95 results about "Dichlofopmethyl" patented technology

The invention discloses a method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative, which belongs to the technical field of organic synthesis and is suitable for industrial large-scale production. Difluorocarbene is produced by using a cheap base free of heavy metals as an additive, and the difluoromethylation of the proline derivative is completed to obtain an important difluoromethyl ether proline derivative pharmaceutical intermediate. Compared with existing synthesis methods, the method has mild reaction conditions, does not require the participation of heavy metals, can produce a large amount of fluorine-free products, uses inexpensive and readily available reagents, and has a high yield.

The present application relates to a kind of preparation method of trifluoromethyl pyrazole compound, belong to the technical field of organic synthesis.The specific method is: (1) trifluoroacetyl ethyl acetate is first with hydrazine hydrate cyclization reaction and generates compound of formula III;(2) under the catalysis of base, compound of formula III is reacted with difluoromethylation reagent and generates compound of formula II;(3) compound of formula II is reacted with methylating agent and obtains compound of formula I;The difluoromethylation reagent is difluoro-monochloromethane or sodium difluoro-monochloroacetate;The methylating agent is chloromethane, bromomethane, iodomethane, dimethyl sulfate or dimethyl carbonate.The present application is prepared by changing reaction route, and the higher-priced raw material methylhydrazine is replaced, and isomer impurity is no longer generated in the product prepared.Not only raw material cost is reduced, but also the purity of product is improved.

The invention discloses a preparation method of a difluoromethyl reagent and application of the difluoromethyl reagent in synthesis of a nickel-catalyzed alkyl difluoromethyl compound. The preparation method of the difluoromethyl reagent comprises the following steps: in an inert gas atmosphere, adding potassium iodide, cuprous iodide and a water-containing dimethylformamide solution into a reaction container, heating, dropwise adding difluorochloroacetic acid of DMF (Dimethyl Formamide) into a reaction system, collecting difluoroiodomethane, and supplementing a 1-methyl-2-pyrrolidone NMP (N-Methyl Pyrrolidone) solution into the system. The invention provides a difluoromethyl reagent which is simple and convenient to operate, low in cost, high in yield, environment-friendly and beneficial to large-scale preparation and application of the reagent in synthesis of difluoromethyl substituted alkane compounds.

The invention discloses a preparation method of a fluorine-containing ester-containing triazole compound, which comprises the following steps of: reacting fluorine-containing ester-containing p-toluenesulfonylhydrazone prepared from cheap and easily available starting raw materials (ketone containing trifluoromethyl or difluoromethyl functional groups) with an aromatic amine compound in tert-butyl hydroperoxide and acetonitrile under the promotion condition of iodine to obtain the fluorine-containing ester-containing triazole compound. And the fluorine-containing ester-containing triazole compound is obtained by a cyclization reaction and a'one-pot method '. In the preparation process, an expensive metal catalyst or ligand does not need to be used, so that the problem of toxicity or use safety caused by metal residues or azide compounds in a pharmaceutical process does not exist; in addition, the raw materials used in the process are bulk, cheap and easily available, the reaction system is green and environment-friendly, and the method has the advantages of simple operation steps and post-treatment process and high yield; the subsequent conversion research of the process can be applied to the synthesis of medical intermediates or related similar compounds.

The invention provides a green synthesis method of a sulfentrazone dichloride intermediate, which is characterized in that 2-chlorphenyl-4-difluoromethyl-4, 5-dihydro-3-methyl-1hydrogen-1, 2-4-triazole-5 (1H) ketone (intermediate I) is used as a reaction raw material, and chlorine and an oxidizing agent are matched to carry out chlorination reaction. The method has the advantages of simple and convenient process route, mild reaction conditions, simple and convenient operation process, reduced chlorine usage amount, high chlorine atom utilization rate, short reaction time, less waste gas generation amount, low production cost and easy industrialization realization, and is suitable for industrial production. The technical problems of low chlorine utilization rate, more three wastes, low safety and the like in the dichlorination reaction in the existing production technology are solved.

This application relates to processes and intermediates for the preparation of the PD-1 / PD-L1 inhibitor (R)-1-((7-cyano-2-(3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, and salts and crystalline forms thereof, where the PD-1 / PD-L1 inhibitor and solid forms and salt forms thereof are useful in the treatment of various diseases including infectious diseases and cancer.

