CN114751801A - Method for preparing deuterated amino acid esters by photocatalysis - Google Patents

Method for preparing deuterated amino acid esters by photocatalysis Download PDF

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CN114751801A
CN114751801A CN202210548493.7A CN202210548493A CN114751801A CN 114751801 A CN114751801 A CN 114751801A CN 202210548493 A CN202210548493 A CN 202210548493A CN 114751801 A CN114751801 A CN 114751801A
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amino acid
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acid ester
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张海波
漆斌
陆静
刘霁
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Anhui Guipeng Functional Material Technology Co ltd
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a method for preparing deuterated amino acid esters by photocatalysis, which is characterized in that amino acid esters are used as raw materials in deuterium water which is cheapest and easy to obtain, direct deuteration of the amino acid esters is realized under mild conditions by adopting multiple catalysts for concerted catalysis, and a target product deuterated amino acid ester compound is obtained.

Description

Method for preparing deuterated amino acid esters by photocatalysis
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a novel method for preparing deuterated amino acid ester through photocatalysis.
Background
Deuterium (D or H) isotope of hydrogen (H)2H) Also known as deuterium, consists of one proton, one neutron, and one electron. The abundance on the earth is 0.015%, and deuterium oxide D is mostly used2O is present in seawater. In chemistry, particularly in the field of pharmaceutical chemistry, research and synthesis of deuterated compounds have become one of the hot spots under investigation. The C-D bond has higher bond energy than the C-H bond, so that more energy is needed for breaking the C-D bond than for breaking the C-H bond, and the breaking of the C-H bond is the most important step in the metabolic process of the drug compound, so that the drug metabolic rate can be reduced by using the deuterated compound containing the C-D bond. Compared with common drug molecules, the deuterated drug molecules have the following advantages: prolonging half-life period and blood concentration of the medicine, reducing dosage or frequency of medicine administration, blocking certain metabolic sites, reducing generation of toxic metabolites, reducing medicine toxicity, etc. 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). Over the last 10 years, a group of companies focusing on deuteration research have had great success in the field of new drug development. Of these, the most famous abroad is Auspex (TEVA) and Concert. Auspex corporation established 2001, with only 35 employees in nasdak in the united states in 2014. After clinical data of the Qinqing star deuterated product SD-809 (deuterated tetrabenazine) were published in 2015, TEVA company withdrew 32 hundred million dollars (the premium rate is 42%) and collected into capsules. In 2017, SD-809 is approved by FDA as the first deuterated drug worldwide for treating abnormal involuntary movement (HD) caused by Huntington's chorea, and is sold under the name of AUSTEDO TM. Compared with non-deuterated tetrabenazine, AUSTEDO can significantly slow down metabolic processes and has a half-life that is approximately 2 times that of non-deuterated tetrabenazine. Thus, by reducing the dose and frequency of administration, the AUSTEDO side effects are less and the patient's depression and suicidal tendency are reduced while the appearance of withdrawal is suppressed. According to Evaluate Pharma prediction, AustedoSales are expected to reach $ 6.67 billion in 2022.
Amino acid is a compound which is quite important in life science, and has important significance in the research of life chemistry. Deuterated amino acids are widely used for researching physiological mechanisms of animals, plants and microorganisms and physicochemical processes of cells in clinical medicine. Meanwhile, the deuterated amino acid is one of important means for researching the transfer, metabolism, action mechanism and toxic and side effects of the novel medicament in organisms. More importantly, the deuterated amino acid can be used for screening the newborn amino acid metabolic disorder. At present, the preparation of deuterated amino acid has the defects of complicated steps, low deuteration rate, high cost and energy consumption, uncontrollable sites and the like (J.biol. chem,1937,120, 531-536; BBA-Gen Subject,1977,497, 1-13; Biochim BiophysActa,1976,446, 479-485.). And/or the preparation of the deuterated amino acid ester in the prior art often needs to prepare corresponding imidate (CN113214099A, CN114436871A, CN111004076A, CN110885294A and the like) or dehydroamino acid ester (CN113200895A, CN112358412A and the like) in advance, and then the preparation can be carried out under the condition of an expensive reaction system in the presence of a reducing agent, so that the development of the corresponding imidate is greatly restricted, but the method of directly taking the amino acid ester as a raw material and carrying out deuteration at a specific position is not reported. Therefore, the development of an efficient, economical and universal method for directly preparing the deuterated amino acid ester at a specific position becomes a hot spot which needs to be researched.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a novel method for directly preparing deuterated amino acid ester compounds at specific positions by directly using amino acid esters as raw materials, and the method is quick, efficient, cheap and high in universality.
