A preparation method of 1,4-diazaspiro[5.5]undecane-3-one

Abstract

The present invention relates to the technical field of organic synthesis of pharmaceutical intermediates, and a preparation method of 1,4-diazaspiro [5.5] undecane-3-one is provided, firstly (1-cyanocyclohexyl) glycine methyl ester is prepared by glycine methyl ester hydrochloride, cyclohexanone and sodium cyanide, then the amino group in (1-cyanocyclohexyl) glycine methyl ester is protected by formyl by adding an acylating agent, and modified (1-cyanocyclohexyl) glycine methyl ester is prepared; next, the obtained modified (1-cyanocyclohexyl) glycine methyl ester is reduced by potassium borohydride or sodium borohydride for ring-closing reaction; finally, the reduced ring-closing system is deprotected of amino group, and 1,4-diazaspiro [5.5] undecane-3-one is prepared. The present invention optimizes the preparation process, significantly reduces the preparation cost, and improves the production stability under the premise of ensuring the quality of the product, and provides a feasible and convenient preparation method for its market development.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis of pharmaceutical intermediates, in particular to a method for preparing 1,4-diazaspiro[5.5]undecane-3-one. Background Art

[0002] 1,4-diazaspiro[5.5]undecan-3-one is an important drug intermediate with beneficial pharmacological activity and chemical structure (it has a unique chemical structure and important pharmacological effects and is an important intermediate for synthesizing anorexigenic peptides). The drugs synthesized from it have a wide range of applications and can be used to treat Alzheimer's disease, improve eating or sleeping disorders, regulate calcium ions, etc. The low-cost and efficient preparation of 1,4-diazaspiro[5.5]undecan-3-one has huge market value and application prospects.

[0003] However, among the commonly used synthesis methods of existing 1,4-diazaspiro[5.5]undecane-3-one, there is a synthesis route in which glycine methyl ester (or ethyl ester) and cyclohexanone are reacted with sodium cyanide to obtain 3-methyl-2-nitrophenol, which is then methylated with iodomethane to obtain intermediate 1, i.e. (1-cyanocyclohexyl)glycine methyl ester, and then the target product (1,4-diazaspiro[5.5]undecane-3-one) is obtained under the action of hydrogen gas under the catalyst of platinum dioxide. The synthesis route is as follows:

[0004]

[0005] The existing literature similar to the above synthesis route is patent CN108299317A "Synthesis method of 1,4-diazaspiro [5,5] undecane hydrochloride - disclosed", and its synthesis route is:

[0006]

[0007] It can be known from practice that the intermediate 1 (or intermediate product B) of the above-mentioned synthesis method is an oily substance, which is difficult to purify and unstable, and is easily decomposed under reaction conditions, so that the subsequent reduction cyclization process has demanding conditions, poor process stability, and unstable yield; in addition, the reduction cyclization process must use a hydrogenation kettle, which has high equipment requirements, and also uses expensive heavy metal catalysts, which significantly increases the equipment cost and preparation cost, brings a heavy economic burden to the enterprise, and restricts its development to a certain extent.

[0008] To this end, the present invention aims to improve the preparation method of 1,4-diazaspiro[5.5]undecan-3-one in view of the many deficiencies in the above-mentioned prior art, creatively performs formyl protection on the intermediate product 1, and combines the use of corresponding additives to improve the stability of the intermediate product, thereby increasing the final yield, improving product quality, and reducing costs, providing a feasible idea for its market development. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing 1,4-diazaspiro[5.5]undecan-3-one with high preparation efficiency, good product quality, high yield and cost saving, so as to solve the problems raised in the above background technology.

[0010] To achieve the above object, the present invention provides the following technical solutions:

[0011] A method for preparing 1,4-diazaspiro[5.5]undecan-3-one comprises the following steps:

[0012] Step S1: Preparation of (1-cyanocyclohexyl)glycine methyl ester: glycine methyl ester hydrochloride is added in batches to a flask containing sodium sulfite and solvent water, cyclohexanone is added under stirring, sodium cyanide is added after stirring evenly, and an extractant is added after stirring for 8-10 hours to extract, sodium sulfate is added to the extract to dry, and sodium sulfate is filtered out after drying to obtain (1-cyanocyclohexyl)glycine methyl ester;

