JPH0225483A - Production of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido(2,3-d)pyrimidine-6-carboxylic acid trihydrate - Google Patents
Production of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido(2,3-d)pyrimidine-6-carboxylic acid trihydrateInfo
- Publication number
- JPH0225483A JPH0225483A JP63176134A JP17613488A JPH0225483A JP H0225483 A JPH0225483 A JP H0225483A JP 63176134 A JP63176134 A JP 63176134A JP 17613488 A JP17613488 A JP 17613488A JP H0225483 A JPH0225483 A JP H0225483A
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- piperazinyl
- dihydro
- oxopyrido
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- URMXYPLWYMOYPG-UHFFFAOYSA-N Pipemidic acid trihydrate Chemical compound O.O.O.N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 URMXYPLWYMOYPG-UHFFFAOYSA-N 0.000 title claims description 4
- 229960003506 piperazine hexahydrate Drugs 0.000 claims abstract description 24
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000013078 crystal Substances 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 3
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000012456 homogeneous solution Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- -1 PPA compound Chemical class 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 7
- 229960005141 piperazine Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 3
- 150000004684 trihydrates Chemical class 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 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
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960002195 perazine Drugs 0.000 description 1
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】
技術分野
本発明は優れた抗菌作用を有し医薬として有用な２−（
１−ピペラジニル）−８−エチル−５８−ジヒドロ−５
−オキソピリド［２，３’−ｄ］ピリミジン−６−カル
ボン酸三水和物の工業的に有利な新規製造方法に関する
ものである。Detailed Description of the Invention Technical Field The present invention provides 2-(
1-piperazinyl)-8-ethyl-58-dihydro-5
-Oxopyrido[2,3'-d]pyrimidine-6-carboxylic acid trihydrate is a novel industrially advantageous production method.
従来技術
２−（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（以下ＰＰＡ化合物、あるいは単にＰＰＡ
と称す）は三水和物の形で医薬として提供され抗菌目的
の化学療法剤として広く実用されている。Prior art 2-(1-piperazinyl)-8-ethyl-5°8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6
-carboxylic acid (hereinafter referred to as PPA compound, or simply PPA)
) is provided as a medicine in the form of trihydrate and is widely used as a chemotherapeutic agent for antibacterial purposes.
従来この２−（１−ピペラジニル）−８−エチル−５，
８−ジヒドロ−５−オキソピリド［２３−ｄ］ピリミジ
ン−６−カルボン酸三水和物の製法として、ＰＰＡを水
または含水媒体から三水和物として生成させ、その結晶
水が脱離しない条件下で乾燥して付着水を除去する方法
が知られている（特公昭５６−１２６３６号）。Conventionally, this 2-(1-piperazinyl)-8-ethyl-5,
As a method for producing 8-dihydro-5-oxopyrido[23-d]pyrimidine-6-carboxylic acid trihydrate, PPA is produced as a trihydrate from water or a water-containing medium, and the water of crystallization is not released. A method of removing adhering water by drying is known (Japanese Patent Publication No. 56-12636).
しかしながらこの方法なと７０℃以下という低温乾燥の
為、多量の付着水を除去するのに長時間を要する。しか
もアルカリ水溶液あるいは酸性水溶液にＰＰＡを一旦溶
解し、しかる後に中和により目的物の結晶を析出させる
なめ操作がはん雑になるだけでなくその際に生じる廃水
の処理といっな問題点をも有していた。However, this method requires a long time to remove a large amount of attached water because of the low temperature drying of 70° C. or lower. Moreover, not only is the licking operation of dissolving PPA in an alkaline or acidic aqueous solution and then neutralizing it to precipitate crystals of the target substance complicated, but it also poses problems such as the treatment of wastewater generated at that time. had.
発明が解決しようとする問題点
そこで合成により純粋な形で得られるＰＰＡ無水物から
医薬として有用なＰＰＡ三水和物を経済的、且つ、工業
的有利に得ることのできる方法を確立することが本発明
目的である。The problem to be solved by the invention is to establish an economically and industrially advantageous method for obtaining pharmaceutically useful PPA trihydrate from PPA anhydride obtained in pure form by synthesis. This is the object of the present invention.
さらにＰＰＡ三水和物をアルカリ性あるいは酸性水溶液
に一旦とかし、中和するはん雑な操作により精製する必
要のないＰＰＡ三水和物の製法を確立することも本発明
目的の一つである。Furthermore, it is one of the objects of the present invention to establish a method for producing PPA trihydrate that does not require purification by complicated operations such as dissolving PPA trihydrate in an alkaline or acidic aqueous solution and neutralizing it.
問題点を解決するための手段
本発明に従えば上記発明目的が２−（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カルボン酸と過剰量のピペ
ラジン６水和物を加熱溶解させ、アルコールを加えた後
、冷却し析出せる結晶を濾取することを特徴とする２−
（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
ン酸三水和物の製造方法により達成せられる。即ち本発
明は２−（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−カルボン酸無水物とじペラジン６水和物を加熱
溶解させた場合、ピペラジン６水和物の結晶水が極めて
効率よ＜１−（１−ピペラジニル）−８−エチル−５８
−ジヒドロ−５−オキソピリド［２，３−ｄ］ピリミジ
ン−６−カルボン酸に移動せしめられ２（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−カルボン酸三水和
物が生成すること、加熱溶融せしめられたピペラジン６
水和物がＰＰＡ無水物は溶かさぬがＰＰＡ三水三水相溶
媒として役立つこと、アルコールがピペラジン無水物お
よびピペラジン６水和物を溶解するがＰＰＡ三水和物の
貧溶媒であること等の重要な発見に基づいて完成された
ものである。Means for Solving the Problems According to the present invention, the above-mentioned object of the invention is achieved by solving the above-mentioned problems with 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5oxopyride [
2,3-d]pyrimidine-6 carboxylic acid and an excess amount of piperazine hexahydrate are dissolved by heating, alcohol is added, and then cooled and precipitated crystals are collected by filtration.
This can be achieved by a method for producing (1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6carboxylic acid trihydrate. That is, the present invention provides 2-(1-piperazinyl)-8-ethyl-5,8-
When dihydro-5-oxopyrido[2,:3-d]pyrimidine-6-carboxylic anhydride and perazine hexahydrate are dissolved under heating, the water of crystallization of piperazine hexahydrate is extremely efficiently <1-( 1-piperazinyl)-8-ethyl-58
-dihydro-5-oxopyrido[2,3-d] transferred to pyrimidine-6-carboxylic acid and 2(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d] Formation of pyrimidine-6-carboxylic acid trihydrate, heated melting of piperazine 6
The hydrate does not dissolve PPA anhydride but serves as a PPA trihydrate triaqueous phase solvent, and the alcohol dissolves piperazine anhydride and piperazine hexahydrate but is a poor solvent for PPA trihydrate. It was completed based on important discoveries.
本発明においては先づ２−（１−ピペラジニル）−８−
エチル−５，８−ジヒドロ−５−オキソピリド［２，１
−ｄ］ピリミジン−６−カルボン酸と過剰量のピペラジ
ン６水和物とが加熱され均質溶液が作られる。ピペラジ
ン６水和物は常温固体であるが約６０℃に加熱せられる
と溶融し液状となる。ＰＰＡ無水物はピペラジン６水和
物溶融液には溶解しないが、その反応物は溶解する特性
がある。従って、前記無水物とピペラジン６水和物が共
存すると、時間の経過と共に、ピペラジン６水和物の結
晶水がＰＰＡ無水物に移行し、ＰＰＡ三水和物が生成し
てピペラジン６水和物溶融液に溶解し他方ピペラジン６
水和物は結晶水を失って無水物の形となる。理論的には
２モルのＰＰＡと１モルのピペラジン６水和物の間で結
晶水の移動が生じ、２モルのＰＰＡ三水和物と１モルの
ピペラジン無水物が生じる筈であるしかしながらこの結
晶水の移動はピペラジン６水和物溶融液がＰＰＡ三水和
物の溶剤として存在するときに容易に生じ、かかる溶剤
の不存在下では充分に行われ難いことが見出された。In the present invention, first, 2-(1-piperazinyl)-8-
Ethyl-5,8-dihydro-5-oxopyride [2,1
-d] pyrimidine-6-carboxylic acid and excess piperazine hexahydrate are heated to form a homogeneous solution. Piperazine hexahydrate is solid at room temperature, but melts and becomes liquid when heated to about 60°C. PPA anhydride does not dissolve in the piperazine hexahydrate melt, but its reactants have the property of dissolving. Therefore, when the anhydride and piperazine hexahydrate coexist, the water of crystallization of piperazine hexahydrate transfers to PPA anhydride over time, and PPA trihydrate is generated to form piperazine hexahydrate. Dissolve the other piperazine 6 in the melt.
