JPH026340B2 - - Google Patents
Info
- Publication number
- JPH026340B2 JPH026340B2 JP13397581A JP13397581A JPH026340B2 JP H026340 B2 JPH026340 B2 JP H026340B2 JP 13397581 A JP13397581 A JP 13397581A JP 13397581 A JP13397581 A JP 13397581A JP H026340 B2 JPH026340 B2 JP H026340B2
- Authority
- JP
- Japan
- Prior art keywords
- bromine
- thymol
- reaction
- solution
- tetrahydrofuran
- 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
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 239000005844 Thymol Substances 0.000 claims description 12
- 229960000790 thymol Drugs 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- ZSIQWWYOUYOECH-UHFFFAOYSA-N 4-bromo-5-methyl-2-propan-2-ylphenol Chemical compound CC(C)C1=CC(Br)=C(C)C=C1O ZSIQWWYOUYOECH-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000507 anthelmentic effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QHPNUEGQPHJYFW-UHFFFAOYSA-N 2,4-dibromo-3-methyl-6-propan-2-ylphenol Chemical compound CC(C)C1=CC(Br)=C(C)C(Br)=C1O QHPNUEGQPHJYFW-UHFFFAOYSA-N 0.000 description 1
- UZVUSORDFOESJG-UHFFFAOYSA-N 2-bromo-3-methyl-6-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(C)C(Br)=C1O UZVUSORDFOESJG-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- VRYMTAVOXVTQEF-UHFFFAOYSA-N acetic acid [4-[2-(dimethylamino)ethoxy]-2-methyl-5-propan-2-ylphenyl] ester Chemical compound CC(C)C1=CC(OC(C)=O)=C(C)C=C1OCCN(C)C VRYMTAVOXVTQEF-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- -1 carbon tetrachloride Chemical compound 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960003509 moxisylyte Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は下記式(1)を有する６−ブロムチモール
の製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 6-bromthymol having the following formula (1).
本発明は、チモールを出発原料として６−ブロ
ムチモールを製造する場合に、チモールを、テト
ラヒドロフランの存在下において、臭素によつて
臭素化することを特徴とするものである。 The present invention is characterized in that when 6-bromothymol is produced using thymol as a starting material, thymol is brominated with bromine in the presence of tetrahydrofuran.
６−ブロムチモールは、そのまま駆虫剤として
用いられる外に、下記式(2)
を有する、循環器系の薬剤として用いられるチモ
キサミンを合成するための原料としても有用な化
合物である。 In addition to being used as an anthelmintic, 6-bromthymol can also be used as an anthelmintic as shown in the formula (2) below. It is a compound that is also useful as a raw material for synthesizing thymoxamine, which is used as a drug for the circulatory system.
一般に活性な芳香核を臭素化するためには、通
常、溶媒として、水、酢酸などの他、クロロホル
ム、四塩化炭素のような塩素化炭化水素、ベンゼ
ンのような不活性な芳香族炭化水素が、被反応物
の性質、反応条件などによつて選択して用いら
れ、この溶液に、臭素を作用せしめて臭素化する
のであるが、従来からの方法では選択的に臭素化
することは困難であり、チモールに臭素を作用さ
せて６−ブロムチモールを得る従来から知られて
いるいくつかの方法のうち、酢酸中で当量の臭素
を用いる方法（Plancer、Gazzetta Chimica
Italiana、23、76；Cross et al.、J.Am.
Pharm.Assoc.、44、637（1955））では、選択的な
モノブロム化反応でなく、ジブロム化合物をも生
成するため、両者の分離操作を必要とし、収率も
低い。この方法において、２当量の臭素をチモー
ルに作用させると、２，６−ジブロムチモールを
生成する（Jost et al.、Ber.、56、122）。Buzas
ら（Bull.Soc.Chim.France、1959、839）の方法
では、あらかじめ、ジオキサンと臭素とからジオ
キサンジブロマイドを生成せしめ、これにチモー
ルのジオキサン溶液を添加して、ブロム化反応を
行なう方法であるが、この場合も過剰の臭素中に
チモールを添加する方法であるので、ジブロム化
合物の副生は免れ得ず、したがつて目的の６−ブ
ロムチモールの収率が低い。 Generally, in order to bromine active aromatic nuclei, in addition to water, acetic acid, etc., chloroform, chlorinated hydrocarbons such as carbon tetrachloride, and inert aromatic hydrocarbons such as benzene are used as solvents. The solution is selected and used depending on the properties of the reactants, reaction conditions, etc., and bromination is carried out by exposing this solution to bromine, but it is difficult to selectively bromine using conventional methods. Among several conventionally known methods for obtaining 6-bromthymol by reacting bromine with thymol, the method using an equivalent amount of bromine in acetic acid (Plancer, Gazzetta Chimica
Italiana, 23 , 76; Cross et al., J.Am.
Pharm.Assoc., 44 , 637 (1955)) does not perform a selective monobromination reaction, but also generates a dibrome compound, which requires a separation operation for both, and the yield is low. In this method, the action of two equivalents of bromine on thymol produces 2,6-dibromthymol (Jost et al., Ber., 56 , 122). Buzas
In the method of Bull. Soc. Chim. However, in this case as well, since thymol is added to excess bromine, the by-product of dibrome compounds cannot be avoided, and therefore the yield of the target 6-bromothymol is low.
本発明者らは、以上に述べた６−ブロムチモー
ルを得る方法において、反応操作の簡便化、目的
物の収率の向上を検討した結果、テトラヒドロフ
ランの共存下でチモールに臭素を作用させること
によつて、６−ブロムチモールを得ることに成功
した。すなわち臭素と反応しない、水に不溶の溶
媒、例えば、ベンゼン、クロロホルムまたは二塩
化エチレンなどにチモールを溶解させ、この溶液
にテトラヒドロフランを１〜10倍モル量を加え
る。ブロム化が進行するにつれて生成する臭化水
素を反応系内で捕捉するためと、反応後の洗浄工
程の効率化をはかるために、添加すべきテトラヒ
ドロフランの量は、チモールに対して、３〜５倍
モル量が好ましい。この混合物に−５〜10℃の温
度で、臭素を単独で、あるいは、チモールを溶解
するのに用いた同一の溶媒に溶かした臭素溶液を
滴下すると、ブロム化は短時間で終了する。反応
液を単に水洗するのみで、副生した臭化水素は除
去できるが、反応液の水洗後、更に炭酸水素ナト
リウムなどの弱アルカリ性の水溶液で洗浄するの
が好ましい。減圧下で溶媒を留去すると、冷後固
化する高純度の６−ブロムチモールが高収率で得
られる。ここに得られた６−ブロムチモールは、
このまま次の反応に使用しうるような純度である
が、必要に応じて減圧蒸留またはヘキサンから再
結晶して精製することもできる。沸点114−116
℃／1.5mmHg、融点54〜55℃であつた。ここで特
筆すべきことは、臭素はジオキサン中では不溶の
付加体を形成するに反し、テトラヒドロフラン中
では生成した付加体は、溶媒に可溶である。従つ
て、本反応においては、所要のテトラヒドロフラ
ンをあらかじめ、チモールと共存させることな
く、滴下すべき臭素中に加えても、同様の結果が
得られる。 The present inventors investigated ways to simplify the reaction operation and improve the yield of the target product in the method for obtaining 6-bromothymol described above, and as a result, the inventors decided to cause bromine to act on thymol in the coexistence of tetrahydrofuran. Thus, we succeeded in obtaining 6-bromthymol. That is, thymol is dissolved in a water-insoluble solvent that does not react with bromine, such as benzene, chloroform, or ethylene dichloride, and 1 to 10 times the molar amount of tetrahydrofuran is added to this solution. In order to capture hydrogen bromide generated as bromination progresses in the reaction system and to improve the efficiency of the washing process after the reaction, the amount of tetrahydrofuran to be added is 3 to 5 ml based on thymol. Double molar amounts are preferred. When bromine alone or a bromine solution dissolved in the same solvent used to dissolve thymol is added dropwise to this mixture at a temperature of -5 to 10°C, bromination is completed in a short time. By-product hydrogen bromide can be removed by simply washing the reaction solution with water, but after washing the reaction solution with water, it is preferable to further wash with a weakly alkaline aqueous solution such as sodium bicarbonate. When the solvent is distilled off under reduced pressure, highly pure 6-bromothymol, which solidifies after cooling, is obtained in high yield. The 6-bromthymol obtained here is
The purity is such that it can be used as is for the next reaction, but if necessary, it can be purified by distillation under reduced pressure or by recrystallization from hexane. boiling point 114−116
°C/1.5 mmHg, melting point was 54-55 °C. It should be noted here that bromine forms an insoluble adduct in dioxane, but in tetrahydrofuran, the adduct formed is soluble in the solvent. Therefore, in this reaction, the same result can be obtained even if the required tetrahydrofuran is added in advance to the bromine to be added dropwise without coexisting with thymol.
