JPH0649698B2 - Pyridine derivative - Google Patents
Pyridine derivativeInfo
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- JPH0649698B2 JPH0649698B2 JP13835488A JP13835488A JPH0649698B2 JP H0649698 B2 JPH0649698 B2 JP H0649698B2 JP 13835488 A JP13835488 A JP 13835488A JP 13835488 A JP13835488 A JP 13835488A JP H0649698 B2 JPH0649698 B2 JP H0649698B2
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Description
【発明の詳細な説明】 (産業上の利用分野) 本発明は、一般式 (式中、Aは、ホルミル基又は保護されたホルミル基、
Yは、-CH2-CH2-で表される基又は-CH=CH-で表される
基であり、nは0,1又は2である。)で表されるピリ
ジン誘導体に関する。本発明の前記一般式(I)で表され
るピリジン誘導体は、ヒスタミンH2受容体拮抗作用に基
づく抗消化性潰瘍剤として有用な化合物の中間体となり
得る化合物である(下記参考例参照)。DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) (In the formula, A is a formyl group or a protected formyl group,
Y is, -CH 2 -CH 2 - is a group represented by or a group represented by -CH = CH-, n is 0, 1 or 2. ) Related to the pyridine derivative. The pyridine derivative represented by the general formula (I) of the present invention is a compound that can be an intermediate of a compound useful as an anti-peptic ulcer agent based on histamine H 2 receptor antagonistic action (see Reference Example below).
(従来の技術) 従来、ヒスタミンH2受容体拮抗作用に基づく抗消化性潰
瘍剤は特開昭61-85365号明細書に で表される化合物が開示されている。更に高活性の化合
物を見出すべく検討した結果 (式中、Yは前記と同じである。) が本出願人により開発された(特願昭62−56434
号)。両化合物共に基本的に共通する合成法として (式中、Wは二置換アミノ基である。) なる化合物と (式中、Yは前記と同じである。) なる化合物の両者を反応させることにより、目的化合物
への中間体 (式中、W及びYは、前記と同じである。) を得ていた。(Prior Art) Conventionally, an anti-peptic ulcer agent based on histamine H 2 receptor antagonistic action is disclosed in JP-A-61-85365. Compounds represented by are disclosed. Results of investigation to find compounds with higher activity (Wherein Y is the same as above) was developed by the present applicant (Japanese Patent Application No. 62-56434).
issue). Both compounds have basically the same synthetic method. (In the formula, W is a disubstituted amino group.) (In the formula, Y is the same as the above.) By reacting both of the compounds (In the formula, W and Y are the same as the above.).
(発明が解決しようとする問題点) しかしながら、前記した従来の合成法は、前記した中間
体Aへの誘導が極めて煩雑であり、前記化合物A及びB
等の簡便な方法とは言いがたく、更によりよい合成法の
開発が望まれていた。(Problems to be Solved by the Invention) However, in the conventional synthesis method described above, the induction to the intermediate A is extremely complicated, and the compounds A and B are
However, it has been desired to develop a better synthesis method.
(問題点を解決するための手段) そのために本発明者等は、 (式中、A及びYは、前記と同じである。) なる化合物を見出した。この化合物は、前記化合物Bに
簡便に誘導することができることが判り、その中間体で
ある本発明の化合物を経由して合成することにより、収
率よく化合物Bを誘導できることを見出し、本発明を完
成した。(Means for Solving Problems) Therefore, the present inventors have (In the formula, A and Y are the same as the above.) It was found that this compound can be easily induced to the compound B, and it was found that the compound B can be derived in good yield by synthesizing via the intermediate compound of the present invention. completed.
(式中、A′は保護されたホルミル基であり、R1はp−
ニトロフェニル、2,4−ジニトロフェニル又はo−ニト
ロフェニル基である。Y,nは前記と同じである。) 〔第一工程〕 本工程は、前記一般式(II)で表されるピリジルオキシア
ミンと前記一般式(III)で表されるフルフリルチオ酢酸
エステルとを反応させることにより前記一般式(I-a)で
表されるアセタールピリジルオキシ誘導体を製造するも
のである。 (In the formula, A ′ is a protected formyl group, and R 1 is p-
A nitrophenyl, 2,4-dinitrophenyl or o-nitrophenyl group. Y and n are the same as above. ) [First step] In this step, the pyridyloxyamine represented by the general formula (II) is reacted with the furfurylthioacetic acid ester represented by the general formula (III) to give the compound represented by the general formula (Ia). It is intended to produce the represented acetal pyridyloxy derivative.
前記一般式(II)で表されるピリジルオキシアミンは、以
下に記載する反応式に従い製造することができる化合物
である。The pyridyloxyamine represented by the general formula (II) is a compound that can be produced according to the reaction formula described below.
(式中、A′は、保護されたホルミル基である。R2は水
酸基の保護基であり、Yは前記と同じである。)即ち、
工業的に入手容易な2−アミノ−4−メチルピリジンよ
り前記反応式に従い製造することができる(下記参考例
参照)。尚、ホルミル基の保護にあたって、使用できる
アルコールとしては例えばメタノール、エタノール、プ
ロパノール、1,2−エチレングリコール、1,3−プロピレ
ングリコール等を又、オルトギ酸エステルとしてはオル
トギ酸メチル、オルトギ酸エチル等を挙げることができ
る。アルコールを反応させるには、酸触媒の存在下に行
なうものである。酸としては塩酸、硫酸、p−トルエン
スルホン酸の鉱酸あるいは有機酸を使用できる。 (In the formula, A ′ is a protected formyl group. R 2 is a hydroxyl group-protecting group, and Y is the same as above.)
It can be produced from 2-amino-4-methylpyridine, which is industrially easily available, according to the above reaction formula (see Reference Example below). In protecting the formyl group, usable alcohols are, for example, methanol, ethanol, propanol, 1,2-ethylene glycol, 1,3-propylene glycol and the like, and as orthoformate esters, methyl orthoformate, ethyl orthoformate and the like. Can be mentioned. The alcohol is reacted in the presence of an acid catalyst. As the acid, hydrochloric acid, sulfuric acid, a mineral acid such as p-toluenesulfonic acid, or an organic acid can be used.
本工程の一方の原料である前記一般式(III)で表される
フルフリルチオエステルは、例えば、2−(フルフリル
スルフィニル)酢酸とニトロフェノールとを脱水縮合剤
(例えばジシクロヘキシルカルボジイミド等)の存在下
反応させることにより得ることができる。The furfuryl thioester represented by the general formula (III), which is one of the starting materials in this step, is obtained by, for example, adding 2- (furfurylsulfinyl) acetic acid and nitrophenol in the presence of a dehydration condensing agent (for example, dicyclohexylcarbodiimide). It can be obtained by reacting.
本工程を実施するには溶媒中で行うことが望ましく、例
えば、エチルエーテル、テトラヒドロフラン(THF)、
ジメトキシエタン(DME)、ジオキサン等のエーテル、
クロロホルム、ジクロロメタン等のハロゲン化炭化水
素、ベンゼン、トルエン等の芳香族炭化水素、ジメチル
ホルムアミド等のアミドを使用することができる。It is desirable to carry out this step in a solvent, for example, ethyl ether, tetrahydrofuran (THF),
Ethers such as dimethoxyethane (DME) and dioxane,
Halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, and amides such as dimethylformamide can be used.
反応は0〜50℃の温度範囲を選択することにより円滑
に進行する。The reaction proceeds smoothly by selecting the temperature range of 0 to 50 ° C.
本工程は前記一般式(I-a)で表されるアセタールピリジ
ルオキシ誘導体を脱保護し、前記一般式(I-b)で表され
るピリジルオキシ誘導体を製造するものである。In this step, the acetal pyridyloxy derivative represented by the general formula (Ia) is deprotected to produce the pyridyloxy derivative represented by the general formula (Ib).
本工程は、酸の存在下に行うことが必要である。酸とし
ては、塩酸、硫酸等の鉱酸、酢酸、p−トルエンスルホ
ン酸、カンファースルホン酸、クエン酸等の有機酸を好
適に使用することができる。酸の使用量は1当量ないし
5当量である。This step needs to be performed in the presence of an acid. As the acid, mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, p-toluenesulfonic acid, camphorsulfonic acid and citric acid can be preferably used. The amount of the acid used is 1 to 5 equivalents.
