CN115093392B - Preparation method of R-lipoic acid - Google Patents
Preparation method of R-lipoic acid Download PDFInfo
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- CN115093392B CN115093392B CN202210708205.XA CN202210708205A CN115093392B CN 115093392 B CN115093392 B CN 115093392B CN 202210708205 A CN202210708205 A CN 202210708205A CN 115093392 B CN115093392 B CN 115093392B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 50
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 title claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 184
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- 238000000034 method Methods 0.000 claims abstract description 45
- 101000810330 Arabidopsis thaliana Eukaryotic translation initiation factor 3 subunit E Proteins 0.000 claims abstract description 35
- 102000008016 Eukaryotic Initiation Factor-3 Human genes 0.000 claims abstract description 35
- 101100317378 Mus musculus Wnt3 gene Proteins 0.000 claims abstract description 31
- OUBORTRIKPEZMG-UHFFFAOYSA-N INT-2 Chemical compound Nc1c(ncn1-c1ccc(F)cc1)C(=N)C#N OUBORTRIKPEZMG-UHFFFAOYSA-N 0.000 claims abstract description 29
- 101001060278 Xenopus laevis Fibroblast growth factor 3 Proteins 0.000 claims abstract description 29
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 claims abstract description 28
- 101100348848 Mus musculus Notch4 gene Proteins 0.000 claims abstract description 26
- 230000008569 process Effects 0.000 claims abstract description 26
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 24
- BVURNMLGDQYNAF-SECBINFHSA-N (1r)-n,n-dimethyl-1-phenylethanamine Chemical compound CN(C)[C@H](C)C1=CC=CC=C1 BVURNMLGDQYNAF-SECBINFHSA-N 0.000 claims abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052979 sodium sulfide Inorganic materials 0.000 claims abstract description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZRFSLYSHAASMCM-UHFFFAOYSA-N heptane-1,3,7-triol Chemical compound OCCCCC(O)CCO ZRFSLYSHAASMCM-UHFFFAOYSA-N 0.000 claims abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 239000011593 sulfur Substances 0.000 claims abstract description 13
- 238000005893 bromination reaction Methods 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 9
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 42
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 26
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- 238000007333 cyanation reaction Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical group [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims description 2
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000006872 improvement Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000000605 extraction Methods 0.000 description 20
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 20
- 238000001035 drying Methods 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- 229960002663 thioctic acid Drugs 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- 238000002390 rotary evaporation Methods 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000012267 brine Substances 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 230000032798 delamination Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- IZFHEQBZOYJLPK-SSDOTTSWSA-N (R)-dihydrolipoic acid Chemical compound OC(=O)CCCC[C@@H](S)CCS IZFHEQBZOYJLPK-SSDOTTSWSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 206010027439 Metal poisoning Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000029549 Muscle injury Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000010501 heavy metal poisoning Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- -1 methanesulfonic acid ester Chemical class 0.000 description 1
- CRUBJJQTENRFEL-UHFFFAOYSA-N methyl 6,8-dihydroxyoctanoate Chemical compound COC(=O)CCCCC(O)CCO CRUBJJQTENRFEL-UHFFFAOYSA-N 0.000 description 1
- MJGRFAJZJNWXBR-UHFFFAOYSA-N methyl 8-chloro-6-hydroxyoctanoate Chemical compound COC(=O)CCCCC(O)CCCl MJGRFAJZJNWXBR-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YYZUSRORWSJGET-UHFFFAOYSA-N octanoic acid ethyl ester Natural products CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention provides a preparation method of R-lipoic acid, which comprises the following steps: the method comprises the steps of reacting 1,3, 7-heptanetriol with 2, 2-dimethoxypropane, carrying out bromination reaction on the obtained compound INT-1 with a brominating reagent to obtain a compound INT-2, then carrying out cyanidation reaction on the compound INT-2 with a cyanidation reagent to obtain a compound INT-3, then carrying out ring opening and hydrolysis reaction under the action of concentrated sulfuric acid to obtain a compound INT-4, carrying out chiral resolution on the compound INT-4 by taking (R) - (+) -N, N-dimethyl-1-phenethylamine as an alkaline resolving agent to obtain a compound INT-5, then carrying out cyclization reaction on the compound INT-5 with p-toluenesulfonyl chloride to obtain a compound INT-6, and carrying out cyclization reaction on the compound INT-6 with sodium sulfide and sulfur to obtain R-lipoic acid. The invention has mild process conditions, easily obtained raw materials, high chiral intermediates and optical purity of the final product, is favorable for quality control and improvement of the raw material medicines of the final product, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a preparation method of R-lipoic acid.
Background
Alpha-lipoic acid is a compound which can eliminate free radicals for accelerating aging and pathopoiesia and is similar to vitamins, has the characteristics of water solubility and fat solubility, can assist coenzyme to perform physiological metabolism which is beneficial to organism immunity, and is a universal antioxidant drug. The alpha-lipoic acid has certain effects on treating liver diseases, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, arsenic, mercury, cadmium and other heavy metal poisoning and other diseases, for example, the alpha-lipoic acid can assist in treating type II diabetes to improve glucose metabolism of islet function, protect nerve cells, prevent cataract, prevent muscle injury and the like.
As shown in the following chemical formula, in the molecular structure of alpha-lipoic acid, one chiral carbon is present in position 3 of dithiolane, and has optical rotation, and the corresponding dextro (R) enantiomer and levo (S) enantiomer are generated. Studies have shown that these two enantiomers of alpha-lipoic acid exhibit different biological and pharmacological properties, wherein the R-form is far more bioactive than the S-form, and the S-form is essentially inactive, but is also free of toxic side effects, probably due to the fact that during metabolism of lipoic acid, a significant amount of R-lipoic acid can be reduced to dihydrolipoic acid through the cell membrane and mitochondrial membrane into cells and mitochondria, while only a small amount of S-form is reduced into cells. Dihydrolipoic acid has stronger antioxidant capacity than lipoic acid, and both the regeneration of endogenous antioxidants and the repair of oxidative damage can be realized through the form of dihydrolipoic acid. R-lipoic acid is a natural form of lipoic acid in human body, has better curative effect than racemic alpha-lipoic acid as a vitamin medicament, has more activity in treating type II diabetes mellitus, promoting skeletal muscle to absorb glucose, reducing plasma insulin and free fatty acid level, improving glycogen synthesis under the action of insulin, glucose oxidation, increasing oxygen content of blood flow of animals and the like, has wider prospect in preventing and treating heart diseases, diabetes mellitus, liver diseases, senile dementia and other diseases, and finally can completely replace the racemic alpha-lipoic acid, thereby becoming a commonly used medicament and nutritional supplement.
