CN102424665A - Preparation method of 1-substituted homotaurine - Google Patents
Preparation method of 1-substituted homotaurine Download PDFInfo
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- CN102424665A CN102424665A CN2011103500320A CN201110350032A CN102424665A CN 102424665 A CN102424665 A CN 102424665A CN 2011103500320 A CN2011103500320 A CN 2011103500320A CN 201110350032 A CN201110350032 A CN 201110350032A CN 102424665 A CN102424665 A CN 102424665A
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Abstract
The invention provides a preparation method of N-phthaloyl protected 1-substituted homotaurine. The method comprises: conducting free radical addition to terminal olefin by dithiocarbonic acid-O-alkyl-S-phthalimidemethyl ester so as to obtain corresponding xanthate, then carrying out oxidation to prepare N-phthaloyl protected 1-substituted homotaurine, then performing acid or base catalyzed hydrolysis or hydrazinolysis, thus obtaining 1-substituted homotaurine. The preparation method of the invention has simple and easily available raw materials, convenient operation, and no need for a tedious desalting and purifying process, thus being especially suitable for large scale industrial production. And the prepared compound can be use as a nutrient, a medicament, an enzyme inhibitor, an antimicrobial agent, a surfactant, a plant growth regulator, and a raw material for preparing sulfono-peptides, etc.
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; Being the gamma-amino propanesulfonic acid, is to separate a kind of aminoalkyl group sulfonic acid that obtains from Grateloupia livida (Harv), because it structurally is similar to the neurotransmitter γ-An Jidingsuan; Through discovering that it has the anticonvulsion effect of γ-An Jidingsuan (Fariello, R. G.; Golden, G. T.; Pisa, M.
Neurology 1982,
32, 241).Homotaurine still is the only nitrogen source of some internal metabolism; Can prevent and treat the sclerosis of conjunctiva sheath; Anti-alopecia, 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.; 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).Present because it is combined disease and Te Fa property autism has better curative effect, and receive people's more concern.Because it can combine with solubility beta amyloid, inhibition can cause the formation of the sedimentary neurotoxin of amyloid patch in the brain, and 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).And be that the medicine calcium bisacetyl homotaurine and the Tramiprosate of staple exploitation obtained better curative effect (Erickson, C. A. with the Homotaurine
WO 2010093859; Wright, T. M.
Drugs Today,
2006,
42, 291).
The replacement Homotaurine that structure is different will show 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 with replace the Homotaurine preparation method and comprise: through hydrosulphite or sulphite to the 3-halogeno-amine carry out the nucleophilic substitution preparation (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 vinyl cyanide or 2-alkyl (aryl) substituted acrylonitrile 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 a-brooethyl, addition and reduction preparation or thioacetic acid are prepared (Abbenante, G to cinnamic addition of a-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); Through N-sulfinyl carbamate and conjugated diolefine Diels-Alder taking place reacts the preparation of hydrolysis again (Stefania, F.; Giovanni, P.; Fabio, P.
Tetrahedron Lett 2006 , 47,1749); Through the transition metal-catalyzed alfa-dizaomethyl sulphonate and the cycloaddition of 1,3-butadiene, ozonize and the preparation of Strecker amino acid building-up reactions (Pellicciari, R.; Marinozzi, M.; Macchiarulo, A.; Fulco, M. C.; Gafarova, J.; Serpi, M.; Giorgi, G.; Nielsen, S.; Thomsen, C.
J. Med. Chem. 2007 , 50,4630); Cycloaddition or allyl sulphonic acid ester and diazonium acetate cycloaddition through transition metal-catalyzed alfa-dizaomethyl sulphonate and corresponding allylamine change into acid azide with product, and follow-up Curtius resets preparation (Fulco, M. C.; Marinozzi, M.; Pellicciari, R.
Tetrahedron 2009,
65, 8756)
Existing these methods can be used for synthesizing the Homotaurine or derivatives thereof; But restricted application often; The replacement Homotaurine that can only synthesize some structure type; The desalting purifying process that maybe need bother, topmost problem are to be difficult for being implemented on the 1-position of Homotaurine introducing multifarious functional group.The present invention obtains corresponding xanthate through dithiocarbonic acid-O-alkyl-S-phthalimide methyl ester to the free radical addition of end group alkene; Prepare 1-through peroxo-again and replace Homotaurine; Entire reaction course need not any inorganic salt; The desalting purifying process that need not bother 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 general 1-replaces Homotaurine, this preparing method's raw material is simple and easy to, and does not need loaded down with trivial details operation, is a kind of effective preparation that is suitable for large-scale commercial prodn
N-phthaloyl protection 1-replaces the short-cut method of Homotaurine and 1-replacement Homotaurine.
