JPS63174938A - Production of optically active allyl alcohol derivative - Google Patents

Abstract

PURPOSE:To obtain the titled substance contained as a partial structure of prostaglandins in high stereoselectivity and yield, by reacting an optically active alcohol and water with lithium aluminum hydride and reducing an enone using the formed complex. CONSTITUTION:A compound expressed by formula I and water are reacted with lithium aluminum hydride in an aprotic solvent, preferably THF, etc., at -10-+25 deg.C for 0.5-10hr in an inert gas atmosphere to form a complex, which is used as a reducing agent to reduce an enone expressed by formula II (R<1> is 1-20C organic group; R<2> is 1-10C aliphatic or aromatic group) in an aprotic solvent in an inert gas atmosphere at -100--30 deg.C for 1-24hr to afford the aimed compound expressed by formula III. The compound expressed by formula I can be mass-produced using tartaric acid available at a low cost as a starting material.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing optically active allyl alcohol derivatives. More specifically, the present invention relates to a method for producing an optically active allyl alcohol derivative contained as a partial structure in prostaglandins or prostaglandin-like compounds useful as pharmaceuticals or veterinary drugs.

<Prior Art> Prostaglandins or prostaglandin-like compounds have a basic skeleton of brostanic acid represented by the following structural formula (X IV ). When introducing an α-configured hydroxyl group to the 15th carbon atom of this brostanic acid, the corresponding 1
A method of reducing the 5-position carbonyl group is often employed. For example, the enone represented by the following formula (■) (wherein Xl and X2 are the same or different and represent a hydroxyl group or a protected hydroxyl group) is reduced to the following formula (IX) (wherein
There is a method for obtaining a prostaglandin F2CX derivative represented by (has the same meaning as above).

In addition, in the production process of prostaglandin such as the above formula (■), the enone represented by the following formula (VI) (wherein, X2 has the same meaning as above) is similarly reduced to the following formula: There is a method for obtaining an optically active furyl alcohol derivative represented by (VI[)○ (wherein x2 has the same meaning as above).

In addition, in prostaglandin-like compounds, enones represented by the following formulas (X) and (XII) (wherein x2 has the same meaning as above) are similarly reduced to produce the following formulas (XI) and (XII), respectively. There is a method for obtaining an optically active allyl alcohol derivative represented by (XI[I> (wherein x2 has the same meaning as above).

In such a reduction reaction, the following formulas (XV), (X
Vl), (XVI[), l:bi(X■) (in the formula, ×1
and Each of the represented compounds may occur as isomers. Since such isomers are not so needed as prostaglandins, a method for selectively obtaining the desired allyl alcohol with α configuration is desired. For this purpose, hydrogenation 1,1'-
A method using a binaphthyl-2,2'-dioxyaluminum lithium compound (JP-A-55-51093) is known.

<Problems to be solved by the invention> However, in the above-mentioned known examples, the 2,2'-dihydroxy-1°1'-binaphthyl compound used as the chiral source is expensive and requires a complicated multi-step process to prepare. Therefore, it is difficult to say that it is suitable for practical use. Further, according to the above-mentioned publicly known publication, although high selectivity is obtained in the reduction of the compound represented by the formula (Vl),
The chemical yield has not reached a practical level.

In view of the drawbacks of the prior art, it is an object of the present invention to provide a method for producing optically active allyl alcohol derivatives with good selectivity and yield.

Means for Solving the Problems> In order to solve the above problems, the present inventors have conducted extensive research and have developed a method using a composite produced by first reacting an optically active alcohol with lithium aluminum hydride. We proposed that optically active alcohols can be produced by reducing ketones. As a result of further studies, it was discovered that the object of the present invention could be more effectively achieved by using a complex mainly formed by reacting a specific optically active alcohol under specific conditions with a specific ketone. , completed the invention. That is, the above object of the present invention is achieved by the following formula (
I) The following formula (n) R1-CH-CH-C-R2...(II) II (wherein, R1 is an organic group having 1 to 20 carbon atoms, and R2 is an aliphatic group or aromatic group having 1 to 10 carbon atoms). Ill
) R1-CH=CH-CH-R2...(III)
This is achieved by employing a method for producing an optically active allyl alcohol derivative represented by H (wherein R1 and R2 have the same meanings as above).

