- Synthesis method of (S)-3-pyrrolidinol hydrochloride
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The invention discloses a synthesis method of (S)-3-pyrrolidinol hydrochloride, which belongs to the field of drug synthesis, and comprises the following steps: dehydrating and amidating L-malic acidand benzylamine as raw materials to obtain (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-diketone, and carrying out one-pot reduction, debenzylation and salification to synthesize (S)-3-pyrrolidinol hydrochloride. The method is short in synthetic route, simple to operate, high in yield, good in product purity and beneficial to industrial production.
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Paragraph 0023-0025; 0028-0030; 0033-0035
(2020/08/27)
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- Substituted pyrazolo[1,5-a]pyrimidine compound and pharmaceutical composition and application thereof
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The invention provides a pharmaceutical composition and application of a substituted pyrazolo[1,5-a]pyrimidine compound. The substituted pyrazolo[1,5-a]pyrimidine compound is a compound shows as the formula (I) (please see the specifications for the formula), or pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, polymorphism, stereisomer or isotope variant of the substituted pyrazolo[1,5-a]pyrimidine compound. The substituted pyrazolo[1,5-a]pyrimidine compound can be used for treating diseases which can be treated through a Trk kinase inhibitor.
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Paragraph 0137; 0139; 0140; 0151; 0152
(2019/03/28)
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- 3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: Inhibition of rat intestinal α-glucosidase
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Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97 ± 0.046 and a KI of 1.18 mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ~90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies.
- Carreiro, Elisabete P.,Louro, Patrícia,Adriano, Gizé,Guedes, Romina A.,Vannuchi, Nicholas,Costa, Ana R.,Antunes, Célia M.M.,Guedes, Rita C.,Burke
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- COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
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Provided are indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which LRRK2 kinase is involved. Also provided are pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK2 kinase is involved.
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Page/Page column 101
(2014/09/29)
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- COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
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The present invention is directed to indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.
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Page/Page column 89
(2014/09/29)
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- COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
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Disclosed are indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which LRRK2 kinase is involved. Also disclosed are pharmaceutical compositions in the prevention or treatment of such diseases in which LRRK2 kinase is involved.
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Page/Page column 87; 88
(2014/09/29)
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- COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
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The present invention is directed to indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.
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Page/Page column 104-105
(2014/09/29)
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- Synthesis of novel enantiopure ionic liquids from (S)-malic acid
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A straightforward and practical synthesis of six novel pyrrolidinium salts based on (S)-malic acid is reported. Two of them were liquid at room temperature, and can be employed as novel chiral ionic liquids for enantioselective applications.ARKAT-USA, Inc.
- Bonanni, Marco,Manuelli, Massimo,Goti, Andrea,Faggi, Cristina,Cardona, Francesca
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- A study on the racemization step in the synthesis of pyrrolidinols via cyclic α-hydroxyimides
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Analytical HPLC methods for the determination of the enantiomeric excess of N-protected malimides 1 as well as the corresponding pyrrolidinol 5 and tartarimides 2 and 3 have been established. On this basis, a study to reveal the racemization step in the synthesis of pyrrolidinols from α-hydroxyacids, via chiral cyclic α-hydroxyimides, has been undertaken. It was confirmed that the known, one-step method for the synthesis of the N-protected chiral cyclic imides from α-hydroxydiacids proceeded with little racemization, and partial racemization has been proven to occur during the reduction of the resultant imide 1a with LAH to yield the corresponding pyrrolidinol 5. Conditions have been defined in order to avoid racemization in the LAH reduction step.
