CN103509080B - A kind of processing method improving epoxy Progesterone and prepare yield and purity - Google Patents
A kind of processing method improving epoxy Progesterone and prepare yield and purity Download PDFInfo
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- CN103509080B CN103509080B CN201210213213.3A CN201210213213A CN103509080B CN 103509080 B CN103509080 B CN 103509080B CN 201210213213 A CN201210213213 A CN 201210213213A CN 103509080 B CN103509080 B CN 103509080B
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Abstract
The present invention relates to a kind of processing method improving epoxy Progesterone and prepare yield and purity, its processing step sequence is the reaction of step one oxo bridge in order, step 2 enrichment process, step 3 walsh is reacted, step 4 rushes the five large steps such as gold-plating operation and step 5 process for refining process, reach the combined technological method such as the reaction process that reduces non-complete reaction oxygen bridge material by the reversed reaction process increased by the reaction conditions changing walsh process in reactant concn and minimizing walsh oxidising process and improve epoxy Progesterone finished product purity and yield, HPLC average measurement content average yield while reaching 99% of epoxy Progesterone is made to reach more than 80%, effective raising epoxy Progesterone final product quality improves unit output simultaneously, reduce wastage of material and meet both at home and abroad the requirement of epoxy Progesterone final product quality, obtain higher economic benefit and meet the high-quality requirement to bulk drug in high-quality medicine preparation process.
Description
Technical field
The present invention relates to a kind of processing method field of improving epoxy Progesterone and preparing yield and purity.
Background technology
Steroid hormone is a kind of large class medicine widely of of a great variety, clinical application at present, and epoxy Progesterone has very important pharmaceutical use as the medicine substance of steroid hormone medicine, the hormones series product such as prednisoni acetas, budesonide, Prednisone acetate, methyltestosterone, ring mifepristone, Androstenedione adopting epoxy Progesterone to carry out prepared by deep processing are the second largest class medicines that the world is only second to antibiotics.Therefore the production of epoxy Progesterone and processing thereof have extremely significant economic benefit and extremely vast potential for future development.The traditional processing technology of current domestic epoxy Progesterone is partly dissolved in methanol solvate by pregnant steroid diene alcohol ketone, in the basic conditions, hydrogen peroxide is utilized to make oxygenant, carry out oxo bridge reaction, after completing, methyl alcohol is all reclaimed, change toluene and make solvent in anhydrous conditions, catalyzer is made with aluminum isopropylate, epoxypregnenolone and pimelinketone are carried out walsh oxidizing reaction, heat up in a steamer after steaming desolventizes through steam punching and be separated to obtain crude product, epoxy Progesterone finished product is obtained by solvent recrystallization, wherein above-mentioned technique the walsh oxidising process that is suitable for be a reversible balanced reaction process, the reversed reaction process increased in reactant concn minimizing walsh oxidizing reaction has extremely important effect to raising epoxy Progesterone finished product purity and yield.The traditional processing technology of above-mentioned epoxy Progesterone is not because solving the technical barriers such as the reversed reaction process increased in reactant concn minimizing walsh oxidizing reaction well, cause the finished product of prepared epoxy Progesterone cannot reach the technical requirements of high purity and high yield, it is that method by reducing yield repeatedly recrystallization realizes that current domestic preparative HPLC measures the high purity epoxy Progesterone of content more than 99%, and production cost is high and waste is serious; The method that yield then taking more than 80% reduces epoxy Progesterone purity realizes, and epoxy Progesterone HPLC measures content lower than 98%, the inferior preparation requirement that cannot meet high-quality medicine of quality product.Preparative HPLC measures content more than 99% and the epoxy Progesterone of the high-purity high-yield of yield more than 80% is the technical barrier being badly in need of at present overcoming, solve this technical barrier for reduction epoxy Progesterone production cost, to cut the waste and the quality that improves medicine has extremely important effect.
Summary of the invention
The present invention will solve and be to provide a kind of processing method improving epoxy Progesterone and prepare yield and purity, the reversed reaction process effectively increased in reactant concn raising catalyst activity minimizing walsh oxidising process by the reaction conditions changing walsh oxidising process reaches the effect reducing non-complete reaction oxygen bridge material, increase reactant concn and reach effects such as the oxygen bridge material of non-complete reaction react completely by re-starting walsh oxidizing reaction after the oxygen bridge material separation and purification of non-complete reaction, improve oxidation reaction condition and effectively improve catalyst activity, the methyl alcohol that last batch is reclaimed and mother liquor can be used in the preparation process of epoxy Progesterone of next batch, reach recycle and avoid effective constituent to run off, the preparation process of epoxy Progesterone is produced by batch cycle flowing, by technological method combined for above-mentioned reaction process being improved purity and the yield of epoxy Progesterone finished product, through synthesis measuring, while often the HPLC average measurement content of epoxy Progesterone of continuous ten batches can reach more than 99%, average yield reaches more than 80%, improve unit output at effective epoxy Progesterone final product quality that improves simultaneously, reduce wastage of material and meet both at home and abroad the requirement of epoxy Progesterone final product quality, improve product yield simultaneously, obtain higher economic benefit and meet the high-quality requirement to bulk drug in high-quality medicine preparation process.
The present invention is for solving the problems of the technologies described above, and the technical scheme of employing is:
A kind ofly improve processing method that epoxy Progesterone prepares yield and purity and comprise the following steps of carrying out in order and be:
Step one, oxo bridge react, and carry out oxo bridge reaction after a certain amount of hydrogen peroxide, diene solution and sheet alkaline solution are added oxo bridge retort and make oxo bridge liquid, the idiographic flow of oxo bridge reaction is in order:
1, ice maker is opened in advance, by brine tank inner salt water for cooling to-10 DEG C;
2, the preparation of diene solution and adition process: first to a certain amount of methyl alcohol of suction in clean oxo bridge retort, add a certain amount of pregnant steroid diene alcohol ketone and stir, make diene solution in oxo bridge retort;
Wherein in order to wash prepare and add diene solution time attach in tank, tank skin, the pregnant steroid diene alcohol ketone of part on stir shaft, also cleaning process is comprised in the preparation and adition process of diene solution, detailed process is: with a small amount of methyl alcohol by tank, tank skin, the pregnant steroid diene alcohol ketone that stir shaft attaches rinses into diene solution, makes in tank, tank skin, stir shaft does not attach oxo bridge retort tank mouth on pregnant steroid diene alcohol ketone bonnet, open exhaust-valve, open stirring and pass into nitrogen protection;
Wherein in last batch epoxy Progesterone preparation process in step 2 the methyl alcohol of institute's recovery in this batch of epoxy Progesterone preparation process for making diene solution.
3, hydrogen peroxide, sheet alkaline solution adition process adopt substep at the uniform velocity drip technological process, detailed process in order:
A), by the hydrogen peroxide accounting for total amount 1/4 in suction hydrogen peroxide high level tank in advance adopt and at the uniform velocity drip mode and add in oxo bridge retort, time for adding controls at 15-20 minute;
B), by the sheet alkaline solution accounting for total amount 1/3 in suction alkali lye high level tank in advance adopt and at the uniform velocity drip mode and add in oxo bridge retort, time for adding controls at 20-30 minute;
C), hydrogen peroxide remaining in hydrogen peroxide high level tank is at the uniform velocity added dropwise in oxo bridge retort, time for adding controls at 35-45 minute, control temperature in dropping process in oxo bridge retort is 34 DEG C, and the mixing solutions be added dropwise to complete in rear oxo bridge retort is oxo bridge liquid;
Solution temperature wherein in step c in oxo bridge retort can continue because of chemical reaction to raise, must the top temperature of solution in oxo bridge retort in dropping process be controlled below 34 DEG C, control temperature in dropping process in oxo bridge retort is the implementation procedure of 34 DEG C: carry out forced cooling when allowing solution in oxo bridge retort naturally be warming up to 34 DEG C in dropping process, the temperature of solution in oxo bridge retort is controlled at 33 DEG C within the scope of 34 DEG C, until complete the follow-up continuation of insurance of dropping process be held in this temperature range remove after 20 minutes temperature control, allow mixing solutions Temperature fall, the temperature of the mixing solutions in whole process in oxo bridge retort all the time must not higher than 34 DEG C.
