CN104327146A - Novel method of synthesizing 17 alpha-hydroxyl progesterone - Google Patents
Novel method of synthesizing 17 alpha-hydroxyl progesterone Download PDFInfo
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- CN104327146A CN104327146A CN201410577370.1A CN201410577370A CN104327146A CN 104327146 A CN104327146 A CN 104327146A CN 201410577370 A CN201410577370 A CN 201410577370A CN 104327146 A CN104327146 A CN 104327146A
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- alpha
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- cyano
- androstene
- ketone
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title abstract 3
- 229960003387 progesterone Drugs 0.000 title abstract 3
- 239000000186 progesterone Substances 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000243 solution Substances 0.000 claims abstract description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 16
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000007259 addition reaction Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- DBPWSSGDRRHUNT-UHFFFAOYSA-N 17alpha-hydroxy progesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)(O)C1(C)CC2 DBPWSSGDRRHUNT-UHFFFAOYSA-N 0.000 claims description 27
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000009413 insulation Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 230000001681 protective effect Effects 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 150000002460 imidazoles Chemical group 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012267 brine Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 230000003068 static effect Effects 0.000 claims description 3
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000004224 protection Effects 0.000 abstract description 14
- 238000007670 refining Methods 0.000 abstract description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000006703 hydration reaction Methods 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000010189 synthetic method Methods 0.000 description 8
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 5
- 229930182490 saponin Natural products 0.000 description 5
- 150000007949 saponins Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 240000001811 Dioscorea oppositifolia Species 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- -1 diene alcohol ketone Chemical class 0.000 description 1
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- 238000010792 warming 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)
- Steroid Compounds (AREA)
Abstract
The invention provides a novel method of synthesizing 17 alpha-hydroxyl progesterone (01). The novel method comprises the following steps: 1) in the presence of trimethylsilyl chloride and a methyl magnesium chloride solution, performing double-protection reaction on 17 bata-cyano-17 alpha-hydroxyl-4-androstene-3-one (02) to produce a compound (03); 2) heating up to perform grignard addition reaction, and transferring into an ammonium chloride aqueous solution to produce a compound (04); 3) preserving the heat and discoloring by active carbon, adding diluted acid water to reflux and perform hydrolysis reaction of double protection groups, and separating and purifying to obtain 17 alpha-hydroxyl progesterone (01). According to the novel method disclosed by the invention, the conventional 3-position ketal protection, 17 alpha-hydroxyl vinyl ether protection, grignard addition, re-hydration of protection groups on position 3 and position 17 and discoloring-refining are simplified into one-step operation.
Description
Technical field
The present invention relates to the synthesis of medicine intermediate, specifically, relate to the novel method of a kind of synthesis 17 Alpha-hydroxy Progesterone.
Background technology
17 Alpha-hydroxy Progesterone are a kind of versatile intermediates producing steroidal corticosteroids medicine.With it for raw material, the multiple common corticosteroids medicines such as medroxyprogestrone Acetate, cyproterone megestrol, hydrocortisone, prednisone can be produced.
The most traditional production method: extract diosgenin from Chinese yam plant; Saponin, through open loop, oxidation, hydrolysis, obtains key intermediate acetic acid gestation diene alcohol ketone (abbreviation diene); Take diene as raw material, through epoxidation, Ovshinsky oxidation, the obtained 17 Alpha-hydroxy Progesterone of upper bromine, debrominate four-step reaction.Because Chinese yam plant resources is petered out, pollute large when extracting saponin, so saponin cost of material is high.In addition subsequent synthetic procedures is long, and yield is low, and pollute large, cost is higher.
As follows from the reaction expression of production of saponin 17 Alpha-hydroxy Progesterone:
In addition, over the past two years, domestic according to foreign literature report, utilize from soybean oil produce residue extract Stigmasterol, through modern biotechnology fermentation technique, obtain another key intermediate 4-AD of synthesizing steroid hormonal medicaments, be called for short 4AD.(or 3 ethers are protected), 17 alpha-hydroxy alkene ether protections, grignard addition, the two many more manipulations such as protecting group, decolorizing and refining of hydrolysis is protected to produce 17 Alpha-hydroxy Progesterone by 4AD through cyano group addition, 3 ketals again.Although raw material 4AD is more cheap than saponin, step is shorter, and yield is higher, less pollution, and cost is lower, but still too complicated, and quality, cost, three wastes aspect still remain to be further improved.
