CN110790808A - Preparation method of 5, 7-pregnadiene-3, 20-diketone-diethylketal - Google Patents
Preparation method of 5, 7-pregnadiene-3, 20-diketone-diethylketal Download PDFInfo
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- CN110790808A CN110790808A CN201911136017.9A CN201911136017A CN110790808A CN 110790808 A CN110790808 A CN 110790808A CN 201911136017 A CN201911136017 A CN 201911136017A CN 110790808 A CN110790808 A CN 110790808A
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- pregnadiene
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- dione
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- 238000002360 preparation method Methods 0.000 title abstract description 20
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound 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 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 30
- JGMOKGBVKVMRFX-LEKSSAKUSA-N (8s,9s,10r,13s,14s,17s)-17-acetyl-10,13-dimethyl-1,2,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 JGMOKGBVKVMRFX-LEKSSAKUSA-N 0.000 claims abstract description 29
- 238000006266 etherification reaction Methods 0.000 claims abstract description 29
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 25
- 239000000186 progesterone Substances 0.000 claims abstract description 23
- 229960003387 progesterone Drugs 0.000 claims abstract description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 5
- NMDKUAWLGSFOCR-LYCSZFELSA-N 1-[(9S,10R,13S,14R,17S)-3,3-diethoxy-10,13-dimethyl-1,2,4,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]ethanone Chemical compound CCOC1(CC[C@]2(C)[C@H]3CC[C@]4(C)[C@H](CC[C@H]4C3=CC=C2C1)C(C)=O)OCC NMDKUAWLGSFOCR-LYCSZFELSA-N 0.000 claims description 30
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 20
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 20
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 16
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 10
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 claims description 9
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 8
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 7
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 16
- 239000012535 impurity Substances 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- -1 methyl ether compound Chemical class 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- UQCWXKSHRQJGPH-UHFFFAOYSA-M tetrabutylazanium;fluoride;hydrate Chemical compound O.[F-].CCCC[N+](CCCC)(CCCC)CCCC UQCWXKSHRQJGPH-UHFFFAOYSA-M 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 1
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 1
- 238000006882 Shapiro reaction Methods 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
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 preparation method of 5, 7-pregnadiene-3, 20-diketone-diethylketal, which comprises the following steps: under the action of a catalyst, progesterone and an etherification reagent generate an etherified substance through etherification reaction; the etherate and a dehydrogenation reagent generate 6-dehydroprogesterone through dehydrogenation reaction; the 6-dehydroprogesterone and ethylene glycol react to generate 5, 7-pregnadiene-3, 20-diketone-diethylketal through ketal under the action of a catalyst and a dehydrating agent. The invention can obtain 5, 7-pregnadiene-3, 20-diketone-diethylketal with less impurities through etherification, dehydrogenation and ketal reaction, has the advantages of short route, high yield, low raw material cost, simple operation and environmental protection, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of 5, 7-pregnadiene-3, 20-diketone-diethylketal.
Background
Dehydroprogesterone is a synthetic progestogen which, compared to naturally occurring progesterone (progesterone), has a trans-configuration and thus is abnormally stable during digestion, absorption and metabolism, and has very high oral activity, studies have found that steroids having the structure 9 β, 10a have a significant physiological effect compared to steroids having the structure 9a, 10 β, with double bonds between the carbon atoms 6 and 7, which has the two advantages of (1) increased metabolic stability for oral activity and (2) no side effects of androgens, estrogens and corticosteroids.
The 5, 7-pregnadiene-3, 20-diketone-diethylketal (compound III) is a key intermediate for synthesizing dehydroprogesterone, and the structural formula is as follows:
in the Journal of Organic Chemistry (1952),17, 1369-:
US patent No. 4464298 improves the above synthesis method by replacing NBS with dibromohydantoin, and the bromo product is isomerized with lithium bromide to convert most of the a-bromo product to β -bromo product, increasing the yield of the bromination reaction, and then debrominating with tetrabutylammonium fluoride monohydrate to obtain compound iii, the improved yield is greatly increased to 67.5% (purity 90%), tetrabutylammonium fluoride used in this route is monohydrate, which contains three crystal waters, and tetrabutylammonium fluoride trihydrate needs to be changed into tetrabutylammonium fluoride monohydrate by lyophilization, which greatly increases the production cost.
