(2S)-2-amino-3-phenylpropanamide -Drug Synthesis Database

【结构式】

【分子编号】19032

【品名】(2S)-2-amino-3-phenylpropanamide

【CA登记号】5241-58-7

【分子式】C₉H₁₂N₂O

【分子量】164.20716

【元素组成】C 65.83% H 7.37% N 17.06% O 9.74%

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：(I)

The condensation of resin bounded L-phenylalanine (I) with N-(tert-butoxycarbonyl)-L-phenylalanine (II) by means of 1,3-diisopropylcarbodiimide (DIC) and HOBT gives the protected, resin bounded dipeptide (III), which is deprotected with TFA to yield the dipeptide (IV). The reductocondensation of (IV) with 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carbaldehyde (V) by means of NaBH3CN affords the protected pseudo tripeptide (VI), which is deprotected with TFA as before yielding the pseudo tripeptide (VII). The condensation of (VII) with the protected L-dimethyltyrosine (VIII) by means of DIC and HOBT affords the protected resin bounded seudotetrapeptide (IX), which is deprotected with TFA as before giving the resin bounded seudotetrapeptide (X). Finally, the target seudotetrapeptide is cleaved from the resin by means of HF and anisole.

参考文献中间体

合成目标

【1】 Chung, N.N.; Weltrowska, G.; Fundytus, M.E.; Merovitz, L.; Schiller, P.W.; Coderre, T.J.; Nguyen, T.M.D.; Lemieux, C.; The opioid mu agonist/delta antagonist DIPP-NH2[psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. J Med Chem 1999, 42, 18, 3520.
【2】 Schiller, P. (AstraZeneca plc); New peptides. EP 0678099; JP 1996505386; WO 9415959 .

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)	19032	(2S)-2-amino-3-phenylpropanamide	5241-58-7	C₉H₁₂N₂O	详情	详情
(II)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(III)	40872	tert-butyl (1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate		C₂₃H₂₉N₃O₄	详情	详情
(IV)	19034	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-phenylpropanamide		C₁₈H₂₁N₃O₂	详情	详情
(V)	40873	tert-butyl 3-formyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₅H₁₉NO₃	详情	详情
(VI)	40874	tert-butyl 3-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)amino]methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₃₃H₄₀N₄O₄	详情	详情
(VII)	40875	(2S)-3-phenyl-2-([(2S)-3-phenyl-2-[(1,2,3,4-tetrahydro-3-isoquinolinylmethyl)amino]propanoyl]amino)propanamide		C₂₈H₃₂N₄O₂	详情	详情
(VIII)	40876	(2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(tert-butoxycarbonyl)oxy]-2,6-dimethylphenyl]propionic acid		C₂₁H₃₁NO₇	详情	详情
(IX)	40877	4-[(2S)-3-[3-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)amino]methyl]-3,4-dihydro-2(1H)-isoquinolinyl]-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-3,5-dimethylphenyl tert-butyl carbonate		C₄₉H₆₁N₅O₈	详情	详情
(X)	40878	(2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-[([2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]methyl)amino]-3-phenylpropanamide		C₃₉H₄₅N₅O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Fmoc-protected phenylalanine (I) is attached to Rink resin by means of DCC and HOBt coupling, to give the amino acid-resin complex (II). Then, N-Fmoc protecting group is removed with piperidine in DMF to afford (III). This is submitted to further sequential amino acid coupling and deprotection cycles with Fmoc-phenylalanine (I) and alpha-Fmoc-omega-pmc-D-arginine (VI) to yield in turn resins (V) and (VII), respectively.

参考文献中间体

合成目标

【1】 Brown, W.; DiMaio, J.; Schiller, P.; Martel, R. (AstraZeneca plc); Novel opioid peptides for the treatment of pain and use thereof. JP 1997509168; WO 9522557 .

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)	19030	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine	35661-40-6	C₂₄H₂₁NO₄	详情	详情
(II)	19031	9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate		C₂₄H₂₂N₂O₃	详情	详情
(III)	19032	(2S)-2-amino-3-phenylpropanamide	5241-58-7	C₉H₁₂N₂O	详情	详情
(IV)	19033	9H-fluoren-9-ylmethyl (1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate		C₃₃H₃₁N₃O₄	详情	详情
(V)	19034	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-phenylpropanamide		C₁₈H₂₁N₃O₂	详情	详情
(VI)	19035	(2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoic acid	119831-72-0	C₃₅H₄₂N₄O₇S	详情	详情
(VII)	19036	9H-fluoren-9-ylmethyl (1R)-1-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)amino]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butylcarbamate		C₅₃H₆₃N₇O₈S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The title compound has been prepared by solid-phase peptide synthesis on a Knorr resin. N-Fmoc-L-Phenylalanine (I) is attached to the resin by means of BOP and HOBt, producing resin (II). Deprotection of the N-Fmoc group of (II) with piperidine in DMF gives the phenylalanine-bound resin (III). Subsequent coupling with N-Fmoc-L-p-fluorophenylalanine (IV) yields the dipeptide resin (V), which is further deprotected to (VI) with piperidine in DMF. Further coupling-deprotection cycles with N-Fmoc-D-alanine (VII) and N-Fmoc-O-tert-butyl-L-tyrosine (IX) provide the peptide resins (VIII) and (X) respectively. Finally, simultaneous cleavage from the resin and side chain deprotection is accomplished by treatment with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Wang, W. (AstraZeneca plc); Novel opioid peptides. EP 0845003; JP 1999512086; US 6337319; WO 9707130 .

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)	19030	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine	35661-40-6	C₂₄H₂₁NO₄	详情	详情
(II)	19031	9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate		C₂₄H₂₂N₂O₃	详情	详情
(III)	19032	(2S)-2-amino-3-phenylpropanamide	5241-58-7	C₉H₁₂N₂O	详情	详情
(IV)	61042	(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(4-fluorophenyl)propanoic acid		C₂₄H₂₀FNO₄	详情	详情
(V)	61043	9H-fluoren-9-ylmethyl (1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethylcarbamate		C₃₃H₃₀FN₃O₄	详情	详情
(VI)	61044	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide		C₁₈H₂₀FN₃O₂	详情	详情
(VII)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(VIII)	61045	(2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-{[(2R)-2-aminopropanoyl]amino}-3-(4-fluorophenyl)propanamide		C₂₁H₂₅FN₄O₃	详情	详情
(IX)	18858	(2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₂₈H₂₉NO₅	详情	详情
(X)	61046	(2S)-2-amino-N-((1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl)-3-[4-(tert-butoxy)phenyl]propanamide		C₃₄H₄₂FN₅O₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

In a different strategy, N-Cbz-p-fluorophenylalanine (I) is activated as the mixed anhydride (II) employing isobutyl chloroformate and N-methylmorpholine. Coupling of anhydride (II) with phenylalanine methyl ester (III) leads to the dipeptide ester (IV), which is further treated with methanolic ammonia to produce amide (V). The dipeptide amide (V) is alternatively obtained by direct coupling of mixed anhydride (II) with phenylalanine amide (VI). Hydrogenolysis of the N-Cbz group of (V) in the presence of Pd/C furnishes the deprotected dipeptide (VII).

参考文献中间体

合成目标

【1】 Franzen, H.M.; Bessidskaia, G.; Abedi, V.; Nilsson, A.; Nilsson, M.; Olsson, L.; Frakefamide, an analgesic tetrapeptide: Development of a pilot-plant-scale process. Org Process Res Dev 2002, 6, 6, 788.
【2】 Franzen, H. (AstraZeneca plc); Process for the preparation of a tetrapeptide. WO 9947548 .
【3】 Nilsson, M.; Ellburg, M.; Franzen, H. (AstraZeneca AB); A process for the preparation of H-Tyr-D-Ala-Phe(F)-Phe-NH2. EP 1212350; JP 2003509437; WO 0119849 .

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)	61047	(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-fluorophenyl)propanoic acid		C₁₇H₁₆FNO₄	详情	详情
(II)	61048			C₂₂H₂₄FNO₆	详情	详情
(III)	12324	methyl (2R)-2-amino-3-phenylpropanoate	21685-51-8	C₁₀H₁₃NO₂	详情	详情
(IV)	61049	methyl (2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-fluorophenyl)propanoyl]amino}-3-phenylpropanoate		C₂₇H₂₇FN₂O₅	详情	详情
(V)	61050	benzyl (1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethylcarbamate		C₂₆H₂₆FN₃O₄	详情	详情
(VI)	19032	(2S)-2-amino-3-phenylpropanamide	5241-58-7	C₉H₁₂N₂O	详情	详情
(VII)	61044	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide		C₁₈H₂₀FN₃O₂	详情	详情

Extended Information