WO2007138613A2 - A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride - Google Patents
A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride Download PDFInfo
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- WO2007138613A2 WO2007138613A2 PCT/IN2007/000101 IN2007000101W WO2007138613A2 WO 2007138613 A2 WO2007138613 A2 WO 2007138613A2 IN 2007000101 W IN2007000101 W IN 2007000101W WO 2007138613 A2 WO2007138613 A2 WO 2007138613A2
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- WO
- WIPO (PCT)
- Prior art keywords
- bis
- methoxyethoxy
- formula
- compound
- solvent
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 42
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 230000002194 synthesizing Effects 0.000 title claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 title claims description 10
- 238000003786 synthesis reaction Methods 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960001433 Erlotinib Drugs 0.000 claims abstract description 11
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims abstract description 11
- 239000012458 free base Substances 0.000 claims abstract description 11
- IBGBGRVKPALMCQ-UHFFFAOYSA-N Protocatechuic aldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- KTOCATSUCSJPCT-UHFFFAOYSA-N COCCOc(ccc(C#N)c1)c1OCCOC Chemical compound COCCOc(ccc(C#N)c1)c1OCCOC KTOCATSUCSJPCT-UHFFFAOYSA-N 0.000 claims abstract description 7
- GPEGMQBVLGNIMY-UHFFFAOYSA-N 3,4-bis(2-methoxyethoxy)benzaldehyde Chemical compound COCCOC1=CC=C(C=O)C=C1OCCOC GPEGMQBVLGNIMY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- XCXKYIJVCWFCLF-UHFFFAOYSA-N 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile Chemical compound COCCOC1=CC(N)=C(C#N)C=C1OCCOC XCXKYIJVCWFCLF-UHFFFAOYSA-N 0.000 claims abstract description 5
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical compound NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 claims abstract description 5
- JNNCLIICKUIURH-UHFFFAOYSA-N 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile Chemical compound COCCOC1=CC(C#N)=C([N+]([O-])=O)C=C1OCCOC JNNCLIICKUIURH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001649 bromium compounds Chemical class 0.000 claims abstract description 3
- 230000001808 coupling Effects 0.000 claims abstract description 3
- 238000010168 coupling process Methods 0.000 claims abstract description 3
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- -1 methoxyethoxy Chemical group 0.000 claims description 6
- 230000000802 nitrating Effects 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 150000001448 anilines Chemical class 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- 239000003638 reducing agent Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical class CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 239000001184 potassium carbonate Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- FXZWPZMCZNJILD-UHFFFAOYSA-N N-[(6-bromopyridin-3-yl)methyl]ethanamine;hydrochloride Chemical compound Cl.CCNCC1=CC=C(Br)N=C1 FXZWPZMCZNJILD-UHFFFAOYSA-N 0.000 claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- VTWKXBJHBHYJBI-VURMDHGXSA-N (NZ)-N-benzylidenehydroxylamine Chemical compound O\N=C/C1=CC=CC=C1 VTWKXBJHBHYJBI-VURMDHGXSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N Propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- CSMWJXBSXGUPGY-UHFFFAOYSA-L Sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical group [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 2
- 239000001187 sodium carbonate Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229940075931 sodium dithionate Drugs 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000002378 acidificating Effects 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 229960005073 Erlotinib Hydrochloride Drugs 0.000 abstract description 9
- DAJSDPMXDPYMCB-UHFFFAOYSA-N N'-[2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylmethanimidamide Chemical compound COCCOC1=CC(N=CN(C)C)=C(C#N)C=C1OCCOC DAJSDPMXDPYMCB-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006396 nitration reaction Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 1
- 238000006170 formylation reaction Methods 0.000 abstract 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N methanoic acid amidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- ZPJLDMNVDPGZIU-UHFFFAOYSA-N 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline Chemical compound C1=NC(Cl)=C2C=C(OCCOC)C(OCCOC)=CC2=N1 ZPJLDMNVDPGZIU-UHFFFAOYSA-N 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 102100010782 EGFR Human genes 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 101700039191 EGFR Proteins 0.000 description 3
