JP2005145833A - Method for producing syn-1,3-diol compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method which can industrially advantageously produce a Syn-1,3-diol compound. <P>SOLUTION: A compound (III) (wherein X is -CH=CH- or the like; R is an inert group under reducing conditions; and R<SP>1</SP>and R<SP>2</SP>are each a lower alkyl group or the like) is reacted with a mixture containing a borane compound (IIa) (wherein R<SP>3</SP>and R<SP>4</SP>are each a lower alkyl group or the like) or a borane compound (IIb) (wherein R<SP>5</SP>is a lower alkyl or the like) and sodium boron hydride in a mixed solvent containing a lower alcohol and tetrahydrofuran to obtain the Syn-1,3-diol compound (I) (wherein one of Y<SP>1</SP>and Y<SP>2</SP>is oxygen and the other is a hydroxy group: and --- is a double bond when Y<SP>1</SP>and Y<SP>2</SP>bonded are oxygens and is a single bond when Y<SP>1</SP>and Y<SP>2</SP>bonded are hydroxy groups; X, R, R<SP>1</SP>and R<SP>2</SP>are the same as defined above). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing a Syn-1,3-diol compound by a stereoselective reduction reaction.

  Formula (V):

(Wherein X represents —CH ₂ CH ₂ —, —CH═CH— (wherein the double bond represents a trans isomer, a cis isomer or a mixture thereof) or —OCH ₂ — (wherein O binds to R.), R represents an aromatic group having a group that is inactive under reducing conditions, and the configuration means a relative configuration. Syn-1,3 -A diol compound (hereinafter also referred to as compound (V)) is useful, for example, as fluvastatin, which is a therapeutic drug for hyperlipidemia.

  As a synthesis method of such a compound (V), for example, a method shown in the following reaction scheme has been reported (see Patent Document 1).

Wherein X is —CH ₂ CH ₂ — or —CH═CH—; R ₁ is an ester group inert to the reaction conditions; R is an aromatic having a group inert to the reducing conditions R ₄ is allyl or lower alkyl having 1 to 4 carbon atoms, R ₃ is primary or secondary alkyl having 2 to 4 carbon atoms, and _one of Z ₁ and Z ₂ One is oxygen and the other is hydroxy.)

  This method is a method in which a cyclic boronate compound (2a) and / or (2b) is used as a reaction intermediate to reduce stereoselectively to an alcohol. The stereoselectivity of this kind of reaction is optimal. It has been reported that the syn / anti ratio is 99: 1 under the conditions (see Non-Patent Document 1).

When water is present in such a reaction system, R ₁ can be hydrolyzed to produce a carboxylic acid form. Since the carboxylic acid form inhibits the formation of the cyclic boronate compounds (2a) and (2b), if the carboxylic acid form is partially generated, the stereoselectivity becomes a factor. Therefore, it is necessary to manage the reaction system so that water is not mixed as much as possible.

Even if the reaction is carried out under water-free conditions, the ester group of the compound represented by the general formula (1) can be easily converted to the corresponding δ-lactone compound by intramolecular transesterification with Z _1. . Since the δ-lactone compound can no longer form a cyclic boronate compound, the formation of a δ-lactone compound in part causes a reduction in stereoselectivity. Accordingly, it is necessary to strictly set the reaction conditions so that the δ-lactone compound is not generated.

  As described above, in the method for producing the Syn-1,3-diol compound, there are various problems due to the presence of an ester group in the molecule, which may be a factor that restricts industrial application.

  On the other hand, in the reduction reaction, as shown in the following scheme, an embodiment in which an ester group is an amide group is disclosed (see Patent Document 2).

(In the formula, R ⁸ or R ⁹ independently represents C1-C10 alkyl or the like, and R ¹⁰ represents C1-C4 alkyl.)
However, Patent Document 2 does not disclose the syn / anti ratio of the reduction reaction. Even if the optimum stereoselectivity of 99: 1 is obtained, the amount of impurities generally needs to be less than 0.1% in the pharmaceutical field where the compound (V) is used. When the compound represented by the formula (5) is used as an intermediate of the compound (V), some purification means is essential. However, the compound represented by the general formula (5) is an oily substance, and non-industrial means such as column chromatography are required to increase the diastereopurity.

It is conceivable to increase the diastereopurity by crystallization after introducing the compound represented by the general formula (5) to a crystalline intermediate. Since the diol group is susceptible to elimination and chemically unstable, it is necessary to protect and deprotect the 1,3-diol group when it is led to a crystalline intermediate (see Patent Document 2). There are also problems such as an increase and complicated operation, which is not an advantageous method.
Japanese Patent No. 2853227 International Publication No. 94/20492 Pamphlet "Organic Process Research & Development, USA, 2001, Vol. 5, pp. 519-527.