Carry out forced cooling when allowing solution in oxo bridge retort naturally be warming up to 34 DEG C in wherein dropping process, the temperature of solution in oxo bridge retort is controlled at 33.5 DEG C to 34 DEG C.
Refer to as far as possible close to 34 DEG C in prior art condition license situation when wherein solution is warming up to 34 DEG C naturally, but can not more than 34 DEG C.
Wherein sheet alkaline solution in clean plastic tank, pours a certain amount of alkali in advance, adds a certain amount of tap water, fully stirs to add a certain amount of water glass after sheet alkali is dissolved completely and make through stirring evenly.
Step 2, enrichment process, oxo bridge liquid in oxo bridge retort is drawn in oxo bridge concentration tank after intensification concentrating under reduced pressure, makes oxygen bridge material, concrete technology flow process is: draw in oxo bridge concentration tank by the oxo bridge liquid in oxo bridge retort, it is clear that oxo bridge concentration tank is evacuated to tank endoscopy, do not open stirring, the interlayer water discharge valve of oxo bridge concentration tank is opened a little the rear steam that slowly passes into and slow heat temperature raising is carried out to oxo bridge concentration tank, oxo bridge liquid is rear concentrated generation oxygen bridge material because methyl alcohol is all steamed, and completes intensification concentrating under reduced pressure.
Wherein intensification concentrating under reduced pressure is made up of the one-level intensification concentrating under reduced pressure sequentially carried out and secondary intensification concentrating under reduced pressure;
Wherein one-level intensification concentrating under reduced pressure slowly passes into steam to carry out slow heat temperature raising to oxo bridge concentration tank, a certain amount of methyl alcohol in oxo bridge concentration tank is distilled out of, oxo bridge liquid because of a certain amount of methyl alcohol be distilled out of after be concentrated to yield one-level oxygen bridge material, one-level oxygen bridge material is moist thick paste.
Wherein secondary temperature elevation concentrating under reduced pressure is: stop after completing one-level intensification concentrating under reduced pressure passing into steam, in the mother liquor suction oxo bridge concentration tank applied mechanically upper batch and one-level oxygen bridge material mix and pass into steam after stirring slow heat temperature raising is carried out to oxo bridge concentration tank, material in oxo bridge concentration tank is because of after methyl alcohol is concentrated into thick paste by being constantly distilled out of, starting stirring turning over materials makes it be concentrated into approximate dry powder further, stop passing into steam after till methyl alcohol in oxo bridge concentration tank is steamed to the greatest extent, in oxo bridge concentration tank, the material of approximate dry powder is oxygen bridge material.
Wherein one-level intensification concentrating under reduced pressure and and secondary intensification concentrating under reduced pressure process in intensification concentrating under reduced pressure be keeping the vapor pressure of oxo bridge concentration tank to be less than 0.1MPa, in tank, vacuum tightness is not less than 0.07MPa, controls gas phase temperature and is no more than and carries out at 75 DEG C.
Wherein controlling the implementation procedure that gas phase temperature is no more than 75 DEG C is: be less than 0.1MPa keeping the vapor pressure of oxo bridge concentration tank, under in tank, vacuum tightness is not less than 0.07MPa situation, slowly pass into temperature and be not less than 73 DEG C but the steam being no more than 75 DEG C, the time passing into steam in one-level intensification concentrating under reduced pressure process is 1 to 2 hour; Pass in secondary intensification concentrating under reduced pressure process steam be till methyl alcohol in oxo bridge concentration tank is steamed to the greatest extent after stop.
Wherein in secondary temperature elevation concentrating under reduced pressure, the upper batch of methanol mother liquor applied mechanically is preparing in last batch epoxy Progesterone process according to technological method of the present invention, the mixed solution of the methyl alcohol reclaimed in step 5 process for refining process and non-complete reaction oxygen bridge material.
Wherein through one-level intensification concentrating under reduced pressure and and the methyl alcohol that steams of secondary intensification concentrating under reduced pressure return in oxo bridge retort and apply mechanically, for preparing diene solution in next batch epoxy Progesterone preparation process;
Wherein after intensification concentrating under reduced pressure completes by last batch epoxy Progesterone preparation process, to dissolve after oxygen bridge material in suction walsh retort in a part of toluene suction oxo bridge concentration tank that step 4 reclaims.
Step 3, walsh react, change toluene and make solvent in anhydrous conditions, make catalyzer with aluminum isopropylate, after the oxygen bridge material made and cyclohexanone are carried out walsh reaction, make walsh reaction solution through step 2, detailed process sequentially:
A), one-level walsh reaction, detailed process is: after the oxygen bridge material be dissolved in a certain amount of toluene is added walsh retort, open thickening system valve, to pass into steam under stirring state and intensification thickening to a certain amount of toluene is carried out to the oxygen bridge material after dissolving be distilled out of not opening, dehydration at least 2 hours, dehydration is until walsh retort visor is clear and bright without the globule, anhydrous in walsh retort, and the material after dehydration in walsh retort is one-level walsh material;
B), the detailed process of secondary walsh reaction is: a certain amount of pimelinketone added walsh retort and one-level walsh mixing of materials after the reaction of one-level walsh and stir, continue intensification thickening to a certain amount of toluene and be distilled out of rear reflux dewatering certain hour, until walsh retort visor is clear and bright without the globule, confirm dehydration complete anhydrous in walsh retort after, stop steam be slightly cooled to whipped state without backflow after terminate, the material in walsh retort is secondary walsh material;
Wherein a certain amount of toluene carries out reflux dewatering after carrying out adding a certain amount of alkaline solution in reflux dewatering process after being distilled out of, and the reflux dewatering time is 30 minutes to 1 hour; Wherein the amount of sheet alkaline solution should guarantee the material in walsh retort fully to dissolve.
C), generate walsh reaction solution, add a certain amount of aluminum isopropylate and secondary walsh mixing of materials fast from the dog-house of walsh retort and stir, being warming up to backflow clock reaction simultaneously and having generated walsh reaction solution after 1.5 hours;
Wherein reflux end, opens steam punching and heat up in a steamer tank condenser recirculated water, heat up in a steamer in tank by the punching of walsh reaction solution suction steam;
Wherein a part of toluene suction steam punching steamed in this step is heated up in a steamer in tank, for the preparation of next batch epoxy Progesterone.
Step 4, rush gold-plating operation, sequentially adopt after rushing gold-plating technique and Oppenauer crude product preparation technology and make Oppenauer crude product; Rush gold-plating technique be divided into carry out in order tentatively rush gold-plating technique and secondary rushes gold-plating technique;
Wherein preliminary punching is heated up in a steamer technique and is: after tank is heated up in a steamer in the punching of walsh reaction solution suction steam, the steam that tank interlayer passes into certain temperature is heated up in a steamer to steam punching, control gas bag pressure 0-0.5kg/cm2, close down steam after punching heats up in a steamer 30 minutes and leave standstill 30 minutes, then rush from steam and heat up in a steamer pot bottom outlet discharge sheet alkaline solution, what the interior retention of tank was heated up in a steamer in steam punching is that preliminary punching heats up in a steamer material;
Wherein secondary punching is heated up in a steamer technique and is: heat up in a steamer in tank to steam punching and add a certain amount of cold water, alkali lye is heated up in a steamer in suction punching, open stir make cold water, alkali lye is heated up in a steamer in punching and preliminary punching is heated up in a steamer mixing of materials even Hou Kai tri-road steam and carried out rushing heating up in a steamer to punching and heat up in a steamer without oily matter in the water of recovery, it is rush to heat up in a steamer material that steam punching heats up in a steamer what retain in tank;
Wherein secondary rushes the vapor pressure heated up in a steamer is 0.5-1.0kg/cm2;
Wherein punching is heated up in a steamer in process to rush and is distillated toluene, takes out rushing the toluene distillated the making returning the epoxy Progesterone being used for next batch in oxo bridge concentration tank;
Wherein Oppenauer crude product preparation process is: heat up in a steamer after alkali lye is heated up in a steamer in a certain amount of punching of suction at the bottom of tank tank from steam punching and add a certain amount of water, mixture is stirred into after heating up in a steamer mixing of materials with punching, open the bottom valve that steam punching heats up in a steamer tank after steam off valve and the steam punching mixture pressure release of heating up in a steamer in tank is entered whizzer, add boiling water washing until mixture makes epoxy Progesterone Oppenauer crude product in neutral rear drying discharging, epoxy Progesterone Oppenauer crude product is weighed.
It is the sheet alkaline solution be made into after adding the proportioning mixing and stirring of 10kg water by every 4kg sheet alkali that rushing wherein described in this step heats up in a steamer alkali lye.
Step 5, process for refining process, by the epoxy Progesterone Oppenauer crude product made, obtain epoxy Progesterone finished product through solvent recrystallization, detailed process is sequentially:
1, whole epoxy Progesterone Oppenauer crude product dropped in the reactor for the treatment of tank, inspection surveys the methyl alcohol that rear epoxy Progesterone Oppenauer crude product quality condition adds proportional quantity, passes into steam and carry out temperature rising reflux after stirring; The timing that wherein refluxes stopped steam after 2 hours;
2, treatment tank interlayer passes into recirculated water and lowers the temperature, until the reactor temperature for the treatment of tank is down to less than 40 DEG C, bleed off interlayer recirculated water, the reactor temperature that logical salt solution is cooled to treatment tank is keep temperature-time to be 1 hour after 0-5 DEG C, more afterwards the material in the reactor for the treatment of tank is put into whizzer and tentatively dry;
3, after preliminary drying, drip washing is carried out with the material in the whizzer that freezing methyl alcohol is right, the liquid flowed out after material in drip washing whizzer is centrifugate, drip washing until flow out the clear and bright clear near colorless of centrifugate after stop drip washing, walsh fine work is made after again drying half an hour to 1 hour being carried out to the material in whizzer, walsh fine work is surveyed after the qualified rear discharging of sample is pulverized and puts baking oven into, prepare epoxy Progesterone finished product after 5 hours 75 DEG C of insulation oven dry;
Oxygen bridge material containing non-complete reaction in the solution wherein thrown away in drying process because of centrifugate and carrying out, mix and puts into mother liquor tank and to carry out after separation and purification suitably concentrated formation mother liquor, be inserted in the production process of next batch epoxy Progesterone;
beneficial effect of the present invention:
By the reversed reaction process in minimizing walsh oxidizing reaction and the concentration and the raising oxidation reaction condition (temperature that increase reactant, pressure), make oxygen bridge material can change epoxy Progesterone fully into as far as possible, another the oxygen bridge material of non-complete reaction is made after separation and purification methanol mother liquor be inserted in the oxo bridge of next batch concentrated in, make the useful compositions such as oxygen bridge material recycle in preparation process of the methyl alcohol in production process and non-complete reaction, without outer row, the comprehensive HPLC of epoxy Progesterone measures yield while content is not less than 99% and has exceeded 80%, meet the specification of quality of current production high-quality medicine to epoxy Progesterone and decrease waste simultaneously, improve product, obtain good economic benefits and improve the market competitiveness.
accompanying drawing illustrates:
The production technological process of accompanying drawing epoxy Progesterone.
Embodiment
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in further detail, completes the detailed process of the embodiment preparing epoxy Progesterone in order:
step one, oxo bridge react
In clean plastic tank, pour 25kg sheet alkali into, add 50kg water, stirring and dissolving is complete, adds 500g water glass and makes 75.5kg sheet alkaline solution, stir evenly for subsequent use.
First to suction methyl alcohol 1440L in clean oxo bridge retort; open stirring to add the pregnant steroid diene alcohol ketone of 160kg and make diene solution; add 5L methyl alcohol by tank, tank skin; the pregnant steroid diene alcohol ketone attached on stir shaft washes in diene solution; cover tank mouth, open emptying make oxo bridge retort become vacuum after pass into nitrogen protection.Be added dropwise in oxo bridge retort by the hydrogen peroxide accounting for hydrogen peroxide 110kg total amount 1/4 27.5kg in hydrogen peroxide high level tank subsequently, time for adding is 20 minutes.3rd, be added dropwise in oxo bridge retort by 1/3 25kg making 75.5kg sheet alkaline solution for subsequent use, time for adding is 30 minutes.4th, remaining hydrogen peroxide is all added dropwise in oxo bridge retort, within 45 minutes, adds, the liquid added in rear oxo bridge retort is oxo bridge liquid, when wherein dripping, tank temperature can continue to raise, and the control temperature in oxo bridge retort is 34 DEG C, and when namely dripping, tank temperature must not more than 34 DEG C.
step 2, enrichment process, concrete technology flow process is:
Oxo bridge liquid is drawn in oxo bridge concentration tank, it is clear that vacuum is pulled to tank endoscopy, do not open stirring, interlayer slightly begin to rehearse water valve lead to steam heating sequentially carry out one-level intensification concentrating under reduced pressure and and secondary intensification concentrating under reduced pressure, slowly heat up concentrated, intensification is evaporated to after methyl alcohol all steams, and remaining in oxo bridge concentration tank is oxygen bridge material, and the 800L methyl alcohol wherein first steamed retracts in the preparation process of oxo bridge retort inner sleeve for next batch epoxy Progesterone.Prepared by last batch in the 2200L toluene suction oxo bridge concentration tank that reclaims in epoxy Progesterone process and to dissolve after oxygen bridge material in suction walsh retort.
step 3, walsh reaction process
Change toluene and make solvent in anhydrous conditions, make catalyzer with aluminum isopropylate, oxygen bridge material and pimelinketone are carried out walsh reaction, and detailed process is:
(1) toluene and oxygen bridge material solution add in walsh retort, open thickening system valve, and logical steam dehydration steams about 1000L to toluene, and dehydration wants slow, do not open that to be stirred to visor clear and bright without the globule.
(2) add pimelinketone 270kg, continue thickening and steam 1200L to toluene, then reflux dewatering about 1 hour, visor is clear and bright without the globule.
(3), after confirming that dehydration completes, stop steam and be slightly cooled to whipped state without backflow.
(4) the outspoken speed that certainly feeds intake adds aluminum isopropylate 21kg, opens stirring and has been warming up to backflow clock reaction 1.5 hours.
(5) during backflow, 15kg sheet alkali and 75kg water are made into 80kg sheet alkaline solution suction washing punching and heat up in a steamer tank.
(6) backflow terminates, and opens washing punching and heats up in a steamer tank condenser recirculated water, open toluene receiving tank vacuum, walsh reaction solution suction washing punching is heated up in a steamer in tank.
step 4, punching heat up in a steamer technological process,the gold-plating technological process of rushing after in tank is heated up in a steamer in walsh reaction solution suction washing punching is:
(1) boiling water is washed punching and is heated up in a steamer tank steam, controls gas bag pressure 0-0.5kg/cm2 punching and heats up in a steamer 30 minutes, stop vapour and leave standstill 30 minutes, discharge sheet alkaline solution from bottom.
(2) heat up in a steamer in tank add cold water 800-1000 liter to washing punching, suction sheet alkaline solution Hou Kai tri-road steam starts punching and heats up in a steamer, vapor pressure 0.5-1.0kg/cm2.
(3) rush the toluene that distillates, be inserted in down after front 800L divides water in batch concentrating, after all the other toluene barrellings, go to rectifying post, do new toluene after recovery and take out and return the preparation of oxo bridge retort for next batch epoxy Progesterone.
(4) steam punching is heated up in a steamer and is heated up in a steamer in the water of recovery without oily matter to rushing.
(5) close steam, turn down and distillate the emptying pressure release of valve open, prevent punching material.
(6) open after pressure release in stirring, whizzer and complete filter cloth, drive bottom valve and material is put into whizzer, centrifugal drying material, with boiling water, material is washed till neutrality, adds 300L water after suction sheet alkaline solution at the bottom of tank, punching is heated up in a steamer and is all put into centrifuge afterwards, boiling water washing, to neutral, dries, discharging.
(7) all wet crude product is weighed.
step 5, process for refining process,
Heat up in a steamer after steaming desolventizes through steam punching and be separated to obtain Oppenauer crude product, obtain epoxy Progesterone finished product by solvent recrystallization
(1) whole Oppenauer crude product is dropped in treatment tank, add the methyl alcohol of proportional quantity depending on crude product quality condition, stir.
(2) temperature rising reflux, backflow timing 2 hours, stops steam.
(3) interlayer to pass in circulating water cooling to reactor below temperature drop to 40 DEG C.
(4) bleed off interlayer recirculated water, logical salt solution is cooled to temperature in the kettle 0-5 DEG C.
(5) lowered the temperature rear insulation 0-5 DEG C one hour, blowing is centrifugal.
(6) time with clear near colorless clear and bright to centrifugate through freezing methyl alcohol drip washing, material is dried half an hour more than, survey the qualified discharging of sample and pulverize into baking oven, dry 5 hours for about 75 DEG C, packaging warehouse-in.Wherein freezing methyl alcohol refers at the liquid methanol carrying out less than cooled 0-5 DEG C with icy salt solution.
(7) control about 200-300L one barrel by the mother liquor amount after separation and purification, cover is used in the preparation process of lower batch of epoxy Progesterone.
Said process is by batch continuous production, the methyl alcohol reclaimed, toluene and mother liquor in the epoxy Progesterone preparation process of each batch are successively in the preparation process of the epoxy Progesterone of lower batch, effectively avoid the loss of effective constituent, improve yield and the purity of product.
Claims (4)
1. improve the processing method that epoxy Progesterone prepares yield and purity, the production technique preparing epoxy Progesterone comprises the following steps of carrying out in order and is:
Step one, oxo bridge react, comprising the adition process of the preparation of diene solution and adition process and hydrogen peroxide, sheet alkaline solution;
Step 2, enrichment process, draw in oxo bridge liquid in oxo bridge concentration tank and make oxygen bridge material by intensification concentrating under reduced pressure process;
Step 3, walsh are reacted, and react comprising one-level walsh;
Step 4, punching heat up in a steamer operation, and wherein punching is heated up in a steamer technique and comprised preliminary punching and heat up in a steamer technique;
Step 5, process for refining process;
It is characterized in that, also cleaning process is comprised in the preparation of the diene solution described in step one and adition process, detailed process is: with a small amount of methyl alcohol by tank, tank skin, the pregnant steroid diene alcohol ketone that stir shaft attaches rinses into diene solution, make in tank, tank skin, stir shaft does not attach pregnant steroid diene alcohol ketone;
It is carry out following process in order that the adition process of the hydrogen peroxide described in step one, sheet alkaline solution adopts substep at the uniform velocity to drip technological process:
A), by the hydrogen peroxide accounting for total amount 1/4 in suction hydrogen peroxide high level tank in advance adopt and at the uniform velocity drip mode and add in oxo bridge retort, time for adding controls at 15-20 minute;
B), by the sheet alkaline solution accounting for total amount 1/3 in suction alkali lye high level tank in advance adopt and at the uniform velocity drip mode and add in oxo bridge retort, time for adding controls at 20-30 minute;
C), be at the uniform velocity added dropwise in oxo bridge retort by hydrogen peroxide remaining in hydrogen peroxide high level tank, time for adding controls at 35-45 minute; Forced cooling is carried out when allowing solution in oxo bridge retort naturally be warming up to 34 DEG C in dropping process, the temperature of solution in oxo bridge retort is controlled at 33 DEG C within the scope of 34 DEG C, until complete the follow-up continuation of insurance of dropping process be held in this temperature range remove after 20 minutes temperature control, allow mixing solutions Temperature fall, the temperature of the mixing solutions in whole process in oxo bridge retort all the time must not higher than 34 DEG C;
Intensification concentrating under reduced pressure described in step 2 carries out secondary intensification concentrating under reduced pressure after sequentially carrying out one-level intensification concentrating under reduced pressure, described secondary intensification concentrating under reduced pressure is: stop after completing one-level intensification concentrating under reduced pressure passing into steam, in the mother liquor suction oxo bridge concentration tank applied mechanically upper batch and one-level oxygen bridge material mix and pass into steam after stirring slow heat temperature raising is carried out to oxo bridge concentration tank, material in oxo bridge concentration tank is because of after methyl alcohol is concentrated into thick paste by being constantly distilled out of, starting stirring turning over materials makes it be concentrated into the oxygen bridge material of approximate dry powder further, stop passing into steam after till methyl alcohol wherein in oxo bridge concentration tank is steamed to the greatest extent, wherein intensification concentrating under reduced pressure process is keeping the vapor pressure of oxo bridge concentration tank to be less than 0.1MPa, in tank, vacuum tightness is not less than 0.07MPa, control gas phase temperature to be no more than and to carry out at 75 DEG C, the implementation procedure that described control gas phase temperature is no more than 75 DEG C is: be less than 0.1MPa keeping the vapor pressure of oxo bridge concentration tank, under in tank, vacuum tightness is not less than 0.07MPa situation, slowly pass into temperature and be not less than 73 DEG C but the steam being no more than 75 DEG C, steam is that till the methyl alcohol in oxo bridge concentration tank is steamed to the greatest extent, rear stopping passes into,
Namely the reaction of secondary walsh is carried out after the one-level walsh described in step 3 has been reacted;
Wherein heat up in a steamer in the preliminary punching described in step 4 and to carry out secondary punching after technique completes and heat up in a steamer technique; Described preliminary punching heat up in a steamer technique complete after carry out secondary punching and heat up in a steamer technique and be: heat up in a steamer in tank to steam punching and add a certain amount of cold water, alkali lye is heated up in a steamer in suction punching, open stir make cold water, alkali lye is heated up in a steamer in punching and preliminary punching is heated up in a steamer mixing of materials even Hou Kai tri-road steam and carried out rushing heating up in a steamer and heat up in a steamer without oily matter in the water of recovery to punching, wherein secondary rushes the vapor pressure heated up in a steamer is 0.5-1.0kg/cm
2, it is the sheet alkaline solution be made into after adding the proportioning mixing and stirring of 10kg water by every 4kg sheet alkali that alkali lye is heated up in a steamer in punching.
2. a kind of processing method improving epoxy Progesterone and prepare yield and purity according to claim 1, it is characterized in that: the mother liquor that wherein in secondary temperature elevation concentrating under reduced pressure, upper batch is applied mechanically is in preparation last batch epoxy Progesterone process, the centrifugate reclaimed in step 5 process for refining process and and the solution mixing carrying out throwing away in drying process put into mother liquor tank carry out separation and purification after the suitable concentrated mixed solution formed.
3. a kind of processing method improving epoxy Progesterone and prepare yield and purity according to claim 1, it is characterized in that: the secondary walsh reaction carried out after the one-level walsh reaction described in step 3 terminates is: a certain amount of pimelinketone added walsh retort and one-level walsh mixing of materials after the reaction of one-level walsh and stir, continue intensification thickening to a certain amount of toluene and be distilled out of rear reflux dewatering certain hour, until walsh retort visor is clear and bright without the globule, confirm dehydration complete anhydrous in walsh retort after, stop steam be slightly cooled to whipped state without backflow after terminate.
4. a kind of processing method improving epoxy Progesterone and prepare yield and purity according to claim 3, it is characterized in that: wherein a certain amount of toluene carries out reflux dewatering after carrying out adding a certain amount of alkaline solution in reflux dewatering process after being distilled out of, the reflux dewatering time is 30 minutes to 1 hour, and wherein the quantity of sheet alkaline solution should guarantee the material in walsh retort fully to dissolve.
Priority Applications (1)
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| CN101544682A (en) * | 2009-05-14 | 2009-09-30 | 赵云现 | 11-keto-16,17-epoxyprogesterone and industrial production method |
| CN102286062A (en) * | 2011-06-15 | 2011-12-21 | 陕西理工学院 | Synthesis method of 16 alpha,17 alpha-epoxy-4-pregnene-3,20-dione |
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| CN101544682A (en) * | 2009-05-14 | 2009-09-30 | 赵云现 | 11-keto-16,17-epoxyprogesterone and industrial production method |
| CN102286062A (en) * | 2011-06-15 | 2011-12-21 | 陕西理工学院 | Synthesis method of 16 alpha,17 alpha-epoxy-4-pregnene-3,20-dione |
Non-Patent Citations (1)
| Title |
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| 用回归设计法优选甾族沃氏氧化反应条件;戴庆骏;《医药工业》;19830401;第5-8页 * |
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