CN102627587A - Method for preparing 1-substituted tramiprosate from alpha, beta-unsaturated nitrile - Google Patents
Method for preparing 1-substituted tramiprosate from alpha, beta-unsaturated nitrile Download PDFInfo
- Publication number
- CN102627587A CN102627587A CN2012101134682A CN201210113468A CN102627587A CN 102627587 A CN102627587 A CN 102627587A CN 2012101134682 A CN2012101134682 A CN 2012101134682A CN 201210113468 A CN201210113468 A CN 201210113468A CN 102627587 A CN102627587 A CN 102627587A
- Authority
- CN
- China
- Prior art keywords
- homotaurine
- preparation
- acid
- replaces
- reduction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical class NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 22
- 150000002825 nitriles Chemical class 0.000 title claims abstract description 12
- 229960003570 tramiprosate Drugs 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 claims abstract description 35
- 230000009467 reduction Effects 0.000 claims abstract description 17
- 230000003647 oxidation Effects 0.000 claims abstract description 12
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 12
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 acetate cyanic acid mercaptan ester Chemical class 0.000 claims description 74
- 238000006722 reduction reaction Methods 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000007259 addition reaction Methods 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 claims description 2
- 150000004967 organic peroxy acids Chemical class 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 229940005605 valeric acid Drugs 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000011033 desalting Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000005648 plant growth regulator Substances 0.000 abstract description 2
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract 1
- LQFBACQDOOBRFT-UHFFFAOYSA-N acetic acid;thiocyanic acid Chemical compound SC#N.CC(O)=O LQFBACQDOOBRFT-UHFFFAOYSA-N 0.000 abstract 1
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 229940125532 enzyme inhibitor Drugs 0.000 abstract 1
- 239000002532 enzyme inhibitor Substances 0.000 abstract 1
- 235000015097 nutrients Nutrition 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 239000004094 surface-active agent Substances 0.000 abstract 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000004799 bromophenyl group Chemical group 0.000 description 6
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 3
- ZWKNLRXFUTWSOY-QPJJXVBHSA-N (e)-3-phenylprop-2-enenitrile Chemical compound N#C\C=C\C1=CC=CC=C1 ZWKNLRXFUTWSOY-QPJJXVBHSA-N 0.000 description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AOSFMYBATFLTAQ-UHFFFAOYSA-N 1-amino-3-(benzimidazol-1-yl)propan-2-ol Chemical compound C1=CC=C2N(CC(O)CN)C=NC2=C1 AOSFMYBATFLTAQ-UHFFFAOYSA-N 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical class NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 201000007930 alcohol dependence Diseases 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 239000000496 cardiotonic agent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940077927 altace Drugs 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000005902 aminomethylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 150000008053 sultones Chemical class 0.000 description 1
- 239000002512 suppressor factor Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing 1-substituted tramiprosate from alpha, beta-unsaturated nitrile. The method comprises the following steps of: performing addition on alpha, beta-unsaturated nitrile through thioacetic acid to obtain corresponding cyano mercaptan acetate; and performing reduction and oxidation to obtain 1-substituted tramiprosate. The preparation method has the advantages of simple and readily available raw materials, convenience in operation, no need of complex desalting purification process and particular suitability for large-scale industrial production. The obtained compound can be used as a nutrient substance, a medicament, an enzyme inhibitor, an antibacterial agent, a surfactant, a plant growth regulator, a raw material for preparing sulphonyl peptide and the like.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the preparation method that 1-replaces Homotaurine.
Background technology
Homotaurine, promptly the 3-aminopropanesulfonic acid is a kind of aminoalkyl group sulfonic acid, it structurally is similar to the neurotransmitter γ-An Jidingsuan, discovers that it has the anticonvulsion effect of γ-An Jidingsuan (Fariello, R. G.; Golden, G. T.; Pisa, M.
Neurology 1982,
32, 241).Homotaurine can also prevent and treat the sclerosis of conjunctiva sheath, anti-alopecia, and treatment alcohol dependence disease, the oxidation that suppresses catecholamine in the body, protection DNA avoid oxidative damage, improve memory, cardiac stimulant, effect (Mayer, J. such as hypotensive; Cook, A. M.
J. Bacteriol.
2009,
191, 6052; Rouhani, S.; Dallava Santucci, J.; Bajenaru, O.; Emmanouilidis, E.; Tran, G.; Manicom, R.; Dinhxuan, A. T.; Poenaru, S.
Pharmacol., Biochem. Behav.
