RS-100975, Ro-70-0004, -Drug Synthesis Database

【结构式】

【药物名称】RS-100975, Ro-70-0004

【化学名称】3-[3-[4-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl]propyl]-5-methylpyrimidine-2,4(1H,3H)-dione

【CA登记号】186386-21-0

【分子式】C₂₀H₂₄F₄N₄O₃

【分子量】444.43288

【开发单位】Roche Bioscience (Originator)

【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1A-Adrenoceptor Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The intermediate arylpiperazine (VI) was prepared as follows: Reaction of 2,4-difluoronitrobenzene (I) with trifluoroethanol (II) in the presence of potassium tert-butoxide yielded the trifluoroethyl ether (III). After catalytic hydrogenation of the nitro group of (III), the resultant aniline (IV) was cyclized with bis(2-chloroethyl) amine hydrochloride (V) in a refluxing mixture of o-dichlorobenzene and n-hexanol to afford the target piperazine (VI).

参考文献中间体

【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 .

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)	32036	2,4-difluoro-1-nitrobenzene	446-35-5	C₆H₃F₂NO₂	详情	详情
(II)	19483	2,2,2-trifluoro-1-ethanol	75-89-8	C₂H₃F₃O	详情	详情
(III)	54365	4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene; 5-fluoro-2-nitrophenyl 2,2,2-trifluoroethyl ether		C₈H₅F₄NO₃	详情	详情
(IV)	54366	4-fluoro-2-(2,2,2-trifluoroethoxy)aniline; 4-fluoro-2-(2,2,2-trifluoroethoxy)phenylamine		C₈H₇F₄NO	详情	详情
(V)	21583	2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine	821-48-7	C₄H₉Cl₂N	详情	详情
(VI)	54367	1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 5-fluoro-2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether		C₁₂H₁₄F₄N₂O	详情	详情

合成路线2

5-Methyluracil (VII) was protected with SEM-Cl (VIII) to yield the 1-SEM derivative (IX), which was subsequently alkylated with 1-bromo-3-chloropropane (X) under phase-transfer conditions to provide chloride (XI). Alkylation of piperazine (VI) with chloride (XI) in the presence of NaI and K2CO3 furnished adduct (XII). The title compound was then obtained by deprotection of (XII) upon treatment with tetrabutylammonium fluoride in THF.

参考文献中间体

【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	54367	1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 5-fluoro-2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether		C₁₂H₁₄F₄N₂O	详情	详情
(VII)	12204	5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine	65-71-4	C₅H₆N₂O₂	详情	详情
(VIII)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(IX)	54368	5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,4(1H,3H)-pyrimidinedione		C₁₁H₂₀N₂O₃Si	详情	详情
(X)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(XI)	54369	3-(3-chloropropyl)-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,4(1H,3H)-pyrimidinedione		C₁₄H₂₅ClN₂O₃Si	详情	详情
(XII)	54370	3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl}propyl)-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,4(1H,3H)-pyrimidinedione		C₂₆H₃₈F₄N₄O₄Si	详情	详情

合成路线3

In a different protection strategy, sulfonylation of 5-methyluracil (VII) by means of p-toluenesulfonyl chloride under Schotten-Baumann conditions furnished the 1-tosyl derivative (XIII). This was condensed with 1-bromo-3-chloropropane (X), yielding chloride (XIV). Removal of the tosyl protecting group of (XIV) by hydrolysis with H2SO4 afforded 3-(3-chloropropyl)-5-methyluracil (XV). Finally, alkylation of piperazine (VI) with chloride (XV) led to the title compound.

参考文献中间体

【1】 Chapman, R.C.; Perkins, J. (F. Hoffmann-La Roche AG); Process for manufacturing alpha1L-adrenoceptor antagonists. EP 0949250 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	54367	1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 5-fluoro-2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether		C₁₂H₁₄F₄N₂O	详情	详情
(VII)	12204	5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine	65-71-4	C₅H₆N₂O₂	详情	详情
(X)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(XIII)	54371	5-methyl-1-[(4-methylphenyl)sulfonyl]-2,4(1H,3H)-pyrimidinedione		C₁₂H₁₂N₂O₄S	详情	详情
(XIV)	54372	3-(3-chloropropyl)-5-methyl-1-[(4-methylphenyl)sulfonyl]-2,4(1H,3H)-pyrimidinedione		C₁₅H₁₇ClN₂O₄S	详情	详情
(XV)	54373	3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione		C₈H₁₁ClN₂O₂	详情	详情

Extended Information