WO2013089189A1 - Optical resolution method for bicyclic compound using hydroxysulfonic acid - Google Patents

Abstract

An optically active bicyclic compound is efficiently produced by performing optical resolution using an optically active amine.

Description

Method for optical resolution of bicyclic compounds via hydroxysulfonic acid

The present invention relates to a bicyclic γ-amino acid derivative or a pharmacologically acceptable salt thereof, particularly a compound having activity as an α ₂ δ ligand and an optically active process for producing an intermediate thereof.

Compounds that exhibit high affinity binding to the α ₂ δ subunit of the voltage-gated calcium channel have been shown to be effective, for example, in the treatment of neuropathic pain (eg, Non-Patent Document 1 and Non-Patent Document 1). Patent Document 2).

Currently, several types of α ₂ δ ligands are known as therapeutic agents for neuropathic pain, and examples of α ₂ δ ligands include gabapentin and pregabalin. Α ₂ δ ligands such as these compounds are useful for the treatment of epilepsy, neuropathic pain and the like (for example, Patent Document 1). Other compounds are disclosed in, for example, Patent Document 2, Patent Document 3, Patent Document 4, and the like. Further, the applicant has previously described Patent Literature 5 and Patent Literature as α ₂ δ ligands and methods for producing the same. 6 is reported.

Examples of optical resolution of hydroxysulfonates have been reported (Patent Document 7, Non-Patent Document 3), but the structure is different from the compounds split according to the present invention.

US 2006/154929 US 2003/220397 US 2004/152779 US 2003/78300 US 2010/249229 WO 2010/110361 EP0074856

J Biol. Chem. 271 (10): 5768-5776, 1996 J Med. Chem. 41: 1838-18445, 1998 Org. Process Res. Dev. 2002, 6, 138

An object of the present invention is to provide a bicyclic γ-amino acid derivative or a pharmacologically acceptable salt thereof, in particular, a compound having activity as an α ₂ δ ligand and an optically active method for producing an intermediate thereof. To do.

Patent Document 5 or Patent Document 6 reports a method for producing compound 6 as described in Scheme 1.
The inventors of the present application have paid attention to the method of stereocontrol of the asymmetric carbon in the production method of Compound 6, and have continued intensive research to develop an efficient method. In the conventional manufacturing method, optical splitting is performed in the process (Step 4) immediately before the final process, but it is possible to establish a more efficient manufacturing method by performing optical splitting in an early process. I thought it would be possible.
That is, the problem to be solved by the present invention is to develop a production method in which an intermediate thereof is an optically active compound in an early step of the production of compound 6. The inventors of the present application continued intensive studies to solve this problem, and as a result, the problem was solved and the present invention was completed.

[Wherein each substituent is defined as follows. R ^1a : a hydrogen atom or a C1-C6 alkyl group]

The present invention will be described below.
[1] A method for producing a compound having the general formula (I) or a compound having the general formula (II),

(1) A racemic mixture of a compound having the general formula (I) and a compound having the general formula (II) is present in the presence of sulfur dioxide (sulfurous acid gas, hereinafter referred to as SO ₂ gas), water, an optically active amine and a solvent. After the lower reaction, either the compound having the general formula (I ′) or the compound having the general formula (II ′) is precipitated as a salt crystal with an optically active amine,

(2) treating the obtained crystals of the salt of either the compound having the general formula (I ′) or the compound having the general formula (II ′) with an alkaline aqueous solution,

[In each formula, R ^{1 is a} hydrogen atom or a C1-C6 alkyl group]
A method for producing a compound having the general formula (I) or a compound having the general formula (II).

Preferred embodiments of the present invention are the following inventions.
[2] A method for producing a compound having the general formula (I),

(1) A racemic mixture of a compound having the general formula (I) and a compound having the general formula (II) is reacted in the presence of SO ₂ gas, water, an optically active amine and a solvent, and then the general formula (I ′ ) As a crystal of a salt with an optically active amine,

(2) treating the resulting salt of the compound having general formula (I ') with an aqueous alkaline solution,

[In each formula, R ^{1 is a} hydrogen atom or a C1-C6 alkyl group]
A process for producing a compound having the general formula (I).
[3] The method according to [1] or [2], wherein R ¹ is a hydrogen atom, a methyl group, or an ethyl group.
[4] The method according to [2] or [3], wherein the optically active amine in (1) is any one selected from the group shown below.

