阅读说明：本技术 一种α,α-二氘代醇类化合物及其制备方法 (Alpha, alpha-dideuterol compound and preparation method thereof ) 是由 刘伟茜 钟霞 于 2019-10-20 设计创作，主要内容包括：本发明涉及一种新的合成方法得到如通式(2)所示的α,α-二氘代醇类化合物的合成方法,合成方法的特征在于通式(1)所示的酰胺类化合物与二价镧系过渡金属化合物、氘供体试剂和路易斯碱在有机溶剂I中反应生成通式(2)所示的α,α-二氘代醇类化合物；与传统方法相比,该方法具有选择性强,产率高,氘代率高,毒副产物少,成本低廉,反应条件温和,操作简单,环境友好等优点。(The invention relates to a novel synthesis method for obtaining a compound shown as a general formula (2) α,α A synthetic method of a dideuteroalcohol compound, which is characterized in that an amide compound shown as a general formula (1) reacts with a bivalent lanthanide transition metal compound, a deuterium donor reagent and a Lewis base in an organic solvent I to generate a compound shown as a general formula (2) α,α -dideuterol compounds;)

1. A compound shown as a general formula (2)α,αA synthetic method of a dideuteroalcohol compound, which is characterized in that an amide compound shown as a general formula (1) reacts with a bivalent lanthanide transition metal compound, a deuterium donor reagent and a Lewis base in an organic solvent I to generate a compound shown as a general formula (2)α,α-dideuterol compounds;

in the general formula (1), R¹Selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; the substituent is alkyl, halogen, alkoxy, nitro, amino, aryl, alkenyl or alkynyl; r²、R³Selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic group; the substituent is alkyl, halogen, alkoxy, aryl, alkenyl or alkynyl; r²、R³May be the same or different;

the deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof;

the molar ratio of the amide compound to the deuterium donor reagent is 1: 4-1: 100;

the molar ratio of the amide compound to the alkali is 1: 4-1: 100;

the molar ratio of the amide compound to the divalent lanthanide transition metal compound is 1: 4-1: 20.

2. According to claim 1, represented by the general formula (2)α,α-a method for synthesizing dideuteroalcohol compounds, characterized in that it comprises the following steps:

step 1: after argon protection is carried out on the reactor, adding an organic solvent I to prepare a divalent lanthanide compound solution;

step 2: introducing lewis base and deuterium donor reagent into the reactor;

and step 3: preparing an amide compound and an organic solvent I into a solution, and adding the solution into a reactor;

and 4, step 4: after stirring the mixed solution, quenching the reaction;

and 5: adding dichloromethane and saturated aqueous solution of sodium hydroxide 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 dry round-bottom flask;

preferably, in step 1 and step 3, the same organic solvent is used;

preferably, in step 2, a quantitative amount of lewis base and deuterium donor is added to the round-bottom flask in sequence under a constant temperature condition;

preferably, in the step 2, the constant temperature is room temperature;

preferably, in step 4, the stirring is vigorous stirring;

preferably, in step 4, the reaction is quenched by passing air through.

3. As defined in claim 1, represented by the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, said deuterium donor reagent being 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 (D)n-PrOD), deuterated isopropanol (i-PrOD), deuterated n-butanol (n-BuOD), deuterated tert-butanol (t-BuOD) in one or more combinations;

more preferably, the deuterium donor reagent is heavy water (D)₂O）。

4. As defined in claim 1, represented by the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, characterized in that: the divalent lanthanide 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, a divalent europium compound and a divalent ytterbium compound;

preferably, the divalent lanthanide compound is selected from 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;

more preferably, the divalent lanthanide compound is samarium diiodide (SmI)₂）。

5. As claimed in claim 1, of the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, characterized in that: the lewis base is selected from amine compounds;

preferably, the Lewis base is selected from the group consisting of n-butylamine, pyrrolidine, diisopropylamine,N,N-one or a combination of two or more of dimethylethylamine, triethylamine, hexamethylphosphoric triamide;

more preferably, the lewis base is triethylamine.

