ZD-4974-药物合成数据库

【药物名称】ZD-4974

化学结构式(Chemical Structure):

参考文献No.	42979
标题:	Naphthalenecarboxamides as tachykinin receptor antagonists
作者:	Bernstein, P.R.; Russell, K.; Ohnmacht, C.J.; Dedinas, R.F.; Shewood, S.A. (AstraZeneca plc)
来源:	EP 1119551; JP 2002526527; WO 0020389

合成路线图解说明: 3-Hydroxy-2-naphthoic acid (I) is iodinated by means of NaI and NaOCl to afford 3-hydroxy-4-iodo-2-naphthoic acid (II). Subsequent alkylation with dimethyl sulfate provides the methoxynaphthoate ester (III). Direct conversion of ester (III) to the corresponding nitrile (IV) is accomplished by treatment with dimethylaluminum amide in boiling xylene. Carbonylation of iodonaphthalene (IV) using carbon monoxide in the presence of Pd(OAc)2 and methanol yields the methyl naphthoate (V). Saponification of ester (V) using LiOH gives acid (VI), which is further activated as the acid chloride (VII) by treatment with oxalyl chloride and DMF

合成路线图解说明: Reductive amination of the N-Boc amino aldehyde (VIII) with (S)-4-(2-methylsulfinylphenyl)piperidine (IX) in the presence of NaBH3CN affords the Boc-protected diamine (X). Deprotection of (X) by means of trifluoroacetic acid yields amine (XI) (1). Acylation of (XI) with acid chloride (VII), followed by treatment with citric acid, gives rise to the title compound

参考文献No.	687587
标题:	Design, synthesis, and SAR of tachykinin antagonists: Modulation of balance in NK1/NK2 receptor antagonist activity
作者:	Albert, J.S.; Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein, P.R.; Bialecki, R.A.; Dedinas, R.; Dembofsky, B.T.; Hill, D.R.; Kirkland, K.M.; Koether, G.M.; Kosmider, B.J.; Ohnmacht, C.J.; Palmer, W.; Potts, W.; Rumsey, W.; Shen, L.; Shenvi, A.; et al.
来源:	J Med Chem 2002,45(18),3972

合成路线图解说明: 3-Hydroxy-2-naphthoic acid (I) is iodinated by means of NaI and NaOCl to afford 3-hydroxy-4-iodo-2-naphthoic acid (II). Subsequent alkylation with dimethyl sulfate provides the methoxynaphthoate ester (III). Direct conversion of ester (III) to the corresponding nitrile (IV) is accomplished by treatment with dimethylaluminum amide in boiling xylene. Carbonylation of iodonaphthalene (IV) using carbon monoxide in the presence of Pd(OAc)2 and methanol yields the methyl naphthoate (V). Saponification of ester (V) using LiOH gives acid (VI), which is further activated as the acid chloride (VII) by treatment with oxalyl chloride and DMF

合成路线图解说明: Reductive amination of the N-Boc amino aldehyde (VIII) with (S)-4-(2-methylsulfinylphenyl)piperidine (IX) in the presence of NaBH3CN affords the Boc-protected diamine (X). Deprotection of (X) by means of trifluoroacetic acid yields amine (XI) (1). Acylation of (XI) with acid chloride (VII), followed by treatment with citric acid, gives rise to the title compound