Chinese patent CN103314004 reports that progesterone is used as a starting material, two carbonyl groups are protected by ethylene glycol condensation, allyl position is selectively oxidized to obtain a 7-ketone compound, the 7-ketone compound reacts with p-toluenesulfonyl hydrazide to obtain hydrazone, and the compound III is obtained by removing hydrazone through Shapiro reaction. However, the method selectively performs allylic oxidation to prepare 7-ketone, generates more impurities and has low yield, so the method has little industrial significance. The synthetic route is as follows:
disclosure of Invention
In view of the above, the present invention provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, so as to solve the technical problems of more impurities, high production cost and great environmental pollution.
In view of the above objects, the present invention provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, comprising:
under the action of a catalyst, progesterone and an etherification reagent generate an etherified substance through etherification reaction;
the etherate and a dehydrogenation reagent generate 6-dehydroprogesterone through dehydrogenation reaction;
under the action of a catalyst and a dehydrating agent, the 6-dehydroprogesterone and ethylene glycol react through ketal to generate 5, 7-pregnadiene-3, 20-diketone-diethylketal;
wherein the structural formula of the etherate is shown in the specification
In some embodiments of the invention, the etherification agent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate; the mass ratio of the etherification reagent to the progesterone is 0.3-1: 1.
In some embodiments of the present invention, the etherification reaction uses a catalyst selected from one of p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride, and pyridine hydrobromide; the mass ratio of the catalyst to the progesterone is no more than 3%.
In some embodiments of the present invention, the etherification reaction is performed at a temperature of 0 to 30 ℃ for 1 to 6 hours.
In some embodiments of the present invention, the dehydrogenation reagent is selected from one of chloranil and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone, and the mass ratio of the dehydrogenation reagent to the etherate is 0.3-2: 1.
In some embodiments of the present invention, the dehydrogenation reaction is performed at a temperature of 10 to 50 ℃ for 2 to 6 hours.
In some embodiments of the invention, the ketal reaction catalyst is selected from one of p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride, pyridine hydrobromide; the mass ratio of the catalyst to the 6-dehydroprogesterone is no more than 5%.
In some embodiments of the invention, the dehydrating agent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate.
In some embodiments of the invention, the mass ratio of the dehydrating agent to the 6-dehydroprogesterone is 0.5-2: 1.
In some embodiments of the present invention, the ketal reaction is performed at a temperature of 20 to 80 ℃ for 1 to 6 hours.
From the above, it can be seen that the preparation method of 5, 7-pregnadiene-3, 20-dione-diethyldiketal provided by the embodiment of the invention can obtain 5, 7-pregnadiene-3, 20-dione-diethyldiketal with less impurities through etherification, dehydrogenation and ketal reaction, has the advantages of short route, high yield, low raw material cost, simple operation and environmental protection, and is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below.
It is to be noted that technical terms or scientific terms used in the embodiments of the present invention should have the ordinary meanings as understood by those having ordinary skill in the art to which the present disclosure belongs, unless otherwise defined. The use of "first," "second," and similar terms in this disclosure is not intended to indicate any order, quantity, or importance, but rather is used to distinguish one element from another.
The embodiment of the invention provides a preparation method of 5, 7-pregnadiene-3, 20-diketone-diethylketal, which comprises the following steps: under the action of a catalyst, progesterone and an etherification reagent generate an etherified substance through etherification reaction; the etherate and a dehydrogenation reagent generate 6-dehydroprogesterone through dehydrogenation reaction; the 6-dehydroprogesterone and ethylene glycol react to generate 5, 7-pregnadiene-3, 20-diketone-diethylketal (compound III) through ketal under the action of a catalyst and a dehydrating agent.
The reaction route is as follows:
wherein R is CH3Or C2H5。
According to the embodiment of the invention, the 5, 7-pregnadiene-3, 20-diketone-diethylketal with less impurities can be obtained through etherification, dehydrogenation and ketal reaction, and the method has the advantages of short route, high yield, low raw material cost, simplicity in operation and environmental friendliness, and is suitable for industrial production. The etherification reaction of the invention can selectively carry out 3-position etherification by controlling the reaction conditions, no 20-position etherification product is observed, the reaction impurities are less, and the yield is high. The dehydrogenation reaction only takes place 6,7 bit dehydrogenation, no 1,2 bit dehydrogenation product is observed, reaction impurities are few, and the yield is high by controlling the reaction conditions. And (3) ketal reaction, namely protecting the 3 and 20-site diketone by controlling reaction conditions, and obtaining the 5, 7-pregnadiene-3, 20-diketone-diethylketal with less impurity.
Optionally, the etherification reagent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate; trimethyl orthoformate and trimethyl orthoacetate are preferred. The mass ratio of the etherification reagent to the progesterone is 0.3-1: 1. Alternatively, the etherification reaction may be carried out in an alcoholic organic solvent, preferably methanol or ethanol.
