JP5468400B2 - Process for producing 4-chloropyridine-2-carboxylic acid chloride - Google Patents
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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Description
本発明は、医薬品、農薬等の中間体原料として有用である４−クロロピリジン−２−カルボン酸クロリドまたはその塩の製造方法に関する。 The present invention relates to a method for producing 4-chloropyridine-2-carboxylic acid chloride or a salt thereof which is useful as an intermediate material for pharmaceuticals, agricultural chemicals and the like.
従来、４−クロロピリジン−２−カルボン酸クロリドの製造方法としては、触媒存在下でピリジン−２−カルボン酸と塩化チオニルとを反応させる製造方法が知られている（非特許文献１及び２並びに特許文献１）。
非特許文献１では、触媒に臭化ナトリウムを用いた製造方法が開示されている。
また、非特許文献２では、触媒にＮ，Ｎ−ジメチルホルムアミドを用いた製造方法が開示されている。
Conventionally, as a method for producing 4-chloropyridine-2-carboxylic acid chloride, a production method in which pyridine-2-carboxylic acid and thionyl chloride are reacted in the presence of a catalyst is known (Non-Patent Documents 1 and 2, and Patent Document 1).
Non-Patent Document 1 discloses a production method using sodium bromide as a catalyst.
Non-Patent Document 2 discloses a production method using N, N-dimethylformamide as a catalyst.
さらに、特許文献１では、触媒に臭化物およびＮ−置換ホルムアミド類を用いた製造方法が開示されている。 Further, Patent Document 1 discloses a production method using bromide and N-substituted formamide as a catalyst.
しかしながら、非特許文献１に記載の方法では反応時間が２０時間以上と長時間を要するため工業的な使用には適さない。触媒である臭化ナトリウムを大過剰に用いることで反応時間が短縮されるという報告はあるものの、その一方で４，５−ジクロロ体等の副生物が増加し、収率低下を招くことから、工業的に満足できる製造法とは言い難い。 However, the method described in Non-Patent Document 1 is not suitable for industrial use because the reaction time is as long as 20 hours or longer. Although there is a report that the reaction time is shortened by using a large excess of sodium bromide as a catalyst, on the other hand, by-products such as 4,5-dichloro form increase, resulting in a decrease in yield. It is hard to say that it is an industrially satisfactory production method.
また、非特許文献２に記載の製造方法においては、反応時間が２４時間と長時間を要するため、工業的に満足できる製造方法とは言い難い。 Further, in the production method described in Non-Patent Document 2, the reaction time is as long as 24 hours, so it is difficult to say that the production method is industrially satisfactory.
さらに、特許文献１に記載の製造方法においては、触媒の組み合わせにより反応が４〜６時間と短時間で終了するものの、４，５−ジクロロ体等の副生物が生成し、目的の４−クロロピリジン−２−カルボン酸クロリドの収率が低いため、工業的に満足できる製造方法とは言い難い。 Furthermore, in the production method described in Patent Document 1, although the reaction is completed in a short time of 4 to 6 hours depending on the combination of the catalysts, a by-product such as a 4,5-dichloro compound is produced, and the desired 4-chloro compound is produced. Since the yield of pyridine-2-carboxylic acid chloride is low, it is difficult to say that it is an industrially satisfactory production method.
そこで、本発明の目的は、４−クロロピリジン−２−カルボン酸クロリドまたはその塩を高純度かつ高収率で得ることができる、工業的に有利な製造方法を提供することにある。 Accordingly, an object of the present invention is to provide an industrially advantageous production method capable of obtaining 4-chloropyridine-2-carboxylic acid chloride or a salt thereof with high purity and high yield.
本発明者らは前述の問題点を解決するため鋭意検討を重ねた結果、ピリジン−２−カルボン酸誘導体またはその塩を塩化チオニルと反応させる方法において、臭素を触媒として用いることで高純度かつ高収率で４−クロロピリジン−２−カルボン酸クロリドが得られる事を見出し、本発明を完成するに至った。 As a result of intensive investigations to solve the above-mentioned problems, the present inventors have used bromine as a catalyst in a method of reacting a pyridine-2-carboxylic acid derivative or a salt thereof with thionyl chloride, thereby achieving high purity and high purity. It was found that 4-chloropyridine-2-carboxylic acid chloride was obtained in a yield, and the present invention was completed.
すなわち本発明は、
（１）下式(Ｉ)
That is, the present invention
(1) The following formula (I)
で表される化合物またはその塩と塩化チオニルとを反応させることにより下式(ＩＩ)
に関する。
By reacting a compound represented by the formula or a salt thereof with thionyl chloride:
About.
本発明によれば、ピリジン−２−カルボン酸誘導体またはその塩を塩化チオニルと反応させる方法において、臭素を触媒として用いることで効率的に高純度かつ高収率で４−クロロピリジン−２−カルボン酸クロリドを工業的に有利な方法で得ることができる。 According to the present invention, in a method of reacting a pyridine-2-carboxylic acid derivative or a salt thereof with thionyl chloride, 4-chloropyridine-2-carboxylic acid can be efficiently obtained in high purity and high yield by using bromine as a catalyst. The acid chloride can be obtained in an industrially advantageous manner.
以下、本発明を実施するための形態について詳述するが、本発明はこれにより限定されるものではない。 Hereinafter, although the form for implementing this invention is explained in full detail, this invention is not limited by this.
本発明において使用する式（Ｉ）で表される化合物は、市販品として入手可能なピリジン−２−カルボン酸またはそれを公知の方法により塩化チオニル等の酸ハロゲン化物で酸ハロゲン化したピリジン−２−カルボン酸クロリド等のピリジン−２−カルボン酸ハライドであり、さらにそれらは塩酸塩などの塩を形成していてもよい。 The compound represented by the formula (I) used in the present invention is a commercially available pyridine-2-carboxylic acid or pyridine-2 obtained by acid-halogenating it with an acid halide such as thionyl chloride by a known method. -Pyridine-2-carboxylic acid halides such as carboxylic acid chlorides, which may further form salts such as hydrochlorides.
本発明において、ハロゲン原子とはフッ素、塩素、臭素及びヨウ素を意味する。 In the present invention, the halogen atom means fluorine, chlorine, bromine and iodine.
式（Ｉ）で表される化合物の塩としては塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、酢酸塩、乳酸塩、安息香酸塩、酒石酸塩、クエン酸塩、スルホン酸塩などを挙げることができるが、好ましくは塩酸塩である。 Salts of the compound represented by the formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, acetate, lactate, benzoate, Tartrate, citrate, sulfonate and the like can be mentioned, and hydrochloride is preferred.
本発明において使用する塩化チオニルの使用量はピリジン−２−カルボン酸またはその塩を用いた場合は出発原料に対し２倍モル以上であれば良く、ピリジン−２−カルボン酸ハライドまたはその塩を用いた場合は出発原料に対し１倍モル以上であれば良い。好ましくは、各基質に対し２．０〜７倍モルの範囲であり、特に好ましくは、各基質に対し２．５〜５倍モルの範囲である。 The amount of thionyl chloride used in the present invention may be two or more moles compared to the starting material when pyridine-2-carboxylic acid or a salt thereof is used, and pyridine-2-carboxylic acid halide or a salt thereof is used. In such a case, it may be at least 1 mol per mol of the starting material. Preferably, it is the range of 2.0-7 times mole with respect to each substrate, Most preferably, it is the range of 2.5-5 times mole with respect to each substrate.
本発明において、触媒には工業的に安価で入手可能な臭素を用いる。臭素の使用量は触媒量で良く、出発物質に対し通常０．０１〜１．０倍モルであり、好ましくは０．０５〜０．５倍モルであり、更に好ましくは０．１〜０．３倍モルである。０．０１倍モル未満の場合は触媒の効果が見られず、また、１．０倍モルを超えて使用した場合は４，５−ジクロロ体等の副生成物が増加して収率が低下する。 In the present invention, bromine, which is industrially inexpensive and available, is used for the catalyst. The amount of bromine used may be a catalytic amount, and is usually 0.01 to 1.0 times mol, preferably 0.05 to 0.5 times mol, more preferably 0.1 to 0. 3 times mole. If it is less than 0.01-fold mol, the effect of the catalyst is not seen, and if it exceeds 1.0-fold mol, by-products such as 4,5-dichloro form increase and the yield decreases. To do.
本発明では臭素を触媒として使用するが、Ｎ−置換ホルムアミドを触媒として併用することはない。Ｎ−置換ホルムアミドとしてはＮ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジエチルホルムアミド、Ｎ，Ｎ−ジイソプロピルホルムアミド、Ｎ，Ｎ−ジブチルホルムアミド、Ｎ−メチルホルムアニリド、１−ホルミルピペリジン、１−ホルミルピロリジンなどを挙げることができるが、これらに限定されるものではない。 In the present invention, bromine is used as a catalyst, but N-substituted formamide is not used as a catalyst. N-substituted formamide includes N, N-dimethylformamide, N, N-diethylformamide, N, N-diisopropylformamide, N, N-dibutylformamide, N-methylformanilide, 1-formylpiperidine, 1-formylpyrrolidine, etc. However, it is not limited to these.
反応溶媒は特に用いなくても反応は進行するが必要により用いても良い。反応溶媒を用いる場合は反応に悪影響を及ぼさないものであれば特に制限はない。例えば、アセトニトリルなどのニトリル類；ベンゼン、トルエン、キシレンなどの芳香族炭化水素類；ヘキサン、ヘプタン、オクタンなどの脂肪族炭化水素類；シクロヘキサン、シクロヘプタン、メチルシクロヘキサンなどの脂環式炭化水素類；ジクロロメタン、クロロホルムなどのハロゲン化炭化水素類；ジエチルエーテル、シクロペンチルメチルエーテル、ＴＨＦなどのエーテル類；酢酸エチル、酢酸プロピルなどのエステル類；これらの混合溶媒などを挙げることができる。 The reaction proceeds even if no reaction solvent is used, but it may be used if necessary. When a reaction solvent is used, there is no particular limitation as long as it does not adversely affect the reaction. For example, nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane, heptane and octane; and alicyclic hydrocarbons such as cyclohexane, cycloheptane and methylcyclohexane; Examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, cyclopentylmethyl ether and THF; esters such as ethyl acetate and propyl acetate; and mixed solvents thereof.
反応温度は溶媒の有無、使用する溶媒の種類によっても異なるが、通常３０〜１４０℃であり、好ましくは５０〜１２０℃であり、更に好ましくは７０〜９０℃である。３０℃未満では著しく反応速度の低下がみられ１４０℃を超えると分解が進み収率が低下する。 The reaction temperature varies depending on the presence or absence of a solvent and the type of solvent used, but is usually 30 to 140 ° C, preferably 50 to 120 ° C, more preferably 70 to 90 ° C. If it is less than 30 degreeC, the fall of reaction rate will be seen remarkably, when it exceeds 140 degreeC, decomposition will progress and a yield will fall.
反応時間は反応溶媒の有無、溶媒の種類、触媒量、反応温度等により異なるが通常は３〜７時間である。 The reaction time varies depending on the presence or absence of the reaction solvent, the type of solvent, the amount of catalyst, the reaction temperature, etc., but is usually 3 to 7 hours.
反応により生成した４−クロロピリジン−２−カルボン酸クロリドは公知の方法（例えば、非特許文献１及び２を参照）によりアミド化またはエステル化等の処理を行い医薬品、農薬等の中間体として使用できる。 4-Chloropyridine-2-carboxylic acid chloride produced by the reaction is treated as an intermediate for pharmaceuticals, agricultural chemicals and the like by performing amidation or esterification by a known method (for example, see Non-Patent Documents 1 and 2). it can.
以下、実施例および比較例により本発明を更に詳細に説明するが本発明はこれらにより何ら限定されるものではない。 EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention further in detail, this invention is not limited at all by these.
目的生成物である４−クロロピリジン−２−カルボン酸クロリドは不安定な化合物であり、そのままでは分析することができない。このため少量の反応液をメタノール中に添加し目的生成物をメチルエステル化した後に下記ＨＰＬＣ条件により分析を行ない４−クロロピリジン−２−カルボン酸メチルの面積百分率としての生成率を確認した。 The target product, 4-chloropyridine-2-carboxylic acid chloride, is an unstable compound and cannot be analyzed as it is. For this reason, a small amount of the reaction solution was added to methanol to methyl esterify the target product, and then analyzed under the following HPLC conditions to confirm the production rate of methyl 4-chloropyridine-2-carboxylate as an area percentage.
ＨＰＬＣ条件
検出器 ：紫外吸収光度計（検出波長 ２５４ｎｍ)
カラム ：ＹＭＣ−Ｐａｃｋ Ｐｒｏ Ｃ１８（４．６×１５０ｍｍ）
カラム温度：２４℃
移動相 ：アセトニトリル／水／７０％過塩素酸水＝４００／６００／１
流量 ：１．０ｍＬ／ｍｉｎ
HPLC condition detector: UV absorption photometer (detection wavelength: 254 nm)
Column: YMC-Pack Pro C18 (4.6 × 150 mm)
Column temperature: 24 ° C
Mobile phase: acetonitrile / water / 70% aqueous perchloric acid = 400/600/1
Flow rate: 1.0 mL / min
実施例１
窒素気流下ピリジン−２−カルボン酸５．０ｇ（４０．６ミリモル）、塩化チオニル２４．１ｇ（原料の５倍モル）、臭素０．６ｇ（原料の０．１倍モル）を仕込み、ゆっくりと温度を上げ８５℃で７時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は８８．５％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は５．２％であった。
Example 1
In a nitrogen stream, 5.0 g (40.6 mmol) of pyridine-2-carboxylic acid, 24.1 g of thionyl chloride (5 times mol of the raw material), and 0.6 g of bromine (0.1 mol of the raw material) were slowly added. Since the disappearance of the raw materials was confirmed when the temperature was raised and the reaction was carried out at 85 ° C. for 7 hours, the reaction was terminated. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 88.5% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 5. 2%.
実施例２
窒素気流下ピリジン−２−カルボン酸５．０ｇ（４０．６ミリモル）、塩化チオニル２４．１ｇ（原料の５倍モル）、臭素１．３ｇ（原料の０．２倍モル）を仕込み、ゆっくりと温度を上げ８５℃で３時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は８９．３％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は２．３％であった。
Example 2
In a nitrogen stream, 5.0 g (40.6 mmol) of pyridine-2-carboxylic acid, 24.1 g of thionyl chloride (5 times mol of the raw material) and 1.3 g of bromine (0.2 times mol of the raw material) were charged slowly. Since the disappearance of the raw materials was confirmed when the temperature was raised and the reaction was carried out at 85 ° C. for 3 hours, the reaction was terminated. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 89.3% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 2. 3%.
実施例３
窒素気流下ピリジン−２−カルボン酸１４５．０ｇ（１．１８モル）、塩化チオニル７００．６ｇ（原料の５倍モル）、臭素３７．６ｇ（原料の０．２倍モル）を仕込み、ゆっくりと温度を上げ８５℃で４時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は８８．０％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は５．０％であった。
Example 3
In a nitrogen stream, 145.0 g (1.18 mol) of pyridine-2-carboxylic acid, 700.6 g of thionyl chloride (5 times mol of the raw material) and 37.6 g of bromine (0.2 times mol of the raw material) were slowly added. Since the disappearance of the raw material was confirmed when the temperature was raised and the reaction was carried out at 85 ° C. for 4 hours, the reaction was terminated. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 88.0% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 5. 0%.
実施例４
窒素気流下ピリジン−２−カルボン酸７．０ｇ（５６．９ミリモル）、アセトニトリル７．０ｍＬ（原料の１倍容量）、塩化チオニル３３．８ｇ（原料の５倍モル）、臭素１．８ｇ（原料の０．２倍モル）を仕込み、ゆっくりと温度を上げ８５℃で４時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は８５．２％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は３．４％であった。
Example 4
Under a nitrogen stream, 7.0 g (56.9 mmol) of pyridine-2-carboxylic acid, 7.0 mL of acetonitrile (1 times the volume of the raw material), 33.8 g of thionyl chloride (5 times the molar amount of the raw material), 1.8 g of bromine (raw material) The reaction was terminated because the disappearance of the raw materials was confirmed when the reaction was carried out at 85 ° C. for 4 hours. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 85.2% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 3. 4%.
実施例５
アセトニトリル２００Ｌ（原料の２倍容量），ピリジン−２−カルボン酸１００Ｋｇ（８１２．３モル）を仕込み、冷却撹拌下塩化チオニル１４５．０Ｋｇ（原料の１．５倍モル）を滴下し、混合液を４０℃で２時間撹拌後、減圧により溶媒を留去した。溶媒留去後、塩化チオニル２８９．９Ｋｇ（原料の３倍モル）、臭素２６．０Ｋｇ（原料の０．２倍モル）を仕込み、ゆっくりと温度を上げ８５℃で３時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は８２．４％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は３．７％であった。
Example 5
200 L of acetonitrile (2 times the volume of the raw material) and 100 kg of pyridine-2-carboxylic acid (812.3 mol) were charged, and 145.0 kg of thionyl chloride (1.5 times the molar amount of the raw material) was added dropwise with cooling and stirring. After stirring at 40 ° C. for 2 hours, the solvent was distilled off under reduced pressure. After distilling off the solvent, 289.9 kg of thionyl chloride (3 times mol of the raw material) and 26.0 kg of bromine (0.2 times mol of the raw material) were added, and the temperature was raised slowly and reacted at 85 ° C. for 3 hours. Since the disappearance of was confirmed, the reaction was terminated. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 82.4% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 3. 7%.
比較例１
窒素気流下ピリジン−２−カルボン酸１．０Ｋｇ（８．１２モル）、塩化チオニル４．８Ｋｇ（原料の５倍モル）、臭化ナトリウム８３．６ｇ（原料の０．１倍モル）を仕込み、ゆっくりと温度を上げ８５℃で行なったところ、原料の消失に２２時間を要した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は７５．４％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は７．１％であった。
Comparative Example 1
In a nitrogen stream, 1.0 kg (8.12 mol) of pyridine-2-carboxylic acid, 4.8 kg of thionyl chloride (5 times mol of the raw material), and 83.6 g of sodium bromide (0.1 mol of the raw material) were charged. When the temperature was raised slowly at 85 ° C., it took 22 hours for the raw materials to disappear. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 75.4% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 7. 1%.
比較例２
窒素気流下ピリジン−２−カルボン酸１００．０ｇ（８１２．３ミリモル）、塩化チオニル４８３．３ｇ（原料の５倍モル）、Ｎ，Ｎ−ジメチルホルムアミド５９．４ｇ（原料の１．０倍モル）を仕込み、ゆっくりと温度を上げ８５℃で１２時間反応を行なった。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は５３．７％（対ピリジン−２−カルボン酸）であり、中間体として生成するピリジンカルボン酸メチルの生成率は３０．８％であり、不純物である４，５−ジクロル体の生成率は２．７％であった。
Comparative Example 2
Under a nitrogen stream, 100.0 g (812.3 mmol) of pyridine-2-carboxylic acid, 483.3 g of thionyl chloride (5 times mol of the raw material), 59.4 g of N, N-dimethylformamide (1.0 times mol of the raw material) And the temperature was slowly raised and the reaction was carried out at 85 ° C. for 12 hours. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 53.7% (vs. pyridine-2-carboxylic acid), and the production rate of methyl pyridinecarboxylate produced as an intermediate was 30. The yield of 4,5-dichloro isomer, which is an impurity, was 2.7%.
比較例３
塩化チオニル１９．３ｇ（原料の４倍モル）、臭化ナトリウム０．４ｇ（原料の０．１倍モル）およびＮ，Ｎ−ジメチルホルムアミド０．５ｇ（原料の０．１５倍モル）を仕込み、ピリジン−２−カルボン酸５．０ｇ（４０．６ミリモル）を添加した。添加終了後、ゆっくりと温度を上げ、８５℃で６．５時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は７６．３％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は６．２％であった。
Comparative Example 3
Charge 19.3 g of thionyl chloride (4 times mol of the raw material), 0.4 g of sodium bromide (0.1 times mol of the raw material) and 0.5 g of N, N-dimethylformamide (0.15 mol of the raw material), 5.0 g (40.6 mmol) of pyridine-2-carboxylic acid was added. After the addition was completed, the temperature was slowly raised, and the reaction was terminated at 85 ° C. for 6.5 hours. As a result of HPLC analysis, the yield of methyl 4-chloropyridine-2-carboxylate was 76.3% (vs. pyridine-2-carboxylic acid), and the yield of 4,5-dichloro compound as an impurity was 6. 2%.
比較例４
塩化チオニル１９．３ｇ（原料の４倍モル）を仕込み、ピリジン−２−カルボン酸臭化水素酸塩８．３ｇ（４０．６ミリモル）およびＮ，Ｎ−ジメチルホルムアミド０．５ｇ（原料の０．１５倍モル）を添加した。添加終了後、ゆっくりと温度を上げ、８５℃で３時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は４９．７％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は６．２％であった。
Comparative Example 4
19.3 g of thionyl chloride (4 times mol of the raw material) was charged, 8.3 g (40.6 mmol) of pyridine-2-carboxylic acid hydrobromide and 0.5 g of N, N-dimethylformamide (0. 15 moles) was added. After the addition was completed, the temperature was slowly raised and the reaction was terminated at 85 ° C. for 3 hours. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 49.7% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 6. 2%.
比較例５
塩化チオニル１９．３ｇ（原料の４倍モル）、臭素０．６５ｇ（原料の０．１倍モル）およびＮ，Ｎ−ジメチルホルムアミド０．５ｇ（原料の０．１５倍モル）を仕込み、ピリジン−２−カルボン酸５．０ｇ（４０．６ミリモル）を添加した。添加終了後、ゆっくりと温度を上げ、８５℃で６時間反応を行なったところで原料の消失を確認したため、反応を終了した。ＨＰＬＣ分析の結果、４−クロロピリジン−２−カルボン酸メチルの生成率は８３．７％（対ピリジン−２−カルボン酸）であり、不純物である４，５−ジクロル体の生成率は５．３％であった。
Comparative Example 5
19.3 g of thionyl chloride (4 times mol of the raw material), 0.65 g of bromine (0.1 mol of the raw material) and 0.5 g of N, N-dimethylformamide (0.15 mol of the raw material) are charged with pyridine- 5.0 g (40.6 mmol) of 2-carboxylic acid was added. After the addition was completed, the temperature was slowly raised and the reaction was terminated at 85 ° C. for 6 hours. As a result of HPLC analysis, the production rate of methyl 4-chloropyridine-2-carboxylate was 83.7% (vs. pyridine-2-carboxylic acid), and the production rate of 4,5-dichloro compound as an impurity was 5. 3%.
以下の表１に実施例の結果をまとめる。 Table 1 below summarizes the results of the examples.
本発明は医薬品、農薬等の中間体原料として有用である４−クロロピリジン−２−カルボン酸クロリドを工業的規模で効率的に高収率ならびに高純度で製造する方法として有用である。 INDUSTRIAL APPLICABILITY The present invention is useful as a method for efficiently producing 4-chloropyridine-2-carboxylic acid chloride, which is useful as an intermediate material for pharmaceuticals, agricultural chemicals, etc., on an industrial scale with high yield and high purity.
Claims (2)
で表される化合物またはその塩と塩化チオニルとを反応させることにより下式（ＩＩ）
Is reacted with thionyl chloride and a compound represented by the following formula (II):
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| PCT/JP2011/051274 WO2011093256A1 (en) | 2010-01-26 | 2011-01-25 | Method for producing 4-chloropyridine-2-carboxylic acid chloride |
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