CN105315169A - Preparation method for cardiovascular disease treatment drug - Google Patents
Preparation method for cardiovascular disease treatment drug Download PDFInfo
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- CN105315169A CN105315169A CN201410375111.0A CN201410375111A CN105315169A CN 105315169 A CN105315169 A CN 105315169A CN 201410375111 A CN201410375111 A CN 201410375111A CN 105315169 A CN105315169 A CN 105315169A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title abstract description 7
- 208000024172 Cardiovascular disease Diseases 0.000 title abstract description 4
- 229940079593 drug Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 238000000034 method Methods 0.000 claims abstract description 25
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960001256 tolvaptan Drugs 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims description 73
- 239000003054 catalyst Substances 0.000 claims description 54
- 239000012442 inert solvent Substances 0.000 claims description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 32
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 21
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 235000015320 potassium carbonate Nutrition 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 235000017550 sodium carbonate Nutrition 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- OKHSVCZDYHBEKX-UHFFFAOYSA-N formyl chloride toluene Chemical compound C(=O)Cl.CC1=CC=CC=C1 OKHSVCZDYHBEKX-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 20
- 239000012279 sodium borohydride Substances 0.000 description 20
- 229910000033 sodium borohydride Inorganic materials 0.000 description 20
- 229960004756 ethanol Drugs 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- 239000003513 alkali Substances 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 229910052700 potassium Inorganic materials 0.000 description 13
- 239000011591 potassium Substances 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- QAWFLJGZSZIZHO-UHFFFAOYSA-N methyl 4-bromobutanoate Chemical compound COC(=O)CCCBr QAWFLJGZSZIZHO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- -1 III compound Chemical class 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- LMDIDOFTXQERLH-UHFFFAOYSA-N 2-methyl-4-nitrobenzoyl chloride Chemical compound CC1=CC([N+]([O-])=O)=CC=C1C(Cl)=O LMDIDOFTXQERLH-UHFFFAOYSA-N 0.000 description 7
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 235000011150 stannous chloride Nutrition 0.000 description 7
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012448 Lithium borohydride Substances 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- BDKZHNJTLHOSDW-UHFFFAOYSA-N [Na].CC(O)=O Chemical compound [Na].CC(O)=O BDKZHNJTLHOSDW-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910017604 nitric acid Inorganic materials 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010021036 Hyponatraemia Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229940077276 samsca Drugs 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- SZISCBBARDWOHK-UHNVWZDZSA-N C1C#C[C@@H]2N[C@H]12 Chemical compound C1C#C[C@@H]2N[C@H]12 SZISCBBARDWOHK-UHNVWZDZSA-N 0.000 description 1
- QQUNYHNQVOMONE-ONEGZZNKSA-N CC(/C=C/C(C(CCN)C(OC)=O)O)Cl Chemical compound CC(/C=C/C(C(CCN)C(OC)=O)O)Cl QQUNYHNQVOMONE-ONEGZZNKSA-N 0.000 description 1
- AHYUSSUFSUFXJP-PVHZACCCSA-N CC(C)C(C)([C@@H](N(CC[C@H]1C)C(CCC(C2)Cl)C2C1=O)O)/C=C\C Chemical compound CC(C)C(C)([C@@H](N(CC[C@H]1C)C(CCC(C2)Cl)C2C1=O)O)/C=C\C AHYUSSUFSUFXJP-PVHZACCCSA-N 0.000 description 1
- BIXYIZILQDRNGQ-UHFFFAOYSA-N CC(C1)=C(C)[I]=CC1[N+]([O-])=O Chemical compound CC(C1)=C(C)[I]=CC1[N+]([O-])=O BIXYIZILQDRNGQ-UHFFFAOYSA-N 0.000 description 1
- OUUNZFJJTMVKQQ-NJOYLGGBSA-N CC/C=C(\[C@H]1C=CC1C)/N Chemical compound CC/C=C(\[C@H]1C=CC1C)/N OUUNZFJJTMVKQQ-NJOYLGGBSA-N 0.000 description 1
- PLCCCMJDLVVFPX-UHFFFAOYSA-N CCC1C(CN)C1 Chemical compound CCC1C(CN)C1 PLCCCMJDLVVFPX-UHFFFAOYSA-N 0.000 description 1
- 0 CCCC(C=CCC(N(CCCCOCOC)C=CC=C(C[C@](C)*)Cl)=O)[N+]([O-])=O Chemical compound CCCC(C=CCC(N(CCCCOCOC)C=CC=C(C[C@](C)*)Cl)=O)[N+]([O-])=O 0.000 description 1
- HRSNILZFYPWVTL-ZCFIWIBFSA-N C[C@H](C1)C([N+]([O-])=O)=CC(C)=C1C(Cl)=O Chemical compound C[C@H](C1)C([N+]([O-])=O)=CC(C)=C1C(Cl)=O HRSNILZFYPWVTL-ZCFIWIBFSA-N 0.000 description 1
- QAZIGNILMCPUKQ-BZNZVWFOSA-N C[C@H](CCN(C)C(C(C)/C=C\C(N)=C)=O)C=O Chemical compound C[C@H](CCN(C)C(C(C)/C=C\C(N)=C)=O)C=O QAZIGNILMCPUKQ-BZNZVWFOSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010021137 Hypovolaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010053198 Inappropriate antidiuretic hormone secretion Diseases 0.000 description 1
- 229940116211 Vasopressin antagonist Drugs 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 201000008284 inappropriate ADH syndrome Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical group [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000003038 vasopressin antagonist Substances 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a preparation method for a cardiovascular disease treatment drug. Specifically, the invention provides a compound represented by a formula (IV) shown in the description and a method for preparing Tolvaptan from the compound represented by the formula (IV). The method provided by the invention has the advantages of being environment-friendly, being easy in raw material obtaining and high in total yield, and the like, thereby being applicable to the industrialized preparation of Tolvaptan.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly, the invention provides a kind of preparation method for the treatment of cardiovascular disease medicine.
Background technology
Tolvaptan English name Tolvaptan, trade(brand)name: Samsca, chemistry N-[4-[(chloro-2,3,4, the 5-tetrahydrochysene-5-hydroxyl-1H-1-benzo-azas of 7-by name
-1-base) carbonyl]-3-aminomethyl phenyl]-2-methyl benzamide.Within 2009, tolvaptan obtains the oral type selectivity vasopressin antagonists of U.S. FDA approval treatment hyponatremia.Within 2011, tolvaptan obtains State Food and Drug Administration's official approval, starts at domestic product and sells.This medicine is a kind of selectivity vassopressin V
2receptor antagonist, can stop the V of AVP and kidney unit far-end
2receptors bind, water movement in urine is increased, but do not change the secretion of urine sodium potassium and blood potassium value, reduce urine osmotic pressure, increase blood sodium value, therefore be used for the treatment of clinically because of liver cirrhosis, the heavy body that in heart failure, antidiuretic hormone secretion abnormal syndrome (SIADH) causes and etc. hypovolemic hyponatremia.This medical instrument has good tolerance, and does not destroy electrolyte balance, and untoward reaction is lighter.Therefore, such structure medicament has good development prospect.
The structure of tolvaptan is as shown in the formula shown in (I).
At present, the preparation were established of the tolvaptan reported has several as follows:
Circuit one:
Patent WO2007/026971, FR2867187, JP2009107972 and Bioorg.Med.Chem., 1999, report a kind of totally 11 steps in 7:17432-1754 and be obtained by reacting the synthetic route of tolvaptan, this reaction has following shortcoming: 1) the single line route synthesis of this reaction, greatly reduces overall yield; 2) the anti-price that have employed of reducing in reaction is high and be that the platinum oxide of heavy metal makees catalyzer, is unsuitable for economic production and environment protection; 3) reaction of each portion all have employed column chromatography method purification, adds production cost; 4) also have employed the organic solvent that some are unfavorable for keeping the safety in production in process in a large number, as chloroform does extraction agent etc.Therefore this route is not suitable for suitability for industrialized production.
Route two:
AlejandroCordero-Vargas etc. are at Bioorg.Med.Chem., 2006, the synthetic method of another kind of tolvaptan is reported in 14 (18): 6165-6173, this preparation method with 4-chloroacetophenone base xanthate for starting raw material, 5-pivaloyl oxygen base-7-chloro-1 is obtained through addition, cyclization, one-tenth oxime, rearrangement, two step reduction, 2,3,4-tetrahydro benzo azepine
again through with 2-methyl-4-nitrobenzoyl chloride acidylate, reduction, with 2-methyl benzoyl chloride acidylate, be hydrolyzed and obtain target product.The shortcomings such as this route has starting raw material to be difficult to obtain, and the first step reaction employing one kind solvent 1,2-ethylene dichloride, is unfavorable for environment protection, and the yield of rearrangement reaction and rear two steps reduction is low, therefore this route is unfavorable for that industrial operation and economic industrialization are produced.
In sum, this area still lacks N-[4-[(chloro-2,3,4, the 5-tetrahydrochysene-5-hydroxyl-1H-1-benzo-azas of 7-that a kind of yield is high, react safety, be applicable to suitability for industrialized production
-1-base) carbonyl]-3-aminomethyl phenyl] preparation method of-2-methyl benzamide.
Summary of the invention
This area still lacks N-[4-[(chloro-2,3,4, the 5-tetrahydrochysene-5-hydroxyl-1H-1-benzo-azas of 7-that a kind of yield is high, react safety, be applicable to suitability for industrialized production
-1-base) carbonyl]-3-aminomethyl phenyl] preparation method of-2-methyl benzamide.
A first aspect of the present invention, provides a kind of as shown in the formula the compound shown in (VI):
A second aspect of the present invention, provide a kind of preparation method of formula (VI) compound as described in the first aspect of the invention, described method comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
In another preference, in described step (2), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, or its combination; Be preferably triethylamine, diisopropylethylamine, or its combination.
In another preference, in described step (2), slowly add formula (V) compound at a suitable temperature.
In another preference, in described step (2), described inert solvent is selected from lower group: methylene dichloride, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, ether, toluene, dimethylbenzene, or its combination; Preferred methylene dichloride, acetonitrile.
In another preference, in described step (2), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 40 DEG C.
In another preference, in described step (2), described compound (IV) is 1:1 ~ 2:1 ~ 5 with 2-methyl-4-nitrobenzoyl chloride (V) and the mol ratio of alkali; Preferred proportion is 1:1.2:2.
A third aspect of the present invention, provides a kind of as shown in the formula the compound shown in (IV):
A fourth aspect of the present invention, provide a kind of preparation method of formula (IV) compound as described in third aspect present invention, described method comprises step:
(1) in inert solvent, with formula (II) compound and the reaction of formula (III) compound, formula (IV) compound is obtained;
In another preference, in described step (1), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, or its combination; Preferred sodium carbonate, salt of wormwood, or its combination.
In another preference, in described step (1), described inert solvent is selected from lower group: methylene dichloride, acetonitrile, propionitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, or its combination; Preferred propionitrile, acetonitrile, or its combination.
