PD-173212, -Drug Synthesis Database

【结构式】

【药物名称】PD-173212

【化学名称】N-(4-tert-Butylbenzyl)-N-methyl-L-leucyl-4-O-(benzyl)-L-tyrosine tert-butylamide

【CA登记号】217171-01-2

【分子式】C₃₈H₅₃N₃O₃

【分子量】599.86441

【开发单位】Elan (Originator), Pfizer (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Non-Opioid Analgesics, Stroke, Treatment of, N-Type Calcium Channel Blockers

合成路线1 合成路线2 合成路线3

合成路线1

Coupling of N-Boc-O-benzyl-L-tyrosine (I) with tert-butylamine by means of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) afforded amide (II). Subsequent acid cleavage of the Boc group of (II) gave O-benzyltyrosine tert-butyl amide (III).

参考文献中间体

【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
(I)	30396	(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid	54784-43-9	C₂₁H₂₅NO₅	详情	详情
(II)	30797	tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethylcarbamate		C₂₅H₃₄N₂O₄	详情	详情
(III)	30798	(2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide		C₂₀H₂₆N₂O₂	详情	详情

合成路线2

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

【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

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

【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

Extended Information

Drug NewChemical Entity Original Patent(1)