CN106866766B - The preparation method and preparation system of a kind of medroxyprogesterone acetate - Google Patents
The preparation method and preparation system of a kind of medroxyprogesterone acetate Download PDFInfo
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- CN106866766B CN106866766B CN201710078673.2A CN201710078673A CN106866766B CN 106866766 B CN106866766 B CN 106866766B CN 201710078673 A CN201710078673 A CN 201710078673A CN 106866766 B CN106866766 B CN 106866766B
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- 229960002985 medroxyprogesterone acetate Drugs 0.000 title claims abstract description 39
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 14
- 238000007670 refining Methods 0.000 claims abstract description 14
- 230000007246 mechanism Effects 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 27
- 235000019441 ethanol Nutrition 0.000 claims description 26
- 239000002699 waste material Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- 238000005119 centrifugation Methods 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 10
- 238000009413 insulation Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000002351 wastewater Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical class CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000003651 drinking water Substances 0.000 claims description 5
- 235000020188 drinking water Nutrition 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 238000003860 storage Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 230000001072 progestational effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 210000004696 endometrium Anatomy 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 206010000242 Abortion threatened Diseases 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000008899 Habitual abortion Diseases 0.000 description 1
- -1 Hydrogen furans Chemical class 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000005985 Threatened Abortion Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 201000003908 endometrial adenocarcinoma Diseases 0.000 description 1
- 208000029382 endometrium adenocarcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000010842 industrial wastewater Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
Abstract
The present invention relates to the preparation field of medicine, a kind of more particularly to preparation method of medroxyprogesterone acetate, it is prepared including acetic acid methine, the step such as hydrogenation and decolorizing and refining, the invention further relates to a kind of preparation system of medroxyprogesterone acetate, it includes the acetic acid methine preparing mechanism being sequentially connected, hydrogenation mechanism and decolorizing and refining mechanism, it is an object of the invention to provide a kind of preparation method of medroxyprogesterone acetate and preparation system, using monoesters as original, acetic acid methine is made by reacting, reacted again by hydrogenation and decolorizing and refining afterwards and medroxyprogesterone acetate is made, and monoesters is simple and easy to get, and then original cost can be reduced, and preparation process is stable, obtained medroxyprogesterone acetate purity is high, it can adapt to produce on a large scale.
Description
Technical field
The present invention relates to the preparation field of medicine, more particularly to a kind of preparation method of medroxyprogesterone acetate and preparation system
System.
Background technology
Medroxyprogesterone acetate is a kind of conventional pharmaceuticals, is mainly used in dysmenorrhoea, functional amenorrhea, dysfunctional uterine go out
Blood, threatened abortion or habitual abortion, endometriosis, treat advanced breast cancer, adenocarcinoma of endometrium and kidney etc..Greatly
Dosage can be used as long acting injectable contraceptives.In addition effect is also embodied in menstrual onset factor Endometrium and loses estrogen and progestational hormone
Support fall off after, artificially complementing estrogen or progestational hormone particularly progestational hormone can be continued, make the intrauterine of " helpless "
Film continues to be supported, the level that maintenance thickens, such endometrium is grown in uterine wall securely, is planted for embryonated egg
Enter to get ready, realize the purpose for postponing menstruation.
Prepared by existing medroxyprogesterone acetate is all that complicated letones after chemical reaction is made mostly, cost of material
Height, large-scale production can not be realized.
The content of the invention
It is an object of the invention to provide a kind of preparation method of medroxyprogesterone acetate and preparation system, using monoesters as former
Come, acetic acid methine is made by reacting, reacted again by hydrogenation and decolorizing and refining medroxyprogesterone acetate is made afterwards, and
Monoesters is simple and easy to get, and then can reduce original cost, and preparation process is stable, and obtained medroxyprogesterone acetate purity is high, energy
It is enough to adapt to large-scale production.
