Preparation method of 1-methylcyclopropylamine hydrochloride

Abstract

The invention discloses a preparation method of 1-methylcyclopropylamine hydrochloride, and belongs to the field of fine chemical engineering and medical intermediates. The preparation method comprises the following steps: taking ethyl acetate as an initial raw material, carrying out a Coulinke Vitch reaction with ethyl magnesium bromide under the catalytic action of isopropyl titanate to synthesize 1-methylcyclopropanol, reacting 1-methylcyclopropanol with diphenyl azido phosphate (DPPA) under the action of DBU to obtain an azide compound, or firstly reacting 1-methylcyclopropanol with sulfonyl chloride to generate active sulfonate, and then reacting 1-methylcyclopropanol with sulfonyl chloride to generate the active sulfonate. Then reacting with sodium azide to generate corresponding azide, finally carrying out reduction reaction, and acidifying hydrogen chloride to form salt to obtain the 1-methylcyclopropylamine hydrochloride. The invention provides a novel synthesis method for synthesizing the 1-methylcyclopropylamine hydrochloride intermediate, the reaction condition is mild, the process operation is simple, the cost is low, and the industrial production can be realized.

Description

Technical Field

[0001] The invention relates to the field of fine chemical industry and pharmaceutical intermediate preparation, and in particular to a method for preparing 1-methylcyclopropylamine hydrochloride. Background Art

[0002] 1-Methylcyclopropylamine hydrochloride is an important pharmaceutical chemical intermediate. The development of its synthesis method is worthy of research by chemists. The main preparation methods reported so far are:

[0003] Method 1: Patent WO2008 / 85316. In the patent, the author uses 1-methylcyclopropanecarboxylic acid as the raw material, first makes an acyl chloride, then reacts with ammonia water to make an amide, and finally the amide is subjected to a Hoffmann degradation reaction to synthesize the target product. The synthetic route is as follows:

[0004]

[0005] Method 2: Patents WO2016 / 92326 and WO2019 / 21208. In the patents, the authors also used 1-methylcyclopropanecarboxylic acid as the raw material, triethylamine as the base, and tert-butyl alcohol as the solvent, first reacting with DPPA to undergo a Curtius rearrangement reaction to obtain an amino Boc protected product, and then removing the protecting group with hydrogen chloride to obtain the final target compound. The synthetic route is as follows:

[0006]

[0007] In the above two methods, the starting material is 1-methylcyclopropanecarboxylic acid, which is expensive and difficult to synthesize. There are related reports on its synthesis, but due to factors such as harsh process conditions, low yield or the use of highly dangerous reagents, it is not conducive to large-scale production.

[0008] In addition, the researchers of patent CN104447293 used methyl acrylate as raw material, first reacted with trihalide in the presence of base to undergo cyclopropylation reaction, then removed the halogen atom on the ring under metal sodium / ethanol conditions, and finally synthesized 1-methylcyclopropanecarboxylic acid through acidification. The synthesis route is as follows:

[0009]

[0010] This method uses a highly dangerous reducing agent, metallic sodium. It is not a problem to use it in small-scale laboratory experiments, but it is extremely dangerous and undesirable for industrial production.

[0011] In the literature Journal of Organic Chemistry, 1983, vol. 48, #15, p. 2472–2476, the authors used cyclopropylcarboxylic acid as a raw material, tetrahydrofuran as a solvent, and LDA as a base to react with iodomethane to synthesize 1-methylcyclopropanecarboxylic acid. In this step of the reaction, the price of iodomethane is relatively high, and the reaction conversion yield is only 32%. The actual separation yield will be even lower. The synthesis route is as follows:

[0012]

[0013] The researchers of patent WO201595651 used acetonitrile as raw material, reacted with ethyl magnesium bromide Grignard reagent under the action of isopropyl titanate to prepare the target compound, and obtained 1-methylcyclopropylamine by distillation after the reaction, and then formed a salt with hydrogen chloride. The synthesis route is as follows:

[0014]

[0015] This method has a short process, but the yield is unknown. The small molecule 1-methylcyclopropylamine compound has poor thermal stability. If this process is scaled up for production, large-scale distillation and purification will take a long time, and the product will easily deteriorate.

