JPH0358977A - Production of quinazolinone derivative - Google Patents
Production of quinazolinone derivativeInfo
- Publication number
- JPH0358977A JPH0358977A JP19636689A JP19636689A JPH0358977A JP H0358977 A JPH0358977 A JP H0358977A JP 19636689 A JP19636689 A JP 19636689A JP 19636689 A JP19636689 A JP 19636689A JP H0358977 A JPH0358977 A JP H0358977A
- Authority
- JP
- Japan
- Prior art keywords
- derivative
- formula
- reacting
- compound
- quinazolinone
- 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.)
- Pending
Links
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title claims description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims abstract description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- -1 Acyl anthranilic acid derivative Chemical class 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 12
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 abstract description 11
- 239000002253 acid Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 239000002249 anxiolytic agent Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 2
- AGBCIDSNZOGTSZ-UHFFFAOYSA-N 6-amino-2-(fluoromethyl)-3-phenylquinazolin-4-one Chemical class O=C1C2=CC(N)=CC=C2N=C(CF)N1C1=CC=CC=C1 AGBCIDSNZOGTSZ-UHFFFAOYSA-N 0.000 abstract 1
- 206010021118 Hypotonia Diseases 0.000 abstract 1
- 230000036640 muscle relaxation Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 150000001448 anilines Chemical class 0.000 description 7
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- MWYDCFDDIWTPGE-UHFFFAOYSA-N 2-[(2-chloroacetyl)amino]-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NC(=O)CCl MWYDCFDDIWTPGE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- OOXVMRVJKBCAND-UHFFFAOYSA-N 2-[(2-fluoroacetyl)amino]-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NC(=O)CF OOXVMRVJKBCAND-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- OFYMACOYOUBHNZ-UHFFFAOYSA-N 5-bromo-2-[(2-chloroacetyl)amino]benzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1NC(=O)CCl OFYMACOYOUBHNZ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- VSHTWPWTCXQLQN-UHFFFAOYSA-N n-butylaniline Chemical compound CCCCNC1=CC=CC=C1 VSHTWPWTCXQLQN-UHFFFAOYSA-N 0.000 description 1
- OXHJCNSXYDSOFN-UHFFFAOYSA-N n-hexylaniline Chemical compound CCCCCCNC1=CC=CC=C1 OXHJCNSXYDSOFN-UHFFFAOYSA-N 0.000 description 1
- FRCFWPVMFJMNDP-UHFFFAOYSA-N n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=CC=C1 FRCFWPVMFJMNDP-UHFFFAOYSA-N 0.000 description 1
- CDZOGLJOFWFVOZ-UHFFFAOYSA-N n-propylaniline Chemical compound CCCNC1=CC=CC=C1 CDZOGLJOFWFVOZ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、マイナートランキライザー作用や中枢性筋弛
緩作用等を有する２−フルオロメチル−３−（０−トリ
ル）−６−アミノ−４（３Ｈ）−キナゾリノン等の一般
式
（Ｒ，はアルキル基を表す。）で示されるキナゾリノン
系医薬の合成中間体であるキナゾリノン誘導体の製造方
法に関するものである。Detailed Description of the Invention [Industrial Field of Application] The present invention provides 2-fluoromethyl-3-(0-tolyl)-6-amino-4 (3H The present invention relates to a method for producing a quinazolinone derivative, which is a synthetic intermediate for a quinazolinone drug represented by the general formula (R represents an alkyl group) such as )-quinazolinone.
