CN106810585A - The synthetic method of the diketone of 6 α methyl, 17 α acetoxyl groups, 19 norpregna, 4 alkene 3,20 - Google Patents
The synthetic method of the diketone of 6 α methyl, 17 α acetoxyl groups, 19 norpregna, 4 alkene 3,20 Download PDFInfo
- Publication number
- CN106810585A CN106810585A CN201611098002.4A CN201611098002A CN106810585A CN 106810585 A CN106810585 A CN 106810585A CN 201611098002 A CN201611098002 A CN 201611098002A CN 106810585 A CN106810585 A CN 106810585A
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- China
- Prior art keywords
- palladium
- methyl
- diketone
- alkene
- norpregna
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract description 5
- -1 acetoxyl groups Chemical group 0.000 title abstract 4
- 150000001336 alkenes Chemical class 0.000 title abstract 4
- 125000005594 diketone group Chemical group 0.000 title abstract 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000000047 product Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000012043 crude product Substances 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 abstract 2
- 239000012535 impurity Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 230000002254 contraceptive effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229960004911 nomegestrol Drugs 0.000 description 2
- KZUIYQJTUIACIG-YBZCJVABSA-N nomegestrol Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 KZUIYQJTUIACIG-YBZCJVABSA-N 0.000 description 2
- 229960004190 nomegestrol acetate Drugs 0.000 description 2
- IIVBFTNIGYRNQY-YQLZSBIMSA-N nomegestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 IIVBFTNIGYRNQY-YQLZSBIMSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of synthetic method of the diketone of 17 α acetoxyl groups of 6 α methyl, 19 norpregna, 4 alkene 3,20, its step is：1st, palladium/carbon is added in ethanol water cyclohexene, is heated with stirring to backflow；2nd, NOMAc is added in step 1 palladium/carbon ethanol water cyclohexene mixed liquor, is heated to temperature for 75~85 DEG C, reaction is filtered while hot after terminating, cooling crystallization, the crude product of the diketone of 6 α methyl, 17 α acetoxyl groups, 19 norpregna, 4 alkene 3,20 is obtained, purity is further purified to obtain>99.5% product.The invention provides a kind of brand-new diketone preparation method of 6 α methyl, 17 α acetoxyl groups, 19 norpregna, 4 alkene 3,20, synthesis technique is brief, and low cost is easy to operate, and conversion ratio reaches 89%, and yield reaches 71%, product purity>99.5%.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, go first pregnant more particularly to a kind of -17 α of 6 Alpha-Methyl-acetoxyl group -19-
Gona-4-ene-3, the synthetic method of 20- diketone.
Background technology
6-17 α of Alpha-Methyl-acetoxyl group-19- norpregna-4- alkene-3,20- diketone is new and effective oral progestational hormone promise
The major impurity (impurity A) of U.S. progesterone acetate.Nomegestrol acetate has that contraceptive effect is good, poison as forth generation contraceptive
Small side effects, it is easy to use, safe the features such as, be applied to contraception, HRT, intrauterine in European countries extensively
Various gynaecology's uncomfortable diseases Chinese Pharmacological Bulletin 2004,20 such as endometriosis, menoxenia
(11), 1215-7；Chinese Journal of New Drugs 2011,20 (19), 1880-1885).Due to 6 Alpha-Methyls-
17 α-acetoxyl group -19- norpregna -4- alkene -3,20- diketone is the major impurity of generation in Nomegestrol synthesis, it is necessary to tight
Lattice are controlled, and are controlled the generation of this impurity and removed extremely important.
At present, 6-17 α of Alpha-Methyl-acetoxyl group-19- norpregna-4- alkene-3, it is pregnant that 20- diketone is mainly synthesis promise U.S.
Ketone final step reaction in produce (FR2271833, GB1515284, US4544555), by purifying Nomegestrol during
Separate and obtain, exist that purity is low, content is few, purification is difficult, it is expensive the shortcomings of, China is there is presently no impurity A standard items
Production.Therefore, simple preparation 6-17 α of Alpha-Methyl-acetoxyl group-19- norpregna-4- alkene-3,20- bis- are researched and developed
The method of ketone, to solve its source extremely important as standard reference material.
The content of the invention
The purpose of the present invention is directed to above-mentioned deficiency, there is provided one kind synthesis 6-17 α of Alpha-Methyl-acetoxyl group-19- goes first pregnant
Gona-4-ene-3, the method for 20- diketone.
What the present invention was realized in：
6-17 α of Alpha-Methyl of one kind-acetoxyl group-19- norpregna-4- alkene-3, the synthetic method of 20- diketone is divided to two
Step is carried out：
1st, palladium/carbon is added in alcohol-water-cyclohexene, is heated with stirring to backflow, wherein, the ethanol body in alcohol-water
Product concentration is 75~95%, and the palladium mass content of the palladium/carbon catalyst for using is 5~10% palladium/carbon；
2nd, NOMAc is added in step 1 palladium/carbon-alcohol-water-cyclohexene mixed liquor, it is 75~85 to be heated to temperature
DEG C, the molar ratio of palladium is 1 in wherein substrate NOMAc and palladium/carbon:0.01~0.05.Reacted with vigorous stirring, maintained
Reaction temperature is 80~85 DEG C, and course of reaction liquid phase detects reaction process, and the reaction time is 3~4 hours, and reaction is taken advantage of after terminating
Heat filtering, cooling crystallization obtains 6-17 α of Alpha-Methyl-acetoxyl group-19- norpregna-4- alkene-3, the crude product of 20- diketone,
It is further purified to obtain purity>99.5% product.
It is provided by the present invention a kind of brand-new, convenient to prepare 6-17 α of Alpha-Methyl-acetoxyl group-19- norpregnas-4-
Alkene -3,20- diketone new methods, the method has filled up effective blank for preparing this compound.Synthesis technique of the present invention is brief, into
This is low, and easy to operate, conversion ratio reaches 89%, and yield reaches 71%, purity>99.5%.
Specific embodiment
With reference to embodiment, the present invention is further described.
- 17 α of 6 Alpha-Methyl of the present invention-acetoxyl group -19- norpregna -4- alkene -3, the synthetic method of 20- diketone,
Its technology path is：
Embodiment
To ethanol 300mL, 10% palladium carbon (3g, 0.0028mol) and cyclohexene 30mL that 85% is added in reaction bulb, stir
Mix and be heated to reflux, add Nomegestrol acetate (30g, 0.081mol), continue to be stirred at reflux reaction 3h, efficient liquid phase detection
Impurity A content is 89%, stops reaction, and suction filtration removes palladium carbon while hot, and removal of solvent under reduced pressure obtains faint yellow solid crude product
29.6g.Faint yellow solid impurity A is placed in the single-necked flask of 250mL, 20mL acetone is added, is stirred at reflux, continue slow benefit
Plus acetone dissolves until it, continues the 30min that flows back, and is cooled to room temperature, is filtrated to get white solid 21.3g (yield 71%, purity
For 99.58%).The spectrogram of obtained product1H NMR(CDCl3,ppm):δ5.87(s,1H),2.5-3.0(dt,1H),2.36-
2.40(m,1H),2.20-2.32(m,3H),2.11(s,3H),2.05(s,3H),1.6-2.0(m,8H),1.53-1.58(m,
2H),1.27-1.33(m,2H),1.09-1.12(d,3H),1.02-1.05(dd,1H),0.9-1.0(q,1H),0.69(s,
3H)。13C NMR(CDCl3,ppm):δ121.57(C-4),50.24(C-14),48.90(C-9),42.78(C-10),40.72
(C-1),40.39(C-8),38.01(C-6),35.55(C-2),31.04(C-16),30.31(C-12),26.37(C-21),
26.12(C-7),25.78(C-11),23.64(C-15),21.27(6-CH3),17.76(17-OCOCH3),14.47(C-18)。
Claims (1)
1. -17 α of a kind of 6 Alpha-Methyl-acetoxyl group -19- norpregna -4- alkene -3, the synthetic method of 20- diketone, it is characterized in that
Step is as follows：
（1）Palladium/carbon is added in alcohol-water-cyclohexene, backflow is heated with stirring to, wherein, the ethanol volume in alcohol-water
Concentration is 75~95%, and the palladium mass content of the palladium/carbon catalyst for using is 5~10% palladium/carbon；
（2）NOMAc is added to step（1）Palladium/carbon-alcohol-water-cyclohexene mixed liquor in, be heated to temperature for 75~85
DEG C, the molar ratio of palladium is 1 in wherein substrate NOMAc and palladium/carbon:0.01~0.05, reacted with vigorous stirring, tie up
Reaction temperature is held for 80~85 DEG C, reaction process is detected with liquid phase, the reaction time is 3~4 hours, reaction terminate after mistake while hot
Filter, cooling crystallization obtains 6-17 α of Alpha-Methyl-acetoxyl group-19- norpregna-4- alkene-3, and the crude product of 20- diketone enters one
Step purifies to obtain purity>99.5% product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611098002.4A CN106810585B (en) | 2016-12-03 | 2016-12-03 | A kind of -17 α of 6 Alpha-Methyl-acetoxyl group -19- norpregna -4- alkene -3,20- diketone synthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611098002.4A CN106810585B (en) | 2016-12-03 | 2016-12-03 | A kind of -17 α of 6 Alpha-Methyl-acetoxyl group -19- norpregna -4- alkene -3,20- diketone synthetic method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106810585A true CN106810585A (en) | 2017-06-09 |
| CN106810585B CN106810585B (en) | 2019-03-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611098002.4A Expired - Fee Related CN106810585B (en) | 2016-12-03 | 2016-12-03 | A kind of -17 α of 6 Alpha-Methyl-acetoxyl group -19- norpregna -4- alkene -3,20- diketone synthetic method |
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| Country | Link |
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| CN (1) | CN106810585B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110655548A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methyl steroid compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3716637A (en) * | 1970-09-30 | 1973-02-13 | Ciba Geigy Corp | Pharmaceutical preparations |
| GB1308849A (en) * | 1970-10-07 | 1973-03-07 | Ciba Geigy Ag | Process for the preparation of 6alpha-methyl-19-nor-pregnenes |
| WO2008148473A2 (en) * | 2007-06-06 | 2008-12-11 | Bayer Schering Pharma Ag | Method for the production of 17 alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate, and megestrol acetate |
| CN102952169A (en) * | 2011-08-16 | 2013-03-06 | 黄云生 | Synthetic method of 6-methyl-17alpha-acetoxyl-19-norpregna-4,6-dialkyl-3,20-diketone |
-
2016
- 2016-12-03 CN CN201611098002.4A patent/CN106810585B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3716637A (en) * | 1970-09-30 | 1973-02-13 | Ciba Geigy Corp | Pharmaceutical preparations |
| GB1308849A (en) * | 1970-10-07 | 1973-03-07 | Ciba Geigy Ag | Process for the preparation of 6alpha-methyl-19-nor-pregnenes |
| WO2008148473A2 (en) * | 2007-06-06 | 2008-12-11 | Bayer Schering Pharma Ag | Method for the production of 17 alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate, and megestrol acetate |
| CN102952169A (en) * | 2011-08-16 | 2013-03-06 | 黄云生 | Synthetic method of 6-methyl-17alpha-acetoxyl-19-norpregna-4,6-dialkyl-3,20-diketone |
Non-Patent Citations (1)
| Title |
|---|
| D. BURN等: "Modified steroid hormones—LI : Application of the Vilsmeier reaction to 11β-hydroxy steroids", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110655548A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN110655548B (en) * | 2018-06-29 | 2022-05-17 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methyl steroid compound |
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| Publication number | Publication date |
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| CN106810585B (en) | 2019-03-05 |
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