CN113788872B - Preparation method of androstane-2-alkene-17-ketone - Google Patents
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- CN113788872B CN113788872B CN202111293969.9A CN202111293969A CN113788872B CN 113788872 B CN113788872 B CN 113788872B CN 202111293969 A CN202111293969 A CN 202111293969A CN 113788872 B CN113788872 B CN 113788872B
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- androstane
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- ketone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 claims abstract description 16
- QGXBDMJGAMFCBF-LUJOEAJASA-N epiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-LUJOEAJASA-N 0.000 claims abstract description 16
- 229940125904 compound 1 Drugs 0.000 claims abstract description 14
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 12
- 238000003379 elimination reaction Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 12
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 12
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 12
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 32
- 239000003814 drug Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 4
- 150000003431 steroids Chemical class 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 18
- ISJVDMWNISUFRJ-HQEMIIEJSA-N 5α-androst-2-ene-17-one Chemical compound C1C=CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC21 ISJVDMWNISUFRJ-HQEMIIEJSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 206010021118 Hypotonia Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000036640 muscle relaxation Effects 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229960003682 rocuronium bromide Drugs 0.000 description 2
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960004298 vecuronium bromide Drugs 0.000 description 2
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- -1 alicyclic amines Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to the technical field of steroid medicine intermediates. The invention provides a preparation method of androstane-2-alkene-17-ketone, which comprises the following steps: 1) Epiandrosterone, a halogen-containing compound, a catalyst and a solvent are mixed and then subjected to halogenation reaction to obtain a compound 1; 2) And (3) mixing the compound 1, a catalyst and a solvent, and then performing elimination reaction to obtain androstane-2-alkene-17-ketone. The invention obviously improves the yield and purity of the target product by reasonably selecting the catalyst and controlling the proportion of raw materials and process conditions; in addition, the reaction condition is mild, the operation is simple, the production cost is low, and the reaction selectivity is good. The yield of androstane-2-alkene-17-ketone obtained by the preparation method is more than or equal to 94%, and the purity is more than or equal to 98.5%.
Description
Technical Field
The invention relates to the technical field of steroid medicine intermediates, in particular to a preparation method of androstane-2-alkene-17-ketone.
Background
Rocuronium bromide, vecuronium bromide and the like are common muscle relaxation steroid hormone medicaments, have the advantages of quick response, no accumulation in vivo, weak inhibition effect on cardiovascular systems, small histamine release and the like, and become important auxiliary medicaments for implementing anesthesia in clinical surgery. The androstane-2-alkene-17-ketone is a general intermediate for producing various muscle relaxation steroid hormone medicines such as rocuronium bromide, vecuronium bromide and the like, the androstane-2-alkene-17-ketone is subjected to 17-position enol esterification, double-ring oxidation, ring opening with different alicyclic amines, reduction, double-esterification, bromomethyl amination and the like to obtain different bromamine muscle relaxation steroid medicines, the androstane-2-alkene-17-ketone occupies an important position in the medicine field, especially in the aspect of steroid medicines, and the demand for the androstane-2-alkene-17-ketone in the market is continuously increased.
The main synthesis method of androstane-2-alkene-17-ketone comprises the following steps: (1) 3-hydroxy sulfonyl of epiandrosterone and elimination reaction to obtain androstane-2-ene-17-one; (2) Directly dehydrating under the acid catalysis to obtain androstane-2-alkene-17-ketone. However, the method for preparing androstane-2-alkene-17-ketone in the prior art has the problems of harsh reaction conditions, low product yield and purity, complex operation, difficult recovery of solvents, impurity doping in products and the like, so that the cost is very high, supply is not required, and therefore, the research on a simple, convenient and efficient industrial preparation method has important practical significance.
Therefore, research on a preparation method of androstane-2-alkene-17-ketone with the advantages of reaction condition reduction, product yield and purity improvement, mild condition and simple operation has important significance.
