Multi-round iteration preparation method of pyridine-d5

Abstract

The invention discloses a multi-round iteration preparation method of pyridine-d5, which comprises the following steps: by taking pyridine as a raw material and heavy water as a deuterium source reagent, carrying out multi-round hydrogen-deuterium exchange reaction on the pyridine and the heavy water in the presence of a catalyst and carbonate, and after one-round hydrogen-deuterium exchange reaction is completed, separating liquid to obtain an organic phase and a water phase; adding new heavy water and potassium carbonate into the organic phase to carry out a next round of hydrogen-deuterium exchange reaction, and after the reaction is finished, separating and purifying to obtain pyridine-d5. According to the method, pyridine and heavy water can be separated by adopting a conventional liquid separation method, so that a multi-round iteration process is realized, the utilization rate of deuterium is increased, and the production cost is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of deuterated compound production, and in particular to a multi-round iterative preparation method of pyridine-d5. Background Art

[0002] Pyridine compounds are an important class of nitrogen heterocyclic compounds and the core structure of many natural products and drug molecules. They are widely used in medicine in anti-tumor, anti-viral, anti-inflammatory, antioxidant, antibacterial, anti-diabetic and anti-cancer aspects. Since the pyridine ring has the ability to carry multi-site substituents, the pharmacokinetics and pharmacodynamics of candidate drugs can be quickly optimized by changing the substituents. Among them, deuteration modification is a strategy to introduce deuterium isotopes (D) into drug molecules. The chemical properties of deuterium are similar to those of hydrogen, but due to its higher stability and lower lipophilicity, it can reduce the metabolic rate and reduce toxic side effects without significantly changing the drug structure. At the same time, it can prolong the half-life of drugs, reduce the frequency of medication, and help study drug metabolic pathways.

[0003] As for the pyridine deuteration process, the applicant's previous application CN117924003A discloses the use of a catalytic system consisting of a divalent palladium salt, a secondary phosphine oxide and an inorganic base to achieve the ortho-deuteration of the nitrogen atom of pyridine and its derivatives. CN117924003A only involves the deuteration of the ortho-position of nitrogen, and does not study the full deuteration. Moreover, the solution does not provide technical inspiration on how to solve the problem of how to perform multiple rounds of full deuteration.

[0004] Patent CN116023324A discloses: in an inert atmosphere, alkali metal salts are used as catalysts, pyridine and its derivatives are used as reactants, and deuterium gas is used as a deuterium source, and a closed reaction is performed at a predetermined temperature to prepare perdeuterated pyridine and its derivatives. Deuterobenzene is used as a reaction solvent, D2 is used as a deuterium source, and a high-pressure reaction is required, which has high material costs and harsh reaction conditions, and is not conducive to the scale-up production of the process. Summary of the invention

[0005] The object of the present invention is to provide a multi-round iterative preparation method of pyridine-d5, which can separate pyridine and heavy water by a conventional liquid separation method, thereby realizing a multi-round iterative process, improving the utilization rate of deuterium and reducing the production cost.

[0006] The technical solution adopted by the present invention to solve its technical problem is: A multi-round iterative preparation method of pyridine-d5, which uses pyridine as a raw material and heavy water as a deuterium source reagent, wherein the pyridine and heavy water are subjected to multiple rounds of hydrogen-deuterium exchange reactions in the presence of a catalyst and a base, after one round of hydrogen-deuterium exchange reactions is completed, liquid separation is performed to obtain an organic phase and an aqueous phase, new heavy water and a base are added to the organic phase to perform the next round of hydrogen-deuterium exchange reactions, and after the reaction is completed, the pyridine-d5 is obtained through separation and purification.

