CN108774279A - 6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone synthetic methods - Google Patents
6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone synthetic methods Download PDFInfo
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- CN108774279A CN108774279A CN201810541947.1A CN201810541947A CN108774279A CN 108774279 A CN108774279 A CN 108774279A CN 201810541947 A CN201810541947 A CN 201810541947A CN 108774279 A CN108774279 A CN 108774279A
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- norpregna
- acetoxyl group
- diketone
- diene
- methylol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of synthetic methods of -17 α of 6- methylols-acetoxyl group -19- norpregna -4,6- diene -3,20- diketone, it is characterized in that（1）By 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（2）It is added in reaction bulb, dichloromethane is added and makes it dissolve, adds metachloroperbenzoic acid, is stirred to react until raw material completely disappears, obtains epoxide 3 and 4 mixtures；（2）Intermediate epoxide 3 and 4 mixtures are dissolved in THF, dilute sulfuric acid is added with stirring, until intermediate completely disappears, dehydration obtains 6-- 17 α of methylol-acetoxyl group-19- norpregnas-4 that product 1 is synthesized using the present invention, 6- diene-3,20- diketone, purity are up to 99.77%.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, in particular it relates to one kind 6-- 17 α of methylol-acetoxyl group-19-
The synthetic method of norpregna -4,6- diene -3,20- diketone.
Background technology
6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone is new and effective oral pregnant
Another being likely to occur in the analog of hormone Nomegestrol acetate, and the technique of synthesis Nomegestrol acetate is miscellaneous
Matter（Impurity B）.Nomegestrol acetate is as forth generation contraceptive with contraceptive effect is good, toxic side effect is small, easy to use, peace
Congruent feature is applied to contraception, hormone replacement therapy, endometriosis, menoxenia etc. in European countries extensively
Various gynaecology's uncomfortable diseases Chinese Pharmacological Bulletin 2004,20 (11), 1215-7；Chinese
Journal of New Drugs 2011,20 (19), 1880-1885）.Since 6-- 17 α of methylol-acetoxyl group-19- goes first
Pregnant steroid -4,6- diene -3,20- diketone be Nomegestrol synthesis in issuable impurity, it is needed carry out technology controlling and process and
The detection of final products.Since the content of this impurity in the final product is very low, structure is not reported, and belongs to new chemical combination
Object.Therefore, simple preparation 6-- 17 α of methylol-acetoxyl group-19- norpregnas-4,6- diene-3 are researched and developed,
The method of 20- diketone, to solve its source extremely important as standard reference material.
Invention content
The goal of the invention of the present invention is to provide 6-- 17 α of methylol of one kind-acetoxyl group-19- norpregna-4,6- diene-
The synthetic method of 3,20- diketone solves 6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
As standard reference material.
Referring to Fig.1,6-- 17 α of methylol of the invention-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, include the following steps：
1, by 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（2）It is added in reaction bulb, adds
Enter dichloromethane to make it dissolve, add metachloroperbenzoic acid, is stirred to react until raw material completely disappears, obtains epoxy compound
Object 3 and 4 mixtures, wherein-17 α of 6-methylene of reactant-acetoxyl group-19- norpregnas-4- alkene-3,20- diketone and
The molar ratio of chloroperoxybenzoic acid is 1:1 ~ 1:5, reaction temperature is 0~40 DEG C.
2, intermediate epoxide 3 and 4 mixtures are dissolved in THF, are added with stirring dilute sulfuric acid, until intermediate
It completely disappears, dehydration obtains product 1, wherein a concentration of 0.1 ~ 1 N of the sulfuric acid of addition, mole of sulfuric acid and epoxides
Ratio is 0.01:1 ~ 0.5:1, reaction temperature is 0 ~ 50 DEG C.
The present invention provides 6-- 17 α of methylol of one kind-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, 6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone is Nomegestrol acetic acid
The analogue of ester may have related progestogens activity, and the impurity that may be brought into synthesis Nomegestrol technique.
In addition, this compound belongs to noval chemical compound, document is not reported.It is detected through HPLC, the 6-methylols-17 synthesized using the present invention
α-acetoxyl group -19- norpregna -4,6- diene -3,20- diketone, purity are up to 99.77%.
Description of the drawings
Fig. 1 is that the synthetic route of 6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone is anti-
Answer formula.
Fig. 2 is 6-- 17 α of methylol-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone testing results.
Specific implementation mode
Embodiment 1
By 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（1.0 g, 2.7 mmol）It is added to
In 25 mL reaction bulbs, dichloromethane is added（5 mL）, mCPBA is added at 0 DEG C in stirring and dissolving（1.0 g, 5.8 mmol）'s
Dichloromethane（5 mL）Solution is warmed to room temperature and is stirred overnight, and reaction solution is poured into ice water, dichloromethane extraction, respectively with 10%
Sodium sulfite aqueous solution, the washing of 10% sodium bicarbonate aqueous solution, anhydrous magnesium sulfate drying filter, it is organic molten that removing are concentrated under reduced pressure
Agent, column chromatography for separation obtain epoxidation product（0.35 g, yield 33.3%）.
