JP2000026344A - Production of optically active 1-(4-isobutylphenyl)butan-1- ol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for the synthesis of an indolidine derivative as a therapeutic agent for hypertrophy of prostate by reducing a specific (isobutylphenyl)butan-one in the presence of a specific ruthenium catalyst and a base by using a hydrogen gas. SOLUTION: This optically active 1-(4-isobutylphenyl)butan-1-on of formula III is obtained by reducing 1-(4-isobutylphenyl)butan-1-one of formula I in the presence of an optically active ruthenium(II) complex of formula II [X is H, a halogen or the like; R1, R3, R4 are each H or an alkyl; R2 is a (substituted) aryl; R5 to R8 are each H, a (substituted) aryl or the like] and a base by using a hydrogen gas. The complex of the formula II is preferably prepared by reacting an optically active 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium(II) halide dimethylformamide complex of formula IV [Me is methyl; (n) is 2-4] with an optically active ethylenediamine compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an important intermediate for the synthesis of indolizine derivatives which are therapeutic agents for benign prostatic hyperplasia.
The present invention relates to a method for producing-(4-isobutylphenyl) butan-1-ol.

[0002]

2. Description of the Related Art In recent years, as the population ages, the number of patients with benign prostatic hyperplasia is increasing. Therapeutic agents for this disease include natural product extracts, antiandrogens, α-1-
Blockers and the like are used. JP-A-5-1788
No. 56 shows that indolizine derivative is testosterone 5α
-A therapeutic agent for benign prostatic hyperplasia with a new mechanism of action having reductase inhibitory activity, and an optically active alcohol important as a synthetic intermediate for its indolizine derivative:
Disclosed is a method for producing the compound using-(4-isobutylphenyl) butan-1-one and a related compound, diisopinocanephenylborane. In addition, as a method for producing an asymmetric secondary alcohol from a prochiral ketone, a method using alpinborane, oxazaborolidine, an enzyme, or the like is generally known.

[0003]

However, the effect and the mechanism of action of the natural product extract are not clear, and the induction of impotence and the α-1-
The blood pressure lowering effect of a blocker is a serious problem as a side effect. In addition, among the methods for producing the indolizine derivative, a method using a reagent such as diisopinocan phenylborane or alpinborane is a stoichiometric asymmetric reduction, and is not necessarily a preferable method in terms of cost. . On the other hand, oxazaborolidine used for catalytic asymmetric reduction produces alcohol with high optical purity,
Obtaining such a product requires a relatively large amount of expensive catalyst, and its reduction reaction is dangerous and requires the use of expensive borane-tetrahydrofuran solution. In addition, a method using an enzyme such as baker's yeast may provide an alcohol having a high degree of optical purity, which is safe, but the yield is low and applicable reaction substrates are limited. Thus, for industrial production of indolizine derivatives, it has been strongly desired to establish a safe and efficient method for synthesizing optically active secondary alcohols, which are synthetic intermediates thereof.

[0004]

SUMMARY OF THE INVENTION As a method for producing an asymmetric secondary alcohol from a prochiral ketone, catalytic asymmetric reduction is generally more efficient than stoichiometric asymmetric reduction. Therefore, the present inventors have conducted intensive research on a production method by catalytic asymmetric reduction in order to solve the above problems, and as a result,
The present invention that achieves the intended purpose has been completed. That is, the present invention relates to formula (1)

Embedded image 1- (4-isobutylphenyl) butane-1 represented by
-On is represented by the general formula (b)

[0005]

Embedded image (Wherein, X represents a hydrogen atom, a halogen atom, an acyloxy group or an acetoacetonate group, the R ¹ is a hydrogen atom or an alkyl group, R ² is an aryl group which may have a substituent, and R ³ R ⁴ is the same or different and is a hydrogen atom or an alkyl group; R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and are a hydrogen atom, an alkyl group, an aryl group or R ⁶ and R ⁷ may be linked to each other to form an alkylene group.) And an optically active ruthenium (II) complex represented by the formula: Equation (c) characterized in that

Embedded image Optically active 1- (4-isobutylphenyl) represented by
Method for producing butan-1-ol, and (2) formula (a)
A complex represented by the general formula (b) is converted into a compound represented by the general formula (d)

Embedded image (In the formula, Me represents a methyl group, n represents 2, 3 or 4,
X, R ¹ and R ² are as defined above. An optically active 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium halide (II) dimethylformamide complex represented by the formula (e):

Embedded image (Wherein, R ³ , R ⁴ R ⁵ , R ⁶ , R ⁷ and R ⁸ have the same meanings as described above), and are prepared by reacting with an optically active ethylenediamine represented by the formula: A manufacturing method according to claim 1.

