JP3420321B2 - Method for producing 2,4,5-trihalogeno-3-methylbenzoic acid - Google Patents
Method for producing 2,4,5-trihalogeno-3-methylbenzoic acidInfo
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- JP3420321B2 JP3420321B2 JP03084994A JP3084994A JP3420321B2 JP 3420321 B2 JP3420321 B2 JP 3420321B2 JP 03084994 A JP03084994 A JP 03084994A JP 3084994 A JP3084994 A JP 3084994A JP 3420321 B2 JP3420321 B2 JP 3420321B2
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- Prior art keywords
- compound
- trihalogeno
- methylbenzoic acid
- reaction
- oxazoline
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Description
【発明の詳細な説明】
【０００１】
【産業上の利用分野】本発明は、抗菌剤等の医薬及び農
薬の合成中間体として有用な下記一般式(III)
【化４】
（式中、Ｘ1,Ｘ2 及びＸ3 は各々独立してハロゲン原子
を表す。）で示される２，４，５−トリハロゲノ−３−
メチル安息香酸の製造方法に関するものである。
【０００２】
【従来の技術】従来、２，４，５−トリハロゲノ−３−
メチル安息香酸(III) の製造については、以下のような
幾つかの方法（従来法１〜３）が知られているが、いず
れも製造工程が長い、収率が低い等の欠点を有し、工業
的に必ずしも満足できるものでは無かった。従来法１：
特開昭６３−２６４４６１号
【化５】
従来法２：特開昭６２−２１５５７２号
【化６】従来法３：特開平３−９５１７６号
【化７】また、本発明に係わる製造方法のうち４，４−ジアルキ
ル−２−（２，４，５−トリハロゲノフェニル）オキサ
ゾリン（Ｉ）から、４，４−ジアルキル−２−（２，
４，５−トリハロゲノ−３−メチルフェニル）オキサゾ
リン(II)を製造する第一工程についても、以下のような
脱プロトン化剤としてリチウムジイソプロピルアミドを
用いる方法（従来法４）は既に知られているが、本脱プ
ロトン化剤を用いてベンゼン環の３位にメチル基を導入
するには−７８℃という極低温で反応を行う必要があ
る、という欠点を有していた。
従来法４：J.Heterocyclic Chem., ２７巻，１６０９頁
（１９９０年）
【化８】
また同論文には、脱プロトン化剤としてn-ブチルリチウ
ムを用いると、ベンゼン環の３位へのメチル化は起こら
ず、２位n-ブチル化体(IV)や６位メチル化体（Ｖ）が得
られるとの記載も認められる。
【化９】尚、本発明に係わる製造方法のうち、化合物(II)を加水
分解して２，４，５−トリハロゲノ−３−メチル安息香
酸(III) を製造する第二工程については、これまで全く
知られていない。
【０００３】
【発明が解決しようとする課題、課題を解決するための
手段】このような背景の下に、本発明者らは該化合物の
製造方法について鋭意検討した結果、新規でしかも極め
て有利に化合物(III) を製造する方法を見い出した。即
ち本発明者らは、従来−７８℃という極低温条件下でし
か可能でなかった化合物（Ｉ）のベンゼン環３位の選択
的脱プロトン化反応を、脱プロトン化剤としてリチウム
ビス（トリメチルシリル）アミドを用いることにより、
工業的に可能な温和な反応温度条件下でも可能であるこ
とを見い出し、しかもこの反応を利用することにより、
抗菌剤等の医薬及び農薬の合成中間体として有用な化合
物(III) を短工程で収率良く製造できることを見い出
し、本発明を完成させた。
【０００４】本発明は、下記反応式に示される如く、
【化１０】
（式中、Ｒ1 及びＲ2 は各々独立して低級アルキル基を
表し、Ｘ1,Ｘ2 及びＸ3は各々独立してハロゲン原子を
表す。）
−１０℃〜室温の温和な反応温度条件下で、４，４−ジ
アルキル−２−（２，４，５−トリハロゲノフェニル）
オキサゾリン（Ｉ）をリチウムビス（トリメチルシリ
ル）アミドで脱プロトン化後メチル化剤と反応させるこ
とにより、４，４−ジアルキル−２−（２，４，５−ト
リハロゲノ−３−メチルフェニル）オキサゾリン(II)を
得たのち、化合物(II)を加水分解することを特徴とする
２，４，５−トリハロゲノ−３−メチル安息香酸(III)
の新規な製造方法を提供するものである。
【０００５】本発明の化合物(I),(II)及び(III) 中、Ｒ
1 及びＲ2 で表される低級アルキル基としては、例え
ば、メチル基，エチル基，n-プロピル基，イソプロピル
基，n-ブチル基，イソブチル基，tert- ブチル基等が挙
げられ、Ｘ1,Ｘ2 及びＸ3 で表されるハロゲン原子とし
ては、例えば、フッ素原子，塩素原子，臭素原子等が挙
げられる。
【０００６】本発明の製造方法において、第一工程の脱
プロトン化に用いる反応溶媒としては、例えば、テトラ
ヒドロフラン，１，４−ジオキサン，ジエチルエーテル
等のエーテル系溶媒、ヘキサン，ペンタン等の炭化水素
系溶媒あるいはこれらの混合溶媒が挙げられる。反応
は、−１０℃〜室温の温度範囲で行われる。また、リチ
ウムビス（トリメチルシリル）アミドは市販されている
が、一般には、ヘキサメチルジシラザンとn-ブチルリチ
ウムから調製し、そのまま反応に供される。
【０００７】また、メチル化の反応は通常脱プロトン化
反応液中にメチル化剤を滴下することにより達成され、
メチル化剤としては、例えば、ヨウ化メチル，臭化メチ
ル，メチル メタンスルホネート，メチル トリフルオ
ロメタンスルホネート，メチル p-トルエンスルホネー
ト等が挙げられ、反応は−１０℃〜室温の温度範囲で行
われる。
【０００８】第二工程の加水分解は塩酸，硫酸，臭化水
素酸等の酸又は、必要に応じてメタノール，エタノー
ル，n-ブタノール，sec-ブタノール，tert- ブタノール
等の有機溶媒との含水溶媒を用い、室温から加熱還流温
度下において行われる。尚、化合物(II)中、Ｘ1 が塩素
原子である化合物の加水分解は、上記酸性条件での加水
分解中間体であるエステル体(VI)を一旦単離し、続いて
化合物(VI)をアルカリ条件下で、常温から加熱還流温度
下にて加水分解することにより行われる。
【化１１】
（式中、Ｒ1,Ｒ2,Ｘ2 及びＸ3 は前述と同意義を表
す。）
【０００９】アルカリ加水分解に用いられるアルカリと
しては、例えば、水酸化ナトリウム，水酸化カリウム等
が挙げられ、反応溶媒としては、例えば、水又はメタノ
ール，エタノール，n-プロパノール，n-ブタノール，se
c-ブタノール，tert- ブタノール等のアルコール系溶
媒、あるいはこれらの混合溶媒等が挙げられる。
【００１０】尚、本発明の出発原料である化合物（Ｉ）
は公知の化合物であり、例えば、J.Heterocyclic Che
m., ２７巻，１６０９頁（１９９０年）の方法に従って
製造することができる。
【００１１】
【実施例】以下、本発明を実施例によって説明するが、
本発明はこれらの例に限定されるものではない。
【００１２】実施例１
４，４−ジメチル−２−（２，４，５−トリフルオロ−
３−メチルフェニル）オキサゾリン
ヘキサメチルジシラザン３２９mlの無水テトラヒドロフ
ラン１．４Ｌ溶液に窒素気流下、４〜７℃でn-ブチルリ
チウムのヘキサン溶液１．６２mol/Ｌを１時間かけて滴
下し、さらに同温で１時間攪拌を続けた。反応液に２−
（２，４，５−トリフルオロフェニル）−４，４−ジメ
チル−２−オキサゾリン１４０ｇの無水テトラヒドロフ
ラン５６０ml溶液を内温２〜４℃で滴下し、同温で２時
間攪拌を続けた。反応液にヨウ化メチル１１４mlを内温
３〜１０℃で滴下し、同温で１時間攪拌した。反応液を
氷水８５０ｇに加え、イソプロピルエーテル１．４Ｌに
て抽出した。抽出液を１Ｎ塩酸及び飽和食塩水で洗浄，
硫酸ナトリウムで乾燥後溶媒を留去し、黄褐色オイル１
６５ｇを得た。n-ヘキサンで結晶化させ、淡黄褐色結晶
として目的化合物１１８ｇ（収率８０％）を得た。本品
は融点，ＮＭＲで文献値（J.Heterocyclic Chem., ２７
巻，１６０９頁（１９９０年））と一致した。
【００１３】実施例２
２−（２−クロロ−４，５−ジフルオロ−３−メチルフ
ェニル）−４，４−ジメチルオキサゾリン
ヘキサメチルジシラザン６６０mlの無水テトラヒドロフ
ラン３．０Ｌ溶液に窒素気流下、−２〜８℃でn-ブチル
リチウムのヘキサン溶液１．６２mol/Ｌを８０分間かけ
て滴下し、さらに同温で１時間攪拌した。反応液に２−
（２−クロロ−４，５−ジフルオロフェニル）−４，４
−ジメチル−２−オキサゾリン３００ｇの無水テトラヒ
ドロフラン１．２Ｌ溶液を−５℃で滴下し、同温で２時
間攪拌を続けた。反応液にヨウ化メチル２２８mlを内温
１０℃以下で３０分間かけて滴下し、さらに同温で１時
間攪拌した。反応液に水１．８Ｌを加え、イソプロピル
エーテル３Ｌで抽出した。抽出液を１Ｎ塩酸３Ｌ及び飽
和食塩水で洗浄，硫酸ナトリウムで乾燥後溶媒を留去
し、褐色オイル４００ｇを得た。減圧蒸留して、沸点１
３９〜１４２℃／１４mmHgの淡赤褐色オイルとして目的
化合物２３１ｇ（収率７３％）を得た。
ＮＭＲスペクトル δ (CDCl3) ppm ： 1.40(6H,s),2.
37(3H,d,J=3Hz),4.12(2H,s),7.41(1H,dd,J=10,8.5Hz)
マススペクトル m/z : 259 , 261 (3:1)
【００１４】比較例
脱プロトン化剤としてリチウムジイソプロピルアミドを
用いた化合物(II)の合成例
ジイソプロピルアミン３．８６mlの無水テトラヒドロフ
ラン４７ml溶液に窒素気流下、−３〜−１℃でn-ブチル
リチウムのヘキサン溶液（１．６６mol/Ｌ）を６分間か
けて滴下し、さらに同温で１時間攪拌した。反応液に２
−（２，４，５−トリフルオロフェニル）−４，４−ジ
メチル−２−オキサゾリン５．０５ｇの無水テトラヒド
ロフラン１７ml溶液を内温−５〜５℃で滴下し、−８〜
−１℃で２時間攪拌を続けた。反応液にヨウ化メチル
３．４８mlを内温−１〜−１℃で滴下し、同温で１．５
時間攪拌した。反応液を氷水３０ｇに加え、イソプロピ
ルエーテルにて抽出した。抽出液を希塩酸で洗浄，硫酸
ナトリウムで乾燥後、溶媒を留去し、暗褐色オイル４．
６９ｇを得た。カラムクロマトグラフィー〔シリカゲ
ル，n-ヘキサン−酢酸エチル（５：１）〕で精製し、橙
色オイル３．３ｇを得た。得られた化合物は、ＮＭＲス
ペクトルより化合物（Ｉ）と化合物(II)の比率が１：
４．９の混合物であることが明らかとなった。実施例
１，２及び比較例の結果を表１にまとめた。
【００１５】
【表１】
【００１６】実施例３
２，４，５−トリフルオロ−３−メチル安息香酸
４，４−ジメチル−２−（２，４，５−トリフルオロ−
３−メチルフェニル）−２−オキサゾリン９０２ｇ，６
Ｎ塩酸１６．２Ｌの混合物を２時間加熱還流した。冷後
反応液をイソプロピルエーテルで抽出し、飽和食塩水で
洗浄後、溶媒を留去し、無色結晶として目的化合物６３
７ｇ（収率９０％）を得た。本品をn-ヘキサンで再結晶
して、文献値（特開昭６２−２１５５７２号）と融点，
ＮＭＲが一致する結晶が得られた。
【００１７】実施例４
２−クロロ−４，５−ジフルオロ−３−メチル安息香酸
（２−アミノ−２−メチル）プロピルエステル・塩酸塩
２−（２−クロロ−４，５−ジフルオロ−３−メチルフ
ェニル）−４，４−ジメチルオキサゾリン５．００ｇ及
び１Ｎ塩酸の混合物を６０℃で１時間加熱攪拌した。冷
後塩化メチレンで抽出し、硫酸ナトリウムで乾燥後減圧
濃縮し、無色結晶として目的化合物６．０５ｇを得た。
エタノールから再結晶して、融点２１８〜２１９℃の無
色針状晶を得た。
元素分析値 Ｃ12Ｈ14ＣｌＦ2 ＮＯ2 ・ＨＣｌ
理論値 Ｃ, 45.88; Ｈ, 4.81; Ｎ, 4.46
実験値 Ｃ, 45.59; Ｈ, 4.79; Ｎ, 4.44
【００１８】実施例５
２−クロロ−４，５−ジフルオロ−３−メチル安息香酸
２Ｎ水酸化ナトリウム５８mlを１１０℃に加熱攪拌し、
２−クロロ−４，５−ジフルオロ−３−メチル安息香酸
（２−アミノ−２−メチル）プロピルエステル塩酸塩
５．３４ｇのメタノール５８ml溶液を滴下し、３０分加
熱還流した。冷後減圧濃縮し、残渣に水を加え、塩化メ
チレンで洗浄後，水層に濃塩酸１０mlを加え酸性とし
た。塩化メチレンで抽出し、抽出液を硫酸ナトリウムで
乾燥後減圧濃縮し、無色結晶として目的化合物３．０ｇ
（収率８５％）を得た。n-ヘキサンから再結晶して、融
点１２０〜１２１℃の無色結晶を得た。
元素分析値 Ｃ8 Ｈ5 ＣｌＦ2 Ｏ2
理論値 Ｃ, 46.51; Ｈ, 2.44
実験値 Ｃ, 46.34; Ｈ, 2.18
【００１９】
【発明の効果】本発明の製造方法によれば、前記一般式
(III) で示される２，４，５−トリハロゲノ−３−メチ
