CN1314416A - 17,21-ester substituted 1,4-diene-3-keto-9,11-epoxy steroid compound - Google Patents
17,21-ester substituted 1,4-diene-3-keto-9,11-epoxy steroid compound Download PDFInfo
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- CN1314416A CN1314416A CN 00114929 CN00114929A CN1314416A CN 1314416 A CN1314416 A CN 1314416A CN 00114929 CN00114929 CN 00114929 CN 00114929 A CN00114929 A CN 00114929A CN 1314416 A CN1314416 A CN 1314416A
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Abstract
The epoxy steroid compound is prepared through introducing 21-p-methyl benzene sulfonate and 17-furoate successively to 1,4-diene-3-keto-9,11-epoxy steroid compound. The compound can find its wide application in organic chemistry and medicine preparation, and various atoms or groups may be introduced to the 21 st position.
Description
The invention relates to the structure formula I is 17 of representative, 1 of 21-ester replacement, and 4-diene-3-ketone-9, the preparation method of 11-epoxy steroid compound belongs to the technical field that chemical substance prepares.
(I) R=here
Mo Meitasong be a kind of local with in imitate cortin, be applicable to the effective dermatosis patient of use cortisone medicine, but amelioration of inflammation, itch, curative effect is obvious, is better than fluocinonide, Triamcinolone Acetonide waits medicine, has consequence clinically.
About synthetic existing many reports of Mo Meitasong, for example: described a kind of synthetic method in the United States Patent (USP) 4472393: with 1,4-diene-3-ketone-9,11-epoxy pregnane compound 1 is a raw material, through 21 chloros, makes compound 2;
Compound 1 compound 2
9-chloro-11-hydroxyl is introduced in compound 3 open loops, promptly obtains compound 4 (Mo Meitasong).
Compound 3 compounds 4 (Mo Meitasong)
After above-mentioned reaction further studied, the present invention had found the route of another synthetic Mo Meitasong, that is: 21 at compound 1 introduce the p-methyl benzenesulfonic acid esters earlier, make compound 5;
Compound 1 compound 5
With compound 5 and the reaction of 2-furoyl chloride, make compound 6 then;
Compound 5 compounds 6
Compound 6 makes compound 3 easily through 21 chloros.
Compound 6 compounds 3
If necessary, can with compound 3 open loops, introduce 9-chloro-11-hydroxyl, and obtain compound 4 (Mo Meitasong) by the method for describing in the United States Patent (USP) 4472393:
Compound 3 compounds 4 (Mo Meitasong)
The objective of the invention is to seek the route of another synthetic Mo Meitasong, simultaneously, this by the present invention developed is 17 of representative with the structure formula I, 1 of 21-ester replacement, 4-diene-3-ketone-9, the 11-epoxy steroid compound, the present invention also is 1 of preparation 21 replacements, 4-diene-3-ketone-9,11-epoxy 17-furoate steroidal compounds provides a kind of new synthetic method.According to method provided by the present invention, can be easily from being 17 of representative with the structure formula I, the 21-ester replace 1,4-diene-3-ketone-9, the 11-epoxy steroid compound begins, and by the method that various chemical field is used always, introduces other various atoms or group at 21.For example: introduce atoms such as chlorine, fluorine, iodine at 21, or at 21 introducing-OAc groups.
Below be the detailed description that the inventive method realizes:
Reaction one: introduce the p-methyl benzenesulfonic acid ester earlier, make compound 5 for 21 at compound 1;
5 these reactions of compound 1 compound can be carried out in the methylene dichloride equal solvent; with the p-methyl benzene sulfonic chloride is acylating agent; alkali such as pyridine or triethylamine is catalyzer; under relatively mild condition, react, make the hydroxyl of 21-position be generated as the p-methyl benzenesulfonic acid ester.
Reaction two:, make compound 6 with compound 5 and the reaction of 2-furoyl chloride;
6 these reactions of compound 5 compounds can be carried out in triethylamine, are acylating agent with the 2-furoyl chloride, and alkali such as pyridine or triethylamine are catalyzer, make the hydroxyl of 17-position be generated as the 2-furoate.Reaction three: compound 6 makes compound 3 easily through 21 chloros.
3 these reactions of compound 6 compounds can be carried out in dimethyl formamide (DMF), add LiCl, in about 80 degrees centigrade of insulation reaction.Terminal point with HPLC control reaction.After reaction is finished, add elutriation in the distilled water; The leaching precipitation; Crude product methanol-water recrystallization promptly gets compound 3 after the drying.
Perhaps, compound 6 carries out halogenating reaction with the salt of chlorine, fluorine, iodine, or reacts with NaOAc, and obtains corresponding reaction product:
Reaction four: if necessary, can with compound 3 open loops, introduce 9-chloro-11-hydroxyl, and obtain compound 4 (Mo Meitasong) by the method for describing in the United States Patent (USP) 4472393.
Compound 3 compounds 4 (Mo Meitasong)
Advantage of the present invention has provided the route of another synthetic Mo Meitasong; The present invention be advantageous in that providing with the structure formula I is 17 of representative, 1 of 21-ester replacement, 4-diene-3-ketone-9, the 11-epoxy steroid compound, this compound can obtain to use widely in organic chemistry, medicine are made; This compound is in particular 1 of preparation 21 replacements, 4-diene-3-ketone-9, and 11-epoxy 17-furoate steroidal compounds provides a kind of new synthetic method.According to method provided by the present invention, can be easily from being 17 of representative with the structure formula I, the 21-ester replace 1,4-diene-3-ketone-9, the 11-epoxy steroid compound begins, and by the method that various chemical field is used always, introduces other various atoms or group at 21.For example: introduce atoms such as chlorine, fluorine, iodine at 21, or at 21 introducing-OAc groups.
It is 17 of representative that following embodiment can further specify structure formula I of the present invention, 1 of 21-ester replacement, 4-diene-3-ketone-9, the preparation method of 11-epoxy steroid compound, but and unrestricted range of application of the present invention.
Adding 3 in 100 milliliters of there-necked flasks, to digest 1,20 milliliter of methylene dichloride of compound be solvent, stirs and make dissolving.Logical nitrogen, the 2.5 gram p-methyl benzene sulfonic chlorides of adding are down stirred in cooling, drip 4.5 milliliters of triethylamines, add in about 1 hour.Insulation reaction 4 hours makes compound 5.
In the foregoing description 1 prepared compound 5, add 4 milliliters of triethylamines, stir and drip 1.65 milliliters of 2-furoyl chlorides down.Add the back in about 0 degree centigrade of insulation reaction 24 hours.Add 2 ml methanol; Refining, remove and desolvate, get compound 6.
Adding 20 in 250 milliliters of there-necked flasks, to digest 1,150 milliliter of methylene dichloride of compound be solvent, stirs and make dissolving.Logical nitrogen, the 16.4 gram p-methyl benzene sulfonic chlorides of adding are down stirred in cooling, drip 24 milliliters of triethylamines, add in about 1 hour.Insulation reaction 2 hours is checked (developping agent: benzene: acetone is 7: 1) with the thin plate chromatography, and disappearing substantially to the raw material thing is reaction end, makes compound 5.
In the foregoing description 6 prepared compounds 5, add 24 milliliters of triethylamines, stir and drip 11 milliliters of 2-furoyl chlorides down.Add the back in about 5 degrees centigrade of insulation reaction 24 hours.Check that with HPLC disappearing substantially to the raw material thing is reaction end.Add 6 ml methanol; Stir, washing twice, collected organic layer is removed most of solvent; Add 100 ml methanol and make dissolving, elutriation; The leaching precipitation promptly gets compound 6.
