Deuterated methylamine intermediate and preparation method thereof

Abstract

The invention discloses a deuterated methylamine intermediate and a preparation method thereof. Specifically, the invention provides a preparation method of a deuterated methylamine intermediate as shown in a formula III, which comprises the following steps: in the presence of a solvent and alkali, reacting a compound as shown in a formula A with a compound as shown in a formula II to obtain the compound as shown in the formula III, wherein the molar ratio of the compound shown in the formula II to the alkali is (1: 1.8)-(1: 2.2); the reaction temperature is 40-70 DEG C. The deuterated methylamine preparation method provided by the invention is low in cost, simple to operate, high in yield and purity and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a deuterated methylamine intermediate and a preparation method thereof. Background Art

[0002] Deuterated drugs are becoming a hot area in the development of new drugs. Many pharmaceutical companies at home and abroad are actively developing deuterated drugs. In April 2017, the U.S. Food and Drug Administration (FDA) approved the world's first deuterated drug, Auspex's deuterated tetrabenazine tablets (deuterabenazine, Antaitan), for the rare autosomal dominant genetic disease Huntington's disease; in May 2020, the National Medical Products Administration (NMPA) also approved the import and marketing of the drug in China after priority review and approval, exempting it from clinical trials. In June 2022, Donafenib mesylate was approved for marketing in China, becoming the first deuterated anti-tumor drug approved for marketing in my country. On September 8, 2022, the FDA approved Bristol-Myers Squibb's Deucravacitinib (deuterated colexitinib, trade name SotyktuTM) as a first-line treatment for moderate to severe plaque psoriasis in adults. The structure is as follows:

[0003]

[0004] From the structure, it can be seen that the deuterium sources of the latter two are introduced through deuterated methylamine. Since the non-Gabriel synthesis method for synthesizing deuterated methylamine cannot control the selectivity of the nucleophilic substitution reaction, it will produce impurities with multiple substitutions on nitrogen, which are difficult to purify. At present, the Gabriel synthesis method is generally used in the industry to synthesize deuterated methylamine. Patent WO2011 / 113366 discloses the following synthesis method of deuterated methylamine:

[0005]

[0006] However, the deprotection of the intermediate formed by phthalamide in the traditional Gabriel synthesis method requires severe conditions, is time-consuming and energy-consuming, and has low yield and purity. Therefore, it is necessary to develop a simple and efficient method for preparing deuterated methylamine and its salts. Summary of the invention

[0007] In order to overcome the technical problems of low yield, low product purity and difficulty in purification in the existing deuterated methylamine preparation technology, the present invention provides a method for preparing deuterated methylamine and its salts with high purity, high yield, mild reaction conditions and low cost.

[0008] The present invention mainly solves the above technical problems through the following technical solutions.

[0009] The present invention provides a method for preparing a compound as shown in formula III, which comprises the following steps: in the presence of a solvent and a base, reacting a compound of formula A with a compound of formula II to obtain a compound of formula III;

[0010]

[0011] Wherein, the molar ratio of the compound of formula II to the base is 1:1.8 to 1:2.2;

[0012] The reaction temperature is 40-70°C.

[0013] In some embodiments, the method for preparing the compound of formula III comprises the following steps: mixing a solvent, a base and a compound of formula A, and mixing them with a compound of formula II at a reaction temperature to react to obtain a compound of formula III;

[0014] In the method for preparing the compound represented by formula III, the solvent may be a conventional solvent used in this type of reaction in the art, such as a polar aprotic solvent, preferably dimethyl sulfoxide.

[0015] In the method for preparing the compound represented by formula III, the base may be a conventional base used in this type of reaction in the art, such as an alkali metal carbonate, preferably potassium carbonate and / or cesium carbonate.

[0016] In some embodiments, in the method for preparing the compound of formula III, the molar ratio of the compound of formula II to the base is 1:2.

[0017] In some embodiments, in the method for preparing the compound of formula III, the molar ratio of the compound of formula II to the compound of formula A is 1:1 to 1:5, preferably 1:1.3.

[0018] In some embodiments, in the method for preparing the compound of formula III, the reaction temperature is 60°C.

[0019] In some embodiments, in the method for preparing the compound of formula III, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The disappearance of the compound of formula II is generally regarded as the reaction endpoint, and the reaction time is generally 3 to 6 hours, preferably 4 hours.

