CN101812108A - Synthesis of hydrocortisone butyrate - Google Patents
Synthesis of hydrocortisone butyrate Download PDFInfo
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- CN101812108A CN101812108A CN200910228789A CN200910228789A CN101812108A CN 101812108 A CN101812108 A CN 101812108A CN 200910228789 A CN200910228789 A CN 200910228789A CN 200910228789 A CN200910228789 A CN 200910228789A CN 101812108 A CN101812108 A CN 101812108A
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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.
Background technology:
Hydrocortisone 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 through being extensive use of, " continuation medical education ", 2006 20 33 phases of volume, 59), be that formulations of active ingredients is comparatively common in market with 17 butyric esters of hydrocortisone, 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 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 by hydrocortisone and of the original acid triethyl reaction, form 17,21 cyclic ortho esters, thus form 21 open loops by sour selectivity.
17,21 cyclic ortho esters, the R=n-propyl
The synthesis technique of 17 butyric esters of in fact above-mentioned hydrocortisone is to 17 common technologies of hydroxy ester synthetic of pregnant steroid, not only 17 butyric esters of hydrocortisone use, 17 hydroxy esters of other pregnant steroids also often use, for example prednicarbate synthesizes (synthesizing of prednicarbate, " Chinese Journal of Pharmaceuticals ", 1999 30 11 phases of volume, 490).But because acid is to 17, in 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 by 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 is with sour, acid anhydrides or acyl chloride reaction all can directly obtain corresponding ester, 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, 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.We are through constantly research, be surprised to find, by adding specific catalyst and post-treating method, hydrocortisone 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 17 iophenoxic acids ester-21-acetic ester, simultaneously by the selective hydrolysis condition, make being hydrolyzed that hydrolysis reaction can highly selective, thereby obtain hydrocortisone 17 iophenoxic acid esters at the 21-acetic ester.
A kind of method for preparing hydrocortisone-17 iophenoxic acid ester is characterized in that:
A. be raw material with the hydrocortisone acetate, in organic solvent 1, carry out acylation reaction with butyryl chloride under the catalyzer condition, it is below 5 that adding acid adjusting pH value is finished in reaction, and dilution or recrystallization obtain hydrocortisone 17 iophenoxic acids ester-21-acetic ester;
B. with hydrocortisone 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 17 iophenoxic acid esters.
Wherein catalyzer is 4-dimethylaminopyridine (DMAP), pyridinium tribromide hydrohalogenic acid salt, tosic acid.Described catalyzer is 0.05-0.1 with mol ratio as the hydrocortisone acetate of raw material: 1.
To steps A
It all is alkaline organic solvent that described organic solvent 1 is selected from; Perhaps part is alkaline organic solvent, and part is the inertia organic solvent.
In in the described organic solvent 1 preferred alkaline organic solvent one or more and the inertia solvent one or more mix use.
Described 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, tetrahydrofuran (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 hydrocortisone acetate and butyryl chloride is 1.1～1.5 times
Wherein sour preferred organic acid or hydrochloric acid, described organic acid is selected from acetic acid, butyric acid.
When described acid was hydrochloric acid, acid was regulated PH preferably at 1-3.
Wherein acid is regulated PH preferably at 1-3.
Wherein butyryl chloride slowly adds or splashes 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, dehydrated alcohol, tetrahydrofuran (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 described hydrocortisone 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, preferred nitrogen in described steps A and the step B reaction process.
In experimentation, the discovery that we are surprised, for step B, really part generates 11 β in butyryl chloride and hydrocortisone acetate reaction process, 17 α-two butyric ester-hydrocortisone acetates, but 11 β-butyric ester is very unstable, in last handling process by 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 by preferred lower temperature of reaction, and the more weak alkali-metal carbonate of preferred 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 17 iophenoxic acid esters, simultaneously because, simultaneously because the major impurity that adopts technical solution of the present invention to produce is hydrocortisone-21-acetic ester unreacted hydrocortisone 17 iophenoxic acids ester-21-acetic ester completely, differ more with the polarity of hydrocortisone-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-17 iophenoxic acid ester.
