JPS63238075A - Production of lactones from highly unsaturated fatty acid - Google Patents
Production of lactones from highly unsaturated fatty acidInfo
- Publication number
- JPS63238075A JPS63238075A JP6959787A JP6959787A JPS63238075A JP S63238075 A JPS63238075 A JP S63238075A JP 6959787 A JP6959787 A JP 6959787A JP 6959787 A JP6959787 A JP 6959787A JP S63238075 A JPS63238075 A JP S63238075A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- lactones
- unsaturated fatty
- highly unsaturated
- fatty acids
- 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.)
- Pending
Links
- 150000002596 lactones Chemical class 0.000 title claims abstract description 51
- 235000021122 unsaturated fatty acids Nutrition 0.000 title claims abstract description 29
- 150000004670 unsaturated fatty acids Chemical class 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
- 239000012264 purified product Substances 0.000 claims abstract description 12
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- -1 alcohol ester Chemical class 0.000 claims abstract description 5
- 150000001735 carboxylic acids Chemical group 0.000 claims abstract description 3
- 238000007248 oxidative elimination reaction Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 2
- 235000021323 fish oil Nutrition 0.000 abstract description 13
- 235000019198 oils Nutrition 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 11
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 abstract description 10
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 abstract description 8
- 238000007254 oxidation reaction Methods 0.000 abstract description 8
- 235000020669 docosahexaenoic acid Nutrition 0.000 abstract description 6
- 229940114079 arachidonic acid Drugs 0.000 abstract description 5
- 235000021342 arachidonic acid Nutrition 0.000 abstract description 5
- 229920000728 polyester Polymers 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 5
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 4
- 229940090949 docosahexaenoic acid Drugs 0.000 abstract description 4
- 235000019197 fats Nutrition 0.000 abstract description 4
- 229930195729 fatty acid Natural products 0.000 abstract description 4
- 239000000194 fatty acid Substances 0.000 abstract description 4
- 150000004665 fatty acids Chemical class 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 abstract 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 abstract 1
- 238000003776 cleavage reaction Methods 0.000 abstract 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 abstract 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 abstract 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000002304 perfume Substances 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- 230000007017 scission Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 102000003820 Lipoxygenases Human genes 0.000 description 8
- 108090000128 Lipoxygenases Proteins 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 7
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 6
- 235000010469 Glycine max Nutrition 0.000 description 6
- 244000068988 Glycine max Species 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 4
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 4
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- PNZVFASWDSMJER-UHFFFAOYSA-N acetic acid;lead Chemical compound [Pb].CC(O)=O PNZVFASWDSMJER-UHFFFAOYSA-N 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 235000014593 oils and fats Nutrition 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 2
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920000064 Ethyl eicosapentaenoic acid Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000000061 acid fraction Substances 0.000 description 2
- 238000005273 aeration Methods 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- NPDDCAZCWJWIBW-UHFFFAOYSA-N dioxiran-3-one Chemical compound O=C1OO1 NPDDCAZCWJWIBW-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 150000003138 primary alcohols Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 2
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- MJOQJPYNENPSSS-XQHKEYJVSA-N [(3r,4s,5r,6s)-4,5,6-triacetyloxyoxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1CO[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O MJOQJPYNENPSSS-XQHKEYJVSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- MMCOUVMKNAHQOY-UHFFFAOYSA-N carbonoperoxoic acid Chemical compound OOC(O)=O MMCOUVMKNAHQOY-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、高度不飽和脂肪酸特に下記式に示すリルイン
酸、アラキドン酸、エイコサペンクエン酸（ＥＰＡ）、
ドコサヘキサエン酸（ＤＨＡ）又はそれらの低紙アルコ
ールエステルや酸クロリド等の混合物或いは精製品より
ラクトン類を製造する方法に関する。Detailed Description of the Invention [Industrial Application Field] The present invention is directed to highly unsaturated fatty acids, particularly liluic acid, arachidonic acid, eicosapencitric acid (EPA),
The present invention relates to a method for producing lactones from docosahexaenoic acid (DHA) or mixtures or purified products thereof such as low paper alcohol esters and acid chlorides.
［従来の技術］
高度不飽和脂肪酸は例えば魚油等の海産物油脂に多く含
まれているｉ又、ＥＰＡ、ＤＨＡについては健康食品及
び動脈硬化、心筋梗塞、抗がん剤等の用途がある。[Prior Art] Highly unsaturated fatty acids are abundantly contained in marine oils and fats such as fish oil, and EPA and DHA are used as health foods and as agents for arteriosclerosis, myocardial infarction, and anticancer agents.
［発明が解決しようとする問題点］
しかし、魚油等の海産物油脂は、従来利用の途が少なか
った。[Problems to be Solved by the Invention] However, marine oils and fats such as fish oil have not been widely used in the past.
又、ＥＰＡＳＤＨＡを医薬品とするためには、高純度品
が必要であるが、この精製法は高度不飽和脂肪酸の不安
定性もあり且つ物性的に類似の脂肪酸が混合しており技
術的に困難であった。In addition, in order to use EPASDHA as a drug, a highly purified product is required, but this purification method is technically difficult due to the instability of highly unsaturated fatty acids and the mixture of fatty acids with similar physical properties. there were.
高度不飽和脂肪酸の化学的特性をいかし、その誘導体を
つくり、その利用を考えることは、有用物質の提供及び
今迄利用の少なかった魚油の高付加価値化につながり産
業上多大な利点かある。Taking advantage of the chemical properties of highly unsaturated fatty acids to create derivatives and consider their use has great industrial advantages, as it provides useful substances and increases the added value of fish oil, which has been little used up until now.
