the relative stereoconfiguration shown in formula (XXVI) is the enantiomer having the compound shown in formula (XXVI). An enantiomer of a compound in absolute stereoconfiguration.

(50) The production method of (43), (44), (48) or (49) above, wherein the stereoselective reduction is an asymmetric hydrogenation reaction using a transition metal catalyst having an asymmetric ligand.

(51) The production method of the above-mentioned (50), wherein the asymmetric ligand is selected from the following formulae:

or

[wherein, Ra, Rb, Rd, Re, Rh, Ri, Rj, Rk, Rl, Rm, Rn and Ro are independently, identical or different, representing phenyl or cyclohexyl that may be substituted; Rc , Rf and Rg are independent, same or different, representing a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or a phenyl group that may be substituted; l, m, n and o are independently representing an integer of 1-6. ] (the following compounds are referred to as (L1)-(L6).) and optically active phosphine derivatives of their enantiomers, using a transition metal catalyst in which the transition metal is ruthenium.

(52) The production method of the above-mentioned (51), wherein the asymmetric ligand is an optically active phosphine selected from the compounds represented by the formulas (L1), (L2), (L3), (L4), (L5) and (L6) Derivatives, and compounds with relative stereoconfigurations shown in formula (XXII) are compounds with absolute stereoconfigurations shown in formula (XXII); or asymmetric ligands are selected from formulas (L1), (L2), ( The optically active phosphine derivatives of the enantiomers of the compounds shown in L3), (L4), (L5) and (L6), and the compound with the relative stereoconfiguration shown in the formula (XXII) are those with the formula (XXII) Enantiomers of compounds of the indicated absolute stereoconfiguration.

(53) A method for producing a compound having a relative stereoconfiguration represented by formula (XV), the method comprising inverting a hydroxyl group of a compound having a relative stereoconfiguration represented by formula (XXVI).

(54) The production method of the above-mentioned (53), which comprises the following steps of (2C) or (2D):

(2C) oxidizing the compound having the relative stereoconfiguration shown in the above formula (XXVI) to obtain the compound having the relative stereoconfiguration shown in the formula (XXVII),

The step of reducing the obtained compound having the relative stereoconfiguration shown in formula (XXVII) to prepare the compound having the relative stereoconfiguration shown in the above formula (XV) relative to the stereo configuration;

(2D) reverse esterification with the compound having the relative stereoconfiguration shown in the formula (XXVI) as a raw material to obtain a compound having the relative stereoconfiguration shown in the formula (XXVIII),

[wherein, R ₉ represents an alkanoyl group in which a hydrogen atom may be substituted by a fluorine atom or a chlorine atom, or a benzoyl group in which a hydrogen atom of a phenyl group may be substituted by a nitro group, a halogen atom, an alkyl group, an alkoxy group or a phenyl group . ] Relative stereo configuration: hydrolyzing the obtained compound having the relative stereo configuration represented by the formula (XXVIII) to prepare the compound having the relative stereo configuration represented by the above formula (XV).

(55) The production method of the above (54), wherein in the step (2D), inverse esterification is carried out in the presence of triphenylphosphine or trialkylphosphine and azodicarboxylate or azodicarboxamide.

(56) The preparation method according to any one of the above-mentioned (53)-(55), wherein the compound having the relative stereoconfiguration represented by the formula (XXVI) is a compound having the absolute stereoconfiguration represented by the formula (XXVI), having the formula The compound of the relative stereoconfiguration shown in (XV) is the compound with the absolute stereoconfiguration shown in formula (XV); Or the compound with the relative stereoconfiguration shown in formula (XXVI) is the absolute stereoconfiguration shown in formula (XXVI). The enantiomer of the compound having the configuration, the compound having the relative stereoconfiguration shown in formula (XV) is the enantiomer of the compound having the absolute stereoconfiguration shown in formula (XV).

Detailed description of the invention

Compounds shown in formulas (A), (B), (C), (I)-(VI), (XIII), (XIX) and (XX) are referred to as compounds (A), (B), ( C), (I)-(VI), (XIII), (XIX) and (XX).

The three-dimensional structures of the compounds (A), (B), (C), (I)-(VI), (XIX) and (XX) of the present invention are not particularly limited, including various isomers and mixing them in any proportion mixtures and all other forms.

In addition, when referring to compounds (XIII) and (XIV), unless otherwise specified, the three-dimensional structure is not particularly limited, and includes all forms such as each isomer and a mixture of them in any ratio.

The optically active form in this specification is used in the meaning of not being a racemic form (non-racemic). For example, the optical active body also includes the following two situations: a mixture of 70% S configuration and 30% R configuration; and (S, S)-configuration 70% and (R, R)-configuration 30% mixture.

Compound (A) may, for example, be compound (I), (II), (III), or (IV). Compound (B) may, for example, be compound (V), (VI) or the like. Compound (C) may, for example, be compound (XIX), (XX) or the like.

The relative stereo configuration of the compound represented by formula (D) can be exemplified as the following formula:

或

or

[In each formula, each symbol has the same meaning as above. ] The compounds represented by ], etc.

The relative stereo configuration of the compound represented by formula (E) can be exemplified as the following formula:

or

[In each formula, each symbol has the same meaning as above. ] The compounds represented by ], etc.

The absolute stereoconfiguration of the preferred compound represented by formula (D) can be exemplified by the following formula:

Indicated compounds, etc.

The compound represented by the formula (F) in the absolute stereoconfiguration may, for example, be a compound represented by the formula (XVII) or (XVIII) in the absolute stereoconfiguration, and the preferred compound represented by the formula (F) in the absolute stereoconfiguration may be The absolute stereo configuration is exemplified as the following formula:

[In each formula, -Bn represents a benzyl group, and -t-Bu represents a tert-butyl group. ] The compounds represented by ], etc.

Salts of compounds represented by formulas (C) and (F) include, for example, bases (organic amines (such as dibenzylamine, benzylamine, dicyclohexylamine, cyclohexylamine, (S)-phenethylamine, etc.), alkali metal (such as potassium, sodium, lithium, etc.), alkaline earth metals (such as magnesium, calcium, barium, etc.), basic amino acids (such as L-phenylalanine methyl ester, glycine methyl ester, etc.), preferably with organic amines, Salts formed of alkali metals are particularly preferably dibenzylamine salts and potassium salts. Organic amines and basic amino acids may be racemates or optical isomers.

The compound represented by formula (D) in relative stereoconfiguration refers to the compound or enantiomer thereof represented by formula (D) in absolute stereoconfiguration, or the compound represented by formula (D) in absolute stereoconfiguration and A mixture of its enantiomers mixed in any proportion (including racemates).

For the compound represented by the formula (E), the compound with the relative stereoconfiguration shown in the formula (VII), the compound with the relative stereoconfiguration shown in the formula (XV), etc., all represent the above-mentioned relative stereoconfiguration The configuration has the same meaning as in the compound represented by the formula (D).

Formulas (A), (B), (C), (D), (E), (F), (I), (IV), (VI), (VII), (X), (XII), ( In XIII) and (XVI)-(XX), the protective groups for the hydroxyl group represented by R, R ₁ , R ₃ , _PG and _PG1 include benzyl, tert-butyl, 1-ethoxyethyl, 3 , 4,5,6-tetrahydro-2H-pyran-2-yl, trityl, 1-methoxy-1-methylethyl, methoxymethyl, ethoxymethyl, trityl Ethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, etc., wherein R and _PG are preferably benzyl, tert-butyl, trityl, and R and _PG are preferably ₁ - Ethoxyethyl, 3,4,5,6-tetrahydro-2H-pyran-2-yl. R ₃ is preferably benzyl, tert-butyl.

However, in formula (A), R ₁ is a hydrogen atom, R is a protecting group of hydroxyl, and when the relative stereoconfiguration of compound (A) is cis, that is, the relative stereoconfiguration of compound (A) is given by

When represented, R represents a protecting group for a hydroxyl group other than benzyl.

In formula (A), (B), (D), (E), (III), (V), (IX) and (XI), R _{4 and} R The lower alkyl represented by R has carbon number 1- 6. Straight-chain or branched-chain alkyl groups with preferably 1-3 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl, etc., wherein _R4 and _R5 are respectively preferably methyl .

In the formulas (A), (B), (D), (E), (III), (V), (IX) and (XI), the lower alkoxy groups represented by _R and _R have carbon atoms of 1 -6. A linear or branched alkoxy group preferably having 1 to 3 carbon atoms, specifically, methoxy, ethoxy, n-propoxy, isopropoxy and the like.

In the formulas (C), (F), (XIII), (XVI), (XVII) and (XIX), the lower alkoxy groups represented by R6 and _R2 have _1-6 carbon atoms, preferably 1 carbon atom -4 linear or branched alkoxy groups, specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc., preferably methoxy base.

In formulas (C), (F), (XIII), (XVI), (XVII) and (XIX), the _lower alkylthio groups represented by R and R have _1-6 carbon atoms, preferably 1 carbon atom The linear or branched alkylthio group of -4 includes, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio and the like.

The compound having the relative stereoconfiguration shown in formula (XXII) refers to the compound or its enantiomer represented by formula (XXII) in absolute stereoconfiguration, or the compound represented by formula (XXII) in absolute stereoconfiguration A mixture of its enantiomers in any proportion (including racemates). Compounds having relative configurations represented by formulas (G), (H), (XXIII)-(XXVIII) and (XV) have the same meanings as compounds having relative configurations represented by formula (XXII). Hereinafter, compounds having relative configurations represented by formulas (G), (H) and (XXII)-(XXVIII) are referred to as compounds (G), (H) and (XXII)-(XXVIII), respectively. In addition, a compound having a relative configuration represented by formula (XV) is hereinafter referred to as compound (XV).

Compound (G) may, for example, be compound (XXII)-(XXIV) or the like. Compound (H) may, for example, be compound (XXV) or the like.

In formula (G) and (H), the protecting group of the hydroxyl represented by R ₇ and R ₈ includes benzyl, tert-butyl, 1-ethoxyethyl, 3,4,5,6-tetrahydro- 2H-pyran-2-yl, trityl, 1-methoxy-1-methylethyl, methoxymethyl, ethoxymethyl, triethylsilyl, tri-n-butylsilane base, tert-butyldimethylsilyl, etc., R ₇ is preferably benzyl, tert-butyl and trityl; R ₈ is preferably 1-ethoxyethyl, 3,4,5,6-tetrahydro- 2H-pyran-2-yl. In formulas (XXI) and (XXII), the protecting group for the hydroxyl group represented by _PG2 can be the same protecting group as exemplified for _R7 in the above formulas (G) and (H).

However, in the compound (G) of the present invention, when R ₈ in the formula (G) is a hydrogen atom and R ₇ is a protecting group for a hydroxyl group, R ₇ is a protecting group for a hydroxyl group other than benzyl.

In the formulas (G), (H), (XXIV) and (XXV), the lower alkyl groups represented by R ₁₀ and R ₁₁ have 1-6 carbon atoms, preferably straight-chain or branched chain alkane with 1-3 carbon atoms Groups, specifically, methyl, ethyl, n-propyl, isopropyl, etc., wherein R ₁₀ and R ₁₁ are each preferably a methyl group.

In formulas (G), (H), (XXIV) and (XXV), lower alkoxy groups represented by R ₁₀ and R ₁₁ have straight or branched chains with 1-6 carbon atoms, preferably 1-3 carbon atoms Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy and the like.

In formula (XXVIII), about the alkanoyl group whose hydrogen atom represented by _R9 can be replaced by a fluorine atom or a chlorine atom, its alkanoyl group has, for example, a straight chain or branched chain alkanoyl group with a carbon number of 1-7, preferably 1-5 . The alkanoyl group whose hydrogen atom may be replaced by a fluorine atom or a chlorine atom includes formyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl, etc., preferably acetyl, trifluoroacetyl, etc. Fluoroacetyl, pivaloyl, etc. The number of the substituents is not particularly limited, preferably 1-3, which may be the same or different.

In formula (XXVIII), about the benzoyl group that the hydrogen atom of the phenyl represented by _R9 can be substituted by nitro, halogen, alkyl, alkoxy or phenyl, the number of substituents is not particularly limited, preferably 1 -3 pcs, can be same or different. The halogen atom of the substituent includes fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom, chlorine atom and the like. The alkyl group of the substituent has, for example, a straight chain or branched chain alkyl group with 1-6 carbon atoms, preferably 1-4, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., preferably methyl, ethyl, tert-butyl, etc. The alkoxy group of the substituent is, for example, a straight chain or branched alkoxy group with a carbon number of 1-8, preferably 1-4, such as methoxy, ethoxy, propoxy, isopropoxy, butyl Oxy, isobutoxy, sec-butoxy, tert-butoxy, etc., preferably methoxy, ethoxy, tert-butoxy, etc.

The preparation method of compound (XIV) of the present invention, especially the compound represented by formula (XV) will be described in detail below. The following scheme 1 shows the production method of compound (XIV). Scheme 2 particularly shows the preparation method of the compound represented by formula (XV) in relative configuration or absolute configuration.

The present invention is characterized in that: cyclization is carried out after compound (XIII) is hydroxyethylated, the method for preparing compound (I); The method for preparing compound (III) with compound (I) as raw material; Compound (III) is reduced, A method for producing compound (V); and a method for producing compound (XIV) by deprotecting and cyclizing compound (V). The present invention is also characterized in: protecting the hydroxyl group of compound (I) to prepare compound (IV); reducing compound (IV) to prepare compound (VI); deprotecting and cyclizing compound (VI) to prepare compound The method of (XIV). The above-mentioned methods of the present invention can be carried out independently, and it is more preferable to carry out a combination of two or more of these methods.

Process 1

[In each formula, each symbol has the same meaning as above. ]

Process 2

[In each formula, each symbol has the same meaning as above. ]

Preparation of Compound (I) from Compound (XIII)

Compound (XIII) as a raw material can be obtained by known methods (for example, methods described in Heterocycles 26, 2841 (1987), USP5399722, etc.).

Regarding compound (XIII) that is an optically active body, for example, the R configuration of compound (XIII) (also referred to as the compound represented by formula (XVI) in this specification) can be obtained according to the method described in Heterocycles 26, 2841 (1987), etc. , the S configuration (also referred to as the enantiomer of the compound represented by formula (XVI) in this specification) can be obtained by, for example, the method described in USP5399722.

Compound (I) can be obtained by subjecting Compound (XIII) to hydroxyethylation followed by cyclization. For example, the compound (XIII ) with 2-(1-ethoxyethoxy) ethyl halide, 2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy) ethyl halide, 2 - Vinyloxyethyl halide, 2-(tert-butoxy)ethyl halide, 2-trimethylsiloxyethyl halide, 2-triethylsiloxyethyl halide, 2-tert-butyldimethylsilyloxyethyl halide or ethylene oxide, etc., and then obtained by cyclization.

The amount of the base used is usually 1.8-2.8 mol, preferably 2-2.4 mol, relative to 1 mol of compound (XIII).

2-(1-ethoxyethoxy)ethyl halides include 2-(1-ethoxyethoxy)ethyl iodide, 2-(1-ethoxyethoxy)ethyl bromide, etc. ; 2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl halide such as 2-(3,4,5,6-tetrahydro-2H-pyran -2-yloxy)ethyl iodide, 2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl bromide, etc.; 2-vinyloxyethyl halide For example, there are 2-vinyloxyethyl iodide, 2-vinyloxyethyl bromide, etc.; 2-(tert-butoxy)ethyl halides include 2-(tert-butoxy)ethyl iodide, 2-( tert-butoxy) ethyl bromide, etc.; etc.; 2-triethylsiloxyethyl halides, such as 2-triethylsiloxyethyl iodide, 2-triethylsiloxyethyl bromide, etc.; 2-tert-butyldi Examples of methylsiloxyethyl halides include 2-tert-butyldimethylsiloxyethyl iodide, 2-tert-butyldimethylsiloxyethyl bromide and the like. Among the above-mentioned hydroxyethylating reagents, 2-(1-ethoxyethoxy)ethyl iodide, 2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy) Ethyl iodide, 2-vinyloxyethyl iodide, 2-(tert-butoxy)ethyl iodide, 2-trimethylsiloxyethyl iodide, 2-triethylsilyloxyethyl iodide , 2-tert-butyldimethylsiloxyethyl iodide and ethylene oxide.

The amount of the above-mentioned hydroxyethylating agent such as 2-(1-ethoxyethoxy)ethyl halide used is usually 0.8-2 moles, preferably 1-1.5 moles, relative to 1 mole of compound (XIII).

This reaction is carried out in tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1,3-dioxolane, 1,4-dioxane , Methylcyclopentyl ether and other reaction solvents, preferably in THF, MTBE. The amount of the reaction solvent used is 1-50 L, preferably 3-20 L, relative to 1 kg of compound (XIII).

The reaction temperature is usually -30°C to 60°C, preferably 0-30°C, and the reaction time is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.