A kind of method for preparing hydrocortisone 17 iophenoxic acids ester-21-acetic ester; it is the described synthetic method of abovementioned steps A; it is characterized in that with the hydrocortisone 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 17 iophenoxic acids ester-21-acetic ester.
It all is alkaline organic solvent that described organic solvent 1 is selected from; Perhaps part is alkaline organic solvent, and part is the inertia organic solvent.
Described 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, tetrahydrofuran (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 described organic solvent 1 preferred alkaline organic solvent one or more and the inertia solvent one or more mix use.
The mol ratio of described hydrocortisone acetate and butyryl chloride is 1.1～1.5 times
Wherein sour preferred organic acid or hydrochloric acid, the preferred acetic acid of described organic acid, butyric acid.
When described acid was hydrochloric acid, acid was regulated PH preferably at 1-3.
Wherein can feed rare gas element, preferred nitrogen in the reaction process.
Wherein butyryl chloride slowly adds or splashes in the reaction process.
Wherein the temperature in the reaction process is controlled at 0-30 ℃, preferred 0-10 ℃.
The described method for preparing hydrocortisone 17 iophenoxic acids ester-21-acetic ester, it is the described synthetic method of abovementioned steps A, really part generates 11 β in butyryl chloride and hydrocortisone acetate reaction process, 17 α-two butyric ester-hydrocortisone acetates, but 11 β-butyric ester is very unstable, and by 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: high performance liquid chromatography
Embodiment 1:
Acidylate:
Get hydrocortisone 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; then under temperature is 0-5 ℃ condition; slowly add the 1.5mmol butyryl chloride; under 0 ℃ condition, stir resultant mixture then; add hydrochloric acid behind the reaction 3h and transfer pH to 2; stir after 10 minutes, wash with water, use methylene dichloride 10ml * 3 time aqueous phase extracted again to neutrality; organic phase merges; concentrate, pour methyl alcohol and carry out recrystallization, cooling; filter hydrocortisone 17 iophenoxic acids ester-21-acetic ester (acylate) 0.86mmol.
Add hydrochloric acid in reaction before, sampling by HPLC, is analyzed and is found hydrocortisone 17 iophenoxic acids ester-21-acetic ester and 11 β, and the ratio of 17 α-two butyric ester-hydrocortisone acetates is 1: 0.16.
Hydrocortisone 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-hydrocortisone 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, after reacting completely under-10 ℃; reaction solution is neutralized to neutrality with Glacial acetic acid; wash three times, each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time; organic phase merges; concentrate, pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃; filter, obtain hydrocortisone 17 iophenoxic acid ester 0.65mmol.
Embodiment 2:
Acidylate:
Get hydrocortisone 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; then under temperature is 0-5 ℃ condition; slowly add the 1.3mmol butyryl chloride; under 0 ℃ condition, stir resultant mixture then; add hydrochloric acid behind the reaction 3h and transfer to 2; stir after 10 minutes, wash with water, use methylene dichloride 10ml * 3 time aqueous phase extracted again to neutrality; organic phase merges; concentrate, pour methyl alcohol and carry out recrystallization, get hydrocortisone 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; add 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; wash three times; each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merging; concentrate; pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃, filter and obtain hydrocortisone 17 iophenoxic acid ester 0.65mmol.
Embodiment 3:
Acidylate:
Get hydrocortisone 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; then under temperature is 0-5 ℃ condition; slowly add the 1.3mmol butyryl chloride; under 0 ℃ condition, stir resultant mixture then; add acetic acid behind the reaction 3h and transfer to 5; stir after 10 minutes, wash with water, use methylene dichloride 10ml * 3 time aqueous phase extracted again to neutrality; organic phase merges; concentrate, pour methyl alcohol and carry out recrystallization, get hydrocortisone 17 iophenoxic acids ester-21-acetic ester (acylate) 0.9mmol.
