A selective deuterium substitution method of pyridine compounds

Abstract

The application discloses a selective deuterium substitution method of pyridine compounds, and reaction raw materials comprise pyridine compounds, a catalytic system, heavy water and an organic solvent, and the reaction is carried out at 80-120 DEG C for 4-12 h to obtain deuterated pyridine compounds in which nitrogen atoms adjacent to pyridine are substituted by deuterium. The application has the advantages of mild reaction condition, short reaction time, precise realization of deuterium substitution of nitrogen atoms adjacent to pyridine and high deuterium substitution degree.

Description

Technical Field

[0001] This invention relates to the field of deuterated compound production technology, and particularly to a selective deuteration method for pyridine compounds. Background Technology

[0002] Deuterated compounds, due to the introduction of the deuterium isotope, undergo a change in relative molecular mass, thus possessing labeling properties. Furthermore, the CD bond is shorter and more stable than the CH bond, requiring a higher activation energy to break, resulting in a lower kinetic reaction rate. This difference in kinetic reaction rate caused by deuteration is called the deuteration kinetic isotope effect. With increasing understanding of deuterated organic compounds, they are becoming increasingly important. Deuterated compounds are widely used in many fields, including NMR detection, life sciences, food safety, and materials science. In NMR detection, deuterated compounds can serve as NMR solvents, dissolving and diluting analytes, avoiding the introduction of interfering hydrogen signals, and providing an NMR lock field. In life sciences, utilizing the labeling properties of deuterated compounds in conjunction with tandem mass spectrometry (TMS) allows for the study of the absorption, distribution, metabolism, and excretion (ADME) processes of drug molecules in vivo. Moreover, the deuteration kinetic isotope effect introduced by deuteration can alter the pharmacokinetics and metabolic pathways of drug molecules, thereby enabling the improvement and development of new drugs. Furthermore, due to the stability of CD bonds, optoelectronic materials synthesized using deuterated compounds as a matrix have a longer luminescence lifetime.

[0003] Pyridine is a six-membered heterocyclic compound containing a nitrogen atom and is one of the most common N-heterocyclic compounds. Pyridine compounds are generally referred to as pyridine bases and are widely used in pharmaceutical intermediates, pesticides, dyes, surfactants, and catalysts. In medicinal chemistry, pyridine is used as the core structure of many drugs. Although it is stable under normal conditions, the uneven electron distribution makes the pyridine ring more susceptible to metabolism and degradation than other aromatic compounds. Deuterium-labeled pyridine rings hold promise for improvement. One such improvement is the ortho-deuteration of the nitrogen atom in pyridine compounds.

[0004] The 1997 paper "HD Exchange of Dimethylpyridine" published in the *Journal of Heterocyclic Chemistry* disclosed a method of separating and purifying deuterated dimethylpyridine by heating dimethylpyridine in a heavy aqueous solution of potassium carbonate to 180°C for 5.5 days, with yields ranging from 65% to 93% and a deuteration degree exceeding 95%. Deuteration occurred at the 2 and 6 positions of the pyridine ring; if substituted by a methyl group, it occurred at the methyl groups at positions 2, 4, and 6. While this article disclosed the ortho-deuteration of the nitrogen atom in dimethylpyridine, it had the following limitations:

[0005] 1) The reaction temperature is too high and the reaction time is too long;

[0006] 2) The reaction produces many byproducts, resulting in a low yield;

[0007] 3) In addition to deuteration at the 2 and 6 positions (ortho) of the pyridine ring, deuteration also occurs at the 4-methyl position, but the selectivity is poor.

[0008] The 2009 paper "HD Exchange between N-Heterocyclic Compounds and D2O using Palladium / Polystyrene Colloidal Catalysts" published in Organometallic Compounds disclosed the use of palladium / polystyrene colloidal catalysts for HD exchange between N-heterocyclic compounds and D2O at the nitrogen atom ortho position. However, this method has the following shortcomings:

[0009] 1) The catalyst needs to be prepared in advance and activated with hydrogen before use;

[0010] 2) The reaction selectivity is not high. For example, when the 3-position of pyridine is replaced by a methyl group, deuteration can occur at all positions on the pyridine ring.

[0011] 3) The substituent tolerance is low. For example, when the 3-position of pyridine is replaced by a cyano group, the ortho position of the cyano group (2-position of pyridine) cannot undergo deuteration. Summary of the Invention

[0012] The purpose of this invention is to provide a selective deuteration method for pyridine compounds, which has mild reaction conditions, short reaction time, and can accurately achieve ortho-deuteration of nitrogen atoms with a high degree of deuteration.

[0013] The technical solution adopted by this invention to solve its technical problem is:

[0014] A selective deuteration method for pyridine compounds, comprising a pyridine compound, a catalytic system, heavy water and an organic solvent, reacting at 80–120 °C for 4–12 h to obtain a deuterated pyridine compound in which the nitrogen atom is deuterated at the ortho position.

[0015] The molecular structural formula of the pyridine compound is as follows:

[0016] R1-R4 are selected from one or a combination of two of the following: H, halogen, methyl, trifluoromethyl, phenyl, hydroxyl, amino, phenoxy, dimethylamino, cyano, nitro, acetyl, ester, amide, benzyl, ether, and steroidal ring-17-yl.

[0017] The catalytic system consists of a divalent palladium salt, a secondary phosphine oxide, and an inorganic base. The molecular structural formula of the secondary phosphine oxide is as follows: R is selected from methyl, phenyl, naphthyl or substituted phenyl.

[0018] In classic co-metallization-deprotonation mechanisms, CMD bases such as pyridones, carboxylic acids, and monoprotected amino acids typically form a stable six-membered ring with the catalytic metal center and the target CH bond for efficient CH bond insertion. In common pyridine-induced aryl CH activation reactions, this process forms a 5 / 6 bicyclic structure that transfers the metal center to the ortho position of the 2-phenyl ring. This invention shortens the spatial structure of the CMD base, reducing the three-atom core to a two-atom core, allowing the metal center to be positioned onto the α-CH bond of the pyridine ring itself, achieving selective deuteration at this site.

[0019] In related technologies, some researchers have used heterogeneous catalysts for selective deuteration at this site, which usually uses D2 as the deuterium source, but this poses significant safety risks during operation. In contrast, the present invention uses a homogeneous catalysis scheme to achieve efficient pyridine α-deuteration, and using heavy water as the deuterium source can further improve the operability and safety of the reaction.

[0020] This invention employs a catalytic system composed of a divalent palladium salt, a secondary phosphine oxide, and an inorganic base. The divalent palladium salt undergoes ligand exchange to form a complex with the secondary phosphine oxide, in which the transition metal palladium coordinates with the nitrogen atom of a pyridine compound. An exogenous inorganic base induces a structural tautomerism in the secondary phosphine oxide, followed by deprotonation to form an endogenous base. Palladium coordinates with the pyridine nitrogen atom, and with the assistance of the secondary phosphine oxide as an endogenous base, the ortho-CH bond of the pyridine nitrogen atom is activated. Under the condition of a protonated deuterium source in the system, the CD bond is retrogradely reconstructed, thereby achieving deuteration of the ortho-CH bond of the pyridine nitrogen atom. This catalytic system can accurately achieve ortho-deuteration of the pyridine nitrogen atom under mild reaction conditions and with a high degree of deuteration.

[0021] The substituents of the substituted phenyl group are methyl, methoxy, or halogen.

[0022] The molar ratio of the pyridine compound, divalent palladium salt, secondary phosphine oxide, inorganic base, heavy water, and organic solvent is 1:0.05-0.10:0.05-0.20:1.0-2.0:27.5-110:5-15.

[0023] The molar ratio of pyridine compounds to divalent palladium salts is 1:0.05 to 0.10. Compared to pyridine compounds, divalent palladium salts are added in small amounts. Excessive addition will make the catalytic system more susceptible to the influence of other coordinating sites in pyridine derivatives, resulting in reduced reaction selectivity and increased cost. Insufficient addition will lead to a significant decrease in reaction rate, resulting in an increase in reaction byproducts during multiple rounds of deuteration.