In order to realize the above object the technical solution adopted by the present invention is：A kind of preparation method of medroxyprogesterone acetate, it
Comprise the following steps：
1., acetic acid methine prepare, be pumped into tetrahydrofuran in a kettle, add monoesters, stirring, be pumped into primitive nail triethylenetetraminehexaacetic acid
Ester, absolute ethyl alcohol, lead to nitrogen, add PTS decolorising agents, in 34-36 DEG C of insulation reaction 1 hour, add 1 PTS decolorising agent, instead
Answer 1.5 hours；Above-mentioned reaction solution is down to 28 DEG C, is pumped into methylphenylamine and formaldehyde successively, is warming up to 34-36 DEG C of reaction 2.5
Hour, reaction solution is pumped into elutriation kettle, is cooled to 15 DEG C, hydrochloric acid 30 minutes is added dropwise after 23-27 DEG C of insulation reaction 1.5 hours ,-
Drinking water elutriation is added, is cooled to 5 DEG C, is stirred 3 hours, centrifugation, neutrality is washed to, dries to obtain acetic acid methine；
2., hydrogenation：DMF is pumped into a kettle（N,N-dimethylformamide）, add what 1. step obtained afterwards
Acetic acid methine, lead to nitrogen, add palladium charcoal, cyclohexene, be heated to 96-100 DEG C and react 40 minutes 2 hours, filter to indexable kettle,
Filtrate is down to 20 DEG C, hydrochloric acid is added, 1.5 hours is incubated at a temperature of 20-22 DEG C after adding, sodium bicarbonate solution is added, adds
It is complete to be cooled to 0 DEG C, 3 hours are incubated, centrifuges, wash, drying, drying and to obtain crude product；
3., decolorizing and refining, add dichloromethane in decolouring kettle, 2. crude product, activated carbon that ethanol, step obtain, heating
Decolourized 30 minutes to 40 DEG C of backflows, filter to concentration kettle, be concentrated into 2（V）Mother liquor, is cooled to 0-5 DEG C of crystallization 2 hours, centrifuges, gets rid of
Do, dry to obtain medroxyprogesterone acetate fine work.
Preferably, the step 1. monoesters of middle addition, tetrahydrofuran, triethyl orthoformate, absolute ethyl alcohol, PTS decolorising agents, N-
Methylaniline, formaldehyde, the mass fraction of hydrochloric acid and water for 150 parts, 450 parts, 60 parts, 80 parts, 3 parts, 45 parts, 45 parts, 180 parts and
1800 parts；The mass fraction of 2. DMF, cyclic ethylene, palladium carbon, hydrochloric acid, sodium acid carbonate and water that step adds be 450 parts, 60 parts, 24
Part, 18 parts, 18 parts and 410 parts；The mass fraction of 3. dichloromethane, ethanol and activated carbon that step adds is 540 parts, 810 parts
With 13.5 parts.
Preferably, it is 50 parts and 2613 parts that 1. step, which centrifuges the obtained vapor of drying and the mass fraction of waste water,.
Preferably, 1. step centrifuges the waste water that drying obtains can isolate 350 parts of tetrahydrofuran by separator.
Preferably, it is 45 parts and 925 parts that 2. step, which centrifuges the obtained vapor of drying and the mass fraction of waste water,.
Preferably, it is 1088.5 parts that 3. step, which concentrates crystallization is recovered to dichloromethane and the mass fraction of ethanol, wherein
Steam is 22 parts.
Preferably, it is 20 parts and 269 parts that 3. step, which centrifuges the obtained alcohol vapour of drying and the mass fraction of waste liquid,.
The present invention a kind of preparation system of medroxyprogesterone acetate of another technical scheme, it is characterised in that it include according to
Acetic acid methine preparing mechanism, hydrogenation mechanism and the decolorizing and refining mechanism of secondary connection, described acetic acid methine draft machine
Structure includes the reactor, elutriation kettle and the first centrifugation drying unit being sequentially connected, and the described first centrifugation drying unit passes through steaming
Vapour collecting pipe is connected to water tank, and the first waste liquid collecting box, the first described waste liquid collecting box are connected to by waste collection pipe
The first separator is connected with, the first described separator is connected with water tank and tetrahydrofuran collecting tank, described hydrogenation
Reaction mechanism includes the reactor, indexable kettle and the second centrifugation drying unit being sequentially connected, the described second centrifugation drying unit
Water tank is connected to by steam collection pipe and waste collection pipe；Described decolorizing and refining mechanism includes the reaction being sequentially connected
Kettle, concentration crystallization device and the 3rd centrifugation drying unit, described concentration crystallization device are connected with mixed liquor collecting tank, and described the
Three centrifugation drying units are connected to ethanol collecting tank and the second waste liquid collecting box by steam collection pipe and waste collection pipe,
The second described waste liquid collecting box is connected with the second separator, and the second described separator is connected with ethanol collecting tank and storage
Water pot.
Preferably, steam is provided with described steam collection pipe and collects meter, is set in described waste collection pipe
There is waste collection meter.
One kind that the PTS decolorising agents of step 1. middle addition are specific to difficult remove of colourity in industrial wastewater and especially researched and developed
New chemical medicament, the macromolecule cation polymer rich in there is-the group such as NH ,-NH2 ,-OH, can not only as in general without
Machine salt coagulant and dye molecule are risen outside electrical neutralization, moreover it is possible to by the group of itself, are formed covalent bond with dyestuff, matched somebody with somebody
Position key and hydrogen bond etc., make decolorizing effect more notable.
Beneficial effects of the present invention are：
1st, it is an object of the invention to provide a kind of preparation method of medroxyprogesterone acetate and preparation system, using monoesters conduct
Originally, acetic acid methine was made by reacting, and was reacted again by hydrogenation and decolorizing and refining medroxyprogesterone acetate is made afterwards,
And monoesters is simple and easy to get, and then original cost can be reduced, and preparation process is stable, obtained medroxyprogesterone acetate purity is high,
It can adapt to produce on a large scale.
2nd, the mass fraction for the raw material that each step is added, can be good at completing corresponding reaction, it is ensured that reaction
Precisely carry out, while unnecessary waste will not be caused, while also ensure the purity of the medroxyprogesterone acetate prepared, and
It is able to ensure that in waste liquor and does not have the complete raw material of unreacted, and then can makes to comprise only the four of collection to be separated in waste liquor
Hydrogen furans or ethanol, are conveniently separated and collected, and then save material cost.
3rd, the centrifugation drying unit in each step can be collected and measure to steam and waste liquid, and then can be passed through
The collecting amount of steam and waste liquid ensures the accurate progress of every step reaction.
4th, preparation system coordinates is reacted without caused by debris and residue completely, and waste water can be collected, can be by
Tetrahydrofuran and ethanol separate recycling from waste liquor.
Brief description of the drawings
Fig. 1 is the preparation system annexation figure of medroxyprogesterone acetate.
Embodiment
In order that those skilled in the art more fully understand technical scheme, the present invention is retouched in detail below
State, the description of this part is only exemplary and explanatory, there should not be any restriction effect to protection scope of the present invention.
Embodiment 1
A kind of preparation method of medroxyprogesterone acetate, it comprises the following steps：
1., acetic acid methine prepare, in a kettle be pumped into 450 parts of tetrahydrofurans, add 150 parts of monoesters, stir, be pumped into
60 parts of triethyl orthoformates, 80 parts of absolute ethyl alcohols, lead to nitrogen, add 1.5 parts of PTS decolorising agents, in 34 DEG C of insulation reactions 1 hour,
1.5 parts of PTS decolorising agents are added, are reacted 1.5 hours；Above-mentioned reaction solution is down to 28 DEG C, is pumped into 45 parts of methylphenylamines successively
And 45 parts of formaldehyde, it is warming up to 36 DEG C and reacts 2.5 hours, reaction solution is pumped into elutriation kettle, is cooled to 15 DEG C, 180 parts of hydrochloric acid are added dropwise
30 minutes after 23 DEG C of insulation reactions 1.5 hours ,-add 1800 parts of drinking water elutriations, be cooled to 5 DEG C, stir 3 hours, centrifugation,
Add 300 parts be washed to neutrality, dry 150 parts of acetic acid methines, 50 parts of vapor and 2613 parts of tetrahydrofurans mix with water
Liquid；
2., hydrogenation：450 parts of DMF are pumped into a kettle（N,N-dimethylformamide）, step is added afterwards 1. to be obtained
The acetic acid methine arrived, lead to nitrogen, add 24 parts of palladium charcoals, 60 parts of cyclohexene, be heated to 100 DEG C and react 40 minutes 2 hours, filtering
To indexable kettle, filtrate is down to 20 DEG C, 18 parts of hydrochloric acid is added, 1.5 hours is incubated at a temperature of 20 DEG C after adding, adds 18 parts of carbon
Sour hydrogen sodium solution, add and be cooled to 0 DEG C, be incubated 3 hours, centrifugation, add 180 parts of water and washed, dried, dried and obtain 135
Part medroxyprogesterone acetate crude product, 45 parts of vapor and 925 parts of waste water.
3., decolorizing and refining, added in decolouring kettle 2. crude product that 540 parts of dichloromethane, 810 parts of ethanol, steps obtain,
13.5 parts of activated carbons, it is heated to 40 DEG C of backflows and decolourizes 30 minutes, filter to concentration kettle, be concentrated into 2（V）Mother liquor, it is cooled to 0 DEG C of analysis
Brilliant 2 hours, centrifuge, dry, drying 106 parts of medroxyprogesterone acetate fine work, 20 parts of alcohol vapours and 269 parts of ethanol mix with water
Liquid.
Embodiment 2
A kind of preparation method of medroxyprogesterone acetate, it comprises the following steps：
1., acetic acid methine prepare, in a kettle be pumped into 450 parts of tetrahydrofurans, add 150 parts of monoesters, stir, be pumped into
60 parts of triethyl orthoformates, 80 parts of absolute ethyl alcohols, lead to nitrogen, add 1.5 parts of PTS decolorising agents, in 36 DEG C of insulation reactions 1 hour,
1.5 parts of PTS decolorising agents are added, are reacted 1.5 hours；Above-mentioned reaction solution is down to 28 DEG C, is pumped into 45 parts of methylphenylamines successively
And 45 parts of formaldehyde, it is warming up to 34 DEG C and reacts 2.5 hours, reaction solution is pumped into elutriation kettle, is cooled to 15 DEG C, 180 parts of hydrochloric acid are added dropwise
30 minutes after 27 DEG C of insulation reactions 1.5 hours ,-add 1800 parts of drinking water elutriations, be cooled to 5 DEG C, stir 3 hours, centrifugation,
Add 300 parts be washed to neutrality, dry 150 parts of acetic acid methines, 50 parts of vapor and 2613 parts of tetrahydrofurans mix with water
Liquid；
2., hydrogenation：450 parts of DMF are pumped into a kettle（N,N-dimethylformamide）, step is added afterwards 1. to be obtained
The acetic acid methine arrived, lead to nitrogen, add 24 parts of palladium charcoals, 60 parts of cyclohexene, be heated to 96 DEG C and react 40 minutes 2 hours, filtering
To indexable kettle, filtrate is down to 20 DEG C, 18 parts of hydrochloric acid is added, 1.5 hours is incubated at a temperature of 22 DEG C after adding, adds 18 parts of carbon
Sour hydrogen sodium solution, add and be cooled to 0 DEG C, be incubated 3 hours, centrifugation, add 180 parts of water and washed, dried, dried and obtain 135
Part medroxyprogesterone acetate crude product, 45 parts of vapor and 925 parts of waste water.
3., decolorizing and refining, added in decolouring kettle 2. crude product that 540 parts of dichloromethane, 810 parts of ethanol, steps obtain,
13.5 parts of activated carbons, it is heated to 40 DEG C of backflows and decolourizes 30 minutes, filter to concentration kettle, be concentrated into 2（V）Mother liquor, it is cooled to 5 DEG C of analysis
Brilliant 2 hours, centrifuge, dry, drying 106 parts of medroxyprogesterone acetate fine work, 20 parts of alcohol vapours and 269 parts of ethanol mix with water
Liquid.
Embodiment 3
A kind of preparation method of medroxyprogesterone acetate, it comprises the following steps：
1., acetic acid methine prepare, in a kettle be pumped into 450 parts of tetrahydrofurans, add 150 parts of monoesters, stir, be pumped into
60 parts of triethyl orthoformates, 80 parts of absolute ethyl alcohols, lead to nitrogen, add 1.5 parts of PTS decolorising agents, in 35 DEG C of insulation reactions 1 hour,
1.5 parts of PTS decolorising agents are added, are reacted 1.5 hours；Above-mentioned reaction solution is down to 28 DEG C, is pumped into 45 parts of methylphenylamines successively
And 45 parts of formaldehyde, it is warming up to 35 DEG C and reacts 2.5 hours, reaction solution is pumped into elutriation kettle, is cooled to 15 DEG C, 180 parts of hydrochloric acid are added dropwise
30 minutes after 25 DEG C of insulation reactions 1.5 hours ,-add 1800 parts of drinking water elutriations, be cooled to 5 DEG C, stir 3 hours, centrifugation,
Add 300 parts be washed to neutrality, dry 150 parts of acetic acid methines, 50 parts of vapor and 2613 parts of tetrahydrofurans mix with water
Liquid；
2., hydrogenation：450 parts of DMF are pumped into a kettle（N,N-dimethylformamide）, step is added afterwards 1. to be obtained
The acetic acid methine arrived, lead to nitrogen, add 24 parts of palladium charcoals, 60 parts of cyclohexene, be heated to 98 DEG C and react 40 minutes 2 hours, filtering
To indexable kettle, filtrate is down to 20 DEG C, 18 parts of hydrochloric acid is added, 1.5 hours is incubated at a temperature of 21 DEG C after adding, adds 18 parts of carbon
Sour hydrogen sodium solution, add and be cooled to 0 DEG C, be incubated 3 hours, centrifugation, add 180 parts of water and washed, dried, dried and obtain 135
Part medroxyprogesterone acetate crude product, 45 parts of vapor and 925 parts of waste water.
3., decolorizing and refining, added in decolouring kettle 2. crude product that 540 parts of dichloromethane, 810 parts of ethanol, steps obtain,
13.5 parts of activated carbons, it is heated to 40 DEG C of backflows and decolourizes 30 minutes, filter to concentration kettle, be concentrated into 2（V）Mother liquor, it is cooled to 2 DEG C of analysis
Brilliant 2 hours, centrifuge, dry, drying 106 parts of medroxyprogesterone acetate fine work, 20 parts of alcohol vapours and 269 parts of ethanol mix with water
Liquid.
It should be noted that herein, term " comprising ", "comprising" or its any other variant are intended to non-row
His property includes, so that process, method, article or equipment including a series of elements not only include those key elements, and
And also include the other element being not expressly set out, or also include for this process, method, article or equipment institute inherently
Key element.
Specific case used herein is set forth to the principle and embodiment of the present invention, the explanation of above example
It is only intended to help the method and its core concept for understanding the present invention.Described above is only the preferred embodiment of the present invention, should
When pointing out due to the finiteness of literal expression, and unlimited concrete structure objectively be present, for the common skill of the art
For art personnel, under the premise without departing from the principles of the invention, some improvement, retouching or change can also be made, can also incited somebody to action
Above-mentioned technical characteristic is combined by rights；These improve retouching, change or combination, or the not improved structure by invention
Think and technical scheme directly applies to other occasions, be regarded as protection scope of the present invention.
Claims (8)
1. a kind of preparation method of medroxyprogesterone acetate, it is characterised in that it comprises the following steps：
1., acetic acid methine prepare, in a kettle be pumped into 450 parts of tetrahydrofurans, add 150 parts of monoesters, stirring, be pumped into 60 parts
Triethyl orthoformate, 80 parts of absolute ethyl alcohols, lead to nitrogen, add 1.5 parts of PTS decolorising agents, in 34-36 DEG C of insulation reaction 1 hour, then
1.5 parts of PTS decolorising agents are added, are reacted 1.5 hours；Above-mentioned reaction solution is down to 28 DEG C, successively be pumped into 45 parts of methylphenylamines and
45 parts of formaldehyde, are warming up to 34-36 DEG C and react 2.5 hours, and reaction solution is pumped into elutriation kettle, is cooled to 15 DEG C, 180 portions of salt are added dropwise
Acid, hydrochloric acid 30 minutes is added dropwise after 23-27 DEG C of insulation reaction 1.5 hours, adds 1800 parts of drinking water elutriations, is cooled to 5 DEG C, stirs
Mix 3 hours, centrifuge, be washed to neutrality, dry to obtain acetic acid methine；
2., hydrogenation：450 parts of DMF are pumped into a kettle（N,N-dimethylformamide）, add what 1. step obtained afterwards
Acetic acid methine, lead to nitrogen, add 24 parts of palladium charcoals, 60 parts of cyclohexene, be heated to 96-100 DEG C and react 40 minutes 2 hours, filtering
To indexable kettle, filtrate is down to 20 DEG C, 18 parts of hydrochloric acid is added, 1.5 hours is incubated at a temperature of 20-22 DEG C after adding, adds 18
Part sodium bicarbonate solution, adds and is cooled to 0 DEG C, is incubated 3 hours, and 180 parts of centrifugation, addition water are washed, dried, dried slightly
Product；
3., decolorizing and refining, 2. crude product, 13.5 parts that 540 parts of dichloromethane, 810 parts of ethanol, steps obtain are added in decolouring kettle
Activated carbon, it is heated to 40 DEG C of backflows and decolourizes 30 minutes, filter to concentration kettle, be concentrated into 2（V）Mother liquor, it is cooled to 0-5 DEG C of crystallization 2
Hour, centrifuge, dry, drying and to obtain medroxyprogesterone acetate fine work.