［従来の技術］
医薬として有用な、マイナートランキライザー作用や、
中枢性筋弛緩作用を有する前記−紋穴〔ａ〕で示される
２フルオロメチル−３−フェニル−６−アミノ−４（３
Ｈ）−キナゾリノン誘導体の合成中間体である（但し、
Ｙはアルキル基、ハロゲン、ニトロ基、アルキルアミノ
基、Ｘはハロゲン、Ｒはアルキル基を表す。）は、種々
の合成経路で製造されているか、その経路の一つとして
、−紋穴
（但し、Ｙ、Ｘ及びＲは前記と同じ。）で示されるアン
スラニル酸誘導体と無水酢酸とを反応させ、（但し、Ｙ
及びＸは前記と同じ。）で示されるベンゾオキサジノン
誘導体を得、これを
（但し、Ｒは前記と同じ。）で示されるアニリ誘導体と
反応さけ、前記−紋穴〔■〕で示されるキナゾリノン誘
導体を製造する方法がある。[Prior art] Minor tranquilizer action, which is useful as a medicine,
2-fluoromethyl-3-phenyl-6-amino-4 (3
H)-A synthetic intermediate for quinazolinone derivatives (however,
Y represents an alkyl group, halogen, nitro group, alkylamino group, X represents a halogen, and R represents an alkyl group. ) is produced by various synthetic routes, or one of the routes is to react an anthranilic acid derivative represented by -Momona (where Y, X and R are the same as above) with acetic anhydride. , (However, Y
and X are the same as above. ) There is a method of producing a quinazolinone derivative represented by the above symbol [■] by obtaining a benzoxazinone derivative represented by the formula and reacting it with an aniline derivative represented by the formula (where R is the same as above). .
ＩＩ
この製造方法では従来、化合物〔１）から化合物［［）
を合成する第１工程で、無水酢酸を化合物〔Ｉ〕に対し
て１５倍モル以上程度とかなり多量に使用して反応を行
い、得られた化合物（ＩＩ）を−旦単離し、ついで化合
物［１）を化合物（［［’ｌと反応させる第２工程が行
われている。II In this production method, conventionally, compound [1) is converted to compound [[]
In the first step of synthesizing the compound [I], acetic anhydride is used in a fairly large amount of about 15 times the molar amount or more relative to the compound [I], and the obtained compound (II) is first isolated, and then the compound [I] is isolated. A second step is carried out in which 1) is reacted with the compound ([['l).
第１工程で得られた化合物（ＩＩ）の単離方法としては
、その種類によって一概には言えないが、得られた化合
物（ＩＩ）を蒸留で分取し、更に再結晶をしたり、系か
ら結晶をが過したりする方法が採用される。The method for isolating compound (II) obtained in the first step cannot be generalized depending on the type, but it may be necessary to separate the obtained compound (II) by distillation and further recrystallize it, or to A method is adopted in which the crystals are passed through the glass.
［発明が解決しようとする課題］
しかし、かかる従来の技術では、ベンゾオキサジノン誘
導体ＣＩＩ）の単離が必要であることから、上述のよう
に蒸留、又はが過等の操作を行わねばならず、２段階の
反応を余儀無くされる。[Problems to be Solved by the Invention] However, in such conventional techniques, since it is necessary to isolate the benzoxazinone derivative CII), distillation or excessive operations must be performed as described above. , forcing a two-step reaction.
工業的な面から考えると２段階反応は１段階反応に比へ
ると不利であることは言うまでもないので、本発明者は
１段階での反応を試み、従来の前記方法を改良すること
を検討した。しかし、該反応をベンゾオキサジノン誘導
体（ＩＩ）を単離することなく１段で反応を行うと、多
量の副生成物が発生したりして目的物の収率や純度に好
ましくないことが明らかとなった。From an industrial standpoint, it goes without saying that a two-step reaction is disadvantageous compared to a one-step reaction, so the present inventor attempted a one-step reaction and considered improving the conventional method. did. However, it is clear that if the reaction is carried out in one step without isolating the benzoxazinone derivative (II), a large amount of by-products will be generated, which is unfavorable for the yield and purity of the target product. It became.
［課題を解決するための手段］
本発明者はその原因が使用する無水酢酸の重に関連する
との知見のもとに、更に鋭意研究を続けたところ、第１
工程で使用する無水酢酸の量を０，９〜１．２倍モルの
少虫に限定することにより、第２工程へ反応を進める際
にベンゾオキサジノン誘導体［ＩＴ〕を単離しなくても
、高品位の目的物が得られることを見出し、本発明を完
成するに至った。[Means for Solving the Problems] Based on the knowledge that the cause of the problem is related to the weight of the acetic anhydride used, the present inventor continued to conduct further research, and found that the first
By limiting the amount of acetic anhydride used in the step to 0.9 to 1.2 times the mole, it is possible to proceed to the second step without isolating the benzoxazinone derivative [IT]. It was discovered that a high-quality target product could be obtained, and the present invention was completed.