[0016] In order to solve the technical and industrial production problems, the present application further studied the synthesis method of the compound, avoided using the more expensive 1-methylcyclopropylcarboxylic acid as the raw material, and developed a new method for synthesizing 1-methylcyclopropylamine hydrochloride. Summary of the invention

[0017] In order to overcome the deficiencies in the prior art, the present invention provides a method for preparing 1-methylcyclopropylamine hydrochloride. Ethyl acetate is used as a starting material. Under the catalysis of isopropyl titanate, the 1-methylcyclopropyl alcohol is subjected to a Kulinkovich reaction with an ethyl magnesium bromide reagent to synthesize 1-methylcyclopropyl alcohol. The 1-methylcyclopropyl alcohol is then reacted with DPPA under the action of DBU to obtain an azide compound or the 1-methylcyclopropyl alcohol can also be first reacted with sulfonyl chloride to generate an active sulfonate, and then subjected to a substitution reaction with sodium azide to obtain the corresponding azide. Finally, the azide is subjected to a reduction reaction and acidified with hydrogen chloride to obtain 1-methylcyclopropylamine hydrochloride. The reaction raw materials are cheap, the operation is simple, the conditions are relatively mild, the process cost is low, and industrial production and preparation can be achieved.

[0018] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0019] The preparation method of 1-methylcyclopropylamine hydrochloride comprises: using ethyl acetate as a raw material and isopropyl titanate as a catalyst to react with ethyl magnesium bromide to generate 1-methylcyclopropyl alcohol; reacting 1-methylcyclopropyl alcohol with diphenylphosphoryl azide DPPA under the action of DBU to obtain an azide or reacting 1-methylcyclopropyl alcohol with sulfonyl chloride to obtain a sulfonate compound; performing an SN2 substitution reaction on the sulfonate compound and sodium azide to obtain an azide; and finally subjecting the azide to a reduction reaction and acidification with hydrogen chloride to obtain a salt to obtain 1-methylcyclopropylamine hydrochloride.

[0020] Wherein, the chemical structural formula of 1-methylcyclopropylamine hydrochloride is as follows:

[0021]

[0022] Its synthetic route is as follows:

[0023]

[0024] As a possible implementation mode, further, in this scheme, the preparation method of 1-methylcyclopropylamine hydrochloride comprises the following steps:

[0025] Step 1), using ethyl acetate as a raw material, and ethyl magnesium bromide under the catalysis of isopropyl titanate to obtain 1-methylcyclopropanol through a Kulinkovich reaction;

[0026] Step 2), 1-methylcyclopropanol reacts with diphenylphosphoryl azide DPPA in the presence of DBU to obtain an azide, or 1-methylcyclopropanol reacts with sulfonyl chloride in the presence of a base to obtain a sulfonate compound, and the sulfonate compound is then subjected to an SN2 substitution reaction with sodium azide to obtain an azide;

[0027] Step 3), using THF and water as solvents and PPh3 as a reducing agent, the azide is subjected to a reduction reaction and chlorinated with hydrogen chloride to obtain 1-methylcyclopropylamine hydrochloride.

[0028] As a preferred implementation option, in step 2) of this scheme, a solvent is used when 1-methylcyclopropanol reacts with diphenylphosphoryl azide DPPA under the action of DBU to obtain azide, and the solvent is one of toluene, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0029] As a preferred implementation option, in step 2) of this scheme, a solvent is used when 1-methylcyclopropanol reacts with sulfonyl chloride under the action of a base to obtain a sulfonate compound, and the solvent is one of DCM, toluene, ethyl acetate, THF, and 2-methyltetrahydrofuran.

[0030] As a preferred implementation option, in step 2) of this scheme, when 1-methylcyclopropanol reacts with sulfonyl chloride under the action of a base to obtain a sulfonate compound, the base used is one of triethylamine, DIEA, pyridine, DMAP, and DBU.

[0031] As a preferred implementation option, in step 2) of this scheme, the sulfonyl chloride is preferably methylsulfonyl chloride, p-toluenesulfonyl chloride, or phenylsulfonyl chloride.

[0032] As a preferred implementation option, in step 2) of this scheme, the temperature when 1-methylcyclopropanol reacts with sulfonyl chloride in the presence of a base to obtain a sulfonate compound is -5-65°C and the reaction time is 1-24h.

[0033] As a preferred implementation option, in step 2) of this scheme, a solvent is used when the sulfonate compound is subjected to an SN2 substitution reaction with sodium azide to obtain an azide. The solvent is one of DMF, DMAC, ethyl acetate, and NMP. The reaction temperature is 50-100° C. and the reaction time is 2-8 h.

[0034] As a preferred implementation option, in step 3) of this scheme, the reaction temperature is preferably 10-60°C and the reaction time is 5-15h.

[0035] Based on the above, the present invention also provides a 1-methylcyclopropylamine hydrochloride, which is prepared by the preparation method described above.

[0036] By adopting the above technical scheme, the present invention has the following beneficial effects compared with the prior art: the scheme of the present invention provides a method for preparing 1-methylcyclopropylamine hydrochloride, which uses ethyl acetate as a raw material, isopropyl titanate as a catalyst, and ethyl magnesium bromide to undergo a Kulinkovich reaction to generate an intermediate I (1-methylcyclopropanol), and then the intermediate I reacts with DPPA under the action of DBU to obtain an intermediate III (azide), and the intermediate I can also react with sulfonyl chloride to obtain a sulfonate intermediate II (sulfonate compound), and the intermediate II is then subjected to an SN2 substitution reaction with sodium azide to obtain an intermediate III (azide), and finally the intermediate III (azide) is subjected to a reduction reaction, and is acidified with hydrogen chloride to obtain 1-methylcyclopropylamine hydrochloride (compound IV). The synthesis method avoids using the relatively expensive 1-methylcyclopropanecarboxylic acid as a starting material, and the raw materials used are easily available and cheap, the reaction conditions are mild, the process operation is simple, the yield is high, and the process cost is low, which is of great significance for the research and development of a preparation method for 1-methylcyclopropylamine hydrochloride and scaled-up production. DETAILED DESCRIPTION

[0037] The present invention will be further described in detail below in conjunction with the embodiments. It is particularly noted that the following embodiments are only used to illustrate the present invention, but are not intended to limit the scope of the present invention. Similarly, the following embodiments are only partial embodiments of the present invention rather than all embodiments, and all other embodiments obtained by those of ordinary skill in the art without creative work are within the scope of protection of the present invention.

[0038] This scheme proposes a compound, which is 1-methylcyclopropylamine hydrochloride, and the chemical structure is as follows:

[0039]

[0040] The preparation method is as follows: ethyl acetate is used as a raw material, and ethylmagnesium bromide is reacted with Kulinkovich reaction to obtain intermediate I (1-methylcyclopropanol), intermediate I is treated with DBU and then reacted with DPPA to obtain azide intermediate (III), intermediate I can also react with sulfonyl chloride to obtain sulfonate (II), and then react with sodium azide to obtain azide (III) by nucleophilic substitution reaction, finally azide (III) is reduced and salted with hydrogen chloride to obtain 1-methylcyclopropylamine hydrochloride (IV).

[0041] The synthetic route of 1-methylcyclopropylamine hydrochloride is as follows:

[0042]

[0043] Wherein R is p-methylphenyl, phenyl, methyl.

[0044] In order to facilitate the elaboration of this solution, the following is an implementation description of the solution in combination with multiple embodiments:

[0045] The terms are as follows:

[0046]

[0047]

[0048] Example 1

[0049] The preparation method of 1-methylcyclopropylamine hydrochloride comprises:

[0050] Step 1

[0051] Ethyl acetate (200g, 2.26mol, 1.0eq) was dissolved in anhydrous THF (400mL), isopropyl titanate (38.54g, 0.06eq) was added, and under nitrogen protection, the temperature was controlled at 10-20°C, and ethyl magnesium bromide THF solution (4.74mol, 2M, 2.37L, 2.1eq) was slowly added dropwise, and the mixture was stirred for 3 hours. The reaction solution was quenched into a 10% aqueous sulfuric acid solution (5-20°C), and dichloromethane (800mL*2) was added to extract twice, the organic phases were combined, and washed with water (1000mL*5) for 5 times, the organic phases were dried over anhydrous sodium sulfate, and the mixture was dried under low vacuum at 25-30°C to obtain 130.4g of compound I (measured yield 80%), i.e., 1-methylcyclopropanol.

[0052] The obtained product was subjected to hydrogen nuclear magnetic resonance spectroscopy, and the result was:

[0053] 1 H NMR(CDCl3)δ0.41-0.48(m,2H),0.74-0.81(m,2H),1.44(s,3H),1.87(br.s.,1H);

[0054] Step 2 (including parallel Step 2 and Step 2AB)

[0055] Step 2

[0056] Take compound I (30 g, 0.416 mol) and dissolve it in toluene (150 mL), add DPPA (125.9 g, 0.46 mol), control the temperature at 0-25°C, add DBU (69.7 g, 0.46 mol) dropwise, stir at room temperature for 10-15 h, add water (100 mL) to quench the reaction, add ethyl acetate water (100 mL*3) and extract 3 times, combine the organic phases, wash once with water (100 mL), dry with anhydrous sodium sulfate, and concentrate at 30-40°C to obtain 39.2 g of compound III (azide) (measured yield 97.03%), which is directly used in the next step reaction.

[0057] Step 2A:

[0058] Compound I (20 g, 0.28 mol) was dissolved in DCM (100 mL), triethylamine (29.4 g, 0.29 mol) was added, the temperature was controlled at -5 to 5 ° C, p-toluenesulfonyl chloride (55.29 g, 0.29 mol) was added in batches, and after the addition was completed, it was stirred at room temperature (20 to 30 ° C) for 3 to 5 h, water (100 mL) was added, and the liquid was extracted. The aqueous phase was extracted twice with DCM (60 mL*2), the organic phases were combined, washed once with saturated sodium bicarbonate aqueous solution (100 mL), washed once with water (100 mL), dried over anhydrous sodium sulfate, and concentrated at 30 to 40 ° C to obtain 63.0 g of compound II (measured yield 99.4%), i.e., sulfonate compound.

[0059] The obtained product was subjected to hydrogen nuclear magnetic resonance spectroscopy, and the result was:

[0060] 1 HNMR(CDCl3)δ7.80(d,2H),7.32(d,2H),2.46(s,3H),1.57(s,3H),1.12(t,2H)0.58(t,2H).

[0061] Step 2B:

[0062] Take compound II (67.89 g, 0.30 mol) and dissolve it in DMF (136 mL), add sodium azide (20.47 g, 0.315 mol), raise the temperature to 80-90 ° C, keep stirring and react for 3-4 hours, return to room temperature (15-25 ° C), add methyl tert-butyl ether (300 mL) and water (300 mL), extract and separate the liquids, wash the organic phase with saturated sodium chloride (240 mL*3) 3 times, separate the organic layer, and concentrate under reduced pressure at 30-45 ° C to obtain 26.31 g of compound III (azide) (measured yield 89.1%), and the crude product is directly used in the next step reaction.

[0063] Step 3:

[0064] Take azide III (28 g, 0.29 mol) and dissolve it in THF (160 mL). Add triphenylphosphine (83.67 g, 0.32 mol) and stir for 30 min. Add water (16 mL) and stir at 10-45 ° C for 5-10 h under nitrogen protection. Add water (140 mL) and ethyl acetate (140 mL). Extract and separate the liquids. The aqueous phase is extracted once with ethyl acetate (84 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and filtered. Hydrogen chloride / ethyl acetate solution (120 mL, 4 M) is added dropwise to the filtrate under stirring to precipitate a solid. Stir at 15-25 ° C for 1-2 hours, concentrate under reduced pressure to remove about half of the solvent, filter, rinse the filter cake with a small amount of ethyl acetate (28 mL), and drain under reduced pressure to obtain 22.4 g of 1-methylcyclopropylamine hydrochloride (IV). The yield is 82%. The product is an off-white solid with a purity of 99.2%.

