JPH08291095A - Production of optically active trans 2-bromoindan-1-ol - Google Patents

Abstract

PURPOSE: To industrially and inexpensively obtain and subject compound by reacting trans (±)-2-bromoidan-1-ol with an ester by using a lipase, preferentially esterifying trans (-)-2-bromoindan-1-ol, separating trans (-)-2-bromoindan-1-ol useful as an intermediate for an anti-HIV medicine from trans (+)-2- bromoindan-1-ol. CONSTITUTION: Trans form (±)-2-bromoindan-1-ol of formula I (X is H; trans- configuration racemic modification) is reacted with a compound of the formula R1 -CO-O-R2 [R1 is an (un)saturated alkyl, a (substituted) aryl or a (substitute) aralkyl; R2 is shown as R1 ] in the presence of a lipase in an organic solvent to preferentially esterify trans (-)-(1R,2R)-2-bromoidan-1-ol, converting it to an optically active trans-(-)-(1R,2R)-2-bromo-1-(acyloxy)indane of formula II and separating it from optically active trans-(+)-(1S,2S)-2-bromoindan-1-ol of formula III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an industrially useful method for producing optically active trans-2-bromoindan-1-ol.

[0002]

BACKGROUND OF THE INVENTION Trans-2-bromoindan-1-ol is useful as a raw material for producing cis-1-aminoindan-2-ol, which is an intermediate for anti-HIV drugs and the like. For example, Japanese Patent Application No. 6-298619, which is a prior application of the applicant of the present application.
, Trans-2-bromoindan-1-ol was reacted with acetonitrile under acidic conditions to give trans-1- (acetamido) -2-bromoindane, which was ring-closed to give a cis-oxazoline derivative. It is described that cis-1-aminoindan-2-ol can be obtained by subsequent hydrolysis. Also,
Gagis et al. [J. Org. Chem. , 3
7, 3181 (1972)].
Treatment of bromoindan-1-ol under basic conditions gives cis-1,2-epoxyindane. In the above-mentioned Japanese Patent Application No. 6-298619, a cis-oxazoline derivative is produced by reacting this epoxy compound with acetonitrile under an acidic condition, and this is hydrolyzed to give cis-1-aminoindane-
It has been shown that 2-ols are obtained.

On the other hand, trans-2-bromoindane-1
-For all, trans-(+)-(1S, 2S) -2-
Bromoindan-1-ol and trans-(-)-(1
R, 2R) -2-Bromoindan-1-ol exists in two types, and when optically active trans-2-bromoindan-1-ol is used in the above reaction,
The product also becomes an optically active substance. Japanese Patent Application No. 6-29861
No. 9 is optically active trans-2-bromoindane-1.
The synthesis of optically active cis-1-aminoindan-2-ol starting from -ol is shown. In recent years, drugs and their intermediates are often optically active substances, and when drugs and their intermediates are produced using optically inactive raw materials, the optically active substance having physiological activity in the final step or intermediate step. It is economically preferable that the intermediate which is as close as possible to the starting material is an optically active substance, because only the separation is required. That is, the optically active trans-2-
Bromoindan-1-ol is a very useful compound for the production of various optically active pharmaceutical products and intermediates thereof.

So far, several methods have been disclosed for the production of optically active trans-2-bromoindan-1-ol. For example, Boyd et al. [J. Chem. Soc. Perkin Trans.
I, 2767 (1982)] is a trans- (±) -2-bromoindane represented by the general formula (I) (wherein, X is a hydrogen atom and is in a racemic configuration of trans). Esterification of -1-ol with (-)-menthyloxyacetyl chloride and separation of the resulting diastereoisomeric mixture by liquid chromatography followed by diborane reduction gave trans-(+)-with an optical purity of 98% or more.
(1S, 2S) -2-Bromoindan-1-ol (V) and trans-(-)-(1R, 2R) -2-Bromoindan-1-ol (III) are obtained (Scheme 1). .

[0005]

[Chemical 11]

According to this method, although each optically active substance having high optical purity can be obtained, the inducing reagent itself is an expensive optically active substance, and liquid chromatography is used to separate diastereoisomers. It cannot be said that this is an industrial manufacturing method.

On the other hand, Kawai et al. [Tetr
ahedron Lett. , 27, 2527 (198
1)], Kasai, etc. [J. Org. Che
m. , 49,675 (1984)] is a kind of fungus, Rhizopus nigrans.
icans) (R-70), and is represented by the general formula (I) (wherein, X is an acetyl group and is a racemic body in the trans configuration), (±) -trans-2- Bromo-1- (acetoxy) indane was kinetically resolved by microbial hydrolysis in a culture system to give trans-(−)-(1R, 2R) -2-bromoindane-1-
All- (III) was obtained in a yield of 32% with trans-(+)-
(1S, 2S) -2-Bromo-1- (acetoxy) indane (VI) is obtained with a yield of 64% (Scheme 2).

[0008]

[Chemical 12]

These documents report that the optical rotation of the obtained alcohol compound is -28.5 ° (c 1.20 ethanol) and the optical purity is 98%. In the previous void report, 98% e. e. The optical activity of the above optically active alcohol (determined by liquid chromatography) is-
Since it is 64.0 ° (ethanol), the optical purity of the alcohol (III) obtained by Kawai, Kasai, etc. is 44.5.
It is thought that it was about%. Furthermore, the optical rotation of the ester (VI) obtained by Kasai et al. Is + 12.5 ° (c2.23
Ethanol) with 98% e.g. voids. e. Ester form (IV) derived from the above alcohol form (III)
Considering that the optical rotation of is 167.5 ° (ethanol), the optical purity is only 7.5%. That is,
Hydrolysis of racemic esters using microorganisms does not yield alcohols or esters with satisfactory optical purity, and the microorganisms are difficult to manage. Therefore, optically active trans-2-bromoindane is used. It is hard to say that it is a simple manufacturing method for -1-ol.

Further, Imuta et al. [J. Or
g. Chem. , 43, 4540 (1978)] is a racemic (±) -2-bromo-1-indanone (VII).
C. Microbial reduction was carried out in a culture system using C. macerans, and trans-(+)-(1S, 2
S) -2-Bromoindan-1-ol (V) is obtained with a yield of about 55% and an optical rotation of + 29.0 ° (c 0.530 ethanol) (Scheme 3).

[0011]

[Chemical 13]

This has an optical purity of 45.3% e. e. Therefore, the optical purity is not practically satisfactory.

As described above, the optically active trans-2-
No industrial and inexpensive method has been known for bromoindan-1-ol and its ester form.

[0014]

SUMMARY OF THE INVENTION An object of the present invention is to provide an optically active trans-2-bromoindan-1-ol and its ester derivative industrially and inexpensively.

[0015]

[Means for Solving the Problems] As described above, Kawai, Kasai, and the like have Rhizopus niglycans (Rhizop).
racemic (±)
-Trans-2-bromo-1- (acetoxy) indane is hydrolyzed. This is because lipase, which is a hydrolase of a microorganism, recognizes the substrate stereo, and trans-(-)-(1R, It is considered that 2R) -2-bromo-1- (acetoxy) indane is preferentially hydrolyzed. That is, since it is presumed that the strength of lipase recognition with respect to the substrate is a factor that determines the optical purity, it is suitable as a lipase capable of specifically recognizing each optical isomer of trans-2-bromoindan-1-ol. If reaction conditions are found, trans-2-bromoindan-1-ol with high optical purity can be produced. Furthermore, it is known that lipase has not only the hydrolysis of ester but also the function of esterification, which is a reverse reaction, and in this case, the reaction in an organic solvent is possible. The present inventors have completed the present invention as a result of earnest research on esterification, which is a more industrial method from the above viewpoints.

That is, the general formula (I)

[0017]

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(Wherein, X is a hydrogen atom and is a racemic body in the trans configuration)
(±) -2-bromoindan-1-ol in the presence of lipase in an organic solvent in the general formula (II)

[0019]

[Chemical 15]

(Wherein R ₁ is a saturated or unsaturated alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, and R ₂ is a saturated or unsaturated alkyl group or a substituted Or an unsubstituted aryl group or a substituted or unsubstituted aralkyl group), which is one of the optical isomers of formula (III)

[0021]

Embedded image

Trans-(-)-(1R,
2R) -2-Bromoindan-1-ol is preferentially esterified to give a compound of the general formula (IV)

[0023]

[Chemical 17]

(In the formula, R ₁ is the above general formula (II)
Of the formula (V), which is the other optical isomer by conversion into trans-(-)-2-bromo-1- (acyloxy) indane represented by

[0025]

Embedded image

Trans-(+)-(1S, 2
It was found that each optically active substance can be produced by leaving S) -2-bromoindan-1-ol and separating it.

The present invention will be described in more detail.

The general formula (I) as a raw material (wherein
X is a hydrogen atom, which is a racemic form of trans configuration)
(±) -trans-2-bromoindane-1 represented by
The oar can be manufactured in various ways. For example, Suter et al. [J. Am. Chem. So
c. , 62, 3473 (1940)] by saturating bromine in an aqueous solution of sodium bromide and reacting with indene in the presence of a large amount of a dispersant to give (±) -trans-
2-bromoindan-1-ol is obtained. Also, Guss et al. [J. Am. Chem. Soc. ，
77, 2549 (1955)] etc. in water with indene and N
By reacting -bromosuccinimide,
(±) -trans-2-bromoindan-1-ol is obtained. Furthermore, Japanese Patent Application No. 7-54, which is the prior application of the applicant.
In No. 213, hydrolysis of 1,2-dibromoindene resulted in (±) -trans-2-bromoindane-1.
-It is stated that the production of oars is possible.

The present inventors separated each optical isomer of racemic (±) -trans-2-bromoindan-1-ol, which can be produced at low cost, using lipase to separate each optical isomer of ester derivative. We considered that kinetic resolution utilizing the difference in the hydrolysis rate of isomers or kinetic resolution utilizing the difference in the esterification rate of each optical isomer of the alcohol was useful. The resolution of racemic alcohols using lipase is a method that has been industrially used in recent years, but if the structure of the active site of lipase is not compatible with the substrate, hydrolysis or esterification does not proceed, If the stereoisomeric ability of the optical isomer in the active site is low, the desired alcohol or ester cannot be obtained with high optical purity. That is, in order to complete this technique, it is essential to search for a lipase that can specifically recognize a substrate, and it is important to set up an environment in which the lipase can function.

In the above-mentioned Kawai and Kasai, the microorganisms themselves are used in the culture system to obtain the compound of the general formula (I) (wherein
X is an acetyl group, which is a racemic body of trans configuration) represented by (±) -trans-2-bromo-1-
Although (acetoxy) indane is hydrolyzed, optically active trans-2-bromoindan-1-ol has not been obtained with satisfactory optical purity.

The causes of this are as follows: 1) Rhizopus
It is considered that the lipase derived from stalonifer has a low stereodiscriminating ability with respect to the substrate, and 2) in water, the lipase cannot sufficiently exhibit the discriminating ability with respect to the substrate.

When the inventors of the present invention tried to hydrolyze an ester in water, a large amount of water was needed because the solubility of the ester in water was extremely poor, and industrially satisfactory volume efficiency could not be secured. Therefore, it is considered effective to esterify the racemic alcohol in an organic solvent (the solubility of the alcohol is extremely large compared to that in water, which enables highly efficient production). The search for a lipase capable of expressing the function was started.

First, lipase PS [derived from Pseudomonas sp., Manufactured by Amano Pharmaceuticals], lipase MY (manufactured by Meito Sangyo), lipase PLL
(Fruca Fine Chemicals), Mucor Javanicus-derived lipase (Fruca Fine Chemicals), and Rhizopus niveus-derived lipase (Fruca Fine Chemicals) were used, and vinyl acetate was used as an acyl donor in diisopropyl ether. Trans-, which is represented by the formula (I) (wherein, X is a hydrogen atom and is in a racemic configuration of trans)
When the esterification of (±) -2-bromoindan-1-ol was attempted, good results were obtained when Lipase PS was used. For example, when the molar ratio of racemic alcohol and vinyl acetate was set to 1: 1 and lipase PS was reacted at 35 ° C. using approximately the same weight as alcohol, the conversion of racemic alcohol was 46.5%. And the obtained general formula (IV) (wherein R ₁ is a methyl group) trans-(−)-(1R, 2R) -2-bromo-
The isolated yield of 1- (acetoxy) indane was 34%, and the optical rotation was [α] _D = −150.0. This corresponds to an optical purity of 89.8% from the above void report. Furthermore, unreacted trans-(+)-(1S, 2
The isolated yield of (S) -2-bromoindan-1-ol (V) was 39.3%, and the optical rotation was [α] _D = + 28.6.
Met. This corresponds to an optical purity of 44.3% (Scheme 4).

[0034]

[Chemical 19]

Next, the present inventors have found that the reaction solvent is lipase PS.
The effect on the function of was investigated. When diisopropyl ether, tetrahydrofuran, benzene, and normal hexane were selected as reaction solvents and the results were compared under the above reaction conditions, the reaction proceeded with a solvent other than tetrahydrofuran. However, when benzene is used as the solvent, the optical purity of the optically active ester represented by the general formula (IV) (wherein R ₁ is a methyl group) is 37.0%, and normal hexane is used as the solvent. And the optical purity of the ester was 13.2%. As a result of these studies, it was found that diisopropyl ether is a good reaction solvent.

Furthermore, the present inventors investigated the effect of esters as an acyl donor. When vinyl acetate, vinyl propionate, vinyl butyrate and vinyl benzoate were selected and diisopropyl ether was used as a solvent and the results were compared under the above reaction conditions, the reaction proceeded except for vinyl benzoate. However, the obtained trans-
The optical purity of (+)-(1S, 2S) -2-bromoindan-1-ol (V) was 26.4% when vinyl propionate was used, and 8.9 when vinyl butyrate was used.
% Was low. From the above examination results, it was found that the substituent R ₁ of the ester represented by the general formula (II) used is preferably a methyl group.

The present inventors further examined the effect of the molar ratio of the substrate on the optically active ester form (IV, R ₁ : CH ₃ ) and the alcohol form (V) produced. A molar ratio of vinyl acetate and an alcohol represented by the general formula (I) (wherein, X is a hydrogen atom and is a racemate of trans configuration) in diisopropyl ether using lipase PS and vinyl acetate. The isolation yield and optical purity of the general formula (IV) (wherein R ₁ is a methyl group) optically active ester and the optically active alcohol (V) produced by changing . The results when the molar ratio of the racemic alcohol to vinyl acetate is 1: 1 have already been described. The molar ratio of alcohol to vinyl acetate is 1: 2.
In the case of (1), the optically active alcohol compound (V) has an isolation yield of 29.6% and an optical purity of 85.4%, and the optically active ester compound (IV, R ₁ : CH ₃ ) has an isolated yield. Rate 49.1%,
Obtained with an optical purity of 54.5%. Furthermore, when the molar ratio of the alcohol compound (I, X = H) and vinyl acetate was 1: 3, the optically active alcohol compound was isolated in a yield of 15.1.
%, Optical purity 94.4%, an optically active ester (I
V, R ₁ : CH ₃ ) has an isolated yield of 55.6% and an optical purity of 2
It was obtained at 7.5%. From the above results, the amount of the ester (II) used is reduced when the ester (IV) having a high optical purity is desired, and the ester (II) is reduced when the alcohol (V) having a high optical purity is desired. I found that the usage amount should be increased.

