(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one -Drug Synthesis Database

【结构式】

【分子编号】19624

【品名】(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one

【CA登记号】

【分子式】C₃₇H₄₀I₂N₂O₅

【分子量】846.54402

【元素组成】C 52.5% H 4.76% I 29.98% N 3.31% O 9.45%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

Diol (I) was protected as the bis(methoxymethyl) ether (III) by reaction with methoxymethyl bromide (II) in the presence of diisopropyl ethylamine in DMF, and then, the carbobenzoxy groups of (III) were removed by hydrogenolysis in the presence of Pd/C to afford diamine (IV). Subsequent treatment of (IV) with carbonyl diimidazole (CDI) and pyridine provided the cyclic urea (V). Alkylation of (V) with m-iodobenzyl bromide (VI) in the presence of NaH in DMF provided the bis(iodobenzyl) diazepinone (VII). The title compound was then obtained by Suzuki coupling of (VII) with the protected pyrazolylboronic acid (VIII) in the presence of Pd(PPh3)4 and K2CO3 to furnish the bis(pyrazolylbenzyl) derivative (IX), followed by deprotection of the (trimethylsilyl)ethoxymethyl groups upon treatment with HCl in dioxan-methanol.

参考文献中间体

合成目标

【1】 Han, Q.; Lam, P.Y.S.; Li, R.; Jadhav, P.K.; Chang, C.-H.; Ru, Y.; Cyclic HIV protease inhibitors: Design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency. J Med Chem 1998, 41, 12, 2019.
【2】 Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Jadhav, P.K.; DeLucca, G.V. (DuPont Pharmaceuticals Co.); Cyclic ureas and analogues useful as retroviral protease inhibitors. EP 0607334; EP 0686151; EP 0765873; JP 1995500324; JP 1996509700; US 5610294; WO 9307128; WO 9419329 .

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)	19618	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate		C₃₄H₃₆N₂O₆	详情	详情
(II)	19619	bromo(methoxy)methane; bromomethyl methyl ether	13057-17-5	C₂H₅BrO	详情	详情
(III)	19620	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-bis(methoxymethoxy)-5-phenylpentylcarbamate		C₃₈H₄₄N₂O₈	详情	详情
(IV)	19621	(2R,3S,4S,5R)-3,4-bis(methoxymethoxy)-1,6-diphenyl-2,5-hexanediamine; (1R,2S,3S,4R)-4-amino-1-benzyl-2,3-bis(methoxymethoxy)-5-phenylpentylamine		C₂₂H₃₂N₂O₄	详情	详情
(V)	19622	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one		C₂₃H₃₀N₂O₅	详情	详情
(VI)	19623	1-(bromomethyl)-3-iodobenzene	49617-83-6	C₇H₆BrI	详情	详情
(VII)	19624	(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one		C₃₇H₄₀I₂N₂O₅	详情	详情
(VIII)	19625	1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-ylboronic acid		C₉H₁₉BN₂O₃Si	详情	详情
(IX)	19626	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1,3-bis[3-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl)benzyl]-1,3-diazepan-2-one		C₅₅H₇₄N₆O₇Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The alkylation of dimethyl malonate (IX) with 4-(methylsulfonyl)phenacyl bromide (VIII) by means of K2CO3 in hot acetone gives the substituted malonic ester (X), which is condensed with 2-(3,5-difluorophenyl)acetyl chloride (XI) by means of MgBr2 and pyridine in acetonitrile yielding the disubstituted malonic ester (XII). The cyclization of (XII) by means of triethylamine affords the cylopentenone dicarboxylic ester (XIII), which is finally decarboxylated with H2SO4 in hot acetic acid to provide the target compound.

参考文献中间体

合成目标

【1】 Grabowski, E.J.J.; Zhaol, D.L.; Prasit, P.; Xu, F.; Ouimet, N.; Tillyer, R.D.; Black, C.; Chen, C.Y.; Reider, P.J.; Efficient syntheses of 2-(3 ',5 '-difluorophenyl)-3-(4 '-methylsulfonylphenyl)-cyclopent-2-enone, a potent COX-2 inhibitor. Tetrahedron 1999, 55, 19, 6001.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	19624	(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one		C₃₇H₄₀I₂N₂O₅	详情	详情
(IX)	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
(X)	31626	dimethyl 2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate		C₁₄H₁₆O₇S	详情	详情
(XI)	28362	2-(3,5-difluorophenyl)acetyl chloride		C₈H₅ClF₂O	详情	详情
(XII)	31624	dimethyl 2-[2-(3,5-difluorophenyl)acetyl]-2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate		C₂₂H₂₀F₂O₈S	详情	详情
(XIII)	31625	dimethyl 3-(3,5-difluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-oxo-3-cyclopentene-1,1-dicarboxylate		C₂₂H₁₈F₂O₇S	详情	详情

Extended Information