JPS632262B2 - - Google Patents
Info
- Publication number
- JPS632262B2 JPS632262B2 JP7471880A JP7471880A JPS632262B2 JP S632262 B2 JPS632262 B2 JP S632262B2 JP 7471880 A JP7471880 A JP 7471880A JP 7471880 A JP7471880 A JP 7471880A JP S632262 B2 JPS632262 B2 JP S632262B2
- Authority
- JP
- Japan
- Prior art keywords
- cyanopyridine
- phosphorus oxychloride
- oxide
- chloro
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 52
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 claims description 21
- WOOVSQCALYYUDO-UHFFFAOYSA-N 1-oxidopyridin-1-ium-3-carbonitrile Chemical compound [O-][N+]1=CC=CC(C#N)=C1 WOOVSQCALYYUDO-UHFFFAOYSA-N 0.000 claims description 17
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000000034 method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 13
- 239000013078 crystal Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000000297 Sandmeyer reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- -1 nicotinic acid amide N-oxide Chemical compound 0.000 description 2
- FJCFFCXMEXZEIM-UHFFFAOYSA-N oxiniacic acid Chemical compound OC(=O)C1=CC=C[N+]([O-])=C1 FJCFFCXMEXZEIM-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XXDJXMMIVUCDGP-UHFFFAOYSA-N 1-oxidopyridin-1-ium-2-carbonitrile Chemical compound [O-][N+]1=CC=CC=C1C#N XXDJXMMIVUCDGP-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Description
【発明の詳細な説明】
本発明は２−クロル−３−シアノピリジン及び
２−クロルニコチン酸の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 2-chloro-3-cyanopyridine and 2-chlornicotinic acid.
２−クロルニコチン酸は医薬等の合成原料とし
て有用な化合物であり、従来より種々の製造法が
研究されている。斯かる製造法として例えば第３
級アミンの存在下にニコチン酸Ｎ−オキシドとオ
キシ塩化リンとを反応させて２−クロルニコチン
酸を得る方法が知られている（東ドイツ特許明細
書第80209号参照）。しかしながら該方法によれ
ば、着色した２−クロルニコチン酸が得られるに
過ぎず、この２−クロルニコチン酸はその後いか
に繰返し再結晶しても脱色することは困難であ
り、それ故該方法は高純度であることが要求され
る医薬等の合成原料の製造法として適用し難い。
このような欠点を解消するために、ニコチン酸Ｎ
−オキシドとオキシ塩化リンとを第３級アミンの
存在下で反応させ、次に生成する２−クロルニコ
チン酸クロリドを反応混合物から一旦蒸留により
精製し、更に精製された２−クロルニコチン酸ク
ロリドを加水分解して２−クロルニコチン酸を得
る方法が開発されている（特開昭52−122377号公
報参照）。しかしながら該方法では、反応混合物
から２−クロルニコチン酸クロリドを一旦精製す
るという煩雑な工程を必要とし、しかも精製され
るべき２−クロルニコチン酸クロリドは不安定な
化合物であり、精製の際慎重な操作が要求され、
それ故該方法は２−クロルニコチン酸を工業的に
有利に製造し得る方法であるとは言い難い。 2-Chlornicotinic acid is a compound useful as a synthetic raw material for pharmaceuticals, etc., and various manufacturing methods have been studied. As such a manufacturing method, for example, the third
A method is known in which 2-chlornicotinic acid is obtained by reacting nicotinic acid N-oxide with phosphorus oxychloride in the presence of a class amine (see East German Patent Specification No. 80209). However, according to this method, only colored 2-chlornicotinic acid is obtained, and it is difficult to decolorize this 2-chlornicotinic acid no matter how many times it is recrystallized. It is difficult to apply this method as a method for producing synthetic raw materials such as pharmaceuticals that require purity.
In order to eliminate these drawbacks, nicotinic acid N
- React the oxide and phosphorus oxychloride in the presence of a tertiary amine, then purify the resulting 2-chlornicotinic acid chloride from the reaction mixture by distillation, and further refine the purified 2-chlornicotinic acid chloride. A method for obtaining 2-chlornicotinic acid by hydrolysis has been developed (see JP-A-52-122377). However, this method requires a complicated step of once purifying 2-chlornicotinic acid chloride from the reaction mixture, and moreover, the 2-chlornicotinic acid chloride to be purified is an unstable compound, so careful attention must be paid during purification. operation is requested,
Therefore, it cannot be said that this method is an industrially advantageous method for producing 2-chlornicotinic acid.
