JP4776810B2 - Method for producing α-position trisubstituted acetic acid - Google Patents

Method for producing α-position trisubstituted acetic acid Download PDF

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JP4776810B2
JP4776810B2 JP2001161832A JP2001161832A JP4776810B2 JP 4776810 B2 JP4776810 B2 JP 4776810B2 JP 2001161832 A JP2001161832 A JP 2001161832A JP 2001161832 A JP2001161832 A JP 2001161832A JP 4776810 B2 JP4776810 B2 JP 4776810B2
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sulfuric acid
reaction
formula
groups
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JP2002356458A (en
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薫 野田
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Nippon Soda Co Ltd
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Nippon Soda Co Ltd
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Description

【0001】
【発明の属する技術分野】
本発明は、農医薬中間体として有用な、α位トリ置換酢酸の製造方法に関する。
【0002】
【従来技術】
α位トリ置換酢酸の製造方法は過去に幾つか報告例があるが、工業的に上記カルボン酸を製造する場合、価格、製造条件を含めた原料の入手しやすさを考慮して、α位トリ置換ニトリルを加水分解してカルボン酸に誘導する方法が最も優れていると考えられる。
【0003】
従来、α位に嵩高い置換基等を有する加水分解が進行し難いとされるニトリルを加水分解してカルボン酸を得る方法としては、例えば、100%リン酸、濃硫酸等を用いて高温、長時間反応させる方法や、一旦アミドに加水分解した後、亜硝酸ナトリウム、亜硝酸アルキル、塩化ニトロシル、酸化窒素等を用いてN−ニトロソ化した後、分解する方法等が知られている。
【0004】
また、α位トリ置換カルボン酸の一つである2,2−ジメチル吉草酸の製造方法として、ドイツ特許2157545号公報には、2,2−ジメチルバレロニトリルを33%硫酸を用いて120〜140℃に加熱した後、さらに10%の濃度まで硫酸を希釈し100℃で反応させ、抽出後蒸留し、未反応のニトリルと目的とするカルボン酸が得られことが記載されている。
【0005】
【発明が解決しようとする課題】
しかし、濃硫酸を用いて高温で長時間反応させる方法は、反応が進行するものの収率が70%前後と低くしかも、タール状の分解生成物が多量に生成するという問題があった。事実、後述するように、本願発明者も、75%硫酸水を用いて120〜140℃で原料の2,2−ジメチルバレロニトリルが消失するまで10時間反応を行ったところ、目的とする2,2−ジメチル吉草酸を得ることができたもののその収率76%と低く、また、タール状の分解物が反応槽に析出することを確認した。また、前述したドイツ特許に見られるように、比較的温和な条件で加水分解を行った場合、原料のニトリル体が残存するという問題があった。
【0006】
亜硝酸ナトリウム等を用いてニトロソ化、分解する方法は、亜硝酸ガスの発生を伴う反応であり、工業的に実施するには問題があった。
本発明は、一般に加水分解が進行しにくいとされる嵩高い置換基を有するニトリルを酸加水分解して対応するカルボン酸を得る製造方法において、収率、純度が高く、分解生成物等の生成しない製造方法を提供することを目的とする。
