Methods for preparing nateglinide crystals

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to methods for preparing N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide). Method for preparing nateglinide crystals of H-type is carried out by addition of inorganic acid to reaction mixture containing nateglinide to provide its acidification. The reaction mixture is prepared by interaction of trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent consisting of a ketone solvent and water in the presence of alkali. The ratio of water to ketone solvent is from 10:1 to 0.5:1. Temperature of the mixture is brought about to 58-72°C and concentration of ketone solvent - up to value above 8 wt.-% and less 22 wt.-% for carrying out precipitation of nateglinide crystals. Invention proposes variant for preparing nateglinide crystals of H-type. Also, invention proposes crystals of nateglinide of H-type showing average value of longitudinal axis from 1 to 5 mm and that for transverse axis from 0.1 to 0.5 mm. Invention provides enhancing effectiveness in isolation of nateglinide crystals.

EFFECT: improved preparing methods.

10 cl, 1 tbl, 13 ex

 

Background of the invention

The present invention relates to methods of producing N-(TRANS-4-isopropylcyclohexane)-D-phenylalanine (its common name of nateglinide and then in the description it is called as nateglinide), which is suitable as a therapeutic agent for diabetes. More specifically, the invention relates to advantageous methods of crystallization of nateglinide.

It is known that nateglinide is suitable as a therapeutic agent for diabetes, because it effectively reduces the concentration of glucose in the blood when administered orally (Japanese patent publication No. Hei 4-15221).

It is also known that nateglinide has polymorphous modifications of the crystals of which are useful crystals of N-type (Japan patent No. 2508949).

On the other hand, when TRANS-4-isopropylcyclohexane and D-phenylalanine interacted in a mixed solvent consisting of a ketone solvent and water, for the synthesis of nateglinide, and in accordance with the method described in Japan patent No. 2508949, the reaction mixture was precipitated crystals nateglinide N-type synthesized crystals were small and when using filtering devices available for industrial scale, required too much time to complete the separation of their Phi is Tricia. Therefore, it was found that the above method is not suitable in practice.

Description of the invention

The purpose of this invention is the provision of methods of deposition of crystals nateglinide that can be extracted on an industrial scale from the reaction mixture containing nateglinide obtained by the interaction of TRANS-4-isopropylcyclohexane with D-phenylalanine.

To address these problems, the applicant has conducted intensive studies and found that the crystals that can be filtered on an industrial scale, can be separated by using as the reaction solvent mixed solvent consisting of a ketone solvent and water, neutralizing the reaction mixture and then select the range of the crystallization temperature and/or the ratio in the mixture of ketone solvent and water. The present invention was created based on this discovery.

Thus, the present invention provides methods for obtaining crystals nateglinide, including stage add acid (acid) to the reaction mixture containing nateglinide, so that it became acidic, while the reaction mixture is produced by the interaction of TRANS-4-isopropylcyclohexane with D-phenylalanine in a mixed solvent consisting of economicactivities and water, in the presence of alkali; and then raising the temperature of the mixture to 58-72°and the concentration of the ketone solvent to a value of more than 8 wt.% and less than 22 wt.% for carrying out the deposition of crystals nateglinide.

The present invention also provides crystals of nateglinide obtained by the above method.

The best option of carrying out the invention

The reaction mixture containing nateglinide, which is used for crystallization of the present invention, was obtained as follows. First D-phenylalanine is dissolved in an aqueous solution of alkali such as potassium hydroxide, to the solution was added the ketone solvent(s). Then for the reaction of Schotten's-Bauman gradually add TRANS-4-isopropylcyclohexane. After completion of the reaction, the reaction mixture is acidified by adding an acid (acid).

