O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate -Drug Synthesis Database

【结构式】

【分子编号】32266

【品名】O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate

【CA登记号】

【分子式】C₁₄H₁₄N₂O₂S

【分子量】274.34344

【元素组成】C 61.29% H 5.14% N 10.21% O 11.66% S 11.69%

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：(VI)

The reaction of N-(2-oxo-2-phenylethyl)acetamide (I) with glyoxylic acid (II) by means of NaHCO3 in water gives threo-(2RS)-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutanoic acid (III), which is reduced with H2 over Pd/C in acetic acid yielding threo-(2RS)-3-acetylamino-2-hydroxy-4-phenylbutanoic acid (IV). The treatment of (IV) with (S)-1-phenylethylamine followed by a fractionated crystallization affords (2S,3R)-3-acetyl-amino-2-hydroxy-4-phenylbutanoic acid (IV), which is hydrolyzed with HCl in refluxing water to afford (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (V). The protection of (V) with benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate (VI) by means of triethylamine in dioxane - water gives (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (VII), which is condensed whh benzyl (S)-leucinate (VIII) by means of di-cyclohexylcarbodiimide and p-toluenesulfonic acid yielding benzyl (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyl-(S)-leucinate (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in acetic acid.

参考文献中间体

合成目标

【1】 Umezawa, H.; Aoyagi, T.; Shirai, T.; Nishizawa, R.; Suzuki, M.; Saino, T. (Nippon Kayaku Co., Ltd.); Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them. DE 2947140; ES 486572; FR 2442227; GB 2090595; US 4281180 .
【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Bestatin. Drugs Fut 1981, 6, 10, 604.

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)	14601	N-(2-oxo-2-phenylethyl)acetamide		C₁₀H₁₁NO₂	详情	详情
(II)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(III)	32263	(2S,3S)-3-(acetamido)-2-hydroxy-4-oxo-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-oxo-4-phenylbutyric acid		C₁₂H₁₃NO₅	详情	详情
(IV)	32264	(2S,3R)-3-(acetamido)-2-hydroxy-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-phenylbutyric acid		C₁₂H₁₅NO₄	详情	详情
(V)	32265	(2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid	62023-63-6	C₁₀H₁₃NO₃	详情	详情
(VI)	32266	O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate		C₁₄H₁₄N₂O₂S	详情	详情
(VII)	32267	(2S,3R)-3-benzyIoxycarbonyIamino-2-hydroxy-4-phenylbutyric acid; (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid		C₁₈H₁₉NO₅	详情	详情
(VIII)	22252	Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate		C₁₃H₁₉NO₂	详情	详情
(IX)	32268	benzyl (2S)-2-[((2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutanoyl)amino]-4-methylpentanoate; benzyl (2S,3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyI-(S)-Ieucinate		C₃₁H₃₆N₂O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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

合成目标

【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3

该中间体在本合成路线中的序号：(II)

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

合成目标

【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

Extended Information