CN114539123A - Method for synthesizing TMC-205 in one step - Google Patents
Method for synthesizing TMC-205 in one step Download PDFInfo
- Publication number
- CN114539123A CN114539123A CN202210185347.2A CN202210185347A CN114539123A CN 114539123 A CN114539123 A CN 114539123A CN 202210185347 A CN202210185347 A CN 202210185347A CN 114539123 A CN114539123 A CN 114539123A
- Authority
- CN
- China
- Prior art keywords
- tmc
- reaction
- tri
- palladium
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- DGRQZYNJXNNHBY-ONEGZZNKSA-N CC(=C)\C=C\C1=CC=C2C(C(O)=O)=CNC2=C1 Chemical compound CC(=C)\C=C\C1=CC=C2C(C(O)=O)=CNC2=C1 DGRQZYNJXNNHBY-ONEGZZNKSA-N 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 32
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 18
- HNVRRHSXBLFLIG-UHFFFAOYSA-N 3-hydroxy-3-methylbut-1-ene Chemical compound CC(C)(O)C=C HNVRRHSXBLFLIG-UHFFFAOYSA-N 0.000 claims abstract description 15
- INNZWYJJSSRJET-UHFFFAOYSA-N 6-bromo-1h-indole-3-carboxylic acid Chemical compound BrC1=CC=C2C(C(=O)O)=CNC2=C1 INNZWYJJSSRJET-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims abstract description 10
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims abstract description 10
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims abstract description 10
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 239000003208 petroleum Substances 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 5
- 239000012267 brine Substances 0.000 claims abstract description 5
- 239000003480 eluent Substances 0.000 claims abstract description 5
- 239000000706 filtrate Substances 0.000 claims abstract description 5
- 238000003818 flash chromatography Methods 0.000 claims abstract description 5
- 238000003760 magnetic stirring Methods 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 239000012044 organic layer Substances 0.000 claims abstract description 5
- 239000011541 reaction mixture Substances 0.000 claims abstract description 5
- 239000000741 silica gel Substances 0.000 claims abstract description 5
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000007789 sealing Methods 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- -1 tris (N-nitroso-N-phenylhydroxylamine) aluminum Chemical compound 0.000 claims description 9
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 8
- 238000007341 Heck reaction Methods 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 3
- OPLCSTZDXXUYDU-UHFFFAOYSA-N 2,4-dimethyl-6-tert-butylphenol Chemical compound CC1=CC(C)=C(O)C(C(C)(C)C)=C1 OPLCSTZDXXUYDU-UHFFFAOYSA-N 0.000 claims description 3
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims description 3
- XESZUVZBAMCAEJ-UHFFFAOYSA-N 4-tert-butylcatechol Chemical compound CC(C)(C)C1=CC=C(O)C(O)=C1 XESZUVZBAMCAEJ-UHFFFAOYSA-N 0.000 claims description 3
- ZRNVROHUPINDBA-UHFFFAOYSA-N CC(C)(CC(CC1(C)C)=O)N1OP(ON(C(C)(C)C1)C(C)(C)CC1=O)ON(C(C)(C)C1)C(C)(C)CC1=O Chemical compound CC(C)(CC(CC1(C)C)=O)N1OP(ON(C(C)(C)C1)C(C)(C)CC1=O)ON(C(C)(C)C1)C(C)(C)CC1=O ZRNVROHUPINDBA-UHFFFAOYSA-N 0.000 claims description 3
- 229920001174 Diethylhydroxylamine Polymers 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 3
- 229950000688 phenothiazine Drugs 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 150000003254 radicals Chemical class 0.000 claims description 3
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000007547 defect Effects 0.000 description 7
- 238000009776 industrial production Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 4
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical group CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 3
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- 238000006619 Stille reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- UBQHFXIRIDEKAL-UHFFFAOYSA-N 3-methylbut-3-enoxyboronic acid Chemical compound CC(=C)CCOB(O)O UBQHFXIRIDEKAL-UHFFFAOYSA-N 0.000 description 1