本工程を実施するにあたっては溶媒の使用が望ましく、
水、アセトン等のケトン、THF、DME等のエーテル、アセ
トニトリル等のニトリルを単独又は混合して使用するこ
とができる。It is desirable to use a solvent in carrying out this step,
Water, ketones such as acetone, ethers such as THF and DME, and nitriles such as acetonitrile can be used alone or as a mixture.
反応は30〜100℃の範囲で行うことができる。The reaction can be performed in the range of 30 to 100 ° C.
以上の如くして得られた一般式(I-b)で表されるピリジ
ルオキシ誘導体は、アミンと反応させた後常套手段によ
り前記化合物Bに導くことができる(下記参考例参
照)。The pyridyloxy derivative represented by the general formula (Ib) obtained as described above can be converted to the compound B by a conventional method after reacting with an amine (see Reference Example below).
以下、実施例及び参考例により本発明を更に詳細に説明
する。Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.
2−アミノ−4−メチルピリジン(108.1g)を47%
臭化水素酸(500m)に溶かし寒剤で0℃にし、臭
素(500g)を滴下した。反応が5℃以下になるよう
に調節しながら亜硝酸ナトリウム(172.5g)の水
(500m)溶液を滴下した。すべて滴下してから1
時間攪拌し水酸化ナトリウム(300g)の水(1)
溶液を滴下し溶液を塩基性にした。酢酸エチルで抽出
し、有機層を水洗し乾燥させた後溶媒を留去した。蒸溜
で精製し2−ブロモ−4−メチルピリジンを126g得
た。収率73%。 47% of 2-amino-4-methylpyridine (108.1 g)
It was dissolved in hydrobromic acid (500 m), adjusted to 0 ° C. with a freezing agent, and bromine (500 g) was added dropwise. A solution of sodium nitrite (172.5 g) in water (500 m) was added dropwise while adjusting the reaction to 5 ° C or lower. 1 after dropping all
Stir for a period of time and add sodium hydroxide (300 g) in water (1)
The solution was added dropwise to make the solution basic. It was extracted with ethyl acetate, the organic layer was washed with water and dried, and then the solvent was distilled off. Purification by distillation yielded 126 g of 2-bromo-4-methylpyridine. Yield 73%.
沸点79〜81℃/4〜5mmHg。1 H-NMR(δ,CDCl3):8.22(1H,d,J=4.9Hz),7.33(1H,
s),7.70(1H,d,J=4.9Hz),2.34(3H,s) 参考例2 2−ブロモ−4−メチルピリジン(50.0g)を濃硫酸
(400m)に溶かし、氷冷下無水クロム酸(87.2
g)を少量ずつ加えた。1時間攪拌し氷水中にいれた。
析出した結晶を濾取し、エタノールから再結晶した。2
−ブロモ−4−ピリジンカルボン酸を48.8g得た。収
率83%。Boiling point 79-81 ° C / 4-5 mmHg. 1 H-NMR (δ, CDCl 3 ): 8.22 (1H, d, J = 4.9Hz), 7.33 (1H,
s), 7.70 (1H, d, J = 4.9Hz), 2.34 (3H, s) Reference example 2 2-Bromo-4-methylpyridine (50.0 g) was dissolved in concentrated sulfuric acid (400 m), and chromic anhydride (87.2) was added under ice cooling.
g) was added in small portions. The mixture was stirred for 1 hour and placed in ice water.
The precipitated crystals were collected by filtration and recrystallized from ethanol. Two
48.8 g of -bromo-4-pyridinecarboxylic acid was obtained. Yield 83%.
融点213.9〜214.4℃ 参考例3 水素化ホウ素ナトリウム(17.4g)をTHF(1.6)に懸
濁させ、メカニカルスターラーで攪拌する。氷−水にて
冷却し、2−ブロモ−4−ピリジンカルボン酸(62.2
g)を少量ずつ加えた。室温まで昇温後、水素の発生が
止むまで攪拌した。三フッ化ホウ素エーテラート(7.5
−8m)のTHF(500m)溶液を室温にて3時間
滴下した。滴下終了後、そのまま20時間攪拌した。反
応溶液を氷−水にて冷却し、1.5N−塩酸を加え、pH1
〜2とした。THFを減圧下留去した。4N−水酸化ナト
リウム溶液を加えpH10〜11とし酢酸エチルにて抽
出、有機層は飽和食塩水で洗浄した。水層はさらに酢酸
エチルにて2回抽出した。有機層は合わせて無水硫酸ナ
トリウムにて乾燥した。減圧下濃縮することにより2−
ブロモ−4−ピリジンメタノールを51.3g得た。収率
88%。Melting point 213.9-214.4 ° C Reference Example 3 Sodium borohydride (17.4g) is suspended in THF (1.6) and stirred with a mechanical stirrer. After cooling with ice-water, 2-bromo-4-pyridinecarboxylic acid (62.2
g) was added in small portions. After the temperature was raised to room temperature, the mixture was stirred until the generation of hydrogen stopped. Boron trifluoride etherate (7.5
-8 m) in THF (500 m) was added dropwise at room temperature for 3 hours. After completion of dropping, the mixture was stirred for 20 hours as it was. The reaction solution was cooled with ice-water and 1.5N-hydrochloric acid was added to adjust the pH to 1
~ 2. THF was distilled off under reduced pressure. The pH was adjusted to 10 to 11 by adding a 4N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. 2-by concentrating under reduced pressure
51.3 g of bromo-4-pyridinemethanol was obtained. Yield 88%.
融点63.3-64.4℃(ジイソプロピルエーテル)1 H-NMR(δ,CDCl3):8.31(1H,d,J=4.5Hz),7.38(1H,
s),7.22(1H,d,J=4.5Hz),4.76(2H,s),2.40〜2.70(1H,m) IR(cm-1,KBr):3268,1598,1382,1070 C6H6BrO:実測値 186.9639 計算値 186.9633 実施例4 2−ブロモ−4−ピリジンメタノール(21.0g)、N
−ブロモコハク酸イミド(32.3g)および無水炭酸ナ
トリウム(23.1g)の混合物をベンゼン(600m
)に懸濁させ4時間加熱還流する(浴温110〜12
0℃)。氷浴で冷却し、飽和炭酸水素ナトリウム溶液を
加えpH9〜10とする。不溶物を去する(酢酸エチル
で洗浄)。有機層を分離し、10%チオ硫酸ナトリウム
溶液次いで飽和食塩水で洗浄し、硫酸ナトリウムで乾燥
する。溶媒を留去することにより2−ブロモ−4−ピリ
ジンアルデヒドを18.2g得た。収率88%。Melting point 63.3-64.4 ° C (diisopropyl ether) 1 H-NMR (δ, CDCl 3 ): 8.31 (1H, d, J = 4.5Hz), 7.38 (1H,
s), 7.22 (1H, d, J = 4.5Hz), 4.76 (2H, s), 2.40 ~ 2.70 (1H, m) IR (cm -1 ,, KBr): 3268,1598,1382,1070 C 6 H 6 BrO: Measured value 186.9639 Calculated value 186.9633 Example 4 2-Bromo-4-pyridinemethanol (21.0 g), N
-A mixture of bromosuccinimide (32.3 g) and anhydrous sodium carbonate (23.1 g) was added to benzene (600 m).
) And heated under reflux for 4 hours (bath temperature 110-12)
0 ° C). It is cooled in an ice bath and saturated sodium hydrogen carbonate solution is added to adjust the pH to 9-10. The insoluble material is removed (washing with ethyl acetate). The organic layer is separated, washed with 10% sodium thiosulfate solution, then saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain 18.2 g of 2-bromo-4-pyridine aldehyde. Yield 88%.
融点52.6〜53.5℃(n−ヘキサン)1 H-NMR(δ,CDCl3):10.03(1H,s),8.64(1H,d,J=4.9H
z)7.90(1H,s),7.68(1H,d,J=4.9Hz) IR(cm-1,KBr):1704,1554,1204 C6H4BrO:実測値 184.9485 :計算値 184.9476 参考例5 2−ブロム−4−ピリジンアルデヒド(60g)をベン
ゼン(600m)に溶解し、エチレングリコール(4
0g)、p−トルエンスルホン酸(6g)を入れ、ディ
ーンスタークトラップを用いて水を除きながら18時間
加熱還流した。反応終了後、氷、飽和炭酸水素ナトリウ
ム水溶液を入れ塩基性にした。有機層を水洗し、乾燥し
て溶媒を留去した。得られた化合物を蒸溜して2−ブロ
ム−4−(1,3−ジオキソラン−2−イル)ピリジンを
60g得た。収率82%。Melting point 52.6-53.5 ° C. (n-hexane) 1 H-NMR (δ, CDCl 3 ): 10.03 (1H, s), 8.64 (1H, d, J = 4.9H)
z) 7.90 (1H, s), 7.68 (1H, d, J = 4.9Hz) IR (cm −1 , KBr): 1704,1554,1204 C 6 H 4 BrO: Measured value 184.9485 : Calculated value 184.9476 Reference example 5 2-Brom-4-pyridinealdehyde (60 g) was dissolved in benzene (600 m), and ethylene glycol (4
0 g) and p-toluenesulfonic acid (6 g) were added, and the mixture was heated under reflux for 18 hours while removing water using a Dean Stark trap. After completion of the reaction, ice and saturated aqueous sodium hydrogen carbonate solution were added to make the mixture basic. The organic layer was washed with water, dried and the solvent was distilled off. The obtained compound was distilled to obtain 60 g of 2-bromo-4- (1,3-dioxolan-2-yl) pyridine. Yield 82%.
沸点121−122℃/3mmHg1 H-NMR(δ,CDCl3):8.39(1H,d,J=5.5Hz),7.60(1H,
s),7.34(1H,d,J=5.5Hz),5.80(1H,s),4.07(2H,d,J=12H
z),4.05(2H,d,J=12Hz) IR(cm-1,film):2894,1594,1553,1367,1121,1097 C8H8BrNO2:実測値 228.9738 計算値 228.9738 参考例6 イソニコチン酸オキシド(87g)、オキシ塩化リン
(350m)、五塩化リン(192g)を混合し、3
時間還流した。反応混合液を氷にあけ、一夜放置した。
生じた沈澱を濾取し、エタノールから再結晶することで
2−クロロ−4−ピリジンカルボン酸を65g得た。収
率66%。Boiling point 121-122 ° C / 3 mmHg 1 H-NMR (δ, CDCl 3 ): 8.39 (1H, d, J = 5.5Hz), 7.60 (1H,
s), 7.34 (1H, d, J = 5.5Hz), 5.80 (1H, s), 4.07 (2H, d, J = 12H
z), 4.05 (2H, d, J = 12Hz) IR (cm −1 , film): 2894,1594,1553,1367,1121,1097 C 8 H 8 BrNO 2 : measured value 228.9738 calculated value 228.9738 Reference example 6 Mix isonicotinic acid oxide (87 g), phosphorus oxychloride (350 m) and phosphorus pentachloride (192 g) and mix 3
Reflux for hours. The reaction mixture was poured onto ice and left overnight.
The resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 65 g of 2-chloro-4-pyridinecarboxylic acid. Yield 66%.
融点:228.1〜228.7℃ IR(cm-1,KBr):1718,1604,1566,1458,1372 C6H4NO2Cl:実測値 156.9940 計算値 156.9931 参考例7 水素化ホウ素ナトリウム(35.59g)をTHF(3)
に懸濁させ、メカニカルスターラーで攪拌した。氷水に
て冷却し、2−クロロ−4−ピリジンカルボン酸(98.
83g)少量ずつ加えた。室温まで昇温後、水素の発生
が止むまで攪拌し、三フッ化ホウ素・エーテラート(1
58m)のTHF(1000m)溶液を室温にて3時
間かけて滴下した。滴下終了後そのまま20時間攪拌し
た。反応溶液を氷水にて冷却し、1.5N−塩酸を加えpH
1〜2とし、THFを減圧下留去した。4N−水酸化ナト
リウム溶液を加えpH10〜11とし、酢酸エチルにて抽
出、有機層は飽和食塩水で洗浄した。水層はさらに酢酸
エチルにて2回抽出し、有機層を飽和食塩水で洗浄し
た。有機層は合わせて無水硫酸ナトリウムにて乾燥し、
減圧下濃縮することにより2−クロロ−4−ピリジンメ
タノールを75.0g得た。収率83%。Melting point: 228.1 to 228.7 ° C IR (cm -1 , KBr): 1718, 1604, 1566, 1458, 1372 C 6 H 4 NO 2 Cl: measured value 156.9940 calculated value 156.9931 reference example 7 Sodium borohydride (35.59g) in THF (3)
And was stirred with a mechanical stirrer. After cooling with ice water, 2-chloro-4-pyridinecarboxylic acid (98.
83 g) was added in small portions. After heating to room temperature, stir until hydrogen generation stops, and then boron trifluoride etherate (1
58m) in THF (1000m) was added dropwise at room temperature over 3 hours. After completion of dropping, the mixture was stirred as it was for 20 hours. The reaction solution was cooled with ice water, and 1.5N hydrochloric acid was added to pH.
1 to 2, and THF was distilled off under reduced pressure. The pH was adjusted to 10 to 11 by adding a 4N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline. The aqueous layer was further extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layers are combined and dried over anhydrous sodium sulfate,
By concentrating under reduced pressure, 75.0 g of 2-chloro-4-pyridinemethanol was obtained. Yield 83%.
融点:65.7〜66.4℃1 H-NMR(δ,CDCl3):8.30(1H,d,J=4.6Hz),7.37(1H,
s),7.22(1H,d,J=4.6Hz),4.76(2H,s),2.70〜2.85(1H,br
-s) IR(cm-1,KBr):3284,1600,1394 実施例8 2−クロロ−4−ピリジンメタノール(69.0g)、N
−ブロモコハク酸イミド(128.3g)、無水炭酸ナト
リウム(101.9g)をベンゼン(1.8)に懸濁し、
4時間還流した。Melting point: 65.7-66.4 ° C. 1 H-NMR (δ, CDCl 3 ): 8.30 (1H, d, J = 4.6 Hz), 7.37 (1H,
s), 7.22 (1H, d, J = 4.6Hz), 4.76 (2H, s), 2.70 to 2.85 (1H, br
-s) IR (cm -1 , KBr): 3284,1600,1394 Example 8 2-chloro-4-pyridinemethanol (69.0 g), N
-Bromosuccinimide (128.3 g) and anhydrous sodium carbonate (101.9 g) were suspended in benzene (1.8),
Refluxed for 4 hours.
冷却後、飽和重曹水を攪拌しながら少量づつ、発泡がお
さまるまで加えた。After cooling, saturated aqueous sodium hydrogen carbonate was added little by little while stirring until foaming subsided.
不溶物を濾過し、有機層を分離、10%−チオ硫酸ナト
リウム溶液で一回、飽和食塩水で二回洗浄、乾燥後留去
し、2−クロロ−4−ピリジンアルデヒドを64.3g得
た。収率95%。1 H-NMR(δ,CDCl3):10.06(1H,s),8.66(1H,d,J=4.7H
z),7.76(1H,s),7.66(1H,d,J=4.7Hz) IR(cm-1,film):2860,1712,1592,1558 参考例9 2−クロロ−4−ピリジンアルデヒド(60g)、オル
トギ酸エチル(90g)をエタノール(600m)に
溶解し、p−トルエンスルホン酸(7g)を加え、1時
間還流した。The insoluble matter was filtered off, the organic layer was separated, washed once with a 10% sodium thiosulfate solution and twice with a saturated saline solution, dried and evaporated to obtain 64.3 g of 2-chloro-4-pyridinealdehyde. . Yield 95%. 1 H-NMR (δ, CDCl 3 ): 10.06 (1H, s), 8.66 (1H, d, J = 4.7H
z), 7.76 (1H, s), 7.66 (1H, d, J = 4.7Hz) IR (cm −1 , film): 2860,1712,1592,1558 Reference Example 9 2-Chloro-4-pyridine aldehyde (60 g) and ethyl orthoformate (90 g) were dissolved in ethanol (600 m), p-toluenesulfonic acid (7 g) was added, and the mixture was refluxed for 1 hour.
冷却後、反応溶液を濃縮し、濃縮液を酢酸エチルにと
り、これを飽和重曹水、ついで飽和食塩水で洗浄、乾燥
後留去した。After cooling, the reaction solution was concentrated, the concentrate was taken up in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried and evaporated.
残渣を減圧蒸溜に付し、2−クロロ−4−ジエトキシメ
チルピリジンを75g得た。収率82%。The residue was subjected to vacuum distillation to obtain 75 g of 2-chloro-4-diethoxymethylpyridine. Yield 82%.
沸点102〜103℃/2mmHg1 H-NMR(δ,CDCl3):8.39(1H,d,J=5.4Hz),7.46(1H,
s),7.32(1H,d,J=5.4Hz),5.48(1H,s),3.50〜3.65(4H,
m),1,26(6H,t,J=7.2Hz) IR(cm-1,film):2984,1596,1556 参考例10 2−ブロモ−4−(1,3−ジオキソラン−2−イル)ピ
リジン(10g)、4−(2−オキシテトラヒドロピラ
ニル)−cis−2−ブテン−1−オール(9.7g)、粉
状水酸化ナトリウム(7.0g)、炭酸カリウム(9.7
g)及び、硫酸水素テトラn−ブチルアンモニウム(1.
3g)をトルエン(150m)に懸濁し、18時間還
流した。Boiling point 102-103 ° C / 2 mmHg 1 H-NMR (δ, CDCl 3 ): 8.39 (1H, d, J = 5.4Hz), 7.46 (1H,
s), 7.32 (1H, d, J = 5.4Hz), 5.48 (1H, s), 3.50-3.65 (4H,
m), 1,26 (6H, t, J = 7.2Hz) IR (cm −1 , film): 2984,1596,1556 Reference example 10 2-Bromo-4- (1,3-dioxolan-2-yl) pyridine (10 g), 4- (2-oxytetrahydropyranyl) -cis-2-buten-1-ol (9.7 g), powder Sodium hydroxide (7.0 g), potassium carbonate (9.7
g) and tetra-n-butylammonium hydrogen sulfate (1.
3 g) was suspended in toluene (150 m) and refluxed for 18 hours.
冷却後、ベンゼンで希釈し、水洗、乾燥後、溶媒を留去
し、2−{4−(2−オキシテトラヒドロピラニル)−
cis−2−ブテン−1−オキシ}−4−(1,3−ジオキソ
ラン−2−イル)ピリジンを12.1g得た。収率87
%。1 H-NMR(δ,CDCl3):8.15(1H,d,J=5.5Hz),6.96(1H,d,
J=5.5Hz),6.85(1H,s),5.79(1H,s),5.70〜5.90(2H,m),
4.93(2H,d,J=5.4Hz),4.65〜4.68(1H,m),4.37(1H,dd,J
=12.5,5.4Hz),4.20(1H,dd,J=12.5,5.4Hz),4.04(4H,d,
J=2Hz),3.82-3.91(1H,m),3.46-3.56(1H,m),1.46-1.92
(6H,m) IR(cm-1):2952,1618,1566,1316 C17H23NO5:実測値 321.1591 計算値 321.1577 参考例11 2−{4−(2−オキシテトラヒドロピラニル)−cis
−2−ブテン−1−オキシ}−4−(1,3−ジオキソラ
ン−2−イル)ピリジン(12.1g)をエタノール(2
50m)に溶解し、p−トルエンスルホン酸ピリジン
塩(1.5g)を加え、55℃(浴温)にて18時間攪拌
した。After cooling, it was diluted with benzene, washed with water and dried, and then the solvent was distilled off to give 2- {4- (2-oxytetrahydropyranyl)-
12.1 g of cis-2-butene-1-oxy} -4- (1,3-dioxolan-2-yl) pyridine was obtained. Yield 87
%. 1 H-NMR (δ, CDCl 3 ): 8.15 (1H, d, J = 5.5Hz), 6.96 (1H, d,
J = 5.5Hz), 6.85 (1H, s), 5.79 (1H, s), 5.70-5.90 (2H, m),
4.93 (2H, d, J = 5.4Hz), 4.65-4.68 (1H, m), 4.37 (1H, dd, J
= 12.5,5.4Hz), 4.20 (1H, dd, J = 12.5,5.4Hz), 4.04 (4H, d,
J = 2Hz), 3.82-3.91 (1H, m), 3.46-3.56 (1H, m), 1.46-1.92
(6H, m) IR (cm -1 ): 2952,1618,1566,1316 C 17 H 23 NO 5 : measured value 321.1591 calculated value 321.1577 reference example 11 2- {4- (2-oxytetrahydropyranyl) -cis
2-butene-1-oxy} -4- (1,3-dioxolan-2-yl) pyridine (12.1 g) was added to ethanol (2
50 m), p-toluenesulfonic acid pyridine salt (1.5 g) was added, and the mixture was stirred at 55 ° C (bath temperature) for 18 hours.
反応終了後、飽和炭酸水素ナトリウム溶液を加え、塩基
性とした後、溶媒を濃縮した。After the reaction was completed, a saturated sodium hydrogen carbonate solution was added to make the solution basic, and the solvent was concentrated.
残渣を酢酸エチルにとり、水洗、乾燥後、溶媒を留去
し、4−{4−(1,3−ジオキソラン−2−イル)ピリ
ジン−2−オキシ}−cis−2−ブテン−1−オールを
定量的に8.9gを得た。1 H-NMR(δ,CDCl3):8.10(1H,d,J=4.5Hz),6.98(1H,d,
J=4.5Hz),6.86(1H,s),5.83-5.92(1H,m),5.78(1H,s),5.
69-5.78(1H,m),5.01(2H,d,J=7.4Hz),4.32(2H,d,J=6.4
Hz),4.01-4.08(4H,m) IR(cm-1,film):3424,2896,1620,1566,1426,1316,1032 C12H15NO4:実測値 237.0998 計算値 237.1001 参考例12 4−{4−(1,3−ジオキソラン−2−イル)ピリジル
−2−オキシ}−cis−2−ブテン−1−オール(10
g)、トリエチルアミン(6g)をクロロホルム(25
0m)に溶解し、氷冷下、チオニルクロリド(6g)
を滴下した。The residue is taken up in ethyl acetate, washed with water and dried, then the solvent is distilled off to give 4- {4- (1,3-dioxolan-2-yl) pyridin-2-oxy} -cis-2-buten-1-ol. 8.9 g was quantitatively obtained. 1 H-NMR (δ, CDCl 3 ): 8.10 (1H, d, J = 4.5Hz), 6.98 (1H, d,
J = 4.5Hz), 6.86 (1H, s), 5.83-5.92 (1H, m), 5.78 (1H, s), 5.
69-5.78 (1H, m), 5.01 (2H, d, J = 7.4Hz), 4.32 (2H, d, J = 6.4
Hz), 4.01-4.08 (4H, m) IR (cm -1 , film): 3424,2896,1620,1566,1426,1316,1032 C 12 H 15 NO 4 : Measured value 237.0998 Calculated value 237.1001 Reference example 12 4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-buten-1-ol (10
g) and triethylamine (6 g) with chloroform (25
0m) and thionyl chloride (6g) under ice cooling.
Was dripped.
同条件にて1時間攪拌後、氷、次いで、飽和炭酸水素ナ
トリウム溶液を加え、塩基性とした後、有機層を水洗、
乾燥し、留去した。After stirring for 1 hour under the same conditions, ice and then saturated sodium hydrogen carbonate solution were added to make the mixture basic, and the organic layer was washed with water,
It was dried and evaporated.
残渣は精製することなく、直ちにアセトニトリル(25
0m)に溶解し、フタルイミドカリウム(8g)、硫
酸水素テトラn−ブチルアンモニウム(1.4g)を加え
一夜還流した。The residue was immediately purified by acetonitrile (25
0 m), potassium phthalimide (8 g) and tetra-n-butylammonium hydrogensulfate (1.4 g) were added, and the mixture was refluxed overnight.
冷後、不溶物を去し、液を濃縮した。濃縮液を酢酸
エチルにとり、1N−水酸化ナトリウム溶液で洗浄後、
水洗、乾燥し、溶媒を留去した。After cooling, the insoluble material was removed and the liquid was concentrated. The concentrate is taken up in ethyl acetate and washed with 1N-sodium hydroxide solution,
It was washed with water and dried, and the solvent was distilled off.
残渣をエタノールから再結晶し、N−〔4−{4−(1.
3−ジオキソラン−2−イル)ピリジル−2−オキシ}
−cis−2−ブテン〕フタルイミドを8g得た。収率5
3%。The residue was recrystallized from ethanol and N- [4- {4- (1.
3-dioxolan-2-yl) pyridyl-2-oxy}
8 g of -cis-2-butene] phthalimide was obtained. Yield 5
3%.
融点 96.9−97.9℃1 H-NMR(δ、CDCl3):8.17(1H,d,J=5.3Hz),7.82(2H,d
d,J=6.3,3.7Hz),7.72(2H,dd,J=6.3,3.7Hz),6.98(1H,
d,J=5.3Hz),6.86(1H,s),5.88-5.96(1H,m),5.80(1H,s),
5.64-5.74(1H,m),5.12(2H,d,J=7.2Hz),4.47(2H,d,J=
7.2Hz),4.00−4.09(4H,m) IR(cm-1,KBr):2496,1770,1716,1614,1568,1120,1092 C20H18N2O5:実測値 366.1221 計算値 366.1216 参考例13 N−〔4−{4−(1,3−ジオキソラン−2−イル)ピ
リジン−2−オキシ}−cis−2−ブテン〕フタルイミ
ド(8.5g)をメタノール(200m)に溶解し、抱
水ヒドラジン(2.3g)を加え10時間還流した。Melting point 96.9-97.9 ° C 1 H-NMR (δ, CDCl 3 ): 8.17 (1H, d, J = 5.3Hz), 7.82 (2H, d)
d, J = 6.3,3.7Hz), 7.72 (2H, dd, J = 6.3,3.7Hz), 6.98 (1H,
d, J = 5.3Hz), 6.86 (1H, s), 5.88-5.96 (1H, m), 5.80 (1H, s),
5.64-5.74 (1H, m), 5.12 (2H, d, J = 7.2Hz), 4.47 (2H, d, J =
7.2Hz), 4.00-4.09 (4H, m) IR (cm -1 , KBr): 2496,1770,1716,1614,1568,1120,1092 C 20 H 18 N 2 O 5 : Measured value 366.1221 Calculated value 366.1216 Reference example 13 N- [4- {4- (1,3-dioxolan-2-yl) pyridin-2-oxy} -cis-2-butene] phthalimide (8.5 g) was dissolved in methanol (200 m) to give hydrazine hydrate. (2.3 g) was added and the mixture was refluxed for 10 hours.
冷後、不溶物を去し、液を濃縮した。After cooling, the insoluble material was removed and the liquid was concentrated.
残渣は放置することにより結晶し、4−{4−(1,3−
ジオキソラン−2−イル)ピリジル−2−オキシ}−ci
s−2−ブテン−1−アミンを10.3g得た。収率78
%。1 H-NMR(δ,CDCl3):8.15(1H,d,J=4.8Hz),6.97(1H,d,
J=4.8Hz),6.85(1H,s),5.78(1H,s),5.68-5.76(2H,m),4.
90(2H,d,J=4.8Hz),4.01-4.07(4H,m),3.45(2H,d,J=4.8
Hz) IR(cm-1,KBr):3068,1666,1082 参考例14 2−クロロ−4−ジエトキシメチルピリジン(20
g)、および、4−(2−オキシテトラヒドロピラニ
ル)−cis−2−ブテン−1−オール(31.92g)を
テトラヒドロフラン(500m)に溶解し、ジメチル
ホルムアミド(10m)を加え、氷冷下、油性水素化
ナトリウム(9.28g)を懸濁させた。室温まで戻し、
徐々に80℃まで加熱し、さらに18時間還流した。冷
却後、氷冷下、水を加え、濃縮し、残渣をベンゼンで希
釈し、不溶物をセライト濾過で除いた。The residue crystallizes on standing and becomes 4- {4- (1,3-
Dioxolan-2-yl) pyridyl-2-oxy} -ci
10.3 g of s-2-buten-1-amine was obtained. Yield 78
%. 1 H-NMR (δ, CDCl 3 ): 8.15 (1H, d, J = 4.8Hz), 6.97 (1H, d,
J = 4.8Hz), 6.85 (1H, s), 5.78 (1H, s), 5.68-5.76 (2H, m), 4.
90 (2H, d, J = 4.8Hz), 4.01-4.07 (4H, m), 3.45 (2H, d, J = 4.8
Hz) IR (cm -1 , KBr): 3068,1666,1082 Reference Example 14 2-chloro-4-diethoxymethylpyridine (20
g) and 4- (2-oxytetrahydropyranyl) -cis-2-buten-1-ol (31.92 g) were dissolved in tetrahydrofuran (500 m), dimethylformamide (10 m) was added, and the mixture was cooled with ice. , Oily sodium hydride (9.28 g) was suspended. Return to room temperature,
The mixture was gradually heated to 80 ° C and further refluxed for 18 hours. After cooling, water was added under ice cooling and the mixture was concentrated. The residue was diluted with benzene, and the insoluble material was removed by Celite filtration.
濾液の有機層を分離し、水層を再度ベンゼンで抽出し、
先の有機層と合わせ、飽和食塩水で洗浄、乾燥、溶媒を
留去し、2−{4−(2−オキシテトラヒドロピラニ
ル)−cis−2−ブテン−1−オキシ}−4−(ジエト
キシメチル)ピリジンを49.62g得た。1 H-NMR(δ,CDCl3):8.13(1H,d,J=5.5Hz),6.98(1H,d,
J=5.5Hz),6.87(1H,s),5.75〜5.95(2H,m),5.44(1H,s),
4.92(2H,d,J=6.4Hz),4.65〜4.70(1H,m),4.40〜4.50(1
H,m),4.20〜4.30(1H,m),3.85〜3.95(1H,m),3.40〜3.70
(5H,m),1.40〜1.90(6H,m),1.24(6H,t,J=7.2Hz) IR(cm-1,film):2948,1616,1566 参考例15 2−{4−(2−オキシテトラヒドロピラニル)−cis
−2−ブテン−1−オキシ}−4−(ジエトキシメチ
ル)ピリジン(49.62g)をエタノール(500m
)に溶解し、p−トルエンスルホン酸(2.64g)を
加え、浴温60℃で3時間攪拌した。The organic layer of the filtrate is separated, the aqueous layer is extracted again with benzene,
The organic layers were combined, washed with saturated saline, dried, and the solvent was distilled off to give 2- {4- (2-oxytetrahydropyranyl) -cis-2-butene-1-oxy} -4- (di 49.62 g of ethoxymethyl) pyridine was obtained. 1 H-NMR (δ, CDCl 3 ): 8.13 (1H, d, J = 5.5Hz), 6.98 (1H, d,
J = 5.5Hz), 6.87 (1H, s), 5.75 ~ 5.95 (2H, m), 5.44 (1H, s),
4.92 (2H, d, J = 6.4Hz), 4.65 ~ 4.70 (1H, m), 4.40 ~ 4.50 (1
H, m), 4.20-4.30 (1H, m), 3.85-3.95 (1H, m), 3.40-3.70
(5H, m), 1.40 to 1.90 (6H, m), 1.24 (6H, t, J = 7.2Hz) IR (cm −1 , film): 2948,1616,1566 Reference Example 15 2- {4- (2-oxytetrahydropyranyl) -cis
2-butene-1-oxy} -4- (diethoxymethyl) pyridine (49.62 g) was added to ethanol (500 m).
), P-toluenesulfonic acid (2.64 g) was added, and the mixture was stirred at a bath temperature of 60 ° C. for 3 hours.
冷却後、氷冷下、飽和重曹水を加え、塩基性とし濃縮し
た。残渣を酢酸エチルにて2回抽出し、抽出液を飽和食
塩水で洗浄、乾燥、濃縮し、4−{4−(ジエトキシメ
チル)ピリジル−2−オキシ}−cis−2−ブテン−1
−オールを29g得た。1 H-NMR(δ,CDCl3):8.7(1H,d,J=5.3Hz),6.99(1H,d,J
=5.3Hz),6.88(1H,s),5.90〜6.00(1H,m),5.70〜5.80(1
H,m),5.43(1H,s),5.01(2H,d,J=6.8Hz),4.33(2H,d,J=
6.5Hz),3.50〜3.70(4H,m),1.24(6H,t,J=7.4Hz) IR(cm-1,film):3416,1616,1586 C14H21NO4:実測値 267.1477 計算値 267.1471 参考例16 4−{4−(ジエトキシメチル)ピリジル−2−オキ
シ}−cis−2−ブテン−1−オール(29g)を塩化
メチレン(500m)に溶解、無水炭酸カリウム(1
2.2g)を懸濁し、氷冷下、塩化チオニル(13.2g)
の塩化メチレン(100m)溶液を滴下した。1時間
攪拌後、固体を濾過し、濾液を濃縮した。After cooling, saturated aqueous sodium hydrogen carbonate was added under ice cooling to make the mixture basic and concentrated. The residue was extracted twice with ethyl acetate, the extract was washed with saturated brine, dried and concentrated to give 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-butene-1.
-29 g of oar was obtained. 1 H-NMR (δ, CDCl 3 ): 8.7 (1H, d, J = 5.3Hz), 6.99 (1H, d, J
= 5.3Hz), 6.88 (1H, s), 5.90 ~ 6.00 (1H, m), 5.70 ~ 5.80 (1
H, m), 5.43 (1H, s), 5.01 (2H, d, J = 6.8Hz), 4.33 (2H, d, J =
6.5Hz), 3.50 to 3.70 (4H, m), 1.24 (6H, t, J = 7.4Hz) IR (cm -1 , film): 3416,1616,1586 C 14 H 21 NO 4 : Measured value 267.1477 Calculated value 267.1471 Reference example 16 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-buten-1-ol (29 g) was dissolved in methylene chloride (500 m), anhydrous potassium carbonate (1
2.2 g) was suspended and thionyl chloride (13.2 g) was added under ice cooling.
Methylene chloride (100 m) solution of was added dropwise. After stirring for 1 hour, the solid was filtered and the filtrate was concentrated.
残渣をトルエン(800m)に溶解し、フタルイミド
カリウム(26.5g)、無水炭酸カリウム(6.9g)、
硫酸水素テトラ−n−ブチルアンモニウム(3.1g)を
懸濁し、激しく攪拌しながら、20時間還流した。The residue was dissolved in toluene (800 m), potassium phthalimide (26.5 g), anhydrous potassium carbonate (6.9 g),
Tetra-n-butylammonium hydrogen sulfate (3.1 g) was suspended and refluxed for 20 hours with vigorous stirring.
冷却後、不溶物を濾過し、酢酸エチルでよく洗浄した。
濾液と洗液を合わせ、水洗し、さらに、水層を酢酸エチ
ルで再抽出した。有機層を合わせ、冷−1N−水酸化ナ
トリウム溶液で3回、飽和食塩水で1回それぞれ洗浄
後、乾燥、留去し、N−〔4−{4−(ジエトキシメチ
ル)ピリジル−2−オキシ}−cis−2−ブテン〕フタ
ルイミドを41.06得た。1 H-NMR(δ,CDCl3):8.15(1H,d,J=5.2Hz),7.80〜7.90
(2H,m),7.70〜7.80(2H,m),6.98(1H,d,J=5.2Hz),6.89(1
H,s),5.90〜6.00(1H,m),5.60〜5.70(1H,m),5.44(1H,s),
5.12(2H,d,J=6.5Hz),4.57(2H,d,J=6.2Hz),3.50〜3.70
(4H,m),1.24(6H,t,J=7.2Hz) IR(cm-1,film):1770,1716,1614 C22H24N2O5:実測値 396.1694 計算値 396.1688 参考例17 N−〔4−{4−(ジエトキシメチル)ピリジル−2−
オキシ}−cis−2−ブテン〕フタルイミド(41.06
g)をメタノール(500m)に溶解し、ヒドラジン
・一水和物(13.93g)を加え、2時間還流した。After cooling, the insoluble matter was filtered and washed well with ethyl acetate.
The filtrate and washings were combined, washed with water, and the aqueous layer was reextracted with ethyl acetate. The organic layers were combined, washed with cold -1N-sodium hydroxide solution 3 times and saturated brine once, dried and evaporated to obtain N- [4- {4- (diethoxymethyl) pyridyl-2-. Oxy} -cis-2-butene] phthalimide was obtained in an amount of 41.06. 1 H-NMR (δ, CDCl 3 ): 8.15 (1H, d, J = 5.2Hz), 7.80 to 7.90
(2H, m), 7.70 ~ 7.80 (2H, m), 6.98 (1H, d, J = 5.2Hz), 6.89 (1
H, s), 5.90 ~ 6.00 (1H, m), 5.60 ~ 5.70 (1H, m), 5.44 (1H, s),
5.12 (2H, d, J = 6.5Hz), 4.57 (2H, d, J = 6.2Hz), 3.50-3.70
(4H, m), 1.24 (6H, t, J = 7.2Hz) IR (cm -1 , film): 1770,1716,1614 C 22 H 24 N 2 O 5 : Actual value 396.1694 Calculated value 396.1688 Reference Example 17 N- [4- {4- (diethoxymethyl) pyridyl-2-
Oxy} -cis-2-butene] phthalimide (41.06
g) was dissolved in methanol (500 m), hydrazine monohydrate (13.93 g) was added, and the mixture was refluxed for 2 hours.
反応液を濃縮し、残渣を塩化メチレンで希釈、不溶物を
濾過し、固体を塩化メチレンで洗浄し、濾液と洗液を合
わせて濃縮した。濃縮後、塩化メチレンを加えて、固体
が析出しなくなるまで、濾過、洗浄、濃縮を繰り返し
た。濃縮液を酢酸エチルに溶解し、2回水洗後、有機層
を冷10%−酢酸で抽出した。抽出液(酢酸溶液)に氷
冷下、無水炭酸カリウム(固体)を加え、塩基性とし、
酢酸エチルで2回抽出し、飽和食塩水で洗浄、乾燥、溶
媒を留去し、4−{4−(ジエトキシメチル)ピリジル
−2−オキシ}−cis−2−ブテン−1−アミンを12.
4g得た。参考例14からの通算収率50%。1 H-NMR(δ,CDCl3):8.13(1H,d,J=4.5Hz),6.97(1H,d,
J=4.5Hz),6.87(1H,s),5.75(2H,m),5.43(1H,s),4.89(2
H,d,J=5.4Hz),3.55(4H,m),3.45(2H,d,J=4.8Hz),1.55
(2H,br-s),1.23(6H,t,J=9Hz) IR(cm-1,film):3400,3200,3000,2950,1680,1620,1570,
1410,1060 C14H22N2O3:実測値 266.1642 計算値 266.1641 実施例1 フルフリルスルフィニル酢酸p−ニトロフェニルエステ
ル(13.5g)をTHF(300m)に懸濁し、氷冷
下、4−{4−(1,3−ジオキソラン−2−イル)ピリ
ジル−2−オキシ}−cis−2−ブテン−1−アミン
(10.3g)のTHF溶液(100m)を滴下した。The reaction solution was concentrated, the residue was diluted with methylene chloride, the insoluble material was filtered, the solid was washed with methylene chloride, and the filtrate and the washing solution were combined and concentrated. After concentration, methylene chloride was added, and filtration, washing, and concentration were repeated until no solid was deposited. The concentrate was dissolved in ethyl acetate, washed twice with water, and the organic layer was extracted with cold 10% -acetic acid. Anhydrous potassium carbonate (solid) was added to the extract (acetic acid solution) under ice cooling to make it basic,
Extract twice with ethyl acetate, wash with saturated brine, dry and evaporate the solvent to remove 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-buten-1-amine. .
4 g was obtained. Total yield 50% from Reference Example 14. 1 H-NMR (δ, CDCl 3 ): 8.13 (1H, d, J = 4.5Hz), 6.97 (1H, d,
J = 4.5Hz), 6.87 (1H, s), 5.75 (2H, m), 5.43 (1H, s), 4.89 (2
H, d, J = 5.4Hz), 3.55 (4H, m), 3.45 (2H, d, J = 4.8Hz), 1.55
(2H, br-s), 1.23 (6H, t, J = 9Hz) IR (cm -1 , film): 3400,3200,3000,2950,1680,1620,1570,
1410,1060 C 14 H 22 N 2 O 3 : Actual value 266.1642 Calculated value 266.1641 Example 1 Furfurylsulfinyl acetic acid p-nitrophenyl ester (13.5 g) was suspended in THF (300 m), and 4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy}-under ice cooling. A THF solution (100 m) of cis-2-buten-1-amine (10.3 g) was added dropwise.
1時間後、室温に戻し、一夜攪拌した。After 1 hour, the mixture was returned to room temperature and stirred overnight.
溶媒を濃縮し、残渣を酢酸エチルにとり、1N−水酸化
ナトリウム溶液で洗浄、水洗、乾燥後、溶媒を留去し、
N−〔4−{4−(1,3−ジオキソラン−2−イル)ピ
リジル−2−オキシ}−cis−2−ブテニル〕−2−
(フルフリルスルフィニル)アセトアミドを16.1g得
た。収率91%。1 H-NMR(δ,CDCl3):8.15(1H,d,J=5.5Hz),7.44(1H,d,
J=2.4Hz),7.10-7.20(1H,br-s),6.98(1H,d,J=5.5Hz),
6.47(1H,d,J=2.8Hz),6.39(1H,dd,J=2.4,2.8Hz),5.79-
5.90(1H,m),5.78(1H,s),5.63-5.72(1H,m),4.95(2H,d,J
=6.9Hz),4.27(1H,d,J=14.2Hz),4.18(1H,d,J=14.2Hz)
4.10(2H,t,J=6.6Hz),4.01-4.07(4H,m)3.59(1H,d,J=1
4.2Hz)3.34(1H,d,J=14.2Hz) IR(cm-1,film):1660,1618,1566,1310,1034 C19H22N2O6S:実測値 406.1208 計算値 406.1199 実施例2 N−〔4−{4−(1,3−ジオキソラン−2−イル)ピ
リジル−2−オキシ}−cis−2−ブテニル〕−2−
(フルフリルスルフィニル)アセトアミド(10.0g)
を水−アセトン(1:4)(200m)に溶解し、p
−トルエンスルホン酸(5.6g)を加え、18時間還流
した。The solvent is concentrated, the residue is taken up in ethyl acetate, washed with 1N-sodium hydroxide solution, washed with water and dried, and then the solvent is distilled off,
N- [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-butenyl] -2-
16.1 g of (furfurylsulfinyl) acetamide was obtained. Yield 91%. 1 H-NMR (δ, CDCl 3 ): 8.15 (1H, d, J = 5.5Hz), 7.44 (1H, d,
J = 2.4Hz), 7.10-7.20 (1H, br-s), 6.98 (1H, d, J = 5.5Hz),
6.47 (1H, d, J = 2.8Hz), 6.39 (1H, dd, J = 2.4,2.8Hz), 5.79-
5.90 (1H, m), 5.78 (1H, s), 5.63-5.72 (1H, m), 4.95 (2H, d, J
= 6.9Hz), 4.27 (1H, d, J = 14.2Hz), 4.18 (1H, d, J = 14.2Hz)
4.10 (2H, t, J = 6.6Hz), 4.01-4.07 (4H, m) 3.59 (1H, d, J = 1
4.2Hz) 3.34 (1H, d, J = 14.2Hz) IR (cm -1 , film): 1660,1618,1566,1310,1034 C 19 H 22 N 2 O 6 S: Measured value 406.1208 Calculated value 406.1199 Example Two N- [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-butenyl] -2-
(Furfurylsulfinyl) acetamide (10.0 g)
Was dissolved in water-acetone (1: 4) (200 m) and p
-Toluenesulfonic acid (5.6 g) was added, and the mixture was refluxed for 18 hours.
冷後、飽和炭酸水素ナトリウム溶液を加え、塩基性と
し、濃縮した。濃縮液を酢酸エチルにとり、水洗、乾燥
し、溶媒を留去した。得られた残渣をカラムクロマトグ
ラフィー(1%メタノール−クロロホルム)に付し、N
−{4−(4−ホルミル−2−ピリジルオキシ)−cis
−2−ブテニル}−2−(フルフリルスルフィニル)ア
セトアミドを4.6g得た。収率52%。After cooling, saturated sodium hydrogen carbonate solution was added to make it basic and concentrated. The concentrate was taken up in ethyl acetate, washed with water and dried, and the solvent was distilled off. The obtained residue was subjected to column chromatography (1% methanol-chloroform), N
-{4- (4-formyl-2-pyridyloxy) -cis
2-butenyl} -2- (furfurylsulfinyl) acetamide (4.6 g) was obtained. Yield 52%.
融点67.6−69.9℃1 H-NMR(δ,CDCl3):10.00(1H,s),8.36(1H,d,J=4.6H
z),7.45(1H,d,J=3Hz),7.30(1H,d,J=4.6Hz),7.16(1H,
s),7.08(1H,br-s),6.47(1H,d,J=3.5Hz),6.40(1H,dd,J
=3.5,3.0Hz),5.82-5.92(1H,m),5.66-5.76(1H,m),5.00
(2H,d,J=6.4Hz),4.27(1H,d,J=14.3Hz),4.18(1H,d,J=
14.3Hz),4.12(2H,t,J=6.3Hz),3.59(1H,d,J=14.1Hz),
3.34(1H,d,J=14.1Hz) IR(cm-1,KBr):3236,1712,1624,1564,1036 C17H18N2O5S:実測値 362.0934 計算値 362.0937 実施例3 4−{4−(ジエトキシメチル)ピリジル−2−オキ
シ}−cis−2−ブテン−1−アミン(12.4g)をTHF
(300m)に溶解し、スルフリルフルフリル酢酸p
−ニトロフェニルエステル(17.3g)を加え、室温で
5時間攪拌後、濃縮した。残渣を酢酸エチルに溶解し、
10%−炭酸カリウム水溶液で二回、水で一回洗浄し
た。水層は酢酸エチルで再抽出し、先の有機層と合わせ
て、飽和食塩水で洗浄し、乾燥、溶媒を留去し、N−
〔4−{4−(ジエトキシメチル)ピリジル−2−オキ
シ}−cis−2−ブテニル〕−2−(フルフリルスルフ
ィニル)アセトアミドを19.83g得た。収率97%。1 H-NMR(δ,CDCl3):8.12(1H,d,J=5.1Hz),7.43(1H,d,
J=1.8Hz),7.11(1H,br-s),6.98(1H,d,J=5.4Hz),6.87(1
H,s),6.47(1H,d,J=3.3Hz),6.40(1H,m),5.86(1H,m),5.6
7(1H,m),5.43(1H,s),4.94(2H,d,J=5.7Hz),4.27(1H,d,J
=18.5Hz),4.18(1H,d,J=18.5Hz),4.11(2H,d,J=6.6H
z),3.58(5H,m),3.33(1H,d,J=14.4Hz),1.23(6H,t,J=9.
0Hz) IR(cm-1,film):3400,2950,1680,1620,1570,1400 C21H28N2O6S:実測値 436.1676 計算値 436.1668 実施例4 N−〔4−{4−(ジエトキシメチル)ピリジル−2−
オキシ}−cis−2−ブテニル〕−2−(フルフリルス
ルフィニル)アセトアミド(19.83g)をアセトン−
水(4:1)の混合溶媒(600m)に溶解し、p−
トルエンスルホン酸・一水和物(1.72g)を加え、3
時間還流した。冷却後、溶液を濃縮し、残渣を酢酸エチ
ルにとり、冷−飽和重曹水に加え、析出した不溶物を濾
過し、有機層を分離した。水層を再度、酢酸エチルで抽
出し、先の有機層と合わせ、飽和食塩水で洗浄後、乾
燥、溶媒を留去し、N−{4−(4−ホルミル−2−ピ
リジルオキシ)−cis−2−ブテニル}−2−(フルフ
リルスルフィニル)アセトアミドを16.64g得た。収
率定量的。Melting point 67.6-69.9 ° C 1 H-NMR (δ, CDCl 3 ): 10.00 (1H, s), 8.36 (1H, d, J = 4.6H
z), 7.45 (1H, d, J = 3Hz), 7.30 (1H, d, J = 4.6Hz), 7.16 (1H,
s), 7.08 (1H, br-s), 6.47 (1H, d, J = 3.5Hz), 6.40 (1H, dd, J
= 3.5,3.0Hz), 5.82-5.92 (1H, m), 5.66-5.76 (1H, m), 5.00
(2H, d, J = 6.4Hz), 4.27 (1H, d, J = 14.3Hz), 4.18 (1H, d, J =
14.3Hz), 4.12 (2H, t, J = 6.3Hz), 3.59 (1H, d, J = 14.1Hz),
3.34 (1H, d, J = 14.1Hz) IR (cm −1 , KBr): 3236,1712,1624,1564,1036 C 17 H 18 N 2 O 5 S: Measured value 362.0934 Calculated value 362.0937 Example 3 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-buten-1-amine (12.4 g) in THF
Dissolved in (300m), sulfuryl furfuryl acetate p
-Nitrophenyl ester (17.3 g) was added, and the mixture was stirred at room temperature for 5 hr and concentrated. Dissolve the residue in ethyl acetate,
It was washed twice with a 10% aqueous potassium carbonate solution and once with water. The aqueous layer was re-extracted with ethyl acetate, combined with the above organic layer, washed with saturated brine, dried, and the solvent was distilled off.
There was obtained 19.83 g of [4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide. Yield 97%. 1 H-NMR (δ, CDCl 3 ): 8.12 (1H, d, J = 5.1Hz), 7.43 (1H, d,
J = 1.8Hz), 7.11 (1H, br-s), 6.98 (1H, d, J = 5.4Hz), 6.87 (1
H, s), 6.47 (1H, d, J = 3.3Hz), 6.40 (1H, m), 5.86 (1H, m), 5.6
7 (1H, m), 5.43 (1H, s), 4.94 (2H, d, J = 5.7Hz), 4.27 (1H, d, J
= 18.5Hz), 4.18 (1H, d, J = 18.5Hz), 4.11 (2H, d, J = 6.6H
z), 3.58 (5H, m), 3.33 (1H, d, J = 14.4Hz), 1.23 (6H, t, J = 9.
0Hz) IR (cm -1 , film): 3400,2950,1680,1620,1570,1400 C 21 H 28 N 2 O 6 S: Measured value 436.1676 Calculated value 436.1668 Example 4 N- [4- {4- (diethoxymethyl) pyridyl-2-
Oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide (19.83 g) was added to acetone-
Dissolve in a mixed solvent (600 m) of water (4: 1), p-
Add toluenesulfonic acid monohydrate (1.72g) and add 3
Reflux for hours. After cooling, the solution was concentrated, the residue was taken up in ethyl acetate, added to cold-saturated aqueous sodium hydrogen carbonate, the precipitated insoluble material was filtered, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate, combined with the above organic layer, washed with saturated brine, dried and evaporated to remove the solvent, and N- {4- (4-formyl-2-pyridyloxy) -cis was added. 16.64 g of 2-butenyl} -2- (furfurylsulfinyl) acetamide was obtained. Yield quantitative.
参考冷18 N−{4−(4−ホルミル−2−ピリジルオキシ)−ci
s−2−ブテニル}−2−(フルフリルスルフィニル)
アセトアミド(4.0g)をエタノール(100m)に
溶解し、氷冷下ピペリジン(2.0g)を加え攪拌した。Reference cold 18 N- {4- (4-formyl-2-pyridyloxy) -ci
s-2-butenyl} -2- (furfurylsulfinyl)
Acetamide (4.0 g) was dissolved in ethanol (100 m), and piperidine (2.0 g) was added under ice cooling and the mixture was stirred.
3時間後、氷冷下、水素化ホウ素ナトリウム(0.5g)
を加え、6時間攪拌した。After 3 hours, under cooling with ice, sodium borohydride (0.5 g)
Was added and stirred for 6 hours.
酢酸を加えハイドライドを分解した後、濃縮した。After acetic acid was added to decompose hydride, it was concentrated.
残渣を酢酸エチルにとり、10%−酢酸にて2回抽出し
た。The residue was taken up in ethyl acetate and extracted twice with 10% acetic acid.
酢酸層を4回、酢酸エチルで洗浄した後、炭酸カリウム
にて塩基性とし、酢酸エチルで抽出した。The acetic acid layer was washed four times with ethyl acetate, made basic with potassium carbonate, and extracted with ethyl acetate.
有機層を水洗、乾燥し、留去した。The organic layer was washed with water, dried and evaporated.
残渣をエーテル−ヘキサンから再結晶し、N−〔4−
{4−(ピペリジノメチル)ピリジル−2−オキシ}−
cis−2−ブテニル〕−2−(フルフリルスルフィニ
ル)アセトアミドを2.2g得た。収率46% 融点92.7−94.9℃ NMR(δ,CDCl3):1.40-1.50(2H,m),1.50-1.65(4H,m),
2.30-2.45(4H,m),3.34(1H,d,J=14.2Hz),3.40(2H,s),3.
69(1H,d,J=14.2Hz),4.15(2H,dd,J=6.1Hz,6.1Hz),4.14
(1H,d,J=14.2Hz),4.38(1H,d,J=14.2Hz),4.93(2H,t,J
=6.1Hz),5.60-5.75(1H,m),5.80-5.90(1H,m),6.40(1H,d
d,J=3.1Hz,1.6Hz),6.47(1H,d,J=3.1Hz),6.73(1H,s),
6.87(1H,d,J=5.1Hz),7.15-7.25(1H,brs),7.44(1H,d,J
=1.6Hz),8.04(1H,d,J=5.1Hz) IR(cm-1,KBr):1645(C=O)1041(S→O) C22H29N3O4S:実測値 431.1883 計算値 431.1879 (発明の効果) 本発明の前記一般式(I)で表されるピリジン誘導体は簡
便に製造できる。又、参考例に示した如く反応に付すこ
とにより容易に前記化合物B等に導くことができる、化
合物B等はすぐれたヒスタミンH2受容体拮抗作用を有す
る。The residue was recrystallized from ether-hexane to give N- [4-
{4- (piperidinomethyl) pyridyl-2-oxy}-
2.2 g of cis-2-butenyl] -2- (furfurylsulfinyl) acetamide was obtained. Yield 46% Melting point 92.7-94.9 ° C NMR (δ, CDCl 3 ): 1.40-1.50 (2H, m), 1.50-1.65 (4H, m),
2.30-2.45 (4H, m), 3.34 (1H, d, J = 14.2Hz), 3.40 (2H, s), 3.
69 (1H, d, J = 14.2Hz), 4.15 (2H, dd, J = 6.1Hz, 6.1Hz), 4.14
(1H, d, J = 14.2Hz), 4.38 (1H, d, J = 14.2Hz), 4.93 (2H, t, J
= 6.1Hz), 5.60-5.75 (1H, m), 5.80-5.90 (1H, m), 6.40 (1H, d)
d, J = 3.1Hz, 1.6Hz), 6.47 (1H, d, J = 3.1Hz), 6.73 (1H, s),
6.87 (1H, d, J = 5.1Hz), 7.15-7.25 (1H, brs), 7.44 (1H, d, J
= 1.6Hz), 8.04 (1H, d, J = 5.1Hz) IR (cm -1 ,, KBr): 1645 (C = O) 1041 (S → O) C 22 H 29 N 3 O 4 S: Measured value 431.1883 Calculated value 431.1879 (Effect of the invention) The pyridine derivative represented by the general formula (I) of the present invention can be easily produced. Further, the compound B and the like have an excellent histamine H 2 receptor antagonistic action, which can be easily led to the compound B and the like by subjecting it to a reaction as shown in Reference Example.
Claims (1)
はホルミル基とアルコール若しくはオルトギ酸エステル
との反応により得られる保護されたホルミル基である。
アルコールとしては、メタノール、エタノール、プロパ
ノール、1,2−エチレングリコール又は1,3−プロ
ピレングリコールであり、オルトギ酸エステルとして
は、オルトギ酸メチル又はオルトギ酸エチルである。Y
は、−CH2−CH2−で表される基又は−CH=CH−
で表される基であり、nは、0,1又は2である。)。1. A general formula (In the formula, A is a formyl group or a protected formyl group obtained by reacting a formyl group with an alcohol or an orthoformate ester.)
The alcohol is methanol, ethanol, propanol, 1,2-ethylene glycol or 1,3-propylene glycol, and the orthoformate is methyl orthoformate or ethyl orthoformate. Y
Is, -CH 2 -CH 2 -, a group represented by or -CH = CH-
And n is 0, 1 or 2. ).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13835488A JPH0649698B2 (en) | 1987-11-17 | 1988-06-07 | Pyridine derivative |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP28833287 | 1987-11-17 | ||
JP62-288332 | 1987-11-17 | ||
JP13835488A JPH0649698B2 (en) | 1987-11-17 | 1988-06-07 | Pyridine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH01230576A JPH01230576A (en) | 1989-09-14 |
JPH0649698B2 true JPH0649698B2 (en) | 1994-06-29 |
Family
ID=26471408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13835488A Expired - Lifetime JPH0649698B2 (en) | 1987-11-17 | 1988-06-07 | Pyridine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0649698B2 (en) |
-
1988
- 1988-06-07 JP JP13835488A patent/JPH0649698B2/en not_active Expired - Lifetime
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Publication number | Publication date |
---|---|
JPH01230576A (en) | 1989-09-14 |
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