KR100726673B1 - METHOD OF PREPARING beta;-AZIDO CARBONYL COMPOUND FOR SYNTHESIS OF BETA;-AMINO ACIDS OR AMINO ALCOHOLS - Google Patents
METHOD OF PREPARING beta;-AZIDO CARBONYL COMPOUND FOR SYNTHESIS OF BETA;-AMINO ACIDS OR AMINO ALCOHOLS Download PDFInfo
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본 발명은 β-아미노산 또는 아미노알콜 유도체의 합성 중간체로 유용한 β-아지도 카보닐 화합물을 효과적으로 제조하는 방법에 관한 것이다.The present invention relates to a method for effectively preparing β-azido carbonyl compounds useful as synthetic intermediates of β-amino acids or aminoalcohol derivatives.
β-아미노산은 다양한 의약품, 특히 베타-락탐 항생제, HIV-단백질 분해 효소 억제제 및 효소 억제제에서 중요한 요소로서 사용되고 있으며, 약리 활성을 나타내는 여러 천연물에서도 중요한 역할을 담당하고 있다. 따라서, 보다 쉽고 효과적으로 β-아미노산을 합성하려는 노력들이 꾸준히 진행되고 있다.β-amino acids are used as important elements in various medicines, especially beta-lactam antibiotics, HIV-proteinase inhibitors and enzyme inhibitors, and plays an important role in various natural products that exhibit pharmacological activity. Therefore, efforts are being made to synthesize β-amino acids more easily and effectively.
현재까지 개발된 β-아미노산 합성법 중 가장 간단한 방법으로는, α, β-불포화 카보닐 화합물에 질소 공급원, 예컨대, 트리아조수소산(HN3)을 도입하여 제조한 β-아지도 카보닐 화합물을 합성 중간체로서 사용하는 방법이 있다 (참조문헌: Lakshmipathi, P. et. al. Tetrahedron Lett. 38: 2551, 1997; Doi, H.et. al. J. Am. Chem. Soc. 125: 2886, 2003; Li, K.; et. al. Eur. J. Org. Chem. 959, 2004; Jin, X. L.; et. al. Tetrahedron 58: 8321, 2002; Sibi, M. P.et. al. J. Am. Chem. Soc. 125: 11796, 2003; 및 Palomo, C. et. al. J. Am. Chem. Soc. 126: 91, 2004).The simplest of the β-amino acid synthesis methods developed to date is the synthesis of β-azido carbonyl compounds prepared by introducing a nitrogen source, such as triazohydrogen (HN 3 ), into α, β-unsaturated carbonyl compounds. There is a method used as an intermediate (Lakshmipathi, P. et. Al. Tetrahedron Lett. 38: 2551, 1997; Doi, H. et. Al. J. Am. Chem. Soc . 125: 2886, 2003; Li, K .; et. Al. Eur. J. Org. Chem . 959, 2004; Jin, XL; et. Al. Tetrahedron 58: 8321, 2002; Sibi, MP et al. J. Am. Chem. Soc . 125: 11796, 2003; and Palomo, C. et.al. J. Am. Chem. Soc. 126: 91, 2004).
그러나, 상기 질소 공급원으로서 사용된 트리아조수소산은 인체에 유독하고 폭발성이 강하기 때문에, 구에린 등(Guerin, D. J. et. al Org. Lett. 1: 1107, 1999)은 안전한 아지드 공급원으로 트리메틸시릴아지드(trimethylsilyl azide; TMSN3)를 아세트산(AcOH)과 혼합하여 사용하는 방법을 제시하였으나, 이 방법은 사용 가능한 기질의 구조가 매우 제한적이므로 다양한 아미노산을 제조할 수 없는 문제점이 있다. However, since triazoic acid used as the nitrogen source is toxic and explosive to the human body, Guerin et al. (Guerin, DJ et. Al Org. Lett. 1: 1107, 1999) is a safe azide source. Although a method of using trimethylsilyl azide (TMSN 3 ) mixed with acetic acid (AcOH) has been proposed, this method has a problem in that various amino acids cannot be prepared because the structure of the substrate is very limited.
