JPS6111233B2 - - Google Patents
Info
- Publication number
- JPS6111233B2 JPS6111233B2 JP53110268A JP11026878A JPS6111233B2 JP S6111233 B2 JPS6111233 B2 JP S6111233B2 JP 53110268 A JP53110268 A JP 53110268A JP 11026878 A JP11026878 A JP 11026878A JP S6111233 B2 JPS6111233 B2 JP S6111233B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- piperazinyl
- pyrido
- piperazinyl group
- pyrimidine
- 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
- -1 1-piperazinyl group Chemical group 0.000 claims description 17
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000004278 2-oxazolin-2-yl group Chemical group [H]C1([H])OC(*)=NC1([H])[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- BWAZCHWAQIJILM-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine-2-carboxylic acid Chemical class C1=CC=NC2=NC(C(=O)O)=NC=C21 BWAZCHWAQIJILM-UHFFFAOYSA-N 0.000 claims description 2
- 159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 2
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- LSIMTRQDJFJBBH-UHFFFAOYSA-N 1-(4,5-dihydro-1,3-oxazol-2-yl)ethanone Chemical class CC(=O)C1=NCCO1 LSIMTRQDJFJBBH-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052500 inorganic mineral Chemical class 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- MQGSFCXWKXXCTE-UHFFFAOYSA-N pyrimidine-4-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=NC=N1 MQGSFCXWKXXCTE-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
【発明の詳細な説明】
本発明は抗菌剤として有用な下記〔〕式で示
される化合物の新規製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing a compound represented by the following formula [] which is useful as an antibacterial agent.
更に詳しくは、一般式
（式中、R1は１−ピロリジニル基、１−ピペラジ
ニル基、４−アシル−１−ピペラジニル基または
４−トリエチル−１−ピペラジニル基を意味し、
R2、R3、R4およびR5は同一または相異なつて水
素原子または低級アルキル基を意味する。）
で表わされる６−（△２−オキサゾリン−２−イ
ル）ピリド〔２・３−ｄ〕ピリミジン誘導体を加
水分解することを特徴とする一般式
（式中、R1′は１−ピロリジニル基または１−ピペ
ラジニル基を意味する。）
〓〓〓〓〓
で表わされるピリド〔２・３−ｄ〕ピリミジンカ
ルボン酸誘導体またはその塩の製法に関する。 For more details, see the general formula (In the formula, R 1 means a 1-pyrrolidinyl group, 1-piperazinyl group, 4-acyl-1-piperazinyl group or 4-triethyl-1-piperazinyl group,
R 2 , R 3 , R 4 and R 5 are the same or different and each represents a hydrogen atom or a lower alkyl group. ) A general formula characterized by hydrolyzing a 6-(△ 2 -oxazolin-2-yl)pyrido[2,3-d]pyrimidine derivative (In the formula, R 1 ' means a 1-pyrrolidinyl group or a 1-piperazinyl group.)
The present invention relates to a method for producing a pyrido[2,3-d]pyrimidinecarboxylic acid derivative or a salt thereof.
上記式〔〕で表わされる化合物の置換基のう
ち、４−アシル−ピペラジニル基としては、４−
ホルミル−１−ピペラジニル基、４−アセチル−
１−ピペラジニル基、４−トリフルオロアセチル
−１−ピペラジニル基、４−ベンゾイル−１−ピ
ペラジニル基、４−エトキシカルボニル−１−ピ
ペラジニル基、４−ベンジルオキシカルボニル−
１−ピペラジニル基または４−ｔ−ブトキシカル
ボニル−１−ピペラジニル基が挙げられる。 Among the substituents of the compound represented by the above formula [], the 4-acyl-piperazinyl group is 4-
formyl-1-piperazinyl group, 4-acetyl-
1-piperazinyl group, 4-trifluoroacetyl-1-piperazinyl group, 4-benzoyl-1-piperazinyl group, 4-ethoxycarbonyl-1-piperazinyl group, 4-benzyloxycarbonyl-
Examples include 1-piperazinyl group and 4-t-butoxycarbonyl-1-piperazinyl group.
この反応は酸または塩基触媒の存在下に原料化
合物〔〕を加水分解することにより実施され
る。例えば、苛性ソーダ、苛性カリの如き苛性ア
ルカリ、または塩酸、硫酸の如き鉱酸と室温乃至
120℃、好ましくは80乃至100℃で加熱する。この
際、R1が保護されたピペラジニル基の場合、そ
の保護基も脱離されR1′が１−ピペラジニル基で
ある化合物を得ることができる。 This reaction is carried out by hydrolyzing the starting compound [ ] in the presence of an acid or base catalyst. For example, with caustic alkalis such as caustic soda and caustic potash, or mineral acids such as hydrochloric acid and sulfuric acid,
Heat at 120°C, preferably 80-100°C. In this case, when R 1 is a protected piperazinyl group, the protecting group is also removed to obtain a compound in which R 1 ' is a 1-piperazinyl group.
この反応において、目的化合物〔〕は原料化
合物および反応条件によつては酸との塩の形で得
られるが、常法により遊離させればよい。 In this reaction, the target compound [ ] may be obtained in the form of a salt with an acid depending on the starting compounds and reaction conditions, but it may be liberated by a conventional method.
本反応に使用される原料化合物〔〕は新規化
合物であつて、例えば２−置換−４−エチルアミ
ノピリミジン−５−カルボン酸クロライドにフエ
ニルリチウム等の存在下、２−メチル−△２−オ
キサゾリン類を反応せしめ、２−置換−４−エチ
ルアミノ−５−ピリミジニル △２−オキサゾリ
ン−２−イルメチル ケトン類と成し、これにオ
ルトギ酸エチルまたはＮ・Ｎ−ジメチルホルムア
ミドジメチルアセタール等を作用させて、原料化
合物〔〕を得ることができる。 The raw material compound [ ] used in this reaction is a new compound, for example, 2-methyl-△ 2 -oxazoline in the presence of phenyllithium etc. to 2-substituted-4-ethylaminopyrimidine- 5 -carboxylic acid chloride are reacted to form 2-substituted-4-ethylamino-5-pyrimidinyl △ 2 -oxazolin-2-ylmethyl ketones, which are then reacted with ethyl orthoformate or N·N-dimethylformamide dimethyl acetal, etc. , the raw material compound [] can be obtained.
以下実施例を挙げて説明する。 This will be explained below with reference to examples.
実施例 １
８−エチル−５・８−ジヒドロ−５−オキソ−
２−（１−ピロリジニル）ピリド〔２・３−
ｄ〕ピリミジン−６−カルボン酸の製法：
８−エチル−５・８−ジヒドロ−５−オキソ−
６−（△２−オキサゾリン−２−イル）−２−（１
−ピロリジニル）ピリド〔２・３−ｄ〕ピリミジ
ン（m.p.183〜184℃）6.3ｇ、水30ml及び15％塩
酸30mlから成る混合物を80〜90℃にて１時間加熱
する。反応後冷却し、析出結晶を濾取し、エタノ
ールにて洗浄、乾燥して目的物4.0ｇを得る。Example 1 8-ethyl-5,8-dihydro-5-oxo-
2-(1-pyrrolidinyl)pyrido [2,3-
d] Process for producing pyrimidine-6-carboxylic acid: 8-ethyl-5,8-dihydro-5-oxo-
6-(△ 2 -oxazolin-2-yl)-2-(1
A mixture of 6.3 g of -pyrrolidinyl)pyrido[2.3-d]pyrimidine (mp 183-184°C), 30 ml of water and 30 ml of 15% hydrochloric acid is heated at 80-90° C. for 1 hour. After the reaction is cooled, the precipitated crystals are collected by filtration, washed with ethanol, and dried to obtain 4.0 g of the desired product.
m.p.305〜310℃（分解）
実施例 ２
８−エチル−５・８−ジヒドロ−５−オキソ−
２−（１−ピペラジニル）ピリド〔２・３−
ｄ〕ピリミジン−６−カルボン酸の塩酸塩の製
法：
８−エチル−５・８−ジヒドロ−５−オキソ−
６−（△２−オキサゾリン−２−イル）−２−（４
−アセチル−１−ピペラジニル）ピリド〔２・３
−ｄ〕ピリミジン（m.p.255〜257℃）1.2ｇを15
％塩酸６mlに溶解し、95〜100℃にて１時間加熱
する。反応後冷却し、析出結晶を濾取する。結晶
をエタノールにて洗浄、乾燥し目的物0.82ｇを得
る。 mp305-310℃ (decomposition) Example 2 8-ethyl-5,8-dihydro-5-oxo-
2-(1-piperazinyl)pyrido [2,3-
d] Process for producing pyrimidine-6-carboxylic acid hydrochloride: 8-ethyl-5,8-dihydro-5-oxo-
6-(△ 2 -oxazolin-2-yl)-2-(4
-acetyl-1-piperazinyl)pyrido [2,3
-d] Pyrimidine (mp255-257℃) 1.2g at 15
Dissolve in 6 ml of % hydrochloric acid and heat at 95-100°C for 1 hour. After the reaction, the mixture is cooled and the precipitated crystals are collected by filtration. The crystals were washed with ethanol and dried to obtain 0.82 g of the desired product.
m.p.300℃（分解）以上
実施例 ３
８−エチル−５・８−ジヒドロ−５−オキソ−
２−（１−ピペラジニル）ピリド〔２・３−
ｄ〕ピリミジン−６−カルボン酸及びその塩酸
塩の製法：
８−エチル−５・８−ジヒドロ−５−オキソ−
６−（△２−オキサゾリン−２−イル）−２−（１
−ピペラジニル）ピリド〔２・３−ｄ〕ピリミジ
ン（油状物質、IR：1645、1605、1260cm-1）3.56
ｇを15％塩酸（30ml）とエタノール（30ml）の混
液に加え、80〜90℃で１時間加熱する。反応後冷
却し、析出した結晶を濾取して、８−エチル−
５・８−ジヒドロ−５−オキソ−２−（１−ピペ
ラジニル）ピリド〔２・３−ｄ〕ピリミジン−６
−カルボン酸の塩酸塩3.30ｇを得る。 mp300℃ (decomposition) or higher Example 3 8-ethyl-5,8-dihydro-5-oxo-
2-(1-piperazinyl)pyrido [2,3-
d] Process for producing pyrimidine-6-carboxylic acid and its hydrochloride: 8-ethyl-5,8-dihydro-5-oxo-
6-(△ 2 -oxazolin-2-yl)-2-(1
-piperazinyl)pyrido[2,3-d]pyrimidine (oil, IR: 1645, 1605, 1260 cm -1 ) 3.56
Add g to a mixture of 15% hydrochloric acid (30 ml) and ethanol (30 ml) and heat at 80-90°C for 1 hour. After the reaction was cooled, the precipitated crystals were collected by filtration and 8-ethyl-
5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d]pyrimidine-6
- 3.30 g of carboxylic acid hydrochloride are obtained.
m.p.300℃（分解）以上
この塩酸塩3.30ｇを2N−水酸化ナトリウム水
溶液25mlに溶解し、酢酸を加えてPH6.5に調整
し、析出結晶を濾取する。エタノールにて洗浄後
加熱乾燥して、８−エチル−５・８−ジヒドロ−
５−オキソ−２−（１−ピペラジニル）ピリド
〔２・３−ｄ〕ピリミジン−６−カルボン酸（無
水物）を取る。 mp 300°C (decomposition) or higher Dissolve 3.30 g of this hydrochloride in 25 ml of 2N aqueous sodium hydroxide solution, adjust the pH to 6.5 by adding acetic acid, and collect the precipitated crystals by filtration. After washing with ethanol and heating drying, 8-ethyl-5,8-dihydro-
Take 5-oxo-2-(1-piperazinyl)pyrido[2.3-d]pyrimidine-6-carboxylic acid (anhydride).
〓〓〓〓〓
〓〓〓〓〓
Claims (1)
ニル基、４−アシル−１−ピペラジニル基または
４−トリチル−１−ピペラジニル基を意味し、
R2、R3、R4およびR5は同一または相異なつて水
素原子または低級アルキル基を意味する。） で表わされる６−（△２−オキサゾリン−２−イ
ル）ピリド〔２・３−ｄ〕ピリミジン誘導体を加
水分解することを特徴とする一般式 （式中、R1′は１−ピロリジニル基または１−ピペ
ラジニル基を意味する。） で表わされるピリド〔２・３−ｄ〕ピリミジンカ
ルボン酸誘導体またはその塩の製法。[Claims] 1. General formula (In the formula, R 1 means a 1-pyrrolidinyl group, 1-piperazinyl group, 4-acyl-1-piperazinyl group or 4-trityl-1-piperazinyl group,
R 2 , R 3 , R 4 and R 5 are the same or different and each represents a hydrogen atom or a lower alkyl group. ) A general formula characterized by hydrolyzing a 6-(△ 2 -oxazolin-2-yl)pyrido[2,3-d]pyrimidine derivative (In the formula, R 1 ' means a 1-pyrrolidinyl group or a 1-piperazinyl group.) A method for producing a pyrido[2.3-d]pyrimidinecarboxylic acid derivative or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11026878A JPS5536436A (en) | 1978-09-07 | 1978-09-07 | Production of pyrido 2,3-d pyrimidinecarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11026878A JPS5536436A (en) | 1978-09-07 | 1978-09-07 | Production of pyrido 2,3-d pyrimidinecarboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5536436A JPS5536436A (en) | 1980-03-14 |
| JPS6111233B2 true JPS6111233B2 (en) | 1986-04-01 |
Family
ID=14531370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11026878A Granted JPS5536436A (en) | 1978-09-07 | 1978-09-07 | Production of pyrido 2,3-d pyrimidinecarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5536436A (en) |
-
1978
- 1978-09-07 JP JP11026878A patent/JPS5536436A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5536436A (en) | 1980-03-14 |
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