[5] The amount of the optically active amine used in (1) is 0.3-0.7 or 0.8 with respect to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II). The method according to any one of [1]-[4], which is 8-1.2 equivalent equivalents.
[6] The method according to any one of [1] to [5], wherein the solvent in (1) is any one selected from the group shown below.
Any one selected from 1,2-dimethoxyethane, isopropyl ether, ethers such as tetrahydrofuran, highly polar solvents such as acetonitrile, esters such as ethyl acetate [7] [2]-[6] A method for producing a compound having the general formula (III) or a salt thereof, using the compound having the general formula (I) produced by the method.

The present invention is useful for optically active production of bicyclic γ-amino acid derivatives or pharmacologically acceptable salts thereof, particularly compounds having activity as α ₂ δ ligands and intermediates thereof.
The present invention is efficient because it is a production method in which an intermediate is used as an optically active compound in an early step of the production.

The C1-C6 alkyl group is a linear or branched alkyl group having 1-6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group , A pentyl group, a hexyl group, and the like, preferably a methyl group, an ethyl group, and a propyl group.

As the compound having the general formula (I) or general formula (II), preferably a compound in which R ¹ has a hydrogen atom, a methyl group or an ethyl group.

Step (1) In the SO ₂ gas used in the present invention, an excess amount is blown into the reaction solution with respect to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II). Added by.

The water used in the present invention is preferably 0.8 to 1.2 equivalents, more preferably a racemic mixture of the compound having the general formula (I) and the compound having the general formula (II). Is 0.9-1.1 equivalent.
In the present invention, the “optically active amine” used when producing the compound having the general formula (I) is preferably an optically active amine as shown in Table 1 below.

Table1

The optically active amine shown in Table 2 is more preferable.
Table2

In addition, when manufacturing the compound which has general formula (II), what is necessary is just to use the enantiomer which has a configuration opposite to the optically active amine used when manufacturing the compound which has general formula (I).
The amount of the optically active amine varies depending on the solvent used or the salt formation ratio with hydroxysulfonic acid, but with respect to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II), 0.3-0.7 or 0.8-1.2 equivalents are preferred, and 0.4-0.6 or 0.9-1.1 equivalents are more preferred.
A compound having the general formula (I) or a compound having the general formula (II) can be produced by appropriately selecting the enantiomer of the optically active amine to be used.
As the solvent, ethers such as 1,2-dimethoxyethane, isopropyl ether and tetrahydrofuran, highly polar solvents such as acetonitrile, and esters such as ethyl acetate are preferable, and 1,2-dimethoxyethane and acetonitrile are preferable. More preferred.
The reaction temperature is desirably cooled to about 0 ° C., and when the temperature rises above room temperature, a salt may not be formed properly.
Step (2) The aqueous alkali solution used may be any aqueous alkaline solution that can return the salt to a free form, but it is preferable to use an aqueous sodium carbonate solution.
By using the compound having the general formula (I) or the compound having the general formula (II), and carrying out the production in the same manner as the method described in Patent Document 6 (WO 2010/110361) described above, the general formula ( Compounds having III) or general formula (III ′) can be prepared.

The “salt” in the present invention is a compound or the like represented by the general formula (III), and forms a salt by reacting with an acid or a base by having an amino group and a carboxyl group in its structure. Says the salt.

A compound having the general formula (III) may be left in the air or recrystallized to absorb moisture and have adsorbed water to form a hydrate. Such hydrates are also included in the salts of the present invention.

The compound having the general formula (III) or a salt thereof exhibits activity as an α ₂ δ ligand, has an affinity for the α ₂ δ subunit of the voltage-gated calcium channel, pain, central nervous disorder, and others It is useful as an active ingredient of a pharmaceutical composition used for the treatment and / or prevention of disorders.

Example 1
(1R, 5S, 6R) -3-Ethyl-6-hydroxybicyclo [3.2.0] hept-3-ene-6-sulfonic acid (R) -1-phenylethylamine (1: 1) salt

To a mixture of 1,2-dimethoxyethane (5 mL), (R) -1-phenylethylamine (445 mg, 3.67 mmol), and water (0.146 mL, 8.08 mmol), SO ₂ gas was added at 20 ° C. After blowing for 10 minutes, 3-ethylbicyclo [3.2.0] hept-3-en-6-one (1.00 g, 7.34 mmol) was added. After stirring at 20 ° C. for several minutes, the mixture was cooled to 0 ° C. and further stirred for 4 hours. The precipitated crystals were filtered, washed with 1,2-dimethoxyethane cooled to 0 ° C., and dried under reduced pressure to obtain the title compound (691.4 mg, 27.8% ee) (yield 24% (N / N)).
¹ H NMR (500 MHz, DMSO-d6) d 1.02 (t, 3H, J = 7.4 Hz), 1.46-1.49 (m, 1H), 1.48 (d, 3H, J = 6.8 Hz), 1.91-1.93 (m , 1H), 2.02-2.12 (m. 2H), 2.36-2.41 (m, 2H), 2.53-2.58 (m, 1H), 3.47 (bs, 1H), 4.40 (q, 1H, J = 6.8 Hz), 4.73 (bs, 1H), 5.27-5.29 (m, 1H), 7.36-7.48 (m, 5H), 8.01 (bs, 3H).
(Example 2)
(1R, 5S, 6R) -3-Ethyl-6-hydroxybicyclo [3.2.0] hept-3-ene-6-sulfonic acid (R) -1-phenylethylamine (1: 2) salt Acetonitrile (5 mL ), (R) -1-phenylethylamine (890 mg, 7.34 mmol) and water (73.0 μL, 4.04 mmol) were blown with SO ₂ gas at 20 ° C. for about 10 minutes, then 3- Ethylbicyclo [3.2.0] hept-3-en-6-one (500 mg, 3.67 mmol) was added. After stirring at 20 ° C. for several minutes, the mixture was cooled to 0 ° C. and further stirred for 5 hours. The precipitated crystals were filtered, washed with acetonitrile (5 mL) cooled to 0 ° C., and dried under reduced pressure to obtain the title compound (599.6 mg, 59.9% ee) (yield 34% (N / G)) ).

1,2-Dimethoxyethane (0.5 mL) was added to the obtained title compound (99.8 mg, 0.204 mmol), and the mixture was stirred at 0 ° C. for 12 hours, and then the crystals were filtered and cooled to 0 ° C. , 2-Dimethoxyethane, and dried under reduced pressure to obtain the title compound (70.7 mg, 90.2% ee) (yield 56.3% (N / N)).
¹ H NMR (500 MHz, DMSO-d6) d 1.02 (t, 3H, J = 7.4 Hz), 1.43 (d, 6H, J = 6.7 Hz), 1.46-1.50 (m, 1H), 1.91-1.93 (m , 1H), 2.02-2.12 (m. 2H), 2.36-2.41 (m, 2H), 2.53-2.58 (m, 1H), 3.47 (bs, 1H), 4.30 (q, 2H, J = 6.7 Hz), 5.27-5.29 (m, 1H), 7.32-7.46 (m, 10H).
(Example 3)
(1R, 5S, 6R) -3-Ethyl-6-hydroxybicyclo [3.2.0] hept-3-ene-6-sulfonic acid (R) -1- (p-tolyl) ethylamine (1: 1) salt

To a mixture of 1,2-dimethoxyethane (5 mL), (R) -1- (p-tolyl) ethylamine (496 mg, 3.67 mmol), water (146 μL, 4.04 mmol) at 20 ° C. with SO ₂ gas Was bubbled in for about 10 minutes before 3-ethylbicyclo [3.2.0] hept-3-en-6-one (1.00 g, 7.34 mmol) was added. After stirring at 20 ° C. for several minutes, the mixture was cooled to 0 ° C. and further stirred for 5 hours. The precipitated crystals were filtered, washed with 1,2-dimethoxyethane (5 mL) cooled to 0 ° C., and dried under reduced pressure to obtain the title compound (582 mg, 57.4% ee) (yield 19% (N / N)).

1,2-Dimethoxyethane (0.5 mL) was added to the obtained title compound (96.7 mg, 0.231 mmol), and the mixture was stirred at room temperature for 12 hours, and then the crystals were filtered and cooled to 0 ° C. Washing with 2-dimethoxyethane and drying under reduced pressure gave the title compound (70.2 mg, 80.3% ee) (yield 59% (N / N)).
¹ H NMR (500 MHz, DMSO-d6) d 1.02 (t, 3H, J = 7.5 Hz), 1.44 (d, 3H, J = 7.0 Hz), 1.46-1.49 (m, 1H), 1.91-1.93 (m , 1H), 2.02-2.12 (m. 2H), 2.31 (s, 3H), 2.36-2.41 (m, 2H), 2.53-2.58 (m, 1H), 3.47 (bs, 1H), 4.32 (q, 1H , J = 6.8 Hz), 4.78 (bs, 1H), 5.29 (s, 1H), 7.23 (d, 2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.3 Hz), 7.75 (bs, 3H ).
(Example 4)
(1R, 5S, 6R) -3-Ethyl-6-hydroxybicyclo [3.2.0] hept-3-ene-6-sulfonic acid (R) -1-cyclohexylethylamine (1: 1) salt

After SO ₂ gas was blown into a mixture of acetonitrile (10 mL), (R) -1-cyclohexylethylamine (934 mg, 7.34 mmol) and water (146 μL, 4.04 mmol) at 20 ° C. for about 10 minutes, 3 -Ethylbicyclo [3.2.0] hept-3-en-6-one (1.00 g, 7.34 mmol) was added. After stirring at 20 ° C. for several minutes, the mixture was cooled to 0 ° C. and further stirred for 5 hours. The precipitated crystals were filtered, washed with acetonitrile (5 mL) cooled to 0 ° C., and dried under reduced pressure to obtain the title compound (1.03 g, 62.7% ee) (yield 37% (N / N)) ).

