CN105566237A - Preparing method of triazole thioglycolic acid compound for curing metabolic arthritis - Google Patents
Preparing method of triazole thioglycolic acid compound for curing metabolic arthritis Download PDFInfo
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- CN105566237A CN105566237A CN201610115891.4A CN201610115891A CN105566237A CN 105566237 A CN105566237 A CN 105566237A CN 201610115891 A CN201610115891 A CN 201610115891A CN 105566237 A CN105566237 A CN 105566237A
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- -1 triazole thioglycolic acid compound Chemical class 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title abstract description 9
- CWERGRDVMFNCDR-UHFFFAOYSA-N alpha-mercaptoacetic acid Natural products OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 title abstract 2
- 206010003246 arthritis Diseases 0.000 title abstract 2
- 230000002503 metabolic effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 33
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 12
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims abstract description 12
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 6
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 22
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 13
- 239000012429 reaction media Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 9
- 229940093916 potassium phosphate Drugs 0.000 claims description 9
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 9
- 235000011009 potassium phosphates Nutrition 0.000 claims description 9
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 claims description 7
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 238000010719 annulation reaction Methods 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 abstract description 10
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 230000007096 poisonous effect Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 201000005569 Gout Diseases 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000011084 recovery Methods 0.000 description 4
- DLKQHBOKULLWDQ-UHFFFAOYSA-N 1-bromonaphthalene Chemical compound C1=CC=C2C(Br)=CC=CC2=C1 DLKQHBOKULLWDQ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 COC(CNC(*1c2ccc(C3CC3)c3c2cccc3)=*C=C1C=*)=O Chemical compound COC(CNC(*1c2ccc(C3CC3)c3c2cccc3)=*C=C1C=*)=O 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- MWZAJEMJQMTNKM-UHFFFAOYSA-N bromomethylbenzene;n,n-diethylethanamine Chemical compound CCN(CC)CC.BrCC1=CC=CC=C1 MWZAJEMJQMTNKM-UHFFFAOYSA-N 0.000 description 2
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- CIDVAVJNVGWYFE-QMMMGPOBSA-N CNc(c(C=C1)c2C=C[C@@H]1I)ccc2Br Chemical compound CNc(c(C=C1)c2C=C[C@@H]1I)ccc2Br CIDVAVJNVGWYFE-QMMMGPOBSA-N 0.000 description 1
- YYEFDSAWHFJGKC-UHFFFAOYSA-N COC(CSc([n]1-c2ccc(C3CC3)c3c2C=CCC3)nnc1Br)=O Chemical compound COC(CSc([n]1-c2ccc(C3CC3)c3c2C=CCC3)nnc1Br)=O YYEFDSAWHFJGKC-UHFFFAOYSA-N 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- UGBIUTRWCZSFRY-UHFFFAOYSA-N OC(CSc([n]1-c2ccc(C3CC3)c3c2cccc3)nnc1Br)O Chemical compound OC(CSc([n]1-c2ccc(C3CC3)c3c2cccc3)nnc1Br)O UGBIUTRWCZSFRY-UHFFFAOYSA-N 0.000 description 1
- HIVIOIZQKKMYTJ-UHFFFAOYSA-M [SH-]=C=Nc1ccc(C2CC2)c2c1cccc2 Chemical compound [SH-]=C=Nc1ccc(C2CC2)c2c1cccc2 HIVIOIZQKKMYTJ-UHFFFAOYSA-M 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960003838 lesinurad Drugs 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- FVYMVLTWIBGEMC-UHFFFAOYSA-M sodium;2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetate Chemical class [Na+].[O-]C(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FVYMVLTWIBGEMC-UHFFFAOYSA-M 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940032415 zurampic Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparing method of a triazole thioglycolic acid compound for curing metabolic arthritis. According to the method, compound II and compound III are utilized as initial materials and are generated into intermediate compound IV through Suzuki reaction; then nucleophilic substitution happens between the intermediate compound IV and 1,1minute-thiocarbonyl polypyridobisinudazole to generate intermediate compound V; the compound V generates intermediate compound VI through cyclization reaction, and then nucleophilic substitution happens between the compound VI and methyl chloroacetate to generate intermediate compound VII; the intermediate compound VII generates intermediate compound VIII through bromination reaction; and a target product 2-((5-bromine-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazole-3-yl)sulfenyl) acetic acid (I) is generated through hydrolysis reaction. The preparing method is high in selectivity and simple to operate and avoids poisonous reagents and rigorous reacting conditions. Compared with an original synthetic method, the reacting time of the preparing method is shortened, the energy consumption is reduced, and the reaction yield is improved.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method treating the triazole mercapto phenylacetic acid compound of gout.
