CN104311619A - Method for synthesizing progesterone by series process - Google Patents
Method for synthesizing progesterone by series process Download PDFInfo
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- CN104311619A CN104311619A CN201410320000.XA CN201410320000A CN104311619A CN 104311619 A CN104311619 A CN 104311619A CN 201410320000 A CN201410320000 A CN 201410320000A CN 104311619 A CN104311619 A CN 104311619A
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- 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
- C07J7/0015—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 not substituted in position 17 alfa
- C07J7/002—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 not substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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Abstract
The invention relates to the field of pharmaceutical and chemical engineering. To overcome the problems that a conventional progesterone production technology is complex in process, low in yield and large in energy consumption and has relatively heavy pollutions, the invention provides a method for synthesizing progesterone by a series process. By adopting a four-step process, the method provided by the invention has high yield and low cost and is environment-friendly.
Description
Technical field
The present invention relates to field of medicine and chemical technology, relate in particular to a kind of processing method adopting series process to synthesize Progesterone.
Background technology
Progesterone is a kind of natural progestogen secreted by corpus luteum, and the uterine endometrium excited oestrogenic hormon in vivo has remarkable Morphology Effects, required by maintaining gestation.The technique generally adopted produced by current Progesterone is utilize walsh oxidation style that Progesterone precursor is oxidized to Progesterone, and Progesterone precursor take aluminum isopropylate as catalyzer in toluene solvant, and the acceptor generation oxidizing reaction using pimelinketone as hydrogen, obtains Progesterone.But traditional production technique exists complex process, yield is not high, and energy-output ratio is large, pollutes the shortcomings such as more serious.
Application number is the Chinese patent of 201310539601.5, discloses a kind of method preparing Progesterone, and the method for raw material, obtains Progesterone through hydroxyl cyaniding, dehydration, protection, hydrogenation, addition hydrolysis reaction with 4-AD (4AD) successively.But owing to using phosphorus oxychloride in the method, not environmentally, pollute.
Summary of the invention
There is complex process for solving traditional Progesterone production technique, yield is not high, and energy-output ratio is large, pollutes the problems such as more serious, the present invention proposes a kind of method adopting series process to synthesize Progesterone, and adopt present method yield high, cost is low, environmental protection.
The present invention is achieved by the following technical solutions: a kind of method adopting series process to synthesize Progesterone is following steps:
(1) 4-androstene-diketone is added in reaction flask, add ether solvents, stir molten clear after add acetone cyanohydrin and organic amine, 20 ~ 60 DEG C of reactions 10 ~ 48 hours, add ammonium chloride saturated solution, stir 0.2 ~ 2 hour, stratification, removing water layer, then wash down with ammonium chloride saturated solution that to be washed till pH value be neutral, then triethyl orthoformate is added, dehydrated alcohol is added after stirring, add tosic acid again, insulation reaction added wet chemical termination reaction after 1 ~ 5 hour, add saturated sodium chloride solution again, stratification after stirring, organic layer removes moisture content,
Described ether solvents is selected from tetrahydrofuran (THF) or methyl furan, and usage quantity is the amount making solute dissolves.As preferably, ether solvents is 5 ~ 15ml:1g with the volume mass ratio of 4-androstene-diketone.
Mass ratio 0.5 ~ the 1.5:1 of acetone cyanohydrin and 4-androstene-diketone, organic amine elects triethylamine, pyridine as, a kind of in quadrol, with the mass ratio 0.5 ~ 1.5:1 of 4-androstene-diketone, triethyl orthoformate is 0.3 ~ 1.5ml:1g with the volume mass ratio of 4-androstene-diketone, the mass ratio of dehydrated alcohol and 4-androstene-diketone is 0.5 ~ 1.5:1, and the mass ratio of tosic acid and 4-androstene-diketone is 0.02 ~ 0.2:1.
As preferably, first stir layering with ammonium chloride saturated solution, ammonium chloride saturated solution is 1 ~ 5ml:1g with the volume mass ratio of 4-androstene-diketone, then washes 3 ~ 6 times with ammonium chloride saturated solution, is neutrality to pH value.
As preferably, add the wet chemical termination reaction that mass concentration is 5%, wet chemical is 0.2 ~ 0.8ml:1g with the volume mass ratio of 4-androstene-diketone.
Add saturated sodium chloride solution, stir stratification fully, as preferably, saturated sodium chloride solution is 2 ~ 10ml:1g with the volume mass ratio of 4-androstene-diketone.
Organic over anhydrous sodium sulfate removes moisture, and as preferably, the mass ratio of anhydrous sodium sulphate and 4-androstene-diketone is 1 ~ 8:1.
As preferably, terminated by chromatography test detection reaction.
(2) in the organic layer of step (1) de-place moisture content, vinyl-n-butyl ether is added, add tosic acid again, stirring reaction 0.5 ~ 5 hour, then adds Grignard reagent, be warming up to reflux state, be in order to partial concentration organic layer, 60 ~ 90 DEG C of insulation reaction 5 ~ 48 hours, concentrate out unnecessary organic layer, then material is poured in frozen water and carry out elutriation, add hydrochloric acid after elutriation to be again hydrolyzed reaction, be down to room temperature, filtering drying obtains 17 Alpha-hydroxy Progesterone crude products;
Vinyl-n-butyl ether is 0.2 ~ 1.5ml:1g with 4-androstene-diketone volume mass ratio, and the mass ratio of tosic acid and 4-androstene-diketone is 0.02 ~ 0.2:1, and Grignard reagent is 2 ~ 10ml:1g with the volume mass ratio of 4-androstene-diketone.Hydrochloric acid is 2 ~ 8ml:1g with 4-androstene-diketone volume mass ratio, and as preferably, hydrochloric acid is mass concentration 36 ~ 37%.
When hydrolysis reaction starts, reaction system is clearly molten, when having a large amount of material to separate out, can judge that reaction finishes when solution turned cloudy.
Form (family name) reagent, i.e. green reagent and alkyl halide magnesium, chemical formula: R-MgX, wherein R acute pyogenic infection of finger tip alkyl.X acute pyogenic infection of finger tip halogen.Grignard reagent can conventionally be prepared.React in absolute ether by organohalogen compound (haloalkane, active halogenated aryl hydrocarbon) and MAGNESIUM METAL and forms organomagnesium reagent, now commonly use halohydrocarbon and magnesium powder anhydrous diethyl ether or tetrahydrofuran (THF) (
tHF) in reaction obtained, carry out under material (as: water, alcohol, ammonia NH3, hydrogen halide, the end alkynes etc.) condition that preparation process must have reactive hydrogen without carbonic acid gas without ethanol etc. at absolute.Grignard reagent is a kind of active organic synthesis reagent, generally has two kinds, 1: chlorobenzene class (Benzyl Chloride) under ether (tetrahydrofuran (THF)) and reactive magnesium, 2: bromocyclopentane is under ether (tetrahydrofuran (THF)) and magnesium (zinc) reaction.
Room temperature is 20 ~ 25 DEG C.
(3) 17 Alpha-hydroxy Progesterone crude products are added in reaction flask, add pyridine or lutidine stir molten clear after, add the pyridine solution (SO that halogenating agent adds sulfurous gas below 0 DEG C
2/ Py), under nitrogen protection, in-15 ~ 5 DEG C of reactions 3 ~ 6 hours, chromatography detect qualified after, then carry out elutriation with frozen water, filtering drying is eliminated thing crude product, process of re-refining obtain refining after eliminate thing;
As preferably, the usage quantity of pyridine or lutidine is the amount making solute dissolves.
As preferably, halogenating agent is selected from N-chlorosuccinimide (NCS) or N-bromo-succinimide (NBS), the mass ratio of consumption and 4-androstene-diketone is 0.6 ~ 1.5:1, the mass concentration of the pyridine solution of sulfurous gas is 25% ~ 35%, and mass concentration is the consumption of the sulfurous gas pyridine solution of 25% ~ 35% and the mass ratio of 4-androstene-diketone is 0.5 ~ 1.5:1.
As preferably, the volume carrying out frozen water during elutriation is 20 ~ 60 times of reactant solution volume.
As preferably, adopt ethanol to refine elimination thing crude product, the volume of ethanol is 5 ~ 15 times of elimination thing crude product volume.
(4) put in reaction flask by eliminating thing after refining, add polar solvent stir molten clear after, add palladium carbon (Pd-C), then add catalysis retarding agent and tetrahydrobenzene, 40 ~ 120 DEG C of insulation reaction 2 ~ 8 hours, filter, feed liquid concentrates, add water and carry out elutriation, filtration is drained, and obtains Progesterone after refining.
Mass percent concentration be 1% ~ 5% palladium carbon with refining after eliminates thing mass ratio be 0.05 ~ 0.2:1, palladium carbon can be applied mechanically after recycling repeatedly.
Catalysis retarding agent is pyrazinoic acid amide, and consumption and the refining rear mass ratio eliminating thing are 0.005 ~ 0.015, and tetrahydrobenzene is 0.5 ~ 1.5:1 with the refining rear volume ratio eliminating thing.
Polar solvent is selected from dimethyl formamide, DMAP, N,N-DIMETHYLACETAMIDE, pyridine a kind of, and the usage quantity of polar solvent is the amount making solute dissolves.As preferably, polar solvent with refining after eliminate thing volume ratio be 5 ~ 15:1.
As preferably, feed liquid adopts concentrating under reduced pressure.
As preferably, this step adopts vinyl acetic monomer to refine.
Reaction structure formula of the present invention is:
Compared with prior art, the invention has the beneficial effects as follows: adopt present method to prepare Progesterone yield high, cost is low, environmental protection.
Embodiment
Below by specific embodiment, the present invention is described in further details, raw materials used all commercially available in embodiment.
Grignard reagent can be prepared according to a conventional method: for chlorobenzene class (Benzyl Chloride) is under ether (tetrahydrofuran (THF)) and reactive magnesium.
Embodiment 1
(1) 4-androstene-diketone 28.6g is added in reaction flask, add 150ml tetrahydrofuran (THF), stir clearly molten, then acetone cyanohydrin 15g and triethylamine 15g is added, 20 DEG C of reactions 10 hours, after chromatography detection is qualified, add 30ml saturated ammonium chloride solution, in stirring 0.2 hour, stratification, removing water layer, 3 times are washed with ammonium chloride saturated solution, be neutral to pH value, then 9ml triethyl orthoformate is added, the dehydrated alcohol of 15g is added again after stirring, add the tosic acid of 0.6g again, insulation reaction 1 hour, after chromatography detection raw material point reacts completely, add 5.8ml, 5% wet chemical termination reaction, then saturated sodium chloride solution 57ml is added, stir stratification fully, organic layer 29g anhydrous sodium sulphate removes remaining moisture.
(2) step (1) removes the vinyl-n-butyl ether adding 5.7ml in the organic layer of moisture, add the tosic acid of 0.6g again, stirring reaction 0.5 hour, then the 57ml Grignard reagent prepared is added, be warming up to reflux state gradually, concentrate out part tetrahydrofuran (THF), 60 DEG C of insulation reaction 5 hours, concentrate out unnecessary tetrahydrofuran (THF), then material is poured in 580ml frozen water and carry out elutriation, adding mass concentration after elutriation is good is again that the hydrochloric acid of the 58ml of 37% is hydrolyzed reaction, when solution turned cloudy and when having a large amount of material to separate out, be cooled to room temperature, filtering drying obtains 17 Alpha-hydroxy Progesterone crude products, content 95%.
(3) 17 Alpha-hydroxy Progesterone crude products are added in dry reaction flask, add the pyridine of 150ml, stir molten clear after, adding 18gNCS, below 0 DEG C, add the concentration prepared be the SO of 25%
2/ Py solution 15g, under nitrogen protection, in-15 DEG C of reactions 3 hours, chromatography detect qualified after, then carry out elutriation with frozen water 1000ml, after material is all separated out, filtering drying is eliminated thing crude product, content 90%; Refine with the dehydrated alcohol of 150ml, obtain refining after eliminate thing, content 98%.
(4) the elimination thing refined is put in reaction flask, the DMF adding 150ml stir molten clear after, add mass concentration 1%, the Pd-C of 1.5g, add the tetrahydrobenzene of 0.2g pyrazinoic acid amide catalysis retarding agent and 15g again, 40 DEG C of insulation reaction 2 hours, chromatography detect raw material primitive reaction completely after, take advantage of heat filtering, can repeatedly apply mechanically after Pd-C recycling, after feed liquid is filtered, concentrating under reduced pressure mother liquor, adds water and carries out elutriation, filtration is drained, then add vinyl acetic monomer to refine, obtain Progesterone, content 98.5%.
