CN110386918B - Preparation method of 5-HT1F agonist compound - Google Patents
Preparation method of 5-HT1F agonist compound Download PDFInfo
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- CN110386918B CN110386918B CN201810368324.9A CN201810368324A CN110386918B CN 110386918 B CN110386918 B CN 110386918B CN 201810368324 A CN201810368324 A CN 201810368324A CN 110386918 B CN110386918 B CN 110386918B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 92
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 102100036311 5-hydroxytryptamine receptor 1F Human genes 0.000 title abstract description 6
- 101710138086 5-hydroxytryptamine receptor 1F Proteins 0.000 title abstract description 6
- 239000000556 agonist Substances 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006482 condensation reaction Methods 0.000 claims abstract description 18
- 238000007112 amidation reaction Methods 0.000 claims abstract description 12
- SIFIJQFBERMWMU-UHFFFAOYSA-N 2,4,6-trifluorobenzoyl chloride Chemical compound FC1=CC(F)=C(C(Cl)=O)C(F)=C1 SIFIJQFBERMWMU-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 238000007259 addition reaction Methods 0.000 claims abstract description 8
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 8
- JGEIDCYULHBRAF-UHFFFAOYSA-N C=NC=1C(=NC(=CC1)C1CCN(CC1)C)C=O Chemical class C=NC=1C(=NC(=CC1)C1CCN(CC1)C)C=O JGEIDCYULHBRAF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000008360 acrylonitriles Chemical class 0.000 claims abstract description 6
- IJVVXIKAPRQSBH-UHFFFAOYSA-N C=NC1=NC(=CC=C1)C(C)=O Chemical class C=NC1=NC(=CC=C1)C(C)=O IJVVXIKAPRQSBH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 93
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 21
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 229960001701 chloroform Drugs 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical group CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 4
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 4
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 4
- 239000001639 calcium acetate Substances 0.000 claims description 4
- 235000011092 calcium acetate Nutrition 0.000 claims description 4
- 229960005147 calcium acetate Drugs 0.000 claims description 4
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 235000010216 calcium carbonate Nutrition 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 150000007529 inorganic bases Chemical group 0.000 claims description 4
- JHHMSRLTZAUMOJ-UHFFFAOYSA-N methanamine;oxolane Chemical compound NC.C1CCOC1 JHHMSRLTZAUMOJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- CMPIGRYBIGUGTH-UHFFFAOYSA-N 2-bromoprop-2-enenitrile Chemical compound BrC(=C)C#N CMPIGRYBIGUGTH-UHFFFAOYSA-N 0.000 claims description 3
- OYUNTGBISCIYPW-UHFFFAOYSA-N 2-chloroprop-2-enenitrile Chemical group ClC(=C)C#N OYUNTGBISCIYPW-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- -1 2-disubstituted methyleneamino-6- (2, 2-dihydroxyethyl) acetylpyridine Chemical class 0.000 description 35
- 239000012295 chemical reaction liquid Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 238000004821 distillation Methods 0.000 description 14
- 239000005457 ice water Substances 0.000 description 13
- 230000035484 reaction time Effects 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 239000007791 liquid phase Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 5
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 4
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- XEDHVZKDSYZQBF-UHFFFAOYSA-N lasmiditan Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(NC(=O)C=2C(=CC(F)=CC=2F)F)=N1 XEDHVZKDSYZQBF-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FLBNYMFKURDCFV-UHFFFAOYSA-N 2-chloro-5,6-dioxoheptanenitrile Chemical compound CC(=O)C(=O)CCC(C#N)Cl FLBNYMFKURDCFV-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- OWXJHHZBARYNCT-UHFFFAOYSA-N 1-(6-aminopyridin-2-yl)ethanone Chemical compound CC(=O)C1=CC=CC(=N)N1 OWXJHHZBARYNCT-UHFFFAOYSA-N 0.000 description 1
- HCKNAJXCHMACDN-UHFFFAOYSA-N 1-methylpiperidine-4-carboxylic acid Chemical compound CN1CCC(C(O)=O)CC1 HCKNAJXCHMACDN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OXQHJIGWZNIQDS-UHFFFAOYSA-N 2,2-dimethoxybutane Chemical compound CCC(C)(OC)OC OXQHJIGWZNIQDS-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- HLQXUKISHXIENR-UHFFFAOYSA-N 2-bromo-5,6-dioxoheptanenitrile Chemical compound CC(=O)C(=O)CCC(C#N)Br HLQXUKISHXIENR-UHFFFAOYSA-N 0.000 description 1
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- UESSEMPSSAXQJC-UHFFFAOYSA-N ethanol;methanamine Chemical compound NC.CCO UESSEMPSSAXQJC-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 229950009142 lasmiditan Drugs 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- MORFIZKYBRXBGO-UHFFFAOYSA-N n,n,1-trimethylpiperidine-4-carboxamide Chemical compound CN(C)C(=O)C1CCN(C)CC1 MORFIZKYBRXBGO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000010626 work up procedure 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation method of a 5-HT1F agonist compound. The method comprises the steps of carrying out 1, 4-addition reaction on 2, 3-butanedione and 2-halogenated acrylonitrile to obtain 2-halogenated-5, 6-dioxo-n-heptanonitrile, carrying out pyridine cyclization with ammonia to protect amino to obtain 2-disubstituted methylene amino-6-acetylpyridine, carrying out hydroxyethylation reaction, sulfoesterification reaction and methylamine condensation reaction to prepare 2-disubstituted methylene amino-6- (1-methylpiperidine-4-yl) formylpyridine, and carrying out deprotection reaction and 2,4, 6-trifluorobenzoyl chloride amidation reaction to obtain the 5-HT1F agonist compound lasiditan. The method has the advantages of easily obtained raw materials, avoidance of ultralow temperature reaction, simple and convenient operation, low cost and easy industrial production of the Lasmidin.
Description
Technical Field
The invention relates to a preparation method of a 5-HT1F agonist compound Lasmidin, belonging to the technical field of medicinal chemistry.
Background
Lasmidinan Hydrochloride (1:1)) is an oral serotonin 5-HT1F agonist drug developed by Gift and Cold pharmaceuticals in combination for the treatment of acute migraine, and the latest phase III clinical study shows excellent treatment results. Meanwhile, clinical research is carried out on other medicinal salts of the Lasmidan, so that the preparation of the free base Lasmidan (I) has important significance for related medicinal research or market popularization.
Lasiditan (i), chemically known as N- [6- [ (1-methyl-4-piperidinyl) carbonyl ] pyridin-2-yl ] -2,4, 6-trifluorobenzamide, having the associated chemical structure shown below:
chinese patent documents CN1642939A and J.C.S.perkin T (24),3597-2(dba)3) Condensing under the action of sodium tert-butoxide, deprotecting triethylamine to prepare 2-amino-6- (1-methylpiperidine-4-) formyl pyridine, amidating with 2,4, 6-trifluorobenzoyl chloride, and salifying with hydrochloric acid to obtain the target product. The reaction equation for the above scheme is depicted as scheme 1 below.
Patent CN100352817 and WO2011123654 propose another preparation route, in which piperidine-4-formic acid is used as a raw material, N-methylation reaction is carried out to obtain 1-methylpiperidine-4-formic acid, oxalyl chloride acylation chlorination is carried out to obtain 1-methylpiperidine-4-formyl chloride, amidation reaction is carried out to prepare N, N-dimethyl-1-methylpiperidine-4-formamide, N-butyllithium ultralow temperature reaction is carried out to prepare 6-bromo-2- (1-methylpiperidine-4-) formyl pyridine, amination reaction is carried out to obtain 2-amino-6- (1-methylpiperidine-4-) formyl pyridine, and amidation reaction and hydrochloric acid salt formation are carried out to the 2,4, 6-trifluorobenzoyl chloride to obtain the target product. The reaction equation for the above scheme is depicted in scheme 2 below (wherein% refers to molar yield):
both routes involve ultralow temperature operation below-70 ℃, have high requirements on process conditions, are complicated in process, have high prices of used raw materials, and are not beneficial to industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of the lasiditan, which is simple and convenient to operate and low in cost.
Description of terms:
a compound of formula II: 2, 3-butanedione;
a compound of formula III: 2-halo-5, 6-dioxo-n-heptanonitrile;
a compound of formula IV: 2-amino-6-acetylpyridine;
a compound of formula V: 2-disubstituted methyleneamino-6-acetylpyridine;
a compound of formula VI: 2-disubstituted methyleneamino-6- (2, 2-dihydroxyethyl) acetylpyridine;
a compound of formula VII: 2-disubstituted methyleneamino-6- (2, 2-disulfonatoethyl) acetylpyridine;
a compound of formula VIII: 2-disubstituted methyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine;
a compound of formula IX: 2-amino-6- (1-methylpiperidin-4-yl) formylpyridine;
a compound of formula I: lasiditan, N- [6- [ (1-methyl-4-piperidinyl) carbonyl ] pyridin-2-yl ] -2,4, 6-trifluorobenzamide.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula.
The technical scheme of the invention is as follows:
a process for the preparation of a compound of formula I, comprising the steps of:
(1) under the action of a solvent A and an alkali catalyst, a compound shown in a formula II and 2-halogenated acrylonitrile are subjected to 1, 4-addition reaction to prepare a compound shown in a formula III; the 2-halogenated acrylonitrile is selected from 2-chloro acrylonitrile or 2-bromo acrylonitrile;
wherein, in the structural formula of the compound shown in the formula III, X is Cl or Br;
(2) in a solvent B, a compound of a formula III and ammonia are subjected to pyridine cyclization reaction to obtain a compound of a formula IV, and then the compound of the formula III and a compound of a formula XI are subjected to condensation reaction to protect amino, so that a compound of a formula V is obtained: 2-disubstituted methyleneamino-6-acetylpyridine;
in the above structural formula, R1、R2、R3、R4Each independently is methyl, ethyl, isopropyl or tert-butyl; the same applies below;
(3) under the action of C and alkali catalyst, the compound of formula V and epoxy ethane are subjected to hydroxyethylation reaction to obtain a compound VI, which is directly subjected to sulfoacid esterification reaction with sulfonyl chloride-alkali A to prepare a compound of formula VII without separation, and then subjected to condensation reaction with methylamine to prepare a compound of formula VIII: 2-disubstituted methyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine;
r is methyl, phenyl, p-methylphenyl;
(4) under the action of a solvent D and an acid catalyst, a compound of a formula VIII undergoes deprotection reaction to obtain a compound of a formula IX, and then undergoes amidation reaction with 2,4, 6-trifluorobenzoyl chloride under the action of a base B to obtain a compound of a formula I:
according to the present invention, preferably, in step (1), the solvent a is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane and isopropyl ether; the mass ratio of the solvent A to the compound shown in the formula II in the step (1) is (3-15) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II in the step (1) is (5-8): 1.
According to the present invention, it is preferred that the base catalyst in step (1) is one or a combination of two or more of potassium hydroxide, lithium hydroxide, piperidine, 4-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN); the dosage of the catalyst is 0.5-5 wt% of the mass of the compound shown in the formula II; preferably, the base catalyst is used in an amount of 1.0 to 2.5 wt.% based on the mass of the compound of formula II.
According to the present invention, it is preferred that in the step (1), the molar ratio of the 2-halogenoacrylonitrile to the compound of II is (0.9-1.2): 1.
According to the present invention, it is preferable that the 1, 4-addition reaction temperature in the step (1) is 20 to 100 ℃; preferably, the temperature of the 1, 4-addition reaction in step (1) is 50-70 ℃. The reaction time is 2-10 hours; preferably, the reaction time is 3 to 5 hours.
According to the present invention, preferably, the solvent B in step (2) is one or a combination of two or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane or acetonitrile; the mass ratio of the solvent B to the compound shown in the formula III in the step (2) is (3-20): 1; further preferably, the mass ratio of the solvent B to the compound of the formula III in the step (2) is (7-10): 1.
Preferably according to the invention, the ammonia in step (2) is derived from ammonia gas, ammonia water, ammonia methanol solution or ammonia ethanol solution; the molar ratio of ammonia to the compound of formula III is (3.0-5.0): 1.
preferably, in step (2), the molar ratio of the compound of formula XI to the compound of formula III is (1.0-2.0): 1.
according to the present invention, the pyridine ring-closure reaction temperature in the step (2) is preferably 30 to 100 ℃, and more preferably 50 to 70 ℃; the pyridine cyclization reaction time is 2-8 hours, and the preferable reaction time is 3-5 hours.
According to the present invention, it is preferable that the condensation reaction temperature in the step (2) is 10 to 100 ℃, and it is further preferable that the condensation reaction temperature is 30 to 70 ℃; the condensation reaction time is 2 to 10 hours, and preferably 5 to 7 hours.
According to the present invention, preferably, the solvent C in step (3) is one or a combination of two or more of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane or chlorobenzene; the mass ratio of the solvent C to the compound shown in the formula V in the step (3) is (5-30) to 1; preferably, the mass ratio of the solvent C to the compound of the formula V in the step (3) is (10-15): 1.
According to the present invention, it is preferable that the base catalyst in the step (3) is one or a combination of two or more of potassium hydroxide, lithium hydroxide, piperidine, 4-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN); the amount of the catalyst is 0.5-5 wt% of the mass of the compound shown in the formula V; preferably, the base catalyst is used in an amount of 1.0 to 2.5 wt.% based on the mass of the compound of formula V.
According to the present invention, preferably, the sulfonyl chloride in step (3) is methylsulfonyl chloride, benzenesulfonyl chloride, p-methylbenzenesulfonyl chloride. The alkali A is inorganic alkali or organic alkali, wherein the inorganic alkali is selected from one or a combination of potassium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate and calcium acetate, and the organic alkali is selected from one or a combination of triethylamine and tri-n-butylamine; in the step (3), the methylamine is an alcoholic methylamine solution or a methylamine tetrahydrofuran solution. Among them, 20 to 35% by weight of methylamine methanol solution, 15 to 30% by weight of methylamine ethanol solution, and 15 to 30% by weight of methylamine tetrahydrofuran solution are preferable.
According to the present invention, it is preferred that the molar ratio of the ethylene oxide, the sulfonyl chloride, the base A, the methylamine and the compound of formula V in step (3) is (2.0-2.5): (1.0-1.5): 1.
According to the present invention, it is preferred that the hydroxyethylation temperature in step (3) is from 10 to 80 ℃, and it is particularly preferred that the hydroxyethylation temperature is from 25 to 45 ℃. The hydroxyethylation reaction time is 2 to 8 hours, preferably 4 to 6 hours.
According to the present invention, it is preferred that the temperature of the sulfoesterification reaction in step (3) is 0 to 50 ℃, and it is particularly preferred that the temperature of the sulfoesterification reaction is 10 to 30 ℃; the sulfoesterification reaction time is 2 to 10 hours, and the preferable reaction time is 4 to 6 hours.
According to the present invention, it is preferred that the condensation reaction temperature in step (3) is 0 to 60 ℃, and it is particularly preferred that the condensation reaction temperature is 20 to 40 ℃; the condensation reaction time is 2 to 10 hours, preferably 4 to 6 hours.
According to the present invention, preferably, in the step (4), the solvent D is one or a combination of two or more of dichloromethane, trichloromethane, 1, 2-dichloroethane, chlorobenzene or water; in the step (4), the mass ratio of the solvent D to the compound of the formula VIII is (5-20) to 1; preferably, the mass ratio of the solvent D and the compound of the formula VIII in the step (4) is (7-14): 1.
According to the present invention, preferably, the acid catalyst in step (4) is one or a combination of two or more of hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid with a certain concentration; the dosage of the acid catalyst is 0.5-5% wt. of the mass of the compound of the formula VIII; preferably, the acid catalyst is used in an amount of 1.5 to 3.0% wt. based on the mass of the compound of formula VIII. Wherein, the mass concentration of the hydrochloric acid is 20-35%, the mass concentration of the hydrobromic acid is 20-40%, the mass concentration of the phosphoric acid is 60-75%, and the mass concentration of the sulfuric acid is 40-75%.
According to the invention, preferably, the base B in step (4) is an inorganic base or an organic base, wherein the inorganic base is selected from one or a combination of potassium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate and calcium acetate, and the organic base is selected from one or a combination of triethylamine and tri-n-butylamine.
According to the present invention, it is preferred that the molar ratio of the 2,4, 6-trifluorobenzoyl chloride, the base B and the compound of formula VIII in step (4) is (1.0-1.5): (1.0-1.5): 1.
Preferably, according to the invention, the deprotection reaction temperature in step (4) is 10-50 ℃; particularly preferably, the deprotection reaction temperature is 20 to 40 ℃. The deprotection reaction time is 1 to 5 hours, and particularly preferably 2 to 4 hours.
According to the invention, the temperature of the amidation reaction in step (4) is preferably from 0 to 80 ℃ and, with particular preference, from 20 to 40 ℃. The amidation reaction time is 2-8 hours; preferably, the amidation reaction time is 3 to 6 hours.
The process of the present invention is depicted as scheme 3 below:
wherein X is Cl or Br; XI are compounds of formula XI
R1、R2、R3、R4Each independently selected from methyl, ethyl, isopropyl or tert-butyl; r is methyl, phenyl or p-methylphenyl.
The invention is not limited in detail, and all the prior arts can be referred to. The work-up of the products in steps (1) to (4) of the process of the invention can be carried out according to the prior art. The following are preferred:
product post-treatment in the step (1): after the reaction is finished, the solvent is recovered by distillation, and then 105-. The gas phase purity is more than 99.2 percent.
Product post-treatment in the step (2): after the pyridine cyclization reaction is finished, cooling to 20-25 ℃, adding the obtained reaction liquid into dichloromethane or a mixture of chloroform and ice water, layering, extracting a water layer by using dichloromethane or chloroform, combining organic phases, drying and filtering to obtain a compound shown in the formula IV; and after the condensation reaction is finished, distilling to recover the solvent, and recrystallizing the residue by using normal hexane to obtain the compound shown in the formula V. The gas phase purity is more than 99.1 percent.
Product post-treatment in the step (3): and after the condensation reaction is finished, pouring the obtained reaction liquid into ice water, layering, extracting a water layer by using dichloromethane, combining organic phases, distilling to recover the solvent, and recrystallizing the remainder by using methyl tertiary butyl ether to obtain the compound shown in the formula VIII. The purity of the liquid phase is more than 99.3 percent.
Product post-treatment in the step (4): after the amidation reaction is completed, the obtained reaction liquid is poured into ice water, layered, the water layer is extracted by dichloromethane, organic phases are combined, the solvent is recovered by distillation, and the remainder is recrystallized by methyl tertiary butyl ether to obtain the compound shown in the formula I: and Lasmiditan.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel preparation method of lasiditan, which comprises the steps of carrying out 1, 4-addition reaction on 2, 3-butanedione and 2-halogenated acrylonitrile to obtain 2-halogenated-5, 6-dioxo-n-heptanonitrile, carrying out pyridine cyclization and amino protection on the 2-disubstituted methyleneamino-6-acetylpyridine with ammonia to obtain 2-disubstituted methyleneamino-6- (1-methylpiperidine-4-yl) formylpyridine, carrying out hydroxyethylation reaction, carrying out sulfonic acid esterification reaction and methylamine condensation reaction to prepare 2-disubstituted methyleneamino-6- (1-methylpiperidine-4-yl) formylpyridine, and carrying out deprotection reaction and 2,4, 6-trifluorobenzoyl chloride amidation reaction to obtain the lasiditan.
2. The method has the advantages of low-cost raw materials, simple and convenient operation, good stability of the raw materials and intermediate products, high reaction selectivity, high product purity and yield, avoidance of ultralow temperature reaction, low operation process cost, less three wastes, greenness, environmental protection and easiness in industrial production of the Lasmidin.
3. Compared with the highest total yield (55.1%) of the Lasmidan reported in the prior art, the total yield of the invention can reach 68.4%, the total yield is improved by 13.3%, and the defects of more steps, high requirement on operating equipment, need of ultralow temperature and large amount of three wastes in the prior art are overcome.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
Example 1: preparation of 2-chloro-5, 6-dioxo-n-heptonitrile (III 1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 250 g of tetrahydrofuran, 43.0 g (0.5 mol) of 2, 3-butanedione (II), 43.5 g (0.5 mol) of 2-chloroacrylonitrile, 0.6 g of lithium hydroxide were charged, stirred at 50 to 55 ℃ for 4 hours, cooled to 20 to 25 ℃, added with 1.0 g of acetic acid, distilled to recover the solvent, and then subjected to reduced pressure distillation to collect a fraction at 90 to 105 ℃/1 to 2mmHg, thereby obtaining 81.2 g of 2-chloro-5, 6-dioxon-heptonitrile (III 1) with a yield of 93.6% and a gas phase purity of 99.5%.
Example 2: preparation of 2-bromo-5, 6-dioxo-n-heptonitrile (III 2)
250 g of isopropyl ether, 43.0 g (0.5 mol) of 2, 3-butanedione (II), 66.0 g (0.5 mol) of 2-bromoacrylonitrile and 0.6 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, the mixture is stirred and reacted for 4 hours at the temperature of 60 to 65 ℃, the solvent is recovered by distillation, and then 105 ion-containing 115 ℃/1-2mmHg fractions are collected by reduced pressure distillation, so that 103.2 g of 2-bromo-5, 6-dioxo-n-heptonitrile (III 2) is obtained, the yield is 94.7 percent and the gas phase purity is 99.2 percent.
Example 3: preparation of 2-dimethylmethyleneamino-6-acetylpyridine (V1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 80 g of methanol, 40.0 g (0.4 mol) of a 17% ammonia methanol solution, 50 to 55 ℃ and a solution of 17.4 g (0.1 mol) of 2-chloro-5, 6-dioxo-n-heptanonitrile (III 1) prepared in example 1 and 80 g of methanol was added dropwise thereto over about 2 hours, after which the reaction was stirred at 55 to 60 ℃ for 4 hours. Cooling to 20 to 25 ℃, adding the obtained reaction liquid to 200 g of dichloromethane and 200 g of ice water, separating layers, extracting the water layer with dichloromethane 3 times, each time 20 g, combining the organic phases, drying with 10.0 g of anhydrous sodium sulfate for 4 hours, filtering, transferring the obtained filtrate to a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser, adding 20.0 g (0.19 mol) of 2, 2-dimethoxypropane, thereafter stirring and reacting at 38 to 40 ℃ for 6 hours, recovering dichloromethane and excess 2, 2-dimethoxypropane by distillation, and recrystallizing the residue with 120.0 g of n-hexane to obtain 15.5 g of 2-dimethylmethyleneamino-6-acetylpyridine (V1), yield 87.5%, and gas phase purity 99.1%.
Example 4: preparation of 2-methylethylmethyleneamino-6-acetylpyridine (V2)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 80 g of ethanol, 40.0 g (0.4 mol) of a 17% aminoethanol solution, and a solution of 21.8 g (0.1 mol) of 2-bromo-5, 6-dioxo-n-heptanonitrile (III 2) prepared in example 2 and 80 g of ethanol was added dropwise at a temperature of between 60 and 65 ℃ over about 2 hours, after which the reaction was stirred at a temperature of between 65 and 70 ℃ for 4 hours. Cooling to 20 to 25 ℃, adding the resulting reaction liquid to 200 g chloroform and 200 g ice water, layering, extracting the aqueous layer with chloroform 3 times, 20 g each time, combining the organic phases, drying with 10.0 g anhydrous sodium sulfate for 4 hours, filtering, transferring the obtained filtrate to a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser, adding 20.0 g (0.17 mol) of 2-dimethoxybutane, thereafter stirring at 60 to 65 ℃ for 4 hours, recovering chloroform and excess 2, 2-dimethoxybutane by distillation, and recrystallizing the residue with 120.0 g n-hexane to obtain 17.1 g 2-methylethylmethylamino-6-acetylpyridine (V2) with a yield of 90.0% and a gas phase purity of 99.2%.
Example 5: preparation of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1)
To a 250 ml autoclave, 120 g of tetrahydrofuran, 17.6 g (0.1 mol) of 2-dimethylmethyleneamino-6-acetylpyridine (V1) obtained in example 3, 0.3 g of DBU, 9.0 g (0.2 mol) of ethylene oxide were charged, the autoclave was closed, the reaction was stirred at 30 to 35 ℃ for 3 hours, cooled to 20 to 25 ℃, the resultant reaction liquid was transferred to a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 23.0 g of triethylamine was charged, a solution of 24.0 g (0.21 mol) of methanesulfonyl chloride and 30 g of tetrahydrofuran was added dropwise at 10 to 15 ℃ over about 2 hours, and thereafter, the reaction was stirred at 15 to 20 ℃ for 4 hours. 11.0 g (0.11 mol) of 30% methylamine methanol solution was added, the reaction was stirred at 20 to 25 ℃ for 4 hours, the obtained reaction liquid was poured into 200 g of ice water, the layers were separated, the aqueous layer was extracted 3 times with dichloromethane, 20 g each, the organic phases were combined, dichloromethane was recovered by distillation, and the residue was recrystallized from 100 g of methyl tert-butyl ether to give 22.5 g of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1) with a yield of 86.9% and a liquid phase purity of 99.3%.
Example 6: preparation of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1)
To a 250 ml autoclave, 120 g of methylene chloride, 17.6 g (0.1 mol) of 2-dimethylmethyleneamino-6-acetylpyridine (V1) obtained in example 3, 0.3 g of DBU, 9.0 g (0.2 mol) of ethylene oxide were charged, the autoclave was closed, the reaction was stirred at 30 to 35 ℃ for 3 hours, cooled to 20 to 25 ℃, the resultant reaction liquid was transferred to a 500 ml four-neck flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 23.0 g of triethylamine was charged, a solution of 40.0 g (0.21 mol) of p-toluenesulfonyl chloride and 80 g of methylene chloride was added dropwise at 10 to 15 ℃ over about 2 hours, and thereafter, the reaction was stirred at 20 to 25 ℃ for 4 hours. 11.0 g (0.11 mol) of 30% methylamine methanol solution was added, the reaction was stirred at 20 to 25 ℃ for 4 hours, the obtained reaction liquid was poured into 200 g of ice water, the layers were separated, the aqueous layer was extracted 3 times with dichloromethane, 20 g each, the organic phases were combined, dichloromethane was recovered by distillation, and the residue was recrystallized from 100 g of methyl tert-butyl ether to give 22.1 g of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1) with a yield of 85.3% and a liquid phase purity of 99.5%.
Example 7: preparation of 2-methylethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 2)
Into a 250 ml autoclave were charged 150 g of tetrahydrofuran, 19.0 g (0.1 mol) of 2-methylethylmethyleneamino-6-acetylpyridine (V2) obtained in example 4, 0.4 g of lithium hydroxide, 9.7 g (0.22 mol) of ethylene oxide, the autoclave was closed, the reaction was stirred at 35 to 40 ℃ for 3 hours, cooled to 20 to 25 ℃, the resultant reaction liquid was transferred to a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 23.0 g of triethylamine, 20 to 25 ℃ were added, a solution of 24.0 g (0.21 mol) of methanesulfonyl chloride and 30 g of tetrahydrofuran was added dropwise over about 2 hours, and thereafter, the reaction was stirred at 20 to 25 ℃ for 4 hours. 11.0 g (0.11 mol) of a 30% methylamine tetrahydrofuran solution was added thereto, and the reaction was stirred at 25 to 30 ℃ for 4 hours, the resulting reaction liquid was poured into 200 g of ice water, the layers were separated, the aqueous layer was extracted 3 times with methylene chloride, 20 g each, the organic phases were combined, methylene chloride and tetrahydrofuran were recovered by distillation, and the residue was recrystallized from 110 g of methyl t-butyl ether to give 22.3 g of 2-methylethylmethylamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 2) in a yield of 81.7% and a liquid phase purity of 99.5%.
Example 8: preparation of 2-methylethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 2)
To a 250 ml autoclave, 120 g of methylene chloride, 19.0 g (0.1 mol) of 2-methylethylmethyleneamino-6-acetylpyridine (V2) obtained in example 4, 0.3 g of DBU, 9.0 g (0.2 mol) of ethylene oxide were charged, the autoclave was closed, the reaction was stirred at 35 to 40 ℃ for 3 hours, cooled to 20 to 25 ℃, the resultant reaction liquid was transferred to a 500 ml four-neck flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 23.0 g of triethylamine was charged, a solution of 40.0 g (0.21 mol) of p-toluenesulfonyl chloride and 80 g of methylene chloride was added dropwise at 10 to 15 ℃ over about 2 hours, and thereafter, the reaction was stirred at 20 to 25 ℃ for 5 hours. 11.0 g (0.11 mol) of 30% methylamine methanol solution was added, the reaction was stirred at 20 to 25 ℃ for 4 hours, the resulting reaction liquid was poured into 200 g of ice water, the layers were separated, the aqueous layer was extracted 3 times with dichloromethane, 20 g each, the organic phases were combined, dichloromethane was recovered by distillation, and the residue was recrystallized from 110 g of methyl tert-butyl ether to give 23.2 g of 2-methylethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 2) with a yield of 85.0% and a liquid phase purity of 99.3%.
Example 9: preparation of Lasmidin (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser, 200 g of methylene chloride, 25.9 g (0.1 mol) of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1) (obtained by the method of example 5), 3.0 g of water, 0.5 g of 30% hydrochloric acid, and stirring at 20 to 25 ℃ for 3 hours, followed by layer separation, drying the organic phase with 5.0 g of anhydrous sodium sulfate for 4 hours, filtering, transferring the obtained filtrate to a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, adding 15.0 g of triethylamine, 21.2 g (0.11 mol) of 2,4, 6-trifluorobenzoyl chloride, and stirring at 20 to 25 ℃ for 4 hours, pouring the obtained reaction liquid into 200 g of ice water, followed by layer separation, extracting the aqueous layer with methylene chloride for 3 times, 20 g each time, and combining the organic phases, the methylene chloride was recovered by distillation and the residue was recrystallized from 200 g of methyl-tert-butyl ether to give 34.9 g of lasiditan (i) in 92.3% yield and 99.8% purity in the liquid phase.
1HNMR(400MHz，DMSO-D6)：
1.52 (multiplet, 2H), 2.01 (multiplet, 2H),2.12 (triplet, 2H),2.28 (singlet, 3H),2.78 (multiplet, 1H), 3.55 (multiplet, 1H), 4.25 (doublet, 1H),6.17 (doublet, 1H),6.74 (multiplet, 2H), 7.44 (triplet, 1H),7.52 (multiplet, 1H),7.93 (singlet, 1H).
Example 10: preparation of Lasmidin (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser, 200 g of chloroform, 27.3 g (0.1 mol) of 2-methylethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 2) (obtained by the method of example 7), 3.0 g of water, 0.5 g of 30% hydrochloric acid, stirring and reacting at 30 to 35 ℃ for 2 hours, layering, drying the organic phase with 5.0 g of anhydrous sodium sulfate for 4 hours, filtering, transferring the obtained filtrate to a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, adding 15.0 g of triethylamine, 21.2 g (0.11 mol) of 2,4, 6-trifluorobenzoyl chloride, stirring and reacting at 30 to 35 ℃ for 3 hours, pouring the obtained reaction liquid into 200 g of ice water, layering, extracting the aqueous layer with chloroform for 3 times, 20 g each time, combining the organic phases, recovering chloroform by distillation, the residue was recrystallized from 200 g of methyl-tert-butyl ether to give 34.7 g of lasiditan (i) in 91.9% yield and 99.7% purity in the liquid phase.
Comparative example 1: preparation of 2-dimethylmethyleneamino-6-acetylpyridine (V1)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 160 g of methanol, 40.0 g (0.4 mol) of a 17% ammonia methanol solution, 17.4 g (0.1 mol) of 2-chloro-5, 6-dioxo-n-heptanonitrile (III 1) prepared in example 1 were charged, and the reaction was stirred at 55 to 60 ℃ for 5 hours. Cooling to 20 to 25 ℃, adding the obtained reaction liquid to 200 g of dichloromethane and 200 g of ice water, separating layers, extracting the water layer with dichloromethane 3 times, each time 20 g, combining the organic phases, drying with 10.0 g of anhydrous sodium sulfate for 4 hours, filtering, transferring the obtained filtrate to a 500 ml four-neck flask equipped with a stirring, thermometer and reflux condenser, adding 20.0 g (0.19 mol) of 2, 2-dimethoxypropane, stirring and reacting at 38 to 40 ℃ for 6 hours, recovering dichloromethane and excess 2, 2-dimethoxypropane by distillation, recrystallizing the residue with 120.0 g of n-hexane, filtering off insoluble substances to obtain 7.3 g of 2-dimethylmethyleneamino-6-acetylpyridine (V1), the yield is 41.5%, and the gas phase purity is 98.7%.
Comparative example 2: preparation of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1)
Into a 250 ml autoclave were charged 150 g of tetrahydrofuran, 17.6 g (0.1 mol) of 2-dimethylmethyleneamino-6-acetylpyridine (V1) obtained in example 3, 0.3 g of DBU, 9.0 g (0.2 mol) of ethylene oxide, the autoclave was closed, and the reaction was stirred at 30 to 35 ℃ for 3 hours, cooled to 20 to 25 ℃ and the resulting reaction liquid was transferred to a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, and 23.0 g of triethylamine, 24.0 g (0.21 mol) of methanesulfonyl chloride were charged and stirred at 15 to 20 ℃ for 5 hours. Adding 17.0 g (0.17 mol) of 30% methylamine methanol solution, stirring and reacting for 4 hours at 20-25 ℃, pouring the obtained reaction liquid into 200 g of ice water, layering, extracting a water layer with dichloromethane for 3 times, 20 g each time, combining organic phases, distilling and recovering dichloromethane, heating and refluxing the residue with 100 g of methyl tert-butyl ether for 1 hour, filtering to remove insoluble substances while hot, cooling the filtrate and recrystallizing to obtain 11.9 g of 2-dimethylmethyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine (VIII 1), wherein the yield is 45.9%, and the liquid phase purity is 99.1%.
Claims (12)
1. A process for the preparation of a compound of formula i comprising the steps of:
(1) under the action of a solvent A and an alkali catalyst, a compound shown in a formula II and 2-halogenated acrylonitrile are subjected to 1, 4-addition reaction to prepare a compound shown in a formula III; the 2-halogenated acrylonitrile is selected from 2-chloro acrylonitrile or 2-bromo acrylonitrile;
wherein, in the structural formula of the compound shown in the formula III, X is Cl or Br;
(2) in a solvent B, a compound of formula III and ammonia are subjected to pyridine cyclization reaction to obtain a compound of formula IV, and then the compound of formula XI is subjected to condensation reaction to protect amino, so as to obtain a compound of formula V: 2-disubstituted methyleneamino-6-acetylpyridine;
in the above structural formula, R1、R2、R3、R4Each independently is methyl, ethyl, isopropyl or tert-butyl; the same applies below;
(3) under the action of a solvent C and an alkali catalyst, carrying out hydroxyethylation reaction on a compound shown in the formula V and ethylene oxide to obtain a compound VI, directly carrying out sulfoesterification reaction with sulfonyl chloride-alkali A to prepare a compound shown in the formula VII without separation, and then carrying out condensation reaction with methylamine to prepare a compound shown in the formula VIII: 2-disubstituted methyleneamino-6- (1-methylpiperidin-4-yl) formylpyridine;
r is methyl, phenyl, p-methylphenyl;
(4) under the action of a solvent D and an acid catalyst, a compound of a formula VIII undergoes deprotection reaction to obtain a compound of a formula IX, and then undergoes amidation reaction with 2,4, 6-trifluorobenzoyl chloride under the action of a base B to obtain a compound of a formula I:
2. the process for preparing a compound of formula i according to claim 1, wherein in step (1), the solvent a is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane and isopropyl ether; the mass ratio of the solvent A to the compound of the formula II is (3-15): 1.
3. The process for preparing a compound of formula i according to claim 1, wherein in step (1) the base catalyst is one or a combination of two or more of potassium hydroxide, lithium hydroxide, piperidine, 4-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN); the dosage of the catalyst is 0.5-5 wt% of the mass of the compound shown in the formula II.
4. The process for preparing a compound of formula I according to claim 1, wherein in step (1), the molar ratio of the 2-haloacrylonitrile to the compound of formula II is (0.9-1.2): 1.
5. The process for the preparation of a compound of formula i as claimed in claim 1, wherein the temperature of the 1, 4-addition reaction in step (1) is 20 to 100 ℃.
6. The process for the preparation of a compound of formula i as claimed in claim 1, wherein the temperature of the 1, 4-addition reaction in step (1) is 50 to 70 ℃.
7. A process for the preparation of a compound of formula i as claimed in claim 1, wherein the reaction in step (2) comprises any one or more of the following conditions:
i. the solvent B is one or the combination of more than two of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane or acetonitrile;
the mass ratio of the solvent B to the compound of the formula III is (3-20): 1;
the ammonia is derived from ammonia gas, ammonia water, ammonia methanol solution or ammonia ethanol solution;
the molar ratio of ammonia to the compound of formula iii is (3.0-5.0): 1;
the molar ratio of the compound of formula XI to the compound of formula III is (1.0-2.0): 1;
the pyridine cyclization reaction temperature is 30-100 ℃;
the condensation reaction temperature is 10-100 ℃.
8. The process for the preparation of a compound of formula i as claimed in claim 1, wherein the pyridine cyclization reaction temperature in step (2) is 50-70 ℃; the condensation reaction temperature is 30-70 ℃.
9. A process for the preparation of a compound of formula i as claimed in claim 1, wherein the reaction in step (3) comprises any one or more of the following conditions:
a. the solvent C is one or the combination of more than two of dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane or chlorobenzene;
b. the mass ratio of the solvent C to the compound of the formula V is (5-30) to 1;
c. the alkali catalyst is one or the combination of more than two of potassium hydroxide, lithium hydroxide, piperidine, 4-methylpiperidine, 1, 8-diazabicycloundecen-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN);
d. the dosage of the catalyst is 0.5-5 wt% of the mass of the compound of the formula V;
e. the sulfonyl chloride is methylsulfonyl chloride, benzene sulfonyl chloride or p-methylbenzene sulfonyl chloride;
f. the alkali A is inorganic alkali or organic alkali, wherein the inorganic alkali is selected from one or a combination of potassium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate and calcium acetate, and the organic alkali is selected from one or a combination of triethylamine and tri-n-butylamine;
g. the methylamine is an alcoholic solution of methylamine or a methylamine tetrahydrofuran solution;
h. the molar ratio of the ethylene oxide to the sulfonyl chloride to the alkali A to the methylamine to the compound of the formula V is (2.0-2.5) to (1.0-1.5) to 1;
i. the temperature of the hydroxyethylation reaction is 10-80 ℃;
j. the temperature of the sulfoacid esterification reaction is 0-50 ℃;
k. the condensation reaction temperature is 0-60 ℃.
10. The process for the preparation of a compound of formula i as claimed in claim 1, wherein the hydroxyethylation temperature in step (3) is from 25 to 45 ℃; the temperature of the sulfoacid esterification reaction is 10-30 ℃; the condensation reaction temperature is 20-40 ℃.
11. A process for the preparation of a compound of formula i as claimed in claim 1, wherein the reaction in step (4) comprises any one or more of the following conditions:
i. the solvent D is one or the combination of more than two of dichloromethane, trichloromethane, 1, 2-dichloroethane, chlorobenzene or water;
the mass ratio of the solvent D to the compound of the formula VIII is (5-20): 1;
the acid catalyst is one or the combination of more than two of hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid with certain concentration; the dosage of the acid catalyst is 0.5-5% wt. of the mass of the compound of the formula VIII;
the base B is an inorganic base or an organic base, wherein the inorganic base is selected from one or a combination of potassium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate and calcium acetate, and the organic base is selected from one or a combination of triethylamine and tri-n-butylamine;
v. the molar ratio of the 2,4, 6-trifluorobenzoyl chloride, the base B and the compound of formula VIII is (1.0-1.5): 1;
the deprotection reaction temperature is 10-50 ℃;
the temperature of the amidation reaction is 0-80 ℃.
12. The process for preparing a compound of formula i according to claim 1, wherein the deprotection reaction temperature in step (4) is 20 to 40 ℃; the temperature of the amidation reaction is 20-40 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642939A (en) * | 2002-03-29 | 2005-07-20 | 伊莱利利公司 | Pyridinoylpiperidines as 5-HTLF agonists |
| WO2011123654A1 (en) * | 2010-04-02 | 2011-10-06 | Colucid Pharmaceuticals, Inc. | Compositions and methods of synthesis of pyridinoylpiperidine 5-ht1f agonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642939A (en) * | 2002-03-29 | 2005-07-20 | 伊莱利利公司 | Pyridinoylpiperidines as 5-HTLF agonists |
| WO2011123654A1 (en) * | 2010-04-02 | 2011-10-06 | Colucid Pharmaceuticals, Inc. | Compositions and methods of synthesis of pyridinoylpiperidine 5-ht1f agonists |
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| Title |
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| 选择性5-羟色胺1F受体激动剂lasmiditan;金玉洁等;《现代药物与临床》;20160831;第31卷(第8期);1300-1303 * |
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Denomination of invention: A Preparation Method of 5-HT1F Agonist Compound Effective date of registration: 20221213 Granted publication date: 20200609 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |
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