JP2784203B2 - Method for producing 6-fluoro-4-chromanone-2-carboxylic acid - Google Patents
Method for producing 6-fluoro-4-chromanone-2-carboxylic acidInfo
- Publication number
- JP2784203B2 JP2784203B2 JP1039294A JP3929489A JP2784203B2 JP 2784203 B2 JP2784203 B2 JP 2784203B2 JP 1039294 A JP1039294 A JP 1039294A JP 3929489 A JP3929489 A JP 3929489A JP 2784203 B2 JP2784203 B2 JP 2784203B2
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- chromanone
- fluoro
- reaction
- producing
- 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 - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は６−フルオロ−４−クロマノン−２−カルボ
ン酸の製造法に関するものである。Description: TECHNICAL FIELD The present invention relates to a method for producing 6-fluoro-4-chromanone-2-carboxylic acid.
従来の技術 ６−フルオロ−４−クロマノン−２−カルボン酸はア
ルドースリダクターゼ阻害作用を有し、糖尿病合併症の
治療剤として有用な６−フルオロ−2,3−ジヒドロ２′,
5′−ジオキソースピロ（4H−１−ベンゾピラン−4,4′
−イミダゾリジン）−２−カルボン酸誘導体（III）
（特願昭61−199924） 製造の為の中間体として有用である。BACKGROUND ART 6-Fluoro-4-chromanone-2-carboxylic acid has an aldose reductase inhibitory action and is useful as a therapeutic agent for diabetic complications.
5'-dioxosepyro (4H-1-benzopyran-4,4 '
-Imidazolidine) -2-carboxylic acid derivative (III)
(Japanese Patent Application No. 61-199924) Useful as an intermediate for production.
４−クロマノン−２−カルボン酸誘導体の製造法につ
いては既にいくつかの方法が知られている。例えば、特
開昭61−200991公報によれば、４−クロマノン誘導体を
クロモン誘導体とした後、トリメチルシリルシアニドを
作用させてシアノ基を導入し、濃塩酸で加水分解させる
ことにより製造される。一方、J.Med.Chem.14,758（197
1）に記載の方法によれば、４−クロロフェノールとα
−ブロモ−γ−ブチロラクトンをWilliamson型の反応に
付し、ついで三酸化クロムによりラクトン環を酸化的に
開裂させてジカルボン酸とし、最後に濃硫酸を用いて閉
環させることにより製造される。更に、特開昭63−2503
73公報によれば、Ｐ−フルオロアニソールと無水マレイ
ン酸のFriedel−Craftsアシル化反応と、それに続く炭
素水素ナトリウムを塩基とした分子内マイケル反応によ
り製造される。Several methods have already been known for producing 4-chromanone-2-carboxylic acid derivatives. For example, according to JP-A-61-200991, the compound is produced by converting a 4-chromanone derivative into a chromone derivative, introducing a cyano group by the action of trimethylsilyl cyanide, and hydrolyzing with concentrated hydrochloric acid. On the other hand, J. Med. Chem. 14 , 758 (197
According to the method described in 1), 4-chlorophenol and α
-Bromo-γ-butyrolactone is prepared by subjecting it to a Williamson-type reaction, followed by oxidative cleavage of the lactone ring with chromium trioxide to form a dicarboxylic acid, and finally ring closure using concentrated sulfuric acid. Further, JP-A-63-2503
According to the 73 publication, it is produced by a Friedel-Crafts acylation reaction of P-fluoroanisole with maleic anhydride, followed by an intramolecular Michael reaction using sodium hydrogencarbonate as a base.
なお４−クロマノン誘導体はクロモン誘導体の接触還
元によっても製造することができる。例えば、J.Am.Che
m.Soc.,68,697（1947）によれば、エリオジエチオール
はルテオリンから次式に示すようにして製造される。The 4-chromanone derivative can also be produced by catalytic reduction of a chromone derivative. For example, J.Am.Che
According to m. Soc., 68 , 697 (1947), eriodiethiol is prepared from luteolin as shown in the following formula.
発明が解決しようとする課題 従来の技術例えば特開昭61−200991公報に記載の方法
では、工程中、高価なトリメチルシリルシアニドを使用
する点及び出発物質である４−クロマノン誘導体の製造
工程まで含めると工程数が非常に多くなる点で、又J.Me
d.Chemに記載の方法では、目的化合物の収率が低く、ま
た重金属を用いるという点で、更に特開昭63−250377公
報に記載の方法では、反応操作及び処理操作がやっかい
であるという点でそれぞれ工業的製造法として有利な方
法とは言い難い。 Problems to be Solved by the Invention In the prior art, for example, the method described in Japanese Patent Application Laid-Open No. 61-200991, the point that expensive trimethylsilyl cyanide is used in the process and the process of producing a 4-chromanone derivative as a starting material are included. And the number of processes becomes very large.
d. In the method described in Chem, the yield of the target compound is low, and in that heavy metals are used, and in the method described in JP-A-63-250377, the reaction operation and the treatment operation are troublesome. Therefore, it is hard to say that each is an advantageous method as an industrial production method.
また、クロモン誘導体の接触還元による４−クロマノ
ン誘導体の製造は一般的に、収率、反応の選択性が低
い。又上述のJ.Am.Chem.Sco.に記載の方法によれば、エ
リオジエチオールの収率は30％と低い。更に、HETEROCY
CLIC COMPOUNDS,Vol.2,P.256〜257（1951）によれば、
触媒として白金、パラジウム、あるいは亜クロム酸銅を
用いてクロモン誘導体を還元す ると、非選択的に反応が進行し、数種の還元生成物の１
つとして４−クロマノン誘導体が得られるにすぎない。In addition, production of a 4-chromanone derivative by catalytic reduction of a chromone derivative generally has low yield and low selectivity of the reaction. Also, according to the method described in J. Am. Chem. Sco., The yield of eriodiethiol is as low as 30%. Furthermore, HETEROCY
According to CLIC COMPOUNDS, Vol.2, P.256-257 (1951)
Reduction of chromone derivatives using platinum, palladium, or copper chromite as a catalyst Then, the reaction proceeds non-selectively, and one of several kinds of reduction products
For one thing, only a 4-chromanone derivative is obtained.
課題を解決するための手段 本発明者らは、上記問題点を解決し、経済性に優れた
６−フルオロ−４−クロマノン−２−カルボン酸の工業
的製造法を確立すべく研究をすすめた結果、６−フルオ
ロクロモン−２−カルボン酸を特定の有機溶媒中、金属
触媒の存在下に接触水素添加反応に付すことにより、高
収率で６−フルオロ−４−クロマノン−２−カルボン酸
が得られることを見い出し、本発明を完成させた。Means for Solving the Problems The present inventors have studied to solve the above-mentioned problems and to establish an economical industrial production method of 6-fluoro-4-chromanone-2-carboxylic acid. As a result, by subjecting 6-fluorochromone-2-carboxylic acid to a catalytic hydrogenation reaction in a specific organic solvent in the presence of a metal catalyst, 6-fluoro-4-chromanone-2-carboxylic acid can be obtained in high yield. The inventors have found out that the present invention has been completed.
即ち、本発明は式（Ｉ） で示される化合物をエーテル、石油エーテル、メタノー
ル、エタノール、イソプロピルアルコール及び酢酸エチ
ルから選ばれる一種又はそれ以上の溶媒中、金属触媒の
存在下に接触水素添加反応させることを特徴とする式
（II） で示される化合物の製造法を提供する。That is, the present invention provides a compound of the formula (I) Wherein the compound represented by the formula (II) is subjected to a catalytic hydrogenation reaction in one or more solvents selected from ether, petroleum ether, methanol, ethanol, isopropyl alcohol and ethyl acetate in the presence of a metal catalyst. And a process for producing the compound represented by the formula:
以下に本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
６−フルオロクロモン−２−カルボン酸の６−フルオ
ロ−４−クロマノン−２−カルボン酸への接触水素添加
反応は有利には次のようにして行なわれる。The catalytic hydrogenation reaction of 6-fluorochromone-2-carboxylic acid to 6-fluoro-4-chromanone-2-carboxylic acid is advantageously carried out as follows.
溶媒は、エーテル、石油エーテル、メタノール、エタ
ノール、イソプロピルアルコール及び酢酸エチルから選
ばれる１種又はそれ以上を用いるが、好ましくはエタノ
ール、イソプロピルアルコールを用いる。その使用量は
６−フルオロクロモン−２−カルボン酸（Ｉ）に対して
通常５〜60倍（重量比）である。使用しうる金属触媒と
しては通常アルケンをアルカンに接触還元する際に用い
られる触媒例えば白金、パラジウム、ニッケル、ルテニ
ウム、ロジウム、鉄、コバルト等の金属又はその化合物
あるいはそれらをカーボン、アルミナ、硫酸バリウム、
炭酸バリウム、炭酸カルシウム、炭酸ストロンチウム、
絹、ケイソウ土等に担持させたものを用いることができ
る。その具体例としてはラネーニッケル、パラジウム−
カーボン、パラジウム−アルミナ、パラジウム−硫酸バ
リウム、パラジウム−炭酸バリウム、パラジウム−ブラ
ック、ロジウム−カーボン、ルテニウム−カーボン、白
金−カーボン、白金−ブラック、酸化白金等を挙げるこ
とができるが、好ましくはパラジウム−アルミナ、パラ
ジウム−硫酸バリウム、白金−カーボンである。触媒の
使用量は通常金属換算で0.005〜0.05mol％であるが、特
にこれに限定されるものではない。又反応温度は使用す
る溶媒、触媒により異なるが、通常は０〜100℃であ
る。反応は水素雰囲気下で行なわれるが、圧力の制限は
特にない。通常は0.1〜20気圧で行われるが、0.1〜10気
圧でも反応は容易に進行する。反応終了後は過により
触媒を取り除き、溶媒を留去すれば目的化合物である６
−フルオロ−４−クロマノン−２−カルボン酸（II）を
得ることができる。回収された触媒は再利用することも
可能である。本発明の製法で得られる式（II）の化合物
は十分な純度を有するものであるがさらに純度を高めた
い時は例えば再結晶法によって精製することが出来る。
式（II）の化合物の純度は液体クロマトグラフィーによ
って容易に測定出来る。As the solvent, one or more selected from ether, petroleum ether, methanol, ethanol, isopropyl alcohol and ethyl acetate is used, and preferably, ethanol and isopropyl alcohol are used. The used amount is usually 5 to 60 times (weight ratio) with respect to 6-fluorochromone-2-carboxylic acid (I). As the metal catalyst that can be used, a catalyst usually used for catalytic reduction of an alkene to an alkane, for example, a metal such as platinum, palladium, nickel, ruthenium, rhodium, iron, cobalt or a compound thereof or carbon, alumina, barium sulfate,
Barium carbonate, calcium carbonate, strontium carbonate,
What carried on silk, diatomaceous earth, etc. can be used. Specific examples thereof include Raney nickel and palladium-
Carbon, palladium-alumina, palladium-barium sulfate, palladium-barium carbonate, palladium-black, rhodium-carbon, ruthenium-carbon, platinum-carbon, platinum-black, platinum oxide, etc., but preferably palladium- Alumina, palladium-barium sulfate, platinum-carbon. The amount of the catalyst used is usually 0.005 to 0.05 mol% in terms of metal, but is not particularly limited thereto. The reaction temperature varies depending on the solvent and catalyst used, but is usually from 0 to 100 ° C. The reaction is carried out in a hydrogen atmosphere, but there is no particular restriction on the pressure. Usually, the reaction is carried out at 0.1 to 20 atm, but the reaction easily proceeds even at 0.1 to 10 atm. After completion of the reaction, the catalyst is removed by filtration, and the solvent is distilled off.
-Fluoro-4-chromanone-2-carboxylic acid (II) can be obtained. The recovered catalyst can be reused. The compound of the formula (II) obtained by the production method of the present invention has a sufficient purity, but when it is desired to further increase the purity, it can be purified, for example, by a recrystallization method.
The purity of the compound of formula (II) can be easily determined by liquid chromatography.
出発原料である６−フルオロクロモン−２−カルボン
酸は塩基の存在下で５−フルオロ−２−ヒドロキシアセ
トフェノンとシュウ酸ジエステルを縮合させ次いで酸で
閉環させることにより製造される。The starting material, 6-fluorochromone-2-carboxylic acid, is produced by condensing 5-fluoro-2-hydroxyacetophenone and oxalic acid diester in the presence of a base, followed by ring closure with an acid.
実施例 以下に実施例により本発明を具体的に説明する。Examples Hereinafter, the present invention will be described specifically with reference to examples.
６−フルオロクロモン−２−カルボン酸の製法 金属ナトリウム25gをエタノール500mlに加えて溶解
し、これにしゅう酸ジエチル66.3gと５−フルオロ−２
−ヒドロキシアセトフェノン70gを加え、１時間還流し
た。冷却後、エタノールを減圧下に留去し、残留物に2N
−塩酸水溶液500ml加え、塩化メチレンで抽出した。塩
化メチレン層を無水硫酸マグネシウムで乾燥後、塩化メ
チレンを留去し、残留物に酢酸230mlと濃塩酸230mlを加
え1.5時間還流した。冷却後、析出物を取し、水洗
い、乾燥することにより６−フルオロクロモン−２−カ
ルボン酸81gを得た（収率86％）。液体クロマトグラフ
ィーによる純度は99％であった。Method for producing 6-fluorochromone-2-carboxylic acid 25 g of metallic sodium was added to and dissolved in 500 ml of ethanol, and 66.3 g of diethyl oxalate and 5-fluoro-2 were added.
-70 g of hydroxyacetophenone was added and the mixture was refluxed for 1 hour. After cooling, the ethanol was distilled off under reduced pressure.
-500 ml of hydrochloric acid aqueous solution was added, and extracted with methylene chloride. After the methylene chloride layer was dried over anhydrous magnesium sulfate, methylene chloride was distilled off, and 230 ml of acetic acid and 230 ml of concentrated hydrochloric acid were added to the residue, and the mixture was refluxed for 1.5 hours. After cooling, the precipitate was collected, washed with water and dried to obtain 81 g of 6-fluorochromone-2-carboxylic acid (yield 86%). The purity by liquid chromatography was 99%.
融点、252.0〜253.0℃（分解） 実施例1. ６−フルオロクロモン−２−カルボン酸5.0gをエタノ
ール250mlに溶解させ、これに５％白金−カーボン0.9g
を加えた。反応は室温下、水素圧を７気圧にして開始
し、水素の吸収が止まるまで行なった。反応終了後、反
応液を過して触媒を除き、減圧下でエタノールを留去
させることにより６−フルオロ−４−クロマノン−２−
カルボン酸4.5gを得た（収率89％）。このものの液体ク
ロマトグラフィーによる純度は96％であった。Melting point, 252.0-253.0 ° C (decomposition) Example 1. 5.0 g of 6-fluorochromone-2-carboxylic acid was dissolved in 250 ml of ethanol, and 0.9 g of 5% platinum-carbon was added thereto.
Was added. The reaction was started at room temperature with a hydrogen pressure of 7 atm until the absorption of hydrogen ceased. After completion of the reaction, the reaction solution was passed to remove the catalyst, and ethanol was distilled off under reduced pressure to give 6-fluoro-4-chromanone-2-.
4.5 g of carboxylic acid was obtained (89% yield). Its purity by liquid chromatography was 96%.
融点 162.5〜163.5℃ IR（KBr）2400〜3500（br）,1755（ｓ）,1655（ｓ）,
1620（ｓ）,1490（ｓ）cm-1 1H−NMR（DMSO−d6）δ3.02（d,1H）,3.05（d,1H）,
5.31（dd,1H）,7.0−7.8（m,3H） 元素分析 C10H7FO4としての 計算値 C:57.15％,H:3.36％ 実測値 C:56.99％,H:3.36％ 実施例２ 溶媒としてイソプロピルアルコール250mlを用いた他
は実施例１と同様に反応させた。反応液を過し、溶媒
を減圧下で留去させることにより、６−フルオロ−４−
クロマノン−２−カルボン酸4.3gを得た（85％）。液体
クロマトグラフィーによる純度92％であった。Melting point 162.5 ~ 163.5 ℃ IR (KBr) 2400 ~ 3500 (br), 1755 (s), 1655 (s),
1620 (s), 1490 (s ) cm -1 1 H-NMR (DMSO-d 6) δ3.02 (d, 1H), 3.05 (d, 1H),
5.31 (dd, 1H), 7.0-7.8 (m, 3H) calculated for elemental analysis C 10 H 7 FO 4 C: 57.15%, H: 3.36% Found C: 56.99%, H: 3.36 % Example 2 The reaction was carried out in the same manner as in Example 1 except that 250 ml of isopropyl alcohol was used as a solvent. The reaction solution was passed, and the solvent was distilled off under reduced pressure to give 6-fluoro-4-.
4.3 g of chromanone-2-carboxylic acid were obtained (85%). The purity by liquid chromatography was 92%.
融点 162.0−163.0℃ 実施例３〜８ 実施例１に準じて種々の反応条件下で接触水素添加反
応を行なった。結果を表にして示す。なお、各実施例に
おいて生成物の物性値は実施例１で得た標品と一致し
た。Melting point: 162.0-163.0 ° C Examples 3-8 A catalytic hydrogenation reaction was carried out according to Example 1 under various reaction conditions. The results are tabulated. In each of the examples, the physical properties of the product were the same as those of the sample obtained in Example 1.
発明の効果 接触還元法により高選択的にかつ高収率で６−フルオ
ロクロモン−２−カルボン酸から６−フルオロ−４−ク
ロマノン−２−カルボン酸を得る方法が確立した。 Effects of the Invention A method for obtaining 6-fluoro-4-chromanone-2-carboxylic acid from 6-fluorochromone-2-carboxylic acid with high selectivity and high yield by a catalytic reduction method has been established.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ｃ０７Ｂ 61/00 ３００ Ｃ０７Ｂ 61/00 ３００ ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code FI C07B 61/00 300 C07B 61/00 300
Claims (1)
ル、エタノール、イソプルピルアルコール及び酢酸エチ
ルから選ばれる１種又はそれ以上の溶媒中、金属触媒の
存在下に接触水素添加反応させることを特徴とする式
（II） で示される化合物の製造法。(1) Formula (I) A catalytic hydrogenation reaction of a compound represented by the formula (I) in one or more solvents selected from ether, petroleum ether, methanol, ethanol, isopropyl alcohol and ethyl acetate in the presence of a metal catalyst. (II) A method for producing a compound represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1039294A JP2784203B2 (en) | 1989-02-21 | 1989-02-21 | Method for producing 6-fluoro-4-chromanone-2-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1039294A JP2784203B2 (en) | 1989-02-21 | 1989-02-21 | Method for producing 6-fluoro-4-chromanone-2-carboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02218674A JPH02218674A (en) | 1990-08-31 |
| JP2784203B2 true JP2784203B2 (en) | 1998-08-06 |
Family
ID=12549123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1039294A Expired - Fee Related JP2784203B2 (en) | 1989-02-21 | 1989-02-21 | Method for producing 6-fluoro-4-chromanone-2-carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2784203B2 (en) |
-
1989
- 1989-02-21 JP JP1039294A patent/JP2784203B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02218674A (en) | 1990-08-31 |
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