[0007] In the hydrogen-deuterium exchange reaction, one round of exchange is difficult to meet the requirements of the degree of deuteration, and multiple rounds of iteration are often required. However, pyridine and heavy water are miscible, and conventional liquid separation operations are difficult to effectively separate, resulting in great waste; in addition, due to the azeotropic phenomenon of pyridine and heavy water, it is also difficult to separate by distillation. Therefore, under normal circumstances, it is impossible to prepare the full deuterated product of pyridine by the method of multiple rounds of iteration, which causes the problem of low utilization rate of deuterium. In order to solve the problem of multiple rounds of iteration of pyridine full deuteration, the present invention is realized by adding a specific amount of base at a specific time. In each round of hydrogen-deuterium exchange reaction, the present invention adds heavy water and base, and by adding base in each round of hydrogen-deuterium exchange reaction, the density of the aqueous phase is increased, thereby separating from the organic phase, and further realizing the process of multiple rounds of iteration, improving the utilization rate of deuterium and reducing production costs. The base in the present invention can also inhibit the binding force of pyridine and heavy water, thereby facilitating the separation of pyridine and heavy water.

[0008] The mass ratio of pyridine: heavy water: base = 1.6: 1-3.2: 1-3.2.

[0009] The amount of catalyst used is 5-15% by weight of pyridine.

[0010] The catalyst is one of palladium carbon, platinum carbon, ruthenium carbon and iridium carbon. The palladium loading in the palladium carbon is preferably 10%.

[0011] The base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium deuteride, potassium hydroxide and potassium deuteride.

[0012] The hydrogen-deuterium exchange reaction is carried out for at least 2 rounds. Preferably, the hydrogen-deuterium exchange reaction is carried out for 4-6 rounds.

[0013] The reaction time of each round of hydrogen-deuterium exchange is 10-30 hours, and the reaction temperature is 90-120°C.

[0014] The amounts of heavy water and base newly added to the organic phase are the same as those used in the first round of hydrogen-deuterium exchange reaction.

[0015] The reaction liquid obtained by the hydrogen-deuterium exchange reaction is separated to obtain an organic phase, 10-12%wt of potassium carbonate and 50-60%wt of cyclohexane are added to the organic phase, and the mixture is stirred for 1-3 hours to remove moisture; the separated liquid is filtered to obtain an organic phase from which moisture has been removed; the organic phase from which moisture has been removed is subjected to atmospheric distillation to obtain purified pyridine-d5. There is still a certain amount of moisture in the organic phase, and the addition of potassium carbonate and cyclohexane is beneficial to the separation of water and pyridine.

[0016] The beneficial effects of the present invention are: pyridine and heavy water can be separated by a conventional liquid separation method, thereby realizing a multi-round iterative process, improving the utilization rate of deuterium, reducing the production cost, and the product purity is greater than 99%, and the deuteration degree is greater than 98%. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a nuclear magnetic resonance detection image of the present invention; Figure 2 It is a gas chromatographic detection diagram of the present invention. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further described in detail below through specific embodiments.

[0019] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.

[0020] Example 1 A multi-round iterative preparation method of pyridine-d5 comprises the following steps: 1. Mix 160 g pyridine, 100 g heavy water, 100 g potassium carbonate and 16 g 10% palladium carbon, control the reaction temperature to 115°C, and perform hydrogen-deuterium exchange reaction for 20 hours.

[0021] 2. After the first round of hydrogen-deuterium exchange reaction, separate the liquid to obtain an organic phase and an aqueous phase, add 200 g of a new mixture of heavy water and potassium carbonate (the mass ratio of heavy water to potassium carbonate is 1:1) to the organic phase, control the reaction temperature to 115°C, and react for 20 hours; a total of five rounds of hydrogen-deuterium exchange reactions are performed.

[0022] 3. The reaction liquid obtained after the hydrogen-deuterium exchange reaction is separated to obtain an organic phase, and potassium carbonate accounting for 10%wt and cyclohexane accounting for 50%wt of the organic phase are added, and the water is removed by stirring for 2 hours; the organic phase is filtered and separated. Then the organic phase is distilled at normal pressure, the top temperature of the distillation tower is controlled at 75°C, the bottom temperature is controlled at 98°C, the reflux ratio is controlled at 20:5, and the fractions are collected after reflux for 2 hours; the purified pyridine-d5 is obtained by distillation.

[0023] The obtained pyridine-d5 was tested, with a mass of 133 g and a yield of 78.2%, see Figure 1 Deuterium degree 98.2%; see Figure 2 Purity 99.2%.

[0024] 1) Deuterium substitution detection: The deuterium substitution is detected by nuclear magnetic resonance hydrogen spectroscopy and calculated using the following formula: Wherein, 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.

