BE895041A - 3-Azino:methyl rifamycin SV derivs. prodn. - by reacting 3-formyl cpd. with amidrazone - Google Patents

Abstract

Prodn. of azinorifamycins of formula (I) comprises reacting 3-formylrifamycin SV (III) in THF, dichloromethane or chloroform with an amidrazone NH2.N=CH.NR1R2 (II). In the formulae, Y is H or acetyl; R1 is 3-4C alkenyl or 1-7C alkyl; R2 is 7-8C aralkyl (opt. ring-substd. by one halo), phenyl, 3-6C ring cycloalkylalkyl, 3-7C cycloalkyl, 3-4C alkenyl, 2-4C alkenyl or 1-7C alkyl, or NR1R2 is a 5-8C ring (opt. substd. by 1 or 2 methyl) or morpholino) morpholino). Alternatively, (I) are made by reacting rifamycin S in the THF and in presence of MnO2 with azine CH2=N.N=CH.NR1R2 (IV). Cpds. (I) are described in GB applicn. no. 8134549.

Description

       

   <EMI ID = 1.1> Process for the preparation of azino-rifamycin compounds.

  
The present invention relates to methods

  
 <EMI ID = 2.1>

  
mule:

  

 <EMI ID = 3.1>


  
in which

  
 <EMI ID = 4.1>

  
substituted by a halogen atom in the aryl group, a phenyl group, a cycloalkylalkyl group containing 3 to 6 carbon atoms in the nucleus &#65533; a cycloalkyl group containing 3 carbon atoms in the nucleus, a C3-C4 alkenyl group &#65533; a C2-C4 chloralkyl group or a group

  
 <EMI ID = 5.1>

  
The compounds of formula (I) are described in British patent application n [deg.] 8134549 * According to a first embodiment of the invention, 3-formylrifamycin SV is reacted in a solvent chosen from the group comprising tetrahydrofuran &#65533; dichloromethane and chloroform, with an amidrazone of formula:

  

 <EMI ID = 6.1>


  
 <EMI ID = 7.1>

  
(II,) by reacting an excess of anhydrous hydrazine with chloroformiminium chloride according to the following scheme:

  

 <EMI ID = 8.1>


  
According to another embodiment of the invention, rifamycin S is reacted in

  
 <EMI ID = 9.1>

  
azino-compound of formula:

  

 <EMI ID = 10.1>


  
 <EMI ID = 11.1>

  
following :

  

 <EMI ID = 12.1>
 

  
The invention is illustrated by the following nonlimiting examples.

  
EXAMPLE 1

  
 <EMI ID = 13.1>

  
0.17 g of hydrazine hydrate and 0.9 ml of triethylamine are dissolved in 20 ml of tetrahydrofuran

  
 <EMI ID = 14.1>

  
1.05 g of chloro-4-methylpiperidyl-formiminium chloride to obtain a compound of formula (II) in

  
 <EMI ID = 15.1>

  
dyle.

  
After stirring for 30 minutes, the mixture is filtered, 3 g of 3-formylrifamycin SV are added and the mixture is left to react at room temperature for a further 30 minutes. 100 ml of ethyl acetate are added and the solution obtained is washed with water.

  
After drying over anhydrous sodium sulfate, the solvent is evaporated off under reduced pressure and the residue is crystallized from methanol.

  
1.3 g of a color compound are obtained

  
 <EMI ID = 16.1>

  
 <EMI ID = 17.1>

  
Mass spectrum: 848 (M +).

  
EXAMPLE 2

  
3 N N- (4-isobutyl) piperidinomethyl-azinomethyl-rifamycin SV

  
We obtain a compound of formula (II) in

  
which

  

 <EMI ID = 18.1>


  
represents a 4-isobutyl- group

  
piperidyl, according to the method of Example 1. Paraformaldehyde is reacted with the above-mentioned compound of formula (II) to obtain a compound of

  
formula (III) in which

  

 <EMI ID = 19.1>


  
has the meaning indicated above. 1.95 g of this compound of formula (III) are added to a mixture of 1 g of rifamy &#65533;

  
 <EMI ID = 20.1>

  
ascorbic and the mixture is reacted at room temperature for an additional 30 minutes while stirring. 100 ml of ethyl acetate are added, the solution obtained is washed with water, the solvent is evaporated off under reduced pressure and the residue is crystallized from methanol.

  
0.5 g of a red-colored compound corresponding to general formula I is obtained in which

  
 <EMI ID = 21.1>

  
Mass spectrum = 890 (M +),

  
 <EMI ID = 22.1>


    

Claims (1)

1. Process for the preparation of compounds <EMI ID = 23.1>  <EMI ID = 24.1> in which  <EMI ID = 25.1> substituted by a halogen atom in the aryl group, a phenyl group, a cycloalkylalkyl group containing 3 to 6 carbon atoms in the nucleus, a cycloalkyl group containing 3 to 7 carbon atoms in the nucleus, an alkenic group  <EMI ID = 26.1> characterized in that 3-formylrifamycin SV is reacted in a solvent chosen from the group comprising tetrahydrofuran, dichloromethane and 1 chloroform, with an amidrazone of formula:  <EMI ID = 27.1>  <EMI ID = 28.1> above.  <EMI ID = 29.1> chloroformiminium chloride according to the following scheme:  <EMI ID = 30.1> 3. Process for the preparation of azino-rifamycin compounds of formula:  <EMI ID = 31.1> in which Y = H or CH3CO;  <EMI ID = 32.1> substituted by a halogen atom in the aryl group, a cycloalkylalkyl group containing 3 to 6 carbon atoms in the nucleus &#65533; a cycloalkyl group containing 3 to 7 carbon atoms in the nucleus, a C3-C4 alkenyl group, a chloralkyl group in  <EMI ID = 33.1> carbon, unsubstituted or substituted by one or two CH- groups, or a morpholino group, characterized in that rifamycin S is reacted  <EMI ID = 34.1>  <EMI ID = 35.1> in which R .. and R2 have the meanings defined above.  <EMI ID = 36.1> characterized in that the azino-compound of formula (III) is prepared by reacting an amidrazone of formula (II) with paraformaldehyde according to the following scheme:  <EMI ID = 37.1>