Technical scheme of the present invention is following:
A kind of 1-replaces the preparation method of Homotaurine, through dithiocarbonic acid-
O-alkyl-
S-phthalimide methyl ester obtains corresponding xanthate to the free radical addition of end group alkene, prepares through peroxo-again
N-phthaloyl protection 1-replaces Homotaurine, removes to obtain 1-behind the N-protected base and replace Homotaurine.
In the above-mentioned reaction formula:
R
1Expression alkyl, naphthenic base, cycloalkylalkyl, aryl, aralkyl, alkoxyalkyl, alkylamino radical alkyl, aryloxy alkyl, aryl amine alkyl, aralkyl oxy, hydroxyalkyl, acyloxyalkyl group, acyl sulfane base, acid amides alkyl etc., R
2Expression alkyl, naphthenic base, cycloalkylalkyl, aryl, aralkyl etc., wherein the alkyl in alkyl, aralkyl, aryloxyalkyl group, alkoxyalkyl and the alkylamino radical alkyl all can be ring-type, 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 3～10 carbon atoms, most preferably has the straight or branched alkyl of 3～8 carbon atoms.
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, 1-menaphthyl, 2-menaphthyl, Biphenylmethyl, replacement menaphthyl etc.
Described alkoxyalkyl is meant the alkoxyalkyl with 2～15 carbon atoms.Be preferably methoxyl methyl, methoxyethyl, methoxycarbonyl propyl, methoxy butyl, methoxy amyl group, methoxy hexyl, 1-methoxy ethyl, 1-methoxy-propyl, 2-methoxy-propyl, ethoxymethyl, ethoxyethyl, ethoxy propyl group, ethoxy butyl, ethoxy amyl group, ethoxy hexyl, the third oxygen methyl, the third oxygen ethyl, the third oxygen propyl group, third oxygen-butyl, the third oxygen amyl group, the third oxygen hexyl etc.
Described alkylamino radical alkyl is meant the alkylamino radical alkyl with 2～15 carbon atoms.Be preferably methylamine methyl, methylamine ethyl, methylamine propyl group, methylamine butyl, methylamine amyl group, methylamine hexyl, 1-methylamino ethyl, 1-methylamino propyl group, 2-methylamino propyl group, ethamine methyl, ethamine ethyl, ethamine propyl group, ethamine butyl, ethamine amyl group, ethamine hexyl, propylamine methyl, propylamine ethyl, propylamine propyl group, propylamine butyl, propylamine amyl group, propylamine hexyl etc.
Described aryloxyalkyl group is meant the aryloxyalkyl group with 7～15 carbon atoms.Be preferably Phenoxymethyl, substituted benzene oxygen methyl, 1-naphthalene oxygen methyl, 2-naphthalene oxygen methyl, biphenyl oxygen methyl, replace naphthalene oxygen methyl etc.
Described arylamine alkyl is meant the arylamine alkyl with 7～15 carbon atoms.Be preferably anilinomethyl, substituted aniline methyl, naphthalidine methyl, 2-naphthylamines methyl, p-diaminodiphenyl methyl, replace naphthylamines methyl etc.
Described aralkyl oxy is meant the aralkyl oxy with 7～15 carbon atoms.Be preferably benzyloxy, substituted benzene methoxy base, 1-naphthalene methoxyl group, 2-naphthalene methoxyl group, biphenyl methoxyl group, replace naphthalene methoxyl group etc.
Described hydroxyalkyl is meant the hydroxyalkyl with 1～15 carbon atom, comprises straight chain and straight chain, and the cyclic hydroxyalkyl.Be preferably methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl, hydroxyl amyl group, hydroxyl hexyl, hydroxyl heptyl, hydroxyl octyl group, hydroxyl nonyl, hydroxy decyl, hydroxyl undecyl, hydroxyl dodecyl, hydroxyl tridecyl, hydroxyl tetradecyl, hydroxyl pentadecyl etc.; Most preferably be methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl, hydroxyl amyl group, hydroxyl hexyl, hydroxyl heptyl, hydroxyl octyl group, hydroxyl nonyl, hydroxy decyl etc.
