JP2012031156A - New method for manufacturing 5-bromo-2-(1-substitution ethyl) benzoic acid ester - Google Patents
New method for manufacturing 5-bromo-2-(1-substitution ethyl) benzoic acid ester Download PDFInfo
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- JP2012031156A JP2012031156A JP2011144178A JP2011144178A JP2012031156A JP 2012031156 A JP2012031156 A JP 2012031156A JP 2011144178 A JP2011144178 A JP 2011144178A JP 2011144178 A JP2011144178 A JP 2011144178A JP 2012031156 A JP2012031156 A JP 2012031156A
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- JP
- Japan
- Prior art keywords
- compound
- general formula
- bromo
- ethyl
- benzoic 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.)
- Granted
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 12
- -1 benzoic acid ester Chemical class 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title abstract description 8
- 239000005711 Benzoic acid Substances 0.000 title abstract 4
- 235000010233 benzoic acid Nutrition 0.000 title abstract 4
- 238000006467 substitution reaction Methods 0.000 title abstract 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 36
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical group CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 7
- 239000001569 carbon dioxide Substances 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000006138 lithiation reaction Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Inorganic materials [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- HBBKPRZFGXDWHG-SNVBAGLBSA-N 2,2-dimethyl-n-[(1r)-1-phenylethyl]propanamide Chemical compound CC(C)(C)C(=O)N[C@H](C)C1=CC=CC=C1 HBBKPRZFGXDWHG-SNVBAGLBSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 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 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WJUKOGPNGRUXMG-UHFFFAOYSA-N 1,2-dibromo-1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)(Br)C(Cl)(Cl)Br WJUKOGPNGRUXMG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- NJQJGRGGIUNVAB-UHFFFAOYSA-N 2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one Chemical compound BrC1=CC(Br)(Br)C=C(Br)C1=O NJQJGRGGIUNVAB-UHFFFAOYSA-N 0.000 description 1
- QRADPXNAURXMSB-UHFFFAOYSA-N 2-bromo-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(Br)C(=O)C2=C1 QRADPXNAURXMSB-UHFFFAOYSA-N 0.000 description 1
- HLAJXHYCSPHGGI-UHFFFAOYSA-N 2-bromo-2-cyano-n,n-dimethylacetamide Chemical compound CN(C)C(=O)C(Br)C#N HLAJXHYCSPHGGI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ITIIHWGGMIGNOE-MRVPVSSYSA-N BrC=1C=CC(=C(C(=O)O)C1)[C@@H](C)NC(C(C)(C)C)=O Chemical compound BrC=1C=CC(=C(C(=O)O)C1)[C@@H](C)NC(C(C)(C)C)=O ITIIHWGGMIGNOE-MRVPVSSYSA-N 0.000 description 1
- 0 C[C@](c(cccc1)c1C(O*)=O)NC(*)=O Chemical compound C[C@](c(cccc1)c1C(O*)=O)NC(*)=O 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- SGZOEIGKCVUCDG-UHFFFAOYSA-N O.[Na].Brn1c(=O)[nH]c(=O)[nH]c1=O Chemical compound O.[Na].Brn1c(=O)[nH]c(=O)[nH]c1=O SGZOEIGKCVUCDG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 description 1
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- OIXMUQLVDNPHNS-UHFFFAOYSA-N methanesulfonic acid;hydrate Chemical compound O.CS(O)(=O)=O OIXMUQLVDNPHNS-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- VDCLSGXZVUDARN-UHFFFAOYSA-N molecular bromine;pyridine;hydrobromide Chemical compound Br.BrBr.C1=CC=NC=C1 VDCLSGXZVUDARN-UHFFFAOYSA-N 0.000 description 1
- NTDJWYOOOCEBTM-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine;hydrobromide Chemical compound [Br-].CN(C)C1=CC=[NH+]C=C1 NTDJWYOOOCEBTM-UHFFFAOYSA-N 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、医薬の製造中間体として重要な５−ブロモ−２−（１−置換エチル）安息香酸エステルの新規製造法に関する。 The present invention relates to a novel process for producing 5-bromo-2- (1-substituted ethyl) benzoic acid ester, which is important as a pharmaceutical production intermediate.
