CN114957331A - Preparation method of phosphate substituted cyclopropyl amide derived quinazoline compound - Google Patents
Preparation method of phosphate substituted cyclopropyl amide derived quinazoline compound Download PDFInfo
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- CN114957331A CN114957331A CN202210428677.XA CN202210428677A CN114957331A CN 114957331 A CN114957331 A CN 114957331A CN 202210428677 A CN202210428677 A CN 202210428677A CN 114957331 A CN114957331 A CN 114957331A
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- -1 quinazoline compound Chemical class 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 15
- 239000010452 phosphate Substances 0.000 title claims abstract description 15
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 title claims abstract description 6
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical class [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 153
- 239000000126 substance Substances 0.000 claims abstract description 147
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000006467 substitution reaction Methods 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 29
- 238000006482 condensation reaction Methods 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 18
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 11
- 230000009471 action Effects 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 48
- 239000002904 solvent Substances 0.000 claims description 43
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- 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 16
- 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 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 238000009833 condensation Methods 0.000 claims description 12
- 230000005494 condensation Effects 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 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 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-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
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-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
- 239000007821 HATU Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012351 deprotecting agent Substances 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 125000003277 amino group Chemical group 0.000 abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000009776 industrial production Methods 0.000 description 8
- 150000003246 quinazolines Chemical class 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- UITGLCUULOSTEG-UHFFFAOYSA-N n-cyclopropylpropanamide Chemical class CCC(=O)NC1CC1 UITGLCUULOSTEG-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 description 2
- 102000008022 Proto-Oncogene Proteins c-met Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052789 astatine Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- SYKLZPMKNBDEOF-UHFFFAOYSA-N 4-chloro-6-methoxy-7-phenylmethoxyquinoline Chemical compound COC1=CC2=C(Cl)C=CN=C2C=C1OCC1=CC=CC=C1 SYKLZPMKNBDEOF-UHFFFAOYSA-N 0.000 description 1
- ORPHLVJBJOCHBR-UHFFFAOYSA-N 403-19-0 Chemical compound OC1=CC=C([N+]([O-])=O)C=C1F ORPHLVJBJOCHBR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 101100001674 Emericella variicolor andI gene Proteins 0.000 description 1
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 1
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 108010074506 Transfer Factor Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- 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
Abstract
The application relates to a preparation method of phosphate ester substituted cyclopropyl amide derivative quinazoline compounds, which comprises the following steps: carrying out a first substitution reaction on the compound shown in the chemical formula I to obtain a compound shown in a chemical formula II; carrying out hydrogenation reaction on the compound shown in the chemical formula II under the action of a palladium catalyst to obtain a compound shown in the chemical formula III; carrying out a first condensation reaction on a compound shown in a chemical formula III to obtain a compound shown in a chemical formula IV; carrying out a second substitution reaction on the compound shown in the chemical formula IV to obtain a compound shown in the chemical formula V; carrying out a second condensation reaction on the compound shown in the chemical formula V to obtain a phosphate-substituted cyclopropylamide-derived quinazoline compound shown in the chemical formula VI; according to the method, the nitro group on the benzene ring is converted into the amino group through the hydrogenation reaction, the hydrogenation reaction in the GMP production step is avoided, the phosphate side chain is constructed through the first condensation reaction and the second substitution reaction, and the environmental friendliness is improved.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a preparation method of a phosphate-substituted cyclopropyl propionamide derived quinazoline compound.
Background
The phosphate ester substituted cyclopropyl amide derivative quinazoline compounds are double inhibitors capable of inhibiting hepatocyte growth factor receptor (c-Met) and vascular endothelial growth factor receptor 2(VEGFR2), and can effectively block two signal paths of c-Met and VEGFR2 which play different roles in tumors, thereby having unique pharmacological action and clinical application prospect. The existing preparation process of phosphate ester substituted cyclopropyl propionamide derived quinazoline compounds has complex steps, relates to the use of some carcinogenic substances and polluting reagents, is not friendly to the production environment, has strict conditions for part of production steps, and cannot meet the requirements of industrial production.
Therefore, the development of a preparation process of phosphate ester substituted cyclopropylamide derived quinazoline compounds, which is environmentally friendly, simple in process and capable of being industrially produced, is urgently needed.
Disclosure of Invention
In order to overcome the defects, the application provides a preparation method of phosphate ester substituted cyclopropyl amide derivative quinazoline compounds, the process is simple, the purity of the prepared product is high, and the preparation method has the advantages of environmental friendliness and industrial production.
In a first aspect, the present application provides a process for preparing phosphate ester-substituted cyclopropylamide-derived quinazolines, comprising the steps of:
carrying out a first substitution reaction on the compound shown in the chemical formula I to obtain a compound shown in a chemical formula II;
carrying out hydrogenation reaction on the compound shown in the chemical formula II under the action of a palladium catalyst to obtain a compound shown in a chemical formula III;
carrying out a first condensation reaction on the compound shown in the chemical formula III to obtain a compound shown in a chemical formula IV;
carrying out a second substitution reaction on the compound shown in the chemical formula IV to obtain a compound shown in the chemical formula V;
carrying out a second condensation reaction on the compound represented by the chemical formula V to obtain a phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the chemical formula VI;
wherein, the chemical formula I:
chemical formula II:
chemical formula III:
chemical formula IV:
chemical formula V:
formula VI:
wherein in the chemical formulas I to VI, R is 1 Any one selected from benzyl, p-methoxybenzyl and benzyloxycarbonyl Cbz;
x is selected from halogen;
the R is 2 And R 3 Each independently selected from any one of C1-C5 alkyl.
