JPH06125789A - Production of optically active 1-aryl-1,3-propanediol by hydrolysis - Google Patents

Abstract

PURPOSE:To obtain an optically active 1-aryl-1,3-propanediol useful as a raw material for producing an antidepressant, etc., by hydrolyzing a racemic 1- aryl-1,3-diacetoxypropane in the presence of lipase in water and isolating a dihydroxy derivative. CONSTITUTION:A racemic 1-aryl-1,3-diacetoxypropane of formula I (X is F or H; Ac is acetyl)(e.g. 1-phenyl-1,3-diacetoxypropane) is hydrolyzed in the presence of lipase derived from a microorganism such as Pseudomonas fragi, Pseudomonas sp., Chromobacterium viscosum, Mucor pusillus, Aspergillus niger, etc., in water to give a mixture of compounds of formula II to formula IV, water is distilled away by vacuum distillation, the residual oil is subjected to liquid chromatography and the compound of formula IV is isolated to give an optically active 1-aryl-1,3-diacetoxypropanediol formula IV useful as a starting raw material for tomoxetine showing strong pharmaceutical activity as an antidepressant.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an optically active 1-aryl-1,3-propanediol useful as a starting material for optically active physiologically active compounds, particularly tomoxetine and fluoxetine which exhibit strong pharmacological activity as antidepressants. The present invention relates to a manufacturing method.

[0002]

[Prior art]

[0003]

[Chemical 4]

It is known that the fluoxetine represented by the formula (5) and the tomoxetine represented by the formula (6) have a strong antidepressant action, but since they have an asymmetric carbon, they have two optical isomers. . Of these, the S-form is effective only as an anti-depressant, and it is preferable to use only the S-form in practical use, and the racemic form or low optical purity does not show sufficient physiological activity. It is clear (Drugs Future, 11 , 134 (1986), SI Ankier, Prog.
Med. Chem., 23 , 121 (1986)).

[0005] In particular, fluoxetine currently in practical use is a racemate, and the use of an optically active substance is desired (DS Risley et al., Analytical Profiles of
Drug Substances, 19, 193 (1990)). When producing optically active tomoxetine (6) and fluoxetine (5), optically active 1-phenyl-1,3-propanediol (7)
Are useful as starting materials. The following method is known as a method for producing optically active tomoxetine (6) and fluoxetine (5) using optically active 1-phenyl-1,3-propanediol (7) as a starting material (Y. Gao and
KB Sharpless, J. Org. Chem., 53, 4081 (1988).

[0006]

[Chemical 5] For example, methanesulfonyl chloride is caused to act on optically active 1-phenyl-1,3-propanediol (7) to form mesylate (8), which is then induced to an amide (9) body.
Furthermore, p-trifluoromethylchlorobenzene acts to produce optically active fluoxetine (5). For practical use, use the hydrochloride (10) treated with hydrogen chloride gas.

Thus, the optically active 1-phenyl-1,3
-Corresponding optically active fluoxetine (5), tomoxetine (6) by using propanediol (7)
Can be efficiently produced, but the optically active 1-
Little is known about how to efficiently produce phenyl-1,3-propanediol (7). Currently known production methods have problems such as low optical yield, low chemical purity of products, and severe reaction conditions, and a production method in which these problems have been solved is desired.

[0008]

[Chemical 6]

[0009] For example, Gao et al.
Optically active epoxy alcohol (12) obtained by Sharpless oxidation of 1) is reduced with Red-Al to obtain optically active 1-phenyl-1,3-propanediol (7).
The regioselectivity of this reduction reaction is by no means good,
The production ratio of 1,3-diol (7) and 1,2-diol (13) is 4.5: 1 to 22: 1, which is not practical (Y. Gao and KB Sharpless, J. Org. Chem.,
53, 4081 (1988)).

[0010]

[Chemical 7]

(In the above formula, R represents an acyl group having 2 to 12 carbon atoms.) Further, vinyl ester was added to racemic 1-phenyl-1,3-propanediol (14) in the presence of lipase. Also known is a method for producing optically active 1-phenyl-1,3-propanediol, which is characterized in that it acts to perform a stereoselective transesterification reaction to obtain an optically active monoester (15) and diester (16). There is. However, i) it requires complicated operations such as column chromatography and distillation to separate the obtained esters (15) and (16), and ii) the optically active 1-phenyl-1 , 3-
There are many problems such as an increase in the number of ester hydrolysis steps to induce propanediol, and iii) the need for vinyl ester as an acyl donor in the enzymatic reaction (Miyazawa et al.
Japanese Patent Application No. 3-162410).

Further, phenyl groups of tomoxetine (6) and fluoxetine (5) (raw material 1-phenyl-1,3-
The physiological activity of analogs having a substituent introduced on the phenyl group derived from the propanediol skeleton) has not been studied so far, but it has a similar skeleton and is expected to have similar pharmacological activity. In addition, a stronger physiological activity can be expected due to the substituent effect.

[0013]

The present invention makes it possible to obtain optically active 1-aryl-1,3-propanediol, which is important as a synthetic intermediate for optically active fluoxetine and its analogs, which is useful as an antidepressant. It is intended to provide a simple manufacturing method.

[0014]

That is, the present invention is based on the formula

[0015]

[Chemical 8]

(In the above formula, X represents a fluorine atom or a hydrogen atom, and Ac represents an acetyl group.) Racemic 1-aryl-1,3-diacetoxypropane represented by water in the presence of lipase. Hydrolyzed with

[0017]

[Chemical 9]

A mixture represented by the formula (2), (3) and (4), wherein X and Ac have the same meanings as described above, and then the compound of the formula (4) is isolated. An expression characterized by

[0019]

[Chemical 10]

(In the above formula, X represents a fluorine atom or a hydrogen atom, and Ac represents an acetyl group.) In the process for producing optically active 1-aryl-1,3-propanediol. The reaction of the present invention is carried out by stirring a mixture of racemic 1-aryl-1,3-diacetoxypropane, lipase and water, but even if the pH of the reaction solution is kept at the optimum pH of the lipase. If so, there is nothing else to keep in mind.

After completion of the reaction, the desired product can be taken out by the following simple method. That is, optically active 1-aryl-1,3-propanediol can be obtained by removing water from the reaction solution by vacuum distillation and recrystallizing the obtained residue from an organic solvent. The racemic 1-aryl-1,3-diacetoxypropane (1) used in the method of the present invention can be produced by various methods. For example, the following route is industrially advantageous. .

[0022]

[Chemical 11]

(In the above formula, X represents a fluorine atom or a hydrogen atom, and Ac represents an acetyl group.) That is, acetophenone (17) and diethyl carbonate (18).
By reducing ethyl benzoylacetate (19), which is easily obtained from the above, and acetylating the obtained diol (20),

[0024]

[Chemical 12]

Alternatively, (1) can be prepared by ring-opening 4-phenyl-1,3-dioxane (22) obtained by treating styrene (21) with formaldehyde in sulfuric acid in the presence of Lewis acid with acetic anhydride. . In the production method of the present invention, the reaction temperature is 0 ° C to 100 ° C, preferably 10 ° C.
℃ to 50 ℃.

The reaction time is 1 hour to 1,000 hours, but it varies depending on the amount of lipase used, the reaction temperature, and the stirring efficiency. The amount of lipase used is 0.1 to 500% by weight of the substrate, preferably 1 to 200% by weight. Any type of lipase can be used as long as it acts on racemic 1-aryl-1,3-diacetoxypropane to catalyze the hydrolysis reaction, but the characteristics differ depending on the type, so it is suitable for the purpose. The lipase to be used must be selected. Table 1 shows optically active 1-phenyl-1,3-propanediol (4) obtained by the method of the present invention using various lipases.
Stereochemistry, reaction rate (mol%), optical yield (% ee),
It showed stereoselectivity (E).

[0027]

[Table 1]

E = 200 · reaction rate / optical purity That is, when both the chemical yield and the optical yield are theoretical values,
That is, when the reaction rate is 50% and the optical yield is 100% ee, the stereoselectivity (E) is 100. * 2: 1-phenyl-1,3-diacetoxypropane was used as a substrate. * 3: 1- (4-fluorophenyl) -1, as a substrate
3-diacetoxypropane was used.

As shown in Table 1, by selecting the kind of lipase, optically active 1-aryl-1,3-propanediol in either R or S form can be produced separately. Further, in order to obtain the optically active 1-aryl-1,3-propanediol of R form from the stereoselectivity (E) shown in the table, lipase B (Sapporo beer),
Lipase PS (Amano Pharmaceutical Co., Ltd.), lipase (Toyo Brewing Co., Ltd.), lipase OF (Meito Sangyo Co., Ltd.) and lipase (Toyobo) are required to obtain lipase LE40 in order to obtain the optically active 1-aryl-1,3-propanediol in S form. It can be seen that (Henkel), paratase A (Novo) and lipase A (Amano Pharmaceutical) are suitable.

Further, in order to reuse the used lipase, it is effective to use immobilized lipase. As the immobilization carrier, either an adsorption type carrier or an entrapping type carrier can be used. Examples of the adsorption type carrier include celite, clay, activated carbon, cellulose and its derivatives, ion exchange resin and the like, and entrapping type carriers include photocurable resin, agar, calcium alginate, κ-carrageenan and the like. The adsorption type carrier is preferably an ion exchange resin Amberlite XAD.
-8, IRA-900 (Rohm and Haas Company),
Dowex MWA-1 (Dow Chemical Company), κ-carrageenan as a comprehensive carrier. Among them, preferred in terms of repeated use is Amberlite XAD-8 as the immobilization carrier and κ-as the entrapping carrier.
Carrageenan is an example.

In order to produce the immobilized lipase used in the present invention, the lipase is first dispersed in ion-exchanged water, distilled water or a buffer solution. When an adsorptive carrier is used, the carrier is dispersed in the above solution and lipase is adsorbed to form an immobilized lipase. When a comprehensive carrier is used, a carrier monomer is mixed with the above solution and then polymerized to obtain an immobilized lipase.

After the completion of the reaction, the immobilized lipase can be recovered from the reaction system by filtration or a gradient method, and can be used in the next reaction without treatment. In the method of the present invention, it is of course possible to use non-immobilized lipase. Optical activity 1-
The optical purity, yield, and stereoselectivity of aryl-1,3-propanediol are no different from those when immobilized lipase is used.

The water used in this reaction is suitably ion-exchanged water, distilled water or a buffer solution, and its amount is 10% by weight of the racemic 1-aryl-1,3-diacetoxypropane. However, it is preferably 1 to 10 times in view of reaction efficiency. Also,
Acetic acid liberated as the reaction proceeds makes the system acidic, but in order to prevent the inactivation of the lipase, it is necessary to maintain the optimal pH of the lipase in the system. As a means therefor, there are a method of using a buffer solution adjusted to the optimum pH of lipase, and a method of maintaining the pH in the system at the optimum pH of lipase by dropping an aqueous sodium hydroxide solution at appropriate times.

After completion of the reaction, the optically active 1-aryl-containing compound was obtained from the residue, which was a crude product obtained by distilling water under reduced pressure.
The method for taking out 1,3-propanediol is Japanese Patent Application No. 3-
It is carried out by using the recrystallization method according to the method described in 332733. That is, a suitable solvent, preferably toluene, heptane, ethyl acetate and a mixture thereof, is added to the above residue, and the mixture is heated and dissolved, cooled, and the precipitated crystals are collected by filtration to obtain optically active 1-aryl-1,3- Propanediol can be obtained. In addition, since the optical purity can be improved in this recrystallization process,
The hydrolysis reaction using lipase does not necessarily have to proceed with 100% stereoselectivity.

[0035]

The effects of the manufacturing method of the present invention are listed below. (1) Since the production method of the present invention is a hydrolysis reaction, the reaction can be performed in an open system without worrying about the inclusion of water. (2) The reaction can be performed at a mild reaction temperature (around room temperature). (3) When the lipase is immobilized, the lipase can be recovered and reused. (4) It is easy to take out the target product from the reaction system. After distilling off the solvent, the residue need only be recrystallized.

[0036]

EXAMPLES The present invention will be further described below with reference to typical examples. Optically active 1-aryl-1, in the examples
The optical purity of 3-propanediol was determined by either of the following two methods. Method 1 When the R form and the S form could be separated by an optical resolution column, the optical purity was determined by liquid chromatography using an optical resolution column. Chiralcel OB (Daicel Chemical Industry Co., Ltd.) was suitable as the optical resolution column.

Method 2 When the R and S forms cannot be separated by the optical resolution column,
The optical purity was calculated by analyzing the diastereomer (23) synthesized from 1-aryl-1,3-propanediol (4) and (-)-menthone according to the following scheme by capillary gas chromatography.

[0038]

[Chemical 13]

Example 1 A mixture of 30 g of Lipase PS (Amano Pharmaceutical Co., Ltd.) and 300 ml of 1/15 M phosphate buffer (pH 7.0) was stirred for 20 hours, insoluble matters were filtered off using a glass filter, and 230 ml of lipase aqueous solution was added to the filtrate. Got On the other hand, 9.2 g of κ-carrageenan was dissolved by heating in 300 ml of deionized water and allowed to cool to about 50 ° C. 230 ml of an aqueous solution of lipase was mixed with this product and then added dropwise to 5 L of a 5% aqueous solution of potassium chloride to obtain 460 g of immobilized lipase as carrageenan beads.

300 g of racemic 1-phenyl-1,3-diacetoxypropane, immobilized lipase obtained by the above process
The mixture of 460 g and 3 L of 1 / 1.5 M phosphate buffer (pH 7.0) was stirred at 37 to 40 ° C. for 140 hours, and then the immobilized lipase was filtered off. Water was distilled off from the filtrate by vacuum distillation, and 251 g of an oily substance was obtained as a residue. By gas chromatography and liquid chromatography analysis, it was found that this oily substance contained 39 mol% of R-1-phenyl-1,3-propanediol having 73% ee.

The residue was recrystallized once with 90 ml of toluene and once with 100 ml of toluene to obtain 48 g of R-1-phenyl-1,3-propanediol as colorless needle crystals. [Α] _D ²⁸ + 68.8 ° (c1.0, CHCl ₃ ) Melting point: 61.5-63.1 ° C. ¹ H-NMR (90 MHz, CDCl ₃ , internal standard TMS); δ: 7.34 (s, 5H), 4.94 (q , 1H), 3.84 (t, 2H), 2.65
(Brs, 2H), 2.07 to 1.92 (m, 2H) Further, the optical purity was measured by liquid chromatography using an optical resolution column by the above-mentioned optical purity determination method 1, and it was 99.1% ee. (Measurement conditions, column: Chiralcel OB (25 cm x 0.46 cm,
Solvent: Hexane / isopropanol (9/1) Flow rate: 0.5 ml / min Example 2 230 ml of lipase aqueous solution prepared in the same manner as in Example 1, ion-exchange resin Amberlite XAD-8 (Rohm and -Haas Co., Ltd.) After stirring 600 g of the mixture for 20 hours, ion exchange resins were collected by filtration to obtain 860 g of immobilized lipase.

300 g of racemic 1-phenyl-1,3-diacetoxypropane, immobilized lipase obtained by the above process
Reaction and post-treatment were carried out in the same manner as in Example 1 using a mixture of 430 g and 3 L of a 1 / 1.5 M phosphate buffer (pH 7.0), and R
45 g of -1-phenyl-1,3-propanediol was obtained. When the optical purity was measured in the same manner as in Example 1,
It was 99.0% ee.

Example 3 Ion exchange resin Amberlite XAD used in Example 2
R-1-phenyl was reacted and post-treated in the same manner as in Example 1 using ion exchange resin Amberlite IRA-900 (Rohm and Haas) instead of -8 (Rohm and Haas). -1,3-Propanediol 46g
Got Further, the optical purity was measured in the same manner as in Example 1 and found to be 99.0% ee.

Example 4 Ion exchange resin Amberlite XAD used in Example 2
Ion exchange resin Dowex MWA-1 (Dow Chemical Company) was used in place of -8 (Rohm and Haas Company) to carry out the reaction and post-treatment in the same manner as in Example 1,
51 g of R-1-phenyl-1,3-propanediol was obtained. Further, the optical purity was measured in the same manner as in Example 1.
It was 99.2% ee.

Example 5 A hydrolysis reaction was carried out in the same manner as in Example 1 except that lipase (Toyobo) was used instead of lipase PS. It was found by gas chromatography and liquid chromatography analysis that the crude product obtained contained 55 mol% of R-1-phenyl-1,3-propanediol with 83% ee.

Example 6 Instead of Lipase PS, Lipase B (Sapporoville)
Was used to carry out the hydrolysis reaction in the same manner as in Example 1. The crude product obtained by gas chromatography and liquid chromatography analysis contained 87% ee of R-1-phenyl-
It was found that 31 mol% of 1,3-propanediol was contained.

Example 7 The hydrolysis reaction was carried out in the same manner as in Example 1 using Lipase LE40 (Henkel) instead of Lipase PS. 69% ee of S-1-phenyl-1, in the crude product obtained by gas chromatography and liquid chromatography analysis,
It was found that the content of 3-propanediol was 46 mol%.

Example 8 Hydrolysis reaction was carried out in the same manner as in Example 1 except that paratase A (Novo) was used instead of lipase PS. It was found by gas chromatography and liquid chromatography analysis that the crude product obtained contained 44 mol% of S-1-phenyl-1,3-propanediol with 59% ee.

Example 9 The same hydrolysis reaction as in Example 1 was carried out using Lipase A (Amano Pharmaceutical Co., Ltd.) instead of Lipase PS. The crude product obtained by gas chromatography and liquid chromatography analysis contained 59% ee of S-1-phenyl-1,3-
It was found that the propanediol content was 36 mol%.

Example 10 A hydrolysis reaction was carried out in the same manner as in Example 1 except that lipase (Toyo Brewing Co., Ltd.) was used instead of Lipase PS. It was found by gas chromatography and liquid chromatography analysis that the crude product obtained contained 53 mol% of R-1-phenyl-1,3-propanediol having 43% ee.

Example 11 A hydrolysis reaction was carried out in the same manner as in Example 1 except that Lipase OF (Meito Sangyo) was used instead of Lipase PS. The crude product obtained by gas chromatography and liquid chromatography analysis contained 41% ee of R-1-phenyl-1,3
-Propanediol was found to be contained at 46 mol%.

Example 12 300 g of racemic 1- (4-fluorophenyl) -1,3-diacetoxypropane, 460 g of immobilized lipase obtained according to the method of Example 1, and a 1 / 1.5 M phosphate buffer solution ( The mixture of 3 L (pH 7.0) was stirred at 37-40 ° C for 110 hours, and then the immobilized lipase was filtered off. Water was distilled off from the filtrate by vacuum distillation to obtain 238 g of an oily substance as a residue. Gas chromatographic analysis showed that 71% ee R was obtained in this crude product.
It was found that 42 mol% of -1- (4-fluorophenyl) -1,3-propanediol was contained.

This residue was washed once with 80 ml of toluene and once with 90 ml of toluene.
By recrystallizing twice, colorless needle-like crystals R-1- (4
-Fluorophenyl) -1,3-propanediol 41 g
Got [Α] _D ³⁰ + 62.7 ° (c1.2, CHCl ₃ ) Melting point: 48.8 to 50.8 ° C. ¹ H-NMR (90 MHz, CDCl ₃ , internal standard TMS); δ: 7.42 to 6.93 (m, 4H), 4.95 (M, 1H), 3.86 (q, 2H),
2.93 (d, 1H), 2.29 (t, 1H), 2.07 to 1.85 (m, 2H) Further, by gas chromatographic analysis using the capillary column Hicap-CBP1 (0.25 μm × 50 m) according to the optical purity determination method 2 described above. The optical purity was measured and found to be 98.9% ee.

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location (C12P 41/00 C12R 1:01) (C12P 41/00 C12R 1:72) (C12P 41/00 C12R 1: 785) (C12P 41/00 C12R 1: 685)

Claims (5)

[Claims] 1. The formula: (In the above formula, X represents a fluorine atom or a hydrogen atom, and Ac represents an acetyl group.) The racemic 1-aryl-1,3-diacetoxypropane was hydrolyzed in water in the presence of lipase. Decompose it and use the following formula (However, in the expressions (2), (3), and (4), X, Ac
Has the same meaning as above. ), A compound represented by the formula (4) is isolated, and a compound represented by the formula: (However, in the above formula, X represents a fluorine atom or a hydrogen atom, and Ac represents an acetyl group.) Optical activity 1
-A method for producing aryl-1,3-propanediol. 2. The production method wherein the lipase used in claim 1 is a lipase originating from Pseudomonas flazi, Pseudomonas species, Chromobacterium viscosum, Candida, Mucor pusillus, or Aspergillus niger. 3. The lipase used in claim 1 is lipase B (original Pseudomonas fragii) or lipase P.
S (Original Pseudomonas species), Lipase (Original Chromobacterium viscosum), Lipase (Original Candida), Lipase (Original Pseudomonas
A method for producing a lipase originating from Lipase A (origin Aspergillus niger), Lipase LE40 (origin Mucor pusillus), Paratase A (origin Aspergillus niger), or Lipase A (origin Aspergillus niger). 4. The production method, wherein the lipase used in claim 3 is immobilized lipase. 5. The immobilized carrier of the immobilized lipase used in claim 4 is Amberlite XAD-8 or κ.
A manufacturing method which is carrageenan.