The synthesis method of R-lipoic acid is many, but the following three types are mainly adopted: firstly, the current industrial production method of R-lipoic acid uses 6, 8-dichloro ethyl octanoate as initial raw material, and adopts the processes of thio-reaction, cyclization and hydrolysis to obtain racemic alpha-lipoic acid, then uses resolving agent to make multiple resolution and refining so as to obtain the R-lipoic acid, and its yield is less than 50%. Although the racemization method of S-lipoic acid has been developed, the conversion of S-lipoic acid into mixed lipoic acid has severe requirements on actual production conditions, has corrosiveness on equipment, and has low yield, so that the production cost is high; secondly, 6, 8-dihydroxyoctanoic acid methyl ester or 6-hydroxy-8-chlorooctanoic acid methyl ester is used as a starting material to prepare methanesulfonic acid ester, and then R-lipoic acid is prepared by stereoselectivity, so that the process is complex, and particularly, pure products are not easy to obtain; thirdly, the racemized ethyl 6, 8-dichloro octoate is hydrolyzed into (+/-) dichloro octoate, and then the (+/-) dichloro octoate is sequentially split, re-thio-ed and cyclized by a splitting agent, so that the method can save the cost to a certain extent, but the cost is higher because about 50 percent of S- (-) -6, 8-dichloro octoate is still not utilized.
The prior art methods for synthesizing R-lipoic acid, including the three methods, have the defects of high cost, low yield and high raw material consumption, can not meet the requirement of industrial scale-up production, and have the defect of being not in line with the requirement of green environment-friendly production due to high waste emission.
In view of the above-described prior art, there is a need to continue to explore a method for synthesizing R-lipoic acid that overcomes the above-described deficiencies.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of R-lipoic acid. The method has mild process conditions, is beneficial to reducing the preparation cost and improving the purity, yield and optical purity of the product, is efficient, green and environment-friendly, and can meet the requirement of industrial amplified production.
To achieve the purpose, the invention adopts the following technical scheme:
In one aspect, the present invention provides a method for preparing R-lipoic acid, the method comprising the steps of:
(1) Reacting 1,3, 7-heptanetriol with 2, 2-dimethoxy propane to obtain compound INT-1, wherein the reaction formula is as follows:
(2) Bromination reaction is carried out on the compound INT-1 and a brominating reagent to obtain a compound INT-2, wherein the reaction formula is as follows:
(3) The compound INT-2 and a cyanation reagent are subjected to cyanation reaction to obtain a compound INT-3, wherein the reaction formula is as follows:
(4) The compound INT-3 is subjected to ring opening and hydrolysis reaction under the action of concentrated sulfuric acid to obtain a compound INT-4, wherein the reaction formula is as follows:
(5) Chiral resolution is carried out on the compound INT-4 by taking (R) - (+) -N, N-dimethyl-1-phenethylamine as an alkaline resolving agent to obtain a compound INT-5, wherein the reaction formula is as follows:
(6) The compound INT-5 reacts with p-toluenesulfonyl chloride to obtain a compound INT-6, and the reaction formula is as follows:
(7) The compound INT-6, sodium sulfide and sulfur undergo cyclization reaction to obtain R-lipoic acid, and the reaction formula is as follows:
preferably, the molar ratio of 1,3, 7-heptanetriol to 2, 2-dimethoxypropane in step (1) is from 1:3 to 4, for example 1:3, 1:3.2, 1:3.5, 1:3.8 or 1:4.
Preferably, the reaction of step (1) is carried out in the presence of p-toluene sulfonic acid.
Preferably, the molar ratio of p-toluene sulfonic acid to 1,3, 7-heptanetriol is from 0.1 to 0.2:1, for example 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1 or 0.2:1.
Preferably, the p-toluenesulfonic acid is added to the reaction system at 0-10deg.C (e.g., 0deg.C, 2deg.C, 4deg.C, 5deg.C, 7deg.C, 9deg.C, or 10deg.C).
Preferably, the solvent of the reaction in the step (1) is any one or a combination of at least two of dichloromethane, methanol, ethanol, isopropanol or acetone.
Preferably, the temperature of the reaction in step (1) is 20-35 ℃ (e.g. 20 ℃, 22 ℃, 25 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃) and the reaction time is 6-12 hours (e.g. 6 hours, 8 hours, 10 hours or 12 hours).
Preferably, the molar ratio of compound INT-1 to brominating agent of step (2) is in the range of 1:1.05 to 1.2, for example 1:1.05, 1:1.08, 1:1, 1:1.1 or 1:1.2.
Preferably, the bromination reaction of step (2) is carried out in the presence of triphenylphosphine.
Preferably, the molar ratio of triphenylphosphine to compound INT-1 is from 1.05 to 1.2:1, for example 1.05:1, 1.08:1, 1.1:1 or 1.2:1.
Preferably, the brominating reagent of step (2) is N-bromosuccinimide or liquid bromine.
Preferably, the brominating reagent of step (2) is added to the reaction system at 0 ℃.
Preferably, the solvent for the bromination reaction in step (2) is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane or chloroform.
Preferably, the bromination reaction in step (2) is carried out at a temperature of 20-35 ℃ (e.g. 20 ℃, 22 ℃,25 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃) and for a reaction time of 2-6 hours (e.g. 2 hours, 3 hours, 4 hours, 5 hours or 6 hours).
Preferably, the cyanating reagent of step (3) is cuprous cyanide or zinc cyanide.
Preferably, the molar ratio of compound INT-2 to cyanating reagent of step (3) is from 1:1 to 1.3, for example 1:1, 1:1.1, 1:1.2 or 1:1.3.
Preferably, the cyanation reaction of step (3) is carried out in the presence of potassium iodide.
Preferably, the molar ratio of potassium iodide to compound INT-2 is from 0.01 to 0.011:1.
Preferably, the solvent for the cyanation reaction of step (3) is N, N-dimethylformamide.
Preferably, the cyanation reaction in step (3) is carried out at a temperature of 90-110 ℃ (e.g. 90 ℃, 95 ℃, 98 ℃, 100 ℃, 105 ℃, 108 ℃ or 110 ℃) for a reaction time of 12-24 hours (e.g. 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours).
Preferably, the molar ratio of compound INT-3 to sulfuric acid in step (4) is in the range of 1:1 to 3.5, for example 1:1, 1:1.5, 1:2, 1:2.5, 1:2.8, 1:3 or 1:3.5.
Preferably, the solvent for the ring-opening and hydrolysis reaction in the step (4) is water or a mixed solvent of water and ethanol.
Preferably, the temperature of the ring opening and hydrolysis reaction of step (4) is 90-110 ℃ (e.g. 90 ℃, 95 ℃, 98 ℃, 100 ℃, 105 ℃, 108 ℃ or 110 ℃), and the reaction time is 6-12 hours (e.g. 6 hours, 8 hours, 10 hours or 12 hours).
In the step (5) of the invention, the (R) - (+) -N, N-dimethyl-1-phenethylamine is used as a resolution agent, the resolution agent can be purchased commercially or prepared by itself, the resolution agent can be recycled, and the method is simple and feasible, has easily controlled working procedures and lower cost, and is beneficial to the popularization of amplified production.
Preferably, the molar ratio of (R) - (+) -N, N-dimethyl-1-phenethylamine to compound INT-4 of step (5) is from 0.55 to 0.75:1, for example 0.55:1, 0.6:1, 0.63:1, 0.65:1, 0.68:1, 0.70:1 or 0.75:1.
Preferably, in the chiral resolution in the step (5), the compound INT-4 is firstly dissolved in a solvent, then (R) - (+) -N, N-dimethyl-1-phenethylamine is added, stirring is carried out for dissolution, the obtained solution is cooled for crystallization and is filtered by suction, and a filter cake is acidified to obtain the compound INT-5.
Preferably, the solvent used in the chiral separation in step (5) is any one or a combination of at least two of methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol or water.
Preferably, the temperature of the reduced temperature crystallization of the chiral resolution of step (5) is-30 to 0 ℃ (e.g., -30 ℃, -20 ℃, -10 ℃, -5 ℃ or 0 ℃), and the crystallization time is 1 to 6 hours (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours).
Preferably, the molar ratio of compound INT-5 to p-toluenesulfonyl chloride in step (6) is in the range of 1:2-2.05, for example 1:2, 1:2.01, 1:2.02, 1:2.03, 1:2.04 or 1:2.05.
Preferably, the reaction of step (6) is carried out in the presence of a basic substance, preferably pyridine and/or triethylamine.
Preferably, the solvent of the reaction of step (6) is toluene.
Preferably, the temperature of the reaction in step (6) is 20-35 ℃ (e.g. 20 ℃, 22 ℃, 25 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃) and the reaction time is 12-24 hours (e.g. 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours).
In the invention, in the step (6), the hydroxyl group is used for generating an OTs group, so that the OTs group has better leaving group property, the substitution and cyclization reaction of S atoms are facilitated, the reaction condition is milder, and the three wastes are fewer.
Preferably, the molar ratio of compound INT-6 to sodium sulphide of step (7) is in the range of 1:1-2, for example 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2.
Preferably, the molar ratio of the compound INT-6 to sulphur of step (7) is from 1:1 to 2, for example 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2.
Preferably, the cyclization reaction of step (7) is performed in a system of phase transfer catalyst and water.
Preferably, the phase transfer catalyst is any one or a combination of at least two of benzyl triethyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium bisulfate, tetramethyl ammonium fluoride, tetramethyl ammonium chloride, tetramethyl ammonium bromide, trioctyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride.
Preferably, the molar ratio of the phase transfer catalyst to the compound INT-6 is from 0.01 to 0.1:1, for example 0.01:1, 0.03:1, 0.05:1, 0.08:1 or 0.1:1.
Preferably, the temperature of the cyclization reaction in step (7) is 75-90 ℃ (e.g. 75 ℃, 78 ℃, 80 ℃, 85 ℃, 88 ℃ or 90 ℃) and the reaction time is 1.5-3 hours (e.g. 1.5 hours, 1.8 hours, 2 hours, 2.5 hours, 2.8 hours or 3 hours).
As a preferable technical scheme, the preparation method of the R-lipoic acid specifically comprises the following steps:
(1) Reacting 1,3, 7-heptanetriol and 2, 2-dimethoxypropane in a molar ratio of 1:3-4 at 20-35 ℃ in the presence of p-toluenesulfonic acid for 6-12 hours to obtain a compound INT-1;
(2) In the presence of triphenylphosphine, carrying out bromination reaction on a compound INT-1 and a brominating reagent for 2-6 hours at the temperature of 20-35 ℃ in a molar ratio of 1:1.05-1.2 to obtain a compound INT-2;
(3) In the presence of potassium iodide, carrying out cyanidation reaction on a compound INT-2 and a cyanidation reagent for 12-24 hours at 90-110 ℃ according to the molar ratio of 1:1-1.3 to obtain a compound INT-3;
(4) The compound INT-3 and concentrated sulfuric acid are subjected to ring opening and hydrolysis reaction for 6-12 hours at 90-110 ℃ in water or a water-ethanol mixed solvent system according to the molar ratio of 1:1-3.5, so as to obtain a compound INT-4;
(5) Dissolving a compound INT-4 in a solvent, adding (R) - (+) -N, N-dimethyl-1-phenethylamine, stirring and dissolving, cooling the obtained solution to a temperature of between 30 ℃ below zero and 0 ℃ for crystallization for 1 to 6 hours, filtering, and acidifying a filter cake, wherein the molar ratio of the (R) - (+) -N, N-dimethyl-1-phenethylamine to the compound INT-4 is 0.55 to 0.75:1, so as to obtain a compound INT-5;
(6) In the presence of alkaline substances, the compound INT-5 and p-toluenesulfonyl chloride react for 12-24 hours at the temperature of 20-35 ℃ in a molar ratio of 1:2-2.05 to obtain a compound INT-6;
(7) In a system of a phase transfer catalyst and water, carrying out cyclization reaction on a compound INT-6, sodium sulfide and sulfur at 75-90 ℃ for 1.5-3 hours, wherein the molar ratio of the compound INT-6 to the sodium sulfide is 1:1-2, and the molar ratio of the compound INT-6 to the sulfur is 1:1-2, so as to obtain the R-lipoic acid.
Compared with the prior art, the invention has the following beneficial effects:
The preparation method of the R-lipoic acid has mild conditions, high optical purity (HPLC content is 98.8-99.3 percent, ee value is 99.0-99.2 percent) of chiral intermediates and final products, and is beneficial to quality control and improvement of bulk drugs of the final products; the process route provided by the invention has the advantages that the raw materials of the used reagents are easy to obtain, the yield reaches 95-96%, the technical route is reasonable in design and environment-friendly, and the process route can be used for mass production to meet the use requirements and is suitable for industrial production.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Chiral gas chromatography conditions for determining ee value of the product in the following examples: the chromatographic column is chiral capillary column CP-chirsil-DEXCB, nitrogen is used as carrier gas, the temperature of the sample inlet is 280 ℃, the temperature of the detector is 280 ℃, the reaction product is acetylated and then analyzed, and the column temperature is 160 ℃.
Example 1
The embodiment provides a preparation method of R-lipoic acid, which comprises the following steps:
(1) Preparation of Compound INT-1:
1,3, 7-heptanetriol (100 g,0.67 mol) was dissolved in methylene chloride (1300 mL), 2-dimethoxypropane (211 g,2.03 mol) was added, the mixture was cooled to 0℃in an ice bath, a solution of p-toluenesulfonic acid (12 g,0.07 mol) in methylene chloride (30 mL) was added dropwise, the reaction was carried out at 20℃for 12 hours, a saturated aqueous sodium bicarbonate solution was added dropwise for quenching, extraction with methylene chloride and recrystallization purification with ethyl acetate-n-hexane (v/v 1:1) and vacuum drying were carried out to give Compound INT-1 (117 g), yield 92% as follows:
(2) Preparation of Compound INT-2:
Compound INT-1 (105 g,0.56 mol) was dissolved in methylene chloride (1200 mL), triphenylphosphine (154 g,0.59 mol) was added, cooled down to below 0deg.C in an ice bath, a solution of N-bromosuccinimide (104 g,0.58 mol) in methylene chloride (200 mL) was slowly added dropwise, the reaction mixture was reacted at 20deg.C for 6 hours, water (50 mL) was slowly added, the organic solvent was removed by concentrating under reduced pressure, cooled down to about 0deg.C and left for 3 hours, crude product was obtained by filtration, and isopropanol was recrystallized to give compound INT-2 (123 g), yield 88%, the reaction formula was as follows:
(3) Preparation of Compound INT-3:
Compound INT-2 (120 g,0.48 mol) was dissolved in N, N-dimethylformamide (1500 mL), cuprous cyanide (43 g,0.48 mol) and potassium iodide (0.8 g,5 mmol) were added, the temperature was raised to 90℃for reaction for 24 hours, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride, aqueous saline, anhydrous sodium sulfate drying and rotary evaporation under reduced pressure to dryness were carried out to give compound INT-3 (82 g), yield 87% was as follows:
(4) Preparation of Compound INT-4:
The compound INT-3 (80 g,0.41 mol), concentrated sulfuric acid (40 g,0.41 mol) are dissolved in water (1200 mL), the temperature is raised to 90 ℃ for reaction for 12h, the temperature is reduced to room temperature, dichloromethane is added for extraction, brine is used for washing, anhydrous sodium sulfate is dried, the solution is decompressed and distilled to dryness, the crude product is recrystallized by isopropanol, and vacuum drying is carried out, thus obtaining the compound INT-4 (65 g), the yield is 91%, and the reaction formula is as follows:
(5) Compound INT-5 in preparation:
Compound INT-4 (85 g,0.48 mol) was dissolved in methanol (1500 mL), (R) - (+) -N, N-dimethyl-1-phenethylamine (40 g,0.27 mol) was dissolved in methanol (500 mL), added to a reaction flask, stirred at room temperature for 1h, cooled to-30 ℃ for crystallization 2h, suction filtered, and the resulting solid was recrystallized with a mixed solvent of methanol and water (1:1) to give compound INT-5 (R) - (+) -N, N-dimethyl-1-phenethylamine salt, dissolved with water (60 mL), dropwise added with 2N HCl solution to ph=1-2, extracted with N-butanol, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give compound INT-5 as a white solid (28 g) having GC content 98.1%, yield 33%, optical rotation value-19.0 °, ee value 99.4%, the reaction formula was as follows:
(6) Preparation of Compound INT-6:
P-toluenesulfonyl chloride (61 g,0.32 mol) was dissolved in toluene (300 mL), cooled to 0deg.C, a toluene solution (100 mL) of Compound INT-5 (28 g,0.16 mol) was added dropwise, pyridine (100 mL) was added dropwise, the temperature was raised to 20deg.C for reaction 35h, ice water was added dropwise to quench the reaction solution, the organic solvent was removed by concentrating under reduced pressure, dichloromethane was added for extraction, diluted hydrochloric acid was added dropwise to neutralize to pH=7, the organic phase was separated, brine was washed, dried over anhydrous sodium sulfate, distilled to dryness under reduced pressure, recrystallized from ethyl acetate-n-hexane mixed solvent, dried under vacuum to give Compound INT-6 (70 g), yield 91% as follows:
(7) The R-lipoic acid is prepared after the preparation of the finished product:
Into a 2L reaction flask, the compound INT-6 (70 g,0.14 mol), sulfur (37 g,0.14 mol), tetrabutylammonium bromide (5 g,16 mmol) and water (450 mL) were added, stirred, heated to 85 ℃, an aqueous solution of sodium sulfide (11 g of sodium sulfide, 120mL of water) was added dropwise, stirred at 85 ℃ for 2 hours after the completion of the dropwise addition, cooled to 60 ℃, left standing for delamination, an oil layer was extracted with toluene, refined and dried to obtain R-lipoic acid (27 g), HPLC content was 98.8%, yield 91%, optical rotation value +112.0 °, ee value 99.2%, the reaction formula was as follows:
Example 2
The embodiment provides a preparation method of R-lipoic acid, which comprises the following steps:
(1) Preparation of Compound INT-1:
1,3, 7-heptanetriol (125 g,0.84 mol) was dissolved in methanol (1500 mL), 2-dimethoxypropane (284 g,2.7 mol) was added, the mixture was cooled to 5℃in an ice bath, a solution of p-toluenesulfonic acid (18 g,0.105 mol) in methanol (100 mL) was added dropwise, the temperature was raised to 25℃for reaction for 8 hours, and saturated aqueous sodium bicarbonate solution was added dropwise for quenching, followed by extraction with methylene chloride and recrystallization for purification to give Compound INT-1 (148 g) in 93% yield;
(2) Preparation of Compound INT-2:
Dissolving compound INT-1 (148 g,0.79 mol) in 1, 2-dichloroethane (2000 mL), adding triphenylphosphine (230 g,0.88 mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a solution of bromine (140 g,0.88 mol) in 1, 2-dichloroethane (150 mL), reacting the reaction mixture at 25 ℃ for 4h, slowly adding water (40 mL), concentrating under reduced pressure to remove the organic solvent, cooling to about 0 ℃ for 3h, filtering to obtain a crude product, recrystallizing with isopropanol to obtain compound INT-2 (178 g) with a yield of 90%;
(3) Preparation of Compound INT-3:
Dissolving compound INT-2 (175 g,0.7 mol) in N, N-dimethylformamide (2000 mL), adding zinc cyanide (94 g,0.8 mol) and potassium iodide (1.2 g,7 mmol), heating to 100 ℃ for reaction for 18h, concentrating under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, and evaporating under reduced pressure to dryness to obtain compound INT-3 (122 g) with yield of 89%;
(4) Preparation of Compound INT-4:
Dissolving a compound INT-3 (120 g,0.61 mol) and concentrated sulfuric acid (120 g,1.2 mol) in a mixed solvent of water and ethanol (250 mL:250 mL), heating to 100 ℃ for reaction for 9 hours, cooling to room temperature, adding dichloromethane for extraction, washing with common salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing the crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4 (100 g) with a yield of 93%;
(5) Preparation of Compound INT-5:
Dissolving compound INT-4 (100 g,0.57 mol) in ethanol (500 mL), (R) - (+) -N, N-dimethyl-1-phenethylamine (55 g,0.37 mol) in ethanol (250 mL), adding into a reaction bottle, stirring at room temperature for 1h, cooling to-20deg.C for crystallization for 1h, suction-filtering, recrystallizing the obtained solid with ethanol and water mixed solvent (1:1) to obtain compound INT-5 (R) - (+) -N, N-dimethyl-1-phenethylamine salt, dissolving with water (300 mL), dripping 2N HCl solution to pH=1-2, extracting with N-butanol, washing the organic phase with salt water, drying with anhydrous sodium sulfate, and steaming under reduced pressure to dryness to obtain compound INT-5 as white solid (28 g), GC content 98.1%, yield 28%, optical rotation value-19.0 °, ee value 99.4%;
(6) Preparation of Compound INT-6:
Dissolving tosyl chloride (62 g,0.33 mol) in toluene (350 mL), cooling to 0 ℃, dropwise adding a toluene solution (100 mL) of a compound INT-5 (28 g,0.16 mol), dropwise adding triethylamine (100 mL), heating to 25 ℃ for reaction 28h, dropwise adding ice water to quench the reaction solution, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, dropwise adding dilute hydrochloric acid for neutralizing to pH=7, separating an organic phase, washing with saline, drying with anhydrous sodium sulfate, evaporating to dryness under reduced pressure in a rotary manner, recrystallizing with an ethyl acetate-n-hexane mixed solvent, and drying in vacuum to obtain the compound INT-6 (65 g) with the yield of 84%;
(7) The R-lipoic acid is prepared after the preparation of the finished product:
In a 2L reaction flask, a compound INT-6 (65 g,0.13 mol), sulfur (35 g,0.14 mol), tetrabutylammonium bromide (5 g,16 mmol) and water (500 mL) were added, stirred, heated to 85 ℃, an aqueous solution of sodium sulfide (11 g of sodium sulfide, 50mL of water) was added dropwise, stirred at 85 ℃ for 2 hours after the completion of the dropwise addition, cooled to 60 ℃, left standing for delamination, an oil layer was extracted with toluene, refined and dried to obtain R-lipoic acid (24 g), the HPLC content was 98.8%, the yield was 87%, the optical rotation value was +112.0 °, and the ee value was 99.2%.
Example 3
The embodiment provides a preparation method of R-lipoic acid, which comprises the following steps:
(1) Preparation of Compound INT-1:
1,3, 7-heptanetriol (150 g,1.01 mol) was dissolved in acetone (2500 mL), 2-dimethoxypropane (365 g,3.5 mol) was added, the mixture was cooled to 10 ℃ in an ice bath, a solution of p-toluenesulfonic acid (26 g,0.15 mol) in acetone (75 mL) was added dropwise, the temperature was raised to 35 ℃ for reaction for 6 hours, saturated aqueous sodium bicarbonate solution was added dropwise for quenching, extraction with methylene chloride and recrystallization purification were carried out to give compound INT-1 (175 g), yield 92%;
(2) Preparation of Compound INT-2:
Dissolving compound INT-1 (175 g,0.93 mol) in chloroform (2000 mL), adding triphenylphosphine (292 g,1.11 mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a chloroform (750 mL) solution of N-bromosuccinimide (198 g,1.21 mol), reacting the reaction mixture at 35 ℃ for 2 hours, slowly adding water (100 mL), concentrating under reduced pressure to remove an organic solvent, cooling to about 0 ℃ for 3 hours, filtering to obtain a crude product, recrystallizing with isopropanol to obtain compound INT-2 (210 g), and obtaining the yield of 90%;
(3) Preparation of Compound INT-3:
Dissolving compound INT-2 (210 g,0.84 mol) in N, N-dimethylformamide (2500 mL), adding cuprous cyanide (97 g,1.1 mol) and potassium iodide (1.4 g,8 mmol), heating to 110 ℃ for reaction for 12h, concentrating under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, and evaporating under reduced pressure to dryness to obtain compound INT-3 (150 g) with yield of 91%;
(4) Preparation of Compound INT-4:
Dissolving a compound INT-3 (150 g,0.76 mol) and concentrated sulfuric acid (260 g,2.65 mol) in water (400 mL), heating to 110 ℃ for reaction for 6 hours, cooling to room temperature, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing the crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4 (125 g) with a yield of 93%;
(5) Preparation of Compound INT-5:
Dissolving compound INT-4 (125 g,0.71 mol) in isopropanol (400 mL), (R) - (+) -N, N-dimethyl-1-phenethylamine (79 g,0.53 mol) in isopropanol (250 mL), adding into a reaction bottle, stirring at room temperature for 1h, cooling to 0 ℃ for crystallization for 6h, carrying out suction filtration, recrystallizing the obtained solid with a mixed solvent of isopropanol and water (1:1) to obtain compound INT-5 (R) - (+) -N, N-dimethyl-1-phenethylamine salt, dissolving with water (200 mL), dropwise adding 2N HCl solution to pH=1-2, extracting with N-butanol, washing an organic phase with water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness to obtain compound INT-5 as white solid (45 g), carrying out GC content of 98.1%, yield of 36%, optical rotation value of-19.0 DEG ee value of 99.4;
(6) Preparation of Compound INT-6:
P-toluenesulfonyl chloride (100 g,0.52 mol) is dissolved in toluene (250 mL), cooled to 0 ℃, pyridine (150 mL) is added dropwise into a toluene solution (200 mL) of a compound INT-5 (45 g,0.26 mol) and reacted for 20h at 35 ℃, ice water is added dropwise to quench the reaction liquid, the organic solvent is removed by decompression concentration, dichloromethane extraction is carried out, dilute hydrochloric acid is added dropwise for neutralization to pH=7, an organic phase is separated, brine is washed, anhydrous sodium sulfate is dried, decompression rotary evaporation is carried out until dryness, and the compound INT-6 (110 g) is obtained by recrystallisation of an ethyl acetate-n-hexane mixed solvent and vacuum drying, and the yield 89% is obtained;
(7) The R-lipoic acid is prepared after the preparation of the finished product:
in a 2L reaction flask, the compound INT-6 (110 g,0.23 mol), sulfur (60 g,0.23 mol), tetrabutylammonium bromide (8 g,25 mmol) and water (2000 mL) were added, stirred, heated to 85℃and an aqueous solution of sodium sulfide (18 g of sodium sulfide, 120mL of water) was added dropwise, stirred at 85℃for 2 hours after the completion of the dropwise addition, cooled to 60℃and allowed to stand for delamination, the oil layer was extracted with toluene, purified and dried to give R-lipoic acid (43 g), HPLC content was 98.8%, yield 92%, optical rotation value +112.0℃and ee value 99.2%.