[0013] Step S2: preparing modified (1-cyanocyclohexyl)glycine methyl ester: adding an acylating agent to the (1-cyanocyclohexyl)glycine methyl ester prepared in step S1 under stirring to carry out formylation reaction for 0.5-0.8h, then adding an extractant to carry out extraction, and the extract is post-treated to obtain modified (1-cyanocyclohexyl)glycine methyl ester;

[0014] Step S3: reduction ring-closing reaction: methanol and anhydrous nickel chloride are added to a flask, and the solution is dissolved by stirring at 30-50°C to form a green solution. After cooling to 10-12°C, the modified (1-cyanocyclohexyl)glycine methyl ester obtained in step S2 is added, and the solution is stirred evenly and cooled to 0-2°C. 0.3w potassium borohydride or sodium borohydride is added, and the temperature is slowly increased to 15-20°C at a heating rate of 2-4°C. During the heating to 15-20°C, the remaining potassium borohydride or sodium borohydride is added in 9 batches, 0.3w per batch, and the final temperature is maintained and stirred for 0.5-0.8h to complete the reduction ring-closing reaction and obtain a cyclized intermediate;

[0015] Step S4: Preparation of 1,4-diazaspiro[5.5]undecane-3-one: glacial acetic acid is added to the cyclized intermediate obtained in step S3, and the mixture is filtered at 0-10°C. Methanol is added to the filtrate, the mixture is heated to 20-50°C, and then p-toluenesulfonic acid monohydrate is added. The mixture is heated to reflux for 16 hours. Methanol is removed under reduced pressure, and then acetone is added. The mixture is cooled to 0-5°C, stirred for 1.0-1.5 hours, and then filtered. The filter cake is dried at 65-70°C to obtain a white solid. Dichloromethane and triethylamine are added to the white solid in sequence and stirred to dissolve. Sodium sulfate is added in batches under stirring at 15-30°C, and then potassium carbonate powder is added. The mixture is stirred and refluxed for 1 hour. After filtering, 6V of toluene is added to the filtrate, the mixture is heated to 110°C and concentrated, cooled to 0-10°C, stirred for 0.5-1.2 hours, and then filtered. The filter cake is dried to obtain 1,4-diazaspiro[5.5]undecane-3-one.

[0016] Preferably, in step S1, the mass ratio of cyclohexanone to solvent water and sodium sulfate is 1:(8-20):(1-2), and the molar ratio of cyclohexanone to sodium sulfite, glycine methyl ester hydrochloride and sodium cyanide is 1:(0.8-1.2):(0.8-1.2):(0.8-1.2);

[0017] The molar ratio of the acylating agent to (1-cyanocyclohexyl)glycine methyl ester in step S2 is (1-2): 1;

[0018] The mass ratio of the modified (1-cyanocyclohexyl)glycine methyl ester to anhydrous nickel chloride, potassium borohydride or sodium borohydride, and methanol in step S3 is 1:(0.2-0.8):(2-4):(5-20);

[0019] In step S4, the mass ratio of the cyclized intermediate to glacial acetic acid, methanol, p-toluenesulfonic acid monohydrate, triethylamine, sodium sulfate, and potassium carbonate is 1: (6-10): (3-5): (1.2-1.5): (0.3-0.5): (1-2): (0.6-0.8), and the volume ratio of the cyclized intermediate to acetone, dichloromethane, and toluene is 1: (2-3): (10-12): (6-8).

[0020] Preferably, the glycine methyl ester hydrochloride in step S1 is added in batches 5-8 times, and the mass of glycine methyl ester hydrochloride added in any batch is equal, that is, 0.2W.

[0021] Preferably, the sodium sulfate drying in step S1 is performed 2-3 times.

[0022] Preferably, the acylating agent in step S2 is composed of formic acid and acetic anhydride, and the mass ratio of the formic acid to acetic anhydride is 1:(2-3).

[0023] Preferably, the acylating agent is added dropwise, and the dropping rate of the acylating agent is 0.5-1.0 g / min.

[0024] Preferably, the extractant in step S1 and step S2 is methyl tert-butyl ether.

[0025] Preferably, the post-processing in step S2 comprises the following steps:

[0026] Step S21: combining the extracted methyl tert-butyl ether layers to obtain a combined liquid;

[0027] Step S22: washing the combined solution obtained in step S21 with water;

[0028] Step S23: the methyl tert-butyl ether layer after washing in step S22 is concentrated by rotary evaporation until the volume of the concentrated liquid is reduced to 1 / 3 of the original volume;

[0029] Step S24: Control the temperature of the concentrated solution obtained in step S23 to 20-30° C., add 6V-10V of n-hexane to the concentrated solution, cool it to -5-5° C., and mix it at 300-600 r / min for 0.8-1.5h to obtain a mixed solution;

[0030] Step S25: filtering the mixed solution obtained in step S24, and rinsing the filter cake with n-hexane for 2-3 times;

[0031] Step S26: drying the filter cake obtained in step S25 at 40-45° C. to obtain modified (1-cyanocyclohexyl)glycine methyl ester.

[0032] Preferably, the sodium sulfate is added in batches 4-6 times in step S4, and the mass of sodium sulfate added in any batch is equal, and 0.25W is added in each batch.

[0033] V is a commonly used chemical process term. For example, 6V means that the volume is 6 times the weight of the main raw material. Similarly, 6W means that the weight is 6 times the weight of the main raw material.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] (1) The present invention creatively protects the amino group in (1-cyanocyclohexyl)glycine methyl ester with a formyl group to obtain modified (1-cyanocyclohexyl)glycine methyl ester, which significantly improves the crystallinity and stability of the intermediate product, facilitates its further crystallization and purification, greatly facilitates the subsequent reduction and cyclization process, and not only improves the preparation efficiency, but also helps to improve the purity and yield of the product.

[0036] (2) The present invention creatively improves the use of catalysts in the reduction cyclization process, avoids the use of hydrogenation kettles and expensive heavy metal catalysts, and enables the preparation process to be carried out in ordinary reactors, significantly reducing the preparation cost and improving production stability, which has great market application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The figure is a schematic flow chart of a method for preparing 1,4-diazaspiro[5.5]undecan-3-one according to the present invention;

[0038] Figure 2 The hydrogen nuclear magnetic resonance spectrum of 1,4-diazaspiro[5.5]undecan-3-one prepared in the present invention. DETAILED DESCRIPTION

[0039] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0040] See also Figure 1-2 The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecane-3-one, and its synthetic route is shown as follows:

[0041]

[0042] Embodiment 1

[0043] The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one, comprising the following steps:

[0044] Step S1: Preparation of (1-cyanocyclohexyl)glycine methyl ester: glycine methyl ester hydrochloride (0.8 eq, added in 5 times, and the mass of glycine methyl ester hydrochloride added in any batch is equal) is added in batches into a flask containing sodium sulfite (0.8 eq) and solvent water (8 W), cyclohexanone (1 eq, 1 W, i.e., the mass and molar amount of cyclohexanone are used as the basis in this step) is added under stirring at 300 r / min, sodium cyanide (0.8 eq) is added after stirring evenly, methyl tert-butyl ether is added after stirring for 8 h for extraction, the methyl tert-butyl ether layers are combined and washed, and sodium sulfate (1 W) is added to the methyl tert-butyl ether layer and dried twice (i.e., drying→filtration→drying→filtration), and sodium sulfate is filtered out after drying to obtain (1-cyanocyclohexyl)glycine methyl ester, i.e., intermediate 1.

[0045] Step S2: Preparation of modified (1-cyanocyclohexyl)glycine methyl ester: Under stirring at 300 r / min, an acylating agent (1 eq, the acylating agent consists of formic acid and acetic anhydride, and the mass ratio of formic acid to acetic anhydride is 1:2) is added dropwise to the (1-cyanocyclohexyl)glycine methyl ester (1 eq, i.e., this step is based on the molar amount of (1-cyanocyclohexyl)glycine methyl ester) prepared in step S1 at a rate of 0.5 g / min for formylation reaction for 0.5 h, and then methyl tert-butyl ether is added for extraction. The extract is post-treated to obtain modified (1-cyanocyclohexyl)glycine methyl ester, i.e., intermediate 2. The post-treatment in this step includes the following steps: Step S21: Combine the extracted methyl tert-butyl ether layers to obtain a combined liquid; Step S22: Wash the combined liquid obtained in Step S21 with water for 3 minutes; Step S23: Concentrate the methyl tert-butyl ether layer after washing in Step S22 by rotary evaporation until the volume of the concentrated liquid is reduced to 1 / 3 of the original volume; Step S24: Control the temperature of the concentrated liquid obtained in Step S23 to 20°C, add n-hexane dropwise to the concentrated liquid, then cool it to -5°C, and mix it at 300r / min stirring for 0.8h to obtain a mixed liquid; Step S25: Filter the mixed liquid obtained in Step S24, and rinse the filter cake with n-hexane twice; Step S26: Dry the filter cake obtained in Step S25 at 40°C to obtain modified (1-cyanocyclohexyl)glycine methyl ester.

[0046] Step S3: reduction cyclization reaction: methanol (5W) and anhydrous nickel chloride (0.2W) were added to a flask, and the mixture was stirred at 30°C to dissolve into a green solution. After cooling to 10°C, the modified (1-cyanocyclohexyl) glycine methyl ester obtained in step S2 (1W, i.e., the mass of the modified (1-cyanocyclohexyl) glycine methyl ester was used as the basis for this step) was added. After stirring evenly, the mixture was cooled to 0°C, and 10% potassium borohydride (0.3W) was added first. The temperature was slowly increased to 15°C at a heating rate of 2°C. The remaining potassium borohydride (2.7W) was added in 9 portions at the final temperature, and the mass of potassium borohydride added in any batch was equal. The final temperature was maintained and stirred for 0.5h to complete the reduction cyclization reaction and obtain a cyclization intermediate, i.e., intermediate 3.

[0047] Step S4: Preparation of 1,4-diazaspiro[5.5]undecane-3-one: Add glacial acetic acid (6W) to the cyclized intermediate (1W, 1V, i.e., the mass and volume of the cyclized intermediate are used as the basis for this step) obtained in step S3 for quenching, and filter at 0°C, add methanol (3W) to the filtrate, heat to 20°C, then add p-toluenesulfonic acid monohydrate (1.2W), heat to reflux for 16h, remove methanol under reduced pressure, then add acetone (2V), slowly cool to 0°C, stir for 1.0h, and then filter, and dry the filter cake at 65°C to obtain a white solid , dichloromethane (10V) and triethylamine (0.3W) were added to the white solid in sequence and stirred to dissolve, sodium sulfate (1W, added in 4 times, and the mass of sodium sulfate added in any batch was equal) was added in batches at 15°C with stirring, and potassium carbonate powder (0.6W) was added, stirred and refluxed for 1h, filtered, toluene (6V) was added to the filtrate, heated to 110°C and concentrated until the volume was concentrated to 1 / 4 of the original volume, cooled to 0°C, stirred for 0.5h and filtered, and the filter cake was dried to obtain 1,4-diazaspiro[5.5]undecan-3-one. Specific embodiments

[0048] The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one, comprising the following steps:

[0049] Step S1: Preparation of (1-cyanocyclohexyl)glycine methyl ester: glycine methyl ester hydrochloride (1.2 eq, added in 8 times, and the mass of glycine methyl ester hydrochloride added in any batch is equal) is added in batches into a flask containing sodium sulfite (1.2 eq) and solvent water (20 W), cyclohexanone (1 eq, 1 W, i.e., the mass and molar amount of cyclohexanone are used as the basis in this step) is added under stirring at 600 r / min, sodium cyanide (1.2 eq) is added after stirring evenly, methyl tert-butyl ether is added after stirring for 10 h for extraction, the methyl tert-butyl ether layers are combined and washed, and sodium sulfate (2 W) is added to the methyl tert-butyl ether layer and dried for 3 times (i.e., drying→filtration→drying→filtration→drying→filtration), and sodium sulfate is filtered out after drying to obtain (1-cyanocyclohexyl)glycine methyl ester, i.e., intermediate 1.

