- Interrupted aza-Wittig reactions using iminophosphoranes to synthesize 11C-carbonyls
-
A direct CO2-fixation methodology couples structurally diverse iminophosphoranes with various nucleophiles to synthesize ureas, carbamates, thiocarbamates, and amides, and is amenable for 11C radiolabeling. This methodology is practical, as demonstrated by the synthesis of >35 products and isolation of the molecular imaging radiopharmaceuticals [11C]URB694 and [11C]glibenclamide. This journal is
- Ismailani, Uzair S.,Munch, Maxime,Mair, Braeden A.,Rotstein, Benjamin H.
-
supporting information
p. 5266 - 5269
(2021/06/06)
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- Preparation method of regorafenib
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The invention relates to a preparation method of regorafenib. The method comprises the following steps: adding 4-chloro-3-trifluoromethylaniline and an alkaline reagent into an organic solvent of triphosgene, and stirring for reaction to obtain a compound 2; and then adding N-methyl-4-(4-amino-3-fluoro) phenoxy pyridine-2-formamide and an alkaline reagent into the organic solvent of the compound 2, and reacting to obtain the regorafenib. The method provided by the invention is short in reaction time, easy for large-scale preparation, easy to operate, good in stability, high in purity and yield, free of intermediate separation and suitable for industrial production.
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Paragraph 0025-0040
(2021/05/29)
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- Synthesis method of regorafenib
-
The invention provides a synthesis method of regorafenib, which adopts 3-fluoro-4-nitrophenol as a raw material to replace the traditional 3-fluoro-4-aminophenol to carry out etherification reaction, and then carries out catalytic hydrogenation to obtain 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide, and has the advantages that the nitro stability is much higher than the amino stability; catalytic hydrogenation is carried out after etherification with the 4-chloro-2-pyridine formamide, such that the hydroxyl group is etherified so that the product stability is improved greatly, the purity and the yield of the product obtained after the catalytic hydrogenation are substantially improved, and the quality of the final product regorafenib is ensured. 3-fluorine-4-nitrophenol is used as a starting material to be subjected to etherification reaction with 4-chlorine-2-pyridine formamide, so that 4-methyl-2-pentanone is not needed to protect amino, and the quality of an intermediate obtained after catalytic hydrogenation and the quality of a final product are better.
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-
- Regorafenib analogues and their ferrocenic counterparts: Synthesis and biological evaluation
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Approved by the FDA in 2012, regorafenib is one of the last chance treatments for colorectal cancer. While various analogues have already been prepared, ferrocenic derivatives have never been evaluated. In this study, we prepared various ferrocene-containing derivatives of regorafenib and recorded their biological activity in kinase and cellular assays. This led to the identification of a squaramide derivative which shows a good cellular activity and three ferrocene analogues with promising activity in both kinase and cellular assays. This journal is
- Wilde, Myron,Arzur, Danielle,Baratte, Blandine,Lefebvre, Dorian,Robert, Thomas,Roisnel, Thierry,Le Jossic-Corcos, Catherine,Bach, Stéphane,Corcos, Laurent,Erb, William
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p. 19723 - 19733
(2020/12/04)
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- A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib
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A practical synthetic route to regorafenib, in which the target compound was obtained via a 10-step synthesis starting from 2-picolinic acid, 4-chloro-3-(trifluoromethyl)aniline, and 3-fluorophenol, is reported. Crucial to the strategy is the preparation of 4-amino-3-fluorophenol via Fries and Beckman rearrangements using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and an acceptable overall yield. A scale-up experiment was carried out to provide regorafenib with 99.96% purity in 46.5% total yield.