[0020] In some embodiments, in the method for preparing the compound of formula III, the reaction materials are the solvent, the base, the compound of formula A and the compound of formula II.

[0021] In some embodiments, in the method for preparing the compound of formula III, the reaction further includes the following specific steps: adding the solvent, the compound of formula A and the base, stirring at the temperature for 10 to 20 minutes (for example, 15 minutes), adding dropwise the compound of formula II, and reacting at the temperature.

[0022] In some embodiments, in the method for preparing the compound of formula III, the reaction further comprises the following post-treatment steps: after the reaction is completed, dichloromethane and water are added for extraction, washing, concentrating, and pulping.

[0023] In some embodiments, the preparation method of the compound shown in formula III may further include a preparation method of the compound shown in formula II, which comprises the following steps: in the presence of a solvent and a base, p-toluenesulfonic acid chloride and the compound of formula I undergo a substitution reaction to generate a compound of formula II;

[0024]

[0025] In the substitution reaction, the solvent may be a conventional solvent in this type of reaction in the art, such as an ether solvent, preferably tetrahydrofuran.

[0026] In the substitution reaction, the base may be a conventional base used in this type of reaction in the art, such as an alkali metal hydroxide, preferably sodium hydroxide.

[0027] In some embodiments, in the substitution reaction, the molar ratio of the compound of formula I to the base is 1:3 to 1:6, preferably 1:4.5.

[0028] In some embodiments, in the substitution reaction, the molar ratio of the compound of formula I to the p-toluenesulfonyl chloride is 1:0.8 to 1.4, preferably 1:1.1 to 1:1.3, and further preferably 1:1.2.

[0029] In some embodiments, in the substitution reaction, the reaction temperature is 0 to 30°C, preferably 5 to 15°C.

[0030] In some embodiments, in the substitution reaction, the reaction materials are the solvent, the base, the compound of formula I and the p-toluenesulfonyl chloride.

[0031] In some embodiments, in the substitution reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The disappearance of the compound of formula I is generally regarded as the reaction endpoint. The reaction time is generally 16 to 20 hours, preferably 18 hours.

[0032] In some embodiments, the substitution reaction comprises the following specific steps: adding the solvent and the p-toluenesulfonyl chloride, adding the compound of formula I at 0-10°C, stirring for 10-20 minutes (preferably 15 minutes), controlling the temperature to the reaction temperature, adding the base dropwise, and reacting at the controlled temperature.

[0033] In some embodiments, in the substitution reaction, the reaction further comprises the following post-treatment steps: after the reaction is completed, dichloromethane and water are added for extraction, washing, and concentration.

[0034] The present invention also provides a method for preparing the compound as shown in formula IV, which comprises the following steps:

[0035] The compound of formula III reacts with a hydrochloric acid solution to obtain a compound of formula IV;

[0036]

[0037] In some embodiments, in the method for preparing the compound of formula IV, the hydrochloric acid solution is a conventional hydrochloric acid solution used in this type of reaction in the art, such as ethanol hydrochloric acid solution.

[0038] In some embodiments, in the method for preparing the compound represented by formula IV, the reaction temperature is 40-80°C, preferably 60°C.

[0039] In some embodiments, in the method for preparing the compound of formula IV, the molar ratio of the compound of formula I to the hydrochloric acid solution is 1:6 to 1:9, preferably 1:7.

[0040] In some embodiments, in the method for preparing the compound of formula IV, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The disappearance of the compound of formula II is generally regarded as the reaction endpoint, and the reaction time is generally 6 to 10 hours, preferably 8 hours.

[0041] In some embodiments, in the method for preparing the compound of formula IV, the reaction materials are the compound of formula III and the hydrochloric acid solution.

[0042] In some embodiments, in the method for preparing the compound of formula IV, the reaction further comprises the following post-treatment steps: after the reaction is completed, concentration and recrystallization are performed.

[0043] In some embodiments, in the method for preparing the compound of formula IV, the reaction further comprises the following specific steps: adding the compound of formula III and the hydrochloric acid solution, controlling the temperature to the reaction temperature, and keeping the temperature for the reaction.

[0044] In some embodiments, the method for preparing the compound of formula IV may further include a method for preparing the compound of formula III, which comprises the following steps:

[0045] In the presence of a solvent and a base, the compound of formula A reacts with the compound of formula II to obtain a compound of formula III;

[0046]

[0047] In some embodiments, the operations and conditions of the preparation method of the compound represented by formula III are as described above.