[0050] Step S2: Preparation of modified (1-cyanocyclohexyl)glycine methyl ester: Under stirring at 600 r / min, an acylating agent (2 eq, the acylating agent consists of formic acid and acetic anhydride, and the mass ratio of formic acid to acetic anhydride is 1:3) is added dropwise to the (1-cyanocyclohexyl)glycine methyl ester (1 eq, i.e., this step is based on the molar amount of (1-cyanocyclohexyl)glycine methyl ester) prepared in step S1 at a rate of 1.0 g / min for formylation reaction for 0.8 h, and then methyl tert-butyl ether is added for extraction. The extract is post-treated to obtain modified (1-cyanocyclohexyl)glycine methyl ester, i.e., intermediate 2. The post-treatment in this step includes the following steps: Step S21: Combine the extracted methyl tert-butyl ether layers to obtain a combined liquid; Step S22: Wash the combined liquid obtained in Step S21 with water for 5 minutes; Step S23: Concentrate the methyl tert-butyl ether layer after washing in Step S22 by rotary evaporation until the volume of the concentrated liquid is reduced to 1 / 3 of the original volume; Step S24: Control the temperature of the concentrated liquid obtained in Step S23 to 30°C, add n-hexane dropwise to the concentrated liquid, then cool it to 5°C, and mix it at 600r / min stirring for 1.5h to obtain a mixed liquid; Step S25: Filter the mixed liquid obtained in Step S24, and rinse the filter cake with n-hexane 3 times; Step S26: Dry the filter cake obtained in Step S25 at 45°C to obtain modified (1-cyanocyclohexyl) glycine methyl ester.

[0051] Step S3: reduction cyclization reaction: methanol (20W) and anhydrous nickel chloride (0.8W) were added to a flask, and the mixture was stirred at 50°C to dissolve into a green solution. After cooling to 12°C, the modified (1-cyanocyclohexyl) glycine methyl ester (1W, i.e., the mass of the modified (1-cyanocyclohexyl) glycine methyl ester in this step was used as the basis) obtained in step S2 was added. After stirring evenly, the mixture was cooled to 2°C. 10% potassium borohydride (0.3W) was first added, and the temperature was slowly increased to 20°C at a heating rate of 4°C. The remaining potassium borohydride (2.7W) was added in 9 portions at the final temperature, and the mass of sodium borohydride added in any batch was equal. The final temperature was maintained and stirred for 0.8h to complete the reduction cyclization reaction and obtain a cyclization intermediate, i.e., intermediate 3.

[0052] Step S4: Preparation of 1,4-diazaspiro[5.5]undecane-3-one: Add glacial acetic acid (10W) to the cyclized intermediate (1W, 1V, i.e., the mass and volume of the cyclized intermediate are used as the basis for this step) obtained in step S3 for quenching, and filter at 10°C, add methanol (5W) to the filtrate, heat to 50°C, then add p-toluenesulfonic acid monohydrate (1.5W), heat to reflux for 16h, remove methanol under reduced pressure, then add acetone (3V), slowly cool to 5°C, stir for 1.5h, and then filter, and dry the filter cake at 70°C to obtain a white solid To the white solid, add dichloromethane (12V) and triethylamine (0.5W) in sequence and stir to dissolve. Add sodium sulfate (2W, added in 6 times, and the mass of sodium sulfate added in any batch is equal) in batches at 30°C under stirring, then add potassium carbonate powder (0.8W), stir and reflux for 1h, filter, add toluene (8V) to the filtrate, heat to 110°C and concentrate until the volume is concentrated to 1 / 3 of the original volume, cool to 10°C, stir for 1.2h and filter, and dry the filter cake to obtain 1,4-diazaspiro[5.5]undecane-3-one. Specific embodiments

[0053] The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one, comprising the following steps:

[0054] Step S1: Preparation of (1-cyanocyclohexyl)glycine methyl ester: glycine methyl ester hydrochloride (1.1 eq, added in 6 times, and the mass of glycine methyl ester hydrochloride added in any batch is equal) is added in batches into a flask containing sodium sulfite (1.0 eq) and solvent water (16 W), cyclohexanone (1 eq, 1 W, i.e., the mass and molar amount of cyclohexanone are used as the basis in this step) is added under stirring at 400 r / min, sodium cyanide (1.2 eq) is added after stirring evenly, methyl tert-butyl ether is added after stirring for 9 hours for extraction, the methyl tert-butyl ether layers are combined and washed, and sodium sulfate (2 W) is added to the methyl tert-butyl ether layer and dried for 3 times (i.e., drying→filtration→drying→filtration→drying→filtration), and sodium sulfate is filtered out after drying to obtain (1-cyanocyclohexyl)glycine methyl ester, i.e., intermediate 1.

