CN117624274A - Preparation method of eplerenone intermediate delta 9,11-canrenone - Google Patents
Preparation method of eplerenone intermediate delta 9,11-canrenone Download PDFInfo
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- CN117624274A CN117624274A CN202311358818.6A CN202311358818A CN117624274A CN 117624274 A CN117624274 A CN 117624274A CN 202311358818 A CN202311358818 A CN 202311358818A CN 117624274 A CN117624274 A CN 117624274A
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- MCNZISFQKMPWRJ-DOYHNPMNSA-N (8s,10r,13s,14s,17r)-10,13-dimethylspiro[2,8,12,14,15,16-hexahydro-1h-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione Chemical compound C([C@H]1[C@H]2C([C@]3(CCC(=O)C=C3C=C2)C)=CC[C@@]11C)C[C@@]11CCC(=O)O1 MCNZISFQKMPWRJ-DOYHNPMNSA-N 0.000 title claims abstract description 20
- 229960001208 eplerenone Drugs 0.000 title abstract description 14
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 12
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims abstract description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 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 abstract description 7
- 235000019253 formic acid Nutrition 0.000 claims abstract description 7
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims abstract description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 238000003379 elimination reaction Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- MZSVIVBSUYFQET-UHFFFAOYSA-N O[Br](=O)=O.C1=CC=NC=C1 Chemical compound O[Br](=O)=O.C1=CC=NC=C1 MZSVIVBSUYFQET-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 238000001816 cooling Methods 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 238000001035 drying Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229960005057 canrenone Drugs 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 229960005471 androstenedione Drugs 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 150000002940 palladium Chemical class 0.000 description 4
- 238000006356 dehydrogenation reaction Methods 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- YCHXNMPJFFEIJG-UHFFFAOYSA-N 3-methyloxiran-2-one Chemical compound CC1OC1=O YCHXNMPJFFEIJG-UHFFFAOYSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 229960002478 aldosterone Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UJVLDDZCTMKXJK-WNHSNXHDSA-N canrenone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CCC(=O)C=C3C=C2)C)CC[C@@]11C)C[C@@]11CCC(=O)O1 UJVLDDZCTMKXJK-WNHSNXHDSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- DETXZQGDWUJKMO-UHFFFAOYSA-N 2-hydroxymethanesulfonic acid Chemical compound OCS(O)(=O)=O DETXZQGDWUJKMO-UHFFFAOYSA-N 0.000 description 1
- SNMVJSSWZSJOGL-PLOWYNNNSA-N 9alpha-hydroxyandrost-4-en-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@@]3(O)CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SNMVJSSWZSJOGL-PLOWYNNNSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- ZAGRKAFMISFKIO-UHFFFAOYSA-N Isolysergic acid Natural products C1=CC(C2=CC(CN(C2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-UHFFFAOYSA-N 0.000 description 1
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 229960001888 ipratropium Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 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
- C07J21/001—Lactones
- C07J21/003—Lactones at 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
The invention provides a preparation method of eplerenone intermediate delta 9, 11-canrenone. Specifically, the method comprises the following steps: (i) In the presence of alkali, enabling the compound (3) and acetylene to carry out an ethynylation reaction to obtain a compound (4); (ii) In the presence of a hydrogenation catalyst and alkali, carrying out hydrogenation reaction on the compound (4) to obtain a compound (5); and (iii) subjecting CO and the compound (5) to a cyclization reaction in the presence of catalysts of formic acid, palladium acetate and diphenylphosphine to obtain the compound (6) delta-9, 11-canrenone. The method has the advantages of easily obtained raw materials, simple and convenient operation, low production cost and high yield.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a preparation method of eplerenone intermediate delta 9, 11-canrenone.