The details of the configuration of the present invention will be explained below.

In the present invention, the enone represented by the formula (II>) is used as a raw material.

In the formula (II), R1 represents an organic group having 1 to 20 carbon atoms, and R2 represents an aliphatic group or aromatic group having 1 to 10 carbon atoms. Such R1 may be, for example, an aliphatic group or an aromatic group, such as methyl, ethyl,
Preferred examples include alkyl groups such as propyl, butyl, hexyl, dodecyl, and octadecyl, cycloalkyl groups such as cyclopentyl and cyclohexyl, aryl groups such as phenyl, naphthyl, biphenyl, and tolyl, and aralkyl groups such as benzyl and phenethyl. Also R
Examples of 2 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group,
Examples include sec'-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-octyl group, benzyl group, and phenethyl group. These aliphatic groups or aromatic groups may have appropriate substituents or functional groups as long as they do not interfere with the reaction, such as alkoxy groups,
It may have an aryloxy group, an alkylthio group, a halogen, an ester, a lactone, an amide, a carbon-carbon unsaturated bond, a hydroxyl group, or a protected hydroxyl group.

Furthermore, in the formula (IV>), x1 and They may be combined to form a ring.

In addition to the hydroxyl group, such x1 and
Preferred examples include butyldimethylsilyloxy group. Further, as R3, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, n-hexyl group, n-octyl group, phenyl group, naphthyl group, Examples include tolyl group, benzyl group, and phenethyl group. In addition, examples of structures in which R3 and Xl combine to form a ring include structures such as the above formulas (VI), (X), and (XII). These aliphatic groups or aromatic groups may have appropriate substituents or functional groups as long as they do not interfere with the reaction, as in the case of R1 or R2.

In the method of the present invention, a reducing agent is first prepared prior to the reduction of the enone represented by the formula (II>).The reducing agent used in the present invention hydrogenates the optically active alcohol represented by the formula (1) and water. It is a complex produced by reacting with aluminum lithium. By using water, the above formulas (VI), (■), (X
) In the reduction of enones as represented by i or (XII), the yield and selectivity are significantly improved. In addition,
The optically active alcohol represented by the formula (I>) can be produced inexpensively and in large quantities using easily available tartaric acid as a starting material, as shown below.

To illustrate the scheme, alcohol E acid is reacted with ethanol by a known method and converted to diethyl tartrate. This is reacted with acetone or acetone dimethyl acetal to convert it into a cyclic acetal. By reacting this cyclic acetal with a phenyl Grignard reagent or a similar organometallic compound, the desired optically active alcohol represented by the formula (I) can be obtained.

The reducing agent is prepared using a suitable solvent under an inert gas atmosphere such as nitrogen or argon. Any solvent may be used as long as it does not participate in the reaction, but aprotic solvents such as diethyl ether, tetrahydrofuran, and dioxane are preferred. The amount of optically active alcohol represented by formula (I) used is 0.9 to 1.4 mol, preferably 0.95 to 1.10 mol, per 1 mol of lithium aluminum hydride. Further, the amount of water added is 0.00% per mole of lithium aluminum hydride.
A molar amount of 55 to 0.95 is preferred. It goes without saying that the optimum amount of water to be added is influenced by the reaction apparatus used and the moisture absorption state of the solvent, chemicals, etc.

Therefore, care must be taken when drying these.

The temperature when preparing the reducing agent in this way is -10'
The temperature range is preferably from C to +25°C, and the time required for preparation is as follows:
Usually it takes about 0.5 to 10 hours.

Although it is possible to isolate the reducing agent thus prepared and then use it for reduction, it is convenient to use the solution as it was prepared for reduction without isolation.

The reduction according to the present invention is carried out using the reducing agent thus obtained.

Reduction according to the method of the invention is carried out using a suitable solvent under an inert gas atmosphere such as nitrogen or argon. Any solvent may be used as long as it does not participate in the reaction, but aprotic solvents such as diethyl ether, tetrahydrofuran, dioxane, and toluene are preferred. The reducing agent may be used in any amount as long as it is 1 mole or more per 1 mole of the enone represented by the above formula (n), but
1 to 10 molar amounts are preferred.