- Du, Fangyu,Zhou, Qifan,Shi, Yajie,Yu, Miao,Sun, Wenjiao,Chen, Guoliang
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p. 576 - 586
(2019/02/01)
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- Direct conversion of carboxylic acids to various nitrogen-containing compounds in the one-pot exploiting curtius rearrangement
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Herein we report, a single-pot multistep conversion of inactivated carboxylic acids to various N-containing compounds using a common synthetic methodology. The developed methodology rendered the use of carboxylic acids as a direct surrogate of primary amines, for the synthesis of primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides, and N-formyls, exploiting the Curtius reaction. This approach has a potential to provide a diversified library of N-containing compounds, starting from a single carboxylic acid, based on the selection of the nucleophile.
- Kumar, Arun,Kumar, Naveen,Sharma, Ritika,Bhargava, Gaurav,Mahajan, Dinesh
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p. 11323 - 11334
(2019/09/10)
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- Two novel platinum(II) complexes with sorafenib and regorafenib: Synthesis, structural characterization, and evaluation of in vitro antitumor activity
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Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt(SRFN)(DMSO)Cl2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl2] (RGFN-Pt), were prepared and characterized by ESI-MS, IR, UV–Vis spectroscopy, elemental analyses, and 1H and 13C NMR, respectively. The anticancer activities of SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt and RGFN-Pt were more effective against the A549/DDP tumor cells (IC50 = 1.18 ± 0.15 μM and 0.13 ± 0.03 μM) than SRFN (45.03 ± 0.79 μM), RGFN (40.11 ± 2.15 μM), and cisplatin (97.63 ± 1.06 μM), respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro antitumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFN-Pt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.
- Qin, Qi-Pin,Wang, Zhen-Feng,Tan, Ming-Xiong,Wang, Shu-Long,Zou, Bi-Qun,Luo, Dong-Mei,Qin, Jiao-Lan,Zhang, Shu-Hua
-
-
- Synthetic method of anti-cancer drug Stivarga
-
The invention provides a synthetic method of an anti-cancer drug Stivarga. The method comprises the steps of taking 3-fluoro-4-nitrophenol as a raw material, performing condensation reaction with N-methyl-4-chloro-2-pyridine carboxamide under the action of alkali to obtain 4-(4-nitryl-3-fluorobenzene)-2-(methyl carbamyl) pyridine, performing catalytic reduction to obtain 4-(4-amino-3-fluorobenzene)-2-(methyl carbamyl) pyridine, then performing condensation reaction with 4-chloro-3-(trifluoromethyl) phenyl isocyanate in tetrahydrofuran, so as to obtain the Stivarga. The synthetic method provided by the invention has the advantages that the adopted raw material is relatively cheap and easy to obtain, the reaction conditions are mild, the operation is simple and safe, the product yield is relatively high, the product purity is high, and the industrialization value is relatively high.
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-
-
- Preparation method of regorafenib hydrate
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The invention belongs to the field of drug synthesis and particularly relates to a preparation method of regorafenib hydrate. 4-methyl-2-pentanone, 4-amino-3-fluorophenol and N-methyl-4-chloro-2-pyridine carboxamide are condensed to obtain a regorafenib intermediate 1, 4-chloro-3-(trifluoromethyl)isocyanate is added for condensation and salt-forming reactions to produce a regorafenib intermediate2, and finally, free hydration is performed in an alkaline acetone aqueous solution to obtain the regorafenib hydrate. The preparation method of the regorafenib hydrate is simple to operate and easy to monitor, has yield up to 90% or above and high efficiency and is applicable to mass industrial production. The prepared regorafenib hydrate has low impurity content, has no solvent residues basically, significantly shortens purification time, has stable properties, keeps stable in accelerated stability tests and has high safety.
