SLV-306, -Drug Synthesis Database

【结构式】

【药物名称】SLV-306

【化学名称】2-[3(S)-[1-[2(R)-(Ethoxycarbonyl)-4-phenylbutyl]cyclopentan-1-ylcarboxamido]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid

【CA登记号】182821-27-8, 182560-84-5 (undefined stereochem.)

【分子式】C₃₁H₃₈N₂O₆

【分子量】534.65831

【开发单位】Solvay (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Endothelin-Converting Enzyme Inhibitors, Neprilysin Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

1) The acylation of the chiral amine (I) with the chiral cyclopentanecarboxylic aid (II) by means of N-methylmorphline (NMM), hydroxybenzotriazole (HOBT) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide (EDT) in dichloromethane gives the amide (III), which is then treated with trifluoroacetic aid to elimnate the tert-butyl ester group.

参考文献中间体

【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27.
【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	20717	tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate	C₁₆H₂₂N₂O₃	详情	详情
(II)	20718	1-[(2R)-2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid	C₁₉H₂₆O₄	详情	详情
(III)	20719	ethyl (2R)-2-([1-[([(3S)-1-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino)carbonyl]cyclopentyl]methyl)-4-phenylbutanoate	C₃₅H₄₆N₂O₆	详情	详情

合成路线2

2a) The chiral intermediate amine (I) has been obtained as follows: The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

参考文献中间体

【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27.
【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
rac-(I)	20728	tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₆H₂₂N₂O₃	详情	详情
(I)	20717	tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₁₆H₂₂N₂O₃	详情	详情
(IV)	20720	3,4-dihydro-1(2H)-naphthalenone	529-34-0	C₁₀H₁₀O	详情	详情
(V)	20721	2-bromo-3,4-dihydro-1(2H)-naphthalenone		C₁₀H₉BrO	详情	详情
(VI)	20722	2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime		C₁₀H₁₀BrNO	详情	详情
(VII)	20723	3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀BrNO	详情	详情
(VIII)	10926	(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium		C₈H₄KNO₂	详情	详情
(IX)	20725	2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione		C₁₈H₁₄N₂O₃	详情	详情
(X)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(XI)	20727	tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₂₅H₂₆N₂O₅	详情	详情

合成路线3

2b) The chiral intermediate acid (II) has been obtained as follows: The alkylation of diethyl malonate (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives diethyl 2-(2-phenylethyl)malonate (XIV), which is treated with KOH in ice-cooled water to afford the corresponding monoester monoacid (XV). The reacction of (XV) with formaldehyde in piperidine/water gives teh acrylate (XVI), which is condensed with cyclopentanecarboxylic acid (XVII) by meansof butyllithium/diisopropylamine in THF to afford racemic (II). Finally, this racemate is submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).

参考文献中间体

【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27.
【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
rac-(II)	20735	1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid		C₁₉H₂₆O₄	详情	详情
(XIII)	20730	1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide	103-63-9	C₈H₉Br	详情	详情
(XIV)	20731	diethyl 2-phenethylmalonate		C₁₅H₂₀O₄	详情	详情
(XV)	20732	2-(ethoxycarbonyl)-4-phenylbutyric acid		C₁₃H₁₆O₄	详情	详情
(XVI)	20733	ethyl 2-phenethylacrylate		C₁₃H₁₆O₂	详情	详情
(XVII)	20734	cyclopentanecarboxylic acid	3400-45-1	C₆H₁₀O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)