The above-mentioned hydroxyethylating agent can be prepared by a known method. For example, 2-(1-ethoxyethoxy)ethyl iodide can be prepared by mixing 2-iodoethanol with ethyl vinyl ether in the presence of p-toluenesulfonic acid; 2-(3,4,5,6 -tetrahydro-2H-pyran-2-yloxy)ethyl iodide can be prepared by mixing 3,4-dihydro-2H-pyran with 2-iodoethanol in the presence of p-toluenesulfonic acid; 2- Vinyloxyethyl iodide can be prepared by reacting 2-vinyloxyethanol with p-toluenesulfonyl chloride in the presence of triethylamine, and then mixing sodium iodide in the presence of sodium bicarbonate; 2-(tert-butoxy ) ethyl iodide can be prepared by mixing isobutene with 2-iodoethanol in the presence of trifluoromethanesulfonic acid; 2-trimethylsiloxyethyl iodide can be prepared by mixing trimethylsilyl in the presence of imidazole Chlorine is prepared by mixing 2-iodoethanol; 2-triethylsilyloxyethyl iodide can be prepared by mixing triethylsilyl chloride with 2-iodoethanol in the presence of imidazole; 2-tert-butyl Dimethylsiloxyethyl iodide can be prepared by mixing t-butyldimethylsilyl chloride with 2-iodoethanol in the presence of imidazole.

Compound (I) can be isolated by a conventional method, for example, injecting the reaction solution into an aqueous hydrochloric acid solution for liquid separation, washing the obtained organic layer with an aqueous alkali solution, and distilling off the solvent to achieve isolation. In addition, in order to completely cyclize the isolated product, it may be reacted in a solvent in the presence of an acid catalyst such as p-toluenesulfonic acid, and then post-treated by a conventional method again. The obtained isolate can be further purified according to conventional methods, and can also be used in the next step of reaction without purification.

Most of the compound (I) obtained by the above method can be obtained in the form of a compound having a relative stereo configuration shown in formula (VII), and can also be recrystallized with, for example, diisopropyl ether to obtain a compound having the formula (VII) with higher purity. VII) Compounds with relative stereo configurations.

Using the optically active compound (XIII) as a raw material to carry out the above method can obtain the compound having the absolute stereo configuration represented by the formula (VII) or its enantiomer. Optically active forms include S configuration, R configuration, and mixtures of S configuration and R configuration other than racemates of compound (XIII). Wherein, if the S configuration of compound (XIII) is used, that is, formula (XVI) is used:

[In the formula, each symbol represents the same meaning as above] as a raw material, the compound with the absolute stereo configuration shown in formula (VII) can be obtained; if the R configuration of compound (XIII) is used, that is, the formula

[In the formula, each symbol has the same meaning as above] If the compound represented by the compound is used as a raw material, the enantiomer of the compound having the absolute stereo configuration represented by the formula (VII) can be obtained. When using a mixture of S configuration and R configuration in any ratio except the racemate as a raw material, a compound having an absolute stereoconfiguration shown in formula (VII) and a mixture of enantiomers thereof can be obtained, using for example Appropriate solvents such as diisopropyl ether and MTBE recrystallize the reaction product obtained by the above method, which can increase the ratio of the compound with the absolute stereoconfiguration shown in formula (VII) or one of its enantiomers.

Preparation of compound (XIV) from compound (I)

Compound (XIV) can be obtained by introducing a protecting group into compound (I), followed by reduction and cyclization. It can be carried out by any one of the following steps (1A) or (1B).

Step (1A) is to use compound (I) as a raw material to obtain compound (III), reduce the obtained compound (III) to obtain compound (V), and deprotect and cyclize the obtained compound (V) to obtain compound (XIV) A step of. Step (1B) is to protect the hydroxyl group of compound (I) to obtain compound (IV), reduce the obtained compound (IV) to obtain compound (VI), deprotect and cyclize the obtained compound (VI) to obtain compound (XIV) A step of.

Step (1A)

Preparation of compound (III) from compound (I)

Compound (III) can be produced by using compound (I) as a raw material, for example, by the following two methods. A method is: compound (I) is deprotected to obtain compound (II), and a protecting group of a diol is introduced into the obtained compound (II) to obtain the method of compound (III) (hereinafter referred to as method (1)); Another method is a method of obtaining compound (III) by directly protecting a diol starting from compound (I) (hereinafter referred to as method (2)). Each method will be described below.

Method (1) (Method for preparing compound (III) from compound (I) via compound (II))

Compound (II) can be obtained by deprotecting compound (I). The deprotecting reagent can be appropriately selected according to the type of protecting group of compound (I). When the protecting group is a tert-butyl group, for example, an acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, strongly acidic ion exchange resin, etc., Preferably trifluoroacetic acid), deprotection is carried out by reacting compound (I) at usually -20°C to 80°C, preferably 0°C to 30°C, for usually 1 minute to 5 hours, preferably 15 minutes to 3 hours. Usually 0.01-10 L, preferably 0.1-5 L of acid is used relative to 1 kg of compound (I). After the reaction, the acid can be distilled off, or neutralized by a conventional method, followed by extraction with an organic solvent, and the solvent is distilled off to isolate compound (II).

When the protecting group is benzyl, for example, in a solvent (such as ethyl acetate, ethanol, methanol, acetic acid, THF, etc., preferably ethyl acetate, acetic acid), using a catalyst (such as Pd/C, Pd(OH) _etc. , Preferably Pd/C), deprotection is carried out by reacting compound (I) at usually -20°C to 100°C, preferably 0°C-50°C, under a hydrogen atmosphere for usually 0.5-12 hours, preferably 1-6 hours.

The amount of solvent used is usually 1-50 L, preferably 3-25 L, relative to 1 kg of compound (I). The reduction catalyst is usually used in an amount of 0.00001-0.5 kg, preferably 0.0001-0.2 kg, relative to 1 kg of compound (I).

The catalyst can be filtered, the solvent can be distilled off, and the compound (II) can be isolated.

The protective reagent used when converting the obtained compound (II) into compound (III) is different according to the types of constituent elements R and _R of the protecting group. For example, when _both R and _R are methyl, ₂ can be used. 2-dimethoxypropane or acetone. At this time, using an acid (for example, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, sulfuric acid, acidic ion exchange resin, boron trifluoride, etc., preferably p-toluenesulfonic acid, pyridinium p-toluenesulfonate), Usually at -20°C to 100°C, preferably at 0°C-50°C, react the obtained compound (II) with 2,2-dimethoxypropane or acetone, usually for 0.5-12 hours, preferably 1-6 hours, for protection . When R ₄ and R ₅ are both lower alkyl, it can be carried out according to the above method.

The amount of protecting reagents such as 2,2-dimethoxypropane is usually 0.5-50 L, preferably 3-20 L, relative to 1 kg of compound (II). The acid is usually used in an amount of 0.0001-0.5 kg, preferably 0.0005-0.2 kg, relative to 1 kg of compound (II).

Compound (III) can be isolated by a conventional method. For example, when an acid is used as described above, it can be obtained by neutralizing the reaction solution with an aqueous alkali solution, separating the liquids, washing the obtained organic layer with an aqueous alkali solution, and distilling off the solvent. separate. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

Method (2) (method for directly preparing compound (III) from compound (I))

Compound (III) can be obtained directly by performing the deprotection of compound (I) and the protection of the diol group simultaneously. This method can be performed by simultaneously adding the deprotection reagent and the protection reagent used in the above method (1), and the reagent can be appropriately selected according to the type of the group to be deprotected and the protective group of the diol. Hereinafter, the case where the group to be deprotected in compound (I) is benzyl and the protecting group of diol is dimethylmethylene will be described as an example, but the present invention is not limited to this method.

For example, the protecting group of compound (I) is benzyl, and when the protecting group of diol is dimethylmethylene, in a solvent (such as THF, ethyl acetate, etc., preferably THF) or without a solvent, a catalyst (such as Pd /C, Pd(OH) ₂ , etc., preferably Pd/C) and acidic ion exchange resins (such as Amberlyst 15E (produced by Rohm & Haas), Nafion SAC13 (produced by Dupont) and the like) or acids (such as phosphoric acid, hydrochloric acid, sulfuric acid , methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, boron trifluoride, phosphorus oxychloride, etc.), usually at -20°C to 100°C, preferably 0°C-50°C, under hydrogen atmosphere , compound (I) is reacted with 2,2-dimethoxypropane and/or acetone as a protecting reagent, usually for 0.5-12 hours, preferably 1-6 hours, to obtain compound (III).

The amount of protecting reagents such as 2,2-dimethoxypropane used is usually 0.5-100 L, preferably 1-50 L, relative to 1 kg of compound (I). The reduction catalyst is usually used in an amount of 0.0001 to 0.5 kg relative to 1 kg of compound (I). The amount of acidic ion exchange resin used is usually 0.001-0.5 kg, preferably 0.005-0.1 kg, per 1 kg of compound (I). When using other acids, the amount of acid used is usually 0.00001-0.1 kg, preferably 0.0001-0.01 kg, per 1 kg of compound (I). When a solvent is used, the amount of the solvent used is usually 0.5-50 L, preferably 1-25 L, per 1 kg of compound (I).

Compound (III) can be isolated by filtering the catalyst and then distilling off the solvent. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

When R as a protective group constituent element is a hydrogen atom, and _R is a lower alkyl group or a phenyl group, alkanal or benzaldehyde and/or acetal of alkanal or benzaldehyde (such as dimethyl acetal, etc.) can be used _. ) instead of 2,2-dimethoxypropane or acetone in the above methods (1), (2), and perform the same reaction as the above methods (1), (2).

R ₄ is lower alkyl or phenyl, and when R ₅ is lower alkyl or phenyl, usually use R ₄ COR ₅ and/or its acetal (such as dimethyl acetal, etc.) to replace the above methods (1), (2 ) in 2,2-dimethoxypropane or acetone, carry out the same reaction as above-mentioned method (1), (2).

R ₄ is a lower alkyl or phenyl group, and R ₅ is a lower alkoxy group, usually using trialkyl orthoalkanoate (such as MeC (OEt) ₃ etc.) or trialkyl orthobenzoate to replace the above method ( 2,2-dimethoxypropane or acetone in 1) and (2) are subjected to the same reaction as in the above-mentioned methods (1) and (2).

R ₄ is a hydrogen atom, R ₅ When being a lower alkoxy group, usually use trialkyl orthoformate to replace 2,2-dimethoxypropane or acetone in the above-mentioned method (1), (2), carry out and The above-mentioned method (1), (2) same reaction.

When R _and R are _all lower alkoxy groups, tetraalkyl orthocarbonate can be used to replace 2,2-dimethoxypropane or acetone in the above-mentioned method (1), (2), and carry out the above-mentioned method ( 1), (2) the same reaction.

Compounds having the relative stereoconfigurations of formulas (VIII) and (IX) can be prepared from compounds having the relative stereoconfigurations of formula (VII) according to the above method (1) or (2).

Compounds with absolute stereoconfigurations represented by formulas (VIII) and (IX) can be prepared from compounds with absolute stereoconfigurations represented by formula (VII) according to the above method (1) or (2). The enantiomer of the compound with absolute stereoconfiguration shown in formula (VIII) and (IX) can be raw material with the enantiomer of the compound with absolute stereoconfiguration shown in formula (VII), according to the above method (1) or (2) preparation.

Preparation of Compound (V) from Compound (III)

Compound (V) can be obtained by reducing compound (III). The reduction reaction can be carried out by a conventional method for reducing a lactone to a lactone, for example, using a reducing agent (such as diisobutylaluminum hydride (DIBAL-H), di-2-methoxyethoxyaluminum sodium hydride, hydrogenated Tri-tert-butoxyaluminum lithium, etc., preferably DIBAL-H, tri-tert-butoxyaluminum lithium hydride), in a solvent (such as dichloromethane, toluene, THF, MTBE, etc., preferably dichloromethane, toluene, THF), The reaction is carried out at -100°C to 50°C, preferably -80°C to 0°C, for 10 minutes to 6 hours, preferably 15 minutes to 3 hours.

The reducing agent is usually used in an amount of 0.8-1.5 moles, preferably 1-1.2 moles, relative to 1 mole of compound (III). The amount of solvent used is usually 1-50 L, preferably 2-20 L, relative to 1 kg of compound (III).

Compound (V) can be isolated by conventional methods, for example, pouring the reaction solution into saturated ammonium chloride aqueous solution, separating the liquid, dehydrating and filtering the obtained organic layer with anhydrous magnesium sulfate, etc., distilling off the solvent, and then can be isolated. The isolate can be purified by a conventional method, and can also be used in the subsequent reaction without purification.

The compound having the relative stereoconfiguration represented by the formula (XI) can be prepared according to the above method using the compound having the relative stereoconfiguration represented by the formula (IX) as a raw material.

The compound having the absolute stereoconfiguration represented by formula (XI) can be prepared according to the above method from the compound having the absolute stereoconfiguration represented by formula (IX) as a raw material. The enantiomers of the compound having the absolute stereoconfiguration represented by formula (XI) can be prepared according to the above method using the enantiomers of the compound having the absolute stereoconfiguration represented by formula (IX) as raw materials.

Preparation of compound (XIV) from compound (V)

Compound (XIV) can be obtained by deprotecting and cyclizing Compound (V). For example, an acid (such as hydrochloric acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, strongly acidic ion exchange resin, etc., preferably hydrochloric acid, sulfuric acid), usually at -30°C to 100°C, preferably 0°C-40°C, the compound (V) is usually reacted The deprotection and cyclization can be performed for 1 minute to 24 hours, preferably 1 minute to 5 hours, more preferably 10 minutes to 3 hours.

The amount of acid used for deprotection and cyclization is usually 0.001-10 L, preferably 0.01-2 L, relative to 1 kg of compound (V). The amount of solvent used for deprotection and cyclization is usually 1-50 L, preferably 2-20 L, relative to 1 kg of compound (V).

Compound (XIV) can be isolated by conventional methods. After the reaction, for example, neutralize the reaction solution with an aqueous alkali solution, then separate the layers, wash the obtained organic layer with brine, dehydrate with anhydrous magnesium sulfate, etc., and distill off the solvent. to separate. The isolate can be further purified by conventional methods.

The compound having the relative stereoconfiguration represented by formula (XV) can be prepared by the above-mentioned method using the compound having the relative stereoconfiguration represented by formula (XI) as a raw material.

The compound having the absolute stereoconfiguration represented by formula (XV) can be prepared by the above-mentioned method from the compound having the absolute stereoconfiguration represented by formula (XI) as a raw material. The enantiomer of the compound having the absolute stereoconfiguration represented by formula (XV) can be prepared according to the method above using the enantiomer of the compound having the absolute stereoconfiguration represented by formula (XI) as a raw material.

Step (1B)

Preparation of Compound (IV) from Compound (I)

Compound (IV) can be obtained by protecting the hydroxyl group of compound (I). The hydroxy protection reaction differs depending on the type of protecting group, and the hydroxy group of compound (I) can be protected by appropriately selecting reaction conditions and protecting reagents according to the type of protecting group. For example, when protecting the hydroxyl group of compound (I) with 1-ethoxyethyl, for example, in a solvent (such as THF, MTBE, 1,2-dimethoxyethane, 1,4-dioxane, toluene, dichloro Methane, etc., preferably THF, MTBE, dichloromethane), in acid (such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, sulfuric acid, boron trifluoride, phosphorus oxychloride, acidic ion exchange resin, etc., Preferably in the presence of p-toluenesulfonic acid, pyridinium p-toluenesulfonate), usually at -30°C to 80°C, preferably 0°C-40°C, react compound (I) with the protective reagent ethyl vinyl ether for 10 minutes- 10 hours, preferably 30 minutes to 3 hours.

The amount of protecting reagents such as ethyl vinyl ether used is usually 0.8-3 moles, preferably 1-1.5 moles, relative to 1 mole of compound (I). The acid is usually used in an amount of 0.00001-0.2 kg, preferably 0.0001-0.1 kg, relative to 1 kg of compound (I). The solvent is usually used in an amount of 1-50 L, preferably 3-40 L, relative to 1 kg of compound (I).

Compound (IV) can be isolated by a conventional method, for example, neutralizing the reaction solution with an aqueous alkali solution, followed by liquid separation, washing the obtained organic layer with an aqueous alkali solution, and distilling off the solvent for isolation. The isolated product can be purified by a conventional method, and can also be used in the subsequent reaction without purification.

The compound having the relative stereoconfiguration represented by the formula (X) can be prepared according to the above-mentioned method from the compound having the relative stereoconfiguration represented by the formula (VII) as a raw material.

The compound having the absolute stereoconfiguration represented by formula (X) can be prepared from the compound having the absolute stereoconfiguration represented by formula (VII) according to the above method. The enantiomers of the compound having the absolute stereoconfiguration represented by formula (X) can be prepared according to the above method using the enantiomers of the compound having the absolute stereoconfiguration represented by formula (VII) as raw materials.

Preparation of compound (VI) from compound (IV)

Compound (VI) can be obtained by reducing compound (IV). Reduction reaction can be carried out according to the conventional method that lactone is reduced into lactone, for example, uses reducing agent (such as DIBAL-H, two 2-methoxyethoxyaluminum sodium hydrides, tri-tert-butoxyaluminum lithium hydrides, etc. , preferably DIBAL-H, lithium tri-tert-butoxyaluminum hydride), in a solvent (such as toluene, THF, MTBE, dichloromethane, etc., preferably toluene, THF), at -100°C to 50°C, preferably -80°C Reaction at 0°C for 10 minutes to 6 hours, preferably 15 minutes to 3 hours.

The reducing agent is usually used in an amount of 0.8-1.5 moles, preferably 1-1.2 moles, relative to 1 mole of compound (IV). The solvent is usually used in an amount of 1-50 L, preferably 2-20 L, relative to 1 kg of compound (IV).