【0007】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく鋭意検討した結果、反応の段階ごとに酸の濃度を適当に調整すること、さらに反応温度を適切に設定することで上記課題を解決できることを見出し、本発明を完成するに至った。
【0008】
すなわち、本発明は、
(1)式(I)
【化5】
(式中、R1、R2、R3はそれぞれ独立にC1〜C20の炭化水素基を表し、R1とR2、R1とR3、R2とR3は一緒になって環を形成していてもよい。)で表される酢酸誘導体の製造方法において、式(II)
【化6】
(式中、R1、R2、R3は前記と同じ意味を表す。)で表されるニトリル誘導体を、65〜98重量%硫酸水を用いて加水分解する工程(1)、次いで30〜65重量%硫酸水を用いて加水分解する工程(2)を有することを特徴とする製造方法に関し、
(2)工程(2)における反応温度が90〜130℃であることを特徴とする(1)に記載の製造方法及び
(3)工程(1)における反応温度が50〜100℃であることを特徴とする(1)または(2)に記載の製造方法に関する。
また、
(4)式(I)
【化7】
(式中、R1、R2、R3はそれぞれ独立にC1〜C20の炭化水素基を表し、R1とR2、R1とR3、R2とR3は一緒になって環を形成していてもよい。)で表される酢酸誘導体の製造方法において、式(III)
【化8】
(式中、R1、R2、R3は前記と同じ意味を表す。)で表されるアミド誘導体を、30〜65%硫酸を用いて反応温度90〜130℃で反応させることを特徴とする製造方法、
に関する。
【0009】
【発明の実施の形態】
本発明の製造方法を用いた場合の目的物である式(I)で表される化合物中、R1、R2、R3はそれぞれ独立にC1〜C20の炭化水素基を表し、R1とR2、R1とR3、R2とR3は一緒になって環を形成していてもよい。R1、R2、R3として具体的には、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、t−ブチル基、s−ブチル基、イソブチル基、n−ペンチル基、s−ペンチル基、イソペンチル基、ネオペンチル基、n−ヘキシル基、s−ヘキシル基、1,1−ジメチル−n−ヘキシル基、n−ヘプチル基、n−デシル基、n−ドデシル基等C1〜C20のアルキル基、ビニル基、アリル基、2−ブテニル基、1−メチル−2−プロペニル基、4−オクテニル基等のC2〜C20のアルキニル基、エチニル基、プロパルギル基、1−メチル−プロピニル基等のC2〜C20のアルキニル基、シクロプロピル基、シクロブチル基、シクロペンチル基、1−メチルシクロペンチル基、1−メチルシクロヘキシル基、1−アダマンチル基、1−メチルアダマンチル基、2−アダマンチル基、2−メチル−2−アダマンチル基、ノルボルニル基等のC3〜C20の脂環式炭化水素基、フェニル基、1−ナフチル基、9−アントラセニル基等のC6〜C20の芳香族炭化水素基等を例示することができる。また、
【0010】
以上のように示したR1〜R3の置換基各々は、適当な炭素上の位置にさらに置換基を有することができる。その置換基としては、フッ素原子、クロル原子、ブロム原子、ヨウ素原子であるハロゲン原子、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、t−ブチル基、n−ヘキシル基、シクロプロプル基、シクロヘキシル基、ビニル基、アリル基、フェニル基、4−クロロフェニル基、4−メトキシフェニル基、3,4−ジメチルフェニル基等の置換フェニル基、プロパルギル基等の炭化水素基、メトキシ基、エトキシ基、n−プロポキシ基、イソプロポキシ基、n−ブトキシ基、s−ブトキシ基、イソブトキシ基、t−ブトキシ基、フェノキシ基、4−クロロフェノキシ基、ベンジルオキシ基、フェネチルオキシ基等のアルコキシ基、アミノ基、メチルアミノ基、ジメチルアミノ基、t−ブトキシカルボニルアミノ基等のアミノ基、メチルチオ基、フェニルチオ基、2−ピリジルチオ基、メチルスルフィニル基、メチルスルホニル基等のアルキル、アリール、もしくはヘテロ環チオ基またはその酸化体、メトキシカルボニル基、エトキシカルボニル基、n−プロポキシカルボニル基、イソプロポキシカルボニル基、n−ブトキシカルボニル基、t−ブトキシカルボニル基等のC1〜C20のアルコキシカルボニル基、アセチル基、プロパノイル基、ベンゾイル基、2−ピリジルカルボニル基等のC2〜C20のアシル基、シアノ基、ニトロ基等を例示することができる。
【0011】