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Paragraph 0045; 0052; 0054; 0055; 0056
(2019/04/06)
-
- Preparation method of crude regorafenib
-
The invention discloses a preparation method of crude regorafenib, which comprises preparing 4-(4-amino-3-trifluorophenoxy)-N-methylpyridin-2-formamide with 4-chloro-N-methylpyridin-2-formamide, 2-fluoro-4-hydroxylaniline(4-amino-3-fluorophenol) and phenyl 4-chloro-3-(trifluoromethyl)isocyanate, preparing 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamyl}amino)-3-fluorophenylamino]-N-methylpyridin-2-formamide, adding crystallizing water to obtain regorafenib (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamyl}amino)-3-fluorophenylamino]-N-methylpiridin-2-formamide monohydrate, and refiningto obtain crude regorafenib. The whole production process involves two steps of reaction and four operating processes, the yield is high, the purity is high, the content of purities is low, the molaryield is higher than 45%, and the weight yield is close to 100%.
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Paragraph 0022; 0027-0029; 0034; 0039-0041
(2019/06/27)
-
- Antitumor drugs and preparation method and application thereof
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The invention relates to antitumor drugs and a preparation method and application thereof, in particular to a compound shown as a following formula (I). The compound adopts Cu-Kalpha radiation and hasa typical powder X-ray diffraction pattern shown in a figure 1. The invention also provides a preparation method of the compound, a pharmaceutical composition comprising the compound and the application of the compound in preparation of the drugs for resisting tumors such as, but not limited to, colon cancer, lymphoma, sarcoma, leukemia, pancreatic cancer, breast cancer, prostate cancer, bone cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, skin cancer, stomach cancer, colorectal cancer, renal cell carcinoma, hepatocellular carcinoma and melanoma. The compound has excellent performance.
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Paragraph 0098; 0106-0111
(2019/10/15)
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- Preparation method of Regorafenib compound
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The invention discloses a preparation method of a Regorafenib compound. The preparation method includes: 4-amino-3-fluorophenol is used to have reaction with a compound III to prepare a compound IV, and the obtained compound IV is allowed to have reaction with a compound V and isobutyryl methyl acetate to obtain the final-product Regorafenib compound. The method is simple in reaction process route, high in total yield, mild in reaction condition, environmentally friendly and suitable for industrial production.
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Paragraph 0014; 0037; 0040; 0043-0046
(2018/08/28)
-
- Preparation method of regorafenib
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The invention relates to a preparation method of regorafenib. The method comprises steps as follows: 4-amino-3-fluorophenol and 4-chloro-N-methylpyridine-2-formamide are subjected to ether condensation reaction under the action of anhydrous potassium carbonate and PEG-400, and an intermediate I is generated; then the intermediate I and 3-trifluoromethyl 4-chlorobenzoic acid are subjected to one-pot reaction with diphenylphosphoryl azide under the action of alkali, a crude regorafenib product is obtained and further purified, and a pure regorafenib product is obtained. The method is high in conversion rate, safe, harmless, pollution-free, high in yield and suitable for industrial production, the reaction conditions are mild, and the product purity is high.
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Paragraph 0038; 0039; 0041; 0043; 0045; 0047; 0049; 0051
(2019/01/08)
-
- A preparation method of switzerland ge feini (by machine translation)
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The invention relates to a preparation method of switzerland ge feini, the method comprises the following steps: the 3 - fluoro - 4 - nitro-phenol heating molten, in KOH under the action of the 4 - chloro - N - methyl pyridine - 2 - carboxamide react, by hydrazine hydrate also primary into intermediate I; I after the intermediate, 3 - trifluoromethyl - 4 - chloroaniline in the catalyst with ethylene carbonate to one-pot reaction, switzerland ge feini pure product after treatment. The method of the invention high conversion rate, without endangering the safe, pollution-free, mild reaction conditions, high yield, high purity of the product and is suitable for industrial production. (by machine translation)
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Paragraph 0038-0039; 0041; 0043; 0045; 0047; 0049; 0051; 005
(2018/10/19)
-
- Preparation method of regorafenib
-
The invention relates to a preparation method of regorafenib. The method comprises the following steps: performing reaction on 3-fluoro-4-nitrophenol and 4-chloro-N-methyl pyridine-2-methylformamide under the effects of anhydrous potassium carbonate and PEG-400, and performing hydrazine reduction to generate an intermediate I; then performing one-pot reaction on the intermediate I, 3-trifluoromethyl-4-chlorophenylamine and dimethyl dithiocarboxylate under the effect of a catalyst, then performing post-treatment to obtain a regorafenib crude product, and further purifying the regorafenib crudeproduct to obtain a regorafenib purified product. The method disclosed by the invention has the advantages of high conversion ratio, security, no harm, no pollution, mild reaction conditions, high yield and high purity of the product; moreover, the method is suitable for industrial production.
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Paragraph 0018; 0038; 0039; 0058; 0059
(2018/09/12)
-
- KINASE INHIBITOR COMPOUNDS, COMPOSITIONS, AND METHODS OF TREATING CANCER
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The present invention relates to a compound having the structure of formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, where X, Y, Z, R, R1, R2, R3, R4, R5, and R6 are as described herein. The present invention also relates to compositions containing the compound having the structure of formula (I), and a method of treating cancer in a subject.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF REGORAFENIB
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The present invention relates to an improved process for the preparation of Regorafenib with genotoxic impurities at well below threshold limit and high yield. The present invention also relates to an improved process for the preparation of regorafenib form-I with high purity.
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- PREPARATION METHOD OF 4-(4-AMINO-3-FLUOROPHENOXY)-N-METHYLPYRIDINE-2-FORMAMIDE
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The present invention relates to a preparation method of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide capable of enabling 4-chlorine-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol in the presence of an inorganic base. The present invention employs the inorganic base to replace potassium t-butoxide in the prior art, thus effectively solving the problem of a potential safety hazard of the potassium t-butoxide in industrial production. In addition, after the reaction is completed, the present invention employs a crystallization method for separation to obtain a reaction product; thus compared with the methods of extraction, concentration and column isolation and purification employed in the prior art, the present invention has a simpler operation and a lower cost, results in less environment pollution and a higher yield, and is very suitable for industrial production.
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Paragraph 0037
(2017/12/27)
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- Preparation method of Stivarga
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The invention discloses a preparation method of Stivarga. New compound 4-(3-fluorophenoxy)-N-methylpyridine-2-methanamide(5) and 4-(3-fluorine-4-aminophenoxy)-N-methylpyridine-2-methanamide(6) are introduced as intermediates. Through the introduction of the intermediates, the invention provides the preparation method of the Stivarga, which is mild in reaction condition, simple in after-treatment, high in reaction yield and purity, low in cost and more reasonable.
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- An efficient and high-yielding protocol for the production of Regorafenib via a new synthetic strategy
-
An improved, high-yielding, and efficient protocol for the production of Regorafenib (1), a novel diaryl urea inhibitor of multiple protein kinases, is described. The highlight of the process chemistry design and development is an optimization of the route for preparing key intermediate 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (7) by O-alkylation, nitration and reduction reactions. The developed process avoids using column chromatography to isolate 7, reduces the reaction requirements and is cost-saving, resulting in an increased overall yield from 35.0 to 57.0 % and purity from 97.0 to 99.8 %.
- Wang, Li-Mei,Du, Bao-Quan,Zuo, Da-Zhuang,Cheng, Ming-Ke,Zhao, Meng,Zhao, Si-Jia,Zhai, Xin,Gong, Ping
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p. 3209 - 3218
(2016/04/05)
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- PROCESS FOR THE PREPARATION OF 4-[4-({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]CARBAMOYL}AMINO)-3-FLUOROPHENOXY]-N-METHYLPYRIDINE-2-CARBOXAMIDE AND ITS POLYMORPHS THEREOF
-
The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3- (trifluoromethyl)phenyl]carbamoyl}amino)-3-fluophenoxy]-N-methylpyridine-2-caroxamide compound of formula- I, its amorphous form and its crystalline polymorph-I which is represented by the following structural formula: (I)
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Page/Page column 17; 18; 19
(2016/04/26)
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- PROCESS FOR THE PREPARATION OF REGORAFENIB AND ITS CRYSTALLINE FORMS
-
The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide or Regorafenib (I): Formula (I). The present invention further relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide or Regorafenib (I) to provide highly pure material. The present invention further relates to a process for the preparation stable crystalline material of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]- N-methyl pyridine-2-carboxamide or Regorafenib (I) useful in the preparation of pharmaceutical compositions for the treatment of cancer.
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Page/Page column 15
(2016/04/26)
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- CRYSTALLINE POLYMORPHIC FORMS OF REGORAFENIB AND PROCESSES FOR THE PREPARATION OF POLYMORPH I OF REGORAFENIB
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The present application relates to the novel crystalline polymorphic form A, B, C and D of Regorafenib and processes thereof. The present application also relates to the processes for the preparation of polymorph I of Regorafenib.
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Page/Page column 25
(2015/02/19)
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- SYNTHETIC METABOLITES OF FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL UREA FOR THE TREATMENT AND PREVENTION DISEASES AND CONDITIONS
-
Synthetic metabolites of compounds of Formula (I); salts thereof, prodrugs thereof, pharmaceutical compositions containing such synthetic metabolites, and use of such compound and compositions to treat diseases mediated by raf, VEGFR, PDGFR, p38 and flt-3. Described are M2, M3, M4, and M5 synthetic metabolites of compounds of formula I, wherein the structures of said compound of formula I and said M2, M3, M4, and M5 synthetic metabolites are:
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- PROCESS FOR THE PREPARATION OF 4- {4-[({[4 -CHLORO-3 -(TRIFLUOROMETHYL)-PHENYL]AMINO}CARBONYL)AMINO]-3-FLUOROPHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE, ITS SALTS AND MONOHYDRATE
-
The present invention relates to a process for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxarnide, its salts and monohydrate.
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- TREATMENT OF CANCERS HAVING RESISTANCE TO CHEMOTHERAPEUTIC AGENTS
-
The present invention provides compositions and methods for treating cancer with DAST, 4{4-[3-(4-chloro-3-trifluoromethyl phenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide of the formula I, including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, prodrugs, solvates or combinations thereof. Any cancer can be treated, including cancers that have acquired resistance to another therapeutic agent, such as kinase inhibitors. DAST can also be used to treat cancers which have become refractory to other chemotherapeutic agents.
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Page/Page column 17
(2008/12/07)
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- TREATMENT OF CANCERS WITH ACQUIRED RESISTANCE TO KIT INHIBITORS
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The present invention provides compositions and methods for treating cancers which have acquired resistance to a KIT inhibitor by administering effective amounts of DAST.
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Page/Page column 14-15
(2008/12/07)
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- POLYMORPH II OF 4-[4-({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]CARBAMOYL}AMINO)-3-FLUOROPHENOXY]-N-METHYLPYRIDINE-2-CARBOXAMIDE
-
The present invention relates to the polymorph II of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders.
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Page/Page column 18
(2008/12/05)
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- Pharmaceutical compositions for the treatment of hyper-proliferative disorders
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This invention relates to novel pharmaceutical compositions comprising a solid dispersion of the compound of Formula I below, to processes for preparing these novel pharmaceutical compositions and to their use for treating hyper-proliferative disorders, such as cancer, either as a sole agent or in combination with other therapies. Formula I is as follows:
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Page/Page column 6
(2010/10/20)
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- FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL UREA FOR THE TREATMENT AND PREVENTION OF DISEASES AND CONDITIONS
-
A compound of Formula (I): (I) salts thereof, prodrugs thereof, metabolites thereof, pharmaceutical compositions containing such a compound, and use of such compound and compositions to treat diseases mediated by raf, VEGFR, PDGFR, p38 and flt-3.
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Page/Page column 47
(2008/06/13)
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