By above-mentioned epoxide（0.35 g, 0.9 mmol）It is added in the reaction bulb of 10mL, tetrahydrofuran is added（5
mL）, stirring and dissolving is cooled to 0 DEG C or so, 0.4 N sulfuric acid is added（1 mL, 0.2 mmol）, it is stirred overnight at room temperature, by reaction solution
It pours into ice water, with dichloromethane extraction, saturated sodium bicarbonate aqueous solution washs, anhydrous magnesium sulfate is dried, and filtering is removed under reduced pressure
Organic solvent, column chromatography for separation obtain-17 α of 6-methylol of white solid product-acetoxyl group-19- norpregnas-4,6- bis-
Alkene -3,20- diketone（290 nm of 0.12 g, 99.73%@of purity), yield 34%, m. p. DEG C.1H NMR (CDCl3,
ppm): δ 6.36 (s, 1H), 6.01 (s, 6.01), 4.32-4.33 (d, 1H), 2.96-3.03 (dt, 1H),
2.55-2.59 (dd, 1H), 2.30-2.35 (m, 3H), 2.16 -2.22 (m, 1H), 2.09 (s, 3H), 2.06
(s, 3H), 1.93-2.02 (m, 4H), 1.55-1.68 (m, 4H), 1.10-1.47 (m, 3H), 0.72 (s,
3H)。DEPT-13C NMR (CDCl3, ppm): δ 139.79 (C-7), 121.43 (C-4), 62.71 (6-CH2-OH),
48.54 (C-14), 45.33 (C-9), 41.01 (C-10), 40.89 (C-8), 37.39 (C-2), 30.99 (C-
12), 30.30 (C-16), 26.85 (C-1), 26.44 (C-21), 24.93 (C-11), 23.18 (C-15),
21.18 (17-OCOCH3), 14.19 (C-18)。MS (ESI): 387.3 (M + H)。
Embodiment 2
By 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（1.0 g, 2.7 mmol）It is added to
In 25 mL reaction bulbs, dichloromethane is added（5 mL）, mCPBA is added in stirring and dissolving at room temperature（2.0 g, 11.6 mmol）'s
Dichloromethane（5 mL）Solution is stirred at room temperature 1 hour, and heating reflux reaction 2 hours pours into reaction solution in ice water, dichloromethane
Alkane extracts, and is washed respectively with 10% sodium sulfite aqueous solution, 10% sodium bicarbonate aqueous solution, and anhydrous magnesium sulfate drying filters, decompression
Concentration removes organic solvent, is added directly into the reaction bulb of 10 mL after obtaining epoxidation product crude product, is dissolved in tetrahydrofuran
（10 mL）, it is cooled to 0 DEG C, 1 N sulfuric acid is added（0.5 mL）, it is warmed to room temperature stirring 1 hour, 50 DEG C is heated to and reacts 3 hours,
Reaction solution is poured into ice water, with dichloromethane extraction, saturated sodium bicarbonate aqueous solution washs, anhydrous magnesium sulfate is dried, filtering,
Organic solvent is removed under reduced pressure, column chromatography for separation obtains-17 α of 6-methylol of white solid product-acetoxyl group-19- norpregnas-
4,6- diene -3,20- diketone（290 nm of 0.37 g, 99.5%@of purity), two step gross production rates 35%.
Embodiment 3
By 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（1.0 g, 2.7 mmol）It is added to
In 25 mL reaction bulbs, dichloromethane is added（5 mL）, mCPBA is added in stirring and dissolving at room temperature（0.5 g, 2.9 mmol）Two
Chloromethanes（5 mL）Solution, agitating and heating are refluxed overnight, and reaction solution is poured into ice water, dichloromethane extraction, respectively with 10% Asia
Aqueous sodium persulfate solution, the washing of 10% sodium bicarbonate aqueous solution, anhydrous magnesium sulfate drying filter, are concentrated under reduced pressure and remove organic solvent,
It is added directly into the reaction bulb of 10 mL after obtaining epoxidation product crude product, is dissolved in tetrahydrofuran（10 mL）, it is cooled to 0
DEG C, 0.1 N sulfuric acid is added（2 mL）, it was stirred at room temperature 1 as a child, and was reacted 2 hours at 35-40 DEG C, reaction solution is poured into ice water
In, with dichloromethane extraction, saturated sodium bicarbonate aqueous solution washs, anhydrous magnesium sulfate is dried, and filtering is removed under reduced pressure organic molten
Agent, column chromatography for separation obtain-17 α of 6-methylol of white solid product-acetoxyl group-19- norpregna-4,6- diene-3,20-
Diketone（290 nm of 0.29 g, 98.8%@of purity), two step gross production rates 28%.