５−ブロモ−２−（１−置換エチル）安息香酸エステルは、医薬の製造中間体として重要な化合物である。たとえば、抗菌剤として使用されている１−シクロプロピル−８−（ジフルオロメトキシ）−７−（１Ｒ）−１−メチル−２，３−ジヒドロ−１Ｈ−イソインドール−５−イル）−４−オキソ−１，４−ジヒドロキノリン−３−カルボン酸メタンスルホン酸塩一水和物（メシル酸ガレノキサシン）は、５−ブロモ−２−（１−（（２，２−ジメチルプロパノイル）アミノ）エチル）安息香酸メチルエステル（以下、「化合物Ａ」とする。）から製造される（特許文献１）。 5-Bromo-2- (1-substituted ethyl) benzoic acid ester is an important compound as a pharmaceutical production intermediate. For example, 1-cyclopropyl-8- (difluoromethoxy) -7- (1R) -1-methyl-2,3-dihydro-1H-isoindol-5-yl) -4-oxo used as an antibacterial agent -1,4-dihydroquinoline-3-carboxylic acid methanesulfonate monohydrate (galenoxacin mesylate) is 5-bromo-2- (1-((2,2-dimethylpropanoyl) amino) ethyl) It is produced from benzoic acid methyl ester (hereinafter referred to as “Compound A”) (Patent Document 1).
化合物Ａは、たとえば、式［１ａ］の化合物をリチオ化後、二酸化炭素と反応し、式［２ａ］の化合物を得た後、式［２ａ］の化合物をエステル化し、式［３ａ］の化合物を得た後、式［３ａ］の化合物を硫酸中でＮ−ブロモイソシアヌル酸ナトリウムを用いて臭素化することによって製造される（特許文献１）。 Compound A is, for example, lithiated a compound of formula [1a], then reacted with carbon dioxide to obtain a compound of formula [2a], and then esterified a compound of formula [2a] to obtain a compound of formula [3a] Is obtained by brominating the compound of formula [3a] in sulfuric acid with sodium N-bromoisocyanurate (Patent Document 1).
しかし、この製造法は、（１）操作が煩雑である、（２）収率が低い、（３）不純物が多い、（４）式［３ａ］の化合物を単離しなければならない、（５）副生成物であるイソシアヌル酸を除去するために強酸性の反応混合物を濾過する工程が必要である、などの欠点を有している。この製造法は、満足できるものではない。 However, in this production method, (1) the operation is complicated, (2) the yield is low, (3) there are many impurities, (4) the compound of formula [3a] must be isolated, (5) In order to remove the by-product isocyanuric acid, there is a disadvantage that a step of filtering the strongly acidic reaction mixture is required. This production method is not satisfactory.
（１）操作が簡便な、（２）収率が高い、（３）不純物が少ない、（４）中間体が単離されない、（５）副生成物が簡便に除去できる、化合物Ａの製造法が強く望まれている。 (1) Simple operation, (2) High yield, (3) Low impurities, (4) Intermediates are not isolated, (5) By-products can be easily removed Is strongly desired.
このような状況下、本発明者は、鋭意検討を行った結果、一般式［３］
さらに、本発明者は、一般式［１］
Furthermore, the inventor has the general formula [1]
本発明の新規な製造法によって、医薬の製造中間体として重要な化合物Ａは、（１）簡便な操作で、（２）高収率で、（３）高純度で、（４）中間体を単離することなく製造できる。
本発明の製造法は、（１）操作が簡便である、（２）収率が高い、（３）純度が高い、（４）中間体を単離する必要がない、（５）副生成物が簡便に除去される、などの特徴を有している。すなわち、本発明の製造法は、化合物Ａの製造法として有用である。
By the novel production method of the present invention, compound A, which is important as a pharmaceutical production intermediate, can be obtained by (1) simple operation, (2) high yield, (3) high purity, and (4) intermediate. It can be produced without isolation.
The production method of the present invention comprises (1) simple operation, (2) high yield, (3) high purity, (4) no need to isolate an intermediate, (5) by-product Is easily removed. That is, the production method of the present invention is useful as a production method of Compound A.
