JPH0477752B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a compound represented by the following general formula (), which is an important intermediate in the synthesis of acaricides, insecticides, and anthelmintic agents, and to the compound represented by the general formula (). In the above formula, R ¹ represents a methyl group, ethyl group, isopropyl group, or sec-butyl group, and R ² represents a hydrogen atom or a lower alkyl group. The compound of formula () above is disclosed in U.S. Pat.
4423209 and is an important intermediate in the synthesis of acaricides, insecticides and anthelmintics. According to the above-mentioned US patent, compounds of formula ( ) can be obtained by treating 13-hydroxy-5-methoxymilbemycins with mercuric acetate and treating the resulting enol 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 hydroxide compound is used, consideration must be given to pollution control. This is not a satisfactory method for mass synthesis of the compound (). In view of the importance of the compound of formula () as a synthetic intermediate, the present inventors have conducted various studies on an advantageous method for producing the compound, and have found the following general formula ()
It has been discovered that the compound represented by formula () can be efficiently produced by treating the compound represented by formula () with selenium dioxide in the presence of a carboxylic acid represented by the following general formula (). R ² —COOH () In the above formula, R ¹ and R ² have the same meanings as described above. The compound of formula () which is a raw material of the present invention is a known compound described in JP-A-59-103785 and the above-mentioned US patent. According to the method of the invention, a compound of formula ()
By treatment with selenium dioxide in the presence of a carboxylic acid of formula (), the 13th position is regioselectively allyl oxidized. When R ² in the carboxylic acid of formula () is a lower alkyl group, R ² is preferably a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl. , isopropyl, butyl, isobutyl. formula()
The carboxylic acid is preferably formic acid and acetic acid, more preferably formic acid. In the method of the present invention, when a compound of formula () is oxidized with selenium dioxide in the presence of a carboxylic acid of formula (), compounds of formula () and formula () are generally produced simultaneously. The ratio varies considerably depending on the reaction conditions, especially the type of carboxylic acid of formula (), the amount of selenium dioxide, etc. For example, when formic acid is used, the amount of the compound of formula () produced is large. The compound of formula () is new and has some acaricidal activity itself, but it has a highly reactive functional group such as a carbonyl group or formyl group at the 13th position, so it is a compound with even stronger activity. It is also important as an intermediate for inducing If the aim is to obtain a compound of formula (), the reactants of the process of the invention (usually in a mixture with a compound of formula (), as mentioned above) are therefore isolated or isolated. The entire amount can be converted into a compound of formula () by subjecting it to a hydrolysis reaction without separating it. When the purpose is to obtain a compound of formula (), the reaction product of the method of the present invention may be separated and purified by a conventional purification method such as column chromatography. In the reaction of formula () and compound of formula (),
The carboxylic acid of formula () is usually used in an amount of 1 mol or more per 1 mol of the compound of formula (). formula()
It is possible to use a large excess amount of the carboxylic acid to also serve as a reaction solvent, and this is an advantageous embodiment 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, for example, hydrocarbons such as hexane and benzene, halogens such as methylene chloride, and chloroform. hydrocarbons, diethyl ether,
Ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, esters such as ethyl acetate and amyl acetate, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, dimethylsulfoxide and Mention may be made of water as well as mixtures of these solvents. The amount of selenium dioxide used is compound 1 of formula ()
The amount is usually 1 to 10 times the mole, preferably 1 to 3 times the mole. The reaction temperature and reaction time are not particularly limited;
The reaction is carried out at 0°C to 80°C, preferably at room temperature or with slight heating for about 30 minutes to overnight. After the reaction is complete, the reactants are treated in a conventional manner. For example, remove the selenium compound from the reaction solution, extract the product from the solution with an appropriate organic solvent,
Upon concentration, a mixture of formulas () and () 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. The compound of formula () remains intact under normal hydrolysis conditions without being adversely affected, so it is not necessary to isolate it before the hydrolysis reaction. Hydrolysis is carried out in a solvent in the presence of an acid or base. Examples of acids used include mineral acids such as hydrochloric acid, nitric acid, and sulfuric acid, preferably hydrochloric acid; examples of bases include sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc. It will be done. The solvent is not particularly limited as long as it does not participate in the reaction, and in addition to the carboxylic acid used in the above reaction, methanol, ethanol,
Alcohols such as propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and water, as well as mixtures of these solvents are used. The reaction temperature and reaction time are not particularly limited;
Usually -10°C to 100°C, preferably 0°C to 50°C
The reaction is carried out at 0.degree. C. for 30 minutes to 15 hours, preferably 1 to 8 hours. After hydrolysis, the compound of formula () can be easily recovered from the reaction mixture according to conventional methods. For example, the reaction mixture is poured into water, and if necessary, after separating off insoluble materials, the liquid is neutralized and extracted with a water-immiscible solvent. After drying the extract, the solvent is distilled off to obtain a compound of formula (). Furthermore, if necessary, the compound of formula () can be purified by conventional methods such as recrystallization and column chromatography. The method of the present invention will be explained in more detail with reference to Examples. Example 1 13-Hydroxy-5-ketomilbemycin A ₄
(R ¹ = C ₂ H ₅ ) Selenium dioxide (0.56 g) was added to a formic acid solution (25 ml) of 5-ketomilbemycin A ₄ (2.0 g), and the mixture was heated at 40°C.
