DPP-728, NVP-DPP-728, -Drug Synthesis Database

【结构式】

【药物名称】DPP-728, NVP-DPP-728

【化学名称】6-[2-[2-[2(S)-Cyanopyrrolidin-1-yl]-2-oxoethylamino]ethylamino]pyridine-3-carbonitrile
　　　　　　1-[2-[2-(5-Cyanopyridin-2-ylamino)ethylamino]acetyl]pyrrolidine-2(S)-carbonitrile

【CA登记号】207556-62-5 (diHCl)

【分子式】C₁₅H₁₈N₆O

【分子量】298.35031

【开发单位】Novartis (Originator)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Dipeptidyl-Peptidase IV Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

The reaction of 6-chloropyridine-3-carbonitrile (I) with carbamate (II) by means of KHCO3 in hot DMF gives the adduct (III), which is treated with TFA in dichloromethane to yield 6-(2-aminoethylamino)pyridine-3-carbonitrile (IV). The cyclization of (IV) with formaldehyde affords 6-(1-imidazoldinyl)pyridine-3-carbonitrile (V), which is condensed with 1-(2-bromoacetyl)piperidine-2(S)-carbonitrile (VI) by means of TEA in THF to provide the adduct (VII). Finally, the cleavage of the imidazolidine ring of (VII) by means of TFA in water, or TFA and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin in dichloromethane, gives rise to the target pyridine-carbonitrile derivative.

参考文献中间体

【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)	57164	2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile	33252-28-7	C₆H₃ClN₂	详情	详情
(II)	13241	N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate	57260-73-8	C₇H₁₆N₂O₂	详情	详情
(III)	57165	tert-butyl 2-[(5-cyano-2-pyridinyl)amino]ethylcarbamate		C₁₃H₁₈N₄O₂	详情	详情
(IV)	54332	6-[(2-aminoethyl)amino]nicotinonitrile	n/a	C₈H₁₀N₄	详情	详情
(V)	57166	6-(1-imidazolidinyl)nicotinonitrile		C₉H₁₀N₄	详情	详情
(VI)	54334	(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile	n/a	C₇H₉BrN₂O	详情	详情
(VII)	57167	6-(3-{2-[(2S)-2-cyanopyrrolidinyl]-2-oxoethyl}-1-imidazolidinyl)nicotinonitrile		C₁₆H₁₈N₆O	详情	详情

合成路线3

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

【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

Drug NewChemical Entity Original Patent(1)