以上述べたように本発明は、従来の方法に比べ
て、安全に、かつ簡便に反応操作を実施すること
ができるのみならず、極めて選択的なブロム化を
行なうことができ、目的とする６−ブロムチモー
ルの収率も高いなど、工業的な製法としてすぐれ
ている。 As described above, the present invention not only allows reaction operations to be carried out more safely and simply than conventional methods, but also allows extremely selective bromination to be achieved. -It is an excellent industrial production method, with a high yield of bromothymol.
以下に本発明の実施例を示す。 Examples of the present invention are shown below.
実施例
チモール47ｇ（0.313モル）を二塩化エチレン
200ml中に溶かし、これに乾燥したテトラヒドロ
フラン90.3ｇ（1.252モル）を加え、この溶液に、
かきまぜながら５℃において、臭素50ｇ（0.313
モル）を二塩化エチレン50mlに溶かした溶液を滴
下し、滴下を終了した後、さらに30分間かきまぜ
をつづけ、この反応液を水200mlで２回洗浄し、
有機層を硫酸マグネシウムによつて乾燥した後、
減圧下で二塩化エチレンを留去し、微黄色の液体
（この液体は冷却すると固化する）を得、この液
体を減圧蒸着し、沸点114〜116℃／1.5mmHgの無
色の液体67.5ｇ（収率94.1％）を得た。この液体
は冷却によつて固化し、ヘキサンを用いて再結晶
すると、融点54〜55℃の無色の針状晶を得た。Example 47g (0.313mol) of thymol was added to ethylene dichloride.
Dissolve in 200 ml, add 90.3 g (1.252 mol) of dry tetrahydrofuran, and add to this solution,
50 g of bromine (0.313
A solution of mol) dissolved in 50 ml of ethylene dichloride was added dropwise, and after the addition was complete, stirring was continued for another 30 minutes, and the reaction solution was washed twice with 200 ml of water.
After drying the organic layer with magnesium sulfate,
Ethylene dichloride was distilled off under reduced pressure to obtain a slightly yellow liquid (this liquid solidifies when cooled), and this liquid was evaporated under reduced pressure to yield 67.5 g of a colorless liquid with a boiling point of 114-116°C/1.5 mmHg (yield). rate of 94.1%). The liquid solidified on cooling and was recrystallized from hexane to give colorless needles with a melting point of 54-55°C.
上記本発明の方法によつて得た６−ブロムチモ
ールと、文献（J.Am.Pharm.Assoc.44、637
（1955））に記載の方法に従つて合成した６−ブロ
ムチモールを混融し、またその赤外吸収スペクト
ルを比較することによつて、両者が同一の６−ブ
ロムチモールであることを確認した。 6-bromthymol obtained by the method of the present invention and the literature (J.Am.Pharm.Assoc. 44 , 637)
(1955)), and by comparing their infrared absorption spectra, it was confirmed that both were the same 6-bromothymol. .
Claims (1)
いて、臭素によつて臭素化することを特徴とする
下記式(1)を有する６−ブロムチモールの製法。 [Scope of Claims] 1. A method for producing 6-bromothymol having the following formula (1), which comprises brominating thymol with bromine in the presence of tetrahydrofuran.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13397581A JPS5835136A (en) | 1981-08-28 | 1981-08-28 | Preparation of 6-bromothymol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13397581A JPS5835136A (en) | 1981-08-28 | 1981-08-28 | Preparation of 6-bromothymol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5835136A JPS5835136A (en) | 1983-03-01 |
| JPH026340B2 true JPH026340B2 (en) | 1990-02-08 |
Family
ID=15117444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13397581A Granted JPS5835136A (en) | 1981-08-28 | 1981-08-28 | Preparation of 6-bromothymol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5835136A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2525116B2 (en) * | 1993-04-05 | 1996-08-14 | 日本ドアーチエック製造株式会社 | Pivot hinge |
| IT201600090701A1 (en) | 2016-09-08 | 2016-12-08 | Univ Degli Studi Di Roma “Tor Vergata” | Process of sustainable synthesis of 4-bromothymol and its use as an antimicrobial. |
-
1981
- 1981-08-28 JP JP13397581A patent/JPS5835136A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5835136A (en) | 1983-03-01 |
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