3,4'-dideoxymycaminosltylonolide derivative and process for producing the same

A compound of the following formula is provided: ##STR1## wherein A represents a carbonyl group which may be protected; B represents an aldehyde group which may be protected; R.sup.1 represents a hydroxyl group which may be protected; R.sup.2 represents a hydrogen atom or acyl group; W represents a hydrogen atom, hydroxyl group, lower alkanoyloxy group or substituted sulfonyloxy group; Y represents a hydrogen atom, halogen atom, hydroxyl group or substituted sulfonyloxy group; and broken line "-------" represents a double bond or single bond. This compound is useful for producing 3,4'-dideoxymycaminosyltylonolide useful as an antimicrobial agent.

TECHNICAL FIELD 
The present invention relates to an intermediate useful for producing 
3,4'-dideoxymycaminosyltylonolide which is an antimicrobial substance 
having an excellent effect of protection from an infection, and a process 
for producing the same. 
BACKGROUND ART 
3,4'-Dideoxymycaminosyltylonolide and salts thereof exhibit an 
antimicrobial activity on Gram-positive and Gram-negative microorganisms, 
and they are usable as antimicrobial agents having particularly excellent 
effect of protection from an infection [see Japanese Patent Unexamined 
Published Application (hereinafter referred to as "J. P. KOKAI") No. Hei 
2-275894]. 
3,4'-Dideoxymycaminosyltylonolide can be produced by protecting functional 
groups of mycaminosyltylonolide which is an acid hydrolyzate of tylosin, 
then converting the hydroxyl groups at the 3-position and 4'-position into 
deoxy groups and further removing the protecting groups. For converting 
the hydroxyl group at the 4'-position into deoxy group, a known process 
can be employed, such as a process wherein the hydroxyl groups at the 
3-position and 4'-position are sulfonylated, then the hydroxyl group at 
the 4' position is halogenated by a method described in J. Antibiotics 34, 
pages 1374 to 1376 or J. P. KOKAI No. Hei 2-191295 and the halogen atom is 
removed by reduction with tributyltin hydride. The sulfonic acid can be 
eliminated from the hydroxyl group at the 3-position to form a double 
bond, which is catalytically reduced to form the deoxy compound. 
However, the above-described process for producing 
3,4'-dideoxymycaminosyltylonolide has a defect in that the yield of the 
intended product is low, since the conversion of the hydroxy groups at the 
3-position and 4'-position into deoxy group necessitates the following 
steps: sulfonylating both hydroxyl groups; halogenating the hydroxyl group 
at the 4'-position and removing the halogen atom by reduction with 
tributyltin hydride; and forming double bond elimitating sulfonyloxy group 
at the 3-position and reducing the double bond. In addition, tributyltin 
hydride used for forming the deoxy group at the 4'-position has an 
offensive odor to make the purification of the reaction product difficult. 
Thus problems are posed when this reaction is employed on an industrial 
scale. 
Therefore, the object of the present invention is to provide a useful 
intermediate for producing 3,4'-dideoxymycaminosyltylonolide. Another 
object of the present invention is to provide a process for efficiently 
converting the groups at the 3- and 4'-positions into deoxy group. 
DISCLOSURE OF THE INVENTION 
As a useful intermediate for producing 3,4'-dideoxymycaminosyltylonolide, 
the present invention provides a compound of the following formula (I): 
##STR2## 
wherein A represents a carbonyl group which may be protected; B represents 
an aldehyde group which may be protected; R.sup.x represents a hydroxyl 
group which may be protected; R.sup.2 represents a hydrogen atom or acyl 
group; W represents a hydrogen atom, hydroxyl group, lower alkanoyloxy 
group or substituted sulfonyloxy group; Y represents a hydrogen atom, 
halogen atom, hydroxyl group or substituted sulfonyloxy group; and broken 
line "-------" represents a double bond or single bond. 
Examples of the compounds of the present invention represented by the 
formula (I) include the following ones: 
(a) compounds of the formula (I) wherein A, B and R.sup.2 are as defined 
above, R.sup.1 represents a group Of the following formula: 
##STR3## 
(Z being CHR.sup.4 or C.dbd.O, and R.sup.4 being a hydroxyl group which 
may be protected), W represents a hydrogen atom or substituted sulfonyloxy 
group, Y represents a hydrogen atom, halogen atom or substituted 
sulfonyloxy group, and broken line "-------" represents a single bond; 
(b) compounds of the formula (I) wherein A, B and R.sup.2 are as defined 
above, R.sup.1 represents a group of the following formula: 
##STR4## 
(Z being CHR.sup.4 or C.dbd.O, and R.sup.4 being a hydroxyl group which 
may be protected), W represents a hydrogen atom or lower alkanoyloxy 
group, Y represents a halogen atom, hydroxyl group or substituted 
sulfonyloxy group, and broken line "-------" represents a double bond when 
W is hydrogen atom and a single bond when W is a lower alkanoyloxy group; 
and 
(c) compounds of the formula (I) wherein A, B and R.sup.2 are as defined 
above, R.sup.1 represents a hydroxyl group which may be protected [with 
the proviso that R.sup.1 cannot be a group of the following formula: 
##STR5## 
(Z being CHR.sup.4 or C.dbd.O, and R.sup.4 being a hydroxyl group which 
may be protected)], W represents a hydrogen atom or lower alkanoyloxy 
group, Y represents a halogen atom, hydroxyl group or substituted 
sulfonyloxy group, and broken line "-------" represents a double bond when 
W is hydrogen atom and a single bond when W is a lower alkanoyloxy group. 
In another embodiment, the present invention provides: 
(d) a process for producing a compound 6f the formula (I) wherein A, B, 
R.sup.1 and R.sup.2 are as defined above, W and Y each represent a 
hydrogen atom and broken line "-------" represents a single bond by 
reducing a compound of the formula (I) wherein A, B, R.sup.1 and R.sup.2 
are as defined above, W represents a substituted sulfonyloxy group, Y 
represents a halogen atom and broken line "-------" represents a single 
bond under an alkaline condition, and 
(e) a process for producing a compound of the formula (I), which comprises 
steps of reacting a compound of the formula (I) wherein A, B, R.sup.1 and 
R.sup.2 are as defined above, W and Y each represent a hydroxyl group and 
broken line "-------" represents a single bond with a sulfonylating agent 
to form a compound of the above formula (I) wherein A, B, R.sup.1 and 
R.sup.2 are as defined above, W and Y each represent a substituted 
sulfonyloxy group and broken line "-------" represents a single bond; 
reacting the resultant compound with a halogenating agent to form a 
compound of the formula (I) wherein A, B, R.sup.1 and R.sup.2 are as 
defined above, W represents a substituted sulfonyloxy group, Y represents 
a halogen atom and broken line "-------" represents a single bond; and 
reducing the resultant compound under an alkaline condition to form a 
compound of the formula (I) wherein A, B, R.sup.1 and R.sup.2 are as 
defined above, W and Y each represent a hydrogen atom and broken line 
"-------" represents a single bond. 
BEST MODE FOR CARRYING OUT THE INVENTION 
In the formula (I) for the compound of the present invention, A represents 
a carbonyl group which may be protected, and B represents an aldehyde 
group which may be protected. The protecting group for the carbonyl and 
aldehyde groups may be any of those well known in the art. They include, 
for example, acetals (or thioacetals) and ketals (or thioketals) which may 
contain substituents such as methyl group; e.g. dimethylacetal 
(dimethylketal), diethylacetal (diethylketal), diethylthioacetal 
(diethylthioketal), ethyleneacetal (ethyleneketal) and propyleneacetal 
(propyleneketal). 
In the formula (I) of the compound of the present invention, R.sup.1 
represents a hydroxyl group which may be protected. The protecting group 
for the hydroxyl group may be any of those well known in the art. They 
include, for example, alkylsilyl groups such as t-butyldimethylsilyl, 
dimethylhexylsilyl, trimethylsilyl, triethylsilyl and tri(t-butyl)silyl 
groups; trityl group; tetrahydropyranyl group; tetrahydrofuranyl group; 
allyl group; lower alkanoyl groups such as substituted and unsubstituted 
acetyl groups; benzoyl group; benzyl group; methoxymethyl group; and 
benzyloxycarbonyl group. The substituted acetyl groups include, for 
example, halogen-substituted acetyl groups such as fluoroacetyl, 
difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, 
trichloroacetyl, bromoacetyl and dibromoacetyl groups; and alkoxyacetyl 
groups such as methoxyacetyl, ethoxyacetyl and phenoxyacetyl groups. 
Mycinosyl group is also usable as the protecting group for the hydroxyl 
group. The hydroxyl group of mycinosyl group may be protected with a 
protecting group listed above for the hydroxyl group. 
In the formula (I) for the compound of the present invention, R.sup.2 
represents a hydrogen atom or acyl group. The acyl groups include, for 
example, lower alkanoyl groups, lower alkenoyl groups, aroyl groups and 
phenyl(lower)alkanoyl groups. The lower alkanoyl groups include, for 
example, linear or branched alkanoyl groups having 1 to 6 carbon atoms. 
They include acyl groups such as formyl, acetyl, propionyl, butyryl, 
isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups; aroyl 
groups such as benzoyl, toluoyl and xyloyl groups; and phenyl(lower) 
alkanoyl groups such as phenylacetyl, phenylpropionyl and phenylhexanoyl 
groups. 
In the formula (I) for the compound of the present invention, W represents 
a hydrogen atom, hydroxyl group, lower alkanoyloxy group or substituted 
sulfonyloxy group. The lower alkanoyloxy groups include, for example, 
linear or branched alkanoyloxy groups having 1 to 6 carbon atoms. In 
particular, the alkanoyloxy groups include acetoxy and propionyloxy 
groups, etc. The substituted sulfonyloxy group is represented by the 
formula: --OSO.sub.2 R.sub.3 wherein R.sup.3 represents, for example, a 
lower alkyl group, trifluoromethyl group, 2-oxo-10-bornanyl group, 
substituted or unsubstituted aryl group or substituted or unsubstituted 
aralkyl group. The lower alkyl groups include, for example, methyl, ethyl, 
propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 1-methylbutyl, 
2-methylbutyl and neopentyl groups. The substituted or unsubstituted aryl 
groups include, for example, phenyl, p-methoxyphenyl, p-nitrophenyl, 
p-fluorophenyl, o,p-difluorophenyl, p-chlorophenyl, m-chlorophenyl, 
o-chlorophenyl, o,p-dichlorophenyl, p-bromophenyl, p-methylphenyl, 
m-methylphenyl, o,p-dimethylphenyl, m,p-dimethylphenyl and naphthyl 
groups. The substituted or unsubstituted aralkyl groups include, for 
example, benzyl, p-nitrobenzyl, o,p-dinitrobenzyl, p-chlorobenzyl, 
m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl, 
o,p-dimethylbenzyl, p-methoxybenzyl and p-fluorobenzyl groups. 
