Gemopatrilat, BMS-189921, -Drug Synthesis Database

【结构式】

【药物名称】Gemopatrilat, BMS-189921

【化学名称】2-[2,2-Dimethyl-7-oxo-6(S)-[3-phenyl-2(S)-sulfanylpropanamido]hexahydro-1H-azepin-1-yl]acetic acid

【CA登记号】160135-92-2

【分子式】C₁₉H₂₆N₂O₄S

【分子量】378.49407

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors, Neprilysin Inhibitors

合成路线1 合成路线2

合成路线1

(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

【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

Removal of phthaloyl protecting group of (VIII) provided amine (IX), which was protected as the tert-butyl carbamate (X) with Boc2O. Alkylation at the lactam nitrogen atom of (X) was then achieved employing LiN(SiMe3)2 and ethyl bromoacetate to afford (XI), which was deprotected under acidic conditions to furnish amine (XII). Alternatively, amine (IX) could be protected using a N-trityl group. Coupling of amine (XII) with 2-(acetylthio)benzenepropanoic acid (XIII) using either BOP or EDC as the condensing reagents produced amide (XIV). Finally, both ethyl ester and acetyl thioester of (XIV) were hydrolyzed with NaOH to yield the title compound.

参考文献中间体

【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	分子式	供应商	用于合成
(VIII)	26847	2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione	C₁₆H₁₈N₂O₃	详情	详情
(IX)	26848	(3S)-3-amino-7,7-dimethyl-2-azepanone	C₈H₁₆N₂O	详情	详情
(X)	26849	tert-butyl (3S)-7,7-dimethyl-2-oxoazepanylcarbamate	C₁₃H₂₄N₂O₃	详情	详情
(XI)	26850	methyl 2-[(6S)-6-[(tert-butoxycarbonyl)amino]-2,2-dimethyl-7-oxoazepanyl]acetate	C₁₆H₂₈N₂O₅	详情	详情
(XII)	26851	methyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate	C₁₁H₂₀N₂O₃	详情	详情
(XIII)	22493	(2S)-2-(acetylsulfanyl)-3-phenylpropionic acid	C₁₁H₁₂O₃S	详情	详情
(XIV)	26852	methyl 2-((6S)-6-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-2,2-dimethyl-7-oxoazepanyl)acetate	C₂₂H₃₀N₂O₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)