WO2018070851A1 - Method for preparing halogen-substituted benzyl alcohol - Google Patents
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- WO2018070851A1 WO2018070851A1 PCT/KR2017/011395 KR2017011395W WO2018070851A1 WO 2018070851 A1 WO2018070851 A1 WO 2018070851A1 KR 2017011395 W KR2017011395 W KR 2017011395W WO 2018070851 A1 WO2018070851 A1 WO 2018070851A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/94—Use of additives, e.g. for stabilisation
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- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
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- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
- C07C63/70—Monocarboxylic acids
Definitions
- the present invention relates to a process for preparing halogen substituted benzyl alcohol from halogen substituted benzoic acid.
- Benzyl alcohol is one of aromatic alcohols. It is a colorless and transparent liquid, and has a distinctive fragrance and a burning taste, and can be used as a solvent and extractant, a volatile preservative, and a food flavoring agent.
- halogen-substituted benzyl alcohol derivatives it can be usefully used as a synthetic intermediate, such as medicine, crop protection agents, and, in particular, Korean Patent Publication No. 10-2000-0017260 is a fluorinated benzyl alcohol Not only is it an important intermediate for preparation, it is disclosed that it can also be used as an antibacterial component.
- a method for preparing benzyl alcohol which comprises converting a nitrile group to a carboxylic acid group and then obtaining a benzyl alcohol through a reduction reaction using lithium aluminum hydride, converting a nitrile group to an aldehyde group and then obtaining a benzyl alcohol through a reduction reaction, or To reduce the benzonitrile derivatives to prepare benzyl amine derivatives and to convert benzyl amines to benzyl alcohols through diazotization reactions (Nystrom, RF et al., J Am Chem Soc., 70 (11), 3738-3740, 1948; Herbert, CB et al., J Am Chem Soc., 78 (11), 2582-2588, 1956; Japanese Patent Application Laid-Open No. 2000-086583) and the like.
- the present invention is a.
- Step 1 reacting at room temperature by mixing a halogen-substituted benzoic acid represented by Formula 1 with a solvent selected from the group consisting of tetrahydrofuran, dioxane and diglyme and sodium borohydride;
- Step 2 mixing any one of the acid additive selected from sulfuric acid or hydrogen chloride to the reactant of the first step and reacting for 2 to 10 hours at 0 ⁇ 65 °C;
- Step 3 distilling and removing the reaction solvent by adding water to the reactants of the second step, by mixing the organic solvent to obtain a halogen-substituted benzyl alcohol of the formula (2);
- It relates to a method for producing a halogen-substituted benzyl alcohol, characterized in that it comprises a.
- X or X ' is halogen, preferably selected from the group consisting of fluorine, chlorine and bromine.
- Sodium borohydride used in the first step is 1 to 1.5 molar equivalents, if less than 1 molar equivalents or more than 1.5 molar equivalents out of the amount of use, the reaction is not sufficiently made or by-products generated, the final produced halogen It is not preferable that the yield and purity of this substituted benzyl alcohol are low.
- the acid additive of the second step is to use an acid containing hydrogen at a concentration of 10 to 100% (v / v), preferably sulfuric acid or hydrogen chloride, most preferably hydrogen chloride.
- the hydrogen chloride may be generated by using gas generated from hydrochloric acid, or may be used by purchasing a hydrogen chloride cylinder commercially sold.
- Sulfuric acid or hydrogen chloride used in the second step is 1 to 1.5 molar equivalents, out of the amount of use, if less than 1 molar equivalent or more than 1.5 molar equivalents, the reaction is not sufficient or by-products are generated, It is not preferable because the yield of the halogen-substituted benzyl alcohol is lowered.
- the reactants mixed with the acid additive of the two step is reacted for 2 to 10 hours at 0 ⁇ 65 °C, preferably for 2 to 10 hours at 40 ⁇ 60 °C.
