JPH0573395B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention is directed to optically active 2-(4-
The present invention relates to a method for producing hydroxyphenoxypropionic acid. 2-(4-hydroxyphenoxy)propionic acid obtained by alkyl esterification of 2-(4-hydroxyphenoxy)propionic acid
-Hydroxyphenoxy)alkyl propionate is disclosed in JP-A-56-16475 (or British Patent Publication GB2042539B), JP-A-54-22371,
It is a compound useful as an intermediate for excellent herbicides disclosed in JP-A-53-40767 and other publications. More importantly, these herbicides that use alkyl 2-(4-hydroxyphenoxy)propionate as an intermediate have an asymmetric carbon atom in their structure, so two types of optically active forms exist. It is known that the (+) form of one type has strong herbicidal activity (for example, Japanese Patent Application Laid-Open No.
(Refer to Publication No. 55372). Therefore, if only optically active forms with strong herbicidal activity are used to make herbicides, the required dosage will be approximately half that of the racemic form;
This method is meaningful not only for environmental protection and resource saving, but also for reducing the cost of herbicide production and herbicide spraying. [Prior art] As a conventional technology for producing optically active 2-(4-hydroxyphenoxy)propionic acid, Japanese Patent Application Laid-open No. 59-
There is a method described in Japanese Patent No. 95237 (hereinafter referred to as conventional method A), that is, a method in which optically active 2-halopropionic acid and hydroquinone are condensed in an aqueous alkaline solution. In addition, optically active 2-(4-
As a conventional technique for producing esters of hydroxyphenoxy)propionic acid, there is a method described in West German Patent Publication GODE 3150233 (hereinafter, conventional method B).
), that is, optically active 2-halopropionic acid ester and hydroquinone were mixed in DMSO solvent,
There is a method of condensation in the coexistence of calcium hydroxide. [Problem to be solved by the invention] The above patent regarding conventional method A contains optically active 2
-(4-Hydroxyphenoxy)propionic acid has almost no concrete description of its production method or physical properties, so the results are unknown. In conventional method B, it is difficult to avoid partial racemization that occurs during the reaction, despite using an expensive optically active material such as optically active n-butyl 2-chloropropionate. 2-(4-hydroxyphenoxy) with high optical purity
Unable to obtain propionic acid alkyl ester (Example 3 of GODE3150233 has optical activity 2
-(4-hydroxyphenoxy)propionic acid n
There is an example of the production of -butyl, and there is a description of the optical rotation of [α] ²⁵ _D +11.8°, but the value of optically active butyl 2-(4-hydroxyphenoxy)propionate produced by the present inventor is , [α] ²⁵ _D +57.6° (neat), it can be seen that racemization has clearly occurred. Furthermore, a problem common to conventional methods A and B is that a large amount of a compound in which both the two hydroxyl groups of hydroquinone are alkylated is produced as a by-product, resulting in low yields and unnecessary use of expensive optically active materials. There are problems with using it. In other words, unless these problems are solved, it cannot be used as an industrial manufacturing method. [Means for Solving the Problems and Aspects of the Invention] As a result of intensive research into the industrial production method of optically active 2-(4-hydroxyphenoxy)propionic acid, the present inventor has found that 2-(4-hydroxyphenoxy)propionic acid with high optical purity has been produced. We have established a method for easily obtaining (4-hydroxyphenoxy)propionic acid without using special equipment. Specifically, racemic lower alkyl 2-(4-hydroxyphenoxy)propionate is asymmetrically hydrolyzed in the presence of readily available commercially available enzymes to produce (+)-2-(4-hydroxyphenol). This is a method for producing (enoxy)propionic acid. Both enzymes derived from mammalian or avian organs and enzymes derived from microorganisms have high stereoselectivity. Two enzymes with excellent stereoselectivity and hydrolysis rate include pancreatin (derived from porcine pancreas) and lipase derived from microorganisms belonging to the Candida genus. In both cases, (+)-2-( 4-hydroxyphenoxy)
Lower alkyl propionate is more susceptible to hydrolysis than lower alkyl (-)-2-(4-hydroxyphenoxy)propionate. Therefore, (+)-2-(4-hydroxyphenoxy)propionic acid and lower alkyl (-)-2-(4-hydroxyphenoxy)propionic acid are obtained as reaction products. Naturally, the smaller the hydrolysis rate, the more optically pure (+)-2-(4-hydroxyphenoxy)propionic acid can be obtained, and conversely, the larger the hydrolysis rate, the more optically pure ( Since lower alkyl -)-2-(4-hydroxyphenoxy)propionic acid is obtained, it can be used appropriately depending on the purpose. One product, (+)-2-(4-hydroxyphenoxy)propionic acid, has an optical purity of 80% e.
e. If it is above, it is possible to improve the optical purity simply by recrystallizing (see Example 16), and furthermore, it can be converted into various alkyl esters without racemization, so the specifications 3rd page 4th
This can lead to the optically active form of the herbicide described in the literature in lines 6 to 6 (see Reference Examples 1 to 3). In addition, the other lower alkyl (-)-2-(4-hydroxyphenoxy)propionate can be easily hydrolyzed without impairing the optical purity (-)-2-
In addition to forming (4-hydroxyphenoxy)propionic acid, the starting material (+)-2-(4-hydroxy It is also possible to reuse it by returning it to lower alkyl phenoxy)propionate. The overall flow of the present invention is shown below. Obtaining (+)-2-(4-hydroxyphenoxy)propionic acid and its usage

〔Effect of the invention〕

Optically active 2-(4-
It has become possible to produce hydroxyphenoxy)propionic acid or its lower alkyl ester with high selectivity, high optical purity, and at low cost.
By using this optically active alkyl ester of (+)-2-(4-hydroxyphenoxy)propionic acid, we can produce 2-(4-heteroaryloxyphenoxy), which is an excellent herbicide active ingredient. It has become possible to obtain the optically active (+) form of alkyl propionate without a racemization reaction. [Examples and Reference Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. In addition, in the following examples and reference examples, 2
Analysis of -(4-hydroxyphenoxy)propionic acid was performed after methylation with diazomethane. Furthermore, optical purity was measured by high performance liquid chromatography using an optically active column under the following conditions. Analysis conditions Column: Daicel CHIRALCEL OB Eluent: Hexane/isopropanol (3/1) Flow rate: 1.0ml/min Detection method: UV280nm Example 1 Racemic 2-(4-hydroxyphenoxy)
Suspend 1.48 g of methyl propionate in 30 ml of 0.2 M sodium phosphate buffer at pH 7.0, and
(Meito Sangyo trademark) 50 mg was added and stirred at 18 to 20°C for 5 hours (hydrolysis rate 22%). After adding 30 ml of ethyl acetate to the resulting reaction mixture and shaking, the mixture was filtered through Celite and separated. 30 ml of ethyl acetate was added to the aqueous layer again and the same operation was repeated. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain 1.18 g of methyl (-)-2-(4-hydroxyphenoxy)propionate. Yield: 80%, optical purity: 23% ee. The aqueous layer after extraction was made acidic by adding 1.25 g of 35% hydrochloric acid, and extracted twice with 30 ml of ethyl acetate. (+)-2-(4-
0.29 g of hydroxyphenoxy)propionic acid was obtained. Yield 21% Optical purity 87%ee Example 2 Racemic 2-(4-hydroxyphenoxy)
Suspend 3.17 g of ethyl propionate in 60 ml of 0.2 M sodium phosphate buffer at pH 7.0, and add pancreatin.
300 mg was added and stirred at 35-40°C for 24 hours. Hereinafter, by the same post-processing as in Example 1, (+)-2-(4
-Hydroxyphenoxy)propionic acid 1.05g
(yield 38%, optical purity 86%ee) and (-)-2
1.87 g of ethyl -(4-hydroxyphenoxy)propionate (yield 59%, optical purity 62%ee) was obtained. Examples 3 to 9 In order to examine the influence of the type of enzyme on the optical resolution efficiency, reactions were carried out under the following conditions using various enzymes of different origins. The results are shown in Table 1 including Example 2. Reaction conditions Substrate: Ceramide 2-(4-hydroxyphenoxy)
Ethyl propionate 1.58g Buffer: 30ml 0.2M sodium phosphate with pH 7.0 Enzyme: Liver acetone powder (pig, cow, chicken) Lipase MY (derived from Candida cylindracea,
Meito Sangyo trademark), Lipase AP-6 (derived from Aspergillus niger, Amano Pharmaceutical trademark), Lipase "Amano" M10 (derived from Mucor sp., Amano Pharmaceutical trademark),
Lipase "Saiken" (derived from Rhizopus japonicus, trademark of Osaka Bacteria Research Institute) Enzyme amount: 50mg Reaction temperature: 18-20℃

[Table] It was conducted under the following conditions.
Examples 10 to 15 In order to examine the influence of the alcohol moiety of lower alkyl 2-(4-hydroxyphenoxy)propionate on optical resolution efficiency, pancreatin and lipase derived from a microorganism belonging to the genus Candida were used under the following conditions. I performed the reaction. The results are shown in Example 1.
2 is also included in Tables 2 and 3. Reaction conditions Substrate: methyl, ethyl, n-propyl, n-2-(4-hydroxyphenoxy)propionic acid
7.5 mmol each of butyl esters Buffer: 30 ml of 0.2 M sodium phosphate at pH 7.0 Enzyme: 50 mg of Lipase MY (Meito Sangyo trademark) or 150 mg of pancreatin Reaction conditions: Lipase MY...18-20℃, 5 hours Creatine...35-40℃, 24 hours

【table】

[Table] Example 16 As a result of investigating the improvement of the optical purity of optically active 2-(4-hydroxyphenoxy)propionic acid by recrystallization, it was found that purification can be easily performed if the optical purity is 80% ee or higher. I understand. The results are shown in Table 4. Recrystallization conditions Optical purity 60%, 70%, 80%, 90% (+)-2
-(4-hydroxyphenoxy)propionic acid 2.0
Recrystallize g from 16.0 g of water (crystallization: 20℃, 17 hours)
did.

[Table] Reference example 1 (+)-2-(4-hydroxyphenoxy)propionic acid {[α] ²⁵ _D +60.5° (c=1.01, acetone)
,
Add 18.2 g of optical purity 100%ee to a mixture of 13.8 g of ethanol and 41.4 g of benzene, and add 97% sulfuric acid.
0.91g was added. The mixture was refluxed for 3 hours while being azeotropically dehydrated, and then the solvent was distilled off at normal pressure. Add 70 ml of benzene and water to the resulting pale yellow oily residue.
50ml was added and extracted. The benzene layer was washed with 50.0 g of a 3% aqueous sodium bicarbonate solution and then with 50 ml of water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain 21.4 g of a pale yellow oily residue. This was purified by vacuum distillation (boiling point: 135-140°C/1 mlHg) to obtain 20.2 g of ethyl (+)-2-(4-hydroxyphenoxy)propionate as a colorless oil. yield
96%. [α] ²⁵ _D +45.7°C (c=1.14, chloroform). The optical purity by NMR analysis using a shift reagent was 100% ee. (As a shift reagent
Eu(hfc) ₃ was used and carbon tetrachloride-heavybenzene (4:1) was used as the solvent. _CH3 and ethyl groups
Optical purity was determined by the intensity ratio of CH ₂ signals. Shift reagent is 7.7mg for sample 8.2mg
It was used. ) Reference example 2 (-)-2-(4-hydroxyphenoxy)propionic acid {[α] ²⁵ _D +60.5° (C=1.01, acetone)
,
Optical purity 100%ee} 18.2g and racemic body 2-(4-
5.46 g of hydroxyphenoxy)propionic acid were mixed and 5.93 g of n-butanol, 16.6 g of benzene and 0.36 g of 95% sulfuric acid were added. The mixture was stirred and refluxed for 4 hours while being azeotropically dehydrated, and then the solvent was distilled off at normal pressure. Benzene to the resulting oily residue
30 ml and 20 ml of water were added for extraction. Add 20ml of 3% sodium bicarbonate aqueous solution to the benzene layer and then add water.
After washing with 30 ml, it was dried with anhydrous sodium sulfate.
After standing overnight, it was filtered, the solvent was distilled off, and (-)-2-(4
9.61 g of n-butyl -hydroxyphenoxy)propionate was obtained as a yellow oil. The optical rotation is
[α] ²² _D -14.4℃ (neat), and the optical purity of the raw material was 25% ee, so the optical purity was 100% ee.
The optical rotation of n-butyl (-)-2-(4-hydroxyphenoxy)propionate is [α] ²² _D -57.6℃
It can be converted to (neat). Reference example 3 2,6-dichloroquinoxaline 3.98g, (+)-
Ethyl 2-(4-hydroxyphenoxy)propionate {[α] ²⁵ _D +45.7° (c = 1.14, chloroform), optical purity 100%ee} 4.33 g, potassium carbonate
2.76g acetonitrile and 19.9g were mixed. The mixture was refluxed for 6 hours with stirring, and then the solvent was distilled off under reduced pressure. The residue was extracted by adding 100 ml of toluene and 50 ml of water. Take the toluene layer and add 50ml of water.
After washing twice, the solvent was distilled off to obtain 7.55 g of a pale yellow oil (solidified upon standing). Add this to ethanol
Recrystallization from 11.9 g gave 6.45 g of ethyl (+)-2-[4-(6-chloro-2-quinoxalyloxy)phenoxy]propionate as colorless crystals.
Yield 87%. The optical purity as determined by NMR analysis using a shift reagent was 100% ee. (Eu(hfc) ₃ was used as the shift reagent, and carbon tetrachloride-deuterbenzene (4:1) was used as the solvent. CH ₃ of the ethyl group
Optical purity was determined by the intensity ratio of the and CH ₂ signals. Shift reagent for 8.2mg of sample
When 10.0 mg was used, the (+) body shifted more toward the lower magnetic field side. )

Claims (1)

[Claims] 1 Lower alkyl (±)-2-(4-hydroxyphenoxy)propionate is asymmetrically hydrolyzed in the presence of pancreatin (derived from pig pancreas) and/or lipase derived from a microorganism belonging to the genus Candida, resulting in an optical purity of 80. %ee or more of (+)-2-(4-hydroxyphenoxy)propionic acid, or (-)-
It is characterized in that after obtaining lower alkyl 2-(4-hydroxyphenoxy)propionic acid, hydrolysis is performed as necessary to obtain (-)-2-(4-hydroxyphenoxy)propionic acid. Optical resolution method of 2-(4-hydroxyphenoxy)propionic acid.