CN103665078B - A kind of preparation method of 17 Alpha-hydroxy steroidal esters - Google Patents
A kind of preparation method of 17 Alpha-hydroxy steroidal esters Download PDFInfo
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- CN103665078B CN103665078B CN201310698856.6A CN201310698856A CN103665078B CN 103665078 B CN103665078 B CN 103665078B CN 201310698856 A CN201310698856 A CN 201310698856A CN 103665078 B CN103665078 B CN 103665078B
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Abstract
The preparation method that the invention discloses a kind of steroidal compounds, the preparation method being specifically related to a kind of 17 Alpha-hydroxy steroidal esters, the present invention is by 17 ��, 21-dihydroxy steroidal compounds reacts with ortho esters, formed containing 1, the steroidal compounds intermediate of 3-dioxanes-5-ketone ring, obtains 17 Alpha-hydroxy steroidal esters again through hydrolysis. Compared with prior art, the present invention effectively avoids the trifluoroacetic anhydride (TFAA) using strong and stimulating, and reaction condition is gentle; solid acid catalysis can be adopted to be hydrolyzed; catalysis acid is recycled, and is conducive to environmental conservation, and low stain, technique are simple, reaction condition is gentle is suitable to industrialized production.
Description
Technical field
The preparation method that the present invention relates to a kind of steroidal compounds, the preparation method being specifically related to a kind of 17 Alpha-hydroxy steroidal esters.
Background technology
The esterification of steroidal compounds 17 Alpha-hydroxy is an important reaction of class of steroidal compounds. By being esterified the ester dissolubility that can improve steroid drugs, and then improve the transdermal absorption factor of such medicine, for instance hydrocortisone butyrate, betamethasone dipropionate etc.; By a series of subsequent reactions can also be carried out after being esterified, 17 ��-remove hydroxyl reaction in the preparation process of ciclesonide, halcinonide, (11BETA,16ALPHA)-16,17-[methylethylidenebis(oxy), budesonide etc.
MichaelJ.Green, etal. trifluoroacetic anhydride (TFAA) carries out being esterified (J.Med.Chem., 25,1492-1495,1982), and the trifluoroacetic anhydride (TFAA) that the method uses has volatility, zest, has limitation in industrialized production.
In the hydrolytic process of formula III compound 1,3-dioxanes-5-ketone ring, US4377575 adopts sulphuric acid to be hydrolyzed; DE2204366 adopts acetic acid to be hydrolyzed.
Document CN101891797 adopts trimethyl orthobutyrate and of the original acid triethyl to be esterified, then is hydrolyzed with aluminum chloride aqueous solution or dilute hydrochloric acid etc.
Summary of the invention
Present invention is primarily targeted to overcome and prior art is prepared 17 Alpha-hydroxy steroidal esters must use the trifluoroacetic anhydride (TFAA) of strong and stimulating, it is unsuitable for the deficiency of industrialized production, it is provided that the method for the preparation 17 Alpha-hydroxy steroidal esters that a kind of low stain, technique are simple, reaction condition is gentle.
In order to realize foregoing invention purpose, the invention provides techniques below scheme:
17 ��, 21-dihydroxy steroidal compounds are reacted by a kind of method preparing 17 Alpha-hydroxy steroidal esters with ortho esters, form the steroidal compounds intermediate containing 1,3-dioxanes-5-ketone ring, obtain 17 Alpha-hydroxy steroidal esters again through hydrolysis.
Further, described ortho esters is formula III compound, wherein R1For H, CH3��CH3CH2, R2For CH3Or CH3CH2��
Preferably, hydrolytic process carries out under the catalytic action of solid acid, it is furthermore preferred that described solid acid is Pidolidone.
Inventor tests discovery, adopts 17 ��, 21-dihydroxy steroidal compounds to react with ortho esters, can effectively avoid the strong and stimulating of trifluoroacetic anhydride (TFAA), and 1, the 3-dioxanes-5-ketone ring that reaction generates can adopt solid acid hydrolysis, such as Pidolidone, reaction condition is gentle. By filtering after being hydrolyzed, Pidolidone is recovered to be applied mechanically, thus avoiding the process adopting the liquid acid such as sulphuric acid, acetic acid to also need to neutralisation treatment after completion of the reaction, environmental conservation is favourable.
Specifically, the present invention prepares the method for 17 Alpha-hydroxy steroidal esters, comprises the following steps:
(1) 17 ��, 21-dihydroxy steroidal compounds (formula II) and ortho esters (formula III) react the steroidal compounds intermediate generated containing 1,3-dioxanes-5-ketone ring, formula IV:
(2) formula IV compound is hydrolyzed under acid conditions and obtains 17 Alpha-hydroxy steroidal esters, type I compound:
Formula I, left bracket in II, IV are elliptical steroidal mother nucleus structure, and other positions that the Pentamethylene. many hydrogen of a pair of horses going side by side are luxuriant and rich with fragrance, in same reaction, mother nucleus structure does not change.
