JPH082805B2 - Method for producing ω-chloro-trans olefin compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to E-4-tridecenyl acetate and E-11-tetradecenyl acetate, which are the sex pheromone components of tomato pinworm and Chacocha scutellariae, Furthermore, a general formula useful as an intermediate for E-3-hexadecenoic acid, which is one of unsaturated fatty acids in plant lipids, etc. The present invention relates to a method for efficiently producing a ω-chloro-transolefin compound represented by the formula (wherein R and n are the same as above).

(Prior Art) It is very important to obtain a trans-olefin compound stereospecifically in the field of synthesis of organic natural products. Examples of this synthetic method include a Wittig reaction, a triple bond hydrogenation reaction (Birch reduction), a elimination reaction, and an isomerization reaction.

(Problems to be Solved by the Invention) However, the reaction (1) requires a special phosphoralidene compound, and the product is usually accompanied by a cis isomer. Requires an excess alkali metal-liquid ammonia reactor and an expensive metal hydride, is difficult to handle, and is not applicable to those having a functional group other than the OH group.
The reaction is poor in stereospecificity, and the operation of leading to a functional group to be eliminated is complicated. The product may be a mixture of cis-trans and the position of the double bond may move. As described above, the known technique has advantages and disadvantages and no industrially satisfactory method is known.

(Means for Solving the Problems) The present inventors more simply and stereospecifically formulae As a result of investigating a method for synthesizing a trans-olefin compound represented by the formula, when a trans allyl acetate substituted with chloro at the ω-position and a Grignard reagent are reacted in the presence of a copper catalyst as shown in the following formula, the trans configuration The present invention was completed by finding that the following ω-chloro-trans-olefin compound can be obtained while the above is retained.

(Wherein R is a linear, branched, or silyl group-substituted alkyl group, alkenyl group, or aryl group, X is a halogen atom, and n is an integer of 2 to 10). Since the above Grignard reagent only needs to be dropped into ω-chloro-transallylacetate, the process is very simple, and the trans configuration of the ω-chloro-transolefin compound produced is at least trans: cis. 95: 5 and above,
The trans configuration of trans allyl acetate is retained.

The trans allyl acetate substituted at the ω-position used in this reaction is a Grignard reagent represented by the general formula XMgC≡C (CH ₂ ) _n Cl (wherein X is a halogen atom and n is an integer of 2 to 10). It is reacted with orthoformate trialkyl ester to give an acetal compound, which is hydrogenated, hydrolyzed and converted into ω-chloro-α, β-unsaturated aldehyde, which is reduced and acetylated to obtain the compound. It is preferable that it is

Since the chloro group of the reaction product according to the present invention remains as it is without participating in the reaction, it can be easily developed into another reaction and is useful as an intermediate. For example, Tomato Pinworm (Ke
E-4, a sex pheromone of iferia Iycopersicella)
-Tridecenyl Acetate, Phyllono
rycterningoniela) sex pheromone E, Z-4,10-
It is effective for the synthesis of compounds having a trans double bond such as tetradecadienyl acetate and E-3-hexadecenoic acid which is one of unsaturated fatty acids in plant lipids.

Hereinafter, the details of the present invention will be described together with the reaction formula. As described above, the present invention uses chloro-substituted transallylacetate as the main raw material. A suitable method for producing this compound is as follows. First, a compound of the general formula XMgC≡C (CH ₂ ) _n Cl (wherein X
Is a Grignard reagent represented by a halogen atom n is an integer of 2 to 10, specifically 4-chloro-1-yl magnesium chloride, 5-chloro-pentyn-1-yl magnesium chloride, 6-chloro-1-hexyne -1-yl magnesium chloride, 12-chloro-1-dodecin-1-
Ilmagnesium bromide and the like orthoformate trialkyl ester are added in equivalence to tetrahydrofuran (hereinafter
THF), n-butyl ether, toluene, xylene, etc. alone or in a mixed solvent at 60 to 100 ° C. for 10 to 30
The reaction is carried out by heating at 80 to 95 ° C. for 15 to 20 hours to give an acetal compound. In this case, it is preferable to use ethyl orthoformate as the orthoformate trialkyl ester because it is easily available.

After the reaction, the acetal compound obtained by distillation is obtained by using P-2Ni, Pd-BaSO ₄ or the like as a catalyst in a ratio of 0.001 to 0.1 equivalent to the reaction substrate, and a hydrogen pressure of 1 to 10 kg / c.
The hydrogenation reaction is performed at m ² and temperature of 10 to 50 ° C. for 0.5 to 3 hours. After the reaction, dilute 2-3 times with a solvent such as n-hexane or methylene chloride, hydrolyze with 20% hydrochloric acid water or formic acid, and remove the solvent under neutral conditions to obtain the corresponding aldehyde ω- Leads to chloro-trans alkenal.

The product ω-chloro-transalkenal was obtained after selective reduction of its formyl group with a reducing agent such as sodium borohydride or lithium aluminum hydride in an amount of 0.5 to 3.0 times equivalent to the aldehyde. The OH group thus obtained is acetylated to obtain ω-chloro-transallylacetate which is the main raw material of the present invention.

In addition, if this reduction is attempted with lithium aluminum hydride, the reducing power is too strong and the chloro group may also be reduced, and the reaction at low temperature in a short time is unavoidable. Is preferably used in 1.0 to 1.5 times equivalent and the reaction is preferably carried out in THF so as not to exceed 40 ° C.

On the other hand, acetylation is carried out in the presence of an equivalent amount of a base such as pyridine or triethylamine, using 300 to 600 g of methylene chloride, n-hexane or THF as a solvent per mole at 0 to 50 ° C. or acetyl chloride or anhydrous. React with acetic acid. After the reaction, water may be added to remove the organic layer, the solvent may be removed, and distillation may be performed.

General formula according to the invention The ω-chloro-trans olefin compound represented by the formula (wherein R and n are the same as those described above) is obtained by the above-mentioned procedure and is substituted with chloro-substituted transallylacetate and the general formula RCH ₂ MgX R is a linear, branched, or silyl group-substituted alkyl group, alkenyl group, or aryl group, and X is a halogen atom), and is obtained by reacting with a Grignard reagent represented by the above formula.

Specific examples of the Grignard reagent used here include R
Represents an alkyl group such as n-hexyl magnesium chloride, isobutyl magnesium bromide, n-octyl magnesium chloride, 7-trimethylsilyl-n-
When R is an alkenyl group such as peptylmagnesium bromide and n-dodecylmagnesium chloride, Z-
4-octenylmagnesium chloride, 5-hexenylmagnesium bromide, 4-methyl-3-pentenylmagnesium chloride, 7-trimethylsilyl-5-heptenylmagnesium chloride, and benzylmagnesium chloride, p-methyl having R as an aryl group. Examples thereof include benzyl magnesium chloride.

This reaction was carried out by adding 1.0 to 1.5 of the above Grignard reagent in ω-chloro-transallylacetate in the presence of a copper catalyst.
It is carried out by dripping double equivalent amount. As the solvent, THF, diethyl ether, n-butyl ether, toluene, xylene, etc. may be used alone or as a mixture at a ratio of 200 to 500 g per mol, and usually 250 to 350 g of THF may be used.

Copper catalysts include cuprous chloride, cuprous bromide, cuprous iodide and other monovalent copper halides, cupric chloride, cupric bromide and other divalent copper halides, and dilithium tetrachloride. There are copper-lithium based catalysts such as copper (Li ₂ CuCl ₄ ), but di-lithium copper tetrachloride is used in 0.01 to 0.1 equivalent to the reaction substrate in THF, -20 to +
If the reaction proceeds at 30 ° C, the reaction proceeds at a high reaction rate. A ω-chloro-trans olefin compound represented by the formula (wherein R and n are the same as above) is obtained.

The above-obtained compound can be easily isolated and purified by usual separation operations such as distillation, column chromatography, preparative thin layer chromatography, preparative gas chromatography and recrystallization. . The stereochemistry of this product has a trans to cis ratio of at least 9
It is a trans form selectively at 5: 5 or more.

Hereinafter, specific examples of the present invention will be shown, but the present invention is not limited thereto.

Examples Example 1. Synthesis of E, Z-4,10-tetradecadienyl chloride: i) Synthesis of 6-chloro-E-2 hexenal: Methyl chloride in 300 ml THF containing 24.3 g magnesium. Is blown in to adjust 1 mol of methylmagnesium chloride. 102.5 g (1 mol) of 5-chloro-1-pectin was added dropwise thereto at 40 to 60 ° C., and after completion, the mixture was stirred at 80 ° C. for 1 hour to obtain 5-chloro-1-pentynyl magnesium halide. Next, 148 g (1 mol) of ethyl orthoformate is added dropwise at 80 ° C., and the mixture is stirred at 80 to 90 ° C. for 20 hours. After the reaction, hydrolysis was carried out with 300% of 5% NH ₄ Cl water, and after separation of the organic layer, 151 g of 6-chloro-2-hexinal diethyl acetal was obtained with a yield of 75%. To this was added P-2Ni catalyst prepared from 6.8 g of nickel acetate, 1.0 g of sodium borohydride and 150 g of ethanol, and hydrogenated in an autoclave at a hydrogen pressure of 5 kg. After the reaction, the catalyst was vortexed and ethanol was removed.
And 100 g of 20% hydrochloric acid water were added, and the mixture was stirred at room temperature for several minutes. When the methylene chloride layer was washed with water and then removed, 6-chloro-
89 g of E-2-hexenal was obtained with a yield of 90%.

ii) Synthesis of 6-chloro-E-2-hexenyl acetate: 200 ml of THF and 24 g of 6-chloro-E-2-hexenal were added to a reactor, and 6.9 g of sodium borohydride (6.9 g) was added while keeping at 20 to 30 ° C. 50 ml of a NaOH solution was added dropwise. After the end 25
Stirred at C for 1 hour. After the reaction, it was extracted with 400 ml of n-hexane, dried over anhydrous sodium sulfate, transferred to another reactor and added with 31 g of triethylamine, and further added to 15 to 25
23 g of acetyl chloride was slowly added dropwise at ℃. After the end 2
After stirring at 5 ° C for 1 hour, 400 ml of pure water was added to separate the liquid and n-
Hexane was removed. When the residue was distilled, 6-chloro-E-2-hexenyl acetate (bp = 103 to 109 ° C.)
/ 10 mmHg) 20 g was obtained with a yield of 64%.

iii) Synthesis of E, Z-4,10-tetradecadienyl chloride: After adding 4 g of metal magnesium to 130 g of THF and adding a small amount of methyl magnesium chloride as an initiator, Z-
22 g of 4-octenyl chloride was added and reacted to prepare a Grignard reagent. Next, 100 g of THF, 0.5 g of anhydrous cupric chloride and 0.3 g of lithium chloride were added to the reactor to prepare dilithium tetrachloride (Li ₂ CuCl ₂ ), and this solution was heated to 0 ° C.
After cooling to 18 ° C., 18 g of 6-chloro-E-2-hexenyl acetate obtained in the preceding paragraph was added, the Grignard reagent described above was added dropwise while maintaining the temperature at −10 ° C., and the mixture was further stirred at 0 ° C. for 2 hours after completion. After the reaction, 5% ammonium chloride-5% hydrochloric acid water
After adding 200 ml to hydrolyze and distilling the residue from which the THF of the organic layer was removed, 19 g of E, Z-4,10-tetradecadienyl chloride (bp = 130-134 ° C / 3 mmHg) was obtained in a yield of 55.4.
Obtained in%.

(Application example 1) Synthesis of E, Z-4,10-tetradecadienyl acetate, a sex pheromone of Physcomitrella patens: To 60 g of anhydrous acetic acid and 60 g of acetic anhydride was added to 19 g of E, Z-4,10-tetradecadienyl chloride. And reacted at 160 ° C. for 7 hours with stirring. After the reaction, it was washed with 400 ml of pure water and 400 ml of 5% sodium hydrogen carbonate, and the organic layer was distilled.
-4,10-Tetradecadienyl acetate (bp = 135-1
18 g at 40 ° C./3 mmHg) was obtained.

Example 2. Synthesis of E-4-tridecenyl chloride: The same operation as in iii) of Example 1 was performed except that 20 g of n-heptyl chloride was used instead of 22 g of Z-4-octenyl chloride. However, 21 g of E-4-tridecenyl chloride (bp = 105 to 107 ° C./2 mmHg) was obtained in a yield of 64.7.
Obtained in%.

(Application Example 2) Synthesis of E-4-tridecenylacetate, a sex pheromone of tomato pinworm: In Application Example 1, E-4-Tride was replaced with 19 g of E, Z-4,10-tetradecadienyl chloride. Cenyl chloride 2
When the same operation was performed except that 1 g was used, E-4
-Tridecenyl acetate (bp = 120-122 ℃ / 0.7mmH
g) 19 g were obtained.

Example 3. Synthesis of E-3-hexadecenyl chloride: i) Synthesis of 5-chloro-E-2-pentenal: In i) of Example 1, 5-chloro-1-pentyne.
When the same operation was performed except that 88.5 g of 4-chloro-1-butyne was used instead of 102.5 g, 5-chloro-E
69.1 g of 2-pentenal was obtained with a yield of 81%.

ii) Synthesis of 5-chloro-E-2-pentenyl acetate: In Example 1 ii), 21 g of 5-chloro-E-2-pentenal was used instead of 24 g of 6-chloro-E-2-hexenal. Did the same operation,
5-chloro-E-2-pentenyl acetate (bp = 96
〜98 ℃ / 11mmHg) 17.5g was obtained with a yield of 63%.

iii) Synthesis of E-3-hexadecenyl chloride: In iii) of Example 1, 35.8 g of n-undecyl chloride was used instead of 22 g of Z-4-octenyl chloride, and 6-chloro-E-2. -Chloro-E-2-pentenyl acetate 15.8 instead of 18 g of hexenyl acetate
When the same operation was performed except that g was used, E-3
-Hexadecenyl chloride (bp = 135-137 ℃ / 2mmHg)
20.4 g was obtained with a yield of 61%.

(Application Example 3) Synthesis of E-3-hexadecenoic acid which is one of unsaturated fatty acids in plant lipids: E-3-hexadecenyl chloride 26 g and anhydrous potassium acetate 6
0 g and 60 g of acetic acid were added, and the mixture was stirred at 170 ° C for 7 hours. After confirming the disappearance of the raw materials by gas chromatography, pour the reaction solution into 400 ml of pure water, remove the organic layer, and then add 50 g of methanol.
And 100 g of 20% NaOH aqueous solution were stirred at 60 ° C. for 1 hour for hydrolysis. After confirming the disappearance of acetate by gas chromatography, the organic layer was distilled, and E-3-hexadecen-1-ol (bp = 141-143 ° C / 2 mmHg) 21
g was obtained. Next, chromic anhydride [chromium oxide (I
V)] was dissolved in 15 ml of pure water, ice-cooled, 36 g of 36N sulfuric acid 16 g was added little by little, and further 29 ml of pure water was added and ice-cooled to obtain Jones reagent. E-3-Hexadecen-1-ol in the reactor
Add 10 g and 100 ml of acetone and cool to 0-5 ° C.
The s reagent was added dropwise over 1 hour so that the temperature did not exceed 10 ° C, and then the mixture was further stirred at 10 ° C for 6 hours. After the reaction, NaHSO ₃ was added until the brown color of chromic acid disappeared, the upper layer was decanted and separated, and the lower layer was extracted with 50 ml of ether and mixed. The extract thus obtained was washed twice with a saturated saline solution to remove ether, and 10 g of crude crystals of E-3-hexadecenoic acid were obtained. This was recrystallized from ether / n-hexane to obtain 4 g of white crystals of E-3-hexadecenoic acid having a melting point of 47 to 49 ° C.

Example 4. Synthesis of E-11-tetradecenyl chloride: i) Synthesis of 13-chloro-E-2-tridecenal: 5-chloro-1-pentyne 10 in i) of Example 1
A similar operation was performed except that 200.5 g of 12-chloro-1-dodecine was used instead of 2.5 g, and 13-chloro-E
145 g of 2-tridecenal was obtained with a yield of 85%.

ii) Synthesis of 13-chloro-E-2-tridecenyl acetate: In Example 1 ii), 42 g of 13-chloro-E-2-tridecenal was used instead of 24 g of 6-chloro-E-2-hexenal. When the same operation was carried out except that, 13g-chloro-E-2-tridecenylacetate 34g
Was obtained with a yield of 65%. The compound was used in the next step without distillation.

iii) Synthesis of E-11-tetradecenyl chloride: In iii) of Example 1, instead of 22 g of Z-4-octenyl chloride, 9 g of methyl chloride and 18 g of 6-chloro-E-2-hexenyl acetate were used. Instead of 13−
A similar operation was performed except that 28 g of chloro-E-2-tridecenyl acetate was used, and 21 g of E-11-tetradecenyl chloride (bp = 136 to 138 ° C./2 mmHg) was obtained in a yield of 8
Obtained in 0.4%.

(Application Example 4) E-11, a kind of sex pheromone of Pleurotus ostreatus
-Synthesis of tetradecenyl acetate: The same operation as in Application Example 1 except that 21 g of E-11-tetradecenyl chloride was used instead of 19 g of E, Z-4,10-tetradecadienyl chloride. When I went, E
-11-Tetradecenyl acetate (bp = 115-117 ° C / m
20 g of mHg) was obtained.

(Effects of the Invention) According to the present invention, the acetate group of allyl acetate selectively reacts with the Grignard reagent, so that the stereochemistry of trans at the allylic position is maintained as it is. At that time, since the chloro group remains as it is without participating in the reaction, it is a useful general formula that can be easily developed into the next reaction. Is a ω-chloro-trans olefin compound.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // B01J 27/122 X C07B 61/00 300 C07C 67/14 69/63

Claims (2)

[Claims] 1. A general formula (Wherein n is an integer of 2 to 10) and chloro-substituted transallylacetate represented by the general formula RCH ₂ MgX
(Wherein R is a linear, branched, or silyl group-substituted alkyl group, alkenyl group, or aryl group, and X is a halogen atom) in the presence of a copper catalyst. The general formula, characterized by A method for producing an ω-chloro-trans olefin compound represented by the formula (wherein R and n are the same as above). 2. A Grignard reagent represented by the general formula XMgC≡C (CH ₂ ) _n C1 (wherein X is a halogen atom and n is an integer of 2 to 10), wherein the trans allyl acetate substituted at the ω-position is chlorine. The ω-chloro according to claim 1, which is obtained by hydrogenating an acetal compound obtained by reacting an orthoformate trialkyl ester with hydrogen, hydrolyzing it, reducing it, and then acetylating it. -A method for producing a trans-olefin compound.