CN115010703A - Ritasol morpholine salt and preparation method and application thereof - Google Patents

Abstract

The invention relates to the technical field of drug synthesis, and particularly relates to a sitagliptin salt, and a preparation method and application thereof. The provided salt of sitagliptin can be dissociated in trace acidic water to remove morpholine, so that high-purity sitagliptin is obtained, the yield is high, the operation is simple, and the generation of waste solvent and waste water in the process of purifying the sitagliptin can be greatly reduced. The preparation method of the sitagliptin morpholine salt provided by the invention is easy to implement, and the prepared sitagliptin morpholine salt has high yield and high purity. In the process of purifying the sitagliptin, the crude product of the sitagliptin is firstly prepared into the sitagliptin morpholine salt, and then the simple acid hydrolysis separation is carried out, so that the process of purifying the sitagliptin can be greatly simplified, the generation of waste solvents and waste water is reduced, the reaction continuity is strong, and the process is safe and controllable.

Description

A kind of lipalast morpholine salt and its preparation method and application

technical field

The invention belongs to the technical field of drug synthesis, and in particular relates to a ritamilast morpholine salt and a preparation method and application thereof.

Background technique

Litalast is a lymphocyte function-associated antigen 1 (LFA-1) antagonist drug for the treatment of dry eye disease.

The preparation process of ritamilast involves its purification, but there are few related literature reports at present, and there are mainly two methods at present. The first method is to directly purify ritamilast in a certain solvent, such as acetonitrile or butanone, but due to its unique physical and chemical properties, this method is easy to form viscous solids during the crystallization process, which cannot be industrially produced. ; If the method of dust separation is adopted, the solid state is good, but the purification effect is poor, and multiple crystallizations are required. The second method is to form a dicyclohexylamine salt into a salt and purify it. Although the purity of the dicyclohexylamine salt is high, the post-processing is very complicated when the dicyclohexylamine salt is dissociated. : The hydrochloride of dicyclohexylamine is insoluble in water and cannot be separated and purified; if phosphoric acid, sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid are used as acidic media to dissociate the salt, due to the dicyclohexylamine salt of these acids It has a certain solubility in the solvent. Even after repeated large-dose extractions, some dicyclohexylamine will remain in the obtained product; if the salt is hydrolyzed under alkaline conditions, a large amount of solvent extraction is required to remove the dicyclohexylamine. amine, and then adjust the acid to precipitate ritamilast, and the residue on ignition of the obtained product exceeds the standard. Therefore, if one wants to obtain an API with qualified residues on ignition, dicyclohexylamine, and solvent residues, post-processing will be very cumbersome, and the whole process will generate a large amount of waste acid aqueous solution and waste organic solvent, which is not conducive to scale-up production.

SUMMARY OF THE INVENTION

In view of the above technical problems, the present invention provides a lipalast morpholine salt and a preparation method and application thereof. The lipastat morpholine salt can be dissociated into a lipamilast in a trace amount of acid water, which can greatly reduce the generation of waste solvent and waste water in the lipalast purification process, and is easy to operate. The preparation method of the tripalast morpholine salt provided by the present invention is easy to implement, and the tripalast morpholine salt of high purity can be prepared. The lipastat morpholine salt and the preparation method thereof can be used for industrial purification of the lipalast crude product.

In order to achieve the above-mentioned purpose of the invention, the embodiment of the present invention adopts the following technical solutions:

A first aspect, the present invention provides a kind of Litalast morpholine salt, and its structural formula is as shown in formula I:

The post-processing of the lipastat morpholine salt is simple, the morpholine can be removed in a trace amount of acidic water, and the lipalast morpholine can be dissociated without using a large-capacity organic solvent, and is more suitable for industrial production. In the purification process of ritamilast, the crude lipalast morpholine salt is prepared first, and then the acid hydrolysis is carried out, which greatly simplifies the purification process of ritamilast, and can obtain pharmaceutical grade of high-purity ritamilast.

In the second aspect, the present invention provides a method for preparing the above-mentioned morpholine salt of lipalast, which specifically includes the following operations: dissolving the crude product of lipalast in a mixed solution of an organic solvent and water or in an organic solvent, adding morpholine , and the solid-liquid separation was performed after the solid was precipitated to obtain the lipalast morpholine salt.

The method is easy to operate, and the obtained crude product of the lipalast morpholine salt has high purity and high yield. The method is used for the preparation and purification of lipalast, which can greatly reduce the amount of solvent, simplify the operation and shorten the production cycle.

Optionally, after adding morpholine, a small amount of ripamilast morpholine salt can be added as a seed crystal to speed up the precipitation of ripamilast morpholine salt in the reaction.

In conjunction with the second aspect, the solvent includes at least one of isopropanol, ethanol, methanol, tetrahydrofuran, butanone, methyl butyl ketone, acetone, acetonitrile, isopropyl acetate and N,N-dimethylformamide kind.

Preferably, the volume ratio of the mixed solution of the organic solvent and water or the volume of the organic solvent to the mass of the crude product of lipalast is 4-30:1 (ml:g).

Preferably, in the mixed solution of the organic solvent and water, the mass of the water does not exceed 3 times the mass of the crude lipalast product.

In combination with the second aspect, the ratio of the molar amount of the morpholine to the molar amount of the crude lipalast product is 0.5-10:1. Among them, the molar amount of the crude ritamilast=the mass of the crude ritamilast ÷ the molecular weight of the ritamilast.

In combination with the second aspect, the preparation method further includes further purifying the product obtained by the solid-liquid separation, so as to further improve the product purity.

Preferably, the purification method is as follows: dissolving the crude product of the lipastat morpholine salt in an organic solvent, heating to 55-65° C., stirring and reacting for 30-60 min; lowering to room temperature, filtering the deritamilast Refined product of morpholine salt.

In a third aspect, the present invention provides the application of the above-mentioned lipastat morpholine salt or a preparation method thereof in purifying a crude lipalast product.

In combination with the third aspect, the application specifically includes the following operations: dissolving the lipastat morpholine salt in water, adding acid to adjust the pH of the solution to 2-6, and separating the solid and liquid after the solid is precipitated to obtain the lipalast morpholine Masterpieces.

Under the dissociation conditions, the above-mentioned lipastat morpholine salt can be used to obtain a high-purity lipalast refined product, the reaction consistency is strong, the process is safe and controllable, and the HPLC purity of the obtained lipalast refined product is more than 99.7% , in line with the requirements of pharmaceutical grade, and the yield is high, above 80%.

Optionally, the acid used to adjust the pH of the solution includes at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and formic acid.

In conjunction with the third aspect, the method further comprises adding an organic solvent before adjusting the pH of the solution. The addition of organic solvent helps to change the solid state of ritamilast and can reduce the water content in the finished product of ritamilast.

Preferably, the organic solvent includes at least one of methanol, ethanol, acetone, butanone, and acetonitrile.

Preferably, the mass ratio of the volume of the organic solvent to the lipalast morpholine salt is 1-5:1 (ml:g).

In combination with the third aspect, the application may further specifically include the following operations: dissolving the lipalast morpholine salt in water, adding dichloromethane and then adding acid to adjust the pH of the solution to 2-6, stirring and reacting for 10-40 min, Liquid separation extraction, the aqueous phase was discarded, the organic layer was concentrated and then added with an organic solvent to dissolve, the obtained solution was added to water, and the reaction was continued for 20-40 minutes, and the solid-liquid separation was performed to obtain ritamilast.

Optionally, the organic solvent is at least one of methanol, ethanol, acetone, butanone, and acetonitrile, and its consumption depends on the dissolving situation of the solid in the organic layer after the concentration, and the solid in the organic layer after the concentration is dissolved. Can.

In the fourth aspect, the embodiment of the present invention provides the application of the above-mentioned lipalast morpholine salt or its preparation method in the preparation of a lipalast crude product, and the lipalast crude product is prepared into a lithastat in the process of preparing the lipalast. Termorpholine salt, and then dissociated to obtain ritamilast refined product.