In another preference, in described step (1), described temperature of reaction is 30 ~ 120 DEG C, preferably 50 ~ 100 DEG C.
In another preference, in described step (1), described formula II compound and the mol ratio of formula III compound and alkali are 1:1 ~ 2:1 ~ 5; Be preferably 1:1:2.
In another preference, in described step (1), the described reaction times is 2-8h.
A fifth aspect of the present invention, provide the preparation method of a kind of formula (VII) compound, described method comprises step:
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
In another preference, in described step (3), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, or its combination; Be preferably sodium tert-butoxide, potassium tert.-butoxide, or its combination.
In another preference, in described step (3), described inert solvent is selected from lower group: methylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene, or its combination; Preferred toluene, dimethylbenzene, or its combination.
In another preference, in described step (3), described temperature of reaction is 80 ~ 150 DEG C, preferably 100 ~ 130 DEG C.
In another preference, in described step (3), described formula VI compound and the mol ratio of alkaline catalysts are 1:1 ~ 5; Be preferably 1:2.
In another preference, in described step (3), the described reaction times is 0.5-2h.
In another preference, described method also comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
In another preference, described method also comprises step:
(1) in inert solvent, with formula (II) compound and the reaction of formula (III) compound, formula (IV) compound is obtained;
A sixth aspect of the present invention, provides a kind of formula (VI) compound as described in the first aspect of the invention or the formula as described in third aspect present invention (IV) the compound purposes for the preparation of formula (I) compound (tolvaptan).
In another preference, the method preparing described formula (I) compound with formula (VI) compound comprises step:
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
With
With formula (VII) preparation of compounds of formula (I) compound.
In another preference, the method preparing described formula (I) compound with formula (IV) compound comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
With
With formula (VII) preparation of compounds of formula (I) compound.
A seventh aspect of the present invention, provide the preparation method of a kind of formula (I) compound, described method comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
(4) in inert solvent, in presence of an acid catalyst, react with formula (VII) compound, obtain formula (VIII) compound;
(5) in inert solvent, carry out hydro-reduction with formula (VIII) compound, obtain formula (IX) compound;
(6) in inert solvent, react with formula (IX) compound and o-methyl-benzene formyl chloride, obtain formula (X) compound;
(7) in inert solvent, with formula (IX) compound and reduction reagent react, formula (I) compound is obtained;
In another preference, in described step (4), described inert solvent is selected from lower group: methyl alcohol, ethanol, water, tetrahydrofuran (THF), 1,4-dioxane, Virahol, or its combination, preferably water.
In another preference, in described step (4), described acid catalyst is selected from lower group: formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or its combination; Preferred acetic acid, hydrochloric acid.
In another preference, in described step (4), described temperature of reaction is 80 ~ 130 DEG C, preferably 80 ~ 110 DEG C.
In another preference, in described step (5), described inert solvent is selected from lower group: methyl alcohol, ethanol, Virahol, or its combination; Particular methanol, ethanol, or its combination.
In another preference, in described step (5), described reaction is carried out under sour reagent exists; Preferably, described sour reagent is selected from lower group: nitric acid, phosphoric acid, hydrochloric acid, sulfuric acid, or its combination; Preferred hydrochloric acid.
In another preference, in described step (5), described hydro-reduction carries out in the presence of a catalyst; Preferably, described catalyzer is selected from lower group: sodium borohydride, acetic acid sodium borohydride, lithium aluminum hydride, POTASSIUM BOROHYDRIDE, lithium borohydride, tindichloride, or its combination; Preferred sodium borohydride, POTASSIUM BOROHYDRIDE, tindichloride, or its combination.
In another preference, in described step (5), described hydro-reduction adds in reaction system at suitable temperature at catalyzer in batches.
In another preference, in described step (5), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C.
In another preference, in described step (5), described formula (VIII) compound and the mol ratio of reducing catalyst are 1:1 ~ 5; Be preferably 1:3.
In another preference, in described step (6), described inert solvent is selected from lower group: methylene dichloride, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene or its combination; Preferred methylene dichloride, acetonitrile, or its combination.
In another preference, in described step (6), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is organic bases and mineral alkali; More preferably, described alkaline catalysts is selected from lower group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, or its combination; Preferred triethylamine, diisopropylethylamine, or its combination.
In another preference, in described step (6), described temperature of reaction is 0 ~ 50 DEG C, preferably 10 ~ 40 DEG C.
In another preference, in described step (6), the mol ratio of described formula (Ⅸ) compound, o-methyl-benzene formyl chloride and alkali is 1:1 ~ 2:1 ~ 5; Be preferably 1:1.2:2.
In another preference, in described step (7), described inert solvent is selected from lower group: methyl alcohol, ethanol, Virahol, or its combination; Particular methanol, ethanol, or its combination.
In another preference, in described step (7), described reaction is carried out under reducing catalyst exists; Preferably, described reducing catalyst is selected from lower group: sodium borohydride, acetic acid sodium borohydride, lithium aluminum hydride, POTASSIUM BOROHYDRIDE, lithium borohydride, or its combination; Preferred sodium borohydride, POTASSIUM BOROHYDRIDE, or its combination.
In another preference, in described step (7), described reducing catalyst adds in reaction system at suitable temperature in batches.
In another preference, in described step (7), described temperature of reaction is-10 ~ 30 DEG C, is preferably-5 ~ 5 DEG C.
In another preference, in described step (7), the mol ratio of described formula (Ⅹ) compound and reducing catalyst is 1:1 ~ 10, is preferably 1:1.5.
In another preference, described method also comprises step:
(1) in inert solvent, with formula (II) compound and the reaction of formula (III) compound, formula (IV) compound is obtained;
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
The present inventor, through long-term and deep research, devises a class such as formula the tolvaptan synthetic intermediate shown in (IV), and described Intermediate Preparation is convenient, raw material is easy to get, reaction conditions is gentle, is applicable to a large amount of preparation, and is used for preparation of industrialization tolvaptan as intermediate.Based on above-mentioned discovery, contriver completes the present invention.
Term
In this article, term " tolvaptan ", " Tolvaptan ", " Samsca " or " N-[4-[(chloro-2,3,4, the 5-tetrahydrochysene-5-hydroxyl-1H-1-benzo-azas of 7-
-1-base) carbonyl]-3-aminomethyl phenyl]-2-methyl benzamide " be used interchangeably, all refer to as shown in the formula the compound shown in (I):
Formula (VI) compound
The invention provides a kind of as shown in the formula the compound shown in (VI):
Described formula (VI) compound can be used as intermediate, for the preparation of formula (I) compound (tolvaptan).
The preparation of formula (VI) compound
Present invention also offers a kind of preparation method of described formula (VI) compound, described method comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
In a preferred embodiment of the invention, described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, or its combination; Be preferably triethylamine, diisopropylethylamine, or its combination.
In another preference, in described step (2), described alkaline catalysts slowly adds formula (V) compound at a suitable temperature.
In another preference, in described step (2), described inert solvent is selected from lower group: methylene dichloride, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene, or its combination; Preferred methylene dichloride, acetonitrile;
In another preference, in described step (2), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 40 DEG C.
In another preference, in described step (2), described compound (IV) is 1:1 ~ 2:1 ~ 5 with 2-methyl-4-nitrobenzoyl chloride (V) and the mol ratio of alkali; Preferred proportion is 1:1.2:2.
Formula (IV) compound
The invention provides a kind of as shown in the formula the compound shown in (IV):
Described formula (IV) compound can be used as intermediate, for the preparation of formula (I) compound (tolvaptan).
The preparation of formula (IV) compound
Present invention also offers a kind of preparation method of described formula (IV) compound, described method comprises step:
(1) in inert solvent, with formula (II) compound and the reaction of formula (III) compound, formula (IV) compound is obtained;
In a preferred embodiment of the invention, in described step (1), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, or its combination; Preferred sodium carbonate, salt of wormwood, or its combination.
In another preference, in described step (1), described inert solvent is selected from lower group: methylene dichloride, acetonitrile, propionitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, or its combination; Preferred propionitrile, acetonitrile, or its combination.
In another preference, in described step (1), described temperature of reaction is 30 ~ 120 DEG C, preferably 50 ~ 100 DEG C.
In another preference, in described step (1), described formula II compound and the mol ratio of formula III compound and alkali are 1:1 ~ 2:1 ~ 5; Be preferably 1:1:2.
The preparation method of formula (I) compound
Present invention also offers the preparation method of a kind of formula (I) compound, described method comprises step:
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
With
With formula (VII) preparation of compounds of formula (I) compound, described preparation can adopt means known in the art to carry out.
In another preference, the method preparing described formula (I) compound with formula (IV) compound comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
With
With formula (VII) preparation of compounds of formula (I) compound, described preparation can adopt means known in the art to carry out.
In a preferred embodiment of the invention, the preparation method of described formula (I) compound, comprises step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
(4) in inert solvent, in presence of an acid catalyst, react with formula (VII) compound, obtain formula (VIII) compound;
(5) in inert solvent, carry out hydro-reduction with formula (VIII) compound, obtain formula (IX) compound;
(6) in inert solvent, react with formula (IX) compound and o-methyl-benzene formyl chloride, obtain formula (X) compound;
(7) in inert solvent, with formula (IX) compound and reduction reagent react, formula (I) compound is obtained;
In another preference, in described step (4), described inert solvent is selected from lower group: methyl alcohol, ethanol, water, tetrahydrofuran (THF), 1,4-dioxane, Virahol, or its combination, preferably water.
In another preference, in described step (4), described acid catalyst is selected from lower group: formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or its combination; Preferred acetic acid, hydrochloric acid.
In another preference, in described step (4), described temperature of reaction is 80 ~ 130 DEG C, preferably 80 ~ 110 DEG C.
In another preference, in described step (5), described inert solvent is selected from lower group: methyl alcohol, ethanol, Virahol, or its combination; Particular methanol, ethanol, or its combination.
In another preference, in described step (5), described reaction is carried out under sour reagent exists; Preferably, described sour reagent is selected from lower group: nitric acid, phosphoric acid, hydrochloric acid, sulfuric acid, or its combination; Preferred hydrochloric acid.
In another preference, in described step (5), described hydro-reduction carries out in the presence of a catalyst; Preferably, described catalyzer is selected from lower group: sodium borohydride, acetic acid sodium borohydride, lithium aluminum hydride, POTASSIUM BOROHYDRIDE, lithium borohydride, tindichloride, or its combination; Preferred sodium borohydride, POTASSIUM BOROHYDRIDE, tindichloride, or its combination.
In another preference, in described step (5), described hydro-reduction adds in reaction system at suitable temperature at catalyzer in batches.
In another preference, in described step (5), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C.
In another preference, in described step (5), described formula (VIII) compound and the mol ratio of reducing catalyst are 1:1 ~ 5; Be preferably 1:3.
