- An efficient, commercially viable, and safe process for preparation of losartan potassium, an angiotensin II receptor antagonist
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An efficient, commercially viable and safe process for the preparation of losartan potassium, an antihypertensive drug substance, with an overall yield of 55.5% and ~99.9% purity (including five chemical reactions and two recrystallizations) and meeting all other regulatory requirements is described. Formation and control of all the possible impurities are also described.
- Madasu, Suri Babu,Vekariya,Koteswaramma, Ch,Islam, Aminul,Sanasi, Paul Douglas,Korupolu, Raghu Babu
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Read Online
- Synthesis, characterization and in vitro screening on bacterial, fungal and malarial strain of piprazinyl cyano biphenyl based compounds
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A series of eight 4′-[4-(3-substituted phenyl-acryloyl)-piprazin-1- ylmethyl]-biphenyl-2-carbonitrile were synthesized using 4′-Bromomethyl- biphenyl-2-carbonitrile and 4-Acetyl piprazine as a starting material. Furthermore, there has been some additional work done investigating effects of these derivatives on biological activities on bacterial, fungal and malarial strain. Synthesized compounds were characterized using FTIR, 1H NMR and 13C NMR spectrometry. These compounds shows good antimalarial, antibacterial and antifungal activity. In fact some compounds are more potent than standard drug quinine and Ampicillin some are with comparable activity with Ampicillin and quinine.
- Malani, Mahesh H.,Dholakiya, Bharat Z.
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Read Online
- Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction
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Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a–m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50value?=?13.16?μM), 5d (IC50value?=?15.66?μM) and 5j (IC50value?=?19.16?μM) had shown good PDF inhibition activity. The compounds 5a (MIC range?=?11.00–15.83?μg/mL), 5b (MIC range?=?23.75–28.50?μg/mL) and 5j (MIC range?=?7.66–16.91?μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range?=?25–50?μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a–m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.
- Khan, Firoz A. Kalam,Patil, Rajendra H.,Shinde, Devanand B.,Sangshetti, Jaiprakash N.
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Read Online
- A high-throughput process for valsartan
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With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4′-methyl-biphenyl-2-carbonitrile (6) to 4′bromomethyl-biphenyl-2- carbonitrile (5), halogenated solvents are no longer used in the whole valsartan production process. The alkylation of (S)-2-amino-3-methyl-butyric acid benzyl ester (8) with 4′-bromomethyl-biphenyl-2-carbonitrile (5), and the acylation of(S)-2-[(2′-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid benzyl ester (4) to (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)-pentanoyl- amino]-3-methyl-butyric acid benzyl ester (3) were thoroughly modified. In the acylation of 4 to 3, N-ethyldiisopro-pylamine was replaced by aqueous sodium hydroxide by using the conditions of the Schotten-Baumann reaction, leading to a better quality of intermediate 3. In the alkylation of 8 with 5, N-ethyldiisopropylamine was indirectly replaced by aqueous sodium hydroxide. The reaction runs under homogenous conditions with (S)-2-amino-3-methyl-butyric acid benzyl ester (8) acting as acceptor for hydrobromic acid; recycling of 8 is performed by extraction with aqueous sodium hydroxide.
- Beutler, Ulrich,Boehm, Matthias,Fuenfschilling, Peter C.,Heinz, Thomas,Mutz, Jean-Paul,Onken, Ulrich,Mueller, Martin,Zaugg, Werner
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Read Online
- Readily Reconfigurable Continuous-Stirred Tank Photochemical Reactor Platform
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A new modular photochemical continuous stirred-tank reactor (CSTR) design is described, based upon the development of light-source units that can be fitted to the previously described fReactor CSTR platform. In addition to use in homogeneous photochemical reactions (e.g., photoredox-catalyzed hydroamination), these units are especially well suited to handling multiphasic mixtures, exemplified here in solid-liquid (Wohl-Ziegler bromination) and gas-liquid (photocatalytic oxidative decarboxylation) reactions. The use of slurries as input feeds allows for the intensification of photochemical brominations, while the modular nature of the system facilitates the simple integration of downstream reaction steps, exemplified here in a continuous synthesis of an intermediate for the antihypertensive drug valsartan.
- Blacker, A. John,Francis, Daniel,Kapur, Nikil,Marsden, Stephen P.
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supporting information
(2022/01/12)
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- Photocatalytic continuous bromination method
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The invention provides a photocatalytic continuous bromination method. The method comprises the following steps: carrying out a first-stage photocatalytic continuous bromination reaction on a materialcontaining an aromatic substrate with a structural general formula I and a bromination reagent in a first continuous illumination reactor to form a first continuous system; overflowing the obtained first continuous system into a second continuous illumination reactor for a second-stage photocatalytic continuous bromination reaction to form a second continuous system; and purifying the second continuous system, wherein the structural general formula I is shown in the specification, R is selected from any one of carboxyl, ester group, NO2, CN, C1 to C8 alkyl and alkoxy, and R1 is C1 to C8 alkyl; n is 1 or 2; X is N or C, and the bromination reagent is Nbromo succinimide or dibromohydantoin. According to the bromination reagent, the selectivity of a product is improved, so the yield of the product is improved; the photocatalytic continuous bromination reaction of the two stages effectively relieves the reaction heat accumulation, and enhances the yield of the target product.
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Paragraph 0070-0071
(2021/04/03)
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- Preparation method of bromoilsartan soluble in 1,2 - dichloroethane (by machine translation)
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The invention discloses a preparation method of brominated sartan biphenyl dissolved 1,2 - dichloroethane, and belongs to the technical field of pharmaceutical chemical engineering. The method uses methylbiphenyl as a raw material, 1,2 - dichloroethane as a solvent, and a brominated reagent, dibromohydantoin, N - bromosuccinimide or sodium bromide and sodium bromate. 2 - Cyano -4 ’ - bromomethylbiphenyl synthesized by the method is good in purity, high in yield, simple in reaction system, low in toxicity, high in atom conversion rate and suitable for industrial application in the field of biological medicine. (by machine translation)
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Paragraph 0036-0054
(2020/07/12)
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- Preparation method of bromo-sartan biphenyl based on hydrogen peroxide-hydrobromic acid system
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The invention discloses a preparation method of bromo-sartan biphenyl based on a hydrogen peroxide-hydrobromic acid system, and belongs to the technical field of pharmaceutical chemicals. The invention discloses a method for preparing substituent-containing bromo-sartan biphenyl by using a flowing photochemical method. According to the method, methyl biphenyl is used as a raw material, hydrobromicacid is used as a bromination reagent, hydrogen peroxide is used as an oxidation reagent, acetonitrile or ethyl acetate is used as a solvent, and after the raw material, the bromination reagent and the oxidation reagent are respectively mixed with the solvent, the mixture flows into a pipeline through an injection pipe, is mixed through a mixer, enters a constant-temperature water bath reactor and undergoes a reaction through illumination. The 2-cyano-4'-bromomethylbiphenyl synthesized by the method is good in purity, high in yield, simple in a reaction system, low in toxicity and high in atom conversion rate, is suitable for industrial application in the field of biological medicines, can be suitable for an automatic continuous production process, and conforms to the development conceptsof green chemical industry, high efficiency and economy.
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Paragraph 0036-0056
(2020/07/15)
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- High-temperature preparation method of 4'-bromomethyl-2-cyanobiphenyl based on bromine
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The invention discloses a high-temperature preparation method of 4'-bromomethyl-2-cyanobiphenyl based on bromine, belongs to the technical field of pharmaceutical chemicals, and particularly disclosesa method for preparing substituent-containing 4'-bromomethyl-2-cyanobiphenyl by using a flowing photochemical method. An oxidant and a radical initiator are not needed; and methyl biphenyl is used asa raw material, bromine is used as a bromination reagent, ethyl acetate, glacial acetic acid or N,N-dimethylformamide is used as a solvent, and after the raw material and the bromination reagent arerespectively mixed with the solvent, the obtained mixtures flow into a pipeline through injection pipes, and are mixed by a mixer, and then the obtained mixture enters a constant-temperature water bath reactor and is subjected to a reaction through illumination. The 4'-bromomethyl-2-cyanobiphenyl synthesized by the method is good in purity, high in yield, simple in reaction system and low in toxicity, is suitable for industrial application in the field of biological medicines, can be suitable for an automatic continuous production process, and conforms to the development concepts of green chemical industry, high efficiency and economy.
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Paragraph 0038-0058
(2020/07/12)
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- Continuous flow method for synthesizing p-bromo-methyl biphenyl carbonitrile and reaction device thereof
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The invention discloses a continuous flow method for synthesizing p-bromo-methyl biphenyl carbonitrile and a reaction device for synthesizing p-bromo-methyl biphenyl carbonitrile. P-methyl biphenyl carbonitrile is used as a raw material; bromine generated by oxidizing hydrobromic acid through hydrogen peroxide is used as a bromination reagent; materials are continuously input into an efficient mixer through a metering pump to be mixed and then enter a pipeline reactor; and temperature control and illumination on reactants in the pipeline reactor are carried out to complete bromination reaction, quenching of a reaction liquid in the pipeline reactor is carried out, continuous liquid separation, and drying, concentration and recrystallization purification on the obtained organic phase are carried out to obtain the pure p-bromo-methyl biphenyl carbonitrile product. The bromination reaction has the advantages of high bromine atom utilization rate, fewer byproducts and fewer solid wastes, and conforms to the concept of green chemistry; the continuous flow synthesis method has the advantages of good safety, convenience in intelligent control, short reaction time, high post-treatment efficiency and the like, and has industrial production and application values.
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Paragraph 0035; 0056-0086
(2020/12/05)
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- Synthesis of 5-Substituted 1 H-Tetrazoles from Nitriles by Continuous Flow: Application to the Synthesis of Valsartan
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An efficient continuous flow process for the synthesis of 5-substituted 1H-tetrazoles is described. The process involves the reaction between a polymer-supported triorganotin azide and organic nitriles. The polymer-supported organotin azide, which is in situ generated with a polystyrene-supported triorganotin alkoxide and trimethylsilylazide, is immobilized in a packed bed reactor. This approach is simple, fast (it takes from 7.5 to 15 min), and guarantees a low concentration of tin residues in the products (5 ppm). The process was developed to aryl-, heteroaryl-, and also alkylnitriles and was applied for the synthesis of valsartan, an angiotensin II receptor antagonist.
- Carpentier, Florian,Felpin, Fran?ois-Xavier,Zammattio, Fran?oise,Le Grognec, Erwan
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p. 752 - 761
(2020/03/13)
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- Normal-temperature 4'-bromomethyl-2-cyanobiphenyl preparation method based on sodium bromide-sodium bromate system
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The invention discloses a normal-temperature 4'-bromomethyl-2-cyanobiphenyl preparation method based on a sodium bromide-sodium bromate system, belongs to the technical field of pharmaceutical chemicals, and particularly discloses a method for preparing substituent-containing 4'-bromomethyl-2-cyanobiphenyl by using a flowing photochemical method. An oxidant and a radical initiator are not needed;and methyl biphenyl is used as a raw material, sodium bromide and sodium bromate are used as bromination reagents, acetone, dichloromethane, petroleum ether or acetonitrile is used as a solvent, and after the raw material and the bromination reagents are respectively mixed with the solvent, the obtained mixtures flow into a pipeline through injection pipes, and are mixed by a mixer, and then the obtained mixture enters a constant-temperature water bath reactor and is subjected to a reaction through illumination. The 4'-bromomethyl-2-cyanobiphenyl synthesized by the preparation method is good in purity, high in yield, simple in reaction system and low in toxicity, is suitable for industrial application in the field of biological medicines, can be suitable for an automatic continuous production process, and conforms to the development concepts of green chemical industry, high efficiency and economy.
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Paragraph 0037-0057
(2020/07/12)
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- Preparation method of normal-temperature bromoethyl cyanobiphenyl based on dibromohydantoin
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The invention discloses a preparation method of normal-temperature bromoethyl cyanobiphenyl based on dibromohydantoin, and belongs to the technical field of pharmaceutical chemicals, and particularlydiscloses a method for preparing substituent-containing bromoethyl cyanobiphenyl by using a flowing photochemical method. According to the method, an oxidant and a radical initiator are not needed; methyl biphenyl is used as a raw material, dibromohydantoin is used as a bromination reagent, acetone, dichloromethane, petroleum ether or acetonitrile is used as a solvent, and after the raw material and the bromination reagent are respectively mixed with the solvent, the mixture flows into a pipeline through an injection pipe, is mixed by a mixer, then enters a constant-temperature water bath reactor and is subjected to a reaction through illumination. The 2-cyano-4 '-bromomethylbiphenyl synthesized by the method is good in purity, high in yield, simple in reaction system and low in toxicity,is suitable for industrial application in the field of biological medicines, can be suitable for an automatic continuous production process, and conforms to the development concepts of green chemicalindustry, high efficiency and economy.
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Paragraph 0037-0057
(2020/07/13)
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- Method for preparing 4'-bromomethyl-2-cyanobiphenyl by using continuous bromination reaction under illumination
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The invention discloses a method for preparing 4'-bromomethyl-2-cyanobiphenyl by using a continuous bromination reaction under illumination. The method comprises that dissolving 4'-methyl-2-cyanobiphenyl and a brominating reagent according to a ratio in an organic solvent in advance, injecting the mixture into a specific light reactor by using a pump, and controlling reaction conditions to obtain4'-bromomethyl-2-cyanobiphenyl. The method is a continuous bromination reaction under illumination conditions, the reaction time is shortened, the production efficiency is improved, the formation of side reactions is reduced, the selectivity and conversion rate of the reaction are improved, and the raw material cost is reduced.
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Paragraph 0030-0067
(2019/10/01)
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- A losartan hypotensor important intermediate 2 - cyano -4 ' - bromomethyl biphenyl preparation method
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The invention discloses a losartan hypotensor important intermediate 2 - cyano - 4 '- bromomethyl biphenyl preparation method, the method is: shown in formula I 2 - cyano - 4' - methyl biphenyl as the raw material, in order to bromine as a bromine source, hydrogen peroxide as the oxidizing agent, under the action of the free radical initiator, in the uniformly mixed in the organic solvent, obtaining mixture, is then added in the mixture of water-sealing, under the illumination condition, in the 25 °C - 100 °C reaction, TLC detection raw materials after the basic full transformation, thereby obtaining a reaction mixed solution after treatment [...] II indicated by the 2 - cyano - 4' - bromomethyl biphenyl; the method of the invention low cost, mild condition, high-efficiency, high atom economy, friendly to the environment.
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Paragraph 0028-0057
(2019/06/12)
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- Method for tubular reaction preparation of substituted benzylically brominated methyl biphenyl and reaction device of method
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The invention discloses a method for tubular reaction preparation of substituted benzylically brominated methyl biphenyl and a reaction device of the method. According to the method, substituted methyl biphenyl is taken as a raw material and bromine is taken as a bromination reagent. The reaction materials are continuously fed into a high-efficiency mixer for mixing through a liquid conveying pump, and the formed mixture enters a reactor in a water bath for a reaction, after the reaction is finished, the reaction system enters a receiving tank, a reducing agent is added to the receiving tank for quenching, liquid separation is carried out, anhydrous sodium sulfate is added into the organic phase, suction filtration is performed, the organic phase is subjected to reduced-pressure concentration for solvent removal, a solvent is added for recrystallization, suction filtration is performed, and the filter cake is dried to obtain a pure product namely the substituted benzylically brominatedmethyl biphenyl. The method of the invention is simple and convenient to control, high in safety, less in generation of by-products and convenient for post-processing, a small trial process can be directly used for amplified production. The method meets the requirements of green chemistry and has a certain industrial application value.
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Paragraph 0038-0055
(2018/06/15)
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- A 4' - bromo methyl -2 - cyano biphenyl preparation method (by machine translation)
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The invention relates to the technical field of chemical engineering, in particular to discloses a 4 '- bromomethyl - 2 - cyano biphenyl preparation method, comprises the following steps: to the reaction bottle adding organic solvent, water and 4' - methyl - 2 - cyano biphenyl, subsequently joined the bromination salt, bromate or chlorate, stirring at the room temperature uniform, controlling the reaction temperature at 15 - 25 °C, drops of hydrochloric acid solution, dropping time is 5 - 20 hours, then completing, control temperature 15 - 45 °C continue to reaction 1 hour, TLC detection end point of the reaction; the reaction end-layered, the organic layer concentrated to dry, it is crude; the crude product is dissolved in the solvent recrystallization, shall be 4' - bromomethyl - 2 - cyano biphenyl pure product. The present invention overcomes the disadvantages of the prior art, mild reaction conditions, the reaction selectivity is high, few by-products, the apparatus corrosiveness is small, the operation is simple, low cost, small environmental pressure, the product is easy to separation, brominated agent is safe and easy to operate, bromine atom utilization rate is high, it is easy to industrial production, high purity of the product. (by machine translation)
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Paragraph 0037-0055; 0057; 0058; 0059; 0061; 0063
(2018/07/06)
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- 2 - R - 4' - bromomethyl biphenyl and its preparation method
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The invention discloses 2-R-4'-bromomethyl biphenyl and a preparation method thereof. According to the method provided by the invention, raw materials such as 2-R-4'-methyl biphenyl, sodium bromate, sodium bromide, concentrated sulfuric acid, water and a first organic solvent are provided. The method comprises the operation of a bromination step, namely 2-R-4'-methyl biphenyl, sodium bromate, sodium bromide and the water serving as a solvent are added in a reactor and are mixed uniformly, concentrated sulfuric acid diluted with water is added dropwise in the stirring reactor at 0-50 DEG C, and the reaction system keeps reacting for 4-12 hours at 0-50 DEG C to obtain a bromination product reaction liquid. According to the preparation method provided by the invention, the required raw materials are easily available, a bromine resource is generated during the reaction process and has high reactivity, the atom economy of bromine atoms is very high, the cost is low, the process condition is stable, the operation is simple, and requirements on a reaction kettle and corollary equipment are low, so that industrialization is easy to realize.
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Paragraph 0040; 0041; 0045; 0046; 0050; 0051; 0055; 0056
(2017/08/26)
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- Design and synthesis of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs as bacterial peptide deformylase inhibitors
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Herein, we report the synthesis and screening of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC50 value?=?139.28?μm), 11g (IC50 value?=?136.18?μm), and 11h (IC50 value?=?131.65?μm) had shown good PDF inhibition activity. The compounds 11b (MIC range?=?103.36–167.26?μg/mL), 11g (MIC range?=?93.75–145.67?μg/mL), and 11h (MIC range?=?63.61–126.63?μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range?=?100.00–250.00?μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.
- Khan, Firoz A. Kalam,Patil, Rajendra H.,Shinde, Devanand B.,Sangshetti, Jaiprakash N.
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p. 938 - 944
(2016/11/11)
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- An efficient and green synthetic route to losartan
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A practical, efficient and green process for the preparation of losartan, an antihypertensive drug, has been developed with an overall yield of 58.6%. The key step is the synthesis of the two key intermediates 2-butyl-4-chloro-3H-imidazole-5-carbaldehyde (BCFI) and 2-cyano-4'-methyl biphenyl (OTBN). BCFI was synthesised from valeronitrile and acetyl chloride by three steps with an overall yield of 69%; OTBN was obtained in 86% yield by the coupling of o-chlorobenzonitrile with p-methylphenylmagnesium chloride in tetrahydrofuran in the presence of manganese chloride and chlorotrimethylsilane. The above route was successfully operated in at a pilot-plant operation.
- Shuangxia, Feng,Zheng, Gu,Yelv, Tang,Hui, Liu,Guofang, Jiang
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p. 451 - 454
(2015/11/03)
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- PPARG MODULATORS FOR TREATMENT OF OSTEOPOROSIS
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The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.
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Page/Page column 241; 266; 267
(2015/11/09)
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- A scalable procedure for light-induced benzylic brominations in continuous flow
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A continuous-flow protocol for the bromination of benzylic compounds with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates containing different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h-1), which is not easily possible in batch photochemical reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h -1 for the desired bromide was achieved.
- Cantillo, David,De Frutos, Oscar,Rincon, Juan A.,Mateos, Carlos,Oliver Kappe
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supporting information
p. 223 - 229
(2014/01/17)
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- Synthesis and evaluation of quinazoline derivatives as phosphodiesterase 7 inhibitors
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The latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7.
- Sánchez, Ana I.,Martínez-Barrasa, Valentín,Burgos, Carolina,Vaquero, Juan J.,Alvarez-Builla, Julio,Terricabras, Emma,Segarra, Víctor
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p. 2370 - 2378
(2013/05/09)
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- N-ARYLYLMETHYLINDAZOLE MODULATORS OF PPARG
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The invention provides molecular entities that bind with high affinity to PPARG (PPARy), inhibit cdJk5-mediated phosphorylation of PP ARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes or obesity. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
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Page/Page column 106; 107
(2013/06/06)
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- Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-α
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The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-α and GSK-3β to AD pathology and AML is ongoing. Thus, the identification of potent GSK-α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-α inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK-α selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay.
- Lo Monte, Fabio,Kramer, Thomas,Gu, Jiamin,Anumala, Upendra Rao,Marinelli, Luciana,La Pietra, Valeria,Novellino, Ettore,Franco, Bénédicte,Demedts, David,Van Leuven, Fred,Fuertes, Ana,Dominguez, Juan Manuel,Plotkin, Batya,Eldar-Finkelman, Hagit,Schmidt, Boris
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experimental part
p. 4407 - 4424
(2012/08/13)
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- Pinacolborane as the boron source in nitrogen-directed borylations of aromatic N, N -dimethylhydrazones
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A mild procedure for the Ir(III)-catalyzed nitrogen-directed ortho borylation of aromatic N,N-dialkylhydrazones using pinacolborane as the boron source has been developed. The methodology relies on a modified, hemilabile N,N ligand built on a 4-N,N-dimethylaminopyridine unit that provides high reactivity while maintaining exclusive ortho-selectivity. This procedure can be combined with Suzuki-Miyaura cross-couplings in a 'one-pot' fashion to afford functionalized biaryl derivatives that, upon subsequent 'one-pot', high yielding transformations, provide a convenient entry for the preparation of advanced benzonitrile intermediates for the synthesis of Sartan-type drugs.
- López-Rodríguez, Rocío,Ros, Abel,Fernández, Rosario,Lassaletta, José M.
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p. 9915 - 9920
(2013/01/15)
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- N-BIPHENYLMETHYLINDOLE MODULATORS OF PPARG
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The invention provides molecular entities that bind with high affinity to PPARG (PPAR3), inhibit kinase-mediated, e.g., cdk5-mediated, phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. In methods of treatment of these conditions using a compound of the invention, the compound can avoid producing side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, in the patient receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
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Page/Page column 127; 128
(2012/12/14)
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- PROCESS FOR THE PREPARATION OF 4-BROMOMETHYL-[1,1'-BIPHENYL]-2'-CARBONITRILE
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Process for the preparation of the compounds of the general formula (I) - where in the formula R represents cyano group, - COOR1or -CONR2R3 group - where R1, R2 and R3 stand for identical or non-identical substituents chosen from the following atom or groups: hydrogen atom, straight or branched C1-7 alkyl group, C3-6 cycloalkyl group; or in one given case a tetrazolyl group substituted with a C1-4 alkyl group or triphenylmethyl group - wherein a compound of the general formula (II) - where the meaning of R is as defined above - is reacted with one of the following reagent pairs as bromine sources: bromate with hydrogen sulfite, or bromate with pyrosulfite, or bromide with percarbonate, or bromide with perborate, in aqueous-organic binary systems, and optionally the resulting compound of the general formula (I) is isolated from the reaction mixture by a method known per se.
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Page/Page column 5
(2011/07/07)
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- Synthesis of amido-N-imidazolium salts and their applications as ligands in suzuki-miyaura reactions: Coupling of hetero- aromatic halides and the synthesis of milrinone and irbesartan
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A new catalytic system based on palladium-amido-N-heterocyclic carbenes for Suzuki-Miyaura coupling reactions of heteroaryl bromides is described. A variety of sterically bulky, amido-N-imidazolium salts were synthesized in high yields from the corresponding anilines. This catalytic system effectively promoted Suzuki-Miyaura couplings of heteroaryl bromides and chlorides with a range of boronic acids to give the corresponding aryl compounds in high yield. The yield was increased with increasing steric bulkiness of the substituted group. Especially, 1-(2,6-diisopropylphenyl)-3-N-(2,4,6-tri-tert- butylphenylacetamido)imidazolium bromide (4bc) exhibited 850,000 TON in the coupling reaction of 2-bromopyridine and phenylboronic acid. In addition, pharmaceutical compounds such as milrinone and irbesartan were synthesized via Suzuki-Miyaura coupling using sterically bulky, amido-N-imidazolium salt (4bc) as a ligand. Copyright
- Kumar, Manian Rajesh,Park, Kyungho,Lee, Sunwoo
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supporting information; experimental part
p. 3255 - 3266
(2011/02/23)
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- ANTI INFLAMMATORY COMPOUNDS
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Biphenyl compounds of Formula (I) and Formula (II), and their pharmaceutically acceptable salts or solvates or prodrugs, their pharmaceutical compositions, their use and process of preparation are provided. Compounds of Formula (I) and Formula (II) are disclosed to exhibit anti-inflammatory properties.
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Page/Page column 13-14; 16
(2010/04/06)
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- Process for the preparation of losartan
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The invention relates to a improved process for the preparation of Losartan and its potassium salt, which comprises: (i) reacting bromo OTBN with BCFI in the presence of a base and a phase transfer catalyst to produce a cyano aldehyde; reacting the formed cyano aldehyde with sodium azide in the presence of tributyl tin chloride to produce aldehyde tetrazole; reducing the formed aldehyde tetrazole with sodium borohydride to produce Losartan; and, if desired, converting the formed Losartan to its potassium salt by known method.
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Page/Page column 7-8
(2010/09/07)
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- PROCESS FOR THE SEPARATION OF 4-BROMOMETHYL-2'-SUBSTITUTED BIPHENYLS FROM 4,4,-DIBROMOMETHYL-2'-SUBSTITUTED BIPHENYLS
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Disclosed herein is process for the separation of 4-bromomethyl-2'-substituted biphenyls of Formula (II) from 4,4-dibromomethyl-2'-substituted biphenyls of Formula (III) and 4-methyl-2'-substituted biphenyl of Formula (I) by stirring a crude reaction mixture comprising compounds of Formula (I), (II) and (III) in suitable organic solvents at a temperature above 50°C; and gradually cooling the reaction mixture below 20°C to obtain pure crystals of Formula (II) with purity of more than 97%.
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Page/Page column 8
(2008/12/06)
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- Synthesis and biological activities of novel nonpeptide angiotensin II receptor antagonists based on benzimidazole derivatives bearing a heterocyclic ring
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A series of benzimidazole derivatives bearing a heterocyclic ring imidazole (1), 5-chloroimidazole (2), 1,2,4-triazol (3), and imidazoline (4) were synthesized and evaluated for angiotensin II antagonistic activities. The synthetic compounds 1-4 were biologically evaluated in vitro using an AT1 receptor binding assay, where compounds 1 and 3 provided weak binding affinity, compound 2 showed moderate binding affinity, and compound 4 showed good binding affinity. Moreover, compound 4 was found to be almost equipotent with telmisartan in vivo biological evaluation study.
- Guo, Xing-Zhou,Shi, Lin,Wang, Rui,Liu, Xiao-Xiao,Li, Bo-Gang,Lu, Xiao-Xia
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experimental part
p. 10301 - 10310
(2009/04/07)
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- Synthesis of valsartan via decarboxylative biaryl coupling
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(Chemical Equation Presented) An efficient synthesis of the angiotensin II inhibitor valsartan (Diovan) is presented. Two routes were evaluated, both making use of an advanced version of our decarboxylative coupling for the construction of the biaryl moiety. Thus, in the presence of a catalyst system consisting of copper(II) oxide, 1,10-phenanthroline, and palladium(II) bromide, 2-cyanocarboxylic acid was coupled with 1-bromo(4-dimethoxymethyl)benzene in 80% yield and with 4-bromotoluene in 71% yield. The valsartan synthesis using 1-bromo(4-dimethoxymethyl)benzene was completed in four steps overall with a total yield of 39%, via a novel route that presents substantial economical and ecological advantages over the literature process, as it is more concise and stoichiometric amounts of expensive organometallic reagents are avoided.
- Goossen, Lukas J.,Melzer, Bettina
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p. 7473 - 7476
(2008/02/12)
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- PROCESS FOR THE PREPARATION OF LOSARTAN
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The invention relates to a improved process for the preparation of Losartan and its potassium salt, which comprises (i) reacting bromo OTBN with BCFI in the presence of a base and a phase transfer catalyst to get cyano aldehyde, reacting the cyano aldehyde sodium azide in the presence of tributyl tin chloride to form aldehyde tetrazole , reducing the aldehyde tetrazole with sodium borohydride to give Losartan and , if desired , converting it to its potassium salt by known method .
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Page/Page column 15-16
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE MANUFACTURE OF LOSARTAN POTASSIUM
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The present invention relates to an improved process for the manufacture of Losartan potassium. The process comprises of condensation of 2-butyl-4-chloro-5-formyl imidazole with 2-cyano-4-bromomethyl biphenyl in a biphasic solvent system under phase transfer catalysis followed by insitu reduction using sodium borohydride. The obtained product is converted to Losartan by treating with sodium azide and an amine salt. Losartan is then converted to its potassium salt by treating it with potassium hydroxide in alcohol.
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Page/Page column 13
(2008/06/13)
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- Method for preparing irbesartan and intermediates thereof
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A method for preparing irbesartan and intermediates thereof. Irbesartan has the structure of formula I,
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Page/Page column 3-4
(2008/06/13)
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- A process for producing an aralkyl compound, a dehalogenation method of an aralkyl halide compound and a method for recovering an aralkyl compound
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The present invention provides a process for producing an aralkyl compound which comprises catalytically hydrogenating an aralkyl halide compound in a two-layer solvent system comprising water and water-insoluble organic solvent, a dehalogenation method of aralkyl halide compounds by subjecting to catalytic reduction in a two-layer solvent system comprising water and a water-insoluble organic solvent, and a method for recovering aralkyl compound from waste occurred in production of aralkyl halide compound by halogenation of aralkyl compound using the dehalogenation method.
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Page/Page column 5
(2008/06/13)
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- PROCESS FOR PRODUCING 2' -(1H-TETRAZOL-5-YL)-BIPHENYL-4-CARBALDEHYDE
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The present invention provides a process for producing 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde which comprises reacting 2'-cyanobiphenyl-4-carbaldehyde with a salt of azide; a process for producing a highly pure crystal of 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde which comprises reacting 2'-cyanobiphenyl-4-carbaldehyde with a salt of azide, obtaining a crystal of 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde, dissolving said crystal obtained and recrystallizing a highly pure crystal in tetrahydrofuran; and the like. According to the present process, 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde which is useful as a synthetic intermediate of medicines can be produced in a short process at high yield and high purity.
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Page/Page column 9
(2008/06/13)
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- 2'-(1H-TETRAZOL-5-YL)BIPHENYL-4-CARBALDEHYDE CRYSTAL AND ITS MANUFACTURING METHOD
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PROBLEM TO BE SOLVED: To provide a method for industrially manufacturing 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde crystal of high purity with a high yield in a short step using an inexpensive reagent. SOLUTION: The manufacturing method of 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde crystal of high purity comprises a step for reacting 2'-cyanobiphenyl-4-carbaldehyde with an azide salt and a step for crystallizing the crude 2'-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde crystal obtained by the above step from tetrahydrofuran.
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Page/Page column 12
(2008/06/13)
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- CRYSTAL AND PROCESS FOR PRODUCING THE SAME
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A process for producing crystals of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimdazole-7-carboxylic acid (compound (I)), characterized by dissolving or suspending the compound (I) or a salt thereof in a solvent comprising an aprotic polar solvent and crystallizing it. By the process, the contaminants which are contained in the compound (I) or its salt and are difficult to remove, such as tin compounds, analogues of the compound (I), and a residual organic solvent, can be easily removed. Crystals of the compound (I) can be efficiently and easily mass-produced in high yield on an industrial scale.
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Page 16; 17-18
(2010/02/06)
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- De novo design and synthesis of HIV-1 integrase inhibitors
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Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3′-processing and 3′- strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity.
- Makhija, Mahindra T.,Kasliwal, Rajesh T.,Kulkarni, Vithal M.,Neamati, Nouri
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p. 2317 - 2333
(2007/10/03)
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- Production method of 4'-bromomethyl-2-cyanobiphenyl
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The present invention relates to a production method of 4′-bromomethyl-2-cyanobiphenyl, which includes reacting 4′-methyl-2-cyanobiphenyl with bromine in the presence of a radical initiator and an oxidant. According to the present invention, since bromine can be regenerated by reacting hydrogen bromide, which is by-produced with the progress of bromination, with an oxidant, inhibition of bromination by hydrogen bromide, coloring by bromine and the like can be prevented. Thus, 4′-bromomethyl-2-cyanobiphenyl useful as a starting material of pharmaceutical products can be produced industrially beneficially.
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Page column 5
(2008/06/13)
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- Use of an angiotensin II receptor antagonist for the preparation of drugs to increase the survival rate of renal transplant patients
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The present invention relates to the use, for the preparation of drugs to increase the survival rate of transplant patients, including renal and heart transplant patients, of a therapeutically effective amount of an angiotension II receptor antagonist compound, such as the class of substituted imidazoles represented by formula (I) and in particular by losartan potassium, 2-butyl-4-chloro-[(2′-tetrazol-5-yl)biphenyl-4-il]methyl]-5-(hydroxymethyl)imidazole potassium salt.
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- Method for preparing bromomenthyl-biphenyl derivatives
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The present invention relates to a process for the preparation of 4′-bromomethyl-biphenyl derivatives of the formula: by reacting a 4′-methyl-biphenyl derivative of the formula: with a brominating agent a in a hydrobromic acid/alkali metal bromate system in a two-phase medium, and under photo-iradiation, where R is as defined in the specification.
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- INSULIN SENSITIVITY WITH ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES
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This invention relates to a novel method of using an Angiotensin II antagonist for the improvement of insulin sensitivity alone or in conjunction with the treatment of hypertension. Angiotensin II antagonists such as the class of substituted imidazoles represented by formula I: STR1 and specifically by Losartan, 2-butyl-4-chloro-1-[(2'-tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(hydroxymethyl)imidazole potassium salt.
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- Process for producing tetrazolylated biphenylmethane derivatives
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The present invention relates to a process for producing a tetrazolylated biphenylmethane derivatives (6) or salts thereof in accordance with the below-described reaction scheme wherein R 1 represents an alkyl; R 2 represents H, etc.; Z represents a halogen, etc.; and A represents a cycloalkene, etc. According to the above process, a tetrazolylated biphenylmethane derivative can be industrially and advantageously produced with short steps.
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- Inhibitors of acyl-CoA:cholesterol O-acetyltransferase (ACAT). Part 1: Identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylmethyl-N'-arylureas
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A series of N-alkyl-N-biphenylylmethyl-N'-arylurea and related derivatives represented by 1 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Linking of two phenyl groups via oxygen and introduction of fluorine at appropriate positions on the biphenyl moiety improved in vitro and in vivo activity. From this series of analogs, compound 40 (FR179254), which had potent in vitro potency (rabbit intestinal microsomes IC50 = 25 nM), showed excellent plasma cholesterol-lowering activity when administered via the diet (ED50 = 0.045 mg/kg). However, the hypocholesterolemic effect of this compound was moderate when dosed by oral gavage in PEG400 as a vehicle (ED50 = 5.3 mg/kg). Modification of the N'-aryl moiety led to the identification of compound 50 (FR182980) which was efficacious in both dosing models (ED50 = 0.034 mg/kg and 0.11 mg/kg, respectively).
- Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
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- NOVEL REAGENT FOR TETRAZOLE SYNTHESIS AND PROCESS FOR PRODUCING TETRAZOLES THEREWITH
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Analkali metal azide and zinc chloride are used in combination as a tetrazole forming agent when producing 1H-tetrazoles of the formula (II): (where R is any substituent) from carbonitriles of the formula (I): R-CN(where R has the same meaning as defined above). The tetrazole forming agent permits many kinds of solvents to be used and can in principle be used with any carbonitriles. In addition, the use of inexpensive zinc chloride leads to cost reduction.
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- Method for producing 4'-bromomethyl-2-cyanobiphenyl
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A method for producing 4'-bromomethyl-2-cyanobiphenyl by the step of treating 4'-methyl-2-cyanobiphenyl with Br2 in a halogenated hydrocarbon solvent or an alkane solvent having 5 to 7 carbon atoms.
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