34 results about "Formamidine hydrochloride" patented technology

The invention discloses a method for preparing 4,6-dihydroxypyrimidine, relates to the method for preparing the 4,6-dihydroxypyrimidine, and belongs to the technical field of a medicine. The method comprises the following steps: firstly, feeding formamidine hydrochloride, malonic ester and alkali to a solvent to reflux, agitate and react for 1-12 hours; washing by acid water until the solvent is neutral; adding water, cooling, agitating and filtering so as to obtain pale yellow crystal after recovering the solvent at reduced pressure; finally re-crystallizing the pale yellow crystal by acetone to obtain the white crystal 4,6-dihydroxypyrimidine. According to the method, the 4,6-dihydroxypyrimidine is prepared from formamidine hydrochloride and malonic ester as materials in a cyclization manner; the used materials are cheap; the reaction yield can be up to over 90%; the content of the 4,6-dihydroxypyrimidine after re-crystallization is greater than 98%.

The invention discloses a method for preparing 2,4-di-substituted-1,3,5-triazine. The method comprises the specific step: with substituted formamidine hydrochloride as a reaction substrate an iodine-containing compound as a catalyst, tert-butyl hydroperoxide as an oxidant, inorganic base as an acid binding agent and aliphatic ether as an organic solvent (also used as a carbon source), carrying outcarbon-hydrogen and carbon-oxygen bond deletion, nucleophilic addition, deaminizing condensation and oxidative aromatization reaction to obtain a 2,4-di-substituted-1,3,5-triazine compound, wherein achemical structural general formula of the substituted formamidine hydrochloride is shown in the description; the iodine-containing compound is selected from one of potassium iodide (KI), tetrabutylammonium iodide (TBAI), elemental iodine (I2) and N-iodosuccinimide (NIS); the inorganic base is selected from one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium hydroxide and potassium tert-butoxide; and the aliphatic ether is selected from one of methyl tert-butyl ether, ethyl ether and ethylene glycol dimethyl ether. The preparation method disclosed bythe invention has the characteristics of easily-obtained raw materials, low price and low toxicity of a catalyst, wide range of the substrate, simplicity and convenience in operation, greenness, environmental protection and the like.

The invention discloses a simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine. The method comprises the following steps: preparing compound (IV) by a dehydrohalogenation reaction between cyanoacetoacetate and haloacetaldehyde glycol, and then preparing a compound (V) by condensation between the compound (V) and formamidine hydrochloride and alkali; preparing a compound (VIII) by amino group protection through a protecting group reagent, methylation of DMFDMA and hydrazine hydrate condensation; preparing a compound (IX) by reacting with a chlorination reagent; and carrying out catalytic hydrodechlorination to obtain 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine. The raw materials used in the invention are cheap and easily available; by using the ''one-pot method'' operation twice, the environmental protection property is high, and the process route is simple; the reaction operation is convenient, and the reaction selectivity is high; the obtained product has high purity, high yield and low cost; and the method is beneficial to green industrial production.

The invention discloses a preparation method of polysubstituent 1,3,5-triazine. Specifically, substituen formamidine hydrochloride is used as a reactive substrate, chlorodifluoroacetic acid sodium salt is used as a carbon synthon, and the symmetrical or asymmetrical polysubstituent 1,3,5-triazine is obtained through fracture of carbon-chlorine, carbon-carbon and carbon-fluorine bonds under the action of equivalent inorganic base. The chemical structural general formula of the substituen formamidine hydrochloride is as shown in specification, and the inorganic is one selected from potassium carbonate, sodium carbonate, cesium carbonate. The preparation method disclosed by the invention has the advantages of easily available raw materials, no need for catalyst or oxidant, a wide variety of substrates, simple and convenient operation and environmental friendliness.

The invention discloses a method for preparing 2,4-di-substituted-1,3,5-triazine. The method comprises the specific step: with substituted formamidine hydrochloride as a reaction substrate an iodine-containing compound as a catalyst, tert-butyl hydroperoxide as an oxidant, inorganic base as an acid binding agent and aliphatic ether as an organic solvent (also used as a carbon source), carrying outcarbon-hydrogen and carbon-oxygen bond deletion, nucleophilic addition, deaminizing condensation and oxidative aromatization reaction to obtain a 2,4-di-substituted-1,3,5-triazine compound, wherein achemical structural general formula of the substituted formamidine hydrochloride is shown in the description; the iodine-containing compound is selected from one of potassium iodide (KI), tetrabutylammonium iodide (TBAI), elemental iodine (I2) and N-iodosuccinimide (NIS); the inorganic base is selected from one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium hydroxide and potassium tert-butoxide; and the aliphatic ether is selected from one of methyl tert-butyl ether, ethyl ether and ethylene glycol dimethyl ether. The preparation method disclosed bythe invention has the characteristics of easily-obtained raw materials, low price and low toxicity of a catalyst, wide range of the substrate, simplicity and convenience in operation, greenness, environmental protection and the like.

The invention discloses a preparation method of riociguat. The preparation method comprises the steps of firstly, taking 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride and 2-aminopropanediamide as basic raw materials, adding strong base and a solvent to perform a reflux reaction, so as to prepare 2-[1-(2-fluorobenzyl) -1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-4,5,6-triamine, namely a compound 3; then taking the compound 3 and dimethyl carbonate as basic raw materials, dissolving the same into methyl alcohol for reaction, so as to prepare 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl methyl carbamate, namely a compound 5, finally, dissolving the compound 5 and the strong base into the methyl alcohol, and adding methyl iodide for reacting, so as to prepare a riociguat crude product, and performing recrystallization on the riociguat crude product to obtain a riociguat refined product. The preparation method provided by the invention is relatively high in total recovery, simplified in operation and easy to industrialize.

The invention discloses a method for synthesizing adenine and derivatives thereof. The method comprises the steps: firstly, subjecting diethyl malonate and dimethyl dioxirane to an oxidation reaction, so as to obtain 2-hydroxyldiethyl malonate; then, carrying out an ammonolysis reaction with ammonia water, so as to obtain 2-hydroxyl malonamide; then, carrying out a cyclization reaction with trimethyl orthoformate, so as to obtain 5-hydroxyl pyrimid-4,6-(1H,5H)-dione; then, carrying out a chlorination reaction with phosgene, so as to obtain 4,5,6-trichloropyrimidine; then, carrying out a cyclization reaction with formamidine hydrochloride, so as to obtain 4-chloro-1H-pyrazol[3, 4-d]pyrimidine; finally, carrying out an ammoniation reaction with ammonia water or an amine compound in the presence of triethylamine, thereby obtaining the adenine and derivatives thereof. According to the method, the raw materials are moderately-priced and readily available, the reaction conditions are mild, the reaction process is safe, the requirements on production equipment are low, particularly, the environmental pollution is light, and the yield is relatively high, so that the method is applicable to industrial large-scale production.

The invention discloses a simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine. The method comprises the following steps: preparing compound (IV) by a dehydrohalogenation reaction between cyanoacetoacetate and haloacetaldehyde glycol, and then preparing a compound (V) by condensation between the compound (V) and formamidine hydrochloride and alkali; preparing a compound (VIII) by amino group protection through a protecting group reagent, methylation of DMFDMA and hydrazine hydrate condensation; preparing a compound (IX) by reacting with a chlorination reagent; and carrying out catalytic hydrodechlorination to obtain 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine. The raw materials used in the invention are cheap and easily available; by using the ''one-pot method'' operation twice, the environmental protection property is high, and the process route is simple; the reaction operation is convenient, and the reaction selectivity is high; the obtained product has high purity, high yield and low cost; and the method is beneficial to green industrial production.

The invention relates to a method for synthesizing riociguat. The method includes the following steps: 1, a compound 1-(2-fluorobenzyl)-1H-[3,4-b] pyridine derivative-3-formamidine hydrochloride (1) and a compound benzeneazomalononitrile (2) are reacted in methylbenzene under the condition that sodium methylate exists to obtain a compound (3); 2, the compound (3) is dissolved into DMF, then raney nickel is added to serve as catalysts, and hydrogenation reduction is carried out to obtain a compound (4); 3, a formyl group is firstly synthesized into the compound (4), then reduction is carried out through boron hydride to obtain a single-methyl compound (5a); 4, isopropyl alcohol is used as solvents to be reacted with methylclhlorofonmate to obtain the product riociguat. The synthesizing method has the advantages of being easy and convenient to operate, gentle in condition, high in total yield and high in product purity, and is suitable for large-scale synthesizing of the high-purity riociguat.

The invention discloses a preparation method for 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate. The method comprises the following steps: contacting liquid sodium alkoxide with formamidine hydrochloride and then contacting an obtained substance with a compound represented by a formula (1) so as to obtain 4-amino-5-formylaminomethylpyrimidine; contacting 4-amino-5-formylaminomethylpyrimidine with an alkaline aqueous solution and then contacting an obtained substance with carbon disulfide and gamma-chloroacetyl propanol so as to obtain a compound represented by a formula (2); contacting an acidic aqueous solution with the compound represented by the formula (2) so as to obtain a compound represented by a formula (3); and contacting the compound represented by the formula (3) with hydrogen peroxide, then contacting an obtained substance with nitrate, carrying out neutralization with alkali and then carrying out solid-liquid separation so as to obtain 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate. With 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate prepared in the invention, accurate qualitative and quantitative analysis of demethylated thiamine can be realized.

A method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine is provided. The method comprises the steps of: preparing methyl p-bromophenylacetate (Intermediate I) by catalytic esterification of p-bromophenylacetic acid, and then reacting with dimethyl carbonate to synthesize 2-(4-bromophenyl)-malonic acid-1,3-dimethyl ester (Intermediate 2), cyclizing with formamidine hydrochloride to obtain 5-(4-bromophenyl)-4,6-dihydroxypyrimidine (Intermediate 3), and then chlorinating to give the product 5-(4-bromophenyl)-4,6-dichloropyrimidine. In the process of preparing Intermediate 1 in the present invention, a solid acid is used as a catalyst. Moreover, in the process of preparing Intermediate 2, sodium methoxide is used as a base in place of sodium hydride or sodium amide used in the prior art. Furthermore, Intermediate 3 is prepared by a one-pot process.

The invention discloses a new method for performing microwave synthesis on gefitinib and a derivative thereof. The method comprises the following steps of: at first, synthesizing 6-methoxyl-7-hydroxyl quinazoline-4-one from 2-iodo (bromo)-4-methoxyl-5-hydroxyl cyanophenyl used as an initial raw material and formamidine hydrochloride in a microwave mode; then performing reaction with 4-(3-bromo propyl) morpholine to introduce an alkyl side chain so as to obtain 7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline-4-ketone; in the presence of a catalyst, performing reaction on the obtained product and a chlorination reagent to obtain 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline; finally, performing reaction on 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline and 3-chloro-4-fluoroaniline to obtain a final product 4-(3-chloro-4-fluoroanilino)-7-methoxyl-6-(3-morpholinyl propoxy) quinazoline (gefitinib). The whole route steps are simplified into four steps, the yield is high, the method is convenient to carry out, the dangerousness is low, and the application of high-pollution reagents is reduced; moreover, the whole route is high in economy and suitable for industrial production, and the product cost is reduced. The reaction formula is as shown in the specification.

The invention discloses a method for compounding riociguat intermediate, firstly 1-(2-fluorine benzyl) 1H-pyrazolo [3, 4-b] pyridine-3-formamidine hydrochloride are used as starting materials, and 2-[1-(2-fluorine benzyl)-1 H- pyrazolo [3, 4-b] pyridine-3-yl]-4, 5, 6-pyrimidine triamine of the riociguat intermediate are prepared by catalyzing and hydrogenating in normal pressure through a catalyst. The method for compounding the riociguat intermediate is mild in reaction conditions, prevents using a high pressure reaction kettle, reduces process demands to equipment, enables product purity to be bigger than 99.0% at last, and is suitable for commercial process.