JPH0153874B2 - - Google Patents
Info
- Publication number
- JPH0153874B2 JPH0153874B2 JP58084953A JP8495383A JPH0153874B2 JP H0153874 B2 JPH0153874 B2 JP H0153874B2 JP 58084953 A JP58084953 A JP 58084953A JP 8495383 A JP8495383 A JP 8495383A JP H0153874 B2 JPH0153874 B2 JP H0153874B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- group
- general formula
- ethyl
- methyl
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- BLFGQHDZMHMURV-UHFFFAOYSA-N 4-oxo-2-phenylchromene-3-carboxylic acid Chemical class O1C2=CC=CC=C2C(=O)C(C(=O)O)=C1C1=CC=CC=C1 BLFGQHDZMHMURV-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 6
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 description 34
- -1 β-piperidino-ethyl Chemical group 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- KMMBBZOSQNLLMN-UHFFFAOYSA-N 3-methylflavone-8-carboxylic acid Chemical compound O1C2=C(C(O)=O)C=CC=C2C(=O)C(C)=C1C1=CC=CC=C1 KMMBBZOSQNLLMN-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 238000005809 transesterification reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MADORZDTLHDDEN-UHFFFAOYSA-N 1-piperidin-1-ylethanol Chemical compound CC(O)N1CCCCC1 MADORZDTLHDDEN-UHFFFAOYSA-N 0.000 description 2
- KZTWONRVIPPDKH-UHFFFAOYSA-N 2-(piperidin-1-yl)ethanol Chemical compound OCCN1CCCCC1 KZTWONRVIPPDKH-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- OSHFQLSUZICPRA-UHFFFAOYSA-N methyl 3-methyl-4-oxo-2-phenylchromene-8-carboxylate Chemical compound COC(=O)C1=CC=CC(C(C=2C)=O)=C1OC=2C1=CC=CC=C1 OSHFQLSUZICPRA-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 125000005023 xylyl group Chemical group 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- LRTSDXDGOFQRSW-UHFFFAOYSA-N 4-oxo-2-phenylchromene-8-carboxylic acid Chemical compound OC(=O)C1=CC=CC(C(C=2)=O)=C1OC=2C1=CC=CC=C1 LRTSDXDGOFQRSW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical compound [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 description 1
- 229910000026 rubidium carbonate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
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
本発明は、フラボンカルボン酸エステル類の製
法に関し、さらに詳しくはアルカリ金属炭酸塩を
触媒としてエステル交換によりフラボンカルボン
酸エステル類を製造する方法に関する。
３−メチル−フラボン−８−カルボン酸の塩基
性エステル、例えばβ−ピペリジノ−エチル、β
−モルホリノ−エチル、β−ジエチルアミノ−エ
チル、β−ジ−ｎ−プロピルアミノ−エチルある
いはβ−ジ−イソプロピルアミノ−エチルなど
は、医薬として公知である。
また、３−メチル−フラボン−８−カルボン酸
の塩基性エステルの製造には、３−メチル−フラ
