492-38-6Relevant academic research and scientific papers
Microbial metabolism of bornaprine, 3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate
Elmarakby,Clark,Baker,Hufford
, p. 614 - 618 (1986)
Metabolism studies of the anticholinergic drug, bornaprine [3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate, an epimeric mixture (1)], in rats, dogs, and humans have been conducted previously, but the identities of the metabolites were not established. Using an in vitro microbial system to study the metabolism of bornaprine resulted in the isolation of four metabolites whose structures were rigorously established using spectroscopic techniques, especially 13C NMR. The four metabolites found (2, 3, 4, and 5) were hydroxylated at C-5 or C-6 in the bicyclic ring.
Insights into the novel hydrolytic mechanism of a diethyl 2-phenyl-2-(2-arylacetoxy)methyl malonate ester-based microsomal triglyceride transfer protein (MTP) inhibitor
Ryder, Tim,Walker, Gregory S.,Goosen, Theunis C.,Ruggeri, Roger B.,Conn, Edward L.,Rocke, Benjamin N.,Lapham, Kimberly,Steppan, Claire M.,Hepworth, David,Kalgutkar, Amit S.
, p. 2138 - 2152 (2012)
Inhibition of intestinal and hepatic microsomal triglyceride transfer protein (MTP) is a potential strategy for the treatment of dyslipidemia and related metabolic disorders. Inhibition of hepatic MTP, however, results in elevated liver transaminases and increased hepatic fat deposition consistent with hepatic steatosis. Diethyl 2-((2-(3-(dimethylcarbamoyl)-4-(4′- (trifluoromethyl)-[1,1′-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)methyl) -2-phenylmalonate (JTT-130) is an intestine-specific inhibitor of MTP and does not cause increases in transaminases in short-term clinical trials in patients with dyslipidemia. Selective inhibition of intestinal MTP is achieved via rapid hydrolysis of its ester linkage by liver-specific carboxylesterase(s), resulting in the formation of an inactive carboxylic acid metabolite 1. In the course of discovery efforts around tissue-specific inhibitors of MTP, the mechanism of JTT-130 hydrolysis was examined in detail. Lack of 18O incorporation in 1 following the incubation of JTT-130 in human liver microsomes in the presence of H218O suggested that hydrolysis did not occur via a simple cleavage of the ester linkage. The characterization of atropic acid (2-phenylacrylic acid) as a metabolite was consistent with a hydrolytic pathway involving initial hydrolysis of one of the pendant malonate ethyl ester groups followed by decarboxylative fragmentation to 1 and the concomitant liberation of the potentially electrophilic acrylate species. Glutathione conjugates of atropic acid and its ethyl ester were also observed in microsomal incubations of JTT-130 that were supplemented with the thiol nucleophile. Additional support for the hydrolysis mechanism was obtained from analogous studies on diethyl 2-(2-(2-(3-(dimethylcarbamoyl)-4-(4′-trifluoromethyl)-[1, 1′-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)ethyl)-2-phenylmalonate (3), which cannot participate in hydrolysis via the fragmentation pathway because of the additional methylene group. Unlike the case with JTT-130, 18O was readily incorporated into 1 during the enzymatic hydrolysis of 3, suggestive of a mechanism involving direct hydrolytic cleavage of the ester group in 3. Finally, 3-(ethylamino)-2-(ethylcarbamoyl)-3-oxo-2-phenylpropyl 2-(3-(dimethylcarbamoyl)-4-(4′-(trifluoromethyl)-[1,1′-biphenyl] -2-ylcarboxamido)phenyl)acetate (4), which possessed an N,N-diethyl-2- phenylmalonamide substituent (in lieu of the diethyl-2-phenylmalonate motif in JTT-130) proved to be resistant to the hydrolytic cleavage/decarboxylative fragmentation pathway that yielded 1, a phenomenon that further confirmed our hypothesis. From a toxicological standpoint, it is noteworthy to point out that the liberation of the electrophilic acrylic acid species as a byproduct of JTT-130 hydrolysis is similar to the bioactivation mechanism established for felbamate, an anticonvulsant agent associated with idiosyncratic aplastic anemia and hepatotoxicity.
Synthesis of well-defined (AB)n multiblock copolymers composed of polystyrene and poly(methyl methacrylate) segments using specially designed living AB diblock copolymer anion
Sugiyama, Kenji,Oie, Toshiyuki,Ei-Magd, Ahmed Abou,Hirao, Akira
, p. 1403 - 1410 (2010)
We have developed a new iterative methodology using α-chain-end- functionalized living AB diblock copolymer anion as a key building block in order to synthesize a series of well-defined (AB)n multiblock copolymers composed of polystyrene (PS) and poly(methyl methacrylate) (PMMA). The methodology involves the following three reaction steps in the entire iterative synthetic sequence: (1) a sequential living anionic block copolymerization to prepare α-chain-end-functionalized living AB diblock copolymer anion with the 3-tert-butyldimethylsilyloxypropyl (SiOP) group, (2) an introduction of α-phenyl acrylate function (PA) via the SiOP group by deprotection followed by Mitsunobu esterification, and (3) a linking reaction of α-cham-end-PA-functionalized AB diblock copolymer with α-chain-end-SiOP-functionalized living AB diblock copolymer anion. The same iterative synthetic sequence involving the three reaction steps was repeated several times to successively synthesize a series of (AB)n multiblock copolymers (n = 2, 3, 4, and 5) with precisely controlled molecular weights and compositions and very narrow molecular weight distributions (M wMn ≤ 1.06). Furthermore, different two series of (AB)n multiblock copolymers (n = 2 and 3) composed of PS and either poly(tert-butyl methacrylate) or poly(2-vinylpyridine) blocks were successfully synthesized by the same methodology using the corresponding α-chain-end- SiOP-functionalized living AB block copolymer anions.
Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens
Fu, Kaiyue,Ma, Yu,Sun, Yaxin,Tang, Bo,Yang, Guang,Yang, Peng,Yue, Jieyu,Zhang, Li,Zhou, Jianrong Steve
supporting information, (2021/11/22)
We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.
Hydrocarboxylation of alkynes with formic acid over multifunctional ligand modified Pd-catalyst with co-catalytic effect
Chen, Xiao-Chao,Guo, Lin,Liu, Lei,Liu, Ye,Lu, Yong,Yao, Yin-Qing,Zhao, Xiao-Li
, p. 322 - 332 (2022/01/06)
Hydrocarboxylation of terminal alkynes with formic acid (FA) was accomplished over a multifunctional ligand (L2) modified Pd-catalyst, advantageous with 100% atom-economy, free use of CO and H2O, mild reaction conditions, and high yields (56–89%) of α,β-unsaturated carboxylic acids with 100% regioselectivity to the branched ones. The multifunctional ligand of L2 as a zwitterion salt containing the phosphino-fragment (-PPh2), Lewis acidic phosphonium cation and sulfonate group (-SO3?), was constructed on the skeleton of 1.1′-binaphthyl-2.2′-diphenyl phosphine (BINAP) upon selective quaternization by 1,3-propanesultone. It was found that L2 conferred to the Pd-catalyst the co-catalytic effect, wherein the phosphino-coordinated Pd-complex was responsible for activation of all the substrates (including CO, FA and alkyne), and the incorporated phosphonium cation was responsible for synergetic activation of FA. The 1H NMR spectroscopic analysis supported that FA was truly activated by the incorporated Lewis acidic phosphonium cation in L2 via “acid-base pair” interaction. The in situ FT-IR spectra demonstrated that, the presence of Ac2O and NaOAc additives in the catalytic amount could dramatically promote the in situ release of CO from FA, which was required to initiate the hydrocarboxylation.
Monosubstituted 3,3-Difluorocyclopropenes as Bench-Stable Reagents: Scope and Limitations
Nosik, Pavel S.,Pashko, Mykola O.,Poturai, Andrii S.,Kvasha, Denys A.,Pashenko, Alexander E.,Rozhenko, Alexander B.,Suikov, Sergiy,Volochnyuk, Dmitriy M.,Ryabukhin, Sergey V.,Yagupolskii, Yurii L.
, p. 6604 - 6615 (2021/12/08)
A general approach to gem-difluorocyclopropenes synthesis based on the reaction of alkynes with Ruppert-Prakash reagent is reported. The proposed method is evaluated for the synthesis of a wide difluorocyclopropenes scope based on their bench lifespan and hydrolytic stability. The tolerance of the method for common functional groups was shown. Previously unavailable difluorocyclopropenes substituted with aliphatic were prepared using the proposed procedure. The retain of stability was proven by the multigram scale synthesis and further storage in the temperature interval ?78 to ?4 °C over a year. This makes them attractive building blocks and intermediates for organic synthesis. The reasons for dropping stability were defined. The relations between the structure of the substituents and the stability of the difluorocyclopropene ring were determined and discussed.
Water-initiated hydrocarboxylation of terminal alkynes with CO2and hydrosilane
Wang, Meng-Meng,Lu, Sheng-Mei,Paridala, Kumaraswamy,Li, Can
supporting information, p. 1230 - 1233 (2021/02/09)
This work discloses a Cu(ii)-Ni(ii) catalyzed tandem hydrocarboxylation of alkynes with polysilylformate formed from CO2and polymethylhydrosiloxane that affords α,β-unsaturated carboxylic acids with up to 93% yield. Mechanistic studies indicate that polysilylformate functions as a source of CO and polysilanol. Besides, a catalytic amount of water is found to be critical to the reaction, which hydrolyzes polysilylformate to formic acid that induces the formation of Ni-H active species, thereby initiating the catalytic cycle.
Method for preparing alpha, beta-unsaturated carboxylic acid compound
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Paragraph 0103-0104; 0503-0510, (2021/05/05)
The invention discloses a method for preparing an alpha, beta-unsaturated carboxylic acid compound, which comprises the following steps: 1) in an atmosphere containing carbon dioxide, heating and reacting a mixture containing hydrosilane and a copper catalyst to obtain a system I; and 2) adding a raw material containing alkyne and a nickel catalyst into the system I in the step 1), and heating to react. The method has the advantages of simple, easily available, cheap and stable raw materials, common, easily available and stable catalyst, mild reaction conditions, simple post-treatment, high yield and the like.
Palladium-Catalyzed Highly Regioselective Hydrocarboxylation of Alkynes with Carbon Dioxide
Chen, Pengquan,Cheng, Ruixiang,Jiang, Huanfeng,Lei, Ming,Lou, Hongming,Qi, Chaorong,Shi, Fuxing,Wang, Lu,Wu, Wanqing,Xiong, Wenfang,Zhu, Baiyao
, p. 7968 - 7978 (2020/08/21)
A Pd-catalyzed highly regioselective hydrocarboxylation of alkynes with carbon dioxide has been established. By the combination of Pd(PPh3)4 and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (binap), a variety of functionalized alkynes, including aryl alkynes, aliphatic alkynes, propargylamines, and propargyl ethers, could be leveraged to provide a wide array of α-acrylic acids in high yields with high regioselectivity under mild reaction conditions. Experimental and DFT mechanistic studies revealed that this reaction proceeded via the cyclopalladation process of alkynes and carbon dioxide in the presence of binap to generate a five-membered palladalactone intermediate and enabled the formation of Markovnikov adducts. Moreover, this strategy provided an effective method for the late-stage functionalization of alkyne-containing complicated molecules, including natural products and pharmaceuticals.
Method for preparing aromatic carboxylic acid compound
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Paragraph 0085-0086; 0168-0170; 0177, (2020/02/14)
The invention discloses a method for preparing an aromatic carboxylic acid compound. The method comprises the following steps: 1) heating carbon dioxide and hydrosilane in the presence of a copper catalyst in a reaction medium A; and 2) adding a reaction medium B, aryl halide, a palladium catalyst and a base to the reaction mixture in the step 1), sealing the reaction system, and performing a heating reaction. The method has the advantages that raw materials are simple and easy to obtain, the raw materials are cheap and stable, the catalyst is common, easy to obtain and stable, the reaction conditionsaremild, the aftertreatment is simple, the yield is high, and the like.
