WO2024094181A1 - 通过非对映酒石酸酯拆分外消旋体制备非奈利酮的方法 - Google Patents
通过非对映酒石酸酯拆分外消旋体制备非奈利酮的方法 Download PDFInfo
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- WO2024094181A1 WO2024094181A1 PCT/CN2023/129647 CN2023129647W WO2024094181A1 WO 2024094181 A1 WO2024094181 A1 WO 2024094181A1 CN 2023129647 W CN2023129647 W CN 2023129647W WO 2024094181 A1 WO2024094181 A1 WO 2024094181A1
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- Prior art keywords
- formula
- racemate
- ethanol
- mixture
- water
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- BTBHLEZXCOBLCY-QGZVFWFLSA-N (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Chemical compound 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 title claims abstract description 15
- 229950004408 finerenone Drugs 0.000 title claims abstract description 10
- 150000002148 esters Chemical class 0.000 title abstract 4
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 73
- 239000001488 sodium phosphate Substances 0.000 claims description 28
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 28
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 23
- 150000003899 tartaric acid esters Chemical class 0.000 claims description 15
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 4
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 3
- 239000004254 Ammonium phosphate Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 3
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 3
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 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
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-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
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 239000012043 crude product Substances 0.000 abstract description 17
- 238000002425 crystallisation Methods 0.000 abstract description 15
- 230000008025 crystallization Effects 0.000 abstract description 15
- 238000010494 dissociation reaction Methods 0.000 abstract description 10
- 230000005593 dissociations Effects 0.000 abstract description 10
- 239000011877 solvent mixture Substances 0.000 abstract description 10
- 238000003756 stirring Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 206010013457 Dissociation Diseases 0.000 abstract description 4
- 208000018459 dissociative disease Diseases 0.000 abstract description 4
- 238000005457 optimization Methods 0.000 abstract description 3
- 238000004904 shortening Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 68
- 239000000047 product Substances 0.000 description 27
- 239000000843 powder Substances 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 23
- 238000004458 analytical method Methods 0.000 description 21
- 239000013078 crystal Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000011521 glass Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- IAJFCAIBAPJCDA-SKDRFNHKSA-N (2R,3S)-2,3-dihydroxy-2-(4-methoxybenzoyl)butanedioic acid Chemical compound C(C1=CC=C(C=C1)OC)(=O)[C@](C(=O)O)(O)[C@H](O)C(=O)O IAJFCAIBAPJCDA-SKDRFNHKSA-N 0.000 description 2
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 2
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101001121408 Homo sapiens L-amino-acid oxidase Proteins 0.000 description 1
- 102100026388 L-amino-acid oxidase Human genes 0.000 description 1
- PPWHTZKZQNXVAE-UHFFFAOYSA-N Tetracaine hydrochloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- YNIRKEZIDLCCMC-UHFFFAOYSA-K trisodium;phosphate;hydrate Chemical compound [OH-].[Na+].[Na+].[Na+].OP([O-])([O-])=O YNIRKEZIDLCCMC-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 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
Definitions
- the present invention belongs to the field of pharmaceutical technology, and in particular relates to a method for preparing finerenone by resolving a racemate through diastereomeric tartaric acid esters, and also relates to diastereomeric salts (VIIa), (VIIb), (VIIc) and/or (VIId).
- “Fenerenone” refers to the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, i.e., the compound of formula (Va).
- the compound of formula (V) is the racemate of finerenone.
- Finerenone (Va) is a nonsteroidal antagonist of mineralocorticoid receptors and can be used as a medicament for preventing and/or treating cardiovascular and renal diseases such as heart failure and diabetic nephropathy.
- the compounds of formula (V) or (Va) and their preparation methods are described in WO2008/104306 and WO2016/016287A1 and L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases [J].
- the racemic mixture of amide (V) must be separated into enantiomers (Va) and (Vb);
- Chinese patent application CN112041318A records the separation of the racemate of formula (V), which uses a chiral substituted tartaric acid ester of general formula (IIIa) or (IIIb) to separate into (Va) and/or (Vb).
- the patent only records the use of D-dibenzoyltartaric acid as a resolving agent, and the actual target isomer recovery rate is about 90%, resulting in a large separation loss.
- multiple dissociations are usually required to make the content of the chiral substituted tartaric acid ester of the resolving agent less than 0.15%.
- the present invention provides a method for resolving a racemate of formula (V), which uses a chiral substituted tartaric acid ester of general formula (VIa) or (VIb) as a resolving agent to resolve the racemate of formula (V) to obtain compounds of formula (Va) and/or (Vb).
- Ar is selected from:
- the * represents a connection point.
- Another aspect of the present invention provides a method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Va), which uses a chiral substituted tartaric acid ester of formula (VIa) as a resolving agent to resolve the racemate of formula (V).
- Ar is selected from:
- the * represents a connection point.
- Ar is selected from:
- the * represents a connection point.
- the resolving agent is selected from:
- the resolving agent is selected from:
- the resolving agent is:
- Another aspect of the present invention provides diastereomeric salts of the following formula:
- Ar is selected from:
- the * represents a connection point.
- the diastereomeric salt of formula (VIIa) precipitates almost quantitatively from the solution and can then be separated from the solution, for example, by filtration, wherein the enantiomer with the R configuration remains in the solution.
- the mirror-image salt of formula (VIIb) is prepared by the reaction of the racemate of formula (V) with the chiral substituted tartaric acid ester of formula (VIb), wherein the enantiomer of the R configuration preferentially participates in the formation of the salt.
- the precipitated diastereomeric salt can be separated almost quantitatively, wherein the S-enantiomer remains in the solution.
- Finerenone (Va) has an S configuration.
- S,S-configured tartaric acid esters are preferably used for racemate resolution, preferably forming diastereomeric salts of the S-enantiomer.
