CN1810824A - Momertasone furoate intermediate 21-ester and its prepn - Google Patents

Momertasone furoate intermediate 21-ester and its prepn Download PDF

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CN1810824A
CN1810824A CN 200510122250 CN200510122250A CN1810824A CN 1810824 A CN1810824 A CN 1810824A CN 200510122250 CN200510122250 CN 200510122250 CN 200510122250 A CN200510122250 A CN 200510122250A CN 1810824 A CN1810824 A CN 1810824A
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chloroform
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CN100436473C (en
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李平
卢俊瑞
李霞
郭建龙
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Tianjin Pharmaceutical Industry Group Corp., Ltd.
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Tianjin University of Technology
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Abstract

The present invention is compound 9beta, 11beta-epoxy-17alpha, 21-dihydroxy-16alpha-methyl-1, 4-pregnanediene-3,20-dione, 21-ester, as the momertasone furoate intermediate, and its production process. The production process of 9beta, 11beta-epoxy-17alpha, 21-dihydroxy-16alpha-methyl-1, 4-pregnanediene-3,20-dione, 21-ester includes the following steps: iodizing 9beta,11beta-epoxy-17alpha-hydroxy-16alpha-methyl-1, 4-pregnanediene-3,20-dione to obtain compound-II; substituting compound-II to obtain the coarse product; and treatment in chromatographic column with flowing phase comprising chlorofo rm and methanol in the weight ratio of 5 to obtain refined product. The production process has short reaction time, low temperature and low power consumption.

