265121-01-5Relevant academic research and scientific papers
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.
Application of borane-pyridine complex in preparation of NK-1 receptor antagonist
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Paragraph 0043-0045; 0050-0052; 0057-0059; 0064-0066, (2021/02/10)
The invention provides an application of a borane-pyridine complex in preparation of an NK-1 receptor antagonist fosaprepitant dimeglumine. The application is characterized by comprising the followingsteps: step 1) catalyzing aprepitant dibenzyl phosphate
Preparation method of pharmaceutical compound
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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.
Preparation method of medicine for preventing chemotherapy-related nausea and vomiting
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Paragraph 0009; 0024-0043, (2021/11/03)
The invention discloses a preparation method of a medicine for preventing chemotherapy-related nausea and vomiting. The preparation method comprises the following steps: dissolving aprepitant and tetrabenzyl pyrophosphate in a tetrahydrofuran solvent, adding sodium bis(trimethylsilyl)amide, adding meglumine, carrying out Pd/C catalytic reaction by taking ammonium formate as a hydrogen source reagent, adding triphenylphosphine and 1,2-propane diamine to remove palladium after the reaction is finished, and performing temperature-controlled crystallization in an ethanol-acetonitrile-acetone mixed solvent for 2 hours so as to finish preparation of fosaprepitant dimeglumine is in a one-pot manner. According to the invention, time is saved, yield is improved, and ammonium formate is used for replacing hydrogen, so safety is higher. According to the method, a process is good in palladium removal effect and high in purity, the three solvents are mixed for crystallization, and the obtained product is not sticky after being dried.
Application of borane-pyridine complexe in preparation of pharmaceutical compound
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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.
Preparation method of NK-1 receptor antagonist
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Paragraph 0043-0045; 0050-0052; 0057-0059; 0064-0066, (2021/03/30)
The invention provides a preparation method of fosaprepitant dimeglumine. The preparation method is characterized by comprising the following steps: step 1) catalyzing aprepitant dibenzyl phosphate under the action of a borane pyridine complex to prepare fosaprepitant; and 2) reacting fosaprepitant with N-methyl- D-glucosamine to generate fosaprepitant dimeglumine. The borane-pyridine complex is used as a catalyst, aprepitant dibenzyl phosphate can directly generate fosaprepitant, then the fosaprepitant dibenzyl phosphate reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine, the reaction is mild, and conversion of raw materials can be completed quickly at the temperature of about room temperature only by using a small amount of the catalyst. The catalytic efficiency ishigh, the reaction conditions are mild and the yield is high. The high-purity and high-yield fosaprepitant can be obtained by recrystallizing the reaction crude product with deionized water, the post-treatment is extremely simple, and the fosaprepitant dimeglumine is generated by reacting the reaction crude product with N-methyl-D-glucosamine, so that the purity and the yield are high.
FOSAPREPITANT PHOSPHATE INTERMEDIATE AND PREPARATION METHOD THEREFOR
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Paragraph 0027, (2019/05/24)
Provided are a fosaprepitant phosphate intermediate (IV) preparation method, a fosaprepitant phosphate intermediate (IV-A) and a method of (AA) for preparing fosaprepitant dimeglumine by using the intermediate (IV-A). IV: R1 and R2 a
Preparation method of fosaprepitant dimeglumine pharmaceutical salt
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Paragraph 0025; 0026, (2019/01/07)
The invention belongs to the technical field of medicine chemistry, and particularly relates to a novel preparation method of fosaprepitant dimeglumine. According to the preparation method, triethyl silane is used for replacing hydrogen, and high-pressure
IMPROVED PROCESS FOR PREPARATION OF FOSAPREPITANT OR SALT THEREOF
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Page/Page column 13-15, (2018/12/12)
The present invention relates to an improved process for the preparation of fosaprepitant or salt thereof. More particularly, the present invention relates to an effective process for the preparation of fosaprepitant dibenzylester, a compound of Formula I
Preparation luck sha pitan b a Meglumine intermediates
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, (2018/10/19)
The invention belongs to the technical field of pharmaceutical production, and relates to a preparation method of fosaprepitant dimeglumine intermediates. The technical scheme of the preparation method is particularly as follows: 3-chloromethyl-1,2,4-triazolin-5-one and a phosphine acylating reagent are subjected to a phosphine acylation reaction under the catalysis of alkali; and under the action of alkali, a product of the phosphine acylation reaction is reacted with [2R-2 alpha (R), 3 alpha]-2-[1-(3,5-di(trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl)-3-morpholine hydrochloride so as to generate a target compound. The phosphine acylation reaction in the technical scheme is simple in operation, mild in reaction condition, high in yield, good in product purity, and simple and efficient in post-processing; and the selected raw materials are stable in physical and chemical properties, convenient to control, low in price and easy to obtain, therefore, the method has a large implementation value, and is suitable for industrialized mass production.
