JP2001031625A - Optical resolution of carboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially practicable method for mass producing a raw material of an optically active substance such as a compound useful as a structural raw material for iloprost, etc., being an antithrombotic agent by subjecting a specific carboxylic acid to optical resolution using quinine, etc. SOLUTION: (A) A carboxylic acid of the formula (R1 and R2 are each a lower alkyl; n is 0-3) [preferably (±)-2-methyl-4-hexynoic acid] is subjected to optical resolution by using (B) quinine or cinchonidine to carry out the optical resolution of the objective compound. In this method, the component A is brought into contact with the component B in a solvent such as methanol, etc., to form a disastereomer salt, which is cooled and/or concentrated to precipitate a slightly soluble diastereomer salt. The diastereomer salt is separated by filtration, recrystallized and further purified. A raw material such as dimethyl 3-methyl-2-oxo-5-heptynylphosphonate, etc., is obtained by the method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to dimethyl 3-methyl-2-oxo used as a raw material for producing the ω side chain of iloprost, cicaprost, eptaprost and beraprost, which are useful as antithrombotic agents in pharmaceuticals, for example. The present invention relates to a method for producing a raw material of an optically active substance of -5-heptynylphosphonate or dimethyl 3-methyl-2-oxo-5-octynylphosphonate.

[0002]

2. Description of the Related Art Conventionally, dimethyl 3-methyl-2-oxo-5-
Heptynyl phosphonate or dimethyl 3-methyl-2
The optically active form of 2-methyl-4-hexynic acid or 2-methyl-4-heptic acid, which is the raw material of 2-oxo-5-octynylphosphonate, is converted to an amide derivative of phenylglycinol and the diastereomer is converted to a column. Purification by chromatography (Angew. Chem. Int. Ed. Engl. 1979, 1
8, 62; ibid. 1979, 18, 63) and asymmetric alkylation using an oxazolidinone derivative obtained from norephedrine as a raw material (Liebig Ann. Chem. 1989, 1081).
Was known.

[0003]

However, of the above-mentioned conventional methods, the former method has a long synthesis route, and cannot be said to be an industrial production method due to purification by column chromatography. In addition, the latter method also has a problem that it must be performed at a low temperature of -78 ° C. and that the recrystallization must be repeated after the reaction because the asymmetric yield is 80%. Furthermore, since the raw material norephedrine is a raw material of a stimulant, it is very difficult to obtain it.

[0004] High-performance liquid chromatography, which is known as an optical purity analysis method, can also be applied to optical resolution, but requires an expensive carrier and requires industrial production at a high cost.

An object of the present invention is to provide an industrially practical production method for obtaining a large amount of the above-mentioned optically active carboxylic acid.

[0006]

Means for Solving the Problems The present inventors have studied diligently to solve the above-mentioned problems, and have obtained an optical resolution for recrystallization of a diastereomer salt of the above-mentioned carboxylic acid and a specific optically active amine. Invented the law.

That is, the present invention provides a compound represented by the general formula (1):

[0008]

Embedded image [Wherein, R ¹ and R ² represent a lower alkyl group, and n represents an integer of 0-3]. This is a method of optically resolving a carboxylic acid represented by the formula: quinine or cinchonidine.

[0009]

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound represented by the general formula (1):

[0010]

Embedded image [Wherein, R ¹ and R ² represent a lower alkyl group, and n represents an integer of 0-3]. This is a method of optically resolving a carboxylic acid represented by the formula: quinine or cinchonidine. And a carboxylic acid of the general formula (1), or a diastereomeric salt of cinchonidine and the carboxylic acid of the general formula (1), and a method for optical resolution using the difference in solubility.

In the carboxylic acid of the general formula (1),
Examples of the lower alkyl group for R ¹ and R ² include an alkyl group having 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, and an n-butyl group. And R ¹ and R ² may be the same or different.
n is preferably 1 or 2. Among them, those in which both R ¹ and R ² are methyl and n is 1 or 2 are preferred.

In the present invention, among the carboxylic acids of the general formula (1) used as raw materials, for example, 2-methyl-4-hexanoic acid in which both R ¹ and R ² are methyl groups and n is 1 is Tetrahedron , 1999, 55, 2449, but of course, there is no problem if it is produced by any other method. The raw material carboxylic acid is
Not only a racemic mixture containing equal amounts of the (+)-form and (-)-form, but also a mixture containing at least one of the optical isomers in an equal amount or more.

In an embodiment of the present invention, first, a carboxylic acid of the general formula (1) is brought into contact with quinine or cinchonidine in a solvent to form a diastereomer salt. Examples of the solvent used here include water, protic solvents such as methanol, ethanol, n-propanol, and isopropanol; organic solvents such as acetone, acetonitrile, ethyl acetate, chloroform, and toluene; and mixed solvents thereof. Among them, methanol, water or a mixed solvent thereof is preferable.

The resolving agents quinine and cinchonidine are both quinacalkaloids obtained from extracts from quinna rind.
And a commercially available compound that is easily available. When quinine is used as a resolving agent,
When cinchonidine is used, a (+)-form carboxylic acid is obtained. Although the amount of quinine or cinchonidine is not particularly limited, it is usually 0.3-1.5 per mole of carboxylic acid.
A mole, preferably 0.5-1.2 mole, of the resolving agent is contacted to form a diastereomer salt. At this time, an amine such as ammonia, dimethylamine, diethylamine or diisopropylamine may coexist.

As a method of bringing the resolving agent into contact with the carboxylic acid (1), the racemic carboxylic acid and the resolving agent may be added to the solvent at once, or they may be added sequentially. Further, a salt prepared from a racemic carboxylic acid and a resolving agent in advance may be dissolved in the solvent.

Next, when the solution containing the diastereomer salt thus obtained is cooled and / or concentrated, a sparingly soluble diastereomer salt crystallizes out of the solution. The temperature at which the sparingly soluble diastereomer salt is precipitated from the solution may be within the range of the freezing point to the boiling point of the solvent used, and is appropriately determined depending on the purpose.
Is sufficient. Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation.

The diastereomer salt obtained by recrystallization is treated with a mineral acid such as sulfuric acid or hydrochloric acid, and then extracted and concentrated with an organic solvent. If necessary, purification operations such as distillation, recrystallization, and column chromatography are performed. Is carried out to obtain a carboxylic acid of the general formula (1) having high optical purity.

All of the resolving agents used in the present invention are hardly soluble in water, can be recovered from diastereomeric salts in high yield, and hardly decompose or racemize during the recovery process. Therefore, since the resolving agent maintains the optical purity, it can be reused to perform optical resolution.

According to the present invention, it has become possible to produce an optically active carboxylic acid represented by the general formula (1) by using a readily available optically active amine. This production method is very useful because it can be applied to both experimental production methods and industrial production methods.

Hereinafter, the present invention will be described in more detail with reference to examples.

[0021]

EXAMPLES Example 1 Optical Resolution of (-)-2-Methyl-4-hexynic acid 155.6 g of (±) -2-methyl-4-hexynic acid was collected from 400 g of quinine and 500 g of methanol, and refluxed with methanol. Dissolved.
After dissolution, 500 g of water was added with stirring, and the mixture was cooled to room temperature. Then, it was left to cool to -10 to + 5 ° C. The precipitated diastereomer salt was filtered and dried under reduced pressure to obtain 226.0 g (crystallization rate).
40.7% and (-) form 67.6% ee). Mother liquor is (+) body 49.0%
was ee.

225 g of the first crystal salt was dissolved by heating in 225 g of methanol. After dissolution, 225 g of water was added with stirring, and the mixture was cooled to 0 ° C. and allowed to stand. The precipitated diastereomer salt was filtered and dried under reduced pressure to give 192 g (crystallization rate: 86.9%, (-) form: 88.1% ee). The mother liquor was (+) form 47.2% ee.

The second crystal salt was further recrystallized and purified eight times using a methanol-water mixed solvent to obtain 35.0 g of a diastereomer salt.
(Total yield 6.3%, (-) form 99.9% ee. [Α] _D = -143.3 ° (c 1.
95, EtOH). The mother liquor of 10 crystals was (-) form 99.6% ee.

After extracting and washing 200 g of 2N H ₂ SO ₄ , 500 ml of ethyl acetate, and 500 ml of 10% saline, 34 g of the salt of the 10th crystal was washed, and the organic phase was dried over MgSO 4. The mixture was filtered, and the filtrate was concentrated and distilled under reduced pressure to give (-)-2-methyl-4-hexamic acid 9.1 g.
(Bp 82.5-84.0 ° C / 1.5-2.0 mmHg, [α] _D = -0.72 ° (c 1
0.0, EtOH) and (-)-form 99.9% ee) were obtained.

Optical Purity Analysis Method Under a nitrogen stream, (-)-2-methyl-4-hexynic acid (126.2 mg), toluene (2 ml) and thionyl chloride (109 μL) were collected and heated to induce acid chloride. Separately under a nitrogen stream L-(-)-α-phenethylamine 243 mg, THF 2.5 mL, triethylamine 278 μ
L was collected and amidated by adding an acid chloride mixed solution under ice cooling (reaction was confirmed by TLC analysis. Ethyl acetate / cyclohexane = 1/2, Rf value: carboxylic acid 0.57, amide 0.26). Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and separated. The organic phase was washed with 1 mol / L hydrochloric acid and 10% brine, dried over MgSO4, and filtered. The filtrate was concentrated to dryness, 20 mg was dissolved in 1 mL of ethanol and analyzed by HPLC.

Column used: YMC-A-014 (SIL) Column temperature: 40 ° C. Detection wavelength: UV 254 nm Developing solution: n-hexane / dichloromethane / ethanol = 88 /
10/2 (v / v / v) Flow rate: 0.8 mL / min Retention time: (-)-2-methyl-4-hexanoic acid amide 40 minutes (+)-2-methyl-4-hexanoic acid amide 32 Example 2 Optical Resolution of (+)-2-Methyl-4-hexynoic Acid The post-treatment and distillation of the mother liquor of the first and second crystals of Example 1 separated by quinine resulted in many (+)-forms. 351.5 g of 2-methyl-4-hexanoic acid containing (bp: 115-118 ° C / 9-10 mmHg, (+) form 49.0% e.
e.), 820 g of cinchonidine and 1 kg of methanol were collected in a 5 L flask and dissolved by heating. After dissolution, add 1.1 kg of water to 0
It was left at -5 ° C for 5 days. The precipitated diastereomer salt was filtered and dried under reduced pressure to give 532 g (crystallization rate 45.4%, (+) form
76.1% ee). The mother liquor was (+) 29.2% ee.

531 g of the first crystal salt was dissolved by heating in 800 g of methanol. After dissolution, with stirring, add 800 g of water, 0-5 ° C
For 7 days. The precipitated diastereomer salt was filtered and dried under reduced pressure to give 361 g (crystallinity: 67.9%, (+) form 89.3%).
% ee). The mother liquor was (+) form 48.1% ee.

The second crystal salt was further recrystallized seven times using a mixed solvent of methanol and water to obtain 80.0 g of a diastereomer salt.
(Total yield 6.8%, (+) form 99.6% ee, [α] _D = -98.1 ° (c 2.
15, EtOH). The mother liquor of 10 crystals was (+)-form 98.8% ee.

After working up, extracting and washing 79 g of the salt of the ninth crystal with 375 mL of 2 mol / L sulfuric acid, 500 mL of ethyl acetate and 500 mL of 10% saline, the organic phase was dried over MgSO 4. This was filtered, and the filtrate was concentrated and distilled under reduced pressure to give (+)-2-methyl-4-hexic acid 21.9 g (bp 79.0-81.0 / 1.5 mmHg, [α] _D = + 0.97 °
(c 10.1, EtOH), (+) form 99.6% ee) were obtained. The optical purity analysis was the same as in Example 1.

[0030]

According to the present invention, (±) -2-methyl-4
It has become possible to produce an optically active α-alkyl-acetylene carboxylic acid represented by -hexyne acid by using a readily available optically active amine. This production method is very useful because it can be applied to both experimental production methods and industrial production methods.

Claims (2)

[Claims] 1. A compound of the general formula (1) Wherein R ¹ and R ² each represent a lower alkyl group, and n represents an integer of 0 to 3; and a carboxylic acid represented by the formula: quinine or cinchonidine. 2. A carboxylic acid represented by the general formula (1):
The method according to claim 1, wherein both R ¹ and R ² are a methyl group and n is 1 (±) -2-methyl-4-hexanoic acid.