CN116003308A

CN116003308A - Abidol crystallization process

Info

Publication number: CN116003308A
Application number: CN202211714924.9A
Authority: CN
Inventors: 程利国; 杜震龙; 沈少雷; 周宇龙
Original assignee: Shijiazhuang Zhongshuo Pharmaceutical Co ltd
Current assignee: Shijiazhuang Zhongshuo Pharmaceutical Co ltd
Priority date: 2022-12-27
Filing date: 2022-12-27
Publication date: 2023-04-25
Anticipated expiration: 2042-12-27
Also published as: CN116003308B

Abstract

The invention relates to the technical field of pharmaceutical chemicals, and provides an Abidol crystallization method, which comprises the following steps: dissolving Abidol, adding ethyl acetate for crystallization, controlling the dripping time and dripping amount of ethyl acetate, controlling the amount of crystal nucleus and growth speed, and reducing the probability of coating impurities. Through the technical scheme, the problems that the process of the crystal of the arbidol is not easy to control, the quality of the arbidol is unstable, the purity of the crystallized arbidol is low, and the light transmittance is low in the prior art are solved.

Description

Abidol crystallization process

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to an Abidol crystallization method.

Background

Abidol is a non-nucleoside broad-spectrum antiviral drug with immune enhancement function, and can be used as a hemagglutinin inhibitor, can block fusion of virus envelope and host cell membrane, can inhibit production of progeny virus, and can induce production of interferon to indirectly realize antiviral effect.

At present, the recrystallization of the arbidol is mainly carried out by utilizing the different solubilities of products in solvents at different temperatures, namely, the products are dissolved in a mixed solvent of ethanol and acetone at high temperature and then cooled to separate out crystals. There are the following disadvantages: (1) High-temperature dissolution causes volatilization of the solvent, and increases the cost of the product; (2) In the process of crystallizing the product by cooling, the cooling speed is influenced by the temperature, pressure, flow speed and the like of the refrigerant, the crystallization speed and the crystallization amount fluctuate greatly, the fluctuation of the product quality is caused to be large, and the purity of the arbidol after crystallization is low and the light transmittance is poor. (3) Abidol is slightly dissolved in ethanol and acetone, so that the Abidol residue in the mother solution is high, the yield loss is large, and the product cost is high. Therefore, a new crystal method of arbidol needs to be developed, the stability of the crystallization process is improved, and the purity and the light transmittance of the arbidol after crystallization are improved.

Disclosure of Invention

The invention provides an Abidol crystallization method, which solves the problems of unstable quality of Abidol, low purity of Abidol after crystallization and low light transmittance caused by difficult control of the Abidol crystallization process in the related technology.

The technical scheme of the invention is as follows:

an arbidol crystallization process comprising the steps of: after the arbidol was dissolved, ethyl acetate was added to crystallize.

As a further technical scheme, the dissolving the arbidol is to dissolve the arbidol in ethanol solution for reflux dissolution.

As a further technical scheme, the mass fraction of the ethanol solution is 50-70%.

As a further technical scheme, the mass ratio of the ethanol solution to the arbidol is (3-4): 1.

As a further technical scheme, the reflux temperature of the arbidol dissolution is 70-80 ℃.

As a further technical scheme, the reflux time of the arbidol dissolution is 0.5-1.5h.

As a further technical scheme, the crystallization is to control the temperature to be 20-25 ℃, dropwise add ethyl acetate for primary crystallization and crystal growth, dropwise add ethyl acetate for secondary crystallization and then cool to obtain the crystallized arbidol.

As a further technical scheme, the mass ratio of the dripping amount of the ethyl acetate to the arbidol at the first crystallization is (2-3): 1, the dripping time is 1-1.5h.

As a further technical scheme, the mass ratio of the dripping amount of the ethyl acetate to the arbidol in the second crystallization is (0.5-1): 1, the dripping time is 0.5-1h.

As a further technical scheme, the crystal growing time is 1-2h.

The working principle and the beneficial effects of the invention are as follows:

1. according to the invention, the dripping time and the dripping amount of ethyl acetate are controlled, the amount and the growth speed of crystal nucleus are controlled, the probability of wrapping impurities is reduced, the purity and the content of the product are finally improved, the impurities are reduced, and the light transmittance is improved.