[0065] The obtained product was subjected to hydrogen nuclear magnetic resonance spectroscopy, and the result was:

[0066] 1 HNMR(d-DMSO)δ8.51(s,3H),1.33(s,3H),0.89(m,2H),0.51~0.56(m,2H).

[0067] Example 2

[0068] The preparation method of 1-methylcyclopropylamine hydrochloride comprises:

[0069] Step 1

[0070] Ethyl acetate (100g, 1.13mol, 1.0eq) was dissolved in anhydrous THF (200mL), isopropyl titanate (12.85g, 0.04eq) was added, and under nitrogen protection, the temperature was controlled at 10-20°C, and ethyl magnesium bromide THF solution (2.37mol, 2M, 1.19L, 2.1eq) was slowly added dropwise, and the mixture was stirred for 3 hours. The reaction solution was quenched into a 10% aqueous sulfuric acid solution (5-20°C), and dichloromethane (400mL*2) was added to extract twice, the organic phases were combined, and washed with water (500mL*5) for 5 times, the organic phases were dried over anhydrous sodium sulfate, and the mixture was dried under low vacuum at 25-30°C to obtain 52.2g of compound I (measured yield 64%), i.e., 1-methylcyclopropanol.

[0071] Step 2 (including parallel Step 2 and Step 2AB)

[0072] Step 2

[0073] Compound I (25 g, 0.347 mol) was dissolved in THF (125 mL), DPPA (105.04 g, 0.382 mol) was added, the temperature was controlled at 0-25°C, DBU (58.11 g, 0.382 mol) was added dropwise, after the addition was completed, it was stirred at room temperature for 14 h, concentrated under reduced pressure to remove the tetrahydrofuran solvent, water (90 mL) was added to quench the reaction, ethyl acetate (90 mL*3) was added and extracted 3 times, the organic phases were combined, washed once with water (90 mL), dried over anhydrous sodium sulfate, and concentrated at 30-40°C to obtain 28.65 g of compound III (azide) (measured yield 85.03%).

[0074] Step 2A:

[0075] Compound I (20 g, 0.28 mol) was dissolved in DCM (100 mL), DIEA (37.47 g, 0.29 mol) was added, the temperature was controlled at -5 to 5 ° C, p-toluenesulfonyl chloride (55.29 g, 0.29 mol) was added in batches, and after the addition was completed, it was stirred at room temperature (20 to 30 ° C) for 5 h, water (100 mL) was added, and the liquid was extracted. The aqueous phase was extracted twice with DCM (60 mL*2), the organic phases were combined, washed once with saturated sodium bicarbonate aqueous solution (100 mL), washed once with water (100 mL), dried over anhydrous sodium sulfate, and concentrated at 30 to 40 ° C to obtain 61.0 g of compound II (yield 96.24%), i.e., sulfonate compound.

[0076] Step 2B:

[0077] Compound II (46 g, 0.203 mol) was dissolved in DMAC (92 mL), sodium azide (13.85 g, 0.213 mol) was added, the temperature was raised to 80-90 ° C, the reaction was stirred for 4 h, the temperature was restored to room temperature (15-25 ° C), methyl tert-butyl ether (200 mL) and water (200 mL) were added, and the liquid was extracted. The organic phase was washed three times with saturated sodium chloride aqueous solution (160 mL*3), the organic phase was separated, and it was concentrated under reduced pressure at 30-45 ° C to obtain 16.54 g of compound III (azide) (yield 83.9%).

[0078] Step 3:

[0079] Take azide III (28 g, 0.29 mol) and dissolve it in THF (160 mL). Add triphenylphosphine (83.67 g, 0.32 mol) and stir for 30 min. Add water (16 mL) and stir at 10-45 ° C for 5-10 h under nitrogen protection. Add water (140 mL) and ethyl acetate (140 mL). Extract and separate the liquids. The aqueous phase is extracted once with ethyl acetate (84 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and filtered. Hydrogen chloride / ethyl acetate solution (120 mL, 4 M) is added dropwise to the filtrate under stirring to precipitate a solid. Stir at 15-25 ° C for 1-2 hours, concentrate under reduced pressure to remove about half of the solvent, filter, rinse the filter cake with a small amount of ethyl acetate (28 mL), and drain under reduced pressure to obtain 22.4 g of 1-methylcyclopropylamine hydrochloride (IV). The yield is 82%. The product is an off-white solid with a purity of 99.2%.

