CN105566237B - 一种治疗痛风的三唑巯乙酸类化合物的制备方法 - Google Patents
一种治疗痛风的三唑巯乙酸类化合物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 triazole mercapto phenylacetic acid compound Chemical class 0.000 title abstract description 9
- 201000005569 Gout Diseases 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 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 17
- 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
- 238000010534 nucleophilic substitution reaction Methods 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
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005893 bromination reaction Methods 0.000 claims abstract description 7
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 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 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 239000012429 reaction media Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 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
- 239000002585 base Substances 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 229910052763 palladium 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 2
- 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 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical class NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims 1
- 238000010719 annulation reaction Methods 0.000 claims 1
- HAMNKKUPIHEESI-UHFFFAOYSA-O carbamohydrazonoylazanium Chemical class NC(N)=N[NH3+] HAMNKKUPIHEESI-UHFFFAOYSA-O 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 9
- 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 description 6
- 238000000034 method Methods 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 3
- 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
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- VZZBXOLWBXJHEK-UHFFFAOYSA-N 1-cyclopropylnaphthalene Chemical compound C1CC1C1=CC=CC2=CC=CC=C12 VZZBXOLWBXJHEK-UHFFFAOYSA-N 0.000 abstract 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 abstract 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000006073 displacement reaction Methods 0.000 abstract 1
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 239000011737 fluorine Substances 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 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 8
- 239000002994 raw material Substances 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 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 4
