(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide -Drug Synthesis Database

【结构式】

【分子编号】54331

【品名】(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide

【CA登记号】n/a

【分子式】C₇H₁₁BrN₂O₂

【分子量】235.08062

【元素组成】C 35.77% H 4.72% Br 33.99% N 11.92% O 13.61%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII),(XII)

The deprotection of the resin (I) with piperidine in DMF gives the amino-resin (II), which is condensed with N-Fmoc-L-proline (III) by means of diisopropylcarbodiimide (DIC) in DMF to yield the anchored proline (IV). The deprotection of (IV) with piperidine in DMF affords compound (V) with a free NH group, which is condensed with 2-bromoacetic acid (VI) by means of DIC DMF to provide the bromoacetyl proline resin (VII). The condensation of (VII) with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in DMSO to give the resin anchored precursor (IX), which is finally cleaved by means of trifluoroacetic anhydride (TFAA) in THF to furnish the target pyrrolidine-carbonitrile. Alternatively, the acylation of L-prolinamide (X) with 2-bromoacetyl bromide (XI) by means of TEA and DMAP in dichloromethane gives the 1-(2-bromoacetyl)-L-prolinamide (XII), which is dehydrated by means of TFAA in dichloromethane to yield the pyrrolidine-carbonitrile (XIII). Finally, this compound is condensed with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in THF to furnish the target pyrrolidine-carbonitrile.

参考文献中间体

合成目标

【1】 Mangold, B.L.; Mone, M.D.; Dunning, B.E.; Russell, M.E.; Brinkman, J.A.; Weldon, S.C.; Hughes, T.E.; Naderi, G.B.; Villhauer, E.B.; 1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidine-carbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2002, 45, 12, 2362.
【2】 Villhauer, E.B. (Novartis AG); N-Substd. 2-cyanopyrrolidines. JP 2000511559; WO 9819998 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V),(X)	36137	(2S)-2-pyrrolidinecarboxamide;L-prolinamide	7531-52-4	C₅H₁₀N₂O	详情	详情
(VII),(XII)	54331	(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide	n/a	C₇H₁₁BrN₂O₂	详情	详情
(I)	28722	9H-fluoren-9-ylmethyl carbamate	84418-43-9	C₁₅H₁₃NO₂	详情	详情
(III)	34762	(2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid	71989-31-6	C₂₀H₁₉NO₄	详情	详情
(IV)	42841	9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate		C₂₀H₂₀N₂O₃	详情	详情
(VI)	23660	2-Bromoacetic acid	79-08-3	C₂H₃BrO₂	详情	详情
(VIII)	54332	6-[(2-aminoethyl)amino]nicotinonitrile	n/a	C₈H₁₀N₄	详情	详情
(IX)	54333	(2S)-1-[2-({2-[(5-cyano-2-pyridinyl)amino]ethyl}amino)acetyl]-2-pyrrolidinecarboxamide	n/a	C₁₅H₂₀N₆O₂	详情	详情
(XI)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(XIII)	54334	(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile	n/a	C₇H₉BrN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The condensation of protected L-proline (I) with RINK RESIN (II) by means of TBTU, HOBT and DIEA in DMF gives the protected, rein bounded proline (III), which is deprotected by means of piperidine in DMF to yield the resin bounded proline (IV). The condensation of (IV) with 2-bromoacetic acid (V) by means of DIC in the same solvent affords the acyl proline (VI), which is treated with ethylene-1,2-diamine (VII) to provide the aminoacetyl proline (VIII). The condensation of (VIII) with 2-acetyldimedone (IX) gives the regioselectively monoprotected diaminoproline compound (X), which is treated with Boc2O and DIEA in dioxane to protect the secondary amino group of (X) and yield (XI). The selective elimination of the dimedone protecting group with hydrazine in DMF affords compound (XII) selectively monoprotected at the secondary amino group, which is condensed with 6-chloropyridine-3-carbonitrile (XIII) by means of DIEA in NMP to provide the resin adduct (XIV). The cleavage of the resin group of (XIV) by means of TFA and TFAA in dichloromethane takes place with simultaneous dehydration of the carboxamide group and removal of the Boc protecting group affording the trifluoroacetamido derivative (XV). Finally, the trifluoroacetyl group is removed by means of NH3 in aqueous methanol to give rise to the target pyridine carbonitrile derivative.

参考文献中间体

合成目标

【1】 Willand, N.; et al.; Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhihitor NVP-DPP728. Tetrahedron 2002, 58, 28, 5741.

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)	34762	(2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid	71989-31-6	C₂₀H₁₉NO₄	详情	详情
(III)	42841	9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate		C₂₀H₂₀N₂O₃	详情	详情
(IV)	36137	(2S)-2-pyrrolidinecarboxamide;L-prolinamide	7531-52-4	C₅H₁₀N₂O	详情	详情
(V)	23660	2-Bromoacetic acid	79-08-3	C₂H₃BrO₂	详情	详情
(VI)	54331	(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide	n/a	C₇H₁₁BrN₂O₂	详情	详情
(VII)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
(VIII)	57168	(2S)-1-{2-[(2-aminoethyl)amino]acetyl}-2-pyrrolidinecarboxamide		C₉H₁₈N₄O₂	详情	详情
(IX)	57169	2-(1-hydroxyethylidene)-5,5-dimethyl-1,3-cyclohexanedione		C₁₀H₁₄O₃	详情	详情
(X)	57170	(2S)-1-{2-[(2-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]amino}ethyl)amino]acetyl}-2-pyrrolidinecarboxamide		C₁₉H₃₀N₄O₄	详情	详情
(XI)	57171	tert-butyl 2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl(2-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]amino}ethyl)carbamate		C₂₄H₃₈N₄O₆	详情	详情
(XII)	57172	tert-butyl 2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl(2-aminoethyl)carbamate		C₁₄H₂₆N₄O₄	详情	详情
(XIII)	57164	2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile	33252-28-7	C₆H₃ClN₂	详情	详情
(XIV)	57173	tert-butyl 2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl{2-[(5-cyano-2-pyridinyl)amino]ethyl}carbamate		C₂₀H₂₈N₆O₄	详情	详情
(XV)	57174	N-{2-[(5-cyano-2-pyridinyl)amino]ethyl}-N-{2-[(2S)-2-cyanopyrrolidinyl]-2-oxoethyl}-2,2,2-trifluoroacetamide		C₁₇H₁₇F₃N₆O₂	详情	详情

Extended Information