(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】31107

【品名】(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

【CA登记号】69-53-4

【分子式】C₁₆H₁₉N₃O₄S

【分子量】349.41068

【元素组成】C 55% H 5.48% N 12.03% O 18.32% S 9.18%

与该中间体有关的原料药合成路线共 5 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1

该中间体在本合成路线中的序号：(III)

The bromination of 4,5-dimethyl-1,3-dioxolen-2-one (I) with N-bromo-succinimide (NBS) and azobisisobutyronitrile (AIBN) in CCl4 gives 4-methyl-5-bromomethyl-1,3-diioxolen-2-one (II), which is then condensed with ampicillin (III) by means of KHCO3 and benzaldehyde in DMF.

参考文献中间体

合成目标

【1】 Sakamoto, F.; Ikeda, S.; Tsukamoto, G.; Utsumi, I. (Kanebo Pharmaceuticals, Ltd.); Novel ampicillin esters and production thereof. EP 0039086; EP 0039477; EP 0061206; US 4389408 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; KB-1585. Drugs Fut 1983, 8, 11, 920.

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)	31106	4,5-dimethyl-1,3-dioxol-2-one	37830-90-3	C₅H₆O₃	详情	详情
(II)	13462	4-(Bromomethyl)-5-methyl-1,3-dioxol-2-one	80715-22-6	C₅H₅BrO₃	详情	详情
(III)	31107	(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid	69-53-4	C₁₆H₁₉N₃O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Compound can be prepared in two different ways: 1) By condensation of ampicilline (aminobenzylpenicilline) (I) with 1-chlorocarbonyl-2-oxo-3-mehylsulfonylimidazolidine (II) by means of NaOH in cool water or triethylamine in THF-water. 2) By condensation of 6-aminopenicillanic acid (III) with D-[(3-methylsulfonyl-2-oxoimidazolidin-1-yl)carbonylamino]phenylacetic acid (IV) by means of tetramethylchloroformamidinium chloride (A) and N-methylmorpholine (B) in methylene chloride - THF. The phenylacetic acid (IV) is obtained by condensation of D-phenylglycine (V) with 1-chlorocarbonyl-2-oxo-3-mehylsulfonylimidazolidine (II) by means of NaOH in dioxane - water. The acid chloride (II) is prepared by reaction of 2-imidazolidone (VI) with methanesulfonyl chloride (VII) in refluxing THF to give N-methylsulfonyl-2-imidazolidone (VIII), which is then condensed with phosgene by means of trimethylchlorosilane and triethylamine in dioxane.

参考文献中间体

合成目标

【1】 Koenig, H.B.; et al.; Penicillin compounds their production and their medicinal use. DE 2152968; FR 2157909; GB 1392850; JP 48049788; JP 48049911 .
【2】 Koenig, H.B.; et al.; Penicillins their production and their medicinal use. DE 2152967; FR 2157908; GB 1392849; JP 48049787; JP 48049910 .
【3】 Schroeck, W.; et al.; Penicillanic acids their production and their medicinal use. DE 2318955; ES 425197; FR 2225151; GB 1465355; JP 49135990 .
【4】 Playle, A.C.; Castañer, J.; Mezlocillin. Drugs Fut 1977, 2, 9, 600.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	28928	4-methylmorpholine	109-02-4	C₅H₁₁NO	详情	详情
(A)	40169	N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride		C₅H₁₂Cl₂N₂	详情	详情
(I)	31107	(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid	69-53-4	C₁₆H₁₉N₃O₄S	详情	详情
(II)	40167	3-(methylsulfonyl)-2-oxo-1-imidazolidinecarbonyl chloride	41762-76-9	C₅H₇ClN₂O₄S	详情	详情
(III)	32631	(2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (+)-6-Aminopenicillanic acid; 6-APA	551-16-6	C₈H₁₂N₂O₃S	详情	详情
(IV)	40168	(2R)-2-([[3-(methylsulfonyl)-2-oxo-1-imidazolidinyl]carbonyl]amino)-2-phenylethanoic acid		C₁₃H₁₅N₃O₆S	详情	详情
(V)	40170	(2R)-2-amino-2-phenylethanoic acid		C₈H₉NO₂	详情	详情
(VI)	36228	2-imidazolidinone	120-93-4	C₃H₆N₂O	详情	详情
(VII)	13467	Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride	124-63-0	CH₃ClO₂S	详情	详情
(VIII)	36229	1-(methylsulfonyl)-2-imidazolidinone	41730-79-4	C₄H₈N₂O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The cyclization of diethyl oxalate (I) with N-ethylethylenediamine (II) in ethanol gives ethyl-2,3-dioxopiperazine (III), which by reaction first with trimethylsilyl chloride and triethytamine and then with phosgene in THF is converted into 4-ethyl-2,3-dioxopiperazine-1-carboxylic acid chloride (IV). Finally, this compound is condensed with 6-D-(-)-alpha-aminophenylacetamidopenicillanic acid (V) by means of triethylamine in THF - water.

参考文献中间体

合成目标

【1】 Saikawa, I.; et al.; Penicillins and cephalosporins and process for producing the same. DE 2519400; FR 2269937; FR 2320295; GB 1508062 .
【2】 Loren, J.G.; Castañer, J.; Piperacillin. Drugs Fut 1978, 3, 11, 829.

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)	17571	Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate	95-92-1	C₆H₁₀O₄	详情	详情
(II)	39928	N(1)-ethyl-1,2-ethanediamine; N-(2-aminoethyl)-N-ethylamine	110-72-5	C₄H₁₂N₂	详情	详情
(III)	39929	1-ethyl-2,3-piperazinedione	59702-31-7	C₆H₁₀N₂O₂	详情	详情
(IV)	24305	4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride	59703-00-3	C₇H₉ClN₂O₃	详情	详情
(V)	31107	(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid	69-53-4	C₁₆H₁₉N₃O₄S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

Reductive condensation of 1,4-butanediamine (I) with glyoxylic acid (II) affords 3,8-diazaoctanoic acid (III). Subsequent acylation of diamino acid (III) with 2,3-diacetoxybenzoyl chloride (IV) provides diamide (V). After activation of (V) as the corresponding mixed anhydride with either methyl or isobutyl chloroformate, condensation with ampicillin (VI) yields the title compound.

参考文献中间体

合成目标

【1】 RF-2691A. Drug Data Rep 1995, 17, 9, 867.
【2】 Berg, A.; Heinisch, L.; Mollmann, U.; Wittmann, S.; Scherlitz-Hofmann, I.; Stoiber, T. (Grunenthal GmbH); Catecholate beta-lactam conjugates, method for producing the same and the use thereof. DE 10111160; WO 0270016 .

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)	42070	1,4-butanediamine; 4-aminobutylamine	110-60-1	C₄H₁₂N₂	详情	详情
(II)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(III)	58505	2-[(4-aminobutyl)amino]acetic acid		C₆H₁₄N₂O₂	详情	详情
(IV)	58506	2-(acetyloxy)-3-(chlorocarbonyl)phenyl acetate		C₁₁H₉ClO₅	详情	详情
(V)	58507	2-[[2,3-bis(acetyloxy)benzoyl](4-{[2,3-bis(acetyloxy)benzoyl]amino}butyl)amino]acetic acid		C₂₈H₃₀N₂O₁₂	详情	详情
(VI)	31107	(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid	69-53-4	C₁₆H₁₉N₃O₄S	详情	详情

合成路线5

该中间体在本合成路线中的序号：(IX)

Catalytic hydrogenolysis of benzyl ester (VII) affords carboxylic acid (VIII) (1). Then, coupling of acid (VIII) with ampicillin (IX) using isobutyl chloroformate provides the target adduct, which is finally converted to the title sodium salt upon treatment with sodium 2-ethylhexanoate in EtOAc.

参考文献中间体

合成目标

【1】 Wittmann, S.; et al.; New synthetic siderophores and their beta-lactam conjugates based on diamino acids and dipeptides. Bioorg Med Chem 2002, 10, 6, 1659.
【2】 Heinisch, L.; Mollmann, U.; Wittmann, S. (Grunenthal GmbH); Siderophore antibiotic conjugates with tetra- or hexadentate iron chelators on the basis of amino acids or peptides, method for producing them and the use thereof. DE 10111163; WO 0270017 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	58520	benzyl (2S)-5-[(benzoyloxy)(methyl)amino]-2-[((2S)-2,6-bis{[2,3-bis(acetyloxy)benzoyl]amino}hexanoyl)amino]-5-oxopentanoate		C₄₈H₅₀N₄O₁₆	详情	详情
(VIII)	58521	(2S)-5-[(benzoyloxy)(methyl)amino]-2-[((2S)-2,6-bis{[2,3-bis(acetyloxy)benzoyl]amino}hexanoyl)amino]-5-oxopentanoic acid		C₄₁H₄₄N₄O₁₆	详情	详情
(IX)	31107	(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid	69-53-4	C₁₆H₁₉N₃O₄S	详情	详情

Extended Information