CN116410145A - 一种mrtx849中间体的制备方法 - Google Patents
一种mrtx849中间体的制备方法 Download PDFInfo
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- CN116410145A CN116410145A CN202111646676.4A CN202111646676A CN116410145A CN 116410145 A CN116410145 A CN 116410145A CN 202111646676 A CN202111646676 A CN 202111646676A CN 116410145 A CN116410145 A CN 116410145A
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- acid
- chloride
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- PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 title claims abstract description 29
- 229940124988 adagrasib Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- -1 compound L-serine ester salt Chemical class 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 30
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 24
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 20
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 20
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000006239 protecting group Chemical group 0.000 claims abstract description 15
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 14
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 10
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims abstract description 10
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 10
- 238000006722 reduction reaction Methods 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000009833 condensation Methods 0.000 claims abstract description 8
- 230000005494 condensation Effects 0.000 claims abstract description 8
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-Serine Natural products OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 229960001153 serine Drugs 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims abstract description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 100
- 239000003054 catalyst Substances 0.000 claims description 34
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 29
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 12
- 238000006482 condensation reaction Methods 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 10
- 239000004471 Glycine Substances 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 9
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- 239000002585 base Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- 229940032330 sulfuric acid Drugs 0.000 claims description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical group CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 claims description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 5