- YZOWMIHUDJVXBH-UHFFFAOYSA-N ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate Chemical compound CCOC(=O)C1=CC(OCCOC)=C(OCCOC)C=C1N YZOWMIHUDJVXBH-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XSLSFNALFKUARJ-UHFFFAOYSA-N 6,7-bis(2-methoxyethoxy)-1H-quinazolin-2-one Chemical compound C1=NC(=O)NC2=C1C=C(OCCOC)C(OCCOC)=C2 XSLSFNALFKUARJ-UHFFFAOYSA-N 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N Adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- KBPUBCVJHFXPOC-UHFFFAOYSA-N Ethyl protocatechuate Chemical compound CCOC(=O)C1=CC=C(O)C(O)=C1 KBPUBCVJHFXPOC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N Potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 229910019020 PtO2 Inorganic materials 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VOHOFZNVWZWVMA-UHFFFAOYSA-N ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate Chemical compound CCOC(=O)C1=CC(OCCOC)=C(OCCOC)C=C1[N+]([O-])=O VOHOFZNVWZWVMA-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- HUJDMSWRGMPHJD-UHFFFAOYSA-M 2-amino-4,5-bis(2-methoxyethoxy)benzoate Chemical compound COCCOC1=CC(N)=C(C([O-])=O)C=C1OCCOC HUJDMSWRGMPHJD-UHFFFAOYSA-M 0.000 description 1
- ASQUQUOEFDHYGP-UHFFFAOYSA-N 2-methoxyethanolate Chemical group COCC[O-] ASQUQUOEFDHYGP-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N Ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 0 COCCOC(C(OCC*)=CC1)=C[C@@]1C=NO Chemical compound COCCOC(C(OCC*)=CC1)=C[C@@]1C=NO 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 102000004278 Receptor protein-tyrosine kinases Human genes 0.000 description 1
- 108090000873 Receptor protein-tyrosine kinases Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor Effects 0.000 description 1
- 229940045988 antineoplastic drugs Protein kinase inhibitors Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 231100000313 clinical toxicology Toxicity 0.000 description 1
- 231100001010 corrosive Toxicity 0.000 description 1
- 231100000078 corrosive Toxicity 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 101500002601 human Epidermal growth factor Proteins 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001613 neoplastic Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002062 proliferating Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The present invention provides a process for synthesizing [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride (Erlitinib Hydrochloride) having the formula (I) comprising reacting 3,4-dihydroxy benzaldehyde with bromo derivative of ethyl methyl ether to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde having formula (III). This is converted to give 3,4- bis (2-methoxyethoxy)-benzonitrile which on furthur nitration we obtain 4,5- bis (2-methoxyethoxy)-2-nitrobenzonitrile which on nitro reduction we get 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile. Formylation of this compound yields N'-[2-cyano-4,5-bis(2methoxyethoxy)phenyl]-N,N-dimethylformamidine. Coupling of this formamidine with 3-ethynyl aniline gives erlotinib free base. On furthur treatment of this free base with methanolic/ethanolic hydrochloric acid gives us erlotinib hydrochloride.
Description
A PROCESS FOR SYNTHESIS OF [6,7-BIS-(2-METHOXYETHOXY)- QUINAZOUN^-Yg-ta-ETHYNYLPHENYLJAMINE HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to a process for synthesis of [ 6,7-bis- (2-methoxyethoxy) - quinazolin -4- yl]-(3-ethynylphenyl)amine hydrochloride of the formula I.
It is a low molecular weight compound used in the treatment of proliferative neoplastic and malignant diseases including multiple forms of solid tumors and psoriasis. It inhibits epidermal growth factor- receptor tyrosine kinase (EGFR-TKI). Receptor protein tyrosine kinases play a key role in signal transduction pathways that regulates cell division and differentiation. Over expression of certain growth factor receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) as well as human epidermal growth factor receptor (HER-2) leads to cancer. Protein kinase inhibitors particularly phosphorylation inhibitors, have become important targets for selective cancer therapies (Bioorganic & Medicinal chemistry Letters 12, 2893-2897 (2002). Further, it exhibits significant anti-tumor activity in a broad range of solid tumor xenografts in vivo. Clinical toxicology studies have demonstrated good oral bio-availability and in long term oral administration it was well tolerated.
