JPS61103884A - 13-substituted-5-ketomilbemycin and its preparation - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate of miticide, insecticide and anthelmintic agent, in high yield, by reacting a 5-ketomilbemycin derivative with selenium dioxide in the presence of a carboxylic acid. CONSTITUTION:A mixture of the compounds of formula II and III can be prepared by reacting the compound of formula I (R<1> is methyl, ethyl, isopropyl or sec-butyl) with selenium dioxide in the presence of a carboxylic acid of formula R<2>-COOH (R<2> is H or lower alkyl) at 0-80 deg.C. The amounts of the compounds of formula II and III depend upon the kind of the carboxylic acid and the amount of selenium dioxide, etc. If necessary, the product can be converted completely to the compound of formula II by hydrolysis. When the compound of formula III is required, it can be prepared by separating and purifying from the reaction mixture. The compound of formula III is novel. The amount of the carboxylic acid is >=1mol, and that of selenium dioxide is 1-10mol, preferably 1-3mol per 1mol of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a compound represented by the following general formula (1), which is an important intermediate in the synthesis of acaricides, insecticides and anthelmintic agents, and a compound represented by the general formula ([)]. with respect to the compounds represented.

In the above formula, R represents a methyl group, an ethyl group, an isopropyl group, or a 5ec-butyl group, and R represents a hydrogen atom or a lower alkyl group.

The compound of formula (1) above is disclosed in U.S. Patent No. 4,423,2
According to the above US patent, the compound of formula (I) is a compound known from US Pat. Obtained by treating ether with acid. However, this method has drawbacks in terms of availability of raw materials, reaction conditions such as reaction temperature, yield, etc. In addition, since a mercury compound is used, consideration must be given to pollution control, and the formula ( This is not a satisfactory method for mass synthesis of the compound 1).

In view of the importance of the compound of formula (I) as a synthetic intermediate, the inventors of the present invention have conducted extensive studies on an advantageous method for producing the compound, and as a result, the compound represented by the following general formula ([)] Formula (I) can be efficiently obtained by treatment with selenium dioxide in the presence of a carboxylic acid represented by the following general formula (5).
It was discovered that the compound of

R2-C0OH (g) In the above formula, R and R have the same meanings as defined above.

The compound of formula (1), which is the raw material of the present invention, is
No. 1,011,785 and the above-mentioned US patent.

According to the method of the present invention, by treating a compound of formula (phantom) with selenium dioxide in the presence of a carboxylic acid of formula (5), its 13th position is selectively allylated.

When R in the carboxylic acid of formula (to) is a lower alkyl group, R is preferably a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl. The carboxylic acid of formula (g) is preferably formic acid and acetic acid, more preferably formic acid.

In the method of the invention, when a compound of formula ([) is oxidized with selenium dioxide in the presence of a carboxylic acid of formula (to),
Usually, the compounds of formula (1) and formula ('') are produced simultaneously.The ratio varies depending on the reaction conditions, especially the type of carvone plate of formula (5), the amount of selenium dioxide, etc.
For example, the use of formic acid results in the production of a large amount of the compound of formula (O). The compound of formula (ff) is new and has some acaricidal activity itself, but it has even stronger activity because it has a highly reactive functional group such as a carbonyl group or formyl group at the 13th position. It is also important as an intermediate for deriving compounds.

If the aim is to obtain a compound of formula (1), the reactants of the process according to the invention (usually, as mentioned above, of the formula (
ff) is subjected to a hydrolysis reaction, with or without isolation, to obtain its total Q
It can be a compound of formula (I).

When the purpose is to obtain a compound of formula (■), the reactant of the method of the present invention may be separated and purified by a conventional purification method such as Calem chromatography.

In the reaction of compounds of formula (1) and formula (g), formula (a)
The carboxylic acid is usually used in an amount of 1 mol or more per 1 mol of the compound of formula (II). The carboxylic acid of formula (g) may be used in large excess to serve as a reaction solvent, and this is an advantageous aspect of the present invention.

When using a solvent other than the above-mentioned carboxylic acid, there is no particular limitation as long as it is inert to this reaction. For example, hydrocarbons such as hexane, benzene, methylene chloride, chloroform, etc. halogenated hydrocarbons, ethers such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, esters such as ethyl acetate and amyl acetate, NjN-dimethylformamide, N,N-dimethylacetamide Amides such as dimethyl sulfoxide and water, as well as mixtures of these solvents. .

The amount of selenium dioxide used is 1 mol of the compound of formula (II).
The amount is usually 1 to 10 times, preferably 1 to 3 times, per mole.

The reaction temperature and reaction time are not immediately limited, and the reaction is carried out at 0° C. to 80° C., preferably at room temperature or with slight heating for about 30 minutes to all day and night.

After the reaction is complete, the reactants are treated in a conventional manner. For example, by removing the selenium compound eF from the reaction solution, extracting the product from the P solution with an appropriate organic solvent, and concentrating it, the formula (
A mixture of 1) and (It) is obtained as a crude product.

In order to optionally hydrolyze the compound of formula ('), the above reaction mixture may be isolated or subjected to a conventional hydrolysis reaction without isolation.

Since the compound of formula (1) remains as it is without being adversely affected under normal hydrolysis conditions, there is no need to pre-prepare it in advance for the hydrolysis reaction.

Hydrolysis is carried out in a solvent in the presence of an acid or a base. For example, hydrochloric acid, nitric acid,
Examples include mineral acids such as sulfuric acid, preferably hydrochloric acid, and examples of bases include sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, and carbonate.

The solvent is not particularly limited as long as it does not participate in the reaction, and the carboxylic acid used in the above reaction can be used, as well as alcohols such as methanol, ethanol, propatool, diethyl ether, tetrahydrofuran, and dioxane. ethers and water, as well as mixtures of these solvents, are used.

The reaction temperature and reaction time are not particularly limited, and are usually -
3 at 10°C to 100°C, preferably 0°C to 50°C.
The reaction is carried out for 0 minutes to 15 hours, preferably 1 to 8 hours.

After hydrolysis, the compound of formula (1) can be easily collected from the reaction mixture according to conventional methods. - For example, pour the reaction mixture into water, if necessary after separating the insolubles kP, neutralize solution F and extract with a water-immiscible solvent. After drying the extract, the solvent is distilled off to obtain the compound of formula (1). Furthermore, if necessary, the compound of formula (I) can be purified by conventional methods such as recrystallization and column chromatography. It can also be made of W.

The method of the present invention will be explained in more detail with reference to Examples.

Example 1 Selenium dioxide (0,56P) was added to a formic acid solution (2smz) of 5-ketomilbemycin A4 (2,Of).
Stir at 0°C for 2 hours. After the reaction is complete, add selenium to the reaction solution to separate the selenium compound. The FM is poured into water, extracted with ethyl acetate, and the extract is dried over magnesium sulfate and concentrated to obtain a crude product of 13-formyloxy-5-ketomilbemycin A4 containing a portion of the 13-hydroxy compound. To this crude product, methanol (120 ml), 2 liters of hydrochloric acid (20 ml), and 1,4-dioxane (30 ml) were added, and the mixture was stirred at room temperature for 5 hours. After the reaction is complete, the reaction solution is poured into water and extracted with ethyl acetate.

The organic layer is dried over magnesium sulfate, concentrated, and the residue is purified by column chromatography to obtain the title compound 1.03 f. Yield: 50 cm.

Mass spectrum (m/　); 5ss (u+).

538 (M+-18) Nuclear magnetic resonance spectrum (CDCt,) δ91m: 1.5
9 (s, 3H, C14CH5) 1°8 B (s
, 3 H# Ca CH3) 3.0~3.15 (m
, IH, C25H) 3.5-3, i55 (m,
2H, C17H, C2H) 3.74 ((LjII(,
C43I (, J-10H2) 1.8f+(ε, IH,
C6H) 4.0 (a, I Hz C70H) 4.65~t8
5 (m, 2a, c8ci2) 5.2-5.9 (m s
5 a, c 1sa + C1q Hx c 1
+ Hs C1oa rC2H) 6-48 (t + C3H) 5.55 (t, C3H)
.

Example 2 Acetic acid solution of 5-ketomilbemycin D (0,56P) (
Add selenium dioxide (0.22f) to 10WL,
Stir at 40°C for 1 hour. After the reaction is completed, selenium) 1- is added to the reaction solution, and P is separated from the selenium compound. The P solution was poured into water, extracted with ethyl acetate, the extract was washed with deuterated water, dried over magnesium sulfate, concentrated, and the residue was purified by column chromatography to obtain 13-acetoxy-5-ketomilbemycin DQ, 12f (harvested). (yield 21) and 13-hydroxy-5-ke) milbemycin po, 1ar (yield 3
2%).

13-acetoxy infrared absorption spectrum ν: 34BQ, 1740°a
x 1715.15i85, 1460cIn'ifspec)y(rn/)2612(u+).

594 (M”-18) Nuclear magnetic resonance spectrum (CDC43) δQpm '1.
55 (s, 3H, C14CC14C, 90(s
, 3H, C4CH5) 2.05(a) and 2.07
(s) (3H-CCH3)6-57 (m II
Hs CsH) 13-hydroxy form nujol.

Infrared absorption spectrum ν, 3450°aX 1735.1715,1580crn' Mass spectrum (''/): 5γO (M+).

552 (M+-18) Nuclear magnetic resonance spectrum (cDcz3) δppm '1,
58 (s, 3H, C14CC14C89 (m s
3 H+ C4CH3) 4-6 to 4-8 (ma 2
H-Ca CH2) 5.23 (t, c15H) s, 3-5.45 (m, cllH, cl, H) 5.6-
5.9 (ffi, C9H, C4°H, C, 5H)
6-57 (m 1CsH) i 52 (m , CsH) Methanol (20
d), 2N hydrochloric acid (5M), 1,4-dioxane (10
Add m) and heat and stir at 50°C for 5 hours. After the reaction, 0.015P of 13-
Hydroxy-5-ketomilbemycin D is obtained.

Example 3 A solution of 5-ketomilbemycin D (0,56F) in formic acid (
Add selenium dioxide (0.17F) to 40
Stir at ℃ for 2 hours. After the reaction was completed, celite was added to the reaction solution, and after separating the selenium compound' (i-F), the P solution was poured into water and extracted with ethyl acetate.The concentrated residue of the extract was purified by silica gel column chromatography. ,a,2
r? c yield 44%) and 0.02
The 13-hydroxy form of F is obtained.

13-formyl body Infrared absorption spectrum ν: 355G.

a1 1730.1685.1460cm' Mass spectrum (I11/): 5913CM+).

58G (M+-18) Nuclear magnetic resonance spectrum (CDC73) δppm '1.
56 (s, 3H, C14CH5)L 91 (m
+ 3 Hr C4CHs ) 5.06 (d, IH, C
13H, J-10H2) 5.35-5.45 (m,
3H, C11H, C1,H, C15H)5, 8-5.
9 (m, 2 H, C'9HjC4゜H) $-58
(m + I HICs H)8.09 (m , i
H, -0CHO) 13-formyloxy-5-ketomilbemycin D (0,2(1)
, meta/-# (25d), 1N hydrochloric acid water (10mJ)
, 1,4-dioxane (15rR1) was added, stirred overnight at room temperature, the reaction solution was poured into water, and extracted with ethyl acetate.The concentrated residue of the extract was purified by silica gel column chromatography. 113-hydroxy-5-ketomilbemycin D is obtained.

Procedural amendment (spontaneous) October 1985, Patent Application No. 225551, filed in 1982, 2, title of the invention 13-Substituted-5-ketomilbemycins and their manufacturing process; 3. Relationship with the case of the person making the amendment: Patent issued; Address: 6, 3-1 Nipponkakuhonmachi, Chuo-ku, Tokyo 103 (185) Sankyo Co., Ltd. Representative Director and President Yoshinori Kawamura 4; Agent residence: 140 Sankyo Co., Ltd., 1-2-58 Hiromachi, Honbunagawa-ku, Tokyo 6, subject of amendment 1, page 12 line 1 of the specification, page 13 line 8, page 15 line 1
The word "residue" on line 4 and line 16 on page 16,
Corrected to "residue".

2 Ming, ia! Page 12, line 8 rr3. a~3.15(
m, IH.

C25H) J is replaced with “3-08 (a t-I
H# C25H-J-λ6, 9.7Hz) Correct as J.

F. On page 12 of the specification, lines 14 to 17, “5, 2 to 5
．． 9 (m, 5H1c15H゛, c19H1c11H1c
1oH.

C, H) 6.48 (t jC3H) 5.55 (t
, C31()J, r 5.25(t, IH
, C45H, J-11, THz) 5.35 to 5.5 (m
, 2H, cl, a, C1, H) 5.75-5.9
(m, 2H, C4°H, C,H) 6.55(
m, IH.

C3H)”.

Claims (2)

[Claims] (1) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R^1 represents a methyl group, ethyl group, isopropyl group or sec-butyl group) , general formula (IV) R^2-COOH (IV) (wherein, R^2 represents a hydrogen atom or a lower alkyl group) by treatment with selenium dioxide in the presence of a carboxylic acid represented by the general formula (IV) (where R^2 represents a hydrogen atom or a lower alkyl group). I) or (II)▲Mathematical formula, chemical formula,
There are tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 and R^2 have the same meanings as above) A method for producing a compound represented by general formula (I), which comprises hydrolyzing a compound represented by general formula (II) according to the method. (2) General formula (II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 represents a methyl group, ethyl group, isopropyl group, or sec-butyl group, and R^2 represents hydrogen. atom or lower alkyl group).