An industrial process for the production of an alamethicin key intermediate

Abstract

The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a production method of a key intermediate of alamorelin, i.e. trimethylhydrazine hydrochloride. The technical scheme of the application comprises the following steps: step 1. synthesis of compound 2 is divided into two stages: stage 1. under the action of an alkali, hydrazine formic acid tert-butyl ester is reacted with a methylating agent to generate a mixture of compound 3 and compound 2. The mixture does not need to be further purified and separated, and is directly used in the second stage; stage 2. the mixture in the above step is further reacted with the methylating agent to be completely converted into compound 2, and step 2. compound 2 is removed from Boc protection in the presence of hydrochloric acid, and is salified to obtain trimethylhydrazine hydrochloride. The application provides a preparation method of trimethylhydrazine hydrochloride suitable for industrial production, and solves the problems of high production cost and safety hazards existing in the prior art.

Description

An industrial production method for a key intermediate of alamolin Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a method for preparing trimethylhydrazine hydrochloride, a key intermediate of alamolin. Background Technology

[0002] Anamorelin is a non-peptide ghrelin receptor agonist that stimulates appetite and promotes protein and fat synthesis by activating ghrelin receptors in the hypothalamus, thereby increasing food intake, maintaining or increasing weight, and improving quality of life problems such as fatigue. It is currently mainly used to treat cancer cachexia and related symptoms.

[0003] International patent WO01034593 (applicant: Novo Nordisk) discloses a method for preparing alamolin, as shown in Formula 1, which is obtained from compound 1 (N,N,N'-trimethylhydrazine dihydrochloride) through multiple steps such as condensation and deprotection.

[0004] .

[0005] Compound 1 (N,N,N'-trimethylhydrazine dihydrochloride) is an important intermediate in the synthesis of alamolin, and its synthesis has always been of great interest to synthesizers. Based on the currently disclosed techniques, the synthesis can be summarized as follows: 1) Using unsymmetrical dimethylhydrazine as a raw material, formamide is obtained through amine transesterification (Organic Process Research & Development, 2004, 8, 360-362), followed by reduction with lithium aluminum hydride (route 1); or it is dehydrated with an aldehyde to obtain an imine (J. Am. Chem. Soc., 1953, 75 (12), 2937-2939), followed by reduction with lithium aluminum hydride (route 2). The specific route is shown in Equation 2.

[0006] 2

[0007] Formula 2

[0008] These two routes have the following drawbacks: First, the raw material unsymmetrical dimethylhydrazine has characteristics such as low boiling point, high toxicity, flammability and explosiveness, making industrial production difficult and resulting in a very high price; second, trimethylhydrazine obtained by reduction of lithium aluminum hydride is stored in organic solutions and cannot be preserved for a long time, so it can only be prepared and used immediately, and even if it is subsequently converted into salt by acid, it is difficult to obtain a high-purity target compound; third, the use of lithium aluminum hydride and the post-reaction treatment during the production process pose significant safety hazards.

[0009] 2) Using 1-tert-butoxycarbonyl-1-methylhydrazine as a raw material (CN108129357), Boc trimethylhydrazine is obtained through two reductive aminations, and finally Boc is removed to obtain trimethylhydrazine hydrochloride. The specific route is shown in Formula 3.

[0010] .

[0011] This route avoids the use of lithium aluminum hydride, reducing the safety risks of industrial production. However, the two palladium carbon hydrogenation processes significantly increase production costs and pose a risk of excessive heavy metal residues in the active pharmaceutical ingredient.

[0012] 3) Using tert-butyl hydrazine carbamate as a raw material, it is substituted with alkylating agent iodomethane in the presence of NaH base to obtain Boc trimethylhydrazine. Subsequently, Boc is removed in the presence of trifluoroacetic acid to obtain trimethylhydrazine trifluoroacetate. The specific route is shown in Formula 4.

[0013]

[0014] This route avoids the use of expensive reagents and uses common industrial materials. However, the first step of alkylation requires a large amount of sodium hydroxide, which poses a huge safety risk to industrial production. Moreover, the yield of this step is only 40%, and column chromatography is required for purification, making it unsuitable for industrial production.

[0015] In summary, although much work has been done on the synthesis of trimethylhydrazine hydrochloride using existing technologies, none of them have a route that can be industrialized. In order to control the cost of the active pharmaceutical ingredient and to make it more accessible to patients, new synthetic technologies are needed. Summary of the Invention

[0016] The purpose of this invention is to overcome the shortcomings of the existing technology and provide a method for synthesizing trimethylhydrazine hydrochloride suitable for industrial production, thereby reducing the production cost of the active pharmaceutical ingredient.

[0017] The objective of this invention is achieved through the following technical solution: The technical solution of this invention is a method for preparing trimethylhydrazine hydrochloride, comprising the following steps: Step 1. Preparation of compound 2: According to the actual feeding process, the preparation of compound 2 is divided into two stages: Stage 1. Tert-butyl hydrazine carbamate reacts with a methylating agent under alkaline conditions to generate a mixture of compound 3 and compound 2. This mixture does not require further purification and separation and is directly used in the second stage.

[0018] Stage 2. The mixture obtained in Stage 1 is further reacted with a methylating agent to convert it into compound 2, as shown in the following route: .

[0019] In stage 1, preferably, the alkali is selected from n-butyllithium, diisopropylaminolithium, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc., and more preferably n-butyllithium.

[0020] Preferably, the amount of tert-butyl hydrazine carbamate used is 1 equivalent, and the amount of base used is 3.0 to 4.0 equivalents, preferably 3.0 equivalents.

[0021] Preferably, the methylating agent is selected from iodomethane, dimethyl sulfate, and dimethyl carbonate, with iodomethane and dimethyl sulfate being more preferred.

[0022] Preferably, the amount of the methylating agent used is 3.0 to 4.0 equivalents, more preferably 4.0 equivalents.

[0023] Preferably, the reaction solvent in this step is selected from tetrahydrofuran, diethyl ether, etc., with tetrahydrofuran being the preferred solvent.

[0024] In stage 2, preferably, the alkali is selected from n-butyllithium, diisopropylaminolithium, sodium hydrogen, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, and carbonic acid in 1.0 to 3.0 equivalents, preferably 1.0 equivalent.

[0025] Preferably, the methylating agent is selected from iodomethane, dimethyl sulfate, and dimethyl carbonate, with iodomethane and dimethyl sulfate being more preferred.

[0026] Preferably, the amount of the methylating agent used is 1.0 to 3.0 equivalents, more preferably 1.0 equivalents.

[0027] Preferably, the reaction solvent in this step is selected from tetrahydrofuran, diethyl ether, etc., with tetrahydrofuran being the preferred solvent.

[0028] Step 2. Preparation of Compound 1 (i.e., trimethylhydrazine hydrochloride): Compound 2 was deprotected from Boc in the presence of hydrochloric acid and then formed into a salt to obtain Compound 1, as shown in the following route: .

[0029] Preferably, the amount of compound 2 used is 1 equivalent, and the amount of hydrochloric acid used is 3.0 to 5.0 equivalents, preferably 3.0 equivalents. Below 3.0 equivalents, the trimethylhydrazine salt formation is incomplete, affecting the product's properties and quality; above 5.0 equivalents, the cost increases.

[0030] Preferably, the reaction solvent in this step is selected from dichloromethane, ethyl acetate, methanol, 1,4-dioxane, etc., with methanol being the preferred solvent.

[0031] Preferably, the reaction temperature is 0~50℃. o C, Preferred 25 o C. Beneficial effects

[0032] This application provides a method for preparing trimethylhydrazine hydrochloride (compound 1) suitable for industrial production, solving the problems of high production cost and safety hazards in existing processes. This invention uses industrially available tert-butyl hydrazine carbamate as the starting material, performs stepwise methylation, and finally decarboxylates the hydrochloric acid to form the salt. The overall yield of the three-step reaction is 70-80%. The technical solution of this application avoids the use of hazardous reagents and column chromatography, which affects production efficiency, greatly reducing the industrial production cost of trimethylhydrazine hydrochloride, thereby reducing the cost of alamolin raw material. Attached Figure Description

[0033] Figure 1 shows a mixture of compounds 2 and 3. 1 H NMR spectrum.

[0034] Figure 2 shows compound 2. 1 H NMR spectrum.

[0035] Figure 3 shows the crude product of compound 1. 1 H NMR spectrum.

[0036] Figure 4 shows the purified compound 1. 1 H NMR spectrum. Detailed Implementation

[0037] To facilitate understanding of the present invention, specific embodiments will be described in detail below. These embodiments will help those skilled in the art to further understand the present invention; however, they are not intended to limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements to the present invention without departing from its conceptual framework, and these modifications and improvements all fall within the scope of protection of the present invention.

[0038] Example 1: Preparation of a mixture of compound 2.

[0039] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (64 mL, 0.16 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a tetrahydrofuran solution (40 mL) of dimethyl sulfate (20.1 g, 0.16 mol) was added dropwise over 1 hour while maintaining the temperature at -40 °C. After the addition was complete, the system was cooled to room temperature and stirred overnight. 20 mL of methanol was added to the system, and the mixture was stirred for 1 hour. 10 mL of saturated ammonium chloride solution was added, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added to the system, and the mixture was extracted. The liquid was separated, the organic phase was dried, and the solution was evaporated to dryness to obtain 7.2 g of a yellow oil, which was analyzed by NMR. Compound 3: 1¹H-NMR (400MHz, CD3OD): δ 2.51 (s, 6H), 1.46 (s, 9H); Compound 2: 1 ¹H-NMR (400MHz, CD3OD): δ 2.90 (s, 3H), 2.56 (s, 6H), 1.49 (s, 9H). The NMR spectra are shown in Figure 1. The molar ratio of compound 2 to compound 3 is 1 / 1.5.

[0040] 7.2 g of the mixture was dissolved in 72 ml of tetrahydrofuran. The system was cooled to -30 °C, and a solution of n-butyllithium (16 ml, 0.04 mol, 2.5 mol / L tetrahydrofuran) was added dropwise. After the addition was complete, the system was kept at -30 °C and stirred for 0.5 hours. Then, a solution of dimethyl sulfate (5.3 g, 0.04 mol) in tetrahydrofuran (10 ml) was added dropwise. After the addition was complete, the system was stirred at room temperature overnight. The mixture was then cooled to room temperature and stirred overnight. 5 ml of methanol was added to the system, and the mixture was stirred for 0.5 hours. 5 ml of saturated ammonium chloride solution was added, and the mixture was stirred for half an hour. Then, 15 ml of ethyl acetate was added to the system. The mixture was extracted, separated, and the organic phase was dried and evaporated to dryness to obtain 5.0 g of compound 2 (yellow oil), with a purity (quantitative NMR detection): 95.2%. 1 H-NMR (400MHz, CD3OD): δ 2.90 (s, 3H), 2.56 (s, 6H), 1.49 (s, 9H), yield 68.2%, NMR spectrum shown in Figure 2.

[0041] Example 2: Preparation of compound 2.

[0042] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (64 mL, 0.16 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a tetrahydrofuran solution (40 mL) of iodomethane (22.7 g, 0.16 mol) was added dropwise over 1 hour while maintaining the temperature at -40 °C. After the addition was complete, the system was cooled to room temperature and stirred overnight. 20 mL of methanol was added to the system, and the mixture was stirred for 1 hour. 10 mL of saturated ammonium chloride solution was added, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added to the system, and the mixture was extracted. The liquid was separated, the organic phase was dried, and the solution was evaporated to dryness to obtain 6.8 g of a yellow oil. 6.8 g of the resulting mixture was dissolved in 68 ml of tetrahydrofuran. The system was cooled to -30°C, and a solution of n-butyllithium (16 ml, 0.04 mol, 2.5 mol / L tetrahydrofuran) was added dropwise. After the addition was complete, the system was kept at -30°C and stirred for 0.5 hours. Then, a solution of iodomethane (5.37 g, 0.04 mol) in tetrahydrofuran (10 ml) was added dropwise. After the addition was complete, the system was stirred overnight at room temperature. The mixture was then cooled to room temperature and stirred overnight. 5 ml of methanol was added to the system, and the mixture was stirred for 0.5 hours. Then, 5 ml of saturated ammonium chloride solution was added, and the mixture was stirred for half an hour. Finally, 15 ml of ethyl acetate was added to the system, and the mixture was extracted. The extract was separated, the organic phase was dried, and the solution was evaporated to dryness to give 4.5 g of compound 2 (yellow oil), with a purity (quantitative NMR detection): 93.5%. The two-step yield was 60.6%.

[0043] Example 3: Preparation of compound 2.

[0044] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (64 mL, 0.16 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a solution of dimethyl carbonate (14.4 g, 0.16 mol) in tetrahydrofuran (40 mL) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. 20 mL of methanol was added to the system, and the mixture was stirred for 1 hour. 10 mL of saturated ammonium chloride solution was added, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added to the system, and the mixture was extracted. The liquid was separated, the organic phase was dried, and the solution was evaporated to dryness to obtain 6.8 g of a yellow oil. 6.8 g of the resulting mixture was dissolved in 68 ml of tetrahydrofuran. The system was cooled to -30°C, and a solution of n-butyllithium (16 ml, 0.04 mol, 2.5 mol / L tetrahydrofuran) was added dropwise. After the addition was complete, the system was kept at -30°C and stirred for 0.5 hours. Then, a solution of dimethyl carbonate (3.6 g, 0.04 mol) in tetrahydrofuran (10 ml) was added dropwise. After the addition was complete, the system was stirred overnight at room temperature. The mixture was then cooled to room temperature and stirred overnight. 5 ml of methanol was added to the system, and the mixture was stirred for 0.5 hours. Then, 5 ml of saturated ammonium chloride solution was added, and the mixture was stirred for half an hour. Finally, 15 ml of ethyl acetate was added to the system, and the mixture was extracted. The extract was separated, the organic phase was dried, and the solution was evaporated to dryness. Column chromatography yielded 4.2 g of compound 2 (yellow oil), with a purity (quantitative NMR detection): 93.3%. The two-step yield was 56.4%.

[0045] Example 4: Preparation of compound 2.

[0046] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of lithium diisopropylaminocarbonate (60 mL, 0.12 mol, 2 mol / L tetrahydrofuran solution) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a tetrahydrofuran solution (40 mL) of dimethyl sulfate (20.1 g, 0.16 mol) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. Add 20 ml of methanol to the system and stir for 1 hour. Add 10 ml of saturated ammonium chloride solution and stir for half an hour. Add 50 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain a yellow oil. Dissolve the oil in 72 ml of tetrahydrofuran. Cool the system to -10°C and add 20 ml of diisopropylaminolithium solution (0.04 mol, 2 mol / L tetrahydrofuran solution). After the addition is complete, maintain the temperature at -10°C and stir for 0.5 hours. Add 10 ml of tetrahydrofuran solution containing 5.3 g of dimethyl sulfate (0.04 mol). After the addition is complete, stir at room temperature overnight. Add 5 ml of methanol to the system and stir for 0.5 hours. Add 5 ml of saturated ammonium chloride solution and stir for half an hour. Add 15 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain 4.2 g of compound 2 (yellow oil). Content (quantitative NMR detection): 92.8%. Two-step yield: 53.7%.

[0047] Example 5: Preparation of compound 2.

[0048] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (48 mL, 0.12 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a solution of dimethyl sulfate (20.1 g, 0.16 mol) in tetrahydrofuran (40 mL) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. Add 20 ml of methanol to the system and stir for 1 hour. Add 10 ml of saturated ammonium chloride solution and stir for half an hour. Add 50 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain a yellow oily substance. Dissolve the oily substance in 72 ml of tetrahydrofuran. Cool the system to -10°C and add sodium methoxide (2 g, 0.04 mol). After the addition is complete, maintain the temperature at -10°C and stir for 0.5 hours. Add 10 ml of a tetrahydrofuran solution containing dimethyl sulfate (5.3 g, 0.04 mol). After the addition is complete, stir at room temperature overnight. Return to room temperature and stir overnight. Add 5 ml of methanol to the system and stir for 0.5 hours. Add 5 ml of saturated ammonium chloride solution and stir for half an hour. Add 15 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain compound 2 (yellow oily substance) 4.1 g. Content (quantitative NMR detection): 91.4%. The two-step yield was 54.9%.

[0049] Example 6: Preparation of compound 2.

[0050] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (48 mL, 0.12 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a solution of dimethyl sulfate (20.1 g, 0.16 mol) in tetrahydrofuran (40 mL) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. Add 20 ml of methanol to the system and stir for 1 hour. Add 10 ml of saturated ammonium chloride solution and stir for half an hour. Add 50 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain a yellow oil. Dissolve the oil in 72 ml of tetrahydrofuran. Cool the system to -10°C and add sodium tert-butoxide (3.6 g, 0.04 mol). After the addition is complete, maintain the temperature at -10°C and stir for 0.5 hours. Add 10 ml of tetrahydrofuran solution of dimethyl sulfate (5.3 g, 0.04 mol). After the addition is complete, stir at room temperature overnight. Return to room temperature and stir overnight. Add 5 ml of methanol to the system and stir for 0.5 hours. Add 5 ml of saturated ammonium chloride solution and stir for half an hour. Add 15 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain compound 2 (yellow oil) 5.8 g. Purity (quantitative NMR detection): 92.4%. The two-step yield was 76.9%.

[0051] Example 7: Preparation of compound 2.

[0052] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (48 mL, 0.12 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a solution of dimethyl sulfate (20.1 g, 0.16 mol) in tetrahydrofuran (40 mL) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. Add 20 ml of methanol to the system and stir for 1 hour. Add 10 ml of saturated ammonium chloride solution and stir for half an hour. Add 50 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain a yellow oil. Dissolve the oil in 72 ml of tetrahydrofuran. Cool the system to -10°C and add potassium carbonate (5.5 g, 0.04 mol). After the addition is complete, maintain the temperature at -10°C and stir for 0.5 hours. Add 10 ml of a tetrahydrofuran solution of dimethyl sulfate (5.3 g, 0.04 mol). After the addition is complete, stir at room temperature overnight. TLC showed that the reaction was incomplete. Heat the system to 50°C and stir for 12 hours. TLC showed that the reaction was complete. Add 5 ml of methanol to the system and stir for 0.5 hours. Add 15 ml of ethyl acetate to the system, extract, separate the liquid, dry the organic phase, and evaporate to dryness to obtain 3.1 g of compound 2 (yellow oil). Content (quantitative NMR detection): 90.7%. Two-step yield: 40.1%.

[0053] Example 8: Preparation of compound 2.

[0054] 5.2 g (0.04 mol) of tert-butyl hydrazine carbamate was dissolved in 150 mL of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (48 mL, 0.12 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1 hour. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a solution of dimethyl sulfate (20.1 g, 0.16 mol) in tetrahydrofuran (40 mL) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. Add 20 ml of methanol to the system and stir for 1 hour. Add 10 ml of saturated ammonium chloride solution and stir for half an hour. Add 50 ml of ethyl acetate to the system, extract, separate the layers, dry the organic phase, and evaporate to dryness to obtain a yellow oil. Dissolve the oil in 72 ml of tetrahydrofuran. Cool the system to -10°C and add sodium hydroxide (0.96 g, 0.04 mol). After the addition is complete, maintain the temperature at -10°C and stir for 0.5 hours. Add 10 ml of a tetrahydrofuran solution of dimethyl sulfate (5.3 g, 0.04 mol). After the addition is complete, stir at room temperature overnight. TLC showed that the reaction was incomplete. Heat the system to 50°C and stir for 12 hours. TLC showed that the reaction was complete. Add 5 ml of methanol to the system and stir for 0.5 hours. Add 15 ml of ethyl acetate to the system, extract, separate the layers, dry the organic phase, and evaporate to dryness to obtain 4.3 g of compound 2 (yellow oil). Content (quantitative NMR detection): 90.5%. Two-step yield: 55.3%.

[0055] Example 9: Preparation of compound 1.

[0056] To a 100 mL three-necked flask, compound 2 (5.0 g, 0.03 mol, purity (quantitative NMR): 92.4%) and 25 mL of methanol were added. While stirring at 0 °C, 22.5 mL of 4 mol / L HCl / dioxane solution (0.09 mol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 6–8 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was evaporated to dryness and distilled twice with methanol to obtain 3.1 g of crude hydrochloride (compound 1), yield: 72.2%. 1 1H-NMR (400MHz, CD3OD): δ 2.89 (s, 6H), 2.79 (s, 3H), content (quantitative NMR detection): 95.4%. See Figure 3 for the NMR spectrum.

[0057] Example 10: Preparation of compound 1.

[0058] To a 100 mL three-necked flask, compound 2 (5.0 g, 0.03 mol, purity (quantitative NMR): 92.4%) and 25 mL of methanol were added. While stirring at 0 °C, 22.5 mL of 4 mol / L hydrochloric acid aqueous solution (0.09 mol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 6–8 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was evaporated to dryness and distilled twice with methanol to obtain 3.5 g of crude hydrochloride (compound 1), with a yield of 82.2% and a purity (quantitative NMR): 96.2%.

[0059] Example 11: Preparation of compound 1.

[0060] 105.6 g (0.8 mol) of tert-butyl hydrazine carbamate was dissolved in 3 L of tetrahydrofuran. The system was cooled to -40 °C, and a solution of n-butyllithium (960 ml, 2.4 mol, 2.5 mol / L tetrahydrofuran) was added dropwise over 1–1.5 hours. After the addition was complete, the system was kept at -40 °C and stirred for 1 hour. Then, a solution of dimethyl sulfate (402.3 g, 3.2 mol) in tetrahydrofuran (800 ml) was added dropwise, maintaining the temperature at -40 °C for 1 hour until the addition was complete. After the addition was complete, the system was brought back to room temperature and stirred overnight. Add 800 ml of methanol to the system and stir for 1 hour. Add 1 L of saturated ammonium chloride solution and stir for half an hour. Add 1 L of ethyl acetate to the system, extract, separate the layers, dry the organic phase, and evaporate to dryness to obtain a yellow oil. Dissolve the oil in 1.4 L of tetrahydrofuran. Cool the system to -10°C and add sodium tert-butoxide (70 g, 0.8 mol). After the addition is complete, maintain the temperature at -10°C and stir for 0.5 hours. Add 200 ml of a tetrahydrofuran solution of dimethyl sulfate (106 g, 0.8 mol). After the addition is complete, stir at room temperature overnight. Return to room temperature and stir overnight. Add 100 ml of methanol to the system and stir for 0.5 hours. Add 100 ml of saturated ammonium chloride solution and stir for half an hour. Add 300 ml of ethyl acetate to the system, extract, separate the layers, dry the organic phase, and evaporate to dryness to obtain 130.2 g of a yellow oil. The above-mentioned oily substance was dissolved in 6.5 L of methanol. Hydrogen chloride gas (approximately 120 g in a 120 g cylinder) was slowly introduced while stirring at 0°C. The reaction mixture was kept at room temperature and stirred for 6–8 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was evaporated to dryness and distilled twice with methanol to obtain crude hydrochloride. The crude product was then slurried with 200 ml of MTBE at 0°C overnight. The slurry was filtered to obtain 83.2 g of a white solid (compound 1), yield: 70.3%. Content (quantitative NMR detection): 97.4%. 1H-NMR (400MHz, CD3OD): δ 2.89 (s, 6H), 2.79 (s, 3H), NMR spectrum shown in Figure 4.

Claims

1. A method for preparing trimethylhydrazine hydrochloride, characterized in that, The process includes the following steps: Step 1. Preparation of compound 2, which consists of two stages: Stage 1. Tert-butyl hydrazinocarbamate reacts with a methylating agent under the action of a base to generate a mixture of compound 3 and compound 2; Stage 2. The mixture obtained in Stage 1 is further reacted with a methylating agent to convert it into compound 2. Step 2. Preparation of compound 1: Compound 2 was deprotected from Boc in the presence of hydrochloric acid and then formed a salt to give compound 1. 。 2. The preparation method according to claim 1, characterized in that, in step 1, stage 1, the alkali is selected from n-butyllithium, diisopropylaminolithium, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, etc., preferably n-butyllithium.

3. The preparation method according to claim 1, characterized in that, in step 1, the amount of tert-butyl hydrazinocarbamate used is 1 equivalent, and the amount of base used is 3.0 to 4.0 equivalents, preferably 3.0 equivalents.

4. The preparation method according to claim 1, characterized in that, in step 1, stage 1, the methylating agent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, preferably iodomethane and dimethyl sulfate.

5. The preparation method according to claim 1, characterized in that, in step 1, stage 1, the amount of the methylating agent is 3.0 to 4.0 equivalents, preferably 4.0 equivalents.

6. The preparation method according to claim 1, characterized in that, in step 1, stage 2, the alkali is selected from n-butyllithium, diisopropylaminolithium, sodium hydrogen hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, etc., more preferably sodium tert-butoxide and potassium tert-butoxide.

7. The preparation method according to claim 1, characterized in that, in step 1, stage 2, the amount of alkali used is 1.0 to 3.0 equivalents, preferably 1.0 equivalents.

8. The preparation method according to claim 1, characterized in that, in step 1, stage 2, the methylating agent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, preferably iodomethane and dimethyl sulfate.

9. The preparation method according to claim 1, characterized in that, in step 1, stage 2, the amount of the methylating agent used is 1.0 to 3.0 equivalents, preferably 1.0 equivalents.

10. The preparation method according to claim 1, characterized in that, in step 2, the amount of compound 2 is 1.0 equivalent, preferably, the amount of compound 2 is 1 equivalent, the amount of hydrochloric acid is 3.0~5.0 equivalent, preferably 3.0 equivalent, and the reaction temperature is 0~50℃, preferably 25℃.

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