- Concise enantioselective synthesis of (+)-sertraline and (-)-CP-52002 using proline catalysis
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A short enantioselective synthesis of (+)-sertraline and its C4 epimer (-)-CP-52002 with an overall yield of 30%, respectively, as its hydrochloride has been described. The key steps are the proline catalyzed Mannich reaction of acetaldehyde and acid catalyzed intramolecular Friedel-Crafts' alkylation reaction of olefin proceeding with high optical purities.
- Kalshetti, Rupali,Venkataramasubramanian,Kamble, Sanjay,Sudalai, Arumugam
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Read Online
- Chiral N,N′-Dioxide/Tm(OTf)3 Complex-Catalyzed Asymmetric Bisvinylogous Mannich Reaction of Silyl Ketene Acetal with Aldimines
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An enantioselective bisvinylogous Mannich reaction of silyl ketene acetal with aldimines has been realized by using a chiral N,N′-dioxide/Tm(OTf)3 complex as catalyst, providing an effective method to synthesize chiral ζ-amino-α,β,γ,δ-unsaturated carbonyl compounds. (Figure presented.).
- Zou, Sijia,Li, Weiwei,Fu, Kai,Cao, Weidi,Lin, Lili,Feng, Xiaoming
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Read Online
- Chiral Bronsted acid-catalyzed tandem aza-ene type reaction/cyclization cascade for a one-pot entry to enantioenriched piperidines
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A chiral monophosphoric acid-catalyzed tandem aza-ene type reaction/cyclization cascade enabled the rapid construction of enantioenriched piperidine derivatives as key structural elements of numerous natural products. The potential of such cascade transformations is highlighted through their ability to achieve a rapid increase in molecular complexity from simple enecarbamates and a broad range of aldimines while also controlling three stereogenic centers in a highly diastereo- and enantioselective manner. Copyright
- Terada, Masahiro,Machioka, Kyoko,Sorimachi, Keiichi
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Read Online
- Synthetic method of dapoxetine and intermediate thereof
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The invention discloses a synthetic method of dapoxetine and its intermediate, i.e., (S)-3-(tert-butyloxycarbonyl)amino-3-phenylpropanol as shown in a formula 5 which is described in the specification. The synthetic method of (S)-3-(tert-butyloxycarbonyl)amino-3-phenylpropanol is as shown in a synthesis route which is described in the specification, wherein a compound 3 and acetaldehyde are subjected to a Mannich reaction in an organic solvent under the action of a supramolecular catalyst constructed by a chiral catalyst and a polymer so as to obtain a compound 4, and the polymer is at least one selected from of the group consisting of PEG 200, PEG 400, PEG 600, MeOPEG 750, PEG 800, PEG 1000, PPG 800 and PPG 1000. The dapoxetine is synthesized from the (S)-3-(tert-butyloxycarbonyl)amino-3-phenylpropanol prepared by using the above method according to steps as shown in the synthesis route. The synthetic method of dapoxetine and the intermediate thereof has the characteristics of usage of cheap and easily available raw materials, high yield and low cost, and is more beneficial to industrial production.
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- Asymmetric synthesis method of chiral beta-amino aldehyde compound
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The invention discloses an asymmetric synthesis method of a chiral beta-amino aldehyde compound as shown in a formula (I) which is described in the specification. The asymmetric synthesis is carried out in an organic solvent with imine as shown in a formula (II) and aldehyde as shown in a formula (III) as reactants. The method is characterized in that the reaction is carried out under the action of a supramolecular catalyst constructed by a chiral catalyst and a polymer, wherein the chiral catalyst is one as described in the specification, and the polymer is PEG and/or PPG. According to the invention, PPG/PEG and the chiral catalyst are utilized to construct the supramolecular catalyst for asymmetric synthesis of the chiral beta-amino aldehyde compound, so product yield is significantly improved.
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Paragraph 0128-0133
(2020/03/11)
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- Asymmetric Mannich Reaction and Construction of Axially Chiral Sulfone-Containing Styrenes in One Pot from α-Amido Sulfones Based on the Waste-Reuse Strategy
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A simultaneous asymmetric Mannich reaction and the construction of axially chiral sulfone-containing styrenes in one pot from α-amido sulfones based on the waste-reuse strategy was demonstrated. A series of chiral β-amino diesters and axially chiral sulfone-containing styrenes with various functional groups were synthesized in good to excellent yields and enantioselectivities under mild conditions. In addition, this protocol has been successfully applied to synthesize the anti-HIV drug Maraviroc and chiral trichloro derivatives.
- Li, Dongmei,Tan, Yu,Peng, Lei,Li, Shan,Zhang, Nan,Liu, Yidong,Yan, Hailong
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p. 4959 - 4963
(2018/08/24)
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- Configurationally Stable (S)- and (R)-α-Methylproline-Derived Ligands for the Direct Chemical Resolution of Free Unprotected β3-Amino Acids
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Reported herein is a chemical method for the direct resolution of unprotected racemic β-substituted-β-amino acids (β3-AAs) that uses specially designed, stable, and recyclable α-methylproline-derived chiral ligands. The versatility of this methodology is unmatched by biocatalytic approaches. The method shows a broad synthetic generality for various aryl- or alkyl-substituted β3-AAs, and the new nonracemizable ligands can be accessed readily. Furthermore, the presented method produces an excellent stereochemical outcome and has a fully recyclable source of chirality, and the reaction conditions are operationally simple and convenient. The procedure has also been successfully applied to the scalable synthesis of the anti-HIV drug maraviroc.
- Zhou, Shengbin,Wang, Shuni,Wang, Jiang,Nian, Yong,Peng, Panfeng,Soloshonok, Vadim A.,Liu, Hong
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p. 1821 - 1832
(2018/04/27)
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- Synthetic method for novel chiral ligand, metal chelate, multiple unnatural amino acids, maraviroc and key intermediate thereof
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The invention discloses a synthetic method for a novel chiral ligand, a metal chelate, multiple unnatural amino acids, maraviroc and a key intermediate thereof. According to the synthetic method, (R)-2-methylproline is selected as a starting material, and asymmetrical resolution is induced by utilizing a nickel chelate, so that (S)-beta3-amino acid is obtained, and (S)-3-amino-3-phenylpropionic acid is taken as the key intermediate for synthesizing maraviroc, so that yield is high, and ee value reaches more than or equal to 98.2%. The method disclosed by the invention has the advantages that source of raw materials is wide, conditions of a synthetic process are mild, control is easy, and optical purity of products is high.
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- A chiral analog of the bicyclic guanidine TBD: Synthesis, structure and Br?nsted base catalysis
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Starting from (S)-β-phenylalanine, easily accessible by lipase-catalyzed kinetic resolution, a chiral triamine was assembled by a reductive amination and finally cyclized to form the title compound 10. In the crystals of the guanidinium benzoate salt the six membered rings of 10 adopt conformations close to an envelope with the phenyl substituents in pseudo-axial positions. The unprotonated guanidine 10 catalyzes Diels-Alder reactions of anthrones and maleimides (25-30% ee). It also promotes as a strong Br?nsted base the retro-aldol reaction of some cycloadducts with kinetic resolution of the enantiomers. In three cases, the retroaldol products (48-83% ee) could be recrystallized to high enantiopurity (≥95% ee). The absolute configuration of several compounds is supported by anomalous X-ray diffraction and by chemical correlation.
- Goldberg, Mariano,Sartakov, Denis,Bats, Jan W.,Bolte, Michael,G?bel, Michael W.
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p. 1870 - 1876
(2016/10/05)
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- Proline-catalyzed α-aminooxylation of β-amino aldehydes: Access to enantiomerically pure syn - And anti -3-Amino-3-aryl-1,2-alkanediols
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A new synthetic method for enantioselective synthesis of syn or anti-3-amino-3-aryl-1,2-alkanediols via proline catalyzed α-aminooxylation of β-amino aldehydes are described. This methodology is successfully applied to a concise and protecting group-free asymmetric synthesis of (-)-cytoxazone, (+)-epi-cytoxazone and formal synthesis of N-thiolated 2-oxazolidinone.
- Venkataramasubramanian,Kiran, I. N. Chaithanya,Sudalai, Arumugam
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p. 355 - 358
(2015/03/05)
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- AN ORGANOCATALYTIC ASYMMETRIC SYNTHESIS OF ANTIDEPRESSANTS
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The present invention relates to a short enantioselective synthesis of 1-amino aryl tetraline compounds of Formula 1 via nucleophilic enamine catalysis using organocatalyst such as proline. wherein R1 and R2 represent independent of each other hydrogen, (un)substituted or substituted amine; R3 and R4 represent independent of each other hydrogen or halogen.
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Page/Page column 14-15
(2016/06/13)
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- One-pot cross double-Mannich reaction of acetaldehyde catalyzed by a binaphthyl-based amino sulfonamide
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A one-pot cross double-Mannich reaction of acetaldehyde was developed, and densely functionalized 1,3-diamines were obtained as a single stereoisomer by use of axially chiral amino sulfonamide (S)-1 as catalyst. Using this catalyst, the one-pot Mannich reaction-aminoxylation was also realized.
- Kano, Taichi,Sakamoto, Ryu,Yamaguchi, Yukako,Itoh, Ken-Ichi,Maruoka, Keiji
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supporting information
p. 1118 - 1120
(2013/02/25)
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- Asymmetric synthesis of maraviroc (UK-427,857)
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The asymmetric synthesis of Maraviroc (UK-427,857), a chemochine receptor 5 (CCR-5) receptor antagonist, based on an expeditious organocatalytic enantioselective assembly of the chiral βamino aldehyde key fragment is presented. The reactions were performed on a gram-scale and allow for the rapid construction of new Maraviroc analogues.
- Zhao, Gui-Ling,Lin, Shuangzheng,Korotvicka, Ales,Deiana, Luca,Kullberg, Martin,Cordova, Armando
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supporting information; experimental part
p. 2291 - 2298
(2010/12/20)
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- Controlling stereoselectivity in the aminocatalytic enantioselective mannich reaction of aldehydes with in situ generated N-carbamoyl imines
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A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines has been developed. Both α-imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N-tert-butoxycarbonyl (Boc) or N-carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configura-tion and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N-carbamate-protected imines are generated in situ from stable and easily handled aamido sulfones. 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
- Galzerano, Patrizia,Agostino, Dario,Bencivenni, Giorgio,Sambri, Letizia,Bartoli, Giuseppe,Melchiorre, Paolo
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experimental part
p. 6069 - 6076
(2010/09/07)
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- Novel hexahydropyrrolo[3,4-c]pyrrole CCR5 antagonists
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Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
- Rotstein, David M.,Melville, Chris R.,Padilla, Fernando,Cournoyer, Dick,Lee, Eun K.,Lemoine, Remy,Petersen, Ann C.,Setti, Lina Q.,Wanner, Jutta,Chen, Lijing,Filonova, Lubov,Loughhead, David G.,Manka, Jason,Lin, Xiao-Fa,Gleason, Shelley,Sankuratri, Surya,Ji, Changhua,deRosier, Andre,Dioszegi, Marianna,Heilek, Gabrielle,Jekle, Andreas,Berry, Pamela,Mau, Cheng-I,Weller, Paul
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scheme or table
p. 3116 - 3119
(2010/10/02)
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- The proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc imines
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(Chemical Equation Presented) Double-cross: Proline catalyzes the double Mannich reaction of acetaldehyde with N-Boc imines in excellent yields (up to 99%; Boc = tert-butoxycarbonyl) and close to perfect diastereo- and enantioselectivities. Depending on t
- Chandler, Carley,Galzerano, Patrizia,Michrowska, Anna,List, Benjamin
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supporting information; experimental part
p. 1978 - 1980
(2009/07/25)
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- A designer axially chiral amino sulfonamide as an efficient organocatalyst for direct asymmetric mannich reactions of N-boc-protected imines
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The moderate nucleophilicity of the axially chiral amino sulfonamide (S)-1 suppresses the problematic side reactions, including aldol reactions, in the asymmetric Mannich reaction of N-Boc-protected imines with aldehydes. The corresponding adducts are obtained in good yield and excellent stereoselectivity (see scheme; Boc=tert-butoxycarbonyl, Tf=trifluoromethanesulfonyl).
- Kano, Taichi,Yamaguchi, Yukako,Maruoka, Keiji
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supporting information; experimental part
p. 1838 - 1840
(2009/08/14)
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- METHOD FOR THE PRODUCTION OF CHIRAL AMINOCARBONYL COMPOUNDS
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Disclosed is a method for producing aminocarbonyl compounds of the general formula (I) wherein R1 and R2 can be identical or different and represents hydrogen, alkyl, alkenyl, alkynyl, or aryl,X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, or OR3, R3 representing hydrogen, alkyl, alkenyl, alkynyl, or aryl. According to said method, an aldehyde of the general formula (II) [in-line-formulae]R1CO??(II)[/in-line-formulae] wherein R1 has the meaning indicated above, is reacted with an imine of the general formula (III) wherein R2 and X have the meaning indicated above, in the presence of a catalyst. Aminocarbonyles are obtained by means of catalyzed Mannich reactions with aldehydes. For example, if α-unbranched aldehydes are reacted with previously formed N-Boc imines in the presence of (S)-proline as a catalyst, the desired β-amino aldehydes are obtained at excellent yields, diastereoselectivities and enantioselectivities.
