Method for manufacturing of vardenafil and its salts
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-487/04
C07D-403/10
출원번호
US-0104285
(2014-12-08)
등록번호
US-9845328
(2017-12-19)
우선권정보
PL-406524 (2013-12-16)
국제출원번호
PCT/PL2014/000135
(2014-12-08)
국제공개번호
WO2015/093994
(2015-06-25)
발명자
/ 주소
Szramka, Roman
Drygas, Jerzy
Szulc, Marcin
Rynkiewicz, Robert
출원인 / 주소
ZAKLADY FARMACEUTYCZNE POLPHARMA S.A.
대리인 / 주소
Cantor Colburn LLP
인용정보
피인용 횟수 :
0인용 특허 :
3
초록▼
The method of synthesizing vardenafil base, in anhydrous conditions, by chlorosulfonation of 2-(2-etoxy-phenyl)-5 -methyl-7-propyl-iH-imidazo5,1-fJ1,2,4triazin-4-one in a mixture of thionyl chloride and sulfurochloridic acid followed by amidation of the product, 4-etoxy-3-(5-methyl-4-oxo-7-propyl-3,
The method of synthesizing vardenafil base, in anhydrous conditions, by chlorosulfonation of 2-(2-etoxy-phenyl)-5 -methyl-7-propyl-iH-imidazo5,1-fJ1,2,4triazin-4-one in a mixture of thionyl chloride and sulfurochloridic acid followed by amidation of the product, 4-etoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo5,1-f1,2,4triazin-2-yl)benzene-sulfonic acid chloride with N-ethylpiperazine, in an aprotic solvent, in the presence of an inorganic base and the method of conversion the product, vardenafil base, to yield vardenafil monohydrochloride trihydrate having a melting point of 234° C. by contacting with water of the anhydrous modification V of vardenafil monohydrochloride in an organic solvent. The subject of the invention is also the anhydrous modification V of vardenafil monohydrochloride and its use in the preparation of vardenafil monohydrochloride trihydrate having a melting point of 234° C.
대표청구항▼
1. A method for manufacturing vardenafil and/or its salts, comprising chlorosulfonating 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one in thionyl chloride mixed with sulfurochloridic acid under reflux at the solvent boiling point, isolating the synthesized 4-ethoxy-3-(5-
1. A method for manufacturing vardenafil and/or its salts, comprising chlorosulfonating 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one in thionyl chloride mixed with sulfurochloridic acid under reflux at the solvent boiling point, isolating the synthesized 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzene-sulfonic acid chloride from the reaction mixture under anhydrous conditions, amidating the 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzene-sulfonic acid chloride with N-ethylpiperazine in an aprotic solvent in the presence of an inorganic base, and after completion of the reaction, isolating the prepared vardenafil base and optionally transforming the vardenafil base into a salt. 2. The method for manufacturing vardenafil of claim 1, wherein the molar ratio of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one to sulfurochloridic acid and thionyl chloride is 1:2.7:11. 3. The method for manufacturing vardenafil of claim 1, wherein the inorganic base is anhydrous sodium carbonate. 4. The method for manufacturing vardenafil of claim 1, wherein the aprotic solvent is toluene. 5. The method for manufacturing vardenafil of claim 1, wherein the ratio of N-ethylpiperazine and inorganic base in relation to the 2 (2 ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one is 1:2.5:5.7. 6. The method for manufacturing vardenafil of claim 1, wherein the amidation reaction are carried out under reflux. 7. The method for manufacturing vardenafil of claim 1, wherein the vardenafil salt is vardenafil hydrochloride. 8. The method for manufacturing vardenafil of claim 1, wherein the vardenafil salt is vardenafil monohydrochloride trihydrate. 9. A method for manufacturing vardenafil monohydrochloride trihydrate having a melting point of 234° C. comprising: a. dissolving vardenafil base in an organic solvent;b. adding a stoichiometric quantity of concentrated hydrochloric acid;c. precipitating anhydrous modification V of vardenafil monohydrochloride;d. contacting a suspension of the anhydrous modification V of vardenafil monohydrochloride with water, e. filtering, washing and drying the suspension of vardenafil monohydrochloride trihydrate to provide the vardenafil monohydrochloride trihydrate having a melting point of 234° C.,wherein anhydrous modification V of vardenafil monahydrochloride is characterized on powder diffractogram by the following set of peak positions, described by interplanar distances d (Å) and diffraction angles 2Θ(°): d(Å)2Θ (°)9.4449.378.52710.377.38611.986.75613.115.55415.965.18517.104.89518.124.49819.744.26320.844.07921.793.36726.453.23727.543.14828.61. 10. The method of claim 9, wherein the vardenafil base contains less than 1.0% of water. 11. The method of claim 9, wherein the organic solvent is a water-miscible solvent with a water content of less than 0.4%. 12. The method of claim 11, wherein the water-miscible organic solvent is acetone. 13. The method of claim 9, wherein the molar ratio of vardenafil monohydrochloride to added water is 1:5.55 and the contacting time of anhydrous modification V of vardenafil monohydrochloride and water is at least 4 hours. 14. The method of claim 9, wherein the vardenafil monohydrochloride trihydrate is vacuum-dried at 30-35° C. 15. An anhydrous modification V of vardenafil monohydrochloride in crystalline form characterized on powder diffractogram by the following set of peak positions, described by interplanar distances d (Å) and diffraction angles 2Θ(°): d(Å)2Θ (°)9.4449.378.52710.377.38611.986.75613.115.55415.965.18517.104.89518.124.49819.744.26320.844.07921.793.36726.453.23727.543.14828.61. 16. The anhydrous modification V of vardenafil monohydrochloride in crystalline form of claim 15, wherein its melting point is 234° C.
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