JPS5920668B2 - Process for producing quinazoline derivatives - Google Patents
Process for producing quinazoline derivativesInfo
- Publication number
- JPS5920668B2 JPS5920668B2 JP50119972A JP11997275A JPS5920668B2 JP S5920668 B2 JPS5920668 B2 JP S5920668B2 JP 50119972 A JP50119972 A JP 50119972A JP 11997275 A JP11997275 A JP 11997275A JP S5920668 B2 JPS5920668 B2 JP S5920668B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- group
- derivative
- formulas
- acid
- 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
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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
【発明の詳細な説明】
本発明は一般式
(但し、R1は低級アルキル基、R2は低級脂肪族アシ
ル基、Xは臭素原子または塩素原子を表わす。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (where R1 is a lower alkyl group, R2 is a lower aliphatic acyl group, and X is a bromine atom or a chlorine atom).
)で示される2−ハロメチル一3−フエニル一6−アミ
ノ−4(3H)−キナゾリノン誘導体の製法に関する。) A method for producing a 2-halomethyl-3-phenyl-6-amino-4(3H)-quinazolinone derivative.
本発明によれば、当該目的化合物〔1〕は下記反応式で
示される如くして合成することが出来る。According to the present invention, the target compound [1] can be synthesized as shown in the following reaction formula.
すなわち、一般式〔〕で示されるN−(2−アミノ−5
−ニトローベンズ)アニリド誘導体の5位ニトロ基を還
元して相当する2,5位ジアミノ体〔〕を製し、この化
合物〔〕とN一低級脂肪族アシル化剤を常法によつて反
応させて一般式〔〕で示されるベンズアニリド誘導体を
製し、ついでこれに一般式〔〕で示されるα−モノハロ
ゲノ酢酸のカルボキシル基における反応性誘導体を反応
させることにより製することが出来る。(但し、Rl,
R2およびXは前記と同一意味を表わし、Yは反応性残
基を表わす。That is, N-(2-amino-5
-Nitrobenz) anilide derivative, the 5-position nitro group is reduced to produce the corresponding 2,5-position diamino compound [], and this compound [] is reacted with an N-lower aliphatic acylating agent by a conventional method. It can be produced by preparing a benzanilide derivative represented by the general formula [], and then reacting it with a reactive derivative of the carboxyl group of α-monohalogenoacetic acid represented by the general formula []. (However, Rl,
R2 and X have the same meanings as above, and Y represents a reactive residue.
)以下、本発明方法を上記反応式に従つて詳細に説明す
る。) Hereinafter, the method of the present invention will be explained in detail according to the above reaction formula.
〔第一工程(〔〕→〔〕)〕
まず、一般式〔〕で示される出発原料たるN−(2−ア
ミノ−5−ニトローベンズ)−アニリド誘導体の好適な
例としては記号R1で示される低級アルキル基が例えば
メチル基、エチル基、プロピル基、イソプロピル基、ブ
チル基、イソブチル基、アミル基である化合物があげら
れ、これらのアルキル置換基はベンゼン環上の0,mま
たはp位のいずれの位置にあつてもよく、それぞれ対応
する目的化合物〔1〕に誘導することが出来る。[First step ([]→[])] First, as a preferable example of the starting material N-(2-amino-5-nitrobenz)-anilide derivative represented by the general formula [], a lower derivative represented by the symbol R1 is used. Examples include compounds in which the alkyl group is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, or amyl group, and these alkyl substituents can be substituted at any of the 0, m, or p positions on the benzene ring. They may be present in any position, and can be guided to the corresponding target compound [1].
上記原料化合物〔〕の5位二トロ基をアミノ基に還元す
る反応は、例えば鉄、亜鉛、錫等を用いる酸性もしくは
アルカリ性還元、あるいはパラジウム、白金、ラネーニ
ツケル等の接触還元用触媒を用いる接触還元により実施
することが出来るが、特に後者の接触還元反応によるの
が反応生成物〔〕を単離することなく次工程の反応に進
むことが出来るので好ましい。接触還元反応による場合
、常圧乃至加圧下に室温乃至加熱して反応を実施すると
よい。反応溶媒としては例えばメタノール、工タノール
、テトラヒドロフラン、ジオキサン、酢酸エチル等が好
適に使用出来る。〔第二工程(〔〕→〔〕)〕
かくして生成した化合物〔〕は空気酸化を受け易い化合
物であるため、この化合物〔〕は単離精製することなく
N一低級脂肪族アシル化剤と反応させるのが好ましい。The reaction of reducing the 5-position ditro group of the above raw material compound [ ] to an amino group is, for example, acidic or alkaline reduction using iron, zinc, tin, etc., or catalytic reduction using a catalytic reduction catalyst such as palladium, platinum, Raney nickel, etc. However, the latter catalytic reduction reaction is particularly preferred because it allows the reaction to proceed to the next step without isolating the reaction product. In the case of a catalytic reduction reaction, the reaction is preferably carried out at room temperature or under heating under normal pressure or increased pressure. As the reaction solvent, for example, methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, etc. can be suitably used. [Second step ([] → [])] Since the compound [] thus produced is a compound that is susceptible to air oxidation, this compound [] is reacted with the N-lower aliphatic acylating agent without isolation and purification. It is preferable to let
N一低級脂肪族アシル化剤としては、例えばギ酸、酢酸
、プロピオン酸、酪酸、アクリル酸、クロトン酸、メタ
クリル酸の如き低級脂肪族カルボン酸のカルボキシル基
における反応性誘導体例えは無水物、酸ハライド(例え
ば酸プロミド、酸クロリド等)、混酸無水物(例えばエ
トキシカルボン酸との無水物等)、活性工スチル(例え
はN−ヒドロキシサクシンイミドエステル、4−ニトロ
フエニルエステル、シアノメチルエステル等)等のN−
アシル化剤を好適に用いることが出来る。かかるN一低
級脂肪族アシル化剤と化合物〔〕との反応において、N
一低級脂肪族アシル化剤に酸無水物、活性エステル等を
使用する場合、反応は適当な溶媒中脱酸剤の存在下もし
くは非存在下に実施するとよく、この場合化合物〔〕に
対して該アシル化剤を当モル乃至やや過剰に作用させる
のが好ましい。Examples of N-lower aliphatic acylating agents include reactive derivatives at the carboxyl group of lower aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, acrylic acid, crotonic acid, and methacrylic acid, such as anhydrides and acid halides. (e.g. acid bromides, acid chlorides, etc.), mixed acid anhydrides (e.g. anhydrides with ethoxycarboxylic acids, etc.), activated stills (e.g. N-hydroxysuccinimide esters, 4-nitrophenyl esters, cyanomethyl esters, etc.) etc. N-
Acylating agents can be suitably used. In the reaction between such N-lower aliphatic acylating agent and compound [], N
When using an acid anhydride, active ester, etc. as a mono-lower aliphatic acylating agent, the reaction is preferably carried out in an appropriate solvent in the presence or absence of an acid deoxidizing agent. It is preferable to use the acylating agent in equimolar to slightly excessive amounts.
またN一低級脂肪族アシル化剤に酸ハライド、混酸無水
物等を使用する場合は反応は適当な溶媒中脱酸剤の存在
下に上記と同様に化合物〔〕に対して該アシル化剤を当
モルもしくはやや過剰に作用させて実施するのが好まし
い。脱酸剤としては例えば炭酸カリウム、炭酸ナトリウ
ムピリジン、トリエチルアミン等を好適に使用すること
が出来る。いずれの場合にも反応は−1『C〜室温付近
にて好適に進行し、反応溶媒としては上記第一工程の反
応で使用したものと同様のものが好適に使用出来る。〔
第三工程(〔〕+〔〕→〔1))〕
かくして化合物〔〕の5位アミノ基のみが選択的に低級
脂肪族アシル化された化合物〔〕が得られる。In addition, when an acid halide, mixed acid anhydride, etc. is used as the N-lower aliphatic acylating agent, the reaction is carried out by applying the acylating agent to the compound [] in the presence of a deoxidizing agent in an appropriate solvent. It is preferable to use the same molar amount or a slight excess amount. As the deoxidizing agent, for example, potassium carbonate, sodium carbonate pyridine, triethylamine, etc. can be suitably used. In either case, the reaction proceeds suitably at -1'C to around room temperature, and the same reaction solvent as that used in the reaction in the first step can be suitably used. [
Third step ([]+[]→[1))] Thus, a compound [] in which only the 5-position amino group of the compound [] is selectively lower aliphatic acylated is obtained.
この化合物〔〕と原料化合物〔〕との反応は適当な溶媒
中で実施するのが好ましい。この場合化合物〔〕に対し
て原料化合物〔〕を当モル以上、とりわけ2〜5モル程
度作用させるのが好適である。ここで原料化合物〔〕た
るα−モノハロゲノ酢酸のカルボキシル基における反応
性誘導体としては、例えばα−ブロモ酢酸、α−クロロ
酢酸の酸無水物、酸ハライド等があげられる。いずれの
形態の原料化合物〔〕を使用しても反応は室温乃至加熱
下、とりわけ100〜150℃付近にて好適に進行し、
反応溶媒としては、例えば酢酸、プロピオン酸等を適宜
使用することが出来る。かくして生成した目的化合物〔
1〕は、例えは反応終了液を減圧下に濃縮し、得られる
残査につき抽出、再結晶等の公知精製操作により容易に
単離することが出来る。本発明の目的化合物〔1〕はい
ずれも新規化合物であり、中枢性筋弛緩剤2−フルオロ
メチル−3−フエニル一6−アミノ−4(3H)−キナ
ゾリノン誘導体の合成中間体として極めて有用な化合物
である。The reaction between this compound [] and the starting compound [] is preferably carried out in a suitable solvent. In this case, it is preferable that the raw material compound [] is allowed to act on the compound [] in an amount equal to or more than the same mole, particularly about 2 to 5 moles. Examples of reactive derivatives at the carboxyl group of α-monohalogenoacetic acid, which is the raw material compound, include acid anhydrides and acid halides of α-bromoacetic acid and α-chloroacetic acid. No matter which form of the raw material compound [] is used, the reaction proceeds suitably at room temperature or under heating, particularly around 100 to 150°C,
As the reaction solvent, for example, acetic acid, propionic acid, etc. can be used as appropriate. The target compound thus produced [
1] can be easily isolated by, for example, concentrating the reaction-completed liquid under reduced pressure and using the resulting residue by known purification operations such as extraction and recrystallization. The object compounds [1] of the present invention are all new compounds, and are extremely useful as intermediates for the synthesis of central muscle relaxant 2-fluoromethyl-3-phenyl-6-amino-4(3H)-quinazolinone derivatives. It is.
例えば本目的化合物〔1〕の一つである2−クロロ(ま
たはブロモ)メチル−3−(0−トリル)−6−アセタ
ミド−4(3H)−キナゾリノンにフツ化アルカリ金属
を作用させて2位クロロ(またはブロモ)メチル基をフ
ルオロメチル基に変えたのち、アセタミド基を常法に従
つてアミノ基に変換させることによりマイナ一・トラン
キライザ一作用を併有する中枢性筋弛緩薬2−フルオロ
メチル−3−(0−トリル)−6−アミノ−4(3H)
−キナゾリノンに誘導することが出来る。実施例 1
2−アミノ−5−ニトローベンズ一0−トルイジド54
,4f1および5%パラジウム炭素6f1をメタノール
1.11にけん濁し、水素圧501bにて50℃に加温
しながら3時間しんとうする。For example, 2-chloro(or bromo)methyl-3-(0-tolyl)-6-acetamido-4(3H)-quinazolinone, which is one of the target compounds [1], is reacted with an alkali metal fluoride to 2-Fluoromethyl, a central muscle relaxant that has both minor and tranquilizer actions, is produced by converting the chloro (or bromo) methyl group to a fluoromethyl group and then converting the acetamide group to an amino group using a conventional method. -3-(0-tolyl)-6-amino-4(3H)
-Can be derived from quinazolinone. Example 1 2-Amino-5-nitrobenz-10-toluidide 54
, 4f1 and 5% palladium on carbon 6f1 were suspended in 1.11 ml of methanol and stirred for 3 hours while heating to 50° C. under hydrogen pressure 501b.
冷後触媒を口去し、口液をO〜5℃に冷却しながら無水
酢酸20.49を含むベンゼン500me溶液を3時間
を要して加える。室温にて1時間かくはんしたのち溶媒
を減圧留去する。得られる残査にイソプロパノールを加
えて結晶を口取し、乾燥することにより、無色結晶とし
て2−アミノ−5−アセタミドーベンズ一0−トルイジ
ド49.09を得る。収率86.4%。本品48.5f
!を酢酸1.71にけん濁し、15℃にてかくはん下に
クロロアセチルクロリド98.09を2時間を要して滴
下する。After cooling, the catalyst is removed, and a benzene 500me solution containing 20.49% of acetic anhydride is added over 3 hours while cooling the solution to 0 to 5°C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Isopropanol is added to the resulting residue, and the crystals are taken and dried to obtain 49.09 g of 2-amino-5-acetamidobenz-10-toluidide as colorless crystals. Yield 86.4%. This product 48.5f
! was suspended in 1.71 g of acetic acid, and while stirring at 15° C., 98.0 g of chloroacetyl chloride was added dropwise over 2 hours.
同温度にて1.5時間かくはんしたのち0.5時間還流
する。還流後反応液を水で冷却し、ついで酢酸を減圧留
去する。得られる残査をクロロホルム1.2!にて抽出
する。この抽出液を水洗し、乾燥したのち濃縮する。得
られる残査にイソプロパノールを加えて結晶し、口取す
る。この結晶をメタノールより再結晶することにより、
無色結晶として2−クロロメチル−3−(0−トリル)
−6−アセタミド−4(3H)−キナゾリノン43.3
gを得る。収率74.0%。参考例2−クロロメチル−
3−(0−トリル)−6ーアセタミド−4(3H)−キ
ナゾリノン17.19および無水フツ化カリウム14.
5f!をジエチレングライコール25dに加え、160
℃にて15分間かくはんする。The mixture was stirred at the same temperature for 1.5 hours, and then refluxed for 0.5 hours. After refluxing, the reaction solution was cooled with water, and then acetic acid was distilled off under reduced pressure. The resulting residue was mixed with chloroform 1.2! Extract with This extract is washed with water, dried, and concentrated. Add isopropanol to the resulting residue to crystallize it, and take it by mouth. By recrystallizing this crystal from methanol,
2-chloromethyl-3-(0-tolyl) as colorless crystals
-6-acetamido-4(3H)-quinazolinone 43.3
get g. Yield 74.0%. Reference example 2-Chloromethyl-
3-(0-tolyl)-6-acetamido-4(3H)-quinazolinone 17.19 and anhydrous potassium fluoride 14.
5f! was added to 25d of diethylene glycol, and 160
Stir for 15 minutes at ℃.
Claims (1)
アシル基を表わす。 )で示されるベンズアニリド誘導体と一般式X−CH_
2−COOH (但し、Xは臭素原子または塩素原子を表わす。 で示されるα−モノハロゲノ酢酸のカルボキシル基にお
ける反応性誘導体とを反応させることを特徴とする一般
式▲数式、化学式、表等があります▼ (但し、R^1、R^2およびXは前記と同一意味を表
わす。 )で示される2−ハロメチル−3−フエニル−4(3H
)−キナゾリノン誘導体の製法。 2 一般式 ▲数式、化学式、表等があります▼ (但し、R^1は低級アルキル基を表わす。 )で示されるN−(2−アミノ−5−ニトロ−ベンズ)
−アニリド誘導体の5位ニトロ基を還元して相当する2
,5位ジアミノ体を製し、この化合物とN−低級脂肪族
アシル化剤を常法に従つて反応させて一般式▲数式、化
学式、表等があります▼ (但し、R^1は前記と同一意味を表わし、R^2は低
級脂肪族アシル基を表わす。 )で示されるベンズアニリド誘導体を製し、ついでこれ
と一般式X−CH_2−COOH (但し、Xは臭素原子または塩素原子を表わす。 )で示されるα−モノハロゲノ酢酸のカルボキシル基に
おける反応性誘導体とを反応させることを特徴とする一
般式▲数式、化学式、表等があります▼ (但し、R^1、R^2およびXは前記と同一意味を表
わす。 )で示される2−ハロメチル−3−フエニル−4(3H
)−キナゾリノン誘導体の製法。[Claims] 1 Benzanilide derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (where R^1 represents a lower alkyl group and R^2 represents a lower aliphatic acyl group) and general Formula X-CH_
2-COOH (where X represents a bromine atom or a chlorine atom) A general formula characterized by reacting with a reactive derivative of the carboxyl group of α-monohalogenoacetic acid ▲There are mathematical formulas, chemical formulas, tables, etc. 2-halomethyl-3-phenyl-4 (3H
)-Production method of quinazolinone derivative. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 represents a lower alkyl group.) N-(2-amino-5-nitro-benz)
-Reducing the 5-position nitro group of the anilide derivative to obtain the corresponding 2
, a diamino compound at the 5-position is prepared, and this compound is reacted with an N-lower aliphatic acylating agent according to a conventional method to obtain the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is the same as above. A benzanilide derivative represented by the formula X-CH_2-COOH (wherein, X represents a bromine atom or a chlorine atom) is prepared. ) is a general formula characterized by reacting with a reactive derivative in the carboxyl group of α-monohalogenoacetic acid ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1, R^2 and 2-halomethyl-3-phenyl-4 (3H
)-Production method of quinazolinone derivative.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50119972A JPS5920668B2 (en) | 1975-10-03 | 1975-10-03 | Process for producing quinazoline derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50119972A JPS5920668B2 (en) | 1975-10-03 | 1975-10-03 | Process for producing quinazoline derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5242888A JPS5242888A (en) | 1977-04-04 |
JPS5920668B2 true JPS5920668B2 (en) | 1984-05-15 |
Family
ID=14774744
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP50119972A Expired JPS5920668B2 (en) | 1975-10-03 | 1975-10-03 | Process for producing quinazoline derivatives |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5920668B2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080255161A1 (en) * | 2007-04-11 | 2008-10-16 | Dmitry Koltun | 3-HYDROQUINAZOLIN-4-ONE DERIVATIVES FOR USE AS STEAROYL CoA DESATURASE INHIBITORS |
CN103613549B (en) * | 2013-10-11 | 2016-04-20 | 浙江工业大学 | A kind of preparation method of afloqualone |
-
1975
- 1975-10-03 JP JP50119972A patent/JPS5920668B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPS5242888A (en) | 1977-04-04 |
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