In the formula (I) for the compound of the present invention, Y represents 
a hydrogen atom, halogen atom, hydroxyl group or substituted sulfonyloxy 
group. The halogen atom may be any of chlorine, bromine and iodine atoms. 
The substituted sulfonyloxy groups are those described above. When Y 
represents a halogen atom, hydroxyl group or substituted sulfonyloxy 
group, the configuration of the substituent Y is such that it is at either 
cis- or trans-position to the adjacent dimethylamino group 
[--N(CH.sub.3).sub.2 ]. Therefore, the compound of the general formula (I) 
include a geometrical isomer in which the configuration of the substituent 
Y is such that it is at either cis- or trans-position to the adjacent 
dimethylamino group [--N(CH.sub.3).sub.2 ] or a mixture of the isomers in 
any proportion. The broken line "-------" represents a double bond or a 
single bond. 
A preferred embodiment of the present invention is a compound (a) of the 
formula (I) wherein A, B and R.sup.2 are as defined above, R.sup.1 
represents a group of the following formula: 
##STR6## 
(Z being CHR.sup.4 or C.dbd.O, and R.sup.4 being a hydroxyl group which 
may be protected), W represents a hydrogen atom or substituted sulfonyloxy 
group, Y represents a hydrogen atom, halogen atom or substituted 
sulfonyloxy group, and broken line "-------" represents a single bond; 
Another preferred embodiement of the present invention is a compound (b) of 
the formula (I) wherein A, B and R.sup.2 are as defined above, R.sup.1 
represents a group of the following formula: 
##STR7## 
(Z being CHR.sup.4 or C.dbd.O, and R.sup.4 being a hydroxyl group which 
may be protected), W represents a hydrogen atom or lower alkanoyloxy 
group, Y represents a halogen atom, hydroxyl group or substituted 
sulfonyloxy group, and broken line "-------" represents a double bond when 
W is hydrogen atom and a single bond when W is a lower alkanoyloxy group. 
Furthermore, another preferred embodiment of the present invention is a 
compound (c) of the formula (I) wherein A, B and R.sup.2 are as defined 
above, R.sup.1 represents a hydroxyl group which may be protected [with 
the proviso that R.sup.1 cannot be a group of the following formula: 
##STR8## 
(Z being CHR.sup.4 or C.dbd.O, and R.sup.4 being a hydroxyl group which 
may be protected)], W represents a hydrogen atom or lower alkanoyloxy 
group, Y represents a halogen atom, hydroxyl group or substituted 
sulfonyloxy group, and broken line "-------" represents a double bond when 
W is hydrogen atom and a single bond when W is a lower alkanoyloxy group. 
In the above-described compounds (a), (b) and (c), Z represents CHR.sup.4 
or C.dbd.O, and R.sup.4 represents a hydroxyl group which may be 
protected. The hydroxyl group which may be protected may be selected from 
among the above-mentioned ones excluding hydroxyl group protected with 
mycinosyl group. 
The compounds of the present invention can be produced by, for example, a 
scheme which will be given below. However, the compounds of the present 
invention and the processes for producing them are not limited to the 
compounds and processes described in the schemes. The numbers of the 
compounds in the schemes correspond to Examples given in this 
specification. 
Abbreviation: 
Ac: acetyl 
Bes: benzylsulfonyl 
DM: desmycosin 
DMT: demycinosyltylosin 
Do: deoxy 
ED: ethylenedioxy 
iVal: isovaleryl 
Ms: methanesulfonyl 
MT: mycaminosyltylonolide 
TBDS: t-butyldimethylsilyl 
TMS: trimethylsilyl 
EDMT: mycaminosyltylonolide 9,20-bis(ethyleneacetal) 
TBDS-EDMT: 23-O-t-butyldimethylsilylmycaminosyltylonolide 
9,20-bis(ethyleneacetal) 
3,4'-Bes-TBDS-EDMT: 
3,4'-di-O-benzylsulfonyl-23-O-t-butyldimethylsilylmycaminosyltylonolide 
9,20-bis(ethyleneacetal) 
3-Bes-4'-I-TBDS-EDMT: 
3-O-benzylsulfonyl-23-O-t-butyldimethylsilyl-4'-deoxy-4'-iodomycaminosylty 
lonolide 9,20-bis(ethyleneacetal) 
3,4'-Do-TBDS-EDMT: 
23-O-t-butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide 
9,20-bis(ethyleneacetal) 
3,4'-Do-MT: 3,4'-dideoxymycaminosyltylonolide 
2'-Ac-EDDM: 2'-O-acetyl desmycosin 9,20-bis(ethyleneacetal) 
2'-Ac-4"-TMS-EDDM: 2'-O-acetyl-4"-O-trimethylsilyl desmycosin 
9,20-bis(ethyleneacetal), 
2',4"-Ac-EDDM: 2',4"-di-O-acetyl desmycosin 9,20-bis(ethyleneacetal), 
2'-Ac-3,4'-Ms-4"-TMS-EDDM: 
