CN113200895A - Method for preparing chiral deuterated methionine by using deuterium source as deuterium source - Google Patents
Method for preparing chiral deuterated methionine by using deuterium source as deuterium source Download PDFInfo
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Abstract
The invention discloses a method for preparing chiral deuterated methionine by using deuterium source as deuterium source, which is characterized in thatN- (tert-butyloxycarbonyl) -dehydromethionine ester and heavy water are used as reaction raw materials, transition metal, Lewis acid and chiral ligand are used as catalysts, and the chiral raw materials are synthesized by reduction reaction in an organic solvent under the action of a reducing agentN- (tert-butyloxycarbonyl) -methionine ester, finally obtaining the chiral deuterated methionine through acid deprotection. The method adopts a metal/Lewis acid concerted catalysis system, takes heavy water as a unique deuterium source, prepares the chiral deuterated methionine through the asymmetric hydrogenation reaction of the alpha-dehydromethionine, and compared with the prior common heavy water exchange method, the method has the advantages that the reaction temperature can be reduced from 150 ℃ to 60 ℃, and the weight is higherThe water amount is only 200 percent of the mole percent of the dehydroamino acid ester compound, and the condition is milder without the atmosphere of heavy water as a solvent. Compared with the traditional deuterium source, the deuterium source of the invention has the advantages of simple operation, high atom economy and high deuterium doping rate and enantioselectivity of chiral deuterated methionine.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing chiral deuterated methionine by using deuterium as a deuterium source.
Background
Methionine is one of essential amino acids constituting the human body, and is involved in protein synthesis. For the human body, methionine plays a very important role: 1. is one of the main components of amino acid transfusion and compound amino acid. 2. Methionine can be used for synthesizing medicinal vitamins, nutritional supplement, and feed additive. 3. Methionine is one of eight essential amino acids and is involved in the metabolism of life. Methionine is not produced in vivo by itself and must be obtained from the outside. Therefore, the synthesis and production of methionine have great application value and prospect. The preparation of deuterated methionine can be used for the in vivo metabolic tracing research so as to diagnose diseases. In biological studies, the structural relationship between deuterated methionine and natural products is utilized to explore biosynthetic pathways and mechanisms in vivo.
At present, the synthesis technology of deuterated methionine is not mature, and the problems of complex synthesis steps or harsh synthesis conditions exist, so that the huge application value and market value of the deuterated methionine cannot be met.
Disclosure of Invention
The invention aims to provide a simple and efficient method for preparing chiral deuterated methionine by using deuterium as a deuterium source, which has high atom economy.
The invention aims to realize that a method for preparing chiral deuterated methionine by using deuterium as a deuterium source is to use deuteriumN- (tert-butyloxycarbonyl) -dehydromethionine ester and heavy water are used as reaction raw materials, transition metal, Lewis acid and chiral ligand are used as catalysts, and the chiral raw materials are synthesized by reduction reaction in an organic solvent under the action of a reducing agentN- (tert-butyloxycarbonyl) -methionine ester, and finally carrying out acid deprotection to obtain a target product, namely chiral deuterated methionine, wherein the reaction formula is as follows:
the invention has the beneficial effects that:
1. compared with the existing common heavy water exchange method, the method can reduce the reaction temperature from 150 ℃ to 60 ℃, the heavy water amount is only 200 percent of the mole percentage of the dehydro-amino acid ester compound, the method does not need to be in the atmosphere using the heavy water as a solvent, and the condition is milder.
2. Conventional deuterium transfer agents such as deuterated methanol, deuterated sodium borate, deuterated tetrahydrofuran, lithium aluminum tetradeuterolate and deuterated sodium formate have the disadvantages of high price, low atom utilization rate, flammability and explosiveness.
Compared with the traditional deuterium source, the deuterium source of the invention is prepared from deuterium, and has the advantages of simple operation, high atom economy, high deuterium doping rate of 96% and high enantioselectivity of 98%, thus providing a new idea and way for the synthesis of chiral deuterated methionine.
