CN108264499A - A kind of preparation method of benzodiazepine * derivatives - Google Patents
A kind of preparation method of benzodiazepine * derivatives Download PDFInfo
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- CN108264499A CN108264499A CN201810003775.2A CN201810003775A CN108264499A CN 108264499 A CN108264499 A CN 108264499A CN 201810003775 A CN201810003775 A CN 201810003775A CN 108264499 A CN108264499 A CN 108264499A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title abstract description 7
- 229940049706 benzodiazepine Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- 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 31
- -1 hexafluorophosphate Chemical compound 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 14
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 9
- 229940102253 isopropanolamine Drugs 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 claims description 7
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 7
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 239000007822 coupling agent Substances 0.000 claims description 7
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- KHVZPFKJBLTYCC-UHFFFAOYSA-N (2-amino-5-bromophenyl)-pyridin-2-ylmethanone Chemical compound NC1=CC=C(Br)C=C1C(=O)C1=CC=CC=N1 KHVZPFKJBLTYCC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000012964 benzotriazole Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 0 C1**COC1 Chemical compound C1**COC1 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 150000008282 halocarbons Chemical group 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- RULINAWEYRMHHQ-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-methoxy-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC)C(O)=O)C3=CC=CC=C3C2=C1 RULINAWEYRMHHQ-SFHVURJKSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CUKXRHLWPSBCTI-UHFFFAOYSA-N 2-amino-5-bromobenzoic acid Chemical compound NC1=CC=C(Br)C=C1C(O)=O CUKXRHLWPSBCTI-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- NTDNEOWLKYXXQX-UHFFFAOYSA-N C1NCC[U]C1 Chemical compound C1NCC[U]C1 NTDNEOWLKYXXQX-UHFFFAOYSA-N 0.000 description 1
- KVTBAGHTJLKAON-UHFFFAOYSA-N CN1CC[U]CC1 Chemical compound CN1CC[U]CC1 KVTBAGHTJLKAON-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- HINRIEKCOPUIHF-UHFFFAOYSA-N O[P-](N1CCNCC1)[NH+]1CCOCC1 Chemical compound O[P-](N1CCNCC1)[NH+]1CCOCC1 HINRIEKCOPUIHF-UHFFFAOYSA-N 0.000 description 1
- LVVIMTPAWDVLBQ-UHFFFAOYSA-N S(=O)(=O)(O)C1=CC=C(C)C=C1.C(CC)(=O)OC Chemical compound S(=O)(=O)(O)C1=CC=C(C)C=C1.C(CC)(=O)OC LVVIMTPAWDVLBQ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003109 amnesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of benzodiazepinesThe preparation method of derivative.In particular it relates to one kind as shown in starting material formula (V) compound shown in preparation of compounds of formula (III), prepare compound shown in formula (II) after the reaction was continued, finally obtain benzodiazepine shown in formula (I)Derivative, its officinal salt preparation method and preparation process in intermediate and preparation method thereof.This method shortens reaction step, improves reaction yield, simple easily manipulation, conducive to industrial expanding production, and specific preparation method is as follows.
Description
Technical Field
The invention relates to a benzodiazepineA preparation method of the derivative.
Background
The chemical name of the compound of formula (Ia) is (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives-4-yl) propionic acid methyl ester,
patent WO0069836A1 reports on carboxylic acid esters and benzodiazepinesThe structured compounds are short-acting Central Nervous System (CNS) inhibitors with sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. They can be used for intravenous administration in clinical treatment regimens: pre-operative sedation, anxiolytic and amnesic uses such as during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics;ICU tranquilization, etc. WO0069836A1 and WO2013029431A1 disclose a benzodiazepineThe preparation method of the derivative and the tosilate thereof comprises the following steps:
according to the method, reactants used in the preparation of the compound shown in the formula (4) need to be subjected to coupling reaction under a heating reflux condition and ring closure reaction under a basic condition, and an acid is added to remove a protecting group Fmoc, so that the yield is 55%; when the compound shown in the formula (6) is prepared, an inert gas protection reaction system is not carried out, the used strong base deprotonating agent is sodium hydride, and the yield is only 37%; the addition of DMSO, oxalyl chloride and methylene chloride used in the preparation of the compound of formula (Ia) is direct mixing, which is disadvantageous for industrial scale-up.
WO2011032692A1 discloses another benzodiazepineThe preparation method of the derivative comprises the following steps:
the method uses the starting reactants in the preparation of the compound shown as the formula (D)tBoc-Glu (OMe) -OH, reacting under the action of coupling agent DCC to obtain a compound shown in a formula (B), adding hydrochloric acid to remove Boc protecting group to obtain a compound shown in a formula (C), adding sodium bicarbonate to carry out cyclization reaction to obtain a compound shown in a formula (D), reacting with dimorpholinyl phosphinic chloride under the action of deprotonating reagent to obtain a compound shown in a formula (E), reacting with R-isopropanolamine with single configuration to obtain a compound shown in a formula (F), and reacting with 1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) ketone (dess-martin)An oxidant, Dess-Martin periodinane) to obtain a compound shown as a formula (G), and adding hydrochloric acid to perform cyclization reaction to obtain a compound shown as a formula (Ia); among them, isopropanolamine used in the reaction for preparing the compound represented by the formula (F) has a single R configuration, the yield is 56%, the chemical purity of the reaction for preparing the compound represented by the formula (Ia) is 93.91%, and the purity of the product obtained by the reaction with the single configuration R-isopropanolamine is low, so that there is a need for improving the existing preparation method.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing the compound shown in the formula (Ia), wherein the purity and the yield of the product are improved by changing the starting raw materials to improve the yield of an intermediate, optimizing reaction conditions such as reaction temperature and the like, and changing post-treatment methods and other ways; the method is simple and easy to control, reactants such as starting materials are simple and easy to purchase, the reaction conditions are simple and controllable, the post-reaction treatment method is simple, the reaction yield is obviously improved, and the method is beneficial to industrial expanded production.
The technical scheme of the invention is as follows:
the invention provides a method for preparing a compound shown as a formula (III), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which is characterized by comprising the following steps:
the first step is that the compound shown in the formula (V) reacts with (2-amino-5-bromophenyl) (pyridine-2-yl) ketone in the presence of a coupling agent to obtain a compound shown in the formula (IV),
the second step is that the compound shown in the formula (IV) reacts under the alkali condition to obtain the compound shown in the formula (III),
wherein,
r is hydrogen or an amino protecting group;
the amino protecting group is preferably an alkoxycarbonyl amino protecting group, an acyl amino protecting group, a sulfonyl amino protecting group or an alkyl amino protecting group,
the alkoxycarbonyl amino protecting group is selected from benzyloxycarbonyl (Cbz), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsiloxyethoxycarbonyl (Teoc), methoxycarbonyl or ethoxycarbonyl;
the acyl amino protecting group is selected from phthaloyl (Pht), trifluoroacetyl (Tfa), pivaloyl, benzoyl, formyl or acetyl;
the sulfonyl amino protecting group is selected from p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrobenzenesulfonyl (p-Ns);
the alkyl amino protecting group is selected from trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn).
In a preferred embodiment of the present invention, R is selected from an alkoxycarbonyl amino-protecting group, preferably benzyloxycarbonyl (Cbz), fluorenyl-methoxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), more preferably fluorenyl-methoxycarbonyl (Fmoc).
Preferably, the method is
More preferably, the method is
In the above scheme, the coupling agent of the first step reaction is selected from Dicyclohexylcarbodiimide (DCC), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), O-benzotriazole-tetramethylureaMethyl urea Hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl), and propylphosphoric anhydride (T)3P), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop), N' -Carbonyldiimidazole (CDI), N-Diisopropylcarbodiimide (DIC) or isobutyl chloroformate, preferably Dicyclohexylcarbodiimide (DCC).
In the above scheme, the second step reaction is a cyclization reaction and a deprotection reaction under the condition of adding alkali into an organic solvent or a mixed organic solvent,
the organic solvent is selected from halogenated hydrocarbon solvents, ether solvents, amide solvents, nitrile solvents or alcohol solvents, the halogenated hydrocarbon solvents are preferably dichloromethane or chloroform, the ether solvents are preferably tetrahydrofuran or diethyl ether, the amide solvents are preferably N, N-dimethylformamide, the nitrile solvents are preferably acetonitrile, the alcohol solvents are preferably methanol or ethanol, the organic solvent mixture is selected from mixed solvents consisting of alcohols, ethers and nitrile solvents or mixed solvents consisting of halogenated hydrocarbons and nitriles, the organic solvent is preferably dichloromethane, the mixed organic solvent is preferably methanol/1, 4-dioxane/acetonitrile or dichloromethane/acetonitrile, the base is selected from morpholine, N-methylmorpholine, diisopropylethylamine, triethylamine, N-dimethylaniline, pyridine or alkali metal bicarbonate, preferably morpholine or triethylamine, the alkali metal bicarbonate is preferably sodium bicarbonate.
The invention also provides a method for preparing the compound shown as the formula (II), the pharmaceutically acceptable salt thereof or the stereoisomer thereof, which is characterized by comprising the following steps:
the first step of reaction is to react a compound shown as a formula (III) with dimorpholinyl phosphinic chloride in the presence of lithium bis (trimethylsilyl) amide (LiHMDS) to obtain a compound shown as a formula (II'),
the second step of reaction is to react the compound shown in the formula (II') with isopropanolamine to obtain the compound shown in the formula (II).
The method also comprises a step of adding acid for post-treatment, wherein the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and is more preferably hydrochloric acid; extracting the aqueous phase with organic solvent and then with saturated NaHCO3Aqueous solution, saturated NH4And washing the Cl aqueous solution and the purified water, and drying, filtering and concentrating the organic phase to obtain the product.
The above method further comprises a step of preparing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the compound shown in the formula (II) is firstly subjected to oxidation reaction and then subjected to cyclization reaction under acidic condition to obtain the compound shown in the formula (I), and the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and more preferably p-toluenesulfonic acid.
Preferably, the method is
In the scheme, the compound shown in the formula (IIIa) is dissolved in an organic solvent, lithium bis (trimethylsilyl) amide (LiHMDS) is added at a low temperature, stirring is carried out, dimorpholinyl phosphinic chloride is added, stirring and reacting are carried out at a low temperature, isopropanolamine is added, after the reaction is finished, a dilute hydrochloric acid aqueous solution is added into a reaction solution, a water phase is extracted by the organic solvent, and after an organic phase is dried, the organic phase is filtered and concentrated to obtain a product; the organic solvent is selected from ether organic solvents, and the ether organic solvent is preferably tetrahydrofuran.
In the scheme, dimethyl sulfoxide is added, oxalyl chloride is added at low temperature, stirring is carried out, a dichloromethane solution of the compound shown in the formula (II) is added, stirring is carried out, triethylamine is added, washing, drying, filtering and concentrating are carried out, the obtained residue is dissolved in an organic solvent, cyclization reaction is carried out under an acidic condition, and the compound shown in the formula (I) is obtained through concentration, washing, drying, filtering, concentrating and column chromatography purification; the organic solvent is selected from alcohols or ester solvents, the alcohols solvent is preferably methanol, and the ester solvent is preferably ethyl acetate; the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, more preferably p-toluenesulfonic acid.
The present invention further provides a method for preparing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the method comprises the steps of:
reacting a compound shown as a formula (V) with (2-amino-5-bromophenyl) (pyridine-2-yl) methanone in the presence of a coupling agent to obtain a compound shown as a formula (IV), reacting the compound shown as the formula (IV) under a base condition to obtain a compound shown as a formula (III), preferably morpholine, reacting the compound shown as the formula (III) with dimorpholinyl phosphinic chloride in the presence of bis (trimethylsilyl) lithium amide (LiHMDS) base to obtain a compound shown as a formula (II '), reacting the compound shown as the formula (II') with tert-butanolamine to obtain a compound shown as a formula (II), and cyclizing the compound shown as the formula (II) under an acidic condition firstly through an oxidation reaction to obtain a compound shown as a formula (I), preferably p-toluenesulfonic acid.
Preferably, the method is
More preferably, the method is
The invention also provides a method for preparing a pharmaceutically acceptable salt of the compound shown in the formula (Ia), which comprises the steps in the scheme and a step of preparing the pharmaceutically acceptable salt by reacting the compound shown in the formula (Ia) with acid, wherein the acid is selected from organic acid or inorganic acid, preferably organic acid; the organic acid is selected from acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
Detailed Description
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "amino protecting group" in the present invention refers to a group capable of protecting an amino group from reaction, and common amino protecting groups include, but are not limited to: formates (prepared by reacting amino with chloroformate, diazoformate or various carbonates), imines (prepared by reacting primary amine with aromatic aldehyde, aromatic ketone or aliphatic ketone), alkoxycarbonyls (benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorene methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsiloxyethoxycarbonyl (Teoc), methoxycarbonyl or ethoxycarbonyl), and amides (prepared by reacting amino with acyl)Chlorine or acid anhydride, such as phthaloyl (Pht), trifluoroacetyl (Tfa), pivaloyl, benzoyl, formyl or acetyl), sulfonyl (aromatic sulfonamides such as p-toluenesulfonyl (Tos or Ts), O-nitrobenzenesulfonyl (O-Ns) or p-nitrobenzenesulfonyl (p-Ns)) or alkyl (trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn)), wherein "alkoxycarbonyl, acyl, sulfonyl" means R-O-C (O) -, R-S (O))2-, wherein R may be a hydrogen atom, an alkyl group or an aryl group, etc.
As used herein, "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 8 membered aryl group, more preferably a phenyl, anthracenyl or phenanthrenyl group.
The term "halo" as used herein means substituted with a "halogen atom" which means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.
The "alkyl" as used herein refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms, including, for example, "C1-6Alkyl group "," C1-4Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
The "amide organic solvent" in the present invention means that the hydroxyl group in the carboxyl group of the carboxylic acid molecule is substituted by an amino group or a hydrocarbylamino group (-NHR or-NR)2) A liquid compound resulting from substitution; can also be regarded as a liquid compound in which hydrogen on a nitrogen atom in ammonia or an amine molecule is substituted with an acyl group; specific examples include, but are not limited to: n, N-dimethylformamide, N-dimethylacetamide.
The "ether solvent" according to the present invention refers to a chain compound or a cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: propylene glycol methyl ether, tetrahydrofuran or 1, 4-dioxane.
The "ester solvent" according to the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.
The "alcoholic solvent" of the present invention refers to a group derived by substituting one or more hydrogen atoms on an "alkyl" group, as defined above, with one or more "hydroxy groups", and specific examples include, but are not limited to: methanol, ethanol, ethylene glycol, n-propanol or 2-propanol.
The "halogenated hydrocarbon solvent" in the present invention refers to a group derived by substituting one or more "halogen atoms" for one or more hydrogen atoms on an "alkyl group", wherein the "halogen atoms" and the "alkyl group" are as defined above, and specific examples include, but are not limited to: methyl chloride, dichloromethane, chloroform or carbon tetrachloride.
The "nitrile solvent" of the present invention refers to a group derived by substituting one or more hydrogen atoms of an "alkyl" group, as defined above, with one or more "cyano groups", and specific examples include, but are not limited to: acetonitrile or propionitrile.
The mixed solvent is a solvent formed by mixing one or more different organic solvents according to a certain proportion, or a solvent formed by mixing an organic solvent and water according to a certain proportion.
Advantageous effects of the invention
Compared with the prior art (WO0069836A1, published as 2000-11-23; WO2011032692A1, published as 2011-03-24), the technical scheme for preparing the compound shown in the formula (I) has the following advantages:
different from the starting raw materials in the prior art, the coupling reaction step in the process of preparing the compound of the formula (III) is simple, the ring-closing reaction and the deprotection reaction conditions can be carried out under the same conditions, and the obtained compound of the formula (III) has high purity; the post-treatment step of an intermediate is avoided in the step of preparing the compound of the formula (II), and the yield is improved on the premise of ensuring the purity; the invention shortens the reaction steps, avoids a multi-step post-treatment method, and has simpler operation method and easier operation compared with the prior art.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The experimental method of the present invention, in which the specific conditions are not specified, is generally carried out under the conventional conditions or the conditions recommended by the manufacturers of the raw materials or the commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-500 NMR spectrometer using deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using FINNIGAN LCQ (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQDECA XPMAX).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Agilent Plus C18150X 4.6mm column).
Example 1, (S) -3- (7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [ e ]][1,4]Diaza derivativesPreparation of methyl (3-yl) propionate
First step of
(2-amino-5-bromophenyl) (pyridin-2-yl) methanone
Tetrahydrofuran (44mL) is added into a reaction bottle, n-butyllithium (51mL) is added at-40 ℃, the internal temperature is controlled not to exceed-20 ℃, the temperature is reduced to-40 ℃, 2-bromopyridine (15.8g) is slowly dripped, the temperature is kept for 1 hour after dripping, a solution of 2-amino-5-bromo-benzoic acid (6.7g) dissolved in tetrahydrofuran (44mL) is dripped at the temperature below-40 ℃, and the temperature is naturally raised to about 0 ℃ after dripping for 3 hours. Slowly dropping saturated ammonium chloride solution (11mL) at the internal temperature of below 10 ℃, stopping the reaction, adding water (50mL), standing, separating, taking an organic layer, extracting an aqueous layer with ethyl acetate (50mL), combining the organic layers, washing with saturated sodium chloride aqueous solution (40mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain an oily substance, purifying by column chromatography (eluent PE: EA is 3:1-1:1, volume ratio), collecting the positive component, and concentrating to obtain a solid product (4.37g, yield 50.7%).
Second step of
(S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5- ((4-bromo-2-pyridinylphenyl) amino) -5-oxopentane
Acid methyl ester
Adding (2-amino-5-bromophenyl) (pyridine-2-yl) ketone (4g) and Fmoc-L-glutamic acid methyl ester (6.2g) into a reaction bottle, dissolving the mixture into dichloromethane (50mL), cooling to-10 ℃, dropwise adding a dichloromethane (8mL) solution of 1, 3-dicyclohexylcarbodiimide (3.0g), controlling the temperature to be-10 ℃ to-5 ℃, preserving the temperature to be-5 ℃ to 0 ℃ for reaction for 48 hours, filtering, concentrating the filtrate under reduced pressure to obtain an oily substance to obtain a crude product, and directly putting the crude product into the next step.
The third step
(S) -3- (7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [ e)][1,4]Diaza derivatives-3-yl) propionic acid methyl ester
Adding 20% morpholine/dichloromethane (35mL) into the oily substance, stirring for dissolving, reacting at room temperature for about 20 hr, washing with water four times after the reaction is finished, washing with morpholine, drying, concentrating, and performing column chromatography (eluent: CH)2Cl2→CH2Cl2:CH3OH 100: 1-50: 1 by volume) to give crude product (3.7g, 63.7% yield, HPLC)>96%), isopropanol (15mL) was added and heated to a clear solution, crystallized at room temperature with stirring, and filtered to give the desired product (2.8g, 48.2% yield, HPLC: 99.84%).
Example 2, (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivativesPreparation of (E) -4-yl) propionic acid methyl ester
First step of
3- ((3S) -7-bromo-2- ((2-hydroxypropyl) amino) -5- (pyridin-2-yl) -3H-benzo [ e][1,4]Diaza derivatives-3-yl) propionic acid methyl ester
Under the protection of argon, adding phosphorus oxychloride (1.2kg) into toluene (6.4kg) in a reaction bottle, stirring to dissolve, cooling to 5 ℃, and dripping morpholine (2.68kg) into the reaction bottle within 2h, wherein the temperature is controlled to be not more than 20 ℃. After dropping, the reaction was carried out at room temperature for 3 hours. Filtering insoluble substances, washing with toluene for three times (1kg × 3), combining filtrates, concentrating under reduced pressure to obtain oily substance, adding toluene (1.92kg), heating to dissolve uniformly, adding petroleum ether (860g) under stirring (if insoluble substances exist, filtering while hot), adding petroleum ether (3.48kg), cooling to room temperature, filtering, washing filter cake with petroleum ether (1.2kg × 2), drying under reduced pressure to obtain dimorpholinyl hypophosphinic chloride solid (1.3kg), and drying for storage.
Adding (S) -3- (7-bromo-2-oxo-5- (pyridine-2-yl) -2, 3-dihydro-1H-benzo [ e) into a reaction bottle][1,4]Diaza derivativesMethyl-3-yl) propionate (800g), tetrahydrofuran (6.8kg), dissolved with stirring under argon. The reaction solution was cooled to-30 ℃ and 2.4L of 1M lithium bis (trimethylsilyl) amide (LiHMDS) in THF (2.5kg) was added dropwise over 1 hour, the reaction was exothermic, the temperature was controlled not to exceed-20 ℃ during the dropwise addition, and stirring was continued at-20 ℃ for 1 hour. Then adding dimorpholinyl phosphinic chloride (1.2kg) in batches within 30min, and stirring for 4h at the temperature of minus 10-0 ℃.
And (3) dropwise adding isopropanolamine (524g) into the reaction solution, controlling the temperature to be not more than 0 ℃, controlling the temperature to be 0 ℃ after dropwise adding, reacting for 15h, supplementing isopropanolamine (149.4g), continuously stirring and reacting for 5h, and stopping the reaction.