According to one of the methods for preparing deuterated amino acid esters by photocatalysis provided by the invention, deuterated water and an amino acid ester compound shown as a formula I are used as reaction raw materials, a catalytic amount of Lewis acid, tetraphenylphosphonium chloride, tetraphenylboron salt, borane derivative and aluminum oxide are used as composite catalysts, and under the protection of nitrogen, the deuterated amino acid esters shown as a formula II are obtained by reaction at room temperature under ultraviolet light, wherein the reaction general formula is as follows:
Figure BDA0003653293240000031
in the formula, R1，R2，R2' and R3Is any group.
Alternatively, R1Is hydrogen, substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20Heteroaryl, substituted or unsubstituted C3-20Cycloalkyl, substituted or unsubstituted C1-20Alkoxycarbonyl, substituted or unsubstituted C1-20Acyl, substituted or unsubstituted C6-20aryl-C1-20Alkyl, substituted or unsubstituted C6-20An aroyl group.
R2Is hydrogen, substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C 6-20Aryl, substituted or unsubstituted C3-20Heteroaryl, substituted or unsubstituted C3-20Cycloalkyl, substituted or unsubstituted C6-20aryl-C1-20An alkyl group.
R2' Definitions and R2Are the same, and when R is2When it is hydrogen, R2' is deuterium.
R3Is hydrogen, substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20Heteroaryl, substituted or unsubstituted C3-20Cycloalkyl, substituted or unsubstituted C6-20aryl-C1-20An alkyl group.
In any part of the present invention, the substituent in said "substituted or unsubstituted" is selected from halogen, C1-6Alkoxy radical, C1-6Alkyl, -CN, -NO2Halogen substituted C1-6Alkyl radical, C1-6One or more alkylthio groups. Preferably fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, -CN, -NO2TrifluromethylOne or more of methyl, methylthio and ethylthio.
In any of the moieties of the invention, the heteroatom of heteroaryl, heterocycloalkyl is selected from N, O, S, P, Se or Si.
In the present invention, said C1-20Alkyl radical, C1-20Acyl radical, C1-20Alkoxycarbonyl, C6-20aryl-C1-20The alkyl group may have a straight or branched alkyl group, and the number of carbons of the alkyl group is preferably 1 to 6, more preferably 1 to 3. Examples of the alkyl group may include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, neopentyl, hexyl, 2-ethylhexyl, 2-butylhexyl, heptyl, octyl, nonyl, decyl, n-undecyl, n-dodecyl and the like.
In the present invention, said C6-20Aryl radical, C6-20Aroyl, C6-20aryl-C1-20The aryl group in the alkyl group is a monocyclic or polycyclic aryl group, and the number of carbon atoms for forming the aryl group may be further preferably 6 to 18, 6 to 14, or 6 to 12. Examples of the aryl group may include phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, biphenyl, terphenyl, benzophenanthryl, pyrenyl, and the like,
Figure BDA0003653293240000041
A phenyl group, a fluoranthene group, and the like.
In the present invention, said C3-20The cycloalkyl group may be a monocyclic or polycyclic cycloalkyl group, and the number of carbon atoms for forming the cycloalkyl group may be further preferably 3 to 12, 3 to 8, or 3 to 6. Examples of cycloalkyl groups may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, bicyclo [3.2.1]Octane, spiro [5.5 ]]Undecane, and the like.
In the present invention, said C3-20The heteroaryl group may be a monocyclic or polycyclic heteroaryl group, and the number of carbons forming the heteroaryl group may be further preferably 2 to 18, 2 to 12, 2 to 8, or 2 to 6. Examples of the heteroaryl group may include a thienyl group, a furyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a triazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazinyl group, an acridinyl group, a pyridazine groupExamples of the substituent include, but are not limited to, a pyridyl group, a quinolyl group, a quinazolinyl group, a quinoxalinyl group, a phenoxazinyl group, a phenothiazinyl group, a pyridopyrimidyl group, a pyridopyrazinyl group, an isoquinolyl group, an indolyl group, a carbazolyl group, a benzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzofuranyl group, a benzothiophenyl group, a phenanthrolinyl group, a thiazolyl group, an isoxazolyl group, a thiadiazolyl group, a dibenzofuranyl group, a thienothienyl group, and the like.
