JPS6159615B2 - - Google Patents
Info
- Publication number
- JPS6159615B2 JPS6159615B2 JP5350780A JP5350780A JPS6159615B2 JP S6159615 B2 JPS6159615 B2 JP S6159615B2 JP 5350780 A JP5350780 A JP 5350780A JP 5350780 A JP5350780 A JP 5350780A JP S6159615 B2 JPS6159615 B2 JP S6159615B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- solution
- trimethoxybenzaldehyde
- dihydroxybenzaldehyde
- methoxy
- 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
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 13
- RRKMWVISRMWBAL-UHFFFAOYSA-N 3,4-dihydroxy-5-methoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(O)=C1O RRKMWVISRMWBAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 23
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000003513 alkali Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- UCTUXUGXIFRVGX-UHFFFAOYSA-N 2,3,4-trimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1OC UCTUXUGXIFRVGX-UHFFFAOYSA-N 0.000 description 2
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- IXWOUPGDGMCKGT-UHFFFAOYSA-N 2,3-dihydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1O IXWOUPGDGMCKGT-UHFFFAOYSA-N 0.000 description 1
- PCYGLFXKCBFGPC-UHFFFAOYSA-N 3,4-Dihydroxy hydroxymethyl benzene Natural products OCC1=CC=C(O)C(O)=C1 PCYGLFXKCBFGPC-UHFFFAOYSA-N 0.000 description 1
- -1 3,4-dihydroxybenzaldehyde Dimethyl sulfuric acid Chemical compound 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は５−メトキシ−３，４−ジヒドロキシ
ベンズアルデヒドをジメチル化して３，４，５−
トリメトキシベンズアルデヒドを製造する方法に
関するものである。３，４，５−トリメトキシベ
ンズアルデヒドは医薬、特にトリメトプリムの中
間体として有用な化合物である。DETAILED DESCRIPTION OF THE INVENTION The present invention dimethylates 5-methoxy-3,4-dihydroxybenzaldehyde to produce 3,4,5-
The present invention relates to a method for producing trimethoxybenzaldehyde. 3,4,5-trimethoxybenzaldehyde is a compound useful as an intermediate for pharmaceuticals, especially trimethoprim.
従来、５−メトキシ−３，４−ジヒドロキシベ
ンズアルデヒドをジメチル化する代表的なものと
して、J.Chem.Soc.，811（1930）及び特公昭51
−36743号公報記載の方法が挙げられる。前者で
は水が溶媒として用いられ反応時間は短縮される
が、大量のジメチル硫酸を必要とし、目的生成物
の収率が低いという欠点があつた。一方、後者で
はジメチル硫酸の使用量が低く抑えられ、目的生
成物の収率も向上するが、非水系の溶媒を必要と
し、反応時間が延長されるという欠点があつた。 Conventionally, as a representative method for dimethylating 5-methoxy-3,4-dihydroxybenzaldehyde, J.Chem.Soc., 811 (1930) and Japanese Patent Publication No. 51
The method described in Publication No.-36743 can be mentioned. In the former method, water is used as a solvent and the reaction time is shortened, but a large amount of dimethyl sulfate is required and the yield of the desired product is low. On the other hand, in the latter method, the amount of dimethyl sulfate used can be kept low and the yield of the desired product can be improved, but it has the drawbacks of requiring a non-aqueous solvent and prolonging the reaction time.
そこで、本発明者は前記のような欠点を改善し
て、水溶液中において短縮された反応時間で高収
率に目的生成物を製造する方法について鋭意検討
した結果、本発明に到達した。 Therefore, the present inventor has conducted extensive research into a method for producing the desired product in a high yield in a shortened reaction time in an aqueous solution by improving the above-mentioned drawbacks, and as a result, has arrived at the present invention.
すなわち、本発明は、５−メトキシ−３，４−
ジヒドロキシベンズアルデヒド１モルに対してジ
メチル硫酸２〜６モルをPH８〜12に保持されたア
ルカリ性水溶液中において、30〜80℃で反応させ
ることを特徴とする３，４，５−トリメトキシベ
ンズアルデヒドの製法に関するものである。 That is, the present invention provides 5-methoxy-3,4-
A process for producing 3,4,5-trimethoxybenzaldehyde, which comprises reacting 1 mole of dihydroxybenzaldehyde with 2 to 6 moles of dimethyl sulfate in an alkaline aqueous solution maintained at a pH of 8 to 12 at 30 to 80°C. It is something.
５−メトキシ−３，４−ジヒドロキシベンズア
ルデヒドとジメチル硫酸との反応は化学量論量的
には１：１（モル比）で十分であるはずである。
しかしジメチル硫酸の２個のメチル基を利用する
ために反応温度を100℃以上に保持すると、目的
生成物の３，４，５−トリメトキシベンズアルデ
ヒドのホルミル基が反応して副生成物が生成する
ので、反応温度を低く保持してジメチル硫酸の１
個のメチル基を利用する方が有利である。従つ
て、ジメチル硫酸の使用量は、５−メトキシ−
３，４−ジヒドロキシベンズアルデヒド１モルに
対して少なくとも２モル以上が必要であり、通
常、２〜６モル、特に4.5〜５モルが好ましい。 Stoichiometrically, a 1:1 (molar ratio) should be sufficient for the reaction of 5-methoxy-3,4-dihydroxybenzaldehyde and dimethyl sulfate.
However, if the reaction temperature is maintained at 100°C or higher in order to utilize the two methyl groups of dimethyl sulfate, the formyl group of the desired product, 3,4,5-trimethoxybenzaldehyde, will react and produce by-products. Therefore, by keeping the reaction temperature low, 1 of dimethyl sulfate
It is advantageous to use methyl groups. Therefore, the amount of dimethyl sulfate used is 5-methoxy-
At least 2 moles or more are required per mole of 3,4-dihydroxybenzaldehyde, and usually 2 to 6 moles, particularly preferably 4.5 to 5 moles.
また本反応はアルカリ水溶液中において行われ
るが、アルカリはジメチル硫酸と反応してモノメ
チル硫酸塩、芒硝等を副生する。従つて、この副
反応をできるだけ抑制し、ジメチル硫酸とフエノ
レートとの間のメチル化反応を優先するように、
アルカリ水溶液をPH８〜12、特にPH９〜11に調節
する必要がある。PH値がこの範囲以外であるとモ
ノフエノール性化合物が生成し、目的生成物の収
率が低下する。アルカリとしてはアルカリ金属、
アルカリ土類金属の水酸化物及び炭酸塩が用いら
れるが、特に水酸化ナトリウム、水酸化カリウム
が好ましい。また添加するアルカリ水溶液の濃度
は0.5〜３規定、特に１〜２規定が好ましい。 Further, this reaction is carried out in an aqueous alkali solution, and the alkali reacts with dimethyl sulfate to produce by-products such as monomethyl sulfate and Glauber's salt. Therefore, in order to suppress this side reaction as much as possible and prioritize the methylation reaction between dimethyl sulfate and phenolate,
It is necessary to adjust the alkaline aqueous solution to pH 8-12, especially pH 9-11. If the PH value is outside this range, monophenolic compounds will be produced and the yield of the desired product will be reduced. Alkali metals as alkalis,
Alkaline earth metal hydroxides and carbonates are used, with sodium hydroxide and potassium hydroxide being particularly preferred. The concentration of the alkaline aqueous solution to be added is preferably 0.5 to 3N, particularly 1 to 2N.
反応温度は30〜80℃、特に40〜60℃が好まし
い。反応温度を高温にすると生成した３，４，５
−トリメトキシベンズアルデヒドのホルミル基が
反応に関与して副生成物を生成し、また反応温度
を低温にすると反応速度が低下するので好ましく
ない。 The reaction temperature is preferably 30 to 80°C, particularly 40 to 60°C. 3, 4, 5 generated when the reaction temperature was increased
-The formyl group of trimethoxybenzaldehyde participates in the reaction and produces by-products, and lowering the reaction temperature is not preferred because the reaction rate decreases.
本発明の方法の一実施態様は、５−メトキシ−
３，４−ジヒドロキシベンズアルデヒドのPH８〜
12に調整されたアルカリ水溶液中に、ジメチル硫
酸を徐々に滴下していき、PH値の低下が生じる際
には直ちにアルカリを加えてPH８〜12に調節しな
がら、所定温度で十分に撹拌し、反応を行われ
る。なお、生成した３，４，５−トリメトキシベ
ンズアルデヒドは溶剤抽出、蒸留、再結晶等、公
知の操作によつて取得される。 One embodiment of the method of the invention is 5-methoxy-
PH8~ of 3,4-dihydroxybenzaldehyde
Dimethyl sulfuric acid is gradually dropped into an aqueous alkali solution adjusted to pH 12, and when the pH value decreases, immediately add alkali to adjust the pH to 8 to 12 while stirring thoroughly at the specified temperature. The reaction is carried out. Note that the generated 3,4,5-trimethoxybenzaldehyde can be obtained by known operations such as solvent extraction, distillation, and recrystallization.
以上、本発明の方法を実施することによつて、
５−メトキシ−３，４−ジヒドロキシベンズアル
デヒドから高収率で３，４，５−トリメトキシベ
ンズアルデヒドを製造することができる。 As described above, by implementing the method of the present invention,
3,4,5-trimethoxybenzaldehyde can be produced in high yield from 5-methoxy-3,4-dihydroxybenzaldehyde.
実施例 １
５−メトキシ−３，４−ジヒドロキシベンズア
ルデヒド33.6ｇ（0.2モル）を水300ml中に加え１
規定の水酸化ナトリウム水溶液でPH10に中和し
た。この水溶液の温度を60℃に昇温後、ジメチル
硫酸57.0ｇ（0.45モル）を反応液のPH値を１規定
の水酸化ナトリウム水溶液で９〜10に調節しなが
ら60分間かけて滴下し、反応させた。反応終了後
の反応液のPH値は9.2であつた。反応液からトル
エンにより３，４，５−トリメトキシベンズアル
デヒドを抽出し、ガスクロマトグラフイー分析し
たところ37.2ｇ生成していた。収率は95％であ
る。Example 1 33.6 g (0.2 mol) of 5-methoxy-3,4-dihydroxybenzaldehyde was added to 300 ml of water.
It was neutralized to pH 10 with a specified aqueous sodium hydroxide solution. After raising the temperature of this aqueous solution to 60°C, 57.0 g (0.45 mol) of dimethyl sulfuric acid was added dropwise over 60 minutes while adjusting the PH value of the reaction solution to 9 to 10 with a 1N aqueous sodium hydroxide solution. I let it happen. The pH value of the reaction solution after the completion of the reaction was 9.2. 3,4,5-trimethoxybenzaldehyde was extracted from the reaction solution with toluene, and gas chromatography analysis revealed that 37.2 g was produced. Yield is 95%.
実施例 ２
５−メトキシ−３，４−ジヒドロキシベンズア
ルデヒド33.6ｇ（0.2モル）を水300ml中に加え１
規定の水酸化カリウム水溶液でPH11に中和した。
この水溶液の温度を50℃に昇温後、ジメチル硫酸
57.0ｇ（0.45モル）を反応液のPH値を１規定の水
酸化カリウム水溶液で10〜11に調節しながら60分
間かけて滴下し、反応させた。反応終了後の反応
液のPH値は10.3であつた。反応液をトルエン抽出
し、ガスクロマトグラフイー分析したところ、
３，４，５−トリメトキシベンズアルデヒドの収
率は93％であつた。Example 2 33.6 g (0.2 mol) of 5-methoxy-3,4-dihydroxybenzaldehyde was added to 300 ml of water.
It was neutralized to pH 11 with a specified aqueous potassium hydroxide solution.
After raising the temperature of this aqueous solution to 50℃, dimethyl sulfate
57.0 g (0.45 mol) was added dropwise to the reaction solution over 60 minutes while adjusting the pH value of the reaction solution to 10 to 11 with a 1N aqueous potassium hydroxide solution to cause a reaction. The pH value of the reaction solution after the completion of the reaction was 10.3. The reaction solution was extracted with toluene and analyzed by gas chromatography.
The yield of 3,4,5-trimethoxybenzaldehyde was 93%.
比較例
５−メトキシ−３，４−ジヒドロキシベンズア
ルデヒド33.6ｇ（0.2モル）を水350ml中に溶かし
たものにジメチル硫酸168ｇ（1.33モル）と10％
濃度の水酸化ナトリウム水溶液672mlを加えた
後、撹拌下に室温で60分間反応させた。反応終了
後の反応液のPH値は13.3であつた。反応液をトル
エン抽出し、ガスクロマトグラフイ分析したとこ
ろ、３，４，５−トリメトキシベンズアルデヒド
の収率は48％であつた。Comparative Example 33.6 g (0.2 mol) of 5-methoxy-3,4-dihydroxybenzaldehyde dissolved in 350 ml of water was mixed with 168 g (1.33 mol) of dimethyl sulfate and 10%
After adding 672 ml of a concentrated aqueous sodium hydroxide solution, the mixture was allowed to react at room temperature for 60 minutes with stirring. The pH value of the reaction solution after the completion of the reaction was 13.3. When the reaction solution was extracted with toluene and analyzed by gas chromatography, the yield of 3,4,5-trimethoxybenzaldehyde was 48%.
Claims (1)
アルデヒド１モルに対してジメチル硫酸２〜６モ
ルをPH８〜12に保持されたアルカリ性水溶液中に
おいて、30〜80℃で反応させることを特徴とする
３，４，５−トリメトキシベンズアルデヒドの製
法。1 3,4 characterized by reacting 1 mole of 5-methoxy-3,4-dihydroxybenzaldehyde with 2 to 6 moles of dimethyl sulfuric acid at 30 to 80°C in an alkaline aqueous solution maintained at pH 8 to 12. , 5-Trimethoxybenzaldehyde production method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5350780A JPS56150034A (en) | 1980-04-24 | 1980-04-24 | Preparation of 3,4,5-trimethoxybenzaldehyde |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5350780A JPS56150034A (en) | 1980-04-24 | 1980-04-24 | Preparation of 3,4,5-trimethoxybenzaldehyde |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56150034A JPS56150034A (en) | 1981-11-20 |
| JPS6159615B2 true JPS6159615B2 (en) | 1986-12-17 |
Family
ID=12944727
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5350780A Granted JPS56150034A (en) | 1980-04-24 | 1980-04-24 | Preparation of 3,4,5-trimethoxybenzaldehyde |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56150034A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2609984B1 (en) * | 1987-01-28 | 1989-05-05 | Rhone Poulenc Chimie | PROCESS FOR THE PREPARATION OF TRIALKOXYBENZALDEHYDE |
| US4914243A (en) * | 1987-12-23 | 1990-04-03 | American Home Products Corporation | Production of 2-alkoxy or aryl(lower)alkoxy-6-methoxy-1-naphthalenecarboxaldehyde |
| CN1034169C (en) * | 1991-07-30 | 1997-03-05 | 中国科学院大连化学物理研究所 | Synthesis method for trimethoxybenz-aldehyde |
-
1980
- 1980-04-24 JP JP5350780A patent/JPS56150034A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56150034A (en) | 1981-11-20 |
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