WO2011054185A1

WO2011054185A1 - Optical isomers of aralkyl piperazine derivative, preparation methods and uses thereof

Info

Publication number: WO2011054185A1
Application number: PCT/CN2010/001766
Authority: WO
Inventors: 王丙林; 刘长鹰; 杨汉煜; 马玉秀; 于普; 郭文敏; 郭小丰; 宋灵杰
Original assignee: 石药集团中奇制药技术（石家庄）有限公司
Priority date: 2009-11-03
Filing date: 2010-11-03
Publication date: 2011-05-12
Also published as: CN102050801B; CN102050801A

Abstract

Preparation methods of optical isomers of compound of formula (B) and preparation methods of optical isomers of compound of formula (A) by using the said optical isomers of compound of formula (B) are disclosed, in which chiral camphor sulfonic acid acts as resolution reagent and the optical isomer mixtures or racemes of compound of formula (B) are chemically resoluted.. By using the optical isomers of the present compound of formula (B), the optical isomers of compound of formula (A) which are useful as antidepressants can be obtained with high yield and high purify.

Description

Optical isomer of aralkyl piperazine derivative, preparation method and application thereof

Technical field

The present invention relates to optical isomers of N ¹ -benzyl-N ⁴ -[l-(5,-chloro-6'-methoxy-2'-naphthoyl)pentyl]piperazine (Compound B) and a preparation method thereof, and using the optical isomer of the above compound B to prepare a 1-butyl-2-hydroxyarkanol piperazine derivative N ¹ -benzyl-N ⁴ -[l-butyl-2-(5, A method of optical isomers of -chloro-6'-methoxy-2,-naphthyl)hydroxyethyl]piperazine (Compound A). Background technique

The applicant first disclosed the 1-butyl-2-hydroxyarkanol piperazine derivative N ¹ -benzyl-N ⁴ -[l-butyl-2-(5'-chloro-) in Chinese patent application CN101712658A. 6'-Methoxy-2,-naphthyl)hydroxyethyl]piperazine (formula of formula A below, sometimes referred to hereinafter as compound of formula A) and optical isomers thereof, and discloses a compound of formula A Its optical isomers have strong antidepressant activity as selective triple reuptake inhibitors of serotonin (5-HT), norepinephrine (NA) and dopamine (DA).

(A) In the above patent application, with respect to the preparation of the compound of formula A, it is disclosed by N ¹ -benzyl-Ν ⁴ -[1-(5'-chloro-6,-methoxy) as described in Reaction Scheme 1 below. Base-2,-naphthoyl)pentyl]piperazine (having a structural formula such as the formula ,, sometimes referred to hereinafter as a hydrazine compound) to prepare a threo (Threo, 1SR, 2SR) or a erythro (Erythro, 1SR) , 2RS) A method of formulating a compound racemate.

Race or Compound Formula A Compound Racemic Reaction Scheme 1 However, the compound of formula A contains two chiral carbon atoms having (1S, 2S:), (1R, 2R), (1S, 2R) and (1R, 2S) Four optical isomers, therefore, only the threo or erythrocyclic compound of formula A can be obtained by the above preparation method. In order to obtain a single optical isomer compound of the compound of formula A, it is also necessary to further resolve the racemic form of the compound of formula A in the threo or erythro form, or to prepare it by other methods.

In order to synthesize a single optical isomer of the compound of formula A, it is also disclosed in the above-mentioned patent application to synthesize the above optical isomers by a method using a prochiral compound and column chromatography. Specifically, as described in the following Reaction Scheme 2, the chiral isoleucine 1 is used as a raw material, the amino group is protected by an phthaloyl group, the carboxyl group is acylated with oxalyl chloride to form a compound 3, and the compound 4 is passed through a Fu- The gram reaction produces the compound 5, the compound 5 is reduced by aluminum isopropoxide, and hydrolyzed to obtain the compound 7, and the compound 7 is condensed with the compound 8 to obtain the compound 9, which is then subjected to column chromatography to obtain the objective product (IX) which is optically pure.

Reaction Scheme 2 The reaction raw materials of the method are easily obtained, and the obtained product does not need to be chemically resolved, and the optical purity is high. However, this method also has the following disadvantages: 1) long synthetic route, complicated process; 2) harsh reaction conditions, requiring no water operation; 3) high toxicity of the intermediate, such as compound 8 has cytotoxicity; 4) low total yield , less than 1%; 5) high product cost, the cost per kilogram of product reached about 150,000 yuan. Therefore, there is an urgent need for a process for producing an optical isomer of a compound of the formula A at low cost, in a simple, high yield, and high purity, thereby realizing industrial production of an optical isomer of the formula A compound. Summary of the invention

In view of the above problems of the prior art, it is an object of the present invention to provide an intermediate which can produce an optical isomer of the compound of the formula A, which is an optical isomer of the compound of the formula B, which is inexpensive, simple, and high in yield and high purity.

Another object of the present invention is to provide a process for the preparation of the above intermediates.

A further object of the present invention is to provide a process for producing an optical isomer of a compound of the formula A inexpensively, simply, and with high yield and high purity using the above intermediate.

In order to achieve the above object, the inventors of the present application conducted intensive studies and found that chirality is employed when using an optical isomer mixture or a racemate of a compound of formula B as a raw material. The camphorsulfonic acid is used as a resolving agent to obtain an optical isomer of a compound of the formula B having high optical purity, thereby completing the present invention.

That is, the present invention provides a process for producing an optical isomer of the compound of the above formula B, characterized in that the optical isomer of the compound of the formula B is used by using chiral camphorsulfonic acid as a resolving agent. The mixture or racemate is chemically resolved. Specifically, the preparation method comprises the following steps (1) and (2):

(1) reacting an optical isomer mixture or a racemate of the compound of the formula B with D- or L-camphorsulfonic acid in a solvent to form an S-form B compound-D-camphorsulfonate or R-form B compound camphorsulfonate, and precipitating the obtained camphor sulfonate; (2) alkalizing the camphorsulfonate obtained in the above step (1), thereby obtaining S represented by the following formula A compound of formula B in the R or R configuration.

S-Form B Compound R-Form B Compound Further, the present invention also provides a process for producing an optical isomer of the compound represented by the above Structural Formula A, which comprises using the compound of the formula B in the S or R configuration obtained by the above production method as The raw material was subjected to a reaction as shown in the following Reaction Scheme 3.

Compound of formula B in R or S configuration

Optical isomers of compounds of formula A

Reaction process 3

According to the method for producing an optical isomer of the compound of the formula B of the present invention, the optical isomer of the compound of the formula B can be obtained simply and with high purity, and the optical isomer can be used in an inexpensive, simple, high-yield, high-purity manner. An optical isomer of a compound of formula A having an antidepressant effect is prepared. detailed description

Hereinafter, the present invention will be described in detail. Preparation of intermediates B compound optical isomers

In the preparation method of the optical isomer of the compound of the formula B of the present invention, the optical isomer mixture or the racemic compound of the compound of the formula B is chemically resolved by using chiral camphorsulfonic acid as a resolving agent. Specifically, as shown in the following Reaction Scheme 4, the preparation method comprises the following steps (1) and (2):

(1) reacting an optical isomer mixture or a racemate of the compound of the formula B with D- or L-camphorsulfonic acid in a solvent to form a S-form B compound camphorsulfonate or an R-form B compound, respectively. Camphor sulfonate, and precipitated camphor sulfonate;

(2) The camphor sulfonate obtained in the above step (1) is subjected to alkalization to obtain a corresponding compound of the formula B in the S or R configuration.

R-form B compound -L-camphorsulfonate

S-form B compound R-form B compound Reaction scheme 4

(1) Step (1)

In this step, an optical isomer mixture or a racemate of the compound of the formula B is reacted with D- or L-camphorsulfonic acid in a solvent to form a diastereomeric salt S-form represented by the lower structural formula. B compound-D-camphorsulfonate or R-form B compound camphoronate.

R-Form B Compound -L-camphorsulfonate The compound of the formula B used in the above reaction can be produced by the method of CN101712658A.

In this reaction, an optical isomer mixture or a racemate of the D- or L-camphoric acid and the compound of the formula B may be used in any ratio. The molar ratio of the optical isomer mixture or racemate of the D- or L-camphorsulfonic acid to the compound of the formula B is preferably from 10:1 to 0.5:1, more preferably from 5:1 to 1 from the viewpoint of cost. :1 , most preferably 2: 1.

As the solvent to be used in the reaction, first, the compound of the formula B has a certain solubility, and it is preferred that the compound of the formula B can be completely dissolved at room temperature or in a heated state. Secondly, as is well known to those skilled in the art, the solubility of the optical isomer of the compound of formula B with the diastereomeric salt formed by D-camphorsulfonic acid or L-camphorsulfonic acid should be somewhat different. The solvent is not particularly limited, and examples thereof include one or more selected from the group consisting of water, an alcohol, an ester, a ketone, a chlorinated hydrocarbon, an ether, a nitrile, an amide, and a sulfoxide. Among them, it is preferably selected from the group consisting of water, methanol, ethanol, 'isopropyl alcohol, ethyl acetate, acetone, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), acetonitrile, dimercaptocarboxamide ( One or more of DMF) and dimethyl sulfoxide (DMSO) are more preferably selected from the group consisting of methanol, ethanol, isopropanol, aqueous alcohol solution, ethyl acetate, and the like in terms of yield and product purity. One or more of acetone, further preferably methanol, ethanol, 1:1 methanol-isopropyl Alcohol, aqueous alcohol solution.

The reaction temperature as the above reaction is not particularly limited and may be, for example, o ° c to the reflux temperature of the solvent.

The reaction time of the above reaction is not particularly limited, and may be, for example, 5 minutes to 72 hours, preferably 10 minutes to 24 hours.

By the above reaction, a precipitate of the S-form B compound-D-camphorsulfonate or the R-form B compound-L-camphorsulfonate is formed, and the separation of the precipitate can be carried out by a method known in the art, for example, filtration. , centrifugation or decantation, etc., wherein the preferred method is filtration.

Further, if necessary, the obtained S-form B compound -D-camphorate or R-form B compound -L-camphorsulfonate precipitate can be further purified by a method such as recrystallization. The solvent for recrystallization is not particularly limited, and one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, and THF can be used. One kind or two or more kinds, and one or two or more of methanol, ethanol, isopropyl alcohol, ethyl acetate and acetone are preferable from the viewpoints of yield and product purity.

(2) Step (2)

In this step, the S-form B compound-D-camphorsulfonate or the R-form B compound-L-camphorsulfonate obtained in the above step (1) is alkalized in a water-insoluble organic solvent. To remove the chiral acid resolving agent, a corresponding S-form B compound or R-form B compound represented by the following formula is obtained.

R-form B compound In this step, the base may be selected from the group consisting of metal hydroxides, oxides, carbonates, hydrogencarbonates and amides, of which metal hydroxides and carbonates, such as hydroxides, are preferred. Sodium, sodium carbonate. Among them, the base may be used in an amount of 0.5 to 10 moles, preferably 1 to 5 moles, more preferably 2 to 4 moles per mole of the camphorsulfonate.

The reaction temperature of the above reaction is not particularly limited and may be, for example, from 0 ° C to the reflux temperature of the solvent.

The reaction time of the above reaction is not particularly limited and may be, for example, 5 minutes.

72 hours, preferably 10 minutes to 24 hours.

Further, as is well known to those skilled in the art, for the preparation of one of the optical isomers, another optical isomer can be obtained after the chiral resolving agent is changed to its enantiomer.

After separating the formed S-form B compound camphorsulfonate or the R-form B compound-L-camphorsulfonate precipitate, the remaining filtrate or supernatant is alkalized to obtain another optical difference. The mixture of the constructs can then be further processed by the methods described above to give another optical isomer. Preparation of optical isomers of the final product of formula A

The optical isomer of the compound of the formula (A) can be obtained by reducing the optical isomer of the obtained S-form B compound or the R-form B compound as shown in the following Reaction Scheme 3 to obtain (1S, 2R), (1S, 2S) Mixture or (1R, 2R), (1R, 2S) a mixture of optical isomers of the compound of formula A, and then separate the mixture of isomers to obtain (1S, 2R), (1S, 2S) optics of the compound of formula A, respectively Isomer or (1R, 2R), (1R, 2S) optical isomer.

Compound of formula B in R or S configuration

Optical isomers of compounds of formula A

Reaction process 3

In the above reaction, the reduction reaction can be carried out, for example, by using NaBH ₄ as a reducing agent in methanol, preferably at room temperature for 0.5 to 1 hour; or aluminum isopropoxide can be used as a reducing agent in isopropanol. It is preferably reacted at 60 to 65 ° C for 24 to 48 hours; or other reduction methods which are considered suitable by those skilled in the art.

The separation can be carried out, for example, using a silica gel column in which 200:1 of dichloromethane:methanol can be used as an eluent, or other separation methods deemed suitable by those skilled in the art can be employed.

The present invention provides a new route for the preparation of optical isomers of the compound of formula A by inexpensive, simple, high yield and high purity by successfully separating the optical isomer mixture or racemate of the compound of formula B. It has opened up a new path for industrial production. Example

The invention is further illustrated by the following examples, but these examples do not constitute any limitation of the invention.

Method for determining optical purity

The optical purity was measured by chiral HPLC, and the measurement conditions were as follows. Column: CHIRALPAK #43⁄4 combined column;

Flow rate: lmL/min;

Measuring wavelength: 236

Eluent: n-hexane: isopropanol: diethylamine = 75: 25: 0.1, the sample was dissolved in the eluent.