And (3) quickly dropwise adding 1N HCl aqueous solution (5L) into the reaction solution, controlling the temperature to be not more than 30 ℃, stirring and reacting for 0.5h, separating liquid, and concentrating an organic layer. The aqueous layer was extracted with dichloromethane (5.4 kg. times.2), and the resulting organic phase was added to the concentrated residue together with a saturated aqueous sodium bicarbonate solution (6kg), sufficiently dissolved, and then separated. The organic phase was washed with saturated aqueous ammonium chloride (4.8kg) and purified water (3.6kg), respectively, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the resulting oil was purified by column chromatography (eluent petroleum ether: ethyl acetate 1:1 → ethyl acetate), the positive fraction was collected and concentrated at 45 ℃ under reduced pressure to give the product (730g, yield 80.0%, HPLC: 98.5%).
Second step of
(S) -3- (8-bromo)-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f]Imidazo [1,2-a ]][1,4]Diaza derivatives-4-yl) propionic acid methyl ester
Dimethyl sulfoxide (493g) and dichloromethane (12.5kg) are added into a reaction bottle, stirred and cooled, oxalyl chloride (413g) is added dropwise at the temperature of-60 ℃ to-70 ℃, the reaction is kept for 1H after the addition, and 3- ((3S) -7-bromine-2- ((2-hydroxypropyl) amino) -5- (pyridin-2-yl) -3H-benzo [ e ] is added][1,4]Diaza derivativesAnd (3) reacting a mixed solution of methyl (725g) and dichloromethane (1.9kg) for 3 hours under stirring at a constant temperature, dropwise adding triethylamine (924g), and naturally raising the temperature to room temperature after dropwise adding, and reacting for 3 hours under stirring. After the reaction was completed, the reaction system was washed with a saturated aqueous sodium bicarbonate solution (8.6kg), water (7kg) and a saturated aqueous sodium chloride solution (8.6kg) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness at 40 ℃ under reduced pressure to obtain a product.
The product obtained above was dissolved in methanol (4.49kg), p-toluenesulfonic acid (120g) was added, the reaction was stirred at 25 ℃ for 16 hours, and the reaction solution was concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (10kg), washed successively with a saturated aqueous sodium hydrogencarbonate solution (8.6kg), water (7kg) and a saturated aqueous sodium chloride solution (8.6kg), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure at 40 ℃. The resulting oil was purified by column chromatography (eluent ethyl acetate: petroleum ether 1:1 → ethyl acetate), and the positive fraction was collected and concentrated under reduced pressure at 40 ℃ to give the objective product (526g, yield 75.9%, HPLC: 99.4%).
Example 3, (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivativesPreparation of (E) -4-yl) propionic acid methyl ester tosylate
(1) Preparation of crude product
Adding (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivatives-4-yl) propionic acid methyl ester (519g) and ethyl acetate (3.76kg) were dissolved with stirring, a methanol (416g) solution of p-toluenesulfonic acid (213.8g) was added dropwise over 30min, and after completion of the addition, the mixture was stirred at room temperature for 50min, filtered to obtain a cake, and dried under reduced pressure to obtain an off-white powdery solid (537g, yield 74.3%, HPLC: 99.81%).
(2) Purification of the product
Into a reaction flask, p- (S) -3- (8-bromo-1-methyl-6- (pyridin-2-yl) -4H-benzo [ f)]Imidazo [1,2-a ]][1,4]Diaza derivativesAdding purified water (6.38kg) at 80-90 ℃ to a crude tosylate (532g) of methyl-4-yl) propionate under stirring, stirring for 5min, filtering while the mixture is hot, carrying out water bath stirring crystallization on the filtrate for 20h, filtering, and drying under reduced pressure at 40 ℃ to obtain a white solid (356g, the yield is 66.9%, and the HPLC (high performance liquid chromatography): 99.89%).