The product can be taken out by combining column chromatography, recrystallization, distillation and the like by utilizing the difference in the physicochemical properties of the alcohol (V) and the ester (IV). .

Further, the ester form (IV) is reduced to the formula (II
It can be converted to an optically active alcoholic compound represented by I).

[0040]

The present invention will be described more specifically with reference to the following examples.

Example 1 In a 200 ml eggplant-shaped flask, (±) -trans-2-
Bromoindan-1-ol (I, X = H) 2.142
g (0.01 mol) and diisopropyl ether 5
0 ml was charged and dissolved. Then, vinyl acetate (I
0.863 g of I, R ₁ : CH ₃ , R ₂ : CH ₂ = CH)
(0.01 mol), lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) 2.
Add 0g, 5-5 molecular sieves and add 40 at 35 ° C.
Stir for hours. The progress of the reaction was followed by thin layer chromatography and gas chromatography to confirm the end point of the reaction. After completion of the reaction, the reaction solution was filtered to remove lipase and insoluble matter, and washed with 50 ml of diisopropyl ether. The filtrate was washed 3 times with saturated brine, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated.
The residue was purified by silica gel column chromatography using hexane: ethyl acetate (40: 1) as a developing solvent to give an optically active trans-(-)-of a pale yellow viscous liquid.
0.81 g of (1R, 2R) -2-bromo-1- (acetoxy) indane (IV, R ₁ : CH ₃ ) {yield 34.1
%, [Α] _D = −150.0 (ethanol), optical purity 89.8%} and white crystals of optically active trans-
0.837 g of (+)-(1S, 2S) -2-bromoindan-1-ol (V) (yield 39.3%, [α] _D =)
+28.6, optical purity 44.3%) was obtained. The IR spectrum and ¹ H-NMR spectrum of each product were in agreement with the data described in the literature (reports by Void, etc.).

Comparative Example 1 Esterification of alcohol compound (I, X = H) using various lipases The procedure of Example 1 was repeated using various lipases. Lipase MY
When Meito Sangyo Co., Ltd. was used, the conversion rate of the racemic alcohol (I, X = H) was 1% or less under the same reaction conditions. In addition, Lipase PLL (manufactured by Fulca Fine Chemicals), Mucor Javanix (Mucor ja
vanicus-derived lipase (Fruca Fine Chemicals), Rhizopus
The reaction did not proceed when a lipase derived from Niveus) (manufactured by Fulca Fine Chemicals) was used.

Example 2 Esterification of alcohol compound (I, X = H) using various reaction solvents Different reaction solvents were used instead of diisopropyl ether, and the same test as in Example 1 was conducted. The results shown were obtained.

[0044]

[Table 1]

Example 3 Esterification with Various Esters (II) Vinyl acetate (II, R ₁ : CH ₃ , R ₂ : CH ₂ ═CH)
Was changed to various esters (II) and the same test as in Example 1 was conducted, and the results shown in Table 2 were obtained.

[0046]

[Table 2]

Example 4 Racemic alcohol (I, X
= H) and vinyl acetate (II, R ₁ : CH ₃ , R ₂ : CH ₂
= CH) in different molar ratios Racemic alcohol (I, X = H) and vinyl acetate (I
The same test as in Example 1 was carried out by changing the molar ratios of I, R ₁ : CH ₃ , R ₂ : CH ₂ = CH), and the results shown in Table 3 were obtained.

