JPH0967382A - Production of optically active 4-trimethylsilyl-3butyn-2-ol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject compound useful as a raw material for medicines, etc., in high yield by reacting 3-triethylsilylpropargylaldehyde with dimethylzinc in the presence of an optically active reactional product of optically active acetonides with a Ti compound as a catalyst. SOLUTION: A 3-trimethylsilylpropargylaldehyde of formula I (TMS is trimethylsilyl) is reacted with dimethylzinc in the presence of an optically active compound prepared by reacting an optically active acetonide derivative of formula II [R<1> and R<2> are each a 1-5C alkyl, a cyclic alkyl or an aryl; R<3> is a (substituted)aryl; * is asymmetric carbon] with a titanium tetraalkoxide of the formula Ti(OR<4> )4 (R<4> is a 1-3C alkyl) as a catalyst to thereby simply afford the objective optically active 4-trimethylsilyl-3-butyn-2-ol of formula III useful as a raw material, etc., for medicines such as steroids, vitamin E, pheromones, leukotrienes or prostaglandins in high yield.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active 4-trimethylsilyl-3-butyn-2-ol. The compounds are steroids, vitamin E, pheromones,
Compounds useful as raw materials for pharmaceuticals such as leukotriene and prostaglandin, for example, 5-lipoxygenase inhibitor A-79175 (Tetrahedron
Letter 36 (16), 2733, 1995).
It is used as a raw material. Further, when the trimethylsilyl group of the compound is converted into hydrogen, it becomes a useful intermediate, which is an optically active 3-butyn-2-ol.

[0002]

2. Description of the Related Art Conventionally, optically active 4-trimethylsilyl-
As the method for producing 3-butyn-2-ol, (1) a method of asymmetric transesterification of racemic 4-trimethylsilyl-3-butyn-2-ol in an organic solvent in the presence of an enzyme such as lipase in the presence of an ester ( Yoshida et al., US Patent No. 48
82451 and K.S. Burgess, J.M. Am. Che
m. Soc. , 1991, 113, 6129), (2)
Optically active lactic acid is reduced with diisobutylaluminum hydride (DIBAL) to give an aldehyde, and CBr ₄ −
After Wittig reaction with P (C ₆ H ₅ ) ₃ , CH ₃ Mg
A method of treating with Br-TMSCl (TMS: trimethylsilyl group) (Tetrahedron Letter)
36 (16), 2733, 1995).

On the other hand, optically active 4-trimethylsilyl-3
The following production method is also known for optically active 3-butyn-2-ol obtained by converting the trimethylsilyl group of -butyn-2-ol into hydrogen. (3) 3-butyne-2-
Method for asymmetric reduction of benzene with optically active borohydride (HC Brown et al, J. Org. Ch.
em. , 1992, 57, 2379), (4) 3-butyn-2-one is reduced with LiAlH ₄ -N-methylephedrine-3,5-dimethylphenol (Te)
trahedron Letter, 21 (18), 1
753, 1980), (5) racemic 3-butyne-2.
A method of forming an inclusion compound of L-brucine with L-olucine and performing optical resolution (JP-A-62-246530), (6)
Racemic 3-butyn-2-ol was converted to N-tosyl-L-
Esterified with phenylalanine or N-tosyl-L-valine (Tetrahedron Asymmetry)
4 (7), 1645, 1993) or esterification with biocartol (Synthesis, 165, 19).
95) followed by optical resolution, (7) 3- of racemic body
A method of asymmetrically hydrolyzing or adding alcohol to butyne-2-ol with an organic acid ester (Japanese Patent Laid-Open No. 3-24
7299, JP-A-3-201996) or a method of asymmetric reduction using an enzyme (J. Org. Chem.,
54 (11), 2646, 1989), (8) Dehydrohalogenation of optically active 4-iodo-3-butyn-2-ol with lithium diisopropylamide (LDA) and LiNH ₂ (Tetrahedron Lette).
r, 30 (50), 7083, 1989) and the like.

[0004]

In the conventional method for producing optically active 4-trimethylsilyl-3-butyn-2-ol, the enzyme method (1) requires a large amount of expensive enzyme, the yield is low, and The complicated operation of separating and purifying from the ester of 4-trimethylsilyl-3-butyn-2-ol which predominantly contains the stereo configuration of (3) is required, and the method using (2) optically active lactic acid as a raw material is expensive. Libutyl dimethylsilyl chloride, DIBAL and CBr ₄ −
_{P (C 6 H 5) 3} , CH 3 requires MgBr-TMSCl the equivalent or more, many reaction steps, there is both industrial problems.

