CN102659643B - A kind of by α, beta-unsaturated acyl amine prepares the method replacing Homotaurine - Google Patents
A kind of by α, beta-unsaturated acyl amine prepares the method replacing Homotaurine Download PDFInfo
- Publication number
- CN102659643B CN102659643B CN201210113527.6A CN201210113527A CN102659643B CN 102659643 B CN102659643 B CN 102659643B CN 201210113527 A CN201210113527 A CN 201210113527A CN 102659643 B CN102659643 B CN 102659643B
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- CN
- China
- Prior art keywords
- homotaurine
- acid
- preparation
- sec
- 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.)
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- -1 beta-unsaturated acyl amine Chemical class 0.000 title claims abstract description 101
- SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical compound NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 37
- 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
- 150000001408 amides Chemical class 0.000 claims abstract description 11
- 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
- 238000006722 reduction reaction Methods 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 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
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-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 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
- 238000007259 addition reaction Methods 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
- 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
- 125000000753 cycloalkyl group Chemical group 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
- 235000019253 formic acid Nutrition 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- 230000001590 oxidative effect Effects 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229910000085 borane Inorganic materials 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
- 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
- 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
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 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
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims 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 1
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- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 2
- 230000000050 nutritive effect Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 22
- 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 18
- 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 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 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 13
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 13
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 13
- 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 13
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
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- 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 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
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- OHLHOLGYGRKZMU-UHFFFAOYSA-N n-benzylprop-2-enamide Chemical compound C=CC(=O)NCC1=CC=CC=C1 OHLHOLGYGRKZMU-UHFFFAOYSA-N 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
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000004967 organic peroxy acids Chemical group 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 239000007787 solid Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960003570 tramiprosate Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of preparation method replacing Homotaurine: by thioacetic acid to α, the addition of beta-unsaturated acyl amine obtains corresponding 3-acetylthio acid amides, then obtains replacing Homotaurine through reduction and oxidation.This preparation method's raw material is simple and easy to get, easy to operate, does not need loaded down with trivial details desalting purifying process, is particularly suitable for large-scale industrial production.The compound obtained can as nutritive substance, medicine, enzyme inhibitors, antiseptic-germicide, tensio-active agent, plant-growth regulator, prepare the raw material etc. of sulfonyl peptide.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the preparation method replacing Homotaurine.
Background technology
Homotaurine, i.e. Homotaurine, be a kind ofly from Grateloupia livida (Harv). Yamaka, be separated the aminoalkyl group sulfonic acid obtained, it is structurally similar to neurotransmitter γ-aminobutyric acid, and research finds that it has anticonvulsion effect (Fariello, R. G. of γ-aminobutyric acid; Golden, G. T.; Pisa, M.
neurology 1982,
32, 241).Homotaurine can also prevent and treat the sclerosis of conjunctiva sheath, Anti-hair loss, treatment alcohol dependence, suppresses the oxidation of catecholamine in body, protection DNA from oxidative damage, Improving memory, cardiac stimulant, effect (Mayer, the 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.; Dinh-xuan, 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).Because it is combined disease and idiopathic autism has good curative effect, and be subject to people and more pay close attention to.Because it can be combined with solubility amyloid beta, suppress the formation that can cause the neurotoxin of amyloid plaque deposition in brain, be used for the treatment of 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).With Homotaurine be main component exploitation medicine calcium bisacetyl homotaurine and Tramiprosate also achieve good curative effect (Erickson, C. A.
wO 2010093859; Wright, T. M.
drugs Today,
2006,
42, 291).
The replacement Homotaurine of different structure has different biological functions and drug effect, and the effective and general synthetic method of development structure multifarious replacement Homotaurine has extremely important meaning for new drug development.The Homotaurine reported and replace the preparation method of Homotaurine and comprise: by hydrosulphite or sulphite to the nucleophilic substitution of 3-halogenated amine prepare (Zhang Qiucai, Ding Min, Li Wenzhong, Cheng Zhipeng, Liang Long,
chinese invention patent prospectus, CN 1451652A; Sen, N. P.
can. J. Chem.
