KR20230114620A - Process for Preparing Guaiacol - Google Patents
Process for Preparing Guaiacol Download PDFInfo
- Publication number
- KR20230114620A KR20230114620A KR1020220011010A KR20220011010A KR20230114620A KR 20230114620 A KR20230114620 A KR 20230114620A KR 1020220011010 A KR1020220011010 A KR 1020220011010A KR 20220011010 A KR20220011010 A KR 20220011010A KR 20230114620 A KR20230114620 A KR 20230114620A
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- mixture
- methoxybenzene
- acetoxy
- dimethoxybenzene
- Prior art date
Links
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960001867 guaiacol Drugs 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 10
- BHJHPYFAYGAPLS-UHFFFAOYSA-N Guaicyl acetate Chemical compound COC1=CC=CC=C1OC(C)=O BHJHPYFAYGAPLS-UHFFFAOYSA-N 0.000 claims abstract description 65
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 239000000126 substance Substances 0.000 claims abstract description 33
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims abstract description 16
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000000903 blocking effect Effects 0.000 abstract description 5
- 231100000024 genotoxic Toxicity 0.000 abstract description 5
- 230000001738 genotoxic effect Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 240000006982 Guaiacum sanctum Species 0.000 description 1
- 235000004440 Guaiacum sanctum Nutrition 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
- C07C41/42—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation by distillation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 구아야콜의 제조방법에 관한 것으로, 보다 상세하게는 합성 중 발생할 수 있는 유전독성물질을 원천적으로 차단하면서 고순도의 구아야콜을 효율적으로 제조하는 방법에 관한 것이다.The present invention relates to a method for producing guayacol, and more particularly, to a method for efficiently producing high-purity guayacol while fundamentally blocking genotoxic substances that may occur during synthesis.
하기 화학식 1의 구아야콜 (2-메톡시페놀)은 거담제, 방부제 및 국소 마취제로 사용되는 약물로서, 유창목(guaiacum)이나 나무 크레오소트(wood creosote)로부터 얻어지는 유기 화합물이다.Guayacol (2-methoxyphenol) of Formula 1 is a drug used as an expectorant, antiseptic and local anesthetic, and is an organic compound obtained from guaiacum or wood creosote.
[화학식 1][Formula 1]
구아야콜의 대량 합성방법으로는 카테콜과 디메틸설페이트를 반응시킨 뒤, 생성된 구아야콜을 분리 정제하는 방법이 알려져 있다.As a method for mass synthesis of guayacol, a method of reacting catechol with dimethyl sulfate and then separating and purifying the produced guayacol is known.
그러나, 이러한 합성법은 의약품규제조화위원회(ICH) 가이드라인에 저촉된다. 구체적으로, 부산물로 생성되는 1,2-디메톡시벤젠이 변이원성이 확인된 물질로 TTC(Threshold of Toxicological Concern)로 관리해야 할 필요가 있다. 그런데, 구아야콜과 1,2-디메톡시벤젠은 물성이 거의 동일하며, 비점이 각각 205℃, 207℃로 거의 차이가 없어 증류 정제가 불가능하다.However, these synthetic methods are in conflict with the ICH Guidelines. Specifically, 1,2-dimethoxybenzene produced as a by-product is a substance for which mutagenicity has been confirmed and needs to be managed as a Threshold of Toxicological Concern (TTC). However, guayacol and 1,2-dimethoxybenzene have almost the same physical properties, and there is almost no difference in boiling points of 205 ° C and 207 ° C, respectively, so distillation and purification are impossible.