- WCCLQCBKBPTODV-UHFFFAOYSA-N 6-bromo-1h-indole-3-carbaldehyde Chemical compound BrC1=CC=C2C(C=O)=CNC2=C1 WCCLQCBKBPTODV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- OSXALYMWITVNTI-UHFFFAOYSA-N diazomethane trimethylsilane Chemical compound C=[N+]=[N-].C[SiH](C)C OSXALYMWITVNTI-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention belongs to the technical field of chemical synthesis, and discloses a method for synthesizing TMC-205 in one step, which comprises the following steps: sequentially adding 6-bromoindole-3-formic acid, palladium acetate, tri (o-methylphenyl) phosphorus, 2, 6-di-tert-butyl-4-methylphenol, N-dimethylformamide, tri-N-propylamine and 1, 1-dimethylallyl alcohol into a sealed tube under the protection of nitrogen by magnetic stirring; sealing the sealed tube, placing the sealed tube in an oil bath for reaction, cooling the reaction mixture to room temperature, filtering a reaction crude product through a silica gel short column, and washing the reaction crude product with ethyl acetate; the filtrate was diluted with ethyl acetate and washed with water and brine; the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture was purified by flash column chromatography as eluent petroleum ether, ethyl acetate to obtain the title compound. The method has the advantages of simple synthesis process, simple and convenient operation, easily obtained synthesis raw materials, lower preparation cost and improvement of the total yield of the reaction and the atom economy of the reaction.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing TMC-205 in one step.
Background
In 2001, TMC-205 was isolated from a secondary metabolite of an unidentified fungal strain TC 1630 by the Japanese scientist Masaaki Sakurai et al, and biological activity tests showed that TMC-205 showed antiproliferative activity against various human cancer cell lines and also activated the SV40 promoter. The Kazunori Koide project group completed the full synthetic work of TMC-205 for the first time in 2014. The synthetic route is shown in FIG. 3.
In the synthetic route, the Kazunori Koide subject group takes 6-bromoindole as an initial raw material, and introduces trifluoroacetyl group into 3-position of an indole ring through Friedel-Crafts acylation with trifluoroacetic anhydride to obtain a compound 2; then, hydrolyzing by using sodium hydroxide, neutralizing by using hydrochloric acid, and converting trifluoroacetyl group at the 3-position into carboxyl to obtain a compound 3; followed by the use of (trimethylsilane) diazomethane TMSCHN2Reacting with carboxyl to generate carboxylic ester to obtain a compound 4; under the action of a zero-valent palladium complex and alkali, 6-bromoindole-3 carboxylate and prenyl borate are subjected to Suzuki-Miyaura coupling reaction to introduce an isoprene group at the 6-position of an indole ring to obtain a compound 5; finally obtaining TMC-205 under the actions of sodium hydroxide hydrolysis and potassium bisulfate neutralization. (five reactions, total yield 64%). This method requires the independent preparation of the isoprene moiety and involves multiple steps to finally construct the 3-carboxy group (see FIG. 4).
The initial idea in the Kazunoni Koide group was to introduce trifluoroacetyl group at the 3-position of the indole ring by Friedel-Crafts acylation with 6-bromoindole as starting material and trifluoroacetic anhydride; the second step was hydrolysis with sodium hydroxide, neutralization with hydrochloric acid followed by conversion of the trifluoroacetyl group in position 3 to a carboxyl group, followed by Suzuki-Miyaura coupling of the carboxylic acid substrate with isopentenyl borate to give the desired product, but without success (see figure 5).
After the failure of scheme 2, the Kazunori Koide project group tried to synthesize the target product by Stille coupling of carboxylic acid substrate and isopentenyl organotin compound, but the yield was only 10%. In view of these three routes, only the first route (longest route) was successful, but this method requires the independent preparation of the isoprene moiety and involves multiple steps to finally construct the 3-carboxyl group.
