JP2000080082A - Production of 5-halogeno-2-substituted pyridine - Google Patents
Production of 5-halogeno-2-substituted pyridineInfo
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- JP2000080082A JP2000080082A JP24803798A JP24803798A JP2000080082A JP 2000080082 A JP2000080082 A JP 2000080082A JP 24803798 A JP24803798 A JP 24803798A JP 24803798 A JP24803798 A JP 24803798A JP 2000080082 A JP2000080082 A JP 2000080082A
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- halogeno
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Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、5−ハロゲノ−2
−置換ピリジンの製造方法に関する。本発明により製造
される5−ハロゲノ−2−置換ピリジンは、医薬及び農
薬の合成中間体として有用な化合物である。例えば5−
ブロモ−2−メチルピリジンは、血圧上昇抑制物質(ア
ンジオテンシンII)レセプター拮抗薬の合成中間体とし
て有用である(バイオオーガニック アンド メディシ
ナル ケミストリー レターズ[Bioorganic & Medicin
al Chemistry Letters]、1994年、4巻、99〜1
04頁参照)。また、5−クロロ−2−メチルピリジン
は、殺虫剤および殺菌剤の合成中間体として有用である
(特開平8−295663号参照)。[0001] The present invention relates to 5-halogeno-2.
It relates to a process for the preparation of substituted pyridines. The 5-halogeno-2-substituted pyridine produced according to the present invention is a compound useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals. For example, 5-
Bromo-2-methylpyridine is useful as a synthetic intermediate of a blood pressure increase inhibitor (angiotensin II) receptor antagonist (Bioorganic & Medicin Chemistry Letters [Bioorganic & Medicin
al Chemistry Letters], 1994, Volume 4, 99-1
See page 04). Also, 5-chloro-2-methylpyridine is useful as an intermediate for synthesizing insecticides and fungicides (see JP-A-8-295563).
【0002】[0002]
【従来の技術】5−ハロゲノ−2−置換ピリジン、例え
ば5−ブロモ−2−メチルピリジンを製造する方法とし
ては、2−ピコリンを分子状臭素によって塩化アルミ
ニウムの存在下に直接臭素化する方法(バイオオーガニ
ック アンド メディシナルケミストリー レターズ
[Bioorganic & Medicinal Chemistry Letters]、19
94年、4巻、99〜104頁参照)、3−ブロモピ
リジン−N−オキシドをMeldrum's Acid(2,2−ジメ
チル−1,3−ジオキサン−4,6−ジオン)と反応さ
せたのち加水分解して5−ブロモ−2−ピリジニル酢酸
へ誘導し、さらに脱炭酸反応させることによりメチル基
を導入する方法(テトラヘドロン[Tetrahedron]、1
997年、8257〜8268頁参照)などが知られて
いる。2. Description of the Related Art As a method for producing 5-halogeno-2-substituted pyridines, for example, 5-bromo-2-methylpyridine, 2-picoline is directly brominated with molecular bromine in the presence of aluminum chloride ( Bioorganic & Medicinal Chemistry Letters, 19
1994, 4, 99-104), 3-bromopyridine-N-oxide is reacted with Meldrum's Acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and then hydrolyzed. To 5-bromo-2-pyridinyl acetic acid, followed by decarboxylation to introduce a methyl group (tetrahedron [Tetrahedron], 1
997, pages 8257-8268) and the like.
【0003】[0003]
【発明が解決しようとする課題】しかしながら、前述
の方法は、臭素化反応においてピリジン環の3位が臭素
化された異性体が44%の割合で副生し、5−ブロモ−
2−メチルピリジンの収率は25%と低い。一方、の
方法も、3−ブロモピリジン−N−オキシドをMeldrum'
s Acidと反応させる際、異性体の副生が避けられず、5
−ブロモ−2−メチルピリジンの収率は13%と低い。
したがって、これらの方法は工業的に有利な製造方法と
は言い難い。However, in the above-mentioned method, in the bromination reaction, the isomer in which the pyridine ring is brominated at the 3-position is by-produced at a rate of 44%, and 5-bromo-
The yield of 2-methylpyridine is as low as 25%. On the other hand, also in the method, 3-bromopyridine-N-oxide was added to Meldrum '
When reacting with s Acid, by-products of the
The yield of -bromo-2-methylpyridine is as low as 13%.
