NSC-658879, -Drug Synthesis Database

【结构式】

【药物名称】NSC-658879

【化学名称】4''-(Hydroxymethyl)-2,2':5',2''-terthiophene-5-carbaldehyde

【CA登记号】

【分子式】C₁₄H₁₀O₂S₃

【分子量】306.4266

【开发单位】Industrial Technol. & Res. Inst. (Originator), Purdue Research Foundation (Originator)

【药理作用】Inhibitors of Signal Transduction Pathways, Protein Kinase C (PKC) Inhibitors

合成路线1 合成路线2

合成路线1

Formylation of 2,2'-bithiophene (I) either under Vilsmeier conditions (1) or by lithiation with LDA, followed by addition of DMF (2), provided aldehyde (II). This was protected as the dimethyl acetal (III) employing trimethyl orthoformate in the presence of montmorillonite K-10. After lithiation of (III) with n-BuLi, treatment with tributyltin chloride gave the stannyl derivative (IV). Stille coupling of (IV) with 2-iodo-4-(hydroxymethyl)thiophene (VI) (prepared by reduction of the corresponding aldehyde (V) with NaBH4), furnished the corresponding terthiophene, which after acid hydrolysis of the acetal protecting group provided the title compound.

参考文献中间体

【1】 Xu, W.-C.; Chang, C.-j.; Zhou, Q.; Ashendel, C.L.; Chang, C.t.; Novel protein kinase C inhibitors: Synthesis and PKC inhibition of beta-substituted polythiophene derivatives. Bioorg Med Chem Lett 1999, 9, 15, 2279.
【2】 Chang, C.-T.; Chang, C.-J.; Lee, C.-T.; Lin, F.-L.; Tsai, J.-D.; Ashendel, C.L.; Chan, T.C.K.; Geahlen, R.L.; Waters, D.J. (Industrial Technology & Research Institute; Purdue Research Foundation); Polythiophene anti-tumor agents. EP 1007035; WO 9823269 .

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)	43130	2,2'-Bithiophene	492-97-7	C₈H₆S₂	详情	详情
(II)	43131	2,2'-Bithienyl-5-carboxaldehyde 2,2'-Bithienyl-5-carboxaldehyde 2,2'-Bithienyl-5-carboxaldehyde	3779-27-9	C₉H₆OS₂	详情	详情
(III)	43132			C₁₁H₁₂O₂S₂	详情	详情
(IV)	43133			C₂₃H₃₈O₂S₂Sn	详情	详情
(V)	43134	5-iodo-3-thiophenecarbaldehyde	18799-85-4	C₅H₃IOS	详情	详情
(VI)	43135	(5-iodo-3-thienyl)methanol		C₅H₅IOS	详情	详情

合成路线2

In an alternative procedure, the bithiophene aldehyde (II) was reduced to alcohol (VII) with NaBH4, and this was protected with dihydropyran to give (VIII). Lithiation and subsequent treatment of (VIII) with tributyltin chloride afforded the stannyl compound (IX). This was then coupled with 2-bromo-4-thiophene-carboxaldehyde (X) in the presence of Pd(PPh3)4 and an additional amount of PPh3 to provide the terthiophene (XI). The reduction of the aldehyde group of (XI) with NaBH4, and then acid hydrolysis of the tetrahydropyranyl protecting group furnished diol (XII). Finally, the oxidation of (XII) by means of DDQ gave rise to a 1:3 mixture of the desired hydroxy aldehyde and its regioisomer (XIII).

参考文献中间体

【1】 Xu, W.-C.; Chang, C.-j.; Zhou, Q.; Ashendel, C.L.; Chang, C.t.; Novel protein kinase C inhibitors: Synthesis and PKC inhibition of beta-substituted polythiophene derivatives. Bioorg Med Chem Lett 1999, 9, 15, 2279.
【2】 Chang, C.-T.; Chang, C.-J.; Lee, C.-T.; Lin, F.-L.; Tsai, J.-D.; Ashendel, C.L.; Chan, T.C.K.; Geahlen, R.L.; Waters, D.J. (Industrial Technology & Research Institute; Purdue Research Foundation); Polythiophene anti-tumor agents. EP 1007035; WO 9823269 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	43131	2,2'-Bithienyl-5-carboxaldehyde 2,2'-Bithienyl-5-carboxaldehyde 2,2'-Bithienyl-5-carboxaldehyde	3779-27-9	C₉H₆OS₂	详情	详情
(VII)	43136	2,2'-Bithien-5-ylmethanol	3515-30-8	C₉H₈OS₂	详情	详情
(VIII)	43137			C₁₄H₁₆O₂S₂	详情	详情
(IX)	43138			C₂₆H₄₂O₂S₂Sn	详情	详情
(X)	31660	5-bromo-3-thiophenecarbaldehyde		C₅H₃BrOS	详情	详情
(XI)	43139			C₁₉H₁₈O₃S₃	详情	详情
(XII)	43140			C₁₄H₁₂O₂S₃	详情	详情
(XIII)	43141			C₁₄H₁₀O₂S₃	详情	详情

Extended Information