JPH0232279B2 - JIHIDOROBENZOPIRANJIOORUNOSEIHO - Google Patents
JIHIDOROBENZOPIRANJIOORUNOSEIHOInfo
- Publication number
- JPH0232279B2 JPH0232279B2 JP13914082A JP13914082A JPH0232279B2 JP H0232279 B2 JPH0232279 B2 JP H0232279B2 JP 13914082 A JP13914082 A JP 13914082A JP 13914082 A JP13914082 A JP 13914082A JP H0232279 B2 JPH0232279 B2 JP H0232279B2
- Authority
- JP
- Japan
- Prior art keywords
- benzopyran
- dihydro
- methoxy
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Landscapes
- Pyrane Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、次式（）で表わされる３，８−ジ
ヒドロキシ−３，４−ジヒドロ−2H−１−ベン
ゾピランの新規な製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3,8-dihydroxy-3,4-dihydro-2H-1-benzopyran represented by the following formula ().
式の化合物（以下DDBと略称する）は、循
環器用薬、抗アレルギー用薬等の製造用中間体と
して公知の化合物である。 The compound of the formula (hereinafter abbreviated as DDB) is a compound known as an intermediate for the production of cardiovascular drugs, antiallergic drugs, etc.
従来ジヒドロ−2H−１−ベンゾピランは、ク
ロモンを環元する方法又はフエノールを原料とし
て閉環する方法により製造されている。しかし３
位に水酸基が導入された３，４−ジヒドロ−2H
−１−ベンゾピラン−３−オールの製法について
は、ほとんど報告されていない。 Conventionally, dihydro-2H-1-benzopyran has been produced by a method of ring-forming chromone or a method of ring-closing using phenol as a raw material. But 3
3,4-dihydro-2H with a hydroxyl group introduced at the position
There are almost no reports on the method for producing -1-benzopyran-3-ol.
本発明者らは、医薬品原料として有用な式の
DDBの製法について種々検討した結果、ｏ−バ
ニリン（）を出発原料とし、これに閉環反応を
適用して得られる８−メトキシ−３，４−ジヒド
ロ−2H−１−ベンゾピラン−３−オン（）を
還元し、次いで脱メチル化することにより有利に
DDBを製造しうることを見出した。これらの反
応は次式により示される。 The present inventors have developed a formula useful as a pharmaceutical raw material.
As a result of various studies on the production method of DDB, we found that 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-one () obtained by applying a ring-closing reaction to o-vanillin () as a starting material. advantageously by reducing and then demethylating
We discovered that DDB can be manufactured. These reactions are shown by the following formula.
式の３−ケト体を還元して式の３−オール
体を得るためには、例えば溶媒中で式の化合物
を還元試薬、例えば水素化硼素ナトリウム、水素
化リチウムアルミニウム等の存在下に撹拌する。 In order to obtain the 3-ol form of the formula by reducing the 3-keto form of the formula, for example, the compound of the formula is stirred in a solvent in the presence of a reducing reagent such as sodium borohydride, lithium aluminum hydride, etc. .
こうして得られた式の化合物の脱メチル化反
応は、例えば式の化合物を臭化水素酸水溶液中
で加熱撹拌することにより容易に進行し、目的の
DDBが得られる。 The demethylation reaction of the compound of formula thus obtained can easily proceed, for example, by heating and stirring the compound of formula in an aqueous solution of hydrobromic acid.
DDB is obtained.
式のｏ−バニリンを閉環反応させて式の化
合物を製造する方法としては種々の方法が可能で
ある。例えば下記の反応式で示す方法があげられ
る。式中のＲ及びR′は低級アルキル基好ましく
はエチル基である。 Various methods are possible for manufacturing the compound of the formula by subjecting o-vanillin of the formula to a ring-closing reaction. For example, the method shown in the following reaction formula can be mentioned. R and R' in the formula are lower alkyl groups, preferably ethyl groups.
これらの方法の各反応工程はいずれも既知であ
る。 Each reaction step of these methods is known.
本発明者らは化合物（）から化合物（）を
製造するためのこれらの方法について検討した結
果、ａ法（クルチウス転位）によれば、他の方法
すなわちｂ法（ロツセン転位）、ｃ法（チーマン
転位）、ｄ法（ホフマン反応）及びｅ法（デイツ
クマン縮合）に比較して高収率で目的の化合物
（）を製造できるので、ａ法が特に優れている
ことを見出した。これらの方法の個々の反応は既
知であり、常法により行うことができる。ａ法に
よる場合には、ｏ−バニリン（）にアクリロニ
トリルを反応させると閉環して３−シアノ−８−
メトキシ−2H−１−ベンゾピラン（）が得ら
れ、これを加水分解して相当するカルボン酸
（）となし、次いでこれをアジド化したのち加
水分解すると、式の化合物が得られる。 The present inventors investigated these methods for producing compound () from compound (), and found that method a (Curtius rearrangement) is different from other methods, namely method b (Lotsen rearrangement) and method c (Chieman rearrangement). It has been found that method a is particularly superior because it can produce the desired compound () in a higher yield than method d (rearrangement), method d (Hoffmann reaction), and method e (Deckmann condensation). The individual reactions in these methods are known and can be carried out by conventional methods. In the case of method a, when o-vanillin () is reacted with acrylonitrile, the ring is closed to form 3-cyano-8-
Methoxy-2H-1-benzopyran () is obtained, which is hydrolyzed to the corresponding carboxylic acid (), which is then azidated and then hydrolyzed to give the compound of formula.
実施例
Ａ ｏ−バリニン1.0Kgをジメチルホルムアミド
6.5に溶解し、撹拌下に水２中の水酸化ナ
トリウム304gの溶液を加える。これにアクリ
ロニトリル1.31を加え、浴温135〜140℃で
1.5時間撹拌下に還流する。次いで、アクリロ
ニトリル1.31とジメチルホルムアミド0.7
の混液を適下し、１時間反応させたのち、更に
アクリロニトリ0.87とジメチルホルムアミド
0.4の混液を滴下し、1.5時間撹拌下に還流す
る。Example A 1.0 kg of o-valinine was dissolved in dimethylformamide.
6.5 and add under stirring a solution of 304 g of sodium hydroxide in 2 parts of water. Add 1.31 of acrylonitrile to this, and at a bath temperature of 135 to 140℃.
Reflux under stirring for 1.5 hours. Then acrylonitrile 1.31 and dimethylformamide 0.7
After dropping a mixture of 0.87 and dimethylformamide and reacting for 1 hour, add acrylonitrile 0.87 and dimethylformamide.
0.4 of the mixture was added dropwise, and the mixture was refluxed with stirring for 1.5 hours.
冷却後、反応液を水30中に加え、酢酸エチ
ルで抽出する。抽出液を10％水酸化ナトリウム
及び飽和食塩水で洗浄したのち溶媒を留去す
る。得られた結晶を含む油状物を、120℃に加
熱し、これに撹拌下に水3.3中の水酸化ナト
リウム840gの溶液を滴下する。1.5時間撹拌還
流したのち冷却し、濃塩酸を加えてPH約2.5と
なし、析出する結晶を取する。水洗後、80〜
90℃で減圧乾燥すると、淡黄色結晶の８−メト
キシ−2H−１−ベンゾピラン−３−カルボン
酸が600g（収率44.3％）が得られる。 After cooling, the reaction solution was poured into 30 ml of water and extracted with ethyl acetate. After washing the extract with 10% sodium hydroxide and saturated brine, the solvent is distilled off. The crystal-laden oil obtained is heated to 120° C. and a solution of 840 g of sodium hydroxide in 3.3 parts of water is added dropwise to it while stirring. After stirring and refluxing for 1.5 hours, cool, add concentrated hydrochloric acid to adjust the pH to approximately 2.5, and collect the precipitated crystals. After washing with water, 80~
Drying under reduced pressure at 90°C yields 600 g (44.3% yield) of 8-methoxy-2H-1-benzopyran-3-carboxylic acid as pale yellow crystals.
Ｂ ８−メトキシ−2H−１−ベンゾピラン−３
−カルボン酸103.2gをアセトン360mlに懸濁し、
トリエチルアミン60.9gを加え、氷冷撹拌下に
内温を０〜５℃に保持しながらクロル炭酸エチ
ル65.2gを滴下する。20分間撹拌したのち、更
に氷冷撹拌下にアジ化ナトリウム39gの水溶液
を、内温２〜５℃で滴下する。2.5時間撹拌し
たのちベンゼンで抽出し、飽和食塩水で洗浄す
る。ベンゼン層に10％硫酸400mlを加え、加温
して撹拌したのち、外温90℃で７時間撹拌下に
還流する。反応終了後、10％硫酸及び飽和食塩
水で洗浄し、ベンゼンを留去すると、３，４−
ジヒドロ−８−メトキシ−2H−１−ベンゾピ
ラン−３−オンが75.4g（収率84.5％）が得られ
る。B 8-methoxy-2H-1-benzopyran-3
- Suspend 103.2 g of carboxylic acid in 360 ml of acetone,
60.9 g of triethylamine is added, and 65.2 g of ethyl chlorocarbonate is added dropwise while stirring and cooling with ice while maintaining the internal temperature at 0 to 5°C. After stirring for 20 minutes, an aqueous solution of 39 g of sodium azide was added dropwise at an internal temperature of 2 to 5°C while stirring and cooling with ice. After stirring for 2.5 hours, extract with benzene and wash with saturated brine. Add 400 ml of 10% sulfuric acid to the benzene layer, heat and stir, and then reflux with stirring at an external temperature of 90°C for 7 hours. After the reaction was completed, the benzene was distilled off after washing with 10% sulfuric acid and saturated saline, and 3,4-
75.4 g (yield 84.5%) of dihydro-8-methoxy-2H-1-benzopyran-3-one is obtained.
Ｃ 得られた化合物をメタノール300mlに溶解し、
水素化硼素ナトリウム10.2gを少量ずつ加え、
室温で30分間撹拌する。20％硫酸でPH４に調整
し、溶媒を留去して得られる残留物を酢酸エチ
ルで抽出し、水洗して乾燥したのち溶媒を留去
すると、褐色油状物が得られる。これにエーテ
ルを加えると、融点78〜81℃の結晶として、
３，４−ジヒドロ−３−ヒドロキシ−８−メト
キシ−2H−１−ベンゾピランが26.3g（収率34.5
％）が得られる。C. Dissolve the obtained compound in 300 ml of methanol,
Add 10.2g of sodium borohydride little by little,
Stir for 30 minutes at room temperature. The pH is adjusted to 4 with 20% sulfuric acid, the solvent is distilled off, the resulting residue is extracted with ethyl acetate, washed with water, dried, and the solvent is distilled off to obtain a brown oil. When ether is added to this, crystals with a melting point of 78-81℃ are formed.
26.3 g of 3,4-dihydro-3-hydroxy-8-methoxy-2H-1-benzopyran (yield: 34.5
%) is obtained.
Ｄ 得られた化合物230gを47％臭化水素酸1.2
に加え、120℃で撹拌する。２時間後、水酸化
ナトリウム水溶液で中和し、酢酸エチルで抽出
する。活性炭で処理したのち溶媒を留去して得
られる残留物にエーテルを加えると、融点124
〜126℃の結晶として、３，４−ジヒドロ−３，
８−ジヒドロキシ−2H−１−ベンゾピランが
197g（収率92.8％）が得られる。D 230g of the obtained compound was mixed with 47% hydrobromic acid 1.2
and stir at 120℃. After 2 hours, neutralize with aqueous sodium hydroxide solution and extract with ethyl acetate. When ether is added to the residue obtained by distilling off the solvent after treatment with activated carbon, the melting point is 124
3,4-dihydro-3, as crystals at ~126°C
8-dihydroxy-2H-1-benzopyran is
197 g (yield 92.8%) is obtained.
Claims (1)
−ベンゾピラン−３−オンを還元し、次いで脱メ
チル化することを特徴とする、３，８−ジヒドロ
キシ−３，４−ジヒドロ−2H−１−ベンゾピラ
ンの製法。 ２ ｏ−バニリンにアクリロニトリルを反応させ
て得られる３−シアノ−８−メトキシ−2H−１
−ベンゾピランを加水分解して８−メトキシ−
2H−１−ベンゾピラン−３−カルボン酸となし、
このカルボン酸をアジド化したのち酸加水分解す
ることにより得られる８−メトキシ−３，４−ジ
ヒドロ−2H−１−ベンゾピラン−３−オンを還
元し、次いで脱メチル化することを特徴とする、
３，８−ジヒドロキシ−３，４−ジヒドロ−2H
−１−ベンゾピランの製法。[Claims] 1 8-methoxy-3,4-dihydro-2H-1
- A method for producing 3,8-dihydroxy-3,4-dihydro-2H-1-benzopyran, which comprises reducing benzopyran-3-one and then demethylating it. 3-cyano-8-methoxy-2H-1 obtained by reacting 2 o-vanillin with acrylonitrile
-Hydrolyzing benzopyran to produce 8-methoxy-
2H-1-benzopyran-3-carboxylic acid and pear,
It is characterized by reducing 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-one obtained by azidating this carboxylic acid and then acid hydrolyzing it, and then demethylating it.
3,8-dihydroxy-3,4-dihydro-2H
-Production method of 1-benzopyran.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13914082A JPH0232279B2 (en) | 1982-08-12 | 1982-08-12 | JIHIDOROBENZOPIRANJIOORUNOSEIHO |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13914082A JPH0232279B2 (en) | 1982-08-12 | 1982-08-12 | JIHIDOROBENZOPIRANJIOORUNOSEIHO |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5929681A JPS5929681A (en) | 1984-02-16 |
| JPH0232279B2 true JPH0232279B2 (en) | 1990-07-19 |
Family
ID=15238476
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13914082A Expired - Lifetime JPH0232279B2 (en) | 1982-08-12 | 1982-08-12 | JIHIDOROBENZOPIRANJIOORUNOSEIHO |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0232279B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6034256A (en) | 1997-04-21 | 2000-03-07 | G.D. Searle & Co. | Substituted benzopyran derivatives for the treatment of inflammation |
| US6077850A (en) * | 1997-04-21 | 2000-06-20 | G.D. Searle & Co. | Substituted benzopyran analogs for the treatment of inflammation |
| TW200927740A (en) * | 2007-11-13 | 2009-07-01 | Bial Portela & Ca Sa | Process |
-
1982
- 1982-08-12 JP JP13914082A patent/JPH0232279B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5929681A (en) | 1984-02-16 |
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