Description of prior art:
As known process for the synthesis of erlotinib hydrochloride , there can be mentioned a method comprising preparation of 6,7-bis(2- methoxyethoxy)quinazo!one and then reacting 4-chloro-6,7-bis(2- methoxyethoxy)quinazoline with 3-ethynylaniline under basic conditions such as pyridine or using excess aniline in solvents like isopropanol ( US patent No. 5,747,498, May 5, 1998), followed by silica gel column chromatographic purification as a free base erlotinib and titration of free base with IM HCI to yield erlotinib hydrochloride in 71% final step yield. Further preparation of 4-chloro-6,7-bis-( 2-methoxyethoxy)quinazoline involved many independent steps like alkylation of ethyl 3,4- dihydroxybenzoate using 2-bromoethylmethyl ether and potassium carbonate, followed by nitration with nitric acid / acetic acid which yielded ethyl 4,5-bis (2-methoxyethoxy)-2-nitrobenzoate. The resulting nitro compound was then reduced to ethyl-2-amino- 4,5-bis-(2- methoxyethoxy)benzoate by hydrogenation in presence of PtO2 with a yield of about 88%. This step involved handling of a combustible gas like hydrogen as well as costly catalyst such as PtO2. Further cyclization of ethyl-2-amino-4,5-bis-(2-methoxyethoxy)benzoate has been achieved using ammonium formate and formaldehyde at a high temperature of 160-1650C yielding 6,7-bis-(2-methoxyethoxy)-quinazolone. Treatment of 6,7-bis(2- methoxyethoxy)-quinazolinone with oxalylchloride / phosphorousoxychloride in presence of suitable solvent yielded 4-chloro-6,7-bis-(2-methoxyethoxy)- quinazoline with yields of 92% and 56% respectively. Thus multiple steps are involved with usage of several costly reagents like platinum oxide, flammable gas like hydrogen and at very high reaction temperatures. Further the penultimate step product namely [6,7-bis-{2-methoxyethoxy)-
quinazolin-4-yl]-(3-ethynylphenyl)amine is purified by silica column chromatography . All these steps not only push the manufacturing cost to a higher side but also take more time. Thus this known method involves various industrial difficulties.
The steps of the process given in US Patent 5,747,498 are:
EthyI-3,4-dihydroxy benzoate EthyI-3,4-bis(2-methoxyethoxy)benzoate
Ethyl-2-amino-4,5-bis(2-methoxyethoxy)benzoate
4-chloro-6,7-bis(2-methoxyethoxy)quinazoline
6 ,7-bi s (2-methoxyethoxy)q ui πazoli ne-4-one
Erlotinib hydrochloride
Summary of the Invention
In view of problems as described in above process, there is provided a process in the present invention a more efficient and convergent process for the synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3- ethynylphenyl)amine hydrochloride (scheme-1) having the above formula I by substantially reducing the number of steps and also intermediates that must be isolated. Further the present invention has significant advantage in terms of cost and time. In present invention, processes are provided for the preparation of key intermediates that must be used in the synthesis of compound of formula I.
One of the objectives of the present invention is to provide a simple and convergent process for preparation of Erlotinib hydrochloride.
According to another objective of this invention there is provided a novel compound of the formula VIII which is an intermediate for the preparation of the compound of formula I and a process for its preparation.
VIiI
DETAILS OF THE INVENTION
To obviate the disadvantages of the prior art, the present invention provides a process for the synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3- ethynylphenyl)amine hydrochloride having the formula I,
comprising
a) reacting 3,4-dihydroxy benzaldehyde having formula
Il
with substituted ethylmethyl ether in presence of an inert solvent and a base to obtain 3,4-bis( 2-methoxyethoxy) benzaldehyde having formula III,
b) converting compound of the formula III in presence of a base and an organic solvent into 3,4-bis(2-
IV
methoxyethoxy)benzaldoxime of the formula IV and dehydrating the said compound to obtain 3,4-bis(2 methoxyethoxy )benzonitrile having formuia V
V
c) nitrating the compound of the formula V with nitrating agent to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitriIe having the formula Vl
Vl d) subjecting the compound of the formula Vl to nitro reduction to get 2- amino-4,5-bis(2methoxyethoxy)benzonitrile having the formuia VII
VII
e) formylating of the compound of formula VII with a formylating agent in the presence of a derivative of formic acid to give N'-[2-cyano- 4,5-bis(2methoxyethoxy)pheny]-N,N-dimethylformamidine of formula VIII
VIII
f) coupling the compound of the formula VIII with an aniline derivative in the presence of a acid catalyst to obtain [6,7-bis-(2-methoxyethoxy)- quinazolin-4-yl]-(3-ethynytphenyl)-amine (erlotinib free base) .
g) treatment of the erlotinib free base with a polar solvent containing hydrochloric acid to obtain the compound of formula (I)
The compound of formula (I) of above process is purified by recrystallisation from solvents to get the compound of acceptable purity.
The inert solvent in step (a) is an aprotic solvent selected from aliphatic ketones and substituted amides, preferably dimethyl formamide .