The beneficial effects of the present invention are as follows: the preparation method of the above-mentioned lipalast morpholine salt provided by the invention can prepare high-purity lipalast morpholine salt, and the yield is high, the post-processing is simple, and it is suitable for industrial production; Compared with the process of producing litamilast dicyclohexylamine salt, the post-treatment process does not need to use a large amount of solvent to extract and wash the free alkali, and the organic alkali morpholine can be removed by directly adding water to adjust acid and precipitation, so as to obtain a medicinal product. High-grade lipastat products.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrum of the neutral tamiast morpholine salt of the embodiment of the present invention 1;

Fig. 2 is the mass spectrum of the neutral morpholine salt of the embodiment of the present invention 1;

Fig. 3 is the HPLC chromatogram of the neutral morpholine salt of the present invention Example 1.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention.

There are currently two main purification processes for ritamilast: recrystallization in a solvent, or refining after making dicyclohexylamine salt. The former is easy to form viscous solids during the crystallization process, which is not conducive to industrial production. Although the latter can obtain a higher-purity Litalast dicyclohexylamine salt, the post-processing of dissociating the Litalast Dicyclohexylamine salt is very complicated. The post-processing of APIs with qualified solvent residues is cumbersome, and the whole process will generate a large amount of waste acid aqueous solution and waste solvent, which is not conducive to scale-up production. Therefore, the importance of developing a simple, economical and suitable for scale-up production of litamilast purification method is particularly prominent.

The present invention obtains a kind of crystallization mode suitable for Litalast through a large amount of experimental research and condition screening, through this crystallization mode can obtain high-purity Litalast morpholine salt (I), this salt is added with trace acid water It can be dissociated into ritamilast, which can greatly reduce the generation of waste solvent and waste water in the purification process of ritamilast, making the synthesis of ritamilast more conducive to industrial production, easier operation, and more conducive to preparation. Medicinal grade ritamilast.

Example 1

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g of ritamilast crude product and add it to 50mL of butanone, stir and dissolve at room temperature at 25±5℃, then add 1.4g of morpholine, stir for 0.5h, a small amount of solid is precipitated, continue to react at room temperature for 16h, a large amount of solid is precipitated, filter, use 10mL The filter cake was washed with butanone, and dried at 50±5° C. to obtain 4.7 g of lipalast morpholine with a yield of 82.05%.

The obtained lipalast morpholine salt is subjected to structural analysis, the hydrogen nuclear magnetic resonance spectrum is shown in Figure 1, and the mass spectrum is shown in Figure 2, and its structure can be determined as shown in formula I.

The HPLC spectrum of the obtained lipalast morpholine salt is shown in Figure 3, and its HPLC purity is 99.82%.

Example 2

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g of crude ritamilast and add it to 40mL of butanone, stir and dissolve at room temperature at 25±5℃, then add 3.5g of morpholine, stir and react for 1h, add 0.05g of seed crystals, and continue the reaction at room temperature for 18h overnight. The filter cake was washed with 10 mL of butanone, and dried at 50±5 °C to obtain 5.0 g of lipastat morpholine salt, the yield was 87.61%; the HPLC purity was 99.79%.

Example 3

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g of crude ritamilast and add it to 135mL of isopropanol, heat to 60±5℃ and stir to dissolve, then add 2.1g of morpholine and 15g of water, stir and react for 1h, add 0.05g of seed crystals, cool down to room temperature and react for 24h, there are a lot of The solid was precipitated, filtered, and the filter cake was washed with 10 mL of isopropanol and dried at 50±5° C. to obtain 5.2 g of lipastat morpholine salt, the yield was 91.12%; the HPLC purity was 99.27%.

Example 4

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g crude ritamilast and add it to 120mL ethanol and 10mL methanol, heat to 60±5℃ and stir to dissolve, then add 5g morpholine, stir and react for 1h, add 0.05g seed crystal, cool down to room temperature and react for 14h overnight, a large amount of solid is precipitated , filtered, the filter cake was washed with 10 mL of ethanol, and dried at 50 ± 5 °C to obtain 5.2 g of morpholine derivatast, the yield was 91.12%; the HPLC purity was 98.82%.

Example 5

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g crude ritamilast, add 20mL methanol and 40mL isopropanol, stir and dissolve at room temperature at 30±5℃, then add 2.1 morpholine, stir and react for 1h, add 0.05g seed crystal, cool down to 0±5℃ and react overnight for 16h, A large amount of solid was precipitated, filtered, and the filter cake was washed with 10 mL of isopropanol, and dried at 50±5 °C to obtain 4.4 g of lipalast morpholine salt, the yield was 77.19%; the HPLC purity was 98.92%.

Example 6

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product and add it to 50 mL of tetrahydrofuran and stir to dissolve at room temperature at 30±5 °C, then add 0.5 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, and continue the reaction at room temperature for 16 h overnight. The filter cake was washed with 10 mL of tetrahydrofuran, and dried at 50±5° C. to obtain 4.8 g of lipastat morpholine salt, the yield was 70.21%; the HPLC purity was 99.74%.

Example 7

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product and add it to 60 mL of methyl butyl ketone and acetonitrile, stir and dissolve at room temperature at 30±5 °C, then add 5.6 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, and continue the reaction at room temperature for 14 h overnight. The solid was precipitated, filtered, and the filter cake was washed with 10 mL of methyl butyl ketone, and dried at 50±5° C. to obtain 4.5 g of lipalast morpholine salt, the yield was 78.95%; the HPLC purity was 99.26%.

Example 8

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product and add it into 50 mL of acetone at room temperature 30±5 °C and stir to dissolve, then add 1.0 g of morpholine, stir and react for 1 h, then add 0.05 g of seed crystals, continue the reaction at room temperature for 16 h overnight, a large amount of solid is precipitated, filter, use The filter cake was washed with 10 mL of acetone, and dried at 50±5° C. to obtain 5.0 g of derivatast morpholine salt, the yield was 87.72%; the HPLC purity was 98.72%.

Dissolve 5.0 g of the above-mentioned ritamilast morpholine salt in 50 mL of acetone, heat to 60±5° C., and stir to react for 30 min; drop to room temperature and filter to obtain 4.8 g of ritamilast morpholine salt. Yield was 96.00%; HPLC purity was 99.72%.

Example 9

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product and add it to 70 mL of acetonitrile at room temperature 30±5 °C to stir and dissolve, then add 1.4 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, continue the reaction at room temperature for 16 h overnight, a large amount of solid is precipitated, filter, use The filter cake was washed with 10 mL of acetonitrile and dried at 50±5° C. to obtain 5.3 g of deritastat morpholine salt, the yield was 92.87%; the HPLC purity was 99.82%.

Example 10

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g of lipalast crude, add 20mL of N,N-dimethylformamide and butanone, stir and dissolve at room temperature at 30±5℃, then add 3.6g of morpholine, stir and react for 1h, add 0.05g of seed crystals, and continue at room temperature overnight After 18 hours of reaction, a large amount of solid was precipitated, filtered, and the filter cake was washed with 10 mL of butanone, and dried at 50±5 °C to obtain 4.8 g of lipastat morpholine salt, the yield was 84.11%; the HPLC purity was 98.69%.

Example 11

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product, add 20 mL of acetonitrile and 2 mL of water, stir and dissolve at room temperature at 30±5 °C, then add 2.1 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, continue to react at room temperature for 24 h, a large amount of solid is precipitated, filter, The filter cake was washed with 10 mL of acetonitrile, and dried at 50±5° C. to obtain 5.1 g of lipastat morpholine salt, the yield was 89.48%; the HPLC purity was 99.72%.

Example 12

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g of crude ritamilast, add 40mL of butanone and 20mL of isopropanol, stir and dissolve at room temperature at 30±5℃, then add 4.2g of morpholine, stir and react for 1h, add 0.05g of seed crystals, continue to react at room temperature for 18h overnight, there are a lot of The solid was precipitated, filtered, and the filter cake was washed with 8 mL of butanone and 4 mL of isopropanol, and dried at 50±5° C. to obtain 5.3 g of lipastat morpholine salt, the yield was 92.87%; the HPLC purity was 99.39%.

Example 13

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product, add 20 mL of acetonitrile and 80 mL of butanone, stir and dissolve at room temperature at 30±5 °C, then add 2.1 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, continue the reaction at room temperature for 18 h overnight, and a large amount of solid is precipitated , filtered, washed the filter cake with 10 mL of acetonitrile, and dried at 50±5 °C to obtain 5.0 g of deritastat morpholine salt, the yield was 87.62%; the HPLC purity was 99.73%.

Example 14

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product, add 50 mL of tetrahydrofuran and 10 mL of isopropyl acetate, stir and dissolve at room temperature at 30±5 °C, then add 1.7 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, and continue to react overnight at room temperature for 18 h. The solid was precipitated, filtered, and the filter cake was washed with 10 mL of tetrahydrofuran and 2 mL of isopropyl acetate, and dried at 50±5 °C to obtain 4.7 g of lipastat morpholine salt, the yield was 82.46%; the HPLC purity was 99.42%.

Example 15

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5 g of ritamilast crude product, add 60 mL of acetonitrile and 5 mL of water, stir and dissolve at room temperature at 30±5 °C, then add 3.4 g of morpholine, stir and react for 1 h, add 0.05 g of seed crystals, continue to react at room temperature for 48 h, a large amount of solid is precipitated, filtered, The filter cake was washed with 10 mL of acetonitrile, and dried at 50±5° C. to obtain 4.9 g of lipastat morpholine salt, the yield was 85.97%; the HPLC purity was 99.76%.

Example 16

This embodiment provides a preparation method of lipalast morpholine salt.

Take 5g of ritamilast crude product, add 40mL of acetone and 1mL of water, stir and dissolve at room temperature at 30±5°C, then add 2.6g of morpholine, stir and react for 1h, add 0.05g of seed crystals, continue to react overnight at room temperature for 16h, a large amount of solid is precipitated, filter , the filter cake was washed with 10 mL of acetone, and dried at 50 ± 5 °C to obtain 4.9 g of lipastat morpholine salt, the yield was 85.70%; the HPLC purity was 99.83%.

Example 17

This embodiment provides a preparation method of lipalast morpholine salt.

Take 100g crude ritamilast, add 800mL butanone and 50mL water to room temperature 30±5℃ and stir to dissolve, then add 28.3g morpholine, stir and react for 4h, a large amount of solid is precipitated, filter, wash the filter cake with 100mL butanone, 50± After drying at 5°C, 100 g of deritastat morpholine salt was obtained, and the yield was 87.77%; the HPLC purity was 99.86%.

Example 18

This embodiment provides a preparation method of lipalast morpholine salt.

Take 100g crude ritamilast, add 600mL butanone and 100mL acetonitrile, stir and dissolve at room temperature at 30±5℃, then add 25.7g morpholine, stir and react for 8h, a large amount of solid is precipitated, filter, wash the filter cake with 120mL butanone, 50 After drying at ±5°C, deritastat morpholine salt was 106 g, and the yield was 92.98%; the HPLC purity was 99.75%.

Example 19

The present embodiment provides a method for preparing lipalast morpholine salt.

Take 10 g of the Litalast morpholine salt obtained in Example 17, add 100 mL of water and stir to dissolve, slowly add dilute hydrochloric acid at 20 ± 10 ° C to adjust the pH to between 4-6 (10 min), and a large amount of solid is precipitated; continue to stir the reaction 30min; filter dritalast, and vacuum dry at 40°C to obtain 8.3 g of white solid with a yield of 95.04% and HPLC purity of 99.89%; chiral HPLC purity of 100%; morpholine content≤0.1%.

Example 20

The present embodiment provides a method for preparing lipalast morpholine salt.

Take 10 g of the Litalast morpholine salt obtained in Example 17, add 150 mL of water and stir to dissolve, then add 30 mL of acetone, slowly add dilute hydrochloric acid at 20 ± 10 ° C to adjust the pH to between 2-4 (10 min), there is a large amount of solid Precipitate; continue to stir for 30min; filter to obtain Litalast, and vacuum dry at 40°C to obtain 7.9 g of white solid, the yield is 90.18%, the HPLC purity is 99.88%; the chiral HPLC purity is 100%; morpholine content≤0.1%.

Example 21

The present embodiment provides a method for preparing lipalast morpholine salt.

Take 10 g of the Litalast morpholine salt obtained in Example 17, add 150 mL of water and stir to dissolve, then add 30 mL of methanol, and slowly add dilute hydrochloric acid at 20 ± 10 ° C to adjust the pH to between 5-6 (10 min), there is a large amount of solid Precipitation; continue to stir for 30 min; filter to obtain lipalast, and vacuum dry at 40°C to obtain 7.0 g of white solid with a yield of 80.00%, HPLC purity of 99.86%; chiral HPLC purity of 100%; morpholine content ≤ 0.1%.

Example 22

The present embodiment provides a method for preparing lipalast morpholine salt.

Take 10 g of the Litalast morpholine salt obtained in Example 17, add 150 mL of water and stir to dissolve, slowly add dilute sulfuric acid at 20 ± 10 ° C to adjust the pH to between 3-4 (10 min), and a large amount of solid is precipitated; continue to stir the reaction 30min; filter dritalast, and vacuum dry at 40°C to obtain 7.8 g of white solid with a yield of 89.04% and HPLC purity of 99.83%; chiral HPLC purity of 100%; morpholine content≤0.1%.

Example 23

The present embodiment provides a method for preparing lipalast morpholine salt.

Take 10 g of the Litalast morpholine salt obtained in Example 17, add 150 mL of water and stir to dissolve, slowly add dilute sulfuric acid at 20 ± 10 ° C to adjust the pH to between 2-3 (10 min), a large amount of solid is precipitated; continue to stir the reaction 30min; filter deritamilast, and vacuum dry at 40°C to obtain 8.0 g of white solid with a yield of 91.32% and HPLC purity of 99.86%; chiral HPLC purity of 100%; morpholine content≤0.1%.

Example 24

The present embodiment provides a method for preparing lipalast morpholine salt.

Take 10 g of the Litalast morpholine salt obtained in Example 17, add 150 mL of water and stir to dissolve, add 100 mL of dichloromethane for extraction, slowly add dilute hydrochloric acid at 20 ± 10 ° C to adjust the pH to between 4 and 5 (10 min), dropwise Continue to stir and react for 20min after the addition; extract by liquid separation, discard the aqueous phase, and concentrate the dichloromethane organic layer until no obvious liquid flows out, stop the concentration, add 30mL of methanol, stir and dissolve, and slowly add it into 150mL of water (10min), there are A large amount of solid was precipitated; continued stirring for 30min; filtered to obtain lipalast, and vacuum-dried at 40°C to obtain 8.1 g of white solid, yield 93.10%, HPLC purity: 99.89%; chiral HPLC purity 100%; morpholine content≤0.1% .

Comparative Example 1

This comparative example provides an alternative purification method for ritamilast.

Take 50g of ritamilast crude product, add 400mL of acetone and 50mL of water, stir and dissolve at room temperature at 30±5°C, slowly add 22.07g of dicyclohexylamine (10min), stir and stir overnight, a large amount of solid is precipitated, filter, and the obtained solid is washed with 100mL of acetone filter cake. The derivatast dicyclohexylamine salt 45g was dried at 50±5°C, the yield was 69.54%; the HPLC purity was 99.68%.

Take 10 g of the dicyclohexylamine salt prepared above, add 100 mL of dichloromethane, and then add 100 mL of water to stir, the solid is dissolved, and slowly add 10% phosphoric acid aqueous solution under stirring until the pH of the water phase is between 3-5. (10min), continue to stir for 30min; extract and layer, discard the aqueous phase; then add 100 mL of water to the organic phase, add 10% aqueous phosphoric acid solution under stirring until the pH of the aqueous phase is between 3-5, and continue to stir 30min; extraction and stratification, and the aqueous phase was discarded; after TLC spotting, it could be seen that there was still free dicyclohexylamine in the dichloromethane layer; repeat the above-mentioned extraction with phosphoric acid aqueous solution once again; the dichloromethane phase was concentrated, and ethyl acetate was added. Residual dichloromethane was replaced by ester, and solid was precipitated, filtered, and the filter cake was washed with 20 mL of ethyl acetate, and vacuum-dried at 40°C for 6.5 g of derivatast refined product, yield: 85%; HPLC purity: 99.59%; The purity of HPLC is 99.9%; the content of dicyclohexylamine is 0.32%, which does not meet the pharmaceutical standard.

Comparative Example 2

Take 10 g of Litalast dicyclohexylamine salt obtained in comparison 1; add 100 mL of methyl tert-butyl ether and 150 mL of water, and slowly add 10% aqueous sodium hydroxide solution under stirring until the pH of the water phase is between 10-11 (10min), continue stirring for 30min after the solid is completely dissolved; extract and layer, discard the tert-butyl methyl ether phase; add 60 mL of methyl tert-butyl ether to the aqueous phase to wash once; extract the layers, discard the organic phase; TLC It can be seen from the dot plate that the dicyclohexylamine is removed cleanly; the obtained aqueous phase is slowly added with dilute hydrochloric acid to adjust the pH to between 3-6 (5min), a large amount of solid is precipitated, the reaction is stirred for 30min, filtered, and the filter cake is washed with 100mL of water, 40 ℃ vacuum-dried deritamilast refined product 7.0g, yield: 90.9%; HPLC purity: 99.61%; chiral HPLC purity: 99.9%; dicyclohexylamine was not detected; residue: 0.31%, which did not meet the pharmaceutical standards .

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements or improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (10)

1. a Litalast morpholine salt, is characterized in that, its structural formula is as shown in formula I:

2. a preparation method of the described Litalast morpholine salt of claim 1, is characterized in that, specifically comprises the following operations: the Litalast crude product is dissolved in the mixed solution of organic solvent and water or in the organic solvent, Morpholine was added, and after the solid was precipitated, the solid-liquid was separated to obtain the lipalast morpholine salt. 3. the preparation method of Litalast morpholine salt according to claim 2, is characterized in that, described solvent comprises isopropanol, ethanol, methanol, tetrahydrofuran, methyl ethyl ketone, methyl butyl ketone, acetone, acetonitrile, At least one of isopropyl acetate and N,N-dimethylformamide. 4. the preparation method of morpholine salt according to claim 2, is characterized in that, the ratio of the mass of the volume of the mixed solution of described organic solvent and water or organic solvent and the crude product of described lipalast It is 4～30:1 (ml:g). 5. the preparation method of the described Litalast morpholine salt according to claim 4, is characterized in that, in the mixed solution of described organic solvent and water, the quality of described water does not exceed the quality of described Litalast crude product 3 times. 6. according to the preparation method of the described Litalast morpholine salt of any one of claim 2～5, it is characterized in that, the ratio of the molar weight of described morpholine to the molar weight of described Litalast crude product is 0.5～10:1. 7 . The application of the preparation method of the lipastat morpholine salt according to claim 1 or the lipalast morpholine salt according to any one of claims 2 to 6 in purifying the crude product of lipamilast. 8 . 8. The application according to claim 7, characterized in that it specifically comprises the following operations: dissolving the lipalast morpholine salt in water, adding acid to adjust the pH of the solution to 2-6, and separating the solid from the liquid after the solid is precipitated. , that is, Tritalast refined products. 9. The application according to claim 7, characterized in that, it specifically comprises the following operations: dissolving the lipalast morpholine salt in water, adding dichloromethane, adding acid to adjust the pH of the solution to 2-6, stirring The reaction is carried out for 10-40 minutes, followed by liquid separation and extraction, the aqueous phase is discarded, the organic layer is concentrated and then dissolved in an organic solvent, the obtained solution is added to water, and the reaction is continued for 20-40 minutes, and the solid-liquid separation is performed to obtain lipalast. 10. The application of the preparation method of the lipalast morpholine salt according to claim 1 or the lipalast morpholine salt according to any one of claims 2 to 6 in the purification of the lipalast morpholine crude product, characterized in that, In the process of preparing lipalast, the crude product of lipalast was prepared into tamilast morpholine salt, and then dissociated to obtain the refined product of lipalast.

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