(4-aminophenyl)methanol -Drug Synthesis Database

【结构式】

【分子编号】34430

【品名】(4-aminophenyl)methanol

【CA登记号】623-04-1

【分子式】C₇H₉NO

【分子量】123.1546

【元素组成】C 68.27% H 7.37% N 11.37% O 12.99%

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：(IX)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(I)

Coupling of 4-aminobenzyl alcohol (I) with diallyl L-glutamylisocyanate (II) produced the urea derivative (III). Subsequent activation of the benzylic alcohol group with 4-nitrophenyl chloroformate (IV) afforded carbonate (V). This was then condensed with doxorubicin (VI) to furnish the corresponding carbamate (VII). Finally, palladium-catalyzed cleavage of the allyl esters of (VII) yielded the title compound.

参考文献中间体

合成目标

【1】 Friedlos, F.; Spooner, R.; Marais, R.; Springer, C.J.; Martin, J.; Niculescu-Duvaz, I.; Niculescu-Duvaz, D.; Self-immolative anthracycline prodrugs for suicide gene therapy. J Med Chem 1999, 42, 13, 2485.

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)	34430	(4-aminophenyl)methanol	623-04-1	C₇H₉NO	详情	详情
(II)	34431	diallyl (2S)-2-isocyanatopentanedioate		C₁₂H₁₅NO₅	详情	详情
(III)	34432	diallyl (2S)-2-([[4-(hydroxymethyl)anilino]carbonyl]amino)pentanedioate		C₁₉H₂₄N₂O₆	详情	详情
(IV)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(V)	34433	diallyl (2S)-2-([[4-([[(4-nitrophenoxy)carbonyl]oxy]methyl)anilino]carbonyl]amino)pentanedioate		C₂₆H₂₇N₃O₁₀	详情	详情
(VI)	11675	(8S,10S)-10-[[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione		C₂₇H₂₉NO₁₁	详情	详情
(VII)	34434			C₄₇H₅₁N₃O₁₈	详情	详情

Extended Information