即ち、本発明は
「前記−紋穴（１）で示されるアシルアンスラニル酸誘
導体と、化合物（１）に対して０．９〜１．２倍モルの
無水酢酸とを反応させて、前記−紋穴〔■〕で示される
ベンゾオキサジノン誘導体を得、ついでこれを系から単
離することなく前記−紋穴［１１１）で示されるアニリ
ン誘導体と反応させることを特徴とする前記−紋穴［Ｉ
Ｖ）で示されるキナゾリノン誘導体の製造方法。］であ
る。That is, the present invention provides the method of "reacting the acylanthranilic acid derivative represented by the above-mentioned formula (1) with acetic anhydride in an amount of 0.9 to 1.2 times the mole of the compound (1), The above-mentioned -Momona [111] is characterized in that a benzoxazinone derivative shown by the above-mentioned -Momona [■] is obtained, and then it is reacted with the aniline derivative shown by the above-mentioned -Momona [111] without isolating it from the system. I
A method for producing a quinazolinone derivative represented by V). ].
本発明の特徴点は、生成したベンゾオキサジノン誘導体
（ｎ）を単離することなく第２工程を行うために、第１
工程で使用する無水酢酸の量を限定する点にある。これ
により、従来法よりも工程が簡略化され、しかも不純物
の生成や、多重のアニリン誘導体の使用等ら避けられる
ので、アシルアンスラニル酸誘導体〔１〕からキナゾリ
ノン誘導体〔■〕までの全収率も８０〜９０％と、従来
の方法と同等又はそれ以上である。The feature of the present invention is that in order to carry out the second step without isolating the generated benzoxazinone derivative (n),
The point is to limit the amount of acetic anhydride used in the process. This simplifies the process compared to the conventional method, and avoids the generation of impurities and the use of multiple aniline derivatives, resulting in a higher overall yield from the acylanthranilic acid derivative [1] to the quinazolinone derivative [■]. It is also 80 to 90%, which is equivalent to or higher than the conventional method.
上述の一般式〔１〕〜〔■〕において、置換基Ｙはアル
キル基、ハロゲン、ニトロ基、アルキルアミノ基を表し
、アルキル基としては、メチル基、エチル基、プロピル
基、ブチル基等の任意の炭素数のものが挙げられるが、
特に炭素数１〜４のものが好ましい。ハロゲンとしては
フッ素、塩素、臭素、ヨウ素等が挙げられる。アルキル
アミノ基としては、モノ及びジアルキルアミノ基が挙げ
られ、かかる置換基に含まれるアルキル基としては、メ
チル基、エチル基、プロピル基等の任意の炭素数のもの
でよく、特に炭素数１〜３のものが好ましい。In the above general formulas [1] to [■], the substituent Y represents an alkyl group, a halogen, a nitro group, an alkylamino group, and the alkyl group can be any arbitrary group such as a methyl group, an ethyl group, a propyl group, a butyl group, etc. Examples include those with a carbon number of
Particularly preferred are those having 1 to 4 carbon atoms. Examples of the halogen include fluorine, chlorine, bromine, and iodine. Examples of the alkylamino group include mono- and dialkylamino groups, and the alkyl group included in such a substituent may be one having any number of carbon atoms such as a methyl group, ethyl group, or propyl group, particularly one having 1 to 1 carbon atoms. 3 is preferred.
置換基Ｘはフッ素、塩素、臭素、ヨウ素等のハロゲンで
ある。Substituent X is a halogen such as fluorine, chlorine, bromine, or iodine.
置換基Ｒはアルキル基であり、メチル基、エチル基、プ
ロピル基、ブチル基等の任意の炭素数のものが挙げられ
、特に炭素数１〜４のものが好ましい。The substituent R is an alkyl group, and examples thereof include those having any number of carbon atoms such as methyl, ethyl, propyl, and butyl groups, and those having 1 to 4 carbon atoms are particularly preferred.
例えば出発物質であるアンスラニル酸誘導体（１）とし
ては、２−（Ｎ−フルオロアセチルアミノ）−５−二ト
ロ安息香酸、２−（Ｎ−クロロアセチルアミノ）−５−
ニトロ安息香酸、２−（Ｎ−ブロモアセチルアミノ）−
５−ニトロ安息香酸１．２− （Ｎ−ブロモアセチルア
ミノ）−５−メチル安息香酸、２−（Ｎ−ヨードアセチ
ルアミノ）−５−ヘキシル安息香酸、２−（Ｎ−フルオ
ロアセチルアミノ）−５−フルオロ安息香酸、２−（Ｎ
−クロロアセチルアミノ）−５−ブロモ安息香酸、２−
（Ｎ−ブロモアセチルアミノ）−５−メチルアミノ安息
香酸、２−（Ｎ−ヨードアセチルアミノ）−５−へキシ
ルアミノ安息香酸等が挙げられる。For example, the starting material anthranilic acid derivative (1) includes 2-(N-fluoroacetylamino)-5-nitrobenzoic acid, 2-(N-chloroacetylamino)-5-
Nitrobenzoic acid, 2-(N-bromoacetylamino)-
5-nitrobenzoic acid 1.2-(N-bromoacetylamino)-5-methylbenzoic acid, 2-(N-iodoacetylamino)-5-hexylbenzoic acid, 2-(N-fluoroacetylamino)-5 -Fluorobenzoic acid, 2-(N
-chloroacetylamino)-5-bromobenzoic acid, 2-
(N-bromoacetylamino)-5-methylaminobenzoic acid, 2-(N-iodoacetylamino)-5-hexylaminobenzoic acid, and the like.
又、アニリン誘導体［１１１）としては、例えばメチル
アニリン（トルイジン）、エチルアニリン、プロピルア
ニリン、イソプロピルアニリン、ブチルアニリン、Ｌｅ
ｒｔ−ブチルアニリン、ヘキシルアニリン等で、該アル
キル基がオルト位、メタ位、パラ位についたものが挙げ
られる。Further, as the aniline derivative [111), for example, methylaniline (toluidine), ethylaniline, propylaniline, isopropylaniline, butylaniline, Le
Examples include rt-butylaniline, hexylaniline, etc., in which the alkyl group is attached to the ortho, meta, or para positions.
本発明で特に有利に行える反応は、アンスラニル酸誘導
体〔１）として２−（Ｎ−フルオロアセチルアミノ）５
−ニトロ安息香酸、２−（Ｎ−クロロアセチルアミノ）
−５−二トロ安息香酸、２−（Ｎ−ブロモアセチルアミ
ノ）−５−ニトロ安息香酸、及びアニリン誘導体［■〕
として、２−メチル−アニリン（０−トルイジン）を用
いて２＝フルオロメヂル−３−（０−トリル）−６−ニ
トロ−４（３Ｈ）キナゾリノン、２−クロロメチル−３
−（０−トリル）−６−二トロー４．（３Ｈ）キナゾリ
ノン、２ブロモメチル−３−（０−トリル）−６−二ト
ロー４（３Ｈ）キナゾリノンを製造する場合である。A particularly advantageous reaction in the present invention is to use 2-(N-fluoroacetylamino)5 as anthranilic acid derivative [1].
-Nitrobenzoic acid, 2-(N-chloroacetylamino)
-5-nitrobenzoic acid, 2-(N-bromoacetylamino)-5-nitrobenzoic acid, and aniline derivative [■]
2=fluoromedyl-3-(0-tolyl)-6-nitro-4(3H)quinazolinone, 2-chloromethyl-3 using 2-methyl-aniline (0-toluidine) as
-(0-tolyl)-6-nitro4. (3H) quinazolinone, 2bromomethyl-3-(0-tolyl)-6-nitro 4(3H) quinazolinone is produced.
本発明の第１工程で使用する無水酢酸の量は、使用する
アシルアンスラニル酸誘導体（ｒ）に対して０．９〜！
。The amount of acetic anhydride used in the first step of the present invention is from 0.9 to the amount of the acylanthranilic acid derivative (r) used!
.
２倍モル、好ましくは１．０〜１．２倍モルである。2 times the mole, preferably 1.0 to 1.2 times the mole.
０．９倍モル未満では、使用されたアシルアンスラニル
酸誘導体（Ｉｌ］を全量閉環するには充分でなく、１．
２倍モルを越えると、第２工程で使用するアニリン誘導
体〔■〕の量が増し、得られたキナゾリノン誘導体中の
不純物量が増加し、好ましくない。If it is less than 0.9 times the mole, it is not sufficient to ring-close the entire amount of the acylanthranilic acid derivative (Il) used, and 1.
If it exceeds twice the molar amount, the amount of aniline derivative [■] used in the second step will increase, and the amount of impurities in the obtained quinazolinone derivative will increase, which is not preferable.
本発明の製造法では、上述の無水酢酸の使用量の限定及
び第１工程での生成物を単離しないこと以外は、通常の
方法と特に相違はない。例えば、アシルアンスラニル酸
誘導体〔１〕をベンゼン、トルエン等の溶媒に加え、加
熱撹拌し、環流下無水酢酸を所定量滴下する。そして０
゜５〜８時間還流を行い、室温まで冷却する。次に第２
工程では、かかる反応液から生成したベンゾオキサジノ
ン誘導体（ｎ）を単離することなく、系にアニリン誘導
体を加えて８０〜１１０℃程度加熱し、０．５〜ｌＯ時
間還流反応を行う。反応終了後は反応液を冷却し、析出
した結晶を濾過し、目的のキナゾリノン誘導体〔■〕を
得る。The production method of the present invention is not particularly different from conventional methods, except for limiting the amount of acetic anhydride used and not isolating the product in the first step. For example, acylanthranilic acid derivative [1] is added to a solvent such as benzene or toluene, heated and stirred, and a predetermined amount of acetic anhydride is added dropwise under reflux. and 0
Reflux for 5-8 hours and cool to room temperature. Then the second
In the step, without isolating the benzoxazinone derivative (n) produced from the reaction solution, the aniline derivative is added to the system, heated to about 80 to 110°C, and refluxed for 0.5 to 10 hours. After the reaction is completed, the reaction solution is cooled and the precipitated crystals are filtered to obtain the desired quinazolinone derivative [■].
又、必要に応じてアセトン、メチルエチルケトン、イソ
プロパツール等で再結晶を行ってもよい。Further, if necessary, recrystallization may be performed using acetone, methyl ethyl ketone, isopropanol, or the like.
［作 用］
本発明の製造方法は、第１工程で使用する無水酢酸の量
を限定することにより、中間生成物のベンゾオキサジノ
ン誘導体Ｃｌ０）の単離を不要にし、目的物を有利に製
造し得る。[Function] By limiting the amount of acetic anhydride used in the first step, the production method of the present invention eliminates the need to isolate the intermediate benzoxazinone derivative Cl0), and advantageously produces the desired product. It is possible.
［実施例］ 次に実施例を挙げて本発明を更に説明する。[Example] Next, the present invention will be further explained with reference to Examples.
以下「部」、「％」とあるのは、特に断りのない限り重
量基準で表したものである。In the following, "parts" and "%" are expressed on a weight basis unless otherwise specified.
実施例１
２−（Ｎ−クロロアセチルアミノ）−５−ニトロ安息香
酸６．０９（０，０２３モル）をトルエン２０ｍ１に加
え加熱撹拌し、還流下、無水酢酸を２．５９（０，０２
５モル）滴下した。その後６時間還流した後、０−トル
イジン２．６ｇ（０，０２４モル）を加えて、更に３時
間還流後冷却し、析出した結晶を濾過により分離して乾
燥し、２−クロロメチル−３−（０−）リル）−６−二
トロ４（３Ｈ）−キナゾリノンが６．６９、全収率８７
％で得られた。融点は１８７．５〜１８９℃であった。Example 1 6.09 (0,023 mol) of 2-(N-chloroacetylamino)-5-nitrobenzoic acid was added to 20 ml of toluene, heated and stirred, and under reflux, 2.59 (0,02 mol) of acetic anhydride was added to 20 ml of toluene.
5 mol) was added dropwise. After refluxing for 6 hours, 2.6 g (0,024 mol) of 0-toluidine was added, and after further refluxing for 3 hours, it was cooled, and the precipitated crystals were separated by filtration and dried. (0-)lyl)-6-nitro-4(3H)-quinazolinone 6.69, total yield 87
Obtained in %. The melting point was 187.5-189°C.
対照例
実施例Ｉで無水酢酸を４．７ｇ（０，０４６モル）及び
０−トルイソン５．４９（０，０５モル）にする以外は
同例と同様にして２−クロロメチル−３−（０−トリル
）６−ニトロ−４（３１−Ｄ−キナゾリノンが１．３９
、全収率５１％で得られた。純度９６％で融点は１８５
〜Ｉ８７ 、 Ｉ ’Ｃであった。Control Example 2-chloromethyl-3-(0 -tolyl)6-nitro-4(31-D-quinazolinone is 1.39
, with an overall yield of 51%. Purity 96%, melting point 185
~I87, I'C.
実施例２
実施例１で２−（Ｎ−クロロアセチルアミノ）−５−二
トロ安息香酸の代わりに２−（Ｎ−フルオロアセチルア
ミノ）−５−二トロ安息香酸５．５９（０，０２，３モ
ル）を用いる以外は同例と同様にして、２−フルオロメ
チル３−（０−トリル）−６−ニトロ−４（３１０−キ
ナゾリノンが５．７９、全収率８０％で得られた。純度
は９８５％で融点は１５５〜１５８℃であった。Example 2 2-(N-fluoroacetylamino)-5-nitrobenzoic acid 5.59 (0,02, 2-fluoromethyl 3-(0-tolyl)-6-nitro-4(310-quinazolinone) was obtained in the same manner as in the same example except that 5.79 mol of 310-quinazolinone was used, with an overall yield of 80%. The purity was 985% and the melting point was 155-158°C.
［効 果］
本発明の製造方法は、アンルアンスラニル酸誘導体〔［
〕からキナゾリノン誘導体（ｆＶ）を製造する場合に、
中間生成物であるベンゾオキサジノン誘導体（ＩＩ）を
単離する必要がなくなるので、製造工程を簡略化するこ
とができ、産業上極めて宵月である。[Effect] The production method of the present invention provides anluanthranilic acid derivative [[
] When producing a quinazolinone derivative (fV),
Since there is no need to isolate the intermediate product benzoxazinone derivative (II), the manufacturing process can be simplified, which is extremely time-saving from an industrial perspective.
Claims (1)
ルアミノ基、Ｘはハロゲンを表す。）で示されるアシル
アンスラニル酸誘導体と、化合物〔 I 〕に対して０．
９〜１．２倍モルの無水酢酸とを反応させて、一般式▲
数式、化学式、表等があります▼〔II〕 （但し、Ｙ及びＸは前記と同じ。）で示されるベンゾオ
キサジノン誘導体を得、次いでこれを系から単離するこ
となく一般式 ▲数式、化学式、表等があります▼〔III〕 （但し、Ｒはアルキル基を表す。）で示されるアリニン
誘導体と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▼（IV） （但し、Ｙ、Ｘ及びＲは前記と同じ。）で示されるキナ
ゾリノン誘導体の製造方法。[Claims] Acyl anthranilic acid derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (However, Y represents an alkyl group, halogen, nitro group, alkylamino group, and X represents a halogen.) and 0 for compound [I].
By reacting with 9 to 1.2 times the mole of acetic anhydride, the general formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (However, Y and , tables, etc. ▼ [III] (However, R represents an alkyl group.) A general formula characterized by reacting with the alinine derivative represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (However, , Y, X and R are the same as above.) A method for producing a quinazolinone derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19636689A JPH0358977A (en) | 1989-07-27 | 1989-07-27 | Production of quinazolinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19636689A JPH0358977A (en) | 1989-07-27 | 1989-07-27 | Production of quinazolinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0358977A true JPH0358977A (en) | 1991-03-14 |
Family
ID=16356659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19636689A Pending JPH0358977A (en) | 1989-07-27 | 1989-07-27 | Production of quinazolinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0358977A (en) |
-
1989
- 1989-07-27 JP JP19636689A patent/JPH0358977A/en active Pending
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