JP2668168B2 - Phenoxy derivatives - Google Patents
Phenoxy derivativesInfo
- Publication number
- JP2668168B2 JP2668168B2 JP2421191A JP2421191A JP2668168B2 JP 2668168 B2 JP2668168 B2 JP 2668168B2 JP 2421191 A JP2421191 A JP 2421191A JP 2421191 A JP2421191 A JP 2421191A JP 2668168 B2 JP2668168 B2 JP 2668168B2
- Authority
- JP
- Japan
- Prior art keywords
- cis
- phenoxy
- pyrimidone
- group
- mol
- 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
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000008318 pyrimidones Chemical class 0.000 description 6
- 208000008469 Peptic Ulcer Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- -1 nitroamino group Chemical group 0.000 description 5
- 208000011906 peptic ulcer disease Diseases 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ORZIHESPONWBAJ-UHFFFAOYSA-N 3-(1,3-dioxolan-2-yl)phenol Chemical compound OC1=CC=CC(C2OCCO2)=C1 ORZIHESPONWBAJ-UHFFFAOYSA-N 0.000 description 1
- YHXFFJHLDMLCJX-UHFFFAOYSA-N 3-(diethoxymethyl)phenol Chemical group CCOC(OCC)C1=CC=CC(O)=C1 YHXFFJHLDMLCJX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- INJSHTCBZFXDQA-DAXSKMNVSA-N 5,6-dimethyl-2-[[(z)-4-[3-(piperidin-1-ylmethyl)phenoxy]but-2-enyl]amino]-1h-pyrimidin-4-one Chemical compound O=C1C(C)=C(C)NC(NC\C=C/COC=2C=C(CN3CCCCC3)C=CC=2)=N1 INJSHTCBZFXDQA-DAXSKMNVSA-N 0.000 description 1
- BYSUEKDQOCICDG-ZULQGGHCSA-N 5,6-dimethyl-2-[[(z)-4-[3-(piperidin-1-ylmethyl)phenoxy]but-2-enyl]amino]-1h-pyrimidin-4-one;hydrochloride Chemical compound Cl.O=C1C(C)=C(C)NC(NC\C=C/COC=2C=C(CN3CCCCC3)C=CC=2)=N1 BYSUEKDQOCICDG-ZULQGGHCSA-N 0.000 description 1
- ZLKSFIQDRGDZCG-UHFFFAOYSA-N 5,6-dimethyl-2-methylsulfanyl-1h-pyrimidin-4-one Chemical compound CSC1=NC(=O)C(C)=C(C)N1 ZLKSFIQDRGDZCG-UHFFFAOYSA-N 0.000 description 1
- UCHLRLIVOPLFBC-CABZTGNLSA-N CCC=C[C@]12C=C(C=C[C@H]1C(=O)NC2=O)Cl Chemical compound CCC=C[C@]12C=C(C=C[C@H]1C(=O)NC2=O)Cl UCHLRLIVOPLFBC-CABZTGNLSA-N 0.000 description 1
- BMRJQUCIICCSCX-WAYWQWQTSA-N CCOC(C1=CC(=CC=C1)OC/C=C\CN)OCC Chemical compound CCOC(C1=CC(=CC=C1)OC/C=C\CN)OCC BMRJQUCIICCSCX-WAYWQWQTSA-N 0.000 description 1
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 229960003320 roxatidine Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は胃酸分泌抑制作用を有す
るピリミドン誘導体を製造するためのフェノキシ誘導体
に関する。The present invention relates to a phenoxy derivative for producing a pyrimidone derivative having a gastric acid secretion inhibitory action.
【０００２】[0002]
【従来の技術】ヒスタミンＨ2 受容体拮抗作用に基づき
優れた胃酸分泌抑制作用を有する消化性潰瘍剤として、
例えばシメチジン、ラニチジン、ファモチジン、ロキサ
チジンが臨床に供されているが、治癒後に薬剤の投与を
中止すると消化性潰瘍が再発することが問題となってい
た。この様な副作用（リバウンド現象）を減じるため
に、胃酸分泌抑制作用と消化管粘膜防御作用を併せ持っ
た消化性潰瘍治療剤として以下の構造を有するピリミド
ン誘導体が知られている（特開平１−１４９７７４号公
報、特願平１−１２５０６７号）。 2. Description of the Related Art As a peptic ulcer agent having an excellent gastric acid secretion inhibitory action based on histamine H 2 receptor antagonism,
For example, cimetidine, ranitidine, famotidine, and roxatidine have been clinically used. However, if administration of the drug is stopped after healing, peptic ulcer recurs. In order to reduce such side effects (rebound phenomenon), a pyrimidone derivative having the following structure is known as a therapeutic agent for peptic ulcer having both a gastric acid secretion inhibitory action and a gastrointestinal mucosa protective action (JP-A-1-149774). No., Japanese Patent Application No. 1-125067).
【０００３】[0003]
【化２】 Embedded image
【０００４】[0004]
【発明が解決しようとする課題】本発明は、上記のピリ
ミドン誘導体を効率的に製造するための新規製造中間体
を提供するものである。The present invention provides a novel intermediate for efficiently producing the above pyrimidone derivative.
【０００５】[0005]
【課題を解決するための手段】本発明者は上記の課題を
解決すべく鋭意努力した結果、新規製造中間体として下
記の一般式（Ｉ）で表される化合物Means for Solving the Problems The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, a compound represented by the following general formula (I) as a novel intermediate for production:
【０００６】[0006]
【化３】 Embedded image
【０００７】を選択し、本発明を完成するに至った。本
発明の式（Ｉ）で示される化合物は、下記の式（II）で
示される化合物The present invention has been completed by selecting The compound represented by the formula (I) of the present invention is a compound represented by the following formula (II)
【０００８】[0008]
【化４】 Embedded image
【０００９】（式中、Ｘはニトロアミノ基、メチルチオ
基、メトキシ基、若しくはハロゲン原子を示す）と反応
させて下記の一般式（III)で表される化合物(Wherein, X represents a nitroamino group, a methylthio group, a methoxy group, or a halogen atom) to react with a compound represented by the following general formula (III):
【００１０】[0010]
【化５】 Embedded image
【００１１】（式中、Ｙは前記定義の通りである）を
得、その後に例えばピペリジン等の２級アミンと還元的
に縮合させることにより消化性潰瘍治療剤として有用な
前記のピリミドン誘導体に変換することができる。本発
明の一般式（Ｉ）で表される化合物において、低級アル
キル基は直鎖であっても分枝していてもよく、アルキル
基として例えばメチル基、エチル基、ｎ−プロピル基、
イソプロピル基、ｎ−ブチル基、イソブチル基、ｎ−ペ
ンチル基、ｎ−ヘキシル基等を挙げることができ、好ま
しくはエチル基である。ｎは１が好ましい。Wherein Y is as defined above, followed by reductive condensation with a secondary amine such as piperidine to convert to the pyrimidone derivative useful as a therapeutic agent for peptic ulcer. can do. In the compound represented by the general formula (I) of the present invention, the lower alkyl group may be linear or branched, and as the alkyl group, for example, a methyl group, an ethyl group, an n-propyl group,
Examples thereof include an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, and an n-hexyl group, and an ethyl group is preferable. n is preferably 1.
【００１２】本発明の式（Ｉ）で表される化合物は、以
下に示すスキームにより公知物質から製造することがで
きる（スキーム中、Ｙは上記の定義の通りであり、１及
び２の化合物は特開昭５７−１６５３４８号公報に記載
されている）。The compound represented by the formula (I) of the present invention can be produced from a known substance by the following scheme (where Y is as defined above, and the compounds of 1 and 2 are JP-A-57-165348).
【００１３】[0013]
【化６】 Embedded image
【００１４】[0014]
【発明の効果】本発明により、優れた消化性潰瘍治療剤
であるピリミドン誘導体の新規製造中間体が提供され
た。本方法により該ピミドン誘導体が安価で効率的に製
造することができる。According to the present invention, a novel intermediate for producing a pyrimidone derivative, which is an excellent therapeutic agent for peptic ulcer, is provided. By this method, the pimidone derivative can be produced inexpensively and efficiently.
【００１５】[0015]
【実施例】以下に本発明の製造方法を参考例及び実施例
によりさらに具体的に説明するが、本発明はこれらに限
定されることはない。 実施例１４−〔３−（１，３−ジオキソラン−２−イル）フェノ
キシ〕−cis −２−ブテニルアミン A) Ｎ−〔４−〔３−（１，３−ジオキソラン−２−イ
ル）フェノキシ〕−cis −２−ブテニル〕フタルイミド ３−（１，３−ジオキソラン−２−イル）フェノール
（３3.２ｇ，0.２モル）をＤＭＳＯ（２００ml）に溶解
し、冷却下６０％油性水素化ナトリウム（8.０ｇ，0.２
モル）を少量ずつ加えた。更に５０℃で３０分間撹拌後
冷却下に４−クロル−cis −２−ブテニルフタルイミド
（４9.６ｇ，0.２１モル）を加えて、室温下２時間撹拌
した。反応終了後に１５００mlの水に注加して、分離し
た油状物を酢酸エチルエステル（２５０ml）で３回注出
した。合わせた有機層を飽和食塩水で洗浄、乾燥後溶媒
を留去し、題記の化合物６2.１（８５％）ｇを得た。EXAMPLES Hereinafter, the production method of the present invention will be described more specifically with reference examples and examples, but the present invention is not limited to these examples. Example 1 4- [3- (1,3-dioxolan-2-yl) pheno
Xy] -cis-2-butenylamine A) N- [4- [3- (1,3-dioxolan-2-i
Phenoxy] -cis-2-butenyl] phthalimide 3- (1,3-dioxolan-2-yl) phenol (33.2 g, 0.2 mol) was dissolved in DMSO (200 ml) and cooled to 60% oil. Sodium hydride (8.0 g, 0.2
Mol) was added in small portions. After further stirring at 50 ° C. for 30 minutes, 4-chloro-cis-2-butenylphthalimide (49.6 g, 0.21 mol) was added under cooling, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was poured into 1500 ml of water, and the separated oil was extracted three times with ethyl acetate (250 ml). The combined organic layer was washed with saturated saline and dried, and then the solvent was distilled off, thereby obtaining 62.1 g (85%) of the title compound.
【００１６】NMR （δ, CDCl3)： 3.95〜4.2(4H, m)、
4.3〜4.5(2H, d)、 4.8〜4.9(2H, d)、 5.5〜6.2(3H,
m)、 6.8〜7.3(4H, m)、 7.6〜7.9(4H, m)。 B) ４−〔３−（１，３−ジオキソラン−２−イル）フ
ェノキシ〕−cis −２−ブテニルアミン 実施例１のA)で得たＮ−〔４−〔３−（１，３−ジオキ
ソラン−２−イル）フェノキシ〕−cis −２−ブテニ
ル〕フタルイミド（６２ｇ，0.１７モル）をエタノール
（１０００ml）に溶解し、ヒドラジン・ヒドラート（３
２ml）を加えて室温下１８時間撹拌した。反応終了後析
出した結晶を吸引ろ過、結晶をエタノールで洗浄した。
ろ液と洗液を合わせ減圧に濃縮し、残渣をシリカゲル・
カラムクロマトを用いて精製し淡黄色油状物として題記
の化合物３5.１ｇ（８８％）を得た。NMR (δ, CDCl 3 ): 3.95 to 4.2 (4H, m),
4.3 to 4.5 (2H, d), 4.8 to 4.9 (2H, d), 5.5 to 6.2 (3H, d)
m), 6.8-7.3 (4H, m), 7.6-7.9 (4H, m). B) 4- [3- (1,3-dioxolan-2-yl) fur
[ Enoxy] -cis-2-butenylamine N- [4- [3- (1,3-dioxolan-2-yl) phenoxy] -cis-2-butenyl] phthalimide obtained in A) of Example 1 (62 g, 0 0.17 mol) was dissolved in ethanol (1000 ml) and hydrazine hydrate (3
2 ml) and stirred at room temperature for 18 hours. After completion of the reaction, the precipitated crystals were suction filtered, and the crystals were washed with ethanol.
The filtrate and washings are combined and concentrated under reduced pressure.
Purification using column chromatography gave 35.1 g (88%) of the title compound as a pale yellow oil.
【００１７】NMR （δ, CDCl3)： 3.3〜3.5(2H, d)、
3.9〜4.2(4H, m)、 4.5〜4.8(2H, d)、 5.6〜5.9(3H,
m)、6.8〜7.4(4H, m)。 実施例２４−（３−ジエトキシメチルフェノキシ）−cis −２−
ブテニルアミン A) Ｎ−〔４−（３−ジエトキシフェノ
キシ）−cis −２−ブテニル〕フタルイミド 実施例１のA)の３−（１，３−ジオキソラン−２−イ
ル）フェノールを３−ジエトキシメチルフェノールに替
える以外は同様に操作して題記の化合物を淡黄色油状物
として得た。NMR (δ, CDCl 3 ): 3.3 to 3.5 (2H, d),
3.9-4.2 (4H, m), 4.5-4.8 (2H, d), 5.6-5.9 (3H,
m), 6.8-7.4 (4H, m). Example 2 4- (3-diethoxymethylphenoxy) -cis-2-
Butenylamine A) N- [4- (3-diethoxypheno
[Xy) -cis-2-butenyl] phthalimide The title compound was prepared in the same manner as in Example 1 A) except that 3- (1,3-dioxolan-2-yl) phenol in Example A) was replaced with 3-diethoxymethylphenol. Was obtained as a pale yellow oil.
【００１８】NMR （δ, CDCl3)： 1.05〜1.3(6H, t)、
3.35〜3.7(4H, q)、 4.3〜4.5(2H, d)、 4.7〜4.9(2H,
d)、 5.4(1H, s) 、 5.5〜6.0(2H, m)、 6.8〜7.4(4H,
m)、7.5 〜7.9(4H, m)。 B) ４−（３−ジエトキシメチル）フェノキシ−cis −
２−ブテニルアミン 実施例２のA)の原料を用いて参考例１のB)と同様に操作
して題記の化合物を得た。NMR (δ, CDCl 3 ): 1.05 to 1.3 (6H, t),
3.35 to 3.7 (4H, q), 4.3 to 4.5 (2H, d), 4.7 to 4.9 (2H,
d), 5.4 (1H, s), 5.5-6.0 (2H, m), 6.8-7.4 (4H,
m), 7.5-7.9 (4H, m). B) 4- (3-Diethoxymethyl) phenoxy-cis-
2-Butenylamine The title compound was obtained in the same manner as in B) of Reference Example 1 using the starting material A) of Example 2.
【００１９】NMR （δ, CDCl3)： 1.05〜1.4(6H, t)、
1.5(2H, s)、 3.3〜3.8(6H, m)、 4.5〜4.7(2H, s)、
5.4(1H, s) 、 5.6〜5.8(2H, t)、 6.7〜7.4(4H, m)。 参考例１５，６−ジメチル−２−〔〔４−（３−ジエトキシメチ
ル）フェノキシ〕−cis −２−ブテニルアミノ〕−４−
（１Ｈ）−ピリミドン 実施例２のB)の４−（３−ジエトキシメチル）フェノキ
シ−cis −２−ブテニルアミン（3.５ｇ，0.0132モル）
及び５，６−ジメチル−２−メチルチオ−４−（１Ｈ）
−ピリミドン（薬学雑誌１９７６年、９６巻、No. ３、
３８４頁に記載の方法で製造した。）（2.５ｇ、0.0147
モル）をトルエン（１００ml）に溶解し、撹拌下に４８
時間還流した。NMR (δ, CDCl 3 ): 1.05 to 1.4 (6H, t),
1.5 (2H, s), 3.3-3.8 (6H, m), 4.5-4.7 (2H, s),
5.4 (1H, s), 5.6-5.8 (2H, t), 6.7-7.4 (4H, m). Reference Example 1 5,6-dimethyl-2-[[4- (3-diethoxymethyi
) Phenoxy] -cis-2-butenylamino] -4-
(1H) -Pyrimidone 4- (3-diethoxymethyl) phenoxy-cis-2-butenylamine of Example 2B) (3.5 g, 0.0132 mol)
And 5,6-dimethyl-2-methylthio-4- (1H)
-Pyrimidone (Pharmaceutical Journal, 1976, Volume 96, No. 3,
It was prepared by the method described on page 384. ) (2.5 g, 0.0147)
Mol) was dissolved in toluene (100 ml) and stirred for 48 hours.
Refluxed for hours.
【００２０】反応終了後、減圧下に溶媒を留去し、残渣
の油状物をカラムクロマトグラフィーにて精製して題記
の化合物1.３８g(２7.０％）を淡黄色油状物として得
た。NMR （δ, CDCl3)： 1.1〜1.4(6H, t)、 1.9(3H,
s) 、2.15(3H, s) 、 3.3〜3.8(4H, m)、 3.9〜4.2(2H,
m)、 4.6〜4.8(2H, d)、 5.5〜6.0(3H, m)、 6.4〜6.8
(1H, b)、 6.7〜7.4(4H, m)。 参考例２５，６−ジメチル−２−〔４−〔３−（１−ピペリジノ
メチル）フェノキシ〕−cis −２−ブテニルアミノ〕−
４−（１Ｈ）−ピリミドン 参考例１で製造した５，６−ジメチル−２−〔〔４−
（３−ジエトキシメチル）フェノキシ〕−cis −２−ブ
テニルアミノ〕−４−（１Ｈ）−ピリミドン（2.０ｇ）
をトルエン（８０ml）に溶解し、ピペリジン（1.５ｇ）
及び蟻酸（８ml）を加えて撹拌下に１２時間還流し、そ
の間に分離する水を反応容器から除去した。反応終了
後、１０％炭酸カリウム水溶液を加えてアルカリ性と
し、有機層を水洗、乾燥後、減圧下に溶媒を留去した。
残渣をカラムクロマトグラフィーに付して精製して題記
の化合物1.５１ｇ（７6.５％）を淡黄色油状物として得
た。After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 1.38 g (27.0%) of the title compound as a pale yellow oil. NMR (δ, CDCl 3 ): 1.1-1.4 (6H, t), 1.9 (3H,
s), 2.15 (3H, s), 3.3-3.8 (4H, m), 3.9-4.2 (2H,
m), 4.6-4.8 (2H, d), 5.5-6.0 (3H, m), 6.4-6.8
(1H, b), 6.7-7.4 (4H, m). Reference Example 2 5,6-dimethyl-2- [4- [3- (1-piperidino
Methyl) phenoxy] -cis-2-butenylamino]-
4- (1H) -pyrimidone 5,6-dimethyl-2-[[4-
(3-Diethoxymethyl) phenoxy] -cis-2-butenylamino] -4- (1H) -pyrimidone (2.0 g)
Dissolved in toluene (80 ml) and piperidine (1.5 g)
And formic acid (8 ml) were added and the mixture was refluxed for 12 hours with stirring, during which time the separated water was removed from the reaction vessel. After completion of the reaction, a 10% aqueous potassium carbonate solution was added to make the mixture alkaline, and the organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure.
The residue was purified by column chromatography to give 1.51 g (76.5%) of the title compound as a pale yellow oil.
【００２１】NMR （δ, CDCl3)： 1.2〜1.7(6H, m)、
1.85(3H, s)、2.1(3H, s)、 2.2〜2.5(4H, m)、 3.4(2
H, s) 、 3.9〜4.2(2H, m)、 4.5〜4.8(2H, d)、 5.5〜
6.0(2H, m)、 4.6〜7.3(4H, m)。 参考例３５，６−ジメチル−２−〔４−〔３−（１，３−ジオキ
ソラン−２−イル）フェノキシ〕−cis −２−ブテニル
アミノ〕−４−（１Ｈ）−ピリミドン 実施例１のB)の方法で製造した４−〔３−（１，３−ジ
オキソラン−２−イル）フェノキシ〕−cis −２−ブテ
ニルアミン（2.３５ｇ，0.０１モル）及び５，６−ジメ
チル−２−ニトロアミン−４−（１Ｈ）−ピリミドン
（特開昭６０−２２８４６５号の参考例に記載の方法を
利用して製造した。）（1.８４ｇ，0.０１モル）をピリ
ジン（５０ml）に溶解し、撹拌下に１５時間還流した。
反応終了後、減圧下に溶媒を留去し、残渣をシリカゲル
カラムクロマトグラフィーにて精製した。題記の化合物
を褐色油状物として得た。収量2.２１ｇ（６２％）。NMR (δ, CDCl 3 ): 1.2 to 1.7 (6H, m),
1.85 (3H, s), 2.1 (3H, s), 2.2 to 2.5 (4H, m), 3.4 (2
H, s), 3.9-4.2 (2H, m), 4.5-4.8 (2H, d), 5.5-
6.0 (2H, m), 4.6 ~ 7.3 (4H, m). Reference Example 3 5,6-Dimethyl-2- [4- [3- (1,3-dioki
Solan-2-yl) phenoxy] -cis-2-butenyl
Amino] -4- (1H) -pyrimidone 4- [3- (1,3-dioxolan-2-yl) phenoxy] -cis-2-butenylamine prepared by the method of B) of Example 1 (2.35 g, 0.01 mol) and 5,6-dimethyl-2-nitroamine-4- (1H) -pyrimidone (prepared using the method described in Reference Example of JP-A-60-228465) (1.84 g). , 0.01 mol) was dissolved in pyridine (50 ml) and refluxed with stirring for 15 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The title compound was obtained as a brown oil. Yield 2.21 g (62%).
【００２２】NMR （δ, CDCl3)： 1.9(3H, s) 、 2.2(3
H, s) 、 3.2〜3.8(4H,m)、 3.8〜4.1(2H, m)、 4.4〜
4.6(2H, d)、 5.6〜5.8(3H, m)、 6.4〜6.7(1H, b)、
6.7〜7.4(4H, m)。 参考例４５，６−ジメチル−２−〔４−〔３−（１−ピペリジノ
メチル）フェノキシ〕−cis −２−ブテニルアミノ〕−
４−（１Ｈ）−ピリミドン・塩酸塩 参考例３で得た５，６−ジメチル−２−〔４−〔３−
（１，３−ジオキソラン−２−イル）フェノキシ〕−ci
s −２−ブテニルアミン〕−４−（１Ｈ）−ピリミドン
（3.６ｇ，0.０１モル）を使用し、参考例２と同様に操
作して得た淡黄色油状物にｎ−ブタノール溶媒中、当モ
ルの塩酸を反応させて題記の化合物1.０ｇを無色の結晶
として得た。NMR (δ, CDCl 3 ): 1.9 (3H, s), 2.2 (3
H, s), 3.2-3.8 (4H, m), 3.8-4.1 (2H, m), 4.4-
4.6 (2H, d), 5.6-5.8 (3H, m), 6.4-6.7 (1H, b),
6.7-7.4 (4H, m). Reference Example 4 5,6-Dimethyl-2- [4- [3- (1-piperidino
Methyl) phenoxy] -cis-2-butenylamino]-
4- (1H) -pyrimidone hydrochloride 5,6-dimethyl-2- [4- [3-
(1,3-Dioxolan-2-yl) phenoxy] -ci
s-2-butenylamine] -4- (1H) -pyrimidone (3.6 g, 0.01 mol) was treated in the same manner as in Reference Example 2 to give a pale yellow oil in n-butanol solvent. Equimolar hydrochloric acid was reacted to obtain 1.0 g of the title compound as colorless crystals.
【００２３】融点：１０１〜２℃（ｄ） NMR （δ, DMSO-d6)： 0.9〜1.15(3H, d) 、 1.4〜2.0
(6H, m)、 2.1(3H, s) 、 2.6〜3.4(4H, m)、3.85〜4.2
(2H, m)、 4.25(2H, s)、 4.1〜4.9(2H, m)、 5.5〜5.9
(2H, m)、 6.7〜7.5(4H, m)。 参考例４で得られるピリミドン誘導体は消化性潰瘍治療
剤としての有用性が知られており（特開平１−１４９７
７４号公報）、本発明の製造中間体の有用性が明らかで
ある。Melting point: 101 to 2 ° C. (d) NMR (δ, DMSO-d 6 ): 0.9 to 1.15 (3H, d), 1.4 to 2.0
(6H, m), 2.1 (3H, s), 2.6-3.4 (4H, m), 3.85-4.2
(2H, m), 4.25 (2H, s), 4.1-4.9 (2H, m), 5.5-5.9
(2H, m), 6.7-7.5 (4H, m). The pyrimidone derivative obtained in Reference Example 4 is known to be useful as a therapeutic agent for peptic ulcer (JP-A-1-14997).
74), and the usefulness of the production intermediate of the present invention is clear.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2421191A JP2668168B2 (en) | 1991-02-19 | 1991-02-19 | Phenoxy derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2421191A JP2668168B2 (en) | 1991-02-19 | 1991-02-19 | Phenoxy derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20870490A Division JP2944165B2 (en) | 1990-08-07 | 1990-08-07 | Method for producing pyrimidone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04217646A JPH04217646A (en) | 1992-08-07 |
| JP2668168B2 true JP2668168B2 (en) | 1997-10-27 |
Family
ID=12131969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2421191A Expired - Lifetime JP2668168B2 (en) | 1991-02-19 | 1991-02-19 | Phenoxy derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2668168B2 (en) |
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1991
- 1991-02-19 JP JP2421191A patent/JP2668168B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| JPH04217646A (en) | 1992-08-07 |
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