4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】16638

【品名】4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde

【CA登记号】939-97-9

【分子式】C₁₁H₁₄O

【分子量】162.23156

【元素组成】C 81.44% H 8.7% O 9.86%

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：(II)

The synthesis of free compound is performed as follows: The condensation of 2-hydroxy-4-(3-methyl-2-butenyloxy)acetophenone (I) with 4-tert-butylbenzaldehyde (II) by means of KOH in hot ethanol gives 3-(4-tert-butylphenyl)-1-[4-hydroxy-4-(3-methyl-2-butenyloxy)phenyl]-2(E)-propen-1-one (III), which is condensed with ethyl bromoacetate (IV) by means of KOH in acetone to afford (E)-2-[2-(4-tert-butylcinnamoyl)-4-(3-methyl-2-butenyloxy)phenoxy] acetic acid ethyl ester (V). Finally, this compound is hydrolyzed with KOH in hot ethanol-water.

参考文献中间体

合成目标

【1】 Yokomori, S.; Saijo, K.; Matsunaga, T.; Nakashima, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Chalcone derivs. EP 0412803; JP 1991163042 .
【2】 Yokomori, S.; Saijo, K.; Hatayama, M. (Taisho Pharmaceutical Co., Ltd.); Antiulcerative agents. JP 1993058885 .
【3】 Rabasseda, X.; Castañer, J.; Mealy, N.; SU-840. Drugs Fut 1994, 19, 10, 923.

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)	16637	1-[2-hydroxy-4-[(3-methyl-2-butenyl)oxy]phenyl]-1-ethanone		C₁₃H₁₆O₃	详情	详情
(II)	16638	4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde	939-97-9	C₁₁H₁₄O	详情	详情
(III)	16639	(E)-3-[4-(tert-butyl)phenyl]-1-[2-hydroxy-4-[(3-methyl-2-butenyl)oxy]phenyl]-2-propen-1-one		C₂₄H₂₈O₃	详情	详情
(IV)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(V)	16641	ethyl 2-[2-[(E)-3-[4-(tert-butyl)phenyl]-2-propenoyl]-5-[(3-methyl-2-butenyl)oxy]phenoxy]acetate		C₂₈H₃₄O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

N-Methyl-L-leucine (IV) was converted to tert-butyl ester (V) by treatment with isobutylene and H2SO4. Formation of the N,N-dialkyl derivative (VIII) was achieved by either alkylation of (V) with p-tert-butylbenzyl bromide (VI) or by reductive condensation of (V) with p-tert-butylbenzaldehyde (VII) and NaBH(OAc)3. Deprotection of the tert-butyl ester of (VIII) with trifluoroacetic acid gave amino acid (IX), which was activated as the mixed anhydride (X) upon treatment with isobutyl chloroformate and a polymer-supported morpholine base. Coupling of (X) with tyrosine amide (III) then afforded the title dipeptide amide. Unreacted starting materials were captured by the addition of polymer-supported polyamine and isocyanate resins.

参考文献中间体

合成目标

【1】 Ryder, T.R.; et al.; Multiple parallel synthesis of N,N-dialkyldipeptidylamines as N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 13, 1813.
【2】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	30798	(2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide		C₂₀H₂₆N₂O₂	详情	详情
(IV)	34642	(2S)-4-methyl-2-(methylamino)pentanoic acid		C₇H₁₅NO₂	详情	详情
(V)	26296	tert-butyl (2S)-4-methyl-2-(methylamino)pentanoate		C₁₁H₂₃NO₂	详情	详情
(VI)	20588	1-(bromomethyl)-4-(tert-butyl)benzene	18880-00-7	C₁₁H₁₅Br	详情	详情
(VII)	16638	4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde	939-97-9	C₁₁H₁₄O	详情	详情
(VIII)	34643	tert-butyl (2S)-2-[[4-(tert-butyl)benzyl](methyl)amino]-4-methylpentanoate		C₂₂H₃₇NO₂	详情	详情
(IX)	34644	(2S)-2-[[4-(tert-butyl)benzyl](methyl)amino]-4-methylpentanoic acid		C₁₈H₂₉NO₂	详情	详情
(X)	34645			C₂₃H₃₇NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

In a related procedure, N-Boc-N-methylleucine (XI) was coupled with O-benzyltyrosine amide (III) in the presence of HBTU to give the protected dipeptide (XII). Trifluoroacetic acid-promoted cleavage of the Boc group of (XII) provided amine (XIII). Finally, reductive alkylation of (XIII) with 4-tert-butylbenzaldehyde (VII) gave rise to the title compound.

参考文献中间体

合成目标

【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Structure-activity relationship of N-methyl-N-aralkyl-peptidylamines as novel N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 15, 2151.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	30798	(2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide		C₂₀H₂₆N₂O₂	详情	详情
(VII)	16638	4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde	939-97-9	C₁₁H₁₄O	详情	详情
(XI)	26295	(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid	609-23-4	C₁₂H₂₃NO₄	详情	详情
(XII)	34646	tert-butyl (1S)-1-([[(1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl(methyl)carbamate		C₃₂H₄₇N₃O₅	详情	详情
(XIII)	34647	(2S)-N-[(1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethyl]-4-methyl-2-(methylamino)pentanamide		C₂₇H₃₉N₃O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

Alkylation of 3-hydroxybenzaldehyde (I) with t-butyl bromoacetate (II) affords t butyl (3-formylphenoxy)acetate (III). Aldehyde (III) is then converted to oxime (IV) upon treatment with hydroxylamine in MeOH. Reduction of oxime (IV) to the benzylic amine (V) is carried out by catalytic hydrogenation in the presence of Raney nickel. Subsequent reductive alkylation of amine (V) with 4-t-butylbenzaldehyde (VI) furnishes the secondary amine (VII). This is then acylated by pyridine-3-sulfonyl chloride (VIII) producing sulfonamide (IX). The t-butyl ester group of (IX) is finally cleaved with trifluoroacetic acid to give the corresponding carboxylic acid.

参考文献中间体

合成目标

【1】 Rosati, R.L.; Lefker, B.A.; Cameron, K.O. (Pfizer Inc.); Prostaglandin agonists and their use to treat bone disorders. EP 1021410; JP 2001519414; US 6498172; WO 9919300 .

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)	28537	3-hydroxybenzaldehyde	100-83-4	C₇H₆O₂	详情	详情
(II)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(III)	64442	tert-butyl 2-(3-formylphenoxy)acetate		C₁₃H₁₆O₄	详情	详情
(IV)	64443	tert-butyl 2-{3-[(hydroxyimino)methyl]phenoxy}acetate		C₁₃H₁₇NO₄	详情	详情
(V)	64444	tert-butyl 2-[3-(aminomethyl)phenoxy]acetate		C₁₃H₁₉NO₃	详情	详情
(VI)	16638	4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde	939-97-9	C₁₁H₁₄O	详情	详情
(VII)	64445	tert-butyl 2-[3-({[4-(tert-butyl)benzyl]amino}methyl)phenoxy]acetate		C₂₄H₃₃NO₃	详情	详情
(VIII)	64446	3-pyridinesulfonyl chloride		C₅H₄ClNO₂S	详情	详情
(IX)	64447	tert-butyl 2-(3-{[[4-(tert-butyl)benzyl](3-pyridinylsulfonyl)amino]methyl}phenoxy)acetate		C₂₉H₃₆N₂O₅S	详情	详情

Extended Information