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 5
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 5
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 239000004280 Sodium formate Substances 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 4
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000012351 deprotecting agent Substances 0.000 claims description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 4
- 229940071870 hydroiodic acid Drugs 0.000 claims description 4
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 4
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 4
- 235000019254 sodium formate Nutrition 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- 239000004111 Potassium silicate Substances 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 3
- COTHYYYVPUZALV-UHFFFAOYSA-N hydroxy(trimethyl)silane;potassium Chemical compound [K].C[Si](C)(C)O COTHYYYVPUZALV-UHFFFAOYSA-N 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- NNHHDJVEYQHLHG-UHFFFAOYSA-N potassium silicate Chemical compound [K+].[K+].[O-][Si]([O-])=O NNHHDJVEYQHLHG-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 3
- JYMVSZGJZRQOFY-UHFFFAOYSA-N (4-nitrobenzoyl) 4-nitrobenzoate Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)OC(=O)C1=CC=C([N+]([O-])=O)C=C1 JYMVSZGJZRQOFY-UHFFFAOYSA-N 0.000 claims description 2
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- JKAPWXKZLYJQJJ-UHFFFAOYSA-N 2,4-dichloro-6-methoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(Cl)=N1 JKAPWXKZLYJQJJ-UHFFFAOYSA-N 0.000 claims description 2
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 claims description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- VYZOFUACMOJPRL-UHFFFAOYSA-N 3-azidoprop-1-ene Chemical compound C=CCN=[N+]=[N-] VYZOFUACMOJPRL-UHFFFAOYSA-N 0.000 claims description 2
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 claims description 2
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 claims description 2
- YHEDXDJJPXGLDE-UHFFFAOYSA-N 7-azido-1-hydroxybenzotriazole Chemical compound ON1N=NC2=C1C(=CC=C2)N=[N+]=[N-] YHEDXDJJPXGLDE-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
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- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 claims description 2
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- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 2