Therefore, these methods cannot be said to be industrially advantageous production methods.
【0004】しかして、本発明の目的は、5−ハロゲノ
−2−置換ピリジンを収率よく、工業的に有利に製造し
得る方法を提供することにある。It is an object of the present invention to provide a method for producing a 5-halogeno-2-substituted pyridine with good yield and industrial advantage.
【0005】[0005]
【課題を解決するための手段】本発明によれば、上記の
目的は、一般式(I)According to the present invention, the above objects have been achieved by the general formula (I)
【0006】[0006]
【化3】 Embedded image
【0007】(式中、R1は置換基を有していてもよい
アルキル基、アリール基またはアラルキル基を表し、R
2、R3およびR4は水素原子または置換基を有していて
もよいアルキル基を表し、Xはハロゲン原子を表す。)
で示される5−ハロゲノ−2−スルホニルピリジン誘導
体(以下、5−ハロゲノ−2−スルホニルピリジン
(I)と略記する。)をアルキル化剤、アルケニル化
剤、アリール化剤またはアラルキル化剤と反応させるこ
とを特徴とする一般式(II)(Wherein, R 1 represents an alkyl group, an aryl group or an aralkyl group which may have a substituent;
2 , R 3 and R 4 represent a hydrogen atom or an alkyl group which may have a substituent, and X represents a halogen atom. )
A 5-halogeno-2-sulfonylpyridine derivative (hereinafter abbreviated as 5-halogeno-2-sulfonylpyridine (I)) represented by the formula (1) with an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent. General formula (II) characterized by the following:
【0008】[0008]
【化4】 Embedded image
【0009】(式中、R2、R3、R4およびXは前記定
義の通りであり、R5は置換基を有していてもよいアル
キル基、アルケニル基、アリール基またはアラルキル基
を表す。)で示される5−ハロゲノ−2−置換ピリジン
(以下、5−ハロゲノ−2−置換ピリジン(II)と略
記する。)の製造方法を提供することによって達成され
る。(Wherein R 2 , R 3 , R 4 and X are as defined above, and R 5 represents an optionally substituted alkyl, alkenyl, aryl or aralkyl group) This is achieved by providing a method for producing a 5-halogeno-2-substituted pyridine (hereinafter abbreviated as 5-halogeno-2-substituted pyridine (II)) represented by the following formula:
【0010】上記一般式中、R1、R2、R3、R4および
R5が表すアルキル基としては、例えばメチル基、エチ
ル基、プロピル基、イソプロピル基、ブチル基、イソブ
チル基、tert−ブチル基などが挙げられる。これら
のアルキル基は置換基を有していてもよく、かかる置換
基としては、例えばフッ素原子、塩素原子、臭素原子、
ヨウ素原子などのハロゲン原子;水酸基;メトキシ基、
エトキシ基、プロポキシ基、ブトキシ基などのアルコキ
シル基;t−ブチルジメチルシリルオキシ基、t−ブチ
ルジフェニルシリルオキシ基などの三置換シリルオキシ
基などが挙げられる。R1およびR5が表すアリール基と
しては、例えばフェニル基、ナフチル基などが挙げら
れ、アラルキル基としては、例えばベンジル基、フェネ
チル基などが挙げられる。これらのアリール基、アラル
キル基は置換基を有していてもよく、かかる置換基とし
ては、例えばフッ素原子、塩素原子、臭素原子、ヨウ素
原子などのハロゲン原子;水酸基;メチル基、エチル
基、プロピル基、イソプロピル基、ブチル基、イソブチ
ル基、tert−ブチル基などのアルキル基;メトキシ
基、エトキシ基、プロポキシ基、ブトキシ基などのアル
コキシル基;t−ブチルジメチルシリルオキシ基、t−
ブチルジフェニルシリルオキシ基などの三置換シリルオ
キシ基;フェニル基、パラメトキシフェニル基などのア
リール基などが挙げられる。In the above general formula, the alkyl groups represented by R 1 , R 2 , R 3 , R 4 and R 5 include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- Butyl group and the like. These alkyl groups may have a substituent, such as a fluorine atom, a chlorine atom, a bromine atom,