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 preparing chiral deuterated methionine by using deuterium source as deuterium source, which comprises the following stepsN- (tert-butyloxycarbonyl) -dehydromethionine ester and heavy water are used as reaction raw materials, transition metal, Lewis acid and chiral ligand are used as catalysts, and the chiral raw materials are synthesized by reduction reaction in an organic solvent under the action of a reducing agentN- (tert-butyloxycarbonyl) -methionine ester, and finally carrying out acid deprotection to obtain a target product, namely chiral deuterated methionine, wherein the reaction formula is as follows:
wherein the catalyst is transition metal, Lewis acid and chiral ligand.
The dosage of the heavy water, the transition metal, the chiral ligand, the Lewis acid and the reducing agent is respectively 50 to 500 percent, 0.01 to 100 percent, 0.01 to 200 percent, 0.01 to 100 percent and 50 to 500 percent of the mole percentage of the dehydroamino acid ester compound.
Preferably, the heavy water, the transition metal, the chiral ligand, the lewis acid and the reducing agent are respectively used in the molar percentages of 200%, 0.01%, 0.012%, 0.01% and 300% of the dehydroamino acid ester compound.
The dosage of the organic solvent is 0.1mol/L-10mol/L, preferably 0.2mol/L of the molar concentration of the dehydroamino acid ester compound.
The transition metal is Pd (OAc)2、Ni(OTf)2、Co(OAc)2、[Ir(COD)Cl]2、RhCl3·3H2O、 Rh(COD)2BF4、 Rh2(OAc)4Or [ RhCl (COD)]2Preferably Pd (OAc)2。
The chiral ligand is: (R)-Seghos、(R)-Binap、(R,R)-BDPP、(R)-Synphos, (R)-P-Phos、(R)-SDP、(R, R) -PhBox or (R) Oxazline, preferably (A)R, R)-PhBox。
The Lewis acid is HB (C)6F5)2、B(C6F5)3、 BF3、 ZnI2、AgOTf、AgBF4Or Cu (OTf)2Preferably AgOTf.
The reducing agent is an inorganic reducing agent, an organic reducing agent or a metal simple substance reducing agent.
The inorganic reducing agent is S8Or H2S; the organic reducing agent is vitamin C (ascorbic acid) or benzaldehyde derivatives; the metal simple substance reducing agent is Fe, Cu, Zn or Na.
The organic solvent is toluene, tetrahydrofuran, tetrahydropyran, methyl tert-butyl ether, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or N, N-dimethylformamide, preferably 1, 2-dichloroethane.
The temperature of the reduction reaction is-50 ℃ to 140 ℃, and preferably 60 ℃.
The invention is further illustrated by the following examples:
example 1
In a water-free and oxygen-free glove box under argon atmosphere, Pd (OAc)2 (0.001 mmol)、(R, R) PhBox (0.0012 mmol), AgOTf (0.002 mmol), Fe (0.6 mmol) andαthe dehydroamino acid ester (0.2 mmol) was added to a 10 mL reaction tube in sequence, followed by 2 mL DCE (1, 2-dichloroethane), and then heavy water (0.4 mmol) was added and taken out of the glove box. Reaction in a 60 ℃ oil bath, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, passing through a silica gel column to obtain white solid, namely chiral N- (tert-butyloxycarbonyl) -methionine ester, wherein the yield is 95 percent,eethe value was 98%, 96% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.1H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.1H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
The above white solid was added to a round bottom flask, a mixed solvent of TFA (0.9 mL) and dichloromethane (1 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction solution was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(5 mL) was refluxed overnight and the reaction was monitored by LCMS until demethylation protection was complete to give a slurry, the pH of the slurry was adjusted to 5.5 by the addition of 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine in 75% yield with 96% deuterated incorporation unchanged and 98% enantioselectivity unchanged.1H NMR (400 MHz, D2O): δ4.11(0.04H, t), 2.89 (2H, t), 2.05 (4.04H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 2
