The method of obtaining methansulfonate of doxazosin

 

(57) Abstract:

The invention relates to an improved process for the preparation of doxazosin, which is known antihypertensive agent used in hypertension and prostate cancer. Describes how to obtain methansulfonate of doxazosin by dissolving the base of doxazosin and methansulfonate in an organic solvent, filtering the resulting solution, followed by separation of the target product, the organic solvent is a mixture of dimethylformamide with butyl acetate in a ratio of from 1:1 to 5:2. Effect: method allows to reduce considerably the process of obtaining methansulfonate of doxazosin and eliminate toxic methanol.

The invention relates to a method for methansulfonate of doxazosin, which is known antihypertensive agent used in hypertension and prostate cancer (M. D. Mashkovsky. Medicines, T. 1, "New Wave", M, 2000, page 252).

A method of obtaining methansulfonate of doxazosin by transferring its founding in acetate in an organic solvent (lower alcohol or US 6140334 class. C 07 D 403/14, 2000).

The disadvantages of this method is the toxicity of the used solvent (methanol) and multi-stage.

The closest to our method is a known method of obtaining methansulfonate of doxazosin by dissolving the base of doxazosin and methansulfonate in an organic solvent (methanol or a mixture of polar aprotic organic solvent), filtering the resulting solution from mechanical impurities with subsequent boiling of the obtained product in ethanol (application PCT/WO 99/35143. class. C 07 D 405/14; 1999).

The disadvantages of this method are to carry out the process in a toxic organic solvent (methanol) and the duration of the process.

Object of the invention is to provide a method for obtaining methansulfonate of doxazosin without the use of toxic solvents, as well as reducing the duration of the process.

This task is solved in that in the process of obtaining methansulfonate of doxazosin by dissolving the base of doxazosin and methansulfonate in an organic solvent, filtering the resulting solution, followed by separation of the target product as organic solvent COI is tion is illustrated by the following specific examples:

Example 1. In a three-neck round bottom flask with a capacity of 250 ml load of 20.0 g of doxazosin and 100 ml of dimethylformamide. With stirring, dropwise poured 3.2 ml of anhydrous methansulfonate, sediment when it dissolves quickly. The resulting solution is filtered, the filtrate taken in the three-neck round bottom flask with a capacity of 250 ml of the Filtered solution, if necessary, cooled to 20-22oAnd to him slowly poured 100 ml of butyl acetate. Drop down when this precipitate dissolves quickly. The resulting solution is heated at a temperature of 85-90oC for 3 h

The precipitation is filtered off and washed twice with 25 ml of a mixture of dimethylformamide-butyl acetate= 1: 1. The product is dried in vacuum at a temperature of 95-105oC. Gain of 22.2 g methansulfonate of doxazosin (91,5% of theoretical).

Example 2. In a three-neck round bottom flask with a capacity of 250 ml download 15.0 g of doxazosin, 75 ml of dimethylformamide and 30 ml of butyl acetate. With stirring, poured dropwise 2.4 ml of anhydrous methansulfonate, the precipitate thus dissolved. The resulting solution is filtered, the filtrate taken in the three-neck round bottom flask with a capacity of 250 ml of the Filtered solution is heated at a temperature of 4 is formamid-butyl acetate= 5: 2. The product is dried in vacuum at a temperature of 95-105oC. Gain of 16.9 g of methanesulfonate of doxazosin (92.9% of theoretical).

Example 3 (prototype). In a three-neck round bottom flask with a capacity of 250 ml was placed a mixture of 12.6 g of doxazosin, 25 ml of N-methylpyrrolidone-2 and 100 ml of methanol. With stirring, add 2 ml of anhydrous methansulfonate. After dissolution of the precipitate, the solution is filtered, the filtrate taken in the three-neck round bottom flask with a capacity of 250 ml Filter washed with 20 ml of methanol and the combined filtrate is stirred for 5 hours Dropped after that, the precipitate is sucked off and washed three times in 5 ml of methanol. The resulting paste is transferred into a three-neck round bottom flask with a capacity of 250 ml, poured 140 ml of ethanol and boiled under stirring for 3 hours the Solution is cooled to room temperature, the precipitate is filtered off, washed on the filter twice with 5 ml of ethanol and dried in vacuum at 70oC. Obtain 12.5 g of methanesulfonate of doxazosin (81.8% of theoretical).

Thus, as seen from the above examples, the inventive method allows to reduce considerably the process of obtaining methansulfonate of doxazosin (3 h vs. 8 h prototype) and to eliminate the toxic methanol.

 

Same patents:

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to novel di - and trivalent small selectin inhibitors of formula II, where X is selected from the group comprising-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)m-CO2H, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H), (CH2)mCO2H,

-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida

The invention relates to the field of medicine

The invention relates to the derivatives of hintline formula (I), where n = 2 and each R2independently halogen; R3- (1-4C)alkoxy; R1di-[(1-4C)alkyl]amino(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)-alkoxy-(2-4C)alkyl] amino-(2-4C)alkoxy, and any R1containing methylene group, which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy, or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of inhibitory activity of compounds to inhibit the receptor tyrosinekinase in the treatment of proliferative diseases, such as cancer

The invention relates to medicine and relates to a pharmaceutical composition comprising: (a) terpyridine derivative, selected from ticlopidine and clopidogrel or one of their pharmaceutically acceptable salts; and (b) an inhibitor of HMG-COA reductase

The invention relates to medicine, namely to the treatment of infectious diseases, and proposed for the treatment of chronic recurrent forms of chlamydial infection

The invention relates to the field of medicine and relates to a composition for local application on the skin to treat skin diseases such as acne, seborrhea, dandruff, etc

The invention relates to medicine
Up!