Preferably, the amino acid ester compound of formula I has the following structure:
Figure BDA0003653293240000051
the second method for preparing deuterated amino acid esters by photocatalysis is characterized in that deuterated water and an amino acid ester compound shown as a formula I-1 are used as reaction raw materials, a catalytic amount of Lewis acid, tetraphenylphosphonium chloride, tetraphenylboron salt, borane derivatives and aluminum oxide are used as composite catalysts, and the deuterated amino acid esters shown as a formula II-1 are obtained by reacting at room temperature under ultraviolet light under the protection of nitrogen, wherein the general reaction formula is as follows:
Figure BDA0003653293240000052
the method for preparing the deuterated amino acid ester by photocatalysis comprises the following specific steps:
(5) dissolving a certain amount of amino acid ester compounds in deuterium water, adding a composite catalyst, and adding N2Fully and uniformly stirring under protection;
(6) the power is 5W-100W, the wavelength is under the irradiation of an ultraviolet lamp with the wavelength of 265-400nm, and the reaction is fully carried out for 0.5-24h at the temperature of 15-35 ℃;
(7) after the reaction is finished, filtering to remove the catalyst, extracting with a solvent with the volume ratio of ethyl acetate/water being 1:1 or butyl acetate/water being 1:1, and taking an organic phase;
(8) and separating by column chromatography to obtain the deuterated amino acid ester compound.
The molar ratio of the amino acid ester compound to the deuterium oxide in the step (1) is 1: 50-100.
The mol ratio of the amino acid ester compound to the composite catalyst in the step (1) is as follows in sequence: n (amino acid ester compound): n (Lewis acid): n (tetraphenylphosphonium chloride): n (tetraphenylboron salt): n (borane): n (aluminum oxide) ═ 1: 0.00005-0.5: 0.00005-0.5: 0.00005-0.5: 0.00005-0.5: 0.00005-0.5.
In the invention, the Lewis acid is FeCl3，HCl，H2SO4，CuCl2，AgNO3And the like.
In the invention, the tetraphenylborate salt is one or more of sodium tetraphenylborate, potassium tetraphenylborate, lithium tetraphenylborate, rubidium tetraphenylborate and cesium tetraphenylborate.
In the invention, the borane derivative is BnHn 2-，BnHn+1 -，BnHn+2，CaBn-aHn-a+2Wherein n is one or more of 6, 7, 8, 9, 10, 12, 20 and 24; a is one of 1, 2, 3 and 4. If the borane needs cation coordination, the cation is one or more of metal cations, such as Li, Na, K, Ru, Cs, Mg, Al and the like.
Compared with the prior art, the invention has the following advantages:
(1) the invention realizes the deuteration reaction of the amino acid ester compound by adopting the composite catalyst under the illumination for the first time;
(2) the invention adopts deuterium water as deuterium source, thus greatly reducing the deuterium cost;
(3) The invention adopts a photocatalysis method to obtain the deuterated amino acid ester compound, realizes the direct use of the amino acid ester compound as a raw material to perform deuteration on a specific site, does not need to prepare the imine acid ester and/or dehydroamino acid ester precursor, effectively saves the process steps, has the advantages of mild reaction, short reaction time, easy operation, good environment and the like, and is beneficial to the industrial production and application of the deuterated amino acid ester compound.
Drawings
FIG. 1 is a schematic representation of the methyl ester of D-BOC-D-alanine prepared in example 11H NMR spectrum.
FIG. 2 is a schematic representation of the preparation of D-CBZ-glycine methyl ester of example 31H NMR spectrum.
FIG. 3 is a schematic representation of the preparation of methyl D-N-Boc-4-oxo-L-proline ester in example 61H NMR spectrum.
FIG. 4 is a schematic representation of the preparation of methyl D-Cbz-L-alanine prepared in example 41H NMR spectrum.
