JPH0471064B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing unsaturated nitriles, and more particularly to (In the formula, R represents a hydrocarbon group, and A is CH ₂ −
It represents CH ₂ or CH=CH, and n represents an integer from 0 to 10. ) By halogenating or esterifying the 4-hydroxy-2-alkenenitrile represented by the general formula (In the formula, R, A and n are as defined above, and X represents a halogen atom or an acyloxy group.) A general formula characterized by subjecting to HX removal reaction (where X is as defined above) (In the formula, R, A and n are as defined above.) Unsaturated nitrile [hereinafter referred to as unsaturated nitrile ()]. ] related to the manufacturing method. Unsaturated nitriles () are useful as synthetic intermediates for vitamin A, vitamin A acid, β-carotene, and the like. Also, αβ, γδ, εζ-unsaturated carboxylic acids or derivatives thereof, such as JP-A-56-140949
No. 57-31615, No. 57-106618 or the same
It has been reported that the compounds described in Publication No. 57-106638 have excellent physiologically active effects such as anticancer effects, and the unsaturated nitriles () produced by the method of the present invention are synthetic intermediates of these compounds. It is also useful as Recently, Nogami et al. have shown that the reaction of alkenyl ketones (e.g. geranylacetone or neryl acetone) with phenylsulfinyl acetonitrile in methanol solvent in the presence of piperidine gives 4-4-
It has been found that hydroxy-2-alkenenitrile can be obtained. This method uses alkenyl ketones with saturated α and β positions that can be easily produced industrially.
This is an interesting method for terpene chain elongation that involves a two-carbon carbonization reaction accompanied by an oxidation reaction. However, the 4-hydroxy-2-alkenenitrile obtained by this method has only been applied to the synthesis of furan derivatives or carene derivatives [Tetrahedron Letters 22, 4489 (1981);
ibid. 22 , 2187 (1981)], it was not possible to derive an unsaturated nitrile () in good yield by directly subjecting this compound to a dehydration reaction. The inventors of the present invention conducted intensive studies to develop 4-hydroxy-2-alkenenitrile products with the above-mentioned industrial advantages into higher value-added products. α,β-unsaturated nitrile represented by the general formula () is obtained by conversion or esterification, and then the α,β-unsaturated nitrile is de-HX
(Reaction, ie, dehydrohalogenation reaction or decarboxylation reaction), it was discovered that unsaturated nitrile (2) can be obtained in good yield, and the present invention was completed. Furthermore, the unsaturated nitrile () produced by the method of the present invention can be converted into vitamin A or useful αβ, γδ, εζ by conventional conversion means.
- It was possible to derive unsaturated carboxylic acids, etc., and in this case, the pure target product could be easily isolated by conventional separation means such as silica gel chromatography. In the general formulas (), () and (), R is a hydrocarbon group, particularly preferably a 2-methyl-1-propen-1-yl group, a 2,6,6-trimethyl-
Represents a 1-cyclohexen-1-yl group, a lower alkyl group, a lower alkoxy group, or a phenyl group optionally substituted with a halogen atom. Further, A represents CH ₂ -CH ₂ or CH-CH, n represents an integer from 0 to 10, and when n≧2, n A's may be the same or different. In the general formula (), X is a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, or an aliphatic or aromatic acyloxy group such as an acetyloxy group, a propionyloxy group, a butyryloxy group, a benzoyloxy group, or a p-methylbenzoyloxy group. represents a group. As mentioned above, the α,β-unsaturated nitrile of general formula () can be easily derived from 4-hydroxy-2-alkenenitrile. α, β of general formula () where X is a halogen atom
-Unsaturated nitrile can be obtained by reacting 4-hydroxy-2-alkenenitrile of the general formula () with 1 equivalent or more of triphenylphosphine in a tetrahalogenated carbon solvent at an internal temperature of 10°C to reflux temperature. I can do it. Carbon tetrachloride is preferably used as the solvent. α of the general formula () where X is an acyloxy group,
β-Unsaturated nitrile can be obtained by reacting 4-hydroxy-2-alkenenitrile of the general formula () with a carboxylic acid or a reactive derivative thereof (carboxylic acid anhydride, carboxylic acid halide, etc.), and is preferably can be obtained by reacting 1 to 2 equivalents of carboxylic acid anhydride at room temperature in the presence of 1 equivalent or more of pyridine. Note that at this time, pyridine may be diluted with a solvent such as benzene, toluene, or diethyl ether. In the HX removal reaction in the method of the present invention, when the α,β-unsaturated nitrile of the general formula () in which X is a halogen atom is 1 equivalent or more, preferably 1 to 10 equivalents of 1,8-diazabicyclo( 5・4・0)-7
- By using strong organic basic compounds such as undecene (DBU), 1,5-diazabicyclo(4.3.0)-5-nonene, and 1,4-diazabicyclo(2.2.0) octane as a de-HX agent. It can be carried out. In this case, the reaction can be carried out at a wide temperature range from 10 to 150°C. If desired, the HX removal reaction can be carried out in a hydrocarbon solvent such as benzene, toluene, xylene, hexane, heptane, or the like. In particular, in the case of α,β-unsaturated nitrile of the general formula () where X is an acyloxy group, the reaction temperature is 10 to 100°C in a solvent such as benzene or toluene.
The decarboxylation reaction can be easily carried out by allowing a zero-valent palladium complex such as tetrakistriphenylphosphine palladium to act on the starting nitrile in an amount of about 0.1 to 10 mol %. As mentioned above, 4-hydroxy- of the general formula ()
2-Alkenenitrile cannot be led to unsaturated nitrile (2) in good yield by directly subjecting it to a dehydration reaction, but the 4-hydroxy-2-
The desired unsaturated nitrile () can be easily obtained by halogenating or esterifying an alkene nitrile to lead to an α,β-unsaturated nitrile of the general formula (), and then dehydrohalogenating or decarboxylating this. It can be obtained in high yield. The unsaturated nitriles () obtained by the process of the invention can be functionally converted into the corresponding aldehydes, carboxylic acids or alcohols by conventional methods. For example, to convert a nitrile group into an aldehyde group, it is easy to use a reducing agent such as diisobutylaluminum hydride, and the obtained aldehyde group can be easily converted into a carboxy group using a general-purpose oxidizing reagent such as silver oxide. can be induced. Furthermore, aldehydes can be converted to the corresponding alcohols using reducing agents such as lithium aluminum hydride and sodium borohydride. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 4-chloro-9-(2,6,6
-trimethyl-1-cyclohexen-1-yl)
-3,7-dimethyl-2,6,8-nonatrienenitrile 0.57 g, 1,8-diazabicyclo(5.
1.13 g of 4.0)-7-undecene (DBU) and 5 ml of dry benzene were taken and stirred at an internal temperature of 45 to 50°C for 12 hours and then at an internal temperature of 55 to 60°C for 10 hours. The reaction mixture was poured into a 10% by weight acetic acid aqueous solution and extracted with benzene. The benzene extract was thoroughly washed with water and then dried over anhydrous sodium sulfate. Benzene was removed using an evaporator, and the remaining oil was subjected to silica gel chromatography [Developing solution: ethyl acetate/
Hexane = 1/9 (volume ratio)], oil content 0.36g
I got it. This product is 9-(2,
6,6-trimethyl-1-cyclohexene-1-
It was confirmed to be yl)-3,7-dimethyl-2,4,6,8-nonatraenenitrile. Infrared absorption spectrum (cm ^-1 ): 2960, 2930,
2860, 2210, 1580, 1450, 970 Reference example 1 (Conversion to vitamin A acetate) 9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7- obtained in Example 1 Dimethyl-2,4,6,8-nonatraenenitrile
0.31 g was dissolved in 10 ml of hexane, and the internal temperature was cooled to -30°C. Next, a hexane solution containing 0.287 g of diisobutyl aluminum hydride was added.
1.15 ml was gradually added dropwise. After dropping, the cooling bath was removed and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The ether extract was washed with water and then dried over anhydrous sodium sulfate. Ether was removed using an evaporator, and the remaining oil was subjected to silica gel chromatography [developing solution: ethyl acetate/hexane = 1/9 (volume ratio)] to obtain 021 g of oil. Next, 0.21 g of this oil was dissolved in 10 ml of ethanol. Next, in this, sodium borohydride
5 ml of an ethanol solution containing 0.014 g was added under water cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into water, extracted with diethyl ether, the extract was washed with water, and then dried over anhydrous sodium sulfate. Remove ether with evaporator, oil content 0.19
I got g. Further, 0.19 g of this oil was dissolved in 5 ml of pyridine, and then 0.2 g of acetic anhydride was added thereto at room temperature, followed by stirring for 3 hours. The reaction mixture was poured into a 10% by weight acetic acid aqueous solution and extracted with hexane. After washing the hexane extract with water, it was dried over anhydrous sodium sulfate. Hexane was removed using an evaporator to obtain 0.21 g of oil. The infrared absorption spectrum of this product matched that of commercially available vitamin A acetate, and further high performance liquid chromatography analysis [column: μ-Porasil; developing solution: isopropyl ether/hexane = 1/9 (volume ratio)]
As a result, this product has over 95% purity of vitamin A.
Contains acetate. Example 2 2.5 g of 4-hydroxy-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenenitrile was dissolved in 10 ml of carbon tetrachloride. To this was added 3.5 g of triphenylphosphine, and after purging with nitrogen, the mixture was stirred at room temperature all day and night. After the reaction is complete,
Carbon tetrachloride was removed using an evaporator, and the remaining oil was directly purified by silica gel chromatography (developing solution: hexane) to obtain 4-chloro-
3,7,11,15-tetramethyl-2,6,10,14
-1.86 g of hexadecatetraenenitrile was obtained.
(yield 70%). The infrared absorption spectrum of this product is as follows. Infrared absorption spectrum (cm ^-1 ): 2970, 2930,
2850, 2210, 1630, 1435, 1380 1.86 g of the above 4-chloro-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenenitrile was dissolved in 5 ml of dry benzene, and then
1.5 ml of DBU was added and stirred at room temperature for 20 hours.
Water was poured into the reaction mixture and extracted with benzene. The benzene extract was thoroughly washed with water and then dried over anhydrous sodium sulfate. Benzene was removed using an evaporator, and the remaining oil was subjected to silica gel chromatography [Developing solution: benzene/hexene = 4/
1 (volume ratio)] to obtain 1.35 g of oil. This product was confirmed to be 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenenitrile based on the following analysis results. Yield 82%. Infrared absorption spectrum (cm ^-1 ): 3050, 2960,
2920, 2850, 2200, 1630, 1605, 1565, 1440,
1370, 1340, 1215, 950, 750 Examples 3 to 4 The same operation as in Example 2 was performed on the 4-hydroxy-2-alkenenitrile listed in Table 1 to obtain the desired unsaturated nitrile (). The results are shown in Table 1. [Table] Example 5 2.0 g of 4-hydroxy-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenenitrile was dissolved in 15 ml of diethyl ether, and 0.8 ml of pyridine and anhydrous 1.3 ml of acetic acid was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with diethyl ether. The ether extract was washed with a saturated aqueous sodium bicarbonate solution, then washed three times with water, and then dried over anhydrous sodium sulfate. After removing the ether with an evaporator, the remaining oil was subjected to silica gel chromatography [developing solution: ethyl acetate/hexane = 1/10 (volume ratio)] to obtain 4-acetoxy-3,7,11,15
2.2 g of -tetramethyl-2,6,10,14-hexadecatetraenenitrile was obtained. The infrared absorption spectrum of this product is as follows. Infrared absorption spectrum (cm ^-1 ): 2970, 2930,
2850, 2210, 1740, 1630, 1435, 1370, 1230,
1020 Next, this product was dissolved in 10 ml of diethyl ether, 138 mg of tetrakistriphenylphosphine palladium was added, and the mixture was stirred at an internal temperature of 40°C for 2 hours. After the reaction, diethyl ether was removed and the remaining oil was subjected to silica gel chromatography [developing solution: ethyl ether/hexane = 1/10 (volume ratio)] to obtain 3,7,11,15-tetramethyl-2. ,6,
1.76 g of 10,14-hexadecapentaenenitrile was obtained. Overall yield 93%. The infrared absorption spectrum of this product matched that of Example 2. Reference example 2 (3,7,11,15-tetramethyl-2,6,
10,14-hexadecapentaenoic acid synthesis) 1.0 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecapentaenonitrile obtained in Example 2 was dissolved in 10 ml of ethyl ether. While cooling in an ice bath, add 3 ml of dibutylaluminum hydride (1.76 M in hexane),
Stirred at that temperature for 1.5 hours. After the reaction was stopped by adding an aqueous ammonium chloride solution, the mixture was extracted with diethyl ether. The ether extract was washed with water and then dried over anhydrous sodium sulfate. After removing diethyl ether, silica gel tomatography of the remaining oil [Developing solution: ethyl ether/hexane =
1/10 (volume ratio)] to obtain 0.75 g of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenaldehyde. This product was dissolved in 2.2 ml of t-butyl alcohol, added dropwise into silver oxide prepared in advance from an aqueous solution of 1.06 g of silver nitrate and 0.53 g of sodium hydroxide, and stirred at room temperature for 10 hours. After the reaction, the solid matter was separated, and the liquid was made weakly acidic with diluted hydrochloric acid and then extracted with diethyl ether. The ether extract was washed with water and then dried over anhydrous sodium sulfate. Diethyl ether was removed to obtain 0.41 g of pale yellow oil. This compound was found to have 3,7,11,15-tetramethyl-2, as its infrared absorption spectrum matched that of the compound described in JP-A-56-140949.
It was confirmed to be 4,6,10,14-hexadecapentaenoic acid.

Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrocarbon group, and A is CH ₂ −
It represents CH ₂ or CH=CH, and n represents an integer from 0 to 10. ) By halogenating or esterifying the 4-hydroxy-2-alkenenitrile represented by the general formula (In the formula, R, A and n are as defined above, and X represents a halogen atom or an acyloxy group.) A general formula characterized by subjecting to HX removal reaction (where X is as defined above) (In the formula, R, A and n are as defined above.) A method for producing an unsaturated nitrile represented by the following. 2 In the general formula (), X is a chlorine atom,
The manufacturing method according to claim 1, wherein the dehydrochlorination reaction is carried out using 1,8-diazabicyclo(5.4.0)-7-undecene. 3. The manufacturing method according to claim 1, wherein in the general formula (), X is an acetyloxy group, and the acetic acid removal reaction is carried out using tetrakistriphenylphosphine palladium.