- Preparation method of aprepitant key intermediate
-
The invention provides a preparation method of an aprepitant key intermediate, which comprises the following steps: S1) carrying out a Grignard reaction on (2R)-4-benzyl-2-[(1R)-1-[3, 5-bis(trifluoromethyl) phenyl] ethyoxyl] morpholine-3-ketone and 4-fluo
- -
-
Paragraph 0046-0065
(2021/06/12)
-
- Preparation methods of aprepitant impurity
-
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.
- -
-
Paragraph 0105; 0114-0117
(2020/07/13)
-
- Preparation method of aprepitant intermediate
-
The invention provides a preparation method of an aprepitant intermediate, and belongs to the technical field of chemical synthesis. According to the invention, (2R)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyoxyl]-3-bromomorpholine is subjected to Suzuki coupling reaction to obtain (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyoxyl]-3-(4- fluorophenyl) morpholine; reacting (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyoxyl]-3-(4- fluorophenyl) morpholine with hydrochloric acid to obtain the aprepitant intermediate (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl) morpholine hydrochloride. In the preparation process, environmental humidity and oxygen content do not need to be controlled, hydrogenation is not needed, operation is safer, simpler and more convenient, industrial scale-up production is easy, few byproducts are produced in the reaction process, and the purity of aprepitant prepared from the obtained key intermediate I is higher.
- -
-
Paragraph 0084-0092
(2020/04/22)
-
- Intermediates for preparing aprepitant, and preparation method and application thereof
-
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.
- -
-
Paragraph 0127-0161
(2020/02/20)
-
- High-purity aprepitant preparation method
-
The invention discloses a high-purity aprepitant preparation method, which specifically comprises: 1, carrying out a reaction on (R)-4-benzyl-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)morpholine-3-one, tetrahydrofuran and 4-fluorophenyl magnesium bromide, carrying out a reaction on the reaction solution, a toluenesulfonic acid monohydrate and a catalyst, leaching with methanol, adding othersubstances, and adding hydrochloric acid, 4-methyl-2-pentanone, ethanol and n-heptane into the organic layer of the product to obtain (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorobenzene)morpholine hydrochloride; and 2, dissolving the product obtained in the step 1 in an alcohol solvent and a reverse solvent, heating until the solution is clear, cooling, and crystallizing toobtain the finished product. According to the invention, the preparation method is easy to control, the purity of the prepared (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorobenzene) morpholine hydrochloride can reach more than 99.5%, the defluorination impurity content is lower than 0.05%, and the purity of the prepared finished product can reach more than 99.9%.
- -
-
Paragraph 0020-0025
(2020/01/25)
-
- Aprepitant intermediate and preparation method thereof
-
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.
- -
-
Paragraph 0040-0041
(2017/04/22)
-
- A kind of preparation method of dimethyl luck Sha Pitan cyclophosphadenosine
-
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 convergent approach to the synthesis of aprepitant: a potent human NK-1 receptor antagonist
-
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
-
p. 8001 - 8004
(2008/03/14)
-
- Understanding the origin of unusual stepwise hydrogenation kinetics in the synthesis of the 3-(4-fluorophenyl)morpholine moiety of NK1 receptor antagonist aprepitant
-
An efficient and highly stereoselective one-pot Grignard addition/hydrogenation procedure is a key step in the synthesis of the NK 1 receptor antagonist aprepitant. The critical influence of pH on the nature and stability of the intermediate Grignard adducts, along with their reactivity in the hydrogenation reaction, is described. The observation of a defluorinated impurity under hydrogen-starved conditions led to mechanistic studies that revealed unusual kinetics in the hydrogenation reaction. Detailed analysis of the kinetic profiles under hydrogen-starved conditions indicated the two steps of the reaction, debenzylation of the Grignard adducts and reduction of the incipient imine, occurred in near perfect stepwise fashion wherein the debenzylation reaction was essentially complete before any imine reduction took place. Under hydrogen-saturated conditions the inhibition of the imine reduction was less complete, but the partial buildup of reactive imine intermediate led to a dramatic spike in reaction rate toward the end of reaction. Possible mechanistic rationales to explain these observation are discussed.
- Brands, Karel M. J.,Krska, Shane W.,Rosner, Thorsten,Conrad, Karen M.,Corley, Edward G.,Kaba, Mahmoud,Larsen, Robert D.,Reamer, Robert A.,Sun, Yongkui,Tsay, Fuh-Rong
-
p. 109 - 117
(2012/12/21)
-
- Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation
-
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.
-
p. 2129 - 2135
(2007/10/03)
-
- Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction
-
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.
-
p. 6743 - 6747
(2007/10/03)
-