With reference to the first aspect, before the subjecting the compound represented by the chemical formula iv to the second substitution reaction, a step of reacting the compound represented by the chemical formula iv with a deprotection reagent is further included.
In combination with the first aspect, the deprotecting agent comprises at least one of TFA, concentrated hydrochloric acid, hydrochloric acid/methanol solution, hydrochloric acid/ethyl acetate solution, and hydrochloric acid/dichloromethane solution.
In combination with the first aspect, the subjecting the compound of formula i to the first substitution reaction to obtain the compound of formula ii comprises: a compound represented by the formula I, a compound represented by the formula VII, a first basic substance and a first solvent are subjected to a first substitution reaction to obtain a compound represented by the formula II, the method comprising at least one of the following features (1) to (7):
(1) the chemical formula VII is
(2) The first basic substance comprises at least one of an organic basic substance and an inorganic basic substance, and the organic basic substance comprises at least one of N, N-diisopropylethylamine, triethylamine, DBU and DMAP;
(3) the first basic substance comprises at least one of an organic basic substance and an inorganic basic substance, and the inorganic basic substance comprises at least one of potassium carbonate, sodium hydroxide and cesium carbonate;
(4) the first solvent comprises at least one of toluene, N-dimethylformamide, DMA and acetonitrile;
(5) the temperature of the first substitution reaction is 90-120 ℃;
(6) the method comprises the following steps of carrying out a first substitution reaction on a compound represented by a chemical formula I, a compound represented by a chemical formula VII, a first basic substance and a first solvent, and then cooling and crystallizing the obtained product;
(7) the method comprises the step of carrying out a first substitution reaction on a compound represented by a chemical formula I, a compound represented by a chemical formula VII, a first alkaline substance and a first solvent, and then cooling and crystallizing the obtained product, wherein the temperature for cooling and crystallizing is 0-30 ℃.
With reference to the first aspect, the step of subjecting the compound represented by the formula ii to hydrogenation reaction under the action of a palladium catalyst to obtain the compound represented by the formula iii comprises: reacting the compound represented by the chemical formula II, hydrogen and a second solvent under the action of a palladium catalyst to obtain a compound represented by the chemical formula III, wherein the method comprises at least one of the following characteristics (1) to (3):
(1) the palladium catalyst comprises at least one of Pd/C and PdOH/C;
(2) the mass ratio of the compound represented by the chemical formula II to the palladium catalyst is 1: (0.01 to 0.1);
(3) the second solvent includes at least one of N, N-dimethylformamide, methanol, ethanol, and acetic acid.
With reference to the first aspect, the subjecting the compound represented by the formula iii to the first condensation reaction to obtain the compound represented by the formula iv includes: subjecting the compound represented by the chemical formula III, the compound represented by the chemical formula VIII, a first condensation reagent and a third solvent to a first condensation reaction to obtain a compound represented by the chemical formula IV, wherein the method comprises at least one of the following characteristics (1) to (3):
(1) the chemical formula VIII is
(2) The first condensation reagent comprises any one of triphenylphosphine/DIAD and triphenylphosphine/DEAD;
(3) the third solvent includes at least one of N, N-dimethylformamide, 2-methyltetrahydrofuran, and tetrahydrofuran.
With reference to the first aspect, the subjecting the compound of formula iv to a second substitution reaction to obtain the compound of formula v includes: subjecting the compound of the formula iv, the compound of the formula ix, the second basic substance and the fourth solvent to a second substitution reaction to produce a compound of the formula v, the method comprising at least one of the following features (1) to (3):
(1) the compound represented by the formula IX is:
wherein Y comprises at least one of p-toluenesulfonyloxy, methylsulfonyloxy, and halogen;
(2) the second basic substance comprises at least one of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine and DBU;
(3) the fourth solvent comprises at least one of THF, acetonitrile and N, N-dimethylformamide.
With reference to the first aspect, the obtaining of the quinazoline compound represented by the chemical formula vi by performing the second condensation reaction on the compound represented by the chemical formula v specifically includes: subjecting the compound represented by the chemical formula V, the compound represented by the chemical formula XI, a second condensation reagent, a fifth solvent and DMAP to a second condensation reaction to obtain a phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the chemical formula VI, wherein the method comprises at least one of the following characteristics (1) to (5):
(1) the compound represented by the formula XI is
(2) The second condensing agent comprises HATU, HOBT/EDCI, DCC, CDI and T 3 At least one of P;
(3) the fifth solvent comprises at least one of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane;
(4) the molar ratio of the compound represented by formula XI to the DMAP is 1: (0.1 to 1.5);
(5) the molar ratio of the compound represented by the chemical formula V to the compound represented by the chemical formula XI is 1 (1-2).
With reference to the first aspect, the phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the formula vi has a purity of 92% to 100%.
With reference to the first aspect, the yield of the phosphate-substituted cyclopropylamide-derived quinazolines represented by formula vi is 15% to 60%.