FIG. 5 is a schematic representation of the preparation of methyl D-N-Cbz-L-leucine ester from example 51H NMR spectrum.
Detailed Description
The invention is explained in more detail below with reference to the figures and examples, without limiting the scope of the invention.
Example 1:
Figure BDA0003653293240000071
(1) dissolving 500mmol of the amino acid ester compound in 25mol of deuterium water, and adding composite catalyst (ferric chloride: 0.025mmol, tetraphenylphosphonium chloride: 0.025mmol, sodium tetraphenylborate: 0.5mmol, Na) 2B12H12:0.5mmol，Al2O3：0.25mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 8 hours at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 5W and the wavelength of 365 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with ethyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated yield 91%, according to1The deuterium incorporation rate of this compound was 97% as calculated by H NMR spectrum.
Figure BDA0003653293240000081
1H NMR(400MHz,D6-DMSO):δ3.68(m,3H),1.34(m,9H),1.29-1.27(m,3H)。
Example 2:
Figure BDA0003653293240000082
(1) dissolving 10mmol of the amino acid ester compound in 500mmol deuterium water, and adding composite catalyst (HCl: 0.1mmol, tetraphenylphosphonium chloride: 0.1mmol, potassium tetraphenylborate: 0.1mmol, Cs)2B10H10:0.05mmol，Al2O3：0.1mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 4 hours at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 25W and the wavelength of 265 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with butyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated yield 88%, according to1The deuterium incorporation efficiency of this compound was calculated to be 95% by H NMR spectroscopy.
Figure BDA0003653293240000083
1H NMR(400MHz,D6-DMSO):δ3.63(m,3H),2.06-1.93(m,1H),1.3(m,9H),0.88-0.85(m,6H)。
Example 3:
Figure BDA0003653293240000091
(1) dissolving 1mol of the amino acid ester compound in 100mol of deuterium water, and adding a composite catalyst (AgNO) 3: 0.05mmol, tetraphenylphosphonium chloride: 0.05mmol, sodium tetraphenylborate: 0.5mmol, C2B3H7:0.05mmol，Al2O3：0.5mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 24 hours at room temperature (30 ℃) under the irradiation of an ultraviolet lamp with the power of 50W and the wavelength of 395 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with butyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated yield 89%, according to1The deuterium incorporation rate of this compound was 96% as calculated by H NMR spectrum
Figure BDA0003653293240000092
:1H NMR(400MHz,D6-DMSO):δ7.37-7.36(m,2H),7.34-7.32(m,2H),7.31-7.30(m,1H),5.07(m,2H),3.6(m,3H)。
Example 4:
Figure BDA0003653293240000093
(1) dissolving 1mmol of the amino acid ester compound in 75mmol deuterium water, and adding composite catalyst (H)2SO4: 0.25mmol, tetraphenylphosphonium chloride: 0.1mmol, sodium tetraphenylborate: 0.05mmol, K2B6H6:0.05mmol mmol，Al2O3：0.00005mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 20 hours at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 100W and the wavelength of 400 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with ethyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated yield 94% according to1The deuterium incorporation rate of this compound was 93% as calculated by H NMR spectrum
Figure BDA0003653293240000101
:1H NMR(400MHz,D6-DMSO):δ7.77(m,1H),7.75-7.34(m,4H),7.32-7.31(m,1H),5.03(m,2H),3.63(m,3H),1.28-1.26(m,3H)。
Example 5:
Figure BDA0003653293240000102
(1) dissolving 0.25mmol of the amino acid ester compound in 20mmol deuterium water, and adding composite catalyst (CuCl) 2: 0.025mmol, tetraphenylphosphonium chloride: 0.125mmol, cesium tetraphenylborate: 0.125mmol, 2,4-C2B5H7:0.125mmol，Al2O3：0.025mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 8.5 hours at room temperature (15 ℃) under the irradiation of an ultraviolet lamp with the power of 50W and the wavelength of 370 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with ethyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated yield 85% according to1The deuterium incorporation rate of this compound was 96% as calculated by H NMR spectrum
Figure BDA0003653293240000111
1H NMR(400MHz,D6-DMSO):δ7.75(m,1H),7.73-7.33(m,4H),7.32-7.30(m,1H),5.04(m,2H),3.63(m,3H),1.66-1.53(m,2H),1.49-1.46(m,1H),0.89-0.84(m,6H)。
Example 6:
Figure BDA0003653293240000112
(1) dissolving 1.5mmol of the amino acid ester compound in 150mmol of deuterium water, and adding composite catalyst (0.3 mmol of ferric nitrate, 0.375mmol of tetraphenylphosphonium chloride, 0.15mmol of tetraphenylbororubidium and Na)2B6H7:0.075mmol，Al2O3：0.75mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 24 hours at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 10W and the wavelength of 365 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with butyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated in 90% yield1The deuterium incorporation rate of this compound was 95% as calculated by H NMR spectrum
Figure BDA0003653293240000113
:1H NMR(400MHz,D6-DMSO):δ3.68(m,1H),1.37(m,3H)。
Example 7:
Figure BDA0003653293240000121
(1) Dissolving 50mmol of the above amino acid ester compounds in 750mmol deuterium water, and adding composite catalyst (ferric chloride: 0.05mmol, tetraphenylphosphonium chloride: 0.5mmol, lithium tetraphenylborate: 5mmol, 1, 12-C)2B10H12:2.5mmol，Al2O3：0.5mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 6 hours at room temperature (15 ℃) under the irradiation of an ultraviolet lamp with the power of 65W and the wavelength of 300 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with ethyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated in 93% yield according to1The deuterium incorporation rate of this compound was 98% as calculated by H NMR spectrum
Figure BDA0003653293240000122
:1H NMR(400MHz,D6-DMSO):δ8.05(s,1H),7.30-7.26(m,2H),6.89-6.86(m,2H),6.78-6.76(m,2H),6.73-6.70(m,2H),3.82(m,6H),3.67(m,3H)。
Example 8:
Figure BDA0003653293240000123
(1) dissolving 0.1mmol of the amino acid ester compound in 8mmol deuterium water, and adding composite catalyst (ferric chloride: 0.01mmol, HCl:0.02mmol, tetraphenylphosphonium chloride: 0.03mmol, sodium tetraphenylborate: 0.03mmol, Na)2B12H12:0.015mmol，RuB10H11:0.015mmol,Al2O3：0.03mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 0.5h at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 100W and the wavelength of 365 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with butyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated in 90% yield 1The deuterium incorporation rate of this compound was 98% as calculated by H NMR spectrum
Figure BDA0003653293240000131
:1H NMR(400MHz,D6-DMSO):δ7.36-7.34(m,1H)，6.96-6.93(m,2H)，6.85-6.83(m,2H)，6.77-6.75(m,2H)，3.81(m,3H)，3.65(m,3H)。
Example 9:
Figure BDA0003653293240000132
(1) dissolving 100mmol of the above amino acid ester compounds in 6mol deuterium water, and adding composite catalyst (Cu (NO)3)2：1mmol，Fe(NO3)3：1mmol,AgNO3: 1mmol, tetraphenylphosphonium chloride: 10mmol, potassium tetraphenylborate: 5mmol of Na2B12H12:0.05mmol，NaCB9H10:0.05mmol，Na2B24H24:0.05mmol，Al2O3：0.1mmol)，N2Protection ofFully stirring uniformly;
(2) fully reacting for 24 hours at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 100W and the wavelength of 395 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with butyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated yield 94% according to1The deuterium incorporation rate of the compound was 99% as calculated by H NMR spectrum
Figure BDA0003653293240000141
:1H NMR(400MHz,D6-DMSO):δ7.35-7.32(m,4H),7.32-7.31(m,1H),7.31-7.30(m,2H)，7.29-7.28(m,2H),7.27-7.26(m,1H),6.79-6.77(m,2H)，6.72-6.70(m,2H),5.33(m,2H),3.80(m,3H)。
Example 10:
Figure BDA0003653293240000142
(1) dissolving 25mmol of the amino acid ester compound in 2.25mol of deuterium water, and adding a composite catalyst (HCl: 1.25mmol, tetraphenylphosphonium chloride: 0.0625mmol, tetraphenylborocesium: 6.25mmol, B)10H12:0.0625mmol，Al2O3：1.25mmol)，N2Fully and uniformly stirring under protection;
(2) fully reacting for 8 hours at room temperature (25 ℃) under the irradiation of an ultraviolet lamp with the power of 45W and the wavelength of 360 nm;
(3) after the reaction is finished, filtering to remove the catalyst, extracting with ethyl acetate/water at a ratio of 1:1, and taking an organic phase;
(4) separating by column chromatography to obtain the deuterated amino acid ester compound shown in the formula. Isolated in 93% yield according to 1The deuterium incorporation rate of this compound was 96% as calculated by H NMR spectrum
Figure BDA0003653293240000151
:1H NMR(400MHz,D6-DMSO):δ8.32(s,1H),7.24-7.21(t,1H),6.90-6.85(m,3H),3.70(s,3H),3.65(s,3H),3.30-3.28(m,2H),1.85(s,3H)。
The foregoing lists merely exemplary embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All changes which can be directly derived or suggested by a person skilled in the art of deuterated drugs from the disclosure of the present invention, such as lewis acids in composite catalysts, tetraphenylborate salts, boranes, etc., which can be single or two or more, for example, examples 8 and 9, etc., and amino acid ester compounds other than the above examples, which can also be amino acid ester compounds with any other groups, etc., should be considered as the protection scope of the present invention.

Claims (10)

1. A method for preparing deuterated amino acid esters by photocatalysis is characterized in that deuterated water and an amino acid ester compound shown in a formula I are used as reaction raw materials, a catalytic amount of Lewis acid, tetraphenylphosphonium chloride, tetraphenylborate salt, borane derivatives and aluminum oxide are used as composite catalysts, and the deuterated amino acid esters are reacted at room temperature under ultraviolet light under the protection of nitrogen to obtain the deuterated amino acid esters shown in a formula II, wherein the reaction general formula is as follows:
Figure 629116DEST_PATH_IMAGE001
；
in the formula, R1，R2，R2' and R3Is any group.
2. The method of claim 1, wherein R is 1Is hydrogen, substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20Heteroaryl, substituted or unsubstituted C3-20Cycloalkyl, substituted or unsubstituted C1-20Alkoxycarbonyl, substituted or unsubstituted C1-20Acyl, substituted or unsubstituted C6-20aryl-C1-20Alkyl, substituted or unsubstituted C6-20Aroyl;
R2is hydrogen, substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20Heteroaryl, substituted or unsubstituted C3-20Cycloalkyl, substituted or unsubstituted C6-20aryl-C1-20An alkyl group;
R2' Definitions and R2Is the same, and when R is2When it is hydrogen, R2' is deuterium;
R3is hydrogen, substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20Heteroaryl, substituted or unsubstituted C3-20Cycloalkyl, substituted or unsubstituted C6-20aryl-C1-20An alkyl group;
wherein the substituent in the "substituted or unsubstituted" is selected from halogen, C1-6Alkoxy radical, C1-6Alkyl, -CN, -NO2Halogen substituted C1-6Alkyl radical, C1-6One or more alkylthio groups.
3. The method of claim 1, wherein the amino acid ester compound of formula I has the following structure:
Figure 483940DEST_PATH_IMAGE003
Figure 935781DEST_PATH_IMAGE005
Figure 767208DEST_PATH_IMAGE006
。
4. a method for preparing deuterated amino acid esters by photocatalysis is characterized in that deuterated water and amino acid ester compounds of formula I-1 are used as reaction raw materials, catalytic amount of Lewis acid, tetraphenylphosphonium chloride, tetraphenylboron salt, borane derivatives and aluminum oxide are used as composite catalysts, and the deuterated amino acid esters of formula II-1 are obtained by room-temperature reaction under the protection of nitrogen and ultraviolet light, wherein the general reaction formula is as follows:
Figure DEST_PATH_IMAGE007
。
5. The method according to any one of claims 1 or 4, characterized by the following specific steps:
dissolving a certain amount of amino acid ester compounds in deuterium water, adding a composite catalyst, and adding N2Fully and uniformly stirring under protection;
the power is 5W-100W, the wavelength is under the irradiation of an ultraviolet lamp with the wavelength of 265-400nm, and the reaction is fully carried out for 0.5-24h at the temperature of 15-35 ℃;
after the reaction is finished, filtering to remove the catalyst, extracting with a solvent with ethyl acetate/water =1:1 or butyl acetate/water volume ratio =1:1, and taking an organic phase;
and separating by column chromatography to obtain the deuterated amino acid ester compound.
6. The method according to claim 5, wherein the molar ratio of the amino acid ester compound to deuterium water in step (1) is 1:50 to 100.
7. The method according to claim 5, wherein the molar ratio between the amino acid ester compound and the composite catalyst in step (1) is, in order: n (amino acid ester compound): n (Lewis acid): n (tetraphenylphosphonium chloride): n (tetraphenylboron salt): n (borane): n (alumina) =1: 0.00005-0.5: 0.00005-0.5: 0.00005-0.5: 0.00005-0.5: 0.00005-0.5.
8. The method according to claim 5, wherein the Lewis acid is FeCl 3，HCl，H2SO4，CuCl2，AgNO3And the like.
9. The preparation method according to claim 5, wherein the tetraphenylboron salt is one or more of sodium tetraphenylboron, potassium tetraphenylboron, lithium tetraphenylboron, rubidium tetraphenylboron and cesium tetraphenylboron.
10. The process of claim 5, wherein the borane derivative is BnHn 2-，BnHn+1 -，BnHn+2，CaBn−aHn−a+2Wherein n is one of 6, 7, 8, 9, 10, 12, 20 and 24, a is one of 1, 2, 3 and 4; if coordination of the borane derivative with a cation is desired, the cation is one or more of the metal cations, such as Li, Na, K, Ru, Cs, Mg or Al.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050084452A1 (en) * 2001-12-19 2005-04-21 Japanese Science And Technology Agency Stable isotope-labeled amino acid and method for incorporating same into target protein
CN110885294A (en) * 2019-12-04 2020-03-17 重庆市中药研究院 Method for preparing chiral amino acid ester and chiral deuterated amino acid ester
CN111004076A (en) * 2019-12-16 2020-04-14 云南民族大学 Method for preparing deuterated amino acid ester by using deuterium source as deuterium source
CN112358412A (en) * 2020-10-23 2021-02-12 云南民族大学 Preparation method of chiral deuterated amino acid ester compound
CN113200895A (en) * 2021-04-28 2021-08-03 云南民族大学 Method for preparing chiral deuterated methionine by using deuterium source as deuterium source
CN113214099A (en) * 2021-04-14 2021-08-06 重庆市中药研究院 Preparation method of deuterated amino acid ester compound
WO2021158781A1 (en) * 2020-02-06 2021-08-12 Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for practical synthesis of deuterated amino acids

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050084452A1 (en) * 2001-12-19 2005-04-21 Japanese Science And Technology Agency Stable isotope-labeled amino acid and method for incorporating same into target protein
CN110885294A (en) * 2019-12-04 2020-03-17 重庆市中药研究院 Method for preparing chiral amino acid ester and chiral deuterated amino acid ester
CN111004076A (en) * 2019-12-16 2020-04-14 云南民族大学 Method for preparing deuterated amino acid ester by using deuterium source as deuterium source
WO2021158781A1 (en) * 2020-02-06 2021-08-12 Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for practical synthesis of deuterated amino acids
CN112358412A (en) * 2020-10-23 2021-02-12 云南民族大学 Preparation method of chiral deuterated amino acid ester compound
CN113214099A (en) * 2021-04-14 2021-08-06 重庆市中药研究院 Preparation method of deuterated amino acid ester compound
CN113200895A (en) * 2021-04-28 2021-08-03 云南民族大学 Method for preparing chiral deuterated methionine by using deuterium source as deuterium source

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HARUKA OHTSUKI等: "Direct asymmetric synthesis of a-deuterated a-amino acid derivatives from the parent a-amino acids via memory of chirality", 《TETRAHEDRON LETTERS》 *
STEPHEN G. DAVIES等: "Asymmetric conjugate reductions with samarium diiodide: asymmetric synthesis of (2S,3R)- and (2S,3S)- [2-2H,3-2H]-leucine-(S)-phenylalanine dipeptides and (2S,3R)-[2-2H,3-2H]-phenylalanine methyl ester", 《ORG.BIOMOL.CHEM.》 *

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