- Polysulfonate supported chiral diamine-nickel catalysts: Synthesis and applications
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A series of chiral polysulfonate cyclohexyldiamine-Ni(II) catalysts were prepared via sulfur (VI) fluoride exchange click-reactions. The catalysts exhibited good catalytic activity and enantioselectivity in the Michael addition of malonates to nitroalkene
- Zhou, Jing-xuan,Zhu, Dong-yu,Chen, Jie,Zhang, Xue-jing,Yan, Ming,Chan, Albert S.C.
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- Synthesis method of flurolipram
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The invention discloses a synthesis method of flurolipram, which comprises the following steps: carrying out catalytic reaction on a compound represented by formula 1 and an alcohol compound represented by formula II by using an N-heterocyclic carbene catalyst to generate an intermediate represented by formula 3.1 and/or 3.2, and carrying out a series of reactions on the intermediate represented by formula 3.1 and/or 3.2 to finally obtain flurolipram.The method is simple to operate, and the substrate is easy to prepare; reaction conditions are mild, and high yield and high stereoselectivity are achieved.
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Paragraph 0089-0097
(2021/03/13)
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- Enantioselective conjugate addition of an α,α-dithioacetonitrile with nitroalkenes using chiral bis(imidazoline)-Pd complexes
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The enantioselective conjugate addition reaction of an α,α-dithioacetonitrile with nitroalkenes was catalysed by chiral bis(imidazoline)-palladium pincer-type complexes. The reaction was applicable to various nitroalkenes to afford products in good yield with high enantioselectivity. The obtained products can be converted to γ-lactam and biologically active rolipram.
- Nakamura, Shuichi,Tokunaga, Akari,Saito, Hikari,Kondo, Masaru
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p. 5391 - 5394
(2019/05/10)
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- Synthesis of β-Substituted γ-Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis
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β-Substituted chiral γ-aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β-substituted γ-aminobutyr
- Ma, Jiajia,Lin, Jiahui,Zhao, Lifang,Harms, Klaus,Marsch, Michael,Xie, Xiulan,Meggers, Eric
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p. 11193 - 11197
(2018/08/11)
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- Highly Enantioselective Synthesis of Chiral γ-Lactams by Rh-Catalyzed Asymmetric Hydrogenation
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A Rh/bisphosphine-thiourea (ZhaoPhos) catalytic system has been identified for the straightforward asymmetric synthesis of chiral γ-lactams. A variety of NH free α,β-unsaturated lactams bearing a β-aryl or β-alkyl substituent were smoothly hydrogenated to
- Lang, Qiwei,Gu, Guoxian,Cheng, Yaoti,Yin, Qin,Zhang, Xumu
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p. 4824 - 4828
(2018/06/08)
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- Efficient synthesis of (?)-(R)- and (+)-(S)-rolipram
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A novel, efficient and protecting group free enantioselective synthetic approach of (?)-(R)-1 and (+)-(S)-rolipram 2 is described employing the organocatalyzed asymmetric Michael addition, Henry condensation, Wittig olefination and reductive lactamization
- Kaur, Ramandeep,Pandey, Satyendra Kumar
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supporting information
p. 4333 - 4335
(2017/10/17)
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- A synthetic γ-amino butyric acid kind of chiral the method for preparing the compound of
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The invention discloses a method for synthesizing a gamma-aminobutyric acid chiral compound. The method comprises the following steps of: adding nitroolefin and malonate to a solvent in the presence of a catalyst A and an additive; carrying out conjugate
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- Identification and in vivo evaluation of a fluorine-18 rolipram analogue, [18F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain
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Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd = 0.26 nM) over R-(-)-rolipram (Kd = 1.6 nM). A deutero-analogue d2-[18F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/μmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4.
- Thomae, David,Morley, Thomas J.,Lee, Hsiaoju S.,Barret, Olivier,Constantinescu, Cristian,Papin, Caroline,Baldwin, Ronald M.,Tamagnan, Gilles D.,Alagille, David
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p. 205 - 213
(2016/05/09)
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- METHOD FOR PREPARING (R)-ROLIPRAM PRECURSOR BY CATALYTIC ENANTIOSELECTIVE MICAHEL REACTION AND METHOD FOR PREPARING (R)-ROLPTRAM USING THE (R)-ROLIPRAM PRECURSOR
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According to the present invention, a method for preparing chiral (R)-rolipram precursors includes a step of enabling an asymmetric Michael reaction of 3-(cyclo pentoxy)-4-methoxyphenyl nitro and malonate in the presence of a soluble chiral catalyst. Accordingly, the present invention can synthesize chiral (R)-rolipram precursors at low costs by using an organic catalyst not including transition metals with high optical selectivity and reactivity in the presence of water, aqueous solution, or a mixed solution of an organic solvent which are not harmful to the human body and do not cause environmental pollution.COPYRIGHT KIPO 2015
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Paragraph 0072-0074
(2016/10/27)
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- Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts
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Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, fo
- Tsubogo, Tetsu,Oyamada, Hidekazu,Kobayashi, Shu
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p. 329 - 332
(2015/05/05)
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- A simple enantioselective route toward (R)- and (S)-Rolipram via anhydride desymmetrization
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A highly enantioselective metal-free synthesis of both enantiomers of Rolipram is reported. The key stereoinductive step is a cinchona alkaloid catalyzed opening of a cyclic anhydride prepared from isovanillin, where both enantiomers are available using t
- Ivsic, Trpimir,Hamersak, Zdenko
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p. 217 - 222
(2013/04/23)
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- Regio- and enantioselective palladium-catalyzed allylic alkylation of nitromethane with monosubstituted allyl substrates: Synthesis of (R)-rolipram and (R)-baclofen
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The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with monosubstituted allyl substrates was realized for the first time to provide corresponding products in high yields with excellent regio- and enantioselectivities. The protocol was applied to the enantioselective synthesis of (R)-baclofen and (R)-rolipram.
- Yang, Xiao-Fei,Ding, Chang-Hua,Li, Xiao-Hui,Huang, Jian-Qiang,Hou, Xue-Long,Dai, Li-Xin,Wang, Pin-Jie
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p. 8980 - 8985,6
(2012/12/12)
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- Regio- and enantioselective palladium-catalyzed allylic alkylation of nitromethane with monosubstituted allyl substrates: Synthesis of (R)-rolipram and (R)-baclofen
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The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with monosubstituted allyl substrates was realized for the first time to provide corresponding products in high yields with excellent regio- and enantioselectivities. The protocol was applied to the enantioselective synthesis of (R)-baclofen and (R)-rolipram.
- Yang, Xiao-Fei,Ding, Chang-Hua,Li, Xiao-Hui,Huang, Jian-Qiang,Hou, Xue-Long,Dai, Li-Xin,Wang, Pin-Jie
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p. 8980 - 8985
(2013/01/15)
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- Practical large-scale preparation of (r)-rolipram using chiral nickel catalyst
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Antidepressant drug (R)-rolipram was readily prepared on a large scale from isovanilline via a succinct route. The key reaction was carried out using a 1 mol% loading of nickel(II)-bis[(S,S)-N,N-dibenzylcyclohexane-1,2-diamine]Br2 complex as the catalyst.
- Wen, Lixin,Tang, Feiyu,Ge, Chengsheng,Wang, Xiaodong,Han, Zhi,Wu, Jianyi
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p. 3288 - 3295
(2012/10/08)
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- Asymmetric synthesis of β-substituted γ-lactams via rhodium/diene-catalyzed 1,4-additions: Application to the synthesis of (R)-baclofen and (R)-rolipram
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An efficient rhodium/diene-catalyzed asymmetric addition of arylboronic acids to α,β-unsaturated γ-lactams has been developed. The power of this methodology is further demonstrated by the concise synthesis of (R)-baclofen and (R)-rolipram.
- Shao, Cheng,Yu, Hong-Jie,Wu, Nuo-Yi,Tian, Ping,Wang, Rui,Feng, Chen-Guo,Lin, Guo-Qiang
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supporting information; experimental part
p. 788 - 791
(2011/04/16)
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- Epi-cinchona based thiourea organocatalyst family as an efficient asymmetric Michael addition promoter: Enantioselective conjugate addition of nitroalkanes to chalcones and α,β-unsaturated N-acylpyrroles
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(Chemical Equation Presented) A small set of easily available epi-cinchona based thiourea organocatalysts have been synthesized and tested in enantioselective Michael addition of nitroalkanes to chalcones. These bifunctional catalyst systems promoted the
- Vakulya, Benedek,Varga, Szilard,Soos, Tibor
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p. 3475 - 3480
(2008/09/20)
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- Organocatalytic asymmetric total synthesis of (R)-rolipram and formal synthesis of (3S,4R)-paroxetine
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(Chemical Equation Presented) An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.
- Hynes, Peter S.,Stupple, Paul A.,Dixon, Darren J.
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supporting information; experimental part
p. 1389 - 1391
(2009/04/12)
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- Rh-catalyzed asymmetric hydrogenation of γ-phthalimido-substituted α,β-unsaturated carboxylic acid esters: An efficient enantioselective synthesis of β-aryl-γ-amino acids
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(Chemical Equation Presented) A series of chiral β-aryl-γ-amino acid ester derivatives were synthesized in high enantioselectivities (93-97% ee) via the Rh-catalyzed asymmetric hydrogenation of γ-phthalimido-α, β-unsaturated carboxylic acid esters using highly modular chiral BoPhoz-type phosphine-aminophosphine ligands. The method has been applied successfully to the synthesis of several chiral pharmaceuticals including (R)-baclofen and (R)-rolipram with high enantioselectivities.
- Deng, Jun,Duan, Zheng-Chao,Huang, Jia-Di,Hu, Xiang-Ping,Wang, Dao-Yong,Yu, Sai-Bo,Xu, Xue-Feng,Zheng, Zhuo
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p. 4825 - 4828
(2008/03/15)
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- Synthesis and evaluation of N-aryl pyrrolidinones as novel anti-HIV-1 agents. Part 1
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The synthesis and preliminary structure-activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
- Wu, Baogen,Kuhen, Kelli,Ngoc Nguyen, Truc,Ellis, David,Anaclerio, Beth,He, Xiaohui,Yang, Kunyong,Karanewsky, Donald,Yin, Hong,Wolff, Karen,Bieza, Kimberly,Caldwell, Jeremy,He, Yun
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p. 3430 - 3433
(2007/10/03)
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- Co-catalyzed reductive cyclization of azido and cyano substituted α,β-unsaturated esters with NaBH4: enantioselective synthesis of (R)-baclofen and (R)-rolipram
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Sodium borohydride in combination with a catalytic amount of CoCl2 has been found to be an excellent catalytic system in reductive cyclizations of suitably substituted azido and cyano groups of α,β-unsaturated esters to afford γ and δ-lactams in high yields. The process has been demonstrated for the enantioselective synthesis of (R)-baclofen, (R)-rolipram, and (R)-4-fluorophenylpiperidinone, a key intermediate for (-)-paroxetine.
- Paraskar, Abhimanyu S.,Sudalai, Arumugam
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p. 4907 - 4916
(2007/10/03)
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- Synthesis of 4-aryl-2-pyrrolidones and β-aryl-γ-amino-butyric acid (GABA) analogues by Heck arylation of 3-pyrrolines with arenediazonium tetrafluoroborates. Synthesis of (±)-rolipram on a multigram scale and chromatographic resolution by semipreparative chiral simulated moving bed chromatography
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(Chemical Equation Presented) We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and β-aryl-γ-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.
- Garcia, Ariel L. L.,Carpes, Marcos J. S.,De Oca, Antonio C. B. M.,Dos Santos, Marco A. G.,Santana, Cesar C.,Correia, Carlos Roque D.
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p. 1050 - 1053
(2007/10/03)
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- Dirhodium catalyzed intramolecular enantioselective C-H insertion reaction of N-cumyl-N-(2-p-anisylethyl)diazoacetamide: Synthesis of (-)-Rolipram
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Cumyl(2,2-dimethyl-benzyl) was used as an N-protecting group for intramolecular C-H insertion reaction of α-diazoacetamide. Excellent chemoselectivity (>98:2) in C-H insertion over the aromatic addition of N-cumyl-N-(2-p-anisylethyl)diazoacetamide was obtained with Rh 2[(4S)-MEOX)]4 catalyst in moderate enantioselectivity (53% ee). The reaction was successfully applied in the synthesis of (-)-Rolipram in 15% total yield.
- Liu, Wei-Jun,Chen, Zhen-Liang,Chen, Zhi-Yong,Hu, Wen-Hao
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p. 1693 - 1698
(2007/10/03)
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- Enantioselective Syntheses of (-)-(R)-Rolipram, (-)-(R)-Baclofen and Other GABA Analogues via Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids
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Highly enantioselective syntheses of two important γ-aminobutyric acid (GABA) analogues, the antispastic drug (-)-(R)-Baclofen and the antidepressant agent (-)-(R)-Rolipram, are reported. Key-steps in both syntheses are the Rh-catalyzed asymmetric 1,4-additions of arylboronic acids to 4-aminobut-2,3-enoic acid derivatives.
- Becht, Jean-Michel,Meyer, Oliver,Helmchen, Guenter
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p. 2805 - 2810
(2007/10/03)
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- Enantioselective Michael additions of nitromethane by a catalytic double activation method using chiral Lewis acid and achiral amine catalysts
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Reactions of nitromethane with 1-(2-alkenoyl)-3,5-dimethylpyrazoles can be effectively catalyzed by R,R-DBFOX/Ph·Ni(ClO4)2·3H2O and achiral amine bases, each in a catalytic loading of 10 mol %, to give 1-(3-substituted 4-n
- Itoh, Kennosuke,Kanemasa, Shuji
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p. 13394 - 13395
(2007/10/03)
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- Development of a catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes for the synthesis of endothelin-A antagonist ABT-546. Scope, mechanism, and further application to the synthesis of the antidepressant rolipram
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The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg
- Barnes, David M.,Wittenberger, Steven J.,Zhang, Ji,Ji, Jianguo,Fickes, Michael G.,Fitzgerald, Michael A.,King, Steven A.,Morton, Howard E.,Plagge, Frederick A.,Preskill, Margo,Wagaw, Seble H.
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p. 13097 - 13105
(2007/10/03)
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- First highly regio- and diastereoselective [3+2] cycloaddition of chiral nonracemic Fischer carbene complexes with azomethine ylides: An enantioselective synthesis of (+)-Rolipram
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A new procedure for the synthesis of 1,3,4-trisubstituted and 1,4-di-substituted pyrrolidin-2-one derivatives in an enantioselective fashion is reported. The 1,3-dipolar cycloaddition of (±)-menthol and (-)-8-phenylmenthol derived Fischer alkoxy alkenyl carbene complexes with in situ generated functionalized azomethine ylides gives the corresponding cycloadducts as chelated tetracarbonyl Fischer carbene complexes. Only one regioisomer is detected in all cases, and the diastereoselectivity of the reaction is very high when (-)-8-phenylmenthol derived carbenes are employed. Oxidation and further transformation of the cycloadducts provide an easy access to pyrrolidin-2-ones. The anti-inflammatory and antidepressant drug (+)-Rolipram is readily prepared in four steps in a 20% overall yield by taking advantage of this newly developed methodology.
- Barluenga, Jose,Fernandez-Rodriguez, Manuel A.,Aguilar, Enrique,Fernandez-Mari, Felix,Salinas, Alejandro,Olano, Bernardo
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p. 3533 - 3544
(2007/10/03)
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- Catalytic enantioselective synthesis of the phosphodiesterase type IV inhibitor (R)-(-)-rolipram via intramolecular C-H insertion process
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A new route to the phosphodiesterase type IV inhibitor (R)-(-)-rolipram (1) has been developed, wherein the key step relies on enantioselective intramolecular C-H insertion of N-alkyl-N-4-nitrophenyl-α-methoxycarbonyl- α-diazoacetamide 7 catalyzed by chir
- Anada, Masahiro,Mita, Orie,Watanabe, Hiroko,Kitagaki, Shinji,Hashimoto, Shunichi
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p. 1775 - 1777
(2007/10/03)
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- A stereoselective synthesis of (R)-(-)-rolipram from L-glutamic acid
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A stereoselective synthesis of (R)-(-)-rolipram from L-glutamic acid is described. The key step is a stereoselective Michael addition of an arylcuprate to a modified pyroglutamic derivative which acts as the template to induce the stereoselectivity. Facile manipulation of the enantiomerically pure Michael product afforded the expected therapeutic agent.
- Diaz, Adolfo,Siro, Jorge G.,García-Navío, José L.,Vaquero, Juan J.,Alvarez-Builla, Julio
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p. 559 - 562
(2007/10/03)
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- Synthesis of the novel antidepressant (R)-(-)-Rolipram
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Enantioselective synthesis of (R)-Rolipram 1 has been achieved through a conjugate addition of cyanide to enantiomerically pure 2-(2-aryl ethenyl)oxazoline 2, followed by selective reduction of the adduct with NaBH4-NiCl2.
- Langlois, Nicole,Wang, Hai-Shan
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p. 3133 - 3144
(2007/10/03)
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- Chiral synthesis of phosphodiesterase inhibitor, (R)-(-)-rolipram, by means of enantioselective deprotonation strategy
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Enantioselective synthesis of the antidepressant (R)-(-)-rolipram (1) has been achieved by using an enantioselective deprotonation of the cyclobutanone derivative as a key step.
- Honda, Toshio,Ishikawa, Fumihiro,Kanai, Kazuo,Sato, Shigeki,Kato, Daishiro,Tominaga, Hideo
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p. 109 - 112
(2007/10/02)
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- The Crystal Structure, Absolute Configuration, and Phosphodiesterase Inhibitory Activity of (+)-1-(4-Bromobenzyl)-4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one
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Chiral HPLC resolution of the phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derivative, (+)-2.X-ray structural analysis of (+)-2 establishad the absolute configuration as
- Baures, Paul W.,Eggleston, Drake S.,Erhard, Karl F.,Cieslinski, Lenora B.,Torphy, Theodore J.,Christensen, Siegfried B.
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p. 3274 - 3277
(2007/10/02)
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- The Synthesis of Aracemic 4-Substituted Pyrrolidinones and 3-Substituted Pyrrolidines. An Asymmetric Synthesis of (-)-Rolipram
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Conjugate additions of RCuCNLi to the chiral α,β-unsaturated lactam 4 gives almost exclusive exo addition - a reversal in stereochemistry when cuprates were added to chiral lactam 1.The lactams 5 were transformed into 4-substituted pyrrolidinones 8 via a three-step sequence which involved decarbalkoxylation, silane reduction and metal-ammonia benzylamine cleavage.The chemical yields as well as the enantiomeric purity were very high for this process.As an example of the usefulness of this scheme, the antidepressant (-)-Rolipram was prepared in good overall yield.Furthermore, the bicyclic lactams 6 were readily transformed, using alane as the reducing agent, to 3-substituted pyrrolidines 11.Absolute configurations of 8 and 11 were confirmed by comparison with literature assignments which also gave strong support to the facial addition of the cuprates to 4.
- Meyers, A. I.,Snyder, Lawrence
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