CN102093194A - New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid - Google Patents
New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid Download PDFInfo
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- CN102093194A CN102093194A CN2010106030958A CN201010603095A CN102093194A CN 102093194 A CN102093194 A CN 102093194A CN 2010106030958 A CN2010106030958 A CN 2010106030958A CN 201010603095 A CN201010603095 A CN 201010603095A CN 102093194 A CN102093194 A CN 102093194A
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- 238000000034 method Methods 0.000 title claims abstract description 9
- UWYKUEVIXZLHIO-UHFFFAOYSA-N 3-cyclopropyl-4-(difluoromethoxy)-2-methoxybenzoic acid Chemical compound COC1=C(C(O)=O)C=CC(OC(F)F)=C1C1CC1 UWYKUEVIXZLHIO-UHFFFAOYSA-N 0.000 title abstract 4
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 7
- -1 3-nitro-4-hydroxybenzoic acid ester Chemical class 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- IGFDIFLMMLWKKY-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid Chemical compound OC(=O)C1=CC=C(OC(F)F)C(OCC2CC2)=C1 IGFDIFLMMLWKKY-UHFFFAOYSA-N 0.000 claims description 21
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 230000035484 reaction time Effects 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 235000015320 potassium carbonate Nutrition 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 230000001035 methylating effect Effects 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 3
- QRYSWXFQLFLJTC-UHFFFAOYSA-N 616-82-0 Chemical compound OC(=O)C1=CC=C(O)C([N+]([O-])=O)=C1 QRYSWXFQLFLJTC-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 abstract description 8
- 229960002586 roflumilast Drugs 0.000 abstract description 8
- 230000029936 alkylation Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- MPNXSZJPSVBLHP-UHFFFAOYSA-N 2-chloro-n-phenylpyridine-3-carboxamide Chemical compound ClC1=NC=CC=C1C(=O)NC1=CC=CC=C1 MPNXSZJPSVBLHP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- LFDXKAABQYAYGA-UHFFFAOYSA-N nitro 4-hydroxybenzoate Chemical compound OC1=CC=C(C(=O)O[N+](=O)[O-])C=C1 LFDXKAABQYAYGA-UHFFFAOYSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
Abstract
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Claims (10)
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CN201010603095.8A CN102093194B (en) | 2010-12-24 | 2010-12-24 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
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CN201010603095.8A CN102093194B (en) | 2010-12-24 | 2010-12-24 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
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CN102093194A true CN102093194A (en) | 2011-06-15 |
CN102093194B CN102093194B (en) | 2014-01-08 |
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CN201010603095.8A Expired - Fee Related CN102093194B (en) | 2010-12-24 | 2010-12-24 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
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Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102336703A (en) * | 2011-07-20 | 2012-02-01 | 北京赛科药业有限责任公司 | Method for preparing roflumilast |
CN102336704A (en) * | 2011-10-19 | 2012-02-01 | 丁克 | Method for preparing Roflumilast |
CN102336705A (en) * | 2011-10-28 | 2012-02-01 | 成都苑东药业有限公司 | Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine |
CN102417449A (en) * | 2012-01-09 | 2012-04-18 | 四川蜀中制药有限公司 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN102617340A (en) * | 2012-03-05 | 2012-08-01 | 山西仟源制药股份有限公司 | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN102617339A (en) * | 2012-03-05 | 2012-08-01 | 山西仟源制药股份有限公司 | 3-cyclopropylmethoxy-4-halogen benzoic acid or derivative and application thereof |
CN102633631A (en) * | 2012-03-05 | 2012-08-15 | 山西仟源制药股份有限公司 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN103304408A (en) * | 2013-06-05 | 2013-09-18 | 威海迪素制药有限公司 | Preparation method of roflumilast intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid |
CN103467294A (en) * | 2012-06-08 | 2013-12-25 | 上海医药工业研究院 | 3-bromo-4-difluoromethoxy methyl benzoate preparation method |
CN103508883A (en) * | 2012-06-17 | 2014-01-15 | 重庆圣华曦药业股份有限公司 | Method for synthesizing roflumilast intermediate |
CN103539671A (en) * | 2012-07-17 | 2014-01-29 | 北京万生药业有限责任公司 | Method for preparing roflumilast intermediate |
CN103992220A (en) * | 2014-06-05 | 2014-08-20 | 山东省医学科学院药物研究所 | Method for preparing roflumilast intermediate |
CN110885291A (en) * | 2019-12-13 | 2020-03-17 | 阿里生物新材料(常州)有限公司 | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine |
CN115417766A (en) * | 2022-08-31 | 2022-12-02 | 天津药明康德新药开发有限公司 | Synthesis method of 3-hydroxy-4, 5-dimethoxy benzoic acid tert-butyl ester |
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WO2006117653A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Azole-based phosphodiesterase inhibitors |
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CN1126468A (en) * | 1993-07-02 | 1996-07-10 | 比克·古尔顿·劳姆贝尔格化学公司 | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
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WO2006117653A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Azole-based phosphodiesterase inhibitors |
Cited By (24)
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---|---|---|---|---|
CN102336703A (en) * | 2011-07-20 | 2012-02-01 | 北京赛科药业有限责任公司 | Method for preparing roflumilast |
CN102336703B (en) * | 2011-07-20 | 2013-09-25 | 华润赛科药业有限责任公司 | Method for preparing roflumilast |
CN102336704A (en) * | 2011-10-19 | 2012-02-01 | 丁克 | Method for preparing Roflumilast |
CN102336704B (en) * | 2011-10-19 | 2013-04-17 | 丁克 | Method for preparing Roflumilast |
CN102336705A (en) * | 2011-10-28 | 2012-02-01 | 成都苑东药业有限公司 | Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine |
CN102336705B (en) * | 2011-10-28 | 2013-03-27 | 成都苑东药业有限公司 | Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine |
CN102417449A (en) * | 2012-01-09 | 2012-04-18 | 四川蜀中制药有限公司 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN102633631B (en) * | 2012-03-05 | 2014-02-26 | 山西仟源制药股份有限公司 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN102617340A (en) * | 2012-03-05 | 2012-08-01 | 山西仟源制药股份有限公司 | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN102617339A (en) * | 2012-03-05 | 2012-08-01 | 山西仟源制药股份有限公司 | 3-cyclopropylmethoxy-4-halogen benzoic acid or derivative and application thereof |
CN102633631A (en) * | 2012-03-05 | 2012-08-15 | 山西仟源制药股份有限公司 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
CN103467294B (en) * | 2012-06-08 | 2015-09-23 | 上海医药工业研究院 | The preparation method of a kind of 3-bromo-4-difluoro-methoxy-benzoic acid methyl esters |
CN103467294A (en) * | 2012-06-08 | 2013-12-25 | 上海医药工业研究院 | 3-bromo-4-difluoromethoxy methyl benzoate preparation method |
CN103508883A (en) * | 2012-06-17 | 2014-01-15 | 重庆圣华曦药业股份有限公司 | Method for synthesizing roflumilast intermediate |
CN103508883B (en) * | 2012-06-17 | 2015-04-01 | 重庆圣华曦药业股份有限公司 | Method for synthesizing roflumilast intermediate |
CN103539671A (en) * | 2012-07-17 | 2014-01-29 | 北京万生药业有限责任公司 | Method for preparing roflumilast intermediate |
CN103539671B (en) * | 2012-07-17 | 2015-01-07 | 北京万生药业有限责任公司 | Method for preparing roflumilast intermediate |
CN103304408A (en) * | 2013-06-05 | 2013-09-18 | 威海迪素制药有限公司 | Preparation method of roflumilast intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid |
CN103304408B (en) * | 2013-06-05 | 2016-10-05 | 威海迪素制药有限公司 | The preparation of roflumilast intermediate 3-ring the third methoxyl group-4-difluoro-methoxy-benzoic acid |
CN103992220A (en) * | 2014-06-05 | 2014-08-20 | 山东省医学科学院药物研究所 | Method for preparing roflumilast intermediate |
CN103992220B (en) * | 2014-06-05 | 2015-11-18 | 山东省医学科学院药物研究所 | A kind of preparation method of roflumilast intermediate |
CN110885291A (en) * | 2019-12-13 | 2020-03-17 | 阿里生物新材料(常州)有限公司 | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine |
CN110885291B (en) * | 2019-12-13 | 2022-04-05 | 阿里生物新材料(常州)有限公司 | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine |
CN115417766A (en) * | 2022-08-31 | 2022-12-02 | 天津药明康德新药开发有限公司 | Synthesis method of 3-hydroxy-4, 5-dimethoxy benzoic acid tert-butyl ester |
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