Background
The alias eplerenone impurity-91,11-dihydro-canrenone in Δ9, 11-canrenone; DELTA-9, 11-canrenone; 17-hydroxy-3-oxopregna-4, 6, 9-triene-21-carboxylic acid GAMMA-lactone; eplerenone intermediate Δ9 (11) -CANRENONE; an intermediate 11-canrenone of the ipratropium; eplerenone impurity-9, 11 lysergic acid canrenone; eplerenone 9,11-DIDEHYDRO CANRENONE impurity; eplerenone 9, 11-dihydro-cantrenone impurity; the English name Delta 9,11-canrenone is an intermediate of eplerenone. Eplerenone is a novel aldosterone antagonist with selective characteristics, can be directly combined with aldosterone to inhibit the action of the aldosterone, has the action similar to that of spironolactone, and has slight adverse reaction to gonads after long-term administration. Eplerenone is clinically used for treating hypertension, and is approved by FDA in 2003 for treating heart failure after myocardial infarction, and has good curative effect on mild to moderate hypertension. Clinical studies have shown that eplerenone can significantly improve symptoms in patients with acute myocardial infarction left ventricular systolic dysfunction and congestive heart failure.
The current preparation method of DELTA-9, 11-canrenone mainly takes 17 beta-hydroxy androstane-4-alkene-3-ketone-17 alpha-propiolactone as raw material, and sequentially carries out dehydrogenation reaction, fermentation of hydroxy, mesylate reaction and elimination reaction; the reaction process has the defects of long route, complex procedure, high production cost and the like; and the starting material 17 beta-hydroxyandrosta-4-ene-3-ketone-17 alpha-propiolactone is also difficult to obtain, and the production cost is high. The process route is as follows:
therefore, there is a need in the art to provide a process for preparing DELTA-9, 11-canrenone that has the advantages of readily available raw materials, simple operation, low production cost, and high yield.
Disclosure of Invention
The invention aims to provide a preparation method of DELTA-9, 11-canrenone, which has the advantages of easily available raw materials, simple operation, low production cost and high yield.
The invention provides a preparation method of delta-9, 11-canrenone, which comprises the following steps:
(i) In the presence of alkali, enabling the compound (3) and acetylene to carry out an ethynylation reaction to obtain a compound (4);
(ii) In the presence of a hydrogenation catalyst and alkali, carrying out hydrogenation reaction on the compound (4) to obtain a compound (5); and
(iii) In the presence of catalysts of formic acid, palladium acetate and diphenyl phosphine, carrying out cyclization reaction on CO and a compound (5) to obtain a compound (6) delta-9, 11-canrenone;
in another preferred embodiment, step (i) further has one or more technical features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dimethylformamide, dimethylacetamide, or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (3) is (3-9) ml to 1g, preferably (4-6) sml to 1g;
(b) The base is selected from the group consisting of potassium hydroxide, sodium hydroxide, or a combination thereof.
(c) The temperature of the reaction is-10-15 ℃, preferably-5-10 ℃, more preferably 0-5 ℃;
(d) The molar ratio of said compound (3) to base is 1 (2-6), preferably 1 (3-5); and/or
(e) The reaction time is 6 to 12 hours, preferably 7 to 8 hours.
In another preferred embodiment, step (i) further comprises the steps of: after the reaction is finished, adding water and hydrochloric acid, regulating the pH to be neutral (7-8), carrying out layered extraction, combining organic layers, concentrating under reduced pressure, cooling, filtering and drying to obtain the compound (4).
In another preferred embodiment, in step (ii), the reaction is carried out in the presence of hydrogen, preferably at a pressure of 0.1 to 0.5MPa, preferably 0.2 to 0.3MPa.
In another preferred embodiment, in step (ii), the hydrogenation catalyst is selected from the group consisting of platinum catalysts, palladium catalysts, nickel catalysts, or combinations thereof; preferably, palladium calcium carbonate, target acetate, pb/C, pt/C, raney nickel, or a combination thereof.
In another preferred embodiment, step (ii) further has one or more technical features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dichloromethane, chloroform, or a combination thereof; preferably, the ratio of the reaction solvent to the compound (4) is (2-8) ml to 1g, preferably (4-6) sml to 1g;
(b) The base is selected from the group consisting of triethylamine, diethylamine, sodium hydroxide, sodium borohydride, or a combination thereof.