Described acyloxyalkyl group is meant the acyloxyalkyl group with 2～15 carbon atoms.Be preferably the methanoyl methyl; The methanoyl ethyl; The methanoyl propyl group; The methanoyl butyl; The methanoyl amyl group; The methanoyl hexyl; The methanoyl heptyl; The methanoyl octyl group; The methanoyl nonyl; The methanoyl decyl; Acetyl-o-methyl; Acetyl oxygen ethyl; Acetyl oxygen propyl group; The acetyl oxygen-butyl; Acetyl oxygen amyl group; Acetyl oxygen hexyl; Acetyl oxygen heptyl; Acetyl oxygen octyl group; Acetyl oxygen nonyl; Acetyl oxygen decyl; Propionyl oxygen methyl; Propionyl oxygen ethyl; Propionyl oxygen propyl group; The propionyl oxygen-butyl; Propionyl oxygen amyl group; Propionyl oxygen hexyl; Propionyl oxygen heptyl; The third oxygen octyl group; Propionyl oxygen nonyl; Propionyl oxygen decyl; Benzoyl oxygen methyl; Benzoyl oxygen ethyl; Benzoyl oxygen propyl group; The benzoyl oxygen-butyl; Benzoyl oxygen amyl group; Benzoyl oxygen hexyl; Benzoyl oxygen heptyl; Benzoyl oxygen octyl group etc.; Most preferably be the methanoyl methyl; The methanoyl ethyl; The methanoyl propyl group; The methanoyl butyl; The methanoyl amyl group; The methanoyl hexyl; Acetyl-o-methyl; Acetyl oxygen ethyl; Acetyl oxygen propyl group; The acetyl oxygen-butyl; Acetyl oxygen amyl group; Acetyl oxygen hexyl; Acetyl oxygen heptyl; Acetyl oxygen octyl group; Acetyl oxygen nonyl; Acetyl oxygen decyl; Benzoyl oxygen methyl; Benzoyl oxygen ethyl; Benzoyl oxygen propyl group; The benzoyl oxygen-butyl; Benzoyl oxygen amyl group; Benzoyl oxygen hexyl; Benzoyl oxygen heptyl; Benzoyl oxygen octyl group etc.
Described acyl sulfane base is meant the acyl sulfane base with 2～15 carbon atoms.Be preferably the formyl thiomethyl; Formyl sulphur ethyl; The formyl thiopropyl; Formyl sulphur butyl; Formyl sulphur amyl group; Formyl sulphur hexyl; Formyl sulphur heptyl; Formyl sulphur octyl group; Formyl sulphur nonyl; Formyl sulphur decyl; The acetyl thiomethyl; Acetyl sulphur ethyl; The acetyl thiopropyl; Acetyl sulphur butyl; Acetyl sulphur amyl group; Acetyl sulphur hexyl; Acetyl sulphur heptyl; Acetyl sulphur octyl group; Acetyl sulphur nonyl; Acetyl sulphur decyl; The propionyl thiomethyl; Propionyl sulphur ethyl; The propionyl thiopropyl; Propionyl sulphur butyl; Propionyl sulphur amyl group; Propionyl sulphur hexyl; Propionyl sulphur heptyl; The rosickyite octyl group; Propionyl sulphur nonyl; Propionyl sulphur decyl; The benzoyl thiomethyl; Benzoyl sulphur ethyl; The benzoyl thiopropyl; Benzoyl sulphur butyl; Benzoyl sulphur amyl group; Benzoyl sulphur hexyl; Benzoyl sulphur heptyl; Benzoyl sulphur octyl group etc.; Most preferably be the formyl thiomethyl; Formyl sulphur ethyl; The formyl thiopropyl; Formyl sulphur butyl; Formyl sulphur amyl group; Formyl sulphur hexyl; The acetyl thiomethyl; Acetyl sulphur ethyl; The acetyl thiopropyl; Acetyl sulphur butyl; Acetyl sulphur amyl group; Acetyl sulphur hexyl; Acetyl sulphur heptyl; Acetyl sulphur octyl group; Acetyl sulphur nonyl; Acetyl sulphur decyl; The benzoyl thiomethyl; Benzoyl sulphur ethyl; The benzoyl thiopropyl; Benzoyl sulphur butyl; Benzoyl sulphur amyl group; Benzoyl sulphur hexyl; Benzoyl sulphur heptyl; Benzoyl sulphur octyl group etc.