Compared with the prior art, the technical scheme at least has the following technical effects: the compound represented by the formula III is obtained by converting the nitro group on the benzene ring into an amino group in advance by hydrogenation, and hydrogenation in the GMP production step is avoided. The preparation method has the advantages that the synthetic route is simple, intermediates and products in each step are obtained by simple extraction washing and recrystallization after reaction post-treatment in each step, no virulent and dangerous reaction reagent is used, the method is friendly to operators, equipment and air, and the method has the advantage of industrial production.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application.
Detailed Description
In order to better understand the technical scheme of the invention, the following detailed description of the embodiments of the invention is provided.
It should be understood that the described embodiments are only some embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The terminology used in the embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the examples of the present invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
It should be understood that the term "and/or" as used herein is merely one type of association that describes an associated object, meaning that three relationships may exist, e.g., a and/or B may mean: a exists alone, A and B exist simultaneously, and B exists alone. In addition, the character "/" herein generally indicates that the former and latter related objects are in an "or" relationship.
It should be noted that "halogen" described in the embodiments of the present invention refers to F, Cl, Br, I, At.
"C1-C5 alkyl" refers to alkyl chains having 1-5 carbon atoms, which may be straight or branched, for example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like. Wherein a hydrogen atom on the alkyl carbon of C1-5 may be further substituted by a specified substituent.
"benzyl" refers to a monovalent radical remaining after removal of one hydrogen atom from a methyl carbon in a toluene molecule, or removal of a hydroxyl group from a benzyl alcohol molecule. The molecular formula is C 6 H 5 CH 2 。
"para-methoxybenzyl" means that the para position of the phenyl ring is benzyl and para-methoxy, respectively.
"Cbz" refers to benzyloxycarbonyl protecting the amine group by formation of a carbamate.
Phosphate-substituted cyclopropylamide-derived quinazolines act primarily on novel multi-target receptor tyrosine kinase inhibitors of hepatocyte growth factor receptor (HGFR or mesenchymal-epithelial transfer factor, c-Met) and vascular endothelial growth factor 2(VEGFR2 or KDR). The phosphate-substituted cyclopropyl amide derivative quinazoline compound can effectively block two signal paths of c-Met and VEGFR2 which play different roles in tumors at the same time, thereby having unique pharmacological action and clinical application prospect.
In the prior art, the preparation process of phosphate ester substituted cyclopropylamide derived quinazoline compounds comprises the following reaction processes:
the above reaction process involves the addition of acetic acid, aqueous formaldehyde solution and trifluoroacetic acid, acetic acid being a strong organic acid and corrosive. Formaldehyde is a compound with definite carcinogenicity, causes certain harm to production operators, is not environment-friendly, and causes certain harm to operating equipment and environment due to the use of trifluoroacetic acid; in addition, the existing synthesis process of the phosphate-substituted cyclopropylamide-derived quinazoline compound involves a large number of operation steps such as repeated extraction by distillation and washing, has high requirements on production conditions, and is not friendly to production environment.
Accordingly, the present application provides a process for the preparation of phosphate-substituted cyclopropylamide-derived quinazolines, comprising the steps of:
step 1, carrying out a first substitution reaction on a compound shown in a chemical formula I to obtain a compound shown in a chemical formula II;
step 2, reacting the compound shown in the chemical formula II with hydrogen under the action of a palladium catalyst to obtain a compound shown in the chemical formula III;
step 3, carrying out a first condensation reaction on the compound shown in the chemical formula III to obtain a compound shown in a chemical formula IV;
step 4, carrying out a second substitution reaction on the compound shown in the chemical formula IV to obtain a compound shown in the chemical formula V;
and 5, carrying out a second condensation reaction on the compound shown in the chemical formula V to obtain the phosphate-substituted cyclopropylamide-derived quinazoline compound shown in the chemical formula VI.
Wherein, the chemical formula I:
chemical formula II:
chemical formula III:
chemical formula IV:
chemical formula V:
formula VI:
wherein in the chemical formulas I to VI, R 1 Is selected from any one of benzyl, p-methoxybenzyl and benzyloxycarbonyl, preferably R 1 Selected from benzyl.
X is selected from halogen, namely X is selected from any one of F, Cl, Br, I and At.
R 2 And R 3 Are respectively and independently selected from C1-C5 alkylAny one of the above. Understandably, R 2 And R 3 Alkyl groups of the same number of carbon atoms may be present simultaneously.
In the scheme, the nitro group on the benzene ring is converted into the amino group in advance through the hydrogenation reaction in the step 2 to obtain the compound represented by the chemical formula III, so that the hydrogenation reaction in the GMP production step is avoided, and the cost is reduced. And then, the phosphate side chain can be constructed by sequentially carrying out the first condensation reaction and the second substitution reaction in the steps 3 and 4, so that a method for conventionally synthesizing the side chain by using formaldehyde is avoided, the environmental friendliness of a synthetic route is improved, and the reaction system has high product purity and less impurities and is suitable for industrial production. The preparation method has the advantages that the synthetic route is simple, the intermediate and the product in each step are obtained by simple extraction, washing and recrystallization after each step of reaction, no virulent and dangerous reaction reagent is used, the preparation method is friendly to operators, equipment and air, and the preparation method can be used for industrial production.
