JPH0615543B2 - Pyrido [1,2-a pyrimidine ester compound and process for producing the same] - Google Patents
Pyrido [1,2-a pyrimidine ester compound and process for producing the same]Info
- Publication number
- JPH0615543B2 JPH0615543B2 JP63240960A JP24096088A JPH0615543B2 JP H0615543 B2 JPH0615543 B2 JP H0615543B2 JP 63240960 A JP63240960 A JP 63240960A JP 24096088 A JP24096088 A JP 24096088A JP H0615543 B2 JPH0615543 B2 JP H0615543B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrido
- oxo
- compound
- pyrimidine
- ester compound
- 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
Links
- -1 pyrimidine ester compound Chemical class 0.000 title claims description 14
- 238000000034 method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000000862 absorption spectrum Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000013078 crystal Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- CRTFYZTUSLIFEV-UHFFFAOYSA-N ethyl 2-[9-(bromomethyl)-4-oxopyrido[1,2-a]pyrimidin-3-yl]acetate Chemical compound BrCC1=CC=CN2C(=O)C(CC(=O)OCC)=CN=C21 CRTFYZTUSLIFEV-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- GWBWGPRZOYDADH-UHFFFAOYSA-N [C].[Na] Chemical compound [C].[Na] GWBWGPRZOYDADH-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- DBVNFIMDBMISCW-UHFFFAOYSA-N butyl 2-[9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidin-3-yl]acetate Chemical compound C=1C=CN2C(=O)C(CC(=O)OCCCC)=CN=C2C=1COC1=CC=C(C(C)=O)C(O)=C1CCC DBVNFIMDBMISCW-UHFFFAOYSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NOWVGXRTFJVPLX-UHFFFAOYSA-N ethyl 2-[7-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidin-3-yl]acetate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CN2C(=O)C(CC(=O)OCC)=CN=C2C=C1 NOWVGXRTFJVPLX-UHFFFAOYSA-N 0.000 description 1
- VGXKVZCRGKTVSY-UHFFFAOYSA-N ethyl 2-[9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-8-methyl-4-oxopyrido[1,2-a]pyrimidin-3-yl]acetate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=C(C)C=CN2C(=O)C(CC(=O)OCC)=CN=C12 VGXKVZCRGKTVSY-UHFFFAOYSA-N 0.000 description 1
- MFGHIHOOMQCWKK-UHFFFAOYSA-N ethyl 3-[7-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidin-3-yl]propanoate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CN2C(=O)C(CCC(=O)OCC)=CN=C2C=C1 MFGHIHOOMQCWKK-UHFFFAOYSA-N 0.000 description 1
- LVKNFELNWKVEPT-UHFFFAOYSA-N ethyl 3-[9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidin-3-yl]propanoate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC=CN2C(=O)C(CCC(=O)OCC)=CN=C12 LVKNFELNWKVEPT-UHFFFAOYSA-N 0.000 description 1
- RWIIGKCDQABFQD-UHFFFAOYSA-N ethyl 3-[9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-7-bromo-4-oxopyrido[1,2-a]pyrimidin-3-yl]propanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCC1=CC(Br)=CN2C(=O)C(CCC(=O)OCC)=CN=C12 RWIIGKCDQABFQD-UHFFFAOYSA-N 0.000 description 1
- GQVUYWCCXRZTEN-UHFFFAOYSA-N ethyl 8-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidine-3-carboxylate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC2=NC=C(C(=O)OCC)C(=O)N2C=C1 GQVUYWCCXRZTEN-UHFFFAOYSA-N 0.000 description 1
- DGIZVWOSFPVSGE-UHFFFAOYSA-N ethyl 9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidine-3-carboxylate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC=CN2C(=O)C(C(=O)OCC)=CN=C12 DGIZVWOSFPVSGE-UHFFFAOYSA-N 0.000 description 1
