CN110577520A - Preparation method of 6-nitro-4-substituted amino quinazoline derivative - Google Patents
Preparation method of 6-nitro-4-substituted amino quinazoline derivative Download PDFInfo
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- CN110577520A CN110577520A CN201810593467.XA CN201810593467A CN110577520A CN 110577520 A CN110577520 A CN 110577520A CN 201810593467 A CN201810593467 A CN 201810593467A CN 110577520 A CN110577520 A CN 110577520A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- -1 6-nitro-4-substituted amino quinazoline Chemical class 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 27
- QUGWQGGABOGQMV-UHFFFAOYSA-N C1=CC(=C(C=C1C2=NC(=NC3=C2C=C(C=C3)[N+](=O)[O-])N)Cl)OCC4=NC=CS4 Chemical compound C1=CC(=C(C=C1C2=NC(=NC3=C2C=C(C=C3)[N+](=O)[O-])N)Cl)OCC4=NC=CS4 QUGWQGGABOGQMV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006467 substitution reaction Methods 0.000 claims abstract description 19
- GFDNDSYEHHSKIF-UHFFFAOYSA-N CONC1=CC(=C(C=C1)C2=NC=CS2)Cl Chemical compound CONC1=CC(=C(C=C1)C2=NC=CS2)Cl GFDNDSYEHHSKIF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 238000007112 amidation reaction Methods 0.000 claims abstract description 15
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- 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 10
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical group Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical group [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 8
- 239000011968 lewis acid catalyst Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 229940117389 dichlorobenzene Drugs 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 4
- JMDLKOHVIXLCOJ-UHFFFAOYSA-N C1=CC(=CC(=C1)[N+](=O)[O-])C(=O)NC2=CC(=C(C=C2)OCC3=NC=CS3)Cl Chemical compound C1=CC(=CC(=C1)[N+](=O)[O-])C(=O)NC2=CC(=C(C=C2)OCC3=NC=CS3)Cl JMDLKOHVIXLCOJ-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 12
- 239000007791 liquid phase Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- UPQPJSUDROLQSJ-UHFFFAOYSA-N 2-chloro-N-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-5-nitrobenzamide Chemical compound C1=CC(=C(C=C1NC(=O)C2=C(C=CC(=C2)[N+](=O)[O-])Cl)Cl)OCC3=NC=CS3 UPQPJSUDROLQSJ-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 229950006605 varlitinib Drugs 0.000 description 7
- RFKKCMAQUCUFOM-UHFFFAOYSA-N NC1=CC=C2N=C(N)N=C(C(C=C3)=CC(Cl)=C3OCC3=NC=CS3)C2=C1 Chemical compound NC1=CC=C2N=C(N)N=C(C(C=C3)=CC(Cl)=C3OCC3=NC=CS3)C2=C1 RFKKCMAQUCUFOM-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- BTMSCTBJDYCGGD-UHFFFAOYSA-N 2-bromo-N-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-5-nitrobenzamide Chemical compound C1=CC(=C(C=C1NC(=O)C2=C(C=CC(=C2)[N+](=O)[O-])Br)Cl)OCC3=NC=CS3 BTMSCTBJDYCGGD-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MGCGMYPNXAFGFA-UHFFFAOYSA-N 2-amino-5-nitrobenzonitrile Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C#N MGCGMYPNXAFGFA-UHFFFAOYSA-N 0.000 description 2
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical compound OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000006088 Dimroth rearrangement reaction Methods 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VCYWZLGOWNCJNJ-UHFFFAOYSA-N methyl 2-chloro-5-nitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl VCYWZLGOWNCJNJ-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZHAKAIBZKYHXJS-UHFFFAOYSA-N 2-(chloromethyl)-1,3-thiazole Chemical compound ClCC1=NC=CS1 ZHAKAIBZKYHXJS-UHFFFAOYSA-N 0.000 description 1
- DAWZPWYDLLEDEC-UHFFFAOYSA-N 6-(dimethylamino)-5-methylidene-3-nitrocyclohexa-1,3-diene-1-carbonitrile Chemical compound CN(C)C1C(=C)C=C(C=C1C#N)[N+](=O)[O-] DAWZPWYDLLEDEC-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- MAMKSCSDSFXMMU-UHFFFAOYSA-N COC1=C(C=CC(=C1Cl)C2=NC=CS2)[N+](=O)[O-] Chemical compound COC1=C(C=CC(=C1Cl)C2=NC=CS2)[N+](=O)[O-] MAMKSCSDSFXMMU-UHFFFAOYSA-N 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- JXOMCDVAPASMML-UHFFFAOYSA-N ethyl 2-chloro-5-nitrobenzoate Chemical compound CCOC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl JXOMCDVAPASMML-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- VSEYYEKRZNRECT-UHFFFAOYSA-N methyl 2-bromo-5-nitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=CC=C1Br VSEYYEKRZNRECT-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a preparation method of a 6-nitro-4-substituted amino quinazoline derivative. The method comprises the steps of carrying out amidation reaction on 2-halogenated-5-nitrobenzoate and 4- (thiazole-2-yl) methoxy-3-chloroaniline in the presence of a catalyst to obtain N- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] -2-halogenated-5-nitrobenzamide, and carrying out substitution and condensation reaction on the N- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] -5-nitrobenzamide and formamidine salt in the presence of an acid binding agent to obtain the 6-nitro-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline. The method has the advantages of cheap and easily-obtained raw materials, good raw material stability, high reaction selectivity, easy reaction operation and high product yield and purity.
