CN115093392A - Preparation method of R-lipoic acid - Google Patents
Preparation method of R-lipoic acid Download PDFInfo
- Publication number
- CN115093392A CN115093392A CN202210708205.XA CN202210708205A CN115093392A CN 115093392 A CN115093392 A CN 115093392A CN 202210708205 A CN202210708205 A CN 202210708205A CN 115093392 A CN115093392 A CN 115093392A
- Authority
- CN
- China
- Prior art keywords
- compound int
- reaction
- hours
- molar ratio
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 184
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 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 32
- 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
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 claims abstract description 29
- 101001060278 Xenopus laevis Fibroblast growth factor 3 Proteins 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 28
- 101100348848 Mus musculus Notch4 gene Proteins 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 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
- 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 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005893 bromination reaction Methods 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
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 4
- 230000031709 bromination Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 61
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 42
- 238000001816 cooling Methods 0.000 claims description 37
- 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 32
- 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
- 238000003756 stirring Methods 0.000 claims description 17
- 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
- 230000035484 reaction time 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 compound 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 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
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 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
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 5
- 238000007333 cyanation reaction Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 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
- 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
- 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
- -1 (R) - (+) -N, N-dimethyl-1-phenylethylamine compound Chemical class 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 239000012467 final product Substances 0.000 abstract description 4
- 230000006872 improvement Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 29
- 238000001035 drying Methods 0.000 description 27
- 238000010438 heat treatment Methods 0.000 description 24
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000003960 organic solvent Substances 0.000 description 15
- 238000002390 rotary evaporation Methods 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- 229960002663 thioctic acid Drugs 0.000 description 15
- 238000000605 extraction Methods 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 239000007787 solid Substances 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 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
- 238000007670 refining Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000001704 evaporation Methods 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
- 238000006386 neutralization reaction Methods 0.000 description 4
- 238000011282 treatment Methods 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
- 238000001953 recrystallisation Methods 0.000 description 3
- 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 2
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 2
- UTUNURLNZXJIEN-UHFFFAOYSA-N 2,2-dichlorooctanoic acid Chemical compound CCCCCCC(Cl)(Cl)C(O)=O UTUNURLNZXJIEN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 229940079593 drug Drugs 0.000 description 2
- RFYDWSNYTVVKBR-UHFFFAOYSA-N ethyl 6,8-dichlorooctanoate Chemical compound CCOC(=O)CCCCC(Cl)CCCl RFYDWSNYTVVKBR-UHFFFAOYSA-N 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
- JGHZJRVDZXSNKQ-UHFFFAOYSA-N methyl octanoate Chemical compound CCCCCCCC(=O)OC JGHZJRVDZXSNKQ-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction 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
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003078 antioxidant effect 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
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 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
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 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
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 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
- 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method 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
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009467 reduction Effects 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
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 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
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of R-lipoic acid, which comprises the following steps: reacting 1,3, 7-heptatriol with 2, 2-dimethoxypropane to obtain a compound INT-1, carrying out bromination reaction on the compound INT-1 and a bromination reagent to obtain a compound INT-2, carrying out cyanidation reaction on the compound INT-2 and a cyanidation reagent to obtain a compound INT-3, 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-phenylethylamine as an alkaline resolving agent to obtain a compound INT-5, carrying out reaction on the compound INT-4 and p-toluenesulfonyl chloride to obtain a compound INT-6, and carrying out cyclization reaction on the compound INT-6 and sodium sulfide and sulfur to obtain R-lipoic acid. The method has the advantages of mild process conditions, easily obtained raw materials, high optical purity of the chiral intermediate and the final product, contribution to quality control and improvement of the raw material medicine of the final product and suitability 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 which accelerate aging and cause diseases and is similar to vitamins, has the characteristics of water solubility and fat solubility, can assist coenzyme to carry out physiological metabolism which is beneficial to the immunity of an organism, and is a universal antioxidant medicine. Alpha-lipoic acid has certain effects on the treatment of liver diseases, diabetes, HIV virus, tumors, nervous system degeneration, radiation injury, heavy metal poisoning such as arsenic, mercury, cadmium and the like, and can be used for assisting in treating type II diabetes, improving islet function glucose metabolism, protecting nerve cells, preventing cataract, preventing muscle damage and the like.
As shown in the chemical structural formula, in the molecular structure of alpha-lipoic acid, a chiral carbon is arranged in the position 3 of dithiolane, so that the dithiolane has optical activity and corresponding dextro (R) enantiomer and levo (S) enantiomer are generated. Research shows that the two enantiomers of alpha-lipoic acid show different biological activity and pharmacological properties, wherein the biological activity of the R-form is far higher than that of the S-form, the S-form is basically inactive, but has no toxic or side effect, which is probably because a large amount of the R-form lipoic acid can enter cells and mitochondria through cell membranes and mitochondrial membranes to be reduced into dihydrolipoic acid, and only a small amount of the S-form can enter the cells to be reduced in the metabolic process of the lipoic acid. The dihydrolipoic acid has stronger oxidation resistance than lipoic acid, and the regeneration of endogenous antioxidants and the repair of oxidative damage can be realized only by the form of the dihydrolipoic acid. R-lipoic acid is a natural form of lipoic acid in a human body, is used as a vitamin medicament, has a curative effect superior to that of racemic alpha-lipoic acid, has higher activity than that of racemic alpha-lipoic acid in the aspects of promoting skeletal muscle to take glucose, reducing the levels of plasma insulin and free fatty acid, improving glycogen synthesis and glucose oxidation under the action of insulin, increasing the blood oxygen content of animals and the like in the treatment of type II diabetes, has a wider prospect in the prevention and treatment of diseases such as heart disease, diabetes, liver disease, senile dementia and the like, and is increasingly replaced by the R-lipoic acid, and finally, the racemic alpha-lipoic acid is completely replaced, so that the R-lipoic acid becomes a commonly used medicament and a nutritional supplement.
The synthesis method of R-lipoic acid is many, but there are three main types: the method for industrially producing the R-lipoic acid at present comprises the steps of taking 6, 8-dichloro ethyl caprylate as an initial raw material, carrying out thio-treatment, cyclization and hydrolysis to obtain raceme alpha-lipoic acid, then carrying out multiple resolution by using a resolving agent, and refining to obtain the R-lipoic acid, wherein the yield of the step is not more than 50%. Although the racemization method of S-lipoic acid has been developed, the conversion of S-lipoic acid into racemic lipoic acid is relatively harsh on practical production conditions, corrosive to equipment, and low in yield, resulting in high production cost; secondly, 6, 8-dihydroxy methyl caprylate or 6-hydroxy-8-chloro methyl caprylate is used as a starting material to prepare mesylate, and then R-lipoic acid is formed stereoselectively, so that the method has complex process and is not easy to obtain a pure product; thirdly, racemic ethyl 6, 8-dichlorooctanoate is hydrolyzed into (+/-) dichlorooctanoic acid, and then the (+/-) dichlorooctanoic acid is split, thionated and cyclized by a splitting agent in sequence, the method can save the cost to a certain extent, but the cost is higher because about 50 percent of S- (-) -6, 8-dichlorooctanoic acid is not utilized.
The prior art methods for synthesizing R-lipoic acid, including the above-mentioned three methods, all have the disadvantages of high cost, low yield, large raw material consumption, incapability of meeting the requirements of industrial scale-up production, and high waste discharge, and incapability of meeting the requirements of green and environment-friendly production.
In view of the above-mentioned prior art, there is a need to continue to search for a method for synthesizing R-lipoic acid that can remedy the above-mentioned 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 product purity, yield and optical purity, is efficient, green and environment-friendly, and can meet the requirement of industrial amplification production.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides a preparation method of R-lipoic acid, said preparation method comprising the steps of:
(1) reaction of 1,3, 7-heptatriol with 2, 2-dimethoxypropane gives the compound INT-1, of the formula:
(2) carrying out bromination reaction on the compound INT-1 and a brominating reagent to obtain a compound INT-2, wherein the reaction formula is as follows:
(3) subjecting the compound INT-2 and a cyaniding reagent to cyanidation reaction to obtain a compound INT-3, wherein the reaction formula is as follows:
(4) carrying out ring opening and hydrolysis reaction on the compound INT-3 under the action of concentrated sulfuric acid to obtain a compound INT-4, wherein the reaction formula is as follows:
(5) carrying out chiral resolution on the compound INT-4 by using (R) - (+) -N, N-dimethyl-1-phenylethylamine as a basic resolving agent to obtain a compound INT-5, wherein the reaction formula is as follows:
(6) reacting the compound INT-5 with p-toluenesulfonyl chloride to obtain a compound INT-6, wherein the reaction formula is as follows:
(7) performing cyclization reaction on the compound INT-6, sodium sulfide and sulfur to obtain R-lipoic acid, wherein the reaction formula is as follows:
preferably, the molar ratio of 1,3, 7-heptatriol to 2, 2-dimethoxypropane in step (1) is 1:3-4, such as 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-toluenesulfonic acid.
Preferably, the molar ratio of p-toluenesulfonic acid to 1,3, 7-heptatriol is from 0.1 to 0.2:1, such as 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 to 10 ℃ (e.g., 0 ℃,2 ℃, 4 ℃,5 ℃,7 ℃, 9 ℃ or 10 ℃).
Preferably, the solvent for the reaction in step (1) is any one of dichloromethane, methanol, ethanol, isopropanol or acetone or a combination of at least two of them.
Preferably, the reaction temperature in step (1) is 20 to 35 ℃ (e.g., 20 ℃, 22 ℃, 25 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃) and the reaction time is 6 to 12 hours (e.g., 6 hours, 8 hours, 10 hours or 12 hours).
Preferably, the molar ratio of compound INT-1 to brominating reagent in step (2) is 1:1.05-1.2, e.g. 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 1.05-1.2:1, e.g. 1.05:1, 1.08:1, 1.1:1 or 1.2: 1.
Preferably, the brominating reagent in step (2) is N-bromosuccinimide or liquid bromine.
Preferably, the brominating reagent in step (2) is added to the reaction system at 0 ℃.
Preferably, the solvent for the bromination reaction in the step (2) is any one of dichloromethane, 1, 2-dichloroethane or chloroform or a combination of at least two of them.
Preferably, the temperature of the bromination reaction in step (2) is 20 to 35 ℃ (e.g., 20 ℃, 22 ℃, 25 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃) and the reaction time is 2 to 6 hours (e.g., 2 hours, 3 hours, 4 hours, 5 hours or 6 hours).
Preferably, the cyaniding reagent in the step (3) is cuprous cyanide or zinc cyanide.
Preferably, the molar ratio of compound INT-2 to cyanating reagent in step (3) is 1:1 to 1.3, e.g. 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 0.01-0.011: 1.
Preferably, the solvent for the cyanation reaction in step (3) is N, N-dimethylformamide.
Preferably, the temperature of the cyanation reaction in step (3) is 90 to 110 ℃ (e.g., 90 ℃, 95 ℃, 98 ℃, 100 ℃, 105 ℃, 108 ℃ or 110 ℃) and the reaction time is 12 to 24 hours (e.g., 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours).
Preferably, the compound INT-3 of step (4) is present in a molar ratio to sulfuric acid of 1:1 to 3.5, such as 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 step (4) is water or a mixed solvent of water and ethanol.
Preferably, the temperature of the ring-opening and hydrolysis reaction in step (4) is 90 to 110 ℃ (e.g., 90 ℃, 95 ℃, 98 ℃, 100 ℃, 105 ℃, 108 ℃ or 110 ℃) and the reaction time is 6 to 12 hours (e.g., 6 hours, 8 hours, 10 hours or 12 hours).
In the step (5), the (R) - (+) -N, N-dimethyl-1-phenylethylamine is used as a resolving agent, the resolving agent can be purchased and prepared by oneself, and the resolving agent can be recycled and reused, so that the method is simple and feasible, the process is easy to control, the cost is low, and the method is favorable for large-scale production and popularization.
Preferably, the molar ratio of (R) - (+) -N, N-dimethyl-1-phenylethylamine to compound INT-4 of step (5) is 0.55-0.75:1, such as 0.55:1, 0.6:1, 0.63:1, 0.65:1, 0.68:1, 0.70:1 or 0.75: 1.
Preferably, 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-phenylethylamine is added and stirred 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 resolution in step (5) is any one of methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol or water or a combination of at least two of them.
Preferably, the temperature of the crystallization in step (5) is-30-0 ℃ (for example, -30 ℃, -20 ℃, -10 ℃, -5 ℃ or 0 ℃), and the crystallization time is 1-6 hours (for example, 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 1:2 to 2.05, such as 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 for the reaction of step (6) is toluene.
Preferably, the reaction of step (6) is carried out at a temperature of 20 to 35 ℃ (e.g., 20 ℃, 22 ℃, 25 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃) for a reaction time of 12 to 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 is used for generating OTs group, which has better leaving group property, is more beneficial to the substitution and cyclization reaction of S atom, and has milder reaction condition and less three wastes.
Preferably, the molar ratio of compound INT-6 to sodium sulphide in step (7) is 1:1-2, such as 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2.
Preferably, the molar ratio of compound INT-6 to sulphur in step (7) is 1:1-2, such as 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2.
Preferably, the cyclization reaction of step (7) is carried out in a system of a phase transfer catalyst and water.
Preferably, the phase transfer catalyst is any one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, tetramethylammonium fluoride, tetramethylammonium chloride, tetramethylammonium bromide, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride, or a combination of at least two thereof.
Preferably, the molar ratio of the phase transfer catalyst to compound INT-6 is 0.01-0.1:1, such as 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 to 90 ℃ (e.g., 75 ℃, 78 ℃, 80 ℃, 85 ℃, 88 ℃ or 90 ℃) and the reaction time is 1.5 to 3 hours (e.g., 1.5 hours, 1.8 hours, 2 hours, 2.5 hours, 2.8 hours or 3 hours).
As a preferred technical scheme, the preparation method of the R-lipoic acid specifically comprises the following steps:
(1) in the presence of p-toluenesulfonic acid, 1,3, 7-heptatriol and 2, 2-dimethoxypropane react for 6-12 hours at the temperature of 20-35 ℃ in the molar ratio of 1:3-4 to obtain a compound INT-1;
(2) in the presence of triphenylphosphine, carrying out bromination reaction on a compound INT-1 and a bromination 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, performing cyanidation reaction on a compound INT-2 and a cyanidation reagent at a molar ratio of 1:1-1.3 at 90-110 ℃ for 12-24 hours to obtain a compound INT-3;
(4) performing ring opening and hydrolysis reaction on the compound INT-3 and concentrated sulfuric acid in a molar ratio of 1:1-3.5 in water or a mixed solvent system of water and ethanol at 90-110 ℃ for 6-12 hours to obtain a compound INT-4;
(5) dissolving a compound INT-4 in a solvent, adding (R) - (+) -N, N-dimethyl-1-phenylethylamine, stirring for dissolving, cooling the obtained solution to-30-0 ℃ for crystallization for 1-6 hours, performing suction filtration, and acidifying a filter cake, wherein the molar ratio of the (R) - (+) -N, N-dimethyl-1-phenylethylamine to the compound INT-4 is 0.55-0.75:1, so as to obtain a compound INT-5;
(6) in the presence of alkaline substances, reacting a compound INT-5 and p-toluenesulfonyl chloride at a molar ratio of 1:2-2.05 at 20-35 ℃ for 12-24 hours to obtain a compound INT-6;
(7) in a system of a phase transfer catalyst and water, a compound INT-6, sodium sulfide and sulfur carry out cyclization reaction for 1.5-3 hours at 75-90 ℃, 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 that the R-lipoic acid is obtained.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the R-lipoic acid has mild conditions, the chiral intermediate and the final product have high optical purity (the HPLC content reaches 98.8-99.3 percent, and the ee value is 99.0-99.2 percent), and the preparation method is beneficial to the quality control and improvement of the raw material medicines of the final product; the method has the advantages of easily obtained raw materials of the reagents used in the process route, high yield of 95-96%, reasonable design of the technical route, environmental friendliness, mass production for meeting the use requirement and suitability for industrial production.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
Chiral gas chromatography conditions for determining the ee of the product in the following examples: the chromatographic column is a chiral capillary column CP-Chirasil-DEXCB, nitrogen is used as carrier gas, the injection port temperature is 280 ℃, the detector temperature is 280 ℃, and the reaction product is acetylated and analyzed, wherein the column temperature is 160 ℃.
Example 1
This example provides a method for preparing R-lipoic acid, the method comprising the steps of:
(1) preparation of Compound INT-1:
dissolving 1,3, 7-heptatriol (100g,0.67mol) in dichloromethane (1300mL), adding 2, 2-dimethoxypropane (211g,2.03mol), cooling to 0 ℃ in an ice bath, dropwise adding a dichloromethane (30mL) solution of p-toluenesulfonic acid (12g,0.07mol), keeping the temperature at 20 ℃ for reaction for 12h, dropwise adding a saturated sodium bicarbonate aqueous solution for quenching, extracting by dichloromethane, recrystallizing and purifying by ethyl acetate-n-hexane (v/v 1:1), and drying in vacuum to obtain a compound INT-1(117g), wherein the yield is 92%, and the reaction formula is as follows:
(2) preparation of Compound INT-2:
dissolving a compound INT-1(105g,0.56mol) in dichloromethane (1200mL), adding triphenylphosphine (154g,0.59mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a dichloromethane (200mL) solution of N-bromosuccinimide (104g,0.58mol), reacting the reaction mixture at 20 ℃ for 6 hours, slowly adding water (50mL), concentrating under reduced pressure to remove an organic solvent, cooling to about 0 ℃ and standing for 3 hours, filtering to obtain a crude product, and recrystallizing isopropanol to obtain a compound INT-2(123g), wherein the yield is 88%, and the reaction formula is as follows:
(3) preparation of Compound INT-3:
dissolving a compound INT-2(120g,0.48mol) in N, N-dimethylformamide (1500mL), adding cuprous cyanide (43g,0.48mol) and potassium iodide (0.8g,5mmol), heating to 90 ℃ to react for 24h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a compound INT-3(82g), wherein the yield is 87%, and the reaction formula is as follows:
(4) preparation of Compound INT-4:
dissolving a compound INT-3(80g, 0.41mol) and concentrated sulfuric acid (40g, 0.411mol) in water (1200mL), heating to 90 ℃ for reaction for 12 hours, cooling to room temperature, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing a crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4(65g), wherein the yield is 91%, and the reaction formula is as follows:
(5) compound INT-5 in preparation:
dissolving compound INT-4(85g, 0.48mol) in methanol (1500mL), (R) - (+) -N, N-dimethyl-1-phenylethylamine (40g, 0.27mol) in methanol (500mL), adding to a reaction flask, stirring at room temperature for 1h, cooling to-30 ℃ for crystallization for 2h, suction-filtering, recrystallizing the obtained solid with a mixed solvent of methanol and water (1:1) to obtain compound INT-5(R) - (+) -N, N-dimethyl-1-phenylethylamine salt, dissolving with water (60mL), dropping 2N HCl solution to pH 1-2, extracting with N-butanol, washing the organic phase with brine, drying with anhydrous sodium sulfate, rotary evaporating under reduced pressure to dryness to obtain compound INT-5, white solid (28g), GC content 98.1%, yield 33%, optical rotation value-19.0 °, ee value 99.4%, the reaction formula is as follows:
(6) preparation of Compound INT-6:
dissolving p-toluenesulfonyl chloride (61g,0.32mol) in toluene (300mL), cooling to 0 ℃, dropwise adding a toluene solution (100mL) of a compound INT-5(28g,0.16mol), dropwise adding pyridine (100mL), heating to 20 ℃ for reaction for 35h, 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 neutralization until the pH value is 7, separating out an organic phase, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, performing recrystallization by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-6(70g), wherein the yield is 91%, and the reaction formula is as follows:
(7) preparing a finished product, namely preparing R-lipoic acid:
adding a compound INT-6(70g,0.14mol), sulfur (37g,0.14mol), tetrabutylammonium bromide (5g,16mmol) and water (450mL) into a 2L reaction bottle, stirring, heating to 85 ℃, dropwise adding a sodium sulfide aqueous solution (11 g of sodium sulfide and 120mL of water), stirring at 85 ℃ for 2 hours, cooling to 60 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain R-lipoic acid (27g), wherein the HPLC content is 98.8%, the yield is 91%, the optical rotation value is + 112.0%, and the ee value is 99.2%, and the reaction formula is as follows:
example 2
This example provides a method for preparing R-lipoic acid, which comprises the following steps:
(1) preparation of Compound INT-1:
dissolving 1,3, 7-heptatriol (125g,0.84mol) in methanol (1500mL), adding 2, 2-dimethoxypropane (285g,2.7mol), cooling to 5 ℃ in an ice bath, dropwise adding a methanol (100mL) solution of p-toluenesulfonic acid (18g,0.105mol), heating to 25 ℃ for reaction for 8 hours, dropwise adding a saturated sodium bicarbonate aqueous solution for quenching, extracting by dichloromethane, recrystallizing and purifying to obtain a compound INT-1(148g), wherein the yield is 93%;
(2) preparation of Compound INT-2:
dissolving a compound INT-1(148g,0.79mol) in 1, 2-dichloroethane (2000mL), adding triphenylphosphine (230g,0.88mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a 1, 2-dichloroethane (150mL) solution of liquid bromine (140g,0.88mol), reacting the reaction mixture at 25 ℃ for 4 hours, slowly adding water (40mL), concentrating under reduced pressure to remove an organic solvent, cooling to about 0 ℃ and standing for 3 hours, filtering to obtain a crude product, and recrystallizing in isopropanol to obtain a compound INT-2(178g), wherein the yield is 90%;
(3) preparation of Compound INT-3:
dissolving a compound INT-2(175g,0.7mol) in N, N-dimethylformamide (2000mL), adding zinc cyanide (94g,0.8mol) and potassium iodide (1.2g,7mmol), heating to 100 ℃ to react for 18h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a compound INT-3(122g), wherein the yield is 89%;
(4) preparation of Compound INT-4:
dissolving a compound INT-3(120g,0.61mol) and concentrated sulfuric acid (120g,1.2mol) in a mixed solvent of water and ethanol (250mL:250mL), heating to 100 ℃ for reaction for 9h, cooling to room temperature, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary-steaming to dryness, recrystallizing a crude product with isopropanol, and drying in vacuum to obtain a compound INT-4(100g) with a yield of 93%;
(5) preparation of Compound INT-5:
dissolving compound INT-4(100g,0.57mol) in ethanol (500mL), (R) - (+) -N, N-dimethyl-1-phenylethylamine (55g,0.37mol) in ethanol (250mL), adding to a reaction flask, stirring at room temperature for 1h, cooling to-20 ℃ for crystallization for 1h, suction-filtering, recrystallizing the obtained solid with a mixed solvent of ethanol and water (1:1) to obtain compound INT-5(R) - (+) -N, N-dimethyl-1-phenylethylamine salt, dissolving with water (300mL), adding dropwise 2N HCl solution to pH 1-2, extracting with N-butanol, washing the organic phase with brine, drying with anhydrous sodium sulfate, rotary evaporating to dryness to obtain compound INT-5, white solid (28g), content 98.1%, yield 28%, optical rotation value-19.0 DEG, GC pressure reduction value-19.0 DEG, ee value 99.4%;
(6) preparation of Compound INT-6:
dissolving p-toluenesulfonyl chloride (62g,0.33mol) in toluene (350mL), cooling to 0 ℃, dropwise adding a toluene solution (100mL) of a compound INT-5(28g,0.16mol), dropwise adding triethylamine (100mL), heating to 25 ℃ for reaction for 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 diluted hydrochloric acid for neutralization until the pH value is 7, separating out an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing with an ethyl acetate-n-hexane mixed solvent, and carrying out vacuum drying to obtain a compound INT-6(65g) with the yield of 84%;
(7) preparing a finished product, namely preparing R-lipoic acid:
adding a compound INT-6(65g,0.13mol), sulfur (35g,0.14mol), tetrabutylammonium bromide (5g,16mmol) and water (500mL) into a 2L reaction bottle, stirring, heating to 85 ℃, dropwise adding a sodium sulfide aqueous solution (11 g of sodium sulfide and 50mL of water), stirring at 85 ℃ for 2h after dropwise adding is finished, cooling to 60 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain R-lipoic acid (24g), wherein the HPLC content is 98.8%, the yield is 87%, the optical rotation value is + 112.0%, and the ee value is 99.2%.
Example 3
This example provides a method for preparing R-lipoic acid, which comprises the following steps:
(1) preparation of Compound INT-1:
dissolving 1,3, 7-heptatriol (150g, 1.01mol) in acetone (2500mL), adding 2, 2-dimethoxypropane (365g,3.5mol), cooling to 10 ℃ in an ice bath, dropwise adding an acetone (75mL) solution of p-toluenesulfonic acid (26g, 0.15mol), heating to 35 ℃ for reaction for 6 hours, dropwise adding a saturated sodium bicarbonate aqueous solution for quenching, extracting by dichloromethane, recrystallizing and purifying to obtain a compound INT-1(175g), wherein the yield is 92%;
(2) preparation of Compound INT-2:
dissolving a compound INT-1(175g, 0.93mol) in chloroform (2000mL), adding triphenylphosphine (292g, 1.11mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a chloroform (750mL) solution of N-bromosuccinimide (198g, 1.21mol), reacting the reaction mixture at 35 ℃ for 2h, slowly adding water (100mL), concentrating under reduced pressure to remove an organic solvent, cooling to about 0 ℃ and standing for 3h, filtering to obtain a crude product, and recrystallizing isopropanol to obtain a compound INT-2(210g) with the yield of 90%;
(3) preparation of Compound INT-3:
dissolving a compound INT-2(210g, 0.84mol) in N, N-dimethylformamide (2500mL), adding cuprous cyanide (97g, 1.1mol) and potassium iodide (1.4g, 8mmol), heating to 110 ℃ to react for 12h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a compound INT-3(150g) with a yield of 91%;
(4) preparation of Compound INT-4:
dissolving a compound INT-3(150g, 0.76mol) and concentrated sulfuric acid (260g, 2.65mol) in water (400mL), heating to 110 ℃ for reaction for 6 hours, cooling to room temperature, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing a crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4(125g) with a yield of 93%;
(5) preparation of Compound INT-5:
dissolving compound INT-4(125g, 0.71mol) in isopropanol (400mL), (R) - (+) -N, N-dimethyl-1-phenylethylamine (79g, 0.53mol) in isopropanol (250mL), adding to a reaction flask, stirring at room temperature for 1h, cooling to 0 ℃ for crystallization for 6h, 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-phenylethylamine salt, dissolving with water (200mL), adding dropwise a 2N HCl solution to pH 1-2, extracting with N-butanol, washing the organic phase with brine, drying with anhydrous sodium sulfate, rotary evaporating to dryness to obtain compound INT-5, white solid (45g), GC content 98.1%, yield 36%, optical rotation value-19.0 °, ee value 99.4%;
(6) preparation of Compound INT-6:
dissolving p-toluenesulfonyl chloride (100g, 0.52mol) in toluene (250mL), cooling to 0 ℃, dropwise adding a toluene solution (200mL) of a compound INT-5(45g, 0.26mol), dropwise adding pyridine (150mL), heating to 35 ℃ for reaction for 20h, dropwise adding ice water to quench the reaction solution, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, dropwise adding diluted hydrochloric acid for neutralization until the pH value is 7, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, performing recrystallization by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-6(110g), wherein the yield is 89%;
(7) preparing a finished product, namely preparing R-lipoic acid:
adding compound INT-6(110g, 0.23mol), sulfur (60g, 0.23mol), tetrabutylammonium bromide (8g, 25mmol) and water (2000mL) into a 2L reaction bottle, stirring, heating to 85 ℃, dropwise adding sodium sulfide water solution (18g of sodium sulfide and 120mL of water), stirring at 85 ℃ for 2h after dropwise adding, cooling to 60 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain R-lipoic acid (43g), wherein the HPLC content is 98.8%, the yield is 92%, the optical rotation value is + 112.0% and the ee value is 99.2%.
Example 4
This example provides a method for preparing R-lipoic acid, which comprises the following steps:
(1) preparation of Compound INT-1:
dissolving 1,3, 7-heptatriol (150g, 1.01mol) in ethanol (2800mL), adding 2, 2-dimethoxypropane (325g,3.12mol), cooling to 3 ℃ in ice bath, dropwise adding an ethanol (75mL) solution of p-toluenesulfonic acid (20g, 0.12mol), heating to 22 ℃ for reaction for 9 hours, dropwise adding a saturated sodium bicarbonate aqueous solution for quenching, extracting by dichloromethane, recrystallizing and purifying to obtain a compound INT-1(176g), wherein the yield is 93%;
(2) preparation of Compound INT-2:
dissolving a compound INT-1(175g, 0.93mol) in dichloromethane (2000mL), adding triphenylphosphine (288g, 1.1mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a dichloromethane (750mL) solution of liquid bromine (176g, 1.1mol), reacting the reaction mixture at 28 ℃ for 3h, slowly adding water (100mL), concentrating under reduced pressure to remove an organic solvent, cooling to about 0 ℃ and standing for 3h, filtering to obtain a crude product, and recrystallizing isopropanol to obtain a compound INT-2(210g), wherein the yield is 90%;
(3) preparation of Compound INT-3:
dissolving a compound INT-2(210g, 0.84mol) in N, N-dimethylformamide (2500mL), adding zinc cyanide (132g, 1.12mol) and potassium iodide (1.4g, 8mmol), heating to 95 ℃ to react for 20h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a compound INT-3(152g) with the yield of 92%;
(4) preparation of Compound INT-4:
dissolving a compound INT-3(150g, 0.76mol) and concentrated sulfuric acid (160g, 1.63mol) in water (300mL), heating to 95 ℃ for reaction for 10 hours, cooling to room temperature, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing a crude product with isopropanol, and performing vacuum drying to obtain a compound INT-4(126g) with a yield of 94%;
(5) preparation of Compound INT-5:
dissolving a compound INT-4(125g, 0.71mol) in N-propanol (400mL), (R) - (+) -N, N-dimethyl-1-phenylethylamine (90g, 0.6mol) in N-propanol (250mL), adding into a reaction bottle, stirring at room temperature for 1h, cooling to-25 ℃ for crystallization for 3h, performing suction filtration, recrystallizing the obtained solid with a mixed solvent of isopropanol and water (1:1) to obtain a compound INT-5(R) - (+) -N, N-dimethyl-1-phenylethylamine salt, dissolving with water (150mL), dropwise adding a 2N HCl solution to a pH of 1-2, extracting with N-butanol, washing the organic phase with brine, drying with anhydrous sodium sulfate, performing rotary evaporation under reduced pressure to dryness to obtain a compound INT-5, a white solid (46g), having a GC content of 98.1%, and a yield of 37%, optical rotation value is-19.0 degrees, ee value is 99.5 percent;
(6) preparation of Compound INT-6:
dissolving p-toluenesulfonyl chloride (100g, 0.52mol) in toluene (250mL), cooling to 0 ℃, dropwise adding a toluene solution (200mL) of a compound INT-5(45g, 0.26mol), dropwise adding pyridine (150mL), heating to 35 ℃ for reaction for 20h, dropwise adding ice water to quench the reaction solution, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, dropwise adding diluted hydrochloric acid for neutralization until the pH value is 7, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, performing recrystallization by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-6(110g), wherein the yield is 89%;
(7) preparing a finished product, namely preparing R-lipoic acid:
adding a compound INT-6(110g, 0.23mol), sulfur (65g, 0.25mol), tetrabutylammonium bromide (9g, 28mmol) and water (2200mL) into a 2L reaction bottle, stirring, heating to 85 ℃, dropwise adding a sodium sulfide aqueous solution (18g of sodium sulfide and 120mL of water), stirring at 85 ℃ for 2 hours after dropwise adding, cooling to 60 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain R-lipoic acid (44g), wherein the HPLC content is 99.1%, the yield is 93%, the optical rotation value is + 112.0% and the ee value is 99.3%.
Example 5
This example provides a method for preparing R-lipoic acid, which comprises the following steps:
(1) preparation of Compound INT-1:
dissolving 1,3, 7-heptatriol (150g, 1.01mol) in isopropanol (2500mL), adding 2, 2-dimethoxypropane (352g,3.4mol), cooling to 10 ℃ in ice bath, dropwise adding an isopropanol (75mL) solution of p-toluenesulfonic acid (24g, 0.14mol), heating to 30 ℃ for reaction for 7 hours, dropwise adding a saturated sodium bicarbonate aqueous solution for quenching, extracting by dichloromethane, recrystallizing and purifying to obtain a compound INT-1(177g) with the yield of 93%;
(2) preparation of Compound INT-2:
dissolving a compound INT-1(175g, 0.93mol) in chloroform (2000mL), adding triphenylphosphine (302g, 1.15mol), cooling to below 0 ℃ in an ice bath, slowly dropwise adding a chloroform (750mL) solution of N-bromosuccinimide (205g, 1.15mol), reacting the reaction mixture at 30 ℃ for 5 hours, slowly adding water (100mL), concentrating under reduced pressure to remove an organic solvent, cooling to about 0 ℃, standing for 3 hours, filtering to obtain a crude product, and recrystallizing isopropanol to obtain a compound INT-2(211g) with the yield of 90%;
(3) preparation of Compound INT-3:
dissolving a compound INT-2(210g, 0.84mol) in N, N-dimethylformamide (2500mL), adding cuprous cyanide (110g, 1.23mol) and potassium iodide (1.4g, 8mmol), heating to 108 ℃ to react for 11h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane to extract, washing with common salt water, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a compound INT-3(151g) with a yield of 91%;
(4) preparation of Compound INT-4:
dissolving a compound INT-3(150g, 0.76mol) and concentrated sulfuric acid (285g, 2.85mol) in water (400mL), heating to 105 ℃ for reaction for 7 hours, cooling to room temperature, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product with isopropanol, and carrying out vacuum drying to obtain a compound INT-4(127g) with a yield of 94%;
(5) preparation of Compound INT-5:
dissolving a compound INT-4(125g, 0.71mol) in tert-butanol (400mL), (R) - (+) -N, N-dimethyl-1-phenylethylamine (105g, 0.7mol) in tert-butanol (220mL), adding to a reaction flask, 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 a compound INT-5(R) - (+) -N, N-dimethyl-1-phenylethylamine salt, dissolving with water (180mL), dropwise adding a 2N HCl solution to a pH of 1-2, extracting with N-butanol, washing the organic phase with brine, drying with anhydrous sodium sulfate, rotary evaporating under reduced pressure to dryness to obtain a compound INT-5, a white solid (47g), having a GC content of 98.3%, and a yield of 38%, the optical rotation value is-19.0 degrees, and the ee value is 99.4 percent;
(6) preparation of Compound INT-6:
dissolving p-toluenesulfonyl chloride (100g, 0.52mol) in toluene (250mL), cooling to 0 ℃, dropwise adding a toluene solution (200mL) of a compound INT-5(45g, 0.26mol), dropwise adding triethylamine (150mL), heating to 30 ℃ for reacting for 18h, dropwise adding ice water to quench a reaction solution, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, dropwise adding dilute hydrochloric acid to neutralize to pH 7, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing with an ethyl acetate-n-hexane mixed solvent, and carrying out vacuum drying to obtain a compound INT-6(112g) with the yield of 90%;
(7) preparing a finished product, namely preparing R-lipoic acid:
adding a compound INT-6(110g, 0.23mol), sulfur (60g, 0.23mol), tetrabutylammonium bromide (8g, 25mmol) and water (2000mL) into a 2L reaction bottle, stirring, heating to 85 ℃, dropwise adding a sodium sulfide aqueous solution (20g of sodium sulfide and 120mL of water), stirring at 85 ℃ for 2 hours after dropwise adding, cooling to 60 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain R-lipoic acid (44g), wherein the HPLC content is 98.9%, the yield is 90%, the optical rotation value is + 112.0% and the ee value is 99.1%.
The applicant states that the present invention is illustrated by the above examples to the preparation method of R-lipoic acid of the present invention, but the present invention is not limited to the above examples, i.e., it does not mean that the present invention must be implemented by relying on the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of R-lipoic acid is characterized by that said preparation method includes the following steps:
(1) reacting 1,3, 7-heptatriol with 2, 2-dimethoxypropane to obtain a compound INT-1, according to the following reaction formula:
(2) carrying out bromination reaction on the compound INT-1 and a brominating reagent to obtain a compound INT-2, wherein the reaction formula is as follows:
(3) subjecting the compound INT-2 and a cyaniding reagent to cyanidation reaction to obtain a compound INT-3, wherein the reaction formula is as follows:
(4) carrying out ring opening and hydrolysis reaction on the compound INT-3 under the action of concentrated sulfuric acid to obtain a compound INT-4, wherein the reaction formula is as follows:
(5) carrying out chiral resolution on the compound INT-4 by using (R) - (+) -N, N-dimethyl-1-phenylethylamine as a basic resolving agent to obtain a compound INT-5, wherein the reaction formula is as follows:
(6) reacting the compound INT-5 with p-toluenesulfonyl chloride to obtain a compound INT-6, wherein the reaction formula is as follows:
(7) performing cyclization reaction on the compound INT-6, sodium sulfide and sulfur to obtain R-lipoic acid, wherein the reaction formula is as follows:
2. the method according to claim 1, wherein the molar ratio of 1,3, 7-heptatriol to 2, 2-dimethoxypropane in the step (1) is 1: 3-4;
preferably, the reaction of step (1) is carried out in the presence of p-toluenesulfonic acid;
preferably, the molar ratio of the p-toluenesulfonic acid to the 1,3, 7-heptatriol is 0.1-0.2: 1;
preferably, the p-toluenesulfonic acid is added into the reaction system at 0-10 ℃;
preferably, 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;
preferably, the reaction temperature of the step (1) is 20-35 ℃, and the reaction time is 6-12 hours.
3. The preparation method according to claim 1 or 2, wherein the molar ratio of the compound INT-1 to the brominating agent in step (2) is 1: 1.05-1.2;
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 1.05-1.2: 1;
preferably, the brominating reagent in the step (2) is N-bromosuccinimide or liquid bromine;
preferably, the brominating reagent in the step (2) is added into the reaction system at 0 ℃;
preferably, the solvent for the bromination reaction in the step (2) is any one of dichloromethane, 1, 2-dichloroethane or chloroform or a combination of at least two of the two;
preferably, the temperature of the bromination reaction in the step (2) is 20-35 ℃ and the reaction time is 2-6 hours.
4. The process according to any one of claims 1 to 3, wherein the cyanating reagent in step (3) is cuprous cyanide or zinc cyanide;
preferably, the molar ratio of the compound INT-2 to the cyanating reagent in step (3) is 1: 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 0.01-0.011: 1;
preferably, the solvent for the cyanation reaction in step (3) is N, N-dimethylformamide;
preferably, the temperature of the cyanidation reaction in the step (3) is 90-110 ℃ and the reaction time is 12-24 hours.
5. The method according to any one of claims 1 to 4, wherein the molar ratio of compound INT-3 to sulfuric acid in step (4) is 1:1 to 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 in the step (4) is 90-110 ℃, and the reaction time is 6-12 hours.
6. The process according to any one of claims 1 to 5, wherein the molar ratio of (R) - (+) -N, N-dimethyl-1-phenylethylamine compound INT-4 of step (5) is 0.55-0.75: 1;
preferably, 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-phenylethylamine is added and stirred 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 for chiral resolution 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 chiral resolution in the step (5) is-30 to 0 ℃, and the crystallization time is 1 to 6 hours.
7. The preparation method according to any one of claims 1 to 6, wherein the molar ratio of compound INT-5 to p-toluenesulfonyl chloride in step (6) is 1:2 to 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 for the reaction of step (6) is toluene;
preferably, the reaction temperature of the step (6) is 20-35 ℃, and the reaction time is 12-24 hours.
8. The preparation method according to any one of claims 1 to 7, wherein the molar ratio of the compound INT-6 to sodium sulfide in step (7) is 1: 1-2;
preferably, the molar ratio of the compound INT-6 to sulfur in the step (7) is 1: 1-2.
9. The production method according to any one of claims 1 to 8, wherein the cyclization reaction of step (7) is carried out in a system of a phase transfer catalyst and water;
preferably, 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 hydrogen sulfate, tetramethylammonium fluoride, tetramethylammonium chloride, tetramethylammonium bromide, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride;
preferably, the molar ratio of the phase transfer catalyst to the compound INT-6 is 0.01-0.1: 1;
preferably, the temperature of the cyclization reaction in the step (7) is 75-90 ℃, and the reaction time is 1.5-3 hours.
10. The method for preparing according to any one of claims 1 to 9, comprising the steps of:
(1) in the presence of p-toluenesulfonic acid, 1,3, 7-heptatriol and 2, 2-dimethoxypropane react for 6-12 hours at the temperature of 20-35 ℃ in the molar ratio of 1:3-4 to obtain a compound INT-1;
(2) in the presence of triphenylphosphine, carrying out bromination reaction on a compound INT-1 and a bromination 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, performing cyanidation reaction on a compound INT-2 and a cyanidation reagent at a molar ratio of 1:1-1.3 at 90-110 ℃ for 12-24 hours to obtain a compound INT-3;
(4) performing ring opening and hydrolysis reaction on the compound INT-3 and concentrated sulfuric acid in a molar ratio of 1:1-3.5 in water or a mixed solvent system of water and ethanol at 90-110 ℃ for 6-12 hours to obtain a compound INT-4;
(5) dissolving a compound INT-4 in a solvent, adding (R) - (+) -N, N-dimethyl-1-phenylethylamine, stirring for dissolving, cooling the obtained solution to-30-0 ℃ for crystallization for 1-6 hours, performing suction filtration, and acidifying a filter cake, wherein the molar ratio of the (R) - (+) -N, N-dimethyl-1-phenylethylamine to the compound INT-4 is 0.55-0.75:1, so as to obtain a compound INT-5;
(6) in the presence of alkaline substances, reacting a compound INT-5 and p-toluenesulfonyl chloride at a molar ratio of 1:2-2.05 at 20-35 ℃ for 12-24 hours to obtain a compound INT-6;
(7) in a system of a phase transfer catalyst and water, a compound INT-6, sodium sulfide and sulfur carry out cyclization reaction for 1.5-3 hours at 75-90 ℃, 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 that the R-lipoic acid is obtained.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210708205.XA CN115093392B (en) | 2022-06-21 | 2022-06-21 | Preparation method of R-lipoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210708205.XA CN115093392B (en) | 2022-06-21 | 2022-06-21 | Preparation method of R-lipoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115093392A true CN115093392A (en) | 2022-09-23 |
| CN115093392B CN115093392B (en) | 2024-04-30 |
Family
ID=83293677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210708205.XA Active CN115093392B (en) | 2022-06-21 | 2022-06-21 | Preparation method of R-lipoic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115093392B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195568A (en) * | 2006-12-06 | 2008-06-11 | 上海医药工业研究院 | (S) or (R)-6-hydroxyl-8-alkoxide octylic acid, its ester, salt, amide, preparation method and application thereof |
| JP2009165440A (en) * | 2008-01-18 | 2009-07-30 | Tadakatsu Bandai | METHOD FOR PRODUCING (S)-3-ACYLOXY-1-ALKENE OR (R)-3-HYDROXY-1-ALKENE, AND METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-LIPOIC ACID |
| CN101654445A (en) * | 2008-08-22 | 2010-02-24 | 四川大学 | Compound for preparing ramelteon, preparation method thereof and application thereof |
| CN102827174A (en) * | 2012-09-03 | 2012-12-19 | 连云港贵科药业有限公司 | Preparation method for aldose reductase inhibitor fidarestat |
| CN108101876A (en) * | 2017-12-25 | 2018-06-01 | 中山市榄商置业发展有限公司 | A kind of synthetic method of Simvastatin intermediate |
-
2022
- 2022-06-21 CN CN202210708205.XA patent/CN115093392B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195568A (en) * | 2006-12-06 | 2008-06-11 | 上海医药工业研究院 | (S) or (R)-6-hydroxyl-8-alkoxide octylic acid, its ester, salt, amide, preparation method and application thereof |
| JP2009165440A (en) * | 2008-01-18 | 2009-07-30 | Tadakatsu Bandai | METHOD FOR PRODUCING (S)-3-ACYLOXY-1-ALKENE OR (R)-3-HYDROXY-1-ALKENE, AND METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-LIPOIC ACID |
| CN101654445A (en) * | 2008-08-22 | 2010-02-24 | 四川大学 | Compound for preparing ramelteon, preparation method thereof and application thereof |
| CN102827174A (en) * | 2012-09-03 | 2012-12-19 | 连云港贵科药业有限公司 | Preparation method for aldose reductase inhibitor fidarestat |
| CN108101876A (en) * | 2017-12-25 | 2018-06-01 | 中山市榄商置业发展有限公司 | A kind of synthetic method of Simvastatin intermediate |
Non-Patent Citations (1)
| Title |
|---|
| EJNANTIOSELHECTIVE TOTAL ISYNTHELSIS OF (+L)- ANDU (–)-VITATALA CTONESINGH YADAV 等: "Enantioselective Total Synthesis of (+)- and (–)-Vittatalactone", SYNTHESIS, vol. 44, pages 628 - 634 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115093392B (en) | 2024-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103058989B (en) | Method for preparing alpha-lipoic acid | |
| US20160318859A1 (en) | Florfenicol synthesizing method | |
| CN113185494B (en) | Preparation method of R-lipoic acid | |
| CN101717359B (en) | Method for synthesizing indapamide | |
| CN106632033A (en) | Preparation method of lenvatinib | |
| CN115093392A (en) | Preparation method of R-lipoic acid | |
| CN108586310A (en) | The catalysis oxidation synthetic method of 3- sulfydryl indole class compounds | |
| CN108003134A (en) | A kind of R-（+）The preparation method of-lipoic acid | |
| EP0030528B1 (en) | Process for the introduction of alkyl, aralkyl or cycloalkyl groups onto a functional group-substituted carbon chain | |
| CN1563014A (en) | New compound ramification of garcinia acid | |
| CN101037435A (en) | (S)-nifuratel, preparation method and application thereof | |
| CN1923781A (en) | Method of synthesizing compound containing difluoromethyl group | |
| WO2019100786A1 (en) | Method for synthesizing 3-ethoxy-4-methoxybenzaldehyde | |
| US10414744B2 (en) | 4-sulfur pentafluoride phenol compound and preparation method therefor, and preparation method for sulfur pentafluoride substituted benzopyran compound | |
| CN111635358B (en) | Preparation method of hydroxychloroquine | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| WO2020238779A1 (en) | Method for synthesizing florfenicol | |
| US20210070781A1 (en) | A process for the preparation of crisaborole | |
| CN106748884B (en) | Preparation method of bicalutamide intermediate | |
| CN108586429A (en) | The purifying process for purification of r-lipoic acid cholinester halide | |
| CN110305083B (en) | Process for preparing 5-chloromethyl furfural from fructose | |
| CN114539168B (en) | Method for synthesizing Piraglatin and analogues thereof | |
| CN113717150A (en) | Preparation method of lipoic acid impurity A | |
| CN112062785B (en) | Preparation method of ozagrel and intermediate thereof | |
| CN107056661A (en) | A kind of preparation method of lapatinib intermediate 2 (methylsulfonyl) ethylamine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |