KR100442768B1 - A process for preparing L-valine as radioabled compound - Google Patents
A process for preparing L-valine as radioabled compound Download PDFInfo
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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Abstract
본 발명은 방사성동위원소 표지화합물로서의 L-발린의 제조방법에 관한 것으로서, 더욱 상세하게는 종래방법이 DL-발린의 라세믹 혼합물을 중간체로 합성하여 분할하므로써 목적하는 L-발린 이외에도 동등량의 D-발린을 부 생성물로 제조하는데 반하여 본 발명은 방사성 원료물질로 비교적 가격이 저렴한 이산화탄소(CO2-14C)를 사용하고, 반응중간체로 DL-발린의 라세믹 혼합물을 생성하지 않으므로 높은 수율로 방사성동위원소 표지화합물로서 약리 및 대사 연구에 유용한 다음 화학식 1로 표시되는 L-발린을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing L-valine as a radioisotope labeling compound, and more particularly, the conventional method synthesizes and divides a racemic mixture of DL-valine into an intermediate to obtain an equivalent amount of D in addition to the desired L-valine. - whereas the present invention for the production of valine as a by-product is relatively inexpensive radioactive carbon dioxide (CO 2 - 14 C) value as a starting material because it does not use, generate a racemic mixture of DL- valine as the reaction intermediate at a high yield of radioactive It relates to a method for preparing L-valine represented by the following formula (1) useful for pharmacological and metabolic studies as an isotope labeling compound.
화학식 1Formula 1
상기 화학식 1에서, *는14C를 의미한다.In Formula 1, * means 14 C.
Description
본 발명은 방사성동위원소 표지화합물로서의 L-발린의 제조방법에 관한 것으로서, 더욱 상세하게는 종래방법이 DL-발린의 라세믹 혼합물을 중간체로 합성하여 분할하므로써 목적하는 L-발린 이외에도 동등량의 D-발린을 부 생성물로 제조하는데 반하여 본 발명은 방사성 원료물질로 비교적 가격이 저렴한 이산화탄소(CO2-14C)를 사용하고, 반응중간체로 DL-발린의 라세믹 혼합물을 생성하지 않으므로 높은 수율로 방사성동위원소 표지화합물로서 약리 및 대사 연구에 유용한 다음 화학식 1로 표시되는 L-발린을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing L-valine as a radioisotope labeling compound, and more particularly, the conventional method synthesizes and divides a racemic mixture of DL-valine into an intermediate to obtain an equivalent amount of D in addition to the desired L-valine. - whereas the present invention for the production of valine as a by-product is relatively inexpensive radioactive carbon dioxide (CO 2 - 14 C) value as a starting material because it does not use, generate a racemic mixture of DL- valine as the reaction intermediate at a high yield of radioactive It relates to a method for preparing L-valine represented by the following formula (1) useful for pharmacological and metabolic studies as an isotope labeling compound.
화학식 1Formula 1
상기 화학식 1에서, *는14C를 의미한다.In Formula 1, * means 14 C.
'방사성동위원소 표지화합물'이라 함은 화합물을 구성하는 원소의 일부가 방사성동위원소로 치환된 화합물을 말하며, 이러한 화합물은 약물의 약리, 대사연구에 없어서는 안되는 필수적인 화합물로 그 가격 역시 매우 고가의 화합물이다.Radioisotope-labeled compound refers to a compound in which some of the elements constituting the compound are substituted with radioisotopes. These compounds are indispensable for drug pharmacology and metabolism, and are very expensive. to be.
이러한 방사성동위원소 표지화합물 중에서 상기 화학식 1 로 표시되는 L-발린은 아미노산의 대사연구 및 비대칭 탄소(Chiral center)를 갖는 약물의 합성 및 이의 대사연구에 중요한 중간체로 사용되는 바 이의 제조방법에 관한 연구가 지속적으로 진행되고 있다.Among these radioisotope labeled compounds, L-valine represented by Chemical Formula 1 is used as an important intermediate for metabolism studies of amino acids, synthesis of drugs having asymmetric carbons (Chiral centers), and metabolism studies thereof. Is ongoing.
상기 화학식 1로 표시 되는 방사성동위원소 화합물로서의 L- 발린의 종래 제조방법을 살펴보면 다음과 같다.Looking at the conventional method for producing L- valine as a radioisotope compound represented by the formula (1) as follows.
상기 종래의 제조방법에서는 방사성동위소로 치환된 포타슘 시아나이드(KCN-14C)로부터 DL-발린을 얻고, 이를 다시 클로로아세틸 클로라이드와 반응시켜 N-클로로아세틸-DL-발린을 얻은 다음, 이를 아실라아제와 함께 37 ℃에서 약 24 시간동안 배양하고 다시 클로로아세틸클로라이드와 반응시키고 다시 N-클로로아세틸-DL-발린을 얻은 다음, 이를 아실라아제와 함께 37 ℃에서 약 24 시간동안 배양하여 최종적으로 99% 이상의 순도를 갖는 표지화합물로서의 L-발린을 포타슘시아나이드로부터15%의 수율로 얻는 방법이 알려져 있다.In the conventional manufacturing method, DL-valine is obtained from potassium cyanide (KCN- 14 C) substituted with radioisotope, and then reacted with chloroacetyl chloride to obtain N-chloroacetyl-DL-valine, which is acila Incubate with aze for about 24 hours at 37 ° C., react with chloroacetyl chloride again to obtain N-chloroacetyl-DL-valine, then incubate with acylase at 37 ° C. for about 24 hours to obtain 99 It is known to obtain L-valine as a labeling compound having a purity of at least% from potassium cyanide in a yield of 15%.
그러나, 상기 종래방법에서 반응 중간체로서 DL-발린 라세믹 혼합물을 합성하여 이를 분할하므로써 L-발린을 수득하는 바, 방사성 원료물질인 포타슘 시아나이드(KCN-14C)가 고가의 화합물인 점을 감안한다면 불필요한 D-발린이 50%가 생성되므로 지극히 비효율적인 방법이라 할 수 있겠다.However, in the conventional method, L-valine is obtained by synthesizing and dividing a DL-valine racemic mixture as a reaction intermediate, considering that the radioactive raw material potassium cyanide (KCN- 14 C) is an expensive compound. If you do, it generates an unnecessary 50% of D-valine, which is extremely inefficient.
본 발명은 종래 방법에서와는 달리 불필요한 D-발린이 생성되지 아니하고 목적하는 방사성동위원소 화합물로서의 고순도 L-발린을 높은 수율로 제조하는 새로운 방법을 제공하는데 그 목적이 있다.The object of the present invention is to provide a new method for producing high-purity L-valine as a desired radioisotope compound in high yield without generating unnecessary D-valine unlike in the conventional method.
본 발명은 방사성동위원소 표지화합물로서의 L-발린의 제조방법에 있어서,The present invention provides a method for producing L-valine as a radioisotope labeling compound,
다음 화학식 2로 표시되는 2-메틸프로필마그네슘 브로마이드와 동위원소로 치환된 이산화탄소(CO2-14C)를 반응시켜서 다음 화학식 3으로 표시되는 3-메틸부틸산을 제조하는 과정; 상기 화학식 3으로 표시되는 화합물과 (S)-4-벤질-2-옥사졸리딘온을 반응시켜 다음 화학식 4로 표시되는 (4S)-3-(3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 제조하는 과정; 상기 화학식 4로 표시되는 화합물과 N-브로모석신이미드를 반응시켜 다음 화학식 5로 표시되는 (4S)-3-((2R)-2-브로모-3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 제조하는 과정; 상기 화학식 5로 표시되는 화합물과 소듐 아자이드를 반응시켜 다음 화학식 6으로 표시되는 (4S)-3-((2S)-2-아지도-3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 제조하는 과정; 상기 화학식 6으로 표시되는 화합물을 리튬 하이드록사이드로 처리하여 다음 화학식 7로 표시되는 (2S)-2-아지도-3-메틸부틸산을 제조하는 과정; 그리고 상기 화학식 7로 표시되는 화합물을 수소 환원반응시켜 다음 화학식 1로 표시되는 방사성동위원소 표지화합물로서의 L-발린을 제조하는 과정이 포함된다.Then the carbon dioxide is substituted by 2-methyl-propyl bromide, and isotopes of the formula 2 (CO 2 - 14 C) the reaction by the process of producing a 3-methyl-butyric acid represented by the following formula (3); (S) -4-benzyl-2-oxazolidinone is reacted with the compound represented by the formula (3), and represented by the following formula (4S) -3- (3-methylbutyryl) -4-benzyl-2- Preparing oxazolidinone; (4S) -3-((2R) -2-bromo-3-methylbutyryl) -4-benzyl represented by the following Chemical Formula 5 by reacting the compound represented by Chemical Formula 4 with N-bromosuccinimide Preparing 2-oxazolidinone; (4S) -3-((2S) -2-azido-3-methylbutyryl) -4-benzyl-2-oxa represented by the following Chemical Formula 6 by reacting the compound represented by Formula 5 with sodium azide Preparing zolidinone; Treating the compound represented by Chemical Formula 6 with lithium hydroxide to prepare (2S) -2-azido-3-methylbutyl acid represented by the following Chemical Formula 7; And a process of preparing L-valine as a radioisotope labeling compound represented by the following Chemical Formula 1 by hydrogen reduction reaction of the compound represented by Chemical Formula 7.
상기 식들 중에서, *는14C 로 치환된 탄소를 나타내고, Bn은 벤질기를 나타낸다.In the formulas, * represents carbon substituted with 14 C, and Bn represents benzyl group.
본 발명에 따른 상기 화학식 1로 표시되는 방사성동위원소 표지화합물로서의 L-발린의 제조방법을 그 과정별로 보다 상세히 설명하면 다음과 같다.Hereinafter, a method for preparing L-valine as a radioisotope labeling compound represented by Chemical Formula 1 according to the present invention will be described in more detail.
먼저, 방사성동위원소로 치환된 이산화탄소(CO2-14C) 기체를 진공 상태에서 상기 화학식 2로 표시되는 2-메틸프로필마그네슘 브로마이드가 용해된 에테르에 이동시켜서 10 ∼ 0 ℃에서 3 ∼ 6 시간 반응시키고, 미 반응 이산화탄소를 제거하여상기 화학식 3으로 표시되는 3-메틸부틸산을 제조한다.First, a carbon substituted with a radioactive isotope (CO 2 - 14 C) gas to vacuum the formula 2-methyl-2-propyl bromide is moved to the dissolved ether 10 ~ 0 ℃ 3 ~ 6 hours at shown by in To remove unreacted carbon dioxide to prepare 3-methylbutyl acid represented by Chemical Formula 3.
그리고, 상기 화학식 3으로 표시되는 3-메틸부틸산과 (4S)-4-벤질-2-옥사졸리딘온, 트라이에틸아민, 피발로일 클로라이드 및 n-부틸 리튬을 테트라하이드로퓨란 용매 하에서 78 ∼ 0 ℃에서 반응시켜 상기 화학식 4로 표시되는 (4S)-3-(3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 제조한다.In addition, 3-methylbutyl acid represented by the formula (3) and (4S) -4-benzyl-2-oxazolidinone, triethylamine, pivaloyl chloride and n-butyl lithium are 78 to 0 ° C. under a tetrahydrofuran solvent. And (4S) -3- (3-methylbutyryl) -4-benzyl-2-oxazolidinone represented by the formula (4).
그리고, 상기 화학식 4로 표시되는 (4S)-3-(3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 디클로로메탄에 녹이고 여기에 디이소프로필에틸아민 및 디부틸보론트리플레이트를 가하고 여기에 N-브로모석신이미드를 디클로로메탄에 녹여 78 ℃에서 서서히 가하고, -78 ℃에서 0.5 ∼ 1 시간동안 교반한 후에 실리카겔 크로마토그래피로 분리하여 상기 화학식 5로 표시되는 (4S)-3-((2R)-2-브로모-3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 제조한다.Then, (4S) -3- (3-methylbutyryl) -4-benzyl-2-oxazolidinone represented by Formula 4 is dissolved in dichloromethane, and diisopropylethylamine and dibutyl boron triplate are added thereto. To this was added N-bromosuccinimide in dichloromethane and added slowly at 78 ° C., stirred at −78 ° C. for 0.5 to 1 hour, and then separated by silica gel chromatography (4S) -3. Prepare-((2R) -2-bromo-3-methylbutyryl) -4-benzyl-2-oxazolidinone.
그리고, 상기 화학식 5로 표시되는 (4S)-3-((2R)-2-브로모-3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 N,N-디메틸포름아미드에 녹이고 여기에 소듐아자이드를 가하고 상온에서 1 ∼ 4 시간 교반하여 용매를 제거한 후, 실리카겔 크로마토그래피로 정제하여 상기 화학식 6으로 표시되는 (4S)-3-((2S)-2-아지도-3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 제조한다.And (4S) -3-((2R) -2-bromo-3-methylbutyryl) -4-benzyl-2-oxazolidinone represented by Formula 5 was dissolved in N, N-dimethylformamide. Sodium azide was added thereto, stirred at room temperature for 1 to 4 hours to remove the solvent, and then purified by silica gel chromatography to obtain (4S) -3-((2S) -2-azido-3- represented by Chemical Formula 6 above. Methylbutyryl) -4-benzyl-2-oxazolidinone is prepared.
그리고, 상기 화학식 6으로 표시되는 (4S)-3-((2S)-2-아지도-3-메틸부티릴)-4-벤질-2-옥사졸리딘온을 테트라하이드로퓨란과 물의 혼합 용매에 녹이고 0 ℃에서 리튬하이드록사이드를 서서히 가하고 1 ∼ 3 시간 동안 상온에서 교반 한 후, 1 N 염산 수용액으로 pH를 약 4로 맞추고 에틸아세테이트로 추출하여 용매를 제거하여상기 화학식 7로 표시되는 (2S)-2-아지도-3-메틸부틸산을 제조한다.Then, (4S) -3-((2S) -2-azido-3-methylbutyryl) -4-benzyl-2-oxazolidinone represented by Chemical Formula 6 is dissolved in a mixed solvent of tetrahydrofuran and water. Lithium hydroxide was slowly added at 0 ° C., stirred at room temperature for 1 to 3 hours, adjusted to pH 4 with 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate to remove the solvent (2S) 2-Azido-3-methylbutyl acid is prepared.
그리고, 상기 화학식 7로 표시되는 (2S)-2-아지도-3-메틸부틸산은 정제 또는 정제과정 없이 메탄올과 테트라하이드로퓨란의 혼합 용매에 녹이고 여기에 촉매로 10% 팔라듐 활성탄을 가하고 수소 기압 하에서 3 ∼ 6 시간 동안 상온에서 교반하고 촉매를 여과하여 제거한 후에 레진을 사용하여 정제 하면 99% 이상의 분광학적 순도를 갖는 상기 화학식 1로 표시되는 L-발린을 높은 수율로 얻을 수 있다.In addition, (2S) -2-azido-3-methylbutyl acid represented by Chemical Formula 7 is dissolved in a mixed solvent of methanol and tetrahydrofuran without purification or purification, and 10% palladium activated carbon is added thereto as a catalyst. After stirring at room temperature for 3 to 6 hours, filtering off the catalyst, and purifying with resin, L-valine represented by Chemical Formula 1 having a spectroscopic purity of 99% or more can be obtained in high yield.
이상의 제조과정중에 또는 최종적으로 생성되는 생성물 각각은 모두 핵자기 공명 스펙트럼(NMR)로 확인되었으며, 분광학적 순도는 분광광도계를 사용하여 측정하였으며, 방사능의 양 및 화합물의 순도는 액체 신틸레이션 계수기 또는 액체크로마토그래피로 확인되었다.Each of the products produced during the production process or finally was confirmed by nuclear magnetic resonance spectrum (NMR), the spectroscopic purity was measured using a spectrophotometer, the amount of radioactivity and the purity of the compound was determined by liquid scintillation counter or liquid chromatograph. It was confirmed by graphy.
이상에서 설명한 바대로, 종래의 방법이 광학적 활성을 가지지 않는 DL-발린의 라세믹 혼합물을 제조하여 이를 광학 분할하므로 불필요한 D-발린이 부 생성물로 생성되어 고가의 방사성 원료물질인 포타슘 시아나이드(KCN-14C)의 낭비가 많았다. 이에 반하여, 본 발명의 제조방법은 비교적 저가의 방사성 원료물질인 이산화탄소(CO2-14C)를 사용하고, 또 제조과정 중에 DL-발린의 라세믹 혼합물을 생성하지 않으므로 불필요한 D-발린의 생성 없이 방사성동위원소로 치환된 고 순도의 L-발린만을 싼 가격에 제조 할 수 있다.As described above, since the conventional method prepares a racemic mixture of DL-valine which does not have optical activity and optically divides it, unnecessary D-valine is formed as a side product, which is an expensive radioactive raw material, potassium cyanide (KCN). -14 C) was a lot of waste. On the other hand, the production method of the present invention is relatively low cost of the radioactive source material of the carbon dioxide (CO 2 - 14 C) and used, and do not form a racemic mixture of DL- valine during the manufacturing process without the production of unwanted D- valine for Only high-purity L-valine substituted with radioisotopes can be produced at a low price.
이와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.
실시예 1Example 1
탄소가 방사성동위원소로 치환된 바륨카보네아트(BaCO3-14C) 1,184 mg(6.0 mmol, 120 mCi)에 진한 황산을 가하여 탄소가 방사성동위원소로 치환된 이산화탄소(CO2-14C)를 발생시켜 2-메틸프로필마그네슘 브로마이드(7.0 mmol)가 녹아 있는 에테르 용액에 진공상태에서 이동시켜 주입시킨 후 0 ℃에서 6시간 교반하면서 반응시켰다. 미 반응 이산화탄소(CO2-14C)를 제거하고 1N HCl 10 mL을 가하고 여기에 에테르를 가하여 추출하였다. 에테르 층에 1 N NaOH 7 mL을 가하여 수용액 층으로 추출한 후 1 N HCl 10 mL로 처리하여 다시 에테르로 추출하여 감압 농축하여 3-메틸부틸산[1-14C]을 얻었다. 액체 신틸레이션 계수기로 측정한 결과, 전방사능 108 mCi의 생성물을 얻었다.(수율 90%).Carbon is substituted with a radioactive isotope Barium car Bonnet art a - - (14 C CO 2) (BaCO 3 14 C) 1,184 mg The carbon dioxide carbon is substituted with a radioactive isotope is added to concentrated sulfuric acid a (6.0 mmol, 120 mCi) After the reaction, the mixture was transferred to a ether solution in which 2-methylpropyl magnesium bromide (7.0 mmol) was dissolved in a vacuum state and reacted with stirring at 0 ° C. for 6 hours. Unreacted carbon dioxide (CO 2 - 14 C) to remove the ether and then extracted by adding here was added 1N HCl 10 mL. 7 mL of 1 N NaOH was added to the ether layer, followed by extraction with an aqueous layer, treatment with 10 mL of 1 N HCl, extraction with ether and concentration under reduced pressure to obtain 3-methylbutyl acid [1- 14 C]. Measurement by a liquid scintillation counter resulted in a product of 108 mCi of forward performance (yield 90%).
실시예 2Example 2
3-메틸부틸산[1-14C] 486 mg(4.59 mmol, 92 mCi)을 테트라하이드로퓨란 30 mL에 녹이고 78 ℃에서 트라이에틸아민 557 mg(5.5 mmol) 및 피발로일클로라이드 580 mg(4.82 mmol)을 차례로 가하고, 이 반응 액을 78 ℃에서 15 분, 0 ℃에서 45 분간 교반하였다. 또, (4S)-벤질-2-옥사졸리딘온 591 mg(5.05 mmol)을 테트라하이드로퓨란에 녹인 용액에 78 ℃에서 1.6 M 농도의 n-부틸리튬 3.2 mL(5.05 mmol)을 첨가하여 제조한 용액을 78 ℃에서 먼저 제조한 용액에 서서히 가하고 78 ℃에서 2시간 동안 반응시켰다. 암모늄클로라이드 용액으로 반응을 정지시키고 디클로로메탄으로 추출한 후 포화 중조수로 씻고 마그네슘설페이트로 건조시킨 후 농축하고 실리카겔 크로마토그래피로 정제하여 (4S)-3-(3-메틸부티릴[1-14C])-4-벤질-2-옥사졸리딘온 883 mg(4.14 mmol. 82.3 mCi, 90 %)을 얻었다.486 mg (4.59 mmol, 92 mCi) of 3-methylbutyl acid [1- 14 C] were dissolved in 30 mL of tetrahydrofuran, 557 mg (5.5 mmol) of triethylamine and 580 mg (4.82 mmol) of pivaloylchloride at 78 ° C. ) Was added sequentially, and this reaction liquid was stirred at 78 degreeC for 15 minutes and 0 degreeC for 45 minutes. A solution prepared by adding 3.2 mL (5.05 mmol) of n-butyllithium at a concentration of 1.6 M at 78 ° C. was dissolved in 591 mg (5.05 mmol) of (4S) -benzyl-2-oxazolidinone in tetrahydrofuran. Was slowly added to the solution prepared first at 78 ° C. and reacted at 78 ° C. for 2 hours. The reaction was stopped with ammonium chloride solution, extracted with dichloromethane, washed with saturated sodium bicarbonate water, dried over magnesium sulfate, concentrated and purified by silica gel chromatography (4S) -3- (3-methylbutyryl [1- 14 C] 883 mg (4.14 mmol. 82.3 mCi, 90%) of 4-benzyl-2-oxazolidinone were obtained.
실시예 3Example 3
(4S)-3-(3-메틸부티릴[1-14C])-4-벤질-2-옥사졸리딘온 700 mg(3.48 mmol, 69.6 mCi)을 디클로로메탄 30 mL에 녹이고 78 ℃로 냉각시켰다. 디이소프로필에틸아민 540 mg(4.18 mmol)과 1.0 M 농도의 디부틸보론트리플레이트 3.65 mL(3.65 mmol)를 가하고, 여기에 N-브로모석신이미드 682 mg(3.83 mmol)을 디클로로메탄 20 mL에 녹여 78 ℃에서 서서히 가하고, -78 ℃에서 1시간 30 분간 교반한 후 5 N 소듐설파이트 용액으로 반응을 종료시켰다. 수용액 층을 디클로로메탄으로 추출하여 유기 층을 물로 씻은 후 마그네슘설페이트로 건조하고 농축한 후, 실리카겔 크로마토그래피로 정제하여 (4S)-3-((2R)-2-브로모-3-메틸부티릴[1-14C])-4-벤질-2-옥사졸리딘온 896 mg(3.20 mmol, 64 mCi, 92 %)을 얻었다.700 mg (3.48 mmol, 69.6 mCi) of (4S) -3- (3-methylbutyryl [1- 14 C])-4-benzyl-2-oxazolidinone was dissolved in 30 mL of dichloromethane and cooled to 78 ° C. . 540 mg (4.18 mmol) of diisopropylethylamine and 3.65 mL (3.65 mmol) of dibutylboron triplate at 1.0 M concentration were added, and 682 mg (3.83 mmol) of N-bromosuccinimide was added to 20 mL of dichloromethane. It was dissolved in the solution, and slowly added at 78 ° C., stirred at −78 ° C. for 1 hour and 30 minutes, and the reaction was terminated with 5 N sodium sulfite solution. The aqueous layer was extracted with dichloromethane, the organic layer was washed with water, dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (4S) -3-((2R) -2-bromo-3-methylbutyryl 896 mg (3.20 mmol, 64 mCi, 92%) of [1- 14 C])-4-benzyl-2-oxazolidinone were obtained.
실시예 4Example 4
(4S)-3-((2R)-2-브로모-3-메틸부티릴[1-14C])-4-벤질-2-옥사졸리딘 504 mg(1.80 mmol, 36 mCi)을 N,N-디메틸포름아미드 10 mL에 녹이고 여기에 소듐아자이드 351 mg(5.40 mmol)을 가하고 상온에서 2 시간 교반하여 용매를 제거 한 후, 실리카겔 크로마토그래피로 정제하여(4S)-3-((2S)-2-아지도-3-메틸부티릴[1-14C])-4-벤질-2-옥사졸리딘온 379 mg(1.57 mmol, 31 mCi, 87 %)을 얻었다.(4S) -3-((2R) -2-bromo-3-methylbutyryl [1- 14 C])-4-benzyl-2-oxazolidine to 504 mg (1.80 mmol, 36 mCi) in N, It was dissolved in 10 mL of N-dimethylformamide, and 351 mg (5.40 mmol) of sodium azide was added thereto, stirred at room temperature for 2 hours to remove the solvent, and then purified by silica gel chromatography (4S) -3-((2S) 379 mg (1.57 mmol, 31 mCi, 87%) of 2-azido-3-methylbutyryl [1- 14 C])-4-benzyl-2-oxazolidinone were obtained.
실시예 5Example 5
(4S)-3-((2S)-2-아지도-3-메틸부티릴)-4-벤질-2-옥사졸리딘온 343 mg(1.42 mmol, 28.4 mCi)을 테트라하이드로퓨란 3 mL와 물 2 mL의 혼합 용매에 녹이고 0 ℃에서 리튬하이드록사이드 119 mg(2.84 mmol)을 서서히 가하고 1 시간 동안 상온에서 교반하였다. 1 N 염산 수용액으로 pH를 약 4로 맞추고 에틸아세테이트 10 mL로 추출하여 용매를 제거하여 (2S)-2-아지도-3-메틸부틸산을 제조하고 더 이상의 정제 과정 없이 이 화합물을 메탄올 10 mL와 트리플루로로아세틸 산 1 mL의 혼합 용매에 녹이고 여기에 촉매로 10% 팔라듐활성탄 34 mg을 가하고 수소 기압 하에서 4 시간 동안 상온에서 교반하였다. 촉매를 여과하여 제거한 후에 음이온 교환 수지를 사용하여 정제하면 99% 이상의 분광학적 순도를 갖는 상기 화학식 1로 표시되는 목적화합물을 139 mg(1.19 mmol, 23.8 mCi, 84 %) 얻을 수 있다.343 mg (1.42 mmol, 28.4 mCi) of (4S) -3-((2S) -2-azido-3-methylbutyryl) -4-benzyl-2-oxazolidinone was added with 3 mL of tetrahydrofuran and water 2 It was dissolved in mL of a mixed solvent and slowly added 119 mg (2.84 mmol) of lithium hydroxide at 0 ° C. and stirred at room temperature for 1 hour. PH was adjusted to about 4 with 1 N aqueous hydrochloric acid solution and extracted with 10 mL of ethyl acetate to remove the solvent to prepare (2S) -2-azido-3-methylbutyric acid. It was dissolved in a mixed solvent of 1 mL of trifluorohydroacetyl acid, and 34 mg of 10% palladium activated carbon was added thereto as a catalyst, followed by stirring at room temperature for 4 hours under hydrogen atmosphere. After the catalyst is filtered off and purified using an anion exchange resin, 139 mg (1.19 mmol, 23.8 mCi, 84%) of the target compound represented by Chemical Formula 1 having a spectroscopic purity of 99% or more can be obtained.
[α]D= 27.2(C=4, 6N HCl)[a] D = 27.2 (C = 4, 6N HCl)
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 방사성동위원소 표지화합물로서 L-발린을 제조함에 있어 비교적 저가의 방사성 원료물질인 이산화탄소(CO2-14C)를 사용하고 있고, 제조과정 중에 DL-발린의 라세믹 혼합물을 생성하지 않으므로 광학 분할과정이 생략될 수 있고 또 불필요한 D-발린이 생성되지 않으므로 경제성이 있는 제조방법이라할 수 있다.As described above, the process according to the invention is a radioactive isotope of carbon dioxide in it a radioactive source material for the production of relatively low-L- valine as labeled compounds, and the use of (CO 2 14 C), DL during the manufacturing process -Because it does not produce a racemic mixture of valine, the optical splitting process can be omitted, and since unnecessary D-valine is not produced, it can be called an economical manufacturing method.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62267253A (en) * | 1986-05-16 | 1987-11-19 | Mitsui Toatsu Chem Inc | Production of alpha-amino acid |
| KR880012763A (en) * | 1987-04-16 | 1988-11-29 | 우다다 가쯔히로 | Method for preparing L-valine by fermentation |
| KR920006507A (en) * | 1990-09-18 | 1992-04-27 | 나까무라 간노수께 | Method for preparing L-valine |
| KR20000029349A (en) * | 1998-10-28 | 2000-05-25 | 데구사-휠스 악티엔게젤샤프트 | Process for the fermentative production of l-amino acids |
| KR20010000196A (en) * | 2000-08-10 | 2001-01-05 | 하현준 | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine from aziridines |
| KR20010108172A (en) * | 1999-02-22 | 2001-12-07 | 아달베르트 베. 플라텐타이히, 하 | Method for microbially producing l-valine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62267253A (en) * | 1986-05-16 | 1987-11-19 | Mitsui Toatsu Chem Inc | Production of alpha-amino acid |
| KR880012763A (en) * | 1987-04-16 | 1988-11-29 | 우다다 가쯔히로 | Method for preparing L-valine by fermentation |
| KR920006507A (en) * | 1990-09-18 | 1992-04-27 | 나까무라 간노수께 | Method for preparing L-valine |
| KR20000029349A (en) * | 1998-10-28 | 2000-05-25 | 데구사-휠스 악티엔게젤샤프트 | Process for the fermentative production of l-amino acids |
| KR20010108172A (en) * | 1999-02-22 | 2001-12-07 | 아달베르트 베. 플라텐타이히, 하 | Method for microbially producing l-valine |
| KR20010000196A (en) * | 2000-08-10 | 2001-01-05 | 하현준 | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine from aziridines |
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