1962,
40, 2189); Restored by the Michael addition of sulphite to unsaturated nitrile and prepare (Ling Jianhong, xuwei,
chinese invention patent prospectus, CN 101362709A; Li, C. S.; Howson, W.; Dolle, R. E.
synthesis 1991,
3, 244); Amination is restored to prepare (Smith, C. W. by the Michael addition of bisulfite salt pair methacrolein; Norton, D. G.; Ballard, S. A.
j. Am. Chem. Soc.
1953,
75, 748); By allylamine sulfonation preparation (Abbenante, G that ammonium bisulfite replaces 2-aryl; Prager, R. H.
aust. J. Chem.
1990,
43, 213; Abbenante, G; Prager, R. H.
aust. J. Chem.
1992,
45, 1791); By ammonium bisulfite to the replacement of a-bromometllylstyrene, addition and reduction preparation or thioacetic acid to the cinnamic addition of a-aminomethyl and oxidation preparation (Abbenante, G; Prager, R. H.
aust. J. Chem.
1992,
45, 1801); By replacement preparation (Millan, the D. S. of primary amine to 3-bromine third SULPHURYL CHLORIDE; Prager, R. H.
aust. J. Chem.
2000,
53, 615); By sulphite to the nucleophilic substitution of aminopropanol sulphonate prepare (congratulate rut, Liu loses pine, and red legend is outstanding, Shao Xueqing, Yan Zhihua, Gu Renhua, Qian Jixin, Zhao Ting,
chinese invention patent prospectus, CN 101759605A); (Erman, Wm. F. is prepared by ammonia, nitrine or the primary amine nucleophilic ring opening to 1,3-third sultone; Kretschmar, H. C.
j. Org. Chem. 1961 , 26,4841; Zhang Qiucai, Ding Min, Li Wenzhong, Cheng Zhipeng, Liang Long,
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); By the cycloaddition of transition metal-catalyzed α-dizaomethyl sulphonate and corresponding allylamine or allyl sulphonic acid ester and diazonium acetate cycloaddition, product conversion is become acid azide, and follow-up Curtius resets preparation (Fulco, M. C.; Marinozzi, M.; Pellicciari, R.
tetrahedron 2009,
65, 8756)
These methods existing can be used for synthesizing Homotaurine or replacing Homotaurine, but often due to raw material restriction, can only synthesize the replacement Homotaurine of some structure type, or need troublesome desalting purifying process.The present invention by thioacetic acid to α; the addition of beta-unsaturated acyl amine obtains corresponding 3-acetylthio acid amides; obtain replacing Homotaurine through reduction and oxidation again; the final step of the method is salt-free process; convenient separation and purification water-soluble ionic-type product being replaced to Homotaurine, can be used for preparing highly purified replacement Homotaurine.
Summary of the invention
The object of this invention is to provide a kind of salt-free preparation method replacing Homotaurine, this preparation method's raw material is simple and easy to get, is the short-cut method that a kind of effective preparation being suitable for large-scale commercial production replaces Homotaurine.
Technical scheme of the present invention is as follows:
Replace a preparation method for Homotaurine, by thioacetic acid to α, the addition of beta-unsaturated acyl amine obtains corresponding 3-acetylthio acid amides, then obtains replacing Homotaurine through reduction and oxidation.
In above-mentioned reaction formula:
R
1, R
2, R
3and R
4represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl etc., the alkyl wherein in alkyl and aralkyl can be all ring-type, and cycloalkyl and aryl can be fused rings, but R
1, R
2, R
3and R
4be asynchronously hydrogen.
Wherein said alkyl refers to the straight or branched alkyl with 1 ~ 15 carbon atom, such as: 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.Preferably there is the straight or branched alkyl of 1 ~ 12 carbon atom, particularly preferably there is the straight or branched alkyl of 3 ~ 10 carbon atoms, most preferably there is the straight or branched alkyl of 3 ~ 8 carbon atoms.
Described cycloalkyl refers to the cyclic alkyl with 3 ~ 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc., preferred cyclopropyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group.