The three synthetic routes are performed by acylation with Friedel-Crafts, esterification (using TMSCHN)2) And the Suzuki-Miyaura coupling as key step, TMC-205 was obtained in 64% overall yield by a 5-step reaction (see FIG. 6). In addition, the first route has inherent limitations such as demanding reaction conditions (strong acid, strong base, etc.) and being expensive and havingToxic reagent (Pd (PPh)3)4，Cs2CO3Etc.). Therefore, previous synthetic methods are complex and not versatile for other similar substrates. In order to better test the biological activity, a simple and efficient synthetic route needs to be developed urgently.
Through the above analysis, the problems and defects of the prior art are as follows: the existing route requires harsh reaction conditions and expensive and toxic reagents (Pd (PPh)3)4，Cs2CO3Etc.), the steps are complicated, the overall yield is low, the atom economy is not good, and the drawbacks of the Pinnick-oxidation reaction in industrial production.
The difficulty in solving the above problems and defects is:
1. how high yields the Heck reaction takes place in the presence of acidic groups.
2. How to complete the coupling and elimination of the Heck reaction in one step in a green, economic and efficient way.
The significance of solving the problems and the defects is as follows:
realizes the reaction without the base in a protective group state in the presence of an acid group.
Avoids the use of toxic reagents and the defects of the Pinnick-oxidation reaction in industrial production, and realizes green, economic and efficient reaction in synthesis.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for synthesizing TMC-205 in one step.
The invention is realized by the method for synthesizing TMC-205 in one step, and the method for synthesizing TMC-205 in one step is characterized in that 6-bromoindole-3-formic acid 5 and 2-methyl-3-butylene-2-alcohol 2 are subjected to Heck reaction in the presence of a palladium catalyst, and the tertiary hydroxyl is removed to obtain TMC-205 with the yield of 75%.
Further, the synthetic route of the TMC-205 is as follows:
further, the method for synthesizing TMC-205 in one step comprises the following steps:
step one, sequentially adding 6-bromoindole-3-formic acid, palladium acetate, tri (o-methylphenyl) phosphorus, 2, 6-di-tert-butyl-4-methylphenol, N-dimethylformamide, tri-N-propylamine and 1, 1-dimethylallyl alcohol into a sealed tube under the protection of nitrogen gas and magnetic stirring;
sealing the sealed tube, placing the sealed tube in an oil bath for reaction, cooling the reaction mixture to room temperature, filtering a reaction crude product through a silica gel short column, and washing the reaction crude product with ethyl acetate;
step three, diluting the filtrate with ethyl acetate and washing with water and brine;
step four, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture was purified by flash column chromatography to obtain the title compound as eluent petroleum ether, ethyl acetate.
Further, in the first step, 0.208mmol of 6-bromoindole-3-carboxylic acid, 0.0208mmol of palladium acetate, 0.052mmol of tris (o-methylphenyl) phosphorus, 0.0208mmol of 2, 6-di-tert-butyl-4-methylphenol, 1.1mL of N, N-dimethylformamide, 0.166mmol of tri-N-propylamine, and 0.936mmol of 1, 1-dimethylallyl alcohol are used.
Further, the solvent in the first step can be replaced by any one of N, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, toluene, benzene, 1, 2-dichloroethane, chlorobenzene, acetonitrile or N-methylpyrrolidone.
The palladium acetate catalyst can be replaced by any one of palladium chloride, palladium tetratriphenylphosphine, tris (dibenzylideneacetone) dipalladium-chloroform adduct, tris (dibenzylideneacetone) dipalladium, palladium carbon, palladium tetratriphenylphosphine chloride, palladium trifluoroacetate or palladium chloride.
The tri (o-methylphenyl) phosphorus can be replaced by any one of triphenylphosphine, trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine fluoborate, tri-n-butylphosphine, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, bis (2-diphenylphosphine phenyl) ether or tris (2-furyl) phosphine or no phosphorus ligand is added.
The acid-binding agent tri-N-propylamine can be replaced by any one of triethylamine, N-diisopropylethylamine, tri-N-octylamine, 1, 8-diazabicycloundecene-7-ene, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylene diamine, potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, sodium phosphate or calcium phosphate or no alkali is added.
The polymerization inhibitor 2, 6-di-tert-butyl-4-methylphenol can be replaced by any one of 2, 4-dimethyl-6-tert-butylphenol, p-tert-butylcatechol, N-diethylhydroxylamine, phenothiazine, tris (N-nitroso-N-phenylhydroxylamine) aluminum, 4-hydroxy-2, 2,6, 6-tetramethylpiperidinyloxy free radical, 4-carbonyl-2, 2,6, 6-tetramethylpiperidinyloxy free radical, tris (4-oxo-2, 2,6, 6-tetramethylpiperidinyloxy) phosphine or 1, 1-diphenyl-2-picrylhydrazino free radical.
Further, the temperature of the oil bath in the second step is 115 ℃, and the reaction time of the oil bath is 6 hours.
Further, the ethyl acetate in the third step was 10 mL.
Further, the volume ratio of the petroleum ether to the ethyl acetate in the fourth step is 2: 1.
Further, the target compound in the fourth step is 35.45mg, and the yield is 75%.
Further, the experimental temperature of the method for synthesizing TMC-205 is between 95 and 125 ℃.
By combining all the technical schemes, the invention has the advantages and positive effects that: the method for synthesizing TMC-205 in one step has the advantages of simple synthesis process, simple and convenient operation, easily obtained synthesis raw materials, lower preparation cost, high yield and good atom economy, improves the total yield of the reaction and the atom economy of the reaction, and simultaneously avoids the defects of the Pinnick-oxidation reaction in industrial production.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments of the present invention will be briefly described below, and it is obvious that the drawings described below are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a flowchart of a method for synthesizing TMC-205 in one step according to an embodiment of the present invention.
Fig. 2 is a synthesis route diagram of TMC-205 provided in the embodiment of the present invention.
FIG. 3 is a schematic diagram of the scheme 1 of the synthesis of TMC-205 by Kazunori Koide according to the present invention.
FIG. 4 is a schematic diagram of the scheme 2 of the synthesis of TMC-205 by Kazunori Koide provided by the present invention.
FIG. 5 is a schematic diagram of the scheme 3 for synthesizing TMC-205 of Kazunori Koide provided by the embodiment of the present invention.
FIG. 6 is a schematic diagram of the synthetic route 4 of TMC-205 of Kazunori Koide according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Aiming at the problems in the prior art, the invention provides a method for synthesizing TMC-205 in one step, and the invention is described in detail below with reference to the accompanying drawings.
As shown in fig. 1, the method for synthesizing TMC-205 in one step provided by the embodiment of the present invention includes the following steps:
s101, sequentially adding 6-bromoindole-3-formic acid, palladium acetate, tri (o-methylphenyl) phosphorus, 2, 6-di-tert-butyl-4-methylphenol, N-dimethylformamide, tri-N-propylamine and 1, 1-dimethylallyl alcohol into a sealed tube under the protection of nitrogen through magnetic stirring;
s102, sealing the sealed tube, placing the sealed tube in an oil bath for reaction, cooling a reaction mixture to room temperature, filtering a reaction crude product through a silica gel short column, and washing the reaction crude product with ethyl acetate;
s103, diluting the filtrate with ethyl acetate and washing with water and brine;
s104, the combined organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture is purified by flash column chromatography as eluent petroleum ether, ethyl acetate to obtain the title compound.
The technical solution of the present invention is further described below with reference to specific examples.
According to the limitations of 3 synthetic routes of Kazunori Koide subject group, the subject group of the invention develops a synthetic route with lower preparation cost, high yield and good atom economy according to some problems in the previous research.
In the synthetic route, cheap 6-bromoindole-3-formaldehyde 1 and 2-methyl-3-butene-2-ol 2 are subjected to Heck reaction in the presence of a palladium catalyst, a tertiary hydroxyl group is removed to obtain a compound 3 with a yield of 94%, and the compound 3 is subjected to Pinnick-oxidation to oxidize a three-position aldehyde into a carboxyl group to obtain TMC-205 with a yield of 78%. The total yield of the whole synthesis step is 73.32% through 2 steps of reaction. This route avoids toxic reagents (Pd (PPh)3)4，Cs2CO3Etc.), a dangerous strong alkali reagent, a highly flammable reagent, etc., simple synthesis process, simple and convenient operation, easily available synthesis raw materials, etc., but has certain limitations, such as the generation of a by-product hypochlorous acid in the course of the Pinnick-oxidation reaction, and the reaction is not suitable for industrial mass production, etc., because the hypochlorous acid is sensitive to metals in the production process. Therefore, the synthetic route needs further optimization.
As shown in figure 2, the synthetic route of the invention takes 6-bromoindole-3-formic acid 5 and 2-methyl-3-butylene-2-ol 2 to perform Heck reaction in the presence of palladium catalyst and remove tertiary hydroxyl to obtain TMC-205 with 75% yield. The whole synthesis step only undergoes one-step reaction to obtain the target compound TMC-205. The former Kazunori Koide group also tried to synthesize the target product by Stille coupling of carboxylic acid substrate and isopentenyl organotin compound, but the yield was only 10%, while the present route also achieved Heck reaction without protecting group and removed tertiary hydroxyl group to obtain the target compound with high yield by starting from carboxylic acid substrate, and avoided some problems encountered in the former research on the route of the present group, such as the defects of Pinnick-oxidation reaction in industrial production. In addition, the method has the advantages of simple synthesis process, simple and convenient operation, easy obtainment of synthesis raw materials and the like.
The technical problems to be solved by the invention are as follows: 1. avoiding the Pinnick-oxidation reaction. 2. The total yield of the reaction is improved. 3. Improving the atom economy of the reaction.
The method for synthesizing TMC-205 in one step provided by the embodiment of the invention specifically comprises the following steps:
50 mg (0.208mmol) of 6-bromoindole-3-carboxylic acid (5), 4.67 mg (0.0208mmol) of palladium acetate, 15.8 mg (0.052mmol) of tris (o-methylphenyl) phosphorus, 4.6 mg (0.0208mmol) of 2, 6-di-tert-butyl-4-methylphenol, 1.1mL of N, N-dimethylformamide, 31. mu.L (0.166mmol) of tri-N-propylamine, and 97.8. mu.L (0.936mmol) of 1, 1-dimethylallyl alcohol were placed into a sealed tube under magnetic stirring and nitrogen atmosphere one after the other. The tube was then sealed and placed in an oil bath at 115 ℃ for about 6 hours, the reaction mixture was cooled to room temperature, and the crude reaction product was then filtered through a short column of silica gel and washed with 10mL of ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture was purified by flash column chromatography using petroleum ether, ethyl acetate (2: 1 by volume) as eluent to obtain 35.45mg of the title compound (75% yield).
yellow solid.1H NMR(400MHz,Acetone-d6)δ10.98(s,1H),8.19–7.96(m,2H),7.61(s,1H),7.44(dd,J＝8.4,1.4Hz,1H),7.00(d,J＝16.1Hz,1H),6.72(d,J＝16.1Hz,1H),5.16–5.01(m,2H),2.00–1.93(m,3H).13C NMR(101MHz,Acetone)δ382.72,319.58,314.57,310.10,309.60,307.34,306.95,303.50,298.36,297.33,293.32,287.67,285.19,206.84,206.64,206.45,206.26,206.07,205.87,205.68,195.19.
The existing routes have certain limitations, such as demanding reaction conditions (strong acid, strong base, etc.) and expensive and toxic reagents (Pd (PPh)3)4，Cs2CO3Etc.), the steps are complicated, the overall yield is low, the atom economy is not good, and the drawbacks of the Pinnick-oxidation reaction in industrial production.
The synthetic process of the route is simple, the operation is simple and convenient, the synthetic raw materials are easy to obtain, the preparation cost is low, the yield is high, the atom economy is good, and the defects of the Pinnick-oxidation reaction in industrial production are avoided.
The alternatives of the invention are as follows:
1. the solvent used in the steps of the invention can be replaced by N, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, toluene, benzene, 1, 2-dichloroethane, chlorobenzene, acetonitrile and N-methylpyrrolidone.
2. The palladium acetate catalyst used in the first step of the invention can be replaced by palladium chloride, tetratriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium-chloroform adduct, tris (dibenzylideneacetone) dipalladium, palladium carbon, tetratriphenylphosphine palladium chloride, palladium trifluoroacetate and palladium chloride.
3. The tri (o-methylphenyl) phosphorus used in the step of the invention can be replaced by triphenylphosphine, trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine fluoborate, tri-n-butylphosphine, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, bis (2-diphenylphosphinophenyl) ether, tris (2-furyl) phosphine or no phosphorus ligand.
4. The acid-binding agent tri-N-propylamine used in the step of the invention can be replaced by triethylamine, N-diisopropylethylamine, tri-N-octylamine, 1, 8-diazabicycloundecene-7-ene, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylenediamine, potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, sodium phosphate, calcium phosphate or no alkali is added.
5. The polymerization inhibitor 2, 6-di-tert-butyl-4-methylphenol used in the steps of the present invention may be replaced with 2, 4-dimethyl-6-tert-butylphenol, p-tert-butylcatechol, N-diethylhydroxylamine, phenothiazine, tris (N-nitroso-N-phenylhydroxylamine) aluminum, 4-hydroxy-2, 2,6, 6-tetramethylpiperidinyloxy free radical, 4-carbonyl-2, 2,6, 6-tetramethylpiperidinyloxy free radical, tris (4-oxo-2, 2,6, 6-tetramethylpiperidinyloxy) phosphine, 1-diphenyl-2-picrylhydrazino free radical.
6. The experimental temperature used in the steps of the invention is between 95 ℃ and 125 ℃.
The above description is only for the purpose of illustrating the present invention and the appended claims are not to be construed as limiting the scope of the invention, which is intended to cover all modifications, equivalents and improvements that are within the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A method for synthesizing TMC-205 in one step is characterized in that 6-bromoindole-3-formic acid 5 and 2-methyl-3-butylene-2-alcohol 2 are subjected to Heck reaction in the presence of a palladium catalyst, and the tertiary hydroxyl is removed to obtain TMC-205 with the yield of 75%.
2. The method for synthesizing TMC-205 in one step as described in claim 1, wherein the synthetic route of TMC-205 is:
3. a method for synthesizing TMC-205 in one step as described in claim 1, wherein the method for synthesizing TMC-205 in one step comprises the steps of:
step one, sequentially adding 6-bromoindole-3-formic acid, palladium acetate, tri (o-methylphenyl) phosphorus, 2, 6-di-tert-butyl-4-methylphenol, N-dimethylformamide, tri-N-propylamine and 1, 1-dimethylallyl alcohol into a sealed tube under the protection of nitrogen gas and magnetic stirring;
sealing the sealed tube, placing the sealed tube in an oil bath for reaction, cooling the reaction mixture to room temperature, filtering a reaction crude product through a silica gel short column, and washing the reaction crude product with ethyl acetate;
step three, diluting the filtrate with ethyl acetate and washing with water and brine;
step four, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture was purified by flash column chromatography as eluent petroleum ether, ethyl acetate to obtain the target compound.