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- WELVGBLTIYSHFZ-UHFFFAOYSA-N benzyl imidazole-1-carboxylate Chemical compound C1=CN=CN1C(=O)OCC1=CC=CC=C1 WELVGBLTIYSHFZ-UHFFFAOYSA-N 0.000 claims description 2
- FHRRJZZGSJXPRQ-UHFFFAOYSA-N benzyl phenylmethoxycarbonyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OC(=O)OCC1=CC=CC=C1 FHRRJZZGSJXPRQ-UHFFFAOYSA-N 0.000 claims description 2
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 2
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 claims description 2
- YBQCZIKWFFYEEM-UHFFFAOYSA-M benzyl(trimethyl)azanium;hydrogen sulfate Chemical compound OS([O-])(=O)=O.C[N+](C)(C)CC1=CC=CC=C1 YBQCZIKWFFYEEM-UHFFFAOYSA-M 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 2
- LRJRPHROCLHMHK-UHFFFAOYSA-N boron;n,n-dimethylmethanamine Chemical compound [B].CN(C)C LRJRPHROCLHMHK-UHFFFAOYSA-N 0.000 claims description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 2
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- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 claims description 2
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003277 amino group Chemical group 0.000 description 2
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种MRTX849中间体的制备方法。
背景技术
MRTX849(Adagrasib,中文名阿达格拉西布),化学名2-((S)-4-(7-(8-氯代萘-1-基)-2-(((S)-1-甲基吡咯啉-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈,是一种针对KRAS G12C突变体的特异性优化口服抑制剂,由美国上市公司Mirati Therapeutics Inc开发。
KRAS G12C是一种特定的KRAS亚突变,是第12个密码子的甘氨酸被半胱氨酸取代,约占所有KRAS突变的44%,其中非小细胞肺癌腺癌中最常见,占14%,其次是大肠腺癌占3~4%,胰腺癌占2%,全球每年超过100000人确诊为KRAS G12C突变。由于KRAS蛋白的自身特性导致其难以成药,既往KRAS G12C突变患者一旦化学疗法或者免疫疗法失败,完全不会有替代的靶向疗法,几乎没有预后可言。
MRTX849的化学式如下,其通过在非活性状态下与KRAS G12C不可逆转地选择性结合,阻止其发送细胞生长信号,恢复细胞的通讯***,让癌细胞自我毁灭,以达到***的效果。
MRTX849在多种KRAS G12C癌症动物模型中表现出跨膜效力,还是唯一一种半衰期约为24小时的KRAS G12C抑制剂,对KRAS G12C突变型的选择性比野生型KRAS和其他蛋白质的选择性高1000倍以上且临床前研究证实安全性和耐受性很高。临床研究显示MRTX849对KRAS G12C突变型非小细胞肺癌和结直肠癌的疾病控制率分别高达96%和94%。2021年6月24日,美国食品药品监督管理局(FDA)已授予Adagrasib突破性疗法认定,用于治疗先前接受过全身治疗的携带KRAS G12C突变的非小细胞肺癌(NSCLC)患者。
目前,已有多篇专利文献公开了关于MRTX849关键中间体式I的合成方法,专利WO2017/201161公开了3-烯丁腈为原料,经溴代后与N,N`-二苄基乙二胺环合,再用氯甲酸氯乙酯脱苄基成盐制得的合成路线。具体反应如方案1所示:
但是该路线起始原料和中间体N,N`-二苄基乙二胺价格昂贵,需要使用到高腐蚀性的溴素,中间体丁烯腈毒性大,路线总收率低于20%,且最终产物是消旋体,拆分损失太大。
另外,专利WO2017/201161公开了另一条以叔丁基-3-羟甲基哌嗪-1-碳酸酯为原料,经环合后得到亚磺酸内酯,氧化成磺酸内酯后被***取代,最后盐酸脱保护基成盐制得的合成路线。具体反应如方案2所示:
但是该路线起始原料价格昂贵且难以制得,需要使用到高腐蚀性的氯化亚砜和价格高昂的高碘酸钠和三氯化钌,***取代反应收率低于30%,路线总收率低。
再有,专利WO2017/201161还公开了另一条以叔丁基-3-羟甲基哌嗪-1-碳酸酯为原料,经氨基保护后,醇羟基缩合成磺酸酯后被***取代,最后盐酸脱保护基成盐制得的合成路线。具体反应如方案3所示:
该路线起始原料价格昂贵且难以制得,路线总收率高但是整体原子经济性不好,最后的保护基脱除不易,不利于工业化生产。
发明内容
针对以上技术问题,本发明的目的在于提供一种反应条件温和,反应无选择性问题、收率较高的MRTX849中间体的制备方法。
为了实现上述目的,本发明所采用的技术方案如下:
一种MRTX849中间体的制备方法,包括采用式II的化合物L-丝氨酸酯盐作为原料,
经缩合、脱保护、环合、还原、上保护基、缩合、取代和脱保护共8步反应,最终得到式I的MRTX849中间体,
其中,R为氢、苄氧羰基、叔丁氧羰基和烯丙氧羰基中的任意一种;X为0-3的自然数,HY为氯化氢、溴化氢、碘化氢、硫酸、甲磺酸、对甲苯磺酸、草酸和磷酸中的至少一种;Rt为甲基、乙基、丙基、异丙基和正丁基中的任意一种,HZ为氯化氢、溴化氢、碘化氢、硫酸、甲磺酸和对甲苯磺酸中的任意一种。
在一些技术方案中,具体包括:
S1、使用式II的化合物L-丝氨酸酯盐与氨基被保护的甘氨酸进行缩合反应,得式III的化合物:
S2、式III的化合物在催化剂作用下,进行脱保护反应得式Ⅳ的化合物:
S3、式Ⅳ的化合物在催化剂或碱的促进下,进行环合反应得式V的化合物:
S4、将式V的化合物进行还原反应,得到式Ⅵ的化合物:
S5、将式Ⅵ的化合物进行上保护反应,得到式Ⅶ的化合物:
其中,R为苄氧羰基、叔丁氧羰基和烯丙氧羰基中的任意一种;
S6、将式Ⅶ的化合物进行缩合反应,得到式Ⅷ的化合物:
其中,X为氯、溴、碘、硫酸酯基、磷酸酯基、甲磺酰氧基、对甲苯磺酰氧基、三氟甲磺酰氧基、全氟丁磺酰氧基和苯磺酰氧基中的任意一种;
S7、将式Ⅷ的化合物进行取代反应,得到式Ⅸ的化合物:
S8、将式Ⅸ的化合物进行脱保护反应,得到式I所示的MRTX849中间体。
本发明采用以上技术方案至少具有如下的有益效果:
1.本申请制备方法中原料性质稳定,便宜易得,成本低廉;
2.本申请中反应条件温和,操作简便,无选择性问题,收率较高,溶剂和试剂回收套用率高,三废少,环境污染小,经济效益好,适合工业化放大生产。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。实施例中所用到的各种常用试剂,均为市售产品。
本申请实施例中,NMR:所有的核磁谱图均由BrukerAV400 MHz核磁共振仪检测,TMS为内标;
MS:所有的质谱图均由LCMS 2020(Shimadzu)检测。
需要说明的是,以下实施例中的所述方法如无特别说明均为常规方法,原材料如无特别说明均能从公开商业途径获得。
本申请提出一种MRTX849中间体的制备方法,包括采用式II的化合物L-丝氨酸酯盐作为原料,经缩合、脱保护、环合、还原、上保护基、缩合、取代和脱保护共8步反应,最终得到式I的MRTX849中间体。
步骤S1的缩合反应中,使用式II的化合物L-丝氨酸酯盐与氨基被保护的甘氨酸在催化剂与碱性条件下与缩合剂进行缩合反应,其中,氨基被保护的甘氨酸为N-叔丁氧羰基甘氨酸(N-Boc-Gly-OH)、N-苄氧羰基甘氨酸(N-Cbz-Gly-OH)或烯丙氧羰基甘氨酸(N-Alloc-Gly-OH);其与式II化合物的摩尔比值为0.8-3:1。
步骤S1中的催化剂为1-羟基苯并***(HOBt)、3-羟基-1,2,3-苯并三氮嗪-4-酮(HOOBt)、1-羟基-7-叠氮苯并***(HOAt)、三乙烯二胺、4-二甲氨基吡啶(DMAP)、N-羟基丁二酰亚胺(HOSu)、N-羟基邻苯二甲酰亚胺、2-肟-氰乙酸甲酯、2-肟-氰乙酸乙酯、N-羟基吡啶-2-酮(HOPO)、吡啶、N-氧化吡啶、咪唑、N-甲基咪唑、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,1,3,3-四甲基胍(TMG)、叠氮化钠、五氟苯酚和苯硫酚中的至少一种;缩合剂为氯甲酸甲酯、氯甲酸乙酯、氯甲酸异丁酯、特戊酰氯、2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉(EEDQ)、2,4-二氯-6-甲氧基-1,3,5-三嗪、N,N`-二异丙基二亚胺(DIC)、N,N`-二环己基二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、四甲基氯代脲六氟磷酸酯(TCFH)、N,N'-羰基二咪唑(CDI)、甲磺酰氯(MsCl)、甲磺酸酐、对甲苯磺酰氯(TsCl)、1-正丙基磷酸酐(T3P)、六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBroP)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、三氟乙酸酐、二碳酸二叔丁酯、4-硝基苯甲酸酐、2,4,6-三氯苯甲酰氯、氯化亚砜、草酰氯、三氯氧磷、三氯化磷、三溴化磷和二苯基氯化膦中的任意一种;碱为三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉、N,N,N`,N`-四甲基乙二胺、吡啶、4-二甲氨基吡啶、三乙烯二胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]-5-壬烯、咪唑、N-甲基咪唑、碳酸氢钠、碳酸钠、碳酸钾、碳酸氢钾和碳酸铯中的一种。
步骤S2的脱保护反应中,式III的化合物在催化剂作用下,进行脱保护反应得式Ⅳ的化合物。所使用的脱保护剂为氯化氢、溴化氢、碘化氢、硫酸、甲磺酸、苯磺酸、对甲苯磺酸、甲酸、乙酸、三氟乙酸、三氟甲磺酸、三甲基硅基三氟甲磺酸酯、三甲基氯硅烷、三甲基溴硅烷、三甲基碘硅烷、磷酸、四正丁基氟化铵、四甲基氟化铵和四正丙基氟化铵中的任意一种。
步骤S2中,式III的化合物为叔丁氧羰基(Boc)保护型化合物时,其与脱保护剂的摩尔比值为0.5-50:1和/或脱保护反应温度为-20℃至130℃;式III的化合物为苄氧羰基(Cbz)保护型化合物时,其与脱保护剂的摩尔比值为0.01-3:1和/或脱保护反应温度为-20℃至80℃和/或所使用的催化剂为氢气、甲酸、甲酸钾、甲酸铵、甲酸钠、5%钯碳催化剂、10%钯碳催化剂、氢氧化钯碳催化剂、雷尼镍催化剂、氢溴酸、氢碘酸、浓硫酸、三氟甲磺酸、氢氧化钠和氢氧化钾中的任意一种;式III的化合物为烯丙氧羰基(Alloc)保护型化合物时,其与脱保护剂的摩尔比值为0.001-3:1和/或脱保护反应温度为-20℃至80℃和/或所使用的催化剂为四(三苯基膦)钯、三(三苯基膦)氢化铑、5%钯碳催化剂、10%钯碳催化剂、氢氧化钯碳催化剂、氢溴酸、氢碘酸、浓硫酸、三氟甲磺酸、氢氧化钠和氢氧化钾中的任意一种。
步骤S3的环合反应中,式Ⅳ的化合物在催化剂或碱的促进下,进行环合反应得式V的化合物,其中,碱的用量与式Ⅳ化合物的摩尔比值为:0.5-3:1;催化剂的用量与式Ⅳ化合物的摩尔比值为:0.1-2:1;环合反应温度为-20℃至80℃。
步骤S3中,碱为三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉、N-乙基吗啉、N,N,N`,N`-四甲基乙二胺、吡啶、三乙烯二胺、4-二甲氨基吡啶、咪唑、N-甲基咪唑、碳酸锂、碳酸氢钠、碳酸钠、碳酸钾、碳酸氢钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、三甲基硅醇钾和硅酸钾中的任意一种;催化剂为甲醇钠、甲醇钾、乙醇钠、甲醇镁、乙醇镁、叔丁醇钠、叔丁醇钾、叔戊醇钠和叔戊醇钾中的任意一种。
步骤S4的还原反应中,将式V的化合物进行还原反应,得到式Ⅵ的化合物,还原剂的用量与式V化合物的摩尔比值为1-8:1;还原反应温度为-20℃至80℃。
步骤S4中,还原剂为氢气、硼氢化钠、氰基硼氢化钠、氢化铝锂、硼烷-四氢呋喃络合物、硼烷-三甲胺络合物、硼烷-二甲硫醚络合物、二异丁基氢化铝、红铝、三乙基硅烷、三氯硅烷、金属锌、金属镁、金属钙和金属锂中的一种。
步骤S5的上保护基反应中,将式Ⅵ的化合物在碱性条件下进行上保护反应,得到式Ⅶ的化合物,保护试剂的用量与式Ⅵ化合物的摩尔比值为1-15:1;上保护反应温度为-20℃至80℃。
步骤S5中,保护基类型为叔丁氧羰基(Boc)时所用的保护试剂为二碳酸二叔丁酯、叠氮甲酸叔丁酯或氯甲酸叔丁酯;保护基类型为苄氧羰基(Cbz)时所用的保护试剂为氯甲酸苄酯、叠氮甲酸苄酯、N-苄氧羰氧基丁二酰亚胺、二碳酸二苄酯、苄氧羰基酚酯和N-苄氧羰基咪唑中的一种;保护基类型为烯丙氧羰基(Alloc)时所用的保护试剂为氯甲酸烯丙醇酯、叠氮甲酸烯丙醇酯、N-烯丙氧羰氧基丁二酰亚胺、二碳酸二烯丙醇酯、烯丙氧羰基酚酯和N-烯丙氧羰基咪唑中的一种;催化剂为四正丁基氟化铵、四正丁基氯化铵、四正丁基溴化铵、四正丁基硫酸氢铵、苄基三甲基氯化铵、苄基三甲基溴化铵、苄基三甲基硫酸氢铵、吡啶、4-二甲氨基吡啶、咪唑、N-甲基咪唑、三乙烯二胺和五氟苯酚中的任意一种;碱为三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉、N-乙基吗啉、N,N,N`,N`-四甲基乙二胺、吡啶、三乙烯二胺、4-二甲氨基吡啶、咪唑、N-甲基咪唑、N-乙基咪唑、碳酸锂、碳酸氢钠、碳酸钠、碳酸钾、碳酸氢钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、三甲基硅醇钾和硅酸钾中的中的一种。
步骤S6的缩合反应中,将式Ⅶ的化合物在碱性条件下进行缩合反应,得到式Ⅷ的化合物,其中,缩合剂的用量与式Ⅶ化合物的摩尔比值为1-15:1;碱的用量与式Ⅶ化合物的摩尔比值为0.5-30:1;缩合反应温度为-20℃至80℃。
步骤S6中,当式Ⅷ的化合物中X是氯时所用的缩合剂为氯化亚砜、三氯化磷、三氯氧磷、对甲苯磺酰氯、甲磺酰氯、三氟甲磺酰氯、氯化锂、氯化钠、氯化钾、三甲基氯硅烷、三苯基膦二氯化物、N-氯代丁二酰亚胺、四正丁基氯化铵和草酰氯中的任一种或几种的组合;当式Ⅷ的化合物中X是溴时所用的缩合剂为溴化亚砜、对甲苯磺酰氯、甲磺酰氯、三氟甲磺酰氯、红磷、三溴化磷、三溴氧磷、甲磺酰溴、三氟甲磺酰溴、溴化锂、溴化钠、溴化钾、三甲基溴硅烷、三苯基膦二溴化物、N-溴代丁二酰亚胺、四正丁基溴化铵、和草酰溴中的任一种或几种的组合;当式Ⅷ的化合物中X是碘时所用的缩合剂为甲磺酰氯、三氟甲磺酰氯、碘化锂、碘化钠、碘化钾、三甲基碘硅烷、碘单质、三苯基膦二碘化物、N-碘代丁二酰亚胺、四正丁基碘铵、四正丁基碘化铵、和红磷中的任一种或几种的组合;当式Ⅷ的化合物中X是硫酸酯基时所用的缩合剂为硫酸氢钠、硫酸氢钾、四正丁基硫酸氢铵、氯磺酸、三氧化硫吡啶络合物、三氧化硫三乙胺络合物、三氧化硫和二氧化硫中的任一种或几种的组合;当式Ⅷ的化合物中X是磷酸酯基时所用的缩合剂为五氧化二磷、多聚磷酸、三氯氧磷和三溴氧磷中的任一种或几种的组合;当式Ⅷ的化合物中X是甲磺酰氧基时所用的缩合剂为甲磺酸、三苯基膦、甲磺酰氯、甲磺酰溴和甲磺酸酐中的任一种或几种的组合;当式Ⅷ的化合物中X是苯磺酰氧基时所用的缩合剂为苯磺酸、三苯基膦、苯磺酰氯、苯磺酰溴和苯磺酸酐中的任一种或几种的组合;当式Ⅷ的化合物中X是对甲苯磺酰氧基时所用的缩合剂为对甲苯磺酸、三苯基膦、对甲苯磺酰氯、对甲苯磺酰溴和对甲苯磺酸酐中的任一种或几种的组合;当式Ⅷ的化合物中X是三氟甲磺酰氧基时所用的缩合剂为三氟甲磺酸、三氟甲磺酰氯、三氟甲磺酸酐和三苯基膦中的任一种或几种的组合;当式Ⅷ的化合物中X是全氟丁磺酰氧基时所用的缩合剂为全氟丁磺酰氯和全氟丁磺酸酐中的任一种。
步骤S7的取代反应中,将式Ⅷ的化合物在碱性条件下进行取代反应,得到式Ⅸ的化合物,取代试剂的用量与式Ⅷ化合物的摩尔比值为0.1-15:1;碱的用量与式Ⅷ化合物的摩尔比值为0.5-30:1;取代反应温度为-20℃至80℃;取代试剂为***、***、氰化锌、氰化亚铜、三甲基氰硅烷、四正丁基氰化铵、碘化钾、碘化钠、溴化钾、溴化钠和丙酮氰醇中的至少一种。
步骤S8的脱保护反应中,脱保护试剂的用量与式Ⅸ化合物的摩尔比值为0.1-500:1;脱保护反应温度为-20℃至120℃。
步骤S8中,脱保护试剂为三氯化铝、三氯化硼、三溴化硼、钯碳催化剂、氢氧化钯催化剂、甲酸钠,甲酸铵、氯甲酸甲酯、氯甲酸乙酯、氯甲酸-1-氯乙酯、氯化氢、溴化氢、碘化氢、硫酸、甲磺酸、苯磺酸、对甲苯磺酸、甲酸、乙酸、三氟乙酸、三氟甲磺酸、氯化锂、氯化镁、氯化锌、三甲基硅基三氟甲磺酸酯、三甲基氯硅烷、三甲基溴硅烷、三甲基碘硅烷、硝酸、磷酸、氢氧化钠、氢氧化钾、四正丁基氟化铵和四甲基氟化铵中的任意一种。
为了充分理解上述方案并明确其应用价值,本申请还给出了如下的具体示例。
步骤S1:(S)-2-(2-((叔丁氧羰基)氨基)乙酰胺基)-3-羟基丙酸甲酯(III)的制备。
室温下,向500mL三口瓶中,加入无水乙醇250mL、式Ⅱ的化合物丝氨酸甲酯盐酸盐(5.0g,32.2mmol,1.0eq.)、N-叔丁氧羰基甘氨酸(6.18g,35.3mmol,1.1eq.)、1-羟基苯并***(0.217g,1.61mmol,0.05eq.)和N-甲基吗啉(16.3g,161mmol,5.0eq.),搅拌溶清后降温到0~5℃,在0~5℃条件下搅拌0.5hr后,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(6.77g,35.3mmol,1.1eq.),加毕,自然升至室温搅拌反应18hrs。
液质联用色谱LCMS中控,反应结束。在搅拌条件下,将反应液慢慢倒入200mL质量分数3%的盐酸中,用二氯甲烷和甲醇为15比1的混合液(300mL*3次)萃取,合并有机相,用水(100mL*3)洗涤,无水硫酸钠干燥,抽滤,浓缩溶剂得式III的化合物。
产量:8.43g,收率:95%。
LCMS:ESI m/z 277[M+H]+
步骤S2:(S)-2-(2-氨基乙酰胺基)-3-羟基丙酸甲酯(Ⅳ)的制备。
室温下,向100mL三口瓶中,加入二氯甲烷(50mL)、式III的化合物(S)-2-(2-((叔丁氧羰基)氨基)乙酰胺基)-3-羟基丙酸甲酯(4.2g,15.2mmol),搅拌溶清后冷却至0℃。然后0~5℃条件下,滴加三氟乙酸(3.59g,152mmol,10.0eq.),滴毕自然升至室温反应18hrs.。
液质联用色谱LCMS中控,原料反应结束。旋干溶剂,剩余物加入水20mL,用固体碳酸钠调节至pH=8,用二氯甲烷和甲醇为15比1的混合液(70mL*3次)萃取,合并有机相,用饱和食盐水(10mL*2)洗涤,无水硫酸钠干燥,抽滤,旋干得式Ⅳ的化合物。
产量:2.4g,收率:88%。
LCMS:ESI m/z 177[M+H]+
步骤S3:(S)-3-羟甲基-2,5-哌嗪二酮(V)的制备。
室温下,向100mL单口瓶中,加入四氢呋喃(20mL)、式Ⅳ的化合物(S)-2-(2-氨基乙酰胺基)-3-羟基丙酸甲酯(1.2g,6.7mmol),搅拌溶清后,室温滴加1,8-二氮杂双环[5.4.0]十一碳-7-烯(1.52g,10mmol,1.5eq.),滴毕室温反应18hrs。
液质联用色谱LCMS中控,原料反应结束。过滤,滤饼用四氢呋喃(5mL)淋洗,烘干得到式V的化合物。
产量:0.92g,收率:96%。
1H NMR(400MHz,DMSO)δ7.97(s,2H),5.13(t,J=5.3Hz,1H),3.79(d,J=17.2Hz,1H),3.74(ddd,J=10.7,5.5,3.2Hz,1H),3.66(d,J=2.8Hz,1H),3.56(dd,J=17.4,3.1Hz,1H),3.54–3.48(m,1H)。
步骤S4:(R)-哌嗪-2-甲醇(Ⅵ)的制备。
在氮气保护下向50mL三口瓶中加入四氢呋喃(5mL)、式V的化合物(S)-3-羟甲基-2,5-哌嗪二酮(0.46g,3.29mmol,1.0eq.)和硼氢化钠(0.75g,17.94mmol,6.0eq.),搅拌下冷却至10℃,滴加质量浓度47%的三氟化硼***溶液(4.2mL,33mmol,10eq.),滴毕升温到70℃反应24hrs。
液质联用色谱LCMS和薄板层析TLC中控,原料反应结束。反应液降温到0~5℃,滴加10mL甲醇到反应液中,搅拌1hr.后浓缩溶剂得粘稠状粗品,加入15%盐酸(10mL)和甲醇(30mL),氮气保护下加热到90℃,保温搅拌2hrs。反应液降温到室温,浓缩溶剂到固体析出后,加入四氢呋喃(1mL)和三乙胺(0.2mL),过滤,滤液浓缩得式Ⅵ的化合物。
产量:0.35g,收率:92%。
LCMS:ESI m/z 117[M+H]++
步骤S5:二苄基(R)-2-(羟甲基)哌嗪-1,4-二甲酸酯(Ⅶ)的制备。
向50mL单口瓶中加入式Ⅵ的化合物(R)-哌嗪-2-甲醇(0.35g,3.0mmol,1.0eq.)和二氯甲烷(5mL),搅拌下滴加三乙胺(0.61g,6mmol,2.0eq.)和氯甲酸苄酯(1.53g,9.0mmol,2.0eq.),滴毕室温反应18hrs。
液质联用色谱LCMS和薄板层析TLC中控,原料反应结束。反应液浓缩溶剂后加入四氢呋喃(3mL),过滤,浓缩溶剂得式Ⅶ的化合物。
产量:1.15g,收率:99%。
1H NMR(400MHz,DMSO)δ7.40–7.28(m,10H),5.13–5.04(m,4H),4.90–4.83(m,1H),4.10–3.99(m,2H),3.93–3.77(m,2H),3.49–3.35(m,2H),3.13–2.99(m,2H),2.98–2.80(m,1H)。
LCMS:ESI m/z 385[M+H]+
步骤S6:二苄基(R)-2-((甲磺酰)氧基)甲基)哌嗪-1,4-二甲酸酯(Ⅷ)的制备。
在氮气保护下向50mL三口瓶中加入二氯乙烷(10mL)、式Ⅶ的化合物二苄基(R)-2-(羟甲基)哌嗪-1,4-二甲酸酯(1.15g,3.0mmol),搅拌下冷却至5℃,滴加三乙胺(0.9g,9mmol,3.0eq.),滴毕在5℃搅拌1.0hr.后,滴加甲基磺酰氯(0.38g,3.3mmol,1.1eq.),滴毕升温至室温搅拌2.0hr。
液质联用色谱LCMS和薄板层析TLC中控,原料反应结束。向反应液中加入水(10mL),混合液用二氯乙烷(30mL*3次)萃取,合并有机相,用3%盐酸(10mL)和饱和食盐水(10mL*2)洗涤,无水硫酸钠干燥,抽滤,旋干得式Ⅷ的化合物。
产量:1.38g,收率:99%。
1H NMR(400MHz,CDCl3)δ7.35–7.22(m,10H),5.16–5.01(m,4H),4.53–4.34(m,1H),4.25–4.06(m,3H),4.06–3.82(m,2H),3.15–3.97(m,2H),2.96–2.86(m,1H),2.85–2.60(m,3H)。
LCMS:ESI m/z 463[M+H]+
步骤S7:二苄基(S)-2-(氰甲基)哌嗪-1,4-二甲酸酯(Ⅸ)的制备。
在氮气保护下向50mL三口瓶中加入二甲亚砜(10mL)、式Ⅷ的化合物二苄基(R)-2-((甲磺酰)氧基)甲基)哌嗪-1,4-二甲酸酯(1.38g,2.99mmol),搅拌溶清后,加入***(0.59g,12mmol,4.0eq.),反应液升温到85℃,保温搅拌反应24hrs。
液质联用色谱LCMS和薄板层析TLC中控,原料反应结束。向反应液中加入质量分数为30%的盐水(50mL),混合液用二氯甲烷(30mL*3次)萃取,合并有机相,用质量分数25%食盐水(10mL*5)洗涤,无水硫酸钠干燥,抽滤,旋干溶剂得式Ⅸ的化合物。
产量:1.01g,收率:85%。
1H NMR(400MHz,CDCl3)δ7.43–7.30(m,10H),5.21–5.11(m,4H),4.65–4.50(m,1H),4.19–3.93(m,3H),3.25–3.14(m,1H),3.13–3.13(m,1H),3.01–2.86(m,1H),2.67–2.50(m,2H)。
LCMS:ESI m/z 394[M+H]+
步骤S8:(S)-2-(哌嗪-2-基|)-乙腈(双盐酸盐型)(I)的制备。
在氮气保护下向50mL三口瓶中加入四氢呋喃(10mL)、式Ⅸ的化合物二苄基(S)-2-(氰甲基)哌嗪-1,4-二甲酸酯(Ⅸ)(1.01g,2.55mmol),搅拌溶清后,加入10%钯碳催化剂(0.5g),反应体系用氢气置换3次后在室温下搅拌24hrs。
液质联用色谱LCMS和薄板层析TLC中控,原料反应结束。反应液过滤,室温滴加质量分数6%的盐酸二氧六环溶液(10mL),过滤,滤饼用正庚烷(10mL)洗涤,烘干得式I的化合物(双盐酸盐型)。
产量:0.49g,收率:98%。
1H NMR(400MHz,DMSO)δ9.83(br,4H),3.90–3.81(m,1H),3.56–3.41(m,3H),3.32–3.25(m,1H),3.19–3.08(m,4H)。
LCMS:ESI m/z 126[M+H]+
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明的保护范围应以所附权利要求为准。
Claims (10)
2.根据权利要求1所述的一种MRTX849中间体的制备方法,其特征在于,包括步骤:
S1、使用式II的化合物L-丝氨酸酯盐与氨基被保护的甘氨酸进行缩合反应,得式III的化合物:
S2、式III的化合物在催化剂作用下,进行脱保护反应得式Ⅳ的化合物:
S3、式Ⅳ的化合物在催化剂或碱的促进下,进行环合反应得式V的化合物:
S4、将式V的化合物进行还原反应,得到式Ⅵ的化合物:
S5、将式Ⅵ的化合物进行上保护反应,得到式Ⅶ的化合物:
其中,R为苄氧羰基、叔丁氧羰基和烯丙氧羰基中的任意一种;
S6、将式Ⅶ的化合物进行缩合反应,得到式Ⅷ的化合物:
其中,X为氯、溴、碘、硫酸酯基、磷酸酯基、甲磺酰氧基、对甲苯磺酰氧基、三氟甲磺酰氧基、全氟丁磺酰氧基和苯磺酰氧基中的任意一种;
S7、将式Ⅷ的化合物进行取代反应,得到式Ⅸ的化合物:
S8、将式Ⅸ的化合物进行脱保护反应,得到如式I所示的MRTX849中间体。
3.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S1中,所述的氨基被保护的甘氨酸为N-叔丁氧羰基甘氨酸(N-Boc-Gly-OH)、N-苄氧羰基甘氨酸(N-Cbz-Gly-OH)或烯丙氧羰基甘氨酸(N-Alloc-Gly-OH);和/或,
甘氨酸与式II化合物的摩尔比值为0.8-3:1;和/或,
该缩合反应中的催化剂为1-羟基苯并***(HOBt)、3-羟基-1,2,3-苯并三氮嗪-4-酮(HOOBt)、1-羟基-7-叠氮苯并***(HOAt)、三乙烯二胺、4-二甲氨基吡啶(DMAP)、N-羟基丁二酰亚胺(HOSu)、N-羟基邻苯二甲酰亚胺、2-肟-氰乙酸甲酯、2-肟-氰乙酸乙酯、N-羟基吡啶-2-酮(HOPO)、吡啶、N-氧化吡啶、咪唑、N-甲基咪唑、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,1,3,3-四甲基胍(TMG)、叠氮化钠、五氟苯酚和苯硫酚中的至少一种;和/或,
反应中的缩合剂为氯甲酸甲酯、氯甲酸乙酯、氯甲酸异丁酯、特戊酰氯、2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉(EEDQ)、2,4-二氯-6-甲氧基-1,3,5-三嗪、N,N`-二异丙基二亚胺(DIC)、N,N`-二环己基二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、四甲基氯代脲六氟磷酸酯(TCFH)、N,N'-羰基二咪唑(CDI)、甲磺酰氯(MsCl)、甲磺酸酐、对甲苯磺酰氯(TsCl)、1-正丙基磷酸酐(T3P)、六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBroP)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、三氟乙酸酐、二碳酸二叔丁酯、4-硝基苯甲酸酐、2,4,6-三氯苯甲酰氯、氯化亚砜、草酰氯、三氯氧磷、三氯化磷、三溴化磷和二苯基氯化膦中的任意一种。