Optionally, the catalyst used in the etherification reaction is selected from one of p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride and pyridine hydrobromide; p-toluenesulfonic acid and pyridine hydrochloride are preferred. The mass ratio of the catalyst to the progesterone is no more than 3%. Optionally, the reaction temperature of the etherification reaction is 0-30 ℃, and the reaction time is 1-6 hours.
Optionally, the dehydrogenation reagent is selected from one of chloranil and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone, and chloranil is preferred. The mass ratio of the dehydrogenation reagent to the etherate is 0.3-2: 1. Alternatively, the dehydrogenation reaction may be carried out in a ketone-based organic solvent, preferably one of acetone and butanone. Optionally, the reaction temperature of the dehydrogenation reaction is 10-50 ℃, and the reaction time is 2-6 hours.
Optionally, the ketal reaction catalyst is selected from one of p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride and pyridine hydrobromide; p-toluenesulfonic acid and pyridine hydrochloride are preferred. Optionally, the mass ratio of the catalyst to the 6-dehydroprogesterone is no more than 5%.
Optionally, the dehydrating agent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate, preferably trimethyl orthoformate and triethyl orthoformate. Optionally, the mass ratio of the dehydrating agent to the 6-dehydroprogesterone is 0.5-2: 1.
Optionally, the reaction temperature of the ketal reaction is 20-80 ℃, and the reaction time is 1-6 hours.
To aid in understanding the protocol of the present invention, several specific preparative procedures are set forth below. The various chemicals and reagents used in the examples were all commercially available unless otherwise specified.
Example 1:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which comprises the following steps:
step (1) etherification reaction
Adding 300ml of anhydrous methanol, 50g of progesterone and 30g of trimethyl orthoformate into a three-necked bottle, cooling to 0-5 ℃, adding 0.5g of p-toluenesulfonic acid, and reacting for 5-6 hours under the condition of heat preservation. TLC tracing reaction, after the reaction is finished, adding 1g of triethylamine, filtering, washing a filter cake with a small amount of methanol to obtain a methyl ether compound, wherein the wet weight is 69 g. Purity 98.2% (HPLC).
Step (2) dehydrogenation (preparation of 6-dehydroprogesterone)
300ml of acetone and 50ml of water, 45g of the methyl ether compound prepared in the example 1 and 45g of tetrachlorobenzoquinone are added into a three-neck flask, nitrogen is introduced to discharge air, and the temperature is raised to 40-45 ℃ for reaction for 3 hours. TLC detection raw material reaction is complete, poured into 1000ml water for water precipitation, filtered, washed and dried to obtain white solid 6-dehydroxanthone 46 g. The yield of 6-dehydroprogesterone prepared from progesterone is 92.6%, and the purity is 97.6%.
Step (3) ketal reaction
Adding 20g of 6-dehydroprogesterone, 80ml of ethylene glycol and 22ml of trimethyl orthoformate into a three-necked bottle, introducing nitrogen to exhaust air, adding 0.8g of p-toluenesulfonic acid, heating to 60-65 ℃ for reacting for 6 hours, detecting by TLC that raw materials are completely reacted, adding 1.5g of triethylamine, cooling to room temperature for crystallization for 2 hours, filtering, and washing a filter cake with a small amount of methanol to obtain a crude product of 5, 7-pregnadiene-3, 20-dione-diethylketal. Recrystallization was carried out with methanol to obtain 18.6g of a pale yellow compound, 5, 7-pregnadiene-3, 20-dione-diethylketal. Yield 72.5% and purity 97.1% (HPLC).
Example 2:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (1), 400ml of absolute ethyl alcohol, 50g of progesterone and 40g of triethyl orthoformate are added into a three-necked bottle, the temperature is reduced to 3-8 ℃, 1g of p-toluenesulfonic acid is added, and the reaction is carried out for 3-4 hours under the condition of heat preservation. TLC tracing reaction, after the reaction is finished, adding 2g of triethylamine, filtering, washing a filter cake with a small amount of ethanol to obtain an ether compound, wherein the wet weight is 73 g. Purity 97.5% (HPLC).
Example 3:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (1), 350ml of anhydrous methanol, 40g of progesterone and 40g of trimethyl orthoacetate are added into a three-necked bottle, the temperature is reduced to 10-15 ℃, 1g of perchloric acid is added, and the heat preservation reaction is carried out for 5-6 hours. TLC tracking reaction, after the reaction is finished, adding 2g of triethylamine, filtering, washing a filter cake with a small amount of methanol to obtain a methyl ether compound, wherein the wet weight is 57 g. Purity 97.9% (HPLC).
