CN105153105B - The synthetic method and its intermediate of 1 (base of 2,2 difluoro benzo [d] [1,3] dioxole 5) cyclopropane-carboxylic acid - Google Patents
The synthetic method and its intermediate of 1 (base of 2,2 difluoro benzo [d] [1,3] dioxole 5) cyclopropane-carboxylic acid Download PDFInfo
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- CN105153105B CN105153105B CN201510502205.4A CN201510502205A CN105153105B CN 105153105 B CN105153105 B CN 105153105B CN 201510502205 A CN201510502205 A CN 201510502205A CN 105153105 B CN105153105 B CN 105153105B
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 title claims abstract description 8
- DGCOGZQDAXUUBY-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole Chemical compound C1=CC=C2OC(F)(F)OC2=C1 DGCOGZQDAXUUBY-UHFFFAOYSA-N 0.000 title claims abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- AZSZCFSOHXEJQE-UHFFFAOYSA-N dibromodifluoromethane Chemical compound FC(F)(Br)Br AZSZCFSOHXEJQE-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 claims description 10
- 150000007530 organic bases Chemical class 0.000 claims description 9
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- 230000032050 esterification Effects 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- 229920006324 polyoxymethylene Polymers 0.000 claims description 6
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims 5
- 229940126214 compound 3 Drugs 0.000 claims 3
- 229940125782 compound 2 Drugs 0.000 claims 2
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical group [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 claims 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims 1
- 150000003457 sulfones Chemical class 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 8
- 239000011734 sodium Substances 0.000 abstract description 8
- 229910052708 sodium Inorganic materials 0.000 abstract description 8
- 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 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 229910052763 palladium Inorganic materials 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 239000002585 base Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229940113088 dimethylacetamide Drugs 0.000 description 9
- 0 *OC(C1(CC1)c(cc1O)ccc1O)=O Chemical compound *OC(C1(CC1)c(cc1O)ccc1O)=O 0.000 description 8
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 7
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 7
- 201000003883 Cystic fibrosis Diseases 0.000 description 7
- -1 alkali metal hydrogen carbonate Salt Chemical class 0.000 description 7
- 230000006837 decompression Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 5
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- UFSKUSARDNFIRC-UHFFFAOYSA-N lumacaftor Chemical compound N1=C(C=2C=C(C=CC=2)C(O)=O)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 UFSKUSARDNFIRC-UHFFFAOYSA-N 0.000 description 3
- 229960000998 lumacaftor Drugs 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- VIESAWGOYVNHLV-UHFFFAOYSA-N 1,3-dihydropyrrol-2-one Chemical group O=C1CC=CN1 VIESAWGOYVNHLV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 description 1
- NNUGNRVZQZBPCF-UHFFFAOYSA-N CCc1ccc2OC(F)(F)Sc2c1 Chemical compound CCc1ccc2OC(F)(F)Sc2c1 NNUGNRVZQZBPCF-UHFFFAOYSA-N 0.000 description 1
- 101150029409 CFTR gene Proteins 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 102000034573 Channels Human genes 0.000 description 1
- 101710128223 Chloride channel protein Proteins 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- RGKFSYDEMAFDQP-UHFFFAOYSA-N N#CC1(CC1)c(cc1O2)ccc1OC2(F)F Chemical compound N#CC1(CC1)c(cc1O2)ccc1OC2(F)F RGKFSYDEMAFDQP-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 description 1
- 229960004508 ivacaftor Drugs 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of synthetic method and its intermediate of 1 (base of 2,2 difluoro benzo [d] [1,3] dioxole 5) cyclopropane-carboxylic acid.It is an object of the present invention to provide a kind of synthetic method of compound (1), methods described includes：A. compound (4) and Boron tribromide reaction synthesis compound (3)B. compound (3) carries out ring closure reaction with difluorodibromomethane and synthesizes compound (2) in the presence of a phase transfer catalystC. compound (2) hydrolysis compound (1)
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of 1- (2,2- difluoro benzo [d] [1,3] dioxas
Cyclopentene -5- bases) cyclopropane-carboxylic acid synthetic method and its intermediate.
Background technology
Cystic fibrosis (CF) is a kind of genetic disease of serious threat life, and the disease adjusts egg by CF transmembrane conductors
It is caused the defects of (CFTR) in vain.Normal CFTR is a kind of chloride channel protein being present on cell membrane, and chlorion can
Cell is freed in and out by this channel protein, cell can also secrete one layer of thin mucus to protect airway epithelia.And 90%
The cftr gene of CF patient occurs that F508del is mutated (missing of 508 phenylalanines in CFTR), and this mutation occurs,
CFTR cannot be folded normally, and it is easily degraded after composition, cause the CFTR quantity on cell to be greatly decreased so that chlorine
Ion can not equally free in and out.Cystic fibrosis is very common in America and Europe, and almost a case just occurs in 25 people.In U.S.
It is due to caused by two kinds of copy F508del gene mutations that, which just there are 22,000 patients of more than 12 years old in state,.
Lu Makat (Lumacaftor) is that the medicine for treating cystic fibrosis diseases is researched and developed by Vertex drugmakers
Thing, Vertex have submitted to US and European a completely by Lu Makat (Lumacaftor) and Yi Wakate respectively
(Ivacaftor) application for quotation of the compound medicine of composition, and FDA approvals are obtained in July, 2015, this compound medicine is first
Using medicine of the basic cause of disease of gene mutation patient's cystic fibrosis as target spot for carrying two kinds of copy F508del.
1- (2,2- difluoros benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid is synthesis lumacaftor
One intermediate, shown in its structural formula such as compound (1)：
Disclosed in patent CN101356170 on 1- (2,2- difluoros benzo [d] [1,3] dioxole -5- bases)
The synthetic method of cyclopropane-carboxylic acid, specific synthetic route are as follows：
Following defect be present in the route：1. reaction raw materials are expensive, it is unfavorable for control cost；2. palladium chtalyst is used in course of reaction
Agent, easily there is palladium residual in product；3. the cyaniding sodium reagent used in reaction is relatively hazardous, it is unsuitable for industrialized production；4. reaction
Overall yield is very low.
The content of the invention
In order to solve the above problems, the invention provides a kind of cost is low, high income, easy to operate 1- (2,2- difluoros
Benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid synthetic method and its intermediate.
It is an object of the present invention to provide a kind of synthetic method of compound (1), methods described includes：
A. compound (4) and Boron tribromide reaction synthesis compound (3)
B. compound (3) carries out ring closure reaction with difluorodibromomethane and synthesizes compound in the presence of a phase transfer catalyst
(2)
C. compound (2) hydrolysis compound (1)
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2Or R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl；
The reaction temperature of the step a is -20-15 DEG C, preferably -10-10 DEG C；
The reaction of the step a is carried out in the conventional organic solvent such as halogenated hydrocarbon solvent, alcohols solvent, ether solvent,
It is preferred that carried out in dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, more preferably in dichloromethane or tetrahydrofuran
Middle progress.
The phase transfer catalyst of the step b be selected from benzyltriethylammoinium chloride (TEBA), TBAB (TBAB),
The conventional phase transfer catalyst such as tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, preferably TBAB (TBAB)；
Compound and the mol ratio of difluorodibromomethane are 1 in the step b:3-1:10, preferably 1:4-1:5, more preferably
1:5；
The step b is reacted in weak base presence, the weak base preferred alkali metal carbonate or alkali metal hydrogen carbonate
Salt, more preferably potassium carbonate, sodium carbonate, saleratus or sodium acid carbonate；
The reaction temperature of the step b is 80-120 DEG C, preferably 90-100 DEG C；
The step b is carried out in high boiling organic solvent, and the high boiling organic solvent refers to that boiling point is higher than 100 DEG C
Organic solvent, it is selected from N- pyrrolidones (NMP), DMF (DMF), DMA
(DMAC), the conventional high boiling organic solvent such as dimethyl sulfoxide (DMSO) (DMSO) or toluene, preferably in N- pyrrolidones, N, N- dimethyl
Carry out in formamide or dimethyl sulfoxide (DMSO) (DMSO), more preferably carried out in dimethyl sulfoxide (DMSO) (DMSO).
The step c is carried out in strong base solution, the highly basic preferred alkali metal hydroxide, more preferably sodium hydroxide or
Potassium hydroxide.
Further, the synthetic method of above-claimed cpd (1) also includes the synthesis of compound (4), comprises the following steps that：
D. compound (7) synthesizes compound (6) through esterification
E. compound (6) synthesizes compound (5) with polyformaldehyde reaction
F. compound (5) synthesizes compound (4) with Trimethylsulfoxonium Iodide in organic base presence
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2Or R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl；
The esterification of the step d is preferably carried out in carbonyl dimidazoles presence；
The reaction of the step d is carried out in the conventional organic solvent such as halogenated hydrocarbon solvent, alcohols solvent, ether solvent,
It is preferred that carried out in dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, more preferably in dichloromethane, tetrahydrofuran
Carry out.
Compound (6) and the mol ratio of paraformaldehyde are 1 in the step e:5-1:15, preferably 1:8-1:10, more preferably
1:10。
The step e is carried out in weak base presence, the weak base preferred alkali metal carbonate or alkali metal hydrogencarbonate, more
It is preferred that sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；
The step e is carried out in the conventional organic solvent such as ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, preferably
Carry out in tetrahydrofuran, dichloromethane, toluene, carried out more preferably in tetrahydrofuran；
Compound (5) and the mol ratio of Trimethylsulfoxonium Iodide are 1 in the step f:1.5-1:3.0, preferably 1:2.0.
Organic base in the step f is selected from the conventional organic bases, preferably methanol such as sodium alkoxide, potassium alcoholate or amido lithium compound
Sodium, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine (LDA), hexamethyldisilazane lithium (LiHMDS) or six
The silicon amido potassium (KHMDS) of methyl two, more preferably potassium tert-butoxide.
The reaction dissolvent of the step f can be selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide
(DMAC), the conventional organic solvent such as dimethyl sulfoxide (DMSO) (DMSO), toluene, preferably DMF (DMF) or N, N- bis-
Methylacetamide (DMAC), more preferably DMF (DMF).
It is a further object of the present invention to provide compound, its structure shown in a kind of formula (4) to be：
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2、R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl.
It is yet another object of the invention to provide a kind of synthetic method of compound (4), specifically comprise the following steps：
D. compound (7) synthesizes compound (6) through esterification
E. compound (6) synthesizes compound (5) with polyformaldehyde reaction
F. compound (5) synthesizes compound (4) with Trimethylsulfoxonium Iodide in organic base presence
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2Or R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl；
The esterification of the step d is preferably carried out in carbonyl dimidazoles presence；
The reaction of the step d is carried out in the conventional organic solvent such as halogenated hydrocarbon solvent, alcohols solvent, ether solvent,
It is preferred that carried out in dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, more preferably in dichloromethane, tetrahydrofuran
Carry out.
Compound (6) and the mol ratio of paraformaldehyde are 1 in the step e:5-1:15, preferably 1:8-1:10, more preferably
1:10。
The step e is carried out in weak base presence, the weak base preferred alkali metal carbonate or alkali metal hydrogencarbonate, more
It is preferred that sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；
The step e is carried out in the conventional organic solvent such as ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, preferably
Carry out in tetrahydrofuran, dichloromethane, toluene, carried out more preferably in tetrahydrofuran；
Compound (5) and the mol ratio of Trimethylsulfoxonium Iodide are 1 in the step f:1.5-1:3.0, preferably 1:2.0.
Organic base in the step f is selected from the conventional organic bases, preferably methanol such as sodium alkoxide, potassium alcoholate or amido lithium compound
Sodium, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine (LDA), hexamethyldisilazane lithium (LiHMDS) or six
The silicon amido potassium (KHMDS) of methyl two, more preferably potassium tert-butoxide.
The reaction dissolvent of the step f can be selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide
(DMAC), the conventional organic solvent such as dimethyl sulfoxide (DMSO) (DMSO), toluene, preferably DMF (DMF) or N, N- bis-
Methylacetamide (DMAC), more preferably DMF (DMF).
The present invention obtains a kind of method of new prepare compound (1) by providing a kind of new compound (4), this
Method can not only improve the overall yield of reaction, while can avoid, using expensive reaction raw materials, largely reducing
The cost of reaction.On the other hand, this method is also avoided that using palladium catalyst and dangerous cyaniding sodium reagent, it is ensured that medicine
The security of production, it is adapted to industrialized production.
Embodiment
The present invention is expanded on further with reference to specific embodiment, it should be appreciated that following examples are merely to illustrate the present invention
Rather than limit the scope of the invention.
Method therefor is conventional method unless otherwise instructed in the following example.Material required in following examples
Material or reagent, are that market is bought unless otherwise specified.
Embodiment 1：Compound 6a synthesis
Compound 7a (50g, 0.255mol) is added into 1L there-necked flask, 250ml dichloromethane, is stirred at room temperature, in batches
Secondary addition carbonyl dimidazoles (62g, 0.382mol), react at room temperature 1h, add 50ml methanol, stir 1h, and reaction solution is poured into point
In liquid funnel, the extraction of 200ml water is added, collected organic layer, anhydrous sodium sulfate drying, is filtered, filtrate decompression is spin-dried for, and obtains 50gization
Compound 6a, yield 93.3%.