(c) The temperature of the reaction is 10-100 ℃, preferably 15-40 ℃, more preferably 20-30 ℃;
(d) The reaction time is 4-12 hours, preferably 5-8 hours;
(e) The weight ratio of the compound (4) to the alkali is 1 (0.1-0.5), preferably 1 (0.2-0.3); and/or
(f) The weight ratio of the compound (4) to the hydrogenation catalyst is 1 (0.001-0.1), preferably 1 (0.01-0.05).
In another preferred embodiment, step (ii) further comprises the steps of: after the reaction is completed, filtering and recovering the catalyst, concentrating under reduced pressure, adding water for water precipitation, cooling, filtering and drying to obtain the compound (5).
In another preferred embodiment, step (iii) has one or more technical features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dichloromethane, chloroform, or a combination thereof; preferably, the ratio of the reaction solvent to the compound (5) is (2-8) ml to 1g, preferably (4-6) sml to 1g;
(b) The weight ratio of palladium acetate to diphenylphosphine is 1 (3-15), preferably 1 (5-10)
(c) The weight ratio of the compound (5) to the sum of palladium acetate and diphenyl phosphine is 1 (0.01-0.1); preferably 1 (0.02-0.05);
(d) The weight ratio of the compound (5) to the formic acid is 1 (0.01-0.2); preferably 1 (0.02-0.1);
(e) In the reaction, the pressure of CO is 0.5-1MPa, preferably 0.6-0.8MPa;
(f) The temperature of the reaction is 90-120 ℃, preferably 100-110 ℃; and/or
(g) The reaction time is 12-24 hours, preferably 15-20 hours.
In another preferred embodiment, the method further comprises a post-treatment step after the step (iii) of cooling, filtering and recovering palladium salt, and concentrating under reduced pressure until the palladium salt is dried; adding methanol for dissolving, heating and refluxing, and dropwise adding water under stirring; cooling and filtering, washing a filter cake with methanol water, and vacuum drying to obtain the compound (6) delta 9, 11-canrenone.
In another preferred embodiment, before step (i), the method further comprises the step of:
(a-i) subjecting the compound (1) to elimination reaction in the presence of concentrated sulfuric acid to obtain a compound (2); and
(a-ii) in the presence of catalysis, carrying out etherification reaction on the compound (2) and triethyl orthoformate to obtain a reaction product; and
(a-iii) reacting the reaction product obtained in step (a-ii) with tetrachlorobenzoquinone to obtain compound (3);
in another preferred embodiment, step (a-i) has one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dichloromethane, chloroform, or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (1) is (3-15) ml to 1g, preferably (4-6) sml to 1g;
(b) The weight ratio of the compound (1) to the concentrated sulfuric acid is 1 (1-3); preferably 1 (1.5-2);
(c) The temperature of the reaction is-10-10 ℃, preferably-5-5 ℃; and/or
(d) The reaction time is 12-36 hours, preferably 18-24 hours.
In another preferred embodiment, step (a-i) comprises: after the reaction was completed, the reaction was terminated by adding an aqueous sodium carbonate solution, the organic layer was washed with water in layers, concentrated to dryness, filtered by water separation, and dried to obtain compound (2).
In another preferred embodiment, step (a-ii) has one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from methanol, ethanol, isopropanol, or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (2) is (1-5) ml to 1g, preferably (2-3) sml to 1g;
(b) The catalyst is selected from p-toluenesulfonic acid, pyridine hydrochloride or pyridine bromate, or a combination thereof;
(c) The weight ratio of the compound (2) to the triethyl orthoformate is 1 (1-2); preferably 1 (1.2-1.5);
(d) The weight ratio of the compound (2) to the catalyst is 1 (0.01-0.2); preferably 1 (0.02-0.1);
(e) The temperature of the reaction is 30-60 ℃, preferably 40-55 ℃; and/or
(f) The reaction time is 2 to 6 hours, preferably 3 to 5 hours.