한편, 쥬 등(Xu, Li-Wen et. al. Tetrahedron Lett. 45: 1219, 2004)은 트리메틸실릴아지드보다 더욱 안전하고 유용한 소듐아지드(NaN3)를 사용하여 β-아지도 카보닐 화합물을 제조하는 방법을 기재하고 있다. 이때, 소듐아지드는 함께 사용되는 아세트산과 반응하여 소듐아세테이트(NaOAc)를 반응부가물로 생성시키는데, 소듐아세테이트는 기존에 반응용매로서 사용된 메틸렌 클로라이드(CH2Cl2)에서는 녹지 않으므로 공정시 교반에 어려움이 있으며, 추가적인 부반응을 일으킬 수 있는 가능성이 있다. 따라서, 상기 방법에서는 유기용매로서 메틸렌 클로라이드 대신 소듐아세테이트를 녹일 수 있는 이온성 용매(예: bmimPF6, bmimBF4, bmimBr)를 사용하였으나, 이들 이온성 용매는 가격이 매우 높은 단점이 있다. Meanwhile, Ju et al. (Xu, Li-Wen et. Al. Tetrahedron Lett. 45: 1219, 2004) use β-azido carbonyl compounds using sodium azide (NaN 3 ), which is safer and more useful than trimethylsilylazide. It describes a method for preparing the same. At this time, sodium azide reacts with acetic acid used together to produce sodium acetate (NaOAc) as a reaction adduct. Sodium acetate does not dissolve in methylene chloride (CH 2 Cl 2 ), which is used as a reaction solvent, in the process of stirring There is difficulty and there is the possibility of causing further side reactions. Therefore, in the above method, an ionic solvent (eg, bmimPF 6 , bmimBF 4 , bmimBr) capable of dissolving sodium acetate instead of methylene chloride was used as an organic solvent, but these ionic solvents have a disadvantage in that the price is very high.
또한, 기존의 합성방법으로 제조가능한 β-아지도 카보닐 화합물은 오직 케톤 뿐이며 그 대부분이 고리형 케톤으로, 이들은 특히 1, 3-아미노알콜이나 β-아미노산으로의 변환이 용이하지 않아, 보다 다양한 구조의 기질에 적용가능한 중간체 제조방법의 개발이 요구되고 있는 실정이다. In addition, β-azido carbonyl compounds which can be prepared by conventional synthetic methods are only ketones, and most of them are cyclic ketones, which are not easily converted to 1,3-aminoalcohol or β-amino acid. There is a need for development of an intermediate manufacturing method applicable to a substrate of a structure.
이에, 본 발명자들은 예의연구한 결과, 염산 및 유기촉매의 존재하에 α, β-불포화 카보닐 화합물을 소듐아지드와 반응시키는 경우, 보다 다양한 기질을 반응시킬 수 있고, 메틸렌 클로라이드와 같은 유기용매하에서도 부반응 없이 β-아지도 카보닐 화합물을 효율적으로 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다. Thus, the present inventors have studied diligently, when the α, β-unsaturated carbonyl compound is reacted with sodium azide in the presence of hydrochloric acid and an organic catalyst, more various substrates can be reacted, and under an organic solvent such as methylene chloride The present invention has been accomplished by discovering that β-azido carbonyl compounds can be efficiently produced without any side reaction.
본 발명의 목적은 α, β-불포화 카보닐 화합물로부터 β-아지도 케톤 또는 알데히드 등의 β-아지도 카보닐 화합물을 보다 효율적으로 합성하는 방법을 제공하는 것이다. An object of the present invention is to provide a method for more efficiently synthesizing β-azido carbonyl compounds such as β-azido ketones or aldehydes from α, β-unsaturated carbonyl compounds.
상기 목적을 달성하기 위하여 본 발명에서는, 유기용매 중에서 염산 및 유기촉매의 존재하에 하기 화학식 2의 α, β-불포화 카보닐 화합물을 소듐아지드와 반응시키는 것을 포함하는, 하기 화학식 1의 β-아지도 카보닐 화합물의 제조방법을 제공한다. In order to achieve the above object, in the present invention, in the presence of hydrochloric acid and an organic catalyst in the organic solvent, comprising the reaction of the α, β-unsaturated carbonyl compound of formula (2) with sodium azide, β- azile of the formula (1) Also provided is a method for preparing a carbonyl compound.
상기 식에서, Where
R1은 수소 또는 C1-6 알킬기이고, R2는 수소; C1-10 알킬기; 벤질옥시, 메톡시, 또는 벤조일옥시로 치환된 하이드록시메틸기; 알릴기 또는 에스터기이다.R 1 is hydrogen or a C 1-6 alkyl group, R 2 is hydrogen; C 1-10 alkyl group; Hydroxymethyl group substituted with benzyloxy, methoxy, or benzoyloxy; An allyl group or an ester group.
이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에 따르면, 유기용매에 소듐아지드를 용해시킨 다음, 여기에 염산을 첨가하여 교반한 후, 생성 혼합물에 상기 화학식 2의 α, β-불포화 카보닐 화합물과 유기촉매를 첨가하여 하기 반응식 1과 같은 반응을 수행함으로써 상기 화학식 1의 β-아지도 카보닐 화합물(알데히드 또는 케톤)을 제조할 수 있으며, 상기 교반 공정은 상온에서 1시간 동안 수행하는 것이 바람직하다. According to the present invention, sodium azide is dissolved in an organic solvent, and then hydrochloric acid is added thereto, followed by stirring. By performing the reaction as described above, β-azido carbonyl compound of formula 1 (aldehyde or ketone) may be prepared, and the stirring process is preferably performed at room temperature for 1 hour.
상기 식에서 R1 및 R2는 앞에서 정의한 바와 같다. Wherein R 1 and R 2 are as defined above.
본 발명에서 사용가능한 유기용매로는 메틸렌 클로라이드, 클로로폼 또는 1,2-디클로로에탄이 있으며, 바람직하게는 메틸렌 클로라이드가 사용될 수 있다.Organic solvents usable in the present invention include methylene chloride, chloroform or 1,2-dichloroethane, preferably methylene chloride may be used.
상기 소듐아지드는 α, β-불포화 카보닐 화합물 100 중량부에 대하여 100 내지 500 중량부, 바람직하게는 200 내지 300 중량부로 사용될 수 있다.The sodium azide may be used in an amount of 100 to 500 parts by weight, preferably 200 to 300 parts by weight, based on 100 parts by weight of the α, β-unsaturated carbonyl compound.
본 발명에서는, 소듐아지드의 반응성을 높이기 위해 염산을 첨가하여 반응을 진행시킨다. 이때 염산은 포화염산 수용액 형태로 사용하는 것이 바람직한데, 이와 같이 수용액 상태의 염산을 첨가하는 경우 약간의 물이 존재하므로, 반응 부가물로서 소듐클로라이드(NaCl)가 생성되더라도 수층에 용해되어 반응물들의 교반에 영향을 미치지 않으며, 부반응에 따른 불리한 영향 없이 원하는 생성물을 고수율로 수득할 수 있다. In the present invention, in order to increase the reactivity of sodium azide, hydrochloric acid is added to advance the reaction. At this time, it is preferable to use hydrochloric acid in the form of saturated hydrochloric acid solution. Thus, when adding hydrochloric acid in aqueous solution, a little water is present, even though sodium chloride (NaCl) is formed as a reaction adduct, it is dissolved in the aqueous layer to stir the reactants. It does not affect, and the desired product can be obtained in high yield without the adverse effect of side reactions.
