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【结 构 式】 
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【分子编号】36137 【品名】(2S)-2-pyrrolidinecarboxamide;L-prolinamide 【CA登记号】7531-52-4 |
【 分 子 式 】C5H10N2O 【 分 子 量 】114.14728 【元素组成】C 52.61% H 8.83% N 24.54% O 14.02% |
合成路线1
该中间体在本合成路线中的序号：(II)The synthesis of thyrotropin releasing hormone (TRH) analogues is described as follows: The reduction of N-benzyloxycarbonylprolinamide (I) with H2 over Pd/C in methanol gives prolinamide (II), which is condensed with N-benzyloxy-carbonylhistidyl hydrazide (III) by means of NaNO2 - HCl in ethyl acetate yielding N-benzyloxycarbonylhistidylprolinamide (IV). The hydrolysis of (IV) with HBr in acetic acid affords histidylprolinamide (V), which is finally condensed with 6-methyl-5-oxothiomorpholinyl-3-carboxylic acid (VI) by means of 1-hydroxybenzotriazole, dicyclohexylcarbodiimide and triethylamine in DMF.
| 【1】 US 4045556 . |
| 【2】 Goren, H.J.; Bauce, L.G.; Synthesis of a series of residue 1-(pyroglutamic acid) analogs of thyrotropin releasing hormone. Intl J Pept Protein Res 1979, 14, 216-226. |
| 【3】 Pento, J.T.; CG-3703. Drugs Fut 1983, 8, 12, 1007. |
| 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) | 36136 | benzyl (2S)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate | 34079-31-7 | C13H16N2O3 | 详情 | 详情 |
| (II) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (III) | 36138 | benzyl (1S)-2-hydrazino-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate | 49706-31-2 | C14H17N5O3 | 详情 | 详情 |
| (IV) | 36139 | benzyl (1S)-2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate | C19H23N5O4 | 详情 | 详情 | |
| (V) | 31253 | (2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide | C11H17N5O2 | 详情 | 详情 | |
| (VI) | 36140 | (3R,6R)-6-methyl-5-oxo-3-thiomorpholinecarboxylic acid | C6H9NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V),(X)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.
| 【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3
该中间体在本合成路线中的序号：(IV)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.
| 【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 |
合成路线4
该中间体在本合成路线中的序号：(I)Prolinamide (I) was coupled with Z-leucylglycine (II) in the presence of DCC and HOBt to give the tripeptide amide (III). The terminal carboxamido group of (III) was then dehydrated to the corresponding nitrile by treatment with SOCl2 and N-methylmorpholine.
| 【1】 Santana, J.; Gullet, C.; Schrével, J.; Frappier, F.; Maoulida, C.; Grellier, P.; Joyeau, R.; Teixeira, A.R.L.; Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi. Eur J Med Chem 2000, 35, 2, 257. |
| 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) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (II) | 46318 | 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]acetic acid | C16H22N2O5 | 详情 | 详情 | |
| (III) | 46319 | benzyl (1S)-1-[([2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl]amino)carbonyl]-3-methylbutylcarbamate | C21H30N4O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The reaction of adamantan-1-amine (I) with HNO3 and H2SO4 gives 3-nitroadamantan-1-amine (II), which is hydrolyzed with KOH in hot water to yield 3-hydroxyadamantan-1-amine (III). On the other hand, the reaction of chloroacetyl chloride (IV) with L-prolinamide (V) by means of K2CO3 in THF gives 1-(chloroacetyl)-L-prolinamide (VI), which is treated with trifluoroacetic anhydride in THF to yield the corresponding nitrile (VII). Finally 3-hydroxyadamantan-1-amine (III) is condensed with the 1-(chloroacetyl)-L-prolinenitrile (VII) by means of K2CO3 in dichloromethane to afford the target adamantane derivative.
| 【1】 Villhauer, E.B. (Novartis AG); N-Substd. 2-cyanopyrrolidines. EP 1137635; JP 2002531547; US 6166063; WO 0034241 . |
| 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) | 60231 | tricyclo[3.3.1.1~3,7~]dec-1-ylamine; tricyclo[3.3.1.1~3,7~]decan-1-amine | C10H17N | 详情 | 详情 | |
| (II) | 60232 | 3-nitrotricyclo[3.3.1.1~3,7~]dec-1-ylamine; 3-nitrotricyclo[3.3.1.1~3,7~]decan-1-amine | C10H16N2O2 | 详情 | 详情 | |
| (III) | 60233 | 3-aminotricyclo[3.3.1.1~3,7~]decan-1-ol | C10H17NO | 详情 | 详情 | |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (VI) | 60234 | 1-(2-chloroacetyl)-2-pyrrolidinecarboxamide | C7H11ClN2O2 | 详情 | 详情 | |
| (VII) | 60235 | 1-(2-chloroacetyl)-2-pyrrolidinecarbonitrile | C7H9ClN2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The condensation of N-(tert-butoxycarbonyl)-L-tert-butyl-glycine N-succinimidyl ester (I) with L-prolinamide (II) by means of DIEA in dichloromethane gives the dipeptide amide (III), which is dehydrated by means of POCl3 and imidazole in pyridine to yield N-(tert-butoxycarbonyl)-L-tert-butylglycyl-L-prolinenitrile (IV). Finally, this compound is deprotected by means of trifluoroacetic acid to provide the target dipeptide nitrile.
| 【1】 Ashworth, D.M.; et al.; 2-Cyanopyrrolidides as potent, stable inhibitors of dipeptidyl peptidase IV. Bioorg Med Chem Lett 1996, 6, 10, 1163. |
| 【2】 Broqua, P. (Ferring BV Group Holding); Compsns. for improving fertility. WO 0056296 . |
| 【3】 Broqua, P. (Ferring BV Group Holding); Compsns. for promoting growth. WO 0056297 . |
| 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) | 57855 | tert-butyl (1S)-1-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-2,2-dimethylpropylcarbamate | C15H24N2O6 | 详情 | 详情 | |
| (II) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (III) | 57856 | tert-butyl (1S)-1-{[(2S)-2-(aminocarbonyl)pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamate | C16H29N3O4 | 详情 | 详情 | |
| (IV) | 57857 | tert-butyl (1S)-1-{[(2S)-2-cyanopyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamate | C16H27N3O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIII)Chlorination of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (I) using (COCl)2 in refluxing CHCl3 gives the corresponding acid chloride (II) , which by condensation with 4-methoxy-3-buten-2-one (III) by means of LiHMDS in THF at –78 °C affords the hepta-1,4-dien-3-one derivative (IV) . Cyclization of intermediate (IV) in the presence of TFA in toluene or benzene produces the pyranone (V) (1-5), which is treated with aqueous NH3 at 65 °C to provide pyridinone (VI). Bromination of compound (VI) with POBr3 in toluene at 80 °C or in dichloroethane at 85 °C leads to the 4-bromopyridine derivative (VII). Subsequent coupling of bromopyridine (VII) with 2-acetamido-4-methylthiazole (VIII) by means of Pd(OAc)2, t-Bu3P·HBF4 and Cs2CO3 in refluxing DMF yields the pyridylthiazole adduct (IX), which by deacetylation using HCl in refluxing EtOH affords the 2-aminothiazole derivative (X) . Acylation of amine (X) with phenyl chloroformate (XI), optionally in the presence of DIEA in THF gives the thiazolylcarbamate (XII), which is finally condensed with L-prolinamide (XIII), optionally in the presence of Et3N in H2O .
Similarly, reaction of amine (X) with carbonyldiimidazole (XIV) in refluxing CH2Cl2 gives the carbamoyl imidazolide (XV), which is finally coupled with L-prolinamide (XIII) in the presence of Et3N in DMF or in DMAc at 65°C .
| 【1】 Furet, P., Guagnano, V., Fairhurst, R.A. et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett 2013, 23(13): 3741-8. |
| 【2】 Caravatti, G., Fairhurst, R.A., Furet, P., Guagnano, V., Imbach, P. (Novartis AG). Organic compounds. kR 2011038737; US 2010105711; US 8710085; CN 102149711; US 2014005232; JP 2012502080; US 8476268; US 8227462; US 2014186469; EP 2331537; WO 2010029082; CA 2734819; US 2012263712. |
| 【3】 Caravatti, G., Guagnano, V., Fairhurst, R. et al. Discovery of a novel 2-aminothiazole derivative (NVP-BYL719) with potent and selective PI3Kalpha inhibitory activity. 22nd Int Symp Med Chem (September 2-6, Berlin) 2012, Abst L25. |
| 【4】 Gallou, I.S., Gauer, C., Stowasser, F. (Novartis AG). A crystalline form of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-(4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl)-amide and its use as PI3K inhibitor. WO 2012016970. |
| 【5】 Caravatti, G., Guagnano, V., Fairhurst, R. et al. 2-Aminothiazoles as potent and selective PI3Kalpha inhibitors: Discovery of NVP-BYL719 and structural basis for the isoform selectivity. 103rd Annu Meet Am Assoc Cancer Res (AACR) (March 31-April 4, Chicago) 2012, Abst 1922. |
| 【6】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071. |
| 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) | 67528 | 3,3,3-trifluoro-2,2-dimethylpropanoic acid | C5H7F3O2 | 详情 | 详情 | |
| (II) | 67529 | 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride | C5H6ClF3O | 详情 | 详情 | |
| (III) | 67530 | 4-methoxy-3-buten-2-one | 51731-17-0 | C5H8O2 | 详情 | 详情 |
| (IV) | 67531 | (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one | C10H13F3O3 | 详情 | 详情 | |
| (V) | 67532 | 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one | C9H9F3O2 | 详情 | 详情 | |
| (VI) | 67533 | 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one | C9H10F3NO | 详情 | 详情 | |
| (VII) | 67534 | 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydropyridine | C9H11BrF3N | 详情 | 详情 | |
| (VIII) | 67535 | 2-acetamido-4-methylthiazole | 7336-51-8 | C6H8N2OS | 详情 | 详情 |
| (IX) | 67536 | N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)acetamide | C15H16F3N3OS | 详情 | 详情 | |
| (X) | 67537 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine | C13H14F3N3S | 详情 | 详情 | |
| (XI) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (XII) | 67538 | phenyl (4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate | C20H18F3N3O2S | 详情 | 详情 | |
| (XIII) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (XIV) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XV) | 67539 | N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-1H-imidazole-1-carboxamide | C17H16F3N5OS | 详情 | 详情 |