A-422885.66, BSF-466895, -Drug Synthesis Database

【结构式】

【药物名称】A-422885.66, BSF-466895

【化学名称】N-[4-[4-Amino-7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide

【CA登记号】262442-90-0, 262443-26-5 (cis-isomer), 262442-91-1 (maleate), 364354-34-7 (undefined isomer)

【分子式】C₂₉H₃₂Cl₂FN₇O₂S

【分子量】632.59249

【开发单位】Abbott (Originator)

【药理作用】Oncolytic Drugs, Angiogenesis Inhibitors, Inhibitors of Signal Transduction Pathways, Tie2 Receptor Inhibitors

合成路线1 合成路线2

合成路线1

4-Bromo-2-fluoroaniline (I) was protected as the N-Boc derivative (II) upon treatment with di-tert-butyl dicarbonate. Subsequent palladium-catalyzed bromide displacement in (II) with bis-pinacolatodiborane (III) furnished the arylboronate derivative (IV). The (dioxaspirodecyl)pyrimidine (VII) was prepared by coupling between 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (V) and 4-hydroxycyclohexanone ethylene ketal (VI) under Mitsunobu conditions. Subsequent Suzuki coupling of iodopyrrolopyrimidine (VII) with boronate (IV) afforded adduct (VIII). Displacement of the 4-chloro of (VIII) with simultaneous N-Boc group cleavage with ammonium hydroxide in dioxan at 120 C in a sealed vessel furnished the diamino compound (IX).

参考文献中间体

【1】 Wishart, N.; Barlozzari, T.; Arnold, L.D.; et al.; Structure activity relationships for a novel series of pyrrolo[2,3-d]pyrimidine Tie-2 inhibitors. Proc Am Assoc Cancer Res 2002, 43, Abst 4205.
【2】 Hirst, G.C.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D. (BASF AG); Pyrrolopyrimidines as protein kinase inhibitors. EP 1114053; WO 0017203 .
【3】 Hirst, G.C.; Rafferty, P.; Arnold, L.D.; Johnston, D.N.; Calderwood, D.; Munschaufer, R. (BASF AG); Pyrrolopyrimidines as tyrosine kinase inhibitors. WO 0172751 .

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)	14723	4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline	367-24-8	C₆H₅BrFN	详情	详情
(II)	53560	tert-butyl 4-bromo-2-fluorophenylcarbamate	n/a	C₁₁H₁₃BrFNO₂	详情	详情
(III)	53561		n/a	C₁₂H₂₆B₂O₄	详情	详情
(IV)	53562	tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate	n/a	C₁₇H₂₅BFNO₄	详情	详情
(V)	53563	4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine	123148-78-7	C₆H₃ClIN₃	详情	详情
(VI)	53564	1,4-dioxaspiro[4.5]decan-8-ol	22428-87-1	C₈H₁₄O₃	详情	详情
(VI)	53565	4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine	n/a	C₁₄H₁₅ClIN₃O₂	详情	详情
(VII)	53566	tert-butyl 4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate	n/a	C₂₅H₂₈ClFN₄O₄	详情	详情
(VIII)	53567	5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylamine	n/a	C₂₀H₂₂FN₅O₂	详情	详情

合成路线2

Acid hydrolysis of the ethylene ketal function of (IX) afforded ketone (X). This was subjected to a reductive amination with N-methylpiperazine (XI) in the presence of sodium triacetoxyborohydride to produce the corresponding disubstituted cyclohexane compound as a 3:1 mixture of cis- and trans-isomers. The desired trans-compound (XII) was then isolated by column chromatography. Finally, acylation of (XII) with 2,3-dichlorobenzenesulfonyl chloride (XIII) provided the title sulfonamide.

参考文献中间体

【1】 Wishart, N.; Barlozzari, T.; Arnold, L.D.; et al.; Structure activity relationships for a novel series of pyrrolo[2,3-d]pyrimidine Tie-2 inhibitors. Proc Am Assoc Cancer Res 2002, 43, Abst 4205.
【2】 Hirst, G.C.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D. (BASF AG); Pyrrolopyrimidines as protein kinase inhibitors. EP 1114053; WO 0017203 .
【3】 Hirst, G.C.; Rafferty, P.; Arnold, L.D.; Johnston, D.N.; Calderwood, D.; Munschaufer, R. (BASF AG); Pyrrolopyrimidines as tyrosine kinase inhibitors. WO 0172751 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	53567	5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylamine	n/a	C₂₀H₂₂FN₅O₂	详情	详情
(X)	53568	4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone	n/a	C₁₈H₁₈FN₅O	详情	详情
(XI)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(XII)	53569	5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine	n/a	C₂₃H₃₀FN₇	详情	详情
(XIII)	53570	2,3-Dichlorobenzenesulfonyl chloride	82417-45-6	C₆H₃Cl₃O₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)