CN105566237B - A kind of preparation method for the triazole mercapto phenylacetic acid compound for treating gout - Google Patents
A kind of preparation method for the triazole mercapto phenylacetic acid compound for treating gout Download PDFInfo
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- CN105566237B CN105566237B CN201610115891.4A CN201610115891A CN105566237B CN 105566237 B CN105566237 B CN 105566237B CN 201610115891 A CN201610115891 A CN 201610115891A CN 105566237 B CN105566237 B CN 105566237B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 201000005569 Gout Diseases 0.000 title abstract description 9
- -1 triazole mercapto phenylacetic acid compound Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 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 15
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical class C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims abstract description 9
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 7
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000002585 base Substances 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012429 reaction media Substances 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 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 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 6
- 235000011009 potassium phosphates Nutrition 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 5
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 4
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical class NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims description 3
- 230000031709 bromination Effects 0.000 claims description 3
- HAMNKKUPIHEESI-UHFFFAOYSA-O carbamohydrazonoylazanium Chemical class NC(N)=N[NH3+] HAMNKKUPIHEESI-UHFFFAOYSA-O 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000010719 annulation reaction Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 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 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 36
- 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 12
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 abstract description 11
- VZZBXOLWBXJHEK-UHFFFAOYSA-N 1-cyclopropylnaphthalene Chemical compound C1CC1C1=CC=CC2=CC=CC=C12 VZZBXOLWBXJHEK-UHFFFAOYSA-N 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 6
- 238000010189 synthetic method Methods 0.000 abstract description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006073 displacement reaction Methods 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract description 3
- 239000011737 fluorine Substances 0.000 abstract description 3
- 230000000269 nucleophilic effect Effects 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 abstract description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 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
- 239000000543 intermediate Substances 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- DLKQHBOKULLWDQ-UHFFFAOYSA-N 1-bromonaphthalene Chemical class C1=CC=C2C(Br)=CC=CC2=C1 DLKQHBOKULLWDQ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 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
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 2
- 229940123769 Xanthine oxidase inhibitor Drugs 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
- 238000009776 industrial production 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 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
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- VSPVHXKKSSJWML-UHFFFAOYSA-N C(C)[N+](CC1=CC=CC=C1)(CC)CC.[Br+] Chemical compound C(C)[N+](CC1=CC=CC=C1)(CC)CC.[Br+] VSPVHXKKSSJWML-UHFFFAOYSA-N 0.000 description 1
- OVYPPWNJXUSRPH-UHFFFAOYSA-N COC(CSc([n]1-c2ccc(C3CC3)c3c2cccc3)nnc1Br)=O Chemical compound COC(CSc([n]1-c2ccc(C3CC3)c3c2cccc3)nnc1Br)=O OVYPPWNJXUSRPH-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NYKSBMRQNSCVMO-UHFFFAOYSA-N Nc1ccc(C2CC2)c2c1cccc2 Chemical compound Nc1ccc(C2CC2)c2c1cccc2 NYKSBMRQNSCVMO-UHFFFAOYSA-N 0.000 description 1
- NZJPHCMCVBJVQG-UHFFFAOYSA-N OC(CSc([n]1-c2ccc(C3=CC3)c3c2cccc3)nnc1Br)O Chemical compound OC(CSc([n]1-c2ccc(C3=CC3)c3c2cccc3)nnc1Br)O NZJPHCMCVBJVQG-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- CCPTWMNSFHCZPB-UHFFFAOYSA-N S=C=Nc1ccc(C2CC2)c2c1cccc2 Chemical compound S=C=Nc1ccc(C2CC2)c2c1cccc2 CCPTWMNSFHCZPB-UHFFFAOYSA-N 0.000 description 1
- 102100021495 Solute carrier family 22 member 12 Human genes 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
- 239000002253 acid Substances 0.000 description 1
- 238000007068 beta-elimination reaction Methods 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 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
- 125000004122 cyclic group Chemical group 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
- COLJYBDTTGVCKH-UHFFFAOYSA-L dichloronickel;diphenylphosphane;propane Chemical compound CCC.Cl[Ni]Cl.C=1C=CC=CC=1PC1=CC=CC=C1 COLJYBDTTGVCKH-UHFFFAOYSA-L 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 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
- 229910001947 lithium oxide Inorganic materials 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
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 125000001424 substituent group Chemical group 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
- 125000003944 tolyl group Chemical group 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002023 wood Substances 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 kind of preparation methods for the triazole mercapto phenylacetic acid compound for treating gout.This method is using compound II and compound III as initial feed, through suzuki reaction generation midbody compound IV；Then nucleophilic displacement of fluorine generation key intermediate compound V occurs with 1,1 ' thio-carbonyldiimidazoles；Compound V cyclization generation midbody compounds VI, nucleophilic substitution generation midbody compound VII occurs with methyl chloroacetate again, midbody compound VII is through bromination reaction generation midbody compound VIII, again through hydrolysis generation target product 2 ((5 bromine 4 (4 cyclopropyl naphthalene, 1 base) 4H 1,2,4 triazole, 3 base) sulfenyl) acetic acid (I).Preparation method reaction selectivity of the present invention is high, easy to operate, avoids the reaction condition using toxic reagent and harshness, shortens the reaction time compared to original synthetic method, reduce energy consumption, improve reaction yield.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of system for the triazole mercapto phenylacetic acid compound for treating gout
Preparation Method.
Background technology
Lesinuard (Zurampic, RDEA594), entitled 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H- of chemistry
1,2,4- triazole -3- bases) sulfenyl) acetic acid is a kind of selective uric acid reuptake inhibithors that Astrazeneca AB develops, mainly
Gout is treated by inhibiting the excretion of renal tubule lithate transport protein 1 (URAT1) increase uric acid.Lesinuard is in 2015
It obtains food and drug administration (FDA) on December 22, in ratify, be used in combination with xanthine oxidase inhibitor (XO),
Treatment and the relevant hyperuricemia of gout, new selection is provided for the drug therapy of ten hundreds of patient with gout.
The synthetic method on Lesinuard is broadly divided into following several at present：
First, using 1- bromonaphthalenes as the synthetic route of starting material：
Patent WO2009070740 discloses the synthetic route prepared using 1- bromonaphthalenes as starting material：
The route is longer, total recovery 9.5%, and the reaction of first step cyclopropylization needs to carry out under the conditions of anhydrous and oxygen-free,
Condition is harsh；Double (diphenylphosphine) propane nickel chloride (NiCl of catalyst 1,3-2And the price of cyclopropyl magnesium bromide ratio (bdppp))
Costly.The thiophosgene used in experimentation, low boiling point, high volatility, foul smelling, toxicity are stronger, therefore industrial production needs
To implement in totally enclosed device, to reach environmental impact assessment requirement, high cost can be increased to the post processing of toxic product.
2nd, using 4- cyclopropyl -1- naphthalene isothiocyanate as the synthetic route of starting material or midbody compound：
Patent WO 2012092395 is disclosed using 4- cyclopropyl -1- naphthalene isothiocyanate as starting material or intermediate
Close the synthetic route of object：
Using 4- cyclopropyl -1- naphthalene isothiocyanate as raw material, in pyridine solvent, with hydrazine, dimethyl carbonate addition cyclization
4- (4- cyclopropyl -1- naphthalenes) -5- sulfydryls -4H-1 is obtained, 2,4- triazole -3- hydroxyls obtain 2- (4- (4- rings with chloracetyl hydrocarbonylation
Propyl -1- naphthalenes) -5- hydroxyls -4H-1,2,4- triazole -3- sulfydryls) acetic acid, successively through being esterified (protection), bromo, hydrolysis (remove-insurance
Shield) Lesinurad sodium salts are obtained by the reaction.The route is longer, and part material price is very expensive, and reaction condition is also very harsh.
3rd, it is the synthetic route of starting material or midbody compound with midbody compound 6：
The compound is first public in international monopoly WO2006026356, is for starting material system with midbody compound 6
Standby, wherein synthetic route is：
It is key intermediate compound with 6, under the alkaline condition of potassium carbonate, with the chloro- N- of 2- (the chloro- 4- sulfonamide phenyls of 2-)
Acetamide occurs alkylation reaction and obtains compound 10, and yield is up to 95%.Then in sodium nitrite, benzyl bromide triethylamine
(BnEt3NBr under conditions of), midbody compound 12, yield 31% are obtained through diazotising and bromo-reaction.Again through sodium hydroxide
Hydrolysis, hydrochloric acid are acidified to obtain Lesinuard.The substituent group 11 that the route uses need to be prepared voluntarily.The route and other route phases
Than having no clear superiority.
Similarly, patent WO2009070740 discloses the synthetic route for midbody compound with midbody compound 6：
It is key intermediate compound with 6, in n,N-Dimethylformamide (DMF) solvent, occurs with ethyl bromide
Alkylation reaction obtains midbody compound 13, yield 87%.Equally in sodium nitrite, benzyl bromide triethylamine (BnEt3NBr item)
Under part, midbody compound 14, yield 47.6% are obtained through diazotising and bromo-reaction.Then in 1molL-1Lithium hydroxide
It neutralizes through beta-elimination reaction and hydrochloric acid to obtain midbody compound 15, yield 78% in tetrahydrofuran/methanol mixed solution.Document
Though the synthetic method by 15 synthesis Lesinuard is not reported in, is easy to be made through alkylation reaction.Route complexity,
Tediously long, yield is relatively low.
In the method for above-mentioned synthesis Lesinuard, using 1- bromonaphthalenes as the synthetic route of raw material, there is toxicity is big, catalyst
The problem of expensive and reflection condition is harsh；Synthetic route using 4- cyclopropyl -1- naphthalene isothiocyanate as starting material exists
The problem of reaction yield is low and starting material is not easy to obtain；And it is the conjunction of raw material or midbody compound with midbody compound 6
Into method, there is the problem of reaction yield is low and the reaction time is long.Therefore need to find it is a kind of more efficiently, there is industrialization
The method of productive value synthesizes Lesinuard and its midbody compound.
The content of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of triazole mercapto phenylacetic acid compound 2- ((5- for treating gout
Bromo- 4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid high efficiency preparation method.This method operates
Easy, total recovery height has industrial production value.
Term explanation：
A kind of triazole mercapto phenylacetic acid compound for treating gout of the present invention, entitled 2- ((5- bromo- 4- (4- rings third
Base naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid, English Lesinuard, with the structure shown in Formulas I：
Technical scheme is as follows：
A kind of preparation method of compound of formula I is as follows including step：
Using following compound represented II and compound III as initial feed, bell occurs under the action of alkali and catalyst
Wood reaction generation midbody compound IV；
Above-mentioned midbody compound IV and 1,1 '-thio-carbonyldiimidazole is made to occur in the key of nucleophilic displacement of fluorine production V
Intermediate compounds therefor V；
The midbody compound VI of the key intermediate compound V cyclic production VI in alkaline conditions；
Make midbody compound VI that nucleophilic substitution generation midbody compound VII occur with methyl chloroacetate；
Midbody compound VII is by bromination generation midbody compound VIII；
Finally, midbody compound VIII generates target product compound of formula I through hydrolysis：2- ((5- bromo- 4- (4- cyclopropyl
Naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid (I),
It is preferred according to the present invention, it is described the step of preparing midbody compound IV in, the alkali is potassium phosphate, institute
The catalyst stated is tetrakis triphenylphosphine palladium.
It is preferred according to the present invention, it is described the step of preparing midbody compound VI in, the alkaline condition is N,
N- diisopropylethylamine.
It is of the invention more detailed, a kind of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases)
Sulfenyl) acetic acid high efficiency preparation method, step is as follows：
(1) by starting material compound II and compound III dissolvings in a solvent, in alkali potassium phosphate and catalyst four
Suzuki reaction generation midbody compound IV occurs under the action of (triphenylphosphine) palladium；Wherein, compound II：Compound III：Phosphorus
Sour potassium：The molar ratio of tetrakis triphenylphosphine palladium is 1.0:1.1-1.8:3.3-4.2:0.1-0.2, the reaction dissolvent are
N,N-dimethylformamide, dimethyl sulfoxide (DMSO) or toluene：The volume ratio of water is 1-50:1 toluene aqueous solution, reaction temperature are
90-110℃；
(2) intermediate compound occurs in non-protonic solvent for midbody compound IV and 1,1 '-thio-carbonyldiimidazole
The nucleophilic substitution generation midbody compound V of object IV；Wherein, compound IV：The molar ratio of 1,1 '-thio-carbonyldiimidazole
For 1.0:0.9-1.5, reaction dissolvent are dichloromethane, chloroform or dichloroethanes, and reaction temperature is 20-30 DEG C；
(3) midbody compound V is added to aminoguanidinium salts hydrochlorate in non-protonic solvent, during generation annulation obtains
Intermediate compounds therefor VI；Compound V：Aminoguanidinium salts hydrochlorate：The molar ratio of N, N- diisopropylethylamine is 1:1.5-2.5:2.5-
3.5, wherein, reaction dissolvent be N-Methyl pyrrolidone, n,N-Dimethylformamide or dimethyl sulfoxide (DMSO), reaction temperature 40-
60℃；
(4) midbody compound VI is dissolved into methyl chloroacetate in non-protonic solvent, under the action of alkali potassium carbonate
The nucleophilic substitution generation midbody compound VII of midbody compound VI occurs；Wherein compound VI：Methyl chloroacetate：
The molar ratio of potassium carbonate is 1:1.0-1.1:1.0-1.5, reaction dissolvent for N-Methyl pyrrolidone, n,N-Dimethylformamide or
Dimethyl sulfoxide (DMSO), reaction temperature are 20-30 DEG C；
(5) midbody compound VII and sodium nitrite, dichloroacetic acid, benzyl triethyl ammonium amine bromide are added to reaction to be situated between
The bromination that midbody compound is carried out in matter obtains midbody compound VIII；Wherein compound VII and sodium nitrite, two chloroethenes
Acid, the molar ratio of benzyl triethyl ammonium amine bromide are 1:15-25:1.0-3.0:2.0-5.0 reaction medium is non-protonic solvent,
Reaction temperature is 20-30 DEG C；
(6) midbody compound VIII is dissolved in reaction medium, adds in lithium hydroxide aqueous solution and carry out intermediate compound
The hydrolysis of object obtains final product Lesinuard (I)；Wherein the molar ratio of compound VIII and lithium hydroxide is 1:1.0-3.0
Reaction medium is property solvent miscible with water, and reaction temperature is 0-10 DEG C.
, according to the invention it is preferred to,
Compound II described in step (1)：Compound III：Potassium phosphate：The molar ratio of tetrakis triphenylphosphine palladium is 1.0:
1.3:3.5:0.1；Reaction dissolvent is toluene：The volume ratio of water is 25:1 toluene aqueous solution；Reaction temperature is 100 DEG C.
In step (2), compound IV：The molar ratio of 1,1 '-thio-carbonyldiimidazole is 1.0:1.5；Reaction dissolvent is two
Chloromethanes；Reaction temperature is 25 DEG C.
In step (3), compound V：Aminoguanidinium salts hydrochlorate：The molar ratio of N, N- diisopropylethylamine is 1.0:2.0:3.0；
Reaction dissolvent is N,N-dimethylformamide；Temperature is 50 DEG C.
In step (4), compound VI：Methyl chloroacetate：The molar ratio of potassium carbonate is 1.0:1.0:1.0-1.5；React molten
Agent is N,N-dimethylformamide；Reaction temperature is 25 DEG C.
In step (5), compound VII and the molar ratio of sodium nitrite, dichloroacetic acid, benzyl triethyl ammonium amine bromide are 1.0:
20.0:2.0-5.0, reaction medium are bromofom, and temperature is 25 DEG C.
In step (6), the molar ratio of compound VIII and lithium hydroxide is 1:1.5, reaction medium is tetrahydrofuran, reaction
Temperature is 0 DEG C.
Using compound II and compound III as initial feed Suzuki occurs under the action of alkali and catalyst for the present invention anti-
Midbody compound IV should be generated；Then nucleophilic displacement of fluorine generation occurs for midbody compound IV and 1,1 '-thio-carbonyldiimidazole
Key intermediate compound V；Key intermediate compound V cyclization generation midbody compound VI under the action of alkali；Intermediate
Nucleophilic substitution generation midbody compound VII occurs again with methyl chloroacetate for compound VI, and midbody compound VII is through bromine
Change reaction generation midbody compound VIII, midbody compound VIII through hydrolysis generation target product 2- ((the bromo- 4- of 5-
(4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid (I).
Synthetic route of the present invention is as follows：
The present invention provides a kind of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyls)
The high efficiency preparation method of acetic acid, this method reaction selectivity is high, easy to operate, and greatly contracts compared to original synthetic method
In the short reaction time, energy consumption is reduced, improves reaction yield, total recovery reaches 38.8%.
The present invention will be further described for case study on implementation With reference to embodiment.Room temperature described in embodiment
It is 25 DEG C ± 5 DEG C.
Specific embodiment
Embodiment 1：
(1) synthesis of compound 4- cyclopropyl-naphthalidine (IV)
By the bromo- naphthalidine II (90mmol, 20.0g) of 4-, cyclopropylboronic acid III (116mmol, 10.0g), potassium phosphate
(300mmol, 64.0g) is added to the in the mixed solvent of 100mL toluene and 4mL water with tetra-triphenylphosphine palladium (6mmol, 7.0g),
12h is reacted in 100 DEG C under nitrogen protection, when reaction solution is cooled to room temperature, the aqueous solution of 100mL is added in into reaction solution,
It is extracted with ethyl acetate and adds in sodium sulphate drying afterwards three times.It is filtered after half an hour, 13.8g intermediate compounds is obtained through vacuum distillation
Object IV, yield 83.6%.1H NMR (400MHz, DMSO) δ 8.25 (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,NH2),2.17-2.10(m,1H,CH),0.94-0.90(m,2H,CH2),0.57-0.53(m,2H,CH2).ESI-MS:
m/z 184.2[M+H]+.C13H13N(Exact Mass:183.10).
(2) synthesis of compound 1-cyclopropyl base -4- α-naphthyl isothiocyanates (V)
Midbody compound IV (33mmol, 6.0g) prepared by upper step, 1,1 '-thio-carbonyldiimidazole (50mmol,
It 8.8g) is added in 100mL dichloromethane, then reacts 12h at room temperature.100mL is added in after solvent is evaporated after reaction
Water, ethyl acetate extraction add in sodium sulphate drying, are filtered after half an hour, 7.1g intermediates are obtained through rapid column chromatography afterwards three times
Close object V, yield 96.2%.1H NMR (400MHz, DMSO) δ 8.48 (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,CH2),0.77-0.73(m,2H,CH2)
.C14H11NS(Exact Mass:225.06).
(3) synthesis of compound 5- amino -4- (4- cyclopropyl -1- naphthalenes) -4H-1,2,4- triazole -3- sulfydryls (VI)：
By midbody compound V (13.3mmol, 3.0g), aminoguanidinium salts hydrochlorate (26.6mmol, 2.9g) is added to 50mL
N,N-Dimethylformamide in, be added with stirring n,N-diisopropylethylamine (39.9mmol, 5.1g), then 50 DEG C reaction
12h adds in the sodium hydroxide of 20mL 2M after solvent is evaporated, then 50 DEG C of the reaction was continued 12h.After stopping reaction, by reaction solution
Filtering, filtrate is neutralized to pH=4 with dilute hydrochloric acid, it is seen that a large amount of white precipitates are precipitated, filtering, then true at a temperature of 45-50 DEG C
Sky is dried to obtain 2.85g midbody compound VI, yield 76.0%.ESI-MS:m/z 283.4[M+H]+.C15H14N4S(Exact
Mass:282.09).
(4) compound 2- ((5- amino -4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid
The synthesis of methyl esters (VII)
Midbody compound VI (7.1mmol, 2.0g) and potassium carbonate (7.8mmol, 1.1g) are added to the N, N- of 40mL
In dimethylformamide, lower instillation methyl chloroacetate (7.4mmol, 0.8g) is stirred, is then reacted for 24 hours, after reaction for 50 DEG C
Reaction solution, which is poured into, Precipitation in ice water, filtering, then vacuum drying obtains 2.21g intermediates at a temperature of 45-50 DEG C
Compound VII, yield 88.0%.ESI-MS:m/z 355.5[M+H]+.C18H18N4O2S(Exact Mass:354.12).
(5) compound 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid first
The synthesis of ester (VIII)
By midbody compound VII (5.6mmol, 2.0g), sodium nitrite (112mmol, 7.7g) and benzyl triethyl ammonium bromine
Change amine (16.8mmol, 4.5g) nominal in round-bottomed flask, stir 30min at room temperature after adding in bromofom, two chloroethenes are then added dropwise
Sour (11.2mmol, 1.4g) stirs 3h.Reaction solution is evaporated addition water after reaction and ethyl acetate extracts 3 times, adds in sulphur
Sour sodium drying, filters after half an hour, 1.89g midbody compound VIII, yield 80.1% is obtained through quick column.ESI-MS:m/z
418.5[M+H]+.C18H16BrN3O2S(Exact Mass:417.01).
(6) compound 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfenyl) acetic acid
The synthesis of (Lesinuard, I)
Midbody compound VIII (2.7mmol, 1.14g) is dissolved in 10mL tetrahydrofurans, hydrogen is added dropwise under ice bath stirring
Continue to stir 45min after lithia aqueous solution.The hydrochloric acid tune pH=7 of 2M is added in, 20mL is added in after boiling off 4/5ths solvent
Water, continue to adjust pH=2~3, solid filtered out, then by the solid of precipitation filtering washing and at a temperature of 55-60 DEG C it is true
Empty dry Lesinuard crude products, then recrystallize, filtration drying obtains sterling Lesinuard 0.99g, yield 90.0%.
ESI-MS:m/z 406.4[M+H]+.C17H14BrN3O2S(Exact Mass: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 (1)
1. a kind of preparation method of compound of formula I, including step：
(1) by starting material compound II and compound III dissolvings in a solvent, in four (triphen of alkali potassium phosphate and catalyst
Base phosphine) suzuki reaction generation midbody compound IV occurs under the action of palladium；Wherein, compound II：Compound III：Potassium phosphate：
The molar ratio of tetrakis triphenylphosphine palladium is 1.0:1.3:3.5:0.1, the reaction dissolvent for n,N-Dimethylformamide,
Dimethyl sulfoxide (DMSO) or toluene：The volume ratio of water is 25:1 toluene aqueous solution, reaction temperature are 100 DEG C；
(2) midbody compound IV occurs in non-protonic solvent for midbody compound IV and 1,1 '-thio-carbonyldiimidazole
Nucleophilic substitution generation midbody compound V；Wherein, compound IV：The molar ratio of 1,1 '-thio-carbonyldiimidazole is
1.0:1.5, reaction dissolvent is dichloromethane, chloroform or dichloroethanes, and reaction temperature is 25 DEG C；
(3) midbody compound V is added to aminoguanidinium salts hydrochlorate in non-protonic solvent, and annulation occurs and obtains intermediate
Compound VI；Compound V：Aminoguanidinium salts hydrochlorate：The molar ratio of N, N- diisopropylethylamine is 1.0:2.0:3.0, wherein, reaction
Solvent be N-Methyl pyrrolidone, n,N-Dimethylformamide or dimethyl sulfoxide (DMSO), 50 DEG C of reaction temperature；
(4) midbody compound VI is dissolved into methyl chloroacetate in non-protonic solvent, is occurred under the action of alkali potassium carbonate
The nucleophilic substitution generation midbody compound VII of midbody compound VI；Wherein compound VI：Methyl chloroacetate：Carbonic acid
The molar ratio of potassium is 1.0:1.0:1.0-1.5, reaction dissolvent are N-Methyl pyrrolidone, n,N-Dimethylformamide or dimethyl
Sulfoxide, reaction temperature are 25 DEG C；
(5) midbody compound VII and sodium nitrite, dichloroacetic acid, benzyl triethyl ammonium amine bromide are added in reaction medium
The bromination for carrying out midbody compound obtains midbody compound VIII；Wherein compound VII and sodium nitrite, dichloroacetic acid,
The molar ratio of benzyl triethyl ammonium amine bromide is 1.0:20.0:1.0:2.0-5.0, reaction medium are non-protonic solvent, reaction temperature
It spends for 25 DEG C；
(6) midbody compound VIII is dissolved in reaction medium, adds in lithium hydroxide aqueous solution and carry out midbody compound
Hydrolysis obtains final product Lesinuard (I)；Wherein the molar ratio of compound VIII and lithium hydroxide is 1.0:1.5, reaction is situated between
Matter is property solvent miscible with water, and reaction temperature is 0 DEG C；
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| CA2785200C (en) * | 2010-01-08 | 2015-02-24 | Ardea Biosciences, Inc. | Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetate, and uses thereof |
| WO2012073314A1 (en) * | 2010-11-29 | 2012-06-07 | 日産化学工業株式会社 | Method for producing isothiocyanate compound |
| CA2898107A1 (en) * | 2013-03-06 | 2014-09-12 | F. Hoffmann-La Roche Ag | Antiviral compounds |
| CN105294585B (en) * | 2014-07-02 | 2019-02-12 | 成都海创药业有限公司 | A kind of compound for treating gout |
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