CN111499599A - Preparation method of orlistat - Google Patents
Preparation method of orlistat Download PDFInfo
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- CN111499599A CN111499599A CN202010519861.6A CN202010519861A CN111499599A CN 111499599 A CN111499599 A CN 111499599A CN 202010519861 A CN202010519861 A CN 202010519861A CN 111499599 A CN111499599 A CN 111499599A
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- orlistat
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- sodium borohydride
- butylsalicylidene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
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Abstract
The invention discloses a preparation method of orlistat. The invention takes the lipstatin as the initial raw material, cuprous chloride catalyzes the lipstatin and sodium borohydride to carry out reduction reaction to obtain orlistat. The raw materials adopted by the preparation method disclosed by the invention are cheap and easy to obtain, the process conditions are mild, the post-treatment is simple, the yield of the obtained product is high, the byproducts are few, and the whole process is very suitable for industrialization.
Description
Technical Field
The invention relates to the field of medicine preparation, in particular to a preparation method of orlistat.
Background
Due to various congenital and acquired factors, the number of obese patients is increasing, and obesity not only increases the economic burden of human beings, but also causes a plurality of diseases, thereby indirectly increasing the death rate, so that the search for an effective and safe method for treating obesity is a focus of attention. At present, when some serious obesity patients are treated in the past, the common medicines comprise fenfluramine, dexfenfluramine, sibutramine, orlistat and the like, and the medicines of fenfluramine or dexfenfluramine have high toxicity and more side effects and are almost completely stopped at present; sibutramine is an effective but dietary inhibitor, and is not suitable for long-term administration. Orlistat is a common, safe and effective antiobesity drug in recent years, and has few side effects, so that orlistat is the only OTC antiobesity drug in the world and has been a strong attractive preparation target.
In the route design and the method for preparing the compound, the defects of long preparation steps, single strategy, difficult operation of individual reaction, expensive reagent, high toxicity, large environmental pollution and low yield exist.
Disclosure of Invention
The invention aims to provide a brand-new orlistat preparation method which is short in route, low in preparation cost, small in environmental pollution, low in toxicity and high in yield.
In order to achieve the purpose, the preparation method of orlistat, which is designed by the invention, comprises the following steps:
mixing (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyl diamine cobalt, nipalustatin, iron pentacarbonyl, sodium borohydride and a solvent, heating to 30-40 ℃, keeping the temperature for reacting for 3-4.5 hours, and performing post-treatment to obtain orlistat.
Further, the molar ratio of the nepastatin to the sodium borohydride, the molar ratio of the (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyl diamine cobalt to the penta-carbonyl iron is 1: 0.7-1.2: 0.3-0.5: 0.01 to 0.02.
Furthermore, the molar ratio of the nepastatin to the sodium borohydride, the (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyl diamine cobalt and the iron pentacarbonyl is 1: 0.7: 0.3: 0.01.
in the present invention, in order to reduce the influence of air on the catalyst and the reduction reaction, the reduction reaction is carried out in the presence of a protective gas; the protective gas is nitrogen and/or helium.
Further, the post-treatment comprises an extraction step.
Furthermore, the extraction reagent is one or more of methanol, ethanol, acetonitrile, petroleum ether, heptane and diethyl ether.
Further, the solvent is one or more of methanol, ethanol and diethyl ether.
The preparation method of orlistat of the invention also comprises a purification step.
Further, the purifying step comprises: the orlistat obtained is dissolved in a polar solvent: and stirring the mixed solvent with the volume ratio of the nonpolar solvent to the mixed solvent of 1: 22-1: 35 at 50-58 ℃ for 15-25 min.
Further, the polar solvent is one or more of acetonitrile, diethyl ether and methanol; the nonpolar solvent is one or more of petroleum ether, heptane and carbon tetrachloride.
The invention has the beneficial effects that:
1. compared with the known method, the preparation method has the advantages of novel preparation route, simple and convenient operation, high product yield, cheap and easily obtained raw materials and reagents and the like.