- Zheng, Jin-Li,Liu, Hui,Zhang, Yu-Feng,Zhao, Wei,Tong, Jin-Shuan,Ruan, Yuan-Ping,Huang, Pei-Qiang
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scheme or table
p. 257 - 263
(2011/05/12)
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- PROCESS FOR PREPARING 3-SUBSTITUTED PYRROLIDINE COMPOUNDS
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Disclosed is a process for preparing 3 -substituted pyrrolidine compounds of formula (VII) or salts thereof, wherein R1 is described herein, which are intermediate compounds useful for the synthesis of darifenacin which is indicated for the treatment of overactive bladder with symptoms of urge, urinary incontinence, and the like, and pharmaceutically acceptable salts thereof. Also disclosed is a process for preparing darifenacin and pharmaceutically acceptable salts thereof.
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Page/Page column 10
(2010/01/12)
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- Synthesis of racemic and enantiomeric 3-pyrrolidinyl derivatives of nucleobases
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The synthesis of novel 3-pyrrolidinyl derivatives of nucleobases is described. Starting from malic acid, we improved the synthesis of both racemic and optically active N-benzyl-3-hydroxypyrrolidine-2,5-diones, which were transformed in four steps into N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines, the key synthons for the alkylation of purine and pyrimidine nucleobases. Alkylations of cesium salts of purines and sodium salts of pyrimidines with N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines proceeded smoothly, giving high yields of 9-substituted purine derivatives and moderate yields of 1-substituted pyrimidine derivatives. Using (S)-N-tert-butyloxycarbonyl-3-mesyloxypyrrolidine as the same intermediate for the synthesis of both enantiomeric N-Boc-3-pyrrolidinyladenines, and considering the results obtained on chiral HPLC analysis of the products, we proved that nucleophilic displacement of the mesyloxy group proceeded with inversion and not with retention of the configuration. Prepared compounds were tested for cytostatic and antiviral properties, but no significant activity was found.
- Ko?alka, Petr,Pohl, Radek,Rejman, Dominik,Rosenberg, Ivan
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p. 5763 - 5774
(2007/10/03)
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- Synthesis of (R)- and (S)-3-(tert-butyldimethylsilyloxy)-1-pyrroline N- oxides - Chiral nitrones for synthesis of biologically active pyrrolidine derivative, Geissman-Waiss lactone
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Tungstate-catalyzed oxidation of O-tert-butyldimethylsilyl (O-TBDMS) protected (R)-3-hydroxypyrrolidine ((R)2), derived from trans-4-hydroxy-L- proline, gave O-TBDMS protected (R)-3-hydroxy-1-pyrroline N-oxide ((R)1), which is a new chiral precursor for the synthesis of Geissman-Waiss lactone. The enantiomeric nitrone (S)-1 was also prepared by the oxidation of (S)-2 derived from L-malic acid.
- Murahashi, Shun-Ichi,Ohtake, Hiroaki,Imada, Yasushi
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p. 2765 - 2766
(2007/10/03)
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- An easy access to protected (4S, 5R)-5-alkyl-4-hydroxy-2-pyrrolidinones and their use as versatile synthetic intermediates
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A versatile approach to enantiopure (4S, 5R)-5-alkyl-4-hydroxy-2- pyrrolidinones is described. The key steps involve a regioselective Grignard reagent addition to (S)-malimides, and diastereoselective reductive dehydroxylation of the resulting hemi-azaketals. The flexibility of this methodology has been demonstrated by the synthesis of (2R, 3R)-3-amino-1- benzyl-2-methylpyrrolidine, the parent diamine of antipsychotic agent, emonapride, and the unnatural enantiomer of the β-hydroxy-γ-amino acid residue of hapalosin in lactam form.
