CP-608039, -Drug Synthesis Database

【结构式】

【药物名称】CP-608039

【化学名称】3(S)-Amino-5(R)-[N6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzyl]adenin-9-yl]-4(R)-hydroxy-N-methyltetrahydrofuran-2(S)-carboxamide
　　　　　　3-Amino-1-[N6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzyl]adenin-9-yl]-1,3-dideoxy-N-methyl-beta-D-ribofuranuronamide

【CA登记号】331727-55-0

【分子式】C₂₃H₂₅ClN₈O₅

【分子量】528.9593

【开发单位】Pfizer (Originator)

【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Adenosine A3 Agonists

合成路线1 合成路线2

合成路线1

Treatment of 1,2,5,6-diisopropylidene-D-glucofuranose (I) with trifluoromethanesulfonic anhydride and pyridine provides triflate (II), which is then displaced with sodium azide to furnish the 3-azido derivative (III). Oxidative cleavage of the 5,6-diol acetonide of (III) by means of periodic acid leads to aldehyde (IV). Further oxidation of (IV) with a catalytic amount of ruthenium trichloride in the presence of sodium periodate affords carboxylic acid (V). After activation of acid (V) with oxalyl chloride, coupling with methylamine provides amide (VI). Acidic hydrolysis of the remaining 1,2-acetonide of (VI) in the presence of acetic anhydride gives rise to diacetate (VII). Silylation of 6-chloropurine (VIII), followed by coupling with the diacetyl ribofuranuronic acid derivative (VII) in the presence of trimethylsilyl triflate yields the purine glycoside (IX). The acetate ester group of (IX) is then removed by methanolysis in the presence of either methylamine or triethylamine, to produce alcohol (X). Subsequent azido group reduction in (X) by means of triphenylphosphine leads to amine (XI), which is then protected as the N-Boc derivative (XII) employing di-t-butyl dicarbonate.

参考文献中间体

【1】 Masamune, H.; Scott, R.W.; Deninno, M.P. (Pfizer Products Inc.); Cpds. for the treatment of ischemia. EP 1216257; JP 2003510331; WO 0123399 .

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)	29141	(3aR,5S,6S,6aR)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol	582-52-5	C₁₂H₂₀O₆	详情	详情
(II)	61299	(3aR,5R,6S,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl trifluoromethanesulfonate		C₁₃H₁₉F₃O₈S	详情	详情
(III)	61300	(3aR,5S,6R,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl azide; (3aR,5S,6R,6aR)-6-azido-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole		C₁₂H₁₉N₃O₅	详情	详情
(IV)	61363	(3aR,5S,6R,6aR)-6-azido-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde		C₈H₁₁N₃O₄	详情	详情
(V)	31364	(5E)-2-[(Z,4E)-6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-methyl-4-hexenylidene]-6,10-dimethyl-5,9-undecadienal		C₂₈H₃₅NO₃	详情	详情
(VI)	31365	tert-butyl[[(2E,6Z,10E)-7-(diethoxymethyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2E,6Z,10E)-7-(diethoxymethyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraenyl ether		C₃₀H₅₆O₃Si	详情	详情
(VII)	31366	2-[(2E,6Z,10E)-7-(hydroxymethyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraenyl]-1H-isoindole-1,3(2H)-dione		C₂₈H₃₇NO₃	详情	详情
(VIII)	17692	6-Chloropurine; 6-chloro-9H-purine	87-42-3	C₅H₃ClN₄	详情	详情
(IX)	61367	(2R,3R,4R,5S)-4-azido-2-(6-chloro-9H-purin-9-yl)-5-[(methylamino)carbonyl]tetrahydro-3-furanyl acetate		C₁₃H₁₃ClN₈O₄	详情	详情
(X)	61368	(2S,3S,4R,5R)-3-azido-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-N-methyltetrahydro-2-furancarboxamide		C₁₁H₁₁ClN₈O₃	详情	详情
(XI)	61369	(2S,3S,4R,5R)-3-amino-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-N-methyltetrahydro-2-furancarboxamide		C₁₁H₁₃ClN₆O₃	详情	详情
(XII)	61370	tert-butyl (2S,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(methylamino)carbonyl]tetrahydro-3-furanylcarbamate		C₁₆H₂₁ClN₆O₅	详情	详情

合成路线2

Coupling between 2-(phthalimidomethyl)-4-chlorophenol (XIII) and 5-(hydroxymethyl)-3-methylisoxazole (XIV) under Mitsunobu conditions provides the ether adduct (XV). Subsequent phthaloyl group hydrazinolysis in (XV) leads to the primary amine (XVI). The 6-chloropurine glycoside (XII) is then condensed with amine (XVI) to furnish the 6-aminopurine derivative (XVII). Finally, Boc group cleavage in (XVII) employing methanesulfonic acid affords the title compound.

参考文献中间体

【1】 Masamune, H.; Scott, R.W.; Deninno, M.P. (Pfizer Products Inc.); Cpds. for the treatment of ischemia. EP 1216257; JP 2003510331; WO 0123399 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	61370	tert-butyl (2S,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(methylamino)carbonyl]tetrahydro-3-furanylcarbamate	C₁₆H₂₁ClN₆O₅	详情	详情
(XIII)	61371	2-(5-chloro-2-hydroxybenzyl)-1H-isoindole-1,3(2H)-dione	C₁₅H₁₀ClNO₃	详情	详情
(XIV)	13343	(3-Methyl-5-isoxazolyl)methanol	C₅H₇NO₂	详情	详情
(XV)	61372	2-{5-chloro-2-[(3-methyl-5-isoxazolyl)methoxy]benzyl}-1H-isoindole-1,3(2H)-dione	C₂₀H₁₅ClN₂O₄	详情	详情
(XVI)	61373	5-chloro-2-[(3-methyl-5-isoxazolyl)methoxy]benzylamine; {5-chloro-2-[(3-methyl-5-isoxazolyl)methoxy]phenyl}methanamine	C₁₂H₁₃ClN₂O₂	详情	详情
(XVII)	61374	tert-butyl (2S,3S,4R,5R)-5-[6-({5-chloro-2-[(3-methyl-5-isoxazolyl)methoxy]benzyl}amino)-9H-purin-9-yl]-4-hydroxy-2-[(methylamino)carbonyl]tetrahydro-3-furanylcarbamate	C₂₈H₃₃ClN₈O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)