CN114149427A - Synthesis method of non-neferitone and intermediate thereof - Google Patents
Synthesis method of non-neferitone and intermediate thereof Download PDFInfo
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- CN114149427A CN114149427A CN202111555792.5A CN202111555792A CN114149427A CN 114149427 A CN114149427 A CN 114149427A CN 202111555792 A CN202111555792 A CN 202111555792A CN 114149427 A CN114149427 A CN 114149427A
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- 238000001308 synthesis method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229940126214 compound 3 Drugs 0.000 claims abstract description 17
- 229940125904 compound 1 Drugs 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 12
- 229940125782 compound 2 Drugs 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000012442 inert solvent Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 8
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 7
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 6
- SSQZBQXJYGNUSC-UHFFFAOYSA-N 4-amino-5-methyl-1h-pyridin-2-one Chemical compound CC1=CNC(=O)C=C1N SSQZBQXJYGNUSC-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZXENVSJZOHXCKL-UHFFFAOYSA-N 4-formyl-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1C=O ZXENVSJZOHXCKL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- -1 lithium aluminum tetrahydride Chemical compound 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 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
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- 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 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- DDTHMESPCBONDT-UHFFFAOYSA-N 4-(4-oxocyclohexa-2,5-dien-1-ylidene)cyclohexa-2,5-dien-1-one Chemical group C1=CC(=O)C=CC1=C1C=CC(=O)C=C1 DDTHMESPCBONDT-UHFFFAOYSA-N 0.000 claims description 2
- SQLWOAWYBWWOBU-UHFFFAOYSA-N CC1=CC=CC=C1.COCCO[AlH]OCCOC.[Na] Chemical compound CC1=CC=CC=C1.COCCO[AlH]OCCOC.[Na] SQLWOAWYBWWOBU-UHFFFAOYSA-N 0.000 claims description 2
- BDJDCXPOAHDGEM-UHFFFAOYSA-N CCCCCCC.C(C(C)C)[AlH]CC(C)C Chemical compound CCCCCCC.C(C(C)C)[AlH]CC(C)C BDJDCXPOAHDGEM-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 2
- QFSUPZRFRLMCMO-UHFFFAOYSA-N bis(2-methylpropyl)alumane oxolane Chemical compound C1CCOC1.[H][Al](CC(C)C)CC(C)C QFSUPZRFRLMCMO-UHFFFAOYSA-N 0.000 claims description 2
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- HTBVGZAVHBZXMS-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] HTBVGZAVHBZXMS-UHFFFAOYSA-N 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000013341 scale-up Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ACMSDYGOIVWQIX-CQSZACIVSA-N (2r)-n-(dicyclopropylmethyl)-4-methyl-2-(2-methylprop-2-enoylamino)pentanamide Chemical compound C1CC1C(NC(=O)[C@H](NC(=O)C(C)=C)CC(C)C)C1CC1 ACMSDYGOIVWQIX-CQSZACIVSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 2
- 229960004127 naloxone Drugs 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BTBHLEZXCOBLCY-QGZVFWFLSA-N (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Chemical group C1([C@@H]2C(=C(C)NC=3C(C)=CN=C(C2=3)OCC)C(N)=O)=CC=C(C#N)C=C1OC BTBHLEZXCOBLCY-QGZVFWFLSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NLMFWVNFGZBORJ-UHFFFAOYSA-N 4-(3,5-dimethyl-4-oxocyclohexa-2,5-dien-1-yl)-2,6-dimethylcyclohexa-2,5-dien-1-one Chemical compound C1=C(C)C(=O)C(C)=CC1C1C=C(C)C(=O)C(C)=C1 NLMFWVNFGZBORJ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a novel synthetic method of a non-neferitone intermediate. The method comprises the following steps: (1) in the presence of acid and in the condition of inert solvent or no solvent, diethyl malonate, 4-cyano-2-methoxybenzaldehyde and 4-amino-5-methyl-2-hydroxypyridine react to prepare a compound 1; (2) carrying out alkylation reaction on the compound 1 obtained in the step (1) and triethyl orthoformate under the catalysis of acid in an inert solvent or in the absence of a solvent to prepare a compound 2; (3) reducing the compound 2 obtained in the step (2) by a reducing agent to prepare a compound 3; (4) in the presence of a catalyst, resolving the compound 3 and alcohol by a chemical method to prepare a chiral compound 4; the reaction formula is shown as follows:
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthetic method of a non-neferitone intermediate, and further relates to a synthetic method of non-neferitone.