以下、本発明を詳細に説明する。
本明細書において、特にことわらない限り、各用語は、次の意味を有する。
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。
Ｃ１−６アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、イソブチル、ｔｅｒｔ−ブチル、ペンチルおよびイソペンチルなどの直鎖状または分枝鎖状のＣ１−６アルキル基を意味する。
脂肪族炭化水素類とは、ペンタン、ヘキサンまたはシクロヘキサンを意味する。
ハロゲン化炭化水素類とは、塩化メチレン、クロロホルムまたはジクロロエタンを意味する。
アルコール類とは、メタノール、エタノール、プロパノール、２−プロパノール、ブタノールまたは２−メチル−２−プロパノールを意味する。
エーテル類とは、ジエチルエーテル、ジイソプロピルエーテル、ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテルまたはジエチレングリコールジエチルエーテルを意味する。
ルイス酸とは、臭化アルミニウム、塩化アルミニウム、三弗化ホウ素、塩化第二鉄、臭化マグネシウム、塩化マグネシウム、三塩化アンチモン、五塩化アンチモン、四塩化スズ、四塩化チタン、臭化亜鉛または塩化亜鉛を意味する。
Hereinafter, the present invention will be described in detail.
In this specification, unless otherwise stated, each term has the following meaning.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C 1-6 alkyl group is a linear or branched C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl. means.
Aliphatic hydrocarbons mean pentane, hexane or cyclohexane.
Halogenated hydrocarbons mean methylene chloride, chloroform or dichloroethane.
Alcohol means methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
Ethers mean diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
Lewis acid means aluminum bromide, aluminum chloride, boron trifluoride, ferric chloride, magnesium bromide, magnesium chloride, antimony trichloride, antimony pentachloride, tin tetrachloride, titanium tetrachloride, zinc bromide or chloride It means zinc.
本発明において、好ましい製造法としては、以下の方法が挙げられる。
Ｒ１が、ｔｅｒｔ−ブチル基である化合物を用いる方法が好ましい。
Ｒ２が、メチル基またはエチル基である化合物を用いる方法が好ましく、メチル基である化合物を用いる方法がより好ましい。
ルイス酸として、塩化亜鉛、四塩化チタンまたは塩化アルミニウムを用いる方法が好ましく、塩化アルミニウムを用いる方法がより好ましい。
臭素化剤として、Ｎ−ブロモコハク酸イミドまたは１，３−ジブロモ−５，５−ジメチルヒダントインを用いる方法が好ましく、１，３−ジブロモ−５，５−ジメチルヒダントインを用いる方法がより好ましい。
In the present invention, as a preferable production method, the following methods may be mentioned.
A method using a compound in which R 1 is a tert-butyl group is preferred.
A method using a compound in which R 2 is a methyl group or an ethyl group is preferable, and a method using a compound in which R 2 is a methyl group is more preferable.
As the Lewis acid, a method using zinc chloride, titanium tetrachloride or aluminum chloride is preferable, and a method using aluminum chloride is more preferable.
As the brominating agent, a method using N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin is preferable, and a method using 1,3-dibromo-5,5-dimethylhydantoin is more preferable.
次に、本発明の製造法について説明する。 Next, the manufacturing method of this invention is demonstrated.
［第一工程］
一般式［２］の化合物は、たとえば、特許文献１記載の方法により、一般式［１］の化合物をリチオ化後、二酸化炭素と反応することにより製造することができる。
使用される溶媒としては、たとえば、エーテル類または脂肪族炭化水素類が挙げられ、これらは混合して使用してもよい。エーテル類が好ましく、テトラヒドロフランがより好ましい。
使用されるリチオ化剤としては、たとえば、ｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム、フェニルリチウムおよびメチルリチウムなどのアルキル金属試薬；または、リチウムジイソプロピルアミドおよびリチウムビストリメチルシリルアミドなどのアミド塩基が挙げられる。アルキル金属試薬が好ましく、ｎ−ブチルリチウムがより好ましい。
リチオ化剤の使用量は、特に限定されないが、一般式［１］の化合物に対して2倍モル以上が好ましく、2〜3倍モルがより好ましい。
この反応は、−100〜50℃、好ましくは、−70〜0℃で1分間〜24時間実施すればよい。
一般式［２］の化合物は、単離せずにそのまま次の反応に用いることが好ましい。
[First step]
The compound of the general formula [2] can be produced, for example, by reacting with a carbon dioxide after lithiation of the compound of the general formula [1] by the method described in Patent Document 1.
Examples of the solvent to be used include ethers or aliphatic hydrocarbons, and these may be used as a mixture. Ethers are preferred, and tetrahydrofuran is more preferred.
Examples of lithiating agents used include alkyl metal reagents such as n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium and methyllithium; or amides such as lithium diisopropylamide and lithium bistrimethylsilylamide A base. Alkyl metal reagents are preferred, and n-butyllithium is more preferred.
Although the usage-amount of a lithiation agent is not specifically limited, 2 times mole or more is preferable with respect to the compound of General formula [1], and 2 to 3 times mole is more preferable.
This reaction may be carried out at −100 to 50 ° C., preferably at −70 to 0 ° C. for 1 minute to 24 hours.
The compound of the general formula [2] is preferably used in the next reaction as it is without being isolated.
［第二工程］
一般式［３］の化合物は、酸またはハロゲン化物の存在下、一般式［２］の化合物をアルコールと反応させることにより製造することができる。
使用される酸としては、たとえば、塩酸、硫酸、リン酸、メタンスルホン酸またはｐ−トルエンスルホン酸が挙げられ、これらは混合して使用してもよい。
使用されるハロゲン化物としては、たとえば、塩化チオニル、臭化チオニルまたはオキシ塩化リンが挙げられる。
ハロゲン化物が好ましく、塩化チオニルがより好ましい。
酸またはハロゲン化物の使用量は、特に限定されないが、一般式［２］の化合物に対して1倍モル以上が好ましく、1〜2倍モルがより好ましい。
使用されるアルコールとしては、たとえば、メタノール、エタノール、プロパノールまたはブタノールが挙げられる。メタノールまたはエタノールが好ましく、メタノールがより好ましい。
アルコールの使用量は、特に限定されないが、一般式［２］の化合物に対して0.5〜10倍量（v/w）が好ましく、1〜5倍量（v/w）がより好ましい。
この反応は、0〜100℃、好ましくは、40〜60℃で1分間〜24時間実施すればよい。
一般式［３］の化合物は、単離せずにそのまま次の反応に用いることが好ましい。
[Second step]
The compound of the general formula [3] can be produced by reacting the compound of the general formula [2] with an alcohol in the presence of an acid or a halide.
Examples of the acid used include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and p-toluenesulfonic acid, and these may be used as a mixture.
Examples of the halide used include thionyl chloride, thionyl bromide, and phosphorus oxychloride.
Halides are preferred, and thionyl chloride is more preferred.
Although the usage-amount of an acid or a halide is not specifically limited, 1 time mole or more is preferable with respect to the compound of General formula [2], and 1-2 times mole is more preferable.
Examples of the alcohol used include methanol, ethanol, propanol, and butanol. Methanol or ethanol is preferred, and methanol is more preferred.
Although the usage-amount of alcohol is not specifically limited, 0.5-10 times amount (v / w) is preferable with respect to the compound of General formula [2], and 1-5 times amount (v / w) is more preferable.
This reaction may be carried out at 0 to 100 ° C., preferably 40 to 60 ° C. for 1 minute to 24 hours.
The compound of the general formula [3] is preferably used in the next reaction as it is without being isolated.