In another preferred embodiment, step (a-ii) further comprises the steps of: and (c) adding a base (such as triethylamine) after the reaction is finished, adjusting the pH of the reaction solution to be neutral, concentrating to be dry, and obtaining a reaction product to carry out the steps (a-iii).
In another preferred embodiment, steps (a-iii) have one or more features selected from the group consisting of:
(a) The solvent of the reaction is selected from acetone, butanone or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (2) is (3-10) ml to 1g, preferably (4-6) sml to 1g;
(b) The dosage ratio of the compound (2) to the chloranil is 1 (0.5-3); preferably 1 (0.8-1.2);
(c) The temperature of the reaction is 30-60 ℃, preferably 40-55 ℃; and/or
(d) The reaction time is 2 to 12 hours, preferably 3 to 10 hours.
In another preferred embodiment, the steps (a-iii) further comprise the steps of: concentrating to dryness after the reaction is finished; separating out alkaline water; filtering, washing with water, and drying to obtain compound (3).
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40 ℃, preferably 25±5 ℃.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor provides a preparation method of eplerenone intermediate delta 9,11-canrenone through extensive and intensive research and mass screening and testing. The method adopts a specific reaction step to efficiently synthesize the compound (4), the compound (5) and the compound (6), and the method does not need a fermentation step, and has the advantages of easily available raw materials, low production cost and high yield. The present invention has been completed on the basis of this finding.
The main advantages of the invention include:
1. the invention provides a novel synthetic route of delta-9, 11-canrenone which takes 4,6, 9-alkene-3, 17-androstenedione (compound 3, CAS number: 187024-20-0) as raw material; in addition, 4,6, 9-ene-3, 17-androstenedione can also be prepared by the process of the invention from the inexpensive and readily available starting compound 9-hydroxyandrostenedione (compound 1).
2. The method of the present invention employs a specific reaction step to synthesize the compound (4) and the compound (5) and the compound (6) efficiently.
3. The method is a full chemical synthesis method, and does not need a fermentation step;
4. the method has the advantages of simple and convenient operation, mild conditions, low production cost and high yield (more than or equal to 74%).
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1
1) Elimination reaction: adding 23g of raw material (1) 9-hydroxy androstenedione and 230ml of dichloromethane into a clean reaction bottle, stirring and cooling to 0 ℃, slowly dropwise adding 46g of concentrated sulfuric acid, controlling the temperature to-5 ℃ for reaction for 24 hours, adding a proper amount of sodium carbonate aqueous solution to adjust ph to be neutral after the reaction is detected to be complete, washing a dichloromethane layer in a layering way, concentrating the dichloromethane layer to be pasty, adding 300ml of water for water precipitation, cooling to 0 ℃, and carrying out suction filtration and drying to obtain 21.2g of compound (2).
2) Etherification and dehydrogenation reaction: adding 40ml of absolute ethyl alcohol and 15g of triethyl orthoformate into a clean reaction bottle, adding 21.2g of compound (2), stirring for 30 minutes at normal temperature, adding 2g of pyridine hydrochloride, heating to 50 ℃, preserving heat for reaction for 4-5 hours, sampling for thin-layer analysis, stopping reaction with 2g of triethylamine after the reaction is completed, concentrating under reduced pressure, controlling the internal temperature to be less than or equal to 70 ℃, and concentrating until no fraction exists. 120ml butanone and 20g of tetrachloroquinone are added into a reaction bottle, and the temperature is controlled to be 30-50 ℃ and the reaction is carried out for 3-10 hours. Concentrating to dryness after the reaction is finished; separating out alkaline water; filtering, washing with water, and drying to obtain 20g of compound (3).
3) Ethynylation reaction: adding 100ml of tetrahydrofuran into a high-pressure reaction kettle, adding 20g of 4,6, 9-alkene-3, 17-androstenedione (3) and 18g of potassium hydroxide, cooling to 0-10 ℃, introducing acetylene gas, keeping the pressure at 0.3MPa, and carrying out heat preservation reaction; the reaction time is kept between 7 and 8 hours, the reaction is complete, water and hydrochloric acid are added, the PH is regulated to be neutral, layering is carried out, tetrahydrofuran is used for extracting a water layer to materials, an organic layer is combined, the concentration is carried out under reduced pressure, 20ml of methanol is carried out, and 18.2g of compound (4) is obtained after cooling, filtering and drying.
4) Hydrogenation reaction: 18.2g of compound (4) was charged into the autoclave, 80ml of methylene chloride was added, 3ml of triethylamine and 0.182g of catalyst calcium carbonate palladium were added. Controlling the temperature to 25 ℃, introducing hydrogen at the pressure of 0.2MPa for 5-8 hours, filtering to recover the catalyst after the reaction is completed, concentrating under reduced pressure, entraining 20ml of methanol to a small amount, adding water for water precipitation, cooling, filtering and drying to obtain 17.3g of compound (5).
5) Cyclization 86.5ml of tetrahydrofuran, 0.069g of palladium acetate, 0.311g of diphenylphosphine, 1.41g of formic acid and 17.3g of compound (5) were charged into a high-pressure reaction vessel. Introducing CO for pressurizing reaction, stirring at 25 ℃ for 20 minutes, heating the mixture to 105 ℃, raising the pressure to 0.7MPa by using CO, keeping the reaction for 18 hours, cooling, filtering, recovering palladium salt, and concentrating under reduced pressure to dryness. 43.25ml of methanol was added thereto for dissolution, and the temperature was raised for reflux, and 43.25ml of water was added dropwise with stirring. Cooling and filtering, 1:1 methanol water and vacuum drying at 70 ℃ gave 17.02g Δ9,11-canrenone (6), total mass yield 74% (based on compound (1)), HPLC content 98.2%, maximum mono-impurity 0.74%.
Example 2
The preparation method specifically comprises the following preparation steps:
1) Elimination reaction: adding 23g of raw material (1) 9-hydroxy androstenedione and 300ml of dichloromethane into a clean reaction bottle, stirring and cooling to 0 ℃, slowly dropwise adding 69g of concentrated sulfuric acid, controlling the temperature to-5 ℃ for reaction for 24 hours, adding a proper amount of sodium carbonate aqueous solution to adjust ph to be neutral after the reaction is detected to be complete, washing a dichloromethane layer in a layering way, concentrating the dichloromethane layer to be pasty, adding 300ml of water for water precipitation, cooling to 0 ℃, and carrying out suction filtration and drying to obtain 21.4g of compound (2).
2) Etherification and dehydrogenation reaction: adding 40ml of absolute ethyl alcohol and 20g of triethyl orthoformate into a clean reaction bottle, adding 21.4g of compound (2), stirring for 30 minutes at normal temperature, adding 4g of pyridine hydrochloride, heating to 50 ℃, preserving heat for reaction for 4-5 hours, sampling for thin-layer analysis, stopping the reaction with 4g of triethylamine after the reaction is completed, concentrating under reduced pressure, controlling the internal temperature to be less than or equal to 70 ℃, and concentrating until no fraction exists. 120ml of acetone is added into a reaction bottle, 20g of tetrachloroquinone is added into the reaction bottle, and the temperature is controlled to be 30-50 ℃ for 3-10 hours for thermal insulation reaction. Concentrating to dryness after the reaction is finished; separating out alkaline water; filtering, washing with water, and drying to obtain 20g of compound (3).
3) Ethynylation reaction: adding 100ml of N, N-dimethylformamide into a high-pressure reaction kettle, adding 20g of 4,6, 9-alkene-3, 17-androstenedione (3) and 18g of potassium hydroxide, cooling to 0-10 ℃, introducing acetylene gas, keeping the pressure at 0.3MPa, and carrying out heat preservation reaction; the reaction time is kept between 6 and 9 hours, the reaction is complete, water and hydrochloric acid are added, the PH is regulated to be neutral, 800ml of water is separated out, and 18.4g of compound (4) is obtained after cooling, filtering and drying.
