KR101136961B1 - The preparation method of Valiolamine - Google Patents
The preparation method of Valiolamine Download PDFInfo
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- KR101136961B1 KR101136961B1 KR1020050071416A KR20050071416A KR101136961B1 KR 101136961 B1 KR101136961 B1 KR 101136961B1 KR 1020050071416 A KR1020050071416 A KR 1020050071416A KR 20050071416 A KR20050071416 A KR 20050071416A KR 101136961 B1 KR101136961 B1 KR 101136961B1
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- AZMVSLJDZCIPCC-OOTUMTAXSA-N OC[C@@](C1[BrH]N2C1[C@@H]([C@H]1O)O)([C@H]1O)OC2=O Chemical compound OC[C@@](C1[BrH]N2C1[C@@H]([C@H]1O)O)([C@H]1O)OC2=O AZMVSLJDZCIPCC-OOTUMTAXSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
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Abstract
본 발명은 발리올아민의 제조방법에 관한 것으로, 보다 상세하게는 발리엔아민을 출발물질로 하여 일련의 과정을 통해 발리올아민을 제조시 탈브롬화 반응 진행후 생성물을 이온교환수지 칼럼 크로마토그래피를 통해 정제함으로써, 종래보다 반응공정 시간이 단축되고 분리의 용이성이 우수하여 상업적 생산에 적합한 발리올아민의 제조방법을 제공한다.The present invention relates to a method for preparing a valenamine, and more particularly, to a product of ion exchange resin column chromatography after a debromination reaction in the production of a valenamine through a series of processes using a valenamine as a starting material. By refining through, the reaction process time is shorter than the conventional method, and the separation is excellent, thereby providing a method for preparing a valenamine suitable for commercial production.
발리올아민, 이온교환수지 컬럼 크로마토그래피 Baliolamine, ion exchange resin column chromatography
Description
본 발명은 당뇨병 치료제로서 사용되는 보글리보스의 모체인 발리올아민의 제조 방법에 관한 것이다.The present invention relates to a process for the preparation of valericamine, the parent of boliboss, used as a diabetes treatment agent.
당뇨병 치료제인 보글리보스의 제조방법에 있어서, 모체인 하기 화학식 4의 발리올아민을 제조하는 방법은 다양한 형태로 보고 되어져 있다.In the method for producing bogliose, a diabetes therapeutic agent, a method for preparing a parental valeline amine of Formula 4 has been reported in various forms.
(화학식 4)(Formula 4)
이중에서 일본 특공평 2-38580, 특공평 1-18904, 특공평 2-34947호 등에서는 하기 반응식 1에서와 같이 발리엔아민(1)을 출발물질로 하여 고리화 카바메이트(3)를 중간체를 만들고, 이것을 탈브롬화시킨 후 가수분해를 시켜 발리올아민(4)을 제조하는 방법을 개시하고 있다.Among them, in Japanese Patent Application Nos. 2-38580, 1-18904, 2-34947 and the like, the cyclized carbamate (3) is used as the starting material, as shown in Scheme 1 below. And a method of debromination, followed by hydrolysis, to prepare a valenamine (4).
(반응식 1)(Scheme 1)
그러나, 발리엔아민(1)을 출발물질로 사용하는 상기 방법들에 있어서, 다음과 같은 문제점들이 제기되고 있다.However, in the above methods using the valenamine (1) as a starting material, the following problems are raised.