본 발명에서 사용가능한 유기촉매로는 2차 아민, 3차 아민, 또는 포스핀 화합물; 예를 들어 트리에틸아민(Et3N), N-메틸이미다졸(methylimidazole), 다이아이소프로필에틸렌아민(diisopropylethylamine; i-pr2NEt), 1,8-다이아자바이사이클로 (5.4.0)운덱-7-엔(1,8-diazabicyclo(5.4.0)undec-7-ene; DBU), N-메틸몰포린(methylmorpholine), 1,5-다이아자바이사이클로(4.3.0)논-5-엔(1,5-diazabicyclo(4.3.0)non-5-ene; DABCO), 피리딘(pyridine), 트리부틸포스핀(P(Bu)3), (+)-스파르테인(sparteine), (+)-신코나인(cinchonine), 및 L-프롤린(proline)으로 이루어진 군으로부터 선택되어 사용될 수 있으며, 그 중에서도 트리에틸아민, N-메틸이미다졸, 1,8-다이아자바이사이클로(5.4.0)운덱-7-엔(DBU)이 바람직하다.Organic catalysts usable in the present invention include secondary amines, tertiary amines, or phosphine compounds; For example triethylamine (Et 3 N), N-methylimidazole, diisopropylethylamine ( i -pr 2 NEt), 1,8-diazabicyclo (5.4.0) -7-ene (1,8-diazabicyclo (5.4.0) undec-7-ene; DBU), N-methylmorpholine, 1,5-diazabicyclo (4.3.0) non-5-ene (1,5-diazabicyclo (4.3.0) non-5-ene; DABCO), pyridine, tributylphosphine (P (Bu) 3 ), (+)-sparteine, (+ ) -Cinchonine, and L-proline (proline) can be used selected from the group, among which triethylamine, N- methylimidazole, 1,8- diazabicyclo (5.4.0) Undec-7-ene (DBU) is preferred.
이들 유기촉매는 α, β-불포화 카보닐 화합물 100 중량부에 대하여 1 내지 100 중량부, 바람직하게는 10 내지 20 중량부로 사용될 수 있다.These organic catalysts may be used in an amount of 1 to 100 parts by weight, preferably 10 to 20 parts by weight, based on 100 parts by weight of the α, β-unsaturated carbonyl compound.
상술한 바와 같은 본 발명의 방법에 따르면, β-아지도 알데히드 또는 β-아지도 케톤과 같은 β-아지도 카보닐 화합물을 고수율로 제조할 수 있으며, 그 대표적인 예를 나타내면 다음과 같다. According to the method of the present invention as described above, β-azido carbonyl compounds such as β-azido aldehydes or β-azido ketones can be prepared in high yield, and representative examples thereof are as follows.
본 발명을 통해 제조된 β-아지도 카보닐 화합물들은 통상적인 공정에 따라 1, 3-아미노알콜 또는 β-아미노산 유도체를 합성하는 데 사용될 수 있다. 예를 들 어, 화학식 1의 β-아지도 카보닐 화합물을 소듐보로하이드라이드와 반응시킨 다음, 에틸아세테이트로 추출하여 건조, 여과, 감압농축시킨 후, 팔라듐차콜(Pd/C) 촉매하에서 수소화 반응시킴으로써 1, 3-아미노알콜을 수득할 수 있다.Β-azido carbonyl compounds prepared through the present invention can be used to synthesize 1, 3-aminoalcohol or β-amino acid derivatives according to conventional procedures. For example, the β-azido carbonyl compound of Formula 1 is reacted with sodium borohydride, extracted with ethyl acetate, dried, filtered and concentrated under reduced pressure, and then hydrogenated under a palladium charcoal (Pd / C) catalyst. By reacting, 1, 3-amino alcohol can be obtained.
이하, 하기 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위를 한정하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention and do not limit the scope of the present invention.
<β-아지도 카보닐 화합물의 제조><Preparation of β-azido carbonyl compound>
실시예 1: 3-아지도-엑산 알데히드Example 1: 3-azido-acid aldehyde
소듐아지드(0.39 g, 6.0 mmol)에 메틸렌 클로라이드(4 ㎖)를 첨가하고, 여기에 포화 염산(0.49 ㎖, 6.0 mmol)을 가하였다. 생성된 혼합물을 상온에서 한 시간 동안 교반한 후, 트랜스-3-헥산-1-알(0.23 ㎖, 2.0 mmol)을 적가하고, 트리에틸아민(0.060 ㎖, 0.04 mmol)을 첨가하였다. 반응물을 상온에서 5시간 동안 교반한 후, 물과 메틸렌 클로라이드로 추출하고, 추출액을 포화 소듐하이드로겐카보네이트 및 소금물로 세척하였다. 유기층을 무수 마그네슘 설페이트로 건조시키고, 여과 및 감압 농축한 후, 칼럼 크로마토그래피로 정제하여, 표제 화합물(0.26 g, 93% 수율)을 무색의 오일로 얻었다. Methylene chloride (4 mL) was added to sodium azide (0.39 g, 6.0 mmol) and saturated hydrochloric acid (0.49 mL, 6.0 mmol) was added thereto. The resulting mixture was stirred at room temperature for one hour, then trans-3-hexane-1-al (0.23 mL, 2.0 mmol) was added dropwise and triethylamine (0.060 mL, 0.04 mmol) was added. The reaction was stirred at room temperature for 5 hours, extracted with water and methylene chloride, and the extract was washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography to give the title compound (0.26 g, 93% yield) as a colorless oil.
1H NMR (200 MHz, CDCl3) 9.79 (t, J = 1.2 Hz, 1H), 3.90 (tt, J = 7.6, 4.4 Hz, 1H), 2.61 (dd, J = 7.6, 1.2 Hz, 2H), 1.34-1.64 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) 199.6, 56.9, 48.2, 36.6, 19.2, 13.7; MS (EI) m/z = 141 (M+)1 H NMR (200 MHz, CDCl 3 ) 9.79 (t, J = 1.2 Hz, 1H), 3.90 (tt, J = 7.6, 4.4 Hz, 1H), 2.61 (dd, J = 7.6, 1.2 Hz, 2H), 1.34 -1.64 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) 199.6, 56.9, 48.2, 36.6, 19.2, 13.7; MS (EI) m / z = 141 (M < + >)
실시예 2: 3-아지도-4-벤질옥시-부틸 알데히드Example 2: 3-azido-4-benzyloxy-butyl aldehyde
출발물질로 트랜스-4-벤질옥시-부트-2-엔알을 사용하는 것을 제외하고는 실시예 1과 동일한 방법으로 표제 화합물(90%)을 얻었다.The title compound (90%) was obtained in the same manner as in Example 1 except for using trans-4-benzyloxy-but-2-enal as a starting material.
1H NMR (200 MHz, CDCl3) 9.77 (t, J = 1.2 Hz, 1H), 7.28-7.43 (m, 5H), 4.59 (s, 2H), 4.13 (tt, J = 7.2, 5.2 Hz, 1H), 3.60 (d, J = 5.2 Hz, 2H), 2.67 (dd, J = 7.2, 1.2 Hz, 2H); 13C NMR (50 MHz, CDCl3) 199.0, 128.6, 128.1, 128.0, 127.8, 73.5, 71.8, 55.9, 44.9 MS (EI) m/z = 219 (M+)1 H NMR (200 MHz, CDCl 3 ) 9.77 (t, J = 1.2 Hz, 1H), 7.28-7.43 (m, 5H), 4.59 (s, 2H), 4.13 (tt, J = 7.2, 5.2 Hz, 1H) , 3.60 (d, J = 5.2 Hz, 2H), 2.67 (dd, J = 7.2, 1.2 Hz, 2H); 13 C NMR (50 MHz, CDCl 3 ) 199.0, 128.6, 128.1, 128.0, 127.8, 73.5, 71.8, 55.9, 44.9 MS (EI) m / z = 219 (M +)
실시예 3: 벤조산 2-아지도-4-옥소-부틸 에스터Example 3: benzoic acid 2-azido-4-oxo-butyl ester
출발물질로 트랜스-벤조산-4-옥소-부트-2-에닐 에스터를 사용하는 것을 제외하고는 실시예 1과 동일한 방법으로 표제 화합물(97%)을 얻었다.As starting material the trans-acid-4-oxo-in Example 1 to obtain the title compound (97%) in the same manner except for the use of the boot-2-enyl ester.
1H NMR (200 MHz, CDCl3) 9.83 (s, 1H), 8.06 (d, J = 7.8 Hz, 3H), 7.44-7.65 (m, 3H), 4.33-4.52 (m, 3H), 2.77 (d, J = 6.6 Hz, 2H) 13C NMR (50 MHz, CDCl3) 198.0, 166.1, 133.6, 129.9, 129.4, 128.7, 66.3, 55.3, 44.7 MS (EI) m/z = 233 (M+)1 H NMR (200 MHz, CDCl 3 ) 9.83 (s, 1H), 8.06 (d, J = 7.8 Hz, 3H), 7.44-7.65 (m, 3H), 4.33-4.52 (m, 3H), 2.77 (d, J = 6.6 Hz, 2H) 13C NMR (50 MHz, CDCl 3 ) 198.0, 166.1, 133.6, 129.9, 129.4, 128.7, 66.3, 55.3, 44.7 MS (EI) m / z = 233 (M +)
실시예 4: 2-아지도-4-옥소-부티릴산 메틸 에스터Example 4: 2-azido-4-oxo-butyryl acid methyl ester
출발물질로 트랜스-4-옥소-부트-2-엔익산 메틸 에스터를 사용하는 것을 제외하고는 실시예 1과 동일한 방법으로 표제 화합물(65%)을 얻었다.The title compound (65%) was obtained in the same manner as in Example 1 except for using the trans-4-oxo-but-2-enoic acid methyl ester as a starting material.
1H NMR (200 MHz, CDCl3) 9.71 (t, J = 0.8 Hz, 1H), 4.45 (t, J = 7.4 Hz, 1H), 3.07 (s, 3H), 2.93 (dd, J = 7.4, 0.8 Hz, 2H; 13C NMR (50 MHz, CDCl3) 197.5, 169.8, 56.4, 53.1, 44.7 MS (EI) m/z = 157 (M+)1 H NMR (200 MHz, CDCl 3 ) 9.71 (t, J = 0.8 Hz, 1H), 4.45 (t, J = 7.4 Hz, 1H), 3.07 (s, 3H), 2.93 (dd, J = 7.4, 0.8 Hz , 2H; 13C NMR (50 MHz, CDCl 3 ) 197.5, 169.8, 56.4, 53.1, 44.7 MS (EI) m / z = 157 (M +)
실시예 5: 3-아지도-4-메틸-펜탄 알데히드Example 5: 3-azido-4-methyl-pentane aldehyde
출발물질로 트랜스-4-메틸-펜트-2-엔알을 사용하는 것을 제외하고는 실시예 1과 동일한 방법으로 표제 화합물(45%)을 얻었다.The title compound (45%) was obtained in the same manner as in Example 1 except for using trans-4-methyl-pent-2-enal as a starting material.
1H NMR (200 MHz, CDCl3) 9.70 (t, J = 1.2 Hz, 1H), 3.90 (dt, J = 8.2, 4.8Hz, 1H), 2.51 (dd, J = 7.2, 1.2 Hz, 2H), 1.60-1.72 (m, 2H), 1.16 (dd, J = 7.6., 3.0 Hz, 3H), 1.09 (dd, J = 7.6., 7.2 Hz, 3H) 13C NMR (50 MHz, CDCl3) 202.8, 63.6, 49.7, 25.4, 11.0,8.7 MS (EI) m/z = 141 (M+)1 H NMR (200 MHz, CDCl 3 ) 9.70 (t, J = 1.2 Hz, 1H), 3.90 (dt, J = 8.2, 4.8 Hz, 1H), 2.51 (dd, J = 7.2, 1.2 Hz, 2H), 1.60 -1.72 (m, 2H), 1.16 (dd, J = 7.6., 3.0 Hz, 3H), 1.09 (dd, J = 7.6., 7.2 Hz, 3H) 13C NMR (50 MHz, CDCl 3 ) 202.8, 63.6, 49.7, 25.4, 11.0,8.7 MS (EI) m / z = 141 (M +)
실시예 6: 3-아지도-사이클로헥사논Example 6: 3-azido-cyclohexanone
출발물질로 사이클로헥-2-에논을 사용하는 것을 제외하고는 실시예 1과 동일 한 방법으로 표제 화합물(93%)을 얻었다.The title compound (93%) was obtained in the same manner as in Example 1 except for using cyclohex-2-enone as starting material.
1H NMR (200 MHz, CDCl3) 3.89 (m, 1H), 3.66 (dd, J = 14.3, 4.8 Hz, 1H), 2.43 (dd, J = 14.3, 8.4 Hz, 2H), 2,35 (m, 2H), 2.09 (m, 2H), 1.70-1.85 (m, 2H); 13C NMR (50 MHz, CDCl3) 207.1, 59.4, 46.4, 40.5, 29.7, 21.3.1 H NMR (200 MHz, CDCl 3 ) 3.89 (m, 1H), 3.66 (dd, J = 14.3, 4.8 Hz, 1H), 2.43 (dd, J = 14.3, 8.4 Hz, 2H), 2,35 (m, 2H), 2.09 (m, 2H), 1.70-1.85 (m, 2H); 13 C NMR (50 MHz, CDCl 3 ) 207.1, 59.4, 46.4, 40.5, 29.7, 21.3.
<1, 3-아미노알콜 화합물의 제조><1, Preparation of 3-amino alcohol compound>
실시예 7: [1-(2-하이드록시-에틸)-부틸]-카바믹 산-티-부틸 에스터Example 7: [1- (2-Hydroxy-ethyl) -butyl] -carbamic acid-thi-butyl ester
실시예 1에서 얻은 3-아지도-엑산 알데히드(350 ㎎, 2.5 mmol)를 메탄올(5 ㎖)에 녹이고, 소듐보로하이드라이드(95 ㎎, 2.5 mmol)를 가한 후 20분 동안 교반하였다. 포화중조로 반응을 종결시킨 후, 에틸아세테이트로 추출하였다. 추출액을 소금물로 세척하고, 무수황산나트륨으로 건조, 여과 및 감압농축한 후 메탄올(6 ㎖)에 녹이고, 디-티-부틸-디카보네이트(650 ㎎, 3.0 mmol)와 10% Pd/C(35 ㎎)을 가하였다. 수소하에서 24시간 교반한 후 여과, 감압농축하고 컬럼 크로마토그래피로 정제하여 순수한 목적 화합물(0.33 g, 65% 수율)을 무색의 오일로 얻었다.The 3-azido-acid aldehyde (350 mg, 2.5 mmol) obtained in Example 1 was dissolved in methanol (5 mL), sodium borohydride (95 mg, 2.5 mmol) was added, followed by stirring for 20 minutes. The reaction was terminated with saturated sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, then dissolved in methanol (6 mL), di-ti-butyl-dicarbonate (650 mg, 3.0 mmol) and 10% Pd / C (35 mg). ) Was added. After stirring for 24 hours under hydrogen, filtered, concentrated under reduced pressure and purified by column chromatography to give the pure target compound (0.33 g, 65% yield) as a colorless oil.
1H NMR (200 MHz, CDCl3) 4.52 (d, J = 8.0 Hz, 1H), 3.72 (s, 1H), 3.62 (m, 3H), 1,72-1.88 (m, 1H), 1.42 (s, 9H), 1.20-1.38 (m, 5H), 0.90 (t, J = 6.0 Hz, 3H); 13C NMR (50 MHz, CDCl3) 157.3, 76.7, 58.8, 47.1, 39.0, 37.9, 28.4, 19.4, 13.9.1 H NMR (200 MHz, CDCl 3 ) 4.52 (d, J = 8.0 Hz, 1H), 3.72 (s, 1H), 3.62 (m, 3H), 1,72-1.88 (m, 1H), 1.42 (s, 9H), 1.20-1.38 (m, 5H), 0.90 (t, J = 6.0 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) 157.3, 76.7, 58.8, 47.1, 39.0, 37.9, 28.4, 19.4, 13.9.
본 발명의 방법에 따르면, 유기용매 중에서 염산 및 유기촉매의 존재하에 α , β-불포화 카보닐 화합물을 소듐아지드와 반응시킴으로써, 1, 3-아미노알콜 또는 β-아미노산의 중간체로서의 다양한 β-아지도 카보닐 화합물(알데히드 또는 케톤)을 보다 효율적으로 합성할 수 있다. According to the method of the present invention, various β-azides as intermediates of 1,3-aminoalcohol or β-amino acids by reacting α, β-unsaturated carbonyl compounds with sodium azide in the presence of hydrochloric acid and an organic catalyst in an organic solvent Also carbonyl compounds (aldehydes or ketones) can be synthesized more efficiently.
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| WO2001005324A1 (en) * | 1999-07-14 | 2001-01-25 | 3M Innovative Properties Company | Occlusal cap for orthodontic bracket |
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