Embodiment 2：Compound 5a synthesis
Into 250mL there-necked flasks, compound 6a (10g, 0.048mol) is added, 80ml tetrahydrofurans, sequentially adds poly
Formaldehyde (15g, 0.48mol), potassium carbonate (20g, 0.144mol), 40 DEG C of reaction 2h.After reaction completely, reaction solution is poured into liquid separation
In funnel, 100ml water, the extraction of 150ml tetrahydrofurans, collected organic layer, anhydrous sodium sulfate drying, filtering, filtrate are separately added into
Decompression is spin-dried for, and obtains 9.6g compound 5a, yield 90.0%.
Embodiment 3：Compound 4a synthesis
Under the protection of nitrogen, Trimethylsulfoxonium Iodide (44.0g, 0.2mol) is added into 250ml round-bottomed flasks,
100ml DMF, potassium tert-butoxide (22.3g, 0.2mol) is added, 45min is stirred at room temperature.By compound 5a (22.2g, 0.1mol)
It is dissolved in 70ml DMF, slowly adds in above-mentioned solution, reaction system is warming up to 35 DEG C.45 DEG C are heated to, reacts 1h, is made anti-
Answer system to be cooled to 0-5 DEG C, 80ml 2N hydrochloric acid solutions are added dropwise, add 250ml ethyl acetate aqueous layer extracteds, anhydrous sodium sulfate is done
Dry, filtering, filtrate decompression is spin-dried for, and obtains 20.8g compound 4a, yield 88.1%.1H NMR (400MHz, DMSO) 6.90 (d, J=
1.7Hz, H), 6.87-6.82 (m, 2H), 3.74 (s, 3H), 3.74 (s, 3H), 3.54 (s, 3H), 1.45 (q, J=3.8Hz,
2H), 1.17 (q, J=4.0Hz, 2H)
Embodiment 4：Compound 4a synthesis
Into 250ml there-necked flasks, compound 6a (21.0g, 0.1mol) is added, 80ml tetrahydrofurans, sequentially adds poly
Formaldehyde (31.3g, 1mol), potassium carbonate (41.7g, 0.3mol), 40 DEG C of reaction 2h.After reaction completely, reaction solution is poured into constant pressure
In dropping funel.Under the protection of nitrogen, Trimethylsulfoxonium Iodide is added into 250ml round-bottomed flasks
(44.0g, 0.2mol), 100ml DMF, potassium tert-butoxide (22.3g, 0.2mol) is added, 45min is stirred at room temperature,
Solution in constant pressure funnel is slowly added in round-bottomed flask, reaction system is warming up to 35 DEG C.45 DEG C are heated to, reaction
1h, reaction system is cooled to 0-5 DEG C, 80ml 2N hydrochloric acid solutions are added dropwise, add 250ml ethyl acetate aqueous layer extracteds, anhydrous sulphur
Sour sodium is dried, and filtering, filtrate decompression is spin-dried for, and 20.4g, yield 86.4% are obtained after being spin-dried for.
Embodiment 5：Compound 3a synthesis
Under the protection of nitrogen, compound 4a (9g, 0.038mol), 50ml dichloromethanes are added into 250ml round-bottomed flasks
Alkane, -20 DEG C are cooled to, Boron tribromide (21g, 0.084mol) is slowly added dropwise, it is -10 DEG C to maintain temperature, reacts 1h, slowly
Add 10ml methanol, system acutely heats up, maintains temperature below 15 DEG C, recover to reduced pressure at room temperature to be spin-dried for, add 40ml methanol after
It is continuous to be spin-dried for, the HBr and trimethylborate in system are taken away, 7.3g compound 3a, yield 92.4% are obtained after being spin-dried for.
Embodiment 6：Compound 2a synthesis
In 100ml autoclave pressure, addition compound 3a (4.2g, 0.02mol), difluorodibromomethane (9.1ml,
0.1mol), potassium carbonate (3.3g, 0.024mol), TBAB (0.3g, 0.04mol), DMSO (30ml), 100 DEG C of reactions are heated to.
After reaction completely, system is down to room temperature, and reaction solution is added in 100ml trash ices and stirred, separates organic layer, anhydrous sodium sulfate is done
Dry, filtering, filtrate decompression is spin-dried for, and obtains 4.7g compound 2a, yield 91.8%.
Embodiment 7：The synthesis of compound 1
Compound 2a (3.3g, 0.013mol) is added in 100ml there-necked flasks, 20ml 5%NaOH solution, is heated to 85
DEG C, react 2h.After reaction completely, pH=7 is adjusted, adds the extraction of 30ml ethyl acetate, anhydrous sodium sulfate drying, filtering, filtrate
Decompression is spin-dried for, and obtains 3.0g compounds 1, yield 95.2%.
Embodiment 8：Compound 6b synthesis
Compound 7b (64.3g, 0.255mol) is added into 1L there-necked flask, 250ml dichloromethane, is stirred at room temperature, point
Batch adds carbonyl dimidazoles (62g, 0.382mol), reacts at room temperature 1h, adds 50ml methanol, stirs 1h, reaction solution is poured into
In separatory funnel, the extraction of 200ml water, collected organic layer are added, anhydrous sodium sulfate drying filters, and filtrate decompression is spin-dried for, obtained
60.4g compound 6b, yield 89.0%.
Embodiment 9：Compound 5a synthesis
According to the embodiment of embodiment 2, study when the molar ratio difference that compound 6a and paraformaldehyde feed intake pair
The influence of reaction, and monitor response situation in real time, compound 6a inventory are 0.048mol, reaction result such as following table institute
Show：
| Compound 6a：Paraformaldehyde | Yield | Yield |
| 1:2 | 6.0g | 56% |
| 1:5 | 7.5g | 70% |
| 1:8 | 9.0g | 84% |
| 1:10 | 9.6g | 90% |
| 1:13 | 9.5g | 89% |
| 1:15 | 9.3g | 87% |
| 1:17 | 6.5g | 61% |
Embodiment 10：Compound 4a synthesis
According to the embodiment of embodiment 3, the molar ratio that research is fed intake with Trimethylsulfoxonium Iodide as compound 5a is not
Influence to reaction simultaneously, and monitor response situation in real time, compound 5a inventory are 0.1mol, reaction result such as following table
It is shown：
| Compound 5a：Trimethylsulfoxonium Iodide | Yield | Yield |
| 1:1.2 | 9.0g | 38.1% |
| 1:1.5 | 17.7g | 75.0% |
| 1:2.0 | 20.8g | 88.1% |
| 1:2.5 | 20.7g | 87.7% |
| 1:3.0 | 20.8g | 88.1% |
Embodiment 11：Compound 2a synthesis
According to the embodiment of embodiment 6, molar ratio that research compound 3a feeds intake with difluorodibromomethane and anti-
The change of temperature is answered to the influence of reaction yield.Individually change mol ratio and the reaction of compound 3a and difluorodibromomethane
Temperature, remaining reaction condition monitors response situation with embodiment 6 in real time, as a result as shown in the table：
Claims (8)
- The synthetic method of 1.1- (2,2- difluoro benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid, its feature exist In comprising the following steps：A. compound 4 and Boron tribromide reaction synthesis compound 3B. compound 3 carries out ring closure reaction with difluorodibromomethane and synthesizes compound 2 in the presence of a phase transfer catalystC. the hydrolysis compound 1 of compound 2Wherein, R1、R2Or R3It is alkyl；The reaction temperature of the step a is -10-10 DEG C；Compound 3 and two in the step b The mol ratio of difluorodibromomethane is 1:4-1:5；The reaction temperature of the step b is 80-120 DEG C.
- 2. according to the method for claim 1, it is characterised in that the phase transfer catalyst of the step b is tetrabutyl phosphonium bromide Ammonium.
- 3. according to the method for claim 1, it is characterised in that the compound 4 is synthesized by following step：D. compound 7 synthesizes compound 6 through esterificationE. compound 6 synthesizes compound 5 with polyformaldehyde reactionF. compound 5 synthesizes compound 4 with Trimethylsulfoxonium Iodide in organic base presenceWherein, R1、R2Or R3It is alkyl.
- 4. compound shown in formula 4 described in claim 1Wherein, R1、R2Or R3It is alkyl.
- 5. the synthetic method of compound 4 described in claim 1, it is characterised in that methods described comprises the following steps：D. compound 7 synthesizes compound 6 through esterificationE. compound 6 synthesizes compound 5 with polyformaldehyde reactionF. compound 5 synthesizes compound 4 with Trimethylsulfoxonium Iodide in organic base presenceWherein, R1、R2Or R3It is alkyl.
- 6. the method according to claim 3 or 5, it is characterised in that compound 6 and paraformaldehyde rubs in the step e Your ratio is 1:5-1:15.
- 7. the method according to claim 3 or 5, it is characterised in that compound 5 and trimethyl iodate are sub- in the step f The mol ratio of sulfone is 1:1.5-1:3.0.
- 8. the method according to claim 3 or 5 is characterized in that, the organic base in the step f is potassium tert-butoxide.
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