Description

Furancarboxylic acid Mo Meitasong intermediate 21-ester and method for making
[technical field]: the present invention relates to the intermediate of a kind of medicine furancarboxylic acid Mo Meitasong, relate in particular to 9 β, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3,20-diketone, 21-ester and preparation method thereof.
[background technology]: furancarboxylic acid Mo Meitasong (Mometasone Furoate; Sch 32088); formal name used at school 9 α; 21-two chloro-17 α-(2-furoyl base)-11 beta-hydroxy-16 Alpha-Methyl-pregnant steroids-1; 4-diene-3; the 20-diketone is a kind of new drug that grows up the 1980s, is produced by U.S. Schering company.1987 at first in U.S. listing, and Canadian Schering-Plough company obtains this medicine nineteen ninety-five and enters the China market permission.Shanghai Schering-Plough company in 1997 obtains the approval of China Ministry of Health and begins to produce ointment formulation, the whole imports of desired raw material.The maximum characteristics of this medicine are potent external application cortin preparations, and U.S.'s psoriatic foundation recommends this product to be the psoriatic choice drug of treatment.Telangiectasis that the rare cortin of this medicine causes and skin atrophy side effect, thereby children recommend to be used in China in Schering-Plough company.
Nineteen eighty-two, Shapiro has at first reported two kinds of synthetic methods of furancarboxylic acid Mo Meitasong.
Method one: with 9 β, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3,20-diketone (be called for short compound 4) be a raw material, and reagent such as the first step use Methanesulfonyl chloride, pyridine, methylene dichloride, lithium chloride carry out 21-position hydroxy chloride generation; Second step was that acylating reagent carries out 17-position acylations with the furoyl chloride in the presence of 4-dimethylaminopyridine, methylene dichloride; The 3rd step carried out 9 in the presence of Glacial acetic acid, concentrated hydrochloric acid, the open loop of 11-position, and gained end product yield is 83%.This method shortcoming is that quantity of solvent is big, and it is lower that each goes on foot yield, the difficult separation.
Method two: then be with 16 Alpha-Methyls-1,4,9 (11)-pregnant steroid triolefin-17 α, 21-glycol-3,20-diketone 21-acetic ester is a raw material.Through the first step, the 17-position furoylization in the presence of 4-dimethylaminopyridine, methylene dichloride obtains intermediate product 16 Alpha-Methyls-1,4,9 (11)-pregnant steroid triolefin-17 α, 21-glycol-3,20-diketone 17-furoate 21-acetic ester.Second step: 21-position chlorination.The 17-ester is dissolved in the methyl alcohol, drip 70% perchloric acid and obtain 16 Alpha-Methyls-1,4, the pregnant steroid triolefin-17 of 9-α, 21-glycol-3,20-diketone 17 esters, in pyridine, drip Methanesulfonyl chloride subsequently and obtain 16 Alpha-Methyls-1,4,9 (11)-pregnant steroid triolefin-17 α, 21-glycol-3,20-diketone-17-chaff ester 21-methanesulfonate ester.This compound is solvent with DMF, carries out lithium chloride 21-position chloro, obtains 21-chloro-16 Alpha-Methyls-1,4,9 (11)-pregnant steroid triolefin-17 α, 21-glycol-3,20-diketone 17-furoate.
The 3rd step: the compound that obtains is dissolved among the THF, drips 70% perchloric acid and water, adds DDH fast, and reaction obtains end product.
1999, Draper proposed a new synthetic route, two-step approach.The first step: 9 β, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3,20-diketone (compound 4) in methylene dichloride with Methanesulfonyl chloride, 4-DMAP reaction handles obtaining 21-position muriate.Second step: 21-position muriate in the presence of triethylamine, 4-DMAP, furoyl chloride, is finished 17-position furoylization and is then directly added HCl-HAc and carry out 9 in methylene dichloride, and the open loop of 11-position obtains furancarboxylic acid Mo Meitasong.Its advantage is a by-products content when having reduced the chlorination of 21-position, and by product also changes product into when making 17-position furoyl simultaneously when open loop, has improved product yield greatly.
1998 and 1999, Kwok has reported its newest research results to furancarboxylic acid Mo Meitasong, he has proposed up to now the greatest improvement of former furancarboxylic acid Mo Meitasong synthetic method has not only been improved its product yield greatly, and reduced the kind and the content of by product.He is also with 9 β, 11 beta epoxides-17 α, and 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3,20-diketone (compound 4) is an initial feed, at first at TsCl, TBA, CH 2Cl 2/ CH 3OH carries out the chlorination of 21-position under existing, and secondly is the 17-position furoylization in the presence of TEA, 2-Fu-Cl, carries out open loop with HCl-HAc at last, and the finished product yield can be up to 95%.
As seen from the above, be to be raw material mostly at present abroad, and the concrete structure of this compound and physicochemical property there is no report, so the bulk drug of domestic production furancarboxylic acid Mo Meitasong can only rely on import with compound 4 to the synthetic method of furancarboxylic acid Mo Meitasong.How to find the production method of compound 4 or the raw materials for production of compound 4 to become the key of producing furancarboxylic acid Mo Meitasong production domesticization.
[summary of the invention]: the intermediate and the production method thereof that the objective of the invention is to seek synthetic furancarboxylic acid Mo Meitasong medicine, a kind of 9 β are provided, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3, the 20-diketone, 21-ester and method for making realize the production domesticization of furancarboxylic acid Mo Meitasong drug manufacture.
Compound 9 β provided by the invention, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3, the 20-diketone, the 21-ester, its structural formula is:
Wherein, R=-CH 3,-C 2H 5,-C 3H 7,-C 4H 9,-H 2PO 4, R is preferred-CH 3
A kind of preparation method of above-claimed cpd, this method comprises successively:---9 β, 11 beta epoxides-17 Alpha-hydroxy-16 Alpha-Methyl-1,4-pregnen diethylene-3, the iodo of 20-diketone (compound 1)
Wherein add 4-8mL methyl alcohol, 0.5-2g calcium chloride stirs and to make it dissolving, adds the 12-25mL chloroform then, and 1 dissolving of 3.56g compound is treated moltenly to be cooled to 6-10 ℃ after clear and to add calcium oxide, continues to reduce to 0 ℃ (0 ℃ ± 2 ℃).Drip iodine liquid, dripped the Bi Jixu insulated and stirred 1-1.5 hour.Reduce to again below 0 ℃, add the aqueous ammonium chloride solution of precooling, added static 25-35 minute, chloroform layer is filtered, water layer divides four extractions with the 10-20mL chloroform, and combined chloroform liquid is concentrated near doing, add 1-3mL methyl alcohol, continue to concentrate, filter light yellow solid.
---displacement
At room temperature with 3.0g iodide (compound 2), 3.0-9.0g Potassium ethanoate is dissolved among the 9-30mLDMF, then by gradient increased temperature: be warming up to be warming up in 30 ℃ → 1 hour in 1 hour and be warming up to 50 ℃ in 40 ℃ → 1 hour, react cooling in 1 hour again in 50 ℃ and carry out aftertreatment, promptly get the thick product of compound 3.
Compound 3 thick products are crossed chromatographic column, and moving phase is chloroform: methyl alcohol=5: 1 promptly gets final elaboration product compound 3.
Chemical equation is:
Chemical equation is:
Advantage of the present invention and positively effect: the present invention provides the intermediate and the production method thereof of synthetic furancarboxylic acid Mo Meitasong medicine first, thoroughly change the situation of the complete dependence on import of raw material of synthetic furancarboxylic acid Mo Meitasong medicine, realized the production domesticization of bulk drug and furancarboxylic acid Mo Meitasong medicine.The required reaction times of the preparation method of compound provided by the invention is short, and temperature is low, and energy consumption is little, is easy to promote.
[description of drawings]:
Fig. 1 is the The compounds of this invention structural formula.
[specific embodiment]:
Embodiment 1
As shown in Figure 1, compound 9 β, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3, the 20-diketone, the structural formula of 21-ester is:
Figure A20051012225000081
Wherein, R=-CH 3,-C 2H 5,-C 3H 7,-C 4H 9,-H 2PO 4, R is preferred-CH 3
Embodiment 2
The preparation method of The compounds of this invention 3 comprises successively:---9 β, 11 beta epoxides-17 Alpha-hydroxy-16 Alpha-Methyl-1,4-pregnen diethylene-3, the iodo of 20-diketone (compound 1)
Add 6mL methyl alcohol, 0.5g calcium chloride stirs and makes it dissolving, adds chloroform then and makes 1 dissolving of 3.56g compound, treats that molten being cooled to below 10 ℃ after clear adds calcium oxide, continues to reduce to 0 ℃ (0 ℃ ± 2 ℃).Drip iodine liquid 2.55g, dripped the Bi Jixu insulated and stirred 1 hour.Reduce to again below 0 ℃, add the aqueous ammonium chloride solution of precooling, added static 30 minutes, chloroform layer is filtered, water layer divides four extractions with the 12mL chloroform, and combined chloroform liquid is concentrated near doing, add 1.5mL methyl alcohol, continue to concentrate, filter light yellow solid compound 2.
Chemical equation is:
Figure A20051012225000082
The structural characterization of compound 2
Ultimate analysis C 22H 27I 2O 4
Measured value (%): C 43.19, and H 4.16;
Calculated value (%): C 43.42, and H 4.27.
By the MS (FAB) of compound 2 as can be known: M/Z is 608.3 M +The peak is numerically consistent with its two iodos thing molecular weight, and thus, we infer that earlier compound 2 is two iodo things.
By the IR (KBr, diffuse-reflectance) of compound 2 as can be known: 3262.12cm -1It is 17 α-OH stretching vibration; 1714.36cm -1, 1657.67cm -1Be the C=O stretching vibration; 1614.34cm -1Illustrate Δ is arranged in the molecule 1,43-ketone structural unit exists.
By compound 2 1HNMR (CDCl 3) collection of illustrative plates can draw δ (ppm): 0.85 (d) is methyl hydrogen on the 16-position; 0.90 (s) be methyl hydrogen on the 18-position; 1.41 (s) be methyl hydrogen on the 19-position; 3.20 (2H) be 17-position hydroxyl hydrogen and 11-position hydrogen; 6.15-6.21 (2H) be 4-position and 2-position hydrogen; 6.55-6.60 (d 1H) is 1-position hydrogen; 5.89 (s 1H) occurs at low, illustrates that this hydrogen haled electronic action, has supported the inference of two iodo molecular ion peaks in the mass spectrum, is 21-position hydrogen therefore.
By above data, we as can be seen, compound 2 mainly exists with the diiodo-form, so we infer that tentatively the existence form of compound 2 is as follows:
---displacement
At room temperature with 3.0g iodide (compound 2), 4.0g Potassium ethanoate is dissolved among the 15mLDMF, then by gradient increased temperature: be warming up to be warming up in 30 ℃ → 1 hour in 1 hour and be warming up to 50 ℃ in 40 ℃ → 1 hour, react cooling in 1 hour again in 50 ℃ and carry out aftertreatment, promptly get the thick product of compound 3.
Compound 3 thick products are crossed chromatographic column, and moving phase is chloroform: methyl alcohol=5: 1 promptly gets final elaboration product compound 3.
Chemical equation is:
The structural characterization of compound 3
Ultimate analysis C 24H 30O 6
Measured value (%): C69.42, H7.14;
Calculated value (%): C69.56, H7.24.
By the MS (FAB) of compound 3 as can be known: M/Z is that 415.0 M+1 peak is numerically consistent with its molecular weight.
By the IR (KBr, diffuse-reflectance) of compound 3 as can be known: 1749.9cm -1, 1727.0cm -1, 1661.69cm -1Be the C=O stretching vibration; 1619.53cm -1Illustrate Δ is arranged in the molecule 1,43-ketone structural unit exists; 1233.81cm -1Illustrate CH is arranged in the molecule 3-CO-OR ester type structural unit exists, and has tentatively affirmed the existence of 21-position acetonyl ester.
By compound 3 1HNMR (CDCl 3) collection of illustrative plates can draw δ (ppm): 0.85,0.88 (d) is methyl hydrogen on the 16-position; 0.92 (s) be methyl hydrogen on the 18-position; 1.43 (s) be methyl hydrogen on the 19-position; 2.14 (s 3H) is 21-position acetate methyl hydrogen; 3.19 (2H) be 17-position hydroxyl hydrogen and 11-position hydrogen; 4.58,4.66 (d, 1H) and 4.97,5.06 (d 1H) is 2 hydrogen in 21-position; 6.23-6.28 (2H) be 4-position and 2-position hydrogen; 6.64 6.69 (d 1H) is 1-position hydrogen.
By above data we as can be seen, compound 3 structures are correct.
Used instrument:
SHIMADZU UV-250 type ultraviolet-visible spectrophotometer
SHIMADZU SPD-10AVP high pressure liquid chromatograph
X-4 type numeral shows micro-fusing point instrument
Bio-Rad FTS135 Fourier infrared spectrograph
BRUKER AC-P200 NMR instrument
The VGZAB-HS mass spectrograph
YANACO CHN CORDER MT-3 type elemental analyser