Stir for 2 hours. After the reaction is completed, celite is added to the reaction solution to separate the selenium compound. The solution 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 13-hydroxy compound. In this crude product,
Methanol (120ml), 2N hydrochloric acid (20ml), 1,
Add 4-dioxane (30 ml) and stir 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 1.03 g of the above compound. Yield 50%. Mass spectrum (m/e); 556 (M ⁺ ), 538 (M ⁺
−18) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 1.59 (s, 3H, C ₁₄ CH ₃ ) 1.88 (s, 3H, C ₄ CH ₃ ) 3.08 (dt, 1H, C ₂₅ H, J = 2.6, 9.7 Hz) 3.5 to 3.65 (m, 2H, C ₁₇ H, C ₂ H) 3.74 (d, 1H, C ₁₃ H, J=10Hz) 3.86 (s, 1H, C ₆ H) 4.0 (s, 1H, C ₇ OH) 4.65 to 4.85 (m, 2H, C ₈ CH ₂ ) 5.25 (t, 1H, C ₁₅ H, J = 8.1Hz) 5.35 to 5.5 (m, 2H, C ₁₉ H, C ₁₁ H) 5.75 to 5.9 ( m, 2H, C ₁₀ H, C ₉ H) 6.55 (m, 1H, C ₃ H) Example 2 13-Hydroxy-5-ketomilbemycin D and
13-cicetoxy-5-ketomilbemycin D
(R ¹ = i-C ₃ H ₇ ) Selenium dioxide (0.22 g) was added to an acetic acid solution (10 ml) of 5-ketomilbemycin D (0.56 g), and 40
Stir at ℃ for 1 hour. After the reaction is completed, celite is added to the reaction solution to separate the selenium compound. The liquid 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 D0.12g
(yield 21%) and 0.18 g (yield 32%) of 13-hydroxy-5-ketomilbemycin D were obtained. 13-acetoxy form Infrared absorption spectrum ν ^KBr _nax : 3480, 1740,
1715, 1685, 1460 cm ^-1 Mass spectrum (m/e): 612 (M ⁺ ), 594 (M ⁺
−18) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 1.55 (s, 3H, C ₁₄ CH ₃ ) 1.90 (s, 3H, C ₄ CH ₃ ) 2.05 (s) and 2.07 (s) (3H,

[Formula]) 6.57 (m, 1H, C ₃ H) 13-hydroxy form Infrared absorption spectrum ν ^nujol _nax : 3450, 1735,
1715, 1580cm ^-1 Mass spectrum (m/e): 570 (M ⁺ ), 552 (M ⁺
−18) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 1.58 (s, 3H, C ₁₄ CH ₃ ) 1.89 (m, 3H, C ₄ CH ₃ ) 4.6-4.8 (m, 2H, C ₈ CH ₂ ) 5.23 ( t, C ₁₅ H) 5.3 to 5.45 (m, C ₁₁ H, C ₁₉ H) 5.6 to 5.9 (m, C ₉ H, C ₁₀ H, C ₁₅ H) 6.57 (m, C ₃ H) 6.52 (m, C ₃ H) 13-acetoxy-5 obtained by the above method
- Methanol (20 ml), 2N hydrochloric acid (5 ml), and 1,4-dioxane (10 ml) were added to ketomilbemycin D (0.10 g), and the mixture was heated and stirred at 50°C for 5 hours. After the reaction is completed, 0.015 g of 13-hydroxy-5-ketomilbemycin D is obtained by post-treatment similar to the hydrolysis of 13-formyloxy-5-ketomilbemycin _A4 . Example 3 13-Formyloxy-5-ketomilbemycin D ( ^R1 = i _{- C3H7} ) Selenium dioxide (0.17 g) was added to a formic acid solution (10 ml) of 5-ketomilbemycin D (0.56 g),
Stir at 40°C for 2 hours. After the reaction is complete, celite is added to the reaction solution to separate the selenium compound, then the solution is poured into water and extracted with ethyl acetate. The concentrated residue of the extract is purified by silica gel column chromatography to obtain 0.27 g (yield 44%) of 13-formyl compound and 0.02 g of 13-hydroxy compound. 13-formyl compound Infrared absorption spectrum ν ^KBr _nax : 3550, 1730,
1685, 1460cm ^-1 Mass spectrum (m/e): 598 (M ⁺ ), 580 (M ⁺
−18) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 1.56 (s, 3H, C ₁₄ CH ₃ ) 1.91 (m, 3H, C ₄ CH ₃ ) 5.06 (d, 1H, C ₁₃ , H, J = 10Hz) 5.35 to 5.45 (m, 3H, C ₁₁ H, C ₁₉ , C ₁₅ H) 5.8 to 5.9 (m, 2H, C ₉ H, C ₁₀ H) 6.58 (m, 1H, C ₃ H) 8.09 (m, 1H , -OCHO) To 13-formyloxy-5-ketomilbemycin D (0.20 g) obtained by the above method, methanol (25 ml), 1N hydrochloric acid water (10 ml), 1,4-
Add dioxane (15 ml) and stir overnight at room temperature.
Pour the reaction solution into water and extract with ethyl acetate. The concentrated residue of the extract was purified by silica gel column chromatography to obtain 0.14 g of 13-hydroxy-
5-Ketomilbemycin D is obtained. Example 4 13-Hydroxy-5-ketomilbemycin A ₄
+A ₃ (3:1 mixture of R ¹ = C ₂ H ₅ and R ¹ = CH ₃ ) Mixture of 5-ketomilbemycin A ₄ and 5-ketomilbemycin A ₃ (mixture ratio A ₄ /A ₃ = 3/1 )
Selenium dioxide (3.83 g) was added to a formic acid solution (8.7 ml) of (12.44 g) and stirred at 40°C for 2 hours. After the reaction was completed, celite was added to the reaction solution, and the selenium compound was filtered off. The filtrate was poured into water, extracted with ethyl acetate, and the extract was dried over magnesium sulfate and concentrated.
A crude product of 13-formyloxy-5-ketomilbemycin A ₄ +A ₃ containing a portion of 13-hydroxy compound was obtained. To this crude product was added methanol (200 ml), 2
Normal hydrochloric acid (50ml), 1,4-dioxane (100ml)
ml) and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate.
The organic layer was dried over magnesium sulfate, concentrated, and the residue was purified by column chromatography to obtain 5.59 g (yield: 44%) of the title compound. Mass spectrum (m/e): 556 (M ⁺ forR ¹ =
C ₂ H ₅ ), 542 (M ⁺ forR ¹ = CH ₃ ), 538 (M ⁺ −
18), 524 (M ⁺ −18) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 3.01−3.15 (m, 0.75H, C ₂₅ H CH ₂ CH ₃ ),
3.28 (m, 0.25H, C ₂₅ H CH ₃ ), 3.73 (d,
1H, C ₁₃ H, J = 10Hz), 3.86 (s, 1H,
C ₆ H), 3.99 (s, 1H, C ₇ OH), 4.71 (br.s,
2H, C ₈ CH ₂ ), 5.22 (m, 1H, C ₁₅ H),
5.32−5.51 (m, 2H, C ₁₁ , C ₁₉ H), 5.60−
5.91 (m, 2H, C ₉ H, C ₁₀ H), 6.54 (br.s,
1H, _C3H )

Claims (1)

[Claims] 1 General formula () (In the formula, R ¹ represents a methyl ^group , an ethyl group, an isopropyl group, or a sec ^- butyl group). is treated with selenium dioxide in the presence of a carboxylic acid represented by the general formula () or (). (wherein R ¹ and R ² have the same meanings as defined above), and if necessary, the compound of general formula () is hydrolyzed. ) A method for producing a compound represented by