상기 발리엔아민(1)을 출발물질로 하여 만들어진 고리화 카바메이트 중간체(3)에 소디움 보로하이드라이드를 이용하여 탈브롬화반응을 진행한 후, 이를 정제할 때에는 활성탄 칼럼 크로마토그라피를 이용한다. 상기 활성탄 칼럼 크로마토그라피 분리법은 활성탄에 반응물을 흡착시킨 후, 물을 이용하여 다량의 염을 제거한 뒤, 메탄올과 물을 이용하여 원하는 탈브롬화된 고리화 카바메이트(4)를 탈착시키는 방법이다. 그런데, 이 방법은 활성탄에 대한 탈브롬화된 고리화 카바메이트(3)의 흡착력이 다소 떨어져서 많은 양의 활성탄을 사용하여야 하고, 이로 인해 용매의 사용량이 과다해지며, 특히 장시간의 분리시간으로 인한 문제점이 발생되어 상업적 생산으로의 적용에 어려움이 있는 공정이다. 또한, 이 단계에서의 생성물인 탈브롬화된 고리화 카바메이트(5)는 고온에서 가수분해시킨 후 이온교환수지 칼럼 크로마토그라피를 이용한 정제를 통해야만 발리올아민(4)이 얻어지므로, 과정이 번 거로운 문제가 있었다.After the debromination reaction using sodium borohydride to the cyclized carbamate intermediate (3) made from the Baliienamine (1) as a starting material, activated carbon column chromatography is used for purification. The activated carbon column chromatography is a method of adsorbing a reactant on activated carbon, removing a large amount of salt using water, and then desorbing the desired debrominated cyclized carbamate (4) using methanol and water. However, in this method, the adsorption power of the debrominated cyclized carbamate (3) to activated carbon is slightly lowered, so that a large amount of activated carbon must be used, and thus the amount of solvent used is excessive, and the problem is caused by long separation time. This occurs and is a process that is difficult to apply to commercial production. In addition, the debrominated cyclized carbamate (5), which is a product at this stage, is hydrolyzed at high temperature, and then purified by ion exchange resin column chromatography to obtain a valenamine (4). There was a troublesome problem.
이에, 본 발명자는 상기 종래기술의 문제점의 보완에 초점을 맞추고 연구를 진행하여, 활성탄을 이용한 분리 정제와 별도의 가수분해 과정을 생략하고 분리 정제가 간편한 이온교환수지만을 이용하여 바로 발리올아민(4)을 얻음으로써, 본 발명을 완성하였다. 즉, 종래 기술의 경우 이온교환수지를 이용하여도 단순히 반응의 정제에만 이용되어 왔지만, 본 발명에서는 적합한 이온교환수지를 선택하여 반응의 정제와 더불어 가수분해라는 반응이 일어나게 함으로써 반응과 정제가 간편한 새로운 방법을 발명하게 되었다.Thus, the present inventors focus on the supplement of the problems of the prior art, and proceed with the research, by using only ion-exchange resin that is easy to separate purification and separation purification and separate hydrolysis process using the activated carbon, and immediately valolamine The present invention was completed by obtaining (4). That is, the prior art has been used only for the purification of the reaction even by using an ion exchange resin, but in the present invention, by selecting a suitable ion exchange resin, the reaction of purification and hydrolysis occurs together with the purification of the reaction. The method was invented.
따라서, 본 발명의 목적은 공정의 간소화를 통해 경제적이며 상업적 생산에 용이하게 적용할 수 있는 발리올아민의 제조방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a process for the preparation of valeolamine which can be easily applied to economical and commercial production through the simplification of the process.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 발리엔아민을 출발물질로 하여, 벤질 클로로포르메이트 및 소디움 바이카보네이트와 반응시켜 화학식 2로 표시되는 카바메이트 화합물을 제조하고,In order to achieve the above object, the present invention is to prepare a carbamate compound represented by the formula (2) by reacting with benzyl chloroformate and sodium bicarbonate as a starting material, the valenamine represented by the formula (1),
상기 화학식 2의 카바메이트 화합물의 브롬화 반응을 통해 하기 화학식 3으로 표시되는 브롬화된 고리화 카바메이트 화합물을 제조하고, 및Preparing a brominated cyclized carbamate compound represented by the following Formula 3 through a bromination reaction of the carbamate compound of Formula 2, and
상기 화학식 3의 브롬화된 고리화 카바메이트 화합물의 탈브롬화 반응을 통해 화학식 4로 표시되는 발리올아민을 제조하는 단계를 포함하며,Comprising the step of preparing a baliolamine represented by the formula (4) through the debromination reaction of the brominated cyclized carbamate compound of Formula 3,
상기 탈브롬화 반응후 생성물은 이온교환수지 칼럼 크로마토그래피를 통해 정제하는 것인 발리올아민의 제조방법을 제공한다.After the debromination reaction, the product is purified by ion exchange resin column chromatography.