- KIJUEHIMUNDVLL-UHFFFAOYSA-N ethyl 9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-6-fluoro-4-oxopyrido[1,2-a]pyrimidine-3-carboxylate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCC1=CC=C(F)N2C(=O)C(C(=O)OCC)=CN=C12 KIJUEHIMUNDVLL-UHFFFAOYSA-N 0.000 description 1
- LQLFHBVXCCWHRO-UHFFFAOYSA-N ethyl 9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-7-methyl-4-oxopyrido[1,2-a]pyrimidine-3-carboxylate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC(C)=CN2C(=O)C(C(=O)OCC)=CN=C12 LQLFHBVXCCWHRO-UHFFFAOYSA-N 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- IMFFNDGCOTWHAE-UHFFFAOYSA-N methyl 3-[9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidin-3-yl]propanoate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC=CN2C(=O)C(CCC(=O)OC)=CN=C12 IMFFNDGCOTWHAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- JVVWRBWZBWQYFU-UHFFFAOYSA-N propan-2-yl 9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidine-3-carboxylate Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC=CN2C(=O)C(C(=O)OC(C)C)=CN=C12 JVVWRBWZBWQYFU-UHFFFAOYSA-N 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XKGLSKVNOSHTAD-UHFFFAOYSA-N valerophenone Chemical compound CCCCC(=O)C1=CC=CC=C1 XKGLSKVNOSHTAD-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、下記一般式［Ｉ］ （式中、Ｒ1は水素原子、ハロゲン原子又はメチル基を
表わし、Ｒ2は炭素数１〜４の直鎖又は分岐状のアルキ
ル基を表わし、ｎは０、１又は２を表わす。）で示され
るピリド［１，２−ａ］ピリミジンエステル化合物（以
下、単に「本発明化合物［Ｉ］という。）及びその製法
に関する。The present invention relates to the following general formula [I]. (In the formula, R 1 represents a hydrogen atom, a halogen atom or a methyl group, R 2 represents a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents 0, 1 or 2.) The present invention relates to the indicated pyrido [1,2-a] pyrimidine ester compound (hereinafter simply referred to as “the present compound [I]”) and a process for producing the same.
従来の技術 本発明化合物［Ｉ］は、本発明者らにより初めて合成さ
れたものであり公知文献未記載の新規な化合物である。2. Description of the Related Art The compound [I] of the present invention is a novel compound which was first synthesized by the present inventors and has not been described in any known literature.
発明が解決しようとする課題 本発明化合物［Ｉ］は、アナフィラキシー遅反応性物質
（以下ＳＲＳ−Ａという。）に対し強力な拮抗作用を持
ち、ＳＲＳ−Ａに起因するＩ型アレルギー疾患治療に有
用な下記一般式［II］ （式中、Ｒ1及びｎは前記と同意義。）で示されるピリ
ド［１，２−ａ］ピリミジンカルボン酸化合物の製造中
間体であるとともに、それ自体も相応するカルボン酸化
合物とほぼ同程度のＳＲＳ−Ａ拮抗作用を有し、抗アレ
ルギー薬として利用できるものである。DISCLOSURE OF INVENTION Problem to be Solved by the Invention The compound [I] of the present invention has a strong antagonistic action against an anaphylactic slow-reacting substance (hereinafter referred to as SRS-A), and is useful for treating type I allergic diseases caused by SRS-A. The following general formula [II] (In the formula, R 1 and n have the same meanings as described above.) It is an intermediate for the production of the pyrido [1,2-a] pyrimidinecarboxylic acid compound, and itself has about the same degree as the corresponding carboxylic acid compound. It has an SRS-A antagonistic effect and can be used as an antiallergic drug.
課題を解決するための手段 本発明化合物は、下記一般式［III］ （式中、Ｒ1、Ｒ2及びｎは前記と同意義であり、Ｘは塩
素原子又は臭素原子を表わす。）で示される化合物と、
１〜６倍モル量の２，４−ジヒドロキシ−３−ｎ−プロ
ピルアセトフェノンとを、酸受容体存在下に縮合させる
ことにより製造することができる。Means for Solving the Problems The compound of the present invention has the following general formula [III]: (Wherein R 1 , R 2 and n have the same meanings as defined above, and X represents a chlorine atom or a bromine atom),
It can be produced by condensing 1 to 6-fold molar amount of 2,4-dihydroxy-3-n-propylacetophenone in the presence of an acid acceptor.
