- Chemoenzymatic synthesis of apremilast: A study using ketoreductases and lipases
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The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED.P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.
- Vega, Kimberly B.,Cruz, Daniel M. V.,Oliveira, Artur R. T.,Da Silva, Marcos R.,De Lemos, Telma L. G.,Oliveira, Maria C. F.,Bernardo, Ricardo D. S.,De Sousa, Jackson R.,Zanatta, Geancarlo,Nasário, Fábio D.,Marsaioli, Anita J.,De Mattos, Marcos C.
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p. 1100 - 1110
(2021/05/19)
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- Chemical synthesis method of lenalidomide key intermediate
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The invention relates to a chemical synthesis method of a lenalidomide key intermediate, i.e., 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. The target compound 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione is prepared by taking a compound 3-nitrophthalic acid as a raw material through cyclization ammoniation, carbonyl reduction, condensation and selective oxidation. The synthesis method has the advantages of few reaction steps, easily available raw materials, mild reaction conditions, low equipment requirements, simple product separation and purification, environmental friendliness, simple operation, good safety, realization of another selection of a lenalidomide synthesis scheme, and good industrial application prospect.
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Paragraph 0021; 0022
(2020/08/26)
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- Luminol or isoluminol synthesizing method by one-pot process
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The invention discloses a luminol or isoluminol synthesizing method by a one-pot process. The luminol or the isoluminol synthesizing method by the one-pot process includes the steps of 1) enabling 3-nitrophthalic acid or 4-nitrophthalic acid as a starting material to react with urea in an organic solvent to obtain 3-nitrophthalimide or 4-nitrophthalimide; 2) enabling the 3-nitrophthalimide or the 4-nitrophthalimide to react with a hydrazine hydrate aqueous solution to obtain 3-nitrophthalhydrazide or 4-nitrophthalhydrazide; 3) enabling the 3-nitrophthalhydrazide or the 4-nitrophthalhydrazide to react with a reducing agent in the presence of a catalyst to obtain luminol or isoluminol. The luminol or the isoluminol synthesizing method by the one-pot process has the advantages of simplicity, convenience in operation, low cost, high yield and less pollution, and can be applicable to industrialized production.
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Paragraph 0060
(2017/08/30)
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- Grinding imidation of anhydrides on smectite clays as recyclable and heterogeneous catalysts under solvent-free conditions
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Imidation of various anhydrides employing solvent-free grindstone technique using smectite clays as recyclable and green catalysts was examined and obtained excellent yields.
- Marvi, Omid
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p. 3501 - 3504
(2017/08/14)
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- An expedient and convenient approach for one-pot synthesis of 1H-isoindole-1,3(2H)-diones
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An easy and expedient method for the one-pot synthesis of 1H-isoindole-1,3(2H)-diones has been developed by the reaction of the corresponding cyclic anhydrides with guanidinium chloride as a nitrogen source in the presence of FeCl3 as a catalyst under mild reaction conditions.
- Ekhtiari, Zeinab,Havasi, Forugh,Nikpour, Farzad
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p. 941 - 944
(2016/10/13)
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- Transition metal-free 1,3-dimethylimidazolium hydrogen carbonate catalyzed hydration of organonitriles to amides
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An efficient hydration of organonitriles to the corresponding amides was accomplished using 1,3-dimethylimidazolium hydrogen carbonate as an organocatalyst. The developed catalytic method was also applicable for the synthesis of metal phthalocyanines.
- Verma, Praveen Kumar,Sharma, Upendra,Bala, Manju,Kumar, Neeraj,Singh, Bikram
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p. 895 - 899
(2013/04/23)
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- Substituent-guided switch between C-H activation and decarboxylative cross-coupling during palladium/copper-catalyzed cascade reactions of 2-aminobenzoates with 2-haloarylaldehydes
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Cascade switch: Phenanthridines, pyrazole[4,3-c]quinolines and isocryptolepine were prepared in one step from the Pd/Cu-catalyzed reaction between potassium 2-aminobenzoates and 2-haloarylaldehydes (see scheme). Although the reactions of 2-aminobenzoates proceeded via a cascade imination/C-H functionalization, the reactions of 6-nitro-2-aminobenzoates ensued via a tandem imination/decarboxylative cross-coupling. Copyright
- Bhowmik, Subhendu,Pandey, Garima,Batra, Sanjay
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supporting information
p. 10487 - 10491
(2013/08/23)
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- Hydrazine-hydroquinone complex as an efficient solid phase hydrazine donor: High yield synthesis of luminol and isoluminol
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Isomeric aminophthalhydrazides, luminol and isoluminol were easily obtained from the corresponding aminoph-thalimides by solid phase hydrazinolysis with the hydrazine-hydroquinone complex in high yields. Synthesis of a novel chemiluminescent agent, a heterocyclic analogue of isoluminol related to aminoimidazolecarboxamide, is also described.
- Chattopadhyay, Gautam,Ray, Partha Sinha
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experimental part
p. 326 - 328
(2011/10/02)
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- Synthesis of some nitrogen mustards (Mannich bases)
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Several Mannich base half nitrogen mustards have been synthesised by the condensation of 3-substituted phthalimides and 4-substituted phthalimides with (2-chloroethyl) amine in ethanol- formalin.
- Sinha, Girish Kumar,Mehra,Kumar, Sharad
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experimental part
p. 1261 - 1264
(2012/04/04)
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- Unexpected reduction of N-hydroxyphthalimides to phthalimides-orthogonal reduction of functionalized N-hydroxyphthalimides
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A chemoselective reduction of N-hydroxyphthalimides to phthalimides under mild conditions has been discovered. It involves reaction of an N-hydroxyimide with bis(pinacolato)diboron in the presence of a base. Other easily reducible functional groups, such as iodo, nitro, or azido groups are unaffected. Alternatively, such functional groups may be selectively reduced without affecting the N-hydroxyimide moiety using a set of classical conditions. Georg Thieme Verlag Stuttgart - New York.
- Jacq, Jér?me,Berthiol, Florian,Einhorn, Cathy,Einhorn, Jacques
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body text
p. 2263 - 2266
(2010/11/24)
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- Formamide, a novel challenging reagent for the direct synthesis of non-N-substituted cyclic imides
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Aliphatic and aromatic cyclic imides have been prepared in high to moderate yields from cyclic carboxylic anhydrides or corresponding dicarboxylic acids, using formamide as reagent at 170-180°C for 5-6 hours. In the case of aromatic products with lower solubility in formamide, we used N-methyl-2-pyrrolidinone (NMP) as supplementary solvent, which facilitates the reaction.
- Chiriac, Constantin I.,Nechifor, Marioara,Tanasǎ, Fulga
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p. 883 - 886
(2008/09/20)
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- A facile and convenient synthesis of 1H-isoindole-1,3(2H)-diones
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A facile synthesis of 1H-isoindole-1,3(2H)-diones (3a-h) has been developed by the reaction of the corresponding anhydrides (1a-h) with potassium cyanate (4a) or sodium thiocyanate (4b). The reactions were carried out in neutral media under reflux or under microwave irradiation without use of catalyst. Good to excellent yields of the products were obtained in high purity with very simple work-up.{A figure is presented}.
- Nikpour, Farzad,Kazemi, Samira,Sheikh, Davood
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p. 1559 - 1564
(2007/10/03)
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- Synthesis of 3-Nitrophthalonitrile and Tetra-α-substituted
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An efficient synthesis of phthalocyanines prepared from ortho-substituted phthalonitriles is described.The precursor to these phthalocyanines, 3-nitrophthalonitrile, is a key reagent for syntheses of phthalonitriles substituted at the 3-position by means of nucleophilic aromatic substitutions.An example of this type of phthalocyanine, prepared from 3-(4-cumylphenoxy)phthalonitrile, is compared with the phthalocyanine derived from 4-(4-cumylphenoxy)phthalonitrile.Substitution of the phthalocyanine at this more sterically crowded site causes a 20 nm bathochromic shift of the Q-band (?-?* transition).
- George, Robert D.,Snow, Arthur W.
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p. 495 - 498
(2007/10/02)
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- Kinetic and equilibrium in the ammonolysis of substituted phthalimides
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Kinetic studies are reported for the base hydrolysis to phthalamic acid anions (H) and ammonolysis to phthalamides (A) for seven phthalimides (P): 1, unsubstituted; 2, 4-NO2; 3, 4-Cl; 4, 4-tBu; 5, 3-NO2; 6, 3-Me; 7, 3-Me3Si.The hydrolysis kinetics require two mechanisms, one which is first order in neutral imide and first order in hydroxide ion, and a second, which is important only in quite concentrated NaOH, which is first order in neutral phthalimide and second order in hydroxide ion.Ammonolysis kinetics for 1-5 revealed the rate law: Rate = kN ->.A mechanism is proposed with rate-determining breakdown of the anionic form of the tetrahedral intermediate derived by addition of NH3 to the phthalimide.The ammonolysis is reversible.The phthalamide hydrolyzes to the phthalamic acid via cyclization to an intermediate phthalimide, which is detected in concentrated base where its formation from phthalamide is more rapid than its subsequent hydrolysis.Rate constants for the cyclization follow the rate law: Rate = kcyc ->.This reaction is the microscopic reverse of the ammonolysis, and the ratio kN/kcyc provides the equilibrium constant Keq for the reaction P + NH3 = A.Values for 1-5 lie in the range 2 x 102 - 4 x 103.With 3-methylphthalimide, kinetics in aqueous ammonia do not obey a first-order relationship, but they could be analyzed by a scheme whereby the phthalimide is converted reversibly to the phthalamide and simultaneously undergoes an irreversible hydrolysis.The value of Keq in the system is 1.8.With 3-trimethylsilylphthalimide the value of Keq is further reduced to 0.01.The ammonolysis reaction does occur more quickly than hydrolysis but the equilibrium is so unfavorable that even in concentrated ammonia only a small amount of the phthalamide is ever formed.
- McClelland, Robert A.,Seaman, N. Esther,Duff, James M.,Branston, R. E.
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p. 121 - 128
(2007/10/02)
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