Compound (VI) can be isolated by a conventional method, for example, adding saturated aqueous ammonium chloride solution to the reaction solution, dehydrating with anhydrous magnesium sulfate or the like, filtering, distilling off the solvent, and isolating. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

The compound having the relative stereoconfiguration represented by formula (XII) can be prepared by the above-mentioned method from the compound having the relative stereoconfiguration represented by formula (X) as a raw material.

The compound having the absolute stereoconfiguration represented by formula (XII) can be prepared from the compound having the absolute stereoconfiguration represented by formula (X) according to the above method. The enantiomers of the compound having the absolute stereoconfiguration represented by formula (XII) can be prepared according to the above method using the enantiomers of the compound having the absolute stereoconfiguration represented by formula (X) as raw materials.

Preparation of compound (XIV) from compound (VI)

Compound (XIV) can be obtained by deprotecting and cyclizing Compound (VI). The reaction conditions differ depending on the types of protecting groups _PG and _PG1 . For example, when protecting groups _PG and _PG1 are benzyl and 1-ethoxyethyl respectively, in a solvent (such as ethyl acetate, acetic acid, ethanol, methanol, THF, methyl isobutyl ketone, etc., preferably ethyl acetate , THF, ethanol), using a catalyst (such as Pd/C, Pd(OH) ₂ , etc., preferably Pd/C), usually at -30°C to 100°C, preferably 0°C-60°C, under a hydrogen atmosphere, make Compound (VI) is reacted for 15 minutes to 12 hours, preferably 0.5 to 6 hours, to remove the benzyl protecting group.

The catalyst used for benzyl deprotection is usually used in an amount of 0.0001-0.5 kg relative to 1 kg of compound (VI). The solvent is usually used in an amount of 0.5-50 L, preferably 2-20 L, relative to 1 kg of compound (VI).

Next, the catalyst is filtered, the solvent is distilled off, and an acid (such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acidic ion exchange resin, etc., preferably hydrochloric acid), usually at -30°C to 100°C, preferably 0°C-60°C, react the resulting reaction mixture for 10 Minutes to 6 hours, preferably 30 minutes to 3 hours, the deprotection and cyclization of the 1-ethoxyethyl group can be carried out.

The amount of acid used for deprotection and cyclization of the 1-ethoxyethyl group is usually 0.001-10 L, preferably 0.01-2 L, relative to 1 kg of compound (VI). The solvent is usually used in an amount of 1-50 L, preferably 2-20 L, relative to 1 kg of compound (VI).

Compound (XIV) can be isolated by a conventional method, for example, by neutralizing the reaction liquid with a base such as anhydrous potassium carbonate, and then distilling off the solvent. Isolates can be purified by conventional methods.

The compound having the relative stereoconfiguration represented by formula (XV) can be prepared by the above-mentioned method using the compound having the relative stereoconfiguration represented by formula (XII) as a raw material.

The compound having the absolute stereoconfiguration represented by formula (XV) can be prepared by the above-mentioned method from the compound having the absolute stereoconfiguration represented by formula (XII) as a raw material. The enantiomer of the compound having the absolute stereoconfiguration represented by formula (XV) can be prepared according to the method above using the enantiomer of the compound having the absolute stereoconfiguration represented by formula (XII) as a raw material.

Next, the production methods of intermediate compound (I) and compound (III) in the process of producing compound (XIV) from compound (XIII) will be described in detail. The preparation methods of Compound (I) and Compound (III) are given in Scheme 3 below. In particular, the preparation method of the compounds represented by formula (VII) and formula (IX) in absolute stereo configuration is given in scheme 4. As shown in Scheme 3, the preparation method is characterized in that: compound (XIII) is used as a raw material, via compound (XIX) and compound (XX). That is, the present invention is characterized in that: using compound (XIII) as a raw material, a method for preparing compound (XIX); a method for preparing compound (XX) by hydrolyzing compound (XIX); and _PG and R of compound (XX) _3. Deprotection, followed by acetalization or ketalization and lactonization to prepare the compound (III). The above-mentioned methods of the present invention can be carried out independently, and it is more preferable to carry out a combination of two or more of these methods. In addition, in the method of the present invention for preparing compound (I) through hydroxyethylation of compound (XIII) and then cyclization, it is preferred to hydroxyethylate compound (XIII) to obtain compound (XIX). (XIX) is hydrolyzed to obtain compound (XX), and the obtained compound (XX) is cyclized to prepare compound (I). Each method will be described in detail below.

Process 3

[In the formula, each symbol has the same meaning as above. ]

Process 4

[In the formula, each symbol has the same meaning as above. ]

Preparation of compound (XIX) from compound (XIII)

Compound (XIX) can be obtained by hydroxyethylating compound (XIII) (introducing R ₃ O-CH ₂ CH ₂ - group (R ₃ represents the same meaning as above)). For example, after adding a base (such as lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc., preferably Under the conditions of lithium diisopropylamide), make compound (XIII) and the compound shown by formula: R ₃ O-CH ₂ CH ₂ -X (in the formula, R ₃ represents the same meaning as above, and X represents leaving group) reaction to get.

Formula: In R ₃ O-CH ₂ CH ₂ -X, the leaving group X includes, for example, halogen atoms (such as iodine atoms, bromine atoms, etc.), methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonate Acyloxy, benzenesulfonyloxy, etc., preferably a halogen atom, particularly preferably an iodine atom; _R3 is the same as the aforementioned compounds (C), (F) and (XVII)-(XX), preferably benzyl, tert-butyl. The compound represented by formula: R ₃ O-CH ₂ CH ₂ -X is preferably 2-benzyloxyethyl iodide and 2-tert-butoxyethyl iodide.

The base is usually used in an amount of 0.9-1.5 moles, preferably 1.0-1.3 moles, relative to 1 mole of compound (XIII).

The amount of the compound represented by the formula: R ₃ O—CH ₂ CH ₂ —X is usually 0.9-2.5 moles, preferably 1.0-1.6 moles, relative to 1 mole of compound (XIII).

Compound (XIX) can usually be prepared in THF, hexane, di-n-butyl ether, MTBE, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1,3-dioxolane, 1,4 - Carried out in reaction solvents such as dioxane and toluene, preferably in THF and hexane. The reaction solvent is usually used in an amount of 1-100 L, preferably 3-30 L, relative to 1 kg of compound (XIII).

The reaction temperature is usually -100°C to 70°C, preferably -80°C to 40°C; the reaction time is usually 0.5-48 hours, preferably 3-24 hours.

The compound represented by the formula: R ₃ O-CH ₂ CH ₂ -X can be prepared by known methods. For example, 2-benzyloxyethyl iodide can react 2-benzyloxyethanol with methanesulfonyl chloride in the presence of a catalyst such as triethylamine to obtain 2-benzyloxyethyl methanesulfonate, which can be reacted with sodium iodide reaction, 2-tert-butoxyethyl iodide can be prepared by using 2-tert-butoxyethanol instead of the above-mentioned 2-benzyloxyethanol.

Compound (XIX) can be isolated by conventional methods, for example, pouring the reaction liquid into aqueous hydrochloric acid solution, washing the organic layer obtained by liquid separation with aqueous alkali solution, distilling off the solvent, and separating.

When using the compound shown in formula (XVI) as a raw material to carry out the above method, a diastereoisomer mixture (containing more trans and a small amount of cis) mainly containing the compound shown in formula (XVII) can be obtained. Mode). And when using the enantiomer of the compound shown in formula (XVI) as raw material to carry out the above-mentioned method, can obtain the diastereomer mainly containing the enantiomer of the compound shown in formula (XVII) absolute stereoconfiguration Mixture of conformers (contains more trans and a small amount of cis).

A diastereomeric mixture mainly containing the compound having the absolute stereoconfiguration shown in formula (XVII), or a diastereomeric mixture mainly containing the enantiomers of the compound having the absolute stereoconfiguration shown in formula (XVII) The isomer mixture can be separated by HPLC to obtain pure enantiomers of the compound with the absolute stereoconfiguration shown in formula (XVII) or the pure compound with the absolute stereoconfiguration shown in formula (XVII), or The diastereoisomeric mixture was used in the following reactions without separation.

Preparation of compound (XX) from compound (XIX)

Compound (XX) can be obtained by hydrolyzing compound (XIX). The hydrolysis can be carried out, for example, by subjecting compound (XIX) to The reaction is usually 0.5-24 hours, preferably 1-12 hours.

For example, when the base is potassium hydroxide, the base used for hydrolysis is usually used in an amount of 1-50 moles, preferably 1.2-10 moles, relative to 1 mole of compound (XIX).

The hydrolysis is carried out in a reaction solvent such as methanol, ethanol, 2-propanol, or water, preferably in a mixed solvent of methanol and water. The reaction solvent is usually used in an amount of 1-100 L, preferably 5-50 L, per 1 kg of compound (XIX).

Compound (XX) can be separated by conventional methods, for example, after hydrolysis, using acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., preferably hydrochloric acid), the reaction solution is adjusted to usually pH 0-7, preferably pH 0.1-3, and it is separated , the obtained organic layer was washed with saturated brine, the solvent was distilled off, and the mixture was separated.

Use the diastereoisomer mixture (containing more trans, containing a small amount of cis) obtained by the above method mainly containing the compound of absolute stereoconfiguration shown in formula (XVII) as raw material, when carrying out the above method, can A diastereoisomer mixture mainly containing the compound with the absolute stereoconfiguration shown in (XVIII) (contains more trans and a small amount of cis) is obtained. And use the diastereomer mixture (containing more trans-form, containing a small amount of cis-form) mainly containing the enantiomer of the compound shown in formula (XVII) as raw material, when carrying out the above method , a diastereoisomer mixture mainly containing the enantiomers of the compound with the absolute stereoconfiguration shown in (XVIII) can be obtained (contains a lot of trans and a small amount of cis).

When the product obtained by the above hydrolysis is a mixture of diastereomers, an organic amine is added after hydrolysis to generate an organic amine salt of compound (XX), and then the obtained salt is recrystallized to further increase the purity.

The organic amine used includes, for example, dibenzylamine, benzylamine, dicyclohexylamine, cyclohexylamine, aniline, diethylamine, diisopropylamine, (S)-phenethylamine, etc., preferably dibenzylamine. The organic amine is usually used in an amount of 0.5-1.5 mol, preferably 0.8-1.3 mol, relative to 1 mol of compound (XX). The formation of organic amine salts is carried out in reaction solvents such as ethanol, methanol, 2-propanol, 1-propanol, tert-butanol, MTBE, diisopropyl ether, methyl isobutyl ketone, ethyl acetate, water, etc. Preference is given to working in ethanol. The reaction solvent is usually used in an amount of 1-100 L, preferably 3-30 L, per 1 kg of compound (XX).

Formation of the organic amine salt can be performed by heating to usually 20°C to 100°C, preferably 40°C to 80°C, and then cooling to usually -20°C to 40°C, preferably -10°C to 25°C.

Solvents used for recrystallization of the obtained organic amine salt include, for example, ethanol, methanol, 2-propanol, 1-propanol, ethyl acetate, diisopropyl ether, water, etc., preferably ethanol. The solvent is usually used in an amount of 1-100 L, preferably 3-30 L, relative to 1 kg of organic amine salt.

The free compound (XX) can be obtained as follows: the organic amine salt of the obtained compound (XX) can be adjusted to a pH of usually 0-7, A solution with a pH of 0.5-4 is preferred, and the organic layer obtained by liquid separation is washed with saturated brine, and then the solvent is distilled off.

By generating the salt of the diastereoisomer mixture (containing more trans-form, containing a small amount of cis-form) and organic amine mainly containing the absolute stereoconfiguration shown in formula (XVIII), can obtain formula (XVIII) The compound or its salt with the absolute stereoconfiguration shown has high stereoselectivity, good optical purity, and almost pure stereostructure. On the other hand, by generating a diastereoisomer mixture mainly containing the enantiomers of the compound having the absolute stereoconfiguration shown in formula (XVIII) (containing more trans, containing a small amount of cis) and organic amine The enantiomers or salts thereof can be obtained with the absolute stereoconfiguration of the compound represented by formula (XVIII), wherein the compound has high stereoselectivity, good optical purity, and almost pure stereostructure.

Preparation of compound (III) from compound (XX)

Compound (III) can be obtained by deprotecting _PG and R ₃ of compound (XX), followed by lactonization and acetalization or ketalization. These steps can be carried out separately, but it is convenient to carry out them at the same time, so they are preferably carried out at the same time. _PG and _R of compound (XX) deprotection, lactonization, and acetalization or ketalization are carried out simultaneously, when compound (III) is obtained, for example, adding an acetalization reagent or a ketalization reagent (i.e. Under the condition of the protection reagent of diol), use catalyst (for example make strongly acidic cation exchange resin (Amberlyst 15 (Dry)), acid catalysts such as phosphoric acid, sulfuric acid, hydrochloric acid and reduction catalysts such as palladium carbon, palladium hydroxide coexist, preferably Strongly acidic cation exchange resin (combination of Amberlyst 15 (Dry)) and palladium carbon), under hydrogen atmosphere, preferably add dehydrating agent such as anhydrous magnesium sulfate, usually at -20°C to 100°C, preferably at 0°C to 60°C Usually, the reaction is carried out at 0.5-24 hours, preferably 1-12 hours.

Acetalization reagents and ketalization reagents (protecting reagents for diols) vary depending on the types of protective group constituents _R4 and _R5 . For example, when _R4 and _R5 are both methyl groups, 2, 2 - dimethoxypropane, acetone.

The amount of an acetalization reagent such as 2,2-dimethoxypropane or a ketalization reagent used is usually 1 to 30 moles, preferably 1 to 10 moles, based on 1 mole of compound (XX). The amount of the catalyst used is generally 0.1-500 g, preferably 1-250 g, of the acid catalyst and the reduction catalyst, respectively, per 1 kg of compound (XX). This reaction can be carried out in a solvent (such as toluene, THF, dichloromethane, etc.), or without using a solvent. When using a solvent, the amount of solvent used is usually 1-50L, preferably 3-30L, relative to 1kg of compound (XX). .

Compound (III) can be isolated by a conventional method, for example, after filtering the reaction liquid, distilling off the solvent, adding an aqueous alkali solution for liquid separation, and distilling off the solvent from the obtained organic layer.

Using the compound obtained by the above-mentioned method with almost pure stereostructure and absolute stereoconfiguration shown in formula (XVIII) as a raw material, carrying out the above-mentioned method can obtain a compound having high stereoselectivity, good optical purity and formula (IX) Compounds with absolute stereoconfigurations shown. In addition, using the obtained compound with high stereoselectivity, high optical purity, and absolute stereoconfiguration shown in formula (IX) as a raw material, for example, the method for preparing compound (V) from the aforementioned compound (III) can be obtained. Selectivity, optical purity are good, have the compound of absolute stereoconfiguration shown in formula (XI); Then take the compound of gained high stereoselectivity, optical purity high, having absolute stereoconfiguration shown in formula (XI) as raw material, carry out For example, the method for preparing compound (XIV) from the aforementioned compound (V) can obtain a compound with high stereoselectivity, good optical purity, and absolute stereo configuration represented by formula (XV). On the other hand, using the enantiomer of the compound with almost pure stereostructure and the absolute stereoconfiguration shown in formula (XVIII) as raw material, carrying out the above method, can obtain high stereoselectivity, good optical purity, and The enantiomers of the compound with the absolute stereoconfiguration shown in formula (IX), the enantiomers of the compound with the absolute stereoconfiguration shown in the formula (XI) and the absolute stereoconfiguration with the formula (XV) Enantiomers of the compound.

Preparation of compound (I) from compound (XX)

Compound (I) can be obtained by cyclizing compound (XX). Specifically, compound (I) can be obtained by deprotecting R ₃ of compound (XX), followed by lactonization. These steps can be carried out separately, but it is convenient to carry out them simultaneously, so it is preferable to carry out them simultaneously. When the deprotection and lactonization of _R3 are carried out simultaneously to obtain compound (I), for example, an acid (such as trifluoromethanesulfonic acid, methanesulfonic acid, etc., preferably trifluoromethanesulfonic acid) can be added for the reaction.

The acid is usually used in an amount of 0.0005-0.5 mol, preferably 0.05-0.5 mol, relative to 1 mol of compound (XX).

The preparation of compound (I) is carried out in THF, 1,2-dimethoxyethane, MTBE and other reaction solvents, preferably in THF. The reaction solvent is usually used in an amount of 1-100 L, preferably 3-30 L, relative to 1 kg of compound (XX).

The reaction temperature is usually -30°C to 100°C, preferably 0°C-60°C; the reaction time is usually 0.5-96 hours, preferably 3-72 hours.

Compound (I) can be isolated by a conventional method, for example, distilling off the solvent of the reaction solution, adding an aqueous alkali solution, separating the layers, washing the obtained organic layer with saturated brine, and then distilling off the solvent for isolation.

Use the compound obtained by the above-mentioned method with almost pure stereostructure and absolute stereoconfiguration shown in formula (XVIII) as a raw material, carry out the above-mentioned method, then can obtain high stereoselectivity, good optical purity, have the compound of formula (XII) Compounds with absolute stereoconfigurations shown. On the other hand, using the enantiomer of the compound with almost pure stereostructure and the absolute stereoconfiguration shown in formula (XVIII) as raw material, carrying out the above method, can obtain high stereoselectivity, good optical purity, and Enantiomers of compounds with absolute stereo configurations represented by formula (VII).

Other production methods of the compound (XV) of the present invention will be described in detail below.

