JPH04262794A - Production of optically active organosilicon compound - Google Patents

Abstract

PURPOSE:To obtain a synthetic intermediate capable of simply and efficiently producing a physiologically active substance with optical activity in high purity. CONSTITUTION:A racemic mixture of silylalcohol expressed by the following general formula is reacted with a carboxylic acid in the presence of a lipase in an organic solvent. Thereby, only either one antipode is esterified and the other antipode is left as a silylalcohol and these antipodes are separated to provide an optically active organosilicon compound (R1, R2 and R3 are each 1-4C alkyl groups and X is 3-5C primary or secondary alcohol).

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a method for producing optically active organosilicon compounds, and its purpose is to easily and efficiently synthesize optically active physiologically active substances and side chains of ferroelectric liquid crystals. The object of the present invention is to provide an optically active silicon compound as an intermediate.

0002

[Prior Art] Traditionally, as a method for obtaining industrially important optically active substances such as physiologically active substances and bulk side chains of ferroelectric liquid crystals, optically active substances such as optically active alcohols are used as synthetic intermediates. method is known.

For example, ferrotropic liquid crystal materials and optically active β-
Epoxypropane, which is an industrially important optically active substance such as a blocker, is manufactured by taking advantage of the fact that optically active 2-bromo-1-propanol can be easily converted into optically active 1,2-epoxypropane.

[0004] Optical resolution is adopted as a method for obtaining these optically active alcohols, in which an optically active acid and a racemic alcohol are esterified and separated by diastereomer preferential crystallization. and enzymatic optical resolution methods using ordinary lipases are widely used.

However, in the former preferential crystallization method, it is difficult to crystallize the produced ester when the number of carbon atoms is small, and alcohols with a small number of carbon atoms are soluble in water, so water is not used in the solvent or in the post-treatment process. There was a problem in that it was difficult to collect because it could not be used.

[0006] Furthermore, in the latter enzymatic and optical resolution methods, not only the optical purity is reduced or no stereoselectivity is observed at all, but also the enzymatic conversion is carried out in an aqueous solution. There was a problem in that it was difficult to recover the target alcohol.

[0007] Therefore, since optically active alcohol, which is a synthetic intermediate, cannot be produced with high purity and efficiency, it is difficult to produce optically active substances such as physiologically active substances and bulk regions of ferroelectric liquid crystals in an efficient manner. It wasn't.

[0008]

[Problems to be Solved by the Invention] In view of the above circumstances, it has been desired to create a synthetic intermediate with high optical purity and for efficiently producing an optically active substance.

[0009]

[Means for Solving the Problems] As a result of extensive studies, the inventors have determined that a racemic mixture of silyl alcohol represented by the general formula (Chemical formula 1) is treated with a carboxylic acid in an organic solvent in the presence of lipase. A method for producing an optically active organosilicon compound, which is characterized by esterifying only one enantiomer, leaving the other enantiomer as alcohol, and separating these enantiomers, solves all of the above problems. I found out what to do.

0010

[Formula 1] (However, R1, R2, and R3 are each an alkyl group having 1 to 4 carbon atoms, and the X group is a primary or secondary alcohol having 3 to 5 carbon atoms.) The structure of this invention will be described in detail below. do.

(Structure of the Invention) This invention uses silyl alcohol (Chemical formula 1), which is an aliphatic alcohol having a trialkylsilyl group in its molecule, as a substrate, and enzymatically processes this substrate using lipase in an organic solvent. It is characterized by reacting with carboxylic acid to form an asymmetric ester.

0012

[Chemical formula 1] (However, R1, R2, and R3 are each an alkyl group having 1 to 4 carbon atoms, and the X group is a primary or secondary alcohol having 3 to 5 carbon atoms.) The silyl alcohol that is the substrate (Chemical formula 1) ), the terminal silyl group has 1 carbon number
-4 trialkylsilyl groups are not particularly limited, but introduction of trimethylsilyl groups is most preferred in terms of economy, ease of availability, and versatility.

The reason for introducing this silyl group is to improve the optical selectivity of the lipase for the substrate, that is, the ability to discriminate the configuration, and to increase the optical purity of the obtained alcohol having a trialkylsilyl group and its ester. be.

Furthermore, the silyl group of the obtained optically active trialkylsilyl group-containing alcohol and its ester can be easily exchanged with other substituents, and the substituted optically active substance can be used as a useful substance or as an intermediate for its synthesis. This is because it functions as a body. In addition, the moiety other than the silyl group of this silyl alcohol (Chemical formula 1) may be a primary or secondary alcohol with 4 or 5 carbon atoms, and more preferably a silyl alcohol with 3 carbon atoms in view of economic efficiency, availability, versatility, etc. Alcohol is preferred.