4) Hydrogenation reaction: 18.4g of compound (4) was charged into the autoclave, 80ml of chloroform was added thereto, 3ml of triethylamine and 0.184g of catalyst calcium carbonate palladium were added thereto. Controlling the temperature to 25 ℃, introducing hydrogen at the pressure of 0.2MPa for 5-8 hours, filtering to recover the catalyst after the reaction is completed, concentrating under reduced pressure, entraining 20ml of methanol to a small amount, adding water for water precipitation, cooling, filtering and drying to obtain 17.6g of compound (5).
5) Cyclization 88ml of tetrahydrofuran, 0.095g of palladium acetate, 0.336g of diphenylphosphine, 1.43g of formic acid and 17.6g of compound (5) were charged into a high-pressure reaction vessel. Introducing CO for pressurizing reaction, stirring at 25 ℃ for 20 minutes, heating the mixture to 105 ℃, raising the pressure to 0.7MPa by using CO, keeping the reaction for 18 hours, cooling, filtering, recovering palladium salt, and concentrating under reduced pressure to dryness. 44ml of methanol was added thereto, and the mixture was heated to reflux, and 44ml of water was added dropwise with stirring. Cooling and filtering, 1:1 methanol in water and drying in vacuo at 70℃gives 17.23g of Δ9,11-canrenone (6), total mass yield 74.9%, HPLC content 97.9% (calculated as compound (1)) max. Mono-impurity 0.83%.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. A method for preparing delta-9, 11-canrenone, comprising the steps of:
(i) In the presence of alkali, enabling the compound (3) and acetylene to carry out an ethynylation reaction to obtain a compound (4);
(ii) In the presence of a hydrogenation catalyst and alkali, carrying out hydrogenation reaction on the compound (4) to obtain a compound (5); and
(iii) In the presence of catalysts of formic acid, palladium acetate and diphenyl phosphine, carrying out cyclization reaction on CO and a compound (5) to obtain a compound (6) delta-9, 11-canrenone;
2. the method of claim 1, wherein step (i) further comprises one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dimethylformamide, dimethylacetamide, or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (3) is (3-9) ml to 1g, preferably (4-6) sml to 1g;
(b) The base is selected from the group consisting of potassium hydroxide, sodium hydroxide, or a combination thereof;
(c) The temperature of the reaction is-10-15 ℃, preferably-5-10 ℃, more preferably 0-5 ℃;
(d) The molar ratio of said compound (3) to base is 1 (2-6), preferably 1 (3-5); and/or
(e) The reaction time is 6 to 12 hours, preferably 7 to 8 hours.
3. The process according to claim 1, wherein in step (ii) the reaction is carried out in the presence of hydrogen, preferably at a pressure of 0.1 to 0.5MPa, preferably 0.2 to 0.3MPa.
4. The method of claim 1, wherein in step (ii), the hydrogenation catalyst is selected from the group consisting of a platinum catalyst, a palladium catalyst, a nickel catalyst, or a combination thereof; preferably, palladium calcium carbonate, target acetate, pb/C, pt/C, raney nickel, or a combination thereof.
5. The method of claim 1, wherein step (ii) further comprises one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dichloromethane, chloroform, or a combination thereof; preferably, the ratio of the reaction solvent to the compound (4) is (2-8) ml to 1g, preferably (4-6) sml to 1g;
(b) The base is selected from the group consisting of triethylamine, diethylamine, sodium hydroxide, sodium borohydride, or a combination thereof;
(c) The temperature of the reaction is 10-100 ℃, preferably 15-40 ℃, more preferably 20-30 ℃;
(d) The reaction time is 4-12 hours, preferably 5-8 hours;
(e) The weight ratio of the compound (4) to the alkali is 1 (0.1-0.5), preferably 1 (0.2-0.3); and/or
(f) The weight ratio of the compound (4) to the hydrogenation catalyst is 1 (0.001-0.1), preferably 1 (0.01-0.05).