The reaction temperature is -100'C to +25°C, preferably -100'C.
It ranges from 0'C to -30'C. Although the reaction time varies depending on the conditions, it is usually preferably about 1 to 24 hours.

In this way, the optically active allyl alcohol derivative represented by the above formula (I[I) is obtained. This product can be isolated and purified from the reaction mixture by conventional separation and purification means, such as recrystallization, column chromatography, and solvent extraction. Further, the optically active alcohol represented by the formula (I) can be recovered from the reaction mixture without impairing the optical purity used in the reaction and can be used repeatedly.

<Examples> The present invention will be explained in more detail below using examples.

Example 1 [Reduction of an enone in which x2 is a benzoyloxy group in the above formula (Vl) (hereinafter referred to as enone (VIa))] In an argon atmosphere, a tetrahydrofuran solution of lithium aluminum hydride (1,00 mol/'J ')10.
(-)-2,3-0-isopropylidene-1 to 0 ml
, 1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound represented by the above formula (I>) in tetrahydrofuran solution (4,90 g/l 11 nl>
was added dropwise under water cooling, and the mixture was further stirred for 1.5 hours. A solution of water in tetrahydrofuran (108my/
6d) was added dropwise under water cooling, and the mixture was roughly stirred for 1 hour. The reaction mixture was cooled to -78°C and the enone (Vl a
) in tetrahydrofuran solution (370 mg/!M) was added dropwise, and the mixture was further stirred at -78°C for 2 hours. The reaction mixture was poured into an aqueous ammonium chloride solution to stop the reaction, the organic layer was separated, and the aqueous layer was Extraction was performed with diethyl ether. The organic layer and the extract were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.

When the obtained residue was analyzed by high performance liquid chromatography (Tsuwo-Tass Co., Ltd. Wj201D), it was found that among the allyl alcohols produced, in the formula (VI), X2 is a benzoyloxy group (hereinafter referred to as α-form (VIa)). The ratio of the β-isomer (XVa) to the β-isomer (XVa) in which x2 is a benzoyloxy group in the formula (XV) is 98:
It was 2. This residue was separated and purified by silica gel column chromatography (cyclohexane-ethyl acetate, gradient elution method) to obtain 325 mg of the desired α-isomer (VIa) (
A yield of 87% was obtained. In addition, 19ffirJ, a mixture of the β form (XVa) and the insufficiently separated α form (Vla), was obtained.

Comparative Example [When water is not added in the reduction of enone (VI a )] In an argon atmosphere, a compound represented by the above formula (I>) was added to 2.4 m of a tetrahydrofuran solution (0.85 mol/l) of lithium aluminum hydride. A solution of enone (VIa) in tetrahydrofuran (934 mg/6.0 d) was added dropwise under water cooling and stirred roughly for 1 hour.The reaction mixture was cooled to -78°C, and a solution of enone (VIa) in tetrahydrofuran (2
22! n9/3rnll> was added dropwise, and the mixture was roughly stirred at -78°C for 2 hours. When the same post-treatment as in Example 1 was carried out and the crude product was analyzed, it was found that α form (VMa) and β
The ratio with body (XVa) was 60:40. This crude product was separated and purified in the same manner as in Example 1, and the α-form (Vl[
a > 98 mg (yield 44%) and β form (XVa)
Example 2 50 mg (yield 22%) was obtained When the enone represented by the formula (Vl) was reduced in the same manner as in Example 1, the results shown in Table 1 below were obtained.

Example 3 The enone represented by the formula (■) was reduced in the same manner as in Example 1, and the results shown in Table 2 below were obtained.