Described acid amides alkyl is meant the acid amides alkyl with 3～15 carbon atoms.Be preferably the methane amide methyl; The methane amide ethyl; The methane amide propyl group; The methane amide butyl; The methane amide amyl group; The methane amide hexyl; The methane amide heptyl; The methane amide octyl group; The methane amide nonyl; The methane amide decyl; The ethanamide methyl; The ethanamide ethyl; The ethanamide propyl group; The ethanamide butyl; The ethanamide amyl group; The ethanamide hexyl; The ethanamide heptyl; The ethanamide octyl group; The ethanamide nonyl; The ethanamide decyl; The propionic acid amide methyl; The propionic acid amide ethyl; The propionic acid amide propyl group; The propionic acid amide butyl; The propionic acid amide amyl group; The propionic acid amide hexyl; The propionic acid amide heptyl; The propylamine octyl group; The propionic acid amide nonyl; The propionic acid amide decyl; The BM methyl; The BM ethyl; The BM propyl group; The BM butyl; The BM amyl group; The BM hexyl; The BM heptyl; The BM octyl group; Methoxy carbonyl amine methyl; Methoxy carbonyl amine ethyl; Methoxy carbonyl amine propyl group; Methoxy carbonyl amine butyl; Methoxy carbonyl amine amyl group; Methoxy carbonyl amine hexyl; Methoxy carbonyl amine heptyl; Methoxy carbonyl amine octyl group; Methoxy carbonyl amine nonyl; Methoxy carbonyl amine decyl; Ethoxy carbonyl amine methyl; Ethoxy carbonyl amine ethyl; Ethoxy carbonyl amine propyl group; Ethoxy carbonyl amine butyl; Ethoxy carbonyl amine amyl group; Ethoxy carbonyl amine hexyl; Ethoxy carbonyl amine heptyl; Ethoxy carbonyl amine octyl group; Ethoxy carbonyl amine nonyl; Ethoxy carbonyl amine decyl; Benzyloxy carbonyl amine methyl; Benzyloxy carbonyl amine ethyl; Benzyloxy carbonyl amine propyl group; Benzyloxy carbonyl amine butyl; Benzyloxy carbonyl amine amyl group; Benzyloxy carbonyl amine hexyl; Benzyloxy carbonyl amine heptyl; Benzyloxy carbonyl amine octyl group; Benzyloxy carbonyl amine nonyl; Benzyloxy carbonyl amine decyl; Phthalimide methyl; The phthalic imidine ethyl; The phthalic imidine propyl group; The phthalic imidine butyl; The phthalic imidine amyl group; The phthalic imidine hexyl; Phthalic imidine heptyl etc.; Most preferably be the methane amide methyl; The methane amide ethyl; The methane amide propyl group; The methane amide butyl; The methane amide amyl group; The methane amide hexyl; The methane amide heptyl; The ethanamide methyl; The ethanamide ethyl; The ethanamide propyl group; The ethanamide butyl; The ethanamide amyl group; The ethanamide hexyl; The ethanamide heptyl; Methoxy carbonyl amine methyl; Methoxy carbonyl amine ethyl; Methoxy carbonyl amine propyl group; Methoxy carbonyl amine butyl; Methoxy carbonyl amine amyl group; Methoxy carbonyl amine hexyl; Methoxy carbonyl amine heptyl; Methoxy carbonyl amine octyl group; Methoxy carbonyl amine nonyl; Methoxy carbonyl amine decyl; Ethoxy carbonyl amine methyl; Ethoxy carbonyl amine ethyl; Ethoxy carbonyl amine propyl group; Ethoxy carbonyl amine butyl; Ethoxy carbonyl amine amyl group; Ethoxy carbonyl amine hexyl; Ethoxy carbonyl amine heptyl; Ethoxy carbonyl amine octyl group; Ethoxy carbonyl amine nonyl; Ethoxy carbonyl amine decyl; Benzyloxy carbonyl amine methyl; Benzyloxy carbonyl amine ethyl; Benzyloxy carbonyl amine propyl group; Benzyloxy carbonyl amine butyl; Benzyloxy carbonyl amine amyl group; Benzyloxy carbonyl amine hexyl; Benzyloxy carbonyl amine heptyl; Benzyloxy carbonyl amine octyl group; Benzyloxy carbonyl amine nonyl; Benzyloxy carbonyl amine decyl; The succimide base; The succimide methyl; Phthalimide-based; Phthalimide methyl; The phthalic imidine ethyl; The phthalic imidine propyl group; The phthalic imidine butyl; The phthalic imidine amyl group; The phthalic imidine hexyl; Phthalic imidine heptyl etc.
Preferred R
1Represent 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, p-methylphenyl, rubigan, to bromophenyl, to fluorophenyl, p-nitrophenyl, p-methoxyphenyl, phenmethyl, styroyl, hydrocinnamyl, benzene butyl, benzene amyl group; More preferably 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, phenyl, phenmethyl, styroyl, hydrocinnamyl, benzene butyl, most preferably hydrogen, 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, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, phenmethyl, styroyl, hydrocinnamyl, methanoyl methyl, methanoyl ethyl, methanoyl propyl group, acetyl-o-methyl, acetyl oxygen ethyl, acetyl oxygen propyl group, acetyl thiomethyl, acetyl sulphur ethyl, acetyl thiopropyl, methoxy carbonyl amine methyl, methoxy carbonyl amine ethyl, methoxy carbonyl amine propyl group, ethoxy carbonyl amine methyl, ethoxy carbonyl amine ethyl, ethoxy carbonyl amine propyl group, benzyloxy carbonyl amine methyl, benzyloxy carbonyl amine ethyl, benzyloxy carbonyl amine propyl group, succimide base, phthalimide-based.
