CN115536717A - Synthesis method of androstane-4,16-diene-3-ketone - Google Patents
Synthesis method of androstane-4,16-diene-3-ketone Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title description 4
- -1 hydrazone compound Chemical class 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims abstract description 22
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims abstract description 20
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 15
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 12
- FUSNOPLQVRUIIM-UHFFFAOYSA-N 4-amino-2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-n-[3-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide Chemical compound O=C1NC(C)(C)CN1C(N=C1N)=NC=C1C(=O)NC1=CC=CC(C(F)(F)F)=C1 FUSNOPLQVRUIIM-UHFFFAOYSA-N 0.000 claims abstract description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012493 hydrazine sulfate Substances 0.000 claims abstract description 12
- 229910000377 hydrazine sulfate Inorganic materials 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 10
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 10
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 10
- 239000011630 iodine Substances 0.000 claims abstract description 10
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 10
- 238000010992 reflux Methods 0.000 claims abstract description 9
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims abstract description 7
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 238000005831 deiodination reaction Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- 238000006192 iodination reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- HNDHDMOSWUAEAW-VMXHOPILSA-N androstadienone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C=CC4)[C@@H]4[C@@H]3CCC2=C1 HNDHDMOSWUAEAW-VMXHOPILSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 230000026045 iodination Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- HNDHDMOSWUAEAW-UHFFFAOYSA-N (8alpha,9beta,10alpha,13alpha,14beta)-Androsta-4,6-dien-3-one Natural products O=C1CCC2(C)C3CCC(C)(C=CC4)C4C3CCC2=C1 HNDHDMOSWUAEAW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003016 pheromone Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 1
- SLINHMUFWFWBMU-UHFFFAOYSA-N Triisopropanolamine Chemical compound CC(O)CN(CC(C)O)CC(C)O SLINHMUFWFWBMU-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- C07J1/0007—Androstane derivatives not substituted in position 17
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
A method for synthesizing androstane-4,16 diene-3-ketone comprises the following steps: 1) Performing condensation reaction, namely dissolving DHEA in a solvent, adding hydrazine hydrate, adding hydrazine sulfate aqueous solution, and completely reacting at 0-50 ℃ to obtain a hydrazone compound 4; 2) In the alkenyl iodination reaction, a hydrazone compound 4 is dissolved in a solvent, alkali is added, 1,1,3,3-tetramethylguanidine is added, iodine is added in batches, and the mixture is stirred at the temperature of 0-50 ℃ until the reaction is completed to obtain alkenyl iodide 5; 3) A deiodination reaction, namely adding alkenyl iodide 5, paraformaldehyde and cesium carbonate into DMSO, adding tetrakis (triphenylphosphine) palladium under the protection of inert gas, and completely reacting at 80-120 ℃ to obtain a deiodinated substance 3; 4) And (3) performing oxidation reaction, namely dissolving the deiodinated substance 3 in toluene, adding cyclohexanone, performing reflux reaction at room temperature, adding aluminum isopropoxide, performing reflux reaction until the reaction is complete, and obtaining the target compound androstane-4,16-diene-3-ketone.
Description
Technical Field
The invention relates to a preparation method of an androstane compound.
Background
Androstane-4,16-dien-3-one is a steroid. Androsta-4,16-dien-3-one is a self-secreted pheromone in mammals, which is found in the human peripheral blood, saliva and axilla (US 5278141 a). As an endogenous pheromone, it is less irritating to the skin and is therefore used as an additive to perfumes.
US6066627 reports the synthesis of androsta-4,16-dien-3-one. The synthetic route takes DHEA as a starting material and TsNHNH 2 Condensing to generate sulfonyl hydrazone 2, reacting with n-butyl lithium to form a compound 3 with 16,17-double bond, and oxidizing with triisopropanolamine to form androstane-4,16-diene-3-ketone. The reaction was carried out for 3 steps in total, with a total yield of 39%. Although the method has a short route, a dangerous reagent of n-butyl lithium is used. In addition, the yield of the step is only 50%, and the total yield is 39%, so that the production cost is high.
Based on the defects in the prior art, the novel synthesis method of androstane-4,16-diene-3-ketone is provided, so that the dangerous reagent n-butyllithium can be avoided, the industrial production is easy to carry out, the reaction yield can be improved, and the problem to be solved in the prior art is urgently solved.
Disclosure of Invention
In order to solve the above problems in the prior art, we provide a technical solution as follows:
a method for synthesizing androstane-4,16 diene-3-ketone is provided, which comprises the following steps
1) Condensation reaction
Dissolving DHEA in a solvent, adding hydrazine hydrate, adding a hydrazine sulfate aqueous solution, reacting completely at 0-50 ℃, pouring a reaction solution into water after the reaction is finished, separating out a white solid, filtering, washing with water, collecting the solid, and drying to obtain a hydrazone compound 4; the solvent is selected from methanol, ethanol, isopropanol, ethylene glycol, acetone, tetrahydrofuran, dioxane, DMF and DMSO, the weight ratio of hydrazine hydrate to DHEA is 0.24-2.45, the weight ratio of hydrazine sulfate to DHEA is 0.05-0.50, and the weight percentage concentration of the aqueous solution of hydrazine sulfate is 15-30%.
Further, the solvent is methanol, the volume weight ratio of the methanol to the DHEA is 8-15, the reaction temperature is preferably 20-25 ℃, the weight ratio of hydrazine hydrate to the DHEA is preferably 0.25-0.50, and the weight ratio of hydrazine sulfate to the DHEA is preferably 0.05-0.10.
Further, the volume weight ratio of the methanol to the DHEA is 9-11, the weight ratio of the hydrazine hydrate to the DHEA is preferably 0.28-0.32, and the weight ratio of the hydrazine sulfate to the DHEA is preferably 0.05-0.07.
2) Iodination of alkenyl groups
Dissolving a hydrazone compound 4 in a solvent, adding alkali, adding 1,1,3,3-tetramethylguanidine, adding iodine in batches, stirring at 0-50 ℃ until the reaction is complete, pouring a reaction solution into a sodium sulfite aqueous solution, separating out a solid, filtering, washing with water, and drying to obtain the alkenyl iodide 5. The solvent is selected from tetrahydrofuran and dioxane; the alkali is selected from triethylamine, N-diisopropylethylamine, DBU, potassium carbonate and sodium carbonate, the weight ratio of 1,1,3,3-tetramethylguanidine to the hydrazone compound 4 is 1.0-3.0, and the weight ratio of iodine to the hydrazone compound 4 is 1.0-2.0.
Further, the solvent is preferably tetrahydrofuran, the volume weight ratio of the tetrahydrofuran to the hydrazone compound 4 is 8-15, the base is preferably triethylamine, the weight ratio of the triethylamine to the hydrazone compound 4 is 0.3-0.4, the weight ratio of the 1,1,3,3-tetramethylguanidine to the hydrazone compound 4 is 1.4-2.0, the dosage ratio of the iodine to the hydrazone compound 4 is 1.5-1.8, and the reaction temperature is 15-30 ℃.
Furthermore, the volume weight ratio of tetrahydrofuran to the hydrazone compound 4 is 9 to 11, the weight ratio of triethylamine to the hydrazone compound 4 is 0.35 to 0.39, the weight ratio of 1, 3-tetramethylguanidine to the hydrazone compound 4 is 1.4 to 1.6, the using amount ratio of iodine to the hydrazone compound 4 is 1.5 to 1.7, the reaction temperature is 20 ℃ to 25 ℃, and the weight percentage concentration of the sodium sulfite aqueous solution is 9% to 11%.
3) Deiodination reaction
Adding alkenyl iodide 5, paraformaldehyde and cesium carbonate into DMSO (dimethylsulfoxide), adding palladium tetrakis (triphenylphosphine) under the protection of inert gas, reacting completely at 80-120 ℃, cooling to 25 ℃, adding water and dichloromethane, stirring, separating, extracting a water phase with dichloromethane, combining dichloromethane phases, washing the dichloromethane phases with water, and concentrating to obtain a deiodinated substance 3; the dosage ratio of the paraformaldehyde to the alkenyl iodide 5 is 0.05-1, the dosage ratio of the cesium carbonate to the alkenyl iodide 5 is 0.5-5, and the dosage ratio of the tetrakis (triphenylphosphine) palladium to the alkenyl iodide 5 is 0.01-0.05.
