7-(bromomethyl)-2-naphthonitrile -Drug Synthesis Database

【结构式】

【分子编号】24988

【品名】7-(bromomethyl)-2-naphthonitrile

【CA登记号】

【分子式】C₁₂H₈BrN

【分子量】246.10626

【元素组成】C 58.56% H 3.28% Br 32.47% N 5.69%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

The bromination of 2,7-dimethylnaphthalene (I) with N-bromosuccinimide (NBS) and UV light in CCl4 gives the monobromo derivative (II), which is treated with 2-nitropropane/NaOMe to yield 7-methylnaphthalene-2-carbaldehyde (III). The reaction of (III) with hydroxylamine-O-sulfonic acid affords the nitrile (IV), which is brominated with NBS as before to give 7-(bromomethyl)naphthalene-2-carbonitrile (V). The condensation of (V) with 2-[4-[1-(tert-butoxycarbonyl)pyrrolidin-3(S)-yloxy]phenyl]acetic acid ethyl ester (VI) by means of lithium bis(trimethylsilyl)amide yields 2-[4-[1-(tert-butoxycarbonyl)pyrrolidin-3(S)-yloxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester (VII) as a diastereomeric mixture. This mixture was worked up as already described to obtain the target compound DX-9065a.

参考文献中间体

合成目标

【1】 Engh, R.A.; Neidlein, R.; Bradstetter, H.; Strein, K.; Koczmierz, R.; Marzenell, K.; Leibert, H.; von der Saal, W.; Kehr, R.; A short synthesis of the factor-Xa inhibitor DX-9065 a using palladium-catalyzed key steps. Helv Chim Acta 1997, 80, 892.

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)	24984	2,7-dimethylnaphthalene	582-16-1	C₁₂H₁₂	详情	详情
(II)	24985	2-(bromomethyl)-7-methylnaphthalene		C₁₂H₁₁Br	详情	详情
(III)	24986	7-methyl-2-naphthaldehyde	52988-18-8	C₁₂H₁₀O	详情	详情
(IV)	24987	7-methyl-2-naphthonitrile		C₁₂H₉N	详情	详情
(V)	24988	7-(bromomethyl)-2-naphthonitrile		C₁₂H₈BrN	详情	详情
(VI)	24989	tert-butyl (3S)-3-[4-(2-ethoxy-2-oxoethyl)phenoxy]-1-pyrrolidinecarboxylate		C₁₉H₂₇NO₅	详情	详情
(VII)	16291	tert-butyl (3S)-3-(4-[1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate		C₃₁H₃₂N₂O₅	详情	详情
(VIII)	24991	tert-butyl (3S)-3-(4-[(1S)-1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate		C₃₁H₃₄N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The intermediate aniline (IV) was synthesized by Mitsunobu coupling between N-Boc-4-piperidinol (I) and p-nitrophenol (II), followed by catalytic hydrogenation of the resultant nitrophenyl ether (III). 7-Formyl-2-naphthalenecarbonitrile (VI) was prepared by oxidation of the bromomethyl(naphthalene) (V) employing either trimethylamine N-oxide or dimethylsulfoxide in the presence of silver tetrafluoroborate. Reductive alkylation of aniline (IV) with aldehyde (VI) by means of sodium triacetoxyborohydride produced the secondary amine (VII), which was subsequently acylated with ethyl 2-(Chlorosulfonyl)acetate (VIII) to furnish sulfonamide (IX). The required amidine (X) was then obtained by Pinner reaction of nitrile (IX) with ethanolic HCl, followed by treatment with ammonium acetate. The deprotected piperidine moiety of (X) was further subjected to condensation with ethyl acetimidate to give the bis-amidine compound (XI). The ethyl ester group of (XI) was finally hydrolyzed under acidic conditions, yielding the target carboxylic acid.

参考文献中间体

合成目标

【1】 Hirayama, F.; et al.; The discovery of YM-60828: A potent, selective and orally-bioavailable factor Xa inhibitor. Bioorg Med Chem 2002, 10, 5, 1509.
【2】 Hirayama, F.; Koshio, H.; Matsumoto, Y.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Yamanouchi Pharmaceutical Co., Ltd.); Novel amidinonaphthyl derivs. or salt thereof. EP 0798295; US 5869501; WO 9616940 .

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)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(II)	11236	4-Nitrophenol; p-Nitrophenol	100-02-7	C₆H₅NO₃	详情	详情
(III)	55852	tert-butyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate		C₁₆H₂₂N₂O₅	详情	详情
(IV)	55853	tert-butyl 4-(4-aminophenoxy)-1-piperidinecarboxylate		C₁₆H₂₄N₂O₃	详情	详情
(V)	24988	7-(bromomethyl)-2-naphthonitrile		C₁₂H₈BrN	详情	详情
(VI)	55854	7-formyl-2-naphthonitrile		C₁₂H₇NO	详情	详情
(VII)	55855	tert-butyl 4-(4-{[(7-cyano-2-naphthyl)methyl]amino}phenoxy)-1-piperidinecarboxylate		C₂₈H₃₁N₃O₃	详情	详情
(VIII)	55856	ethyl 2-(chlorosulfonyl)acetate		C₄H₇ClO₄S	详情	详情
(IX)	55857	tert-butyl 4-(4-{[(7-cyano-2-naphthyl)methyl][(2-ethoxy-2-oxoethyl)sulfonyl]amino}phenoxy)-1-piperidinecarboxylate		C₃₂H₃₇N₃O₇S	详情	详情
(X)	55858	ethyl 2-{[({7-[amino(imino)methyl]-2-naphthyl}methyl)-4-(4-piperidinyloxy)anilino]sulfonyl}acetate		C₂₇H₃₂N₄O₅S	详情	详情
(XI)	55859	ethyl 2-({({7-[amino(imino)methyl]-2-naphthyl}methyl)-4-[(1-ethanimidoyl-4-piperidinyl)oxy]anilino}sulfonyl)acetate		C₂₉H₃₅N₅O₅S	详情	详情

Extended Information