  The problem to be solved by the present invention is to solve the above-mentioned problems and to provide a method capable of industrially advantageously producing a Syn-1,3-diol compound.

  The present inventors paid attention to an amide group that is chemically more stable than an ester group, and found that highly stereoselective reduction can be performed even when R is an aromatic group. Furthermore, by recrystallizing the obtained Syn-1,3-diol compound as it is, it was found that sufficient purity as a pharmaceutical product can be easily achieved, and the present invention has been completed. That is, the present invention is as follows.

(1) General formula (I) characterized by including the following first and second steps:

(Wherein X represents —CH═CH— (wherein the double bond represents a trans isomer, a cis isomer or a mixture thereof), —CH ₂ CH ₂ — or —OCH ₂ — (wherein O is bonded to R.), R represents an aromatic group having a group that is inactive under reducing conditions, R ¹ and R ² are the same or different and each independently represents a lower alkyl group Or R ¹ and R ² together with the adjacent nitrogen atom may form a non-aromatic heterocyclic ring that may contain one oxygen in addition to the nitrogen atom. A process for producing a compound represented by formula (hereinafter also referred to as compound (I));
First step: Borane represented by the general formula (IIa): (R ³ ) ₂ B—OR ⁴ (wherein R ³ represents a lower alkyl group and R ⁴ represents a lower alkyl group or an allyl group). A borane compound (hereinafter referred to as borane) represented by a compound (hereinafter also referred to as a borane compound (IIa)) or a general formula (IIb): (R ⁵ ) ₃ B (wherein R ⁵ represents a lower alkyl group). A mixture of compound (IIb)) and sodium borohydride in a mixed solvent containing a lower alcohol and tetrahydrofuran;
Second step: General formula (III):

(Wherein, Y ¹ and Y ^2, one is an oxygen atom and the other represents a hydroxyl group. --- is when Y ¹ or Y ² is bonded to an oxygen atom indicates a double bond, when the hydroxyl group Represents a single bond, and the other symbols have the same meanings as described above.) A compound (I) is reacted with the mixture obtained in the first step to give compound (I )
(2) Hydrolyzing the compound (I) obtained by the method described in the above (1), the general formula (V):

(Wherein each symbol and configuration are as defined above) (hereinafter also referred to as compound (V)) or a salt thereof, and / or general formula (VI):

(Wherein each symbol and steric configuration are as defined above), a method for producing a compound (hereinafter also referred to as compound (VI)).
(3) Compound (III) is represented by the general formula (IIIa):

(Wherein each symbol has the same meaning as described above), the production method according to (1) or (2) above, which is a compound represented by the following (hereinafter also referred to as compound (IIIa)).
(4) General formula (VII):

(Wherein each symbol has the same meaning as above) (hereinafter also referred to as compound (VII)) is reacted with sodium hydride and alkyllithium to give the corresponding dianion, then the general formula (VIII): Compound (IIIa) obtained by reacting with a compound represented by R—X—CHO (wherein each symbol is as defined above) (hereinafter also referred to as Compound (VIII)). The manufacturing method according to (3) above, which is used.
(5) R—X— represents the following formula

(Hereinafter, also referred to as substituents (IXa), (IXb), (IXc), and (IXd)), respectively, the production method according to any one of (1) to (4) above .
(6) Compound (IIIa).
(7) The compound according to (6) above, wherein R—X— is the substituent (IXa).
(8) General formula (Ia):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (Ia)).

  According to the production method of the present invention, there is little concern about hydrolysis or lactonization of ester groups that can cause a reduction in stereoselectivity in the reduction reaction. Thus, a highly stereoselective reduction reaction can be performed stably. In addition, since the resulting compound (I) has good crystallinity, it can be purified by recrystallization as it is, without leading to a crystalline intermediate through protection and deprotection of the Syn-1,3-diol group. In addition, it is industrially advantageous because sufficient purity can be achieved as a pharmaceutical intermediate with only one recrystallization.

The definition of symbols in the present invention will be described.
The “lower alkyl group” represented by R ¹ , R ² and R ⁵ is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, Examples thereof include isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl and the like, preferably methyl, ethyl and the like.

Examples of the “non-aromatic heterocyclic ring which may contain one oxygen atom in addition to the nitrogen atom” that R ¹ and R ² may form together with the adjacent nitrogen atom include pyrrolidine, piperidine, Examples include homopiperidine and morpholine.

Examples of the “lower alkyl group” represented by R ³ include the same as the above lower alkyl group, preferably methyl and ethyl.

Examples of the “lower alkyl group” represented by R ⁴ include the same as the above lower alkyl group, preferably methyl and ethyl.

  The “aromatic group having a group which is inactive under reducing conditions” represented by R is not particularly limited, but is preferably represented by the following general formula (A), (B), (C) or (D). (Hereinafter also referred to as substituents (A), (B), (C) and (D), respectively).

(Wherein R ^1a represents a lower alkyl group (the same as the above lower alkyl group is exemplified), a lower cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like, and R ^2a , R ^3a and R ^4a are the same or different and each represents a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, etc.), a lower alkyl group (the same as the above lower alkyl group is exemplified), and the like. , R ^5a and R ^6a are the same or different and are a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, etc.), a lower alkyl group (the same as the above lower alkyl group is exemplified), etc. Is shown.)

(Wherein R ^1b represents a lower alkyl group (the same as the above lower alkyl group is exemplified), a lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), etc., and R ^2b , R ^3b and R ^4b are the same or different and each represents a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, etc.), a lower alkyl group (the same as the above lower alkyl group is exemplified), and the like. , R ^5b represents a lower alkyl group (the same as the above lower alkyl group is exemplified) and the like, and R ^6b is a lower alkyl group (the same as the above lower alkyl group is exemplified). Is shown.)

(Wherein R ^1c represents a lower alkyl group (the same as the above lower alkyl group is exemplified), a lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) etc., and R ^2c , R ^3c and R ^4c are the same or different and each represents a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, etc.), a lower alkyl group (the same as the above lower alkyl group is exemplified), and the like. , R ^5c and R ^6c are the same or different and are a hydrogen atom, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, etc.), a lower alkyl group (the same as the above lower alkyl group is exemplified), etc. Is shown.)

(Wherein R ^1d represents a lower alkyl group (the same as the above lower alkyl group is exemplified), a lower cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), etc., and R ^2d , R ^3d and R ^4d are the same or different and each represents a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, etc.), a lower alkyl group (the same as the above lower alkyl group is exemplified), and the like. , R ^5d and R ^6d are the same or different and each represents a hydrogen atom, a phenyl group which may have a substituent, —CONHR ^7d, etc. Here, the substituent which the phenyl group may have is as follows: A lower alkyl group (the same as the above lower alkyl group is exemplified), a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, etc.) and the like. As the R ^7d, (synonymous with even a phenyl optionally having the substituent.) Phenyl which may have a substituent, and the like.)

  The configuration of Compound (I), Compound (V) and Compound (VI) means a relative configuration, and includes diastereomeric racemates having the relative configuration and optically active forms thereof.

  Examples of the salt of the compound (V) include carboxylates such as alkali metal salts (eg, sodium salt, potassium salt, lithium salt), alkaline earth metal salts (eg, calcium salt, magnesium salt), organic base salts. (E.g., trimethylamine salt, triethylamine salt, pyridine salt, etc.).

  A preferred embodiment of the present invention will be described below.

R ¹ and R ² are preferably lower alkyl groups, more preferably methyl or ethyl.

X is preferably —CH ₂ CH ₂ — or —CH═CH—. In this case, the geometric isomerism of —CH═CH— is preferably a trans isomer.

  R is preferably a substituent (A), (B), (C) or (D), more preferably a substituent (A).

  Furthermore, as R—X—, the substituent (IXa), (IXb), (IXc) or (IXd) is preferable, and the substituent (IXa) is more preferable.

Y ¹ and Y ² are preferably such that Y ¹ is a hydroxyl group and Y ² is an oxygen atom.

As the borane compound, borane compound (IIa) is preferable, and those in which R ³ is methyl or ethyl and R ⁴ is methyl or ethyl, specifically, diethylmethoxyborane, dimethylmethoxyborane or the like is preferable.

  The present invention is represented in the following scheme.

(In the formula, each symbol, --- and configuration are as defined above.)
That is, the present invention provides a first step of obtaining a mixture of borane compound (IIa) or borane compound (IIb) and sodium borohydride in a mixed solvent containing a lower alcohol and tetrahydrofuran; It is a method for producing compound (I), comprising a second step of reacting with the mixture obtained in the step to obtain compound (I), and further, as a third step, compound (I) obtained in the second step This is a method for producing compound (V) or a salt thereof and / or compound (VI) by hydrolysis.