［問題点を解決するための手段］
本発明はこれらの問題を解決するため、高度不飽和脂肪
酸を酸化してヒドロキシ基を導入することにより分子内
閉環してラクトン類としを用物質を提供することを目的
とする。[Means for Solving the Problems] In order to solve these problems, the present invention provides a lactone-based substance by oxidizing a highly unsaturated fatty acid to introduce a hydroxy group and thereby performing intramolecular ring closure. The purpose is to
すなわち、本発明は高度不飽和脂肪酸及びその低級アル
コールエステルの精製品又は粗製品を酸化して誘導した
ヒドロキシル基或いはジヒドロキシル基を酸化開裂して
得られるヒドロキシル基と末端カルボン酸を閉環せしめ
てラクトンを合成することを特徴とする高度不飽和脂肪
酸からのラクトン類の製造法にかかるものである。That is, the present invention produces a lactone by ring-closing a hydroxyl group and a terminal carboxylic acid obtained by oxidative cleavage of a hydroxyl group or dihydroxyl group derived by oxidizing a purified product or a crude product of a highly unsaturated fatty acid and its lower alcohol ester. The present invention relates to a method for producing lactones from highly unsaturated fatty acids, which is characterized by the synthesis of lactones.
高度不飽和脂肪酸にヒドロキシル基を導入するために種
々の酸化反応がある。例えば、大豆リポキシゲナーゼに
よりヒドロキシ基の導入か可能である。又過酸や過酸化
水素により二重結合をエポキシ化或いはグリコールとし
てもよい。There are various oxidation reactions for introducing hydroxyl groups into highly unsaturated fatty acids. For example, it is possible to introduce hydroxyl groups using soybean lipoxygenase. Further, the double bond may be epoxidized or converted into glycol using peracid or hydrogen peroxide.
この他バナジウム触媒によるハイドロパーオキシドによ
る酸化も可能である。In addition, oxidation with hydroperoxide using a vanadium catalyst is also possible.
得られたヒドロキシル基やグリコール類は２級アルコー
ルである。１級アルコールを得たい場合はグリコール四
酢酸鉛や過ヨウ素酸のような酸化剤で酸化開裂を行い、
得られるアルデヒド基を還元してヒドロキシ基とする。The obtained hydroxyl groups and glycols are secondary alcohols. If you want to obtain a primary alcohol, perform oxidative cleavage with an oxidizing agent such as lead glycol tetraacetate or periodic acid.
The resulting aldehyde group is reduced to a hydroxy group.
得られたオキシ酸をラクトンとする場合は縮合後熱分解
する方法、リパーゼによる方法、チオピリジルエステル
を経由する方法等何れでもよい。得られたラクトンは、
環内に二重結合を含むので必要により還元することもよ
い。When the obtained oxyacid is used as a lactone, any method such as thermal decomposition after condensation, a method using lipase, or a method via thiopyridyl ester may be used. The obtained lactone is
Since the ring contains a double bond, it may be reduced if necessary.
以下に、本発明の製造法の反応経路を例示する。The reaction route of the production method of the present invention is illustrated below.
［作 用］
反応の選択率を上げるためには、最初の酸化反応が重要
で、ω位の二重結合が酸化できれば大環状ラクトンが生
成する。しかし実際は最終のラクトンは混合物であって
も精製は蒸留等の容易な方法により可能であり昏鉋段階
の途中でも種々の精製手法が適用できる。[Effect] In order to increase the selectivity of the reaction, the first oxidation reaction is important, and if the double bond at the ω position can be oxidized, a macrocyclic lactone will be produced. However, in reality, even if the final lactone is a mixture, it can be purified by an easy method such as distillation, and various purification techniques can be applied even during the decomposition stage.
このように本発明によって得られるラクトン類は夫々の
環の大きさによってポリエステル原料や香料のほか有機
中間体として、新しい用途が期待できる。As described above, the lactones obtained by the present invention can be expected to find new uses as organic intermediates in addition to polyester raw materials and fragrances, depending on the size of each ring.
原料として用いるリルイン酸、アラキドン酸、ＥＰＡ、
ＤＨＡ等は夫々精製してもよいし、又粗精製品や混合物
を用いてもよい。Riluic acid, arachidonic acid, EPA used as raw materials,
DHA etc. may be purified individually, or crudely purified products or mixtures may be used.
［実 施 例］
以下、本発明を実施例により更に具体的に説明するが、
本発明はこれらの実施例に限定されるものではない。[Example] Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these examples.
実施例１−１
リルイン酸ｔｇを０．０２ Ｍ ＮＨａ ＯＨ水溶液１
５０１１に溶かしホウ酸緩衝液１２５１１を加え、その
溶液に大豆リポキシゲナーゼ５０ｍｇを加え通気攪拌し
ながらその０℃に保つ。１時間２０分後すポキシゲーゼ
１０ａ＋ｇを加え、２時間１０分反応せしめる。Example 1-1 Riluic acid tg in 0.02 M NHaOH aqueous solution 1
Borate buffer solution 12511 was dissolved in 5011, and 50 mg of soybean lipoxygenase was added to the solution and kept at 0° C. with aeration and stirring. After 1 hour and 20 minutes, Poxygase 10a+g was added and allowed to react for 2 hours and 10 minutes.
０℃でエタノール５１！を加え２Ｎ ＨＣｊでｐＨ４，
０とする。エーテルで３回抽出し、飽和食塩水で３回洗
浄した後ロークリエバポレータでエーテルを留去し、メ
タノール５ Ｇ ’１１を加えＮａＢＨ４２，５ｇを２
０分間で０℃にて添加する。室温に３０分放置後２Ｎ
ＩＣｆでｐＨ４，０としエーテル３回抽出し、飽和食塩
水で３回洗浄し、Ｍｇ５Ｏａを加えて一夜放置する。Ｍ
ｇＳＯ４を）戸別し、エーテルを留去したあと、シリカ
ゲルクロマトグラフにより、エーテル／ヘキサン（１：
１）溶媒で展開溶出し、オキシカルボン酸成分を得る
。Ethanol 51 at 0℃! and pH 4 with 2N HCj.
Set to 0. After extracting with ether three times and washing three times with saturated saline, the ether was distilled off using a low evaporator, and 5 G'11 of methanol was added, and 2.5 g of NaBH was added.
Add for 0 minutes at 0°C. 2N after leaving at room temperature for 30 minutes
Adjust the pH to 4.0 with ICf, extract with ether three times, wash three times with saturated saline, add Mg5Oa, and leave overnight. M
After distilling off the ether, ether/hexane (1:
1) Develop and elute with a solvent to obtain an oxycarboxylic acid component.
実施例１−２
実施例１−１で得られたヒドロキシリルイン酸２９０ｍ
ｇを無水塩化メチレン２０ ｘｉに溶かし、無水トリエ
チルアミン２００ｍｇを加えて攪拌しながら一１θ℃で
２−チオピリジルクロロホルメート１７０ｍｇを含む無
水塩化メチレン溶液２０１１を添加する。０℃で３０分
攪拌した後、冷１０％ＮａＨＣＯｚ ６１ノと冷塩化メ
チレンを加え分液する。有機層を冷１０％ ＮａＨＣＯ
３３０ｘｌ及び冷０．０２Ｎ ＩＣｊ３０１１７及び冷
飽和食塩水で洗浄した後硫酸マグネシウムにより脱水す
る。Ｍｇ５Ｏａを除去し、溶媒留去後無水ベンゼンを３
回加えて留去し脱水する。残渣と無水トルエン８０１１
１中で１００℃２時間加熱し２−ピリジルチオエステル
を閉環しラクトンとする。Example 1-2 Hydroxylylic acid 290m obtained in Example 1-1
g was dissolved in 20 xi of anhydrous methylene chloride, 200 mg of anhydrous triethylamine was added thereto, and while stirring, 2011 of an anhydrous methylene chloride solution containing 170 mg of 2-thiopyridyl chloroformate was added at -1θ°C. After stirring at 0° C. for 30 minutes, 61 g of cold 10% NaHCOz and cold methylene chloride were added and the mixture was separated. Cool the organic layer with 10% NaHCO
After washing with 330xl and cold 0.02N ICj30117 and cold saturated saline, it is dehydrated with magnesium sulfate. After removing Mg5Oa and distilling off the solvent, anhydrous benzene was added to
Add twice and evaporate to dehydrate. Residue and anhydrous toluene 8011
1 at 100° C. for 2 hours to ring-close the 2-pyridylthioester and form a lactone.
トルエン留去後シリカゲルクロマトグラフでｎ−ヘキサ
ン／エーテル（５： １）で溶出せしめオキシエイコサ
ペンクエン酸を得る。After distilling off the toluene, the residue was chromatographed on silica gel and eluted with n-hexane/ether (5:1) to obtain oxyeicosapene citric acid.
実施例１−３
実施例１−２で得られたラクトンをメタノール溶液とし
５％Ｒｈ−ｃを触媒として常圧常温で水素添加反応を行
った。得られたオイルは原料同様芳香を認めなかった。Example 1-3 The lactone obtained in Example 1-2 was dissolved in methanol, and a hydrogenation reaction was carried out at normal pressure and temperature using 5% Rh-c as a catalyst. The obtained oil, like the raw material, had no aroma.
実施例２−１
エイコサペンクエン酸１ｇを０．０２Ｍ ＮＨ４０Ｈ水
溶液１５０１１に溶かし、ホウ酸緩衝液１２５ ｘｌと
大豆リポキシゲナーゼ４５ｍｇを添加し、０℃において
通気攪拌し、４５分後にリポキシゲナーゼ１０ｍｇを追
加し、７０分間反応せしめる。以下、実施例１−１と同
様に処理しシリカゲルクロマトグラフにより精製し、オ
キシカルボン酸成分を得る。Example 2-1 1 g of eicosapene citric acid was dissolved in 0.02 M NH40H aqueous solution 15011, 125 xl of borate buffer and 45 mg of soybean lipoxygenase were added, aerated and stirred at 0°C, and 10 mg of lipoxygenase was added after 45 minutes. , react for 70 minutes. Thereafter, it is treated in the same manner as in Example 1-1 and purified by silica gel chromatography to obtain the oxycarboxylic acid component.
実施例２−２
実施例２−１で得られたオキシエイコサンペンクエン酸
を実施例１−２の方法で２−ピリジルチオエステルとし
、トルエン中で閉環してラクトンとした。Example 2-2 The oxyeicosampene citric acid obtained in Example 2-1 was converted into 2-pyridylthioester by the method of Example 1-2, and the ring was closed in toluene to form a lactone.
実施例２−３
実施例２−２で得られたラクトンを実施例１−３と同様
に処理したが、やはり原料ラクトン同様芳香を認めなか
った。Example 2-3 The lactone obtained in Example 2-2 was treated in the same manner as in Example 1-3, but like the raw material lactone, no aroma was observed.
実施例３−１
リルイン酸ｌｏｇを酢酸４０１１１に溶かし、濃硫酸０
、４１１１を加えて攪拌下４０℃で３０％過酸化水素
５．０ｇ（１，２当量）を２５分間で滴下する。４時間
攪拌後、水を加え２Ｎ Ｎａｚ ＣＯ３でｐＨ３とし、
エーテルで２回抽出し、エーテル層をロータリーエバポ
レータで留去し、残渣油をシリカゲルクロマトグラフに
てｎ−ヘキサン／エーテル（１： １）で溶出させて、
ジオキシリルイン酸画分を得る。Example 3-1 Dissolve riluic acid log in acetic acid 40111, add concentrated sulfuric acid 0
, 4111, and 5.0 g (1.2 equivalents) of 30% hydrogen peroxide was added dropwise at 40° C. over 25 minutes while stirring. After stirring for 4 hours, water was added and the pH was adjusted to 3 with 2N Naz CO3.
Extracted twice with ether, the ether layer was distilled off using a rotary evaporator, and the residual oil was chromatographed on silica gel, eluting with n-hexane/ether (1:1).
A dioxylylic acid fraction is obtained.
実施例３−２
四酢酸鉛２．４ｇをベンゼン５０１１、酢酸５′１！の
混合溶媒に溶かし、実施例３−１で得られたジオキシリ
ルイン酸１．５ｇを加える。窒素雰囲気下５時間常温で
攪拌する。Example 3-2 2.4 g of lead tetraacetate was mixed with 5011 of benzene and 5'1 of acetic acid! 1.5 g of dioxylylic acid obtained in Example 3-1 was added. Stir at room temperature for 5 hours under nitrogen atmosphere.
反応液を傾潟し、メタノールを加えて氷冷し、ＮａＢＨ
ａ ８．ＯＯＩＩｌｇを加える。還元終了後、水を加え
２Ｎ Ｈ（ＪでｐＨ３とし、エーテル抽出２回、飽和食
塩水で２回洗浄し、エーテル層を留去する。残渣をシリ
カゲルクロマトグラフに付しｎ−ヘキサン／エーテル（
５： １）で溶出せしめ、オキシカルボン酸を得る。The reaction solution was decanted, methanol was added, cooled on ice, and NaBH
a8. Add OOIIlg. After completion of the reduction, water was added to adjust the pH to 3 with 2N H (J), and the ether extraction was carried out twice, and the ether layer was distilled off. The residue was subjected to silica gel chromatography, and n-hexane/ether (
Elute with 5:1) to obtain oxycarboxylic acid.
実施例３−３
実施例３−２で得られたオキシカルボン酸を実施例１−
２の方法で２−ピリジルチオエステルとし、トルエン中
で閉環し、ラクトンとする。Example 3-3 The oxycarboxylic acid obtained in Example 3-2 was converted into Example 1-
2-pyridylthioester is prepared by method 2, and the ring is closed in toluene to obtain a lactone.
実施例１−２．２−２に比べやや芳香を認めた。A slight aroma was observed compared to Example 1-2.2-2.
実施例４−１
ＥＰＡエチルエステルｌｏＯｍｇと重曹５０ｍｇを塩化
メチレンｔ ｏ ｉｐに溶かし、メタクロル過安息香酸
ｌＯＬＩ１ｇを加え０℃で３０分反応せしめる。エーテ
ル２０ｉＪと加え、２Ｎ Ｎａ２ＣＯ３で３回、飽和食
塩水で３回洗浄し、Ｍｇ５Ｏａを加えて脱水する。Ｍｇ
５Ｏａを炉別後、溶媒を留去し、シリカゲルクロマトグ
ラフにてｎ−ヘキサン／エーテル（１０：１〜５：１）
で溶出し、モノエポキシドを得る。次いで、硫酸水溶液
を反応せしめジオキシカルボン酸を得る。Example 4-1 EPA ethyl ester loOmg and sodium bicarbonate 50mg are dissolved in methylene chloride to ip, methachloroperbenzoic acid lOLI 1g is added and reacted at 0°C for 30 minutes. Add 20 iJ of ether, wash three times with 2N Na2CO3 and three times with saturated saline, and dehydrate by adding Mg5Oa. Mg
After removing 500a from the furnace, the solvent was distilled off, and n-hexane/ether (10:1 to 5:1) was analyzed using silica gel chromatography.
Elute with to obtain monoepoxide. Next, a dioxycarboxylic acid is obtained by reacting with an aqueous sulfuric acid solution.
実施例５−１
リルイン酸塩化物４００ｍｇを塩化メチレン１００νｌ
に溶かし、重曹１ｌ１０ｌｌ１を加え０℃で脱水過酸化
水素のエーテル溶液２６１１を加える。３０分後ピリジ
ンを２滴加え、室温に２時間放置する。Example 5-1 400 mg of riluinate chloride was added to 100 νl of methylene chloride
Dissolve the solution in water, add 1 liter of baking soda, add 1 liter of baking soda, and at 0°C add 261 liters of an ether solution of dehydrated hydrogen peroxide. After 30 minutes, add 2 drops of pyridine and leave at room temperature for 2 hours.
反応液と２Ｎ ＨＣｆ、２Ｎ Ｆｅ５Ｏａ飽和食塩水で
洗浄し、無水芒硝で乾燥するとモノエポキシカルボン酸
が得られる。これを酢酸中酢酸ナトリウムを加えて８５
℃にて反応させるとジヒドロキシカルボン酸が得られる
。The reaction solution is washed with 2N HCf and 2N Fe5Oa saturated saline, and dried over anhydrous sodium sulfate to obtain monoepoxycarboxylic acid. Add sodium acetate in acetic acid to this and add 85
When reacted at ℃, dihydroxycarboxylic acid is obtained.
［発明の効果］
以上述べたように本発明の高度不飽和脂肪酸からのラク
トン類の製造法によれば、魚油等の海産物油脂に多量に
含まれる高度不飽和脂肪酸及びそのエステルを酸化して
ヒドロキシル基、ジヒドロキシル基とし、次いで酸化開
裂して得られるヒドロキシ基と末端カルボン酸とで分子
内閉環することによりラクトンが得られ、比較的多量に
存在し、入手が容易であるが用途の限られていた魚油等
の海産物油から、種々の環の大きさの安定なラクトンが
収率よく得られ、ポリエステル原料、香料、有機中間体
等の幅広い用途に用いることができ、資源の有効利用が
図れる。[Effects of the Invention] As described above, according to the method for producing lactones from highly unsaturated fatty acids of the present invention, highly unsaturated fatty acids and their esters contained in large amounts in marine fats and oils such as fish oil are oxidized to produce hydroxyl. A lactone is obtained by intramolecular ring closure with a hydroxyl group obtained by oxidative cleavage and a terminal carboxylic acid, and is present in relatively large amounts and is easy to obtain, but its uses are limited. Stable lactones with various ring sizes can be obtained in good yields from marine oils such as fish oil, which can be used for a wide range of applications such as raw materials for polyesters, fragrances, and organic intermediates, allowing for effective use of resources. .
手続補正書（自発）
昭和６２年５月２０日
昭和６２年 特 許 願 第６９５９７号２、発明の名
称
高度不飽和脂肪酸からのラクトン類の
製造法
３、補正をする者
事件との関係 特許出願人
宮城県柴田郡村田町村田字西ケ丘１２−１三丸化学株式
会社
４、代理人
東京都千代田区内神田三丁目５番３号
５、補正の対象
明細書の特許請求の範囲の欄、発明の詳細な６、補正の
内容
明細書の補正
明細書全文を別紙の如く補正する。Procedural amendment (spontaneous) May 20, 1988 Patent Application No. 69597 2, Title of invention Process for producing lactones from highly unsaturated fatty acids 3, Relationship to the case of the person making the amendment Patent application Person: Sanmaru Kagaku Co., Ltd. 4, 12-1 Nishigaoka, Murata, Murata-cho, Shibata-gun, Miyagi Prefecture, Agent: 3-5-3-5 Uchikanda, Chiyoda-ku, Tokyo, Claims column of the specification subject to amendment , Detailed Description of the Invention 6. The entire text of the amended specification of the contents of the amendment is amended as shown in the attached sheet.
但し補正の対象に記載した事項以外に変更はない。However, there are no changes other than those stated in the subject of amendment.
７、添付書類の目録
（１）補正明細書 １通補
正 明 細 書
１、発明の名称
高度不飽和脂肪酸からのラクトン類の製造法２、特許請
求の範囲
１）高度不飽和脂肪酸及びその低級アルコールエステル
の精製品又は組積製品を酸化して誘導したヒドロキシ基
或いはジヒドロキシ基を酸化開裂して得られるヒドロキ
シ基と末端カルボン酸を閉環せしめてラクトンを合成す
ることを特徴とする高度不飽和脂肪酸からのラクトン類
の製造法。7. List of attached documents (1) 1 supplementary amended specification
True description 1, Title of the invention Process for producing lactones from highly unsaturated fatty acids 2, Claims 1) Derived by oxidizing purified products or masonry products of highly unsaturated fatty acids and their lower alcohol esters 1. A method for producing lactones from highly unsaturated fatty acids, which comprises synthesizing lactones by ring-closing a hydroxy group obtained by oxidative cleavage of a hydroxy group or dihydroxy group and a terminal carboxylic acid.
３、発明の詳細な説明
［産業上の利用分野］
本発明は、高度不飽和脂肪酸特に下記式に示すリルイン
酸、アラキドン酸、エイコサペンクエン酸（ＥＰＡ）、
ドコサヘキサエン酸（ＤＨＡ）又はそれらの低級アルコ
ールエステルや酸クロリド等の混合物或いは精製品より
ラクトン類を製造する方法に関する。3. Detailed Description of the Invention [Field of Industrial Application] The present invention relates to highly unsaturated fatty acids, particularly liluic acid, arachidonic acid, eicosapencitric acid (EPA) shown in the following formula,
The present invention relates to a method for producing lactones from docosahexaenoic acid (DHA) or mixtures or purified products thereof such as lower alcohol esters and acid chlorides.
［従来の技術］
高度不飽和脂肪酸は例えば魚油等の海産物油脂に多く含
まれている。又、ＥＰＡ、ＤＭＡについては健康食品及
び動脈硬化、心筋梗塞の予防及び治療剤、抗がん剤等の
用途がある。[Prior Art] Highly unsaturated fatty acids are contained in large amounts in marine fats and oils such as fish oil. Furthermore, EPA and DMA have uses such as health foods, preventive and therapeutic agents for arteriosclerosis and myocardial infarction, and anticancer agents.
［発明が解決しようとする問題点コ
しかし、魚油等の海産物油脂は、従来利用の途が少なか
った。[Problems to be Solved by the Invention] However, marine oils and fats such as fish oil have hitherto had little use.
又、ＥＰＡ、ＤＭＡを医薬品とするためには、高純度品
が必要であるが、この精製法は高度不飽和脂肪酸の不安
定性もあり且つ物性的に類似の脂肪酸か混合しており技
術的に困難であった。In addition, in order to use EPA and DMA as pharmaceutical products, highly purified products are required, but this purification method involves the instability of highly unsaturated fatty acids and the fact that fatty acids with similar physical properties are mixed, making it technically difficult. It was difficult.
高度不飽和脂肪酸の化学的特性をいかし、その誘導体を
つくり、その利用を考えることは、有用物質の提供及び
今迄利用の少なかった魚油の高付加価値化につながり産
業上多大な利点がある。Taking advantage of the chemical properties of highly unsaturated fatty acids to create derivatives and consider their use has great industrial advantages, as it provides useful substances and increases the added value of fish oil, which has been little used up until now.
Ｅ問題点を解決するための手段］
本発明はこれらの問題を解決するため、高度不飽和脂肪
酸を酸化してヒドロキシ基を導入することにより分子内
閉環してラクトン類とし有用物質を提供することを目的
とする。Means for Solving Problem E] In order to solve these problems, the present invention provides useful substances by oxidizing highly unsaturated fatty acids and introducing hydroxyl groups, resulting in intramolecular ring closure and converting them into lactones. With the goal.
すなわち、本発明は高度不飽和脂肪酸及びその低級アル
コールエステルの精製品又は粗精製品を暖化して誘導し
たヒドロキシ基或いはジヒドロキシ基を酸化開裂して得
られるヒドロキシ基と末端カルボン酸を閉環せしめてラ
クトンを合成することを特徴とする高度不飽和脂肪酸か
らのラクトン類の製造法にかかるものである。That is, the present invention produces lactones by ring-closing hydroxyl groups and terminal carboxylic acids obtained by oxidative cleavage of hydroxyl groups or dihydroxyl groups derived by warming purified or crudely purified products of highly unsaturated fatty acids and lower alcohol esters thereof. The present invention relates to a method for producing lactones from highly unsaturated fatty acids, which is characterized by the synthesis of lactones.
高度不飽和脂肪酸にヒドロキシ基を導入するために種々
の酸化反応がある。例えば、大豆リポキシゲナーゼによ
りヒドロキシ基の導入が可能である。又過酸や過酸化水
素により二重結合をエポキシ化或いはグリコールとして
もよい。There are various oxidation reactions for introducing hydroxyl groups into highly unsaturated fatty acids. For example, introduction of hydroxyl groups is possible using soybean lipoxygenase. Further, the double bond may be epoxidized or converted into glycol using peracid or hydrogen peroxide.
この他バナジウム触媒によるヒドロペルオキシドを経た
酸化も可能である。In addition, oxidation via hydroperoxide using a vanadium catalyst is also possible.
得られたヒドロキシ基やグリコール類は２級アルコール
である。１級アルコールを得たい場合はグリコールを四
酢酸鉛や過ヨウ素酸のような酸化剤で酸化開裂を行い、
得られるアルデヒド基を還元してヒドロキシ基とする。The obtained hydroxy groups and glycols are secondary alcohols. If you want to obtain a primary alcohol, oxidatively cleave the glycol with an oxidizing agent such as lead tetraacetate or periodic acid.
The resulting aldehyde group is reduced to a hydroxy group.
得られたオキシ酸をラクトンとする場合は縮合後熱分解
する方法、リパーゼによる方法、チオピリジルエステル
を経由する方法等何れでもよい。得られたラクトンは、
環内に二重結合をむので必要により還元することもよい
。When the obtained oxyacid is used as a lactone, any method such as thermal decomposition after condensation, a method using lipase, or a method via thiopyridyl ester may be used. The obtained lactone is
Since the ring contains a double bond, it may be reduced if necessary.
以下に、本発明の製造法の反応経路を例示する。The reaction route of the production method of the present invention is illustrated below.
［作 用］
反応の選択率を上げるためには、最初の酸化反応か重要
で、ω位に近い二重結合が選択的に酸化できれば大環状
ラクトンが生成する。しかし、実際には存在する二重結
合の数により酸化生成物は混合物となるが、最終のラク
トンに至るまでの間、精製は蒸留等の容易な方法により
可能であり、原料のＥＰＡ、、ＤＨＡ等の精製の困難さ
に比べて反応段階の途中でも種々の精製手法が適用でき
る利点がある。[Effect] In order to increase the selectivity of the reaction, the first oxidation reaction is important; if the double bond near the ω position can be selectively oxidized, a macrocyclic lactone will be produced. However, in reality, the oxidation product is a mixture depending on the number of double bonds present, but purification is possible by easy methods such as distillation until the final lactone is obtained. Compared to the difficulty of purification, it has the advantage that various purification techniques can be applied even during the reaction stage.
このように本発明によって得られるラクトン類は夫々の
環の大きさによってポリエステル原料や香料のほか有機
中間体として、新しい用途が期待できる。As described above, the lactones obtained by the present invention can be expected to find new uses as organic intermediates in addition to polyester raw materials and fragrances, depending on the size of each ring.
原料として用いるリルイン酸、アラキドン酸、ＥＰＡ、
ＤＨＡ等は夫々精製してもよいし、又粗精製品や混合物
を用いてもよい。Riluic acid, arachidonic acid, EPA used as raw materials,
DHA etc. may be purified individually, or crudely purified products or mixtures may be used.
［実 施 例］
以下、本発明を実施例により更に具体的に説明するが、
本発明はこれらの実施例に限定されるものではない。[Example] Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these examples.
実施例１−１
リルイン酸１ｇを０．０２ Ｍ ＮＨ４ＯＨ水溶液１５
０１１１に溶かしホウ酸緩衝液１２５１１１を加え、そ
の溶液に大豆リポキシゲナーゼ５０ａ＋ｇを加え通気攪
拌しながらその０℃に保つ。１時間２０分後すポキシゲ
ーゼ１１０ｌｌ１を加え、２時間１０分反応せしめる。Example 1-1 1 g of liluic acid was added to 0.02 M NH4OH aqueous solution 15
Boric acid buffer solution 125111 was dissolved in 0111, and soybean lipoxygenase 50a+g was added to the solution and kept at 0°C with aeration and stirring. After 1 hour and 20 minutes, 110 ml of poxygase was added and allowed to react for 2 hours and 10 minutes.
０℃でエタノール５１！を加え２Ｎ ＨＣｆでｐＨ４，
０とする。エーテルで３回抽出し、飽和食塩水で３回洗
浄した後ロータリエバポレータでエーテルを留去し、メ
タノール５０１１を加えＮａＢＨａ ２．５ｇを２０分
間で０℃にて添加する。室温に３０分放置後２Ｎ ＨＣ
ｊでＩ）Ｈ４，Ｏとしエーテル３回抽出し、飽和食塩水
で３回洗浄し、Ｍｇ５Ｏａを加えて一夜放置する。Ｍｇ
５Ｏａを戸別し、エーテルを留去したあと、シリカゲル
クロマトグラフによりエーテル／ヘキサン（１： １）
溶媒で展開溶出し、オキシカルボン酸成分を得る。Ethanol 51 at 0℃! and pH 4 with 2N HCf.
Set to 0. After extraction with ether three times and washing three times with saturated brine, the ether was distilled off using a rotary evaporator, methanol 5011 was added, and 2.5 g of NaBHa was added over 20 minutes at 0°C. After leaving at room temperature for 30 minutes, add 2N HC.
I) Extract with ether three times with H4,O, wash three times with saturated brine, add Mg5Oa and leave overnight. Mg
After separating 5Oa and distilling off the ether, ether/hexane (1:1) was extracted using silica gel chromatography.
Develop and elute with a solvent to obtain the oxycarboxylic acid component.
実施例１−２
実施例１−１で得られたヒドロキシリルイン酸２９０ｍ
ｇを無水塩化メチレン２０ν！に溶かし、無水トリエチ
ルアミン２００＋ｎｇを加えて攪拌しながら一１０℃で
２−チオピリジルクロロホルメート１７０ｍｇを含む無
水塩化メチレン溶液２ｏ１１を添加する。０℃で３０分
攪拌した後、冷１０％ＮａＨＣＯｚ ６１１と冷塩化メ
チレンを加え分液する。有機層を冷ｌＯ％ ＮａＨＣＯ
３３０ｘｌ及び冷０．０２Ｎ ＨＣｌ３０ｘ１及び冷飽
和食塩水で洗浄した後硫酸マグネシウムにより脱水する
。Ｍｇ５Ｏａを除去し、溶媒留去後無水ベンゼンを３回
加えて留去し脱水する。残渣の２−ピリジルチオエステ
ルを無水トルエン８０ Ｉｆ中で１００℃２時間加熱す
る。トルエン留去後シリカゲルクロマトグラフでｎ−ヘ
キサン／工Ｌチル（５： １）で溶出せしめラクトンを
得る。Example 1-2 Hydroxylylic acid 290m obtained in Example 1-1
g of anhydrous methylene chloride 20ν! Add 200+ ng of anhydrous triethylamine, and add 2011 of an anhydrous methylene chloride solution containing 170 mg of 2-thiopyridyl chloroformate at -10°C while stirring. After stirring at 0°C for 30 minutes, cold 10% NaHCOz 611 and cold methylene chloride were added and the mixture was separated. Cool the organic layer with lO% NaHCO
After washing with 330 x 1 and 30 x 1 cold 0.02N HCl and cold saturated saline, it is dehydrated with magnesium sulfate. After removing Mg5Oa and distilling off the solvent, anhydrous benzene was added three times and the mixture was distilled off for dehydration. The residual 2-pyridylthioester is heated in anhydrous toluene 80 If at 100° C. for 2 hours. After distilling off the toluene, the lactone was obtained by chromatography on silica gel and eluting with n-hexane/distillate (5:1).
実施例１−３
実施例１−２で得られたラクトンをメタノール溶液とし
５％Ｒｈ−Ｃを触媒として常圧常温で水素添加反応を行
った。得られたオイルは原料同様芳香を認めなかった。Example 1-3 The lactone obtained in Example 1-2 was dissolved in methanol, and a hydrogenation reaction was carried out at normal pressure and temperature using 5% Rh-C as a catalyst. The obtained oil, like the raw material, had no aroma.
実施例２−１
エイコサペンクエン酸１ｇを０．０２Ｍ ＮＨａ Ｏ１
ｌ水溶液１５０１１に溶かし、ホウ酸緩衝液１２５１＋
１と大豆リポキシゲナーゼ４５Ｂを添加し、０℃におい
て通気攪拌し、４５分後にリポキシゲナーゼ１０ｍｇを
追加し、７０分間反応せしめる。以下、実施例１−１と
同様に処理しシリカゲルクロマトグラフにより精製し、
オキシカルボン酸成分を得る。Example 2-1 1 g of eicosapene citric acid was added to 0.02M NHaO1
Dissolve in aqueous solution 15011, borate buffer 1251+
1 and soybean lipoxygenase 45B were added, aerated and stirred at 0° C. After 45 minutes, 10 mg of lipoxygenase was added and reacted for 70 minutes. Hereinafter, it was treated in the same manner as in Example 1-1 and purified by silica gel chromatography,
Obtain an oxycarboxylic acid component.
実施例２−２
実施例２−１で得られたオキシエイコサンペンタエン酸
を実施例１−２の方法で２−ピリジルチオエステルとし
、トルエン中で閉環してラク゛トンとした。Example 2-2 The oxyeicosanpentaenoic acid obtained in Example 2-1 was converted into 2-pyridylthioester by the method of Example 1-2, and the ring was closed in toluene to form a lactone.
実施例２−３
実施例２−２で得られたラクトンを実施例１−３と同様
に処理したが、やはり原料ラクトン同様芳香を認めなか
った。Example 2-3 The lactone obtained in Example 2-2 was treated in the same manner as in Example 1-3, but like the raw material lactone, no aroma was observed.
実施例３−１
リルイン酸１０ｇを酢酸４０１！に溶かし、濃硫酸０
、４１７を加えて攪拌下４０℃で３０％過酸化水素５．
０ｇ（１，２当量）を２５分間で滴下する。４時間攪拌
後、水を加え２Ｎ Ｎａ２ＣＯ３でｐＨ３とし、エーテ
ルで２回抽出し、エーテル層をロータリーエバポレータ
で留去し、残渣油をシリカゲルクロマトグラフにてｎ−
ヘキサン／エーテル（１：１〜１：４）で溶出させて、
ジオキシカルボン酸画分を得る。Example 3-1 10 g of liluic acid was mixed with 401 g of acetic acid! Dissolve in concentrated sulfuric acid 0
, 417 and 30% hydrogen peroxide at 40°C with stirring5.
0 g (1.2 eq.) is added dropwise over 25 minutes. After stirring for 4 hours, water was added and the pH was adjusted to 3 with 2N Na2CO3, extracted twice with ether, the ether layer was distilled off using a rotary evaporator, and the residual oil was purified using silica gel chromatography.
Elute with hexane/ether (1:1 to 1:4),
A dioxycarboxylic acid fraction is obtained.
実施例３−２
四酢酸鉛２．４ｇをベンゼン５０ν！、酢８５−１１（
１’）混合溶媒に溶かし、実施例３−１で得られたジオ
キシカルボン酸１．５ｇを加える。窒素雰囲気下５時間
常温で攪拌する。Example 3-2 2.4 g of lead tetraacetate was mixed with 50 ν of benzene! , Vinegar 85-11 (
1') Dissolve in a mixed solvent and add 1.5 g of dioxycarboxylic acid obtained in Example 3-1. Stir at room temperature for 5 hours under nitrogen atmosphere.
反応液を傾瀉し、メタノールを加えて氷冷し、ＮａＢＩ
（ａ １．ｅｇを加える。還元終了後、水を加え２Ｎ１
（Ｃ４でｐｌ（３とし、エーテル抽出２回、飽和食塩水
で２回洗浄し、エーテル層を留去する。残渣をシリカゲ
ルクロマトグラフに付しｎ−ヘキサン／エーテル（５：
１〜１：１）で溶出せしめ、オキシカルボン酸を得る。The reaction solution was decanted, methanol was added, cooled on ice, and NaBI
(a 1. Add eg. After reduction, add water and 2N1
(The pl was adjusted to 3 with C4, extracted with ether twice and washed twice with saturated saline, and the ether layer was distilled off. The residue was subjected to silica gel chromatography and n-hexane/ether (5:
1 to 1:1) to obtain the oxycarboxylic acid.
実施例３−３
実施例３−２で得られたオキシカルボン酸を実施例１−
２の方法で２−ピリジルチオエステルとし、トルエン中
で閉環し、ラクトンとする。Example 3-3 The oxycarboxylic acid obtained in Example 3-2 was converted into Example 1-
2-pyridylthioester is prepared by method 2, and the ring is closed in toluene to obtain a lactone.
実施例１−２．２−２に比べやや芳香を認めた。A slight aroma was observed compared to Example 1-2.2-2.
実施例４
ＥＰＡエチルエステルＬＱＱｍｇと重曹５０ｍｇを塩化
メチレンｌＯ′ＩＩに溶かし、メタクロル過安息香酸１
０ｍｇを加え０℃で３０分反応せしめる。エーテル２０
１１を加え、２Ｎ Ｎａ２ＣＯ３で３回、飽和食塩水で
３回洗浄し、ＭｇＳＯ４を加えて脱水する。Ｍｇ５Ｏａ
を）戸別後、溶媒を留去し、シリカゲルクロマトグラフ
にてｎ−ヘキサン／エーテル（１０：１〜５：１）で溶
出し、モノエポキシドを得る。次いで、硫酸水溶液を反
応せしめジオキシカルボン酸を得る。以下、実施例３−
２．３−３と同様の操作によりラクトンとする。Example 4 EPA ethyl ester LQQ mg and 50 mg of baking soda were dissolved in methylene chloride 1O'II, and methachloroperbenzoic acid 1
Add 0 mg and react at 0°C for 30 minutes. ether 20
11 is added, washed three times with 2N Na2CO3 and three times with saturated saline, and dehydrated by adding MgSO4. Mg5Oa
) After separation, the solvent was distilled off and chromatographed on silica gel with n-hexane/ether (10:1 to 5:1) to obtain monoepoxide. Next, a dioxycarboxylic acid is obtained by reacting with an aqueous sulfuric acid solution. Below, Example 3-
A lactone is obtained by the same operation as in 2.3-3.
実施例５
リルイン酸塩化物４００ｍｇを塩化メチレン１００ ｘ
ｌに溶かし、重曹１１０ｍｇを加え０℃で脱水過酸化水
素のエーテル溶液２０″１１を加える。３０分後ピリジ
ンを２滴加え、室温に２時間放置する。Example 5 400 mg of riluinate chloride was mixed with 100× methylene chloride.
Add 110 mg of baking soda, and add 20"11 of an ether solution of dehydrated hydrogen peroxide at 0°C. After 30 minutes, add 2 drops of pyridine and leave at room temperature for 2 hours.
反応液と２Ｎ ＨＣオ、２Ｎ Ｆｅ５Ｏａ飽和食塩水で
洗浄し、無水芒硝で乾燥するとモノエポキシカルボン酸
が得られる。これを酢酸中酢酸ナトリウムを加えて８５
℃にて反応させるとジオキシカルボン酸か得られる。以
下、実施例３−２．３−３と同様の操作、によりラクト
ンとする。The reaction solution is washed with 2N HCl and 2N Fe5Oa saturated saline, and dried over anhydrous sodium sulfate to obtain monoepoxycarboxylic acid. Add sodium acetate in acetic acid to this and add 85
When reacted at ℃, dioxycarboxylic acid is obtained. Hereinafter, a lactone is obtained by the same operation as in Example 3-2.3-3.
［発明の効果］
以上述べたように本発明の高度不飽和脂肪酸からのラク
トン類の製墳法によれば、魚油等の海産物油脂に多量に
含まれる高度不飽和脂肪酸及びそのエステルを酸化して
ヒドロキシ基、ジヒドロキシ基とし、次いで酸化開裂し
て得られるヒドロキシ基と末端カルボン酸とで分子内閉
環することによりラクトンが得られ、比較的多量に存在
し、入手が容易であるが用途の限られていた魚油等の海
産物油から、種々の環の大きさの安定なラクトンが収率
よく得られ、ポリエステル原料、香料、有機中間体等の
幅広い用途に用いることができ、資源の有効利用が図れ
る。[Effects of the Invention] As described above, according to the method for forming lactones from highly unsaturated fatty acids of the present invention, highly unsaturated fatty acids and their esters contained in large amounts in marine fats and oils such as fish oil can be oxidized. Lactone is obtained by forming a hydroxy group or dihydroxy group, and then intramolecularly closing the hydroxy group obtained by oxidative cleavage with a terminal carboxylic acid.It is present in relatively large amounts and is easy to obtain, but its uses are limited. Stable lactones with various ring sizes can be obtained in good yields from marine oils such as fish oil, which can be used for a wide range of applications such as raw materials for polyesters, fragrances, and organic intermediates, allowing for effective use of resources. .
Claims (1)
の精製品又は粗製品を酸化して誘導したヒドロキシル基
或いはジヒドロキシル基を酸化開裂して得られるヒドロ
キシル基と末端カルボン酸を閉環せしめてラクトンを合
成することを特徴とする高度不飽和脂肪酸からのラクト
ン類の製造法。1) Synthesize a lactone by ring-closing the hydroxyl group obtained by oxidative cleavage of a hydroxyl group or dihydroxyl group derived by oxidizing a purified or crude product of a highly unsaturated fatty acid and its lower alcohol ester and a terminal carboxylic acid. A method for producing lactones from highly unsaturated fatty acids, characterized by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6959787A JPS63238075A (en) | 1987-03-24 | 1987-03-24 | Production of lactones from highly unsaturated fatty acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6959787A JPS63238075A (en) | 1987-03-24 | 1987-03-24 | Production of lactones from highly unsaturated fatty acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63238075A true JPS63238075A (en) | 1988-10-04 |
Family
ID=13407402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6959787A Pending JPS63238075A (en) | 1987-03-24 | 1987-03-24 | Production of lactones from highly unsaturated fatty acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63238075A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5168054A (en) * | 1989-08-04 | 1992-12-01 | Pernod-Ricard | Process for the microbiological production of gamma- and delta-lactones |
| JP2008520739A (en) * | 2004-11-19 | 2008-06-19 | マーテック・バイオサイエンシーズ・コーポレーション | Oxylipins derived from long-chain polyunsaturated fatty acids and methods for their preparation and use |
| WO2012115285A1 (en) * | 2011-02-25 | 2012-08-30 | Takasago International Corporation | Macrocyclic triene lactones having unconjugated triene structure, its production method and its synthetic intermediate |
-
1987
- 1987-03-24 JP JP6959787A patent/JPS63238075A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5168054A (en) * | 1989-08-04 | 1992-12-01 | Pernod-Ricard | Process for the microbiological production of gamma- and delta-lactones |
| JP2008520739A (en) * | 2004-11-19 | 2008-06-19 | マーテック・バイオサイエンシーズ・コーポレーション | Oxylipins derived from long-chain polyunsaturated fatty acids and methods for their preparation and use |
| WO2012115285A1 (en) * | 2011-02-25 | 2012-08-30 | Takasago International Corporation | Macrocyclic triene lactones having unconjugated triene structure, its production method and its synthetic intermediate |
| US9085545B2 (en) | 2011-02-25 | 2015-07-21 | Takasago International Corporation | Macrocyclic triene lactones having unconjugated triene structure, its production method and its synthetic intermediate |
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