CN102675165A - Preparation method of N-carbobenzoxy-2-amino-alkyl sulfonamide - Google Patents
Preparation method of N-carbobenzoxy-2-amino-alkyl sulfonamide Download PDFInfo
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Abstract
The invention provides a preparation method of N-carbobenzoxy-2-amino-alkyl sulfonamide. The preparation method of N-carbobenzoxy-2-amino-alkyl sulfonamide includes using vicinal alkamine as material, and sequentially performing carboxybenzyl protection, Mitsunobu reaction, NCS (N-chlorosuccinimide) oxidation and ammonolysis reaction to obtain the N-carbobenzoxy-2-amino-alkyl sulfonamide. The materials used in the method are nontoxic and easy to obtain, simple and convenient to operate, high in reproducibility and high in yield. The preparation method is a current most effective method of synthesizing amino-alkyl sulfonamide. The obtained compound can be used as an enzymatic inhibitor, raw materials to prepare sulfonopeptide and the like.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide.
Background technology
2-aminoalkyl group sulphonamide is one type of organic micromolecule compound with important biomolecule function, and this compounds is widely used as the suppressor factor of enzyme.For example, can be used as suppressor factor (Piscitelli, the F. of wild-type non-nucleoside HIV-1-1; Coluccia, A.; Brancale, A.; Regina, G. L.; Sansone, A.; Giordano, C.; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; Cirilli, R.; Torre, F. L.; Lavecchia, A.; Novellino, E.; Silvestri, R.
J. Med.Chem. 2009,
52,1922), thrombin inhibitors (Lowik, D. W. P. M.; Liskamp, R. M. J.
Eur. J. Org. Chem. 2000, 1219) etc.2-aminoalkyl group sulphonamide also is amino acid whose one type of important analogue (Moree, the W. J. with tetrahedral structure of native protein; Van der Marel, G. A. van Boom, J. H.; Liskamp, R. M. J.
Tetrahedron,
1993,
49, 11055), the 2-aminoalkyl group sulphonamide of N-protected is important source material and monomer (He, the F. D. of synthetic sulfonyl peptide and some hybridization peptides; Meng, F. H.; Song, X. Q.; Hu, W. X.; Xu, J. X.
Org. Lett.
2009,
17, 3922; Meng, F. H.; He, F. D.; Song, X. Q.; Zhang, L. L.; Hu, W. X.; Liu, G.; Xu, J. X.
Amino Acids, 2011, online published.).Sulfonyl peptide can be simulated the transition state of ester bond and amido linkage hydrolysis as the another kind of sulfur containing analogs with tetrahedral structure of native peptides, therefore also is widely used in enzyme inhibitors and induces haptin (.Moree, the W. J. of abzyme; Van der Marel, G. A.; Liskamp, R. M. J.
Tetrahedron Lett. 1991 , 32 (3),409; Gennari, C.; Longari, C.; Ressel, S.; Salonm B.; Piarulli, U.; Ceccarelli, S.; Mielgo, A.
Eur. J. Org. Chem. 1998, 2437; Xu, J. X.
Chin J. Org. Chem. 2003,
23, 1; Carson, K. G.; Schwender, C. F.; Shroff, H. N.; Cochran, N. A.; Gallant, D. L.; Briskin, M. J.
Bioorg. Med. Chem. Lett. 1997,
7,711).
2-aminoalkyl group sulphonamide with different structure will show different biological functions, and the method for therefore developing the multifarious 2-aminoalkyl group of a kind of effective composite structure sulphonamide is extremely important.
NThe preparation method that the 2-aminoalkyl group sulphonamide of-protection has been reported comprises: with
NThe amino acid of-protection is starting raw material; Successively make aminoalkyl group sulfonic acid through reduction reaction, esterification, nucleophilic substitution reaction and oxidizing reaction; Obtain corresponding aminoalkyl group SULPHURYL CHLORIDE with the reaction of phosgene or TRIPHOSGENE 99.5 again, this aminoalkyl group SULPHURYL CHLORIDE directly ammonia separate/aminolysis makes
NAminoalkyl group sulphonamide (Brouwer, the A.J. of-protection; Monnee, M. C. F.; Liskamp, R. M. J.
Synthesis, 2000, 1579); Perhaps also can aminoalkyl group SULPHURYL CHLORIDE and reaction of sodium azide be processed the aminoalkyl group sulfuryl azide makes through reduction reaction again
NAminoalkyl group sulphonamide (Rijkers, the D. T. S. of-protection; Merkx, R.; Yim, C. B.; Brouwer, A. J.; Liskamp, R. M. J.
J. Pept. Sci. 2010,
16, 1-5); Also can make aminoalkyl group sulphonamide (Brouwer, the A. J of N-protected through the Staudinger reaction; Merkx, R.; Dabrowska, K.; Rijkers, D. T. S.; Liskamp, R. M. J.
Synthesis 2005,455); Perhaps with
NThe amino alcohol of-protection is a starting raw material, converts it into aminoalkyl group sulfonic acid, makes the aminoalkyl group SULPHURYL CHLORIDE with thionyl chloride or oxalyl chloride reaction again, and ammonia is separated and made then
NAminoalkyl group sulphonamide (He, the F. D. of-protection; Meng, F. H.; Song, X. Q.; .Hu, W. X.; Xu, J. X.
Org. Lett.
2009,
17, 3922. Hara, T.; Durell, S. R.; Myers, M.C.; Appella, D. H.,
J. Am. Chem. Soc. 2006, 128,1995); Perhaps with
NThe amino acid of-protection is starting raw material; Successively make acetate amineothiot ester through reduction reaction, esterification, nucleophilic substitution reaction or a step Mitsunobu reaction; Through chlorination sulfone or chlorine it is oxidized to the aminoalkyl group sulphinyl chlorine again, this aminoalkyl group sulphinyl chlorine separates through ammonia and oxidizing reaction obtains
NAminoalkyl group sulphonamide (Lowik, the D. W. P. M. of-protection; Liskamp, R. M. J.
Eur. J. Org. Chem. 2000, 1219; Moree, W. J.; Van der Marel, G. A.; Liskamp, R. J.
J. Org. Chem. 1995,
60, 5157); Perhaps with
NThe amino alcohol of-protection is a starting raw material, and reaction makes acetate amineothiot ester through Mitsunobu, through the chlorination sulfone it is oxidized to the aminoalkyl group sulphinyl chlorine again, and this aminoalkyl group sulphinyl chlorine separates through ammonia and oxidizing reaction obtains
NAminoalkyl group sulphonamide (Moree, the W. J. of-protection; Van der Marel, G. A.; Liskamp, R. J.
J. Org. Chem. 1995,
60, 5157); Be that starting raw material makes disulfide compound with adjacent amineothiot perhaps, become SULPHURYL CHLORIDE or sulphinyl chlorine through chlorine oxidation again, the further ammonia of SULPHURYL CHLORIDE is separated or sulphinyl chlorine ammonia makes through peroxidation after separating again
NAminoalkyl group sulphonamide (Moree, the W. J. of-protection; Van Gent, L. C.; Van der Marel, G. A.; Liskamp, R.M. J.
Tetrahedron 1993,
49, 1133; Moree, W. J.; Van der Marel, G. A.; Liskamp, R. M. J.
Tetrahedron Lett. 1992,
33, 6389; Luisi, G. Calcagni, A. Pinnen, F.
Tetrahedron Lett. 1993,
34, 2391).
Above method all exists reaction scheme long, aftertreatment trouble, and shortcomings such as the low and poor reproducibility of productive rate are unfavorable for scale operation.Particularly in the preparation method; What have has also used poisonous even poisonous reagents such as phosgene, TRIPHOSGENE 99.5, chlorine, chlorination sulfone; And with the vicinal amino alcohols be raw material in the process of preparation aminoalkyl group sulfonic acid because aminoalkyl group sulfonic acid itself is a kind of inner salt, character is very similar with inorganic salt; The aftertreatment trouble, and can cause product in desalting process, to lose seriously.
Summary of the invention
The present invention is in order to solve the complex process of existing preparation 2-aminoalkyl group sulphonamide; The aftertreatment trouble; Low and the poor reproducibility of productive rate is unfavorable for the technical problem of scale operation, provides a kind of raw material to be simple and easy to; Do not need loaded down with trivial details operation, be suitable for the preparation method of the 2-aminoalkyl group sulphonamide of large-scale commercial prodn.