In the method of the present invention, as shown in the above scheme, the reaction intermediate is a cyclic boronate compound represented by the above general formulas (IVa) to (IVc) (hereinafter also referred to as a cyclic boronate compound). It is considered that the Syn isomer can be obtained stereoselectively.
Since there is no ester group in the raw material compound (III), there is almost no concern about hydrolysis or lactonization of the ester group, which is a factor inhibiting the formation of cyclic boronate compounds, etc. in the second step. The syn isomer can be obtained with a stable selectivity (syn: anti = 97: 3 or more) without any water-restricted conditions and process control, and the resulting syn isomer has a good crystallinity, so that Since diastereopurity can be easily increased by recrystallization or the like, it is industrially advantageous. Hereinafter, each step will be described.

1. First Step The first step includes, for example, borane compound (IIa) or borane compound (IIb) (hereinafter also referred to as a borane compound) and sodium borohydride in a mixed solvent containing a lower alcohol and tetrahydrofuran. Add simultaneously or sequentially; add sodium borohydride to a borane compound or the like previously charged in a mixed solvent containing a lower alcohol and tetrahydrofuran; or borohydride previously charged in a mixed solvent containing a lower alcohol and tetrahydrofuran It is carried out by adding a borane compound or the like to sodium.

  The amount of the borane compound used is usually 0.5 to 2 equivalents, preferably 0.8 to 1.5 equivalents, relative to compound (III) used in the second step.

  The usage-amount of sodium borohydride is 1-10 equivalent normally with respect to a borane compound etc., Preferably it is 1.2-6 equivalent.

  The lower alcohol used in the first step is a linear or branched alcohol having 1 to 4 carbon atoms, and examples thereof include methanol, ethanol, isopropyl alcohol, and preferably methanol.

  In the mixed solvent, the mixing ratio of lower alcohol and tetrahydrofuran is usually 1: 2 to 1: 6 (v / v), preferably 1: 3 to 1: 5 (v / v).

  The amount of the mixed solvent used is usually 5 to 100 times, preferably 10 to 50 times the weight of the borane compound and the like.

  The first step is usually performed in a temperature range of −100 to 30 ° C., preferably −90 to −60 ° C. The reaction time is usually 10 minutes to 120 minutes, preferably 15 minutes to 60 minutes.

2. Second Step The second step is, for example, adding (preferably dropwise) the compound (III) solution to the mixture obtained in the first step; or obtaining the compound (III) solution in the first step It can be carried out by adding (preferably dropping) the mixture.

  Examples of the solution of compound (III) include lower alcohol, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether and the like, or a mixed solvent thereof. Preferably, the lower alcohol and tetrahydrofuran used in the first step are mixed. It is a solvent, and a preferable mixing ratio is the same as that in the first step.

  The amount of the solvent to be used is generally 3 to 100 times weight, preferably 5 to 20 times weight, with respect to compound (III).

The second step is usually performed in a temperature range of −100 to −40 ° C., preferably −90 to −70 ° C. In order to maintain the same temperature range, the solution of the mixture and compound (III) obtained in the first step is preferably maintained in the temperature range and dropped over 10 minutes to 12 hours.
After the addition is completed, the reaction is usually further performed for 1 hour to 8 hours, preferably 1.5 hours to 4 hours.

  After completion of the reaction in the second step, it is considered that the reaction mixture contains a cyclic boronate compound or the like, but the cyclic boronate compound or the like can be opened by ordinary post-treatment to lead to compound (I). it can. For example, the reaction is stopped by adding an aqueous sodium carbonate solution and / or an organic solvent (for example, n-heptane, n-hexane, etc.) to the reaction mixture, extracted with ethyl acetate, toluene, methyl isobutyl ketone, etc., washed with water and dried The crude product of compound (I) can be isolated by concentration, etc. Furthermore, it can be purified by recrystallization or silica gel chromatography.

  In the compound (I) obtained in the second step, R—X— is a substituent (IXa), that is, the compound (Ia) is a novel compound, and a synthetic intermediate of fluvastatin, which is a therapeutic drug for hyperlipidemia Useful as.

3. Third Step The third step can be performed by reacting compound (I) with an ordinary hydrolysis condition, for example, an acid or a base in an aqueous solvent. Under acidic conditions, the hydroxyl group of compound (I) is Since side reactions such as β elimination may occur, it is preferable to react with a base.