1,2-Dimethoxyethane (0.5 mL) was added to the obtained title compound (102 mg, 0.272 mmol), and the mixture was stirred at room temperature for 12 hours. The crystals were filtered and cooled to 0 ° C. Washing with dimethoxyethane and drying under reduced pressure gave the title compound (70.2 mg, 97.3% ee) (yield 58% (N / N)).
¹ H NMR (500 MHz, DMSO-d6) d0.92-1.02 (m, 2H), 1.02 (t, 3H, J = 7.4 Hz), 1.05-1.23 (m, 3H), 1.11 (d, 3H, J = 6.7 Hz), 1.39-1.50 (m, 2H), 1.62-1.74 (m, 5H), 1.91-1.93 (m, 1H), 2.02-2.12 (m. 2H), 2.36-2.41 (m, 2H), 2.53-2.58 (m, 1H), 3.00 (td, 1H, J = 6.7, 6.7 Hz), 3.47 (bs, 1H), 4.77 (bs, 1H), 5.27-5.29 (m, 1H), 7.58 (bs, 3H).
(Example 5)
The optical purity of the optically active compound obtained in Example 1-4 was determined by the following method.
About 10 mg of the amine salt described in the title of each example was taken and dissolved in 1 mL of 5% aqueous sodium carbonate solution, 5 mL of toluene was added, and the mixture was stirred at room temperature for about 1 hour. After standing, only the toluene layer was sampled and analyzed by HPLC (analysis conditions are as described below).
(HPLC analysis conditions)
Column: CHIRALPAK AS-H 4.6 × 250mm; 40 ° C
Wavelength: 305nm
Flow rate: 1 mL / min
Eluent: IPA / hexane = 5/95
Analysis time: 15 minutes Retention time:
(1S, 5R) -3-Ethylbicyclo [3.2.0] hept-3-en-6-one 4.8 min;
(1R, 5S) -3-Ethylbicyclo [3.2.0] hept-3-en-6-one 5.4 min

Claims (7)

A method for producing a compound having the general formula (I) or a compound having the general formula (II),

(1) A racemic mixture of a compound having the general formula (I) and a compound having the general formula (II) is present in the presence of sulfur dioxide (sulfurous acid gas, hereinafter referred to as SO ₂ gas), water, an optically active amine and a solvent. After the lower reaction, either the compound having the general formula (I ′) or the compound having the general formula (II ′) is precipitated as a salt crystal with an optically active amine,

(2) By treating the resulting salt crystals of either the compound having the general formula (I ′) or the compound having the general formula (II ′) with an alkaline aqueous solution,

[In each formula, R ^{1 is a} hydrogen atom or a C1-C6 alkyl group]
A method for producing a compound having the general formula (I) or a compound having the general formula (II). A process for producing a compound having the general formula (I)

(1) A racemic mixture of a compound having the general formula (I) and a compound having the general formula (II) is reacted in the presence of SO ₂ gas, water, an optically active amine and a solvent, and then the general formula (I ′ ) As a crystal of a salt with an optically active amine,

(2) By treating the obtained salt of the compound having the general formula (I ′) with an alkaline aqueous solution,

[In each formula, R ^{1 is a} hydrogen atom or a C1-C6 alkyl group]
A process for producing a compound having the general formula (I). The method according to claim 1 or 2, wherein R ¹ is a hydrogen atom, a methyl group or an ethyl group. The method according to claim 2 or 3, wherein the optically active amine in (1) is any one selected from the group shown below.

The amount of the optically active amine used in (1) is 0.3-0.7 or 0.8-1 relative to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II). The process according to any one of claims 1-4, which is 2 equivalents. The method according to any one of claims 1 to 5, wherein the solvent in (1) is any one selected from the group shown below.
1,2-dimethoxyethane, ethers such as isopropyl ether and tetrahydrofuran, highly polar solvents such as acetonitrile, esters such as ethyl acetate A method for producing a compound having the general formula (III) or a salt thereof, using the compound having the general formula (I) prepared according to any one of claims 2-6.