- Method for preparing intermediate of the Fosaprepitant
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The invention discloses a method for preparing an intermediate of the Fosaprepitant, and specifically relates to a new method for preparing a drug 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one, i.e., Aprepitant. The method comprises the steps of: synthesizing a compound (IV) in the presence of a condensation system, and then performing cyclization on the compound (IV) at 139 DEG C or below to obtain the target compound (I). The preparation method is green, environmentally friendly and efficient and has easy industrialization.
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Paragraph 0017; 0030-0039
(2018/05/16)
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- Efficient aprepitant preparation process
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The invention discloses an efficient aprepitant preparation process. The preparation process comprises the steps that firstly, a 2R-[1R-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy)-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl group-2-aminohydrazonyl)-morpholine is prepared from a (2R,3S)-2-[(1R)-1-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy]-3-(4-fluorophenyl)-morpholine hydrochloride; an aprepitant crude is prepared from the 2R-[1R-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy)-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl group-2-aminohydrazonyl)-morpholine; then the aprepitant crude is refined and an aprepitant finished product is obtained. According to the efficient aprepitant preparation process, the prepared aprepitant has the advantages of high recovery rate, good efficacy, low cost of the whole process, safety and no pollution.
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Paragraph 0032-0033; 0044
(2017/08/29)
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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 0042-0044
(2017/04/07)
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- PREPARATION METHOD OF 5-[[2(R)-[1(R)-[3,5-BIS(TRIFLUOROMETHYL) PHENYL]ETHOXY]-3(S)-4-FLUOROPHENYL-4-MORPHOLINYL]METHYL]-1,2-DIHYDRO-3H-1,2,4-TRIAZOLE-3-ONE
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Disclosed is a synthesis method of a compound of formula 1,5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxyl]-3(S)-4-fluorophenyl-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one (i.e. aprepitant), which comprises cyclizing a compound of formula 4 in a solvent, wherein R is C1-C5 alkyl. The intermediate for preparing aprepitant is also disclosed. The present method is especially suitable for industrial production of aprepitant.
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Paragraph 0045; 0046
(2013/05/09)
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- A METHOD OF PREPARING 3- ( ( (2R, 3S) -2- ( (R) -1- (3, 5 -BIS (TRIFLUOROMETHYL) PHENYL) ETHOXY) -3 - (4 - FLUOROPHENYL) MORPHOLINO) METHYL) - 1H- 1, 2, 4 -TRIAZOL- 5 (4H) -ONE (APREPITANT) IN POLYMORPH FORM I OR II
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The present solution relates to a method of preparing aprepitant of formula (1) in the desired crystalline form II or I, wherein the intermediate of formula (12) is extracted with a water immiscible high-boiling solvent selected from an alcohol, ester or ketone and, after washing with water and/or brine, the solution is heated up to the boiling point of the given solvent, which results in cyclization to aprepitant, and, after cooling, the produced aprepitant is isolated.
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Page/Page column 6; 7
(2013/09/26)
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- Synthesis of all enantiomerically pure diastereomers of aprepitant
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Syntheses of all eight enantiomerically pure diastereomers of aprepitant and assignment of absolute configuration at newly generated stereocenters by NMR and X-ray crystallographic analysis were achieved. Copyrigh
- Gangula, Srinivas,Elati, Chandrashekhar R.,Mudunuru, Satish Varma,Nardela, Anitha,Dongamanti, Ashok,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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experimental part
p. 2254 - 2268
(2010/09/11)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT
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The present invention relates to an improved process for the preparation of aprepitant compound of formula- (I) as well as novel polymorphs of its intermediates.
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Page/Page column 10; 14
(2009/10/22)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT
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The present invention relates to an improved process for the preparation of Aprepitant of formula (I) and its intermediates. More particularly the present invention relates to the preparation of 3-(-S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of Formula (III) or its salts thereof by reacting N-benzyl-(S)-(4-fluorophenyl) glycine of formula (II) with 1,2 dibromoethane in presence of an organic base.
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Page/Page column 9
(2009/03/07)
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- A convergent approach to the synthesis of aprepitant: a potent human NK-1 receptor antagonist
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A simple and convergent approach to enantiomerically pure 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one 1, a potent orally active antagonist of the human neurokinin-1 (NK-1) receptor, is described. The synthetic procedure starts from p-fluorobenzaldehyde to access the racemic morpholinone 2 via a modified Strecker synthesis and utilizes a diastereomeric salt resolution technique to accomplish the synthesis of 1 in enantiomerically pure form and good yield.
- Elati, Chandrashekar R.,Kolla, Naveenkumar,Gangula, Srinivas,Naredla, Anitha,Vankawala, Pravinchandra J.,Avinigiri, Muttu L.,Chalamala, Subrahmanyeswararao,Sundaram, Venkatraman,Mathad, Vijayavitthal T.,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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p. 8001 - 8004
(2008/03/14)
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- PREPARATION OF APREPITANT
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A process for preparing aprepitant.
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Page/Page column 36
(2010/11/27)
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- PROCESS FOR PREPARATION OF APREPITANT
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The present invention relates to a highly pure (2R,3S)-4-benzyl-3-(4- fluorophenyl)morpholin-2-yl 3,5-bis(trifluoromethyl)benzoate of Formula II, and a process for its preparation. The present invention further provides a process for preparation of Aprepitant of Formula I or pharmaceutically acceptable salt thereof, using the highly pure compound of Formula II. The present invention also provides a process for preparation of Aprepitant of Formula I or pharmaceutically acceptable salt thereof which comprises of cyclising the compound of Formula VII at elevated temperature, in the absence of solvent.
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Page/Page column 15
(2010/11/26)
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- Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation
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An efficient stereoselective synthesis of the orally active NK1 receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired α-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
- Brands, Karel M. J.,Payack, Joseph F.,Rosen, Jonathan D.,Nelson, Todd D.,Candelario, Alexander,Huffman, Mark A.,Zhao, Matthew M.,Li, Jing,Craig, Bridgette,Song, Zhiguo J.,Tschaen, David M.,Hansen, Karl,Devine, Paul N.,Pye, Philip J.,Rossen, Kai,Dormer, Peter G.,Reamer, Robert A.,Welch, Christopher J.,Mathre, David J.,Tsou, Nancy N.,McNamara, James M.,Reider, Paul J.
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p. 2129 - 2135
(2007/10/03)
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- PROCESS FOR 5-[[2(R)-[1(R)-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY]-3(S)-(4-FLUOROPHENYL)-4-MORPHOLINYL]METHYL]-1,2-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE
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The present invention is concerned with a novel process for the preparation of the compound 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one. This compound is useful as a substance P (neurokinin-1) receptor antagonist. In particular, the compound is useful e.g., in the treatment of psychiatric disorders, inflammatory diseases and emesis.
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Page/Page column 7-8
(2008/06/13)
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