A method for synthesizing a perdeuterated nitrogen heterocycle compound

Abstract

This invention provides a method for synthesizing fully deuterated nitrogen heterocyclic compounds, relating to the field of organic chemical synthesis technology. The method includes the following steps: under nitrogen protection, a nitrogen heterocyclic compound, a palladium-on-carbon catalyst, a sodium borohydride co-catalyst, and deuterated water are mixed, and a hydrogen-deuterium exchange reaction is performed to obtain the fully deuterated nitrogen heterocyclic compound. This invention employs a palladium-on-carbon and sodium borohydride synergistic catalytic system, using inexpensive and readily available deuterated water as the sole deuterium source, and efficiently achieves the fully deuterated labeling of various nitrogen heterocyclic compounds under mild conditions of 130°C without the need for external hydrogen. This method has advantages such as mild reaction conditions, simple operation, readily available and inexpensive deuterium source, wide substrate applicability, high deuteration rate, and excellent yield, providing a safe, economical, and efficient new route for the research and synthesis of deuterated drugs.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a method for synthesizing fully deuterated nitrogen heterocyclic compounds. Background Technology

[0002] Holodeuterated nitrogen heterocyclic compounds have significant applications in organic synthesis, medicinal chemistry, and life sciences. Nitrogen heterocyclic compounds are a class of organic molecules containing at least one nitrogen atom in their cyclic structure, widely found in nature; common types include pyridine, quinoline, and indole. These compounds possess a variety of biological activities, including antibacterial, antiviral, antitumor, anti-inflammatory, nervous system activity, enzyme inhibition, and antimalarial activity, and are widely used in food, health care, pharmaceuticals, and daily chemical industries. Studies have shown that deuteration strategies can significantly improve the pharmacokinetics and metabolic stability of drugs, a phenomenon known as the "deuteration effect." Therefore, holodeuterated nitrogen heterocyclic compounds have unique research value and application prospects in nuclear energy, military applications, analytical testing, medical testing, polymer synthesis and modification, and pharmaceuticals. Based on this, developing efficient, safe, and economical synthetic methods for holodeuterated nitrogen heterocyclic compounds is of significant practical importance.

[0003] Currently, the synthetic methods for fully deuterated nitrogen heterocyclic compounds can be mainly divided into the following two categories:

[0004] Method 1 is a transition metal-catalyzed hydrogen-deuterium exchange method. This method involves mixing a nitrogen heterocyclic compound, a deuterating agent, and a transition metal catalyst (such as palladium or platinum), reacting them under a nitrogen or inert gas atmosphere to obtain the deuterated product. However, this technical route has the following drawbacks: firstly, the reaction conditions are harsh, typically requiring high temperatures (above 150°C) or hydrogen as a promoter to maintain the catalytic cycle; secondly, the substrate applicability is limited, mainly suitable for structurally simple nitrogen heterocyclic compounds, and its adaptability is poor for structurally complex drug molecules. The general reaction formula is as follows:

[0005] ;

[0006] Method two is the condensation-oxidation method. This method involves heating ethyl deuterated acetoacetate, an aldehyde, and ammonia in ethanol under reflux to condense them into deuterated 1,4-dihydropyridine, which is then oxidized with an oxidizing agent to obtain the fully deuterated pyridine derivative. The drawbacks of this technical route are: it cannot synthesize the target product in one step, the reaction steps are cumbersome, and the post-processing is complex. Its general reaction formula is:

[0007] .

[0008] In summary, existing methods for synthesizing fully deuterated nitrogen heterocyclic compounds suffer from drawbacks such as demanding reaction conditions (high temperature, hydrogen requirement), high cost of deuterium sources, narrow substrate applicability, and cumbersome synthesis steps. Therefore, there is an urgent need to develop a method for synthesizing fully deuterated nitrogen heterocyclic compounds that offers mild reaction conditions, safety and reliability, readily available and inexpensive deuterium sources, broad substrate applicability, and simple operation. Summary of the Invention

[0009] The purpose of this invention is to provide a method for synthesizing fully deuterated nitrogen heterocyclic compounds.

[0010] In a first aspect, the present invention provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps: under nitrogen protection, mixing a nitrogen heterocyclic compound, a palladium on carbon catalyst, a sodium borohydride co-catalyst, and deuterium water, and obtaining the fully deuterated nitrogen heterocyclic compound through a hydrogen-deuterium exchange reaction.

[0011] Optionally, the nitrogen heterocyclic compound is an aromatic heterocyclic compound containing at least one nitrogen atom; the nitrogen heterocyclic compound includes one of pyridine compounds, quinoline compounds, phenanthroline compounds, or indole compounds.

[0012] Optionally, the structural formula of the nitrogen heterocyclic compound includes one of the following formulas (I), (II), (III) or (IV);

[0013] ;

[0014] ;

[0015] ;

[0016] ;

[0017] R includes one of the following: methyl, hydroxyl, amino, halogen, methoxy, carboxyl, ethyl, acetic acid, acetyl, and aldehyde.

[0018] Optionally, the hydrogen-deuterium exchange reaction is carried out under heating and stirring conditions, with a reaction temperature of 120-140℃ and a reaction time of 12-24h.

[0019] Optionally, the palladium-on-carbon catalyst is a 10% palladium-on-carbon catalyst; the molar ratio of the 10% palladium-on-carbon catalyst to the nitrogen heterocyclic compound is (0.5-1.5):10.

[0020] Optionally, the molar ratio of the sodium borohydride cocatalyst to the nitrogen heterocyclic compound is (0.5-1.5):10.

[0021] Optionally, the amount of deuterium water used is 0.5-1 mL per 0.25 mmol of nitrogen heterocyclic compound.

[0022] Optionally, the method includes the following steps: adding the nitrogen heterocyclic compound, palladium on carbon catalyst, and solubilizer into a reaction tube, purging with nitrogen three times, then adding sodium borohydride co-catalyst and deuterium water, and heating and stirring to obtain a fully deuterated nitrogen heterocyclic compound.

[0023] Optionally, the solubilizer is tetrabutylammonium bromide.

[0024] Compared with the prior art, the present invention has the following advantages:

[0025] (1) The synthesis method provided by the present invention can efficiently realize the hydrogen-deuterium exchange reaction without the need for external hydrogen as a carrier gas by using a palladium on carbon and sodium borohydride synergistic catalytic system, avoiding the safety hazards caused by using flammable and explosive hydrogen, and reducing the need for high-pressure equipment, making the reaction operation safer and simpler.

[0026] (2) The synthesis method provided by the present invention has a reaction temperature of only 130°C, which is milder than the conditions that usually require temperatures of 150°C or even higher in the prior art. At the same time, the reaction time is controlled at 12-24 hours, achieving an optimized balance between energy consumption and efficiency.

[0027] (3) The synthesis method provided by the present invention uses green and inexpensive deuterated water as the only deuterium source, without the need to use expensive deuterated reagents or gaseous deuterium gas, which significantly reduces the production cost and has good economic feasibility and industrial application prospects.

[0028] (4) The synthesis method provided by the present invention has a wide range of substrate applications. It is not only applicable to simple nitrogen heterocyclic compounds such as pyridine, quinoline, phenanthroline, and indole, but also compatible with derivatives containing sensitive functional groups such as hydroxyl, amino, and halogen. It can even be successfully applied to the full deuteration modification of complex natural products and drug molecules such as quinine, omeprazole, and levofloxacin, demonstrating excellent functional group tolerance and substrate universality.

[0029] (5) The synthesis method provided by the present invention, through the synergistic effect of palladium on carbon / sodium borohydride catalytic system and deuterium water, can obtain a high deuteration rate of 74%-99% and a good to excellent yield of 55%-99%, thus realizing efficient and highly selective full deuteration labeling;

[0030] (6) The synthesis method provided by the present invention is simple in post-reaction processing. It only requires conventional extraction, drying and column chromatography separation to obtain pure products. The operation process is simple and easy to promote and apply to fields such as drug development, metabolic mechanism research and environmental assessment. Attached Figure Description

[0031] Figure 1 This is the 1H NMR spectrum of compound 1b in deuterated CDCl3 in this invention;

[0032] Figure 2 This is the carbon NMR spectrum of compound 2b in deuterated CDCl3 in this invention;

[0033] Figure 3 This is the 1H NMR spectrum of compound 3b in deuterated CDCl3 in this invention;

[0034] Figure 4 This is the carbon NMR spectrum of compound 4b in deuterated CDCl3 in this invention;

[0035] Figure 5 This is the 1H NMR spectrum of compound 5b in deuterated CDCl3 in this invention;

[0036] Figure 6 This is the carbon NMR spectrum of compound 6b in deuterated CDCl3 in this invention;

[0037] Figure 7 This is the 1H NMR spectrum of compound 7b in deuterated CDCl3 in this invention;

[0038] Figure 8 This is the carbon NMR spectrum of compound 8b in deuterated CDCl3 in this invention;

[0039] Figure 9 This is the 1H NMR spectrum of compound 9b in deuterated CDCl3 in this invention;

[0040] Figure 10 This is the carbon NMR spectrum of compound 10b in deuterated D2O in this invention;

[0041] Figure 11 This is the 1H NMR spectrum of compound 11b in deuterated CD3OD in this invention;

[0042] Figure 12 This is the carbon NMR spectrum of compound 12b in deuterated CDCl3 in this invention;

[0043] Figure 13 This is the 1H NMR spectrum of compound 13b in deuterated CDCl3 in this invention;

[0044] Figure 14 This is the carbon NMR spectrum of compound 14b in deuterated CDCl3 in this invention;

[0045] Figure 15 This is the carbon NMR spectrum of compound 15b in deuterated CD3OD in this invention;

[0046] Figure 16 This is the carbon NMR spectrum of compound 16b in deuterated CDCl3 in this invention;

[0047] Figure 17 This is the carbon NMR spectrum of compound 17b in deuterated CD3OD in this invention;

[0048] Figure 18 This is the carbon NMR spectrum of compound 18b in deuterated CD3OD. Detailed Implementation

[0049] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0050] This invention provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps: under nitrogen protection, mixing a nitrogen heterocyclic compound, a palladium on carbon catalyst, a sodium borohydride co-catalyst, and deuterium water, and then performing a hydrogen-deuterium exchange reaction to obtain the fully deuterated nitrogen heterocyclic compound.

[0051] In fact, in the synthetic method of this invention, palladium interacts with sodium borohydride to generate a highly active metal hydride intermediate in situ. This intermediate preferentially coordinates with the nitrogen atom of the nitrogen heterocyclic compound and further activates the CH bond on the aromatic ring. Subsequently, the activated hydrogen atom undergoes an efficient hydrogen-deuterium exchange reaction with deuterium water in the system, thereby achieving full deuteration labeling of the nitrogen heterocyclic compound molecule. This method uses a palladium-on-carbon and sodium borohydride synergistic catalytic system, with green and inexpensive deuterium water as the sole deuterium source, and can efficiently achieve full deuteration labeling of various nitrogen heterocyclic compounds under mild conditions that do not require high temperatures (above 150°C) and external hydrogen. The synthetic method used in this invention has the advantages of mild reaction conditions, simple operation, inexpensive and readily available deuterium source, wide substrate applicability, high deuteration rate, and excellent yield, providing a safe, economical, and efficient new route for the research and synthesis of deuterated drugs.

[0052] In some embodiments, the nitrogen heterocyclic compound used is an aromatic heterocyclic compound containing at least one nitrogen atom; the nitrogen heterocyclic compound includes one of pyridine compounds, quinoline compounds, phenanthroline compounds, or indole compounds.

[0053] In some embodiments, the nitrogen heterocyclic compound used has a structural formula including one of the following formulas (I), (II), (III) or (IV);

[0054] ;

[0055] ;

[0056] ;

[0057] ;

[0058] R includes one of the following: methyl, hydroxyl, amino, halogen, methoxy, carboxyl, ethyl, acetic acid, acetyl, and aldehyde.

[0059] In some embodiments, the hydrogen-deuterium exchange reaction is carried out under heating and stirring conditions at a temperature of 120-140°C for a time of 12-24 hours.

[0060] Specifically, the preferred reaction temperature is 130°C.

[0061] Specifically, the reaction formula of the synthesis method of the present invention includes one of the following formulas (V), (VI), (VII) or (VIII);

[0062] ;

[0063] ;

[0064] ;

[0065] .

[0066] In some embodiments, the palladium on carbon (Pd / C) catalyst used is a 10% palladium on carbon catalyst; 55% wet basis; the molar ratio of the 10% palladium on carbon catalyst to the nitrogen heterocyclic compound is (0.5-1.5):10.

[0067] Specifically, the preferred molar ratio of the 10% palladium catalyst on carbon to the nitrogen heterocyclic compound is 0.88:10.

[0068] In some embodiments, the molar ratio of sodium borohydride (NaBH4) cocatalyst to nitrogen heterocyclic compound is (0.5-1.5):10.

[0069] Specifically, the preferred molar ratio of sodium borohydride cocatalyst to nitrogen heterocyclic compound is 1:10.

[0070] In some embodiments, the amount of deuterium water (D2O) used is 0.5-1 mL per 0.25 mmol of nitrogen heterocyclic compound.

[0071] Specifically, the amount of deuterium water used is 0.5 mL for every 0.25 mmol of nitrogen heterocyclic compound.

[0072] In some embodiments, the synthesis method includes the following steps: adding a nitrogen heterocyclic compound, a palladium catalyst on carbon, and a solubilizer into a reaction tube, purging with nitrogen three times, then adding sodium borohydride co-catalyst and deuterium water, and heating and stirring to obtain a fully deuterated nitrogen heterocyclic compound.

[0073] In some embodiments, the solubilizer used is tetrabutylammonium bromide (TBAB).

[0074] Example 1

[0075] Example 1 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0076] Weigh out 55% wet basis, 10% Pd / C catalyst (23 mg, 0.22 mmol), and solubilizer TBAB (80 mg, 0.25 mmol) respectively, and add them sequentially to a Young's tube. Then, purge with nitrogen three times to maintain the nitrogen environment. Next, add 0.5 mL of D₂O, 4-methylquinoline 1a (31 μL, 0.25 mmol), and co-catalyst NaBH₄ (1 mg, 0.025 mmol). Seal the Young's tube, heat to 130 °C, and stir for 12 h. Extract three times with ethyl acetate, filter, and wash three times with water. Combine the organic phases and dry them with anhydrous sodium sulfate. Then, evaporate the organic phase using a rotary evaporator to obtain the fully deuterated 4-methylquinoline derivative 1b. The product is a colorless liquid with a deuteration rate of 89% and a yield of 95%. The synthetic route is as follows:

[0077]

[0078] The fully deuterated 4-methylquinoline derivative 1b synthesized in Example 1 was characterized by 1H NMR (600MHz, CDCl3) as follows: Figure 1 As shown, the specific data is as follows: 1 H NMR (600MHz, CDCl3) δ 8.65 (s, 0.03H), 7.98 (s, 0.04H), 7.86 (s, 0.53H), 7.57 (s, 0.04H), 7.44 (d, J=8.45Hz, 0.04H), 7.10 (s, 0.06H), 4.04-3.96 (m, 6.00H), 2.54 (s, 0.10H).

[0079] Example 2 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0080] Weigh out 55% wet basis, 10% Pd / C catalyst (23 mg, 0.22 mmol), and solubilizer TBAB (80 mg, 0.25 mmol) respectively, and add them sequentially to a Young's tube. Then, purge with nitrogen three times to maintain the nitrogen environment. Next, add 0.5 mL D₂O, quinoline 2a (29 μL, 0.25 mmol), and co-catalyst NaBH₄ (1 mg, 0.025 mmol). Seal the Young's tube, heat to 130 °C, and stir for 12 h. Extract three times with ethyl acetate, filter, and wash three times with water. Combine the organic phases and dry them with anhydrous sodium sulfate. Then, evaporate the organic phase using a rotary evaporator to obtain the fully deuterated quinoline derivative 2b. The product is a colorless liquid with a deuteration rate of 90% and a yield of 87%. The synthetic route is as follows:

[0081]

[0082] The fully deuterated quinoline derivative 2b synthesized in Example 2 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 2 As shown; the fully deuterated quinoline derivative 2b synthesized in Example 2 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ 8.82 (s, 0.03H), 8.06 (s, 0.03H), 8.02 (s, 0.03H), 7.72 (t, J=0.28Hz, 11H), 7.61 (s, 0.10H), 7.48-7.39 (m, 0.22H), 7.29 (s, 0.03H), 4.04-3.96 (m, 6.00H).

[0083] Example 3 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0084] 36 mg (0.25 mmol) of 8-hydroxyquinoline 3a, 55% wet basis, 23 mg (0.22 mmol) of 10% Pd / C catalyst, and 80 mg (0.25 mmol) of solubilizer TBAB were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain a nitrogen atmosphere. 0.5 mL of D₂O and 1 mg (0.025 mmol) of co-catalyst NaBH₄ were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 12 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated quinoline derivative 3b. The product was a white solid with a deuteration rate of 96% and a yield of 99%. The synthetic route is as follows:

[0085]

[0086] The fully deuterated quinoline derivative 3b synthesized in Example 3 was characterized by 1H NMR (600MHz, CDCl3) as follows: Figure 3 As shown, the specific data is as follows: 1 H NMR (600MHz, CDCl3) δ 8.69 (s, 0.04H), 8.05 (s, 0.05H), 7.35 (s, 0.04H), 7.32 (s, 0.04H), 7.23 (s, 0.04H), 7.08 (s, 0.04H), 4.04 -3.96 (m, 6.00H).

[0087] Example 4 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0088] 36 mg (0.25 mmol) of 8-aminoquinoline 4a, 55% wet basis, 23 mg (0.22 mmol) of 10% Pd / C catalyst, and 80 mg (0.25 mmol) of solubilizer TBAB were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. 0.5 mL of D₂O and 1 mg (0.025 mmol) of co-catalyst NaBH₄ were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 12 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated quinoline derivative 4b. The product was a white solid with a deuteration rate of 97% and a yield of 99%. The synthetic route is as follows:

[0089]

[0090] The fully deuterated quinoline derivative 4b synthesized in Example 4 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 4 As shown; the fully deuterated quinoline derivative 4b synthesized in Example 4 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ 8.65 (s, 0.03H), 7.95 (s, 0.03H), 7.24 (s, 0.03H), 7.21 (s, 0.03H), 7.03 (s, 0.04H), 6.82 (s, 0.04H), 4.04 -3.96 (m,6.00H).

[0091] Example 5 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0092] 40 mg (0.25 mmol) of 6-fluoro-2-methylquinoline 5a, 55% wet basis, 23 mg (0.22 mmol) of 10% Pd / C catalyst, and 80 mg (0.25 mmol) of solubilizer TBAB were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain a nitrogen atmosphere. 0.5 mL of D₂O and 1 mg (0.025 mmol) of co-catalyst NaBH₄ were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 12 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated quinoline derivative 5b. The product was a white solid with a deuteration rate of 74% and a yield of 95%. The synthetic route is as follows:

[0093]

[0094] The fully deuterated quinoline derivative 5b synthesized in Example 5 was characterized by 1H NMR (600MHz, CDCl3) as follows: Figure 5 As shown, the specific data is as follows: 1 H NMR (600MHz, CDCl3) δ 7.93 (d, J = 4.54 Hz, 0.04H), 7.92-7.89 (m, 0.11H), 7.35 (d, J = 8.36 Hz, 0.10H), 7.30 (d, J = 8.81 Hz, 0.43H), 7.21 (s, 0.32H), 4.04-3.96 (m, 6.00H), 2.62 (d, J = 11.17 Hz, 0.24H).

[0095] Example 6 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0096] 45 mg (0.25 mmol) of 1,10-phenanthroline 6a, 55% wet basis, 23 mg (0.22 mmol) of 10% Pd / C catalyst, and 80 mg (0.25 mmol) of solubilizer TBAB were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain a nitrogen atmosphere. 0.5 mL of D₂O and 1 mg (0.025 mmol) of co-catalyst NaBH₄ were added. The Young's tube was then sealed and heated to 130 °C, stirred for 24 h, extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated phenanthroline derivative 6b. The product was a white solid with a deuteration rate of 96% and a yield of 96%. The synthetic route is as follows:

[0097]

[0098] The fully deuterated phenanthroline derivative 6b synthesized in Example 6 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 6 As shown; the fully deuterated phenanthroline derivative 6b synthesized in Example 6 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ9.10 (s, 0.07H), 8.14 (s, 0.08H), 7.68 (s,0.08H), 7.53 (s, 0.08H), 4.05-3.96 (m, 6.00H).

[0099] Example 7 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0100] 40 mg (0.25 mmol) of 1-methyl-2-quinolinone 7a, 55% wet basis, 23 mg (0.22 mmol) of 10% Pd / C catalyst, and 80 mg (0.25 mmol) of solubilizer TBAB were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain a nitrogen atmosphere. 0.5 mL of D₂O and 1 mg (0.025 mmol) of co-catalyst NaBH₄ were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 12 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated quinolinone derivative 7b. The product was a white solid with a deuteration rate of 68% and a yield of 88%. The synthetic route is as follows:

[0101]

[0102] The fully deuterated quinolinone derivative 7b synthesized in Example 7 was characterized by 1H NMR (600MHz, CDCl3) as follows: Figure 7 As shown, the specific data is as follows: 1 H NMR (600MHz, CDCl3) δ7.56 (s, 0.13H), 7.49-7.43 (m,0.55H), 7.16-7.10 (m, 0.44H), 7.07-7.03 (m, 0.14H), 6.89 (dt, J = 16.80, 4.13Hz, 0.35H), 6.60-6.57 (m, 0.07H), 4.00 (dq, J = 8.13, 7.05 Hz, 6.00H), 3.61(s, 1.43H).

[0103] Example 8 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0104] Indole 8a (29 mg, 0.25 mmol), 55% wet basis, and 10% Pd / C catalyst (23 mg, 0.22 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. Next, 0.5 mL of D₂O and the co-catalyst NaBH₄ (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with dichloromethane, filtered, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated indole derivative 8b. The product was a white solid with a deuteration rate of 91% and a yield of 55%. The synthetic route is as follows:

[0105]

[0106] The fully deuterated indole derivative 8b synthesized in Example 8 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 8 As shown; the fully deuterated indole derivative 8b synthesized in Example 8 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ8.57-8.54 (m, 1H), 7.52 (d, J = 2.84 Hz, 0.06H), 7.26 (d, J = 2.89 Hz, 0.08H), 7.12 (d, J = 1.63 Hz, 0.11H), 7.08-7.03 (m, 0.15H), 6.98 (d, J = 2.88 Hz, 0.12H), 6.41 (d, J = 2.13 Hz, 0.07H), 4.04-3.96 (m, 6.00H).