The foregoing description 7 prepared compounds 6 are got 1 gram, are dissolved in the methylene dichloride; Carry out purifying with H type silica gel column chromatography.Use 1000 milliliters of methylene dichloride, 300 milliliters of mixed solvent wash-outs of forming by methylene dichloride and ethyl acetate (5: 1) successively.Collection contains the elutriant of compound 6, concentrates, and recrystallization promptly gets pure compound 6 about 0.4 grams after the drying.
Compound behind the purifying 6 is carried out infrared absorption spectrum analysis, see accompanying drawing 1.
| Absorption wavenumber cm -1 | Absorption peak strength | Group and oscillatory type |
| 1300、1195 | By force | Sulphonate-SO 2-OR stretching vibration |
| 1460 | By force | CH(CH 3CH 2) scissoring vibration |
| 1626、1600 | A little less than | The benzene skeletal vibration |
| 1664 | By force | The ketenes stretching vibration |
| 1719 | By force | The ketone stretching vibration |
| 1117 | By force | The ether stretching vibration |
| 805 | By force | The cyclic ethers skeletal vibration |
| 3213 | By force | Water |
Sample: pressing potassium bromide troche.Above infrared absorption spectrum data point out to exist the unsaturated conjugated ketone of α, β system, unsaturated double-bond, cyclic ethers, phenyl ring and sulphonate, the structural formula of basic symbols combination compound 6.Compound behind the purifying 6 is carried out ultraviolet absorption spectroscopy, see accompanying drawing 2.Ultraviolet absorption spectroscopy instrument: Perkin Elmer UV/Vis Lambda 20 solvents: dehydrated alcohol
| Compound | ????Maximum | ?????Minimum | The absorption band ownership | ||
| λ nm | ????ε | ?λ ?nm | ????ε | 251nm is the unsaturated conjugated ketone of α, β and α-carboxyl furans, and 228nm is a substituted-phenyl | |
| | 251 | ?11153 | ?228 | ?9171 | |
Compound behind the purifying 6 is carried out the mass spectrum spectroscopic analysis, see accompanying drawing 3,4.
Mass-spectrometric data points out that maximum mass-to-charge ratio is 620+1, and carbonatoms is 34, and possible molecular formula is: C
32H
36O
9S presses international atomic weight table and calculates, and molecular weight is 620.72044, and mass spectra peak is pointed out molecular ion peak M/Z=620.5, and above-mentioned molecular formula conforms to this analysis sample with molecular weight.Compound behind the purifying 6 is carried out nuclear magnetic resonance spectroscopy, see accompanying drawing 5,6,7,8.The chemical shift of proton NMR spectrum
| δ(ppm) | 0.78(3H,d.J=6.8＞Hz) | 16α-CH 3 |
| 0.83(3H,S) | 18-CH 3 | |
| 1.37(3H,S) | 19-CH 3 | |
| 2.43(3H,d,J=8.24Hz) | CH on the phenyl ring 3 | |
| 6.11(1H,S) | C-4-H | |
| 6.13(1H,d,J=5.22Hz) | C-2-H | |
| 4.77 (1H, d, J=15.9) and 4.91 (1H, d, J=15.7) | C-21-H |
6.64 (1H), 6.71 (1H), 7.47 (3H), 7.79 (2H, d, J=8.2) and these eight protons of 8.03 (1H) represent C-1-H respectively, C-3 ' on the furan nucleus-H, C-4 '-H, the chemical shift of 4 hydrogen on C-5 '-H3 hydrogen and the phenyl ring.
13The chemical shift of C nuclear magnetic resonance spectrum
| δ(ppm) | ?C-1?C-2?C-3???C-4??C-5?16α-CH 3C-17 ?152?124?185???127??157????16????95 ?18-CH 319-CH 3C-20?C-21 ?17?????24?????196??72 |
The chemical shift of 17-furancarboxylic acid ester
| δ(ppm) | Carboxyl C-2 ' C-3 ' C-4 ' C-5 ' 21 142 127 130 132 |
The chemical shift of 21-p-toluenesulfonic esters
| δ(ppm) | CH 3C-1 " C-2 " and C-6 " 165 145 120 C-3 " and C-5 " C-4 " 112 148 |
In addition, δ (ppm): 29.1,30.7,30.9,34.3 four CH
2, δ (ppm): 43.7,65.8 quaternary carbons, δ (ppm): 33.9,34.6,47.8,62.5 is C-8, C-11, the chemical shift of C-14 and four carbon of C-16.Spectroscopic data of the nuclear magnetic resonance shows: the chemical shift of proton NMR spectrum reaches
13The chemical shift of C nuclear magnetic resonance spectrum conforms to this analysis sample molecule formula.
