12,13-dihydroxypropane tylosin, the method of production thereof

 

The invention relates to 12,13-dihydroxypropane tylosin General formula I, where R, R1CHO, CH=NOH, CH(OCH3)2; R2- H, mikrosil; R3- N(CH3)2NO(CH3)2;- double or a simple link, a new semisynthetic compounds of the macrolide class and the way they are received. According to the invention by oxidation of 13-hydroxy receive 12,13-dihydroxytoluene, which may subsequently be subjected to a series of reactions, such as oxymorphine restoration (catalytic, electrochemical or hydrolysis, yielding the corresponding dihydro or tetrahydro-12,13-dihydroxypropane. 2 C. and 16 h.p. f-crystals.

Description text in facsimile form (see graphic part).

Claims

1. 12,13-Dihydroxypropane tylosin formula (I)

in which R represents O; R1is Cho, CH=NOH, or CH(och3)2; R2represents H or mikrosil; R3is N(CH3)2or NR(CH3)2and the dotted line indicates a single or double tie or R represents NOH; R1is Cho or CH(och3)2; R2represents H or mikrosil; R3is N(CH3)2or NR(CH3)2and the dotted line indicates a single or double bond, provided that R3is N(CH3)2,when the dotted line represents a simple bond.

2. Connection on p. 1, characterized in that R is Oh, R1is CH(och3)2, R2represents H, R3represents NR(CH3)2and the dotted line represents a double bond.

3. Connection on p. 1, characterized in that R is Oh; R1is CH(och3)2; R2is mikrosil; R3represents NR(CH3)2and the dotted line represents a double bond.

4. Connection on p. 1, characterized in that R represents PONT, R1is CH(och3)2, R2represents H, R3is NO(CH3)2and the dotted line represents a double bond.

5. Connection on p. 1, characterized in that R represents Oh, R1is CH(och3)2, R2represents H, R3is N(CH3)2and the dotted line defaults CH(och3)2, R2represents H, R3is N(CH3)2and the dotted line indicates a simple relationship.

7. Connection on p. 1, characterized in that R represents NOH, R1is CH(och3)2, R2represents H, R3is N(CH3)2and the dotted line indicates a simple relationship.

8. Connection on p. 1, characterized in that R represents NOH, R1is CH(och3)2, R2represents H, R3is N(CH3)2and the dotted line represents a double bond.

9. Connection on p. 1, characterized in that R represents NOH, R1is SNO, R2represents H, R3is N(CH3)2and the dotted line represents a double bond.

10. Connection on p. 1, characterized in that R represents Oh, R1is SNO, R2represents H, R3is N(CH3)2and the dotted line represents a double bond.

11. Connection on p. 1, characterized in that R represents Oh, R1is SN=MON, R2represents H, R3is N(CH3)2and the dotted line represents a double bond.

12 is ora R is Oh; R1is Cho, CH=NOH, or CH(och3)2; R2represents H or mikrosil; R3is N(CH3)2or NR(CH3)2and the dotted line indicates a single or double bond, provided that R3is N(CH3)2when the dotted line represents a simple bond; or R represents NOH; R1is Cho or CH(och3)2; R2represents H or mikrosil; R3is N(CH3)2or NR(CH3)2and the dotted line indicates a single or double bond, provided that R3is N(CH3)2when the dotted line represents a simple link,

characterized in that the compound of formula (II)

in which R represents H or mikrosil,

subjected to oxidation, after which the compound obtained of the formula I, in which R is Oh, R1is CH(och3)2, R2represents H or mikrosil, R3represents NR(CH3)2and the dotted line represents a double bond, optionally subjected to A) restore N-oxide; or optionally (B) recovering the N-oxide and C10-C11double St is yet NOH, R1is CH(och3)2R2represents H or mikrosil, R3represents NR(CH3)2and the dotted line represents a double bond, is subjected to the recovery of N-oxide; or optional recovery N-oxide and C10-C11the double bond by catalytic hydrogenation; or optionally the compound of formula (I) in which R is Oh, R1is CH(och3)2, R2represents H or mikrosil, R3is N(CH3)2and the dotted line indicates a single or double bond, are occimiano; or optionally the compound of formula (I) in which R represents NOH, R1is CH(och3)2, R2represents H or mikrosil, R3is N(CH3)2and the dotted line indicates a single or double bond, is subjected to hydrolysis.

13. The method according to p. 12, characterized in that the oxidation is carried out with the help of 3-8 equivalents m-chlormadinone acid in a halogenated hydrocarbon, preferably methylene chloride, for 6-20 h at room temperature.

14. The method according to p. 12, characterized in that the recovery of the N - oxide is carried out using Zn powder in the mixture messagepattern in the range from 5.0 to 5.5 at room temperature for 3-6 hours

15. The method according to p. 12, characterized in that the recovery of N - oxide and C10-C11double bond is carried out by catalytic hydrogenation in an organic solvent, preferably in the lower C1-C3aliphatic alcohol in the presence of 2-5% W/W palladium on charcoal under hydrogen pressure of 0.2 to 0.5 MPa at room temperature for 5-8 hours

16. The method according to p. 12, characterized in that the recovery of N - oxide and C10-C11the double bond is carried out using electrochemical reduction in an electrochemical cell with separate chambers for the anode and cathode, and as a working electrode (cathode) use Nd-tank, as the opposite electrode using graphite and a saturated calomel electrode is used as the reference electrode in phosphate buffer (pH 5,4) at a constant potential of-1.4 V relative to the saturated calomel electrode at room temperature for 40 min and the loss of charge of 80 C.

17. The method according to p. 12, characterized in that oxymorphine is carried out using from 1 to 8 equivalents of hydroxylamine hydrochloride in pyridine or lower C1-C3aliphatic alcohol with the addition of a base (pyridine liposom under item 12, characterized in that the hydrolysis is carried out in a mixture of acetonitrile and 0.2 norms. HCl (2:1) or acetonitrile and 1% aqueous solution triperoxonane acid (1:2) at room temperature for 2 hours

 

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2 ex

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