Salts of the AAK1 inhibitor (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and solid forms thereof are disclosed, as are pharmaceutical formulations comprising them and methods of their preparation.

The invention relates to a synthesis method of a difluoroalkyl sulfone compound and / or a difluoroalkyl sulfoxide compound. The synthesis method comprises the following steps: taking a compound 1 and a compound 2 as raw materials, adding alkali, reacting in a solvent, oxidizing and decarboxylating; the structure of the compound 1 is shown as a formula (I-1) or a formula (I-2); the structures of the difluoroalkyl sulfone compound and the difluoroalkyl sulfoxide compound are respectively shown as a formula (II) and a formula (III); ; wherein M is selected from Na, K, NH4 or a hydrogen atom; r1 is selected from C1-C8 straight chain or straight chain alkyl; r2 is selected from a C1-C8 straight chain or branched chain alkylene group; r is selected from C1-C8 linear chain or branched chain alkyl; the structural general formula of the compound 2 is ClRf; and Rf is selected from a linear chain or branched chain alkyl group containing a difluoromethyl group of C1-C15. The one-pot method is adopted, the alkyl sulfone and the alkyl sulfoxide are prepared by using the same synthetic route, the synthetic reaction is simple, the substrate limitation is less, the cost is low, the reaction is fast, the yield is high, and the industrial production can be realized.

To provide: compounds useful in treating central nervous system diseases and other diseases; pharmaceutical compositions; and processes for the manufacture of the same.SOLUTION: The present invention relates to: difluoromethyl-pyridin-2-yl triazoles of general formula (I), which are modulators of GABAA receptors containing the α5 subunit; pharmaceutical compositions containing the compounds; and processes for the manufacture of the compounds.SELECTED DRAWING: None

The present application provides a crystal which is at least one crystal selected from the group consisting of a Ra1-type crystal, a Ra2-type crystal and a Ra3-type crystal each having the diffraction peaks described in the specification in powder X-ray diffraction based on Cu-Kα rays, of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide.

The present invention relates to an emulsion concentrate (EC) formulation of succinate dehydrogenase inhibitor fungicides, the manufacture of such a formulation, and the use of its diluted form for the control of fungal pathogens, in particular in crops of useful plants. More specifically, the present invention relates to an emulsion concentrate of-difluoromethyl-1-methyl-1H-pyrazol-4-methoxyl-[1-methyl-2-(2, 4, 6-trichlorophenyl)-ethyl]-amide comprising a blend of at least three surfactants and an aromatic ester solvent.

The present invention discloses an α-difluoromethylstyrene derivative and a preparation method thereof. The structure of the α-difluoromethylstyrene derivative of the present invention is as shown in formula (I), and the α-difluoromethylstyrene derivative is formed by reacting 3,3-difluoroallyl hydrazine, a transition metal salt and an additive in a solvent. The α-difluoromethylstyrene derivative of the present invention contains both gem-difluoromethylene and double bond structural units, and can be used as a potential pharmaceutical lead compound or a synthetic intermediate of a drug active molecule, providing an opportunity for the synthesis of macromolecular drugs. At the same time, the present invention provides a preparation method of the compound. The method is direct, simple, efficient, has a wide range of substrate applicability, and the raw materials are economically available and easy to obtain, and is suitable for large-scale production of α-difluoromethylstyrene derivatives.

Provided is a resist composition which generates an acid upon exposure to light, and the solubility of which in a developer solution is changed by the action of the acid. The present invention contains: a resin component (A1), the solubility of which in a developer solution is changed by the action of an acid; an acid generator component (B) which generates an acid upon exposure to light; and a surfactant (G01). The acid generator component (B) and the surfactant (G01) do not contain a difluoromethyl group or a trifluoromethyl group. However, cases where the structure is represented by formula (np1), (np2) or (np3) are excluded. X1 represents -OR1, -N(R2)R1, or -N(R1)2. X2 represents a methyl group or the like. X3 represents a methylene group or the like. R1 and R1 each represent a methylene group or the like.