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical group BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 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
- NYKSBMRQNSCVMO-UHFFFAOYSA-N 4-cyclopropylnaphthalen-1-amine Chemical compound C12=CC=CC=C2C(N)=CC=C1C1CC1 NYKSBMRQNSCVMO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- 238000005804 alkylation reaction Methods 0.000 description 3
- CWERGRDVMFNCDR-UHFFFAOYSA-N alpha-mercaptoacetic acid Natural products OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 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
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-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
- 229950005228 bromoform Drugs 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000007787 solid Substances 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
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- 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
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- 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
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- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
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- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
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- 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
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- 230000002194 synthesizing effect Effects 0.000 description 1
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Abstract
本发明公开了一种治疗痛风的三唑巯乙酸类化合物的制备方法。该方法以化合物II和化合物III为初始原料，经铃木反应生成中间体化合物IV；然后与1,1’‑硫代羰基二咪唑发生亲核取代生成关键中间体化合物V；化合物V成环生成中间体化合物VI，再与氯乙酸甲酯发生亲核取代反应生成中间体化合物VII，中间体化合物VII经溴化反应生成中间体化合物VIII，再经水解反应生成目标产物2‑((5‑溴‑4‑(4‑环丙基萘‑1‑基)‑4H‑1,2,4‑三唑‑3‑基)硫基)乙酸(I)。本发明制备方法反应选择性高，操作简单，避免了使用有毒试剂及苛刻的反应条件，相比于原来的合成方法缩短了反应时间，减小了能耗，提高了反应产率。
Description
技术领域
本发明属于药物化学领域，具体涉及到一种治疗痛风的三唑巯乙酸类化合物的制备方法。
背景技术
Lesinuard(Zurampic,RDEA594)，化学名为2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸，是阿斯利康公司开发的一种选择性尿酸再吸收抑制剂，主要通过抑制肾小管尿酸盐转运蛋白1(URAT1)增加尿酸的排泄来治疗痛风。Lesinuard于2015年12月22日获得美国食品和药物管理局(FDA)批准，与黄嘌呤氧化酶抑制剂(XO)联合使用，治疗与痛风相关的高尿酸血症，为数以万计的痛风患者的药物治疗提供了新的选择。
目前关于Lesinuard的合成方法主要分为以下几种：
一、以1-溴萘为起始原料的合成路线：
专利WO2009070740公开了以1-溴萘为起始原料制备的合成路线：
该路线较长，总收率9.5％，且第一步环丙基化反应需要在无水无氧条件下进行，条件苛刻；催化剂1,3-双(二苯基膦)丙烷氯化镍(NiCl2(bdppp))及环丙基溴化镁的价格比较昂贵。实验过程中使用的硫光气，沸点低、挥发性强、有恶臭、毒性较强，因此工业生产需要在全封闭的装置中实施，为达到环评要求，对毒性产物的后处理会增加高昂的成本。