The preparation method of the present application, which is described in detail in the following examples, the preparation method of the phosphate ester substituted cyclopropyl amide derivative quinazoline compound of the present application, comprises the following steps:
step 1, carrying out a first substitution reaction on the compound represented by the chemical formula I, the compound represented by the chemical formula VII, a first basic substance and a first solvent to obtain a compound represented by the chemical formula II.
In some embodiments, the base comprises at least one of an organic base comprising at least one of N, N-diisopropylethylamine, triethylamine, DBU (1, 8-diazabicycloundecen-7-ene), and DMAP (4-dimethylaminopyridine), and an inorganic base comprising at least one of potassium carbonate, sodium hydroxide, and cesium carbonate; preferably, the base is N, N-diisopropylethylamine.
In some embodiments, the first solvent comprises at least one of toluene, N-dimethylformamide, DMA (dioxydimethyl ether acetate), and acetonitrile, preferably the first solvent is toluene.
In some embodiments, the temperature of the first substitution reaction is 90 ℃ to 120 ℃, and the temperature of the first substitution reaction may be, for example, 90 ℃, 100 ℃, 110 ℃, 120 ℃, etc., and may also be other values within the above range, which is not limited herein.
In some embodiments, the first substitution reaction of the compound of formula i, the compound of formula vii, the base and the first solvent further comprises a step of cooling crystallization of the obtained product, i.e., step 100 comprises: carrying out a first substitution reaction on the compound represented by the chemical formula I, the compound represented by the chemical formula VII, a first basic substance and a first solvent, and cooling the first substitution reactant to precipitate crystals to obtain the compound represented by the chemical formula II.
In some embodiments, the temperature for temperature reduction is 0 to 30 ℃, and the temperature for temperature reduction may be, for example, 0 ℃,5 ℃,10 ℃, 15 ℃, 20 ℃, 25 ℃ and 30 ℃, and may also be other values within the above range, which is not limited herein. Preferably, the temperature for reducing the temperature is 0-10 ℃.
And 2, reacting the compound shown in the chemical formula II obtained in the step 100, hydrogen and a second solvent under the action of a palladium catalyst to obtain a compound shown in a chemical formula III.
In the above step, the benzyl group and the nitro group can be simultaneously removed by a one-step hydrogenation reaction to obtain the compound represented by the formula III.
In some embodiments, the palladium catalyst comprises at least one of Pd/C and PdOH/C, preferably the palladium catalyst is Pd/C.
In some embodiments, the mass ratio of the compound of formula ii to the palladium catalyst is 1: (0.01 to 0.1), the mass ratio of the compound represented by the formula II to the palladium catalyst may be, for example, 1: 0.01, 1: 0.05 and 1: 0.1, etc., but of course other values within the above range are possible, and the application is not limited thereto. Preferably, the mass ratio of the compound represented by formula ii to the palladium catalyst is 1: 0.01.
in some embodiments, the second solvent comprises at least one of N, N-dimethylformamide, methanol, ethanol, and acetic acid, preferably the second solvent is N, N-dimethylformamide.
In some embodiments, after the reaction is finished, the catalyst is filtered, water (45v) is added dropwise into the reaction system for crystallization, then the reaction system is filtered and dried to obtain a crude product, then the crude product is added into a methanol/acetic acid/water mixed system, activated carbon is added for decolorization, the activated carbon is filtered out, water is added, and the pH value is adjusted by sodium hydroxide, oxalic acid and triethylamine in sequence until the product is separated out.
And 3, carrying out a first condensation reaction on the compound represented by the chemical formula III, the compound represented by the chemical formula VIII, a first condensation reagent and a third solvent to obtain a compound represented by the chemical formula IV.
In some embodiments, formula VIII is
In some embodiments, the first condensation reagent comprises any of triphenylphosphine/DIAD (diisopropyl azodicarboxylate) and triphenylphosphine/DEAD (diethyl azodicarboxylate), it being understood that the first condensation reagent used herein is a mixing reagent, preferably the first condensation reagent is a triphenylphosphine/DIAD mixing reagent.
In some embodiments, the third solvent comprises at least one of N, N-dimethylformamide, 2-methyltetrahydrofuran, and Tetrahydrofuran (THF). Preferably, the third solvent is tetrahydrofuran.
In some embodiments, after the first condensation reaction is finished, filtering with diatomite, adding ethyl acetate for concentration, dropwise adding an oxalic acid/ethyl acetate solution, stirring for crystallization, filtering, adding ethyl acetate and a sodium carbonate aqueous solution into the obtained solid, layering, removing an aqueous phase, concentrating an ethyl acetate phase, adding methyl tert-butyl ether, stirring for crystallization, and filtering to obtain a purified product.
And 4, carrying out a second substitution reaction on the compound shown in the chemical formula IV, the compound shown in the chemical formula IX, a second basic substance and a fourth solvent to generate the compound shown in the chemical formula V.
In some embodiments, the step of reacting the compound of formula iv with a deprotection reagent is further included before the step of subjecting the compound of formula iv to the second substitution reaction, i.e. step 4 includes: reacting the compound of formula IV with a deprotecting reagent to obtain a compound of formula X, and subjecting the compound of formula X, the compound of formula IX, a second basic substance, and a fourth solvent to a second substitution reaction to produce a compound of formula V.
