公开(公告)号：US3870719A

公开(公告)日：1975-03-11

申请号：US26355972

申请日：1972-06-16

申请人： US HEALTH

发明人： KNOTT ROGER L ,  TAUNTON-RIGBY ALISON

IPC分类号： A61K31/505 ,  A61K31/519 ,  A61P35/02 ,  C07D475/04 ,  C07D487/14 ,  C07D51/48

CPC分类号： C07D487/14 ,  C07D475/04 ,  Y10S514/908

摘要： The preparation of N5-methyltetrahydrohomofolic acid and alkali metal salts thereof is from homofolic acid starting material (HFA) by catalytic reduction with platinum oxide in the dark under hydrogen at a slight overpressure to produce tetrahydrohomofolate (THHF), then immediately reacting this product with formaldehyde to produce 5,11methylenetetrahydrohomofolate and reducing this methylene intermediate without isolation with sodium borohydride to give the desired 5-methyltetrahydrohomofolate in the disodium salt form. The 5-methyl product is recovered by precipitating side products at a pH of about 3.8 with acetic acid and refrigerating the product filtrate overnight at about 3*-10*C. The filtrate containing the product 5-methyltetrahydrohomofolate (5-MeTHHF) is treated with charcoal, concentrated to an oil and the 5-methyl product is precipitated with absolute ethanol. The 5,11methylenetetrahydrofolate may be separately recovered and in a second reaction an additional product known as the 5,11-methenyl is formed by reaction with formic acid. These products show increased stability over folate analogues and show biological promise in the treatment of cancer and leukemia as antifolates and specifically against L1210-FR8 tumor in mice.

摘要翻译： N5-甲基四氢异佛尔酮酸及其碱金属盐的制备通过在黑暗中在氧气中在氧气中在稍微超压下通过催化还原与氢氧化铝反应生成四氢异佛酸酯（THHF），然后立即使该产物与甲醛反应，由均聚酸原料（HFA） 生成5,11-亚甲基四氢异佛酸酯并且用硼氢化钠分离而还原该亚甲基中间体，得到所需的二钠盐形式的5-甲基四氢异佛酸酯。 通过用乙酸在约3.8的pH下沉淀副产物回收5-甲基产物，并将产物滤液在约3℃-10℃下冷冻过夜。将含有5-甲基四氢异佛酸酯（5-MeTHHF）的产物的滤液处理 用木炭，浓缩成油，用无水乙醇沉淀出5-甲基产物。 可以单独回收5,11-亚甲基四氢叶酸，在第二反应中，通过与甲酸反应形成称为5,11-亚甲基的另外的产物。 这些产品显示出比叶酸类似物更高的稳定性，并且在治疗作为抗叶酸剂的癌症和白血病以及特异性地针对小鼠中的L1210-FR8肿瘤方面表现出生物学上的前景。