The substitution of the ethylmethylether in step (a) is chloro, bromo, iodo, hydroxy or a methoxy group preferably bromo derivative.
The base in step (a) is alkali or alkaline earth carbonate and hydroxide preferably sodium and potassium carbonate.
The reaction mixture in step (a) is maintained at a temperature from ambient to reflux temperature preferably from 80° C to 100° C .
The solvent in step (b) is aliphatic alcohol preferably methanol or isopropanol. The base in step (b) is organic or inorganic bases wherein the organic base is pyridine, dimethylaminopyridine, or triethylamine and the inorganic base is sodium acetate or ammonium acetate; the organic base used preferably is pyridine.
The dehydration in step (b) is carried out in the presence of thionyl chloride, phosphorous oxy chloride, propionic anhydride or acetic anhydride ; preferably acetic anhydride.
The reaction in step (b) is from ambient to reflux temperature from 50° C to 120° C ; preferably reaction is carried out at 110 ° C .
The nitrating agent in step (c )can be selected from nitric acid /sulphuric acid and potassium nitrate.
The nitro reduction in step (d) is carried out in the presence of suitable catalyst on an inert carrier and in an inert solvent or in the presence of an inorganic reducing agent .
The reduction of the nitro group in step (d) is carried out in the presence of the catalyst selected from palladium .platinum or iron , inert carrier is carbon, and the inert solvent is selected from water, ethanol, methanol or acetic acid or the
inorganic reducing agent used in step (d) is sodium dithionate at a temperature in the range from 30 to 50 ° C conveniently at 30 ° C ..
The fomylating agent used in step (e) is N,N-dimethylformamide dimethyl acetal in the presence of a polar aprotic solvent , an aromatic solvent or a dipolar aprotic solvents , preferably N1N dimethyl formamide at a temperature range from 20 to 140 ° C. , preferably at 115 ° C.
The process in step (e) wherein the • polar aprotic solvent is tetrahydrofuran, 1 ,4 dioxane
• aromatic solvent used is toluene
• a dipolar aprotic solvent used is N1N- dimethylacetamide
The aniline derivative coupled to the compound of formula VIII in step (f) in one pot procedure is a 3-ethynyl aniline in the presence of acid catalyst at a temperature range from 300C to 140° C preferably at 130° C.
The acid catalyst is selected from trifluroacetic acid , formic acid , preferably acetic acid.
The polar solvent used in step (h) is selected from methanolic hydrochloric acid or ethanolic hydrochloric acid.
The process of the present invention provides the following distinct advantages over the prior art.
(a) Reduction in the number of steps:
The usage of costly reducing agent like platinum oxide in reducing nitro compound and higher temperatures used in cyclization of 2-amino-4,5-bis-(2- methoxyethoxy)benzoate are reported in US patent 5,747,498. Further 4-
chloro-6,7-bis( 2-methoxyethoxy)quinazoline is coupled with suitably substituted aniline in the presence of additional base and isolated erlotinib as a free base and purified it by silica column chromatography. All these steps involve several independent operations including usage of flammable hydrogen gas and subjecting to silica column chromatographic purifications. In contrast, according to the processes of present invention erlotinib free base preparation is accomplished in one go from N'-[2-cyano-4, 5-bis (2- methoxyethoxy) phenyl]-N, N-dimethylformamidine without using corrosive chemicals like POCI3/SOCI2 and purified by crystallization techniques alone.
The process of preparation of 6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3- ethynylphenyl)amine hydrochloride , is herein described with reference to the following examples:
EXAMPLES a) 3,4-bis (2-methoxyethoxy) benzaldehyde:
To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dϊmethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. Evaporation yielded 3,4-bis (2- methoxyethoxy) benzaldehyde of formula III (45g, 98%).
NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(S1 1H)1 7.45(d, 1 H) and 9.83(s, 1 H).
b) 3,4- bis (2-methoxyethoxy) benzonitrile:
To 3,4-bis(2-methoxyethoxy) benzaldehyde of the formula III (45g, 0.177 mole)and hydroxylamine hydrochloride (45g, 0.6521 mole), in methanol (200ml) was added pyridine (52ml, 0.6521 mole). This reaction mixture was stirred at reflux temperature for about 3 hours. Methanol was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed the organic layer with water and dil. HCI, dried over anhydrous sodium sulphate. To the residue obtained after evaporation of ethylacetate was added acetic anhydride (75ml) and heated to 1100C for 4 hours, then cooled the reaction mixture to room temperature, quenched in water and adjusted the PH to 8 with sodium bicarbonate and extracted with methylene chloride. Organic layer was washed with water and dried over calcium chloride. On evaporation of the solvent, a brown liquid i.e. 3,4- bis (2-methoxyethoxy) benzonitrile (42g, 95%) of the formula V.