2. According to the invention, the arbidol is insoluble in ethyl acetate, so that the residue of the arbidol in a solvent can be reduced, the product yield is improved, and the product cost is reduced.

3. According to the invention, the dissolution temperature is controlled, so that the dissolution of the arbidol in the ethanol solution is improved, the reaction process is mild, the reaction conditions are easy to control, the product cost is reduced, and the stability of the product quality is improved.

Detailed Description

The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The following examples and comparative examples were prepared by crystallizing the same batch of arbidol, and the light transmittance was measured by: adding the crystallized Abidol into ethanol for dissolution to prepare a 20g/L solution, and measuring by using a spectrophotometer at 425nm wavelength and with pure water as a reference.

Example 1

50g of Abidol is dissolved in 200g of 70% ethanol solution, the temperature is controlled to be 25 ℃ and the reflux is carried out for 0.5h, 150g of ethyl acetate is dripped, the dripping time is 1.5h for carrying out the first crystallization and crystal growing for 1h, then 25 g of ethyl acetate is dripped, the dripping time is 0.5h, the second crystallization and cooling are carried out, and 43.7g of crystallized Abidol is obtained, the yield is 87.4%, the purity is 99.2%, and the light transmittance is 99.1%.

Example 2

50g of Abidol is dissolved in 150g of 65% ethanol solution and refluxed for 1.5h at 50 ℃, the temperature is controlled to be 20 ℃, 100g of ethyl acetate is dripped, the dripping time is 1h for carrying out primary crystallization and crystal growth for 2h, 50g of ethyl acetate is dripped again, the dripping time is 1h, and cooling is carried out after the secondary crystallization, 43.4g of crystallized Abidol is obtained, the yield is 86.8%, the purity is 99.3%, and the light transmittance is 99.1%.

Example 3

50g of Abidol is dissolved in 170g of 60 percent ethanol solution, the reflux is carried out for 1h at 53 ℃, the temperature is controlled at 23 ℃, 130g of ethyl acetate is dripped, the dripping time is 1.2h for carrying out the first crystallization and crystal growth for 1.5h, 40g of ethyl acetate is dripped, the dripping time is 0.7h, the second crystallization and cooling are carried out, 43.5g of crystallized Abidol is obtained, the yield is 86.8 percent, the purity is 99.3 percent, and the light transmittance is 99.2 percent.

Example 4

50g of Abidol is dissolved in 200g of 50% ethanol solution, the temperature is controlled to be 25 ℃ and the reflux is carried out for 0.5h, 150g of ethyl acetate is dripped, the dripping time is 1.5h for carrying out the first crystallization and crystal growing for 2h, 50g of ethyl acetate is dripped again, the dripping time is 0.5h, the second crystallization is carried out and then the cooling is carried out, thus obtaining 43.9g of crystallized Abidol, the yield is 87.8%, the purity is 99.6%, and the light transmittance is 99.5%.

Example 5

50g of arbidol is dissolved in 170g of 70% ethanol solution, the temperature is controlled to be 25 ℃ and the reflux is carried out for 0.5h, 150g of ethyl acetate is dripped, the dripping time is 1.5h for carrying out the first crystallization and crystal growth for 1h, then 25 g of ethyl acetate is dripped, the dripping time is 0.5h, the second crystallization and cooling are carried out, and 43.8g of crystallized arbidol is obtained, the yield is 87.6%, the purity is 99.4%, and the light transmittance is 99.3%.

Comparative example 1

Comparative example 1 was conducted at a reflux temperature of 65℃as compared with example 1, and 41.7g of crystallized Abidol was obtained in the same manner as in example 1, the yield was 83.4%, the purity was 98.1% and the light transmittance was 98.0%.

Comparative example 2

As compared with example 1, 90g of ethyl acetate was added dropwise to the first crystallization of comparative example 2, and 40.9g of crystallized Abidol was obtained in the same manner as in example 1, with a yield of 81.8%, a purity of 97.7% and a light transmittance of 97.6%.

Comparative example 3

The time for the first crystallization drop of comparative example 2 was 2 hours as compared with example 1, and 41.2g of crystallized arbidol was obtained in the same manner as in example 1, with a yield of 82.4%, a purity of 97.5% and a light transmittance of 97.4%.

Comparative example 4

As compared with example 1, 70g of ethyl acetate was added dropwise to the second crystals of comparative example 4, and 41.1g of crystallized arbidol was obtained in the same manner as in example 1, with a yield of 82.2%, a purity of 97.4% and a light transmittance of 97.3%.

Comparative example 5

The time for the second crystallization drop of comparative example 5 was 1.5 hours as compared with example 1, and 41.3g of crystallized arbidol was obtained in the same manner as in example 1, with a yield of 82.6%, a purity of 98.2% and a light transmittance of 98.2%.

Comparative example 6

Comparative example 6 was conducted by substituting ethyl acetate with an equivalent amount of petroleum ether as in example 1, and 41.9g of crystallized arbidol was obtained in a yield of 83.8%, a purity of 97.3% and a light transmittance of 97.2%.

The yield of the crystallized arbidol prepared in the embodiments 1-5 is 99.2-99.6% of purity, 99.1-99.5% of light transmittance, and the product has higher stability.

Comparative example 1 changed the reflux temperature compared to example 1, comparative example 6 replaced ethyl acetate with an equal amount of petroleum ether, and as a result, both the purity and transmittance of the crystallized arbidol obtained in comparative example 1 and comparative example 6 were lower than those of example 1. The dissolution temperature defined in the present invention is described as being capable of improving the yield, purity and transmittance of arbidol after crystallization, and the substitution of ethyl acetate for other substances for crystallization affects the yield, purity and transmittance of arbidol after crystallization.

Comparative example 2 the amount of ethyl acetate added for the first crystallization, comparative example 3 the amount of ethyl acetate added for the first crystallization, comparative example 4 the amount of ethyl acetate added for the second crystallization, and comparative example 5 the amount of ethyl acetate added for the second crystallization, resulted in comparative examples 2-5 having lower purity and light transmittance of the crystallized arbidol than example 1, indicating that changing the amount of ethyl acetate added and the time of addition at the time of crystallization affects the yield, purity and light transmittance of the product, presumably due to the fact that the change in the time of ethyl acetate addition and the amount of addition affects the amount and speed of nucleation.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. An arbidol crystallization method, characterized by comprising the steps of: after the arbidol was dissolved, ethyl acetate was added to crystallize.

2. The process for the crystallization of arbidol according to claim 1, characterized in that said dissolution of arbidol is carried out by dissolution of arbidol in an ethanol solution with reflux.

3. The method for crystallizing an arbidol according to claim 2, wherein the mass fraction of the ethanol solution is 50-70%.

4. The process for the crystallization of arbidol according to claim 2, characterized in that the mass ratio of the ethanol solution to the arbidol is (3-4): 1.

5. The process for the crystallization of arbidol according to claim 2, characterized in that the reflux temperature of the dissolution of arbidol is 70-80 ℃.

6. The process for the crystallization of arbidol according to claim 2, characterized in that the reflux time of the dissolution of arbidol is between 0.5 and 1.5h.

7. The method for crystallizing arbidol according to claim 1, wherein the crystallization is performed at a controlled temperature of 20-25 ℃, ethyl acetate is added dropwise for the first crystallization and crystal growth, ethyl acetate is added dropwise for the second crystallization, and then the mixture is cooled to obtain the crystallized arbidol.

8. The process for the crystallization of arbidol according to claim 7, characterized in that the ratio of the amount of ethyl acetate added dropwise to the mass of arbidol at the time of the first crystallization is (2-3): 1, the dripping time is 1-1.5h.

9. The method of crystallizing an arbidol as claimed in claim 7, wherein a mass ratio of a dropping amount of ethyl acetate to the arbidol at the time of the second crystallization is (0.5 to 1): 1, the dripping time is 0.5-1h.

10. The method of crystallizing an arbidol as claimed in claim 7, wherein the crystallization time is 1 to 2 hours.