Other preparation methods of the present invention are characterized in that: (1) compound (XXII) is obtained from compound (XXI) as a starting material, (2) compound (XXII) is obtained from compound (XXII) via compound (XXIV) and compound (XXV) (XXVI), (3) compound (XXVI) is reversed to obtain compound (XV). That is, the present invention is characterized in that: stereoselective reduction of compound (XXI), the method for preparing compound (XXII); the method for preparing compound (XXIV) comprising step (2A) or step (2B), wherein step (2A) is Compound (XXII) is used as a raw material, and deprotection and introduction of protecting groups are carried out simultaneously to prepare compound (XXIV). Step (2B) is to deprotect compound (XXII) to obtain compound (XXIII), and introduce Protecting group, preparation of compound (XXIV); reduction of compound (XXIV), method for preparation of compound (XXV); deprotection and cyclization of compound (XXV), method for preparation of compound (XXVI); and making the hydroxyl group of compound (XXVI) Reverse, the method for preparing compound (XV). The above-mentioned methods of the present invention can be carried out independently, but it is more preferable to carry out a combination of two or more of these methods.

(1) Preparation of compound (XXII) from compound (XXI)

Compound (XXI) as a raw material can be obtained by a known method (for example, the method described in JP-A-10-218881, etc.).

Compound (XXII) can be obtained by stereoselective reduction of compound (XXI).

The method of stereoselective reduction can adopt various stereoselective reduction reactions, but usually due to reasons such as high asymmetric yield and high number of catalyst rotations, the asymmetric hydrogenation reaction carried out by transition metal catalysts with asymmetric ligands is preferred.

The asymmetric hydrogenation reaction using a transition metal catalyst having an asymmetric ligand will be described in detail below.

Compound (XXII) can be produced, for example, by reacting compound (XXI) with hydrogen in a solvent in the presence of a transition metal catalyst having an asymmetric ligand.

The asymmetric ligands are, for example, optically active phosphine derivatives, optically active diamine derivatives, optically active aminoalcohol derivatives, optically active bisoxazoline (bisoxazoline) derivatives, optically active salen derivatives, etc. For reasons such as symmetrical yield and high number of rotations of the catalyst, it is preferable to use an optically active phosphine derivative.

Optically active phosphine derivatives, for example, compound (L1)-compound (L6) and its enantiomers, etc., preferred compound (L1) and its enantiomers, from the perspective of synthesis and convenient purchase, the preferred compound ( In L1) and its enantiomers, Ra and Rb are phenyl, and Rc is an optically active BINAP (optical activity-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) of a hydrogen atom ), more preferably (S)-BINAP and its enantiomer (R)-BINAP.

In the formulas (L1)-(L6), the substituents of the phenyl groups that may be substituted, represented by Ra, Rb, Rd, Re, Rh, Ri, Rj, Rk, Rl, Rm, Rn, and Ro, include, for example, halogen atoms , alkyl, alkoxy, etc., preferably halogen atoms, alkyl, etc. The number of the substituents is not particularly limited, preferably 1-3, which may be the same or different.

In formulas (L1)-(L6), the substituents of the cyclohexyl groups that may be substituted, represented by Ra, Rb, Rd, Re, Rh, Ri, Rj, Rk, Rl, Rm, Rn and Ro, include, for example, methyl , ethyl, isopropyl, tert-butyl and other alkyl groups, preferably methyl, tert-butyl and the like. The number of the substituents is not particularly limited, preferably 1-3, which may be the same or different.

The halogen atom as the substituent includes fluorine atom, chlorine atom, bromine atom and iodine atom, preferably chlorine atom and bromine atom.

The alkyl group as the substituent is preferably a straight chain or branched chain alkyl group with 1-6 carbon atoms, more preferably 1-4, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., preferably methyl, tert-butyl, etc.

The alkoxy group as the substituent is preferably a straight-chain or branched alkoxy group with 1-6 carbon atoms, more preferably 1-4, such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc., preferably methoxy, tert-butoxy Base etc.

In the formulas (L1) and (L2), the halogen atoms represented by Rc, Rf and Rg are the same as the above-mentioned halogen atoms as substituents, preferably chlorine atoms and bromine atoms.

In formula (L1) and (L2), the alkyl represented by Rc, Rf and Rg preferably has 1-6 carbon atoms, more preferably straight chain or branched chain alkyl of 1-4, such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., preferably methyl, tert-butyl, etc.

In formulas (L1) and (L2), the alkoxy groups shown by Rc, Rf and Rg are preferably 1-6 carbon atoms, more preferably 1-4 linear or branched alkoxy groups, such as methoxy, Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, Isohexyloxy and the like, preferably methoxy, tert-butoxy and the like.

In the formulas (L1) and (L2), the substituents of the phenyl groups that may be substituted represented by Rc, Rf and Rg include, for example, the same substituents as the substituents of the "phenyl groups that may be substituted" shown in the aforementioned Ra, etc. Group, preferably methyl, tert-butyl and the like. The number of the substituents is not particularly limited, preferably 1-3, which may be the same or different.

The transition metal in the transition metal catalyst is not particularly limited, for example, group VIII transition metals such as ruthenium, rhodium, palladium, iridium, platinum are preferred, and ruthenium is particularly preferred.

The transition metal catalyst may be a catalyst formed by coordinating one of the above-mentioned asymmetric ligands with a transition metal, or may be a catalyst formed by coordinating two or more asymmetric ligands with a transition metal at the same time.

The preparation method of the transition metal catalyst with asymmetric ligand is not particularly limited, for example, in the transition metal complex formed by preferred transition metal catalyst-optical activity phosphine derivative and ruthenium (hereinafter also referred to as phosphine-ruthenium In the case of a complex), it can be prepared according to a known method such as the method described in J. Chem. Soc., Chem. Commun., 922 (1985). Specifically, a phosphine-ruthenium complex can be prepared by reacting a ruthenium salt or its complex (for example, phenylruthenium(II) chloride dimer, etc.) with an optically active phosphine derivative in a solvent. Alternatively, the ruthenium salt or its complex and the optically active phosphine derivative may be directly added to the reaction solvent of the reduction reaction, and the reduction reaction may be performed simultaneously with the preparation of the phosphine-ruthenium complex.

The mixing ratio of the asymmetric ligand and the transition metal is: relative to 1 mole of the asymmetric ligand, the transition metal is 0.3-3 moles, preferably 0.5-2 moles.

The transition metal catalyst having an asymmetric ligand is usually used in an amount of 0.00001-0.2 mol, preferably 0.0001-0.1 mol, relative to 1 mol of compound (XXI).

The pressure of hydrogen used is usually 0.1-10 MPa, preferably 0.3-3 MPa.

The solvent for the reduction reaction includes, for example, ethanol, methanol, 2-propanol, 1-propanol, ethyl acetate, acetic acid, DMF, etc., preferably ethanol, 1-propanol, and the like. The solvent is usually used in an amount of 1-30 L, preferably 3-15 L, relative to 1 kg of compound (XXI).

The reaction temperature of the reduction reaction is usually 0°C-150°C, preferably 50°C-120°C; the reaction time is related to the reagents, reaction temperature or hydrogen pressure, etc., and is usually 1-24 hours.

Compound (XXII) can be isolated by conventional methods such as pouring the reaction solution into aqueous sodium bicarbonate solution, extracting with a solvent, separating the layers, then washing the organic layer, and removing the catalyst by flash chromatography, etc., whereby compound (XXII) can be isolated. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

In the above preparation method, by selecting an asymmetric ligand, the compound having the absolute stereoconfiguration shown in formula (XXII) and its enantiomer can be prepared. For example, when compound (L1)-compound (L6) is usually used as an asymmetric ligand, a compound having an absolute stereo configuration shown in formula (XXII) can be prepared, that is, the (1'R, 2R)-configuration can be prepared; and When using the enantiomer of compound (L1)-compound (L6) as an asymmetric ligand, the enantiomer of the compound with the absolute stereoconfiguration shown in formula (XXII) can be prepared, that is, (1'S , 2S)-configuration. Specifically, for example, when using optically active BINAP as an asymmetric ligand, if (S)-BINAP is used, a compound having an absolute stereoconfiguration shown in formula (XXII) can be prepared, that is, (1'R, 2R )-configuration; while using (R)-BINAP, the enantiomer of the compound having the absolute stereoconfiguration shown in formula (XXII) can be prepared, that is, the (1'S, 2S)-configuration can be prepared.

(2) Preparation of compound (XXVI) from compound (XXII)

Compound (XXVI) can be obtained by introducing a protecting group into compound (XXII), followed by reduction and cyclization. That is, compound (XXIV) is obtained by introducing a protecting group into compound (XXII), compound (XXIV) is obtained by reducing compound (XXIV) obtained, and compound (XXVI) is obtained by deprotecting and cyclizing compound (XXV) obtained.

Compound (XXIV) is prepared from compound (XXII)

Compound (XXIV) can use compound (XXII) as a raw material, for example, by (2A): simultaneously carrying out the step of deprotecting the hydroxyl group of compound (XXII) and introducing a diol protecting group to directly obtain compound (XXIV), or (2B) : Compound (XXII) is deprotected to obtain compound (XXIII), and a diol protecting group is introduced into the obtained compound (XXIII) to obtain compound (XXIV). Among them, step (2A) is simpler and thus preferred.

A method for obtaining compound (XXIV) by simultaneously deprotecting compound (XXII) and protecting a diol will be described below. This method can be carried out by simultaneously adding a deprotection reagent and a protection reagent, and the reagent can be appropriately selected according to the type of the group to be deprotected and the protective group of the diol. Hereinafter, the case where the group to be deprotected in compound (XXII) is benzyl and the protecting group of diol is dimethylmethylene will be described as an example, but the present invention is not limited to this method.

For example, when the protecting group of compound (XXII) is benzyl and the protecting group of diol is dimethylmethylene, in a solvent (such as THF, ethyl acetate, etc., preferably THF, etc.) or without a solvent, use a catalyst ( For example, Pd/C, Pd(OH) ₂ , etc., preferably Pd/C, etc.) and acidic ion exchange resins (such as Amberlyst 15E (Rohm & Haas), Nafion SAC13 (produced by Dupont Company), etc.) or acids (such as phosphoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, boron trifluoride, phosphorus oxychloride, etc.), usually at -20°C to 100°C, preferably 0°C to 50°C, under a hydrogen atmosphere , compound (XXII) is reacted with the protecting reagent 2,2-dimethoxypropane and/or acetone usually for 0.5-48 hours, preferably 1-24 hours, to obtain compound (XXIV).

The amount of protecting reagents such as 2,2-dimethoxypropane used is usually 0.5-100 L, preferably 1-50 L relative to 1 kg of compound (XXII). The reducing catalyst is usually used in an amount of 0.0001 to 0.5 kg relative to 1 kg of compound (XXII). The amount of acidic ion exchange resin used is usually 0.001-0.5 kg, preferably 0.005-0.1 kg, relative to 1 kg of compound (XXII). When other acids are used, the amount of the acid used is usually 0.00001-0.1 kg, preferably 0.0001-0.01 kg, per 1 kg of compound (XXII). When a solvent is used, the amount of the solvent used is usually 0.5-50 L, preferably 1-25 L, per 1 kg of compound (XXII).

Compound (XXIV) can be isolated by filtering the catalyst and distilling off the solvent. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

When R ₁₀ is a hydrogen atom and R ₁₁ is a lower alkyl group or phenyl group, it is generally possible to use alkanal or benzaldehyde and/or acetal of alkanal or benzaldehyde (such as dimethyl acetal etc.) instead of the above-mentioned 2,2-dimethoxypropane or acetone, the same reaction as above was carried out.

When R ₁₀ is lower alkyl or phenyl, and R ₁₁ is lower alkyl or phenyl, usually R ₁₀ COR ₁₁ and/or its acetal (such as dimethyl acetal, etc.) can be used instead of the above-mentioned 2,2-di Methoxypropane or acetone is subjected to the same reaction as above.

When R ₁₀ is lower alkyl or phenyl, and R ₁₁ is lower alkoxy, usually trialkyl orthoalkanoate (such as MeC(OEt) ₃ , etc.) or trialkyl orthobenzoate can be used instead of the above 2 , 2-dimethoxypropane or acetone, carry out the same reaction as above.

When R ₁₀ is a hydrogen atom and R ₁₁ is a lower alkoxy group, usually a trialkyl orthoformate can be used instead of the above-mentioned 2,2-dimethoxypropane or acetone, and the same reaction as above can be carried out.

When R ₁₀ and R ₁₁ are both lower alkoxy groups, usually tetraalkyl orthocarbonate can be used instead of the above-mentioned 2,2-dimethoxypropane or acetone, and the same reaction as above can be carried out.

The compound having the absolute stereoconfiguration represented by formula (XXIV) can be prepared by the above-mentioned method from the compound having the absolute stereoconfiguration represented by formula (XXII) as a raw material. The enantiomers of the compound having the absolute stereoconfiguration represented by formula (XXIV) can be prepared according to the above method using the enantiomers of the compound having the absolute stereoconfiguration represented by formula (XXII) as raw materials.

Compound (XXV) is prepared from compound (XXIV)

Compound (XXV) can be obtained by reducing compound (XXIV). The reduction reaction can be carried out according to a conventional method for reducing a lactone to a lactone. For example, using a reducing agent (such as DIBAL-H, sodium 2-methoxyethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, etc., preferably DIBAL-H, lithium tri-tert-butoxyaluminum hydride, etc.), in In a solvent (such as dichloromethane, toluene, THF, MTBE, etc., preferably dichloromethane, toluene, THF, etc.), react at -100°C to 50°C, preferably -80°C to 0°C for 10 minutes to 6 hours, preferably 15 minutes - 3.5 hours to carry out.

The reducing agent is usually used in an amount of 0.8 to 1.5 moles, preferably 1 to 1.2 moles, relative to 1 mole of compound (XXIV). The solvent is usually used in an amount of 1-50 L, preferably 2-20 L, per 1 kg of compound (XXIV).

Compound (XXV) can be isolated by a conventional method, for example, pouring the reaction solution into a saturated aqueous ammonium chloride solution for liquid separation, dehydrating the obtained organic layer with anhydrous magnesium sulfate, filtering, and distilling off the solvent to obtain isolation. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

The compound having the absolute stereoconfiguration represented by formula (XXV) can be prepared by the above-mentioned method from the compound having the absolute stereoconfiguration represented by formula (XXIV) as a raw material. The enantiomers of the compound having the absolute stereoconfiguration represented by formula (XXV) can be prepared according to the above method using the enantiomers of the compound having the absolute stereoconfiguration represented by formula (XXIV) as raw materials.

Preparation of compound (XXVI) from compound (XXV)

Compound (XXVI) can be obtained by deprotecting and cyclizing Compound (XXV). For example, in a solvent (such as THF, 1,4-dioxane, MTBE, di-n-butyl ether, 1,2-dimethoxyethane, toluene, etc., preferably THF, toluene, etc.), using an acid (such as hydrochloric acid , sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, strongly acidic ion exchange resins, etc., preferably hydrochloric acid, sulfuric acid, etc.), usually at -30°C to 100°C, preferably 0°C-40°C, to make compound (XXV) The reaction usually takes 1 minute to 48 hours, preferably 1 minute to 24 hours, more preferably 10 minutes to 16 hours for deprotection and cyclization.

The amount of the acid used in the deprotection and cyclization is usually 0.001-10 L, preferably 0.01-2 L, relative to 1 kg of compound (XXV). The solvent used in the deprotection and cyclization is usually used in an amount of 1-50 L, preferably 2-20 L, per 1 kg of compound (XXV).

Compound (XXVI) can be separated by conventional methods. After the reaction, for example, neutralize the reaction solution with an aqueous alkali solution, then separate the layers, wash the obtained organic layer with brine, dehydrate with anhydrous magnesium sulfate, etc., and distill off the solvent to separate . The isolated product can be purified by conventional methods or used in subsequent reactions without purification.

The compound having the absolute stereoconfiguration represented by formula (XXVI) can be prepared from the compound having the absolute stereoconfiguration represented by formula (XXV) according to the above method. The enantiomers of the compound having the absolute stereoconfiguration represented by formula (XXV) can be prepared according to the above method using the enantiomers of the compound having the absolute stereoconfiguration represented by formula (XXV) as raw materials.

(3) Preparation of compound (XV) from compound (XXVI)

Compound (XV) can be obtained by inverting the hydroxyl group of compound (XXVI). The inversion of the hydroxyl group can be carried out, for example, through step (2C): oxidation of compound (XXVI), conversion to compound (XXVII), and then reduction to obtain the step of compound (XV); or step (2D): direct inversion of compound (XXVI) Esterification, conversion into compound (XXVIII), and hydrolysis to obtain compound (XV) are carried out.

Step (2C)

Compound (XXVII) is prepared from compound (XXVI)

Compound (XXVII) can be obtained by oxidizing compound (XXVI).

The oxidation reaction can be carried out by conventional methods for the oxidation of alcohols to ketones, for example by using oxalyl chloride and dimethylsulfoxide in the presence of a base such as triethylamine in a solvent such as dichloromethane, chlorobenzene, ethyl acetate , tert-butanol, etc., preferably dichloromethane, etc.), at -100°C to 50°C, preferably -80°C to 0°C, for 10 minutes to 12 hours, preferably 30 minutes to 5 hours.

The amount of oxalyl chloride used is usually 1-4 moles, preferably 1.5-3 moles, relative to 1 mole of compound (XXVI). The amount of dimethyl sulfoxide used is usually 1 mol to 5 mol, preferably 2 to 4 mol, relative to 1 mol of compound (XXVI). The solvent is usually used in an amount of 1-100 L, preferably 5-50 L, relative to 1 kg of compound (XXVI). The base such as triethylamine is usually used in an amount of 3 to 30 moles, preferably 5 to 20 moles, relative to 1 mole of compound (XXVI).

Compound (XXVII) can be isolated by a conventional method, for example, pouring the reaction solution into a saturated aqueous ammonium chloride solution for liquid separation, washing the obtained organic layer with a saturated aqueous ammonium chloride solution, and distilling off the solvent. The isolated product can be purified by conventional methods or used in subsequent reactions without purification.

Preparation of compound (XV) from compound (XXVII)

Compound (XV) can be obtained by reducing compound (XXVII).

The reduction reaction can be carried out by a conventional method for reducing a ketone to an alcohol, for example, using a reducing agent (such as lithium aluminum hydride, sodium borohydride, lithium borohydride, DIBAL-H, etc., preferably lithium aluminum hydride, sodium borohydride, etc.) in a solvent (such as THF, MTBE, methanol, ethanol, 2-propanol, etc., preferably THF, methanol, ethanol, etc.), at -30°C to 100°C, preferably 0°C-50°C for 10 minutes to 12 hours, preferably 30 minutes -5 hours to proceed.

The reducing agent is usually used in an amount of 0.25-1.5 mol, preferably 0.25-0.75 mol, relative to 1 mol of compound (XXVII). The solvent is usually used in an amount of 2-100 L, preferably 5-50 L, per 1 kg of compound (XXVII).

Compound (XV) can be isolated by a conventional method, for example, adding aqueous sodium hydroxide solution to the reaction solution, filtering, washing with THF, dehydrating the filtrate with anhydrous magnesium sulfate, filtering, and distilling off the solvent. Isolates can be purified by conventional methods.

step (2D)

Compound (XXVIII) is prepared from compound (XXVI)

Compound (XXVIII) can be obtained by inverse esterification of the hydroxyl group of compound (XXVI). Inverse esterification, for example, can be carried out as follows: in the condensing agent triphenylphosphine or trialkylphosphine (such as tricyclohexylphosphine, tributylphosphine, trihexylphosphine, trioctylphosphine, etc., preferably triphenylphosphine, tricyclohexylphosphine Phosphine, etc.), and azodicarboxylates (such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, dimethyl azodicarboxylate, azodicarboxylate dibenzyl formate, etc., preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or azodicarboxamide (such as 1,1'-azobis(N,N-dimethyl formamide), 1,1'-(azodicarbonyl) bispiperidine, etc., preferably in the presence of 1,1'-(azodicarbonyl) bispiperidine, etc.), compound (XXVI) and formula: R ₉ OH[wherein, R ₉ represents the same meaning as above. ] The compound reaction shown. For example, using the condensing agent, in a solvent (such as toluene, xylene, 1,3,5-trimethylbenzene, THF, MTBE, 1,2-dimethoxyethane, dichloromethane, chlorobenzene, etc., preferably Toluene, xylene, THF, etc.), react at -20°C to 100°C, preferably 0°C-60°C, for 0.5-48 hours, preferably 2-24 hours.

Formula: Compounds represented by R ₉ OH are, for example, benzoic acid, 4-methoxybenzoic acid, 4-nitrobenzoic acid, 3,5-dinitrobenzoic acid, 4-phenylbenzoic acid, acetic acid, formic acid, three Fluoroacetic acid, etc., preferably benzoic acid, acetic acid, etc. Relative to 1 mole of compound (XXVI), the amount of the compound represented by the formula: R ₉ OH is usually 1-4 moles, preferably 1-2.5 moles, and relative to 1 kg of compound (XXVI), the amount of solvent used is usually 2-100 L, Preferably 5-50L.

Triphenylphosphine or trialkylphosphine is usually used in an amount of 1 to 4 moles, preferably 1 to 2.5 moles, relative to 1 mole of compound (XXVI). The azodicarboxylate or azodicarboxamide is usually used in an amount of 1 to 4 moles, preferably 1 to 2.5 moles, relative to 1 mole of compound (XXVI).

Compound (XXVIII) can be isolated by a conventional method, for example, separating the reaction liquid, washing the organic layer with water, and distilling off the solvent. The isolate can be purified by a conventional method, or it can be used in the subsequent reaction without purification.

Preparation of compound (XV) from compound (XXVIII)

Compound (XV) can be obtained by hydrolyzing compound (XXVIII).

The hydrolysis can be carried out, for example, by a conventional method with a base. The reaction can be carried out in the presence of a base (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, ammonia, etc., preferably sodium hydroxide, potassium carbonate, etc.) in a solvent (such as methanol, ethanol, 2-propanol, water or their mixed solvents, preferably methanol, ethanol, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, etc.), react at 0°C-80°C, preferably 10°C-50°C, for 10 minutes to 24 hours, It is preferably carried out for 0.5 hours to 12 hours.

The base is usually used in an amount of 1-200 mol, preferably 2-130 mol, relative to 1 mol of compound (XXVIII). The solvent is usually used in an amount of 1-1000 L, preferably 5-500 L, relative to 1 kg of compound (XXVIII).

Compound (XV) can be isolated by conventional methods, such as distilling off the solvent of the reaction solution, adding water to the residue, adding common salt to the aqueous layer washed with toluene to make it saturated, then separating the layers, and washing the organic layer with anhydrous Separation can be achieved by dehydrating with magnesium sulfate and distilling off the solvent. Isolates can be purified by conventional methods.

The compound having the absolute stereoconfiguration represented by formula (XV) can be prepared from the compound having the absolute stereoconfiguration represented by formula (XXVI) according to the method of the above step (2C) or (2D). The enantiomer of the compound with the absolute stereoconfiguration shown in formula (XV) can be a raw material with the enantiomer of the compound with the absolute stereoconfiguration shown in formula (XXVI), according to the above steps (2C) or Prepared by the method of (2D).

Example

The following examples illustrate the present invention specifically, but the present invention is not limited by these examples. * indicates relative stereo configuration, (±) indicates racemate.

Example 1 (1'R ^* , 2S ^* )-2-[2'-(1,1-dimethylethoxy)-1'-hydroxyethyl]-4-butyrolactone (with formula (Compounds with relative stereo configurations shown in (VII))

Ethyl 4-tert-butoxyacetoacetate (20.0 g), which can be synthesized according to the method described in Heterocycles 26, 2841 (1987), was dissolved in methanol (150 mL), and sodium borohydride (1.68 g), stirred for 1 hour, then added water (100 mL). Most of the solvent was distilled off, extracted twice with MTBE (150mL), the organic layer was fully washed with water, and then MTBE was distilled off to obtain (±)-ethyl 4-tert-butoxy-3-hydroxybutyrate (16.9g) . A 1.5M solution of lithium diisopropylamide in cyclohexane (73 mL) was added to THF (100 mL), and (±)-4-tert-butoxy - A solution of ethyl 3-hydroxybutyrate (10.66 g) in THF (30 mL) was then warmed to -20°C. Separately, 2-(1-ethoxyethoxy ) ethyl iodide (19.1 g), 15.3 g of it was added dropwise at about -20°C to 0°C to the previously mentioned solution warmed to -20°C, and then stirred overnight at room temperature. The reaction solution was poured into 1N aqueous hydrochloric acid solution (100 mL), MTBE (100 mL) was added, extracted, washed with saturated aqueous sodium bicarbonate solution, and the solvent was distilled off. Ethanol (150 mL) and p-toluenesulfonic acid monohydrate (1.3 g) were added to the residue, followed by stirring at room temperature for 6 hours. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction liquid, and most of the solvent was distilled off, followed by extraction with MTBE (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was flash chromatographed using heptane/ethyl acetate (3:1) as eluent to give the title compound (2.0 g) as pale yellow crystals.

¹ H-NMR (CDCl ₃ , δppm): 1.20 (3H, s), 2.17-2.28 (1H, m), 2.37-2.44 (1H, m), 2.77-2.82 (1H, m), 3.38 (1H (- OH), d, J=2Hz), 3.49(1H,dd, J=9Hz, J=4Hz), 3.56(1H,dd, J=9Hz, J=6Hz), 3.90-3.96(1H,m), 4.22 -4.28(1H, m), 4.39-4.45(1H, m).

Example 2 Synthesis of (1'R ^* , 2S ^* )-2-(1', 2'-dihydroxyethyl)-4-butyrolactone (compound with relative configuration shown in formula (VIII))

(1'R ^* ,2S ^* )-2-[2'-(1,1-dimethylethoxy)-1'-hydroxyethyl]-4-butyrolactone (1.3 g) was added to tris Fluoroacetic acid (4 mL) was stirred in an ice bath for 90 minutes, and then the trifluoroacetic acid was directly distilled off under reduced pressure to obtain the title compound (1.0 g).

¹ H-NMR (CDCl ₃ , δppm): 2.10-2.20 (1H, m), 2.37-2.44 (1H, m), 2.80-2.87 (1H, m), 3.6-3.8 (1H (-OH), br) , 3.67(1H,dd, J=12Hz, J=6Hz), 3.75(1H,dd, J=12Hz, J=3Hz), 3.86-3.90(1H,m), 4.24-4.30(1H,m), 4.43 (1H, dt, J=9Hz, J=3Hz), 4.4-4.5(1H(-OH), br).

Example 3 (2S ^* , 4'R ^* )-2-(2', 2'-dimethyl-[1', 3']dioxolan-4'-yl)-4-butyrolactone Synthesis (compounds with relative stereoconfiguration shown in formula (IX))

To (1'R ^* ,2S ^* )-2(1',2'-dihydroxyethyl)-4-butyrolactone (1.0 g) was added 2,2-dimethoxypropane (15 mL), then p-Toluenesulfonic acid monohydrate (50 mg) was added, followed by stirring at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (100 mL), extracted twice with MTBE (50 mL), the organic layer was washed well with saturated aqueous sodium bicarbonate, and the solvent was distilled off to obtain the title compound (0.75 g).

¹ H-NMR (CDCl ₃ , δppm): 1.36 (3H, s), 1.42 (3H, s), 2.18-2.28 (1H, m), 2.37-2.47 (1H, m), 2.88-2.95 (1H, m ), 3.97(1H, dd, J=9Hz, J=6Hz), 4.08(1H,dd, J=9Hz, J=7Hz), 4.19-4.36(1H, m), 4.37-4.45(1H, m), 4.45-4.49(1H, m). Example 4 (3S*, 4'R*)-3-(2', 2'-dimethyl-[1', 3']dioxolane-4'- base) synthesis of tetrahydrofuran-2-alcohol (with the compound of relative stereoconfiguration shown in formula (XI))

(2S ^* , 4'R ^* )-2-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)-4-butyrolactone (400mg) Dissolve in dichloromethane (4 mL), add DIBAL-H 1.0 M toluene solution (2.4 mL) at around -78°C, and stir at the same temperature for 1 hour. Pour the reaction solution into saturated aqueous ammonium chloride solution (2 mL), extract with MTBE (7.5 mL), dehydrate the organic layer with anhydrous magnesium sulfate, add a small amount of filter aid (diatomaceous earth, celite company) to filter, distill off solvent to obtain the title compound (340 mg).

¹ H-NMR (CDCl ₃ , δppm): 1.35 (3H, s), 1.44 (3H, s), 1.45-1.58 (1H, m), 1.78-1.85 (1H, m), 2.08-2.35 (2H, m ), 3.62-3.72(1H, m), 3.86-4.08(3H, m), 4.10-4.17(0.5H, s), 4.27-4.33(0.5H, m).

Example 5 Synthesis of (3R ^* , 3aS ^* , 6aR ^* )-hexahydrofuro[2,3-b]furan-3-ol (compound with relative configuration shown in formula (XV))

(3S ^* , 4'R ^* )-3-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)tetrahydrofuran-2-ol (120mg) was dissolved in THF (2 mL), 6N hydrochloric acid (0.1 mL) was added, and stirred at room temperature for 20 minutes. A 10% aqueous solution of sodium bicarbonate (2 mL) was added to the reaction liquid, extracted with ethyl acetate (2 mL), washed with 10% brine (2 mL), dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (50 mg ). ¹ H-NMR showed no stereoisomer peaks. ¹ H-NMR (CDCl ₃ , δppm): 1.73 (1H (-OH), d, J=6Hz), 1.82-1.93 (1H, m), 2.28-2.34 (1H, m), 2.82-2.89 (1H, m), 3.65(1H, dd, J=9Hz, J=7Hz), 3.88-3.94(1H, m), 3.97-4.02(2H, m), 4.42-4.49(1H, m), 5.70(1H, d , J＝5Hz).

Example 6 Synthesis of (1'R ^* , 2S ^* )-2-[2'-benzyloxy-1'-hydroxyethyl]-4-butyrolactone (with relative configuration shown in formula (VII) compound of)

Dissolve ethyl 4-benzyloxyacetoacetate (42.1g) which can be synthesized according to the method described in USP5399722 in methanol (300mL), then add sodium borohydride (3.03g) at 5°C-10°C, stir for 1 hour and then add water (300 mL). Most of the solvent was distilled off, extracted twice with MTBE (300 mL), the organic layer was washed twice with 2% sodium bicarbonate (100 mL), washed twice with saturated brine (150 mL), dehydrated with anhydrous magnesium sulfate, and then filtered , MTBE was distilled off to obtain ethyl (±)-4-benzyloxy-3-hydroxybutyrate (38.8 g). A 1.5M cyclohexane solution (190 mL) of lithium diisopropylamide was added to THF (200 mL), and (±)-4-benzyloxy- A solution of ethyl 3-hydroxybutyrate (29.4 g) in THF (50 mL) was then warmed to -20°C. Separately, 2-(1-ethoxyethoxy ) ethyl iodide (47.9g), 39.3g of which was added dropwise at about -20°C to 0°C into the above-mentioned solution heated to -20°C, and stirred overnight at room temperature. The reaction solution was poured into 1N aqueous hydrochloric acid solution (450 mL), extracted twice with MTBE (200 mL), washed with saturated aqueous sodium bicarbonate solution, and the solvent was distilled off. Methanol (300 mL) and p-toluenesulfonic acid monohydrate (5.3 g) were added to the residue, followed by stirring at room temperature for 6 hours. After adding triethylamine (2.0 g) to the reaction liquid, most of the solvent was distilled off, followed by extraction with ethyl acetate (300 mL). The organic layer was washed with water (150 mL) and saturated aqueous sodium bicarbonate (150 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off. Diisopropyl ether (120 mL) was added to the residue, and the title compound (5.65 g) (light yellow crystals) was obtained by recrystallization. No cis-form (1'R ^* , 2R ^* -body) peak was detected in either NMR or HPLC under the following conditions.

¹ H-NMR (CDCl ₃ , δppm): 2.06-2.17 (1H, m), 2.27-2.33 (1H, m), 2.78-2.85 (1H, m), 3.62 (1H (-OH), br), 3.61 -3.67(2H, m), 3.97-4.01(1H, m), 4.18-4.24(1H, m), 4.39(1H, dt, J=9Hz, J=3Hz), 4.55(1H, d, J=12Hz ), 4.63 (1H, d, J=12Hz), 7.26-7.37 (5H, m).

HPLC conditions: Daicel Chiralcel OD-H (0.46cmφ×25cm, 9/1 hexane/2-propanol; 1ml/min, 254nm) cis-(1'R, 2R)t _r = 15 minutes; cis- (1'S,2S)t _r =17 minutes; trans-(1'R,2S) or trans-(1'S,2R)t _r =19 minutes or t _r =24 minutes.

Example 7 Synthesis of (1'R ^* , 2S ^* )-2-(1', 2'-dihydroxyethyl)-4-butyrolactone (compound with relative configuration shown in formula (VIII))

Dissolve (1'R ^* , 2S ^* )-2-(2'-benzyloxy-1'-hydroxyethyl)-4-butyrolactone (2.00g) in ethyl acetate (30mL) and add 10% Pd/C (NEChemcat, hydrous PE-type) (200 mg) was stirred at about 25° C. for 3 hours under normal pressure hydrogen. The catalyst was filtered, and the solvent was distilled off to obtain the title compound (1.27 g). Its spectrum data is consistent with embodiment 2.

Example 8 (1'R ^* , 2S ^* )-2-[2'-benzyloxy-1'-(1"-ethoxyethoxy) ethyl]-4-butyrolactone (with Compounds with relative stereo configurations shown in formula (X))

Dissolve (1'R ^* , 2S ^* )-2-(2'-benzyloxy-1'-hydroxyethyl)-4-butyrolactone (1.00 g) in THF (10 mL) and MTBE (20 mL) To the mixed solvent, p-toluenesulfonic acid monohydrate (60 mg) was added, and ethyl vinyl ether (1.1 g) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, poured into a saturated aqueous sodium bicarbonate solution, extracted with MTBE, washed well with a saturated aqueous sodium bicarbonate solution, and the solvent was distilled off to obtain the title compound (1.24 g).

¹ H-NMR (CDCl ₃ , δppm): 1.15 (1.5H, t, J=7Hz), 1.19 (1.5H, t, J=7Hz), 1.29 (1.5H, d, J=6Hz), 1.31 (1.5 H, d, J=6Hz), 2.17-2.37 (2H, m), 2.92-2.98 (1H, m), 3.42-3.62 (2H, m), 3.70-3.78 (2H, m), 4.08-4.37 (3H , m), 4.54 (2H, s), 4.82 (1H, q, J=5Hz), 7.26-7.36 (5H, m).

Example 9 Synthesis of (1'R ^* , 3S ^* )-3-[2'benzyloxy-1'-(1"-ethoxyethoxy)ethyl]tetrahydrofuran-2-alcohol (with formula ( XII) The compound with the relative stereo configuration)

Dissolve (1'R ^* ,2S ^* )-2-[2'-benzyloxy-1'-(1"-ethoxyethoxy)ethyl]-4-butyrolactone (1.22g) in Add toluene (10mL), add DIBAL-H 1.0M toluene solution (4.4mL) around -78°C, and stir at the same temperature for 1 hour. Add saturated ammonium chloride aqueous solution (5mL) to the reaction solution, add anhydrous sulfuric acid Magnesium was filtered through a filter aid (diatomaceous earth, Celite Co.), and the solvent was distilled off to obtain the title compound (1.23 g).

¹ H-NMR (CDCl ₃ , δppm): 1.11-1.24 (3H, m), 1.31 (3H, d, J=5Hz), 1.62-1.83 (2H, m), 2.00-2.08 (0.5H, m), 2.20-2.38(0.5H, m), 2.40-2.51(0.5H, m), 2.63-2.80(0.5H, m), 3.44-4.21(7H, m), 4.48-4.61(2H, m), 4.75- 4.91(1H, m), 5.39-5.53(1H, m), 7.26-7.36(5H, m).

Example 10 Synthesis of (3R ^* , 3aS ^* , 6aR ^* )-hexahydrofuro[2,3-b]furan-3-ol (compound with relative configuration shown in formula (XV))

Dissolve (1'R ^* ,3S ^* )-3-[2'-benzyloxy-1'-(1"-ethoxyethoxy)ethyl]tetrahydrofuran-2-ol (1.22 g) in acetic acid Ethyl ester (20 mL), add 10% Pd/C (NEChemcat, aqueous PE-Type) (242 mg), under normal pressure hydrogen, stir at around 25 ° C for 1 hour. After the catalyst is filtered, the solvent is distilled off, and THF (10 mL ) and 6N hydrochloric acid (0.05mL), stirred for 1 hour near 25°C. Anhydrous potassium carbonate was added to the reaction solution, and the solvent was removed by distillation to obtain the title compound (0.49g). The spectrum data of this compound was consistent with that of Example 5 .Example 11 (2S ^* , 4'R ^* )-2-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)-4-butyrolactone The synthesis of (by the method for the direct synthesis compound (IX) of compound (VII))

Dissolve (1'R ^* , 2S ^* )-2-(2'-benzyloxy-1'-hydroxyethyl)-4-butyrolactone (97mg) in acetone (2.5mL) and add 2,2- Dimethoxypropane (0.5 mL), 10% Pd/C (NEChemcat, aqueous PE-Type) (48 mg) and ion exchange resin (Amberlyst15E (Dry), Rohm & Haas) (1 mg), under normal pressure hydrogen, Stir at around 25°C for 2 hours. After the catalyst was filtered, the solvent was distilled off to obtain the title compound (70 mg). The spectral data of this compound is consistent with embodiment 3.

Synthesis of Example 12 (3S, 3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-ol

Use, for example, (S)-4-benzyloxy-3-hydroxybutyrate ethyl ester that can be synthesized according to the method described in USP5399722 to replace (±)-4-benzyloxy-3-hydroxybutyrate ethyl ester in Example 6 , carried out in the same manner as in Example 6, (1'S, 2R)-2-[2'-benzyloxy-1'-hydroxyethyl]-4-butyrolactone can be prepared, and then, by carrying out Example 7, it is possible to prepare (1'S, 2R)-2-(1', 2'-dihydroxyethyl)-4-butyrolactone, and then by carrying out Example 3, (2R, 4'S)-2-(2', 2' can be prepared -Dimethyl-[1', 3']dioxolan-4'-yl)-4-butyrolactone, then by carrying out Example 4, (3R, 4'S)-3-(2', 2'-dimethyl-[1',3']dioxolan-4'-yl)tetrahydrofuran-2-alcohol, then by carrying out Example 5, (3S, 3aR, 6aS)-hexahydrofuran can be prepared And[2,3-b]furan-3-ol.

Synthesis of Example 13 (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol

Use, for example, (R)-4-tert-butoxy-3-hydroxybutyrate ethyl ester that can be synthesized according to the method described in Heterocycles 26, 2841 (1987) to replace (±)-4-tert-butoxy in Example 1 -Ethyl 3-hydroxybutyrate, also carry out Example 1, can prepare (1'R, 2S)-2-[2'-(1,1-dimethylethoxy)-1'-hydroxyethyl ]-4-butyrolactone, then carry out embodiment 2, can prepare (1 ' R, 2S)-2-(1 ', 2'-dihydroxyethyl)-4-butyrolactone, carry out embodiment 3 again , can prepare (2S,4'R)-2-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)-4-butyrolactone, followed by Example 4, (3S, 4'R)-3-(2', 2'-dimethyl-[1', 3']dioxolan-4'-yl)tetrahydrofuran-2-ol can be prepared, Following Example 5, (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol can be prepared.

The synthesis of reference example 1 2-benzyloxyethyl iodide

2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 mL), methanesulfonyl chloride (76.8 g) was added dropwise at 0°C-10°C, and stirred for 3 hours. Inject 10% aqueous sodium bicarbonate (300 mL) into the reaction solution, then separate the layers, extract the aqueous phase with MTBE (300 mL), combine the extracts, wash with 10% aqueous sodium bicarbonate and saturated brine, wash with anhydrous magnesium sulfate After dehydration, the solvent was distilled off to obtain 2-benzyloxyethyl methanesulfonate (124.0 g). 2-Benzyloxyethyl methanesulfonate (124.0 g) was dissolved in acetone (500 mL), sodium iodide (130.0 g) was added, and the mixture was stirred at 50°C to 60°C for 3 hours. After filtering the reaction solution, the solvent was distilled off, water (300 mL) was added, and extraction was performed twice with toluene (300 mL). The toluene phase was successively washed with aqueous sodium bisulfite, water and brine, dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain the title compound (127.0 g).

Example 14 Synthesis of (2S, 3R)-4-benzyloxy-3-hydroxyl-2-(2'-benzyloxyethyl) ethyl butyrate (compound shown in formula (XVII))

Under nitrogen flow, THF (140 mL) was added to diisopropylamine (20.9 g), and a 15 wt % n-butyllithium hexane solution (120 mL) was added to the resulting solution at -60°C to -65°C, and then - From 55°C to -65°C, ethyl (R)-4-benzyloxy-3-hydroxybutyrate (20.0 g) (above 99% ee), which can be synthesized according to the method described in USP5399722, was added dropwise. After the reaction solution was heated to -25°C, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (60g) was added dropwise at about -15°C according to 2-benzyloxyethyl iodide (27g) synthesized in reference example 1. The reaction solution was stirred at -15°C to -10°C for 23 hours, then 2 mol/L hydrochloric acid aqueous solution (160mL) was added, extracted twice with toluene (300mL), washed with 10% aqueous sodium bicarbonate solution, and then removed by distillation solvent to obtain the title compound and its diastereoisomer (2R,3R)-4-benzyloxy-3-hydroxy-2-(2'-benzyloxyethyl)butanoic acid in a 3:1 ratio Mixture of esters (35.9 g). A portion was isolated by preparative HPLC to afford the pure title compound.

The NMP spectrum of (2S,3R)-4-benzyloxy-3-hydroxy-2-(2’-benzyloxyethyl)butanoic acid ethyl ester

¹ H-NMR (CDCl ₃ , δppm): 1.19 (3H, t, J=7Hz), 1.84-1.92 (1H, m), 2.00-2.10 (1H, m), 2.78-2.83 (1H, m), 3.43 -3.57(4H, m), 3.89-3.95(1H, m), 4.08(2H, q, J=7Hz), 4.47(2H, s), 4.53(2H, s), 7.24-7.36(10H, m) .

Example 15 Synthesis of (2S, 3R)-4-benzyloxy-3-hydroxyl-2-(2'-benzyloxyethyl) butanoic acid (compound or salt thereof shown in formula (XVIII))

Will contain ethyl (2S,3R)-4-benzyloxy-3-hydroxy-2-(2'-benzyloxyethyl)butanoate and its diastereomer (2R, 3R)-4-benzyloxy-3-hydroxy-2-(2'-benzyloxyethyl)butyric acid ethyl ester mixture (27.0g) was dissolved in methanol (200mL), and 10% potassium hydroxide aqueous solution ( 57.8 g), heated at 60°C for 2 hours. Water (600 mL) was added to the reaction solution, washed with toluene (200 mL), adjusted to pH 1 with 2 mol/L hydrochloric acid aqueous solution, and extracted three times with toluene (300 mL). The toluene phase was washed with saturated brine (300 mL), then concentrated, ethanol (100 mL) was added to the resulting residue, the resulting solution was heated to 65° C., then dibenzylamine (27.0 g) was added, and the salt was obtained by cooling. It was recrystallized from ethanol (273 mL) and again recrystallized from ethanol (77 mL) to obtain the dibenzylamine salt (17.7 g) of the title compound with a de of 99% or more.

NMR spectrum of dibenzylamine salt

¹ H-NMR (CDCl ₃ , δppm): 1.89-2.07 (2H, m), 2.67-2.72 (1H, m), 3.48-3.60 (4H, m), 3.78 (4H, s), 3.87-3.91 (1H , m), 4.46 (2H, s), 6.4-6.7 (3H, br), 7.22-7.36 (20H, m).

The above compound (17.5g) was adjusted to pH below 1 with 2 mol/L hydrochloric acid (100mL), the aqueous phase was extracted 3 times with 150mL and 100mL toluene, washed with saturated brine and concentrated to obtain the title compound (9.4g ).

¹ H-NMR (CDCl ₃ , δppm): 1.86-1.97 (1H, m), 1.99-2.08 (1H, m), 2.81-2.86 (1H, m), 3.50-3.61 (4H, m), 3.97-4.01 (1H, m), 4.49 (2H, s), 4.53 (2H, s), 7.24-7.35 (10H, m).

Optical rotation [α] _D ²⁶ -3.5°(C=4.0, MeOH)

Example 16 (2S, 4'R)-2-(2', 2'-dimethyl-[1', 3'] dioxolane-4'-yl)-4-butyrolactone synthesis ( Compound shown in formula (IX))

Dissolve (2S,3R)-4-benzyloxy-3-hydroxy-2-(2'-benzyloxyethyl)butanoic acid (8.36 g) in 2,2-dimethoxypropane (80 mL), Anhydrous magnesium sulfate (1.4 g), Amberlyst 15 (Dry) (1.3 g), and 10% palladium on carbon (1.7 g) were reacted under normal pressure hydrogen for 3 hours. The reaction solution was filtered, the solvent was distilled off, 10% aqueous sodium bicarbonate (200 mL) was added, washed with heptane (100 mL), and extracted three times with ethyl acetate (200 mL). The organic phase was dehydrated with anhydrous magnesium sulfate, followed by distillation in accordance with Example 3.

Optical rotation [α] _D ²⁸ +16.4° (C=4.0, MeOH)

Example 17 (3S, 4'R)-3-(2', 2'-dimethyl-[1', 3'] dioxolane-4'-yl) tetrahydrofuran-2-alcohol synthesis (formula Compound shown in (XI))

(2S,4'R)-2-(2',2'-Dimethyl-[1',3']dioxolan-4'-yl)-4-butyrolactone (2.7 g) was dissolved In toluene (30mL), cooled to -78°C, then added 1.0 M DIBAL-H toluene solution (16mL), stirred at the same temperature for 2 hours. Saturated ammonium chloride aqueous solution (25 mL) and MTBE (20 mL) were added to the reaction liquid, anhydrous magnesium sulfate (10 g) and diatomaceous earth (5 g) were added, and the mixture was filtered. The residue was sufficiently extracted with ethyl acetate, combined with the filtrate, and the solvent was distilled off to obtain the title compound (2.4 g).

The NMR spectrum data of this compound is consistent with Example 4.

Example 18 Synthesis of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol (compound represented by formula (XV))

Dissolve (3S,4'R)-3-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)tetrahydrofuran-2-ol (2.4g) in THF (20 mL), 2 mol/L hydrochloric acid (3.2 mL) was added, and stirred at room temperature for 16 hours. Water (30 mL) and sodium bicarbonate (5 g) were added to the reaction solution, washed twice with heptane (15 mL), salt was added to the aqueous phase until saturated, and extracted 10 times with ethyl acetate (50 mL). The almost pure title compound (1.4 g) was obtained by concentrating the ethyl acetate.

The NMR spectrum data of this compound is consistent with Example 5.

Optical rotation [α] _D ²⁶ -12.0° (C=5.6, MeOH)

Embodiment 19 (2S, 3R)-4-benzyloxy-3-hydroxyl-2-[2'-(1,1-dimethylethoxy) ethyl] synthetic (formula (XVII) ) compound)

Under a nitrogen stream, THF (200 mL) was added to diisopropylamine (23.4 g), and a 15 wt % n-butyllithium hexane solution (140 mL) was added to the resulting solution at -60°C to -65°C, and then - Ethyl (R)-4-benzyloxy-3-hydroxybutyrate (25.0 g) (more than 99% ee), which can be synthesized according to the method described in USP5399722, was added dropwise at 55°C to -65°C. The reaction solution was heated to -25°C, and then 2-tert-butoxyethyl iodide (26.4g) was added dropwise at about -20°C (using 2-tert-butoxyethanol as a raw material instead of 2-benzyloxyethanol, according to Synthesis of reference example 1). The reaction solution was stirred at room temperature for 24 hours, then 2 mol/L hydrochloric acid aqueous solution (200mL) was added, extracted twice with MTBE (250mL), washed with 10% aqueous sodium bicarbonate solution, and the solvent was removed by distillation to obtain 3:1 The ratio contains the title compound and its diastereoisomer (2R,3R)-4-benzyloxy-3-hydroxy-2-[2'-(1,1-dimethylethoxy)ethyl]butyl A mixture of ethyl esters (35.9 g). A portion was isolated by preparative HPLC to afford the pure title compound.

NMR Spectrum of (2S, 3R)-4-benzyloxy-3-hydroxy-2-[2'-(1,1-dimethylethoxy)ethyl]butyric acid ethyl ester

¹ H-NMR (CDCl ₃ , δppm): 1.15 (3H, s), 1.23 (3H, t, J=7Hz), 1.74-1.82 (1H, m), 1.93-2.02 (1H, m), 2.76-2.81 (1H, m), 3.30-3.62 (4H, m), 3.90-3.98 (1H, m), 4.11 (2H, q, J=7Hz), 4.54 (2H, s), 7.24-7.35 (5H, m) .

Embodiment 20 (2S, 3R)-4-benzyloxy-3-hydroxyl-2-[2'-(1,1-dimethylethoxy) ethyl] butanoic acid synthesis (formula (XVIII) indicated compound or its salt)

Will contain (2S,3R)-4-benzyloxy-3-hydroxy-2-[2'-(1,1-dimethylethoxy)ethyl]butanoic acid ethyl ester and its A mixture of diastereoisomers (2R, 3R)-4-benzyloxy-3-hydroxy-2-[2'-(1,1-dimethylethoxy)ethyl]butanoic acid ethyl ester ( 10.3 g) was dissolved in methanol (30 mL), 20% potassium hydroxide aqueous solution (13 g) was added, and the mixture was heated at 60° C. for 2 hours. After methanol was distilled off, water (200 mL) was added, washed twice with toluene (100 mL), adjusted to pH 1 with 2 mol/L aqueous hydrochloric acid, and extracted twice with toluene (100 mL). The toluene phase was washed with saturated brine (100 mL), then concentrated, methanol (18 mL) was added to the concentrated residue, the solution was heated to 65° C., and dibenzylamine (4.2 g) was added, and the salt was obtained by cooling, which was dissolved in ethanol (25 mL) and recrystallized again from 77 mL and 60 mL of ethanol to obtain the dibenzylamine salt of the title compound (2.03 g) with a de greater than 99%. The compound (2.0 g) was adjusted to a pH below 1 with 2 mol/L hydrochloric acid (10 mL), and the aqueous phase was extracted with 20 mL and 50 mL of toluene, washed with saturated brine and concentrated to obtain the title compound (1.2 g).

Example 21 (1'R, 2S)-2-[2'-benzyloxy-1'-hydroxyethyl]-4-butyrolactone synthesis (compound shown in formula (VII))

Dissolve (2S,3R)-4-benzyloxy-3-hydroxy-2-[2'-(1,1-dimethylethoxy)ethyl]butanoic acid (0.80 g) in THF (10 mL) , trifluoromethanesulfonic acid (122 mg) was added, and stirred at room temperature for 3 days. After distilling off the solvent, the reaction solution was washed with heptane (100 mL), then extracted into the aqueous phase with 10% aqueous sodium bicarbonate (100 mL), (200 mL), and the aqueous phase was extracted three times with ethyl acetate (100 mL). It was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (0.37 g) as pale yellow crystals.

The NMR spectrum of this compound is consistent with Example 6.

Under the conditions of HPLC using the optical activity column of Example 6, only the peak corresponding to the anti-(1'R, 2S)-configuration was seen, and the peaks of other isomers were all below the detection sensitivity. Example 22 (1'R, 2R)-2-[2'-benzyloxy-1'-hydroxyethyl]-4-butyrolactone synthesis (compound (XXII))

2-benzyloxyacetyl-γ-butyrolactone (29.7 g), which can be synthesized according to the method described in JP-A-10-218881, was dissolved in ethanol (300 mL), and then heated under a hydrogen atmosphere at 500 kPa, 100 At °C, a DMF (30 mL) solution of (S)-(-)-BINAP (791 mg) and (S)-(-)-BINAP (791 mg) dimer (318 mg) was reacted for 3 hours. The reaction solution was poured into 5% aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, and the catalyst was removed by flash chromatography to obtain a mixture of isomers (23.5 g) mainly containing the title compound. The obtained cis:trans diastereoisomer ratio was 11:2, and the optical purity of the cis isomer (1'R, 2R configuration) was 78% ee.

Cis: ¹ H-NMR (CDCl ₃ , δppm): 2.14-2.22 (1H, m), 2.33-2.43 (1H, m), 2.73 (1H, dt, J=10Hz, J=4Hz), 2.79 (1H (-OH), d, J=5Hz), 3.55(2H, d, J=6Hz), 4.16-4.23(1H, m), 4.28-4.33(1H, m), 4.36(1H, dt, J=9Hz , J=3Hz), 4.54(1H, d, J=12Hz), 4.57(1H, d, J=12Hz), 7.26-7.38(5H, m).

HPLC conditions: Daicel Chiralcel OD-H (0.46cmφ×25cm, 9/1 hexane/2-propanol; 0.8ml/min, 254nm) cis-(1'R, 2R)t _r = 16 minutes; cis -(1'S, 2S) t _r =19 minutes; trans-(1'R, 2S) or trans-(1'S, 2R) t _r =21 minutes or t _r =26 minutes Example 23 (2R, 4' Synthesis of R)-2-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)-4-butyrolactone (compound (XXIV))

(1'R, 2R)-2-(2'-benzyloxy-1'-hydroxyethyl)-4-butyrolactone (23.5 g) obtained in Example 22 was dissolved in acetone (150 mL), and 2 , 2-dimethoxypropane (40 mL), 10% Pd/C (N.E. Chemcat, aqueous PE-Type) (3.0 g), Amberlyst 15E (Dry) (0.94 g), stirred under atmospheric hydrogen for 22 hours. After the catalyst was filtered, the solvent was distilled off to obtain the title compound (17.7 g).

¹ H-NMR (CDCl ₃ , δppm): 1.36 (3H, s), 1.42 (3H, s), 2.28-2.44 (2H, m), 2.68-2.74 (1H, m), 3.85 (1H, dd, J =9Hz, J=6Hz), 4.22(1H, dd, J=9Hz, J=6Hz), 4.26-4.30(1H, m), 4.35-4.44(2H, m).

Example 24 (3R, 4'R)-3-(2', 2'-dimethyl-[1', 3'] dioxolane-4'-yl) tetrahydrofuran-2-alcohol synthesis (compound (XXV))

(2R, 4'R)-2-(2', 2'-dimethyl-[1', 3']dioxolan-4'-yl)-4-butyrolactone obtained in Example 23 ( 17.7 g) was dissolved in THF (150 mL), and a 1.0 M toluene solution (100 mL) of DIBAL-H was added at around -70°C, followed by stirring at the same temperature for 3.5 hours. Pour the reaction solution into saturated aqueous ammonium chloride solution (120 mL), extract with MTBE (100 mL), dehydrate the organic layer with anhydrous magnesium sulfate, add a small amount of filter aid (diatomaceous earth), filter, and distill off the solvent to obtain the title Compound (13.8 g).

¹ H-NMR (CDCl ₃ , δppm): 1.36, 1.37 (calculated 3H, each s), 1.43, 1.44 (calculated 3H, each s), 1.82-1.93, 2.03-2.43 (calculated 3H, each m), 3.15- 3.43(1H, -OH, br), (1H, m), 3.62-3.71(1H, m), 3.84-4.43(4H, m), 5.24-5.26, 5.33-5.36 (1H, each m).

Example 25 (3R, 3aR, 6aS)-synthesis of hexahydrofuro[2,3-b]furan-3-ol (compound (XXVI))

(3R, 4'R)-3-(2', 2'-dimethyl-[1', 3']dioxolan-4'-yl)tetrahydrofuran-2-ol (13.8 g) Dissolve in THF (120 mL), add 6N hydrochloric acid (4 mL), and stir overnight at room temperature. Anhydrous potassium carbonate (25 g) was added to the reaction solution, filtered, and the concentrated residue was dissolved in toluene (20 mL) under heating, then diisopropyl ether (30 mL) was added, and the crystals generated by stirring at room temperature were filtered, After drying, the almost pure cis-isomer of the title compound (2.8 g, 88% ee) was obtained.

¹ H-NMR (CDCl ₃ , δppm): 1.67-1.75 (1H, m), 1.95-2.05 (1H (-OH), br), 2.13-2.23 (1H, m), 2.79-2.84 (1H, m) , 3.81-3.91(3H, m), 3.98(1H, dd, J=10Hz, J=3Hz), 4.23(1H, d, J=3Hz), 5.89(1H, d, J=5Hz).

Example 26 Synthesis of (3S, 3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-ylbenzoate (compound (XXVIII))

(3R, 3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-ol (125 mg) obtained in Example 25 was dissolved in toluene (2 mL), and then benzoic acid (214 mg), azobis A 40 wt% solution of diethyl formate in toluene (705 mg) and triphenylphosphine (416 mg) was stirred overnight. After the reaction, an amount corresponding to 10% of the solution was purified by flash chromatography to obtain the almost pure trans-isomer of the title compound (12 mg) (88% ee).

¹ H-NMR (CDCl ₃ , δppm): 1.94-2.01 (1H, m), 2.10-2.15 (1H, m), 3.17-3.23 (1H, m), 3.94 (1H, dd, J=10Hz, J= 6Hz), 3.99-4.05(2H, m), 4.20(1H, dd, J=10Hz, J=6Hz), 5.45-5.51(1H, m), 5.80(1H, d, J=5Hz), 7.47(2H , t, J=8 Hz), 7.58(1H, t, J=8Hz), 8.04(1H, d, J=8Hz)

Example 27 Synthesis of (3S, 3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-ol (compound (XV))

Toluene (20 mL) was added to 90% of the reacted solution obtained in Example 26, followed by washing with water (20 mL) three times, and the solvent was distilled off. Methanol (20 mL) was added to the residue, 10% sodium hydroxide aqueous solution (20 mL) was passed through, and after stirring for 30 minutes, the solvent was distilled off, water (30 mL) was passed into the residue, washed twice with toluene (20 mL), and Salt was added to the aqueous layer to make it saturated, then extracted three times with ethyl acetate (20 mL), dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain the almost pure trans-isomer title compound (98 mg, 88%ee).

¹ H-NMR (CDCl ₃ , δppm): 1.73 (1H (-OH), d, J=6Hz), 1.82-1.93 (1H, m), 2.28-2.34 (1H, m), 2.82-2.89 (1H, m), 3.65(1H, dd, J=9Hz, J=7Hz), 3.88-3.94(1H, m), 3.97-4.02(2H, m), 4.42-4.49(1H, m), 5.70(1H, d , J=5 Hz). The optical purity was determined by benzoylation by conventional methods, by HPLC under the following conditions.

HPLC conditions: Daicel Chiralcel OD-H (0.46cmφ×25cm, 19/1 hexane/2-propanol; 1ml/min, 254nm) (3S, 3aR, 6aS)-configuration t _r =13 minutes, (3R, 3aS,6aR)-configuration t _r = 1 min

Example 28 Synthesis of (3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-one (compound (XXVII))

A solution of oxalyl chloride (510 mg) in dichloromethane (10 mL) was cooled to -78°C, a solution of dimethyl sulfoxide (421 mg) in dichloromethane (2 mL) was added dropwise, stirred for 10 minutes, and then added dropwise at the same temperature A solution of (3R, 3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-ol (260 mg, 88%ee) obtained in Example 25 in dichloromethane (5 mL) was stirred for 15 minutes. The temperature of the reaction solution was raised to -45°C over 1 hour, then triethylamine (2.4 mL) was passed through, and the temperature was raised to 0°C. Saturated ammonium chloride aqueous solution (8 mL) was added to the reaction liquid, followed by extraction with ethyl acetate (20 mL) twice. The organic layer was washed with a saturated aqueous ammonium chloride solution, and the solvent was distilled off, and the residue was purified by flash chromatography to obtain the title compound (82 mg, 88% ee) as crystals.

¹ H-NMR (CDCl ₃ , δppm): 2.20-2.26 (2H, m), 2.97-3.01 (1H, m), 3.77-3.83 (1H, m), 4.03-4.07 (1H, m), 4.15 (2H , s), 6.07 (1H, d, J=5Hz).

Example 29 Synthesis of (3S, 3aR, 6aS)-hexahydrofuro[2,3-b]furan-3-ol (compound (XV))

Lithium aluminum hydride (15 mg) was dispersed in THF (0.2 mL) to form a suspension, and (3aR, 6aS)-hexahydrofuro[2,3-b]furan obtained in Example 28 was added dropwise at 0°C A solution of 3-ketone (64 mg) in THF (0.5 mL) was stirred for 1 hour. Water (0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL), and water (0.3 mL) were sequentially added to the reaction solution at intervals of 30 minutes, followed by filtration and washing well with THF. The filtrate was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain the title compound (57 mg, 88% ee) in almost pure trans form as an oily liquid. Spectrum data are consistent with Example 27.

Example 30 (1'S, 2S)-2-[2'-benzyloxy-1'-hydroxyethyl]-4-butyrolactone synthesis (compound (XXII))

Use 2-benzyloxyacetyl-γ-butyrolactone (14.2g), use (R)-(+)-BINAP instead of (S)-(-)-BINAP, except that it is the same as Example 22 Worked up to give the title compound (10.8 g) as an oily liquid. The obtained cis:trans diastereomer ratio was 12:1, and the optical purity of the cis (1'S, 2S configuration) was 82% ee. Spectrum data are consistent with Example 22.

Example 31 (2S, 4'S)-2-(2', 2'-dimethyl-[1', 3']dioxolan-4'-yl)-4-butyrolactone synthesis (compound ( XXIV))

Use (1'S, 2S)-2-[2'-benzyloxy-1'-hydroxyethyl]-4-butyrolactone (10.7g) obtained in Example 30 instead of (1'R, 2R)-2- Except for (2'-benzyloxy-1'-hydroxyethyl)-4-butyrolactone, the same procedure as in Example 23 was carried out to obtain the title compound (6.8 g) as an oily liquid. Spectrum data is consistent with Example 23.

Example 32 (3S, 4'S)-3-(2', 2'-dimethyl-[1', 3'] dioxolane-4'-yl) tetrahydrofuran-2-alcohol synthesis (compound (XXV ))

(2S, 4'S)-2-(2', 2'-dimethyl-[1', 3']dioxolan-4'-yl)-4-butyrolactone (5.4 g) instead of (2R,4'R)-2-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)-4-butyrolactone, except Except for the same procedure as in Example 24, the title compound (4.7 g) was obtained as an oily liquid. Spectrum data are consistent with Example 24.

Example 33 (3S, 3aS, 6aR)-Synthesis of hexahydrofuro[2,3-b]furan-3-ol (compound (XXVI))

(3S, 4'S)-3-(2', 2'-dimethyl-[1', 3']dioxolane-4'-yl)tetrahydrofuran-2-alcohol (3.2 g) obtained in Example 32 Instead of (3R,4'R)-3-(2',2'-dimethyl-[1',3']dioxolan-4'-yl)tetrahydrofuran-2-ol, in addition, The same procedure as in Example 25 was carried out to obtain the title compound (1.5 g) as pale yellow crystals. Spectrum data is consistent with Example 25.

Example 34 Synthesis of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ylbenzoate (compound (XXVIII))

Use (3S, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol (1.0 g) obtained in Example 33 instead of (3R, 3aR, 6aS)-hexahydrofuro[2,3 -b] furan-3-ol, except that it was carried out in the same manner as in Example 26, and a part was collected and purified to obtain the title compound as an oily liquid. Spectrum data are consistent with Example 26. The optical purity was 89% ee.

Example 35 Synthesis of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol (compound (XV))

Use (3S, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol (1.0 g) obtained in Example 33 instead of (3R, 3aR, 6aS)-hexahydrofuro[2,3 -b] Furan-3-ol was carried out in the same manner as in Examples 26 and 27 except that the title compound (0.72 g, 89% ee) was obtained as an oily liquid. Spectrum data are consistent with Example 27.

Industrial applicability

According to the present invention, it is possible to provide a method for preparing the formula (XIV) that can be used as an anti-AIDS drug intermediate, especially the compound represented by the formula (XV) without using ozone oxidation or strong toxic reagents, and the method used Intermediates and preparation methods thereof; It also provides a method for efficiently preparing compounds with absolute stereoconfigurations shown in formula (XV) and enantiomers thereof without using methods such as optical resolution and without using highly toxic reagents , and intermediates used in the process and methods for their preparation. Then, the present invention can supply the compound represented by formula (XIV), especially formula (XV) on an industrial scale at low cost.

This application is based on Japanese Patent Application No. 2002-382584 and Japanese Patent Application No. 2003-171303 filed in Japan, the contents of which are entirely included in this specification.

Claims (56)

1. Compound shown in formula (A):

In the formula, R and _R are independently, identical or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing a group represented by the following formula:

In the formula, R ₄ and R ₅ are independently, the same or different, representing a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group; When R ₁ is a hydrogen atom, R is a protecting group for a hydroxyl group, and the relative stereo configuration of the compound shown in formula (A) is cis, R represents a protecting group for a hydroxyl group other than benzyl. 2. Compound shown in formula (B): In the formula, R and _R are independently, identical or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing a group represented by the following formula:

In the formula, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. 3. The compound of claim 1, its relative stereo configuration is shown in formula (D):

In the formula, R and R have the same meaning as in claim ₁ . 4. The compound of claim 2, its relative stereo configuration is shown in formula (E): In the formula, R and _R have the same meaning as in claim 2. 5. The compound of claim 1, which is a compound or its enantiomer represented by formula (D) in absolute stereo configuration: In the formula, R and R have the same meaning as in claim ₁ . 6. The compound of claim 2, which is a compound or its enantiomer represented by formula (E) in absolute stereo configuration: In the formula, R and _R have the same meaning as in claim 2. 7. The compound of claim 1, 3 or 5, wherein R ₁ is a hydrogen atom, and R is a tert-butyl group. 8. The compound of any one of claims 1-6, wherein R and _R together represent the formula:

The group shown, where R ₄ and R ₅ are methyl groups. 9. The compound of any one of claims 1-6, wherein R is benzyl or tert-butyl, R is ₁ -ethoxyethyl or 3,4,5,6-tetrahydro-2H-pyran -2-base. 10. The compound of claim 3 or 5, wherein _R is a hydrogen atom, and R is benzyl. 11. Compounds or salts thereof represented by formula (C):

In the formula, R, _R1 and _R3 are independently, the same or different, and represent a protecting group of a hydroxyl group or a hydrogen atom, and _R6 represents a hydroxyl group, a lower alkoxy group or a lower alkylthio group. 12. The compound of claim 11, which is a compound or an enantiomer thereof represented by formula (F) in absolute stereoconfiguration:

In the formula, R, R ₁ , R ₃ and R ₆ have the same meaning as in claim 11. 13. The compound of claim 11 or 12, wherein R is benzyl, _R is a hydrogen atom, R is _benzyl or tert-butyl, R is _hydroxyl or ethoxy. 14. A compound represented by formula (G) in relative configuration: In the formula, R ₇ and R ₈ are independently, the same or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing a group represented by the following formula:

In the formula, R ₁₀ and R ₁₁ are independently, the same or different, representing a hydrogen atom, lower alkyl, lower alkoxy or phenyl; When R ₈ is a hydrogen atom and R ₇ is a protecting group for a hydroxy group, R ₇ represents a protecting group for a hydroxy group other than benzyl. 15. A compound represented by formula (H) in relative configuration:

In the formula, R ₇ and R ₈ are independently, the same or different, representing a protecting group of a hydroxyl group or a hydrogen atom, or together representing a group represented by the following formula: In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. 16. The compound of claim 14, which is a compound or an enantiomer thereof represented by formula (G) in absolute stereoconfiguration:

In the formula, R ₇ and R ₈ have the same meaning as in claim 14. 17. The compound according to claim 15, which is a compound or an enantiomer thereof whose absolute stereoconfiguration is represented by formula (H): In the formula, R ₇ and R ₈ have the same meaning as in claim 15. 18. The preparation method of the compound shown in formula (I), said method is to hydroxyethylate the compound shown in formula (XIII), and then make it cyclized,

In the formula, _PG represents a protecting group of a hydroxyl group, and _R represents a lower alkoxy group or a lower alkylthio group;

In the formula, _PG has the same meaning as above. 19. The preparation method of claim 18, wherein the compound shown in formula (I) is a compound having a relative stereo configuration shown in formula (VII):

In the formula, _PG has the same meaning as in claim 18. 20. The preparation method according to claim 18 or 19, wherein the compound represented by the formula (XIII) is an optically active compound. 21. The preparation method of claim 18, wherein the compound shown in formula (XIII) is a compound shown in formula (XVI):