Hydrates lose their water of crystallization and become anhydrous. Theoretically, the movement of crystal water should occur between 2 moles of PPA and 1 mole of piperazine hexahydrate, resulting in 2 moles of PPA trihydrate and 1 mole of piperazine anhydride. It has been found that water migration occurs easily when the piperazine hexahydrate melt is present as a solvent for PPA trihydrate, and is difficult to achieve satisfactorily in the absence of such a solvent.
従って本発明においてはピペラジン６水和物が理論量よ
りもかなり過剰に用いられ、ＰＰＡ三永和物の溶剤とし
ても役立てられるのである。Therefore, in the present invention, piperazine hexahydrate is used in a considerably excess amount compared to the theoretical amount, and it also serves as a solvent for PPA trihydrate.
既に述べた如く、ＰＰＡ無水物は溶融ピペラジン６水和
物に溶解しないが、ＰＰＡ三水和物に変換されると溶融
ピペラジン６水和物に溶解する。そこで本発明方法の第
１工程に於ては、２−（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−カルボン酸と過剰量のピペラジン６水和物
とが加熱され、均質な溶液が作られるのである。As previously mentioned, PPA anhydride is not soluble in molten piperazine hexahydrate, but when converted to PPA trihydrate, it is soluble in molten piperazine hexahydrate. Therefore, in the first step of the method of the present invention, 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine 6-carboxylic acid and an excess amount of piperazine 6-carboxylic acid are used. The hydrate is heated to create a homogeneous solution.
本発明の特に好ましい一具体例においては、先ずピペラ
ジン６水和物が加熱溶融せしめられ、ここへＰＰＡ無水
物が添加され、撹拌により、ＰＰ一
Ａ無水物が順次ＰＰＡ三水和物に変換され溶融ピペラジ
ン６水和物中に溶解せしめられる。本発明者らはかかる
態様においてＰＰＡ無水物からＰＰＡ三水和物への変換
が極めて容易且つスムースに進行せしめられ短時間内に
均質溶液が得られ、ＰＰＡ無水物の残存が全く認められ
ぬことを知見し得た。In a particularly preferred embodiment of the present invention, piperazine hexahydrate is first heated and melted, PPA anhydride is added thereto, and the PP-A anhydride is sequentially converted into PPA trihydrate by stirring. Dissolved in molten piperazine hexahydrate. The present inventors have discovered that in such an embodiment, the conversion from PPA anhydride to PPA trihydrate proceeds extremely easily and smoothly, a homogeneous solution is obtained within a short time, and no residual PPA anhydride is observed. I was able to find out.
次に本発明方法に於ては、上記溶融物にアルコールが加
えられ冷却せしめられる。ＰＰＡ無水物が完全に消失し
た溶融物には、ＰＰＡ三水和物、ピペラジン無水物、お
よびピペラジン６水和物が含まれる。これらの内ＰＰＡ
三水和物のみがアルコールに対する溶解度が小である。Next, in the method of the present invention, alcohol is added to the melt and allowed to cool. The melt in which PPA anhydride has completely disappeared contains PPA trihydrate, piperazine anhydride, and piperazine hexahydrate. Among these PPA
Only the trihydrate has low solubility in alcohol.
従って冷却によりＰＰＡ三水和物の結晶が析出してくる
から、これを濾取し、付着エタノールを揮発させること
により、目的とする２−（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−カルボン酸三水和物の純粋な結
晶を得ることができる。残液はアルコールを留去し、ピ
ペラジン６水和物として再利用が可能であるから、従来
法の如く廃液の生じる問題もなく、経済性、作業性の点
で極めて優れた２−（１−ピペラジニル）−８エチル−
５８−ジヒドロ−５−オキソピリド［２，３−ｄ］ピリ
ミジン−６−カルボン酸三水和物の製法が提供せられる
のである。Therefore, crystals of PPA trihydrate precipitate upon cooling, and by filtering them and volatilizing the adhering ethanol, the desired 2-(1-piperazinyl)-8-ethyl-5,8- Dihydro-5-oxopyrido [2,3-
d]-pyrimidine-6-carboxylic acid trihydrate can be obtained. Since the residual liquid can be reused as piperazine hexahydrate by distilling off the alcohol, there is no problem of waste liquid as in conventional methods, and the 2-(1- piperazinyl)-8ethyl-
A method for producing 58-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid trihydrate is provided.
以下実施例により本発明を説明する。The present invention will be explained below with reference to Examples.
実施例１
ピペラジン６水和物３ｇを６０℃に加熱して溶融させ、
これに２−（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１ｇを加え１〜２時間撹拌して均質な
溶液を得た。次にエタノール１０−を加え室温に冷却し
、析出せる結晶を濾取した。付着エタノールを揮発させ
２（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
ルボン酸三水和物の無色針状結晶、融点２５３〜２５５
℃１．０ｇを得た。Example 1 3 g of piperazine hexahydrate was heated to 60°C to melt it,
To this, 2-(1-piperazinyl)-8ethyl-5,8-
1 g of dihydro-5-oxopyrido[2:3-d]pyrimidine-6-carboxylic acid was added and stirred for 1 to 2 hours to obtain a homogeneous solution. Next, 10-mL of ethanol was added, and the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The adhering ethanol was volatilized to produce colorless needle-shaped crystals of 2(1-piperazinyl-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid trihydrate, melting point 253~ 255
℃1.0g was obtained.
特許出願代理人patent application agent
Claims (2)
−ジヒドロ−５−オキソピリド［２，３−ｄ］ピリミジ
ン−６−カルボン酸と過剰量のピペラジン６水和物を加
熱溶解させ、アルコールを加えた後、冷却し析出せる結
晶を濾取することを特徴とする２−（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−カルボン酸三水和物の
製造方法。(1) 2-(1-piperazinyl)-8-ethyl-5,8
-Dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid and an excess amount of piperazine hexahydrate are dissolved by heating, alcohol is added, and the crystals that precipitate are collected by filtration after cooling. A method for producing 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid trihydrate.
−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］ピリジン−６−カルボン
酸を加えピペラジン６水和物の溶解液に溶解せしめる請
求項第１項記載の方法。(2) After heating and dissolving piperazine hexahydrate, 2-(1
-piperazinyl)-8-ethyl-5,8-dihydro-5
2. The method according to claim 1, wherein -oxopyrido[2,3-d]pyridine-6-carboxylic acid is added and dissolved in the piperazine hexahydrate solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63176134A JPH0225483A (en) | 1988-07-14 | 1988-07-14 | Production of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido(2,3-d)pyrimidine-6-carboxylic acid trihydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63176134A JPH0225483A (en) | 1988-07-14 | 1988-07-14 | Production of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido(2,3-d)pyrimidine-6-carboxylic acid trihydrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0225483A true JPH0225483A (en) | 1990-01-26 |
Family
ID=16008256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63176134A Pending JPH0225483A (en) | 1988-07-14 | 1988-07-14 | Production of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido(2,3-d)pyrimidine-6-carboxylic acid trihydrate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0225483A (en) |
-
1988
- 1988-07-14 JP JP63176134A patent/JPH0225483A/en active Pending
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