KR19980059276A - Method for producing racemic DL-phenylglycine using ultrasound - Google Patents
Method for producing racemic DL-phenylglycine using ultrasound Download PDFInfo
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Abstract
본 발명은 초음파를 이용한 라세미 DL-페닐글리신의 제조방법에 관한 것으로서, 더욱 상세하기로는 라세미 DL-페닐글리신 니트릴을 염기의 존재하에서 가수분해하여 다음 화학식 1로 표시되는 라세미 DL-페닐글리신을 제조하는 과정에서 초음파를 적용시켜 반응시간을 크게 단축하고 반응조건을 온화하는 방법에 관한 것이다.The present invention relates to a method for producing racemic DL-phenylglycine using ultrasonic waves, and more particularly, to racemic DL-phenylglycine represented by Formula 1 by hydrolyzing racemic DL-phenylglycine nitrile in the presence of a base. It relates to a method for shortening the reaction time and mild reaction conditions by applying ultrasonic waves in the process of manufacturing.
Description
본 발명은 초음파를 이용한 라세미 DL-페닐글리신의 제조방법에 관한 것으로서, 더욱 상세하기로는 라세미 DL-페닐글리신 니트릴을 염기의 존재하에서 가수분해하여 다음 화학식 1로 표시되는 라세미 DL-페닐글리신을 제조하는 과정에서 초음파를 적용시켜 반응시간을 크게 단축하고 반응조건을 온화하는 방법에 관한 것이다.The present invention relates to a method for producing racemic DL-phenylglycine using ultrasonic waves, and more particularly, to racemic DL-phenylglycine represented by Formula 1 by hydrolyzing racemic DL-phenylglycine nitrile in the presence of a base. It relates to a method for shortening the reaction time and mild reaction conditions by applying ultrasonic waves in the process of manufacturing.
[화학식 1][Formula 1]
페닐글리신은 자연계에서 얻을 수 없는 아미노산으로서 주로 공업적으로 제조하고 있으며 의약품 제조시 중간체로서 사용되고 있는 중요 물질이다. 특히, 페니실린계 항생제, 세파로스로린계 항생제인 아목시실린, 세파드록실, 엠피실린, 세파렉신, 세파클러 등의 제조에서 핵심 중간체로 이용되고 있다.Phenylglycine is an amino acid that cannot be obtained in nature and is mainly produced industrially and is an important substance used as an intermediate in the manufacture of pharmaceuticals. In particular, penicillin-based antibiotics, Sepharoserin-based antibiotics Amoxicillin, Sephadroxyl, Empicillin, Separexin, Sephacler and the like are used as a key intermediate in the manufacture.
라세미 DL-페닐글리신을 제조하는 일반적인 방법은 다음과 같다.The general method for preparing racemic DL-phenylglycine is as follows.
영국특허 제1418870호(1975)에서는 라세미 DL-페닐글리신 니트릴을 합성한 후, 이를 30%의 수산화나트륨 수용액으로 가수분해하여 라세미 DL-페닐글리신을 제조하였다. 그러나, 이 방법에서는 100℃에서 12시간의 장시간 반응과 30%의 고농도 염기를 사용하는 문제점이 있다.In British Patent No. 1418870 (1975), racemic DL-phenylglycine nitrile was synthesized and hydrolyzed with 30% aqueous sodium hydroxide to prepare racemic DL-phenylglycine. However, this method has a problem of using a long time reaction at 100 ° C. for 12 hours and using a high concentration of 30% base.
프랑스특허 제2141354호(1973)에서는 DL-페닐글리신 니트릴과 광학활성을 갖는 카르본산의 반응에서 얻어진 D-페닐글리신 니트릴의 염 화합물에 23% 염산용액을 넣고 100℃에서 2 ~ 4시간 환류 교반하여 84% 수율로 D-페닐글리신을 얻었다.In French Patent No. 2141354 (1973), 23% hydrochloric acid solution was added to a salt compound of D-phenylglycine nitrile obtained by the reaction of DL-phenylglycine nitrile and carboxylic acid having optical activity, and refluxed at 100 ° C. for 2 to 4 hours. D-phenylglycine was obtained in 84% yield.
미국특허 제4072698호(1978)에서는 라세미 DL-페닐글리신 니트릴과 광학활성을 갖는 카르본산을 반응시켜서 얻어진 D-페닐글리신 니트릴의 염 화합물에 40% 브롬산 수용액을 넣고 95℃에서 2시간 동안 환류 교반하여 63% 수율로 D-페닐글리신을 얻었다.In US Patent No. 4072698 (1978), 40% aqueous bromic acid solution is added to a salt compound of D-phenylglycine nitrile obtained by reacting racemic DL-phenylglycine nitrile with carboxylic acid having optical activity and refluxed at 95 ° C. for 2 hours. Stirring gave D-phenylglycine in 63% yield.
상기에서 예시한 종래 라세미 DL-페닐글리신의 제조방법에서는 라세미 DL-페닐글리신 니트릴의 가수분해시 반응온도가 95 ~ 100℃의 고온이며, 30%의 강염기나 20% 이상의 강산을 사용하며 특히 강염기의 사용시 12시간의 긴 반응시간이 필요하다.In the conventional method for producing racemic DL-phenylglycine as exemplified above, when the hydrolysis of racemic DL-phenylglycine nitrile is performed at a high temperature of 95 to 100 ° C., 30% strong base or 20% or more strong acid is used. The use of strong bases requires a long reaction time of 12 hours.
한편, 초음파를 사용하는 반응에 대한 연구에서 일반적으로 받아들여지고 있는 '핫-스팟(hot-spot)' 이론에 의하면 반응 매개물내에 도입된 고주파의 음파는 매개물인 용매내에 순간적으로 눈으로는 볼 수 없을 정도의 아주 작은 공동들을 형성하며 이 공동이 붕괴되는 과정에서 일순간 국부적으로 1000℃ 이상의 아주 높은온도와 1000 bar 이상의 높은 압력을 발생시키게 된다. 이러한 효과는 다양한 반응에서 반응속도를 증가시켜 반응시간을 줄이고, 수율과 선택성을 향상시키며 많은 경우에 초음파는 보통의 반응에 요구되는 온도와 압력을 상당히 줄일 수 있어 산업적으로 매우 유용한 것으로 알려져 있다.On the other hand, according to the 'hot-spot' theory generally accepted in the study of the reaction using ultrasonic waves, the high frequency sound waves introduced into the reaction medium are momentarily invisible to the medium solvent. Very small cavities of degree are formed, and in the course of the collapse of these cavities, one instantaneously generates very high temperatures above 1000 ° C and high pressures above 1000 bar. This effect is known to be very useful industrially by increasing the reaction rate in various reactions to reduce the reaction time, improve the yield and selectivity, and in many cases ultrasonic waves can significantly reduce the temperature and pressure required for the normal reaction.
최근 다양한 반응에 초음파를 이용하고 있다. 예를들면, 카르본산 에스테르의 가수분해 반응에 초음파를 이용하여 반응시간을 90분에서 10분으로 현저히 단축시키는 효과를 얻은 바 있다[Tetrahedron Lett., 3917(1979)]. 또한, 수소주석화 반응과 수소화 환원반응에 초음파를 도입함으로써 통상적으로 50 ~ 100℃에서 진행되는 반응을 0℃ 정도로 낮추는 효과를 확인한 바도 있다[J. Am. Chem. Soc., Vol.111, p.6849(1989)]. 즉, 상기와 같은 효과는 초음파의 공동의 붕괴시 국부적이고 순간적으로 생성되는 1000℃ 이상의 고온효과에 의한 것이다.Recently, ultrasonic waves have been used for various reactions. For example, the use of ultrasonic waves in the hydrolysis reaction of carboxylic acid esters has significantly reduced the reaction time from 90 minutes to 10 minutes (Tetrahedron Lett., 3917 (1979)). In addition, by introducing ultrasonic waves into the hydrogen tinization reaction and hydrogenation reduction reaction has been confirmed that the effect of lowering the reaction usually proceeds at 50 ~ 100 ℃ to about 0 ℃ [J. Am. Chem. Soc., Vol. 111, p. 6849 (1989). That is, the above effect is due to the high temperature effect of 1000 ° C. or higher generated locally and instantaneously during the collapse of the ultrasonic cavity.
본 발명에서는 DL-페닐글리신 니트릴 화합물의 가수분해 과정에서 초음파의 특이성을 도입하면 보다 온화한 반응조건으로도 고수율의 라세미 D,L-페닐글리신 을 얻을 수 있음을 알게됨으로써 본 발명을 완성하였다.In the present invention, by incorporating the specificity of the ultrasonic wave in the hydrolysis process of the DL-phenylglycine nitrile compound, the present invention was completed by finding that high yield of racemic D, L-phenylglycine can be obtained even under milder reaction conditions.
따라서, 본 발명은 초음파를 적용하여 온화한 반응조건으로 라세미 D,L-페닐글리신을 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for producing racemic D, L-phenylglycine under mild reaction conditions by applying ultrasonic waves.
도1은 본 발명에서 이용되는 반응장치를 개략적으로 도시한 것이다.Figure 1 schematically shows a reactor used in the present invention.
본 발명은 라세미 DL-페닐글리신 니트릴을 염기의 존재하에서 가수분해하여 라세미 DL-페닐글리신을 제조하는 방법에 있어서, 20 ~ 80 kHz의 초음파를 적용하는 것을 그 특징으로 한다.The present invention is characterized in that, in the method for producing racemic DL-phenylglycine by hydrolyzing racemic DL-phenylglycine nitrile in the presence of a base, an ultrasonic wave of 20 to 80 kHz is applied.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 20 ~ 80 kHz의 초음파를 이용하여 염기의 존재하에서 상압 및 낮은 반응온도와 짧은 시간에 높은 수율로 라세미 DL-페닐글리신을 제조하는 제법에 관한 것이다 본 발명에 따른 제조공정에서는 첨부된 도1에 나타낸 바와 같이 통상의 반응기에 초음파 반응기를 설치한다.The present invention relates to a process for producing racemic DL-phenylglycine in high yield in a short time with atmospheric pressure and low reaction temperature in the presence of a base using ultrasonic waves of 20 ~ 80 kHz in the manufacturing process according to the present invention As shown in FIG. 1, an ultrasonic reactor is installed in a conventional reactor.
본 발명에 따른 라세미화 과정을 보다 구체적으로 설명하면 다음과 같다.Referring to the racemization process according to the present invention in more detail as follows.
반응기에 초음파 발생 장치를 설치하고 20 ~ 80 KHz 파수, 바람직하기로는 20 ~ 50 KHz 파수를 발생시키면서 1N 수산화나트륨 용액을 넣고 반응온도를 50 ~ 80℃로 유지하면서 2 ~ 3시간 반응시켜 93 ~ 95%의 수율로 라세미 DL-페닐글리신을 얻는다.An ultrasonic generator was installed in the reactor and 1N sodium hydroxide solution was added while generating 20 to 80 KHz wavenumber, preferably 20 to 50 KHz wavenumber, and the reaction temperature was maintained at 50 to 80 ° C for 2 to 3 hours to react. Obtained racemic DL-phenylglycine in% yield.
상기 가수분해 반응 조건에 있어서, 20 kHz 미만의 초음파가 적용되면 본 발명에서 기대하는 효과를 얻을 수 없고, 80 kHz 이상의 고주파 음파는 일반적인 초음파 발생장치로는 얻기 어렵다. 그리고 반응온도가 50℃ 미만이면 반응이 느려 상대적으로 반응시간이 길어지는 문제가 있다.Under the above hydrolysis reaction conditions, if an ultrasonic wave of less than 20 kHz is applied, the effect expected in the present invention cannot be obtained, and high frequency sound waves of 80 kHz or more are difficult to obtain with a general ultrasonic wave generator. And if the reaction temperature is less than 50 ℃ there is a problem that the reaction is relatively long because the reaction is slow.
상기와 같은 가수분해 과정을 마친 반응액으로부터 라세미 혼합물을 수득하기 위해서는 통상의 분리 정제 방법 예를들면 결정화, 여과, 건조 등을 수행한다. 이들 분리 정제 방법에 있어서, 특히 바람직하기로는 결정화이다. 결정화에 의하면, 반응액을 2 ~ 5℃로 냉각한 상태에서 산용액을 투입하여 반응액의 pH를 5 ~ 6으로 맞추어 석출된 결정을 여과하여 회수한다.In order to obtain the racemic mixture from the reaction solution after the hydrolysis process as described above, a conventional separation and purification method such as crystallization, filtration, drying and the like is performed. In these separation purification methods, crystallization is particularly preferable. According to the crystallization, an acid solution is added while the reaction solution is cooled to 2 to 5 ° C., and the precipitated crystals are filtered and recovered by adjusting the pH of the reaction solution to 5 to 6.
반면에, 본 발명과 동일한 조건하에서 초음파를 사용하지 않은 경우에는 DL-페닐글리신으로의 반응이 진행되지 않았다.On the other hand, when ultrasonic waves were not used under the same conditions as the present invention, the reaction with DL-phenylglycine did not proceed.
이하 본 발명을 실시예에 의거하여 더욱 상세히 설명하는 바, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
실시예 1 :Example 1:
첨부된 도1에 도시한 바와 같이 초음파 발생기에 물을 채운다. 100 ㎖ 평평한 바닥 플라스크에 라세미 DL-페닐글리신 니트릴(1.32 g, 10.0 mmol)과 1N 수산화나트륨 용액(50 ㎖, 50.0 mmol)을 넣고, 이를 초음파 발생기에 장치한다. 50℃를 유지하면서 3시간동안 반응시킨 후, 반응액을 2 ~ 5℃으로 냉각한 상태에서 35% 염산을 이용하여 반응액의 pH를 5 ~ 6으로 맞추고 30분 교반한 후 여과한다. 아세톤(5 ㎖)으로 세척하고 60℃에서 건조시켜 흰색의 라세미 DL-페닐글리신 1.23g(수율 93%)을 얻는다.As shown in FIG. 1, water is filled in the ultrasonic generator. In a 100 mL flat bottom flask, racemic DL-phenylglycine nitrile (1.32 g, 10.0 mmol) and 1N sodium hydroxide solution (50 mL, 50.0 mmol) are placed in an ultrasonic generator. After reacting for 3 hours while maintaining 50 ℃, the reaction solution was cooled to 2 ~ 5 ℃ adjusted the pH of the reaction solution to 5 ~ 6 with 35% hydrochloric acid and stirred for 30 minutes and then filtered. Wash with acetone (5 mL) and dry at 60 ° C. to yield 1.23 g (93% yield) of white racemic DL-phenylglycine.
녹는점 : 290 ~ 291℃Melting Point: 290 ~ 291 ℃
1H-NMR(D2O+NaOD, ppm) : δ 7.4(m, 5H), 4.3(s, 1H) 1 H-NMR (D 2 O + NaOD, ppm): δ 7.4 (m, 5H), 4.3 (s, 1H)
실시예 2 :Example 2:
첨부된 도1에 도시한 바와 같이 초음파 발생기에 물을 채운다. 100 ㎖ 평평한 바닥 플라스크에 라세미 DL-페닐글리신 니트릴(1.32 g, 10.0 mmol)과 1N 수산화나트륨 용액(50 ㎖, 50.0 mmol)을 넣고 초음파 발생기에 장치한다. 승온하여 80℃를 유지하면서 2시간동안 반응시킨 후, 반응액을 2 ~ 5℃로 냉각한 상태에서 35% 염산을 이용하여 반응액의 pH를 5 ~ 6으로 맞추고 30분 교반한 후 여과한다. 아세톤(5 ㎖)으로 세척하고 60℃에서 건조시켜 흰색의 라세미 DL-페닐글리신 1.26g(수율 95%)을 얻는다.As shown in FIG. 1, water is filled in the ultrasonic generator. The racemic DL-phenylglycine nitrile (1.32 g, 10.0 mmol) and 1N sodium hydroxide solution (50 mL, 50.0 mmol) were placed in a 100 mL flat bottom flask and placed in an ultrasonic generator. After the reaction was conducted for 2 hours while maintaining the temperature at 80 ° C., the pH of the reaction solution was adjusted to 5 to 6 with 35% hydrochloric acid while the reaction solution was cooled to 2 to 5 ° C., stirred for 30 minutes, and filtered. Wash with acetone (5 mL) and dry at 60 ° C. to yield 1.26 g (95% yield) of white racemic DL-phenylglycine.
비교예 1 :Comparative Example 1:
3구 100 ㎖ 둥근 바닥 플라스크에 라세미 DL-페닐글리신 니트릴(1.32 g, 10.0 mmol)과 1N 수산화나트륨 용액(50 ㎖, 50.0 mmol)을 넣는다. 50℃를 유지하면서 6시간 동안 반응시킨 후, 반응액을 2 ~ 5℃로 냉각한 상태에서 35% 염산을 이용하여 반응액의 pH를 5 ~ 6으로 맞추고 30분 교반한 후 여과한다. 여과한 고체를 핵자기 공명 분석기기를 이용하여 분석한 결과 DL-페닐글리신은 생성되지 않음을 확인할 수 있었다.In a three neck 100 mL round bottom flask was placed racemic DL-phenylglycine nitrile (1.32 g, 10.0 mmol) and 1N sodium hydroxide solution (50 mL, 50.0 mmol). After the reaction was carried out for 6 hours while maintaining 50 ℃, the reaction solution was cooled to 2 ~ 5 ℃ to adjust the pH of the reaction solution to 5 ~ 6 with 35% hydrochloric acid and stirred for 30 minutes and then filtered. The filtered solid was analyzed using a nuclear magnetic resonance analyzer to confirm that DL-phenylglycine was not produced.
상기 실시예 1과 비교예 1을 비교하여 보면, 50℃의 동일한 온도조건을 주었을때 초음파를 적용하지 않은 경우에는 라세미 DL-페닐글리신이 생성되지 않은데 반하여 초음파를 적용한 경우에는 라세미 DL-페닐글리신을 93%의 고수율로 얻을 수 있었다. 또한 실시예 2와 종래 방법(영국특허 제1418870호)을 비교하여 보면, 반응온도를 80℃로 유지한 경우 초음파를 적용하지 않은 경우의 반응시간이 12시간에서 2시간으로 6배의 반응시간을 단축할 수 있었고, 수율 역시 95%로 매우 높음을 알 수 있다.Comparing Example 1 and Comparative Example 1, racemic DL-phenylglycine was not produced when ultrasonic waves were not applied under the same temperature condition of 50 ° C., whereas racemic DL-phenyl was applied when ultrasonic waves were applied. Glycine was obtained at high yield of 93%. In addition, when comparing Example 2 with the conventional method (UK Patent No. 1418870), when the reaction temperature is maintained at 80 ℃ reaction time when the ultrasonic wave is not applied 6 times the reaction time from 12 hours to 2 hours It can be shortened, and the yield is also very high, 95%.
라세미 DL-페닐글리신 니트릴의 가수분해 반응에 초음파를 적용하고 있는 본 발명에 따른 제조방법에서는 비교적 낮은 온도와 짧은 반응 시간의 조건에서도 높은 수율로 라세미 DL-페닐글리신을 제조할 수 있다.In the production method according to the present invention in which ultrasonic waves are applied to the hydrolysis reaction of racemic DL-phenylglycine nitrile, racemic DL-phenylglycine can be produced in high yield even under relatively low temperature and short reaction time.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4111980A (en) * | 1976-03-11 | 1978-09-05 | Stamicarbon, B.V. | Process for preparing optically active phenyl glycine |
| US4215223A (en) * | 1977-10-18 | 1980-07-29 | Gerard Kessels | Process for the preparation of D(-)αphenylglycine |
| KR940007311A (en) * | 1992-09-14 | 1994-04-27 | 변무원 | Construction method of slope slope |
| KR980009225A (en) * | 1996-07-31 | 1998-04-30 | 이승웅 | Preparation method of D - (-) - 4-hydroxyphenylglycine |
| KR101418870B1 (en) * | 2012-06-13 | 2014-07-17 | 한국광기술원 | Method for manufacturing lens with multi-refraction |
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- 1996-12-31 KR KR1019960078613A patent/KR19980059276A/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4111980A (en) * | 1976-03-11 | 1978-09-05 | Stamicarbon, B.V. | Process for preparing optically active phenyl glycine |
| US4215223A (en) * | 1977-10-18 | 1980-07-29 | Gerard Kessels | Process for the preparation of D(-)αphenylglycine |
| KR940007311A (en) * | 1992-09-14 | 1994-04-27 | 변무원 | Construction method of slope slope |
| KR980009225A (en) * | 1996-07-31 | 1998-04-30 | 이승웅 | Preparation method of D - (-) - 4-hydroxyphenylglycine |
| KR101418870B1 (en) * | 2012-06-13 | 2014-07-17 | 한국광기술원 | Method for manufacturing lens with multi-refraction |
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