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【结 构 式】

【药物名称】AG-5473

【化学名称】4-Cyclopentyl-13-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-5,8-dione
      2-Cyclopentyl-12-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-8,9,10,11-tetrahydro-7,11-imino-2H-pyrazino[1,2-a]azocine-3,6(4H,7H)-dione

【CA登记号】255910-29-3

【 分 子 式 】C26H31N3O7

【 分 子 量 】497.55287

【开发单位】Agouron (Originator)

【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Neurotrophic Agents, Peptidylprolyl Isomerase Inhibitors

合成路线1

Pyridine-2,6-dicarboxylic acid (I) was hydrogenated to the corresponding piperidine, which was subsequently protected as the N-benzyloxycarbonyl derivative (II). The dicarboxylic acid (II) was converted into the cyclic anhydride (III) upon heating with Ac2O. Anhydride (III) was then dissolved in MeOH to produce the mono ester (IV). The electrochemical oxidation of acid (IV) in methanol gave rise to the methoxypiperidine (V). The methoxy group of (V) was then displaced by allyl trimethylsilane (VI) in the presence of TiCl4 to furnish the allyl piperidine (VII), which was further oxidized to diol (VIII) employing OsO4 and N-methylmorpholine-N-oxide. Then, oxidative cleavage of diol (VIII) by means of NaIO4 gave aldehyde (IX). After aldehyde (IX) ketalization with trimethyl orthoformate, basic hydrolysis of the methyl ester group provided carboxylic acid (X). This was activated as the mixed anhydride with isobutyl chloroformate and then treated with ammonia to afford amide (XI). The cyclization of the ketal amide (XI) upon treatment with pyridinium p-toluenesulfonate gave rise to the bicyclic derivative (XII). Upon bromination of (XII) in the presence of NaOMe, the bicyclic compound (XII) rearranged to the ketal lactam (XIII). Alkylation of the lactam nitrogen of (XIII) with ethyl bromoacetate and NaH produced ester (XIV), which was then hydrolyzed to the carboxylic acid (XV).

1 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 .
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) 43290 2,6-pyridinedicarboxylic acid 499-83-2 C7H5NO4 详情 详情
(II) 43291 1-[(benzyloxy)carbonyl]-2,6-piperidinedicarboxylic acid C15H17NO6 详情 详情
(III) 43292 benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate C15H15NO5 详情 详情
(IV) 43293 1-[(benzyloxy)carbonyl]-6-(methoxycarbonyl)-2-piperidinecarboxylic acid C16H19NO6 详情 详情
(V) 43294 1-benzyl 2-methyl 6-methoxy-1,2-piperidinedicarboxylate C16H21NO5 详情 详情
(VI) 15775 Allyltrimethylsilane; allyl(trimethyl)silane 762-72-1 C6H14Si 详情 详情
(VII) 43295 1-benzyl 2-methyl (2S,6R)-6-allyl-1,2-piperidinedicarboxylate C18H23NO4 详情 详情
(VIII) 43296 1-benzyl 2-methyl (2S,6R)-6-(2,3-dihydroxypropyl)-1,2-piperidinedicarboxylate C18H25NO6 详情 详情
(IX) 43297 1-benzyl 2-methyl (2S,6R)-6-(2-oxoethyl)-1,2-piperidinedicarboxylate C17H21NO5 详情 详情
(X) 43298 (2S,6R)-1-[(benzyloxy)carbonyl]-6-(2,2-dimethoxyethyl)-2-piperidinecarboxylic acid C18H25NO6 详情 详情
(XI) 43299 benzyl (2S,6R)-2-(aminocarbonyl)-6-(2,2-dimethoxyethyl)-1-piperidinecarboxylate C18H26N2O5 详情 详情
(XII) 43300 benzyl 2-oxo-3,10-diazabicyclo[4.3.1]dec-4-ene-10-carboxylate C16H18N2O3 详情 详情
(XIII) 43301 benzyl 2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C18H24N2O5 详情 详情
(XIV) 43302 benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H30N2O7 详情 详情
(XV) 43303 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid C20H26N2O7 详情 详情

合成路线2

Carboxylic acid (XV) was coupled with cyclopentylamine (XVI) using EDC and HOBt to produce amide (XVII), which was cyclized to the fused pyrazinone derivative (XVIII) by treatment with pyridinium p-toluenesulfonate in toluene. The benzyloxycarbonyl group of (XVIII) was then removed by catalytic hydrogenation to give amine (XIX). This was finally coupled with (3,4,5-trimethoxyphenyl)glyoxylic acid (XX) to yield the title amide.

1 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307.
2 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 43303 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid C20H26N2O7 详情 详情
(XVI) 28850 cyclopentanamine 1003-03-8 C5H11N 详情 详情
(XVII) 43313 benzyl 3-[2-(cyclopentylamino)-2-oxoethyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C25H35N3O6 详情 详情
(XVIII) 43314 benzyl 4-cyclopentyl-5,8-dioxo-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-13-carboxylate C23H27N3O4 详情 详情
(XIX) 43315 4-cyclopentyl-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-5,8-dione C15H21N3O2 详情 详情
(XX) 30046 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid C11H12O6 详情 详情

合成路线3

The synthesis of the intermediate carboxylic acid (XV) has been reported by an alternative procedure. The cyclic anhydride (III) was condensed with glycine ethyl ester (XXI) in refluxing Ac2O, yielding the cyclic imide (XXII). Reduction of the imide (XXII) with NaBH4 produced the aminal (XXIII), which was subsequently converted to the more reactive acetoxyamide (XXIV). Boron trifluoride-catalyzed addition of propargyl trimethylsilane (XXV) to the acetoxyamide (XXIV) gave rise to allene (XXVI). This underwent smooth ozonolysis to the aldehyde (XXVII). After protection of the aldehyde (XXVII) as the dimethyl acetal (XIV), hydrolysis of the ethyl ester group gave the intermediate carboxylic acid (XV).

1 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307.
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) 43292 benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate C15H15NO5 详情 详情
(XIV) 43302 benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H30N2O7 详情 详情
(XV) 43303 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid C20H26N2O7 详情 详情
(XXI) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(XXII) 43307 benzyl 3-(2-ethoxy-2-oxoethyl)-2,4-dioxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C19H22N2O6 详情 详情
(XXIII) 43308 benzyl 3-(2-ethoxy-2-oxoethyl)-2-hydroxy-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C19H24N2O6 详情 详情
(XXIV) 43309 benzyl 2-(acetoxy)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C21H26N2O7 详情 详情
(XXV) 43310 trimethyl(2-propynyl)silane 13361-64-3 C6H12Si 详情 详情
(XXVI) 43311 benzyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-4-(1,2-propadienyl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H26N2O5 详情 详情
(XXVII) 43312 benzyl 3-(2-ethoxy-2-oxoethyl)-2-formyl-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C20H24N2O6 详情 详情
Extended Information