- 0.5 to 3.0 equivalents of the chiral substituted tartaric acid ester of formula (VIa) or (VIb) is used as a resolving agent for optical resolution, preferably 0.5 to 1.5 equivalents, more preferably 0.5 to 1.0 equivalents, most preferably 0.55 equivalents.
- the diastereomeric salts are formed in an organic solvent or a solvent mixture consisting of water and a water-miscible organic solvent.
- Suitable organic solvents include ethanol, methanol, isopropanol, n-propanol, dichloromethane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether or acetone, but ethanol is preferably used.
- the following solvents are used: methanol/water 3:1; methanol/acetonitrile 1:1; isopropanol/water 3:1; tetrahydrofuran/water 3:1; acetonitrile/water 3:1.
- the ratio of the solvent ratio refers to the volume to volume ratio (v/v).
- a solvent mixture consisting of ethanol/water 3:1 contains 60 mL of ethanol and 20 mL of water. Therefore, the volume is based on the total volume of the solvent.
- the mixture can be prepared in advance, or prepared in situ after all components are loaded into a container.
- the solvent mixture can be used in 5 to 30 times excess, based on the racemate of formula (V), i.e., 5 to 30L of solvent mixture is used per 1Kg of racemate. Preferably, 5 to 15 times excess.
- Optical resolution is usually carried out as follows: first, the racemate of formula (V) is added to a solvent mixture at room temperature, then heated to 0-78°C, but preferably 70-78°C, and continued to stir at 70-78°C to dissolve, most preferably at a temperature of 75°C. Subsequently, a resolving agent is added to the above system and stirred at 70-78°C for 0.5-3 hours, preferably 0.5-1 hour. Then, it is cooled to 0-30°C, preferably 15-25°C, within 3-15 hours, preferably 3-5 hours. Thereafter, stirring is continued at 15-25°C for 12-24 hours, preferably 12-18 hours, and very preferably 12-14 hours.
- the racemate is added to the solvent mixture and first heated to dissolve, and then the resolving agent is added to obtain a homogeneous system, and the stirring and crystallization are performed for resolution.
- the optimization of the addition order can ensure sufficient salt formation, thereby greatly shortening the crystallization time.
- the precipitated diastereomeric salts (VIIa), (VIIb), (VIIc) and/or (VIId) are subsequently isolated.
- the separation is carried out by methods known to those skilled in the art, for example by filtration or using a centrifuge.
- the filter cake obtained in this way can be washed once or several times with a solvent or a solvent mixture. It is then dried under reduced pressure at a temperature (45 to 65° C., preferably 55° C.).
- diastereomeric salts of very high chemical purity can be prepared.
- the enantiomeric excess of the diastereomeric salts is usually >97.0% e.e.
- the diastereomeric salt is not necessarily required to be dried, and a wet diastereomeric salt may be used in the next step.
- the diastereomeric salts are treated with a base.
- the diastereomeric salts of formula (VIIa), (VIIb), (VIIc) or (VIId) must be treated with a base, and the corresponding tartrate of formula (VIa) or (VIb) remains in the solution in the form of a salt.
- suitable bases are inorganic bases or organic bases.
- inorganic bases ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium phosphate, sodium phosphate or potassium phosphate can be used.
- sodium hydroxide, sodium phosphate or potassium phosphate are used.
- sodium phosphate or potassium phosphate is used. It is important that the inorganic base can be used in anhydrous form or in the form of a hydrate thereof; for example, sodium phosphate anhydrate and sodium phosphate hydrate can be successfully used.
- aliphatic or aromatic bases can be used, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, 1,3-propylenediamine, 1,2-propylenediamine, tripropylamine, cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine, aniline, diphenylamine, triphenylamine, monoethanolamine, diethanolamine, triethanolamine, N-methylmorpholine, pyridine, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide or sodium methoxide. Preference is given to triethylamine, N-methylmorpholine, N,N-diisopropylethylamine or aniline.
- an inorganic base is added at a temperature of 0 to 60° C. to adjust the pH of the system to 6.9 to 9.5.
- an organic base is added at a temperature of 0 to 60° C., and the organic base equivalent is 1.5 to 6.0.
- the mixture can be prepared in advance, or prepared in situ after all components are loaded into the container.
- the amount of the mixture can be 8 to 35 times the amount of the diastereomeric salt (VIIa or VIIb or VIIc or VIId) used, that is, for example, 8 to 35 L of the mixture in 1 Kg. It is preferred to use 15 to 35 times the amount of the mixture, more preferably 25 to 35 times the amount of the mixture, and most preferably 30 times the amount of the mixture.
- the target compound (Va) or (Vb) is released by first adding the diastereomeric salt (VIIa or VIIb or VIIc or VIId) to a mixed solvent at 0°C to 80°C, preferably 20°C to 55°C, and then adding an organic or inorganic base (in solid form or in solution, preferably in water) to adjust the pH to 6.9 to 9.5, preferably 7.1 to 8.0, particularly preferably 7.5.
- the base can be added very quickly (within a few minutes) or very slowly (within a few hours), for example within 3 minutes to up to 2 hours. In any case, faster addition is preferred.
- the addition is metered in 3 to 30 minutes.
- This purpose can be achieved by a pH meter installed in the reactor, which is used to control the adjustment and gradually meter the base. It has been found that it is advantageous to continue stirring again at 10°C to 80°C, preferably 20°C to 65°C, preferably 45°C to 55°C after the pH is established.
- the time for continuous stirring can be 1 to 20 hours, preferably 2 to 6 hours, more preferably 2 to 3 hours.
- the mixture is then cooled to 20°C to 30°C and may then be stirred again for 1 to 40 hours, preferably 3 to 24 hours, more preferably 10 to 18 hours.
- the separation is carried out by methods known to those skilled in the art, for example by filtering or using a centrifuge.
- the filter cake obtained in this way can be washed once or more than once with a solvent or a solvent mixture. It is then dried under reduced pressure (preferably ⁇ 100 mbar) at a temperature (50 to 80° C., preferably 55° C.).
- crude products with very high chemical purity can be prepared.
- the enantiomeric excess of the crude products (Va) and (Vb) is usually >97% e.e., preferably >99% e.e.; the content of the resolving agent tartaric acid ester is ⁇ 0.05%.
- racemate resolution is preferably carried out in an ethanol/water mixture. Subsequently, (Va) is released preferably using sodium phosphate or sodium hydroxide as a base in an ethanol/water mixture:
- the present invention can also separate the target enantiomer from the mother liquor.
- a suitable diastereomeric salt (VIa), (VIb), (VIc) or (VId) is prepared from formula (Va) or (Vb), separated by filtration, and then the corresponding enantiomer is separated by adding a base.
- the organic solvent preferably ethanol, is distilled off at atmospheric pressure or more gently under reduced pressure; this causes the precipitation of the corresponding other enantiomer.
- the product is filtered off, washed with water or a water/organic solvent mixture and dried.
- the present invention adds the racemate to the solvent mixture and heats it to dissolve it first, then adds the resolving agent to obtain a homogeneous system, stirs and crystallizes to perform resolving, and the optimization of the adding sequence can ensure sufficient salt formation, thereby greatly shortening the crystallization time.
- the diastereomeric salt of the present invention can be dissociated once in the alkaline dissociation step to obtain a crude product with very high chemical purity and enantiomeric purity, and the content of the resolving agent tartaric acid ester is less than 0.05%, avoiding the three wastes caused by multiple dissociations, and greatly reducing the production cost.
- FIG1 is an X-ray powder diffraction (XRPD) spectrum of the compound of formula (VII-1).
- Ethanol Ethanol
- DMSO dimethyl sulfoxide
- Yield theoretical value (of th.)
- HPLC high performance liquid chromatography
- 1H nuclear magnetic resonance spectrum (1H-NMR
- room temperature RT
- X-ray powder diffraction XRPD
- differential scanning calorimetry DSC
- thermogravimetric analysis TGA
- hour h
- volume vol
- the off-white crystalline powder (VII-1) obtained according to Example 1a was characterized by X-ray powder diffraction at room temperature. The results are shown in FIG. 1 and Table 1.
- Enantiomeric purity (e.e.%): 97.0% e.e.;
- racemic phenareline (V) 100 g (0.2642 mol) was suspended in a mixture of 900 mL of ethanol and 300 mL of water and heated to 75 ° C. and stirred to dissolve. 52.07 g (0.1453 mol) of D-dibenzoyltartaric acid was added using a solid glass funnel and stirred at 75 ° C. for crystallization for 3.0 hours. The mixture was then cooled to 25 ° C. over 3 hours and stirred at this temperature for 16 hours. The precipitated crystals were filtered out and washed twice with 200 mL of ethanol/water (3:1, v/v). The product was dried under reduced pressure at 55 ° C.
- Enantiomeric purity (e.e.%): 96.7% e.e.
- Enantiomeric purity (e.e.%): 96.5% e.e.;
- Example 1b and Example 2b The crude products obtained after dissociation of the salts of different resolving agents in Example 1b and Example 2b were tested for the residual content of the resolving agent. It was found that when D-di-o-methylbenzoyltartaric acid was used as the resolving agent, the resolving agent content after dissociation was less than 0.10%, which was 0.04%; when D-dibenzoyltartaric acid was used as the resolving agent, the resolving agent content after dissociation was 0.50%, requiring two or more dissociations.
- Example 1a The resolution effects of Example 1a, Example 2a and (+)-O,O-di-p-anisyl (p-anisoyl)-D-tartaric acid disclosed in Patent CN112041318A were compared, and the enantiomeric excess values of different (Va) were measured and summarized in Table 2.
- the resolving agent D-di-o-methylbenzoyltartaric acid of the present invention has the best resolving effect, which is better than the resolving effects of D-dibenzoyltartaric acid and (+)-O,O-di-p-anisyl (p-anisoyl)-D-tartaric acid.
- Enantiomeric purity (e.e.%): 97.0% e.e.
- Enantiomeric purity (e.e.%): 99.3% e.e.;
- the precipitated crystals were filtered out and washed with 100 g of water.
- the wet product was then hot-beaten at 50°C for 1 hour with 100 g of purified water, cooled to 23°C and stirred for 1 hour, the solid was filtered out, rinsed with 100 g of purified water, and dried under reduced pressure at 55°C to obtain the final product. Yield: 45.8 g (92.6% of theoretical value) of off-white crystalline powder.
- Enantiomeric purity (e.e.%): 98.0% e.e.;
- Enantiomeric purity (e.e.%): 100.0% e.e.
- Enantiomeric purity (e.e.%): 96.5% e.e.
- Enantiomeric purity (ee%): 98.1% ee.
- This crude product can be used to prepare pure form of phenerenone (Va) in a manner similar to that described in Example 5c.
- Enantiomeric purity (e.e.%): 90.7% e.e.
- Enantiomeric purity (e.e.%): 90.5% e.e.;
- Enantiomeric purity (e.e.%): 88.1% e.e.
- Enantiomeric purity (e.e.%): 88.0% e.e.;
- Enantiomeric purity (e.e.%): 93.1% e.e.
- Enantiomeric purity (e.e.%): 93.3% e.e.;
- Enantiomeric purity (e.e.%): 95.6% e.e.
- Enantiomeric purity (e.e.%): 95.5% e.e.;
- Enantiomeric purity (e.e.%): 92.7% e.e.
- Enantiomeric purity (e.e.%): 92.7% e.e.;
- Enantiomeric purity (e.e.%): 92.9% e.e.