Further, among the conventional methods for producing optically active 3-butyn-2-ol, the above method (3) requires an expensive reactant in an equivalent amount or more, and the step of 3-butyn-2-one synthesis is also required. It is not practical because it is long and the optical purity of the product is not so high. In the method of (4), the product is 7
Only a low purity of about 9% ee can be obtained. (5),
In the method of (6), L-brucine and biocartol used are expensive, and N-tosyl-L-phenylalanine,
The method using N-tosyl-L-valine is complicated in operation and the yield is very low at 28%. The method using lipase or the like in (7) is not practical because both the substrate concentration and the optical purity of the product are low, and the separation is not easy. The dehalogenation method (8) has a drawback that the synthesis route of the raw material is long.

[0006]

DISCLOSURE OF THE INVENTION The present inventors do not have the problems of the conventional method and can directly and easily produce the desired optically active 4-trimethylsilyl-3-butyn-2-ol. The present invention has been achieved as a result of extensive studies on the method.

In the present invention, a reaction of 3-trimethylsilylpropargyl aldehyde represented by the following formula (2) with an optically active acetonide derivative represented by the formula (3) and titanium tetraalkoxide represented by the formula (4). An optically active compound represented by the formula (1), characterized in that the optically active compound obtained by
-A method for producing trimethylsilyl-3-butyn-2-ol.

[0008]

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[0009]

[Chemical 6]

[0010]

[Chemical 7]

[0011]

Embedded image

However, in the above formulas (1) to (4),
TMS is a trimethylsilyl group, R ¹ and R ² are groups each selected from an alkyl group having 1 to 5 carbon atoms, a cyclic alkyl group and an aryl group, R ³ is an aryl group which may have a substituent, R ⁴ Represents an alkyl group having 1 to 3 carbon atoms, and * represents an asymmetric carbon.

In the formula (3) of the catalyst component used in the present invention, R ¹ and R ² are alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl, and cyclopentyl. ，
Cyclic alkyl such as cyclohexyl and cycloheptyl,
Examples include aryl groups such as phenyl and naphthyl. R
³ is an aryl group which may have one or two or more substituents, examples of the aryl group include phenyl and naphthyl, and examples of the substituent include methyl, tertiary butyl and trifluoromethyl. The acetonide derivative represented by the formula (3) can be synthesized from optically active tartaric acid by a known method.

In the formula (4) of the catalyst component used in the present invention, R ⁴ is an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl.

The dimethylzinc used in the present invention is obtained by distilling a product obtained by the reaction of methyl iodide and zinc, methylmagnesium halide and zinc halide, trimethylaluminum and zinc halide or zinc acetate, or the like. Is used as a mixture with an organic solvent.

In the present invention, the reaction is carried out by reacting the starting material 3-trimethylsilylpropargylaldehyde with dimethylzinc using the reaction product of the acetonide derivative of the formula (3) and the titanium tetraalkoxide of the formula (4) as a catalyst. To be achieved. The reaction is preferably carried out in an atmosphere of a gas inert to dimethylzinc, such as nitrogen or argon. The reaction temperature is appropriately selected to maintain the reaction rate and improve the stereoselectivity. For example, it can be performed at -20 to 15 ° C, but is not limited thereto. The reaction is considered to be completed when the disappearance of the raw materials is confirmed.

The inert solvent used in the reaction may be an organic solvent inert to dimethylzinc, for example, diethyl ether, diisopropyl ether, tertiary butyl methyl ether, toluene, chloroform, tetrahydrofuran, toluene-diethyl ether mixture, etc. Is preferably used.

The optically active catalyst used in the present invention is prepared as follows. That is, a predetermined amount of the compound of formula (3) and formula (4) is dissolved in an inert solvent such as dichloroethane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, chlorobenzene and the like to react, and then the solvent is distilled off under reduced pressure. It is obtained by removing the generated alcohol. It is also possible to add a molecular sieve to an inert solvent in which the compounds of the formulas (3) and (4) are dissolved, adsorb the produced alcohol, and then use the catalyst solution obtained by filtration or decantation as it is. The molar ratio of the compound of formula (3) to the compound of formula (4) at the time of catalyst preparation is about 1: 1. However, this reaction, that is, optically active 4-trimethylsilyl-3-
When synthesizing butyn-2-ol, the compound of the formula (4) is 0.8 to 1.5 with respect to the starting material 3-trimethylsilylpropargylaldehyde as a whole including the catalyst preparation.
It is preferable to use a molar equivalent, preferably 1.0 to 1.4 molar equivalent, in order to obtain a target product having high optical purity. The excess amount of the compound of the formula (4) may be added in excess when preparing the catalyst, or may be added after preparing the catalyst. As a method of addition, it may be added as a solution of an inert solvent used in this reaction.