Claims (3)
1, a kind of is 17 of representative with the structure formula I, 1 of 21-ester replacement, and 4-diene-3-ketone-9, the 11-epoxy steroid compound,
(I) R=here
2, a kind of is 17 of representative with the structure formula I, 1 of 21-ester replacement, 4-diene-3-ketone-9, the preparation method of 11-epoxy steroid compound, R=wherein
Comprise following two reactions steps: one: compound 1 is an acylating agent with the p-methyl benzene sulfonic chloride, and alkali such as pyridine or triethylamine are catalyzer, make compound 5; Two: compound 5 is an acylating agent with the 2-furoyl chloride, and alkali such as pyridine or triethylamine are catalyzer, makes compound G.
3,, it is characterized in that two included reactions steps carry out continuously by the described method of claim 2.
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| CNB001149296A CN1137899C (en) | 2000-03-16 | 2000-03-16 | 17,21-ester substituted 1,4-diene-3-keto-9,11-epoxy steroid compound |
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| CNB001149296A CN1137899C (en) | 2000-03-16 | 2000-03-16 | 17,21-ester substituted 1,4-diene-3-keto-9,11-epoxy steroid compound |
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| CN1137899C CN1137899C (en) | 2004-02-11 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8609645B2 (en) | 2004-08-13 | 2013-12-17 | Intervet Inc. | Pharmaceutical formulation |
| CN105481933A (en) * | 2015-12-25 | 2016-04-13 | 山东京卫制药有限公司 | Method for synthesizing mometasone furoate |
| CN105566437A (en) * | 2015-12-30 | 2016-05-11 | 山东京卫制药有限公司 | 8DM derivative, and method for synthesizing mometasone furoate from 8DM derivative |
| CN107266519A (en) * | 2016-04-08 | 2017-10-20 | 天津金耀集团有限公司 | 9 β of one kind, the diketone novel crystal forms of 11 β epoxies, 17 α hydroxyls, 16 α methyl, 21 chloro, 1,4 pregnen diethylene 3,20 and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266518B (en) * | 2016-04-08 | 2021-03-30 | 天津金耀集团有限公司 | Mometasone furoate crystal form and preparation method thereof |
-
2000
- 2000-03-16 CN CNB001149296A patent/CN1137899C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8609645B2 (en) | 2004-08-13 | 2013-12-17 | Intervet Inc. | Pharmaceutical formulation |
| CN105481933A (en) * | 2015-12-25 | 2016-04-13 | 山东京卫制药有限公司 | Method for synthesizing mometasone furoate |
| CN105566437A (en) * | 2015-12-30 | 2016-05-11 | 山东京卫制药有限公司 | 8DM derivative, and method for synthesizing mometasone furoate from 8DM derivative |
| CN107266519A (en) * | 2016-04-08 | 2017-10-20 | 天津金耀集团有限公司 | 9 β of one kind, the diketone novel crystal forms of 11 β epoxies, 17 α hydroxyls, 16 α methyl, 21 chloro, 1,4 pregnen diethylene 3,20 and preparation method thereof |
| CN107266519B (en) * | 2016-04-08 | 2021-06-29 | 天津金耀集团有限公司 | Novel crystal form of 9 beta, 11 beta-epoxy-17 alpha-hydroxy-16 alpha-methyl-21-chloro-1, 4 pregnadiene-3, 20-diketone and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN1137899C (en) | 2004-02-11 |
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