2'-O-acetyl-3,4'-di-O-methanesulfonyl-4"-O-trimethylsilyl desmycosin 
9,20-bis(ethyleneacetal), 
2'-Ac-4'-I-3Ms-4"-TMS-EDDM: 
2'-O-acetyl-4'-deoxy-4'-iodo-3-O-methanesulfonyl -4"-O-trimethylsilyl 
desmycosin 9,20-bis(ethyleneacetal), 
3,4'-Do-EDDM: 3,4'-dideoxy desmycosin 9,20-bis(ethyleneacetal), 
2'-Ac-3,4'-Do-EDDM: 2'-O-acetyl-3,4'-dideoxy desmycosin 
9,20-bis(ethyleneacetal), 
2'-Ac-3,4'-Do-4"-Oxo-EDDM: 2'-O-acetyl-3,4'-dideoxy-4"-oxo desmycosin 
9,20-bis(ethyleneacetal), 
3,4'-Do-EDMT: 3,4'-dideoxymycaminosyltylonolide 9,20-bis(ethyleneacetal), 
3,2',4"-Ac-EDDM: 3,2',4"-tri-O-acetyl desmycosin 9,20-bis(ethyleneacetal), 
2',4"-Ac-.DELTA..sup.2 -EDDM: 2',4"-di-O-acetyl-2,3-dehydro-3-deox y 
desmycosin 9,20-bis(ethyleneacetal), 
2',4"-Ac-.DELTA..sup.2 -4'-Ms-EDDM: 
2',4"-di-O-acetyl-2,3-dehydro-3-deoxy-4'-O-methanesulfonyl desmycosin 
9,20-bis(ethyleneacetal), 
2',4"-Ac-.DELTA..sup.2 -4'-I-EDDM: 
2',4"-O-acetyl-2,3-dehydro-3,4'-dideoxy-4'-iodo desmycosin 
9,20-bis(ethyleneacetal), 
3,2',4"-Ac-4'-Ms-EDDM: 3,2',4"-tri-O-acetyl-4'-O-methanesulfonyl desmycosin 
9,20-bis(ethyleneacetal), 
3,2',4"-Ac-4'-I-EDDM: 3,2',4"-tri-O-acetyl-4'-deoxy-4'-iodo desmycosin 
9,20-bis(ethyleneacetal), 
3,2'-Ac-4"-iVal-DMT: 3,2'-di-O-acetyl-4"-O-isovaleryldemycinosyltylosin, 
3,2'-Ac-MT: 3,2'-di-O-acetylmycaminosyltylonolide, 
3,2'-Ac-EDMT: 3,2'-di-O-acetylmycaminosyltylonolide 
9,20-bis(ethyleneacetal) 
3,2'-Ac-TBDS-EDMT: 
3,2'-di-O-acetyl-23-O-t-butyldimethylsilylmycaminosyltylonolide 
9,20-bis(ethyleneacetal) 
2'-Ac-.DELTA..sup.2 -TBDS-EDMT: 2-O-acetyl-23-O-t-butyldimethylsilyl-2, 
3-dehydro-3-deoxymycaminosyltylonolide, 9,20-bis(ethyleneacetal) 
2'-Ac-.DELTA..sup.2 -4'-Ms-TBDS-EDMT: 
2'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro 
-3-deoxy-4'-O-methanesulfonylmycaminosyltylonolide 
9,20-bis(ethyleneacetal) 
2'-Ac-.DELTA..sup.2 -4'-I-TBDS-EDMT: 
2'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro 
-3,4'-dideoxy-4'-iodomycaminosyltylonolide 9,20-bis(ethyleneacetal) 
3,2'-Ac-4'-Ms-TBDS-EDMT: 
3,2'-di-O-acetyl-23-O-t-butyldimethylsilyl-4'-O-methanesulfonylmycaminosyl 
tylonolide 9,20-bis(ethyleneacetal), and 
3,2'-Ac-4'-I-TBDS-EDMT: 
3,2'-di-O-acetyl-23-O-t-butyldimethylsilyl-3,4'-dideoxy-4'-iodomycaminosyl 
tylonolide 9,20bis(ethyleneacetal). 
##STR9## 
The present invention provides: 
(d) a process for producing a compound of the above formula (I) wherein A, 
B, R.sup.1 and R.sup.2 are as defined above, W and Y each represent a 
hydrogen atom and the broken line "-------" represents a single bond by 
reducing a compound of the formula (I) wherein A, B, R.sup.1 and R.sup.2 
are as defined above, W represents a substituted sulfonyloxy group, Y 
represents a halogen atom and the broken line "-------" represents a 
single bond under an alkaline condition; and 
(e) a process for producing a compound of the above formula (I) wherein A, 
B, R.sup.1 and R.sup.2 are as defined above, W and Y each represent a 
hydrogen atom and the broken line "-------" represents a single bond, 
which comprises steps of reacting a compound of the formula (I) wherein A, 
B, R.sup.1 and R.sup.2 are as defined above, W and Y each represent a 
hydroxyl group and the broken line "-------" represents a single bond with 
a sulfonylating agent to form a compound of the above formula (I) wherein 
A, B, R.sup.1 and R.sup.2 are as defined above, W and Y each represent a 
substituted sulfonyloxy group and the broken line "-------" represents a 
single bond; reacting the compound thus obtained with a halogenating agent 
to form a compound of the above formula (I) wherein A, B, R.sup.1 and 
R.sup.2 are as defined above, W represents a substituted sulfonyloxy 
group, Y represents a halogen atom and the broken line "-------" 
represents a single bond; and reducing the compound thus obtained under an 
alkaline condition to obtain a compound of the above formula (I) wherein 
A, B, R.sup.1 and R.sup.2 are as defined above, W and Y each represent a 
hydrogen atom and the broken line "-------" represents a single bond. 
The compounds of the above-mentioned formula wherein A, B, R.sup.1 and 
R.sup.2 are as defined above, W and Y each represent a hydrogen atom and 
the broken line "-------" represents a single bond, thus produced by the 
above-described processes, are also preferred ones in the present 
invention. 
