CN114276406B - Preparation method of intermediate of deoxomilpine - Google Patents
Preparation method of intermediate of deoxomilpine Download PDFInfo
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- CN114276406B CN114276406B CN202210009721.3A CN202210009721A CN114276406B CN 114276406 B CN114276406 B CN 114276406B CN 202210009721 A CN202210009721 A CN 202210009721A CN 114276406 B CN114276406 B CN 114276406B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000007069 methylation reaction Methods 0.000 claims abstract description 5
- 230000011987 methylation Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 150000007529 inorganic bases Chemical class 0.000 claims description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 10
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 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 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- -1 copper halide Chemical class 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 5
- 239000010949 copper Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 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
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- UFEOMHFPJREVTP-PTRHGPIFSA-N [2-[(8s,10s,13s,14s)-10,13-dimethyl-3-oxo-6,7,8,12,14,15-hexahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound O=C1C=C[C@]2(C)C3=CC[C@]4(C)C(C(=O)COC(=O)C)=CC[C@H]4[C@@H]3CCC2=C1 UFEOMHFPJREVTP-PTRHGPIFSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 238000011010 flushing procedure Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 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
- 238000001556 precipitation Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 8
- 238000001311 chemical methods and process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical group F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- VHHPDZDTKZOHTB-UHFFFAOYSA-M [Br-].[Mg+]C.C1CCOC1 Chemical compound [Br-].[Mg+]C.C1CCOC1 VHHPDZDTKZOHTB-UHFFFAOYSA-M 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of a desoxymilsone intermediate, which adopts 21-hydroxy pregna-1, 4,9 (11), 16-tetraene-3, 20-diketone-21-acetate as a starting material, and sequentially carries out bromohydroxylation, epoxidation, methylation and hydrolysis reaction to obtain the desoxymilsone intermediate 9 beta, 11 beta-epoxy-21-hydroxy-16 alpha-methyl progesterone-1, 4-diene-3, 20-diketone. The preparation process route provided by the invention has fewer reaction steps, the quality and the yield of the product have obvious competitiveness, and the preparation process route does not involve dangerous chemical processes, is green and clean, and improves the atom economy; the preparation process has wide industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and pharmaceutical chemistry, and particularly relates to a preparation method of a deoxomipsone intermediate.
Background
Dermosin is a very useful class of glucocorticoid drugs, belonging to the class of topical corticosteroids, mainly used for the treatment of skin disorders. Deoxymethylene was originally developed by the Loose company (Roussel). The main synthetic literature is shown in U.S. patent No. 3099654A1, and the synthesis method is to use 16 alpha-methyl-11 alpha, 21-dihydroxyl-1, 4-pregnene-3, 20-dione-21-acetate as a starting material, and to obtain the desoxymilpine through six steps of transformation at positions 9, 11 and 21, wherein the whole synthetic route is longer, the yield from the starting material to the final product is about 28%, and the starting material is not easy to obtain.
Chinese patent CN101397322a discloses a process for preparing deoxolol, which uses 1,4,9, 16-tetraene-pregna-3, 20-dione (CN 1896090) as starting material, and obtains deoxolol and its 21-position esterified product by 16, 17-grignard, 9, 11-position and 21-position modification.
However, the existing preparation techniques including the above patents still have long reaction routes and unsatisfactory product yields.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a deoxomipsone intermediate, which uses low price of initial raw materials, has few reaction steps and simple synthesis line; the intermediate of the deoxomilpine prepared by the method can be conveniently obtained after the intermediate is synthesized by hydrofluoric acid ring opening, and the production cost and the product yield are superior to those of the prior art.
The invention adopts the following technical scheme:
the preparation method of the intermediate of the deoxomipsone adopts a compound I shown in the following formula as a raw material, wherein the compound I is 21-hydroxy pregna-1, 4,9 (11), 16-tetraene-3, 20-dione-21-acetate, and the compound IV is 9 beta, 11 beta-epoxy-21-hydroxy-16 alpha-methyl progesterone-1, 4-diene-3, 20-dione through bromohydroxylation, epoxidation, methylation and hydrolysis reaction in sequence, and the reaction formula is as follows:
wherein the reaction steps are as follows:
s1 bromohydroxylation and epoxidation reaction:
dissolving 1 part by weight of compound I in 10-20 parts by volume of acetone, adding 0.1-0.4 part by volume of acid water to adjust to an acidic environment, adding 0.5-1.2 parts by weight of brominating reagent, adding alkaline water after the reaction is finished, performing epoxidation reaction in an alkaline environment, adding water to separate out materials after the reaction is finished, filtering, and drying to obtain compound II.
S2 methylation reaction:
under the protection of nitrogen, 1 part by weight of compound II is taken and dissolved in 9-10.5 parts by volume of tetrahydrofuran, 0.09-0.11 part by weight of copper halide is added, stirring is carried out, 3.5-5 parts by volume of format reagent is added dropwise, and the compound III solution is obtained after the reaction is completed.
S3, hydrolysis reaction:
and (3) adding 0.15-0.2 part by volume of glacial acetic acid into the solution of the compound III prepared in the step (S2) under the protection of nitrogen, regulating the pH to 6-7, dropwise adding an inorganic base/methanol solution, flushing 20-30 parts by volume of water after the reaction is finished, and obtaining the compound IV after water separation, filtration, decolorization and drying.
It is further preferred that the composition of the present invention,
in the step S1, the concentration of acid water is 10%, wherein the acid is one or more of formic acid, acetic acid, perchloric acid and periodic acid; the brominating reagent is NBS or dibromohydantoin; the concentration of the alkaline water is 40%, wherein the alkaline water is one or more of sodium carbonate, potassium carbonate and sodium hydroxide.
In the step S2, tetrahydrofuran is anhydrous tetrahydrofuran; the copper halide is one or more of cuprous chloride, cupric bromide and cupric iodide; the formative reagent is one or more of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide.
In the step S3, the preparation method of the inorganic base/methanol solution comprises the following steps: under the protection of nitrogen, adding 0.43-0.5 part by weight of inorganic base into 3.25-3.75 parts by volume of methanol, and stirring to obtain an inorganic base/methanol solution; wherein the inorganic base is sodium hydroxide, potassium hydroxide or a mixture of the two.
The beneficial effects of the invention are as follows:
1. the 21-hydroxy pregna-1, 4,9 (11), 16-tetraene-3, 20-diketone-21-acetate is adopted as a starting material, and the material is derived from microbial fermentation, so that the cost is low, the goods source is stable, and the control and the production cost reduction are facilitated;
2. the intermediate of the deoxomipsone prepared by the method can conveniently obtain the deoxomipsone after the ring-opening synthesis of hydrofluoric acid, and the production cost and the product yield are superior to those of the prior art;
3. the intermediate of the deoxomilpine prepared by the method can be used as a preparation starting material of high-end steroids such as flucorulon, bifluoro-corulon and the like, is favorable for realizing industrial production of corresponding steroid products, and has great economic value.
Drawings
FIG. 1 is a liquid chromatogram of Compound II in example 1 of the present invention;
FIG. 2 is a liquid chromatogram of Compound IV in example 3 of the invention;
FIG. 3 is a liquid chromatogram of Compound IV in example 3 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments.
EXAMPLE 1 preparation of Compound II
50g of Compound I (21-hydroxy pregna-1, 4,9 (11), 16-tetraene-3, 20-dione-21-acetate) are dissolved in 500mL of acetone, cooled to 10℃and 10mL of perchloric acid and 100mL of water are added. After completion of the reaction, 30g of NBS was added in two portions and TLC (ethyl acetate: methanol=4:1) was used to measure the reaction, 40% NaOH solution (80 g of NaOH+200mL of water) was added dropwise, the temperature was raised to 35℃and after completion of the incubation reaction, 1000mL of water was added, and 49.7g of Compound II was obtained by filtration and drying.
EXAMPLE 2 preparation of Compound III solution
Under the protection of nitrogen, 400ml of tetrahydrofuran is placed in a dry reaction tank, 40g of compound II is added, the temperature is reduced to 0-2 ℃, 4g of cuprous chloride is added, the temperature is continuously reduced to minus 15-minus 10 ℃, 150ml of format reagent (1 mol/L methyl magnesium bromide tetrahydrofuran) is dropwise added, the reaction is kept at a temperature until TLC (ethyl acetate: methanol=4:1) detects that the reaction is complete, dropwise addition is continued for 10-15 minutes, stirring is carried out, and the temperature is kept at minus 15-minus 10 ℃ for more than 15 minutes, thus obtaining compound III solution.
EXAMPLE 3 preparation of Compound IV
Preparing sodium hydroxide/methanol solution: under the protection of nitrogen, 20g of sodium hydroxide is taken and put into 140ml of methanol to be stirred for standby.
Adding 8ml of glacial acetic acid into the solution of the compound III prepared in the step S2 under the protection of nitrogen for neutralization, and measuring the pH value to be 6-7; and dropwise adding a sodium hydroxide/methanol solution, wherein the dropwise adding temperature is set to be-13 to-10 ℃, the dropwise adding time is controlled to be 20-40 minutes, the temperature is kept for 1-2 hours after the dropwise adding is finished, and TLC (phenylacetone=4:1) detection is carried out. Neutralizing with 30ml glacial acetic acid after the reaction, pressing into 1000ml ice purified water for water separation, adding 400ml chloroform for extraction, filtering the organic layer and the emulsion layer, and adding 30g neutral alumina into the filter; the aqueous layer was extracted three times with 400ml chloroform.
Placing the organic layer into a decoloring tank, adding 3.2g of medicinal active carbon, and adding reflux for 40-60 minutes; filtering, concentrating under reduced pressure until the mixture is nearly dry, adding 100ml of ethyl acetate into the mixture twice, continuously concentrating the residual mother liquor, and cooling the mother liquor to 0-5 ℃; discharging, centrifuging, drying in an oven (60-80 ℃) for 10-15 hours, and collecting 36.35g of compound IV, namely 9 beta, 11 beta-epoxy-21-hydroxy-16 alpha-methyl progesterone-1, 4-diene-3, 20-dione. The liquid chromatography data of compound IV prepared in this example are shown in the following table:
as can be seen from the data in the table, the area ratio of the main peak was 98.3%, the residence time of the main peak was 12.265s, and the composition thereof was compound IV-9β,11β -epoxy-21-hydroxy-16α -methyl progesterone-1, 4-diene-3, 20-dione. The peak area ratio of the impurity 9 beta, 11 beta-epoxy-21-hydroxy-16 beta-methyl progesterone-1, 4-diene-3, 20-dione is about 1%.
In summary, the invention provides a preparation method of the intermediate of the deoxomilpine, which adopts 21-hydroxy pregna-1, 4,9 (11), 16-tetraene-3, 20-diketone-21-acetate as a starting material, and the material is derived from microbial fermentation, has low price and stable goods source, and is beneficial to control and reduction of production cost; the prepared intermediate of the deoxomipsone can conveniently obtain the deoxomipsone after ring-opening synthesis of hydrofluoric acid, the total weight yield reaches 90.3 percent, and the production cost and the product yield are superior to the prior art. In addition, the synthesis method has simple and convenient process operation and easy amplification, and can further improve the yield by recycling the mother liquor in actual industrial production, thereby having good application prospect.
It will be apparent to those skilled in the art that various modifications to the above embodiments may be made without departing from the general spirit and concepts of the invention. Which fall within the scope of the present invention. The protection scheme of the invention is subject to the appended claims.
Claims (8)
1. The preparation method of the intermediate of the deoxomipsone is characterized by adopting a compound I shown in the following formula as a raw material, wherein the compound I is 21-hydroxy pregna-1, 4,9 (11), 16-tetraene-3, 20-dione-21-acetate, and the compound IV is 9 beta, 11 beta-epoxy-21-hydroxy-16 alpha-methyl progesterone-1, 4-diene-3, 20-dione through bromohydroxylation, epoxidation, methylation and hydrolysis reaction in sequence, and the reaction formula is as follows:
the method specifically comprises the following reaction steps:
s1 bromohydroxylation and epoxidation reaction:
dissolving the compound I in acetone, adding acid water to adjust to an acidic environment, adding a brominating reagent, adding alkaline water after the reaction is completed, performing epoxidation reaction in an alkaline environment, adding water to separate out materials after the reaction is completed, filtering, and drying to obtain a compound II;
s2 methylation reaction:
under the protection of nitrogen, dissolving the compound II in tetrahydrofuran, adding copper halide, stirring, dripping a format reagent, and reacting to obtain a compound III solution;
s3, hydrolysis reaction:
and (3) under the protection of nitrogen, regulating the solution of the compound III prepared in the step (S2) to neutral meta-acid, dropwise adding an inorganic base/methanol solution, flushing, discharging and filtering after the reaction is finished, so as to obtain the compound IV.
2. The preparation method of the intermediate of the deoxomilpine according to claim 1, wherein in the step S1, 1 part by weight of the compound I is taken and dissolved in 10-20 parts by volume of acetone, 0.1-0.4 part by volume of acid water is added to adjust the mixture to an acidic environment, 0.5-1.2 parts by weight of brominating reagent is added, alkaline water is added after the reaction is finished, epoxidation reaction is carried out in an alkaline environment, water is added after the reaction is finished, and the material is separated out, filtered and dried to obtain the compound II.
3. The process for preparing a deoxomilsone intermediate according to claim 1 or 2, wherein in step S1 the concentration of acid water is 10%, wherein the acid is one or more of formic acid, acetic acid, perchloric acid and periodic acid; the brominating reagent is NBS or dibromohydantoin; the concentration of the alkaline water is 40%, wherein the alkaline water is one or more of sodium carbonate, potassium carbonate and sodium hydroxide.
4. The preparation method of the intermediate of the deoxomilpine according to claim 1, wherein in the step S2, 1 part by mass of the compound II is dissolved in 9-10.5 parts by volume of tetrahydrofuran, 0.09-0.11 part by mass of copper halide is added, stirring is carried out, a format reagent is added dropwise, and a compound III solution is obtained after the reaction is completed.
5. The process for the preparation of a deoxomipsone intermediate according to claim 1 or 4, wherein in step S2, tetrahydrofuran is anhydrous tetrahydrofuran; the copper halide is one or more of cuprous chloride, cupric bromide and cupric iodide; the formative reagent is one or more of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide.
6. The preparation method of the intermediate of the deoxomilpine according to claim 1, wherein in the step S3, 0.15-0.2 parts by volume of glacial acetic acid is added into the solution of the compound III prepared in the step S2, the pH is regulated to 6-7, an inorganic base/methanol solution is dropwise added, 20-30 parts by volume of water is added after the reaction is completed, and the compound IV is obtained after water precipitation, filtration, decolorization and drying.
7. The process for preparing a deoxomipsone intermediate according to claim 6, wherein the process for preparing the inorganic base/methanol solution comprises: under the protection of nitrogen, adding 0.43-0.5 part by weight of inorganic base into 3.25-3.75 parts by volume of methanol, and stirring to obtain an inorganic base/methanol solution.
8. The process for preparing an intermediate of deoxomipsone according to claim 1, 6 or 7, wherein in step S3, the inorganic base is sodium hydroxide, potassium hydroxide or a mixture of both.
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| CN114276406B true CN114276406B (en) | 2023-12-19 |
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