JPS61155352A - 4-chloro-3-alkenoic acid and production thereof - Google Patents

Abstract

NEW MATERIAL:A 4-chloro-3-alkenoic acid shown by the formula I (R is alkyl, aralkyl, alkenyl, or aryl; alkyl includes one containing ether substituent group). EXAMPLE:4-Chloro-3-nonenoic acid. USE:Useful as a raw material for synthesizing a 4-oxoalkanoic acid, 4-hydroxy-2- alkenoic acid, and 4-oxo-2-alkenoic acid useful as an intermediate for perfume and antibiotics. PREPARATION:beta-Chlorovinyl-beta-propiolactone shown by the formula II is reacted with an organometallic compound shown by the formula III or formula IV (X is Cl, Br, or I) by the use of dimethyl ether or tetrahydrofuran as a solvent, more preferably by adding dimethyl sulfide, at -30--80 deg.C, preferably at -40--60 deg.C, to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 4-chloro-3-alkenoic acid and a method for producing the same.

4-Chloro-3-alkenoic acid has chlorine, carbon-carbon double bonds, and various useful carboxylic substances in its molecule, i.e., it has a scent similar to coconut or peach, and is a raw material for perfumes and antibiotics. -Oxoalkanoic acid, 4-hydroxy-2-alkenoic acid and 4-oxo-2-alkenoic acid can be produced.

Conventionally, 1,3-dichloro-2-butene and cyanide 1@
A method for synthesizing 4-chloro-3-pentenoic acid in a two-step reaction is known. However, this method
-When trying to produce 4-chloro-3-alkenoic acids other than chloro-3-be/thenic acid, 4-substituted-1
゜It is necessary to use 3-dichloro-2-butene, and it is necessary to prepare raw materials corresponding to each 4-chloro-3-alkenoic acid, which is the purpose of synthesis, and the reaction process becomes extremely complicated. There are some drawbacks, and there is no case where the 4-chloro-3-alkenoic acid according to the present invention has been synthesized by such a method.

The present inventors investigated the amount of 4-chloro-3-alkenoic acid in order to solve the problems mentioned above. As a result, by using β-chlorovinyl-β-propiolactone and reacting it with an organocopper complex or Grignard reagent,
The present invention was completed based on the discovery that 4-chloro-3-alkenoic acid can be easily obtained in good yield.

As can be seen from the above description, the purpose of the present invention is to synthesize 4-oxoalkanoic acid, 4-hydroxy-2-alkenoic acid, and 4-oxo-2-alkenoic acid, which are extremely useful as intermediates for fragrances and antibiotics. It is an object of the present invention to provide a manufacturing method for obtaining raw materials 4-chloro-3-alkenoic acid and 4-chloro-3-alkenoic acid in a simple manner and in good yield.

The present invention has the following configuration.

4-chloro-3-alkenoic acid.

(However, R represents an alkyl group, an aralkyl group, an alkenyl group, or an aryl group. Alkyl groups include those having an ether substituent.) (2) β-chlorovinyl-β-propiolactonization-3- Method for producing alkenoic acids.

(However, R represents an alkyl group, an aralkyl group, an alkenyl group, and an aryl group. The alkyl group includes those having an ether substituent.

X represents Ct%Br or ■. ) The reaction of the present invention is expressed as follows.

■.

H, HI+ (4-Chloro-3-alkenoic acid) β-chlorovinyl-β-propiolactone, the raw material used in the present invention, is prepared from kechi/ and α-chloroacrolein in the presence of a boron trifluoride ethylate catalyst. Can be easily synthesized.

In addition, in the production of the 4-chloro-3-alkenoic acid of the present invention, an ether type solvent is generally used as a linear solvent, but tetrahydrofuran (hereinafter referred to as THF) is preferable, and when dimethyl sulfide is added to the solvent, an organic copper complex or It increases the stability of the Grignard reagent and is effective in improving reaction yield.

Further, the addition ratio of dimethyl sulfide was 1 part of the solvent.

It is preferably 2 to 20 parts by volume.

The reaction temperature is preferably in the range of -30 to -80°C, but more preferably in the range of -40 to -60°C.

A reaction time of 30 minutes to 1 hour is sufficient.

Furthermore, the reaction molar ratio between β-chlorovinyl-β-propiolactone and the organocopper complex or Grignard reagent is 1.
:1. O~1:1.2 is suitable.

Reactions using organic class bodies are carried out as follows.

i.e. inert gas (N7, argon, helium, etc.)
After preparing an organocopper complex from 2 equivalents of Grignard reagent and 1 equivalent of cuprous iodide in a reaction vessel substituted with This is done by The reaction proceeds very mildly. The organic group of the organocopper complex used in the reaction is
Methyl group, n-butyl group, 5ec-butyl group, t-butyl group, n-pentyl group, 7enethyl group, phenyl group, 4
Examples include -methylphenyl group, vinyl group, and allyl group.

4-ri as a new compound obtained by this reaction
Examples of the ychloro-alkenoic acid include the following substances.

That is, 4-chloro-3-hexenoic acid, 4-chloro-
3-nonenoic acid, 4-chloro-3-decenoic acid, 4-chloro-6-methyl-3-octenoic acid, 4-chloro-6,6-
Dimethyl-3-heptenoic acid, 4-chloro-7-7enyl-3-heptenoic acid, 4-chloro-5-7enyl-3-pentenoic acid, 4-chloro-5-(4-methylphenyl)-
These include 3-pentenoic acid, 4-chloro-3,6-hebutadienoic acid, and 4-chloro-3,7-octadienoic acid.

Further, a reaction using a Grignard reagent is carried out as follows.

That is, a catalytic amount of iodized tJcl steel and β-chlorovinyl-β-propiolactone are dissolved in a reaction solvent in a reaction vessel purged with an inert gas, and then a Grignard reagent is gradually added. It will be done.

Further, the proportion of steel iodide used as a catalyst used in the reaction is suitably 2 to 10 mol %, more preferably 3 to 5 mol %, based on the Grignard reagent.

In addition to the organic groups of the organocopper complex, the organic groups of the Grignard reagent used in the reaction of the present invention include a 3゜3-trimethylenedioxypropyl group, a 4-tetrahydrobyranyloxybutyl group, and a 10-tetrahydropyranyloxyunion group. An alkyl group having an ether bond such as a decyl group can also be exemplified.

In addition to the novel compound obtained using the above-mentioned organocopper complex, 4-chloro-3-alkenoic acid as a new compound obtained by this reaction includes 4-trichloro, 8-trichloro,
) dimethylenedioxy-3-octenoic acid, 4-chloro-
Examples include 9-tetrahydropyranyloxy-3-decenoic acid and 15-tetrahydropyranyloxy-7-3-hexadecenoic acid.

By using the present invention described above, 4-chloro-3-alkenoic acid can be produced in high yield from β-chlorovinyl-β-propiolactone and a Grignard reagent in the presence of an organocopper complex or a catalytic amount of copper iodide. Various types of 4-chloro-3 that can be obtained from
- It has been confirmed that alkenoic acids can be easily synthesized.

In addition, as shown in the reference example, K, the novel 4-
Among chloro-3-alkenoic acids, 4-chloro-3-decenoic acid in which R is an n-pentyl group is a useful intermediate in the synthesis of dihydrojasmone, and R is an alkyl group having 4 to 9 carbon atoms. It has been confirmed that 4-chloro-3-alkenoic acid is a useful synthetic intermediate for r-substituted-r-butyrolactone, which is used as a variety of fragrances.

Furthermore, it was confirmed that 4-chloro-3-alkenoic acid in which R is a 10-tetrahydropyranyloxyundecyl group is a useful synthetic intermediate for the macrolide antibiotic A26771B.

EXAMPLES The present invention will be specifically explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 Under an argon atmosphere, 1 ml of dimethyl sulfide was added to 1st iodide @419η (2.20 mmol), followed by T
After adding and dissolving 4 ml of HF, the mixture was cooled to -50°C, 4.2 ml of a tetrahydrofuran solution of n-butylmagnesium bromide with a concentration of 1.05 mol/l was gradually added, and the temperature was lowered to -50°C. Stir for 30 minutes while maintaining temperature. Then β-chlorovinyl-β-propiolactone 26
A solution prepared by dissolving 5.5 (2.00 mmol) in 2 ml of THF was added, and the mixture was stirred at a temperature of -50°C for 5.0 minutes.

Then, 5 ml of 2 mol/l hydrochloric acid aqueous solution was added, and T
After separating the HF reaction solution and the aqueous hydrochloric acid solution, an operation of extracting the aqueous hydrochloric acid solution once and adding K 5 wl of diethyl ether to extract the reaction product was performed four times in total. After adding the diethyl ether 2ON used in the extraction to the above THF reaction solution, 10 ml of water was added to wash the reaction solution, and after separating the water, diethyl ether and THF were distilled off, and 0.2 Distillation under reduced pressure of nHg yields 4-chloro-3-nonenoic acid 30 from K.
5 capes (1.6 mmol) were obtained. The yield was 80%.

Boiling point 132-134°C/0.2 fiHg.

The obtained product was identified by infrared absorption spectrum (IR) and nuclear magnetic resonance spectrum (NMR) measurements.

IR absorption spectrum (KBr plate): 250
0~3300,1700,1400,1090,900
°780 (cWI-1).

IHNMR (CC4, TMS) δ (PPm): 0.
90 (3H.

t, J-61-1x), 1.10~2.00 (
6H, m), 2.35 (2H, t, J-7Hz), 8
．． 25 (2H, d, J-61(z).

5.65 (IH, t, J-6 gate), 11.5 (IE, s
).

Examples 2 to 9 β-chlorovinyl-β-propiolactone was reacted with various organocopper complexes listed in Table 1 under the same reaction conditions and reaction operations as in Example 1.

Example 10 Iodized steel 19. under argon atmosphere. OMg(0,0
996 mmol) to 0.5 ml of dimethyl sulfide,
Then, after adding and dissolving THFSsl, -50°
CK cool and dissolve β-chlorovinyl-β-propiolactone 3009 (2,26 mmol) in 9 THF solution 2
ml of THF solution of 0.83 mol/l 10-tetrahydropyranyloxyundecylmagnesium bromide was gradually added and stirred for 50 minutes while maintaining the temperature at -50°C. The hindlimb reaction solution was treated in the same manner as in Example 1 and purified by silica gel thin layer chromatography.
mil J mol) was obtained. The yield was 90%.

Rf 0.5 (CH2C4: Ac0Et: Ac
OH-200:20:1). The reaction product was identified in the same manner as in Example 1.

IR spectrum (KBr plate): 3000°28
50.2840, 2760, 1680, 1100゜Proverb 6
) 1x), 1.10-110 (24H, m), 2.30
(2H.

t, J dew 6l-1x), i3.20 (2H, d
, J-6-an), 3.35-4.20 (3H, m), 4
．． 65 (IH, brs), 5.65 (IH, t, J■6
Hz), 10.60 (IH, brs) Example 1
1-19 Under the same reaction conditions and reaction operations as in Example 10, β-chlorovinyl-β-propiolactone and various Gu17 Niyard reagents listed in Table 2 were used in the same manner as the catalyst.

→←Rosal age reference example 1 Dihydrojasmonmel II/-le 32011v (10 mmol), water 18 (
1 (10 mmol), acetone 871'/(15 mmol) in methylene chloride 5 yxl was cooled to 0°C, and a solution of titanium tetrachloride 4.749 (25 mmol) in methylene chloride 5 yxl was slowly added at this temperature. After stirring for 10 minutes, 4-chloro-3-decenoic acid 1.02F (5
,00 mmol) in methylene chloride was slowly added dropwise.

Then, the reaction vessel was returned to room temperature and stirred for 64 hours.

Thereafter, the mixture was cooled to 0°C again, water was added slowly, extracted with methylene chloride, washed with water, concentrated, and then subjected to silica gel thin layer chromatography (Rfo, 5, cH, ct, : Ac0Et :
AcOH=200:20:1) to obtain 4-oxodecanoic acid 6301F (8.38 mol). (Yield 68%) 559 ~ (8,00 mmol) of 4-oxodecanoic acid and 304 ~ (a, OO mmol) of triethylamine were dissolved in T H
Dissolved in F 5 wl and cooled to -20°C, 0-methoxybenzoic acid chloride 512JIF (8,00 mmol)
5 d of THF solution was added dropwise and stirred at this temperature for 2 hours. Then, it was cooled to -78°C and a 1.00 mol/l methylmagnesium bromide solution in diethyl ether was added.
．． After slowly dropping OOO12, the mixture was stirred at this temperature for 20 minutes. After adding a saturated aqueous ammonium chloride solution to stop the reaction, treatment and purification were carried out by conventional methods to obtain undecane-2,5-dione 404"F. (Yield 73%) Undecane-2,5-dione 191My (1.03 mmol) in 0.5 mol/l aqueous sodium hydroxide solution2.
The mixture was dissolved in a mixed solution of 5 ml of ethanol and 5 ml of ethanol, and heated under reflux for 6 hours. After cooling, treatment was carried out in a conventional manner to obtain dihydrojasmone 113''P (yield: 88%).Reference Example 2 4-oxononanoic acid methanol 68.6q (2.14 mmol), water 80.
5Mg (4,47 mmol), acetone 354W (6,
A solution of 0.09 mmol) dissolved in 2 ml of methylene chloride was cooled to 0°C, and a solution of 1.951 (10.3 mmol) of titanium tetrachloride dissolved in 2 ml of methylene chloride was slowly added and stirred at this temperature for 10 minutes. , 4- at 0゛C
A solution of 385q (2.02 mmol) of chloro-3-nonene in 2 ml of methylene chloride was slowly added dropwise. Then, the reaction vessel was returned to room temperature and stirred for 64 hours. Then again 0°
Cool CK, slowly add water, extract with methylene chloride,
After washing with water and concentrating, silica gel thin layer chromatography (Rf
O, 5, CHtClt: Ac0Et: AcOH
200:20:1) to give 4-oxononanoic acid 303 (1,76 mmol).

(Yield 87%) One 4-chloro-15-tetrahydropyranyloxy-3-
To 397q (1.02 mmol) of hexadecenoic acid was added 10 hours of a 2 mol/l aqueous potassium hydroxide solution, and the mixture was heated under reflux for 3 hours. This was cooled, 10% sulfuric acid was added until it became neutral, extracted with ethyl acetate, washed with water, and concentrated to obtain a crude product of 4-hydroxy-15-tetrahydropyranyloxy-■-2-hexadecene. This was dissolved in acetate without purification and cooled to 0°C. 1.
One equivalent of chromium trioxide sulfuric acid solution was slowly added dropwise and stirred at this temperature for 30 minutes. Add a saturated aqueous solution of sodium hydrogen carbonate to this solution until it becomes aqueous, remove the ethyl acetate bath, wash with water, concentrate and 4-
Oxo-15-tetrahydropyranyl 7-(t)-
A crude product of 2-hexadecenoic acid was obtained. Acetic acid-THF-
In a mixed solvent of water (4:2:1), the protecting group was removed and 4-okino 15-hydroxy-2-hexadecenoic acid 161'
i' (0.5 mmol) was obtained. (Yield 56%) This 4-okino 15-hydroxy-■-2-hexadecenoic acid 13911F (0,488 mmol) and triethylamine 49.4FC (0,488 mmol) were dissolved in THF3*
2.4.6-Dolichlorobenzoyl chloride 131.2jljl (0,538 mmol) of TH
2 ml of F solution was added dropwise at room temperature, and after stirring at this temperature for 30 minutes, the precipitate of triethylamine hydrochloride formed was washed off and removed. This filtrate was diluted with 300- toluene and 4-dimethylaminopyridine 190IIIy (1,56
50 d of a toluene solution of 1 mmol) was added dropwise over 5 hours while heating under reflux. After the dropwise addition, heating under reflux was continued for 30 minutes, then cooled and concentrated.

Diedel ether is added to the concentrate to form a solution, which is washed sequentially with a saturated aqueous sodium bicarbonate solution, 1 mol/l hydrochloric acid, a saturated aqueous sodium carbonate solution, and a saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and then dissolved in silica gel. Thin layer chromatography (hexane:ether-s:l)
15-methyl-1- which is a precursor of LA26771B manufactured by
60.0w9 (0.225 mmol) of oxa-(2)-3-cyclohexadecene-2°5-dione was obtained. (Yield: 46%) Amendment of the above procedure June 1985 Patent Application No. 169656 & Title of Invention 4-Chloro-3-alkenoic acid and process for producing the same & Person making amendment Relationship Patent applicant: 3-6-32 Nakanoshima, Kita-ku, Osaka-shi, Osaka (530)
(207) Chisso Corporation Representative Sadao Nogi Sub-Agent 2-8-1 Shinjuku, Shinjuku-ku, Tokyo (〒160) Date of amendment order +-1 -〆-0-- a. "Detailed Description of the Invention" Column J Contents of the Amendment (1) In the second line from the bottom of page 5 of the specification, "From an organometallic compound, represented by the general formula CI)" is changed to "From an organometallic compound, the general formula is amended. .

that's all

Claims (6)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼〔 I
] 4-chloro-3-alkenoic acid. (However, R represents an alkyl group, an aralkyl group, an alkenyl group, and an aryl group. Alkyl groups include those having an ether substituent.) (2) In the general formula [I], R is C_4H_9 to C_
Claim No. 1 which is an alkyl group of 9H_1_9
4-chloro-3-alkenoic acid described in item ). (3) In the general formula [I], R is a 10-tetrahydropyranyloxyundecyl group (
4-chloro-3-alkenoic acid according to item 1). (4) 4-chloro-3-decenoic acid according to any one of claims (1) and (2), wherein in the general formula [I], R is an n-pentyl group. (5) β-chlorovinyl-β-propiolactone ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] and general formula (R)_2
A method for producing 4-chloro-3-alkenoic acid represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] from the organometallic compound represented by CuMgX [III] or RMgX [IV]. (R represents an alkyl group, an aralkyl group, an alkenyl group, or an aryl group. Alkyl groups include those having an ether substituent. X represents Cl, Br, or I.) (6) The method for producing 4-chloro-3-alkenoic acid according to claim (5), which uses diethyl ether or tetrahydrofuran as a reaction solvent.