LY-438434, -Drug Synthesis Database

【结构式】

【药物名称】LY-438434

【化学名称】2-Methylalanyl-5-phenyl-D-norvalyl-4-amino-1H-imidazol-1-ylacetyl-N1-benzyl-L-prolinamide
　　　　　　N-[2-[4-[2(R)-(2-amino-2-methylpropanamido)-5-phenylpentanamido]-1H-imidazol-1-yl]acetyl]-L-proline benzylamide

【CA登记号】

【分子式】C₃₂H₄₁N₇O₄

【分子量】587.72807

【开发单位】Lilly (Originator)

【药理作用】ENDOCRINE DRUGS, Pituitary Disorder Therapy, Treatment of Growth Hormone Deficiency, Treatment of Growth Hormone Secretion Disorders, Growth Hormone Secretagogues

合成路线1 合成路线2

合成路线1

Alkylation of diethyl acetamidomalonate (I) with 1-bromo-3-phenylpropane (II) in the presence of NaOEt afforded phenylpropyl malonate (III). Hydrolysis and subsequent decarboxylation of malonate ester (III) yielded racemic 2-(acetylamino)-5-phenylpentanoic acid (IV). Kinetic resolution was achieved by enantioselective hydrolysis of the (S)-acetamide to give amino acid (VI). The desired (R)-enantiomer (V) was then hydrolyzed with HCl and further esterified with HCl-EtOH to provide amino ester (VII). Coupling with N-Boc-alpha-aminoisobutyric acid (VIII) via activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine (IX) furnished dipeptide (X). The ethyl ester group of (X) was then hydrolyzed to acid (XI) using LiOH.

参考文献中间体

【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 .

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)	16710	Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate	1068-90-2	C₉H₁₅NO₅	详情	详情
(II)	20884	1-(3-bromopropyl)benzene	637-59-2	C₉H₁₁Br	详情	详情
(III)	35758	diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate		C₁₈H₂₅NO₅	详情	详情
(IV)	38799	N-acetyl-5-phenylnorvaline		C₁₃H₁₇NO₃	详情	详情
(V)	35759	(2R)-2-(acetamido)-5-phenylpentanoic acid		C₁₃H₁₇NO₃	详情	详情
(VI)	35760	(2S)-2-amino-5-phenylpentanoic acid		C₁₁H₁₅NO₂	详情	详情
(VII)	35761	ethyl (2R)-2-amino-5-phenylpentanoate		C₁₃H₁₉NO₂	详情	详情
(VIII)	18471	N-(tert-butoxycarbonyl)-2-methylalanine	30992-29-1	C₉H₁₇NO₄	详情	详情
(IX)	38798	2-chloro-4,6-dimethoxy-1,3,5-triazine; 4-chloro-6-methoxy-1,3,5-triazin-2-yl methyl ether	3140-73-6	C₅H₆ClN₃O₂	详情	详情
(X)	35762	ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate		C₂₂H₃₄N₂O₅	详情	详情
(XI)	18473	(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid		C₂₀H₃₀N₂O₅	详情	详情

合成路线2

Alkylation of 4-nitroimidazole (XII) by means of ethyl bromoacetate (XIII) gave ethyl 2-(4-nitro-1-imidazolyl)acetate (XIV). Reduction of (XIV) to the corresponding amine (XV) was effected by catalytic hydrogenation over Pd/C. Coupling of (XV) with dipeptide (XI) gave (XVI), which was hydrolyzed to carboxylic acid (XVII) using LiOH. This was finally coupled with proline amide (XIX), (obtained by treatment of L-proline (XVIII) with benzylamine and CDI), to furnish the title compound.

参考文献中间体

【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(XI)	18473	(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid		C₂₀H₃₀N₂O₅	详情	详情
(XII)	35764	4-nitro-1H-imidazole	3034-38-6	C₃H₃N₃O₂	详情	详情
(XIII)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(XIV)	38800	ethyl 2-(4-nitro-1H-imidazol-1-yl)acetate		C₇H₉N₃O₄	详情	详情
(XV)	38801	ethyl 2-(4-amino-1H-imidazol-1-yl)acetate		C₇H₁₁N₃O₂	详情	详情
(XVI)	38802	ethyl 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetate		C₂₇H₃₉N₅O₆	详情	详情
(XVII)	38803	2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetic acid		C₂₅H₃₅N₅O₆	详情	详情
(XVIII)	16731	L-proline	147-85-3	C₅H₉NO₂	详情	详情
(XIX)	38804	(2S)-N-benzyl-2-pyrrolidinecarboxamide		C₁₂H₁₆N₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)