A halogen atom such as an iodine atom; a hydroxyl group; a methoxy group;
An alkoxyl group such as an ethoxy group, a propoxy group and a butoxy group; and a trisubstituted silyloxy group such as a t-butyldimethylsilyloxy group and a t-butyldiphenylsilyloxy group. Examples of the aryl group represented by R 1 and R 5 include a phenyl group and a naphthyl group, and examples of the aralkyl group include a benzyl group and a phenethyl group. These aryl groups and aralkyl groups may have a substituent. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a hydroxyl group; a methyl group, an ethyl group and a propyl group. Alkyl groups such as isopropyl, butyl, isobutyl, and tert-butyl groups; alkoxyl groups such as methoxy, ethoxy, propoxy, and butoxy groups; t-butyldimethylsilyloxy group;
A trisubstituted silyloxy group such as a butyldiphenylsilyloxy group; and an aryl group such as a phenyl group and a paramethoxyphenyl group.
【0011】R5が表すアルケニル基としてはビニル基
などが挙げられる。このアルケニル基は置換基を有して
いてもよく、かかる置換基としては、例えばフッ素原
子、塩素原子、臭素原子、ヨウ素原子などのハロゲン原
子;水酸基;メチル基、エチル基、プロピル基、イソプ
ロピル基、ブチル基、イソブチル基、tert−ブチル
基などのアルキル基;メトキシ基、エトキシ基、プロポ
キシ基、ブトキシ基などのアルコキシル基;t−ブチル
ジメチルシリルオキシ基、t−ブチルジフェニルシリル
オキシ基などの三置換シリルオキシ基;フェニル基、パ
ラメトキシフェニル基などのアリール基などが挙げられ
る。また、Xが表す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、ヨウ素原子などが挙げら
れる。The alkenyl group represented by R 5 includes a vinyl group. The alkenyl group may have a substituent. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a hydroxyl group; a methyl group, an ethyl group, a propyl group and an isopropyl group. Alkyl groups such as butyl, isobutyl and tert-butyl groups; alkoxyl groups such as methoxy, ethoxy, propoxy and butoxy groups; trialkyl groups such as t-butyldimethylsilyloxy group and t-butyldiphenylsilyloxy group. A substituted silyloxy group; and an aryl group such as a phenyl group and a paramethoxyphenyl group. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
【0012】反応は通常、溶媒の存在下に行われる。使
用する溶媒は、反応に悪影響を与えない限り特に限定さ
れるものではなく、例えばペンタン、ヘキサン、ヘプタ
ン、オクタン、石油エーテルなどの脂肪族炭化水素;ベ
ンゼン、トルエン、キシレン、クメンなどの芳香族炭化
水素;ジエチルエーテル、テトラヒドロフラン、ジイソ
プロピルエーテル、ジメトキシエタン、ジブチルエーテ
ルなどのエーテルなどを使用することができる。これら
の溶媒は1種類を単独で用いてもよいし2種類以上を混
合して用いてもよい。溶媒の使用量は5−ハロゲノ−2
−スルホニルピリジン(I)に対して5〜50重量倍の
範囲が好ましい。[0012] The reaction is usually carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aliphatic hydrocarbons such as pentane, hexane, heptane, octane and petroleum ether; and aromatic hydrocarbons such as benzene, toluene, xylene and cumene. Hydrogen; ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, dimethoxyethane and dibutyl ether can be used. These solvents may be used alone or as a mixture of two or more. The amount of the solvent used is 5-halogeno-2.
-Sulfonylpyridine (I) is preferably in a range of 5 to 50 times by weight.
【0013】アルキル化剤、アルケニル化剤、アリール
化剤またはアラルキル化剤としては、例えばメチルマグ
ネシウムクロリド、メチルマグネシウムブロミド、エチ
ルマグネシウムクロリド、ブチルマグネシウムブロミド
などのアルキルマグネシウム化合物;ビニルマグネシウ
ムクロリド、ブテニルマグネシウムブロミドなどのアル
ケニルマグネシウム化合物;フェニルマグネシウムクロ
リド、フェニルマグネシウムブロミドなどのアリールマ
グネシウム化合物;ベンジルマグネシウムクロリドなど
のアラルキルマグネシウム化合物;メチルリチウム、エ
チルリチウムなどのアルキルリチウム化合物;フェニル
リチウムなどのアリールリチウム化合物などが挙げられ
る。これらのアルキル化剤、アルケニル化剤、アリール
化剤またはアラルキル化剤の使用量は、5−ハロゲノ−
2−スルホニルピリジン(I)1モルに対して0.1〜
10モル当量の範囲が好ましく、5−ハロゲノ−2−置
換ピリジン(II)を収率よく得る観点からは、5−ハ
ロゲノ−2−スルホニルピリジン(I)1モルに対して
1〜2モル当量用いるのがより好ましい。Examples of the alkylating, alkenylating, arylating or aralkylating agents include alkylmagnesium compounds such as methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride and butylmagnesium bromide; vinylmagnesium chloride, butenylmagnesium Alkenyl magnesium compounds such as bromide; aryl magnesium compounds such as phenyl magnesium chloride and phenyl magnesium bromide; aralkyl magnesium compounds such as benzyl magnesium chloride; alkyl lithium compounds such as methyl lithium and ethyl lithium; aryl lithium compounds such as phenyl lithium. Can be The amount of the alkylating agent, alkenylating agent, arylating agent or aralkylating agent used is 5-halogeno-
0.1 to 1 mol of 2-sulfonylpyridine (I)
The range of 10 molar equivalents is preferable, and from the viewpoint of obtaining the 5-halogeno-2-substituted pyridine (II) in good yield, 1-2 molar equivalents are used per 1 mol of 5-halogeno-2-sulfonylpyridine (I). Is more preferred.
【0014】反応は、窒素などの不活性ガス雰囲気下で
5−ハロゲノ−2−スルホニルピリジン(I)を溶媒に
溶解し、得られた溶液にアルキル化剤、アルケニル化
剤、アリール化剤またはアラルキル化剤を添加して行う
ことが好ましい。反応温度は、−30〜70℃の範囲が
好ましく、−30〜30℃の範囲がより好ましい。In the reaction, 5-halogeno-2-sulfonylpyridine (I) is dissolved in a solvent under an atmosphere of an inert gas such as nitrogen, and an alkylating agent, an alkenylating agent, an arylating agent or an aralkyl It is preferable to add an agent. The reaction temperature is preferably in the range of -30 to 70C, more preferably in the range of -30 to 30C.
【0015】反応温度が−30℃よりも低い場合、反応
速度が著しく低下し、生産性が低下する傾向にある。ま
た、反応温度が70℃よりも高い場合、原料である5−
ハロゲノ−2−スルホニルピリジン(I)のピリジン環
に結合したハロゲン原子が置換された副生成物が生成
し、5−ハロゲノ−2−置換ピリジン(II)の選択性
を低下させる原因となり易い。When the reaction temperature is lower than -30.degree. C., the reaction rate is remarkably reduced, and the productivity tends to be reduced. When the reaction temperature is higher than 70 ° C., the starting material 5-
A by-product in which a halogen atom bonded to the pyridine ring of halogeno-2-sulfonylpyridine (I) is substituted is generated, which is likely to cause a decrease in selectivity of 5-halogeno-2-substituted pyridine (II).
【0016】このようにして得られた5−ハロゲノ−2
−置換ピリジン(II)は、通常の有機化合物の単離・
精製に用いられる方法により単離・精製することができ
る。例えば、反応混合物を塩化アンモニウム水溶液で加
水分解後、酢酸エチル、トルエン、ヘキサンのような溶
媒で抽出し、水洗後濃縮し、得られる粗生成物を必要に
応じて再結晶、蒸留、クロマトグラフィ、昇華などの操
作に付すことにより精製することができる。The thus obtained 5-halogeno-2
-Substituted pyridine (II) can be used to isolate common organic compounds
It can be isolated and purified by the method used for purification. For example, the reaction mixture is hydrolyzed with an aqueous ammonium chloride solution, extracted with a solvent such as ethyl acetate, toluene, and hexane, washed with water and concentrated, and the obtained crude product is recrystallized, distilled, chromatographed, and sublimated as necessary. It can be purified by subjecting it to such an operation.
【0017】なお、原料である5−ハロゲノ−2−スル
ホニルピリジン(I)は、下記一般式(III)The starting material, 5-halogeno-2-sulfonylpyridine (I), has the following general formula (III):
【0018】[0018]
【化5】 Embedded image
【0019】(式中、R2、R3、R4およびXは前記定
義の通りである。)で示されるα−ハロゲノ−α,β−
不飽和カルボニル化合物を、下記一般式(IV)(Wherein R 2 , R 3 , R 4 and X are as defined above).
An unsaturated carbonyl compound is represented by the following general formula (IV)
【0020】[0020]
【化6】 Embedded image
【0021】(式中、R1は前記定義の通りである。)
で示されるスルホニルシアニド類と反応させることによ
り、容易に製造することができる。(In the formula, R 1 is as defined above.)
Can be easily produced by reacting with a sulfonyl cyanide represented by
【0022】[0022]
【実施例】以下、実施例により本発明をさらに詳しく説
明するが、本発明はこれらの実施例により何ら限定され
るものではない。EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.
【0023】参考例1 温度計、マグネチックスターラ、ディーンシュターク型
水分定量受器、冷却管を装備した内容積50mlの3口
フラスコに2−ブロモ−2−ブテナール14.9g(1
00mmol)、ベンゼンスルホニルシアニド8.35
g(50.0mmol)を入れ、溶媒としてトルエン1
5mlおよびブタノール1.5mlを加え、続いてホウ
酸トリブチル1.30g(5.65mmol)を添加し
た後、窒素雰囲気下として内温121℃にて攪拌し、生
成する水を分離除去しながら7時間加熱還流した。この
溶液を室温まで冷却後、溶媒などの低沸分をロータリー
エバポレーターで濃縮し、氷浴にて冷却して結晶を析出
させた。この結晶をグラスフィルターで濾過し、5℃以
下に冷却したトルエン10mlで洗浄後、真空ポンプで
2時間真空乾燥し、無色の結晶として5−ブロモ−2−
ベンゼンスルホニルピリジン14.4gを得た(純度9
8%、ベンゼンスルホニルシアニド基準の収率:95
%)。REFERENCE EXAMPLE 1 14.9 g of 2-bromo-2-butenal (14.9 g) was placed in a 50-ml three-necked flask equipped with a thermometer, a magnetic stirrer, a Dean-Stark moisture meter, and a condenser.
00 mmol), benzenesulfonyl cyanide 8.35.
g (50.0 mmol), and toluene 1
After adding 5 ml and butanol 1.5 ml, and subsequently adding 1.30 g (5.65 mmol) of tributyl borate, the mixture was stirred under an atmosphere of nitrogen at an internal temperature of 121 ° C., and the resulting water was separated and removed for 7 hours. Heated to reflux. After the solution was cooled to room temperature, low-boiling components such as a solvent were concentrated by a rotary evaporator and cooled in an ice bath to precipitate crystals. The crystals were filtered through a glass filter, washed with 10 ml of toluene cooled to 5 ° C. or lower, and then dried under vacuum with a vacuum pump for 2 hours to give 5-bromo-2- as colorless crystals.
14.4 g of benzenesulfonylpyridine was obtained (purity 9
8%, yield based on benzenesulfonyl cyanide: 95
%).
【0024】実施例1 温度計、マグネチックスターラを装備し、窒素雰囲気下
とした内容積30mlの3口フラスコに、5−ブロモ−
2−ベンゼンスルホニルピリジン1.47g(4.93
mmol)、溶媒としてテトラヒドロフラン10mlを
添加した後、この溶液を−25℃にて攪拌しながら、1
mol/Lメチルマグネシウムブロミド(テトラヒドロ
フラン溶液)6.0ml(6.0mmol)を反応液の
温度を−25〜−20℃に保ちながら30分間で滴下し
た。同温度にて2時間攪拌後、飽和塩化アンモニウム水
溶液10mlを加え、酢酸エチル10mlで3回抽出し
た。抽出液を合わせて硫酸ナトリウムにより乾燥後、ロ
ータリーエバポレーターで濃縮し、得られた粗生成物を
カラムクロマトグラフィーにより精製し、白色結晶とし
て、下記の物性を有する5−ブロモ−2−メチルピリジ
ン0.72gを得た(純度98%、収率95%)。Example 1 A 3-necked flask equipped with a thermometer and a magnetic stirrer and having a 30-ml internal volume under a nitrogen atmosphere was charged with 5-bromo-nitrogen.
1.47 g (4.93) of 2-benzenesulfonylpyridine
mmol) and 10 ml of tetrahydrofuran as a solvent.
6.0 ml (6.0 mmol) of mol / L methylmagnesium bromide (tetrahydrofuran solution) was added dropwise over 30 minutes while maintaining the temperature of the reaction solution at -25 to -20 ° C. After stirring at the same temperature for 2 hours, 10 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with 10 ml of ethyl acetate. The extracts were combined, dried over sodium sulfate, concentrated on a rotary evaporator, and the obtained crude product was purified by column chromatography to give 5-bromo-2-methylpyridine 0. 72 g (purity 98%, yield 95%) were obtained.
【0025】1H−NMRスペクトル(270MHz,
CDCl3,TMS,ppm) δ:2.51(s,3
H)、7.06(d,1H,J=8.4Hz)、7.6
8(dd,1H,J=2.5Hz,8.4Hz)、8.
55(d,1H,J=2.5Hz) 融点:32〜33℃ 1 H-NMR spectrum (270 MHz,
CDCl 3 , TMS, ppm) δ: 2.51 (s, 3
H), 7.06 (d, 1H, J = 8.4 Hz), 7.6
8. (dd, 1H, J = 2.5 Hz, 8.4 Hz);
55 (d, 1H, J = 2.5 Hz) Melting point: 32-33 ° C
【0026】実施例2 1mol/Lメチルマグネシウムブロミド(テトラヒド
ロフラン溶液)6.0ml(6.0mmol)の代わり
に、3mol/Lメチルマグネシウムクロリド(テトラ
ヒドロフラン溶液)2.0ml(6.0mmol)を用
いた以外は実施例1と同様の方法で反応および後処理を
行い、白色結晶として5−ブロモ−2−メチルピリジン
0.69gを得た(純度98%、収率90%)。Example 2 Instead of using 6.0 ml (6.0 mmol) of 1 mol / L methylmagnesium bromide (tetrahydrofuran solution), 2.0 ml (6.0 mmol) of 3 mol / L methylmagnesium chloride (tetrahydrofuran solution) was used. Was reacted and post-treated in the same manner as in Example 1 to obtain 0.69 g of 5-bromo-2-methylpyridine as white crystals (purity 98%, yield 90%).
【0027】実施例3 温度計、マグネチックスターラを装備し、窒素雰囲気下
とした内容積50mlの3口フラスコに、5−クロロ−
2−ベンゼンスルホニルピリジン5.01g(19.8
mmol)、溶媒としてテトラヒドロフラン20mlを
添加した後、この溶液を5℃にて攪拌しながら、3mo
l/Lメチルマグネシウムクロリド(テトラヒドロフラ
ン溶液)7.0ml(21.0mmol)を反応液の温
度を5℃に保ちながら30分間で滴下した。同温度にて
1時間攪拌後、飽和塩化アンモニウム水溶液10mlを
加え、酢酸エチル20mlで3回抽出した。抽出液を合
わせてロータリーエバポレーターで濃縮し、得られた粗
生成物をカラムクロマトグラフィーにより精製し、淡黄
色の油状物質として、下記の物性を有する5−クロロ−
2−メチルピリジン2.42gを得た(純度99%、収
率95%)。Example 3 A 3-neck flask equipped with a thermometer and a magnetic stirrer and having a 50 ml internal volume under a nitrogen atmosphere was placed in a 3-neck flask.
5.01 g of 2-benzenesulfonylpyridine (19.8
mmol) and 20 ml of tetrahydrofuran as a solvent.
7.0 ml (21.0 mmol) of 1 / L methylmagnesium chloride (tetrahydrofuran solution) was added dropwise over 30 minutes while maintaining the temperature of the reaction solution at 5 ° C. After stirring at the same temperature for 1 hour, 10 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The extracts were combined and concentrated on a rotary evaporator, and the obtained crude product was purified by column chromatography to give 5-chloro- as a pale yellow oily substance having the following physical properties.
2.42 g of 2-methylpyridine was obtained (purity 99%, yield 95%).
【0028】1H−NMRスペクトル(270MHz,
CDCl3,TMS,ppm) δ:2.53(s,3
H)、7.10(d,1H,J=8.2Hz)、7.5
4(dd,1H,J=2.5Hz,8.2Hz)、8.
45(d,1H,J=2.5Hz) 1 H-NMR spectrum (270 MHz,
CDCl 3 , TMS, ppm) δ: 2.53 (s, 3
H), 7.10 (d, 1H, J = 8.2 Hz), 7.5
7. 4 (dd, 1H, J = 2.5 Hz, 8.2 Hz);
45 (d, 1H, J = 2.5 Hz)
【0029】実施例4 3mol/Lメチルマグネシウムクロリド(テトラヒド
ロフラン溶液)7.0ml(21.0mmol)の代わ
りに、1mol/Lメチルマグネシウムブロミド(テト
ラヒドロフラン溶液)20.0ml(20.0mmo
l)を用いた以外は実施例3と同様の方法で反応および
後処理を行い、淡黄色の油状物質として、5−クロロ−
2−メチルピリジン2.46gを得た(純度99%、収
率96%)。Example 4 Instead of 7.0 ml (21.0 mmol) of 3 mol / L methylmagnesium chloride (tetrahydrofuran solution), 20.0 ml (20.0 mmol) of 1 mol / L methylmagnesium bromide (tetrahydrofuran solution)
The reaction and work-up were carried out in the same manner as in Example 3 except that l) was used, and 5-chloro-chloroform was obtained as a pale yellow oily substance.
2.46 g of 2-methylpyridine was obtained (purity 99%, yield 96%).
【0030】[0030]
【発明の効果】5−ハロゲノ−2−置換ピリジンを、温
和な条件下に収率よく、工業的に有利に製造し得る方法
が提供される。According to the present invention, there is provided a method for industrially and advantageously producing a 5-halogeno-2-substituted pyridine under mild conditions with good yield.
Claims (1)
アリール基またはアラルキル基を表し、R2、R3および
R4は水素原子または置換基を有していてもよいアルキ
ル基を表し、Xはハロゲン原子を表す。)で示される5
−ハロゲノ−2−スルホニルピリジン誘導体をアルキル
化剤、アルケニル化剤、アリール化剤またはアラルキル
化剤と反応させることを特徴とする一般式(II) 【化2】 (式中、R2、R3、R4およびXは前記定義の通りであ
り、R5は置換基を有していてもよいアルキル基、アル
ケニル基、アリール基またはアラルキル基を表す。)で
示される5−ハロゲノ−2−置換ピリジンの製造方法。1. A compound of the general formula (I) (Wherein, R 1 is an alkyl group which may have a substituent,
Represents an aryl group or an aralkyl group, R 2 , R 3 and R 4 represent a hydrogen atom or an alkyl group which may have a substituent, and X represents a halogen atom. 5 indicated by)
Reacting a -halogeno-2-sulfonylpyridine derivative with an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent, characterized by the general formula (II): (Wherein, R 2 , R 3 , R 4 and X are as defined above, and R 5 represents an alkyl group, an alkenyl group, an aryl group or an aralkyl group which may have a substituent). A method for producing the indicated 5-halogeno-2-substituted pyridine.
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JP24803798A JP4176201B2 (en) | 1998-09-02 | 1998-09-02 | Method for producing 5-halogeno-2-substituted pyridine |
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JP2000080082A true JP2000080082A (en) | 2000-03-21 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002173483A (en) * | 2000-12-07 | 2002-06-21 | Kuraray Co Ltd | Method for producing 2-sulfonyl-4-oxypyridine derivative |
WO2004009553A1 (en) * | 2002-07-23 | 2004-01-29 | Kuraray Co., Ltd. | Process for producing 5-(2'-pyridyl)-2-pyridone derivative |
WO2004009551A1 (en) * | 2002-07-23 | 2004-01-29 | Kuraray Co., Ltd. | Process for producing 2-substituted pyridine derivative |
WO2008078424A1 (en) | 2006-12-25 | 2008-07-03 | Tohoku University | Benzoxazole derivatives |
WO2009004914A1 (en) | 2007-07-04 | 2009-01-08 | Tohoku University | Pet probe having alkoxy group substituted by fluorine and hydroxy group |
-
1998
- 1998-09-02 JP JP24803798A patent/JP4176201B2/en not_active Expired - Fee Related
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002173483A (en) * | 2000-12-07 | 2002-06-21 | Kuraray Co Ltd | Method for producing 2-sulfonyl-4-oxypyridine derivative |
JP4663105B2 (en) * | 2000-12-07 | 2011-03-30 | 株式会社クラレ | Method for producing 2-sulfonyl-4-oxypyridine derivative |
WO2004009553A1 (en) * | 2002-07-23 | 2004-01-29 | Kuraray Co., Ltd. | Process for producing 5-(2'-pyridyl)-2-pyridone derivative |
WO2004009551A1 (en) * | 2002-07-23 | 2004-01-29 | Kuraray Co., Ltd. | Process for producing 2-substituted pyridine derivative |
US7524967B2 (en) | 2002-07-23 | 2009-04-28 | Kuraray Co., Ltd. | Process for producing 5-(2′-pyridyl)-2-pyridone derivative |
US7560563B2 (en) | 2002-07-23 | 2009-07-14 | Kuraray Co., Ltd. | Process for producing 2-substituted pyridine derivative |
WO2008078424A1 (en) | 2006-12-25 | 2008-07-03 | Tohoku University | Benzoxazole derivatives |
WO2009004914A1 (en) | 2007-07-04 | 2009-01-08 | Tohoku University | Pet probe having alkoxy group substituted by fluorine and hydroxy group |
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