- the reaction conditions are out of the reaction conditions below 0 ° C or above 65 ° C, or even when the reaction is carried out at the reaction temperature of 0 to 65 ° C, the reaction time of 2 hours to 10 hours or less is less than 2 hours or 10 hours.
- the reaction solution is bumped due to sudden heat generation and the like, so that the yield of the halogen-substituted benzyl alcohol which is finally prepared is low or the production time is long, so it is not economical.
- the organic solvent of the three steps is not particularly limited, but is preferably selected from the group consisting of dichloromethane, ethyl acetate, toluene, benzene, hexane, methyl ethyl ketone.
- the method of distillation or extraction in the above three steps is not particularly limited, and two halogens, which are final products, are replaced by fractionation or purification using a method in which a known method used for distillation or extraction is used alone or in combination. Benzyl alcohol can be obtained.
- the present invention relates to a process for the preparation of halogen substituted benzyl alcohol from halogen substituted benzoic acid.
- the halogen-substituted benzyl alcohol is prepared using the method of the present invention, since sodium borohydride and an inexpensive inorganic acid are used, it is possible to prepare benzyl alcohol without using a special reactor, and thus the manufacturing process is convenient. Industrial waste is reduced and high yield and high purity benzyl alcohol can be produced, which facilitates mass production of benzyl alcohol, which is useful as a raw material for herbicide and hepatic synthesis.
- FIG. 1 is a flowchart illustrating a method for preparing a halogen-substituted benzyl alcohol from a halogen-substituted benzoic acid according to an embodiment of the present invention.
- halogen-substituted benzyl alcohol compound of the present invention was synthesized with reference to Scheme 1 below.
- 2,6-difluorobenzyl alcohol of Examples 3-2 and 3-3 was obtained using dioxane or diglyme instead of tetrahydrofuran as a solvent.
- Example 4-1 Proceed in the same manner as in the reaction of Example 3-1, but instead of 2,6-difluorobenzoic acid, halogen-substituted benzoic acid, 2,4-difluorobenzoic acid, 2-chloro-6-fluorobenzoic acid and 2 2,4-difluorobenzyl alcohol of Example 4-1, 2-chloro-6-fluorobenzyl alcohol of Example 4-2 and Example 4-3 using bromo-6-fluorobenzoic acid 2-bromo-6-fluorobenzyl alcohol was obtained.
- Comparative Example 1-1 or 1-2 in which no acid additive is used or the acid additive is used instead of sulfuric acid or hydrogen chloride, and the solvent is tetrahydrofuran, dioxane.
- the solvent is tetrahydrofuran, dioxane.
- Comparative Example 1-3 using toluene instead of diglyme, no reaction was made or the yield was lower than 80%, and in Comparative Example 1-4 using benzenedicarboxylic acid instead of halogen-substituted benzoic acid, the yield was decreased by side reaction. While it was confirmed that 81%, Examples 2 to 4 of the present invention showed a yield of more than 85% and purity of more than 90% it was confirmed that the method of obtaining benzyl alcohol of high yield and high purity.
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Abstract
Description
본 발명은 할로겐이 치환된 벤조산으로부터 할로겐이 치환된 벤질 알코올을 제조하는 방법에 관한 것이다.The present invention relates to a process for preparing halogen substituted benzyl alcohol from halogen substituted benzoic acid.
벤질 알코올(benzyl alcohol)은 방향족 알코올류 중의 하나로 무색투명한 액체이며, 특유의 향기와 타는 듯한 맛이 있어 용해제 및 추출제, 휘발보류제, 식품 착향료 등으로 사용될 수 있다. 또한, 할로겐이 치환된 벤질 알코올 유도체의 경우, 의약, 작물보호제 등의 합성 중간체로서 유용하게 사용될 수 있으며, 특히, 한국공개특허 제10-2000-0017260호에는 플루오르화 벤질 알코올이 약제 및 작물 보호제의 제조를 위한 중요한 중간체일 뿐 아니라, 항균제 성분으로써도 사용될 수 있음이 개시되어 있다.Benzyl alcohol is one of aromatic alcohols. It is a colorless and transparent liquid, and has a distinctive fragrance and a burning taste, and can be used as a solvent and extractant, a volatile preservative, and a food flavoring agent. In addition, in the case of halogen-substituted benzyl alcohol derivatives, it can be usefully used as a synthetic intermediate, such as medicine, crop protection agents, and, in particular, Korean Patent Publication No. 10-2000-0017260 is a fluorinated benzyl alcohol Not only is it an important intermediate for preparation, it is disclosed that it can also be used as an antibacterial component.
벤질 알코올을 제조하는 방법으로써, 니트릴기를 카르복실산기로 변환시킨 후 수소화리튬알루미늄을 사용한 환원반응을 통해 벤질 알코올을 얻는 방법, 니트릴기를 알데하이드기로 변환시킨 후 환원반응을 통해 벤질 알코올을 얻는 방법, 또는, 벤조니트릴 유도체를 환원시켜서 벤질 아민 유도체를 제조하고 디아조화 반응을 통해 벤질 아민을 벤질 알코올로 변환시키는 방법(Nystrom, R. F. et al., J Am Chem Soc., 70(11), 3738-3740, 1948; Herbert, C. B. et al., J Am Chem Soc., 78(11), 2582-2588, 1956; 일본공개특허 제2000-086583호) 등이 선행문헌에 개시되었다.A method for preparing benzyl alcohol, which comprises converting a nitrile group to a carboxylic acid group and then obtaining a benzyl alcohol through a reduction reaction using lithium aluminum hydride, converting a nitrile group to an aldehyde group and then obtaining a benzyl alcohol through a reduction reaction, or To reduce the benzonitrile derivatives to prepare benzyl amine derivatives and to convert benzyl amines to benzyl alcohols through diazotization reactions (Nystrom, RF et al., J Am Chem Soc., 70 (11), 3738-3740, 1948; Herbert, CB et al., J Am Chem Soc., 78 (11), 2582-2588, 1956; Japanese Patent Application Laid-Open No. 2000-086583) and the like.
그러나, 상기 벤질 알코올을 제조하는 방법 중에서 수소화리튬알루미늄을 사용하는 경우 발화하기가 쉬워 취급이 용이하지 않으므로 대량으로 사용하기에는 적절하지 않다. 또한, 니트릴기를 알데하이드기로 변환시킨 후 환원반응을 통해 벤질 알코올을 얻는 방법은 벤즈알데히드의 수율이 낮아 경제성이 없으며, 디아조화 반응을 통해 벤질 아민을 벤질 알코올로 변환시키는 방법은 생산성이 낮고 다량의 폐수가 발생한다는 문제점이 있다. However, when lithium aluminum hydride is used in the method for producing benzyl alcohol, it is easy to ignite and is not easy to handle, so it is not suitable for use in large quantities. In addition, the method of obtaining benzyl alcohol through the reduction reaction after converting the nitrile group to the aldehyde group is not economical because the yield of benzaldehyde is not low. There is a problem that occurs.
한편, 벤즈아미드로부터 벤조산으로 변환시킨 후 수소화붕소나트륨과 값싼 무기산을 사용함으로써, 제조공정의 편리성, 산업 폐기물의 감소, 고수율 및 고순도의 벤질 알코올을 제조할 수 있는 신규한 제조방법에 대해서는 아직까지 개시된 바 없다.On the other hand, by converting benzamide to benzoic acid and using sodium borohydride and inexpensive inorganic acid, there is still a new manufacturing method for producing benzyl alcohol of high production yield and high purity by reducing the manufacturing process convenience, reducing industrial waste. It is not disclosed until.
본 발명의 목적은 할로겐이 치환된 벤조산으로부터 할로겐이 치환된 벤질 알코올의 제조방법을 제공하는 데 있다.It is an object of the present invention to provide a method for preparing halogen-substituted benzyl alcohol from halogen-substituted benzoic acid.
본 발명은 The present invention
(1공정) 하기 화학식 1로 표시되는 할로겐이 치환된 벤조산과 테트라히드로퓨란, 다이옥산 및 다이글림으로 이루어진 군에서 선택되는 용매 및 수소화붕소나트륨을 혼합하여 상온에서 반응하는 단계;(Step 1) reacting at room temperature by mixing a halogen-substituted benzoic acid represented by Formula 1 with a solvent selected from the group consisting of tetrahydrofuran, dioxane and diglyme and sodium borohydride;
(2공정) 상기 1공정의 반응물에 황산 또는 염화수소 중 선택되는 어느 하나의 산 첨가제를 혼합하고 0~65℃에서 2~10시간 동안 반응하는 단계; 및(Step 2) mixing any one of the acid additive selected from sulfuric acid or hydrogen chloride to the reactant of the first step and reacting for 2 to 10 hours at 0 ~ 65 ℃; And
(3공정) 상기 2공정의 반응물에 물을 더하여 반응용매를 증류 및 제거하고, 유기용매를 혼합하여 하기 화학식 2의 할로겐이 치환된 벤질 알코올을 추출하여 얻는 단계;(Step 3) distilling and removing the reaction solvent by adding water to the reactants of the second step, by mixing the organic solvent to obtain a halogen-substituted benzyl alcohol of the formula (2);
를 포함하는 것을 특징으로 하는 할로겐이 치환된 벤질 알코올의 제조방법에 관한 것이다.It relates to a method for producing a halogen-substituted benzyl alcohol, characterized in that it comprises a.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 화학식 1 및 2에서, X 또는 X′은 할로겐이며, 바람직하게는 플루오린, 클로린 및 브로민으로 이루어진 군에서 선택된다.In Formulas 1 and 2, X or X 'is halogen, preferably selected from the group consisting of fluorine, chlorine and bromine.
상기 1공정에서 사용되는 수소화붕소나트륨은 1 내지 1.5몰당량이며, 상기 사용량을 벗어나서 1몰당량 미만이거나 1.5몰당량을 초과하는 경우, 반응이 충분하게 이루어지지 않거나 부산물이 발생하여, 최종 제조된 할로겐이 치환된 벤질 알코올의 수율 및 순도가 낮아 바람직하지 않다.Sodium borohydride used in the first step is 1 to 1.5 molar equivalents, if less than 1 molar equivalents or more than 1.5 molar equivalents out of the amount of use, the reaction is not sufficiently made or by-products generated, the final produced halogen It is not preferable that the yield and purity of this substituted benzyl alcohol are low.
상기 2공정의 산 첨가제는 수소가 포함된 산을 10~100%(v/v)의 농도로 사용하며, 바람직하게는 황산 또는 염화수소를 사용하고, 가장 바람직하게는 염화수소를 사용한다. 이때, 상기 염화수소는 염산으로부터 가스로 발생시켜 사용하거나 공업적으로 판매하는 염화수소봄베를 구매하여 사용할 수 있다.The acid additive of the second step is to use an acid containing hydrogen at a concentration of 10 to 100% (v / v), preferably sulfuric acid or hydrogen chloride, most preferably hydrogen chloride. At this time, the hydrogen chloride may be generated by using gas generated from hydrochloric acid, or may be used by purchasing a hydrogen chloride cylinder commercially sold.
상기 2공정에서 사용되는 황산 또는 염화수소는 1 내지 1.5몰당량이며, 상기 사용량을 벗어나서, 1몰당량 미만으로 사용하거나 1.5몰당량을 초과하는 경우, 반응이 충분하게 이루어지지 않거나 부산물이 발생하여, 최종 제조된 할로겐이 치환된 벤질 알코올의 수율이 저하되므로 바람직하지 않다.Sulfuric acid or hydrogen chloride used in the second step is 1 to 1.5 molar equivalents, out of the amount of use, if less than 1 molar equivalent or more than 1.5 molar equivalents, the reaction is not sufficient or by-products are generated, It is not preferable because the yield of the halogen-substituted benzyl alcohol is lowered.
또한, 상기 2공정의 산 첨가제를 혼합한 반응물은 0~65℃에서 2~10시간 동안 반응하며, 바람직하게는 40~60℃에서 2~10시간 동안 반응한다. 그러나, 상기 반응 조건을 벗어나서 0℃ 미만이거나 65℃를 초과하는 경우, 또는, 상기 반응 온도인 0~65℃에서 반응을 실시하여도 2~10시간의 반응 시간을 벗어나 2시간 미만이거나 10시간을 초과하는 경우, 급작발열 등으로 반응액이 범핑하여 최종 제조된 할로겐이 치환된 벤질 알코올의 수율이 낮아지거나 제조시간이 길어지므로 경제적이지 않다.In addition, the reactants mixed with the acid additive of the two step is reacted for 2 to 10 hours at 0 ~ 65 ℃, preferably for 2 to 10 hours at 40 ~ 60 ℃. However, when the reaction conditions are out of the reaction conditions below 0 ° C or above 65 ° C, or even when the reaction is carried out at the reaction temperature of 0 to 65 ° C, the reaction time of 2 hours to 10 hours or less is less than 2 hours or 10 hours. When exceeding, the reaction solution is bumped due to sudden heat generation and the like, so that the yield of the halogen-substituted benzyl alcohol which is finally prepared is low or the production time is long, so it is not economical.
상기 3공정의 유기용매는 특별히 제한되지는 않지만, 디클로로메탄, 에틸아세테이트, 톨루엔, 벤젠, 헥산, 메틸에틸키톤으로 이루어진 군에서 선택하여 사용하는 것이 바람직하다.The organic solvent of the three steps is not particularly limited, but is preferably selected from the group consisting of dichloromethane, ethyl acetate, toluene, benzene, hexane, methyl ethyl ketone.
또한, 상기 3공정에서 증류 또는 추출하는 방법은 특별히 제한되지는 않으며, 증류 또는 추출에 이용되는 공지의 방법을 단독 또는 적합하게 조합한 방법을 이용하여 분획 또는 정제하여 최종 생성물인 두 개의 할로겐이 치환된 벤질 알코올을 얻을 수 있다. In addition, the method of distillation or extraction in the above three steps is not particularly limited, and two halogens, which are final products, are replaced by fractionation or purification using a method in which a known method used for distillation or extraction is used alone or in combination. Benzyl alcohol can be obtained.
본 발명은 할로겐이 치환된 벤조산으로부터 할로겐이 치환된 벤질 알코올의 제조방법에 관한 것이다. 본 발명의 방법을 이용하여 할로겐이 치환된 벤질 알코올을 제조하는 경우, 수소화붕소나트륨과 저가의 무기산을 사용하므로, 특수 반응기를 사용하지 않고도 벤질 알코올을 제조하는 것이 가능하여, 제조공정이 편리하고, 산업 폐기물이 감소되며, 고수율 및 고순도의 벤질 알코올을 제조할 수 있어, 제초제 및 간전제 합성의 원료로서 유용한 벤질 알코올의 대량생산에 용이하다.The present invention relates to a process for the preparation of halogen substituted benzyl alcohol from halogen substituted benzoic acid. When the halogen-substituted benzyl alcohol is prepared using the method of the present invention, since sodium borohydride and an inexpensive inorganic acid are used, it is possible to prepare benzyl alcohol without using a special reactor, and thus the manufacturing process is convenient. Industrial waste is reduced and high yield and high purity benzyl alcohol can be produced, which facilitates mass production of benzyl alcohol, which is useful as a raw material for herbicide and hepatic synthesis.
도 1은 본 발명의 실시예에 따른 할로겐이 치환된 벤조산으로부터 할로겐이 치환된 벤질 알코올의 제조방법을 나타내는 순서도이다. 1 is a flowchart illustrating a method for preparing a halogen-substituted benzyl alcohol from a halogen-substituted benzoic acid according to an embodiment of the present invention.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the information provided herein is to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.
<< 실시예Example 1. 할로겐이 치환된 벤조산의 합성> 1.Synthesis of Halogen Substituted Benzoic Acid>
본 발명의 할로겐이 치환된 벤질 알코올 화합물은 하기 반응식 1을 참고하여 합성하였다.The halogen-substituted benzyl alcohol compound of the present invention was synthesized with reference to Scheme 1 below.
[반응식 1] Scheme 1
구체적으로, 상온에서, 2,6-디플루오로벤즈아미드 50g을 75%의 황산 100g에 더한 다음, 150℃까지 승온하여 6시간 동안 반응한 후, 상기 반응물을 상온으로 냉각하였다. 이후, 얼음 50g 및 에틸아세테이트 150g을 혼합하고, 수층을 제외한 유기층 만을 취한 다음, 유기용매를 제거하여 수율 97.4%, 순도 99.8%의 2,6-디플루오로벤조산 49g을 고체로 얻었다.Specifically, at room temperature, 50 g of 2,6-difluorobenzamide was added to 100 g of 75% sulfuric acid, and then heated to 150 ° C. for 6 hours, and then the reaction mass was cooled to room temperature. Thereafter, 50 g of ice and 150 g of ethyl acetate were mixed, and only the organic layer was removed except for the aqueous layer. Then, the organic solvent was removed to obtain 49. g of 2,6-difluorobenzoic acid having a yield of 97.4% and a purity of 99.8% as a solid.
<< 실시예Example 2. 2,6- 2. 2,6- 디플루오로벤질알코올의Difluorobenzyl alcohol 합성①-황산 사용> Synthesis ①-Sulfate Use>
상온에서, 상기 실시예 1에서 합성한 2,6-디플루오로벤조산 15.8g을 테트라히드로퓨란 100㎖에 용해한 다음, 수소화붕소나트륨 4.2g과 테트라히드로퓨란 200㎖가 혼합된 혼합물에 천천히 적가하였다. 이후, 수소가스의 발생이 멈추면 황산 9.8g을 천천히 적가한 다음, 승온하여 6시간 동안 환류하였다. 6시간 후, 물 80g을 더하여 테트라히드로퓨란을 증류하고, 디클로로메탄 80g을 더하여 수층을 제외한 유기층 만을 취한 다음, 용매를 제거하여 2,6-디플루오로벤질알코올을 얻었다.At room temperature, 15.8 g of 2,6-difluorobenzoic acid synthesized in Example 1 was dissolved in 100 ml of tetrahydrofuran, and then slowly added dropwise to a mixture of 4.2 g of sodium borohydride and 200 ml of tetrahydrofuran. Then, when generation of hydrogen gas stopped, 9.8 g of sulfuric acid was slowly added dropwise, and the temperature was raised to reflux for 6 hours. After 6 hours, tetrahydrofuran was distilled out by adding 80 g of water, and 80 g of dichloromethane was added to take only the organic layer except for the aqueous layer, and then the solvent was removed to obtain 2,6-difluorobenzyl alcohol.
<< 실시예Example 3. 2,6- 3. 2,6- 디플루오로벤질알코올의Difluorobenzyl alcohol 합성②-염화수소 사용> Synthesis ②-Use Hydrogen Chloride>
상온에서, 상기 실시예 1에서 합성한 2,6-디플루오로벤조산 15.8g을 테트라히드로퓨란 100㎖에 용해한 다음, 수소화붕소나트륨 4.2g과 테트라히드로퓨란 200㎖가 혼합된 혼합물에 천천히 적가하였다. 수소가스의 발생이 멈추면 염화수소 1.4g을 천천히 버블링한 다음, 승온하여 6시간 동안 환류하였다. 6시간 후, 물 80g을 더하여 테트라히드로퓨란을 증류하고, 디클로로메탄 80g을 더하여 수층을 제외한 유기층 만을 취한 다음, 용매를 제거하여 실시예 3-1의 2,6-디플루오로벤질알코올을 얻었다.At room temperature, 15.8 g of 2,6-difluorobenzoic acid synthesized in Example 1 was dissolved in 100 ml of tetrahydrofuran, and then slowly added dropwise to a mixture of 4.2 g of sodium borohydride and 200 ml of tetrahydrofuran. When generation of hydrogen gas stopped, 1.4 g of hydrogen chloride was slowly bubbled, and the temperature was raised to reflux for 6 hours. After 6 hours, 80 g of water was added to distill tetrahydrofuran, and 80 g of dichloromethane was added to take only the organic layer except for the aqueous layer, and then the solvent was removed to obtain 2,6-difluorobenzyl alcohol of Example 3-1.
또한, 이때 상기 과정에서, 용매인 테트라히드로퓨란 대신 다이옥산 또는 다이글림(diglyme)을 사용하여 실시예 3-2 및 3-3의 2,6-디플루오로벤질알코올을 얻었다. In this case, 2,6-difluorobenzyl alcohol of Examples 3-2 and 3-3 was obtained using dioxane or diglyme instead of tetrahydrofuran as a solvent.
<< 실시예Example 4. 2,4- 4. 2,4- 디플루오로벤질알코올Difluorobenzyl alcohol , 2-, 2- 클로로Chloro -6--6- 플루오로벤질알코올Fluorobenzyl alcohol 및 2-브로모-6-플루오로벤질알코올의 합성> And the synthesis of 2-bromo-6-fluorobenzyl alcohol>
상기 실시예 3-1의 반응 조건과 동일하게 진행하되, 할로겐이 치환된 벤조산인 2,6-디플루오로벤조산 대신 2,4-디플루오로벤조산, 2-클로로-6-플루오로벤조산 및 2-브로모-6-플루오로벤조산을 사용하여 실시예 4-1의 2,4-디플루오로벤질알코올, 실시예 4-2의 2-클로로-6-플루오로벤질알코올 및 실시예 4-3의 2-브로모-6-플루오로벤질알코올을 얻었다.Proceed in the same manner as in the reaction of Example 3-1, but instead of 2,6-difluorobenzoic acid, halogen-substituted benzoic acid, 2,4-difluorobenzoic acid, 2-chloro-6-fluorobenzoic acid and 2 2,4-difluorobenzyl alcohol of Example 4-1, 2-chloro-6-fluorobenzyl alcohol of Example 4-2 and Example 4-3 using bromo-6-fluorobenzoic acid 2-bromo-6-fluorobenzyl alcohol was obtained.
<< 비교예Comparative example 1. 비교대상 할로겐이 치환된 벤질알코올 또는 1. Benzyl alcohol in which the halogen to be compared is substituted or 벤젠디메탄올의Benzenedimethanol 합성> Synthesis>
상기 실시예 2의 반응 조건과 동일하게 진행하되, 할로겐이 치환된 벤조산, 산첨가제 및 용매를 하기 표 1을 참고하여 비교예 1-1 내지 1-3의 2,6-디플루오로벤질알코올 및 2,6-디플루오로-1,4-벤젠디메탄올의 비교예 1-4를 제조하였다.Proceed in the same manner as in the reaction conditions of Example 2, the halogen-substituted benzoic acid, acid additives and solvent with reference to Table 1 2,6-difluorobenzyl alcohol and Comparative Examples 1-1 to 1-3 Comparative Example 1-4 of 2,6-difluoro-1,4-benzenedimethanol was prepared.
<< 실험예Experimental Example 1. 할로겐이 치환된 1. Halogen substituted 벤질benzyl 알코올의 수율 및 순도 비교> Yield and Purity Comparison of Alcohols>
상기 실시예 및 비교예로부터 제조된 할로겐이 치환된 벤질 알코올의 수율을 비교하면 하기 표 2와 같다.Comparing the yield of the halogen-substituted benzyl alcohol prepared from the above Examples and Comparative Examples are shown in Table 2.
표 2의 결과를 참고하면, 본 발명의 조건과는 다르게 산첨가제를 사용하지 않거나 산첨가제를 황산 또는 염화수소 대신 인산을 사용한 비교예 1-1 또는 1-2, 및, 용매를 테트라히드로퓨란, 다이옥산 또는 다이글림 대신 톨루엔을 사용한 비교예 1-3의 경우 반응이 이루어지지 않거나 수율이 80% 이하로 낮았으며, 할로겐이 치환된 벤조산 대신 벤젠디카복실산을 사용한 비교예 1-4의 경우 부반응에 의해 수율이 81%로 확인된 반면, 본 발명 실시예 2 내지 4의 경우 85% 이상의 수율 및 90% 이상의 순도를 나타내어 고수율 및 고순도의 벤질 알코올을 얻는 방법임을 확인할 수 있었다.Referring to the results of Table 2, unlike the conditions of the present invention, Comparative Example 1-1 or 1-2, in which no acid additive is used or the acid additive is used instead of sulfuric acid or hydrogen chloride, and the solvent is tetrahydrofuran, dioxane. Alternatively, in case of Comparative Example 1-3 using toluene instead of diglyme, no reaction was made or the yield was lower than 80%, and in Comparative Example 1-4 using benzenedicarboxylic acid instead of halogen-substituted benzoic acid, the yield was decreased by side reaction. While it was confirmed that 81%, Examples 2 to 4 of the present invention showed a yield of more than 85% and purity of more than 90% it was confirmed that the method of obtaining benzyl alcohol of high yield and high purity.
또한, 황산을 산첨가제로 사용하는 실시예 2와 다르게, 염화수소(염산가스)를 산 첨가제로 사용하는 실시예 3-1 내지 3-3, 4-1 내지 4-3의 경우, 산업 폐기물 감소와 함께 고수율 및 고순도의 벤질 알코올을 제조할 수 있음을 알 수 있었다.In addition, unlike Examples 2 using sulfuric acid as an acid additive, Examples 3-1 to 3-3 and 4-1 to 4-3 using hydrogen chloride (hydrochloric acid gas) as an acid additive, It was found that benzyl alcohol with high yield and high purity can be prepared together.
Claims (7)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0688994B2 (en) * | 1985-10-09 | 1994-11-09 | 三菱化成株式会社 | Method for producing benzyl alcohol compound |
| WO1998008795A1 (en) * | 1996-08-29 | 1998-03-05 | Showa Denko K. K. | Benzonitrile and process for preparing benzyl alcohol |
| JP2000086553A (en) * | 1998-08-13 | 2000-03-28 | Bayer Ag | Production of fluorinated benzyl alcohol and benzaldehyde |
| KR20080090521A (en) * | 2006-01-24 | 2008-10-08 | 스미또모 가가꾸 가부시키가이샤 | Process for producing halogen substituted benzenedimethanol |
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2016
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0688994B2 (en) * | 1985-10-09 | 1994-11-09 | 三菱化成株式会社 | Method for producing benzyl alcohol compound |
| WO1998008795A1 (en) * | 1996-08-29 | 1998-03-05 | Showa Denko K. K. | Benzonitrile and process for preparing benzyl alcohol |
| JP2000086553A (en) * | 1998-08-13 | 2000-03-28 | Bayer Ag | Production of fluorinated benzyl alcohol and benzaldehyde |
| KR20080090521A (en) * | 2006-01-24 | 2008-10-08 | 스미또모 가가꾸 가부시키가이샤 | Process for producing halogen substituted benzenedimethanol |
Non-Patent Citations (1)
| Title |
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| ZHU, HUA-JIE: "Reductions of Carboxylic Acids and Esters with NaBH4 in Di glyme at 162° C", SYNTHETIC COMMUNICATIONS, vol. 33, no. 10, 2003, pages 1733 - 1750, XP055603315, ISSN: 0039-7911, DOI: 10.1081/SCC-120018935 * |
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