JP5853957B2 - 2−ブロモ−4,5−ジアルコキシ安息香酸の製造法 - Google Patents
2−ブロモ−4,5−ジアルコキシ安息香酸の製造法 Download PDFInfo
- Publication number
- JP5853957B2 JP5853957B2 JP2012547868A JP2012547868A JP5853957B2 JP 5853957 B2 JP5853957 B2 JP 5853957B2 JP 2012547868 A JP2012547868 A JP 2012547868A JP 2012547868 A JP2012547868 A JP 2012547868A JP 5853957 B2 JP5853957 B2 JP 5853957B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- acid
- bromine
- concentrated hydrochloric
- hydrochloric acid
- 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
- 238000000034 method Methods 0.000 title claims description 24
- 239000002253 acid Substances 0.000 title claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 29
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- -1 amine compound Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000005749 Copper compound Substances 0.000 claims description 8
- 150000001880 copper compounds Chemical class 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 229960004889 salicylic acid Drugs 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 6
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- 229960000355 copper sulfate Drugs 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 229960004643 cupric oxide Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 229940112669 cuprous oxide Drugs 0.000 claims description 2
- 125000005265 dialkylamine group Chemical group 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- KOPRMBXEMNEOOQ-UHFFFAOYSA-N methyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C1=CSC(NC(=O)C=2C(=CC(OC)=C(OC)C=2)O)=N1 KOPRMBXEMNEOOQ-UHFFFAOYSA-N 0.000 description 4
- HWFCHCRFQWEFMU-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(Br)=C(C(O)=O)C=C1OC HWFCHCRFQWEFMU-UHFFFAOYSA-N 0.000 description 3
- RUBXSZYVSFYJQR-UHFFFAOYSA-N 2-hydroxy-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(O)=C(C(O)=O)C=C1OC RUBXSZYVSFYJQR-UHFFFAOYSA-N 0.000 description 3
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- JXURAFZSOJQXKD-UHFFFAOYSA-N phenyl 2-hydroxy-4,5-dimethoxybenzoate Chemical compound C1=C(OC)C(OC)=CC(O)=C1C(=O)OC1=CC=CC=C1 JXURAFZSOJQXKD-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- ZYCLQXMMFJREPJ-UHFFFAOYSA-N 1,2-dibromo-4,5-dimethoxybenzene Chemical compound COC1=CC(Br)=C(Br)C=C1OC ZYCLQXMMFJREPJ-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- DHQSZIOBZPWPHM-UHFFFAOYSA-N 2,3-dibromo-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=C(Br)C(Br)=C1OC DHQSZIOBZPWPHM-UHFFFAOYSA-N 0.000 description 1
- FKRJFKVLZQBSFH-UHFFFAOYSA-N 2,6-dibromo-3,4-dimethoxybenzoic acid Chemical compound COC1=CC(Br)=C(C(O)=O)C(Br)=C1OC FKRJFKVLZQBSFH-UHFFFAOYSA-N 0.000 description 1
- ZODURELBYVOPGP-UHFFFAOYSA-N 3-bromo-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(Br)=C1OC ZODURELBYVOPGP-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- QFQQFHLOFSFILV-UHFFFAOYSA-N COc(c(C(O)=O)c1)cc(O)c1O Chemical compound COc(c(C(O)=O)c1)cc(O)c1O QFQQFHLOFSFILV-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- GPDXFYPVHRESMA-UHFFFAOYSA-N OC(c(c(O)c1)cc(O)c1O)=O Chemical compound OC(c(c(O)c1)cc(O)c1O)=O GPDXFYPVHRESMA-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WYVZZWKIKAKUKV-UHFFFAOYSA-N methyl 2-amino-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C1=CSC(N)=N1 WYVZZWKIKAKUKV-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- MFIGJRRHGZYPDD-UHFFFAOYSA-N n,n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)NCCNC(C)C MFIGJRRHGZYPDD-UHFFFAOYSA-N 0.000 description 1
- VQEKQYLTAIVCBW-UHFFFAOYSA-N n-[2-[di(propan-2-yl)amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC(O)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 VQEKQYLTAIVCBW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
で表されるように、2,4,5−トリアルコキシ安息香酸(a)にエステル系、ケトン系又はアミド系溶媒中、ルイス酸を反応させることにより、2位のメトキシ基を選択的に脱メチル化する方法が知られている(特許文献1)。
従って本発明の課題は、安価な原料から効率良く4,5−ジアルコキシ−2−ヒドロキシ安息香酸を製造する方法を提供することにある。
で表される3,4−ジアルコキシ安息香酸に、濃塩酸中で臭素を反応させることを特徴とする一般式(2)
で表される2−ブロモ−4,5−ジアルコキシ安息香酸の製造法を提供するものである。
で表される3,4−ジアルコキシ安息香酸に、濃塩酸中で臭素を反応させ、次いで得られる一般式(2)
で表される2−ブロモ−4,5−ジアルコキシ安息香酸を、銅化合物及びアミン化合物の存在下に加水分解することを特徴とする一般式(3)
で表される4,5−ジアルコキシ−2−ヒドロキシ安息香酸の製造法を提供するものである。
工程1は、一般式(1)で表される3,4−ジアルコキシ安息香酸(以下、化合物(1)ともいう)に、濃塩酸中で臭素を反応させて、一般式(2)で表される2−ブロモ−4,5−ジアルコキシ安息香酸(以下、化合物(2)ともいう)を得る工程である。
工程2は、化合物(2)を、銅化合物及びアミン化合物の存在下に加水分解して一般式(3)で表される4,5−ジアルコキシ−2−ヒドロキシ安息香酸(以下、化合物(3)ともいう)を得る工程である。
(化合物(1)→化合物(2))
3,4−ジメトキシ安息香酸25.0gを濃塩酸(35%)500mLに懸濁し、25℃で臭素23.0g(1.05当量)を滴下した。その後、7時間攪拌した。水500mLを加え、1時間攪拌後、析出晶を濾取した。減圧乾燥し、2−ブロモ−4,5−ジメトキシ安息香酸粗結晶34.47gを収率96.2%で得た。
1H−NMR(DMSO−d6,δ):3.79(s,3H),3.84(s,3H),7.21(s,1H),7.37(s,1H),13.08(bs,1H).
特許文献2の実施例によれば、化合物(1)に酢酸エチル中で臭素1.8当量添加し、65℃で7時間反応させて、化合物(2)を収率78%で得ている。特許文献2記載の方法に比べて、本発明方法が工業的に有利であることがわかる。
(化合物(2)→化合物(3))
実施例1で得られた、2−ブロモ−4,5−ジメトキシ安息香酸粗結晶20.0gと炭酸ナトリウム10.1gに水80mLを加えた。80℃に加熱攪拌し、硫酸銅五水和物1.91g、水20mL、ピリジン3.1mLから別途調製した硫酸銅溶液を添加した。さらに加熱し、90〜100℃で1時間攪拌した。50℃に冷却し、濃塩酸16.0gを滴下した。冷却後、析出晶を濾取、減圧乾燥し、2−ヒドロキシ−4,5−ジメトキシ安息香酸粗結晶15.08gを収率99.3%で得た。
1H−NMR(DMSO−d6,δ):3.71(s,3H),3.81(s,3H),6.56(s,1H),7.17(s,1H),11.22(bs,1H),13.58(bs,1H).
(1)アルゴン気流下、トルエン1.5gにP(OPh)3 2.35g、2−ヒドロキシ−4,5−ジメトキシ安息香酸1.5g、及びH2SO4 40.3μLを混合し、反応液を加熱還流させ、2.5時間攪拌した。反応液を放冷し、メタノール5gを加え、30分間攪拌、次いで水2.5gを加え、30分間攪拌した。析出結晶をろ取、減圧乾燥させ、2−ヒドロキシ−4,5−ジメトキシ安息香酸フェニル2.0gを収率96%で得た。
1H−NMR(DMSO−d6,δ):3.19(s,3H),3.79(s,3H),3.83(s,3H),3.84(s,3H),4.05〜4.15(bs,1H),6.61(s,1H),7.63(s,1H),8.13(s,1H),11.77(s,1H),12.40(s,1H).
さらに100℃で減圧乾燥を行い、2−〔(2−ヒドロキシ−4,5−ジメトキシベンゾイル)アミノ〕−1,3−チアゾール−4−カルボン酸メチルエステルを得た。
1H−NMR(DMSO−d6,δ):3.79(s,3H),3.83(s,3H),3.84(s,3H),6.61(s,1H),7.63(s,1H),8.13(s,1H),11.77(s,1H),12.40(s,1H).
1H−NMR(DMSO−d6,δ):1.32(d,6H,J=6.4Hz),1.35(d,6H,J=6.4Hz),3.16−3.19(m,2H),3.59−3.67(m,4H),3.78(s,3H),3.82(s,3H),6.89(s,1H),7.50(s,1H),7.91(s,1H),8.74(t,1H,J=5.9Hz),9.70(s,1H),11.80(s,1H),12.05−12.15(bs,1H).
Claims (13)
- 濃塩酸が塩化水素濃度33%以上である請求項1記載の製造法。
- 臭素の使用量が1.0〜1.1当量である請求項1又は2記載の製造法。
- 反応温度が10〜35℃である請求項1〜3のいずれか1項記載の製造法。
- 式(1)及び(2)中、R1及びR2がメチル基である請求項1〜4のいずれか1項記載の製造法。
- 銅化合物が、硫酸銅、塩化第一銅、塩化第二銅、臭化第一銅、臭化第二銅、酸化第一銅、酸化第二銅、酢酸銅及び銅粉末から選ばれる化合物である請求項6記載の製造法。
- アミン化合物がピリジン、ジアルキルアミン、モルホリン、ピペリジン、ピロリジン、ピペラジン及びトリアルキルアミンから選ばれる化合物である請求項6又は7記載の製造法。
- 加水分解反応が、アルカリ条件下で行われる請求項6〜8のいずれか1項記載の製造法。
- 濃塩酸が塩化水素濃度33%以上である請求項6〜9のいずれか1項記載の製造法。
- 臭素の使用量が1.0〜1.1当量である請求項6〜10のいずれか1項記載の製造法。
- 臭素を反応させる反応温度が10〜35℃である請求項6〜11のいずれか1項記載の製造法。
- 式(1)、(2)及び(3)中、R1及びR2がメチル基である請求項6〜12のいずれか1項記載の製造法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012547868A JP5853957B2 (ja) | 2010-12-07 | 2011-12-06 | 2−ブロモ−4,5−ジアルコキシ安息香酸の製造法 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010272668 | 2010-12-07 | ||
JP2010272668 | 2010-12-07 | ||
PCT/JP2011/078169 WO2012077673A1 (ja) | 2010-12-07 | 2011-12-06 | 2-ブロモ-4,5-ジアルコキシ安息香酸の製造法 |
JP2012547868A JP5853957B2 (ja) | 2010-12-07 | 2011-12-06 | 2−ブロモ−4,5−ジアルコキシ安息香酸の製造法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2012077673A1 JPWO2012077673A1 (ja) | 2014-05-19 |
JP5853957B2 true JP5853957B2 (ja) | 2016-02-09 |
Family
ID=46207161
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012547868A Active JP5853957B2 (ja) | 2010-12-07 | 2011-12-06 | 2−ブロモ−4,5−ジアルコキシ安息香酸の製造法 |
Country Status (15)
Country | Link |
---|---|
US (1) | US9096511B2 (ja) |
EP (1) | EP2650277B1 (ja) |
JP (1) | JP5853957B2 (ja) |
KR (1) | KR101906617B1 (ja) |
CN (1) | CN103237781B (ja) |
AU (1) | AU2011339438B2 (ja) |
BR (1) | BR112013013256B1 (ja) |
CA (1) | CA2819119C (ja) |
ES (1) | ES2679280T3 (ja) |
MX (1) | MX338808B (ja) |
RU (1) | RU2576520C2 (ja) |
SG (1) | SG190721A1 (ja) |
TW (1) | TWI498318B (ja) |
WO (1) | WO2012077673A1 (ja) |
ZA (1) | ZA201303500B (ja) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447612A (zh) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | 阿考替胺水合物晶型及其制备方法和用途 |
CN103508893A (zh) * | 2013-10-09 | 2014-01-15 | 江苏弘和药物研发有限公司 | 一种2-羟基-4,5-二甲氧基苯甲酸苯酯的合成方法 |
CN103896873B (zh) * | 2013-10-23 | 2015-11-25 | 山东诚创医药技术开发有限公司 | 一种盐酸阿考替胺的精制方法 |
CN104672163A (zh) * | 2013-12-03 | 2015-06-03 | 山东富创医药科技有限公司 | 一种盐酸阿考替胺的制备方法 |
CN104045606B (zh) * | 2014-07-11 | 2015-09-30 | 杭州新博思生物医药有限公司 | 一锅法制备阿考替胺盐酸盐的方法 |
CN105439977A (zh) * | 2014-09-26 | 2016-03-30 | 广州朗圣药业有限公司 | 一种阿考替胺及其盐酸盐的制备方法 |
EP3284734B1 (en) * | 2015-04-13 | 2021-12-01 | Sumitomo Seika Chemicals Co., Ltd. | Method for producing 2-halogenated benzoic acids |
CN105924406B (zh) * | 2016-05-04 | 2018-04-10 | 河北国龙制药有限公司 | 一种盐酸阿考替胺三水合物的制备方法 |
CN106316979B (zh) * | 2016-08-22 | 2018-11-27 | 山东罗欣药业集团股份有限公司 | 一种盐酸阿考替胺的制备方法 |
EP3421081B1 (en) | 2017-06-30 | 2020-04-15 | GTX medical B.V. | A system for neuromodulation |
WO2019110400A1 (en) | 2017-12-05 | 2019-06-13 | Ecole Polytechnique Federale De Lausanne (Epfl) | A system for planning and/or providing neuromodulation |
DE18205821T1 (de) | 2018-11-13 | 2020-12-24 | Gtx Medical B.V. | Steuerungssystem zur bewegungsrekonstruktion und/oder wiederherstellung für einen patienten |
EP3695878B1 (en) | 2019-02-12 | 2023-04-19 | ONWARD Medical N.V. | A system for neuromodulation |
EP3827871A1 (en) | 2019-11-27 | 2021-06-02 | ONWARD Medical B.V. | Neuromodulation system |
CN111440128A (zh) * | 2020-05-27 | 2020-07-24 | 廊坊市泽康医药科技有限公司 | 一种盐酸阿考替胺杂质的制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0827059A (ja) * | 1994-07-04 | 1996-01-30 | Bayer Ag | 3,5−ジヒドロキシ−4−ブロモ安息香酸の製法 |
WO2006022252A1 (ja) * | 2004-08-23 | 2006-03-02 | Zeria Pharmaceutical Co., Ltd. | アミノチアゾール誘導体の製造法及び製造中間体 |
JP2009528374A (ja) * | 2006-03-01 | 2009-08-06 | アムゲン インコーポレイティッド | ホスホジエステラーゼ10阻害剤 |
JP2010511043A (ja) * | 2006-11-28 | 2010-04-08 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | ヒドロキシ芳香族酸の合成方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU76781A1 (ru) * | 1948-11-05 | 1948-11-30 | Н.М. Косникова | Способ получени альфа-бромпиридина |
JP2003252826A (ja) | 2002-02-26 | 2003-09-10 | Mitsui Chemicals Inc | アルコキシ安息香酸類の製造方法 |
US8586761B2 (en) | 2004-08-23 | 2013-11-19 | Zeria Pharmaceutical Co., Ltd. | Method for producing aminothiazole derivative and production intermediate |
-
2011
- 2011-12-06 JP JP2012547868A patent/JP5853957B2/ja active Active
- 2011-12-06 SG SG2013041397A patent/SG190721A1/en unknown
- 2011-12-06 RU RU2013130734/04A patent/RU2576520C2/ru active
- 2011-12-06 TW TW100144918A patent/TWI498318B/zh active
- 2011-12-06 AU AU2011339438A patent/AU2011339438B2/en active Active
- 2011-12-06 KR KR1020137012478A patent/KR101906617B1/ko active IP Right Grant
- 2011-12-06 CA CA2819119A patent/CA2819119C/en active Active
- 2011-12-06 CN CN201180058574.9A patent/CN103237781B/zh active Active
- 2011-12-06 MX MX2013006405A patent/MX338808B/es active IP Right Grant
- 2011-12-06 EP EP11847027.7A patent/EP2650277B1/en active Active
- 2011-12-06 BR BR112013013256-6A patent/BR112013013256B1/pt active IP Right Grant
- 2011-12-06 WO PCT/JP2011/078169 patent/WO2012077673A1/ja active Application Filing
- 2011-12-06 US US13/991,242 patent/US9096511B2/en active Active
- 2011-12-06 ES ES11847027.7T patent/ES2679280T3/es active Active
-
2013
- 2013-05-14 ZA ZA2013/03500A patent/ZA201303500B/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0827059A (ja) * | 1994-07-04 | 1996-01-30 | Bayer Ag | 3,5−ジヒドロキシ−4−ブロモ安息香酸の製法 |
WO2006022252A1 (ja) * | 2004-08-23 | 2006-03-02 | Zeria Pharmaceutical Co., Ltd. | アミノチアゾール誘導体の製造法及び製造中間体 |
JP2009528374A (ja) * | 2006-03-01 | 2009-08-06 | アムゲン インコーポレイティッド | ホスホジエステラーゼ10阻害剤 |
JP2010511043A (ja) * | 2006-11-28 | 2010-04-08 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | ヒドロキシ芳香族酸の合成方法 |
Also Published As
Publication number | Publication date |
---|---|
US20130253222A1 (en) | 2013-09-26 |
KR20130140006A (ko) | 2013-12-23 |
EP2650277A4 (en) | 2015-01-21 |
CA2819119A1 (en) | 2012-06-14 |
CN103237781A (zh) | 2013-08-07 |
KR101906617B1 (ko) | 2018-10-10 |
EP2650277A1 (en) | 2013-10-16 |
WO2012077673A1 (ja) | 2012-06-14 |
MX338808B (es) | 2016-04-29 |
SG190721A1 (en) | 2013-07-31 |
JPWO2012077673A1 (ja) | 2014-05-19 |
EP2650277B1 (en) | 2018-07-11 |
BR112013013256B1 (pt) | 2020-10-27 |
BR112013013256A2 (pt) | 2016-09-13 |
CA2819119C (en) | 2018-02-13 |
CN103237781B (zh) | 2016-01-20 |
ZA201303500B (en) | 2014-07-30 |
ES2679280T3 (es) | 2018-08-23 |
TWI498318B (zh) | 2015-09-01 |
MX2013006405A (es) | 2013-08-26 |
AU2011339438B2 (en) | 2016-05-26 |
AU2011339438A1 (en) | 2013-06-27 |
RU2576520C2 (ru) | 2016-03-10 |
RU2013130734A (ru) | 2015-01-20 |
TW201229024A (en) | 2012-07-16 |
US9096511B2 (en) | 2015-08-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5853957B2 (ja) | 2−ブロモ−4,5−ジアルコキシ安息香酸の製造法 | |
EP1792888B1 (en) | Method for producing aminothiazole derivative and production intermediate | |
JP5642067B2 (ja) | 1−(2−ハロビフェニル−4−イル)−シクロプロパンカルボン酸の誘導体を調製する方法 | |
JP6001112B2 (ja) | 1−(2−ハロビフェニル−4−イル)−シクロプロパンカルボン酸の誘導体の調製方法 | |
JP2013043882A (ja) | 1,2−ベンズイソチアゾリン−3−オン化合物の製造方法 | |
JP4634609B2 (ja) | 4,4′−ジハロゲン−o−ヒドロキシジフェニル化合物の製造方法 | |
JP4032861B2 (ja) | β−オキソニトリル誘導体又はそのアルカリ金属塩の製法 | |
JP5205971B2 (ja) | テトラヒドロピラン化合物の製造方法 | |
JP2004331515A (ja) | 3−アセトキシスチレンの製造方法 | |
JP2005325026A (ja) | フェノキシエチルハライド及びその誘導体の製造方法 | |
JP2005112807A (ja) | アミノアルコキシカルボスチリル誘導体の製造方法。 | |
JP2004051642A (ja) | 含フッ素アルコキシ芳香族化合物の製造法 | |
JP2005225852A (ja) | α−ヒドロキシメチル−α、β−不飽和カルボン酸及びその製造方法 | |
JP2009167142A (ja) | クロロスルホニル安息香酸化合物の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20141016 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150707 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150907 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20151110 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20151123 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5853957 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |