A kind of industrial preparation method of orlistat

Abstract

The present invention discloses an industrial preparation method of orlistat. The present invention performs scaled-up production on the basis of the prior art, adjusts the reaction solvent and the purification process, and ultimately effectively improves the yield after scaled-up production, significantly reduces the solvent residue, improves the safety of the product, and is more suitable for industrialization.

Description

Technical Field

[0001] The present invention relates to the field of drug preparation, and in particular to an industrial preparation method of orlistat. Background Art

[0002] Due to various congenital and acquired factors, the number of obese patients is increasing. Obesity not only increases the economic burden of human beings, but also causes many diseases, which indirectly increases the mortality rate. Therefore, finding an effective and safe method to treat obesity is a hot topic of concern. At present, in the past, when treating some severely obese patients, the commonly used drugs include fenfluramine, dexfenfluramine, orlistat, etc., but fenfluramine or dexfenfluramine are highly toxic and have many side effects, and now almost all of them have been discontinued. Orlistat is a commonly used, safe and effective type of weight loss drug in recent years. It is precisely because of its few side effects that it is the only OTC weight loss drug in the world, and it has always been a highly attractive preparation target for people.

[0003] The route design and method of the existing technology have the disadvantages of long preparation steps, single strategy, difficult operation of individual reactions, expensive and highly toxic reagents, serious environmental pollution and low yield.

[0004] In Chinese patent application CN106632157A, in the presence of (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt, cuprous chloride catalyzes the reduction reaction of nipostatin with sodium borohydride to obtain orlistat. The reaction uses acetonitrile or tetrahydrofuran as solvent. After the reaction is complete, a mixed solvent of dichloromethane / petroleum ether is used for recrystallization. This case is a laboratory test reaction method. After amplification, its yield is low, and there is solvent residue in the recrystallized product.

[0005] In Chinese patent application CN111499599A, (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt, nipostatin, pentacarbonyl iron, sodium borohydride, and solvent are mixed, then heated to 30-40°C, maintained at the temperature for 3-4.5 hours, and post-treated to obtain orlistat. Among them, methanol, ethanol, etc. are used as solvents. After the reaction is complete, acetonitrile, heptane, petroleum ether, methanol, carbon tetrachloride, etc. are used for recrystallization. This case is still a small laboratory test reaction, using highly toxic carbon tetrachloride solvents. After amplification, its yield is low, and there is also a certain amount of solvent residue in the recrystallized product. Summary of the invention

[0006] Based on the above problems, the purpose of the present invention is to provide a method for producing orlistat that is suitable for large-scale industrial production, which has a high yield, low residual solvent in the final product and high safety.

[0007] In order to achieve the above object, the preparation method of orlistat designed by the present invention comprises the following steps:

[0008] (1) (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt, nipostatin, pentacarbonyl iron, and sodium borohydride are added to a mixed solvent of ethanol and isopropanol and maintained at a temperature of 20 to 40°C until the reaction is complete;

[0009] (2) After the solvent is recovered from the reaction solution, the mixture is extracted with a mixed solvent of dichloromethane and petroleum ether and a dilute acid aqueous solution. The organic phase is washed with water until it is neutral. After the solvent is recovered, ethanol is added to dissolve the mixture, and water is added to recrystallize the mixture to obtain orlistat.

[0010] In the large-scale production method of the present invention, the amount of (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt used is more than 500g, and the amount of nipostatin used is more than 1000g.

[0011] The present invention has found that if ethanol or acetonitrile is used alone as a solvent, the yield will be significantly reduced in the amplified production process, but the experiment also found that if methanol is used as a solvent, the yield will be improved. However, methanol is highly toxic, and in order to improve production safety, the present invention abandons the use of methanol as a solvent. In the production attempt, it was accidentally discovered that if an appropriate amount of isopropanol is added to ethanol, the reaction yield can be effectively improved.

[0012] The molar ratio of nipostatin to sodium borohydride, (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt and pentacarbonyl iron is 1:0.7-1.2:0.3-0.5:0.01-0.02.

[0013] The molar ratio of nipostatin to sodium borohydride, (R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexyldiamine cobalt and pentacarbonyl iron is 1:0.7:0.3:0.01.

[0014] Among them, the ratio of ethanol to isopropanol is 5:1-2.

[0015] Among them, the ratio of dichloromethane to petroleum ether is 1:15-25.

[0016] Among them, water accounts for 20-50% of the ethanol usage.

[0017] In the present invention, dichloromethane and petroleum ether are first used for extraction, and then ethanol water is used for recrystallization, which effectively avoids the residual amount of organic solvent in the finished drug product and improves the product safety.

[0018] The beneficial effects of the present invention are:

[0019] The preparation method of the present invention is different from the known laboratory method, and the present invention belongs to a large-scale production method. The present invention found the problems of low yield and solvent residue in the prior art during the scale-up production. Through the improvement of the reaction solvent, purification method, etc., the present invention finally effectively improves the yield of large-scale production, effectively reduces the residual amount of organic solvent, and improves the safety of the product medicine. DETAILED DESCRIPTION

[0020] In order to better explain the present invention, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0021] Example 1

[0022] Under nitrogen protection, 600 g of (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiaminecobalt, 20 g of pentacarbonyl iron, 2000 g of nipostatin, and 5 L of solvent (ethanol:isopropanol=5:1) were mixed in a reaction container and stirred. At 25°C, 1500 g of sodium borohydride was added and the temperature was maintained for 3 to 5 hours. After the reaction was complete, the mixture was extracted with dichloromethane / petroleum ether 1:20 and dilute hydrochloric acid aqueous solution. The organic phase was washed with water until neutral. After the organic phase recovered the solvent, ethanol was added to heat and dissolve, and then water with an amount of 20% of the ethanol was added. The mixture was cooled and allowed to stand for filtration and dried to obtain refined orlistat with a yield of 88.0% and a purity of 99.89%.

[0023] GC was used for detection, and no isopropanol, dichloromethane or petroleum ether residue was detected.

[0024] Example 2

[0025] Under nitrogen protection, 1000 g of (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiaminecobalt, 40 g of pentacarbonyl iron, 4000 g of nipostatin, and 10 L of solvent (ethanol:isopropanol=5:1) were mixed in a reaction container and stirred. At 30°C, 3000 g of sodium borohydride was added and the temperature was maintained for 3 to 5 hours. After the reaction was complete, the mixture was extracted with dichloromethane / petroleum ether 1:15 and dilute hydrochloric acid aqueous solution. The organic phase was washed with water until neutral. After the organic phase recovered the solvent, ethanol was added and heated to dissolve. Then, water with a dosage of 40% of the ethanol was added. The mixture was cooled and allowed to stand for filtration and dried to obtain refined orlistat with a yield of 85% and a purity of 99.61%.

[0026] GC was used for detection, and no isopropanol or dichloromethane residues were detected, and the petroleum ether residue was very low, about 0.0005%.

[0027] Comparative Example 1

[0028] Under nitrogen protection, 600 g of (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiaminecobalt, 20 g of pentacarbonyl iron, 2000 g of nipostatin and 5 L of ethanol were mixed in a reaction container, stirred and heated to 30°C, then 1500 g of sodium borohydride was added, the temperature was maintained and the reaction was carried out for 3 hours. After the reaction was completed, -5°C to 5°C circulating water cooling was turned on, and petroleum ether was added as an extractant for extraction, and the mixture was washed twice with dilute hydrochloric acid and water respectively. The organic phase was transferred to a distillation kettle and distilled until there was no fraction, and then a Roots pump was used to distill under reduced pressure at -0.098 MPa until no droplets flowed out to obtain orlistat. The distilled petroleum ether was weighed in barrels and applied. The obtained orlistat was dissolved in a mixed solvent of acetonitrile / petroleum ether (volume ratio 1:25), then heated to 50°C and stirred for 15-20 minutes, filtered, the filtrate was cooled, suction filtered, and vacuum dried to obtain refined orlistat with a yield of 75.0% and a purity of 99.67%.

[0029] GC was used to detect the residues of acetonitrile and petroleum ether, wherein the content of acetonitrile was about 0.02% and that of petroleum ether was 0.04%.

[0030] Comparative Example 2

[0031] Under nitrogen protection, 600 g of (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiaminecobalt, 20 g of pentacarbonyl iron, 2000 g of nipostatin, and 5 L of acetonitrile were mixed in a reaction container, stirred, and heated to 30°C. Then, 1500 g of sodium borohydride was added, and the temperature was maintained for 3 hours. After the reaction was complete, extraction was performed with dichloromethane / petroleum ether at a ratio of 1:20, washed with water, the organic phase was heated, cooled and allowed to stand, filtered, and dried to obtain refined orlistat with a yield of 62% and a purity of 99.75%.

[0032] GC was used to detect the residues of dichloromethane and petroleum ether, wherein the content of dichloromethane was about 0.01% and that of petroleum ether was 0.03%.

Claims

1. A method for preparing orlistat, characterized in that: The steps include: (1) (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt, nipostatin, pentacarbonyl iron, and sodium borohydride are added to a mixed solvent of ethanol and isopropanol and maintained at a temperature of 20 to 40°C until the reaction is complete; (2) After the reaction solution is distilled under reduced pressure to recover the solvent, it is extracted with a mixed solvent of dichloromethane and petroleum ether and a dilute acid aqueous solution, the organic phase is washed with water until it is neutral, and after the solvent is recovered, ethanol is added to dissolve it, and then water accounting for 20 to 50% of the amount of ethanol is added for recrystallization to obtain orlistat; The ratio of ethanol to isopropanol is 5:1-2; the ratio of dichloromethane to petroleum ether is 1:15-25; the ethanol is selected from 95% ethanol; The amount of the (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt is more than 500 g, and the amount of nipostatin is more than 1000 g.

2. The method for preparing oselita according to claim 1, characterized in that: The molar dosage ratio of nipostatin to sodium borohydride, (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexyldiamine cobalt and pentacarbonyl iron is 1:0.7-1.2:0.3-0.5:0.01-0.

02.

3. The preparation method according to claim 2, characterized in that: The molar ratio of nipostatin to sodium borohydride, (R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexyldiamine cobalt and pentacarbonyl iron is 1:0.7:0.3:0.01.