Deoxynegamycin, VRC-3573, -Drug Synthesis Database

【结构式】

【药物名称】Deoxynegamycin, VRC-3573

【化学名称】2-[2-[3(R),6-Diaminohexanoyl]-1-methylhydrazino]acetic acid
　　　　　　3(R),6-Diaminohexanoic acid 2-(carboxymethyl)-2-methylhydrazide

【CA登记号】58773-33-4

【分子式】C₉H₂₀N₄O₃

【分子量】232.28475

【开发单位】Vicuron Pharmaceuticals (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Protection of (R)-beta-lysine (I) by means of benzyl S-(4,6-dimethylpyrimidin-2-yl)thiol carbonate (II) affords the bis-(benzyloxycarbonyl) derivative (III). After activation of the carboxyl group of (III) as the corresponding succinimidyl ester (IV), its coupling with 1-methylhydrazinoacetic acid (V) furnishes hydrazide (VI). The benzyloxycarbonyl protecting groups of (VI) are finally removed by catalytic hydrogenolysis to provide the title compound.

参考文献中间体

【1】 Umezawa, H.; Kondo, S. (Microbial Chemistry Research Foundation); delta-Substd. negamycin derivs. and syntheses. US 4065495 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	61218	(3R)-3,6-diaminohexanoic acid	C₆H₁₄N₂O₂	详情	详情
(II)	32266	O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate	C₁₄H₁₄N₂O₂S	详情	详情
(III)	61219	(3R)-3,6-bis{[(benzyloxy)carbonyl]amino}hexanoic acid	C₂₂H₂₆N₂O₆	详情	详情
(IV)	61220	benzyl (1R)-4-{[(benzyloxy)carbonyl]amino}-1-{2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl}butylcarbamate	C₂₆H₂₉N₃O₈	详情	详情
(V)	61221	2-(1-methylhydrazino)acetic acid	C₃H₈N₂O₂	详情	详情
(VI)	61222	2-[2-((3R)-3,6-bis{[(benzyloxy)carbonyl]amino}hexanoyl)-1-methylhydrazino]acetic acid	C₂₅H₃₂N₄O₇	详情	详情

合成路线2

In a different procedure, starting from negamycin (I), protection with benzyl S-(4,6-dimethylpyrimidin-2-yl)thiol carbonate (II) yields the bis-(benzyloxycarbonyl) derivative (III). Subsequent esterification of acid (III) employing diazomethane leads to methyl ester (IV). The free hydroxyl group of (IV) is then converted to the mesylate (V) by means of methanesulfonyl chloride in cold pyridine. Further mesylate group displacement in (V) with NaI gives rise to the alkyl iodide (VI). Finally, simultaneous cleavage of the N-carbobenzoxy groups and iodide hydrogenolysis in (VI) is accomplished by hydrogenation in the presence of Pd/BaCO3.

参考文献中间体

【1】 Umezawa, H.; Kondo, S. (Microbial Chemistry Research Foundation); delta-Substd. negamycin derivs. and syntheses. US 4065495 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	61223	2-{2-[(3R,5R)-3,6-diamino-5-hydroxyhexanoyl]-1-methylhydrazino}acetic acid	C₉H₂₀N₄O₄	详情	详情
(II)	32266	O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate	C₁₄H₁₄N₂O₂S	详情	详情
(III)	61224	2-[2-((3R,5R)-3,6-bis{[(benzyloxy)carbonyl]amino}-5-hydroxyhexanoyl)-1-methylhydrazino]acetic acid	C₂₅H₃₂N₄O₈	详情	详情
(IV)	61225	methyl 2-[2-((3R,5R)-3,6-bis{[(benzyloxy)carbonyl]amino}-5-hydroxyhexanoyl)-1-methylhydrazino]acetate	C₂₆H₃₄N₄O₈	详情	详情
(V)	61226	methyl 2-(2-{(3R,5R)-3,6-bis{[(benzyloxy)carbonyl]amino}-5-[(methylsulfonyl)oxy]hexanoyl}-1-methylhydrazino)acetate	C₂₇H₃₆N₄O₁₀S	详情	详情
(VI)	61227	methyl 2-[2-((3S)-3,6-bis{[(benzyloxy)carbonyl]amino}-5-iodohexanoyl)-1-methylhydrazino]acetate	C₂₆H₃₃IN₄O₇	详情	详情

合成路线3

In an alternative method, N,N'-bis-(benzyloxycarbonyl)-(R)-ornithine (I) is treated with PCl5 to afford the corresponding acid chloride, which is then converted to diazo ketone (II) with ethereal diazomethane. Rearrangement of (II) under Arndt-Eistert conditions in the presence of silver benzoate leads to the beta-lysine derivative (III). After saponification of the methyl ester (III), the resultant carboxylic acid (IV) is coupled to ethyl 1-methylhydrazinoacetate (V) via the mixed anhydride with isobutyl chloroformate, to give hydrazide (VI). Alkaline hydrolysis of the ethyl ester (VI) yields acid (VII). The N-carbobenzoxy groups are finally removed by hydrogenolysis to furnish the title compound.

参考文献中间体

【1】 Curran, W.V.; Boothe, J.H.; The synthesis of deoxynegamycin and some related compounds. J Antibiot 1978, 31, 9, 914.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	61228	(2R)-2,5-bis{[(benzyloxy)carbonyl]amino}pentanoic acid	C₂₁H₂₄N₂O₆	详情	详情
(II)	61229		C₂₂H₂₄N₄O₅	详情	详情
(III)	61230	methyl (3R)-3,6-bis{[(benzyloxy)carbonyl]amino}hexanoate	C₂₃H₂₈N₂O₆	详情	详情
(IV)	61219	(3R)-3,6-bis{[(benzyloxy)carbonyl]amino}hexanoic acid	C₂₂H₂₆N₂O₆	详情	详情
(V)	61231	ethyl 2-(1-methylhydrazino)acetate	C₅H₁₂N₂O₂	详情	详情
(VI)	61232	ethyl 2-[2-((3R)-3,6-bis{[(benzyloxy)carbonyl]amino}hexanoyl)-1-methylhydrazino]acetate	C₂₇H₃₆N₄O₇	详情	详情
(VII)	61222	2-[2-((3R)-3,6-bis{[(benzyloxy)carbonyl]amino}hexanoyl)-1-methylhydrazino]acetic acid	C₂₅H₃₂N₄O₇	详情	详情

合成路线4

In a closely related method, N5-(benzyloxycarbonyl)-N2-Boc-(R)-ornithine (I) is coupled to diazomethane, via activation with isobutyl chloroformate, to afford the diazo ketone (II). Rearrangement of (II) in the presence of silver benzoate gives the beta-lysine derivative (III). After saponification of the methyl ester (III), the resultant carboxylic acid (IV) is coupled to benzyl 1-methylhydrazinoacetate (V) yielding hydrazide (VI). Hydrogenolysis of the N-carbobenzoxy groups of (VI) provides the Boc-protected precursor (VII), which is finally deprotected to the title compound under acidic conditions.

参考文献中间体

【1】 Raju, B.; Anandan, S.K.; Gu, S.; et al. ; Conformationally restricted analogs of deoxynegamycin. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1684.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	61233	(2R)-5-{[(benzhydryloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoic acid	C₂₄H₃₀N₂O₆	详情	详情
(II)	61234		C₁₉H₂₆N₄O₅	详情	详情
(III)	61235	methyl (3R)-6-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoate	C₂₀H₃₀N₂O₆	详情	详情
(IV)	61236	(3R)-6-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoic acid	C₁₉H₂₈N₂O₆	详情	详情
(V)	61237	benzyl 2-(1-methylhydrazino)acetate	C₁₀H₁₄N₂O₂	详情	详情
(VI)	61238	benzyl 2-(2-{(3R)-6-{[(benzhydryloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoyl}-1-methylhydrazino)acetate	C₃₅H₄₄N₄O₇	详情	详情
(VII)	61239	2-(2-{(3R)-6-amino-3-[(tert-butoxycarbonyl)amino]hexanoyl}-1-methylhydrazino)acetic acid	C₁₄H₂₈N₄O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)