CN113292393A - Method for synthesizing alpha, alpha-dideuterol and deuterated drugs by reducing and deuterating acyl fluoride compounds - Google Patents
Method for synthesizing alpha, alpha-dideuterol and deuterated drugs by reducing and deuterating acyl fluoride compounds Download PDFInfo
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Abstract
The invention relates to an alpha, alpha-dideuterol compound and a reduction deuteration method of an acyl fluoride compound for preparing the alpha, alpha-dideuterol compound, which is characterized in that the acyl fluoride compound shown in a general formula (1) reacts with a bivalent lanthanide series transition metal compound and a deuterium donor reagent in an organic solvent I to generate the alpha, alpha-dideuterol compound shown in a general formula (2). The invention provides a reduction deuteration method of acyl fluoride compounds based on single electron transfer reduction deuteration reaction, which solves the problems of using flammable reducing agent, poor selectivity, poor atom economy and the like in the preparation of alpha, alpha-dideuterol compounds in the prior art. The method can be used for preparing the alpha, alpha-dideuterol compounds and has the advantages of high deuteration rate of the product, good zone selectivity, good chemical selectivity, low reagent price, simple operation, mild condition and wide application range of the substrate.
Description
Technical Field
The invention relates to alpha, alpha-dideuterol, a deuterated drug and a reduction deuteration method of an acyl fluoride compound for synthesizing the alpha, alpha-dideuterol compound.
Background
Deuterated organic compounds are widely used in the fields of life science, material science, instrument analysis, organic reaction mechanism research and the like. Because of the kinetic isotope effect (DKIE), the C-D bond is more stable, and deuterium introduced into a drug molecule can improve the kinetic characteristics of the drug, reduce metabolic toxicity and improve the activity of the drug. The research and development of deuterated drugs gradually become a hot field. Alcohol compounds and their derivatives are important fragments for the synthesis of many active compounds. The synthesis of deuterium labeled drugs and other active molecules is of great significance for the metabolism and toxicological studies of drugs and the development of new drugs. Therefore, the synthesis of the alpha, alpha-dideuterol compounds is of great significance to the research and development of deuterated drugs.
The synthesis of α, α -dideuterol mainly uses the introduction of deuterium into a specific position in the molecule by reducing deuterated carboxylic acids and their derivatives, the conventional reductive deuteration using metal deuterides (e.g. NaBD)4And LiAlD4) As a reducing agent, the reaction has the advantages of high deuteration rate, good regioselectivity and the like, but metal deuterides are expensive and flammable, and the application range of the reaction is limited (Molecules,2015,20(9): 16741). In contrast, the one-electron transfer reduction of deuterated esters to synthesize α, α -dideuterol is a more attractive strategy, allowing higher deuteration rates and good regioselectivity to be achieved using less expensive reagents and relatively safe conditions. However, recently reported alkali/deuterated alcohols and Smi2/D2O/Et3N reduction deuteration systems (j.org.chem.2017,82,1285, chem.commun.2011,47,10254.) have mild conditions and high deuteration rate, but the reduction capability of the systems is strong, and many sensitive groups are, for example: halogen, olefinic bond, acetylene bond, cyano and the like are reduced, and the selectivity of the reaction is poor. Reported in our as Smi2/D2In the method for selectively synthesizing alpha, alpha-dideuterol by reducing deuterated pentafluorophenol ester by using O as a medium, sensitive functional groups are not reduced, so that a novel method is provided for synthesizing alpha, alpha-dideuterol with various functional groups. However, pentafluorophenol ester as a carboxylic acid derivative is reductively deuterated to produce α, α -dideuterol, which is a reaction atom less economical, and pentafluorophenol as a by-product is produced. As carboxylic acid derivatives, reductive deuteration of acyl fluorides to α, α -dideuterol has never been reported, and the atom economy is greatly improved in comparison. Therefore, the development is more efficientThe reaction of selective formation of alpha, alpha-dideuterol by reductive deuteration of an economical carboxylic acid derivative is extremely important.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide
The invention provides a reduction deuteration method of acyl fluoride compounds based on single electron transfer reduction deuteration reaction, which aims to solve the problems of using flammable reducing agent, poor selectivity, poor atom economy and the like in the preparation of alpha, alpha-dideuterol compounds in the prior art. The method can be used for preparing the alpha, alpha-dideuterol compounds and has the advantages of high deuteration rate of the product, good zone selectivity, good chemical selectivity, low reagent price, simple operation, mild condition and wide application range of the substrate.
The synthesis method of the alpha, alpha-dideuterol compound shown in the general formula (2) is characterized in that the acyl fluoride compound shown in the general formula (1) reacts with a bivalent lanthanide series transition metal compound and a deuterium donor reagent in an organic solvent I to generate the alpha, alpha-dideuterol compound shown in the general formula (2);
in the general formula (1), R1Selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl; r1Wherein the substituent is alkyl, halogen, alkoxy, alkylthio, trifluoroalkyl and ester group.
The deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof.
A method for synthesizing alpha, alpha-dideuteroalcohol compounds represented by the general formula (2) is characterized by comprising the following steps:
step 1: after argon protection is carried out on the reactor, constant temperature treatment is carried out, and organic solvent I is added to prepare divalent lanthanide series transition metal compound solution;
step 2: preparing a solution from an acyl fluoride compound and an organic solvent I, and adding the solution into a reactor;
and step 3: adding a deuterium donor reagent to the reactor;
and 4, step 4: stirring the mixed solution for a certain time, and then quenching the reaction;
and 5: adding an organic solvent II and an acid solution for extraction, drying and concentrating an organic phase, and purifying to obtain a compound with a general formula (2);
preferably, in step 1, the reactor is a round-bottom flask;
preferably, in step 1 and step 2, the same organic solvent is used;
preferably, in step 3, a quantitative amount of deuterium donor reagent is added to the reactor under constant temperature conditions;
preferably, in step 4, the stirring is vigorous stirring;
preferably, in step 4, the quenching reaction is carried out by introducing air;
preferably, the step 5 is adding ethyl acetate and hydrogen chloride solution (1M) for extraction, drying and concentrating the organic phase, and performing column chromatography to obtain the compound of the general formula (2)
The deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof;
preferably, the deuterated alcohol is one in which the hydroxyl group is deuterated;
preferably, the deuterium donor reagent is heavy water (D)2O), deuterated methanol (MeOD), deuterated ethanol (EtOD), deuterated n-propanol (n-PrOD), deuterated isopropanol (i-PrOD), deuterated n-butanol (n-BuOD) and deuterated tert-butanol (t-BuOD);
more preferably, the deuterium donor reagent is heavy water (D)2O)。
The divalent lanthanide transition metal compound is selected from one or the combination of more than two of a divalent samarium compound, a divalent dysprosium compound, a divalent neodymium compound, a divalent ytterbium compound, a divalent cerium compound and a divalent europium compound;
preferably, the divalent lanthanide transition metal compound is selected from samarium diiodide (SmI)2) Dysprosium diiodide (DyI)2) Neodymium diiodide (NdI)2) Ytterbium diiodide (YbI)2) Cerium diiodide (CeI)2) And europium (II) perchlorate (Eu (ClO)4)2) One or two or more kinds ofCombining;
preferably, the divalent lanthanide transition metal compound is samarium diiodide (SmI)2)。
The organic solvent I is selected from one or the combination of more than two of micromolecular alkane, naphthenic hydrocarbon, aromatic hydrocarbon, ether and cyclic ether solvents;
preferably, the organic solvent I is one or a combination of more than two of n-hexane, n-pentane, hexane, cyclohexane, toluene, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;
preferably, the organic solvent I is tetrahydrofuran.
The ratio of the organic solvent I to the acyl fluoride compound is 1 mL: 1-300 mg.
The reaction temperature is-40 to 60 ℃; the reaction time is 0.1-60 min.
Deuterated cinacalcet and deuterated 2, 4-D-2-ethylhexyl ester synthesized by using alpha, alpha-dideuterol compounds shown as a general formula (2) as raw materials.
Preferably, the α, α -dideuteroalcohol compound represented by the general formula (2) is characterized in that: the following specific formula (2) compound, preferably the following specific formula (2) compound:
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention.
Example 1
To a 100mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)50.0mL of a solution in tetrahydrofuran (0.100mol/L), 150mg (1.00mmol) of Compound 1a, and 601mg (30.0mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reactionShould be used. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 131mg of a target compound 2a, wherein the yield is 95%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2a obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.33–7.24(m,2H),7.21–7.16(m,3H),2.71(t,J＝7.7Hz,2H),1.88(t,J＝7.7Hz,2H),1.43(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ141.9,128.5(×2),125.9,61.6(m),34.1,32.1.
example 2
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 54.7mg (0.300mmol) of Compound 1b, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 49.5mg of a target compound 2b, wherein the yield is 98%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2b obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.11(m,2H),6.83(m,2H),3.78(s,3H),2.64(t,J＝7.7Hz,2H),1.84(t,J＝7.7Hz,2H),1.70(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ157.8,133.9,129.4,113.9,61.5(m),55.3,34.3,31.1.
example 3
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2) Solution in tetrahydrofuran (0.100mol/L)15.0mL, Compound1c 49.9mg (0.300mmol), 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 44.8mg of a target compound 2c, wherein the yield is 98 percent, and the deuteration rate is 98 percent.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2c obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.11–7.07(m,4H),2.66(t,J＝7.8Hz,2H),2.31(s,3H),1.85(t,J＝7.8Hz,2H),1.65(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ138.8,135.4,129.1,128.4,61.6(m),34.2,31.6,21.0.
example 4
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 51.1mg (0.300mmol) of the compound 1d, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 45.9mg of a target compound 2d, wherein the yield is 98% and the deuteration rate is 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2d obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.14(m,2H),6.96(m,2H),2.68(t,J＝7.8Hz,2H),1.85(t,J＝7.8Hz,2H),1.51(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ161.3(d,JC-F＝243.5Hz),137.5(d,JC-F＝2.9Hz),129.8(d,JC-F＝7.5Hz),115.2(d,JC-F＝21.1Hz),61.4(m),34.2,31.2.
example 5
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 56.0mg (0.300mmol) of compound 1e, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 50.2mg of a target compound 2e, wherein the yield is 97%, and the deuteration rate is 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2e obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.24(m,2H),7.12(m,2H),2.67(t,J＝7.7Hz,2H),1.84(t,J＝7.7Hz,2H),1.62(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ140.3,131.6,129.8,128.5,61.3(m),33.9,31.4.
example 6
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 69.3mg (0.300mmol) of the compound 1f, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 62.5mg of a target compound 2f, wherein the yield is 96 percent, and the deuteration rate is 98 percent.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2f obtained by the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.39(m,2H),7.07(m,2H),2.65(t,J＝7.7Hz,2H),1.84(t,J＝7.7Hz,2H),1.67(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ140.8,131.5,130.3,119.6,61.3(m),33.8,31.4.
example 7
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 84.4mg (0.300mmol) of the compound 1g, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 80.1mg of a target compound 2g, wherein the yield is 96 percent, and the deuteration rate is 98 percent.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on 2g of the target product obtained by the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.59(m,2H),6.95(m,2H),2.65(t,J＝7.7Hz,2H),1.84(t,J＝7.7Hz,2H),1.62(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ141.5,137.5,130.6,90.9,61.5(m),33.8,31.6.
example 8
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 1h 59.5mg (0.300mmol) of the compound, and 180mg of heavy water (9.00 mmol). The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 54.2mg of a target compound, namely the target compound for 2h, wherein the yield is 98 percent, and the deuteration rate is 98 percent.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2h obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.20(m,2H),7.12(m,2H),2.66(t,J＝7.7Hz,2H),2.46(s,3H),1.84(t,J＝7.7Hz,2H),1.67(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ139.0,135.4,129.0,127.2,61.4(m),34.0,31.5,16.4.
example 9
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 58.3mg (0.300mmol) of Compound 1i, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 37.9mg of a target compound 2i, wherein the yield is 70%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2i obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.33(m,2H),7.15(m,2H),2.80(s,2H),1.86(br,1H),1.30(s,9H)；13C{1H}NMR(126MHz,CDCl3)δ149.3,135.4,128.7,125.5,62.9(m),38.5,34.4,31.4.
example 10
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 46.2mg (0.300mmol) of the compound 1j, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 41.2mg of a target compound 2j, wherein the yield is 98%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2j obtained by the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.27(m,2H),6.89(m,2H),3.80(s,3H),1.84(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ159.3,133.1,128.7,114.0,64.4(m),55.4.
example 11
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 51.1mg (0.300mmol) of compound 1k, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 42.2mg of a target compound 2k, wherein the yield is 90%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2k obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.39–7.08(m,4H),2.48(s,3H),1.76(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ137.9,137.7,127.7,126.9,64.3(m),16.0.
example 12
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 50.2mg (0.300mmol) of the compound 1L, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M sodium hydroxide solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 41.4mg of a target compound 2l, wherein the yield is 90%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2l obtained by the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.24(m,2H),6.72(m,2H),2.94(s,6H),1.61(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ150.4,128.9,128.7,112.7,64.7(m),40.7.
example 13
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 54.7mg (0.300mmol) of the compound 1m, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 49.5mg of a target compound 2M, wherein the yield is 98% and the deuteration rate is 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2m obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ1.99(m,3H),1.75–1.72(m,3H),1.67–1.63(m,3H),1.51(m,6H),1.41(br,1H)；13C NMR(126MHz,CDCl3)δ73.1(m),39.1,37.3,34.4,28.2.
example 14
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 55.3mg (0.300mmol) of the compound 1n, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 50.1mg of a target compound 2n, wherein the yield is 98%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2n obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ2.18(td,J＝7.1,2.6Hz,2H),1.94(t,J＝2.6Hz,1H),1.63(br,1H),1.58–1.48(m,4H),1.41–1.27(m,10H)；13C{1H}NMR(126MHz,CDCl3)δ84.8,68.1,62.3(m),32.6,29.5,29.4,29.1,28.8,28.5,25.7,18.4.
example 15
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 1o 57.1mg (0.300mmol) of the compound, and 180mg of heavy water (9.00 mmol). The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain a target compound 2o of 42.3mg, wherein the yield is 80%, and the deuteration rate is 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2o obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ3.67(s,3H),2.31(t,J＝7.5Hz,2H),1.63(m,2H),1.54(m,2H),1.37–1.32(m,6H)；13C{1H}NMR(126MHz,CDCl3)δ174.4,62.2(m),51.5,34.1,32.5,29.1(×2),25.5,24.9.
example 16
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 77.5mg (0.300mmol) of Compound 1p, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 68.2mg of a target compound 2p, wherein the yield is 93 percent and the deuteration rate is 98 percent.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2p obtained by the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ1.55(t,J＝7.2Hz,2H),1.36–1.23(m,26H),0.88(t,J＝6.9Hz,3H)；13C{1H}NMR(126MHz,CDCl3)δ62.4(m),32.7,32.0,29.8(×4),29.7(×4),29.5(×2),25.8,22.8,14.2.
example 17
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 85.3mg (0.300mmol) of the compound 1q, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 77.1mg of a target compound 2q, wherein the yield is 95% and the deuteration rate is 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2q obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ5.35(m,2H),2.01(m,4H),1.55(m,2H),1.45–1.13(m,22H),0.88(t,J＝6.9Hz,3H)；13C{1H}NMR(126MHz,CDCl3)δ130.0,129.9,62.3(m),32.7,32.0,29.8(×2),29.6(×2),29.5,29.4(×2),29.3,27.3(×2),25.2,22.8,14.2.
example 18
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 50.4mg (0.300mmol) of the compound 1r, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.0Extracting with 0M hydrochloric acid solution, drying the organic phase, concentrating, and separating by column chromatography to obtain target compound 2r 41.6mg with yield of 90% and deuteration rate of more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2r obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ6.87(m,1H),6.83–6.77(m,2H),5.95(s,2H),1.71(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ147.9,147.2,134.8,120.6,108.3,108.0,101.1,64.7(m).
example 19
To a 50mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)15.0mL of a solution in tetrahydrofuran (0.100mol/L), 62.5mg (0.300mmol) of the compound 1s, and 180mg (9.00mmol) of heavy water. The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 52.5mg of a target compound, namely the target compound for 2s, wherein the yield is 90%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2s obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.15–7.10(m,4H),2.92(q,J＝7.0Hz,1H),2.45(d,J＝7.2Hz,2H),1.85(m,1H),1.60(br,1H),1.26(d,J＝7.1Hz,3H),0.90(d,J＝6.6Hz,6H)；13C{1H}NMR(126MHz,CDCl3)δ140.8,140.2,129.5,127.2,68.1(m),45.1,41.9,30.3,22.5,17.7.
example 20
To a 100mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2) Solution in tetrahydrofuran (0.100 m)ol/L)50.0mL, compound 1t 220mg (1.00mmol), and heavy water 601mg (30.0 mmol). The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 202mg of a target compound 2t, wherein the yield is 98 percent, and the deuteration rate is 98 percent.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2t obtained by adopting the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.47–7.42(m,2H),7.41–7.38(m,2H),2.77(t,J＝7.8Hz,2H),1.89(t,J＝7.8Hz,2H),1.75(br,1H)；13C{1H}NMR(126MHz,CDCl3)δ142.8,131.9,130.8(q,JC-F＝32.1Hz),128.9,125.2(q,JC-F＝4.1Hz),124.3(q,JC-F＝272.1Hz),122.8(q,JC-F＝3.9Hz),61.2(m),33.8,31.9.
example 21
To a 100mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)2)50.0mL of a solution in tetrahydrofuran (0.100mol/L), 1u 146mg (1.00mmol) of the compound, and 601mg of heavy water (30.0 mmol). The reaction mixture was stirred at room temperature for 30.0min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1.00M hydrochloric acid solution for extraction, drying and concentrating an organic phase, and performing column chromatography separation to obtain 119mg of a target compound 2u, wherein the yield is 90%, and the deuteration rate is more than 98%.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2u obtained by the synthesis method, and the test results are as follows:1H NMR(500MHz,CDCl3)δ1.42–1.25(m,9H),0.90(t,J＝6.8Hz,6H)；13C{1H}NMR(126MHz,CDCl3)δ64.7(m),41.9,30.2,29.2,23.4,23.2,14.2,11.2.
application examples
Partial hydrogen atoms in the commercial drug are deuterated to form a deuterated drug, and the deuterated drug is important for drug consistency evaluation, drug metabolism research and drug residue detection. To illustrate the practical application of the α, α -dideuterol compound of claim 8, the following deuterated drugs were synthesized by using α, α -dideuterol as a synthesis block.
Application example 1
With reference to the reported non-deuterated drug synthesis method (org. Lett.2019,21,65-69), the deuterated drug Cinacalcet ((+ -.) Cinacalcet-d can be synthesized by taking 2t as a synthesis block2)。
Deuterated cinacalcet
The synthetic route for deuterated cinacalcet is as follows:
the synthesized deuterated drugs are subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows:1H NMR(500MHz,CDCl3)δ10.50(br,1H),9.97(br,1H),8.22(d,J＝7.2Hz,1H),8.00–7.87(m,3H),7.65–7.53(m,3H),7.31(m,1H),7.24(m,1H),7.21–7.17(m,2H),5.21(m,1H),2.54(m,2H),2.25(m,2H),1.97(d,J＝6.7Hz,3H)；13C{1H}NMR(126MHz,CDCl3)δ140.9,133.9,132.2,131.6,130.8,130.7(q,JC-F＝32.0Hz),129.6,129.5,128.9,127.4,126.3,126.2,125.0,124.95(q,JC-F＝3.7Hz),124.0(q,JC-F＝272.3Hz),123.1(q,JC-F＝4.0Hz),121.3,53.5,44.9(m),32.5,27.1,21.4.
application example 2
Reference is made to the reported synthetic methods of non-deuterated drugs (j. org. chem.2014,79,6743.)
2u is taken as a synthesis building block to synthesize the deuterated drug 2, 4-D-2-ethylhexyl ester (2, 4-D-ethylhexyl ester-D)2)。
2, 4-Di-2-ethylhexyl ester
The synthetic route of deuterated 2, 4-d-2-ethylhexyl ester is as follows:
the synthesized deuterated drugs are subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows:1H NMR(500MHz,CDCl3)δ7.40(m,1H),7.16(dd,J＝8.7,2.6Hz,1H),6.77(m,1H),4.70(s,2H),1.56(m,1H),1.27–1.21(m,8H),0.89–0.84(m,6H)；13C{1H}NMR(126MHz,CDCl3)δ168.4,152.5,130.4,127.6,127.1,124.3,114.5,67.3(m),66.4,38.6,30.3,29.8,29.0,23.7,14.1,11.0.
the above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (9)
1. A synthesis method of alpha, alpha-dideuterol compounds shown in a general formula (2) is characterized in that acyl fluoride compounds shown in the general formula (1) react with bivalent lanthanide series transition metal compounds and deuterium donor reagents in an organic solvent I to generate alpha, alpha-dideuterol compounds shown in the general formula (2);
in the general formula (1), R1Selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl; r1Wherein the substituent is alkyl, halogen, alkoxy, alkylthio, trifluoroalkyl and ester group;
the deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof.
2. The method of claim 1, wherein the method comprises the steps of:
step 1: after argon protection is carried out on the reactor, constant temperature treatment is carried out, and organic solvent I is added to prepare divalent lanthanide series transition metal compound solution;
step 2: preparing a solution from an acyl fluoride compound and an organic solvent I, and adding the solution into a reactor;
and step 3: adding a deuterium donor reagent to the reactor;
and 4, step 4: stirring the mixed solution for a certain time, and then quenching the reaction;
and 5: adding an organic solvent II, extracting with an acid solution, drying and concentrating an organic phase, and purifying to obtain a compound of a general formula (2);
preferably, in step 1, the reactor is a round-bottom flask;
preferably, in step 1 and step 2, the same organic solvent is used;
preferably, in step 3, a quantitative amount of deuterium donor reagent is added to the reactor under constant temperature conditions;
preferably, in step 4, the stirring is vigorous stirring;
preferably, in step 4, the quenching reaction is carried out by introducing air;
preferably, in step 5, ethyl acetate and hydrogen chloride solution (1M) are added for extraction, and the organic phase is dried, concentrated and subjected to column chromatography to obtain the compound of the general formula (2).
3. The method for synthesizing α, α -dideuterol compounds represented by general formula (2) according to claim 1, wherein said deuterium donor agent is selected from deuterium oxide, deuterated alcohol, or a mixture thereof;
preferably, the deuterated alcohol is one in which the hydroxyl group is deuterated;
preferably, the deuterium donor reagent is heavy water (D)2O), deuterated methanol (MeOD), deuterated ethanol (EtOD), deuteriumOne or more of n-propanol (n-PrOD), deuterated isopropanol (i-PrOD), deuterated n-butanol (n-BuOD) and deuterated tert-butanol (t-BuOD) are substituted;
more preferably, the deuterium donor reagent is heavy water (D)2O)。
4. The method for synthesizing α, α -dideuterol compounds represented by the general formula (2) according to claim 1, wherein the divalent lanthanide transition metal compound is one or a combination of two or more selected from the group consisting of a divalent samarium compound, a divalent dysprosium compound, a divalent neodymium compound, a divalent ytterbium compound, a divalent cerium compound, and a divalent europium compound;
preferably, the divalent lanthanide transition metal compound is selected from samarium diiodide (SmI)2) Dysprosium diiodide (DyI)2) Neodymium diiodide (NdI)2) Ytterbium diiodide (YbI)2) Cerium diiodide (CeI)2) And europium (II) perchlorate (Eu (ClO)4)2) One or a combination of two or more of them;
preferably, the divalent lanthanide transition metal compound is samarium diiodide (SmI)2)。
5. The method for synthesizing α, α -dideuterol compounds represented by general formula (2) according to claim 1, wherein the organic solvent I is one or a combination of two or more selected from the group consisting of small-molecule alkanes, cycloalkanes, aromatic hydrocarbons, ethers, and cyclic ether solvents;
preferably, the organic solvent I is one or a combination of more than two of n-hexane, n-pentane, hexane, cyclohexane, toluene, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;
preferably, the organic solvent I is tetrahydrofuran.
6. The method for synthesizing α, α -dideuterol compounds represented by general formula (2) according to claim 1, wherein the ratio of organic solvent I to acyl fluoride compound is 1 mL: 1-300 mg.
7. The method for synthesizing α, α -dideuterol compounds represented by general formula (2) according to claim 1, wherein the reaction temperature is-40 to 60 ℃; the reaction time is 0.1-60 min.
8. Deuterated cinacalcet and deuterated 2, 4-D-2-ethylhexyl ester synthesized by using alpha, alpha-dideuterol compounds shown as a general formula (2) as raw materials.
9. The compound of the general formula (2) prepared by the synthesis method using the α, α -dideuterol compound as the raw material according to claims 1 to 7, preferably the compound of the following specific general formula (2):
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