Retention time of optical isomers of compounds of formula A

The four optical isomers of the compound of the formula A were synthesized by the method described in CN1017126 ⁵ 8A, and the respective retention times (t _R ) were measured under the above chiral HPLC conditions. The results are shown in Table 1. Retention time (t _R ) of four optical isomers of the compound of formula A

Example 1 Preparation of S-Form B Compound - D-camphorsulfonate

The R, S-form B compound racemate (prepared by the method described in CN101712658A) 10g (0.0215mol) was added to 300ml of methanol, heated to dissolve, and added D-camphorsulfonic acid 10g (0.043 lmol) at 65° C reacted for 3 h. After the reaction, stir at 20 ° C

After 2 h, crystals were precipitated and suction filtered to obtain 5.6 g of the compound of formula -D-camphorsulfonate. The optical purity was 91.1% as determined by chiral liquid chromatography.

The above camphor sulfonate was recrystallized from ethanol to obtain 4.6 g of the S-form B compound camphorsulfonate having an optical purity of more than 99%.

Mp=204.5-205.5°C

Elemental analysis

Found: C 65.05%, H 7.01%, C1 5.108%, 4.06%, O 13.92%, S 4.81 % Calculated: C ₂₈ H ₃₃ ClN ₂ O ₂ 'C ₁₀ H ₁₆ O ₄ S: C 65.43%, H 7.08%, CI 5.08%, N 4.02%, O 13.77%, S 4.62%. Example 2 Preparation of R-Form B Compound-L-camphorsulfonate

The R, S-form B compound racemate (prepared by the method described in CN101712658A) 20g (0.043mol) was added to 500ml of absolute ethanol, heated to dissolve, and added L-camphorsulfonic acid 20g (0.0862mol), The reaction was carried out at 68 ° C for 2.5 h. After the reaction, at 10 Stir at °C for 2 h. The crystal was precipitated and suction filtered to obtain 12 g of the compound of formula R---camphorsulfonate. The optical purity was 91.0% as determined by chiral liquid chromatography.

The above camphorsulfonate was recrystallized from acetone to obtain 9 g of an R-form B compound -L-camphorsulfonate having an optical purity of more than 99%.

Mp=200.2-201.2°C

Elemental analysis

Found: C 65.02%, H 7.06%, C1 5.11%, N 4.00%, O 13.98%, S 4.86% Calculated: C ₂₈ H ₃₃ ClN ₂ O ₂ 'C ₁₀ H ₁₆ O ₄ S: C 65.43%, H 7.08%, CI 5.08%, N 4.02%, 0 13,77%, S 4.62%. Example 3~: 制备 Preparation of S-form B compound camphorsulfonate under different solvent conditions

Referring to the preparation method of Example 1, the S-form B compound-D-camphorsulfonate was prepared under different reaction solvents, and recrystallized and purified. The results of the experiment are shown in Table 2 below: Table 2 Examples 3 ~ 11 experimental results

It can be seen from the above-mentioned actual risk results that under the actual conditions of the above embodiments, Higher purity diastereomeric salts. Example 12 Preparation of S-Form B Compound-D-camphorsulfonate and R-Form B Compound-L-camphorsulfonate

The S-form B compound camphorsulfonate 4.6 g was obtained by the preparation method of Example 1, and the optical purity was 99.3% as measured by chiral HPLC.

The filtered mother liquor is treated with a saturated sodium carbonate solution to obtain an optical isomer mixture of the compound of formula B rich in R isomer. Referring to the preparation method of Example 2, an R-form B compound-L-camphorsulfonic acid is obtained. The salt was 4.8 g, and the optical purity was 99.1% as determined by chiral HPLC. Example 13 Preparation of S-Formula B Compound

4.6 g of the compound of the formula S-D-camphoric acid salt was added to 100 ml of dichloromethane and 100 ml of water, stirred, and the pH was adjusted to 9-10 with a saturated sodium carbonate solution, the organic phase was separated, and the organic phase was removed by evaporation. The solvent was used to obtain 3 g of an S-form B compound, and the optical purity was determined by chiral HPLC to be 99.1%.

Mp=80.6-81, 4°C

[a] i) = 32.84 (cl , CHC1 ₃ ) Example 14 Preparation of R-Form B Compound

9 g of R-form B compound-L-camphorsulfonate was added to 200 ml of dichloromethane and

In 200 ml of water, stir, adjust the pH to 9-10 with 2N sodium hydroxide solution, separate the organic phase, and remove the organic solvent in the organic phase to obtain R-form B compound 5.8 g, by chirality.

