7-Nitro-2-Benzofurancarboximidamide Hydrochloride is useful as an antidepressant.

This invention is concerned with the chemical compound 
7-nitro-2-benzofurancarboximidamide. It possesses pharmacological activity 
affecting the central nervous system. When administered perorally to 
animals, it exhibits an antidepressant effect. Such effect is evidenced in 
the control of tetrabenazine induced ptosis in mice. Thus, an oral dose of 
50 mg/kg to mice receiving intraperitoneally 35 mg/kg of tetrabenazine 
counteracts the ptosis producing propensity of tetrabenazine. 
The compound of this invention can be combined with various adjuvants and 
excipients commonly employed in the pharmaceutical art to provide various 
pharmaceutical dosage forms such as tablets, suspensions, solutions, 
capsules, elixirs, and the like.

The method which is currently used for the preparation of the compound of 
this invention is illustrated by the following description. 
A. PREATION OF COUMARILALDEHYDE 
A solution of benzofuran (163 g, 1.39 mole) in dimethylformamide (264 g, 
dried over magnesium sulfate overnight) in a 2-1, 3-necked flask was 
stirred and treated dropwise with phosphorus oxychloride (233 g, 136 ml). 
The solution was heated and stirred on a steam bath for 8 hrs. Another 88 
g of dry dimethylformamide, followed by 70 g (42 ml) of phosphorus 
oxychloride, was added and the heating and stirring were continued 
overnight. After cooling, the solution was slowly poured into a stirred 
solution of 260 g of sodium acetate in 1500 ml of water. The solution was 
extracted four times with 500 ml of ether. The ether extracts were washed 
with dilute aqueous sodium hydroxide solution and then with water. The 
solution was then dried over magnesium sulfate and filtered. 
The ether was evaporated and the residue was distilled at reduced pressure 
to give 13 g of benzofuran in the forerun. The product, a yellow liquid 
that turned dark on standing, was collected at 67.degree.-70.degree. at 
0.1 mm in a yield of 99 g (54%). 
B. PREATION OF 7-NITROCOUMARILALDEHYDE DIACETATE 
Coumarilaldehyde (88 g, 0.6 mole) was dissolved in acetic anhydride (400 
ml) with cooling and six drops of concentrated sulfuric acid were added 
dropwise with ice bath cooling and stirring. The stirred solution was 
treated dropwise with concentrated nitric acid (50 ml) at 
0.degree.-5.degree. and then allowed to warm to room temperature with 
stirring. A yellow solid precipitated. The mixture was cooled in an ice 
bath for 1/2 hour with continued stirring. The solid was filtered, washed 
with a 1:1 solution of ether and hexane, and air dried on the funnel to 
yield 70 g (39%), m.p. 129.degree.-130.degree.. Several recrystallizations 
of a sample from isopropanol (20 ml/g, Darco) gave tan needles, m.p. 
130.degree.-132.degree.. 
Anal. Calcd. for C.sub.13 H.sub.11 NO.sub.7 : C, 53.24; H, 3.78; N, 4.78. 
Found: C, 53.42,53.34; H, 3.88,3.83; N, 4.80,4.74. 
C. PREATION OF 7-NITROCOUMARILALDEHYDE 
B. (73 g, 0.25 mole) was added in portions to concentrated sulfuric acid 
(365 ml) with stirring and cooling to keep the temperature below 
30.degree.. The resulting green solution was stirred at room temperature 
for 20 min. and poured over ice to give a tan solid. The solid was 
collected by filtration, washed with water and dried at 60.degree. to 
yield 45 g (95%), m.p. 100.degree.-130.degree.. Recrystallization from 
benzene (20 ml/g, Darco) gave 32 g of light tan needles, m.p. 
180.degree.-181.degree.. Several recrystallizations of sample from benzene 
(30 ml/g) raised the melting point to 181.degree.-182.degree. (corr). 
Anal. Calc'd. for C.sub.9 H.sub.5 NO.sub.4 : C, 56.55; H, 2.64; N, 7.33. 