Claims (4)

1. compound 9 β, 11 beta epoxides-17 α, 21-dihydroxyl-16 Alpha-Methyl-1,4-pregnen diethylene-3,20 diketone, the 21-ester, its structural formula is:
Wherein, R=-CH 3,-C 2H 5,-C 3H 7,-C 4H 9,-H 2PO 4
2. compound according to claim 1, it is characterized in that R preferred-CH 3
3. the preparation method of the described compound of claim 1 is characterized in that this method comprises successively:
---9 β, 11 beta epoxides-17 Alpha-hydroxy-16 Alpha-Methyl-1,4-pregnen diethylene-3, the iodo of 20-diketone (compound 1)
Add 4-8mL methyl alcohol, 0.5-2g calcium chloride stirs and makes it dissolving, adds the 12-25mL chloroform then, and 1 dissolving of 3.56g compound is treated moltenly to be cooled to 6-10 ℃ after clear and to add calcium oxide, continues to reduce to 0 ℃ (0 ℃ ± 2 ℃); Drip iodine liquid, dripped the Bi Jixu insulated and stirred 1-1.5 hour; Reduce to again below 0 ℃, add the aqueous ammonium chloride solution of precooling, added static 25-35 minute, chloroform layer is filtered, water layer divides four extractions with the 10-20mL chloroform, and combined chloroform liquid is concentrated near doing, add 1-3mL methyl alcohol, continue to concentrate, filter light yellow solid;
---displacement
At room temperature with 3.0g iodide (compound 2), 3.0-9.0g Potassium ethanoate is dissolved among the 9-30mLDMF, then by gradient increased temperature: be warming up to be warming up in 30 ℃ → 1 hour in 1 hour and be warming up to 50 ℃ in 40 ℃ → 1 hour, react cooling in 1 hour again in 50 ℃ and carry out aftertreatment, promptly get the thick product of compound 3.
4, according to the preparation method of the described compound of claim 3, it is characterized in that compound 3 thick products cross chromatographic column, moving phase is chloroform: methyl alcohol=5: 1 promptly gets final elaboration product compound 3.
CNB2005101222503A 2005-12-09 2005-12-09 Momertasone furoate intermediate 21-ester and its prepn Active CN100436473C (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102477064A (en) * 2010-11-23 2012-05-30 天津金耀集团有限公司 Novel 16,17-ketal intermediate for preparing ciclesonide
CN102477065A (en) * 2010-11-23 2012-05-30 天津金耀集团有限公司 Novel 16, 17-ketal intermediate for preparing budesonide
CN102477058A (en) * 2010-11-23 2012-05-30 天津金耀集团有限公司 New 16,17-dihydroxy intermediate for preparing budesonide

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE8790T1 (en) * 1981-02-02 1984-08-15 Schering Corporation AROMATIC HETEROCYCLIC STEROID ESTER, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
IL99437A (en) * 1990-09-10 1995-05-29 Schering Corp Mometasone furoate monohydrate process for making same and pharmaceutical compositions
JP4269110B2 (en) * 1996-06-28 2009-05-27 シェーリング コーポレイション Process for the preparation of the 17-ester of 9α, 21-dihalo-pregnane-11β, 17α-diol-20-one

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102477064A (en) * 2010-11-23 2012-05-30 天津金耀集团有限公司 Novel 16,17-ketal intermediate for preparing ciclesonide
CN102477065A (en) * 2010-11-23 2012-05-30 天津金耀集团有限公司 Novel 16, 17-ketal intermediate for preparing budesonide
CN102477058A (en) * 2010-11-23 2012-05-30 天津金耀集团有限公司 New 16,17-dihydroxy intermediate for preparing budesonide
CN102477058B (en) * 2010-11-23 2014-06-11 天津金耀集团有限公司 New 16,17-dihydroxy intermediate for preparing budesonide
CN102477064B (en) * 2010-11-23 2014-06-11 天津金耀集团有限公司 Novel 16,17-ketal intermediate for preparing ciclesonide
CN102477065B (en) * 2010-11-23 2014-06-11 天津金耀集团有限公司 Novel 16, 17-ketal intermediate for preparing budesonide

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