[0055] Step S2: Preparation of modified (1-cyanocyclohexyl)glycine methyl ester: Under stirring at 400 r / min, an acylating agent (2 eq, the acylating agent consists of formic acid and acetic anhydride, and the mass ratio of formic acid to acetic anhydride is 1:2) is added dropwise to the (1-cyanocyclohexyl)glycine methyl ester (1 eq, i.e., this step is based on the molar amount of (1-cyanocyclohexyl)glycine methyl ester) prepared in step S1 at a rate of 0.8 g / min for formylation reaction for 0.6 h, and then methyl tert-butyl ether is added for extraction. The extract is post-treated to obtain modified (1-cyanocyclohexyl)glycine methyl ester, i.e., intermediate 2. The post-treatment in this step includes the following steps: Step S21: Combine the extracted methyl tert-butyl ether layers to obtain a combined liquid; Step S22: Wash the combined liquid obtained in Step S21 with water for 4 minutes; Step S23: Concentrate the methyl tert-butyl ether layer after washing in Step S22 by rotary evaporation until the volume of the concentrated liquid is reduced to 1 / 3 of the original volume; Step S24: Control the temperature of the concentrated liquid obtained in Step S23 to 25°C, add n-hexane dropwise to the concentrated liquid, then cool it to 3°C, and mix it at 400r / min stirring for 1.2h to obtain a mixed liquid; Step S25: Filter the mixed liquid obtained in Step S24, and rinse the filter cake with n-hexane 3 times; Step S26: Dry the filter cake obtained in Step S25 at 42°C to obtain modified (1-cyanocyclohexyl)glycine methyl ester.

[0056] Step S3: reduction cyclization reaction: methanol (16W) and anhydrous nickel chloride (0.6W) were added to a flask, and the mixture was stirred at 40°C to dissolve into a green solution. After cooling to 12°C, the modified (1-cyanocyclohexyl) glycine methyl ester (1W, i.e., the mass of the modified (1-cyanocyclohexyl) glycine methyl ester was used as the basis for this step) obtained in step S2 was added. After stirring evenly, the mixture was cooled to 1°C, and 10% potassium borohydride (0.3W) was first added. The temperature was slowly increased to 18°C ​​at a heating rate of 3°C. The remaining potassium borohydride (2.7W) was added in 9 portions at the final temperature, and the mass of potassium borohydride added in any batch was equal. The final temperature was maintained and stirred for 0.6h to complete the reduction cyclization reaction and obtain a cyclization intermediate, i.e., intermediate 3.

[0057] Step S4: Preparation of 1,4-diazaspiro[5.5]undecane-3-one: Add glacial acetic acid (8W) to the cyclized intermediate (1W, 1V, i.e., the mass and volume of the cyclized intermediate are used as the basis for this step) obtained in step S3 for quenching, and filter at 8°C. Add methanol (4W) to the filtrate, raise the temperature to 30°C, and then add p-toluenesulfonic acid monohydrate (1.3W). Heat and reflux for 16h. After removing the methanol under reduced pressure, add acetone (2V), slowly cool to 3°C, stir for 1.2h, and then filter. The filter cake is dried at 68°C to obtain a white solid. , dichloromethane (12V) and triethylamine (0.4W) were added to the white solid in sequence and stirred to dissolve, sodium sulfate (2W, added in 5 times, and the mass of sodium sulfate added in any batch was equal) was added in batches at 25°C with stirring, and potassium carbonate powder (0.7W) was added, stirred and refluxed for 1h, filtered, toluene (7V) was added to the filtrate, heated to 110°C and concentrated until the volume was concentrated to 1 / 4 of the original volume, cooled to 2°C, stirred for 0.8h and filtered, and the filter cake was dried to obtain 1,4-diazaspiro[5.5]undecan-3-one.

[0058] Figure 2 The hydrogen nuclear magnetic resonance spectrum of 1,4-diazaspiro[5.5]undecane-3-one prepared in the present invention is as follows: Figure 2 It can be shown that the product structure is correct and the product purity is good, which is consistent with the 1,4-diazaspiro[5.5]undecan-3-one molecule, indicating that the present invention successfully prepares 1,4-diazaspiro[5.5]undecan-3-one.

[0059] The present invention calculates and analyzes the preparation process of 1,4-diazaspiro[5.5]undecan-3-one obtained in specific examples 1 to 3, and obtains the purity and yield as shown in the following table:

[0060] Table 1 Purity and yield of 1,4-diazaspiro[5.5]undecan-3-one prepared in the present invention

[0061] Table 1

[0062] Serial number Product purity% Product yield% Specific embodiment 1 99.5 73 Specific embodiment 2 99.8 76 Specific embodiment 3 99.6 75

[0063] It can be seen from the above table that the target product 1,4-diazaspiro[5.5]undecane-3-one prepared by the present invention has excellent purity and good yield, the purity can reach up to 99.8%, the yield reaches 73-76%, and the stability of the yield is improved, indicating that the preparation method of 1,4-diazaspiro[5.5]undecane-3-one designed by the present invention is feasible; in addition, it can be seen that the method significantly improves the stability and crystallinity of the intermediate product, and avoids the use of a hydrogenation kettle and expensive heavy metal catalysts, so that the preparation process can be carried out in a common reactor, which significantly reduces the preparation cost and has great market application value, and provides a convenient preparation method for obtaining high-quality and low-cost 1,4-diazaspiro[5.5]undecane-3-one with high yield.

[0064] It can be seen from the above examples that the present invention obtains intermediate product 2 (i.e., modified (1-cyanocyclohexyl)glycine methyl ester) by protecting the intermediate product 1 (i.e., (1-cyanocyclohexyl)glycine methyl ester) with a formyl group, which significantly improves the crystallinity and stability of the intermediate product, facilitates its further crystallization and purification, greatly facilitates the subsequent reduction and cyclization process, not only improves the preparation efficiency, but also helps to improve the purity and yield of the product; improves the use of catalysts in the reduction and cyclization process, avoids the use of hydrogenation kettles and expensive heavy metal catalysts, and enables the preparation process to be carried out in ordinary reactors, significantly reduces the preparation cost, and improves the production stability, which has great market application value.

[0065] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 1,4-diazaspiro[5.5]undecane-3-one, characterized in that: The following steps are involved: Step S1: Preparation of (1-cyanocyclohexyl)glycine methyl ester: glycine methyl ester hydrochloride is added in batches to a flask containing sodium sulfite and solvent water, and cyclohexanone is added under stirring. This step is based on the weight of cyclohexanone. After stirring evenly, sodium cyanide is added. After stirring for 8-10 hours, an extractant is added for extraction. Sodium sulfate is added to the extract for drying. After drying, sodium sulfate is filtered out to obtain (1-cyanocyclohexyl)glycine methyl ester; Step S2: Preparation of modified (1-cyanocyclohexyl)glycine methyl ester: Under stirring conditions, in this step, based on the weight of (1-cyanocyclohexyl)glycine methyl ester, an acylating agent is added to the (1-cyanocyclohexyl)glycine methyl ester prepared in step S1 for formylation reaction for 0.5-0.8h, and then an extractant is added for extraction. The extract is post-treated to obtain modified (1-cyanocyclohexyl)glycine methyl ester, whose molecular structure is: Step S3: reduction ring-closing reaction: methanol and anhydrous nickel chloride are added to a flask, stirred at 30-50°C to dissolve into a green solution, cooled to 10-12°C, the modified (1-cyanocyclohexyl) glycine methyl ester obtained in step S2 is added, stirred evenly and cooled to 0-2°C, 0.3W potassium borohydride or sodium borohydride is added, this step is based on the weight of the modified (1-cyanocyclohexyl) glycine methyl ester, the temperature is slowly increased to 15-20°C at a heating rate of 2-4°C, and the remaining potassium borohydride or sodium borohydride is added in 9 batches during the heating process to 15-20°C, 0.3W per batch, the final temperature is maintained and stirred for 0.5-0.8h, the reduction ring-closing reaction is completed, and a cyclized intermediate is obtained, the molecular structure of which is: Step S4: Preparation of 1,4-diazaspiro[5.5]undecane-3-one: Add glacial acetic acid to the cyclized intermediate obtained in step S3. This step is based on the weight of the cyclized intermediate, and filter at 0-10°C. Add methanol to the filtrate and heat it to 20-50°C, then add p-toluenesulfonic acid monohydrate, heat and reflux for 16h, remove methanol under reduced pressure, then add acetone, cool to 0-5°C, stir for 1.0-1.5h, and then filter. The filter cake is heated to 65 After drying at -70°C, a white solid was obtained. Dichloromethane and triethylamine were added to the white solid in sequence and stirred to dissolve. Sodium sulfate was added in batches under stirring at 15-30°C, and then potassium carbonate powder was added. The mixture was stirred and refluxed for 1 hour. After filtering, 6-8V of toluene was added to the filtrate, and the mixture was heated to 110°C for concentration. The mixture was cooled to 0-10°C, stirred for 0.5-1.2 hours, and then filtered. After drying the filter cake, 1,4-diazaspiro[5.5]undecane-3-one was obtained.

2. The method for preparing 1,4-diazaspiro[5.5]undecane-3-one according to claim 1, characterized in that: In step S1, the mass ratio of cyclohexanone to solvent water and sodium sulfate is 1:(8-20):(1-2), and the molar ratio of cyclohexanone to sodium sulfite, glycine methyl ester hydrochloride and sodium cyanide is 1:(0.8-1.2):(0.8-1.2):(0.8-1.2); The molar ratio of the acylating agent to (1-cyanocyclohexyl)glycine methyl ester in step S2 is (1-2): 1; The mass ratio of the modified (1-cyanocyclohexyl)glycine methyl ester to anhydrous nickel chloride, potassium borohydride or sodium borohydride, and methanol in step S3 is 1:(0.2-0.8):(2-4):(5-20); In step S4, the mass ratio of the cyclized intermediate to glacial acetic acid, methanol, p-toluenesulfonic acid monohydrate, triethylamine, sodium sulfate, and potassium carbonate is 1: (6-10): (3-5): (1.2-1.5): (0.3-0.5): (1-2): (0.6-0.8), and the volume ratio of the cyclized intermediate to acetone, dichloromethane, and toluene is 1: (2-3): (10-12): (6-8).

3. The method for preparing 1,4-diazaspiro[5.5]undecane-3-one according to claim 1 or 2, characterized in that: The glycine methyl ester hydrochloride in step S1 is added in batches 5-8 times, and the mass of glycine methyl ester hydrochloride added in any batch is equal, that is, 0.2W.

4. The method for preparing 1,4-diazaspiro[5.5]undecane-3-one according to claim 3, characterized in that: The sodium sulfate drying in step S1 is performed 2-3 times.

5. The method for preparing 1,4-diazaspiro[5.5]undecane-3-one according to claim 1 or 2, characterized in that: In step S2, the acylating agent is composed of formic acid and acetic anhydride, and the mass ratio of the formic acid to the acetic anhydride is 1:(2-3).

6. The method for preparing 1,4-diazaspiro[5.5]undecan-3-one according to claim 5, characterized in that: The acylating agent is added dropwise, and the dropping rate of the acylating agent is 0.5-1.0 g / min.

7. The method for preparing 1,4-diazaspiro[5.5]undecane-3-one according to claim 1, characterized in that: The extractant in step S1 and step S2 is methyl tert-butyl ether.

8. The method for preparing 1,4-diazaspiro[5.5]undecane-3-one according to claim 1, characterized in that: The post-processing in step S2 comprises the following steps: Step S21: combining the extracted methyl tert-butyl ether layers to obtain a combined liquid; Step S22: washing the combined solution obtained in step S21 with water; Step S23: the methyl tert-butyl ether layer after washing in step S22 is concentrated by rotary evaporation until the volume of the concentrated liquid is reduced to 1 / 3 of the original volume; Step S24: controlling the temperature of the concentrated solution obtained in step S23 to be 20-30° C., and dropping 6V-10V of n-hexane based on the weight of (1-cyanocyclohexyl)glycine methyl ester into the concentrated solution, then cooling to -5-5° C., and mixing at 300-600 r / min for 0.8-1.5 h to obtain a mixed solution; Step S25: filtering the mixed solution obtained in step S24, and rinsing the filter cake with n-hexane for 2-3 times; Step S26: drying the filter cake obtained in step S25 at 40-45° C. to obtain modified (1-cyanocyclohexyl)glycine methyl ester.

9. The method for preparing 1,4-diazaspiro[5.5]undecan-3-one according to claim 1, characterized in that: The sodium sulfate is added in batches 4-6 times in step S4, and the mass of sodium sulfate added in any batch is equal, and 0.25W is added in each batch based on the weight of the cyclized intermediate.

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