265121-01-5Relevant articles and documents
Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs
Hale, Jeffrey J.,Mills, Sander G.,MacCoss, Malcolm,Dorn, Conrad P.,Finke, Paul E.,Budhu, Richard J.,Reamer, Robert A.,Huskey, Su-Er W.,Luffer-Atlas, Debra,Dean, Brian J.,McGowan, Erin M.,Feeney, William P.,Chiu, Shuet-Hing Lee,Cascieri, Margaret A.,Chicchi, Gary G.,Kurtz, Marc M.,Sadowski, Sharon,Ber, Elzbieta,Tattersall, F. David,Rupniak, Nadia M. J.,Williams, Angela R.,Rycroft, Wayne,Hargreaves, Richard,Metzger, Joseph M.,MacIntyre, D. Euan
, p. 1234 - 1241 (2000)
The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl- 3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.
Preparation method of pharmaceutical compound
-
Paragraph 0033-0035; 0040-0042; 0047-0049; 0054-0056, (2021/03/23)
The invention provides a preparation method of fosaprepitant. The preparation method comprises the following step of: catalyzing aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to prepare fosaprepitant. The borane-pyridine complex is used as the catalyst, aprepitant dibenzyl phosphate can directly generate fosaprepitant, the reaction is mild, the conversion of the raw materials can be quickly completed at the temperature of about room temperature only by using a small amount of catalyst, the catalytic efficiency is high, the reaction condition is mild, and the yieldis high. The high-purity and high-yield fosaprepitant can be obtained by recrystallizing the reaction crude product by using deionized water, the post-treatment is extremely simple, and the deionizedwater is used as a solvent, so that the method is more economical and environment-friendly.
Application of borane-pyridine complexe in preparation of pharmaceutical compound
-
Paragraph 0033-0035; 0040-0042; 0047-0049; 0054-0056, (2021/03/13)
The invention provides an application of a borane-pyridine complex in preparation of a pharmaceutical compound fosaprepitant. The application is characterized by comprising the following step: catalyzing aprepitant dibenzyl phosphate under the action of the borane-pyridine complex to prepare fosaprepitant. The borane-pyridine complex is used as the catalyst, aprepitant dibenzyl phosphate can directly generate fosaprepitant, the reaction is mild, the conversion of the raw materials can be quickly completed at the temperature of about room temperature only by using a small amount of catalyst, the catalytic efficiency is high, the reaction condition is mild, and the yield is high. The high-purity and high-yield fosaprepitant can be obtained by recrystallizing the reaction crude product by using deionized water, the post-treatment is extremely simple, and the deionized water is used as a solvent, so that the method is more economical and environment-friendly.
