benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate -Drug Synthesis Database

【结构式】

【分子编号】26843

【品名】benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate

【CA登记号】

【分子式】C₂₂H₂₃NO₅

【分子量】381.42836

【元素组成】C 69.28% H 6.08% N 3.67% O 20.97%

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：(IV)

(S)-6-Hydroxy-2-phthalimidohexanoic acid (I) was converted to benzyl ester (II) by treatment with benzyl bromide and Cs2CO3. Subsequent Swern oxidation of the alcohol function of (II) followed by reaction of the resulting aldehyde (III) with Me3Al afforded secondary alcohol (IV). A new Swern oxidation of (IV) provided ketone (V). Introduction of a further methyl group to give the tertiary alcohol (VI) was achieved by means of methyltitanium trichloride, generated in situ from MeLi and TiCl4. Azide (VII) was then obtained by treatment of (VI) with Me3SiN3 and BF3-Et2O. Palladium-catalyzed hydrogenation effected both reduction of the azide to amine and hydrogenolysis of the benzyl ester. Then, EDC-mediated cyclization of the intermediate amino acid gave azepinone (VIII).

参考文献中间体

合成目标

【1】 Robl, J.A.; Sulsky, R.; Sieber-McMaster, E.; Ryono DE; Cimarusti MP; Simpkins LM; Karanewsky, D.S.; Chao, S.; Asaad, M.M.; Seymour, A.A.; Fox, M.E.; Smith, P.L.; Trippodo, N.C.; Vasopeptidase inhibitors: Incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides. J Med Chem 1999, 42, 2, 305.
【2】 Karanewsky, D.S.; Barrish, J.C.; Petrillo, E.W. Jr.; Robl, J.A.; Ryono, D.E. (Bristol-Myers Squibb Co.); Dual action inhibitors. EP 0599444; US 5552397 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	22512	(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid		C₁₄H₁₅NO₅	详情	详情
(II)	26841	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate		C₂₁H₂₁NO₅	详情	详情
(III)	26842	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate		C₂₁H₁₉NO₅	详情	详情
(IV)	26843	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate		C₂₂H₂₃NO₅	详情	详情
(V)	26844	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate		C₂₂H₂₁NO₅	详情	详情
(VI)	26845	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate		C₂₃H₂₅NO₅	详情	详情
(VII)	26846	benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate		C₂₃H₂₄N₄O₄	详情	详情
(VIII)	26847	2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione		C₁₆H₁₈N₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The reaction of (S)-2-amino-6-hydroxyhexanoic acid (I) with N-(ethoxycarbonyl)phthalimide (II) by means of Na2CO3 in water gives 6-hydroxy-2(S)-(phthalimido)hexanoic acid (III), which is esterified with benzyl bromide and Cs2CO3 in DMF yielding the benzyl ester (IV). The oxidation of the terminal OH group of (IV) with (COCl)2 in dichloromethane affords the aldehyde (V), which is methylated with AlMe3 in dichloromethane giving 6-hydroxy-2(S)-(phthalimido)heptanoic acid (VI). The oxidation of (VI) with oxalyl chloride as before yields the ketone (VII), which is methylated with TiCl4 and methylmagnesium chloride to provide the carbinol (VIII). The reaction of (VIII) with trimethylsilyl azide in dichloromethane gives the azido derivative (IX), which is cyclized by reduction with H2 over Pd/C in DMF yielding the perhydroazepinone (X). Elimination of phthalimido protecting group of (X) with hydrazine in methanol/dichloromethane affords 3(S)-amino-7,7-dimethylperhydroazepin-2-one (XI), which is protected with trityl chloride and TEA in dichloromethane to give the tritylamino compound (XII). The condensation of (XII) with ethyl 2-bromoacetate (XIII) by means of LHMDS, followed by deprotection with TFA affords the adduct (XIV) with a free amino group, which is acylated with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) by means of HOBT and EDAD in dichloromethane providing the amide (XVI). The formylation of (XVI) with formic acid and acetic anhydride gives the formamide (XVII), which is deprotected with H2 over Pd/C in ethanol yielding intermediate (XVIII). Finally, this compound is hydrolyzed with NaOH in methanol.

参考文献中间体

合成目标

【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257.
【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	22502	(2S)-2-amino-6-hydroxyhexanoic acid	6033-32-5	C₆H₁₃NO₃	详情	详情
(II)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(III)	22512	(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid		C₁₄H₁₅NO₅	详情	详情
(IV)	26841	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate		C₂₁H₂₁NO₅	详情	详情
(V)	26842	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate		C₂₁H₁₉NO₅	详情	详情
(VI)	26843	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate		C₂₂H₂₃NO₅	详情	详情
(VII)	26844	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate		C₂₂H₂₁NO₅	详情	详情
(VIII)	26845	benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate		C₂₃H₂₅NO₅	详情	详情
(IX)	26846	benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate		C₂₃H₂₄N₄O₄	详情	详情
(X)	26847	2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione		C₁₆H₁₈N₂O₃	详情	详情
(XI)	26848	(3S)-3-amino-7,7-dimethyl-2-azepanone		C₈H₁₆N₂O	详情	详情
(XII)	37281	(3S)-7,7-dimethyl-3-(tritylamino)-2-azepanone		C₂₇H₃₀N₂O	详情	详情
(XIII)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(XIV)	37282	ethyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate		C₁₂H₂₂N₂O₃	详情	详情
(XV)	37283	(2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid		C₁₇H₁₉NO₃	详情	详情
(XVI)	37284	ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate		C₂₉H₃₉N₃O₅	详情	详情
(XVII)	37285	ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate		C₃₀H₃₉N₃O₆	详情	详情
(XVIII)	37286	ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate		C₂₃H₃₃N₃O₆	详情	详情

Extended Information