The optical purity by HPLC was 99.2%.

Mp=82.2-82.8°C

[a] 3⁄4 ⁾ = -32.68 (c = l , CHC1 ₃ ) Example 15 Preparation of (1S, 2R) and (1S, 2S) Compound A Optical Isomers from S-Formula B Compounds

4.65 g (0.01 mol) of the S-form B compound isomer was dissolved in 70 ml of isopropanol, 7.14 g (0.035 mol) of aluminum isopropoxide was added, and anhydrous A1C1 ₃ 0.46 g (0.0035 mol) was added at 70 ° C. The reaction was heated for 6 h. The solvent was evaporated, and chloroform (100 ml×3), water (100 ml) was added, and the mixture was extracted, and the chloroform layer was combined, dried over magnesium sulfate and evaporated to remove chloroform to give (1S, 2R). And a mixture of (1S, 2S) compounds of formula A.

The above mixture was subjected to silica gel column separation (eluent: dichloromethane:methanol = 200:1), and the first (1S, 2S) isomer of the column, t _R = 30.24 min, weight 2 g, yield The optical purity was determined by chiral HPLC to be 43%.

The post-column is (1S, 2R) isomer, t _R = 5.998min, weight is 1.8g, yield

The optical purity was 39.9% by chiral HPLC. Example 16 Preparation of (1R, 2S) and (1R, 2R) Formula A Compounds from R-Formula B Optical Isomers

Using the same method and material feeding amount of 15 cases, to obtain (1R, 2S) isomer 1.9 g, yield 41%, t _R = 7.08min, chiral liquid chromatography measured by an optical purity of 99.2%; The R, 2R) isomer was obtained in an amount of 1.7 g, yield 36%, t _{R -} 14.15 min, and the optical purity was 99.6% as determined by chiral liquid chromatography.

From the above, it is understood that the optical isomer of the compound of the formula B of the present invention can be used to obtain an optical isomer of the compound of the formula B in a simple and high-purity manner, and the optical isomer can be used at a low cost, in a simple manner, and in a high yield. The optical isomer of the compound of the formula A having an antidepressant effect is prepared in a high-purity manner. In the specification of the present application, the entire contents of the Chinese patent application CN101712658A are incorporated by reference. In addition, it is to be understood by those skilled in the art that any changes, modifications, and alterations of the present invention may be made without departing from the spirit and scope of the invention.

Claims

Rights request

A method for producing an optical isomer of a compound represented by the following structural formula B, which comprises using a chiral camphorsulfonic acid as a resolving agent for an optical isomer mixture or a racemate of a compound of the formula B. Perform chemical resolution.

(B)

The preparation method according to claim 1, comprising the following steps (1) and (2):

(1) reacting an optical isomer mixture or a racemate of the compound of the formula B with D- or L-camphorsulfonic acid in a solvent to form an S-form B compound-D-camphorsulfonate or R-form B compound-L-camphorsulfonate, and precipitated the obtained camphor sulfonate;

(2) The camphorsulfonate obtained in the above step (1) is subjected to alkalization to obtain a corresponding compound of the formula B in the S or R configuration.

The method according to claim 2, wherein the solvent is one or more selected from the group consisting of water, an alcohol, an ester, a ketone, a chlorinated hydrocarbon, an ether, a nitrile, an amide, and a sulfoxide. .

The preparation method according to claim 3, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, chloroform, diethyl ether, and methyl tert-butyl. One or more of a group ether, tetrahydrofuran, acetonitrile, dimethylformamide, and dimethyl sulfoxide.

The preparation method according to any one of claims 2 to 4, further comprising the step of recrystallizing the obtained camphor sulfonate precipitate in the step (1).

The method according to claim 5, wherein the solvent for recrystallization is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetone, and dichloromethane. One or more of chloroform, diethyl ether, methyl tert-butyl ether and tetrahydrofuran.

7. R-form B compound represented by the following structural formula: camphorsulfonate or S-form B compound - D-camphorsulfonate.

R-form B compound camphorate

S-form B compound camphorate

8. A compound of the formula B in the R or S configuration represented by the following structural formula.

S-form B compound R-form B compound

9. Use of a compound of formula B of the R or S configuration of claim 8 for the preparation of optical isomers of the compound of formula A below.

(A)

A method for producing an optical isomer of a compound represented by the following structural formula A, which comprises using the compound of the formula B of the R or S configuration according to claim 8 as a raw material, and performing a reaction represented by the following chemical formula.

(1) Restore

(2) Separation

Compound of formula B in R or S configuration

Optical isomers of compounds of formula A