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287930-75-0Relevant academic research and scientific papers
Production process of aprepitant key intermediate
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, (2022/03/27)
The invention relates to the field of chemical pharmacy, in particular to a production process of an aprepitant key intermediate, which comprises the following steps: dissolving a glyoxylic acid aqueous solution in tetrahydrofuran, adding benzyl ethanolamine, distilling to recover tetrahydrofuran, crystallizing, filtering, washing and drying to obtain an intermediate AR-B; dissolving the intermediate AR-B in acetonitrile, adding trifluoroacetic anhydride and boron trifluoride acetonitrile, carrying out reduced pressure distillation to obtain acetonitrile, carrying out extraction, washing, configuration overturning and acetic acid quenching, adding a sodium bicarbonate solution, and carrying out extraction, filtration, washing and drying to obtain an intermediate AR-0; dropwise adding a tetrahydrofuran solution of p-phenylfluoro magnesium bromide into a mixture of the intermediate AR-0 and tetrahydrofuran, adding methanol and toluenesulfonic acid, filtering, adding toluenesulfonic acid and palladium carbon, hydrogenating, filtering out palladium carbon, extracting, washing and drying to obtain the key intermediate AR-1. The synthesis efficiency of the aprepitant key intermediate can be effectively improved, and the production cost is reduced.
Preparation methods of aprepitant impurity
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, (2020/07/13)
The invention discloses preparation methods of an aprepitant impurity, which comprise isomer impurity synthesis method of six aprepitant key intermediates (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl)-phenyl] ethoxy]-3-(4-fluorophenyl) morpholine, respectively, synthesis of four diastereomer impurities, synthesis of one enantiomer impurity and synthesis of one by-product impurity. The methods have the beneficial effects that the five synthesis methods are simple and feasible, the raw materials are easy to obtain, the conditions are mild, the cost is low, the production is facilitated, and meanwhile, the isomer impurities of the synthesized aprepitant key intermediate provide a new intermediate raw material for the preparation of aprepitant.
A preparation method of the midbody arab league swiss tanzania (by machine translation)
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Paragraph 0025; 0028; 0029; 0032; 0033; 0036; 0037; 0040, (2019/04/14)
The invention discloses a method of preparing intermediates of arab league swiss tanzania, the method to (R)- 1 - [3, 5 - di (trifluoromethyl) phenyl] ethanol as the starting material, and trifluoroacetic anhydride reaction the compound of formula II, the formula II compound in the catalyst and under strongly alkaline conditions with 4 - benzyl - 2 - hydroxy - morpholine - 3 - one the response results in the type I the target compound (2 R) - 4 - benzyl - 2 - [(1 R) - 1 - [3, 5 - double-(trifluoromethyl) phenyl] ethoxy] morpholine - 3 - one. The method of simple process steps, operation is simple and easy, the resulting product has high purity, high yield, low production cost, and the reagent for economic and environmental protection, and is suitable for industrial production. (by machine translation)
Method for separating morpholone isomer
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Paragraph 0045-0047, (2019/01/04)
The invention discloses a method for separating morpholone isomer. The method comprises the following steps: under the action of a solvent, recrystallizing the morpholone isomer; wherein the solvent is selected from one or more kinds of solvents including an ether solvent, an alcohol solvent and an alkane solvent; the morpholine isomer refers to a mixture containing a compound 1 and a compound 2,the molar ratio of the compound 1 to the compound 2 is 6:4-99.8:0.02. By using the method, the yield of the compound 1 is high, and the purity is good, the operation is simple, the cost is low, the environment-friendly effect is achieved, and the method is more suitable for industrial production.
Preparation method of morpholine derivative
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Paragraph 0039; 0040; 0041; 0042; 0043; 0044; 0045-0065, (2017/08/28)
The invention provides a preparation method of a morpholine derivative represented as the formula (I), wherein the preparation method includes the steps of: (1) dissolving trialkyl (aryl) phosphine, azodicarboxylic acid diester, (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol, and (R)-4-benzyl-2-hydroxyl-morpholine-3-one in a reaction solvent; (2) adding the azodicarboxylic acid diester so that the trialkyl (aryl) phosphine and the azodicarboxylic acid diester are subjected to an addition reaction quickly in the reaction solvent to generate zwitter-ions, which are then converted into quaternary phosphonium salt by means of a hydrogen proton supplied by the hydroxyl group in the (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol; (3) enabling the hydroxyl group on the 2-position of the (R)-4-benzyl-2-hydroxyl-morpholine-3-one to be reacted with the quaternary phosphonium salt to generate morpholine oxy-phosphonium salt; and (4) with the (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol, which loses the hydrogen proton, as a nucleophilic reagent, performing an SN2 reaction with the morpholine oxy-phosphonium salt to obtain a product which has turned configuration. The method has high stereo-selectivity, avoids generation of an isomer byproduct during the reaction process, and reduces the load of separation and purification of the product in the later period.
Aprepitant intermediate and preparation method thereof
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Paragraph 0040-0041, (2017/04/22)
The invention relates to the technical field of medicinal chemical production, in particular to an aprepitant intermediate and a preparation method thereof. The preparation method comprises the following preparation steps: by using 4-benzyl-2-hydroxy-morpholine-3-ketone II and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl alcohol III as raw materials, making a condensation reaction under the effect of a catalyst to obtain a compound IV; adding the obtained compound IV into a Grignard reagent to make a Grignard reaction; converting the compound IV into a compound V under reducing conditions; making a hydrochlorination reaction on the obtained compound V to obtain a target compound I. The aprepitant intermediate and the preparation method have the advantages that the preparation flow process is simple; the total effectiveness is high; the intermediate purification is convenient; the purity of a target product is high, and the like. The aprepitant intermediate and the preparation method are suitable for industrial production.
A kind of preparation method of dimethyl luck Sha Pitan cyclophosphadenosine
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Paragraph 0031; 0034-0036, (2017/04/07)
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.
A process for the preparation of intermediates luck Sha Pitan
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Paragraph 0020; 0024; 0025; 0026; 0027, (2019/02/02)
The invention relates to a method for preparing a fosaprepitant intermediate which is a compound shown in a formula (I). The method includes the steps of reacting a compound in a formula (II) and glyoxylic acid to generate a compound in a formula (III), reacting the compound in the formula (III) and (R)-1-(3,5-bi(trifluoromethyl) phenyl) ethanol, and then separating and purifying. According to the method, preparation steps are simple, the reaction yield is high, and the fosaprepitant intermediate is suitable for large-scale production of medical industry.
Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation
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.
, p. 2129 - 2135 (2007/10/03)
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.
