JPH0478631B2 - - Google Patents
Info
- Publication number
- JPH0478631B2 JPH0478631B2 JP10123283A JP10123283A JPH0478631B2 JP H0478631 B2 JPH0478631 B2 JP H0478631B2 JP 10123283 A JP10123283 A JP 10123283A JP 10123283 A JP10123283 A JP 10123283A JP H0478631 B2 JPH0478631 B2 JP H0478631B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- hypobromite
- halo
- aminopyridine
- aqueous solution
- 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
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 11
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229960004979 fampridine Drugs 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 6
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical compound NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 description 4
- 239000012736 aqueous medium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- QRXBTPFMCTXCRD-UHFFFAOYSA-N 2-chloropyridine-4-carbonitrile Chemical compound ClC1=CC(C#N)=CC=N1 QRXBTPFMCTXCRD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NZUWTGHVOISMHN-UHFFFAOYSA-N 1-oxidopyridin-1-ium-4-carboxamide Chemical compound NC(=O)C1=CC=[N+]([O-])C=C1 NZUWTGHVOISMHN-UHFFFAOYSA-N 0.000 description 1
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 1
- WYSRTEVFLQJJDN-UHFFFAOYSA-N 2-chloro-1-oxidopyridin-1-ium Chemical compound [O-][N+]1=CC=CC=C1Cl WYSRTEVFLQJJDN-UHFFFAOYSA-N 0.000 description 1
- YSTCMHHKDOVZDA-UHFFFAOYSA-N 2-chloro-4-nitro-1-oxidopyridin-1-ium Chemical compound [O-][N+](=O)C1=CC=[N+]([O-])C(Cl)=C1 YSTCMHHKDOVZDA-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- -1 amino compound Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910001919 chlorite Inorganic materials 0.000 description 1
- 229910052619 chlorite group Inorganic materials 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Description
【発明の詳細な説明】
本発明は医薬、農薬等の中間原料として有用な
２−ハロ−４−アミノピリジンの新規な製造法に
関し、更に詳しくは、
一般式〔〕：
（式中、ＹはCN、CONH2をまたＸはハロゲン
原子を表わす。）
で示される化合物を水媒体中、アルカリの存在
下、次亜鉛素酸塩又は次亜臭素酸塩によりホフマ
ン反応させて
一般式〔〕：
（式中、Ｘはハロゲン原子を表わす。）
で示される２−ハロ−４−アミノピリジンの製造
する方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 2-halo-4-aminopyridine, which is useful as an intermediate raw material for pharmaceuticals, agricultural chemicals, etc. More specifically, it has the general formula []: (In the formula, Y represents CN or CONH 2 and X represents a halogen atom.) A compound represented by the following is subjected to a Hoffmann reaction with hypozinc mate or hypobromite in an aqueous medium in the presence of an alkali. General formula []: (In the formula, X represents a halogen atom.) The present invention relates to a method for producing 2-halo-4-aminopyridine represented by the following formula.
一般に当該２−ハロ−４−アミノピリジンの製
造法としては、例えばアミノピリジン類のハロゲ
ン化の場合は酸性溶媒中、塩素、臭素などを反応
させれば、アミノ基のオルソ、パラ位がハロゲン
化され、アミノ基のメタ位にハロゲンを導入する
事は至難であり、本発明の化合物も４−アミノピ
リジンから直接ハロゲン化する方法は報告されて
いない。従来、本発明の化合物を得る方法として
下記のような方法が報告されている。 In general, the method for producing the 2-halo-4-aminopyridine is, for example, in the case of halogenating aminopyridines, by reacting chlorine, bromine, etc. in an acidic solvent, the ortho and para positions of the amino group are halogenated. Therefore, it is extremely difficult to introduce a halogen into the meta-position of an amino group, and no method has been reported for directly halogenating 4-aminopyridine in the compounds of the present invention. Conventionally, the following methods have been reported as methods for obtaining the compounds of the present invention.
Rec.trav、chim.69、673〜699（1950）
Helv.chim.Acta.34、496〜500（1951）
Indian.J.chem.4(9)403〜405（1966）
しかしながらの方法は出発原料である２，４
−ジクロルピリジンを得るのが難しく且つ、それ
から目的物への収率も約20％と低く工業的な方法
とはいい難い。又の方法は爆発の危険がある２
−クロル−イソニコチノイルアミドを経由するも
のであり工業的な製法とは成り難いものである。
そして、の方法は、出発原料である２−クロル
−４−ニトロピリジン−Ｎ−オキシドを熱に対し
て不安定な２−クロルピリジン−Ｎ−オキシドか
ら低い収率で製造され入手しがたいものであり決
して満足できる方法とは言えない。 Rec.trav, chim.69, 673–699 (1950) Helv.chim.Acta.34, 496–500 (1951) Indian.J.chem.4(9)403-405 (1966) However, the method uses starting materials 2,4
-It is difficult to obtain dichloropyridine, and the yield of the target product from it is low at about 20%, making it difficult to call it an industrial method. The other method has the risk of explosion2.
-Chloro-isonicotinoylamide is used, and it is difficult to realize an industrial production method.
In this method, the starting material 2-chloro-4-nitropyridine-N-oxide is produced in low yield from 2-chloropyridine-N-oxide, which is unstable to heat and is difficult to obtain. This is by no means a satisfactory method.
そこで本発明者らは各種反応を検討した結果、
一般式〔〕で示される化合物にアルカリの存在
下、水媒体中に次亜鉛素酸塩又は次亜臭素酸塩の
水溶液を作用させた後、過熱脱炭酸することによ
り、目的物である一般式〔〕で示される２−ハ
ロ−４−アミノピリジンが容易に得られることを
見い出し、本発明を完成するに至つたものであ
る。 Therefore, as a result of examining various reactions, the present inventors found that
The compound represented by the general formula [] is reacted with an aqueous solution of subzincinate or hypobromite in an aqueous medium in the presence of an alkali, and then heated and decarboxylated to obtain the desired product, the general formula The present inventors have discovered that 2-halo-4-aminopyridine represented by [] can be easily obtained, and have completed the present invention.
本発明の出発原料となる一般式〔〕で示され
る化合物は例えばイソニコチノニトリル又はイソ
ニコチンアミドのＮ−オキシドをオキシ塩化リン
等でハロゲン化すれば容易に得られるものであ
る。本発明の出発原料としは通常一般式〔〕の
Ｙがニトリルである化合物又はアミドである化合
物を単独で使用するがそれらの混合物であつても
差しつかえない。 The compound represented by the general formula [ ], which is a starting material for the present invention, can be easily obtained by halogenating isonicotinonitrile or isonicotinamide N-oxide with phosphorus oxychloride or the like. As the starting material for the present invention, a compound in which Y in the general formula [] is nitrile or amide is usually used alone, but a mixture thereof may also be used.
反応はアルカリの存在下、水媒体系で行なわれ
るが、アルカリの種類としては、苛性ソーダ、苛
性カリなどの通常のものでよく、一般式〔〕に
対して１〜３倍モルの使用で充分であり、又その
濃度は10〜20％で使用される。次亜塩素酸塩およ
び次亜臭素酸塩の陽性イオン構成成分の種類とし
てはナトリウム、カリウムが使用でき、通常、有
効ハロゲン含量８〜15％の水溶液が使用される。
また、かかる次亜塩素酸塩又は、次亜臭素酸塩と
してアルカリ水溶液に塩素又は、臭素を反応させ
たものをそのまま用いることができる。 The reaction is carried out in an aqueous medium in the presence of an alkali, and the type of alkali may be any ordinary alkali such as caustic soda or caustic potash, and it is sufficient to use 1 to 3 times the molar amount of the general formula []. , and its concentration is 10-20%. Sodium and potassium can be used as the positive ion constituents of hypochlorite and hypobromite, and an aqueous solution having an effective halogen content of 8 to 15% is usually used.
Moreover, such a hypochlorite or a hypobromite obtained by reacting chlorine or bromine with an alkaline aqueous solution can be used as is.
反応方法としては、原料ニトリル或いは原料ア
ミドのカルボン酸への加水分解を防ぐ為、できる
だけ低温で亜塩素酸塩或いは次亜臭素酸塩水溶液
を作用させるのが良く、０〜30℃で好ましくは10
〜20℃で加えるのが適当である。こうして得られ
た反応液を、70〜100℃に加熱するか、加熱水溶
液中に滴下すれば脱炭酸が起り、目的物のアミノ
体が得られる。かかる反応液から目的物を分離す
る方法としては種々の方法が採用できるが、通常
反応液を室温に冷却し晶出する目的物をろ別し、
その後ろ液を濃縮・抽出すれば、80％以上の好収
率で得ることができる。 As for the reaction method, in order to prevent hydrolysis of the raw material nitrile or raw material amide to carboxylic acid, it is preferable to react with an aqueous solution of chlorite or hypobromite at as low a temperature as possible, preferably at 0 to 30°C.
It is appropriate to add at ~20°C. When the reaction solution thus obtained is heated to 70 to 100°C or dropped into a heated aqueous solution, decarboxylation occurs and the amino compound of the target product is obtained. Various methods can be used to separate the target product from the reaction solution, but usually the reaction solution is cooled to room temperature and the crystallized target product is filtered out.
By concentrating and extracting the residual liquid, it can be obtained with a good yield of 80% or more.
以上、述べた如く、本発明は２−ハロ−４−ア
ミノピリジンの製造法として新規でかつ好適な方
法であり、反応形態としても水媒体中という非常
に安全な製法を提供するものである。したがつて
本発明は工業的に有利な方法である。 As described above, the present invention is a novel and suitable method for producing 2-halo-4-aminopyridine, and provides a very safe production method in which the reaction form is in an aqueous medium. Therefore, the present invention is an industrially advantageous method.
以下、実施例を挙げ本発明を説明する。 The present invention will be explained below with reference to Examples.
実施例 １
２−クロル−イソニコチノニトリル30ｇを14％
NaOH水溶液130ｇに加え、撹拌下15℃に保つ。
有効塩素10％の次亜塩素酸ソーダ水溶液200ｇを
１時間30分で滴下する。この間、内容物は懸濁状
態から次第に溶解し褐色液となる。Example 1 30g of 2-chloro-isonicotinonitrile at 14%
Add to 130 g of NaOH aqueous solution and keep at 15°C while stirring.
Add 200 g of sodium hypochlorite aqueous solution containing 10% available chlorine dropwise over 1 hour and 30 minutes. During this time, the contents gradually dissolve from a suspended state to become a brown liquid.
滴下後、徐々に昇温し80〜90℃に約１時間保
つ。この間、反応液は赤色均一溶液となる。反応
後、冷却すると微黄色の２−クロル−４−アミノ
ピリジンが析出する。ろ過後、乾燥して得られた
収量は18ｇ、mp89〜91℃であつた。又、上記ろ
液を硫酸でPH10に調整後、濃縮乾固し、熱メタノ
ールで抽出すると更に５ｇの２−クロル−４−ア
ミノピリジンが回収される。２−クロル−４−ア
ミノピリジンの収率は82.6％である。 After dropping, gradually raise the temperature and keep at 80-90°C for about 1 hour. During this time, the reaction solution becomes a red homogeneous solution. After the reaction, when the mixture is cooled, slightly yellow 2-chloro-4-aminopyridine is precipitated. After filtration and drying, the yield was 18 g, mp 89-91°C. Further, the filtrate was adjusted to pH 10 with sulfuric acid, concentrated to dryness, and extracted with hot methanol to recover an additional 5 g of 2-chloro-4-aminopyridine. The yield of 2-chloro-4-aminopyridine is 82.6%.
実施例 ２
２−クロル−イソニコチノニトリル14ｇを15％
NaOH水溶液60ｇに加え、撹拌下10〜15℃に保
つ。そこに、20％NaOH水溶液59ｇに臭素20ｇ
を加え調整した次亜臭素酸ソーダ水溶液を１時間
で滴下した。この間内容物は懸濁状態から次第に
均一となり黄褐色液となる。この後、実施例１と
同様に、加熱、処理して、目的物である２−クロ
ル−４−アミノピリジン10ｇを得た。Example 2 14g of 2-chloro-isonicotinonitrile at 15%
Add to 60 g of NaOH aqueous solution and keep at 10-15°C while stirring. There, 20g of bromine is added to 59g of 20% NaOH aqueous solution.
An aqueous solution of sodium hypobromite prepared by adding was added dropwise over 1 hour. During this time, the contents gradually become homogeneous from a suspended state to a yellowish brown liquid. Thereafter, the mixture was heated and treated in the same manner as in Example 1 to obtain 10 g of 2-chloro-4-aminopyridine, which was the desired product.
Claims (1)
原子を表わす。） で示される２−ハロ−イソニコチノニトリル及
び／又は２−ハロ−イソニコチンアミドに水媒体
中、アルカリの存在下、次亜塩素酸塩又は次亜臭
素酸塩を作用させた後、加熱脱炭酸させることを
特徴とする 一般式〔〕： （式中、Ｘは前記と同じ。） で示される２−ハロ−４−アミノピリジンの製造
法。 ２ 一般式〔〕の化合物に次亜塩素酸塩又は次
亜臭素酸塩を０〜30℃で作用させることを特徴と
する特許請求の範囲第１項記載の方法。 ３ 一般式〔〕および一般式〔〕中のＸが塩
素である特許請求の範囲第１又は２項記載の方
法。 ４ 次亜塩素酸塩又は次亜臭素酸塩アルカリ水溶
液に塩素又は臭素を反応させたものである特許請
求の範囲第１、２又は３項記載の方法。 ５ アルカリが苛性ソーダ又は苛性カリである特
許請求の範囲第１、２、３又は４項記載の方法。[Claims] 1 General formula []: (In the formula, Y represents CN, CONH 2 and X represents a halogen atom.) In the presence of an alkali, 2-halo-isonicotinonitrile and/or 2-halo-isonicotinamide represented by , which is characterized by being treated with hypochlorite or hypobromite, followed by heating and decarboxylation. General formula []: (In the formula, X is the same as above.) A method for producing 2-halo-4-aminopyridine. 2. The method according to claim 1, characterized in that the compound of general formula [] is treated with hypochlorite or hypobromite at 0 to 30°C. 3. The method according to claim 1 or 2, wherein X in general formula [] and general formula [] is chlorine. 4. The method according to claim 1, 2 or 3, wherein the hypochlorite or hypobromite aqueous aqueous solution is reacted with chlorine or bromine. 5. The method according to claim 1, 2, 3 or 4, wherein the alkali is caustic soda or caustic potash.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10123283A JPS59225163A (en) | 1983-06-06 | 1983-06-06 | Preparation of 2-halo-4-aminopyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10123283A JPS59225163A (en) | 1983-06-06 | 1983-06-06 | Preparation of 2-halo-4-aminopyridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59225163A JPS59225163A (en) | 1984-12-18 |
| JPH0478631B2 true JPH0478631B2 (en) | 1992-12-11 |
Family
ID=14295148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10123283A Granted JPS59225163A (en) | 1983-06-06 | 1983-06-06 | Preparation of 2-halo-4-aminopyridine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59225163A (en) |
-
1983
- 1983-06-06 JP JP10123283A patent/JPS59225163A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59225163A (en) | 1984-12-18 |
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