CN118146082A - Preparation method of 8-hydroxy-6-oxo-octanoic acid - Google Patents
Preparation method of 8-hydroxy-6-oxo-octanoic acid Download PDFInfo
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- CN118146082A CN118146082A CN202211567007.2A CN202211567007A CN118146082A CN 118146082 A CN118146082 A CN 118146082A CN 202211567007 A CN202211567007 A CN 202211567007A CN 118146082 A CN118146082 A CN 118146082A
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- trimethylsilyl
- acid
- oxo
- ethoxy
- ethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- RVYNWKZJNVDBDG-UHFFFAOYSA-N 8-hydroxy-6-oxooctanoic acid Chemical compound OCCC(=O)CCCCC(O)=O RVYNWKZJNVDBDG-UHFFFAOYSA-N 0.000 title claims abstract description 37
- -1 {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane Chemical compound 0.000 claims abstract description 45
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims abstract description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 27
- ZPVFXRKEMJWSBG-UHFFFAOYSA-N 6-oxo-6-(2-trimethylsilylethoxy)hexanoic acid Chemical compound C[Si](C)(C)CCOC(=O)CCCCC(O)=O ZPVFXRKEMJWSBG-UHFFFAOYSA-N 0.000 claims abstract description 26
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000011037 adipic acid Nutrition 0.000 claims abstract description 14
- 239000001361 adipic acid Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 12
- MPXYHFPQDPRCNM-UHFFFAOYSA-N tris(ethylsulfanyl)phosphane Chemical compound CCSP(SCC)SCC MPXYHFPQDPRCNM-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZNGINKJHQQQORD-UHFFFAOYSA-N 2-trimethylsilylethanol Chemical compound C[Si](C)(C)CCO ZNGINKJHQQQORD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 16
- 239000011230 binding agent Substances 0.000 claims description 16
- 238000005886 esterification reaction Methods 0.000 claims description 16
- 229910052725 zinc Inorganic materials 0.000 claims description 16
- 239000011701 zinc Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000008096 xylene Substances 0.000 claims description 12
- 238000006076 Fukuyama coupling reaction Methods 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 150000003458 sulfonic acid derivatives Chemical class 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 5
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- YHGKEORTCHVBQH-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonic acid Chemical compound CC(C)C1=CC(C(C)C)=C(S(O)(=O)=O)C(C(C)C)=C1 YHGKEORTCHVBQH-UHFFFAOYSA-N 0.000 claims description 3
- KWXICGTUELOLSQ-UHFFFAOYSA-N 4-dodecylbenzenesulfonic acid Chemical compound CCCCCCCCCCCCC1=CC=C(S(O)(=O)=O)C=C1 KWXICGTUELOLSQ-UHFFFAOYSA-N 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- ONMOULMPIIOVTQ-UHFFFAOYSA-N 98-47-5 Chemical compound OS(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1 ONMOULMPIIOVTQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- DOWCWUCBOQRQJE-UHFFFAOYSA-N ditert-butylphosphane;hydrochloride Chemical compound Cl.CC(C)(C)PC(C)(C)C DOWCWUCBOQRQJE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000003752 zinc compounds Chemical class 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 238000004128 high performance liquid chromatography Methods 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 239000003960 organic solvent Substances 0.000 description 25
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 24
- 238000000605 extraction Methods 0.000 description 19
- 235000019136 lipoic acid Nutrition 0.000 description 19
- 238000001035 drying Methods 0.000 description 17
- 229960002663 thioctic acid Drugs 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 238000005406 washing Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 9
- 230000006837 decompression Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 208000029549 Muscle injury Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 230000003064 anti-oxidating 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 208000019423 liver disease Diseases 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
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 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
- 229960002446 octanoic acid Drugs 0.000 description 1
- 150000002886 octanoic acid esters Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 238000003634 thiocyclization reaction Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Abstract
The invention provides a preparation method of 8-hydroxy-6-oxo-octanoic acid, which comprises the following steps: adipic acid is reacted with 2-trimethylsilylethanol to give 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid, which is reacted with triethyltrithiophosphite to give ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate, 2-iodoethanol is reacted with 2- (trimethylsilyl) ethoxymethyl chloride to give {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, zinc compounds of which are reacted with ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate to give ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate, and deprotection to give 8-hydroxy-6-oxo octanoic acid. The preparation method provided by the invention has the advantages of mild process conditions, low cost and high safety, and can meet the requirements of industrial scale-up production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of 8-hydroxy-6-oxo-octanoic acid.
Background
Alpha-lipoic acid can eliminate free radical for accelerating aging and pathopoiesia, is a vitamin-like compound, has water solubility and fat solubility, can assist coenzyme to perform physiological metabolism which is beneficial to immunity of organisms, and is a medicament with universal antioxidation. The alpha-lipoic acid has certain effects on the treatment of liver diseases, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, heavy metals (such as arsenic, mercury, cadmium and the like) 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.
The literature and patents disclose a large number of synthetic routes for alpha-lipoic acid, and the synthesis of lipoic acid is mainly divided into two stages: firstly, constructing an 8 carbon chain to synthesize octanoic acid or octanoic acid ester with hydroxyl or sulfhydryl, halogen or other groups on 6, 8-carbon, and secondly, preparing the alpha-lipoic acid by one-step or multi-step thio cyclization reaction of the 6, 8-disubstituted octanoic acid or the 6, 8-disubstituted octanoic acid ester.
In the existing alpha-lipoic acid synthesis method, most of the existing alpha-lipoic acid synthesis methods have the defects of long steps, large waste acid emission, high cost and the like, so that people continuously seek to improve the technology and improve the production capacity to obtain key lipoic acid intermediates with better preparation quality and lower cost, and lay a foundation for the industrialized preparation of lipoic acid bulk drugs.
The 8-hydroxy-6-oxo-octanoic acid or 8-hydroxy-6-oxo-octanoic acid ester can be used as a key intermediate to prepare alpha-lipoic acid or R-lipoic acid through a plurality of different routes, for example, the 8-hydroxy of the 8-hydroxy-6-oxo-octanoic acid or 8-hydroxy-6-oxo-octanoic acid ester can be subjected to chlorination, bromination, sulfonylation, thio and the like, and the oxygen at the 6-position of the 8-hydroxy-6-oxo-octanoic acid or 8-hydroxy-6-oxo-octanoic acid ester can be reduced by NaBH 4 to obtain the 6-hydroxy of a corresponding substrate, then converted into other substituents, and the chiral intermediate can be constructed by chiral reduction such as a biological enzyme reduction method, so that the R-lipoic acid is prepared finally.
Accordingly, it is desirable in the art to develop an efficient, low cost process for preparing 8-hydroxy-6-oxooctanoic acid, an intermediate of α -lipoic acid or R-lipoic acid.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 8-hydroxy-6-oxo-octanoic acid. The preparation method disclosed by the invention has the advantages of mild process conditions, low preparation cost and high safety, is favorable for controlling the product quality of the intermediate 8-hydroxy-6-oxo-octanoic acid, and can meet the requirements of industrial large-scale production.
To achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides a method for preparing 8-hydroxy-6-oxooctanoic acid. The preparation method comprises the following steps:
(1) Esterification reaction is carried out on adipic acid and 2-trimethylsilyl ethanol to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid, and the reaction formula is as follows:
(2) Esterification reaction is carried out on 6-oxo-6- [2- (trimethylsilyl) ethoxy ] caproic acid and triethyl trithiophosphite to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate, wherein the reaction formula is as follows:
(3) 2-iodoethanol reacts with 2- (trimethylsilyl) ethoxymethyl chloride to obtain {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, and the reaction formula is as follows:
(4) The organic zinc compound shown in the formula A and 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate are subjected to Fukuyama coupling reaction to obtain 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester, wherein the reaction formula is as follows:
(5) Deprotection of 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoic acid (2-trimethylsilyl) ethyl ester in the presence of tetrabutylammonium fluoride gives 8-hydroxy-6-oxooctanoic acid of the formula:
In the present invention, the molar ratio of adipic acid to 2-trisilylethanol in step (1) is 1:1.2-1.7, for example 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6 or 1:1.7.
In the present invention, the esterification reaction of step (1) is carried out in the presence of a sulfonic acid derivative.
Preferably, the sulfonic acid derivative is selected from any one or a combination of at least two of p-toluenesulfonic acid, methanesulfonic acid, p-dodecylbenzenesulfonic acid, benzenesulfonic acid, 2,4, 6-triisopropylbenzenesulfonic acid or m-nitrobenzenesulfonic acid.
In the present invention, the molar ratio of the sulfonic acid derivative to adipic acid is from 0.005 to 0.05:1, for example 0.005:1, 0.007:1, 0.01:1, 0.025:1 or 0.05:1.
In the present invention, the esterification reaction of step (1) is carried out in a solvent which is toluene and/or xylene;
In the present invention, the temperature of the esterification reaction in the step (1) is 90 to 110 ℃ (e.g., 90 ℃, 100 ℃, 105 ℃ or 110 ℃), and the reaction time is 2 to 6 hours (e.g., 2 hours, 4 hours, 5 hours or 6 hours).
In the present invention, the molar ratio of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid to triethyl trithiophosphite of step (2) is 1:1-1.3, such as 1:1, 1:1.1, 1:1.2 or 1:1.3.
In the present invention, the reaction of step (2) is carried out in the presence of an acid-binding agent.
Preferably, the acid-binding agent is selected from any one or a combination of at least two of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, trimethylamine, triisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-lutidine, 4-dimethylaminopyridine or N-methylpyrrolidone.
In the present invention, the molar ratio of the acid-binding agent to 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid is 2-3:1, e.g., 2:1, 2.2:1, 2.5:1, 2.8:1, or 3:1.
In the present invention, the esterification reaction of step (2) is carried out in a solvent which is any one or a combination of at least two of toluene, xylene or N, N-dimethylformamide.
In the present invention, the temperature of the esterification reaction of step (2) is 100-120 ℃, e.g., 100 ℃, 105 ℃, 110 ℃, 115 ℃, or 120 ℃; the reaction time is 12-24 hours, for example 12 hours, 16 hours, 18 hours, 20 hours or 24 hours.
In the present invention, the molar ratio of 2-iodoethanol to 2- (trimethylsilyl) ethoxymethyl chloride in step (3) is 1:1-1.5, e.g., 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.
In the present invention, the reaction of step (3) is carried out in the presence of an acid-binding agent;
preferably, the acid-binding agent is selected from any one or a combination of at least two of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, trimethylamine, triisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine or 1, 8-diazabicyclo [5.4.0] undec-7-ene.
In the present invention, the molar ratio of the acid-binding agent to 2-iodoethanol is 1.3-2:1, such as 1.3:1, 1.5:1, 1.6:1, 1.8:1, or 2:1.
In the present invention, the reaction of step (3) is carried out in a solvent which is any one or a combination of at least two of an ether-based solvent, an amide-based solvent, a nitrile-based solvent, or a sulfone-based solvent.
In the present invention, the temperature of the reaction in step (3) is 20 to 50 ℃, for example 20 ℃,25 ℃,30 ℃, 40 ℃, 45 ℃ or 50 ℃; the reaction time is 6 to 12 hours, for example 6 hours, 8 hours, 10 hours or 12 hours.
In the present invention, the molar ratio of the ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate of step (4) to the organozinc compound of formula A is 1:1.5-3.1, e.g., 1:1.5, 1:1.8, 1:2, 1:2.5, or 1:3.
In the present invention, the Fukuyama coupling reaction of step (4) is performed in the presence of a palladium catalyst;
preferably, the palladium catalyst is any one or a combination of two of bis (triphenylphosphine) palladium dichloride or bis (di-tert-butylphosphine chloride) palladium dichloride.
In the present invention, the molar ratio of palladium catalyst to ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate is 0.05-0.1:1, e.g., 0.05:1, 0.07:1, 0.08:1, or 0.1:1.
In the present invention, the Fukuyama coupling reaction of step (4) is performed in a solvent which is any one or a combination of at least two of toluene, xylene, N-Dimethylformamide (DMF) or Tetrahydrofuran (THF).
According to the invention, the framework of the lipoic acid main chain is constructed by utilizing Fukuyama coupling reaction, so that the chlorination reaction step involving a large amount of waste acid emission is effectively avoided, the used organic zinc reagent is low in toxicity, safe and effective, no toxic or side reaction occurs, and the quality of the intermediate 8-hydroxy-6-oxo-octanoic acid product is controlled.
In the present invention, the temperature of the Fukuyama coupling reaction is 20-35 ℃, e.g., 20 ℃, 25 ℃, 30 ℃, 32 ℃, or 35 ℃; the reaction time is 1 to 6 hours, for example 1 hour, 3 hours, 4 hours or 6 hours.
In the present invention, the organozinc compound represented by formula A in step (4) is obtained by reacting {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane with zinc.
In the present invention, the molar ratio of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane to zinc is 1:1.5-3, such as 1:1.5, 1:1.7, 1:1.9, 1:2.0, 1:2.3, 1:2.5, 1:2.8, or 1:3.
In the invention, the solvent for the reaction of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane and zinc is any one or a combination of at least two of tetrahydrofuran, methyl tertiary butyl ether or DMF.
In the present invention, the {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane is reacted with zinc at a temperature of 45-90 ℃ (e.g., 45 ℃, 48 ℃, 50 ℃, 55 ℃, 60 ℃, 70 ℃, 80 ℃, or 90 ℃) for a time of 6-12 hours (e.g., 6 hours, 8 hours, 10 hours, 11 hours, or 12 hours).
In the present invention, the molar ratio of 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoic acid (2-trimethylsilyl) ethyl ester to tetrabutylammonium fluoride described in step (5) is 1:2-4.5, e.g., 1:2, 1:2.5, 1:3, 1:3.5, 1:4, or 1:4.5.
In the present invention, the deprotection reaction of step (5) is carried out in a solvent which is any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether or 1, 4-dioxane.
In the present invention, the temperature of the deprotection reaction of step (5) is 50 to 100 ℃, for example, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃; the reaction time is 2 to 6 hours, for example 2 hours, 4 hours, 5 hours or 6 hours.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) In the presence of sulfonic acid derivative, adipic acid and 2-trimethylsilyl ethanol are subjected to esterification reaction for 2-6 hours at 90-110 ℃ in a molar ratio of 1:1.2-1.6 to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid;
(2) In the presence of an acid binding agent, 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid and triethyl trithiophosphite are reacted for 12-24 hours at the temperature of 100-120 ℃ in a molar ratio of 1:1-1.3 to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate;
(3) Reacting 2-iodoethanol and 2- (trimethylsilyl) ethoxymethyl chloride for 6-12 hours at 20-50 ℃ in the presence of an acid binding agent according to the molar ratio of 1:1-1.5 to obtain {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane;
(4) In the presence of a palladium catalyst, the {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane and zinc generate an organozinc compound, and 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate and the organozinc compound are subjected to Fukuyama coupling reaction for 1-6 hours at 20-35 ℃ in a molar ratio of 1:1.5-3.1 to obtain 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester;
(5) Deprotection of 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoic acid (2-trimethylsilyl) ethyl ester in the presence of tetrabutylammonium fluoride at 50-100℃for 2-6 hours afforded 8-hydroxy-6-oxooctanoic acid.
Compared with the prior art, the invention has the following beneficial effects:
The preparation method disclosed by the invention has the advantages of mild process conditions, low preparation cost, high safety and no toxic or side reaction, is favorable for controlling the product quality of 8-hydroxy-6-oxo-octanoic acid, is suitable for preparing racemic lipoic acid or chiral lipoic acid quickly and in a large scale, and is favorable for industrial production and popularization of lipoic acid bulk drugs.
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.
Example 1
In this embodiment, a preparation method of 8-hydroxy-6-oxo-octanoic acid is provided, which specifically includes the following steps:
(1) Preparation of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid:
Adipic acid (50 g,0.34 mol), 2-trimethylsilylethanol (49 g,0.41 mol), p-toluenesulfonic acid (0.3 g,1.7 mmol) were dissolved in toluene (600 mL), heated to 110 ℃ and reacted for 2h, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with common salt, dried over anhydrous sodium sulfate, distilled to dryness under reduced pressure to give 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (45 g), yield 53% HPLC purity 95.6％;1H NMR(400MHz,CDCl3)δppm 4.18-4.11(m,2H),2.41-2.26(m,4H),1.66(q,4H),1.00-0.93(m,2H),0.03(s,9H).
(2) Preparation of ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate:
6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (45 g,0.18 mol), triethylamine (37 g,0.37 mol) are dissolved in toluene (1200 mL), triethyl trithiophosphite (40 g,0.19 mol) is added dropwise, the temperature is slowly increased to 100 ℃ for reaction for 24 hours, the organic solvent is removed by decompression concentration, dichloromethane extraction, common salt water washing, anhydrous sodium sulfate drying and decompression rotary evaporation to dryness are carried out, 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate (44 g) is obtained, the yield is 83 percent, and the HPLC purity is high performance liquid chromatography 96.4％;1H NMR(400MHz,CDCl3)δppm 4.18-4.10(m,2H),2.87(q,2H),2.48-2.35(m,4H),1.65(q,4H),1.22(t,3H),1.00-0.94(m,2H),0.01(s,9H).
(3) Preparation of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane:
2-iodoethanol (42 g,0.24 mol), triethylamine (32 g,0.32 mol) are dissolved in methyl tertiary butyl ether (500 mL), ice bath cooling is carried out, 2- (trimethylsilyl) ethoxymethyl chloride (41 g,0.25 mol) is added dropwise, the temperature is raised to 20 ℃ for reaction for 12h, the organic solvent is removed by decompression concentration, dichloromethane extraction, common salt water washing, anhydrous sodium sulfate drying and decompression rotary evaporation to dryness are carried out, and {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane (70 g) is obtained, the yield is 95 percent, and the HPLC purity is 97.2 percent; 1H NMR(400MHz,CDCl3 ) Delta ppm 5.32 (s, 2H), 3.75-3.23 (m, 6H), 0.90 (t, 2H), 0.01 (s, 9H).
(4) Preparation of 2-trimethylsilyl ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate:
Ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (44 g,0.15 mol), bis (triphenylphosphine) palladium dichloride (5.3 g,7.6 mmol) and toluene (1000 mL) are mixed, stirred, cooled in an ice bath, and a solution of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, which is an organozinc compound formed by zinc first (83.5 g,0.23 mol), in toluene (1000 mL) is slowly added dropwise, the reaction is carried out at 20 ℃ for 6h, the organic solvent is removed by vacuum concentration, dichloromethane extraction is added, brine wash, anhydrous sodium sulfate drying and vacuum spin-evaporation to dryness is carried out to obtain ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate (2-trimethylsilyl) ethyl ester (55 g), the yield is 90% HPLC purity 98.5％;1H NMR(400MHz,CDCl3)δppm 5.32(s,2H),4.18-4.10(m,2H),3.99-3.73(m,4H),3,21(m,2H),2.45-2.36(m,4H),1.65(m,4H),1.02-0.93(m,4H),0.01(s,18H).
(5) Preparation of 8-hydroxy-6-oxooctanoic acid:
6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester (55 g,0.14 mol), tetrabutylammonium fluoride (72 g,0.28 mol) are dissolved in tetrahydrofuran (1000 mL), the temperature is raised to 50 ℃ for reaction for 6h, the temperature is reduced to room temperature, kieselguhr is filtered, the filtrate is collected, the organic solvent is removed by decompression concentration, dichloromethane extraction, salt water washing, anhydrous sodium sulfate drying, decompression rotary evaporation to dryness, the crude product is purified by a chromatographic column, 8-hydroxy-6-oxo caprylic acid (22 g) is obtained, the yield is 93 percent, and the HPLC purity is 99.2 percent; 1H NMR(400MHz,CDCl3 ) Delta ppm 3.60 (m, 2H), 2.50-2.35 (m, 6H), 1.57 (m, 4H).
Example 2
In this embodiment, a preparation method of 8-hydroxy-6-oxo-octanoic acid is provided, which specifically includes the following steps:
(1) Preparation of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid:
adipic acid (30 g,0.21 mol), 2-trimethylsilylethanol (32 g,0.27 mol), methanesulfonic acid (0.3 g,3 mmol) were dissolved in xylene (400 mL), heated to 105℃and reacted for 3h, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride was performed, brine was performed, dried over anhydrous sodium sulfate, and spin-evaporated to dryness under reduced pressure to give 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (26 g), yield 51%, HPLC purity 95.5%.
(2) Preparation of ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate:
6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (25 g,0.1 mol), N-diisopropylethylamine (29 g,0.22 mol) were dissolved in xylene (400 mL), triethyl trithiophosphite (24 g,0.11 mol) was added dropwise, the temperature was slowly raised to 105℃for reaction 21h, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride, brine wash, drying over anhydrous sodium sulfate, spin-evaporating to dryness under reduced pressure to give ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (25 g), yield 85%, HPLC purity 96.5%.
(3) Preparation of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane:
2-iodoethanol (35 g,0.2 mol), N-diisopropylethylamine (40 g,0.31 mol) were dissolved in DMF (800 mL), cooled in an ice bath, 2- (trimethylsilyl) ethoxymethyl chloride (38 g,0.23 mol) was added dropwise, the temperature was raised to 25℃and reacted for 10 hours, the organic solvent was removed by concentration under reduced pressure, dichloromethane extraction was added, brine washing, anhydrous sodium sulfate drying was performed, and spin-drying was performed under reduced pressure to give {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane (57.5 g), yield 94% and HPLC purity of 97.4%.
(4) Preparation of 2-trimethylsilyl ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate:
Ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (25 g,86 mmol), bis (di-tert-butylphosphino) dichloride (3 g,6 mmol) and xylene (500 mL) are mixed, stirred, cooled in an ice bath, and a solution of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, which is an organozinc compound formed from zinc first (57 g,0.16 mol), in xylene (250 mL) is slowly added dropwise, the temperature is raised to 25 ℃ and reacted for 2h, the organic solvent is removed by concentrating under reduced pressure, dichloromethane extraction is added, brine is carried out, anhydrous sodium sulfate is dried, and the mixture is distilled to dryness under reduced pressure to obtain ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate (2-trimethylsilyl) ethyl ester (32 g) in 92% yield and HPLC purity of 98.4%.
(5) Preparation of 8-hydroxy-6-oxooctanoic acid:
6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester (32 g,79 mmol), tetrabutylammonium fluoride (52 g,0.2 mol) were dissolved in methyl tert-butyl ether (450 mL), heated to 60℃for reaction for 5h, cooled to room temperature, filtered through celite, the filtrate collected, concentrated under reduced pressure to remove the organic solvent, extracted with dichloromethane, washed with salt, dried over anhydrous sodium sulfate, distilled to dryness under reduced pressure, and the crude product was purified by chromatography column to give 8-hydroxy-6-oxooctanoic acid (12 g) in 87% yield and 99.2% HPLC purity.
Example 3
In this embodiment, a preparation method of 8-hydroxy-6-oxo-octanoic acid is provided, which specifically includes the following steps:
(1) Preparation of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid:
Adipic acid (20 g,0.14 mol), 2-trimethylsilylethanol (23 g,0.2 mol) and p-dodecylbenzenesulfonic acid (1 g,3 mmol) were dissolved in toluene (350 mL), reacted at 100℃for 4 hours, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, and distilled to dryness under reduced pressure to give 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (18 g) in 53% yield and 95.4% HPLC purity.
(2) Preparation of ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate:
6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (18 g,73 mmol), pyridine (14 g,0.18 mol) were dissolved in N, N-dimethylformamide (450 mL), triethyl trithiophosphite (18 g,84 mmol) was added dropwise, the temperature was slowly raised to 110℃for reaction 19h, the organic solvent was removed by concentration under reduced pressure, dichloromethane extraction, brine washing, anhydrous sodium sulfate drying, spin evaporation under reduced pressure to dryness to give ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (18 g), yield 85%, HPLC purity 96.2%.
(3) Preparation of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane:
2-iodoethanol (21 g,0.12 mol), pyridine (16 g,0.2 mol) were dissolved in acetonitrile (200 mL), cooled in an ice bath, 2- (trimethylsilyl) ethoxymethyl chloride (24 g,0.14 mol) was added dropwise, the temperature was raised to 30℃and reacted for 9 hours, the organic solvent was removed by concentrating under reduced pressure, extraction was performed with methylene chloride, washing with common salt, drying with anhydrous sodium sulfate, and spin-evaporation to dryness under reduced pressure was performed to give {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane (34 g), yield 92%, HPLC purity 97.4%.
(4) Preparation of 2-trimethylsilyl ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate:
Ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (18 g,62 mmol), bis (triphenylphosphine) palladium dichloride (4 g,6 mmol) and DMF (500 mL) are mixed, stirred, cooled in an ice bath, and a solution of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane in DMF (300 mL) of an organozinc compound (40 g,0.11 mol) formed from zinc is slowly added dropwise, the temperature is raised to 25 ℃ for 3h, the organic solvent is removed by vacuum concentration, dichloromethane extraction, salt water washing and anhydrous sodium sulfate drying are carried out, and vacuum spin evaporation is carried out to dryness to obtain ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate (23 g) with a yield of 92% and HPLC purity of 98.0%.
(5) Preparation of 8-hydroxy-6-oxooctanoic acid:
6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester (23 g,57 mmol) and tetrabutylammonium fluoride (45 g,0.17 mol) are dissolved in 1, 4-dioxane (400 mL), the temperature is raised to 70 ℃ for reaction for 4h, the temperature is reduced to room temperature, kieselguhr is filtered through suction, the filtrate is collected, the organic solvent is removed through reduced pressure concentration, dichloromethane extraction, common salt water washing, anhydrous sodium sulfate drying, reduced pressure rotary evaporation to dryness are carried out, the crude product is purified through a chromatographic column, 8-hydroxy-6-oxo caprylic acid (9 g) is obtained, the yield is 91%, and the HPLC purity is 99.2%.
Example 4
In this embodiment, a preparation method of 8-hydroxy-6-oxo-octanoic acid is provided, which specifically includes the following steps:
(1) Preparation of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid:
Adipic acid (15 g,0.1 mol), 2-trimethylsilylethanol (18 g,0.15 mol), benzenesulfonic acid (0.6 g,4 mmol) were dissolved in xylene (300 mL), heated to 95℃and reacted for 5 hours, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride was performed, brine was performed, dried over anhydrous sodium sulfate, and spin-evaporated to dryness under reduced pressure to give 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (14 g), yield 55%, HPLC purity 95.6%.
(2) Preparation of ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate:
6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (14 g,57 mmol), N-diethylaniline (23 g,0.15 mol) were dissolved in xylene (300 mL), triethyl trithiophosphite (15 g,70 mmol) was added dropwise, the temperature was slowly raised to 115℃to react for 16h, the organic solvent was removed by concentrating under reduced pressure, dichloromethane extraction, brine washing, anhydrous sodium sulfate drying, spin evaporation under reduced pressure to dryness to give ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (14 g), yield 85%, HPLC purity 96.5%.
(3) Preparation of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane:
2-iodoethanol (27 g,0.16 mol), 1, 8-diazabicyclo [5.4.0] undec-7-ene (45 g,0.3 mol) were dissolved in tetrahydrofuran (700 mL), cooled in an ice bath, 2- (trimethylsilyl) ethoxymethyl chloride (34 g,0.2 mol) was added dropwise, the temperature was raised to 40℃for reaction for 8h, the organic solvent was removed by concentration under reduced pressure, extraction with dichloromethane, aqueous brine, drying over anhydrous sodium sulfate, and spin-evaporation to dryness under reduced pressure gave {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane (45 g), yield 95%, HPLC purity 97.4%.
(4) Preparation of 2-trimethylsilyl ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate:
ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (14 g,48 mmol), bis (di-tert-butylphosphino) dichloride (2.5 g,5 mmol) and THF (400 mL) are mixed, stirred, cooled in an ice bath, a solution of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, which is first reacted with zinc to form an organozinc compound (53 g,0.14 mol) in THF (500 mL), is heated to 35 ℃ for 1h, concentrated under reduced pressure to remove the organic solvent, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate (2-trimethylsilyl) ethyl ester (17 g) in 87% yield and 98.1% HPLC purity.
(5) Preparation of 8-hydroxy-6-oxooctanoic acid:
6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester (17 g,42 mmol), tetrabutylammonium fluoride (43 g,0.16 mol) were dissolved in methyl tert-butyl ether (250 mL), heated to 100deg.C for 2h, cooled to room temperature, filtered through celite, the filtrate collected, concentrated under reduced pressure to remove the organic solvent, extracted with dichloromethane, washed with salt, dried over anhydrous sodium sulfate, distilled to dryness under reduced pressure, and the crude product purified by chromatography column to give 8-hydroxy-6-oxooctanoic acid (6 g) in 82% yield with HPLC purity of 99.2%.
Example 5
In this embodiment, a preparation method of 8-hydroxy-6-oxo-octanoic acid is provided, which specifically includes the following steps:
(1) Preparation of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid:
Adipic acid (75 g,0.51 mol), 2-trisilylethanol (97 g,0.82 mol), 2,4, 6-triisopropylbenzenesulfonic acid (7 g,25 mmol) were dissolved in toluene (1000 mL), reacted at 90℃for 6h, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, and distilled to dryness under reduced pressure to give 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (65 g), yield 51%, HPLC purity 95.5%.
(2) Preparation of ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate:
6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid (65 g,0.26 mmol), N-methylpyrrolidone (78 g,0.79 mol) were dissolved in toluene (1000 mL), triethyl trithiophosphite (73 g,0.34 mol) was added dropwise, the temperature was slowly raised to 120℃for reaction for 12h, the organic solvent was removed by concentration under reduced pressure, dichloromethane extraction, brine washing, drying over anhydrous sodium sulfate, spin-evaporation under reduced pressure to dryness, ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (63 g) was obtained in 82% yield and 96.6% HPLC purity.
(3) Preparation of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane:
2-iodoethanol (118 g,0.69 mol), N-methylpyrrolidone (136 g,1.37 mol) were dissolved in N, N-dimethylacetamide (2500 mL), cooled in an ice bath, 2- (trimethylsilyl) ethoxymethyl chloride (171 g,1 mol) was added dropwise, the temperature was raised to 50℃for reaction for 6 hours, the organic solvent was removed by concentration under reduced pressure, dichloromethane extraction was added, brine washing, anhydrous sodium sulfate drying, and spin evaporation under reduced pressure to dryness gave {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane (197 g), yield 95% and HPLC purity of 97.4%.
(4) Preparation of 2-trimethylsilyl ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate:
Ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate (63 g,0.21 mol), bis (triphenylphosphine) palladium dichloride (15 g,21 mmol) and toluene (1200 mL) are mixed, stirred, cooled in an ice bath, and a solution of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, which is an organozinc compound formed from zinc, in toluene (1600 mL) is slowly added dropwise, the temperature is raised to 35 ℃ for 2h, the organic solvent is removed by concentrating under reduced pressure, dichloromethane extraction, brine washing and anhydrous sodium sulfate drying are carried out, and the solution is distilled to dryness under reduced pressure to obtain ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate (2-trimethylsilyl) ethyl ester (80 g) with a yield of 91% and an HPLC purity of 98.2%.
(5) Preparation of 8-hydroxy-6-oxooctanoic acid: 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester (80 g,0.2 mol), tetrabutylammonium fluoride (232 g,0.89 mol) are dissolved in tetrahydrofuran (1200 mL), the temperature is raised to 0 ℃ for 2h, the reaction is carried out, the temperature is reduced to room temperature, kieselguhr is pumped and filtered, the filtrate is collected, the organic solvent is removed by decompression concentration, dichloromethane extraction, salt water washing, anhydrous sodium sulfate drying and decompression rotary evaporation to dryness are carried out, the crude product is purified by a chromatographic column, 8-hydroxy-6-oxo caprylic acid (30 g) is obtained, the yield is 87 percent, and the HPLC purity is 99.2 percent.
The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be practiced in dependence upon 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 (10)
1. A process for the preparation of 8-hydroxy-6-oxooctanoic acid, characterized in that it comprises the following steps:
(1) Esterification reaction is carried out on adipic acid and 2-trimethylsilyl ethanol to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid, and the reaction formula is as follows:
(2) Esterification reaction is carried out on 6-oxo-6- [2- (trimethylsilyl) ethoxy ] caproic acid and triethyl trithiophosphite to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate, wherein the reaction formula is as follows:
(3) 2-iodoethanol reacts with 2- (trimethylsilyl) ethoxymethyl chloride to obtain {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane, and the reaction formula is as follows:
(4) The organozinc compound of formula A formed from {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane is subjected to Fukuyama coupling reaction with ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate to give (2-trimethylsilyl) ethyl 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoate, of the formula:
(5) Deprotection of 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoic acid (2-trimethylsilyl) ethyl ester in the presence of tetrabutylammonium fluoride gives 8-hydroxy-6-oxooctanoic acid of the formula:
2. the process of claim 1, wherein the molar ratio of adipic acid to 2-trisilylethanol in step (1) is 1:1.2-1.7;
Preferably, the esterification reaction of step (1) is carried out in the presence of a sulfonic acid derivative;
Preferably, the sulfonic acid derivative is selected from any one or a combination of at least two of p-toluenesulfonic acid, methanesulfonic acid, p-dodecylbenzenesulfonic acid, benzenesulfonic acid, 2,4, 6-triisopropylbenzenesulfonic acid or m-nitrobenzenesulfonic acid;
preferably, the molar ratio of the sulfonic acid derivative to adipic acid is from 0.005 to 0.05:1.
3. The process according to claim 1 or 2, wherein the esterification reaction of step (1) is carried out in a solvent which is toluene and/or xylene;
Preferably, the temperature of the esterification reaction in the step (1) is 90-110 ℃, and the reaction time is 2-6 hours.
4. A process according to any one of claims 1 to 3, wherein the molar ratio of 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid to triethyl trithiophosphite of step (2) is 1:1 to 1.3;
Preferably, the reaction of step (2) is carried out in the presence of an acid-binding agent;
Preferably, the acid-binding agent is selected from any one or a combination of at least two of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, trimethylamine, triisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-lutidine, 4-dimethylaminopyridine or N-methylpyrrolidone;
Preferably, the molar ratio of the acid-binding agent to 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid is 2-3:1;
Preferably, the esterification reaction of step (2) is carried out in a solvent which is any one or a combination of at least two of toluene, xylene or N, N-dimethylformamide;
preferably, the temperature of the esterification reaction in the step (2) is 100-120 ℃ and the reaction time is 12-24 hours.
5. The process according to any one of claims 1 to 4, wherein the molar ratio of 2-iodoethanol to 2- (trimethylsilyl) ethoxymethyl chloride in step (3) is 1:1 to 1.5;
Preferably, the reaction of step (3) is carried out in the presence of an acid-binding agent;
Preferably, the acid-binding agent is selected from any one or a combination of at least two of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, trimethylamine, triisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine or 1, 8-diazabicyclo [5.4.0] undec-7-ene;
preferably, the molar ratio of the acid-binding agent to the 2-iodoethanol is 1.3-2:1;
preferably, the reaction of step (3) is carried out in a solvent which is any one or a combination of at least two of an ether solvent, an amide solvent, a nitrile solvent or a sulfone solvent.
6. The process according to any one of claims 1 to 5, wherein the temperature of the reaction in step (3) is 20 to 50 ℃ and the reaction time is 6 to 12 hours.
7. The process according to any one of claims 1 to 6, wherein the molar ratio of ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate to the organozinc compound of formula a in step (4) is 1:1.5 to 3.1;
preferably, the Fukuyama coupling reaction of step (4) is carried out in the presence of a palladium catalyst;
Preferably, the palladium catalyst is any one or a combination of two of bis (triphenylphosphine) palladium dichloride or bis (di-tert-butylphosphine chloride) palladium dichloride;
Preferably, the molar ratio of the palladium catalyst to the ethyl 6-oxo-6- [2- (trimethylsilyl) ethoxy ] thiocaproate is 0.05-0.1:1;
preferably, the Fukuyama coupling reaction of step (4) is carried out in a solvent which is any one or a combination of at least two of toluene, xylene, N-dimethylformamide or tetrahydrofuran;
Preferably, the temperature of the Fukuyama coupling reaction is 20-35 ℃ and the reaction time is 1-6 hours.
8. The process according to any one of claims 1 to 7, wherein the organozinc compound represented by formula a in step (4) is obtained by reacting {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane with zinc;
Preferably, the molar ratio of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane to zinc is 1:1.5-3;
preferably, the solvent for the reaction of {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane with zinc is any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether or DMF;
Preferably, the {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane is reacted with zinc at a temperature of 45-90 ℃ for a period of 6-12 hours.
9. The process according to any one of claims 1 to 8, wherein the molar ratio of 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoic acid (2-trimethylsilyl) ethyl ester to tetrabutylammonium fluoride of step (5) is 1:2-4.5;
Preferably, the deprotection reaction of step (5) is carried out in a solvent which is any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether or 1, 4-dioxane;
Preferably, the temperature of the deprotection reaction in step (5) is 50-100 ℃ and the reaction time is 2-6 hours.
10. The preparation method according to any one of claims 1 to 9, characterized in that the preparation method comprises the steps of:
(1) In the presence of sulfonic acid derivative, adipic acid and 2-trimethylsilyl ethanol are subjected to esterification reaction for 2-6 hours at 90-110 ℃ in a molar ratio of 1:1.2-1.6 to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid;
(2) In the presence of an acid binding agent, 6-oxo-6- [2- (trimethylsilyl) ethoxy ] hexanoic acid and triethyl trithiophosphite are reacted for 12-24 hours at the temperature of 100-120 ℃ in a molar ratio of 1:1-1.3 to obtain 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate;
(3) Reacting 2-iodoethanol and 2- (trimethylsilyl) ethoxymethyl chloride for 6-12 hours at 20-50 ℃ in the presence of an acid binding agent according to the molar ratio of 1:1-1.5 to obtain {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane;
(4) In the presence of a palladium catalyst, the {2- [ (2-iodoethoxy) methoxy ] ethyl } trimethylsilane and zinc generate an organozinc compound, and 6-oxo-6- [2- (trimethylsilyl) ethoxy ] ethyl thiocaproate and the organozinc compound are subjected to Fukuyama coupling reaction for 1-6 hours at 20-35 ℃ in a molar ratio of 1:1.5-3.1 to obtain 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } caprylic acid (2-trimethylsilyl) ethyl ester;
(5) Deprotection of 6-oxo-8- { [2- (trimethylsilyl) ethoxy ] methoxy } octanoic acid (2-trimethylsilyl) ethyl ester in the presence of tetrabutylammonium fluoride at 50-100℃for 2-6 hours afforded 8-hydroxy-6-oxooctanoic acid.
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