In a dry, oxygen-free glove box under argon atmosphere, [ RhCl (COD)]2 (0.002 mmol)、(R)-Seghos (0.0024 mmol)、HB(C6F5)3 (0.01mmol)、S8(0.1 mmol) andαthe dehydroamino acid ester (0.1 mmol) was added to a 10 mL reaction tube in sequence, followed by 2 mL tetrahydrofuran and then heavy water (0.1 mmol) and taken out of the glove box. Reaction in an oil bath at-50 deg.C, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield is 20 percent,eethe value was 88%, 85% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.15H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.15H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (0.9 mL) and dichloromethane (1 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction solution was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the deuterated methionine A without Boc into a round-bottom flaskEster, and adding 4N H2SO4(5 mL) was refluxed overnight and reaction was checked by LCMS until demethylation protection was complete to give a slurry, pH of the slurry was adjusted to 5.5 by addition of 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine in 75% yield with no change in 85% deuterium incorporation and no change in 88% enantioselectivity.1H NMR (400 MHz, D2O): δ4.11(0.15H, t), 2.89 (2H, t), 2.05 (4.15H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 3
Step 1: in a water-free and oxygen-free glove box under argon atmosphere, Ni (OTf)2 (0.01 mmol)、(R)-Binap (0.012 mmol)、B(C6F5)3 (0.2 mmol)、H2S (0.8mmol) andαthe dehydroamino acid ester (0.3 mmol) was added to a 10 mL reaction tube in sequence, followed by 2 mL tetrahydrofuran and then water (0.8mmol) and taken out of the glove box. Reaction in an oil bath at 80 ℃, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield was 75%,eethe value was 88%, 87% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.13H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.13H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (1.8 mL) and dichloromethane (2 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction solution was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(5 mL) reflux overnight and detection by LCMS until demethylation protection was complete to give a slurry, which was slurried with 4N NaOHAdjusting the H to 5.5, stirring and filtering the mixed solution, and concentrating the filtrate to obtain the target product deuterated methionine, wherein the yield is 75%, the deuterated doping rate is not changed by 87%, and the enantioselectivity is not changed by 88%.1H NMR (400 MHz, D2O): δ4.11(0.13H, t), 2.89 (2H, t), 2.05 (4.13H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 4
Step 1: in a water-free and oxygen-free glove box under argon atmosphere, Co (OAc)2 (0.12 mmol)、(R,R)-BDPP (0.16 mmol)、BF3(0.26 mmol), vitamin C (0.1 mmol) andαthe dehydroamino acid ester (0.5 mmol) was added to a 10 mL reaction tube in sequence, followed by addition of 2 mL of toluene and addition of heavy water (1 mmol) and taken out of the glove box. Reaction in 50 ℃ oil bath, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield was 65%,eethe value was 70%, 87% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.13H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.13H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (1.8 mL) and dichloromethane (2 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction solution was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(5 mL) was refluxed overnight and reaction was detected by LCMS until demethylation protection was complete to give a slurry, pH of the slurry was adjusted to 5.5 by adding 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine with a yield of 75% and with a deuterated incorporation of 87% unchanged and an enantioselectivity of 70% unchanged.1H NMR (400 MHz, D2O): δ4.11(0.13H, t), 2.89 (2H, t), 2.05 (4.13H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 5
Step 1: in an anhydrous oxygen-free glove box under argon atmosphere, RhCl is added3·3H2O (1 mmol)、(R)-Synphos (1.2 mmol)、ZnI2(1 mmol), benzaldehyde (2 mmol) andαthe dehydroamino acid ester (1 mmol) was added to a 10 mL reaction tube in sequence followed by 5 mL methyl tert-butyl ether and then by addition of heavy water (5 mmol) and taken out of the glove box. Reaction in a 70 ℃ oil bath, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield is 50 percent,eethe value was 46%, 80% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.2H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.2H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (4.5 mL) and dichloromethane (5 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(10 mL) was refluxed overnight and reaction was checked by LCMS until demethylation protection was complete to give a slurry, pH of the slurry was adjusted to 5.5 by adding 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine with a yield of 75% and 80% unchanged deuterated incorporation and 46% unchanged enantioselectivity.1H NMR (400 MHz, D2O): δ4.11(0.2H, t), 2.89 (2H, t), 2.05 (4.2H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 6
Step 1: in a water-free and oxygen-free glove box under argon atmosphere, Rh (COD)2BF4 (0.1 mmol)、(R)-P-Phos (0.12 mmol)、AgBF4(0.05 mmol), Cu (0.5 mmol) andαthe dehydroamino acid ester (0.2 mmol) was added to a 10 mL reaction tube in sequence, followed by 2 mL of 1, 4-dioxane, and then heavy water (0.7 mmol) and taken out of the glove box. Reaction in 100 ℃ oil bath, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield was 79%,eethe value was 65%, 80% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.2H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.2H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (0.9 mL) and dichloromethane (1 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction solution was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(5 mL) was refluxed overnight and reaction was checked by LCMS until demethylation protection was complete to give a slurry, pH of the slurry was adjusted to 5.5 by adding 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine with a yield of 75% and 80% unchanged deuterated incorporation and 65% unchanged enantioselectivity.1H NMR (400 MHz, D2O): δ4.11(0.2H, t), 2.89 (2H, t), 2.05 (4.2H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 7
Step 1: in an anhydrous oxygen-free glove box under argon atmosphere, [ Ir (COD) Cl]2 (0.2 mmol)、(R)-SDP (0.24 mmol)AgOTf (0.2 mmol), Zn (1 mmol) andαthe dehydroamino acid ester (1 mmol) was added to a 10 mL reaction tube in sequence followed by 2 mL dichloromethane and then heavy water (2 mmol) and taken out of the glove box. Reaction in a 20 ℃ oil bath, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield was 78%,eethe value was 30%, 50% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.5H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.5H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7。
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (4.5 mL) and dichloromethane (5 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(10 mL) was refluxed overnight and reaction was checked by LCMS until demethylation protection was complete to give a slurry, pH of the slurry was adjusted to 5.5 by adding 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine with 75% yield, 50% deuterated incorporation without change, and 30% enantioselectivity without change.1H NMR (400 MHz, D2O): δ4.11(0.5H, t), 2.89 (2H, t), 2.05 (4.5H, m).13C NMR (100 MHz, D2O):δ163.7, 42.7, 19.5, 18.7, 3.8。
Example 8
Step 1: in a water-free and oxygen-free glove box under argon atmosphere, Rh is added2(OAc)4 (0.1 mmol)、(R)-Oxazline (0.24 mmol)、Cu(OTf)2(0.2 mmol), Na (0.6 mmol) andαthe dehydroamino acid ester (0.2 mmol) was added to a 10 mL reaction tube in sequence followed by 2 mLN, NDimethylformamide, with addition of heavy water: (1 mmol) were taken out of the glove box. Reaction in 140 ℃ oil bath, TLC monitoring and I2Detecting the reaction in a color development mode, concentrating after the reaction is finished, and passing through a silica gel column to obtain a white solid. The yield is 80 percent,eethe value was 88%, 80% deuterium incorporation efficiency.1 H NMR (400 MHz, CDCl3): δH = 1.32 (9H, s), 1.82 (0.2H, dq), 1.93-2.06 (4H, m), 2.42 (2H, t), 3.63 (3H, s), 4.29 (0.2H, m), 5.27 (1H, d). 13C NMR (100 MHz, CDCl3): δC = 15.3, 28.2, 29.9, 31.9, 52.2, 52.6, 79.7, 155.3, 172.7.
Step 2: the above white solid was added to a round bottom flask, a mixed solvent of TFA (0.9 mL) and dichloromethane (1 mL) was added, stirred at room temperature, and the reaction was checked using LCMS until the Boc removal reaction was complete, the reaction solution was rotary concentrated, and the solvent was removed. The concentrated material was dissolved in ethyl acetate and 5% Na2CO3Adjusting the pH value of the solution to 8, and removing the solvent to obtain the Boc-removed deuterated methionine methyl ester with the yield of 90%. Adding the de-Boc deuterated methionine methyl ester into a round-bottom flask, and adding 4N H2SO4(5 mL) was refluxed overnight and reaction was checked by LCMS until demethylation protection was complete to give a slurry, pH of the slurry was adjusted to 5.5 by addition of 4N NaOH, the mixed solution was stirred and filtered, and the filtrate was concentrated to give the desired product deuterated methionine with 75% yield, 80% deuterated incorporation unchanged and 88% enantioselectivity unchanged.1H NMR (400 MHz, D2O): δ4.11(0.2H, t), 2.89 (2H, t), 2.05 (4.2H, m). 13C NMR (100 MHz, D2O): δ163.7, 42.7, 19.5, 18.7, 3.8。
Claims (10)
1. A method for preparing chiral deuterated methionine by using deuterium source as deuterium source is characterized in thatN- (tert-butyloxycarbonyl) -dehydromethionine ester and heavy water are used as reaction raw materials, transition metal, Lewis acid and chiral ligand are used as catalysts, and the chiral raw materials are synthesized by reduction reaction in an organic solvent under the action of a reducing agentN- (tert-butyloxycarbonyl) -methionine ester, and finally carrying out acid deprotection to obtain a target product, namely chiral deuterated methionine, wherein the reaction formula is as follows:
2. the method for preparing chiral deuterated methionine by using deuterium oxide as a deuterium source as claimed in claim 1, wherein the amounts of deuterium oxide, transition metal, chiral ligand, lewis acid and reducing agent are 50% -500%, 0.01% -100%, 0.01% -200%, 0.01% -100% and 50% -500% respectively based on the molar percentage of the dehydroamino acid ester compound.
3. The method for preparing chiral deuterated methionine using heavy water as deuterium source as claimed in claim 1, wherein the organic solvent is used in an amount of 0.1-10 mol/L of the molar concentration of the dehydroamino acid ester compound.
4. The method for preparing chiral deuterated methionine by using deuterium as a deuterium source as claimed in claim 1 or 2, wherein the transition metal is Pd (OAc)2、Ni(OTf)2、Co(OAc)2、[Ir(COD)Cl]2、RhCl3·3H2O、 Rh(COD)2BF4、 Rh2(OAc)4Or [ RhCl (COD)]2。
5. The method for preparing chiral deuterated methionine using deuterium as a deuterium source according to claim 1 or 2, wherein the chiral ligand is (A)R)-Seghos、(R)-Binap、(R,R)-BDPP、(R)-Synphos, (R)-P-Phos、(R)-SDP、(R, R) -PhBox or (R)-Oxazline。
6. The method for preparing chiral deuterated methionine using deuterium as a deuterium source according to claim 1 or 2, wherein the lewis acid is HB (C)6F5)2、B(C6F5)3、 BF3、 ZnI2、AgOTf、AgBF4Or Cu (OTf)2。
7. The method for preparing chiral deuterated methionine by using deuterium as a source of deuterium as claimed in claim 1 or 2, wherein said reducing agent is an inorganic reducing agent, an organic reducing agent or a metallic simple substance reducing agent.
8. The method for preparing chiral deuterated methionine using deuterium as a deuterium source as claimed in claim 7, wherein said inorganic reducing agent is S8Or H2S; the organic reducing agent is ascorbic acid or benzaldehyde derivatives; the metal simple substance reducing agent is Fe, Cu, Zn or Na.
9. The method for preparing chiral deuterated methionine using heavy water as a deuterium source according to claim 1 or 3, wherein the organic solvent is toluene, tetrahydrofuran, tetrahydropyran, methyl tert-butyl ether, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or N, N-dimethylformamide.
10. The method for preparing chiral deuterated methionine using deuterium as a deuterium source as claimed in claim 1, wherein the temperature of the reduction reaction is-50 ℃ to 140 ℃.
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| CN114751801A (en) * | 2022-05-20 | 2022-07-15 | 安徽贵朋功能材料科技有限公司 | Method for preparing deuterated amino acid esters by photocatalysis |
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| CN114751801A (en) * | 2022-05-20 | 2022-07-15 | 安徽贵朋功能材料科技有限公司 | Method for preparing deuterated amino acid esters by photocatalysis |
| 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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