Preparation of a macrocyclic lactone

Details Preparation of a macrocyclic lactone Preparation of a macrocyclic lactone

2002-05-08

2004-10-26

Lilling, Herbert J. (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound containing saccharide radical

Reexamination Certificate

active

06808903

ABSTRACT:

The present invention relates to a process for the preparation of a macrocyclic lactone, a process for the preparation of the intermediate compounds and the intermediate compounds used in the said process. More particularly the invention relates to a process for the preparation a compound of the formula
in which
R
1
-R
9
represent, independently of each other hydrogen or a substituent,
m is 0, 1 or 2;
n is 0, 1, 2 or 3; and
the bonds marked with A, B, C, D, E and F indicate, independently of each other, that two adjacent carbon atoms are connected by a double bond, a single bond, a single bond and a epoxide bridge of the formula
or a single bond and a methylene bridge of the formula
including, where applicable, an E/Z isomer, a mixture of E/Z isomers, and/or a tautomer thereof, in each case in free form or in salt form, which process comprises,
1) bringing a compound of the formula
wherein
R
1
-R
7
, m, n, A, B, C, D, E and F have the same meanings as given for formula (I) above, into contact with a biocatalyst that is capable of specifically oxidising the alcohol at position 4″ in order to form a compound of the formula
in which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, m, n, A, B, C, D, E and F have the meanings given for formula (I); and
2) reacting the compound of the formula (II) with an amine of the formula HN(R
8
)R
9
, wherein R
8
and R
9
have the same meanings as given for formula (I), and which is known, in the presence of a reducing agent;
and, in each case, if desired, converting a compound of formula (I) obtainable in accordance with the process or by another method, or an E/Z isomer or tautomer thereof, in each case in free form or in salt form, into a different compound of formula (I) or an E/Z isomer or tautomer thereof, in each case in free form or in salt form, separating a mixture of E/Z isomers obtainable in accordance with the process and isolating the desired isomer, and/or converting a free compound of formula (I) obtainable in accordance with the process or by another method, or an E/Z isomer or tautomer thereof, into a salt or converting a salt, obtainable in accordance with the process or by another method, of a compound of formula (I) or of an E/Z isomer or tautomer thereof into the free compound of formula (I) or an E/Z isomer or tautomer thereof or into a different salt.
Methods of synthesis for the compounds of formula (I) are described in the literature. It has been found, however, that the processes known in the literature cause considerable problems during production basically on account of the low yields and the tedious procedures which have to be used. For example EP-A 0 465 121 discloses 4″-Keto- and 4″-amino-4″-deoxy avermectin compounds and substituted amino derivatives thereof. The 4″ hydroxy group on the avermectin compounds are oxidized to a ketone group or replaced with a (substituted) amino group. The hydroxy groups at the 5 and 23-positions need to be protected in order to avoid unwanted oxidations. The 4″-keto compound is aminated to provide the compound corresponding to that of formula (I) above. Accordingly, the known processes are not satisfactory in that respect, giving rise to the need to make available improved preparation processes for those compounds.
The compounds (I), (II) and (III) may be in the form of tautomers. Accordingly, herein-before and hereinafter, where appropriate the compounds (I), (II) and (III) are to be understood to include corresponding tautomers, even if the latter are not specifically mentioned in each case.
The compounds (I), (II) and (III) are capable of forming acid addition salts. Those salts are formed, for example, with strong inorganic acids, such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as unsubstituted or substituted, for example halo-substituted, C
1
-C
4
alkanecarboxylic acids, for example acetic acid, saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric or phthalic acid, hydroxycarboxylic acids, for example ascorbic, lactic, malic, tartaric or citric acid, or benzoic acid, or with organic sulfonic adds, such as unsubstituted or substituted, for example halo-substituted, C
1
-C
4
alkane- or aryl-sulfonic acids, for example methane- or p-toluene-sulfonic acid. Furthermore, compounds of formula (I), (II) and (III) having at least one acidic group are capable of forming salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, diethyl-, triethyl- or dimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lower alkylamine, for example mono-, di- or tri-ethanolamine. In addition, corresponding internal salts may also be formed. Preference is given within the scope of the invention to agrochemically advantageous salts. In view of the close relationship between the compounds of formula (I), (II) and (III) in free form and in the form of their salts, any reference hereinbefore or hereinafter to the free compounds of formula (I), (II) and (III) or to their respective salts is to be understood as including also the corresponding salts or the free compounds of formula (I), (II) and (III), where appropriate and expedient. The same applies in the case of tautomers of compounds of formula (I), (II) and (III) and the salts thereof. The free form is generally preferred in each case.
Preferred within the scope of this invention is a process for the preparation of compounds of the formula (I), in which
n is 1;
m is 1;
A is a double bond;
B is single bond or a double bond,
C is a double bond,
D is a single bond,
E is a double bond,
F is a double bond; or a single bond and a epoxy bridge; or a single bond and a methylene bridge;
R
1
, R
2
and R
3
are H;
R
4
is methyl;
R
5
is C
1
-C
10
-alkyl, C
3
-C
8
-cycloalkyl or C
2
-C
10
-alkenyl;
R
6
is H;
R
7
is OH;
R
8
and R
9
are independently of each other H; C
1
-C
10
-alkyl or C
1
-C
10
-acyl; or together form —(CH
2
)
q
—; and
q is 4, 5 or 6.
Especially preferred within the scope of this invention is a process for the preparation of a compound of the formula (I) in which
n is 1;
m is 1;
A, B, C, E and F are double bonds;
D is a single bond;
R
1
, R
2
, and R
3
are H;
R
4
is methyl;
R
5
is s-butyl or isopropyl;
R
6
is H;
R
7
is OH;
R
8
is methyl
R
9
is H.
Very especially preferred is a process for the preparation of Emamectin, more particularly the benzoate salt of Emamectin. Emamectin is a mixture of 4″-deoxy-4″-N-methylamino avermectin B
1a
/B
1b
and is described in U.S. Pat. No. 4,4874,749 and as MK-244 in Journal of Organic Chemistry, Vol. 59 (1994), 7704-7708. Salts of emamectin that are especially valuable agrochemically are described in U.S. Pat. No. 5,288,710. The compounds of the formula (I) are valuable pesticides, especially for combating insect and representatives of the order Acarina. The pests mentioned include, for example, those that are mentioned on page 5, lines 55 to 58, page 6 and page 7, lines 1 to 21 in European Patent Application EP-A 736,252. The pests mentioned therein are included thereto in the present subject matter of the invention.
The general terms used hereinbefore and hereinafter have the following meanings, unless defined otherwise:
Carbon-containing groups and compounds each contain from 1 up to and including 8, preferably from 1 up to and including 6, especially from 1 up to and including 4, and more especially 1 or 2, carbon atoms.
Alkyl is either straight-chained, i.e. methyl, ethyl, propyl, butyl, pentyl or hexyl, or branched, e.g. isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl or isohexyl.
Alkeyl, both as a group per se and as a structural element of other groups and compounds, for example haloalkenyl and

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