Production process of medroxyprogesterone acetate

Abstract

The invention relates to the technical field of medicine preparation, in particular to a medroxyprogesterone acetate production process, which comprises the following steps: adding 182.4 kg of N, N-dimethylformamide into a reaction kettle through a head tank, then extracting 60 kg of cyclohexene, adding the cyclohexene into the reaction kettle through the head tank, starting the reaction kettle, starting to stir and mix in the reaction kettle, adding the cyclohexene into the reaction kettle through the head tank, adding the cyclohexene into the reaction kettle through the head tank; adding 40kg of methine into the reaction kettle through a feeding port, introducing nitrogen, continuously stirring for 30 minutes, weighing 2kg of palladium-carbon, adding into the reaction kettle through a feeding port, stopping introducing nitrogen, slowly heating in a steam bath of the reaction kettle, controlling the internal temperature to 110 + / -2 DEG C, distilling for 60 minutes under normal pressure, controlling the internal temperature of the reaction kettle to 110 + / -2 DEG C, and refluxing for 60 minutes; according to the method, the problems that an existing medroxyprogesterone acetate production process flow is relatively complex, more intermediates exist, and the material utilization rate is relatively low can be effectively solved.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, in particular to a production process of medroxyprogesterone acetate. Background Art

[0002] Medroxyprogesterone acetate is mainly used to treat dysmenorrhea, functional amenorrhea, functional uterine bleeding, threatened abortion or habitual abortion, endometriosis, advanced breast cancer, endometrial adenocarcinoma and renal cancer. Its large dose can be used as a long-acting contraceptive injection. In addition, its effect is also reflected in the fact that after the endometrium loses the support of estrogen and progesterone and falls off during menstruation, it can continue to artificially supplement estrogen or progesterone, especially progesterone, so that the "helpless" endometrium continues to be supported and maintains a level of continuous thickening. In this way, the endometrium grows firmly on the uterine wall, preparing for the implantation of the fertilized egg, and achieving the purpose of delaying menstruation. Its structural formula is:

[0003] However, the existing medroxyprogesterone acetate production process still has shortcomings, specifically: the existing medroxyprogesterone acetate production process is relatively complicated, there are many intermediates, and the material utilization rate is low.

[0004] Therefore, a medroxyprogesterone acetate production process is needed to solve the problems raised in the above background technology. Summary of the invention

[0005] The object of the present invention is to provide a production process of medroxyprogesterone acetate to solve the problems raised in the above background technology.