Embodiment 4
By 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（1.0 g, 2.7 mmol）It is added to
In 25 mL reaction bulbs, dichloromethane is added（5 mL）, mCPBA is added in stirring and dissolving at room temperature（1.5 g, 8.7 mmol）Two
Chloromethanes（5 mL）Solution is stirred to react 1 hour at room temperature, and heating reflux reaction 2 hours pours into reaction solution in ice water, two
Chloromethanes extracts, and is washed respectively with 10% sodium sulfite aqueous solution, 10% sodium bicarbonate aqueous solution, and anhydrous magnesium sulfate drying filters,
It is concentrated under reduced pressure and removes organic solvent, be added directly into the reaction bulb of 10 mL after obtaining epoxidation product crude product, be dissolved in tetrahydrochysene
Furans（10 mL）, it is cooled to 0 DEG C, 0.6 N sulfuric acid is added（2 mL）, it was stirred at room temperature 1 as a child, and was heated to reflux stirring 2 hours,
Reaction solution is poured into ice water, with dichloromethane extraction, saturated sodium bicarbonate aqueous solution washs, anhydrous magnesium sulfate is dried, filtering,
Organic solvent is removed under reduced pressure, column chromatography for separation obtains-17 α of 6-methylol of white solid product-acetoxyl group-19- norpregnas-
4,6- diene -3,20- diketone（290 nm of 0.33 g, 99.3%@of purity), two step gross production rates 32%.
Claims (6)
1. a kind of synthetic method of -17 α of 6- methylols-acetoxyl group -19- norpregna -4,6- diene -3,20- diketone, special
Sign is
（1）By 6-- 17 α of methylene-acetoxyl group-19- norpregna-4- alkene-3,20- diketone（2）It is added in reaction bulb, adds
Enter dichloromethane to make it dissolve, add metachloroperbenzoic acid, is stirred to react until raw material completely disappears, obtains epoxy compound
Object 3 and 4 mixtures；
（2）Intermediate epoxide 3 and 4 mixtures are dissolved in THF, dilute sulfuric acid is added with stirring, until intermediate is complete
Mistake is totally disappeared, dehydration obtains product 1.
2.-17 α of 6-methylol according to claim 1-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, it is characterised in that step（1）Reaction temperature be 0~40 DEG C.
3.-17 α of 6-methylol according to claim 1-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, it is characterised in that step（1）- 17 α of middle 6-methylene of reactant-alkene-3 acetoxyl group-19- norpregna-4-,
The molar ratio of 20- diketone and metachloroperbenzoic acid is 1:1 ~ 1:5.
4.-17 α of 6-methylol according to claim 1-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, it is characterised in that step（2）The middle sulfuric acid concentration used is 0.1 ~ 1 N.
5.-17 α of 6-methylol according to claim 1-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, it is characterised in that step（2）The molar ratio of middle sulfuric acid and epoxides is 0.01:1 ~ 0.5:1.
6.-17 α of 6-methylol according to claim 1-acetoxyl group-19- norpregna-4,6- diene-3,20- diketone
Synthetic method, it is characterised in that step（2）Reaction temperature be 0~50 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810541947.1A CN108774279B (en) | 2018-05-30 | 2018-05-30 | Synthesis method of 6-hydroxymethyl-17 alpha-acetoxyl-19-norpregna-4, 6-diene-3, 20-diketone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810541947.1A CN108774279B (en) | 2018-05-30 | 2018-05-30 | Synthesis method of 6-hydroxymethyl-17 alpha-acetoxyl-19-norpregna-4, 6-diene-3, 20-diketone |
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| Publication Number | Publication Date |
|---|---|
| CN108774279A true CN108774279A (en) | 2018-11-09 |
| CN108774279B CN108774279B (en) | 2021-01-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201810541947.1A Active CN108774279B (en) | 2018-05-30 | 2018-05-30 | Synthesis method of 6-hydroxymethyl-17 alpha-acetoxyl-19-norpregna-4, 6-diene-3, 20-diketone |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5795884A (en) * | 1991-07-18 | 1998-08-18 | Laboratoire Theramex Sa | 3-keto-nor-pregnenes substituted in the 6-position and treatment of menopause |
-
2018
- 2018-05-30 CN CN201810541947.1A patent/CN108774279B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5795884A (en) * | 1991-07-18 | 1998-08-18 | Laboratoire Theramex Sa | 3-keto-nor-pregnenes substituted in the 6-position and treatment of menopause |
Non-Patent Citations (3)
| Title |
|---|
| C. COMBES等: "Crystal growth and structure of a new hormonal derived compound", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| DAVID CLEMENTE-TEJEDA等: "Oxidation of unsaturated steroid ketones with hydrogen peroxide catalyzed by Fe(bpmen)(OTf)2. New methodology to access biologically active steroids by chemo-, and stereoselective processes", 《TETRAHEDRON》 * |
| WILLIAMS . JOHNSON等: "Studies Relating to the Formation and Reactions of Glycidic Esters", 《FORMATIAONDN R EACTIONOSF GLYCIDICE STERS》 * |
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