Example 4 [Reduction of an enone in which X2 is an acetoxy group in the formula (X) (hereinafter referred to as enone (X))] Under a nitrogen atmosphere,
To 14.5 m of a tetrahydrofuran solution (1,00 mol/11) of lithium aluminum hydride was added the formula
) A tetrahydrofuran solution of the compound represented by (7,
105g/16d) was added dropwise under water cooling, and the mixture was roughly stirred for 2 hours. A solution of water in tetrahydrofuran (157 my/4 ml) was added dropwise to the reaction mixture under water cooling, and the mixture was roughly stirred for 1 hour. The reaction mixture was cooled to -78°C, and a solution of enone (X) in tetrahydrofuran (1,00 g/l) was added.
5d> was added dropwise, and the mixture was roughly stirred at -78°C for 12 hours. 0.87 ml of acetic acid and 1.0 ml of water were added to the reaction mixture to stop the reaction, and 307 ml of ethyl acetate was added to the reaction mixture. and magnesium sulfate were added for drying, and after filtration, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (cyclohexane-ethyl acetate, gradient elution method), and the crude product, that is, the one in the above formula (XI) where ×2 is an acetoxy group (hereinafter referred to as α-form (XI)) )
A mixture of 761 m'J (yield 76%) of the above formula <x vm > in which x2 is an acetoxy group (hereinafter referred to as β form (X VI )) was obtained. This crude product was subjected to high performance liquid chromatography (Waters Co., Ltd. 20
When analyzed using
(2)) was 84:16.

Example 5 In the same manner as in Example 4, in the formula (XII), X2
When reducing the necessary enone with an acetoxy group, among the crude products obtained, x2 in the above formula (XIII)
is an acetoxy group, and in the above formula (X■), ×2
The ratio of acetoxy group to that of acetoxy group was 80:20.

<Effect of the invention> The present invention has the following effects.

a1 In the method of the present invention, the prostaglandin derivatives used to obtain the desired isomer were:
It is a natural type of tartaric acid.

Since this product is a natural type, it can be obtained at low cost and is industrially advantageous.

b0 In the method of the present invention, the above formula (
The optically active alcohol represented by I) can be synthesized through a relatively simple process and is therefore suitable for on-site production.

C9 The method of the present invention has both high stereoselectivity and high chemical yield.

Claims (6)

[Claims] (1) The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(I
) Using a complex produced by reacting an optically active alcohol and water represented by the formula with lithium aluminum hydride, the following formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(II) (In the formula, R^1 is an organic group having 1 to 20 carbon atoms, and R^2 is an aliphatic group or aromatic group having 1 to 10 carbon atoms.) The following formula (I
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(III
) (In the formula, R^1 and R^2 have the same meanings as above)
A method for producing an optically active allyl alcohol derivative represented by (2) Enone is represented by the following formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(IV) (In the formula, R^2 is an aliphatic group or an aromatic group having 1 to 10 carbon atoms. , X^1 and X^2 are the same or different and represent a hydroxyl group or a protected hydroxyl group, and R^3 has a carbon number of 1
~15 aliphatic or aromatic groups, R^3 and X^1 may be bonded to form a ring), and the optically active allyl alcohol derivative is represented by the following formula ( V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(V) (In the formula, R^2, R^3, X^1 and X^2 have the same meanings as above) A method for producing an optically active allyl alcohol derivative according to claim 1, which is a compound comprising: (3) A compound where the enone is represented by the following formula (VI) ▲Mathematical formula, chemical formula, table, etc.▼・・・・・・(VI) (wherein, X^2 represents a hydroxyl group or a protected hydroxyl group) And the optically active allyl alcohol derivative is the following formula (VII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(VII
) (wherein X^2 has the same meaning as defined above), the method for producing an optically active allyl alcohol derivative according to claim 2. (4) Enone has the following formula (VIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(VII
I) (wherein X^1 and X^2 are the same or different and represent a hydroxyl group or a protected hydroxyl group), and the optically active allyl alcohol derivative is a compound represented by the following formula (IX) ▲ Numerical formula, chemical formula There are tables, etc.▼・・・・・
...(IX) (In the formula, X^1 and X^2 have the same meanings as above)
A method for producing an optically active allyl alcohol derivative according to claim 2, which is a compound represented by: (5) Enone is a compound represented by the following formula (X) ▲Mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(X) (In the formula, X^2 represents a hydroxyl group or a protected hydroxyl group) And the optically active allyl alcohol derivative has the following formula (X I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(X
The method for producing an optically active allyl alcohol derivative according to claim 2, which is a compound represented by I) (wherein X^2 has the same meaning as defined above). (6) Enone has the following formula (XII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(XI
I) (wherein, X^2 has the same meaning as above), and the optically active allyl alcohol derivative is the following formula (XIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... ...(XI
II) The method for producing an optically active allyl alcohol derivative according to claim 2, which is a compound represented by the following formula (wherein X^2 has the same meaning as defined above).