JPH0456034B2 - - Google Patents
Info
- Publication number
- JPH0456034B2 JPH0456034B2 JP57088153A JP8815382A JPH0456034B2 JP H0456034 B2 JPH0456034 B2 JP H0456034B2 JP 57088153 A JP57088153 A JP 57088153A JP 8815382 A JP8815382 A JP 8815382A JP H0456034 B2 JPH0456034 B2 JP H0456034B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- general formula
- defined above
- reacted
- 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 - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【発明の詳細な説明】
本発明は、一般式(1)：
〔式中、R1は低級アルキル基を表わし；R2は
水酸基、炭素数１〜６個を有するアルコキシ基又
は式−NR3R4（式中、R3及びR4は、それぞれ、水
素原子又は炭素数１〜６個を有するアルキル基を
表わす。）で示される基を表わし；ｎは１又は０
である〕
で示されるピラジン誘導体の製造方法に関するも
のである。[Detailed Description of the Invention] The present invention relates to general formula (1): [In the formula, R 1 represents a lower alkyl group; R 2 is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or the formula -NR 3 R 4 (wherein, R 3 and R 4 are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; n is 1 or 0;
The present invention relates to a method for producing a pyrazine derivative represented by the following.
一般式(1)（式中、R1は上に定義したとおりで
あり、R2は水酸基を表わし、ｎは０である。）で
表わされるピラジン誘導体は、本発明によれば、
一般式(2)：
を有するジアミノマレオニトリルと、一般式
OHCCOR1の化合物（ここで、R1は上に定義し
たとおりである。）とを極性溶媒中、温度35〜85
℃で縮合させ、生成した、一般式(3)：
（式中、R1は上に定義したとおりである。）を
有する化合物を、極性溶媒中、100℃以下の温度
で、酸と反応させることを特徴とする方法によつ
て製造することができる。 According to the present invention, pyrazine derivatives represented by general formula (1) (wherein R 1 is as defined above, R 2 represents a hydroxyl group, and n is 0) are:
General formula (2): Diaminomaleonitrile having the general formula
A compound of OHCCOR 1 (where R 1 is as defined above) in a polar solvent at a temperature of 35 to 85
General formula (3) produced by condensation at °C: (wherein R 1 is as defined above) can be produced by a method characterized in that it is reacted with an acid in a polar solvent at a temperature below 100°C. .
ジアミノマレオニトリルとα−ケトアルデヒド
との縮合のための適切な溶媒は、水、炭素数１〜
６個を含むアルコール又はそれらの混合物であ
る。この縮合反応は、酸の存在下で行われること
が好ましい。 Suitable solvents for the condensation of diaminomaleonitrile and α-ketaldehyde include water,
6 alcohols or mixtures thereof. This condensation reaction is preferably carried out in the presence of an acid.
ジシアノピラジン(3)を酸と反応させると、極め
て驚くべきことであるが、R2が水酸基を表わし、
ｎが０である式(1)の化合物のみが得られる。適切
な酸は、硫酸、メタンスルホン酸、燐酸、トリフ
ルオロメタンスルホン酸及び塩酸である。適切な
溶媒は水である。酸の濃度は、30〜50％が都合が
よい。 When dicyanopyrazine (3) is reacted with an acid, it is quite surprising that R 2 represents a hydroxyl group,
Only compounds of formula (1) where n is 0 are obtained. Suitable acids are sulfuric acid, methanesulfonic acid, phosphoric acid, trifluoromethanesulfonic acid and hydrochloric acid. A suitable solvent is water. Conveniently, the acid concentration is between 30 and 50%.
ｎが１及び／又はR2が水酸基以外のものであ
る一般式(1)の化合物は、本発明によれば、上述の
方法に次いで、酸化及び／又は水酸基R2をアル
コキシ基もしくは式−NR3R4（式中、R3及びR4は
上に定義したとおりである。）で表わされる基に
変換することによつて製造することができる。 According to the present invention, compounds of general formula (1) in which n is 1 and/or R 2 is other than a hydroxyl group can be prepared by oxidation and/or replacing the hydroxyl group R 2 with an alkoxy group or with the formula -NR 3 R 4 (wherein R 3 and R 4 are as defined above).
式(1)の化合物の酸化は、その場で生成した過酸
によつて行うことが好ましい。水酸基R2のアル
コキシ基への変換は、有機化学の通常の方法に従
つてエステル化によつて行う。又、R2を式−
NR3R4で表わされる基に変換するには、式中
COR2がカルボキシ基又はその反応性誘導体、例
えばハロゲン化物（ハイライド）もしくは混合酸
無水物である式(1)の化合物と、アンモニア又は式
HNR3R4（式中、R3及びR4は上に定義されたとお
りである）で示されるアミンとを反応させること
によつて行う。 Oxidation of the compound of formula (1) is preferably carried out with a peracid generated in situ. The conversion of the hydroxyl group R 2 into an alkoxy group is carried out by esterification according to the usual methods of organic chemistry. Also, R 2 is expressed as −
To convert to a group represented by NR 3 R 4 , in the formula
A compound of formula (1) in which COR 2 is a carboxy group or a reactive derivative thereof, such as a halide or a mixed acid anhydride, and ammonia or a compound of formula
by reaction with an amine of the formula HNR 3 R 4 where R 3 and R 4 are as defined above.
式(1)の化合物及びかかる更に付加される工程に
ついては、英国特許第1361967号明細書に述べら
れかつ特許請求されている。 Compounds of formula (1) and such additional steps are described and claimed in GB 1361967.
一般式(1)の化合物のいくつかのものは、ピラジ
ン誘導体の副作用を有さず、血中脂質低下作用及
び血糖降下作用を示し、他のいくつかのものは、
それらの有用な中間体である。 Some of the compounds of general formula (1) do not have the side effects of pyrazine derivatives and exhibit blood lipid-lowering and hypoglycemic effects, and some others are
They are useful intermediates.
次に、実施例によつて本発明を詳細に説明す
る。 Next, the present invention will be explained in detail with reference to Examples.
実施例 １
ａ 水800ml、エタノール900ml及び酢酸45mlの混
合物にジアミノマレオニトリル100ｇを懸濁さ
せ、それにピルビンアルデヒド（170ｇ；10％
水溶液ｗ／ｖ）を攪拌しながら室温で滴下し
た。20分後、完全に溶解したところで、温度を
80℃まで上げ、更に30分間攪拌を続けた。次に
反応混合物を０℃まで冷却し、ろ過によつて生
成物を採取した。洗液が中性になるまで水洗し
た後、乾燥し、112ｇの未精製の２，３−ジシ
アノ−５−メチル−ピラジンを得た。Example 1 a 100 g of diaminomaleonitrile is suspended in a mixture of 800 ml of water, 900 ml of ethanol and 45 ml of acetic acid, and pyruvic aldehyde (170 g; 10%
The aqueous solution w/v) was added dropwise at room temperature with stirring. After 20 minutes, when it has completely dissolved, lower the temperature.
The temperature was raised to 80°C, and stirring was continued for an additional 30 minutes. The reaction mixture was then cooled to 0° C. and the product was collected by filtration. After washing with water until the washing liquid became neutral, it was dried to obtain 112 g of unpurified 2,3-dicyano-5-methyl-pyrazine.
融点：98−100℃。 Melting point: 98-100℃.
プロント核磁気共鳴吸収スペクトル（PMR）
（CDCl3）、TMS標準、δppm：2.8（ｓ，CH3）；
8.85（ｓ、芳香族プロトン）。 Pronto nuclear magnetic resonance absorption spectrum (PMR)
( CDCl3 ), TMS standard, δppm: 2.8 (s, CH3 ); 8.85 (s, aromatic protons).
ｂ 100mlの硫酸（水溶液、50％ｖ／ｖ）に、ａ）
で述べた方法で得られた未精製の２，３−ジシ
アノ−５−メチル−ピラジン10ｇを懸濁し、こ
れを攪拌しながら、３時間、温度100℃に保つ
た。次にこの反応混合物に砕氷100ｇを加えて
冷却し、水酸化ナトリウム水溶液（20％ｗ／
ｖ）270mlを加えてPHを１とした。水相をメチ
ルエチルケトンで抽出し、抽出液を一緒にした
後、洗液が中性になるまで塩化ナトリウム飽和
溶液で洗浄した。減圧下で溶媒を蒸発させる
と、固体状の残留物が得られ、これを水から結
晶させると６ｇの５−メチル−２−ピラジンカ
ルボン酸が得られた。b) In 100 ml of sulfuric acid (aqueous solution, 50% v/v), a)
10 g of unpurified 2,3-dicyano-5-methyl-pyrazine obtained by the method described above was suspended and maintained at a temperature of 100° C. for 3 hours while stirring. Next, 100 g of crushed ice was added to the reaction mixture, cooled, and aqueous sodium hydroxide solution (20% w/
v) Add 270 ml to bring the pH to 1. The aqueous phase was extracted with methyl ethyl ketone and the combined extracts were washed with saturated sodium chloride solution until the washings were neutral. Evaporation of the solvent under reduced pressure gave a solid residue which was crystallized from water to give 6 g of 5-methyl-2-pyrazinecarboxylic acid.
融点：163−167℃。 Melting point: 163-167℃.
PMR（CDCl3）、TMS標準、δppm：2.8（ｓ，
CH3）；
8.9，9.3（２つのｓ、芳香族プロトン）；10.8
（ｓ，COOH）。 PMR (CDCl 3 ), TMS standard, δppm: 2.8 (s,
CH 3 ); 8.9, 9.3 (two s, aromatic protons); 10.8
(s, COOH).
参考例
実施例１で述べた方法で調製した５−メチル−
２−ピラジンカルボン酸（9.7ｇ）の乾燥ジオキ
サン（114ml）溶液及びトリブチルアミン（17.7
ml）を、０〜５℃でクロロギ酸エチル（7.5ml）
で処理した。10分後、アンモニアを飽和させたジ
オキサン（190ml）を加え、この混合液を室温で
３時間攪拌した。ジオキサンを留去し、残留物を
炭酸水素ナトリウムの飽和水溶液（20ml）に溶か
した。混合液をろ過し、生成物を水洗すると２−
カルバモイル−５−メチルピラジン（9.2ｇ）が
得られた。融点：204−206℃。Reference Example 5-Methyl- prepared by the method described in Example 1
A solution of 2-pyrazinecarboxylic acid (9.7 g) in dry dioxane (114 ml) and tributylamine (17.7 g)
ml) and ethyl chloroformate (7.5 ml) at 0-5°C.
Processed with. After 10 minutes, ammonia-saturated dioxane (190ml) was added and the mixture was stirred at room temperature for 3 hours. The dioxane was distilled off and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (20 ml). When the mixture is filtered and the product is washed with water, 2-
Carbamoyl-5-methylpyrazine (9.2g) was obtained. Melting point: 204-206℃.
この化合物（７ｇ）を、70℃で７時間、氷酢酸
（30ml）及び35％過酸化水素（20ml）と共に、攪
拌下、加熱した。冷却後、生成物をろ別し、水洗
すると２−カルバモイル−５−メチルピラジン−
４−オキシド（5.5ｇ）が得られた。融点：206−
208℃。 This compound (7g) was heated with stirring at 70°C for 7 hours with glacial acetic acid (30ml) and 35% hydrogen peroxide (20ml). After cooling, the product is filtered and washed with water to give 2-carbamoyl-5-methylpyrazine-
4-oxide (5.5g) was obtained. Melting point: 206−
208℃.
Claims (1)
れるジシアノピラジン誘導体を、極性溶媒中、
100℃以下の温度で、酸と反応させることを特徴
とする、一般式： （式中、R1は上に定義したとおりである）で
示されるピラジン誘導体の製造方法。 ２ ジシアノピラジンと反応させる酸が、硫酸、
メタンスルホン酸、燐酸、トリフルオロメタンス
ルホン酸又は塩酸である特許請求の範囲第１項に
記載の製造方法。 ３ ジシアノピラジンと反応させる酸の極性溶媒
中の濃度が30〜50％である特許請求の範囲第１項
又は第２項に記載の製造方法。[Claims] 1. General formula: (In the formula, R 1 represents a lower alkyl group) in a polar solvent,
General formula, characterized by reaction with an acid at a temperature below 100°C: A method for producing a pyrazine derivative represented by the formula (wherein R 1 is as defined above). 2 The acid to be reacted with dicyanopyrazine is sulfuric acid,
The manufacturing method according to claim 1, which is methanesulfonic acid, phosphoric acid, trifluoromethanesulfonic acid, or hydrochloric acid. 3. The manufacturing method according to claim 1 or 2, wherein the concentration of the acid to be reacted with dicyanopyrazine in the polar solvent is 30 to 50%.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8116263 | 1981-05-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57200368A JPS57200368A (en) | 1982-12-08 |
| JPH0456034B2 true JPH0456034B2 (en) | 1992-09-07 |
Family
ID=10522093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57088153A Granted JPS57200368A (en) | 1981-05-28 | 1982-05-26 | Manufacture of pyrazine derivative |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS57200368A (en) |
| AT (1) | AT387217B (en) |
| AU (1) | AU8412682A (en) |
| BE (1) | BE893317A (en) |
| CA (1) | CA1237724A (en) |
| CH (1) | CH649763A5 (en) |
| CS (1) | CS226741B2 (en) |
| DE (1) | DE3219407A1 (en) |
| DK (1) | DK155325C (en) |
| FI (1) | FI73669C (en) |
| FR (1) | FR2506768B1 (en) |
| GR (1) | GR76417B (en) |
| HU (1) | HU187716B (en) |
| IE (1) | IE52992B1 (en) |
| IL (1) | IL65864A (en) |
| IT (1) | IT1210478B (en) |
| NL (1) | NL8202105A (en) |
| SE (1) | SE462971B (en) |
| YU (1) | YU42766B (en) |
| ZA (1) | ZA823660B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1201417B (en) * | 1985-05-17 | 1989-02-02 | Montedison Spa | PROCEDURE FOR THE PREPARATION OF 2-CARBOXYPYRAZINE 4 OXIDE |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU470007B2 (en) * | 1972-04-28 | 1976-02-26 | Farmitalia Carlo Erba S.R.L. | Pyrazine 4-oxide derivatives and process for their preparation |
| JPS565742B2 (en) * | 1973-09-29 | 1981-02-06 | ||
| JPS5134175A (en) * | 1974-09-18 | 1976-03-23 | Sagami Chem Res | Pirajinjudotai no seizohoho |
| JPS52153980A (en) * | 1976-06-17 | 1977-12-21 | Nippon Soda Co Ltd | Synthesis of 2,3-dicyanopyrazine |
| JPS5488281A (en) * | 1977-12-20 | 1979-07-13 | Nitsupou Kagaku Kk | Manufacture of pyrazine monocarboxylic acid |
| JPS5488280A (en) * | 1977-12-20 | 1979-07-13 | Nitsupou Kagaku Kk | Manufacture of dicyanopyradines |
-
1982
- 1982-05-21 NL NL8202105A patent/NL8202105A/en active Search and Examination
- 1982-05-24 AT AT0203682A patent/AT387217B/en not_active IP Right Cessation
- 1982-05-24 DE DE19823219407 patent/DE3219407A1/en active Granted
- 1982-05-24 FI FI821832A patent/FI73669C/en not_active IP Right Cessation
- 1982-05-24 IL IL65864A patent/IL65864A/en not_active IP Right Cessation
- 1982-05-25 AU AU84126/82A patent/AU8412682A/en not_active Abandoned
- 1982-05-25 FR FR8209038A patent/FR2506768B1/en not_active Expired
- 1982-05-25 CA CA000403636A patent/CA1237724A/en not_active Expired
- 1982-05-25 CS CS823842A patent/CS226741B2/en unknown
- 1982-05-25 GR GR68246A patent/GR76417B/el unknown
- 1982-05-26 ZA ZA823660A patent/ZA823660B/en unknown
- 1982-05-26 SE SE8203273A patent/SE462971B/en not_active IP Right Cessation
- 1982-05-26 JP JP57088153A patent/JPS57200368A/en active Granted
- 1982-05-26 IE IE1261/82A patent/IE52992B1/en not_active IP Right Cessation
- 1982-05-27 HU HU821712A patent/HU187716B/en unknown
- 1982-05-27 BE BE0/208187A patent/BE893317A/en not_active IP Right Cessation
- 1982-05-27 CH CH3285/82A patent/CH649763A5/en not_active IP Right Cessation
- 1982-05-27 YU YU1131/82A patent/YU42766B/en unknown
- 1982-05-27 DK DK239482A patent/DK155325C/en not_active IP Right Cessation
- 1982-05-27 IT IT8221517A patent/IT1210478B/en active Protection Beyond IP Right Term
Also Published As
| Publication number | Publication date |
|---|---|
| FI73669B (en) | 1987-07-31 |
| JPS57200368A (en) | 1982-12-08 |
| AT387217B (en) | 1988-12-27 |
| IE52992B1 (en) | 1988-04-27 |
| ATA203682A (en) | 1988-05-15 |
| NL8202105A (en) | 1982-12-16 |
| CS226741B2 (en) | 1984-04-16 |
| DE3219407C2 (en) | 1990-09-06 |
| YU113182A (en) | 1985-03-20 |
| DE3219407A1 (en) | 1983-01-05 |
| BE893317A (en) | 1982-11-29 |
| IL65864A0 (en) | 1982-08-31 |
| IL65864A (en) | 1985-08-30 |
| DK155325C (en) | 1989-09-18 |
| ZA823660B (en) | 1983-03-30 |
| SE462971B (en) | 1990-09-24 |
| DK239482A (en) | 1982-11-29 |
| CH649763A5 (en) | 1985-06-14 |
| FI821832A0 (en) | 1982-05-24 |
| GR76417B (en) | 1984-08-10 |
| AU8412682A (en) | 1982-12-02 |
| SE8203273L (en) | 1982-11-29 |
| FI73669C (en) | 1987-11-09 |
| IT8221517A0 (en) | 1982-05-27 |
| FR2506768B1 (en) | 1985-06-21 |
| IE821261L (en) | 1982-11-28 |
| CA1237724A (en) | 1988-06-07 |
| YU42766B (en) | 1988-12-31 |
| HU187716B (en) | 1986-02-28 |
| IT1210478B (en) | 1989-09-14 |
| FR2506768A1 (en) | 1982-12-03 |
| DK155325B (en) | 1989-03-28 |
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