ル安息香酸を、短工程でしかも収率よく得ることができ
る。この様にして製造される化合物(III) は、抗菌剤等
の医薬又は農薬の合成中間体として極めて有用である。Description: BACKGROUND OF THE INVENTION The present invention relates to the following general formula (III) which is useful as an intermediate for synthesizing pharmaceuticals such as antibacterial agents and agricultural chemicals. (Wherein X 1 , X 2 and X 3 each independently represent a halogen atom.) 2,4,5-Trihalogeno-3-
The present invention relates to a method for producing methylbenzoic acid. [0002] Conventionally, 2,4,5-trihalogeno-3-
For the production of methylbenzoic acid (III), the following several methods (conventional methods 1 to 3) are known, but all have disadvantages such as a long production step and a low yield. However, it was not always satisfactory industrially. Conventional method 1:
JP-A-63-264461. Conventional method 2: JP-A-62-215572 Conventional method 3: JP-A-3-95176 In the production method according to the present invention, 4,4-dialkyl-2- (2,4,5-trihalogenophenyl) oxazoline (I) is converted to 4,4-dialkyl-2- (2,2).
Regarding the first step for producing 4,5-trihalogeno-3-methylphenyl) oxazoline (II), the following method (conventional method 4) using lithium diisopropylamide as a deprotonating agent is already known. However, there has been a drawback that in order to introduce a methyl group at the 3-position of the benzene ring using the present deprotonating agent, it is necessary to carry out the reaction at an extremely low temperature of -78 ° C. Conventional method 4: J. Heterocyclic Chem., 27, 1609 (1990) Also, in the same paper, when n-butyllithium is used as a deprotonating agent, methylation at the 3-position of the benzene ring does not occur, and n-butylated compound (IV) at the 2-position and methylated compound at the 6-position (V ) Is obtained. Embedded image In the production method according to the present invention, the second step of producing 2,4,5-trihalogeno-3-methylbenzoic acid (III) by hydrolyzing compound (II) has not been known at all. Not. [0003] Against this background, the present inventors have conducted intensive studies on a method for producing the compound, and as a result, have found that the method is novel and extremely advantageous. A method for producing compound (III) has been found. That is, the present inventors carried out the selective deprotonation reaction of compound (I) at the 3-position on the benzene ring of compound (I), which was conventionally only possible under the extremely low temperature condition of -78 ° C, by using lithium bis (trimethylsilyl) as a deprotonating agent. By using an amide,
It has been found that it is possible even under industrially possible mild reaction temperature conditions, and by utilizing this reaction,
The present inventors have found that compound (III), which is useful as an intermediate for synthesizing pharmaceuticals such as antibacterial agents and agricultural chemicals, can be produced in a short process with high yield, and the present invention has been completed. The present invention provides a compound represented by the following reaction formula: (In the formula, R 1 and R 2 each independently represent a lower alkyl group, and X 1 , X 2 and X 3 each independently represent a halogen atom.) Mild reaction temperature conditions from −10 ° C. to room temperature Under 4,4-dialkyl-2- (2,4,5-trihalogenophenyl)
Oxazoline (I) is deprotonated with lithium bis (trimethylsilyl) amide and reacted with a methylating agent to give 4,4-dialkyl-2- (2,4,5-trihalogeno-3-methylphenyl) oxazoline (II ), And hydrolyzing the compound (II) to obtain 2,4,5-trihalogeno-3-methylbenzoic acid (III)
Of the present invention. In the compounds (I), (II) and (III) of the present invention, R
The lower alkyl group represented by 1 and R 2, for example, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, etc. tert- butyl group, X 1, Examples of the halogen atom represented by X 2 and X 3 include a fluorine atom, a chlorine atom, and a bromine atom. In the production method of the present invention, the reaction solvent used for the deprotonation in the first step includes, for example, ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether, and hydrocarbon solvents such as hexane and pentane. A solvent or a mixed solvent thereof is used. The reaction is performed in a temperature range from -10C to room temperature. Lithium bis (trimethylsilyl) amide is commercially available, but is generally prepared from hexamethyldisilazane and n-butyllithium, and is directly used for the reaction. The methylation reaction is usually achieved by dropping a methylating agent into a deprotonation reaction solution,
Examples of the methylating agent include methyl iodide, methyl bromide, methyl methanesulfonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and the reaction is carried out in a temperature range from -10 ° C to room temperature. The hydrolysis in the second step is carried out using an acid such as hydrochloric acid, sulfuric acid or hydrobromic acid or, if necessary, a water-containing solvent with an organic solvent such as methanol, ethanol, n-butanol, sec-butanol or tert-butanol. The reaction is carried out from room temperature to a reflux temperature. In the compound (II), the compound in which X 1 is a chlorine atom is hydrolyzed by isolating the ester (VI), which is a hydrolysis intermediate under the above acidic conditions, and then converting the compound (VI) to an alkali. It is carried out by hydrolyzing under ordinary conditions from a room temperature to a heating reflux temperature. Embedded image (In the formula, R 1 , R 2 , X 2 and X 3 have the same meanings as described above.) Examples of the alkali used for alkali hydrolysis include sodium hydroxide and potassium hydroxide. As the reaction solvent, for example, water or methanol, ethanol, n-propanol, n-butanol, se
Examples thereof include alcohol solvents such as c-butanol and tert-butanol, and mixed solvents thereof. The starting material of the present invention, compound (I)
Is a known compound, for example, J. Heterocyclic Che
m., 27, 1609 (1990). Hereinafter, the present invention will be described with reference to examples.
The present invention is not limited to these examples. Example 1 4,4-Dimethyl-2- (2,4,5-trifluoro-
To a solution of 329 ml of 3-methylphenyl) oxazoline hexamethyldisilazane in 1.4 L of anhydrous tetrahydrofuran was added dropwise 1.62 mol / L of a hexane solution of n-butyllithium over 4 hours at 4 to 7 ° C under a nitrogen stream. Stirring was continued at warm for 1 hour. 2-
A solution of 140 g of (2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline in 560 ml of anhydrous tetrahydrofuran was added dropwise at an internal temperature of 2 to 4 ° C., and stirring was continued at the same temperature for 2 hours. To the reaction solution, 114 ml of methyl iodide was added dropwise at an internal temperature of 3 to 10 ° C, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was added to 850 g of ice water, and extracted with 1.4 L of isopropyl ether. Wash the extract with 1N hydrochloric acid and saturated saline,
After drying over sodium sulfate, the solvent was distilled off, and a yellow-brown oil 1
65 g were obtained. Crystallization from n-hexane gave 118 g (yield 80%) of the target compound as pale yellow-brown crystals. This product has melting point and NMR values according to literature values (J. Heterocyclic Chem., 27
Vol., P. 1609 (1990)). Example 2 A solution of 660 ml of 2- (2-chloro-4,5-difluoro-3-methylphenyl) -4,4-dimethyloxazoline hexamethyldisilazane in 3.0 L of anhydrous tetrahydrofuran was subjected to a stream of nitrogen under a stream of nitrogen in an amount of -2. 1.62 mol / L of a hexane solution of n-butyllithium was added dropwise at ８8 ° C. over 80 minutes, and the mixture was further stirred at the same temperature for 1 hour. 2-
(2-chloro-4,5-difluorophenyl) -4,4
A solution of 300 g of -dimethyl-2-oxazoline in 1.2 L of anhydrous tetrahydrofuran was added dropwise at -5 ° C, and stirring was continued at the same temperature for 2 hours. To the reaction solution, 228 ml of methyl iodide was added dropwise at an internal temperature of 10 ° C. or lower over 30 minutes, and the mixture was further stirred at the same temperature for 1 hour. 1.8 L of water was added to the reaction solution, and extracted with 3 L of isopropyl ether. The extract was washed with 3 L of 1N hydrochloric acid and saturated saline, dried over sodium sulfate, and the solvent was distilled off to obtain 400 g of a brown oil. Vacuum distillation and boiling point 1
231 g (yield 73%) of the target compound was obtained as a pale reddish brown oil of 39 to 142 ° C./14 mmHg. NMR spectrum δ (CDCl 3 ) ppm: 1.40 (6H, s), 2.
37 (3H, d, J = 3Hz), 4.12 (2H, s), 7.41 (1H, dd, J = 10,8.5Hz) Mass spectrum m / z: 259,261 (3: 1) Example of Synthesis of Compound (II) Using Lithium Diisopropylamide as Deprotonating Agent A solution of 3.86 ml of diisopropylamine in 47 ml of anhydrous tetrahydrofuran under a nitrogen stream at -3 to -1 ° C. in a hexane solution of n-butyllithium (1. (66 mol / L) was added dropwise over 6 minutes, and the mixture was further stirred at the same temperature for 1 hour. 2 in the reaction solution
A solution of 5.05 g of-(2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline in 17 ml of anhydrous tetrahydrofuran was added dropwise at an internal temperature of -5 to 5 ° C.
Stirring was continued at -1 ° C for 2 hours. To the reaction solution, 3.48 ml of methyl iodide was added dropwise at an internal temperature of -1 to -1 ° C, and 1.5 ml at the same temperature.
Stirred for hours. The reaction solution was added to 30 g of ice water, and extracted with isopropyl ether. The extract was washed with dilute hydrochloric acid and dried over sodium sulfate, and the solvent was distilled off.
69 g were obtained. Purification by column chromatography [silica gel, n-hexane-ethyl acetate (5: 1)] gave 3.3 g of an orange oil. The obtained compound had a ratio of compound (I) to compound (II) of 1: based on the NMR spectrum.
It was found to be a mixture of 4.9. Table 1 summarizes the results of Examples 1 and 2 and Comparative Example. [Table 1] Example 3 4,4-Dimethyl-2- (2,4,5-trifluoro-2,4,5-trifluoro-3-methylbenzoic acid)
3-methylphenyl) -2-oxazoline 902 g, 6
A mixture of 16.2 L of N hydrochloric acid was heated to reflux for 2 hours. After cooling, the reaction solution was extracted with isopropyl ether, washed with saturated saline, and the solvent was distilled off.
7 g (yield 90%) were obtained. This product was recrystallized from n-hexane to obtain literature values (JP-A-62-215572) and melting points.
Crystals having the same NMR were obtained. Example 4 2-chloro-4,5-difluoro-3-methylbenzoic acid (2-amino-2-methyl) propyl ester hydrochloride 2- (2-chloro-4,5-difluoro-3- A mixture of 5.00 g of (methylphenyl) -4,4-dimethyloxazoline and 1N hydrochloric acid was heated and stirred at 60 ° C. for 1 hour. After cooling, the mixture was extracted with methylene chloride, dried over sodium sulfate, and concentrated under reduced pressure to obtain 6.05 g of the desired compound as colorless crystals.
Recrystallization from ethanol gave colorless needles having a melting point of 218-219 ° C. Elemental analysis C 12 H 14 ClF 2 NO 2 .HCl Theoretical C , 45.88; H, 4.81; N, 4.46 Experimental C , 45.59; H, 4.79; N, 4.44 Example 5 2-chloro-4 58 ml of 2N sodium hydroxide of 5,5-difluoro-3-methylbenzoic acid was heated and stirred at 110 ° C.
A solution of 5.34 g of 2-chloro-4,5-difluoro-3-methylbenzoic acid (2-amino-2-methyl) propyl ester hydrochloride in 58 ml of methanol was added dropwise, and the mixture was heated under reflux for 30 minutes. After cooling, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with methylene chloride. The aqueous layer was acidified by adding 10 ml of concentrated hydrochloric acid. The mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate and concentrated under reduced pressure to obtain 3.0 g of the desired compound as colorless crystals.
(85% yield). Recrystallization from n-hexane gave colorless crystals having a melting point of 120 to 121 ° C. Elemental analysis value C 8 H 5 ClF 2 O 2 Theoretical value C , 46.51; H, 2.44 Experimental value C , 46.34; H, 2.18 According to the production method of the present invention, the general formula
2,4,5-Trihalogeno-3-methylbenzoic acid represented by the formula (III) can be obtained in a short step and in good yield. The compound (III) produced in this manner is extremely useful as a synthetic intermediate of a pharmaceutical or agricultural chemical such as an antibacterial agent.
フロントページの続き (56)参考文献 特開 昭63−264461（ＪＰ，Ａ) 特開 昭62−215572（ＪＰ，Ａ) 特開 平３−95176（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 63/00 C07C 51/00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)Continuation of the front page (56) References JP-A-63-264461 (JP, A) JP-A-62-215572 (JP, A) JP-A-3-95176 (JP, A) (58) Fields investigated (Int) .Cl. 7 , DB name) C07C 63/00 C07C 51/00 CA (STN) REGISTRY (STN)
Claims (1)
表し、Ｘ1,Ｘ2 及びＸ3は各々独立してハロゲン原子を
表す。）で示される４，４−ジアルキル−２−（２，
４，５−トリハロゲノフェニル）オキサゾリンをリチウ
ムビス（トリメチルシリル）アミドで脱プロトン化後、
メチル化剤と反応させることにより下記一般式(II) 【化２】 （式中、Ｒ1,Ｒ2,Ｘ1,Ｘ2 及びＸ3 は前述と同意義を表
す。）で示される４，４−ジアルキル−２−（２，４，
５−トリハロゲノ−３−メチルフェニル）オキサゾリン
を得たのち、化合物(II)を加水分解することを特徴とす
る下記一般式(III) 【化３】 （式中、Ｘ1,Ｘ2 及びＸ3 は前述と同意義を表す。）で
示される２，４，５−トリハロゲノ−３−メチル安息香
酸の製造方法。(57) [Claims] [Claim 1] The following general formula (I): (In the formula, R 1 and R 2 each independently represent a lower alkyl group, and X 1 , X 2 and X 3 each independently represent a halogen atom.) (2,
After deprotonating 4,5-trihalogenophenyl) oxazoline with lithium bis (trimethylsilyl) amide,
By reacting with a methylating agent, the following general formula (II): (Wherein R 1 , R 2 , X 1 , X 2 and X 3 have the same meanings as described above).
(5-Trihalogeno-3-methylphenyl) oxazoline is obtained, and then compound (II) is hydrolyzed. (Wherein, X 1 , X 2 and X 3 have the same meanings as described above.) A process for producing 2,4,5-trihalogeno-3-methylbenzoic acid represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03084994A JP3420321B2 (en) | 1994-02-03 | 1994-02-03 | Method for producing 2,4,5-trihalogeno-3-methylbenzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03084994A JP3420321B2 (en) | 1994-02-03 | 1994-02-03 | Method for producing 2,4,5-trihalogeno-3-methylbenzoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07215913A JPH07215913A (en) | 1995-08-15 |
| JP3420321B2 true JP3420321B2 (en) | 2003-06-23 |
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|---|---|---|---|
| JP03084994A Expired - Fee Related JP3420321B2 (en) | 1994-02-03 | 1994-02-03 | Method for producing 2,4,5-trihalogeno-3-methylbenzoic acid |
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| DE19908504C2 (en) * | 1999-02-26 | 2003-04-30 | Boehringer Ingelheim Pharma | Large-scale process for the preparation of derivatives of biphenyl-2-carboxylic acid by saponifying a (2-oxazolinyl) -2-biphenyl derivative with hydrochloric acid |
| CN102531887B (en) * | 2012-01-05 | 2014-05-14 | 连云港威远精细化工有限公司 | Method for preparing 2,4,5-trifluoro-3-methyl benzoic acid |
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| JPH07215913A (en) | 1995-08-15 |
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