Example 4
The embodiment provides a preparation method of R-lipoic acid, which comprises the following steps:
(1) Preparation of Compound INT-1:
1,3, 7-heptanetriol (150 g,1.01 mol) was dissolved in ethanol (2800 mL), 2-dimethoxypropane (325 g,3.12 mol) was added, the mixture was cooled to 3℃in an ice bath, a solution of p-toluenesulfonic acid (20 g,0.12 mol) in ethanol (75 mL) was added dropwise, the temperature was raised to 22℃for reaction for 9 hours, and saturated aqueous sodium bicarbonate solution was added dropwise for quenching, followed by extraction with methylene chloride and recrystallization purification to give Compound INT-1 (176 g) in 93% yield;
(2) Preparation of Compound INT-2:
Dissolving compound INT-1 (175 g,0.93 mol) in dichloromethane (2000 mL), adding triphenylphosphine (288 g,1.1 mol), cooling to below 0deg.C in ice bath, slowly dropping bromine (176 g,1.1 mol) in dichloromethane (750 mL), reacting the reaction mixture at 28deg.C for 3h, slowly adding water (100 mL), concentrating under reduced pressure to remove organic solvent, cooling to about 0deg.C, standing for 3h, filtering to obtain crude product, recrystallizing with isopropanol to obtain compound INT-2 (210 g), and obtaining yield 90%;
(3) Preparation of Compound INT-3:
Compound INT-2 (210 g,0.84 mol) was dissolved in N, N-dimethylformamide (2500 mL), zinc cyanide (132 g,1.12 mol) and potassium iodide (1.4 g,8 mmol) were added, the temperature was raised to 95℃for reaction for 20 hours, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride was carried out, washing with common salt, drying with anhydrous sodium sulfate, spin-evaporating to dryness under reduced pressure, to give compound INT-3 (152 g), yield 92%;
(4) Preparation of Compound INT-4:
Dissolving a compound INT-3 (150 g,0.76 mol) and concentrated sulfuric acid (160 g,1.63 mol) in water (300 mL), heating to 95 ℃ for reaction for 10 hours, cooling to room temperature, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, performing rotary evaporation under reduced pressure to dryness, recrystallizing the crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4 (126 g) with a yield of 94%;
(5) Preparation of Compound INT-5:
Dissolving compound INT-4 (125 g,0.71 mol) in N-propanol (400 mL), (R) - (+) -N, N-dimethyl-1-phenethylamine (90 g,0.6 mol) in N-propanol (250 mL), adding into a reaction bottle, stirring at room temperature for 1h, cooling to-25 ℃ for crystallization for 3h, carrying out suction filtration, recrystallizing the obtained solid with a mixed solvent of isopropanol and water (1:1) to obtain compound INT-5 (R) - (+) -N, N-dimethyl-1-phenethylamine salt, dissolving with water (150 mL), dropwise adding 2N HCl solution to pH=1-2, extracting with N-butanol, washing an organic phase with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness to obtain compound INT-5, white solid (46 g), GC content 98.1%, yield 37%, optical rotation value-19.0 degree ee value 99.5;
(6) Preparation of Compound INT-6:
P-toluenesulfonyl chloride (100 g,0.52 mol) is dissolved in toluene (250 mL), cooled to 0 ℃, pyridine (150 mL) is added dropwise into a toluene solution (200 mL) of a compound INT-5 (45 g,0.26 mol) and reacted for 20h at 35 ℃, ice water is added dropwise to quench the reaction liquid, the organic solvent is removed by decompression concentration, dichloromethane extraction is carried out, dilute hydrochloric acid is added dropwise for neutralization to pH=7, an organic phase is separated, brine is washed, anhydrous sodium sulfate is dried, decompression rotary evaporation is carried out until dryness, and the compound INT-6 (110 g) is obtained by recrystallisation of an ethyl acetate-n-hexane mixed solvent and vacuum drying, and the yield 89% is obtained;
(7) The R-lipoic acid is prepared after the preparation of the finished product:
In a 2L reaction flask, the compound INT-6 (110 g,0.23 mol), sulfur (65 g,0.25 mol), tetrabutylammonium bromide (9 g,28 mmol) and water (2200 mL) were added, stirred, heated to 85 ℃, an aqueous solution of sodium sulfide (18 g of sodium sulfide, 120mL of water) was added dropwise, stirred at 85 ℃ for 2 hours after the completion of the dropwise addition, cooled to 60 ℃, left standing for delamination, the oil layer was extracted with toluene, refined and dried to obtain R-lipoic acid (44 g), the HPLC content was 99.1%, the yield was 93%, the optical rotation value was +112.0 °, and the ee value was 99.3%.
Example 5
The embodiment provides a preparation method of R-lipoic acid, which comprises the following steps:
(1) Preparation of Compound INT-1:
1,3, 7-heptanetriol (150 g,1.01 mol) was dissolved in isopropanol (2500 mL), 2-dimethoxypropane (352 g,3.4 mol) was added, the ice bath was cooled to 10 ℃, a solution of p-toluenesulfonic acid (24 g,0.14 mol) in isopropanol (75 mL) was added dropwise, the temperature was raised to 30 ℃ for reaction for 7h, saturated aqueous sodium bicarbonate solution was added dropwise for quenching, extraction with methylene chloride and recrystallization purification were carried out to give compound INT-1 (177 g), yield 93%;
(2) Preparation of Compound INT-2:
Dissolving compound INT-1 (175 g,0.93 mol) in chloroform (2000 mL), adding triphenylphosphine (302 g,1.15 mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding chloroform (750 mL) solution of N-bromosuccinimide (205 g,1.15 mol), reacting the reaction mixture at 30 ℃ for 5h, slowly adding water (100 mL), concentrating under reduced pressure to remove the organic solvent, cooling to about 0 ℃ for 3h, filtering to obtain a crude product, recrystallizing isopropanol to obtain compound INT-2 (211 g), and obtaining the yield of 90%;
(3) Preparation of Compound INT-3:
Dissolving compound INT-2 (210 g,0.84 mol) in N, N-dimethylformamide (2500 mL), adding cuprous cyanide (110 g,1.23 mol) and potassium iodide (1.4 g,8 mmol), heating to 108 ℃ for reaction for 11h, concentrating under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, and evaporating under reduced pressure to dryness to obtain compound INT-3 (151 g) with yield of 91%;
(4) Preparation of Compound INT-4:
Dissolving a compound INT-3 (150 g,0.76 mol) and concentrated sulfuric acid (284 g,2.85 mol) in water (400 mL), heating to 105 ℃ for reaction for 7h, cooling to room temperature, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, performing rotary evaporation under reduced pressure to dryness, recrystallizing the crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4 (127 g) with a yield of 94%;
(5) Preparation of Compound INT-5:
Dissolving compound INT-4 (125 g,0.71 mol) in tert-butanol (400 mL), (R) - (+) -N, N-dimethyl-1-phenethylamine (105 g,0.7 mol) in tert-butanol (220 mL), adding into a reaction bottle, stirring at room temperature for 1h, cooling to-22 ℃ for crystallization for 3.5h, suction-filtering, recrystallizing the obtained solid with a mixed solvent of isopropanol and water (1:1) to obtain compound INT-5 (R) - (+) -N, N-dimethyl-1-phenethylamine salt, dissolving with water (180 mL), dripping 2N HCl solution to pH=1-2, extracting with N-butanol, washing the organic phase with salt water, drying with anhydrous sodium sulfate, and steaming under reduced pressure until dry to obtain compound INT-5 as white solid (47 g), wherein GC content is 98.3%, yield is 38%, optical rotation value is-19.0 degree ee value is 99.4%;
(6) Preparation of Compound INT-6:
P-toluenesulfonyl chloride (100 g,0.52 mol) is dissolved in toluene (250 mL), cooled to 0 ℃, a toluene solution (200 mL) of a compound INT-5 (45 g,0.26 mol) is added dropwise, triethylamine (150 mL) is added dropwise, the temperature is raised to 30 ℃ for reaction for 18h, ice water is added for quenching the reaction liquid, the organic solvent is removed by decompression concentration, dichloromethane extraction is carried out, dilute hydrochloric acid is added for neutralization to pH=7, an organic phase is separated, brine washing, anhydrous sodium sulfate is dried, decompression rotary evaporation is carried out until dryness, and the compound INT-6 (112 g) is obtained by recrystallisation of an ethyl acetate-n-hexane mixed solvent and vacuum drying, and the yield is 90%;
(7) The R-lipoic acid is prepared after the preparation of the finished product:
In a 2L reaction flask, a compound INT-6 (110 g,0.23 mol), sulfur (60 g,0.23 mol), tetrabutylammonium bromide (8 g,25 mmol) and water (2000 mL) were added, stirred, heated to 85 ℃, an aqueous solution of sodium sulfide (20 g of sodium sulfide, 120mL of water) was added dropwise, stirred at 85 ℃ for 2 hours after the completion of the dropwise addition, cooled to 60 ℃, left standing for delamination, an oil layer was extracted with toluene, refined and dried to obtain R-lipoic acid (44 g), HPLC content was 98.9%, yield was 90%, optical rotation value +112.0 °, ee value was 99.1%.
The applicant states that the present invention describes the preparation method of R-lipoic acid of the present invention by the above examples, but the present invention is not limited to the above examples, i.e., it does not mean that the present invention must be practiced by relying on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (31)
1. A process for the preparation of R-lipoic acid, characterized in that it comprises the following steps:
(1) Reacting 1,3, 7-heptanetriol with 2, 2-dimethoxy propane to obtain compound INT-1, wherein the reaction formula is as follows:
(2) Bromination reaction is carried out on the compound INT-1 and a brominating reagent to obtain a compound INT-2, wherein the reaction formula is as follows:
(3) The compound INT-2 and a cyanation reagent are subjected to cyanation reaction to obtain a compound INT-3, wherein the reaction formula is as follows:
(4) The compound INT-3 is subjected to ring opening and hydrolysis reaction under the action of concentrated sulfuric acid to obtain a compound INT-4, wherein the reaction formula is as follows:
(5) Chiral resolution is carried out on the compound INT-4 by taking (R) - (+) -N, N-dimethyl-1-phenethylamine as an alkaline resolving agent to obtain a compound INT-5, wherein the reaction formula is as follows:
(6) The compound INT-5 reacts with p-toluenesulfonyl chloride to obtain a compound INT-6, and the reaction formula is as follows:
(7) The compound INT-6, sodium sulfide and sulfur undergo cyclization reaction to obtain R-lipoic acid, and the reaction formula is as follows:
the reaction is carried out in the presence of p-toluenesulfonic acid, the bromination reaction is carried out in the presence of triphenylphosphine, the bromination reagent is N-bromosuccinimide or liquid bromine, the cyanidation reagent is cuprous cyanide or zinc cyanide, the cyanidation reaction is carried out in the presence of potassium iodide, the reaction is carried out in the presence of alkaline substances, the alkaline substances are pyridine and/or triethylamine, and the cyclization reaction is carried out in a system of a phase transfer catalyst and water.
2. The process of claim 1, wherein the molar ratio of 1,3, 7-heptanetriol to 2, 2-dimethoxypropane in step (1) is 1:3-4.
3. The process according to claim 1, wherein the molar ratio of p-toluene sulfonic acid to 1,3, 7-heptanetriol is 0.1-0.2:1.
4. The method according to claim 1, wherein the p-toluenesulfonic acid is added to the reaction system at 0 to 10 ℃.
5. The method according to claim 1, wherein the solvent for the reaction in step (1) is any one or a combination of at least two of dichloromethane, methanol, ethanol, isopropanol or acetone.
6. The process according to claim 1, wherein the reaction in step (1) is carried out at a temperature of 20 to 35 ℃ for a reaction time of 6 to 12 hours.
7. The process according to claim 1, wherein the molar ratio of the compound INT-1 to the brominating reagent in step (2) is from 1:1.05 to 1.2.
8. The preparation method according to claim 1, wherein the molar ratio of triphenylphosphine to compound INT-1 is 1.05-1.2:1.
9. The process of claim 1, wherein the brominating reagent of step (2) is added to the reaction system at 0 ℃.
10. The method according to claim 1, wherein the solvent for the bromination reaction in step (2) is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane or chloroform.
11. The process of claim 1, wherein the bromination reaction in step (2) is carried out at a temperature of 20 to 35 ℃ for a reaction time of 2 to 6 hours.
12. The process according to claim 1, wherein the molar ratio of the compound INT-2 to the cyanating agent of step (3) is from 1:1 to 1.3.
13. The process according to claim 1, wherein the molar ratio of potassium iodide to compound INT-2 is from 0.01 to 0.011:1.
14. The process according to claim 1, wherein the solvent for the cyanation reaction in step (3) is N, N-dimethylformamide.
15. The process according to claim 1, wherein the cyanation reaction in step (3) is carried out at a temperature of 90 to 110℃for a period of 12 to 24 hours.
16. The process according to claim 1, wherein the molar ratio of compound INT-3 to sulfuric acid in step (4) is from 1:1 to 3.5.
17. The method according to claim 1, wherein the solvent for the ring-opening and hydrolysis reaction in the step (4) is water or a mixed solvent of water and ethanol.
18. The method according to claim 1, wherein the temperature of the ring-opening and hydrolysis reaction in the step (4) is 90-110 ℃ and the reaction time is 6-12 hours.
19. The process according to claim 1, wherein the molar ratio of (R) - (+) -N, N-dimethyl-1-phenethylamine to compound INT-4 in step (5) is 0.55-0.75:1.
20. The preparation method of claim 1, wherein the chiral resolution in the step (5) is that the compound INT-4 is firstly dissolved in a solvent, then (R) - (+) -N, N-dimethyl-1-phenethylamine is added, stirring is carried out for dissolution, the obtained solution is cooled for crystallization and suction filtration, and a filter cake is acidified to obtain the compound INT-5.
21. The method according to claim 1, wherein the solvent used for the chiral separation in step (5) is any one or a combination of at least two of methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, and water.
22. The preparation method according to claim 1, wherein the temperature of the chiral separation in the step (5) is-30-0 ℃ and the crystallization time is 1-6 hours.
23. The process according to claim 1, wherein the molar ratio of the compound INT-5 to the p-toluenesulfonyl chloride in step (6) is from 1:2 to 2.05.
24. The process of claim 1, wherein the solvent for the reaction of step (6) is toluene.
25. The process according to claim 1, wherein the reaction in step (6) is carried out at a temperature of 20 to 35 ℃ for a period of 12 to 24 hours.
26. The process according to claim 1, wherein the molar ratio of compound INT-6 to sodium sulphide in step (7) is 1:1-2.
27. The process according to claim 1, wherein the molar ratio of the compound INT-6 to sulfur in step (7) is 1:1-2.
28. The method according to claim 1, wherein the phase transfer catalyst is any one or a combination of at least two of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium bisulfate, tetramethylammonium fluoride, tetramethylammonium chloride, tetramethylammonium bromide, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride.
29. The process according to claim 1, wherein the molar ratio of phase transfer catalyst to compound INT-6 is from 0.01 to 0.1:1.
30. The process according to claim 1, wherein the temperature of the cyclization reaction in step (7) is 75-90 ℃ and the reaction time is 1.5-3 hours.
31. The preparation method according to claim 1, characterized in that the preparation method comprises the steps of:
(1) Reacting 1,3, 7-heptanetriol and 2, 2-dimethoxypropane in a molar ratio of 1:3-4 at 20-35 ℃ in the presence of p-toluenesulfonic acid for 6-12 hours to obtain a compound INT-1;
(2) In the presence of triphenylphosphine, carrying out bromination reaction on a compound INT-1 and a brominating reagent for 2-6 hours at the temperature of 20-35 ℃ in a molar ratio of 1:1.05-1.2 to obtain a compound INT-2;
(3) In the presence of potassium iodide, carrying out cyanidation reaction on a compound INT-2 and a cyanidation reagent for 12-24 hours at 90-110 ℃ according to the molar ratio of 1:1-1.3 to obtain a compound INT-3;
(4) The compound INT-3 and concentrated sulfuric acid are subjected to ring opening and hydrolysis reaction for 6-12 hours at 90-110 ℃ in water or a water-ethanol mixed solvent system according to the molar ratio of 1:1-3.5, so as to obtain a compound INT-4;
(5) Dissolving a compound INT-4 in a solvent, adding (R) - (+) -N, N-dimethyl-1-phenethylamine, stirring and dissolving, cooling the obtained solution to a temperature of between 30 ℃ below zero and 0 ℃ for crystallization for 1 to 6 hours, filtering, and acidifying a filter cake, wherein the molar ratio of the (R) - (+) -N, N-dimethyl-1-phenethylamine to the compound INT-4 is 0.55 to 0.75:1, so as to obtain a compound INT-5;
(6) In the presence of alkaline substances, the compound INT-5 and p-toluenesulfonyl chloride react for 12-24 hours at the temperature of 20-35 ℃ in a molar ratio of 1:2-2.05 to obtain a compound INT-6;
(7) In a system of a phase transfer catalyst and water, carrying out cyclization reaction on a compound INT-6, sodium sulfide and sulfur at 75-90 ℃ for 1.5-3 hours, wherein the molar ratio of the compound INT-6 to the sodium sulfide is 1:1-2, and the molar ratio of the compound INT-6 to the sulfur is 1:1-2, so as to obtain the R-lipoic acid.
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