Further, the dosage ratio of the paraformaldehyde to the alkenyl iodide 5 is 0.08 to 1, and the dosage ratio of the cesium carbonate to the alkenyl iodide 5 is 1.2 to 1.4. The dosage ratio of the tetrakis (triphenylphosphine) palladium to the alkenyl iodide 5 is 0.03-0.04, and the reaction temperature is 100-120 ℃.
Furthermore, the dosage ratio of the paraformaldehyde to the alkenyl iodide 5 is 0.08 to 0.09, and the dosage ratio of the cesium carbonate to the alkenyl iodide 5 is 1.30 to 1.35. The dosage ratio of the tetrakis (triphenylphosphine) palladium to the alkenyl iodide 5 is 0.030 to 0.033, and the reaction temperature is 110 to 115 ℃.
4) Oxidation reaction
Dissolving the deiodinated substance 3 in toluene, adding cyclohexanone, carrying out reflux reaction at room temperature, adding aluminum isopropoxide, carrying out reflux reaction until the reaction is complete, cooling, adding water, concentrating to remove an organic phase, adding water, and extracting with chloroform. The organic phases were combined and concentrated. Recrystallizing in alcohol solvent to obtain target compound androstane-4,16-diene-3-ketone; the weight ratio of the cyclohexanone to the deiodinated substance 3 is 1.0 to 10.0, and the weight ratio of the aluminum isopropoxide to the deiodinated substance 3 is 0.5 to 5.
Further, the weight ratio of the cyclohexanone to the deiodinate 3 is 3.0 to 3.5 w/w. The weight ratio of the aluminum isopropoxide to the deiodinated substance 3 is 0.6 to 0.8 w/w, and the reaction temperature is reflux temperature 130 o C。
Further, the weight ratio of the cyclohexanone to the deiodinated substance 3 is 3.2 to 3.4 w/w. The weight ratio of the aluminum isopropoxide to the deiodinated substance 3 is 0.6 to 0.7 w/w, the weight volume ratio of the toluene to the deiodinated substance 3 is 14 to 16, and the alcohol solvent is methanol.
The method for synthesizing androstane-4,16-diene-3-ketone provided by the invention also takes DHEA as a raw material, and performs condensation reaction with hydrazine hydrate to form a hydrazone compound 4, then forms alkenyl iodide 5 under the action of iodine, and then carries out catalytic deiodination by tetrakis (triphenylphosphine) palladium to obtain a deiodinate 3. The deiodinated substance 3 is oxidized to obtain the target compound androstane-4,16-diene-3-ketone. Although the route has 4 steps, the overall molar yield of the route is as high as 72%, and the hazardous reagent n-butyllithium is avoided. The process cost is reduced, the safety of the process is greatly improved, and the method is more favorable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
The synthesis methods described in examples 1 to 4 are shown by the following formula,
example 1 condensation reaction:
100g of DHEA is dissolved in 1L of methanol, 30g of hydrazine hydrate is added, and aqueous hydrazine sulfate solution (6 g of hydrazine hydrate dissolved in 30mL of water) is added to react and stir for 24 hours at room temperature (20 ℃ -25 ℃). After the reaction, the reaction mixture was poured into 4L of water to precipitate a white solid. Filtration and water washing, collection of the solid and drying gave 102.8g of hydrazone compound 4 in 98% molar yield.
Example 2 alkenyliodination:
100g of the hydrazone compound 4 prepared in example 2 was dissolved in 1L of tetrahydrofuran, 36.5g of triethylamine was added, 150g of 1, 3-tetramethylguanidine was added, 155g of iodine was added in portions, and the mixture was stirred at room temperature for 1 hour to complete the reaction, and the reaction solution was poured into 4L of a 10% aqueous solution of sodium sulfite to precipitate a solid, which was then filtered, washed with water, and dried to obtain 125.1g of alkenyl iodide 5 with a molar yield of 95%.
Example 3 deiodination reaction:
500 mL of DMSO, 50g of alkenyl iodide 5 prepared in example 3, 4.29 g of paraformaldehyde, 66.4 g of cesium carbonate are added to a reaction flask, 1.57 g of tetrakis (triphenylphosphine) palladium is added under nitrogen protection, the reaction is carried out at 110-115 ℃ for 11 hours, TLC shows completion of the reaction, and the reaction is cooled to room temperature. 500 mL water and 300mL dichloromethane were added, stirred, separated, extracted twice with 300mL dichloromethane, combined dichloromethane, washed with 300mL water, washed with 150mL saturated brine, and concentrated to give 31.6g of deiodinated 3 as a white solid in 93% molar yield.
Example 4 oxidation reaction:
20 g deiodinated 3 prepared in example 3, 66.0g cyclohexanone and 300mL toluene were refluxed at 130 deg.C for 1 hour, 12 g aluminum isopropoxide was added and the reaction was continued under reflux for 21 hours, TLC showed completion. After cooling, 100 mL water was added, the organic phase was concentrated off, 100 mL water was added and extracted four times with chloroform, 100 mL each time. The organic phases are combined, concentrated and pulped by 40mL of methanol to obtain 16.6 g white crystal androstane-4,16-diene-3-ketone with the molar yield of 83 percent.
Claims (9)
1. A method for synthesizing androstane-4,16 diene-3-ketone is characterized by comprising the following steps:
1) Condensation reaction
Dissolving DHEA in a solvent, adding hydrazine hydrate, adding a hydrazine sulfate aqueous solution, reacting completely at 0-50 ℃, pouring a reaction solution into water after the reaction is finished, separating out a white solid, filtering, washing with water, collecting the solid, and drying to obtain a hydrazone compound 4; the solvent is selected from methanol, ethanol, isopropanol, ethylene glycol, acetone, tetrahydrofuran, dioxane, DMF and DMSO, the weight ratio of hydrazine hydrate to DHEA is 0.24-2.45, the weight ratio of hydrazine sulfate to DHEA is 0.05-0.50, and the weight percentage concentration of the aqueous solution of hydrazine sulfate is 15-30%;
2) Iodination of alkenyl groups
Dissolving a hydrazone compound 4 in a solvent, adding alkali, adding 1,1,3,3-tetramethylguanidine, adding iodine in batches, stirring at 0-50 ℃ until the reaction is complete, pouring a reaction solution into a sodium sulfite aqueous solution, separating out a solid, filtering, washing with water, and drying to obtain an alkenyl iodide 5; the solvent is selected from tetrahydrofuran and dioxane, the base is selected from triethylamine, N-diisopropylethylamine, DBU, potassium carbonate and sodium carbonate, the weight ratio of 1,1,3,3-tetramethylguanidine to the hydrazone compound 4 is 1.0 to 3.0, and the weight ratio of iodine to the hydrazone compound 4 is 1.0 to 2.0;
3) Deiodination reaction
Adding alkenyl iodide 5, paraformaldehyde and cesium carbonate into DMSO (dimethylsulfoxide), adding palladium tetrakis (triphenylphosphine) under the protection of inert gas, reacting completely at 80-120 ℃, cooling to 25 ℃, adding water and dichloromethane, stirring, separating, extracting a water phase with dichloromethane, combining dichloromethane phases, washing the dichloromethane phases with water, and concentrating to obtain a deiodinated substance 3; the dosage ratio of the paraformaldehyde to the alkenyl iodide 5 is 0.05-1, the dosage ratio of the cesium carbonate to the alkenyl iodide 5 is 0.5-5, and the dosage ratio of the tetrakis (triphenylphosphine) palladium to the alkenyl iodide 5 is 0.01-0.05;
4) Oxidation reaction
Dissolving the deiodinated substance 3 in toluene, adding cyclohexanone, carrying out reflux reaction at room temperature, adding aluminum isopropoxide, carrying out reflux reaction until the reaction is complete, cooling, adding water, concentrating to remove an organic phase, adding water, extracting with chloroform, combining the organic phases, concentrating, and recrystallizing in an alcohol solvent to obtain a target compound androstane-4,16-diene-3-ketone; the weight ratio of the cyclohexanone to the deiodinated substance 3 is 1.0-10.0, and the weight ratio of the aluminum isopropoxide to the deiodinated substance 3 is 0.5-5.
2. The method for synthesizing androstane-4,16 diene-3-one as claimed in claim 1, wherein in step 1), the solvent is methanol, the volume-to-weight ratio of methanol to DHEA is 8 to 15, the reaction temperature is preferably 20 to 25 ℃, the weight ratio of hydrazine hydrate to DHEA is 0.25 to 0.50, and the weight ratio of hydrazine sulfate to DHEA is 0.05 to 0.10.
3. The method for synthesizing androstane-4,16 diene-3-one as claimed in claim 2, wherein in step 1), the volume-to-weight ratio of methanol to DHEA is 9 to 11, and the weight ratio of hydrazine hydrate to DHEA is 0.28 to 0.32 w/w, and the weight ratio of hydrazine sulfate to DHEA is 0.05 to 0.07.
4. The method for synthesizing androstane-4,16 diene-3-one as claimed in claim 1, wherein in the step 2), the agent is tetrahydrofuran, the volume-to-weight ratio of tetrahydrofuran to hydrazone compound 4 is 8 to 15, the base is triethylamine, the weight ratio of triethylamine to hydrazone compound 4 is 0.3 to 0.4, the weight ratio of 1,1,3,3-tetramethylguanidine to hydrazone compound 4 is 1.4 to 2.0, the dosage ratio of iodine to hydrazone compound 4 is 1.5 to 1.8, and the reaction temperature is 15 to 30 ℃.
5. The method for synthesizing androstane-4,16 diene-3-one as in claim 4, wherein in the step 2), the volume to weight ratio of tetrahydrofuran to hydrazone compound 4 is 9 to 11, the weight ratio of triethylamine to hydrazone compound 4 is 0.35 to 0.39, the weight ratio of 1, 3-tetramethylguanidine to hydrazone compound 4 is 1.4 to 1.6, the use amount ratio of iodine to hydrazone compound 4 is 1.5 to 1.7, the reaction temperature is 20 to 25 ℃, and the weight percentage concentration of the sodium sulfite aqueous solution is 9 to 11 percent.
6. The method for synthesizing androstane-4,16 diene-3-one as claimed in claim 1, wherein in step 3), the dosage ratio of paraformaldehyde to alkenyl iodide 5 is 0.08 to 1, the dosage ratio of cesium carbonate to alkenyl iodide 5 is 1.2 to 1.4, the dosage ratio of tetrakis (triphenylphosphine) palladium to alkenyl iodide 5 is 0.03 to 0.04, and the reaction temperature is 100 ℃ to 120 ℃.
7. The method for synthesizing androstane-4,16 diene-3-one as claimed in claim 6, wherein in step 3), the dosage ratio of paraformaldehyde to alkenyl iodide 5 is 0.08 to 0.09, the dosage ratio of cesium carbonate to alkenyl iodide 5 is 1.30 to 1.35, the dosage ratio of tetrakis (triphenylphosphine) palladium to alkenyl iodide 5 is 0.030 to 0.033, and the reaction temperature is 110 ℃ to 115 ℃.
8. The method for synthesizing androstane-4,16 diene-3-one according to claim 1, wherein in the step 4), the weight ratio of cyclohexanone to deiodinate 3 is 3.0 to 3.5, the weight ratio of aluminum isopropoxide to deiodinate 3 is 0.6 to 0.8, and the reaction temperature is reflux temperature 130 o C。
9. The method for synthesizing androstane-4,16 diene-3-one according to claim 8, wherein in step 4), the weight ratio of cyclohexanone to deiodinate 3 is 3.2 to 3.4, the weight ratio of aluminum isopropoxide to deiodinate 3 is 0.6 to 0.7, the weight/volume ratio of toluene to deiodinate 3 is 14 to 16, and the alcohol solvent is methanol.
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