Disclosure of Invention
The invention aims to provide a preparation method of androstane-2-alkene-17-ketone aiming at the defects of the prior art, which is used for solving the problems of harsh reaction conditions, low product yield and low purity in the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of androstane-2-alkene-17-ketone, which takes epiandrosterone as a raw material and prepares androstane-2-alkene-17-ketone through the following route:
the preparation method of the androstane-2-alkene-17-ketone comprises the following steps:
1) Epiandrosterone, a halogen-containing compound, a catalyst and a solvent are mixed and then subjected to halogenation reaction to obtain a compound 1;
2) And (3) mixing the compound 1, a catalyst and a solvent, and then performing elimination reaction to obtain androstane-2-alkene-17-ketone.
Preferably, the halogen-containing compound of step 1) comprises bromosuccinimide, N-bromosuccinimide or carbon tetrachloride.
Preferably, the catalyst in the step 1) is triphenylphosphine; the solvent comprises one or more of dichloromethane, acetone, dimethyl sulfoxide and N, N-dimethylacetamide.
Preferably, the mass volume ratio of epiandrosterone, halogen-containing compound, catalyst and solvent in the step 1) is 5-6.5 g: 8-15 g: 8-12 g: 150-180 mL.
Preferably, the temperature of the halogenation reaction in the step 1) is 40-60 ℃ and the time is 2-4 h.
Preferably, the catalyst in the step 2) comprises lithium carbonate and lithium bromide, wherein the mass ratio of the lithium carbonate to the lithium bromide is 2-3:4-6.
Preferably, the mass-volume ratio of the compound 1, the catalyst and the solvent in the step 2) is 6-8 g: 9-12 g: 120-150 mL; the solvent comprises one or more of toluene, ethyl acetate, cyclohexanone and N, N-dimethylacetamide.
Preferably, the temperature of the elimination reaction in step 2) is 55 to 70 ℃ and the time is 5 to 8 hours.
The beneficial effects of the invention include:
the invention obviously improves the yield and purity of the target product by reasonably selecting the catalyst and controlling the proportion of raw materials and process conditions; in addition, the reaction condition is mild, the operation is simple, the production cost is low, and the reaction selectivity is good.
Detailed Description
The invention provides a preparation method of androstane-2-alkene-17-ketone, which takes epiandrosterone as a raw material and prepares androstane-2-alkene-17-ketone through the following route:
the preparation method of the androstane-2-alkene-17-ketone comprises the following steps:
1) Epiandrosterone, a halogen-containing compound, a catalyst and a solvent are mixed and then subjected to halogenation reaction to obtain a compound 1;
2) And (3) mixing the compound 1, a catalyst and a solvent, and then performing elimination reaction to obtain androstane-2-alkene-17-ketone.
The halogen-containing compounds of step 1) of the present invention preferably comprise bromosuccinimide, N-bromosuccinimide or carbon tetrachloride.
The catalyst in step 1) of the present invention is preferably triphenylphosphine; the solvent preferably comprises one or more of dichloromethane, acetone, dimethyl sulfoxide and N, N-dimethylacetamide; when the solvent contains several components at the same time, the components are preferably mixed in equal volume ratios.
The mass volume ratio of epiandrosterone, halogen-containing compound, catalyst and solvent in step 1) of the invention is preferably 5-6.5 g: 8-15 g: 8-12 g:150 to 180mL, more preferably 5.5 to 6g: 10-12 g: 9-11 g: 160-170 mL, more preferably 6g:11g:10g: 163-166 mL.
The temperature of the halogenation reaction in step 1) of the present invention is preferably 40 to 60 ℃, more preferably 45 to 55 ℃, still more preferably 48 to 52 ℃; the time of the halogenation reaction is preferably 2 to 4 hours, more preferably 2.5 to 3.5 hours, still more preferably 3 hours; the mixing and halogenation reactions are preferably carried out under stirring.
The catalyst according to step 2) of the present invention preferably comprises lithium carbonate and lithium bromide, the mass ratio of which is preferably 2-3:4-6, more preferably 2.5:5.
The mass volume ratio of the compound 1, the catalyst and the solvent in the step 2) is preferably 6-8 g: 9-12 g:120 to 150mL, more preferably 6.5 to 7.5g: 10-11 g:130 to 140mL, more preferably 7g:10g: 133-136 mL; the solvent preferably comprises one or more of toluene, ethyl acetate, cyclohexanone and N, N-dimethylacetamide; when the solvent contains several components at the same time, the components are preferably mixed in equal volume ratios.
The temperature of the elimination reaction in step 2) of the present invention is preferably 55 to 70 ℃, more preferably 58 to 67 ℃, and even more preferably 62 to 65 ℃; the time for the elimination reaction is preferably 5 to 8 hours, more preferably 6 to 7 hours; the mixing and elimination reactions are preferably carried out under stirring.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
5g of epiandrosterone, 9g of bromosuccinimide and 9g of triphenylphosphine are added into a reaction kettle filled with 155mL of dichloromethane, the mixture is uniformly mixed, the halogenation reaction is carried out for 4 hours at 45 ℃, and the TLC confirms the end point of the reaction. After the completion of the reaction, the reaction solution was cooled to room temperature, washed with an ethanol solution to remove triphenylphosphine, then washed twice with 100mL of a saturated aqueous sodium bicarbonate solution, concentrated under reduced pressure, and dried over anhydrous sodium sulfide to give compound 1.
6.5g of Compound 1, 3g of lithium carbonate and 6g of lithium bromide were mixed well in 125mL of ethyl acetate, the reaction was eliminated at 55℃for 7h, and TLC confirmed the end of the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, washed with 25% by mass of hydrochloric acid solution to remove lithium carbonate and lithium bromide, then washed twice with 100mL of saturated brine, concentrated under reduced pressure, and dried over anhydrous sodium sulfate to obtain androstan-2-en-17-one.
The product obtained in example 1 was obtained in a yield of 94% and a purity of 98.5%.
Example 2
6.5g of epiandrosterone, 13g of carbon tetrachloride and 11g of triphenylphosphine are added into a reaction kettle filled with a mixed solvent of 90mL of acetone and 85mL of dimethyl sulfoxide, the mixture is uniformly mixed, the halogenation reaction is carried out for 2 hours at 55 ℃, and the TLC confirms the end point of the reaction. After the completion of the reaction, the reaction solution was cooled to room temperature, washed with an ethanol solution to remove triphenylphosphine, then washed twice with 130mL of a saturated aqueous sodium bicarbonate solution, concentrated under reduced pressure, and dried over anhydrous sodium sulfide to give compound 1.
7.5g of Compound 1, 3g of lithium carbonate and 9g of lithium bromide were mixed uniformly in 145mLN, N-dimethylacetamide, the reaction was eliminated at 65℃for 5 hours, and TLC confirmed the end point of the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, washed with 27% by mass of hydrochloric acid solution to remove lithium carbonate and lithium bromide, then washed twice with 125mL of saturated brine, concentrated under reduced pressure, and dried over anhydrous sodium sulfate to obtain androstan-2-en-17-one.
The product obtained in example 2 was obtained in a yield of 96% and a purity of 98.8%.
Example 3
6g of epiandrosterone, 12g N-bromosuccinimide and 10g of triphenylphosphine were added to a reaction vessel containing 165mLN, N-dimethylacetamide, and the mixture was uniformly mixed, and halogenated at 50℃for 3 hours, and TLC confirmed the end point of the reaction. After the completion of the reaction, the reaction solution was cooled to room temperature, washed with an ethanol solution to remove triphenylphosphine, then washed twice with 120mL of a saturated aqueous sodium bicarbonate solution, concentrated under reduced pressure, and dried over anhydrous sodium sulfide to give compound 1.
7g of Compound 1, 3.5g of lithium carbonate and 7g of lithium bromide were uniformly mixed in 135mL of cyclohexanone, the reaction was eliminated at 60℃for 6 hours, and the TLC confirmed the end of the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, washed with 25% by mass of hydrochloric acid solution to remove lithium carbonate and lithium bromide, then washed twice with 120mL of saturated brine, concentrated under reduced pressure, and dried over anhydrous sodium sulfate to obtain androstan-2-en-17-one.
The product obtained in example 3 was obtained in a yield of 97% and in a purity of 99%.
Comparative example 1
3.5g of lithium carbonate and 7g of lithium bromide of example 3 were replaced with 50mL of an ethanol solution of sodium hydroxide (mass of sodium hydroxide: 10 g), and cyclohexanone was changed to an equal volume of acetone, under the same conditions as in example 3.
The yield of the product obtained in comparative example 1 was 78% and the purity was 88%.
Comparative example 2
The conditions were the same as in example 3 except that 6g of epiandrosterone and 10g of triphenylphosphine in example 3 were changed to 5g of epiandrosterone and 13g of triphenylphosphine, the temperature of the halogenation reaction was changed to 30℃and the time was changed to 8 hours.
The yield of the product obtained in comparative example 2 was 83% and the purity was 90%.
Comparative example 3
The triphenylphosphine of example 3 was changed to equal mass of ferric bromide, and the temperature of the elimination reaction was changed from 60℃to 80℃under the same conditions as in example 3.
The yield of the product obtained in comparative example 3 was 72% and the purity was 89%.
According to examples 1 to 3, the preparation method of the invention can significantly improve the yield and purity of the target product androsta-2-en-17-one. As is clear from comparative examples 1 to 3, the yield and purity of the objective androstane-2-en-17-one can be reduced by changing the raw materials and the amount thereof, and the process parameters such as the reaction temperature, the reaction time and the like.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (1)
1. The preparation method of the androstane-2-alkene-17-ketone is characterized in that epiandrosterone is used as a raw material, and the androstane-2-alkene-17-ketone is prepared through the following route:
the preparation method of the androstane-2-alkene-17-ketone comprises the following steps:
1) Epiandrosterone, a halogen-containing compound, a catalyst and a solvent are mixed and then subjected to halogenation reaction to obtain a compound 1;
2) After mixing the compound 1, a catalyst and a solvent, carrying out elimination reaction to obtain androstane-2-alkene-17-ketone;
step 1) the halogen-containing compound comprises bromosuccinimide, N-bromosuccinimide, or carbon tetrachloride;
the catalyst in the step 1) is triphenylphosphine; the solvent comprises one or more of dichloromethane, acetone, dimethyl sulfoxide and N, N-dimethylacetamide;
the mass volume ratio of epiandrosterone, halogen-containing compound, catalyst and solvent in the step 1) is 5-6.5 g: 8-15 g: 8-12 g: 150-180 mL;
the temperature of the halogenation reaction in the step 1) is 40-60 ℃ and the time is 2-4 h;
the mass volume ratio of the compound 1 to the catalyst to the solvent in the step 2) is 6-8 g: 9-12 g: 120-150 mL; the solvent comprises one or more of toluene, ethyl acetate, cyclohexanone and N, N-dimethylacetamide;
the temperature of the elimination reaction in the step 2) is 55-70 ℃ and the time is 5-8 h;
the catalyst in the step 2) comprises lithium carbonate and lithium bromide, wherein the mass ratio of the lithium carbonate to the lithium bromide is 2-3:4-6.
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| CN112625077A (en) * | 2020-12-30 | 2021-04-09 | 成都新恒创药业有限公司 | Preparation method of androst-2-ene-17-one and androst-2-ene-17-one |
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2021
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| Publication number | Priority date | Publication date | Assignee | Title |
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