Found: C, 56.58,56.56; H, 2.56,2.57; N, 7.18,7.21. 
D. PREATION OF 7-NITROCOUMARILALDEHYDE OXIME 
A mixture of 7-nitrocoumarilaldehyde (24.8 g, 0.13 mole), hydroxylamine 
hydrochloride (9 g., 0.13 mole), and 2-methoxyethanol (250 ml.) was heated 
to boiling to give a yellow solution. Heating was continued on a steam 
bath for 1 hr. The warm solution was diluted with water (500 ml.) to give 
a cream colored solid. After cooling in an ice bath, the solid was 
collected by filtration, washed with water and dried at 100.degree. to 
yield 25 g. (93%), m.p. 180.degree.-184.degree.. Recrystallization from 
isopropanol (10 ml./g., Darco) and drying at 100.degree. gave 20 g. of 
cream colored needles; m.p. 182.degree.-184.degree.. Several 
recrystallizations of a sample from isopropanol increased the melting 
point to 182.5.degree.-184.degree. (corr.). 
Anal. Calc'd. for C.sub.9 H.sub.6 N.sub.2 O.sub.4 : C, 52.43; H, 2.93; N, 
13.59. Found: C, 52.18,52.24; H, 2.76,2.80; N, 13.21,13.35. 
F. 7-NITRO-2-BENZOFURANCARBOXIMIDAMIDE HYDROCHLORIDE 
A mixture of 8.9 g (0.043 mole) of D. in 100 ml of acetic anhydride and 2 g 
of anhydrous sodium acetate was heated to reflux for 51/2 hrs. After 
cooling, the dark solution was poured onto crushed ice. Grayish solid 
separated and was filtered, washed well with water and air-dried. The 
crude nitrile (5.3 g) was boiled in 800 ml of methylcyclohexane and a 
minimum amount of benzene. The mixture was filtered while still hot. 
Crystalline solid separated from the yellow solution. The solid was 
filtered, washed with hexane and air-dried to give 4.0 g of product. 
Concentration of the filtrate gave another 0.4 of the nitrile. 
The nitrile (4.4 g) was placed in 360 ml of anhydrous MeOH and heated to 
boiling on a steam bath. Only about half of solid dissolved after 5 min. 
of boiling. Two small spatulas of sodium methoxide powder was added and a 
red solution resulted very readily. The solution was allowed to stir 
without heating and in about 10-15 minutes crystalline solid separated. 
The mixture was allowed to cool gradually with stirring. The solid was 
collected, washed with ether and air-dried. The yield of the imidate was 
2.8 g. A second crop of 2.0 g was obtained from the filtrate. 
The combined imidate (4.8 g) was placed in 350 ml of anhydrous MeOH and 
warmed on a steam bath until a clear solution resulted (5-10 min.). After 
slight cooling, 1.17 g of anhydrous ammonium chloride was added with 
stirring. The solid NH.sub.4 Cl dissolved in about 5 min. and 10-15 min. 
later, yellow solid started to separate. After being stirred overnight at 
ambient temperature, the mixture was heated at reflux for 2 hrs. The 
reaction mixture was filtered and the filtrate was concentrated at reduced 
pressure to give a yellow solid residue. The solid was triturated with 
water and filtered. The water insoluble material was shown by infrared 
spectrum to be starting imidate. The recovered imidate was further heated 
with ammonium chloride in anhydrous MeOH. The reaction mixture was worked 
up as before. The combined aqueous filtrate was made alkaline with conc. 
NH.sub.4 OH and jelly like solid separated. The solid was collected, 
washed well with water and dried. The free amidine was then pulverized and 
triturated with an ethanolic HCl solution. The color of the solid changed 
from light brown to white. The solid was collected, washed well with ether 
and air-dried to give 2.1 g (20% overall yield). 
Anal. Calc'd. for C.sub.9 H.sub.7 N.sub.3 O.sub.3.HCl: C, 44.73%; H, 3.34%; 
N, 17.39%. Found: C, 45.00%; H, 3.50%; N, 17.15%.