Used in the reaction of D-phenylalanine receive the following way. First, DL-phenylalanine, obtained by the method of synthesis is subjected to, for example, acetylation for the synthesis of N-acetyl-DL-phenylalanine. Then, N-acetyl-DL-phenylalanine is subjected to enzymatic degradation by acylate obtaining neprevzoidennogo N-acetyl-D-phenylalanine. Then nepovsemestnoy N-acetyl-D-phenylalanine synthetically hydrolyzing with obtaining D-phenylalanine. It can also be obtained above is this way, except that obtained by the fermentation of L-phenylalanine is subjected to racemization for the synthesis of DL-phenylalanine.

Used in the reaction of TRANS-4-isopropylcyclohexane produced by interaction of TRANS-4-isopropylcyclohexane acid, which is the corresponding carboxylic acid, for example, chloride, phosphorus (Non-examination of the patent application of Japan No. Hei-7-17899). It can also be obtained from a conventional method for the synthesis of carboxylic acids from carboxylic acids, such as reaction with thionyl chloride.

The molar ratio of the reacting substances, i.e. D-phenylalanine to TRANS-4-isopropylcyclohexane, in the above reaction Schotten's-Bauman is preferably from 0.5:1 to 2:1 and more preferably from 0.9:1 to 1.5:1. The concentration of D-phenylalanine and TRANS-4-isopropylcyclohexane in the reaction is preferably from 2 wt.% up to 15 wt.% in the calculation of the concentration of D-phenylalanine, if the molar ratio of each substance is in the given range.

To prevent side reactions, the reaction temperature is preferably 20°s or less and more preferably 15°s or less.

The alkali is preferably potassium hydroxide, but may also be used hydroxide, other alkali metal, such as Hydra is xed sodium, or other alkaline substance. Particularly preferably, the pH of the mixture in the reaction was maintained in the range from 10 to 13.9. In the reaction mixture to maintain the pH in the specified range can be added to any other alkaline chemicals.

As the ketone solvent used in the above reaction Schotten's-Bauman and crystallization from the reaction mixture, can be used acetone, methyl ethyl ketone and the like solvents. The solvent in the reaction and crystallization must be the same, because after crystallization and separation of the solvent is collected. Therefore, from the point of view of the yield of the reaction and treatment, most preferred is acetone.

In addition, from the viewpoint of the yield of the reaction, the ratio of water to the ketone solvent (mass ratio) should be from 10:1 to 0.5:1 and preferably from 6:1 to 1:1. For reaction usually important in this reaction is a ketone(s) solvent(s). However, a large amount of acetone in the reaction causes the formation of a large proportion of the by-product. Therefore, it is preferable that the amount of ketone solvent was in the reaction is relatively small.

Target crystals nateglinide can be obtained by crystallization of the reaction mixture, which is acidified by the addition of acid p is after completing the above, the reaction of the Schotten's-Bauman. Added to the reaction mixture, the acid can be selected from any acids that make the reaction mixture acidic. Can be used hydrochloric acid, sulfuric acid and the like acid is preferred is hydrochloric acid. the pH of crystallization of the mixture must be acidic and it is preferably 2 or less and more preferably 1.5 or less.

To separate the target crystals of the present invention, i.e. leavingtruman crystals, the concentration of the ketone solvent in the reaction mixture should be adjusted. As to the above reaction mixture is added the acid(s)to bring the concentration of the ketone solvent in the crystallization mixture to the desired values ketone solvent as a rule must be added to the reaction mixture. Acceptable are two ways: add acid (acid) to the reaction mixture and adding the reaction mixture to acid(s). In addition, acceptable as adding a ketone solvent after acidification of the mixture with acid(s)and add acid (acid) after addition of the ketone solvent.

For the above reasons, the ratio of ketone solvent to water in the reaction mixture generally lower relationship just ketone solvent, necessary operacii crystallization of the present invention. Therefore, when carrying out the present invention the concentration of the ketone solvent is often preferably adjusted by adding additional quantities of ketone solvent after neutralization of the reaction mixture.

The crystals are precipitated by operation of crystallization, and the concentration of the ketone solvent, if necessary, adjusted to values of more than 8 wt.% and less than 22 wt.% and preferably from 12 wt.% up to 16 wt.% and the crystallization temperature is in the range from 58°to 72°C. After crystallization temperature is set at the required value can be added to the seed crystal. Crystallization can be carried out under stirring or during quiet standing. Crystallization is carried out under stirring, provides easier operation, following after crystallization.

When the present invention the concentration of the ketone solvent is more than 8 wt.% and less than 22 wt.%, the precipitated crystals are easily filtered out and filtering can be completed within a short period of time on an industrial scale.

In addition, when the crystallization temperature is between 58°to 72°With separated crystals are easily filtered out and filtering can be completed within a short period of time in industrial wt is the tab.

It is most preferable to conduct the reaction so that the concentration of the ketone solvent in the reaction mixture ranged from 10 wt.% up to 20 wt.% and then, after neutralization of the reaction mixture of ketone solvent so that the concentration of the ketone solvent in the mixture was in the range of from 12 wt.% up to 16 wt.%.

The time required for crystallization (maturing time crystals), is from 10 minutes to 24 hours and preferably from 30 minutes to about 3 hours.

When carrying out the crystallization at the temperature and concentration of the ketone solvent, as defined in the present invention, the deposited crystals, the formation of bundles of numerous needle-shaped crystals, as well as regular crystals. However, the crystals of the present invention can be obtained in the form of more grown up, besieged and easily filterable crystals having a middle longitudinal axis (average longitudinal diameter of from 1 mm to 5 mm and the average transverse axis (average transverse diameter) of 0.1 to 0.5 mm.

Formed crystals can be precipitated from the mother liquor by centrifuge and similar funds for their Department.

Obtained in the present invention, the crystals can be filtered in a short period of time, in particular by means of a separator used is about on an industrial scale. In addition, the crystals after filtration sticks fewer stock solution and therefore can be effectively obtained crystals with a high degree of purification.

Crystals nateglinide obtained in the above manner, in the case of their use as the main ingredient in pharmaceutical preparations, can be recrystallized for further purification in accordance, for example, with a method of Japan patent No. 2508949.

The present invention is additionally illustrated by the following examples and comparative examples, which in no way limit the invention.

Example 1

24,36 g D-phenylalanine was dissolved in 155 g of water and for 93.9 g of 10 wt.% an aqueous solution of KOH. Added of 70.4 g of acetone and then the solution for 1.5 h were additionally added 22,77 g of TRANS-4-isopropylcyclohexane. Meanwhile, to maintain the pH of the mixture is between 13.7 to 14.3 to the reaction mixture were added 71,8 g 10 wt.% an aqueous solution of KOH and the reaction mixture was cooled to maintain a constant temperature of 15°s or less. Thus received 438,2 g of acidified reaction mixture containing nateglinide.

For regulating the concentration of the mixture of part (202,5 g) acylated reaction mixture was added of 12.6 ml of water and 11.0 g of acetone. For 1.5 h, to the mixture was added a mixture consisting of 120 g of 35 wt.% aqueous HCl and 60.2 g of water. The obtained crystallized suspension (concentration of acetone: a 14.6 wt.%) was stirred at 66°With during the night. After deposition of the suspension stirring was stopped, precipitated crystals were separated and examined under a microscope. Crystals were obtained in the form of bundles of needle-shaped crystals. Crystals in the form of beams had an average width of about 0.2 mm and a length of about 2 mm When the analysis of the obtained crystals in the powder x-ray diffractometer, it was determined that the diffraction peaks: 8,1°, 13,1°and 19.6° and 19.9° (2θ) and, therefore, it was confirmed the existence of crystals in the form of crystals of N-type.