Example 4:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (1), 400ml of absolute ethyl alcohol, 45g of progesterone and 40g of triethyl orthoacetate are added into a three-necked bottle, the temperature is reduced to 1-6 ℃, 0.5g of pyridine hydrochloride is added, and the reaction is carried out for 1-2 hours under the condition of heat preservation. TLC tracing reaction, after the reaction is finished, adding 2g of triethylamine, filtering, washing a filter cake with a small amount of ethanol to obtain an ether compound, wherein the wet weight is 66 g. Purity 97.7% (HPLC).
Example 5:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (1), 380ml of absolute ethyl alcohol, 55g of progesterone and 35g of triethyl orthoacetate are added into a three-necked bottle, the temperature is reduced to 8-13 ℃, 1g of pyridine hydrobromide is added, and the reaction is carried out for 3-4 hours under the condition of heat preservation. And tracking the reaction by TLC, adding 2g of triethylamine after the reaction is finished, filtering, and washing a filter cake by using a small amount of ethanol to obtain an ether compound with the wet weight of 75 g. Purity 97.2% (HPLC).
Example 6:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (2), 200ml of butanone, 50ml of water, the ether compound prepared in the example 2 and 40g of chloranil are added into a three-necked bottle, nitrogen is introduced into the three-necked bottle to exhaust air, and the temperature is raised to 30-35 ℃ for reaction for 4 hours. TLC detects that the raw material completely reacts, and the raw material is poured into 1000ml of water for water precipitation, filtered, washed and dried to obtain 47.6g of white-like solid 6-dehydroprogesterone. The yield of 6-dehydroprogesterone prepared from progesterone is 95.8%, and the purity is 96.1%.
Example 7:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (2), 350ml of acetone, 60ml of water, 36g of the ether compound prepared in the example 2 and 36g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone are added into a three-necked bottle, nitrogen is introduced into the bottle to exhaust air, and the temperature is raised to 45-50 ℃ for reaction for 1.5 hours. TLC detection raw material reaction is complete, pouring into 1000ml water for water precipitation, filtering, water washing and drying to obtain white solid 6-dehydroprogesterone 40.2 g. The yield of 6-dehydroprogesterone prepared from progesterone is 80.9%, and the purity is 95.2%.
Example 8:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (2), 400ml of butanone and 40ml of water, the methyl ether compound prepared in the example 1 and 44g of chloranil are added into a three-necked bottle, nitrogen is introduced into the three-necked bottle to exhaust air, and the temperature is raised to 20-30 ℃ for reaction for 5 hours. TLC detects that the raw material completely reacts, and the raw material is poured into 1000ml of water for elutriation, filtered, washed and dried to obtain 45.4g of white-like solid 6-dehydroprogesterone. The yield of 6-dehydroprogesterone prepared from progesterone is 91.4%, and the purity is 97.1%.
Example 9:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (2), 200ml of butanone and 50ml of water, 42g of the dimethyl ether compound prepared in the example 3 and 42g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone are added into a three-necked bottle, nitrogen is introduced into the three-necked bottle to exhaust air, and the temperature is raised to 38-43 ℃ for reaction for 3 hours. TLC detection raw material reaction is complete, pouring into 1000ml water for water precipitation, filtering, water washing and drying to obtain white solid 6-dehydroprogesterone 34.1 g. The yield of 6-dehydroprogesterone prepared from progesterone is 85.8%, and the purity is 95.6%.
Example 10:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (3), 40g of 6-dehydroprogesterone, 200ml of ethylene glycol and 70ml of triethyl orthoformate are added into a three-necked bottle, nitrogen is introduced to exhaust air, 1.2g of p-toluenesulfonic acid is added, the temperature is increased to 65-70 ℃ for reaction for 5 hours, TLC is used for detecting that raw materials are completely reacted, 2g of triethylamine is added, the mixture is cooled to room temperature for crystallization for 2 hours, the mixture is filtered, and a filter cake is washed by a small amount of methanol to obtain a crude product of 5, 7-pregnadiene-3, 20-dione-diethyl ketal. Recrystallization from methanol gave 38.4g of the pale yellow compound 5, 7-pregnadiene-3, 20-dione-diethylketal. Yield 74.9% and purity 97.8% (HPLC).