The most suitable ones are shown below: 1-trimethylsilylpropan-2-ol (formula 2), 1-trimethylsilylpropan-1-ol (formula 3), or 2-trimethylsilylpropan-1-ol (formula 3).
-trimethylsilylpropan-1-ol (Formula 4) is preferred.

[0016]

[Case 2]

[Chemical formula 3]

[C4]

[0017] The type of lipase used in this reaction differs depending on the substrate, and any lipase that reacts with the substrate may be used, and more preferably Candida cylind.
racea derived lipase OF 360 (manufactured by Meito Sangyo), Rizopus japonicus derived lipase OF 360 (manufactured by Osaka Saiken),
Steapsin (manufactured by Tokyo Kasei), which is a lipase derived from pig pancreas, is preferable.

[0018] These lipases may be used alone or in the form of immobilization. This immobilized lipase includes immobilized lipase entrappingly immobilized on a polymer such as polyacrylamide, k-carrageenan, and calcium alginate, immobilized lipase adsorbed on an inorganic carrier such as silica gel, diatomaceous earth, and even Sepharose. Examples include immobilized lipase covalently bonded to porous glass, etc., and more preferably celite-immobilized lipase adsorbed and immobilized to diatomaceous earth.

Next, this lipase will be explained in more detail using Celite-immobilized lipase as an example. Immobilized lipase is prepared by adding deionized water to lipase to form a paste, then adding Celite and mixing thoroughly until the mixture becomes homogeneous, thereby adsorbing the lipase onto Celite.

[0020] The blending amount of this Celite-immobilized lipase is:
Although it varies depending on the amount and type of substrate, it is sufficient to mix it in excess to ensure the reaction, and usually 10 mg to 100 mg.
mg (dry weight) is used. The reaction temperature of this lipase is preferably 20°C to 80°C, more preferably room temperature to
40°C is desirable.

The reaction time is preferably about 10 to 70 hours, more preferably 20 to 30 hours. The stirring/shaking speed for reacting the lipase is not particularly limited, but is preferably 100 to 300 strokes/min, and preferably 10 to 150 rpm.

[0022] In this reaction, monohydric carboxylic acids ranging from C1 to C6 can be suitably used as the carboxylic acid used in the reaction. Specific examples include butyric acid, acetic acid, valeric acid, propionic acid, isobutyric acid, isovaleric acid, caproic acid, phenylvaleric acid, phenylbutyric acid, and more preferably phenylvaleric acid.

[0023] The solvent used in the reaction may be any solvent as long as it can dissolve the substrate, and more preferably a water-saturated hydrocarbon having 5 to 8 carbon atoms, taking into account the effect on lipase. Among these, isooctane (water saturated) is particularly suitable for use. Furthermore, the amounts of silyl alcohol (Chemical formula 1) and carboxylic acid used in the reaction are both 1μ.
M to 1M is the optimum range, more preferably 10 to 10
0 mM is good. Further, in this reaction, the silyl alcohol (Formula 1) and the carboxylic acid can be suitably used in an equimolar mixing ratio.

As described above, silyl alcohol (chemical formula 1
) and carboxylic acid, only one enantiomer is esterified, the other enantiomer remains in the reaction system as alcohol, and by separating these enantiomers, an optically active organosilicon is produced. Compounds, namely an optically active ester and an optically active alcohol, are produced.

[0025] As a method for separating the optically active ester and the optically active alcohol, there may be mentioned a method of separating the optically active ester and the optically active alcohol by column chromatography such as silica gel chromatography.

The optically active organosilicon compound obtained as above, for example, 2-trimethylsilylpropane-1
- The ol is reacted with dihydropyran in tetrahydrofuran in the presence of a catalytic amount of acid and is converted to 1-tetrahydropyranyloxy-2-trimethylsilylpropane. This was further reacted with 30% hydrogen peroxide and treated with 15% potassium hydroxide/methanol solution to obtain 1-
After conversion to tetrahydropyranyloxypropan-2-ol, it is subjected to tosylation and bromination steps according to conventional methods,
Other functionalities were added so that 1-tetrohydrapyranyloxypropane-2-bromopropane was obtained, which was easily converted to optically active 2-bromo-1-propanol by further deprotecting the tetrahydropyranyl group. It is a compound that can be easily substituted with a group, and is a useful substance as an intermediate for the synthesis of various optically active substances.

