- Further evidence on the PET cyclization of α-silylmethylamines tethered with non-activated olefins: Demonstration by the total synthesis of (-)-retronecanol
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The total synthesis of (-)-retronecanol, in order to provide convincing evidence for the PET cyclization of α-trimethylsilylmethyl amines with tethered non-activated olefins, is reported.
- Pandey, Ganesh,Chakrabarti, Debasish
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Read Online
- Enantioselective addition of diethylzinc to aromatic aldehydes catalysed by chiral ligands derived from L-hydroxyproline
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The lithium salts of chiral auxiliaries 2-4 derived from L-hydroxyprolin (2S,4R)-1 catalysed the enantioselecive addition of diethylzinc to aromatic aldehydes to afford sec alcohols in up to 80% optical purity.
- Mehler,Martens,Wallbaum
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Read Online
- Synthesis of (3R)-carboxy pyrrolidine (a β-proline analogue) and its oligomer
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A decamer of a β-amino acid analogue of L-proline, (3R)-carboxy pyrrolidine (β-proline), was synthesized from a readily available (R)-glycidol. It was found to possess a rigid secondary structure, as evidenced by its CD spectrum. The β-proline decamer, however, failed to bind to profilin, whereas the corresponding α-L-proline decamer bound tightly to this protein. (C) 2000 Published by Elsevier Science Ltd.
- Kim, Yong Jip,Kaiser, Donald A.,Pollard, Thomas D.,Ichikawa, Yoshitaka
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- A NOVEL DECARBOXYLATION OF α-AMINO ACIDS. A FACILE METHOD OF DECARBOXYLATION BY THE USE OF 2-CYCLOHEXEN-1-ONE AS A CATALYST
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In the presence of a catalytic amount of 2-cyclohexen-1-one, decarboxylation of α-amino acids proceeds smoothly and affords the corresponding amino compounds in good yields.Optically active amino compounds, (3R)-(-)-3-hydroxypyrrolidine and (2R)-(-)-2-hydroxypropylamine are obtained in 93percent and 80percent yields, respectively.
- Hashimoto, Mitsunori,Eda, Yutaka,Osanai, Yasutomo,Iwai, Toshiaki,Aoki, Seiichi
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Read Online
- Constrained β-alanine based GpIIb/IIIa antagonists
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The concepts of centrally constrained and peptide based fibrinogen receptor antagonists have been successfully combined into a single series of analogs which have been demonstrated to be potent inhibitors of platelet aggregation.
- Klein, Scott I.,Czekaj, Mark,Molino, Bruce F.,Valeria, Chu
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Read Online
- Enzymatic ammonolysis of ethyl (±)-4-chloro-3-hydroxybutanoate. Chemoenzymatic syntheses of both enantiomers of pyrrolidin-3-ol and 5- (chloromethyl)-1,3-oxazolidin-2-one
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Lipase B from Candida antarctica efficiently catalysed the kinetic resolution of ethyl (±)-4-chloro-3-hydroxybutanoate through an ammonolysis reaction. Using this methodology, both enantiomers of 4-chloro-3- hydroxybutanamide were prepared and converted into pyrrolidin-3-ol and 5- (chloromethyl)-1,3-oxazolidin-2-one by simple processes consisting of a reduction reaction and a Hofmann rearrangement, respectively.
- Garcia-Urdiales, Eduardo,Rebolledo, Francisca,Gotor, Vicente
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Read Online
- Decarboxylation of α-amino acids containing two and three stereogenic centers: A simple one-step procedure to prepare two optically active β- amino alcohols and a bicyclic pyrrolidine derivative
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The decarboxylation of L-threonine (2S,3R)-1, L-hydroxyproline (2S,4R)-2 and D-2-azabicyclo[3.3.0]octan-3-carboxylic acid (1R,3R,5R)-5 yield in a simple one-step procedure the corresponding optically active β-amino alcohols (R)-3 and (R)-4 and the bicyclic pyrrolidine derivative (1R,5R)-6 in 72-82% yield and >99% ee.
