Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ ~Ba~
.
M~C FOLIO: 52835 WANGDOC: 0636H
PROCESS FOR PRODUCING 13-SUBSTITUTED
MILBEMYCIN DERIVATIVES
The present invention relates ~o a novel process for
preparing certain 13-substituted milbemycin derivatives,
which have valuable insecticidal, acaricidal and
anthelmintic activities.
The compounds which may be prepared by the process
of the present invention are those compound~ of formula
(I)
CR~--~c~l3
I~ 0~0 Il)
~,
0 ~ 3
OH ~ :
wherein:
R repre6ents a methyl group, an ethyl group, an
~ isopropyl group or a sec-butyL group;
,., :
:
,
'
, ' ..
~ ~884;~6
X represents a halogen atom or a group of formula
R2-(O)n-COO-;
n i 6 0 or 1; and
R2 represents a Cl-Cl8 alkyl group, a C3-C10
cycloalkyl group, a C7-Cg aralkyl group, a C2-C6
alkenyl group, a C2-C6 alkynyl group, a C5-C10
cycloalkenyl group, a C6-ClO carbocyclic aryl group
or a he~erocyclic group having from 5 to 14 ring atoms
of which from l to 5 are hetero-atoms selected from the
group consisting of oxygen, sulphur and nitrogen atoms,
or said alkyl, alkenyl or alkynyl group having at least
one substituent selected from the group consisting of
substituents (a), or said cycloalkyl, cycloalkenyl,
aralkyl, aryl or heterocyclic group having at least one
substituent selected from the group consisting of
substituents (a) and (b):
substituents (a): Cl-C6 alkoxy groups, C2-C7
alkoxycarbonyl groups, halogen a~oms, hydroxy
geoups, carboxy groups, amino groups, Cl-C6
alkylamino groups, dialkylamino groups where each
- alkyl part is Cl-C6, carboxylic acylamino
groups, cyano groups, carbamoyl groups,
alkylcarbamoyl groups where the alkyl part is
Cl-C6, dialkylcarbamoyl groups where each alkyl
part is Cl-C6, mercapto groups, Cl-C6
alkylthio groups, Cl-C6 alkylsulphinyl groups,
Cl-C6 alkylsulphonyl groups, nitro groups,
phenoxy groups, phenoxy groups having from 1 to 5
halogen substituents and heterocyclic groups having
5 or 6 ring atoms of which from 1 to 3 are
he~ero-atoms selected from the group consisting of
nitrogen, oxygen and sulphur atoms, said
heterocyclic groups being unsubstituted or having at
least one substituent selected from the group
consifiting of substituents (a) and (b); and
substituents (b): Cl-C6 alkyl groups, C2-C6
alkenyl groups, C2-C6 alkenyl groups having at
least one halogen substituent, alkoxyalkyl groups
where both the alkoxy and the alkyl parts are
Cl-C6 and Cl-C6 alkyl groups having at least
one halogen substituent.
Thos~ compounds of formula (I) where X represents a
halogen atom are disclosed in US Patents No. 4,093,629
and No. 4,173,571. Those compounds where X represents
the aforesaid group of formula R2-(O)n-C00- are
disclosed in Japanese Patent Application Kokai No.
180787/~6, published after the priori~y date hereof but
before the filing date.
8426
We have now discovered a new process for preparing
these known compounds, which process is believed to be
better suited to practical commercial production than
are the prior processes.
Thus, in accordance with the present invention,
there is provided a process for preparing compounds of
formula (I), defined above, which comprises reducing a
compound of formula (II):
CH3 ~,CH3
CH/ O 1R1
~ 0~,0 111)
~ .
~CH
(in which X and pl are as defined above).
Compounds of formula (II) in which X represents said
group of formula R2-(O)n~C00- are disclosed in
European Patent Publication No. 0184308.
