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【结 构 式】 
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【药物名称】NVC-422;AL-46383A;DCDMT 【化学名称】2-(Dichloroamino)-2-methylpropane-1-sulfonic acid；N,N-Dichloro-2,2-dimethyltaurine 【CA登记号】846056-87-9 【 分 子 式 】C4H9Cl2NO3S 【 分 子 量 】222.09 |
【开发单位】NovaBay Pharmaceuticals, Inc. (US) 【药理作用】Antiinfective Agent;Treatment of Impetigo;Treatment of Conjunctivitis;Treatment of Urinary Tract Infections |
合成路线1
N-Protection of 2-methylalanine with Boc2O, optionally in the presence of NaHCO3, in THF/H2O yields N-Boc-2-methylalanine (II) , which is then methylated with Me3SiCHN2 in MeOH/THF or with MeI using KHCO3 in DMF to give the methyl ester (III) . Reduction of the ester (III) by means of LiBH4 in THF /EtOH affords the primary alcohol (IV) , which can also be prepared from 2-amino-2-methyl-1-propanol (V) by N-protection with Boc2O in CH2Cl2 . After conversion of alcohol (IV) to the corresponding mesylate (VI) with MsCl and Et3N in CH2Cl2, N-deprotection with HCl in dioxane provides amine (VII), which by reaction with Na2SO3 in H2O yields the aminosulfonic acid (VIII) . Finally, compound (VIII) is N-chlorinated using trichloroisocyanuric acid , Cl2 , HOCl or NaOCl/HCl .
The aminosulfonic acid (VIII) can also be prepared by the following two strategies: Condensation of acetone (IX) with t-BuSONH2 by means of Ti(OEt)4 gives the N-sulfinylimine (X), which is then coupled with ethyl methanesulfonate (XI) in the presence of BuLi and HMPA in THF to produce the propanesulfonate derivative (XII). Finally, hydrolysis of the sulfonate ester (XII) with LiOH in THF/MeOH/H2O, followed by removal of the sulfinyl protecting group with HCl in MeOH furnishes aminosulfonic acid (VIII) .
Reduction of 2-hydroxy-2-methylpropanenitrile (XIII) by means of LiAlH4 yields 1-amino-2-methylpropan-2-ol (XIV), which is then Nprotected with Boc2O to give N-Boc-1-amino-2-methylpropan-2-ol (XV). Mesylation of the alcohol (XV) with MsCl using Et3N in CH2Cl2 and subsequent N-deprotection of the resulting mesylate (XVI) with HCl in dioxane affords the amino mesylate (XVII). Finally, substitution of the tertiary mesylate (XVII) with Na2SO3 occurs with rearrangement of the primary amino group generating aminosulfonic acid (VIII) .
| 【1】 Shiau, T.P., Houchin, A., Nair, S., Xu, P., Low, E., Najafi, R., Jain, R. Stieglitz rearrangement of N,N-dichloro-beta,beta-disubstituted taurines under mild aqueous conditions. Bioorg Med Chem Lett 2009, 19(4): 1110-4. |
| 【2】 Braghiroli, D., DiBella, M. New methods for the preparation of 2-amino-2-methylpropanesulfonic acid. Tetrahedron Lett 1996, 37(40): 7319-. |
| 【3】 Ilson, B.E. et al. Effect of a new synthetic hexapetide to selectively stimulate growth hormone release in healthy human subjects. J Clin Endocrinol Metab 1989, 69(1): 212. |
| 【4】 Wang, L., Khosrovi, B., Najafi, R. N-Chloro-2,2-dimethyltaurines: A new class of remarkably stable N-chlorotaurines. Tetrahedron Lett 2008, 49(14): 2193-5. |
| 【5】 Debabov, D. NVC-422, a novel n-chlorotaurine derivative as topical antimicrobial. Drug Discov Chem 2010, Abst. |
| 【6】 Najafi, R., Wang, L., Bassiri, M., Yang, J. (NovaBay Pharmaceuticals, Inc.). N,N-Dihalogenated amino acids and derivatives. CA 2535926, EP 1656095, JP 2007502826, US 2005065115, US 7462361, WO 2005020896. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 31173 | 2-methylalanine；2-Aminoisobutyric acid;2-Amino-2-methylpropionic acid;alpha-Aminoisobutyric acid | 62-57-7 | C4H9NO2 | 详情 | 详情 |
| (II) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (III) | 68833 | methyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate | C10H19NO4 | 详情 | 详情 | |
| (IV) | 68834 | tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate;tert-ButylN-(2-hydroxy-1,1-dimethylethyl)carbamate;tert-Butyl(2-hydroxy-1,1-dimethylethyl)carbamate;1,1-Dimethylethyl(2-hydroxy-1,1-dimethylethyl)carbamate;(2-Hydroxy-1,1-dimethylethyl)carbamicacid tert-butyl ester | 102520-97-8 | C9H19NO3 | 详情 | 详情 |
| (V) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (VI) | 68835 | 2-((tert-butoxycarbonyl)amino)-2-methylpropyl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (VII) | 68836 | 2-amino-2-methylpropyl methanesulfonate hydrochloride | C5H13NO3S.HCl | 详情 | 详情 | |
| (VIII) | 68837 | 2-amino-2-methylpropyl hydrogen sulfate | C4H11NO4S | 详情 | 详情 | |
| (IX) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (X) | 68838 | 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide | C7H15NOS | 详情 | 详情 | |
| (XI) | 48097 | ethyl methanesulfonate；ethylmesylate;ethyl methanesulphonate；O-ethylmethylsulfonate | 62-50-0 | C3H8O3S | 详情 | 详情 |
| (XII) | 68839 | ethyl 2-(1,1-dimethylethylsulfinamido)-2-methylpropane-1-sulfonate | C10H23NO4S2 | 详情 | 详情 | |
| (XIII) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (XIV) | 25008 | 1-amino-2-methylpropan-2-ol;1-amino-2-methyl-2-propanol;1,1-Dimethylethanolamine;2-Amino-a,a-dimethylethanol;2-Hydroxy-2-methyl-1-propylamine;2-Hydroxyisobutylamine;2-Methyl-2-hydroxypropylamine;3-Amino-2-methyl-2-propanol | 2854-16-2 | C4H11NO | 详情 | 详情 |
| (XV) | 68840 | tert-butyl (2-hydroxy-2-methylpropyl)carbamate;(2-hydroxy-2-methylpropyl)-1,1-dimethylethyl ester Carbamicacid;N-(2-hydroxy-2-methylpropyl)-1,1-dimethylethyl ester Carbamic acid | 183059-24-7 | C9H19NO3 | 详情 | 详情 |
| (XVI) | 68841 | 1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (XVII) | 68842 | 1-amino-2-methylpropan-2-yl methanesulfonate hydrochloride | C5H13NO3S.HCl | 详情 | 详情 |