JP2773627B2 - Process for producing O, O'-diacyltartaric anhydride - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing O, O'-diacyltartaric anhydride.

[0002] Optically active O, O'-diacyltartaric anhydride is a useful substance and is used for various purposes. For example, when an optically active amine or an optically active alcohol is reacted, an optically active monoamide or an optically active monoester is formed, and a chromatographic filler can be prepared by utilizing this reaction (US Pat. No. 4,318,819). . The optically active O, O'-diacyltartaric anhydride becomes a diastereomeric compound when reacted with a racemic amine, a racemic amino acid, a racemic hydroxy acid, a racemic amino alcohol or a racemic alcohol, and these diastereomeric compounds are Optical resolution can be achieved by chromatography or fractional crystallization. For example, it has been reported that the β-blocker which is an amino alcohol is optically resolved by chromatography (J. Chromat).
ogr. 316 P605-616 (1984)). Similarly, the β-blocker timolol has been optically resolved by fractional crystallization (Netherlands Patent No. 8500939).

[0003]

2. Description of the Related Art Conventionally, O, O'-diacyltartaric anhydride is known as O, O'-diacetyltartaric anhydride and O, O'-dibenzoyltartaric anhydride.

As a method of synthesizing O, O'-diacetyl-L-tartaric anhydride, (1) a method of using 4.9 mol of acetic anhydride in the presence of concentrated sulfuric acid per 1 mol of L-tartaric acid (Or)
ganic Syntheses Coll. Vo
l. P242 (1963)), and the method for producing O, O'-dibenzoyl-L-tartaric anhydride includes (2)
A method in which 3.2 mol of benzoyl chloride is reacted with 1 mol of L-tartaric acid (J. Am. Chem. Soc.
55 , P2605 (1933)).

[0005]

The above-mentioned methods (1) and (2) are methods using at least 3 moles of an acid anhydride or acid chloride per 1 mole of tartaric acid to remove by-produced carboxylic acid. High purity optically active O, O
It is not easy to obtain '-diacyltartaric anhydride. Therefore, a method of industrially producing O, O'-diacyltartaric anhydride with high purity and high yield has been desired.

[0006]

Means for Solving the Problems Accordingly, the present inventors have:
A high-purity O, O'-diacyltartaric anhydride with good yield,
In addition, as a result of diligent studies on industrial production methods, O, O'-diacyltartaric anhydride is obtained in high purity by reacting tartaric acid with a specific carboxylic acid chloride or acid anhydride in the presence of a chlorinating agent. An efficient and industrial production method was found.

That is, the present invention relates to a compound represented by the following general formula (I) or (II) R ¹ COCl (I) (R ¹ CO) ₂ O (II) in the presence of a chlorinating agent. R ¹ represents an alkyl group having ¹ to 4 carbon atoms.) Lower aliphatic carboxylic acid chloride or acid anhydride represented by the following general formula (III) or (IV)

Embedded image

Embedded image Wherein R ² and R ³ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom, and reacting an aromatic carboxylic acid chloride or an acid anhydride with tartaric acid. This is a method for producing O, O'-diacyltartaric anhydride.

Hereinafter, the configuration of the present invention will be described in detail.

The above formula (I) applied in the present invention,
The carboxylic acid chloride represented by (III) includes lower aliphatic carboxylic acid chlorides such as acetyl chloride, propionic acid chloride and butyric acid chloride, benzoic acid chloride, o-toluic acid chloride, m-toluic acid chloride, p- Monosubstituted aromatic carboxylic acid chlorides such as toluic acid chloride, o-chlorobenzoic acid chloride, m-chlorobenzoic acid chloride, p-chlorobenzoic acid chloride, and disubstituted aromatics such as 3,4-dimethylbenzoic acid chloride Carboxylic acid chlorides. Further, the above formulas (II) and (IV) corresponding to these acid chlorides
And a carboxylic acid anhydride represented by the formula:

