BQ-788, -Drug Synthesis Database

【结构式】

【药物名称】BQ-788

【化学名称】N-(cis-2,6-Dimethylpiperidin-1-ylcarbonyl)-L-(4-methyl)leucyl-D-(N1-methoxycarbonyl)tryptophyl-D-norleucine sodium salt

【CA登记号】156161-89-6

【分子式】C₃₄H₅₀N₅NaO₇

【分子量】663.7967

【开发单位】Banyu (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin ETB Receptor Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The intermediate dipeptide ester (V) was prepared as follows. Coupling between D-norleucine tert-butyl ester (I) and N-Boc-D-tryptophan (II) by means of EDC and HOBt provided the protected dipeptide (III). Subsequent acylation of the indole N with methyl chloroformate under phase-transfer conditions yielded the N-(methoxycarbonyl)indole derivative (IV). The N-Boc protecting group was then selectively removed from (IV) by treatment with trifluoroacetic acid at 0 C.

参考文献中间体

【1】 Ishikawa, K.; Fukami, T.; Nagase, T.; Mase, T.; Ihara, M.; Yano, M.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); Endothelin antagonistic substance. EP 0555537; JP 1994107680 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	55970	tert-butyl (2R)-2-aminohexanoate	C₁₀H₂₁NO₂	详情	详情
(II)	48341	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid	C₁₆H₂₀N₂O₄	详情	详情
(III)	55971	tert-butyl (2R)-2-{[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino}hexanoate	C₂₆H₃₉N₃O₅	详情	详情
(IV)	55972	methyl 3-((2R)-2-[(tert-butoxycarbonyl)amino]-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate	C₂₈H₄₁N₃O₇	详情	详情
(V)	55973	methyl 3-((2R)-2-amino-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate	C₂₃H₃₃N₃O₅	详情	详情

合成路线2

Benzyl ester (VII) was prepared by reaction of N-Boc-L-gamma-methylleucine (VI) with benzyl bromide in the presence of Cs2CO3. Subsequent N-Boc group cleavage in (VII) by means of HCl in dioxane furnished gamma-methylleucine benzyl ester (VIII). Amino ester (VIII) was converted into urea (X) by condensation with 2,6-dimethylpiperidine (IX) either in the presence of carbonyl diimidazole or diphosgene. Then, hydrogenolysis of the benzyl ester group of (X) in the presence of Pd/C led to the N-carbamoyl aminoacid (XI). Coupling of amino acid (XI) with dipeptide (V) in the presence of EDC and HOBt gave the tripeptide derivative (XII). The tert-butyl ester group of (XII) was then cleaved under acidic conditions, and the resultant carboxylic acid was finally converted to the corresponding sodium salt by treatment with NaHCO3.

参考文献中间体

【1】 He, J.X.; et al.; An efficient preparation of the pseudopeptide endothelin-B receptor selective antagonist BQ-788. J Org Chem 1995, 60, 25, 8262.
【2】 Ishikawa, K.; Fukami, T.; Nagase, T.; Mase, T.; Ihara, M.; Yano, M.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); Endothelin antagonistic substance. EP 0555537; JP 1994107680 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	55973	methyl 3-((2R)-2-amino-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate	C₂₃H₃₃N₃O₅	详情	详情
(VI)	55974	(2S)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpentanoic acid	C₁₂H₂₃NO₄	详情	详情
(VII)	55975	benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpentanoate	C₁₉H₂₉NO₄	详情	详情
(VIII)	55976	benzyl (2S)-2-amino-4,4-dimethylpentanoate	C₁₄H₂₁NO₂	详情	详情
(IX)	32229	(2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine	C₇H₁₅N	详情	详情
(X)	55977	benzyl (2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoate	C₂₂H₃₄N₂O₃	详情	详情
(XI)	55978	(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoic acid	C₁₅H₂₈N₂O₃	详情	详情
(XII)	55979	methyl 3-((2R)-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate	C₃₈H₅₉N₅O₇	详情	详情

合成路线3

In a related synthetic method, N-Boc-tryptophan (II) was coupled with benzyl alcohol using EDC and HOBt to produce the corresponding benzyl ester (XIII). Incorporation of the methoxycarbonyl group into the indole N (XIV) was accomplished by treatment of (XIII) with dimethyl carbonate in the presence of DMAP. The Boc protecting group of (XIV) was then removed under acidic conditions to afford amino ester (XV). The dipeptide derivative (XVI) was prepared by coupling of amino ester (XV) with the N-carbamoyl aminoacid (XI). After hydrogenolysis of the benzyl ester group of (XVI), acid (XVII) was coupled with norleucine benzyl ester (XVIII) yielding tripeptide (XIX). Further benzyl ester hydrogenolysis in (XIX) gave the corresponding carboxylic acid, which was finally converted into the title sodium salt.

参考文献中间体

【1】 He, J.X.; et al.; An efficient preparation of the pseudopeptide endothelin-B receptor selective antagonist BQ-788. J Org Chem 1995, 60, 25, 8262.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	48341	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid	C₁₆H₂₀N₂O₄	详情	详情
(XI)	55978	(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoic acid	C₁₅H₂₈N₂O₃	详情	详情
(XIII)	27719	benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate	C₂₃H₂₆N₂O₄	详情	详情
(XIV)	55980	methyl 3-{(2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-1H-indole-1-carboxylate	C₂₅H₂₈N₂O₆	详情	详情
(XV)	55981	methyl 3-[(2R)-2-amino-3-(benzyloxy)-3-oxopropyl]-1H-indole-1-carboxylate	C₂₀H₂₀N₂O₄	详情	详情
(XVI)	55982	methyl 3-((2R)-3-(benzyloxy)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate	C₃₅H₄₆N₄O₆	详情	详情
(XVII)	55983	(2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-[1-(methoxycarbonyl)-1H-indol-3-yl]propanoic acid	C₂₈H₄₀N₄O₆	详情	详情
(XVIII)	55984	benzyl (2R)-2-aminohexanoate	C₁₃H₁₉NO₂	详情	详情
(XIX)	55985	methyl 3-((2R)-3-({(1R)-1-[(benzyloxy)carbonyl]pentyl}amino)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate	C₄₁H₅₇N₅O₇	详情	详情

Extended Information