1998,
59, 955; Biasetti, M.; Dawson, R. Jr.
Amino Acids. 2002,
22, 351; Messina, S. A.; Dawson, R. Jr.
Adv. Exp. Med. Biol. 2000,
483, 355).Since its can with Zulkovsky starch appearance protein binding, inhibition can cause the formation of the sedimentary neurotoxin of amyloid patch in the brain, is used to treat Alzheimer (Alzheimer) sick (Aisen, P.S.; Gauthier, S.; Vellas, B.; Eriand, R.; Saumier, D.; Laulin, J.; Garceau, D.
Curr. Alzheimer Res. 2007,
4, 473; Gauthier, S.; Aisen, P. S.; Ferris, S. H.; Saumier, D.
J. Nutr. Health Aging. 2009,
13, 550).
The replacement Homotaurine of different structure has different biological functions, and the effective and general compound method of the multifarious replacement Homotaurine of development structure has extremely important meaning for new drug development.The Homotaurine of having reported comprises with the preparation method who replaces Homotaurine: through hydrosulphite or sulphite to the nucleophilic substitution preparation of 3-halogenated amine (Zhang Qiucai, fourth is quick, Li Wenzhong, Cheng Zhipeng, beam is grand,
The Chinese invention patent prospectus, CN 1451652A; Sen, N. P.
Can. J. Chem.
1962,
40, 2189); Through sulphite the Michael addition of unsaturated nitrile is restored and to prepare (Ling Jianhong, xuwei,
The Chinese invention patent prospectus, CN 101362709A; Li, C. S.; Howson, W.; Dolle, R. E.
Synthesis 1991,
3, 244); Michael addition through bisulfite salt pair methacrolein restores amination and prepares (Smith, C. W.; Norton, D. G.; Ballard, S. A.
J. Am. Chem. Soc.
1953,
75, 748); Substituted allylamine sulfonation prepares (Abbenante, G to the 2-aryl through ammonium bisulfite; Prager, R. H.
Aust. J. Chem.
1990,
43, 213; Abbenante, G; Prager, R. H.
Aust. J. Chem.
1992,
45, 1791); Through ammonium bisulfite the cinnamic replacement of α-brooethyl, addition and reduction preparation or thioacetic acid are prepared (Abbenante, G to cinnamic addition of α-aminomethyl and oxidation; Prager, R. H.
Aust. J. Chem.
1992,
45, 1801); Through replacement preparation (Millan, the D. S. of primary amine to 3-bromine third SULPHURYL CHLORIDE; Prager, R. H.
Aust. J. Chem.
2000,
53, 615); Through sulphite to the preparation of the nucleophilic substitution of aminopropanol sulphonate (congratulate rut, Liu loses pine, and red legend is outstanding, Shao Xueqing, Yan Zhihua, Gu Renhua, Qian Jixin, Zhao Ting,
The Chinese invention patent prospectus, CN 101759605A); To 1, the nucleophilic ring opening of 3-third sultone prepares (Erman, Wm. F. through ammonia, nitrine or primary amine; Kretschmar, H. C.
J. Org. Chem. 1961 , 26,4841; Zhang Qiucai, fourth is quick, Li Wenzhong, Cheng Zhipeng, beam is grand,
The Chinese invention patent prospectus, CN 1442405A; Dieter, E.; Wacharee, H.
Synthesis 2004 , 17,2910; Kong, X.; Migneault, D.; Wu, X.
WO 2004113391; Kong, X.; Migneault, D.; Valade, I.; Wu, X.; Gervais, F.
US 20070010573).
Existing these methods can be used for synthesizing the Homotaurine or derivatives thereof, but often because the raw material restriction can only be synthesized the replacement Homotaurine of some structure type, the desalting purifying process that maybe need bother.The present invention passes through thioacetic acid to α; The addition of alpha, beta-unsaturated nitriles obtains corresponding acetate cyanic acid mercaptan ester; Obtain 1-replacement Homotaurine through reduction and oxidation again; The final step of this method is a salt-free process, and the convenient separation and purification that water-soluble ionic-type product 1-is replaced Homotaurine can be used for preparing highly purified 1-and replaces Homotaurine.
Summary of the invention
The purpose of this invention is to provide the salt-free preparation method that a kind of 1-replaces Homotaurine, this preparing method's raw material is simple and easy to, and is the short-cut method that a kind of effective preparation 1-that is suitable for large-scale commercial prodn replaces Homotaurine.
Technical scheme of the present invention is following:
A kind of 1-replaces the preparation method of Homotaurine, and to α, the addition of alpha, beta-unsaturated nitriles obtains corresponding acetate cyanic acid mercaptan ester through thioacetic acid, obtains 1-replacement Homotaurine through reduction and oxidation again.
In the above-mentioned reaction formula:
R representes alkyl, naphthenic base, cycloalkylalkyl, aryl, aralkyl etc., and wherein the alkyl in alkyl and the aralkyl all can be ring-type, and naphthenic base and aryl can be fused rings.
Wherein said alkyl is meant the straight or branched alkyl with 1～15 carbon atom, for example: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, neo-pentyl, hexyl, isohexyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji etc.The straight or branched alkyl that preferably has 1～12 carbon atom especially preferably has the straight or branched alkyl of 1～9 carbon atom, most preferably has the straight or branched alkyl of 1～6 carbon atom.
Described naphthenic base is meant the cyclic alkyl with 3～15 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc., preferably cyclopropyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group.
Described cycloalkylalkyl is meant the cyclic alkyl with 4～15 carbon atoms; For example cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl, ring octyl group methyl, cyclopropyl ethyl, cyclobutyl ethyl, cyclopentyl ethyl, cyclohexyl ethyl, suberyl ethyl, ring octyl group ethyl, cyclopropyl propyl group, cyclobutyl propyl group, cyclopentyl propyl group, cyclohexyl propyl group, suberyl propyl group, ring octyl group propyl group etc., preferred cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl, cyclopropyl ethyl, cyclopentyl ethyl, cyclohexyl ethyl, suberyl ethyl, cyclopropyl propyl group, cyclopentyl propyl group, cyclohexyl propyl group, suberyl propyl group.
Described aryl is meant the aryl with 6～15 carbon atoms.Be preferably phenyl, substituted-phenyl, 1-naphthyl, 2-naphthyl, xenyl, substituted naphthyl etc.
Described aralkyl is meant the aralkyl with 7～15 carbon atoms.Be preferably phenmethyl, substituted benzene methyl, styroyl, substituted benzene ethyl, hydrocinnamyl, benzene butyl, 1-menaphthyl, 2-menaphthyl, Biphenylmethyl, replacement menaphthyl etc.
Preferred R represent methylidene, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, neo-pentyl, hexyl, isohexyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, o-bromophenyl, a bromophenyl, to bromophenyl, phenmethyl, styroyl, hydrocinnamyl, benzene butyl; More preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, hexyl, isohexyl, Sec-Hexyl, heptyl, different heptyl, Zhong Gengji, cyclopropyl, cyclopentyl, cyclohexyl, suberyl, phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, o-bromophenyl, a bromophenyl, to bromophenyl, phenmethyl, styroyl, hydrocinnamyl, most preferable, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, o-bromophenyl, a bromophenyl, to bromophenyl, phenmethyl.
Prepared 1
-It is for example following to replace Homotaurine
4a～
4fSix kinds of compounds:
4a：R?=?Me;
4b：R?=?Ph;
4c：R?=?4-MeC
6H
4;
4d：R?=?2-ClC
6H
4;
4e：R?=?3-ClC
6H
4;
4f：R?=?4-ClC
6H
4;
Above-mentioned preparation method normally passes through thioacetic acid to α, and the addition of alpha, beta-unsaturated nitriles obtains corresponding acetate cyanic acid mercaptan ester, obtains 1-replacement Homotaurine through reduction and oxidation again.
Above-mentioned preparation method, the α that said raw material is used, alpha, beta-unsaturated nitriles can buy through disclosed commercial market channel, or prepares through the compound method of bibliographical information.
Above-mentioned preparation method, the catalyzer alkali of said addition reaction is the organic bases tertiary amine normally, like Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, triamylamine, ethyl diisopropyl amine etc.; N, accelerine, N, N-Diethyl Aniline, pyridine; Lutidine, trimethylpyridine etc.
Above-mentioned preparation method, the miscellany reduction of the normally lithium aluminium hydride reduction of said method of reducing, borane reduction, Peng Qinghuana and boron trifluoride, catalytic hydrogenation etc.
Above-mentioned preparation method, said oxygenant is organic peracid, amine normally
N-oxide compound, and other oxygenants.
Above-mentioned preparation method is usually 0
oC～110
oStirring reaction 1～24 h under the temperature of C.
Above-mentioned preparation method, addition reaction used solvent usually is halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane, zellon, aromatic hydrocarbons such as benzene,toluene,xylene, trimethylbenzene, or their miscellany.
