Preparation method of 1-aminocyclohexylmethylamine hydrochloride

Abstract

The invention discloses a preparation method of 1-aminocyclohexyl methylamine hydrochloride. The preparation method comprises the following steps: S1, cyclohexanone, a cyaniding reagent and ammonia water react to produce 1-aminocyclohexyl cyanide; and S2, reducing the 1-aminocyclohexyl cyanide, and salifying to prepare the 1-aminocyclohexyl methylamine hydrochloride. The method has the advantages that the reaction conditions are mild, strict control of anhydrous conditions is not needed, additional catalysts are not needed, the 1-aminocyclohexyl cyanide can be obtained by the Strerecker reaction with high yield under the mild reaction conditions, and the average yield is 90% or above. The obtained 1-aminocyclohexyl cyanide is reduced by lithium aluminum hydride, so that the 1-aminocyclohexyl methylamine hydrochloride can be obtained at high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing 1-aminocyclohexylmethylamine hydrochloride. Background Art

[0002] 1-Aminocyclohexanemethanamine (1-Aminocyclohexanemethanamine) is a cyclic amine compound with diverse applications due to its structural properties. Cyclohexanemethanamine derivatives are often used as key intermediates in pharmaceutical synthesis. For example, compounds with similar structures may be used in the preparation of antidepressants, antivirals, or analgesics. The presence of amino and methylamine groups makes it susceptible to reactions such as amidation and alkylation, further enabling the construction of complex drug molecules. It can also be used as a catalyst ligand and as a material.

[0003] The synthesis of substituted cyanamides typically involves a three-component nucleophilic addition reaction involving an aldehyde or ketone, a cyaniding agent, and an ammonia source in a suitable reaction system. This reaction, proposed by Adolph Strecker in 1850, is used to prepare α-amino acids. Commonly used cyaniding agents include inorganic cyanides such as sodium cyanide and potassium cyanide, organic cyaniding agents such as acetone cyanohydrin and trimethylsilyl cyanide, and some transition metal cyanides. Inorganic cyanides such as sodium cyanide and potassium cyanide have long been the preferred choice for the synthesis of amino acid derivatives due to their water solubility, easy ionization, strong nucleophilicity, and low cost. However, due to their high toxicity and extremely low lethal doses for humans and animals, they pose a significant risk, leading to stricter regulations and restrictions on their use worldwide. Transition metal cyanides such as cuprous cyanide and zinc cyanide, on the other hand, have limited solubility and ionization, resulting in fewer free cyanide ions and poor activity, making them less useful in amino acid synthesis. The toxicity of the organic cyanide acetone cyanohydrin is slightly lower than that of inorganic cyanides such as sodium cyanide. It is easily decomposed under acidic conditions to produce highly toxic hydrogen cyanide gas, posing an extremely high safety risk. Another organic cyanide reagent, trimethylsilyl cyanide, has the characteristics of low toxicity and easy release of cyanide under appropriate conditions. It has been widely used as an alternative in organic synthesis, especially in the safe synthesis of amino acid derivatives.

[0004] Aminocyclohexylmethylamine hydrochloride is prepared by reducing 1-aminocyclohexyl cyanide to form a salt. The preparation of 1-aminocyclohexyl cyanide in the prior art includes the following methods: Patents US20060223855, WO2006028545, WO20080128058, etc. describe the preparation of 1-aminocyclohexylcyanide by the Strecker reaction using highly toxic sodium cyanide or potassium cyanide, ammonium chloride, ammonia water, and cyclohexanone. This process uses highly toxic substances, poses high safety risks, and is almost unusable under existing regulatory regulations.

[0005] Patents WO201805865, WO20220148354, etc. describe the Strecker reaction of trimethylsilyl cyanide, ammonia, and cyclohexanone in tetrahydrofuran in an anhydrous system catalyzed by tetraisopropoxytitanium. The reaction conditions are relatively harsh, the cost is high, and it is not conducive to production scale-up.