- Enantiomeric purity (e.e.%): 92.6% e.e.;
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Abstract
提供一种通过非对映酒石酸酯拆分外消旋体制备非奈利酮的方法,还涉及非对映体盐(VIIa)、(VIIb)、(VIIc)和/或(VIId)。拆分方法使用通式(VIa)或(VIb)的手性取代的酒石酸酯作为拆分剂,拆分式(V)的外消旋体以获得式(Va)和/或(Vb)的化合物。将外消旋体加入溶剂混合物中先加热溶清,后加入拆分剂得到均相体系,搅拌析晶进行拆分,加料顺序的优化可以保证成盐充分,从而大大缩短结晶的时间。在碱解离的步骤中,可以一次解离获得化学纯度和对映体纯度非常高的粗产品,拆分剂酒石酸酯的含量<0.05%,避免多次解离造成的三废,大大降低生产成本。
Description
本发明要求2022年11月04日向中国国家知识产权局提交的,专利申请号为202211374807.2,发明名称为“通过非对映酒石酸酯拆分外消旋体制备非奈利酮的方法”的在先申请的优先权。上述在先申请的全文通过引用的方式结合于本发明中。
本发明属于医药技术领域,具体涉及一种通过非对映酒石酸酯拆分外消旋体制备非奈利酮的方法,还涉及非对映体盐(VIIa)、(VIIb)、(VIIc)和/或(VIId)。
“非奈利酮”涉及化合物(4S)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺,即式(Va)的化合物,式(V)的化合物为非奈利酮的外消旋体,
表述“非奈利酮的对映体”或“式(V)的化合物的对映体”涉及式(Va)和(Vb)的化合物,
非奈利酮(Va)作为盐皮质激素受体的非甾体拮抗剂,并且可用作预防和/或治疗心血管和肾脏疾病例如心力衰竭和糖尿病肾病的药剂。式(V)或(Va)的化合物及其制备方法记载于WO2008/104306和和WO2016/016287A1以及L,Kuhl A,Hillisch A,et al.Discovery of BAY 94‐8862:a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases[J].ChemMedChem,2012,7(8):1385-1403.为了获得光学纯的式(V)化合物,必须将酰胺的外消旋混合物(V)分离成对映体(Va)和(Vb);
因为仅式(Va)具有活性;
中国专利申请CN112041318A记载了式(V)的外消旋体拆分,其使用通式(IIIa)或(IIIb)的手性取代的酒石酸酯而拆分为(Va)和/或(Vb)。但该专利仅记载了采用D-二苯甲酰基酒石酸作为拆分剂,实际目标异构体回收率约为90%,拆分损失较大。且在用碱处理非对映异构体盐的步骤,通常需要多次解离才能使得拆分剂手性取代的酒石酸酯含量低于0.15%。
发明内容
本发明提供一种式(V)的外消旋体的拆分方法,其使用通式(VIa)或(VIb)的手性取代的酒石酸酯作为拆分剂,拆分式(V)的外消旋体以获得式(Va)和/或(Vb)的化合物,
其中Ar选自:
其中*代表连接点。
本发明另一方面提供一种制备式(Va)的(4S)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的方法,其使用式(VIa)的手性取代的酒石酸酯作为拆分剂,拆分式(V)的外消旋体,
其中Ar选自:
其中*代表连接点。
优选地,Ar选自:
其中*代表连接点。
本发明实施例中,拆分剂选自:
优选地,拆分剂选自:
特别优选地,拆分剂为:
本发明另一方面还提供下式的非对映体盐:
其中Ar选自:
其中*代表连接点。
非对映体盐(VIIa至VIId)的制备如下进行:
式(V)的外消旋体与式(VIa)或(VIb)的手性取代的酒石酸酯的反应导致形成非对映体盐的4种选择(VIIa、VIIb、VIIc和VIId)。如果式(V)的外消旋体与式(VIa)的手性取代的酒石酸酯反应,则得到的是式(VIIa)的非对映体盐,其中S构型的对映体优先参与盐的形成。式(VIIa)的非对映体盐几乎定量地从溶液中沉淀出来,然后例如可通过过滤将其从溶液中分离出来,其中具有R构型的对映体保留在溶液中。式(VIIb)的镜像盐是通过式(V)的外消旋体与式(VIb)的手性取代的酒石酸酯的反应制备的,其中R构型的对映体优先参与盐的形成。沉淀的非对映体盐可以几乎定量地分离出来,此处S-对映体保留在溶液中。
(V)与(VIa)/(VIb)的化学计量比以及溶剂的选择可用于优化收率和对映体纯度。
非奈利酮(Va)具有S构型。S,S-构型的酒石酸酯优选用于外消旋体拆分,优选形成S-对映体的非对映体盐。
0.5至3.0当量的式(VIa)或(VIb)的手性取代的酒石酸酯作为拆分剂用于光学拆分,优选0.5至1.5当量,更优选0.5至1.0当量,最优选0.55当量。
非对映体盐在有机溶剂或由水和水混溶性有机溶剂组成的溶剂混合物中形成。
合适的有机溶剂的实例包括乙醇、甲醇、异丙醇、正丙醇、二氯甲烷、四氢呋喃、乙腈、甲基叔丁基醚或丙酮,但优选使用乙醇。此外,还使用了以下溶剂:甲醇/水3:1;甲醇/乙腈1:1;异丙醇/水3:1;四氢呋喃/水3:1;乙腈/水3:1。其中溶剂比的比率是指体积与体积之比(v/v)。例如,由乙醇/水3:1组成的溶剂混合物包含60mL乙醇和20mL水。因此,体积基于溶剂的总体积计。
优选在乙醇/水中进行光学拆分,其中混合比(v/v)在乙醇:水=1:1至9:1的范围内。但优选使用乙醇:水=3:1至9:1的混合物。特别优选乙醇:水=3:1的混合物。混合物可以预先制备,或者在容器中装入所有组分后原位制备。溶剂混合物可以5至30倍过量使用,基于式(V)的外消旋体计,即每1Kg外消旋体使用5至30L溶剂混合物。优选5至15倍过量。
光学拆分通常如下进行:首先在室温下将式(V)的外消旋体加入溶剂混合物中,然后加热至0~78℃,但优选70~78℃,并在70~78℃下继续搅拌溶清,最优选在75℃的温度。随后,将拆分剂加入上述体系中,在70~78℃下搅拌0.5~3小时、优选0.5~1小时。然后在3~15小时、优选3~5小时内冷却至0~30℃,优选15~25℃。此后,在15~25℃下继续搅拌12~24小时,优选12~18小时,非常优选12~14小时。本发明将外消旋体加入溶剂混合物中先加热溶清,后加入拆分剂得到均相体系,搅拌析晶进行拆分,加料顺序的优化可以保证成盐充分,从而大大缩短结晶的时间。
随后分离沉淀的非对映体盐(VIIa)、(VIIb)、(VIIc)和/或(VIId)。
通过本领域技术人员已知的方法进行分离,例如通过过滤或使用离心机。以这种方式获得的滤饼可以用溶剂或溶剂混合物洗涤一次或几次。然后在减压下,在温度(45~65℃,优选55℃)下进行干燥。
使用上述步骤,可以制备化学纯度非常高的非对映体盐。所述非对映体盐的对映体过量通常>97.0%e.e.
非对映体盐不一定非要干燥,在下一个工序中也可以使用湿的非对映体盐。
在下一步中,使用碱处理非对映体盐。为了制备手性化合物(Va)和(Vb),式(VIIa)、(VIIb)、(VIIc)或(VIId)的非对映体盐必须用碱进行处理,式(VIa)或(VIb)的相应酒石酸酯以盐的形式保留在溶液中。
在本发明的上下文中,合适的碱是无机碱或有机碱。对于无机碱,可以使用氨、氢氧化钠、氢氧化锂、氢氧化钾、碳酸铵、碳酸钠、碳酸钾、碳酸锂、碳酸氢铵、碳酸氢钠、碳酸氢钾、磷酸铵、磷酸钠或磷酸钾。优选使用氢氧化钠、磷酸钠或磷酸钾。特别优选使用磷酸钠或磷酸钾。重要的是无机碱可以无水形式或其水合物的形式使用;例如,可以成功地使用磷酸钠无水物和磷酸钠水合物。对于有机碱,可以使用脂族或芳族碱,如甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、丙胺、异丙胺、1,3-丙二胺、1,2-丙二胺、三丙胺、环己胺、二环己胺、N,N-二异丙基乙胺、苯胺、二苯胺、三苯胺、一乙醇胺、二乙醇胺、三乙醇胺、N-甲基吗啉、吡啶、叔丁醇钠、叔丁醇钾、乙醇钠或甲醇钠。优选三乙胺、N-甲基吗啉、N,N-二异丙基乙胺或苯胺。
本发明某实施例,在0~60℃的温度下,添加无机碱将体系的pH调节至6.9至9.5。
本发明某实施例,在0~60℃的温度下,添加有机碱,有机碱当量为1.5至6.0。
目标化合物(Va)或(Vb)在水和水混溶性有机溶剂(如乙醇、异丙醇、甲醇或丙酮)的混合物中释放,优选为乙醇。已经发现使用水和乙醇的混合物是有利的,其中混合
比(v/v)为乙醇∶水=1∶20至1∶3。但优选使用乙醇∶水=1∶19的混合物。混合物可以预先制备,或者在容器中装入所有组分后原位制备。该混合物的用量可以是所使用的非对映体盐(VIIa或VIIb或VIIc或VIId)的8至35倍,即例如,1Kg中有8至35L的该混合物。优选使用该混合物量的15至35倍,更优选该混合物量的25至35倍,最优选该混合物量的30倍。
目标化合物(Va)或(Vb)通过以下步骤释放:首先在0℃至80℃、优选20℃至55℃下将非对映体盐(VIIa或VIIb或VIIc或VIId)加入混合溶剂中,然后加入有机或无机碱(固体形式或溶液形式,优选在水中)以将pH调节至6.9至9.5、优选7.1至8.0、特别优选7.5。可以非常快速地(在几分钟内),或非常缓慢地(在几小时内)添加碱,例如在3分钟至最高达2小时内。在任何情况下都优选更快速地添加。优选在3分钟至30分钟内计量添加。此目的可以通过安装在反应器中的pH计来实现,使用其来控制调节并逐渐计量加入碱。已发现在建立pH后再次在10℃~80℃,优选20℃~65℃,优选45℃~55℃下持续搅拌是有利的。持续搅拌的时间可以是1~20小时,优选2~6小时,更优选2~3小时。然后将混合物冷却至20℃~30℃,然后可再次搅拌1~40小时,优选3~24小时,更优选10~18小时。
分离通过本领域技术人员已知的方法进行,例如通过过滤或使用离心机。以这种方式获得的滤饼可以用溶剂或溶剂混合物洗涤一次或多于一次。然后在减压(优选<100mbar)下在温度(50~80℃,优选55℃)下进行干燥。
使用上述步骤,可以制备化学纯度非常高的粗产品。所述粗产物(Va)和(Vb)的对映体过量通常>97%e.e.,优选的>99%e.e.;拆分剂酒石酸酯的含量<0.05%。
作为特别优选的方法,特别是用于在工业规模上实施,使用D-二邻甲基苯甲酰酒石酸(VI-1)作为拆分剂:
外消旋体拆分优选在乙醇/水混合物中进行。随后,优选在乙醇/水混合物中使用磷酸钠或者氢氧化钠作为碱释放(Va):
本发明还可以从母液中分离目标对映体。本文中,由式(Va)或(Vb)制备合适的非对映体盐(VIa)、(VIb)、(VIc)或(VId),通过过滤分离,然后通过添加碱将包含相应的
其他非对应体的母液的pH调节至pH>7、优选pH=7.5,所述碱为氨、氢氧化钠、氢氧化锂、氢氧化钾、碳酸铵、碳酸钠、碳酸钾、碳酸锂、碳酸氢铵、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾、磷酸铵,优选使用氢氧化钠、磷酸钠或磷酸钾,特别优选使用磷酸钠或磷酸钾。然后再大气压下或更温和地在减压蒸馏出有机溶剂,优选乙醇;这引起相应的其他对映体沉淀。将产物滤出,用水或水/有机溶剂混合物洗涤并干燥。
有益效果:本发明将外消旋体加入溶剂混合物中先加热溶清,后加入拆分剂得到均相体系,搅拌析晶进行拆分,加料顺序的优化可以保证成盐充分,从而大大缩短结晶的时间。此外本发明的非对映体盐在碱解离的步骤中,可以一次解离获得化学纯度和对映体纯度非常高的粗产品,拆分剂酒石酸酯的含量<0.05%,避免多次解离造成的三废,大大降低生产成本。
图1是式(VII-1)化合物的X-射线粉末衍射(XRPD)谱图。
试剂缩写和首字母缩略词如下所示:
乙醇(EtOH)、二甲基亚砜(DMSO)、(收率)理论值的(of th.)、高效液相色谱(HPLC)、1H核磁共振谱(1H-NMR)、室温(RT)、X-射线粉末衍射(XRPD)、差示扫描量热(DSC)、热重分析(TGA)、小时(h)、体积(vol)。
实施例1
实施例1a
非对映体盐(VII-1)的制备:
将100g(0.2642mol)外消旋非奈利酮(V)悬浮于900mL乙醇和300mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加56.15g(0.1453mol)D-二邻甲基苯甲酰酒石酸,在75℃搅拌析晶1.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用200mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:100.2g(理论值的99.2%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):97.2%e.e.;1H-NMR(400MHz,DMSO-d6):δ=7.90-7.85(m,2H),7.70(s,1H),7.58-7.52(m,3H),7.42-7.35(m,5H),7.29(dd,J=7.9,1.5Hz,1H),7.16(d,J=7.9Hz,1H),6.73(d,J=33.4Hz,2H),5.88(s,2H),5.38(s,1H),4.01(qt,J=6.7,3.4Hz,2H),3.83(s,3H),2.55(s,6H),2.19(s,3H),2.13(s,3H),1.05(t,J=7.0Hz,
3H).
根据实施例1a获得的类白色晶体粉末(VII-1)在室温下表征X-射线粉末衍射,结果示于图1和表1中。
表1
实施例1b
制备粗产物(Va):
将100g实施例1a中制备的化合物(VII-1)悬浮于150mL乙醇和2850mL水组成的混合物中。随后,在1小时内线性匀速加入356.5g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用200mL乙醇/水(5:95,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:47.0g(理论值的95.0%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):97.0%e.e.;
D-二邻甲基苯甲酰酒石酸的含量:0.04%;
1H-NMR(400MHz,DMSO-d6):δ=7.69(s,1H),7.56(s,1H),7.37(d,J=1.5Hz,1H),7.28(dd,J=7.9,1.5Hz,1H),7.15(d,J=7.8Hz,1H),6.72(d,J=29.6Hz,2H),5.38(s,1H),4.02(qt,J=7.0,3.2Hz,2H),3.83(s,3H),2.16(d,J=25.7Hz,6H),1.05(t,J=7.0Hz,3H).
实施例2
实施例2a
非对映体盐(VII-2)的制备:
将100g(0.2642mol)外消旋非奈利酮(V)悬浮于900mL乙醇和300mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加52.07g(0.1453mol)D-二苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用200mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:100.0g(理论值的100.0%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):96.7%e.e.。
实施例2b
制备粗产物(Va):
将100g实施例2a中制备的化合物悬浮于100mL乙醇和900mL水组成的混合物中。随后,在1小时内线性匀速加入367.2g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用200mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:45.0g(理论值的87.6%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):96.5%e.e.;
D-二苯甲酰酒石酸的含量:0.50%。
实施例3
将实施例1b和实施例2b中不同拆分剂的盐解离后得到的粗品进行拆分剂残留含量的检测可知,使用D-二邻甲基苯甲酰酒石酸作为拆分剂,解离后其拆分剂含量小于0.10%,为0.04%;使用D-二苯甲酰酒石酸作为拆分剂,解离后其拆分剂含量为0.50%,需要二次或更多次解离。
实施例4
将实施例1a、实施例2a以及根据专利CN112041318A中公布的(+)-O,O-二-对茴香酰基(p-anisoyl)-D-酒石酸的拆分效果进行对比,测量不同(Va)的对映体过量值总结于表2中。
表2
由上表可知,本发明的拆分剂D-二邻甲基苯甲酰酒石酸,拆分效果最好,优于D-二苯甲酰酒石酸及(+)-O,O-二-对茴香酰基(p-anisoyl)-D-酒石酸的拆分效果。
实施例5
实施例5a
非对映体盐(VII-1)的制备:
将100g(0.2642mol)外消旋非奈利酮(V)悬浮于900mL乙醇和300mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加56.15g(0.1453mol)D-二邻甲基苯甲酰酒石酸,在75℃搅拌析晶1.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用200mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:100.3g(理论值的99.3%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):97.0%e.e.。
实施例5b
制备粗产物(Va):
将100g实施例5a中制备的化合物(VII-1)悬浮于500mL乙醇中,在40℃下逐步计量加入2.0当量(33.80g,0.2615mol)的N,N-二异丙基乙胺,在此温度下将混合物搅拌1小时。降温至5℃后在此温度下将混合物搅拌1小时。过滤出沉淀的固体。将产物在40℃下在减压干燥。收率:42.1g(理论值的85.1%)白色结晶粉末。
分析结果:
对映体纯度(e.e.%):99.3%e.e.;
D-二邻甲基苯甲酰酒石酸的含量:0.08%。
实施例5c
制备粗产物(Va):
将100g外消旋非奈利酮(V)参考实施例5a再制备一批非对映体盐(VII-1);将100
g非对映体盐(VII-1)悬浮于3000mL水中。随后,在10分钟内线性匀速加入88.8g氢氧化钠水溶液(8.8g氢氧化钠溶解于80g水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至23℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用100g水洗涤。湿品再用纯化水100g于50℃热打浆1小时,降温至23℃搅拌1小时,过滤出固体,以纯化水100g淋洗,在55℃下减压干燥得最终产物。收率:45.8g(理论值的92.6%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):98.0%e.e.;
D-二邻甲基苯甲酰酒石酸的含量:未检出。
实施例5d
制备纯产物(Va):
将40g在实施例5b中制备的粗品悬浮在880mL乙醇中,然后加热至回流。加热时,产物溶解。在此温度下继续搅拌1小时。通过加热的压滤器(T=75℃)过滤溶液。然后蒸馏溶剂直至获得最终体积的约四倍(相对于所用物质:40g×4~160mL)(蒸馏掉约720mL)。然后将混合物冷却至内部温度23℃(经过约1.5至2小时)。然后将混合物在内部温度3℃下搅拌2小时。过滤产物,并用80mL冲洗一次。将湿产物在减压下干燥48h。收率:36.6g(理论值的91.5%)无色结晶粉末。
分析结果:
对映体纯度(e.e.%):100.0%e.e.。
实施例6
非奈利酮对映体(Vb)的分离。
实施例6a
L-二邻甲基苯甲酰酒石酸盐的制备:
将100g(0.2642mol)外消旋非奈利酮(V)悬浮于900mL乙醇和300mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加56.15g(0.1453mol)L-二邻甲基苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用200mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:100.7g(理论值的99.7%)类白色结晶粉末。
对映体纯度(e.e.%):96.5%e.e.。
实施例6b
从母液中分离非奈利酮(Va):
在室温下,通过加入磷酸钠水溶液(100g磷酸钠溶解于1000mL水中)将实施例6a中合并的母液和洗涤液调节至pH=7.5。然后开启减压蒸馏将乙醇全部蒸出,使得剩余体积为约0.4L。将混合物冷却至25℃,并在25℃下搅拌3小时。过滤产物,并用200mL冲洗4次。将湿产物在减压(48h)。收率:46.8g(理论值的93.6%)无色结晶粉末。
分析结果:
对映体纯度(e.e.%):98.1%e.e.。
L-二邻甲基苯甲酰酒石酸的含量:0.51%。
以类似于实施例5c中所述的方式,该粗产物可用于制备纯的形式的非奈利酮(Va)。
实施例7
实施例7a
非对映体盐(VII-3)的制备:
将10g(0.02642mol)外消旋非奈利酮(V)悬浮于90mL乙醇和30mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加6.21g(0.01454mol)D-二邻氯苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用20mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:9.1g(理论值的85.5%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):90.7%e.e.。
实施例7b
制备粗产物(Va):
将5g实施例7a中制备的化合物悬浮于5mL乙醇和45mL水组成的混合物中。随后,在1小时内线性匀速加入10.2g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用10mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:2.1g(理论值的89.4%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):90.5%e.e.;
D-二邻氯苯甲酰酒石酸的含量:0.63%。
实施例8
实施例8a
非对映体盐(VII-4)的制备:
将10g(0.02642mol)外消旋非奈利酮(V)悬浮于90mL乙醇和30mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加6.21g(0.01454mol)D-二间氯苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用20mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:9.2g(理论值的86.4%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):88.1%e.e.。
实施例8b
制备粗产物(Va):
将5g实施例8a中制备的化合物悬浮于5mL乙醇和45mL水组成的混合物中。随后,在1小时内线性匀速加入10.2g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用10mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:2.0g(理论值的85.2%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):88.0%e.e.;
D-二间氯苯甲酰酒石酸的含量:0.65%。
实施例9
实施例9a
非对映体盐(VII-5)的制备:
将10g(0.02642mol)外消旋非奈利酮(V)悬浮于90mL乙醇和30mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加7.50g(0.01454mol)D-二邻溴苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用20mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:10.3g(理论值的87.1%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):93.1%e.e.。
实施例9b
制备粗产物(Va):
将5g实施例9a中制备的化合物悬浮于5mL乙醇和45mL水组成的混合物中。随后,在1小时内线性匀速加入10.1g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用10mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:1.9g(理论值的89.8%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):93.3%e.e.;
D-二邻溴苯甲酰酒石酸的含量:0.35%。
实施例10
实施例10a
非对映体盐(VII-6)的制备:
将10g(0.02642mol)外消旋非奈利酮(V)悬浮于90mL乙醇和30mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加6.08g(0.01454mol)D-二间甲氧基苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用20mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:9.9g(理论值的94.0%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):95.6%e.e.。
实施例10b
制备粗产物(Va):
将5g实施例10a中制备的化合物悬浮于5mL乙醇和45mL水组成的混合物中。随后,在1小时内线性匀速加入10.3g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用10mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:2.2g(理论值的92.6%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):95.5%e.e.;
D-二间甲氧基苯甲酰酒石酸的含量:0.13%。
实施例11
实施例11a
非对映体盐(VII-7)的制备:
将10g(0.02642mol)外消旋非奈利酮(V)悬浮于90mL乙醇和30mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加6.84g(0.01454mol)D-二对叔丁基苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用20mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:10.5g(理论值的93.6%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):92.7%e.e.。
实施例11b
制备粗产物(Va):
将5g实施例11a中制备的化合物悬浮于5mL乙醇和45mL水组成的混合物中。随后,在1小时内线性匀速加入10.2g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用10mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:1.9g(理论值的85.2%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):92.7%e.e.;
D-二对叔丁基苯甲酰酒石酸的含量:0.45%。
实施例12
实施例12a
非对映体盐(VII-8)的制备:
将10g(0.02642mol)外消旋非奈利酮(V)悬浮于90mL乙醇和30mL水组成的混合物中,并加热至75℃搅拌溶清。使用固体玻璃漏斗添加5.94g(0.01454mol)D-二邻氰基苯甲酰酒石酸,在75℃搅拌析晶3.0小时。随后将混合物通过3小时降温至25℃,并在该温度下搅拌16小时,过滤出沉淀的晶体并用20mL乙醇/水(3:1,v/v)洗涤两次。在55℃下在减压下干燥产物。
收率:9.5g(理论值的91.4%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):92.9%e.e.。
实施例12b
制备粗产物(Va):
将5g实施例12a中制备的化合物悬浮于5mL乙醇和45mL水组成的混合物中。随后,在1小时内线性匀速加入10.4g磷酸钠水溶液(100g磷酸钠溶解于1000mL水中),并将pH调节至pH=7.5。在1小时内,将混合物加热至内温为55℃,并在该温度下搅拌3.0小时。将混合物在1小时内降温至20℃,并在该温度下再搅拌1小时。过滤出沉淀的晶体并用10mL乙醇/水(10:90,v/v)洗涤两次。在55℃下在减压下干燥产物。收率:2.2g(理论值的91.5%)类白色结晶粉末。
分析结果:
对映体纯度(e.e.%):92.6%e.e.;
D-二邻氰基苯甲酰酒石酸的含量:0.15%。
Claims (14)
- 一种式(V)的外消旋体的拆分方法,使用通式(VIa)或(VIb)的手性取代的酒石酸酯作为拆分剂,拆分式(V)的外消旋体以获得式(Va)和/或(Vb)的化合物,
其中Ar选自:
其中*代表连接点。 - 一种制备式(Va)的(4S)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的方法,使用式(VIa)的手性取代的酒石酸酯作为拆分剂,拆分式(V)的外消旋体,
其中Ar选自:
其中*代表连接点。 - 根据权利要求1或2所述的方法,所述外消旋体的拆分在乙醇/水二元溶剂体系中进行。
- 根据权利要求3所述的方法,所述外消旋体的拆分在60~80℃的温度范围内进行。
- 根据权利要求4所述的方法,所述拆分剂选自:
- 根据权利要求5所述的方法,所述拆分剂选自:
- 根据权利要求1或2所述的方法,分离沉淀的非对映体盐(VIIa)、(VIIb)、(VIIc)和/或(VIId)。
- 根据权利要求7所述的方法,用碱处理非对映体盐,并除去溶剂。
- 根据权利要求8所述的方法,所述碱为无机碱,选自氨、氢氧化钠、氢氧化锂、氢氧化钾、碳酸铵、碳酸钠、碳酸钾、碳酸锂、碳酸氢铵、碳酸氢钠、碳酸氢钾、磷酸铵、磷酸钠或磷酸钾。
- 根据权利要求8所述的方法,所述碱为有机碱,选自甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、丙胺、异丙胺、1,3-丙二胺、1,2-丙二胺、三丙胺、环己胺、二环己胺、N,N-二异丙基乙胺、苯胺、二苯胺、三苯胺、一乙醇胺、二乙醇胺、三乙醇胺、N-甲基吗啉、吡啶、叔丁醇钠、叔丁醇钾、乙醇钠或甲醇钠。
- 根据权利要求8所述的方法,式(V)的外消旋体与式(VI-1)的D-二邻甲基苯甲酰酒石酸,
在乙醇/水二元溶剂体系中反应得到式(VII-1)的非对映体盐,
随后,在乙醇/水的二元溶剂体系中,使用磷酸钠或氢氧化钠水溶液来解离非奈利酮(Va),
- 下式的非对映体盐,
其中Ar选自:
其中*代表连接点。 - 式(VII-1)的非对映体盐,
- 根据权利要求13所述的非对映体盐,式(VII-1)的非对映体盐为结晶形式,其XRPD图谱在2θ为8.2°±0.2°、11.1°±0.2°、14.6°±0.2°、14.9°±0.2°、16.6°±0.2°、16.9°±0.2°、18.8°±0.2°、19.2°±0.2°、21.9°±0.2°和25.7°±0.2°处具有衍射峰。
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CN112041318A (zh) * | 2018-04-24 | 2020-12-04 | 拜耳公司 | 通过外消旋体拆分使用非对映体酒石酸酯制备(4s)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的方法 |
CN114555598A (zh) * | 2019-10-17 | 2022-05-27 | 拜耳公司 | 制备(4r,4s)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的光化学方法 |
CN114605410A (zh) * | 2022-04-06 | 2022-06-10 | 浙江科聚生物医药有限公司 | 一种非奈利酮原料药的制备方法 |
CN114698375A (zh) * | 2019-10-17 | 2022-07-01 | 拜耳公司 | 通过非对映酒石酸酯拆分外消旋体制备2-氰基乙基(4s)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-羧酸酯的方法 |
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CN112041318A (zh) * | 2018-04-24 | 2020-12-04 | 拜耳公司 | 通过外消旋体拆分使用非对映体酒石酸酯制备(4s)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的方法 |
CN114555598A (zh) * | 2019-10-17 | 2022-05-27 | 拜耳公司 | 制备(4r,4s)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的光化学方法 |
CN114698375A (zh) * | 2019-10-17 | 2022-07-01 | 拜耳公司 | 通过非对映酒石酸酯拆分外消旋体制备2-氰基乙基(4s)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-羧酸酯的方法 |
CN114605410A (zh) * | 2022-04-06 | 2022-06-10 | 浙江科聚生物医药有限公司 | 一种非奈利酮原料药的制备方法 |
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