CN106928069B - A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate - Google Patents
A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate Download PDFInfo
- Publication number
- CN106928069B CN106928069B CN201710170599.7A CN201710170599A CN106928069B CN 106928069 B CN106928069 B CN 106928069B CN 201710170599 A CN201710170599 A CN 201710170599A CN 106928069 B CN106928069 B CN 106928069B
- Authority
- CN
- China
- Prior art keywords
- ethyl
- bis
- acid
- methoxy ethoxy
- preparation side
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000003223 protective agent Substances 0.000 claims abstract description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 4
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 2
- YQUVCSBJEUQKSH-UHFFFAOYSA-N 3,4-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims description 2
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims description 2
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- QWELSYQNDFTISP-UHFFFAOYSA-N 1-chloro-1-methoxyethane Chemical compound COC(C)Cl QWELSYQNDFTISP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 5
- 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 description 5
- 229940120982 tarceva Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- XGLJSPFXMGSGKC-UHFFFAOYSA-N 1-bromo-1-methoxyethane Chemical compound COC(C)Br XGLJSPFXMGSGKC-UHFFFAOYSA-N 0.000 description 1
- ZDHMXCUHUAZBOT-UHFFFAOYSA-N 1-iodo-1-methoxyethane Chemical compound COC(C)I ZDHMXCUHUAZBOT-UHFFFAOYSA-N 0.000 description 1
- BVZLOXBXCDSRNS-UHFFFAOYSA-N 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid Chemical compound COCCOC1=CC(C(O)=O)=C([N+]([O-])=O)C=C1OCCOC BVZLOXBXCDSRNS-UHFFFAOYSA-N 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 108010072039 Histidine kinase Proteins 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- CPNMAYYYYSWTIV-UHFFFAOYSA-N ethyl 2-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC=C1[N+]([O-])=O CPNMAYYYYSWTIV-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- -1 first Chemical compound 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical group C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
One kind 4 of the invention; the preparation method of 5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate; include the following steps: (1) by 4; 5- dihydric ethyl benzoate is first reacted with protective agent; then 6- nitro -4', 5'- methylene-dioxy ethyl benzoate is obtained with nitric acid reaction under acid catalysis；(2) it by the first Deprotection in the presence of alkali of 6- nitro -4', 5'- methylene-dioxy ethyl benzoate, is directly added into the chloro- 2- Ethyl Methyl Ether of 1- and a small amount of catalyst reaction obtains product.The present invention provides more pratical and feasible and economic method, yield is higher and product is purer；Cost is relatively low, and using the reagent being easily obtained, can be carried out large-scale production, have a good application prospect.
Description
Technical field
The present invention relates to Tarceva intermediate preparation fields, in particular to one kind 4,5- bis- (2- methoxy ethoxy)-
The preparation method of 2- ethyl nitrobenzoate.
Background technique
Tarceva (Erlotinib) is by Roche (Roche), western (OSI) biopharmaceutical company difficult to understand and Genentech
(Genentech) a kind of cancer treatment drugs of drugmaker's joint development are to lose for treating at least one chemotherapy regimen
The original new drug of the Locally Advanced or Metastatic Nsclc (NSCLC) that lose.It is epidermal growth factor that Tarceva, which is a kind of,
Sub- receptor tyrosine kinase inhibitors (EGFR-TK), it can selectively block human epidermal growth factor acceptor (EGFR) junket
Histidine kinase and the autophosphorylation for reducing EGFR grow stopping and apoptosis so as to cause cell, swell to EGFR overexpression
The phosphate cpd of oncocyte has apparent inhibitor effect.
4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate is the key that intermediate during preparing Tarceva
Body.The published method for preparing 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate is (see document WO9630347；
US5747498；CN1137037):
Existing preparation method causes to produce because having used the bromo- 2- Ethyl Methyl Ether of 1- or the iodo- 2- Ethyl Methyl Ether of 1-
The production cost of object is higher.
Summary of the invention
The main purpose of the present invention is to provide a kind of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoates
Preparation method, this method provides more pratical and feasible and economic method, yield is higher and product is purer；Cost is relatively low, and
And using the reagent being easily obtained, it can be carried out large-scale production, have a good application prospect.