[0027] This optically active 2-bromo-1-propanol can be easily converted into optically active epoxypropane, which is of industrial importance, by alkali treatment (potassium hydroxide/methanol solution system, etc.) according to a known method.

[0028]

EXAMPLES The effects of this invention will be made clearer by showing examples below. (Example 1) Lipase OF 360 (manufactured by Meito Sangyo)
After adding 100 ml of deionized water to 100 mg to make a paste, 250 mg of Celite (No. 535) was added and mixed well until uniform, thereby preparing Celite-immobilized lipase. This Celite-immobilized lipase OF360
100 mg (dry weight) was charged into a 100 ml flask with a stopper.

Known synthesis method of Davis et al. (J.Org
Anometallic Chem. 206. (
1981) A water-saturated isooctane solution of 100 mM of 1-trimethylsilylpropan-2-ol synthesized according to 33-47) and 100 mM of phenylvaleric acid.
ml into this flask. This mixture with lipase was shaken at a constant temperature of 30° C. and 120 strokes/min to react. Samples were taken at regular intervals, and the conversion rate was analyzed using gas chromatography, and the optical purity was measured using high performance liquid chromatography. As a result, the optical purity (regarding the remaining alcohol) at 50% conversion was 93% e. e
, the conversion of substrate was 49%.

The analysis conditions for gas chromatography used in this measurement were as follows. Filler: PEG-HT 5% (Support
t: Uniport R) Column temperature: 60-200°C
(16℃/min temperature increase) Carrier: N2 Detector: FID Internal standard: n-pentadecane

The analysis conditions for high performance liquid chromatography were as follows. Column: SUMICHIRAL OA-460
0 Column temperature: Room temperature Mobile phase: Hexane/isopropanol flow rate
:1.0 ml/min Detector :U
V (254nm) Alcohol is 3,5-dinitr
The measurement was performed after derivatization with ophenyl isocyanate.

(Examples 2 to 9) 1-Trimethylsilylpropan-1-ol and 2-trimethylsilylpropan-1-ol were obtained by synthesis method 1 and synthesis method 2. (Synthesis method 1) Synthesis example of 1-trimethylsilylpropan-1-ol. Metallic magnesium (40 g) was charged into a 2 liter reactor, and the system was replaced with argon. Dry tetrahydrofuran (75 ml) and iodine (a small amount) were added to the reactor, stirred vigorously, and a solution of 1-bromo-1-propene (200 g) dissolved in 850 ml of tetrahydrofuran solution was added dropwise over about 1 hour. did. After the dropwise addition was completed, the mixture was stirred for 30 minutes.

After the reaction was completed, 25 liters of pentane was added and tetrahydrofuran was removed by washing with water. After washing with saturated sodium chloride, the pentane layer was dried, and the pentane was distilled off at 45° C. under normal pressure. The residual oil was distilled to obtain 225 g of 1-trimethylsilyl-1-propene. The boiling point of this material was 65-90°C.

Furthermore, the system of the 2 liter four-necked flask was replaced with argon, and the borane/tetrahydrofuran solution (1
M) 1 liter of solution was added. In this flask, 1-trimethylsilyl-1-propene (171 g) obtained above was added.
was added dropwise over about 30 minutes under ice-cooling. After the dropwise addition was completed, the ice bath was removed and stirring was continued for 2 hours. After the reaction is complete,
Water (200 ml) was slowly added dropwise, followed by 3M sodium hydroxide solution (400 ml).

30% hydrogen peroxide (188 m
After adding 1) dropwise, the mixture was heated under reflux for 1 hour. Next, anhydrous sodium carbonate was added until the aqueous layer was saturated to obtain an organic layer. The aqueous layer was further extracted with ether, and the extracted layer and organic layer were combined and dried. Furthermore, the solvent was distilled off from this dried product under normal pressure, and 120 g of the target product 1-trimethylsilylpropan-1-ol was obtained by distillation. This boiling point is 58-6
0℃/28mmHg. Met.

(Synthesis method 2) Synthesis example of 2-trimethylsilylpropan-1-ol. Metallic magnesium (9.9 g) was added to a 1-liter reactor, and the atmosphere in the system was replaced with argon. Dry tetrahydrofuran (20 ml) and iodine (a small amount) were added to the reactor, stirred, and a solution of 2-bromo-1-propene (50 g) dissolved in tetrahydrofuran (200 ml) was added dropwise, followed by stirring for 30 minutes.