[0006]

Embodiments of the present invention will be described below in more detail. First, the raw material of the present invention is 1- (4-isobutylphenyl) butan-1-one represented by the above formula (a). The catalyst used in this reaction is 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium halide (II) 1,2-ethylenediamine complex represented by the general formula (b). This compound is structurally optically active 1,1'-binaphthyl-
It can be divided into three groups: a 2,2'-bisarylphosphine moiety, a ruthenium halide (II) moiety and an optically active 1,2-ethylenediamine moiety.
There are various complexes based on a combination of a 1'-binaphthyl-2,2'-bisdiarylphosphine moiety and an optically active 1,2-ethylenediamine moiety. In the general formula (b), the “alkyl group” represented by R ¹ includes, for example, C 1-6 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl and n-hexyl.
And an alkyl group having 1 to 3 carbon atoms is particularly preferable. Examples of the “aryl group” of the “aryl group optionally having substituent (s)” for R ² include phenyl, naphthyl and the like, and the “substituent” includes, for example, methoxy, ethoxy, n- Propoxy, isopropoxy, n-butoxy, n-pentoxy,
C1-C6 alkoxy groups such as n-hexoxy, C1-C6 alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; halogens such as chlorine, bromine and iodine Atoms. The number of substituents is not particularly limited, but usually 1 to 3 is appropriate. Particularly preferred examples of R ² include a phenyl group, a phenyl group substituted with a C _1-6 alkyl group or a C _1-6 alkoxy group, and specific examples thereof include 2-,
3- or 4-methylphenyl, 2,3-, 3,4- or 3,5-dimethylphenyl and the like can be mentioned.

In the general formula (b), the “alkyl group” of the “optionally substituted alkyl group” represented by R ⁵ , R ⁶ , R ⁷ and R ⁸ is the “alkyl group” of R ¹ like it can be mentioned a group ". as the" substituent ", those similar to the" substituent which may be aryl groups have "are mentioned in R ^2. As the “optionally substituted aryl group” represented by R ⁵ , R ⁶ , R ⁷ and R ⁸ , the same as the “optionally substituted aryl group” for R ² However, as the "aralkyl group" of the "aralkyl group optionally having substituent (s)", for example, a aralkyl group having an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl, for example, a carbon atom such as methyl, ethyl and n-propyl Examples thereof include alkyl groups of formulas 1 to 3, and specific examples include benzyl, phenethyl, phenylpropyl, and naphthylmethyl. Examples of the “substituent which the aralkyl group may have” include the same as the “substituent that the aryl group may have” in R ² . R ⁶
And R ⁷ may be linked together to form, for example, a C _4-5 alkylene, ie, butylene, pentylene.
Particularly preferred as R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen, an alkyl group having 1 to 3 carbon atoms, a phenyl group, a 4-methoxyphenyl group or a naphthyl group. In the general formula (b), as the “halogen atom” represented by X, for example, fluorine, chlorine, bromine, iodine, etc., and as the “acyloxy group”, an aliphatic or aromatic carboxylic acid having about 1 to 12 carbon atoms is used. Derived acyloxy groups,
For example, acetoxy, propionyloxy, benzoyloxy and the like can be mentioned.

Specific examples of the optically active 1,1'-binaphthyl-2,2'-bisdiphenylphosphine moiety of the compound represented by formula (b) include 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine and 1,1'-binaphthyl-2,2'-bis (bis-4-methylphenyl) phosphine.
Examples of the optically active 1,2-ethylenediamine moiety include 1,2-diphenylethylenediamine,
2,3-dimethyl-2,3-butanediamine, 2,2-
Diphenyl-1-methylethylenediamine, 2,2-diphenyl-1-isopropylethylenediamine, 2,2
-Diphenyl-1-isobutylethylenediamine, 2,
2-di (p-methoxyphenyl) -1-methylethylenediamine, 2,2-di (p-methoxyphenyl) -1-
Isopropylethylenediamine, 2,2-di (p-methoxyphenyl) -1-isobutylethylenediamine, 1
-Benzyl-2,2-di (p-methoxyphenyl) ethylenediamine, 2,2-dinaphthyl-1-methylethylenediamine, 2,2-dinaphthyl-1-isopropylethylenediamine, 2,2-dinaphthyl-1-isobutylethylenediamine, , 2-cyclohexanediamine,
1,2-cycloheptanediamine and the like can be mentioned. It is also possible to use not only the optically active ethylenediamine derivative exemplified above but also an optically active amino alcohol derivative.