In some embodiments, the deprotection reagent comprises at least one of trifluoroacetic acid, concentrated hydrochloric acid, hydrochloric acid/water solution, hydrochloric acid/methanol solution, hydrochloric acid/ethyl acetate solution, and hydrochloric acid/dichloromethane solution. Preferably, the deprotecting reagent is aqueous hydrochloric acid at a concentration of 37%.
In some embodiments, the compound of formula iv is reacted with a deprotection reagent to obtain a compound of formula x, the pH of the system is adjusted to about 9, the mixture is stirred for 1 hour, filtered, and the filter cake is rinsed with demineralized water (20mL,2V) and dried under reduced pressure at 55 ℃ for 16 hours to obtain a product, and the product is ready for the next reaction.
In some embodiments, the compound of formula ix is:
wherein Y comprises at least one of p-toluenesulfonyloxy, methylsulfonyloxy and halogen, and the halogen element may be Cl, Br andI。
in some embodiments, the compound of formula ix is prepared by a process comprising:
in some embodiments, the second basic material comprises at least one of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene).
In some embodiments, the fourth solvent comprises at least one of THF, acetonitrile and N, N-dimethylformamide, preferably, the fourth solvent is acetonitrile.
And 5, carrying out a second condensation reaction on the compound represented by the chemical formula V, the compound represented by the chemical formula XI, a second condensation reagent, a fifth solvent and DMAP to obtain the phosphate substituted cyclopropyl propionamide derivative quinazoline compound represented by the chemical formula VI.
In some embodiments, the compound of formula XI is
X is selected from halogen.
In some embodiments, the second condensation reagent comprises HATU, HOBT/EDCI, DCC, CDI and T 3 At least one of P, preferably the second condensing agent is T 3 P。
In some embodiments, the fifth solvent comprises at least one of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane, and preferably, the fifth solvent comprises any one of ethyl acetate and tetrahydrofuran.
In some embodiments, the molar ratio of the compound of formula XI to DMAP (4-dimethylaminopyridine) is 1: (0.1-1.5), DMAP is used as an activation catalyst, so that the reaction rate and the yield of the second condensation reaction can be improved. The molar ratio of the compound of formula XI to DMAP can be, for example, 1: 0.1, 1: 0.3, 1: 0.1, 1: 1. 1: 1.2 and 1: 1.5, etc., but other values within the above range are also possible, without limitation. Preferably, the molar ratio of the compound represented by formula XI to DMAP is 1: (1-1.5).
In some embodiments, the molar ratio of the compound of formula V to the compound of formula XI is 1 (1-2), and the molar ratio of the compound of formula V to the compound of formula XI can be, for example, 1: 1. 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7 and 1: 1.8, 1: 1.9 and 1: 2, etc., but other values within the above range are also possible, and are not limited herein. Preferably, the molar ratio of the compound of formula v to the compound of formula XI is 1: (1.1-1.2).
In some embodiments, the phosphate-substituted cyclopropylamide-derived quinazoline compound represented by formula vi has a purity of 92% to 100%, specifically, the purity may be 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, and the like, and the phosphate-substituted cyclopropylamide-derived quinazoline compound prepared by the preparation process of the present application has a high purity, has fewer reaction byproducts, is convenient for separation and purification, and can meet the needs of industrial production.
In some embodiments, the yield of the phosphate-substituted cyclopropylamide-derived quinazoline compound represented by formula vi is 16% to 60%, specifically, the yield may be 15%, 25%, 35%, 45%, 60%, and the like.
According to the preparation method of the phosphate ester substituted cyclopropyl propionamide derived quinazoline compound, the conversion rate of raw materials in each step is high, the complex operation steps of repeated extraction by distillation and washing, column chromatography separation and the like which are not suitable are not needed, the reaction condition is mild, a high-purity intermediate and a high-purity finished product are directly obtained through recrystallization, the finally prepared phosphate ester substituted cyclopropyl propionamide derived quinazoline compound is high in purity and yield, reaction byproducts are few, and the requirement of industrial production can be met.
The examples of the present application are further illustrated below in the context of several examples. The present embodiments are not limited to the following specific examples. The present invention can be modified and implemented as appropriate within the scope of the main claim.
Example 1
(1) Adding toluene (4.5V) into a reaction kettle, starting stirring, sequentially adding 13.0 kg of 7-benzyloxy-4-chloro-6-methoxyquinoline (SM1), 14.05kg of DIPEA (Dipea) and 10.27kg of 2-fluoro-4-nitrophenol, carrying out nitrogen displacement, reacting at the temperature of 110-.
(2) Adding a first intermediate (15.9kg) into a solvent N, N-dimethylformamide (7.5v), adding Pd/C (1.60kg, 0.1w/w), replacing a reaction system with hydrogen, pressurizing, stirring at 30-40 ℃, reacting completely, filtering out a catalyst, dropwise adding water (45v) into the reaction solution to crystallize, filtering, drying to obtain a crude product, adding the crude product into a mixed system of methanol (5 v)/acetic acid (4 v)/water (2v), adding activated carbon (0.1w/w) for decoloring, filtering out the activated carbon, adding water (10v), adjusting the pH value to precipitate a product by using sodium hydroxide, oxalic acid and triethylamine successively, stirring, filtering out the product, and drying to obtain a second intermediate (5.84 kg).
