JP2014218442A - Method for benzylating hydroxy tricarboxylic acid - Google Patents
Method for benzylating hydroxy tricarboxylic acid Download PDFInfo
- Publication number
- JP2014218442A JP2014218442A JP2013096549A JP2013096549A JP2014218442A JP 2014218442 A JP2014218442 A JP 2014218442A JP 2013096549 A JP2013096549 A JP 2013096549A JP 2013096549 A JP2013096549 A JP 2013096549A JP 2014218442 A JP2014218442 A JP 2014218442A
- Authority
- JP
- Japan
- Prior art keywords
- salt
- acid
- amine
- benzylation
- hydroxytricarboxylic
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 49
- -1 hydroxy tricarboxylic acid Chemical class 0.000 title claims abstract description 19
- 150000001412 amines Chemical class 0.000 claims abstract description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 238000005574 benzylation reaction Methods 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 23
- ZMJBYMUCKBYSCP-UHFFFAOYSA-N Hydroxycitric acid Chemical compound OC(=O)C(O)C(O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-UHFFFAOYSA-N 0.000 claims description 16
- 229940089491 hydroxycitric acid Drugs 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 150000001768 cations Chemical class 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 150000003512 tertiary amines Chemical class 0.000 claims description 7
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910001424 calcium ion Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 229910001414 potassium ion Inorganic materials 0.000 claims description 4
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 3
- ODBLHEXUDAPZAU-ZAFYKAAXSA-N D-threo-isocitric acid Chemical compound OC(=O)[C@H](O)[C@@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-ZAFYKAAXSA-N 0.000 claims description 3
- ODBLHEXUDAPZAU-FONMRSAGSA-N Isocitric acid Natural products OC(=O)[C@@H](O)[C@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-FONMRSAGSA-N 0.000 claims description 3
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 3
- 229910001431 copper ion Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910001415 sodium ion Inorganic materials 0.000 claims description 3
- ODBLHEXUDAPZAU-UHFFFAOYSA-N threo-D-isocitric acid Natural products OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 claims description 3
- 125000005270 trialkylamine group Chemical group 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- SJOHMMKAEJOQRW-UHFFFAOYSA-N tribenzyl 1,2-dihydroxypropane-1,2,3-tricarboxylate Chemical compound C=1C=CC=CC=1COC(=O)CC(O)(C(=O)OCC=1C=CC=CC=1)C(O)C(=O)OCC1=CC=CC=C1 SJOHMMKAEJOQRW-UHFFFAOYSA-N 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 229940091181 aconitic acid Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 3
- VYYWVGGAJXBBCA-UHFFFAOYSA-K tripotassium;1,2-dihydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[O-]C(=O)C(O)C(O)(C([O-])=O)CC([O-])=O VYYWVGGAJXBBCA-UHFFFAOYSA-K 0.000 description 3
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- VNJOEUSYAMPBAK-UHFFFAOYSA-N 2-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC=C1S(O)(=O)=O VNJOEUSYAMPBAK-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GJLRZGHZTYKENL-UHFFFAOYSA-N OC(=O)CC(C(O)=O)=C(O)C(O)=O Chemical compound OC(=O)CC(C(O)=O)=C(O)C(O)=O GJLRZGHZTYKENL-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 150000001261 hydroxy acids Chemical class 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- VEAZEPMQWHPHAG-UHFFFAOYSA-N n,n,n',n'-tetramethylbutane-1,4-diamine Chemical compound CN(C)CCCCN(C)C VEAZEPMQWHPHAG-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- VYLZSGQQVHTICN-UHFFFAOYSA-N tribenzyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound C=1C=CC=CC=1COC(=O)CC(C(=O)OCC=1C=CC=CC=1)(O)CC(=O)OCC1=CC=CC=C1 VYLZSGQQVHTICN-UHFFFAOYSA-N 0.000 description 2
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- KLVVBSVHRFWHLZ-UHFFFAOYSA-N 1-N,1-N,4-N,4-N-tetramethylhexane-1,4-diamine Chemical compound CN(C(CCCN(C)C)CC)C KLVVBSVHRFWHLZ-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical group CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CCNIFFFSAIFLGL-UHFFFAOYSA-N 2-hydroxy-2-[2-[hydroxy(phenyl)methoxy]-2-oxoethyl]butanedioic acid Chemical compound C1=CC=C(C=C1)C(O)OC(=O)CC(CC(=O)O)(C(=O)O)O CCNIFFFSAIFLGL-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- XFOSOYZCQOPDSQ-XMYIDBJESA-K calcium;potassium;(1s,2s)-1,2-dihydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[Ca+2].[O-]C(=O)[C@@H](O)[C@](O)(C([O-])=O)CC([O-])=O XFOSOYZCQOPDSQ-XMYIDBJESA-K 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- LAWOZCWGWDVVSG-UHFFFAOYSA-N dioctylamine Chemical compound CCCCCCCCNCCCCCCCC LAWOZCWGWDVVSG-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- HTDJPCNNEPUOOQ-UHFFFAOYSA-N hexamethylcyclotrisiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O1 HTDJPCNNEPUOOQ-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- ITOXMFKNJNRZDT-UHFFFAOYSA-N n,n-diethylethanamine;n,n-dipropylpropan-1-amine Chemical compound CCN(CC)CC.CCCN(CCC)CCC ITOXMFKNJNRZDT-UHFFFAOYSA-N 0.000 description 1
- DIAIBWNEUYXDNL-UHFFFAOYSA-N n,n-dihexylhexan-1-amine Chemical compound CCCCCCN(CCCCCC)CCCCCC DIAIBWNEUYXDNL-UHFFFAOYSA-N 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- PXSXRABJBXYMFT-UHFFFAOYSA-N n-hexylhexan-1-amine Chemical compound CCCCCCNCCCCCC PXSXRABJBXYMFT-UHFFFAOYSA-N 0.000 description 1
- JACMPVXHEARCBO-UHFFFAOYSA-N n-pentylpentan-1-amine Chemical compound CCCCCNCCCCC JACMPVXHEARCBO-UHFFFAOYSA-N 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical group O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- DTIFFPXSSXFQCJ-UHFFFAOYSA-N tetrahexylazanium Chemical class CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC DTIFFPXSSXFQCJ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- GJSGYPDDPQRWPK-UHFFFAOYSA-N tetrapentylammonium Chemical class CCCCC[N+](CCCCC)(CCCCC)CCCCC GJSGYPDDPQRWPK-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical class CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
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Abstract
Description
本発明は、ヒドロキシトリカルボン酸のカルボキシル基を収率よくベンジル化する方法に関する。 The present invention relates to a method for benzylating a carboxyl group of hydroxytricarboxylic acid with high yield.
ヒドロキシクエン酸に代表されるヒドロキシトリカルボン酸類は、痩身効果・美白作用などを有することが知られており、主に化粧品・医薬品分野において有用とされている物質である。特にヒドロキシル基にパルミチン酸等を付加させ誘導体化した場合、その活性が向上することが知られている（特許文献１・２）。 Hydroxytricarboxylic acids represented by hydroxycitric acid are known to have a slimming effect and a whitening action, and are substances that are mainly useful in the cosmetics and pharmaceutical fields. In particular, it is known that the activity is improved when palmitic acid or the like is added to a hydroxyl group for derivatization (Patent Documents 1 and 2).
ヒドロキシトリカルボンのヒドロキシル位部分を例えば脂肪酸とのエステル化反応などをさせ誘導体化しようとした場合、その反応を阻害しないために、予めカルボキシル基をベンジル等の保護基にて保護しておく必要性が生じる場合がある。しかしながら従来知られたベンジルアルコールをベンジル化剤として用いた反応の場合、あまり収率が高くないという問題点があった。（特許文献３） When trying to derivatize the hydroxyl position of hydroxytricarboxylic acid by, for example, esterification reaction with a fatty acid, it is necessary to protect the carboxyl group in advance with a protecting group such as benzyl in order not to inhibit the reaction. May occur. However, the conventional reaction using benzyl alcohol as a benzylating agent has a problem that the yield is not so high. (Patent Document 3)
本発明の目的は、ヒドロキシトリカルボン酸のカルボキシル基をベンジル化する際、ベンジル化体を収率よく得る方法を提供することである。 An object of the present invention is to provide a method for obtaining a benzylated product in a high yield when the carboxyl group of hydroxytricarboxylic acid is benzylated.
本発明者らは、上記の課題を解決すべく鋭意検討を重ねた結果、ヒドロキシトリカルボン酸のカルボキシル基をベンジル化する際、アミンとハロゲン化ベンジルを用いることでベンジル化が効率的に実施できることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that when benzylating the carboxyl group of hydroxytricarboxylic acid, benzylation can be efficiently carried out by using an amine and a benzyl halide. The headline and the present invention were completed.
すなわち、本発明は以下の［１］〜［１３］に関する。
[１]
アミンの存在下、ヒドロキシトリカルボン酸またはその塩と、ハロゲン化ベンジルを反応させることを特徴とする、ヒドロキシトリカルボン酸のベンジル化方法であって、前記ヒドロキシトリカルボン酸は、分子内に３つのカルボキシル基と、前記カルボキシル基のγ位またはδ位のうち少なくとも一か所にヒドロキシル基を有する化合物である、ベンジル化方法。
[２]
アミンを反応系に添加する際、添加開始から添加終了までの間が１時間以上となるようにすることを特徴とする、[１]に記載のベンジル化方法。
[３]
前記アミンを反応系に添加する方法が、アミンを一定速度で反応系に滴下する方法、または複数回に分けて反応系にアミンを添加する方法である、[２]に記載のベンジル化方法。
[４]
さらに４級アンモニウム化合物の塩を用いることを特徴とする、[１]〜[３]のいずれかに記載のベンジル化方法。
[５]
前記ヒドロキシトリカルボン酸が、分子内に３つのカルボキシル基と、そのγ位に少なくとも１つのヒドロキシル基を有する化合物であることを特徴とする、[１]〜[４]のいずれかに記載のベンジル化方法。
[６]
アミンとして、少なくとも一種の３級アミンを含む、[１]〜[５]のいずれかに記載のベンジル化方法。
[７]
前記３級アミンが、各アルキル基本の炭素数が各々独立に[１]〜[５]でのトリアルキルアミンであることを特徴とする、請求項６に記載のベンジル化方法。
[８]
前記３級アミンが、トリエチルアミン、トリプロピルアミン、トリブチルアミンから選択されるいずれか１種以上である、[７]に記載のベンジル化方法。
[９]
前記４級アンモニウム化合物が、炭素数１〜１０のアルキル基によって窒素原子が４置換された化合物であり、かつフッ素・塩素・臭素・ヨウ素のいずれかより選ばれるアニオンとの塩であることを特徴とする、[４]に記載のベンジル化方法。
[１０]
前記ヒドロキシトリカルボン酸またはその塩が、ヒドロキシクエン酸・イソクエン酸またはその塩から選択されるいずれか１種以上である、[１]〜[９]のいずれかに記載のベンジル化方法。
[１１]
前記ヒドロキシトリカルボン酸の塩が、カルシウムイオン、カリウムイオン、ナトリウムイオン、銅イオン、アンモニウムイオンから選択されるいずれか１種以上のカチオンとの塩である、[１]〜[１０]のいずれかに記載のベンジル化方法。
[１２]
前記ヒドロキシトリカルボン酸の塩が、少なくともカルシウムイオンを含むカチオンとの塩である、[１１]に記載のベンジル化方法。
[１３]
前記ハロゲン化ベンジルにおけるハロゲンが、塩素、臭素から選択されるいずれか１種以上である、[１]〜[１２]に記載のベンジル化方法。
That is, the present invention relates to the following [1] to [13].
[1]
A method for benzylating hydroxytricarboxylic acid, comprising reacting hydroxytricarboxylic acid or a salt thereof with benzyl halide in the presence of an amine, wherein said hydroxytricarboxylic acid has three carboxyl groups in its molecule. The benzylation method, which is a compound having a hydroxyl group at least at one of the γ-position or δ-position of the carboxyl group.
[2]
The benzylation method according to [1], wherein the amine is added to the reaction system so that the time from the start of addition to the end of addition is 1 hour or longer.
[3]
The benzylation method according to [2], wherein the method of adding the amine to the reaction system is a method of dropping the amine into the reaction system at a constant rate or a method of adding the amine to the reaction system in a plurality of times.
[4]
Furthermore, the benzylation method according to any one of [1] to [3], wherein a salt of a quaternary ammonium compound is used.
[5]
The benzylation according to any one of [1] to [4], wherein the hydroxytricarboxylic acid is a compound having three carboxyl groups in the molecule and at least one hydroxyl group at the γ-position. Method.
[6]
The benzylation method according to any one of [1] to [5], wherein the amine contains at least one tertiary amine.
[7]
7. The benzylation method according to claim 6, wherein the tertiary amine is a trialkylamine in which each alkyl basic carbon number is independently [1] to [5].
[8]
The benzylation method according to [7], wherein the tertiary amine is at least one selected from triethylamine, tripropylamine, and tributylamine.
[9]
The quaternary ammonium compound is a compound in which a nitrogen atom is tetrasubstituted by an alkyl group having 1 to 10 carbon atoms, and is a salt with an anion selected from fluorine, chlorine, bromine and iodine. The benzylation method according to [4].
[10]
The benzylation method according to any one of [1] to [9], wherein the hydroxytricarboxylic acid or a salt thereof is at least one selected from hydroxycitric acid / isocitric acid or a salt thereof.
[11]
In any one of [1] to [10], the salt of the hydroxytricarboxylic acid is a salt with any one or more kinds of cations selected from calcium ions, potassium ions, sodium ions, copper ions, and ammonium ions. The benzylation method described.
[12]
The benzylation method according to [11], wherein the salt of hydroxytricarboxylic acid is a salt with a cation containing at least calcium ions.
[13]
The benzylation method according to [1] to [12], wherein the halogen in the benzyl halide is one or more selected from chlorine and bromine.
＜ヒドロキシトリカルボン酸＞
ヒドロキシトリカルボン酸とは、分子内にカルボキシル基を３つと、ヒドロキシル基を１つ以上有する化合物のことを指す。本願発明の反応は特に、3か所あるカルボキシル基それぞれに対するγ位またはδ位の全箇所のうち、いずれか少なくとも一か所の位置にヒドロキシル基を有する、ヒドロキシトリカルボン酸に関する。少なくとも一か所のγ位にヒドロキシル基を有するものをγ-ヒドロキシトリカルボン酸、少なくとも一か所のδ位にヒドロキシル基を有するものをδ-ヒドロキシトリカルボン酸と以下表記する（下記化学式参照）。γ位とδ位の両方にヒドロキシル基を有していてもよい。本願におけるヒドロキシトリカルボン酸は、γ-ヒドロキシトリカルボン酸であることが特に好ましい。
本願におけるヒドロキシトリカルボン酸は、分子内に炭素を４〜３０個有するものであることが好ましく、炭素数４〜２０がより好ましく、炭素数４〜１０が最も好ましい。
Hydroxytricarboxylic acid refers to a compound having three carboxyl groups and one or more hydroxyl groups in the molecule. The reaction of the present invention particularly relates to a hydroxytricarboxylic acid having a hydroxyl group at any one of the γ-position or δ-position for each of the three carboxyl groups. Those having a hydroxyl group at at least one γ-position are hereinafter referred to as γ-hydroxytricarboxylic acid, and those having at least one δ-position are referred to as δ-hydroxytricarboxylic acid (see the following chemical formula). You may have a hydroxyl group in both γ-position and δ-position. The hydroxytricarboxylic acid in the present application is particularly preferably γ-hydroxytricarboxylic acid.
The hydroxytricarboxylic acid in the present application preferably has 4 to 30 carbon atoms in the molecule, more preferably 4 to 20 carbon atoms, and most preferably 4 to 10 carbon atoms.
γ-ヒドロキシトリカルボン酸の具体的な化合物としては、ヒドロキシクエン酸、イソクエン酸、ヒドロキシアコニット酸、などが挙げられ、中でもヒドロキシクエン酸が好ましい。なおヒドロキシクエン酸とは、クエン酸の炭素鎖部分にヒドロキシル基を付加させた誘導体である（下記化学式）。ひとつのカルボキシル基に対してγ位の箇所にヒドロキシル基を有するため、本願でいうところのγ-ヒドロキシトリカルボン酸に相当する。本願の請求する範囲に包含されるヒドロキシアコニット酸とは、下記化学式に示すアコニット酸の、＊の位置（いずれかのカルボキシル基のγ位にあたる箇所）の１か所以上にヒドロキシル基を付加させた誘導体のことを指す。（なおアコニット酸にはtrans体とcis体があるが、いずれの誘導体でもよい）
Specific compounds of γ-hydroxytricarboxylic acid include hydroxycitric acid, isocitric acid, hydroxyaconitic acid, etc. Among them, hydroxycitric acid is preferable. Hydroxycitric acid is a derivative obtained by adding a hydroxyl group to the carbon chain portion of citric acid (the following chemical formula). Since it has a hydroxyl group at the γ-position relative to one carboxyl group, it corresponds to γ-hydroxytricarboxylic acid as referred to in the present application. The hydroxyaconitic acid included in the scope of claims of the present application means that a hydroxyl group is added to one or more of the positions of * (position corresponding to the γ position of any carboxyl group) of aconitic acid represented by the following chemical formula. It refers to a derivative. (Note that aconitic acid has trans form and cis form, but any derivative may be used)
ヒドロキシトリカルボン酸は、安定性の面から金属イオンのカチオンとの塩であるほうが好ましい。前記カチオンは特に限定されないが、具体的にはカルシウムイオン、カリウムイオン、ナトリウムイオン、銅イオン、アンモニウムイオンなどが挙げられ、中でもカルシウムイオン、カリウムイオンが好ましい。前記カチオンは単一種で用いるほか、複数を混合して用いても良い。 The hydroxytricarboxylic acid is preferably a salt with a cation of a metal ion from the viewpoint of stability. Although the said cation is not specifically limited, Specifically, a calcium ion, a potassium ion, a sodium ion, a copper ion, an ammonium ion etc. are mentioned, Among these, a calcium ion and a potassium ion are preferable. The cation may be used as a single species or a mixture of a plurality of cations.
＜ハロゲン化ベンジル＞
ヒドロキシ酸のカルボキシル基をベンジル化するためのベンジル化剤としては、ハロゲン化ベンジルを用いる。
ハロゲン化ベンジルにおけるハロゲンは、例えばフッ素・塩素・臭素・ヨウ素などが挙げられ、中でも臭素が好ましい。
<Benzyl halide>
A benzyl halide is used as a benzylating agent for benzylating the carboxyl group of the hydroxy acid.
Examples of the halogen in the benzyl halide include fluorine, chlorine, bromine, and iodine. Among them, bromine is preferable.
他に一般に用いられるベンジル化剤としてベンジルアルコールがあるが、これを本反応において用いることは好ましくない。ベンジルアルコールを用いた場合、その反応性が低いために酸触媒を反応系内に添加する必要がある場合が多い。しかしヒドロキシトリカルボン酸は、カルボキシル基とそのγ位またはδ位にあるヒドロキシル基が、酸性条件下においては容易に反応し５員環または６員環のラクトンを形成してしまうため、目的とする生成物の収率が低下するという問題点がある。 Another commonly used benzylating agent is benzyl alcohol, but it is not preferred to use this in this reaction. When benzyl alcohol is used, it is often necessary to add an acid catalyst to the reaction system because of its low reactivity. However, the hydroxytricarboxylic acid is a desired product because the carboxyl group and the hydroxyl group at the γ- or δ-position easily react under acidic conditions to form a 5-membered or 6-membered lactone. There is a problem that the yield of the product decreases.
＜アミン＞
本発明において用いられるアミンは特に限定されないが、３級アミンが好ましく、中でもトリアルキルアミン（アルキル鎖の炭素数が好ましくは１〜１０、より好ましくは１〜５）が好ましい。
<Amine>
The amine used in the present invention is not particularly limited, but a tertiary amine is preferable, and among them, a trialkylamine (the alkyl chain preferably has 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms) is preferable.
アミンとしては具体的にはトリエチルアミン、トリプロピルアミン、トリブチルアミン、トリアミルアミン、トリヘキシルアミン、トリオクチルアミン、ジエチルアミン、ジプロピルアミン、ジブチルアミン、ジアミルアミン、ジヘキシルアミン、ジオクチルアミン、ブチルアミン、アミルアミン、ヘキシルアミン、オクチルアミン、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチル−１，４−ジアミノブタン、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチル−１，４−ジアミノヘキサン、ピロリジン、Ｎ−メチル−ピロリジン、ピペリジン、Ｎ−メチル−ピペリジン、ピペラジン、Ｎ，Ｎ’−ジメチルピペラジン、モルフォリン、Ｎ−メチル−モルフォリン、ピリジン、ピラジン、ピロール、Ｎ−メチル−ピロール、イミダゾール、Ｎ−メチル−イミダゾール、ピラゾール、Ｎ−メチル−ピラゾール、などが挙げられ、中でもトリエチルアミン・トリプロピルアミン・トリブチルアミンが最も好ましい。
上記の中でも、塩基性、反応性の面から分子量が３００以下程度のものが特に好ましい。
Specific examples of amines include triethylamine, tripropylamine, tributylamine, triamylamine, trihexylamine, trioctylamine, diethylamine, dipropylamine, dibutylamine, diamylamine, dihexylamine, dioctylamine, butylamine, amylamine, hexyl. Amine, octylamine, N, N, N ′, N′-tetramethyl-1,4-diaminobutane, N, N, N ′, N′-tetramethyl-1,4-diaminohexane, pyrrolidine, N-methyl -Pyrrolidine, piperidine, N-methyl-piperidine, piperazine, N, N'-dimethylpiperazine, morpholine, N-methyl-morpholine, pyridine, pyrazine, pyrrole, N-methyl-pyrrole, imidazole, N-methyl-imidazole , Pyrazo , N- methyl - pyrazole, and the like, among which triethylamine tripropylamine, tributylamine being most preferred.
Among these, those having a molecular weight of about 300 or less are particularly preferable from the viewpoint of basicity and reactivity.
