- Preparation methods of aprepitant impurity
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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.
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Paragraph 0105; 0108
(2020/07/13)
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- Synthesis of the major isomers of Aprepitant and Fosaprepitant
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The synthesis of two isomers of Aprepitant (APT) and three isomers of Fosaprepitant (FPT), crucial components for quality control in manufacturing, is described. Herein, three chiral centers in the isomers of Aprepitant are established in high yield by in
- Wan, Wei-Li,He, Yun,Guan, Mei,Li, Xiao-Long,Cheng, Xu,Wu, Yong
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p. 1118 - 1122
(2014/01/06)
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- Chemodivergent synthesis of 7-aryl/alkyl-6-hydroxy-1,4-oxazepan-5-ones and 2-[aryl/alkyl(hydroxy)methyl]morpholin-3-ones from a common epoxyamide precursor
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We present here a regiospecific synthesis of 7-alkyl- or 7-aryl-6-hydroxy-1,4-oxazepan-5-ones and 2-[aryl(hydroxy)methyl]- or 2-(1-hydroxyalkyl)morpholin-3-ones from a diastereomeric mixture of trans-3-alkyl- or -3-aryl-N-(2-hydroxyethyl)-N-(1-phenylethyl)oxirane-2- carboxamides. This chemodivergent synthesis is easily controlled by an appropriate choice of cyclization reaction conditions. Georg Thieme Verlag Stuttgart - New York.
- Aparicio, David M.,Teran, Joel L.,Roa, Luis F.,Gnecco, Dino,Juarez, Jorge R.,Orea, Maria L.,Mendoza, Angel,Flores-Alamo, Marcos,Micouin, Laurent
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scheme or table
p. 2310 - 2320
(2011/09/16)
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- Practical asymmetric preparation of azetidine-2-carboxylic acid
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Facile and straightforward syntheses of both enantiomers of azetidine-2-carboxylic acid are described. The syntheses depart from inexpensive chemicals and allow for the production, in five to six steps, of practical quantities of each enantiomer. Synthetic highlights include the construction of the azetidine ring using an intramolecular alkylation and the use of optically active α-methylbenzylamine as chiral auxiliary.
- Couty, Francois,Evano, Gwilherm,Vargas-Sanchez, Monica,Bouzas, Gloria
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p. 9028 - 9031
(2007/10/03)
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- Syntheses of morpholine-2,3-diones and 2-hydroxymorpholin-3-ones: Intermediates in the synthesis of aprepitant
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The preparation of morpholine-2,3-diones and 2-hydroxymorpholin-3-ones from N-substituted β-amino alcohols is reported. These were useful intermediates in the synthesis and development of aprepitant.
- Nelson, Todd D.,Rosen, Jonathan D.,Brands, Karel M.J.,Craig, Bridgette,Huffman, Mark A.,McNamara, James M.
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p. 8917 - 8920
(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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- Structural studies on bioactive compounds. 34.1 Design, synthesis, and biological evaluation of triazenyl-substituted pyrimethamine inhibitors of Pneumocystis carinii dihydrofolate reductase
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The triazenyl-pyrimethamine derivative 3a (TAB), a potent and selective inhibitor of Pneumocystis carinii DHFR, was selected as the starting point for a lead optimization study. Molecular modeling studies, corroborated by a recent crystal structure determination of the ternary complex of P. carinii DHFR-NADPH bound to TAB, predicted that modifications to the acetoxy residue of the lead inhibitor could exploit binding opportunities in the vicinity of an active site pocket bounded by residues Ile33, Lys37, and Leu72. Substitutions in the benzyl moiety with electron-donating and electron-withdrawing groups were predicted to probe face-edge interactions with amino acid Phe69 unique to the P. carinii enzyme. New triazenes 10a-v and 12a-f were prepared by coupling the diazonium tetrafluoroborate salt 6b of aminopyrimethamine with substituted benzylamines or phenethylamines. The most potent of the new inhibitors against P. carinii DHFR was the naphthylmethyl-substituted triazene 10t (IC50: 0.053 μM), but a more substantial increase in potency against the rat liver DHFR led to a reduction in selectivity (ratio rat liver DHFR IC50/P. carinii DHFR IC50: 5.36) compared to the original lead structure 3a (ratio rat liver DHFR IC50/P. carinii DHFR IC50: 114).
- Chan,Laughton,Queener,Stevens
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p. 2555 - 2564
(2007/10/03)
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- Process for preparation of pyrimidine derivatives
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The present invention relates to a process for preparation of 5,6-dimethyl-2-(4-fluorophenyl-amino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I), STR1 and its acid addition salts by reacting a pyrimidi
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- The Use of Heterocycles for the Conformational Restriction of Biologically Active Peptoids
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A series of piperazinone ring systems have been synthesized as a means of evaluating the effect of conformational restriction of high affinity non-peptide NK1, NK3 and CCK-B receptor ligands.The synthesis of the targeted heterocycles is described along with a discussion of their affinities for their respective receptor types.
- Horwell, David C.,Lewthwaite, Russell A.,Pritchard, Martyn C.,Ratcliffe, Giles S.,Rubin, J. Ronald
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p. 4591 - 4606
(2007/10/03)
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- DERIVATIVES OF OPTICALLY ACTIVE (1-PHENYLETHYL)AMINE IN COMPLEXES WITH LITHIUM ALUMINUM HYDRIDE FOR THE ASYMMETRIC REDUCTION OF A CARBONYL GROUP
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(R)-1-Phenylethanol is formed preferentially in the reduction of acetophenone by the complexes of lithium aluminum hydride with (-)-(2-hydroxyethyl)(1-phenylethyl)amine and (-)-methyl(2-hydroxyethyl)(1-phenylmethyl)amine.
- Potapov, V. M.,Dem'yanovich, V. M.,Maleev, V. I.
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p. 1606 - 1609
(2007/10/02)
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- Phospholipids Chiral at Phosphorus. 5. Synthesis and Configurational Analysis of Chiral Phosphatidylethanolamine
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We report the synthesis and configurational analysis of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) chirally labeled with 17O and 18O at the phosphate head group.Condensation of (S)-1,2-dipalmitoyl-sn-glycerol, P17OCl3, and N-(1-phenylethyl)-2-aminoethanol gives a diastereomeric mixture of cyclic oxazaphospholidines.The two diastereomers were separated by coloumn chromatography.Ring opening with H218O followed by hydrogenolysis with H2/Pd gives (Rp)- and (Sp)-DPPE.The relative configuration and isotopic enrichments of DPPE can be analyzed by 31P NMR following silylation of DPPE.To determine the absolute configuration, the two diastereomers of DPPE are converted, by a combined organic and biochemical procedure, into (Rp)- and (Sp)-1-phospho-(R)-propane-1,2-diol, with all P-O bonds intact.The configuration of the latter compound is then analyzed by 31P NMR as reported previously (Buchwald, S.L.; Knowles, J.R.J.Am.Chem.Soc. 1980, 102, 6601-6603).
- Bruzik, Karol,Tsai, Ming-Daw
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p. 747 - 754
(2007/10/02)
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