【结 构 式】 |
【分子编号】29453 【品名】methyl 4-benzylbenzyl(2-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-4-phenylbutyl)phosphinate 【CA登记号】 |
【 分 子 式 】C30H32NO6P 【 分 子 量 】533.560982 【元素组成】C 67.53% H 6.05% N 2.63% O 17.99% P 5.81% |
合成路线1
该中间体在本合成路线中的序号:(XI)Michael addition of bis(trimethylsilyl)phosphonite (II) to benzyl 2-phenethylacrylate (I) afforded phosphinic acid (III). 4-Benzoylbenzyl bromide (IV) was reduced using triethylsilane and trifluoroacetic acid to give 4-benzylbenzyl bromide (V). Subsequent Arbuzov reaction of phosphinic acid (III) with bromide (V) generated the disubstituted phosphinic acid (VI), which was protected as the methyl ester (VII) employing trimethylsilyl diazomethane. Hydrogenolysis of the benzyl ester of (VII) then yielded carboxylic acid (VIII). This was coupled with (S)-tert-leucinamide (IX) by means of BOP to furnish the corresponding diamide (X). Alternatively, acid (VIII) was treated with N-hydroxysuccinimide (NHS) and EDC, and the resulting succinimidyl ester (XI) was coupled with amine (IX) to produce (X). The methyl phosphinate ester (X) was then deprotected by treatment with aqueous trifluoroacetic acid, and the required (S,S)-diastereoisomer was isolated by reverse phase flash chromatography.
【1】 Reiter, L.A.; Rizzi, J.P.; Pandit, J.; et al.; Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket. Bioorg Med Chem Lett 1999, 9, 2, 127. |
【2】 Reiter, L.A. (Pfizer Inc.); Phosphinate based inhibitors of matrix metalloproteases. EP 0923585; JP 1999514673; WO 9803516 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 29448 | trimethyl-N-[(Z)-1-(trimethylsilyl)ethylidene]silanamineN-(trimethylsilyl)-N-[(Z)-1-(trimethylsilyl)ethylidene]amine | C8H21NSi2 | 详情 | 详情 | |
(I) | 29443 | benzyl 2-phenethylacrylate | C18H18O2 | 详情 | 详情 | |
(II) | 29444 | bis[(trimethylsilyl)methyl]phosphine | C8H23PSi2 | 详情 | 详情 | |
(III) | 29445 | 2-[(benzyloxy)carbonyl]-4-phenylbutylphosphinic acid | C18H21O4P | 详情 | 详情 | |
(IV) | 29446 | [4-(bromomethyl)phenyl](phenyl)methanone | C14H11BrO | 详情 | 详情 | |
(V) | 29447 | 1-benzyl-4-(bromomethyl)benzene | C14H13Br | 详情 | 详情 | |
(VI) | 29449 | 4-benzylbenzyl[2-[(benzyloxy)carbonyl]-4-phenylbutyl]phosphinic acid | C32H33O4P | 详情 | 详情 | |
(VII) | 29450 | benzyl 2-[[(4-benzylbenzyl)(methoxy)phosphoryl]methyl]-4-phenylbutanoate | C33H35O4P | 详情 | 详情 | |
(VIII) | 29451 | 2-[[(4-benzylbenzyl)(methoxy)phosphoryl]methyl]-4-phenylbutyric acid | C26H29O4P | 详情 | 详情 | |
(IX) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
(X) | 29452 | methyl 4-benzylbenzyl[2-[([(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]amino)carbonyl]-4-phenylbutyl]phosphinate | C33H43N2O4P | 详情 | 详情 | |
(XI) | 29453 | methyl 4-benzylbenzyl(2-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-4-phenylbutyl)phosphinate | C30H32NO6P | 详情 | 详情 |