[0006] The literature Russian Journal of Organic Chemistry, 2014, vol. 50 (1), p. 21-24 reported the Strecker reaction of acetone cyanohydrin, ammonia and cyclohexanone. The severe toxicity of acetone cyanohydrin also limits its large-scale use and has no economic value. Summary of the Invention

[0007] The object of the present invention is to provide a method for preparing 1-aminocyclohexylmethylamine hydrochloride, so as to solve the technical problems in the prior art of using highly toxic reagents or having harsh reaction conditions and high costs that are not suitable for large-scale industrial production.

[0008] To achieve the above objectives, the present invention provides the following technical solutions: The present invention provides a method for preparing 1-aminocyclohexylmethylamine hydrochloride, comprising the following steps: S1, cyclohexanone, cyaniding reagent and ammonia water react to produce 1-aminocyclohexane cyanide; S2, 1-aminocyclohexyl cyanide reduction and salt formation to prepare 1-aminocyclohexylmethylamine hydrochloride; The route is as follows: .

[0009] Furthermore, the cyaniding reagent includes but is not limited to sodium cyanide, potassium cyanide, trimethylsilyl cyanide, zinc cyanide, cuprous cyanide and other cyanide-containing compounds.

[0010] Furthermore, the cyaniding agent is trimethylsilyl cyanide.

[0011] Furthermore, the solvent used in the reaction in S1 includes but is not limited to methanol-water, ethanol-water and other alcohol-water mixed solvents, acetone-water, butanone-water and other ketone-water mixed solvents, dichloromethane-water, dichloroethane-water and other halogenated hydrocarbon-water mixed solvents.

[0012] Furthermore, the reducing agent in S2 includes but is not limited to lithium aluminum tetrahydride, NaBH4+Lewis acid, and heavy metal reducing agent.

[0013] Furthermore, the reducing agent in S2 is lithium aluminum tetrahydride.

[0014] Furthermore, the NaBH4+Lewis acid can specifically be NaBH4 / NiCl2·6H2O, NaBH4 / CoCl2·6H2O, NaBH4 / LiCl, NaBH4 / I2 or NaBH4 / InCl3.

[0015] Furthermore, the heavy metal reducing agent can specifically be Raney Ni, Pd / C, Pd(OH)2 / C, or PtO2.

[0016] Furthermore, the 1-aminocyclohexyl cyanide reduction can also adopt BH3·THF or BH3·Me2S reduction method.

[0017] Because trimethylsilyl cyanide readily breaks its carbon-silicon bond in alcoholic or alkaline conditions, releasing cyanide ions, the present invention utilizes this property. Using cyclohexanone, an ammonia source (ammonia water, ammonium chloride, etc.), and low-toxic trimethylsilyl cyanide as the cyanide source, the reaction is conducted directly in a water-solvent two-phase system. Trimethylsilyl cyanide releases cyanide ions in situ and directly participates in the reaction. The reaction conditions are mild, requiring no strict anhydrous conditions or additional catalysts. Under these mild reaction conditions, a high-yield Strecker reaction is achieved to produce 1-aminocyclohexyl cyanide, with an average yield exceeding 90%. The resulting 1-aminocyclohexyl cyanide is then reduced with lithium aluminum tetrahydride to produce 1-aminocyclohexylmethylamine hydrochloride in high yield.

[0018] Based on the above technical solution, the embodiments of the present invention can produce at least the following technical effects: (1) The materials used in the present invention avoid the use of highly toxic substances such as sodium cyanide and potassium cyanide, and use low-toxic trimethylsilyl cyanide. The raw materials are cheap and easy to obtain, and the cost is low; (2) The Strecker reaction conditions used in the present invention have high conversion rate, high yield, simple process and easy operation; (3) The process scheme used in the present invention has low cost, mild reaction conditions, easy operation, and is suitable for industrial large-scale production. DETAILED DESCRIPTION

[0019] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0020] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any intermediate value within a stated value or stated range and any other stated value or intermediate value within the stated range is also encompassed by the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0021] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0022] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be exemplary only.

