- Understanding the origin of unusual stepwise hydrogenation kinetics in the synthesis of the 3-(4-fluorophenyl)morpholine moiety of NK1 receptor antagonist aprepitant
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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
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Read Online
- 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 0044-0045
(2021/11/03)
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- Preparation method of aprepitant intermediate
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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.
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Paragraph 0041-0083
(2020/04/22)
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- Reduction of organic compounds with low amounts of hydrogen
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The present invention relates to a process for the reaction of a compound with hydrogen wherein the reaction is conducted using a hydrogen-containing gas comprising up to about 10 vol.% hydrogen and at least about 90 vol.% of an inert gas and wherein the
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Page/Page column 9
(2011/06/23)
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- REDUCTION OF ORGANIC COMPOUNDS WITH LOW AMOUNTS OF HYDROGEN
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The present invention relates to a process for the reaction of a compound with hydrogen wherein the reaction is conducted using a hydrogen-containing gas comprising up to about 10 vol.% hydrogen and at least about 90 vol.% of an inert gas and wherein the
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Page/Page column 11
(2011/06/23)
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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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Page/Page column 17-18
(2009/10/21)
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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 35
(2010/11/27)
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- Mammalian metabolites of a tachykinin receptor antagonist
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This invention is concerned with mammalian metabolites of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist that is useful
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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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- 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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- MORPHOLINE AND THIOMORPHOLINE TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis, and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.
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- MORPHOLINE AND THIOMORPHOLINE TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis, and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.
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- PROCESS FOR PREPARING MORPHOLINE TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis, and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.
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- MORPHOLINE COMPOUNDS ARE PRODRUGS USEFUL AS TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, and emesis.
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- TREATMENT OF EMESIS WITH MORPHOLINE TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, emesis and nausea.
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