BE579867A - - Google Patents

Description

       

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 EMI1.1
 



  THE NORWICH PHARMACAL COMPANY A process for the preparation of novel antiseptic and disinfecting agents, as well as compositions containing these agents.



   The invention relates to a process for the preparation of two new chemical compounds, which have a very valuable antiseptic and disinfecting effect, while, moreover, one of the two is very suitable for use as an intermediate for the preparation of the other. to serve. The new compounds are the nitric acid and the hydroiodic acid ester of 5-nitro-2-furfuryl alcohol according to the formula
 EMI1.2
 wherein X represents an iodine atom or a -ONO2 group.



   It has been found that both new compounds are extremely effective

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 broad scope against microbes. Even in small quantities, both successfully fight bacteria, fungi and protozoa. Their broad scope also at low concentrations makes them very valuable as a disinfectant and for the preparation of preparations which can be used in the treatment of superficial infections. They are also valuable for protecting organic matter from attack by microorganisms.



   The degree of activity of the new compounds is clearly expressed in the following tables showing the results of tests to which the compounds were subjected. According to these tests, standardized research methods were carried out:
TABLE I.
5-nitro 2-furfuryl nitrate
 EMI2.1
 
<tb> minimum <SEP> concentration <SEP> required
<tb> species <SEP> for <SEP> protection <SEP> (mg.%)
<tb>
<tb> Staphylococcus <SEP> aureus <SEP> 0.8 <SEP> - <SEP> 2
<tb>
<tb> Eascherichia <SEP> coli <SEP> 0.4 <SEP> - <SEP> 2
<tb>
<tb> Salmonella <SEP> typhosa <SEP> 0.4 <SEP> - <SEP> 0.8
<tb>
<tb> Proteus <SEP> vulgaris <SEP> 0.6 <SEP> - <SEP> 1.0
<tb>
<tb> S.

   <SEP> chaleraesuis <SEP> 0.4 <SEP> - <SEP> 0.8
<tb>
<tb> Brucella <SEP> abortion <SEP> 0.8 <SEP> - <SEP> 3
<tb>
 

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 TABLE II
 EMI3.1
 5-nitro 2-furfuryl nitrate
 EMI3.2
 
<tb> Inhibition zones <SEP> in <SEP> mm
<tb>
 
 EMI3.3
 ¯ Aar¯¯¯¯¯¯¯¯¯¯Agar Serum Conc. daen¯¯¯ Species mg. % 2 J 2 31.8 1 70 6o! t'39 "39 36! C. Albicans 3.18 9t5'Ó ::: 15 9.0 1.8 - 0 73, 71 60 M.can1s .18 - 36 20-o - '31.8¯¯C 65 1 T .meiita-srophytes ¯ ¯¯¯3.18 - 2 6, ''32'
 EMI3.4
 
<tb> 31.8 <SEP> - <SEP> - <SEP> C <SEP> - <SEP> - <SEP> - <SEP> 70
<tb> E. <SEP> floccosum <SEP> 3.18 <SEP> - <SEP> -
<tb>
<tb> 31.8 <SEP> - <SEP> - <SEP> C <SEP> 70 <SEP> 63
<tb>
 
 EMI3.5
 rtlbrum 3.18 - f 70 - 'z 31.8¯¯¯¯¯ 70 61 violaceuia 3.18. 65- 31 21 .8 - - - - - C T.tonsurans¯¯¯¯3.18J bzz¯¯¯31 31 8 li - 0 M. audouini -; - j - Bzz - - 2'7
C = complete inhibition.



   In experiments with E. histolytica, T. vaginalis and T. fetus, complete inhibition of growth was obtained with concentrations as high as about 1 part of 5-niro 2-furfuryl nitrate at about 1.25 to 1.5 x 10 5 parts. trial medium.



   TABLE III
 EMI3.6
 
<tb> 5-nitro <SEP> 2-furfuryl iodide
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Inhibition <SEP> zone <SEP> in <SEP> mm
<tb>
<tb> C. <SEP> albicans
<tb>
<tb>
<tb> Conc. <SEP> in <SEP> days <SEP> - <SEP> @
<tb>
 
 EMI3.7
 Connection¯¯¯¯¯m. 2 4 6 8
 EMI3.8
 
<tb> 5-nitro <SEP> 2-furfuryl <SEP> 5.1 <SEP> 25 <SEP> 17 <SEP> 17 <SEP> 17
<tb>
<tb> iodide <SEP> 2. <SEP> 0 <SEP> @ <SEP> 18 <SEP> 12 <SEP> 12 <SEP> 12
<tb>
<tb> 1.0 <SEP> 12 <SEP> 10 <SEP> 9 <SEP> 9
<tb>
<tb>
 

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 TABLE IV
 EMI4.1
 
<tb> 5-nitro <SEP> 2-furfuryl iodide
<tb>
<tb>
<tb> Inhibition zones <SEP> in <SEP> mm
<tb> Conc.in <SEP> 14 <SEP> ears
<tb>
 
 EMI4.2
 Yerbindin.

   A.ni there Trich. sep.
 EMI4.3
 
<tb> 5-nitro <SEP> 2-furfuryl <SEP> 25- <SEP> iodide <SEP> 10- <SEP> -
<tb>
<tb> Control <SEP> 1. <SEP> 25 <SEP> - <SEP> -
<tb>
 TABLE V.
 EMI4.4
 
<tb> 5-nitro <SEP> 2-furfuryl iodide
<tb>
<tb>
<tb> Inbition zones <SEP> in <SEP> mm
<tb> M. <SEP> canis
<tb> Conc. <SEP> in <SEP> '<SEP> days
<tb>
<tb> Connection <SEP> Conc. <SEP> in <SEP> 4 <SEP> 8
<tb>
<tb> 5-nitro <SEP> 2-furefuryl
<tb>
<tb>
<tb> iodide <SEP> 20 <SEP> 50 <SEP> 44 <SEP> 34
<tb>
 
When 5-nitro-2-furfuryl iodide was tested against Candida albicans at a concentration of 10 mg%, complete sterilization of the medium was achieved in about 2 to 5 hours.



   Although both new compounds have a remarkably broad field of activity against microbes at low concentration, they still differ from each other in some respects, and these differences can be exploited when used for certain particular purposes. For example, when an aqueous solution for disinfectant and antiseptic use is required, the use of 5-nitro 2-furfuryl nitrate is preferred as its solubility in water is about 1500 mg per liter and aqueous solutions of this substance can be very easily. be prepared, however, when it is desired to resist

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 fungal attack on an insulating layer for cables or wires, consisting of a vinyl plastic derived from vinyl chloride or vinyl esters or a combination thereof,

   then 5-nitro-2-furfuryl iodide is preferred since an effective amount of this compound (about 0.4% by weight) does not impart an undesired color change to the plastic nor adversely affect the dielectric properties, while the compound is resistant to leaching.



   The compounds can be easily processed with the usual pharmaceutical excipients to form powders, solutions, suppositories, tinctures, jellies and the like. The following examples are provided by way of illustration :,
 EMI5.1
 
<tb> Suppo <SEP> si <SEP> torium <SEP> parts
<tb>
<tb>
<tb> polyethylene glycol <SEP> (MW 1000) <SEP> 84.0%
<tb>
<tb>
<tb> polyoxyethylene palmitate <SEP> 15.9%
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl iodide <SEP> 0.1%
<tb>
<tb>
<tb> Powder
<tb>
<tb> talk <SEP> 50 <SEP>%
<tb>
<tb>
<tb>
<tb> corn flour <SEP> 25 <SEP>%
<tb>
<tb>
<tb> polyoxyethylene glycol <SEP> (MW 6000) <SEP> 24.8%
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl iodide <SEP> 0.2%
<tb>
<tb>
<tb> Tincture
<tb>
<tb>
<tb> ethanol <SEP> 50.00%
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl nitral <SEP> 0.01%
<tb>
<tb>
<tb> water,

   <SEP> as much <SEP> as <SEP> needed <SEP> is <SEP> 100.00%
<tb>
<tb>
<tb> Ointment
<tb>
<tb>
<tb> carbowax <SEP> 1540 <SEP> 50.0%
<tb>
<tb>
<tb> caebowax <SEP> 300 <SEP> 49.9%
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl nitrate <SEP> 0.1%
<tb>
 

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 EMI6.1
 
<tb> Suppository <SEP> parts
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> carbowax <SEP> 1000 <SEP> 80.00%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> palmitic acid polyoxyethylene derivative
<tb>
<tb>
<tb>
<tb> that <SEP> 20 <SEP> contains oxyethylene units / mol <SEP> <SEP> 19.95%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl nitrate <SEP> 0.05%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Jelly
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> methylcellulose <SEP> 3.0 <SEP>% <SEP>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> glycerine <SEP> 10,

  0 <SEP>%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> water <SEP> 86.9 <SEP>% <SEP>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl nitrate <SEP> 0.1 <SEP>%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Solution
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> propylene glycol <SEP> 20.00%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> water <SEP> 79.99%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 5-nitro <SEP> 2-furfuryl nitrate <SEP> 0.01%
<tb>
 
The toxicity of the compounds of the invention is relatively low. In mice the LD50 is about 650 to 760 mg / kg. When compositions according to the preceding examples are applied to the shaved skin or conjunctiva of rats, no intolerable irritation or poisoning symptoms are observed.