Add hydrochloric acid in reaction before, sampling by HPLC, is analyzed and is found hydrocortisone 17 iophenoxic acids ester-21-acetic ester and 11 β, and the ratio of 17 α-two butyric ester-hydrocortisone acetates is 1: 0.19.
Hydrocortisone 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-hydrocortisone acetates is 1: 0.05.
Hydrolysis:
Acylate is dissolved in methylene dichloride, adds the methyl alcohol of equivalent, logical N
2Protection; add 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; wash three times; each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merging; concentrate; pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃, filter and obtain hydrocortisone 17 iophenoxic acid ester 0.68mmol.
Embodiment 4:
Acidylate:
Get hydrocortisone 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; wash with water to 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 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; add 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; wash three times; each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merging; concentrate; pour methyl alcohol and carry out recrystallization, be cooled to 0 ℃, obtain hydrocortisone 17 iophenoxic acid ester 0.71mmol.
Claims (10)
1. method for preparing hydrocortisone-17 iophenoxic acid ester is characterized in that:
A. be raw material with the hydrocortisone acetate, in organic solvent 1, carry out acylation reaction with butyryl chloride under the catalyzer condition, it is below 5 that adding acid adjusting pH value is finished in reaction, and dilution or recrystallization obtain hydrocortisone 17 iophenoxic acids ester-21-acetic ester;
B. with hydrocortisone 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 17 iophenoxic acid esters.
2. synthetic method as claimed in claim 1 is characterized in that described catalyzer is 4-dimethylaminopyridine (DMAP), pyridinium tribromide hydrohalogenic acid salt, tosic acid, and described catalyzer is 0.05-0.1 with mol ratio as the hydrocortisone acetate of raw material: 1.
3. as the synthetic method of claim 1 or 2, it is characterized in that it all is alkaline organic solvent that described organic solvent 1 is selected from that described organic solvent 1 is selected from; Perhaps part is alkaline organic solvent, part is the inertia organic solvent, described 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, described alkaline organic solvent is selected from amine.
4. as arbitrary described synthetic method among the claim 1-3, the mol ratio that it is characterized in that described hydrocortisone acetate and butyryl chloride is 1.1～1.5 times.
5. as arbitrary described synthetic method among the claim 1-4, it is characterized in that the temperature in the reaction process of steps A is controlled at 0-30 ℃.
6. as arbitrary described synthetic method among the claim 1-5, it is characterized in that organic solvent described in the step B 2 is six carbon with the haloalkane of interior ether, two carbon, four carbon with in the interior alcohol one or more.
7. as arbitrary described synthetic method among the claim 1-7, it is characterized in that mineral alkali is selected from NaOH, KOH, yellow soda ash, salt of wormwood described in the B step.
8. synthetic method as claimed in claim 7, it is characterized in that alkalimetal ion in described hydrocortisone 17 iophenoxic acids ester-21-acetic ester and the mineral alkali mol ratio be 1: 1.1-1.3.
9. as arbitrary described synthetic method among the claim 1-8, it is characterized in that in the B step in the reaction process that temperature is-20-0 ℃.
10. as arbitrary described synthetic method among the claim 1-9, all can feed rare gas element in described steps A and the step B reaction process.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880907A (en) * | 2014-03-11 | 2014-06-25 | 天津金耀集团有限公司 | Hydrocortisone-17-butyrate semihydrate |
| 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 |
-
2009
- 2009-11-26 CN CN2009102287895A patent/CN101812108B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880907A (en) * | 2014-03-11 | 2014-06-25 | 天津金耀集团有限公司 | Hydrocortisone-17-butyrate semihydrate |
| 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 |
| EP4071160A1 (en) | 2021-04-06 | 2022-10-12 | Farmabios S.p.A. | Process for the preparation of cortexolone 17 a-propionate and new hydrated crystalline form thereof |
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| Publication number | Publication date |
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| CN101812108B (en) | 2012-05-23 |
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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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