- Wallbaum,Mehler,Martens
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Read Online
- 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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- Synthesis method of (R)-3-hydroxypyrrolidine
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The invention relates to the technical field of organic synthesis, in particular to a synthesis method of (R)-3-hydroxy pyrrolidine, which comprises the following steps: reacting Lhydroxyproline in a reaction medium at 80-160 DEG C under the action of a decarboxylation catalyst, and carrying out reduced pressure distillation after the reaction is completed, thereby obtaining the (R)-3-hydroxy pyrrolidine, and the carboxylic acid decarboxylation catalyst is selected from methyl isobutyl or cyclohexanone. The (R)-3-hydroxy pyrrolidine synthesis method provided by the invention uses the cheap, safe and non-toxic decarboxylation catalyst and the reaction medium which is easier to recover, achieves higher yield than the prior art, and is suitable for industrial large-scale production.
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Paragraph 0021-0026
(2021/04/17)
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- Redox Condensations of o-Nitrobenzaldehydes with Amines under Mild Conditions: Total Synthesis of the Vasicinone Family
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A total synthesis of the vasicinone family of natural products from bulk chemicals was developed. Reductive condensation of o-nitrobenzaldehydes with amines utilizing iron pentacarbonyl as a reducing agent followed by subsequent oxidation leads to a great variety of polycyclic nitrogen-containing heterocycles under mild conditions. Enantiomerically pure vasicinone, rutaecarpine, isaindigotone, and luotonin were synthesized from readily available starting materials like hydroxyproline, nitrobenzaldehyde, pyrrolidine, and piperidine in two to four operational steps without chromatography. The antifungal activity of all products was tested.
- Afanasyev, Oleg I.,Podyacheva, Evgeniya,Rudenko, Alexander,Tsygankov, Alexey A.,Makarova, Maria,Chusov, Denis
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p. 9347 - 9360
(2020/08/14)
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- A fang chanfu law compound and its preparation method, pharmaceutical composition and use thereof
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The invention relates to a new compound for conversion of auricular fibrillation, as shown in the general formula i in the specification (n in the formula is equal to 0 to 4), or pharmaceutically acceptable salt thereof. The invention also provides a novel compound used as a preventive medicine or therapeutic drug for atrial fibrillation, a preparation method and a pharmaceutical composition containing the compound.
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Paragraph 0022; 0023; 0024; 0025; 0026
(2018/03/02)
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- A practical procedure for reduction of primary, secondary and tertiary amides to amines
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A mild and general procedure for reduction of primary, secondary, and tertiary amides using catalytic triruthenium dodecacarbonyl and 1,1,3,3-tetramethyldisiloxane as reductant is described. The reaction is tolerant of numerous functional groups, and the amine products can often be isolated by direct crystallization as hydrochloride salts. The catalyst and silane are commercially available, air stable, and inexpensive, making the procedure accessible for both laboratory and large-scale applications. Copyright
- Reeves, Jonathan T.,Tan, Zhulin,Marsini, Maurice A.,Han, Zhengxu S.,Xu, Yibo,Reeves, Diana C.,Lee, Heewon,Lu, Bruce Z.,Senanayake, Chris H.
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supporting information
p. 47 - 52
(2013/03/13)
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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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- METHOD OF PRODUCING (S)-3-(1-CYANO-1,1-DIPHENYLMETHYL)-PYRROLIDINE
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The present application relates to a method of (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine by reacting an (S)-1-protected-3-(sulfonyloxy)-pyrrolidine having an easily deprotectable protecting group with diphenylacetonitrile in the presence of a base to obtain an (S)-1-protected-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine and then deprotecting the obtained compound under a mild condition. According to the method of the present invention, it is possible to efficiently produce (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine, which is an important intermediate in the process of producing a muscarinic receptor antagonist such as darifenacin.
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Page/Page column 13
(2010/12/30)
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- NOVEL PROCESS FOR THE PREPARATION OF (3SM-[2-(2 J-DIHYDRO-5- BENZOFURANYL?ETHYL]-α.α -DIPHENYL-3-PYRROLIDINEACETAMIDE HYDROBROMIDE
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The present invention is directed to a novel, industrially viable and cost effective process for manufacturing (3 S)- 1 -[2-(2,3-Dihydro-5-benzofuranyl)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide hydrobromide also known as Darifenacin hydrobromide.
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Page/Page column 11; 15-16
(2009/11/29)
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- IMPROVED PROCESS FOR PRODUCING DARIFENACIN
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The present invention discloses an improved process for producing darifenacin, the process comprising decarboxylating (2S,4R)-4-hydroxy-2-pyrrolidine carboxylic acid followed by in situ tosylation to give l-tosyl-3-(R)-(-)-hydroxypyrrolidine, tosylating the l-tosyl-3-(R)-(-)-hydroxypyrrolidine with methyl-p-toluenesuolphonate to give l-tosyl-3- (S)-(-)-tosyloxy pyrrolidine, reacting l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine with diphenyl acetonitrile in presence of a base to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine, de-protecting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine in the presence of phenol in acidic medium to give 3-(S)-(+)-(l-cyano- 1,1-diphenylmethyl) pyrrolidine, hydrolyzing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine followed by salt formation to obtain 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine.L-(+)-tartrate, condensing 3-(S)-(+)-( 1 -carbamoyl- 1,1- diphenylmethyl)pyrrolidine-L(+)-tartrate with 5-(2-bromoethyl)-2,3-dihydrobenzofuran employing a base in a solvent to give darifenacin.
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Page/Page column 7; 9
(2009/11/29)
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- PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXY PYRROLIDINE AND DERIVATIVES THEREOF
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The present invention relates to an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof. The process comprises (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid, (b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound, (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3-hydroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine or derivatives thereof. The process provides 3-hydroxypyrrolidine or derivatives thereof with high optical purity, because optical purity of the starting material is substantially retained. In the process, each of the steps is carried out in a mild condition and does not require any special purification. This means that the process is useful and adequate for industrial mass production of 3-hydroxypyrrolidine and derivatives thereof having high optical purity.
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Page/Page column 15-16
(2009/03/07)
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- Synthetic Method of Optically Pure (S)-3-Hydroxypyrrolidine
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A method of preparing optically pure (S)-3-hydroxypyrrolidine is disclosed. The present invention provides a method of economically and industrially preparing optically and chemically pure (S)-3-hydroxypyrrolidine, through a process comprising introducing an amine protecting group by using optically pure 4-amino-(S)-2-hydroxybutylic acid as a starting material, reducing a carboxylic acid group into a primary alcohol, removing the amine protecting group to form an amine salt, halogenating the primary alcohol, and amine cyclization; and through a simple purification process, i.e., distillation under reduced pressure. As another method, the present invention provides a method of preparing optically and chemically pure (S)-3-hydroxypyrrolidine, through a process comprising esterifying optically pure 4-amino-(S)-2-hydroxybutylic acid as a starting material, lactam cyclization, and reduction.
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Page/Page column 6
(2008/12/08)
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- PROCESS FOR PRODUCTION OF BENZYLOXYPYRROLIDINE DERIVATIVE, AND PROCESS FOR PRODUCTION OF HYDROCHLORIDE SALT POWDER OF OPTICALLY ACTIVE BENZYLOXYPYRROLIDINE DERIVATIVE
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Provided are: a process for production of a benzyloxypyrrolidine derivative in high yield and safety, and a process for production of a hydrochloride powder of a benzyloxypyrrolidine derivative in high yield and safety; the process for production of a benzyloxypyrrolidine derivative expressed by the general formula (2) [Chemical formula 2], in reacting a pyrrolidinol derivative represented by the general formula (1) [Chemical formula 1 with a benzyl halide derivative in the presence of an alkali metal hydroxide, wherein the reaction is carried out in either of the following conditions A or B; condition A: an aprotic polar solvent, and condition B: an aliphatic ether solvent containing a phase transfer catalyst:
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Page/Page column 14
(2008/12/07)
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- SYNTHETIC METHOD OF OPTICALLY PURE (S)-3-HYDROXYPYRROLIDINE
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A method of preparing optically pure (S)-3-hydroxypyrrolidine is disclosed. The present invention provides a method of economically and industrially preparing optically and chemically pure (S)-3-hydroxypyrrolidine, through a process comprising introducing an amine protecting group by using optically pure 4-amino-(S)-2-hydroxybutylic acid as a starting material, reducing a carboxylic acid group into a primary alcohol, removing the amine protecting group to form an amine salt, halogenating the primary alcohol, and amine cyclization; and through a simple purification process, i.e., distillation under reduced pressure. As another method, the present invention provides a method of preparing optically and chemically pure (S)-3-hydroxypyrrolidine, through a process comprising esterifying optically pure 4-amino-(S)-2-hydroxybutylic acid as a starting material, lactam cyclization, and reduction.
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Page/Page column 13
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF CHIRAL 3-HYDROXY PYRROLIDINE COMPOUND AND DERIVATIVES THEREOF HAVING HIGH OPTICAL PURITY
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The present invention relates to an effective process for the preparation of optically pure chiral 3-hydroxypyrrolidine or derivatives thereof. More particularly, the present invention relates to an efficient process for the preparation of chiral 3-hydroxypyrrolidine or derivatives thereof, comprised of introducing a suitable protecting group to the starting material 4-chloro-3-hydroxybutyronitrile. Introduction of the hydroxy-protecting group provides advantages: efficient prevention of formation of side products, enhanced performance of the reduction of the nitrile group of the starting material, and enhanced performance of in-situ in? tramolecular cyclization. The chiral 3-hydroxypyrrolidine compound is produced in high yield and with high purity.
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Page/Page column 18
(2010/11/26)
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- Syntheses of ureas
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The present invention provides intermediates, synthetic methods and novel urea compositions of matter.
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Page/Page column 18
(2010/02/15)
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- PROCESS FOR PRODUCING NITROGENOUS HETEROCYCLIC COMPOUND
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A nitrogenous heterocyclic compound such as 3-aminopyrrolidine derivative is produced by hydrogenolysis of an N-substituted nitrogenous heterocyclic compound with normal pressure hydrogen in a water-based solvent in presence of a catalyst. In the case an optically active 1-substituted-3-aminopyrrrolidine derivative is used as a raw material, an optically active 3-aminopyrrolidine derivative can be obtained as a product practically without racemination.
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Page/Page column 12
(2010/11/08)
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- Process for preparing amines
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A process for preparing an amine which comprises in preparing an amine by decarboxylating an α-amino acid under heating in a high boiling liquid polymer having average molecular weight 200 to 6000, and directly recovering this amine by distillation in the same reaction system, namely in one pot.
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Page/Page column 2
(2008/06/13)
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- Process for preparing optically active 1- (4-nitrophenyl) -3-pyrrolidinol derivatives, and chiral para-phenylenediamines containing a pyrrolidinyl group
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A process for preparing an optically active 1-(4-nitrophenyl)-3-pyrrolidinol derivative corresponding to formula (I) below: para-Phenylenediamine derivatives substituted by a chiral pyrrolidinyl group, of formula (II), and their addition salts: A dyeing composition comprising a para-phenylenediamine derivative of formula (II). A method of oxidation-dyeing keratin fibers which employs said composition. Multicompartment devices in which a first compartment contains the said dyeing composition and a second compartment contains an oxidizing agent.
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Page/Page column 12-13
(2008/06/13)
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- A NMR and theoretical study of the aggregates between alkyllithium and chiral lithium amides: Control of the topology through a single asymmetric center
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The complexes between methyllithium and chiral 3-aminopyrrolidine (3-AP) lithium amides bearing a second asymmetric center on their lateral amino group were studied using multinuclear (1H, 6Li, 13C, 15N) low-temperature NMR spectroscopies in tetrahydrofuran-d8. The results indicate that lithium chelation forces the pyrrolidine ring of the 3-AP to adopt a norbornyl-like conformation and that robust 1:1 noncovalent complexes between methyllithium and 3-AP lithium amides form in the medium. A set of 1H-1H and 1H-6Li NMR cross-coupling correlations shows that the binding of methyllithium can take place along the "exo" or the "endo" face of this puckered structure, depending on the relative configuration of the lateral chiral group. This aggregation step renders the nitrogen of the 3-amino group chiral, the "exo" and "endo" topologies corresponding to the (S) and (R) configurations, respectively, of this atom. Density functional theory calculations show that the "exo" and "endo" arrangements are, for both diastereomers, almost isoenergetic even when solvent is taken into account. This result suggests that the formation of the mixed aggregates is under strict kinetic control. A relationship between the topology of these complexes and the sense of induction in the enantioselective alkylation of aromatic aldehydes by alkyllithiums is proposed.
- Corruble, Aline,Davoust, Daniel,Desjardins, Stephanie,Fressigne, Catherine,Giessner-Prettre, Claude,Harrison-Marchand, Anne,Houte, Henri,Lasne, Marie-Claire,Maddaluno, Jacques,Oulyadi, Hassan,Valnot, Jean-Yves
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p. 15267 - 15279
(2007/10/03)
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- 3-pyrrolidinyloxy-3'-pyridyl ether compounds useful for controlling chemical synaptic transmission
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A series of 3-pyrrolidinyloxy-3′-pyridyl ether compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions including these compounds. Preferred compounds are 3-pyrrolidinylmethoxy-3′-(5′-and/or 6′-substituted) pyridyl ethers.