   The new compounds can be prepared easily and economically. 5-Nitro-2-furfuryl nitrate can be prepared in high yield and in pure form by nitriding the normal water miscible form of furfuryl alcohol in unlimited amounts. According to the invention, the alcohol is treated with a nitriding agent, such as that composed of acetic anhydride and nitric acid, at a temperature of about 0-50 ° C, then the reaction mixture is heated for a short period at a temperature of about 30-5000, after which it is cooled and neutralized.

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   It has further been found that 5-nitro 2-furfuryl nitrate is an excellent intermediate for the preparation of 5-nitro 2-furfuryl iodide. According to the invention, 5-nitro-2-furfuryl nitrate can be converted into iodide in a simple manner; for this purpose it is only necessary to bring the nitrate and sodium iodide together in the presence of acetone, after which reaction takes place. The inorganic salt formed in the reaction precipitates and can be removed by filtration.



  The 5-nitro 2-furfuryl iodide can then be isolated from the filtrate.



   The following examples may be given to further illustrate the invention.



    EXAMPLE I.
720 ml of acetic anhydride are placed in a three liter three-neck flask. To this is added 189 g (2.0 moles) of nitric acid, followed by 108 g (1.1 moles) of furfuryl alcohol, keeping the temperature at 20-25 ° C by means of an ice bath. The total time required for the addition is about 12 to 15 minutes. The mixture is heated to 40 ° C for 1 hour, cooled to 25 ° C, then 1000 ml of water and 300 g of trisodium phosphate are added.



  The temperature is raised to 60 ° C for one hour, then cooled to 10-15 ° C whereupon the solid which precipitates is separated by filtration. The yield of 5-nitro 2-furfuryl nitrate is 88 g (42%); melting point 36.5 C.
 EMI7.1
 
<tb>



  Analysis <SEP>: <SEP> C <SEP> H <SEP> N
<tb>
<tb> calculated <SEP> 31.92 <SEP> 2.14 <SEP> 14.89
<tb>
<tb> found <SEP> 32.05 <SEP> 2.34 <SEP> 14.75
<tb>
 

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 EXAMPLE II
A solution of 300 g (2 mol) of sodium iodide in 1 liter of acetone is treated in a three liter Erlenmeyer flask with a solution of 375 g (1.995 mol) of 5-nitro 2-furfuryl nitrate in 500 ml of acetone and placed in a refrigerator overnight. chilled. The precipitated sodium nitrate is removed by filtration and washed with 300 ml of acetone; after drying. it weighs 163 g (the theoretical amount is 170 g). The filtrate is combined with the acetone washing liquid and diluted with 10 liters of water. The separated oil crystallizes when the mixture is stirred for one hour.

   The yield of crude 5-nitro-2-furfuryl iodide after air drying is 500 g (theoretically 506 g). The crude material is crystallized from 3 liters of isopropanol and decolorized with activated carbon. The product separates as an oil which crystallizes on stirring. This material is crystallized from 2 liters of isopropanol. The hot solution is stirred vigorously for 2 hours while cooling in an ice bath.



  There are obtained 326 g of yellow crystals m.p. 58 DEG C., corresponding to a yield of 65% 5-nitro-2-furfuryl iodide.


    

Claims (1)

C O N C L U S I E S A chemical compound with disinfectant and antiseptic properties represented by the formula EMI9.1 wherein X represents a radical selected from the group consisting of an iodine atom and an ONO2 group. 2. The chemical compound 5-nitro 2-furfuryl iodide. 3. The chemical compound 5-nitro-2-furfuryl nitrate. 4. A process for the preparation of 5-nitrofurfuryl iodide, which comprises reacting 5-nitro 2-furfuryl nitrate with sodium iodide in the presence of acetone. 5. A process for the preparation of 5-nitro 2-furfuryl nitrate, comprising nitriding furfuryl alcohol. 6. Disinfectant and antiseptic preparations, d o o r, a content of 5-nitro 2-furfuryl iodide and / or 5-nitro 2-furfuryl nitrate