In the present invention, the above formulas (I), (II),
When producing O, O'-diacyltartaric anhydride from carboxylic acid chloride or acid anhydride represented by (III) or (IV) and tartaric acid, the acid chloride or acid anhydride converts the hydroxyl group of tartaric acid to O-acylation. Reaction and a reaction in which tartaric acid or a tartaric acid derivative is converted to an anhydride. In the O-acylation reaction of tartaric acid, when carboxylic acid chloride is used as the O-acylating agent, 2 moles of carboxylic acid chloride is consumed for O-acylation of two hydroxyl groups of tartaric acid with respect to 1 mole of tartaric acid. At the same time, one mole of carboxylic acid chloride is consumed for the anhydration of the dicarboxyl group of tartaric acid or a tartaric acid derivative, and one mole of carboxylic acid is by-produced. When an acid anhydride is used, two moles of the acid anhydride are consumed for O-acylation of two hydroxyl groups of tartaric acid with respect to one mole of tartaric acid, and one mole of the acid anhydride is tartaric acid or tartaric acid. It is consumed for dehydration of the dicarboxyl group of the derivative, and 4 mol of carboxylic acid is by-produced. The reaction rate difference between the O-acylation reaction and the anhydride conversion reaction is small, and it is not easy to distinguish them. Therefore, the conventional method usually requires 3 mol or more of carboxylic acid chloride or acid anhydride.

Therefore, in the conventional method, 3 mol or more of carboxylic acid chloride or acid anhydride is usually required. At least 1 mol of carboxylic acid is by-produced, so that high-purity O, O'-diacyltartaric anhydride is produced. It was not obtained in high yield. In order to reuse by-produced carboxylic acid, it is conceivable to convert carboxylic acid to acid chloride in the system, but in the presence of tartaric acid and chlorinating agent used to convert carboxylic acid to acid chloride. Since the secondary hydroxyl group of tartaric acid may react with a chlorinating agent and be converted into a chloro derivative of tartaric acid, no attempt has been made to chlorinate carboxylic acid by-produced in the system.

However, surprisingly, according to the present invention, the reaction between tartaric acid and the chlorinating agent does not occur, and the reaction between the selectively produced by-produced carboxylic acid and the chlorinating agent takes precedence. It can be converted to acid chloride in The reason is,
When carboxylic acid and tartaric acid co-produced in the solvent used in the reaction of the present invention at the time of chlorination coexist with tartaric acid, the secondary hydroxyl group of tartaric acid or the carboxyl group of tartaric acid is very insoluble in those solvents. It is because chlorination of carboxylic acid hardly occurs and by-product carboxylic acid which is relatively soluble in a solvent reacts preferentially with the chlorinating agent. That is, it became possible to control the reaction of the chlorinating agent based on the difference in solubility between tartaric acid and the by-produced carboxylic acid in the solvent. Moreover,
The by-produced carboxylic acid can be converted again into an acid chloride by a chlorinating agent in the system. Therefore, the amount of the carboxylic acid chloride and the acid anhydride used as the O-acylating agent can be reduced from 3 moles in the conventional method to 2 moles, so that the removal of the by-produced carboxylic acid becomes unnecessary, and O, O'-diacyltartaric acid is eliminated. Anhydride can be produced with high purity and high yield.

From the above, 2 moles of carboxylic acid chloride and carboxylic anhydride of the O-acylating agent are equivalent to 1 mole of tartaric acid. Therefore, their use amount is 2.0 to 2.8 mol, preferably 2.0 to 2.4 mol, per 1 mol of tartaric acid. If 2.8 mol or more is used, it becomes more difficult to remove by-produced carboxylic acid or excess acid chloride or acid anhydride. To chlorinate 1 mole of by-produced carboxylic acid, 1 mole of chlorinating agent is required. Therefore, when the O-acylating agent is carboxylic acid chloride, the amount of chlorinating agent used is 1 mole of tartaric acid. At least 1.0 mole is required. Therefore, the amount of the chlorinating agent is 1.0 to 2.0 per mole of tartaric acid.
Mol, preferably 1.0 to 1.5 mol. When the amount is less than 1.0 mol, the carboxylic acid is not quantitatively converted into the acid chloride, and the yield of O, O'-diacyltartaric anhydride is reduced. The agent must be removed. However, when the O-acylating agent is a carboxylic acid anhydride, if 2 moles of the carboxylic acid anhydride is used per 1 mole of tartaric acid, 2 moles of the carboxylic acid are by-produced. At 0 mol, 1 mol of the carboxylic acid remains, but if the by-produced carboxylic acid is a liquid, there is no effect on the purity of the produced O, O'-diacyltartaric anhydride. However, when the by-produced carboxylic acid is solid, the O, O'-
The chlorinating agent is used in an amount of 1.0 to 4.0 with respect to 1 mol of tartaric acid, since it may be mixed with diacyl tartaric anhydride.
Mol, preferably 1.0 to 3.0 mol. By using the chlorinating agent in an equimolar amount with respect to the by-produced carboxylic acid, the by-produced solid carboxylic acid can be removed as a liquid acid chloride and the converted acid chloride can be subjected to O-acylation. Can be used effectively as an agent,
The yield of O, O'-diacyltartaric anhydride is further improved.