これら置換基を有するR1〜R3の具体例としては、クロロメチル基、フルオロメチル基、ブロモメチル基、ジクロロメチル基、ジフロロメチル基、ジブロモメチル基、トリクロロメチル基、トリフルオロメチル基、トリブロモメチル基、トリクロロメチル基、トリフルオロエチル等のはハロアルキル基、ペンタフルオロエチル基、テトラフルオロエテニル基、2,2−ジフロロエテニル基等のハロアルケニル基、メトキシメチル基、メトキシエチル基、フェノキシメチル等のアルコキシアルキル基、メチルチオメチル基、フェニルチオメチル基等のアルキルチオアルキル基またはアリールチオアルキル基、ベンジル基、ジフェニルメチル基、トリチル基、フェネチル基等のアラルキル基等を例示することができる。
【0012】
式(I)で表される化合物として具体的には、下記表に示す化合物を例示することができる。
【0013】
【表1】
【0014】
【表2】
【0015】
本発明に用いられる式(II)、及び式(III)で表される化合物中、R1〜R3は前記と同じ意味を表し、同様の具体例を例示することができる。また、式(II)及び式(III)で表される化合物の具体例として、第1表に例示された化合物に対応する化合物を例示することができる。
【0016】
本発明の方法は、式(II)で表されるニトリル誘導体を、65〜98重量%硫酸水を用いて加水分解する工程(1)、次いで30〜65重量%硫酸水を用いて加水分解する工程(2)を有することを特徴とする。65〜98重量%硫酸水のみを用いて加水分解反応を行った場合、式(III)で表されるアミド化合物は収率よく得られることは反応途中で確認したが、該アミド化合物から、目的とするカルボン酸誘導体への加水分解反応が進行しにくく、タール状の分解生成物が多く生成するという問題がある。また、30〜65重量%硫酸水のみを用いて加水分解反応を行った場合、式(II)で表されるニトリル化合物の加水分解反応が進行しにくく、原料である該ニトリルが反応しないという問題がある。
【0017】
65〜98重量%硫酸水は、市販の濃硫酸(95−98%)をそのまま使用する以外は、あらかじめ濃硫酸を適当量の水で希釈して調製するのが好ましいが、式(II)で表される化合物と濃硫酸を混合した後、水を添加して、または式(II)で表される化合物と水を混合した後、濃硫酸を添加して調製することもできる。
【0018】
用いる65〜98重量%の硫酸水の量は、含まれる水の量が、式(II)で表される化合物1モルに対して、少なくとも1モル以上であれば、特に制限されないが、5モル以上用いるのがこのましく、さらに10モル以上用いるのが好ましい。
【0019】
65〜98重量%硫酸水を用いて加水分解する工程(1)の反応温度は、反応系中の化合物が分解しない温度範囲であれば特に制限されず高温で反応を行うことができるが、50〜100℃で行うのが好ましい。
【0020】
反応方法は特に制限されないが、例えば(1)硫酸水と式(II)で表され化合物を室温で混合し、加熱する方法、(2)加熱した硫酸水に式(II)で表される化合物を添加する方法、また、少量の水または有機溶媒に懸濁した式(II)で表され化合物中、加熱下滴下する方法等がいずれの方法も採用することができる。
【0021】
工程(1)における反応時間は、原料となる式(II)で表される化合物及び生成物が分解しない範囲であれば、特に制限されないが、原料が消失した時点で加熱を停止し反応を終了させるのが好ましい。生成物、式(III)で表されるアミド化合物が主生成物であるが、式(I)で表されるカルボン酸を含有していても構わない。
【0022】
本発明における式(II)で表されるニトリル誘導体を、65〜98重量%硫酸水を用いて加水分解する工程(1)と30〜65重量%硫酸水を用いて加水分解する工程(2)は、連続的に行うことも、また、工程(1)終了後生成物を単離し新たに工程(2)を行うこともできる。
【0023】
工程(1)、工程(2)を連続的に行う場合、反応液に必要量の水を、加熱下もしくは反応液を冷却後添加することにより、硫酸濃度を調節するのが反応操作上好ましいが、反応液を適当量の水に加熱下、もしくは室温下に添加して硫酸濃度を調整することもできる。
【0024】
反応を工程(1)で生成物を単離し、新たに工程(2)を行う場合の操作については、先に示した工程(1)と原料、硫酸濃度が異なるだけで同様に反応することができる。
工程(2)における反応温度は、90〜130℃の範囲であるのが好ましい。
【0025】
加水分解工程に供される式(II)で表されるニトリル誘導体、または式(III)で表されるアミド誘導体は、何も希釈せずにそのまま加水分解に用いることもできるが、適当な有機溶媒で希釈して用いることもできる。用いる有機溶媒としては、上記ニトリル誘導体、アミド誘導体を溶解させ、酸加水分解条件に不活性な溶媒であれば特に制限されないが、具体的にはトルエン、キシレン、クロロベンゼン等の有機溶媒を例示することができる。
【0026】
希釈濃度は、特に制限されないが、10〜60重量%の範囲が好ましい。また、ニトリル誘導体またはアミド誘導体は完全に溶解している必要はなく、懸濁した状態で用いることもできる。
【0027】
式(II)で表されるニトリル誘導体、式(III)で表されるアミド誘導体は、市販品、または、α−位モノ置換もしくはジ置換体をアルキル化することにより得られる合成品を用いることができる。特に、合成品の場合、反応後精製工程を経ていない不純物を含む粗生成物をそのまま反応に供することもできる。但し、不純物等に塩基性化合物を含有する場合には、その分硫酸を多めに使用する必要がある。
【0028】
以下、実施例を用いて本発明をさらに詳細に説明するが、本発明の範囲は実施例に限定されるものではない。
【0029】
【実施例】
実施例1
水4.1gに濃硫酸(96重量%)14.7gを加えて75重量%硫酸水を調製し、2,2−ジメチルバレロニトリル6.0g(0.05モル、純度96%)をくわえ、85〜90℃で2時間反応させた。反応液の一部を取り出し、高速液体クロマトグラフィー(HPLC)で定量したところほぼ定量的に2,2−ジメチルペンタンアミドが生成していることを確認した。反応液にさらに9.4gの水を加え50重量%硫酸水としたのち115℃で2時間反応を行った。反応後室温に冷却し、水80ml、エーテル50mlを加えて分液し、有機層を水50mlで水洗し、乾燥後エーテルを留去したところ6.27gの油状物を得た。1HNMRで化合物を同定し、HPLCで定量したところ、目的とする2,2−ジメチル吉草酸を収率90%(純度97%)で得られたことがわかった。
【0030】
実施例2
実施例1と同様の条件下、2−エチル−2−メチル−ブチロニトリル6.0g(0.05モル、純度96%)を用いて同様に反応を行ったところ、2−エチル−2−メチル−酪酸を6.0g(収率87%、純度98%)得た。
【0031】
実施例3
2,2−ジメチルバレロニトリル103.4g(0.292mol)のトルエン31.3重量%溶液に75%硫酸109.8gを加えて95〜100℃で5時間反応させた。反応液の一部を取り出して高速液体クロマトグラフィー(HPLC)で分析したところほぼ定量的に2,2−ジメチルペンタンアミドが生成していることを確認した。反応液にさらに55gの水を加え、50%硫酸水とした後に反応温度が120〜125℃となるようにトルエンの一部を留去し、その後そのままの温度で8時間反応させた。反応液を室温まで冷却し、水100mlを加え分液し、有機層を水50mlで洗浄し、溶媒を留去して約36gの油状物質を得た。1HNMRで化合物を同定し、HPLCで定量したところ、目的とする2,2−ジメチル吉草酸を収率90%(純度95%)で得た。
【0032】
比較例1
水4.1gに濃硫酸(96重量%)14.7gを加えて75重量%硫酸水を調製し、2,2−ジメチルバレロニトリル6.0g(0.05モル、純度96%)をくわえ、85〜90℃で2時間反応させ、さらに、還流温度(およそ130℃)で18時間反応を行ったところ、途中生成したアミド化合物が消失した。実施例1と同様の後処理操作を行ったところ、2,2−ジメチル吉草酸を5.1g(収率76%、純度97%)で得た。また、反応槽には黒色のタール状成分が付着していた。
【0033】
比較例2
50重量%硫酸水を用いて還流温度で18時間反応を行う以外比較例1と同様に反応を行ったところ、反応は完結せず、原料のニトリルを59%回収し、2,2−ジメチル吉草酸を14%得るにとどまった。
【0034】
【発明の効果】
以上、述べたように本発明の方法を用いることにより、従来加水分解が困難とされていた嵩高いα位トリ置換アセトニトリルを操作性よく加水分解して、α位トリ置換酢酸を収率、純度よく得ることができるようになった。α位トリ置換酢酸を、農医薬の中間体として有用な化合物であり、本発明の製造方法は産業上の利用価値は高いといえる。
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing an α-position trisubstituted acetic acid useful as an agricultural pharmaceutical intermediate.
