methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate -Drug Synthesis Database

【结构式】

【分子编号】20416

【品名】methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate

【CA登记号】

【分子式】C₁₂H₁₄N₂O₂

【分子量】218.25544

【元素组成】C 66.04% H 6.47% N 12.84% O 14.66%

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)

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

参考文献中间体

合成目标

【1】 Daugan, A.; Grondin, P.; Ruault, C.; et al.; The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem 2003, 46, 21, 4533.
【2】 Martin, L.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; IC-351. Drugs Fut 2001, 26, 1, 15.
【3】 Daugan, A.C.-M. (Icos Corp.); Tetracyclic derivs., process of preparation and use. EP 0740668; JP 1997508113; US 5859006; US 6025494; US 6127542; WO 9519978 .
【4】 Daugan, A.C.-M. (Icos Corp.); Use of cGMP-phosphodiesterase inhibitors to treat impotence. JP 1999509221; US 6140329; WO 9703675 .
【5】 Gellibert, F.; Daugan, A.C.-M. (Icos Corp.); Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use. US 6143746 .

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)	20416	methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate		C₁₂H₁₄N₂O₂	详情	详情
(II)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(III)	43790	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate		C₂₀H₁₈N₂O₄	详情	详情
(IV)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(V)	43791	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate		C₂₂H₁₉ClN₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Acylation of D-tryptophan methyl ester (I) with 5-bromo-2-thiophenesulfonyl chloride (II) yields sulfonamide (III). Subsequent Heck coupling of aryl bromide (III) with 4-methylphenylacetylene (IV) in the presence of copper and palladium catalysts gives rise to the diaryl acetylene (V). Finally, hydrolysis of the methyl ester group of (V) under alkaline conditions furnishes the target carboxylic acid

参考文献中间体

合成目标

【1】 Watanabe, F.; Tsuzuki, H.; Ohtani, M. (Shionogi & Co. Ltd.); Sulfonated amino acid derivs. and metalloproteinase inhibitors containing the same. EP 0950656; JP 2001316254; US 6207698; US 6235768; US 6441021; WO 9727174 .

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)	20416	methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate		C₁₂H₁₄N₂O₂	详情	详情
(II)	60039	5-bromo-2-thiophenesulfonyl chloride	55854-46-1	C₄H₂BrClO₂S₂	详情	详情
(III)	60040	methyl (2R)-2-{[(5-bromo-2-thienyl)sulfonyl]amino}-3-(1H-indol-3-yl)propanoate		C₁₆H₁₅BrN₂O₄S₂	详情	详情
(IV)	60041	1-ethynyl-4-methylbenzene		C₉H₈	详情	详情
(V)	60042	methyl (2R)-3-(1H-indol-3-yl)-2-[({5-[2-(4-methylphenyl)ethynyl]-2-thienyl}sulfonyl)amino]propanoate		C₂₅H₂₂N₂O₄S₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Treatment of D-tryptophan methyl ester (XI) with N,N'-disuccinimidyl carbonate (XII) gave the intermediate succinimidyl carbamate (XIII), which was subsequently converted to urea (XV) upon reaction with spiro(indene-1,4'-piperidine) (XIV). Saponification of the ester function of (XV) with LiOH afforded the carboxylic acid (XVI), and this was then coupled with the Boc-protected chiral diamine (X) using EDC and HOBt. The resulting precursor (XVII) was finally deprotected with HCl in EtOAc to provide the title compound.

参考文献中间体

合成目标

【1】 Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	20415	tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate		C₁₃H₂₆N₂O₂	详情	详情
(XI)	20416	methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate		C₁₂H₁₄N₂O₂	详情	详情
(XII)	20417	1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione	74124-79-1	C₉H₈N₂O₇	详情	详情
(XIII)	20418	methyl (2R)-2-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]amino)-3-(1H-indol-3-yl)propanoate		C₁₇H₁₇N₃O₆	详情	详情
(XIV)	20419	Spiro[indene-1,4'-piperidine]		C₁₃H₁₅N	详情	详情
(XV)	20420	N-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophan methyl ester		C₂₆H₂₇N₃O₃	详情	详情
(XVI)	20421	N-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophan		C₂₅H₂₅N₃O₃	详情	详情
(XVII)	20422	N-[3(R)-[N-alpha-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophanamidomethyl]cyclohex-1(S)-ylmethyl]carbamic acid tert-butyl ester		C₃₈H₄₉N₅O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Sajja E, Vetukuri VR, Ningam SR, et aL. 2007. Process for producing tadalafiL. W0 2007100387

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)	66758	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate hydrochloride		C₂₀H₁₈N₂O₄.HCl	详情	详情
(I)	20416	methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate		C₁₂H₁₄N₂O₂	详情	详情
(II)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(IV)	32138	Sarcosine ethyl ester; Ethyl 2-(methylamino)acetate	52605-49-9	C₅H₁₁NO₂	详情	详情

Extended Information