6. As claimed in claim 1, of the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, characterized in that: 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 selected from one or more of pentane, hexane, cyclohexane, toluene, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;

more preferably, the organic solvent I is tetrahydrofuran.

7. As claimed in claim 1, of the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, characterized in that: the ratio of the organic solvent I to the amide compound is 1 mL: 1-300 mg.

8. As claimed in claim 1, of the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, characterized in that: the reaction temperature is-40 to 60 ℃; the reaction time is 0.1-60 min.

9. A method as claimed in any one of claims 1 to 8α,α-dideuteroalcohol compounds, the compounds of general formula (2) being prepared by a process for the synthesis of dideuteroalcohol compounds:

。

Technical Field

The invention belongs to the field of organic synthesis, and relates toα,α-dideuterol compounds and their use in synthesisα,αA novel amide organic matter reduction deuteration method of dideuterol compounds.

Background

The use of deuterated compounds in biopharmaceuticals, new materials, metabolomics research, analytical chemistry, etc. is increasing (Angew. Chemie Int. Ed.2018, 57(7), 1758-1784.). For example, in the aspect of food safety detection, the deuterated compound plays an important role, and by selecting a proper deuterated compound as an internal standard, the amounts of nutrient components and harmful substances in food can be accurately quantified, so that data support is provided for the establishment of food safety detection standards. In addition, in the research of the reaction mechanism and toxicology of the drug, the deuterated compound can be widely used, and in the cell experiment and animal experiment for developing new drugs, the action mechanism and the metabolic pathway of the drug can be better researched by tracking and researching the content change and the position change of the deuterium labeled part of the drug. In addition, the C-D bond is more stable than the C-H bond according to the kinetic isotope effect, and the deuterium-substituted drug is more stable than the non-deuterium drug in terms of pharmacokinetics, so that the importance of various large pharmaceutical companies to the deuterium-substituted drug is higher and higher. A large number of deuterated drugs have been developed in recent years and have entered the clinical trial stage: (J. Med. Chem.2019, 62 (11), 5276–5297.）。

Existingα,αThe synthesis method of the (di) deuterated alcohol organic compound is mainly divided into two typesJ. Org. Chem.2017, 82(2) 1285-1290.), are respectively: 1. sodium boron deuteride (NaBD) was used₄) Or lithium aluminum deuteride (LiAlD)₄) As reducing agents, reducing carboxylic acids or carboxylic acid derivatives toα,α-organic compounds of dideuteroalcohols. 2. By hydrogenThe/deuterium exchange converts the unlabeled alcohol compound to a deuterated alcohol compound. Although the existing method can synthesizeα, αDideuteroalcohol compounds, but metal-deuteride-mediated reductive deuteration requires the use of expensive and flammable metal deuterides and has limited applicability. The hydrogen/deuterium cross-linking method often suffers from low deuteration rate and poor location selectivity.

Disclosure of Invention

In order to overcome the prior artα,αThe invention relates to a method for synthesizing a dideuteroalcohol compound, which solves the problems of using expensive inflammable metal deuteride or having low deuteration rate and poor site selectivity in the preparation synthesis method of the dideuteroalcohol compound, and synthesizes an amide organic compound which accords with a general formula (1), a bivalent lanthanide transition metal compound, a Lewis base and a deuterium donor reagent in an organic solvent by a novel single electron transfer reduction deuteration method to synthesize the dideuteroalcohol compound which accords with a general formula (2)α,α-dideuterol compounds. The synthesis method is simple and easy to implement, low in cost, mild in synthesis conditions and environment-friendly, and can be widely applied to the reduction deuteration reaction of amide compounds.

As shown in the general formula (2)α,α-a method for the synthesis of dideuteroalcohol compounds, characterized in that: the amide compound shown in the general formula (1) reacts with a bivalent lanthanide transition metal compound, a deuterium donor reagent and a Lewis base in an organic solvent I to generate the compound shown in the general formula (2)α,α-dideuterol compounds;

in the general formula (1), R¹Selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; the substituent is alkyl, halogen, alkoxy, nitro, amino, aryl, alkenyl or alkynyl; r² _、R³Selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic group; the substituent is alkyl, halogen,Alkoxy, aryl, alkenyl, alkynyl; r²、R³May be the same or different;

the deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof;

the molar ratio of the amide compound to the deuterium donor reagent is as follows: 1: 4-1: 100;

the molar ratio of the amide compound to the alkali is as follows: 1: 4-1: 100; (ii) a

The molar ratio of the amide compound to the divalent lanthanide transition metal compound is as follows: 1: 4-1: 20.

The method is characterized by comprising the following steps:

step 1: after argon protection is carried out on the reactor, adding an organic solvent I to prepare a divalent lanthanide compound solution;

step 2: introducing lewis base and deuterium donor reagent into the reactor;

and step 3: preparing an amide compound and an organic solvent I into a solution, and adding the solution into a reactor;

and 4, step 4: after stirring the mixed solution, quenching the reaction;

and 5: adding dichloromethane and saturated sodium hydroxide 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 dry round-bottom flask;

preferably, in step 1 and step 3, the same organic solvent is used;

preferably, in step 2, a quantitative amount of lewis base and deuterium donor is added to the round-bottom flask in sequence under a constant temperature condition;

preferably, in the step 2, the constant temperature is room temperature;

preferably, in step 4, the stirring is vigorous stirring;

preferably, in step 4, the reaction is quenched by passing air through.

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), deuteriumEthanol (EtOD), deuterated n-propanol (C)n-PrOD), deuterated isopropanol (i-PrOD), deuterated n-butanol (n-BuOD), deuterated tert-butanol (t-BuOD) in one or more combinations;

more preferably, the deuterium donor reagent is heavy water (D)₂O）。

The divalent lanthanide 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, a divalent europium compound and a divalent ytterbium compound;

preferably, the divalent lanthanide compound is selected from 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;

more preferably, the divalent lanthanide compound is samarium diiodide (SmI)₂). The lewis base is selected from amine compounds;

preferably, the Lewis base is selected from the group consisting of n-butylamine, pyrrolidine, diisopropylamine,N,N-one or a combination of two or more of dimethylethylamine, triethylamine, hexamethylphosphoric triamide;

more preferably, the lewis base is triethylamine.

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;

more preferably, the organic solvent I is tetrahydrofuran.

The proportion of the organic solvent I and the amide compound is 1 mL: 1-300 mg.

The reaction temperature is-40 to 60 ℃; the reaction time is 0.1-120 min.

The above-mentionedα,αSynthetic method of (E) -dideuterol compoundPreparing a compound of formula (2):

the invention has the beneficial effects that:

(1) in the invention, bivalent lanthanide series transition metal compound is used for reducing and deuterating amide organic compound into amide organic compoundα,αThe compound is a dideuteroalcohol compound, the reaction condition is mild, the operation is simple, and the byproducts are few;

(2) the method can ensure that the reduction deuteration reaction only occurs on amido bonds without influencing other chemical structures, so the method has high selectivity and has the advantages of wide application range, good zone selectivity, high product purity, high deuteration rate and the like.

Detailed Description

The following examples are given to further illustrate the embodiments of the present invention.

Example 1

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.40 mmol, 0.1 mol/L), triethylamine (3.6 mmol), heavy water (3.6 mmol), and compound 1a (0.1 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying and concentrating an organic phase to obtain the target compound 2a with the yield of 90 percent and the deuteration rate of 96.0 percent.