Described cycloalkylalkyl refers to the cyclic alkyl with 4 ~ 15 carbon atoms, such as Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, CycloheptylmethyI, ring octyl methyl, cyclopropylethyl, CYCLOBUTYLETHYL, cyclopentyl ethyl, cyclohexyl-ethyl, cycloheptylethyl, ring octyl group ethyl, Cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyi, Cyclohexylpropyl, cycloheptylpropyl, ring octyl group propyl group etc., preferred Cvclopropvlmethvl, cyclopentyl-methyl, cyclohexyl methyl, CycloheptylmethyI, cyclopropylethyl, cyclopentyl ethyl, cyclohexyl-ethyl, cycloheptylethyl, Cyclopropylpropyl, cyclopentylpropyi, Cyclohexylpropyl, cycloheptylpropyl.
Described aryl refers to the aryl with 6 ~ 15 carbon atoms.Be preferably phenyl, substituted-phenyl, 1-naphthyl, 2-naphthyl, xenyl, substituted naphthyl etc.
Described aralkyl refers to the aralkyl with 7 ~ 15 carbon atoms.Be preferably phenmethyl, substituted benzene methyl, 1-menaphthyl, 2-menaphthyl, Biphenylmethyl, replacement menaphthyl etc.
Preferred R
1represent hydrogen, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 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, phenmethyl, styroyl, hydrocinnamyl, most preferable, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, phenmethyl.
Preferred R
2represent hydrogen, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 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, phenmethyl, styroyl, hydrocinnamyl, most preferable, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, phenmethyl.
Preferred R
3represent hydrogen, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 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, phenmethyl, styroyl, hydrocinnamyl, most preferable, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, phenmethyl.
Preferred R
4represent hydrogen, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 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, phenmethyl, styroyl, hydrocinnamyl, most preferable, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, phenmethyl.
Prepared replacement Homotaurine is such as following
4a~
4fsix kinds of compounds:
4a：R
1= Me, R
2= R
3= R
4= H;
4b：R
1= R
3= R
4= H, R
2= Me;
4c：R
1= R
3= R
4= H, R
2= Ph;
4d：R
1= R
2= Me, R
3= R
4= H;
4e：R
1= R
2= R
3= H, R
4= Bn;
4f：R
1= R
2= H, R
3= R
4= Bn
Above-mentioned preparation method, normally by thioacetic acid to α, the addition of beta-unsaturated acyl amine obtains corresponding 3-acetylthio acid amides, then through reduction and oxidation obtain replace Homotaurine.
Above-mentioned preparation method, the α of described raw material, beta-unsaturated acyl amine can be bought by disclosed commercial market channel, or is prepared by the synthetic method of bibliographical information.
Above-mentioned preparation method, the catalyzer alkali normally organic bases tertiary amine of described addition reaction, as Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, triamylamine, ethyl diisopropyl amine etc., DMA, N, N-Diethyl Aniline, pyridine, lutidine, trimethylpyridine etc.
Above-mentioned preparation method, the miscellany reduction, catalytic hydrogenation etc. of described method of reducing normally Lithium aluminum hydride reduction, borane reduction, sodium borohydride and boron trifluoride.
Above-mentioned preparation method, described oxygenant is organic peracid, amine normally
n-oxide compound, and other oxygenants.
Above-mentioned preparation method, usually stirring reaction 1 ~ 24 h at the temperature of 0 ° of C ~ 110 ° C.
Above-mentioned preparation method, addition reaction solvent usually used is halohydrocarbon or their miscellanys such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane, zellon.
Above-mentioned preparation method, reduction reaction solvent usually used is ether, propyl ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether or their miscellany.
Above-mentioned preparation method, oxidizing reaction solvent usually used is formic acid, acetic acid, 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:
Replacement Homotaurine prepared by the present invention has potential pharmaceutical use because of its biological activity, can as the raw material etc. of the haptens of medicine, enzyme inhibitors, antiseptic-germicide, tensio-active agent, plant-growth regulator, Dispersal risk enzyme, synthesis sulfonyl peptide.
Preparation method provided by the invention, with α simple and easy to get, beta-unsaturated acyl amine is raw material, and it can be bought by disclosed commercial market channel or prepare by the currently known methods of bibliographical information.The method is simple to operate, may be used for the multifarious replacement Homotaurine of composite structure, is suitable for large-scale industrial production, is of great significance for aminoalkyl group sulfonic acid research and apply tool.
Embodiment
Mode below by embodiment further illustrates the present invention, among the scope therefore not limiting the present invention to described embodiment.
Embodiment one
1-amino-3-fourth sulfonic acid
4apreparation
In 50 mL there-necked flasks, 2-butylene acid amides 0.851 g (10 mmol) is joined 15 mL CH
2cl
2in, instill 5 anhydrous triethylamines subsequently.Be heated to backflow under nitrogen protection, drip thioacetic acid 0.952 g (12.5 mmol), and 20 h that reflux.Be cooled to room temperature, obtain intermediate 3-acetylthio butyramide 1.251 g, yield 77.6% except silica gel column chromatography after desolventizing is separated [sherwood oil (PE): ethyl acetate (EA)=1:2, v/v].
In 100 mL single port bottles, by 1.520 g (40 mmol) LiAlH under ice-water bath
4join in the anhydrous THF of 30 mL.Drip the 5 mL THF solution containing 0.645 g (4 mmol) 3-acetylthio butyramide subsequently, reflux 18 h, go out with shrend under ice-water bath after recovering room temperature, add 10 mL water and stir 12 h.Filter, filtrate CH
2cl
2extract three times (10 mL ' 3), obtain yellow oil except after desolventizing.Yellow oil is placed in 25 mL single port bottles, adds 5 mL formic acid, drip peroxyformic acid (5 mL formic acid+2 mL30% hydrogen peroxide), under normal temperature, stir 15 h.After desolventizing, obtain 1-amino-3-fourth sulfonic acid 0.120 g with methanol-diethyl ether recrystallization, yield 19.6%.White solid, fusing point: 281-283
oc, document fusing point: 288-289
oC.
1H NMR (400 MHz, D
2O) δ: 3.16-3.04 (m, 2H, CH
2N), 2.94 (ddq,
J= 6.8, 6.8, 6.8 Hz, 1H in CH), 2.12 (ddt,
J= 6.8, 14.8, 6.4 Hz, 1H in CH
2), 1.82 (ddt,
J= 6.8, 14.8, 6.4 Hz, 1H in CH
2), 1.25 (d,
J= 6.8 Hz, 3H in CH
3);
13C NMR (100 MHz, D
2O) δ: 53.0, 37.3, 29.2, 14.6.
Embodiment two
2-methyl-3-aminopropanesulfonicacid acid
4bpreparation
By the method described in embodiment one, replace 2-butylene acid amides to be raw material with 2-Methacrylamide, the productive rate with 95% obtains 2-methyl-3-acetylthio propionic acid amide clear crystal intermediate, fusing point 84-86
oc; Clear crystal 2-methyl-3-aminopropanesulfonicacid acid is obtained, productive rate 70%, fusing point 234-238 after reduction and oxidation
oc.Document fusing point: 260-265
oc.
1H NMR (400 MHz, D
2O) δ: 3.15 (dd,
J= 6.0, 13.2 Hz, 1H in SCH
2), 2.93 (dd,
J= 6.8, 14.4 Hz, 1H in NCH
2), 2.90 (dd,
J= 6.8, 13.2 Hz, 1H in SCH
2), 2.87 (dd,
J= 6.0, 14.4 Hz, 1H in NCH
2), 2.32 (ttq,
J= 6.8, 6.0,6.8 Hz, 1H, CH), 1.10 (d,
J= 6.8 Hz, 3H, CH
3);
13C NMR (100 MHz, D
2O) δ: 54.7, 44.2, 28.7, 17.0; IR
n(cm
-1): 3451 (br, s, NH, OH), 1280 (SO), 1176 (SO).
Embodiment three
2-methyl isophthalic acid-amino-3-fourth sulfonic acid
4cpreparation
By the method described in embodiment one, replace 2-butylene acid amides to be raw material with 2-methyl-2-butene acid amides, the productive rate with 75% obtains 2-methyl-3-acetylthio butyramide clear crystal intermediate, fusing point 136-138
oc; Oily 2-methyl isophthalic acid-amino-3-fourth sulfonic acid is obtained, productive rate 40% after reduction and oxidation.
1H NMR (400 MHz, D
2O) δ: 3.27 (dd,
J= 5.6, 13.2 Hz, 1H in NCH
2), 2.96 (dq,
J= 2.8, 7.2 Hz, 1H, SCH), 2.82 (dd,
J= 8.4, 13.2 Hz, 1H in NCH
2), 2.42 (dddq,
J= 2.8, 5.6, 8.4, 7.2 Hz, 1H, CH), 1.21 (d,
J= 7.2 Hz, 3H, CH
3), 1.05 (d,
J= 7.2 Hz, 3H, CH
3);
13C NMR (100 MHz, D
2O) δ: 58.5, 41.2, 32.3, 15.4, 9.8; IR
n(cm
-1): 2976 (br, s, NH, OH), 1205 (SO), 1030 (SO). HRMS (ESI,
m/z) calcd. for C
5H
13NO
3S [M+H]
+ m/z: 168.0689; found: 168.0682.
Embodiment four
2-phenyl-Homotaurine
4dpreparation
By the method described in embodiment one, replace 2-butylene acid amides to be raw material by 2-Phenyl Acrylamide, the productive rate with 70% obtains 2-phenyl-3-acetylthio propionic acid amide clear crystal intermediate, fusing point 116-117
oc; Clear crystal 2-phenyl-Homotaurine is obtained, productive rate 74%, fusing point 220-225 after reduction and oxidation
oC, document fusing point: 260-265
oC.
1H NMR (400 MHz, D
2O) δ: 7.40-7.30 (m, 5H, ArH), 3.53 (dd,
J= 5.2, 12.8 Hz, 1H in SCH
2), 3.46-3.38 (m, 1H, CH), 3.28 (dd,
J= 6.4, 14.4 Hz, 1H in NCH
2), 3.24 (m, 1H in SCH
2), 3.22 (dd,
J= 6.4, 14.4 Hz, 1H in NCH
2);
13C NMR (100 MHz, D
2O) δ: 134.7, 129.4, 128.9, 58.6, 30.3, 16.8; IR
n(cm
-1): 2960 (br, s, NH, OH), 1180 (SO), 1142 (SO).
Embodiment five
3-benzyl aminopropanesulfonic acid
4epreparation
By the method described in embodiment one, replace 2-butylene acid amides to be raw material with N-benzylacrylamide, the productive rate with 94% obtains N-benzyl-3-acetylthio propionic acid amide clear crystal intermediate, fusing point 80-80.5
oc; Clear crystal 3-benzyl aminopropanesulfonic acid is obtained, productive rate 22%, fusing point 241-243 after reduction and oxidation
oc, document fusing point 302-303
oc.
1H NMR (400 MHz, D
2O) δ: 7.42 (s, 5H, ArH), 4.17 (s, 2H, CH
2), 3.15 (t,
J= 7.2 Hz, 2H, SCH
2), 2.91 (t,
J= 7.2 Hz, 2H, NCH
2), 2.06 (quint,
J= 7.2 Hz, 2H, CH
2);
13C NMR (100 MHz, D
2O) δ: 130.6, 129.8, 129.7, 129.3, 51.1, 47.9, 45.7, 21.3; IR
n(cm
-1): 3452 (br, s, NH, OH), 1245 (SO), 1184, (SO).
Embodiment six
3-dibenzyl aminopropanesulfonic acid
4fpreparation
By the method described in embodiment one, replace 2-butylene acid amides to be raw material with N, N-dibenzyl acrylamide, obtain N with the productive rate of 77%, N-dibenzyl-3-acetylthio propionic acid amide oily intermediate; Oily 3-dibenzyl aminopropanesulfonic acid is obtained, productive rate 76% after reduction and oxidation.
1H NMR (400 MHz, D
2O) δ: 7.45-7.32 (m, 10H, ArH), 4.22 (s, 4H, 2CH
2), 3.16 (m, 2H, SCH
2), 2.75 (t,
J= 7.2Hz, 2H, NCH
2), 2.11 (quint,
J= 7.2Hz, 2H, CH
2);
13C NMR (100 MHz, D
2O) δ: 131.0, 130.2, 129.4, 128.9, 57.1, 51.1, 47.9, 19.2; IR
n(cm
-1): 3424 (br, s, OH), 1215 (SO), 1151 (SO); HRMS (ESI,
m/z) calcd. for C
17H
21NO
3S [M+H]
+ m/z: 320.1315; found: 320.1313.
Claims (8)
1. one kind replaces the preparation method of Homotaurine, by the α shown in thioacetic acid and formula [1], beta-unsaturated acyl amine carries out addition and obtains the 3-acetylthio acid amides shown in corresponding formula [2], then obtains the replacement Homotaurine shown in formula [4] through reduction and oxidation;
Wherein: R
1, R
2, R
3and R
4represent hydrogen, there is the alkyl of 1 ~ 15 carbon atom, there is the cycloalkyl of 3 ~ 15 carbon atoms, there is the cycloalkylalkyl of 4 ~ 15 carbon atoms, there is the aryl of 6 ~ 15 carbon atoms, there is the aralkyl of 7 ~ 15 carbon atoms, but R
1, R
2, R
3and R
4be asynchronously hydrogen.
2. the preparation method replacing Homotaurine as claimed in claim 1; it is characterized in that the catalyzer of described addition reaction is Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, triamylamine, ethyl diisopropyl amine, N; accelerine, N; N-Diethyl Aniline, pyridine; lutidine, trimethylpyridine.
3. the preparation method replacing Homotaurine as claimed in claim 1, is characterized in that described method of reducing is the miscellany reduction of Lithium aluminum hydride reduction, borane reduction, sodium borohydride and boron trifluoride.
4. the as claimed in claim 1 preparation method replacing Homotaurine, is characterized in that oxidizing reaction catalyzer used is peroxyformic acid, Peracetic Acid, N-methylmorpholine N-oxide compound.
5. the preparation method replacing Homotaurine as claimed in claim 1, is characterized in that addition reaction solvent for use is selected from: methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane, zellon or their miscellany.
6. the preparation method replacing Homotaurine as claimed in claim 1, is characterized in that reduction reaction solvent for use is selected from: ether, propyl ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether or their miscellany.
7. the as claimed in claim 1 preparation method replacing Homotaurine, is characterized in that oxidizing reaction solvent for use is selected from: formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, water or their miscellany.
8. the preparation method replacing Homotaurine as claimed in claim 1, is characterized in that described reaction is 0
oc ~ 110
ostirring reaction at the temperature of C.
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| CN110668980A (en) * | 2018-07-03 | 2020-01-10 | 浙江京新药业股份有限公司 | 2-substituted homotaurine derivative |
| CN115160097B (en) * | 2022-07-22 | 2024-05-28 | 温州大学 | Method for synthesizing amide by reducing N-O bond by thioacetic acid |
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| CN101255126A (en) * | 2007-03-02 | 2008-09-03 | 北京大学 | Preparation of taurine and derivatives thereof |
| CN101337914A (en) * | 2008-08-14 | 2009-01-07 | 北京化工大学 | Method for preparing taurine and substituted taurine |
| CN101851181A (en) * | 2010-06-03 | 2010-10-06 | 北京化工大学 | Preparation method of 1-substituted taurine |
| CN101851182A (en) * | 2010-06-03 | 2010-10-06 | 北京化工大学 | Salt-free preparation method for substituted taurine |
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| CN101255126A (en) * | 2007-03-02 | 2008-09-03 | 北京大学 | Preparation of taurine and derivatives thereof |
| CN101337914A (en) * | 2008-08-14 | 2009-01-07 | 北京化工大学 | Method for preparing taurine and substituted taurine |
| CN101851181A (en) * | 2010-06-03 | 2010-10-06 | 北京化工大学 | Preparation method of 1-substituted taurine |
| CN101851182A (en) * | 2010-06-03 | 2010-10-06 | 北京化工大学 | Salt-free preparation method for substituted taurine |
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