JPS6058754B2 - Nicotinic acid esters - Google Patents
Nicotinic acid estersInfo
- Publication number
- JPS6058754B2 JPS6058754B2 JP13848576A JP13848576A JPS6058754B2 JP S6058754 B2 JPS6058754 B2 JP S6058754B2 JP 13848576 A JP13848576 A JP 13848576A JP 13848576 A JP13848576 A JP 13848576A JP S6058754 B2 JPS6058754 B2 JP S6058754B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- nicotinic acid
- mixture
- phenyl
- benzene
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
【発明の詳細な説明】 本発明は一般式（Ｉ） Ｒ、１ＣＯＯＲ。[Detailed description of the invention] The present invention relates to general formula (I) R, 1COOR.
ｕ（Ｉ） Ｒ。u(I) R.
（式中、Ｒ１およびＲ２は低級アルキル基またはフェニ
ル基を、Ｒ。(In the formula, R1 and R2 represent a lower alkyl group or a phenyl group, R.
は低級アルキル基を表わす）で示されるニコチン酸エス
テル類に関する。本発明のニコチン酸エステル類はいず
れも文献未記載の新規化合物であり、本発明者らがその
薬理学的作用に興味を持ち合成したものであるが、その
作用はグラム陽性、グラム陰性菌に対し抗菌的に働らく
ことが判明し、本発明を完成させるに至つた。一般式（
Ｉ）中Ｒ、、Ｒ。represents a lower alkyl group). The nicotinic acid esters of the present invention are all new compounds that have not been described in any literature, and were synthesized by the present inventors with an interest in their pharmacological action. It was found that the antibacterial effect was antibacterial, leading to the completion of the present invention. General formula (
I) Medium R,,R.
およびＲ。で表わされる低級アルキル基としては、メチ
ル、エチル、プロピル、イソプロピル、ブチル、第２級
ブチル、第３級ブチル基などのＣ１〜Ｃ４程度のアルキ
ル基があげられ、したがつて本発明の化合物（Ｉ）とし
’てより具体的には次のものを挙げることができる。す
なわち、４−ヒドロキシー５−メチルー６−フェニルニ
コチン酸エチル、４−ヒドロキシ−６−メチルー５−フ
ェニルニコチン酸エチル、４−ヒドロキシー５｜６−ジ
フェニルニコチン酸工、チルなどである。本発明の化合
物（Ｉ）は次の様に製造される。and R. Examples of the lower alkyl group represented by include C1 to C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, and tertiary butyl groups. More specifically, the following can be mentioned as I). That is, ethyl 4-hydroxy-5-methyl-6-phenylnicotinate, ethyl 4-hydroxy-6-methyl-5-phenylnicotinate, 4-hydroxy-5|6-diphenylnicotinate, chill, and the like. Compound (I) of the present invention is produced as follows.
すなわち、一般式（■）Ｒ１ ＣＯＯＲ。That is, the general formula (■) R1 COOR.
、〔Ｎ１ＣＯＯＲ３（ｎ） Ｒ。, [N1COOR3(n) R.
（式中、Ｒ、、Ｒ。(In the formula, R,,R.
およびＲ。は前記定義と同一）で示されるエナミン化合
物を閉環する方法が採用される。本閉環反応は具体的に
は次の様にして行なわれる。すなわち化合物（■）を適
当な溶媒中、加熱下に熱閉環する手段である。用いられ
る溶媒は比較的高沸点のしかも反応に直接の影響を与え
ないものならば良く、例えばジフェニルエーテル、フタ
ル酸ジエチル、シリコンオイルなどが挙げられる。反応
温度は２００〜３００℃程度が好ましく、ジフェニルエ
ーテルを溶媒として採用する場合にはその沸点附近が好
ましい。反応時間は用いる溶媒、反応温度によソー概に
言えないが、０．１〜３時間程度て十分である。目的物
の採取手段は有機化学上用いられる公知手段（抽出、転
溶、クロマトグラフィー、再結晶など）が採用され、多
くのニコチン酸エステル類（１）は結晶として単離され
る。本閉環反応における出発原料となる式（■）で表わ
される文献未知のエナミン化合物は次の方法により製造
される。and R. is the same as defined above) is employed. Specifically, this ring-closing reaction is carried out as follows. That is, it is a means of thermally ring-closing the compound (■) under heating in a suitable solvent. The solvent used may be one that has a relatively high boiling point and does not directly affect the reaction, such as diphenyl ether, diethyl phthalate, silicone oil, etc. The reaction temperature is preferably about 200 to 300°C, and when diphenyl ether is used as a solvent, it is preferably near its boiling point. Although the reaction time cannot be generalized depending on the solvent used and the reaction temperature, about 0.1 to 3 hours is sufficient. Known methods used in organic chemistry (extraction, dissolution, chromatography, recrystallization, etc.) are used to collect the target product, and many nicotinic acid esters (1) are isolated as crystals. The enamine compound represented by formula (■) and unknown in the literature, which is the starting material in this ring-closing reaction, is produced by the following method.
すなわち一般式（■）（式中、Ｒ１およびＲ２は低級ア
ルキル基又はフェニル基を表わす）で示されるケトン体
に一般式（■）（式中、Ｒ３は低級アルキル基を表わす
）で示されるアミノメチレンマロン酸エステル体を脱水
．縮合することにより得られる。That is, an amino compound represented by the general formula (■) (in the formula, R3 represents a lower alkyl group) is added to a ketone body represented by the general formula (■) (in the formula, R1 and R2 represent a lower alkyl group or a phenyl group). Dehydrate methylene malonic acid ester. Obtained by condensation.
本脱水縮合反応は化合物（■）および（■）を適当な溶
媒中生成する水を分離しながら加熱することにより行な
われ、そのような溶媒としては、ベンゼン、トルエン、
キシレン、テトラリン、デカリンなどが挙げ！られ、好
ましくはキシレン、デカリンである。もちろん本反応は
無触媒でも進行するが、適当な酸触媒を添加することが
好ましく、そのような触媒としてバラトルエンスルフォ
ン酸、塩酸、硫酸などが挙げられる。以下に本発明を実
施例にて詳細に説明するが、これらに限定されるもので
はない。実施例１
エナミン体（■：Ｒ１＝メチル，Ｒ４＝フエニル、Ｒ３
＝エチル）の製造法。This dehydration condensation reaction is carried out by heating compounds (■) and (■) in a suitable solvent while separating the water produced. Such solvents include benzene, toluene,
Examples include xylene, tetralin, decalin, etc. and preferably xylene or decalin. Of course, this reaction proceeds without a catalyst, but it is preferable to add a suitable acid catalyst, and examples of such catalysts include valatoluenesulfonic acid, hydrochloric acid, and sulfuric acid. The present invention will be explained in detail below with reference to Examples, but the present invention is not limited thereto. Example 1 Enamine body (■: R1 = methyl, R4 = phenyl, R3
= ethyl) production method.
プロプオフエノン５ｙ１アミ
酸ジエチル７′、バラトルエンスルフォン酸０．１ｙお
よびデカリン８ｍ１の混合物を油浴中攪拌しながら１８
５℃にて２峙間加熱する。A mixture of propofenone 5y1 diethyl amate 7', balatoluenesulfonic acid 0.1y and decalin 8ml was stirred in an oil bath for 18 hours.
Heat at 5°C for 2 hours.
反応終了後ベンゼン抽出、水洗、乾燥（硫酸ソーダ）後
ベンゼンを留去し、得られる油状物をシリカゲルを用い
たカラムクロマトグラフィーに付しベンゼンにて流出し
エナミン体を油状物として得る。赤外線吸収スペクトル
（Ｌｉｇ）
１７１０ｃｗ１−１（エステル）
核磁気共鳴スペクトル（δ：ＣＤＣｌ３）１．９０およ
び１．７０（メチル、訓、二重線、Ｊ＝７Ｈｚ）７．３
３（フェニル、■、一重線）
なお、本物質は立体化学上Ｅ−Ｚ体の混合物であるが、
そのまま次の閉環反応に用いてよい。After the reaction is completed, the benzene is extracted, washed with water, and dried (soda sulfate), and then the benzene is distilled off. The resulting oil is subjected to column chromatography using silica gel and eluted with benzene to obtain the enamine compound as an oil. Infrared absorption spectrum (Lig) 1710cw1-1 (ester) Nuclear magnetic resonance spectrum (δ: CDCl3) 1.90 and 1.70 (methyl, doublet, J = 7Hz) 7.3
3 (phenyl, ■, singlet) Although this substance is a mixture of E-Z forms stereochemically,
It may be used as it is in the next ring-closing reaction.
実施例２エナミン体（Ｈ：Ｒ１＝フエニル、Ｒ２＝メチ
ル、Ｒ３＝エチル）の製造法。Example 2 Method for producing an enamine compound (H: R1=phenyl, R2=methyl, R3=ethyl).
フェニルアセトン２．７ｙ１アミノメチレンマロン酸ジ
エチル４．５ｙ１バラトルエンスルフォン酸０．１５ｙ
およびキシレン２０ｍ１の混合物を油浴中生成する水を
除きながら５時間還流。Phenylacetone 2.7y1 Amino methylene diethyl malonate 4.5y1 Valatoluenesulfonic acid 0.15y
A mixture of 20 ml of xylene and 20 ml of xylene was refluxed for 5 hours while removing the water produced in an oil bath.
冷後反応混合物全体をシリカゲルを用いたカラムクロマ
トグラフィーに付し、ベンゼンにて流出すればエナミン
体を油状物として得る。赤外線吸収スペクトル（Ｌｌｇ
）
３００００−１（ＮＨ）
１７２０ｃ１ｎ−１（エステル）
核磁気共鳴スペクトル（δ：ＣＣｌ４）
２．２３（メチル、狙、一重線）
７．２７（フェニル、明、一重線）
なお、本物質は立体化学上Ｅ−Ｚ体の混合物であるが、
そのまま次の反応に用いてよい。After cooling, the entire reaction mixture is subjected to column chromatography using silica gel and eluted with benzene to obtain the enamine compound as an oil. Infrared absorption spectrum (Llg
) 30000-1 (NH) 1720c1n-1 (ester) Nuclear magnetic resonance spectrum (δ: CCl4) 2.23 (methyl, aim, singlet) 7.27 (phenyl, bright, singlet) Note that this substance has a three-dimensional Although it is chemically a mixture of E-Z form,
It may be used as is for the next reaction.
実施例３
エナミン体（■：Ｒ１＝Ｒ２＝フエニル、Ｒ３＝エチル
）の製造法。Example 3 Method for producing an enamine compound (■: R1=R2=phenyl, R3=ethyl).
ベンジルフェニルケトン８ｙ１アミノメチレンマロン酸
ジエチル８ｙ１バラトルエンスルフォン酸０．２ｙおよ
びキシレン３５ｍ１の混合物を油浴中生成する水を除き
ながら２弼間還流する。A mixture of benzyl phenyl ketone 8y1 aminomethylene diethyl malonate 8y1 valatoluenesulfonic acid 0.2y and xylene 35ml is refluxed for 2 hours in an oil bath while removing the water formed.
反応後ベンゼン抽出、水洗、乾燥（硫酸ソーダ）後溶媒
を留去。得られる残留物をシリカゲルカラムクロマトグ
ラフイーに付し、ベンゼンおよびベンゼン−クロロホル
ム混液にて流出すればエナミン体を油状物として得る。
赤外線吸収スペクトル（Ｌｉｇ）
１７１０ｃ『１（エステル）
核磁気共鳴スペクトル（δ：ＣＣｌ４）
７．２〜７．５（フェニル×２、１０Ｈ１多重線）なお
、本物質も立体化学上Ｅ−Ｚ体の混合物であるが、その
まま次の反応に用いてよい。After the reaction, extract with benzene, wash with water, dry (sodium sulfate), and then distill off the solvent. The resulting residue is subjected to silica gel column chromatography and eluted with benzene and a benzene-chloroform mixture to obtain the enamine compound as an oil.
Infrared absorption spectrum (Lig) 1710c "1 (ester) Nuclear magnetic resonance spectrum (δ: CCl4) 7.2-7.5 (phenyl x 2, 10H1 multiplet) This substance also has an E-Z form due to stereochemistry. Although it is a mixture, it may be used as it is in the next reaction.
実施例４
４−ヒドロキシー５−メチルー６−フェニルニコチン酸
エチルの製造法。Example 4 Method for producing ethyl 4-hydroxy-5-methyl-6-phenylnicotinate.
実施例１で得たエナミン体１ｙおよびジフェニルエーテ
ル６．５ｍ１の混合物を油浴中約２７０℃にて１．５Ａ
間加熱下攪拌。A mixture of the enamine compound 1y obtained in Example 1 and 6.5ml of diphenyl ether was heated at 1.5A at about 270°C in an oil bath.
Stir while heating.
冷後、反応混合物をシリカゲルを用いたカラムクロマト
グラフィーに付し、ベンゼン−ヘキサン混液およびベン
ゼンにて流出すれば、ニコチン酸誘導体０．４５ｙ（５
３％）を得、エタノールより再結晶すれば無色針状晶を
与える。融点１７６〜１７ＴＣ０赤外線吸収スペクトル
（ＫＢｒ）
３０００〜２５００ｃｍ−１（０Ｈ）
１７００ｃｍ−１（エステル）
核磁気共鳴スペクトル（δ：ＣＤＣｌ３）２．２４（Ｃ
Ｈ３、狙、一重線）
７．４５（フェニル、胆、一重線）
８．８４（Ｃ２−ＨｌｌＨｌ一重線）
元素分析：Ｃｌ５Ｈｌ５ＮＯ３
計算値：Ｃｌ７Ｏ．Ｏ２；Ｈｌ５．８８；Ｎｌ５．４４
実験値：Ｃｌ６９．７５；Ｈｌ６．２７；Ｎｌ５．４７
実施例５４−ヒドロキシー６−メチルー５−フェニルニ
コチン酸エチルの製造法。After cooling, the reaction mixture was subjected to column chromatography using silica gel, and if a benzene-hexane mixture and benzene were eluted, 0.45y (5 y) of nicotinic acid derivative was obtained.
3%), and recrystallization from ethanol gives colorless needle crystals. Melting point 176-17 TCO Infrared absorption spectrum (KBr) 3000-2500 cm-1 (0H) 1700 cm-1 (ester) Nuclear magnetic resonance spectrum (δ: CDCl3) 2.24 (C
H3, aim, singlet) 7.45 (phenyl, bile, singlet) 8.84 (C2-HllHl singlet) Elemental analysis: Cl5Hl5NO3 Calculated value: Cl7O. O2; Hl5.88; Nl5.44
Experimental values: Cl69.75; Hl6.27; Nl5.47
Example 5 Process for producing ethyl 4-hydroxy-6-methyl-5-phenylnicotinate.
実施例２で得たエナミン体１．８２ｙおよびジフェニル
エーテル３５ｍ１の混合物を油浴中２６５〜２８５゜Ｃ
にて０．時間加熱下攪拌。A mixture of 1.82y of the enamine compound obtained in Example 2 and 35ml of diphenyl ether was heated in an oil bath at 265-285°C.
At 0. Stir under heat for an hour.
反応終了後、シリカゲルを用いたカラムクロマトグラフ
ィーに付し、ベンゼンおよびクロロホルムで流出すれば
ニコチン酸誘導体０．９９ｙ（６４％）を得。エタノー
ルから再結晶すれば無色プリズム晶を与える。融点１７
８〜１８０℃。赤外線吸収スペクトル（ＫＢｒ）
３６００〜２８００ｃｍ−１（０Ｈ）
ノ １７００ｃｍ−“１（エステル）
核磁気共鳴スペクトル（δ：ＣＤＣｌ３）１．３８（Ｃ
Ｈ３、？、一重線）
７．１〜７．６（フェニル、明、多重線）８．４６（Ｃ
２−ＨｌｌＨｌ一重線）
元素分析：Ｃｌ５Ｈｌ５ＮＯ３
計算値：Ｃｌ７Ｏ．Ｏ２；Ｈｌ５．８８；Ｎｌ５．４４
実験値：Ｃｌ６９．８６；Ｈｌ５．４９：Ｎｌ５．４３
実施例６４−ヒドロキシー５，６−ジフェニルニコチン
酸エチルの製造法。After the reaction was completed, the product was subjected to column chromatography using silica gel and eluted with benzene and chloroform to obtain 0.99y (64%) of a nicotinic acid derivative. Recrystallization from ethanol gives colorless prismatic crystals. Melting point 17
8-180℃. Infrared absorption spectrum (KBr) 3600-2800cm-1 (0H) - 1700cm-1 (ester) Nuclear magnetic resonance spectrum (δ: CDCl3) 1.38 (C
H3? , singlet) 7.1-7.6 (phenyl, bright, multiplet) 8.46 (C
2-HllHl singlet) Elemental analysis: Cl5Hl5NO3 Calculated value: Cl7O. O2; Hl5.88; Nl5.44
Experimental value: Cl69.86; Hl5.49: Nl5.43
Example 6 Process for producing ethyl 4-hydroxy-5,6-diphenylnicotinate.
実施例３で得られたエナミン体３．５ｙおよびジフェニ
ルエーテル２５ｍ１の混合物を油浴中２６５〜２７０℃
にて５紛加熱、攪拌。A mixture of 3.5y of the enamine compound obtained in Example 3 and 25ml of diphenyl ether was heated at 265-270°C in an oil bath.
Heat and stir the powder.
反応終了後実施例５と同様の処理を得ない、エタノール
から再結晶し無色プリズム晶の結晶としてニコチン酸誘
導体１．５９ｇ（５２％）を得る。融点２２５〜２２６
℃。赤外線吸収スペクトル（ＫＢｒ）１７００ｃ『１（
エステル）
核磁気共鳴スペクトル（δ：ＣＤＣｌ３）７．２０（フ
ェニル×２、１０Ｈ１一重線）８．９７（Ｃ２−Ｈｌｌ
Ｈｌ一重線）元素分析：Ｃ２Ｏｌｌｌ７ＮＯ３After completion of the reaction, the same treatment as in Example 5 was not performed, but the product was recrystallized from ethanol to obtain 1.59 g (52%) of a nicotinic acid derivative as colorless prismatic crystals. Melting point 225-226
℃. Infrared absorption spectrum (KBr) 1700c '1 (
ester) Nuclear magnetic resonance spectrum (δ: CDCl3) 7.20 (phenyl x 2, 10H1 singlet) 8.97 (C2-Hll
Hl singlet) elemental analysis: C2Olll7NO3
Claims (1)
ェニル基を、Ｒ＿３は低級アルキル基を表わす）で示さ
れるニコチン酸エステル類。[Claims] 1 Nicotinic acid esters represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 represent a lower alkyl group or a phenyl group, and R_3 represents a lower alkyl group) .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13848576A JPS6058754B2 (en) | 1976-11-19 | 1976-11-19 | Nicotinic acid esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13848576A JPS6058754B2 (en) | 1976-11-19 | 1976-11-19 | Nicotinic acid esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5363382A JPS5363382A (en) | 1978-06-06 |
| JPS6058754B2 true JPS6058754B2 (en) | 1985-12-21 |
Family
ID=15223180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13848576A Expired JPS6058754B2 (en) | 1976-11-19 | 1976-11-19 | Nicotinic acid esters |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6058754B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0298154U (en) * | 1989-01-20 | 1990-08-06 |
-
1976
- 1976-11-19 JP JP13848576A patent/JPS6058754B2/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0298154U (en) * | 1989-01-20 | 1990-08-06 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5363382A (en) | 1978-06-06 |
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