Above-mentioned preparation method, reduction reaction used solvent usually are ether, propyl ether, THF, dioxane, glycol dimethyl ether or their miscellany.
Above-mentioned preparation method, oxidizing reaction usually used solvent are formic acid, acetate, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, water or their miscellany.
Advantage of the present invention and positively effect:
The replacement Homotaurine of the present invention's preparation is because of its biological activity has the potential pharmaceutical use, and the haptin of enzyme medicine, cardiac stimulant and Altace Ramipril, treatment Alzheimer medicine, suppressor factor, antiseptic-germicide, tensio-active agent, plant-growth regulator, preparation abzyme, the raw material of synthetic sulfonyl peptide etc. are remembered in the sclerosis and anti-alopecia medicine, treatment alcohol dependence disease drug, the improvement that can be used as anticonvulsant drug, prevent and treat the conjunctiva sheath.
Preparing method provided by the invention, be simple and easy to α, alpha, beta-unsaturated nitriles is a raw material, it can buy or prepare by the currently known methods of bibliographical information through disclosed commercial market channel.This method is simple to operate, can be used for the multifarious 1-of composite structure and replace Homotaurine, is suitable for large-scale industrial production, and research has crucial meaning with application for aminoalkyl group sulfonic acid.
Embodiment
Mode through embodiment further specifies the present invention below, does not therefore limit the present invention among the scope of said embodiment.
Embodiment one
1-amino-3-fourth sulfonic acid
4aPreparation
With 5 mmol α, alpha, beta-unsaturated nitriles is dissolved in the 20 mL toluene, adds the alkali Bu of catalytic amount
3N, nitrogen protection, controlled temperature is at 75-85
oBetween the C, to wherein dripping 456 mg (6 mmol) thioacetic acid, reaction 6 h under this temperature.Reaction finishes to remove desolvates, and separates (sherwood oil: ETHYLE ACETATE=8:1 is an eluent), product R through silica gel column chromatography
f Between 0.55-0.65, obtain suc as formula the red-brown oily adduct acetate cyanic acid mercaptan ester shown in 2, productive rate 46%.
With 8 mmol LiAlH
4Be dissolved in the 20 mL anhydrous diethyl ethers, under the ice-water bath, slowly drip the diethyl ether solution of acetate cyanic acid mercaptan ester of 0.1 mol/L of 10 mL.After dripping end, in ice-water bath, continue to stir 2 h.Reaction finishes, and adds shrend and goes out, and filters out insoluble impurity, and water is used CH
2Cl
2And ethyl acetate extraction, merge organic phase, drying, remove desolvate yellow thick liquid, add 4 mL formic acid, fully mix, slowly drip 30% H
2O
2The aqueous solution 1 mL continues stirring reaction 3 h.After reaction finishes, remove and desolvate, obtain yellow oily liquid, solidify with methanol, solid obtains colorless solid with recrystallizing methanol, productive rate 54.0%; M. p. 290-292
oC;
1H NMR (400 MHz, D
2O)
δ: 1.25 (d,
J=6.9 Hz, 3H, CH
3), 1.83 (m, 1H in CH
2), 2.12 (m, 1H in CH
2), 2.95 (m, 1H in CH
2N), 3.10 (m, 1H in CH
2N), 3.10 (m, 1H, CHSO
3).
13C NMR (100 MHz, D
2O/HCO
2H)
δ: 15.1,29.1,37.8,53.5; IR (
ν, cm
-1): 3447.7 (br, s, OH, NH), and 1214.7 (S=O), 1169.4 (S=O). HRMS (ESI) Calcd. for C
4H
12NO
3S [M+H]
+ M/z: 154.0538; Found 154.0535.
Embodiment two
1-phenyl-3-N-morpholinopropanesulfonic acid
4bPreparation
Press the method for describing among the embodiment one, use cinnamyl nitrile to be raw material, the productive rate with 42% obtains the light yellow crystal adduct, m. p. 76-77
oC; Obtain the colorless solid product, productive rate 64% after reduction and the oxidation.m.?p.?313-314?
oC;?
1H?NMR?(400?MHz,?D
2O)?
δ:?7.34?(s,?5H,?ArH),?4.03?(dd,?
J?=?4.8,?10.8?Hz,?1H,?CHSO
3);?2.93?(ddd,?
J?=?4.8,?10.8,?10.8?Hz,?1H?in?CH
2N);?2.76?(ddd,?
