AT-1362, -Drug Synthesis Database

【结构式】

【药物名称】AT-1362

【化学名称】4-[2(R)-[2(S)-[2-(6-Amidino-1-ethylindol-2-yl)ethyl]pyrrolidin-1-ylcarbonyl]pyrrolidin-1-yl]-2(S)-amino-4-oxobutyric acid

【CA登记号】200183-43-3

【分子式】C₂₆H₃₆N₆O₄

【分子量】496.61462

【开发单位】C & C Research (Originator), Chugai (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Electrophilic nitration of p-tolunitrile (I) afforded the 3-nitro derivative (II), which was condensed with diethyl oxalate in the presence of sodium ethoxide to produce the sodium enolate of the alpha-keto ester (III). Compound (III) was then subjected to Reissert indole synthesis by means of Zn and HOAc to furnish ethyl 6-cyanoindole-2-carboxylate (IV). N-alkylation of indole (IV) with iodoethane and NaH in DMF gave (V), whose carboxylate group was reduced to alcohol (VI) employing in situ-generated calcium borohydride (obtained from NaBH4 and CaI2 in THF in the presence of NaHCO3). Treatment of alcohol (VI) with PBr3 in methylene chloride yielded the corresponding bromide (VII), which was then converted into the phosphonium salt (VIII) by means of triphenylphosphine in refluxing toluene.

参考文献中间体

【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 .

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)	15458	4-methylbenzonitrile; p-tolunitrile	104-85-8	C₈H₇N	详情	详情
(II)	50428	4-methyl-3-nitrobenzonitrile		C₈H₆N₂O₂	详情	详情
(III)	50429	sodium (Z)-1-(4-cyano-2-nitrophenyl)-3-ethoxy-3-oxo-1-propen-2-olate		C₁₂H₉N₂NaO₅	详情	详情
(IV)	50430	ethyl 6-cyano-1H-indole-2-carboxylate		C₁₂H₁₀N₂O₂	详情	详情
(V)	50431	ethyl 6-cyano-1-ethyl-1H-indole-2-carboxylate		C₁₄H₁₄N₂O₂	详情	详情
(VI)	50432	1-ethyl-2-(hydroxymethyl)-1H-indole-6-carbonitrile		C₁₂H₁₂N₂O	详情	详情
(VII)	50433	2-(bromomethyl)-1-ethyl-1H-indole-6-carbonitrile		C₁₂H₁₁BrN₂	详情	详情
(VIII)	50434	[(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide		C₃₀H₂₆BrN₂P	详情	详情

合成路线2

Fischer esterification of L-proline (IX) with MeOH and HCl gave (X). Treatment of (X) with di-tert-butyl dicarbonate provided N-Boc-proline methyl ester (XI). The ester function of (XI) was then reduced to aldehyde (XII) by employing DIBAL in toluene at -78 C. Wittig condensation between aldehyde (XII) and phosphonium bromide (VIII) in the presence of DBU yielded the (indolylvinyl)pyrrolidine (XIII), which was further hydrogenated to (XIV) in the presence of Pd/C. The N-Boc group of (XIV) was then cleaved by treatment with trifluoroacetic acid to furnish (XV).

参考文献中间体

【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	50434	[(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide		C₃₀H₂₆BrN₂P	详情	详情
(IX)	16731	L-proline	147-85-3	C₅H₉NO₂	详情	详情
(X)	29552	methyl (2S)-2-pyrrolidinecarboxylate	2133-40-6	C₆H₁₁NO₂	详情	详情
(XI)	50435	1-(tert-butyl) 2-methyl (2S)-1,2-pyrrolidinedicarboxylate		C₁₁H₁₉NO₄	详情	详情
(XII)	16724	tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal	69610-41-9	C₁₀H₁₇NO₃	详情	详情
(XIII)	50436	tert-butyl (2S)-2-[(E)-2-(6-cyano-1-ethyl-1H-indol-2-yl)ethenyl]-1-pyrrolidinecarboxylate		C₂₂H₂₇N₃O₂	详情	详情
(XIV)	50437	tert-butyl (2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]-1-pyrrolidinecarboxylate		C₂₂H₂₉N₃O₂	详情	详情
(XV)	50438	1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile		C₁₇H₂₁N₃	详情	详情

合成路线3

Pyrrolidine (XV) was coupled with N-Boc-D-proline (XVI) using EDC to provide amide (XVII). After acid cleavage of the Boc protecting group of (XVII), the resultant amine (XVIII) was further coupled with N-Boc-L-aspartic acid alpha-benzyl ester (XIX) to yield peptide (XX). Pinner reaction of nitrile (XX) with EtOH and HCl, with concomitant transesterification and Boc group cleavage, furnished imidate (XXI). Subsequent treatment of the imidate (XXI) with methanolic ammonia produced the corresponding amidine ester (XXII) along with some amide analogue (XXIII). Finally, basic hydrolysis of this mixture yielded the desired amidino acid.

参考文献中间体

【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XV)	50438	1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile	C₁₇H₂₁N₃	详情	详情
(XVI)	19061	(2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline	C₁₀H₁₇NO₄	详情	详情
(XVII)	50439	tert-butyl (2R)-2-([(2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl]carbonyl)-1-pyrrolidinecarboxylate	C₂₇H₃₆N₄O₃	详情	详情
(XVIII)	50440	1-ethyl-2-(2-[(2S)-1-[(2R)pyrrolidinylcarbonyl]pyrrolidinyl]ethyl)-1H-indole-6-carbonitrile	C₂₂H₂₈N₄O	详情	详情
(XIX)	50441	(3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid	C₁₆H₂₁NO₆	详情	详情
(XX)	50442	benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-2-([(2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl]carbonyl)pyrrolidinyl]-4-oxobutanoate	C₃₈H₄₇N₅O₆	详情	详情
(XXI)	50445	ethyl (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[ethoxy(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate	C₃₀H₄₃N₅O₅	详情	详情
(XXII)	50443	ethyl (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate	C₂₈H₄₀N₆O₄	详情	详情
(XXIII)	50444	(2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanamide	C₂₆H₃₇N₇O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)