- Preparation method of NK1 receptor antagonist
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The invention discloses a preparation method of an NK1 receptor antagonist. According to the invention, chiral resolution adopts a mixed solvent, CaCl2 is added for a reaction in an alkaline environment, CaCl2 does not participate in the reaction but needs to be added in advance for better devitrification, water is added for quenching after the reaction is finished, and CaCl2 is dissolved at the same time, so devitrification efficiency is further improved; and then 5-hydroxymethyl-2,4-dihydro-[1,2,4]triazin-3-one is used as a raw material for synthesis of aprepitant under the catalysis of DBU at room temperature.
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Paragraph 0029; 0031; 0032; 0034; 0035; 0037; 0038; ...
(2021/11/03)
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- Intermediates for preparing aprepitant, and preparation method and application thereof
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The invention belongs to the technical field of compounds and synthesis thereof, and provides intermediates for preparing aprepitant, and a preparation method and an application thereof. The inventionprovides the aprepitant preparation intermediate represented by formula I and the aprepitant preparation intermediate represented by formula II. The aprepitant is prepared from the two intermediatesthrough condensation and reduction reactions. Compared with existing methods for preparing aprepitant, the method of the invention has the advantages of avoiding of the disadvantages of complex reaction process, multiple transition states and multiple byproducts in the intermediate preparation process and the disadvantage of complex quality control, simple synthesis process of aprepitant, enhancement of the safety and process controllability of industrial production, high yield, no pollution, easily available raw materials, simplicity in industrial operation, low energy consumption, low cost,safety and environment friendliness, and is suitable for industrial application.
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- Preparation process of aprepitant
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The invention discloses a preparation process of aprepitant. The process comprises the steps as follows: Step 1, a compound A and a compound B are firstly added to a mixed solvent of N,N-dimethylformamide and triethylamine to be stirred and dissolved to obtain a mixed solution; Step2, adding lithium diisopropylamide to the mixed solution in a nitrogen atmosphere and performing uniform mixing; Step3, dropwise adding a diethyl sulfate xylene solution under conditions of nitrogen shielding and stirring; Step 4, after addition, conducting a stirring reaction at 30-35 DEG C for 12-15 h under shielding of nitrogen; Step 5, separating and purifying a reaction product in Step 4 to obtain a final aprepitant product. By process improvement and formula optimization, the aprepitant synthesis processhas the characteristics of mild reaction condition, low cost and the like and is suitable for large-scale industrial production; the synthesized aprepitant product has low impurity content and high purity, and the yield of aprepitant is greatly increased.
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Paragraph 0038-0094
(2019/03/29)
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- 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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- 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 0045-0047
(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 0043; 0044
(2013/05/09)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT
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The present invention provides a process for the preparation of 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-triazol-3-one (Aprepitant) comprising condensation of 2-(R)-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(S)-(4-fluorophenyl)morpholine hydrochloride salt with 2-(2-chloro-1-iminoethyl)hydrazinecarboxylic acid methyl ester to obtain the reaction mixture containing 2-[2-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4- fluorophenyl)-4-morpholinyl]-1-iminoethyl]hydrazinecarboxylic acid methyl ester, which is in-situ cyclized in the presence of dimethylsulfoxide and a polar protic solvent at a low temperature to yield aprepitant having purity ≥ 99.5%.
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Page/Page column 17
(2013/09/12)
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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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- PREPARATION OF MORPHOLINE DERIVATIVES
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This invention relates to processes and intermediates for the stereoselective morpholine derivatives. The invention in particular allows the stereoselective preparation of the drugs aprepitant and fosaprepitant.
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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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- PROCESS FOR PURIFICATION OF APREPITANT
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The present invention relates to a process for obtaining pure aprepitant substantially free of undesired diastereomeric isomer, namely 5-[2(S)-[I (RS)- [3,5-bis(trifluoromethyl)-phenyl)ethoxy]-3-(S)-(4-fluorophenyl)-morpholin-4-yl- methyl]-3,4-dihydro-2H-1,2,4-triazol-3-one. The present invention further provides an improved process for preparation aprepitant crystalline form II. The present invention also relates to novel amorphous form of aprepitant, process for its preparation and to a pharmaceutical composition comprising it. The present invention further relates to aprepitant having mean particle size of less than about 11.5 microns, process for its preparation and to a pharmaceutical composition comprising it. Thus, for example, aprepitant having the content of diastereomeric impurity of 1.1 % is dissolved in ethyl acetate at 700C, the solution is concentrated to half the initial volume by distilling off ethyl acetate, and the resulting solid is collected at 0 - 50C to give pure aprepitant substantially free of diastereomeric impurity.
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Page/Page column 9-10; 10-11; 11-12
(2008/06/13)
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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 10
(2009/03/07)
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- POLYMORPH FORM OF APREPITANT AND PROCESS FOR THE PREPARATION THEREOF
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Disclosed herein is a novel stable polymorph of aprepitant, designated polymorph Form III. Also disclosed is a process for its preparation and pharmaceutical compositions containing same.
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Page/Page column 15
(2008/06/13)
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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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- 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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- Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction
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A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.
- Zhao, Matthew M.,McNamara, James M.,Ho, Guo-Jie,Emerson, Khateeta M.,Song, Zhiguo J.,Tschaen, David M.,Brands, Karel M. J.,Dolling, Ulf-H,Grabowski, Edward J. J.,Reider, Paul J.,Cottrell, Ian F.,Ashwood, Michael S.,Bishop, Brian C.
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p. 6743 - 6747
(2007/10/03)
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- A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist
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Chlorotriazolinone 4 has been synthesised in a single step via the novel condensation of semicarbazide hydrochloride with orthoester 8. Alkylation of secondary amine 3 with compound 4 proceeds in 99% yield to afford the target NK1 antagonist 1. (C) 2000 Published by Elsevier Science Ltd.
- Cowden,Wilson,Bishop,Cottrell,Davies,Dolling
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p. 8661 - 8664
(2007/10/03)
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