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Preparation method of N-carbobenzoxy-2-amino-alkyl sulfonamide

A technology of amino alkyl sulfonamide and amino alkyl sulfonyl chloride, which is applied in the preparation of sulfonic acid amide, organic chemistry, etc., can solve the problems of troublesome post-processing, poor reproducibility, low yield, etc., and achieves high biological activity and operation Simple, reproducible results

Inactive Publication Date: 2012-09-19
BEIJING UNIV OF CHEM TECH
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Problems solved by technology

[0005] The present invention aims to solve the technical problems that the existing preparation process of 2-aminoalkylsulfonamide is complicated, post-processing is troublesome, the yield is low and the reproducibility is poor, and it is unfavorable for large-scale production. Need loaded down with trivial details operation, be suitable for the preparation method of the 2-amino alkyl sulfonamide of large-scale industrial production

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  • Preparation method of N-carbobenzoxy-2-amino-alkyl sulfonamide

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preparation example Construction

[0031] The present invention provides a N -The preparation method of benzyloxycarbonyl-2-aminoalkylsulfonamide, the steps comprise:

[0032] S1: using o-amino alcohol represented by formula [1] as raw material, reacting with benzyl chloroformate to obtain N - benzyloxycarbonyl-2-aminoalcohol;

[0033] S2: Take the result of step S1 N - Benzyloxycarbonyl-2-aminoalcohol and thioacetic acid undergo Mitsunobu reaction (Mitsunobu) to obtain the acetate of aminothiol;

[0034] S3: use the acetate of aminothiol obtained in step S2 N -Oxidation of chlorosuccinimide to N - benzyloxycarbonyl-2-aminoalkylsulfonyl chloride;

[0035] S4: the obtained step S3 N -benzyloxycarbonyl-2-aminoalkylsulfonyl chloride is obtained through ammonolysis shown in formula [5] N - benzyloxycarbonyl-2-aminoalkylsulfonamide;

[0036] Formula 1] Formula [5];

[0037] Wherein, the R is selected from one of hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, alkylaminoalkyl, and aryloxya...

Embodiment 1

[0060] (1) Dissolve 50 mmol of ethanolamine as o-amino alcohol in 165 mL CH 2 Cl 2 in, at 0 o Under C conditions, 8.6 mL (10.2 g, 60 mmol) of benzyl chloroformate was added dropwise to the system, followed by 35 mL (25.3 g, 250 mmol) of Et 3 N, stirred overnight at room temperature, stopped the reaction, removed the solvent under reduced pressure to obtain an oil, separated and purified by silica gel column chromatography to obtain N - O-aminoalcohol protected by benzyloxycarbonyl.

[0061] (2) at -10 o Under C conditions, the Ph 3 P (10.48 g, 40 mmol) was dissolved in 48 mL of anhydrous THF, and it was slowly added dropwise (over 30 min) to 24 mL containing diisopropyl azodicarboxylate (DIAD) (8.0 g, 40 mmol ) in anhydrous THF solution, and then at -10 o Under the condition of C, react for 0.5 h, and a white precipitate will form during the reaction. will subsequently N - 48 mL of anhydrous THF solution of benzyloxycarbonyl-protected o-amino alcohol (20 mmol) and HSAc...

Embodiment 2

[0065] ( S The preparation of )-2-benzyloxycarbonylaminopropyl sulfonamide 5b

[0066] Adopt the method identical with embodiment 1 to prepare ( S )-2-Benzyloxycarbonylaminopropylsulfonamide 5b , the difference is that the o-amino alcohol used in the step (1) is (S)-alaninol, and a colorless needle-like solid is obtained with a yield of 63% and a melting point of 150-151 o C, [α] 20 D = +10.8 (c, 1.0, MeOH).IR v (cm-1): 1668 (C=O), 1342 & 1142 (SO 2 ); 1 H 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 2 SO 2 ), 3.25 (dd, J = 5.3, 13.9 Hz, 1H in CH 2 SO 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); 13 C 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 11 h 17 N 2 o 4 S [M+H]+ m / z 273.0904; Found 273.0902.

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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 [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to N - A process for the preparation of benzyloxycarbonyl-2-aminoalkylsulfonamides. Background technique [0002] 2-Aminoalkylsulfonamides are a class of small organic molecules with important biological functions, which are widely used as enzyme inhibitors. For example, as inhibitors of wild-type non-nucleoside HIV-1 (Piscitelli, F.; 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.; 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-Aminoalkylsulfonamides are also an important class of tetrahedral analogs of natural protein amino acids (Moree, W. J.; van der Marel, G. A. van Boom, J. H.; Liskamp, ​​R. M. J. Tetrahedron , 1993, 49 , 11055), N-protec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/47C07C303/38
Inventor 许家喜孟凡华
Owner BEIJING UNIV OF CHEM TECH
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