Furthermore, trimethylchlorosilane (45g)
was added dropwise, and after stirring for 30 minutes, 200 ml of water was added to terminate the reaction. 2 liters of pentane was added to this reaction solution, and tetrahydrofuran was removed by washing with water (2 liters x 3 times). Next, the pentane layer was dried, and the pentane was distilled off at 45° C. and normal pressure to obtain a residue.

The inside of a 2-liter four-necked flask was replaced with argon, and 800 ml of a tetrahydrofuran solution (0.5 M) of 9-holabicyclo[3,3,1]nonane was added thereto.
added. After stirring for 1 hour, 51 g of the above residue was added dropwise to this flask at room temperature, and 3M aqueous sodium hydroxide solution (160 m
After adding 1), 30% hydrogen peroxide solution (164 ml) was added dropwise at 50°C or lower, and the mixture was heated under reflux for 1 hour.

After refluxing, the mixture was cooled to room temperature and washed with saturated brine. After extracting the aqueous layer with ether, the extracted layer and the organic layer were combined and dried, and the solvent was distilled off at normal pressure, followed by distillation to obtain 20 g of the target product, 2-trimethylpropan-1-ol. Ta. Using the 1-trimethylsilylpropan-1-ol and 2-trimethylsilylpropan-1-ol obtained in this manner and the same 1-trimethylsilylpropan-2-ol as in Example 1 above, and using various lipases, Examples 2 to 9 were carried out in the same manner as in Example 1 using the combinations shown in Table 1.

The results of the 50% conversion rate and optical purity were measured in the same manner as in Example 1. The difference in the measurement method from Example 1 is that 2-trimethylsilylpropane-1-
When measuring the optical purity of ol, the mobile phase was changed to hexane/isopropanol = 98:2, and the column O
The point is that a column is used in which a column OA-4000 is connected in series to A-4600.

The results of these measurements are summarized in Table 1. Regarding the silyl alcohols in the table, (1) is 1-trimethylsilylpropan-2-ol, and (2) is 1-trimethylsilylpropan-2-ol.
trimethylsilylpropan-1-ol, (3) is 2
-trimethylsilylpropan-1-ol.

[0042]

[Table 1]

[0043]

[Effects of the Invention] The method for producing an optically active organosilicon compound according to the present invention includes adding a racemic mixture of silyl alcohol to a racemic mixture of silyl alcohol;
Optical technology characterized by esterifying only one enantiomer by acting carboxylic acid in an organic solvent in the presence of lipase, leaving the other enantiomer as alcohol, and separating these enantiomers. Since this is a method for producing an active organosilicon compound, it has the following effects.

That is, by using silyl alcohol, the optical selectivity of esterification by lipase is improved, and the solubility in water is lowered, so that the recovery rate of alcohol after separation is improved. Furthermore, by using an organic solvent in this reaction system, the substrate concentration is increased and productivity is improved.

[0045] In the thus obtained optically active alcohol into which a silyl group has been introduced and its ester, the silyl group can be easily desorbed and other functional groups can be introduced. Therefore, this optically active organosilicon compound is an optically active alcohol and an optically active ester that can be used as various synthetic intermediates, and the present invention has the effect that these synthetic intermediates can be obtained at a practical level.

Claims (5)

[Claims] Claim 1: A racemic mixture of silyl alcohols represented by the general formula (Chemical formula 1) is treated with carboxylic acid in an organic solvent in the presence of lipase to esterify only one enantiomer, and the other enantiomer is esterified. A method for producing an optically active organosilicon compound, characterized in that the body remains as alcohol and these enantiomers are separated. [Chemical formula 1] (However, R1, R2, and R3 each have 1 to 1 carbon atoms.
The alkyl group of 4 and the X group are primary or secondary alcohols having 3 to 5 carbon atoms. ) 2. The racemic mixture of silyl alcohols comprises 1-trimethylsilylpropan-2-ol (Formula 2), 1-trimethylsilylpropan-1-ol (
3) or 2-trimethylsilylpropan-1-ol (Formula 4). [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] 3. The lipase is Candida c.
Lipase from ylindracea, Rhizop
2. The method according to claim 1, wherein the method is a Celite-immobilized lipase obtained by adsorbing on Celite one or more selected from lipase derived from P. us japonicus and lipase derived from porcine pancreas. 4. The method of claim 1, wherein the carboxylic acid is 5-phenylvaleric acid. 5. The organic solvent has 5 carbon atoms and is saturated with water.
A method according to claim 1, characterized in that the hydrocarbon is a hydrocarbon of .about.8.