4. The one-step synthesis of TMC-205 of claim 3, wherein in step one, 6-bromoindole-3-carboxylic acid is 0.208mmol, the palladium acetate is 0.0208mmol, the tris (o-methylphenyl) phosphorus is 0.052mmol, the 2, 6-di-tert-butyl-4-methylphenol is 0.0208mmol, the N, N-dimethylformamide is 1.1mL, the tri-N-propylamine is 0.166mmol, and the 1, 1-dimethylallyl alcohol is 0.936 mmol.
5. The one-step synthesis process of TMC-205 of claim 3, wherein the solvent in step one is replaced by any one of N, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, toluene, benzene, 1, 2-dichloroethane, chlorobenzene, acetonitrile or N-methylpyrrolidone;
the palladium acetate catalyst can be replaced by any one of palladium chloride, tetratriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium-chloroform adduct, tris (dibenzylideneacetone) dipalladium, palladium carbon, tetratriphenylphosphine palladium chloride, palladium trifluoroacetate or palladium chloride;
the tri (o-methylphenyl) phosphorus can be replaced by any one of triphenylphosphine, trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine fluoborate, tri-n-butylphosphine, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, bis (2-diphenylphosphine phenyl) ether or tris (2-furyl) phosphine or a phosphorus ligand is not added;
the acid-binding agent tri-N-propylamine can be replaced by any one of triethylamine, N-diisopropylethylamine, tri-N-octylamine, 1, 8-diazabicycloundecene-7-ene, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylene diamine, potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, sodium phosphate or calcium phosphate or no alkali is added;
the polymerization inhibitor 2, 6-di-tert-butyl-4-methylphenol can be replaced by any one of 2, 4-dimethyl-6-tert-butylphenol, p-tert-butylcatechol, N-diethylhydroxylamine, phenothiazine, tris (N-nitroso-N-phenylhydroxylamine) aluminum, 4-hydroxy-2, 2,6, 6-tetramethylpiperidinyloxy free radical, 4-carbonyl-2, 2,6, 6-tetramethylpiperidinyloxy free radical, tris (4-oxo-2, 2,6, 6-tetramethylpiperidinyloxy) phosphine or 1, 1-diphenyl-2-picrylhydrazino free radical.
6. The one-step process for the synthesis of TMC-205 of claim 3, wherein in step two the oil bath temperature is 115 ℃ and the oil bath reaction time is 6 h.
7. A method for the one-step synthesis of TMC-205 as claimed in claim 3, wherein the amount of ethyl acetate in step three is 10 mL.
8. The one-step synthesis method of TMC-205 of claim 3, wherein the volume ratio of petroleum ether to ethyl acetate in step four is 2: 1.
9. A one-step synthesis of TMC-205 according to claim 3, wherein the target compound in step four is 35.45mg with a yield of 75%.
10. A method for the one-step synthesis of TMC-205 as claimed in claim 3, wherein the experimental temperature of the method for the synthesis of TMC-205 is between 95 ℃ and 125 ℃.
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| CN114890932A (en) * | 2022-06-24 | 2022-08-12 | 大理大学 | First total synthesis process of indole alkaloid Luteoride A |
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| CN107935905A (en) * | 2017-11-28 | 2018-04-20 | 大理大学 | The synthetic method of Indiacens A |
| CN109867678A (en) * | 2019-04-08 | 2019-06-11 | 浙江工业大学 | A kind of preparation method of tetracyclic indole quinoline class compound |
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Cited By (3)
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| CN114890932A (en) * | 2022-06-24 | 2022-08-12 | 大理大学 | First total synthesis process of indole alkaloid Luteoride A |
| CN115477631A (en) * | 2022-10-09 | 2022-12-16 | 大理大学 | Synthesis method of compound containing dimethyl enol group |
| CN115477631B (en) * | 2022-10-09 | 2024-02-09 | 大理大学 | Synthesis method of compound containing dimethyl enol group |
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