The 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium chloride (II) 1,2-ethylenediamine complex (b) used in this reaction is described in Organic Synthesis, Vol. 71. ,
1,1'-binaphthyl-2,2 'represented by the general formula (d) obtained according to the method described on page 1-13 (1993).
-Bisdiphenylphosphine ruthenium halide (II)
It can be prepared by reacting a dimethylformamide complex with the above-mentioned optically active ethylenediamine derivative (e). The complex (b) can be prepared in the reaction system by adding the compound (d) and the compound (e) to the reaction system.
In this reaction, a complex (b) generally comprising a 1,1'-binaphthyl-2,2'-bisdiphenylphosphine moiety having a steric configuration of S or a racemic body and a 1,2-ethylenediamine moiety having a steric configuration of S is used. In some cases, the configuration is 1- (4-isobutylphenyl) butan-1-ol having the configuration R, and the configuration is R or racemic 1,1 '.
When a complex (b) comprising -binaphthyl-2,2'-bisdiphenylphosphine moiety and 1,2-ethylenediamine moiety of R configuration is used, 1-configuration of S-configuration is 1-.
Produces (4-isobutylphenyl) butan-1-ol.

Although the amount of the complex (b) used in this reaction varies depending on the scale or economical efficiency of the reaction, the equivalent ratio is about 1 to 1- (4-isobutylphenyl) butan-1-one as a reaction substrate. / 1,000,000 to 1/1
00 equivalent, preferably 1 / 5,000 to 1/50
It is 0 equivalent. Examples of the base used in the reaction include alkali hydroxides and alkali metal alkoxides, specifically, KOH, K ₂ CO ₃ , KOCH ₃ , KOC
H (CH ₃ ) ₂ , KOC (CH ₃ ) ₃ , NaOH, Na ₂ C
O ₃ , NaOCH ₃ , NaOCH (CH ₃ ) ₂ , NaOC
(CH ₃ ) ₃ , LiOH, LiOCH ₃ , LiOCH (C
H ₃ ) ₂ and LiO (CH ₃ ) ₃ .
The use amount of these bases is 0.5 to
It is 500 equivalents, preferably 2 to 20 equivalents. The solvent used is usually an alcohol such as methanol, ethanol, propanol, 2-propanol or butanol, but it is also possible to use a mixed solvent with tetrahydrofuran, dioxane, benzene, toluene, xylene and the like. The amount of the solvent used is 1- (4) as the substrate.
-Isobutylphenyl) butan-1-one;
It is 500 equivalents, preferably 2-10 equivalents. The reaction temperature is usually -50 to 100C, preferably 0 to 50C. The pressure of hydrogen is appropriately selected in a range from normal pressure to 100 atm. After the reaction, 1- (4-isobutylphenyl) butan-1-ol can be isolated and purified by a conventional method such as extraction, precipitation, or chromatography.

[0011]

The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the present invention. Example 1 (S) -1,1'-binaphthyl-2,2'-bis (bis (4-methylphenyl)) phosphine ruthenium chloride (II) (2S) -1,1-bis ( 4-methoxyphenyl) ethylenediamine complex (1
After adding 1.6 mg), the inside of the vessel was replaced with argon gas. Next, 1- (4-isobutylphenyl) butane-
1-one (1 g), a 1-molar calcium t-butoxide solution in 2-methyl-2-propanol (80 μl) was added to 2-propanol (8 ml), and the mixture was sufficiently purged with argon gas. Added. The reaction tube was then charged with 8 atm of hydrogen and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained oil was subjected to silica gel chromatography to obtain (R) 1-
(4-isobutylphenyl) butan-1-ol (0.
9 g) were obtained. This target compound was subjected to high performance liquid chromatography (column: CHIRALCEL O
D, Solvent: enantiomeric excess measured with n-hexane (100 volumes) and 2-propanol (1 volume) (hereinafter simply referred to as “enantiomeric excess”): 96.
5%. ^{IR cm -1: 3200-3700 (OH)} IH-NMR (CHC1 3, δ): 0.90 (9H, m), 1.30 (1H, bs), 1.42 (1
H, bs), 1.68 (1H, m), 1.81 (2H, m), 1.84 (1H, bs), 2.47 (2
H, m), 4.52 (1H, bs), 7.10 (2H, m), 7.24 (2H, m).

EXAMPLE 2 (S) -1,1'-Binaphthyl-2,2'-bis (diphenyl) phosphineruthenium chloride (II) (1S, 2S) -1,2-diphenylethylenediamine complex was placed in a pressure-resistant glass tube. (7.5 mg) was added, and the inside of the vessel was replaced with argon gas. Next, 1- (4-isobutylphenyl) butan-1-one (1 g), a 1 molar solution of potassium t-butoxide in 2-methyl-2-propanol (80 μl) was added to 2-propanol (7 ml) and toluene (1 ml). ), And sufficiently purged with argon gas, and then added to the reaction tube. The reaction tube was then charged with 8 atm of hydrogen and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained oil was subjected to silica gel chromatography to obtain (R) 1- (4-isobutylphenyl) butan-1-ol (0.85 g). Enantiomeric excess: 96.5%.

Example 3 (S) -1,1'-Binaphthyl-2,2'-bis (bis (4-methylphenyl)) phosphine ruthenium chloride (II) (1S, 2S) -1 was placed in a pressure-resistant glass tube. ,
After adding 2-diphenylethylenediamine complex (3.8 mg), the inside of the vessel was replaced with argon gas. Next, 1-
(4-isobutylphenyl) butan-1-one (10
g) A 2-methyl-2-propanol solution (800 μl) of 1 molar potassium t-butoxide was added to 2-propanol (25 ml), and the mixture was sufficiently purged with argon gas, and then added to the reaction tube. Next, the reaction tube was charged with 8 atm of hydrogen and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the obtained oil was subjected to silica gel chromatography to obtain (R) 1- (4-isobutylphenyl) butan-1-ol (9.4 g). Enantiomeric excess: 97.4%.

Example 4 (S) -1,1'-Binaphthyl-
2,2'-bisphenylphosphine ruthenium chloride (II) dimethylformamide complex (16.6 mg) was charged. Next, a mixed solution of (1S, 2S) -1,2-diphenylethylenediamine (3.75 mg), a 2-propanol solution of 0.5 molar potassium hydroxide (70 μl) and 2-propanol (10 ml) was prepared. After degassing, the mixture was added to the complex and subjected to ultrasonic treatment for 10 minutes. Further, a mixed solution of 1- (4-isobutylphenyl) butan-1-one (10 g) and 2-propanol (30 ml) was added, followed by degassing, filling with 8 atm of hydrogen, and stirring the mixture for 20 hours. did. Thereafter, the same treatment as in Example 3 was performed to obtain 1- (4-isobutylphenyl) butan-1-ol (9.1 g). Enantiomeric excess: 95.8%.

[0015]

According to the present invention, 1- (4-isobutylphenyl) butan-1-one can be used to prepare high-purity optically active
-(4-Isobutylphenyl) butan-1-ol can be produced safely and in high yield.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07M 7:00 (72) Inventor Ryoji Noyori 135-417 Nitta Umemoricho Nisshin City, Aichi F-term (Reference) 4H006 AA02 AC41 AC81 BA23 BA48 BA69 BA81 BE20 FC52 FE11 4H039 CA60 CB20

Claims (2)

[Claims] 1. A compound of the formula (a) 1- (4-isobutylphenyl) butane-1 represented by
The -one is represented by the general formula (b): (Wherein, X represents a hydrogen atom, a halogen atom, an acyloxy group or an acetoacetonate group, the R ¹ is a hydrogen atom or an alkyl group, R ² is an aryl group which may have a substituent, and R ³ R ⁴ is the same or different and is a hydrogen atom or an alkyl group; R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and are a hydrogen atom, an alkyl group, an aryl group or R ⁶ and R ⁷ may be linked to each other to form an alkylene group.) And an optically active ruthenium (II) complex represented by the formula: Formula (c) characterized by the following: Optically active 1- (4-isobutylphenyl) represented by
A method for producing butan-1-ol. 2. A complex represented by the general formula (b) is converted into a compound represented by the general formula (d) in a reaction system for reducing the compound represented by the formula (a). (In the formula, Me represents a methyl group, n represents 2, 3 or 4,
X, R ¹ and R ² are as defined above. An optically active 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium halide (II) dimethylformamide complex represented by the general formula (e): (Wherein, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ have the same meanings as described above), and are prepared by reacting with an optically active ethylenediamine represented by the formula: Claim 1
The manufacturing method as described.