NMR (CDCI3): δ 3.45 (s, 6H), 3.79(m, 4H), 4.18(m, 4H), 6.93(d, 1 H), 7.14(d, 1 H) and 7.26(dd, 1 H)
c) 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile: To 70% nitric acid (84ml) maintained at 400C was added 3,4-bis(2- methoxyethoxy) benzonitrile (42g) of the formula V slowly over a period of 2 hours under stirring. After complete addition of the compound, stirring continued for further an hour, quenched the reaction mass in ice-water, filtered, washed the precipitate with water and dried the material at 500C to get yellow solid i.e. 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile of the formula Vl (44.5g, 90%); m.p. 139-1430C.
NMR (CDCI3)I δ 3.45 (s, 6H), 3.82(m, 4H), 4.30(m, 4H), 7.28(s, 1 H) and 7.85(s, 1 H).
(d) Synthesis of 2-amino-4, 5-bis (2-methoxyethoxy) benzonitrile:
To 4,5-bis (2-methoxyethoxy)-2-nitrobenzonitriIe(10 g) was added acetic acid (75ml) and water(75ml), stirred the reaction mass for about 10 min, added Iron powder (7g) in portions over a period of 2hrs, Stirred the reaction mixture for about Vz hr at 300C adjusted PH of the reaction mass to 7. Extracted the material into ethylacetate, the organic layer was dried over sodium sulfate and concentrated to yield crystalline yellow solid, Which was further recrystallized from methanol (6g) mp 74-77 0C
1HNMR (CDCI3): δ 3.43(s, 6H), 3.73(m, 4H), 4.08(m, 4H), 4.20(brs, 2H), 6.25(s, 1H)1 6.90(S1 1H) e) Synthesis of N'-[2-cyano-4, 5-bis (2-methoxyethoxy) phenyl]-N, N- dimethylformamidine:_
To a solution of DMF(12ml) and N,N-dimethylformamide dimethylacetal(DMA, 6ml, 0.045 moles) was added 2-amino-4,5-bis(2- methoxyethoxy)benzonitrile(6g, 0.0225moles) and refluxed for about 3hrs, concentrated excess DMF-DMA to obtain light brown liquid(6.5g)
1HNMR (CDCI3): δ 3.06(s, 6H), 3.44(s, 6H), 3.75(m, 4H), 4.13(m, 4H), 6.48(s, • 1 H), 7.02(s, 1H)1 7.55(s, 1 H)
(f) [6, 7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyI) amine:
To N'-[2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N- dimethylformamidine(6.5g, 0.0202 moles) was added 3-ethynylaniline(2.37g, 0.0202 moles) and acetic acid(25ml) heated the reaction mixture to 125°C, stirred the reaction mixture for about 3hrs, quenched in ice water, neutralized with sodium bicarbonate, extracted the product into ethyl acetate, the organic layer was dried over sodium sulfate and concentrated to yield crude material which was further crystallized from ethyl acetate to get off-white crystalline compound(δ.Og) having the mp 149-153 0C.
(g) [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride (Erlotinib hydrochloride):
To a stirred solution of Erlotinib (6g) in methanol (50ml) was passed dry hydrochloric acid stirred the reaction mass for about 1/2hr the solid precipitated was filtered to get the white crystalline material of erlotinib hydrochloride (6g) having the mp 228-230 0C
UV, IR, NMR spectral data together with elemental analysis is in complete agreement with those of standard substance of erlotinib Hydrochloride.
Scheme-1:
Erlotinib free base
VIII
Erlotinib HCI
In our copending application 1483/CHE/2005 we have described the process for preparing 6,7-bis-(2methoxyethoxy)-quinazolin-4-yl]-(3- ethynylphenyl)amine hydrochloride (erlotinib hydrochloride)
Claims
1. A process for the synthesis of [ 6,7-bis(2-methoxyethoxy)quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride having formula (I)
K with substituted ethylmethyl ether in presence of an inert solvent and a base to obtain 3,4-bis( 2-methoxyethoxy) benzaldehyde having formula III,
b) converting compound of the formula III in presence of a base and an organic solvent into 3,4-bis(2- 
IV methoxyethoxy)benzaldoxime of the formula IV and dehydrating the said compound to obtain 3,4-bis(2 methoxyethoxy )-benzonitrile having formula V
V c) nitrating the compound of the formula V with nitrating agent to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile having the formula Vl
Vl
d) subjecting the compound of the formula Vl to nitro reduction to get 2- amino-4,5-bis(2methoxyethoxy)benzonitrile having the formula VII
VII e) formylating of the compound of formula VlI with a formylating agent in the presence of a derivative of formic acid to give N'-[2-cyano-4,5- bis(2mehtoxyethoxy)pheny]-N,N-dimethylformamidine of formula VIII
VIII
f) coupling the compound of the formula VIII with an aniline derivative in the presence of acidic catalysts to obtain [6,7-bis-(2-methoxyethoxy)- quinazolin-4-yl]-(3-ethynylphenyl)-amine (erlotinib free base) . g) treatment of the erlotinib free base with a polar solvent containing hydrochloric acid to obtain the compound of formula (I)
2. The process as claimed in claim 1 wherein the compound of formula (I) is purified by recrystallisation from polar solvents to get the compound of acceptable purity.
3. The process as claimed in claim 1 , wherein the inert solvent in step (a) is an aprotic solvent selected from aliphatic ketones and substituted amides, preferably dimethyl formamide.
4. The process as claimed in claim 1, wherein the substitution of the ethylmethylether in step (a) is chloro, bromo, iodo, hydroxy or a methoxy group preferably bromo derivative.
5. The process as claimed in claim 1 , wherein the base in step (a) is alkali or alkaline earth carbonate and hydroxide preferably sodium and potassium carbonate.
6. The process as claimed in claim 1 , wherein the reaction mixture in step (a) is maintained at a temperature from ambient to reflux temperature preferably from 80° C to 100° C.
7. The process as claimed in claim 1, wherein the solvent in step (b) is aliphatic alcohol preferably methanol or isopropanol.
8. The process as claimed in claim 1 , wherein the base in step (b) is organic or inorganic bases wherein the organic base is pyridine, dimethylaminopyridine, or triethylamine and the inorganic base is sodium acetate or ammonium acetate; the organic base used preferably is pyridine.
9. The process as claimed in claim 1 , wherein the dehydration in step (b) is carried out in the presence of thionyl chloride, phosphorous oxy chloride, propionic anhydride or acetic anhydride ; preferably acetic anhydride.
10. The process as claimed in claim 1 , wherein the reaction in step (b) is from ambient to reflux temperature from 50° C to 120° C ; preferably reaction is carried out at 110 ° C .
11. The process as claimed in claim 1, wherein the nitrating agent in step
(c) is nitric acid
12. The process as claimed in claim 1, wherein the reaction in step (c ) is carried out in the temperature range from 25° C to 50° C ; preferably at
45 0 C .
13. The process as claimed in claim 1 wherein the nitro reduction in step
(d) is carried out in the presence of suitable catalyst on an inert carrier and in an inert solvent or in the presence of an inorganic reducing agent .
14. The process as claimed in claim 1 under step (d) wherein the catalyst is selected from palladium .platinum or iron or the inorganic reducing agent sodium dithionate and the solvent is selected from water, ethanol, methanol or acetic acid at a temperature in the range from 30 to 50 ° C conveniently at 30 0 C .
15. The process as claimed in claim 1, wherein the fomylating agent used in step (e) is N,N-dimethylformamide dimethyl acetal in the presence of a polar aprotic solvent , an aromatic solvent or a dipolar aprotic solvents , preferably N, N dimethyl formamide at a temperature range from 20 to 140 ° C. , preferably at 115 ° C.
16. The process as claimed in step (e) wherein the
• polar aprotic solvent is tetrahydrofuran, 1 ,4 dioxane
• aromatic solvent used is toluene
• a dipolar aprotic solvent used is N1N- dimethylacetamide
17. The process as claimed in claim 1 , wherein the aniline derivative coupled to the compound of formula VIII in step (T) in one pot procedure is a 3-ethynyl aniline in the presence of acid catalyst at a temperature range from 300C to 140° C preferably at 130° C.
18. The process as claimed in step (f) wherein the acidic catalyst is selected from trifiuroacetic acid , formic acid , preferably acetic acid.
19. The process as claimed in claim, 1 wherein the polar solvent used in step (g) is selected from methanolic hydrochloric acid or ethanolic hydrochloric acid.
20. The process of preparation of 6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride , is substantially as herein described with reference to the foregoing examples.
21. [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride wherever prepared by the process as claimed in any of the preceding claims
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