Method for preparing chiral amino acid ester and chiral deuterated amino acid ester
阅读说明：本技术 一种制备手性氨基酸酯和手性氘代氨基酸酯的方法 (Method for preparing chiral amino acid ester and chiral deuterated amino acid ester ) 是由 樊保敏 杨大坚 詹永 罗杨 李娟� 陈景超 周永云 沈国礼 于 2019-12-04 设计创作，主要内容包括：本发明公开了一种高效制备手性氨基酸酯和手性氘代氨基酸酯的方法,是在惰性气体氛围下以水或重水为氢源或氘源实现对亚胺酸酯的不对称转移氢化或氘化,得到手性氨基酸酯和手性氘代氨基酸酯衍生物。本发明提供了一种操作简单便捷、温和、高效、绿色的手性氨基酸酯和手性氘代氨基酸酯的制备方法。(The invention discloses a method for efficiently preparing chiral amino acid ester and chiral deuterated amino acid ester, which is used for realizing asymmetric transfer hydrogenation or deuteration of imido ester by taking water or heavy water as a hydrogen source or a deuterium source in an inert gas atmosphere to obtain the chiral amino acid ester and the chiral deuterated amino acid ester derivative. The invention provides a preparation method of chiral amino acid ester and chiral deuterated amino acid ester, which is simple, convenient, mild, efficient and green to operate.)
1. A method for preparing chiral amino acid ester and chiral deuterated amino acid ester is characterized in that an imidate compound, water or heavy water is used as a reaction raw material, transition metal, Lewis acid or chiral ligand is used as a catalyst, and the target chiral amino acid ester and chiral deuterated amino acid ester compound are synthesized in an organic solvent, wherein the reaction general formula is as follows:
in the formula, R1,R2,R3Is alkyl or aryl.
2. The method of claim 1, wherein the catalyst is a transition metal.
3. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound according to claim 1 or 2, wherein the transition metal catalyst is Pd (CH)3CN)2Cl2,Pd(CH3CN)2(BF4)2,Pd(CH3CN)2(OTf)2,C6H10Cl2Pd2,C10H14O4Pd,PdCl2,Pd2(dba)3,Pd(OAc)2,Ni(OTf)2,Co(OAc)2,[Ir(COD)Cl]2,Rh(COD)2BF4Or C11H14F6N3PRu, etc.
4. The method of claim 2, wherein the transition metal catalyst is used in an amount of 0.01 to 100 mol% based on the imide ester compound.
5. The method for preparing the organic compound of chiral amino acid ester and chiral deuterated amino acid ester according to claim 1 or 2, wherein the chiral ligand is (R) -Seghos, (R) -Binap, (R, R) -BDPP, (R) -Phanephos, (R) -Synphos, (R) -Difluorphos, (R) -P-Phos, (R) -SDP, (R) -SKP, (R, R) -Phox, (R, S) -PPF-PtBu2(R) -DuanPhos.
6. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound as claimed in claim 5, wherein the amount of the chiral ligand is 0.02-200% of the mole number of the imidate compound.
7. The method of claim 1, wherein the catalyst is a lewis acid.
8. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound according to claim 1 or 7, wherein the lewis acid is HB (C)6F5)2,B(C6F5)3,BF3,ZnI2,AgOTf,AgBF4,Cu(OTf)2,CuCl,Zn(OTf)2,Fe(OTf)2,FeCl3Or is orAlCl3One kind of (1).
9. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound as claimed in claim 7, wherein the lewis acid is used in an amount of 0.01-100% by mole based on the imidate compound.
10. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound according to claim 1, wherein the reducing agent is an inorganic reducing agent, an organic reducing agent or a metal simple substance reducing agent.
11. The method for preparing the chiral amino acid ester and chiral deuterated amino acid ester organic compound as claimed in claim 1 or 10, wherein the inorganic reducing agent is S8,H2S,FeSO4,Na2SO3,SnCl2,CO,SO2,HSiCl3One or more of the above; the organic reducing agent is one or more of vitamin C (ascorbic acid) and benzaldehyde derivatives; the metal simple substance reducing agent is one or more of Fe, Al, Mg, Cu, Zn, Mn, Na, K and In.
12. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound as recited in claim 11, wherein said reducing agent is used in an amount of 50-500% by mole based on the imidate compound.
13. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound as claimed in claim 1, wherein the solvent is one or more selected from toluene, tetrahydrofuran, tetrahydropyran, methyl tert-butyl ether, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, and dimethylsulfoxide.
14. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound according to claim 1, wherein the temperature is between-50 ℃ and 200 ℃.
15. The method for preparing chiral amino acid ester and chiral deuterated amino acid ester organic compound as claimed in claim 1, wherein said water or deuterium oxide is used in an amount of 50-500% by mole based on the imidate compound.
Technical Field
The invention belongs to the technical field of chemistry, further belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a chiral amino acid ester and a chiral deuterated amino acid ester organic compound.
Background
Amino acids (aminoacids) are a generic term for a class of organic compounds containing both amino and carboxyl groups in the molecule. Amino acids are a very useful class of compounds. For the human body, amino acids have a very important role: 1. digestion and absorption of proteins in the body are accomplished by amino acids; 2. the nitrogen balance function is realized; 3. conversion to sugar or fat; 4. participating in constituting enzymes, hormones, partial vitamins, etc. Also, amino acids have very important roles in industrial production and human life, and have irreplaceable roles in medical health, material base, food, and the like. Amino acids also play an important role in synthetic chemistry. Therefore, the synthetic amino acid has great application value and prospect.
At present, many methods for producing amino acids have been reported, and among them, the most common and widely used method is reduction of imido ester, which can produce amino acid ester efficiently, and then amino acid can be obtained by simple deprotection. The reduction method of the imidate mainly includes two methods of direct hydrogenation and transfer hydrogenation. In 2006, the Zhang Mou topic group reported asymmetric hydrogenation of imidoesters with hydrogen as the hydrogen source to give higher enantioselectivity of amino acid ester compounds (Angew. chem. int. Ed.2006,45, 6360-. However, the reaction uses a rhodium catalyst with high price and uses hydrogen with high pressure, so that the reaction has certain danger. In 2007, JonC.Antilla task group reported that hans esters are asymmetric transfer hydrogenation reactions of hydrogen source imidoesters, yielding higher enantioselectivity amino acid ester compounds (J. am. chem. Soc.2007,129, 5830-5831.). However, the reaction adopts an equivalent amount of hans ester as a hydrogen source, and reaction atoms are poor in economy, so that a large amount of hydrogen source is wasted. Therefore, the development of a mild, efficient, economic and universal chiral amino acid synthesis method has very important value.
The deuterated amino acid is one of the deuterated compounds with the most application value. The deuterated amino acid has the same structure and similar properties with the common amino acid, and can be widely applied as a tracer and an internal standard substance. In clinical medicine, the deuterated amino acid can be used for researching some physiological mechanisms of human and animals, plants and microorganisms and disclosing physicochemical processes in biological cells. In biological studies, deuterated amino acids can be used to measure the rate of protein synthesis by monitoring the rate at which a free isotopically labeled amino acid assembles into protein via multimeric ribosomes per unit time. The deuterated amino acid is one of the indispensable means for developing innovative medicaments, and many new medicaments use isotope-labeled amino acid to determine the transfer, transformation, curative effect, action mechanism, toxic and side effect and the like of the deuterated amino acid in vivo, thereby providing important basis for the research, curative effect and administration of the medicaments. Meanwhile, the deuterated amino acid can be used for analyzing the nutrient components of amino acid in foods such as fruits, vegetables, beer, traditional Chinese medicinal materials and the like and measuring the content of the amino acid. More importantly, the deuterated amino acid can be used for screening diseases with newborn amino acid metabolism disorder.
Currently, deuterated amino acids are synthesized by complicated steps or under harsh conditions, and the synthetic techniques are not mature and cannot be selectively deuterated (J.biol. chem,1937,120, 531-536; BBA-Gen Subject,1977,497, 1-13; Biochim Biophys Acta,1976,446, 479-485.). Meanwhile, the synthesis of chiral deuterated amino acid is rarely reported, in 2012, Takahiko Akiyama reports asymmetric transfer deuteration reaction (org. lett.2012,14,3312-3315.) of p-imidate taking deuterated benzothiazoline as a deuterium source to obtain chiral deuterated amino acid ester, but the deuterium source used in the reaction is expensive and difficult to prepare, and the reaction atom has poor economy, so that a large amount of deuterium source is wasted. Therefore, the traditional synthesis of the deuterated amino acid cannot meet the huge application value and market value of the deuterated amino acid. Therefore, the development of a chiral deuterated amino acid synthesis method which is mild, efficient, economical, universal and high in deuterium doping level has very important value.
Disclosure of Invention
The invention aims to provide a preparation method of a chiral amino acid ester and a chiral deuterated amino acid ester organic compound.
The purpose of the invention is realized by taking an imidate compound, water or heavy water as reaction raw materials, taking transition metal, Lewis acid and chiral ligand as catalysts, and reacting and synthesizing in an organic solvent to obtain a target chiral amino acid ester and a chiral deuterated amino acid ester compound, wherein the reaction general formula is as follows:
in the formula R1,R2,R3＝aryl,alkyl。
The transition metal is Pd (CH)3CN)2Cl2,Pd(CH3CN)2(BF4)2,Pd(CH3CN)2(OTf)2,C6H10Cl2Pd2,C10H14O4Pd,PdCl2,Pd2(dba)3,Pd(OAc)2,Ni(OTf)2,Co(OAc)2,[Ir(COD)Cl]2,Rh(COD)2BF4,C11H14F6N3PRu, etc., preferably PdCl2。
The amount of the transition metal is 0.01-100 mol% of the imido ester compound.
The chiral ligand is (R) -Seghos, (R) -Binap, (R, R) -BDPP, (R) -Phanephos, (R) -Synphos, (R) -Difluorphos, (R) -P-Phos, (R) -SDP, (R) -SKP, (R, R) -PhBox, (R, S) -PPF-PtBu2(R) -DuanPhos et al chiral phosphine and chiral oxazoline ligand, preferably (R) -SDP.
The dosage of the chiral ligand is 0.02 to 200 percent of the mole percentage of the imido acid ester compound.
The Lewis acid is HB (C)6F5)2,B(C6F5)3,BF3,ZnI2,AgOTf,AgBF4,Cu(OTf)2,CuCl,Zn(OTf)2,Fe(OTf)2,FeCl3,AlCl3Etc., preferably Fe (OTf)2。
The Lewis acid is used in an amount of 0.01 to 100 mole percent, preferably 0.01 mole percent, of the imidate compound.
The inorganic reducing agent is S8,H2S,FeSO4,Na2SO3,SnCl2,CO,SO2,HSiCl3And the like reducing substances; the organic reducing agent is organic compound such as vitamin C (ascorbic acid) and benzaldehyde derivatives; the metal simple substance reducing agent is a metal simple substance such as Fe, Al, Mg, Cu, Zn, Mn, Na, K, In and the like, and Mn is preferred.
The reducing agent is used in an amount of 50 to 500 mole percent, preferably 300 mole percent, of the imidate compound.
The solvent is organic solvent such as toluene, tetrahydrofuran, tetrahydropyran, methyl tert-butyl ether, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, and dimethyl sulfoxide, preferably tetrahydrofuran.
The solvent is used in an amount of 0.1mol/L to 10mol/L, preferably 1.0mol/L, in terms of the molar concentration of the imidate compound.
The temperature is-50 ℃ to 200 ℃, preferably 60 ℃.
The amount of water and heavy water used is 100% to 500%, preferably 100%, mole percent of the imidate compound.
The invention has the advantages that: the invention provides a preparation method of chiral amino acid ester and chiral deuterated amino acid ester compounds, which is simple to operate, mild, efficient and green.
Drawings
FIG. 1 is a mass spectrum of a chiral amino acid ester compound;
FIG. 2 is a mass spectrum of a chiral deuterated amino acid ester compound;
FIG. 3 HPLC chart of chiral amino acid ester compound;
FIG. 4 HPLC chart of chiral deuterated amino acid ester compound
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to be limiting in any way, and any modifications or alterations based on the teachings of the present invention are intended to fall within the scope of the present invention.
The invention relates to a method for synthesizing target chiral amino acid ester and chiral deuterated amino acid ester organic compounds by taking an imido ester compound, water or heavy water as reaction raw materials and transition metal, Lewis acid and chiral ligand as catalysts in an organic solvent, wherein the reaction general formulas are as follows:
in the formula R1,R2,R3Is alkyl or aryl.
The invention is further illustrated by the following specific examples: