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【结 构 式】 
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【药物名称】ABH 【化学名称】2(S)-Amino-6-(borono)hexanoic acid 【CA登记号】 【 分 子 式 】C6H14BNO4 【 分 子 量 】174.99378 |
【开发单位】Boston University (Originator), Temple University (Originator), University of Pennsylvania (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Treatment of Erectile Dysfunction, Treatment of Male Sexual Dysfunction, Arginase, Inhibitors |
合成路线1
The protected glutamic acid (I) is converted to the mixed anhydride (II) using ethyl chloroformate, and subsequently reduced to alcohol (III) by means of NaBH4. Swern oxidation of (III) provides aldehyde (IV), which is subjected to a Wittig condensation with triphenyl methylenephosphorane to afford olefin (V). Hydroboration of (V), followed by reaction with (+)-pinanediol (VI) leads to the boronate (VII). Finally, complete deprotection of (VII) with BCl3 yields the desired boronic acid.
| 【1】 Ash, D.E.; Carroll, P.J.; Baggio, R.; Cavalli, R.C.; Christianson, D.W.; Kanyo, Z.F.; Elbaum, D.; Inhibition of Mn2+2-arginase by borate leads to the design of a transition state analogue inhibitor, 2(S)-amino-6-boronohexanoic acid. J Am Chem Soc 1997, 119, 34, 8107. |
| 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) | 57915 | (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | C14H25NO6 | 详情 | 详情 | |
| (II) | 57916 | C17H29NO8 | 详情 | 详情 | ||
| (III) | 57917 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-hydroxypentanoate | C14H27NO5 | 详情 | 详情 | |
| (IV) | 57918 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoate | C14H25NO5 | 详情 | 详情 | |
| (V) | 57919 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-hexenoate | C15H27NO4 | 详情 | 详情 | |
| (VI) | 16644 | (-)-Pinanediol; (1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol | 20536-52-1 | C10H18O2 | 详情 | 详情 |
| (VII) | 57920 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]hexanoate | C25H44BNO6 | 详情 | 详情 |
合成路线2
The enantioselective alkylation of the nickel complex (I) of the Schiff base derived from glycine and (S)-2-[N'-(N-benzylprolyl)amino]benzophenone with 4-bromo-1-butene (II) affords the corresponding complex (III) of (S)-2-amino-5-hexenoic acid, which is subsequently hydrolyzed to the free aminoacid (IV) under mild acidic conditions. Esterification of (IV) by means of SOCl2 in methanol leads to amino ester (V), and further protection with di-tert-butyl dicarbonate provides the N-Boc derivative (VI). Hydroboration of the double bond of (VI) with diisopinocampheylborane, followed by in situ oxidation with acetaldehyde gives rise to the diethyl boronate (VII). This is then converted to the isolable pinanediol boronate (IX) upon treatment with (+)-pinanediol (VIII). Finally, total deprotection of (IX) by refluxing with 12 M HCl furnishes the title compound.
| 【1】 Collet, S.; et al.; Synthesis and evaluation of omega-borono-alpha-amino acids as active-site probes of arginase and nitric oxide synthases. J Chem Soc - Perkins Trans I 2000, 2, 177. |
| 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) | 57921 | C27H25N3NiO3 | 详情 | 详情 | ||
| (II) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (III) | 57922 | C31H31N3NiO3 | 详情 | 详情 | ||
| (IV) | 57923 | (2S)-2-amino-5-hexenoic acid | C6H11NO2 | 详情 | 详情 | |
| (V) | 57924 | methyl (2S)-2-amino-5-hexenoate | C7H13NO2 | 详情 | 详情 | |
| (VI) | 57925 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-hexenoate | C12H21NO4 | 详情 | 详情 | |
| (VII) | 57926 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(diethoxyboryl)hexanoate | C16H32BNO6 | 详情 | 详情 | |
| (VIII) | 16644 | (-)-Pinanediol; (1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol | 20536-52-1 | C10H18O2 | 详情 | 详情 |
| (IX) | 57927 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]hexanoate | C22H38BNO6 | 详情 | 详情 |