The mycaminosyltylonolide derivatives shown in the above production schemes 
1 and 2 can be produced from easily available tylosin. For example, they 
can be produced by hydrolyzing tylosin with an acid and then protecting, 
if necessary, hydroxyl, aldehyde and carbonyl groups of the obtained 
mycaminosyltylonolide with the abovedescribed protecting group. Another 
process is disclosed in Journal of Antibiotics (35, 661, 1982) wherein 
tylosin is treated with an acid anhydride to obtain 2'-o-acyltylosin, 
which is then hydrolyzed with an acid and simultaneously or therafter 
protected with the protecting group to obtain a mycaminosyltylonolide 
having a mycinosyl group. 
By reacting the thus-obtained mycaminosyltylonolide derivative with a 
sulfonylating agent, the hydroxyl groups at the 3-position and 4'-position 
are converted into the substituted sulfonyloxy groups to form the 
corresponding compound. The sulfonylating agents are, for example, halides 
and anhydrides. The sulfonylating agent for giving a desired substituted 
sulfcnyloxy group can be easily selected by those skilled in the art. 
Examples of the sulfonylating agents include methanesulfonyl chloride, 
methanesulfonic anhydride, ethanesulfonyl chloride, propanesulfonyl 
chloride, butanesulfonyl chloride, pentanesulfonyl chloride, 
trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, 
benzenesulfonyl chloride, pmethoxyphenylsulfonyl chloride, 
p-nitrophenylsulfonyl chloride, p-fluorophenylsulfonyl chloride, 
o,p-difluorophenylsulfonyl chloride, p-chlorophenylsulfonyl 
fluorophenylsulfonylchloride, m-chlorophenylsulfonyl chloride, 
o-chlorophenylsulfonyl chloride, o,p-dichlorophenylsulfonyl chloride, 
p-bromophenylsulfonyl chloride, p-methylphenylsulfonyl chloride, 
p-methylphenylsuflonic anhydride, m-methylphenylsulfonyl chloride, 
o,p-dimethylphenylsulfonyl chloride, m,p-dimethylphenylsulfonyl chloride, 
naphthylsulfonyl chloride, camphorsulfonyl chloride, benzylsulfonyl 
chloride, p-nitrobenzylsulfonyl chloride, o,p-dinitrobenzylsulfonyl 
chloride, p-chlorobenzylsulfonyl chloride, m-chlorobenzylsulfonyl 
chloride, p-methylbenzylsulfonyl chloride, m-methylbenzylsulfonyl 
chloride, o-methylbenzylsulfonyl chloride, o,p-dimethylbenzylsulfonyl 
chloride, p-methoxybenzylsulfonyl chloride and p-fluorobenzylsulfonyl 
chloride. The sulfonylating agents are not limited to those listed above. 
The sulfonylation reaction with the above-described sulfonylating agent is 
conducted usually in an organic solvent at a temperature ranging from 
-40.degree. to +50.degree. C. The solvents usable herein include, for 
example, acetonitrile, acetone, methyl ethyl ketone, dimethyl sulfoxide, 
dioxane and toluene. It is also possible to use pyridine, 
4-dimethylaminopyridine, triethylamine or the like as the basic catalyst 
and/or solvent. 
The compound produced by selectively introducing a halogen into the 
4'-position can be obtained by reacting the mycaminosyltylonolide 
derivative in which the hydroxyl groups at the 3-position and 4'-position 
have been converted into the substituted sulfonyloxy group with a 
halogenating agent such as sodium iodide, potassium iodide, lithium 
bromide, tetrabutylammonium bromide or tetrabutylammonium chloride in an 
inert solvent such as acetone, methyl ethyl ketone, dimethoxyethane or 
dimethylformamide. The halogenation reaction is conducted usually at room 
temperature to 100.degree. C. depending on the kind of the substituted 
sulfonyloxy group. Depending on the halogenation conditions, a compound 
having a double bond at 2- and 3-positions or at 3- and 4-positions is 
partially formed, which can be used as a starting compound in the 
subsequent step. 
By reducing the above-described compound having the substituted sulfonyloxy 
group and halogen atom in place of the hydroxyl groups at the 3-position 
and 4'-position under the alkaline condition, the groups at the 3-position 
and 4'-position can be simultaneously replaced with hydrogen to form 
3,4'-dideoxy derivative. This reaction can be conducted by, for example, a 
catalytic reduction in the presence of a catalyst in a solvent inert to 
the reaction. The bases usable for realizing the alkaline condition 
include, for example, sodium hydroxide, sodium carbonate, sodium 
hydrogencarbonate, potassium carbonate and potassium hydrogencarbonate. 
Among them, potassium carbonate is preferred. Such a base is used usually 
in an amount of 1 to 5 mol per mol of the 3-substituted 
sulfonyloxy-4'-halogen compound used as the substrate. The catalysts 
usable for the catalytic reduction include, for example, platinum, 
palladium and Raney nickel. Among them, Raney nickel is preferred. The 
amount of the catalyst which varies depending on the variety of the 
catalyst is usually 1/10 to 1/1 part by weight per part by weight of the 
compound used as the substrate. The inert solvents include, for example, 
methanol, ethanol and tetrahydrofuran. The catalytic reduction is 
conducted under cooling or at room temperature, preferably at a reaction 
temperature of -10.degree. to +30.degree. C. under a hydrogen pressure 
ranging from atmospheric pressure to 5 kg/cm.sup.2. These conditions which 
vary depending on the starting compounds and the catalyst are suitably 
selected by those skilled in the art. 
The groups at the 3-position and 4'-position of the 3-substituted 
sulfonyloxy-4'-halogen compound can be replaced with hydrogen at once by 
the above-described reaction. Thus, a high yield of 3,4'-deoxy compound 
can be obtained in one step. By removing the protecting groups from the 
3,4'-deoxy compound by an ordinary method, it can be converted into 
3,4'-dideoxymycaminosyltylonolide or a salt thereof useful as an 
antimicrobial agent. The protecting group can be removed usually by 
treatment with a mineral acid such as hydrochloric acid or sulfuric acid 
or with an organic acid such as acetic acid, trifluoroacetic acid or 
trichloroacetic acid in the presence of water. The protecting group can be 
removed also by treatment with an arylsulfonic acid such as 
p-toluenesulfonic acid or an alkylsulfonic acid such as methanesulfonic 
acid in a solvent such as dioxane, dimethylformamide, dimethyl sulfoxide 
or acetonitrile at room temperature or under heating. When the protecting 
group for the hydroxyl group is mycinosyl group, this group can be 
oxidized to form a corresponding ketone, which is then treated with an 
acid or base. 
Compounds of the formula (I) of the present invention wherein A, B and 
R.sup.2 are as defined above, W represents a hydrogen atom, Y represents a 
hydroxyl group, R.sup.1 represents a protected hydroxyl group and the 
broken line "-------" represents a double bond 
(2',4"-di-O-acyl-.DELTA..sup.2 -desmycosin bisacetal) can be produced by 
the process of the above production scheme 3-1. By this process, 
3-O-acetyltylosin easily available on the market (see Journal of 
Antibiotics 27, 542, 1979) is acylated to form 2',4"'-di- or 
2',4",4"'-tri-O-acyl-3-O-acetyltylosin by, for example, a method described 
in Journal of Antibiotics 35, 661, 1982, then the resultant compound is 
treated with a dehydrating agent and an alcohol in the presence of about 
1.1 to 1.5 mol, per mol of the compound, of an acid catalyst in an inert 
solvent such as toluene at a temperature of about 5.degree. to 80.degree. 
C. to form a 9,20-bisacetal of 2',4"-di-O-acyl-3-O-acetyl desmycosin, and 
finally the resultant compound is treated with about 1.0 to 5.0 mol, per 
mol of the compound, of a base in an inert solvent such as dimethyl 
sulfoxide. 
The alcohols usable in the above-described reaction include, for example, 
methanol, ethanol, propanol, butanol, ethylene glycol, propanediol and 
2,3-butanediol. Such an alcohol is used in an amount of about 5 to 20 mol, 
per mol of the starting compound. The dehydrating agents include, for 
example, ethyl orthoformate, methyl orthoformate, anhydrous calcium 
chloride, anhydrous sodium sulfate, anhydrous magnesium sulfate and 
molecular sieves. The acid catalysts include, for example. camphorsulfonic 
acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, 
sulfuric acid and Amberlyst 15. The bases usable in the acetic 
acid-removing step include, for example, sodium hydride, 
tert-butoxypotassium, magnesium methoxide, magnesium ethoxide, sodium 
methoxide, sodium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undecene and 
1,5-diazabicyclo[4.3.0]-5-nonene. 
The above-described compound can be converted into a compound of the 
formula [I] wherein Y represents a substituted sulfonyloxy group by 
reacting it with the above-described sulfonylating agent in the presence 
of an organic base such as pyridine, collidine, lutidine, triethylamine or 
diisopropylethylamine in an inert solvent at a temperature of about 
-25.degree. to +25.degree. C. It is also possible to obtain a compound of 
the above formula [I] wherein Y represents a halogen atom by reacting the 
compound of the above formula [I] wherein Y represents a substituted 
sulfonyloxy group with about 1 to 5 mol, per mol of the compound, a 
halogenating agent in a solvent such as acetone, methyl ethyl ketone, 
dimethoxyethane, acetonitrile, dimethyl sulfoxide or dimethylformamide at 
a temperature of about 50.degree. to 100.degree. C. 
The compound of the formula (I) of the present invention wherein A, B and 
R.sup.2 are as defined above, W represents a hydrogen atom, Y represents a 
halogen atom, R.sup.1 represents a protected hydroxyl group and the broken 
line "-------" represents a double bond can be converted into a 
corresponding 3,4'-deoxycompound by the hydrogen replacement at the 
3-position and 4'-position at once by, for example, catalytic reduction 
under alkaline condition in the same manner as those described above. Then 
the protecting groups are removed by an ordinary method to obtain 
3,4'-dideoxymycaminosyltylonolide or a salt thereof useful as the 
antimicrobial agent. 
The compound of the present invention can be produced from 
3-O-acetyltylosin according to, for example, the production scheme 3-2. 
For example, 3-O-acetyltylosin is acylated by a method described in 
Journal of Antibiotics (35, 661, 1982) to form 2',4"'-di- or 
2',4",4"'-tri-O-acyl-3-O-acetyltylosin and then the resultant compound is 
converted into an acetal with a dehydrating agent, an alcohol and an acid 
catalyst to obtain 9,20-bisacetal of 2',4"-di-O-acyl-3-O-acetyl 
desmycosin. 
In the acetalization reaction, an alcohol capable of forming an intended 
acetal or ketal is used either singly or in combination with an inert 
solvent. The alcohols include methanol, ethanol, propanol, butanol, 
ethylene glycolo, propanediol, 2,3-butanediol, etc. The alcohol is used in 
an amount of 5 to 20 mol per mol of the macrolide compound. The inert 
solvents usable herein include toluene, benzene, ethyl acetate, 
chloroform, dichloromethane, etc. The dehydrating agents include ethyl 
orthoformate as well as methyl orthoformate, anhydrous calcium chloride, 
anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves, 
etc. The acid catalysts include p-toluenesulfonic acid as well as 
benzenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, sulfuric 
acid, Amberlyst 15, etc. The acid catalyst is preferably used in an amount 
of 1.1 to 1.5 mol per mol of the starting compound. The reaction 
temperature is 5.degree. to 80.degree. C., preferably 20.degree. to 
70.degree. C. and particularly room temperature to 50.degree. C. 
The compound thus obtained can be converted into a compound sulfonylated at 
the 4'-position by reacting it with a sulfonylating agent under the 
above-described reaction conditions. The compound thus sulfonylated at the 
4'-position is relatively unstable and, therefore, it is preferably 
subjected to the subsequent reaction without isolation or purification. 
This compound can be converted into a compound halogenated at the 
4'-position by halogenation under the above-described conditions. 
This compound can be converted into 
2',4"-di-O-acyl-2,3-dehydro-3,4'-dideoxy-4'-halo-desmycosin bisacetal by 
removing acetic acid at the 2- and 3-positions as follows: the compound 
halogenated at the 4'-position is dissolved in an inert solvent such as 
toluene, diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, 
dimethyl sulfoxide or dimethylformamide, and then treated with a base such 
as sodium hydride, tert-butoxypotassium, maqnesium methoxide, magnesium 
ethoxide, sodium methoxide, sodium ethoxide, 
1,8-diazabicyclo[5.4.0]-7-undecene or 1,5-diazabicyclo[4.3.0]-5-nonene. 
This reaction is conducted at, for example, a temperature of -10.degree. 
to 80.degree. C. The base is used in an amount of 1.0 to 5.0 mol, 
preferably 1.0 to 3.0 mol, per mol of the starting compound. 
The compound thus obtained is dissolved in, for example, methanol or 
ethanol and catalytically reduced in the presence of a catalyst such as 
Raney nickel and a base under a hydrogen pressure ranging from atmospheric 
pressure to about 4.0 kg/cm.sup.2 according to the production scheme 3--3 
to obtain 3,4'-dideoxy desmycosin bisacetal. This reaction can be 
conducted at, for example, room temperature, and 1 to 3 mol of a base such 
as sodium hydrogencarbonate, potassium hydrogencarbonate, potassium 
carbonate or sodium carbonate is used per mol of the macrolide compound. 
When Raney nickel is used as the catalyst, the variety thereof is not 
particularly limited. For example, NDT-65 or NDHT-90 (a product of Kawaken 
Fine Chemicals, Co., Ltd.) is usable. It is preferred to conduct the 
reaction in the presence of 0.1 to 1.0 part by weight of the catalyst per 
part by weight of the macrolide compound. The resultant compounnd is 
treated with about 1.1 equivalent of an acid anhydride to introduce an 
acyl group into the 2'-position, thereby obtaining a corresponding 
2'-O-acyl-3,4'-dideoxy desmycosin bisacetal. 
This compund is treated with an oxidizing agent to oxidize the hydroxyl 
group at the 4"-position and to obtain a high yield of the intended 
compound. The oxidizing agents include, for example, combinations of 
dimethyl sulfoxide/acetic anhydride, dimethyl sulfoxide/trifluoroacetic 
anhydride, dimethyl 
sulfoxide/dicyclohexylcarbodiimide/pyridine/trifluoroacetic acid, dimethyl 
sulfide/N-chlorosuccinimide/triethylamine and 
tetrahydrothiophene/N-chlorosuccinimide/triethylamine as well as ordinary 
oxidizing agents having a secondary hydroxyl group. The oxidizing agent is 
used in an amount of about 2 to 10 mol per mol of the starting compound. 
Although the reaction conditions vary depending on the variety of the 
oxidizing agent, the reaction temperature ranges -20.degree. C. to 
80.degree. C. 
The mycinose part can be easily removed by treating the 4"-oxo compound 
obtained by the above-described process with a base in an inert solvent. 
For example, the 4"-oxo compound is treated with a base such as sodium 
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, 
ammonium acetate, 1,8-diazabicyclo[5.4.0]-7-undecene or 
1,5-diazabicyclo[4.3.0]-5-nonene in an organic solvent such as methanol, 
ethanol, dioxane, tetrahydrofuran, dimethoxyethane, dimethylformamide or a 
mixture of two or more of them or a mixture of such an organic solvent 
with water. Though the reaction temperature ranges from 0.degree. to 
100.degree. C., a temperature below room temperature is preferred. 
The acetyl group at the 2'-position can be removed by an alcoholysis 
reaction in a solvent such as methanol or ethanol prior to the 
mycinose-removing reaction or, alternatively, by the alcholysis reaction 
after the mycinose-removing reaction. 3,4'-dideoxymycaminosyltylonolide 
bisacetal thus obtained is dissolved in an organic solvent such as 
tetrahydrofuran or dioxane and then treated with dilute hydrochloric acid 
to conduct the deacetalization (deketalization), thereby obtaining 
3,4'-dideoxymycaminosyltylonolide. 
According to the production scheme 4-1, a 
3-O-acetyl-4"-O-isovaleryldemycinosyltylosin (a compound described in J.P. 
KOKOKU No. Sho 60-16960) can be converted into a corresponding 
2'-O-acyl-3-O-acetyl-4"-O -isovaleryldemycinosyltylosin by treating it 
with an acid anhydride selected from various ones as described in, for 
example, Journal of Antibiotics (35, 661, 1982). When the resultant 
compound is hydrolyzed under an acid condition realized in, for example, 
an aqueous solution of sulfuric acid, hydrochloric acid or phosphoric acid 
at -10.degree. to 100.degree. C., preferably 10.degree. to 60.degree. C., 
a corresponding 2'-O-acyl-3-O-acetylmycaminosyltylonolide is obtained. 
Further, this compound can be converted into 9,20-bisacetal of the 
2'-O-acyl-3-O-acetylmycaminosyltylonolide by acetalizing it with a 
dehydrating agent, alcohol and acid catalyst under the above-described 
reaction conditions. On the other hand, when the 
2'-O-acyl-3-O-acetyl-4"-O-isovaleryldemycinosyltylosin is subjected to the 
acetalization reaction under the above-described reaction conditions, 
acetalization and hydrolysis of the terminal saccharide occur at the same 
time to obtain 9,20-bisacetal of the 
2'-O-acyl-3-O-acetylmycaminosyltylonolide in one step. 
When 9,20-bisacetal of the 2'-O-acyl-3-O-acetylmycaminosyltylonolide thus 
obtained is reacted with, for example, a reactive silyl compound in the 
presence of a base, a corresponding compound having protected hydroxyl 
group at the 23-position can be obtained. The solvents usable for this 
reaction include dimethylformamide as well as acetone, acetonitrile, 
tetrahydrofuran, toluene and chloroform. The basic catalysts include 
inorganic and organic bases such as sodium carbonate, potassium carbonate, 
sodium hydrogencarbonate, pyridine, lutidine, picoline, triethylamine, 
diisopropylethylamine and imidazole. The reactive silyl compounds usable 
herein include trimethylsilyl chloride, triethylsilyl chloride, 
tripropylsilyl chloride, t-butyldimethylsilyl chloride, 
dimethoxymethylsilyl chloride, dimethylphenylsilyl chloride, etc. The 
reaction can be conducted at -10.degree. to 50 .degree. C. 
The compound having the protected hydroxyl group at the 23-position is 
dissolved in an inert solvent such as toluene, diethyl ether, 
tetrahydrofuran, dimethoxyethane, dioxane, dimethyl sulfoxide or 
dimethylformamide, and then reacted with a base such as sodium hydride, 
t-butoxypotassium, magnesium methoxide, magnesium ethoxide, sodium 
methoxide, sodium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undecene or 
1,5diazabicyclo[4.3.0]-5-nonene at -10.degree. to 80.degree. C. to obtain 
a corresponding 2'-O-acyl-2,3-dehydro-mycaminosyltylonolide bisacetal 
which is a 2,3-deacetylation product. The base is used in an amount of 1.0 
to 5.0 mol, preferably 1.0 to 3.0 mol, per mol of the macrolide compound. 
A compound sulfonylated at the 4'-position can be produced from this 
compound by reacting it with the above-described sulfonylating agent in 
the presence of a base such as pyridine, collidine, lutidine, 
triethylamine or diisopropylethylamine in an inert solvent such as 
acetone, methyl ethyl ketone, dimethoxyethane, acetonitrile, toluene, 
dimethyl sulfoxide or dimethylformamide at -25.degree. to 25.degree. C. 
Although the compound thus sulfonylated at the 4'-position can be isolated 
and purified prior to the subsequent reaction, it is preferably subjected 
to the halogenation reaction at the 4'-position thereof without the 
isolation, since this compound is relatively unstable. By the halogenation 
reaction conducted under the abovedescribed reaction conditions, the 
compound halogenated at the 4'-position, i.e. 
2'-O-acyl-2,3-dehydro-3,4'-dideoxy-4'-halomycaminosyltylonolide bisacetal, 
can be obtained. 
According to the production scheme 4-2, the halogenated compound can be 
obtained also by protecting the hydroxyl group at the 23-position of 
9,20-bisacetal of the 2'-O-acyl-3-O-acetylmycaminosyltylonolide, then 
sulfonylating this compound at the 4'-position thereof under the 
above-described reaction conditions, halogenating the resultant compound 
under the above-described reaction conditions, and deacylating it under 
the above-described reaction conditions. Although the compound sulfonylted 
at the 4'-position can be isolated and purified prior to the subsequent 
reaction, it is preferably subjected to the subsequent reaction without 
the isolation, since the compound itself is relatively unstable. 
When the 2'-O-acyl-2,3-dehydro-3,4'-dideoxy-4'-halomycaminosyltylonolide 
bisacetal produced as described above is dissolved in, for example, 
methanol or ethanol and catalytically reduced in the presence of a 
catalyst such as a Raney nickel and a base under a hydrogen pressure 
ranging from atmospheric pressure to about 4.0 kg/cm.sup.2 under the 
above-described reaction conditions according to the production scheme 
4-3, a corresponding 3,4'-dideoxymycaminosyltylonolide bisacetal is 
obtained. 3,4'-dideoxymycaminosyltylonolide can be produced by dissolving 
this compound in an organic solvent such as tetrahydrofuran, dioxane or 
acetone, and then treating it with dilute hydrochloric acid to conduct 
both deacetalization and removal of the protecting group at the 
23-position.