J?=?4.8,?10.8,?10.8?Hz,?1H?in?CH
2N);?2.50?(dddd,?
J?=?4.8,?4.8,?10.8,?10.8?Hz,?1H?in?CH
2);?2.35?(dddd,?
J?=?4.8,?10.8,?10.8,?10.8?Hz,?1H?in?CH
2).?
13C?NMR?(100?MHz,?D
2O/HCO
2H)
δ:28.3,?37.5,?63.4,?128.7,?128.9,?129.1,?134.4.?IR?(
ν,?cm
-1):?3406.8?(br,?s,?OH,?NH),?1238.1?(S=O),?1177.0?(S=O).?HRMS?(ESI)?Calcd.?for?C
9H
14NO
3S?[M+H]
+ m/z:?216.0694;?Found?216.0691.
Embodiment three
1-p-methylphenyl-3-N-morpholinopropanesulfonic acid
4cPreparation
Press the method for describing among the embodiment one, use the methyl cinnamyl nitrile is raw material, the productive rate with 31% obtains the pale yellow crystals adduct, m. p. 68-69
oC; Obtain the colorless solid product, productive rate 82.3% after reduction and the oxidation; M. p. 350-352
oC;
1H NMR (400 MHz, D
2O)
δ: 2.16 (s, 3H, CH
3), 2.25 (dddd,
J=5.2,10.4,10.4,13.6 Hz, 1H in CH
2), 2.41 (dddd,
J=4.8,6.0,10.4,13.6 Hz, 1H in CH
2), 2.66 (ddd,
J=5.2,10.4,12.4 Hz, 1H in CH
2N), 2.84 (ddd,
J=6.0,10.4,12.4 Hz, 1H in CH
2N), 3.91 (dd,
J=4.8,10.4 Hz, 1H, CHSO
3), 7.09-7.17 (m, 4H, ArH).
13C NMR (D
2O/HCO
2H)
δ: 14.8,22.9,32.1,57.6,123.6,124.0,125.9,133.5. IR (
ν, cm
-1): 3423.1 (br, s, OH, NH), and 1208.2 (S=O), 1169.9 (S=O). HRMS (ESI) Calcd. for C
10H
15NNaO
3S [M+ Na]
+ M/z: 252.0670; Found 252.0678.
Embodiment four
1-(2-chloro-phenyl-)-3-N-morpholinopropanesulfonic acid
4dPreparation
Press the method for describing among the embodiment one, use adjacent chlorine cinnamyl nitrile to be raw material, the productive rate with 69% obtains the light yellow crystal adduct, m. p. 73-74
oC; Obtain the colorless solid product, productive rate 75.2% after reduction and the oxidation; M. p. 332-333
oC;
1H NMR (400 MHz, D
2O)
δ: 2.35 (dddd,
J=4.8,5.2,12.0,13.7 Hz, 1H in CH
2), 2.57 (dddd,
J=5.2,10.0,12.0,13.7 Hz, 1H in CH
2); 2.77 (ddd,
J=5.2,12.0,12.0 Hz, 1H in CH
2N); 3.02 (ddd,
J=5.2,12.0,12.0 Hz, 1H in CH
2N); 4.74 (dd,
J=4.8,10.0 Hz, 1H, CHSO
3); 7.30-7.57 (m, 4H, ArH).
13C NMR (100 MHz, D
2O/HCO
2H)
δ: 23.4,31.9,53.1,122.2,123.2,124.4,124.5,126.8,129.5. IR (
ν, cm
-1): 3436.7 (br, s, OH, NH), and 1224.5 (S=O), 1175.2 (S=O). HRMS (ESI) Calcd. for C
9H
13ClNO
3S [M+H]
+ M/z: 250.0305; Found 250.0313.
Embodiment five
1-(3-chloro-phenyl-)-3-N-morpholinopropanesulfonic acid
4ePreparation
Press the method for describing among the embodiment one, use the m-chloro cinnamyl nitrile to be raw material, the productive rate with 64% obtains the light yellow crystal adduct, m. p. 65-67
oC; Obtain the colorless solid product, productive rate 74.8% after reduction and the oxidation; M. p. 330-332
oC;
1H NMR (400 MHz, D
2O)
δ: 7.18-7.35 (m, 4H, ArH), 4.07 (dd,
J=4.9,10.3 Hz, 1H, CHSO
3); 3.00 (m, 1H in CH
2N); 2.74 (m, 1H in CH
2N); 2.47 (m, 1H in CH
2); 2.30 (m, 1H in CH
2).
13C NMR (100 MHz, D
2O/HCO
2H)
δ: 21.1,30.3,55.7,118.6,120.4,121.5,121.8,123.1,126.8; IR (
ν, cm
-1): 3406.8 (br, s, OH, NH), and 1197.4 (S=O), 1141.5 (S=O). HRMS (ESI) Calcd. for C
9H
12ClNNaO
3S [M+Na]
+ M/z: 272.0124; Found 272.0124.
Embodiment six
1-(4-chloro-phenyl-)-3-N-morpholinopropanesulfonic acid
4fPreparation
Press the method for describing among the embodiment one, use the chlorine cinnamyl nitrile is raw material, the productive rate with 66% obtains the light yellow crystal adduct, m. p. 82-83
oC; Obtain the colorless solid product, productive rate 85.6% after reduction and the oxidation; M. p. 334-336
oC;
1H NMR (400 MHz, D
2O)
δ: 7.34-7.40 (m, 4H, ArH), 4.07 (dd,
J=4.9,10.4 Hz, 1H, CHSO
3), 2.96 (ddd,
J=6.0,10.4,12.7 Hz, 1H in CH
2N), 2.79 (ddd,
J=6.0,10.4,12.7 Hz, 1H in CH
2N), 2.53 (dddd,
J=5.3,10.4,10.4,12.7 Hz, 1H in CH
2), 2.34 (dddd,
J=4.9,5.3,10.4,12.7 Hz, 1H in CH
2).
13C NMR (100 MHz, D
2O/HCO
2H)
δ: 22.1,31.3,56.5,122.7,124.4,127.0,127.7; IR (
ν, cm
-1): 3438.3 (br, s, OH, NH), and 1194.3 (S=O), 1170.2 (S=O). HRMS (ESI) Calcd. for C
9H
13ClNO
3S [M+H]
+ M/z: 250.0305; Found 250.0303.
Claims (8)
1. a 1-replaces the preparation method of Homotaurine, and with the α shown in thioacetic acid and the formula [1], alpha, beta-unsaturated nitriles carries out addition reaction and obtains corresponding acetate cyanic acid mercaptan ester, obtains the 1-replacement Homotaurine shown in the formula [4] through reduction and oxidation again;
Formula 1 formula 4
Wherein: R represent to have 1～15 carbon atom alkyl, have 3～15 carbon atoms naphthenic base, have 4～15 carbon atoms cycloalkylalkyl, have 6～15 carbon atoms aryl, have the aralkyl of 7～15 carbon atoms etc.
2. 1-as claimed in claim 1 replaces the preparation method of Homotaurine; The catalyzer alkali that it is characterized in that described addition reaction is the organic bases tertiary amine normally, like Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, triamylamine, ethyl diisopropyl amine etc., N; Accelerine, N; N-Diethyl Aniline, pyridine, lutidine, trimethylpyridine etc.
3. 1-as claimed in claim 1 replaces the preparation method of Homotaurine, it is characterized in that the miscellany reduction, catalytic hydrogenation of the normally lithium aluminium hydride reduction of described method of reducing, borane reduction, Peng Qinghuana and boron trifluoride etc.
4. 1-as claimed in claim 1 replaces the preparation method of Homotaurine, it is characterized in that described oxygenant is the oxynitride of organic peracid or amine.
5. 1-as claimed in claim 1 replaces the preparation method of Homotaurine; It is characterized in that the addition reaction solvent for use is selected from: halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane, zellon; Aromatic hydrocarbons such as benzene,toluene,xylene, trimethylbenzene, or their miscellany.
6. 1-as claimed in claim 1 replaces the preparation method of Homotaurine, it is characterized in that the reduction reaction solvent for use is selected from: ether, propyl ether, THF, dioxane, glycol dimethyl ether or their miscellany.
7. 1-as claimed in claim 1 replaces the preparation method of Homotaurine, it is characterized in that the oxidizing reaction solvent for use is selected from: formic acid, acetate, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, water or their miscellany.
8. 1-as claimed in claim 1 replaces the preparation method of Homotaurine, it is characterized in that saidly being reflected at 0
oC～110
oStirring reaction under the temperature of C.
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| CN111302981A (en) * | 2018-12-11 | 2020-06-19 | 万华化学集团股份有限公司 | Method for preparing taurine |
| CN111302981B (en) * | 2018-12-11 | 2022-04-19 | 万华化学集团股份有限公司 | Method for preparing taurine |
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