  As the aqueous solvent, a mixed solvent of water and a lower alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.) is preferable, and a mixed solvent of water and methanol or water and ethanol is more preferable. As the usage-amount of a solvent, it is 5-100 times weight with respect to compound (I), Preferably it is 10-50 times weight.

  Examples of the base used for the hydrolysis include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and sodium hydroxide is preferable. The base is preferably used as an aqueous solution, and the amount of the base used is 1 to 10 equivalents, preferably 1.5 to 5 equivalents, relative to compound (I).

  Examples of the acid used for the hydrolysis include hydrochloric acid, sulfuric acid, methanesulfonic acid and the like, and hydrochloric acid is preferable. The amount of the acid used is 0.001 to 0.5 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (I).

  The third step is usually performed in a temperature range of 0 to 100 ° C, preferably 20 to 80 ° C. The reaction time is usually 30 minutes to 8 hours, preferably 1 hour to 3 hours.

When hydrolysis is performed using a base, a reaction mixture containing a salt of compound (V) with the base is obtained. The reaction mixture can be concentrated to dryness or extracted with a polar solvent (eg, n-butanol, tetrahydrofuran, etc.), washed with water, and concentrated to isolate the salt of compound (V) and the base. Further, it can be purified by crystallization or the like.
Further, the reaction mixture is neutralized with an acid (hydrochloric acid, sulfuric acid, etc.) to pH 0-4, extracted with ethyl acetate, washed with water, and concentrated to give a free form of compound (V) and / or compound (VI). It can be isolated.

  When hydrolysis is performed using an acid, a free mixture of compound (V) and / or a reaction mixture containing compound (VI) is obtained. The reaction mixture can be isolated by a conventional method, for example, extraction with ethyl acetate or the like, washing with water, and concentration to isolate the free form of compound (V) and / or compound (VI). By treating the reaction mixture with a base (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), a salt of compound (V) and the base can be obtained.

  The borane compound (IIa) used in the present invention is a known compound such as Ann., P.352 (1975), Tetrahedron Letters, 28, p.155 (1987), Chemistry Letters, p.1923-1926 ( 1987) or the like, or a commercially available product may be used. The borane compound (IIb) is a known compound, and a commercially available product can be used.

  Compound (III) which is a raw material of the present invention, for example, compound (IIIa), is a novel compound and is useful as a synthetic intermediate for fluvastatin, which is a therapeutic drug for hyperlipidemia.

  Compound (IIIa) can be produced according to the method described in US Pat. No. 4,773,073. That is, as shown in the following scheme, compound (VII) was reacted with sodium hydride and alkyllithium in a solvent to obtain a dianion represented by general formula (VIIa) (hereinafter also referred to as dianion (VIIa)). Thereafter, it is produced by reacting with compound (VIII).

(In the formula, each symbol is as defined above.)
Hereinafter, the manufacturing method of compound (IIIa) is demonstrated.

  Any solvent may be used as long as it does not inhibit the reaction. Examples thereof include tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, diglyme, methylcyclopentyl ether, and a mixed solvent thereof. Preferred are tetrahydrofuran and methyl tert-butyl ether.

  First, a solution of compound (VII) is dropped into sodium hydride charged in a solvent to obtain a monoanion in which active methylene is anionized, and then alkyllithium is dropped to produce dianion (VIIa). Is preferred.

  The amount of compound (VII) to be used is generally 0.8 to 1.5 equivalents, preferably 1 to 1.3 equivalents, relative to compound (VIII).

  The amount of sodium hydride to be used is generally 1 to 1.5 equivalents, preferably 1.05 to 1.3 equivalents, relative to compound (VII).

  Examples of the alkyl lithium include n-butyl lithium, sec-butyl lithium, n-hexyl lithium and the like, and preferably n-butyl lithium. The amount of alkyl lithium used is usually 0.8 to 1.5 equivalents, preferably 0.9 to 1.2 equivalents, relative to compound (VII).

  The reaction for generating dianion (VIIa) is usually performed at a temperature range of -40 to 50 ° C, preferably -20 to 30 ° C. The reaction time is usually 10 minutes to 3 hours for reacting with sodium hydride, preferably 20 minutes to 90 minutes, and the reaction time with alkyllithium is usually 30 minutes to 5 hours, preferably 1 hour to 3 hours. It is.

  Compound (IIIa) can be produced by adding (preferably dropwise) a solution of compound (VIII) to the mixture containing dianion (VIIa) thus obtained.

  The reaction between the dianion (VIIa) and the compound (VIII) is usually performed at a temperature range of -40 to 50 ° C, preferably -20 to 30 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 3 hours to 12 hours.

  The obtained compound (IIIa) can be isolated and purified by a conventional method. For example, the reaction mixture can be quenched by pouring into an acidic aqueous solution (for example, acetic acid aqueous solution, ammonium chloride aqueous solution, dilute hydrochloric acid aqueous solution, etc.), extraction with ethyl acetate or the like, washing with water, and concentration. Furthermore, it can be purified by recrystallization, silica gel chromatography, or the like.

  When an optically active substance is used as compound (III), an optically active substance of compound (I), compound (V) or compound (VI) is obtained, which is preferable. The optically active form of compound (III) can be synthesized, for example, according to the method described in JP-A-2003-277324, JP-A-3-58967, or a modified method thereof.

Compound (VII) which is a raw material of compound (IIIa) is a known compound and can be produced by a known method.
For example, it can be produced by reacting an amine represented by R ¹ R ² NH (wherein each symbol has the same meaning as described above) with acetoacetate or diketene (US Pat. No. 4,129,596). reference)

  Compound (VIII) is a known compound and can be produced by a known method. For example, compound (VIII) in which R—X— is a substituent (IXa) is Patent Document 1, and compound (VIII) in which R—X— is a substituent (IXb) is Japanese Patent No. 2664897, R—X—. Compound (VIII) in which is a substituent (IXc) is produced by the method described in Japanese Patent No. 3130342, and Compound (VIII) in which R—X— is a substituent (IXd) is produced by the method described in Japanese Patent No. 2010432, respectively. Can do.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Example 1
7- [3- (4-Fluorophenyl) -1-isopropyl-1H-indol-2-yl] -5-hydroxy-3-oxo-hept-6E-enoic acid Synthesis of dimethylamide Sodium hydride (60% In a liquid solution of liquid paraffin, 420 mg, 10.5 mmol) in THF (10 ml), a solution of acetoacetic acid dimethylamide (1.16 g, 9.0 mmol) in THF (2.5 ml) at about −5 ° C. for about 30 minutes. After dropping, the mixture was aged at room temperature for 30 minutes. The obtained slurry was cooled to 0 to 5 ° C., and n-butyllithium (1.6 M in hexane, 5.63 ml, 9.0 mmol) was added dropwise, followed by stirring for 50 minutes. A solution of 3- [3- (4-fluorophenyl) -1-isopropyl-1H-indol-2-yl] -propanal (2.31 g, 7.5 mmol) in THF (6.5 ml) was added at −5 to 0 ° C. Then, it was added dropwise over 35 minutes and stirred until the end of the reaction. The reaction solution was poured into an acetic acid (1.5 ml) -water (25 ml) solution and then separated. The aqueous layer was re-extracted with ethyl acetate (50 ml) and the organic layers were combined. The organic layer was washed with brine (20 ml × 2 times), dried over anhydrous magnesium sulfate, filtered and concentrated to give a brown oily crude product. Furthermore, it was purified by silica gel column chromatography (n-heptane: acetone = 3: 1) to obtain 2.11 g of the title compound as a slightly yellow solid. Yield 64.5%

¹ H-NMR (400MHz, in CDCl ₃ ) δ in ppm: 1.65 (6H, d, J = 7Hz), 2.37 (0.1H, m), 2.66 (0.9H, dd, J = 15, 4Hz), 2.68 ( 0.9H, dd, J = 15, 3Hz), 2.98 (3H, s), 3.00 (3H, s), 3.51 (1H, d, J = 4Hz), 3.52, 3.54 (each 0.9H, d, J = 15Hz ), 4.80 (0.1H, broad s), 5.12 (0.1H, s), 4.72 (1H, m), 4.84 (1H, m), 5.68 (1H, dd, J = 16, 6Hz), 6.73 (1H, dd, J = 16, 2Hz), 7.05-7.13 (3H, m), 7.18 (1H, m), 7.40 (2H, m), 7.52 (2H, m).
LC-MS m / z: 436.8 (M + H) ⁺ , 419.1 (MH ₂ O + H) ⁺ . (Measuring device: LCQ advantage.)
Mp 142.7-143.1 ℃ (Measuring device: Mettler FP62)

Example 2
Synthesis of 7- [3- (4-fluorophenyl) -1-isopropyl-1H-indol-2-yl] -3,5-syn-dihydroxyhept-6E-enoic acid dimethylamide 4: 1 (v / v ) In THF-methanol mixed solvent (5 ml) was cooled to −78 ° C., sodium borohydride (189 mg, 5 mmol) and diethylmethoxyborane (103 mg, 1 mmol) were added, and the mixture was stirred for 20 minutes. Next, 7- [3- (4-fluorophenyl) -1-isopropyl-1H-indol-2-yl] -5-hydroxy-3-oxo-hept-obtained in Example 1 cooled to −78 ° C. A solution of 6E-enoic acid dimethylamide (436 mg, 1 mmol) in THF-methanol (4: 1, 3 ml) was added dropwise over 35 minutes, and then the reaction solution was stirred for 2.5 hours. To the reaction solution were added 5% aqueous sodium hydrogen carbonate (0.5 ml) and n-heptane (1 ml), and the mixture was stirred to room temperature. Ethyl acetate (15 ml) and water (5 ml) were added, stirred and separated. The obtained ethyl acetate layer was washed with brine (5 ml × 2 times), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 0.45 g of a crude oily product.

HPLC measurement (column: Symmetry C18, 39 mm × 150 mm, 35 ° C., moving bed: 70% (v / v) MeOH—H ₂ O, 1 ml / min, UV: 254 nm, retention time: syn isomer: 9.0 min. , Anti isomer: 9.7 min), the syn / anti ratio of 1,3-diol was 98: 2. The obtained crude product was crystallized from a mixed solvent of ethyl acetate (3 ml) -n-heptane (6 ml) to obtain 346 mg of the title compound as a white solid. The 1,3-diol syn / anti ratio was 99.9: 0.1 as measured under the same HPLC conditions as above. Yield 79.4%

Mp 136.4-136.6 ° C (measuring device: Mettler FP62).
¹ H-NMR (400 MHz, in CDCl ₃ ) δ in ppm: 1.42-1.61 (2H, m), 1.66 (6H, dd, J = 7, 2 Hz), 2.35 (1H, dd, J = 16, 9 Hz), 2.43 (1H, dd, J = 16, 3Hz), 2.97 (3H, s), 3.00 (3H, s), 4.25 (1H, m), 4.51 (1H, m), 4.87 (1H, m), 5.70 ( 1H, dd, J = 16, 5Hz), 6.71 (1H, dd, J = 16, 2Hz), 7.05-7.11 (3H, m), 7.18 (1H, m), 7.41 (2H, m), 7.53 (2H , m).

¹³ C-NMR (125 MHz, in CDCl ₃ ) δ in ppm: 21.8, 35.2, 37.1, 39.5, 42.3, 47.7, 68.9, 72.2, 111.6, 115.0 (d, J = 22Hz), 117.8, 119.2, 119.4, 121.5, 128.3, 131.9, 132.0, 134.0, 134.8, 139.1, 161.2 (d, J = 240Hz), 172.0.
LC-MS m / z: 438.9 (M + H) ⁺ , 420.9 (MH ₂ O + H) ⁺ , 403.1 (M-2H ₂ O + H) ⁺ .

Example 3
Synthesis of 7- [3- (4-Fluorophenyl) -1-isopropyl-1H-indol-2-yl] -3,5-syn-dihydroxy-hept-6E-enoic acid sodium salt obtained in Example 2 7- [3- (4-Fluorophenyl) -1-isopropyl-1H-indol-2-yl] -3,5-syn-dihydroxy-hept-6E-enoic acid dimethylamide (95.4 mg, 0.218 mmol) Was mixed with methanol (3 ml), 1 M aqueous sodium hydroxide solution (0.87 ml, 0.87 mmol) was added, and the mixture was heated to reflux for about 10 hours. After cooling, the reaction solution was concentrated under reduced pressure, n-butanol (5 ml) -water (4 ml) was added, and the mixture was stirred and separated. The aqueous layer was re-extracted with n-butanol (4 ml) and the organic layers were combined. Ion exchange water (2 ml × 3 times) was washed and concentrated under reduced pressure to give 94 mg of the title compound. Apparent yield 99.7%.

  HPLC measurement (column: Symmetry C18, 39 mm × 150 mm, 43 ° C., moving bed: 65% (v / v) methanol-0.1% (v / v) trifluoroacetic acid water, 1 ml / min, UV254 nm, retention time : Syn isomer: 10.9 minutes, anti isomer: 12.6 minutes), the syn / anti ratio of the 1,3-diol was 99.6: 0.4.