As a chlorinating agent for converting the by-produced carboxylic acid into acid chloride, commonly used phosphorus pentachloride, phosphorus trichloride, thionyl chloride and the like can be used.
-A chlorinating agent which does not hinder the acylation reaction and which does not enter the crystals when the O, O'-diacyltartaric anhydride formed after the O-acylation reaction is taken out is preferred. Therefore, thionyl chloride which becomes hydrogen chloride or sulfurous acid gas and flows out of the system is preferable.

Here, a solvent may or may not be used.
But, O as the solvent to be used, without allowed to alter the O'- diacyl tartaric anhydride, and may be any one which does not interfere with the acylation reactions, benzene, toluene, xylene, aromatic such as chlorobenzene, dioxane And aliphatic hydrocarbons such as hexane and cyclohexane.

The chlorination reaction of the by-produced carboxylic acid depends on the kind of the carboxylic acid and the chlorinating agent, but is generally carried out at room temperature to 110 ° C. or lower, and the O-acylation reaction of tartaric acid is 30 to 160. C., preferably at 40-140.degree. The reaction time can be appropriately selected depending on other conditions such as the reaction temperature, and is generally completed in 1 to 40 hours.

Next, a method for reacting tartaric acid with carboxylic acid chloride or acid anhydride will be described. For example, tartaric acid and a carboxylic acid chloride or an acid anhydride or, if necessary, a solvent are charged at once, and an O-acylation reaction and an anhydride reaction are performed. Next, an O-acylation reaction and an anhydride reaction are performed simultaneously with the chlorination of the by-produced carboxylic acid by adding a chlorinating agent. Further, tartaric acid and carboxylic acid chloride or acid anhydride, a chlorinating agent or, if necessary, a solvent may be charged at once. These methods can be applied to lower aliphatic carboxylic acid chlorides or acid anhydrides in which the O-acylation reaction proceeds at a low temperature. When the O-acylation reaction of tartaric acid proceeds at a higher reaction temperature than the chlorination reaction of by-produced carboxylic acid, tartaric acid is O-acylated and anhydrided with carboxylic acid chloride or acid anhydride, On the way, the temperature is lowered to convert the by-produced carboxylic acid into acid chloride with a chlorinating agent, and then the temperature in the system is raised to perform the O-acylation reaction and the anhydride reaction again.

After completion of the reaction, the desired O, O'-diacyltartaric anhydride can be easily isolated by a known method such as filtration, washing, or, if necessary, concentration and filtration. The isolated O, O'-diacyltartaric anhydride has high purity, and retains optical activity when optically active tartaric acid is a raw material. Also unfortunately O
When the solid carboxylic acid of the acylating agent is mixed, O, O′-diacyltartaric anhydride is recrystallized and purified with an organic solvent such as toluene, acetonitrile, or acetone;
The carboxylic acid can be removed as a liquid acid chloride by re-treatment with a chlorinating agent such as thionyl chloride.

[0019]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

In the examples, the amount of O, O'-diacyltartaric anhydride present in the reaction filtrate was determined by O, O'-
The diacyl tartaric anhydride was reacted with isopropylamine to form a monoamidated compound, and then analyzed by high performance liquid chromatography (HPLC). Optical purity is O, O'-
O, O 'obtained by hydrolyzing diacyl tartaric anhydride
- diacyl tartaric using CHIRA L CEL OJ (manufactured by Daicel), and analyzed by HPLC.

Example 1 4 equipped with a thermometer, a dropping funnel, a condenser and a stirrer
L-tartaric acid 30.0 g (0.2
00 mol) and 36.1 g of toluene. Under sufficient stirring, S was generated by slightly depressurizing the upper part of the condenser.
68.0 g of p-toluic acid chloride (0. 0 g) was removed from the dropping funnel while refluxing toluene while extracting O ₂ and hydrochloric acid gas.
440 mol) was added dropwise over 2 hours. During the dropping, the bath temperature was kept at 13 to 15 ° C. higher than the liquid temperature. Crystallization started when ２ of p-toluic acid chloride was dropped. After dropping, the mixture was aged for 1 hour under reflux, then the bath temperature was lowered to 80 ° C, and 28.6 g of thionyl chloride was maintained while maintaining the liquid temperature at 75 to 85 ° C.
(0.240 mol) was added dropwise over 1 hour. After dripping 1
After aging for an hour, the bath temperature was raised to 130 ° C., and the mixture was further stirred under reflux for 6 hours. The liquid temperature at this time was about 115 ° C. Next, after adding 68.1 g of toluene and cooling, the reaction solution was filtered, and the crystals were washed with 43.0 g of toluene. After drying under reduced pressure at 60 ° C., white crystals O, O′-di-
67.5 g of p-toluoyl-L-tartaric anhydride (0.1
83 mol). The yield is 91.5%. The analysis results of the obtained compound were as follows. P-Toluic acid contained in the obtained crystal was 0.1%, and the optical purity was 9%.
It was 9.5% ee.

Melting point: 204-205 ° C. IR: 2974, 2954, 1883, 1809, 17
32, 1707, 1610, 1267, 1058, 10
19 cm ^-1 NMR: 2.42 ppm (6H), 6.64 ppm (2
H), 7.35 to 8.02 ppm (8H)

Example 2 4 equipped with a thermometer, a dropping funnel, a condenser and a stirrer
L-tartaric acid 30.0 g (0.2
00 mol) and 36.1 g of toluene. Under sufficient stirring, S was generated by slightly depressurizing the upper part of the condenser.
While extracting O ₂ and hydrochloric acid gas, keep the liquid temperature at 110 ° C,
61.9 g (0.44 g) of benzoyl chloride from the dropping funnel.
0 mol) was added dropwise over 3 hours. 1 benzoyl chloride
When / 2 drops, crystallization started. Bath temperature during dropping is 122
１２４124 ° C. After aging at a liquid temperature of 110 ° C. for 2 hours, the bath temperature was lowered to 80 ° C., and 28.6 g (0.240 mol) of thionyl chloride was added while maintaining the liquid temperature at 75 to 85 ° C.
Dropped in time. After dropping, aging for 1 hour, liquid temperature 110
Stirred at C for 6 hours. Next, 68.5 g of toluene was added and cooled. The reaction solution was filtered, and the crystals were dissolved in toluene 40.0.
g. After drying under reduced pressure at 50 ° C., white crystals O, O
54.8 g of '-dibenzoyl-L-tartaric anhydride (0.
161 mol) (yield: 80.5%). Benzoic acid contained in the obtained crystals was 0.2%, and the optical purity was 99.5% ee.

Melting point: 194 ° -196 ° C. IR: 2968, 2950, 1880, 1823, 17
38, 1706, 1568, 1266, 1058, 10
27, 709 cm ^-1 NMR: 6.75 ppm (2H), 7.45 to 8.20 p
pm (10H)

Example 3 3.0 g (0.020 mol) of DL-tartaric acid, 4.0 g of toluene and 8.5 g (0.05 g of p-toluic acid chloride) were placed in a 50 ml two-necked flask equipped with a condenser and a dropping funnel.
5 mol), and the mixture was stirred for 4 hours with stirring at a bath temperature of 130 ° C. while extracting the generated SO ₂ and hydrochloric acid gas by slightly reducing the pressure from the upper part of the condenser. Next, the bath temperature was lowered to 90 ° C, and thionyl chloride (3.0 g, 0.025
Mol) was added and stirred for 1 hour. After the bath temperature was raised to 130 ° C. and the mixture was stirred for 4 hours, 30 g of toluene was added to dissolve the whole and cooled slowly. Filter and wash the reaction solution, 60 ° C
Under reduced pressure to obtain 5.9 g (0.016 mol) of white crystals O, O'-di-p-toluoyl-DL-tartaric anhydride.

Example 4 A 50 ml two-necked flask equipped with a condenser and a dropping funnel was charged with 7.3 g (0.072 mol) of acetic anhydride and 4.5 g (0.030 mol) of L-tartaric acid. After heating for an hour, 9.5 g of thionyl chloride (0.08
(0 mol) was added dropwise over 4 hours with stirring with a stirrer, followed by stirring for 2 hours. After cooling, 3.5 g of toluene was added and stirred. The reaction solution was filtered, washed and dried at 50 ° C. under reduced pressure to obtain white O, O
5.6 g of '-diacetyl-L-tartaric anhydride (0.02
6 mol). 86% yield, 132-134 melting point.
° C.

[0027] Example 5 a condenser, xylene 6.0g to 50ml2 neck flask equipped with a dropping funnel, o- chloro benzoic acid chloride 1
1.6 g (0.066 mol) and 4.5 g of L-tartaric acid
(0.030 mol). The mixture was stirred at a bath temperature of 130 ° C. for 4.5 hours while extracting generated SO ₂ and hydrochloric acid gas by slightly reducing the pressure from the upper part of the condenser. Next, the bath temperature was lowered to 90 ° C., and 5.1 g of thionyl chloride (0.0 g) was added.
43 mol) and stirred for 1.5 hours. Further, the bath temperature was raised to 130 ° C. and the mixture was stirred for 2.5 hours. 30 g of toluene was added, and the mixture was slowly cooled to room temperature with stirring. The reaction solution was filtered, washed and dried at 50 ° C. under reduced pressure to obtain white crystals O, O
'- di -o- chloro benzoyl -L- tartaric anhydride 6.
6 g (0.016 mol) were obtained. The analysis results of the obtained compound were as follows. Yield 54%.

Melting point: 165-169 ° C IR: 2936, 1888, 1805, 1735, 15
90, 1249, 1142, 1131, 1057, 10
47, 952, 738 cm ^-1 NMR: 6.80 ppm (2H), 7.40 to 8.15 p
pm (8H)

Example 6 6.0 g of xylene and 10.2 of m-toluic acid chloride were placed in a 50 ml two-necked flask equipped with a condenser and a dropping funnel.
g (0.066 mol) and 4.5 g of L-tartaric acid (0.
030 mol), the bath temperature was raised to 130 ° C., and the mixture was stirred for 3.5 hours while extracting the generated SO ₂ and hydrochloric acid gas by slightly reducing the pressure from the upper part of the condenser. Next, the bath temperature was lowered to 90 ° C, and 5.8 g of thionyl chloride (0.049
Mol) was added and stirred for 1.5 hours. Further bath temperature 1
It raised to 30 degreeC and stirred for 5 hours. 30 g of xylene was added, and the mixture was slowly cooled to room temperature with stirring. The reaction solution was filtered, washed, and dried under reduced pressure at 60 ° C. to obtain white crystals O, O′-.
8.4 g of di-m-toluoyl-L-tartaric anhydride (0.
023 mol). The analysis results of the obtained compound were as follows. O contained in the reaction filtrate by HPLC analysis, O'reaction yield 82% of di -m- toluoyl -L- tartaric acid anhydride combined with, isolation yield was 76%.

Melting point: 142-147 ° C. IR: 2962, 1881, 1820, 1734, 17
04, 1590, 1333, 1276, 1196, 10
60, 1016 cm, 740 cm ^-1 NMR: 2.40 ppm (6H), 6.68 ppm (2
H), 7.35 to 8.00 ppm (8H)

Example 7 D-tartaric acid was placed in a 300 ml reactor equipped with a stirrer, thermometer, condenser and dropping funnel. 0 g ( 0 .
(200 mol) and 40 g of toluene. Under sufficient stirring, the SO generated by pulling a small vacuum from the top of the condenser
Under toluene reflux extracted ₂ and hydrochloric acid gas, dropping funnel - Toyori 3,4-dimethylbenzoic acid chloride 74.2
g (0.440 mol) was added dropwise over 3 hours. After dropping, the mixture was aged for 2 hours under reflux, then the bath temperature was lowered to 80 ° C, and while maintaining the liquid temperature at 75 to 85 ° C, thionyl chloride 2
8.6 g (0.240 mol) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was aged for 1 hour and stirred for 6 hours under reflux of toluene. Next, 68.0 g of toluene was added and cooled. The reaction solution was filtered, and the crystals were washed with 40.0 g of toluene. 4
After drying under reduced pressure at 0 ° C., white crystals of O, O′-di- (3,4
-Dimethylbenzoyl) -D-tartaric anhydride 71.4 g
(0.180 mol). The melting point was 180-182 ° C and the yield was 90.1%.

[0032]

According to the present invention, O,
O'-diacyltartaric anhydride can be produced industrially at low cost.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 307/56 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) In the presence of a chlorinating agent, the following general formula (I) or (II): R ¹ COCl (I) (R ¹ CO) ₂ O (II) wherein R ¹ is 1 A lower aliphatic carboxylic acid chloride or acid anhydride represented by the following general formula (III) or (IV): Embedded image Wherein R ² and R ³ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom, and reacting an aromatic carboxylic acid chloride or an acid anhydride with tartaric acid. A process for producing O, O'-diacyltartaric anhydride. 2. The method for producing O, O'-diacyltartaric anhydride according to claim 1, wherein the chlorinating agent is thionyl chloride.