In the formula, each symbol has the same meaning as in claim 18, The compound shown in formula (I) is the compound with the absolute stereo configuration shown in formula (VII): In the formula, P _G has the same meaning as in claim 18; Or the compound shown in formula (XIII) is the compound shown in the following formula: In the formula, each symbol has the same meaning as in claim 18, and the compound represented by the formula (I) is an enantiomer of the compound having the absolute stereo configuration represented by the formula (VII). 22. The preparation method of claim 18, the method is to make the compound shown in the formula (XIII) hydroxyethylation, obtain the compound shown in the formula (XIX), the compound shown in the gained formula (XIX) is hydrolyzed, obtain the formula (XX ), the compound shown in the obtained formula (XX) is cyclized to make the compound shown in the above formula (I), In the formula, _PG represents a protecting group of a hydroxyl group, _R2 represents a lower alkoxy group or a lower alkylthio group, and _R3 represents a protecting group of a hydroxyl group or a hydrogen atom;

In the formula, _PG and _R3 have the same meanings as above. 23. The preparation method of claim 22, wherein the compound shown in formula (XIII) is a compound shown in formula (XVI): In the formula, _PG represents a protecting group for hydroxyl, _R represents a lower alkoxy group or a lower alkylthio group, and the compound shown in the formula (XIX) is a compound having the absolute configuration shown in the formula (XVII): In the formula, each symbol has the same meaning as claim 22, The compound shown in formula (XX) is the compound with the absolute stereo configuration shown in formula (XVIII): In the formula, each symbol has the same meaning as claim 22, And the compound shown in formula (I) is the compound with the absolute stereo configuration shown in formula (VII): In the formula, _PG represents the protecting group of hydroxyl; Or the compound shown in formula (XIII) is the enantiomer of the compound shown in the formula (XVI), and the compound shown in the formula (XIX) is the enantiomer of the compound with the absolute stereo configuration shown in the formula (XVII) , the compound shown in formula (XX) is the enantiomer of the compound with the absolute stereoconfiguration shown in formula (XVIII), and the compound shown in formula (I) is the enantiomer with the absolute stereoconfiguration shown in formula (VII) Enantiomers of a compound. 24. The preparation method of the compound represented by the formula (III), which uses the compound represented by the formula (I) as a raw material,

In the formula, _PG represents the protecting group of hydroxyl;

In the formula, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. 25. The preparation method of claim 24, the method is to deprotect the compound shown in formula (I) to obtain formula (II):

Shown compound, the compound shown in gained formula (II) is converted into the compound shown in formula (III). 26. The preparation method of the compound shown in formula (V), the method is to reduce the compound shown in formula (III), In the formula, R ₄ and R ₅ are independently, the same or different, representing a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group; In the formula, R ₄ and R ₅ represent the same meaning as above. 27. The preparation method of the compound shown in formula (XIV),

The method is to deprotect and cyclize the compound shown in formula (V),

In the formula, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. 28. The preparation method of the compound shown in formula (IV), the method protects the hydroxyl group of the compound shown in formula (I): In the formula, _PG represents the protecting group of hydroxyl;

In the formula, _PG and _PG1 are independently, the same or different, and represent a protecting group for a hydroxyl group. 29. The preparation method of the compound shown in formula (VI), the method is to reduce the compound shown in formula (IV):

In the formula, _PG and _PG1 are independently, the same or different, and represent the protecting group of hydroxyl;

In the formula, _PG and _PG1 represent the same meaning as above. 30. The preparation method of the compound shown in formula (XIV),

The method is to deprotect and cyclize the compound shown in formula (VI):

In the formula, _PG and _PG1 are independently, the same or different, and represent a protecting group for a hydroxyl group. 31. The preparation method of the compound shown in formula (XIV),

The method includes any of the steps of (1A) or (1B) below: (1A) using the compound shown in formula (I) as raw material to obtain the compound shown in formula (III), and reducing the compound shown in the gained formula (III) to obtain the compound shown in the formula (V), and the compound shown in the gained formula (V) Show compound deprotection and cyclization, obtain the step of compound shown in above-mentioned formula (XIV),

In the formula, _PG represents the protecting group of the hydroxyl group, In the formula, R ₄ and R ₅ are independently, the same or different, representing a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group,

In the formula, R ₄ and R ₅ represent the same meaning as above; (1B) protecting the hydroxyl group of the compound shown in the formula (I) to obtain the compound shown in the formula (IV), reducing the compound shown in the gained formula (IV) to obtain the compound shown in the formula (VI), and obtaining the compound shown in the gained formula (VI) Show compound deprotection and cyclization, obtain the step of compound shown in above-mentioned formula (XIV),

In the formula, _PG and _PG1 are independently, the same or different, representing the protecting group of hydroxyl,

In the formula, _PG and _PG1 represent the same meaning as above. 32. The preparation method of claim 31, wherein in step (1A), the compound shown in formula (I) as raw material is deprotected to obtain formula (II):

Shown compound, the compound shown in gained formula (II) is converted into the compound shown in formula (III). 33. The preparation method of claim 31 or 32, wherein the compound shown in formula (I) is a compound having a relative stereo configuration shown in formula (VII): In the formula, _PG represents the protecting group of the hydroxyl group, And the compound shown in formula (XIV) has formula (XV):

Compounds with relative stereoconfiguration shown. 34. The preparation method according to claim 31 or 32, wherein the compound shown in formula (I) is a compound having an absolute stereo configuration shown in formula (VII): In the formula, _PG represents the protecting group of the hydroxyl group, And the compound shown in formula (XIV) has formula (XV)

The compound of the absolute stereoconfiguration shown in the formula; or the compound shown in the formula (I) is the enantiomer of the compound shown in the absolute stereoconfiguration with the formula (VII), and the compound shown in the formula (XIV) is a compound with the formula ( XV) Enantiomers of compounds of the absolute stereoconfiguration shown. 35. The preparation method of the compound shown in formula (XIX), the method uses the compound shown in formula (XIII) as raw material, In the formula, _PG represents a protecting group of a hydroxyl group, and _R represents a lower alkoxy group or a lower alkylthio group; In the formula, _PG and _R2 represent the same meaning as above, and _R3 represents a protecting group of a hydroxyl group or a hydrogen atom. 36. The preparation method of the compound shown in formula (XX), the method is to hydrolyze the compound shown in formula (XIX),

In the formula, _PG represents a protecting group of a hydroxyl group, _R2 represents a lower alkoxy group or a lower alkylthio group, and _R3 represents a protecting group of a hydroxyl group or a hydrogen atom;

In the formula, _PG and _R3 have the same meanings as above. 37. The production method according to claim 36, wherein the organic amine is added after hydrolysis. 38. The preparation method of claim 36, wherein the compound shown in formula (XIX) is prepared from the compound shown in formula (XIII): In the formula, _PG and R ₂ have the same meaning as in claim 36. 39. The preparation method of the compound shown in formula (III), this method is _PG and _R of the compound shown in formula (XX) Deprotection, then carry out acetalization or ketalization and lactonization,

In the formula, _PG represents a protecting group of a hydroxyl group, and _R represents a protecting group of a hydroxyl group or a hydrogen atom;

In the formula, R ₄ and R ₅ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. 40. the preparation method of claim 39, this method is to use the compound shown in formula (XIII) as starting material, obtain the compound shown in formula (XX):

In the formula, _PG represents a protecting group for a hydroxyl group, and R ₂ represents a lower alkoxy group or a lower alkylthio group. 41. The preparation method of the compound shown in formula (XIV), The method is to use the compound shown in the formula (XIII) as a raw material to obtain the compound shown in the formula (XIX), and the compound shown in the gained formula (XIX) is hydrolyzed to obtain the compound shown in the formula (XX), and then the obtained formula (XX) _PG and _R of the compound shown are deprotected, followed by acetalization or ketalization and lactonization to obtain the compound shown in formula (III), and the compound shown in the gained formula (III) is reduced to obtain the compound shown in formula (V ) shown in the compound, the compound shown in the gained formula (V) is deprotected and cyclized to make the compound shown in the formula (XIV),

In the formula, _PG represents a protecting group of a hydroxyl group, and _R represents a lower alkoxy group or a lower alkylthio group; In the formula, _PG and R ₂ represent the same meaning as above, and R ₃ represents a protecting group of a hydroxyl group or a hydrogen atom; In the formula, _PG and R ₃ represent the same meaning as above; In the formula, R ₄ and R ₅ are independently, the same or different, representing a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group; In the formula, P ₄ and R ₅ represent the same meaning as above. 42. the preparation method of claim 41, wherein, the compound shown in formula (XIII) is the compound shown in formula (XVI):

In the formula, P _G and R ₂ have the same meaning as in claim 41, The compound shown in formula (XIX) is the compound with the absolute stereo configuration shown in formula (XVII):

In the formula, P _G , R ₂ and R ₃ have the same meaning as in claim 41, The compound shown in formula (XX) is the compound with the absolute stereo configuration shown in formula (XVIII): In the formula, _PG and R ₃ have the same meaning as in claim 41, The compound shown in formula (III) is the compound with the absolute stereo configuration shown in formula (IX): In the formula, R ₄ and R ₅ have the same meaning as in claim 41, The compound shown in formula (V) is the compound with absolute stereo configuration shown in formula (XI): In the formula, R ₄ and R ₅ have the same meaning as in claim 41, And the compound shown in formula (XIV) has formula (XV):

The compound shown in the absolute stereo configuration; or the compound shown in formula (XIII) is an enantiomer of the compound shown in formula (XVI), and the compound shown in formula (XIX) has the absolute stereo configuration shown in formula (XVII) The enantiomer of the compound of formula (XX), the compound shown in formula (XX) is the enantiomer of the compound with the absolute stereo configuration shown in formula (XVIII), the compound shown in formula (III) is the enantiomer of the compound shown in formula (IX) ) shown in the enantiomer of the compound of the absolute stereoconfiguration, the compound shown in the formula (V) is an enantiomer of the compound with the absolute stereoconfiguration shown in the formula (XI), shown in the formula (XIV) The compound is an enantiomer of the compound having the absolute stereo configuration shown in formula (XV). 43. The preparation method of the compound having the relative stereo configuration shown in formula (XXII), this method carries out stereoselective reduction to the compound shown in formula (XXI):

In the formula, P _G2 represents the protecting group of hydroxyl;

In the formula, P _G2 represents the same meaning as above. 44. The preparation method according to claim 43, wherein the compound having the relative stereoconfiguration represented by the formula (XXII) is the compound having the absolute stereoconfiguration represented by the formula (XXII) or an enantiomer thereof. 45. A method for preparing a compound having a relative stereoconfiguration shown in formula (XXIV), the method comprising the following steps of (2A) or (2B):

In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, (2A) using a compound having a relative stereoconfiguration shown in formula (XXII) as a raw material, simultaneously performing deprotection and introducing a protecting group to prepare a compound having a relative stereoconfiguration shown in formula (XXIV) above;

In the formula, P _G2 represents the protecting group of hydroxyl; (2B) Deprotecting the compound having the relative stereo configuration shown in formula (XXII) to obtain the compound having formula (XXIII)

Steps for preparing a compound having the relative stereoconfiguration shown in the formula (XXIV) above by introducing a protecting group into the compound having the relative stereoconfiguration shown in the formula (XXIII) obtained. 46. A method for preparing a compound having a relative stereoconfiguration shown in formula (XXV), the method is to reduce a compound having a relative stereoconfiguration shown in formula (XXIV), In the formula, R ₁₀ and R ₁₁ are independently, the same or different, representing a hydrogen atom, lower alkyl, lower alkoxy or phenyl;

In the formula, R ₁₀ and R ₁₁ have the same meaning as above. 47. A method for preparing a compound having a relative stereoconfiguration shown in formula (XXVI), the method comprising deprotecting and cyclizing a compound having a relative stereoconfiguration shown in formula (XXV),

In the formula, R ₁₀ and R ₁₁ are independently, the same or different, and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. 48. A method for preparing a compound having a relative stereoconfiguration shown in formula (XXVI), the method is to stereoselectively reduce a compound shown in formula (XXI) to obtain a compound having a relative stereoconfiguration shown in formula (XXII), and The compound having the relative stereoconfiguration shown in the gained formula (XXII) is used as raw material to obtain the compound having the relative stereoconfiguration shown in the formula (XXIV), and the compound having the relative stereoconfiguration shown in the gained formula (XXIV) is reduced to obtain A compound having a relative stereoconfiguration shown in formula (XXV), deprotecting and cyclizing the compound having a relative stereoconfiguration shown in formula (XXV) to obtain a compound having a relative stereoconfiguration shown in formula (XXVI) ,

In the formula, P _G2 represents the protecting group of hydroxyl; In the formula, P _G2 has the same meaning as above;

In the formula, R ₁₀ and R ₁₁ are independently, the same or different, representing a hydrogen atom, lower alkyl, lower alkoxy or phenyl;

In the formula, R ₁₀ and R ₁₁ have the same meaning as above. 49. The preparation method of claim 48, wherein, the compound having the relative stereoconfiguration shown in formula (XXII) is the compound having the absolute stereoconfiguration shown in formula (XXII), having the relative stereoconfiguration shown in formula (XXIV) The compound is a compound with absolute stereoconfiguration shown in formula (XXIV), the compound with relative stereoconfiguration shown in formula (XXV) is a compound with absolute stereoconfiguration shown in formula (XXV), and the compound with formula (XXVI ) is a compound with an absolute stereoconfiguration shown in formula (XXVI); or a compound with a relative stereoconfiguration shown in formula (XXII) is a compound with an absolute stereoconfiguration shown in formula (XXII) The enantiomer of the compound, the compound with the relative stereoconfiguration shown in the formula (XXIV) is the enantiomer of the compound with the absolute stereoconfiguration shown in the formula (XXIV), with the compound shown in the formula (XXV) The compound of relative stereo configuration is the enantiomer of the compound with the absolute stereo configuration shown in formula (XXV), and the compound with the relative stereo configuration shown in formula (XXVI) is the absolute stereo configuration shown in formula (XXVI). Enantiomers of a compound. 50. The method of preparation according to claim 43, 44, 48 or 49, wherein the stereoselective reduction is an asymmetric hydrogenation using a transition metal catalyst with an asymmetric ligand. 51. The preparation method of claim 50, wherein the asymmetric ligand is an optically active phosphine derivative selected from the compound represented by the following formula and its enantiomers, using a transition metal catalyst in which the transition metal is ruthenium,

and

In the formula, Ra, Rb, Rd, Re, Rh, Ri, Rj, Rk, Rl, Rm, Rn and Ro are independently, the same or different, and represent a phenyl group that may be substituted or a cyclohexyl group that may be substituted; Rc, Rf and Rg are independently the same or different, and represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or a phenyl group that may be substituted; l, m, n and o are independently, representing an integer of 1-6. 52. The preparation method of claim 51, wherein the asymmetric ligand is an optically active phosphine derivative selected from compounds represented by formulas (L1), (L2), (L3), (L4), (L5) and (L6) , the compound having the relative stereoconfiguration shown in formula (XXII) is the compound having the absolute stereoconfiguration shown in formula (XXII); Or the asymmetric ligand is selected from formula (L1), (L2), (L3), The optically active phosphine derivatives of the enantiomers of the compounds represented by (L4), (L5) and (L6), the compound having the relative stereo configuration represented by the formula (XXII) has the absolute stereo configuration represented by the formula (XXII) Enantiomers of a compound. 53. Has the formula (XV)

The preparation method of the compound of shown relative stereo configuration, this method is to make have formula (XXVI)

The hydroxyl groups of the compounds of the relative stereoconfiguration shown are inverted. 54. The preparation method of claim 53, the method comprising the following steps of (2C) or (2D): (2C) Oxidize the compound with the relative stereoconfiguration shown in the above formula (XXVI) to obtain the compound with the relative stereoconfiguration shown in the formula (XXVII), and obtain the compound with the relative stereoconfiguration shown in the formula (XXVII) Reduction, the step of preparing a compound having the relative stereo configuration shown in the above formula (XV); (2D) The compound having the relative stereoconfiguration shown in the above formula (XXVI) is used as a raw material for reverse esterification to obtain a compound having the relative stereoconfiguration shown in formula (XXVIII), and the obtained compound having the formula (XXVIII) The hydrolysis of the compound of relative stereoconfiguration, the step of preparing the compound having the relative stereoconfiguration shown in above-mentioned formula (XV),

In the formula, _R9 represents an alkanoyl group in which a hydrogen atom may be substituted by a fluorine atom or a chlorine atom, or a benzoyl group in which a hydrogen atom of a phenyl group may be substituted by a nitro group, a halogen, an alkyl group, an alkoxy group or a phenyl group. 55. The preparation method according to claim 54, wherein, in step (2D), inverse esterification is carried out in the presence of triphenylphosphine or trialkylphosphine and azodicarboxylate or azodicarbamide. 56. The preparation method according to any one of claims 53-55, wherein the compound having the relative stereoconfiguration shown in formula (XXVI) is a compound having the absolute stereoconfiguration shown in formula (XXVI), having formula (XV) The compound with the relative stereoconfiguration shown is the compound with the absolute stereoconfiguration shown in formula (XV); or the compound with the relative stereoconfiguration shown in formula (XXVI) is the compound with the absolute stereoconfiguration shown in formula (XXVI). As for the enantiomers of the compound, the compound having the relative stereoconfiguration represented by the formula (XV) is the enantiomer of the compound having the absolute stereoconfiguration represented by the formula (XV).