Further, 17 prepared Alpha-hydroxy steroidal esters include but not limited to following compound:
11 ��, the 17 pregnant Gona-4-ene-3s of ��, 21-trihydroxy, 20-diketone-17-propionic ester.
9 ��-fluoro-11 ��, 17 ��, 21-trihydroxy-16 Beta-methyls-pregnant steroid-1,4-diene-3,20-diketone-17-propionic ester.
11 ��, 17 ��, 21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-propionic ester.
17 ��, 21-trihydroxy pregnant steroid-1,4-diene-3,11,20-triketone-17-propionic ester.
6 alpha, 9 alpha-difluoro-11 ��, 17 ��, 21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-propionic ester.
11 ��, the 17 pregnant Gona-4-ene-3s of ��, 21-trihydroxy, 20-diketone-17-acetas.
9 ��-fluoro-11 ��, 17 ��, 21-trihydroxy-16 Beta-methyls-pregnant steroid-1,4-diene-3,20-diketone-17-acetas.
11 ��, 17 ��, 21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-acetas.
17 ��, 21-trihydroxy pregnant steroid-1,4-diene-3,11,20-triketone-17-acetas.
6 alpha, 9 alpha-difluoro-11 ��, 17 ��, 21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-acetas.
Further, the reaction in step (1) carries out in the organic solvent such as dichloromethane, ethyl acetate.
Specifically, in one embodiment of the invention, step (1) is: by 17 ��, 21-dihydroxy steroidal compounds, ortho esters are put in organic solvent, addition catalyst p-methyl benzenesulfonic acid, stirring reaction, after completion of the reaction, the dry steroidal compounds intermediate obtained containing 1,3-dioxanes-5-ketone ring. Preferably, reaction temperature is 40-50 DEG C. Preferably, the response time is 2-3 hour.
Specifically, in one embodiment of the invention, step (2) is: will containing 1, the steroidal compounds intermediate of 3-dioxanes-5-ketone ring, adds aqueous solvent and the solid acid of low mass molecule alcohol, stirs the reaction that is hydrolyzed, filter, collect filtrate, dry and obtain 17 Alpha-hydroxy steroidal esters.Preferably, reaction temperature is 40-50 DEG C. Preferably, the response time is 2-3 hour.
Further, in step (1), after completion of the reaction, first decompression and solvent recovery, then desciccate.
Further, in step (2), collect filtrate, first recovered under reduced pressure low mass molecule alcohol, then desciccate.
Compared with prior art, beneficial effects of the present invention: effectively avoid the trifluoroacetic anhydride (TFAA) using strong and stimulating, reaction condition is gentle. Intermediate is 1,3-dioxanes-5-ketone ring, it is possible to adopting solid acid catalysis hydrolysis, catalysis acid is recycled, and is conducive to environmental conservation, the method for the 17 Alpha-hydroxy steroidal esters being suitable to industrialized production that low stain, technique are simple, reaction condition is gentle.
Detailed description of the invention
Below in conjunction with test example and detailed description of the invention, the present invention is described in further detail. But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to below example, and all technology realized based on present invention belong to the scope of the present invention. Percentage ratio not specified in the present invention is all weight percentage.
Embodiment 1
9 ��-fluoro-11 ��, 17 ��, 21-trihydroxy-16 Beta-methyls-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone 50g(127.4mmol), ethyl acetate 300ml, triethyl orthopropionate 50g(283.7mmol), p-methyl benzenesulfonic acid 1g put in reaction bulb, 50 DEG C of stirring reactions 2.5 hours. React complete, recovered under reduced pressure ethyl acetate. Being subsequently adding ethanol 500ml, Pidolidone 8g, water 300ml, 50 DEG C of stirring reactions react 2 hours, leach insoluble matter (insoluble matter is Pidolidone, recyclable apply mechanically), use ethanol in proper amount washing leaching cake, merging filtrate, decompression recycling ethanol. Residue obtains 9 ��-fluoro-11 �� through filtering, drying, 17 ��, 21-trihydroxy-16 Beta-methyls-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-17-propionic ester white powder 53.7g, yield 94.0%.
Fusing point: 230-235 DEG C
1H-NMR(CDCl3, 400MHZ): 1.06,1.14,1.16,1.30,1.36,1.38,1.41,1.55,1.63,1.68,1.91,2.01,2.29,2.49,3.43,4.69,6.09,6.28,6.34.
Embodiment 2
According to embodiment 1 method, use 11 ��, 17 ��, 21-trihydroxy DELTA4-pregn-3,20-dione replaces 11 ��, 17 ��, the pregnant Gona-4-ene-3 of 21-trihydroxy, 20-diketone, is obtained by reacting 11 �� with triethly orthoacetate, 17 ��, the pregnant steroid-1 of 21-trihydroxy, 4-diene-3,20-diketone-17-acetas white powder 53.8g, yield 96.4%.
Fusing point: 162-166 DEG C
1H-NMR(CDCl3, 400MHZ): 1.16,1.24,1.26,1.35,1.38,1.40,1.41,1.49,1.52,1.60,1.63,1.88,1.91,2.01,2.29,2.35,2.89,3.16,5.85.
