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1. 发明公开

EP0843013A3 Novel bioprocess for preparing 7-ADCA 失效
标题翻译：用于制备7-ADCA的新型生物过程
公开(公告)号：EP0843013A3
公开(公告)日：1998-06-17
申请号：EP97203374.0
申请日：1992-09-11
申请人： GIST-BROCADES B.V.
发明人： Crawford, Lorilee , Conder, Michael J. , McAda, Phyllis C. , Rambosek, John A.
IPC分类号： C12N15/52 , C12P35/00 , C12N9/00 , C12N1/21
CPC分类号： C12N9/0071 , C12P35/00 , C12P37/04 , Y10S435/935
摘要： An important intermediate for preparing cephalopsporin antibotics, 7-aminodesacetoxy cephalosporanic acid (7-ADCA), is prepared by a novel bioprocess in which a transformed Penicillium chrysogenum strain is cultured in the presence of an adipate feedstock to produce adipoyl-6-APA (6-amino penicillanic acid); and the in situ expression of an expandase gene, e.g., from Streptomyces clavuligerus , with which the P.chrysogenum has been transformed, converts the adipoyl-6-APA by ring expansion to the novel compound adipoyl-7-ADCA. The final product, 7-ADCA, is then prepared by cleavage of the adipoyl side chain using an adipoyl acylase. The entire synthesis, accordingly, is carried out using bioprocesses, and is efficient and economical.
摘要翻译：制备头孢菌素类抗生素7-氨基脱乙酰氧基头孢菌酸（7-ADCA）的重要中间体是通过新型生物过程制备的，其中在己二酸酯原料存在下培养转化的产黄青霉菌菌株以产生己二酰-6-APA（6 - 氨基青霉烷酸）; 并且就地表达扩环酶基因，例如来自链霉菌（Streptomyces clavuligerus）的，已经转化产青霉菌的扩环酶基因通过环扩环将己二酰-6-APA转化为新化合物己二酰-7-ADCA。然后使用己二酰基酰基转移酶切割己二酰侧链制备最终产物7-ADCA。相应地，整个合成使用生物过程进行，并且是高效和经济的。

2. 发明公开

EP0856516A1 Novel bioprocess for preparing 7-aca and 7-adac 失效
标题翻译： Neues biologisches Verfahren zur Herstellung von 7-ACA und 7-ADAC
公开(公告)号：EP0856516A1
公开(公告)日：1998-08-05
申请号：EP97204046.3
申请日：1992-10-14
申请人： GIST-BROCADES B.V.
发明人： Conder, Michael J. , Stepan, Anthony Michael , Crawford, Lorilee , Rambosek, John A. , McAda, Phyllis C. , Reeves, Christopher D.
IPC分类号： C07D501/20
CPC分类号： C12N9/0071 , C12N9/00 , C12N9/1029 , C12P35/00 , C12P37/04 , Y10S435/935
摘要： Important intermediates for preparing cephalosporin antibiotics, 7-amino-cephalosporanic acid (7-ACA) and 7-aminodeacetylcephalosporanic acid (7-ADAC), are prepared by a novel bioprocess in which a transformed Penicillium chrysogenum strain is cultured in the presence of an adipate feedstock to produce adipoyl-6-APA (6-amino penicillanic acid); followed by the in situ expression of the following genes with which the P. chrysogenum has been transformed:

1) an expandase gene, e.g., from Cephalosporium acremonium , whose expression product converts the adipoyl-6-APA by ring expansion to adipoyl-7-ADCA;
2) an hydroxylase gene whose expression product converts the 3-methyl side chain of adipoyl-7-ADCA to 3-hydroxymethyl, to give the first product, adipoyl-7-aminodeacetylcephalosporanic acid (7-ADAC); and
3) an acetyltransferase gene whose expression product converts the 3-hydroxymethyl side chain to the 3-acetyloxymethyl side chain of adipoyl-7-ACA. The final product, 7-ACA, is then prepared by cleavage of the adipoyl side chain using an adipoyl acylase. The entire synthesis, accordingly, is carried out using bioprocesses, and is efficient and economical.
摘要翻译：通过新型生物工艺制备头孢菌素抗生素，7-氨基头孢菌素（7-ACA）和7-氨基脱乙酰头孢菌酸（7-ADAC）的重要中间体，其中转化的产黄青霉菌株在己二酸存在下培养生产己二酰-6-APA（6-氨基青霉烷酸）的原料; 其次是产生产黄青霉的以下基因的原位表达：1）扩增酶基因，例如头孢霉头孢菌，其表达产物将己二酰基-6-APA通过环扩展转化为己二酰-7- ADCA; 2）其表达产物将己二酰-7-ADCA的3-甲基侧链转化为3-羟甲基的羟化酶基因，得到第一产物，己二酰-7-氨基乙酰基头孢烷酸（7-ADAC）; 和3）其表达产物将3-羟甲基侧链转化为己二酰-7-ACA的3-乙酰氧甲基侧链的乙酰转移酶基因。然后通过使用己二酰酰化酶裂解己二酰侧链制备最终产物7-ACA。因此，整个合成使用生物工艺进行，并且是高效和经济的。

3. 发明授权

EP0532341B1 Novel bioprocess for preparing 7-ADCA 失效
标题翻译： 7-ADCA的制备新生物过程
公开(公告)号：EP0532341B1
公开(公告)日：1998-11-04
申请号：EP92308286.1
申请日：1992-09-11
申请人： GIST-BROCADES B.V.
发明人： Conder, Michael J. , Crawford, Lorilee , McAda, Phyllis C. , Rambosek, John A.
IPC分类号： C12N15/52 , C12N1/15 , C12N9/00 , C12P35/02
CPC分类号： C12N9/0071 , C12P35/00 , C12P37/04 , Y10S435/935

4. 发明公开

EP0843013A2 Novel bioprocess for preparing 7-ADCA 失效
标题翻译： Neues Bio-Verfahren zur Herstellung von 7-ADCA
公开(公告)号：EP0843013A2
公开(公告)日：1998-05-20
申请号：EP97203374.0
申请日：1992-09-11
申请人： GIST-BROCADES B.V.
发明人： Crawford, Lorilee , Conder, Michael J. , McAda, Phyllis C. , Rambosek, John A.
IPC分类号： C12N15/52 , C12P35/00 , C12N9/00 , C12N1/21
CPC分类号： C12N9/0071 , C12P35/00 , C12P37/04 , Y10S435/935
摘要： An important intermediate for preparing cephalopsporin antibotics, 7-aminodesacetoxy cephalosporanic acid (7-ADCA), is prepared by a novel bioprocess in which a transformed Penicillium chrysogenum strain is cultured in the presence of an adipate feedstock to produce adipoyl-6-APA (6-amino penicillanic acid); and the in situ expression of an expandase gene, e.g., from Streptomyces clavuligerus , with which the P.chrysogenum has been transformed, converts the adipoyl-6-APA by ring expansion to the novel compound adipoyl-7-ADCA. The final product, 7-ADCA, is then prepared by cleavage of the adipoyl side chain using an adipoyl acylase. The entire synthesis, accordingly, is carried out using bioprocesses, and is efficient and economical.
摘要翻译：通过新型生物工艺制备头孢菌素类抗生素7-氨基乙酰氧基头孢菌素酸（7-ADCA）的重要中间体，其中转化的产黄青霉菌株在己二酸原料存在下培养以产生己二酰基-6-APA（6 氨基青霉烷酸）; 并且例如来自产黄青霉的链霉菌（Streptomyces clavuligerus）的扩环酶基因的原位表达通过环扩增将己二酰基-6-APA转化为新化合物己二酰-7-ADCA。然后通过使用己二酰酰化酶裂解己二酰侧链制备最终产物7-ADCA。因此，整个合成使用生物工艺进行，并且是高效和经济的。

5. 发明公开

EP0532341A1 Novel bioprocess for preparing 7-ADCA 失效
标题翻译： Neues生物学Verfahren zur Herstellung von 7-ADCA。
公开(公告)号：EP0532341A1
公开(公告)日：1993-03-17
申请号：EP92308286.1
申请日：1992-09-11
申请人： GIST-BROCADES B.V.
发明人： Conder, Michael J. , Crawford, Lorilee , McAda, Phyllis C. , Rambosek, John A.
IPC分类号： C12N15/52 , C12N1/15 , C12N9/00 , C12P35/02
CPC分类号： C12N9/0071 , C12P35/00 , C12P37/04 , Y10S435/935
摘要： An important intermediate for preparing cephalosporin antibiotics, 7-aminodesacetoxy cephalosporanic acid (7-ADCA), is prepared by a novel bioprocess in which a transformed Penicillium chrysogenum strain is cultured in the presence of an adipate feedstock to produce adipoyl-6-APA (6-amino penicillanic acid); and the in situ expression of an expandase gene, e.g., from Streptomyces clavuligerus , with which the P. chrysogenum has been transformed, converts the adipoyl-6-APA by ring expansion to adipoyl-7-ADCA. The final product, 7-ADCA, is then prepared by cleavage of the adipoyl side chain using an adipoyl acylase. The entire synthesis, accordingly, is carried out using bioprocesses, and is efficient and economical.
摘要翻译：通过新型生物工艺制备头孢菌素类抗生素7-氨基乙酰氧基头孢菌素酸（7-ADCA）的重要中间体，其中转化的产黄青霉菌株在己二酸原料存在下培养产生己二酰基-6-APA（6 氨基青霉烷酸）; 并且已经转化了产黄青霉的膨胀酶基因例如来自链霉菌的原位表达通过环扩展将己二酰基-6-APA转化为己二酰-7-ADCA。然后通过使用己二酰酰化酶裂解己二酰侧链制备最终产物7-ADCA。因此，整个合成使用生物工艺进行，并且是高效和经济的。

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