CN101812108B - Synthesis of hydrocortisone butyrate - Google Patents
Synthesis of hydrocortisone butyrate Download PDFInfo
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- CN101812108B CN101812108B CN2009102287895A CN200910228789A CN101812108B CN 101812108 B CN101812108 B CN 101812108B CN 2009102287895 A CN2009102287895 A CN 2009102287895A CN 200910228789 A CN200910228789 A CN 200910228789A CN 101812108 B CN101812108 B CN 101812108B
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Abstract
The invention relates to synthesis of hydrocortisone butyrate, which comprises the following steps of: A. carrying out acylation reaction on hydrocortisone acetate adopted as a raw material and butyl chloride in an organic solvent I under the condition of existence of a catalyst; after the reaction is finished, adding acid to adjust a PH value being smaller than 5; diluting or recrystallizing to obtain hydrocortisone 17alpha-butyrate-21-acetate; and B. adopting the hydrocortisone 17alpha-butyrate-21-acetate as a raw material, adding inorganic alkali in an organic solvent II and carrying out selective hydrolysis reaction to obtain hydrocortisone 17alpha-butyrate.
Description
Invention field
The present invention relates to the preparation method of 17 butyric esters of HYDROCORTISONE INJECTIONS.
Background technology:
HYDROCORTISONE INJECTIONS 17 iophenoxic acid ester (Hydrocortisone-17-butyrate; CAS:13609-67-1) be a kind of common skin medicine, at home should (hydrocortisone butyrate be in the application of Dermatology Department, " continuation medical education " through being widely used; 2006 20 33 phases of volume; 59), be that formulations of active ingredients is comparatively common in market with 17 butyric esters of HYDROCORTISONE INJECTIONS, the emulsifiable paste of the commodity " You Zhuoer " by name of for example Tianjin Pharmaceutical Group Corp., Ltd's production.
The synthetic technology of 17 butyric esters of HYDROCORTISONE INJECTIONS last century the seventies study with regard to scientist is arranged; For example JP52136157, JP 56040700, Synthesis; (8), documents such as 700-1 1984, JP 60048998 show that all the synthetic of this compound is through HYDROCORTISONE INJECTIONS and of the original acid triethyl reaction, form 17; 21 cyclic ortho esters, thus form 21 open loops through sour selectivity.
17,21 cyclic ortho esters, the R=n-propyl
The synthesis technique of 17 butyric esters of in fact above-mentioned HYDROCORTISONE INJECTIONS is to 17 common technologies of ester OH synthetic of pregnant steroid; Not only 17 butyric esters of HYDROCORTISONE INJECTIONS use; 17 ester OHs of other pregnant steroids also often use, for example synthetic (prednicarbate synthetic, " Chinese Journal of Pharmaceuticals " of prednicarbate; 1999 30 11 phases of volume, 490).But because acid is in 17, the 21 cyclic ortho ester open loop processes, though the corresponding 17-ester of most of generation; But the corresponding 21-ester of part also can occur, cause product impure, especially the polar phase of 17-ester and 21-ester seemingly; Be not easy to separate through means re-crystallization; In order to obtain satisfactory product, will increase the purified number of times accordingly, reduce yield.
The method of synthetic ester is a lot of in fact; For example alcohol all can directly obtain corresponding ester with acid, acid anhydrides or acyl chloride reaction; Since there is tangible problem in aforesaid method; Why also can adopt the method for the obvious problem of above-mentioned existence? Its reason is that 17 of pregnane compounds exist β-acetone side chain, Alpha-hydroxy, and is because the existence of β-acetone side chain makes alpha-hydroxy direct esterification have bigger steric hindrance, especially just all the more so when also there is ester group (being the 21-ester) in the other end of β-acetone side chain; Cause 17 Alpha-hydroxies can't pass through the direct method esterification; Even if simultaneously the researchist also worry 17 can direct esterification, the hydroxyl of 11 same existence is esterification simultaneously also, causes more impurity and can not get highly purified product.
Summary of the invention
The present invention relates to the preparation method of 17 butyric esters of HYDROCORTISONE INJECTIONS.We are through constantly research; Be surprised to find, through adding specific catalyst and post-treating method, HYDROCORTISONE INJECTIONS 21 bit esterified things and butyryl chloride react the esterification that can avoid 11 hydroxyls; The α hydroxyl that the highly selective esterification is 17 and obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester; Simultaneously through the selective hydrolysis condition, make being hydrolyzed that hydrolysis reaction can highly selective, thereby obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid esters to the 21-acetic ester.
A kind of method for preparing HYDROCORTISONE INJECTIONS-17 iophenoxic acid ester is characterized in that:
A. be raw material with the HYDROCORTONE ACETATE, in organic solvent 1, under the catalyzer condition, carry out acylation reaction with butyryl chloride, it is below 5 that adding acid adjusting pH value is finished in reaction, and dilution or recrystallization obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester;
B. with HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester be raw material in organic solvent matchmaker 2, add mineral alkali, carry out the selective hydrolysis reaction, obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid esters.
Wherein catalyzer is 4-dimethylaminopyridine (DMAP), pyridinium tribromide hydrohalogenic acid salt, tosic acid.Said catalyzer is 0.05-0.1 with mol ratio as the HYDROCORTONE ACETATE of raw material: 1.
To steps A
It all is alkaline organic solvent that said organic solvent 1 is selected from; Perhaps part is alkaline organic solvent, and part is the inertia organic solvent.
In in the said organic solvent 1 preferred alkaline organic solvent one or more and the inertia solvent one or more mix use.
Said inertia organic solvent be selected from six carbon with interior ether, four carbon with the haloalkane of interior acid amides, two carbon, four carbon with in the interior nitrile one or more; Include but are not limited to methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, acetonitrile, N; Dinethylformamide, THF, ether, in one or more, one or both in preferred methylene dichloride and the trichloromethane.
Described alkaline organic solvent is selected from amine, preferred triethylamine and/or pyridine.
The mol ratio of described HYDROCORTONE ACETATE and butyryl chloride is 1.1～1.5 times
Wherein sour preferred organic acid or hydrochloric acid, said organic acid is selected from acetic acid, butyric acid.
When said acid was hydrochloric acid, acid was regulated PH preferably at 1-3.
Wherein acid is regulated PH preferably at 1-3.
Wherein butyryl chloride splashes into slow the adding perhaps in the reaction process.
Wherein the temperature in the reaction process is controlled at 0-30 ℃, preferred 0-10 ℃.
Step B
Wherein organic solvent described in the above-mentioned steps B 2 is six carbon with the haloalkane of interior ether, two carbon, four carbon with in the interior alcohol one or more, includes but are not limited in methylene dichloride, trichloromethane, ethylene dichloride, methyl alcohol, absolute ethyl alcohol, THF, the ether one or more; The haloalkane of preferred two carbon and the mixture in the alcohol, more preferably methylene dichloride and methanol mixture.
Mineral alkali is selected from NaOH, KOH, yellow soda ash, salt of wormwood in the wherein above-mentioned B step; The carbonate of preferred as alkali; Be salt of wormwood, yellow soda ash, in said HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester and the mineral alkali alkalimetal ion mol ratio be 1: 1.1-1.3.
In the wherein above-mentioned B step in the reaction process temperature be-20-0 ℃ preferred-10-20 ℃.
All can feed rare gas element, nitrogen in said steps A and the step B reaction process.
In experimentation, the discovery that we are surprised is for step B; Really part generates 11 β in butyryl chloride and HYDROCORTONE ACETATE reaction process, 17 α-two butyric ester-HYDROCORTONE ACETATEs, but 11 β-butyric ester is very unstable; In last handling process through regulating pH value less than after 5; Hydrolysis will take place in 11 β-butyric ester, forms 11 beta-hydroxies, thereby improves the selectivity of reaction greatly.
Compared with prior art; Technical scheme provided by the invention is through preferred lower temperature of reaction, and the preferred more weak alkali-metal carbonate of alkalescence reacts with control hydrolysis, adopted slow dropping alkaline solution method simultaneously; Controlled the speed of hydrolysis reaction; Make that astoundingly hydrolysis reaction has had selectivity, can optionally generate HYDROCORTISONE INJECTIONS 17 iophenoxic acid esters, simultaneously because; Simultaneously because the major impurity that adopts technical scheme of the present invention to produce is HYDROCORTISONE INJECTIONS-21-acetic ester unreacted HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester completely; Differ more with the polarity of HYDROCORTISONE INJECTIONS-17 iophenoxic acid ester, when carrying out further making with extra care, be easier under the prerequisite of higher yields, obtain the higher product of purity with conventional method---HYDROCORTISONE INJECTIONS-17 iophenoxic acid ester.
A kind of method for preparing HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester; It is the described compound method of abovementioned steps A; It is characterized in that with the HYDROCORTONE ACETATE being raw material, in organic solvent 1, under the catalyzer condition, carry out acylation reaction with butyryl chloride; It is below 5 that adding acid adjusting pH value is finished in reaction, and dilution or recrystallization obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester.
It all is alkaline organic solvent that said organic solvent 1 is selected from; Perhaps part is alkaline organic solvent, and part is the inertia organic solvent.
Said inertia organic solvent be selected from six carbon with interior ether, four carbon with the haloalkane of interior acid amides, two carbon, four carbon with in the interior nitrile one or more; Include but are not limited to methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, acetonitrile, N; Dinethylformamide, THF, ether, in one or more, one or both in preferred methylene dichloride and the trichloromethane.
Described alkaline organic solvent is selected from amine, preferred triethylamine and/or pyridine.
In in the said organic solvent 1 preferred alkaline organic solvent one or more and the inertia solvent one or more mix use.
The mol ratio of described HYDROCORTONE ACETATE and butyryl chloride is 1.1～1.5 times
Wherein sour preferred organic acid or hydrochloric acid, the preferred acetic acid of said organic acid, butyric acid.
When said acid was hydrochloric acid, acid was regulated PH preferably at 1-3.
Wherein can feed rare gas element, nitrogen in the reaction process.
Wherein butyryl chloride splashes into slow the adding perhaps in the reaction process.
Wherein the temperature in the reaction process is controlled at 0-30 ℃, preferred 0-10 ℃.
The said method for preparing HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester, promptly the described compound method of abovementioned steps A partly generates 11 β really in butyryl chloride and HYDROCORTONE ACETATE reaction process; 17 α-two butyric ester-HYDROCORTONE ACETATEs; But 11 β-butyric ester is very unstable, and through regulating pH value less than after 5, hydrolysis will take place 11 β-butyric ester in last handling process; Form 11 beta-hydroxies, thereby improve the selectivity of reaction greatly.
Embodiment
The DMAP:4-dimethyl aminopyridine
HPLC: performance liquid chromatography
Embodiment 1:
Acidylate:
Get HYDROCORTONE ACETATE 1mmol and place the 10ml methylene dichloride, the solution of gained is cooled to 0～5 ℃, and under this temperature, add 4ml triethylamine and 0.05mmolDMAP; Under temperature is 0-5 ℃ condition, slowly add the 1.5mmol butyryl chloride then, under 0 ℃ condition, stir resultant mixture then; Add hydrochloric acid behind the reaction 3h and transfer pH to 2, stir after 10 minutes, water is washed till neutrality; Use methylene dichloride 10ml * 3 time aqueous phase extracted again, organic phase merges, and concentrates; Pour methyl alcohol and carry out recrystallization, cool off, filter excessively HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester (acylate) 0.86mmol.
Before in reaction, adding hydrochloric acid, sampling through HPLC, is analyzed and is found HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester and 11 β, and the ratio of 17 α-two butyric ester-HYDROCORTONE ACETATEs is 1: 0.16.
HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester and 11 β in the product that obtains after the reaction, the ratio of 17 α-two butyric ester-HYDROCORTONE ACETATEs is 1: 0.02.
Hydrolysis:
Acylate is dissolved in methylene dichloride, adds the methyl alcohol of equivalent, logical N
2Protection slowly adds the 0.1g salt of wormwood that is dissolved in methyl alcohol, and after reacting completely under-10 ℃, reaction solution is neutralized to neutrality with Glacial acetic acid min. 99.5; Wash three times, each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time; Organic phase merges, and concentrates, and pours methyl alcohol and carries out recrystallization; Be cooled to 0 ℃, filter, obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid ester 0.65mmol.
Embodiment 2:
Acidylate:
Get HYDROCORTONE ACETATE 1mmol and place the 10ml trichloromethane, the solution of gained is cooled to 0～5 ℃, and under this temperature, add 4ml pyridine and 0.1mmol pyridinium tribromide hydrohalogenic acid salt; Under temperature is 0-5 ℃ condition, slowly add the 1.3mmol butyryl chloride then, under 0 ℃ condition, stir resultant mixture then; Add hydrochloric acid behind the reaction 3h and transfer to 2, stir after 10 minutes, water is washed till neutrality; Use methylene dichloride 10ml * 3 time aqueous phase extracted again, organic phase merges, and concentrates; Pour methyl alcohol and carry out recrystallization, get HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester (acylate) 0.83mmol.
Hydrolysis:
Acylate is dissolved in methylene dichloride, adds the methyl alcohol of equivalent, logical N
2Protection adds the 0.1g salt of wormwood that is dissolved in methyl alcohol, after reacting completely under-20 ℃; Reaction solution is neutralized to neutrality with Glacial acetic acid min. 99.5, washes three times, each 20ml water; And with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, and concentrates; Pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃, filter and obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid ester 0.65mmol.
Embodiment 3:
Acidylate:
Get HYDROCORTONE ACETATE 1mmol and place the 10ml methylene dichloride, the solution of gained is cooled to 0～5 ℃, and under this temperature, add 4ml pyridine and 0.05mmolDMAP; Under temperature is 0-5 ℃ condition, slowly add the 1.3mmol butyryl chloride then, under 0 ℃ condition, stir resultant mixture then; Add acetic acid behind the reaction 3h and transfer to 5, stir after 10 minutes, water is washed till neutrality; Use methylene dichloride 10ml * 3 time aqueous phase extracted again, organic phase merges, and concentrates; Pour methyl alcohol and carry out recrystallization, get HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester (acylate) 0.9mmol.
Before in reaction, adding hydrochloric acid, sampling through HPLC, is analyzed and is found HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester and 11 β, and the ratio of 17 α-two butyric ester-HYDROCORTONE ACETATEs is 1: 0.19.
HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester and 11 β in the product that obtains after the reaction, the ratio of 17 α-two butyric ester-HYDROCORTONE ACETATEs is 1: 0.05.
Hydrolysis:
Acylate is dissolved in methylene dichloride, adds the methyl alcohol of equivalent, logical N
2Protection adds the 0.1g salt of wormwood that is dissolved in methyl alcohol, after reacting completely under-15 ℃; Reaction solution is neutralized to neutrality with Glacial acetic acid min. 99.5, washes three times, each 20ml water; And with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, and concentrates; Pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃, filter and obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid ester 0.68mmol.
Embodiment 4:
Acidylate:
Get HYDROCORTONE ACETATE 1mmol and 0.1mmol pyridinium tribromide hydrohalogenic acid salt places the 10ml pyridine, the solution of gained is cooled to 0～5 ℃, then under temperature is 0-5 ℃ condition; Slowly add the 1.2mmol butyryl chloride, under 0 ℃ condition, stir resultant mixture then, add hydrochloric acid behind the reaction 3h and transfer pH to 1-2; Stir after 10 minutes, water is washed till neutrality, uses methylene dichloride 10ml * 3 time aqueous phase extracted again; Organic phase merges; Concentrate, pour methyl alcohol and carry out recrystallization, get HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester (acylate) 0.85mmol.
Hydrolysis:
Acylate is dissolved in methylene dichloride, adds the methyl alcohol of equivalent, logical N
2Protection adds the 0.08g yellow soda ash that is dissolved in methyl alcohol, after reacting completely under-20 ℃; Reaction solution is neutralized to neutrality with Glacial acetic acid min. 99.5, washes three times, each 20ml water; And with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, and concentrates; Pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃, obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid ester 0.71mmol.
Claims (34)
1. method for preparing HYDROCORTISONE INJECTIONS-17 iophenoxic acid ester is characterized in that:
A. with the HYDROCORTONE ACETATE raw material; In organic solvent 1; Under the catalyzer condition, carry out acylation reaction with butyryl chloride, it is below 5 that the adding acid for adjusting pH value is finished in reaction, and dilution or recrystallization obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester; It all is alkaline organic solvent that organic solvent 1 is selected from; Perhaps part is alkaline organic solvent, and part is the inertia organic solvent, and described alkaline organic solvent is selected from amine; Said inertia organic solvent be selected from six carbon with interior ether, methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, four carbon with interior acid amides, four carbon with in the interior nitrile one or more, said catalyzer is 4-dimethylaminopyridine, pyridinium tribromide hydrohalogenic acid salt, tosic acid;
B. be that raw material is in organic solvent matchmaker 2 with HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester; Add mineral alkali; Carry out the selective hydrolysis reaction; Obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acid esters, organic solvent 2 is six carbon with interior ether, methylene dichloride, trichloromethane, ethylene dichloride, four carbon with in the interior alcohol one or more
2. the method for claim 1 is characterized in that said catalyzer and mol ratio as the HYDROCORTONE ACETATE of raw material are 0.05-0.1: 1.
3. the method for claim 1, it is characterized in that said organic solvent 1 be selected from the alkaline organic solvent one or more with the inertia organic solvent in one or more mix use.
4. the method for claim 1 is characterized in that described alkaline organic solvent is selected from triethylamine and/or pyridine.
5. the method for claim 1 is characterized in that described inertia organic solvent is selected from methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, acetonitrile, N, one or more in dinethylformamide, THF, the ether.
6. method as claimed in claim 3 is characterized in that described inertia organic solvent is selected from one or both in methylene dichloride and the trichloromethane.
7. the method for claim 1, the mol ratio that it is characterized in that said HYDROCORTONE ACETATE and butyryl chloride is 1.1～1.5.
8. the method for claim 1 is characterized in that, said acid is selected from organic acid or hydrochloric acid.
9. method as claimed in claim 8 is characterized in that described organic acid is selected from acetic acid, butyric acid.
10. method as claimed in claim 8 is characterized in that said acid is hydrochloric acid, and acid for adjusting pH is at 1-3.
11. the method for claim 1 is characterized in that said butyryl chloride splashes into slow the adding perhaps.
12. the method for claim 1 is characterized in that the temperature in the reaction process of steps A is controlled at 0-30 ℃.
13. method as claimed in claim 12 is characterized in that the temperature in the reaction process of steps A is controlled at 0-10 ℃.
14. the method for claim 1 is characterized in that organic solvent 2 described in the step B is selected from one or more in methylene dichloride, trichloromethane, ethylene dichloride, methyl alcohol, absolute ethyl alcohol, THF, the ether.