The purpose of this invention is to provide a kind of
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide, step comprises:
S1: the vicinal amino alcohols with shown in the formula [1] is a raw material, obtains with the chloroformic acid benzyl ester reaction
N-carbobenzoxy-(Cbz)-2-amino alcohol;
S2: with step S1 gained
N-carbobenzoxy-(Cbz)-2-amino alcohol and thioacetic acid prolong the acetic ester that reaction (Mitsunobu) obtains amineothiot through light;
S3: the acetic ester of step S2 gained amineothiot is used
NThe oxidation of-chlorosuccinimide gets
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE;
S4: with step S3 gained
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE solves shown in the formula [5] through ammonia
N-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide;
Wherein, said R is selected from a kind of in hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, alkylamino radical alkyl, the aryloxyalkyl group.
Reaction formula is exemplified as:
Wherein, R is selected from a kind of in hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, alkylamino radical alkyl, the aryloxyalkyl group.
Wherein, alkyl comprises alkyl group and naphthenic base, and naphthenic base and aryl can be fused rings.
Wherein, the alkyl in aralkyl, aryloxyalkyl group, alkoxyalkyl and the alkylamino radical alkyl also all comprises naphthenic base.
Wherein, Alkyl group preferably has the straight or branched alkyl of 1～16 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 further preferably has 1～12 carbon atom especially preferably has the straight or branched alkyl of 1～10 carbon atom, most preferably has the straight or branched alkyl of 1～8 carbon atom.
Naphthenic base preferably has the cyclic alkyl of 3～12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc., preferably cyclopropyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group.
Aryl preferably has the aryl of 6～15 carbon atoms.Be preferably phenyl, substituted-phenyl, 1-naphthyl, 2-naphthyl, xenyl, substituted naphthyl etc.
Aralkyl preferably has the aralkyl of 7～15 carbon atoms.Be preferably phenmethyl, substituted benzene methyl, 1-menaphthyl, 2-menaphthyl, Biphenylmethyl, replacement menaphthyl etc.
Aryloxyalkyl group preferably has the aryloxyalkyl group of 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.
Alkoxyalkyl preferably has the alkoxyalkyl of 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.
The alkylamino radical alkyl preferably has the alkylamino radical alkyl of 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.
Further preferred R is 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, 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 a kind of in 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, the hydrocinnamyl.
Advantage of the present invention and positively effect:
The present invention is raw material with the vicinal amino alcohols, through amido protecting, light prolong reaction,
N(NCS) oxidation of-chlorosuccinimide and ammonolysis reaction make
N-carbobenzoxy-(Cbz)
-2-aminoalkyl group sulphonamide, this method not only advantages of nontoxic raw materials is easy to get, and easy and simple to handle, favorable reproducibility, productive rate is higher, and it is multifarious to be used for composite structure
N-carbobenzoxy-(Cbz)
-2-aminoalkyl group sulphonamide is suitable for large-scale industrial production, has crucial meaning for the research and the application of sulphonamide.
The present invention makes
N-carbobenzoxy-(Cbz)
-2-aminoalkyl group sulphonamide; Has higher biological activity; Have potential medical value and synthetic using value, can be used as the raw material etc. of suppressor factor, antiseptic-germicide, plant-growth regulator, the haptin of preparation abzyme, synthetic sulfonyl peptide and the hybridization peptide of enzyme.
Embodiment
The invention provides a kind of
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide, step comprises:
S1: the vicinal amino alcohols with shown in the formula [1] is a raw material, obtains with the chloroformic acid benzyl ester reaction
N-carbobenzoxy-(Cbz)-2-amino alcohol;
S2: with step S1 gained
N-carbobenzoxy-(Cbz)-2-amino alcohol and thioacetic acid prolong the acetic ester that reaction (Mitsunobu) obtains amineothiot through light;
S3: the acetic ester of step S2 gained amineothiot is used
NThe oxidation of-chlorosuccinimide gets
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE;
S4: with step S3 gained
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE solves shown in the formula [5] through ammonia
N-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide;
Wherein, said R is selected from a kind of of hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, alkylamino radical alkyl, aryloxyalkyl group.
Preferably, vicinal amino alcohols is photoactive amino alcohol.
