JPH01110656A - Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acid - Google Patents
Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acidInfo
- Publication number
- JPH01110656A JPH01110656A JP26648987A JP26648987A JPH01110656A JP H01110656 A JPH01110656 A JP H01110656A JP 26648987 A JP26648987 A JP 26648987A JP 26648987 A JP26648987 A JP 26648987A JP H01110656 A JPH01110656 A JP H01110656A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- dimethoxycinnamoyl
- dimethoxystyryl
- added
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 239000002253 acid Substances 0.000 title abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 14
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 238000010992 reflux Methods 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 8
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 238000003915 air pollution Methods 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000000172 allergic effect Effects 0.000 abstract 1
- 208000010668 atopic eczema Diseases 0.000 abstract 1
- 238000000034 method Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- NZHGWWWHIYHZNX-UHFFFAOYSA-N 2-((3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl)amino)benzoic acid Chemical compound C1=C(OC)C(OC)=CC=C1C=CC(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- -1 for example Chemical group 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 4
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical class O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 150000004679 hydroxides Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 235000011118 potassium hydroxide Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- HJBWJAPEBGSQPR-GQCTYLIASA-N 3,4-dimethoxycinnamic acid Chemical class COC1=CC=C(\C=C\C(O)=O)C=C1OC HJBWJAPEBGSQPR-GQCTYLIASA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は、N −(S’、4’−ジメトキシシンナモイ
ル)アントラニル酸の新規な製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel method for producing N-(S',4'-dimethoxycinnamoyl)anthranilic acid.
本発明の目的は、アレルギーに起因する疾患の治療剤と
して有用なN −(3’、4’−ジメトキシシンナモイ
ル)アントラニル酸およびその塩を工業的に、かつ、高
収率で製造することにある。The purpose of the present invention is to industrially produce N-(3',4'-dimethoxycinnamoyl)anthranilic acid and its salts in high yield, which are useful as therapeutic agents for diseases caused by allergies. be.
(従来の技術)
N −(3’、4’−ジメトキシシンナモイル)−アン
トラニル酸の製造方法は、すでに種々の方法によって行
なわれている。例えば1次のとおりである。(Prior Art) Various methods have already been used to produce N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. For example, the first order is as follows.
(I)特公昭56−4(I71(I号公報に記載されて
いる方法は1次式(In)
訴される5’、 4’−ジメトキシケイ皮酸の反応性官
能的誘導体と、次式(IV)
で示されるアントラニル酸とを反応させる仁とからなる
。(I) Japanese Patent Publication No. 56-4 (I71) The method described in Publication I is based on the linear formula (In). (IV) It consists of a compound that is reacted with anthranilic acid represented by (IV).
(2)特公昭5B−48545号公報に記載されている
方法は、削代(III)で示される5’、 4’−ジメ
トキシケイ皮酸と、−数式M
(式中、Rは水素原子または低級アルキル基を表わす。(2) The method described in Japanese Patent Publication No. 5B-48545 uses 5', 4'-dimethoxycinnamic acid represented by the cutting allowance (III) and the formula M (wherein R is a hydrogen atom or Represents a lower alkyl group.
)
で示されるアントラニル酸またはそのエステルとを、縮
合剤の存在下反応させ、所望に応じては。) with anthranilic acid or an ester thereof in the presence of a condensing agent, if desired.
常法に工りエステル基を加水分解することからなる。It consists of hydrolyzing the ester group in a conventional manner.
(3)特開昭57−58759号公報に記載されている
方法u、5.4−ジメトキシベンズアルデヒドと、次式
(VI)
で示されるマロンアニル酸誘導体とを、塩基性物質の存
在下で反応させることからなる。(3) Method u described in JP-A No. 57-58759, in which 5,4-dimethoxybenzaldehyde and a malonic acid derivative represented by the following formula (VI) are reacted in the presence of a basic substance. Consists of things.