[0023] Example 1 A preparation method of 1-aminocyclohexylmethylamine hydrochloride, specifically: (1) Cyclohexanone (200 g, 2.04 mol, 1 eq), ammonium chloride (109 g, 2.04 mol, 1.0 eq), 25% ammonia water (854 ml, 3.0 eq), and 400 mL of methanol were added to the reaction flask, and then the temperature was lowered to 0 °C. Trimethylsilyl cyanide (181.5 g, 1.836 mol, 0.9 eq) was added dropwise, and the temperature was controlled at 0-10 °C. After the addition, the reaction was continued at 10-20 °C for 4 h. When there was no cyclohexanone residue on the plate (solid precipitated after the reaction was completed), 20% sodium thiosulfate (253 ml) was added to quench the reaction. After filtration, the filtrate was concentrated to remove methanol at 40-45 °C, and extracted with dichloromethane (400 mL*4) four times. The organic phases were combined and washed once with 400 mL of saturated brine. The organic phase was dried over sodium sulfate and concentrated to 240.4 g, with a yield of 95%. The plate was a single point.

[0024] (2) Add THF (1440 mL) to the reaction bottle under nitrogen protection, cool to 0-10 ° C, add lithium aluminum tetrahydride (66.2 g, 1.75 mol, 1.2 eq), control the temperature to T ≤ 30 ° C, add a mixed solution of 1-aminocyclohexanecarbonitrile (180 g, 1.45 mol) and THF (270 mL) dropwise, control the temperature to T ≤ 20 ° C, and continue the reaction at 15-20 ° C for 4 hours. After the reaction is completed, the plate is monitored and the temperature is cooled to 0-10 ° C. THF (560 mL) is added, and the reaction is continued in sequence. When T≦30℃, water (66.2ml) and 15% sodium hydroxide (66.2mL) were added in sequence to quench the reaction. Magnesium sulfate (66.6g) was added and stirred at room temperature for 30min. The mixture was filtered and rinsed with THF (600mL). The filter cake was slurried and filtered with THF (1.5L*2). The filtrate was adjusted to pH=2-3 with concentrated hydrochloric acid and concentrated to a viscous state of 140g. Isopropanol (1.177kg) was added and slurried at 70-80℃ for 1h. The mixture was cooled to 15℃ and filtered and dried to obtain 247.7g with a purity of 98.6% and a yield of 85%.

[0025] Example 2 A preparation method of 1-aminocyclohexylmethylamine hydrochloride, specifically: (1) Cyclohexanone (200 g, 2.04 mol, 1 eq), ammonium chloride (109 g, 2.04 mol, 1.0 eq), 25% ammonia water (854 ml, 3.0 eq), and 500 mL of ethanol were added to the reaction flask, and then the temperature was lowered to 0 °C. Trimethylsilyl cyanide (181.5 g, 1.836 mol, 0.9 eq) was added dropwise, and the temperature was controlled at 0-10 °C. After the addition, the mixture was reacted at 10-20 °C for 4 h. When there was no cyclohexanone residue on the plate (solid precipitated after the reaction was completed), 20% sodium thiosulfate (253 ml) was added to quench the reaction. After filtration, the filtrate was concentrated to remove methanol at 40-45 °C and extracted with dichloromethane (400 mL*4) four times. The organic phases were combined and washed once with 400 mL of saturated brine. The organic phase was dried over sodium sulfate and concentrated to 240.4 g, with a yield of 95%. The plate was a single point.

[0026] (2) Add THF (1440 mL) to the reaction bottle under nitrogen protection, cool to 0-10 ° C, add lithium aluminum tetrahydride (66.2 g, 1.75 mol, 1.2 eq), control the temperature to T ≤ 30 ° C, add a mixed solution of 1-aminocyclohexanecarbonitrile (180 g, 1.45 mol) and THF (270 mL) dropwise, control the temperature to T ≤ 20 ° C, and continue the reaction at 15-20 ° C for 4 hours. After the reaction is completed, the plate is monitored and the temperature is cooled to 0-10 ° C. THF (560 mL) is added, and the reaction is continued in sequence. When T≦30℃, water (66.2ml) and 15% sodium hydroxide (66.2mL) were added in sequence to quench the reaction. Magnesium sulfate (66.6g) was added and stirred at room temperature for 30min. The mixture was filtered and rinsed with THF (600mL). The filter cake was slurried and filtered with THF (1.5L*2). The filtrate was adjusted to pH=2-3 with concentrated hydrochloric acid and concentrated to a viscous state of 140g. Isopropanol (1.177kg) was added and slurried at 70-80℃ for 1h. The mixture was cooled to 15℃ and filtered and dried to obtain 247.7g with a purity of 98.6% and a yield of 85%.

