JP2001089431A - Method of producing tertranilic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing a tertranilic acid which neither needs a time-consuming process of distilling off acetic acid and an excessive quantity of acetic anhydride from the effluent mixture nor isolation of chemically unstable diacetyl tartrate anhydride produced. SOLUTION: This method produces a tertranilic acid, comprising steps of (1) reacting tartaric acid with acetic anhydride in an organic solvent which causes no interference with the process, (2) mixing the effluent solution with an aniline without isolating the diacetyl tartrate, produced in the above step, from the effluent, to react the effluent and aniline with each other, and (3) hydrolysis of the diacetyl tertramilic acid, produced in the above step, in the presence of an alkali, or steps of (1) reacting tartaric acid with acetic anhydride in a hydrophobic, organic solvent which causes no interference with the process, (2) mixing the effluent solution with an aniline without isolating the diacetyl tartrate, produced in the above step, from the effluent, to react the effluent and aniline with each other, and (3) hydrolysis of the diacetyl tertranilic acid, produced in the above step, by bringing the hydrophobic, organic solution of the diacetyl tertranilic acid into contact with an aqueous, alkaline solution, to produce an alkaline solution of tetranilic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing tartanyl acids. More specifically, it is useful as an optical resolving agent for racemic basic organic compounds (Japanese Patent Publication No. 57-8102).
Publication; Montzka et al., The Journal of Organic Chemistry (J. Org. Chem.) 33, 39
93 (1968); U.S. Pat. No. 3,452,086), and also relates to an industrial method for producing tartanyl acids which can be suitably used as a chiral auxiliary in optical resolution of alcohols and asymmetric organic reactions.

[0002]

2. Description of the Related Art As a method for producing tartanyl acids, L.
-Reacting tartaric acid and acetic anhydride by the action of a catalytic amount of sulfuric acid, organic sulfonic acid, etc. without the presence of other solvents (first step), reacting the resulting diacetyltartaric anhydride with anilines (Second step) to obtain diacetyltartaric acid monoanilide (diacetyltartanilic acid), and then hydrolyze it to obtain L-tertranylic acid (third step). Pressmann et al., Journal of American Chemical Society (J. Am. Chem. Soc.) 31, 13,
52 (1948); Montzka et al., The Journal.
Of Organic Chemistry (J. Org. Chem.) 3
3, 3993 (1968); JP-A-10-218847].

The method for producing diacetyltartaric anhydride in the first step is described, for example, in N. Rabjohn, edited by Organic Syntheses, Coll. Vol.
IV, John Wiley and Sons, Inc.
Wiley & Sons, INC.), New York NY, 1963, p242
And so on. According to these descriptions, tartaric acid and acetic anhydride are reacted violently in the presence of a catalytic amount of sulfuric acid, particularly in the absence of other reaction solvents, leading to boiling of the acetic acid formed. The reaction product is cooled, and the precipitated diacetyltartaric anhydride is filtered and washed on a funnel with benzene, ether, or the like to obtain diacetyltartaric anhydride. Since this compound is somewhat unstable and cannot withstand long-term storage, it is considered desirable to prepare it as needed.

In the second step, the reaction between diacetyltartaric anhydride and anilines is carried out in an inert solvent such as methylene chloride at room temperature to the reflux temperature of the solvent. Usually heated for several hours.

[0005] In the third step, the resulting diacetyltartanilates are brought into contact with an aqueous alkali solution, left for a while at room temperature to under heating to hydrolyze the acetyl group, and after acidification, are cooled with ice to precipitate. Tartaranilic acids are filtered.

[0006] According to the method described in JP-A-10-218847, in the reaction between tartaric acid and acetic anhydride in the first step, instead of the sulfuric acid catalyst required so far,
By using a mild catalyst such as an uncatalyzed or organic sulfonic acid or a Lewis acid, it is possible to directly remove by-produced acetic acid and excess acetic anhydride from the reaction mixture,
As a result, the reaction with the aniline in the second step can be immediately performed without isolating chemically unstable diacetyltartaric anhydride.

However, this method has a drawback in that a complicated operation of removing by-produced acetic acid and excess acetic anhydride from the reaction mixture of the first step after completion of the reaction in the first step is required. .

[0008]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the prior art, and requires a complicated operation of distilling off acetic acid produced as a by-product in the first step and excess acetic anhydride from a reaction mixture. It is an object of the present invention to provide a method capable of producing tartanilic acids without isolating the chemically unstable diacetyltartaric anhydride produced in the first step.

[0009]

Means for Solving the Problems After completing the reaction of the first step, the inventors of the present invention did not distill off the by-produced acetic acid and excess acetic anhydride from the reaction mixture of the first step, and furthermore, Without isolating the chemically unstable diacetyltartaric anhydride as the target compound in one step, and immediately after the completion of the first step in the same reaction vessel used in the first step, If the reaction can be carried out, the acetyl group can be immediately hydrolyzed (third step) without isolating diacetyltertranilic acids after the completion of the reaction in the second step. Under the new task that a series of reaction operations can be streamlined from the reaction to the production of tartanyl acids, the present inventors have conducted intensive studies and completed the present invention.

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, in the first step, a special solvent was previously used in the reaction between tartaric acid and acetic anhydride. However, if the reaction is carried out using an organic solvent which does not inhibit the reaction in the first step, acetic acid and excess acetic anhydride by-produced in the reaction are not distilled off from the reaction mixture, and the first step Without isolating the chemically unstable diacetyltartaric anhydride, which is the target compound in step 2, immediately after the completion of the reaction in the first step, carry out the reaction in the second step in the same solution and container used in the first step. If the reaction solution obtained in the second step is mixed with an aqueous alkali solution to hydrolyze the acetyl group, tertranyl acids useful as an optical resolving agent can be industrially produced in high yield and high purity. Standard In found that can be manufactured, thereby completing the present invention.

That is, according to the production method of the present invention, a series of reaction operations from the reaction between tartaric acid and acetic anhydride in the first step to the production of tartanyl acids in the third step can be efficiently performed. .

The gist of the present invention is that (1) tartaric acid and acetic anhydride are reacted in an organic solvent which does not inhibit the reaction, and diacetyltartaric anhydride formed from the resulting reaction solution is isolated without isolating the reaction solution. And anilines, and reacting diacetyltartaric anhydride with anilines, and alkali-hydrolyzing the resulting diacetyltartranilic acids. (2) Inhibiting the reaction Tartaric acid and acetic anhydride are reacted in a hydrophobic organic solvent not to be mixed, without isolating diacetyltartaric anhydride formed from the obtained reaction solution, mixing the reaction solution with anilines, and diacetyltartaric anhydride and Reaction with anilines, contacting the resulting aqueous solution of diacetyl tertranyl acids in a hydrophobic organic solvent with an aqueous alkali solution to convert the diacetyl tertranyl acids into (3) The method for producing tartanyl acids according to (1) or (2), wherein the aqueous solvent is hydrolyzed to obtain an aqueous alkaline solution of tartanilates, (3) the organic solvent is an aromatic organic solvent. (4) wherein the organic solvent is toluene.
(3) The method for producing tartanyl acids according to any of the above,
(5) The method for producing tartanilic acids according to any one of (1) to (4), wherein the aniline is 2-chloroaniline and the tartanilic acid is 2-chlorotartranilic acid, (6) tartaric acid and acetic anhydride (1) The method for producing tartanyl acids according to any one of (1) to (5) above, wherein the tartaric acid is L-tartaric acid or D-tartaric acid, and the tartanyl acids are L-form or D-tartaric acid. The method for producing tartanyl acids according to any one of the above (1) to (6), wherein (8) tartaric acid is L-tartaric acid, aniline is 2-chloroaniline, and tartanilic acid is L-
The present invention relates to the method for producing tertranilic acids according to any one of the above (1) to (7), which is 2-chlorotartranilic acid.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The production method of the present invention is represented, for example, by the following scheme.

[0014]

Embedded image

In the present invention, first, as a first step, tartaric acid and acetic anhydride are reacted in an organic solvent which does not inhibit the reaction.

The tartaric acid may be any of L-tartaric acid and D-tartaric acid. Further, even if it is a DL body, it does not obstruct the object of the present invention. When L-tartaric acid is used as tartaric acid, the target compound, tartanilic acids, becomes L-form, and when D-tartaric acid is used, the tartanyl acids become D-form.

The amount of acetic anhydride is stoichiometrically at least 3 moles per mole of tartaric acid in order to complete the reaction, but it is usually from 3.0 to 3.3 moles. Is preferred. When the aniline used in the second step is expensive, the stoichiometric amount may be less than the stoichiometric amount.

In the reaction between tartaric acid and acetic anhydride, a catalyst such as sulfuric acid, organic sulfonic acid and Lewis acid can be used. However, when sulfuric acid is used as a catalyst,
When the resulting diacetyltartaric anhydride is chemically unstable and a strongly acidic substance such as sulfuric acid or Lewis acid is used, the corresponding amount of aniline is converted to a salt (sulfuric acid) in the next reaction in the second step. Salts, etc.) and no longer participate in the reaction, and consequently it is necessary to add an excess of anilines. Therefore, in the present invention, it is preferable that no catalyst is used.

The term "organic solvent which does not inhibit the reaction" as used herein means a solvent which does not inhibit the reaction in the first step and the second step. Among these organic solvents, the hydrophobic organic solvent is used in the alkaline hydrolysis reaction in the third step.
It is preferable from the viewpoint that the liquid separation operation with an alkaline aqueous solution can be easily performed, and at that time impurities can be left in the organic layer to easily separate the organic layer and the hydrolysis product. As the hydrophobic organic solvent, benzene,
Aromatic solvents such as chlorobenzene, toluene, and xylene, among which toluene can be particularly preferably used. Incidentally, acetic anhydride is not naturally the organic solvent mentioned here. The amount of the organic solvent is not particularly limited, but is usually preferably about 2 to 10 parts by weight per 1 part by weight of tartaric acid.

The reaction between tartaric acid and acetic anhydride is usually carried out at 70
It is desirable to carry out at a temperature of at least 80 ° C, preferably at 80 to 120 ° C. Since the reaction between tartaric acid and acetic anhydride is performed in the organic solvent, the reaction temperature can be controlled by refluxing the reaction.

After the completion of the reaction between tartaric acid and acetic anhydride, the resulting diacetyltartaric anhydride was isolated from the reaction solution,
The reaction solution is used as it is for the second step, the reaction between diacetyltartaric anhydride and anilines.

In the reaction between diacetyltartaric anhydride and anilines in the second step, acetic acid by-produced in the first step and residual acetic anhydride are distilled off from the reaction solution obtained in the first step. Instead, the reaction solution and anilines are mixed as they are to react diacetyltartaric anhydride with anilines.

As the anilines, for example, aniline,
Examples thereof include halogen-substituted aniline derivatives such as 2-chloroaniline and the like, and these can be used alone or in combination of two or more. Among them, 2-chloroaniline can be suitably used in the present invention.
When 2-chloroaniline is used as the aniline, 2-chlorotartranilic acid is obtained as the target compound of the present invention.

Although the amount of the aniline is not particularly limited, usually, the amount of the aniline is
1.05 to 1.1 mol. When expensive anilines are used, the aniline may be used in an amount of 1 mol or less per 1 mol of diacetyltartaric anhydride produced in consideration of economy.

In the case where a strongly acidic substance such as sulfuric acid or Lewis acid is used as a catalyst in the first step, the catalyst undergoes a neutralization reaction with anilines to form a salt. The amount of the class is preferably determined in consideration of the amount used in the neutralization reaction.

After the 2-chloroaniline is mixed with the reaction solution obtained in the first step and stirred for several hours, the reaction between diacetyltartaric anhydride and the aniline can be completed.

The reaction temperature is usually preferably from room temperature to 50 ° C. At the time of the reaction, there is no remarkable heat generation, but if necessary, cooling with running water or the like is possible.

The time required for the reaction is not particularly limited, and is usually about 10 minutes to 2 hours.

Next, after the completion of the reaction between diacetyltartaric anhydride and anilines in the second step,
Performs alkaline hydrolysis of diacetyltertranyl acids.

The hydrolysis of diacetyl tertranyl acids is performed by isolating the diacetyl tertranyl acids from the reaction solution obtained in the second step by, for example, distilling off the organic solvent, and then distilling the reaction mixture with an alcohol such as methanol. It can be carried out by alkali hydrolysis using a caustic alkali solution, a caustic alkali aqueous solution or the like. Examples of the caustic alkali include sodium hydroxide, potassium hydroxide and the like.

When a hydrophobic organic solvent is used as the organic solvent in the first step and the second step, the diacetyl tertranyl acids formed in the second step are not isolated from the reaction solution, but are separated from the excess alkali aqueous solution. By contact, the acetyl group can be hydrolyzed as it is. At that time, various impurities and reaction by-products remain in the organic solvent layer,
High purity tertranyl acids can be precipitated without further purification only by acid precipitation of the alkaline aqueous solution.

When the hydrolysis is carried out by alkali hydrolysis, the amount of the caustic alkali used in the first step is taken into consideration in consideration of the hydrolysis of the acetyl group, the hydrolysis of the residual acetic anhydride and the neutralization of the generated tertranyl acids. The minimum amount calculated from the amount of acetic anhydride used is required. Usually, the amount of the caustic is preferably 7 to 8 mol per 1 mol of tartaric acid from the viewpoint of preventing the decomposition of the amide bond of the generated tartanyl acids.

As a method for hydrolyzing diacetyl tertranilic acids, a method in which diacetyl tertranilic acids are added to an aqueous alkali solution to perform hydrolysis, and a method in which an aqueous alkali solution is added to diacetyl tertranilic acids to perform hydrolysis. Method. Among these methods, the former method is apt to be accompanied by hydrolysis of an amide bond due to strong alkaline contact, but has the advantage of a high hydrolysis rate. The latter method has a slow hydrolysis rate and requires a little heating, but has the advantage of requiring only one reaction vessel and is less likely to cause side reactions.

The hydrolysis of diacetyl tertranyl acids can be usually carried out at a temperature of about 40 to 70 ° C.

The isolation of tartanilic acids can be usually carried out by acidifying a hydrolysis solution obtained by hydrolysis of diacetyl tartanilic acids with concentrated hydrochloric acid or the like, and collecting the precipitated tartanilic acids by filtration.

In the case of hydrolysis with an alcohol-caustic alkali, an aqueous solution is prepared by dissolving an alkali metal salt of tertranyl acids obtained by distilling an organic solvent from the hydrolysis solution into water, and adding an aqueous solution based on the calculated amount. It is also preferable to add a slight excess of concentrated hydrochloric acid or the like for acid precipitation.

When the acetyl group of diacetyltertranyl acids is hydrolyzed in an aqueous alkaline solution, it is preferable to add an excess of concentrated hydrochloric acid or the like to the reaction solution after the completion of the hydrolysis reaction and perform acid precipitation.

The produced tartanilic acids may be isolated by filtration or the like and then purified by recrystallization or the like. However, in the first and second steps, a hydrophobic organic solvent is used to prepare acetyl tartranyl acid. When the acids are brought into contact with an aqueous alkali solution without being isolated from the reaction solution and the acetyl group is hydrolyzed as it is, as described above, various impurities and reaction by-products remain in the organic solvent layer. The tartranilic acids isolated by acid precipitation have high purity and do not require further purification. Further, the number of times of recrystallization can be greatly reduced even when further purification is performed, so that the purification operation can be greatly simplified.

Thus, tartanilic acids are obtained. In the present invention, tartaric acid is L-tartaric acid, aniline is 2-chloroaniline, and tartanilic acid is L-2-chlorotartranilic acid. , The L-
2-Chlorotartranilic acid is a useful intermediate of paroxetine, trans- (±)-(3S, 4R)-(4-
It can be suitably used for optically resolving the (-) form from (fluorophenyl) -3-hydroxymethylpiperidine.

[0040]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples.

Example 1 [Production of L-2-chlorotartranilic acid] To 30.02 g (0.2 mol) of L-tartaric acid were added 150 ml of toluene and 61.26 g (0.6 mol) of acetic anhydride, and the mixture was refluxed for 40 minutes. Cool, inoculate to a slurry solution, at 38-46 ° C 2-
Chloroaniline (28.07 g, 0.22 mol) was added dropwise to this slurry solution over 15 minutes, and after 2 hours, completion of the reaction was confirmed by high performance liquid chromatography (HPLC) to obtain a reaction solution.

Separately, an aqueous solution was prepared by dissolving 81.83 g (1.4 mol) of 96% potassium hydroxide in 600 ml of water.

Next, the reaction solution obtained above was dropped into this aqueous solution at 21 to 25 ° C. over 17 minutes, and after 30 minutes, the completion of the reaction was confirmed by HPLC, and the temperature was raised to about 50 ° C. Warm, 96
PH adjusted to 11.8-12.0 with 2.34g of potassium hydroxide,
Separation was performed to remove impurities from the toluene layer, thereby obtaining an aqueous layer.

The obtained aqueous layer was charged with 152.10 g of 35% hydrochloric acid (1.46 g).
Mol) was added dropwise over about 25 minutes at about 50 ° C, allowed to precipitate out, cooled, aged at 3-5 ° C for 1 hour, filtered, washed with 240 ml of cold water, dried and dried to give L-2-chlorotartra. 34.26 g of nitric acid was obtained (66.0% yield).

Example 2 [Production of L-2-chlorotartranilic acid] To 37.52 g (0.25 mol) of L-tartaric acid was added 93.8 ml of toluene.
At about 90 ° C., 76.57 g (0.75 mol) of acetic anhydride was added, and 88-10
After reacting at 9 ° C for 1 hour and 20 minutes, cool, inoculate to form a slurry solution, and at 43 to 45 ° C, 35.08 g of 2-chloroaniline.
(0.275 mol) was added dropwise over 15 minutes, and after 30 minutes, completion of the reaction was confirmed by HPLC.

To this reaction solution, 431.5 g of water was added, and a further 25%
288.0 g (1.8 mol) of an aqueous sodium hydroxide solution was added dropwise at 57 to 63 ° C over 1 hour, the pH was adjusted to 10.5 ± 0.5, and after 30 minutes had passed, the completion of the reaction was confirmed by HPLC, and then liquid separation was performed. The impurities were removed to the toluene layer by the above to obtain an aqueous layer.

To this aqueous layer, 190.11 g (1.82 mol) of 35% hydrochloric acid was added dropwise at about 60 ° C. over 5 minutes to cause acid precipitation, cooling and
After aging at 5 ° C for 30 minutes, the mixture was filtered, washed with 112.6 ml of cold water,
Drying yielded 48.68 g of L-2-chlorotartranilic acid (yield
75.0%).

The L-2-chlorotertranyl acid obtained in Examples 1 and 2 had the following physical properties. Optical rotation [α] ²⁰ _D +98 to + 102 ° Melting point 180 to 183 ° C

[0049]

According to the method for producing tartanyl acids of the present invention, in the first step, no special solvent has been used before in the reaction between tartaric acid and acetic anhydride. In the present invention, since an organic solvent that does not inhibit the reaction is used, acetic acid by-produced in the reaction and excess acetic anhydride are not distilled off from the reaction mixture, and the unstable product which is a reaction product in this reaction is not removed. Without isolating diacetyltartaric anhydride, use the reaction solution of the first step as it is, and in the same reaction vessel as in the first step, immediately after the completion of the first step, diacetyltartaric anhydride and aniline in the second step. If the reaction solution is brought into contact with an aqueous alkali solution to hydrolyze the acetyl group of diacetyltartranyl acids, the reaction can be carried out in a high yield and a high purity. Handling easily, the effect that can be produced on an industrial scale useful tartranilic acids as an optical resolution agent is exerted Te.

Therefore, according to the production method of the present invention, there is an excellent effect that a series of reaction operations from the reaction between tartaric acid and acetic anhydride to the production of tartanyl acids can be rationalized.

Claims (8)

[Claims] 1. A reaction between tartaric acid and acetic anhydride in an organic solvent which does not inhibit the reaction, and mixing of the reaction solution with anilines without isolating diacetyltartaric anhydride formed from the resulting reaction solution. A process for producing tartaranilic acids, which comprises reacting diacetyltartaric anhydride with anilines and subjecting the resulting diacetyltartranilic acids to alkaline hydrolysis. 2. A reaction between tartaric acid and acetic anhydride in a hydrophobic organic solvent which does not hinder the reaction, and without isolating diacetyltartaric anhydride formed from the resulting reaction solution, the reaction solution and anilines are separated. Mixing, reacting diacetyl tartaric anhydride and anilines, contacting the resulting hydrophobic organic solvent solution of diacetyl tartranyl acids with an aqueous alkali solution, hydrolyzing diacetyl tartranyl acids, and producing tartranyl acids. A method for producing tartranyl acids, comprising obtaining an aqueous alkali solution. 3. The method for producing tartanyl acids according to claim 1, wherein the organic solvent is an aromatic organic solvent. 4. The method according to claim 1, wherein the organic solvent is toluene.
The method for producing any of the tartanyl acids described in any of the above. 5. The method according to claim 1, wherein the aniline is 2-chloroaniline and the tertranylic acid is 2-chlorotartranilic acid. 6. The method for producing tartanyl acids according to claim 1, wherein the reaction between tartaric acid and acetic anhydride is carried out without a catalyst. 7. The method according to claim 1, wherein the tartaric acid is L-tartaric acid or D-tartaric acid, and the tartanyl acids are L-form or D-form. 8. The tartaric acid is L-tartaric acid, the anilines are 2-chloroaniline, and the tartanyl acids are L-tartaric acids.
The method for producing tartanyl acids according to any one of claims 1 to 7, which is 2-chlorotartranilic acid.