[0048]

[Table 3]

[0049]

As described above, according to the present invention,
Trans- (±) -2-bromoindan-1-ol and esters are reacted in the presence of lipase in an organic solvent to give trans-(−)-(1R, 2R) -2-bromoindan-1- The ester is preferentially esterified to give optically active trans-(-)-(1R, 2R) -2-bromo-1.
-(Acyloxy) indane is converted to the optically active trans-(+)-(1S, 2S) -2.
By separating from -bromoindan-1-ol, optically active trans-2-bromoindan-1-ol and its ester form can be industrially and inexpensively produced.

[0050]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location C07M 7:00 (72) Inventor Shigeru Nakano 1-133 Shimogawa, Izumimachi, Iwaki, Fukushima Prefecture Inside Chemical Co., Ltd.

Claims (8)

[Claims] 1. A compound of the general formula (I) (Wherein, X is a hydrogen atom and is a racemic body with a trans configuration) and trans- (±) -2-bromoindan-1-ol represented by the general formula (II): (Wherein R ₁ is a saturated or unsaturated alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, and R ₂ is a saturated or unsaturated alkyl group, a substituted or unsubstituted Is an aryl group, which is a substituted or unsubstituted aralkyl group), and is reacted in an organic solvent in the presence of lipase,
Formula (III): Represented by trans-(-)-(1R, 2R) -2-
Bromoindan-1-ol is preferentially esterified to give a compound of general formula (IV) (In the formula, R ₁ is a saturated or unsaturated alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group.) Optically active trans-(-)-(1R , 2R) -2-Bromo-1- (acyloxy) indane and the compound of formula (V) The optically active trans-(+)-(1S, 2
S) -2-bromoindan-1-ol is separated, and the optically active trans-(+)-(1S, 2S) -2-bromoindan-1- is represented by the formula (V).
All manufacturing method. 2. The production of the optically active trans-(+)-(1S, 2S) -2-bromoindan-1-ol according to claim 1, wherein the lipase is a Pseudomonas-derived lipase. Method. 3. The optically active trans-(+)-(1S, 2S) -2-bromoindane- according to claim 1, wherein the organic solvent is diisopropyl ether.
1-ol manufacturing method. 4. The optically active trans according to claim 1, wherein the ester represented by the general formula (II) is vinyl acetate (R ₁ : CH ₃ , R ₂ : CH ₂ ═CH). -(+)-(1S, 2S) -2-Bromoindane-1-
All manufacturing method. 5. A compound represented by the general formula (I): (Wherein, X is a hydrogen atom and is a racemic body in the trans configuration) and trans- (±) -2-bromoindan-1-ol represented by the general formula (II): (Wherein R ₁ is a saturated or unsaturated alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, and R ₂ is a saturated or unsaturated alkyl group, a substituted or unsubstituted Is an aryl group, which is a substituted or unsubstituted aralkyl group), and is reacted in an organic solvent in the presence of lipase,
Formula (III): Represented by trans-(-)-(1R, 2R) -2-
Bromoindan-1-ol is preferentially esterified to give a compound of general formula (IV) (In the formula, R ₁ is a saturated or unsaturated alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group.) Optically active trans-(-)-(1R , 2R) -2-Bromo-1- (acyloxy) indane and the compound of formula (V) The optically active trans-(+)-(1S, 2
S) -2-bromoindan-1-ol is separated, and the optically active trans-(−)-(1R, 2R) -2-bromo-1- is represented by the general formula (IV). Method for producing (acyloxy) indane. 6. The optically active trans-(−)-(1R, 2R) -2-bromo- according to claim 5, wherein the lipase is a lipase derived from the genus Pseudomonas.
Process for producing 1- (acyloxy) indane. 7. The production of optically active trans-(−)-(1R, 2R) -2-bromo-1- (acyloxy) indane according to claim 5, wherein the organic solvent is diisopropyl ether. Method. 8. The optically active trans according to claim 5, wherein the ester represented by the general formula (II) is vinyl acetate (R ₁ : CH ₃ , R ₂ : CH ₂ ═CH). A method for producing-(-)-(1R, 2R) -2-bromo-1- (acyloxy) indane.