(3) Adding a second intermediate (100g), SM3(2.0eq), triphenylphosphine (2.5eq) into a reaction bottle in sequence, controlling the temperature to be minus 5-5 ℃, dropwise adding DIAD (2.5eq), after the dropwise adding is finished, heating to room temperature (20-30 ℃), stirring for reaction, after the raw materials are completely converted, filtering by using kieselguhr, adding ethyl acetate for concentration till dryness, adding ethyl acetate (18v), controlling the temperature to be dropwise added oxalic acid/ethyl acetate solution, stirring for crystallization, filtering, adding ethyl acetate and sodium carbonate aqueous solution into the obtained solid, layering, discarding the aqueous phase, concentrating the ethyl acetate phase, adding methyl tert-butyl ether, stirring for crystallization, filtering, drying the obtained solid in vacuum to obtain a third intermediate 72.21g, and obtaining the HPLC purity of 99.0%.
(4) The third intermediate (10g), purified water (50mL,5V), tetrahydrofuran (20mL,2V) were added to the reaction flask at 20 deg.C-30 deg.C. Dropwise adding concentrated hydrochloric acid (6.7mL,4eq) at 20-30 ℃, heating to 45-50 ℃, reacting for 16h, and cooling to 15-25 ℃ after the reaction is finished. And dropwise adding the prepared sodium hydroxide solution, adjusting the pH to be about 9, stirring for 1h, filtering, wherein the filtering speed is slow, (or adjusting the pH to be 7, and dropwise adding the residual sodium hydroxide too fast), leaching the filter cake with softened water (20mL,2V), and drying the material at 55 ℃ under reduced pressure for 16h to obtain a fourth intermediate.
(5) Sequentially adding a fourth intermediate (15.0g,1.0eq.) acetonitrile (150mL,10V) and sodium carbonate (12.0g,3.0eq.) into a 500m bottle at 15-25 ℃, dropwise adding diethyl p-toluenesulfonyloxyphosphate (14.6g,1.2eq.) and heating to 80-85 ℃ for reaction. Reacting for 16h, cooling to 15-25 ℃, adding water (105mL,7V) and ethyl acetate (75mL,5V), stirring, separating, and collecting an organic phase. Concentrating an organic phase to 2-2.5V, adding absolute ethyl alcohol (105mL,7V), continuously concentrating to 2-2.5V, adding absolute ethyl alcohol (30mL,2V) into a concentrated solution, heating to 75-80 ℃, stirring to dissolve, cooling to 15-25 ℃, preserving heat for 1.5h, filtering, washing a filter cake with absolute ethyl alcohol (30mL,2V), adding the filter cake into a 250mL reaction bottle at 15-25 ℃, adding N, N-dimethylformamide (60mL,4V), dissolving a system, controlling the temperature to 15-25 ℃, dripping water (60mL,4V), separating out solids, heating to 85-90 ℃, dissolving a system, slowly cooling to 15-25 ℃, and preserving heat for 1.5 h. Filtering, eluting the filter cake with softened water (30mL,2V), drying the solid filter cake at 55 ℃ under reduced pressure for 16h, taking out the dried filter cake to obtain a fifth intermediate (13.2g) with HPLC purity of 98.9%.
(6) At 20-30 ℃, the fifth intermediate (1.0g,1.0eq.), SM5(0.5g,1.2eq.), ethyl acetate (10mL,10V), and 4-dimethylaminopyridine (0.3g,1.35eq.) were added to the reaction flask. N, N-diisopropylethylamine (0.6g,2.5eq.) was added dropwise and stirred for 30 min. Dropwise adding 50% of T 3 And (3) reacting the solution of ethyl acetate P (2.1g,1.8eq.) at 20-30 ℃ until the fifth intermediate is less than 1%. Water (8mL,8V) was added to the reaction mixture,stirring and separating liquid, collecting an organic phase, concentrating the organic phase to 2V, dropwise adding absolute ethyl alcohol (8mL,8V), stirring at 15-25 ℃, slowly separating out solids, filtering, and leaching a filter cake with absolute ethyl alcohol (2mL, 2V). The filter cake weighed 0.89g and had an HPLC purity of 98.6%.
Mass spectrum m/z: 753.6(M + H).
Nuclear magnetism 1 HNMR(400MHz，DMSO-d6)：δ＝10.41(s，1H)、10.04(s，1H)，8.48(d，J＝5.2，1H)，7.92(dd，J＝13.2，2.3，1H),7.72-7.59(m，2H),7.53(m，2H),7.49-7.36(m，2H),7.17(t,J＝8.9，2H),6.42(d,J＝5.3，1H),4.13-3.93(m，9H),3.09-3.05
(d,J＝11，2H),2.78(d,J＝11，2H),2.23-2.08(m，2H),1.89-1.73(m，3H),1.24-1.20(m，12H)。
Example 2
Unlike in example 1, the substitution in step 5 is R 2 And R 3 A different compound, replacing "diethyl p-toluenesulfonyloxyphosphate" in step (5) with:
the finally prepared quinazoline compound has the chemical formula as follows:
the compound prepared in this example was 96% pure.
Mass spectrum m/z: 781.6(M + H).
Nuclear magnetism 1 HNMR(400MHz，DMSO-d6)：δ＝10.39(s，1H)、10.01(s，1H)，8.45(d，J＝5.2，1H)，7.89(dd，J＝13.2，2.3，1H),7.71-7.55(m，2H),7.49(m，2H),7.44-7.31(m，2H),7.15(t,J＝8.9，2H),6.42(d,J＝5.3，1H),4.10-4.21(m，4H),3.91(s，3H)，3.05-3.01(d,J＝11，2H),2.76(d,J＝11，2H),2.21-2.01(m，2H),1.78-1.65(m，3H),1.24-1.20(m，18H)。
Example 3
Unlike in example 1, the substitution in step 5 is R 2 And R 3 A different compound, replacing "diethyl p-toluenesulfonyloxyphosphate" in step (5) with:
the chemical formula of the finally prepared quinazoline compound is as follows:
the compound prepared in this example was 97% pure.
Mass spectrum m/z: 725.6(M + H).
Nuclear magnetism 1 HNMR(400MHz，DMSO-d6)：δ＝10.41(s，1H)、10.04(s，1H)，8.48(d,1H)，7.92(dd,1H),7.72-7.59(m，2H),7.53(m，2H),7.49-7.36(m，2H),7.17(t,2H),6.42(d,1H),4.21-4.10(m,2H),3.92(s，3H),3.71(s，6H),3.09-3.05(d,2H),2.84(d,2H),2.23-2.08(m，2H),1.89-1.73(m，3H),1.24-1.20(m，6H)。
Example 4
Unlike example 1, step (1) R 1 The reaction equation of step (1) is replaced by p-methoxybenzyl:
the finally prepared quinazoline compound has the chemical formula as follows:
the compound prepared in this example was 98.2% pure.
Mass spectrum m/z: 753.6(M + H).
Nuclear magnetism 1 HNMR(400MHz，DMSO-d6)：δ＝10.39(s，1H)、10.01(s，1H)，8.46(d，J＝5.2，1H)，7.89(dd，J＝13.2，2.3，1H),7.69-7.55(m，2H),7.51(m，2H),7.44-7.33(m，2H),7.14(t,J＝8.9，2H),6.39(d,J＝5.3，1H),4.09-3.90(m，9H),3.05-3.01(d,J＝11，2H),2.73(d,J＝11，2H),2.19-2.03(m，2H),1.85-1.70(m，3H),1.21-1.18(m，12H)。
Example 5
Unlike example 1, step (1) R 1 Replacement by N-benzyloxycarbonyl.
The chemical formula of the finally prepared quinazoline compound is as follows:
the compound prepared in this example was 96% pure.
Mass spectrum m/z: 753.5(M + H).
Nuclear magnetism 1 HNMR(400MHz，DMSO-d6)：δ＝10.41(s，1H)、10.04(s，1H)，8.48(d，J＝5.2，1H)，7.92(dd，J＝13.2，2.3，1H),7.72-7.59(m，2H),7.53(m，2H),7.49-7.36(m，2H),7.17(t,J＝8.9，2H),6.42(d,J＝5.3，1H),4.13-4.01(m，6H),3.95(s，3H),3.09-3.05(d,J＝11，2H),2.78(d,J＝11，2H),2.23-2.08(m，2H),1.89-1.73(m，3H),1.24-1.20(m，12H)。
Comparative example 1
The quinazoline compound is prepared by the existing method, and the reaction formula is as follows:
the purity of the compound prepared in this comparative example was 90.5%.
Mass spectrum m/z: 753.5(M + H).
Nuclear magnetism 1 HNMR(400MHz，DMSO-d6)：δ＝10.45(s，1H)、10.10(s，1H)，8.51(d，J＝5.2，1H)，7.97(dd，J＝13.2，2.3，1H),7.78-7.65(m，2H),7.58(m，2H),7.56-7.42(m，2H),7.26(t,J＝8.9，2H),6.51(d,J＝5.3，1H),4.19-4.08(m，6H),3.98(s，3H),3.11-3.07(d,J＝11，2H),2.81(d,J＝11，2H),2.27-2.11(m，2H),1.93-1.76(m，3H),1.27-1.23(m，12H)
The preparation method has the advantages of simple synthetic route, no use of highly toxic and dangerous reaction reagents, high purity and yield of the prepared phosphate ester substituted cyclopropyl amide derived quinazolines, and friendly operation personnel, equipment and air in the production process, and can be used for industrial production.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The preparation method of the phosphate substituted cyclopropyl amide derivative quinazoline compound is characterized by comprising the following steps:
carrying out a first substitution reaction on the compound shown in the chemical formula I to obtain a compound shown in a chemical formula II;
carrying out hydrogenation reaction on the compound shown in the chemical formula II under the action of a palladium catalyst to obtain a compound shown in a chemical formula III;
carrying out a first condensation reaction on the compound shown in the chemical formula III to obtain a compound shown in a chemical formula IV;
carrying out a second substitution reaction on the compound shown in the chemical formula IV to obtain a compound shown in the chemical formula V;
carrying out a second condensation reaction on the compound represented by the chemical formula V to obtain a phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the chemical formula VI;
wherein, the chemical formula I:
chemical formula II:
chemical formula III:
chemical formula IV:
chemical formula V:
formula VI:
wherein in the chemical formulas I to VI, R is 1 Any one selected from benzyl, p-methoxybenzyl and benzyloxycarbonyl;
x is selected from halogen;
the R is 2 And R 3 Each independently selected from any one of C1-C5 alkyl.
2. The method according to claim 1, wherein the step of subjecting the compound of formula iv to a second substitution reaction further comprises a step of subjecting the compound of formula iv to a reaction with a deprotection reagent.
3. The method of claim 2, wherein the deprotecting agent comprises at least one of trifluoroacetic acid, concentrated hydrochloric acid, hydrochloric acid/methanol solution, hydrochloric acid/ethyl acetate solution, and hydrochloric acid/dichloromethane solution.
4. The method of claim 1, wherein the subjecting the compound of formula i to the first substitution reaction to obtain the compound of formula ii comprises: a compound represented by the formula I, a compound represented by the formula VII, a first basic substance and a first solvent are subjected to a first substitution reaction to obtain a compound represented by the formula II, the method comprising at least one of the following features (1) to (7):
(1) said chemical formula VIIIs composed of
(2) The first basic substance comprises at least one of an organic basic substance and an inorganic basic substance, and the organic basic substance comprises at least one of N, N-diisopropylethylamine, triethylamine, DBU and DMAP;
(3) the first basic substance comprises at least one of an organic basic substance and an inorganic basic substance, and the inorganic basic substance comprises at least one of potassium carbonate, sodium hydroxide and cesium carbonate;
(4) the first solvent comprises at least one of toluene, N-dimethylformamide, DMA and acetonitrile;
(5) the temperature of the first substitution reaction is 90-120 ℃;
(6) the method comprises the following steps of carrying out a first substitution reaction on a compound represented by a chemical formula I, a compound represented by a chemical formula VII, a first basic substance and a first solvent, and then cooling and crystallizing the obtained product;
(7) the method comprises the step of carrying out a first substitution reaction on a compound represented by a chemical formula I, a compound represented by a chemical formula VII, a first alkaline substance and a first solvent, and then cooling and crystallizing the obtained product, wherein the temperature for cooling and crystallizing is 0-30 ℃.
5. The preparation method according to claim 1, wherein the step of hydrogenating the compound of formula ii in the presence of a palladium catalyst to obtain the compound of formula iii comprises: reacting the compound represented by the formula II, hydrogen and a second solvent in the presence of a palladium catalyst to obtain a compound represented by the formula III, wherein the method comprises at least one of the following features (1) to (3):
(1) the palladium catalyst comprises at least one of Pd/C and PdOH/C;
(2) the mass ratio of the compound represented by the chemical formula II to the palladium catalyst is 1: (0.01 to 0.1);
(3) the second solvent includes at least one of N, N-dimethylformamide, methanol, ethanol, and acetic acid.
6. The method of claim 1, wherein the subjecting the compound of formula iii to a first condensation reaction to obtain a compound of formula iv comprises: subjecting the compound represented by the chemical formula III, the compound represented by the chemical formula VIII, a first condensation reagent and a third solvent to a first condensation reaction to obtain a compound represented by the chemical formula IV, wherein the method comprises at least one of the following characteristics (1) to (3):
(1) the chemical formula VIII is
(2) The first condensation reagent comprises any one of triphenylphosphine/DIAD and triphenylphosphine/DEAD;
(3) the third solvent includes at least one of N, N-dimethylformamide, 2-methyltetrahydrofuran, and tetrahydrofuran.
7. The method of claim 1, wherein the subjecting the compound of formula iv to a second substitution reaction to obtain the compound of formula v comprises: subjecting the compound of the formula iv, the compound of the formula ix, the second basic substance and the fourth solvent to a second substitution reaction to produce a compound of the formula v, the method comprising at least one of the following features (1) to (3):
(1) the compound represented by the formula IX is:
wherein Y comprises at least one of p-toluenesulfonyloxy, methylsulfonyloxy, and halogen;
(2) the second basic substance comprises at least one of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine and DBU;
(3) the fourth solvent includes at least one of THF, acetonitrile, and N, N-dimethylformamide.
8. The preparation method according to claim 1, wherein the second condensation reaction of the compound of formula v to obtain the phosphate-substituted cyclopropylamide-derived quinazoline compound of formula vi specifically comprises: subjecting the compound represented by the chemical formula V, the compound represented by the chemical formula XI, a second condensation reagent, a fifth solvent and DMAP to a second condensation reaction to obtain a phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the chemical formula VI, wherein the method comprises at least one of the following characteristics (1) to (5):
(1) the compound represented by the formula XI is
(2) The second condensing agent comprises HATU, HOBT/EDCI, DCC, CDI and T 3 At least one of P;
(3) the fifth solvent comprises at least one of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane;
(4) the molar ratio of the compound represented by formula XI to the DMAP is 1: (0.1 to 1.5);
(5) the molar ratio of the compound represented by the chemical formula V to the compound represented by the chemical formula XI is 1 (1-2).
9. The preparation method according to claim 1, wherein the phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the formula vi has a purity of 92 to 100%.
10. The preparation method according to claim 1, wherein the yield of the phosphate-substituted cyclopropylamide-derived quinazoline compound represented by the formula vi is 15 to 60%.
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| WO2022013307A1 (en) * | 2020-07-15 | 2022-01-20 | Chiesi Farmaceutici S.P.A. | Pyridazinyl amino derivatives as alk5 inhibitors |
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