4.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S2中,所使用的脱保护剂为氯化氢、溴化氢、碘化氢、硫酸、甲磺酸、苯磺酸、对甲苯磺酸、甲酸、乙酸、三氟乙酸、三氟甲磺酸、三甲基硅基三氟甲磺酸酯、三甲基氯硅烷、三甲基溴硅烷、三甲基碘硅烷、磷酸、四正丁基氟化铵、四甲基氟化铵和四正丙基氟化铵中的任意一种;和/或,
式III的化合物为叔丁氧羰基(Boc)保护型化合物时,其与脱保护剂的摩尔比值为0.5-50:1和/或脱保护反应温度为-20℃至130℃;
式III的化合物为苄氧羰基(Cbz)保护型化合物时,其与脱保护剂的摩尔比值为0.01-3:1和/或脱保护反应温度为-20℃至80℃和/或所使用的催化剂为氢气、甲酸、甲酸钾、甲酸铵、甲酸钠、5%钯碳催化剂、10%钯碳催化剂、氢氧化钯碳催化剂、雷尼镍催化剂、氢溴酸、氢碘酸、浓硫酸、三氟甲磺酸、氢氧化钠和氢氧化钾中的任意一种;
式III的化合物为烯丙氧羰基(Alloc)保护型化合物时,其与脱保护剂的摩尔比值为0.001-3:1和/或脱保护反应温度为-20℃至80℃和/或所使用的催化剂为四(三苯基膦)钯、三(三苯基膦)氢化铑、5%钯碳催化剂、10%钯碳催化剂、氢氧化钯碳催化剂、氢溴酸、氢碘酸、浓硫酸、三氟甲磺酸、氢氧化钠和氢氧化钾中的任意一种。
5.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S3中,碱的用量与式Ⅳ化合物的摩尔比值为:0.5-3:1;和/或,
催化剂的用量与式Ⅳ化合物的摩尔比值为:0.1-2:1;和/或,
环合反应温度为-20℃至80℃;和/或,
催化剂为甲醇钠、甲醇钾、乙醇钠、甲醇镁、乙醇镁、叔丁醇钠、叔丁醇钾、叔戊醇钠和叔戊醇钾中的任意一种;和/或,
碱为三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉、N-乙基吗啉、N,N,N`,N`-四甲基乙二胺、吡啶、三乙烯二胺、4-二甲氨基吡啶、咪唑、N-甲基咪唑、碳酸锂、碳酸氢钠、碳酸钠、碳酸钾、碳酸氢钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、三甲基硅醇钾和硅酸钾中的任意一种。
6.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S4中,还原剂的用量与式V化合物的摩尔比值为1-8:1;和/或,
还原反应温度为-20℃至80℃;和/或,
还原剂为氢气、硼氢化钠、氰基硼氢化钠、氢化铝锂、硼烷-四氢呋喃络合物、硼烷-三甲胺络合物、硼烷-二甲硫醚络合物、二异丁基氢化铝、红铝、三乙基硅烷、三氯硅烷、金属锌、金属镁、金属钙和金属锂中的一种。
7.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S5中,保护试剂的用量与式Ⅵ化合物的摩尔比值为1-15:1;和/或,上保护反应温度为-20℃至80℃;和/或,
保护基类型为叔丁氧羰基(Boc)时所用的保护试剂为二碳酸二叔丁酯、叠氮甲酸叔丁酯或氯甲酸叔丁酯;
保护基类型为苄氧羰基(Cbz)时所用的保护试剂为氯甲酸苄酯、叠氮甲酸苄酯、N-苄氧羰氧基丁二酰亚胺、二碳酸二苄酯、苄氧羰基酚酯和N-苄氧羰基咪唑中的一种;
保护基类型为烯丙氧羰基(Alloc)时所用的保护试剂为氯甲酸烯丙醇酯、叠氮甲酸烯丙醇酯、N-烯丙氧羰氧基丁二酰亚胺、二碳酸二烯丙醇酯、烯丙氧羰基酚酯和N-烯丙氧羰基咪唑中的一种;和/或,
催化剂为四正丁基氟化铵、四正丁基氯化铵、四正丁基溴化铵、四正丁基硫酸氢铵、苄基三甲基氯化铵、苄基三甲基溴化铵、苄基三甲基硫酸氢铵、吡啶、4-二甲氨基吡啶、咪唑、N-甲基咪唑、三乙烯二胺和五氟苯酚中的任意一种。
8.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S6中,缩合剂的用量与式Ⅶ化合物的摩尔比值为1-15:1;和/或,
碱的用量与式Ⅶ化合物的摩尔比值为0.5-30:1;和/或,
缩合反应温度为-20℃至80℃。
9.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S7中,取代试剂的用量与式Ⅷ化合物的摩尔比值为0.1-15:1;和/或,
碱的用量与式Ⅷ化合物的摩尔比值为0.5-30:1;和/或,
取代反应温度为-20℃至80℃;和/或,
取代试剂为***、***、氰化锌、氰化亚铜、三甲基氰硅烷、四正丁基氰化铵、碘化钾、碘化钠、溴化钾、溴化钠和丙酮氰醇中的至少一种。
10.根据权利要求2所述的一种MRTX849中间体的制备方法,其特征在于,步骤S8中,脱保护试剂的用量与式Ⅸ化合物的摩尔比值为0.1-500:1;和/或,
脱保护反应温度为-20℃至120℃;和/或,
脱保护试剂为三氯化铝、三氯化硼、三溴化硼、钯碳催化剂、氢氧化钯催化剂、甲酸钠,甲酸铵、氯甲酸甲酯、氯甲酸乙酯、氯甲酸-1-氯乙酯、氯化氢、溴化氢、碘化氢、硫酸、甲磺酸、苯磺酸、对甲苯磺酸、甲酸、乙酸、三氟乙酸、三氟甲磺酸、氯化锂、氯化镁、氯化锌、三甲基硅基三氟甲磺酸酯、三甲基氯硅烷、三甲基溴硅烷、三甲基碘硅烷、硝酸、磷酸、氢氧化钠、氢氧化钾、四正丁基氟化铵和四甲基氟化铵中的任意一种。
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