本発明の目的は２−クロルニコチン酸を工業的
に有利に製造し得る方法を提供することにある。 An object of the present invention is to provide a method for industrially advantageously producing 2-chlornicotinic acid.
本発明の方法によれば、目的とする２−クロル
ニコチン酸が工業的に有利に製造される。即ち本
発明の方法に従えば、純度の高い白色の２−クロ
ルニコチン酸の簡易な操作で収率よく得ることが
できる。しかも本発明では、３−シアノピリジン
Ｎ−オキシドとオキシ塩化リンとを反応させて得
られる反応混合物から２−クロル−３−シアノピ
リジンを単離精製することなく、該反応混合物を
そのまま加水分解した場合でも上記効果が発揮さ
れる。さらに本発明では次の利点をも有する。即
ち本発明の反応式は（）式で表わされ、一方ニ
コチン酸Ｎ−オキシドを出発原料とする従来法の
反応式は（）式で表わされる。 According to the method of the present invention, the desired 2-chlornicotinic acid can be industrially advantageously produced. That is, according to the method of the present invention, highly pure white 2-chlornicotinic acid can be obtained in good yield with simple operations. Furthermore, in the present invention, 2-chloro-3-cyanopyridine is not isolated and purified from the reaction mixture obtained by reacting 3-cyanopyridine N-oxide and phosphorus oxychloride, but the reaction mixture is directly hydrolyzed. The above effect can be achieved even in the case of Furthermore, the present invention also has the following advantages. That is, the reaction formula of the present invention is represented by formula (), while the reaction formula of the conventional method using nicotinic acid N-oxide as a starting material is represented by formula ().
従来法ではカルボキシル基もオキシ塩化リンで
塩素化されて酸クロリドとなるのに対し、本発明
では原料である３−シアノピリジンＮ−オキシド
のシアノ基は塩素化を受けない。従つて本発明の
方法は従来法と比べてオキシ塩化リンの使用量は
それだけ少なくて済み、非常に経済的な方法であ
る。 In the conventional method, the carboxyl group is also chlorinated with phosphorus oxychloride to form an acid chloride, whereas in the present invention, the cyano group of 3-cyanopyridine N-oxide, which is the raw material, is not chlorinated. Therefore, the method of the present invention requires less phosphorus oxychloride than the conventional method, making it a very economical method.
本発明の方法によれば、まず３−シアノピリジ
ンＮ−オキシドとオキシ塩化リンとを反応させて
２−クロル−３−シアノピリジンを生成させる。
３−シアノピリジンＮ−オキシドとオキシ塩化リ
ンとを反応させて２−クロル−３−シアノピリジ
ンを製造した例は今日まで全く見当たらない。２
−クロル−３−シアノピリジンの製造法として
は、例えばオキシ塩化リンの存在下ニコチン酸ア
ミドＮ−オキシドに五塩化リンを作用させて２−
クロル−３−シアノピリジンを得る方法〔J.Org.
Chem.、19、第1633〜1636頁（1954年）参照〕、
２−クロル−３−アミノピリジンのサンドマイヤ
ー反応により２−クロル−３−シアノピリジンを
得る方法〔Bull.Soc.Chim.Belges、75（５−６）、
第321〜327頁（1966年）参照〕等が知られてい
る。しかしながらこれらの方法はいずれも２−ク
ロル−３−シアノピリジンを工業的に有利に製造
し得るものではない。即ち前者の方法では、２−
クロル−３−シアノピリジンを純度よく得ること
ができず、しかも２−クロル−３−シアノピリジ
ンが30〜40％程度の収率で得られるに過ぎない。
また後者の方法では、サンドマイヤー反応を行な
う際にシアン化カリウム等の有害な試薬を用いる
必要があり、環境衛生上の観点から問題がある。
これに対して本発明の方法によれば、簡易な分離
操作により反応混合物から２−クロル−３−シア
ノピリジンを高純度で得ることができ、また収率
も約50％以上であり、従来法のそれを上回つてい
る。さらに本発明の方法では、出発原料として使
用される３−シアノピリジンＮ−オキシドは入手
容易な化合物であり、また有害試薬を用いる必要
はなく環境衛生の観点からも好適である。 According to the method of the present invention, 3-cyanopyridine N-oxide and phosphorus oxychloride are first reacted to produce 2-chloro-3-cyanopyridine.
To date, no example has been found of producing 2-chloro-3-cyanopyridine by reacting 3-cyanopyridine N-oxide with phosphorus oxychloride. 2
-Chloro-3-cyanopyridine can be produced, for example, by reacting phosphorus pentachloride with nicotinic acid amide N-oxide in the presence of phosphorus oxychloride.
Method for obtaining chloro-3-cyanopyridine [J.Org.
Chem., 19 , pp. 1633-1636 (1954)]
Method for obtaining 2-chloro-3-cyanopyridine by Sandmeyer reaction of 2-chloro-3-aminopyridine [Bull.Soc.Chim.Belges, 75 (5-6),
321-327 (1966)] are known. However, none of these methods can advantageously produce 2-chloro-3-cyanopyridine industrially. That is, in the former method, 2-
Chloro-3-cyanopyridine cannot be obtained with high purity, and moreover, 2-chloro-3-cyanopyridine can only be obtained with a yield of about 30 to 40%.
Furthermore, the latter method requires the use of harmful reagents such as potassium cyanide when carrying out the Sandmeyer reaction, which poses problems from the viewpoint of environmental hygiene.
In contrast, according to the method of the present invention, 2-chloro-3-cyanopyridine can be obtained with high purity from the reaction mixture by a simple separation operation, and the yield is about 50% or more. It exceeds that of . Furthermore, in the method of the present invention, 3-cyanopyridine N-oxide used as a starting material is an easily available compound, and there is no need to use harmful reagents, which is suitable from the viewpoint of environmental hygiene.
本発明において出発原料として用いられる３−
シアノピリジンＮ−オキシドは入手容易な公知の
化合物であり、例えば３−シアノピリジンに過酸
化水素を反応させることにより定量的に製造され
得る。３−シアノピリジンＮ−オキシドとオキシ
塩化リンとの使用割合としては特に限定されず広
い範囲内で適宜選択できるが、通常前者に対して
後者を等モル以上、好ましくは２〜８倍モル用い
るのがよい。本発明では、オキシ塩化リンは反応
溶媒としても作用するが、適当な溶媒を併用して
も差し支えない。斯かる溶媒としては例えばトル
エン、キシレン等の芳香族炭化水素等を挙げるこ
とができる。また本発明ではトリエチルアミン、
トリ−ｎ−プロピルアミン、トリ−ｎ−ブチルア
ミン、Ｎ・Ｎ−ジエチルアニリン、ピリジン等の
第３級アミンを反応系内に存在させることもでき
る。本発明方法の好ましい一実施態様を挙げれ
ば、通常60〜100℃、好ましくは80〜95℃の温度
に保つたオキシ塩化リン中に該温度を保ちながら
３−シアノピリジンＮ−オキシドを徐々に添加
し、添加終了後１〜10時間還流すればよい。また
本発明方法の好ましい他の一実施態様を挙げれ
ば、オキシ塩化リン中に３−シアノピリジンＮ−
オキシドを懸濁させ、この懸濁液に室温下第３級
アミンを徐々に滴下し、滴下終了後１〜10時間程
度還流すればよい。 3- used as starting material in the present invention
Cyanopyridine N-oxide is a known compound that is easily available, and can be quantitatively produced, for example, by reacting 3-cyanopyridine with hydrogen peroxide. The ratio of 3-cyanopyridine N-oxide and phosphorus oxychloride to be used is not particularly limited and can be appropriately selected within a wide range, but the latter is usually used in moles or more equal to or more than the former, preferably 2 to 8 times the mole. Good. In the present invention, phosphorus oxychloride also acts as a reaction solvent, but an appropriate solvent may be used in combination. Examples of such solvents include aromatic hydrocarbons such as toluene and xylene. Furthermore, in the present invention, triethylamine,
Tertiary amines such as tri-n-propylamine, tri-n-butylamine, N·N-diethylaniline, and pyridine can also be present in the reaction system. In a preferred embodiment of the method of the present invention, 3-cyanopyridine N-oxide is gradually added to phosphorus oxychloride kept at a temperature of usually 60 to 100°C, preferably 80 to 95°C while maintaining the temperature. After the addition is complete, the mixture may be refluxed for 1 to 10 hours. In another preferred embodiment of the method of the present invention, 3-cyanopyridine N-
The oxide may be suspended, a tertiary amine may be gradually added dropwise to this suspension at room temperature, and the suspension may be refluxed for about 1 to 10 hours after completion of the dropwise addition.
本発明では次に上記反応混合物から２−クロル
−３−シアノピリジンを単離精製した後この化合
物を加水分解するかまたは上記反応混合物をその
まま加水分解する。加水分解条件としては従来の
加水分解条件を広く適用でき、例えば苛性ソーダ
水溶液等のアルカリ水溶液に２−クロル−３−シ
アノピリジンを添加し、次いで加熱すればよい。
２−クロルニコチン酸は反応液を冷却後該液を酸
性（例えばPH２）にし、さらに再結晶等の慣用手
段により反応液から容易に単離精製される。 In the present invention, 2-chloro-3-cyanopyridine is then isolated and purified from the above reaction mixture and then this compound is hydrolyzed, or the above reaction mixture is hydrolyzed as it is. As the hydrolysis conditions, conventional hydrolysis conditions can be widely applied. For example, 2-chloro-3-cyanopyridine may be added to an alkaline aqueous solution such as a caustic soda aqueous solution, and then heated.
2-Chlornicotinic acid is easily isolated and purified from the reaction solution by cooling the reaction solution, making the solution acidic (for example, pH 2), and further using conventional means such as recrystallization.
以下に実施例を掲げる。 Examples are listed below.
実施例 １
オキシ塩化リン300mlを85℃に保ち、３−シア
ノピリジンＮ−オキシド60ｇを反応温度が90℃を
越えないように注意しながら２時間要して徐々に
添加する。その後反応溶液が均一となつてから加
熱し、還流下５時間反応を続ける。反応終了後オ
キシ塩化リンを減圧留去し、残渣に水300mlを加
え、水中に分散する粗生成物を取する。該粗生
成物を減圧蒸留し、沸点156℃／50mmHgの留分を
集めて白色の２−クロル−３−シアノピリジン
43.4ｇを得る。Example 1 300 ml of phosphorus oxychloride is maintained at 85°C, and 60 g of 3-cyanopyridine N-oxide is gradually added over 2 hours while being careful not to let the reaction temperature exceed 90°C. Thereafter, after the reaction solution becomes homogeneous, it is heated and the reaction is continued for 5 hours under reflux. After the reaction is complete, phosphorus oxychloride is distilled off under reduced pressure, 300 ml of water is added to the residue, and the crude product dispersed in water is collected. The crude product was distilled under reduced pressure, and the fraction with a boiling point of 156°C/50mmHg was collected to obtain white 2-chloro-3-cyanopyridine.
Obtain 43.4g.
収率63％、融点107〜108℃
実施例 ２
オキシ塩化リン250mlを90℃に保ち、３−シア
ノピリジンＮ−オキシド60ｇを反応温度が95℃を
越えないように注意しながら２時間要して徐々に
添加する。その後反応溶液が均一となつてから加
熱し、還流下６時間反応を続ける。反応終了後オ
キシ塩化リンを減圧留去し、残渣に水300mlを加
え、水中に分散する粗生成物を取する。該粗生
成物を活性炭の存在下メタノール中で脱色し、次
いで熱時過にて別し、冷却して白色結晶の２
−クロル−３−シアノピリジン40.5ｇを析出させ
る。 Yield 63%, melting point 107-108°C Example 2 250ml of phosphorus oxychloride was kept at 90°C, and 60g of 3-cyanopyridine N-oxide was added over 2 hours while being careful not to let the reaction temperature exceed 95°C. Add gradually. Thereafter, after the reaction solution becomes homogeneous, it is heated and the reaction is continued for 6 hours under reflux. After the reaction is complete, phosphorus oxychloride is distilled off under reduced pressure, 300 ml of water is added to the residue, and the crude product dispersed in water is collected. The crude product was decolorized in methanol in the presence of activated carbon, separated by hot filtration, and cooled to give two white crystals.
-40.5 g of chloro-3-cyanopyridine is precipitated.
収率58％、融点107〜108℃
実施例 ３
オキシ塩化リン100mlを75℃に保ち、３−シア
ノピリジンＮ−オキシド60ｇを反応温度が85℃を
越えないように注意しながら２時間要して徐々に
添加する。その後反応溶液が均一となつてから加
熱し、還流下12時間反応を続ける。反応終了後反
応液を500ｇの氷上に徐々に注ぎ、過剰のオキシ
塩化リンを分解させると共に２−クロル−３−シ
アノピリジンを結晶として析出させる。この結晶
を取、乾燥後減圧蒸留により沸点157℃／52mm
Hgの留分を集めて白色の２−クロル−３−シア
ノピリジン35.3ｇを得る。 Yield 58%, melting point 107-108°C Example 3 100ml of phosphorus oxychloride was kept at 75°C, and 60g of 3-cyanopyridine N-oxide was added over 2 hours while being careful not to let the reaction temperature exceed 85°C. Add gradually. After the reaction solution becomes homogeneous, it is heated and the reaction is continued under reflux for 12 hours. After the reaction is completed, the reaction solution is gradually poured onto 500 g of ice to decompose excess phosphorus oxychloride and precipitate 2-chloro-3-cyanopyridine as crystals. After drying, distill the crystals under reduced pressure to obtain a boiling point of 157℃/52mm.
The Hg fraction was collected to obtain 35.3 g of white 2-chloro-3-cyanopyridine.
収率51％、融点107〜108℃
実施例 ４
３−シアノピリジンＮ−オキシド60ｇをオキシ
塩化リン300ml中に懸濁させ、該懸濁液にトリエ
チルアミン52ｇを室温下反応温度が60℃を越えな
いように注意しながら２時間要して滴下する。そ
の後この溶液を110℃で３時間加熱する。反応終
了後オキシ塩化リンを減圧留去し、得られる残渣
を300mlの水中に注ぎ込み２−クロル−３−シア
ノピリジンを結晶として析出させる。得られる粗
結晶を減圧蒸留して沸点145℃／30mmHgの留分を
集めて２−クロル−３−シアノピリジン35.7ｇを
得る。 Yield 51%, melting point 107-108°C Example 4 60 g of 3-cyanopyridine N-oxide was suspended in 300 ml of phosphorus oxychloride, and 52 g of triethylamine was added to the suspension at room temperature with a reaction temperature not exceeding 60°C. It takes 2 hours to drip while being careful. This solution is then heated at 110° C. for 3 hours. After the reaction is complete, phosphorus oxychloride is distilled off under reduced pressure, and the resulting residue is poured into 300 ml of water to precipitate 2-chloro-3-cyanopyridine as crystals. The obtained crude crystals were distilled under reduced pressure and a fraction with a boiling point of 145°C/30 mmHg was collected to obtain 35.7 g of 2-chloro-3-cyanopyridine.
収率52％、融点107〜108℃
実施例 ５
上記実施例１で得られる２−クロル−３−シア
ノピリジン70ｇを2N−苛性ソーダ水溶液300mlに
加え70℃で２時間加熱する。その後反応溶液に
3N−塩酸水溶液を加えPH２に調整すると結晶が
析出する。析出する結晶を取、水洗、乾燥して
２−クロルニコチン酸73.2ｇを得る。 Yield 52%, melting point 107-108°C Example 5 70 g of 2-chloro-3-cyanopyridine obtained in Example 1 above was added to 300 ml of 2N aqueous sodium hydroxide solution and heated at 70°C for 2 hours. Then in the reaction solution
When the pH is adjusted to 2 by adding 3N-hydrochloric acid aqueous solution, crystals will precipitate. The precipitated crystals were collected, washed with water, and dried to obtain 73.2 g of 2-chlornicotinic acid.
収率92％、融点182〜183℃
実施例 ６
オキシ塩化リン300mlを90℃に保ち、３−シア
ノピリジンＮ−オキシド60ｇを反応温度が95℃を
越えないように注意しながら２時間要して徐々に
添加する。その後反応溶液が均一となつてから加
熱し、還流下５時間反応を続ける。反応終了後オ
キシ塩化リンを減圧留去し、残渣に水300mlを加
え、水中に分散する粗生成物を取する。次に該
粗生成物を2N−苛性ソーダ水溶液300ml中に添加
し、80℃で２時間加熱する。次いでこの反応液に
活性炭５ｇを加え脱色した後別する。液に
3N−塩酸水溶液を加えてPH２に調整すると淡黄
色結晶が析出する。析出する結晶を取し、メタ
ノール中で活性炭処理した後熱時過する。液
に水を加え再結晶させると、白色結晶の２−クロ
ルニコチン酸42ｇを得る。 Yield 92%, melting point 182-183℃ Example 6 300ml of phosphorus oxychloride was kept at 90℃, and 60g of 3-cyanopyridine N-oxide was added over 2 hours while being careful not to let the reaction temperature exceed 95℃. Add gradually. Thereafter, after the reaction solution becomes homogeneous, it is heated and the reaction is continued for 5 hours under reflux. After the reaction is complete, phosphorus oxychloride is distilled off under reduced pressure, 300 ml of water is added to the residue, and the crude product dispersed in water is collected. The crude product is then added to 300 ml of 2N aqueous sodium hydroxide solution and heated at 80°C for 2 hours. Next, 5 g of activated carbon was added to this reaction solution to decolorize it, and then it was separated. into liquid
When the pH is adjusted to 2 by adding 3N-hydrochloric acid aqueous solution, pale yellow crystals are precipitated. The precipitated crystals are collected, treated with activated carbon in methanol, and then heated. Water is added to the liquid and recrystallized to obtain 42 g of 2-chlornicotinic acid as white crystals.
収率53％、融点182〜183℃ Yield 53%, melting point 182-183℃
Claims (1)
化リンとを反応させることを特徴とする２−クロ
ル−３−シアノピリジンの製造法。 ２ オキシ塩化リン中に３−シアノピリジＮ−オ
キシドを添加し、無触媒で反応させる特許請求の
範囲第１項記載の製造法。 ３ 60〜100℃の温度に保つたオキシ塩化リン中
に該温度を保ちながら３−シアノピリジンＮ−オ
キシドを添加して反応させる特許請求の範囲第２
項記載の製造法。 ４ ３−シアノピリジンＮ−オキシドとオキシ塩
化リンとを反応させ、生成する２−クロル−３−
シアノピリジンを次いで加水分解することを特徴
とする２−クロルニコチン酸の製造法。 ５ ３−シアノピリジンＮ−オキシドとオキシ塩
化リンとを反応させて得られる反応混合物を加水
分解する特許請求の範囲第４項記載の製造法。[Scope of Claims] 1. A method for producing 2-chloro-3-cyanopyridine, which comprises reacting 3-cyanopyridine N-oxide and phosphorus oxychloride. 2. The manufacturing method according to claim 1, wherein 3-cyanopyridi N-oxide is added to phosphorus oxychloride and reacted without a catalyst. 3. Claim 2, in which 3-cyanopyridine N-oxide is added to phosphorus oxychloride maintained at a temperature of 60 to 100°C and reacted.
Manufacturing method described in section. 4 2-chloro-3- produced by reacting 3-cyanopyridine N-oxide with phosphorus oxychloride
A method for producing 2-chlornicotinic acid, which comprises subsequently hydrolyzing cyanopyridine. 5. The production method according to claim 4, which comprises hydrolyzing a reaction mixture obtained by reacting 3-cyanopyridine N-oxide and phosphorus oxychloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7471880A JPS56169672A (en) | 1980-06-02 | 1980-06-02 | Preparation of 2-chloro-3-cyanopyridine and 2- chloronicotinic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7471880A JPS56169672A (en) | 1980-06-02 | 1980-06-02 | Preparation of 2-chloro-3-cyanopyridine and 2- chloronicotinic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56169672A JPS56169672A (en) | 1981-12-26 |
| JPS632262B2 true JPS632262B2 (en) | 1988-01-18 |
Family
ID=13555273
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7471880A Granted JPS56169672A (en) | 1980-06-02 | 1980-06-02 | Preparation of 2-chloro-3-cyanopyridine and 2- chloronicotinic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56169672A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4504665A (en) * | 1982-04-12 | 1985-03-12 | Ishihara Sangyo Kaisha Ltd. | Process for producing chloronicotinic acid compounds |
| JPS59144759A (en) * | 1983-02-07 | 1984-08-18 | Yuki Gosei Yakuhin Kogyo Kk | Preparation of 2-chloronicotinic acid |
| CN104072409B (en) * | 2014-06-27 | 2016-08-24 | 温州大学 | A kind of synthetic method of pyridine amides |
| CN109836376B (en) * | 2019-04-10 | 2022-03-22 | 江苏汉阔生物有限公司 | Method for preparing 2-chloronicotinic acid by using 2, 3-dipicolinic acid as raw material |
-
1980
- 1980-06-02 JP JP7471880A patent/JPS56169672A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56169672A (en) | 1981-12-26 |
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