- Application of borane-pyridine complex in preparation of NK-1 receptor antagonist
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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
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Paragraph 0043; 0048-0050; 0053; 0054-0057; 0062-0064; 0069
(2021/02/10)
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- Preparation method of medicine for preventing chemotherapy-related nausea and vomiting
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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.
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Paragraph 0009; 0024-0043
(2021/11/03)
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- Preparation method of NK-1 receptor antagonist
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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.
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Paragraph 0043; 0046-0050; 0053-0057; 0060-0064; 0067-0072
(2021/03/30)
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- Synthesis method of fosaprepitant dimeglumine (by machine translation)
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The invention discloses a synthesis method of fosaprepitant dimeglumine, and belongs to the technical field of medicines. The synthesis method mainly comprises the following steps: reaction of tetra-benzyl pyrophosphate, adsorption of impurities, carbon hydrogenation of palladium mesoporous carbon, refining and the like. The method comprises the following steps: firstly, carrying out quenching reaction by adding sodium carbonate, adding mesoporous carbon to adsorb impurities and tar, avoiding deactivation of the palladium carbon catalyst, directly using a tetrahydrofuran system for reaction. (by machine translation)
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Paragraph 0015-0025
(2020/09/23)
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- A luck sha pitan preparation method of dimethyl Meglumine
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The invention provides a preparation method of fosaprepitant dimeglumine. The preparation method comprises the following steps: by taking aprepitant as a raw material, carrying out phosphorylation on the raw material under an alkaline condition to obtain a dibenzyl ester intermediate; further hydrolyzing the intermediate to obtain fosaprepitant; and further reacting with N-methyl-D-glucosamine to obtain the fosaprepitant dimeglumine. The method provided by the invention is simple to operate and mild in reaction condition, and avoids pressurization and v, so that the method is safe and effective and suitable for industrial production on a large scale.
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- luck Sha Pitan preparation method of dimethyl Meglumine
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The invention relates to a preparation method of fosaprepitant dimeglumine. Fosaprepitant dimeglumine is a compound shown in the formula I. The preparation method is characterized in that a compound shown in the formula II reacts with tetrabenzyl pyrophos
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Paragraph 0033-0035
(2017/08/23)
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- A PROCESS FOR PREPARATION OF FOSAPREPITANT DIMEGLUMINE AND AN INTERMEDIATE THEREOF
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The present invention relates to a novel process for the preparation of intermediate of fosaprepitant dimeglumine. The present invention particularly relates to a process for the preparation of fosaprepitant dibenzyl ester, an intermediate of fosaprepitant dimeglumine, which is simple, easy to handle on commercial scale and efficient.
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Page/Page column 17; 18
(2017/07/06)
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- Crystalline Fosaprepitant Dicyclohexylamine Salt And Its Preparation
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The present invention provides dicyclohexylamine salt of fosaprepitant (fosaprepitant DCHA), a process for preparing fosaprepitant DCHA, and a use of fosaprepitant DCHA in the preparation of pharmaceutically acceptable fosaprepitant dimeglumine with high purity. Fosaprepitant dimeglumine is prepared by treating fosaprepitant DCHA with an acid to form fosaprepitant, followed by adding N-methyl-D-glucamine to fosaprepitant.
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Paragraph 0057
(2016/12/22)
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- A process for preparing luck Sha Pitan b a Meglumine method
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The invention discloses a fosaprepitant dimeglumine preparation method, fosaprepitant dimeglumine has a structure shown as the formula I, and the route of synthesis of the method comprises the following two steps: (1) reacting compound di(benzhydryl) phosphoryl chloride (shown as the formula III) with aprepitant (shown as the formula II) under the action of a steric hindrance strong alkali to produce a new phosphorylation product intermediate (shown as the IV); (2) removing protecting group diphenylmethane of the new compound by catalytic reduction to obtain fosaprepitant and simultaneously to obtain a target product by salifying with N-methyl-D - glucosamine. A phosphorylation reagent used by the method has two higher steric hindrance protecting groups, due to the space steric hindrance effect, the regional selectivity and intermediate stability of the first step reaction can be enhanced, the intermediate stability can be enhanced, and the reaction yield can be improved.
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Paragraph 0049; 0050; 0051; 0052; 0053; 0060-0064; 0071-0075
(2017/06/24)
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- A kind of preparation method of dimethyl luck Sha Pitan cyclophosphadenosine
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The invention relates to a method for preparing fosaprepitant. The fosaprepitant is shown as a formula (I). The method comprises steps 1, 2, 3 and 4, finally, a compound shown as the formula (I) is obtained through hydrogenation reduction; in the step 1, a compound in a formula (II) reacts with a Grignard reagent to generate a compound shown as a formula (III) in the presence of palladium carbon and ammonium formate. The method for preparing is simple in production step, has high reaction yield and less side products, is easy in control of the reaction conditions and is suitable for medical industrial production.
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Paragraph 0048-0053
(2017/04/07)
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- A PROCESS OF MAKING FOSAPREPITANT DIMEGLUMINE
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A process of effectively reducing palladium content in fosaprepitant dimeglumine to below 0.3 ppm which is the detection limit using the current analytical method.
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Page/Page column 7
(2016/12/26)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF FOSAPREPITANT HAVING IMPROVED PURITY
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The present invention relates to an improved process for the preparation of [3-{[(2R,3S)-2- [(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4- yl]methyl}-5-oxo-2H-1,2,4-triazol-1-yl]phosphonic acid (Fosaprepitant or the compound of formula I) or its pharmaceutically acceptable salt, having palladium (Pd) content less than 1 ppm comprising catalytic hydrogenation of the compound of formula II with Pd catalyst optionally in the presence of base, to give the compound of formula I or the pharmaceutically acceptable salt thereof, optionally isolating the compound of formula I or the pharmaceutically acceptable salt and treating the compound of formula I or the pharmaceutically acceptable salt thereof twice with the metal scavenger to obtain the compound of formula I or the pharmaceutically acceptable salt thereof having Pd content less than 1 ppm.
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Page/Page column 11
(2015/06/18)
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- PROCESS FOR FOSAPREPITANT
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The present invention provides a novel process for reducing palladium content in fosaprepitant dimeglumine.
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Page/Page column 6-7
(2013/02/27)
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- PROCESS FOR THE PREPARATION OF FOSAPREPITANT, INTERMEDIATE AND PHARMACEUTICAL ACCEPTABLE SALT THEREOF
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The present invention relates to an improved process for the manufacture of phosphorylated Aprepitant and intermediate thereof. The present invention further relates to an improved process for the manufacture of Fosaprepitant dimeglumine from the said int
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Page/Page column 13
(2011/05/05)
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- FOSAPREPITANT DIMEGLUMINE INTERMEDIATE, NEUTRAL FOSAPREPITANT, AND AMORPHOUS FOSAPREPITANT DIMEGLUMINE AND PROCESSES FOR THEIR PREPARATIONS
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The present invention generally relates to a process for the preparation of fosaprepitant dimeglumine intermediate and its use in the preparation of fosaprepitant dimeglumine; to a neutral form of fosaprepitant in a solid state and processes for the prepa
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- FOSAPREPITANT DIMEGLUMINE INTERMEDIATE, NEUTRAL FOSAPREPITANT, AND AMORPHOUS FOSAPREPITANT DIMEGLUMINE AND PROCESSES FOR THEIR PREPARATIONS
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The present invention generally relates to a process for the preparation of fosaprepitant dimeglumine intermediate and its use in the preparation of fosaprepitant dimeglumine; to a neutral form of fosaprepitant in a solid state and processes for the preparation thereof; and to a stable amorphous fosaprepitant dimeglumine, having a stability at temperatures of about 2°C to about 8°C and at a relative humidity below at least 60%; and a process for the preparation thereof.
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Page/Page column 26
(2010/04/03)
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- PROCESS FOR [3-[3(R)-[(R)-1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]HOXY]-3(S)-(4-FLUOROPHENYL)MORPHOLIN-4-YL-5-OxO-4,5-DIHYDRO-[1,2,4]-TRIAZOL-1-YL PHOSPHONIC ACID
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The present invention is concerned with a process for the preparation of the compound {3-[2(R)-[(1R)-1-[3,5-bis(tri-fluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid, and pharmaceutically acceptable salts thereof. This compound is useful as a substance P (neurokinin-1) receptor antagonist. In particular, the compound is useful e.g., in the treatment of emesis and inflammatory diseases.
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Page/Page column 6-7
(2008/06/13)
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- Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs
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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.
- 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
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p. 1234 - 1241
(2007/10/03)
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