ボン−８−カルボン酸またはその低級アルキルエ
ステルと、アミノアルコール等とのエステル化反
応、あるいはエステル変換反応を利用することも
公知である。
例えば特公昭51−4983号公報の実施例９には、
３−メチル−フラボン−８−カルボン酸のβ−ピ
ペリジノ−エチルエステルを製造する方法とし
て、エチルエステルをピペリジノーエタノールで
エステル交換する方法が開示されており、触媒と
してナトリウム金属をピペリジノ−エタノールに
溶解させて用いられている。しかしナトリウムピ
ペリジノーエタノラートを触媒とする場合は、原
料の転化率およびピペリジノーエチルエステルの
収率がいずれも低い。
本発明は、３−メチル−フラボン−８−カルボ
ン酸等のフラボンカルボン酸のエステル類を高い
原料転化率でかつ高い収率で製造する方法を提供
するものであり、触媒としてアルカリ金属炭酸塩
を用い、エステル変換により、フラボンカルボン
酸エステル類を製造する方法に関する。
すなわち、本発明は、一般式〔〕
（式中、R1はアルキル基、アラルキル基または
アリール基を示し、R2およびR3はそれぞれ水素、
アルキル基またはハロゲンを示し、R4は水素、
アルキル基またはアリール基を示す。）で表わさ
れるフラボンカルボン酸エステル類と、一般式
〔〕
R5OH 〔〕
（式中、R5は上記R1とは異なるアルキル基、ア
ラルキル基、モノヒドロキシアルキル基またはア
ミノアルキル基を示す。）で表わされるアルコー
ル類とを反応させて一般式〔〕
（式中、R2、R3、R4およびR5は上記と同じ）で
表わされるフラボンカルボン酸エステル類を製造
する方法において、触媒としてアルカリ金属炭酸
塩を用いることを特徴とするフラボンカルボン酸
エステル類の製法に関する。
本発明において使用される前記一般式〔〕で
示されるフラボンカルボン酸エステル類として
は、一般式〔〕中R1がメチル、エチル、ｎ−
プロピル、イソプロピル、ｎ−ブチル、イソブチ
ルなどのアルキル基、とくに好ましくは炭素数５
以下のアルキル基、ベンジル、フエネチルなどの
アラルキル基、またはフエニル、トリル、キシリ
ルなどアリール基であり、R2およびR3はそれぞ
れ、水素、メチル、エチル、ｎ−プロピル、イソ
プロピル、ｎ−ブチル、イソブチルなどのアルキ
ル基、とくに好ましくは炭素数５以下のアルキル
基または塩素、臭素、ヨウ素、フツ素などのハロ
ゲンであり、R2は、５−位、６−位または７−
位に位置し、さらにR4は、メチル、エチル、ｎ
−プロピル、イソプロピル、ｎ−ブチル、イソブ
チルなどのアルキル基、とくに好ましくは炭素数
５以下のアルキル基、またはフエニル、トリル、
キシリルなどのアリール基で示される化合物であ
る。このような化合物として、さらに具体的に
は、３−メチル−フラボン−８−カルボン酸のメ
チルエステル、エチルエステル等や３−エチル−
フラボン−８−カルボン酸のメチルエステル、エ
チルエステル等を挙げることができる。
また本発明において使用される前記一般式
〔〕で示されるアルコール類としては、一般式
中R5が前記一般式〔〕におけるR1と異なるア
ルキル基、アラルキル基、モノヒドロキシアルキ
ル基またはアミノアルキル基である化合物であ
る。アルキル基には、メチル、エチル、ｎ−プロ
ピル、イソプロピル、ｎ−ブチル、イソブチルな
どのアルキル基、ベンジル、フエネチルなどのア
ラルキル基、β−ヒドロキシ−エチル、γ−ヒド
ロキシ−ｎ−プロピルなどのモノヒドロキシアル
キル基などが例示され、アミノアルキル基には、
β−ピペリジノーエチル、β−モルホリノ−エチ
ル、β−ジメチルアミノ−エチル、β−ジエチル
アミノ−エチル、β−ジ−ｎ−プロピルアミノ−
エチル、β−ジ−イソプロピルアミノ−エチル、
ジメチルアミノプロピル、ジエチルアミノプロピ
ルなどが例示される。
本発明で使用される触媒は、アルカリ金属炭酸
塩から選ばれる少なくとも一種類以上の化合物で
あり、例えば炭酸カリウム、炭酸水素カリウム、
炭酸ナトリウム、炭酸水素ナトリウム、炭酸ルビ
ジウム、炭酸セシウムなどを挙げることができ、
中でも炭酸カリウム、炭酸水素カリウムが好適で
ある。
アルカリ金属炭酸塩は通常、前記一般式〔〕
で示される原料フラボンカルボン酸エステル類１
モルに対して通常約0.001ないし約１モルの範囲
で使用され、特に好ましくは約0.005ないし約0.5
モルの範囲で使用される。
本発明の反応は、通常反応に不活性な溶媒の存
在下に実施される。溶媒として具体的には、ジメ
チルホルムアミド、ジメチルアセトアミド、ジエ
チルホルムアミド、Ｎ−メチルピロリドン、テト
ラメチル尿素、ジメチルスルホキシド、ヘキサメ
チルホスホアミド、アセトニトリル、プロピオニ
トリル、スルホランなどを挙げることができる。
これらの溶媒は、前記一般式〔〕で示される
原料フラボンカルボン酸エステル類１重量部に対
して、通常約0.1ないし約100重量部、好ましくは
約１ないし約10重量部の割合で使用され、反応に
際して必要に応じて追加添加される。
本発明の反応における一般式〔〕で示される
原料フラボンカルボン酸エステル類と一般式
〔〕で示されるアルコール類の比率は、とくに
限定されるものではないが、中でもアルコール類
を原料フラボンカルボン酸エステル類１モルに対
して、約0.9ないし約10モル、好ましくは約１な
いし約２モルとすると、反応の効率が良い。
このため、上記の比率で原料を仕込む方法や、
上記範囲となるように随時原料を添加する方法を
採用することができる。
本発明の反応は、通常反応温度約50ないし約
200℃で約１ないし約24時間、好ましくは約３な
いし約12時間程度行われる。
反応が進行するにつれ、エステル交換により生
成するアルコール類またはフエノール類は、反応
系から随時除去することが望ましく、例えば約10
ないし約500mmHgの減圧下で留去しながら反応を
行うか、あるいは反応に不活性な気体、例えば、
窒素、アルゴンなどを反応系内へ吹き込み、留去
しながら反応を行うことが望ましい。
本発明の反応は、工業上の見地からエステル交
換がほぼ終了するまで行うことが望ましい。エス
テル交換反応が実質的に終了するとは、エステル
交換反応をさらに２時間継続しても、分析の誤差
範囲内において前記一般式〔〕で示される目的
化合物の収率の変化がみられない状態を示す。
本発明の反応は、回分式、連続式いずれでも行
うことができる。また本発明の反応には、必ずし
も特別な装置を必要とせず、例えば撹拌装置、加
熱装置、添加装置、留出装置等を備えた反応容器
によつて、本発明を行うことができる。
本発明の反応によつて得られる前記一般式
〔〕で示される目的化合物は、従来公知の方法、
例えば蒸留、再結晶等の方法により、分離、精製
される。
本発明によれば３−メチル−フラボン−８−カ
ルボン酸のβ−ピペリジノーエチルエステルをは
じめとするフラボンカルボン酸エステル類を、高
い原料転化率、高収率でかつ高選択率を製造する
ことができる。
次に、本発明を実施例によつて具体的に説明す
る。
実施例 １
撹拌器、冷却器、温度計およびガス吹き込み管
を備え付けた100ml四ツ口フラスコに、３−メチ
ル−フラボン−８−カルボン酸メチルエステル
5.886ｇ（0.02モル）、β−ピペリジノーエタノー
ル3.101ｇ（0.024モル）、炭酸カリウム0.276ｇ
（0.002モル）およびジメチルホルムアミド40mlを
入れ、乾燥した窒素ガスを100ml／minで吹き込
みながら、100℃で12hr反応を行つた。反応混合
物にトルエンおよび水を加えて分液し、トルエン
溶液を水洗乾操後濃縮すると、３−メチル−フラ
ボン−８−カルボン酸のβ−ピペリジノーエチル
エステルが7.62ｇ（ガスクロ分析による純度99.5
％）得られた。
一方、水層を塩酸で酸性にし酢酸エチルで抽出
し、水洗乾燥後濃縮すると３−メチル−フラボン
−８−カルボン酸が0.14ｇ得られた。メチルエス
テルの転化率は99.4％、β−ピペリジノーエチル
エステルの収率は96.8％、選択率は97.4％、カル
ボン酸の収率は2.6％であつた。
実施例 ２〜５
実施例１の炭酸カリウムの代りに表１に記載し
た触媒を用いた以外は実施例１と同様に反応を行
つたところ、表１の結果が得られた。
The present invention relates to a method for producing flavonecarboxylic acid esters, and more particularly to a method for producing flavonecarboxylic acid esters by transesterification using an alkali metal carbonate as a catalyst. Basic esters of 3-methyl-flavone-8-carboxylic acid, such as β-piperidino-ethyl, β
-morpholino-ethyl, β-diethylamino-ethyl, β-di-n-propylamino-ethyl or β-di-isopropylamino-ethyl, etc. are known as pharmaceuticals. In addition, to produce the basic ester of 3-methyl-flavone-8-carboxylic acid, esterification reaction of 3-methyl-flavone-8-carboxylic acid or its lower alkyl ester with amino alcohol, etc., or ester conversion It is also known to utilize reactions. For example, in Example 9 of Japanese Patent Publication No. 51-4983,