Preferably, among the step S1,
NThe preparation of-carbobenzoxy-(Cbz)-2-amino alcohol, being reflected in first solvent of vicinal amino alcohols and chloroformic acid benzyl ester carried out, and said first solvent is selected from one or both the miscellany in methylene dichloride, trichloromethane, water, acetonitrile or the ETHYLE ACETATE.The temperature of reaction of step S1 is-30
oC～0
oC, the general reaction of vicinal amino alcohols and chloroformic acid benzyl ester 6～12 hours, the back is separated and is purified
NThe vicinal amino alcohols of-carbobenzoxy-(Cbz) protection promptly
N-carbobenzoxy-(Cbz)-2-amino alcohol separates the not restriction of method the present invention of purifying, and can adopt to well known to a person skilled in the art the whole bag of tricks, for example separates with silica gel column chromatography and purifies.
Preferably, among the step S2, light prolongs reaction, is reflected in second solvent and carries out, and said second solvent is selected from a kind of in methylene dichloride, trichloromethane, THF, toluene, benzene, acetonitrile, sherwood oil or the ETHYLE ACETATE.The reaction conditions of step S2 is-30
oC～20
oStir under the temperature of C.
Preferably, step S2 comprises triphenylphosphine (Ph
3P) with diisopropyl azodiformate (DIAD) reaction, back and step S1 gained
N-carbobenzoxy-(Cbz)-2-amino alcohol and thioacetic acid react the acetic ester of amineothiot.For example can let triphenylphosphine (Ph
3P) generate white solid with diisopropyl azodiformate (DIAD) reaction after, again with step S1 gained
NThe vicinal amino alcohols of-carbobenzoxy-(Cbz) protection and thiacetic mixed solution slowly are added drop-wise in the reaction system reacted 12 hours.Stopped reaction, decompression is removed second solvent and must be glued oil, this sticking oil with the amount of ethyl acetate dissolving after, add bulk petroleum ether, will have a large amount of white solid triphen phosphine oxides to separate out, filter, remainder with column chromatography separate product acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester.
Preferably, among the step S3, oxidation is carried out in the 3rd solvent, and said the 3rd solvent is selected from a kind of in acetonitrile, THF, ETHYLE ACETATE, methylene dichloride, trichloromethane, benzene or the toluene.Oxidizing temperature among the step S3 is-10
oC～20
oC.For example can be for inciting somebody to action
N-chlorosuccinimide joins in the mixed solution of HCl and acetonitrile (MeCN), is cooled to-10
oC～20
oC is with step S2 gained acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester is dissolved among the MeCN ,-10
oC～20
oBe added drop-wise to below the C in the system, after reaction finishes, add isopropyl ether (IPE) dilution, get organic phase with the NaCl solution washing after, use anhydrous Na
2SO
4Drying, decompression is removed the 3rd solvent and is got
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE.
Preferably, among the step S4, ammonia is separated in the 4th solvent and is carried out, and said the 4th solvent is selected from a kind of in methylene dichloride, trichloromethane, THF, benzene or the toluene.The temperature of reaction of step S4 is-30
oC～0
oC.For example can for
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE is used anhydrous CH
2Cl
2After the dilution ,-30
oC～0
oSlowly be added drop-wise under the C condition in 25% the strong aqua, reaction is removed the 4th solvent after finishing, and the back gets 2-aminoalkyl group sulphonamide with ethanol or water recrystallization.
Concrete steps can for:
A. 50 mmol vicinal amino alcohols are dissolved in first solvent ,-30
oC～0 ° C
oUnder the C condition, to wherein slowly d add chloroformic acid benzyl ester, the back adds 250 mmol triethylamine (Et
3N), stirring at normal temperature 12-24 h, first solvent is removed in the back decompression, purify with the silica gel column chromatography separation
NThe vicinal amino alcohols of-carbobenzoxy-(Cbz) protection;
B. under ° C condition of-30 ° of C～20, with 40 mmol triphenylphosphine (Ph
3P) be dissolved among the anhydrous THF, after slowly be added drop-wise in anhydrous tetrahydro furan (THF) solution that contains 40 mmol diisopropyl azodiformates (DIAD), then-30
oC～20
oReact 1～2 h under the C condition and get reaction system, with step a gained
NVicinal amino alcohols 20 mmol of-carbobenzoxy-(Cbz) protection and the anhydrous THF solution of 40 mmol thioacetic acids (HSAc) slowly add in the reaction system ,-30
oC～20
oStir 12～24 h under the C condition, second kind solvent is removed in decompression, the back with the amount of ethyl acetate dissolving after, add bulk petroleum ether, separate out the triphen phosphine oxide, filter, the back with column chromatography separate product acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester;
C. with 120 mmol
N-chlorosuccinimide joins in the mixed solution of HCl and acetonitrile (MeCN), is cooled to-10
oC～20
oC is with step b gained acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester 30 mmol are dissolved among the MeCN ,-10
oC～20
oBe added drop-wise to below the C in the system, continue to keep temperature of reaction to be lower than-10
oC～20
oC stirred after 1～2 hour, added isopropyl ether (IPE) dilution, organic phase with the NaCl solution washing after, use anhydrous Na
2SO
4Drying, removal of solvent under reduced pressure gets
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE;
D. with step c gained
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE is used anhydrous CH
2Cl
2After the dilution ,-30
oC～0
oSlowly add under the C condition in the strong aqua, behind stirring 12～24h, remove and desolvate, the back gets 2-aminoalkyl group sulphonamide with ethanol or water recrystallization.
Wherein, vicinal amino alcohols, chloroformic acid benzyl ester, triethylamine, triphenylphosphine, diisopropyl azodiformate and
N-chlorosuccinimide all can commercially availablely also can prepare by literature method.
Mode through embodiment further specifies the present invention below, does not therefore limit the present invention among the scope of said embodiment.
Embodiment 1-5 makes following R group respectively
5a～
5e N-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide
5a：R = H;
5b： R = Me；
5c： R =
i Pr；
5d： R =
i Bu；
5e： R =Bn；
Implement 1
(1) thanomin with 50 mmol is dissolved in 165 mL CH as vicinal amino alcohols
2Cl
2In, 0
oUnder the C condition, in this system, drip 8.6 mL (10.2 g, 60 mmol) chloroformic acid benzyl ester, add 35 mL (25.3 g, 250 mmol) Et subsequently again
3N, stirring at normal temperature is spent the night, stopped reaction, removal of solvent under reduced pressure gets oily matter, separates to purify obtaining with silica gel column chromatography
NThe vicinal amino alcohols of-carbobenzoxy-(Cbz) protection.
(2)-10
oUnder the C condition, with Ph
3P (10.48 g, 40 mmol) is dissolved among the anhydrous THF of 48 mL, it is slowly dripped (dripping off greater than 30 min) contain in the anhydrous THF solution of diisopropyl azodiformate (DIAD) (8.0 g, 40 mmol), then-10 to 24 mL
oReaction 0.5 h under the C condition generates the adularescent deposition in reaction process.Subsequently will
NThe vicinal amino alcohols (20 mmol) of-carbobenzoxy-(Cbz) protection slowly is added drop-wise in the reaction system with anhydrous THF solution 48 mL of HSAc (3.04 g, 40 mmol) and (drips off greater than 45 min) ,-10
oStirred overnight under the C condition.Stopped reaction, removal of solvent under reduced pressure must be glued oil, this sticking oil with the amount of ethyl acetate dissolving after, add bulk petroleum ether, will have a large amount of white solid triphen phosphine oxides to separate out, filter, remainder with column chromatography separate product acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester.
(3) NCS (16 g, 120 mmol) is joined in the mixed solution of 2 M HCl (8 mL) and MeCN (40 mL), be cooled to 10
oC is with acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester (30 mmol) is dissolved among the MeCN (8 mL), 20
oBe added drop-wise to below the C in the system, continue to keep temperature of reaction to be lower than 20
oAfter C stirs 30 min, add isopropyl ether (IPE) (156 mL) dilution, organic phase with NaCl solution washing (12%, 3 ' 78 mL) after, use anhydrous Na
2SO
4Drying, removal of solvent under reduced pressure gets product
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE.
(4) will
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE is used anhydrous CH
2Cl
2After (20 mL) dilution ,-10
oSlowly be added drop-wise under the C condition in the strong aqua (100 mL), stir 1h after, stopped reaction, remove desolvate crude product, get product 2-benzyloxycarbonyl amino ethyl sulfonamide with ethanol or water recrystallization
5aThe white needles solid, productive rate 81%, fusing point 138.5-140
oC, Lit. m.p. 138.5-140
oC (He, F. D.; Meng, F. H.; Song, X. Q.; . Hu, W. X.; Xu, J. X.
Org. Lett.
2009,
17, 3922).
1H NMR (400 MHz, DMSO-
d 6)
δ: 3.12 (t,
J=7.0 Hz, 2H, CH
2), 3.40 (dt,
J=6.8,7.0 Hz, 2H, CH
2), 5.02 (s, 2H, CH
2), 6.90 (s, 2H, NH
2), 7.30-7.39 (m, 6H, ArH, NH).
13C NMR (100.6 MHz, DMSO-
d 6)
δ: 36.2,54.4,66.0,128.2,128.3,128.8,137.4,156.5.
Embodiment 2
(
SThe preparation of)-2-benzyloxycarbonyl amino sulfonyl propyl amine 5b
Adopt with embodiment 1 identical method and prepare (
S)-2-benzyloxycarbonyl amino sulfonyl propyl amine
5b, different is that used vicinal amino alcohols is (S)-Propanolamine in the step (1), gets colourless needle-like solid, productive rate 63%, fusing point 150-151
oC, [α]
20 D=+10.8 (c, 1.0, MeOH). IR
v(cm-1): 1668 (C=O), 1342 &, 1142 (SO
2);
1H NMR (300 MHz, DMSO-d6)
δ: 1.24 (d, J=6.6 Hz, 3H, CH
3), 3.04 (dd, J=7.5,13.9 Hz, 1H in CH
2SO
2), 3.25 (dd, J=5.3,13.9 Hz, 1H in CH
2SO
2), 4.01 (ddq, J=5.3,13.9,7.5 Hz, 1H, CHN), 5.03 (s, 2H, OCH
2), 6.90 (s, 2H, NH
2), 7.28-7.42 (m, 6H, ArH & NH);
13C NMR (75 MHz, DMSO-d6)
d: 20.4,43.2,59.8,65.3,127.7,127.8,128.3,137.0,155.2; HRMS (ESI) Calcd. for C
11H
17N
2O
4S [M+H]+
M/z273.0904; Found 273.0902.
Embodiment 3
(
SThe preparation of)-2-benzyloxycarbonyl amino-3-methylbutyl sulphonamide 5c
Adopt with embodiment 1 identical method and prepare (
S)-2-benzyloxycarbonyl amino-3-methylbutyl sulphonamide
5c, different is in the step (1) used vicinal amino alcohols for (
S)-valerian ammonia alcohol gets white solid, and productive rate is 80%.Fusing point 113-114
oC. [α]
20 D=+17.2 (
c, 1.0, MeOH). IR
v(cm
-1): 1696 (C=O), 1327 &, 1143 (SO
2);
1H NMR (300 MHz, DMSO-
d 6)
d: 0.82 (d,
J=6.4 Hz, 6H, 2CH
3), 1.81-1.90 (m, 1H,
CH(CH
3)
2), 3.10 (d,
J=6.0 Hz, 2H, CH
2SO
2), 3.85-3.94 (m, 1H, CHN), 5.03 (s, 2H, OCH
2), 6.81 (s, 2H, NH
2), 7.30-7.36 (m, 6H, ArH & NH);
13C NMR (75MHz, DMSO-
d 6)
d: 17.3,18.6,31.6,51.9,56.0,65.1,127.5,127.6,128.3,137.2,155.8; HRMS (ESI,
M/z) Calcd. for C
13H
21N
2O
4S [M+H]
+ M/z301.1217; Found 301.1214.
Embodiment 4
(
SThe preparation of)-2-benzyloxycarbonyl amino-4-methyl amyl sulphonamide 5d
Adopt with embodiment 1 identical method and prepare (
S)-2-benzyloxycarbonyl amino-4-methyl amyl sulphonamide
5d, different is that used vicinal amino alcohols is (S)-leucinol in the step (1), gets white solid, productive rate is 70%.Fusing point 128-129
oC. [α]
20 D=-7.5 (
c, 1.0, MeOH). IR
v(cm
-1): 1683 (C=O), 1326 &, 1152 (SO
2);
1H NMR (300 MHz, DMSO-
d 6)
d: 0.86 (d,
J=6.3 Hz, 6H, 2CH
3), 1.42-1.48 (m, 2H, CH
CH 2 ), 1.56-1.65 (m, 1H,
CH(CH
3)
2), 3.04 (dd,
J=6.0,13.8 Hz, 1H in CH
2SO
2), 3.22 (dd,
J=6.3,13.8 Hz, 1H in CH
2SO
2), 3.94-4.05 (m, 1H, CHN), 5.02 (s, 2H, CH
2Ph), 6.81 (s, 2H, NH
2), 7.29-7.36 (m, 6H, ArH & NH);
13C NMR (75MHz, DMSO-
d 6)
d: 21.4,23.1,24.1,42.7,45.4,59.2,65.1,127.5,127.7,128.2,137.1,155.5; HRMS (ESI) Calcd. for C
14H
22N
2O
4S [M+H]
+ M/z315.1373; Found 315.1370.
Embodiment 5
(
S)-2-benzyloxycarbonyl amino-3-phenyl propyl sulphonamide 5e
Adopt with embodiment 1 identical method and prepare (
S)-2-benzyloxycarbonyl amino-3-phenyl propyl sulphonamide
5e, different is that used vicinal amino alcohols is (S)-phenylalaninol in the step (1), gets white solid, productive rate is 74%.Fusing point 168-169
oC. Lit. m.p. 168-170
oC (He, F. D.; Meng, F. H.; Song, X. Q.; . Hu, W. X.; Xu, J. X.
Org. Lett.
2009,
17, 3922). [α]
20 D=-14.4 (
c, 1.0, MeOH).
1H NMR (400 MHz, DMSO-
d 6)
d: 2.81 (dd,
J=9.0,13.5 Hz, 1H in PhCH
2), 3.02 (dd,
J=5.1,13.6 Hz, 1H in PhCH
2), 3.14 (dd,
J=6.0,14.0 Hz, 1H in CH
2SO
2), 3.25 (dd,
J=6.4,14.0 Hz, 1H in CH
2SO
2), 4.15 (m, 1H, NCH), 5.0 (s, 2H, OCH
2), 6.90 (s, 2H, NH
2), 7.20 7.40 (m, 11H, ArH & NH);
13C NMR (75MHz, DMSO-
d 6)
d: 39.2,48.7,58.1,65.0,126.2,127.3,127.6,128.1,128.2,129.2,137.1,138.0,155.3.
Claims (8)
1. one kind
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide is characterized in that, step comprises,
S1: the vicinal amino alcohols with shown in the formula [1] is a raw material, obtains with the chloroformic acid benzyl ester reaction
N-carbobenzoxy-(Cbz)-2-amino alcohol;
S2: with step S1 gained
N-carbobenzoxy-(Cbz)-2-amino alcohol and thioacetic acid prolong the acetic ester that reaction (Mitsunobu) obtains amineothiot through light;
S3: the acetic ester of step S2 gained amineothiot is used
NThe oxidation of-chlorosuccinimide gets
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE;
S4: with step S3 gained
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE solves shown in the formula [5] through ammonia
N-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide;
Wherein, said R is selected from a kind of in hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, alkylamino radical alkyl, the aryloxyalkyl group.
2. as claimed in claim 1
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide is characterized in that said vicinal amino alcohols is photoactive amino alcohol.
3. as claimed in claim 1
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide; It is characterized in that; Among the said step S1; Being reflected in first solvent of vicinal amino alcohols and chloroformic acid benzyl ester carried out, and said first solvent is selected from one or both the miscellany in methylene dichloride, trichloromethane, water, acetonitrile or the ETHYLE ACETATE;
The temperature of reaction of said step S1 is-30
oC～0
oC, the reaction times is 6～12 hours.
4. as claimed in claim 1
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide; It is characterized in that; Among the said step S2, light prolongs to be reflected in second solvent and carries out, and said second solvent is selected from a kind of in methylene dichloride, trichloromethane, THF, toluene, benzene, acetonitrile, sherwood oil or the ETHYLE ACETATE; The reaction conditions of said step S2 is-30
oC～20
oStir under the temperature of C.
5. as claimed in claim 1
NThe preparation method of-carbobenzoxy-(Cbz)-2-aminoalkyl group sulphonamide is characterized in that said step S2 comprises triphenylphosphine (Ph
3P) with diisopropyl azodiformate (DIAD) reaction, back and step S1 gained
N-carbobenzoxy-(Cbz)-2-amino alcohol and thioacetic acid react the acetic ester of amineothiot.
6. the preparation method of N-carbobenzoxy-(Cbz) as claimed in claim 1-2-aminoalkyl group sulphonamide; It is characterized in that; Among the said step S3; Oxidation is carried out in the 3rd solvent, and said the 3rd solvent is selected from a kind of in acetonitrile, THF, ETHYLE ACETATE, methylene dichloride, trichloromethane, benzene or the toluene; Oxidizing reaction temperature among the said step S3 is-10
oC～20
oC, oxidation time are 1～2 hour.
7. as claimed in claim 1
NThe preparation method of-carbobenzoxy-(Cbz) 2-aminoalkyl group sulphonamide is characterized in that, among the said step S4, ammonia is separated in the 4th solvent and carried out, and said the 4th solvent is selected from a kind of in methylene dichloride, trichloromethane, THF, benzene or the toluene; The temperature of reaction of said step S4 is-30
oC～0
oC, the reaction times is 12～24 hours.
8. as claimed in claim 1
NThe preparation method of-carbobenzoxy-(Cbz) 2-aminoalkyl group sulphonamide is characterized in that said step comprises:
A. 50 mmol vicinal amino alcohols are dissolved in first solvent ,-30
oC～0
oUnder the C condition, to wherein slowly dripping chloroformic acid benzyl ester, the back adds 250 mmol triethylamine (Et
3N), stirring at normal temperature 12～24 h, first solvent is removed in the back decompression, purify with the silica gel column chromatography separation
NThe vicinal amino alcohols of-carbobenzoxy-(Cbz) protection;
B.-30
oC～20
oUnder the C condition, with 40 mmol triphenylphosphine (Ph
3P) be dissolved in the anhydrous tetrahydro furan (THF), after slowly be added drop-wise in the anhydrous tetrahydrofuran solution that contains 40 mmol diisopropyl azodiformates (DIAD), then-30
oC～20
oReact 1～2 h under the C condition and get reaction system, with step a gained
NVicinal amino alcohols 20 mmol of-carbobenzoxy-(Cbz) protection and the anhydrous tetrahydrofuran solution of 40 mmol thioacetic acids (HSAc) slowly are added drop-wise in the reaction system ,-30
oC～20
oStir 12～24 h under the C condition, removal of solvent under reduced pressure, the back adds bulk petroleum ether with after the amount of ethyl acetate dissolving, separates out the triphen phosphine oxide, filter, the back with column chromatography separate acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester;
C. with 120 mmol
N-chlorosuccinimide joins in the mixed solution of HCl and acetonitrile (MeCN), is cooled to-10
oC～20
oC gets reaction system, with step b gained acetate
N-carbobenzoxy-(Cbz)-2-amineothiot ester 30 mmol are dissolved in the acetonitrile ,-10
oC～20
oBe added drop-wise to below the C in the reaction system, continue to keep temperature of reaction-10
oC～20
oC stirred 1～2 hour, and the back adds isopropyl ether (IPE) dilution, get organic phase and use the NaCl solution washing, after use anhydrous Na
2SO
4Drying, removal of solvent under reduced pressure gets
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE;
D. with step c gained
N-carbobenzoxy-(Cbz)-2-aminoalkyl group SULPHURYL CHLORIDE is used anhydrous CH
2Cl
2After the dilution ,-30
oC～0
oSlowly add under the C condition in the strong aqua, behind stirring 12～24h, remove and desolvate, the back gets 2-aminoalkyl group sulphonamide with ethanol or water recrystallization.
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Cited By (3)
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|---|---|---|---|---|
| CN105585517A (en) * | 2016-03-08 | 2016-05-18 | 北京化工大学 | N-chloro-aryl sulphinyl sulfimide and preparation method thereof |
| CN111909060A (en) * | 2020-08-20 | 2020-11-10 | 苏州亚科科技股份有限公司 | Preparation process of N- (2-acetamido) -2-aminoethanesulfonic acid |
| CN115806577A (en) * | 2023-02-03 | 2023-03-17 | 北京鑫开元医药科技有限公司 | Preparation method of breynolone |
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| CN105585517A (en) * | 2016-03-08 | 2016-05-18 | 北京化工大学 | N-chloro-aryl sulphinyl sulfimide and preparation method thereof |
| CN111909060A (en) * | 2020-08-20 | 2020-11-10 | 苏州亚科科技股份有限公司 | Preparation process of N- (2-acetamido) -2-aminoethanesulfonic acid |
| CN111909060B (en) * | 2020-08-20 | 2022-12-27 | 苏州亚科科技股份有限公司 | Preparation process of N- (2-acetamido) -2-aminoethanesulfonic acid |
| CN115806577A (en) * | 2023-02-03 | 2023-03-17 | 北京鑫开元医药科技有限公司 | Preparation method of breynolone |
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