2. The preparation method has the advantages of simple and reasonable design of the preparation route, simple and convenient operation process, mild reaction conditions, few linear steps, capability of greatly reducing the production cost, little environmental pollution and high purity, and is suitable for industrial preparation.
Detailed Description
In order to better explain the present invention, the present invention is further described in detail with reference to the following specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Under the protection of nitrogen, 6.0g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.2g of iron pentacarbonyl, 20g of nepistatin and 50ml of methanol are mixed in a reaction vessel, stirred, heated to 30 ℃, then 14g of sodium borohydride is added, the temperature is kept, the reaction is carried out for 3 hours, after the reaction is finished, circulating water cooling at-5 ℃ to 5 ℃ is started, an extractant petroleum ether is added for extraction, diluted hydrochloric acid and water are respectively used for washing for 2 times, an organic phase is transferred into a distillation kettle, distillation is carried out until no fraction is produced, a roots pump is used for carrying out reduced pressure distillation under-0.098 MPa until no liquid drop is produced, orlistat is obtained, and the distilled petroleum ether is barreled and weighed and used for application. Dissolving the orlistat in acetonitrile/petroleum ether mixed solvent (volume ratio is 1:25), heating to 50 ℃, stirring for 15-20 min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 18.6g of refined orlistat, wherein the yield is 93.0%, and the purity is 99.76%.
Example 2
Under the protection of helium, 10g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.4g of iron pentacarbonyl, 20g of nepistatin and 50ml of ethanol are mixed in a reaction container, stirred, heated to 33 ℃, then added with 24g of sodium borohydride, kept at the temperature for 3.5 hours, cooled by circulating water at-5 ℃ after the reaction is finished, added with an extractant diethyl ether for extraction, washed for 2 times respectively by dilute hydrochloric acid and water, an organic phase is transferred into a distillation kettle, distilled to be free of distillate, then subjected to reduced pressure distillation by a Roots pump at-0.098 MPa until no liquid drops are discharged to obtain orlistat, and the distilled diethyl ether is barreled and weighed for reuse. Dissolving the orlistat in a methanol/carbon tetrachloride mixed solvent (volume ratio is 1:35), heating to 54 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 18.9g of refined orlistat, wherein the yield is 94.5%, and the purity is 99.72%.
Example 3
Under the protection of nitrogen, 8g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.3g of iron pentacarbonyl, 20g of nepistatin and 50ml of diethyl ether are mixed in a reaction container, stirred, heated to 33 ℃, then added with 16g of sodium borohydride, kept at the temperature for 4.5 hours, cooled by circulating water at-5 ℃ after the reaction is finished, added with an extractant heptane for extraction, washed for 2 times respectively by dilute hydrochloric acid and water, an organic phase is transferred into a distillation kettle, distilled to be free of distillate, then subjected to reduced pressure distillation by a Roots pump at-0.098 MPa until no liquid drops are discharged to obtain orlistat, and the distilled heptane is barreled and weighed for use. Dissolving the orlistat in an acetonitrile/heptane mixed solvent (volume ratio of 1:29), heating to 58 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 19.1g of refined orlistat, wherein the yield is 95.5%, and the purity is 99.75%.
Example 4
Under the protection of helium, 9g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.15g of iron pentacarbonyl, 20g of nepistatin and 50ml of methanol are mixed in a reaction container, stirred, heated to 33 ℃, then added with 22g of sodium borohydride, kept at the temperature for 4 hours, cooled by circulating water at-5 ℃ after the reaction is finished, added with an extractant, extracted by ethanol, washed by dilute hydrochloric acid and water for 2 times respectively, an organic phase is transferred into a distillation kettle, distilled to be free of distillate, and then subjected to reduced pressure distillation by a Roots pump at-0.098 MPa until no liquid drops flow out to obtain orlistat, and the distilled ethanol is barreled and weighed for reuse. Dissolving the orlistat in acetonitrile/petroleum ether mixed solvent (volume ratio is 1:32), heating to 58 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 19.2g of refined orlistat, wherein the yield is 96.0%, and the purity is 99.69%.
Example 5
Under the protection of nitrogen, 8g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.3g of iron pentacarbonyl, 20g of nepistatin and 50ml of methanol are mixed in a reaction container, stirred, heated to 33 ℃, then added with 17g of sodium borohydride, kept at the temperature for 35 hours, cooled by circulating water at-5 ℃ after the reaction is finished, added with an extractant methanol for extraction, washed for 2 times respectively by dilute hydrochloric acid and water, an organic phase is transferred into a distillation kettle, distilled to be free of distillate, and then subjected to reduced pressure distillation by a Roots pump at-0.098 MPa until no liquid drops flow out to obtain orlistat, and the distilled methanol is barreled and weighed for reuse. Dissolving the orlistat in acetonitrile/petroleum ether mixed solvent (volume ratio is 1:30), heating to 58 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 18.8g of refined orlistat, wherein the yield is 94.0%, and the purity is 99.66%.
Example 6
Under the protection of helium, 6g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.3g of iron pentacarbonyl, 20g of nepistatin and 50ml of diethyl ether are mixed in a reaction container, stirred, heated to 33 ℃, then added with 19g of sodium borohydride, kept at the temperature for 3.3 hours, cooled by circulating water at-5 ℃ to 5 ℃ after the reaction is finished, added with an extractant acetonitrile for extraction, washed for 2 times respectively by dilute hydrochloric acid and water, an organic phase is transferred into a distillation kettle, distilled to no fraction and then subjected to reduced pressure distillation by a roots pump at-0.098 MPa until no liquid drops are discharged to obtain orlistat, and the distilled acetonitrile is barreled and weighed for reuse. Dissolving the orlistat in an ether/petroleum ether mixed solvent (volume ratio is 1:27), heating to 52 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 18.6g of refined orlistat, wherein the yield is 93.0%, and the purity is 99.64%.
Example 7
Under the protection of helium, 7g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.2g of iron pentacarbonyl, 20g of nepistatin and 50ml of ethanol are mixed in a reaction container, stirred, heated to 33 ℃, then 20g of sodium borohydride is added, the temperature is kept, the reaction is carried out for 3.7 hours, after the reaction is finished, circulating water cooling at-5 ℃ to 5 ℃ is started, an extracting agent methanol is added for extraction, diluted hydrochloric acid and water are respectively used for washing for 2 times, an organic phase is transferred into a distillation kettle, distillation is carried out until no fraction is produced, a Roots pump is used for carrying out reduced pressure distillation under-0.098 MPa until no liquid drop is produced, and orlistat is obtained, and the distilled methanol is barreled and weighed for reuse. Dissolving the orlistat in a methanol/petroleum ether mixed solvent (volume ratio is 1:22), heating to 58 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 18.7g of refined orlistat, wherein the yield is 93.5%, and the purity is 99.71%.
Example 8
Under the protection of helium, 8g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.4g of iron pentacarbonyl, 20g of nepistatin and 50ml of methanol are mixed in a reaction container, stirred, heated to 36 ℃, then 20g of sodium borohydride is added, the temperature is kept, the reaction is carried out for 3.2 hours, after the reaction is finished, circulating water cooling at-5 ℃ to 5 ℃ is started, an extracting agent heptane is added for extraction, diluted hydrochloric acid and water are respectively used for washing for 2 times, an organic phase is transferred into a distillation kettle, the distillation is carried out until no fraction is produced, a roots pump is used for carrying out reduced pressure distillation under-0.098 MPa until no liquid drop is produced, and orlistat is obtained, and the distilled heptane is barreled and weighed for application. Dissolving the orlistat in an ethanol/heptane mixed solvent (volume ratio of 1:24), heating to 57 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 19.1g of refined orlistat, wherein the yield is 95.5%, and the purity is 99.67%.
Example 9
Under the protection of nitrogen, 9g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.4g of iron pentacarbonyl, 20g of nepistatin and 50ml of diethyl ether are mixed in a reaction container, stirred, heated to 36 ℃, then 20g of sodium borohydride is added, the temperature is kept, the reaction is carried out for 3.4 hours, after the reaction is finished, circulating water cooling at-5 ℃ to 5 ℃ is started, an extracting agent heptane is added for extraction, diluted hydrochloric acid and water are respectively used for washing for 2 times, an organic phase is transferred into a distillation kettle, the distillation is carried out until no fraction is produced, a Roots pump is used for carrying out reduced pressure distillation under-0.098 MPa until no liquid drop is produced, and orlistat is obtained, and the distilled heptane is barreled and weighed for. Dissolving the obtained orlistat in an ethanol/heptane mixed solvent (volume ratio is 1:29), heating to 58 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 19.1g of refined orlistat, wherein the yield is 95.5%, and the purity is 99.63%.
Example 10
Under the protection of nitrogen, 8g of (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt, 0.3g of iron pentacarbonyl, 20g of nepistatin and 50ml of ether are mixed in a reaction vessel, stirred, heated to 36 ℃, then 20g of sodium borohydride is added, the temperature is kept, the reaction is carried out for 4.2 hours, after the reaction is finished, circulating water cooling at-5 ℃ to 5 ℃ is started, an extractant petroleum ether is added for extraction, diluted hydrochloric acid and water are respectively used for washing for 2 times, an organic phase is transferred into a distillation kettle, distillation is carried out until no fraction is produced, a roots pump is used for carrying out reduced pressure distillation under-0.098 MPa until no liquid drop is produced, and orlistat is obtained, and the distilled petroleum ether is barreled and weighed for application. Dissolving the orlistat in an ethanol/petroleum ether mixed solvent (volume ratio is 1:33), heating to 51 ℃, stirring for 15-25min, filtering, cooling the filtrate, performing suction filtration, and performing vacuum drying to obtain 18.4g of refined orlistat, wherein the yield is 92.0%, and the purity is 99.59%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The preparation method of orlistat is characterized by comprising the following steps:
mixing (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyl diamine cobalt, nipalustatin, iron pentacarbonyl, sodium borohydride and a solvent, heating to 30-40 ℃, keeping the temperature, reacting for 3-4.5 hours, and performing post-treatment to obtain orlistat.
2. The process for the preparation of orlistat according to claim 1, wherein the molar ratio of nepastatin to sodium borohydride, to cobalt (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine, to iron (pentacarbonyl) is 1: 0.7-1.2: 0.3-0.5: 0.01 to 0.02.
3. The preparation method of claim 3, wherein the molar ratio of the parabens to the sodium borohydride, the (R, R) - (-) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexylenediamine cobalt and the iron pentacarbonyl is 1: 0.7: 0.3: 0.01.
4. the production method according to claim 1, wherein the reduction reaction is carried out in the presence of a protective gas; the protective gas is nitrogen and/or helium.
5. The method of claim 1, wherein the post-treatment comprises an extraction step.
6. The preparation method according to claim 6, wherein the extraction reagent is one or more of methanol, ethanol, acetonitrile, petroleum ether, heptane and diethyl ether.
7. The preparation method according to claim 1, wherein the solvent is one or more of methanol, ethanol and diethyl ether.
8. The method of claim 1, further comprising a purification step.
9. The method of claim 8, wherein the purifying step comprises: the orlistat obtained is dissolved in a polar solvent: and stirring the mixed solvent with the volume ratio of the nonpolar solvent being 1: 22-35 at 50-58 ℃ for 15-25 min.
10. The preparation method according to claim 9, wherein the polar solvent is one or more of acetonitrile, diethyl ether and methanol; the nonpolar solvent is one or more of petroleum ether, heptane and carbon tetrachloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010519861.6A CN111499599A (en) | 2020-06-09 | 2020-06-09 | Preparation method of orlistat |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010519861.6A CN111499599A (en) | 2020-06-09 | 2020-06-09 | Preparation method of orlistat |
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| Publication Number | Publication Date |
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| CN111499599A true CN111499599A (en) | 2020-08-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202010519861.6A Withdrawn CN111499599A (en) | 2020-06-09 | 2020-06-09 | Preparation method of orlistat |
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| CN (1) | CN111499599A (en) |
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2020
- 2020-06-09 CN CN202010519861.6A patent/CN111499599A/en not_active Withdrawn
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