NVP-LAF-389, LAF-389, -Drug Synthesis Database

【结构式】

【药物名称】NVP-LAF-389, LAF-389

【化学名称】Cyclohexanecarboxylic acid 7-oxo-6(S)-[(2R,3R,4S,5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-6-nonenamido]perhydroazepin-3(R)-yl ester

【CA登记号】270902-51-7, 374602-77-4 (undefined isomer)

【分子式】C₂₅H₄₂N₂O₈

【分子量】498.62209

【开发单位】Novartis (Originator)

【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Methionine Aminopeptidase-1 Inhibitors, Methionine Aminopeptidase-2 Inhibitors

合成路线1 合成路线2

合成路线1

alpha-D-Glucoheptonic acid gamma-lactone (I) was protected as the bis(acetonide) (II) upon treatment with a catalytic amount of I2 in acetone. The free hydroxyl group of (II) was then alkylated with iodomethane in the presence of silver oxide, yielding the methyl ether (III). Selective hydrolysis of the 1,2-acetonide of (III) was accomplished by treatment of the bis(acetonide) (III) with aqueous acetic acid. Oxidative cleavage of the resultant vicinal diol (IV) using NaIO4 gave aldehyde (V). Then, olefination of aldehyde (V) with the low-valent organochromium species generated in situ from 1,1-diiodoneopentane (VI) and CrCl2 produced the target E-olefin (VII) as the major isomer.

参考文献中间体

【1】 Kinder, F.R. Jr.; Versace, R.W.; Bair, K.W.; et al.; Synthesis and antitumor activity of ester-modified analogues of bengamide B. J Med Chem 2001, 44, 22, 3692.
【2】 Bair, K.W.; Wattanasin, S.; Versace, R.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and a process for their preparation. US 6239127 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	47767	(3R,4S,5S)-3,4-dihydroxy-5-[(1R,2R)-1,2,3-trihydroxypropyl]dihydro-2(3H)-furanone	C₇H₁₂O₇	详情	详情
(II)	47768	(4R,4aS,7R,7aS)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-hydroxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one	C₁₃H₂₀O₇	详情	详情
(III)	47769	(4R,4aS,7R,7aS)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one	C₁₄H₂₂O₇	详情	详情
(IV)	47770	(4R,4aR,7R,7aS)-4-[(1R)-1,2-dihydroxyethyl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one	C₁₁H₁₈O₇	详情	详情
(V)	47771	(4S,4aS,7R,7aS)-7-methoxy-2,2-dimethyl-6-oxotetrahydro-4H-furo[3,2-d][1,3]dioxine-4-carbaldehyde	C₁₀H₁₄O₆	详情	详情
(VI)	54664	1,1-Diiodo-2,2-dimethypropane	C₅H₁₀I₂	详情	详情
(VII)	54665	(4R,4aR,7R,7aS)-4-[(E)-3,3-dimethyl-1-butenyl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one	C₁₅H₂₄O₅	详情	详情

合成路线2

Cyclization of (5R)-5-hydroxy-L-lysine (VIII) by means of EDC and HOBt afforded the caprolactam (IX). The amino group of (IX) was then protected as the N-Boc derivative (X) by treatment with Boc2O. Hydroxyl group acylation in (X) with cyclohexanecarbonyl chloride (XI) produced ester (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid, yielding the aminocaprolactam (XIII). Coupling of amine (XIII) with lactone (VII) in refluxing isopropanol produced amide (XIV). The title compound was then obtained by acidic hydrolysis of the remaining acetonide function of (XIV).

参考文献中间体

【1】 Kinder, F.R. Jr.; Versace, R.W.; Bair, K.W.; et al.; Synthesis and antitumor activity of ester-modified analogues of bengamide B. J Med Chem 2001, 44, 22, 3692.
【2】 Bair, K.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and their use in treating tumors. EP 1131297; WO 0029382 .
【3】 Bair, K.W.; Wattanasin, S.; Versace, R.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and a process for their preparation. US 6239127 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	54665	(4R,4aR,7R,7aS)-4-[(E)-3,3-dimethyl-1-butenyl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one		C₁₅H₂₄O₅	详情	详情
(VIII)	47774	(2S,5R)-2,6-diamino-5-hydroxyhexanoic acid		C₆H₁₄N₂O₃	详情	详情
(IX)	47775	(3S,6R)-3-amino-6-hydroxy-2-azepanone		C₆H₁₂N₂O₂	详情	详情
(X)	47776	tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate		C₁₁H₂₀N₂O₄	详情	详情
(XI)	17220	cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride	2719-27-9	C₇H₁₁ClO	详情	详情
(XII)	54666	(3R,6S)-6-[(tert-butoxycarbonyl)amino]-7-oxoazepanyl cyclohexanecarboxylate		C₁₈H₃₀N₂O₅	详情	详情
(XIII)	54667	(3R,6S)-6-amino-7-oxoazepanyl cyclohexanecarboxylate		C₁₃H₂₂N₂O₃	详情	详情
(XIV)	54668	(3R,6S)-6-[((2R)-2-{(4R,5R,6R)-6-[(E)-3,3-dimethyl-1-butenyl]-5-hydroxy-2,2-dimethyl-1,3-dioxan-4-yl}-2-methoxyethanoyl)amino]-7-oxoazepanyl cyclohexanecarboxylate		C₂₈H₄₆N₂O₈	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)