Background
The chemical name of the non-nekinone is (4s) 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-formamide, and the structural formula is as follows:
it is a non-steroidal mineralocorticoid receptor antagonist and is used for the treatment of chronic kidney disease.
Patent documents WO2008104306A, CN106795155A, CN101641352A and CN107849043A all report methods for preparing non-naloxone. As can be seen from the above patent applications, many synthesis steps require chiral column resolution, which is expensive, technically time-consuming and labor-consuming, and the solvent consumption is high, resulting in high cost, and is not suitable for industrial production.
Therefore, there is a need to develop a method for preparing pharmaceutically active compounds with high yield, high purity, simplicity, high efficiency, low cost, and easy industrial production, so as to meet the requirements of clinical trials and registration applications. The invention provides a synthesis method of a non-neferitone intermediate, which has the advantages of high yield, simple post-treatment, low cost and easy industrialization, and simultaneously ensures that the product has purity meeting the requirement of registration of raw material medicaments.
Disclosure of Invention
One of the objectives of the present invention is to provide a novel method for synthesizing a non-neferide ketone intermediate, so as to solve the problems of low preparation yield, high cost, complex post-treatment and being not suitable for industrial production in the existing method for synthesizing a non-neferide ketone intermediate.
In order to achieve the above object, the present invention provides, in a first aspect, a novel synthesis method of a non-neferitone intermediate compound 4, comprising the steps of:
(1) in the presence of acid and in the condition of inert solvent or no solvent, diethyl malonate, 4-cyano-2-methoxybenzaldehyde and 4-amino-5-methyl-2-hydroxypyridine react to prepare a compound 1;
(2) carrying out alkylation reaction on the compound 1 obtained in the step (1) and triethyl orthoformate under the catalysis of acid in an inert solvent or in the absence of a solvent to prepare a compound 2;
(3) reducing the compound 2 obtained in the step (2) by a reducing agent to prepare a compound 3;
(4) in the presence of a catalyst, the compound 3 and alcohol are resolved by a chemical method to prepare a chiral compound 4.
The process route is as follows:
the second aspect of the present invention also provides a non-neferitone intermediate compound 4, wherein the non-neferitone intermediate compound 4 is prepared by the above synthesis process.
The third aspect of the present invention also provides a novel method for synthesizing non-neferitone, which comprises the following steps: and (3) reacting the compound 4 with ammonia water in a solvent to obtain the non-neferitone I.
The fourth aspect of the present invention also provides the non-neferitone prepared by the synthesis process.
By applying the technical scheme of the invention, the chiral column resolution method is avoided, and the cost is reduced; the chemical method is adopted for splitting, so that the raw material loss is reduced, the post-treatment is simple, and the industrial scale-up production is facilitated.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the existing synthetic method of non-naloxone has the problems of low preparation yield, high cost, complex post-treatment and being not beneficial to industrial production. In order to solve the above technical problems, the present application provides a novel method for synthesizing non-neferide ketone and its intermediate compound 4, and first, the method for synthesizing the non-neferide ketone intermediate compound 4 comprises the following steps:
(1) in the presence of acid and in the condition of inert solvent or no solvent, diethyl malonate, 4-cyano-2-methoxybenzaldehyde and 4-amino-5-methyl-2-hydroxypyridine react to prepare a compound 1;
(2) carrying out alkylation reaction on the compound 1 obtained in the step (1) and triethyl orthoformate under the catalysis of acid in an inert solvent or in the absence of a solvent to prepare a compound 2;
(3) reducing the compound 2 obtained in the step (2) by a reducing agent to prepare a compound 3;
(4) in the presence of a catalyst, the compound 3 and alcohol are resolved by a chemical method to prepare a chiral compound 4.
The process route is as follows:
preferably, the inert solvent in steps (1) and (2) is an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, an aromatic hydrocarbon solvent or an amide solvent; the alcohol solvent includes but is not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane, chloroform, tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, chlorobenzene or chlorotoluene; the ether solvent includes but is not limited to diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane; the aromatic hydrocarbon solvents include, but are not limited to, benzene, toluene, xylene, nitrobenzene; the amide solvent includes but is not limited to N, N-dimethylacetamide and N, N-dimethylformamide.
