CN1496971A - Method of separating 3-aminovaleric nitrile conglomerate - Google Patents
Method of separating 3-aminovaleric nitrile conglomerate Download PDFInfo
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- CN1496971A CN1496971A CNA2003101028788A CN200310102878A CN1496971A CN 1496971 A CN1496971 A CN 1496971A CN A2003101028788 A CNA2003101028788 A CN A2003101028788A CN 200310102878 A CN200310102878 A CN 200310102878A CN 1496971 A CN1496971 A CN 1496971A
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- Prior art keywords
- acid
- enantiomer
- enriching
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- amino
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 150000002825 nitriles Chemical class 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 150000007524 organic acids Chemical class 0.000 claims abstract description 20
- FVPPLRDSFQDFLX-UHFFFAOYSA-N 3-aminopentanenitrile Chemical compound CCC(N)CC#N FVPPLRDSFQDFLX-UHFFFAOYSA-N 0.000 claims abstract description 7
- RPMBPYXLPIWSFJ-UHFFFAOYSA-N 2-aminopentanenitrile Chemical compound CCCC(N)C#N RPMBPYXLPIWSFJ-UHFFFAOYSA-N 0.000 claims description 87
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 19
- -1 N-protected amino Chemical group 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 13
- 238000001953 recrystallisation Methods 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 claims description 9
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- WXNXCEHXYPACJF-ZETCQYMHSA-N N-acetyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229940024606 amino acid Drugs 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical class CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims description 2
- AYMLQYFMYHISQO-QMMMGPOBSA-N (2s)-3-(1h-imidazol-3-ium-5-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CN=CN1 AYMLQYFMYHISQO-QMMMGPOBSA-N 0.000 claims description 2
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 claims description 2
- FHOAKXBXYSJBGX-YFKPBYRVSA-N (2s)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(O)=O FHOAKXBXYSJBGX-YFKPBYRVSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 2
- QUXYAXXUSVTQAP-UHFFFAOYSA-N C(C)(=O)O.NC(=N)N.COC1=CC=CC=C1 Chemical compound C(C)(=O)O.NC(=N)N.COC1=CC=CC=C1 QUXYAXXUSVTQAP-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-QTBDOELSSA-N L-gulonic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O RGHNJXZEOKUKBD-QTBDOELSSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 2
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical group 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- 238000000354 decomposition reaction Methods 0.000 claims description 2
- 150000001983 dialkylethers Chemical class 0.000 claims description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 2
- 150000002366 halogen compounds Chemical class 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 claims 1
- IMUSLIHRIYOHEV-ZETCQYMHSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@@H](C(O)=O)NC(=O)OC(C)(C)C IMUSLIHRIYOHEV-ZETCQYMHSA-N 0.000 claims 1
- LLHOYOCAAURYRL-RITPCOANSA-N (2s,3r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)OC(C)(C)C LLHOYOCAAURYRL-RITPCOANSA-N 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- KAJBMCZQVSQJDE-YFKPBYRVSA-N Nalpha-(tert-butoxycarbonyl)-l-aspartic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(O)=O KAJBMCZQVSQJDE-YFKPBYRVSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000002904 solvent Substances 0.000 description 40
- 239000000047 product Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 19
- 238000000605 extraction Methods 0.000 description 16
- 239000000725 suspension Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004821 distillation Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000007788 liquid Substances 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- RPMBPYXLPIWSFJ-YFKPBYRVSA-N (2S)-2-aminopentanenitrile Chemical compound CCC[C@H](N)C#N RPMBPYXLPIWSFJ-YFKPBYRVSA-N 0.000 description 5
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ISBHMJZRKAFTGE-ONEGZZNKSA-N (e)-pent-2-enenitrile Chemical compound CC\C=C\C#N ISBHMJZRKAFTGE-ONEGZZNKSA-N 0.000 description 2
- NWDUUMKBQJCPDE-UHFFFAOYSA-N 2-aminopentanenitrile;methanesulfonic acid Chemical compound CS(O)(=O)=O.CCCC(N)C#N NWDUUMKBQJCPDE-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- HXYXTCJDWHHCBW-UHFFFAOYSA-N acetonitrile;toluene Chemical compound CC#N.CC1=CC=CC=C1 HXYXTCJDWHHCBW-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- CFEYBLWMNFZOPB-UHFFFAOYSA-N pent-4-enenitrile Chemical compound C=CCCC#N CFEYBLWMNFZOPB-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- JCBPETKZIGVZRE-BYPYZUCNSA-N (2s)-2-aminobutan-1-ol Chemical class CC[C@H](N)CO JCBPETKZIGVZRE-BYPYZUCNSA-N 0.000 description 1
- VIUQEVFZJAFLTR-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) ethaneperoxoate Chemical compound CC(C)C1CCC(C)CC1OOC(C)=O VIUQEVFZJAFLTR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000006208 butylation Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- KAKLNLNNCNIZRC-UHFFFAOYSA-N pent-2-enenitrile Chemical compound C(C=CCC)#N.C(C=CCC)#N KAKLNLNNCNIZRC-UHFFFAOYSA-N 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Abstract
By means of a new process for the resolution of racemic 3-aminopentanenitrile, enantiomerically enriched 3-aminopentanenitrile or its salts can be obtained. For this, racemic 3-aminopentanenitrile is reacted with an enantiomerically enriched organic acid and one of the two diastereomeric salts formed is separated off and then converted into the enantiomerically enriched 3-aminopentanenitrile or its salts.
