CN116239577A - Method for preparing cudexestat - Google Patents
Method for preparing cudexestat Download PDFInfo
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- CN116239577A CN116239577A CN202310305289.7A CN202310305289A CN116239577A CN 116239577 A CN116239577 A CN 116239577A CN 202310305289 A CN202310305289 A CN 202310305289A CN 116239577 A CN116239577 A CN 116239577A
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- reaction
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- propyl
- fluoro
- pyrazol
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 124
- RKIHOTZGEDSSDP-UHFFFAOYSA-N ethyl 3-[2,6-dichloro-7-fluoro-1-(1-propylpyrazol-4-yl)indol-3-yl]sulfanyl-2-fluorobenzoate Chemical compound ClC=1N(C2=C(C(=CC=C2C1SC=1C(=C(C(=O)OCC)C=CC1)F)Cl)F)C=1C=NN(C1)CCC RKIHOTZGEDSSDP-UHFFFAOYSA-N 0.000 claims abstract description 18
- XWBTZHDDWRNOQH-UHFFFAOYSA-N 3-chloro-2-fluoroaniline Chemical compound NC1=CC=CC(Cl)=C1F XWBTZHDDWRNOQH-UHFFFAOYSA-N 0.000 claims abstract description 10
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960002327 chloral hydrate Drugs 0.000 claims abstract description 10
- 239000012467 final product Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000002253 acid Chemical class 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- VGYPDZONLCXCTP-UHFFFAOYSA-N ethyl 3-[6-chloro-7-fluoro-1-(1-propylpyrazol-4-yl)indol-3-yl]sulfanyl-2-fluorobenzoate Chemical compound ClC1=CC=C2C(=CN(C2=C1F)C=1C=NN(C1)CCC)SC=1C(=C(C(=O)OCC)C=CC1)F VGYPDZONLCXCTP-UHFFFAOYSA-N 0.000 claims description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 18
- OPEAQMMQYFSXKX-UHFFFAOYSA-N 6-chloro-7-fluoro-1h-indole Chemical compound FC1=C(Cl)C=CC2=C1NC=C2 OPEAQMMQYFSXKX-UHFFFAOYSA-N 0.000 claims description 16
- 239000011261 inert gas Substances 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 16
- CLMJYIQSMYNJEP-UHFFFAOYSA-N 6-chloro-7-fluoro-1-(1-propylpyrazol-4-yl)indole Chemical compound ClC1=CC=C2C=CN(C2=C1F)C=1C=NN(C1)CCC CLMJYIQSMYNJEP-UHFFFAOYSA-N 0.000 claims description 15
- KPIXRLPJNJURAJ-UHFFFAOYSA-N 6-chloro-7-fluoro-1h-indole-2,3-dione Chemical compound C1=C(Cl)C(F)=C2NC(=O)C(=O)C2=C1 KPIXRLPJNJURAJ-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- POEZGGAVBDAFFG-UHFFFAOYSA-N 4-iodo-1-propylpyrazole Chemical compound CCCN1C=C(I)C=N1 POEZGGAVBDAFFG-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 229950000188 halopropane Drugs 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 9
- KZMQZNAMQSWTRW-UHFFFAOYSA-N ethyl 2-fluoro-3-sulfanylbenzoate Chemical compound CCOC(=O)C1=CC=CC(S)=C1F KZMQZNAMQSWTRW-UHFFFAOYSA-N 0.000 claims description 9
- -1 3-chloro-2-fluorophenyl Chemical group 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 7
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims description 6
- LLNQWPTUJJYTTE-UHFFFAOYSA-N 4-iodopyrazole Chemical compound IC=1C=NNC=1 LLNQWPTUJJYTTE-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 6
- 239000001307 helium Substances 0.000 claims description 6
- 229910052734 helium Inorganic materials 0.000 claims description 6
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229910052754 neon Inorganic materials 0.000 claims description 6
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 2
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 2
- 229960003105 metformin Drugs 0.000 claims description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims description 2
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 8
- 239000000047 product Substances 0.000 abstract description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000000227 grinding Methods 0.000 abstract description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003747 Grignard reaction Methods 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229940125782 compound 2 Drugs 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- NMDFAQXLJQRHMS-UHFFFAOYSA-N 3-[2,6-dichloro-7-fluoro-1-(1-propylpyrazol-4-yl)indol-3-yl]sulfanyl-2-fluorobenzoic acid Chemical compound C1=NN(CCC)C=C1N1C2=C(F)C(Cl)=CC=C2C(SC=2C(=C(C(O)=O)C=CC=2)F)=C1Cl NMDFAQXLJQRHMS-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000007872 degassing Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 2
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 description 2
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940126342 cudetaxestat Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RBAHXNSORRGCQA-UHFFFAOYSA-N 1-chloro-2-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Cl)=C1F RBAHXNSORRGCQA-UHFFFAOYSA-N 0.000 description 1
- 238000006159 Bartoli reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a method for preparing cudexesat, and belongs to the technical field of medicines. The specific steps of the scheme of the invention are that 3-chloro-2-fluoroaniline and chloral hydrate are used for constructing indole mother nucleus through condensation, cyclization and reduction reaction, so that Grignard reaction and ultralow temperature reaction conditions are not needed, and meanwhile, the reaction conditions in preparation of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester and a final product Cudetaxest are optimized. The purity of the product is 99.85%, the total yield of the route is 7.05%, and the product is improved by 10 times compared with the original grinding route. The method provided by the invention has the characteristics of low-cost and easily-obtained raw materials, mild reaction conditions, simple and convenient post-treatment, suitability for industrialization and the like, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines. In particular to a method for preparing Cudestoxestat.
Background
Cudexesat is a potent, selective, non-competitive and oral Autotaxin (ATX) inhibitor, in the phase of clinical phase II development. Cudexesat showed strong inhibitory activity against various fibrotic markers and was able to regulate key fibrotic genes, qualifying as orphan drugs in month 2 of 2021 for potential treatment of idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF). The chemical structural formula is shown as formula I:
patent (WO 2015077503) discloses a process for the preparation of cudexesat. However, this method has the following disadvantages:
1. the 3-chloro-2-fluoronitrobenzene is used as a starting material, and is subjected to bartoli indole synthesis reaction with a large excess of vinyl magnesium bromide to prepare 6-chloro-7-fluoroindole, wherein the reaction has severe temperature requirements and needs to be carried out at the temperature of minus 40 ℃, and the vinyl magnesium bromide needs to strictly control anhydrous and anaerobic conditions in the use process, so that the economy of reaction atoms is poor and the yield is only about 10%, and therefore, a more efficient and simple method for synthesizing the 6-chloro-7-fluoroindole needs to be developed.
2. The preparation of ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate from ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate requires the addition of an excessive amount of a chloro reagent in batches, is cumbersome in operation process, is unfavorable for industrial production, and increases the yield of byproducts in the presence of the excessive chloro reagent, resulting in the reduction of the purity and yield of the product.
3. The hydrolysis reaction in the process of preparing the cudexesttat from 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester adopts expensive lithium hydroxide, the alkalinity of the lithium hydroxide is weaker, and the reaction yield of the step is lower and is about 30.0 percent.
The reported route has 7 steps of reactions, the total yield is only about 0.6 percent, and the preparation method of the Cudetaxestat needs to be improved in order to meet the clinical research demands.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a method for preparing Cudestoxestat, which aims at providing a method which has the advantages of simple process, low-cost and easily available raw materials, mild reaction conditions, high yield and suitability for industrial preparation of Cudestoxestat. The invention provides a method for preparing Cudestoxestat, which comprises the following steps:
(1) Dissolving 4-iodo-1H-pyrazole (compound 1) in an organic solvent, adding alkali, stirring, adding 1-halopropane, and reacting to obtain 4-iodo-1-propyl-1H-pyrazole (compound 2);
(2) Dissolving chloral hydrate in water under the condition of stirring at room temperature, sequentially adding anhydrous sodium sulfate, 3-chloro-2-fluoroaniline (a compound A), acid salt of hydroxylamine and acid, reacting to obtain N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide (an intermediate B), and then adding concentrated acid into the reaction solution to react to obtain 6-chloro-7-fluoroindole-2, 3-dione (a compound C);
(3) Dissolving 6-chloro-7-fluoroindole-2, 3-dione (compound C) in a reducing agent, slowly dropwise adding an organic solvent for reaction to obtain 6-chloro-7-fluoroindole (compound D);
(4) Dissolving 6-chloro-7-fluoroindole (compound D) in an organic solvent, sequentially adding 4-iodo-1-propyl-1H-pyrazole (compound 2), alkali, ligand and CuI, and carrying out inert gas degassing for 10-30 min to obtain 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E);
(5) Under the condition of stirring at room temperature, 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E) is dissolved in an organic solvent, a chloro reagent is added, the reaction is carried out under the protection of inert gas, then ethyl 2-fluoro-3-mercaptobenzoate is added, and 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F) is obtained by the reaction;
(6) Under the condition of stirring at room temperature, dissolving 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound F) in an organic solvent, adding a chloro reagent, and reacting under the protection of inert gas to obtain 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G);
(7) Under the condition of stirring at room temperature, 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G) is dissolved in a mixed solvent, and alkali is added for reaction to obtain a final product Cudetaxestat. The 1-halopropane in step (1) above comprises one of 1-iodopropane, 1-bromopropane or 1-chloropropane; the organic solvent includes, but is not limited to, one of dichloromethane, tetrahydrofuran, toluene, 1, 4-dioxane, N-Dimethylformamide (DMF) or ethyl acetate; the base includes, but is not limited to, one of sodium hydroxide, potassium hydroxide, sodium t-butoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, or potassium hydride;
the molar ratio of the 4-iodo-1H-pyrazole (compound 1), the base and the 1-halopropane in the step (1) is 1: (1.8-2.2): (1.8-2.2);
the reaction in the step (1) is specifically carried out for 0.5 to 1.5 hours at the temperature of 25 to 100 ℃;
the step (1) is characterized in that 1-halopropane is added, and the 1-halopropane is dropwise and slowly added;
the acid salt of hydroxylamine in the above step (2) comprises one of hydroxylamine hydrochloride or hydroxylamine sulfate; the acid includes, but is not limited to, one of hydrochloric acid, sulfuric acid, nitric acid, or acetic acid; the concentration of the acid is 1.0N-12.0N; the concentrated acid includes, but is not limited to, one of concentrated nitric acid, polyphosphoric acid, concentrated hydrochloric acid, or concentrated sulfuric acid;
in the step (2), the molar ratio of the 3-chloro-2-fluoroaniline (compound A) to chloral hydrate, acid salt of hydroxylamine, anhydrous sodium sulfate and acid is 1: (1.0-1.4): (2.8-3.2): (6.5-7.5): (0.1 to 5.0); the molar volume ratio of N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide (intermediate B) to concentrated acid is 1: (1.0 to 4.0);
in the step (2), the N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide (intermediate B) is obtained after the reaction, and the reaction is carried out for 0.5 to 2.5 hours at the temperature of 70 to 110 ℃; the reaction is carried out after the concentrated acid is added, specifically, the reaction is carried out for 0.5 to 2.5 hours at the temperature of 70 to 90 ℃;
the reducing agent in the step (3) comprises, but is not limited to, boron trifluoride, sodium borohydride or one of borane tetrahydrofuran complexes; the organic solvent includes, but is not limited to, one of 1, 4-dioxane, diethyl ether, toluene or tetrahydrofuran;
the concentration of the reducing agent in the step (3) is 1N-6N, and the molar ratio of the 6-chloro-7-fluoroindole-2, 3-dione (compound C) to the reducing agent is 1: (0.5-1.8);
the reaction in the step (3) is specifically carried out for 1.5 to 3.5 hours at the temperature of 18 to 37 ℃;
the alkali in the step (4) comprises one of cesium carbonate, potassium phosphate, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide; the organic solvent includes, but is not limited to, one of 1, 4-dioxane, toluene, tetrahydrofuran or DMF; the ligand includes but is not limited to one of 1, 10-phenanthroline, metformin or N, N' -dimethylethylenediamine (DMEDA);
the inert gas in the step (4) includes but is not limited to helium, neon or argon;
the molar ratio of the 6-chloro-7-fluoroindole (compound D) to the 4-iodo-1-propyl-1H-pyrazole (compound 2), the ligand, the CuI and the base in the step (4) is 1: (1.0-1.4): (0.1-0.6): (0.01-0.15): (1.0 to 3.5);
the reaction in the step (4) is specifically carried out for 8-16 h at the temperature of 90-110 ℃;
the organic solvent in the step (5) includes, but is not limited to, one of 1, 4-dioxane, toluene, tetrahydrofuran, DMF or dichloromethane;
the inert gas in the step (5) includes but is not limited to helium, neon or argon;
the chlorinating agent in the step (5) includes, but is not limited to, one of phosphorus oxychloride, oxalyl chloride, thionyl chloride or N-chlorosuccinimide (NCS);
the molar ratio of the 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E) to the ethyl 2-fluoro-3-mercaptobenzoate and the chloro reagent in the step (5) is 1: (0.8-1.2): (0.8-1.2);
the reaction is carried out under the protection of the inert gas in the step (5), specifically, the reaction is carried out for 1.0 to 2.0 hours at the temperature of 18 to 37 ℃; the reaction to obtain 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound F) is specifically that the reaction is carried out for 12 to 20 hours at normal temperature;
the chlorinating agent in the above step (6) includes, but is not limited to, one of phosphorus oxychloride, oxalyl chloride, thionyl chloride or N-chlorosuccinimide (NCS); the organic solvent includes, but is not limited to, one of 1, 4-dioxane, toluene, tetrahydrofuran, DMF, or dichloromethane;
the inert gas in the step (6) includes but is not limited to helium, neon or argon;
in the step (6), the molar ratio of 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound F) to the chlorinating agent is 1: (1.2-5.0);
the reaction is carried out under the protection of the inert gas in the step (6), specifically, the reaction is carried out for 12 to 20 hours at the temperature of 18 to 37 ℃;
the alkali in the step (7) comprises one of sodium hydroxide and potassium hydroxide; the mixed solvent comprises, but is not limited to, a mixed solvent composed of ethanol and water or a mixed solvent composed of ethanol, water and tetrahydrofuran; the mass volume ratio (G: ml) of the mixed solvent to 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G) is 1: (3.0-20.0), wherein the volume ratio of water, ethanol and tetrahydrofuran in the mixed solvent is 1: (0.5-1.5): (1.0 to 3.0);
in the step (7), the molar ratio of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G) to the base is 1: (4.0 to 9.0);
the reaction in the step (7) is carried out to obtain the compound Cudestoxestat, and the reaction is concretely carried out for 0.5-1.5 h at 18-37 ℃.
Aiming at the defects of the prior art, the method for preparing the Cudestoxestat has the following beneficial effects:
according to the method, 3-chloro-2-fluoroaniline and chloral hydrate are subjected to condensation, cyclization and reduction reaction to construct an indole mother nucleus, so that Grignard reaction and ultralow-temperature reaction conditions are not required, and meanwhile, the reaction conditions in preparation of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G) and a compound shown in a formula I are optimized. The purity of the product is 99.85%, the total yield of the route is 7.05%, and the product is improved by 10 times compared with the original grinding route. The method provided by the invention has the characteristics of low-cost and easily-obtained raw materials, mild reaction conditions, simple and convenient post-treatment, suitability for industrialization and the like, and has good application prospect.
The method adopts cheap and easily available 3-chloro-2-fluoroaniline as a starting material, reacts with chloral hydrate and hydroxylamine hydrochloride, then cyclizes under the action of acid to obtain 6-chloro-7-fluoroindole-2, 3-dione (compound C), and reduces by borane tetrahydrofuran complex to obtain 6-chloro-7-fluoroindole (compound D). Then synthesizing the target compound Cudestaxestat through coupling, addition, chlorination and hydrolysis reactions. Compared with the existing synthetic route, the route has the following advantages: 1) The construction of the indole parent nucleus does not need to adopt Grignard reaction and ultralow temperature reaction conditions, the reaction effect is improved, the yield is greatly improved, and the post-treatment process is simpler and more convenient; 2) The feeding mode of indole 2-position chlorination reaction is simplified, the problem that polychlorinated byproducts are generated by stepwise feeding in the original grinding route is solved, and the unreacted complete compound (F) can be recovered and reacted again after post-treatment, so that raw material waste is effectively avoided; 3) The hydrolysis reaction of the compound (G) uses a mixed solvent and cheap sodium hydroxide, so that the reaction time is greatly shortened, the reaction efficiency is improved, and the reaction cost is reduced. The purity of the product obtained by the method is 99.85%, the total yield of the route is 7.05%, and the product is improved by 10 times compared with the original grinding route. The method provided by the invention has the characteristics of low-cost and easily-obtained raw materials, mild reaction conditions, simple and convenient post-treatment, suitability for industrialization and the like, and has good application prospect.
Drawings
FIG. 1 is a synthetic scheme of the compound Cudestoxestat according to the present invention.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The term "reacting" as used herein is to be understood in a broad sense and may be any manner that enables at least two reactants to react chemically, for example by mixing the two reactants under appropriate conditions. The reactants to be reacted may be mixed under stirring as needed, and thus the type of stirring is not particularly limited, and for example, magnetic stirring, that is, stirring under the action of magnetic force, may be used.
The manner of all chemical reactions involved in the embodiments of the present invention is not particularly limited;
in embodiments of the present invention, the chemical reactions described herein may be performed according to any method known in the art. The source of the starting materials for preparing 4-iodo-1-propyl-1H-pyrazole (compound 2), N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide (intermediate B), 6-chloro-7-fluoroindole-2, 3-dione (compound C), 6-chloro-7-fluoroindole (compound D), 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E), 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound F), 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G) is not particularly limited, and may be prepared by any known method or commercially available.
Example 1
Synthesis of 4-iodo-1-propyl-1H-pyrazole (Compound 2):
the molar ratio of the 4-iodine-1H-pyrazole (compound 1), sodium hydride and 1-bromopropane is 1:2.0:2.0.
under the ice bath stirring condition, 0.15mol of 4-iodo-1H-pyrazole (compound 1) is dissolved in DMF (180 mL), 0.31mol of sodium hydride is added for continuous stirring for 15min, then 0.31mol of 1-bromopropane is slowly dripped dropwise, the ice bath is removed, the temperature is raised to 40 ℃ for reaction stirring reaction for 1H. After the completion of the reaction, the reaction solution was cooled to room temperature, 100mL of a saturated ammonium chloride solution was added thereto, concentrated under reduced pressure, water (1L) was added, the organic phase was washed with a 5% lithium chloride solution (500 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a nearly colorless oil of 36g, yield: 98%.
MS(ESI)m/z：237.1[M+H].
Example 2
Synthesis of 4-iodo-1-propyl-1H-pyrazole (Compound 2):
4-iodo-1H-pyrazole (Compound 1) (30.0 g,0.15 mol) was dissolved in DMF (180 mL) with stirring in an ice bath, sodium hydride (14.0 g,0.34 mol) was added thereto and stirring was continued for 15min, then 1-bromopropane (41 mL,0.34 mol) was slowly dropped dropwise thereto, the ice bath was removed, and the temperature was raised to 100℃for reaction stirring for 0.5H. After the completion of the reaction, the reaction solution was cooled to room temperature, a saturated ammonium chloride solution (100 mL) was added thereto, concentrated under reduced pressure, water (1L) was added, the organic phase was extracted with ethyl acetate (500 ml×2), and a 5% lithium chloride solution was washed (500 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning to give a nearly colorless oily substance, 33g, yield: 88%.
Example 3
Synthesis of 4-iodo-1-propyl-1H-pyrazole (Compound 2):
4-iodo-1H-pyrazole (Compound 1) (30.0 g,0.15 mol) was dissolved in DMF (180 mL) under stirring in an ice bath, sodium hydride (11.0 g,0.28 mol) was added thereto and stirring was continued for 15min, then 1-bromopropane (33 mL,0.28 mol) was slowly dropped dropwise thereto, the ice bath was removed, and the reaction was stirred at 25℃for 1.5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, a saturated ammonium chloride solution (100 mL) was added thereto, concentrated under reduced pressure, water (1L) was added, the organic phase was extracted with ethyl acetate (500 ml×2), a 5% lithium chloride solution was washed (500 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning to give 34g of a nearly colorless oil, yield: 91%.
Example 4
Synthesis of 6-chloro-7-fluoroindole-2, 3-dione (Compound C):
chloral hydrate (24.0 g,0.15 mol) was dissolved in water (1.0L) with stirring at room temperature, and Na was added sequentially 2 SO 4 (120.0 g,0.85 mol), 3-chloro-2-fluoroaniline (17.4 g, 0)12 mol), hydroxylamine hydrochloride (25.2 g,0.36 mol) and hydrochloric acid (12N, 45mL,0.54 mol), heating to 95 ℃ to react for 1.5h, then adding concentrated sulfuric acid (150 mL), cooling to 80 ℃ to continue the reaction for 1.5h, cooling the reaction liquid to room temperature after the reaction is completed, filtering to keep a filter cake, obtaining yellow solid 24.9g, yield: 80%.
1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),7.39(d,J＝8.0Hz,1H),7.24(dd,J＝8.0,6.1Hz,1H).
Example 5
Synthesis of 6-chloro-7-fluoroindole-2, 3-dione (Compound C):
chloral hydrate (27.9 g,0.17 mol) was dissolved in water (1.0L) with stirring at room temperature, and Na was added sequentially 2 SO 4 (24.0 g,0.14 mol), 3-chloro-2-fluoroaniline (17.4 g,0.12 mol), hydroxylamine hydrochloride (25.2 g,0.36 mol) and hydrochloric acid (12N, 50mL,0.61 mol), were heated to 70℃for 1.0h, then concentrated sulfuric acid (200 mL) was added, the reaction was continued at 90℃for 1.0h, after completion of the reaction, the reaction solution was cooled to room temperature, and the cake was retained by suction filtration to give 18.7g of a yellow solid, yield: 60%.
Example 6
Synthesis of 6-chloro-7-fluoroindole-2, 3-dione (Compound C):
chloral hydrate (20.1 g,0.12 mol) was dissolved in water (1.0L) with stirring at room temperature, and Na was added sequentially 2 SO 4 (111.3 g,0.78 mol), 3-chloro-2-fluoroaniline (17.4 g,0.12 mol), hydroxylamine hydrochloride (23.4 g,0.33 mol) and hydrochloric acid (12N, 30mL,0.42 mol), heating to 100 ℃ for 2.5h, then adding concentrated sulfuric acid (105 mL), cooling to 70 ℃ for 2.5h, cooling the reaction solution to room temperature after the reaction, filtering to retain a filter cake, and obtaining yellow solid 15.6g, yield: 50%.
Example 7
Synthesis of 6-chloro-7-fluoroindole (Compound D)
6-chloro-7-fluoroindole-2, 3-dione (compound C) (29.8 g,0.15 mol) was dissolved in dry tetrahydrofuran (60 mL) with stirring in an ice bath, borane tetrahydrofuran solution (1N, 150mL,0.15 mol) was slowly added dropwise, the reaction was allowed to react at room temperature for 2.5h, after completion of the reaction, a small amount of water (15 mL) was slowly added dropwise to the reaction solution, concentrated under reduced pressure, 150mL of water was added, DCM was extracted (150 mL. Times.3), and the product was obtained by spin-drying, and purified by column chromatography (PE: EA=5:1) to give 14.5g of brown crystals. Yield: 57%.
MS(ESI)m/z：168.0[M-H].
1 H NMR(400MHz,DMSO-d 6 )δ11.81(s,1H),7.46(t,J＝2.8Hz,1H),7.39(d,J＝8.5Hz,1H),7.07(dd,J＝8.4,6.6Hz,1H),6.55(td,J＝3.3,2.0Hz,1H).
Example 8
Synthesis of 6-chloro-7-fluoroindole (Compound D)
6-chloro-7-fluoroindole-2, 3-dione (compound C) (29.8 g,0.15 mol) was dissolved in dry tetrahydrofuran (60 mL) with stirring in an ice bath, borane tetrahydrofuran solution (1N, 270mL,0.27 mol) was slowly added dropwise, the reaction was allowed to react at room temperature for 1.5h, after completion of the reaction, a small amount of water (15 mL) was slowly added dropwise to the reaction solution, concentrated under reduced pressure, water 150mL was added, DCM was extracted (150 mL. Times.3), and the product was obtained by spin-drying, and purified by column chromatography (PE: EA=5:1) to give 13.0g of brown crystals. Yield: 51%.
Example 9
Synthesis of 6-chloro-7-fluoroindole (Compound D)
6-chloro-7-fluoroindole-2, 3-dione (compound C) (29.8 g,0.15 mol) was dissolved in dry tetrahydrofuran (60 mL) with stirring in an ice bath, borane tetrahydrofuran solution (1N, 80mL,0.08 mol) was slowly added dropwise, the reaction was allowed to react at room temperature for 3.5h, after completion of the reaction, a small amount of water (15 mL) was slowly added dropwise to the reaction solution, concentrated under reduced pressure, 150mL of water was added, DCM was extracted (150 mL. Times.3), and the product was obtained by spin-drying, and purified by column chromatography (PE: EA=5:1) to give 12.0g of brown crystals. Yield: 48%.
Example 10
Synthesis of 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (Compound E)
6-chloro-7-fluoroindole (Compound D) (29.0 g,0.17 mol) was dissolved in dry toluene (300 mL), 4-iodo-1-propyl-1H-pyrazole (Compound 2) (49.5 g,0.21 mol), cesium carbonate (85.4 g,0.26 mol), DMEDA (2.2 g,25.5 mmol) and CuI (3.2 g,17.0 mmol) were added sequentially, the reaction was carried out for 12H at room temperature under argon degassing for 10min at 100℃and after completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate (400 mL), suction filtration was carried out with celite, the filter cake was washed with ethyl acetate (300 mL. Times.2), the filtrate was washed with saturated brine (500 mL), and then dried by spin-drying after separation, and purification by column chromatography (PE: EA=5:1) to give an orange liquid, yield: 65%.
MS(ESI)m/z：278.1[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ8.16(d,J＝1.8Hz,1H),7.76–7.71(m,1H),7.47(d,J＝3.1Hz,1H),7.45(d,J＝8.5Hz,1H),7.17(dd,J＝8.5,6.3Hz,1H),6.72(t,J＝2.8Hz,1H),4.11(t,J＝6.9Hz,2H),1.84(h,J＝7.2Hz,2H),0.87(t,J＝7.4Hz,3H).
Example 11
Synthesis of 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (Compound E):
6-chloro-7-fluoroindole (Compound D) (29 g,0.17 mol) was dissolved in dry toluene (300 mL), 4-iodo-1-propyl-1H-pyrazole (Compound 2) (56.1 g,0.24 mol), cesium carbonate (193.9 g,0.59 mol), DMEDA (8.9 g,102.0 mmol) and CuI (4.8 g,25.5 mmol) were added sequentially, the reaction was carried out at room temperature for 16H under argon degassing for 10min, after completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (400 mL) was added for dilution, celite was added for suction filtration, the filter cake was washed with ethyl acetate (300 mL. Times.2), the filtrate was washed with saturated brine (500 mL), and then dried by spin-drying after separation, and purification by column chromatography (PE: EA=5:1) was finally obtained as an orange liquid 29g, yield: 61%.
Example 12 synthesis of 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E):
6-chloro-7-fluoroindole (Compound D) (29 g,0.17 mol) was dissolved in dry toluene (300 mL), 4-iodo-1-propyl-1H-pyrazole (Compound 2) (40.1 g,0.17 mol), cesium carbonate (55.3 g,0.17 mol), DMEDA (1.5 g,17.0 mmol) and CuI (2.4 g,12.8 mmol) were added sequentially, the reaction was allowed to proceed at room temperature for 8H under argon degassing for 10min at 110℃and after completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (400 mL) was added for dilution, celite was used for suction filtration, the filter cake was washed with ethyl acetate (300 mL. Times.2), the filtrate was washed with saturated brine (500 mL), and then dried by spin-drying after separation, and purified by column chromatography (PE: EA=5:1) to give an orange liquid 26g, yield: 54%.
Example 13 synthesis of ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F):
6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E) (30.4 g,0.11 mol) was dissolved in methylene chloride (300 mL) with stirring at room temperature, NCS (14.7 g,0.11 mol) was added, the reaction was carried out for 1.5 hours under nitrogen protection, then ethyl 2-fluoro-3-mercaptobenzoate (22.0 g,0.11 mol) was added, stirring was continued at room temperature for 16 hours, after completion of the reaction, water (500 mL) was added to dilute the reaction solution, DCM (500 mL. Times.3) was extracted, saturated brine (500 mL) was washed, and after separation, the crude product was obtained by spin-drying, and column chromatography purification (PE: DCM=1:5) gave a white solid of 23g, yield: 42%.
1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),8.07(s,1H),7.83(s,1H),7.63(td,J＝7.3,1.8Hz,1H),7.29(d,J＝1.9Hz,2H),7.15(t,J＝7.8Hz,1H),7.06(td,J＝7.5,1.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.14(t,J＝6.9Hz,2H),1.85(h,J＝7.2Hz,2H),1.32(t,J＝7.1Hz,3H),0.88(t,J＝7.4Hz,3H).
According to one embodiment of the present invention, in step (5), further, based on 0.11mol of 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E), the amount of ethyl 2-fluoro-3-mercaptobenzoate is 0.11mol, and the amount of NCS is 0.11mol, the efficiency of the reaction of 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E) with ethyl 2-fluoro-3-mercaptobenzoate, NCS can be improved, the loss of the reaction material can be reduced, and the efficiency of preparing ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F) by the method can be further improved.
Example 14 synthesis of ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F):
6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E) (30.4 g,0.11 mol) was dissolved in methylene chloride (300 mL) with stirring at room temperature, NCS (17.4 g,0.13 mol) was added, the reaction was carried out for 1.5 hours under nitrogen protection, then ethyl 2-fluoro-3-mercaptobenzoate (26.0 g,0.13 mol) was added, the stirring was continued at room temperature for 12 hours, after completion of the reaction, water (500 mL) was added to dilute the reaction solution, DCM (500 mL. Times.3) was extracted, saturated brine (500 mL) was washed, and after separation, the crude product was obtained by spin-drying, and column chromatography purification (PE: DCM=1:5) gave a white solid of 20g, yield: 36%
Example 15 synthesis of ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F):
6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole (compound E) (30.4 g,0.11 mol) was dissolved in methylene chloride (300 mL) with stirring at room temperature, NCS (12.0 g,0.09 mol) was added, the reaction was carried out for 1.5 hours under nitrogen protection, then ethyl 2-fluoro-3-mercaptobenzoate (18.0 g,0.09 mol) was added, the reaction was continued at room temperature for 20 hours with stirring, after completion of the reaction, water (500 mL) was added to dilute the reaction solution, DCM (500 mL. Times.3) was extracted, saturated brine (500 mL) was washed, and after separation, the crude product was obtained by spin-drying, and column chromatography purification (PE: DCM=1:5) gave 22g of a white solid, yield: 40 percent of
Example 16 synthesis of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G):
ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F) (15.0 g,31.5 mmol) was dissolved in DCM (90 mL), NCS (18.6 g,139.3 mmol) was added, the reaction was carried out at 35℃under nitrogen protection for 16H, after the completion of the reaction, water (300 mL) was added to the reaction mixture for dilution, DCM (200 mL. Times.3) was extracted, saturated brine (400 mL) was washed, and dried to give a crude product which was separated by column chromatography (DCM) to give 10.4g of a white solid with a conversion of 65%.
1 H NMR(400MHz,DMSO-d 6 )δ8.30(s,1H),7.84(s,1H),7.68(td,J＝7.2,1.9Hz,1H),7.40–7.31(m,2H),7.19(t,J＝7.8Hz,1H),7.12(td,J＝8.0,7.5,1.9Hz,1H),4.34(q,J＝7.1Hz,2H),4.17(t,J＝6.7Hz,2H),1.85(h,J＝7.2Hz,2H),1.32(t,J＝7.1Hz,3H),0.86(t,J＝7.4Hz,3H).
According to one embodiment of the invention, in step (6), further, based on 31.5mmol of ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F), the amount of NCS used is 139.3mmol, and at this amount of reaction, the efficiency of the reaction of ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F) with NCS can be improved, the loss of the reaction mass can be reduced, and the efficiency of preparing ethyl 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound G) by this method can be further improved.
Example 17 synthesis of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G):
ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F) (15.0 g,31.5 mmol) was dissolved in DCM (90 mL), NCS (21.0 g,157.3 mmol) was added, the reaction was carried out at 35℃under nitrogen atmosphere for 12H, after the completion of the reaction, water (300 mL) was added to the reaction mixture for dilution, DCM (200 mL. Times.3) was extracted, saturated brine (400 mL) was washed, and dried by spin-on to give crude product, which was separated by column chromatography (DCM) to give 8.9g of a white solid with a conversion of 56%.
Example 18, synthesis of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound G):
ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound F) (15.0 g,31.5 mmol) was dissolved in DCM (90 mL), NCS (5.1 g,38.2 mmol) was added, the reaction was carried out at 35℃under nitrogen protection for 20H, after the completion of the reaction, water (300 mL) was added to the reaction mixture for dilution, DCM (200 mL. Times.3) was extracted, saturated brine (400 mL) was washed, and dried to give a crude product which was separated by column chromatography (DCM) to give 9.4g of a white solid with a conversion of 59%.
Example 19 synthesis of cudestoxestat:
as shown in FIG. 1, ethyl 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (Compound G) (10.0G, 19.6 mmol) was dissolved in a mixed solvent (tetrahydrofuran: etOH: H) with stirring at room temperature 2 O=2: 1:1, 100 mL) of sodium hydroxide solid (5.1 g,127.4 mmol) was added) Reacting for 1h at 35 ℃, concentrating under reduced pressure after the reaction is finished, adding water (300 mL) for dilution, adjusting the pH value to 3 with hydrochloric acid solution (12N), filtering to obtain a white filter cake, pulping with normal hexane to obtain 8.2g of white solid, and obtaining 87% of yield and 99.85% of purity.
MS(ESI)m/z：481.9[M+H],479.8[M-H].
1 H NMR(400MHz,DMSO-d 6 )δ13.40(s,1H),8.30(s,1H),7.84(s,1H),7.66(td,J＝7.2,2.0Hz,1H),7.37–7.34(m,2H),7.16(t,J＝7.7Hz,1H),7.10(td,J＝8.1,7.4,2.0Hz,1H),4.17(t,J＝6.8Hz,2H),1.85(q,J＝7.1Hz,2H),0.86(t,J＝7.4Hz,3H).
According to one embodiment of the invention, in the step (7), further, based on 19.6mmol of ethyl 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound G), the consumption of sodium hydroxide is 127.4mmol, and at the reaction dosage, the reaction efficiency of the ethyl 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate (compound G) and sodium hydroxide can be improved, so that the loss of reaction materials is reduced, and the efficiency of preparing the compound shown in the formula I by the method is further improved.
Example 20 synthesis of cudestoxestat:
3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (Compound G) (10.0G, 19.6 mmol) was dissolved in a mixed solvent (tetrahydrofuran: etOH: H) with stirring at room temperature 2 O=2: 1:1, 100 mL), sodium hydroxide solid (7.1 g,176.4 mmol) is added for reaction for 0.5h at 30 ℃, after the reaction is finished, the solution is concentrated under reduced pressure, diluted by water (300 mL), the pH value of the solution is adjusted to 3 by hydrochloric acid (12N), a white filter cake is obtained by suction filtration, and 7.6g of white solid is obtained by pulping normal hexane, and the yield is 81% and the purity is 99.80%.
Example 21 synthesis of cudestoxestat:
3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (Compound G) (10.0G, 19.6 mmol) was dissolved in a mixed solvent (tetrahydrofuran: etOH: H) with stirring at room temperature 2 O=2: 1:1, 100 mL) of sodium hydroxide is added to the mixtureThe reaction of the mixture (3.1 g,78.4 mmol) at 40 ℃ for 1.5h, after the reaction, the mixture is concentrated under reduced pressure, diluted by adding water (300 mL), the pH of the hydrochloric acid solution (12N) is adjusted to 3, a white filter cake is obtained by suction filtration, and 7.1g of white solid is obtained by pulping N-hexane, and the yield is 76% and the purity is 99.81%.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. A method of preparing cudestaxestat, comprising the steps of:
(1) Dissolving 4-iodine-1H-pyrazole in an organic solvent, adding alkali, stirring, adding 1-halopropane, and reacting to obtain 4-iodine-1-propyl-1H-pyrazole;
(2) Dissolving chloral hydrate in water under the condition of stirring at room temperature, sequentially adding anhydrous sodium sulfate, 3-chloro-2-fluoroaniline, acid salt of hydroxylamine and acid, reacting to obtain N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide, and then adding concentrated acid into the reaction solution to react to obtain 6-chloro-7-fluoroindole-2, 3-dione;
(3) Dissolving 6-chloro-7-fluoroindole-2, 3-dione in a reducing agent, slowly dropwise adding an organic solvent for reaction to obtain 6-chloro-7-fluoroindole;
(4) Dissolving 6-chloro-7-fluoroindole in an organic solvent, sequentially adding 4-iodo-1-propyl-1H-pyrazole, alkali, ligand and CuI, and carrying out a reaction after inert gas is degassed for 10-30 min to obtain 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole;
(5) Under the condition of stirring at room temperature, dissolving 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole in an organic solvent, adding a chloro reagent, reacting under the protection of inert gas, then adding ethyl 2-fluoro-3-mercaptobenzoate, and reacting to obtain ethyl 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoate;
(6) Under the condition of stirring at room temperature, dissolving 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester into an organic solvent, adding a chloro reagent, and reacting under the protection of inert gas to obtain 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester;
(7) Under the condition of stirring at room temperature, 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester is dissolved in a mixed solvent, and alkali is added for reaction to obtain a final product Cudestoxestat.
