- Asymmetric hydrogenation of itaconic acids with rhodium(I)-phenyl-CAPP complex; a correction
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Asymmetric hydrogenation of itaconic acids 2 under homogeneous catalysis of neutral Rh-complex 3 gives substituted succinic acids 4 of (S)-configuration with > 95% ee.
- Jendralla
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Read Online
- A kind of improved mitiglinide industrial preparation method
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The invention provides an improved mitiglinide calcium (I) preparation method, and is characterized in that the preparation method successively comprises the steps: step 1, preparation of 2-benzyl succinic acid; step 2, preparation of (S)-2-benzyl succinic acid; step 3, preparation of 2-(S)-benzyl-4-oxo-(cis-perhydroisoindole-2-yl)butyric acid; and step 4, preparation of mitiglinide calcium. The invention provides the mitiglinide calcium industrialized preparation method having the advantages of being economical and practical, simple to operate, short in reaction period and high in yield.
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Paragraph 0035; 0038
(2017/08/25)
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- Preparation method of (S)-2-benzylsuccinic acid
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The invention provides a preparation method of (S)-2-benzylsuccinic acid, and relates to a method for preparing (S)-2-benzylsuccinic acid from (R)-2-benzylsuccinic acid. After EDTA is added in an alkaline aqueous solution containing the (R)-2-benzylsuccinic acid, racemization can be implemented effectively. By the method provided by the invention, the (S)-2-benzylsuccinic acid can be prepared from a solution of 2-benzylsuccinic acid (R)-alpha-phenylethanammonium generated in a production process of mitiglinide calcium, and economic benefit is improved further.
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Paragraph 0024; 0025; 0026; 0027
(2016/12/01)
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- 5-AMINO-4-CARBAMOYL-PYRAZOLE COMPOUNDS AS SELECTIVE AND IRREVERSIBLE T790M OVER WT-EGFR KINASE INHIBITORS AND USE THEREOF????
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Disclosed are compounds of Formula (I), pharmaceutical compositions comprising the same, processes for the preparation thereof, and the use thereof.
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Paragraph 0197
(2016/03/13)
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- A practical and efficient preparation of (S)-2-benzylsuccinic acid: A key acid synthon of KAD-1229
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This report describes a practical and an efficient synthesis of (S)-2-benzyl-succinic acid, which was employed as a key intermediate for hypoglycemic KAD-1229 by means of asymmetric alkylation of N-acylsultam. The condensation of D-(-)-camphorsultam with 3-phenylpropionyl chloride gave N-acylsultam 1. N-acylsultam 1 reacted with 1.1 equimolar amount of sodium amide base to form chiral enolate, followed by alkylation with tert-butyl bromoacetate to afford 2. Cleavage of ester and saponification with H 2O2-LiOH provided the desired compound 5 with excellent yield and high optical purity.
- Liu, Jian-Chao,Yang, Yu-She,Ji, Ru-Yun
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p. 2633 - 2640
(2007/10/03)
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- Diastereoselective conjugate addition of Grignard reagents to a homochiral fumaramide derived from Oppolzer's sultam
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Conjugate addition of Grignard reagents to N,N′-fumaroylbis[(2R)- bornane-10,2-sultam] 1 occurred with moderate to high levels of diastereoselectivity. Diastereomeric excesses were estimated by analysis of the 1H NMR spectra of the succinamide mixtures and enantiomeric excesses from 19F NMR spectra of the bis Mosher esters of the diols produced by reductive cleavage of the succinamides. Saponification of the succinamides gave the corresponding (R)-succinic acids with ees up to 92% showing that addition of the Grignard reagents takes place selectively on the re-face of 1.
- Reid, Gary P.,Brear, Kieron W.,Robins, David J.
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p. 793 - 801
(2007/10/03)
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- Preparation of (R)-(-)- and (S)-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of new CNS drugs, via resolution of precursors
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The preparation of (R)-(-)- and (S)-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of new CNS drugs in the aminobutyrophenone family, has been developed via classical resolutions or lipase-catalyzed kinetic resolution of one of their precursors.