MS m/z(ESI):439.09[M–C7H8SO3+1]
1H-NMR(500MHz,CD3OD)δ8.56-8.57(d,1H),8.14-8.16(d,1H),8.03-8.05(m,1H),7.99-8.01(dd,1H),7.80-7.82(d,1H),7.67-7.70(m,3H),7.57-7.59(m,1H),7.45(d,1H),7.20-7.22(d,2H),4.45-4.48(m,1H),3.69(s,3H),2.77-2.86(m,2H),2.67-2.74(m,1H),2.57-2.64(m,1H),2.49-2.49(s,3H),2.35(s,3H)。
Claims (15)
1. A process for preparing a compound of formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the steps of:
the first step is that the compound shown in the formula (V) reacts with (2-amino-5-bromophenyl) (pyridine-2-yl) ketone in the presence of a coupling agent to obtain a compound shown in the formula (IV),
the second step is that the compound shown in the formula (IV) reacts under the alkali condition to obtain the compound shown in the formula (III),
wherein,
r is hydrogen or an amino protecting group.
2. The process for preparing a compound of formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein,
r is selected from an alkoxycarbonyl amino-protecting group, preferably benzyloxycarbonyl, fluorenyl methoxycarbonyl or allyloxycarbonyl, more preferably fluorenyl methoxycarbonyl.
3. The process of claim 2 for preparing a compound of formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the process is
4. The process of claim 3 for preparing a compound of formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof
5. A process for preparing a compound of formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1 to 4, characterized in that the coupling agent of the first step reaction is selected from dicyclohexylcarbodiimide, 2- (7-benzotriazole oxide) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, propylphosphoric anhydride, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, N, N ' -carbonyldiimidazole, N, N-diisopropylcarbodiimide or isobutyl chloroformate, preferably dicyclohexylcarbodiimide.
6. The process for producing a compound represented by the formula (III), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 4, wherein the second reaction is a cyclization reaction and a deprotection reaction in an organic solvent or a mixed organic solvent with the addition of a base,
the organic solvent is preferably dichloromethane, the mixed organic solvent is preferably methanol/1, 4-dioxane/acetonitrile or dichloromethane/acetonitrile, and the base is preferably morpholine or triethylamine.
7. A process for preparing a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the steps of:
the first step of reaction is to react a compound shown as a formula (III) with dimorpholinyl phosphinic chloride in the presence of lithium bis (trimethylsilyl) amide (LiHMDS) to obtain a compound shown as a formula (II'),
the second step of reaction is to react the compound shown in the formula (II') with isopropanolamine to obtain the compound shown in the formula (II).
8. The process for preparing a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 7, further comprising a step of post-treatment by addition of an acid, preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid, more preferably hydrochloric acid.
9. The method of preparing a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 8, further comprising the step of preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the compound shown in the formula (II) is firstly subjected to oxidation reaction and then subjected to cyclization reaction under acidic condition to obtain the compound shown in the formula (I), and the acid is preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and more preferably p-toluenesulfonic acid.
10. The process of claim 7 for preparing a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof
11. The process of claim 9 for preparing a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof
12. A process for preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the steps of:
reacting a compound shown as a formula (V) with (2-amino-5-bromophenyl) (pyridine-2-yl) methanone in the presence of a coupling agent to obtain a compound shown as a formula (IV), reacting the compound shown as the formula (IV) under a base condition to obtain a compound shown as a formula (III), reacting the compound shown as the formula (III) with dimorpholinyl phosphinic chloride in the presence of bis (trimethylsilyl) lithium amide (LiHMDS) base to obtain a compound shown as a formula (II '), reacting the compound shown as the formula (II') with isopropanolamine to obtain a compound shown as a formula (II), and cyclizing the compound shown as the formula (II) under an acidic condition firstly through an oxidation reaction to obtain a compound shown as a formula (I).
13. The process of claim 12 for preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof
14. The process of claim 13 for preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof
15. A process for the preparation of a pharmaceutically acceptable salt of a compound of formula (Ia) comprising the steps of any one of claims 12 to 14, and the step of preparing a pharmaceutically acceptable salt thereof by reacting a compound of formula (Ia) with an acid selected from an organic acid or an inorganic acid, preferably an organic acid; the organic acid is selected from acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
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| WO2019020790A1 (en) * | 2017-07-28 | 2019-01-31 | Moehs Iberica S.L. | Method for preparing 3-[(3s)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1h-[1,4]-benzodiazepin-3-yl] propionic acid methyl ester, and compounds useful in that method |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
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| CN115974835A (en) * | 2022-12-16 | 2023-04-18 | 湖南复瑞生物医药技术有限责任公司 | A kind of synthetic method of remazolam key intermediate |
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