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Page/Page column 5-6
(2009/12/04)
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- PIPERIDINE-4-ACETIC ACID DERIVATIVES AND THEIR USE
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The present invention is directed to compounds of formula (I) compositions comprising them and their use.
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Page/Page column 152
(2009/03/07)
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- Asymmetric synthesis of aza-diospongin A as an iNOS inducer
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The synthesis of the aza-analogue of diospongin A is described. The key steps in the synthetic sequence are Mitsunobu inversion, cross olefin metathesis and intramolecular aza-Michael addition reactions. The biological activity of this new analogue was also evaluated in the induction of nitric oxide synthase and was found to be better when compared to its natural counterpart.
- Chandrasekhar,Kiran Babu,Raji Reddy
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experimental part
p. 2216 - 2219
(2010/03/25)
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- OCTAHYDROPYRROLO [3, 4-C] PYRROLE DERIVATIVES AN THEIR USE AS ANTIVIRAL AGENTS
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Chemokine receptor antagonists, in particular, 3,7-diazabicyclo [3.3.0] octane compounds according to formula (I) wherein R1-R3 and Ar are as defined herein are antagonists of chemokine CCR5 receptors which are useful for treating or preventing an human immunodeficiency virus (HIV) infection, or treating AIDS or ARC. The invention further provides methods for treating diseases that are alleviated with CCR5 antagonists. The invention includes pharmaceutical compositions and methods of using the compounds for the treatment of these diseases. The invention further includes processes for the preparation of compounds according to formula (I).
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- Direct organocatalytic Mannich reaction of acetaldehyde: An improved catalyst and mechanistic insight from a computational study
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(Chemical Equation Presented) A chiral diaryl prolinol silyl ether organocatalyst with an acidis used for the direct catalytic asymmetric Mannich reaction of acetaldehyde and imines. N-Benzoyl-, N-tert-butoxycarbonyl-, and N-toluene-4-sulfonylimines can be employed to produce synthetically useful β-amino aldehydes in goodyield s andwith excellent enantioselectivity (see scheme). The reaction mechanism was investigated quantum-mechanically.
- Hayashi, Yujiro,Okano, Tsubasa,Itoh, Takahiko,Urushima, Tatsuya,Ishikawa, Hayato,Uchimaru, Tadafumi
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supporting information; experimental part
p. 9053 - 9058
(2009/02/08)
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- Discovery of a novel CCR5 antagonist lead compound through fragment assembly
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CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4- yl)piperazin-1-yl)butane-1,4-dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminary SARs were obtained, which are in good agreement with the molecular binding model and should prove helpful for future antagonist design. The novel scaffold presented here might also be useful in the development of maraviroc-derived second generation CCR5 antagonists.
- Liu, Yanqing,Zhou, Enkun,Yu, Kunqian,Zhu, Jin,Zhang, Yu,Xie, Xin,Li, Jian,Jiang, Hualiang
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experimental part
p. 2426 - 2441
(2009/04/11)
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- Substituted monocyclic CGRP receptor antagonists
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Compounds of formula I: (wherein variables A1, A2, A3, A4, m, n, J, Q, R4, Ea, Eb, Ec, R6, R7, Re, Rf, RPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. 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 CGRP is involved.
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Page/Page column 57
(2008/06/13)
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- HETEROCYCLIC ANTIVIRAL COMPOUNDS
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Chemokine receptor antagonists, in particular, 3,7-diazabicyclo [3.3.0] octane compounds according to formula (I) are antagonists of chemokine CCR5 receptors which are useful for treating or preventing an human immunodeficiency virus (HIV) infection, or treating AIDS or ARC. The invention further provides methods for treating diseases that are allieviated with CCR5 antagonists. The invention includes pharmaceutical compositions and methods of using the compounds for the treatment of these diseases. The invention further includes processes for the preparation of compounds according to formula (I).
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- PIPERIDINE DERIVATIVES AS CCR5 RECEPTOR MODULATORS
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Compounds of formula (I) wherein R1, R2, R3, A and n are as defined; and X is S(O)2 NR4R5 or NR6S(O)2R7; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
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Page/Page column 51-52
(2010/02/10)
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- Initial synthesis of UK-427,857 (Maraviroc)
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The initial synthesis of UK-427,857 (Maraviroc) is described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilizing a polymer supported reagent.
- Price, David A.,Gayton, Simon,Selby, Matthew D.,Ahman, Jens,Haycock-Lewandowski, Sarah,Stammen, Blanda L.,Warren, Andrew
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p. 5005 - 5007
(2007/10/03)
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- N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
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The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: wherein, generally, Q is R1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C1-4alkyl or halogen, such as methyl, fluorine or bromine; R2 is hydrogen or C1-4alkyl such as methyl; R3 is phenyl; R4 is hydrogen; R5 is hydrogen or C1-6alkylcarbonyl such as methylcarbonyl; X is —SO2— or —C(O)N(R2)SO2— where R2 is preferably hydrogen; Y is a bond, CH2 or Z1 where Z1 is —N(Rf)— in which Rf is C1-6alkylcarbonyl such as ethylcarbonyl; and R6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C1-6alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.
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Page/Page column 37-38
(2010/11/30)
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- N-4-PIPERIDINYL COMPOUNDS AS CCR5 MODULATORS
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The invention provides a compound of formula (I):[Chemical formula should be inserted here. Please see paper copy.] wherein R1, R2, R3, R3a, R4, R4a, R5, and R6 are as defined; or a pharmaceutically acceptable salt thereof or a solvate thereof; compositions containing these compounds, processes for preparing them and their use as modulators of chemokine activity (especially CCR5 activity).
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- NOVEL PIPERIDINE DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR CCR5
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Compounds of formula (I) wherein R1, R2, R3, R4, A, X, m and n are as defined; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
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Page 92 - 93
(2010/02/07)
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- Modulators of CCR5 chemokine receptor activity
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Compounds of Formula I: (wherein R1, R2, R3, R4, Q, and X are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
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- Tropane derivatives useful in therapy
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The present invention provides compounds of the formula: wherein R1 is C3-6 cycloalkyl optionally substituted by one or more fluorine atoms, or C1-6 alkyl optionally substituted by one or more fluorine atoms, or C3-6 cycloalkylmethyl optionally ring-substituted by one or more fluorine atoms; and R2 is phenyl optionally substituted by one or more fluorine atoms, to pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.
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- Studies directed toward the synthesis of viridenomycin. Route 1: Assembly of three advanced intermediates
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Three enantiomerically and geometrically pure building blocks representing fragments of the antifungal antibiotic viridenomycin have been prepared.
- Kruger, Albert W.,Meyers
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p. 4301 - 4304
(2007/10/03)
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- Synthesis of homochiral N-Boc-β-aminoaldehydes from N-Boc-β-aminonitriles
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Enantiopure N-Boc-β-aminoaldehydes are efficiently prepared in good yields from N-Boc-β-aminonitriles by reduction of the nitrile function with diisobutylaluminium hydride (DIBAL-H) - Keywords: β-aminoaldehyde; β-aminonitrile; α-aminoacid; homochiral; enantiomeric excess; reduction; DIBAL-H
- Toujas, Jean-Louis,Jost, Eric,Vaultier, Michel
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p. 713 - 718
(2007/10/03)
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- Carbohydrates as Chiral Templates: Diastereoselective Synthesis of N-Glycosyl-N-homoallylamines and and β-Amino Acids from Imines
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Complexing properties and chirality of carbohydrates were utilized in diastereoselective reactions of O-pivaloylated N-galactosylimines with allylsilanes and -stannanes.With allyltrimethylsilane in the presence of SnCl4 imines 2 of aromatic and heteroaromatic aldehydes were converted to homoallylamines 3, giving ratios of diastereomers higher than 7:1.No addition products derived from α-anomeric aromatic imines were formed.Aliphatic homoallylamines 3 were synthesized by using allyltributylatannane in the presence of SnCl4.Both α- and β-anomeric aliphatic imines reacted with the allylstannane.They gave the same ratio of diastereomers and showed the same sense of asymmetric induction.
- Laschat, Sabine,Kunz, Horst
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p. 5883 - 5889
(2007/10/02)
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