Embodiment 3
According to embodiment 1 method, use 11 ��, the 17 pregnant steroids-1 of ��, 21-trihydroxy, 4-diene-3,20-diketone, it is obtained by reacting 11 �� with triethly orthoacetate, 17 ��, pregnant steroid-Isosorbide-5-Nitrae-diene-3 of 21-trihydroxy, 20-diketone-17-acetas white powder 55.8g, yield 96.5%.
Fusing point: 162-166 DEG C
1H-NMR(CDCl3, 400MHZ): 1.12,1.14,1.16,1.35,1.36,1.38,1.40,1.41,1.56,1.60,1.61,1.87,1.91,2.01,2.12,2.29,3.26,4.69,6.09,6.28,6.34.
Claims (2)
1. the method preparing 17-hydroxy steroid ester, it is characterised in that comprise the following steps:
(1) by 17,21-dihydroxy steroidal compounds, formula II, with ortho esters, formula III, puts in organic solvent, adds catalyst p-methyl benzenesulfonic acid, 40��50 DEG C, stirring reaction 2��3 hours, after completion of the reaction, dries and obtains containing 1, the steroidal compounds intermediate of 3-dioxanes-5-ketone ring, formula IV;
Wherein R1For H, CH3��CH3CH2, R2For CH3Or CH3CH2;
Described organic solvent is dichloromethane or ethyl acetate;
(2) formula IV compound is hydrolyzed under acid conditions and obtains 17-hydroxy steroid ester, type I compound;
Hydrolytic process carries out under the catalytic action of Pidolidone.
2. the method preparing 17-hydroxy steroid ester as claimed in claim 1, it is characterised in that prepared type I compound is one of following compound:
The pregnant Gona-4-ene-3 of 11,17,21-trihydroxy, 20-diketone-17-propionic ester;
9-fluoro-11,17,21-trihydroxy-16-methyl-pregnant steroid-1,4-diene-3,20-diketone-17-propionic ester;
11,17,21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-propionic ester;
17,21-trihydroxy pregnant steroid-1,4-diene-3,11,20-triketone-17-propionic ester;
6,9-bis-fluoro-11,17,21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-propionic ester;
The pregnant Gona-4-ene-3 of 11,17,21-trihydroxy, 20-diketone-17-acetas;
9-fluoro-11,17,21-trihydroxy-16-methyl-pregnant steroid-1,4-diene-3,20-diketone-17-acetas;
11,17,21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-acetas;
17,21-trihydroxy pregnant steroid-1,4-diene-3,11,20-triketone-17-acetas;
6,9-bis-fluoro-11,17,21-trihydroxy pregnant steroid-1,4-diene-3,20-diketone-17-acetas.
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| CN105646630A (en) * | 2015-08-10 | 2016-06-08 | 山东泰华生物科技有限公司 | One-pot preparation method of clobetasol propionate intermediate |
| CN107021992B (en) * | 2017-04-05 | 2019-02-15 | 浙江仙居仙乐药业有限公司 | A kind of synthetic method of budesonide intermediate budesonide -17- acetate |
| CN113087754B (en) * | 2021-04-09 | 2022-04-19 | 弘健制药(上海)有限公司 | Preparation method of betamethasone-17 alpha-propionate |
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| US5159091A (en) * | 1989-10-26 | 1992-10-27 | Ss Pharmaceutical Co., Ltd. | Process for preparing 21-desoxyprednisolone 17-esters |
| CN1269835C (en) * | 2002-12-13 | 2006-08-16 | 中国科学院大连化学物理研究所 | Method for preparing low-polarity ginseng saponin and its aglycone by catalytic pyrolysis |
| CN1931870A (en) * | 2006-10-11 | 2007-03-21 | 汪家振 | Synthesis process of methyl prednisolone aceponate |
| CN101323638A (en) * | 2007-06-12 | 2008-12-17 | 河南大学 | Hydrolytic method of Chinese potato saponin |
| CN101891797A (en) * | 2010-07-08 | 2010-11-24 | 浙江仙琚制药股份有限公司 | Method for preparing sterides compound 17-alpha ester |
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2013
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Patent Citations (5)
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| US5159091A (en) * | 1989-10-26 | 1992-10-27 | Ss Pharmaceutical Co., Ltd. | Process for preparing 21-desoxyprednisolone 17-esters |
| CN1269835C (en) * | 2002-12-13 | 2006-08-16 | 中国科学院大连化学物理研究所 | Method for preparing low-polarity ginseng saponin and its aglycone by catalytic pyrolysis |
| CN1931870A (en) * | 2006-10-11 | 2007-03-21 | 汪家振 | Synthesis process of methyl prednisolone aceponate |
| CN101323638A (en) * | 2007-06-12 | 2008-12-17 | 河南大学 | Hydrolytic method of Chinese potato saponin |
| CN101891797A (en) * | 2010-07-08 | 2010-11-24 | 浙江仙琚制药股份有限公司 | Method for preparing sterides compound 17-alpha ester |
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