2. the preparation method of a kind of medroxyprogesterone acetate according to claim 1, it is characterised in that 1. step centrifuges drying
Obtained vapor and the mass fraction of waste water is 50 parts and 2613 parts.
3. the preparation method of a kind of medroxyprogesterone acetate according to claim 2, it is characterised in that 1. step centrifuges drying
Obtained waste water can isolate 350 parts of tetrahydrofuran by separator.
4. the preparation method of a kind of medroxyprogesterone acetate according to claim 1, it is characterised in that 2. step centrifuges drying
Obtained vapor and the mass fraction of waste water is 45 parts and 925 parts.
5. the preparation method of a kind of medroxyprogesterone acetate according to claim 1, it is characterised in that 3. step concentrates crystallization
The dichloromethane and the mass fraction of ethanol being recovered to are 1088.5 parts, and wherein steam is 22 parts.
6. the preparation method of a kind of medroxyprogesterone acetate according to claim 1, it is characterised in that 3. step centrifuges drying
Obtained alcohol vapour and the mass fraction of waste liquid is 20 parts and 269 parts.
A kind of 7. preparation system of medroxyprogesterone acetate as described in claim any one of 1-6, it is characterised in that it include according to
Acetic acid methine preparing mechanism, hydrogenation mechanism and the decolorizing and refining mechanism of secondary connection, described acetic acid methine draft machine
Structure includes the reactor, elutriation kettle and the first centrifugation drying unit being sequentially connected, and the described first centrifugation drying unit passes through steaming
Vapour collecting pipe is connected to water tank, and the first waste liquid collecting box, the first described waste liquid collecting box are connected to by waste collection pipe
The first separator is connected with, the first described separator is connected with water tank and tetrahydrofuran collecting tank, described hydrogenation
Reaction mechanism includes the reactor, indexable kettle and the second centrifugation drying unit being sequentially connected, the described second centrifugation drying unit
Water tank is connected to by steam collection pipe and waste collection pipe；Described decolorizing and refining mechanism includes the reaction being sequentially connected
Kettle, concentration crystallization device and the 3rd centrifugation drying unit, described concentration crystallization device are connected with mixed liquor collecting tank, and described the
Three centrifugation drying units are connected to ethanol collecting tank and the second waste liquid collecting box by steam collection pipe and waste collection pipe,
The second described waste liquid collecting box is connected with the second separator, and the second described separator is connected with ethanol collecting tank and storage
Water pot.
8. the preparation system of a kind of medroxyprogesterone acetate according to claim 7, it is characterised in that described steam is collected
Steam is provided with pipe and collects meter, waste collection meter is provided with described waste collection pipe.
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| CN107573395A (en) * | 2017-09-04 | 2018-01-12 | 江苏远大信谊药业有限公司 | A kind of preparation method of medroxyproges-terone acetate |
| CN108409824A (en) * | 2018-03-13 | 2018-08-17 | 岳阳环宇药业有限公司 | The preparation process of cyproterone acetate |
| CN110655548B (en) * | 2018-06-29 | 2022-05-17 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN110655549B (en) * | 2018-06-29 | 2022-06-14 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methylprednisolone |
| CN109627277A (en) * | 2018-12-19 | 2019-04-16 | 上海新华联制药有限公司 | A kind of preparation method of medroxyprogesterone acetate |
| CN114057821B (en) * | 2021-11-30 | 2022-12-09 | 黑龙江中医药大学 | Preparation method of medroxyprogesterone acetate for perimenopausal syndrome |
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