본 발명자들은 구아야콜의 제조에 있어서 상기한 문제점을 해결하고자 예의 연구 검토한 결과, 카테콜과 디메틸설페이트를 반응시켜 구아야콜과 1,2-디메톡시벤젠의 혼합물을 수득한 후, 이를 아세틸클로라이드와 반응시켜 1-아세톡시-2-메톡시벤젠과 1,2-디메톡시벤젠의 혼합물을 수득하고, 상기 1-아세톡시-2-메톡시벤젠과 1,2-디메톡시벤젠의 혼합물을 증류하여 1-아세톡시-2-메톡시벤젠을 분리한 다음, 상기 1-아세톡시-2-메톡시벤젠을 가수분해반응시킴으로써 고순도의 구아야콜을 고수율로 대량생산할 수 있음을 알아내고, 본 발명을 완성하게 되었다.As a result of intensive research and study to solve the above problems in the production of guayacol, the present inventors obtained a mixture of guayacol and 1,2-dimethoxybenzene by reacting catechol with dimethyl sulfate, and then acetylated it. reacted with chloride to obtain a mixture of 1-acetoxy-2-methoxybenzene and 1,2-dimethoxybenzene, and the mixture of 1-acetoxy-2-methoxybenzene and 1,2-dimethoxybenzene After separating 1-acetoxy-2-methoxybenzene by distillation, it was found that high-purity guaiacol can be mass-produced in high yield by hydrolyzing the 1-acetoxy-2-methoxybenzene, The present invention has been completed.
따라서, 본 발명의 목적은 합성 중 발생할 수 있는 유전독성물질을 원천적으로 차단하면서 고순도의 구아야콜을 효율적으로 제조하는 방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a method for efficiently producing high-purity guayacol while fundamentally blocking genotoxic substances that may occur during synthesis.
본 발명의 일 실시형태는 하기 화학식 1의 구아야콜의 제조방법에 관한 것으로, 본 발명의 제조방법은 One embodiment of the present invention relates to a method for producing guaiacol represented by the following Chemical Formula 1, the method for producing
(i) 하기 화학식 2의 카테콜과 하기 화학식 3의 디메틸설페이트를 염기 존재 하에 반응시켜 하기 화학식 1의 구아야콜과 하기 화학식 4의 1,2-디메톡시벤젠의 혼합물을 수득하는 단계; (i) reacting catechol of Chemical Formula 2 with dimethyl sulfate of Chemical Formula 3 in the presence of a base to obtain a mixture of Guayacol of Chemical Formula 1 and 1,2-dimethoxybenzene of Chemical Formula 4;
(ii) 상기 구아야콜과 1,2-디메톡시벤젠의 혼합물을 염기 존재 하에 하기 화학식 5의 아세틸클로라이드와 반응시켜 하기 화학식 6의 1-아세톡시-2-메톡시벤젠과 하기 화학식 4의 1,2-디메톡시벤젠의 혼합물을 수득하는 단계; (ii) reacting the mixture of guayacol and 1,2-dimethoxybenzene with acetyl chloride of formula 5 below in the presence of a base to obtain 1-acetoxy-2-methoxybenzene of formula 6 and 1 of formula 4 below obtaining a mixture of ,2-dimethoxybenzene;
(iii) 상기 1-아세톡시-2-메톡시벤젠과 1,2-디메톡시벤젠의 혼합물을 증류하여 1-아세톡시-2-메톡시벤젠을 분리하는 단계; 및(iii) separating 1-acetoxy-2-methoxybenzene by distilling the mixture of 1-acetoxy-2-methoxybenzene and 1,2-dimethoxybenzene; and
(iv) 상기 1-아세톡시-2-메톡시벤젠을 가수분해반응시키는 단계를 포함한다.(iv) hydrolyzing the 1-acetoxy-2-methoxybenzene;
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
이하, 본 발명의 제조방법을 하기 반응식 1을 참조로 보다 상세히 설명한다. 하기 반응식 1에 기재된 방법은 대표적으로 사용된 방법을 예시한 것일 뿐 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다.Hereinafter, the preparation method of the present invention will be described in more detail with reference to Scheme 1 below. The method described in Reaction Scheme 1 below is merely an example of a method typically used, and reaction reagents, reaction conditions, etc. may be changed as needed.
[반응식 1][Scheme 1]
제1 단계: 화학식 1의 구아야콜과 화학식 4의 1,2-디메톡시벤젠의 혼합물의 제조Step 1: Preparation of a mixture of guayacol of formula 1 and 1,2-dimethoxybenzene of formula 4
화학식 1의 구아야콜과 화학식 4의 1,2-디메톡시벤젠의 혼합물은 화학식 2의 카테콜과 화학식 3의 디메틸설페이트를 염기 존재 하에 반응시켜 제조할 수 있다.A mixture of guayacol of Chemical Formula 1 and 1,2-dimethoxybenzene of Chemical Formula 4 may be prepared by reacting catechol of Chemical Formula 2 with dimethyl sulfate of Chemical Formula 3 in the presence of a base.
상기 단계 (i)에서 염기는 포타슘카보네이트 및 세슘카보네이트 중 하나 이상일 수 있다.In step (i), the base may be at least one of potassium carbonate and cesium carbonate.
상기 단계 (i)에서 반응 용매로는 아세톤, 디클로메탄 또는 이들의 혼합용매가 사용될 수 있다.In the step (i), acetone, dichloromethane or a mixed solvent thereof may be used as the reaction solvent.
상기 단계 (i)에서 반응 온도는 25 내지 60℃가 적합하고, 반응 시간은 1 내지 3 시간이 바람직하다.In the step (i), the reaction temperature is preferably 25 to 60 ° C, and the reaction time is preferably 1 to 3 hours.
제2 단계: 화학식 6의 1-아세톡시-2-메톡시벤젠과 화학식 4의 1,2-디메톡시벤젠의 혼합물 제조Step 2: Preparation of a mixture of 1-acetoxy-2-methoxybenzene of Formula 6 and 1,2-dimethoxybenzene of Formula 4
화학식 6의 1-아세톡시-2-메톡시벤젠과 화학식 4의 1,2-디메톡시벤젠의 혼합물은 상기 화학식 1의 구아야콜과 화학식 4의 1,2-디메톡시벤젠의 혼합물을 염기 존재 하에 화학식 5의 아세틸클로라이드와 반응시켜 제조할 수 있다.A mixture of 1-acetoxy-2-methoxybenzene of Formula 6 and 1,2-dimethoxybenzene of Formula 4 is a mixture of guayacol of Formula 1 and 1,2-dimethoxybenzene of Formula 4 in the presence of a base It can be prepared by reacting with acetyl chloride of Formula 5 under
상기 단계 (ii)에서 염기는 트리에틸아민 및 디이소프로필에틸아민 중 하나 이상일 수 있다.In step (ii), the base may be at least one of triethylamine and diisopropylethylamine.
상기 단계 (ii)에서 반응 용매로는 디클로로메탄, 톨루엔 또는 이들의 혼합용매가 사용될 수 있다.In step (ii), dichloromethane, toluene or a mixed solvent thereof may be used as the reaction solvent.
상기 단계 (i)에서 반응 온도는 0 내지 25℃가 적합하고, 반응 시간은 1 내지 3 시간이 바람직하다.In the step (i), the reaction temperature is preferably 0 to 25 ° C, and the reaction time is preferably 1 to 3 hours.
제3 단계: 화학식 6의 1-아세톡시-2-메톡시벤젠의 분리Step 3: Separation of 1-acetoxy-2-methoxybenzene of Formula 6
화학식 6의 1-아세톡시-2-메톡시벤젠은 화학식 6의 1-아세톡시-2-메톡시벤젠과 화학식 4의 1,2-디메톡시벤젠의 혼합물을 증류하여 분리할 수 있다.1-acetoxy-2-methoxybenzene of formula 6 can be separated by distilling a mixture of 1-acetoxy-2-methoxybenzene of formula 6 and 1,2-dimethoxybenzene of formula 4.
화학식 6의 1-아세톡시-2-메톡시벤젠은 비점이 122-124℃이고, 화학식 4의 1,2-디메톡시벤젠은 비점이 206-207℃이다. 따라서, 이들은 비점 차이가 커서 증류 방법으로 분리가 가능하다.1-acetoxy-2-methoxybenzene of Formula 6 has a boiling point of 122-124°C, and 1,2-dimethoxybenzene of Formula 4 has a boiling point of 206-207°C. Therefore, they have a large boiling point difference and can be separated by distillation.
제4 단계: 화학식 1의 구아야콜의 제조Step 4: Preparation of Guayacol of Formula 1
화학식 1의 구아야콜은 화학식 6의 1-아세톡시-2-메톡시벤젠을 가수분해반응시켜 제조할 수 있다.Guayacol of Chemical Formula 1 can be prepared by hydrolyzing 1-acetoxy-2-methoxybenzene of Chemical Formula 6.
상기 단계 (iv)에서 가수분해반응은 수산화나트륨, 수산화칼륨 및 수산화리튬 중에서 선택된 하나 이상의 염기를 사용하여 수행될 수 있으며, 특히 수산화리튬이 생성물의 성상 및 물리적 특성면에서 바람직하다.The hydrolysis reaction in step (iv) may be performed using one or more bases selected from among sodium hydroxide, potassium hydroxide and lithium hydroxide, and lithium hydroxide is particularly preferred in terms of properties and physical properties of the product.
상기 단계 (iv)에서 가수분해반응 용매는 메탄올, 에탄올, 아세톤, 테트라하이드로퓨란, 디메틸설폭사이드, 디메틸포름아마이드, 디메틸아세트아마이드, 물 또는 이들의 혼합용매일 수 있다.In step (iv), the hydrolysis reaction solvent may be methanol, ethanol, acetone, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dimethylacetamide, water, or a mixture thereof.
상기 단계 (iv)에서 가수분해반응 온도는 20 내지 80℃가 적합하고, 반응 시간은 1 내지 3 시간이 바람직하다.In the step (iv), the hydrolysis reaction temperature is suitably 20 to 80 ° C, and the reaction time is preferably 1 to 3 hours.
본 발명에 따른 구아야콜의 제조방법은 카테콜과 디메틸설페이트의 반응에 의해 구아야콜과 1,2-디메톡시벤젠의 혼합물을 얻은 다음, 이를 아세틸클로라이드와 반응시켜 구아야콜만 선택적으로 1-아세톡시-2-메톡시벤젠으로 전환시킨 뒤, 1,2-디메톡시벤젠과의 비점 차이를 이용하여 증류 방법으로 1-아세톡시-2-메톡시벤젠만을 회수한 후, 이를 가수분해시킴으로써 합성 중 발생할 수 있는 유전독성물질을 원천적으로 차단하면서 고순도의 구아야콜을 효율적으로 제조할 수 있다.In the method for preparing guayacol according to the present invention, a mixture of guayacol and 1,2-dimethoxybenzene is obtained by reacting catechol and dimethyl sulfate, and then reacted with acetyl chloride to selectively release only 1 guayacol. -After converting to acetoxy-2-methoxybenzene, recovering only 1-acetoxy-2-methoxybenzene by distillation using the difference in boiling point with 1,2-dimethoxybenzene, and then hydrolyzing it High-purity Guayacol can be efficiently produced while fundamentally blocking genotoxic substances that may occur during synthesis.
본 발명의 제조방법에 따라 수득한 화학식 1의 구아야콜은 99% 이상, 바람직하게는 99.5% 이상의 순도를 가질 수 있다.Guayacol of Formula 1 obtained according to the production method of the present invention may have a purity of 99% or more, preferably 99.5% or more.
본 발명의 제조방법에 따르면, 합성 중 발생할 수 있는 유전독성물질을 원천적으로 차단하면서 고순도의 구아야콜을 효율적으로 대량생산할 수 있다.According to the manufacturing method of the present invention, it is possible to efficiently mass-produce high-purity guayacol while fundamentally blocking genotoxic substances that may occur during synthesis.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.Hereinafter, the present invention will be described in more detail by examples. It is apparent to those skilled in the art that these examples are only for illustrative purposes and the scope of the present invention is not limited to these examples.
실시예 1: 화학식 1의 구아야콜과 화학식 4의 1,2-디메톡시벤젠의 혼합물의 제조Example 1: Preparation of a mixture of guayacol of formula 1 and 1,2-dimethoxybenzene of formula 4
화학식 2의 카테콜 50kg을 아세톤 500L에 용해시켰다. 여기에, 포타슘카보네이트 59.62kg을 첨가한 후, 화학식 3의 디메틸설페이트 51.55kg을 첨가하였다. 45℃로 승온 후, 2시간동안 교반하였다. 반응 완료를 확인한 후, 상온으로 냉각하였다. 상기 반응물을 여과한 후 감압농축하였다. 에틸아세테이트 500L와 10% 수산화나트륨 수용액 300L를 첨가한 후 추출하였다. 추출된 유기층에 10% 염산을 천천히 첨가하여 pH=5로 맞추었다. 유기층을 추출 후, 무수황산마그네슘 5kg을 가한 다음 교반하여 수분을 제거하였다. 여과 후 감압농축하여 미정제 구아야콜, 즉 화학식 1의 구아야콜과 화학식 4의 1,2-디메톡시벤젠의 혼합물 52.33kg을 얻었다.50 kg of catechol of Formula 2 was dissolved in 500 L of acetone. Here, after adding 59.62 kg of potassium carbonate, 51.55 kg of dimethyl sulfate of Formula 3 was added. After raising the temperature to 45 ℃, it was stirred for 2 hours. After confirming the completion of the reaction, it was cooled to room temperature. The reactant was filtered and then concentrated under reduced pressure. After adding 500 L of ethyl acetate and 300 L of 10% sodium hydroxide aqueous solution, extraction was performed. 10% hydrochloric acid was slowly added to the extracted organic layer to adjust pH=5. After extracting the organic layer, 5 kg of anhydrous magnesium sulfate was added thereto, followed by stirring to remove moisture. After filtration, the mixture was concentrated under reduced pressure to obtain 52.33 kg of crude guayacol, that is, a mixture of guayacol of Chemical Formula 1 and 1,2-dimethoxybenzene of Chemical Formula 4.
화학식 1의 구아야콜의 G.C 순도: 85.71%G.C purity of Guayacol of Formula 1: 85.71%
실시예 2: 화학식 6의 1-아세톡시-2-메톡시벤젠과 화학식 4의 1,2-디메톡시벤젠의 혼합물 제조Example 2: Preparation of a mixture of 1-acetoxy-2-methoxybenzene of Formula 6 and 1,2-dimethoxybenzene of Formula 4
상기 실시예 1에서 수득한 미정제 구아야콜 52.33kg을 디클로로메탄 530L에 용해시켰다. 0~5℃로 냉각 후, 트리에틸아민 85.31kg을 첨가하였다. 여기에, 화학식 5의 아세틸클로라이드 33.09kg을 천천히 적가하였다. 상온으로 승온 후, 1시간동안 교반하였다. 반응 종료 뒤 탄산수소나트륨수용액 500L를 천천히 첨가한 후 추출하였다. 유기층에 1N HCl 500L를 천천히 첨가 후 추출하였다. 유기층에 무수황산마그네슘 5kg을 가한 후 교반하여 수분을 제거하였다. 여과 후 감압농축하여 화학식 6의 1-아세톡시-2-메톡시벤젠과 화학식 4의 1,2-디메톡시벤젠의 혼합물을 얻었다.52.33 kg of crude Guayacol obtained in Example 1 was dissolved in 530 L of dichloromethane. After cooling to 0-5° C., 85.31 kg of triethylamine was added. Here, 33.09 kg of acetyl chloride of Formula 5 was slowly added dropwise. After raising the temperature to room temperature, the mixture was stirred for 1 hour. After completion of the reaction, 500L of an aqueous sodium bicarbonate solution was slowly added, followed by extraction. 500L of 1N HCl was slowly added to the organic layer, followed by extraction. After adding 5 kg of anhydrous magnesium sulfate to the organic layer, it was stirred to remove moisture. After filtration, the mixture was concentrated under reduced pressure to obtain a mixture of 1-acetoxy-2-methoxybenzene of Formula 6 and 1,2-dimethoxybenzene of Formula 4.
