-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】Acetyl-(4-phosphono)-L-tyrosyl-L-leucine N-[1(S)-(4-isopropylphenyl)ethyl]amide

【CA登记号】222737-09-9

【分子式】C₂₈H₄₀N₃O₇P

【分子量】561.6207

【开发单位】Boehringer Ingelheim (Originator)

【药理作用】Oncolytic Drugs, Inhibitors of Signal Transduction Pathways, Tyrosine Kinase Inhibitors

合成路线1 合成路线2

合成路线1

The intermediate (S)-1-(4-isopropylphenyl)ethylamine (VII) was prepared as shown in Scheme 1. Condensation of (4-isopropylphenyl)acetyl chloride (I) with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (II) produced the chiral N-acyl oxazolidinone (III). Diastereoselective alkylation of (III) with MeI in the presence of lithium hexamethyldisilazide provided (IV). Removal of the chiral auxiliary of (IV) was accomplished by treatment with lithium hydroperoxide to afford the (S)-arylpropionic acid (V). Subsequent Curtius rearrangement of (V) using diphenyl phosphoryl azide, followed by treatment of the intermediate isocyanate with benzyl alcohol, furnished the benzyl carbamate (VI). Then, catalytic hydrogenation of (VI) over Pd/C yielded the target amine (VII).

参考文献中间体

【1】 Llinas-Brunet, M.; et al.; Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain. J Med Chem 1999, 42, 4, 722.

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)	26166	2-(4-isopropylphenyl)acetyl chloride		C₁₁H₁₃ClO	详情	详情
(II)	12867	(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone	17016-83-0	C₆H₁₁NO₂	详情	详情
(III)	26167	(4S)-4-isopropyl-3-[2-(4-isopropylphenyl)acetyl]-1,3-oxazolidin-2-one		C₁₇H₂₃NO₃	详情	详情
(IV)	26168	(4S)-4-isopropyl-3-[(2S)-2-(4-isopropylphenyl)propanoyl]-1,3-oxazolidin-2-one		C₁₈H₂₅NO₃	详情	详情
(V)	26169	(2S)-2-(4-isopropylphenyl)propionic acid		C₁₂H₁₆O₂	详情	详情
(VI)	26170	benzyl (1S)-1-(4-isopropylphenyl)ethylcarbamate		C₁₉H₂₃NO₂	详情	详情
(VII)	26171	(1S)-1-(4-isopropylphenyl)ethylamine; (1S)-1-(4-isopropylphenyl)-1-ethanamine		C₁₁H₁₇N	详情	详情

合成路线2

Reaction of N-acetyl-L-tyrosine (VIII) with tert-butyldimethylsilyl chloride and N-methylmorpholine (NMM), followed by phosphitylation with dibenzyldiisopropylamine phosphoramidite produced the intermediate phosphite ester (IX), which was oxidized to phosphate (X) using tert-butyl hydroperoxide. Subsequent coupling of (X) with protected leucine (XI) in the presence of DCC and HOBt afforded dipeptide (XII). Deprotection of the allyl ester of (XII) by means of Pd(PPh3)4 and pyrrolidine provided acid (XIII). After conversion of (XIII) to the corresponding mixed anhydride with isobutyl chloroformate, condensation with the chiral amine (VII) yielded amide (XIV). Finally, the benzyl ester groups of (XIV) were eliminated by catalytic hydrogenation over Pd/C.

参考文献中间体

【1】 Llinas-Brunet, M.; et al.; Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain. J Med Chem 1999, 42, 4, 722.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40669			C₁₇H₂₂NO₂P	详情	详情
(VII)	26171	(1S)-1-(4-isopropylphenyl)ethylamine; (1S)-1-(4-isopropylphenyl)-1-ethanamine		C₁₁H₁₇N	详情	详情
(VIII)	26159	N-Acetyl-L-tyrosine; (2S)-2-(acetamido)-3-(4-hydroxyphenyl)propionic acid	537-55-3	C₁₁H₁₃NO₄	详情	详情
(IX)	26160	tert-butyl(dimethyl)silyl (2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphino]oxy]phenyl)propanoate		C₃₁H₄₀NO₆PSi	详情	详情
(X)	26161	(2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propionic acid		C₂₅H₂₆NO₇P	详情	详情
(XI)	26172	allyl (2S)-2-amino-4-methylpentanoate		C₉H₁₇NO₂	详情	详情
(XII)	26173	allyl (2S)-2-[[(2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propanoyl]amino]-4-methylpentanoate		C₃₄H₄₁N₂O₈P	详情	详情
(XIII)	26174	(2S)-2-[[(2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propanoyl]amino]-4-methylpentanoic acid		C₃₁H₃₇N₂O₈P	详情	详情
(XIV)	26175	4-((2S)-2-(acetamido)-3-[[(1S)-1-([[(1S)-1-(4-isopropylphenyl)ethyl]amino]carbonyl)-3-methylbutyl]amino]-3-oxopropyl)phenyl dibenzyl phosphate		C₄₂H₅₂N₃O₇P	详情	详情

Extended Information