A multi-round iterative preparation method for pyridine-d5

Abstract

The present invention discloses a multi-round iterative preparation method for pyridine-d5. 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 carbonate, the pyridine and heavy water are subjected to multiple rounds of hydrogen-deuterium exchange reactions. After one round of hydrogen-deuterium exchange reaction is completed, the liquid is separated to obtain an organic phase and an aqueous phase. New heavy water and potassium carbonate are added to the organic phase for the next round of hydrogen-deuterium exchange reaction. After the reaction is completed, the pyridine-d5 is obtained by separation and purification. The present invention uses a conventional liquid separation method to separate pyridine and heavy water, thereby realizing a multi-round iterative process, improving the utilization rate of deuterium, and reducing production costs.

Description

Technical Field

[0001] The present 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 have a wide range of medical applications in anti-tumor, anti-viral, anti-inflammatory, antioxidant, antibacterial, anti-diabetic and anti-cancer. Because the pyridine ring has the ability to carry multiple 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] Regarding the pyridine deuteration process, the applicant's previous application, CN117924003A, discloses a catalytic system consisting of a divalent palladium salt, a secondary phosphine oxide, and an inorganic base to achieve ortho-deuteration of the nitrogen atom in pyridine and its derivatives. CN117924003A only addresses deuteration of the ortho-nitrogen position and does not address full deuteration. Furthermore, the proposal provides no technical guidance on how to implement multiple rounds of full deuteration.

[0004] Patent CN116023324A discloses a method for preparing perdeuterated pyridine and its derivatives in an inert atmosphere using an alkali metal salt as a catalyst, pyridine and its derivatives as reactants, and deuterium gas as a deuterium source, in a sealed reaction at a predetermined temperature. Deuterated benzene is used as the reaction solvent, D2 is used as the deuterium source, and the high-pressure reaction is required. This method results in high material costs and harsh reaction conditions, making it difficult to scale up the process. Summary of the Invention

[0005] The present invention aims to provide a multi-round iterative preparation method for pyridine-d5, in which pyridine and heavy water can be separated by conventional liquid separation methods, thereby realizing a multi-round iterative process, improving the utilization rate of deuterium, and reducing production costs.

[0006] The technical solution adopted by the present invention to solve its technical problem is:

[0007] A multi-round iterative preparation method for pyridine-d5 comprises the following steps: using pyridine as a raw material and heavy water as a deuterium source reagent; carrying out multiple rounds of hydrogen-deuterium exchange reactions between the pyridine and heavy water in the presence of a catalyst and a base; and after one round of hydrogen-deuterium exchange reactions, separating the liquids to obtain an organic phase and an aqueous phase. Fresh heavy water and a base are added to the organic phase to carry out the next round of hydrogen-deuterium exchange reactions. After the reaction is completed, the mixture is separated and purified to obtain pyridine-d5.

[0008] In a hydrogen-deuterium exchange reaction, a single round of exchange is insufficient to meet the required degree of deuteration, often requiring multiple rounds of iteration. However, pyridine and heavy water are miscible, making conventional liquid separation difficult, resulting in significant waste. Furthermore, due to the azeotropic nature of pyridine and heavy water, separation by distillation is also difficult. Therefore, conventionally, it is not possible to prepare fully deuterated pyridine products through multiple rounds of iteration, resulting in low deuterium utilization. The present invention addresses the issue of multiple rounds of iteration for fully deuterated pyridine by adding a specific amount of base at specific times. In each round of hydrogen-deuterium exchange, the present invention adds heavy water and a base. The addition of the base in each round of hydrogen-deuterium exchange increases the density of the aqueous phase, allowing it to separate from the organic phase. This further enables multiple rounds of iteration, improving deuterium utilization and reducing production costs. The base in the present invention can also inhibit the binding force between pyridine and heavy water, thereby facilitating the separation of the two.

[0009] The mass ratio of pyridine: heavy water: base = 1.6: 1-3.2: 1-3.2.

[0010] The amount of catalyst used is 5-15% by weight of pyridine.

[0011] The catalyst is one of palladium-carbon, platinum-carbon, ruthenium-carbon and iridium-carbon. The palladium loading in the palladium-carbon is preferably 10%.

[0012] The base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium deuteride, potassium hydroxide, and potassium deuteride.

[0013] 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.

[0014] The reaction time of each round of hydrogen-deuterium exchange is 10-30 hours, and the reaction temperature is 90-120°C.

[0015] 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.

[0016] The reaction solution obtained from the hydrogen-deuterium exchange reaction is separated to obtain an organic phase. 10-12% by weight of potassium carbonate and 50-60% by weight of cyclohexane are added to the organic phase and stirred for 1-3 hours to remove moisture. The separated liquid is filtered to obtain the dehydrated organic phase. The dehydrated organic phase is subjected to atmospheric distillation to obtain purified pyridine-d5. The organic phase still contains a certain amount of moisture, and the addition of potassium carbonate and cyclohexane facilitates the separation of water and pyridine.

[0017] 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 production costs, and the product purity is greater than 99% and the deuteration degree is greater than 98%. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is the nuclear magnetic resonance detection image of the present invention;

[0019] Figure 2 It is a gas chromatographic detection diagram of the present invention. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further described in detail below through specific embodiments.

[0021] 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 examples, unless otherwise specified, are all conventional methods in the art.

[0022] Example 1

[0023] A multi-round iterative preparation method of pyridine-d5 comprises the following steps:

[0024] 1. Mix 160 g of pyridine, 100 g of heavy water, 100 g of potassium carbonate, and 16 g of 10% palladium on carbon. Control the reaction temperature to 115° C. and perform hydrogen-deuterium exchange reaction for 20 hours.

[0025] 2. After the first round of hydrogen-deuterium exchange reaction, the liquid was separated to obtain an organic phase and an aqueous phase. 200 g of a new mixture of heavy water and potassium carbonate (heavy water and potassium carbonate mass ratio of 1:1) was added to the organic phase. The reaction temperature was controlled at 115°C and the reaction was carried out for 20 hours. A total of five rounds of hydrogen-deuterium exchange reactions were performed.

[0026] 3. The reaction solution obtained after the hydrogen-deuterium exchange reaction was separated to obtain an organic phase. 10% by weight of potassium carbonate and 50% by weight of cyclohexane were added to the organic phase and stirred for 2 hours to remove moisture. The organic phase was filtered and separated. The organic phase was then subjected to atmospheric distillation, with the top temperature of the distillation tower controlled at 75°C and the bottom temperature at 98°C. The reflux ratio was controlled at 20:5, and fractions were collected after 2 hours of reflux. Purified pyridine-d5 was obtained by distillation.

[0027] The obtained pyridine-d5 was detected, with a mass of 133 g and a yield of 78.2%. Figure 1 Deuterium substitution 98.2%; see Figure 2 Purity 99.2%.

[0028] 1) Deuterium substitution detection: The deuterium substitution is detected by nuclear magnetic resonance hydrogen spectroscopy and calculated using the following formula:

[0029]

[0030] 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.

[0031] 2) Purity detection: gas chromatography is used for detection.

[0032] The preparation processes of Examples 2-9 are the same as those of Example 1, except for the addition amount of raw materials and process parameters, as shown in Table 1.

[0033] 3) Yield detection: The calculation formula is actual weight / theoretical weight*%.

[0034] Table 1

[0035]

[0036]

[0037] 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.

[0038] 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.

[0039] Example 8 differs from Example 1 in that the reaction solution obtained after the hydrogen-deuterium exchange reaction is separated to obtain an organic phase, 12% by weight of potassium carbonate and 60% by weight of cyclohexane are added to the organic phase, and the mixture is stirred for 3 hours to remove moisture. The separated liquid is filtered to obtain the organic phase. The organic phase is then subjected to atmospheric distillation, with the top temperature of the distillation tower controlled at 75°C and the bottom temperature at 98°C, and the reflux ratio controlled at 20:5. Fractions are collected after reflux for 2 hours, and purified pyridine-d5 is obtained by distillation.

[0040] The embodiment described above is only a preferred solution of the present invention and does not limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solution described in the claims.

Claims

1. A multi-round iterative preparation method of pyridine-d5, characterized in that: Using pyridine as a raw material and heavy water as a deuterium source reagent, 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 reaction is completed, the liquid is separated to obtain an organic phase and an aqueous phase. New heavy water and potassium carbonate are added to the organic phase to carry out the next round of hydrogen-deuterium exchange reaction. After the reaction is completed, the mixture is separated and purified to obtain pyridine-d5; The catalyst is one of palladium carbon, platinum carbon, and ruthenium carbon; the base is one of potassium carbonate, sodium carbonate, and cesium carbonate; The hydrogen-deuterium exchange reaction is carried out for 4-6 rounds; the reaction time of each round of hydrogen-deuterium exchange is 10-30 hours, and the reaction temperature is 90-120° C.; 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.

2. The multi-round iterative preparation method of pyridine-d5 according to claim 1, characterized in that the mass ratio of pyridine: heavy water: base is 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% of the weight of pyridine.

4. 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 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 liquid is filtered to obtain an organic phase from which moisture has been removed; and the organic phase from which moisture has been removed is subjected to atmospheric distillation to obtain purified pyridine-d5.

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