| 摘要 |
#CMT# #/CMT# Preparing (P1) methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate (I), involves cleavage of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine by catalytic hydrogenation, and isolation of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine without intermediate formation of salts. #CMT# : #/CMT# Preparing (P1) methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate (I), involves: either cleavage of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine by catalytic hydrogenation, and isolation of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine without intermediate formation of salts; or reactionof 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine with methyl chloroformate or dimethyl dicarbonate to give methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate via a pyridine-free reaction route. Independent claims are included for the following: (1) purifying methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate, involving dissolving crude methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate in dimethyl sulfoxide; isolating the resulting methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate sulfinyldimethane; and removing the dimethyl sulfoxide by boiling in a solvent; (2) new methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate sulfinyldimethane (II); and (3) methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate is prepared by the process (P1). #CMT#ACTIVITY : #/CMT# Cardiovascular-Gen.; Cardiant; Antianginal; Vasotropic; Antiarrhythmic; Thrombolytic; Cerebroprotective; Thrombolytic; Antiarteriosclerotic; Antiasthmatic; Cytostatic; Endocrine-Gen.; Osteopathic; Ophthalmological; Hypotensive; Respiratory-Gen.; Uropathic. No biological data given. #CMT#MECHANISM OF ACTION : #/CMT# Soluble guanylate cyclase stimulator. #CMT#USE : #/CMT# For treating cardiovascular disorders or erectile dysfunction in human or animal (claimed). Also useful for high blood pressure, heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, thromboembolic disorders and ischemias such as myocardial infarction, stroke, transitory and ischemic attacks, disturbances of peripheral blood flow, prevention of restenosis such as following thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), arteriosclerosis, asthmatic disorders, prostate hypertrophy, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, and incontinence. #CMT#ADVANTAGE : #/CMT# The process is simple and safe, and is carried out on an industrial scale which supports an active compound in high yield and high purity; provides direct isolation of the 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine (free base) without intermediate formation of the salt (i.e. trihydrochloride), thus increases the yield of the compound (I); and is simple industrial practice (no acid-proof parts of the plant). #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation: No general method for preparation of the methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate sulfinyldimethane (II). Preferred Process: In the process (P1), methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate is reacted with a methylating agent to give methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate. #CMT#EXAMPLE : #/CMT# Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrim- idinylcarbamate (1630 g) was suspended in tetrahydrofuran (16.3 l), at 20-25[deg] C. The suspension was cooled to -6 to -4[deg] C, and 1M solution of bis(trimethylsilyl)sodium amide (3480 g) were metered in. The mixture was stirred, methyl iodide (596 g) were metered in, the mixture was stirred briefly and slowly allowed to warm to 5[deg] C. The mixture was stirred at this temperature until the reaction had ended (4 hours). The reaction mixture was washed 4 times with 15% strength ammonium chloride solution (4.1 l). After work up, methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate (75.2%) was obtained. |