[0048] The present invention also provides a method for preparing a deuterated methylamine solution, which comprises the following steps:

[0049] (S1) preparing a compound of formula IV by the preparation method described in any one of the present invention, and preparing an aqueous solution of the compound of formula IV;

[0050] (S2) adding an aqueous solution of the compound of formula IV to a solid base, and passing the generated deuterated methylamine gas as shown in formula V into a solvent to obtain a deuterated methylamine solution.

[0051]

[0052] In the step (S2), the solid base is a conventional base for this type of reaction in the art, such as an alkali metal hydroxide, preferably sodium hydroxide.

[0053] In some embodiments, in step (S2), the molar ratio of the compound of formula IV to the solid base is 1:4 to 1:6.5, preferably 1:5.4.

[0054] In step (S2), the solvent is a conventional solvent for this type of reaction in the art, such as a polar solvent, preferably methanol or water.

[0055] In some embodiments, in step (S2), the solvent is a cooled solvent, such as cooled methanol or cooled water, preferably -20°C methanol or 0°C water.

[0056] In some embodiments, in step (S2), the reaction further comprises the step of drying the deuterated methylamine gas, preferably drying the gas by passing through soda lime.

[0057] The present invention also provides a compound as shown in formula III,

[0058] CD3N(Boc)2

[0059] III.

[0060] The positive and progressive effects of the present invention are:

[0061] (1) In the preparation of the compound shown in III of the present invention, di-tert-butyl iminodicarbonate is used as a nitrogen source. As an improved Gabriel reagent, it can avoid the high cost problem of the Gabriel reagent used in the prior art, provide a preparation method with lower cost, higher yield and purity, and is more suitable for industrial production.

[0062] (2) The preparation of the compound of formula IV provides a more energy-efficient, efficient and easy-to-purify preparation method through mild deprotection conditions and cleaner by-products, compared with deprotection with concentrated hydrochloric acid aqueous solution at high temperature and the difficult-to-completely remove phthalic acid by-product.

[0063] (3) Preparation step of deuterated methylamine solution: Deuterated methylamine hydrochloride aqueous solution is added dropwise to a solid base to obtain free deuterated methylamine gas, which is then absorbed by water or methanol to prepare an aqueous solution and an alcohol solution of deuterated methylamine, thereby increasing the application range of the deuterated methylamine reagent. DETAILED DESCRIPTION

[0064] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0065]

[0066] Embodiment 1:

[0067] Synthesis of Compounds of Formula II

[0068] Add tetrahydrofuran (1L) to a 5L reaction bottle, add p-toluenesulfonyl chloride (634.0g, 3.33mol, 1.2eq), cool to 0-10°C while stirring, add deuterated methanol (100.0g, 2.77mol, 1.0eq), stir for 15min, control the reaction temperature to 5-15°C, dropwise add 33% sodium hydroxide aqueous solution (1500g, 13.86mol, 4.5eq), and keep warm at 5-15°C for 18h. After the reaction, add dichloromethane (1.5L), separate the layers, wash the organic phase with water (1L×2) twice, dry the organic phase and spin dry to obtain 480g D3-p-toluenesulfonyl methyl ester (Formula II compound), with a yield of 92% and a purity of 99.1% (HPLC).

[0069] 1H-NMR (400MHz, CDC13): 3.20 (s, 3H), 7.71-7.75 (m, 2H), 7.84-7.88 (m, 2H).

[0070] Embodiment 2:

[0071] Synthesis of compound of formula III

[0072] To a 1L three-necked flask, dimethyl sulfoxide (400mL), di-tert-butyl iminodicarbonate (compound of formula A) (126.0g, 0.68mol, 1.3eq), and potassium carbonate (146.0g, 1.06mol, 2.0eq) were added, the temperature was raised to 60°C and stirred for 15min, D3-toluenesulfonyl methyl ester (compound of formula II) (100.0g, 0.53mol, 1.0eq) was slowly added dropwise, the mixture was incubated for 4h, and after the reaction, dichloromethane (500mL) and water (500mL) were added. The mixture was separated and the organic phase was washed once with water (500mL). The organic phase was dried and spin-dried to obtain a crude product, which was slurried with petroleum ether (300mL), filtered with suction, and the filter cake was spin-dried to obtain 115g of (tert-butyloxycarbonyl) (methyl-d3) tert-butyl carbamate (compound of formula III), with a yield of 93% and a purity of 98.1% (HPLC).