使用する酸受容体としては、炭素ナトリウムもしくは炭
酸カリウム等のアルカリ金属炭酸塩又は水酸化ナトリウ
ムもしくは水酸化カリウム等のアルカリ金属水酸化物が
挙げられる。なお反応促進剤としてヨウ化カリウムを共
存させてもよい。Examples of the acid acceptor used include alkali metal carbonates such as sodium carbon or potassium carbonate or alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. Note that potassium iodide may be allowed to coexist as a reaction accelerator.
反応溶媒としては、アセトン、メチルエチルケトン、ジ
エチルケトン、シクロヘキサノン、ジメチルホルムアミ
ドもしくはジメチルスルホキシド又はこれらの二種以上
からなる混合液が挙げられる。反応は、50〜110℃で１
分間〜72時間加熱することにより行う。Examples of the reaction solvent include acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, dimethylformamide or dimethyl sulfoxide, or a mixed solution of two or more of these. Reaction is 1 at 50-110 ℃
It is performed by heating for about 72 minutes to 72 minutes.
なお、前記一般式［III］で示される化合物は、 下記一般式［IV］ （式中、Ｒ1、Ｒ2及びｎは前記と同意義。）で示される
化合物を、Ｎ−ブロモスクシンイミド又はＮ−クロロス
クシンイミドを用いてハロゲン化するか、あるいは下
記一般式［Ｖ］ （式中、Ｒ1、Ｒ2及びｎは前記と同意義。）で示される
化合物を、塩化チオニル、塩化ホスホリル、臭化ホスホ
リル、三塩化リン又は三臭化リン等のハロゲン化剤を用
いてハロゲン化するか、あるいは下記一般式［VI］ （式中、Ｒ1、Ｒ2及びｎは前記と同意義。）で示される
化合物を、塩化ホスホリル又は臭化ホスホリルとポリリ
ン酸との混合液を用い、閉環と同時にハロゲン化するこ
とにより製造することができる。The compound represented by the general formula [III] has the following general formula [IV] (In the formula, R 1 , R 2 and n have the same meanings as described above.) The compound represented by the following general formula [V] is halogenated with N-bromosuccinimide or N-chlorosuccinimide. (Wherein R 1 , R 2 and n have the same meanings as described above) are prepared by using a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphoryl bromide, phosphorus trichloride or phosphorus tribromide. Halogenated or the following general formula [VI] (Wherein R 1 , R 2 and n have the same meanings as defined above), and a halogenated compound is produced at the same time as ring closure using a mixed solution of phosphoryl chloride or phosphoryl bromide and polyphosphoric acid. be able to.
作用及び発明の効果 本発明化合物［Ｉ］は、酸又はアルカリで加水分解し、
ついで必要に応じて造塩処理することにより、強力なＳ
ＲＳ−Ａ拮抗作用を持ち、ＳＲＳ−Ａに起因するＩ型ア
レルギー疾患治療に有用なピリド［１，２−ａ］ピリミ
ジンカルボン酸化合物［II］に変換することができると
ともに、それ自体も良好なＳＲＳ−Ａ拮抗作用を示すこ
とが試験管内（in vitro）試験で認められた。Action and Effect of the Invention The compound [I] of the present invention is hydrolyzed with an acid or an alkali,
Then, if necessary, salt treatment is performed to obtain a strong S
It has an RS-A antagonism and can be converted to a pyrido [1,2-a] pyrimidinecarboxylic acid compound [II] which is useful for the treatment of type I allergic diseases caused by SRS-A, and itself is good. It was confirmed in an in vitro test that it has an SRS-A antagonism.
本発明を実施例をもって更に説明する。The present invention will be further described with reference to examples.