[0024] The molar ratio of pyridine compounds and secondary phosphine oxides is 1:0.05 to 0.20. Compared with pyridine compounds, secondary phosphine oxides are added in small amounts. If the amount added is too large, the coordination sites of palladium will be occupied by secondary phosphine oxides, and the pyridine nitrogen atom will not be able to coordinate effectively with palladium, resulting in a significant decrease in the reaction rate or even no reaction. If the amount added is too small, the endogenous base that coordinates with palladium will be reduced, and the deuteration reaction will not be able to occur effectively.

[0025] The molar ratio of pyridine compounds to inorganic bases is 1:1.0–2.0. Compared to pyridine compounds, inorganic bases are added in excess. Excessive addition leads to decreased reaction selectivity and reduces the deuterium yield of base-intolerant pyridine derivatives. Insufficient addition results in an excessively low deprotonation rate of secondary phosphine oxides, thus significantly reducing the reaction rate. Therefore, this invention controls the molar ratio of inorganic bases within the range specified herein.

[0026] In pyridine compounds, the H atom on the adjacent carbon of the nitrogen atom is deuterated, the H atom on the adjacent methyl atom is deuterated, or both are deuterated simultaneously.

[0027] The inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, sodium pivalate, sodium oxalate, and sodium hydroxide.

[0028] The divalent palladium salt is selected from palladium acetate, palladium trifluoroacetate, palladium pivalate, and palladium chloride.

[0029] The organic solvent is selected from one of isopropanol, hexafluoroisopropanol, dichloroethane, toluene, tetrahydrofuran, and dioxane.

[0030] The molecular structural formula of the secondary phosphine oxide is shown in any one of L1-L4:

[0031]

[0032] Secondary phosphine oxides are bifunctional ligands in which both O and P atoms can coordinate with metals. In this catalytic system, secondary phosphine oxides tend to coordinate the P atom with palladium. The electron-rich aromatic ring attached to phosphine in the above molecular structure enhances the coordination ability of the P atom and facilitates the deprotonation process of secondary phosphine oxides, thus enabling them to participate in the CH bond breaking process as an endogenous base.

[0033] The deuterated pyridine compounds are one of formulas 1-12:

[0034]

[0035] The beneficial effects of this invention are: by using a catalytic system composed of divalent palladium salt, secondary phosphine oxide and inorganic base, the ortho-deuteration of nitrogen atoms in pyridine and its derivatives can be accurately achieved, and the reaction temperature is low, the time is short, the degree of deuteration is high, and the yield is high. The degree of deuteration can reach more than 90%, and the yield is more than 85%. Detailed Implementation

[0036] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0037] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available or commonly used in the field. The methods described in the following embodiments are conventional methods in the field, unless otherwise specified.

[0038] Example 1: A method for preparing deuterated pyridine.

[0039]

[0040] In a 15 mL dry sealed tube, 79.1 mg (1.0 mmol) of pyridine, 106.0 mg (1.0 mmol) of sodium carbonate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 26.2 mg (0.10 mmol) of secondary phosphine oxide L4, 1.0 mL of hexafluoroisopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was then reacted at 80 °C for 6 h under a nitrogen atmosphere.

[0041] The 1H NMR spectrum of pyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) 8.62 (dt, J=4.3, 1.7Hz, 2H), 7.68 (tt, J=7.6, 1.8Hz, 1H), 7.25 (ddd, J=7.6, 4.2, 1.5Hz, 2H);

[0042] The 1H NMR spectrum of deuterated pyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ 8.63 (d, J = 2.0, 0.20H, Labelled), 7.67 (t, J = 7.8Hz, 1H), 7.25 (d, J = 8.0Hz, 2H).

[0043] Example 2: A method for preparing deuterated 4-phenylpyridine

[0044]

[0045] In a 15 mL dry sealed tube, 155.2 mg (1.0 mmol) of 4-phenylpyridine, 106.0 mg (1.0 mmol) of sodium carbonate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 13.1 mg (0.05 mmol) of secondary phosphine oxide L4, 1.0 mL of hexafluoroisopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was then reacted at 100 °C for 6 h under a nitrogen atmosphere.

