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【结 构 式】 
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【分子编号】32631 【品名】(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 【CA登记号】551-16-6 |
【 分 子 式 】C8H12N2O3S 【 分 子 量 】216.26096 【元素组成】C 44.43% H 5.59% N 12.95% O 22.19% S 14.83% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Compound (VII) can also be obtained by condensation of 6-aminopenicillanic acid (VIII) with the N-succinimido ester of alpha-[2-(2-nitrophenylsulfonylamino)-3-(N-methylcarbamoyl)propionamido]-alpha-(4-hydroxyphenyl)acetic acid (IX). Finally, the sulfonic group of (VII) is eliminated by treatment with thiobenzamide (A) in ethanol-THF.
| 【1】 Kawazu, M.; et al. (Tanabe Seiyaku Co., Ltd.); Penicillins and processes for preparing the same. DE 2638067; FR 2323384; NL 7610151; US 4053609 . |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; TA-058. Drugs Fut 1980, 5, 3, 151. |
| 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) | 32629 | Thiobenzamide; Benzenecarbothioamide | 2227-79-4 | C7H7NS | 详情 | 详情 |
| (VII) | 32628 | (2S,5R,6R)-6-([(2R)-2-(4-hydroxyphenyl)-2-[((2R)-4-(methylamino)-2-[[(2-nitrophenyl)sulfonyl]amino]-4-oxobutanoyl)amino]ethanoyl]amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; 6-[alpha[2-(2-nitrophenylsulfonylamino)-3-N-methylcarbamoylpropionamido]-alpha-(4-hydroxyphenyl)acetamido]penicillanic acid | C27H30N6O11S2 | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 32630 | (2R)-N(1)-[(1R)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-(4-hydroxyphenyl)-2-oxoethyl]-N(4)-methyl-2-[[(2-nitrophenyl)sulfonyl]amino]butanediamide | C23H23N5O11S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：6-APAFCE 22891 in the ester prodrug formulation of FCE 22101. Reaction of the latter (sodium salt) with acetoxymethyl bromide (DMF) is the traditional synthetic route to FCE 22891. This route is also the preferred one as long as manufacturing involves both compounds (the reverse process, conversion of FCE 22891 into the parent acid FCE 22101, can be conveniently realized by enzymic hydrolysis catalyzed by porcine liver esterase or lipase A6 from Aspergillus niger). Direct synthesis of FCE 22891 can be performed using two major strategies. The total synthetic approaches start from chiral amino or hydroxy acids (threonine, 3-hydroxybutyric acid) and have (3R,4R)-4-acetoxy-3-[(R)-1-hydroxyethyl]-2-oxo-1H-azetidine (Ia) or its 4-benzoyloxy analogue (Ib), usually protected as the tert-butyldimethylsilyl ethers, as common intermediates. These compounds, in particular (Ia), can also be found on the market (Kaneka). Reaction of either (Ia) or (Ib) with the sodium salt of 2-carbamoyloxyethanethioic acid gives the azetidinone thiolester (II), which is condensed with acetoxymethyl oxalyl chloride. Reductive carbonyl condensation (triethyl phosphite, refluxing toluene) and desilylation (tetrabutylammonium fluoride buffered with acetic acid) affords FCE 22891. The hemisynthetic route utilizes 6-APA as a chiral template. Introduction of the alpha-hydroxyethyl chain on the penam nucleus is satisfactorily achieved by deaminative bromination, metal exchange with EtMgBr, aldol reaction (acetaldehyde, THF, -70 C) and reductive dehalogenation (Zn-AcOH), MeOH, -10 C). During this process, the acetoxymethyl promoiety characterizing the final product is conveniently introduced. According to an original procedure, beta-eliminative ring opening of the thiazolidine ring (AgCl/DBN) and in situ acylation of the intermediate silver mercaptide with carbamoyloxyacetyl chloride affords the key azetidone thioester (VII). Ozonolysis (CH2Cl2, -50 C) and reductive carbonyl condensation completes the sequence, without resorting to protective groups other than trimethylsilyl, which is removed at the end by simple acidic work-up.
| 【1】 Franceschi, G.; Foglio, M.; Alpegiani, M.; Battistini, C.; Bedeschi, A.; Perrone, E.; Zarini, F.; Arcamone, F.; Della Bruna, C.; Sanfilippo, A.; Synthesis and biological properties of sodium (5R,6S, 8R)-6alpha-hydroxyethyl-2-carbamoyloxymethyl-2-penem-3-carboxylate (FCE 22101) and its orally absorbed esters FCE 22553 and FCE 22891. J Antibiot 1983, 36, 7, 938-41. |
| 【2】 Perrone, E.; FCE 22891. Drugs Fut 1991, 16, 4, 313. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63804 | 2-[(aminocarbonyl)oxy]ethanethioic S-acid | C3H5NO3S | 详情 | 详情 | ||
| 63805 | [(2-chloro-2-oxoacetyl)oxy]methyl acetate | C5H5ClO5 | 详情 | 详情 | ||
| (Ia) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (Ib) | 13689 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl benzoate | C18H27NO4Si | 详情 | 详情 | |
| (IIIa) | 13691 | (acetoxy)methyl 2-[(2R,3S)-2-([2-[(aminocarbonyl)oxy]acetyl]sulfanyl)-3-(1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxoacetate | C19H30N2O10SSi | 详情 | 详情 | |
| (IIIb) | 13692 | (acetoxy)methyl 2-((2R,3S)-2-([2-[(aminocarbonyl)oxy]acetyl]sulfanyl)-4-oxo-3-[1-[(trimethylsilyl)oxy]ethyl]azetidinyl)-2-oxoacetate | C16H24N2O10SSi | 详情 | 详情 | |
| (VIa) | 13695 | (acetoxy)methyl (2S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H19NO6S | 详情 | 详情 | |
| (VIb) | 13696 | (acetoxy)methyl (2S,5R,6S)-3,3-dimethyl-7-oxo-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H27NO6SSi | 详情 | 详情 | |
| FCE 22101 | 63806 | sodium 3-{[(aminocarbonyl)oxy]methyl}-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C10H11N2NaO6S | 详情 | 详情 | |
| (II) | 13690 | S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl] 2-[(aminocarbonyl)oxy]ethanethioate | C14H26N2O5SSi | 详情 | 详情 | |
| (IV) | 13693 | (acetoxy)methyl (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H13Br2NO5S | 详情 | 详情 | |
| (V) | 13694 | (acetoxy)methyl (2S,5R,6S)-6-bromo-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H18BrNO6S | 详情 | 详情 | |
| 6-APA | 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 |
| (VII) | 13697 | (acetoxy)methyl 2-[(2R,3S)-2-([2-[(aminocarbonyl)oxy]acetyl]sulfanyl)-3-[(1R)-1-methyl-2-(trimethylsilyl)ethyl]-4-oxoazetidinyl]-3-methyl-2-butenoate | C20H32N2O8SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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.
| 【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 |