The reaction expression following (CN103467555A) of 3 ketal protection routes:
3 ketal protection yields are not high, and content is not high, and has the isomer of 4 double bonds, and this isomer can not get desired product when carrying out grignard addition, therefore last overall yield is lower, and quality is difficult to reach high standard requirement.
The reaction expression following (CN103910775A) of 3 ether protection routes:
3 ether protection is reversible, reaction is incomplete, and color is comparatively dark, and second-rate, yield is not high, therefore overall yield is lower, and quality is difficult to reach high standard requirement.
So comprehensive above synthesis technique is considered, develop a kind of simple synthetic method, environmental protection, yield is high, and cost is low, and quality is good, and the route being applicable to suitability for industrialized production just seems and is even more important.
Summary of the invention
In order to solve problems of the prior art, the object of this invention is to provide the novel method that a kind of simple, high quality and high yield synthesize 17 Alpha-hydroxy Progesterone.
In order to realize the object of the invention, technical scheme of the present invention is as follows:
A novel method for synthesis 17 Alpha-hydroxy Progesterone, reaction mechanism as shown in Figure 1.
1) by 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) under trimethylchlorosilane and methyl magnesium chloride solution exist, low temperature carries out two protective reaction, generates compound (03);
2) grignard addition reaction is carried out in intensification, proceeds in aqueous ammonium chloride solution, generates compound (04);
3) through gac insulation decolouring, add the hydrolysis reaction that two protecting group is carried out in the backflow of diluted acid water, after separation and purification, obtain 17 Alpha-hydroxy Progesterone (01).
Further, the novel method of described synthesis 17 Alpha-hydroxy Progesterone (01), is specially:
17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) are suspended from toluene, add catalyzer, cooling, add trimethylchlorosilane, the methyl magnesium chloride solution of slow dropping 2M, (03 is generated) after low temperature carries out two protective reaction for some time, then slowly heat up and carry out grignard addition reaction, after some plate reacts completely, cooling, slowly proceed in aqueous ammonium chloride solution and (generate 04), static point is fallen brine layer, washing once, add gac insulation decolouring, insulation is filtered, toluene wash, filtrate adds the hydrolysis reaction (generating 01) that two protecting group is carried out in the backflow of diluted acid water, after some plate reacts completely, cooling, PH=7 ~ 8 are neutralized to 30% liquid caustic soda (sodium hydroxide solution), intensification normal pressure is concentrated into 100 DEG C, and check distillate without toluene after, be cooled to less than 40 DEG C, rejection filter, be washed to neutrality, dry, do not dry, ethanol is pulled an oar, rejection filter, washing with alcohol, dry, dry, obtain 17 Alpha-hydroxy Progesterone (01).
The mass ratio of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and toluene is 1:2 ~ 10, preferred 1:5.
Described catalyzer is imidazoles or Methylimidazole.
The mol ratio of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02), trimethylchlorosilane and catalyzer is 1:2 ~ 3:1 ~ 3, preferred 1:2.2:2.
The mass ratio of the methyl magnesium chloride solution of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and 2M is 1:10 ~ 15, preferred 1:12.
The methyl magnesium chloride solution of described 2M and the mass ratio of ammonium chloride are 1:0.1 ~ 0.3, preferred 1:0.2.
Described sour water is the aqueous solution of sulfuric acid, concentrated hydrochloric acid, phosphoric acid or Glacial acetic acid, preferably the dilute hydrochloric acid of 10%.
Described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and 10% the mass ratio of dilute hydrochloric acid be 1:1 ~ 3, preferred 1:2.
The mass ratio of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and gac is 1:0.01 ~ 0.05, preferred 1:0.03.
The reaction conditions of described pair of protective reaction: temperature of reaction is-10 DEG C ~ 10 DEG C, preferably-5 DEG C ~ 0 DEG C.Reaction times is 1 ~ 3 hour, preferably 2 hours.
The reaction conditions of described addition reaction: temperature of reaction is 30 DEG C ~ 80 DEG C, preferably 55 DEG C ~ 60 DEG C.Reaction times is 2 ~ 6 hours, preferably 4 hours.
The reaction conditions of described hydrolysis reaction: the reaction times is 1 ~ 3 hour, preferably 2 hours.
Described decolorization condition: temperature is 30 DEG C ~ 80 DEG C, preferably 55 DEG C ~ 60 DEG C.Reaction times is 1 ~ 3 hour, preferably 2 hours.
Beneficial effect of the present invention is:
Traditional 3 ketals are protected by the method for the invention, 17 alpha-hydroxy alkene ether protections, grignard addition, the protecting group being hydrolyzed 3 and 17 again and the operation of decolorizing and refining five step are simplified to single stepping.Technique is simple, consumes supplementary material few, and aftertreatment is simple, and yield is high, and cost is low, environmental protection, thus not only economic environmental protection but also be convenient to industrializing implementation.
Accompanying drawing explanation
Fig. 1 is the reaction mechanism figure of synthesis 17 Alpha-hydroxy Progesterone of the present invention.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
The synthesis of embodiment 1 17 Alpha-hydroxy Progesterone (01)
Under room temperature, be equipped with in the 5000L enamel reaction still of thermometer and agitator one, add toluene 1000L, stir, add 17 beta-cyano-17 Alpha-hydroxy-4-androstene-3-ketone (02) 200kg, add imidazoles 87kg, be cooled to-5 ~ 0 DEG C, add trimethylchlorosilane 153kg, after stirring, the methyl magnesium chloride solution 2400kg of slow dropping 2M,-5 ~ 0 DEG C of insulation reaction is after 2 hours, slowly be warming up to 55 DEG C ~ 60 DEG C, insulation reaction 4 hours, after some plate reacts completely, icy salt solution is cooled to less than 10 DEG C, slowly proceed in the aqueous ammonium chloride solution of cover circulating water cooling, stir 30 minutes, static 30 minutes, divide clean brine layer, with 200kg tap water once, divide clean tap water, add gac 6kg, 55 ~ 60 DEG C are incubated decolouring 2 hours, insulation is filtered, q. s. toluene washs, filtrate proceeds in hydrolysis kettle, add the dilute hydrochloric acid 400kg of 10%, back hydrolysis 2 hours, after some plate reacts completely, be cooled to less than 40 DEG C, liquid caustic soda (sodium hydroxide solution) with 30% is neutralized to PH=7 ~ 8, intensification normal pressure is concentrated into 100 DEG C, and check distillate without toluene after, be cooled to less than 40 DEG C, rejection filter, be washed to neutrality, dry, do not dry, 300kg ethanol is pulled an oar, rejection filter, 100kg washing with alcohol, dry, dry, obtain 17 Alpha-hydroxy Progesterone (01) 196.15kg, weight yield 98.08%, molar yield 93.02%, fusing point 216.0 ~ 220.0 DEG C.
The synthesis of embodiment 2 17 Alpha-hydroxy Progesterone (01)
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, the imidazoles of the 87kg in example 1 is changed into the glyoxal ethyline of 105kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 195.92kg, weight yield 97.96%, molar yield 92.91%, fusing point 216.0 ~ 220.0 DEG C.The synthesis of embodiment 3 17 Alpha-hydroxy Progesterone
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, and the methyl magnesium chloride solution 2400kg of the 2M in example 1 is reduced to 2000kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 194.87kg, weight yield 97.44%, molar yield 92.42%, fusing point 215.0 ~ 219.0 DEG C.The synthesis of embodiment 4 17 Alpha-hydroxy Progesterone
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, and the methyl magnesium chloride solution 2400kg of the 2M in example 1 is increased to 3000kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 196.20kg, weight yield 98.10%, molar yield 93.05%, fusing point 215.5 ~ 219.5 DEG C.Embodiment 5
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, changes the trimethylchlorosilane 153kg in example 1 into 139kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 194.84kg, weight yield 97.42%, molar yield 92.41%, fusing point 215.0 ~ 219.0 DEG C.
Embodiment 6
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, changes the trimethylchlorosilane 153kg in example 1 into 208kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 194.36kg, weight yield 97.18%, molar yield 92.18%, fusing point 215.0 ~ 219.0 DEG C.
Embodiment 7
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, changes the trimethylchlorosilane 153kg in example 1 into 125kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 173.95kg, weight yield 86.98%, molar yield 82.50%, fusing point 214.0 ~ 218.5 DEG C.