[0002]
[Prior art]
There are several reports on the production method of α-substituted tri-substituted acetic acid in the past. However, when the above carboxylic acid is industrially produced, the α-position is considered in consideration of the availability of raw materials including price and production conditions. The method of hydrolyzing the tri-substituted nitrile to derive the carboxylic acid is considered to be the best.
[0003]
Conventionally, as a method of obtaining a carboxylic acid by hydrolyzing a nitrile that is difficult to proceed with hydrolysis having a bulky substituent at the α-position, for example, 100% phosphoric acid, concentrated sulfuric acid or the like is used at a high temperature, A method of reacting for a long time, a method of once hydrolyzing to an amide, N-nitrosating with sodium nitrite, alkyl nitrite, nitrosyl chloride, nitric oxide or the like and then decomposing are known.
[0004]
In addition, as a method for producing 2,2-dimethylvaleric acid, which is one of α-substituted tricarboxylic acids, German Patent No. 2157545 discloses that 2,2-dimethylvaleronitrile is used in an amount of 120 to 140 using 33% sulfuric acid. It is described that after heating to ° C., sulfuric acid is further diluted to a concentration of 10%, reacted at 100 ° C., extracted and distilled to obtain unreacted nitrile and the target carboxylic acid.
[0005]
[Problems to be solved by the invention]
However, the method in which concentrated sulfuric acid is used for a long time at a high temperature has a problem that although the reaction proceeds, the yield is as low as about 70%, and a large amount of tar-like decomposition products are generated. In fact, as will be described later, the present inventor also reacted for 10 hours using 75% sulfuric acid aqueous solution at 120 to 140 ° C. until 2,2-dimethylvaleronitrile as a raw material disappeared. Although 2-dimethylvaleric acid could be obtained, the yield was as low as 76%, and it was confirmed that tar-like decomposition products were deposited in the reaction vessel. Further, as seen in the aforementioned German patent, there is a problem that the raw material nitrile body remains when hydrolysis is performed under relatively mild conditions.
[0006]
The method of nitrosation and decomposition using sodium nitrite or the like is a reaction accompanied by generation of nitrite gas, and has a problem in industrial implementation.
The present invention is a method for producing a corresponding carboxylic acid by acid hydrolysis of a nitrile having a bulky substituent, which is generally considered to be difficult to proceed with hydrolysis. An object of the present invention is to provide a manufacturing method that does not.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by appropriately adjusting the acid concentration for each stage of the reaction, and further setting the reaction temperature appropriately. The present invention has been completed.
[0008]
That is, the present invention
(1) Formula (I)
[Chemical formula 5]
(Wherein R 1 , R 2 and R 3 each independently represents a C1 to C20 hydrocarbon group, R 1 and R 2 , R 1 and R 3 , and R 2 and R 3 together form a ring. In the method for producing an acetic acid derivative represented by formula (II):
[Chemical 6]
(Wherein R 1 , R 2 , R 3 represent the same meaning as described above) (1), and then 30-30 A production method characterized by having a step (2) of hydrolyzing with 65% by weight sulfuric acid water,
(2) The reaction temperature in step (2) is 90 to 130 ° C, and the production method according to (1) and (3) the reaction temperature in step (1) is 50 to 100 ° C. The manufacturing method according to (1) or (2), which is characterized.