(화학식 4)(Formula 4)
(화학식 3)(Formula 3)
(화학식 2) (화학식 1)(Formula 2) (Formula 1)
이하에서 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 발리올아민(Valiolamine)의 제조방법은 하기 반응식 2에 나타낸 바와 같이, 화학식 1의 발리엔아민(Valienamine)을 출발물질로 하여 3단계의 과정을 거쳐 화학식 4의 발리올아민을 제조한다.According to the present invention, a method of preparing a valolinamine (Valiolamine) is prepared by using a valienamine (Valienamine) of Formula 1 as a starting material through a three-step process, as shown in Scheme 2 below. .
(반응식 2)(Scheme 2)
본 발명의 발리올아민의 바람직한 일실시예는, 하기 반응식 3을 따른다.One preferred embodiment of the valerian amine of the present invention follows the reaction scheme 3.
(반응식 3)(Scheme 3)
상기 반응식들에서, 제 1단계 반응은 화학식 1로 표시되는 발리엔아민을 출발물질로 하여 벤질 클로로포메이트와 소디움 바이카보네이트를 반응시켜 화학식 2로 표시되는 카바메이트 화합물을 생성하게 된다.In the above Reaction Schemes, the first step reaction produces a carbamate compound represented by Chemical Formula 2 by reacting benzyl chloroformate and sodium bicarbonate by using a valenamine represented by Chemical Formula 1 as a starting material.
상기 1단계 반응에서 반응시간은 0 ℃ 내지 상온에서 2 내지 5시간 정도 수행하는 것이 바람직하다. 상기 벤질 클로로포메이트와 소디움 바이카보네이트는 각각 화학식 1의 발리엔아민에 대하여 1 내지 3 당량으로 사용하는 것이 바람직하다.In the one-step reaction, the reaction time is preferably performed at 0 ° C. to room temperature for 2 to 5 hours. The benzyl chloroformate and sodium bicarbonate are preferably used in an amount of 1 to 3 equivalents based on the valenamine of Formula 1, respectively.
상기 제 2단계 반응은 브롬을 이용하여 화학식 3으로 표시되는 브롬화된 고 리화 카바메이트 화합물을 생성하는 단계이다. 상기 반응의 반응시간은 0 내지 10 ℃에서 1 내지 5시간 정도 수행하는 것이 바람직하다. 반응용매로는 물 또는 메탄올, 에탄올 등의 알코올을 사용하는 것이 바람직하다. 브롬화 반응에 사용되는 브롬의 양은 바람직하게는 화학식 2의 카바메이트 화합물에 대해 1 내지 1.2 당량으로 사용하는 것이 좋다.The second step reaction is to produce a brominated cyclized carbamate compound represented by Formula 3 using bromine. The reaction time of the reaction is preferably carried out at 0 to 10 ℃ 1 to 5 hours. It is preferable to use water or alcohols such as methanol and ethanol as the reaction solvent. The amount of bromine used in the bromination reaction is preferably used in 1 to 1.2 equivalents relative to the carbamate compound of formula (2).
상기 제 3단계 반응은 소디움 보로하이드라이드를 사용하여 탈브롬화 반응을 진행하고, 산으로 중화한 후 이온교환수지 컬럼 크로마토그래피를 통해 발리올아민을 제조하는 단계이다. 상기 이온교환수지 컬럼 크로마토그래피는 음이온교환수지 및 양이온교환수지를 포함하며, 이들을 순차적으로 실시하는 것이 바람직하다.The third step of the reaction is a step of debromination reaction using sodium borohydride, neutralization with an acid, and then preparing a balolamine through ion exchange resin column chromatography. The ion exchange resin column chromatography includes an anion exchange resin and a cation exchange resin, and these are preferably performed sequentially.
구체적으로, 본 발명에 따르면 상기 산으로 중화된 생성물을 음이온교환수지에 넣고 교반하면 가수분해가 되고, 이것을 칼럼을 통해 물과 함께 흘려주면 염 등이 제거된다. 여기에 암모니아수를 흘려주면 크루드(Crude) 발리올아민이 탈착되어 나온다. 이것을 양이온 교환수지에 물과 함께 흘려주면 나머지 염 등이 모두 제거된다. 여기에 다시 암모니아수를 흘려준 후 감압농축시키고 동결건조시키면 최종으로 순수한 발리올아민이 생성되게 되는 것이다.Specifically, according to the present invention, when the acid neutralized product is added to an anion exchange resin and stirred, hydrolysis is performed, and salt and the like are removed by flowing it with water through a column. Aqueous ammonia water flows through and desorbs Crude Baliolamine. When this is poured into the cation exchange resin together with water, all remaining salts are removed. After flowing ammonia water again, the mixture was concentrated under reduced pressure and lyophilized to finally form pure valenamine.
본 발명은 상기 3단계의 반응에 따라 종래와 같이 별도로 고온에서 장시간 동안 가수분해를 실시하지 않고도 음이온교환수지를 통해 가수분해의 과정을 실시할 수 있으며, 양이온교환수지를 통해 순수한 발리올아민을 얻을 수 있다.The present invention can be subjected to a hydrolysis process through an anion exchange resin without performing hydrolysis for a long time separately at a high temperature as in the prior art according to the reaction of the three steps, to obtain a pure valolamine through a cation exchange resin Can be.
상기 3단계 반응은 0 내지 30 ℃이하에서 실시하는 것이 바람직하며, 반응속도를 고려할 때 이온교환수지의 온도는 20 ℃를 유지하는 것이 더욱 바람직하다.The three-stage reaction is preferably carried out at 0 to 30 ℃ or less, and considering the reaction rate, the temperature of the ion exchange resin is more preferably maintained at 20 ℃.
본 반응에서 중화에 사용되는 산으로는 아세트산, 묽은 염산, 묽은 개미산, 묽은 황산 등이 가능하며, 아세트산을 사용하는 것이 더욱 바람직하다.The acid used for neutralization in this reaction may be acetic acid, dilute hydrochloric acid, dilute formic acid, dilute sulfuric acid, and the like, more preferably using acetic acid.
상기 양이온 교환수지는 활성그룹으로 술폰산기를 가지고 있는 강한 산성형을 사용하는 것이 바람직하며, 예를 들면 다이아이온 SK1B, 듀오라이트 C-20H, 앰버라이트 IR-120 플러스, 다우엑스 50Wx8, 다우엑스 50Wx10 등이 있다.The cation exchange resin is preferably to use a strong acid type having a sulfonic acid group as the active group, for example, Diion SK1B, Duolite C-20H, Amberlite IR-120 Plus, Dow X 50Wx8, Dow X 50Wx10, etc. There is this.
상기 음이온 교환수지는 활성그룹으로 4급 암모늄염기를 가지고 있는 강한 염기형을 사용하는 것이 바람직하며, 예를 들면 다이아이온 SA 10A, 다이아이온 SA 12A, 듀오라이트 A101D, 앰버라이트 IRA-402OH, 앰버제트 4400OH, 다우엑스 1x2, 다우엑스 1x4 등이 있다The anion exchange resin is preferably a strong base type having a quaternary ammonium base as the active group, for example, diion SA 10A, diion SA 12A, duolite A101D, amberlite IRA-402OH, amber jet 4400OH , Dow X 1x2, Dow X 1x4, etc.
이하, 본 발명은 하기 실시 예에 의하여 상세히 설명될 것이나, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples, but the present invention is not limited thereto.
(실시예 1)(Example 1)
발리엔아민 100 g과 소디움 바이카보네이트 100 g을 물 400 mL에 녹이고 반응온도를 0 내지 10 ℃로 냉각하였다. 여기에 벤질 클로로포메이트 203 g과 톨루엔 300 mL의 혼합액을 동일온도에서 적가하였다. 적가 후 상온에서 약 2-5시간 정도 교반시킨 후 다시 내부온도를 0-10 ℃로 냉각하였다. 이것을 여과하고 톨루엔과 냉수로 세척하였다. 생성된 결정을 진공건조하여 카바메이트 화합물(화학식 2) 164g (수율: 93%)를 얻었다.100 g of valenamine and 100 g of sodium bicarbonate were dissolved in 400 mL of water, and the reaction temperature was cooled to 0 to 10 ° C. A mixture of 203 g of benzyl chloroformate and 300 mL of toluene was added dropwise thereto at the same temperature. After dropping, the mixture was stirred at room temperature for about 2-5 hours, and the internal temperature was cooled to 0-10 ° C. It was filtered and washed with toluene and cold water. The resulting crystals were vacuum dried to obtain 164 g (yield: 93%) of carbamate compound (Formula 2).
NMR (D2O) d : 5.02 (s, 2H), 5.46 (d, 1H), 6.67 (d, 1H), 7.33 (s, 5H)NMR (D 2 O) d: 5.02 (s, 2H), 5.46 (d, 1H), 6.67 (d, 1H), 7.33 (s, 5H)
(실시예 2)(Example 2)
상기 실시예 1의 생성물인 카바메이트 화합물(화학식 2) 164g을 메탄올 1.4 L에 분산시킨 후 반응온도를 0-10 ℃로 냉각하였다. 여기에 브롬 85g과 메탄올 600 mL의 혼합용액을 동일온도에서 적가하였다. 적가가 완료되면 동일온도에서 약 1-5시간 정도 교반시킨 후 이것을 감압증류시켰다. 이후, 상기 용액에 1:10의 부피비로 혼합된 에탄올/에틸 아세테이트 혼합용액 2.2 L를 투입하고 냉동실에서 5시간 이상 보관하였다. 이것을 여과하고 에틸 아세테이트로 세척하였다. 생성된 결정을 진공건조하여 브롬화된 고리화 카바메이트(화학식 3) 152g (수율: 96%)를 얻었다.164 g of the carbamate compound (Formula 2), which is the product of Example 1, was dispersed in 1.4 L of methanol, and the reaction temperature was cooled to 0-10 ° C. A mixed solution of 85 g of bromine and 600 mL of methanol was added dropwise at the same temperature. When the dropping was completed, the mixture was stirred at the same temperature for about 1-5 hours and then distilled under reduced pressure. Thereafter, 2.2 L of ethanol / ethyl acetate mixed solution mixed in a volume ratio of 1:10 was added to the solution, and the mixture was stored in the freezer for at least 5 hours. It was filtered and washed with ethyl acetate. The resulting crystals were dried in vacuo to give 152 g (yield: 96%) of brominated cyclized carbamate (Formula 3).
NMR (D2O) d : 3.66 (t, 1H), 3.93 (t, 1H), 3.95 (d, 1H), 4.14 (d, 1H), 4.18 (d, 1H), 4.34 (dd, 1H), ~4.75 (1H)NMR (D 2 O) d: 3.66 (t, 1H), 3.93 (t, 1H), 3.95 (d, 1H), 4.14 (d, 1H), 4.18 (d, 1H), 4.34 (dd, 1H), ~ 4.75 (1H)
(실시예 3)(Example 3)
상기 실시예 2의 생성물인 브롬화된 고리화 카바메이트(화학식 3) 152 g을 2.4 L의 물에 녹이고, 90 g의 소디움 보로하이드라이드를 약 20 ℃에서 소량씩 가하였다. 같은 온도로서 2시간 동안 교반하여 주고 반응이 종결되면 아세트산을 사용하여 pH를 5로 조절하고 감압증류하였다. 이렇게 얻어진 생성물은 다우엑스(Dowex) 1x2(OH-형) 수지(Dow 사) 2L에 넣고 교반한 후 이것을 칼럼을 통해 물 6L와 함께 흘려주어 염들을 완전히 제거시켰다. 여기에 0.5N 암모니아수 6L를 흘려준 후, 감압농축시켰다. 이것을 다시 앰버라이트 IR-120 플러스 칼럼(Rohm and Haas사) 1L에 넣고 물 3L를 흘려준 후, 0.5N 암모니아수 3L를 흘려주었다. 이것을 감압농축 시킨 후 동결 건조시켜 순수한 발리올아민 80g (수율: 81%)을 얻었다.152 g of the brominated cyclized carbamate (Formula 3), the product of Example 2, were dissolved in 2.4 L of water and 90 g of sodium borohydride were added in small portions at about 20 ° C. The mixture was stirred at the same temperature for 2 hours, and when the reaction was completed, the pH was adjusted to 5 using acetic acid and distilled under reduced pressure. The product thus obtained was added to 2 L of Dowex 1 × 2 (OH − type) resin (Dow Co., Ltd.) and stirred, followed by flowing it through a column with 6 L of water to completely remove salts. 6L of 0.5N ammonia water was poured into it, and it concentrated under reduced pressure. This was put back into 1L of Amberlite IR-120 Plus column (Rohm and Haas Co., Ltd.), 3L of water, and 3L of 0.5N ammonia water. The resultant was concentrated under reduced pressure and freeze-dried to obtain 80 g (yield: 81%) of pure valenamine.
NMR (D2O) d : 1.85 (dd, 1H), 2.07 (dd, 1H), 3.4~3.6 (2H), 3.63 (2H), 3.72 (dd, 1H), 3.99 (t, 1H)NMR (D 2 O) d: 1.85 (dd, 1H), 2.07 (dd, 1H), 3.4 to 3.6 (2H), 3.63 (2H), 3.72 (dd, 1H), 3.99 (t, 1H)
(비교예 1)(Comparative Example 1)
(USP 4,701,559호에 제시된 공정)(Process presented in USP 4,701,559)
발리엔아민 300 g을 6L의 물에 녹이고 2L의 에틸아세테이트를 첨가하였다. 여기에 0.5L의 벤질 클로로포메이트를 첨가하고 240 g의 소디움 바이카보네이트를 첨가한 후, 0 ℃로 냉각하고 3시간동안 교반하여 주었다. 이후 반응액을 2N 염산 수용액을 사용하여 pH를 6으로 맞추고 수층을 분리하여 에틸 아세테이트로 씻어 주었다. 수층을 감압증류하여 3L까지 줄이고 하룻밤 동안 냉장고에 방치하여 328 g(수율: 62%)의 생성물을 얻었다.300 g of valenamine was dissolved in 6 L of water and 2 L of ethyl acetate was added. 0.5L of benzyl chloroformate was added thereto, followed by 240 g of sodium bicarbonate, followed by cooling to 0 ° C. and stirring for 3 hours. The reaction solution was then adjusted to pH 6 using 2N aqueous hydrochloric acid solution, and the aqueous layer was separated and washed with ethyl acetate. The aqueous layer was distilled under reduced pressure to 3 L and left in the refrigerator overnight to yield 328 g (yield: 62%) of product.
(비교예 2)(Comparative Example 2)
7 L의 물을 5-10 ℃로 냉각시키고, 상기 비교예 1에서 얻은 출발물질 186 g을 녹이고, 여기에 브롬 106 g을 녹인 5L 수용액을 천천히 조금씩 적가하였다. 같은 온도로 1시간 교반하여 주고 반응이 종결되면 소디움 바이카보네이트 포화수용액을 사용하여 pH를 6으로 맞추고 에틸 아세테이트를 사용하여 씻어주었다. 수층을 분리하여 감압 증류하고 MCI 젤 CHP-20P로서 컬럼하고 모은 생성물을 감압 증류하여 1L까지 줄이고 냉장고에 하룻밤 동안 방치하여 130g(수율: 73%)의 생성물을 얻었다.7 L of water was cooled to 5-10 ° C., 186 g of the starting material obtained in Comparative Example 1 was dissolved, and 5 L aqueous solution of 106 g of bromine was slowly added dropwise thereto. The mixture was stirred at the same temperature for 1 hour, and when the reaction was completed, the pH was adjusted to 6 using saturated aqueous sodium bicarbonate solution and washed with ethyl acetate. The aqueous layer was separated, distilled under reduced pressure, the column was purified by MCI gel CHP-20P, and the collected product was distilled under reduced pressure to 1 L and left in the refrigerator overnight to obtain 130 g (yield: 73%) of product.
(비교예 3)(Comparative Example 3)
상기 비교예 2의 생성물 100 g을 5 L의 물에 녹이고 50 g의 소디움 보로하이드라이드를 상온에서 소량씩 가하였다. 같은 온도에서 2시간 동안 교반하여 주고 반응이 종결되어지면 아세트산을 사용하여 pH를 5로 조절하고 감압증류하였다. 크루드(curde) 생성물은 활성탄 칼럼(활성탄, 180 L)을 통해 분리 정제하여주고, 물 30L를 사용하여 씻어준 후, 50% 수용성 메탄올 30L을 사용하여 씻어주었다. 생성물을 모은 후 감압증류한 후, 메탄올:에탄올(1:10)의 수용액에서 하룻밤 동안 냉장고에 방치하여 56 g(수율: 76%)의 생성물을 얻었다.100 g of the product of Comparative Example 2 was dissolved in 5 L of water and 50 g of sodium borohydride were added in small portions at room temperature. After stirring at the same temperature for 2 hours, the reaction was terminated, the pH was adjusted to 5 using acetic acid and distilled under reduced pressure. The crude product was separated and purified through an activated carbon column (activated carbon, 180 L), washed with 30 L of water, and washed with 30 L of 50% aqueous methanol. After the product was collected and distilled under reduced pressure, the product was left in a refrigerator overnight in an aqueous solution of methanol: ethanol (1:10) to obtain 56 g (yield: 76%) of the product.
(비교예 4)(Comparative Example 4)
상기 비교예 3의 생성물 40 g을 물에 녹이고 160 g의 수산화바륨을 첨가하고 70-80 ℃의 온도로 4시간 이상 환류교반하여 주었다. 가수분해 반응이 종결되어지면 상온까지 식히고 이산화탄소에 반응액을 노출시켜서 바륨 카보네이트로 석출시켜서 여과하였다. 이후 감압 증류하여 앰버라이트 CG-50 2L를 사용하여 물 6L를 흘려준 후, 암모니아수 6L를 흘려주어 정제하고 다시 다우엑스 1x2 3L를 사용하여 물 3L를 흘려주어 생성물을 모은후 감압증류하여 33 g(수율: 97%)의 발리올아민을 얻었다.40 g of the product of Comparative Example 3 was dissolved in water, 160 g of barium hydroxide was added, and the mixture was stirred under reflux for 4 hours at a temperature of 70-80 ° C. After the completion of the hydrolysis reaction, the reaction mixture was cooled to room temperature, exposed to carbon dioxide, precipitated with barium carbonate, and filtered. After distillation under reduced pressure, 6L of water was poured using 2L of Amberlite CG-50, 6L of ammonia water was refined by flowing, and 3L of water was collected using DowX 1x2 3L. Yield: 97%).
상기 결과들로부터 본 발명의 방법은 이온교환수지 컬럼을 실시함으로써, 별도의 가수분해 과정을 생략하여 공정이 간소화되어 경제적임을 알 수 있다. 반면, 비교예의 방법들은 활성탄을 이용한 분리정제를 실시하여 용매의 사용량이 과다하였으며, 또한 가수분해 과정을 별도로 실시하여 공정이 매우 번거로움을 알 수 있 다.From the above results, it can be seen that the method of the present invention is simplified and economical by omitting a separate hydrolysis process by implementing an ion exchange resin column. On the other hand, the method of the comparative example was performed by separation and purification using activated carbon, the amount of solvent used was excessive, and the hydrolysis process was carried out separately, it can be seen that the process is very cumbersome.
본 발명의 방법은 발리올아민을 제조할 때 탈브롬화반응 후 이온교환수지를 통해 종래의 방법들에 비하여 반응의 단계를 축소시키고, 분리의 용이성이 매우 높아 상업적 생산에 적합한 효과가 있다.The method of the present invention reduces the step of the reaction compared to the conventional methods through the ion exchange resin after the debromination reaction in the preparation of the valenamine, the ease of separation is very high, there is an effect suitable for commercial production.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0056194A1 (en) | 1981-01-05 | 1982-07-21 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
| US4824943A (en) | 1986-03-05 | 1989-04-25 | Takeda Chemical Industries, Ltd. | Inosose derivatives and production thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0056194A1 (en) | 1981-01-05 | 1982-07-21 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
| US4824943A (en) | 1986-03-05 | 1989-04-25 | Takeda Chemical Industries, Ltd. | Inosose derivatives and production thereof |
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| Title |
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| CARBOHYDRATE RESEARCH, 1985, 140, 185-200 * |
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