[0046] The 1H NMR spectrum of 4-phenylpyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ8.71–8.60(m,2H),7.67–7.61(m,2H),7.53–7.42(m,5H);

[0047] The 1H NMR spectrum of deuterated 4-phenylpyridine is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.70–8.63 (m, 0.12H, Labelled), 7.67–7.62 (m, 2H), 7.54–7.41 (m, 5H).

[0048] Example 3: A method for preparing deuterated 3-phenylpyridine

[0049]

[0050] In a 15 mL dry sealed tube, 155.2 mg (1.0 mmol) of 3-phenylpyridine, 138.2 mg (1.0 mmol) of potassium carbonate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 38.7 mg (0.15 mmol) of secondary phosphine oxide L3, 1.0 mL of hexafluoroisopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of 3-phenylpyridine was extracted.

[0051] The 1H NMR spectrum of 3-phenylpyridine is characterized as follows: 1 H NMR(400MHz,Chloroform-d)δ8.86(dd,J=2.5,0.9Hz,1H),8.60(dd,J=4.9,1.6Hz,1H),7.88(dt,J=7 .9,2.0Hz,1H),7.63–7.54(m,2H),7.52–7.45(m,2H),7.44–7.39(m,1H),7.37(dd,J=7.9,4.8Hz,1H);

[0052] The 1H NMR spectrum of deuterated 3-phenylpyridine is as follows: 1H NMR (400MHz, Chloroform-d) δ8.86 (dd, J=2.4, 0.9Hz, 0.27H, Labelled), 8.59 (dd, J=4.8, 1.7Hz, 0.10H, Labelle d),7.88(dd,J=7.9,1.7Hz,1H),7.61–7.56(m,2H),7.51–7.46(m,2H),7.44–7.39(m,1H),7.37(d,J=7.8Hz,1H).

[0053] Example 4: A method for preparing deuterated 2-phenylpyridine

[0054]

[0055] In a 15 mL dry sealed tube, 155.2 mg (1.0 mmol) of 2-phenylpyridine, 325.8 mg (1.0 mmol) of cesium carbonate, 16.8 mg (0.075 mmol) of palladium acetate, 26.2 mg (0.10 mmol) of secondary phosphine oxide L4, 1.0 mL of isopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of 2-phenylpyridine was extracted.

[0056] The 1H NMR spectrum of 2-phenylpyridine is characterized as follows: 1 H NMR(400MHz,Chloroform-d)δ8.73–8.67(m,1H),8.02–7.97(m,2H),7.79–7.71( m,2H),7.51–7.45(m,2H),7.45–7.39(m,1H),7.23(ddd,J=6.7,4.9,2.2Hz,1H);

[0057] The 1H NMR spectrum of deuterated 2-phenylpyridine is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.72–8.69(m,0.06H,Labelled),8.05–7.95(m,2H),7 .79–7.71(m,2H),7.52–7.45(m,2H),7.45–7.39(m,1H),7.24(dd,J=6.6,2.1Hz,1H).

[0058] Example 5: A method for preparing deuterated 2,2-bipyridine

[0059]

[0060] In a 15 mL dry sealed tube, 156.2 mg (1.0 mmol) of 2,2-bipyridine, 40.0 mg (1.0 mmol) of sodium hydroxide, 17.8 mg (0.10 mmol) of palladium chloride, 23.2 mg (0.10 mmol) of secondary phosphine oxide L2, 1.0 mL of hexafluoroisopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of 2,2-bipyridine was extracted.

[0061] The 1H NMR spectrum of 2,2-bipyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ8.68(ddd,J=4.8,1.8,0.9Hz,2H),8.40(dt,J=8.0,1.1Hz,2H),7.82(td,J=7.7,1.8Hz,2H),7.31(ddd,J=7.5,4.8,1.2Hz,2H);

[0062] The 1H NMR spectrum of deuterated 2,2-bipyridine is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.68 (ddd, J=4.8, 1.8, 0.9Hz, 1.20H, Labeled), 8.40 ( dt,J=8.0,1.2Hz,2H),7.82(td,J=7.7,1.6Hz,2H),7.31(ddt,J=7.5,3.4,1.3Hz,2H).