Preferred R
2Represent 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, 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 1
-It is for example following to replace Homotaurine
3a～
3iNine kinds of compounds:
3a：R
1?=?
n Am,?R
2?=?Et;
3b：R
1?=?
n Pr?H,?R
2＝Et;
3c：R
1?=?
cHex,?R
2?=?Et;
3d：R
1?=?Ph(CH
2)
2,?R
2?=?Et;
3e：R
1?=?Bn,?R
2＝?Et;
3f：R
1?=?Ph,?R
2＝?Et;
3g：R
1?=?OH,?R
2?=?Et;
3h:R
1=SO
3H, R
2=Et; (annotate: in this embodiment, in formula 1 and formula 2, R
1=SAc)
3i：R
1?=?PhthN,?R
2?=?Et;
Above-mentioned preparation method normally obtains corresponding xanthate through dithiocarbonic acid-O-alkyl-S-phthalimide methyl ester to the free radical addition of end group alkene, again through oxygenant oxidation preparation
NThe 1-of-phthaloyl protection replaces Homotaurine, can obtain 1-at acid or alkali catalyzed hydrolysis or hydrazinolysis then and replace Homotaurine.
Above-mentioned preparation method, the dithiocarbonic acid that said raw material is used-
O-alkyl-
S-phthalimide methyl ester and end group alkene can buy through disclosed commercial market channel, or prepare through the compound method of bibliographical information.
Above-mentioned preparation method, described dithiocarbonic acid-
O-alkyl-
SCatalyzer in-phthalimide methyl ester and the end group olefine reaction is a radical initiator, can be superoxide, like peroxide lauryl (DLP), BPO (BPO), tertbutyl peroxide (TBHP); Also can be azo compound, like Diisopropyl azodicarboxylate (AIBN), ABVN (ABVN) etc.
Above-mentioned preparation method, said oxygenant is organic peracid, amine normally
N-oxide compound, and other oxygenants.
Above-mentioned preparation method,
NThe 1-substituted taurine of-phthaloyl protection is through removing
N-protection obtains the 1-substituted taurine; The method that removes the protection base can adopt through hydrazinolysis, acid or basic hydrolysis etc.
Above-mentioned preparation method, stirring reaction 1～24 h under the temperature of 0 ° of C～100 ° C usually.
Above-mentioned preparation method, free radical addition reaction used solvent usually is halohydrocarbon or their miscellanys such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane, zellon.
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.
Above-mentioned preparation method, deprotection reaction usually used solvent is formic acid, acetate, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, water, THF, dioxane, acetonitrile, methyl alcohol, ethanol, propyl alcohol, Virahol or their miscellany.
Advantage of the present invention and positively effect:
The 1-of the present invention's preparation replaces Homotaurine because of its biological activity has the potential pharmaceutical use, can be used as the haptin of medicine, enzyme inhibitors, antiseptic-germicide, tensio-active agent, plant-growth regulator, preparation abzyme, the raw material of synthetic sulfonyl peptide etc.
Preparing method provided by the invention, be simple and easy to dithiocarbonic acid-
O-alkyl-
S-phthalimide methyl ester and end group alkene are raw material, and 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-phthalimide-based-3-sulfonic acid in the ninth of the ten Heavenly Stems
3aPreparation
Add in the 50 mL there-necked flasks dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester (xanthate) (562 mg, 2 mmol) vacuumizes N
2Protection adds positive octene (448 mg down; 4 mmol) 1 mL 1; 2-ethylene dichloride (DCE) solution adds 21 mg lauroyl peroxides (DLP) (2.5 mol%), TLC detection reaction behind 90 ℃ of oil bath refluxed 5 min; Whenever complete at a distance from 45 min adding DLP (1.25-10 mol%) up to the raw material xanthogenate reaction, stopped reaction.Reaction solution revolves and desolventizes after the silicagel column separation obtains suc as formula the adduct shown in 2.
Add above-mentioned adduct (353 mg, 1 mmol) in the 25 mL round-bottomed flasks, add 1 mL THF dissolving after, add 5 mL anhydrous formic acids, in ice-water bath, place 10 min, slowly drip 30% H under the magnetic agitation
2O
2(1 mL), the reaction stirred overnight.Revolve and desolventize, silicagel column separates that (eluent sherwood oil: ETHYLE ACETATE=3:1 is to 0:1 or methyl alcohol: methylene dichloride=1:12) obtains 1-phthalimide-based-3-sulfonic acid in the ninth of the ten Heavenly Stems, brown oily liquids, productive rate 66%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?0.48?(s,?3H,?CH
3),?0.82-1.09?(m,?8H,?4CH
2),?1.28?(s,?1H?in?CH
2),?1.62?(s,?2H?in?2CH
2),?1.87?(s,?1H?in?CH
2),?2.49?(s,?1H,?SCH),?3.51?(s,?2H,?NCH
2),?7.53?(d,?
J?=?7.3?Hz,?4H,?ArH).?
13C?NMR?(D
2O
,?100MHz)?
d?ppm:?13.5,?22.0,?26.1,?28.0,?28.5,?29.4,?31.2,?36.1,?51.7,?123.1,?132.1,?134.5,?169.3.
Embodiment two
1-phthalimide-based-3-sulfonic acid in heptan
3bPreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and n-hexylene are that raw material obtains 1-phthalimide-based-3-sulfonic acid in heptan, brown oily liquids, productive rate 57%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?0.63?(t,?
J?=?7.0?Hz,?3H,?CH
3),?1.03-1.26?(m,?4H,?2CH
2),?1.34-1.42?(m,?1H?in?CH
2),?1.62-1.72?(m,?2H?in?2CH
2),?1.91?(dddd,?
J?=?13.1,?6.6,?6.5,?6.3?Hz,?1H?in?NCH
2),?2.53-2.58?(m,?1H,?SCH),?3.52?(t,?
J?=?7.1?Hz,?2H,?NCH
2),?7.50-7.57?(m,?4H,?ArH).?
13C?NMR?(D
2O
,?100MHz)?
d?ppm:?13.1,?21.9,?28.0,?29.0,?28.3,?35.9,?57.8,?123.2,?130.9,?134.7,?170.0.
Embodiment three
1-cyclohexyl-4-phthalimide-based-2-fourth sulfonic acid
3cPreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and 3-cyclohexyl-1-propylene are that raw material obtains 1-cyclohexyl-4-phthalimide-based-2-butane sulfonic acid, pale yellow oily liquid body, productive rate 73%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?0.50-1.48?(m,?13H,?CH
2?&?H?in?cyclohexyl),?1.69?(s,?1H?in?CH
2),?1.90?(s,?1H?CH
2),?2.63?(s,?1H,?SCH),?3.56?(s,?1H,?1H?in?NCH
2),?3.61?(s,?1H?in?NCH
2),?7.58?(s,?4H,?ArH).?
13C?NMR?(D
2O
,?100MHz)?
d?ppm:?25.6,?25.9,?26.0,?28.6,?31.8,?33.6,?34.5,?36.3,?37.3,?55.2,?123.2,?132.0,?134.7,?169.9,?214.2.
Embodiment four
1-phthalimide-based-own the sulfonic acid of 6-phenyl-3-
3dPreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and 5-phenyl-1-amylene are that raw material obtains 1-phthalimide-based-3-sulfonic acid in the ninth of the ten Heavenly Stems, brown oily liquids, productive rate 67%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?1.11-1.34?(m,?3H,?CH
2?&?1H?in?CH
2),?1.48?(dddd,?
J?=?13.3,?6.9,?6.8,?6.4?Hz,?1H?in?CH
2),?1.50-1.65?(m,?1H?in?CH
2),?1.73?(dddd,?
J?=?13.3,?6.9,?6.7,?6.6?Hz,?1H?in?CH
2),?2.09?(ddd,?
J?=?14.9,?7.5,?7.4?Hz,?1H?in?CH
2),?2.68?(ddd,?
J?=?14.5,?7.4,?6.9?Hz,?1H?in?CH
2),?2.44?(dddd,?
J?=?5.4,?5.4,?4.9,?4.7?Hz,?1H,?SCH),?3.30?(t,?
J?=?7.1?Hz,?2H,?NCH
2),?6.67(dd,
?J?=?7.8,?7.8?Hz,?3H,?ArH),?6.75?(d,
?J?=?7.2?Hz,?1H,?ArH),?6.77?(d,
?J?=?7.5?Hz,?1H,?ArH),?7.24?(s,?4H,?ArH).?
13C?NMR?(D
2O
,?100MHz)?
d?ppm:?27.9,?29.0,?34.9,?35.8,?57.6,?123.0,?125.5,?128.0,?128.1,?130.9,?134.3,?142.0,?169.1.
Embodiment five
1-phthalimide-based-5-phenyl-3-penta sulfonic acid
3ePreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and 4-phenyl-1-butylene are that raw material obtains 1-phthalimide-based-3-penta sulfonic acid, brown oily liquids, productive rate 76%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?1.50-1.65?(m,?2H,?CH
2),?1.84-2.01?(m,?2H,?CH
2),?2.30-2.38?(m,?1H,?SCH),?2.45?(s,?2H,?CH
2),?3.36-3.48?(m,?2H,?NCH
2),?6.81?(s,?5H,?ArH),?7.30-7.44?(m,?4H,?ArH).?
13C?NMR?(D
2O
,?100MHz)?
d?ppm:?27.9,?30.5,?31.8,?35.8,?56.6,?123.2,?125.9,?128.1,?128.4,?130.9,?134.5,?140.9,?169.7.
Embodiment six
4-phthalimide-based-1-phenyl-2-fourth sulfonic acid
3fPreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and 3-phenyl-1-propylene are that raw material obtains 4-phthalimide-based-1-phenyl-2-fourth sulfonic acid, brown oily liquids, productive rate 66%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?1.46-1.53?(m,?1H?in?CH
2),?1.81?(dddd,?
J?=?15.0,?5.3,?5.2,?4.8?Hz,?1H?in?CH
2),?2.17?(dd,?
J?=?12.5,?12.4?Hz,?1H?in?CH
2),?2.60-2.65?(m,?1H,?SCH),?2.93?(dd,?
J?=?13.3,?2.5?Hz,?1H?in?CH
2),?3.11?(ddd,?
J?=?14.2,?4.7,?4.6?Hz,?1H?in?NCH
2),?3.27-3.35?(m,?1H?in?NCH
2),?6.40?(dd,
?J?=?7.4,?7.2?Hz,?1H,?ArH),?6.53?(dd,
?J?=?7.4,?6.8?Hz,?2H,?ArH),?6.66?(d,
?J?=?7.7?Hz,?2H,?ArH),?7.20-7.23?(m,?2H,?ArH),?7.37-7.40?(m,?2H,?ArH).?
13C?NMR?(D
2O
,?100MHz)?
d?ppm:?27.2,?36.2,?36.8,?59.6,?123.1,?126.2,?128.3,?128.7,?130.6,?134.4,?137.6,?169.6.
Embodiment seven
4-phthalimide-based-1-hydroxyl-2-fourth sulfonic acid
3gPreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and vinyl carbinol are raw material, and rotary evaporation desolventized after reaction was accomplished, and resistates is used water dissolution; Remove impurity with washed with dichloromethane; Again water is removed and obtained 4-phthalimide-based-1-hydroxyl-2-fourth sulfonic acid, white solid, fusing point 80 ~ 81
oC, productive rate 59%.
1H?NMR?(D
2O
,?400MHz)?
d?ppm:?1.87?(dddd,?
J?=?14.1,?7.2,?7.0,?7.0?Hz,?1H?in?CH
2),?2.14?(dddd,?
J?=?14.1,?7.6,?7.6,?5.6?Hz,?1H?in?CH
2),?2.82?(dddd,?
J?=?6.1,?6.1,?5.6,?5.6?Hz,?1H,?SCH
2),?3.69?(dd,?
J?=?12.0,?6.8?Hz,?1H?in?OCH
2),?3.88?(dd,?
J?=?12.0,?5.1?Hz,?1H?in?SCH
2),?7.61?(s,?4H,?ArH).?
13C?NMR?(CDCl
3,?100MHz)?
d?ppm:?25.8,?35.9,?59.4,?60.4,?123.2,?131.1,?134.6,?170.3?.
Embodiment eight
4-phthalimide-based-1,2-fourth disulfonic acid
3hPreparation
Press among the embodiment seven method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester and acetate allyl mercaptan ester are that raw material obtains 4-phthalimide-based-1,2-fourth disulfonic acid, faint yellow solid, fusing point 175 ~ 176
oC, productive rate 36%.
1H?NMR?(CDCl
3,?400MHz)?
d?ppm:?2.16?(dddd,?
J?=?14.0,?7.4,?6.5,?6.5?Hz,?1H?in?CH
2),?2.29?(dddd,?
J?=?14.0,?7.6,?6.5,?6.5?Hz,?1H?in?CH
2),?2.92?(dd,?
J?=?14.1,?10.8?Hz,?1H?in?SCH
2),?3.20?(dddd,?
J?=?10.8,?10.2,?7.8,?7.8?Hz,?1H?in?SCH),?3.30?(dd,?
J?=?14.0,?1.6?Hz,?1H?in?SCH
2),?3.79?(ddd,?
J?=?12.4,?6.2,?6.2?Hz,?1H?in?NCH
2),?3.87?(ddd,?
J?=?12.4,?6.4,?6.4?Hz,?1H?in?NCH
2),?7.69-7.76?(m,4H,?ArH)?
13C?NMR?(CDCl
3,?100MHz)?
d?ppm:?28.4,?33.06.4,?51.3,?54.8,?123.2,?131.4,?134.5,?170.7.
Embodiment nine
1,4-two phthalimide-baseds-2-fourth sulfonic acid
3iPreparation
Press among the embodiment one method of describing, with dithiocarbonic acid-
O-ethyl-
S-phthalimide methyl ester with
N-allyl group phthalic imidine is that raw material obtains 1,4-two phthalimide-baseds-2-fourth sulfonic acid, white solid, fusing point 167 ~ 168
oC, productive rate 36%.
Claims (8)
1. one kind
N-phthalyl protection 1-replaces the preparation method of Homotaurine, xanthate shown in the formula [1] and end group alkene are carried out addition reaction obtain corresponding xanthate [2], again through and oxygenant stir the generation oxidizing reaction, obtain shown in the formula [3]
NThe 1-of-phthaloyl protection replaces Homotaurine;
Formula 1 formula 2
Formula 3 formulas 4
Wherein: R
1Expression has the alkyl of 1～15 carbon atom; Naphthenic base with 3～15 carbon atoms; Cycloalkylalkyl with 4～15 carbon atoms; Aryl with 6～15 carbon atoms; Aralkyl with 7～15 carbon atoms; Alkoxyalkyl with 2～15 carbon atoms; Alkylamino radical alkyl with 2～15 carbon atoms; Aryloxyalkyl group with 7～15 carbon atoms; Arylamine alkyl with 7～15 carbon atoms; Aralkyl oxy with 7～15 carbon atoms; Hydroxyalkyl with 1～15 carbon atom; Acyloxyalkyl group with 3～15 carbon atoms; Acyl sulfane base with 3～15 carbon atoms; Has the acid amides alkyl of 3～15 carbon atoms etc.; R
2The expression have 1～10 carbon atom alkyl, have 3～10 carbon atoms naphthenic base, have 4～10 carbon atoms cycloalkylalkyl, have 6～10 carbon atoms aryl, have the aralkyl of 7～10 carbon atoms etc.
2. among the preparation method of substituted taurine as claimed in claim 1, by
NShown in the allylamine of-protection and the xanthogenate reaction synthesis type [3]
NThe catalyzer of-protection aminoalkyl group xanthate is a radical initiator, it is characterized in that its catalyzer can be selected from: peroxide lauryl, BPO, tertbutyl peroxide, Diisopropyl azodicarboxylate, ABVN etc.
3. as claimed in claim 1
N-protection 1-replaces the preparation method of Homotaurine, it is characterized in that described oxygenant is the oxynitride of organic peracid or amine.
4. the preparation method of substituted taurine as claimed in claim 1 is characterized in that the addition reaction solvent for use is selected from: halohydrocarbon or their miscellanys such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane, zellon.
5. the preparation method of substituted taurine as claimed in claim 1 is characterized in that the addition 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.
6. as claimed in claim 1
N-protection 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.
7. as claimed in claim 1
N-protection 1-replaces the preparation method of Homotaurine, it is characterized in that synthesizing two amino Homotaurines and two sulfo group Homotaurines.
8. claim 1 is described
N-protection 1-replaces the preparation method of Homotaurine, it is characterized in that
N-protection 1-replaces Homotaurine and can prepare 1-through acid or alkali catalyzed hydrolysis or hydrazinolysis and replace Homotaurine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898335A (en) * | 2012-09-27 | 2013-01-30 | 北京化工大学 | Method for preparing 1-substituted taurine |
| CN106588708A (en) * | 2016-11-18 | 2017-04-26 | 塔里木大学 | Method for synthesizing Gemini surfactant |
| CN109265364A (en) * | 2018-09-21 | 2019-01-25 | 中国烟草总公司郑州烟草研究院 | A kind of preparation and application of pendimethalin haptens and antigen |
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| JPS5142093B1 (en) * | 1970-06-30 | 1976-11-13 | ||
| 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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| JPS5142093B1 (en) * | 1970-06-30 | 1976-11-13 | ||
| 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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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898335A (en) * | 2012-09-27 | 2013-01-30 | 北京化工大学 | Method for preparing 1-substituted taurine |
| CN106588708A (en) * | 2016-11-18 | 2017-04-26 | 塔里木大学 | Method for synthesizing Gemini surfactant |
| CN108047098A (en) * | 2016-11-18 | 2018-05-18 | 塔里木大学 | The method for synthesizing Gemini surface active agent |
| CN108117498A (en) * | 2016-11-18 | 2018-06-05 | 塔里木大学 | A kind of synthetic method of Gemini surface active agent |
| CN108047098B (en) * | 2016-11-18 | 2020-04-07 | 塔里木大学 | Method for synthesizing gemini surfactant |
| CN108117498B (en) * | 2016-11-18 | 2020-04-07 | 塔里木大学 | Synthesis method of gemini surfactant |
| CN109265364A (en) * | 2018-09-21 | 2019-01-25 | 中国烟草总公司郑州烟草研究院 | A kind of preparation and application of pendimethalin haptens and antigen |
| CN109265364B (en) * | 2018-09-21 | 2021-02-02 | 中国烟草总公司郑州烟草研究院 | Preparation and application of pendimethalin hapten and antigen |
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