Also,
(4) Formula (I)
[Chemical 7]
(Wherein R 1 , R 2 and R 3 each independently represents a C1 to C20 hydrocarbon group, R 1 and R 2 , R 1 and R 3 , and R 2 and R 3 together form a ring. In the method for producing an acetic acid derivative represented by formula (III):
[Chemical 8]
(Wherein R 1 , R 2 , and R 3 represent the same meaning as described above), and the amide derivative is reacted at a reaction temperature of 90 to 130 ° C. using 30 to 65% sulfuric acid. Manufacturing method,
About.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
In the compound represented by the formula (I) which is the target product when the production method of the present invention is used, R 1 , R 2 and R 3 each independently represent a C1 to C20 hydrocarbon group, and R 1 and R 2 , R 1 and R 3 , R 2 and R 3 may be combined to form a ring. Specific examples of R 1 , R 2 and R 3 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, s-butyl group, isobutyl group and n-pentyl group. , S-pentyl group, isopentyl group, neopentyl group, n-hexyl group, s-hexyl group, 1,1-dimethyl-n-hexyl group, n-heptyl group, n-decyl group, n-dodecyl group, etc. C2-C20 alkynyl group such as C20 alkyl group, vinyl group, allyl group, 2-butenyl group, 1-methyl-2-propenyl group, 4-octenyl group, ethynyl group, propargyl group, 1-methyl-propynyl group Such as C2-C20 alkynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, 1-methylcyclopentyl group, 1-methylcyclohexyl group, 1-adamantyl 1-methyladamantyl group, 2-adamantyl group, 2-methyl-2-adamantyl group, norbornyl group, etc., C3-C20 alicyclic hydrocarbon group, phenyl group, 1-naphthyl group, 9-anthracenyl group, etc. A C6-C20 aromatic hydrocarbon group etc. can be illustrated. Also,
[0010]
Each of the substituents R 1 to R 3 shown above can further have a substituent at an appropriate carbon position. As the substituent, fluorine atom, chloro atom, bromine atom, halogen atom which is iodine atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, n-hexyl group , Cyclopropyl group, cyclohexyl group, vinyl group, allyl group, phenyl group, 4-chlorophenyl group, 4-methoxyphenyl group, substituted phenyl group such as 3,4-dimethylphenyl group, hydrocarbon group such as propargyl group, methoxy group Alkoxy such as ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, isobutoxy group, t-butoxy group, phenoxy group, 4-chlorophenoxy group, benzyloxy group, phenethyloxy group Group, amino group, methylamino group, dimethylamino group, t-butoxycarbonylamino group, etc. Mino group, methylthio group, phenylthio group, 2-pyridylthio group, methylsulfinyl group, methylsulfonyl group and other alkyl, aryl, or heterocyclic thio groups or their oxidants, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group C1-C20 alkoxycarbonyl groups such as isopropoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group, etc., C2-C20 acyl groups such as acetyl group, propanoyl group, benzoyl group, 2-pyridylcarbonyl group, etc. A cyano group, a nitro group, etc. can be illustrated.
[0011]
Specific examples of R 1 to R 3 having these substituents include chloromethyl group, fluoromethyl group, bromomethyl group, dichloromethyl group, difluoromethyl group, dibromomethyl group, trichloromethyl group, trifluoromethyl group, tribromomethyl. Group, trichloromethyl group, trifluoroethyl, and the like are haloalkyl groups, pentafluoroethyl groups, tetrafluoroethenyl groups, haloalkenyl groups such as 2,2-difluoroethenyl groups, methoxymethyl groups, methoxyethyl groups, phenoxymethyl, etc. Examples thereof include alkylthioalkyl groups such as alkoxyalkyl groups, methylthiomethyl groups and phenylthiomethyl groups or arylthioalkyl groups, aralkyl groups such as benzyl groups, diphenylmethyl groups, trityl groups and phenethyl groups.
[0012]
Specific examples of the compound represented by formula (I) include the compounds shown in the following table.
[0013]
[Table 1]
[0014]
[Table 2]
[0015]
In the compounds represented by formula (II) and formula (III) used in the present invention, R 1 to R 3 have the same meaning as described above, and the same specific examples can be exemplified. Further, specific examples of the compounds represented by formula (II) and formula (III) include compounds corresponding to the compounds exemplified in Table 1.
[0016]
In the method of the present invention, the nitrile derivative represented by the formula (II) is hydrolyzed using 65 to 98% by weight sulfuric acid aqueous solution, and then hydrolyzed using 30 to 65% by weight sulfuric acid aqueous solution. It has the process (2). It was confirmed during the reaction that the amide compound represented by the formula (III) was obtained in a good yield when the hydrolysis reaction was carried out using only 65 to 98% by weight sulfuric acid aqueous solution. There is a problem that the hydrolysis reaction to the carboxylic acid derivative does not proceed easily and a large amount of tar-like decomposition products are generated. Further, when the hydrolysis reaction is carried out using only 30 to 65% by weight sulfuric acid, the hydrolysis reaction of the nitrile compound represented by the formula (II) is difficult to proceed, and the nitrile as a raw material does not react. There is.
[0017]
65-98 wt% sulfuric acid aqueous solution is preferably prepared by diluting concentrated sulfuric acid with an appropriate amount of water in advance, except that commercially available concentrated sulfuric acid (95-98%) is used as it is. It can also be prepared by mixing the compound represented by the formula and concentrated sulfuric acid and then adding water, or by mixing the compound represented by the formula (II) and water and then adding concentrated sulfuric acid.
[0018]
The amount of 65-98% by weight sulfuric acid used is not particularly limited as long as the amount of water contained is at least 1 mol or more with respect to 1 mol of the compound represented by the formula (II). It is preferable to use the above amount, and it is preferable to use 10 mol or more.
[0019]
The reaction temperature in the step (1) of hydrolysis using 65 to 98% by weight sulfuric acid is not particularly limited as long as the compound in the reaction system is not decomposed, and the reaction can be performed at a high temperature. It is preferable to carry out at ~ 100 ° C.
[0020]
The reaction method is not particularly limited. For example, (1) a method in which sulfuric acid water and a compound represented by formula (II) are mixed at room temperature and heated, (2) a compound represented by formula (II) in heated sulfuric acid water Any method may be employed, for example, a method of adding a bisphenol, or a method of dropping a compound represented by formula (II) suspended in a small amount of water or an organic solvent under heating.
[0021]
The reaction time in the step (1) is not particularly limited as long as the compound represented by the formula (II) and the product as a raw material are not decomposed, but when the raw material disappears, the heating is stopped and the reaction is completed. It is preferable to do so. The product, the amide compound represented by formula (III), is the main product, but it may contain a carboxylic acid represented by formula (I).
[0022]
The step (1) of hydrolyzing the nitrile derivative represented by the formula (II) in the present invention using 65 to 98% by weight sulfuric acid and the step (2) of hydrolyzing using 30 to 65% by weight sulfuric acid. Can be carried out continuously, or after completion of step (1), the product can be isolated and step (2) can be newly carried out.
[0023]
In the case where the step (1) and the step (2) are continuously performed, it is preferable in terms of the reaction operation to adjust the sulfuric acid concentration by adding a necessary amount of water to the reaction solution under heating or cooling the reaction solution. The sulfuric acid concentration can be adjusted by adding the reaction solution to an appropriate amount of water under heating or at room temperature.
[0024]
Regarding the operation in the case where the product is isolated in the step (1) and the step (2) is newly performed, the reaction may be the same as the step (1) described above except that the raw material and sulfuric acid concentrations are different. it can.
The reaction temperature in step (2) is preferably in the range of 90 to 130 ° C.
[0025]
The nitrile derivative represented by the formula (II) or the amide derivative represented by the formula (III) subjected to the hydrolysis step can be used as it is without being diluted, It can also be diluted with a solvent. The organic solvent to be used is not particularly limited as long as it dissolves the nitrile derivative and amide derivative and is inert to the acid hydrolysis conditions. Specifically, organic solvents such as toluene, xylene, chlorobenzene and the like are exemplified. Can do.
[0026]
The dilution concentration is not particularly limited, but is preferably in the range of 10 to 60% by weight. Further, the nitrile derivative or amide derivative does not need to be completely dissolved, and can be used in a suspended state.
[0027]
For the nitrile derivative represented by the formula (II) and the amide derivative represented by the formula (III), use a commercially available product or a synthetic product obtained by alkylating a mono-substituted or disubstituted α-position. Can do. In particular, in the case of a synthetic product, a crude product containing impurities that have not undergone a post-reaction purification step can be directly subjected to the reaction. However, when a basic compound is contained in impurities or the like, it is necessary to use a larger amount of sulfuric acid accordingly.
[0028]
EXAMPLES Hereinafter, although this invention is demonstrated further in detail using an Example, the scope of the present invention is not limited to an Example.
[0029]
【Example】
Example 1
Concentrated sulfuric acid (96 wt%) 14.7 g was added to 4.1 g of water to prepare 75 wt% sulfuric acid aqueous solution, and 6.0 g (0.05 mol, purity 96%) of 2,2-dimethylvaleronitrile was added. The reaction was carried out at 85 to 90 ° C. for 2 hours. A part of the reaction solution was taken out and quantified by high performance liquid chromatography (HPLC). As a result, it was confirmed that 2,2-dimethylpentanamide was produced almost quantitatively. 9.4 g of water was further added to the reaction solution to make 50% by weight sulfuric acid solution, and then reacted at 115 ° C. for 2 hours. After the reaction, the mixture was cooled to room temperature, and 80 ml of water and 50 ml of ether were added for liquid separation. The organic layer was washed with 50 ml of water, dried and the ether was distilled off to obtain 6.27 g of an oily substance. When the compound was identified by 1HNMR and quantified by HPLC, it was found that the desired 2,2-dimethylvaleric acid was obtained in a yield of 90% (purity 97%).
[0030]
Example 2
The reaction was conducted in the same manner as in Example 1 using 6.0 g (0.05 mol, purity 96%) of 2-ethyl-2-methyl-butyronitrile. 6.0 g (yield 87%, purity 98%) of butyric acid was obtained.
[0031]
Example 3
109.8 g of 75% sulfuric acid was added to a solution of 33.4% by weight of toluene in 103.4 g (0.292 mol) of 2,2-dimethylvaleronitrile and reacted at 95-100 ° C. for 5 hours. A part of the reaction solution was taken out and analyzed by high performance liquid chromatography (HPLC), and it was confirmed that 2,2-dimethylpentanamide was produced almost quantitatively. An additional 55 g of water was added to the reaction solution to make 50% sulfuric acid solution, and then a part of toluene was distilled off so that the reaction temperature became 120 to 125 ° C., and then reacted at the same temperature for 8 hours. The reaction solution was cooled to room temperature, and 100 ml of water was added for liquid separation. The organic layer was washed with 50 ml of water, and the solvent was distilled off to obtain about 36 g of an oily substance. When the compound was identified by 1HNMR and quantified by HPLC, the desired 2,2-dimethylvaleric acid was obtained in a yield of 90% (purity 95%).
[0032]
Comparative Example 1
Concentrated sulfuric acid (96 wt%) 14.7 g was added to 4.1 g of water to prepare 75 wt% sulfuric acid aqueous solution, and 6.0 g (0.05 mol, purity 96%) of 2,2-dimethylvaleronitrile was added. When the reaction was carried out at 85 to 90 ° C. for 2 hours and further at the reflux temperature (approximately 130 ° C.) for 18 hours, the amide compound produced during the disappearance disappeared. The post-treatment operation was performed in the same manner as in Example 1. As a result, 5.1 g (yield 76%, purity 97%) of 2,2-dimethylvaleric acid was obtained. Further, a black tar-like component was adhered to the reaction tank.
[0033]
Comparative Example 2
A reaction was carried out in the same manner as in Comparative Example 1 except that the reaction was carried out using 50% by weight sulfuric acid at reflux temperature for 18 hours. As a result, the reaction was not completed, and 59% of the starting nitrile was recovered. Only 14% of herbal acid was obtained.
[0034]
【The invention's effect】
As described above, by using the method of the present invention, bulky α-positioned trisubstituted acetonitrile, which has been conventionally difficult to hydrolyze, is hydrolyzed with good operability, and α-positioned trisubstituted acetic acid is obtained in a yield and purity. I can get well. The α-position tri-substituted acetic acid is a useful compound as an intermediate for agricultural medicine, and the production method of the present invention has high industrial utility value.

Claims (1)

式(I)
(式中、R1、R2、R3はそれぞれ独立にメチル基、エチル基又はn−プロピル基を表す。)で表される酢酸誘導体の製造方法において、式(II)
(式中、R1、R2、R3は前記と同じ意味を表す。)で表されるニトリル誘導体を、65〜98重量%硫酸水を用いて50〜100℃の反応温度で加水分解する工程(1)、次いで30〜65重量%硫酸水を用いて90〜130℃の反応温度で加水分解する工程(2)を有することを特徴とする製造方法。
Formula (I)
(Wherein, R 1, R 2, R 3 each independently represents a methyl group, an ethyl group or n- propyl Table to.) In the process for the production of acetic acid derivative represented by the formula (II)
(Wherein R 1 , R 2 , and R 3 represent the same meanings as described above), and hydrolyzing the nitrile derivative at a reaction temperature of 50 to 100 ° C. using 65 to 98 wt% sulfuric acid water. A production method comprising a step (1) and then a step (2) of hydrolyzing at a reaction temperature of 90 to 130 ° C using 30 to 65 wt% sulfuric acid aqueous solution.
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