CN106317154A - Method for preparing 17alpha-hydroxyprogesterone - Google Patents
Method for preparing 17alpha-hydroxyprogesterone Download PDFInfo
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- CN106317154A CN106317154A CN201610685508.9A CN201610685508A CN106317154A CN 106317154 A CN106317154 A CN 106317154A CN 201610685508 A CN201610685508 A CN 201610685508A CN 106317154 A CN106317154 A CN 106317154A
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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
- C07J7/004—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
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Abstract
The invention discloses a method for preparing 17alpha-hydroxyprogesterone. According to the method, 4-androstenedione I serves as the raw material, a 17-site branched chain is introduced through ethynylation reaction, a 17-site beta-hydroxyl group is converted into an alpha-hydroxyl group through catalytic reaction, and finally 17alpha-hydroxyprogesterone is prepared through carbonylation reaction. The reaction formula is shown in the description. Four steps of reaction are conducted with 4-androstenedione as the raw material, a 17-site side chain is introduced through ethynylation reaction, the 17beta-hydroxyl group is converted into the 17alpha-hydroxyl group through transposition reaction, the weight yield of each step ranges from 85% to 109%, the total weigh yield is 85% or above, use of virulent acetone cyanohydrin is avoided, the raw material conversion rate is high, selectivity is good, production cost of 17alpha-hydroxyprogesterone is reduced, the process is safe, and large-scale industrial production is easy.
Description
Technical field
The present invention relates to the preparation method of a kind of chemicals, particularly relate to a kind of method preparing 17 Alpha-hydroxy Progesterone.
Background technology
A kind of endogenous progesterone is not only by 17 Alpha-hydroxy Progesterone, for prevention of preterm birth or a kind of very important
Medicine intermediate, market prospect is very big, can be used for synthesizing medroxyprogestetone acetate, prednisone, prednisolone, hydrogenation as initiation material
The multi-medicaments such as cortisone.The structural formula of 17 Alpha-hydroxy Progesterone is:
In prior art as follows about several the process routes preparing 17 Alpha-hydroxy Progesterone:
The most current 17 Alpha-hydroxy Progesterone produce in the most traditional technique be exactly with Saponin as initiation material, through open loop, oxidation,
Hydrolysis three-step reaction obtains intermediate acetic acid gestation diene alcohol ketone, then with acetic acid gestation diene alcohol ketone for raw material through epoxy, walsh
Oxidation, addition, catalytic hydrogenation prepare." whole nation crude drug technique compilation " has just included this process route.But this technique road
Line length, yield is low, pollutes big, and cost is high, is gradually being substituted.
2., with 4-AD as raw material, 17 carbonyls use .alpha.-hydroxyisobutyronitrile. to carry out addition and build chirality side chain, then with contracting
Ketone 3 carbonyls of protection, with 3,17 hydroxyls of 4-dihydropyran etherification protection, finally carry out methylating, hydrolysis obtains 17 α-
Hydroxyl progesterone.Patent (CN 103467555A) just reports this process route, and its reaction equation is as follows:
This synthesis route operation complexity, by-product is many, and cost of supplementary product is high, uses toxic articles .alpha.-hydroxyisobutyronitrile. the most in a large number, to life
Produce safety and environmental protection brings certain pressure.
3., with 4-AD as raw material, 17 carbonyls use .alpha.-hydroxyisobutyronitrile. to carry out addition and build chirality side chain, by etherificate
Protecting 3 carbonyls, protect 17 hydroxyls with vinyl-n-butyl ether, then methylate with methyl-magnesium-chloride, final hydrolysis obtains 17
Alpha-hydroxy Progesterone, patent (CN 103910775A) just reports this process route, and its reaction equation is as follows:
3 carbonyl reactions of etherification protection are reversible, it is difficult to reaction thoroughly, causes overall yield on the low side, uses toxic articles third the most in a large number
, there is production safety hidden danger in ketone cyanalcohol.
4., with 4-AD as raw material, 17 carbonyls use .alpha.-hydroxyisobutyronitrile. to carry out additive reaction, protect 3 with ketal
Carbonyl, then carry out methylation reaction with zinc chloride methane, final hydrolysis obtains 17 Alpha-hydroxy Progesterone, patent (CN
104072565A) just reporting this process route, its reaction equation is as follows:
Although this route is on the basis of forefathers, eliminate the protection to 17 hydroxyls, substitute methyl chloride with zinc chloride methane
Magnesium methylates, but its operation is the most complicated, it is desired nonetheless to use toxic articles .alpha.-hydroxyisobutyronitrile..
5. 17 beta-cyano-17 Alpha-hydroxy-4-androstene-3-ketone are existed at trim,ethylchlorosilane and methyl magnesium chloride solution
Under, first low temperature carries out double protection reaction, then intensification carries out grignard additive reaction, and finally hydrolysis obtains 17 Alpha-hydroxy Progesterone, specially
Profit (CN 104327146A) just reports this process route, and its reaction equation is as follows:
Although 3 ketals are protected by this route, 17 etherification of hydroxyl groups, grignard addition, hydrolysis are reduced to one pot, but it initiates former
Expect that 17 beta-cyano-17 Alpha-hydroxy-4-androstene-3-ketone must use toxic articles .alpha.-hydroxyisobutyronitrile. to prepare.
Summary of the invention
It is an object of the invention to the cost of material for solving to be currently used for preparing 17 Alpha-hydroxy Progesterone high, synthetic route
Long, yield is low, needs to use toxic articles .alpha.-hydroxyisobutyronitrile., is unfavorable for the technical problem of production safety and environmental protection.
In order to solve above-mentioned technical problem, the present invention provides a kind of method preparing 17 Alpha-hydroxy Progesterone, including as follows
Step:
(1) ethynylation: first add alkali, oxolane and solvent in there-necked flask, be heated to 50 DEG C under nitrogen protection, reaction
1 hour, it is cooled to the first preset temperature, logical acetylene gas certain time under described first preset temperature；Then with 4-androstene two
Ketone I is dissolved in the tetrahydrofuran solution of oxolane preparation 4-AD I, under described first preset temperature, to described three mouthfuls
The tetrahydrofuran solution of described 4-AD I, insulation reaction 2 hours it is slowly added dropwise in Ping；The most backward described there-necked flask adds
Entering aqueous hydrochloric acid solution adjusts pH value to 3～4, is heated to reflux half an hour, removal of solvent under reduced pressure, adds water elutriation, sucking filtration, washing, subtract
Press dry dry, obtain acetylide II；Reaction equation is
；
(2) nitration reaction: first adding acetic anhydride and acetylide II in reaction bulb, stirring is cooled to the second preset temperature；Then
In described reaction bulb, it is slowly added dropwise nitric acid under nitrogen protection, drips rear insulation reaction the first Preset Time；Through TLC after
When detection is without raw material point, in described reaction bulb, pours frozen water elutriation, sucking filtration, washing, decompression drying into, obtain itrated compound III；Instead
Ying Shiwei
；
(3) translocation reaction: first add oxolane, water and itrated compound III in reaction bulb, stir under the 3rd preset temperature；So
Rear addition silver nitrate, reactant liquor stirs reaction the second Preset Time under described 3rd preset temperature；Last concentrating under reduced pressure removes
Oxolane, adds nitric acid, adds dichloromethane extractive reaction liquid, layering, and organic facies concentrating under reduced pressure removes solvent, obtains indexing
Product IV；Reaction equation is
；
(4) carbonylation: adding acetone and indexing product IV in reaction bulb, stirring and dissolving obtains the acetone of indexing product IV
Solution, adds Mercury bisulfate., concentrated sulphuric acid and water, is heated to the 4th preset temperature reaction the 3rd Preset Time, and concentrating under reduced pressure removes third
Ketone, residual reaction liquid is poured in frozen water, adds saturated sodium bicarbonate solution and adjusts pH value to be neutral, and stirring adds ethyl acetate extraction
Extracting reaction solution, layering, be dried organic facies with anhydrous sodium sulfate, be evaporated to surplus monoploid and amass mother solution, cooling discharge, decompression is dried
Dry obtain 17 Alpha-hydroxy Progesterone V；Reaction equation is
。
Further, described in step (1), alkali is potassium hydroxide or potassium tert-butoxide.
Further, 4-AD I described in step (1) is 1W:1W～1W:4W with the ratio of alkali.
Further, described in step (1), solvent is the one in ethanol, isopropanol and acetone.
Further, in described step (1), the time of logical acetylene gas is 1～4 hour.
Further, described in step (1), the first preset temperature is-5～5 DEG C.
Further, the ratio of acetic anhydride, acetylide II and nitric acid described in step (2) be 5.4W:1W:0.71W～
10.8W:1W:1.42W。
Further, described in step (2), the second preset temperature is-30 DEG C～-20 DEG C, and described first Preset Time is 1
～3 hours.
Further, described in step (3), oxolane, water, itrated compound III and silver nitrate ratio are 1.78W:2W:1W:
0.05W～8.89W:10W:1W:0.5W.
Further, described in step (3), the 3rd preset temperature is 20 DEG C～30 DEG C, described second Preset Time be 36～
100 hours.
Further, the ratio of indexing product IV described in step (4), Mercury bisulfate., concentrated sulphuric acid and water is 1W:0.01W:
0.18W:0.5W～1W:0.04W:0.55W:2W.
Further, the acetone soln concentration of indexing product IV described in step (4) is 0.1～0.5mol/L.
Further, described in step (4), the 4th preset temperature is 40 DEG C～56 DEG C, and described 3rd Preset Time is 5～7
Hour.
The present invention is with 4-AD as raw material, and four-step reaction altogether, with ethynylation 17 side chains of introducing, by indexing
17 β hydroxyl indexings are 17 α hydroxyls by reaction, the weight yield often walked all between 85%～109%, weight total recovery 85% with
On, it is to avoid the use of toxic articles .alpha.-hydroxyisobutyronitrile .s, feed stock conversion is high, and selectivity is good, reduce the life of 17 Alpha-hydroxy Progesterone
Product cost, and process safety, it is easy to industrial scale produces.
Detailed description of the invention
Presently in connection with embodiment, the present invention is further detailed explanation, and the application of the present invention is not limited to following
Embodiment, any pro forma accommodation being the present invention falls within protection scope of the present invention.
In following embodiment, the reaction equation of the ethynylation of the first step is:
；
The reaction equation of the nitration reaction of second step is:
；
The reaction equation of the translocation reaction of the 3rd step is:
；
The reaction equation of the carbonylation of the 4th step is:
。
Embodiment 1
The first step, ethynylation: addition potassium hydroxide (200g, 2W) in dry there-necked flask, oxolane (1000ml,
10V) with ethanol (120ml, 1.2V), it is heated to 50 DEG C under nitrogen protection and reacts 1 hour, be cooled to 3 DEG C, lead to second at this temperature
Alkynes gas 2 hours.The tetrahydrofuran solution of preparation 4-AD (I): 4-AD (I) (100g, 1W) is dissolved in oxolane
(200ml, 2V), is slowly added dropwise this solution, insulation reaction 2 hours.Aqueous hydrochloric acid solution with 10% adjusts pH value to 3～4, heats back
Flow half an hour, removal of solvent under reduced pressure, add water (1000ml, 10V) elutriation, sucking filtration, washing, in 60 DEG C of drying under reduced pressure, obtain alkynes
Compound II (109.3g), weight yield 109%, HPLC content 96%.
Second step, nitration reaction: add acetic anhydride (700ml, 7V) and acetylide II (100g, 1W), stirring in reaction bulb
It is cooled to-25 DEG C.It is slowly added dropwise nitric acid (60ml, 0.6V) ,-25 DEG C of insulation reaction 1 hour after dripping under nitrogen protection.
When TLC detection is without raw material point, pours frozen water (2000ml, 20V) elutriation, sucking filtration, washing into, in 60 DEG C of decompression dryings, obtain nitrification
Thing III (107g), weight yield 107%, HPLC content 95%.
3rd step, translocation reaction: add oxolane (300ml, 3V), water (300ml, 3V) and itrated compound in reaction bulb
III (100g, 1W), stirs at 25 DEG C.Adding silver nitrate (10g, 0.1W), reactant liquor stirs reaction 72 hours at 25 DEG C.Subtract
Pressure concentrates and removes oxolane, the nitric acid (150ml, 1.5V) of addition 65%, addition dichloromethane extractive reaction liquid, and layering is organic
Phase concentrating under reduced pressure removes solvent, obtains indexing product IV (85g), weight yield 85%, HPLC content 93%.
4th step, carbonylation: add acetone (800ml, 10V) and indexing product IV (80g, 1W) in reaction bulb, stir
Mix dissolving, add Mercury bisulfate. (1.6g, 0.02W), concentrated sulphuric acid (13.6ml, 0.17V), water (80ml, 1.0V), be heated to 50
～55 DEG C react 6 hours, concentrating under reduced pressure remove acetone, residual reaction liquid is poured in frozen water (800ml, 10V), add unsaturated carbonate
Hydrogen sodium solution adjusts pH value to be neutral, stirs 0.5 hour, adds ethyl acetate extractive reaction liquid, and anhydrous sodium sulfate is dried organic facies,
It is evaporated to about remain monoploid and amasss mother solution, be cooled to zero degree discharging, obtain 17 Alpha-hydroxy Progesterone V in 60 DEG C of decompression dryings
(68.8g), weight yield 86%, HPLC content 96%.
Embodiment 2
The first step, ethynylation: addition potassium hydroxide (100g, 1W) in dry there-necked flask, oxolane (1000ml,
10V) with acetone (120ml, 1.2V), it is heated to 50 DEG C under nitrogen protection and reacts 1 hour, be cooled to-5 DEG C, lead at this temperature
Acetylene gas 4 hours.The tetrahydrofuran solution of preparation 4-AD (I): 4-AD (I) (100g, 1W) is dissolved in tetrahydrochysene furan
Mutter (200ml, 2V), is slowly added dropwise this solution, insulation reaction 2 hours.Aqueous hydrochloric acid solution with 10% adjusts pH value to 3～4, heats
Reflux half an hour, removal of solvent under reduced pressure, add water (1000ml, 10V) elutriation, sucking filtration, washing, in 60 DEG C of drying under reduced pressure, obtain
Acetylide II (108g), weight yield 108%, HPLC content 93%.
Subsequent step is with embodiment 1.
Embodiment 3
The first step, ethynylation: addition potassium tert-butoxide (400g, 4W) in dry there-necked flask, oxolane (1000ml,
10V) with isopropanol (120ml, 1.2V), it is heated to 50 DEG C under nitrogen protection and reacts 1 hour, be cooled to 5 DEG C, lead at this temperature
Acetylene gas 1 hour.The tetrahydrofuran solution of preparation 4-AD (I): 4-AD (I) (100g, 1W) is dissolved in tetrahydrochysene furan
Mutter (200ml, 2V), is slowly added dropwise this solution, insulation reaction 2 hours.Aqueous hydrochloric acid solution with 10% adjusts pH value to 3～4, heats
Reflux half an hour, removal of solvent under reduced pressure, add water (1000ml, 10V) elutriation, sucking filtration, washing, in 60 DEG C of drying under reduced pressure, obtain
Acetylide II (105g), weight yield 105%, HPLC content 90%.
Subsequent step is with embodiment 1.
Embodiment 4
The first step, with embodiment 2；
Second step, nitration reaction: add acetic anhydride (1000ml, 10V) and acetylide II (100g, 1W), stirring fall in reaction bulb
Temperature is to-30 DEG C.It is slowly added dropwise nitric acid (100ml, 1V) ,-30 DEG C of insulation reaction 3 hours after dripping under nitrogen protection.TLC examines
When surveying without raw material point, pour frozen water (2000ml, 20V) elutriation, sucking filtration, washing into, in 60 DEG C of decompression dryings, obtain itrated compound III
(105g), weight yield 105%, HPLC content 92%；
Subsequent step is with embodiment 1.
Embodiment 5
The first step, with embodiment 3；
Second step, nitration reaction: add acetic anhydride (500ml, 5V) and acetylide II (100g, 1W), stirring cooling in reaction bulb
To-20 DEG C.It is slowly added dropwise nitric acid (50ml, 0.5V) ,-20 DEG C of insulation reaction 1 hour after dripping under nitrogen protection.TLC examines
When surveying without raw material point, pour frozen water (2000ml, 20V) elutriation, sucking filtration, washing into, in 60 DEG C of decompression dryings, obtain itrated compound III
(103g), weight yield 103%, HPLC content 90%；
Subsequent step is with embodiment 1.
Embodiment 6
The first step is with embodiment 1；Second step is with embodiment 4；
3rd step, translocation reaction: add oxolane (200ml, 2V), water (200ml, 2V) and itrated compound III in reaction bulb
(100g, 1W), stirs at 20 DEG C.Adding silver nitrate (5g, 0.05W), reactant liquor stirs reaction 100 hours at 20 DEG C.Subtract
Pressure concentrates and removes oxolane, the nitric acid (150ml, 1.5V) of addition 65%, addition dichloromethane extractive reaction liquid, and layering is organic
Phase concentrating under reduced pressure removes solvent, obtains indexing product IV (80g), weight yield 80%, HPLC content 90%；
Subsequent step is with embodiment 1.
Embodiment 7
The first step is with embodiment 2；Second step is with embodiment 4；
3rd step, translocation reaction: add oxolane (1000ml, 10V), water (1000ml, 10V) and itrated compound in reaction bulb
III (100g, 1W), stirs at 30 DEG C.Adding silver nitrate (50g, 0.5W), reactant liquor stirs reaction 36 hours at 30 DEG C.Subtract
Pressure concentrates and removes oxolane, adds the nitric acid (150ml, 1.5V) of 65%, adds dichloromethane extractive reaction liquid, layering, has
Machine phase concentrating under reduced pressure removes solvent, obtains indexing product IV (82g), weight yield 82%, HPLC content 85%；
Subsequent step is with embodiment 1.
Embodiment 8
The first step is with embodiment 1；Second step is with embodiment 4；3rd step with embodiment 6,
4th step, carbonylation: add acetone (560ml, 7V) and indexing product IV (80g, 1W) in reaction bulb, stir molten
Solve, add Mercury bisulfate. (0.8g, 0.01W), concentrated sulphuric acid (8ml, 0.1V), water (40ml, 0.5V), be heated to 40～45 DEG C of reactions
7 hours, concentrating under reduced pressure removed acetone, and residual reaction liquid is poured in frozen water (800ml, 10V), adds saturated sodium bicarbonate solution and adjusts
PH value is neutral, stirs 0.5 hour, adds ethyl acetate extractive reaction liquid, and anhydrous sodium sulfate is dried organic facies, is evaporated to
About remain monoploid and amass mother solution, be cooled to zero degree discharging, obtain 17 Alpha-hydroxy Progesterone V (62.4g) in 60 DEG C of decompression dryings, weight
Amount yield 78%, HPLC content 95%.
Embodiment 9
The first step is with embodiment 2；Second step is with embodiment 5；3rd step is with embodiment 7；
4th step, carbonylation: add acetone (2400ml, 30V) and indexing product IV (80g, 1W) in reaction bulb, stir molten
Solve, add Mercury bisulfate. (3.2g, 0.04W), concentrated sulphuric acid (24ml, 0.3V), water (160ml, 2.0V), be heated to 50～56 DEG C instead
Answering 5 hours, concentrating under reduced pressure removes acetone, and residual reaction liquid is poured in frozen water (800ml, 10V), adds saturated sodium bicarbonate solution
It is neutral for adjusting pH value, stirs 0.5 hour, adds ethyl acetate extractive reaction liquid, and anhydrous sodium sulfate is dried organic facies, concentrating under reduced pressure
Amass mother solution to about remaining monoploid, be cooled to zero degree discharging, obtain 17 Alpha-hydroxy Progesterone V (65g) in 60 DEG C of decompression dryings, weight
Amount yield 81%, HPLC content 93%.
The 17 Alpha-hydroxy Progesterone V prepared in various embodiments above are detected, mass spectrum: m/z 331 (M+H+), with
17 Alpha-hydroxy Progesterone reference materials compare, and comply fully with the characteristic of 17 Alpha-hydroxy Progesterone.
With the above-mentioned desirable embodiment according to the present invention for enlightenment, by above-mentioned description, relevant staff is complete
Entirely can carry out various change and amendment in the range of without departing from this invention technological thought.The technology of this invention
The content that property scope is not limited in description, it is necessary to determine its technical scope according to right.