The present application relates to a kind of 7-difluoromethyl-5-aryl pyrazolopyrimidine compound and preparation and application, the structural general formula of the compound is as shown in formula a, it is a kind of compound with inhibiting HIF-2 alpha activity, can block HIF-2 alpha / ARNT dimerization and play the role of HIF-2 transcription inhibition.The present application is proved by multiple experiments, the synthesized compound all has excellent HIF-2 transcription inhibition effect, in human renal clear cell carcinoma cell strain 786-O, show good VEGF protein inhibitory activity.The compound described in the present application can be applied in the preparation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) inhibitor for treating VHL deletion or / and HIF-2 alpha abnormal expression disease.This kind of compound can inhibit the overexpression and activation of HIF-2 alpha, to achieve the treatment and prevention of target disease, such as VHL deletion or / and HIF-2 alpha abnormal expression disease.

The application discloses a synthesis method of 3-difluoromethyl-1-methylpyrazole-4-methyl ethyl formate. The synthesis method is to synthesize 3-difluoromethyl-1-methylpyrazole-4-methyl ethyl formate by taking 5-difluoromethyl-1-methylpyrazole-4-methyl ethyl formate and dimethyl carbonate as raw materials and under the action of a porous organic polymer catalyst with solidified Lewis acid. The porous organic polymer catalyst with solidified Lewis acid comprises a porous organic polymer, and the porous organic polymer is solidified with Lewis acid. In the synthesis method, under the action of the porous organic polymer catalyst with solidified Lewis acid, not only a high reaction conversion rate can be obtained at normal temperature, but also a large number of side reactions caused by high temperature can be effectively avoided, thereby the impurity content can be obviously reduced, and the synthesis method has the advantages of simple operation, good catalyst activity, mild reaction condition, few side reactions, fast reaction rate, high yield and the like, is suitable for industrial application, and has a good market prospect.

Provided are a method for preparing a metalloenzyme inhibitor compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, and an important intermediate for preparing the compound.

Solid forms comprising (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one (Compound (I)), compositions comprising the same, and methods of making and using the same, for example, in the prevention or treatment of a central nervous system disease.

The present invention relates to a novel salt of a bicyclic heterocyclyl compound and a crystalline form thereof. The novel salt of a bicyclic heterocyclyl compound is N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)cinnolin-4-amine hydrochloride, has excellent photostability, heat / moisture stability, bioavailability, and the like, can be effectively used in pharmaceutical formulation, and can exhibit an excellent effect on the prevention or treatment of cancer.

The invention relates to a preparation method of 2, 2-difluoroethyl acetate, and belongs to the field of preparation of 2, 2-difluoroethyl acetate. The preparation method comprises the following steps: reacting bromomethyl acetate with (difluoromethyl) trimethylsilane in an organic solvent in the presence of alkali and a cuprous iodide catalyst to prepare the 2, 2-difluoroethyl acetate. According to the invention, the method for preparing the acetic acid 2, 2-difluoroethyl ester by reacting the bromomethyl acetate with the (difluoromethyl) trimethylsilane is provided for the first time. The raw materials are stable in physical state at high temperature, are not easy to leak, have low requirements on air tightness and pressure resistance of a reaction device, and are convenient to realize; and the reaction raw materials have stable chemical properties, are not easy to decompose and are convenient to store and use.

The present invention provides novel polymorphs of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) that are useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reserved ejection fraction (HFrEF), and conditions associated with left and / or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the polymorphs is described, as well as methods for treating systolic dysfunction, DCM, HFrEF, and other forms of heart disease.

The invention discloses a preparation device of difluoromethyl alkyl pyrazole carboxylic acid and a using method, and relates to the technical field of pesticide preparation.The preparation device comprises a supporting shell, a stirring box, a stirring rod, a first box, a first motor and an automatic dripping assembly.The stirring box is installed on the inner wall of the supporting shell, and the first box is installed at the top of the supporting shell; a stirring rod is mounted at the tops of the stirring box and the supporting shell in a penetrating manner, and a first motor is mounted at one end of the stirring rod. A first spring moves to enable a first T-shaped rod to drive a second rod to move, the second rod moves to drive a sealing block to move away from a second pipe, the second pipe is opened to enable reaction liquid to enter a stirring box to react difluoromethyl alkyl pyrazole carboxylic acid, and meanwhile the second rod moves to drive an arc-shaped flow dividing head to stir the reaction liquid; according to the preparation device of the difluoromethyl alkyl pyrazole carboxylic acid, the function that the reaction liquid is stirred to prevent layering of the reaction liquid while the reaction liquid is automatically added is achieved.