15. method as claimed in claim 14 is characterized in that organic solvent described in the step B 2 is methylene dichloride and methanol mixture.
16. the method for claim 1 is characterized in that mineral alkali is selected from NaOH, KOH, yellow soda ash, salt of wormwood described in the B step.
17. method as claimed in claim 16 is characterized in that described mineral alkali is selected from yellow soda ash, salt of wormwood.
18., it is characterized in that the mol ratio of alkalimetal ion in said HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester and the mineral alkali is 1: 1.1-1.3 like claim 16 or 17 described methods.
19. the method for claim 1 is characterized in that in the B step in the reaction process that temperature is-20-0 ℃.
20. the method for claim 1 all feeds rare gas element in said steps A and the step B reaction process.
21. method as claimed in claim 20 is characterized in that said rare gas element is a nitrogen.
22. method for preparing HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester; It is characterized in that with the HYDROCORTONE ACETATE being raw material; In organic solvent 1, under the catalyzer condition, carry out acylation reaction with butyryl chloride, it is below 5 that the adding acid for adjusting pH value is finished in reaction; Dilution or recrystallization obtain HYDROCORTISONE INJECTIONS 17 iophenoxic acids ester-21-acetic ester, and it all is alkaline organic solvent that said organic solvent 1 is selected from; Perhaps part is alkaline organic solvent; Part is the inertia organic solvent; Said inertia organic solvent be selected from six carbon with interior ether, four carbon with interior acid amides, methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, four carbon with in the interior nitrile one or more; Described alkaline organic solvent is selected from amine, and said catalyzer is 4-dimethylaminopyridine, pyridinium tribromide hydrohalogenic acid salt, tosic acid
23. method as claimed in claim 22 is characterized in that said catalyzer and mol ratio as the HYDROCORTONE ACETATE of raw material are 0.05-0.1: 1.
24. method as claimed in claim 22, it is characterized in that said organic solvent 1 in the alkaline organic solvent one or more with the inertia organic solvent in one or more mix use.
25. method as claimed in claim 22 is characterized in that said alkaline organic solvent is selected from triethylamine and/or pyridine.
26. method as claimed in claim 22 is characterized in that described inertia organic solvent is selected from methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, acetonitrile, N, one or more in dinethylformamide, THF, the ether.
27. method as claimed in claim 26 is characterized in that described inertia organic solvent is selected from one or both in methylene dichloride and the trichloromethane.
28. method as claimed in claim 22, the mol ratio that it is characterized in that said HYDROCORTONE ACETATE and butyryl chloride is 1.1～1.5.
29. method as claimed in claim 22 is characterized in that said acid is selected from organic acid or hydrochloric acid.
30. method as claimed in claim 29 is characterized in that described organic acid is selected from acetic acid, butyric acid.
31. method as claimed in claim 29 is characterized in that said acid is hydrochloric acid, acid for adjusting pH is at 1-3.
32. method as claimed in claim 22 is characterized in that said butyryl chloride splashes into slow the adding perhaps.
33. method as claimed in claim 22 is characterized in that the temperature in the reaction process is controlled at 0-30 ℃.
34. method as claimed in claim 33 is characterized in that the temperature in the reaction process is controlled at 0-10 ℃.
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| CN112028956A (en) * | 2020-09-10 | 2020-12-04 | 那路新 | Method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione |
| IT202100008429A1 (en) | 2021-04-06 | 2022-10-06 | Farmabios Spa | Process for the preparation of cortexolone 17α-propionate and its new hydrated crystalline form |
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Application publication date: 20100825 Assignee: Pharmaceutical Co., Ltd. Tianjin Jin Yao Assignor: Tianjin Jinyao Group Co., Ltd. Contract record no.: 2014120000072 Denomination of invention: Synthesis of hydrocortisone butyrate Granted publication date: 20120523 License type: Common License Record date: 20140903 |
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