[0080] The obtained product was subjected to hydrogen nuclear magnetic resonance spectroscopy, and the result was:

[0081] 1 HNMR(d-DMSO)δ8.51(s,3H),1.33(s,3H),0.89(m,2H),0.51~0.56(m,2H).

[0082] Example 3

[0083] The preparation method of 1-methylcyclopropylamine hydrochloride comprises:

[0084] Step 1

[0085] Ethyl acetate (100g, 1.13mol, 1.0eq) was dissolved in anhydrous THF (200mL), isopropyl titanate (25.7g, 0.08eq) was added, and under nitrogen protection, the temperature was controlled at 10-20°C, and ethyl magnesium bromide THF solution (2.37mol, 2M, 1.19L, 2.1eq) was slowly added dropwise, and the mixture was stirred for 3 hours. The reaction solution was quenched into a 10% aqueous sulfuric acid solution (5-20°C), and dichloromethane (400mL*2) was added to extract twice, the organic phases were combined, and washed with water (500mL*5) for 5 times, the organic phases were dried over anhydrous sodium sulfate, and the mixture was dried under low vacuum at 25-30°C to obtain 64.4g of compound I (measured yield 79%), i.e., 1-methylcyclopropanol.

[0086] Step 2 (including parallel Step 2 and Step 2AB)

[0087] Step 2

[0088] Compound I (32 g, 0.444 mol) was dissolved in 2Me-THF (160 mL), DPPA (134.4 g, 0.488 mol) was added, the temperature was controlled at 0-25°C, DBU (74.37 g, 0.488 mol) was added dropwise, and after the addition was completed, it was stirred at room temperature for 14 h, water (105 mL) was added to quench the reaction, ethyl acetate (105 mL*3) was added and extracted three times, the organic phases were combined, washed once with water (105 mL), dried over anhydrous sodium sulfate, and concentrated at 30-40°C to obtain 34.93 g of compound III (azide) (measured yield 81.02%).

[0089] Step 2A:

[0090] Take compound I (20 g, 0.28 mol) and dissolve it in DCM (100 mL), add pyridine (23.73 g, 0.30 mol), control the temperature at -5 to 5 ° C, add p-toluenesulfonyl chloride (57.20 g, 0.30 mol) in batches, stir at room temperature (20 to 30 ° C) for 5 h, add water (100 mL), extract and separate the liquids, extract the aqueous phase with DCM (60 mL*2) twice, combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution (100 mL), wash once with water (100 mL), dry over anhydrous sodium sulfate, and concentrate at 30 to 40 ° C to obtain 55.0 g of compound II (measured yield 86.8%), i.e., sulfonate compound.

[0091] Step 2B:

[0092] Take compound II (46 g, 0.203 mol) and dissolve it in NMP (92 mL), add sodium azide (13.85 g, 0.213 mol), raise the temperature to 80-90 ° C, keep stirring and react for 4 hours, return to room temperature (15-25 ° C), add methyl tert-butyl ether (200 mL) and water (200 mL), extract and separate the liquids, wash the organic phase with saturated sodium chloride aqueous solution (160 mL*3) 3 times, separate the organic phase, and concentrate under reduced pressure at 30-45 ° C to obtain 15.6 g of compound III (azide) (measured yield 79.02%).

[0093] Step 3:

[0094] Take azide III (28g, 0.29mol) and dissolve it in THF (160mL), add triphenylphosphine (83.67g, 0.32mol), stir for 30min, add water (16mL), protect with nitrogen, stir at 10-45℃ for 5-10h, add water (140mL) and ethyl acetate (140mL), extract and separate, extract the aqueous phase with ethyl acetate (84mL) once, combine the organic phases, dry over anhydrous sodium sulfate, filter, add hydrogen chloride / ethyl acetate solution (120mL, 4M) dropwise to the filtrate under stirring, precipitate solid, stir at 15-25℃ for 1-2h, concentrate under reduced pressure to remove about half of the solvent, filter, rinse the filter cake with a small amount of ethyl acetate (28mL), and drain under reduced pressure to obtain 22.4g 1-methylcyclopropylamine hydrochloride (IV), with a yield of 82%. The product has an off-white solid appearance and a purity of 99.2%.