実施例１ ［９−ブロモメチル−４−オキソ−ピリド［１，２−
ａ］ピリミジン−３−イル］酢酸エチルエステル2.40ｇ
（7.38ミリモル）、２，４−ジヒドロシキ−３−ｎ−プ
ロピルアセトフェノン1.45ｇ（7.47ミリモル）及び無水
炭酸カリウム1.50ｇを、メチルエチルケトン200ml中で
２時間、撹拌下に加熱還流した。冷後、この反応液中の
不溶物を濾別し、濾液を減圧留去し、得られた残渣をシ
リカゲルカラムクロマトグラフィーに付して精製した。
目的物を含む分画液を採取し、これを減圧乾固した。得
られた残渣をエタノールで再結晶し、［９−（４−アセ
チル−３−ヒドロキシ−２−ｎ−プロピルフェノキシメ
チル）４−オキソ−ピリド［１，２−ａ］ピリミジン−
３−イル］酢酸エチルエステル2.30ｇ（収率70％）を得
た。融点は134〜135℃であった。Example 1 [9-Bromomethyl-4-oxo-pyrido [1,2-
a] Pyrimidin-3-yl] acetic acid ethyl ester 2.40 g
(7.38 mmol), 2,4-dihydro-3--3-n-propylacetophenone (1.45 g, 7.47 mmol) and anhydrous potassium carbonate (1.50 g) were heated to reflux in 200 ml of methyl ethyl ketone for 2 hours with stirring. After cooling, the insoluble matter in this reaction solution was filtered off, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography.
A fractionated liquid containing the target substance was collected and dried under reduced pressure. The obtained residue was recrystallized from ethanol to give [9- (4-acetyl-3-hydroxy-2-n-propylphenoxymethyl) 4-oxo-pyrido [1,2-a] pyrimidine-
Obtained 2.30 g (yield 70%) of 3-yl] acetic acid ethyl ester. The melting point was 134-135 ° C.
赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1740,1685,1635 元素分析値（Ｃ24Ｈ26Ｎ2Ｏ6として）： 論理値(%)；Ｃ，65.74Ｈ，5.98Ｎ，6.39 実測値(%)；Ｃ，65.63Ｈ，6.15Ｎ，6.23 ［９−ブロモメチル−４−オキソ−ピリド［１，２−
ａ］ピリミジン−３−イル］酢酸エチルエステル2.40ｇ
（7.38ミリモル）を、相応する化合物［III］に変更
し、反応モル比及び反応条件を若干変更した以外は上述
とほぼ同様に操作し、以下の実施例２〜６の化合物を製
造した。Infrared absorption spectrum (cm -1 , KBr): 1740,1685,1635 Elemental analysis value (as C 24 H 26 N 2 O 6 ): Logical value (%); C, 65.74H, 5.98N, 6.39 Measured value (%) ); C, 65.63H, 6.15N, 6.23 [9-bromomethyl-4-oxo-pyrido [1,2-
a] Pyrimidin-3-yl] acetic acid ethyl ester 2.40 g
(7.38 mmol) was changed to the corresponding compound [III], and the reaction was performed in substantially the same manner as above except that the reaction molar ratio and the reaction conditions were slightly changed, to produce the compounds of Examples 2 to 6 below.
実施例２ ９−（４−アセチル−３−ヒドロキシ−２−ｎ−プロピ
ルフェノキシメチル）４−オキソ−ピリド［１，２−
ａ］ピリミジン−３−カルボン酸エチルエステル。Example 2 9- (4-Acetyl-3-hydroxy-2-n-propylphenoxymethyl) 4-oxo-pyrido [1,2-
a] Pyrimidine-3-carboxylic acid ethyl ester.
白色結晶；収量2.38ｇ（収率76％） 融点：165〜171℃（メチルエチルケトンで再結晶） 赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1735,1680,1620 元素分析値（Ｃ23Ｈ24Ｎ2Ｏ6として）： 論理値(%)；Ｃ，65.08Ｈ，5.70Ｎ，6.60 実測値(%)；Ｃ，65.34Ｈ，5.98Ｎ，6.80 実施例３ ［９−（４−アセチル−３−ヒドロキシ−２−ｎ−プロ
ピルフェノキシメチル）−８−メチル−４−オキソ−ピ
リド［１，２−ａ］ピリミジン−３−イル］酢酸エチル
エステル。White crystal; Yield 2.38 g (yield 76%) Melting point: 165-171 ° C. (recrystallized with methyl ethyl ketone) Infrared absorption spectrum (cm -1 , KBr): 1735, 1680, 1620 Elemental analysis value (C 23 H 24 N 2) O 6 ): Logical value (%); C, 65.08H, 5.70N, 6.60 Actual value (%); C, 65.34H, 5.98N, 6.80 Example 3 [9- (4-acetyl-3-hydroxy- 2-n-Propylphenoxymethyl) -8-methyl-4-oxo-pyrido [1,2-a] pyrimidin-3-yl] acetic acid ethyl ester.
白色結晶；収量1.37ｇ（収率41％） 融点：144〜145℃（エタノールで再結晶） 赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1735,1685,1635 元素分析値（Ｃ25Ｈ28Ｎ2Ｏ6として）： 論理値(%)；Ｃ，66.36Ｈ，6.24Ｎ，6.19 実測値(%)；Ｃ，66.53Ｈ，6.37Ｎ，6.39 実施例４ ３−［９−（４−アセチル−３−ヒドロキシ−２−ｎ−
プロピルフェノキシメチル）−４−オキソ−ピリド
［１，２−ａ］ピリミジン−３−イル］プロピオン酸エ
チルエステル。White crystal; Yield 1.37 g (Yield 41%) Melting point: 144-145 ° C. (recrystallized with ethanol) Infrared absorption spectrum (cm -1 , KBr): 1735, 1685, 1635 Elemental analysis value (C 25 H 28 N 2 as O 6): the logical value (%); C, 66.36H, 6.24N, 6.19 Found (%); C, 66.53H, 6.37N, 6.39 example 4 3- [9- (4-acetyl-3 Hydroxy-2-n-
Propylphenoxymethyl) -4-oxo-pyrido [1,2-a] pyrimidin-3-yl] propionic acid ethyl ester.
白色結晶；収量3.04ｇ（収率91％） 融点：116〜118℃（エタノールで再結晶） 赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1730,1680,1630 元素分析値（Ｃ25Ｈ28Ｎ2Ｏ6として）： 論理値(%)；Ｃ，66.36Ｈ，6.24Ｎ，6.19 実測値(%)；Ｃ，66.18Ｈ，6.13Ｎ，6.14 実施例５ ３−［９−（４−アセチル−３−ヒドロキシ−２−ｎ−
プロピルフェノキシメチル）−７−ブロモ−４−オキソ
−ピリド［１，２−ａ］ピリミジン−３−イル］プロピ
オン酸エチルエステル。White crystal; yield 3.04 g (yield 91%) Melting point: 116 to 118 ° C. (recrystallized from ethanol) Infrared absorption spectrum (cm −1 , KBr): 1730,1680,1630 Elemental analysis value (C 25 H 28 N 2 as O 6): the logical value (%); C, 66.36H, 6.24N, 6.19 Found (%); C, 66.18H, 6.13N, 6.14 example 5 3- [9- (4-acetyl-3 Hydroxy-2-n-
Propylphenoxymethyl) -7-bromo-4-oxo-pyrido [1,2-a] pyrimidin-3-yl] propionic acid ethyl ester.
白色結晶；収量2.63ｇ（収率67％） 融点：153〜155℃（メチルエチルケトンで再結晶） 赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1740,1680,1620 元素分析値（Ｃ25Ｈ27ＢｒＮ2Ｏ6として）： 論理値(%)；Ｃ，56.51Ｈ，5.12Ｎ，5.27 実測値(%)；Ｃ，56.69Ｈ，5.24Ｎ，5.32 実施例６ ３−［７−（４−アセチル−３−ヒドロキシ−２−ｎ−
プロピルフェノキシメチル）−４−オキソ−ピリド
［１，２−ａ］ピリミジン−３−イル］プロピオン酸エ
チルエステル。White crystal; yield 2.63 g (yield 67%) Melting point: 153-155 ° C (recrystallized with methyl ethyl ketone) Infrared absorption spectrum (cm -1 , KBr): 1740, 1680, 1620 Elemental analysis value (C 25 H 27 BrN 2). as O 6): the logical value (%); C, 56.51H, 5.12N, 5.27 Found (%); C, 56.69H, 5.24N, 5.32 example 6 3- [7- (4-acetyl-3 Hydroxy-2-n-
Propylphenoxymethyl) -4-oxo-pyrido [1,2-a] pyrimidin-3-yl] propionic acid ethyl ester.
白色結晶；収量2.10ｇ（収率63％） 融点：157〜159℃（エタノールで再結晶） 赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1720,1670,1620 元素分析値（Ｃ25Ｈ28Ｎ2Ｏ6として）： 論理値(%)；Ｃ，66.36Ｈ，6.24Ｎ，6.19 実測値(%)；Ｃ，66.28Ｈ，6.33Ｎ，6.26 そのほか、実施例１に準じて以下に列記する五化合物も
製造した。White crystal; Yield 2.10 g (63% yield) Melting point: 157-159 ° C (recrystallized with ethanol) Infrared absorption spectrum (cm -1 , KBr): 1720,1670,1620 Elemental analysis value (C 25 H 28 N 2 O 6 ): Logical value (%); C, 66.36H, 6.24N, 6.19 Measured value (%); C, 66.28H, 6.33N, 6.26 In addition, the five compounds listed below according to Example 1 are also included. Manufactured.
８−（４−アセチル−３−ヒドロキシ−２−ｎ−プロピ
ルフェノキシメチル）−４−オキソ−ピリド［１，２−
ａ］ピリミジン−３−カルボン酸エチルエステル。8- (4-acetyl-3-hydroxy-2-n-propylphenoxymethyl) -4-oxo-pyrido [1,2-
a] Pyrimidine-3-carboxylic acid ethyl ester.
９−（４−アセチル−３−ヒドロキシ−２−ｎ−プロピ
ルフェノキシメチル）−６−フルオロ−４−オキソ−ピ
リド［１，２−ａ］ピリミジン−３−カルボン酸エチル
エステル； ９−（４−アセチル−３−ヒドロキシ−２−ｎ−プロピ
ルフェノキシメチル）−７−メチル−４−オキソ−ピリ
ド［１，２−ａ］ピリミジン−３−カルボン酸エチルエ
ステル； ［７−（４−アセチル−３−ヒドロキシ−２−ｎ−プロ
ピルフェノキシメチル）−４−オキソ−ピリド［１，２
−ａ］ピリミジン−３−イル］酢酸エチルエステル； ［７−（４−アセチル−３−ヒドロキシ−２−ｎ−プロ
ピルフェノキシメチル）−８−クロロ−４−オキソ−ピ
リド［１，２−ａ］ピリミジン−３−イル］酢酸エチル
エステル。9- (4-Acetyl-3-hydroxy-2-n-propylphenoxymethyl) -6-fluoro-4-oxo-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester; 9- (4- Acetyl-3-hydroxy-2-n-propylphenoxymethyl) -7-methyl-4-oxo-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester; [7- (4-acetyl-3- Hydroxy-2-n-propylphenoxymethyl) -4-oxo-pyrido [1,2
-A] pyrimidin-3-yl] acetic acid ethyl ester; [7- (4-acetyl-3-hydroxy-2-n-propylphenoxymethyl) -8-chloro-4-oxo-pyrido [1,2-a]. Pyrimidin-3-yl] acetic acid ethyl ester.
実施例７ ９−クロロメチル−４−オキソ−ピリド［１，２−ａ］
ピリミジン−３−カルボン酸イソプロピルエステル2.07
ｇ（7.38ミリモル）、２，４−ジヒドロキシ−３−ｎ−
プロピルアセトフェノン1.45ｇ（7.47ミリモル）及び無
水炭酸カリウム1.50ｇを、メチルエチルケトン200ml中
で２時間、撹拌下に加熱還流した。冷後、この反応液中
の不溶物を濾別し、濾液を減圧留去し、得られた残渣を
シリカゲルカラムクロマトグラフィーに付して精製し
た。目的物を含む分画液を採取し、これを減圧乾固し
た。得られた残渣をメチルエチルケトンで再結晶し、９
−（４−アセチル−３−ヒドロキシ−２−ｎ−プロピル
フェノキシメチル）−４−オキソ−ピリド［１，２−
ａ］ピリミジン−３−カルボン酸イソプロピルエステル
1.81ｇ（収率56％）を得た。融点は130〜140℃であっ
た。Example 7 9-Chloromethyl-4-oxo-pyrido [1,2-a]
Pyrimidine-3-carboxylic acid isopropyl ester 2.07
g (7.38 mmol), 2,4-dihydroxy-3-n-
1.45 g (7.47 mmol) of propyl acetophenone and 1.50 g of anhydrous potassium carbonate were heated to reflux with stirring in 200 ml of methyl ethyl ketone for 2 hours. After cooling, the insoluble matter in this reaction solution was filtered off, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. A fractionated liquid containing the target substance was collected and dried under reduced pressure. The obtained residue was recrystallized from methyl ethyl ketone to give 9
-(4-Acetyl-3-hydroxy-2-n-propylphenoxymethyl) -4-oxo-pyrido [1,2-
a] Pyrimidine-3-carboxylic acid isopropyl ester
1.81 g (yield 56%) was obtained. The melting point was 130-140 ° C.
赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1725,1685,1620 元素分析値（Ｃ24Ｈ26Ｎ2Ｏ6として）： 論理値(%)；Ｃ，65.74Ｈ，5.98Ｎ，6.39 実測値(%)；Ｃ，65.26Ｈ，5.79Ｎ，6.04 ９−クロロメチル−４−オキソ−ピリド［１，２−ａ］
ピリミジン−３−カルボン酸イソプロピルエステル2.07
ｇ（7.38ミリモル）を［９−ブロモメチル−４−オキソ
−ピリド［１，２−ａ］ピリミジン−３−イル］酢酸ｎ
−ブチルエステル2.40ｇ（7.38ミリモル）に変更し、反
応条件を若干変更した以外は上述とほぼ同様に操作し、
以下の実施例８の化合物を製造した。Infrared absorption spectrum (cm -1 , KBr): 1725,1685,1620 Elemental analysis value (as C 24 H 26 N 2 O 6 ): Logical value (%); C, 65.74H, 5.98N, 6.39 Measured value (%) ); C, 65.26H, 5.79N, 6.04 9-chloromethyl-4-oxo-pyrido [1,2-a]
Pyrimidine-3-carboxylic acid isopropyl ester 2.07
g (7.38 mmol) of [9-bromomethyl-4-oxo-pyrido [1,2-a] pyrimidin-3-yl] acetic acid n
-Butyl ester was changed to 2.40 g (7.38 mmol) and the reaction conditions were slightly changed, and the same operation as above was performed.
The following compound of Example 8 was prepared.
実施例８ ［９−（４−アセチル−３−ヒドロキシ−２−ｎ−プロ
ピルフェノキシメチル）−４−オキソ−ピリド［１，２
−ａ］ピリミジン−３−イル］酢酸ｎ−ブチルエステ
ル。Example 8 [9- (4-Acetyl-3-hydroxy-2-n-propylphenoxymethyl) -4-oxo-pyrido [1,2
-A] pyrimidin-3-yl] acetic acid n-butyl ester.
白色結晶；収量2.79ｇ（収率81％） 融点：113〜126℃（エタノールで再結晶） 赤外線吸収スペクトル（cm-1，ＫＢｒ）： 1730,1680,1620 元素分析値（Ｃ26Ｈ30Ｎ2Ｏ6として）： 論理値(%)；Ｃ，66.94Ｈ，6.48Ｎ，6.00 実測値(%)；Ｃ，66.50Ｈ，6.61Ｎ，6.23 更に、実施例７に準じて以下の化合物も製造した。White crystal; Yield 2.79 g (Yield 81%) Melting point: 113 to 126 ° C. (recrystallized with ethanol) Infrared absorption spectrum (cm -1 , KBr): 1730,1680,1620 Elemental analysis value (C 26 H 30 N 2 O 6 ): Logical value (%); C, 66.94H, 6.48N, 6.00 Actual value (%); C, 66.50H, 6.61N, 6.23 Further, the following compound was also prepared according to Example 7.
３−［９−（４−アセチル−３−ヒドロキシ−２−ｎ−
プロピルフェノキシメチル）−４−オキソ−ピリド
［１，２−ａ］ピリミジン−３−イル］プロピオン酸メ
チルエステル。3- [9- (4-acetyl-3-hydroxy-2-n-
Propylphenoxymethyl) -4-oxo-pyrido [1,2-a] pyrimidin-3-yl] propionic acid methyl ester.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 大村 茂樹 東京都世田谷区下馬６丁目29番１号 東京 田辺製薬世田谷寮内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shigeki Omura 6-29-1, Shimouma, Setagaya-ku, Tokyo Tokyo Tanabe Pharma Setagaya Dormitory
Claims (2)
表わし、Ｒ2は炭素数１〜４の直鎖又は分岐状のアルキ
ル基を表わし、ｎは０、１又は２を表わす。）で示され
るピリド［１，２−ａ］ピリミジンエステル化合物。1. A general formula (In the formula, R 1 represents a hydrogen atom, a halogen atom or a methyl group, R 2 represents a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents 0, 1 or 2.) The indicated pyrido [1,2-a] pyrimidine ester compound.
表わし、Ｒ2は炭素数１〜４の直鎖又は分岐状のアルキ
ル基を表わし、Ｘは塩素原子又は臭素原子を表わし、ｎ
は０、１又は２を表わす。）で示される化合物と、２，
４−ジヒドロキシ−３−ｎ−プロピルアセトフェノンと
を、酸受容体存在下に縮合させることを特徴とする一般
式 （式中、Ｒ1、Ｒ2及びｎは前記と同意義。）で示される
ピリド［１，２−ａ］ピリミジンエステル化合物の製
法。2. General formula (In the formula, R 1 represents a hydrogen atom, a halogen atom or a methyl group, R 2 represents a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a chlorine atom or a bromine atom, n
Represents 0, 1 or 2. ) A compound represented by
General formula characterized by condensing 4-dihydroxy-3-n-propylacetophenone in the presence of an acid acceptor (In the formula, R 1 , R 2 and n have the same meanings as described above.) A process for producing a pyrido [1,2-a] pyrimidine ester compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63240960A JPH0615543B2 (en) | 1988-09-28 | 1988-09-28 | Pyrido [1,2-a pyrimidine ester compound and process for producing the same] |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63240960A JPH0615543B2 (en) | 1988-09-28 | 1988-09-28 | Pyrido [1,2-a pyrimidine ester compound and process for producing the same] |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61086034A Division JPS62242682A (en) | 1986-04-16 | 1986-04-16 | Novel pyrido(1,2-a)pyrimidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01125380A JPH01125380A (en) | 1989-05-17 |
| JPH0615543B2 true JPH0615543B2 (en) | 1994-03-02 |
Family
ID=17067214
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63240960A Expired - Lifetime JPH0615543B2 (en) | 1988-09-28 | 1988-09-28 | Pyrido [1,2-a pyrimidine ester compound and process for producing the same] |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0615543B2 (en) |
-
1988
- 1988-09-28 JP JP63240960A patent/JPH0615543B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01125380A (en) | 1989-05-17 |
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