Description
Technical Field
The invention relates to a preparation method of a 6-nitro-4-substituted amino quinazoline derivative, in particular to a preparation method of 6-nitro-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] amino quinazoline, which is used for preparing varlitinib and belongs to the technical field of chemical intermediates of medicines.
Background
Varlitinib (Varlitinib), the chemical name of which is (R) -N4- [ 3-chloro-4- (thiazol-2-ylmethoxy) phenyl ] -N6- (4-methyl-4, 5-dihydrooxazol-2-yl) quinazoline-4, 6-diamine, is a potent small molecule reversible pan-HER inhibitor, which was developed by Array biopharmaceutical company, and developed for multiple indications, such as biliary tract cancer, gastric cancer, metastatic breast cancer, and metastatic colorectal cancer, with global development and commercialization ownership of Singapore lion (ASLAN Pharmaceuticals).
Regarding the preparation method of varlitinib, the patent CN102432552 applied in china by Array biopharmaceutical company in the original research company, discloses two synthetic routes, synthetic route 1: 6-amino-4- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] aminoquinazoline is used as a starting material, condensed with sulfo-CDI in a mixture of appropriate organic solvent such as THF and DCE, the obtained intermediate is directly condensed with amino alcohol without treatment to obtain a thiourea derivative, and finally, the thiourea derivative is obtained through intramolecular cyclization and elimination. Scheme 2: the preparation method comprises the following steps of taking 6-amino-4- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] aminoquinazoline as a raw material, coupling the raw material with N-cyano carbodiimido diphenyl ester in the presence of alkali such as sodium hydride or triethylamine to obtain a cyano isourea compound, and coupling the cyano isourea compound with amino alcohol to obtain a product. The synthesis route 1 generates hydrogen sulfide gas in the synthesis process, has large pollution and is not suitable for industrialization; the raw material 6-amino-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline used in the synthetic route 1 and the synthetic route 2 is high in price and is not easy to obtain.
Another synthetic method is reported in 2015, wherein 2-chloro-4-nitrophenol and 2-cyano-4-nitroaniline are used as starting materials, and Vallitinib is synthesized through seven-step reaction, wherein the total yield is 18.2%. The process is depicted as scheme 3: 2-chloro-4-nitrophenol is taken as a starting material, the 4- (thiazole-2-yl) methoxy-3-chloronitrobenzene is obtained by substitution reaction with 2-chloromethyl thiazole, the 4- (thiazole-2-yl) methoxy-3-chloroaniline is obtained by reduction reaction of iron powder, then the 6-nitro-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline is prepared by Dimroth rearrangement reaction with 2-dimethylamino methylene-5-nitrobenzonitrile (prepared by condensation of 2-amino-5-nitrobenzonitrile and DMFDMA), and the 6-amino-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline is obtained by reduction of iron powder, then preparing varlitinib by using a method similar to the synthetic route 2; see synthetic chemistry 2015, 23. In the synthetic route 3, a large amount of iron is used for reduction, so that the generated solid waste is large in amount, heavy in pollution, uneconomical and environment-friendly.
The preparation process of the 6-amino-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline related in the synthetic route 3 is complicated, and the side products of isomers in the Dimroth rearrangement reaction are more, which is not beneficial to product purification and quality guarantee of the varlitinib.
The synthetic routes all relate to a Vallitinib intermediate 6-amino-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] amino quinazoline or a precursor 6-nitro-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] amino quinazoline (I), so that a preparation route of the 6-nitro-4- [4- (thiazole-2-yl) methoxy-3-chlorophenyl ] amino quinazoline (I) which is simple and convenient to operate, safe, environment-friendly, low in cost, high in yield and purity is established, and the method has important significance for production of Vallitinib.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of 6-nitro-4- [4- (thiazole-2-yl) methoxy-3-chlorphenyl ] aminoquinazoline (I). The technical task of the invention is as follows: provides a new synthesis method of 6-nitro-4- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] aminoquinazoline (I), which has the advantages of cheap and easily obtained raw materials, simple and convenient operation, less waste water and acid, safety, environmental protection, low cost, good product yield and high purity.
Description of terms:
a compound of formula II: 2-halo-5-nitrobenzoate; starting materials for the present invention;
A compound of formula III: n- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-halo-5-nitrobenzamide;
A compound of formula I: 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline; the target product of the invention.
In the specification, the compound numbers are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
A process for the preparation of a compound of formula I,
The method comprises the following steps:
(1) Carrying out amidation reaction on the compound shown in the formula II and 4- (thiazole-2-yl) methoxy-3-chloroaniline to obtain a compound shown in the formula III;
Wherein R is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl or sec-butyl, and X is chlorine or bromine;
(2) Carrying out substitution and condensation reaction on a compound shown in a formula III and a formamidine salt to obtain a compound shown in a formula I: 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline.
according to the present invention, it is preferred that the reaction of step (1) is carried out in the presence of a Lewis acid catalyst in the solvent A. Further preferred solvents and catalysts are as follows:
in the step (1), the solvent A is one or a combination of toluene, xylene, chlorobenzene or dichlorobenzene; the mass ratio of the solvent A to the compound shown in the formula II is (5-25) to 1; particularly preferably, the mass ratio of the solvent A to the compound of the formula II is (8-15): 1.
The Lewis acid catalyst in the step (1) is selected from ammonium chloride, zinc chloride, ferric chloride or cuprous chloride; the Lewis acid catalyst is 1.0-3.0% of the compound of formula II by mass.
According to the present invention, it is preferred that the molar ratio of the compound of formula II in step (1) to 2-halo-5-nitrobenzoate to 4- (thiazol-2-yl) methoxy-3-chloroaniline is (0.9-1.5): 1; further preferably, the molar ratio of the compound of formula II, 2-halo-5-nitrobenzoate to 4- (thiazol-2-yl) methoxy-3-chloroaniline, is (1.0-1.1): 1. Preferably, a slight excess of the compound of formula II is advantageous to promote a thorough reaction of the relatively expensive 4- (thiazol-2-yl) methoxy-3-chloroaniline and, due to the better solubility of the compound of formula II, the slight excess of the compound of formula II can be easily removed by recrystallization.
According to the present invention, it is preferred that, in the step (1), the amidation reaction temperature is 60 to 135 ℃; preferably, the amidation reaction temperature is 90-120 ℃. Too low a temperature is not favorable for removing alcohol generated in the reaction process and for carrying out amidation reaction, while too high a temperature may cause decomposition of the raw material 4- (thiazol-2-yl) methoxy-3-chloroaniline. The amidation reaction time is 3 to 10 hours; preferably, the reaction time is 4 to 6 hours.
according to the present invention, it is preferred that the reaction of step (2) is carried out in the presence of a solvent B and an acid-binding agent. The reaction conditions of step (2) are preferably as follows:
In the step (2), the solvent B is one or a combination of N, N-dimethylformamide, N-dimethylacetamide, chlorobenzene or dichlorobenzene; wherein the most preferred solvent B is N, N-dimethylformamide; the mass ratio of the solvent B to the compound shown in the formula III is (2-15) to 1; particularly preferably, the mass ratio of the solvent B to the compound of the formula III is (4-10): 1.
In the step (2), the acid-binding agent is one or a combination of sodium methoxide, sodium methoxide methanol solution, sodium ethoxide ethanol solution, potassium carbonate, sodium carbonate and calcium carbonate; the formamidine salt is formamidine hydrochloride or formamidine acetate; the molar ratio of the formamidine salt, the acid-binding agent and the compound shown in the formula III is (1.0-2.0): (1.0-2.0): 1. Wherein, the mole number of the formamidine salt is slightly higher than that of the acid-binding agent, for example, the mole ratio of the formamidine salt to the acid-binding agent is 1.05-1.15: 1; preferably, the molar ratio of the formamidine salt to the acid-binding agent is 1.09-1.1: 1. The residual small amount of formamidine hydrochloride in the system can play the role of a weak acid catalyst, and is beneficial to intramolecular dehydration of the subsequent condensation reaction.
According to the present invention, it is preferable that in the step (2), the substitution and condensation reaction is carried out in a reactor having a vacuum distillation apparatus, and a low boiling substance is distilled off simultaneously during the reaction. If methanol and water are present in the system, the thiazole ring is liable to be decomposed at high temperature.
According to the invention, preferably, in the step (2), the substitution reaction and the condensation reaction are sequentially carried out in stages, the substitution reaction is carried out at the temperature of 30-70 ℃, and then the condensation reaction is carried out at the temperature of 85-135 ℃; further preferably, the substitution reaction temperature is 45-60 ℃, and the condensation reaction temperature is 95-115 ℃.
According to the present invention, preferably, the substitution and condensation reaction conditions in step (2) are: stirring and reacting for 5 hours at 50-55 ℃, then stirring and reacting for 5 hours at 105-110 ℃, and evaporating low-boiling-point substances while reacting.
According to the invention, in the step (2), the substitution reaction time is preferably 3-10 hours, and particularly preferably 4-6 hours; the condensation reaction time is 4-10 hours, and particularly preferably 6-8 hours.
The substitution and condensation reaction of the step (2) is carried out by a one-pot method.
the process of the present invention is depicted as scheme 4 below:
wherein R is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl or sec-butyl, and X is chlorine or bromine.
Synthesis scheme 4
The process of the invention is not defined in detail and can be carried out according to the prior art. The product post-treatment of step (1) of the present invention can be carried out according to the prior art, and the preferred method for post-treatment of the product of step (1) is as follows: after the reaction is finished, cooling to 20-25 ℃, adding water, layering, distilling an organic phase, recovering the solvent, and recrystallizing the remainder by using methyl tertiary butyl ether to obtain the compound shown in the formula III. The yield can reach more than 96 percent, and the liquid phase purity is more than 99.3 percent.
the product post-treatment of step (2) of the present invention can be carried out according to the prior art, and the preferred product post-treatment method of step (2) is as follows:
After the reaction is finished, cooling to 20-25 ℃, filtering, washing a filter cake by using N, N-dimethylformamide, combining filtrates, carrying out reduced pressure distillation to recover the solvent, and recrystallizing residues by using isopropanol to obtain the compound shown in the formula I: 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I). The yield can reach 90.2 percent, and the liquid phase purity is more than 99.6 percent.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel preparation method of a varlitinib intermediate 6-nitro-4- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] amino quinazoline, which takes 2-halogeno-5-nitrobenzoate as a starting material, firstly carries out amidation reaction with 4- (thiazole-2-yl) methoxyl-3-chloroaniline to obtain N- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] -2-halogeno-5-nitrobenzamide, then the 6-nitro-4- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] amino quinazoline (I) is prepared by the substitution and condensation reaction of the derivative and formamidine salt through a one-pot method.
2. The unit involved in the reaction route of the invention has high reaction activity and high reaction specificity, the amidation reaction of the 2-halogeno-5-nitrobenzoate and the 4- (thiazole-2-yl) methoxy-3-chloroaniline has specific selectivity, the operation is environment-friendly, the reaction controllability is high, the nitro group of the N- [4- (thiazole-2-yl) methoxy-3-chlorphenyl ] -2-halogeno-5-nitrobenzamide obtained by the amidation reaction activates para-halogen atoms, so that the substitution reaction is easy to carry out, and the excessive formamidine salt catalyzes the further dehydration condensation to obtain the thermodynamically stable 6-nitro-4- [4- (thiazole-2-yl) methoxyl-3-chlorphenyl ] amino quinazoline.
3. The invention has the advantages of cheap and easily obtained raw materials, good raw material stability, high reaction selectivity and less side reaction, and is beneficial to the purification post-treatment of the product. The method has mild reaction conditions, easy operation, good product yield and high purity.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products.
In the examples, "%" is a mass percentage unless otherwise specified. The yields in the examples are all molar yields.
Example 1: preparation of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 500 g of toluene, 43.1 g (0.2 mol) of methyl 2-chloro-5-nitrobenzoate (II 1), 48.1 g (0.2 mol) of 4- (thiazol-2-yl) methoxy-3-chloroaniline, 5.0 g of ammonium chloride, and the reaction was stirred at 95 to 100 ℃ for 5 hours, and the resulting methanol was distilled off. Cooling to 20-25 deg.c, adding 50 g of water, layering, distilling the organic phase, recovering the solvent toluene, and recrystallizing the residue with methyl tert-butyl ether to obtain 81.8 g of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (iii 1), with a yield of 96.5% and a liquid phase purity of 99.7%.
example 2: preparation of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-bromo-5-nitrobenzamide (III 2)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 250 g of toluene, 26.0 g (0.1 mol) of methyl 2-bromo-5-nitrobenzoate (II 2), 24.1 g (0.1 mol) of 4- (thiazol-2-yl) methoxy-3-chloroaniline, 3.5 g of zinc chloride, and the reaction was stirred at 90 to 95 ℃ for 5 hours, and the resulting methanol was distilled off. Cooling to 20-25 deg.c, adding 20 g of water, layering, distilling the organic phase, recovering the solvent toluene, and recrystallizing the residue with methyl tert-butyl ether to obtain 45.3 g of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-bromo-5-nitrobenzamide (iii 2), with a yield of 96.7% and a liquid phase purity of 99.3%.
Example 3: preparation of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 250 g of xylene, 23.0 g (0.1 mol) of ethyl 2-chloro-5-nitrobenzoate (II 3), 24.1 g (0.1 mol) of 4- (thiazol-2-yl) methoxy-3-chloroaniline, 3.0 g of ammonium chloride, and the reaction was stirred at 105 to 110 ℃ for 4 hours, and the ethanol produced was distilled off. Cooling to 20-25 deg.c, adding 20 g of water, layering, distilling the organic phase, recovering xylene as solvent, and recrystallizing the residue with methyl tert-butyl ether to obtain 41.1 g of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1), with a yield of 96.9% and a liquid phase purity of 99.5%.
Example 4: preparation of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a vacuum distillation apparatus were charged 300 g of N, N-dimethylformamide, 42.5 g (0.1 mol) of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1) obtained in example 1, 10.0 g (0.12 mol) of formamidine hydrochloride and 22.0 g (0.11 mol) of a 27% sodium methoxide methanol solution, followed by stirring at 50 to 55 ℃ for 5 hours, then stirring at 105 to 110 ℃ for 5 hours, and simultaneously distilling off low boiling substances (methanol and N, N-dimethylformamide containing water). Cooling to 20-25 ℃, filtering, washing a filter cake with 50 g of N, N-dimethylformamide, combining filtrates, recovering the solvent by reduced pressure distillation, and recrystallizing the residue with isopropanol to obtain 37.3 g of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I), wherein the yield is 90.2% and the liquid phase purity is 99.7%.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(400MHz,DMSO-d6)δ(ppm)：
9.35(s,1H),8.58(s,1H),8.41(d,1H),8.10(d,1H),7.83(d,1H),7.79(d,1H),7.64-7.69(m,2H),7.31(d,1H),7.05(d,1H),5.52(s,2H).
example 5: preparation of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a vacuum distillation apparatus were charged 300 g of N, N-dimethylformamide, 46.7 g (0.1 mol) of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-bromo-5-nitrobenzamide (III 1) obtained in example 2, 12.5 g (0.12 mol) of formamidine acetate and 2.2 g (0.11 mol) of a 27% sodium methoxide methanol solution, followed by stirring at 50 to 55 ℃ for 4 hours and then at 105 to 110 ℃ for 5 hours, and the reaction was carried out while distilling off low boiling substances (methanol and N, N-dimethylformamide containing water) by using the distillation apparatus. Cooling to 20-25 ℃, filtering, washing a filter cake with 50 g of N, N-dimethylformamide, combining filtrates, recovering the solvent by reduced pressure distillation, and recrystallizing the residue with isopropanol to obtain 35.7 g of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I), wherein the yield is 86.3% and the liquid phase purity is 99.6%.
comparative example 1: preparation of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 250 g of toluene, 21.6 g (0.1 mol) of methyl 2-chloro-5-nitrobenzoate (II 1), 24.1 g (0.1 mol) of 4- (thiazol-2-yl) methoxy-3-chloroaniline, and the reaction was stirred at 100 to 105 ℃ for 6 hours, and the resulting methanol was distilled off. Cooling to 20-25 deg.c, adding 20 g of water, layering, distilling the organic phase, recovering the solvent toluene, and recrystallizing the residue with methyl tert-butyl ether to obtain 23.8 g of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (iii 1), 56.2% yield and 98.2% liquid phase purity.
Comparative example 2: preparation of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-bromo-5-nitrobenzamide (III 2)
The reaction was stirred at 140 to 145 ℃ for 5 hours, as described in example 2, except that the amidation reaction was carried out. After-treatment 36.7 g of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-bromo-5-nitrobenzamide (III 2) were obtained in 78.3% yield and 96.2% purity in the liquid phase.
The importance of the catalyst for the amidation reaction in step (1) of the process of the present invention is shown by the above comparative example 1. It is shown by the comparison of Belgium 2 that too high a temperature in step (1) leads to a decrease in the yield of the amidation reaction.
Comparative example 3: preparation of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a vacuum distillation apparatus were charged 150 g of N, N-dimethylformamide, 21.2 g (0.05 mol) of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1) obtained by the method of example 1, 5.0 g (0.06 mol) of formamidine hydrochloride, and 14.0 g (0.07 mol) of a 27% sodium methoxide methanol solution, followed by stirring at 50 to 55 ℃ for 5 hours, followed by stirring at 105 to 110 ℃ for 5 hours while distilling off low boiling substances (methanol and N, N-dimethylformamide containing water). Cooling to 20-25 ℃, filtering, washing a filter cake with 50 g of N, N-dimethylformamide, combining filtrates, recovering the solvent by reduced pressure distillation, and recrystallizing the residue with isopropanol to obtain 14.6 g of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I), wherein the yield is 70.6% and the liquid phase purity is 97.6%.
Comparative example 3 shows that after formamidine hydrochloride is reacted with a 27% sodium methoxide methanol solution to be dissociated, the formamidine hydrochloride remained in the system can act as a weakly acidic catalyst after the reaction of the activated N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1) is finished in a low temperature stage, and is favorable for the intramolecular dehydration reaction thereafter. On the other hand, if the amount of the base is excessive, the intramolecular dehydration reaction is not favorable.
Comparative example 4: preparation of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I)
into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a vacuum distillation apparatus were charged 300 g of N, N-dimethylformamide, 42.5 g (0.1 mol) of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1) obtained in example 1, 10.0 g (0.12 mol) of formamidine hydrochloride and 22.0 g (0.11 mol) of a 27% sodium methoxide methanol solution, followed by stirring at 75 to 80 ℃ for 5 hours, then at 105 to 110 ℃ for 5 hours, and low boiling substances (methanol and N, N-dimethylformamide containing water) were distilled off. Cooling to 20-25 ℃, filtering, washing a filter cake with 50 g of N, N-dimethylformamide, merging filtrate, distilling under reduced pressure to recover the solvent, adding 120 g of isopropanol into the residue, heating, refluxing and dissolving for 1 hour, filtering while hot to remove insoluble substances, cooling the filtrate to 15-20 ℃, filtering and drying to obtain 23.5 g of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I), wherein the yield is 56.8 percent, and the purity of a liquid phase is 98.3 percent.
Comparative example 4 shows that the high temperature in the first stage results in more byproducts in the substitution reaction, formamidine has two nitrogen atoms capable of participating in the substitution reaction after being dissociated, and the high temperature results in poor selectivity, increased series side reactions and more byproducts insoluble in isopropanol.
comparative example 5: preparation of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 300 g of N, N-dimethylformamide, 42.5 g (0.1 mol) of N- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] -2-chloro-5-nitrobenzamide (III 1) obtained in example 1, 10.0 g (0.12 mol) of formamidine hydrochloride and 22.0 g (0.11 mol) of a 27% sodium methoxide methanol solution, followed by stirring at 50 to 55 ℃ for 5 hours and then at 105 to 110 ℃ for 5 hours without distilling off low boiling substance methanol and water. Cooling to 20-25 ℃, filtering, washing a filter cake with 50 g of N, N-dimethylformamide, combining filtrates, recovering the solvent by reduced pressure distillation, and recrystallizing the residue with isopropanol to obtain 30.5 g of 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline (I), wherein the yield is 73.8% and the liquid phase purity is 97.6%.
Comparative example 5 shows that methanol and water, which are low boiling substances during the reaction of step (2), cause decomposition of thiazole rings at high temperature, thereby lowering yield and purity, if not distilled out.
Claims (10)
1. A process for the preparation of a compound of formula I,
The method comprises the following steps:
(1) carrying out amidation reaction on the compound shown in the formula II and 4- (thiazole-2-yl) methoxy-3-chloroaniline to obtain a compound shown in the formula III;
Wherein R is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl or sec-butyl, and X is chlorine or bromine;
(2) Carrying out substitution and condensation reaction on a compound shown in a formula III and a formamidine salt to obtain a compound shown in a formula I: 6-nitro-4- [4- (thiazol-2-yl) methoxy-3-chlorophenyl ] aminoquinazoline.
2. A process for the preparation of compounds of formula i as claimed in claim 1, characterized in that the reaction of step (1) is carried out in a solvent a in the presence of a lewis acid catalyst.
3. A process for the preparation of a compound of formula i according to claim 2, characterized in that the solvent a is one or a combination of toluene, xylene, chlorobenzene or dichlorobenzene; the mass ratio of the solvent A to the compound shown in the formula II is (5-25) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (8-15): 1.
4. A process for the preparation of a compound of formula i according to claim 2, characterized in that the lewis acid catalyst is selected from ammonium chloride, zinc chloride, ferric chloride or cuprous chloride; preferably, the Lewis acid catalyst is 1.0 to 3.0% by mass of the compound of formula II.
5. A process for the preparation of a compound of formula i as claimed in claim 1 wherein in step (1) the molar ratio of the compound of formula ii, 2-halo-5-nitrobenzoate to 4- (thiazol-2-yl) methoxy-3-chloroaniline is (0.9-1.5): 1; preferably, the molar ratio of the compound of formula II, 2-halo-5-nitrobenzoate to 4- (thiazol-2-yl) methoxy-3-chloroaniline, is (1.0-1.1): 1.
6. the process for the preparation of a compound of formula i as claimed in claim 1, wherein in step (1), the amidation reaction temperature is 60-135 ℃; preferably, the amidation reaction temperature is 90-120 ℃.
7. the process for preparing a compound of formula i according to claim 1, wherein the reaction of step (2) is carried out in the presence of a solvent B and an acid-binding agent.
8. the process for the preparation of a compound of formula i according to claim 7, wherein solvent B is one or a combination of N, N-dimethylformamide, N-dimethylacetamide, chlorobenzene or dichlorobenzene; preferably, the mass ratio of the solvent B to the compound of the formula III is (2-15): 1.
9. The method for preparing the compound of formula I according to claim 7, wherein the acid-binding agent is one or a combination of sodium methoxide, sodium methoxide methanol solution, sodium ethoxide ethanol solution, potassium carbonate, sodium carbonate and calcium carbonate; the formamidine salt is formamidine hydrochloride or formamidine acetate; preferably, the molar ratio of the formamidine salt, the acid-binding agent and the compound of formula III is (1.0-2.0): 1.
10. the method for preparing the compound of formula I according to claim 1, wherein in the step (2), the substitution and condensation reactions are sequentially performed in stages, the substitution reaction is performed at a temperature of 30-70 ℃, and then the condensation reaction is performed at a temperature of 85-135 ℃; preferably, low-boiling-point substances are simultaneously distilled during the substitution and condensation reaction; further preferably, the substitution reaction temperature is 45-60 ℃, and the condensation reaction temperature is 95-115 ℃.
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Denomination of invention: Preparation method of 6-nitro-4-substituted aminoquinoline derivatives Effective date of registration: 20231205 Granted publication date: 20201201 Pledgee: Hengfeng bank Limited by Share Ltd. Dongying branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980069314 |