Comparative example 1

Acylated reaction mixture obtained by the method in example 1, were mixed and were led at 45°With 8 wt.% acetone during the night. The resulting suspension had no ability to sedimentation. As a result of its observation under a microscope, it was found that needle crystals formed beams, but each needle-like crystal was smaller and the degree of Pochtovaya was less than the degree of Pochtovaya crystals in example 1. The obtained crystals in the form of beams had an average width of about 0.02 mm and a length of about 0.1 mm

Comparative example 2

In acidified reaction mixture obtained by the method of example 1, and drove concentration of Aceto is a to 22 wt.% and was stirred at 73° With during the night. Formed mixture was in the form of oil and not crystallized.

Examples 2-11 and comparative examples 3-13

Following the suspensions of examples 2-10 and comparative examples 3 to 12 were obtained by reaction and crystallization in example 1, except that the concentration of acetone and crystallization temperature were changed. Investigated the conditions for the deposition of crystals and the crystals were examined under a microscope.

Example 12

(1 assess the capacity of the Department: the concentration of acetone 14%, a crystallization temperature of 65°)

38,14 kg D-phenylalanine, 40.1 per kg of TRANS-4-isopropylcyclohexane, the appropriate amount of water, 10 wt.% an aqueous solution of KOH and acetone was used in the ratio given in example 1 for the reaction of acylation in the mold having a capacity of 2 CL. As a result received 728 kg acylated reaction mixture containing nateglinide. The resulting reaction mixture was added to the mixture 249 liters of water and 45,1 kg 35 wt.% aqueous HCl. Then to bring the total concentration of acetone of up to 14.4 wt.% additionally added 62 l of acetone. The mixture was stirred and subjected to aging at a temperature of from 63°to 65°C for 17 hours and then was cooled to 30°C. monitoring the resulting suspension under the microscope it was found sticking needle Krista is fishing. The total number of suspensions, equal to about 1200 l, divided the three times, i.e. each time about 400 l, solid and liquid centrifugal precipitator, the diameter of the basket which was 36 inches. After separating the suspension into solid and liquid, each of the crystals in the precipitant was washed with 150 l of water. On average took about 16 minutes to obtain a filtrate after infusion rinse water.

In the three divisions received generally 104,9 kg of wet crystals. Their average loss on drying at 105°C for 2 hours was 35.9 per cent.

Comparative example 13

(2 assess the ability of division: the concentration of acetone and 8 wt.%, crystallization temperature of 45°)

In the acylation of D-phenylalanine in the same scale and using the equipment of example 11 was obtained 727 kg acylated reaction mixture containing nateglinide. The concentration of acetone in the mixture brought up to 8 wt.%, mixed and subjected to aging at 45°C for 17 hours and then was cooled to 30°C. monitoring the resulting suspension under the microscope, it was revealed the formation of needle-shaped crystals that stick together with difficulty.

The total number of suspensions, equal to about 1200 l, divided four times, i.e. each time about 300 l, solid and liquid centrifugal precipitator. Each is first obtained from the separation of the crystals were washed with 110 l of water. On average took about 30 minutes to obtain a filtrate after infusion rinse water.

In the four divisions received generally 162,3 kg of wet crystals. Their average loss on drying was 60.8 per cent.

All the results of examples 2-11 and comparative examples 3-13 shown in table 1.

Table 1
The concentration of acetone (wt.%)The crystallization temperature (°)PrecipitationObservation under the microscope
Comparative example 3845NoThe same as in Srpm
Comparative example 4855NoThe same as in Srpm
Example 21070YesThe same as in Note 1
Comparative example 511.557NoThe same as in Srpm
Example 31265YesThe same as in Note 1
Example 41270YesThe same as in Note 1
Comparative examples is 6 1355NoThe same as in Srpm
Example 51360YesThe same as in Note 1
Comparative example 713.573(in the form of oil)(in the form of oil)
Comparative example 81450NoThe same as in Srpm
Example 61472YesThe same as in Note 1
Comparative example 914.573(in the form of oil)(in the form of oil)
Comparative example 1014.578(in the form of oil)(in the form of oil)
Example 714.666YesThe same as in Note 1
Example 81560YesThe same as in Note 1
Example 91665YesThe same as in Note 1
Example 101667YesThe same as in Note 1
Comparative example 11 2050NoThe same as in Srpm
Example 112058YesThe same as in Note 1
Comparative example 122265(in the form of oil)(in the form of oil)
Comparative example 132273(in the form of oil)(in the form of oil)

From the results of the above examples and comparative examples, it is obvious that under the conditions of crystallization in the methods of obtaining crystals of the present invention are deposited easily filterable crystals from the reaction mixture and can be efficiently selected crystals nateglinide when they get on an industrial scale.

1. The method of obtaining crystals nateglinide N-type, including the stage of adding an inorganic acid to the reaction mixture containing nateglinide to make it acidic, while the reaction mixture is produced by the interaction of TRANS-4-isopropylcyclohexane with D-phenylalanine in a mixed solvent consisting of a ketone solvent and water having a ratio of water to the ketone solvent is from 10:1 to 0.5:1, PR is the presence of alkali; then bring the temperature of the mixture to 58-72°and the concentration of the ketone solvent to a value of more than 8 wt.% and less than 22 wt.% for carrying out the deposition of crystals nateglinide N-type.

2. The method according to claim 1, where the concentration of the ketone solvent is adjusted by adding a ketone solvent to the reaction mixture.

3. The method according to claim 1, where the concentration of the ketone solvent is adjusted by the addition of acetone to the acidified reaction mixture.

4. The method according to claim 1, where all of the ketone solvents are acetone and the concentration of acetone in the reaction mixture during crystallization is from 12 wt.% up to 16 wt.%.

5. The method according to claim 1, where the crystals nateglinide N-type have an average long axis equal to from 1 mm to 5 mm, and the average transverse axis, equal to from 0.1 mm to 0.5 mm

6. The method of obtaining crystals nateglinide N-type, including the stage of adding an inorganic acid to the reaction mixture containing nateglinide to make it acidic, while the reaction mixture is produced by the interaction of TRANS-4-isopropylcyclohexane with D-phenylalanine in a mixed solvent consisting of acetone and water with the ratio of water to the acetone from 10:1 to 0.5:1, in the presence of alkali; then raising the temperature of the mixture to 58-72°and the concentration of acetone to the value of more than 8 wt.% and less than 22 wt.% for holding academicisation of nateglinide N-type.

7. The method according to claim 6, where the concentration of acetone was adjusted by the addition of acetone to the acidified reaction mixture.

8. The method according to claim 6, where the concentration of acetone in the reaction mixture during crystallization is from 12 wt.% up to 16 wt.%.

9. The method according to claim 6, where the crystals nateglinide N-type have an average long axis equal to from 1 mm to 5 mm, and the average transverse axis, equal to from 0.1 mm to 0.5 mm

10. Crystals nateglinide N-type having a middle longitudinal axis, equal to from 1 mm to 5 mm, and the average transverse axis, equal to from 0.1 mm to 0.5 mm, obtained by the method according to claim 1.



 

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SUBSTANCE: invention relates to methods for preparing N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide). Method for preparing nateglinide crystals of H-type is carried out by addition of inorganic acid to reaction mixture containing nateglinide to provide its acidification. The reaction mixture is prepared by interaction of trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent consisting of a ketone solvent and water in the presence of alkali. The ratio of water to ketone solvent is from 10:1 to 0.5:1. Temperature of the mixture is brought about to 58-72°C and concentration of ketone solvent - up to value above 8 wt.-% and less 22 wt.-% for carrying out precipitation of nateglinide crystals. Invention proposes variant for preparing nateglinide crystals of H-type. Also, invention proposes crystals of nateglinide of H-type showing average value of longitudinal axis from 1 to 5 mm and that for transverse axis from 0.1 to 0.5 mm. Invention provides enhancing effectiveness in isolation of nateglinide crystals.

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