In the present invention, the amount of the optically active catalyst used is
0.01-based on the acetonide derivative of formula (3) based on the starting material 3-trimethylsilylpropargyl aldehyde
It is 0.5 molar equivalent, preferably 0.05 to 0.2 molar equivalent. The amount of the reactant dimethylzinc used is 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1.1 to 2 molar equivalents, relative to the above raw materials.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION Typical examples will be given below as examples, but the present invention is not limited thereto.

[0021]

【Example】

Example 1 265 mg of an optically active compound of the formula (3) (R ¹ ═CH ₃ , R ² ═R ³ ═C ₆ H ₅ , hereinafter referred to as an optically active catalyst R, R-3-A) in a Schlenk tube substituted with argon. (0.5m
mol) and 2 ml of toluene was added. Titanium tetraisopropoxide 0.15 ml (0.
The mixture was stirred for 20 hours. The solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure for 1 hour to obtain a solid product. The obtained solid product was dissolved in 2 ml of diethyl ether, and titanium tetraisopropoxide was 0.9 ml.
(3.0 mmol) was added, the solution was cooled to −20 ° C., a diethyl ether solution of 4.5 mmol of dimethylzinc was added, and then the mixture was stirred for 40 minutes while warming to 0 ° C. Next, 0.38 ml (2.5 mmol) of 3-trimethylsilylpropargylaldehyde was added dropwise, and the mixture was stirred at 0 ° C for 3 days. The reaction solution was poured into about 10 ml of 1N HCl aqueous solution and stirred for 1 hour, the organic layer was separated, and the aqueous layer was extracted 3 times with 15 ml of dichloromethane. Anhydrous sodium sulfate was added to the combined organic layer and dichloromethane to dry the organic layer, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: diethyl ether = 19: 1) to obtain 197 mg of S-form 4-trimethyl-3-butyn-2-ol. The yield was 56% and the optical purity was 96% ee. The optical purity was measured by inducing a sample into 3,5-dinitrobenzoate, and then performing an HPLC analysis (optical resolution column “CHIRALPAK AD” manufactured by Daicel Chemical Industries, Ltd., hexane containing 0.01% of trifluoroacetic acid: 2-propanol = 10
0: 1). The measurements are the same in the following examples.

Example 2 Instead of the optically active catalyst R, R-3-A, an optically active catalyst R,
R-3-B (in the formula (3), R ¹ = CH ₃ , R ² = C
₆ H ₅ , R ³ = 4-tertiarybutylphenyl optically active compound) 376 mg (0.5 mmol) was used in the same manner as in Example 1, except that S-form 4-trimethylsilyl-3-butyne-2- was used. All 350 mg was obtained. Yield 9
It was 8% and the optical purity was 94% ee.

Example 3 The amounts of the optically active catalysts R and R-3-B used were 15 m each with respect to 3-trimethylsilylpropargylaldehyde.
ol%, 10 mol% and 5 mol% were used, but in the same manner as in Example 2, S-form 4-trimethylsilyl-3-
I got Butyn-2-ol. Yields are 88% and 7 respectively
4% and 80%, optical purity is 92% e, respectively
e, 88% ee and 85% ee.

Example 4 S was carried out in the same manner as in Example 2 except that the reaction temperatures were 15 ° C., 0 ° C. and −20 ° C. and the reaction time was 24 hours.
The body of 4-trimethylsilyl-3-butyn-2-ol was obtained. The yields are 99%, 98% and 79%, respectively, and the optical purities are 93% ee, 94% ee and 9%, respectively.
It was 5% ee.

Example 5 Titanium tetraethoxide and titanium tetramethoxide were used in place of titanium tetraisopropoxide.
-S-form of 4-trimethylsilyl-3-butyn-2-ol was obtained in the same manner as in Example 2 except that 1.4 mol equivalent was used for each of -trimethylsilylpropargylaldehyde and the reaction time was 48 hours. The yields are 78% and 40% respectively, and the optical purities are 65% respectively.
ee and 44% ee.

Example 6 Titanium tetraisopropoxide was used in an amount of 1.4 mol equivalent to 3-trimethylsilylpropargyl aldehyde, and toluene, diisopropyl ether, tertiary butyl methyl ether and toluene-diethyl ether (1: were used instead of diethyl ether. 1) S-isomer 4-trimethylsilyl-3-butyn-2-ol was obtained in the same manner as in Example 2 except that the mixed solvent was used and the reaction time was 48 hours. The yields are 84%, 91%, 95% and 83%, respectively, and the optical purities are 92% ee and 93%, respectively.
% Ee, 94% ee and 92% ee.