[0063] Example 6: A method for preparing deuterated 2,3-dimethylpyridine.

[0064]

[0065] In a 15 mL dry sealed tube, 107.2 mg (1.0 mmol) of 2,3-dimethylpyridine, 82.0 mg (1.0 mmol) of sodium acetate, 15.3 mg (0.05 mmol) of palladium pentovalerate, 26.2 mg (0.10 mmol) of secondary phosphine oxide L4, 1.0 mL of hexafluoroisopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of 2,3-dimethylpyridine was extracted.

[0066] The 1H NMR spectrum of 2,3-dimethylpyridine is characterized as follows: 1¹H NMR (400MHz, Chloroform-d) δ 8.31 (dd, J = 5.0, 1.7Hz, 1H), 7.39 (d, J = 7.4Hz, 1H), 7.02 (dd, J = 7.6, 4.9Hz, 1H), 2.49 (s, 3H), 2.27 (s, 3H); ¹H NMR characterization of deuterated 2,3-dimethylpyridine is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.32 (dd, J=4.9, 1.8Hz, 0.07H, Labelled), 7.38 (d, J=7.5Hz, 1H), 7.02 (d, J=7.5Hz, 1H), 2.51–2.45 (m, 1.5H, Labelled), 2.27 (s, 3H).

[0067] Example 7: A method for preparing deuterated 4-dimethylaminopyridine

[0068]

[0069] In a 15 mL dry sealed tube, 122.2 mg (1.0 mmol) of 2,3-dimethylpyridine, 53.0 mg (1.0 mmol) of sodium pentovaperate, 22.4 mg (0.10 mmol) of palladium acetate, 40.2 mg (0.20 mmol) of secondary phosphine oxide L1, 1.0 mL of dichloroethane, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of 4-dimethylaminopyridine was extracted.

[0070] The 1H NMR spectrum of 4-dimethylaminopyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ8.24–8.18(m,2H),6.49–6.46(m,2H),2.98(s,6H);

[0071] The 1H NMR spectrum of deuterated 4-dimethylaminopyridine is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.24–8.17 (m, 0.83H, Labelled), 6.48 (t, J = 2.3Hz, 2H), 2.99 (s, 6H).

[0072] Example 8: A method for preparing deuterated 5-fluoropyridine-3-amine

[0073]

[0074] In a 15 mL dry sealed tube, 112.1 mg (1.0 mmol) of 5-fluoropyridine-3-amine, 106.0 mg (1.0 mmol) of sodium carbonate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 10.1 mg (0.05 mmol) of secondary phosphine oxide L1, 1.0 mL of hexafluoroisopropanol, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 80 °C for 12 h under a nitrogen atmosphere, and the deuterated product of 5-fluoropyridine-3-amine was extracted.

[0075] The 1H NMR spectrum of 5-fluoropyridine-3-amine is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.90(t,J=1.8Hz,1H),7.86(d,J=2.4Hz,1H),6.69(dt,J=10.4,2.4Hz,1H),3.76(s,2H);

[0076] The 1H NMR spectrum of deuterated 5-fluoropyridine-3-amine is as follows: 1 H NMR (400MHz, Chloroform-d) δ7.93–7.89 (m, 0.57H, Labeled), 7.87 (d, J=2.3Hz, 0.64H, Labeled), 6.70 (ddt, J=10.3, 2.5, 1.2Hz, 1H), 3.82 (s, 2H).

[0077] Example 9: A method for preparing deuterated 3-cyanopyridine

[0078]

[0079] In a 15 mL dry sealed tube, 104.1 mg (1.0 mmol) of 3-cyanopyridine, 106.0 mg (1.0 mmol) of sodium acetate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 13.1 mg (0.05 mmol) of secondary phosphine oxide L4, 1.0 mL of dioxane, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 120 °C for 4 h under a nitrogen atmosphere, and the deuterated product of 3-cyanopyridine was extracted.

[0080] The 1H NMR spectrum of 3-cyanopyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ8.90(d,J=2.1Hz,1H),8.82(dd,J=5.0,1.7Hz,1H),7.97(dt,J=7.9,1.9Hz,1H),7.45(ddd,J=8.0,4.9,0.9Hz,1H);

[0081] The 1H NMR spectrum of deuterated 3-cyanopyridine is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.90 (dd, J=2.2, 0.9Hz, 0.53H, Labeled), 8.82 (dd, J=5 .0, 1.7Hz, 0.17H, Labeled), 7.98 (dt, J=8.0, 1.1Hz, 1H), 7.45 (dd, J=7.9, 1.5Hz, 1H).

[0082] Example 10: A method for preparing deuterated 3-trifluoromethylpyridine.

[0083]

[0084] In a 15 mL dry sealed tube, 147.1 mg (1.0 mmol) of 3-trifluoromethylpyridine, 106.0 mg (1.0 mmol) of sodium carbonate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 13.1 mg (0.05 mmol) of secondary phosphine oxide L4, 1.0 mL of toluene, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of 3-trifluoromethylpyridine was extracted.

[0085] The 1H NMR spectrum of 3-trifluoromethylpyridine is characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ8.90(d,J=2.4Hz,1H),8.81(dd,J=4.9,1.6Hz,1H),7.94(dt,J=8.0,2.1Hz,1H),7.45(dd,J=8.0,4.9Hz,1H);

[0086] The 1H NMR spectrum of deuterated 3-trifluoromethylpyridine is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.90–8.85 (m, 0.32H, Labeled), 8.78 (d, J = 4.3Hz, 0.11H, Labeled), 8.01 (d, J = 7.7Hz, 1H), 7.52 (d, J = 8.0Hz, 1H).

[0087] Example 11: A preparation method for deuterated pranoprofen.

[0088]

[0089] In a 15 mL dry sealed tube, 255.3 mg (1.0 mmol) of pranoprofen, 212.0 mg (2.0 mmol) of sodium oxalate, 16.6 mg (0.05 mmol) of palladium trifluoroacetate, 13.1 mg (0.05 mmol) of secondary phosphine oxide L4, 1.0 mL of tetrahydrofuran, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere to extract the deuterated product of pranoprofen.

[0090] The 1H NMR spectrum of pranoprofen is characterized as follows: 1 H NMR(400MHz, DMSO-d6)δ8.14(dd,J=4.9,1.9Hz,1H),7.73(dd,J=7.4,1.8Hz,1H),7.21–7.1 2(m,3H),7.08(d,J=8.1Hz,1H),4.12(s,2H),3.66(q,J=7.1Hz,1H),1.36(d,J=7.1Hz,3H);

[0091] The 1H NMR spectrum of deuterated pranoprofen is characterized as follows: 1 H NMR (400MHz, DMSO-d6) δ8.13 (dd, J=4.9, 1.9Hz, 0.50H, Labeled), 7.73 (dt, J=7.4, 1.1Hz, 1H), 7. 20–7.13(m,3H),7.08(d,J=8.1Hz,1H),4.12(s,2H),3.66(q,J=7.1Hz,1H),1.36(d,J=7.2Hz,3H).

[0092] Example 12: A preparation method for deuterated abiraterone acetate.

[0093]

[0094] In a 15 mL dry sealed tube, 255.3 mg (1.0 mmol) of abiraterone acetate, 106.0 mg (2.0 mmol) of sodium carbonate, 17.8 mg (0.10 mmol) of palladium chloride, 39.3 mg (0.15 mmol) of secondary phosphine oxide L4, 1.0 mL of tetrahydrofuran, and 2 mL of heavy water (99.9%) were added sequentially. The mixture was reacted at 100 °C for 6 h under a nitrogen atmosphere, and the deuterated product of abiraterone acetate was obtained by extraction.