In another preference, in described step (6), described inert solvent is selected from lower group: methylene dichloride, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, toluene, dimethylbenzene or its combination; Preferred methylene dichloride, acetonitrile, or its combination.
In another preference, in described step (6), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is organic bases and mineral alkali; More preferably, described alkaline catalysts is selected from lower group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, or its combination; Preferred triethylamine, diisopropylethylamine, or its combination.
In another preference, in described step (6), described temperature of reaction is 0 ~ 50 DEG C, preferably 10 ~ 40 DEG C.
In another preference, in described step (6), the mol ratio of described formula (Ⅸ) compound, o-methyl-benzene formyl chloride and alkali is 1:1 ~ 2:1 ~ 5; Be preferably 1:1.2:2.
In another preference, in described step (7), described inert solvent is selected from lower group: methyl alcohol, ethanol, Virahol, or its combination; Particular methanol, ethanol, or its combination.
In another preference, in described step (7), described reaction is carried out under reducing catalyst exists; Preferably, described reducing catalyst is selected from lower group: sodium borohydride, acetic acid sodium borohydride, lithium aluminum hydride, POTASSIUM BOROHYDRIDE, lithium borohydride, or its combination; Preferred sodium borohydride, POTASSIUM BOROHYDRIDE, or its combination.
In another preference, in described step (7), described reducing catalyst adds in reaction system at suitable temperature in batches.
In another preference, in described step (7), described temperature of reaction is-10 ~ 30 DEG C, is preferably-5 ~ 5 DEG C.
In another preference, in described step (7), the mol ratio of described formula (Ⅹ) compound and reducing catalyst is 1:1 ~ 10, is preferably 1:1.5.
In another preferred embodiment of the present invention, described preparation method is as follows:
The invention provides following technical scheme, one prepares N-[4-[(chloro-2,3,4, the 5-tetrahydrochysene-5-hydroxyl-1H-1-benzo-azas of 7-
-1-base) carbonyl]-3-aminomethyl phenyl] novel method of-2-methyl benzamide.This reaction comprises the following steps:
(1) preparation of compound (IV):
To be distributed in suitable solvent to 2-amino-5-chloro benzoic ether (II) and 4-bromo butyric acid methyl ester (III), and add appropriate alkaline catalysts, react completely at a suitable temperature, just can obtain compound (IV) through suitable aftertreatment.
Wherein: suitable solvent is methylene dichloride, acetonitrile, propionitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane etc., preferred propionitrile, acetonitrile; Suitable alkaline catalysts can be divided into sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate etc., preferred sodium carbonate, salt of wormwood.Temperature is 30 ~ 120 DEG C, preferably 50 ~ 100 DEG C; Appropriate 2-amino-5-chloro benzoic ether (II) and 4-bromo butyric acid methyl ester (III) are 1:1 ~ 2:1 ~ 5 with the ratio of alkali; Preferred proportion is 1:1:2.
(2) preparation of compound (VI):
Compound (IV) is distributed in suitable solvent, add suitable alkaline catalysts successively, slowly add 2-methyl-4-nitrobenzoyl chloride (V) at a suitable temperature, after having reacted, obtain compound (VI) through suitable process.
Wherein: suitable solvent is methylene dichloride, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene etc., preferred methylene dichloride, acetonitrile; Suitable alkaline catalysts is triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU etc., preferred triethylamine, diisopropylethylamine.Temperature is 0 ~ 50 DEG C, preferably 10 ~ 40 DEG C; Appropriate compound (IV) and 2-methyl-4-nitrobenzoyl chloride (V) are 1:1 ~ 2:1 ~ 5 with the ratio of alkali; Preferred proportion is 1:1.2:2.
(3) preparation of compound (VII):
Compound (VI) is dissolved in suitable solvent, adds suitable catalyzer, carry out Guan Huan at a suitable temperature, obtain compound (VII) through suitable process.
Wherein: suitable solvent is methylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene etc., preferred toluene, dimethylbenzene; Suitable alkaline catalysts sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide etc., preferred tertiary sodium butylate, potassium tert.-butoxide.Temperature is 80 ~ 150 DEG C, preferably 100 ~ 130 DEG C; Appropriate compound (VI) is 1:1 ~ 5 with the ratio of alkali; Preferred proportion is 1:2.
(4) preparation of compound (VIII):
Compound (VII) is dispersed in suitable acid mixed solution, reacts at a proper temperature, obtain compound (VIII).
Wherein: suitable solvent is methyl alcohol, ethanol, water, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, Virahol etc., preferably water; Suitable acid catalyst is formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., preferred acetic acid, hydrochloric acid; Suitable temperature is 80 ~ 130 DEG C, preferably 80 ~ 110 DEG C.
(5) preparation of compound (Ⅸ):
By compound (VIII) dispersion in a suitable solvent, add suitable reducing catalyst, carry out hydro-reduction at a proper temperature, compound (Ⅸ) can be obtained through suitable process.
Wherein: suitable solvent is methyl alcohol, ethanol, Virahol, particular methanol, ethanol; Suitable sour reagent is nitric acid, phosphoric acid, hydrochloric acid, sulfuric acid etc., preferred hydrochloric acid; Suitable reducing catalyst is sodium borohydride, acetic acid sodium borohydride, lithium aluminum hydride, POTASSIUM BOROHYDRIDE, lithium borohydride, tindichloride etc., preferred sodium borohydride, POTASSIUM BOROHYDRIDE, tindichloride; Suitable temperature adds in batches, and temperature is 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C; Appropriate compound (VIII) and reducing catalyst are than being 1:1 ~ 5, and preferred proportion is 1:3.
(6) preparation of compound (Ⅹ):
By compound (Ⅸ) dispersion in a suitable solvent, add suitable catalyzer, and then add appropriate o-methyl-benzene formyl chloride, carry out amidate action at a proper temperature, after having reacted, compound (Ⅹ) can be obtained through suitable process.
Wherein: suitable solvent is methylene dichloride, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene etc., preferred methylene dichloride, acetonitrile; Suitable alkaline catalysts can be divided into organic bases and mineral alkali, and organic bases is triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU etc.; Mineral alkali is sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate etc., preferred triethylamine, diisopropylethylamine.Temperature is 0 ~ 50 DEG C, preferably 10 ~ 40 DEG C; Appropriate compound (Ⅸ) is 1:1 ~ 2:1 ~ 5 with the ratio of o-methyl-benzene formyl chloride and alkali; Preferred proportion is 1:1.2:2.
(7) N-[4-[(chloro-2,3,4, the 5-tetrahydrochysenes of 7---5-hydroxyl-1H-1-benzo-aza
-1-base) carbonyl]-3-aminomethyl phenyl] preparation of-2-methyl benzamide (I):
By compound (Ⅹ) dispersion in a suitable solvent, at suitable temperature, add suitable original reagent of going back carry out hydrogenation, just can obtain N-[4-[(chloro-2,3,4, the 5-tetrahydrochysenes of 7---5-hydroxyl-1H-1-benzo-aza
-1-base) carbonyl]-3-aminomethyl phenyl]-2-methyl benzamide (I).
Wherein: suitable solvent is methyl alcohol, ethanol, Virahol, particular methanol, ethanol; Suitable reducing catalyst is sodium borohydride, acetic acid sodium borohydride, lithium aluminum hydride, POTASSIUM BOROHYDRIDE, tindichloride and lithium borohydride etc., preferred sodium borohydride, POTASSIUM BOROHYDRIDE; Suitable temperature adds in batches, and temperature is-10 ~ 30 DEG C, is preferably-5 ~ 5 DEG C; Appropriate compound (Ⅹ) and reducing catalyst are than being 1:1 ~ 10, and preferred proportion is 1:1.5.
Compared with prior art, major advantage of the present invention comprises:
The object of this invention is to provide one and prepare N-[4-[(chloro-2,3,4, the 5-tetrahydrochysenes of 7---5-hydroxyl-1H-1-benzo-aza
-1-base) carbonyl]-3-aminomethyl phenyl] novel method of-2-methyl benzamide, this synthetic route not only yield is high, and purity is good, the 7-avoiding traditional price high chloro-5-hydroxyl-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
for raw material, reduce reactions steps, shorten process cycle, greatly reduce production cost, and raw material 2-amino-5-chloro benzoic ether is totally easy to get, and operates more simple, the advantages such as security is better.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Embodiment 1:
(1) synthesis of compound (IV)
By 2-amino-5-chloro benzoic ether (30.0g, 161.63mmol) and and 4-bromo butyric acid methyl ester (III) (29.26g, 161.63mmol) be dissolved in acetonitrile (600mL), add sodium carbonate (34.26g, 323.26mmol), be then heated with stirring to 80 DEG C, reaction 5h, TLC detects, and reaction completes.Be chilled to room temperature, reaction solution is poured into water in (300mL), get organic phase, aqueous phase is extracted with ethyl acetate twice (200mLx2), merge organic phase, and wash with water twice (200mLx2), anhydrous sodium sulfate drying, revolve desolventizing and obtain compound (IV) 43.41g, yield is 94.0%.
1H-NMR(400MHz,DMSO):δ7.69(s,1H),7.50(s,1H),6.75(s,1H),6.61(s,1H),3.85(s,3H),3.65(s,3H),3.33(m,2H),2.50(m,2H),2.03(m,2H)。C
13H
16ClNO
4(M+H)
+Calcd:285.0768,found:285.0771。
(2) synthesis of compound (VI)
By compound (IV) (40.0g, 140.00mmol) be dissolved in methylene dichloride (600mL), triethylamine (39.03mL is added under stirring, 280.00mmol), at room temperature, 2-methyl-4-nitrobenzoyl chloride (V) (33.53g is slowly added, 168.00mmol), reaction 4h, TLC detect, and reaction completes.Reaction solution is poured in water (300mL), organic phase washed with water (200mL) and saturated aqueous common salt (200mL) wash, and anhydrous sodium sulfate drying, is spin-dried for, obtain compound (VI) 54.04g, yield is 86.0%.
1H-NMR(400MHz,DMSO):δ8.31(s,1H),8.24(s,1H),8.17(s,1H),7.88(s1H),7.75(s,1H),7.65(s,1H),4.22(m,2H),3.85(s,3H),3.66(s,3H),2.43～2.48(m,5H),2.09(m,2H)。C
21H
21ClN
2O
7(M+H)
+Calcd:448.1037,found:448.1042。
(3) synthesis of compound (VII)
Be dissolved in toluene (500mL) by compound (VI) (50.0g, 111.40mmol), add potassium tert.-butoxide (25.0g, 222.79mmol), be warming up to 120 DEG C, stir 1h, TLC and detect, reaction completes.Be chilled to room temperature.Use water (2x200mL) and saturated aqueous common salt (200mL) to wash successively, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain compound (VII) 39.93g, yield is 86.0%.
(4) synthesis of compound (VIII)
Compound (VII) (30.0g, 71.98mmol) is dissolved in acetic acid (150mL), in concentrated hydrochloric acid (75mL) and water (15mL) mixing solutions, be heated to 100 DEG C, stir 6h, TLC to detect, reaction completes.Be chilled to room temperature, pour in frozen water (150mL), stir 15min, stir lower 4N sodium hydroxide solution by pH=7-8, methylene dichloride (200mLx3) extracts.Use water (200mL) and saturated aqueous common salt (200mL) washing successively, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain product 22.88g, yield is 88.6%.
(5) synthesis of compound (Ⅸ)
In the concentrated hydrochloric acid (70mL) and ethanol (140mL) suspension liquid of compound (VIII) (22.0g, 61.32mmol), add SnCl in batches
22H
2o (41.51g, 183.96mmol), in room temperature reaction 4h after finishing.TLC detection reaction is complete, and ethanol is revolved in decompression, and residual reaction liquid is placed refrigerator freezing and spent the night, a large amount of solid is had to separate out, suction filtration, filter cake with after a small amount of water washing, then uses 150ml water dissolution, drip 20% sodium hydroxide solution while stirring and be adjusted to pH=9, filter, with dehydrated alcohol, filter cake is carried out recrystallization, obtain light yellow solid, for compound (Ⅸ) (16.13g, 80.0%).
(6) synthesis of compound (Ⅹ)
By compound (Ⅸ) (16.0g, 48.66mmol) be dissolved in methylene dichloride (400mL), add triethylamine (13.57mL, 97.33mmol), stir 15min, and then add o-methyl-benzene formyl chloride (9.03g in batches, 58.40mmol), react 2h at ambient temperature, TLC detects, and reaction completes.Reaction solution is poured into water in (200mL), organic phase washing twice (200mlx2), anhydrous sodium sulfate drying, revolves methylene dichloride and obtains product 2-methyl-4-(2-methyl benzamide base) phenylformic acid (19.21g, 88.3%).
(7) N-[4-[(chloro-2,3,4, the 5-tetrahydrochysenes of 7---5-hydroxyl-1H-1-benzo-aza
-1-base) carbonyl]-3-aminomethyl phenyl] preparation of-2-methyl benzamide (I)
By chloro-for 7-5-hydroxyl-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
(19.0g, 42.51mmol) is dissolved in methyl alcohol (200ml) solvent, under 0 DEG C of condition, add sodium borohydride (2.42g, 63.77mmol) in batches, continues to stir 2h, TLC detection reaction and complete after reinforced.Be poured into water by reaction solution, dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration and underpressure distillation obtain crude product, utilize methyl alcohol: sherwood oil (2:1) recrystallization, obtain white solid tolvaptan (18.33g, 96.0%).
Embodiment 2:
(1) synthesis of compound (IV)
By 2-amino-5-chloro benzoic ether (30.0g, 161.63mmol) and and 4-bromo butyric acid methyl ester (III) (29.26g, 161.63mmol) be dissolved in acetonitrile (600mL), add salt of wormwood (44.68g, 323.26mmol), be then heated with stirring to 80 DEG C, reaction 5h, TLC detects, and reaction completes.Be chilled to room temperature, reaction solution is poured into water in (300mL), get organic phase, aqueous phase is extracted with ethyl acetate twice (200mLx2), merge organic phase, and wash with water twice (200mLx2), anhydrous sodium sulfate drying, revolve desolventizing and obtain compound (IV) 42.49g, yield is 92.0%.
(2) synthesis of compound (VI)
By compound (IV) (40.0g, 140.00mmol) be dissolved in methylene dichloride (600mL), diisopropylethylamine (36.19g is added under stirring, 280.00mmol), at room temperature, 2-methyl-4-nitrobenzoyl chloride (V) (33.53g is slowly added, 168.00mmol), reaction 4h, TLC detect, and reaction completes.Reaction solution is poured in water (300mL), organic phase washed with water (200mL) and saturated aqueous common salt (200mL) wash, and anhydrous sodium sulfate drying, is spin-dried for, obtain compound (VI) 55.74g, yield is 88.7%.
(3) synthesis of compound (VII)
Be dissolved in toluene (500mL) by compound (VI) (50.0g, 111.40mmol), add potassium tert.-butoxide (25.0g, 222.79mmol), be warming up to 120 DEG C, stir 1h, TLC and detect, reaction completes.Be chilled to room temperature.Use water (2x200mL) and saturated aqueous common salt (200mL) to wash successively, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain compound (VII) 39.0g, yield is 84.0%.
(4) synthesis of compound (VIII)
Compound (VII) (30.0g, 71.98mmol) is dissolved in acetic acid (150mL), in concentrated hydrochloric acid (75mL) and water (15mL) mixing solutions, be heated to 100 DEG C, stir 5h, TLC to detect, reaction completes.Be chilled to room temperature, pour in frozen water (150mL), stir 15min, stir lower 4N sodium hydroxide solution by pH=7-8, methylene dichloride (200mLx3) extracts.Use water (200mL) and saturated aqueous common salt (200mL) washing successively, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain product 21.95g, yield is 85.0%.
(5) synthesis of compound (Ⅸ)
In the concentrated hydrochloric acid (70mL) and ethanol (140mL) suspension liquid of compound (VIII) (20.0g, 55.75mmol), add SnCl in batches
22H
2o (37.74g, 167.23mmol), in room temperature reaction 4h after finishing.TLC detection reaction is complete, and ethanol is revolved in decompression, and residual reaction liquid is placed refrigerator freezing and spent the night, a large amount of solid is had to separate out, suction filtration, filter cake with after a small amount of water washing, then uses 150ml water dissolution, drip 20% sodium hydroxide solution while stirring and be adjusted to pH=9, filter, with dehydrated alcohol, filter cake is carried out recrystallization, obtain light yellow solid, for compound (Ⅸ) (14.90g, 81.3%).
(6) synthesis of compound (Ⅹ)
By compound (Ⅸ) (14.0g, 42.58mmol) be dissolved in methylene dichloride (350mL), add diisopropylethylamine (11.0g, 85.16mmol), stir 15min, and then add o-methyl-benzene formyl chloride (7.90g in batches, 51.10mmol), react 2h at ambient temperature, TLC detects, and reaction completes.Reaction solution is poured into water in (200mL), organic phase washing twice (200mlx2), anhydrous sodium sulfate drying, revolves methylene dichloride and obtains product 2-methyl-4-(2-methyl benzamide base) phenylformic acid (17.24g, 90.6%).
(7) N-[4-[(chloro-2,3,4, the 5-tetrahydrochysenes of 7---5-hydroxyl-1H-1-benzo-aza
-1-base) carbonyl]-3-aminomethyl phenyl] preparation of-2-methyl benzamide (I)
By chloro-for 7-5-hydroxyl-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
(17.0g, 38.04mmol) is dissolved in methyl alcohol (200ml) solvent, under 0 DEG C of condition, add sodium borohydride (2.16g, 57.06mmol) in batches, continues to stir 2h, TLC detection reaction and complete after reinforced.Be poured into water by reaction solution, dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration and underpressure distillation obtain crude product, utilize methyl alcohol: sherwood oil (2:1) recrystallization, obtain white solid tolvaptan (16.22g, 95.0%).
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. one kind as shown in the formula the compound shown in (VI):
2. the preparation method of formula (VI) compound as claimed in claim 1, is characterized in that, comprise step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
3. preparation method as claimed in claim 2, is characterized in that, in described step (2), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, or its combination; Be preferably triethylamine, diisopropylethylamine, or its combination.
4. one kind as shown in the formula the compound shown in (IV):
5. the preparation method of formula (IV) compound as claimed in claim 4, is characterized in that, comprise step:
(1) in inert solvent, with formula (II) compound and the reaction of formula (III) compound, formula (IV) compound is obtained;
6. preparation method as claimed in claim 5, is characterized in that, in described step (1), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, or its combination; Preferred sodium carbonate, salt of wormwood, or its combination.
7. a preparation method for formula (VII) compound, is characterized in that, comprise step:
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
8. the purposes of formula (VI) compound as claimed in claim 1 or formula (IV) compound as claimed in claim 4, is characterized in that, for the preparation of formula (I) compound (tolvaptan).
9. a preparation method for formula (I) compound, is characterized in that, comprise step:
(2) in inert solvent, react with formula (IV) compound and formula (V) compound, obtain formula (VI) compound;
(3) in inert solvent, under alkaline catalysts exists, react with formula (VI) compound, obtain formula (VII) compound:
(4) in inert solvent, in presence of an acid catalyst, react with formula (VII) compound, obtain formula (VIII) compound;
(5) in inert solvent, carry out hydro-reduction with formula (VIII) compound, obtain formula (IX) compound;
(6) in inert solvent, react with formula (IX) compound and o-methyl-benzene formyl chloride, obtain formula (X) compound;
(7) in inert solvent, with formula (IX) compound and reduction reagent react, formula (I) compound is obtained;
10. preparation method as claimed in claim 9, it is characterized in that, described method also comprises step:
(1) in inert solvent, with formula (II) compound and the reaction of formula (III) compound, formula (IV) compound is obtained;
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315212A (en) * | 2014-07-31 | 2016-02-10 | 上海天慈生物谷生物工程有限公司 | Preparation method for vasopressin antagonist |
| CN107663171A (en) * | 2017-10-10 | 2018-02-06 | 常州市阳光药业有限公司 | The preparation method of high-purity tolvaptan |
| CN108503586A (en) * | 2017-02-24 | 2018-09-07 | 江苏恒瑞医药股份有限公司 | The method for preparing high-purity tolvaptan intermediate |
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| WO2005085183A1 (en) * | 2004-03-02 | 2005-09-15 | Centre National De La Recherche Scientifique | Method of preparing benzazepines and derivatives thereof |
| CN103012265A (en) * | 2012-11-23 | 2013-04-03 | 天津药物研究院 | Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine |
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| WO2005085183A1 (en) * | 2004-03-02 | 2005-09-15 | Centre National De La Recherche Scientifique | Method of preparing benzazepines and derivatives thereof |
| CN103012265A (en) * | 2012-11-23 | 2013-04-03 | 天津药物研究院 | Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315212A (en) * | 2014-07-31 | 2016-02-10 | 上海天慈生物谷生物工程有限公司 | Preparation method for vasopressin antagonist |
| CN105315212B (en) * | 2014-07-31 | 2019-06-18 | 上海天慈生物谷生物工程有限公司 | A kind of preparation method of vasopressin antagonistic drug |
| CN108503586A (en) * | 2017-02-24 | 2018-09-07 | 江苏恒瑞医药股份有限公司 | The method for preparing high-purity tolvaptan intermediate |
| CN108503586B (en) * | 2017-02-24 | 2020-11-17 | 江苏恒瑞医药股份有限公司 | Process for the preparation of tolvaptan intermediates |
| CN107663171A (en) * | 2017-10-10 | 2018-02-06 | 常州市阳光药业有限公司 | The preparation method of high-purity tolvaptan |
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