Embodiment 8
Synthetic method is with embodiment 1, and distinctive points is only in the present embodiment, changes the trimethylchlorosilane 153kg in example 1 into 243kg.Finally obtain 17 Alpha-hydroxy Progesterone (01) 181.57kg, weight yield 90.79%, molar yield 86.11%, fusing point 2140 ~ 218.5 DEG C.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. synthesize a novel method for 17 Alpha-hydroxy Progesterone (01), it is characterized in that, comprise the following steps:
1) by 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) under trimethylchlorosilane and methyl magnesium chloride solution exist, low temperature carries out two protective reaction, generates compound (03);
2) grignard addition reaction is carried out in intensification, proceeds in aqueous ammonium chloride solution, generates compound (04);
3) through gac insulation decolouring, add the hydrolysis reaction that two protecting group is carried out in the backflow of diluted acid water, after separation and purification, obtain 17 Alpha-hydroxy Progesterone (01).
2. method according to claim 1, it is characterized in that, described method is specially: be suspended from toluene by 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02), add catalyzer, cooling, add trimethylchlorosilane, the methyl magnesium chloride solution of slow dropping 2M, after low temperature carries out two protective reaction for some time, generate compound (03), then slowly heat up and carry out grignard addition reaction, after some plate reacts completely, cooling, slowly proceed in aqueous ammonium chloride solution, generate compound (04), static point is fallen brine layer, washing once, add gac insulation decolouring, insulation is filtered, toluene wash, filtrate adds the hydrolysis reaction that two protecting group is carried out in the backflow of diluted acid water, generate (01), after some plate reacts completely, cooling, PH=7 ~ 8 are neutralized to 30% liquid caustic soda, after intensification normal pressure is concentrated into and distillates without toluene, be cooled to less than 40 DEG C, rejection filter, be washed to neutrality, dry, do not dry, ethanol is pulled an oar, rejection filter, washing with alcohol, dry, dry, obtain 17 Alpha-hydroxy Progesterone (01).
3. method according to claim 1 and 2, is characterized in that, described catalyzer is imidazoles or Methylimidazole.
4. method according to claim 3, is characterized in that, the mol ratio of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02), trimethylchlorosilane and catalyzer is 1:2 ~ 3:1 ~ 3, preferred 1:2.2:2.
5. method according to claim 3, is characterized in that, the mass ratio of the methyl magnesium chloride solution of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and 2M is 1:10 ~ 15, preferred 1:12.
6. method according to claim 3, is characterized in that, the methyl magnesium chloride solution of described 2M and the mass ratio of ammonium chloride are 1:0.1 ~ 0.3, preferred 1:0.2.
7. method according to claim 3, is characterized in that, described sour water is the aqueous solution of sulfuric acid, concentrated hydrochloric acid, phosphoric acid or Glacial acetic acid, preferably the dilute hydrochloric acid of 10%.
8. method according to claim 3, is characterized in that, described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and 10% the mass ratio of dilute hydrochloric acid be 1:1 ~ 3, preferred 1:2.
9. method according to claim 3, is characterized in that, the mass ratio of described 17 beta-cyano-17 Alpha-hydroxies-4-androstene-3-ketone (02) and gac is 1:0.01 ~ 0.05, preferred 1:0.03.
10. method according to claim 3, is characterized in that, the reaction conditions of described pair of protective reaction: temperature of reaction is-10 DEG C ~ 10 DEG C, preferably-5 DEG C ~ 0 DEG C.Reaction times is 1 ~ 3 hour, preferably 2 hours;
The reaction conditions of described addition reaction: temperature of reaction is 30 DEG C ~ 80 DEG C, preferably 55 DEG C ~ 60 DEG C; Reaction times is 2 ~ 6 hours, preferably 4 hours;
The reaction conditions of described hydrolysis reaction: the reaction times is 1 ~ 3 hour, preferably 2 hours;
Described decolorization condition: temperature is 30 DEG C ~ 80 DEG C, preferably 55 DEG C ~ 60 DEG C; Reaction times is 1 ~ 3 hour, preferably 2 hours.
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| CN109456381A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of Delmadinone |
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| CN109627275A (en) * | 2018-12-18 | 2019-04-16 | 湖南科瑞生物制药股份有限公司 | A kind of bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 1,6- |
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| CN112175034B (en) * | 2020-09-08 | 2023-03-28 | 山东赛托生物科技股份有限公司 | Method for preparing 17 alpha-hydroxyprogesterone |
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