二、以4-环丙基-1-萘异硫氰酸酯为起始原料或中间体化合物的合成路线：
专利WO 2012092395公开了以4-环丙基-1-萘异硫氰酸酯为起始原料或中间体化合物的合成路线：
以4-环丙基-1-萘异硫氰酸酯为原料，在吡啶溶剂中，与肼、碳酸二甲酯加成环合得到4-(4-环丙基-1-萘)-5-巯基-4H-1,2,4-三唑-3-羟基，与氯乙酰烃化得到2-(4-(4-环丙基-1-萘)-5-羟基-4H-1,2,4-三唑-3-巯基)乙酸，依次经酯化(保护)、溴代、水解(脱保护)反应得到Lesinurad钠盐。该路线较长，部分原料价格非常昂贵，反应条件也十分苛刻。
三、以中间体化合物6为起始原料或中间体化合物的合成路线：
该化合物首次公开于国际专利WO2006026356，是以中间体化合物6为起始原料制备的，其中合成路线为：
以6为关键中间体化合物，在碳酸钾的碱性条件下，与2-氯-N-(2-氯-4-磺酰胺苯)乙酰胺发生烃化反应得到化合物10，收率达95％。接着在亚硝酸钠、苄基溴三乙胺(BnEt3NBr)的条件下，经重氮化和溴代反应得到中间体化合物12，收率31％。再经氢氧化钠水解、盐酸酸化得到Lesinuard。该路线使用的取代基11需自行制备。该路线与其他路线相比，并无明显优势。
类似地，专利WO2009070740公开了以中间体化合物6为中间体化合物的合成路线：
以6为关键中间体化合物，在N,N-二甲基甲酰胺(DMF)溶剂中，与溴丙酸乙酯发生烃化反应得到中间体化合物13，收率87％。同样在亚硝酸钠、苄基溴三乙胺(BnEt3NBr)的条件下，经重氮化和溴代反应得到中间体化合物14，收率47.6％。然后在1mol·L-1氢氧化锂的四氢呋喃/甲醇混合溶液中经β-消除反应及盐酸中和得到中间体化合物15，收率78％。文献中虽未报道通过15合成Lesinuard的合成方法，但是很容易经烃化反应制得。该路线复杂、冗长，产率较低。
上述合成Lesinuard的方法中，以1-溴萘为原料的合成路线存在着毒性大、催化剂昂贵以及反映条件苛刻的问题；以4-环丙基-1-萘异硫氰酸酯为起始原料的合成路线存在着反应收率低和起始原料不易得的问题；而以中间体化合物6为原料或中间体化合物的合成方法存在着反应收率低和反应时间久的问题。因此需要寻找一种更加高效、具有工业化生产价值的方法来合成Lesinuard及其中间体化合物。
发明内容
针对现有技术的不足，本发明提供一种治疗痛风的三唑巯乙酸类化合物2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸的高效制备方法。该方法操作简便、总收率高、具有工业化生产价值。
术语说明：
本发明所述的一种治疗痛风的三唑巯乙酸类化合物，名称为2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸，英文Lesinuard，具有式I所示的结构：
本发明的技术方案如下：
一种式I化合物的制备方法，包括步骤如下：
以下列所示的化合物II和化合物III为初始原料，在碱和催化剂的作用下发生铃木反应生成中间体化合物IV；
使上述中间体化合物IV与1,1’-硫代羰基二咪唑发生亲核取代生成式V的关键中间体化合物V；
所述关键中间体化合物V在碱性条件下成环生成式VI的中间体化合物VI；
使中间体化合物VI与氯乙酸甲酯发生亲核取代反应生成中间体化合物VII；
中间体化合物VII经过溴化生成中间体化合物VIII；
最后，中间体化合物VIII经水解生成目标产物式I化合物：2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸(I)，
根据本发明优选的，所述的制备中间体化合物IV的步骤中，所述的碱是磷酸钾，所述的催化剂是四(三苯基膦)钯。
根据本发明优选的，所述的制备中间体化合物VI的步骤中，所述的碱性条件是N,N-二异丙基乙胺。
本发明更为详细的，一种2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸的高效制备方法，步骤如下：
(1)将起始原料化合物II和化合物III溶解在溶剂中，在碱磷酸钾以及催化剂四(三苯基膦)钯的作用下发生铃木反应生成中间体化合物IV；其中，化合物II：化合物III：磷酸钾：四(三苯基膦)钯四者的摩尔比为1.0:1.1-1.8:3.3-4.2:0.1-0.2，所述的反应溶剂为N,N-二甲基甲酰胺、二甲基亚砜或甲苯：水的体积比为1-50:1的甲苯水溶液，反应温度为90-110℃；
(2)中间体化合物IV和1,1’-硫代羰基二咪唑于非质子性溶剂中发生中间体化合物IV的亲核取代反应生成中间体化合物V；其中，化合物IV：1,1’-硫代羰基二咪唑的摩尔比为1.0:0.9-1.5，反应溶剂为二氯甲烷、三氯甲烷或者二氯乙烷，反应温度为20-30℃；
(3)中间体化合物V与氨基胍盐酸盐加入到非质子性溶剂中，发生成环反应得到中间体化合物VI；化合物V：氨基胍盐酸盐：N,N-二异丙基乙胺的摩尔比为1:1.5-2.5:2.5-3.5，其中，反应溶剂为N-甲基吡咯烷酮、N,N-二甲基甲酰胺或者二甲基亚砜，反应温度40-60℃；
(4)中间体化合物VI与氯乙酸甲酯溶解到非质子性溶剂中，在碱碳酸钾的作用下发生中间体化合物VI的亲核取代反应生成中间体化合物VII；其中化合物VI：氯乙酸甲酯：碳酸钾的摩尔比为1:1.0-1.1:1.0-1.5，反应溶剂为N-甲基吡咯烷酮、N,N-二甲基甲酰胺或二甲基亚砜，反应温度为20-30℃；
(5)将中间体化合物VII与亚硝酸钠、二氯乙酸、苄基三乙基溴化胺加入到反应介质中进行中间体化合物的溴化得到中间体化合物VIII；其中化合物VII与亚硝酸钠、二氯乙酸、苄基三乙基溴化胺的摩尔比为1:15-25:1.0-3.0:2.0-5.0，反应介质为非质子性溶剂，反应温度为20-30℃；
(6)将中间体化合物VIII溶于反应介质中，加入氢氧化锂水溶液进行中间体化合物的水解得到最终产物Lesinuard(I)；其中化合物VIII与氢氧化锂的摩尔比为1:1.0-3.0，反应介质为与水互溶性溶剂，反应温度为0-10℃。
根据本发明，优选的，
步骤(1)中所述的化合物II：化合物III：磷酸钾：四(三苯基膦)钯的摩尔比为1.0:1.3:3.5:0.1；反应溶剂为甲苯：水的体积比为25:1的甲苯水溶液；反应温度为100℃。
步骤(2)中，化合物IV：1,1’-硫代羰基二咪唑的摩尔比为1.0:1.5；反应溶剂为二氯甲烷；反应温度为25℃。
步骤(3)中，化合物V：氨基胍盐酸盐：N,N-二异丙基乙胺的摩尔比为1.0:2.0:3.0；反应溶剂为N,N-二甲基甲酰胺；温度为50℃。
步骤(4)中，化合物VI：氯乙酸甲酯：碳酸钾的摩尔比为1.0:1.0:1.0-1.5；反应溶剂为N,N-二甲基甲酰胺；反应温度为25℃。
步骤(5)中，化合物VII与亚硝酸钠、二氯乙酸、苄基三乙基溴化胺的摩尔比为1.0:20.0:2.0-5.0，反应介质为溴仿，温度为25℃。
步骤(6)中，化合物VIII与氢氧化锂的摩尔比为1:1.5，反应介质为四氢呋喃，反应温度为0℃。
本发明以化合物II和化合物III为初始原料，在碱和催化剂的作用下发生铃木反应生成中间体化合物IV；然后中间体化合物IV与1,1’-硫代羰基二咪唑发生亲核取代生成关键中间体化合物V；关键中间体化合物V在碱的作用下成环生成中间体化合物VI；中间体化合物VI再与氯乙酸甲酯发生亲核取代反应生成中间体化合物VII，中间体化合物VII经溴化反应生成中间体化合物VIII，中间体化合物VIII经水解反应生成目标产物2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸(I)。
本发明合成路线如下：
本发明提供了一种2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸的高效制备方法，本方法反应选择性高，操作简单，且相比于原来的合成方法大大地缩短了反应时间，减小了能源消耗，提高了反应产率，总收率达到38.8％。
下面结合具体实施方式的实施案例对本发明做进一步说明。实施例中所述的室温是25℃±5℃。
具体实施方式
实施例1：
(1)化合物4-环丙基-1-萘胺(IV)的合成
将4-溴-1-萘胺II(90mmol,20.0g)、环丙基硼酸III(116mmol,10.0g)、磷酸钾(300mmol,64.0g)与四三苯基膦钯(6mmol,7.0g)加入到100mL甲苯与4mL水的混合溶剂中，在氮气保护下于100℃反应12h，待反应液冷却到室温时，向反应液中加入100mL的水溶液，用乙酸乙酯萃取三次后加入硫酸钠干燥。半小时后过滤，经减压蒸馏得到13.8g中间体化合物IV，收率83.6％。1H NMR(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,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)化合物1-环丙基-4-异硫氰酸萘酯(V)的合成
将上步制备的中间体化合物IV(33mmol,6.0g)，1,1’-硫代羰基二咪唑(50mmol,8.8g)加入到100mL二氯甲烷中，然后室温下反应12h。反应结束后将溶剂蒸干后加入100mL水，乙酸乙酯萃取三次后加入硫酸钠干燥，半小时后过滤，经快速柱层析得到7.1g中间体化合物V，收率96.2％。1H NMR(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,CH2),0.77-0.73(m,2H,CH2).C14H11NS(Exact Mass:225.06).
(3)化合物5-氨基-4-(4-环丙基-1-萘基)-4H-1,2,4-三唑-3-巯基(VI)的合成：
将中间体化合物V(13.3mmol，3.0g)，氨基胍盐酸盐(26.6mmol，2.9g)加入到50mL的N,N-二甲基甲酰胺中，搅拌下加入N,N-二异丙基乙胺(39.9mmol，5.1g)，然后50℃反应12h，将溶剂蒸干后加入20mL 2M的氢氧化钠，然后50℃继续反应12h。停止反应后，将反应液过滤，滤液用稀盐酸中和至pH＝4，可见大量白色沉淀析出，过滤，然后45-50℃的温度下真空干燥得到2.85g中间体化合物VI，收率76.0％。ESI-MS:m/z 283.4[M+H]+.C15H14N4S(ExactMass:282.09).
(4)化合物2-((5-氨基-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸甲酯(VII)的合成
将中间体化合物VI(7.1mmol，2.0g)与碳酸钾(7.8mmol，1.1g)加入到40mL的N,N-二甲基甲酰胺中，搅拌下滴入氯乙酸甲酯(7.4mmol，0.8g)，然后50℃反应24h，反应结束后将反应液倒入冰水中有沉淀析出，过滤，然后45-50℃的温度下真空干燥得到2.21g中间体化合物VII，收率88.0％。ESI-MS:m/z 355.5[M+H]+.C18H18N4O2S(Exact Mass:354.12).
