N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione -Drug Synthesis Database

【结构式】

【分子编号】30663

【品名】N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione

【CA登记号】13139-17-8

【分子式】C₁₂H₁₁NO₅

【分子量】249.22308

【元素组成】C 57.83% H 4.45% N 5.62% O 32.1%

与该中间体有关的原料药合成路线共 6 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(II)

The acylation of 3',4'-dideoxykanamycin B (dibekacin) (I) with N-benzyloxycarbonyloxysuccinimide (II) and zinc acetate in DMSO gives 3,2,6'-tri-N-benzyloxycarbonydibekacin (III), which is then treated with the N-hydroxysuccinimide ester of 2-hydroxy-4-aminobutyric acid (IV) and finally deprotected by hydrogenation with H2 over Pd/C in acidic water dioxane.

参考文献中间体

合成目标

【1】 Umezawa, H.; Umezawa, S.; Tsuchiya, T.; Takagi, Y.; Jikihara, T. (Microbial Chemistry Research Foundation); Production of a selectively protected N-acylated derivative of an aminoglycosidic antibiotic. BE 0879925; DE 2945010; FR 2441631; FR 2482109; GB 2036020; GB 2065123; JP 80164696; JP 8064598; US 4297485 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

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)	30662	Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₇N₅O₈	详情	详情
(II)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(III)	30664	3,2,6'-tri-N-benzyloxycarbonydibekacin; Benzyl (1S,2R,3S,4S,5R)-5-amino-4-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexylcarbamate		C₄₂H₅₅N₅O₁₄	详情	详情
(IV)	30665	1-[[(2S)-4-amino-2-hydroxybutanoyl]oxy]-2,5-pyrrolidinedione		C₈H₁₂N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The acylation of 3,2,6'-tri-N-benzyloxycarbonydibekacin (III) with ethyl trifluoroacetate and K2CO3 gives 3,2',6'-tri-N-benzyloxycarbonyl-3''-trifluoroacetyldibekacin (VI), which is acylated again with (IV) yielding the protected habekacin (VII). Finally, this compound is deprotected by hydrolysis with ammonia in aqueous THF, followed by hydrogenolysis with H2 over Pd/C.

参考文献中间体

合成目标

【1】 Tsuchiya, T.; Takagi, Y.; Umezawa, S.; 1-N-Acylation of aminocyclitol antibiotics via zinc chelation and regiospecific N-trifluoroacetylation. Tetrahedron Lett 1979, 51, 4951-54.
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

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)	30662	Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₇N₅O₈	详情	详情
(II)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(III)	30664	3,2,6'-tri-N-benzyloxycarbonydibekacin; Benzyl (1S,2R,3S,4S,5R)-5-amino-4-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexylcarbamate		C₄₂H₅₅N₅O₁₄	详情	详情
(IV)	30665	1-[[(2S)-4-amino-2-hydroxybutanoyl]oxy]-2,5-pyrrolidinedione		C₈H₁₂N₂O₅	详情	详情
(VI)	30667	3,2',6'-tri-N-benzyloxycarbonyl-3''-trifluoroacetyldibekacin; Benzyl (1S,2R,3S,4S,5R)-5-amino-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4-([(2R,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl]oxy)-3-hydroxycyclohexylcarbamate		C₄₄H₅₄F₃N₅O₁₅	详情	详情
(VII)	30668	benzyl (1S,2R,3S,4S,5R)-5-[[(2S)-4-amino-2-hydroxybutanoyl]amino]-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4-([(2R,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl]oxy)-3-hydroxycyclohexylcarbamate		C₄₈H₆₁F₃N₆O₁₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

The known pentasaccharide (IX) was reacted with N-(benzyloxycarbonyl)succinimide (X) yielding carbamate (XI). Sulfation of the free hydroxyl groups of (XI) with triethylamine-sulfur trioxide complex gave the sulfated compound which, after acid cleavage of the formed N-SO3- groups, was converted to the corresponding sodium salt (XII). Hydrogenolysis of the N-benzyloxycarbonyl group then liberated amine (XIII).

参考文献中间体

合成目标

【1】 Buijsman, R.C.; van Boeckel, C.A.A.; van der Marel, G.A.; Basten, J.E.M.; van Dinther, T.G.; van Boom, J.H.; Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999, 9, 14, 2013.
【2】 Van Boeckel, C.A.A.; Basten, J.E.M.; Dreef-Tromp, C.M.; Buijsman, R.C. (Akzo Nobel N.V.; Universiteit Leiden); Antithrombotic cpds.. WO 9965934 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	37323			C₄₁H₇₁NO₃₁	详情	详情
(X)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(XI)	37324			C₄₉H₇₇NO₃₃	详情	详情
(XII)	37325			C₄₉H₆₄NNa₁₃O₆₆S₁₁	详情	详情
(XIII)	37326			C₄₁H₅₈NNa₁₃O₆₄S₁₁	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

6-Methoxy-alpha-tetralone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine in the presence of sodium acetate. Subsequent Beckmann rearrangement of (II) employing polyphosphoric acid produced a mixture of two regioisomeric lactams from which the required 1-benzazepine (III) was isolated by flash chromatography. Iodination of (III) to give (IV) was carried out following a previously described metodolgy. Displacement of the iodolactam (IV) with ammonia in aqueous ethanol furnished the racemic primary amine, which was resolved by means of L-pyroglutamic acid. The desired (S)-amine (V) was protected as the benzyl carbamate (VII) by treatment with N-(benzyloxycarbonyloxy)succinimide (VI). Then, selective alkylation of the lactam ring nitrogen of (VII) with tert-butyl bromoacetate in the presence of lithium hexamethyldisilazide provided ester (VIII). After hydrogenolysis of the carbobenzoy moiety of (VIII), the resulting amino lactam (IX) was condensed with benzylsulfonyl chloride (X) to give sulfonamide (XI). Deprotection of the tert-butyl ester of (XI) with trifluoroacetic acid afforded carboxylic acid (XII), which was coupled with nitroargininal ethyl aminal (XIII), yielding amide (XIV).

参考文献中间体

合成目标

【1】 Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(I)	17594	6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone	1078-19-9	C₁₁H₁₂O₂	详情	详情
(II)	38125	6-methoxy-3,4-dihydro-1(2H)-naphthalenone oxime		C₁₁H₁₃NO₂	详情	详情
(III)	38126	7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₁H₁₃NO₂	详情	详情
(IV)	38127	3-iodo-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₁H₁₂INO₂	详情	详情
(V)	38128	(3S)-3-amino-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₁H₁₄N₂O₂	详情	详情
(VI)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(VII)	38129	benzyl (3S)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate		C₁₉H₂₀N₂O₄	详情	详情
(VIII)	38130	tert-butyl 2-((3S)-3-[[(benzyloxy)carbonyl]amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₂₅H₃₀N₂O₆	详情	详情
(IX)	38131	tert-butyl 2-[(3S)-3-amino-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₁₇H₂₄N₂O₄	详情	详情
(X)	25151	phenylmethanesulfonyl chloride	1939-99-7	C₇H₇ClO₂S	详情	详情
(XI)	38132	tert-butyl 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₂₄H₃₀N₂O₆S	详情	详情
(XII)	38133	2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid		C₂₀H₂₂N₂O₆S	详情	详情
(XIII)	38136			C₈H₁₇N₅O₃	详情	详情
(XIV)	38134			C₂₈H₃₇N₇O₈S	详情	详情

合成路线5

该中间体在本合成路线中的序号：(II)

The amino groups of pseudomycin B (I) were protected by treatment with N-(benzyloxycarbonyloxy)succinimide (II). The resulting pseudomycin B tribenzyl carbamate (III) was then coupled with cyclopropylamine (IV) by using TBTU to yield amide (V).

参考文献中间体

合成目标

【1】 Sun, X.; Chen, S.-H.; Zhang, Y.-Z.; Current, W.L.; Rodriguez, M.; Sachs, R.K.; Gidda, J.; Zeckner, D.J.; Synthesis and antifungal activities of novel 3-amido bearing pseudomycin analogues. Bioorg Med Chem Lett 2001, 11, 7, 903.
【2】 Vasudevan, V.; Rodriguez, M.J.; Hellman, S.L.; Krstenansky, J.L.; Sun, X.D.; Chen, S.H.; Usyatinsky, A.Y.; Galka, C.S.; Zweifel, M.J. (Eli Lilly and Company); Pseudomycin amide and ester analogs. WO 0105817 .
【3】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .

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)	50469	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-aminobutyl)-15,24-bis(2-aminoethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₅₁H₈₇ClN₁₂O₁₉	详情	详情
(II)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(III)	51197	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₇₅H₁₀₅ClN₁₂O₂₅	详情	详情
(IV)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(V)	51198	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-21-[2-(cyclopropylamino)-2-oxoethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₇₈H₁₁₀ClN₁₃O₂₄	详情	详情

合成路线6

该中间体在本合成路线中的序号：(A)

The precursor triamine (VI) is prepared as follows. Ethanolamine (I) is protected as the N-Cbz derivative (II) upon treatment with N-(benzyloxycarbonyloxy)succinimide. Subsequent tosylation of (II) to yield (III), followed by displacement of the tosylate of (III) with trimethyl propanediamine (IV) furnishes the protected triamine (V). Then, Cbz group hydrogenolysis in (V) in the presence of Pd/C gives rise to triamine (VI).

参考文献中间体

合成目标

【1】 Dziadulewicz, E.K.; et al.; Nonpeptide bradykinin B2 receptor antagonists: Conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists. J Med Chem 2002, 45, 11, 2160.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(I)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情
(II)	32497	benzyl 2-hydroxyethylcarbamate	77987-49-6	C₁₀H₁₃NO₃	详情	详情
(III)	42170	2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate		C₁₇H₁₉NO₅S	详情	详情
(IV)	28165	N-[3-(dimethylamino)propyl]-N-methylamine	4543-96-8	C₆H₁₆N₂	详情	详情
(V)	61665	benzyl 2-[[3-(dimethylamino)propyl](methyl)amino]ethylcarbamate		C₁₆H₂₇N₃O₂	详情	详情
(VI)	61664	N~1~-(2-aminoethyl)-N~1~,N~3~,N~3~-trimethyl-1,3-propanediamine		C₈H₂₁N₃	详情	详情

Extended Information