本反応においては、その作用機序は明らかではないが、アミンを加えることにより反応の収率が向上するという効果がある。ヒドロキシ酸は塩の状態、特にカルシウム塩の状態ではしばしば溶媒に対する溶解性が悪く、反応が良好に進行しないという問題がある。そのような場合において系内にアミンを添加すると、ヒドロキシ酸塩が溶媒に対して良好に溶解するため、反応がスムーズに進行するためであると考えられる。 In this reaction, the mechanism of action is not clear, but the addition of an amine has the effect of improving the yield of the reaction. Hydroxy acids often have poor solvent solubility in the salt state, particularly in the calcium salt state, and there is a problem that the reaction does not proceed well. In such a case, it is considered that when an amine is added to the system, the hydroxy acid salt dissolves well in the solvent and the reaction proceeds smoothly.
＜４級アンモニウム塩＞
本発明の反応においては、反応系にさらに４級アミンを添加することが好ましい。
4級アンモニウム塩としてはテトラアルキルアミン（アルキル鎖の炭素数が好ましくは１〜２０、より好ましくは２〜１０）が好ましい。
４級アミンとしては具体的には、テトラエチルアンモニウム塩、テトラプロピルアンモニウム塩、テトラブチルアンモニウム塩、テトラアミルアンモニウム塩、テトラヘキシルアンモニウム塩、トリオクチルメチル塩、などが挙げられる。中でも窒素原子が炭素数３〜６のアルキル基で置換されたものが好ましく、フッ素、塩素、ヨウ素、臭素などのハロゲンとの塩であることが好ましい。中でも最も好ましいのは、テトラブチルアンモニウムのハロゲンとの塩である。
<Quaternary ammonium salt>
In the reaction of the present invention, it is preferable to add a quaternary amine to the reaction system.
The quaternary ammonium salt is preferably a tetraalkylamine (the alkyl chain preferably has 1 to 20 carbon atoms, more preferably 2 to 10 carbon atoms).
Specific examples of the quaternary amine include tetraethylammonium salt, tetrapropylammonium salt, tetrabutylammonium salt, tetraamylammonium salt, tetrahexylammonium salt, and trioctylmethyl salt. Among them, those in which a nitrogen atom is substituted with an alkyl group having 3 to 6 carbon atoms are preferable, and a salt with a halogen such as fluorine, chlorine, iodine or bromine is preferable. Of these, tetrabutylammonium salt with halogen is most preferable.
＜アミン添加方法＞
本発明の反応においては、まずヒドロキシトリカルボン酸とハロゲン化ベンジルを混合し、そこにアミンを添加して反応させることが好ましい。アミンを添加する際には、アミンを添加開始してから全量のアミンを添加終了するまでの時間を、一時間以上かけることが好ましい。
<Amine addition method>
In the reaction of the present invention, it is preferable to first mix a hydroxytricarboxylic acid and a benzyl halide, and add an amine thereto for reaction. When the amine is added, it is preferable that the time from the start of addition of amine to the end of addition of the entire amount of amine is one hour or longer.
この方法によれば、過剰なアミンが系内に存在することでベンジル化反応の生成物が壊れてしまうことを防ぐことができ、収率よく反応の目的物を得ることができる。
具体的な添加方法としては、（１） アミンを少量ずつ一定速度で反応系内に滴下し、滴下開始から終了までを1時間以上とする方法 （２） アミンを複数回（３回以上が好ましい）に分けて反応系内に添加し、初回に添加した時刻から最終回に添加した時刻までを一時間以上とする方法、の２つが具体的には挙げられる。中でも（１）の方法がより好ましい。
溶媒は、ヒドロキシトリカルボン酸の塩が溶解しやすいという観点から、テトラヒドロフラン、１，３−ジオキサン、N,N-ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチルリン酸トリアミドなどが好適に用いられる。
According to this method, it is possible to prevent the product of the benzylation reaction from being broken due to the presence of excess amine in the system, and the target product of the reaction can be obtained with high yield.
As specific addition methods, (1) A method in which an amine is dropped into a reaction system little by little at a constant rate, and the time from the start to the end of the addition is 1 hour or more. Specifically, there are two methods, namely, adding to the reaction system separately and setting the time from the first addition to the last addition to one hour or more. Among these, the method (1) is more preferable.
As the solvent, tetrahydrofuran, 1,3-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and the like are preferably used from the viewpoint that the salt of hydroxytricarboxylic acid is easily dissolved.
＜反応条件＞
反応時間は、アミンを添加してから反応を終了させるまでの時間が、０．５〜１０時間程度であることが好ましく、１〜３時間がより好ましい
反応温度は、アミン存在下では生成したトリベンジル体の分解が進行するためあまり高い温度は好ましくなく、９０℃以下が好ましい。また低い温度では反応の進行が遅いことから４０℃以上が好ましく、より好ましくは６０〜８０℃である。
<Reaction conditions>
The reaction time is preferably about 0.5 to 10 hours from the addition of the amine to the completion of the reaction, more preferably 1 to 3 hours. The reaction temperature is the tribenzyl produced in the presence of the amine. Since decomposition of the body proceeds, a very high temperature is not preferable, and 90 ° C. or less is preferable. Moreover, since progress of reaction is slow at low temperature, 40 degreeC or more is preferable, More preferably, it is 60-80 degreeC.
＜分析方法＞
以下の実施例において、ヒドロキシクエン酸トリベンジルの定量は、液体クロマトグラフ分析（ 以下ＬＣ ともいう。） 法を用いて行った。
分析カラム：Ｓｈｏｄｅｘ ＤＥ−６１３ ６．０ｍｍφ×１５０ｍｍ
カラム槽温度：４０℃
溶離液：アセトニトリル／水＝６５：３５（ｖ／ｖ）
溶離液流量：１ｍＬ／ｍｉｎ
注入量：１０μＬ
検出器：ＵＶ ２１０ｎｍ
<Analysis method>
In the following examples, tribenzyl hydroxycitrate was quantified using a liquid chromatographic analysis (hereinafter also referred to as LC) method.
Analytical column: Shodex DE-613 6.0 mmφ × 150 mm
Column bath temperature: 40 ° C
Eluent: acetonitrile / water = 65: 35 (v / v)
Eluent flow rate: 1 mL / min
Injection volume: 10 μL
Detector: UV 210nm
＜収率計算方法＞
また、収率を計算する際のヒドロキシクエン酸トリベンジル標準品純度の検定方法は以下のＮＭＲを用いた方法で実施した。
装置 ：ＢｒｕｋｅｒＢｉｏｓｐｉｎ Ａｖａｎｃｅ５００
試料調整 ：ヒドロキシクエン酸トリベンジル約１５ｍｇ と基準物質（ヘキサメチルシクロトリシロキサン）約２ｍｇをそれぞれ精秤し、ＣＤＣｌ３
に溶解させ室温で１Ｈ−ＮＭＲを測定し、面積比により算出した。
<Yield calculation method>
In addition, the assay method for the purity of a tribenzyl hydroxycitrate standard product when calculating the yield was carried out by the following method using NMR.
Apparatus: BrukerBiospin Avance 500
Sample preparation: About 15 mg of tribenzyl hydroxycitrate and about 2 mg of a reference substance (hexamethylcyclotrisiloxane) were weighed accurately, and CDCl 3
1H-NMR was measured at room temperature and calculated by area ratio.
実施例１：
冷却管を付けた２Ｌ セパラブルフラスコにヒドロキシクエン酸カルシウムカリウム塩４６．６ｇ（Phytotech社製、Garnia
Cambogia抽出物。ヒドロキシクエン酸の含量６４．４％ （０．１４ｍｏｌ）、カルシウム含量８．２%、カリウム含量１２．７％） 、テトラブチルアンモニウムブロミド１４．４ｇ（０．０４ｍｏｌ）、Ｎ，Ｎ−ジメチルホルムアミド２８５ ｇ（３．９ｍｏｌ）
を仕込み、撹拌しながらオイルバスにより８０℃まで加温した。ベンジルブロミド１４７．９ｇ（０．８６ｍｏｌ）を３０分でかけて加え、７．５ 時間加熱撹拌を行った後、トリエチルアミン２０．９ｇ（０．２１ｍｏｌ）を２時間かけてゆっくり滴下し、終了後１０ｍｉｎ程度撹拌した。
冷却後、減圧蒸留を行い得られた濃縮液に酢酸エチル３２０ｍＬ、純水４３０ｍＬを加えた。不溶分を減圧濾過により除去した後、水層を分離し、更に飽和塩化ナトリウム水溶液２００ｍＬを加え、油層を洗浄した後、水層を分離した。油層を減圧留去して得られた残渣にエタノールを１１０ｍＬ加え、６５℃まで加温し、残渣を溶解させた後、冷却することによって固体が析出した。これを減圧濾過後、４０℃で減圧乾燥することにより５０．４ｇ（収率７３％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Example 1:
In a 2 L separable flask with a condenser, 46.6 g of calcium potassium hydroxycitrate (Phytotech, Garnia)
Cambogia extract. Hydroxycitric acid content 64.4% (0.14 mol), calcium content 8.2%, potassium content 12.7%), tetrabutylammonium bromide 14.4 g (0.04 mol), N, N-dimethylformamide 285 g (3.9 mol)
Was heated to 80 ° C. with an oil bath while stirring. After adding 147.9 g (0.86 mol) of benzyl bromide over 30 minutes and heating and stirring for 7.5 hours, 20.9 g (0.21 mol) of triethylamine was slowly added dropwise over 2 hours, and about 10 minutes after completion. Stir.
After cooling, 320 mL of ethyl acetate and 430 mL of pure water were added to the concentrate obtained by distillation under reduced pressure. Insoluble matter was removed by filtration under reduced pressure, the aqueous layer was separated, 200 mL of a saturated aqueous sodium chloride solution was added, the oil layer was washed, and then the aqueous layer was separated. 110 mL of ethanol was added to the residue obtained by evaporating the oil layer under reduced pressure, and the mixture was heated to 65 ° C. to dissolve the residue, and then cooled to precipitate a solid. This was filtered under reduced pressure and then dried under reduced pressure at 40 ° C. to obtain 50.4 g (yield 73%) of hydroxycitric acid tribenzyl ester as a white solid.
実施例２：
トリエチルアミンの滴下方法を３分割で変更したほかは、実施例１と同様に操作した。３分割とはすなわち、実施例１におけるベンジルブロミド添加後８０℃での加熱攪拌を７．５時間行ったのち、トリエチルアミン２０．９ｇ（０．２１ｍｏｌ）の1／３量を１０分かけて反応系内に滴下し、５０分加熱攪拌した。トリエチルアミンの滴下と加熱攪拌の操作を３回繰り返したのち、冷却し、実施例１と同様に処理した。
その結果、４６．２ｇ（収率６７％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Example 2:
The operation was performed in the same manner as in Example 1 except that the dropping method of triethylamine was changed into three parts. That is, after the addition of benzyl bromide in Example 1 and heating and stirring at 80 ° C. for 7.5 hours, 1/3 amount of 20.9 g (0.21 mol) of triethylamine was added to the reaction system over 10 minutes. The solution was added dropwise and stirred with heating for 50 minutes. The operation of dropping triethylamine and heating and stirring was repeated three times, followed by cooling and processing in the same manner as in Example 1.
As a result, 46.2 g (yield 67%) of hydroxycitric acid tribenzyl ester was obtained as a white solid.