[0095] The 1H NMR characterization of abiraterone acetate is as follows: 1H NMR(400MHz,Chloroform-d)δ8.62(dd,J=2.3,0.9Hz,1H),8.46(dd,J=4.9,1.6Hz,1H),7.66(dt ,J=7.9,1.9Hz,1H),7.23(ddd,J=8.0,4.8,0.9Hz,1H),6.00(dd,J=3.3,1.8Hz,1H),5.45–5.37(m ,1H),4.68–4.54(m,1H),2.41–2.31(m,2H),2.27(ddd,J=15.8,6.6,3.3Hz,1H),2.11-2.00(m,6H ),1.91–1.82(m,2H),1.82–1.54(m,6H),1.48(td,J=12.0,5.0Hz,1H),1.08(s,3H),1.04(s,3H);

[0096] The 1H NMR characterization of deuterated abiraterone acetate is as follows: 1 H NMR (400MHz, Chloroform-d) δ8.62 (dd, J=2.4, 0.9Hz, 0.92H, Labeled), 8.46 (dd, J=4.8, 1.6Hz, 0.37H , Labeled),7.68(dt,J=7.9,1.9Hz,1H),7.26–7.22(m,1H),6.01(dd,J=3.3,1.8Hz,1H),5.42(dt,J=5. 2,1.8Hz,1H),4.68–4.56(m,1H),2.40–2.32(m,2H),2.28(ddd,J=15.8,6.5,3.3Hz,1H),2.10-2.00(m, 6H),1.92–1.83(m,2H),1.82–1.55(m,6H),1.49(td,J=12.0,5.0Hz,1H)1.21–1.06(m,3H),1.05(s,3H).

[0097] Comparative Example 1: No secondary phosphorus oxides were added compared to Example 1.

[0098] Comparative Example 2: Compared with Example 1, Pd / C was used as the catalyst.

[0099] Comparative Example 3: Compared with Example 1, secondary phosphorus oxide was replaced with MPAA.

[0100] Comparative Example 4: Compared with Example 1, secondary phosphorus oxide was replaced with pyridinone.

[0101] Comparative Example 5: Compared with Example 1, secondary phosphorus oxides were replaced with acetate.

[0102] No reaction occurred in Comparative Examples 1-5. The following tests were performed on the obtained examples and comparative examples:

[0103] 1) The degree of deuteration was determined using proton nuclear magnetic resonance spectroscopy, and calculated using the following formula:

[0104]

[0105] Where A is the hydrogen peak area of ​​the deuterated sample, D is the degree of deuteration, m1 is the added mass of the deuterated sample in g, n1 is the number of H atoms to be deuterated in the deuterated sample, M1 is the relative molecular mass of the sample before deuteration in g, m2 is the added mass of the internal standard in g, n2 is the number of H atoms in the deuterated sample, and M2 is the relative molecular mass of the internal standard.

[0106] 2) Yield detection: The calculation formula is theoretical weight obtained / actual weight obtained * %.

[0107] The specific test results are shown in Table 1.

[0108] Table 1. Degree of deuteration and yield of examples and comparative examples.

[0109]

[0110]

[0111] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for selective deuteration of a pyridine compound, characterized by: The reaction raw materials include pyridine compounds, a catalytic system, heavy water and an organic solvent. The reaction is carried out in a nitrogen atmosphere at 80–120 °C for 4–12 h to obtain deuterated pyridine compounds. The catalytic system consists of divalent palladium salt, secondary phosphine oxide, and inorganic base; The structures of the pyridine compounds are as follows: , , , , , , , , , , , ; The structures of deuterated pyridine compounds are as follows: ； The organic solvent is selected from one of isopropanol, hexafluoroisopropanol, dichloroethane, toluene, tetrahydrofuran, and dioxane; The molecular structural formula of the secondary phosphine oxide is shown in any one of L1-L4: 。 2. The selective deuteration method for pyridine compounds according to claim 1, characterized in that: The molar ratio of the pyridine compound, divalent palladium salt, secondary phosphine oxide, inorganic base, heavy water, and organic solvent is 1:0.05~0.10:0.05~0.20:1.0~2.0:27.5~110:5~15.

3. The selective deuteration method for pyridine compounds according to claim 1, characterized in that: The inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, sodium pivalate, sodium oxalate, and sodium hydroxide.

4. The selective deuteration method for pyridine compounds according to claim 1, characterized in that: The divalent palladium salt is selected from palladium acetate, palladium trifluoroacetate, palladium pivalate, and palladium chloride.