실시예 3: 화학식 6의 1-아세톡시-2-메톡시벤젠의 분리Example 3: Isolation of 1-acetoxy-2-methoxybenzene of Formula 6
상기 실시예 2에서 수득한 화학식 6의 1-아세톡시-2-메톡시벤젠과 화학식 4의 1,2-디메톡시벤젠의 혼합물을 증류하여 화학식 6의 1-아세톡시-2-메톡시벤젠 60.35kg을 분리하였다.A mixture of 1-acetoxy-2-methoxybenzene of Formula 6 and 1,2-dimethoxybenzene of Formula 4 obtained in Example 2 was distilled to obtain 1-acetoxy-2-methoxybenzene of Formula 6 60.35 kg was separated.
실시예 4: 화학식 1의 구아야콜의 제조Example 4: Preparation of Guayacol of Formula 1
수산화나트륨 24.07kg을 물 192L에 용해시켰다. 여기에, 에탄올 300L를 첨가한 후, 상기 실시예 3에서 수득한 화학식 6의 1-아세톡시-2-메톡시벤젠 50kg을 첨가하였다. 2시간 동안 25℃에서 교반하였다. 반응완료 확인 후, 감압농축하였다. 3N 염산 120L를 천천히 적가하여 pH=7로 맞춘 후, 에틸아세테이트 200kg을 첨가하였다. 이를 추출하여 물층을 제거한 후, 유기층에 물 200L를 가하였다. 이를 추출 후 물층을 제거하였다. 유기층에 무수황산마그네슘 10kg을 가한 후 교반하여 수분을 제거하였다. 이를 여과 후 감압농축하여 화학식 1의 구아야콜 30.47kg을 얻었다.24.07 kg of sodium hydroxide was dissolved in 192 L of water. After adding 300 L of ethanol to this, 50 kg of 1-acetoxy-2-methoxybenzene of Formula 6 obtained in Example 3 was added. Stir at 25 °C for 2 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure. 120 L of 3N hydrochloric acid was slowly added dropwise to adjust the pH to 7, and then 200 kg of ethyl acetate was added. After extracting and removing the water layer, 200 L of water was added to the organic layer. After extraction, the water layer was removed. After adding 10 kg of anhydrous magnesium sulfate to the organic layer, it was stirred to remove moisture. This was filtered and concentrated under reduced pressure to obtain 30.47 kg of Guayacol of Chemical Formula 1.
화학식 1의 구아야콜의 G.C 순도: 99.79%G.C purity of Guayacol of Formula 1: 99.79%
실시예 5: 화학식 1의 구아야콜의 제조Example 5: Preparation of Guayacol of Formula 1
수산화리튬 14.41kg을 물 192L에 용해시켰다. 여기에, 에탄올 300L를 첨가한 후, 상기 실시예 3에서 수득한 화학식 6의 1-아세톡시-2-메톡시벤젠 50kg을 첨가하였다. 2시간 동안 25℃에서 교반하였다. 반응완료 확인 후, 감압농축하였다. 3N 염산 120L를 천천히 적가하여 pH=7로 맞춘 후, 에틸아세테이트 200kg을 첨가하였다. 이를 추출하여 물층을 제거한 후, 유기층에 물 200L를 가하였다. 이를 추출 후 물층을 제거하였다. 유기층에 무수황산마그네슘 10kg을 가한 후 교반하여 수분을 제거하였다. 이를 여과 후 감압농축하여 화학식 1의 구아야콜 30.23kg을 얻었다.14.41 kg of lithium hydroxide was dissolved in 192 L of water. After adding 300 L of ethanol to this, 50 kg of 1-acetoxy-2-methoxybenzene of Formula 6 obtained in Example 3 was added. Stir at 25 °C for 2 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure. 120 L of 3N hydrochloric acid was slowly added dropwise to adjust the pH to 7, and then 200 kg of ethyl acetate was added. After extracting and removing the water layer, 200 L of water was added to the organic layer. After extraction, the water layer was removed. After adding 10 kg of anhydrous magnesium sulfate to the organic layer, it was stirred to remove moisture. This was filtered and concentrated under reduced pressure to obtain 30.23 kg of Guayacol of Chemical Formula 1.
화학식 1의 구아야콜의 G.C 순도: 99.50%G.C purity of Guayacol of Formula 1: 99.50%
실시예 6: 화학식 1의 구아야콜의 제조Example 6: Preparation of Guayacol of Formula 1
수산화리튬 33.76kg을 물 192L에 용해시켰다. 여기에, 에탄올 300L를 첨가한 후, 상기 실시예 3에서 수득한 화학식 6의 1-아세톡시-2-메톡시벤젠 50kg을 첨가하였다. 2시간 동안 25℃에서 교반하였다. 반응완료 확인 후, 감압농축하였다. 3N 염산 120L를 천천히 적가하여 pH=7로 맞춘 후, 에틸아세테이트 200kg을 첨가하였다. 이를 추출하여 물층을 제거한 후, 유기층에 물 200L를 가하였다. 이를 추출 후 물층을 제거하였다. 유기층에 무수황산마그네슘 10kg을 가한 후 교반하여 수분을 제거하였다. 이를 여과 후 감압농축하여 화학식 1의 구아야콜 29.65kg을 얻었다.33.76 kg of lithium hydroxide was dissolved in 192 L of water. After adding 300 L of ethanol to this, 50 kg of 1-acetoxy-2-methoxybenzene of Formula 6 obtained in Example 3 was added. Stir at 25 °C for 2 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure. 120 L of 3N hydrochloric acid was slowly added dropwise to adjust the pH to 7, and then 200 kg of ethyl acetate was added. After extracting and removing the water layer, 200 L of water was added to the organic layer. After extraction, the water layer was removed. After adding 10 kg of anhydrous magnesium sulfate to the organic layer, it was stirred to remove moisture. This was filtered and concentrated under reduced pressure to obtain 29.65 kg of Guayacol of Chemical Formula 1.
화학식 1의 구아야콜의 G.C 순도: 99.71%G.C purity of Guayacol of Formula 1: 99.71%
Claims (6)
(ii) 상기 구아야콜과 1,2-디메톡시벤젠의 혼합물을 염기 존재 하에 하기 화학식 5의 아세틸클로라이드와 반응시켜 하기 화학식 6의 1-아세톡시-2-메톡시벤젠과 하기 화학식 4의 1,2-디메톡시벤젠의 혼합물을 수득하는 단계;
(iii) 상기 1-아세톡시-2-메톡시벤젠과 1,2-디메톡시벤젠의 혼합물을 증류하여 1-아세톡시-2-메톡시벤젠을 분리하는 단계; 및
(iv) 상기 1-아세톡시-2-메톡시벤젠을 가수분해반응시키는 단계를 포함하는 하기 화학식 1의 구아야콜의 제조방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[화학식 6]
(i) reacting catechol of Chemical Formula 2 with dimethyl sulfate of Chemical Formula 3 in the presence of a base to obtain a mixture of Guayacol of Chemical Formula 1 and 1,2-dimethoxybenzene of Chemical Formula 4;
(ii) reacting the mixture of guayacol and 1,2-dimethoxybenzene with acetyl chloride of formula 5 below in the presence of a base to obtain 1-acetoxy-2-methoxybenzene of formula 6 and 1 of formula 4 below obtaining a mixture of ,2-dimethoxybenzene;
(iii) separating 1-acetoxy-2-methoxybenzene by distilling the mixture of 1-acetoxy-2-methoxybenzene and 1,2-dimethoxybenzene; and
(iv) a method for preparing guaiacol represented by the following formula 1, comprising the step of hydrolyzing the 1-acetoxy-2-methoxybenzene:
[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
[Formula 6]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220011010A KR20230114620A (en) | 2022-01-25 | 2022-01-25 | Process for Preparing Guaiacol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220011010A KR20230114620A (en) | 2022-01-25 | 2022-01-25 | Process for Preparing Guaiacol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20230114620A true KR20230114620A (en) | 2023-08-01 |
Family
ID=87561837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020220011010A KR20230114620A (en) | 2022-01-25 | 2022-01-25 | Process for Preparing Guaiacol |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20230114620A (en) |
-
2022
- 2022-01-25 KR KR1020220011010A patent/KR20230114620A/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| New Journal of Chemistry, 2006, 30, 1228-1234 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101115412B1 (en) | New preparation of hydroxychloroquine | |
| KR20230114620A (en) | Process for Preparing Guaiacol | |
| US20120022282A1 (en) | Process for the preparation of 2,4,6-octatriene-1-oic acid and 2,4,6-octatriene-1-ol | |
| RU2458050C2 (en) | Method for preparing methylulphate neostigmine and iodide neostigmine | |
| CN113416142B (en) | Preparation method of 5-ALA intermediate 5-bromolevulinate | |
| US11384041B2 (en) | Process for preparing an alkoxymethyl alkynyl ether compound having a terminal triple bond | |
| KR100743278B1 (en) | Process for the production of 9-cis retinoic acid | |
| WO2015128504A1 (en) | Process for preparing 2,4-diamino-3-hydroxybutyric acid derivatives | |
| JP2002114737A (en) | METHOD FOR PRODUCING OPTICALLY ACTIVE o-CHLOROMANDELIC ACID | |
| KR100415520B1 (en) | Process for Producing 1-(2-Chlorophenyl)-5(4H)-Tetrazolinone | |
| KR20160061542A (en) | A Novel Method for Separation of Luliconazole Isomers | |
| CN113651715B (en) | Method for synthesizing coumaroyl dopamine by one-pot method | |
| TWI828123B (en) | Method for purification of terpenoid amino alcohol derivatives | |
| KR101659624B1 (en) | Method for preparation of -thujaplicin | |
| KR100985251B1 (en) | Separation of d-muscone and l-muscone from dl-muscone | |
| JP3824826B2 (en) | Method for producing phenylethanolamine derivative | |
| US10150731B2 (en) | Method for preparing 4-cyanopiperidine hydrochloride | |
| KR20070082985A (en) | Preparation method of oseltamivir | |
| KR20060024550A (en) | THE METHOD OF PREPARING beta-HYDROXYBUTYRIC ACID ALKYL ESTERS | |
| US20160318851A1 (en) | Process for preparing levomilnacipran | |
| JP2006022019A (en) | Sphingomyelin analogue and method for producing the same | |
| JP2002047234A (en) | Method for recovering ditrimethylolpropane | |
| CN115073313A (en) | Method for synthesizing terbutaline sulfate impurity C | |
| KR100483317B1 (en) | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE | |
| CN111269248A (en) | Novel method for recovering nucleoside phosphoramidate medicine mother liquor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E902 | Notification of reason for refusal |