[0025] 2) Purity detection: gas chromatography is used for detection.

[0026] For Examples 2-9, the preparation process thereof is the same as that of Example 1, except for the addition amount of raw materials and process parameters, as shown in Table 1.

[0027] 3) Yield detection: The calculation formula is actual weight / theoretical weight*%.

[0028] Table 1

[0029] The process of Comparative Example 1 is similar to that of Example 2, except that potassium carbonate is not added in all rounds of hydrogen-deuterium exchange reactions.

[0030] The process of Comparative Example 2 is the same as that of Example 2, except that potassium carbonate is not added starting from the second round of hydrogen-deuterium exchange reaction.

[0031] The difference between Example 8 and Example 1 is that: the reaction liquid obtained after the hydrogen-deuterium exchange reaction is separated to obtain an organic phase, 12%wt of potassium carbonate and 60%wt of cyclohexane are added to the organic phase, and the water is removed by stirring for 3 hours; the organic phase is filtered and separated. Then, the organic phase is subjected to atmospheric distillation, the top temperature of the distillation tower is controlled to be 75°C, the bottom temperature is controlled to be 98°C, the reflux ratio is controlled to be 20:5, and the fraction is collected after reflux for 2 hours; and the purified pyridine-d5 is obtained by distillation.

[0032] The above-described embodiment is only a preferred solution of the present invention and does not limit the present invention in any form. There are other variations and modifications without exceeding the technical solution described in the claims.

Claims

1. A multi-round iterative preparation method of pyridine-d5, characterized in that: Pyridine is used as a raw material and heavy water is used as a deuterium source reagent. In the presence of a catalyst and a base, the pyridine and heavy water undergo multiple rounds of hydrogen-deuterium exchange reactions. After one round of hydrogen-deuterium exchange reactions is completed, the liquids are separated to obtain an organic phase and an aqueous phase. New heavy water and potassium carbonate are added to the organic phase to perform the next round of hydrogen-deuterium exchange reactions. After the reaction is completed, pyridine-d5 is obtained through separation and purification.

2. A multi-round iterative preparation method of pyridine-d5 according to claim 1, characterized in that the mass ratio of pyridine: heavy water: base = 1.6: 1-3.2: 1-3.

2.

3. The multi-round iterative preparation method of pyridine-d5 according to claim 2, characterized in that: The amount of catalyst used is 5-15% by weight of pyridine.

4. A multi-round iterative preparation method of pyridine-d5 according to claim 1, 2 or 3, characterized in that: The catalyst is one of palladium carbon, platinum carbon, ruthenium carbon and iridium carbon.

5. A multi-round iterative preparation method of pyridine-d5 according to claim 1, 2 or 3, characterized in that: The base is one of potassium carbonate, sodium carbonate and cesium carbonate.

6. A multi-round iterative preparation method of pyridine-d5 according to claim 1, 2 or 3, characterized in that: The hydrogen-deuterium exchange reaction is performed for at least 2 rounds.

7. The multi-round iterative preparation method of pyridine-d5 according to claim 6, characterized in that: The hydrogen-deuterium exchange reaction was carried out for 4-6 cycles.

8. A multi-round iterative preparation method of pyridine-d5 according to claim 1, 2 or 3, characterized in that: The reaction time of each round of hydrogen-deuterium exchange is 10-30 hours, and the reaction temperature is 90-120°C.

9. The multi-round iterative preparation method of pyridine-d5 according to claim 1, characterized in that: The amounts of heavy water and potassium carbonate newly added to the organic phase are the same as those used in the first round of hydrogen-deuterium exchange reaction.

10. The multi-round iterative preparation method of pyridine-d5 according to claim 1, characterized in that: The reaction liquid obtained by the hydrogen-deuterium exchange reaction is separated to obtain an organic phase, 10-12%wt potassium carbonate and 50-60%wt cyclohexane are added to the organic phase, and the mixture is stirred for 1-3 hours to remove moisture; the separation is filtered to obtain an organic phase from which moisture has been removed; the organic phase from which moisture has been removed is distilled at normal pressure to obtain purified pyridine-d5.

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