[0006] To achieve the above object, the present invention provides the following technical solutions: A production process of medroxyprogesterone acetate comprises the following steps: S1, add 182.4kgN,N-dimethylformamide to the reactor through the header tank, then extract 60kg of cyclohexene and add cyclohexene to the reactor through the header tank, open the reactor, start stirring and mixing the reactor, then add 40kg of methine to the reactor through the feed port and introduce nitrogen, continue stirring for 30 minutes, then weigh 2kg of palladium carbon and add it to the reactor through the feed port, stop introducing nitrogen, slowly heat the reactor in a steam bath, control the internal temperature to 110±2°C, distill at normal pressure for 60 minutes, control the internal temperature of the reactor to 110±2°C and reflux for 60 minutes, stop heating the reactor and exhaust the remaining steam in the jacket, cool the reaction solution to 80°C, sample the medroxyprogesterone acetate hydrogenation reaction solution and perform HPLC detection, and the reaction endpoint is qualified; S2, after the reaction is completed, the temperature inside the reactor is controlled to 85±5°C and the vacuum degree is controlled to above -0.06MPa, and reduced pressure distillation is performed. After the distillation is completed, nitrogen is introduced into the reactor, and the reaction liquid is placed in a filter with an insulation jacket through the bottom valve of the reactor for filtration. The filtered reaction liquid flows into a new reactor, and the residue in the old reactor is cleaned up. 7.2kg of hydrochloric acid is extracted into a storage tank for standby use, and the sodium bicarbonate solution is then sent to a high-level tank for standby use. Cooling water is injected into the jacket of the new reactor to cool the internal temperature of the new reactor to 33°C, and the hydrochloric acid in the storage tank is added into the reactor, and the internal temperature of the reactor is controlled to 20 ~25℃, stir and react for 60 minutes, sample the medroxyprogesterone acetate transposition reaction liquid for HPLC detection until qualified, add the medroxyprogesterone acetate transposition reaction liquid into the new reactor through the high-level tank, then drain the remaining water in the reactor jacket and inject the frozen brine into the reactor jacket, cool the internal temperature to -5℃, control the internal temperature to -5±2℃, maintain stirring for 3 hours, so that the crystals are completely precipitated, put the materials in the new reactor into a centrifuge for centrifugal filtration, filter out the mother liquor, beat the filter cake with 40±5℃ warm water, stop the centrifuge, centrifuge the crude medroxyprogesterone acetate for central control sampling and detection, collect the filter cake and weigh it to obtain the crude medroxyprogesterone acetate; S3, extract 119.2kg of dichloromethane and add it to the reactor through the high-level tank, start stirring, and then add the wet crude medroxyprogesterone acetate to the reactor through the feed port. The reactor is heated by a jacket water bath to raise the temperature in the reactor to 30±2°C, and stirred for 30 minutes to fully dissolve the material. The reactor stops stirring, and the feed liquid is allowed to stand for 30 minutes, and the feed liquid is decolorized, and the decolorized feed liquid is sent to the crystallization kettle to check whether the solution is clear, start the crystallization kettle to stir, heat in a water bath, and perform atmospheric distillation to raise the internal temperature to 61±2°C. After the distillation is completed, the feed liquid is cooled, and the material in the crystallization kettle is placed in a flat plate closed centrifuge, centrifuged and filtered, and the mother liquor is filtered out. The filtered mother liquor is put into a storage tank, and barreled for three wastes. The filter cake is washed with 31.2kg of methanol, dried, and the washing liquid is combined with the mother liquor. The flat plate closed centrifuge is stopped and stopped, and the medroxyprogesterone acetate centrifugal central control sampling is tested, and the filter cake is collected; S4, check the production conditions, fill in the "operation" status card of the double cone rotary vacuum dryer, hang it in the specified location, confirm that the equipment has been cleaned and is within the validity period, preheat the double cone rotary vacuum dryer with hot water to an internal temperature of 65±5℃, put the collected medroxyprogesterone acetate wet product into the double cone rotary vacuum dryer, close the double cone rotary vacuum dryer cover, open the vacuum to a vacuum degree of -0.06Mpa or above, run the double cone rotary vacuum dryer to dry the material, heat the double cone rotary vacuum dryer with hot water to maintain an internal temperature of 65±5℃ and a vacuum degree of -0.06 or above, dry for 4 hours, start sampling and testing at the central control of medroxyprogesterone acetate drying, stop drying when it is qualified, and collect the medroxyprogesterone acetate dry product.

[0007] As a preferred solution of the present invention, the distillation temperature is recorded every 10 minutes during atmospheric distillation in S1, and the reflux temperature is recorded every 10 minutes during reflux. After each sampling test, the internal temperature needs to be raised to 110±2°C for reflux.

[0008] As a preferred solution of the present invention, the cleaning process of the residue of the old reactor in S2 is as follows: when the palladium carbon in the old reactor is almost dry, 38 kg of N,N-dimethylformamide is weighed and heated to 45°C, and the heated N,N-dimethylformamide is used to rinse out the residual palladium carbon in the reactor. The rinse liquid is filtered through a filter and sent to a new reactor. Stop injecting nitrogen into the old reactor, put the palladium carbon residue in the filter into an enamel barrel, immerse it with purified water, collect a certain amount, put it into a centrifuge, rinse it with purified water, and filter it. After draining the water, put it into a double-layer plastic bag for recycling.

[0009] As a preferred solution of the present invention, the temperature is recorded every 10 minutes during the reduced pressure distillation in S2, the sodium bicarbonate solution is prepared by mixing 4.8 kg of sodium bicarbonate with 56 kg of purified water, the temperature is recorded every 10 minutes during the stirring reaction, the temperature is recorded every 30 minutes during the crystallization, and the mother liquor filtered out during centrifugal filtration is transferred to a storage tank and barreled for the three wastes.

[0010] As a preferred solution of the present invention, the filter cake beating method in S2 is to rinse the filter cake with 40±5°C warm water for 60 minutes under centrifugal state, spin dry and send the discarded waste liquid to the factory waste liquid pool for centralized treatment, and the distillation is stopped after the volume of the distillate reaches 40L during the reduced pressure distillation, and the distillate is sent to the storage tank and barreled for the three wastes.

[0011] As a preferred embodiment of the present invention, the cooling treatment method in S3 is: inject circulating water into the interlayer of the crystallization kettle, cool the temperature inside the crystallization kettle to 40°C, drain the interlayer circulating water, inject chilled brine to cool to 0°C, and let it stand for 1 hour.

[0012] As a preferred solution of the present invention, the specific method of decolorization treatment in S3 is: the organic layer in the reactor is sent to the decolorization reactor, the water layer in the reactor is removed, the decolorization reactor is started and stirred, 158.4 kg of methanol is drawn and added to the decolorization reactor through the high-level tank, and then 2 kg of activated carbon is weighed and added to the decolorization reactor from the feeding port. The decolorization reactor is heated in a water bath using a jacket to raise the internal temperature to 40 ± 2 ° C, reflux decolorization for 2 hours, and the temperature is recorded every 20 minutes. The feed liquid in the decolorization reactor is filtered through a filter and sent to a crystallization kettle, and then 15.8 kg of methanol and 10.6 kg of dichloromethane are mixed together to obtain a mixed solution, and the mixed solution is used to rinse the decolorization kettle, and the rinse liquid is filtered through a filter and sent to the crystallization kettle.

[0013] As a preferred solution of the present invention, during the atmospheric distillation in S3, the distillation is stopped after the volume of the distillate reaches 100L, the distillate is put into a storage tank, barreled and handed over to the three wastes, and the temperature is recorded every 30 minutes during the atmospheric distillation.

[0014] Compared with the prior art, the present invention has the following beneficial effects: 1. In the present invention, N, N-dimethylformamide, cyclohexene, methine and palladium carbon are added to a reactor and nitrogen is introduced, mixed and stirred, and slowly heated in a steam bath, followed by atmospheric distillation, and after the reaction solution is cooled, the medroxyprogesterone acetate hydrogenation reaction solution is sampled and tested by HPLC, and the reaction end point is the qualified detection. After the reaction is completed, reduced pressure distillation is performed, and the reaction solution is placed in a filter with a heat-insulating jacket through the bottom valve of the reactor for filtration. The filtered reaction solution flows into a new reactor, and the residue in the old reactor is cleaned up, hydrochloric acid is added to the reactor and stirred for reaction, and the medroxyprogesterone acetate transposition reaction solution is sampled and tested by HPLC until it is qualified, and the medroxyprogesterone acetate transposition reaction solution is passed through a high pressure The new reactor is cooled and stirred to completely precipitate crystals. The material in the new reactor is placed in a centrifuge for centrifugal filtration. The filter cake is collected and weighed to obtain a crude medroxyprogesterone acetate. Dichloromethane and the wet crude medroxyprogesterone acetate are placed in the reactor, heated in a water bath and stirred, and allowed to stand after being fully dissolved. The feed liquid is decolorized and distilled at normal pressure in turn. After the distillation, the feed liquid is cooled. The material in the crystallization kettle is placed in a flat closed centrifuge, centrifuged and filtered, and the filter cake is collected when it stops running. The collected wet medroxyprogesterone acetate is placed in a double cone rotary vacuum dryer for drying. The dry medroxyprogesterone acetate can reach a yield of 57.0%-77.0%. The operation process is relatively simple, and there are fewer intermediates in the process, which can greatly improve the utilization rate of raw materials. DETAILED DESCRIPTION

[0015] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0016] To facilitate understanding of the present invention, the present invention will be described more comprehensively below and several embodiments of the present invention are given. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the disclosure of the present invention more thorough and comprehensive.

[0017] It should be noted that when an element is referred to as being "fixed on" another element, it may be directly on the other element or there may also be a central element. When an element is considered to be "connected to" another element, it may be directly connected to the other element or there may also be a central element. The terms "vertical", "horizontal", "left", "right" and similar expressions used in this article are for illustrative purposes only.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0019] Embodiment, the present invention provides a technical solution: A production process of medroxyprogesterone acetate comprises the following steps: S1, add 182.4kgN,N-dimethylformamide to the reactor through the header tank, then extract 60kg of cyclohexene and add cyclohexene to the reactor through the header tank, open the reactor, start stirring and mixing the reactor, then add 40kg of methine to the reactor through the feed port and introduce nitrogen, continue stirring for 30 minutes, then weigh 2kg of palladium carbon and add it to the reactor through the feed port, stop introducing nitrogen, slowly heat the reactor in a steam bath, control the internal temperature to 110±2°C, distill at normal pressure for 60 minutes, control the internal temperature of the reactor to 110±2°C and reflux for 60 minutes, stop heating the reactor and exhaust the remaining steam in the jacket, cool the reaction solution to 80°C, sample the medroxyprogesterone acetate hydrogenation reaction solution and perform HPLC detection, and the reaction endpoint is qualified; S2, after the reaction is completed, the temperature inside the reactor is controlled to 85±5°C and the vacuum degree is controlled to above -0.06MPa, and reduced pressure distillation is performed. After the distillation is completed, nitrogen is introduced into the reactor, and the reaction liquid is placed in a filter with an insulation jacket through the bottom valve of the reactor for filtration. The filtered reaction liquid flows into a new reactor, and the residue in the old reactor is cleaned up. 7.2kg of hydrochloric acid is extracted into a storage tank for standby use, and the sodium bicarbonate solution is then sent to a high-level tank for standby use. Cooling water is injected into the jacket of the new reactor to cool the internal temperature of the new reactor to 33°C, and the hydrochloric acid in the storage tank is added into the reactor, and the internal temperature of the reactor is controlled to 20 ~25℃, stir and react for 60 minutes, sample the medroxyprogesterone acetate transposition reaction liquid for HPLC detection until qualified, add the medroxyprogesterone acetate transposition reaction liquid into the new reactor through the high-level tank, then drain the remaining water in the reactor jacket and inject the frozen brine into the reactor jacket, cool the internal temperature to -5℃, control the internal temperature to -5±2℃, maintain stirring for 3 hours, so that the crystals are completely precipitated, put the materials in the new reactor into a centrifuge for centrifugal filtration, filter out the mother liquor, beat the filter cake with 40±5℃ warm water, stop the centrifuge, centrifuge the crude medroxyprogesterone acetate for central control sampling and detection, collect the filter cake and weigh it to obtain the crude medroxyprogesterone acetate; S3, extract 119.2kg of dichloromethane and add it to the reactor through the high-level tank, start stirring, and then add the wet crude medroxyprogesterone acetate to the reactor through the feed port. The reactor is heated by a jacket water bath to raise the temperature in the reactor to 30±2°C, and stirred for 30 minutes to fully dissolve the material. The reactor stops stirring, and the feed liquid is allowed to stand for 30 minutes, and the feed liquid is decolorized, and the decolorized feed liquid is sent to the crystallization kettle to check whether the solution is clear, start the crystallization kettle to stir, heat in a water bath, and perform atmospheric distillation to raise the internal temperature to 61±2°C. After the distillation is completed, the feed liquid is cooled, and the material in the crystallization kettle is placed in a flat plate closed centrifuge, centrifuged and filtered, and the mother liquor is filtered out. The filtered mother liquor is put into a storage tank, and barreled for three wastes. The filter cake is washed with 31.2kg of methanol, dried, and the washing liquid is combined with the mother liquor. The flat plate closed centrifuge is stopped and stopped, and the medroxyprogesterone acetate centrifugal central control sampling is tested, and the filter cake is collected; S4, check the production conditions, fill in the "operation" status card of the double cone rotary vacuum dryer, hang it in the specified location, confirm that the equipment has been cleaned and is within the validity period, preheat the double cone rotary vacuum dryer with hot water to an internal temperature of 65±5℃, put the collected medroxyprogesterone acetate wet product into the double cone rotary vacuum dryer, close the double cone rotary vacuum dryer cover, open the vacuum to a vacuum degree of -0.06Mpa or above, run the double cone rotary vacuum dryer to dry the material, heat the double cone rotary vacuum dryer with hot water to maintain an internal temperature of 65±5℃ and a vacuum degree of -0.06 or above, dry for 4 hours, start sampling and testing at the central control of medroxyprogesterone acetate drying, stop drying when it is qualified, and collect the medroxyprogesterone acetate dry product.

[0020] Furthermore, in the S1, the distillation temperature is recorded every 10 minutes during atmospheric distillation, and the reflux temperature is recorded every 10 minutes during reflux. After each sampling test, the internal temperature needs to be raised to 110±2°C for reflux.

[0021] Furthermore, the cleaning process of the residues in the old reactor in S2 is as follows: when the palladium carbon in the old reactor is almost dry, 38 kg of N,N-dimethylformamide is weighed and heated to 45°C, and the heated N,N-dimethylformamide is used to rinse out the residual palladium carbon in the reactor. The rinse liquid is filtered through a filter and sent to the new reactor. Stop injecting nitrogen into the old reactor, put the palladium carbon residue in the filter into an enamel barrel, immerse it with purified water, collect a certain amount, and put it into a centrifuge to rinse and filter with purified water. After filtering out the water, put it into a double-layer plastic bag for recycling.

[0022] Furthermore, the temperature is recorded every 10 minutes during the reduced pressure distillation in S2, the sodium bicarbonate solution is prepared by mixing 4.8 kg of sodium bicarbonate with 56 kg of purified water, the temperature is recorded every 10 minutes during the stirring reaction, the temperature is recorded every 30 minutes during the crystallization, and the mother liquor filtered out during centrifugal filtration is transferred to a storage tank and barreled for the three wastes.

[0023] Furthermore, the filter cake beating method in S2 is to rinse the filter cake with 40±5°C warm water for 60 minutes under centrifugal state, spin dry and send the discarded waste liquid to the factory waste liquid pool for centralized treatment, and the distillation is stopped when the volume of the distillate reaches 40L during the reduced pressure distillation, and the distillate is sent to the storage tank and barreled for the three wastes.

[0024] Furthermore, the cooling treatment method in S3 is: inject circulating water into the interlayer of the crystallization kettle, cool the temperature inside the crystallization kettle to 40°C, drain the interlayer circulating water, inject chilled brine to cool to 0°C, and let it stand for 1 hour.

[0025] Furthermore, the specific method of the decolorization treatment in S3 is: the organic layer in the reactor is sent to the decolorization reactor, the water layer in the reactor is removed, the decolorization reactor is started and stirred, 158.4 kg of methanol is drawn and added to the decolorization reactor through the high-level tank, and then 2 kg of activated carbon is weighed and added to the decolorization reactor from the feeding port. The decolorization reactor is heated in a water bath using a jacket to raise the internal temperature to 40±2°C, reflux decolorization for 2 hours, and the temperature is recorded every 20 minutes. The feed liquid in the decolorization reactor is filtered through a filter and sent to a crystallization kettle, and then 15.8 kg of methanol and 10.6 kg of dichloromethane are mixed together to obtain a mixed solution, and the mixed solution is used to rinse the decolorization reactor, and the rinse liquid is filtered through a filter and sent to the crystallization kettle.

[0026] Furthermore, during the atmospheric distillation in S3, the distillation is stopped after the volume of the distillate reaches 100 L, the distillate is put into a storage tank, and the barrel is used for the three wastes. The temperature is recorded every 30 minutes during the atmospheric distillation.

[0027] 182.4 kg of N, N-dimethylformamide was added to the reactor through the header tank, and then 60 kg of cyclohexene was extracted and added to the reactor through the header tank. The reactor was opened and stirred and mixed in the reactor. Then 40 kg of methine was added to the reactor through the feed port and nitrogen was introduced. Stirring was continued for 30 minutes. Then 2 kg of palladium carbon was weighed and added to the reactor through the feed port. The introduction of nitrogen was stopped. The reactor was slowly heated in a steam bath, and the internal temperature was controlled to 110° C., and distilled at normal pressure for 60 minutes. The distillation temperature was recorded every 10 minutes. The internal temperature of the reactor was controlled to 110° C. and refluxed for 60 minutes. The reflux temperature was recorded every 10 minutes. The reactor was stopped from heating and the residual steam in the jacket was exhausted. The reaction solution was cooled to 80° C., and the medroxyprogesterone acetate hydrogenation reaction solution was sampled and tested by HPLC. After each sampling test, the internal temperature needed to be raised to 110° C. and refluxed. The reaction endpoint was qualified. After the reaction is completed, the temperature inside the reactor is controlled to 85°C and the vacuum degree is controlled to be above -0.06MPa, and reduced pressure distillation is performed. The temperature is recorded every 10 minutes. The distillation is stopped when the volume of the distillate reaches 40L. The distillate is transferred to a storage tank and barreled to the three wastes. After the distillation is completed, nitrogen is introduced into the reactor. The reaction liquid is placed in a filter with an insulation jacket through the bottom valve of the reactor for filtration. The filtered reaction liquid flows into a new reactor. When the palladium carbon in the old reactor is almost dry, 38kg of N,N-dimethylformamide is weighed and heated to 45°C. The heated N,N-dimethylformamide is used to rinse the residual palladium carbon in the reactor. The rinse liquid is filtered through the filter and then sent to the new reactor. Stop injecting nitrogen into the old reactor, put the palladium carbon residue in the filter into an enamel barrel, immerse it with purified water, collect a certain amount, put it into a centrifuge, rinse it with purified water, and filter it. After the water is filtered, put it into a double-layer plastic bag for recycling. 7.2 kg of hydrochloric acid was extracted into a storage tank for standby use, 4.8 kg of sodium bicarbonate was mixed with 56 kg of purified water to prepare a sodium bicarbonate solution, and the sodium bicarbonate solution was sent to a high-level tank for standby use, cooling water was injected into the jacket of the new reactor, and the internal temperature of the new reactor was cooled to 33 ° C, the hydrochloric acid in the storage tank was added to the reactor, and the internal temperature of the reactor was controlled to 25 ° C, and the reaction was stirred for 60 minutes. During the stirring reaction, the temperature was recorded every 10 minutes, and the medroxyprogesterone acetate transposition reaction liquid was sampled and tested by HPLC until it was qualified; The medroxyprogesterone acetate transposition reaction liquid is added to the new reactor through the high-level tank, and then the residual water in the reactor jacket is drained and the frozen brine is injected into the reactor jacket, so that the internal temperature is cooled to -5°C, and the internal temperature is controlled to -5°C, and stirring is maintained for 3 hours to allow the crystals to precipitate completely. During the crystallization, the temperature is recorded every 30 minutes, and the materials in the new reactor are placed in a centrifuge for centrifugal filtration to filter out the mother liquor. The mother liquor filtered out during the centrifugal filtration is put into the storage tank, and the three wastes are loaded into barrels. The filter cake is pulped with 40±5°C warm water, and the filter cake is washed with 40°C warm water under centrifugal state for 60 minutes, and the waste liquid is spun off and sent to the waste liquid pool in the plant for centralized treatment. The centrifuge is stopped, and the crude medroxyprogesterone acetate is centrifuged for central control sampling and testing. The filter cake is collected and weighed to obtain the crude medroxyprogesterone acetate; 119.2 kg of dichloromethane was drawn and added to the reactor through the high-level tank, stirring was started, and then the wet crude medroxyprogesterone acetate was added to the reactor through the feed port. The reactor was heated in a jacketed water bath to raise the temperature in the reactor to 30°C. Stirring was performed for 30 minutes to fully dissolve the material. The reactor was stopped from stirring, and the feed liquid was allowed to stand for 30 minutes. The organic layer in the reactor was sent to the decolorization kettle, and the water layer in the reactor was removed. The decolorization kettle was started and stirred, and 158.4 kg of methanol was drawn and added to the reactor through the high-level tank. The tank is added to the decolorization kettle, and then 2kg of activated carbon is weighed and added to the decolorization kettle from the feeding port. The decolorization kettle is heated in a water bath with a jacket to raise the internal temperature to 40°C, and refluxed for 2 hours. The temperature is recorded every 20 minutes, and the feed liquid in the decolorization kettle is filtered through a filter and then sent to a crystallization kettle, and then 15.8kg of methanol and 10.6kg of dichloromethane are mixed together to obtain a mixed solution, and the mixed solution is used to rinse the decolorization kettle, and the rinse liquid is filtered through a filter and then sent to the crystallization kettle; The decolorized liquid is sent to the crystallization kettle, and the solution is checked to be clear. The crystallization kettle is opened for stirring, heated in a water bath, and distilled at normal pressure. During the distillation at normal pressure, the distillate is stopped after the volume of the distillate reaches 100L. The distillate is placed in a storage tank, barreled and handed over to the three wastes. During the distillation at normal pressure, the temperature is recorded every 30 minutes to raise the internal temperature to 61°C. After the distillation is completed, circulating water is injected into the interlayer of the crystallization kettle, and the temperature in the crystallization kettle is cooled to 40°C. The interlayer circulating water is drained, and then chilled brine is injected to cool to 0°C. The mixture is allowed to stand for 1 hour, and the material in the crystallization kettle is placed in a flat plate closed centrifuge, centrifuged and filtered, and the mother liquor is filtered out. The filtered mother liquor is put into the storage tank, barreled and handed over to the three wastes, and the filter cake is washed with 31.2kg of methanol, dried, and the washing liquid is combined with the mother liquor. The flat plate closed centrifuge is stopped and stopped, and the medroxyprogesterone acetate centrifugal central control sampling is tested, and the filter cake is collected; Check the production conditions, fill in the "operation" status card of the double-cone rotary vacuum dryer, hang it in the specified location, confirm that the equipment has been cleaned and is within the validity period, preheat the double-cone rotary vacuum dryer with hot water to an internal temperature of 65°C, put the collected wet medroxyprogesterone acetate into the double-cone rotary vacuum dryer, close the double-cone rotary vacuum dryer cover, open the vacuum to a vacuum degree of more than -0.06Mpa, run the double-cone rotary vacuum dryer to dry the material, heat the double-cone rotary vacuum dryer with hot water to maintain an internal temperature of 65°C and a vacuum degree of more than -0.06, dry for 4 hours, start sampling and testing at the central control of medroxyprogesterone acetate drying, stop drying when it is qualified, and collect the medroxyprogesterone acetate dry product.

[0028] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A production process of medroxyprogesterone acetate, characterized in that: The following steps are involved: S1, add 182.4kgN,N-dimethylformamide to the reactor through the header tank, then extract 60kg of cyclohexene and add cyclohexene to the reactor through the header tank, open the reactor, start stirring and mixing the reactor, then add 40kg of methine to the reactor through the feed port and introduce nitrogen, continue stirring for 30 minutes, then weigh 2kg of palladium carbon and add it to the reactor through the feed port, stop introducing nitrogen, slowly heat the reactor in a steam bath, control the internal temperature to 110±2°C, distill at normal pressure for 60 minutes, control the internal temperature of the reactor to 110±2°C and reflux for 60 minutes, stop heating the reactor and exhaust the remaining steam in the jacket, cool the reaction solution to 80°C, sample the medroxyprogesterone acetate hydrogenation reaction solution and perform HPLC detection, and the reaction endpoint is qualified; S2, after the reaction is completed, the temperature inside the reactor is controlled to 85±5°C and the vacuum degree is controlled to above -0.06MPa, and reduced pressure distillation is performed. After the distillation is completed, nitrogen is introduced into the reactor, and the reaction liquid is placed in a filter with an insulation jacket through the bottom valve of the reactor for filtration. The filtered reaction liquid flows into a new reactor, and the residue in the old reactor is cleaned up. 7.2kg of hydrochloric acid is extracted into a storage tank for standby use, and the sodium bicarbonate solution is then sent to a high-level tank for standby use. Cooling water is injected into the jacket of the new reactor to cool the internal temperature of the new reactor to 33°C, and the hydrochloric acid in the storage tank is added into the reactor, and the internal temperature of the reactor is controlled to 20 ~25℃, stir and react for 60 minutes, sample the medroxyprogesterone acetate transposition reaction liquid for HPLC detection until qualified, add the medroxyprogesterone acetate transposition reaction liquid into the new reactor through the high-level tank, then drain the remaining water in the reactor jacket and inject the frozen brine into the reactor jacket, cool the internal temperature to -5℃, control the internal temperature to -5±2℃, maintain stirring for 3 hours, so that the crystals are completely precipitated, put the materials in the new reactor into a centrifuge for centrifugal filtration, filter out the mother liquor, beat the filter cake with 40±5℃ warm water, stop the centrifuge, centrifuge the crude medroxyprogesterone acetate for central control sampling and detection, collect the filter cake and weigh it to obtain the crude medroxyprogesterone acetate; S3, extract 119.2kg of dichloromethane and add it to the reactor through the high-level tank, start stirring, and then add the wet crude medroxyprogesterone acetate to the reactor through the feed port. The reactor is heated by a jacket water bath to raise the temperature in the reactor to 30±2°C, and stirred for 30 minutes to fully dissolve the material. The reactor stops stirring, and the feed liquid is allowed to stand for 30 minutes, and the feed liquid is decolorized, and the decolorized feed liquid is sent to the crystallization kettle to check whether the solution is clear, start the crystallization kettle to stir, heat in a water bath, and perform atmospheric distillation to raise the internal temperature to 61±2°C. After the distillation is completed, the feed liquid is cooled, and the material in the crystallization kettle is placed in a flat plate closed centrifuge, centrifuged and filtered, and the mother liquor is filtered out. The filtered mother liquor is put into a storage tank, and barreled for three wastes. The filter cake is washed with 31.2kg of methanol, dried, and the washing liquid is combined with the mother liquor. The flat plate closed centrifuge is stopped and stopped, and the medroxyprogesterone acetate centrifugal central control sampling is tested, and the filter cake is collected; S4, check the production conditions, fill in the "operation" status card of the double cone rotary vacuum dryer, hang it in the specified position, confirm that the equipment has been cleaned and is within the validity period, preheat the double cone rotary vacuum dryer with hot water to an internal temperature of 65±5℃, put the collected wet medroxyprogesterone acetate into the double cone rotary vacuum dryer, close the double cone rotary vacuum dryer cover, open the vacuum to a vacuum degree of more than -0.06Mpa, run the double cone rotary vacuum dryer to dry the material, heat the double cone rotary vacuum dryer with hot water to maintain an internal temperature of 65±5℃ and a vacuum degree of more than -0.06, dry for 4 hours, start sampling and testing of the medroxyprogesterone acetate drying central control, stop drying when it is qualified, and collect the medroxyprogesterone acetate dry product.

2. A medroxyprogesterone acetate production process according to claim 1, characterized in that: In the S1, the distillation temperature is recorded every 10 minutes during atmospheric distillation, and the reflux temperature is recorded every 10 minutes during reflux. After each sampling test, the internal temperature needs to be raised to 110±2°C for reflux.

3. A medroxyprogesterone acetate production process according to claim 1, characterized in that: The cleaning process of the old reactor residue in S2 is as follows: when the palladium carbon in the old reactor is almost dry, 38 kg of N,N-dimethylformamide is weighed and heated to 45°C, and the heated N,N-dimethylformamide is used to rinse out the residual palladium carbon in the reactor. The rinse liquid is filtered through a filter and sent to the new reactor. Stop injecting nitrogen into the old reactor, put the palladium carbon residue in the filter into an enamel barrel, immerse it with purified water, collect a certain amount of it, put it into a centrifuge, rinse it with purified water, and filter it. After filtering out the water, put it into a double-layer plastic bag for recycling.

4. A medroxyprogesterone acetate production process according to claim 1, characterized in that: The temperature is recorded every 10 minutes during the reduced pressure distillation in S2, the sodium bicarbonate solution is prepared by mixing 4.8 kg of sodium bicarbonate with 56 kg of purified water, the temperature is recorded every 10 minutes during the stirring reaction, the temperature is recorded every 30 minutes during the crystallization, and the mother liquor filtered out during centrifugal filtration is transferred to a storage tank and barreled for the three wastes.

5. A medroxyprogesterone acetate production process according to claim 1, characterized in that: The filter cake beating method in S2 is to rinse the filter cake with 40±5°C warm water for 60 minutes under centrifugal state, spin dry and send the discarded waste liquid to the factory waste liquid pool for centralized treatment. When the volume of the distillate reaches 40L during the reduced pressure distillation, the distillation is stopped, and the distillate is sent to the storage tank and barreled for the three wastes.

6. A medroxyprogesterone acetate production process according to claim 1, characterized in that: The cooling treatment method in S3 is: inject circulating water into the interlayer of the crystallization kettle, cool the temperature inside the crystallization kettle to 40°C, drain the interlayer circulating water, inject frozen brine to cool to 0°C, and let it stand for 1 hour.

7. A medroxyprogesterone acetate production process according to claim 1, characterized in that: The specific method of the decolorization treatment in S3 is: the organic layer in the reactor is sent to the decolorization reactor, the water layer in the reactor is removed, the decolorization reactor is started to stir, 158.4 kg of methanol is drawn and added to the decolorization reactor through the high-level tank, and then 2 kg of activated carbon is weighed and added to the decolorization reactor through the feeding port, the decolorization reactor is heated in a water bath with a jacket to raise the internal temperature to 40±2°C, reflux decolorization for 2 hours, and the temperature is recorded every 20 minutes. The feed liquid in the decolorization reactor is filtered through a filter and then sent to a crystallization kettle, and then 15.8 kg of methanol and 10.6 kg of dichloromethane are mixed together to obtain a mixed solution, and the mixed solution is used to rinse the decolorization kettle, and the rinse liquid is filtered through a filter and then sent to the crystallization kettle.

8. A medroxyprogesterone acetate production process according to claim 1, characterized in that: During the atmospheric distillation in S3, the distillation is stopped after the volume of the distillate reaches 100L, the distillate is put into a storage tank, and the three wastes are put into barrels. The temperature is recorded every 30 minutes during the atmospheric distillation.

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