CN113214099A - Preparation method of deuterated amino acid ester compound - Google Patents
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- CN113214099A CN113214099A CN202110410663.0A CN202110410663A CN113214099A CN 113214099 A CN113214099 A CN 113214099A CN 202110410663 A CN202110410663 A CN 202110410663A CN 113214099 A CN113214099 A CN 113214099A
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Abstract
The invention discloses a method for efficiently preparing chiral deuterated amino-acid ester, which is characterized in that imido ester is taken as a raw material, deuterated methanol is taken as a deuterium source, and transition metal catalysis is adopted to realize asymmetric transfer deuteration of imido ester in a common organic solvent. Obtaining the target product chiral deuterated amino-acid ester, wherein the reaction formula is as follows:
the method for preparing the chiral deuterated amino acid ester by using the deuterated methanol as the deuterium source comprises the steps of reaction system establishment, main reaction and post-treatment. Provides a deutero-hand with simple operation, mild, high efficiency, green and high deutero-rateA method for preparing amino acid ester.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of chiral deuterated amino-acid ester.
Background
Deuterium (D or2H) Is an isotope of hydrogen (H) with twice the atomic mass of hydrogen, also known as deuterium. Deuterium, non-toxic and non-radioactive. Deuterated compounds are a very important class of high value-added chemicals. At present, methods for preparing deuterated compounds mainly comprise methods such as hydrogen-deuterium exchange, direct deuteration and dehalogenation deuteration (J.Am.Chem.Soc.2019,141, 1467-1472; J.Am.Chem.Soc.2018,140, 10970-10974; adv.Synth.Catal.2018,360, 637-641). In the field of medicinal chemistry, the effect of deuterated compounds is increasingly prominent. When the C-H bond at a certain position or several positions in the drug molecule is replaced by the C-D bond, the selectivity and the activity of the drug can still be kept unchanged. And compared with the C-H bond, the C-D bond has lower vibration frequency and larger bond energy and is more difficult to break in organisms, and through the kinetic isotope effect, the deuterated drug not only can directly influence the absorption and metabolism of the drug, but also can improve the action time and tolerance of the drug and reduce toxic and active metabolites. In 2017, Deutetrabenazine, the first example of a deuterated drug, was officially approved by the Food and Drug Administration (FDA), and was effective in treating Huntington's chorea. At present, deuterated drugs have great market value and application 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 not well-developed and have complex synthetic steps or harsh synthetic conditions, while being incapable of selective deuteration (J.biol.chem., 1937,120, 531-536; BBA-Gen Subject,1977,497, 1-13; Biochim Biophys Acta,1976,446, 479-485.). 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 mild, efficient, economic, universal and high-level deuterium-doped deuterated amino acid synthesis method has very important value.
Disclosure of Invention
The invention aims to provide an efficient and rapid preparation method of chiral deuterated amino-acid ester.
The purpose of the invention is realized by using deuterated methanol as a deuterium source to prepare chiral deuterated amino acid ester. The method comprises the following steps of taking an imido ester derivative compound and deuterated methanol as reaction raw materials, taking transition metal and Lewis acid as a cocatalyst, and reacting in an organic solvent to synthesize the target chiral deuterated amino-acid ester, wherein the reaction general formula is as follows:
in the formula R1,R2,R3Derived from an alkyl or aryl group.
The Lewis acid is HB (C)6F5)2,BF3,ZnI2,ZnBr2,ZnCl2,ZnF2,AgOTf,AgBF4,CuCl,Zn(OTf)2,Cu(OTf)2,Cu(OTf),FeCl3,AlCl3,AgBF4,Bu4NI、Bu4NBr、Bu4NCl, etc., preferably Zn (OTf)2。
The Lewis acid is used in an amount of 0.01 to 100 mole percent, preferably 0.01 mole percent, based on the mole percent of the imidate derivative.
The chiral ligand is (R) -BINAP, (R) -SEGPHOS, (R) -SIPHOS, (R) -P-Phos, (R) -SYNPHOS, (R) -SDP, (R) -PHANEPHOS, etc., preferably (R) -SEGPHOS.
The dosage of the chiral ligand is 0.01 to 100 percent of the mole percentage of the imine acid ester derivative, and preferably 0.012 percent
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. 1, 2-dichloroethane
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 derivative.
The temperature is from 0 ℃ to 200 ℃ and preferably 70 ℃.
The amount of deuterated methanol is 100-500 mol%, preferably 500 mol% of the imine acid ester derivative.
The invention has the advantages that: the invention provides a preparation method of chiral deuterated amino-acid ester, which is simple to operate, mild, efficient and high in deuterium doping level.
Drawings
Figure 1 NMR spectrum of chiral deuterated imidate derivative described in example 11;
figure 2 NMR spectrum of chiral deuterated imidate derivative described in example 5.
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 deuterated amino-acid ester by taking an imido ester derivative and deuterated methanol as reaction raw materials and taking transition metal and Lewis acid as a cocatalyst in an organic solvent, wherein the reaction general formula is as follows:
in the formula R1,R2,R3Derived from an alkyl or aryl group.
The invention is further illustrated by the following specific examples:
example 1
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. The reaction was carried out in an oil bath at 70 ℃ and monitored by TLC, after completion of the reaction, concentration was carried out, and a white solid was obtained by passing through silica gel column with a yield of 89% and an ee value of 87%, and the deuterium incorporation efficiency of this compound was 97% as calculated from 1H NMR spectrum.
1H NMR(400MHz,CDCl3):δ7.49-7.44(m,2H),7.38-7.29(m,3H),6.74-6.71(m,2H),6.55-6.51(m,2H),5.01(s,0.03H),4.66(s,1H),3.71(d,J＝7.16Hz,6H)。
Example 2
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. Reacting in oil bath at 70 deg.C, detecting by TLC, concentrating after the reaction is completed, and passing through silica gel column to obtain white solid with yield of 92% and ee value of 88%, and deuterium incorporation rate of 78% according to 1H NMR spectrum.1H NMR(400MHz,DMSO-d6)δ8.33(s,1H)，7.63–6.97(m,5H)，4.45(dd,J＝9.3,7.8Hz,0.21H)，3.59(s,3H),3.00(d,J＝13.7Hz,0.24H)，2.87(d,J＝13.2Hz,1H)，1.79(s,3H).
Example 3
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. Reacting in oil bath at 70 deg.C, detecting by TLC, concentrating after the reaction is completed, and passing through silica gel column to obtain white solid with yield of 95% and ee value of 90%, and deuterium incorporation rate of 78% according to 1H NMR spectrum.1H NMR(400MHz,Chloroform-d)δ8.33(d,J＝7.8Hz,1H),7.19(td,J＝7.5,1.0Hz,1H),6.78(dt,J＝9.0,1.4Hz,3H),4.44(ddd,J＝9.4,7.7,5.4Hz,022H),3.72(s,3H),3.60(s,3H),2.98(dd,J＝13.7,5.5Hz,0.20H),2.84(dd,J＝13.7,9.4Hz,1H),1.79(s,3H).
Example 4
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. The reaction was carried out in an oil bath at 70 ℃ and monitored by TLC, after completion of the reaction, concentration was carried out, and a white solid was obtained by passing through silica gel column with a yield of 89% and an ee value of 85%, and the deuterium incorporation rate of this compound was 97% as calculated from 1H NMR spectrum.
1H NMR(400MHz,CDCl3):δ7.50-7.47(m,2H),7.37-7.25(m,3H),7.14-7.09(m,2H),6.72-6.68(m,1H),6.57-6.55(m,2H),5.08(s,0.03H),4.93(s,1H),3.73(s,3H).
Example 5
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. Reacting in 70 deg.C oil bath, detecting by TLC, concentrating after the reaction is completed, passing through silica gel column to obtain white solid with yield of 98% and ee value of 92%, and calculating deuterium incorporation rate of the compound according to 1H NMR spectrum>99％。
1H NMR(400MHz,CDCl3):δ7.49-7.46(m,2H),7.36-7.26(m,3H),6.73-6.69(m,2H),6.55-6.51(m,2H),5.07-4.97(s,1H),4.65(s,1H),3.69(s,3H),1.25(d,J＝6.3Hz,3H),1.07(d,J＝6.2Hz,3H).
Example 6
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. The reaction was carried out in an oil bath at 70 ℃ and monitored by TLC, after completion of the reaction, concentration was carried out, and a white solid was obtained by passing through silica gel column with a yield of 92% and an ee value of 87%, and the deuterium incorporation rate of this compound was 98% as calculated from 1H NMR spectrum.
1H NMR(400MHz,CDCl3):δ7.45-7.41(m,2H),7.33-7.30(m,2H),6.73-6.69(m,2H),6.51-6.47(m,2H),4.98(s,0.02H),4.69(s,1H),3.85(s,3H),3.71(d,J＝9.2Hz,6H).
Example 7
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. The reaction was carried out in an oil bath at 70 ℃ and monitored by TLC, after completion of the reaction, concentration was carried out, and a white solid was obtained by passing through silica gel column with a yield of 94% and an ee value of 82%, and the deuterium incorporation rate of this compound was 85% as calculated from 1H NMR spectrum.
1H NMR(400MHz,CDCl3)δ7.24(dd,J＝5.1,1.2Hz,1H),7.16–7.09(m,1H),6.97(dd,J＝5.1,3.6Hz,1H),6.79–6.70(m,2H),6.66–6.56(m,2H),5.28(s,0.02H),4.65(s,1H),3.77(s,3H),3.71(s,3H).
Example 8
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. Reacting in oil bath at 70 deg.C, detecting by TLC, concentrating after the reaction is completed, and passing through silica gel column to obtain white solid with yield of 97% and ee value of 90%, and deuterium incorporation rate of 96% according to 1H NMR spectrum.
1H NMR(400MHz,CDCl3)δ7.54–7.43(m,2H),7.37–7.24(m,6H),7.21–7.08(m,2H),6.76–6.64(m,2H),6.60–6.43(m,2H),5.18(d,J＝12.4Hz,0.04H),5.13–5.01(m,2H),4.67(s,1H),3.68(s,3H).
Example 9
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. The reaction was carried out in an oil bath at 70 ℃ and monitored by TLC, after completion of the reaction, concentration was carried out, and a white solid was obtained by passing through silica gel column with a yield of 90% and an ee value of 83%, and the deuterium incorporation efficiency of this compound was 89% as calculated from 1H NMR spectrum.
1H NMR(400MHz,CDCl3)δ7.46–7.35(m,2H),6.93–6.82(m,2H),6.77–6.63(m,2H),6.59–6.45(m,2H),4.96(s,0.11H),4.62(s,1H),3.79(s,3H),3.71(d,J＝4.5Hz,6H).
Example 10
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. Reacting in 70 deg.C oil bath, detecting by TLC, concentrating after the reaction is completed, and purifying with silica gel column to obtain white solid with yield of 96% and ee value of 89%, based on 1H NMR spectrumThe deuterium incorporation efficiency of this compound was calculated to be 95%.
1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.1Hz,2H),7.15(d,J＝7.8Hz,2H),6.79–6.60(m,2H),6.60–6.41(m,2H),4.98(s,0.08H),4.64(s,1H),3.70(d,J＝4.2Hz,6H),2.32(s,3H).
Example 11
In a dry, oxygen-free glove box under argon atmosphere, (R) -SEGPHOS (0.012mmol) Pd (OAc)2(0.005mmol) was added to the reaction tube in order, then 1ml of 1, 2-dichloroethane was added and stirred for 30min, and Zn (OTf) was further added2(Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of the imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1, 2-dichloroethane were added. Reacting in oil bath at 70 ℃, detecting the reaction by TLC, concentrating after the reaction is finished, and passing through silica gel column to obtain white solid with the yield of 93% and the ee value of 80%, wherein the deuterium incorporation rate of the compound is 98% according to the 1H NMR spectrum.
1H NMR(400MHz,CDCl3):δ7.48-7.45(m,2H),7.38-7.29(m,3H),7.07-7.03(m,2H),6.48-6.44(m,2H),5.02(s,0.02H),4.99(s,1H),3.73(s,3H)。
Claims (9)
1. A preparation method of chiral deuterated amino-acid ester is characterized by comprising the following steps: the method comprises the following steps of taking an amino acid ester compound and deuterated methanol as reaction raw materials, taking a transition metal and Lewis acid as a cocatalyst, and reacting in an organic solvent to synthesize the target chiral deuterated amino acid ester compound, wherein the reaction general formula is as follows:
in the formula, R1,R3,R2Derived from an alkyl or aryl group.
2. The method of preparing a chiral deuterated amino-acid ester as recited in claim 1, wherein: the catalyst is Lewis acid.
3. The method of preparing a chiral deuterated amino-acid ester as recited in claim 1, wherein: the chiral ligand is (R) -SEGPHOS.
4. The method of preparing chiral deuterated amino-acid ester according to claim 1 or 2, characterized in that the lewis acid is HB (C)6F5)2,BF3,ZnI2,ZnBr2,ZnCl2,ZnF2,AgOTf,AgBF4,CuCl,Zn(OTf)2,Cu(OTf)2,Cu(OTf),FeCl3,AlCl3,AgBF4,Bu4NI、Bu4NBr、Bu4NCl and the like.
5. The method of preparing a chiral deuterated amino-acid ester according to claim 4, wherein: the dosage of the Lewis acid is 0.01 to 100 percent of the mole percentage of the imido acid ester compound.
6. The method of preparing a chiral deuterated amino-acid ester as recited in claim 1, wherein: the solvent is organic solvent such as toluene, tetrahydrofuran, tetrahydropyran, methyl tert-butyl ether, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.
7. The method of preparing a chiral deuterated amino-acid ester as recited in claim 6, wherein: the dosage of the solvent is 0.1mol/L-10mol/L of the molar concentration of the imidic acid ester compound.
8. The method of preparing a chiral deuterated amino-acid ester according to claim 1, wherein the temperature is from 0 ℃ to 200 ℃.
9. The method of preparing a chiral deuterated amino-acid ester as recited in claim 1, wherein: the dosage of the deuterated methanol is 50 to 500 percent of the mole percentage of the imido ester compound.
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| CN114751801B (en) * | 2022-05-20 | 2022-12-27 | 安徽贵朋功能材料科技有限公司 | Method for preparing deuterated amino acid ester by photocatalysis |
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Application publication date: 20210806 |