p-cresol -Drug Synthesis Database

【结构式】

【分子编号】37678

【品名】p-cresol

【CA登记号】106-44-5

【分子式】C₇H₈O

【分子量】108.13992

【元素组成】C 77.75% H 7.46% O 14.8%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：

This compound can be prepared by two different methods: 1) By cyclocondensation of p-anisidine (I) with 2-oxocyclohexanecarboxylate (II) to 7-methoxy-1,2,3,4-tetrahydroacridone (III), which by treatment with refluxing POCl3 is converted to 9-chloro-7-methoxy-1,2,3,4-tetrahydroacridine (IV). This compound is converted to final product by treatment with NH3 in refluxing p-cresol. 2) By cyclocondensation of 5-methoxyisatin (V) and cyclohexanone (VI) in concentrated aqueous ammonia at 150 C to 7-methoxy-1,2,3,4-tetrahydroacridine-9-carboxamide (VII), followed by a Hoffman degradation with potassium hypobromite.

参考文献中间体

合成目标

【1】 Sigal, M.V. Jr.; Brent, B.J.; Marchini, P.; 7,8,9,10-Tetrahalo-6H-cyclohepta[b]quinolines. US 3232945 .
【2】 Bielavsky, J.; Analogues of 9-amino-1,2,3,4-tetrahydroacridine. Coll Czech Chem Commun 1977, 42, 2802-7.
【3】 Dejmek, L.; 7-MEOTA. Drugs Fut 1990, 15, 2, 126.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	37678	p-cresol	106-44-5	C₇H₈O	详情	详情
(I)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(II)	11889	ethyl 2-oxocyclohexanecarboxylate; Ethyl 2-cyclohexanonecarboxylate	1655-07-8	C₉H₁₄O₃	详情	详情
(III)	11890	7-Methoxy-1,3,4,10-tetrahydro-9(2H)-acridinone		C₁₄H₁₅NO₂	详情	详情
(IV)	11891	9-Chloro-5,6,7,8-tetrahydro-2-acridinyl methyl ether; 9-Chloro-7-methoxy-1,2,3,4-tetrahydroacridine		C₁₄H₁₄ClNO	详情	详情
(V)	11892	5-Methoxy-1H-indole-2,3-dione	39755-95-8	C₉H₇NO₃	详情	详情
(VI)	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
(VII)	11894	7-Methoxy-1,2,3,4-tetrahydro-9-acridinecarboxamide		C₁₅H₁₆N₂O₂	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 process for the preparation of tolterodine has been described: The cyclization of trans-cinnamic acid (I) with p-cresol (II) by means of hot sulfuric acid gives 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (III), which is reduced with DIBAL in toluene, yielding 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol (IV). The reductocondensation of (IV) with diisopropylamine (V) by means of H2 over Pd/C in methanol affords racemic tolterodine (VI), which is finally submitted to optical resolution with L-tartaric acid in dichloromethane/water.

参考文献中间体

合成目标

【1】 Gage, J.R.; Cabaj, J.E. (Pharmacia Corp.); Process to prepare tolterodine. US 5992914; WO 9829402 .

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)	37680	(2E)-3-phenyl-2-propenoic acid; trans-Cinnamic acid; trans-3-Phenylacrylic acid	140-10-3	C₉H₈O₂	详情	详情
(II)	37678	p-cresol	106-44-5	C₇H₈O	详情	详情
(III)	13561	6-Methyl-4-phenyl-2-chromanone		C₁₆H₁₄O₂	详情	详情
(IV)	37679	6-methyl-4-phenyl-2-chromanol		C₁₆H₁₆O₂	详情	详情
(V)	13565	N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine	108-18-9	C₆H₁₅N	详情	详情
(VI)	13567	2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol		C₂₂H₃₁NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of p-cresol (I) with phenylacetylene (II) by means of acid activated alumina in refluxing dichlorobenzene gives 4-methyl-2-(1-phenylvinyl)phenol (III), which is hydroformylated with CO, H2 and a Rh catalyst in hot toluene to yield 3-(2-hydroxy-5-methylphenyl)-3-phenylpropionaldehyde (IV), mostly in the hemiacetalic form (V). The reaction of (V) with diisopropylamine (VI) in hot toluene catalyzed by molecular sieves gives the enamine (VII), which is finally hydrogenated with H2 over PtO2 in refluxing toluene to afford the target racemic tolterodine. Alternatively, the reductocondensation of hemiacetal (V) with diisopropylamine (VI) by means of H2 over Pd/C in hot methanol provides directly the target racemic tolterodine.

参考文献中间体

合成目标

【1】 Paganelli, S.; Piccolo, O.; Botteghi, C.; Marchetti, M.; Corrias, T.; A new efficient route to tolterodine. Org Process Res Dev 2002, 6, 7, 379.

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)	37678	p-cresol	106-44-5	C₇H₈O	详情	详情
(II)	20597	1-ethynylbenzene	536-74-3	C₈H₆	详情	详情
(III)	56853	4-methyl-2-(1-phenylvinyl)phenol		C₁₅H₁₄O	详情	详情
(IV)	56854	3-(2-hydroxy-5-methylphenyl)-3-phenylpropanal		C₁₆H₁₆O₂	详情	详情
(V)	37679	6-methyl-4-phenyl-2-chromanol		C₁₆H₁₆O₂	详情	详情
(VI)	13565	N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine	108-18-9	C₆H₁₅N	详情	详情
(VII)	56855	2-[(E)-3-(diisopropylamino)-1-phenyl-2-propenyl]-4-methylphenol		C₂₂H₂₉NO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Reaction of 4-methylphenol (I) with NaH in DMF and 3-fluorobenzaldehyde (II) yields aldehyde (III), which will be converted into secondary amine (V) via a reductive amination with amine (IV) in presence of NaBH3CN in MeOH and catalytic HOAc. Amine (V) couples with dianhydride (VI) in THF in presence of NMM or alternatively in toluene and Et3N. Final treatment with Na2CO3 in THF yields the desired product.

参考文献中间体

合成目标

【1】 Sullivan, G.M.; Rosenberg, S.H.; Prasad, R.N.; O'Connor, S.J.; Donner, B.G.; Fakhoury, S.A.; Fung, K.L.; Stout, D.M.; Rockway, T.W.; Baker, W.R.; Shen, W.; Garvey, D.S. (Abbott Laboratories Inc.); Benzene, pyridine, naphthalene or benzophenone derivs. as inhibitors of squalene synthetase and protein farnesyltransferase. WO 9634851 .

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)	37678	p-cresol	106-44-5	C₇H₈O	详情	详情
(II)	18887	3-Fluorobenzaldehyde	456-48-4	C₇H₅FO	详情	详情
(III)	41482	3-(4-methylphenoxy)benzaldehyde	79124-75-7	C₁₄H₁₂O₂	详情	详情
(IV)	38253	2-ethoxybenzylamine; (2-ethoxyphenyl)methanamine		C₉H₁₃NO	详情	详情
(V)	41483	N-(2-ethoxybenzyl)[3-(4-methylphenoxy)phenyl]methanamine; N-(2-ethoxybenzyl)-N-[3-(4-methylphenoxy)benzyl]amine	n/a	C₂₃H₂₅NO₂	详情	详情
(VI)	41484	1H,3H-furo[3,4-f][2]benzofuran-1,3,5,7-tetrone	89-32-7	C₁₀H₂O₆	详情	详情

Extended Information