[0073] 1H-NMR (400MHz, CDC13): 1.51 (s, 18H)).

[0074] Embodiment 3:

[0075] Synthesis of compound of formula III

[0076] To a 1L three-necked flask, add dimethyl sulfoxide (400mL), di-tert-butyl iminodicarbonate (compound of formula A) (126.0g, 0.68mol, 1.3eq), cesium carbonate (189.0g, 0.58mol, 1.1eq), stir for 15min, slowly add D3-toluenesulfonyl methyl ester (compound of formula II) (100.0g, 0.53mol, 1.0eq), raise the temperature to 80°C after the dropwise addition, keep warm for 4h, add dichloromethane (500mL) and water (500mL) after the reaction, separate the layers, wash the organic phase once with water (500mL), dry the organic phase and spin-dry to obtain 93g of (tert-butyloxycarbonyl) (methyl-d3) carbamic acid tert-butyl ester (compound of formula III), with a yield of 75% and a purity of 98.1% (HPLC).

[0077] 1H-NMR (400MHz, CDC13): 1.51 (s, 18H).

[0078] Embodiment 4:

[0079] Synthesis of compound of formula III

[0080] Add dimethyl sulfoxide (400 mL), di-tert-butyl iminodicarbonate (compound of formula A) (126.0 g, 0.68 mol, 1.3 eq), potassium carbonate (80.3 g, 0.58 mol, 1.1 eq) into a 1L three-necked flask, stir for 15 min, slowly dropwise add D3-toluenesulfonyl methyl ester (2) (100.0 g, 0.53 mol, 1.0 eq), raise the temperature to 80°C after the dropwise addition, and keep warm for 4 h. After the reaction, add dichloromethane (500 mL) and water (500 mL), separate the layers, wash the organic phase once with water (500 mL), dry the organic phase and spin dry to obtain 87 g of (tert-butyloxycarbonyl) (methyl-d3) carbamic acid tert-butyl ester (compound of formula III), with a yield of 70% and a purity of 97.1% (HPLC).

[0081] 1H-NMR (400MHz, CDC13): 1.51 (s, 18H).

[0082] Embodiment 5:

[0083] Synthesis of compound of formula III

[0084] To a 1L three-necked flask, dimethyl sulfoxide (400 mL), di-tert-butyl iminodicarbonate (compound of formula A) (126.0 g, 0.68 mol, 1.3 eq), and potassium carbonate (146.0 g, 1.06 mol, 2.0 eq) were added and stirred for 15 min, and D3-toluenesulfonyl methyl ester (compound of formula II) (100.0 g, 0.53 mol, 1.0 eq) was slowly added dropwise. After the addition was complete, the temperature was raised to 60°C and kept warm for 4 h. After the reaction was complete, dichloromethane (500 mL) and water (500 mL) were added. The layers were separated and the organic phase was washed once with water (500 mL). The organic phase was dried and spin-dried to obtain a crude product, which was slurried with petroleum ether (300 mL), filtered with suction, and the filter cake was spin-dried to obtain 102 g of (tert-butyloxycarbonyl) (methyl-d3) carbamic acid tert-butyl ester (compound of formula III) with a yield of 82% and a purity of 98.1% (HPLC).

[0085] 1H-NMR (400MHz, CDC13): 1.51 (s, 18H)).

[0086] Embodiment 6:

[0087] Synthesis of compound of formula III

[0088] To a 1L three-necked flask, dimethyl sulfoxide (400 mL), di-tert-butyl iminodicarbonate (compound of formula A) (126.0 g, 0.68 mol, 1.3 eq), and potassium carbonate (146.0 g, 1.06 mol, 2.0 eq) were added, and the mixture was stirred for 15 min. D3-toluenesulfonyl methyl ester (2) (100.0 g, 0.53 mol, 1.0 eq) was slowly added dropwise. After the addition, the temperature was raised to 80°C and kept warm for 4 h. After the reaction, dichloromethane (500 mL) and water (500 mL) were added. The layers were separated, and the organic phase was washed once with water (500 mL). The organic phase was dried and spin-dried to obtain 94 g of (tert-butyloxycarbonyl) (methyl-d3) carbamic acid tert-butyl ester (compound of formula III), with a yield of 76% and a purity of 97.1% (HPLC).

[0089] 1H-NMR (400MHz, CDC13): 1.51 (s, 18H).

[0090] Embodiment 7:

[0091] Synthesis of Compounds of Formula IV

[0092] Add (tert-butyloxycarbonyl)(methyl-d3)carbamic acid tert-butyl ester (Formula III compound) (80.0 g, 0.34 mol, 1.0 eq) to a 3L reaction bottle, add 6M hydrochloric acid ethanol (400 mL), heat to 60 ° C after addition, keep warm for 8 hours, spin dry after reaction to obtain crude deuterated methylamine hydrochloride (Formula IV compound), the crude product is recrystallized and purified with anhydrous ethanol (100 mL) to obtain 20 g pure deuterated methylamine hydrochloride (Formula IV compound), the yield is 83%, and the deuterated abundance is 99.8% (1H-NMR)

[0093] 1H-NMR (400MHz, DMSO-d6): 8.05 (br, 2H).

[0094] Embodiment 8:

[0095] Synthesis of Deuterated Methylamine Methanol Solution

[0096] Sodium hydroxide (60 g, 1.5 mol, 5.4 eq) was added to a 250 mL reaction bottle, and an aqueous solution of deuterated methylamine hydrochloride (compound of formula IV) (20.0 g, 0.28 mol, 1.0 eq) was added dropwise to generate deuterated methylamine gas, which was dried by soda lime and then passed into methanol cooled to -20°C. The solution was determined to be a 30-33% deuterated methylamine methanol solution, and the yield of deuterated methylamine was 80%.

[0097] Embodiment 9:

[0098] Synthesis of Deuterated Methylamine Aqueous Solution

[0099] Sodium hydroxide (60 g, 1.5 mol, 5.4 eq) was added to a 250 mL reaction bottle, and an aqueous solution of deuterated methylamine hydrochloride (compound of formula IV) (20.0 g, 0.28 mol, 1.0 eq) was added dropwise to generate deuterated methylamine gas which was passed into water cooled to 0° C. The solution was determined to be a 30-35% aqueous solution of deuterated methylamine, and the recovery rate of deuterated methylamine was 80%.

[0100] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A method for preparing a compound as shown in formula III, characterized in that: The method comprises the following steps: in the presence of a solvent and a base, reacting a compound of formula A with a compound of formula II to obtain a compound of formula III; Wherein, the molar ratio of the compound of formula II to the base is 1:1.8 to 1:2.2; The reaction temperature is 40-70°C.

2. The preparation method according to claim 1, characterized in that The preparation method of the compound represented by formula III satisfies one or more of the following conditions: (1) The method for preparing the compound represented by formula III comprises the following steps: mixing a solvent, a base and a compound represented by formula A, and mixing them with a compound represented by formula II at a reaction temperature to react to obtain a compound represented by formula III; (2) In the method for preparing the compound represented by formula III, the solvent is a polar aprotic solvent, preferably dimethyl sulfoxide; (3) In the method for preparing the compound represented by formula III, the base is an alkali metal carbonate, preferably potassium carbonate and / or cesium carbonate; (4) In the method for preparing the compound represented by formula III, the molar ratio of the compound represented by formula II to the base is 1:2; (5) In the method for preparing the compound of formula III, the molar ratio of the compound of formula II to the compound of formula A is 1:1 to 1:5, preferably 1:1.3; (6) In the method for preparing the compound represented by formula III, the reaction temperature is 60°C; (7) In the method for preparing the compound represented by formula III, the reaction time is 3 to 6 hours, preferably 4 hours; (8) In the method for preparing the compound represented by formula III, the reaction materials are the solvent, the base, the compound represented by formula A and the compound represented by formula II; (9) In the method for preparing the compound represented by formula III, the reaction further comprises the following post-treatment steps: after the reaction is completed, dichloromethane and water are added for extraction, washing, concentrating, and pulping; Preferably, in the method for preparing the compound of formula III, the reaction further comprises the following specific steps: adding the solvent, the compound of formula A and the base, controlling the temperature to the temperature, stirring for 10 to 20 minutes (e.g., 15 minutes), dropwise adding the compound of formula II, and reacting at the temperature.

3. The preparation method according to claim 1, characterized in that: The preparation method of the compound shown in formula III further includes the preparation method of the compound shown in formula II, which comprises the following steps: in the presence of a solvent and a base, p-toluenesulfonic acid chloride and the compound of formula I undergo a substitution reaction to obtain a compound of formula II; 4. The preparation method according to claim 3, characterized in that: The method for preparing the compound represented by formula II satisfies one or more of the following conditions: (1) In the substitution reaction, the solvent is an ether solvent, preferably tetrahydrofuran; (2) In the substitution reaction, the base is an alkali metal hydroxide, preferably sodium hydroxide; (3) In the substitution reaction, the molar ratio of the compound of formula I to the base is 1:3 to 1:6, preferably 1:4.5; (4) In the substitution reaction, the molar ratio of the compound of formula I to the p-toluenesulfonyl chloride is 1:0.8 to 1.4, preferably 1:1.1 to 1:1.3, and more preferably 1:1.2; (5) In the substitution reaction, the reaction temperature is 0 to 30° C., preferably 5 to 15° C.; (6) In the substitution reaction, the reaction materials are the solvent, the base, the compound of formula I and the p-toluenesulfonyl chloride; (7) In the substitution reaction, the reaction time is 16 to 20 hours, preferably 18 hours; (8) In the substitution reaction, the reaction further comprises the following post-treatment steps: after the reaction is completed, dichloromethane and water are added for extraction, washing, and concentration; Preferably, in the substitution reaction, the reaction further comprises the following specific steps: adding the solvent and the p-toluenesulfonyl chloride, controlling the temperature to 0-10° C., adding the compound of formula I, stirring for 10-20 min (preferably 15 min), adding the base dropwise under temperature control and reacting under temperature control.

5. A method for preparing a compound as shown in formula IV, characterized in that: It includes the following steps: The compound of formula III reacts with a hydrochloric acid solution to obtain a compound of formula IV; 6. The preparation method according to claim 5, characterized in that: The preparation method of the compound shown in formula IV satisfies one or more of the following conditions: (1) In the method for preparing the compound represented by formula IV, the hydrochloric acid solution is a hydrochloric acid ethanol solution; (2) In the method for preparing the compound represented by formula IV, the reaction temperature is 40 to 80°C, preferably 60°C; (3) In the method for preparing the compound of formula IV, the molar ratio of the compound of formula III to the hydrochloric acid solution is 1:6 to 1:9, preferably 1:7; (4) In the method for preparing the compound represented by formula IV, the reaction time is 6 to 10 hours, preferably 8 hours; (5) In the method for preparing the compound represented by formula IV, the reaction materials are the compound represented by formula III and the hydrochloric acid solution; (6) In the method for preparing the compound represented by formula IV, the reaction further comprises the following post-treatment steps: after the reaction is completed, concentration and recrystallization; Preferably, in the method for preparing the compound of formula IV, the reaction further comprises the following specific steps: adding the compound of formula III and the hydrochloric acid solution, and reacting at a controlled temperature.

7. The preparation method according to claim 6, characterized in that: The method for preparing the compound of formula IV further includes the method for preparing the compound of formula III as described in any one of claims 1 to 4.

8. A method for preparing a deuterated methylamine solution, characterized in that: It includes the following steps: Step (S1) preparing the compound of formula IV according to any one of the preparation methods of claims 5 to 7, and preparing an aqueous solution of the compound of formula IV; Step (S2) adding an aqueous solution of the compound of formula IV to a solid base, and passing the generated deuterated methylamine gas as shown in formula V into a solvent to obtain a deuterated methylamine solution 9. The preparation method according to claim 8, characterized in that: The preparation method of the deuterated methylamine solution satisfies one or more of the following conditions: (1) In the step (S2), the solid base is an alkali metal hydroxide, preferably sodium hydroxide; (2) In step (S2), the molar ratio of the compound of formula IV to the solid base is 1:4 to 1:6.5, preferably 1:5.4; (3) In step (S2), the solvent is a conventional solvent for this type of reaction in the art, such as a polar solvent, preferably methanol or water; (4) In step (S2), the solvent is a cooled solvent, such as cooled methanol or cooled water, preferably -20°C methanol or 0°C water; (5) In step (S2), the reaction further comprises the following step: drying the deuterated methylamine gas, preferably drying the gas by passing it through soda lime.

10. A compound as shown in formula III, CD3N(Boc)2 III.

Images