- Huang, Pei Qiang,Wang, Shi Li,Ye, Jian Liang,Ruan, Yuan Ping,Huang, You Qing,Zheng, Hong,Gao, Jing Xing
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p. 12547 - 12560
(2007/10/03)
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- Preparative and structural chemistry of chiral 3-(diphenylphosphanyl)pyrrolidines and their palladium(II) complexes
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The preparation of both enantiomers of 3-diphenylphosphanylpyrrolidine (2) and several N-substituted derivatives together with two Pd complexes of this ligand is reported. From L-malic acid and L-hydroxyproline both enantiomers of 3-hydroxypyrrolidine are prepared without any problems due to epimerization. KPPh2 in the presence of LiCl is shown to be the most effective reagent for the synthesis of 2. The reported X-ray structure determinations of PdI2 complexes show a rather rigid bicyclic hetero-norbornane skeleton. The flexibility of the other parts of the molecules is obvious in several polymorphs revealed by this method. This polymorphism is additionally investigated by a 31P-CP-MAS study. From solution 'H-, 13C- and 31P-NMR studies it is concluded that the bicyclic hetero-norbornane skeleton is retained in solution. VCH Verlagsgesellschaft mbH.
- Nagel, Ulrich,Nedden, Hans Guenter
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p. 385 - 397
(2007/10/03)
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- First asymmetric synthesis of (2R,3R)-3-amino-1-benzyl-2-methylpyrrolidine via a highly diastereoselective reductive alkylation
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The first asymmetric synthesis of (2R,3R)-3-amino-1-benzyl-2-methylpyrrolidine, the parent diamine of antipsychotic agent, emonapride, from (S)-malic acid was achieved via a highly diastereoselective reductive alkylation.
- Huang, Pei Qiang,Wang, Si Li,Zheng, Hong,Fei, Xiang Su
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p. 271 - 272
(2007/10/03)
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- Lipase-catalyzed practical synthesis of (R)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione and its related compounds
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A practical method for preparing (R)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (1) was investigated by the use of the enzymatic hydrolysis of its acetate (2a). Among several hydrolases examined here, lipase PS from Pseudomonas cepacia gave the best result: In a mixed solvent (1:1 v/v) of dioxane and a phosphate buffer (pH 7), the hydrolysis took place smoothly with a high enantioselectivity (E > 3000). Several 3-alkanoyl derivatives of 1 were subjected to the lipase PS-catalyzed hydrolysis. The chain length of the alkanoyl does not noticeably influence the reaction rate or the enantioselectivity. In contrast, the hydrolysis of the 1-benzoyl derivative proceeded slowly with a low enantioselectivity (E = 19). The syntheses of optically active 3-hydroxypyrrolidines and 3-hydroxypiperidines were also achieved under the reaction conditions similar to the lipase PS-catalyzed hydrolysis of 2a.
- Tomori, Hiroshi,Shibutani, Kuniko,Ogura, Katsuyuki
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p. 207 - 215
(2007/10/03)
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- Method of producing optically active pyrrolidines with high enantiomeric purity
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A method of producing optically active pyrrolidines of the general formula STR1 in which R1 is hydrogen or OH, R2 is a benzyl group which can have one or more alkyl-, alkoxy- and/or halogen substituents on the aromatic, and * is and/or can be an asymmetric center, by reducing the corresponding, enantiomerically pure pyrrolidinediones using activated alkali boron hydride.
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- Stereoselectivity of a Potent Calcium Antagonist, 1-Benzyl-3-pyrrolidinyl Methyl 2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
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Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated.The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a*HBr as well as 3a*HCl.The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation.The potency order of the four enantiomers was (S,S)-3a > (S,R)-3b > (R,R)-3d > (R,S)-3c.Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a*HCl or 3a*HBr.On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5.The conformational restriction may be a factor causing stereoselectivity of antagonism.
- Tamazawa, Kazuharu,Arima, Hideki,Koijma, Tadao,Isomura, Yasuo,Okada, Minoru,et al.
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p. 2504 - 2511
(2007/10/02)
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- SYNTHETIC ROUTES TO CHIRAL 3-PYRROLIDINOLS
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Short convenient syntheses of chiral 3-pyrrolidinols and related compounds are described.
- Bhat, Krishna L.,Flanagan, Denise M.,Joullie, Madeleine M.
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p. 587 - 598
(2007/10/02)
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