- Caro, Yolanda,Masaguer, Christian F.,Ravina, Enrique
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p. 381 - 387
(2007/10/03)
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- (S)-3-methyl-2-phenylbutylamine, a versatile agent to resolve chiral, racemic carboxylic acids
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(S)-Ibuprofen 2, (S)-ketoprofen 3, and (S)-naproxen 4 are all obtained by optical resolution of the respective racemates with (S)-3-methyl-2-phenylbutylamine (PBA) 1: (S)-2, 98.7% ee, 39.8% yield; (S)-3, 99.4% ee, 36.7% yield; (S)-4, 99.2% ee, 35.1% yield. (S)-PBA 1 is also useful in resolving other racemic carboxylic acids of pharmaceutical importance; (R)-2-hydroxy-4-phenylbutanoic acid (HPBA) 5, a key intermediate for ACE inhibitors such as benazapril 7, and (S)-2-benzylsuccinic acid (BSA) 6, a key intermediate for hypoglycemic KAD-1229 8, are obtained in 99% ee and 34.4% yield, and in 99% ee and 32.2% yield, respectively.
- Chikusa, Yasuo,Fujimoto, Taizo,Ikunaka, Masaya,Inoue, Toru,Kamiyama, Shunji,Maruo, Koichi,Matsumoto, Jun,Matsuyama, Keisuke,Moriwaki, Masafumi,Nohira, Hiroyuki,Saijo, Shigeya,Yamanishi, Masato,Yoshida, Kazuto
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p. 291 - 296
(2013/09/06)
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- Preparation of optically active succinic acid derivatives. II. Efficient and practical synthesis of KAD-1229
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For large-scale synthesis of monocalcium bis[(2s)-2-benzyl-3-(cis- hexahydroisoindolin-2-ylcarbonyl)propionate]dihydrate (1, KAD-1229), we investigated regioselective reactions of (S)-2-benzylsuccinic acid (2) with cis-hexahydroisoindoline (4). It was difficult to obtain a half amide regioselectively through coupling reaction of the (S)-acid 2 with the amine 4. Therefore, the succinic acid 2 was converted to bis-activated esters 3a-c and these were reacted with 4 to give the amides 5a-c in good yields, regioselectively. The amides 5a-c were derived to KAD-1229, which has a potent hypoglycemic effect, in good yields.
- Yamaguchi, Toshiaki,Yanagi, Takashi,Hokari, Hiroshi,Mukaiyama, Yuko,Kamijo, Tetsuhide,Yamamoto, Iwao
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p. 337 - 340
(2007/10/03)
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- First asymmetric synthesis of the Kelatorphan-like enkephalinase inhibitor (1S,2R,2′S)-2-[2′-(N-hydroxycarbamoylmethyl)-3′- phenylpropionylamino]cyclohexane-1-carboxylic acid
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The first asymmetric synthesis of Kelatorphan-like enkephalinase inhibitor (1S,2R,2′S)-2-[2′-(N-hydroxycarbamoylmethyl)-3′- phenylpropionylamino]cyclohexane-1-carboxylic acid is achieved using lithium amide (R)-5 and pyrrolidinone auxiliary (R)-6; the pyrrolidinone auxiliary is used to create (2S)-benzylsuccinic acid derivative (S)-4 while lithium amide (R)-5 is used to synthesize tert-butyl (1S,2R)-2-aminocyclohexanecarboxylate 3.
- Davies, Stephen G.,Dixon, Darren J.
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p. 2629 - 2634
(2007/10/03)
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- Enantioselective alkylation of lactams and lactones via lithium enolate formation using a chiral tetradentate lithium amide in the presence of lithium bromide
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Enantioselective alkylation of lactams and lactones can be realized up to 98% ee by deprotonation with a chiral tetradentate lithium amide (4b) in the presence of lithium bromide, and subsequent alkylation with active alkylating agents in non-chelating solvents.
- Matsuo, Jun-Ichi,Kobayashi, Shu,Koga, Kenji
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p. 9723 - 9726
(2007/10/03)
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- Synthetic study of AAL-toxins: Efficient construction of two vicinal diol moieties by asymmetric dihydroxylation
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Asymmetric dihydroxylation has been applied to syntheses of two vicinal anti-diol moieties in key intermediates of AAL-toxins. The strategy allowed efficient construction of left- and right segments of AAL-toxin main chain.
- Oikawa, Hideaki,Kagawa, Takashi,Kobayashi, Tomonori,Ichihara, Akitami
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p. 6169 - 6172
(2007/10/03)
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- Mechanistic aspects of the rhodium-catalyzed enantioselective transfer hydrogenation of α,β-Unsaturated carboxylic acids using formic acid/triethylamine (5:2) as the hydrogen source
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The mechanism of the rhodium-catalyzed enantioselective transfer hydrogenation of methylenebutanedioic acid (itaconic acid) (1) and related α,β-unsaturated carboxylic acids using formic acid/triethylamine (5:2) as the hydrogen source is investigated. Kinetic studies using 1H NMR spectroscopy are presented. Formic acid decomposition is shown to be the rate-limiting step with 1 as the substrate, while hydrogen transfer turns out to be rate determining in the case of (E)-(phenylmethylene)butanedioic acid ((E)-phenylitaconic acid) (3). Furthermore, extensive use is made of deuterium labeling and the analysis of part-deuterated products by 1H and 13C{1H,2H} NMR spectroscopy. Firstly it is demonstrated that transfer deuteration of (E)-phenylitaconic acid (3) using DCO2D as the deuterium source leads to (2R*,1′S*)-2-deuterio-2-(1′-deuteriophenylmethyl) butanedioic acid (9d) as the only isotopomer. The same isotopomer is obtained using gaseous D2 under otherwise identical conditions. Use of HCO2D or DCO2H leads to a mixture of d0, d1, and d2 isotopomers 9a-d. Further information is obtained from the transfer hydrogenation of (RS)-, (R)-, and (S)-2-methylene-3-methylbutanedioic acid (β-methylitaconic acid) (4a) with the asymmetric in-situ catalyst 8 consisting of [Rh(norbornadiene)Cl]2 and (2S,4S)-1-(tert-butoxycarbonyl)-4-(diphenylphosphino)-2-((diphenylphosphino) methyl)pyrrolidine (bppm). The pure enantiomers react at rates differing only by a factor of 2, but kinetic resolution of the racemate is efficient with a selectivity factor of 18. Additionally, the reaction of HCO2NH4 or HCO2K with intermediates [Rh(dppe)Ln]+ (dppe = 1,2-bis(diphenylphosphino)ethane; L = MeOH, n = 2, 11; L = methyl α-acetamidocinnamate, n = 1, 12) of the catalytic cycle of hydrogenation using gaseous hydrogen is followed by 31P NMR spectroscopy at variable temperature. No indication of a formate coordination to rhodium is observed in these experiments. Taken together, these results indicate that the mechanism of rhodium-catalyzed transfer hydrogenation with formic acid/triethylamine as the hydrogen source most likely involves decarboxylation of a transient formate species to form hydridic complexes of rhodium, in which the Rh-H entity has a long lifetime relative to hydrogen transfer to the substrate.
- Leitner, Walter,Brown, John M.,Brunner, Henri
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p. 152 - 159
(2007/10/02)
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- Asymmetric hydrogenation of prochiral carboxylic acids and functionalized carbonyl compounds catalysed by ruthenium(II)-binap complexes with aryl nitriles (binap=(R)- or (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)
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Complexes RuCl2(ArCN)2(binap), II (binap=(R)- or (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; ArCN=benzonitrile, a; 2-furancarbonitrile, b; pentafluorobenzonitrile, c) were prepared, and their solution properties were investigated by 31P NMR measurements.The catalytic aactivities and enantioselectivities for IIa-c catalysed hydrogenation of some prochiral acids were very similar to those provided by Ru2Cl4(binap)2(NEt3), I.In the hydrogenation of β-functionalized carbonyl compounds, however, IIa-c showed considerably lower activities and/or selectivities, compared with complex I.The differences in IIa-c catalysed reactions are discussed in relation to the coordinating abilities of ArCN in II.
- Shao, Liming,Takeuchi, Kasumi,Ikemoto, Makoto,Kawai, Toshiyasu,Ogasawara, Masamichi,et al.
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p. 133 - 147
(2007/10/02)
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- Asymmetric hydrogenation of prochiral carboxylic acids catalyzed by the five-coordinate ruthenium(II)-hydride complex PF6 (binap = (R)- or (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)
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The five-coordinate complex PF6 (1, binap = (R)- or (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) has been found to have sufficient catalytic activity for asymmetric hydrogenation of itaconic acid and other prochiral carboxylic acids under mild conditions.The catalytic hydrogenation of itaconic acid by I was examined under a variety of conditions, and the addition of triethylamine was found to effect high enantioselectivities (above 90percent ee). 1H and 31 P NMR examinations of reaction mixtures of I and itaconic acid under conditions similar to the hydrogenation suggested the formation of ruthenium species containing one binap chelate.
- Saburi, Masahiko,Takeuchi, Hiroshi,Ogasawara, Masamichi,Tsukahara, Touru,Ishii, Youichi,et al.
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p. 155 - 167
(2007/10/02)
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- HIGHLY EFFICIENT ASYMMETRIC HYDROGENATION OF ITACONIC ACID DERIVATIVES CATALYZED BY A MODIFIED DIOP-RHODIUM COMPLEX
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A modified DIOP analogue bearing 4-methoxy and 3,5-dimethyl groups on each phenyl group has been synthesized.The rhodium complex of the ligand has been found to give very high optical yields in the asymmetric hydrogenation of itaconic acid and its derivatives bearing β-aryl groups, the products of which are key-intermediates for optically active lignan derivatives.
- Morimoto, Toshiaki,Chiba, Mitsuo,Achiwa, Kazuo
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p. 735 - 738
(2007/10/02)
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- Asymmetric Hydrogenation of Prochiral Alkenes Catalysed by Ruthenium Complexes of (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
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Two chiral ruthenium(II) complexes containing (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl were found to be effective catalysts for the asymmetric hydrogenation of 2-acylaminoacrylic and 2-acylaminocinnamic acids under mild conditions, to afford N-acyl-(R)-α-amino acids with 49 - 95 percent optical purity.The differences between the asymmetric hydrogenations effected by RuII- and RhI-(R)-BINAP systems are discussed.Asymmetric hydrogenation of methylenesuccinic acid and its derivatives with Ru-(R)-BINAP is also described.
- Kawano, Hiroyuki,Ikariya, Takao,Ishii, Youichi,Saburi, Masahiko,Yoshikawa, Sadao,et al.
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p. 1571 - 1575
(2007/10/02)
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- RUTHENIUM(II)-BINAP COMPLEX CATALYZED ASYMMETRIC HYDROGENATION OF UNSATURATED DICARBOXYLIC ACIDS
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Asymmetric hydrogenation of unsaturated dicarboxylic acids employing ruthenium-BINAP complexes as catalyst gave optically active 2-alkylsuccinic acids with high enantioselectivities.
- Kawano, Hiroyuki,Ishii, Youichi,Ikariya, Takao,Saburi, Masahiko,Yoshikawa, Sadao,et. al
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p. 1905 - 1908
(2007/10/02)
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- Stereospecific and Stereoselective Reactions. V. Alkylation of Active Methylene Compounds by the Use of Alcohols, Diethyl Azodicarboxylate, and Triphenylphosphine
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The reagent formed by the reaction of diethyl azodicarboxylate (1) and triphenylphosphine (2) reacted with alcohols and ethyl cyanoacetate (6) to give alkylated products in 30 - 80percent yields.When ethyl acetoacetate, 1,3-1,3-coclopentanedione, or 1,3-cyclohexanedione was used in place of 6, the corresponding O-alkylated products were obtained.The reaction of either (S)-(-)-ethyl lactate or (S)-(-)-ethyl 2-hydroxy-3-phenylpropionate with 1, 2, and 6, followed by hydrolysis resulted in the formation of (S)-(-)-methylsuccinic acid or (S)-(-)-benzylsuccinic acid.The results indicate that nearly complete inversion of the configuration takes place in the alkylation step.
- Kurihara, Toshio,Sugizaki, Masaru,Kime, Itaru,Wada, Makoto,Mitsunobu, Oyo
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p. 2107 - 2112
(2007/10/02)
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