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 (400 MHz, CDCl₃) δ 0.91 (t, J = 7.3 Hz, 3H), 1.24-1.43 (m, 15H), 1.56 (t, J = 7.3 Hz, 2H), 1.67 (br, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.3, 22.9, 25.9, 29.5, 29.6, 29.9, 29.8, 32.0, 32.9, 62.6 (m)。

example 2

To a 50 mL single-neck round-bottom flask under argon shield, an n-pentane solution containing samarium dichloride (0.50 mmol, 0.1 mol/L), pyrrolidine (7.2 mmol), deuterated ethanol (7.2 mmol), and compound 1a (0.1 mmol) were added in that order. The reaction mixture was stirred vigorously at room temperature for 45 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2a with the yield of 95% and the deuteration rate of 93.0%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is performed on the target product 2a obtained by the synthesis method, and the test result is the same as that in example 1.

Example 3

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.1 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1b (0.1 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 60 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2b with the yield of 94% and the deuteration rate of 95%.

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 (400 MHz, CDCl₃) δ 0.92 (t, J = 7.0 Hz, 3 H), 1.25-1.44 (m, 15 H), 1.59 (t, J = 7.0 Hz, 2 H), 1.69 (br, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 22.4, 25.5, 29.0, 29.1, 29.3, 29.2, 31.7, 32.4, 62.2 (m)。

example 4

To a 50 mL single neck round bottom flask under argon shield, Sm (hmds) -containing solution was added in this order₂Tetrahydrofuran solution (0.40 mmol, 0.10 mol/L), N, N-dimethylethylamine (3.6 mmol), deuterated N-propanol (3.6 mmol), and compound 1b (0.1 mmol). The reaction mixture was stirred vigorously at 40 deg.C for 60 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2b with the yield of 94% and the deuteration rate of 96%.

And (3) performing nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection on the target product 2b obtained by the synthesis method, wherein the test result structure is the same as that of the embodiment 3.

Example 5

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.60 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1c (0.1 mmol) were added in this order. The reaction mixture was stirred vigorously at 60 ℃ for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2c with the yield of 94% and the deuteration rate of 96.0%.

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 (400 MHz, CDCl₃) δ 0.90-0.96 (m, 6H), 1.22 (br, 1H), 1.28-1.38 (m, 16H), 1.44-1.50 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.4, 23.0, 23.5, 27.3, 29.4, 30.0, 30.9, 31.3, 32.2, 40.6, 65.3 (m)。

example 6

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1d (0.1 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2d with the yield of 91% and the deuteration rate of 96.0%.

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 (400 MHz, CDCl₃) δ 1.29 (br, 1H), 1.53-1.58 (m, 6H), 1.66-1.74 (m, 3H), 1.75-1.81 (m, 3H), 2.01-2.07 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 27.9, 34.0, 36.9, 38.8, 72.8 (m)。

example 7

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1e (0.1 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2e with the yield of 88% and the deuteration rate of 95%.

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 (400 MHz, CDCl₃) δ 1.35 (br, 1H), 1.90 (t, J = 7.3 Hz, 2H), 2.70 (t, J = 7.9 Hz, 2H), 3.82 (s, 3 H), 6.89 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 30.9, 34.0, 55.0, 61.3 (m), 113.2, 128.9, 133.1, 157.0。

example 8

To a 50 mL single-neck round-bottom flask under argon shield were added a solution of samarium dibromide in n-hexane (2.0 mmol, 0.10 mol/L), n-butylamine (7.2 mmol), deuterated methanol (7.2 mmol), and compound 1e (0.1 mmol) in that order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2e with the yield of 95% and the deuteration rate of 98%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection of the target product 2e obtained by the synthesis method is performed, and the test results are the same as those in example 7.

Example 9

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (2.0 mmol, 0.10 mol/L), triethylamine (10.0 mmol), heavy water (10.0 mmol), and compound 1f (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at 0 ℃ for 0.1 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2f with the yield of 92% and the deuteration rate of 97%.

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 (400 MHz, CDCl₃) δ 1.50 (br, 1H), 1.81 (t, J = 7.6 Hz, 2H), 2.70 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 32.0, 33.9, 61.3 (m), 124.7 (q, J = 272.3 Hz), 125.4 (q, J = 4.0 Hz), 129.0 (q, J = 35.0 Hz), 129.1, 146.4; ¹⁹F (470 MHz, CDCl₃) δ -62.3。

example 10

To a 50 mL single-neck round-bottom flask under argon shield were added a tetrahydrofuran solution containing samarium diiodide (0.6 mmol, 0.10 mol/L), triethylamine (3.6 mmol), heavy water (3.6 mmol), and 1g of the compound (0.1 mmol) in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Dichloromethane and saturated sodium hydroxide solution are added for extraction, and the organic phase is dried and concentrated to obtain 2g of the target compound with the yield of 93 percent and the deuteration rate of 97 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 (400 MHz, CDCl₃) δ 1.20-1.38 (m, 13H), 1.53 (t, J = 7.7 Hz, 2H), 1.99 -2.05 (m, 2H), 4.89 - 5.00 (m, 2H), 5.76 - 5.84 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 26.0, 29.2, 29.4, 29.7, 30.0, 32.9, 34.1, 62.7 (m), 114.2, 139.3。

example 11

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.40 mmol, 0.10 mol/L), triethylamine (2.4 mmol), heavy water (2.4 mmol), and a compound (1 h (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at-40 ℃ for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound for 2h, wherein the yield is 95%, and the deuteration rate is 96%.

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 (400 MHz, CDCl₃) δ 1.61 (br, 1H), 3.08-3.10 (m, 2H), 7.12 (m, 1H), 7.19 (m, 1H), 7.28 (m, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 8.10 (br, 1H); ¹³C NMR (125 MHz, CDCl3) δ 28.2, 61.6 (m), 110.9, 111.8, 118.5, 119.1, 129.9, 122.1, 127.2, 136.1。

example 12

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.40 mmol, 0.10 mol/L), triethylamine (0.4 mmol), heavy water (0.4 mmol), and compound 1i (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at 60 ℃ for 60 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying and concentrating an organic phase to obtain the target compound 2i with the yield of 98 percent and the deuteration rate of 97 percent.

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 (400 MHz, CDCl₃) δ 0.80 (d, J = 7.2 Hz, H), 1.18 (br, 1 H), 1.78-1.85 (m, 1H), 2.31 (m, 1H), 2.59 (m, 1H), 7.04-7.08 (m, 3H), 7.15-7.19 (m, 2H); ¹³C NMR (125 MHz, CDCl3) δ 16.0, 37.2, 39.3, 66.6 (m), 125.6, 128.5, 129.7, 141.1。

example 13

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1j (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2j with the yield of 93% and the deuteration rate of 96%.

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 (400 MHz, CDCl₃) δ 1.30 (br, 1H), 1.85 (t, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.73 (t, J = 7.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃) δ 16.2, 31.9, 34.1, 61.7 (m), 127.5, 128.9, 135.5, 138.8。

example 14

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1k (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2k with the yield of 94% and the deuteration rate of 97.0%.

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 (400 MHz, CDCl₃) δ 1.40 (br, 1H), 1.81 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.9 Hz, 2H), 6.90-6.94 (m, 2H), 7.08-7.13 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 31.5, 34.5, 61.8 (m), 115.2 (d, J = 22.1 Hz), 130.1 (d, J = 8.1 Hz), 138.1 (d, J = 3.2 Hz), 162.3 (d, J = 245.8 Hz); ¹⁹F (470 MHz, CDCl₃) δ -116.8。

example 15

To a 50 mL single-neck round-bottom flask under argon shield were added a dioxane solution containing ytterbium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1k (0.10 mmol) in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2k with the yield of 94% and the deuteration rate of 95.0%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection was performed on the target product 2k obtained by the above synthesis method, and the test results were the same as in example 14.

Example 16

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1L (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2l with the yield of 61% and the deuteration rate of 97%.