2. A process for preparing cudestoxestat according to claim 1, wherein the 1-halopropane in step (1) comprises one of 1-iodopropane, 1-bromopropane or 1-chloropropane; the organic solvent comprises one of dichloromethane, tetrahydrofuran, toluene, 1, 4-dioxane, N-Dimethylformamide (DMF) or ethyl acetate; the alkali comprises one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride or potassium hydride.
3. A process for preparing cudestoxestat according to claim 1, wherein the molar ratio of 4-iodo-1H-pyrazole (compound 1), base, 1-halopropane in step (1) is 1: (1.8-2.2): (1.8-2.2); the reaction is carried out for 0.5 to 1.5 hours at the temperature of between 25 and 100 ℃; the 1-halopropane is added, in particular, the 1-halopropane is slowly dripped dropwise.
4. A process for preparing cudestoxestat according to claim 1, wherein the acid salt of hydroxylamine in step (2) comprises one of hydroxylamine hydrochloride or hydroxylamine sulfate; the acid comprises one of hydrochloric acid, sulfuric acid, nitric acid or acetic acid; the concentration of the acid is 1.0N-12.0N; the concentrated acid comprises one of concentrated nitric acid, polyphosphoric acid, concentrated hydrochloric acid or concentrated sulfuric acid.
5. The method for preparing cudexesat according to claim 1, wherein in the above step (2), the molar ratio of 3-chloro-2-fluoroaniline (compound a), chloral hydrate, acid salt of hydroxylamine, anhydrous sodium sulfate and acid is 1: (1.0-1.4): (2.8-3.2): (6.5-7.5): (0.1 to 5.0); the molar volume ratio of N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide (intermediate B) to concentrated acid is 1: (1.0 to 4.0); the N- (3-chloro-2-fluorophenyl) -2- (hydroxyimino) acetamide is obtained after the reaction, specifically, the reaction is carried out for 0.5 to 2.5 hours at the temperature of 70 to 110 ℃; the reaction is carried out after the concentrated acid is added, specifically, the reaction is carried out for 0.5 to 2.5 hours at the temperature of 70 to 90 ℃.
6. A process for preparing cudestoxestat according to claim 1, wherein the reducing agent in step (3) above comprises one of boron trifluoride, sodium borohydride or borane tetrahydrofuran complex; the organic solvent comprises one of 1, 4-dioxane, diethyl ether, toluene or tetrahydrofuran; the concentration of the reducing agent is 1N-6N; the molar ratio of the 6-chloro-7-fluoroindole-2, 3-dione (compound C) to the reducing agent is 1: (0.5-1.8); the reaction is carried out specifically for 1.5-3.5 h at 18-37 ℃.
7. A process for preparing cudexesat according to claim 1, wherein said base in step (4) comprises one of cesium carbonate, potassium phosphate, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide; the organic solvent comprises one of 1, 4-dioxane, toluene, tetrahydrofuran or DMF; the ligand comprises one of 1, 10-phenanthroline, metformin or N, N' -dimethylethylenediamine (DMEDA); the inert gas comprises one of helium, neon or argon; the molar ratio of the 6-chloro-7-fluoroindole to the 4-iodo-1-propyl-1H-pyrazole, the ligand, the CuI and the alkali is 1: (1.0-1.4): (0.1-0.6): (0.01-0.15): (1.0 to 3.5); the reaction is specifically carried out at 90-110 ℃ for 8-16 h.
8. A process for preparing cudestoxestat according to claim 1, wherein the organic solvent in step (5) comprises one of 1, 4-dioxane, toluene, tetrahydrofuran, DMF or dichloromethane; the inert gas comprises one of helium, neon or argon; the chlorinating agent comprises one of phosphorus oxychloride, oxalyl chloride, thionyl chloride or N-chlorosuccinimide (NCS); the molar ratio of the 6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indole to the ethyl 2-fluoro-3-mercaptobenzoate to the chlorinating agent is 1: (0.8-1.2): (0.8-1.2); the reaction is carried out under the protection of inert gas, specifically, the reaction is carried out for 1.0 to 2.0 hours at the temperature of 18 to 37 ℃; the reaction is carried out to obtain 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester, which is concretely carried out for 12 to 20 hours at normal temperature.
9. A process for preparing cudexesat according to claim 1, wherein said chlorinating agent in step (6) comprises one of phosphorus oxychloride, oxalyl chloride, thionyl chloride or N-chlorosuccinimide (NCS); the organic solvent comprises one of 1, 4-dioxane, toluene, tetrahydrofuran, DMF or dichloromethane; the inert gas comprises one of helium, neon or argon; the molar ratio of 3- ((6-chloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester (compound F) to the chlorinating agent is 1: (1.2-5.0); the reaction is carried out under the protection of inert gas, specifically, the reaction is carried out for 12-20 h at the temperature of 18-37 ℃.
10. A process for preparing cudestoxestat according to claim 1, wherein the base in step (7) comprises one of sodium hydroxide or potassium hydroxide; the mixed solvent comprises a mixed solvent composed of ethanol and water or a mixed solvent composed of ethanol, water and tetrahydrofuran; the mass volume ratio of the mixed solvent to the 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester is 1: (3.0 to 20.0); the volume ratio of water, ethanol and tetrahydrofuran in the mixed solvent is 1: (0.5-1.5): (1.0 to 3.0); the molar ratio of 3- ((2, 6-dichloro-7-fluoro-1- (1-propyl-1H-pyrazol-4-yl) -1H-indol-3-yl) thio) -2-fluorobenzoic acid ethyl ester to base is 1: (4.0 to 9.0); the reaction is carried out to obtain the compound Cudestoxestat, and the reaction is concretely carried out for 0.5-1.5 h at the temperature of 18-37 ℃.
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