Description
Technical field
The present invention relates to decompose the amino valeronitrile of racemize 3-, and obtain the amino valeronitrile of 3-or its salt of enantiomer enriching by the organic acid reaction that makes amino valeronitrile of racemize 3-and enantiomer enriching.
Background technology
(R)-the amino valeronitrile of 3-and salt thereof are the important source material of the synthetic usefulness of medicinal activity compound.Because described medicinal activity is usually only from a kind of isomer, so preferably prepare or obtain this required enantiomer of high-optical-purity.Therefore, its objective is and to design a kind of synthetic route, make described racemize intermediate compound be divided into their enantiomer, to obtain the homochiral product.
At US-A-4, in 260,556, illustrated in the presence of metal catalyst, to make 2-pentenenitrile (pentenenitrile) and ammonia react prepare the amino valeronitrile of racemize 3-.
At US-A-4, in 496,474, disclosed the reaction of 2-pentenenitrile and alkylamine, and formed corresponding racemize cyano compound.In EP-A-0 449 297, illustrated that the improvement of the alkali reaction of 2-pentenenitrile and alkylamine under the condition that has 15-60 weight % water changes.
US-A-5,902,883 have illustrated the cyano group butylation of ammonia, alkylamine or hydrazine and 3-and allyl acetonitrile or its mixture and the method that forms the racemic alkyl amino-nitrile.
In above-mentioned prior art, do not provide the isolating prompting of gained racemic mixture under each situation.
In J.Nat.Prod.65 (2002), among the 29-31, illustrated by what begin and inferred (R) that synthetic route prepares enantiomeric pure-and (S)-amino valeronitrile of 3-by (R)-or (S)-2-amino-butanols.
Up to now, do not mention in the prior art by decomposing the amino valeronitrile of racemize 3-at all and be prepared into (R) enantiomeric pure or enriching-or (S)-amino valeronitrile of 3-.
Summary of the invention
Because from J.Nat.Prod.65 (2002), the method that only has that 29-31 learns is used to close the amino valeronitrile of 3-of enantiomer enriching is required great effort very much, so the object of the present invention is to provide a kind of appropriate method that is used for decomposing the amino valeronitrile of racemize 3-and two kinds of enantiomers of enriching.
The present invention relates to prepare the amino valeronitrile of 3-of enantiomer enriching or the method for its salt from the amino valeronitrile of racemize 3-by following steps:
1) make the organic acid reaction of amino valeronitrile of racemize 3-and enantiomer enriching, and form 3-amino-valeronitrile and two kinds of diastereoisomeric salt of described organic acid,
2) from described reaction mixture, isolate a kind of diastereoisomeric salt,
3) this diastereoisomeric salt is changed into the amino valeronitrile of 3-or its salt of enantiomer enriching.
The amino valeronitrile of the 3-of enantiomer enriching is meant the mixture of the amino valeronitrile of compound (R)-3-of described enantiomeric pure and (S)-amino valeronitrile of 3-or the amino valeronitrile of this two kinds of enantiomers (R)-3-and (S)-amino valeronitrile of 3-among the present invention, wherein, a kind of enantiomer is compared the excessive existence of another enantiomer, and this is also referred to as ee hereinafter.This enantiomer is excessive to be 2-100%ee, especially is preferably 60-100%, is more preferably 85-100%.Among the embodiment that is defined in the application of described ee value explanation is arranged.
The organic acid of the used enantiomer enriching of the present invention is the carboxylic acid of enantiomer enriching, the sulfonic acid of enantiomer enriching or the phosphoric acid of enantiomer enriching.
The preferred carboxylic acid that uses the enantiomer enriching.Can use as follows in the method for the invention:
Hydroxycarboxylic acidAs (L)-(+)-lactic acid, (L)-(-)-oxysuccinic acid and (L)-(-)-Tartaric acid and their derivative (S)-(-)-phenyl amino formyl lactic acid, (-)-O, O '-dibenzoyl-(L)-tartrate and (-)-two-O-toluoyl-(L)-tartrate, (S)-(+)-amygdalic acid and derivative (S)-anisole guanidine-acetic acid thereof and gulonic acid are as (-)-acetone-2-ketone-L-gulonic acid
Replace propionic acid, as (S)-(+)-6-methoxyl group-alpha-methyl-2-naphthyl acetic acid, (S)-(+)-2-(4-isobutyl phenenyl)-propionic acid and 2-(2-fluoro-4-xenyl)-propionic acid,
The N-protected amino acid derivativeAs (L)-N-Boc-L-Ala, the acid of (L)-N-Boc-asparagus fern oxygen, (L)-N-Boc-Histidine, (L)-N-Boc-Isoleucine, (L)-N-Boc-leucine, (L)-N-Boc-methionine(Met), (L)-N-Boc-phenylalanine, (L)-N-Boc-proline(Pro), (L)-N-Boc-Serine, (L)-N-Boc-Threonine, (L)-N-Boc-tyrosine, (L)-N-Boc-Xie Ansuan and (L)-N-ethanoyl-leucine
Menthol derivative, as (-)- oxygen base (menthoxy) acetate or (S)-(-)-2-Pyrrolidone-5-carboxylic acid.
Similarly, also can use all enantiomers of above-mentioned concrete carboxylic acid.
For the amino valeronitrile of the 3-that obtains (S)-enantiomer enriching or its salt, the carboxylic acid below should in the step 1) of the inventive method, using: (S)-anisole guanidine-acetic acid, (-)- ethoxyacetic acid with (S)-(-)-2-Pyrrolidone-5-carboxylic acid.Especially preferred (-)-diacetone-2-ketone-L-gulonic acid.Described step 2 in the inventive method) mother liquor that separates described diastereoisomeric salt formation in can further be handled, and forms the amino valeronitrile of 3-or its salt of another (R)-enantiomer enriching then accordingly.
The carboxylic acid that is preferred for preparing the amino valeronitrile of 3-of described (R)-enantiomer enriching is to replace propionic acid and N-protected amino acid derivative.Especially preferred (L)-N-Boc-Isoleucine and (L)-N-Boc-Serine.Described step 2 in the inventive method) mother liquor that separates described diastereoisomeric salt formation in can further be handled, and forms the amino valeronitrile of 3-or its salt of another (S)-enantiomer enriching then accordingly.
Can buy organic acid such as carboxylic acid, sulfonic acid or the phosphoric acid of such enantiomer enriching from the market, be preferably carboxylic acid.In the present invention, term " organic acid/carboxylic acid of enantiomer enriching/sulfonic acid/phosphoric acid " is meant the organic acid/carboxylic acid/sulfonic acid/phosphoric acid of each enantiomeric pure or the mixture of described each enantiomer, wherein a kind of enantiomer is compared the excessive existence of another enantiomer, and this is also referred to as ee hereinafter.This ee value is 10-100%, especially is preferably 60-100%, is more preferably 95-100%.
In the step 1) of the inventive method, make the organic acid reaction of amino valeronitrile of 3-and described enantiomer enriching form two kinds of diastereoisomeric salt can be easily 0 ℃ to described reactant decomposition temperature, be preferably in 20-120 ℃ the temperature range and carry out.Described reaction especially should be carried out under 60-80 ℃.
Reaction in the described step 1) is carried out in the presence of solvent usually.Solvent for use can be polarity or non-polar organic solvent, and for example ether is preferably dialkyl ether, especially is preferably diethyl ether and t-butyl methyl ether; Perhaps cyclic ethers, especially tetrahydrofuran (THF); Straight or branched C
1-C
10-alcohol is preferably methyl alcohol, ethanol, n-propyl alcohol or Virahol; Straight or branched C
1-C
10-alcohol derivate is as partially halogenated C
1-C
10-alcohol; Monocycle and polycyclic aromatic carbocyclic ring and heterocyclic hydrocarbon are preferably toluene; Aliphatic series C
1-C
10-hydrocarbon; And functionalized hydrocarbon such as nitrile, for example acetonitrile, carboxylicesters are preferably ethyl acetate, ketone and halogen compounds.The amount of solvent for use is not critical.
Can use described reactant with any required amount is the organic acid and the amino valeronitrile of described racemize 3-of enantiomer enriching.Should use the normal organic acid of 0.1-1, especially use suitable about 0.5 equivalent organic acid.
By making the organic acid reaction of amino valeronitrile of racemize 3-and described enantiomer enriching, form the amino valeronitrile of 3-and two kinds of diastereoisomeric salt of organic acid in the method for the invention.Described diastereoisomeric salt is for example:
(S)-the amino valeronitrile (L)-(-) of 3--diacetone-2-ketone gulose salt,
(S)-the amino valeronitrile (S) of 3--1-methoxyl group-1-phenylacetic acid salt,
(R)-the amino valeronitrile N-Boc-L-of 3-Isoleucine salt,
(R)-the amino valeronitrile N-Boc-L-of 3-leucine salt,
(R)-the amino valeronitrile N-Boc-L-of 3-Serine salt,
(S)-the amino valeronitrile (S)-(-) of 3--2-Pyrrolidone-5-carboxylate salt
(R)-the amino valeronitrile (S)-(+) of 3--6-methoxyl group-alpha-methyl-2-naphthyl acetic acid salt,
(R)-the amino valeronitrile (S)-(+) of 3--2-(4-isobutyl phenenyl)-propionic salt (propion-carboxylate),
(R)-the amino valeronitrile (S)-(-) of 3--O-(phenyl amino formyl)-lactic acid salt,
(R)-the amino valeronitrile (-) of 3--O, O '-dibenzoyl-L-tartaric acid salt,
(R)-the amino valeronitrile (-) of 3--two-O-toluoyl base-L-tartrate,
(S)-amino valeronitrile (-) of 3-ethoxyacetic acid salt,
(R)-the amino valeronitrile N-of 3-ethanoyl-L-leucine salt,
And their enantiomers separately.
In the reaction of step 1), one of described two kinds of diastereoisomeric salt precipitate with the solid form usually.In step 2) in, by filtration or centrifugation this diastereoisomeric salt is separated from described reaction mixture usually.
If need, described remove by filter described diastereoisomeric salt after residual reaction mixture can process, make described second kind of diastereoisomeric salt.
In the replacement embodiment of the inventive method, in the step 3) of this method, make before the amino valeronitrile of 3-or its salt of described enantiomer enriching, make step 2) in to carry out the one or many recrystallization as the isolated diastereoisomeric salt of solid be favourable.For these recrystallizations, it is suitable using the solvent of mentioning in step 1) verified.
Then in step 3, make the amino valeronitrile of 3-or its salt of required enantiomer enriching from the amino valeronitrile of the 3-of required enantiomer enriching or the isolated diastereoisomeric salt of its salt.This can be undertaken by chemical mode.
For this reason, make described diastereoisomeric salt and alkali reaction, and extract with organic solvent after holding; Described alkali is stronger than the amine functional group in the amino valeronitrile of 3-, for example alkali metal hydroxide, alkaline earth metal hydroxides, be preferably sodium hydroxide or potassium hydroxide, alkaline carbonate or alkaline earth metal carbonate are preferably yellow soda ash or salt of wormwood.Solvent for use can be above-mentioned organic solvent.Should use alkaline solution at 0-100 ℃ of following 1-5N.Especially the preferred sodium hydroxide solution that uses at 15-40 ℃ of following 1N, and extract with methylene dichloride subsequently.In the process that makes described diastereoisomeric salt and alkali reaction, make the amino valeronitrile of 3-of described enantiomer enriching, itself is free alkali.
Perhaps, described diastereoisomeric salt also can react with strong acid in organic solvent, and described strong acid is stronger than the organic acid of enantiomer enriching used in the step 1).About this point, for example can use hydrochloric acid, hydroiodic acid HI, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid or methylsulfonic acid.Preferred hydrochloric acid, Hydrogen bromide, sulfuric acid and the methylsulfonic acid of using.Step 3) be reflected at 0 ℃ of temperature of decomposing to described reactant, be preferably 20-150 ℃, especially be preferably in 40-90 ℃ the temperature range and carry out.Used solvent can be above-mentioned organic solvent.Should use ether, especially t-butyl methyl ether is as solvent.Perhaps, directly make the amino valeronitrile of 3-of required enantiomer enriching with the salt of described strong acid.Make the salt of the amino valeronitrile of following 3-, for example:
The enantiomer enriching fluoridize the amino valeronitrile of 3-
The amino valeronitrile of the chlorination 3-of enantiomer enriching
The amino valeronitrile of the bromination 3-of enantiomer enriching
The amino valeronitrile of the iodate 3-of enantiomer enriching
The amino valeronitrile vitriol of the 3-of enantiomer enriching
The amino valeronitrile hydrosulfate of the 3-of enantiomer enriching
The amino valeronitrile phosphoric acid salt of the 3-of enantiomer enriching
The amino valeronitrile hydrophosphate of the 3-of enantiomer enriching
The amino valeronitrile dihydrogen phosphate of the 3-of enantiomer enriching
The amino valeronitrile nitrate of the 3-of enantiomer enriching
The amino valeronitrile perchlorate of the 3-of enantiomer enriching.
Described salt can be used to prepare the medicinal activity compound.
Embodiment
Embodiment:
In following all embodiment, the optical purity of the amino valeronitrile of described (R)-or (S)-3-determines with vapor-phase chromatography (gamma-Dex 225) on the chiral column material, and in order to undefined ee (enantiomer is excessive) (S) or (R) value represent.
Herein, described ee value is by following formulate:
In the formula, ee (S) or ee (R) are the optical purities of enantiomer S or R, and m (S) is the amount of enantiomer S, and m (R) is the amount of enantiomer R.(embodiment: for racemoid: R=S=＞ee=0; For pure (S) form: ee (S)=100%; Ratio S: R=9: 1, ee (S)=80%)
Embodiment 1:
Use (-)-diacetone-2-ketone-L-gulonic acid to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in each solvent of measuring shown in the table 1a.1.77g (7.65mmol) (-)-diacetone-2-ketone-L-gulonic acid is added in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.The productive rate and the ee value of gained are listed among the table 1a.
Table 1a
| Solvent | ???EtOH | Toluene | ????MTBE | ??EtOAc | ??CH 3CN | ???MeOH |
| Amount (ml) | ????60 | ????75 | ????90 | ????40 | ????75 | ????45 |
| ??ee(S)(％) | ????69.5 | ????35.2 | ????17.6 | ????38.6 | ????42.8 | ????57.3 |
| Productive rate (%) | ????33.4 | ????40.0 | ????56.0 | ????37.0 | ????37.0 | ????31.0 |
EtOH=ethanol, MTBE=methyl tertiary butyl ether, EtOAc=ethyl acetate, MeOH=methyl alcohol
Embodiment 1b
By in as the ethanol of solvent to make the amino valeronitrile of racemize 3-and (-)-diacetone-2-ketone-L-gulonic acid reaction with embodiment 1 similar mode, make the throw out of diastereoisomeric salt.Carry out recrystallization again, can further improve the optical purity and the ee value of the amino valeronitrile of 3-of described (S) enantiomer enriching thus.After carrying out embodiment 1 similar extraction, described ee (s) value that is used for diastereoisomeric salt of recrystallization is 59.6.
In order to carry out recrystallization, under boiling temperature, the diastereoisomeric salt of 1.5g is dissolved in each solvent of measuring shown in the table 1b.As sedimentary salt during further processing cooling as described in the embodiment 1.
Table 1b
| Solvent | ???EtOH | ???CH 3CN | Toluene | ???MTBE | ???EtOAc | ???MeOH |
| Amount (ml) | ????40 | ????40 | ????50 | ????40 | ????50 | ????35 |
| ?ee(S)(％) | ????67.8 | ????65.6 | ????61.5 | ????61.3 | ????64.2 | ????82.4 |
| Productive rate (%) | ????93.3 | ????94.7 | ????98.0 | ????98.7 | ????94.4 | ????68.0 |
Embodiment 2
Use (S)-anisole guanidine-acetic acid to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in each solvent of the amount of Table 2.With 1.27g (7.64mmol) (S)-the anisole guanidine-acetic acid adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
The productive rate and the ee value of gained are listed in the table 2.
Table 2
| Solvent | ???EtOH | Toluene | ???MTBE | ???EtOAc | ???CH 3CN | ????MeOH |
| Amount (ml) | ????60 | ????40.0 | ????45 | ????30 | ????15 | ????15 |
| ?ee(S)(％) | ????50.7 | ????54.7 | ????55.8 | ????49.7 | ????471.6 | ????81.6 |
| Productive rate (%) | ????40.0 | ????28.0 | ????3.0 | ????31.0 | ????53.0 | ????15.0 |
Embodiment 3
Use (S)-(+)-6-methoxyl group-alpha-methyl-2-naphthyl acetic acid to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in the 10ml ethanol.With 1.76g (7.64mmol) (S)-(+)-6-methoxyl group-alpha-methyl-2-naphthyl acetic acid adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
Make the amino valeronitrile of 0.60g (40.0%) colourless liquid (R)-3-.Described ee (R) value is 27.4%.
Embodiment 4
Use (S)-(+)-2-(4-isobutyl phenenyl)-propionic acid to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in the 10ml ethanol.With 1.58g (7.64mmol) (S)-(+)-2-(4-isobutyl phenenyl)-propionic acid adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
Make the amino valeronitrile of 0.78g (52.0%) colourless liquid (R)-3-.Described ee (R) value is 2.4%.
Embodiment 5
Use (L)-N-Boc-Isoleucine to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in each solvent of measuring shown in the table 3a.With 1.77g (7.64mmol) (L)-the N-Boc-Isoleucine adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
The productive rate and the ee value of gained are listed among the table 3a.
Table 3a
| Solvent | ??EtOH | Toluene | ???MTBE | ??EtOAc | ??CH 3CN |
| Amount (ml) | ????10 | ????15 | ????15 | ????15 | ????15 |
| ee(R)(％) | ????92.2 | ????68.7 | ????85.7 | ????81.4 | ????82.5 |
| Productive rate (%) | ????6.7 | ????42.0 | ????35.0 | ????36.0 | ????29.0 |
Embodiment 5b
By in as the ethanol of solvent to make the amino valeronitrile of racemize 3-and (L)-N-Boc-Isoleucine reaction with embodiment 5 similar modes, make the throw out of diastereoisomeric salt.Carry out recrystallization again, can further improve the optical purity and the ee value of the amino valeronitrile of 3-of described (R) enantiomer enriching thus.After carrying out embodiment 5 similar extractions, described ee (R) value that is used for diastereoisomeric salt of recrystallization is 90.4.
In order to carry out recrystallization, under boiling temperature, the diastereoisomeric salt of 1.25g is dissolved in each solvent of measuring shown in the table 3b.As sedimentary salt during further processing cooling as described in the embodiment 5.
Table 3b
| Solvent | ???EtOH | ???CH 3CN | Toluene | ???MTBE | ???EtOAc | ???MeOH |
| Amount (ml) | ????4 | ????10 | ????5 | ????45 | ????5 | ????2 |
| ?ee(R)(％) | ????98.5 | ????98.3 | ????95.3 | ????98.7 | ????96.8 | ????98.0 |
| Productive rate (%) | ????34.9 | ????32.2 | ????80.6 | ????69.8 | ????56.4 | ????29.5 |
Embodiment 6
Use (L)-N-Boc-Isoleucine to take racemoid apart, precipitate the amino valeronitrile mesylate of 3-of enantiomer enriching afterwards
The amino valeronitrile of 33.05g (336.7mmol) 3-is dissolved in the 830ml t-butyl methyl ether.With 39.0g (168.6mmol) (L)-the N-Boc-Isoleucine adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and washing 2 times with each 50ml t-butyl methyl ether.The described product of recrystallization once from the 1650ml t-butyl methyl ether.Be cooled to after 20 ℃, bleeding solids removed by filtration, and washing 2 times with the 50ml t-butyl methyl ether.
Make the 35.0g colorless solid.
This material is suspended in the 700ml t-butyl methyl ether.In this suspension, drip 10.22g (106.3mmol) methylsulfonic acid then.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, in the down solids removed by filtration of bleeding, with each 25ml t-butyl methyl ether washing 2 times, and under 50 ℃ under reduced pressure drying 10 hours.
Make 19.8g (30.3%) (R)-the amino valeronitrile mesylate of 3-colorless solid.
In order to determine described optical purity, the 1g products therefrom is dissolved in the 20ml 1N sodium hydroxide solution, and with twice of the described solution of each 10ml dichloromethane extraction.Under reduced pressure,, from residue, determine described ee value by gas-chromatography except that after desolvating.Described ee (R) value is 99.0%.
NMR(400MHz，D
2O)：δ(ppm)＝1.00(t，J＝7.5Hz，3H)，1.83(dt，J＝7.3/7.3Hz，2H)，2.80(s，3H)，3.02(d，J＝5.3Hz，2H)，3.63(tt，J＝6.3/6.3Hz，1H)，4.75(s，3H)。
Melting range: 109-111 ℃
Ultimate analysis: calculated value: C=37.11 observed value: C=37.3
Calculated value: H=7.27 observed value: H=7.4
Calculated value: N=14.42 observed value: N=14.1
Calculated value: S=16.48 observed value: S=16.4
Embodiment 7:
Use (L)-N-Boc-Serine to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in each solvent of the amount of Table 4.With 1.57g (7.64mmol) (L)-the N-Boc-Serine adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
The productive rate and the ee value of gained are listed in the table 4.
Table 4
| Solvent | ???EtOH | Toluene | ???MTBE | ???EtOAc | ??CH 3CN | ??MeOH |
| Amount (ml) | ????10 | ????60 | ????30 | ????60 | ????60 | ????8 |
| ?ee(R)(％) | ????70.0 | ????70.7 | ????76.0 | ????80.4 | ????63.3 | ????86.8 |
| Productive rate (%) | ????29.3 | ????26.0 | ????43.0 | ????30.0 | ????32.0 | ????55.0 |
Embodiment 8:
Use (S)-(-)-phenyl amino formyl lactic acid to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in the 10ml ethanol.With 1.60g (7.64mmol) (S)-(-)-this together solution of phenyl amino formyl lactic acid part in.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
Make the amino valeronitrile of 0.16g (10.6%) colourless liquid (R)-3-.Described ee (R) value is 23.1%.
Embodiment 9:
Use (-)-O, O '-dibenzoyl-(L)-tartrate is taken racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in the 20ml ethanol.With 2.74g (7.64mmol) (-)-O, O '-dibenzoyl-(L)-tartrate adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
Make the amino valeronitrile of 0.84g (56.0%) colourless liquid (R)-3-.Described ee (R) value is 4.4%.
Embodiment 10:
Use (-)-two-O-toluoyl-(L)-tartrate to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in the 15ml ethanol.2.95g (7.64mmol) (-)-two-O-toluoyl-(L)-tartrate is added in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
Make the amino valeronitrile of 1.04g (69.3%) colourless liquid (R)-3-.Described ee (R) value is 17.4%.
Embodiment 11:
Use (-)- base to take racemoid apart for acetate
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in the 10ml ethanol.1.64g (7.64mmol) (-)- ethoxyacetic acid is added in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
Make the amino valeronitrile of 0.30g (20.0%) colourless liquid (S)-3-.Described ee (S) value is 55.2%.
Embodiment 12:
Use (S)-(-)-2-Pyrrolidone-5-carboxylic acid to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in each solvent of the amount of Table 5.With 0.99g (7.6mmol) (S)-(-)-2-Pyrrolidone-5-carboxylic acid adds in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
The productive rate and the ee value of gained are listed in the table 5.
Table 5
| Solvent | ???EtOH | ???MTBE | ???EtOAc | ??CH 3CN |
| Amount (ml) | ????15 | ????15 | ????15 | ????15 |
| ??ee(S)(％) | ????55.2 | ????39.0 | ????35.9 | ????26.3 |
| Productive rate (%) | ????29.3 | ????43.0 | ????30.0 | ????32.0 |
Embodiment 13:
Use N-ethanoyl-(L)-leucine to take racemoid apart
The amino valeronitrile of 1.50g (15.3mmol) 3-is dissolved in each solvent of measuring shown in the table 6a.1.32g (7.64mmol) N-ethanoyl-(L)-leucine is added in this solution together.Heat described suspension to seething with excitement 5 minutes.Be cooled to after 20 ℃, removing by filter the product that forms as solid, and under 40 ℃, drying is 10 hours under reduced pressure.Then, described product is dissolved in the sodium hydroxide solution of 20ml 1N.With the described water of each 10ml dichloromethane extraction 2 times.The solvent of the organic phase of described merging is removed in distillation under reduced pressure.
The productive rate and the ee value of gained are listed among the table 6a.
Table 6a
| Solvent | ???EtOH | Toluene | ???MTBE | ???EtOAc | ???CH 3CN | ???MeOH |
| Amount (ml) | ????15 | ????25 | ????25 | ????25 | ????25 | ????15 |
| ?ee(R)(％) | ????66.4 | ????46.7 | ????50.7 | ????42.4 | ????41.2 | ????71.1 |
| Productive rate (%) | ????46.0 | ????47.0 | ????50.0 | ????48.0 | ????45.0 | ????25.0 |
Embodiment 13b
By in as the ethanol of solvent to make the amino valeronitrile of racemize 3-and N-ethanoyl-(L)-leucine reaction with embodiment 13 similar modes, make the throw out of diastereoisomeric salt.Carry out recrystallization again, can further improve the optical purity and the ee value of the amino valeronitrile of 3-of described (R)-enantiomer enriching thus.After carrying out embodiment 13 similar extractions, described ee (R) value that is used for diastereoisomeric salt of recrystallization is 56.0.
In order to carry out recrystallization, under boiling temperature, the diastereoisomeric salt of 1.2g is dissolved in each solvent of measuring shown in the table 6b.As sedimentary salt during further processing cooling as described in the embodiment 13.
Table 1b
| Solvent | ???EtOH | ??CH 3CN | ???MeOH |
| Amount (ml) | ????20 | ????60 | ????8 |
| ??ee(R)(％) | ????78.8 | ????65.3 | ????87.4 |
| Productive rate (%) | ????50.7 | ????62.2 | ????36.9 |
Claims (15)
1. one kind makes the amino valeronitrile of 3-of enantiomer enriching or the method for its salt, and described method is made by the amino valeronitrile of racemize 3-by following steps:
1) make the organic acid reaction of the amino valeronitrile of racemize 3-and enantiomer enriching, formation 3-amino-valeronitrile and two kinds of diastereoisomeric salt of described organic acid,
2) from described reaction mixture, isolate a kind of diastereoisomeric salt,
3) this diastereoisomeric salt is transformed the amino valeronitrile of 3-or its salt of enantiomer enriching.
2. the described method of claim 1 is characterized in that, the organic acid of used enantiomer enriching is the carboxylic acid of enantiomer enriching, the sulfonic acid of enantiomer enriching or the phosphoric acid of enantiomer enriching.
3. claim 1 or 2 described methods; it is characterized in that the carboxylic acid of used enantiomer enriching is the replacement propionic acid of enantiomer enriching hydroxycarboxylic acid or derivatives thereof, enantiomer enriching, the N-protected amino acid of enantiomer enriching or the menthol derivative of enantiomerism enriching.
4. each described method of claim 1-3; it is characterized in that; use (L)-(+)-lactic acid; (L)-(-)-oxysuccinic acid; (L)-(-)-tartrate or their derivative; (S)-(-)-phenyl amino formyl lactic acid; (-)-O; O '-dibenzoyl-(L)-tartrate; (-)-two-O-is right-toluoyl-(L)-tartrate; (S)-(+)-amygdalic acid; (S)-the anisole guanidine-acetic acid; gulonic acid is preferably (-)-diacetone-2-ketone-L-gulonic acid; (S)-(+)-6-methoxyl group-alpha-methyl-2-naphthyl acetic acid; (S)-(+)-2-(4-isobutyl phenenyl)-propionic acid and 2-(2-fluoro-4-xenyl)-propionic acid; (L)-the N-Boc-L-Ala; (L)-the N-Boc-aspartic acid; (L)-the N-Boc-Histidine; (L)-the N-Boc-Isoleucine; (L)-the N-Boc-leucine; (L)-the N-Boc-methionine(Met); (L)-the N-Boc-phenylalanine; (L)-the N-Boc-proline(Pro); (L)-the N-Boc-Serine; (L)-the N-Boc-Threonine; (L)-N-Boc-tyrosine; (L)-and N-Boc-Xie Ansuan and (L)-N-ethanoyl-leucine, (-)- ethoxyacetic acid or (S)-(-)-2-Pyrrolidone-5-carboxylic acid or their enantiomers separately.
5. the method for the amino valeronitrile of the 3-of each described preparation (S)-enantiomer enriching of claim 1-4 or its salt, it is characterized in that, the carboxylic acid of used enantiomer enriching is (S)-anisole guanidine-acetic acid, (-)-lid ethoxyacetic acid and (S)-(-)-2-Pyrrolidone-5-carboxylic acid, is preferably (-)-diketone-2-ketone-L-gulonic acid.
6. the method for the amino valeronitrile of the 3-of each described making (R)-enantiomer enriching of claim 1-5 or its salt; it is characterized in that; the carboxylic acid of used enantiomer enriching is to replace propionic acid or N-protected amino acid derivative, is preferably (L)-N-Boc-Isoleucine or (L)-N-Boc-Serine.
7. each described method of claim 1-6 is characterized in that, is reflected at 0 ℃ to described reactant decomposition temperature in the step 1), is preferably 20-120 ℃, especially should carry out under 60-80 ℃.
8. each described method of claim 1-7 is characterized in that, carries out under the existence that is reflected at polarity or non-polar organic solvent in the step 1), and described organic solvent is preferably ether, especially is preferably dialkyl ether, is specially diethyl ether and t-butyl methyl ether; Perhaps cyclic ethers specifically is a tetrahydrofuran (THF); Straight or branched C
1-C
10-alcohol especially is preferably methyl alcohol, ethanol, n-propyl alcohol or Virahol; Straight or branched C
1-C
10-alcohol derivate especially is preferably partially halogenated C
1-C
10-alcohol; Monocycle and polycyclic aromatic carbocyclic ring and heterocyclic hydrocarbon especially are preferably toluene; Aliphatic series C
1-C
10-hydrocarbon and functionalized hydrocarbon especially are preferably nitrile, specifically are acetonitrile, carboxylicesters, are preferably ethyl acetate, ketone and halogen compounds.
9. each described method of claim 1-8 is characterized in that, uses the 0.1-1 equivalent, especially should use about 0.5 normal organic acid.
10. each described method of claim 1-9 is characterized in that, this diastereoisomeric salt is undertaken by making described diastereoisomeric salt and alkali reaction to the conversion of the amino valeronitrile of the 3-of enantiomer enriching or its salt in step 3); Described alkali is stronger than the amine functional group in the amino valeronitrile of 3-, and it is preferably alkali metal hydroxide or alkaline earth metal hydroxides, is specially sodium hydroxide or potassium hydroxide; Alkaline carbonate or alkaline earth metal carbonate are specially yellow soda ash or salt of wormwood.
11. the method for the salt of the amino valeronitrile of each described 3-that makes the enantiomer enriching of claim 1-10, it is characterized in that, in step 3), by making described diastereoisomeric salt and institute than the strong acid-respons of organic acid of used enantiomer enriching in the step 1), and the salt of the amino valeronitrile of 3-that forms the enantiomer enriching of this acid makes the salt of the 3-amino valeronitrile of described enantiomer enriching.
Make the method for muriate, bromide, vitriol or mesylate of the amino valeronitrile of 3-of enantiomer enriching 12. claim 11 is described, it is characterized in that, in step 3), use hydrochloric acid, hydroiodic acid HI, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid or methylsulfonic acid.
13. each described method of claim 1-12 is characterized in that, by filtering from step 2) described in isolate diastereoisomeric salt the reaction mixture.
14. the described method of claim 13 is characterized in that, in order to make second kind of diastereoisomeric salt, handles in step 2) in remove by filter residual reaction mixture after diastereoisomeric salt.
15. each described method of claim 1-14 is characterized in that, in step 2) in from described reaction mixture isolated diastereoisomeric salt after carrying out step 3), carry out the one or many recrystallization again.
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| CNA2003101028788A CN1496971A (en) | 2002-10-22 | 2003-10-22 | Method of separating 3-aminovaleric nitrile conglomerate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910124B (en) * | 2007-12-27 | 2013-07-03 | 东丽精细化工株式会社 | Optically active 3-aminopyrrolidine salt, process for production thereof, and method for optical resolution of 3-aminopyrrolidine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101910124B (en) * | 2007-12-27 | 2013-07-03 | 东丽精细化工株式会社 | Optically active 3-aminopyrrolidine salt, process for production thereof, and method for optical resolution of 3-aminopyrrolidine |
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