6. The method of claim 1, wherein step (iii) has one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dichloromethane, chloroform, or a combination thereof; preferably, the ratio of the reaction solvent to the compound (5) is (2-8) ml to 1g, preferably (4-6) sml to 1g;
(b) The weight ratio of palladium acetate to diphenylphosphine is 1 (3-15), preferably 1 (5-10)
(c) The weight ratio of the compound (5) to the sum of palladium acetate and diphenyl phosphine is 1 (0.01-0.1); preferably 1 (0.02-0.05);
(d) The weight ratio of the compound (5) to the formic acid is 1 (0.01-0.2); preferably 1 (0.02-0.1);
(e) In the reaction, the pressure of CO is 0.5-1MPa, preferably 0.6-0.8MPa;
(f) The temperature of the reaction is 90-120 ℃, preferably 100-110 ℃; and/or
(g) The reaction time is 12-24 hours, preferably 15-20 hours.
7. The method of claim 1, wherein prior to step (i), the method further comprises the steps of:
(a-i) subjecting the compound (1) to elimination reaction in the presence of concentrated sulfuric acid to obtain a compound (2); and
(a-ii) in the presence of catalysis, carrying out etherification reaction on the compound (2) and triethyl orthoformate to obtain a reaction product; and
(a-iii) reacting the reaction product obtained in step (a-ii) with tetrachlorobenzoquinone to obtain compound (3);
8. the method of claim 7, wherein steps (a-i) have one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from tetrahydrofuran, dichloromethane, chloroform, or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (1) is (3-15) ml to 1g, preferably (4-6) sml to 1g;
(b) The weight ratio of the compound (1) to the concentrated sulfuric acid is 1 (1-3); preferably 1 (1.5-2);
(c) The temperature of the reaction is-10-10 ℃, preferably-5-5 ℃; and/or
(d) The reaction time is 12-36 hours, preferably 18-24 hours.
9. The method of claim 7, wherein steps (a-ii) have one or more features selected from the group consisting of:
(a) The solvent for the reaction is selected from methanol, ethanol, isopropanol, or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (2) is (1-5) ml to 1g, preferably (2-3) sml to 1g;
(b) The catalyst is selected from p-toluenesulfonic acid, pyridine hydrochloride or pyridine bromate, or a combination thereof;
(c) The weight ratio of the compound (2) to the triethyl orthoformate is 1 (1-2); preferably 1 (1.2-1.5);
(d) The weight ratio of the compound (2) to the catalyst is 1 (0.01-0.2); preferably 1 (0.02-0.1);
(e) The temperature of the reaction is 30-60 ℃, preferably 40-55 ℃; and/or
(f) The reaction time is 2 to 6 hours, preferably 3 to 5 hours.
10. The method of claim 7, wherein steps (a-iii) have one or more features selected from the group consisting of:
(a) The solvent of the reaction is selected from acetone, butanone or a combination thereof; preferably, the ratio of the amount of the reaction solvent to the amount of the compound (2) is (3-10) ml to 1g, preferably (4-6) sml to 1g;
(b) The dosage ratio of the compound (2) to the chloranil is 1 (0.5-3); preferably 1 (0.8-1.2);
(c) The temperature of the reaction is 30-60 ℃, preferably 40-55 ℃; and/or
(d) The reaction time is 2 to 12 hours, preferably 3 to 10 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1839145A (en) * | 2003-03-21 | 2006-09-27 | 法玛西雅公司 | Steroid spirolactonization |
| CN104327150A (en) * | 2014-09-11 | 2015-02-04 | 浙江神洲药业有限公司 | Synthesis method of spironolactone intermediate canrenone |
| CN112062805A (en) * | 2020-08-10 | 2020-12-11 | 浙江神洲药业有限公司 | High-efficiency delta9,11Process for the preparation of (E) -canrenone |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1839145A (en) * | 2003-03-21 | 2006-09-27 | 法玛西雅公司 | Steroid spirolactonization |
| CN104327150A (en) * | 2014-09-11 | 2015-02-04 | 浙江神洲药业有限公司 | Synthesis method of spironolactone intermediate canrenone |
| CN112062805A (en) * | 2020-08-10 | 2020-12-11 | 浙江神洲药业有限公司 | High-efficiency delta9,11Process for the preparation of (E) -canrenone |
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