(5)化合物2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸甲酯(VIII)的合成
将中间体化合物VII(5.6mmol，2.0g)、亚硝酸钠(112mmol，7.7g)与苄基三乙基溴化胺(16.8mmol，4.5g)共称于圆底烧瓶中，加入溴仿后室温下搅拌30min，然后滴加二氯乙酸(11.2mmol，1.4g)，搅拌3h。反应结束后将反应液蒸干加入水和乙酸乙酯萃取3次，加入硫酸钠干燥，半小时后过滤，经快速柱得到1.89g中间体化合物VIII，收率80.1％。ESI-MS:m/z418.5[M+H]+.C18H16BrN3O2S(Exact Mass:417.01).
(6)化合物2-((5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基)硫基)乙酸(Lesinuard，I)的合成
将中间体化合物VIII(2.7mmol,1.14g)溶于10mL四氢呋喃中，冰浴搅拌下滴加氢氧化锂水溶液后继续搅拌45min。加入2M的盐酸调pH＝7，蒸去五分之四的溶剂后加入20mL的水，继续调pH＝2～3，将固体滤出，然后将析出的固体过滤水洗并于55-60℃的温度下真空干燥得Lesinuard粗品，然后重结晶，过滤干燥得到纯品Lesinuard 0.99g，收率90.0％。ESI-MS:m/z 406.4[M+H]+.C17H14BrN3O2S(Exact Mass:403.00).
此合成路线的总收率为83.6％×96.2％×76.0％×88.0％×80.1％×90.0％＝38.8％。
Claims (1)
1.一种式I化合物的制备方法，包括步骤：
(1)将起始原料化合物II和化合物III溶解在溶剂中，在碱磷酸钾以及催化剂四(三苯基膦)钯的作用下发生铃木反应生成中间体化合物IV；其中，化合物II：化合物III：磷酸钾：四(三苯基膦)钯四者的摩尔比为1.0:1.3:3.5:0.1，所述的反应溶剂为N,N-二甲基甲酰胺、二甲基亚砜或甲苯：水的体积比为25:1的甲苯水溶液，反应温度为100℃；
(2)中间体化合物IV和1,1’-硫代羰基二咪唑于非质子性溶剂中发生中间体化合物IV的亲核取代反应生成中间体化合物V；其中，化合物IV：1,1’-硫代羰基二咪唑的摩尔比为1.0:1.5，反应溶剂为二氯甲烷、三氯甲烷或者二氯乙烷，反应温度为25℃；
(3)中间体化合物V与氨基胍盐酸盐加入到非质子性溶剂中，发生成环反应得到中间体化合物VI；化合物V：氨基胍盐酸盐：N,N-二异丙基乙胺的摩尔比为1.0:2.0:3.0，其中，反应溶剂为N-甲基吡咯烷酮、N,N-二甲基甲酰胺或者二甲基亚砜，反应温度50℃；
(4)中间体化合物VI与氯乙酸甲酯溶解到非质子性溶剂中，在碱碳酸钾的作用下发生中间体化合物VI的亲核取代反应生成中间体化合物VII；其中化合物VI：氯乙酸甲酯：碳酸钾的摩尔比为1.0:1.0:1.0-1.5，反应溶剂为N-甲基吡咯烷酮、N,N-二甲基甲酰胺或二甲基亚砜，反应温度为25℃；
(5)将中间体化合物VII与亚硝酸钠、二氯乙酸、苄基三乙基溴化胺加入到反应介质中进行中间体化合物的溴化得到中间体化合物VIII；其中化合物VII与亚硝酸钠、二氯乙酸、苄基三乙基溴化胺的摩尔比为1.0:20.0:1.0:2.0-5.0，反应介质为非质子性溶剂，反应温度为25℃；
(6)将中间体化合物VIII溶于反应介质中，加入氢氧化锂水溶液进行中间体化合物的水解得到最终产物Lesinuard(I)；其中化合物VIII与氢氧化锂的摩尔比为1.0:1.5，反应介质为与水互溶性溶剂，反应温度为0℃；
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