As a method for producing β-piperidino-ethyl ester of 3-methyl-flavone-8-carboxylic acid, a method is disclosed in which ethyl ester is transesterified with piperidinoethanol, in which sodium metal is used as a catalyst to convert piperidino-ethanol into It is used after being dissolved. However, when sodium piperidino ethanolate is used as a catalyst, both the conversion rate of the raw material and the yield of piperidino ethyl ester are low. The present invention provides a method for producing esters of flavonecarboxylic acids such as 3-methyl-flavone-8-carboxylic acid with a high raw material conversion rate and high yield, and uses an alkali metal carbonate as a catalyst. This invention relates to a method for producing flavonecarboxylic acid esters by ester conversion using the present invention. That is, the present invention provides general formula [] (In the formula, R 1 represents an alkyl group, an aralkyl group, or an aryl group, and R 2 and R 3 are hydrogen, respectively.
Indicates an alkyl group or halogen, R 4 is hydrogen,
Indicates an alkyl group or an aryl group. ) and the flavonecarboxylic acid esters represented by the general formula [] R 5 OH [] (wherein R 5 represents an alkyl group, an aralkyl group, a monohydroxyalkyl group, or an aminoalkyl group different from R 1 above). ) is reacted with alcohols represented by the general formula [ ] (In the formula, R 2 , R 3 , R 4 and R 5 are the same as above) A method for producing flavone carboxylic acid esters, characterized in that an alkali metal carbonate is used as a catalyst. Concerning the production method of esters. As the flavonecarboxylic acid esters represented by the general formula [] used in the present invention, R 1 in the general formula [] is methyl, ethyl, n-
Alkyl groups such as propyl, isopropyl, n-butyl, isobutyl, particularly preferably 5 carbon atoms
The following alkyl groups, aralkyl groups such as benzyl and phenethyl, or aryl groups such as phenyl, tolyl, and xylyl, where R 2 and R 3 are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, respectively. , particularly preferably an alkyl group having 5 or less carbon atoms, or a halogen such as chlorine, bromine, iodine, or fluorine, and R 2 is the 5-position, the 6-position, or the 7-position.
and R 4 is methyl, ethyl, n
- Alkyl groups such as propyl, isopropyl, n-butyl, isobutyl, particularly preferably alkyl groups having 5 or less carbon atoms, or phenyl, tolyl,
It is a compound represented by an aryl group such as xylyl. More specifically, such compounds include methyl ester, ethyl ester, etc. of 3-methyl-flavone-8-carboxylic acid, and 3-ethyl-8-carboxylic acid.
Examples include methyl ester and ethyl ester of flavone-8-carboxylic acid. Furthermore, in the alcohols represented by the above general formula [] used in the present invention, R 5 in the general formula is an alkyl group, an aralkyl group, a monohydroxyalkyl group, or an aminoalkyl group different from R 1 in the above general formula []. It is a compound that is Alkyl groups include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, aralkyl groups such as benzyl and phenethyl, and monohydroxy groups such as β-hydroxy-ethyl and γ-hydroxy-n-propyl. Examples include alkyl groups, and aminoalkyl groups include
β-Piperidinoethyl, β-morpholino-ethyl, β-dimethylamino-ethyl, β-diethylamino-ethyl, β-di-n-propylamino-
ethyl, β-di-isopropylamino-ethyl,
Examples include dimethylaminopropyl and diethylaminopropyl. The catalyst used in the present invention is at least one compound selected from alkali metal carbonates, such as potassium carbonate, potassium hydrogen carbonate,
Examples include sodium carbonate, sodium hydrogen carbonate, rubidium carbonate, and cesium carbonate.
Among them, potassium carbonate and potassium hydrogen carbonate are preferred. Alkali metal carbonates usually have the general formula []
Raw material flavonecarboxylic acid esters 1 shown by
It is usually used in a range of about 0.001 to about 1 mol, particularly preferably about 0.005 to about 0.5 mol.
Used in molar range. The reaction of the present invention is usually carried out in the presence of a solvent inert to the reaction. Specific examples of the solvent include dimethylformamide, dimethylacetamide, diethylformamide, N-methylpyrrolidone, tetramethylurea, dimethylsulfoxide, hexamethylphosphoamide, acetonitrile, propionitrile, and sulfolane. These solvents are usually used in a proportion of about 0.1 to about 100 parts by weight, preferably about 1 to about 10 parts by weight, per 1 part by weight of the starting flavonecarboxylic acid ester represented by the general formula []. It is additionally added as necessary during the reaction. In the reaction of the present invention, the ratio of the raw material flavonecarboxylic acid esters represented by the general formula [] to the alcohols represented by the general formula [] is not particularly limited. The reaction efficiency is good when the amount is about 0.9 to about 10 mol, preferably about 1 to about 2 mol, per 1 mol of the compound. For this reason, the method of preparing raw materials in the above ratio,
A method may be adopted in which raw materials are added as needed so that the above range is achieved. The reaction of the present invention is generally carried out at a reaction temperature of about 50 to about
The treatment is carried out at 200° C. for about 1 to about 24 hours, preferably about 3 to about 12 hours. As the reaction progresses, it is desirable to remove alcohols or phenols produced by transesterification from the reaction system as needed; for example, about 10
The reaction is carried out under reduced pressure of 500 mmHg to about 500 mmHg, or an inert gas, e.g.
It is desirable to carry out the reaction while blowing nitrogen, argon, etc. into the reaction system and distilling it off. From an industrial standpoint, the reaction of the present invention is desirably carried out until the transesterification is almost completed. The term "the transesterification reaction is substantially completed" means that even if the transesterification reaction is continued for an additional 2 hours, no change in the yield of the target compound represented by the general formula [] is observed within the analytical error range. show. The reaction of the present invention can be carried out either batchwise or continuously. Further, the reaction of the present invention does not necessarily require any special equipment; for example, the present invention can be carried out using a reaction vessel equipped with a stirring device, a heating device, an addition device, a distillation device, and the like. The target compound represented by the general formula [] obtained by the reaction of the present invention can be obtained by a conventionally known method.
For example, it is separated and purified by methods such as distillation and recrystallization. According to the present invention, flavonecarboxylic acid esters including β-piperidinoethyl ester of 3-methyl-flavone-8-carboxylic acid can be produced with high raw material conversion, high yield, and high selectivity. be able to. Next, the present invention will be specifically explained using examples. Example 1 3-Methyl-flavone-8-carboxylic acid methyl ester was added to a 100 ml four-necked flask equipped with a stirrer, condenser, thermometer and gas injection tube.
5.886g (0.02mol), β-piperidinoethanol 3.101g (0.024mol), potassium carbonate 0.276g
(0.002 mol) and 40 ml of dimethylformamide were added, and a reaction was carried out at 100°C for 12 hours while blowing dry nitrogen gas at 100 ml/min. Toluene and water were added to the reaction mixture to separate the layers, and the toluene solution was washed with water, dried, and concentrated to yield 7.62 g of β-piperidinoethyl ester of 3-methyl-flavone-8-carboxylic acid (purity 99.5 by gas chromatography).
%) obtained. On the other hand, the aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and concentrated to obtain 0.14 g of 3-methyl-flavone-8-carboxylic acid. The conversion rate of methyl ester was 99.4%, the yield of β-piperidino ethyl ester was 96.8%, the selectivity was 97.4%, and the yield of carboxylic acid was 2.6%. Examples 2 to 5 The reaction was carried out in the same manner as in Example 1, except that the catalyst shown in Table 1 was used instead of potassium carbonate in Example 1, and the results shown in Table 1 were obtained.
【表】
実施例 ６〜９
実施例１のβ−ピペリジノ−エタノールの代り
に表２に記載したアルコールを用いた以外は、実
施例１と同様に反応を行い、表２の結果を得た。[Table] Examples 6 to 9 The reaction was carried out in the same manner as in Example 1, except that the alcohol listed in Table 2 was used instead of β-piperidino-ethanol in Example 1, and the results shown in Table 2 were obtained.
【表】【table】
【表】
実施例 10〜13
実施例１の３−メチル−フラボン−８−カルボ
ン酸メチルエステルの代りに表３に記載したエス
テルを用いた以外は、実施例１と同様に反応を行
つたところ、表３の結果が得られた。[Table] Examples 10 to 13 The reaction was carried out in the same manner as in Example 1, except that the esters listed in Table 3 were used in place of the 3-methyl-flavone-8-carboxylic acid methyl ester in Example 1. , the results shown in Table 3 were obtained.
【表】【table】
【表】
実施例 14
実施例１において乾燥した窒素ガスを吹き込む
代りに減圧下（200mmHg）にメタノールを系外へ
留去しながら反応させた以外は、実施例１と同様
に反応を行つたところ、転化率は99.8％、収率は
97.4％、選択率は97.6％、酸の収率は2.4％であつ
た。
実施例 15
実施例１のジメチルホルムアミドの代りにジメ
チルスルホキシドを用いた以外は、実施例１と同
様に反応を行つたところ、転化率は99.6％、収率
は94.2％、選択率は94.6％であつた。
比較例 １〜３
実施例１の炭酸カリウムの代りに、表４に記載
した触媒を用いた以外は実施例１と同様に反応を
行い、表４の結果を得た。[Table] Example 14 The reaction was carried out in the same manner as in Example 1, except that instead of blowing dry nitrogen gas in Example 1, the reaction was carried out while distilling methanol out of the system under reduced pressure (200 mmHg). , conversion rate is 99.8%, yield is
The selectivity was 97.4%, the selectivity was 97.6%, and the acid yield was 2.4%. Example 15 The reaction was carried out in the same manner as in Example 1 except that dimethyl sulfoxide was used in place of dimethylformamide in Example 1. The conversion rate was 99.6%, the yield was 94.2%, and the selectivity was 94.6%. It was hot. Comparative Examples 1 to 3 The reaction was carried out in the same manner as in Example 1, except that the catalyst shown in Table 4 was used instead of potassium carbonate in Example 1, and the results shown in Table 4 were obtained.
Claims (1)
アリール基を示し、R2およびR3はそれぞれ水素、
アルキル基またはハロゲンを示し、R4は水素、
アルキル基またはアリール基を示す。）で表わさ
れるフラボンカルボン酸エステル類と、一般式
〔〕 R5OH （式中、R5は上記R1とは異なるアルキル基、ア
ラルキル基、モノヒドロキシアルキル基またはア
ミノアルキル基を示す。）で表わされるアルコー
ル類とを反応させて一般式〔〕 （式中、R2、R3、R4およびR5は上記と同じ）で
表わされるフラボンカルボン酸エステル類を製造
する方法において、触媒としてアルカリ金属炭酸
塩を用いることを特徴とするフラボンカルボン酸
エステル類の製法。[Claims] 1. General formula [] (In the formula, R 1 represents an alkyl group, an aralkyl group, or an aryl group, and R 2 and R 3 are hydrogen, respectively.
Indicates an alkyl group or halogen, R 4 is hydrogen,
Indicates an alkyl group or an aryl group. ) with the general formula [] R 5 OH (wherein R 5 represents an alkyl group, an aralkyl group, a monohydroxyalkyl group, or an aminoalkyl group different from R 1 above). By reacting with the alcohols represented by the general formula [] (In the formula, R 2 , R 3 , R 4 and R 5 are the same as above) A method for producing flavone carboxylic acid esters, characterized in that an alkali metal carbonate is used as a catalyst. Production method of esters.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58084953A JPS59212485A (en) | 1983-05-17 | 1983-05-17 | Preparation of flavonecarboxylic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58084953A JPS59212485A (en) | 1983-05-17 | 1983-05-17 | Preparation of flavonecarboxylic acid ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59212485A JPS59212485A (en) | 1984-12-01 |
| JPH0153874B2 true JPH0153874B2 (en) | 1989-11-15 |
Family
ID=13844994
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58084953A Granted JPS59212485A (en) | 1983-05-17 | 1983-05-17 | Preparation of flavonecarboxylic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59212485A (en) |
-
1983
- 1983-05-17 JP JP58084953A patent/JPS59212485A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59212485A (en) | 1984-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4667691B2 (en) | Process for the preparation of nitroxyalkyl esters of naproxen | |
| Koh et al. | Stereoselective SN2 Reactions of the (R)-Pantolactone Ester of Racemic. alpha.-Halo Carboxylic Acids with Aryl Oxides. A Synthesis of (S)-2-Aryloxy and (S)-2-Hydroxy Acids | |
| KR101529403B1 (en) | 3,4-dialkylbiphenyldicarboxylic acid compound, 3,4-dicarboalkoxybiphenyl-3',4'-dicarboxylic acid and corresponding acid anhydrides, and processes for producing these compounds | |
| JP3085469B2 (en) | Production of amide ester compound | |
| JPH11140019A (en) | Hydroquinone diester derivative and its production | |
| JPH0153874B2 (en) | ||
| JPH11246549A (en) | Production of alpha-tocopherol ester | |
| EP0829472B1 (en) | Improved process for producing 4-hydroxy-2-pyrrolidone | |
| JP2773587B2 (en) | Process for producing O, O'-diacyltartaric anhydride | |
| US4439368A (en) | One solvent process for preparation of esters of 3,5-dibromo-4-hydroxybenzonitrile | |
| JP3823385B2 (en) | Process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof | |
| EP0968994A1 (en) | Substituted trifluorobenzoic acids, esters thereof, and process for producing the same | |
| JPH0212472B2 (en) | ||
| JPH0212473B2 (en) | ||
| EP0123719B1 (en) | Processes for preparing 5-acyloxymethyloxazolidin-2-one-derivatives | |
| JP3944876B2 (en) | Method for producing citrate esters | |
| JP2903233B2 (en) | Method for producing high-purity dimethyl diphenyldicarboxylate | |
| JPH0478638B2 (en) | ||
| JPH0372054B2 (en) | ||
| JP2911296B2 (en) | Method for producing tris (4-hydroxybenzyl) isocyanurate compound | |
| JP2000191592A (en) | Manufacture of hydroquinone, diester derivative | |
| US6180801B1 (en) | Method for manufacturing 3-isochromanone | |
| JPH027305B2 (en) | ||
| US4982010A (en) | Method of producing 4-biphenyl p-tolyl ether | |
| JP2591111B2 (en) | Method for inverting the configuration of an optically active α-oxy acid ester |