Background technology
Lesinuard (Zurampic, RDEA594), chemistry 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1 by name, 2,4-triazole-3-base) sulfenyl) acetic acid, being a kind of selectivity uric acid reuptake inhibithors of Astrazeneca AB's exploitation, increasing the excretion of uric acid to treat gout mainly through suppressing uriniferous tubules urate translocator 1 (URAT1).Lesinuard obtains food and drug administration (FDA) approval on December 22nd, 2015, with xanthine oxidase inhibitor (XO) conbined usage, treat the hyperuricemia relevant to gout, the pharmacological agent for ten hundreds of patient with gout provides new selection.
Synthetic method at present about Lesinuard is mainly divided into following several:
One, with the synthetic route that 1-bromonaphthalene is starting raw material:
Patent WO2009070740 discloses the synthetic route prepared for starting raw material with 1-bromonaphthalene:
This route is longer, total recovery 9.5%, and the first step cyclopropyl reaction needed is carried out under anhydrous and oxygen-free condition, and condition is harsh; Two (diphenylphosphine) propane nickelous chloride (NiCl of catalyzer 1,3-
2(bdppp)) and the price comparison of cyclopropyl magnesium bromide expensive.The thiophosgene used in experimentation, boiling point is low, high volatility, foul smelling, toxicity are comparatively strong, and therefore industrial production needs to implement in totally enclosed device, for reaching environmental impact assessment requirement, can increase high cost to the aftertreatment of toxic product.
Two, with the synthetic route that 4-cyclopropyl-1-ANIT is starting raw material or midbody compound:
The synthetic route that it is starting raw material or midbody compound that patent WO2012092395 discloses with 4-cyclopropyl-1-ANIT:
With 4-cyclopropyl-1-ANIT for raw material; in pyridine solvent; 4-(4-cyclopropyl-1-naphthalene)-5-sulfydryl-4H-1 is obtained with hydrazine, methylcarbonate addition cyclization; 2; 4-triazole-3-hydroxyl, obtains 2-(4-(4-cyclopropyl-1-naphthalene)-5-hydroxyl-4H-1,2 with chloracetyl hydrocarbonylation; 4-triazole-3-sulfydryl) acetic acid, be obtained by reacting Lesinurad sodium salt through esterification (protection), bromo, hydrolysis (deprotection) successively.This route is longer, and part material price is very expensive, and reaction conditions is also very harsh.
Three, take midbody compound 6 as the synthetic route of starting raw material or midbody compound:
This compound is first public in international monopoly WO2006026356, and with midbody compound 6 for prepared by starting raw material, wherein synthetic route is:
With 6 for key intermediate compound, under the alkaline condition of salt of wormwood, obtain compound 10 with the chloro-N-of 2-(the chloro-4-sulfonamide phenyl of 2-) ethanamide generation alkylation reaction, yield reaches 95%.Then at Sodium Nitrite, bromotoluene triethylamine (BnEt
3nBr) under condition, midbody compound 12 is obtained through diazotization and bromo-reaction, yield 31%.Lesinuard is obtained again through sodium hydroxide hydrolysis, hcl acidifying.The substituting group 11 that this route uses need be prepared voluntarily.This route, compared with other routes, there is no clear superiority.
Similarly, the synthetic route that it is midbody compound that patent WO2009070740 discloses with midbody compound 6:
With 6 for key intermediate compound, in DMF (DMF) solvent, obtain midbody compound 13 with ethyl bromide generation alkylation reaction, yield 87%.Same at Sodium Nitrite, bromotoluene triethylamine (BnEt
3nBr) under condition, midbody compound 14 is obtained through diazotization and bromo-reaction, yield 47.6%.Then at 1molL
-1midbody compound 15 is obtained, yield 78% through β-eliminative reaction and hydrochloric acid neutralization in the tetrahydrofuran (THF)/methanol mixed solution of lithium hydroxide.Though do not report the synthetic method by 15 synthesis Lesinuard in document, but be easy to obtain through alkylation reaction.This route is complicated, tediously long, and productive rate is lower.
In the method for above-mentioned synthesis Lesinuard, the synthetic route being raw material with 1-bromonaphthalene also exists that toxicity is large, the problem of expensive catalyst and reflection condition harshness; The synthetic route being starting raw material with 4-cyclopropyl-1-ANIT also exists the low problem be not easy to obtain with starting raw material of reaction yield; And there is with the synthetic method that midbody compound 6 is raw material or midbody compound the problem that reaction yield is low and the reaction times is of a specified duration.Therefore need to find a kind of more efficient, there is the method for industrial production value to synthesize Lesinuard and midbody compound thereof.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of triazole mercapto phenylacetic acid compound 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1 treating gout, 2,4-triazole-3-base) sulfenyl) high efficiency preparation method of acetic acid.The method is easy and simple to handle, total recovery is high, have industrial production value.
Term illustrates:
A kind of triazole mercapto phenylacetic acid compound for the treatment of gout of the present invention, name is called 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) acetic acid, English Lesinuard, has the structure shown in formula I:
Technical scheme of the present invention is as follows:
A preparation method for formula I, comprises step as follows:
With the Compound II per shown in following and compound III for initial feed, under the effect of alkali and catalyzer, there is suzuki reaction generate midbody compound IV;
Make above-mentioned midbody compound IV and 1, the key intermediate compound V of 1 '-thio-carbonyldiimidazole generation nucleophilic substitution production V;
Described key intermediate compound V becomes the midbody compound VI of ring production VI in the basic conditions;
Midbody compound VI and methyl chloroacetate generation nucleophilic substitution reaction is made to generate midbody compound VII;
Midbody compound VII generates midbody compound VIII through bromination;
Finally, midbody compound VIII generates target product formula I through hydrolysis: 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) acetic acid (I),
Preferred according to the present invention, described prepares in the step of midbody compound IV, and described alkali is potassiumphosphate, and described catalyzer is tetrakis triphenylphosphine palladium.
Preferred according to the present invention, described prepares in the step of midbody compound VI, and described alkaline condition is DIPEA.
The present invention specifically, the high efficiency preparation method of a kind of 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) acetic acid, step is as follows:
(1) starting material compound II and compound III are dissolved in a solvent, under the effect of alkali potassiumphosphate and catalyzer tetrakis triphenylphosphine palladium, suzuki reaction occurs and generate midbody compound IV; Wherein, Compound II per: compound III: potassiumphosphate: the mol ratio of tetrakis triphenylphosphine palladium is 1.0:1.1-1.8:3.3-4.2:0.1-0.2, described reaction solvent is N, dinethylformamide, dimethyl sulfoxide (DMSO) or toluene: the volume ratio of water is the toluene aqueous solution of 1-50:1, and temperature of reaction is 90-110 DEG C;
(2) midbody compound IV and 1, the nucleophilic substitution reaction that midbody compound IV occurs 1 '-thio-carbonyldiimidazole in non-protonic solvent generates midbody compound V; Wherein, compound IV: 1, the mol ratio of 1 '-thio-carbonyldiimidazole is 1.0:0.9-1.5, and reaction solvent is methylene dichloride, trichloromethane or ethylene dichloride, and temperature of reaction is 20-30 DEG C;
(3) midbody compound V and aminoguanidine monohydrochloride join in non-protonic solvent, annulation occurs and obtains midbody compound VI; Compound V: aminoguanidine monohydrochloride: the mol ratio of DIPEA is 1:1.5-2.5:2.5-3.5, wherein, reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), temperature of reaction 40-60 DEG C;
(4) midbody compound VI and methyl chloroacetate are dissolved in non-protonic solvent, and the nucleophilic substitution reaction that midbody compound VI occurs under the effect of alkali salt of wormwood generates midbody compound VII; Wherein compound VI: methyl chloroacetate: the mol ratio of salt of wormwood is 1:1.0-1.1:1.0-1.5, and reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), and temperature of reaction is 20-30 DEG C;
(5) midbody compound VII and Sodium Nitrite, dichloro acetic acid, benzyl triethyl ammonium amine bromide are joined the bromination of carrying out midbody compound in reaction medium and obtain midbody compound VIII; Wherein the mol ratio of compound VI I and Sodium Nitrite, dichloro acetic acid, benzyl triethyl ammonium amine bromide is 1:15-25:1.0-3.0:2.0-5.0, and reaction medium is non-protonic solvent, and temperature of reaction is 20-30 DEG C;
(6) midbody compound VIII is dissolved in reaction medium, adds the hydrolysis that lithium hydroxide aqueous solution carries out midbody compound and obtain final product Lesinuard (I); Wherein the mol ratio of compound VI II and lithium hydroxide is 1:1.0-3.0, and reaction medium is and water mutual solubility solvent, and temperature of reaction is 0-10 DEG C.
According to the present invention, preferably,
Compound II per described in step (1): compound III: potassiumphosphate: the mol ratio of tetrakis triphenylphosphine palladium is 1.0:1.3:3.5:0.1; Reaction solvent is toluene: the volume ratio of water is the toluene aqueous solution of 25:1; Temperature of reaction is 100 DEG C.
In step (2), compound IV: 1, the mol ratio of 1 '-thio-carbonyldiimidazole is 1.0:1.5; Reaction solvent is methylene dichloride; Temperature of reaction is 25 DEG C.
In step (3), compound V: aminoguanidine monohydrochloride: the mol ratio of DIPEA is 1.0:2.0:3.0; Reaction solvent is DMF; Temperature is 50 DEG C.
In step (4), compound VI: methyl chloroacetate: the mol ratio of salt of wormwood is 1.0:1.0:1.0-1.5; Reaction solvent is DMF; Temperature of reaction is 25 DEG C.
In step (5), the mol ratio of compound VI I and Sodium Nitrite, dichloro acetic acid, benzyl triethyl ammonium amine bromide is 1.0:20.0:2.0-5.0, and reaction medium is bromofom, and temperature is 25 DEG C.
In step (6), the mol ratio of compound VI II and lithium hydroxide is 1:1.5, and reaction medium is tetrahydrofuran (THF), and temperature of reaction is 0 DEG C.
For initial feed, under the effect of alkali and catalyzer, suzuki reaction is there is generates midbody compound IV in the present invention with Compound II per and compound III; Then midbody compound IV and 1,1 '-thio-carbonyldiimidazole generation nucleophilic substitution generates key intermediate compound V; Key intermediate compound V becomes ring to generate midbody compound VI under the effect of alkali; Midbody compound VI generates midbody compound VII with methyl chloroacetate generation nucleophilic substitution reaction again, midbody compound VII generates midbody compound VIII through bromination reaction, midbody compound VIII generates target product 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1 through hydrolysis reaction, 2,4-triazole-3-base) sulfenyl) acetic acid (I).
Synthetic route of the present invention is as follows:
The invention provides a kind of 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) high efficiency preparation method of acetic acid, present method reaction preference is high, simple to operate, and shorten the reaction times widely compared to original synthetic method, reduce energy consumption, improve reaction yield, total recovery reaches 38.8%.
Below in conjunction with the case study on implementation of embodiment, the present invention will be further described.Room temperature described in embodiment is 25 DEG C ± 5 DEG C.
Embodiment
Embodiment 1:
(1) synthesis of compound 4-cyclopropyl-naphthalidine (IV)
By bromo-for 4-naphthalidine II (90mmol; 20.0g), cyclopropylboronic acid III (116mmol; 10.0g), potassiumphosphate (300mmol; 64.0g) with tetra-triphenylphosphine palladium (6mmol; 7.0g) join in the mixed solvent of 100mL toluene and 4mL water, under nitrogen protection in 100 DEG C of reaction 12h, during question response liquid cool to room temperature; in reaction solution, add the aqueous solution of 100mL, after being extracted with ethyl acetate three times, add dried over sodium sulfate.Filter after half an hour, obtain 13.8g midbody compound IV through underpressure distillation, yield 83.6%.
1HNMR(400MHz,DMSO)δ8.25(d,J＝7.9Hz,1H,Naph-H),8.07(d,J＝8.2Hz,1H,Naph-H),7.49(ddd,J＝8.2,6.8,1.1Hz,1H,Naph-H),7.39(ddd,J＝8.1,6.8,1.2Hz,1H,Naph-H),7.00(d,J＝7.6Hz,1H,Naph-H),6.59(d,J＝7.7Hz,1H,Naph-H),5.54(s,2H,NH
2),2.17-2.10(m,1H,CH),0.94-0.90(m,2H,CH
2),0.57-0.53(m,2H,CH
2).ESI-MS:m/z184.2[M+H]
+.C
13H
13N(ExactMass:183.10).
(2) synthesis of compound 1-cyclopropyl base-4-α-naphthyl isothiocyanate (V)
Midbody compound IV (33mmol, 6.0g) prepared by upper step, 1,1 '-thio-carbonyldiimidazole (50mmol, 8.8g) joins in 100mL methylene dichloride, then reacts 12h under room temperature.Add 100mL water by after solvent evaporate to dryness after reaction terminates, add dried over sodium sulfate after extraction into ethyl acetate three times, filter after half an hour, obtain 7.1g midbody compound V through rapid column chromatography, yield 96.2%.
1HNMR(400MHz,DMSO)δ8.48(d,J＝9.4Hz,1H,Naph-H),8.02(d,J＝9.4Hz,1H,Naph-H),7.76-7.71(m,2H,Naph-H),7.55(d,J＝7.7Hz,1H,Naph-H),7.24(d,J＝7.7Hz,1H,Naph-H),2.46-2.39(m,1H,CH),1.11-1.07(m,2H,CH
2),0.77-0.73(m,2H,CH
2).C
14H
11NS(ExactMass:225.06).
(3) synthesis of compound 5-amino-4-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfydryl (VI):
By midbody compound V (13.3mmol, 3.0g), aminoguanidine monohydrochloride (26.6mmol, 2.9g) joins in the DMF of 50mL, N is added under stirring, N-diisopropylethylamine (39.9mmol, 5.1g), then 50 DEG C of reaction 12h, to add the sodium hydroxide of 20mL2M after solvent evaporate to dryness, then 50 DEG C are continued reaction 12h.After stopped reaction, by reacting liquid filtering, filtrate is neutralized to pH=4 with dilute hydrochloric acid, and visible a large amount of white precipitate is separated out, and filters, and then at the temperature of 45-50 DEG C, vacuum-drying obtains 2.85g midbody compound VI, yield 76.0%.ESI-MS:m/z283.4[M+H]
+.C
15H
14N
4S(ExactMass:282.09).
(4) synthesis of compound 2-((5-amino-4-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) methyl acetate (VII)
By midbody compound VI (7.1mmol, 2.0g) with salt of wormwood (7.8mmol, 1.1g) join in the DMF of 40mL, under stirring, instill methyl chloroacetate (7.4mmol, 0.8g), then 50 DEG C of reaction 24h, pour into reaction solution in frozen water after reaction terminates and have Precipitation, filter, then at the temperature of 45-50 DEG C, vacuum-drying obtains 2.21g midbody compound VII, yield 88.0%.ESI-MS:m/z355.5[M+H]
+.C
18H
18N
4O
2S(ExactMass:354.12).
(5) synthesis of compound 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) methyl acetate (VIII)
By midbody compound VII (5.6mmol, 2.0g), Sodium Nitrite (112mmol, 7.7g) with benzyl triethyl ammonium amine bromide (16.8mmol, 4.5g) nominal is in round-bottomed flask, add stirred at ambient temperature 30min after bromofom, then drip dichloro acetic acid (11.2mmol, 1.4g), stir 3h.After reaction terminates reaction solution evaporate to dryness added water and extraction into ethyl acetate 3 times, add dried over sodium sulfate, filter after half an hour, obtain 1.89g midbody compound VIII through quick post, yield 80.1%.ESI-MS:m/z418.5[M+H]
+.C
18H
16BrN
3O
2S(ExactMass:417.01).
(6) synthesis of compound 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) acetic acid (Lesinuard, I)
Be dissolved in by midbody compound VIII (2.7mmol, 1.14g) in 10mL tetrahydrofuran (THF), ice bath continues to stir 45min after stirring lower dropping lithium hydroxide aqueous solution.The hydrochloric acid adding 2M adjusts pH=7, the water of 20mL is added after boiling off the solvent of 4/5ths, continue to adjust pH=2 ~ 3, solid is leached, then by the solid filtering of precipitation washing and at the temperature of 55-60 DEG C vacuum-drying obtain Lesinuard crude product, then recrystallization, filtration drying obtains sterling Lesinuard0.99g, yield 90.0%.ESI-MS:m/z406.4[M+H]
+.C
17H
14BrN
3O
2S(ExactMass:403.00).
The total recovery of this synthetic route is 83.6% × 96.2% × 76.0% × 88.0% × 80.1% × 90.0%=38.8%.
Claims (10)
1. a preparation method for formula I, comprises step as follows:
With the Compound II per shown in following and compound III for initial feed, under the effect of alkali and catalyzer, there is suzuki reaction generate midbody compound compound IV;
Make above-mentioned midbody compound compound IV and 1, the key intermediate compound compound V of 1 '-thio-carbonyldiimidazole generation nucleophilic substitution production V;
Described key intermediate compound compound V becomes the midbody compound compound VI of ring production VI in the basic conditions;
Midbody compound compound VI and methyl chloroacetate generation nucleophilic substitution reaction is made to generate midbody compound compound VI I;
Midbody compound compound VI I generates midbody compound compound VI II through bromination;
Finally, midbody compound compound VI II generates target product formula I through hydrolysis: 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulfenyl) acetic acid (I),
2. preparation method according to claim 1, is characterized in that, described prepares in the step of midbody compound IV, and described alkali is potassiumphosphate, and described catalyzer is tetrakis triphenylphosphine palladium.
3. preparation method according to claim 1, is characterized in that, described prepares in the step of midbody compound VI, and described alkaline condition is DIPEA.
4., according to the arbitrary described preparation method of claim 1-3, it is characterized in that, step is as follows:
(1) starting material compound II and compound III are dissolved in a solvent, under the effect of alkali potassiumphosphate and catalyzer tetrakis triphenylphosphine palladium, suzuki reaction occurs and generate midbody compound IV; Wherein, Compound II per: compound III: potassiumphosphate: the mol ratio of tetrakis triphenylphosphine palladium is 1.0:1.1-1.8:3.3-4.2:0.1-0.2, described reaction solvent is N, dinethylformamide, dimethyl sulfoxide (DMSO) or toluene: the volume ratio of water is the toluene aqueous solution of 1-50:1, and temperature of reaction is 90-110 DEG C;
(2) midbody compound IV and 1, the nucleophilic substitution reaction that midbody compound IV occurs 1 '-thio-carbonyldiimidazole in non-protonic solvent generates midbody compound V; Wherein, compound IV: 1, the mol ratio of 1 '-thio-carbonyldiimidazole is 1.0:0.9-1.5, and reaction solvent is methylene dichloride, trichloromethane or ethylene dichloride, and temperature of reaction is 20-30 DEG C;
(3) midbody compound V and aminoguanidine monohydrochloride join in non-protonic solvent, annulation occurs and obtains midbody compound VI; Compound V: aminoguanidine monohydrochloride: the mol ratio of DIPEA is 1:1.5-2.5:2.5-3.5, wherein, reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), temperature of reaction 40-60 DEG C;
(4) midbody compound VI and methyl chloroacetate are dissolved in non-protonic solvent, and the nucleophilic substitution reaction that midbody compound VI occurs under the effect of alkali salt of wormwood generates midbody compound VII; Wherein compound VI: methyl chloroacetate: the mol ratio of salt of wormwood is 1:1.0-1.1:1.0-1.5, and reaction solvent is N-Methyl pyrrolidone, DMF or dimethyl sulfoxide (DMSO), and temperature of reaction is 20-30 DEG C;
(5) midbody compound VII and Sodium Nitrite, dichloro acetic acid, benzyl triethyl ammonium amine bromide are joined the bromination of carrying out midbody compound in reaction medium and obtain midbody compound VIII; Wherein the mol ratio of compound VI I and Sodium Nitrite, dichloro acetic acid, benzyl triethyl ammonium amine bromide is 1:15-25:1.0-3.0:2.0-5.0, and reaction medium is non-protonic solvent, and temperature of reaction is 20-30 DEG C;
(6) midbody compound VIII is dissolved in reaction medium, adds the hydrolysis that lithium hydroxide aqueous solution carries out midbody compound and obtain final product Lesinuard (I); Wherein the mol ratio of compound VI II and lithium hydroxide is 1:1.0-3.0, and reaction medium is and water mutual solubility solvent, and temperature of reaction is 0-10 DEG C.
5. preparation method according to claim 4, is characterized in that, the Compound II per described in step (1): compound III: potassiumphosphate: the mol ratio of tetrakis triphenylphosphine palladium is 1.0:1.3:3.5:0.1; Reaction solvent is toluene: the volume ratio of water is the toluene aqueous solution of 25:1; Temperature of reaction is 100 DEG C.
6. preparation method according to claim 4, is characterized in that, in step (2), and compound IV: 1, the mol ratio of 1 '-thio-carbonyldiimidazole is 1.0:1.5; Reaction solvent is methylene dichloride; Temperature of reaction is 25 DEG C.
7. preparation method according to claim 4, is characterized in that, in step (3), and compound V: aminoguanidine monohydrochloride: the mol ratio of DIPEA is 1.0:2.0:3.0; Reaction solvent is DMF; Temperature is 50 DEG C.
8. preparation method according to claim 4, is characterized in that, in step (4), and compound VI: methyl chloroacetate: the mol ratio of salt of wormwood is 1.0:1.0:1.0-1.5; Reaction solvent is DMF; Temperature of reaction is 25 DEG C.
9. preparation method according to claim 4, is characterized in that, in step (5), the mol ratio of compound VI I and Sodium Nitrite, dichloro acetic acid, benzyl triethyl ammonium amine bromide is 1.0:20.0:2.0-5.0, and reaction medium is bromofom, and temperature is 25 DEG C.
10. preparation method according to claim 4, is characterized in that, in step (6), the mol ratio of compound VI II and lithium hydroxide is 1:1.5, and reaction medium is tetrahydrofuran (THF), and temperature of reaction is 0 DEG C.
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| CN106866560A (en) * | 2017-03-30 | 2017-06-20 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Lesinurad |
| CN106866560B (en) * | 2017-03-30 | 2023-05-30 | 浙江美诺华药物化学有限公司 | Lesinurad synthesis method |
| CN111763218A (en) * | 2020-07-14 | 2020-10-13 | 山东大学 | Thienopyrimidinone thioglycolic acid derivative and preparation method and application thereof |
| CN111763218B (en) * | 2020-07-14 | 2021-05-28 | 山东大学 | Thienopyrimidinone thioglycolic acid derivative and preparation method and application thereof |
| CN113336769A (en) * | 2021-04-30 | 2021-09-03 | 山东大学 | Thienopyrimidone acylsulfonamide derivative and preparation method and application thereof |
| CN113336769B (en) * | 2021-04-30 | 2022-06-24 | 山东大学 | Thienopyrimidine ketone acyl sulfonamide derivative as well as preparation method and application thereof |
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