［第三工程］
一般式［４］の化合物は、ルイス酸の存在下、一般式［３］の化合物を、臭素化剤を用いて臭素化することにより製造することができる。
使用されるルイス酸としては、たとえば、塩化亜鉛、四塩化チタンまたは塩化アルミニウムが挙げられる。塩化アルミニウムが好ましい。
ルイス酸の使用量は、特に限定されないが、一般式［３］の化合物に対して3倍モル以上が好ましく、3〜6倍モルがより好ましい。
使用される臭素化剤としては、たとえば、臭素、ベンジルトリメチルアンモニウムブロミド、Ｎ−ブロモアセトアミド、２−ブロモ−２−シアノ−Ｎ，Ｎ−ジメチルアセトアミド、ブロモイソシアヌル酸モノナトリウム塩水和物、Ｎ−ブロモフタルイミド、Ｎ−ブロモサッカリン、Ｎ−ブロモコハク酸イミド、ブロモトリクロロメタン、１，３−ジブロモ−５，５−ジメチルヒダントイン、５，５−ジブロモメルドラム酸、１，２−ジブロモ−１，１，２，２−テトラクロロエタン、４−ジメチルアミノピリジニウムブロミドペルブロミド、フェニルトリメチルアンモニウムトリブロミド、ピリジニウムブロミドペルブロミド、２，４，４，６−テトラブロモ−２，５−シクロヘキサジエノンまたはテトラ−ｎ−ブチルアンモニウムトリブロミドが挙げられる。Ｎ−ブロモコハク酸イミドまたは１，３−ジブロモ−５，５−ジメチルヒダントインが好ましく、１，３−ジブロモ−５，５−ジメチルヒダントインがより好ましい。
臭素化剤の使用量は、特に限定されないが、一般式［３］の化合物に対して0.5〜5倍モルが好ましく、0.5〜2倍モルがより好ましい。
使用される溶媒としては、たとえば、脂肪族炭化水素類、ハロゲン化炭化水素類またはエーテル類が挙げられる。ハロゲン化炭化水素類が好ましく、塩化メチレンがより好ましい。
この反応は、0〜100℃、好ましくは、0〜20℃で1分間〜24時間実施すればよい。
反応終了後、一般式［４］の化合物は、抽出および／または溶媒希釈などの常法によって単離することができる。また、一般式［４］の化合物は、単離せずに、そのまま次の反応に用いてもよい。
[Third step]
The compound of the general formula [4] can be produced by brominating the compound of the general formula [3] using a brominating agent in the presence of a Lewis acid.
Examples of the Lewis acid used include zinc chloride, titanium tetrachloride, and aluminum chloride. Aluminum chloride is preferred.
Although the usage-amount of a Lewis' acid is not specifically limited, 3 times mole or more is preferable with respect to the compound of General formula [3], and 3-6 times mole is more preferable.
Examples of the brominating agent used include bromine, benzyltrimethylammonium bromide, N-bromoacetamide, 2-bromo-2-cyano-N, N-dimethylacetamide, bromoisocyanuric acid monosodium salt hydrate, N-bromo. Phthalimide, N-bromosaccharin, N-bromosuccinimide, bromotrichloromethane, 1,3-dibromo-5,5-dimethylhydantoin, 5,5-dibromomerdramic acid, 1,2-dibromo-1,1,2 , 2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, phenyltrimethylammonium tribromide, pyridinium bromide perbromide, 2,4,4,6-tetrabromo-2,5-cyclohexadienone or tetra-n-butylammonium Tribro De, and the like. N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin is preferred, and 1,3-dibromo-5,5-dimethylhydantoin is more preferred.
Although the usage-amount of a brominating agent is not specifically limited, 0.5-5 times mole is preferable with respect to the compound of General formula [3], and 0.5-2 times mole is more preferable.
Examples of the solvent used include aliphatic hydrocarbons, halogenated hydrocarbons, and ethers. Halogenated hydrocarbons are preferred, and methylene chloride is more preferred.
This reaction may be carried out at 0 to 100 ° C., preferably at 0 to 20 ° C. for 1 minute to 24 hours.
After completion of the reaction, the compound of the general formula [4] can be isolated by a conventional method such as extraction and / or solvent dilution. In addition, the compound of the general formula [4] may be used in the next reaction as it is without being isolated.
次に、本発明を実施例および比較例を挙げて説明するが、本発明はこれらに限定されるものではない。
純度は、HPLC面積％である。
HPLC測定条件
検出器：紫外吸光光度計
測定波長：230nm
カラム：Symmetry C18、内径4.6mm×長さ150mm、粒子径5μm（Waters）
移動相：アセトニトリル：水：1.0mol／Lリン酸緩衝液（pH7.0）＝500mL：480mL：20mL
温度：40℃
流量：1mL／分
EXAMPLES Next, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited to these.
Purity is HPLC area%.
HPLC measurement conditions Detector: UV absorptiometer Measurement wavelength: 230nm
Column: Symmetry C18, inner diameter 4.6mm x length 150mm, particle diameter 5μm (Waters)
Mobile phase: Acetonitrile: Water: 1.0 mol / L phosphate buffer (pH 7.0) = 500 mL: 480 mL: 20 mL
Temperature: 40 ° C
Flow rate: 1mL / min
実施例１
NMR(CDCl3)δ値：1.16(9H,s),1.45(3H,d,J=7.1Hz),3.93(3H,s),5.3-5.7(1H,m),6.8-7.0(1H,m),7.29(1H,d,J=8.3Hz),7.58(1H,dd,J=8.3,2.2Hz),8.01(1H,d,J=2.0Hz)
Example 1
NMR (CDCl 3 ) δ value: 1.16 (9H, s), 1.45 (3H, d, J = 7.1Hz), 3.93 (3H, s), 5.3-5.7 (1H, m), 6.8-7.0 (1H, m ), 7.29 (1H, d, J = 8.3Hz), 7.58 (1H, dd, J = 8.3, 2.2Hz), 8.01 (1H, d, J = 2.0Hz)
実施例２
得られた反応混合物130gを塩化メチレン150mLに溶解し、20〜28℃で塩化アルミニウム166gを分割添加した後、−1〜6℃で１，３−ジブロモ−５，５−ジメチルヒダントイン55.7gを分割添加し、0〜10℃で約6時間攪拌した。反応混合物を亜硫酸水素ナトリウム30.4gの水475mL溶液に添加し、塩化メチレン100mLを加えた。有機層を分取し、塩化ナトリウム10ｇの水90mL溶液で洗浄した。次いで塩化ナトリウム5gおよび炭酸カリウム10gの水90mL溶液で洗浄し、活性炭5gを加えた。不溶物を濾去し、濾滓を塩化メチレン100mLで洗浄した。濾液と洗液を併せ、メタノール300mLを加え、常圧下で溶媒385mLを留去した。得られた残留物を64〜68℃で約30分間攪拌した後、水150mLを滴下し、5℃まで冷却した。固形物を濾取し、白色固体の５−ブロモ−２−（（１Ｒ）−１−（（２，２−ジメチルプロパノイル）アミノ）エチル）安息香酸メチル66.6g（純度：98.9％）を得た。
NMR(CDCl3)δ値は、実施例１と同様であった。
Example 2
Dissolve 130 g of the resulting reaction mixture in 150 mL of methylene chloride, add 166 g of aluminum chloride in portions at 20 to 28 ° C., and then split 55.7 g of 1,3-dibromo-5,5-dimethylhydantoin at −1 to 6 ° C. The mixture was added and stirred at 0-10 ° C. for about 6 hours. The reaction mixture was added to a solution of 30.4 g of sodium bisulfite in 475 mL of water, and 100 mL of methylene chloride was added. The organic layer was separated and washed with a 90 mL solution of 10 g sodium chloride. Subsequently, it was washed with a 90 mL water solution of 5 g sodium chloride and 10 g potassium carbonate, and 5 g activated carbon was added. Insoluble materials were removed by filtration, and the filter cake was washed with 100 mL of methylene chloride. The filtrate and the washing solution were combined, 300 mL of methanol was added, and 385 mL of the solvent was distilled off under normal pressure. The obtained residue was stirred at 64-68 ° C. for about 30 minutes, and then 150 mL of water was added dropwise and cooled to 5 ° C. The solid was collected by filtration to obtain 66.6 g (purity: 98.9%) of methyl 5-bromo-2-((1R) -1-((2,2-dimethylpropanoyl) amino) ethyl) benzoate as a white solid. It was.
The NMR (CDCl 3 ) δ value was the same as in Example 1.
比較例１（特許文献１、実施例II−１）
NMR(CDCl3)δ値：1.17(9H,s),1.47(3H,d,J=7.1Hz),3.93(3H,s),5,4-5.6(1H,m),7.1-7.6(4H,m),7.86(1H,dd,J=7.1,1.2Hz)
Comparative Example 1 (Patent Document 1, Example II-1)
NMR (CDCl 3 ) δ value: 1.17 (9H, s), 1.47 (3H, d, J = 7.1Hz), 3.93 (3H, s), 5,4-5.6 (1H, m), 7.1-7.6 (4H , m), 7.86 (1H, dd, J = 7.1,1.2Hz)
比較例２（特許文献１、実施例II−２）
NMR(CDCl3)δ値：1.16(9H,s),1.45(3H,d,J=7.1Hz),3.93(3H,s),5.3-5.7(1H,m),6.8-7.0(1H,m),7.28(1H,d,J=8.3Hz),7.59(1H,dd,J=8.3,2.2Hz),8.00(1H,d,J=2.2Hz)
Comparative Example 2 (Patent Document 1, Example II-2)
NMR (CDCl 3 ) δ value: 1.16 (9H, s), 1.45 (3H, d, J = 7.1Hz), 3.93 (3H, s), 5.3-5.7 (1H, m), 6.8-7.0 (1H, m ), 7.28 (1H, d, J = 8.3Hz), 7.59 (1H, dd, J = 8.3, 2.2Hz), 8.00 (1H, d, J = 2.2Hz)
実施例および比較例の対比を表１に示す。 Table 1 shows a comparison between Examples and Comparative Examples.
実施例２の収率は、８０％であった。比較例の収率は、６３％であった。実施例の収率は、比較例の収率よりも１７％向上した。
比較例は、強酸性である硫酸を含有する反応混合物を濾過する工程を含んでいた。一方、実施例２は、硫酸を使用せず、濾過工程も含まなかった。
以上の結果から明らかなように、本発明の製造法は、従来の製造法よりも工業的製造法として優れている。
The yield of Example 2 was 80%. The yield of the comparative example was 63%. The yield of the example was improved by 17% over the yield of the comparative example.
The comparative example included the step of filtering the reaction mixture containing sulfuric acid that was strongly acidic. On the other hand, Example 2 did not use sulfuric acid and did not include a filtration step.
As apparent from the above results, the production method of the present invention is superior to the conventional production method as an industrial production method.
本発明の製造法は、５−ブロモ−２−（１−置換エチル）安息香酸エステルの工業的製造法として有用である。 The production method of the present invention is useful as an industrial production method of 5-bromo-2- (1-substituted ethyl) benzoate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999021849A1 (en) * | 1997-10-27 | 1999-05-06 | Toyama Chemical Co., Ltd. | Processes for producing 7-isoindolinequinolonecarboxylic derivatives and intermediates therefor, salts of 7-isoindolinequinolonecarboxylic acids, hydrates thereof, and composition containing the same as active ingredient |
| JP2000001462A (en) * | 1998-04-14 | 2000-01-07 | Toyama Chem Co Ltd | Production of 4-halogenobenzylamine derivative or its salt |
| JP2010168376A (en) * | 2008-12-25 | 2010-08-05 | Toyama Chem Co Ltd | New method for producing 5-bromo-2-(1-(substituted amino)ethyl)benzoic acid ester |
| WO2011099232A1 (en) * | 2010-02-12 | 2011-08-18 | 共栄社化学株式会社 | Process for production of halogenated aromatic compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999021849A1 (en) * | 1997-10-27 | 1999-05-06 | Toyama Chemical Co., Ltd. | Processes for producing 7-isoindolinequinolonecarboxylic derivatives and intermediates therefor, salts of 7-isoindolinequinolonecarboxylic acids, hydrates thereof, and composition containing the same as active ingredient |
| JP2000001462A (en) * | 1998-04-14 | 2000-01-07 | Toyama Chem Co Ltd | Production of 4-halogenobenzylamine derivative or its salt |
| JP2010168376A (en) * | 2008-12-25 | 2010-08-05 | Toyama Chem Co Ltd | New method for producing 5-bromo-2-(1-(substituted amino)ethyl)benzoic acid ester |
| WO2011099232A1 (en) * | 2010-02-12 | 2011-08-18 | 共栄社化学株式会社 | Process for production of halogenated aromatic compounds |
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