Embodiment 2
(1) 4-androstene-diketone 28.6g is added in reaction flask, add 280ml methyl furan, stir clearly molten, then 30g acetone cyanohydrin and 30g triethylamine is added, 40 DEG C of reactions 30 hours, after chromatography detection is qualified, add 70ml ammonium chloride saturated solution, stir 1 hour, stratification, removing water layer, 5 times are washed with ammonium chloride saturated solution, be neutral to pH value, then 30ml triethyl orthoformate is added, the dehydrated alcohol of 30g is added again after stirring, add the tosic acid of 3g again, insulation reaction 3 hours, after chromatography detection raw material point reacts completely, add 14ml, 5% wet chemical termination reaction, then saturated sodium chloride solution 140ml is added, stir stratification fully, organic layer 140g anhydrous sodium sulphate removes remaining moisture.
(2) vinyl-n-butyl ether of 28ml is added in the tetrahydrofuran (THF) feed liquid of de-good moisture, add the tosic acid of molar equivalent 3g again, stirring reaction 3 hours, then the 150ml Grignard reagent prepared is added, be warming up to reflux state gradually, concentrate out part tetrahydrofuran (THF), 80 DEG C of insulation reaction 30 hours, concentrate out unnecessary tetrahydrofuran (THF), then material is poured in 1500ml frozen water and carry out elutriation, 150ml is added again after elutriation is good, mass concentration be 37% hydrochloric acid to be hydrolyzed reaction, when solution turned cloudy and when having a large amount of material to separate out, be cooled to room temperature, filtering drying obtains 17 Alpha-hydroxy Progesterone crude products, content 97%.
(3) 17 Alpha-hydroxy Progesterone crude products are added in dry reaction flask, the lutidine adding 350ml stir molten clear after, add 30g NBS, below 0 DEG C, add the concentration prepared is 30%SO
2/ Py solution 30g; under nitrogen protection; in 0 DEG C of reaction 4 hours; after chromatography detection is qualified, then carry out elutriation, after material is all separated out with frozen water 1200ml; filtering drying is eliminated thing crude product; content 91%, with the dehydrated alcohol of 300ml carry out refinement treatment obtain refining after eliminate thing, content 97%.
(4) the elimination thing refined is put in reaction flask, the DMAP adding 300ml stir molten clear after, add the Pd-C of the 3g of 3%, add the pyrazinoic acid amide catalysis retarding agent of 0.03g and the tetrahydrobenzene of 30ml again, 80 DEG C of insulation reaction 5 hours, chromatography detect raw material primitive reaction completely after, take advantage of heat filtering, can repeatedly apply mechanically, after feed liquid is filtered after Pd-C recycling, concentrating under reduced pressure mother liquor, add water and carry out elutriation, filtration is drained, and then adds vinyl acetic monomer and refines, obtain Progesterone, content 99%.
Embodiment 3
(1) by 4-androstene-diketone 28.6g(0.1mol) add in reaction flask, add 420ml tetrahydrofuran (THF), stir clearly molten, then 43g acetone cyanohydrin and 43g triethylamine is added, 60 DEG C of reactions 48 hours, after chromatography detection is qualified, add 140ml ammonium chloride saturated solution, in stirring 2 hours, stratification, removing water layer, 6 times are washed with ammonium chloride saturated solution, be neutral to pH value, then 42ml triethyl orthoformate is added, the dehydrated alcohol of 40g is added again after stirring, add the tosic acid of 5g again, insulation reaction 5 hours, after chromatography detection raw material point reacts completely, add 23ml, 5% wet chemical termination reaction, then saturated sodium chloride solution 286ml is added, stir stratification fully, organic layer 220g anhydrous sodium sulphate removes remaining moisture.