[0027] Example 3 (1) Cyclohexanone (100 kg, 1 eq), ammonium chloride (54.5 kg, 1.0 eq), 25% ammonia water (427 L, 3.0 eq), and 200 L methanol were added to the reactor, and then the temperature was lowered to 0 ° C. Trimethylsilyl cyanide (90.75 kg, 0.9 eq) was added dropwise, and the temperature was controlled at 0-10 ° C. After the addition, the reaction was carried out at 10-20 ° C for 4 h. After the reaction was completed, solid precipitated. 20% sodium thiosulfate was added to quench the reaction. The filtrate was concentrated to remove methanol at 40-45 ° C, and extracted with dichloromethane. The organic phases were combined and washed once with saturated brine. The organic phase was dried over sodium sulfate and concentrated to 112.5 kg, with a yield of 88.9%.

[0028] (2) Add THF (720 L) to the reactor under nitrogen protection, cool to 0-10 ° C, add lithium aluminum tetrahydride (33.1 kg, 1.2 eq), control the temperature to T ≤ 30 ° C, add a mixed solution of 1-aminocyclohexanecarbonitrile 90 kg and THF (135 L), control the temperature to T ≤ 20 ° C, and continue the reaction at 15-20 ° C. After the reaction is completed, cool to 0-10 ° C, add THF (280 L), and add water (33.1 kg, 1.2 eq) in sequence at T ≤ 30 ° C. 1L), 15% sodium hydroxide (33.1L), quench the reaction, add magnesium sulfate (33.3kg), stir at room temperature for 30min, filter and rinse with THF (300L), slurry and filter the filter cake with THF (750L*2), adjust the pH of the filtrate to 2-3 with concentrated hydrochloric acid, concentrate to viscous 140kg, add isopropanol (588.5kg), slurry at 70-80℃ for 1h, cool to 15℃, filter and dry to obtain 90kg with a purity of 98.6% and a yield of 80%.

[0029] The above description is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the creative concept of the present invention, which all fall within the scope of protection of the present invention.

Claims

1. A method for preparing 1-aminocyclohexylmethylamine hydrochloride, characterized in that: The following steps are involved: S1, cyclohexanone, cyaniding reagent and ammonia water react to produce 1-aminocyclohexane cyanide; S2. 1-aminocyclohexyl cyanide is reduced and salted to prepare 1-aminocyclohexylmethylamine hydrochloride; the specific structural route is as follows: 。 2. The preparation method of 1-aminocyclohexylmethylamine hydrochloride according to claim 1, wherein The cyaniding reagent includes but is not limited to sodium cyanide, potassium cyanide, trimethylsilyl cyanide, zinc cyanide, cuprous cyanide and other cyanide-containing compounds.

3. The preparation method of 1-aminocyclohexylmethylamine hydrochloride according to claim 2, wherein The cyaniding agent is trimethylsilyl cyanide.

4. The preparation method of 1-aminocyclohexylmethylamine hydrochloride according to claim 1, wherein The solvent used in the reaction in S1 includes but is not limited to methanol-water, ethanol-water and other alcohol-water mixed solvents, acetone-water, butanone-water and other ketone-water mixed solvents, dichloromethane-water, dichloroethane-water and other halogenated hydrocarbon-water mixed solvents.

5. The preparation method of 1-aminocyclohexylmethylamine hydrochloride according to claim 1, wherein The reducing agent in S2 includes but is not limited to lithium aluminum tetrahydride, NaBH4+Lewis acid, and heavy metal reducing agent.

6. The method for preparing 1-aminocyclohexylmethylamine hydrochloride according to claim 5, wherein The reducing agent in S2 is lithium aluminum tetrahydride.

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