¹ H-NMR (400MHz, in CD ₃ OD) δ in ppm: 1.48-1.53 (1H, m), 1.64 (6H, d, J = 7Hz), 1.64-1.69 (1H, m), 2.26 (1H, dd , J = 15, 7Hz), 2.34 (1H, dd, J = 15, 5Hz), 3.96 (1H, m), 4.37 (1H, m), 4.92 (1H, m), 5.72 (1H, dd, J = 16, 6Hz), 6.68 (1H, d, J = 16Hz), 6.99 (1H, m), 7.10-7.16 (3H, m), 7.39-7.43 (3H, m), 7.56 (1H, d, J = 8Hz ).

¹³ C-NMR (125 MHz, in CD ₃ OD) δ in ppm: 21.9, 44.7, 45.1, 68.4, 71.7, 112.6, 115.4, 115.9, 116.1, 119.8, 119.9, 120.4, 122.5, 129.5, 133.0, 133.1, 134.8, 136.4, 140.7, 162.6 (d, J = 249Hz), 180.3.
LC-MS m / z: 410.4 (M-Na) ^- .

Claims (8)

General formula (I) characterized in that it comprises the following first and second steps:

(Wherein X represents —CH═CH— (wherein the double bond represents a trans isomer, a cis isomer or a mixture thereof), —CH ₂ CH ₂ — or —OCH ₂ — (wherein O is bonded to R.), R represents an aromatic group having a group that is inactive under reducing conditions, R ¹ and R ² are the same or different and each independently represents a lower alkyl group Or R ¹ and R ² together with the adjacent nitrogen atom may form a non-aromatic heterocyclic ring that may contain one oxygen in addition to the nitrogen atom. A process for producing a compound represented by:
First step: Borane represented by the general formula (IIa): (R ³ ) ₂ B—OR ⁴ (wherein R ³ represents a lower alkyl group and R ⁴ represents a lower alkyl group or an allyl group). Contains a lower alcohol and tetrahydrofuran of a compound or a general formula (IIb): (R ⁵ ) ₃ B (wherein R ⁵ represents a lower alkyl group) and sodium borohydride Obtaining a mixture in a mixed solvent;
Second step: General formula (III):

(Wherein, Y ¹ and Y ^2, one is an oxygen atom and the other represents a hydroxyl group. --- is when Y ¹ or Y ² is bonded to an oxygen atom indicates a double bond, when the hydroxyl group Represents a single bond, and the other symbols are as defined above.) The compound represented by the above general formula (I) is obtained by reacting the compound represented by the first step with the mixture obtained in the first step. General formula (I) obtainable by the method according to claim 1:

(Wherein X represents —CH═CH— (wherein the double bond represents a trans isomer, a cis isomer or a mixture thereof), —CH ₂ CH ₂ — or —OCH ₂ — (wherein O is bonded to R.), R represents an aromatic group having a group that is inactive under reducing conditions, R ¹ and R ² are the same or different and each independently represents a lower alkyl group Or R ¹ and R ² together with the adjacent nitrogen atom may form a non-aromatic heterocyclic ring that may contain one oxygen in addition to the nitrogen atom. The compound represented by formula (V) is hydrolyzed:

(Wherein each symbol and configuration are as defined above) or a salt thereof, and / or general formula (VI):

(Wherein each symbol and steric configuration are as defined above). The compound represented by the general formula (III) is represented by the general formula (IIIa):

The method according to claim 1 or 2, wherein each symbol is as defined above. General formula (VII):

(In the formula, each symbol is as defined above.) The compound represented by the formula (VIII): R—X—CHO (formula) is reacted with sodium hydride and alkyllithium to give the corresponding dianion. Wherein each symbol has the same meaning as described above.) General formula (IIIa) obtained by reacting with the compound represented by:

The manufacturing method of Claim 3 using the compound represented by (In formula, each symbol shows the same meaning as the above.). R—X— represents the following formula

The manufacturing method in any one of Claims 1-4 chosen from group represented by these. General formula (IIIa):

(Wherein X represents —CH═CH— (wherein the double bond represents a trans isomer, a cis isomer or a mixture thereof), —CH ₂ CH ₂ — or —OCH ₂ — (wherein O is bonded to R.), R represents an aromatic group having a group that is inactive under reducing conditions, R ¹ and R ² are the same or different and each independently represents a lower alkyl group Or R ¹ and R ² together with the adjacent nitrogen atom may form a non-aromatic heterocyclic ring which may contain one oxygen other than the nitrogen atom). . R—X— represents the formula (IXa):

The compound of Claim 6 which is group represented by these. Formula (Ia):

(Wherein R ¹ and R ² are the same or different and each independently represents a lower alkyl group, or R ¹ and R ² together with the adjacent nitrogen atom, A non-aromatic heterocyclic ring which may contain oxygen. The configuration means a relative configuration.)