[0095] The obtained product was subjected to hydrogen nuclear magnetic resonance spectroscopy, and the result was:

[0096] 1 HNMR(d-DMSO)δ8.51(s,3H),1.33(s,3H),0.89(m,2H),0.51~0.56(m,2H).

[0097] In each embodiment of this scheme, the azide used in step three is used after being mixed with the product obtained in step two, and the preparation of step three is carried out in the same group.

[0098] The above descriptions are only some embodiments of the present invention, and are not intended to limit the protection scope of the present invention. Any equivalent device or equivalent process transformation made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. The preparation method of 1-methylcyclopropylamine hydrochloride is characterized in that, It includes: Ethyl acetate is used as a raw material and isopropyl titanate is used as a catalyst to undergo a Kulinkovich reaction with ethyl magnesium bromide to generate 1-methylcyclopropanol. 1-methylcyclopropanol reacts with diphenylphosphoryl azide DPPA under the action of DBU to obtain an azide or 1-methylcyclopropanol reacts with sulfonyl chloride to obtain a sulfonate compound. The sulfonate compound then undergoes an SN2 substitution reaction with sodium azide to obtain an azide. Finally, the azide is subjected to a reduction reaction and salted with hydrogen chloride to obtain 1-methylcyclopropylamine hydrochloride.

2. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 1, wherein It includes the following steps: Step 1), using ethyl acetate as a raw material, and ethyl magnesium bromide under the catalysis of isopropyl titanate to obtain 1-methylcyclopropanol through a Kulinkovich reaction; Step 2), 1-methylcyclopropanol reacts with diphenylphosphoryl azide DPPA in the presence of DBU to obtain an azide, or 1-methylcyclopropanol reacts with sulfonyl chloride in the presence of a base to obtain a sulfonate compound, and the sulfonate compound is then subjected to an SN2 substitution reaction with sodium azide to obtain an azide; Step 3), using THF and water as solvents and PPh3 as a reducing agent, the azide is subjected to a reduction reaction and chlorinated with hydrogen chloride to obtain 1-methylcyclopropylamine hydrochloride.

3. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, wherein In step 2), a solvent is used when 1-methylcyclopropanol reacts with diphenylphosphoryl azide DPPA under the action of DBU to obtain azide, and the solvent is one of toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

4. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, wherein In step 2), a solvent is used when 1-methylcyclopropanol reacts with sulfonyl chloride under the action of a base to obtain a sulfonate compound. The solvent is one of DCM, toluene, ethyl acetate, THF, and 2-methyltetrahydrofuran.

5. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, wherein In step 2), when 1-methylcyclopropanol reacts with sulfonyl chloride in the presence of a base to obtain a sulfonate compound, the base used is one of triethylamine, DIEA, pyridine, DMAP, and DBU.

6. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, wherein In step 2), the sulfonyl chloride is methanesulfonyl chloride, p-toluenesulfonyl chloride or phenylsulfonyl chloride.

7. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, characterized in that: In step 2), the temperature when 1-methylcyclopropanol reacts with sulfonyl chloride in the presence of a base to obtain a sulfonate compound is -5-65°C and the reaction time is 1-24h.

8. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, wherein In step 2), a solvent is used when the sulfonate compound is subjected to SN2 substitution reaction with sodium azide to obtain an azide. The solvent is one of DMF, DMAC, ethyl acetate, and NMP. The reaction temperature is 50-100° C. and the reaction time is 2-8 h.

9. The method for preparing 1-methylcyclopropylamine hydrochloride according to claim 2, wherein In step 3), the reaction temperature is 10-60°C and the reaction time is 5-15h. 10.1-Methylcyclopropylamine hydrochloride, characterized in that: It is prepared by the preparation method according to any one of claims 1 to 9.

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