- Syntheses of [14C]BAY 59-7939 and its radiolabeled metabolite M-4
-
BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic diseases. Radiolabeled BAY 59-7939 was required for drug absorption, distribution, metabolism and excretion (ADME studies). The BAY 59-7939 was labeled with carbon-14 in the carboxamide group in one step in an overall radiochemical yield of 85% starting from 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyl}mor-pholin-3-one and 5-chlorothiophene-2-[14C]carboxylic acid. The radiolabeled metabolite M-4 was prepared in 77% yield starting from [1-14C]glycine and 5-chlorothiophene-5-carboxylic acid. Copyright
- Pleiss,Seidel,Grosser
-
-
Read Online
- Enantioselective Allylic Substitution of Morita-Baylis-Hillman Adducts Catalyzed by Chiral Bifunctional Ferrocenylphosphines
-
A series of air-stable chiral ferrocenylphosphines (LB1-LB4) were prepared and used in the asymmetric allylic substitution of Morita-Baylis-Hillman (MBH) adducts with phthalimide under mild reaction conditions; the (R,SFc)-ferrocenylphosphine LB4 afforded the desired amination products 3 in moderate yields with excellent enantioselectivities. The absolute configuration of 3o was confirmed by X-ray analysis.
- Zhu, Linglong,Hu, Haiwen,Qi, Liang,Zheng, Yi,Zhong, Weihui
-
-
Read Online
- Benzo[1,2-b:4,5- b ′]diselenophene-fused nonfullerene acceptors with alternative aromatic ring-based and monochlorinated end groups: A new synergistic strategy to simultaneously achieve highly efficient organic solar cells with the energy loss of 0.49 eV
-
Herein, a new synergistic strategy using electron-rich core units and alternative aromatic structure-based 1,1-dicyanomethylene-3-indanone (IC) end-groups for nonfullerene PSCs was reported and investigated in an attempt to simultaneously obtain excellent PCE with extremely low Eloss. Specifically, two benzo[1,2-b:4,5-b′]diselenophene-based, A-D-A-type chlorinated NF-SMAs (BDSeThCl and BDSePhCl) were synthesized, which were linked with a new 2-chlorothienyl-based IC and a conventional monochlorinated phenyl-based IC as end-groups, respectively. BDSePhCl exhibited a wider and red-shifted absorption and downshifted energy levels than BDSeThCl. The blend films of BDSePhCl:PM7 exhibited better charge generation properties, more suitable phase separation, and more balanced charge mobilities as compared to those of BDSeThCl:PM7. Therefore, compared to the BDSeThCl:PM7 blends with the best PCE of 11.91% and the Eloss of 0.58 eV, the optimal BDSePhCl:PM7 blends showed the enhanced PCE of 13.68% with the reduced Eloss of 0.49 eV. Notably, the excellent PCE of 13.68% is the highest value recorded to date for A-D-A-type NF-SMAs with a monochlorinated IC group in binary PSCs. The Eloss of 0.49 eV is the lowest value reported to date for A-D-A-type NF-SMAs in binary PSCs with the PCE > 13%. These results demonstrate that tailoring of the monochlorinated aromatic ring-based IC is an effective strategy to simultaneously improve the PCE and reduce the Eloss in binary PSCs.
- Wan, Shi-Sheng,Xu, Xiaopeng,Wang, Jin-Liang,Yuan, Gui-Zhou,Jiang, Zhao,Ge, Gao-Yang,Bai, Hai-Rui,Li, Zheng,Peng, Qiang
-
-
Read Online
- Exploiting the HSP60/10 chaperonin system as a chemotherapeutic target for colorectal cancer
-
Over the past few decades, an increasing variety of molecular chaperones have been investigated for their role in tumorigenesis and as potential chemotherapeutic targets; however, the 60 kDa Heat Shock Protein (HSP60), along with its HSP10 co-chaperone, have received little attention in this regard. In the present study, we investigated two series of our previously developed inhibitors of the bacterial homolog of HSP60/10, called GroEL/ES, for their selective cytotoxicity to cancerous over non-cancerous colorectal cells. We further developed a third “hybrid” series of analogs to identify new candidates with superior properties than the two parent scaffolds. Using a series of well-established HSP60/10 biochemical screens and cell-viability assays, we identified 24 inhibitors (14%) that exhibited > 3-fold selectivity for targeting colorectal cancer over non-cancerous cells. Notably, cell viability EC50 results correlated with the relative expression of HSP60 in the mitochondria, suggesting a potential for this HSP60-targeting chemotherapeutic strategy as emerging evidence indicates that HSP60 is up-regulated in colorectal cancer tumors. Further examination of five lead candidates indicated their ability to inhibit the clonogenicity and migration of colorectal cancer cells. These promising results are the most thorough analysis and first reported instance of HSP60/10 inhibitors being able to selectively target colorectal cancer cells and highlight the potential of the HSP60/10 chaperonin system as a viable chemotherapeutic target.
- Ray, Anne-Marie,Salim, Nilshad,Stevens, Mckayla,Chitre, Siddhi,Abdeen, Sanofar,Washburn, Alex,Sivinski, Jared,O'Hagan, Heather M.,Chapman, Eli,Johnson, Steven M.
-
-
- Nickel-Catalyzed Oxidative Transamidation of Tertiary Aromatic Amines with N -Acylsaccharins
-
The use of tertiary amines as surrogates for secondary amines has prominent advantages in terms of stabilization and ease of handling. A Ni-catalyzed transamidation of N -acylsaccharins with tertiary aromatic amines is reported. By using tert -butyl hydroperoxide as the terminal oxidant, this reaction permits selective cleavage of the C(sp 3)-N bonds of unsymmetrical tertiary aromatic amines depending on the sizes of the alkyl substituents.
- Liu, Shengzhang,Yang, Lingyun,Tao, Jiasi,Yu, Weijie,Wang, Tao,Fu, Junkai
-
supporting information
p. 1642 - 1646
(2021/06/21)
-
- Pine Rosin as a Valuable Natural Resource in the Synthesis of Fungicide Candidates for Controlling Fusarium oxysporum on Cucumber
-
To improve the effect of pine rosin in plant fungicides, four series of dehydroabietyl-1,3,4-thiadiazole derivatives from the natural product rosin were synthesized. Based on the evaluation of the in vitro antifungal activity against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium oxysporum, and Magnaporthe oryzae, rosin-based 1,3,4-thiadiazole compounds containing thiophene heterocycles were screened. Notably, compound 3e [dehydroabietyl-(1,3,4-thiadiazol-2-yl)-5-nitrothiophene-2-carboxamide] exhibited excellent antifungal property against F. oxysporum with an EC50 of 0.618 mg/L, which was lower than that of the positive control carbendazim (0.649 mg/L). The in vivo antifungal activity results showed that 3e exerted a protective effect on cucumber plants. Physiological and biochemical studies showed that the primary mechanism of action of compound 3e on F. oxysporum was it changed the mycelial morphology, increased the cell membrane permeability, and inhibited the synthesis of ergosterol in the mycelia. Furthermore, the quantitative structure-activity relationship studies revealed that the frontier orbital energy in the molecule had a key role in the antifungal activity through the conjugation and electrostatic interaction between compound 3e and the receptors of the target. Thus, the present study highlighted the application of rosin-based fungicidal candidates and exploited efficient plant pesticides for sustainable crop production.
- Mao, Shiying,Wu, Chengyu,Gao, Yanqing,Hao, Jin,He, Xiaohua,Tao, Pan,Li, Jian,Shang, Shibin,Song, Zhanqian,Song, Jie
-
p. 6475 - 6484
(2021/06/28)
-
- Highly regioselective and stereoselective synthesis of C-Aryl glycosidesvianickel-catalyzedortho-C-H glycosylation of 8-aminoquinoline benzamides
-
C-Aryl glycosides are of high value as drug candidates. Here a novel and cost-effective nickel catalyzedortho-CAr-H glycosylation reaction with high regioselectivity and excellent α-selectivity is described. This method shows great functional group compatibility with various glycosides, showing its synthetic potential. Mechanistic studies indicate that C-H activation could be the rate-determining step.
- Chen, Xi,Ding, Ya-Nan,Gou, Xue-Ya,Liang, Yong-Min,Luan, Yu-Yong,Niu, Zhi-Jie,Shi, Wei-Yu,Zhang, Zhe,Zheng, Nian
-
supporting information
p. 8945 - 8948
(2021/09/10)
-
- Synthesis of 1,3,4-oxadiazoles as selective T-type calcium channel inhibitors
-
– Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular Ca2+ concentration through a dysfunction of T-type Ca2+ channels. Thus, T-type calcium channels could be a target in drug discovery for the treatments of neuropathic pain and epilepsy. From rational drug design approach, a group of 2,5-disubstituted 1,3,4-oxadiazole molecules was synthesized and their selective T-type channel inhibitions were evaluated. The synthetic strategy consists of a short sequence of three reactions: (i) condensation of thiosemicarbazide with acid chlorides; (ii) ring closing by 1,3-dibromo-5,5-dimethylhydantoin; and (iii) coupling with various acid chlorides. 5-Chloro-N-(5-phenyl-1,3,4-oxadiazol-2-yl)thiophene-2-carboxamide (11) was found to selectively inhibit T-type Ca2+ channel over Na+ and K+ channels in mouse dorsal root ganglion neurons and/or human embryonic kidney (HEK)-293 cells and to suppress seizure-induced death in mouse model. Consequently, compound 11 is a useful probe for investigation of physiologic and pathophysiologic roles of the T-channel, and provides a basis to develop a novel therapeutic to treat chronic neuropathic and inflammatory pains.
- Zhang, Man,Zou, Bende,Gunaratna, Medha J.,Weerasekara, Sahani,Tong, Zongbo,Nguyen, Thi D.T.,Koldas, Serkan,Cao, William S.,Pascual, Conrado,Xie, Xinmin Simon,Hua, Duy H.
-
p. 145 - 164
(2020/02/04)
-
- Antifungal Application of Rosin Derivatives from Renewable Pine Resin in Crop Protection
-
In the current work, we synthesized two series of dehydroabietyl amide derivatives from natural product rosin and evaluated their antifungal effects on Valsa mali, Phytophthora capsici, Botrytis cinerea, Sclerotinia sclerotiorum, and Fusarium oxysporum. In vitro and in vivo antifungal activities results indicated that rosin-based amide compounds containing thiophene heterocycles had better inhibitory effects on B. cinerea. In particular, compound 5b (5-fluoro-2-thiophene dehydroabietyl amide) exhibited the excellent antifungal properties against B. cinerea with an EC50 of 0.490 mg/L, which was lower compared to the positive control penthiopyrad (0.562 mg/L). Physiological and biochemical studies showed that the primary action mechanism of compound 5b on B. cinerea changes mycelial morphology, increases cell membrane permeability, and inhibits the TCA pathway in respiratory metabolism. Furthermore, QSAR and SAR studies revealed that charge distribution of rosin-based amides derivatives have a key role in the antifungal activity through the hydrogen bonding, conjugation, and electrostatic interaction between the compounds and the receptors of the target. To sum up, this study contributes to the development of rosin-based antifungal agents with a novel structure and preferable biological activity.
- Gao, Yanqing,Hao, Jin,He, Xiaohua,Li, Jian,Shang, Shibin,Song, Jie,Song, Zhanqian,Tao, Pan,Wu, Chengyu
-
p. 4144 - 4154
(2020/04/30)
-
- THIOPHENE END GROUPS OF NON-FULLERENE ACCEPTORS FOR ELECTRONIC AND PHOTONIC APPLICATIONS
-
Provided herein are small molecular acceptor compounds containing thiophene end groups, methods for their preparation and intermediates used therein, the use of formulations containing the same as semiconductors in organic electronic devices, especially in organic photovoltaic and organic field-effect transistor devices, and to organic electronic and organic photovoltaic devices made from these formulations.
- -
-
Paragraph 0166; 0167
(2020/12/01)
-
- THIOPHENE END GROUPS OF NON-FULLERENE ACCEPTORS FOR ELECTRONIC AND PHOTONIC APPLICATIONS
-
Provided herein are small molecular acceptor compounds containing thiophene end groups, methods for their preparation and intermediates used therein, the use of formulations containing the same as semiconductors in organic electronic devices, especially in organic photovoltaic and organic field-effect transistor devices, and to organic electronic and organic photovoltaic devices made from these formulations.
- -
-
Paragraph 0216-0219
(2020/11/22)
-
- Synthesis method of rivaroxaban intermediate 5-chlorine-2-thiophenecarbonyl chloride
-
The invention discloses a synthesis method of a rivaroxaban intermediate 5-chlorine-2-thiophenecarbonyl chloride, and belonging to the pharmaceutical field. The synthesis method is characterized in that 2-chlorothiophene reacts with halogenated acetylchloride in the presence of catalyst to prepare 5-chlorine-2-thiophenecarbonyl chloride. The reaction process comprises the following steps: 1) uniformly mixing halogenated acetylchloride, catalyst and solvent A, introducing protective gas, controlling that pressure at 3-5 atmospheres, controlling the temperature to 80 to 115 DEG C, and dropping 2-chlorothiophene and solvent B solution, controlling the adding time to be 20-30min, adding, raising the reaction temperature to 145-155 DEG C, raising the pressure to 7-9 atmospheres, and then continuing the reaction for 20-35h to finish the reaction; 2) cooling that system, filtering to remove solids, adding the filtrate into 2-4 times volume of water, extracting with solvent C, drying the extracted solution with desiccant, concentrating and distilling off the solvent to obtain the product. The synthesis method of the invention is safe and reliable, has low production cost, basically has nothree wastes, and is suitable for industrial production.
- -
-
Paragraph 0040-0045
(2019/02/10)
-
- Low cost preparation method of high purity 5-chlorothiophene-2-formyl chloride
-
The invention relates to a low cost preparation method of high purity 5-chlorothiophene-2-formyl chloride. According to the preparation method, 2-chlorothiophene and a formylation reagent carry out reactions to generate 5-chlorothiophene-2-formaldehyde, then 5-chlorothiophene-2-formaldehyde is oxidized by an oxidant to generate 5-chlorothiophene-2-formic acid, and finally 5-chlorothiophene-2-formic acid and an acyl-chlorination reagent carry out acyl-chlorination reactions to generate 5-chlorothiophene-2-formyl chloride. 5-chlorothiophene-2-formyl chloride can be used as a key intermediate inrivaroxaban preparation. The preparation method has the advantages of cheap and easily-available raw materials, simple technical route, low raw material cost, little discharge amount of wastewater, low salt content of wastewater, environmental friendliness, and high reaction selectivity. The purity of obtained 5-chlorothiophene-2-formyl chloride is high, and the industrial production of high purity rivaroxaban is promoted.
- -
-
Paragraph 0063-0071
(2019/03/26)
-
- Design and synthesis of heteroaromatic-based benzenesulfonamide derivatives as potent inhibitors of H5N1 influenza A virus
-
Influenza A virus is an enveloped negative single-stranded RNA virus that causes febrile respiratory infection and represents a clinically challenging threat to human health and even lives worldwide. Even more alarming is the emergence of highly pathogenic avian influenza (HPAI) strains such as H5N1, which possess much higher mortality rate (60%) than seasonal influenza strains in human infection. In this study, a novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as M2 proton channel inhibitors. A systematic investigation of the structure-activity relationships and a molecular docking study demonstrated that the sulfonamide moiety and 2,5-dimethyl-substituted thiophene as the core structure played significant roles in the anti-influenza activity. Among the derivatives, compound 11k exhibited excellent antiviral activity against H5N1 virus with an EC50 value of 0.47 μM and selectivity index of 119.9, which are comparable to those of the reference drug amantadine.
- Yu, Yongshi,Tazeem,Xu, Zhichao,Du, Liaoqi,Jin, Mengyu,Dong, Chune,Zhou, Hai-Bing,Wu, Shuwen
-
-
- Palladium-Catalyzed Electrochemical C-H Bromination Using NH4Br as the Brominating Reagent
-
The palladium-catalyzed electrochemical C-H bromination of benzamide derivatives under divided cells is developed, in which NH4Br serves as a brominating reagent and electrolyte. The protocol avoids the use of chemical oxidants and provides an alternative method for the synthesis of aryl bromides.
- Yang, Qi-Liang,Wang, Xiang-Yang,Wang, Tong-Lin,Yang, Xiang,Liu, Dong,Tong, Xiaofeng,Wu, Xin-Yan,Mei, Tian-Sheng
-
supporting information
p. 2645 - 2649
(2019/04/17)
-
- A [...] intermediate 5 - chloro - N - (2 - oxirane ylmethyl) -2 - thiophene carboxamide preparation method
-
The invention provides a preparation method for a Rivaroxaban intermediate 5-chloro-N-(2-oxiranylmethyl)-2-thiophene methanamide. First, 5-chlorothiophene-2-formic acid and toluene are added into a reaction container, the temperature is risen to 80-85 DEG C slowly, then thionyl chloride is dripped slowly, and the temperature is risen to 95-105 DEG C; the reaction solution is cooled to 50-60 DEG C, equal-temperature reduced pressure distillation is carried out, the solvent is evaporated, and after toluene is added, a toluene solution of 5-chlorothiophene-2-formyl chloride is obtained; then propane is added in the toluene solution of 5-chlorothiophene-2- formyl chloride, then ammonia water is dripped under an ice-bath condition, and 5-chlorothiophene-2-methanamide is obtained; then 5-chlorothiophene-2-methanamide and potassium carbonate are added in a reaction container, then epoxy chloropropane is added, and after heating and stirring, 5-chloro-N-(2-oxiranylmethyl)-2-thiophene methanamide is obtained. In the technology route, reaction conditions are optimized, the reaction is mild, operation is simple, and the yield is high.
- -
-
Paragraph 0024-0027
(2018/11/22)
-
- The preparation method of the [...] (by machine translation)
-
The invention provides a method for preparing [...], using 4 - (4 - aminophenyl) - 3 - morpholone and 5 - chloro - N - (2 - ethylene oxide-based methyl) - 2 - thiophene carboxamide reaction to obtain 5 - [...] - 2 - {(R)- 2 - hydroxy - 3 - [4 - (3 - oxo - 4 - morpholinyl) phenyl amino] - propyl} amide, then adding N, N' - carbonyl di-imidazole, 4 - dimethylamino pyridine, begins to stir, heating reaction to obtain the - 5 - chloro - N - (( (5 S) - 2 - oxo - 3 - (4 - (3 - oxo-morpholine - 4 - yl) phenyl) - 1, 3 - Oxacillin - 5 - yl) methyl) thiophene - 2 - carboxamide. The technique of the invention route after the condition is optimized, mild reaction, high yield. (by machine translation)
- -
-
Paragraph 0045; 0046; 0047; 0048
(2018/11/22)
-
- Synthesis, Characterization, and Antioxidant Activity of a New Class of Amido linked Azolyl Thiophenes
-
A new class of amido linked azolyl thiophenes was prepared from the synthetic intermediates azolyl amines and 5-chlorothiophene-2-carbonyl chloride adopting conventional and ultrasonication methodologies. It was observed that the reaction took place in shorter reaction times with higher yields under ultrasonication. The structures of the synthesized compounds were characterized by spectral parameters and also tested for antioxidant activity. Among all the tested compounds, methoxy substituted oxazolyl thiophene carboxamide (8c) displayed promising antioxidant activity. Besides, the electron donating groups on the phenyl ring enhanced the antioxidant activity when compared with the electron withdrawing groups.
- Thatha, Sreenivasulu,Ummadi, Nagarjuna,Venkatapuram, Padmavathi,Adivireddy, Padmaja
-
p. 1410 - 1418
(2018/06/20)
-
- A [...] related substance diamine synthesis method
-
The invention relates to a rivaroxaban related substance diamine which can be used as a reference substance to research and control rivaroxaban. The preparation method is simple, and the raw materials are easily available. The structural formula of the diamine is shown as follows: FORMULA shown in the description and the formula is C25H24CL2N4O4S2, and the molecular weight is 610.5. The rivaroxaban related substance diamine provided by the invention can be used as a reference substance for monitoring impurities of the rivaroxaban. The synthetic method for the rivaroxaban related substance diamine provided by the invention is simple to operate, has excellent practicality, and can bringrelatively good economic and social benefits.
- -
-
Paragraph 0030-0031
(2018/09/12)
-
- METHOD FOR PREPARATION OF THIOPHENE-2-CARBONYL CHLORIDES WITH OXALYL CHLORIDE
-
The invention discloses a method for the preparation of thiophene-2-carbonyl chlorides starting from thiophenes with oxalyl chloride at elevated temperature with short reaction time.
- -
-
Page/Page column 19
(2017/06/19)
-
- METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES WITH TWO REAGENTS
-
The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride and a chlorinating reagent.
- -
-
Page/Page column 33
(2017/01/26)
-
- The preparation method of the the advantage cuts down Sha Ban
-
The invention provides a preparation method of rivaroxaban, which uses 4-(4-iodophenyl)-3-morpholone and (S)-(+)-N-(3-amino-2-hydroxyisopropyl)phthalimide as initial raw materials. The synthesis route is simple, the reaction conditions in each reaction are mild, and the product is easy to separate; and thus, the reaction yield is high, the product purity is high, and the method can be used for industrial production.
- -
-
Paragraph 0137-0140
(2017/04/21)
-
- Darbey adds the group derivative and its preparation and use
-
The invention belongs to the field of medicines, and specifically relates to dabigatran derivatives or the pharmaceutical salts thereof, a preparation method for the derivatives, a medicine composition containing the dabigatran derivatives, and an application of the derivatives and the medicine composition in preparation for anticoagulant medicines and treatment for related diseases.
- -
-
Paragraph 0054; 0057
(2017/07/23)
-
- Synthesis and thrombin, factor Xa and U46619 inhibitory effects of non-amidino and amidino N2-thiophenecarbonyl- and N2-tosylanthranilamides
-
Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 1-20 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 21-26 were synthesized to evaluate their activated partial thromboplastin time (aPTT) and prothrombin time (PT) using human plasma at a concentration of 30 μg/mL in vitro. As a result, compounds 5, 9, and 21-23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21-23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21-23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced by U46619 in vitro and ex vivo. Among the derivatives evaluated, N-(30-amidinophenyl)-2-((thiophen-200-yl)carbonylamino)benzamide (21) was the most active compound.
- Lee, Soo Hyun,Lee, Wonhwa,Nguyen, ThiHa,Um, Il Soo,Bae, Jong-Sup,Ma, Eunsook
-
-
- Design, synthesis and activity evaluation study of novel substituted N-sulfonyl homoserine lactone derivatives as bacterial quorum sensing inhibitors
-
A novel series of N-sulfonyl homoserine lactone derivatives 7a–7m has been designed, synthesized, and evaluated for quorum sensing inhibitory activities through the violacein inhibition in Chromobacterium violaceum CV026. Compound 7e displayed the high level of inhibitory activity among all the compounds synthesized. Studies of structure-activity relationship indicated that compounds with thiophene group in side chain showed better activity than those substituted by furan, pyrrole, pyridyl, and phenethyl group. Thiophene substituted compounds which connected electron withdrawing group exhibited better inhibitory activity relate to those connected electron donating group. Further analysis indicated that compound bearing an electron withdrawing substituent at the position 2 of their thiophene ring exhibited superior activity against violacein production to those bearing the substituent at the position 3 and 4. Compound 7e in particular, with IC50 value of 6.19 μM, were identified as promising lead compounds for further development.
- Sun, Qi,Zhao, Mingming,Liang, Jingwei,Xiao, Junhai,Meng, Fanhao
-
p. 3345 - 3353
(2017/11/16)
-
- NOVEL MORPHOLINE DIPHOSPHATE SALT, AND METHOD FOR MANUFACTURING HIGH PURITY RIVAROXABAN USING SAME
-
The present invention relates to a method of producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide (hereinafter, andPrime;rivaroxabanandPrime;, chemical formula 1) with high purity in an economical and mass-producible manner by using novel 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one disphosphate salts (hereinafter, andPrime;morpholine disphosphate saltsandPrime;, chemical formula 2).COPYRIGHT KIPO 2017
- -
-
Paragraph 0064-0068; 0085-0087
(2017/12/15)
-
- METHOD FOR PREPARATION OF THIOPHENECARBONYL CHLORIDES
-
The invention discloses a method for the preparation of thiophenecarbonyl chlorides starting from acetylthiophenes with thionyl chloride in the presence of a base.
- -
-
Page/Page column 27
(2016/10/11)
-
- METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES
-
The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride.
- -
-
Page/Page column 30
(2017/01/02)
-
- Method for synthesizing 5-chlorin-2-formyl chloride thiofuran by micro-channel reactor
-
The invention provides a method for synthesizing 5-chlorin-2-formyl chloride thiofuran by a micro-channel reactor. The micro-channel reactor is formed by sequentially connecting preheating modules, a reaction module group and a temperature reducing module in series, wherein more than two preheating modules are respectively connected in series with the same reaction module group. The method comprises the reaction steps that raw materials of 5-chlorin-2-formic acid thiofuran are dissolved in a solvent to form a 5-chlorin-2-formic acid thiofuran solution; DMF (dimethyl fumarate) is added to be prepared into a material 1; triphosgene is dissolved in a solvent to be prepared into a triphosgene solution to obtain a material 2; the material 1 and the material 2 respectively enter different preheating modules; after being preheated, the materials enter the reaction module group for reaction, then enter the temperature reducing module and flow out of the reactor; reaction liquid is collected; after reduced pressure distillation, the 5-chlorin-2-formyl chloride thiofuran is obtained. The method provided by the invention has the advantages that the reaction temperature is accurate; the feeding proportion can be conveniently controlled; the reaction period is short; green and environment-friendly effects are achieved.
- -
-
Paragraph 0031; 0032; 0033; 0034; 0035; 0036; 0037-0049
(2017/02/17)
-
- 5-chlorothiophene-2-carbonylchloride intermediate and preparation method thereof
-
The invention discloses a 5-chlorothiophene-2-carbonylchloride intermediate and a preparation method thereof. The preparation method comprises the following step that a compound 3 is subjected to a hydrolysis reaction shown as follows (please see the hydrolysis reaction in the description). According to the preparation method, the process is safe and simple, aftertreatment is convenient, both an intermediate product and a final product are easy to purify, the purity and the yield are high, the production cost is low, and industrialized production is easy to achieve.
- -
-
Paragraph 0074; 0075; 0076
(2016/12/22)
-
- PROCESS FOR THE PREPARATION OF RIVAROXABAN
-
The present invention relates to an environmentally friendly process for preparing rivaroxaban. The present invention provides a process for preparing rivaroxaban of formula I, the process comprising: reacting a compound of formula VI with a base in the presence of a solvent to form a compound of formula VII; and condensing the compound of formula VII with a compound of formula VIII or a compound of formula IX in the presence of a solvent to prepare rivaroxaban of formula I, wherein the solvent used in both steps comprises water.
- -
-
Page/Page column 29
(2016/03/22)
-
- Synthesis and in Vitro and in Vivo anticoagulant and antiplatelet activities of amidino- and non-amidinobenzamides
-
Three amidino- and ten non-amidinobenzamides were synthesized as 3-aminobenzoic acid scaffold-based anticoagulant and antiplatelet compounds. The anticoagulant activities of thirteen synthesized compounds 1-13, and 2b and 3b as prodrugs were preliminary evaluated by screening the prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) in vitro. From the aPTT results obtained, two amidinobenzamides, N-(3′-amidinophenyl)-3-(thiophen-2″-ylcarbonylamino) benzamide (1, 33.2 ± 0.7 s) and N-(4′-amidinophenyl)-3-(thiophen-2″-ylcarbonylamino) benzamide (2, 43.5 ± 0.6 s) were selected to investigate the further anticoagulant and antiplatelet activities. The aPTT results of 1 (33.2± 0.7 s) and 2 (43.5 ± 0.6 s) were compared with heparin (62.5 ± 0.8 s) in vitro at 30 μM. We investigated the effect of 1 and 2 on blood anticoagulant activity (ex vivo) and on tail bleeding time (in vivo) on mice. A tail cutting/bleeding time assay revealed that both 1 and 2 prolonged bleeding time in mice at a dose of 24.1 g/mouse and above. Compounds 1 and 2 dose-dependently inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In addition, 1 and 2 were evaluated on the inhibitory activities of thrombin and FXa as well as the generation of thrombin and FXa in human umbilical vein endothelial cells (HUVECs). Collectively, 1 and 2 possess some antiplatelet and anticoagulant activities and offer a basis for development of a novel antithrombotic product.
- Lee, Soo Hyun,Lee, Wonhwa,Bae, Jong-Sup,Ma, Eunsook
-
-
- AN IMPROVED PROCESS FOR PREPARATION OF RIVAROXABAN
-
The present invention relates to an improved process for the preparation of Rivaroxaban of formula (I) in high yield and purity. More particularly, the present invention is directed to an improved and greener process for preparation of Rivaroxaban employing isolated compound of formula (II) in high yield which substantially eliminates potential impurities.
- -
-
Page/Page column 20
(2016/12/26)
-
- Substituted 1,3-miscellaneous azole compound, preparation method thereof, pharmaceutical composition containing substituted 1,3-miscellaneous azole compound and purpose thereof
-
The invention relates to a substituted 1,3-miscellaneous azole compound, a preparation method thereof, a pharmaceutical composition containing the substituted 1,3-miscellaneous azole compound and a purpose thereof. The invention relates to the compound in a formula I, or its pharmaceutically acceptable salt, a stereisomer or a solvate, wherein R1, R2, R3 and X are defined as a specification; and the invention also relates to the preparation method, the pharmaceutical composition containing the substituted 1,3-miscellaneous azole compound and the purpose thereof. The compound of the present invention is the novel antituberculous compound, is effective to mycobacterium tuberculosis-susceptible strains, also possesses activity on strains with tolerance on traditional first-line antituberculous drugs such as isoniazide and rifampicin, and has good selectivity to mycobacterium tuberculosis.
- -
-
Paragraph 0140
(2017/04/03)
-
- SUBSTITUTED HETEROCYCLIC COMPOUNDS AS CRAC MODULATORS
-
The invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine for the treatment of diseases, disorders associated with the modulation of calcium release-activated calcium (CRAC) channel. The invention also relates to pharmaceutical compositions containing such compounds in treating diseases disorders associated with calcium release-activated calcium (CRAC) channel modulators. wherein, ring D is Formula (a) or Formula (b): A and B, which may be same or different, are independently CR3 or N; Y is CR3 or N; L is selected from —NR2C(O)—, —C(O)NR2— and —NR2CRaRb—; Ra and Rb are independently hydrogen, halogen or substituted or unsubstituted alkyl; ring E is selected from the Formula (i) to (vii).
- -
-
Paragraph 0276
(2016/06/13)
-
- One-Step Conversion of Methyl Ketones to Acyl Chlorides
-
Treatment of aromatic and heteroaromatic methyl ketones with sulfur monochloride and catalytic amounts of pyridine in refluxing chlorobenzene leads to the formation of acyl chlorides. Both electron-rich and electron-poor aryl methyl ketones can be used as starting materials. The resulting C1-byproduct depends on the precise reaction conditions chosen.
- Zaragoza, Florencio
-
p. 10370 - 10374
(2015/11/03)
-
- PROCESS FOR THE PREPARATION OF RIVAROXABAN
-
The present invention provides processes for the preparation of rivaroxaban. The present invention also provides processes for the preparation of a rivaroxaban intermediate.
- -
-
Page/Page column 9
(2015/02/19)
-
- A PROCESS FOR THE PREPARATION OF RIVAROXABAN
-
Described is an improved, industrially feasible and environmental friendly process for the preparation of Rivaroxaban. Also described are novel compounds which may be used as intermediates in preparation of Rivaroxaban.
- -
-
Page/Page column 22
(2015/03/13)
-
- Identification of anthranilamide derivatives as potential factor Xa inhibitors: Drug design, synthesis and biological evaluation
-
The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 Combining double low line 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM.
- Xing, Junhao,Yang, Lingyun,Li, Hui,Li, Qing,Zhao, Leilei,Wang, Xinning,Zhang, Yuan,Zhou, Muxing,Zhou, Jinpei,Zhang, Huibin
-
supporting information
p. 388 - 399
(2015/04/14)
-
- PROCESS FOR THE SYNTHESIS OF RIVAROXABAN AND INTERMEDIATE FOR THE PRODUCTION THEREOF
-
A process is described for the production of Rivaroxaban, a compound having the following structural formula: (I) by means of obtaining a novel intermediate of said process.
- -
-
Page/Page column 7
(2016/01/12)
-
- IMPROVED PROCESS FOR PREPARATION OF RIVAROXABAN
-
The present invention relates to a process for the preparation of 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophen-carboxamide (I) by reacting 5-chlorothiphene-2-carbonyl chloride and 4-[4-((S)-4-aminomethyl-2- oxoimidazolidin-1-yl)phenyl]morpholine-3-one hydrochloride in the presence of buffer reagent. (I)
- -
-
Page/Page column 7
(2014/02/16)
-
- PROCESS FOR OBTAINING RIVAROXABAN AND INTERMEDIATE THEREOF
-
This invention relates to a procedure for obtaining a thiophene-2-carboxamide compound, specifically rivaroxaban, which comprises the (i) fragmentation of the N═C bond of a compound of formula 23 where R1 is selected among hydrogen, halogen, and (C1-C6)alkyl; and (ii) acylation of the resulting intermediate with 5-chloro-tiofen-2-carbonyl chloride in a solvent medium, in the presence of a base. The invention also relates to the compounds of formula 23 and their use in the obtention of rivaroxaban.
- -
-
Paragraph 0067
(2014/05/20)
-
- TARTRATE SALT OF 5-CHLORO-THIOPHENE-2-CARBOXYLIC ACID [(S)-2-[METHYL-3-(2-OXO-PYRROLIDIN-1-YL)-BENZENESULFONYLAMINO]-3-(4-METHYL PIPERAZIN-1 -YL)-3-OXO-PROPRYL]AMIDE
-
The invention relates to the tartrate salt of 5-chloro-thiophene-2- carboxylic acid [(S)-2-[methyl-3-(2-oxo-pyrrolidin-l-yl)- benzenesulfonylamino]-3-(4-methyl-piperazin-l-yl)-3-oxo- propryl]amide, to its crystalline form, to its preparation and to its therapeutic use.
- -
-
Page/Page column 6
(2014/11/13)
-
- PROCESSES AND INTERMEDIATES FOR PREPARING RIVAROXABAN
-
The invention discloses processes for the preparation of rivaroxaban and its pharmaceutically acceptable salts, solvates, and hydrates thereof. The invention also relates to novel intermediates for the preparation of rivaroxaban.
- -
-
Paragraph 0203; 0217
(2015/01/07)
-
- PROCESS FOR PREPARING FACTOR XA INHIBITORS
-
The present invention relates to a process for the manufacturing of a rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1,3-oxozoladine-3- yl]phenyl}morpholin-3-one, and reacting the acid addition salt with the suitable reagents to obtain rivaroxaban or a salt thereof.
- -
-
Page/Page column 34
(2013/04/25)
-
- PROCESSES AND INTERMEDIATES FOR PREPARING RIVAROXABAN
-
The invention discloses processes for the preparation of rivaroxaban and its pharmaceutically acceptable salts, solvates, and hydrates thereof. The invention also relates to novel intermediates for the preparation of rivaroxaban.
- -
-
Page/Page column 40
(2013/07/19)
-
- A PROCESS FOR THE PREPARATION OF RIVAROXABAN BASED ON THE USE OF (S)-EPICHLOROHYDRIN
-
The invention relates to the stereoisomers of 4-{4-[(S/R)-5-[(((aryl)methylene)- amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-ones described by the chemical formulae (S)-(9) and (R)-(9). The optical isomer of compound (9) with the (S)- configuration is industrially applicable for the manufacture of the antithrombotic drug rivaroxaban (1). The new preparation process of rivaroxaban comprises a reaction of (S)-1- chloro-3-(((aryl)methylene)amino)propan-2-ols (S)-(14) with alkyl 4-(3-oxomorpholine-4- yl)phenylcarbamates (15) providing the key intermediate (S)-(9), which is further subjected to hydrolytic deprotection and subsequent acylation, producing rivaroxaban. The commercially available (S)-epichlorohydrin has been conveniently used as the chiral building block for the production of the key intermediate.
- -
-
Page/Page column 37
(2013/08/28)
-
- PROCESSES FOR THE PREPARATION OF 5-CHLORO-N-({(5S)-2-OXO-3-[4-(3-OXO-4-MORPHOLINYL) PHENYL]-1,3-OXAZOLIDIN-5-YL}METHYL)-2-THIOPHENE-CARBOXAMIDE AND INTERMEDIATES THEREOF
-
TThe present invention provides processes for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide (I) and intermediates thereof. Also provides novel intermediates and their use in the synthesis of oxazolidine derivatives.
- -
-
Page/Page column 48; 49
(2013/04/13)
-