The present invention provides the preparation method of one kind 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate, packets
Include following steps:
(1) by 4,5- dihydric ethyl benzoate in organic solvent A first with reacted under protective agent room temperature (16 DEG C -30 DEG C)
1-2h adds water quenching to go out, liquid separation, concentration, and then 24-36h with 0-20 DEG C of nitric acid is reacted in 1:1 ~ 2 in molar ratio under acid catalysis, uses
Organic solvent B extraction, dry, concentration obtains 6- nitro -4', 5'- methylene-dioxy ethyl benzoate；
(2) 6- nitro -4', 5'- methylene-dioxy ethyl benzoate is dissolved in organic solvent A and is taken off in the presence of alkali
Protecting group, 1-3h is reacted with chloro- 40-80 DEG C of 2- Ethyl Methyl Ether of 1- in 1:1 ~ 3 in molar ratio, is extracted with organic solvent B, dry,
Concentration, obtains 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate.
Further, protective agent is methylchloroformate, ethyl chloroformate, triphosgene, orthoformic acid front three in the step (1)
One of ester, triethyl orthoformate, trimethyl orthoacetate, triethly orthoacetate；Protective agent and 4,5- dihydroxy-benzoic acid second
The molar ratio of ester is 1-1.2:1.
Preferably, the protective agent is ethyl chloroformate.
Further, the acid in the step (1) is organic acid or inorganic acid；Acid and 4,5- dihydric ethyl benzoate
Molar ratio is 0.8-1:1.
Further, the organic acid is acetic acid；Inorganic acid is sulfuric acid or phosphoric acid.
Preferably, the acid is acetic acid.
Further, the organic solvent A in the step (1) and (2) is methanol, ethyl alcohol, ethyl acetate, acetonitrile, tetrahydro
One or more of the tertiary ether of furans, petroleum ether, first, methylene chloride.
Preferably, the organic solvent A is methanol.
Further, the organic solvent B in the step (1) and (2) be methylene chloride, tetrahydrofuran, acetonitrile, ether,
One or more of ethyl acetate, chloroform.
Preferably, the organic solvent B is methylene chloride or ethyl acetate.
Further, the alkali in the step (2) is organic base or inorganic base；Alkali and 6- nitro -4', 5'- (methylenedioxy)
The molar ratio of yl benzoic acid ethyl ester is 3-4:1.
Further, the organic base is triethylamine, diisopropylethylamine or pyridine；Inorganic base be sodium carbonate, potassium carbonate,
Sodium bicarbonate, sodium hydroxide or potassium hydroxide.
Preferably, alkali is sodium carbonate.
Further, potassium iodide is added in the step (2) as catalyst.
Preferably, the reaction temperature in the step (1) is 0-5 DEG C.
The present invention is used for the starting material of the method and reagent can be commercially available or known in the literature.It holds
Technology needed for this reaction of row and purified reaction product is known to those of ordinary skill in the art.Method of purification includes
Crystallization, distillation, positive or RP chromatography.
Beneficial effect
The present invention for preparation 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate provide it is more pratical and feasible and
Economic method, yield is higher and product is purer；Cost is relatively low, and using the reagent being easily obtained, can be carried out extensive
Production, has a good application prospect.
Detailed description of the invention
The attached drawing constituted part of this application is used to provide further understanding of the present invention, schematic reality of the invention
It applies example and its explanation is used to explain the present invention, do not constitute improper limitations of the present invention.In the accompanying drawings:
Fig. 1 is the HMNR figure of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate that embodiment 1 obtains；
Fig. 2 is the HPLC figure of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate that embodiment 1 obtains；
Fig. 3 is the MS figure of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate that embodiment 1 obtains.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.The present invention will be described in detail below with reference to the accompanying drawings and embodiments.
In order to enable those skilled in the art to better understand the solution of the present invention, below in conjunction in the embodiment of the present invention
Attached drawing, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is only
The embodiment of a part of the invention, instead of all the embodiments.Based on the embodiments of the present invention, in ordinary skill
Personnel do not make every other embodiment obtained under the premise of creative work, and protection model of the invention all should belong to
It encloses.
It should be noted that description and claims of this specification and term " first " in above-mentioned attached drawing, "
Two " etc. be to be used to distinguish similar objects, without being used to describe a particular order or precedence order.It should be understood that using in this way
Data be interchangeable under appropriate circumstances, so as to the embodiment of the present invention described herein can in addition to illustrating herein or
Sequence other than those of description is implemented.In addition, term " includes " and " having " and their any deformation, it is intended that cover
It covers and non-exclusive includes.
Embodiment 1
(1) preparation of 6- nitro -4', 5'- methylene-dioxy ethyl benzoate
4,5- dihydric ethyl benzoate (45.5g, 0.25mol) it is molten arrive 50ml tetrahydrofuran, be added triethylamine (50.5g,
0.5mol), (0-5 DEG C) is added dropwise to triphosgene (77g, 0.26mol) under ice-water bath, mechanical stirring 2h, and 300ml water quenching is added and goes out,
Liquid separation, dry concentration.It is then dissolved in 100ml acetic acid, temperature in reaction flask is controlled in ice-water bath and is not higher than 5 DEG C, 19ml is added dropwise
(65%, 0.27mol) concentrated nitric acid.It is added dropwise, at room temperature mechanical stirring 24 hours.Reaction solution is poured into 1000mL water, second is used
Acetoacetic ester extracts (5*150ml), and anhydrous sodium sulfate is 2 hours dry, is concentrated to give 54g pale yellow oily liquid, it is not necessary to purify, directly
For the next step.
(2) preparation of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate
The resulting oily liquids of upper step (54g) and sodium carbonate (75.3g, 0.711mol) are dissolved in 200mL first alcohol and water
In mixed solution (V:V=3:1), about 65 DEG C of return stirring 1.5h(), be then added dropwise the chloro- 2- Ethyl Methyl Ether of 1- (49.2g,
Methanol solution 0.52mol), and 0.1 gram of potassium iodide is added as catalyst, mechanic whirl-nett reaction two hours.After cooling, will
The NaHCO of pH=11 is poured into reaction3It in aqueous solution, is extracted with ethyl acetate (200mL × 5), merges organic layer, use anhydrous slufuric acid
Magnesium is dry, and vacuum concentration obtains yellow oily liquid 60g.As 4,5- bis- (2- methoxy ethoxy) -2- nitrobenzoic acid second
Ester, two step yields 70%, HPLC purity are 97%.HNMR(CDCl3):7.5(s,1H),7.1(S,1H),4.36 (q, 2H, J=
7.2 Hz),4.23 (m, 4H), 3.80 (m, 4H), 3.45 (s, 6H),1.35 (t, 2H, J=7.2 Hz); M/e:
344(M+H+);361 (M+NH4+), are shown in Fig. 1-3.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. one kind 4, the preparation method of 5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate, include the following steps:
(1) 4,5- dihydric ethyl benzoate is first reacted into 1-2h with protective agent in organic solvent A at room temperature, water quenching is added to go out,
Liquid separation, concentration, then 24-36h with 0-20 DEG C of nitric acid is reacted in 1:1 ~ 2 in molar ratio under acid catalysis, is extracted with organic solvent B,
Dry, concentration obtains 6- nitro -4', 5'- methylene-dioxy ethyl benzoate；
(2) 6- nitro -4', 5'- methylene-dioxy ethyl benzoate is dissolved in organic solvent A and is deprotected in the presence of alkali
Base, 1-3h is reacted with chloro- 40-80 DEG C of 2- Ethyl Methyl Ether of 1- in 1:1 ~ 3 in molar ratio, is extracted with organic solvent B, dry, concentration,
Obtain 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate.
2. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the protective agent in the step (1) is methylchloroformate, ethyl chloroformate, triphosgene, orthoformic acid front three
One of ester, triethyl orthoformate, trimethyl orthoacetate, triethly orthoacetate；Protective agent and 4,5- dihydroxy-benzoic acid second
The molar ratio of ester is 1-1.2:1.
3. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the acid in the step (1) is organic acid or inorganic acid；Acid rubs with 4,5- dihydric ethyl benzoate
You are than being 0.8-1:1.
4. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 3
Method, it is characterised in that: the organic acid is acetic acid；Inorganic acid is sulfuric acid or phosphoric acid.
5. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the organic solvent A in the step (1) and (2) is methanol, ethyl alcohol, ethyl acetate, acetonitrile, tetrahydro furan
It mutters, one or more of petroleum ether, the tertiary ether of first, methylene chloride.
6. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the alkali in the step (2) is organic base or inorganic base；Alkali and 6- nitro -4', 5'- methylenedioxybenzenes
The molar ratio of Ethyl formate is 3-4:1.
7. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 6
Method, it is characterised in that: the organic base is triethylamine, diisopropylethylamine or pyridine；Inorganic base is sodium carbonate, potassium carbonate, carbon
Sour hydrogen sodium, sodium hydroxide or potassium hydroxide.
8. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the organic solvent B in the step (1) and (2) is methylene chloride, tetrahydrofuran, acetonitrile, ether, acetic acid
One or more of ethyl ester, chloroform.
9. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: 6- nitro -4', 5'- methylene-dioxy ethyl benzoate and the chloro- 2- methoxyl group of 1- in the step (2)
Ethane is previously dissolved in methanol.
10. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: potassium iodide is added in the step (2) as catalyst.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710170599.7A CN106928069B (en) | 2017-03-21 | 2017-03-21 | A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710170599.7A CN106928069B (en) | 2017-03-21 | 2017-03-21 | A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106928069A CN106928069A (en) | 2017-07-07 |
| CN106928069B true CN106928069B (en) | 2019-03-19 |
Family
ID=59432409
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710170599.7A Active CN106928069B (en) | 2017-03-21 | 2017-03-21 | A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106928069B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004206B (en) * | 2019-12-12 | 2021-05-11 | 苏州诚和医药化学有限公司 | Synthetic method of biphenyl diester intermediate |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0817775B1 (en) * | 1995-03-30 | 2001-09-12 | Pfizer Inc. | Quinazoline derivatives |
| EP1650196B1 (en) * | 2003-07-30 | 2011-03-30 | Ube Industries, Ltd. | Process for producing 6,7-bis(2-methoxyethoxy)-quinazolin-4-one |
| KR101441930B1 (en) * | 2007-04-04 | 2014-09-19 | 시플라 리미티드 | Process for the preparation of erlotinib and its pharmaceutically acceptable salts |
| PT2947072T (en) * | 2008-03-17 | 2016-12-06 | Ambit Biosciences Corp | 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea as raf kinase modulator in the treatment of cancer diseases |
| CN101863844B (en) * | 2009-04-16 | 2012-10-03 | 欧美嘉股份有限公司 | Synthetic method of 6,7-substituent-4-aniline quinazoline |
| CN102249945A (en) * | 2010-05-21 | 2011-11-23 | 复旦大学 | Salicyloyl anilines compound as well as preparation method and application thereof |
| BR112012028964A2 (en) * | 2010-05-21 | 2016-07-26 | Shanghai Inst Pharm Industry | polycyclic quinazolines, their method of preparation and their uses |
| WO2011147102A1 (en) * | 2010-05-28 | 2011-12-01 | 翔真生物科技股份有限公司 | Synthetic method for 6,7-substituents-4-aniline quinazoline |
| CN103193722B (en) * | 2012-01-10 | 2016-02-24 | 北京师范大学 | Novel quinazoline quinoline nitrogen mustards compound and preparation method thereof and cancer therapeutic applications |
| CN102827086A (en) * | 2012-08-03 | 2012-12-19 | 浙江理工大学 | Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline |
| CN103070868B (en) * | 2013-01-08 | 2015-08-19 | 复旦大学 | A kind of IDO inhibitor containing NH-1,2,3-triazole and preparation method thereof |
| CN103709110B (en) * | 2013-12-13 | 2016-05-04 | 浙江普洛康裕制药有限公司 | A kind of preparation method of erlotinid hydrochloride key intermediate |
| CN104725327B (en) * | 2015-03-03 | 2017-08-25 | 山东大学 | A kind of environment-friendly preparation method of erlotinib Hydrochloride |
-
2017
- 2017-03-21 CN CN201710170599.7A patent/CN106928069B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN106928069A (en) | 2017-07-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102584795B (en) | Preparing method of crizotinib | |
| US20100267949A1 (en) | Method of Synthesizing 6,7-Substituted 4-Anilino Quinazoline | |
| CN108892670B (en) | Preparation method of high-purity ticagrelor | |
| CN106928069B (en) | A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate | |
| ZA200400844B (en) | Process for producing pyridine compound | |
| CN103242303B (en) | Afatinib preparation method | |
| CN104356109A (en) | Preparation method of 2-(( 4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate | |
| CN104926798A (en) | High purity preparation method of Afatinib intermediate | |
| CN102153601A (en) | Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity | |
| CN103204890B (en) | A kind of phosphorylation prepares the method for vidarabine phosphate | |
| CN103896940B (en) | A kind of synthetic method of Eliquis | |
| CN104710347B (en) | (R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 | |
| CN103113357B (en) | Preparation method of statin intermediate and derivatives thereof | |
| US9926283B2 (en) | Intermediate compound for preparing rosuvastatin calcium and method for preparing rosuvastatin calcium therefrom | |
| CN104910080B (en) | A kind of Tarceva related substances and preparation method thereof | |
| CN103396371A (en) | Preparation method of erlotinib hydrochloride crystal form A | |
| CN103435582B (en) | A kind of preparation method of La Nina meter Wei monooctyl ester | |
| CN102442947B (en) | Preparation method of Montelukast Sodium intermediate | |
| CN101555248B (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| CN105503719A (en) | Preparation method of bosutinib | |
| CN105218519A (en) | A kind of preparation method of dabigatran etexilate intermediate | |
| CN103848756B (en) | Preparation method of teriflunomide and intermediate thereof | |
| CN106916067B (en) | Preparation method of erlotinib hydrochloride key intermediate | |
| CN106632158B (en) | The preparation method of 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs | |
| CN116217644B (en) | Anti-coronavirus ribonucleoside compound, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |