CN111995565B - Preparation method of (S) -2-piperidinecarboxylic acid - Google Patents
Preparation method of (S) -2-piperidinecarboxylic acid Download PDFInfo
- Publication number
- CN111995565B CN111995565B CN202010721140.3A CN202010721140A CN111995565B CN 111995565 B CN111995565 B CN 111995565B CN 202010721140 A CN202010721140 A CN 202010721140A CN 111995565 B CN111995565 B CN 111995565B
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- Prior art keywords
- compound
- reaction
- ethyl acetate
- iii
- piperidinecarboxylic acid
- Prior art date
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- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 title abstract description 29
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 title abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 82
- 238000000034 method Methods 0.000 abstract description 17
- 230000009471 action Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000002841 Lewis acid Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 150000007517 lewis acids Chemical class 0.000 abstract description 5
- 230000029936 alkylation Effects 0.000 abstract description 4
- 238000005804 alkylation reaction Methods 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 150000002466 imines Chemical class 0.000 abstract description 2
- 238000007171 acid catalysis Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- 238000006243 chemical reaction Methods 0.000 description 89
- 235000019439 ethyl acetate Nutrition 0.000 description 55
- 239000012074 organic phase Substances 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000126 substance Substances 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000003208 petroleum Substances 0.000 description 20
- 238000001514 detection method Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- QUGJYNGNUBHTNS-UHFFFAOYSA-N ethyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OCC)C1=CC=CC=C1 QUGJYNGNUBHTNS-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229960000846 camphor Drugs 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 229940124530 sulfonamide Drugs 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 7
- -1 amido diene methyl ester Chemical class 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 7
- BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 7
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 description 4
- MCULRUJILOGHCJ-UHFFFAOYSA-N triisobutylaluminium Chemical compound CC(C)C[Al](CC(C)C)CC(C)C MCULRUJILOGHCJ-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- WVEBQVBMPNXJCK-UHFFFAOYSA-N hexane;trimethylalumane Chemical compound C[Al](C)C.CCCCCC WVEBQVBMPNXJCK-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 description 2
- ROUYUBHVBIKMQO-UHFFFAOYSA-N 1,4-diiodobutane Chemical compound ICCCCI ROUYUBHVBIKMQO-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- FBDABANESAZHNX-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)O.CCCC Chemical compound CC1=CC=C(C=C1)S(=O)(=O)O.CCCC FBDABANESAZHNX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- CXHZRNBRZBJFGY-UHFFFAOYSA-N butane;methanesulfonic acid Chemical compound CCCC.CS(O)(=O)=O CXHZRNBRZBJFGY-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229930000044 secondary metabolite Natural products 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- WZDUMISBAHEPLN-UHFFFAOYSA-N tert-butyl 2-methoxypiperidine-1-carboxylate Chemical compound COC1CCCCN1C(=O)OC(C)(C)C WZDUMISBAHEPLN-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- GVVCHDNSTMEUCS-UAFMIMERSA-N (2r,5r)-1-[2-[(2r,5r)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane Chemical compound CC[C@@H]1CC[C@@H](CC)P1C1=CC=CC=C1P1[C@H](CC)CC[C@H]1CC GVVCHDNSTMEUCS-UAFMIMERSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- MXJGZAMERDEUKM-UHFFFAOYSA-N N[Li].C[Si](N[Si](C)(C)C)(C)C Chemical compound N[Li].C[Si](N[Si](C)(C)C)(C)C MXJGZAMERDEUKM-UHFFFAOYSA-N 0.000 description 1
- 108010030975 Polyketide Synthases Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000007295 Wittig olefination reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- JPUHCPXFQIXLMW-UHFFFAOYSA-N aluminium triethoxide Chemical compound CCO[Al](OCC)OCC JPUHCPXFQIXLMW-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- OAFMYIADTCIEFV-UHFFFAOYSA-N hexane;triethylalumane Chemical compound CCCCCC.CC[Al](CC)CC OAFMYIADTCIEFV-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- VLECDMDGMKPUSK-UHFFFAOYSA-N hydron;piperidin-3-ol;chloride Chemical compound Cl.OC1CCCNC1 VLECDMDGMKPUSK-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- NVLIMKIQSSOEJO-UHFFFAOYSA-N lithium;di(propan-2-yl)azanide;hexane Chemical compound [Li+].CCCCCC.CC(C)[N-]C(C)C NVLIMKIQSSOEJO-UHFFFAOYSA-N 0.000 description 1
- NIXOIRLDFIPNLJ-UHFFFAOYSA-M magnesium;benzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=[C-]C=C1 NIXOIRLDFIPNLJ-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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)
- Hydrogenated Pyridines (AREA)
Abstract
一种(S)‑2‑哌啶甲酸的制备方法：在路易斯酸催化下，L‑樟脑磺酰胺(I)与二苯基亚胺酯(II)发生缩合反应，生成化合物(III)；化合物(III)与化合物(IV)经强碱作用下的不对称烷基化、酸性条件下的亚胺水解、分子内环合“一锅法”制得化合物(V)；化合物(V)在碱性条件下脱去手性辅助基，得到目标化合物(S)‑2‑哌啶甲酸(TM)；本发明方法总共经过三步就可以得到目标产物，该法具有原料价廉易得、路线简短、收率高、立体选择性好等优点，目前(S)‑2‑哌啶甲酸为诸多药物的重要手性中间体，具有良好的市场前景； A preparation method of (S)-2-piperidinecarboxylic acid: under Lewis acid catalysis, L-camphorsulfonamide (I) and diphenylimide ester (II) undergo condensation reaction to generate compound (III); Compound (III) Compound (V) is obtained by asymmetric alkylation under the action of strong base, imine hydrolysis under acidic conditions, and intramolecular cyclization "one-pot method" with compound (IV); The target compound (S)-2-piperidinecarboxylic acid (TM) can be obtained by removing the chiral auxiliary group under the natural conditions; the target product can be obtained in three steps in the method of the invention, and the method has the advantages of cheap and easy-to-obtain raw materials and short route. , high yield, good stereoselectivity and other advantages, at present (S)-2-piperidinecarboxylic acid is an important chiral intermediate of many drugs, and has a good market prospect; 
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a drug intermediate (S) -2-piperidinecarboxylic acid.
Background
(S) -2-piperidine formic acid is a nonprotein amino acid, widely exists in plants, animals and microorganisms, and is also a main component of several secondary metabolites in plants and fungi, and the chemical structural formula of (S) -2-piperidine formic acid is as follows:
(S) -2-piperidinecarboxylic acid is frequently used as a substrate for peptides or polyketide synthase and is capable of producing secondary metabolites having good pharmacological activity, such as rapamycin, FK506, an antitumor antibiotic, sandomycin or the like. Has wide market demand as a very useful drug intermediate, and is receiving more and more attention from organic synthetic chemists. Representative drugs containing (S) -2-piperidinecarboxylic acid are:
the chemical asymmetric synthesis method of (S) -2-piperidinecarboxylic acid mainly comprises the following steps:
in The literature (The Journal of organic chemistry,2010,75(6):2077-2080), chiral amide is used as a raw material, chiral N-iminopyridine salt is synthesized under The activation of trifluoromethanesulfonic anhydride, then phenyl is introduced under The action of Grignard reagent PhMgBr. LiBr, and (S) -2-piperidinecarboxylic acid is obtained through hydrogenation reduction, chiral auxiliary group removal, amino protection by trifluoroacetyl, phenyl oxidation and hydrolysis. The product of the synthetic route has good stereoselectivity, but the reaction steps are more complicated, and the synthetic route is not suitable for industrial production.
The literature (Organic letters,2000,2(2):155-158) uses 3-hydroxypiperidine hydrochloride as raw material, and obtains N-Boc-piperidyl methyl ether through three-step reaction, and the N-Boc-piperidyl methyl ether is converted into unsaturated piperidine derivative under the catalysis of catalyst S-BuLi/TMEDA, and then is subjected to (S) -BINAP-RuCl2Under the action of the catalyst, asymmetric catalytic hydrogenation reaction is carried out to obtain (S) -N-Boc-piperidine formic acid, and finally, a protecting group is removed to obtain a target product. The chiral ligand catalyst used in the route is expensive and high in cost, and is not suitable for industrial application.
In the literature (Chemical Communications,2002(9):978-979), amido diene methyl ester is used as a raw material to perform asymmetric hydrogenation, asymmetric carbonylation and intramolecular cyclization reactions under the action of Rh (R, R) Et-DuPHOS system and Rh-BIPH system to obtain an unsaturated piperidine derivative with optical activity, and then the unsaturated piperidine derivative is subjected to Pd catalytic hydrogenation, acidic hydrolysis to form a salt, and chromatographic separation to obtain high-purity (S) -piperidinecarboxylic acid. The route requires the use of a ruthenium metal reagent, which is not only costly, but also severely polluting. In addition, the product needs column chromatography separation, is not easy to enlarge production and has higher cost.
The literature (Tetrahedron letters,2002,43(5):779-782) uses allyl alcohol derivative as raw material, and obtains unsaturated piperidine derivative through asymmetric epoxidation, epoxy ring opening and RCM reaction, and then obtains N-Boc- (S) -piperidine formic acid as target product through catalytic hydrogenation and oxidation. The route has high stereoselectivity, but the catalyst is expensive and has high production cost, so the route is not suitable for industrial production.
In the literature (Tetrahedron: Asymmetry,2005,16(23): 3858-. The process has complex steps and harsh reaction conditions.
In the literature (Synthetic communications,2003,33(13):2197-2208), a lactone is obtained by a three-step reaction using beta-amino alcohol as a substrate, and the lactone is reacted with Br (CH) under the action of sodium hexamethyldisilazane (NaHMDS)2)4OTf substitution reaction to produce bromoalkyl lactone. Then the bromine alkyl lactone is subjected to benzyloxycarbonyl cleavage, ring closure and benzyl removal under the action of a catalyst to obtain the piperidine acid. The reaction steps of the method are simple, but the reaction yield is low, expensive catalyst palladium is needed, and the reaction cost is high.
The literature (Tetrahedron: Asymmetry,2014,25(16-17):1246-4Oxidizing, Wittig olefination, debenzylating, cyclizing to obtain piperidone, and finally amide reducing, KMnO4Oxidizing to obtain the (S) -2-piperidinecarboxylic acid. The method has more steps, fussy operation and low yield, and is difficult to realize large-scale industrial production.
In conclusion, the research on the synthesis of (S) -2-piperidinecarboxylic acid has been receiving much attention from organic synthetic chemists. The (S) -2-piperidinecarboxylic acid serving as a medicine intermediate with wide application has larger and larger market demand, and the synthesis research thereof also has more and more importance. With the continuous development of synthetic technology, biotechnology and pharmaceutical research, it can be expected that the piperidine acid must have wider application prospects. Therefore, it is necessary to develop a simple, practical and effective method for synthesizing (S) -2-piperidinecarboxylic acid.
Disclosure of Invention
The invention provides a preparation method of (S) -2-piperidinecarboxylic acid, which takes cheap and easily-obtained natural L-camphorsulfonamide as a chiral auxiliary agent to prepare the (S) -2-piperidinecarboxylic acid through amidation, asymmetric alkylation, deprotection, cyclization and hydrolysis, wherein the three steps of reactions of asymmetric alkylation, deprotection and cyclization are completed in a one-pot method, a piperidine skeleton is successfully constructed, a chiral center is introduced, and the (S) -2-piperidinecarboxylic acid is finally obtained.
The technical scheme of the invention is as follows:
a preparation method of (S) -2-piperidinecarboxylic acid comprises the following steps:
step A: under the catalysis of Lewis acid, carrying out condensation reaction on L-camphor sulfonamide (I) and diphenyl imine ester (II) to generate a compound (III);
and B: the compound (III) and the compound (IV) are subjected to asymmetric alkylation under the action of strong alkali, imine hydrolysis under acidic condition and intramolecular cyclization to prepare a compound (V) by a one-pot method;
and C: removing the chiral auxiliary group from the compound (V) under an alkaline condition to obtain a target compound (S) -2-piperidinecarboxylic acid (TM); the reaction equation is as follows:
in the formula (II), R is Me, Et or t-Bu;
in the formula (IV), X is chlorine, bromine, iodine, p-toluenesulfonyl or methanesulfonyl.
Specifically, the preparation method of the (S) -2-piperidinecarboxylic acid comprises the following steps:
the step A is operated according to the following method: dissolving L-camphor sulfonamide (I) in an organic solvent, adding Lewis acid under the protection of nitrogen, and uniformly stirring to obtain a mixed solution; dissolving diphenyl imido ester (II) in an organic solvent, dropwise adding the solution into the obtained mixed solution, reacting for 10-40 h (preferably 15-20 h) at 25-80 ℃ (preferably 40-50 ℃), and after the reaction is finished (TLC detection), carrying out post-treatment on the reaction solution to obtain a compound (III);
the mass ratio of the L-camphor sulfonamide (I), the diphenyl imine ester (II) and the Lewis acid is 1.0: 1.0-1.5, preferably 1.0:1.1: 1.2;
the Lewis acid is selected from trimethylaluminum, triethylaluminum, triisobutylaluminum, aluminum trichloride or triethoxyaluminum, and is preferably trimethylaluminum;
the organic solvent used for dissolving the L-camphorsulfonamide (I) is tetrahydrofuran, 2-methyltetrahydrofuran, toluene or dimethyl sulfoxide; the organic solvent used for dissolving the diphenylimido ester (II) is as defined above;
the volume consumption of the organic solvent for dissolving the L-camphorsulfonamide (I) is 5-10 mL/g calculated by the mass of the L-camphorsulfonamide (I); the volume consumption of the organic solvent for dissolving the diphenyl imine ester (II) is 5-10 mL/g based on the mass of the diphenyl imine ester (II);
the post-treatment method comprises the following steps: after the reaction is finished, adding saturated sodium bicarbonate and water into the reaction liquid in sequence, separating the liquid, extracting the water phase by using ethyl acetate, combining organic phases, washing the organic phases with water, concentrating the organic phases, performing column chromatography separation, collecting eluent containing the target compound by using a mixed liquid of petroleum ether and ethyl acetate with a volume ratio of 4:1 as an eluent, evaporating the solvent, and drying to obtain a compound (III);
the step B is operated according to the following method: dissolving a compound (III) in an organic solvent, adding an alkaline substance under the protection of inert gas, then cooling to-78 ℃, adding a compound (IV), reacting at room temperature (20-30 ℃) for 1-6 h (preferably 2-3 h), and after the reaction is finished (TLC detection), carrying out post-treatment on the reaction solution to obtain a compound (V);
the mass ratio of the compound (III), the compound (IV) and the alkaline substance is 1.0: 1.0-1.5, preferably 1.0:1.1: 1.1;
the alkaline substance is selected from sodium hydride, potassium tert-butoxide, sodium tert-amylate, n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide, preferably lithium hexamethyldisilazide; recommending that the alkaline substance is added into the reaction system in a form of dissolving in an ether or alkane solvent;
the organic solvent is toluene, anhydrous tetrahydrofuran or 1, 4-dioxane;
the volume dosage of the organic solvent is 5-10 mL/g based on the mass of the compound (III);
the post-treatment method comprises the following steps: after the reaction is finished, quenching the reaction liquid by glacial acetic acid, adding ethyl acetate and water for liquid separation, extracting a water phase by using ethyl acetate, combining organic phases, washing by using saturated ammonium chloride, concentrating the organic phase, performing column chromatography separation, collecting eluent containing a target compound by using a mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, evaporating the solvent, and drying to obtain a compound (V);
the step C is operated according to the following method: dissolving the compound (V) in an organic solvent, adding an alkaline substance, reacting for 1-5 h (preferably 2-3 h) at-5-50 ℃ (preferably 5-20 ℃), and after the reaction is finished (TLC detection), carrying out post-treatment on the reaction solution to obtain a target product (S) -2-piperidinecarboxylic acid (TM);
the mass ratio of the compound (V) to the basic substance is 1.0:2.0 to 4.0, preferably 1.0: 3.0;
the alkaline substance is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide or potassium carbonate, preferably lithium hydroxide;
the alkaline substance is recommended to be added into the reaction system in the form of 2.5mol/L aqueous solution;
the organic solvent is methanol, ethanol or tetrahydrofuran;
the volume dosage of the organic solvent is 5-10 mL/g based on the mass of the compound (V);
the post-treatment method comprises the following steps: after the reaction is finished, concentrating the reaction liquid, adding 1M hydrochloric acid to adjust the pH to 1-2, adjusting the pH to 6-7 with 1M sodium bicarbonate, concentrating to remove the solvent, performing column chromatography separation, collecting eluent containing the target product by taking a mixed liquid of ethyl acetate and methanol in a volume ratio of 2:1 as an eluent, evaporating to remove the solvent, and drying to obtain (S) -2-piperidinecarboxylic acid (TM).
Compared with the prior art, the invention has the beneficial effects that: the method can obtain the target product through three steps in total, has the advantages of cheap and easily-obtained raw materials, short route, high yield, good stereoselectivity and the like, and has good market prospect because (S) -2-piperidinecarboxylic acid is an important chiral intermediate of a plurality of medicines at present.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope.
In the following examples, trimethylaluminum was purchased from Saien chemical technology (Shanghai) Co., Ltd, and was a 1.0mol/L n-hexane solution having a CAS number of 75-24-1;
triethylaluminum was purchased from Saen chemical technology (Shanghai) Co., Ltd, and was a 2.0mol/L n-hexane solution with CAS number of 97-93-8;
triisobutylaluminum was purchased from Saen chemical technology (Shanghai) Co., Ltd, and its specification was 1.1mol/L of n-hexane solution, CAS number was 100-99-2;
sodium hydride was purchased from sahn chemical technology (shanghai) ltd, 60% mineral oil specification, CAS No. 7646-69-6;
the potassium tert-butoxide is purchased from Saen chemical technology (Shanghai) Co., Ltd, with the specification of 98% and the CAS number of 865-47-4;
the n-butyl lithium is purchased from Saen chemical technology (Shanghai) Co., Ltd, and is 2.5mol/L n-hexane solution with CAS number of 109-72-8;
lithium diisopropylamide was purchased from Saien chemical technology (Shanghai) Co., Ltd, 2.0mol/L n-hexane solution, CAS number 4111-54-0;
hexamethyldisilazane lithium amide was purchased from Sahn chemical technology (Shanghai) Co., Ltd, and was a 1.0mol/L tetrahydrofuran solution with CAS number 4039-32-1.
Example 1: synthesis of Compound (III)
According to the mol ratio of L-camphor sulfonamide: diphenylmethylene glycine ethyl ester: trimethylaluminum 1.0:1.0:1.0 the following reaction was carried out:
0.50g of camphorsulfonamide is dissolved in 5mL of toluene, and 2.33mL of trimethylaluminum n-hexane solution (1.0mol/L) is added dropwise at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.53g of a toluene solution of diphenylmethylene glycine ethyl ester (5mL) was added dropwise to the reaction mixture, and the temperature was raised to 40 ℃ to conduct a reaction for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 0.82g of a pale yellow oily substance with a yield of 81.0%.
The analytical data for compound (III) are as follows: light yellow oil; rf＝0.30(Petroleum ether:EtOAc＝4:1)；1H NMR(500MHz,CDCl3)δ7.66(dd,J＝5.2,3.3Hz,2H),7.49-7.42(m,3H),7.38(dd,J＝4.9,3.6Hz,1H),7.33(t,J＝7.5Hz,2H),7.25–7.15(m,2H),4.63(d,J＝4.5Hz,2H),3.90(dd,J＝7.8,4.9Hz,1H),3.42(d,J＝12.4Hz,2H),2.14-2.03(m,1H),1.41-1.38(m,1H),1.35(d,J＝6.7Hz,1H),1.13(s,4H),0.95(s,6H)ppm.
Example 2: synthesis of Compound (III)
According to the mol ratio of L-camphor sulfonamide: diphenylmethylene glycine ethyl ester: trimethylaluminum 1.0:1.1:1.0 the following reaction was carried out:
0.5g of L-camphorsulfonamide was dissolved in 5mL of toluene, and 2.33mL of trimethylaluminum n-hexane solution (1.0mol/L) was added dropwise thereto at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.79g of a toluene solution (5mL) of ethyl diphenylmethyleneglycinate was added dropwise to the reaction mixture, and the temperature was raised to 40 ℃ to conduct the reaction for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to purify the mixture to obtain 0.84g of a pale yellow oily substance, with a yield of 83.1%.
Example 3: synthesis of Compound (III)
According to the mol ratio of L-camphor sulfonamide: diphenylmethylene glycine ethyl ester: trimethylaluminum 1.0:1.1:1.2 the following reaction was carried out:
0.5g of L-camphorsulfonamide was dissolved in 5mL of toluene, and 2.8mL of trimethylaluminum n-hexane solution (1.0mol/L) was added dropwise thereto at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.58g of a toluene solution of diphenylmethylene glycine ethyl ester (5mL) was added dropwise to the reaction mixture, and the temperature was raised to 40 ℃ to conduct a reaction for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 0.91g of a pale yellow oily substance with a yield of 90.0%.
Example 4: synthesis of Compound (III)
According to the mol ratio of L-camphor sulfonamide: diphenylmethylene glycine ethyl ester: triethylaluminum ═ 1.0:1.1:1.2 the following reaction was carried out:
1.5g of L-camphorsulfonamide was dissolved in 15mL of toluene, and 4.2mL of triethylaluminum n-hexane solution (2.0mol/L) was added dropwise thereto at room temperature under nitrogen. After the reaction mixture was further stirred at room temperature for 30 minutes, 1.74g of a toluene solution (15mL) of ethyl diphenylmethyleneglycinate was added dropwise to the reaction mixture, and the temperature was raised to 40 ℃ to conduct a reaction for 20 hours. The reaction was completed by TLC detection. 25mL of saturated sodium bicarbonate and 20mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 100mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 2.48g of a pale yellow oily substance, with a yield of 82.0%.
Example 3: synthesis of Compound (III)
According to the mol ratio of L-camphor sulfonamide: diphenylmethylene glycine ethyl ester: triisobutylaluminum as 1.0:1.1:1.2 was reacted as follows:
1.0g of L-camphorsulfonamide was dissolved in 10mL of toluene, and 5.1mL of a triisobutylaluminum-n-hexane solution (1.1mol/L) was added dropwise thereto at room temperature under nitrogen protection. After the reaction mixture was stirred at room temperature for 15 minutes, 1.16g of a toluene solution of diphenylmethylene glycine ethyl ester (10mL) was added dropwise to the reaction mixture, and the temperature was raised to 40 ℃ to conduct a reaction for 20 hours. The reaction was completed by TLC detection. 20mL of saturated sodium bicarbonate and 20mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 50mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 1.62g of a pale yellow oily substance with a yield of 80.0%.
Example 6: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: sodium hydride 1.0:1.0:1.0 the following reaction was carried out:
1.05g of compound (III) and 10mL of anhydrous THF solution are added, 58mg of sodium hydride are added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 0.29mL of 1, 4-dibromobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, and then the mixture was transferred to room temperature to react for 3 hours, after the completion of the TLC detection reaction, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added to separate the solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain 0.52g of compound (V) with a yield of 66%.
Analytical data for compound (V) are as follows: light yellow oil; rf＝0.24(Petroleum ether:EtOAc＝4:1)；1H NMR(400MHz,Chloroform-d)δ3.43(q,J＝6.3Hz,1H),3.19-3.10(m,3H),3.07(dd,J＝8.0,4.7Hz,1H),2.81-2.70(m,1H),2.18-1.55(m,10H),1.49-1.38(m,1H),1.34-1.21(m,2H),1.14(s,3H),0.92(s,3H).13C NMR(101MHz,CDCl3)δ67.9,49.8,47.5,44.6,43.2,43.1,35.7,33.2,32.2,30.4,30.2,26.9,26.4,25.2,20.4,20.0ppm.MS(ESI):C16H26N2O3S[M-H]+325.35。
Example 7: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: potassium tert-butoxide ═ 1.0:1.0:1.0, the following reaction was carried out:
1.05g of compound (III) are dissolved in 10mL of anhydrous THF, 0.27g of potassium tert-butoxide is added under nitrogen protection, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 0.29mL of 1, 4-dibromobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, and then the mixture was transferred to room temperature to react for 3 hours, after the completion of the TLC detection reaction, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added to separate the solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain 0.49g of the compound (V), with a yield of 62.5%.
Example 8: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: n-butyllithium was reacted at 1.0:1.0:1.0 as follows:
1.05g of the compound (III) is dissolved in 10mL of anhydrous THF, 0.96mL of an n-butyllithium-n-hexane solution (2.5mol/L) is added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 0.29mL of 1, 4-dibromobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, and then the mixture was transferred to room temperature to react for 3 hours, after the completion of TLC detection, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added to separate the solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain 0.48g of compound (V), with a yield of 74.0%.
Example 9: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: lithium diisopropylamide was reacted at 1.0:1.0:1.0 as follows:
1.05g of the compound (III) is dissolved in 10mL of anhydrous THF, 1.21mL of lithium diisopropylamide n-hexane solution (2.0mol/L) is added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 0.29mL of 1, 4-dibromobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, and then the mixture was transferred to room temperature to react for 3 hours, after the completion of the TLC detection reaction, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added to separate the solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain 0.59g of compound (V), with a yield of 75.3%.
Example 10: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: hexamethyldisilazane lithium amide-base (1.0: 1.0: 1.0) was reacted as follows:
1.05g of compound (III) was dissolved in 10mL of anhydrous THF, 2.46mL of lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under nitrogen, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 0.29mL of 1, 4-dibromobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, and then the mixture was transferred to room temperature to react for 3 hours, after the completion of the TLC detection reaction, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added to separate the solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain 0.61g of compound (V), with a yield of 77.9%.
Example 11: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.0) was reacted as follows:
1.05g of compound (III) was dissolved in 10mL of anhydrous THF, 2.41mL of lithium hexamethyldisilazide tetrahydrofuran solution (2.5mol/L) was added under nitrogen, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 0.32mL of 1, 4-dibromobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, and then the mixture was transferred to room temperature to react for 3 hours, after the TLC detection reaction was completed, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added to separate the solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain 0.62g of the compound (V) with a yield of 78.6%.
Example 12: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dibromobutane: hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.1) was reacted as follows:
1.05g of the compound (III) was dissolved in 10mL of anhydrous TH, 2.65mL of a lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under nitrogen, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 0.32mL of 1, 4-dibromobutane is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, the organic phases are combined, saturated ammonium chloride is used for washing, the organic phases are concentrated, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 668mg of the compound (V) with the yield of 85 percent.
Example 13: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-dichlorobutane: hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.1) was reacted as follows:
872g (2.0mmol) of compound (III) are dissolved in 10mL of anhydrous THF, 2.2mL (2.2mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) are added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 280mg (2.2mmol) of 1, 4-dichlorobutane was added, the reaction was maintained at the temperature for 10 minutes, the mixture was then transferred to room temperature for reaction for 3 hours, TLC detection was performed to complete the reaction, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added for liquid separation, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 2:1) was performed to obtain 496mg of compound (V) with a yield of 76%.
Example 14: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-diiodobutane: hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.1) was reacted as follows:
1.09g (2.5mmol) of compound (III) was dissolved in 15mL of anhydrous THF, 2.75mL (2.75mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under nitrogen, and the reaction temperature was lowered to-78 ℃. After 15 minutes, 853mg (2.75mmol) of 1, 4-diiodobutane was added, the reaction was carried out for 15 minutes while maintaining the temperature, the mixture was then transferred to room temperature to react for 3 hours, TLC detection was carried out after the reaction was completed, glacial acetic acid was used for quenching, 30mL of ethyl acetate and water were added for liquid separation, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and the compound (V) was obtained by purification through column chromatography (petroleum ether: ethyl acetate ═ 2:1) in 717mg and 88% yield.
Example 15: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-bis (p-toluenesulfonate) butane: hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.1) was reacted as follows:
872g (2.0mmol) of compound (III) are dissolved in 10mL of anhydrous THF, 2.2mL (2.2mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) are added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 876mg (2.2mmol) of 1, 4-bis (p-toluenesulfonate) butane was added, the reaction was carried out at this temperature for 10 minutes, the mixture was then allowed to shift to room temperature for 3 hours, TLC detection was carried out, the reaction was terminated, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added for liquid separation, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and column chromatography was carried out (petroleum ether: ethyl acetate ═ 2:1) to obtain 528mg of compound (V) with a yield of 81%.
Example 16: synthesis of Compound (V)
According to the molar ratio, the compound (III): 1, 4-bis (mesylate) butane: hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.1) was reacted as follows:
872g (2.0mmol) of compound (III) are dissolved in 10mL of anhydrous THF, 2.2mL (2.2mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) are added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 541mg (2.2mmol) of 1, 4-bis (methanesulfonate) butane was added, the reaction was maintained at the temperature for 10 minutes, the mixture was transferred to room temperature for reaction for 3 hours, TLC detection was performed, the reaction was quenched with glacial acetic acid, 20mL of ethyl acetate and water were added for liquid separation, the aqueous phase was extracted with ethyl acetate for 3 times, the organic phases were combined, washed with saturated ammonium chloride, the organic phase was concentrated, and column chromatography was performed (petroleum ether: ethyl acetate: 2:1) to obtain 541mg of compound (V), the yield of which was 83%.
Example 17: synthesis of (S) -2-piperidinecarboxylic acid
Compound (V): sodium hydroxide 1.0:3.0 the following reaction was carried out:
0.48g of compound (V) and 5ml of THF were added. 1.78mL of an aqueous NaOH solution (2.5mol/L) was added at 0 ℃ and the reaction was maintained at this temperature for 3 hours. After completion of the reaction by TLC, the organic phase was concentrated. The pH was adjusted to 1-2 by addition of 1M hydrochloric acid, to 6-7 with 1M sodium bicarbonate, the organic phase was concentrated and purified by column chromatography (ethyl acetate: methanol 2:1) to give 0.165g of a white solid product in 86.8% yield.
Example 18: synthesis of (S) -2-piperidinecarboxylic acid
Compound (V): potassium hydroxide 1.0:3.0 the following reaction was carried out:
0.48g of Compound (V) and 5mL of THF were added. 1.78mL of an aqueous KOH solution (2.5mol/L) was added thereto at 0 ℃ and the reaction was maintained at this temperature for 3 hours. After completion of the reaction by TLC, the organic phase was concentrated. The pH was adjusted to 1-2 by addition of 1M hydrochloric acid, to 6-7 with 1M sodium bicarbonate, the organic phase was concentrated and purified by column chromatography (ethyl acetate: methanol ═ 2:1) to give 0.159g of the product as a white solid in 83.7% yield.
Example 19: synthesis of (S) -2-piperidinecarboxylic acid
Compound (V): lithium hydroxide 1.0:3.0 the following reaction was carried out:
0.48g of Compound (V) and 5mL of THF were added. 1.78mL of an aqueous LiOH solution (2.5mol/L) was added at 0 ℃ and the reaction was maintained at this temperature for 3 hours. After completion of the reaction by TLC, the organic phase was concentrated. The pH was adjusted to 1-2 by addition of 1M hydrochloric acid, to 6-7 with 1M sodium bicarbonate, the organic phase was concentrated and purified by column chromatography (ethyl acetate: methanol 2:1) to give 0.177g of the product as a white solid in 93.2% yield.
Analytical data for (S) -2-piperidinecarboxylic acid are as follows: a white solid; m.p.269.5-270.5 deg.C (lit.272 deg.C); rf＝0.28(EtOAc:MeOH＝2:1)；
＝-25.70(c＝5,H2O),lit.
-26.20(c＝5,H2O)；1H NMR(400MHz,D2O)δ3.45(m,1H),3.33-3.22(m,1H),2.87(m,1H),2.15-2.00(m,1H),1.81-1.65(m,2H),1.63-1.39(m,3H).13C NMR(101MHz,CDCl3)δ174.5,58.9,43.6,26.5,21.8,21.5ppm.MS(ESI):C6H11NO2[M]+130.03。
It should be noted that the above-mentioned embodiments are only for illustrating the concept and features of the present invention, and the purpose of the present invention is to make the skilled person understand the present invention and implement the present invention, but not to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (6)
1. A preparation method of (S) -2-piperidinecarboxylic acid is characterized by comprising the following steps:
step A: under the catalysis of Lewis acid, carrying out condensation reaction on L-camphor sulfonamide (I) and diphenyl imine ester (II) to generate a compound (III);
the step A is operated according to the following method: dissolving L-camphor sulfonamide (I) in an organic solvent, adding Lewis acid under the protection of nitrogen, and uniformly stirring to obtain a mixed solution; dissolving diphenyl imido ester (II) in an organic solvent, dropwise adding the solution into the obtained mixed solution, reacting at 25-80 ℃ for 10-40 h, and after the reaction is finished, carrying out post-treatment on the reaction solution to obtain a compound (III); the ratio of the amounts of the L-camphorsulfonamide (I), the diphenylimido ester (II) and the Lewis acid is 1.0: 1.0-1.5; the Lewis acid is selected from trimethylaluminum, triethylaluminum, triisobutylaluminum, aluminum trichloride or triethoxyaluminum;
and B: the compound (III) and the compound (IV) are subjected to asymmetric alkylation under the action of strong alkali, imine hydrolysis under acidic condition and intramolecular cyclization to prepare a compound (V) by a one-pot method;
the step B is operated according to the following method: dissolving a compound (III) in an organic solvent, adding an alkaline substance under the protection of inert gas, cooling to-78 ℃, adding a compound (IV), reacting at room temperature for 1-6 h, and after the reaction is finished, carrying out post-treatment on a reaction solution to obtain a compound (V); the ratio of the amounts of the compound (III), the compound (IV) and the alkaline substance is 1.0: 1.0-1.5; the alkaline substance is selected from sodium hydride, potassium tert-butoxide, sodium tert-amylate, n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide; the post-treatment method comprises the following steps: after the reaction is finished, quenching the reaction liquid by glacial acetic acid, adding ethyl acetate and water for liquid separation, extracting a water phase by using ethyl acetate, combining organic phases, washing by using saturated ammonium chloride, concentrating the organic phase, performing column chromatography separation, collecting eluent containing a target compound by using a mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, evaporating the solvent, and drying to obtain a compound (V);
and C: removing the chiral auxiliary group from the compound (V) under an alkaline condition to obtain a target compound (S) -2-piperidinecarboxylic acid (TM);
the step C is operated according to the following method: dissolving the compound (V) in an organic solvent, adding an alkaline substance, reacting at-5-50 ℃ for 1-5 h, and after the reaction is finished, carrying out post-treatment on the reaction solution to obtain a target product (S) -2-piperidinecarboxylic acid (TM); the amount ratio of the compound (V) to the basic substance is 1.0: 2.0-4.0; the alkaline substance is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide or potassium carbonate;
the reaction equation is as follows:
in the formula (II), R is Me, Et or t-Bu;
in the formula (IV), X is chlorine, bromine, iodine, p-toluenesulfonyl or methanesulfonyl.
2. The process for producing (S) -2-piperidinecarboxylic acid according to claim 1, wherein the organic solvent used for dissolving L-camphorsulfonamide (I) in the step A is tetrahydrofuran, 2-methyltetrahydrofuran, toluene or dimethyl sulfoxide; the organic solvent used for dissolving the diphenylimido ester (II) is as defined above.
3. A process for the preparation of (S) -2-piperidinecarboxylic acid according to claim 1, wherein the post-treatment in step a is: after the reaction is finished, adding saturated sodium bicarbonate and water into the reaction liquid in sequence, separating the liquid, extracting the water phase by using ethyl acetate, combining organic phases, washing the organic phases by using water, concentrating the organic phases, carrying out column chromatography separation, collecting eluent containing the target compound by using a mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 4:1 as an eluent, evaporating the solvent, and drying to obtain the compound (III).
4. The process for producing (S) -2-piperidinecarboxylic acid according to claim 1, wherein the organic solvent in step B is toluene, anhydrous tetrahydrofuran or 1, 4-dioxane.
5. The process for producing (S) -2-piperidinecarboxylic acid according to claim 1, wherein the organic solvent in step C is methanol, ethanol or tetrahydrofuran.
6. A process for the preparation of (S) -2-piperidinecarboxylic acid according to claim 1, wherein the post-treatment in step C is: after the reaction is finished, concentrating the reaction liquid, adding 1M hydrochloric acid to adjust the pH to 1-2, adjusting the pH to 6-7 with 1M sodium bicarbonate, concentrating to remove the solvent, performing column chromatography separation, collecting eluent containing the target product by taking a mixed liquid of ethyl acetate and methanol in a volume ratio of 2:1 as an eluent, evaporating to remove the solvent, and drying to obtain (S) -2-piperidinecarboxylic acid (TM).
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