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- Regioselective synthesis of nitrones by decarboxylative oxidation of N- alkyl-α-amino acids and application to the synthesis of 1-azabicyclic alkaloids
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Tungstate-catalyzed oxidation of N-alkyl-2a-amino acids with 30% H2O2 solution under phase-transfer conditions gives nitrones regioselectively in good yields: Using this method, stereodivergent synthesis of (R)- and (S)-4- (t-butyldimethylsilyloxy)-1-pyrroline N-oxides ((R)-17a and (S)-17a) was achieved. In addition, (R)- and (S)-3-(t-butyldimethylsilyloxy)-1-pyrroline N-oxides ((R)-45 and (S)-45) were prepared by catalytic oxidation of the corresponding chiral pyrrolidines in a regioselective manner. These chiral cyclic nitrones, 17 and 45 are versatile intermediates for the synthesis of optically active nitrogen heterocycles, since stereoselective additions of carbon nucleophiles to these chiral nitrones can be readily performed. Typically, ZnI2-mediated addition of ketene t-butyldimethylsilyi methyl acetal (29a): to (R)-17a gave the' cis-adduct, methyl (2R,4R)-[1,4-bis(t- butyldimethylsilyloxy)pyrrolidin-2-yl]acetate (cis-30). In contrast, the addition of lithium acetylides 34 to the nitrone (R)-17a gave the trans- adducts, (2S,4R)-2-(1-alkynyl)-4-(t-butyldimethylsilyloxy)-1- hydroxypyrrolidines trans-35. These adducts are useful intermediates for syntheses of the nitrogen heterocycles (3R,5R)-1-aza-3- hydroxybicyclo[3.3.0]octane (37) and (6R,8R)-1-aza-8- hydroxybicyclo[4.30]nonane (38), respectively. The ZnI2-mediated addition of ketene silyl acetal 29a to the nitrone (R)-45 gave methyl (2S, 3R)-[1,3- bis(t-butyldimethylsilyloxy)pyrrolidin-2-yl]acetate (trans-50a), which was used for asymmetric synthesis of the Geissman-Waiss lactone ((-)-49).
- Ohtake, Hiroaki,Imada, Yasushi,Murahashi, Shun-Ichi
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p. 2737 - 2754
(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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- 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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- 2-Dibenzylaminobutane-1,4-diol: A Versatile Intermediate for a Chirospecific β-amino Acid Synthesis
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Starting from the chiral building block 1, which is readily available from natural aspartic acid, a concise and versatile synthesis of optically active β-amino acids including β-proline derivatives is reported.Regioselective transformations of the 1,4-bis-electrophile 2 are facilitated by an anchimeric participation.
- Gmeiner, Peter,Orecher, Florian,Thomas, Christoph,Weber, Klaus
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p. 381 - 382
(2007/10/02)
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- 4-[(Alkylamino)methyl]furo[3,2-c]pyridines: A new series of selective κ- receptor agonists
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The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2- c]pyridines (16-23, 26, 27) and their activities as κ-opioid receptor agonists are described. κ-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (κ- specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (μ- specific and δ-specific tissues, respectively), 17 showed only weak antagonist activity (pK(B) > 5.5), underlining its selectivity for the κ- opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).
- Naylor,Judd,Scopes,Hayes,Birch
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p. 2138 - 2144
(2007/10/02)
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- Process for the preparation of 3-pyrrolidinols and intermediates therefor
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3-Pyrrolidinol or its salt is economically produced by cyclizing an aminobutanol derivative of the formula: STR1 wherein R is an alkyl or a substituted or unsubstituted phenyl group, or its salt.
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- Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3- amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity
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A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1- pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl- 6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3- quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3- quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S- (R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1-cyclopropyl- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).
- Sanchez,Domagala,Heifetz,Priebe,Sesnie,Trehan
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p. 1764 - 1773
(2007/10/02)
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- Pharmaceutically useful furo[3,2-c]pyridines
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Compounds are disclosed of formula (I) STR1 wherein R1 represents hydrogen, unsubstituted or substituted C1-6 alkyl, halogen, --COR4 or --CO2 R4 (where R4 represents hydrogen or unsubstituted or substituted C1-6 alkyl); R2 and R3 are the same or different and are C1-6 alkyl or C3-6 alkenyl; or --NR2 R3 forms a 5-membered (optionally containing an oxygen atom adjacent to the nitrogen) or a 6-membered ring, which ring optionally contains one unit of unsaturation and which is unsubstituted or substituted by hydroxy, C1-6 acyloxy, oxo, optionally substituted methylidene, --COR5 (where R5 represents C1-6 alkyl, OR6 or --NHR6, and R6 represents hydrogen, C1-6 alkyl, aryl or ar(C1-6)alkyl) or said ring is substituted by =NOR7 (where R7 represents C1-6 alkyl); Z represents --O-- or --S--; X represents a direct bond, --CH2 -- or --CH2 O--; Ar represents a substituted phenyl moiety; and pharmaceutically acceptable salts thereof. The compounds are indicated as useful in the treatment of pain and cerebral ischaemia. Processes and intermediates for their preparation and pharmaceutical compositions containing them are also disclosed.
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- Chemical compounds
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Compounds are disclosed of formula (I) STR1 wherein R1 represents --COR4, --CO2 R4, --COCO2 R4 or --CONR4 R5 (where R4 and R5 may be the same or different and represent a hydrogen atom or a C1-3 alkyl group); R2 represents a hydrogen atom or a hydroxy or oxo group, with the proviso that when R1 is --COR4, --CO2 R4 or --COCO2 R4, R2 is not a hydrogen atom; R3 represents a hydrogen atom or a hydroxy group; X represents a direct bond, --CH2 -- or --CH2 O--; Ar represents a substituted phenyl moiety; and physiologically acceptable salts thereof. The compounds are indicated as useful in the treatment of pain. Processes for their preparation and pharmaceutical compositions containing them are also disclosed.
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- Process for preparing 3-pyrrolidinol
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A process for preparing 3-pyrrolidinol having the formula (II): STR1 or a salt thereof, which comprises reducing 4-chloro-3-hydroxybutyronitrile having the formula (I): STR2 to convert said 4-chloro-3-hydroxybutyronitrile (I) into said 3-pyrrolidinol (II). According to the present invention, 3-pyrrolidinol, particularly optically active 3-pyrrolidinol can be prepared economically and efficiently.
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- (S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
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The novel (S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-n phthyridine-3-carboxylic acid, lower alkyl esters and pharmaceutically acceptable salts thereof are described as well as a method for its manufacture, formulation, and use in treating bacterial infections.
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- 3- or 4-substituted oxotremorine derivatives
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This disclosure describes novel 3 or 4 substituted oxotremorine derivatives having polar substituted oxygen or sulfur groups. The compounds have cholinergic activity. Also disclosed are methods for treating diseases of the central nervous system in mammals employing the compounds, pharmaceutical preparations containing the compounds and processes for the production of the compounds.
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- Anodic Methoxylation of Pyrrolidinol Derivatives. Enantioselective Synthesis of cis- and trans-(3R)-3-Hydroxyprolines
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Anodic α-methoxylations of (3R)-1-methoxycarbonylpyrrolidin-3-ol and two O-protected analogs display modest regioselectivities (yield of 3 54percent; yield of 4 72percent).Substitution of the 2-methoxy group with a cyano group causes enhanced cis stereoselectivity (86percent) when a tert-butyldimethylsilyloxy substituent was present in the 3-position.Hydrolysis of the isomeric cyano compounds gave cis-3-hydroxy-L-proline and trans-3-hydroxy-D-proline.
- Thaning, Mikkel,Wistrand, Lars-G.
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p. 290 - 295
(2007/10/02)
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- Naphthyridine antibacterial agents containing an α-amino acid in the side chain of the 7-substituent
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Novel quinolone and naphthyridine antibacterial agents are herein described having improved in vivo activity both orally and subcutaneously where the 7-side chain of such compounds contain an α-amino acid; also described are its corresponding optical isomers, methods of preparation as well as compositions and methods of treating infections diseases.
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- SYNTHESIS OF 3S-PYRROLIDINOL FROM L-GLUTAMIC ACID
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A partial synthesis of 3S-pyrrolidinol and derivatives from L-glutamic acid is described.
- Harris, Bruce D.,Bhat, Krishna L.,Joullie, Madeleine M.
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p. 1815 - 1822
(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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