Example 7 Titanium tetraisopropoxide was used in an amount of 1.4 mol equivalent to 3-trimethylsilylpropargyl aldehyde, tertiary butyl methyl ether was used in place of diethyl ether, the reaction time was 48 hours, and the optically active catalyst was used. Instead of R, R-3-B, an optically active catalyst R, R-
3-C (in the formula (3), R ¹ = CH ₃ , R ² = C ₆ H
₅ , R ³ = optically active compound of 4-methylphenyl) and an optically active catalyst R, R-3-D (in the formula (3), R ¹ =
CH ₃ , R ² = C ₆ H ₅ , and R ³ = 3,5-dimethylphenyl optically active compound) were used in the same manner as in Example 2 to obtain S-form 4-trimethylsilyl-3-butyne-2-.
Got an oar. The yields were 77% and 75%, respectively, and the optical purities were 94% ee and 83% ee, respectively.

Example 8 Optically active catalysts S and S-3 (in the formula (3), R ¹ ═CH
₃ , R ² = C ₆ H ₅ , R ³ = 4-tertiarybutylphenyl optically active compound), and the amount of dimethylzinc used is 1.5 mol equivalent and 1.2 mol equivalent to 3-trimethylsilylpropargylaldehyde. R was used in the same manner as in Example 2 except that the reaction time was 24 hours.
The body of 4-trimethylsilyl-3-butyn-2-ol was obtained. The yields were 75% and 50%, respectively, and the optical purities were 94% ee and 95% ee, respectively. The yield and optical purity were 90% ee and 93% ee, respectively, when the amount of dimethylzinc used was 1.2 mol equivalent and the reaction time was 48 hours.

[0029]

INDUSTRIAL APPLICABILITY According to the present invention, each isomer of optically active 4-trimethylsilyl-3-butyn-2-ol can be directly and inexpensively produced by a simple operation, and the yield and optical purity are high. It is important as a raw material of optically active 3-butyn-2-ol which is a deprotected form of

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication C07M 7:00

Claims (5)

[Claims] 1. A 3-trimethylsilylpropargyl aldehyde represented by the formula (2) is obtained by a reaction with an optically active acetonide derivative represented by the formula (3) and a titanium tetraalkoxide represented by the formula (4). A method for producing optically active 4-trimethylsilyl-3-butyn-2-ol represented by the formula (1), which comprises reacting the optically active compound with dimethylzinc as a catalyst. Embedded image Embedded image Embedded image Embedded image However, in the above formulas (1) to (4), TMS is a trimethylsilyl group, R ¹ and R ² are each a group selected from an alkyl group having 1 to 5 carbon atoms, a cyclic alkyl group and an aryl group, and R ³ is An aryl group which may have a substituent, R
⁴ represents an alkyl group having 1 to 3 carbon atoms, and * represents an asymmetric carbon. 2. The method for producing optically active 4-trimethylsilyl-3-butyn-2-ol according to claim 1, wherein the reaction is carried out in an inert solvent. 3. The optically active 4-according to claim 2, wherein the inert solvent is a solvent selected from diethyl ether, toluene, diisopropyl ether, tertiary butyl methyl ether, chloroform, tetrahydrofuran and a mixed solvent of toluene and diethyl ether. Trimethylsilyl-
Method for producing 3-butyn-2-ol. 4. An optically active acetonide represented by the formula (3):
The derivative is R¹= CH_Three, R²= R^Three= C₆H_FiveR, R
Body compound, R¹= CH_Three, R²= C₆H_Five, R^Three= 4-
Tertiary butylphenyl R, R compound, R¹=
CH_Three, R ²= C₆H_Five, R^Three= 4-methylphenyl
R, R compound, R¹= CH_Three, R ²= C₆H_Five, R^Three
= 3,5-dimethylphenyl R, R compound and R¹
= CH_Three, R²= C₆H_Five, R^Three= 4-tertiary
It is a compound selected from the S and S form compounds of tylphenyl.
4. The optically active 4-trime according to claim 1.
Method for producing chill-3-butyn-2-ol. 5. The optically active 4-trimethylsilyl-3-, according to any one of claims 1 to 4, wherein the titanium tetraalkoxide is selected from titanium tetramethoxide, titanium tetraethoxide and titanium tetraisopropoxide. Butyn-2-ol manufacturing method.