Compounds of formula (Il) may be prepared by
reacting a 13-hydroxy-5~ketomilbemycin derivative of
formula ~III):
9 ~ 2~j
CH~ , ,CH3
CH ~
~ IIlI)
~1 '
~CH3
tin which Rl is a6 defined above) with ~ halogenating
agent or with a carboxylic acid of formula (IV):
R2-(O)n-COOH (IV)
(in which R2 and n are as defined above) or with a
reactive derivative thereof. Compounds of formula (III)
are known from U.S. Patent No. 4,423,209.
Reaction of the compound of formula (III) with the
halogenating agent or with the carboxylic acid (IV) or
reactive derivative thereof is a simple halogenation
reaction or esterification reaction which takes place at
the 13-position of the 13-hydroxy-5-ketomilbemycin
~III). Accordingly, this reaction may be carried out by
any method known for such reactions.
~ ~38~
Halogenating agents which &ay be employed to prepare
a compound where X represents a halogen atom include,
for example diethylaminosulphur trifluoride, thionyl
chloride and phosphorus tribromide.
The precise carboxylic acid (IV) employed in the
reaction to produce a compound where X represents a
group of formula R2-tO)n-COO- will, of course,
depend upon the nature of the group which ~t is desired
to introduce. Where a reactive derivative of the acid
is to be employed, this may be, for example: an acid
halide, such as the acid chloride, acid bromide or acid
iodide; an acid anhydride or mixed acid anhydride; an
active ester, such as the P-nitrobenzyl ester; or an
active amide. All of these reactive derivatives are
well known for use in esterification reactions.
In the process of the present invention, the
carbonyl group at the 5-position of the milbemycin
derivative (II) is reduced to a hydroxy group and any
known method of reduction may be employed. However, it
is important not to damage (at least to an unacceptable
extent) any part of the molecule other than the
5-position and hence it is desirable that the reducing
agent employed should either only affect the carbonyl
group at the 5-position or, at least, should have a
relatively minor effect on other parts of the molecule,
~ ~38~26
so as to minimize side reactions. In general, we have
found that reduction with anionic hydrogen is
preferred. Reagents capable of liberating anionic
hydrogen are well known and examples include sodium
borohydride and diborane, of which sodium borohydride is
~referred. There is no particular restriction on the
amount of reducing agent to be employed, although we
generally prefer to use at least an equimolar amount
with respect to the compound of formula (II); an amount
of from 1 to 5 equivalents, more preferably from l to 2
equivalents, per mole of the compound of formula (II) is
generally preferred.
The reaction is normally performed in the presence
of a solvent, the nature of which is not critical,
provided that it does not have any adverse effect upon
the reaction. Examples of suitable solvents include:
alcohols, such a~ methanol or ethanol; ethers, such as
diethyl ether or tetrahydrofuran; and hydrocarbons,
particularly aromatic hydrocarbons, such as benzene.
The reaction will take place over a wide range of
tempera~ures and the precise temperature chosen is not
critical to the invention. In general, we find it
convenient to carry out the reaction a~ a temperature in
the range from -10C to +50C, more preferably from 0C
to 2~C. The time required for the reaction may vary
42Ç~
widely, depending upon many factors, notably the
reaction temperature; however, a period of ~rom 30
minutes to 3 hours will normally suffice.
After Gompletion of the reaction, the desired
compound of formula ~I) may be recovered from the
reaction mixture by well known means and, if necessary,
further purified by such conventional techniques as the
chroma~ography techniques, notably column chromatography.
In the compounds of formulae (I) and (II) where X
represents a halogen atom, it may be, for example,
chlorine, bromine, fluorine or iodine, preferably
chlorine or fluorine.
In the compounds of formulae (I) and (IV), where
R2 represents a Cl-C18 alkyl group, this may be a
straight or branched chain alkyl group for example a
methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,
t-pentyl, hexyl, isohexyl, l-ethylbutyl, heptyl, octyl,
isooctyl, 2-ethylhexyl, nonyl, decyl, isodecyl, undecyl,
dodecyl, tetradecyl, hexadecyl or octadecyl group.
Where R2 represents a cycloalkyl group, this has
from 3 to 10, pre~erably ~rom 3 to 7, ~ing carbon atoms
and may be a monocyclic or polycyclic, preferably
.
3842~;
bicyclic, group; examples of such groups include the
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
bicyclo[2.2.1~heptyl groups.
Where R2 represents a cycloalkenyl group having
from S to 10 ring atoms, it may be any one of the
cycloalkyl groups listed above but having at least one
unsaturated carbon-carbon bond in the ring. Examples
include the cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, tetrahydronaphthyl and octahydronaphthyl
groups, of which the cyclohexenyl, especially
l-cyclohexenyl, groups are preferred.
Where R2 represents an aralkyl group having from 7
to 9 carbon atoms, it is preferably a Cl-C3 alkyl
group having a phenyl substituent, for example a benzyl,
a-methylbenzyl, a,a-dimethylbenzyl, phenethyl or
3-phenylpropyl group.
~ here R2 represents an alkenyl or alkynyl group
having from 2 to 6 carbon atoms, it is more preferably
such a group having from 2 to ~ carbon atoms and having
1 or 2 unsaturated carbon-carbon double or triple bonds,
for example the vinyl, propenyl (e.g. allyl),
isopropenyl, butenyl, butadienyl, methallyl, hexadienyl,
ethynyl or propynyl groups.
,
3842~i
Where R2 represents a carbocyclic aryl group
having from 6 ~o lO carbon atoms, it is preferably a
phenyl or naphthyl (1- or 2-naphthyl) group.
Where R2 represents a heterocyclic group, this
contains from 5 to 14, preferably from 5 to lO, ring
atoms, of which at least one, preferably from 1 to 5 and
more preferably from l to 3, are hetero-ato~s selected
from the group consisting of nitrogen, oxygen and
sulphur atoms. The atoms of the heterocyclic group may
be fully saturated or they may be unsaturated and, if
unsaturated, they may be aromatic in character.
Examples of such group6 include the furyl, thienyl,
pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,
isooxazolyl, imidazolyl, pyrazolyl, pyranyl, pyrazinyl,
pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl,
indolyl, quinolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl and xanthenyl groups, and
their partly or fully saturated analogues, for example
the tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,
thiazolidinyl, imidazolidinyl, imidazolinyl, oxazolinyl,
pyrazolidinyl, piperazinyl, tetrahydropyrimidinyl,
dihydropyridazinyl, morpholinyl, indolinyl and
tetrahydroquinolyl groups.
Any of the groups defined above and represented by
R can be unsubstituted or they can have one or more
substituents. There is no general limitation upon the
number of subs'ituents which any group may bear,
although there may, in any individual case, be practical
limitations upon the maximum number of such
substituents. Thus, in all cases, the maximum number of
substituents which any group may bear is determined by
the number of substitutable positions on that group and
hence groups with more atoms can, in general, bear more
substituents. Also, the number of substituents may be
limited by ste~ic considerations. For exam21e, where
the group to be substituted is relatively small and the
substituent is relatively bulky, the number of
substituents which can, in practice, be accommodated may
be less than the theoretical maximum. Such matters are,
however, well-known to those skilled in the art and
~equire no further discussion or definition here.
Where the substituent is an alkyl group, it may be a
straight or branched chain alkyl group having from 1 to
6 carbon atoms and examples include the methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,
pentyl and hexyl groups.
Where the substituent is an alkoxy group, it may
likewise be a straight or branched chain group having
from 1 to 6 carbon atoms and examples include the
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
~1 2~ 2~;
t-butoxy, pentyloxy and hexyloxy groups.
Where the substituent is an alkoxyalkyl group, both
the alkoxy part and the alkyl part may be straight or
branched chain groups and each has from 1 to 6 carbon
atoms; examples of the alkoxy and alkyl parts are
included within the alkyl and alkoxy groups defined
above. More preferably, the alkoxyalkyl group has a
total of up to 6 carbon atoms and preferred examples of
such groups include the methoxymethyl, ethoxymethyl,
propoxymethyl, butoxymethyl, 2-me~hoxyethyl,
2-ethoxyethyl, 2-butoxyethyl and 3-propoxypropyl groups.
Where the substituent is an alkoxycarbonyl group, it
has a total of from 2 to 7, preferably from 2 to 5,
carbon atoms and the alkoxy part may be any one of those
alkoxy groups described above. Preferred examples of
such alkoxycarbonyl groups include the methoxycarbonyl,
ethoxycarhonyl, propoxycarbonyl, butoxycarbonyl and
t-butoxycarbonyl groups.
Where the substituent is a haloalkyl group, it has
from 1 to 6, preferably from 1 to 3, carbon atoms and
may be a straight or branched chain group, including
halogenated analogues of the Cl-C6 alkyl groups
described above. The number of halogen atoms may range
from a minimum of 1 to a maximum of complete
9 2~3~342~i
halogenation (i.e. a perhaloalkyl group), although, in
practice, groups with from 1 to 3 halogen atoms are
generally most conveniently available. Examples of such
haloalkyl groups include the chloromethyl, bromomethyl,
iodomethyl, fluoromethyl, dichloromethyl,
trifluoromethyl, 2-chloroethyl, 2,2,2-trichloroethyl,
2-bromopropyl and 2,3-dibromopropyl groups.
Where the substituent is an alkenyl group having
from 2 to 6 carbon atoms, it may be a straight or
branched chain group, for example a vinyl, propenyl
(e.g. allyl), isopropenyl, butenyl, butadienyl,
methallyl or hexadienyl group.
Where the substituent is an alkenyl group having at
least one halogen (e.g. fluorine, chlorine, bromine or
iodine, preferably chlorine) substituent, it may be a
halogenated analogue of any of the alkenyl groups listed
above, ranging from a monohalo to a perhalo (preferably
trihalo) compound. Preferred haloalkenyl groups are
2-chlorovinyl, 2,2-dichlorovinyl, 3-chloroallyl,
2,2-difluorovinyl and 1,2,2-trichlorovinyl groups.
Where the substituent is a halogen atom, it is
preferably a chlorine, bromine, fluorine or iodine atom.
Where the substituent is a mono- or di-alkylamino
38~26
group, the or each alkyl part is Cl-C6, preferably
Cl-C4, alkyl and examples are the alkyl groups given
above. Preferred such alkylamino groups include the
methylamino, ethylamino, propylamino, isopropylamino,
isobutylamino, dimethylamino, diethylamino,
methyl(e~hyl~amino and methyl(butyl)amino group6.
Where the substituent is a carboxylic acylamino
group, the carboxylic acyl part may be an aromatic,
aliphatic, cycloaliphatic or heterocyclic acyl group in
which the aromatic, aliphatic, cycloaliphatic and
heterocyclic parts are as defined above in relation to
the aryl, alkyl, alkenyl, alkynyl, cycloalkyl and
heterocyclic groups, respectively. However, it iS most
preferably a Cl-C7, more preferably C2-C5,
alkanoylamino group, for example the acetylamino,
propionylamino or butyrylamino groups.
Where the substituent is a mono- or
di-alkylcarbamoyl group, the or each alkyl part is a
Cl-C6, preferably Cl-C4, alkyl group, examples
of which are as given above. Preferred examples of such
alkylcarbamoyl groups include the methylcarbamoyl,
ethylcarbamoyl, butylcarbamoyl and dimethylcarbamoyl
groups.
Where the substituent is an alkylthio group, it may
.
, , ;
,
: , ' , '
~ ~88~6
be a straigh~ or branched chain group having from 1 to
6, more preferably from 1 tO 4, carbon atoms and the
alkyl part may be any one of those alkyl groups defined
above. Preferred examples of such alkylthio groups
include the methylthio, ethylthio, propylthio, bùtylthio
and sec-butylthio groups.
~ here the substituent is an alkylsulphinyl group,
the alkyl part may be a s~raight or branched chain
Cl-C6, preferably Cl-C4, alkyl group and may be
any one of those alkyl groups exemplified above.
Preferred examples of such alkylsulphinyl groups include
the methylsulphinyl, ethylsulphinyl, propylsulphinyl and
butylsulphinyl groups.
Where the substituent is an alkylsulphonyl group,
the alkyl part may be a straight or branched chain
Cl-C6, preferably Cl-C4, alkyl group, for
example any one of those alkyl groups exemplified
above. Preferred examples of such alkylsulphonyl groups
include the methanesulphonyl, ethanesulphonyl,
propanesulphonyl and butanesulphonyl groups.
~ here the substituent is a halogenated phenoxy
group, this may have from 1 to 5, preferably from 1 to
3, halogen substituents, ~he halogen substituents being,
for example, chlorine, bromine, iodine or fluorine
.
342~
16
atoms. Examples of such halogenated phenoxy groups
include the chlorophenoxy, bromophenoxy, fluorophenoxy,
iodophenoxy and dichlorophenoxy groups.
~ here the substituent is a heterocyclic group having
5 or 6 ring atoms, of which from 1 to 3 are hetero-atoms
selected from the group consisting of nit~ogen, oxygen
and sulphur atoms, i~ may be any one of those 5- and
6-membered heterocyclic groups exemplified above in
relation to the heterocyclic group which may be
represented by R , or a 2,2-dimethyl-1,3-dioxolanyl
group.
Preferred examples of groups which may be
represented by R2 include: ~he methyl, ethyl,
isopropyl, butyl, t-butyl, pentyl, octyl, trifluoro-
methyl, 2-chloroethyl, 2,2,2-trichloroethyl,
2,2,2-trifluoroethyl, l-chloropropyl, methoxymethyl,
2-methoxyethyl, 2-ethoxyethyl, phenoxymethyl,
4-fluorophenoxymethyl, ~-hydroxyethyl, 2-mercaptoethyl,
2-carboxyethyl, cyclopropyl, 2-~2,2-dichlorovinyl)-3,3-
dimethylcyclopropyl, cyclobutyl, 2-furfuryl, 2-thenyl,
2,2-dimethyl-1,3-dioxolan-4-ylmethyl, 2,2-dichlorovinyl,
1,2,2-tri-chlorovinyl, 2,2-~ifluorovinyl, 1-propenyl,
allyl, isopropenyl, l-butenyl, 2-butenyl, 2-methylallyl,
ethynyl, 2-propynyl, l-cyclohexenyl, benzyl,
a-methylbenzyl, a,a-dimethylbenzyl, phe~yl,
~-x~
o-chlorophenyl, _-chlorophenyl, p-chlorophenyl,
Q-fluorophenyl, _-fluorophenyl, P-fluorophenyl,
o-bromophenyl, m-bromophenyl, ~-bromophenyl,
~-methoxyphenyl, ~-nitrophenyl, p-t-butylphenyl,
o-trifluoromethylphenyl, m-trifluoromethylphenyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, l-pyrrolyl,
2-pyrrolyl, l-pyrrolidinyl, 2-pyridyl, 2-quinolinyl,
6-fluoro-2-pyridyl, 5-chloro-2-thienyl and
5-fluoro-2-furyl groups.
The compounds of formula (I) produced by the process
of the invention have a strong acaricidal activity
against, for example, adults, imagos and eggs of
Tetranvchus, Panon~chus and rust mites, which are
parasitic to fruit trees, vegetables and flowers. They
are also active against Ixodidac, DermanYssidae and
SarcoPtidae, which are parasitic to animals. Further,
they are active against: exoparasites, such as Oestrus,
Lucilia, HYPoderma~ GautroPhilus, lice and fleas, which
are parasitic to animals and birds, particularly
livestock and poultry; domestic insects, such as
cockroaches and houseflies: and various harmful insects
in agricultural and horticultural areas, such as aphids
and larval LePidoPtera. They are also effective against
Meloidoqvne in the soil, BursaPhelenchus and
PhiæoglYphus. They are al50 effective against insects
of the orders ColeoPtera, Homo~tera, Hetero~tera,
8~Z6
18
Diptera, ThvsanoPtera, Orthoptera, AnoPlura,
SiphonaPtera, Mallophaae, Thysanura, Isoptera,
PsocoPtera, and HymenoPtera.
The compounds of formula tI) equally can be used to
control other plant-damaging insects, particularly
insects tha~ damage plants by eating them. The
compounds can be used to protect both ornamental plants
and productive plants, particularly cotton (e.g. against
SPodoptera littoralis and Heliothis virescens), as well
as vegetable crops (e.g. against LePtinotarsa
decemlineata and MYZUS persica_) and rice crops (e.g.
against Chilo suppressalis and Laodelphax).
Moreover, the compounds of formula (I) are effective
against various parasitical helminths. These parasites
can attack livestock, poultry and pet animals (such as
pigs, sheep, goats, cows, horses, dogs, cats and fowl)
and can cause grave economic damage. Among the
helminths, the nematodes in particular often cause
serious infection.
Compounds of formulae (I) and (II) are derivatives
of the milbemycins and the nomenclature of these
compounds is based upon ~he milbemycins as the paren~
structures as recommended by the International Union of
Pure and Applied Chemistry. Specifically, compounds in
2~;
19
which Rl represents a methyl group are named as
derivatives of milbemycin A3, compounds in which Rl
represents an ethyl group are named as derivatives of
milbemycin A4 and compounds in which R represents
an isopropyl group are named as derivatives of
milbemycin D. In both the compounds of formula (I) and
the compounds of formula (II), ~he hydrogen atom at
13-position of the parent milbemycin is replaced by an
atom or group represented by X and such compounds are
named simply as 13-substituted milbemycins. In the
compounds of formula (II), the hydroxy group present at
the 5-position of the parent milbemycin is replaced by a
doubly-bonded oxygen atom and such compounds are named
as 5-ketomilbemycins.
The process of the present invention is further
illustrated by the following Examples. The preparation
of certain of the starting materials employed in the
Examples is illustrated in the following Preparations 1
and 2; the other starting materials employed in the
Examples may be produced in a similar way.
PP~EPARATION 1
13-Fluoro-5-ketomilbemYcin A4
70 mg of diethylaminosulphur trifluoride were added
dropwise to a solution of 560 mg of
13-hydroxy-5-ketomilbemycin A4 in 25 ml of methylene
chloride, whilst cooling at -60C. After completion of
the addition, stirring was continued for a further 15
minutes, after which the reaction mixture was poured
into water. The mixture was then extracted with ethyl
acetate and the extract was dried over anhydrous sodium
sulphate. The solvent was removed by distillation and
the residue was purified by silica gel column
chromatography, eluted with a 3:1 by volume mixture of
hexane and ethyl acetate, to give 320 mg of the title
compound.
Mass spectrum (m/e): 559 (M+).
Nuclear Magnetic Resonance Spectrum (270 ~Hz, CDC13)
ppm:
3.88 (lH, singlet);
4.02 (lH, singlet);
4.40 (lH, doublet of doublets).
PREpARATI~oN ?
:
13-(p-FluoroPhenoxy)acetoxy-5-ketomilbemYcin A
23 mg of 1,3-dicycIohexylcarbodiimide and 62 mg of
13-hydroxy-5-ketomilbemycin A4 were added, in turn, to
,
,
a4~i
a solution of 17 mg of p-fluorophenoxyacetic acid in 15
ml of methylene chloride, followed by a trace amount of
4-pyrrolidinopyridine, and then the mixture was stirred
at room temperature for 30 minutes. At the end of this
time, the reaction mixture was ~iltered and the filtrate
was poured into water and then extracted with ethyl
acetate. The extrac~ was washed, in turn, with water
and with a saturated aqueous solution of sodium chloride
and then dried over anhydrous magnesium sulphate. The
solvent was removed by distillation and the residue was
purified by column chromatography through silica gel,
eluted with a 3:1 by volume mixture of hexane and ethyl
acetate, to give 44 mg of the title compound.
Mass spectrum (mte): 708 tM~.
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13)
ppm:
3.86 (lH, singlet);
g.01 (lH, singlet);
5.06 (lH, doublet, J=10.3Hz).
EXAMPLE 1
13~Fluoromilbemycin A4
10 mg of sodium borohydride were added to a solution
842~;
of 90 mg of 13-fluoro-5-ketomilbemycin A4 in 15 ml of
ethanol, and then the mixture was stirred for 15
minutes. At the end of this time, the reaction mixture
was poured into water and extracted with ethyl acetate.
The extract was washed, in turn, with water and with a
saturated aqueous solu~ion of sodium chloride and then
dried over anhydrous magnesium sulphate. The solvent
was removed by distillation and the residue was purified
by column chromatography through silica gel, using the
gradient system of elution with mixtures of hexane and
ethyl acetate ranging from 4:1 to 1:1 by volume, to give
58 mg (yield 65%) of the title compound.
Mass spectrum (m~e): 560 (M~).
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13)
ppm:
3.96 (lH, doublet, J=6.2Hz);
4.05 (lH, singlet);
4.41 (lH, doublet of doublets, J=9.8 ~ 98.8Hz).
Following the procedure described in Example 1, the
compounds of the following Examples 2-10 we~e prepared.
- : .
'
342~;
EXAMPLE 2
13-~P-chlorobenzovlox~)milbemycin A4
Mass spectrum (m/e): 696 (M~), 568, 522.
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13)
ppm:
3.97 (lH, doublet, J=6.2Hz);
5.19 (1H, doublet, J=10.3Hz).
EXAMPLE 3
13-(P-Fluorophenoxyacetoxy)milbemycin A4
Mass spectrum (m/e): 540 (M~ -170), 522, 504.
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13)
ppm:
3.96 (lH, doublet, J=6.2Hz);
5.05 (lH, doublet, J=10.6Hz).
EXAMPLE 4
13-Methox~carbon~loxvmilbemycin A4
Mass spectrum (m~e): 616 (M+).
24
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC133
ppm:
3.96 (lH, doublet, J=6.2Hz);
4.73 (lH, doublet, J=9.9Hz).
EXAMPLE 5
- 13-EthoxYcarbonyloxymilbemvcin A4
Mass spectrum (m/e): 630 (M ).
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13)
ppm:
3.96 (lH, doublet, J=6.2Hz);
4.74 ~lH, doublet, J=10.7Hz).
EXAMPLE 6
13-(2,2,2-Trichloroethoxycarbonyloxy)milbemycin Ag
Mass spectrum (m/e): 732 (M~, calculated Cl as 35).
Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13)
ppm:
3.97 (lH, doublet, J=6.2Hz);
4.68 ~lH, doublet, J=8.8Hz3.
42~
EXAMPLE 7
13-PivaloyloxYmilbemycin D
Nuclear Magnetic Resonance Spectrum (300 MHz, CDC13)
ppm:
1.19 (9H, singlet);
1.56 (3H, broad singlet);
4.90 (lH, doublet, J=10.6Hz).
EXAMPLE 8
13-Pivaloyloxymilbemycin A4
Nuclear Magnetic Resonance Spectrum (300 MHz, CDC13)
ppm:
0.98 (3H, triplet, J=7Hz);
1.20 (9H, singlet);
1.53 (3H, broad singlet);
.90 (lH, doublet, J=10.5Hz).
~ ~B8426
EXAMPLE 9
13-AcetoxYmilbemYcin D
Nuclear Magnetic Resonance Spectrum (300 MHz, CDC13)
ppm:
1.56 (3H, broad singlat);
1.87 (3H, broad singlet);
2.04 (3H, singlet);
4.94 (lH, doublet, J=10.5Hz).
EXAMPLE 10
13-FormYloxYmilbemycin D
Mass spectrum (m~e): 600 (M ), 472, 426, 293, 209,
181, 151.
Nuclear Magnetic Resonance Spectrum (300 M~lz, CDC13)
ppm:
1.56 (3H, broad singlet);
1.87 (3H, broad singlet);
5.05 (lH, doublet, J=10.5Hz);
8.08 (lH, singlet).
:
