JPS6317066B2 - - Google Patents
Info
- Publication number
- JPS6317066B2 JPS6317066B2 JP7937480A JP7937480A JPS6317066B2 JP S6317066 B2 JPS6317066 B2 JP S6317066B2 JP 7937480 A JP7937480 A JP 7937480A JP 7937480 A JP7937480 A JP 7937480A JP S6317066 B2 JPS6317066 B2 JP S6317066B2
- Authority
- JP
- Japan
- Prior art keywords
- pyridinol
- dimethyl
- reaction
- clopidol
- water
- 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
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZDPIZLCVJAAHHR-UHFFFAOYSA-N Clopidol Chemical compound CC1=NC(C)=C(Cl)C(O)=C1Cl ZDPIZLCVJAAHHR-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- PRAFLUMTYHBEHE-UHFFFAOYSA-N 2,6-dimethyl-1h-pyridin-4-one Chemical compound CC1=CC(O)=CC(C)=N1 PRAFLUMTYHBEHE-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 22
- 229960000731 clopidol Drugs 0.000 description 21
- 239000012535 impurity Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000005660 chlorination reaction Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000004287 Dehydroacetic acid Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 7
- 229940061632 dehydroacetic acid Drugs 0.000 description 7
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 7
- 235000019258 dehydroacetic acid Nutrition 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- IKNQBQLXQVSYRN-UHFFFAOYSA-N 3,5-dichloro-2,6-dimethylpyridin-4-amine Chemical compound CC1=NC(C)=C(Cl)C(N)=C1Cl IKNQBQLXQVSYRN-UHFFFAOYSA-N 0.000 description 5
- 239000012456 homogeneous solution Substances 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- VUARCKRMSQVGQQ-UHFFFAOYSA-N 3,5-dichloro-2,6-dimethylpyridine Chemical compound CC1=NC(C)=C(Cl)C=C1Cl VUARCKRMSQVGQQ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003674 animal food additive Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000208 phytotoxic Toxicity 0.000 description 2
- 230000000885 phytotoxic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ZJXMKPARTVOUAM-UHFFFAOYSA-N 2,6-dimethylpyridin-4-amine Chemical compound CC1=CC(N)=CC(C)=N1 ZJXMKPARTVOUAM-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- 208000003495 Coccidiosis Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 231100000674 Phytotoxicity Toxicity 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- -1 alicyclic hydrocarbons Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
【発明の詳細な説明】
本発明は２，６―ジメチル―４―ピリジノール
から不純物の少ない高品質の３，５―ジクロル―
２，６―ジメチル―４―ピリジノールを工業的に
有利に製造する方法に関するものである。Detailed Description of the Invention The present invention provides high quality 3,5-dichloro- with few impurities from 2,6-dimethyl-4-pyridinol.
The present invention relates to an industrially advantageous method for producing 2,6-dimethyl-4-pyridinol.
３，５―ジクロル―２，６―ジメチル―４―ピ
リジノール（以下慣用名に従いクロピドールと称
する）は家禽のコクシジウム症に対する予防及び
治療に効果があるので家禽の飼料添加剤として使
用されているが、その品質は高度のものが要求さ
れ、就中不純物としての４―アミノ―３，５―ジ
クロル―２，６―ジメチルピリジンは二次的なフ
イトトキシツクな被害を与えるため、製品クロピ
ドール中の４―アミノ―３，５―ジクロル―２，
６―ジメチルピリジンの含有量は10ppm以下と厳
重に規制されている。 3,5-dichloro-2,6-dimethyl-4-pyridinol (hereinafter referred to as clopidol according to its common name) is effective in preventing and treating coccidiosis in poultry, and is therefore used as a feed additive for poultry. Its quality is required to be of a high standard, and in particular, 4-amino-3,5-dichloro-2,6-dimethylpyridine as an impurity causes secondary phytotoxic damage. -3,5-dichlor-2,
The content of 6-dimethylpyridine is strictly regulated at 10 ppm or less.
さてクロピドールは２，６―ジメチル―４―ピ
リジノールを塩素化することによつて得られる
が、この塩素化反応後の反応液から過により分
離したクロピドールは４―アミノ―３，５―ジク
ロル―２，６―ジメチルピリジンを300〜
1000ppm程度も含んでいるのが実状である。クロ
ピドール製造の基本特許である特公昭40−20977
号公報（特許第467992号）には、過分離後のク
ロピドールを有機溶媒から再結晶したり水洗いし
たりすることにより純粋にすることができるとの
教示があるが、クロピドールは通常の有機溶媒へ
の溶解度が非常に小さいため有機溶媒による再結
晶法は到底実用的精製手段となりえず、又水洗や
有機溶媒による洗浄も結晶内部の不純物までは効
果的に除去しえない。加えて前記過操作後の母
液には薬害成分たる４―アミノ―３，５―ジクロ
ル―２，６―ジメチルピリジンが相当量含まれて
いるので二次薬害を起こさないようその廃棄を図
らねばならないが、水溶液の状態では焼却ができ
ないためその処理が極めて困難である。 Now, clopidol can be obtained by chlorinating 2,6-dimethyl-4-pyridinol, and clopidol separated from the reaction solution after this chlorination reaction by filtration is 4-amino-3,5-dichloro-2. , 6-dimethylpyridine from 300 to
The reality is that it contains about 1000 ppm. Special Publication No. 40-20977, which is the basic patent for the production of clopidol
The publication (Patent No. 467992) teaches that clopidol after over-separation can be purified by recrystallizing it from an organic solvent or washing with water. Since the solubility of the crystal is extremely low, recrystallization using an organic solvent cannot be a practical means of purification, and washing with water or an organic solvent cannot effectively remove impurities inside the crystal. In addition, the mother liquor after the over-operation contains a considerable amount of 4-amino-3,5-dichloro-2,6-dimethylpyridine, which is a phytotoxic component, so it must be disposed of to avoid secondary phytotoxicity. However, it is extremely difficult to dispose of it because it cannot be incinerated in the form of an aqueous solution.
しかるに本発明者らは鋭意研究を重ねた結果、
下記の方法を見出し、本発明を完成するに至つ
た。 However, as a result of intensive research by the present inventors,
The following method was discovered and the present invention was completed.
２，６―ジメチル―４―ピリジノールを酸性
ないしはアルカリ性の水媒体中で塩素と反応さ
せることによつて目的物たるクロピドールを含
む反応液を得る。 A reaction solution containing the target clopidol is obtained by reacting 2,6-dimethyl-4-pyridinol with chlorine in an acidic or alkaline aqueous medium.
この反応液は、の塩素化反応を酸性ないし
中性で行つたときはクロピドールが微粒子状に
分散したスラリー状を呈し、一方反応をアルカ
リ性下で行つたときは均一溶液となる（ただし
アルカリ性の程度或いは系の水の量によつては
スラリー状を呈することもある）。そこでスラ
リー状の場合はこの反応液にアルカリを加える
ことによつて析出しているクロピドールを溶解
して均一水溶液とする。 This reaction solution takes the form of a slurry in which clopidol is dispersed in fine particles when the chlorination reaction of Alternatively, depending on the amount of water in the system, it may take on the form of a slurry). Therefore, in the case of a slurry, an alkali is added to the reaction solution to dissolve the precipitated clopidol and make a homogeneous aqueous solution.
次に、アルカリ性下に均一水溶液状態にある
反応液を水と非相溶性の有機溶剤で抽出処理
し、この処理により目的物たるクロピドールを
水層に残し、不純物たる４―アミノ―３，５―
ジクロル―２，６―ジメチルピリジンを有機溶
剤層に移行せしめる。 Next, the reaction solution, which is in the state of a homogeneous aqueous solution under alkaline conditions, is extracted with an organic solvent that is incompatible with water. Through this process, the target product, clopidol, remains in the aqueous layer, and the impurity, 4-amino-3,5-
Dichloro-2,6-dimethylpyridine is transferred to the organic solvent layer.
ついで抽出後の水層を中和することによつて
目的物たるクロピドールを析出せしめ、これを
分離取得する。 The aqueous layer after extraction is then neutralized to precipitate clopidol, which is the target product, and is separated and obtained.
上記の本発明の方法を採用することにより次の
ようなすぐれた効果が奏される。 By employing the method of the present invention described above, the following excellent effects can be achieved.
(1) 不純物である薬害成分４―アミノ―３，５―
ジクロル―２，６―ジメチルピリジンは有機溶
剤層に極めて高い分配率で抽出されるので、こ
の有機溶剤層から有機溶剤を追い出せば残渣を
容易に焼却処理することができ、薬害成分の廃
棄に伴う二次薬害の恐れがない。なお追い出し
た有機溶剤は抽剤としてリサイクルできる。(1) Drug-damaging component 4-amino-3,5- which is an impurity
Dichloro-2,6-dimethylpyridine is extracted into the organic solvent layer at an extremely high distribution rate, so if the organic solvent is expelled from this organic solvent layer, the residue can be easily incinerated. There is no risk of secondary drug damage. The expelled organic solvent can be recycled as an extractant.
(2) 一方水層の中和によつて取得される製品クロ
ピドール中の前記不純物の含量は飼料添加剤と
しての厳しい規格内におさめることができる。(2) On the other hand, the content of the impurities in the clopidol product obtained by neutralizing the aqueous layer can be kept within the strict specifications for feed additives.
(3) 塩素化反応後の反応液がスラリー状態の場合
であつても、この反応液から析出物と母液（水
溶液）との過等による分離を行わないので、
母液に含まれる前記薬害成分の処理、廃棄を顧
慮しなくてもよい。水溶液の形態の母液中の薬
害成分の処理・廃棄は実際上は容易ではない。(3) Even if the reaction solution after the chlorination reaction is in a slurry state, the precipitate and mother liquor (aqueous solution) are not separated from the reaction solution by filtration.
There is no need to consider the treatment and disposal of the harmful components contained in the mother liquor. In practice, it is not easy to treat and dispose of harmful components in the mother liquor in the form of an aqueous solution.
本発明の方法を実施するにあたつて原料として
用いられる２，６―ジメチル―４―ピリジノール
は、通常デヒドロ酢酸を水性アンモニアと反応し
て得られる。反応条件としては
反応温度 150〜250℃
反応圧力 10〜30Kg／cm2
反応時間 0.5〜10hr
アンモニア／デヒドロ酢酸モル比 1.0〜2.0
水／デヒドロ酢酸比 200〜2000ｇ／モル
が適当であり、この範囲から大きくはずれると目
的物である２，６―ジメチル―４―ピリジノール
の生成率が低下したり、不純物である４―アミノ
―２，６―ジメチルピリジンの副生量が多くな
る。 2,6-dimethyl-4-pyridinol used as a raw material in carrying out the method of the present invention is usually obtained by reacting dehydroacetic acid with aqueous ammonia. The reaction conditions are: reaction temperature: 150-250℃, reaction pressure: 10-30Kg/ cm2 , reaction time: 0.5-10hr, ammonia/dehydroacetic acid molar ratio: 1.0-2.0, water/dehydroacetic acid ratio: 200-2000g/mol, and from this range. If it deviates significantly, the production rate of the target product 2,6-dimethyl-4-pyridinol will decrease, and the amount of by-product of the impurity 4-amino-2,6-dimethylpyridine will increase.
反応終了後は反応液を室温又はそれ以下にまで
冷却すれば目的物が析出するが、一部は反応液層
に溶解している。この析出物を分離し、さらに反
応液層に溶解している目的物も分離精製して次の
塩素化工程に供するが、反応液から目的物である
２，６―ジメチル―４―ピリジノールを分離する
ことなく反応液をそのまま次の塩素化工程に供す
る方が分離工程が省略できる点で工業上一段と有
利である。 After the reaction is completed, the target product is precipitated by cooling the reaction solution to room temperature or lower, but some of it is dissolved in the reaction solution layer. This precipitate is separated, and the target substance dissolved in the reaction liquid layer is also separated and purified for the next chlorination step, but the target substance, 2,6-dimethyl-4-pyridinol, is separated from the reaction liquid. It is industrially more advantageous to directly submit the reaction solution to the next chlorination step without any chlorination step, since the separation step can be omitted.
この後者の方法、即ちデヒドロ酢酸を水性アン
モニアと反応させて得られるスラリー状反応液か
ら目的物を分離することなく次の塩素化工程に供
する方法によれば、先に述べた(1)、(2)、(3)の効果
に加えてさらに次の効果が奏される。 According to this latter method, that is, the method in which the target product is subjected to the next chlorination step without separating it from the slurry-like reaction liquid obtained by reacting dehydroacetic acid with aqueous ammonia, as described above (1), ( In addition to the effects 2) and (3), the following effect is produced.
(4) 生成物である２，６―ジメチル―４―ピリジ
ノールの分離が不要となるので、分離に要する
工程が一切省略でき、又分離時の母液（水溶
液）中の生成物の回収及び不純物の処理を考慮
しなくてもよい。(4) Since it is not necessary to separate the product 2,6-dimethyl-4-pyridinol, all steps required for separation can be omitted, and it is also possible to recover the product and remove impurities from the mother liquor (aqueous solution) during separation. There is no need to consider processing.
(5) 不純物を含んだままの反応液を次の塩素化工
程に供するにもかかわらず、最終目的物たるク
ロピドールの収率が良い。(5) Even though the reaction solution containing impurities is subjected to the next chlorination step, the yield of clopidol, which is the final target product, is good.
さて２，６―ジメチル―４―ピリジノールの塩
素化工程は次のようにして行われる。 Now, the chlorination step of 2,6-dimethyl-4-pyridinol is carried out as follows.
２，６―ジメチル―４―ピリジノールは酸性な
いしアルカリ性の水媒体中で塩素と反応せられる
が、酸性条件下に反応を行うことが好ましい。系
を酸性にするには通常塩酸が使用され、又他の酸
であつても差支えない。酸は２，６―ジメチル―
４―ピリジノールが溶解し、系が均一溶液となる
まで添加すれば充分であり、塩酸使用の場合で
HCl／２，６―ジメチル―４―ピリジノールのモ
ル比は0.3〜2.0の範囲から選ぶことが多い。又こ
の塩素化反応は中性或いはアルカリ性条件下に行
うこともできる。この場合反応を均一系で行うこ
とが望ましいので、水量を多くするかアルカリ添
加量をコントロールして均一溶解を図るようにす
る。 2,6-dimethyl-4-pyridinol can be reacted with chlorine in an acidic or alkaline aqueous medium, but it is preferable to carry out the reaction under acidic conditions. Hydrochloric acid is usually used to make the system acidic, but other acids may also be used. The acid is 2,6-dimethyl-
It is sufficient to add the 4-pyridinol until it dissolves and the system becomes a homogeneous solution.
The molar ratio of HCl/2,6-dimethyl-4-pyridinol is often selected from the range of 0.3 to 2.0. This chlorination reaction can also be carried out under neutral or alkaline conditions. In this case, it is desirable to carry out the reaction in a homogeneous system, so uniform dissolution is achieved by increasing the amount of water or controlling the amount of alkali added.
２，６―ジメチル―４―ピリジノールの塩素化
反応条件としては
水／２，６―ジメチル―４―ピリジノール比
約500〜3000ｇ／モル或いはそれ以上
塩素／２，６―ジメチル―４―ピリジノールモ
ル比 約1.5〜3.5
反応温度 約80℃以下、特に−５〜30℃
が適当であり、この範囲から大きくはずれると
２，６―ジメチル―４―ピリジノールの変化率、
クロピドールの収率或いは装置効率や操作の面で
不利となる。 The chlorination reaction conditions for 2,6-dimethyl-4-pyridinol are water/2,6-dimethyl-4-pyridinol ratio.
Approximately 500 to 3000 g/mol or more Chlorine/2,6-dimethyl-4-pyridinol molar ratio Approximately 1.5 to 3.5 Reaction temperature Appropriately approximately 80°C or less, especially -5 to 30°C; , change rate of 6-dimethyl-4-pyridinol,
This is disadvantageous in terms of clopidol yield, equipment efficiency, and operation.
塩素の吹込みを開始すると酸性ないし中性系で
は直ちに白濁を生じ、系はしだいに懸濁状を呈す
るようになる。所定時間に所定量の塩素を吹込ん
だ後必要に応じさらに撹拌を続けて反応を追い込
む。得られた反応液は生成クロピドールが懸濁し
たスラリー状をしている。系がアルカリ性の場合
はアルカリの量や水量に応じ塩素化反応中に生成
物が析出することもあり、反応終了まで均一溶液
状が保たれることもある。 When chlorine injection is started, acidic to neutral systems immediately become cloudy, and the system gradually becomes suspended. After blowing in a predetermined amount of chlorine for a predetermined period of time, stirring is continued as necessary to drive the reaction. The resulting reaction solution is in the form of a slurry in which the produced clopidol is suspended. If the system is alkaline, products may precipitate during the chlorination reaction depending on the amount of alkali and water, and a homogeneous solution may be maintained until the reaction is completed.
反応液がスラリー状の場合は水酸化ナトリウ
ム、水酸化カリウム、炭酸ナトリウム、炭酸カリ
ウム、アンモニアなどのアルカリの水溶液を反応
液中の析出物が溶解し、系が均一溶液となるまで
加える。この際水を追加することもしばしば行わ
れる。 If the reaction solution is in the form of a slurry, add an aqueous alkali solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or ammonia until the precipitate in the reaction solution is dissolved and the system becomes a homogeneous solution. Water is often added at this time.
次にアルカリ性下に均一水溶液状態の反応液を
水と非相溶性の有機溶剤によつて抽出処理する。
この処理により不純物は抽剤（有機溶剤）層に移
行し、目的物（クロピドール）は水層に残る。抽
剤としてはベンゼン、トルエン、キシレンなどの
芳香族炭化水素、ｎ―ヘキサン、シクロヘキサン
などの脂肪族又は脂環式炭化水素、イソプロピル
エーテルなどの含酸素有機溶剤、二塩化エチレン
などの含ハロゲン有機溶剤等が用いられる。 Next, the reaction solution in the form of a homogeneous aqueous solution is extracted under alkaline conditions with an organic solvent that is incompatible with water.
Through this treatment, impurities are transferred to the extractant (organic solvent) layer, and the target product (clopidol) remains in the aqueous layer. Extractants include aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic or alicyclic hydrocarbons such as n-hexane and cyclohexane, oxygen-containing organic solvents such as isopropyl ether, and halogen-containing organic solvents such as ethylene dichloride. etc. are used.
抽剤／アルカリ性反応液の割合は容積比で0.05
以上、特に0.1以上とするのが通常であり、回分
抽出なら２回程度の抽出操作で充分に精製が達成
される。 The ratio of extraction agent/alkaline reaction liquid is 0.05 by volume.
As mentioned above, it is usually set to 0.1 or more, and in the case of batch extraction, sufficient purification can be achieved with about two extraction operations.
なお抽出操作前の水溶液又は抽出後の水層と活
性炭とを接触させて脱色ないし不純物吸着処理を
行うこともでき、これにより収得生成物の外観、
色相、純度をより向上させることができる。 It is also possible to perform decolorization or impurity adsorption treatment by bringing the aqueous solution before the extraction operation or the aqueous layer after the extraction into contact with activated carbon, thereby improving the appearance of the obtained product,
Hue and purity can be further improved.
抽出操作後の抽残水層に塩酸、硫酸、酢酸など
の酸を加えて中和すると目的物たるクロピドール
が析出してくるので、これを分離し、必要に応じ
て水洗し、ついで乾燥すれば、不純物である４―
アミノ―３，５―ジクロル―２，６―ジメチルピ
リジン含量の極めて少ない高品質のクロピドール
が好収率で取得できる。 When the raffinate aqueous layer after the extraction operation is neutralized by adding an acid such as hydrochloric acid, sulfuric acid, or acetic acid, clopidol, the target product, will precipitate.This can be separated, washed with water if necessary, and then dried. , 4- which is an impurity
High quality clopidol with extremely low content of amino-3,5-dichloro-2,6-dimethylpyridine can be obtained in good yield.
一方抽出層からは有機溶剤を蒸留により回収し
て抽剤としてリサイクル使用し、蒸留缶残は通常
焼却して不純物、特に薬害成分たる４―アミノ―
３，５―ジクロル―２，６―ジメチルピリジンの
完全廃棄を行う。 On the other hand, the organic solvent is recovered from the extraction layer by distillation and recycled as an extractant, and the residue of the still is usually incinerated to remove impurities, especially 4-amino-
Completely dispose of 3,5-dichloro-2,6-dimethylpyridine.
次に実施例をあげて本発明の方法をさらに説明
する。 Next, the method of the present invention will be further explained with reference to Examples.
実施例 １
デヒドロ酢酸を水性アンモニアと反応して得ら
れた純度95.7％の粗２，６―ジメチル―４―ピリ
ジノール結晶128.7ｇ（純量で1.0モル）を２フ
ラスコ中で水1000ｇに分散させ、撹拌下に濃塩酸
50.0ｇ（0.48モル）を加えて溶解させた。この溶
液を温度５℃に保ち塩素を通じると直ちに白濁を
生じ、しだいに懸濁状を呈するようになつた。２
時間かけて163.1ｇ（2.3モル）の塩素を通じた
後、スラリー状の反応液に水4400ｇを加えて希釈
し、さらに2.5N水酸化ナトリウム水溶液1942.2ｇ
を加えたところ懸濁物は溶解し、系は均一な溶液
となつた。系のPHは約12であつた。この溶液を
1150ｇ（抽剤／抽料比は0.15）のトルエンで１回
抽出し、抽残をさらにもう１回同様に抽出した。
抽残水層を2.5N塩酸でPH７にまで中和し、析出
した結晶を過し、その上から水1500ｇを注いで
洗浄し、ついで乾燥して168.6ｇのクロピドール
を得た。分析の結果、得られたクロピドールの純
度は99.8％、収率は２，６―ジメチル―４―ピリ
ジノール基準で87.6％、不純物たる４―アミノ―
３，５―ジクロル―２，６―ジメチルピリジンの
含量は5.0ppmであつた。Example 1 128.7 g (1.0 mol in pure amount) of crude 2,6-dimethyl-4-pyridinol crystals with a purity of 95.7% obtained by reacting dehydroacetic acid with aqueous ammonia were dispersed in 1000 g of water in two flasks. Concentrated hydrochloric acid under stirring
50.0g (0.48mol) was added and dissolved. When this solution was kept at a temperature of 5°C and chlorine was passed through it, it immediately became cloudy and gradually became suspended. 2
After passing 163.1g (2.3 moles) of chlorine over time, 4400g of water was added to the slurry-like reaction solution to dilute it, and 1942.2g of 2.5N sodium hydroxide aqueous solution was added.
The suspension was dissolved and the system became a homogeneous solution. The pH of the system was approximately 12. This solution
It was extracted once with 1150 g of toluene (extraction agent/extractant ratio 0.15), and the raffinate was extracted once more in the same manner.
The raffinate aqueous layer was neutralized to pH 7 with 2.5N hydrochloric acid, the precipitated crystals were filtered, washed by pouring 1500 g of water over them, and then dried to obtain 168.6 g of clopidol. As a result of analysis, the purity of the clopidol obtained was 99.8%, the yield was 87.6% based on 2,6-dimethyl-4-pyridinol, and the impurity 4-amino-
The content of 3,5-dichloro-2,6-dimethylpyridine was 5.0 ppm.
実施例 ２
デヒドロ酢酸168.15ｇ（1.0モル）、水500ｇ及
び28％アンモニア水溶液73.0ｇ（1.2モル）を１
オートクレーブに仕込み、撹拌下に温度200℃
に加熱した。内温が140〜160℃になると内圧が急
上昇するので、以後内圧を17〜18Kg／cm2になるよ
うに時々パージを行い、内温を190〜200℃に保つ
た。最初のパージ後3.5時間加熱を続け、ついで
オートクレーブを冷却した。オートクレーブより
取り出した２，６―ジメチル―４―ピリジノール
のスラリー状反応液670ｇに直接水450ml及び濃塩
酸52.1ｇ（0.50モル）を加えて溶解した。この水
溶液を冷却し、温度５℃に保ちながら、２時間か
けて塩素163.1ｇを通じて塩素化を行つた。得ら
れたスラリー状の反応液に水4400ｇを加えて希釈
し、さらに2.5N水酸化ナトリウム水溶液を系が
均一溶液となるまで加えた（1940ｇ添加）。この
水溶液を抽剤／抽料比0.15の条件でベンゼンによ
り２回抽出し、抽残水層を2.5N塩酸でPH７にな
るまで中和した。かかる操作により析出した生成
物を過し、水洗し、ついで乾燥して163.9ｇの
クロピドールを得た。分析の結果、得られたクロ
ピドールの純度は99.6％、収率はデヒドロ酢酸基
準で85.0％、不純物たる４―アミノ―３，５―ジ
クロル―２，６―ジメチルピリジンの含量は
8.7ppmであつた。Example 2 168.15 g (1.0 mol) of dehydroacetic acid, 500 g of water, and 73.0 g (1.2 mol) of 28% ammonia aqueous solution were
Place in an autoclave and heat to 200°C while stirring.
heated to. When the internal temperature reached 140 to 160°C, the internal pressure rose rapidly, so purging was performed from time to time to keep the internal pressure at 17 to 18 kg/cm 2 and the internal temperature was maintained at 190 to 200°C. Heating was continued for 3.5 hours after the first purge and then the autoclave was cooled. 450 ml of water and 52.1 g (0.50 mol) of concentrated hydrochloric acid were directly added to 670 g of the slurry-like reaction solution of 2,6-dimethyl-4-pyridinol taken out from the autoclave to dissolve it. This aqueous solution was cooled and chlorinated by passing 163.1 g of chlorine over 2 hours while maintaining the temperature at 5°C. The resulting slurry-like reaction solution was diluted by adding 4400 g of water, and further 2.5N aqueous sodium hydroxide solution was added until the system became a homogeneous solution (1940 g added). This aqueous solution was extracted twice with benzene at an extractant/extraction ratio of 0.15, and the raffinate aqueous layer was neutralized with 2.5N hydrochloric acid until the pH reached 7. The product precipitated by this operation was filtered, washed with water, and then dried to obtain 163.9 g of clopidol. As a result of analysis, the purity of the clopidol obtained was 99.6%, the yield was 85.0% based on dehydroacetic acid, and the content of 4-amino-3,5-dichloro-2,6-dimethylpyridine, which was an impurity, was 99.6%.
It was 8.7ppm.
Claims (1)
ないしアルカリ性の水媒体中で塩素と反応させ、
かくして得られた反応液をアルカリ性下に均一水
溶液状態において水と非相溶性の有機溶剤によつ
て抽出処理し、ついで抽出後の水層を中和して目
的物を析出せしめることを特徴とする３，５―ジ
クロル―２，６―ジメチル―４―ピリジノールの
製造法。1. Reacting 2,6-dimethyl-4-pyridinol with chlorine in an acidic or alkaline aqueous medium,
The reaction solution thus obtained is extracted in a homogeneous aqueous state under alkaline conditions with an organic solvent that is incompatible with water, and then the aqueous layer after the extraction is neutralized to precipitate the target product. A method for producing 3,5-dichloro-2,6-dimethyl-4-pyridinol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7937480A JPS574973A (en) | 1980-06-10 | 1980-06-10 | Preparation of 3,5-dichloro-2,6-dimethyl-4-pyridinol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7937480A JPS574973A (en) | 1980-06-10 | 1980-06-10 | Preparation of 3,5-dichloro-2,6-dimethyl-4-pyridinol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS574973A JPS574973A (en) | 1982-01-11 |
| JPS6317066B2 true JPS6317066B2 (en) | 1988-04-12 |
Family
ID=13688089
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7937480A Granted JPS574973A (en) | 1980-06-10 | 1980-06-10 | Preparation of 3,5-dichloro-2,6-dimethyl-4-pyridinol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS574973A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220068194A (en) * | 2020-11-18 | 2022-05-25 | 고려대학교 산학협력단 | Low-temperature NOx adsorbent with improved repeated adsorption performance and manufacturing method thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6111948A (en) * | 1984-06-26 | 1986-01-20 | Matsushita Electric Ind Co Ltd | Information recording carrier |
| JPS6139950A (en) * | 1984-07-31 | 1986-02-26 | Matsushita Electric Ind Co Ltd | Flat information recording medium |
| JPS61160848A (en) * | 1985-01-09 | 1986-07-21 | Matsushita Electric Ind Co Ltd | Optical disk |
-
1980
- 1980-06-10 JP JP7937480A patent/JPS574973A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220068194A (en) * | 2020-11-18 | 2022-05-25 | 고려대학교 산학협력단 | Low-temperature NOx adsorbent with improved repeated adsorption performance and manufacturing method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS574973A (en) | 1982-01-11 |
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