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 (500 MHz, CDCl₃) δ 1.23 (br, 1H), 1.82 (t, J = 7.2 Hz, 2 H), 2.56 (t, J = 7.8 Hz, 2H), 3.61 (br, 2H), 6.65 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 31.3, 34.5, 62.6 (m), 115.3, 129.5, 131.6, 144.2。

example 17

To a 50 mL single-neck round-bottom flask under argon shield, a toluene solution containing neodymium diiodide (0.80 mmol, 0.10 mol/L), hexamethylphosphoric triamide (HMPA) (3.6 mmol), deuterated n-butanol (7.2 mmol), and compound 1L (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2l with the yield of 53 percent and the deuteration rate of 97 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection was performed on the target product 2l obtained by the above synthesis method, and the test results were the same as in example 16.

Example 18

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (1.00 mmol, 0.10 mol/L), triethylamine (9.0 mmol), heavy water (9.0 mmol), and compound 1m (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2m with the yield of 82% and the deuteration rate of 96%.

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 (500 MHz, CDCl₃) δ 1.63 (br, 1H), 1.94 (t, J = 7.8 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 31.7, 34.1, 61.5 (m), 129.1, 128.2, 130.1, 139.8。

example 19

To a 50 mL single-neck round-bottom flask under argon shield, a diethyl ether solution containing cerium diiodide (1.00 mmol, 0.10 mol/L), triethylamine (9.0 mmol), deuterated tert-butanol (9.0 mmol), and compound 1m (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2m with the yield of 79 percent and the deuteration rate of 94 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection was performed on the target product 2m obtained by the above synthesis method, and the test results were the same as in example 18.

Example 20

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1n (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2n with the yield of 98% and the deuteration rate of 93%.

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 (500 MHz, CDCl₃) δ 0.90 (d, J = 7.2 Hz, 6H), 1.31 (d, J = 7.2 Hz, 3H), 1.34 (br, 1H), 1.81-1.91 (m, 1H), 2.50 (d, J = 7.7 Hz, 2H), 2.96 (q, J = 7.0 Hz, 1H), 7.13-7.21 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ17.0, 21.9, 29.5, 41.1, 44.5, 67.5 (m), 126.7, 129.0, 139.5, 139.8。

example 21

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 0.10 mol/L), triethylamine (7.2 mmol), heavy water (7.2 mmol), and compound 1o (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2o, wherein the yield is 82%, and the deuteration rate is 97.0%.

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 (300 MHz, CDCl₃) δ 1.59 (br, 1H), 4.59 (s, 2H), 6.90 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 55.6, 64.8 (m), 114.2, 129.3, 133.6, 159.6。

example 22

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 1.0 mol/L), triethylamine (2.25 mmol), heavy water (2.25 mmol), and compound 1r (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2r with the yield of 95% and the deuteration rate of 97.0%.

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 (500 MHz, CDCl₃) δ 7.34-7.26 (m, 4H), 7.20-7.17 (m, 1H), 2.04 – 1.97 (m, 2H), 1.90 – 1.81 (m, 2H), 1.78 – 1.65 (m, 4H), 1.21 (br, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 147.1, 128.8, 128.0, 126.9, 70.1 (m), 53.4, 34.5, 24.0。

example 23

To a 50 mL single-neck round-bottom flask under argon shield, a tetrahydrofuran solution containing samarium diiodide (0.80 mmol, 1.0 mol/L), triethylamine (2.25 mmol), heavy water (2.25 mmol), and compound 1s (0.10 mmol) were added in this order. The reaction mixture was stirred vigorously at room temperature for 15 min. Air was then added to quench the reaction. Adding dichloromethane and saturated sodium hydroxide solution for extraction, drying an organic phase, and concentrating to obtain the target compound 2s with the yield of 80% and the deuteration rate of 97.0%.

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 (500 MHz, CDCl₃) δ 7.35-7.28 (m, 4H), 7.23-7.20 (m, 1H), 2.06 – 1.98 (m, 2H), 1.92 – 1.83 (m, 2H), 1.80 – 1.65 (m, 4H), 1.21 (br, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 147.0, 129.0, 128.1, 126.9, 70.5 (m), 54.0, 34.7, 24.5。

the above examples illustrate the technical concept and features of the present invention, and are intended to enable persons skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.