JPH0212232B2 - - Google Patents
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- Publication number
- JPH0212232B2 JPH0212232B2 JP56121365A JP12136581A JPH0212232B2 JP H0212232 B2 JPH0212232 B2 JP H0212232B2 JP 56121365 A JP56121365 A JP 56121365A JP 12136581 A JP12136581 A JP 12136581A JP H0212232 B2 JPH0212232 B2 JP H0212232B2
- Authority
- JP
- Japan
- Prior art keywords
- hydrocarbon group
- acid
- formula
- polyphosphoric acid
- ethyl
- 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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- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は一般式
（式中、R1、R2はそれぞれ炭化水素基を示すか、
又は互いに連結した炭化水素基あるいは含窒素炭
化水素基を示す。R3は炭化水素基を示す。）で表
わされるピリドピリミジン誘導体の製造法に関す
る。
医薬品として有用な前記の式〔〕で示される
ピリドピリミジン誘導体を製造する方法に関して
はすでにいくつかの方法がある。その中で本発明
者らは、特願昭55−925号において、一般式
（式中、R1、R2、R3は前記と同じ。R4、R5はそ
れぞれ炭化水素基を示す。）で表わされるピリミ
ジノアミノメチレンマロン酸環状エステルをポリ
リン酸の存在下で反応させることにより、一段階
で一般式〔〕で表わされるピリドピリミジン誘
導体を得る方法を提案した。しかしながら前記提
案によれば、一般式〔〕で表わされるピリドピ
リミジン誘導体を得るには、一般式〔〕で表わ
されるピリミジノアミノメチレンマロン酸環状エ
ステルをポリリン酸とともに高温で加熱する必要
があり、又その収率もまた充分高いものとは言え
なかつた。
本発明者らは式〔〕で示される化合物の収率
向上を目ざし、且つ比較的低温で行える方法を鋭
意検討した結果、本発明を完成するに至つた。す
なわち、本発明は前記一般式〔〕で表わされる
ピリミジノアミノメチレンマロン酸環状エステル
を、(A)ポリリン酸と(B)五酸化リンおよび／または
オキシ塩化リンの共存下で反応させることを特徴
とする前記一般式〔〕で表わされるピリドピリ
ミジン誘導体の製造法に関する。
前記一般式〔〕で示されるピリミジノアミノ
メチレンマロン酸環状エステル中、R1、R2はそ
れぞれ炭化水素基、例えば、炭素数１ないし６の
アルキル基を示すか、又は互いに連結した炭化水
素基、例えば炭素数４ないし５のアルキレン基あ
るいは含窒素炭化水素基を示す。より具体的に
は、
The present invention is based on the general formula (In the formula, R 1 and R 2 each represent a hydrocarbon group, or
Alternatively, it represents a hydrocarbon group or a nitrogen-containing hydrocarbon group connected to each other. R 3 represents a hydrocarbon group. ) The present invention relates to a method for producing a pyridopyrimidine derivative represented by There are already several methods for producing the pyridopyrimidine derivatives represented by the above formula [] that are useful as pharmaceuticals. Among them, the present inventors proposed the general formula in Japanese Patent Application No. 55-925. (In the formula, R 1 , R 2 and R 3 are the same as above. R 4 and R 5 each represent a hydrocarbon group.) In the presence of polyphosphoric acid, a pyrimidinoamino methylene malonic acid cyclic ester represented by We proposed a method to obtain the pyridopyrimidine derivative represented by the general formula [] in one step by reaction. However, according to the above proposal, in order to obtain the pyridopyrimidine derivative represented by the general formula [], it is necessary to heat the pyrimidinoamino methylene malonic acid cyclic ester represented by the general formula [] together with polyphosphoric acid at a high temperature. However, the yield was also not high enough. The present inventors aimed at improving the yield of the compound represented by the formula [], and as a result of intensive study on a method that can be carried out at a relatively low temperature, the present invention was completed. That is, the present invention involves reacting the pyrimidinoamino methylene malonic acid cyclic ester represented by the general formula [] in the coexistence of (A) polyphosphoric acid and (B) phosphorus pentoxide and/or phosphorus oxychloride. The present invention relates to a method for producing a pyridopyrimidine derivative represented by the above general formula []. In the pyrimidinoamino methylene malonic acid cyclic ester represented by the general formula [], R 1 and R 2 each represent a hydrocarbon group, for example, an alkyl group having 1 to 6 carbon atoms, or hydrocarbons connected to each other. It represents a group such as an alkylene group having 4 to 5 carbon atoms or a nitrogen-containing hydrocarbon group. More specifically,
【式】基で表示して（CH3）2N−、[Formula] expressed as a group (CH 3 ) 2 N-,
【式】（C2H5）2N−、[Formula] (C 2 H 5 ) 2 N−,
【式】【formula】
【式】（ただし、R6は炭化水素基、
例えばCH3−、C2H5−ｎ−C3H7−、
[Formula] (where R 6 is a hydrocarbon group, e.g. CH 3 −, C 2 H 5 −n−C 3 H 7 −,
【式】C6H5−、C6H3CH2−のような炭
素数１ないし10程度の炭化水素基）などを例示す
ることができる。
又、R3は炭化水素基、好ましくは炭素数１な
いし６のアルキル基、とくに好ましくはエチル基
である。さらにR4、R5は、それぞれ炭化水素基、
好ましくは炭素数１ないし３のアルキル基、とく
に好ましくはメチル基である。一般式（）の化
合物、例えばＮ−エチル−Ｎ−〔２−（４−ベンジ
ル−１−ピペラジル）ピリミジル〕アミノメチレ
ンマロン酸イソプロピリデンは２−（４−ベンジ
ル−１−ピペラジル）−４−エチルアミノピリミ
ジンとメトキシメチレンマロン酸イソプロピリデ
ンとをTHF中、窒素気流中室温で20hr撹拌反応
させることにより、容易に合成ることができる。
反応に用いるポリリン酸としては、例えばピロ
リン酸、三リン酸、四リン酸、五リン酸、六リン
酸、これらの混合物などであり、オルトリン酸を
一部含んでいてもよい。本発明においてはポリリ
ン酸と共に、五酸化リンおよび／またはオキシ塩
化リンが用いられる。ポリリン酸と五酸化リンを
混合使用する場合、その使用割合を、五酸化リン
１重量部に対し、ポリリン酸１ないし20重量部、
とくに３ないし10重量部とするのが好ましい。ポ
リリン酸およびオキシ塩化リンを混合使用する場
合、その使用割合は、オキシ塩化リン１重量部に
対し、ポリリン酸0.5ないし20重量部、とくに１
ないし10重量部とするのが好ましい。ポリリン酸
とともに、五酸化リンおよびオキシ塩化リンの両
者を混合使用する場合には、その使用割合は、五
酸化リン１重量部に対しオキシ塩化リン0.1ない
し10重量部程度、ポリリン酸0.5ないし20重量部
程度とするのが好ましい。
反応に際し、トルエン、キシレンなどの炭化水
素、クロロホルム、ジクロロエタンなどのハロゲ
ン炭化水素、ジオキサン、ジメトキシエタンなど
のエーテル等、ポリリン酸、五酸化リン、オキシ
塩化リンと反応しない溶媒を共存させて反応を行
つてもよい。反応温度は、20ないし250℃、とく
に50ないし200℃の範囲が適当である。
反応後、目的物を単離するには、水またはアル
カリ水溶液を反応混合物と混ぜたのち中和し、抽
出、再結晶、クロマトグラフイーなどの通常の分
離手段を適宜採用することによつて行うことがで
きる。
次に実施例により説明する。
実施例 １
100ml三つ口フラスコにポリリン酸17.8ｇと五
酸化リン2.2ｇを入れ、170℃にて１時間撹拌した
のち、100℃に下げ、その中にＮ−エチル−Ｎ−
〔２−（４−ベンジル−１−ピペラジニル）ピリミ
ジニル〕アミノメチレンマロン酸イソプロピリデ
ン225ｇを加え、１時間反応させた、冷却後、反
応混合物に水50mlを加え、6N NaOHでPH11とし
た。次にトルエンで中性、塩基物質を抽出後、水
層を6N HClにてPH9.0次いで酢酸にてPH6.0とし、
クロロホルムで抽出した。抽出液を無水硫酸ナト
リウムで乾燥後クロロホルムを留去して、1.31ｇ
の粗結晶が得られた（収率66％）。このものをジ
メチルホルムアミド−エタノールから再結晶し
取することにより２−（４−ベンジル−１−ピペ
ラジニル）−８−エチル−５，８−ジヒドロ−５
−オキソピリド〔２，３−ｄ〕ピリミジン−６−
カルボン酸の純品が得られた。
実施例 ２
30ml二つ口フラスコにポリリン酸３ｇと五酸化
リン１ｇを入れ180℃で１時間撹拌したのち100℃
に下げその中にＮ−エチル−Ｎ−〔２−（４−ベン
ジル−１−ピペラジル）ピリミジニル〕アミノメ
チレンマロン酸イソプロピリデン0.45ｇを加え、
１時間反応させた。冷却後水300mlを加え、炭酸
ナトリウムを用いてPH6.0にし、次いでクロロホ
ルムで抽出した。抽出液を無水硫酸ナトリウムで
乾燥後、クロロホルムを留去し、残渣をジメチル
ホルムアミド−エタノールから再結晶し取する
ことにより0.25ｇの２−（４−ベンジル−１−ピ
ペラジル）−８−エチル−５，８−ジヒドロ−５
−オキソピリド〔２，３−ｄ〕ピリミジン−６−
カルボン酸が得られた（収率64％）。
実施例 ３
ポリリン酸3.3ｇと五酸化リン0.7ｇを用いて実
施例２と同様に反応させ処理したところ、0.23ｇ
の２−（４−ベンジル−１−ピペラジル）−８−エ
チル−５，８−ジヒドロ−５−オキソ〔２，３−
ｄ〕ピリミジン−６−カルボン酸が得られた（収
率59％）。実施例 ４
30ml二つ口フラスコにポリリン酸5.0ｇと五酸
化リン1.0ｇを入れ140℃に加熱撹拌した中に、Ｎ
−エチル−Ｎ−〔２−（４−ベンジル−１−ピペラ
ジル）ピリミジン〕アミノメチレンマロン酸イソ
プロピリデン0.45ｇを加え、１時間反応させた。
実施例２と同様に処理したところ、0.22ｇの２−
（４−ベンジル−１−ピペラジニル）−８−エチル
−５，８−ジヒドロ−５−オキソピリド〔２，３
−ｄ〕ピリミジン−６−カルボン酸が得られた
（収率56％）。
実施例 ５
50ml二つ口フラスコに窒素気流下ポリリン酸
4.0ｇ、オキシ塩化リン2.0ｇおよびトルエン10ml
を入れ、100℃に加熱撹拌し、その中にＮ−エチ
ル−Ｎ−〔２−（４−ベンジル−１−ピペラジニ
ル）ピリミジニル〕アミノメチレンマロン酸イソ
プロピリデン0.45ｇを加えて１時間反応させた。
実施例２と同様に処理することにより、0.24ｇの
２−（４−ベンジル−１−ピペラジニル）−８−エ
チル−５，８−ジヒドロ−５−オキソピリド
〔２，３−ｄ〕ピリミジン−６−カルボン酸が得
られた（収率61％）。
実施例 ６
30ml二つ口フラスコにポリリン酸4.0ｇとオキ
シ塩化リン0.5ｇを入れ、窒素気流下140℃に加熱
撹拌し、その中にＮ−エチル−Ｎ−〔２−（４−ベ
ンジル−１−ピペラジニル）ピリミジニル〕アミ
ノメチレンマロン酸イソプロピリデン0.45ｇを加
え、１時間反応させた。実施例２と同様に処理す
ることにより、0.20ｇの２−（４−ベンジル−１
−ピペラジニル）−８−エチル−５，８−ジヒド
ロ−５−オキソピリド〔２，３−ｄ）ピリミジン
−６−カルボン酸が得られた（収率50％）。[Formula] Hydrocarbon groups having about 1 to 10 carbon atoms such as C 6 H 5 - and C 6 H 3 CH 2 - can be exemplified. Further, R 3 is a hydrocarbon group, preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably an ethyl group. Furthermore, R 4 and R 5 are each a hydrocarbon group,
Preferably it is an alkyl group having 1 to 3 carbon atoms, particularly preferably a methyl group. A compound of general formula (), for example, N-ethyl-N-[2-(4-benzyl-1-piperazyl)pyrimidyl]isopropylidene aminomethylenemalonate is 2-(4-benzyl-1-piperazyl)-4-ethyl It can be easily synthesized by stirring aminopyrimidine and isopropylidene methoxymethylenemalonate in THF at room temperature in a nitrogen stream for 20 hours. Examples of the polyphosphoric acid used in the reaction include pyrophosphoric acid, triphosphoric acid, tetraphosphoric acid, pentaphosphoric acid, hexaphosphoric acid, and mixtures thereof, and may partially contain orthophosphoric acid. In the present invention, phosphorus pentoxide and/or phosphorus oxychloride are used together with polyphosphoric acid. When using a mixture of polyphosphoric acid and phosphorus pentoxide, the ratio is 1 to 20 parts by weight of polyphosphoric acid to 1 part by weight of phosphorus pentoxide.
In particular, it is preferably 3 to 10 parts by weight. When polyphosphoric acid and phosphorus oxychloride are mixed and used, the ratio is 0.5 to 20 parts by weight, especially 1 part by weight of polyphosphoric acid per 1 part by weight of phosphorus oxychloride.
The amount is preferably from 1 to 10 parts by weight. When using a mixture of phosphorus pentoxide and phosphorus oxychloride together with polyphosphoric acid, the ratio of use is approximately 0.1 to 10 parts by weight of phosphorus oxychloride to 1 part by weight of phosphorus pentoxide, and 0.5 to 20 parts by weight of polyphosphoric acid. It is preferable to set it to about 1.5 parts. During the reaction, the reaction is carried out in the coexistence of a solvent that does not react with polyphosphoric acid, phosphorus pentoxide, or phosphorus oxychloride, such as hydrocarbons such as toluene and xylene, halogen hydrocarbons such as chloroform and dichloroethane, and ethers such as dioxane and dimethoxyethane. It's good to wear. The reaction temperature is suitably in the range of 20 to 250°C, particularly 50 to 200°C. After the reaction, the target product can be isolated by mixing water or aqueous alkaline solution with the reaction mixture, neutralizing it, and appropriately employing conventional separation means such as extraction, recrystallization, and chromatography. be able to. Next, an example will be explained. Example 1 17.8 g of polyphosphoric acid and 2.2 g of phosphorus pentoxide were placed in a 100 ml three-necked flask, stirred at 170°C for 1 hour, then lowered to 100°C, and N-ethyl-N-
225 g of isopropylidene [2-(4-benzyl-1-piperazinyl)pyrimidinyl]aminomethylenemalonate was added and reacted for 1 hour. After cooling, 50 ml of water was added to the reaction mixture, and the pH was adjusted to 11 with 6N NaOH. Next, after extracting neutral and basic substances with toluene, the aqueous layer was adjusted to pH 9.0 with 6N HCl and then adjusted to pH 6.0 with acetic acid.
Extracted with chloroform. After drying the extract over anhydrous sodium sulfate, chloroform was distilled off to give 1.31 g.
Crude crystals were obtained (yield 66%). By recrystallizing this product from dimethylformamide-ethanol, 2-(4-benzyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5
-Oxopyrido[2,3-d]pyrimidine-6-
A pure carboxylic acid was obtained. Example 2 Put 3 g of polyphosphoric acid and 1 g of phosphorus pentoxide into a 30 ml two-necked flask, stir at 180°C for 1 hour, and then raise the temperature to 100°C.
0.45 g of isopropylidene N-ethyl-N-[2-(4-benzyl-1-piperazyl)pyrimidinyl]aminomethylenemalonate was added thereto.
The reaction was allowed to proceed for 1 hour. After cooling, 300 ml of water was added, the pH was adjusted to 6.0 using sodium carbonate, and the mixture was extracted with chloroform. After drying the extract over anhydrous sodium sulfate, chloroform was distilled off, and the residue was recrystallized from dimethylformamide-ethanol to obtain 0.25 g of 2-(4-benzyl-1-piperazyl)-8-ethyl-5. ,8-dihydro-5
-Oxopyrido[2,3-d]pyrimidine-6-
Carboxylic acid was obtained (yield 64%). Example 3 When 3.3 g of polyphosphoric acid and 0.7 g of phosphorus pentoxide were reacted in the same manner as in Example 2, 0.23 g
2-(4-benzyl-1-piperazyl)-8-ethyl-5,8-dihydro-5-oxo[2,3-
d] Pyrimidine-6-carboxylic acid was obtained (yield 59%). Example 4 5.0 g of polyphosphoric acid and 1.0 g of phosphorus pentoxide were placed in a 30 ml two-necked flask, heated to 140°C and stirred, and N
-Ethyl-N-[2-(4-benzyl-1-piperazyl)pyrimidine]aminomethylenemalonate 0.45 g of isopropylidene was added and reacted for 1 hour.
When treated in the same manner as in Example 2, 0.22g of 2-
(4-Benzyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido [2,3
-d] pyrimidine-6-carboxylic acid was obtained (yield 56%). Example 5 Polyphosphoric acid was added to a 50ml two-necked flask under nitrogen flow.
4.0g, phosphorus oxychloride 2.0g and toluene 10ml
was heated and stirred at 100°C, and 0.45 g of isopropylidene N-ethyl-N-[2-(4-benzyl-1-piperazinyl)pyrimidinyl]aminomethylenemalonate was added thereto and reacted for 1 hour.
By treating in the same manner as in Example 2, 0.24 g of 2-(4-benzyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6- Carboxylic acid was obtained (yield 61%). Example 6 4.0 g of polyphosphoric acid and 0.5 g of phosphorus oxychloride were placed in a 30 ml two-necked flask, heated and stirred at 140°C under a nitrogen stream, and N-ethyl-N-[2-(4-benzyl-1 -Piperazinyl)pyrimidinyl]aminomethylenemalonate 0.45 g of isopropylidene was added and reacted for 1 hour. By treating in the same manner as in Example 2, 0.20 g of 2-(4-benzyl-1
-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d)pyrimidine-6-carboxylic acid was obtained (yield 50%).
Claims (1)
又は互いに連結した炭化水素基あるいは含窒素炭
化水素基を示す。R3、R4、R5はそれぞれ炭化水
素基を示す。）で表わされるピリミジノアミノメ
チレンマロン酸環状エステルを、(A)ポリリン酸と
(B)五酸化リンおよび／またはオキシ塩化リンの存
在下で反応させることを特徴とする一般式 （式中、R1、R2、R3は前記と同じ。）で表わされ
るピリドピリミジン誘導体の製造法。[Claims] 1. General formula (In the formula, R 1 and R 2 each represent a hydrocarbon group, or
Alternatively, it represents a hydrocarbon group or a nitrogen-containing hydrocarbon group connected to each other. R 3 , R 4 and R 5 each represent a hydrocarbon group. ) pyrimidinoamino methylene malonic acid cyclic ester represented by (A) polyphosphoric acid
(B) General formula characterized by the reaction in the presence of phosphorus pentoxide and/or phosphorus oxychloride A method for producing a pyridopyrimidine derivative represented by the formula (wherein R 1 , R 2 and R 3 are the same as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56121365A JPS5823692A (en) | 1981-08-04 | 1981-08-04 | Preparation of pyridopyrimidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56121365A JPS5823692A (en) | 1981-08-04 | 1981-08-04 | Preparation of pyridopyrimidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5823692A JPS5823692A (en) | 1983-02-12 |
| JPH0212232B2 true JPH0212232B2 (en) | 1990-03-19 |
Family
ID=14809438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56121365A Granted JPS5823692A (en) | 1981-08-04 | 1981-08-04 | Preparation of pyridopyrimidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5823692A (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52139094A (en) * | 1976-05-18 | 1977-11-19 | Sumitomo Chem Co Ltd | 1-fluoralkyl-1,4-dihydro-4-oxo-3-pyridinecarboxylic acid derivatives |
-
1981
- 1981-08-04 JP JP56121365A patent/JPS5823692A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5823692A (en) | 1983-02-12 |
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