Example 11:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (3), 35g of 6-dehydroprogesterone, 120ml of ethylene glycol and 50ml of trimethyl orthoacetate are added into a three-necked bottle, nitrogen is introduced to exhaust air, 1.3g of perchloric acid is added, the temperature is raised to 33-45 ℃ for reaction for 6 hours, TLC is used for detecting that raw materials are completely reacted, 2g of triethylamine is added, the mixture is cooled to room temperature for crystallization for 2 hours, the mixture is filtered, and a filter cake is washed by a small amount of methanol to obtain a crude product of 5, 7-pregnadiene-3, 20-dione-diethyl ketal. Recrystallization from methanol gave 25.4g of the pale yellow compound 5, 7-pregnadiene-3, 20-dione-diethylketal. The yield was 56.6% and the purity 98.3% (HPLC).
Example 12:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (3), 25g of 6-dehydroprogesterone, 100ml of ethylene glycol and 60ml of triethyl orthoformate are added into a three-necked bottle, nitrogen is introduced to exhaust air, 1.4g of pyridine hydrochloride is added, the temperature is raised to 75-80 ℃ for reaction for 2 hours, TLC is used for detecting that raw materials are completely reacted, 2.2g of triethylamine is added, the mixture is cooled to room temperature for crystallization for 2 hours, the mixture is filtered, and a filter cake is washed by a small amount of methanol to obtain a crude product of 5, 7-pregnadiene-3, 20-dione-diethyl ketal. Recrystallization from methanol gave 22.5g of the pale yellow compound 5, 7-pregnadiene-3, 20-dione-diethylketal. Yield 70.2% and purity 97.9% (HPLC).
Example 13:
this example provides a method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal, which differs from the preparation method of example 1 in that: in the step (3), 36g of 6-dehydroprogesterone, 150ml of ethylene glycol and 40ml of triethyl orthoacetate are added into a three-necked bottle, nitrogen is introduced to exhaust air, 1.7g of pyridine hydrobromide is added, the temperature is increased to 72-78 ℃ to react for 4 hours, TLC is used for detecting that the raw materials completely react, 1.7g of triethylamine is added, the mixture is cooled to room temperature to crystallize for 2 hours, the obtained product is filtered, and a filter cake is washed by a small amount of methanol to obtain a crude product of the compound III. Recrystallization from methanol gave 32.6g of the pale yellow compound 5, 7-pregnadiene-3, 20-dione-diethylketal. The yield was 70.6% and the purity 97.0% (HPLC).
The preparation method of the 5, 7-pregnadiene-3, 20-dione-diethyldiketal provided by the embodiment of the invention can obtain the 5, 7-pregnadiene-3, 20-dione-diethyldiketal with less impurities through etherification, dehydrogenation and ketal reaction, has the advantages of short route, high yield, low raw material cost, simple operation and environmental protection, and is suitable for industrial production.
Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the idea of the invention, also technical features in the above embodiments or in different embodiments may be combined, steps may be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
The present embodiments are intended to embrace all such alterations, modifications and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, substitutions, improvements and the like that may be made without departing from the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal is characterized by comprising the following steps:
under the action of a catalyst, progesterone and an etherification reagent generate an etherified substance through etherification reaction;
the etherate and a dehydrogenating agent generate 6-dehydroprogesterone through dehydrogenation reaction;
the 6-dehydroprogesterone and ethylene glycol react through ketal under the action of a catalyst and a dehydrating agent to generate 5, 7-pregnadiene-3, 20-diketone-diethylketal;
wherein the structural formula of the etherate is shown in the specification
2. The method for preparing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the etherification agent is one selected from trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate; the mass ratio of the etherification reagent to the progesterone is 0.3-1: 1.
3. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the etherification reaction is carried out using a catalyst selected from the group consisting of p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride and pyridine hydrobromide; the mass ratio of the catalyst to the progesterone is no more than 3%.
4. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the etherification reaction is carried out at a reaction temperature of 0 to 30 ℃ for 1 to 6 hours.
5. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the dehydrogenation reagent is one selected from tetrachlorobenzoquinone and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone, and the mass ratio of the dehydrogenation reagent to the etherate is 0.3 to 2: 1.
6. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the dehydrogenation reaction is carried out at a temperature of 10 to 50 ℃ for 2 to 6 hours.
7. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the ketal reaction catalyst is one selected from the group consisting of p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride and pyridine hydrobromide; the mass ratio of the catalyst to the 6-dehydroprogesterone is no more than 5%.
8. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 1, wherein the dehydrating agent is one selected from trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate.
9. The method for producing 5, 7-pregnadiene-3, 20-dione-diethylketal according to claim 8, wherein the mass ratio of the dehydrating agent to the 6-dehydroprogesterone is 0.5 to 2: 1.
10. The method of claim 1, wherein the reaction temperature of the ketal reaction is 20 to 80 ℃ and the reaction time is 1 to 6 hours.
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