(2) 42ml vinyl-n-butyl ether is added in the tetrahydrofuran (THF) feed liquid of de-good moisture, add the tosic acid of 5g again, stirring reaction 5 hours, then add the 290ml Grignard reagent prepared, be warming up to reflux state gradually, concentrate out part tetrahydrofuran (THF), 90 DEG C of insulation reaction 48 hours, concentrate out unnecessary tetrahydrofuran (THF), then material is poured in 2000ml frozen water and carry out elutriation, after elutriation is good, add 200ml again.Mass concentration be 37% hydrochloric acid to be hydrolyzed reaction, when having a large amount of material to separate out, be cooled to room temperature when solution turned cloudy, filtering drying obtains 17 Alpha-hydroxy Progesterone crude products, content 96%.
(3) 17 Alpha-hydroxy Progesterone crude products are added in dry reaction flask, add the pyridine of 580ml, stir molten clear after, add 43gNCS, below 0 DEG C, add the concentration prepared is the SO of 35%
2/ Py solution 43g; under nitrogen protection; in 5 DEG C of reactions 6 hours; after chromatography detection is qualified, then carry out elutriation, after material is all separated out with frozen water 1500ml; filtering drying is eliminated thing crude product; content 92%, then with the dehydrated alcohol of 400ml carry out refinement treatment obtain refining after eliminate thing, content 97%.
(4) the elimination thing refined is put in reaction flask, the DMAC adding 400ml stir molten clear after, add the Pd-C of the 5.5g of mass concentration 5%, add the tetrahydrobenzene of 0.4g pyrazinoic acid amide catalysis retarding agent and 40ml again, 120 DEG C of insulation reaction 8 hours, after chromatography detection raw material primitive reaction is complete, take advantage of heat filtering, can repeatedly apply mechanically, after feed liquid is filtered after Pd-C recycling, concentrating under reduced pressure mother liquor, add water and carry out elutriation, filtration is drained, and then adds vinyl acetic monomer and refines, obtain Progesterone, content 99.5%.
Claims (8)
1. adopt series process to synthesize a method for Progesterone, it is characterized in that, described preparation method is following steps:
(1) 4-androstene-diketone is added in reaction flask, add ether solvents, stir molten clear after add acetone cyanohydrin and organic amine, 20 ~ 60 DEG C of reactions 10 ~ 48 hours, add ammonium chloride saturated solution, stir 0.2 ~ 2 hour, stratification, removing water layer, then 3 ~ 6 times are washed with ammonium chloride saturated solution, be neutral to pH value, then triethyl orthoformate is added, dehydrated alcohol is added after stirring, add tosic acid again, insulation reaction added wet chemical termination reaction after 1 ~ 5 hour, add saturated sodium chloride solution again, stratification after stirring, organic layer removes moisture content,
(2) remove in the organic layer of moisture content in step (1) and add vinyl-n-butyl ether, add tosic acid again, stirring reaction 0.5 ~ 5 hour, then add Grignard reagent, be warming up to reflux state, 60 ~ 90 DEG C of insulation reaction 5 ~ 48 hours, then material is poured in frozen water and carry out elutriation, add hydrochloric acid after elutriation to be again hydrolyzed reaction, be down to room temperature, filtering drying obtains 17 Alpha-hydroxy Progesterone crude products;
(3) 17 Alpha-hydroxy Progesterone crude products are added in reaction flask, add pyridine or lutidine stir molten clear after, add the pyridine solution that halogenating agent adds sulfurous gas below 0 DEG C, under nitrogen protection, in-15 ~ 5 DEG C of reactions 3 ~ 6 hours, then carry out elutriation with frozen water, filtering drying is eliminated thing crude product, process of re-refining obtain refining after eliminate thing;
(4) put in reaction flask by eliminating thing after refining, add polar solvent stir molten clear after, add palladium carbon, then add catalysis retarding agent and tetrahydrobenzene, 40 ~ 120 DEG C of insulation reaction 2 ~ 8 hours, filter, feed liquid concentrating under reduced pressure, add water and carry out elutriation, filtration is drained, and obtains Progesterone after refining.
2. a kind of method adopting series process to synthesize Progesterone according to claim 1, it is characterized in that, the ether solvents described in step (1) is selected from tetrahydrofuran (THF) or methyl furan, and usage quantity is the amount making solute dissolves.
3. a kind of method adopting series process to synthesize Progesterone according to claim 1, it is characterized in that, mass ratio 0.5 ~ the 1.5:1 of acetone cyanohydrin and 4-androstene-diketone, organic amine elects triethylamine, pyridine as, a kind of in quadrol, mass ratio 0.5 ~ the 1.5:1 of organic amine and 4-androstene-diketone, triethyl orthoformate is 0.3 ~ 1.5ml:1g with the volume mass ratio of 4-androstene-diketone, the mass ratio of dehydrated alcohol and 4-androstene-diketone is 0.5 ~ 1.5:1, and the mass ratio of tosic acid and 4-androstene-diketone is 0.02 ~ 0.2:1.
4. a kind of method adopting series process to synthesize Progesterone according to claim 1 or 2 or 3, it is characterized in that, step adds wet chemical termination reaction in (1), and organic over anhydrous sodium sulfate removes moisture.
5. a kind of method adopting series process to synthesize Progesterone according to claim 1, it is characterized in that, step (2) medium vinyl butyl ether is 0.2 ~ 1.5ml:1g with the volume mass ratio of 4-androstene-diketone, the mass ratio of tosic acid and 4-androstene-diketone is 0.02 ~ 0.2:1, Grignard reagent is 2 ~ 10ml:1g with the volume mass ratio of 4-androstene-diketone, and hydrochloric acid is 2 ~ 8ml:1g with the volume mass ratio of 4-androstene-diketone.
6. a kind of method adopting series process to synthesize Progesterone according to claim 1, it is characterized in that, step (3) halogenating agent is selected from N-chlorosuccinimide or N-bromo-succinimide, the mass ratio of consumption and 4-androstene-diketone is 0.6 ~ 1.5:1, the mass concentration of the pyridine solution of sulfurous gas is 25% ~ 35%, and mass concentration is the consumption of the sulfurous gas pyridine solution of 25% ~ 35% and the mass ratio of 4-androstene-diketone is 0.5 ~ 1.5:1.
7. a kind of method adopting series process to synthesize Progesterone according to claim 1, it is characterized in that, in step (4), mass concentration is the palladium carbon of 1% ~ 5% and the mass ratio of 4-androstene-diketone is 0.05 ~ 0.2:1, catalysis retarding agent is pyrazinoic acid amide, the mass ratio of consumption and 4-androstene-diketone is 0.005 ~ 0.015, and the volume ratio of tetrahydrobenzene and 4-androstene-diketone is 0.5 ~ 1.5:1.
8. a kind of method adopting series process to synthesize Progesterone according to claim 1 or 6 or 7, it is characterized in that, polar solvent in step (4) is selected from dimethyl formamide, DMAP, N,N-DIMETHYLACETAMIDE, pyridine a kind of, and the usage quantity of polar solvent is the amount making solute dissolves.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563637A (en) * | 2019-09-24 | 2019-12-13 | 千福石油化工有限公司 | Pyridine sulfur dioxide production process and pyridine sulfur dioxide |
| CN110713511A (en) * | 2019-11-19 | 2020-01-21 | 湖南新合新生物医药有限公司 | Synthetic method of triene acetate |
| CN112940062A (en) * | 2021-02-23 | 2021-06-11 | 浙江神洲药业有限公司 | Preparation method of 16-dehydroprogesterone |
| CN111560047B (en) * | 2020-05-09 | 2021-07-20 | 浙江神洲药业有限公司 | Preparation method of budesonide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563637A (en) * | 2019-09-24 | 2019-12-13 | 千福石油化工有限公司 | Pyridine sulfur dioxide production process and pyridine sulfur dioxide |
| CN110713511A (en) * | 2019-11-19 | 2020-01-21 | 湖南新合新生物医药有限公司 | Synthetic method of triene acetate |
| CN111560047B (en) * | 2020-05-09 | 2021-07-20 | 浙江神洲药业有限公司 | Preparation method of budesonide |
| CN112940062A (en) * | 2021-02-23 | 2021-06-11 | 浙江神洲药业有限公司 | Preparation method of 16-dehydroprogesterone |
| CN112940062B (en) * | 2021-02-23 | 2022-09-06 | 浙江神洲药业有限公司 | Preparation method of 16-dehydroprogesterone |
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Application publication date: 20150128 |