[0107] Example 9 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0108] Weigh out 55% wet basis and 10% Pd / C catalyst (23 mg, 0.22 mmol), add to a Young's tube, then purge with nitrogen three times to maintain a nitrogen environment. Next, add 0.5 mL of D₂O, 39 μL (0.25 mmol) of 4-chloroindole 9a, and NaBH₄ (1 mg, 0.025 mmol) as a co-catalyst. Seal the Young's tube, heat to 130 °C, and stir for 24 h. Extract three times with dichloromethane, filter, and dry the organic phase with anhydrous sodium sulfate. Then, evaporate the organic phase using a rotary evaporator to obtain the fully deuterated indole derivative 9b. The product is a yellow liquid with a deuteration rate of 88% and a yield of 99%. The synthetic route is as follows:

[0109]

[0110] The fully deuterated indole derivative 9b synthesized in Example 9 was characterized by 1H NMR (600MHz, CDCl3) as follows: Figure 9 As shown, the specific data is as follows: 1 H NMR (600MHz, CDCl3) δ7.20-7.16 (m, 0.16H), 7.08 (s, 0.04H), 6.94 (s, 0.27H), 6.75 (s, 0.05H), 6.49 (s, 0.06H), 4.04-3.96 (m,6.00H).

[0111] Example 10 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0112] D-tryptophan 10a (51 mg, 0.25 mmol), 55% wet basis, and 10% Pd / C catalyst (23 mg, 0.22 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. Next, 0.5 mL of D₂O and the co-catalyst NaBH₄ (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with dichloromethane, filtered, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated tryptophan derivative 10b. The product was a white solid with a deuteration rate of 81% and a yield of 99%. The synthetic route is as follows:

[0113]

[0114] The fully deuterated tryptophan derivative 10b synthesized in Example 10 was characterized by carbon NMR (600 MHz, D2O) as follows: Figure 10 As shown; the fully deuterated tryptophan derivative 10b synthesized in Example 10 was characterized by 1H NMR (600MHz, D2O), and the specific data are as follows:1 H NMR (600MHz, D2O) δ7.59-7.54 (m, 0.34H), 7.38-7.35 (m, 0.03H), 7.13-7.09 (m, 0.22H), 7.05-7.01 (m, 0.25H), 6.98 (dt, J = 7.63, 3.59 Hz, 0.08H), 4.05-3.96 (m, 6.00H), 3.86 (s, 0.28H), 3.30 (d, J = 4.63 Hz, 0.02H), 2.84 (s, 0.01H).

[0115] Example 11 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0116] 5-Hydroxytryptophan 11a (55 mg, 0.25 mmol), 55% wet basis, and 10% Pd / C catalyst (23 mg, 0.22 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. Next, 0.5 mL of D₂O and the co-catalyst NaBH₄ (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with dichloromethane, filtered, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated 5-hydroxytryptophan derivative 11b. The product was a white solid with a deuteration rate of 80% and a yield of 99%. The synthetic route is as follows:

[0117]

[0118] The fully deuterated 5-hydroxytryptophan derivative 11b synthesized in Example 11 was characterized by 1H NMR (600MHz, CD3OD) as follows: Figure 11 As shown, the specific data is as follows: 1 H NMR (600MHz, CD3OD) δ7.14- 7.08 (m, 0.13H), 7.05 (d, J = 5.99 Hz, 0.12H), 7.01 (t, J = 7.22 Hz, 0.06H), 6.62-6.59 (m, 0.04H), 4.05-3.96 (m, 6.00H), 3.73 (s, 0.53H), 3.32 (d, J = 4.00 Hz, 0.10H), 3.22 (s, 0.31H).

[0119] Example 12 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0120] 2-Aminopyridine 11a (24 mg, 0.25 mmol), 55% wet basis, and 10% Pd / C catalyst (23 mg, 0.22 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. Next, 0.5 mL of D₂O and the co-catalyst NaBH₄ (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated 2-aminopyridine derivative 12b. The product was a white solid with a deuteration rate of 97% and a yield of 76%. The synthetic route is as follows:

[0121]

[0122] The fully deuterated 2-aminopyridine derivative 12b synthesized in Example 12 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 12 As shown; the fully deuterated 2-aminopyridine derivative 12b synthesized in Example 12 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ7.92 (s, 0.02H), 7.29 (s,0.03H), 6.49 (s, 0.03H), 6.40 (s, 0.03H), 4.58 (s, 0.94H), 4.00 (dq, J =8.08, 7.08 Hz, 6.00H).

[0123] Example 13 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0124] Weigh out 55% wet basis and 10% Pd / C catalyst (23 mg, 0.22 mmol), add to a Young's tube, then purge with nitrogen three times to maintain a nitrogen environment. Then add 0.5 mL D₂O, 2-dimethylaminopyridine 13a (30 μL, 0.25 mmol), and co-catalyst NaBH₄ (1 mg, 0.025 mmol). Seal the Young's tube, heat to 130 °C, and stir for 24 h. Extract three times with ethyl acetate, filter, and wash three times with water. Combine the organic phases and dry them with anhydrous sodium sulfate. Then, evaporate the organic phase using a rotary evaporator to obtain the fully deuterated 2-dimethylaminopyridine derivative 13b. The product is a colorless liquid with a deuteration rate of 86% and a yield of 99%. The synthetic route is as follows:

[0125]

[0126] The fully deuterated 2-dimethylaminopyridine derivative 13b synthesized in Example 13 was characterized by 1H NMR (600MHz, CDCl3) as follows: Figure 13 As shown, the specific data is as follows: 1 H NMR (600MHz, CDCl3) δ8.06 (d, J = 4.90Hz, 0.10H), 7.41-7.36 (m, 0.02H), 7.36-7.30 (m, 0.14H), 6.42 (t, J = 8.54 Hz,0.29H), 4.00 (dq, J = 8.08, 7.08 Hz, 6.00H), 2.98 (s, 0.85H).

[0127] Example 14 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0128] 58 mg (0.25 mmol) of terpyridine 14a, 55% wet basis, and 23 mg (0.22 mmol) of 10% Pd / C catalyst were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. 0.5 mL of D₂O and 1 mg (0.025 mmol) of NaBH₄ co-catalyst were then added. The Young's tube was sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated terpyridine derivative 14b. The product was a white solid with a deuteration rate of 92% and a yield of 91%. The synthetic route is as follows:

[0129]

[0130] The fully deuterated terpyridine derivative 14b synthesized in Example 14 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 14 As shown; the fully deuterated terpyridine derivative 14b synthesized in Example 14 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ8.59 (s, 0.09H), 8.51 (s, 0.44H), 8.36 (d, J = 5.36 Hz, 0.12H), 7.84 (s, 0.04H), 7.73 (s, 0.09H), 7.21 (s,0.09H), 4.05-3.96 (m, 6.00H).

[0131] Example 15 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0132] 58 mg (0.25 mmol) of 3,4-diaminopyridine 15a, 55% wet basis, and 23 mg (0.22 mmol) of 10% Pd / C catalyst were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. 0.5 mL L₂O and 1 mg (0.025 mmol) of NaBH₄ co-catalyst were then added. The Young's tube was sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated 3,4-diaminopyridine derivative 15b. The product was a white solid with a deuteration rate of 99% and a yield of 22%. The synthetic route is as follows:

[0133]

[0134] The fully deuterated 3,4-diaminopyridine derivative 15b synthesized in Example 15 was characterized by carbon NMR (600 MHz, CD3OD) as follows: Figure 15 As shown; the fully deuterated 3,4-diaminopyridine derivative 15b synthesized in Example 15 was characterized by 1H NMR (600MHz, MeOD), and the specific data are as follows: 1 H NMR (600MHz, MeOD) δ7.61 (s, 0.01H), 7.49 (s, 0.01H), 6.47 (s, 0.01H), 4.05-3.96 (m, 6.00H).

[0135] Example 16 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0136] Quinine 16a (81 mg, 0.25 mmol), 55% wet basis, 10% Pd / C catalyst (23 mg, 0.22 mmol), and solubilizer TBAB (80 mg, 0.25 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain a nitrogen atmosphere. Next, 1 mL of D₂O and co-catalyst NaBH₄ (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated quinine derivative 16b. The product was a white solid with a deuteration rate of 88% and a yield of 54%. The synthetic route is as follows:

[0137]

[0138] The fully deuterated quinine derivative 16b synthesized in Example 16 was characterized by carbon NMR (600 MHz, CDCl3) as follows: Figure 16 As shown; the fully deuterated quinine derivative 16b synthesized in Example 16 was characterized by 1H NMR (600MHz, CDCl3), and the specific data are as follows: 1 H NMR (600MHz, CDCl3) δ8.62 (d, J = 6.18 Hz, 0.01H), 7.70 (s, 0.07H), 7.39 (s, 0.07H), 7.15 (s, 0.08H), 6.59 (s, 0.08H), 5.33 (s, 1.64 (s, 1.16H), 1.36 (q, J = 7.99 Hz, 1.26H).

[0139] Example 17 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0140] Omeprazole 17a (81 mg, 0.25 mmol), 55% wet basis, 10% Pd / C catalyst (23 mg, 0.22 mmol), and solubilizer TBAB (80 mg, 0.25 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain a nitrogen atmosphere. Next, 1 mL of D2O and co-catalyst NaBH4 (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated omeprazole derivative 17b. The product was a white solid with a deuteration rate of 88% and a yield of 94%. The synthetic route is as follows:

[0141]

[0142] The fully deuterated omeprazole derivative 17b synthesized in Example 17 was characterized by carbon NMR (600 MHz, CD3OD) as follows: Figure 17 As shown; the fully deuterated omeprazole derivative 17b synthesized in Example 17 was characterized by 1H NMR (600MHz, MeOD), and the specific data are as follows: 1H NMR (600MHz, MeOD) δ8.20 (s, 0.07H), 7.45 (s, 0.08H), 7.16(d, J = 9.45 Hz, 0.23H), 6.91 (d, J = 11.08 Hz, 0.08H), 6.85 (d, J = 6.90 Hz, 0.34H), 4.05-3.96 (m, 6.00H), 3.86 (s, 0.49H), 3.83 (s, 0.37H), 2.76 (d, J =4.27 Hz, 0.03H), 2.32 (d, J = 7.99 Hz, 0.48H).

[0143] Example 18 provides a method for synthesizing a fully deuterated nitrogen heterocyclic compound, comprising the following steps:

[0144] Levofloxacin 18a (90 mg, 0.25 mmol), 55% wet basis, and 10% Pd / C catalyst (23 mg, 0.22 mmol) were weighed and added sequentially to a Young's tube. The tube was then purged with nitrogen three times to maintain the nitrogen atmosphere. Next, 1 mL of D₂O and the co-catalyst NaBH₄ (1 mg, 0.025 mmol) were added. The Young's tube was then sealed, heated to 130 °C, and stirred for 24 h. The mixture was extracted three times with ethyl acetate, filtered, and washed three times with water. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated using a rotary evaporator to obtain the fully deuterated levofloxacin derivative 18b. The product was a white solid with a deuteration rate of 66% and a yield of 92%. The synthetic route is as follows:

[0145]

[0146] The fully deuterated levofloxacin derivative 18b synthesized in Example 18 was characterized by carbon NMR (600 MHz, CD3OD) as follows: Figure 18 As shown; the fully deuterated levofloxacin derivative 18b synthesized in Example 18 was characterized by 1H NMR (600MHz, MeOD), and the specific data are as follows: 1H NMR (600MHz, MeOD) δ8.86 (s, 0.34H), 7.67 (d, J =12.17 Hz, 0.37H), 4.62 (d, J = 11.53 Hz, 0.39H), 4.48 (d, J = 14.17 Hz, 0.36H), 4.05-3.96 (m, 6.00H), 3.67 (d, J = 7.08 Hz, 0.05H), 3.52 (d, J = 12.44Hz, 1.51H), 2.79 (s, 1.29H), 2.52 (s, 1.04H), 1.63 (d, J = 6.81 Hz, 1.07H).

[0147] While embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations fall within the scope and spirit of the invention as set forth in the claims. Furthermore, the invention described herein may have other embodiments and can be implemented or carried out in various ways.

Claims

1. A method for synthesizing a fully deuterated nitrogen heterocyclic compound, characterized in that, Includes the following steps: Under nitrogen protection, a nitrogen heterocyclic compound, a palladium catalyst on carbon, a sodium borohydride co-catalyst, and deuterium water were mixed and subjected to a hydrogen-deuterium exchange reaction to obtain a fully deuterated nitrogen heterocyclic compound.

2. The method according to claim 1, characterized in that, The nitrogen heterocyclic compound is an aromatic heterocyclic compound containing at least one nitrogen atom; the nitrogen heterocyclic compound includes one of pyridine compounds, quinoline compounds, phenanthroline compounds, or indole compounds.

3. The method according to claim 2, characterized in that, The structural formula of the nitrogen heterocyclic compound includes one of the following formulas (Ⅰ), (Ⅱ), (Ⅲ) or (Ⅳ); ； ； ； ； R includes one of the following: methyl, hydroxyl, amino, halogen, methoxy, carboxyl, ethyl, acetic acid, acetyl, and aldehyde.

4. The method according to claim 1, characterized in that, The hydrogen-deuterium exchange reaction is carried out under heating and stirring conditions at a temperature of 120-140℃ for a time of 12-24 hours.

5. The method according to claim 1, characterized in that, The palladium-on-carbon catalyst is a 10% palladium-on-carbon catalyst; the molar ratio of the 10% palladium-on-carbon catalyst to the nitrogen heterocyclic compound is (0.5-1.5):

10.

6. The method according to claim 1, characterized in that, The molar ratio of the sodium borohydride cocatalyst to the nitrogen heterocyclic compound is (0.5-1.5):

10.

7. The method according to claim 1, characterized in that, The amount of deuterium water used is 0.5-1 mL for every 0.25 mmol of nitrogen heterocyclic compound.

8. The method according to claim 1, characterized in that, The process includes the following steps: adding the nitrogen heterocyclic compound, palladium on carbon catalyst, and solubilizer into the reaction tube, purging with nitrogen three times, then adding sodium borohydride co-catalyst and deuterium water, and heating and stirring to obtain the fully deuterated nitrogen heterocyclic compound.

9. The method according to claim 8, characterized in that, The solubilizer is tetrabutylammonium bromide.

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