(4)特公昭58−55138号公報に記載されている
方法は1次式(■)
で示されるベンゾオキサジノン誘導体と、3.4−ジメ
トキシベンズアルデヒドを脱水縮合剤の存在下に反応さ
せて1次式(■)
1づれるアズラクトン誘導体を形成させ、次いで。(4) The method described in Japanese Patent Publication No. 58-55138 involves reacting a benzoxazinone derivative represented by the linear formula (■) with 3,4-dimethoxybenzaldehyde in the presence of a dehydration condensation agent. The azlactone derivative of the following formula (■) is formed, and then.
これを加水分解処理、開環することからなる。This consists of hydrolysis treatment and ring opening.
(5)特公昭58−55139号公報に記載されている
方法は、 3’、4’−ジメトキシケイ皮酸(■■)の
反応官的誘導体と1次式(IX)
で示されるアントラニルとを反応させて、削代(■)で
示されるアズラクトン誘導体を形成させ、次いで、これ
を加水分解処理して、開環することからなる。(5) The method described in Japanese Patent Publication No. 58-55139 involves combining a reactive functional derivative of 3',4'-dimethoxycinnamic acid (■■) and anthranyl represented by the primary formula (IX). The process consists of reacting to form an azlactone derivative indicated by a cutting margin (■), and then hydrolyzing this to open the ring.
(発明が解決しようとする問題点)
しかしく1)お工び(5)の方法においては、副反応が
起こり、製品の純度の低下および製造中に発生する有毒
ガスの問題がある。また、(2)の方法では。(Problems to be Solved by the Invention) However, 1) In the method of (5), side reactions occur, resulting in a decrease in the purity of the product and the generation of toxic gases during production. Also, in method (2).
原料となる3: 41−ジメトキシケイ皮酸および目的
化合物であるN −(5’、4’−ジメトキシシンナモ
イル)アントラニル酸が酸性物質であるため、精製が困
難である。(3)の方法では、原料であるマロンアント
ラニル誘導体(VI)が熱に対して不安定であるため、
その取り扱いに特別の注意を必要とし、工業的実施プロ
セスとはいいがたい。さらに、(4)の方法においては
、ベンゾオキサジノン(■)と5.4−ジメトキシベン
ズアルデヒドとの脱水縮合剤によって、中間化合物であ
るアズラクトン誘導体(Vlll)が製造されるが1反
応には脱水縮合剤が必要であり、副生物の生成が認めら
れるなど、経済的かつ工業的製造方法としては満足でき
るものではない。Since the raw material 3:41-dimethoxycinnamic acid and the target compound N-(5',4'-dimethoxycinnamoyl)anthranilic acid are acidic substances, purification is difficult. In method (3), the raw material malonanthranyl derivative (VI) is unstable to heat;
It requires special care in its handling and cannot be called an industrial implementation process. Furthermore, in method (4), an intermediate compound, an azlactone derivative (Vllll), is produced using a dehydration condensation agent of benzoxazinone (■) and 5,4-dimethoxybenzaldehyde, but one reaction involves dehydration condensation. This method is not satisfactory as an economical and industrial production method because it requires a chemical agent and the production of by-products.
本発明は、従来技術の上述の諸問題を解決し、工業的か
つ経済的なN −(3’、4’−ジメトキシシンナモイ
ル)アントラニル酸の製造方法を提供するものである。The present invention solves the above problems of the prior art and provides an industrial and economical method for producing N-(3',4'-dimethoxycinnamoyl)anthranilic acid.
(問題点を解決するための手段および作用)上記の問題
点を解決するため鋭意検討した結果。(Means and effects for solving the problems) The results of intensive studies to solve the above problems.
−数式(I)
(式中、Xはハロゲンまたは低級アルコキシ基を表わし
、nはΩ〜3の整数を表わす。)で示される2 −(3
’、4’−ジメトキシスチリル)−3−アリールキナゾ
リノンを塩基で加水分解した後、さらに酸で加水分解す
ることによる次式(n)で示されるN −(3’、4’
−ジメトキシシンナモイル)アントラニル酸の製造方法
を見い出した。- 2 -(3
N -(3',4'
A method for producing -dimethoxycinnamoyl)anthranilic acid has been discovered.
上記式(I)において、Xはノ\ロゲンまたは低級アル
コキシ基であり、例えば、ノ10グンとしてはBrまた
はCtが好ましい。また、Xが低級アルコキシ基である
場合は1例えば、メトキシ基、エトキシ基などが好まし
い。さらに0式中、Xは0から5までの整数を表わして
いる。In the above formula (I), X is a nitrogen or a lower alkoxy group, and, for example, the nitrogen is preferably Br or Ct. Further, when X is a lower alkoxy group, for example, methoxy group, ethoxy group, etc. are preferable. Furthermore, in the formula 0, X represents an integer from 0 to 5.
この際、出発物質として一般式(X)
(6中、RはHまたはアルキル基を表わす。)で示され
る5位がHまたはアルキル基で置換されたキナゾリノン
化合物を用いても反応は進行せず。At this time, even if a quinazolinone compound represented by general formula (X) (in 6, R represents H or an alkyl group) is substituted with H or an alkyl group as a starting material, the reaction does not proceed. .
目的物質(n)は得られない。しかし1本発明者らは、
5位の置換基がアリール基である場合のみ。Target substance (n) cannot be obtained. However, the inventors
Only when the substituent at position 5 is an aryl group.
目的とする(II)が高収率で得られることを発見し。It was discovered that the target (II) could be obtained in high yield.
本発明を完成するに至った。The present invention has now been completed.
本発明に用いられる一数式〇)で示される化合物は、以
下のようにして製造される。The compound represented by the formula 〇) used in the present invention is produced as follows.
−数式σ)で示される2 −(5’、4’−ジメトキシ
スチリル)−3−アリールキナゾリノンは、−数式(式
中、Xはハロゲンまたは低級アルコキシ基を表わし、n
は0〜3の整数を表わす。)で示される2−メチル−3
−アリール−(3H)−キナゾリノンと、次式(Xll
)
で示される3、4−ジメトギシペンズアルデヒドとを、
無溶媒あるいは不活性溶媒中で、100〜250Cの間
で、1へ10時間、望ましくは1へ5時間反応させるこ
とにより製造することができる。2-(5',4'-dimethoxystyryl)-3-arylquinazolinone represented by the formula σ) is a 2-(5',4'-dimethoxystyryl)-3-arylquinazolinone represented by the formula
represents an integer from 0 to 3. ) 2-methyl-3
-aryl-(3H)-quinazolinone and the following formula (Xll
) with 3,4-dimethoxypenzaldehyde,
It can be produced by reacting 1 with 1 for 10 hours, preferably 5 hours, at a temperature of 100 to 250 C without a solvent or in an inert solvent.
また、この際、酸性触媒の存在下1本反応を行なうと、
反応時間が短縮でき、かつ、収率を向上させることが可
能である。この時、用いることができる酸性触媒として
は1例えば、硫酸や塩酸のような鉱酸、無水リン酸やビ
ロリン酸のようなリン酸a、特Cパラトルエンスルホン
酸やメタンスルホン酸のようなスルホン酸化合物を用い
ることが望ましい。この際用いられる酸性触媒の当量は
、−数式(■)に対して0.01へ1倍当量1%に望ま
しくは0.01〜0.2倍当量である。次に1本反応に
用いられる不活性溶液としては1例えば、ベンゼン、ト
ルエン、キシレン、クメンなどの芳香族系溶媒、あるい
はT HF、 1.4−ジオキサン、ダイグライムな
どのエーテル系溶媒またはDMF。Moreover, at this time, if one reaction is carried out in the presence of an acidic catalyst,
It is possible to shorten reaction time and improve yield. Examples of acidic catalysts that can be used at this time include mineral acids such as sulfuric acid and hydrochloric acid, phosphoric acid a such as phosphoric anhydride and birophosphoric acid, and sulfonic acid catalysts such as C para-toluenesulfonic acid and methanesulfonic acid. Preferably, acid compounds are used. The equivalent of the acidic catalyst used at this time is 0.01 to 1 times equivalent to 1%, preferably 0.01 to 0.2 times equivalent relative to formula (■). Examples of inert solutions used in one reaction include aromatic solvents such as benzene, toluene, xylene, and cumene; ether solvents such as THF, 1,4-dioxane, and diglyme; and DMF.
DMSOなどを挙げることができる。特に酸性触媒を用
いる場合には、脱離した水と共沸混合物を生じ、共沸留
去後、水と分離が可能な溶媒を用いることが望ましい。Examples include DMSO. Particularly when using an acidic catalyst, it is desirable to use a solvent that forms an azeotropic mixture with the desorbed water and that can be separated from the water after azeotropic distillation.
本発明に用いられる溶媒としては1例えば、メタノール
、エタノール、プロパツール、イソプロパツールなどの
アルコール系溶媒&1#2−ジメトキシエタン、THF
、ジオキサン、ダイグライムなどのエーテル系溶媒、ア
セトニトリル、プロピオニトリルのようなニトリル系溶
媒、DAM。Solvents used in the present invention include 1 alcoholic solvents such as methanol, ethanol, propatool, and isopropanol; 1 #2-dimethoxyethane, THF;
, ether solvents such as dioxane and diglyme, nitrile solvents such as acetonitrile and propionitrile, and DAM.
DMF、N−メチルピロリドンなどのアミド系溶媒、ま
たはDMSOやスルホランなどのスルホキシド系溶媒な
どを挙げることができる。特に本発明を好適に実施する
ためには、エタノールまたはイソプロパツールなどを用
いることが望ましい。Examples include amide solvents such as DMF and N-methylpyrrolidone, and sulfoxide solvents such as DMSO and sulfolane. In particular, in order to suitably carry out the present invention, it is desirable to use ethanol, isopropanol, or the like.
本発明に用いることができる塩基としては1例えば、水
酸化リチウム、水酸化ナトリウム、水酸化カリウムのよ
うなアルカリ金属の水酸化物、水酸化マグネシウム、水
酸化カルシウムなどのアルカリ土類金属の水酸化物、特
に水酸化す) IIウムまたは水酸化カリウムを用いる
ことが好ましい。Examples of bases that can be used in the present invention include 1. For example, hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and hydroxides of alkaline earth metals such as magnesium hydroxide and calcium hydroxide. Preference is given to using hydroxides, in particular iumium hydroxide or potassium hydroxide.
本発明に用いられる酸としては、例えば、塩酸。Examples of acids used in the present invention include hydrochloric acid.
硝酸、硫酸、過塩素酸などを挙げることができる。Nitric acid, sulfuric acid, perchloric acid, etc. can be mentioned.
特に塩酸を使用することが好ましい。反応は2−(xl
、al−ジメトキシスチリル)−3−アリールキナゾリ
ノン(I)および塩基の水溶液を溶媒に加え、1〜10
時間、望ましくFi3〜5時間、50Cから還流温度、
望ましくは還流下で反応させる。この際塩基の量は、
2− (3’、4’−ジメトキシスチリル)−3−ア
リールキナゾリノンσ)に対して1〜20倍モル、望ま
しくは10〜15倍モルである。In particular, it is preferable to use hydrochloric acid. The reaction is 2-(xl
, al-dimethoxystyryl)-3-arylquinazolinone (I) and a base were added to the solvent, and 1 to 10
time, preferably Fi 3 to 5 hours, 50C to reflux temperature,
The reaction is preferably carried out under reflux. At this time, the amount of base is
The amount is 1 to 20 times mole, preferably 10 to 15 times mole, relative to 2-(3',4'-dimethoxystyryl)-3-arylquinazolinone σ).
続いて、その反応溶液を30〜50Cに冷却した後に酸
を加え、1〜30分間望ましくは10〜15分間攪拌す
ることにより行なわれる。この際用いられる塩基の量は
、 2− (3’、4’−ジメトキシスチリル)−3−
了り−ルキナゾリノン(I)に対して2A−40倍モル
、望ましくは15A−20倍モルである。目的のN
< sJ、al−ジメトキシシンナモイル)−アントラ
ニル酸は酸性物質であり、公刊の精製操作により容易に
単離することができる。Subsequently, the reaction solution is cooled to 30 to 50C, and then an acid is added thereto, followed by stirring for 1 to 30 minutes, preferably 10 to 15 minutes. The amount of base used at this time is 2-(3',4'-dimethoxystyryl)-3-
The amount is 2A-40 times, preferably 15A-20 times, based on luquinazolinone (I). Purpose N
< sJ, al-dimethoxycinnamoyl)-anthranilic acid is an acidic substance and can be easily isolated by published purification procedures.
(発明の効果)
本発明によれば、 2− (3’、4’−ジメチルスチ
リル)−6−フェニルキナゾリノン(I)を加水分解す
ることにより、従来法での大気汚染や副生成物の問題を
解決して、目的物のN −(s′、41−ジメトキシシ
ンナモイル)−アントラニル酸(II)を高収率で製造
することが可能になった。(Effects of the Invention) According to the present invention, by hydrolyzing 2-(3',4'-dimethylstyryl)-6-phenylquinazolinone (I), problems of air pollution and by-products caused by conventional methods can be solved. By solving this problem, it became possible to produce the target product N-(s',41-dimethoxycinnamoyl)-anthranilic acid (II) in high yield.
サラに、原料である2 −(5’、4’−ジメチルスチ
リル)−3−了り−ルキナゾリノン(I)は、化合物(
X])より高収率で得られるため1本発明は、工業的か
つ経済的プロセスであると言うことができる。In general, the raw material 2-(5',4'-dimethylstyryl)-3-ruquinazolinone (I) is a compound (
X]) can be obtained in higher yields, the present invention can be said to be an industrial and economical process.
(実施例)
実施例1
2− (3’、4’−ジメトキシスチリル)−6−フェ
ニルキナゾリノンo、s 1t (I,s mmot)
のエタノール3〇−溶液に、水酸化す) IJウム0.
66 S’(I7mmot)の水溶液1.3−を加え、
5時間還流撹拌した。40〜50Cに冷却後、濃塩酸2
.31R1を徐々に滴下し、10分間攪拌した。反応終
了後、水3(lx/を添加し、クロロホルムで抽出t、
7t。さらに、そのクロロホルム層を飽和炭酸水素ナト
リウム水溶液30nttで、カルボン酸塩として抽出し
た。その水層を1N−塩酸でpH2とし、析出した結晶
を戸果して、 N −(3’、4’−ジメトキシシンナ
モイル)−アントラニルpO,52?(収率73%)を
得た。(Example) Example 1 2-(3',4'-dimethoxystyryl)-6-phenylquinazolinone o,s 1t (I,s mmot)
(30% ethanol solution, hydroxide) IJum 0.
Add 1.3- of an aqueous solution of 66 S' (I7mmot),
The mixture was stirred under reflux for 5 hours. After cooling to 40-50C, add concentrated hydrochloric acid 2
.. 31R1 was gradually added dropwise and stirred for 10 minutes. After the reaction was completed, 3 lx/ of water was added and extracted with chloroform.
7t. Furthermore, the chloroform layer was extracted as a carboxylate salt with 30 ntt of a saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid, the precipitated crystals were removed, and N-(3',4'-dimethoxycinnamoyl)-anthranyl pO, 52? (yield 73%).
mp 209 A−210C
N M R(da−DMSO) :δ 3.87(3H
,s)。mp 209 A-210C NMR (da-DMSO): δ 3.87 (3H
,s).
5.92(5H,S)。5.92 (5H, S).
6.0〜9.0
(tOH,m)
IR(KBr):2900o+s−’(νcOOH)1
6700ツl−鳳 (ν C0)
12550m’(シc−0−C)
元素分析値
C,、H,、OSNとして
計算値 C: 66.05%
H: 5.24チ
N: 4.28チ
実測値 C: 66.01チ
H: 5.19チ
N: 4.23%
実施例2
2− (3’、4’−ジメトキシスチリル)−5−フェ
ニルキナゾリノy O,51f (I,5mmot)の
DMS O20−溶液に、水酸化ナトリウム0.66
? (I7mm o L )の水溶液1.3−を加え、
5時間還流攪拌した。40〜50Cに冷却後1m塩酸2
.3−を徐々に滴下し、10分間攪拌した。実施例1と
同様の後処理を行なうことにより、 N−(sl、41
−ジメトキシシンナモイル)−アントラニル(Iio、
15?(50チ)を得た。6.0 to 9.0 (tOH, m) IR (KBr): 2900o+s-'(νcOOH)1
6700 Tsu l-Otori (ν C0) 12550 m' (Si c-0-C) Elemental analysis value C,, H,, Calculated value as OSN C: 66.05% H: 5.24 Chi N: 4.28 Chi Actual value C: 66.01 h H: 5.19 h N: 4.23% Example 2 2-(3',4'-dimethoxystyryl)-5-phenylquinazolino y O,51f (I,5mmot ) in DMS O20− solution, sodium hydroxide 0.66
? Add 1.3- of an aqueous solution of (I7 mm o L),
The mixture was stirred under reflux for 5 hours. After cooling to 40-50C, add 1 m of hydrochloric acid 2
.. 3- was gradually added dropwise and stirred for 10 minutes. By performing the same post-processing as in Example 1, N-(sl, 41
-dimethoxycinnamoyl)-anthranyl (Iio,
15? (50 chi) was obtained.
実施例3
2− (3’、4’−ジメトキシスチリル)−5−(p
−クロロフェニル)キナゾリノン0.549 (I,3
mmot)のインプロパツール3〇−溶液に、水酸化ナ
トリウムo、66 t (I7mmot)の水溶液1.
3−を加え、5時間還流攪拌した。40〜50Cに冷却
後、濃塩酸2.3−を徐々に滴下し、10分間攪拌した
。反応終了後、実施例1と同様の後処理を行なうことに
より、 N< 3′、al−ジメトキシシンナモイル)
−アントラニル@0.50 f (88チ)を得た。Example 3 2-(3',4'-dimethoxystyryl)-5-(p
-chlorophenyl)quinazolinone 0.549 (I,3
mmot) Improper Tool 30-solution, sodium hydroxide o, 66 t (I7mmot) aqueous solution 1.
3- was added, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, concentrated hydrochloric acid 2.3- was gradually added dropwise and stirred for 10 minutes. After completion of the reaction, by performing the same post-treatment as in Example 1, N <3', al-dimethoxycinnamoyl)
-anthranyl@0.50 f (88 h) was obtained.
実施例4
2− (3’、4’−ジメトキシスチリル)−3−(p
−メトキシフェニル)キナゾリノン0,54 t(I,
3mmot)のイソプロパツール5〇−溶液に。Example 4 2-(3',4'-dimethoxystyryl)-3-(p
-methoxyphenyl)quinazolinone 0,54 t(I,
3 mmot) of isopropanol 50-solution.
水酸化ナトリウA O,66t (I7mmot)の水
溶液1.3dを加え、5時間還流攪拌した740〜50
Cに冷却後、1#塩酸2.3dを徐々に滴下し、10分
間攪拌した。反応終了後、実施例1と同様の後処理を行
なうことによfi、 N −(3’、4’−ジメトキシ
シンナモイル)−アントラニルfio、37 f (6
5%)を得た。Added 1.3 d of an aqueous solution of sodium hydroxide A O, 66t (I7mmot) and stirred under reflux for 5 hours.
After cooling to C., 2.3 d of 1# hydrochloric acid was gradually added dropwise and stirred for 10 minutes. After completion of the reaction, the same post-treatment as in Example 1 was performed to obtain fi, N-(3',4'-dimethoxycinnamoyl)-anthranyl fio, 37 f (6
5%).
比較例1
z + (61,al−ジメトキシスチリル)キナゾリ
ンy 0.40 f (L5 mmot)のエタノール
5〇−溶液に、水酸化ナトリウムo、6,6 t (t
y mmot)の水溶液1.3−を加え、5時間還流
攪拌した。40〜50Cに冷却後、−塩酸2.3−を徐
々に滴下し。Comparative Example 1 To a solution of z + (61,al-dimethoxystyryl)quinazoline y 0.40 f (L5 mmot) in ethanol 50, was added sodium hydroxide o, 6,6 t (t
y mmot) was added thereto, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, -hydrochloric acid 2.3- was gradually added dropwise.
10分間攪拌した。反応終了後、実施例1と同様の後処
理を行なったが、目的とするN−(5’、4’−ジメト
キシシンナモイル)−アントラニル酸ハ得られなかった
。抽出クロロホルム層から溶媒留去した結果、 2−
(5’、4’−ジメトキシスチリル)キナゾリノン0.
399 (回収率97%)が得られた。Stirred for 10 minutes. After the reaction was completed, the same post-treatment as in Example 1 was carried out, but the desired N-(5',4'-dimethoxycinnamoyl)-anthranilic acid was not obtained. As a result of distilling off the solvent from the extracted chloroform layer, 2-
(5',4'-dimethoxystyryl)quinazolinone 0.
399 (recovery rate 97%) was obtained.
2− (5’、4’−ジメトキシスチリル)キナゾリノ
ンmp 269 へ27Q7:
N M R(d6−DMSO) :δ 4.o 7 (
3H、s )4.10(3H,s)
7.0−8.7
(9H、m )
I R(KBr): 3180m−” yN−H16
70傷1 νC0
1270傷−1シC−0−C
元素分析値 cts I(ta N、o。2-(5',4'-dimethoxystyryl)quinazolinone mp 269 to 27Q7: NMR(d6-DMSO): δ 4. o 7 (
3H, s) 4.10 (3H, s) 7.0-8.7 (9H, m) IR (KBr): 3180m-"yN-H16
70 scratches 1 νC0 1270 scratches-1C-0-C Elemental analysis value cts I(ta N, o.
計算値 C: 70.13%
H: 5.19 係
N: 9.09%
実測値 C: 70.20チ
H: 5.21 チ
N: s、qs 係
比較例2
2− (3’、4’−ジメトキシスチリル)−3−プロ
ピルキナゾリノン0.46 t (I,3mmot)の
エタノール5Otttl溶液に、水酸化ナトリウム0.
66t(I7mmot)の水溶液1.3−を加え、5時
間還流攪拌した。40〜50Cに冷却後、濃塩酸2.3
−を徐々に滴下し、10分間攪拌した。反応終了後。Calculated value C: 70.13% H: 5.19 Coordination N: 9.09% Actual value C: 70.20C H: 5.21 Coordination N: s, qs Coordination comparative example 2 2- (3', 4 A solution of 0.46 t (I, 3 mmot) of 0.46 t of '-dimethoxystyryl)-3-propylquinazolinone in 5 Otttl of ethanol was added with 0.46 t of sodium hydroxide.
66t (I7mmot) of an aqueous solution of 1.3% was added, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, add concentrated hydrochloric acid 2.3
- was gradually added dropwise and stirred for 10 minutes. After the reaction is complete.
実施例1と同様の後処理を行なったが、目的とするN−
(5′、4′−ジメトキシシンナモイル)−アントラニ
ル酸は得られなかった。抽出クロロホルム層から溶媒留
去した結果、2−(5′、4′−ジメトキシスチリル)
−3−プロピルキナゾリノン0.449(回収率93チ
)が得られた。The same post-treatment as in Example 1 was carried out, but the target N-
(5',4'-dimethoxycinnamoyl)-anthranilic acid was not obtained. As a result of solvent distillation from the extracted chloroform layer, 2-(5',4'-dimethoxystyryl)
-3-Propylquinazolinone 0.449 (recovery rate 93) was obtained.
2−(5’、4’−ジメトキシスチリル)−3−プロピ
ルキナゾリン
mp 138A−140C
NMR(CD CAm ): δ o、ya(3u
、t)。2-(5',4'-dimethoxystyryl)-3-propylquinazoline mp 138A-140C NMR (CD CAm): δ o, ya (3u
, t).
1.70(2H,t、q)、 183(3H,s)、5
.86 (3H,s)、 4.29(3H,t)
。1.70 (2H, t, q), 183 (3H, s), 5
.. 86 (3H, s), 4.29 (3H, t)
.
6、q −8,2(tp H、m )
IR(KBr):2850m−1y−CH2−1670
GB” WCO
1270鋤叫 シC−0−C
元素分析値 C,、H,、N、 o。6, q -8,2 (tpH, m) IR (KBr): 2850m-1y-CH2-1670
GB” WCO 1270 Plow C-0-C Elemental analysis value C,, H,, N, o.
計算値 C: 71.98チ
H: 6.55%
N: 8.00憾
実測値 C: 71.72係
H: 6.17チ
N: 8.01チ
参考例
一般式(I)の化合物の一例である2−(3’、4’−
ジメトキシスチリル)−5−フェニルキナゾリノンの製
造例を以下に示す。Calculated value C: 71.98% H: 6.55% N: 8.00 Actual value C: 71.72% H: 6.17% N: 8.01% Reference example Compound of general formula (I) An example is 2-(3', 4'-
An example of the production of dimethoxystyryl-5-phenylquinazolinone is shown below.
2−メチル−3−フェニル−(3H)−キナシリ/ 7
2.679 (I0mmoj)と5.4−ジメトキシベ
ンズアルデヒド1.83f(I1mmOt)を、190
Cで4時間攪拌した。反応液を冷却後、エタノールから
再結し、黄色針状結晶の2−(5’、4’−ジメトキシ
スチリル)−3−フェニルキナゾリノン3.79 (9
5係)を得た。2-Methyl-3-phenyl-(3H)-quinashiri/7
2.679 (I0 mmoj) and 5.4-dimethoxybenzaldehyde 1.83 f (I1 mmOt), 190
The mixture was stirred at C for 4 hours. After cooling the reaction solution, it was recrystallized from ethanol to give yellow needle-shaped crystals of 2-(5',4'-dimethoxystyryl)-3-phenylquinazolinone (3.79 (9
Section 5) was obtained.
mp 167へ168C
NMR(CDCt、):δ s、74(3H,t)、3
.81 (3H,S L
6.1 − 8.5
(I4H%m)
IR(KBr): 1670cIR−” yc。168C NMR (CDCt, ) to mp 167: δ s, 74 (3H, t), 3
.. 81 (3H, SL 6.1-8.5 (I4H%m) IR (KBr): 1670cIR-"yc.
1260偏−1シC−0−C 元素分析値 C24H,。N、0゜ 計算値 C: 74.98壬 H: 5.24% N: 7.29係 実測値 C: 74,72壬 H:5,09チ Nニア、11憾1260 bias-1 C-0-C Elemental analysis value C24H. N, 0° Calculated value C: 74.98 壬 H: 5.24% N: 7.29 Section Actual value C: 74,72 壬 H: 5,09ch Nia, 11 regrets
Claims (1)
、nは0〜3の整数を表わす。) で示される2−(3′,4′−ジメトキシスチリル)−
3−アリールキナゾリノンを塩基で加水分解した後、さ
らに酸で加水分解することを特徴とする次式(II) ▲数式、化学式、表等があります▼(II) で示されるN−(2′,4′−ジメトキシシンナモイル
)アントラニル酸の製造方法。[Claims] General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents a halogen or a lower alkoxy group, and n represents an integer from 0 to 3.) 2-(3',4'-dimethoxystyryl)-
N-(2', Method for producing 4'-dimethoxycinnamoyl)anthranilic acid.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP26648987A JPH01110656A (en) | 1987-10-23 | 1987-10-23 | Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acid |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP26648987A JPH01110656A (en) | 1987-10-23 | 1987-10-23 | Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH01110656A true JPH01110656A (en) | 1989-04-27 |
JPH0584301B2 JPH0584301B2 (en) | 1993-12-01 |
Family
ID=17431641
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP26648987A Granted JPH01110656A (en) | 1987-10-23 | 1987-10-23 | Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acid |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH01110656A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006296905A (en) * | 2005-04-25 | 2006-11-02 | Okamura Corp | Commodity display utensil |
-
1987
- 1987-10-23 JP JP26648987A patent/JPH01110656A/en active Granted
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006296905A (en) * | 2005-04-25 | 2006-11-02 | Okamura Corp | Commodity display utensil |
Also Published As
Publication number | Publication date |
---|---|
JPH0584301B2 (en) | 1993-12-01 |
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