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【结 构 式】

【分子编号】18985

【品名】4'-methyl[1,1'-biphenyl]-4-carbaldehyde

【CA登记号】

【 分 子 式 】C14H12O

【 分 子 量 】196.24868

【元素组成】C 85.68% H 6.16% O 8.15%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

Grignard reagent (II) prepared from 1,4-dibromobenzene (I) was condensed with biphenylaldehyde (III) to afford alcohol (IV), which was oxidized to ketone (V) under Swern conditions with oxalyl chloride and DMSO at low temperature. Then, allylic bromination with N-bromosuccinimide (NBS) in the presence of azobisisobutyronitrile (AIBN) gave (VI). Finally, N-allyl-N-methylamine (VII) was alkylated with bromide (VI) to provide the tertiary amine.

1 Aebi, J.; Guerry, P.; Jolidon, S.; Morand, O. (F. Hoffmann-La Roche AG); Use of phenylalkylamines for producing cholesterol lowering agents. EP 0636367; JP 1995053479; US 5637771 .
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) 18983 1,4-dibromobenzene 106-37-6 C6H4Br2 详情 详情
(II) 18984 bromo(4-bromophenyl)magnesium C6H4Br2Mg 详情 详情
(III) 18985 4'-methyl[1,1'-biphenyl]-4-carbaldehyde C14H12O 详情 详情
(IV) 18986 (4-bromophenyl)(4'-methyl[1,1'-biphenyl]-4-yl)methanol C20H17BrO 详情 详情
(V) 18987 (4-bromophenyl)(4'-methyl[1,1'-biphenyl]-4-yl)methanone C20H15BrO 详情 详情
(VI) 18988 [4'-(bromomethyl)[1,1'-biphenyl]-4-yl](4-bromophenyl)methanone C20H14Br2O 详情 详情
(VII) 18989 N-allyl-N-methylamine; N-methyl-2-propen-1-amine 627-37-2 C4H9N 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

A new large-scaleable synthesis of TAK-779 has been developed: The reduction of 4'-methylbiphenyl-4-carbonitrile (I) with sodium bis(2-methoxyethoxy)aluminum hydride (SBMEA) in THF gives the corresponding aldehyde (II), which is submitted to a Wittig condensation with the phosphonium bromide (III) by means of NaOMe in methanol to yield the pentenoic acid derivative (IV). Reduction of the double bond of (IV) with H2 over Pd/C in THF, followed by cyclization with hot PPA affords the benzocycloheptanone (V), which is treated with refluxing dimethyl carbonate and NaOMe to provide the beta-ketoester (VI). The reduction of (VI) with NaBH4 in THF gives the hydroxyester (VII), which is dehydrated with Ms-Cl and DBU and hydrolyzed with NaOH to yield 8-(4-methylphenyl)benzocyclohept-1-ene-2-carboxylic acid (VIII). Condensation of (VIII) with 4-aminobenzyl alcohol (IX) by means of (COCl)2 and TEA in THF affords the corresponding amide (X), which is treated with SOCl2 in THF to provide the chloromethyl derivative (XI). Finally, this compound is condensed with 4-(dimethylamino)tetrahydropyran (XII) in hot DMF to furnish the target ammonium salt. The tertiary amine (XII) has been obtained by reductive condensation of tetrahydropyran-4-one (XIII) with dimethylamine by means of H2 over Pd/C in THF.

1 Ikemoto, T.; Hashimoto, H.; Kaarasaki, T.; Tomimatsu, K.; Ito, T.; Nishiguchi, A.; Wakimasu, M.; Mitsudera, H.; Development of a new synthetic route of a non-peptide CCR5 antagonist, TAK-779, for large-scale preparation. Org Process Res Dev 2000, 4, 6, 520.
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) 45764 4'-methyl[1,1'-biphenyl]-4-carbonitrile C14H11N 详情 详情
(II) 18985 4'-methyl[1,1'-biphenyl]-4-carbaldehyde C14H12O 详情 详情
(III) 37404 (3-carboxypropyl)(triphenyl)phosphonium bromide 17857-14-6 C22H22BrO2P 详情 详情
(IV) 45765 (Z)-5-(4'-methyl[1,1'-biphenyl]-4-yl)-4-pentenoic acid C18H18O2 详情 详情
(V) 31555 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one C18H18O 详情 详情
(VI) 33422 methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate C20H20O3 详情 详情
(VII) 45766 methyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate C20H22O3 详情 详情
(VIII) 31560 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid C19H18O2 详情 详情
(IX) 34430 (4-aminophenyl)methanol 623-04-1 C7H9NO 详情 详情
(X) 33424 N-[4-(hydroxymethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide C26H25NO2 详情 详情
(XI) 33425 N-[4-(chloromethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide C26H24ClNO 详情 详情
(XII) 33426 N,N-dimethyltetrahydro-2H-pyran-4-amine; N,N-dimethyl-N-tetrahydro-2H-pyran-4-ylamine C7H15NO 详情 详情
(XIII) 31563 tetrahydro-4H-pyran-4-one 29943-42-8 C5H8O2 详情 详情
Extended Information