Claims (13)
1. the method preparing 17 Alpha-hydroxy Progesterone, it is characterised in that comprise the steps:
(1) ethynylation: first add alkali, oxolane and solvent in there-necked flask, be heated to 50 DEG C under nitrogen protection, reaction
1 hour, it is cooled to the first preset temperature, logical acetylene gas certain time under described first preset temperature；Then with 4-androstene two
Ketone I is dissolved in the tetrahydrofuran solution of oxolane preparation 4-AD I, under described first preset temperature, to described three mouthfuls
The tetrahydrofuran solution of described 4-AD I, insulation reaction 2 hours it is slowly added dropwise in Ping；The most backward described there-necked flask adds
Entering aqueous hydrochloric acid solution adjusts pH value to 3～4, is heated to reflux half an hour, removal of solvent under reduced pressure, adds water elutriation, sucking filtration, washing, subtract
Press dry dry, obtain acetylide II；Reaction equation is
；
(2) nitration reaction: first adding acetic anhydride and acetylide II in reaction bulb, stirring is cooled to the second preset temperature；Then
In described reaction bulb, it is slowly added dropwise nitric acid under nitrogen protection, drips rear insulation reaction the first Preset Time；Through TLC after
When detection is without raw material point, in described reaction bulb, pours frozen water elutriation, sucking filtration, washing, decompression drying into, obtain itrated compound III；Instead
Ying Shiwei
；
(3) translocation reaction: first add oxolane, water and itrated compound III in reaction bulb, stir under the 3rd preset temperature；So
Rear addition silver nitrate, reactant liquor stirs reaction the second Preset Time under described 3rd preset temperature；Last concentrating under reduced pressure removes
Oxolane, adds nitric acid, adds dichloromethane extractive reaction liquid, layering, and organic facies concentrating under reduced pressure removes solvent, obtains indexing
Product IV；Reaction equation is
；
(4) carbonylation: adding acetone and indexing product IV in reaction bulb, stirring and dissolving obtains the acetone of indexing product IV
Solution, adds Mercury bisulfate., concentrated sulphuric acid and water, is heated to the 4th preset temperature reaction the 3rd Preset Time, and concentrating under reduced pressure removes third
Ketone, residual reaction liquid is poured in frozen water, adds saturated sodium bicarbonate solution and adjusts pH value to be neutral, and stirring adds ethyl acetate extraction
Extracting reaction solution, layering, be dried organic facies with anhydrous sodium sulfate, be evaporated to surplus monoploid and amass mother solution, cooling discharge, decompression is dried
Dry obtain 17 Alpha-hydroxy Progesterone V；Reaction equation is
。
Method the most according to claim 1, it is characterised in that described in step (1), alkali is potassium hydroxide or potassium tert-butoxide.
Method the most according to claim 1, it is characterised in that described in step (1), 4-AD I with the ratio of alkali is
1W:1W～1W:4W.
Method the most according to claim 1, it is characterised in that described in step (1), solvent is ethanol, isopropanol and acetone
In one.
Method the most according to claim 1, it is characterised in that in described step (1), the time of logical acetylene gas is 1～4 little
Time.
Method the most according to claim 1, it is characterised in that described in step (1), the first preset temperature is-5～5 DEG C.
Method the most according to claim 1, it is characterised in that acetic anhydride, acetylide II and nitric acid described in step (2)
Ratio is 5.4W:1W:0.71W～10.8W:1W:1.42W.
Method the most according to claim 1, it is characterised in that the second preset temperature described in step (2) be-30 DEG C～-
20 DEG C, described first Preset Time is 1～3 hour.
Method the most according to claim 1, it is characterised in that oxolane described in step (3), water, itrated compound III and
Silver nitrate ratio is 1.78W:2W:1W:0.05W～8.89W:10W:1W:0.5W.
Method the most according to claim 1, it is characterised in that described in step (3), the 3rd preset temperature is 20 DEG C～30
DEG C, described second Preset Time is 36～100 hours.
11. methods according to claim 1, it is characterised in that indexing product IV, Mercury bisulfate., dense sulfur described in step (4)
The ratio of acid and water is 1W:0.01W:0.18W:0.5W～1W:0.04W:0.55W:2W.
12. methods according to claim 1, it is characterised in that the acetone soln of indexing product IV described in step (4) is dense
Degree is 0.1～0.5mol/L.
13. methods according to claim 1, it is characterised in that described in step (4), the 4th preset temperature is 40 DEG C～56
DEG C, described 3rd Preset Time is 5～7 hours.
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| CN114085261A (en) * | 2021-12-07 | 2022-02-25 | 浙江仙琚制药股份有限公司 | Preparation method of megestrol and intermediate thereof |
| CN114409724A (en) * | 2022-01-10 | 2022-04-29 | 南京联智医药科技有限公司 | Novel preparation method of danazol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107033207A (en) * | 2017-05-04 | 2017-08-11 | 山东赛托生物科技股份有限公司 | A kind of preparation method of the steroid nucleus derivative containing alkynyl |
| CN109517027A (en) * | 2019-01-23 | 2019-03-26 | 江苏联环药业股份有限公司 | A kind of preparation method of danazol |
| CN109517027B (en) * | 2019-01-23 | 2020-07-03 | 江苏联环药业股份有限公司 | Preparation method of danazol |
| CN114085261A (en) * | 2021-12-07 | 2022-02-25 | 浙江仙琚制药股份有限公司 | Preparation method of megestrol and intermediate thereof |
| CN114409724A (en) * | 2022-01-10 | 2022-04-29 | 南京联智医药科技有限公司 | Novel preparation method of danazol |
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Application publication date: 20170111 |