This invention relates to the visible light-induced synthesis of α-aryl-β-difluoromethyl-substituted ketone compounds. The method utilizes a photocatalytic strategy to construct valuable α-aryl-β-difluoromethyl-substituted ketone compounds through radical-mediated difluoromethylation and migration of 1,2-aryl groups. The method and synthetic steps include: Step 1: Using 80W blue light as a visible light source, α,α-diphenylallyl alcohol (1a), difluoromethyl ylide (2), photocatalyst fac-Ir(ppy)3, sodium acetate, and methanol are added to a 10 mL reaction tube and placed in a nitrogen atmosphere; Step 2: Under visible light irradiation, the reaction is stopped when the starting material α,α-diphenylallyl alcohol (1a) is completely consumed; Step 3: After the reaction is complete, the solvent is removed by vacuum distillation. The crude product is purified by rapid column chromatography to obtain α-aryl-β-difluoromethyl-substituted ketone compounds (3a). This reaction has the advantages of mild conditions, simple operation, broad substrate compatibility, and good functional group tolerance.

The invention discloses a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-formic acid, which comprises the following steps: (1) reacting methylhydrazine with benzaldehyde substances in an organic solvent to obtain a reaction solution A, (2) firstly adding 2-(dimethylaminomethylene)-4, 4 '-diazole-4-carboxylic acid into the reaction solution A, and (3) adding 2-(dimethylaminomethylene)-4, 4'-diazole-4 '-carboxylic acid into the reaction solution A to obtain the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. And (3) adding a basic salt into the reaction liquid B for reaction, then separating a water phase, adding hydrochloric acid into the water phase for reaction to obtain a reaction liquid C, and filtering the reaction liquid C to obtain a solid product, namely 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-formic acid. According to the method, the hidden danger of isomer generation is eliminated, the separation and purification mode is simplified, the overall yield of the reaction is greatly increased, the reaction condition is mild, the organic solvent can be used mechanically, the preparation cost is reduced, three wastes are reduced, the practical value is high, and the method is suitable for industrial production.

Crystalline polymorph forms of(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino) propanamide (GDC-0077), having the structure, Formula I:or stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, processes of preparing the polymorph forms, and uses of the polymorph forms for the treatment of cancer.

The invention belongs to the technical field of organic fluorine chemical industry, and particularly relates to hexafluoro-1, 3-butadiene as well as a synthesis method and a synthesis device thereof. The synthesis method of hexafluoro-1, 3-butadiene comprises the following synthesis process routes: firstly, triphenylphosphine and difluorochloromethane are subjected to a reaction, obtained triphenyl difluoromethyl phosphorus halide and sodium hydride are subjected to a reaction, and difluoromethyl triphenylphosphine is prepared; then reacting trifluoroethylene with carbonyl chloride fluoride to generate an enoyl fluoride intermediate; and finally, reacting the enoyl fluoride intermediate with difluoromethyl triphenylphosphine to generate hexafluoro-1, 3-butadiene. The synthesis method of hexafluoro-1, 3-butadiene provided by the invention is mild in condition, stable and low in risk; the hexafluoro-1, 3-butadiene product synthesized by the synthesis method disclosed by the invention is good in selectivity, high in purity and high in yield; the synthesis device and equipment used in the synthesis method are low in cost and low in energy consumption.

The invention relates to soluble guanylate cyclase (sGC) activators, preferably (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid (runcaciguat) and / or substituted pyrazolo piperidine carboxylic acids, preferably selected from the list consisting of 1-[1-{4-Chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-Chloro-4′-(4-isobutylpiperazin-1yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride, 1-{3(R)-1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate or 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoro-methyl)-1H-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 1) for use in the treatment and / or prophylaxis of heart failure with preserved ejection fraction (HFpEF) in women and their use for preparing medicaments for the use in the treatment and / or prophylaxis of heart failure with preserved ejection fraction (HFpEF) in women.