Preferably, the reaction in the step (1) is carried out under the condition of no solvent, and the reaction temperature is room temperature-110 ℃. The acid is acetic acid, trifluoroacetic acid, methane sulfonic acid or p-toluenesulfonic acid, preferably acetic acid.
Preferably, the reaction of step (2) is carried out in the absence of a solvent. The reaction temperature is room temperature-100 ℃. The acid in the step (2) is sulfuric acid, the molar ratio of the sulfuric acid to the compound 1 is 1: 20-1: 5, and the amount of triethyl orthoformate is 5-10 mL/g of the compound 1.
Preferably, the reducing agent in step (3) is any one of sodium borohydride, lithium aluminum tetrahydride, diisobutylaluminum hydride tetrahydrofuran solution, diisobutylaluminum hydride toluene solution, diisobutylaluminum hydride cyclohexane solution, diisobutylaluminum hydride heptane solution, sodium aluminum hydride tetrahydrofuran solution, aluminum hydride, lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution or sodium bis (2-methoxyethoxy) aluminum hydride toluene solution (60 wt%).
Preferably, the catalyst in step (4) is selected from one or more compounds represented by the following structural formula:
the molar ratio of the catalyst to the compound 3 is 0.02-0.5: 1.
Preferably, the step (4) further comprises a base and an oxidizing agent, wherein the base is one or more of sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, potassium phosphate, 4-dimethylaminopyridine, N-diisopropylethylamine, triethylamine, pyridine, imidazole, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, 1, 8-diazabicyclo [5.4.0] -7-undecene; the molar ratio of the alkali to the compound 3 is 2-5: 1; the oxidant is 4,4' -diphenoquinone, 3, 5-dimethyl-3 ',5' -di-tert-butyl-4, 4' -diphenoquinone, 3, 5-dimethyl-3 ',5' -diisopropyl-4, 4' -diphenoquinone, 3' -dimethyl-5, 5' -di-tert-butyl-diphenoquinone, 3',5,5' -tetra-tert-butyl- [1,1' -bis (cyclohexyl) ] -2,2', one or more of 5,5 '-tetraene-4, 4' -dione or 4- (3, 5-dimethyl-4-oxo-2, 5-cyclohexadien-1-yl) -2, 6-dimethyl-2, 5-cyclohexadien-1-one; the molar ratio of the oxidant to the compound 3 is 0.5-2: 1.
The raw materials and reagents used in the above preparation methods are known compounds in the prior art and are commercially available, and among them, the catalyst described in the step (4) can be prepared by a synthetic method described in, for example, chinese patent application publication No. CN101220039A, etc.
The second aspect of the present invention also provides a non-neferitone intermediate compound 4, wherein the non-neferitone intermediate compound 4 is prepared by the above synthesis process.
The third aspect of the present invention also provides a novel method for synthesizing non-neferitone, which comprises the following steps:
the specific synthesis method comprises the following steps: and (3) reacting the compound 4 with ammonia water in a solvent to obtain the non-neferitone I.
Preferably, the solvent is an alcohol, including but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; the reaction temperature in the step is 0-room temperature, preferably 0-10 ℃, and the reaction time is 10-20 hours, preferably 16-20 hours.
The fourth aspect of the present invention also provides the non-neferitone prepared by the synthesis process.
By applying the technical scheme of the invention, the chiral column resolution method is avoided, and the cost is reduced; the chemical method is adopted for splitting, so that the raw material loss is reduced, the post-treatment is simple, and the industrial scale-up production is facilitated.
EXAMPLE 1 preparation of Compound 1
200mL of acetic acid and 35.2g (0.22mol, 1.1eq) of diethyl malonate are added into a 500mL four-neck flask, after the diethyl malonate is dissolved, 32.2g (0.2mol, 1.0eq) of 4-cyano-2-methoxybenzaldehyde is added, the mixture is stirred for 30 minutes at room temperature, 24.8g (0.2mol, 1.0eq) of 4-amino-5-methyl-2-hydroxypyridine is added, the mixture is reacted for 8 hours at 80 ℃, the reaction progress is monitored by TLC, after the reaction is completed, the reaction liquid drops are added into ice water, the pH value is adjusted to 7-8 by sodium bicarbonate, ethyl acetate is used for extraction, an organic phase is dried and concentrated, and the mixture is pulped by methyl tert-butyl ether to obtain 65.4g of compound 1, the yield is 86.2%, and the purity is 97%.
LC-MS(M+H)+:380.1。
EXAMPLE 2 preparation of Compound 2
Suspending 38g of the compound 1 in 200mL of triethyl orthoformate, heating to 130 ℃, then dropwise adding 5.4mL of concentrated sulfuric acid (2-3 drops per minute) into the reaction system, and stirring overnight at 130 ℃ after dropwise adding. Detecting the reaction is complete, cooling, concentrating the reaction solution to about 50mL, adding 300mL of water, extracting with 500mL of ethyl acetate, drying and concentrating the organic phase, and performing reaction by using n-hexane: ethyl acetate = 10: 1 pulping, purifying, filtering and vacuum drying to obtain 37g of compound 2, with the yield of 91 percent and the purity of 98 percent.
LC-MS(M+H)+:408.2。
EXAMPLE 3 preparation of Compound 3
Under the protection of nitrogen, 150mL of tetrahydrofuran and 20.4g (0.05mol, 1.0eq) of compound 2 are added into a 500mL four-mouth bottle, the reaction solution is cooled to 0 ℃, 2.1g (0.05mol, 1.1eq) of sodium borohydride is added in batches, after the addition is finished, the temperature of the reaction system is controlled to be 45-50 ℃, the reaction is carried out for 2-3 hours, the reaction is detected to be complete by a point plate, diluted hydrochloric acid of 0.5N is used for quenching, the pH value is adjusted to 7-8 by sodium bicarbonate, ethyl acetate is added for extraction, organic coherent concentration is carried out, and the mixed solvent of ethyl acetate/N-hexane =15:1 is used for pulping and purification, so that 15.6g of compound 3 is obtained, the yield is 86%, and the purity is 97%.
LC-MS(M+H)+:364.0。
EXAMPLE 4 preparation of Compound 4
Under nitrogen protection, 15g of Compound 3 (41.3mmol), 6.6g of catalyst cat 7, are introduced into a 500mL four-necked flask
(15mmol), 16.8g of the oxidizing agent 3,5,3',5' -tetra-tert-butyldicyclohexyl-2, 5,2',5' -tetraene-4, 4' -dione (41.3mmol), 150mL of anhydrous dichloromethane, then 9.5g of ethanol (206.5 mmol) and 6.4g N, N-diisopropylethylamine (49.6 mmol) were added, after which the reaction mixture was heated to 40 ℃ overnight, checked for completion by HPLC, then cooled to room temperature, filtered with celite, the filter cake was washed with 200mL of dichloromethane, the filtrate was concentrated at 60 ℃ to remove the solvent, 100mL of ethyl acetate was added to the residue, dissolved by heating to 50 ℃ and then 10mL of N-hexane was added, the mixture was slowly cooled to 10 ℃ (about 6 h), stirred overnight at 10 ℃ and filtered, the filter cake was washed with cold ethyl acetate 3 times to give 13.3g of compound 4, the yield is 79%, the purity is 98%, the ee value is 99.5% (the filling material of the chiral column is selected from poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide), and the mobile phase is ethyl acetate).
LC-MS(M+H)+:408.2。
EXAMPLE 5 preparation of Compound I
Adding 20.4g of compound 4 and 300mL of ethanol into a 1000mL flask, cooling a reaction solution to 0 ℃, then dropwise adding ammonia water (33 percent and 150 mL) into a reaction system, controlling the temperature of the system to be below 5 ℃, continuing to react and stir at the temperature of below 5 ℃ for 16 hours after the addition is finished, separating out solids, detecting that the reaction is complete by using a dot plate, filtering, washing a filter cake by using cold water and ethanol, crystallizing by using ethyl acetate and petroleum ether, stirring the obtained solution for 1 hour, filtering, and drying in a vacuum drying oven at the temperature of 40 ℃ to obtain 16.3g of compound I, wherein the yield is 86.4 percent, the purity is 99.5 percent, and the ee value is 99.4 percent (the filler of a chiral column is selected from poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide), and the mobile phase is 0.5 percent of isopropylamine and ethyl acetate).
LC-MS(M+H)+: 379.0。
1H-NMR (DMSO-d6, 400 MHz) δ: 7.71(s, 1H), 7.54(s, 1H), 7.39-7.37(m, 1H), 7.30-7.27(m, 1H), 7.15-7.13 (m, 1H), 6.79-6.75 (m, 2H), 5.39 (s, 1H), 4.06-4.00 (m, 2H), 3.82 (s, 3H), 2.20 (s, 3H), 2.14(s, 3H), 1.07-1.04 (m, 3H)。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A novel synthesis method of a non-neferitone intermediate compound 4, comprising the following steps:
(1) in the presence of acid and in the condition of inert solvent or no solvent, diethyl malonate, 4-cyano-2-methoxybenzaldehyde and 4-amino-5-methyl-2-hydroxypyridine react to prepare a compound 1;
(2) carrying out alkylation reaction on the compound 1 obtained in the step (1) and triethyl orthoformate under the catalysis of acid in an inert solvent or in the absence of a solvent to prepare a compound 2;
(3) reducing the compound 2 obtained in the step (2) by a reducing agent to prepare a compound 3;
(4) in the presence of a catalyst, resolving the compound 3 and alcohol by a chemical method to prepare a chiral compound 4;
the process route is as follows:
2. the synthesis method according to claim 1, wherein the reaction in the step (1) is carried out under a solvent-free condition, and the reaction temperature is room temperature to 110 ℃; the acid is acetic acid, trifluoroacetic acid, methane sulfonic acid or p-toluenesulfonic acid, preferably acetic acid.
3. The synthesis method according to claim 1, wherein the reaction in step (2) is carried out in the absence of a solvent; the reaction temperature is room temperature-100 ℃; the acid is sulfuric acid, the molar ratio of the sulfuric acid to the compound 1 is 1: 20-1: 5, and the amount of triethyl orthoformate is 5-10 mL/g of the compound 1.
4. The method according to claim 1, wherein the reducing agent in step (3) is any one of sodium borohydride, lithium aluminum tetrahydride, diisobutylaluminum hydride tetrahydrofuran solution, diisobutylaluminum hydride toluene solution, diisobutylaluminum hydride cyclohexane solution, diisobutylaluminum hydride heptane solution, sodium aluminum hydride tetrahydrofuran solution, aluminum hydride, lithium aluminum tri-tert-butoxyhydride tetrahydrofuran solution or sodium bis (2-methoxyethoxy) aluminum hydride toluene solution (60 wt%).
5. The synthesis method of claim 1, wherein the catalyst in step (4) is selected from one or more compounds represented by the following structural formula:
6. the synthesis method according to claim 1, wherein the molar ratio of the catalyst in the step (4) to the compound 3 is 0.02-0.5: 1.
7. The method of claim 1, wherein step (4) further comprises a base selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, potassium phosphate, 4-dimethylaminopyridine, N-diisopropylethylamine, triethylamine, pyridine, imidazole, tetrabutylammonium fluoride, 2, 6-lutidine, 1, 8-diazabicyclo [5.4.0] -7-undecene; the molar ratio of the alkali to the compound 3 is 2-5: 1.
8. The synthesis method according to claim 1, wherein the step (4) further comprises an oxidizing agent, wherein the oxidizing agent is 4,4' -diphenoquinone, 3, 5-dimethyl-3 ',5' -di-tert-butyl-4, 4' -diphenoquinone, 3, 5-dimethyl-3 ',5' -diisopropyl-4, 4' -diphenoquinone, 3' -dimethyl-5, 5' -di-tert-butyl-diphenoquinone, 3',5,5' -tetra-tert-butyl- [1,1' -bis (cyclohexyl) ] -2,2',5,5' -tetraene-4, 4' -dione or 4- (3, 5-dimethyl-4-oxo-2, 5-cyclohexadien-1-yl) -2, one or more of 6-dimethyl-2, 5-cyclohexadiene-1-one; the molar ratio of the oxidant to the compound 3 is 0.5-2: 1.
9. The synthesis method of the novel non-neferitone comprises the following steps: reacting compound 4 obtained by the synthesis method of claims 1-8 with ammonia water in a solvent to obtain the non-neferitone I.
10. The method of claim 9, wherein the solvent is an alcohol, and the alcoholic solvent includes but is not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, or t-butanol; the reaction temperature in the step is 0-room temperature, preferably 0-10 ℃, and the reaction time is 10-20 hours, preferably 16-20 hours.
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| CN115322194A (en) * | 2022-08-23 | 2022-11-11 | 浙江国邦药业有限公司 | Method for resolving carboxylic acid of non-neferone intermediate |
| WO2023109968A3 (en) * | 2021-12-18 | 2023-08-03 | 上海鼎雅药物化学科技有限公司 | Synthesis method for finerenone and intermediate thereof |
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