(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid -Drug Synthesis Database

【结构式】

【分子编号】58938

【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid

【CA登记号】

【分子式】C₁₄H₂₅NO₄

【分子量】271.35684

【元素组成】C 61.97% H 9.29% N 5.16% O 23.58%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VIII)

The aminoacid building block (VIII) can be prepared by two different ways. The oxidative cleavage of 7-octene-1,2-diol (I) by means of NaIO4 yields aldehyde (II). Partial hydrolysis of diethyl 2-acetamidomalonate (III) provides monoacid (IV), which is subjected to Knoevenagel-type condensation with 6-heptenal (II) in the presence of Ac2O and pyridine to afford enamide (V). Enantioselective hydrogenation of the enamide double bond to the (S)-amidoester (VI) is then achieved by using the Burk's method. In order to replace the N-acetyl protecting group of (VI), the acetamide nitrogen is protected with Boc2O, and the resulting imide (VII) is further hydrolyzed to the target N-Boc aminoacid (VIII) under standard basic conditions.

参考文献中间体

合成目标

【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	58933	7-Octene-1,2-diol		C₈H₁₆O₂	详情	详情
(II)	27179	6-heptenal		C₇H₁₂O	详情	详情
(III)	16170	1,2-dichloroethane	107-06-2	C₂H₄Cl₂	详情	详情
(IV)	58934	Ethyl 2-acetamidomalonate		C₇H₁₁NO₅	详情	详情
(V)	58935	ethyl (2Z)-2-(acetylamino)-2,8-nonadienoate		C₁₃H₂₁NO₃	详情	详情
(VI)	58936	ethyl (2S)-2-(acetylamino)-8-nonenoate		C₁₃H₂₃NO₃	详情	详情
(VII)	58937	(2S)-2-[acetyl(tert-butoxycarbonyl)amino]-8-nonenoic acid		C₁₆H₂₇NO₅	详情	详情
(VIII)	58938	(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid		C₁₄H₂₅NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Alternatively, 8-bromo-1-octene (IX) is converted into the corresponding Grignard reagent (X) which is further carboxylated by solid carbon dioxide in cold THF to produce acid (XI). Coupling of acid (XI) with the lithium derivative of (S)-4-benzyl-2-oxazolidinone (XII), via activation with pivalic anhydride, leads to the chiral N-acyl oxazolidinone (XIII). Stereoselective alpha-azidation of the potassium enolate of (XIII) with trizylazide forms the (S)-azide (XIV). Subsequent reduction of azide (XIV) employing SnCl2 leads to amine (XV), which is further protected as the N-Boc derivative (XVI) with Boc2O in the presence of NaHCO3. Then, hydrolysis of the chiral auxiliary of (XVI) by means of lithium hydroperoxide gives rise to the desired N-Boc aminoacid (VIII).

参考文献中间体

合成目标

【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	58938	(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid	C₁₄H₂₅NO₄	详情	详情
(IX)	58939	8-Bromo-1-octene	C₈H₁₅Br	详情	详情
(X)	58940	bromo(7-octenyl)magnesium	C₈H₁₅BrMg	详情	详情
(XI)	58941	8-nonenoic acid	C₉H₁₆O₂	详情	详情
(XII)	58942		C₁₀H₁₀LiNO₂	详情	详情
(XIII)	58943	(4S)-4-benzyl-3-(8-nonenoyl)-1,3-oxazolidin-2-one	C₁₉H₂₅NO₃	详情	详情
(XIV)	58944	(4S)-3-[(2S)-2-azido-8-nonenoyl]-4-benzyl-1,3-oxazolidin-2-one	C₁₉H₂₄N₄O₃	详情	详情
(XV)	58945	(4S)-3-[(2S)-2-amino-8-nonenoyl]-4-benzyl-1,3-oxazolidin-2-one	C₁₉H₂₆N₂O₃	详情	详情
(XVI)	58946	tert-butyl (1S)-1-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-7-octenylcarbamate	C₂₄H₃₄N₂O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Coupling between the Boc-aminoacid (VIII) and dipeptide ester (XV) affords the linear tripeptide (XVI). Macrocyclization of (XVI) to produce (XVII) is accomplished by intramolecular olefin metathesis in the presence of Hoveyda's catalyst. Subsequent catalytic hydrogenation of (XVII) leads to a mixture of the desired saturated macrocycle (XIX) and compound (XVIII), produced by hydrogenolysis of the cyclopropane ring. Mitsunobu coupling of (XIX) with methyl 4-hydroxy-7-methoxyquinoline-2-carboxylate (XX) gives rise to quinolinyl ether (XXI). The quinoline carboxylate group of (XXI) is then selectively hydrolyzed by NaOH to furnish the sodium carboxylate salt (XXII).

参考文献中间体

合成目标

【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	58938	(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid	C₁₄H₂₅NO₄	详情	详情
(XV)	58947	methyl (1R,2S)-1-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)-2-vinylcyclopropanecarboxylate	C₁₂H₁₈N₂O₄	详情	详情
(XVI)	58948	methyl (1R,2S)-1-{[((2S,4R)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoyl}-4-hydroxypyrrolidinyl)carbonyl]amino}-2-vinylcyclopropanecarboxylate	C₂₆H₄₁N₃O₇	详情	详情
(XVII)	58949	methyl (2R,6S,13aS,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate	C₂₄H₃₇N₃O₇	详情	详情
(XVIII)	58950	methyl (13S,17R,18aS)-13-[(tert-butoxycarbonyl)amino]-17-hydroxy-1,14-dioxooctadecahydropyrrolo[1,2-a][1,4]diazacyclohexadecine-3-carboxylate	C₂₄H₄₁N₃O₇	详情	详情
(XIX)	58951	methyl (2R,6S,13aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate	C₂₄H₃₉N₃O₇	详情	详情
(XX)	58952	methyl 4-hydroxy-7-methoxy-2-quinolinecarboxylate	C₁₂H₁₁NO₄	详情	详情
(XXI)	58953	methyl (2R,6S,13aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-{[7-methoxy-2-(methoxycarbonyl)-4-quinolinyl]oxy}-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate	C₃₆H₄₈N₄O₁₀	详情	详情
(XXII)	58954	sodium 4-{[(2R,6S,13aR,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-(methoxycarbonyl)-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl]oxy}-7-methoxy-2-quinolinecarboxylate	C₃₅H₄₅N₄NaO₁₀	详情	详情

Extended Information