Synthesis of Monofluoro Building Blocks Designed from Fine Chemistry Viewpoint and Development of Fluorine-containing Medicinals

从精细化学角度设计单氟砌块的合成及含氟药物的开发

• 批准号: 02557086
• 负责人: TAKEUCHI Yoshio
• 金额: $ 3.46万
• 依托单位: Toyama Medical & Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02557086/
• 关键词: Monofluoro Building Blocks; Multifunctional Carbon Compounds; Tertiary Alkyl Fluorides; alpha-Fluoro-alpha-amino Acid; Fluorinated Tropanes; Fluorine-containing Medicinals; NMAD Receptor; Molecular Design; 合成ブロック; バートン法; ブロモフルオロアルカン; モノフルオロ化合物

1) Among the various monofluoro building blocks designed, 1-6, synthesis of the four compounds 1-4 was achieved. However, the isolation of the selenenyl derivative 5 and the fluoroethene equivalent 6 was unsuccessful due to the instability caused by the multifunctional carbon structures.2) Synthesis of the chiral tropane precursors, 7 and 8, was achieved. However. further efforts to convert them into chiral tropanes was abandoned because this pathway involves some reactions with unsatisfactory yields.3) As to the development of the general entry to the novel tertiary alkyl fluorides, we succeeded to get to the target structure 13 by two routes, i. e., the alkylation of 11 obtained from 9 via 10 and the alkylation of 12 obtained from 9.4) The synthesis of various precursors for alpha-fluoro-alpha-amino acids, including 15 and 16, has been achieved. However, the target compounds could not be isolated due to the rather drastic reaction conditions employed for the final stage and also to the instability of the target compounds.5) Four compounds 14-17 were tested for fencyclidine inhibitory activity and monofluorotropane 18 was tested for nicotinic activity. However, all of them were found to be not so effective as we had expected.

1)在设计的各种单氟结构单元1-6中，实现了四种化合物1-4的合成。然而，由于多官能碳结构引起的不稳定性，硒基衍生物5和氟乙烯等价物6的分离是不成功的。2）实现了手性托烷前体7和8的合成。然而. 3）在新的叔烷基氟化合物的合成方面，我们通过两条路线成功地得到了目标结构13，即：1.例如，由9得到的11经10的烷基化和由9.4得到的12的烷基化）已经实现了α-氟-α-氨基酸的各种前体，包括15和16的合成。然而，由于最后阶段采用的反应条件相当激烈，并且目标化合物不稳定，因此不能分离目标化合物。5）测试了四种化合物14-17的苯环利定抑制活性，并测试了单氟托烷18的烟碱活性。然而，所有这些都被发现并不像我们预期的那样有效。

项目成果

Takeuchi,Yoshio: "Synthetic Studies for Novel Structure of α-Nitrogenously Functionalized α-Fluorocarboxylic Acids.II.Synthesis and Some Reactions of α-Fluoro-α-nitrocarboxylic Ester and Carboxamide Derivatives" Chem.Pharm.Bull.39. 3120-3122 (1991)

Takeuchi, Yoshio：“α-含氮官能化 α-氟代羧酸新结构的合成研究。II. α-氟-α-硝基羧酸酯和羧酰胺衍生物的合成和一些反应”Chem.Pharm.Bull.3120-3122。 (1991)

TAKEUCHI,Yoshio: "The First General and Efficient Entry to the Synthesis of Tertiary Alkyl Fluorides" J.Org.Chem.

TAKEUCHI, Yoshio：“首次全面有效地合成叔烷基氟化物”J.Org.Chem。

T.Takahashi, A.Fujii, J.Sugita, T.Hagi, K.Kitano, Y.Araki, T.Koizumi, and M.Shiro: "Asymmetric 1,3-Dipolar Cycloaddition of Chiral Sulphinylethenes with 1-Methyl-3-Oxidopyridinium and Some Nitrones" Tetrahedron: Asymmetry. 2. 1379-1390 (1991)

T.Takahashi、A.Fujii、J.Sugita、T.Hagi、K.Kitano、Y.Araki、T.Koizumi 和 M.Shiro：“手性亚磺酰乙烯与 1-甲基-3 的不对称 1,3-偶极环加成反应

TAKEUCHI,Yoshio: "Synthetic Studies for Novel Structure of α-Nitrogenously Function-alized α-Fluorocarboxylic Acids.II.Synthesis and Some Reactions of α-Fluoro-α-nitrocarboxylic Ester and Carboxamide Derivatives" Chem.Pharm.Bull.39. 3120-3122 (1991)

TAKEUCHI, Yoshio：“α-含氮官能化 α-氟代羧酸新结构的合成研究。II. α-氟-α-硝基羧酸酯和羧酰胺衍生物的合成和一些反应”Chem.Pharm.Bull.3120。 -3122 (1991)

TAKEUCHI,Yoshio: "Chemistry of Novel Compounds with Multifunctional Carbon Structure.7.Synthetic Studies of the Potentially Versatile Monofluoro Mole-cules,α Functionalized α-Fluoro-βketoesters" J.Org.Chem.57. 2196-2199 (1992)

TAKEUCHI, Yoshio：“具有多功能碳结构的新型化合物的化学。7.潜在多功能单氟分子的合成研究，α 功能化 α-氟-β 酮酯”J.Org.Chem.57（1992）。