実施例３：
テトラブチルアンモニウムブロミドを加えないこと以外は実施例２と同様に操作した。その結果、４３．５ｇ（収率６３％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Example 3:
The same operation as in Example 2 was performed except that tetrabutylammonium bromide was not added. As a result, 43.5 g (yield 63%) of hydroxycitric acid tribenzyl ester was obtained as a white solid.
比較例１：
トリエチルアミン加えないこと以外は実施例１と同様に操作した。その結果、６．８ｇ（収率１０％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Comparative Example 1:
The same operation as in Example 1 was carried out except that triethylamine was not added. As a result, 6.8 g (yield 10%) of hydroxycitric acid tribenzyl ester was obtained as a white solid.
実施例４：
原料としてヒドロキシクエン酸カリウム塩５４．３ｇ（ヒドロキシクエン酸としての含量５５．２％ （０．１４ｍｏｌ））を使用すること以外は実施例２と同様に操作した。その結果、４８．６ｇ（収率７１％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Example 4:
The same operation as in Example 2 was carried out except that 54.3 g of hydroxycitrate potassium salt (content 55.2% (0.14 mol) as hydroxycitric acid) was used as a raw material. As a result, 48.6 g (yield 71%) of hydroxycitric acid tribenzyl ester was obtained as a white solid.
実施例５：
トリエチルアミンを一括で投入したこと以外は実施例１と同様に操作した。その結果、４４．２ｇ（収率６４％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Example 5:
The same operation as in Example 1 was conducted except that triethylamine was added all at once. As a result, 44.2 g (yield 64%) of hydroxycitric acid tribenzyl ester was obtained as a white solid.
比較例２：
原料としてヒドロキシクエン酸カリウム塩５４．３ｇ（ヒドロキシクエン酸としての含量５５．２％ （０．１４ｍｏｌ））を使用し、かつトリエチルアミン加えないこと以外は実施例１と同様に操作した。その結果、３８．７ｇ（収率５６．１％）のヒドロキシクエン酸トリベンジルエステルを白色固体として得た。
Comparative Example 2:
The same operation as in Example 1 was carried out except that 54.3 g of hydroxycitrate potassium salt (a content of 55.2% (0.14 mol) as hydroxycitric acid) was used as a raw material and no triethylamine was added. As a result, 38.7 g (yield 56.1%) of hydroxybenzyl citrate was obtained as a white solid.
比較例３：
ディーン・スターク装置を付けた２ Ｌナスフラスコにヒドロキシクエン酸カリウム塩２５．０ｇ（ヒドロキシクエン酸としての含量５５．２％ （０．０７ｍｏｌ）） 、トルエンスルホン酸一水和物４５．９ ｇ（０．２４ｍｏｌ） 、ベンジルアルコール１００ｇ（０．９２ｍｏｌ）、トルエン２００ｍＬ
を仕込み、窒素雰囲気下、還流状態にて攪拌した。放冷した後、酢酸エチルを５００ｍＬ加え、良く攪拌した。
これを５質量％
炭酸水素ナトリウム水溶液１Ｌの入った５Ｌビーカー中に少しずつ攪拌しながら加えた。不溶物を除き、水層を分離した後、有機層を水で洗浄し、さらに無水硫酸ナトリウム上で乾燥させた。溶媒とベンジルアルコールを減圧留去して得られた残渣をＬＣ法で分析すると、成分中のヒドロキシクエン酸トリベンジルは１１．１ｇ（収率３５％）であった。それ以外の成分として、ヒドロキシクエン酸が分子内環化を起こしたラクトン体が同量程度生成していた。
Comparative Example 3:
Hydroxycitrate potassium salt 25.0 g (content 55.2% (0.07 mol) as hydroxycitric acid), toluene sulfonic acid monohydrate 45.9 g (2 L eggplant flask equipped with a Dean-Stark apparatus) 0.24 mol), benzyl alcohol 100 g (0.92 mol), toluene 200 mL
Was stirred under reflux in a nitrogen atmosphere. After allowing to cool, 500 mL of ethyl acetate was added and stirred well.
5% by mass of this
It was added little by little in a 5 L beaker containing 1 L of an aqueous sodium bicarbonate solution. After removing insolubles and separating the aqueous layer, the organic layer was washed with water and further dried over anhydrous sodium sulfate. When the residue obtained by distilling off the solvent and benzyl alcohol under reduced pressure was analyzed by the LC method, tribenzyl hydroxycitrate in the component was 11.1 g (yield 35%). As other components, the same amount of lactone form in which hydroxycitric acid caused intramolecular cyclization was produced.
参考例１：
冷却管を付けた２ Ｌ セパラブルフラスコにクエン酸ナトリウム２水和物４６．６ｇ（０．１４ｍｏｌ） 、テトラブチルアンモニウムブロミド１４．４ｇ（０．０４ｍｏｌ）、Ｎ，Ｎ−ジメチルホルムアミド２８５ ｇ（３．９ｍｏｌ）
を仕込み、撹拌しながらオイルバスにより８０℃まで加温した。ベンジルブロミド１４７．９ｇ（０．８６ｍｏｌ）を３０分で滴下し、７．５ 時間加熱撹拌を行った後、トリエチルアミン２０．９ｇ（０．２１ｍｏｌ）を２時間かけてゆっくり滴下し、終了後１０ｍｉｎ程度撹拌した。
冷却後、減圧蒸留を行い得られた濃縮液に酢酸エチル３２０ｍＬ、純水４３０ｍＬを加えた。不溶分を減圧濾過により除去した後、水層を分離し、更に飽和塩化ナトリウム水溶液２００ｍＬを加え、油層を洗浄した後、水層を分離した。油層を減圧留去して得られた残渣にエタノールを１１０ｍＬ加え、６５℃まで加温し、残渣を溶解させた後、冷却することによって固体が析出した。これを減圧濾過後、４０℃で減圧乾燥することにより５６．６ｇ（収率８５％）のクエン酸トリベンジルエステルを白色固体として得た。
Reference example 1:
In a 2 L separable flask equipped with a condenser, sodium citrate dihydrate 46.6 g (0.14 mol), tetrabutylammonium bromide 14.4 g (0.04 mol), N, N-dimethylformamide 285 g (3 .9 mol)
Was heated to 80 ° C. with an oil bath while stirring. 147.9 g (0.86 mol) of benzyl bromide was added dropwise over 30 minutes, heated and stirred for 7.5 hours, then 20.9 g (0.21 mol) of triethylamine was slowly added dropwise over 2 hours, and about 10 minutes after completion. Stir.
After cooling, 320 mL of ethyl acetate and 430 mL of pure water were added to the concentrate obtained by distillation under reduced pressure. Insoluble matter was removed by filtration under reduced pressure, the aqueous layer was separated, 200 mL of a saturated aqueous sodium chloride solution was added, the oil layer was washed, and then the aqueous layer was separated. 110 mL of ethanol was added to the residue obtained by evaporating the oil layer under reduced pressure, and the mixture was heated to 65 ° C. to dissolve the residue, and then cooled to precipitate a solid. This was filtered under reduced pressure and then dried under reduced pressure at 40 ° C. to obtain 56.6 g (yield 85%) of tribenzyl citrate as a white solid.
参考例２：
ディーン・スターク装置を付けた２ Ｌナスフラスコにクエン酸ナトリウム２水和物１９．５ｇ（０．０７ｍｏｌ） 、トルエンスルホン酸一水和物４５．９ ｇ（０．２４ｍｏｌ） 、ベンジルアルコール１００ｇ（０．９２ｍｏｌ）、トルエン２００ｍＬ を仕込み、窒素雰囲気下、還流状態にて攪拌した。放冷した後、酢酸エチルを５００ｍＬ加え、良く攪拌した。
これを５質量％ 炭酸水素ナトリウム水溶液１Ｌの入った５Ｌビーカー中に少しずつ攪拌しながら加えた。不溶物を除き、水層を分離した後、有機層を水で洗浄し、さらに無水硫酸ナトリウム上で乾燥させた。溶媒とベンジルアルコールを減圧留去して得られた残渣をＬＣ法で分析すると、成分中のクエン酸トリベンジルは２７．０ｇ（収率８８％）であった。
Reference example 2:
In a 2 L eggplant flask equipped with a Dean-Stark apparatus, 19.5 g (0.07 mol) of sodium citrate dihydrate, 45.9 g (0.24 mol) of toluenesulfonic acid monohydrate, 100 g of benzyl alcohol (0 .92 mol) and 200 mL of toluene were charged and stirred under reflux in a nitrogen atmosphere. After allowing to cool, 500 mL of ethyl acetate was added and stirred well.
This was added little by little to a 5 L beaker containing 1 L of 5 mass% sodium hydrogen carbonate aqueous solution while stirring. After removing insolubles and separating the aqueous layer, the organic layer was washed with water and further dried over anhydrous sodium sulfate. When the residue obtained by distilling off the solvent and benzyl alcohol under reduced pressure was analyzed by the LC method, tribenzyl citrate in the component was 27.0 g (yield 88%).
ＢｎＯＨ：ベンジルアルコール
ＴｓＯＨ：ｐ−トルエンスルホン酸
ＴＢＡＢ：テトラブチルアンモニウムブロミド
ＴＥＡ：トリエチルアミン
Claims (13)
The benzylation method according to claim 1, wherein the halogen in the benzyl halide is at least one selected from chlorine and bromine.
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| JPS57122061A (en) * | 1981-01-22 | 1982-07-29 | Nippon Chemiphar Co Ltd | Novel cyclohexanecarboxylic acid derivative and its preparation |
| JP2003089683A (en) * | 2001-09-19 | 2003-03-28 | Meiji Milk Prod Co Ltd | Method for producing 2-amino-3-carboxy-1,4- naphthoquinone |
| JP2007031415A (en) * | 2004-09-24 | 2007-02-08 | Showa Denko Kk | Hydroxycitric acid derivatives and external preparation for skin containing the same |
| WO2012077456A1 (en) * | 2010-12-08 | 2012-06-14 | 国立大学法人 長崎大学 | Production method for ether, ester, and thioether |
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| JPS57122061A (en) * | 1981-01-22 | 1982-07-29 | Nippon Chemiphar Co Ltd | Novel cyclohexanecarboxylic acid derivative and its preparation |
| JP2003089683A (en) * | 2001-09-19 | 2003-03-28 | Meiji Milk Prod Co Ltd | Method for producing 2-amino-3-carboxy-1,4- naphthoquinone |
| JP2007031415A (en) * | 2004-09-24 | 2007-02-08 | Showa Denko Kk | Hydroxycitric acid derivatives and external preparation for skin containing the same |
| WO2012077456A1 (en) * | 2010-12-08 | 2012-06-14 | 国立大学法人 長崎大学 | Production method for ether, ester, and thioether |
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| US20180065992A1 (en) * | 2016-09-08 | 2018-03-08 | Glykon Technologies Group, Llc | Monomeric bimetal hydroxycitric acid compounds and methods of making and using the same |
| CN110087646A (en) * | 2016-09-08 | 2019-08-02 | 格利康科技集团有限责任公司 | Monomer bimetallic hydroxycitrate acid compound and its preparation and application |
| US11066423B2 (en) | 2016-09-08 | 2021-07-20 | Glykon Technologies Group, Llc | Monomeric bimetal hydroxycitric acid compounds and methods of making and using the same |
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Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
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| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |