JPH06279425A - Production of o,o'-diacyltartaric acid anhydride - Google Patents

Abstract

PURPOSE:To produce the subject compound useful e.g. as a raw material for filler for chromatography, optical resolution agent, etc., in high purity and yield on an industrial scale at a low cost by reacting tartaric acid with a specific carboxylic acid chloride or acid anhydride in the presence of a chlorination agent. CONSTITUTION:An O,O'-diacyltartaric acid anhydride is produced by reacting a lower aliphatic carboxylic acid chloride of the formula R<1>COCl (R<1> is 1-4C alkyl) or its anhydride of the formula (R<1>CO)2O or an aromatic carboxylic acid chloride of formula I (R<2> and R<3> are H, 1-4C alkyl or halogen) or its anhydride of formula II with tartaric acid. The chlorination agent is especially preferably thionyl chloride.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing O, O'-diacyltartaric anhydride.

Optically active O, O′-diacyl tartaric 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 obtained, and this reaction can be used to produce a chromatographic packing material (US Pat. No. 4,318,819). . Further, the optically active O, O′-diacyl tartaric acid anhydride becomes a diastereomer compound when reacted with a racemic amine, a racemic amino acid, a racemic hydroxy acid, a racemic amino alcohol or a racemic alcohol. It can be optically resolved by chromatography or fractional crystallization. For example, chromatography has been reported to optically resolve β-blockers, which are amino alcohols (J. Chromat.
ogr. 316 P605-616 (1984)). Similarly, β-blocker timolol is optically resolved by the fractional crystallization method (Dutch Patent No. 8500939).

[0003]

2. Description of the Related Art Conventionally known O, O'-diacyl tartaric anhydride is O, O'-diacetyl tartaric anhydride and O, O'-dibenzoyl tartaric anhydride.

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

[0005]

The methods (1) and (2) described above are methods in which 3 mol or more of an acid anhydride or acid chloride is used per 1 mol of tartaric acid, and carboxylic acid produced as a by-product is removed. Must be done, and high purity optically active O, O
It is not easy to obtain'-diacyl tartaric anhydride. Therefore, a method for industrially producing O, O'-diacyltartaric anhydride with high purity and high yield has been desired.

[0006]

Therefore, the present inventors have
High-purity O, O′-diacyltartaric acid anhydride in good yield,
Moreover, as a result of diligent examination of the industrial production method, the tartaric acid was reacted with a specific carboxylic acid chloride or acid anhydride in the presence of a chlorinating agent to collect O, O'-diacyltartaric anhydride with high purity. We have found a method of manufacturing efficiently and industrially.

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

[Chemical 3]

[Chemical 4] (Wherein R ² and R ³ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom), and an aromatic carboxylic acid chloride or acid anhydride is reacted with tartaric acid. This is a method for producing O, O'-diacyl tartaric anhydride.

The structure of the present invention will be described in detail below.

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, butyric acid chloride, benzoic acid chloride, o-toluic acid chloride, m-toluic acid chloride, p- Mono-substituted aromatic carboxylic acid chlorides such as toluic acid chloride, o-chlorobenzoic acid chloride, m-chlorobenzoic acid chloride and p-chlorobenzoic acid chloride, or disubstituted aromatics such as 3,4-dimethylbenzoic acid chloride Examples thereof include carboxylic acid chlorides. Further, the above formulas (II) and (IV) corresponding to these acid chlorides
The carboxylic acid anhydride represented by

In the present invention, the above formulas (I), (II),
In the case of producing O, O'-diacyl tartaric anhydride from carboxylic acid chlorides or acid anhydrides represented by (III) and (IV) and tartaric acid, the acid chlorides or acid anhydrides O-acylate the hydroxyl groups of tartaric acid. And the reaction in which tartaric acid or a tartaric acid derivative is anhydrate. In the O-acylation reaction of tartaric acid, when carboxylic acid chloride is used as an O-acylating agent, 2 mol of carboxylic acid chloride is consumed for O-acylation of two hydroxyl groups of tartaric acid with respect to 1 mol of tartaric acid. At the same time, 1 mol of carboxylic acid chloride is consumed for dehydrating the dicarboxyl group of tartaric acid or a tartaric acid derivative, and 1 mol of carboxylic acid is by-produced. When an acid anhydride is used, 2 mol of acid anhydride is consumed for O-acylation of two hydroxyl groups of tartaric acid, and at the same time, 1 mol of acid anhydride is tartaric acid or tartaric acid. The dicarboxylic group of the derivative is consumed as an anhydride, and 4 mol of carboxylic acid is produced as a by-product. The difference in the reaction rate between the O-acylation reaction and the anhydride 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, the amount of carboxylic acid chloride or acid anhydride is usually required to be 3 mol or more, and since at least 1 mol or more of carboxylic acid is by-produced, high purity O, O'-diacyl tartaric anhydride is obtained. It could not be obtained in high yield. In order to reuse the by-produced carboxylic acid, it is possible to convert the carboxylic acid into an acid chloride in the system, but in the coexistence of tartaric acid with a chlorinating agent used to convert the carboxylic acid into an acid chloride, However, since the secondary hydroxyl group of tartaric acid may react with a chlorinating agent to be converted into a chloro derivative of tartaric acid, chlorination of a carboxylic acid by-produced in the system has not been attempted.

Surprisingly, however, according to the present invention, the reaction between tartaric acid and the chlorinating agent does not occur, and the reaction between the carboxylic acid and the chlorinating agent which are selectively by-produced is prioritized. In which it can be converted to the acid chloride. The reason is,
When by-product carboxylic acid and tartaric acid coexist in the solvent used in the reaction of the present invention at the time of chlorination, tartaric acid is very hardly soluble in those solvents. Therefore, the secondary hydroxyl group of tartaric acid or the carboxyl group of tartaric acid is used. The carboxylic acid as a by-product, which is less likely to be chlorinated and is relatively soluble in a solvent, preferentially reacts with the chlorinating agent. That is, it became possible to control the reaction of the chlorinating agent from the difference in the solubility of tartaric acid and the by-produced carboxylic acid in the solvent. Moreover,
By-produced carboxylic acid can be converted into acid chloride again in the system by a chlorinating agent. Therefore, the amount of the carboxylic acid chloride or acid anhydride used as the O-acylating agent can be reduced from 3 mol in the conventional method to 2 mol, so that it is not necessary to remove the carboxylic acid produced as a by-product, and O, O′-diacyl tartaric acid is eliminated. An anhydride can be produced with high purity and high yield.

From the above, 2 moles of the carboxylic acid chloride or carboxylic acid anhydride of the O-acylating agent is equivalent to 1 mole of tartaric acid. Therefore, the amount thereof used 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 difficult to remove the by-produced carboxylic acid or the excess amount of acid chloride or acid anhydride. Since 1 mol of the chlorinating agent is required to chlorinate 1 mol of the carboxylic acid produced as a by-product, when the O-acylating agent is carboxylic acid chloride, the amount of the chlorinating agent used is 1 mol of tartaric acid. Therefore, at least 1.0 mol is required. Therefore, the chlorinating agent is 1.0 to 2.0 with respect to 1 mol of tartaric acid.
Molar, preferably 1.0 to 1.5 mol. When the amount is 1.0 mol or less, the carboxylic acid is not quantitatively converted into acid chloride, and the yield of O, O'-diacyltartaric acid anhydride is low, and when 2.0 mol or more is used, excessive chlorination occurs. You have to remove the agent. However, when the O-acylating agent is a carboxylic acid anhydride, 2 mol of the carboxylic acid anhydride is used as a by-product when 2 mol of the carboxylic acid anhydride is used per 1 mol of tartaric acid, so that the amount of the chlorinating agent used is 1. When 0 mol is used, 1 mol of carboxylic acid remains, but if the by-produced carboxylic acid is a liquid, there is no influence on the purity of the produced O, O′-diacyltartaric acid anhydride. However, when the by-produced carboxylic acid is a solid, O, O'-
Since it may be mixed with diacyl tartaric anhydride, the amount of the chlorinating agent used is 1.0 to 4.0 with respect to 1 mol of tartaric acid.
The molar amount is preferably 1.0 to 3.0 mol. By using an equimolar amount of the chlorinating agent 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 O-acylated. Can be effectively used as an agent,
The yield of O, O′-diacyl tartaric anhydride is further improved.

As the chlorinating agent for converting the by-produced carboxylic acid into an acid chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride and the like which are commonly used can be used.
A chlorinating agent that does not interfere with the acylation reaction and does not mix with the crystals when the O, O′-diacyltartaric acid anhydride formed after the O-acylation reaction is taken out is preferable. Therefore, thionyl chloride which is hydrogen chloride or sulfurous acid gas and flows out of the system is preferable.

Here, the solvent used is O, O '-
As long as it does not deteriorate the diacyl tartaric anhydride and does not interfere with the acylation reaction, benzene,
Examples include aromatics such as toluene, xylene and chlorobenzene, ethers such as 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 or the chlorinating agent, but it 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 40-140.degree. The reaction time can be appropriately selected depending on other conditions such as reaction temperature, and is generally 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 carboxylic acid chloride or acid anhydride, or if necessary, a solvent is charged all at once, and O-acylation reaction and anhydride reaction are carried out. Then, a chlorinating agent is added to simultaneously chlorinate the by-produced carboxylic acid, and simultaneously perform an O-acylation reaction and an anhydride reaction. Further, tartaric acid and carboxylic acid chloride or acid anhydride, a chlorinating agent, or, if necessary, a solvent may be charged all at once. These methods can be applied to the case where the lower aliphatic carboxylic acid chloride or the acid anhydride is used and 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 the by-produced carboxylic acid, tartaric acid is subjected to O-acylation and anhydride conversion with carboxylic acid chloride or acid anhydride. During the process, the temperature is lowered to convert the by-produced carboxylic acid into an 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.

The desired O, O'-diacyl tartaric anhydride can be easily isolated by a known method after the reaction, such as filtration, washing, or if necessary, concentration and then filtration. The isolated O, O'-diacyl tartaric anhydride has a high purity and retains optical activity when optically active tartaric acid is used as a raw material. Also unfortunately O
-When a solid carboxylic acid as an acylating agent is mixed, recrystallize and purify O, O'-diacyl tartaric anhydride with an organic solvent such as toluene, acetonitrile, or acetone, or
The carboxylic acid can also be removed as a liquid acid chloride by reprocessing 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 as O, O'-.
Diacyl tartaric anhydride was reacted with isopropylamine for monoamidation, and then analyzed by high performance liquid chromatography (HPLC). Optical purity is O, O'-
O and O'obtained by hydrolyzing diacyl tartaric anhydride
-Diacyl tartaric acid was analyzed by HPLC using CHIRACEL OJ (manufactured by Daicel).

Example 1 4 equipped with a thermometer, a dropping funnel, a condenser and a stirrer
30.0 g of L-tartaric acid (0.2
(00 mol) and 36.1 g of toluene were charged. S generated by pulling a slight decompression from the top of the condenser with sufficient stirring
While extracting O ₂ and hydrochloric acid gas, under reflux of toluene, 68.0 g of p-toluic acid chloride was added from a dropping funnel (0.
(440 mol) was added dropwise over 2 hours. During the dropping, the bath temperature was kept 13 to 15 ° C. higher than the liquid temperature. Crystallization started when 1/2 drop of p-toluyl chloride was added. After dripping and aging under reflux for 1 hour, the bath temperature was lowered to 80 ° C, and while the liquid temperature was kept at 75 to 85 ° C, thionyl chloride 28.6 g was added.
(0.240 mol) was added dropwise over 1 hour. After dropping 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 68.1 g of toluene was added and cooled, the reaction solution was filtered and the crystals were washed with 43.0 g of toluene. White crystals O, O'-di-
67.5 g of p-toluoyl-L-tartaric anhydride (0.1
83 mol) was obtained. Yield 91.5%. The analysis results of the obtained compound were as follows. The p-toluic acid contained in the obtained crystals was 0.1%, and the optical purity was 9%.
It was 9.5% ee.

Melting point: 204 to 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
30.0 g of L-tartaric acid (0.2
(00 mol) and 36.1 g of toluene were charged. S generated by pulling a slight decompression from the top of the condenser with sufficient stirring
Keeping the liquid temperature at 110 ° C while extracting O ₂ and hydrochloric acid gas,
61.9 g (0.44 g) of benzoyl chloride was added from the dropping funnel.
0 mol) was added dropwise over 3 hours. 1 benzoyl chloride
Crystallization started when the mixture was added dropwise at / 2. Bath temperature is 122 during dripping
Keep at ~ 124 ° C. After aging for 2 hours at a liquid temperature of 110 ° C., the bath temperature was lowered to 80 ° C., and 28.6 g (0.240 mol) of thionyl chloride was added to 1 while keeping the liquid temperature at 75 to 85 ° C.
Dropped over time. After dripping, aging for 1 hour, liquid temperature 110
The mixture was stirred at 0 ° C for 6 hours. Next, 68.5 g of toluene was added and cooled. The reaction solution was filtered and the crystals were washed with toluene 40.0
washed with g. White crystals O, O after drying under reduced pressure at 50 ° C
54.8 g (0.-dibenzoyl-L-tartaric acid anhydride)
161 mol) was obtained (yield 80.5%). The benzoic acid contained in the obtained crystals was 0.2%, and the optical purity was 99.5% ee.

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

Example 3 In a 50 ml two-necked flask equipped with a condenser and a dropping funnel, DL-tartaric acid 3.0 g (0.020 mol), toluene 4.0 g, p-toluic acid chloride 8.5 g (0.05
(5 mol) was charged, and the mixture was stirred with a stirrer for 4 hours while slightly reducing the pressure from the top of the condenser at a bath temperature of 130 ° C. while extracting the generated SO ₂ and hydrochloric acid gas. Next, the bath temperature was lowered to 90 ° C., and thionyl chloride 3.0 g (0.025
Mol) and stirred for 1 hour. The bath temperature was raised to 130 ° C. and the mixture was stirred for 4 hours, then 30 g of toluene was added to completely dissolve it and slowly cooled. The reaction solution is filtered, washed, 60 ° C
After drying under reduced pressure, 5.9 g (0.016 mol) of white crystals O, O'-di-p-toluoyl-DL-tartaric acid anhydride were obtained.

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 at a bath temperature of 67 ° C. After heating for an hour, 9.5 g of thionyl chloride (0.08
(0 mol) was added dropwise with stirring for 4 hours and then stirred for 2 hours. After cooling, 3.5 g of toluene was added and stirred. The reaction solution is filtered, washed, and dried under reduced pressure at 50 ° C. to obtain white O, O.
5.6 g (0.02) of'-diacetyl-L-tartaric anhydride
6 mol) was obtained. Yield 86%, melting point 132-134
It was ℃.

Example 5 In a 50 ml two-necked flask equipped with a condenser and a dropping funnel, 6.0 g of xylene and o-chlorobenzoic acid chloride 1 were added.
1.6 g (0.066 mol) and L-tartaric acid 4.5 g
(0.030 mol) was charged. The mixture was stirred for 4.5 hours while the bath temperature was 130 ° C. and the generated SO ₂ and hydrochloric acid gas were pulled out from the top of the condenser by slight decompression. Next, the bath temperature was lowered to 90 ° C., and 5.1 g (0.0
(43 mol) was added and stirred for 1.5 hours. Furthermore, 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 is filtered, washed, and dried under reduced pressure at 50 ° C. to obtain white crystals O, O
′ -Di-o-chlorobenzoyl-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 to 169 ° C. IR: 2936, 1888, 1805, 1735, 15
90, 1249, 1142, 1131, 1057, 10
47, 952, 738 cm ^-1 NMR: 6.80 ppm (2H), 7.40-8.15 p
pm (8H)

Example 6 In a 50 ml two-necked flask equipped with a condenser and a dropping funnel, 6.0 g of xylene and 10.2 of m-toluic acid chloride.
g (0.066 mol) and 4.5 g of L-tartaric acid (0.
(030 mol) was added, the bath temperature was raised to 130 ° C., and slight decompression was applied from the top of the condenser, and the generated SO ₂ and hydrochloric acid gas were extracted, and the mixture was stirred for 3.5 hours. Then, the bath temperature was lowered to 90 ° C. and thionyl chloride 5.8 g (0.049
Mol) and stirred for 1.5 hours. Bath temperature 1
The temperature was raised to 30 ° C. and the mixture was stirred for 5 hours. 30 g of xylene was added and slowly cooled to room temperature with stirring. The reaction solution is 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) was obtained. The analysis results of the obtained compound were as follows. The reaction yield of the O, O'-di-m-toluoyl-L-tartaric anhydride contained in the reaction filtrate by HPLC analysis was 82% and the isolated 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 30 ml of D-tartaric acid was added to a 300 ml reactor equipped with a stirrer, thermometer, condenser and dropping funnel. Og (O.
200 mol) and 40 g of toluene were charged. SO generated by sufficiently reducing the pressure from the top of the condenser with sufficient stirring
While extracting ₂ and hydrochloric acid gas under reflux of toluene, 3,4-dimethylbenzoic acid chloride 74.2 was added from a dropping funnel.
g (0.440 mol) was added dropwise over 3 hours. After dripping, the mixture was aged under reflux for 2 hours, then the bath temperature was lowered to 80 ° C, and thionyl chloride 2 was added while keeping the liquid temperature at 75 to 85 ° C.
8.6 g (0.240 mol) was added dropwise over 1 hour. After completion of dropping, the mixture was aged for 1 hour and stirred under reflux of toluene for 6 hours. Next, 68.0 g of toluene was added and cooled. The reaction solution was filtered, and the crystal was washed with 40.0 g of toluene. Four
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) was obtained. The melting point was 180 to 182 ° C. and the yield was 90.1%.

[0032]

According to the present invention, high yield, high purity O,
O'-diacyl tartaric anhydride can be industrially manufactured at low cost.

Claims (2)

[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 Represents an alkyl group having 4 to 4 carbon atoms) or a lower aliphatic carboxylic acid chloride or acid anhydride represented by the following general formula (III) or (IV): [Chemical 2] (Wherein R ² and R ³ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom), and an aromatic carboxylic acid chloride or acid anhydride is reacted with tartaric acid. Process for producing O, O'-diacyl tartaric anhydride. 2. The method for producing an O, O′-diacyltartaric anhydride according to claim 1, wherein the chlorinating agent is thionyl chloride.