Preparation method of 3-oxa-9-azaspiro [5.5] undecane

Abstract

The invention discloses a preparation method of 3-oxa-9-azaspiro [5.5] undecane, and belongs to the technical field of pharmaceutical synthesis.The preparation method comprises the steps that 4, 4-bis (2-hydroxyethyl)-1-piperidinecarboxylic acid tert-butyl ester is used as a raw material to react with paratoluensulfonyl chloride to generate 3-oxa-9-azaspiro [5.5] undecane-9-carboxylic acid tert-butyl ester, then the 3-oxa-9-azaspiro [5.5] undecane-9-carboxylic acid tert-butyl ester reacts with paratoluensulfonyl chloride to generate 3-oxa-9-azaspiro [5.5] undecane, and finally the 3-oxa-9- carrying out deprotection reaction on the undecane hydrochloride and an ethyl acetate hydrochloride solution to generate 3-oxo-9-azaspiro [5.5] undecane hydrochloride; and finally, carrying out reaction on the 3-oxo-9-azaspiro [5.5] undecane hydrochloride and sodium hydroxide to generate the 3-oxa-9-azaspiro [5.5] undecane. The route provided by the invention has the advantages of high reaction yield, mild conditions and high product purity.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for preparing 3-oxa-9-azaspiro[5.5]undecane. Background Art

[0002] 3-Oxa-9-azaspiro[5.5]undecane is an organic compound with a specific structure. Its spirocyclic structure gives it rigidity and stability. Due to the particularity of its structure, it can be used as a ligand or catalyst in asymmetric catalytic reactions to improve the stereoselectivity of the reaction. Due to its special structural characteristics, 3-Oxa-9-azaspiro[5.5]undecane has unique luminescent properties and can be used to prepare new luminescent materials. In the field of pesticides, this compound can also be used as an active ingredient or synergist of pesticides to improve the insecticidal, fungicidal or herbicidal effects of pesticides. In addition, in the field of polymer adhesives, 3-Oxa-9-azaspiro[5.5]undecane may be used as a modifier or additive to improve the performance of adhesives, such as improving adhesion, heat resistance or chemical corrosion resistance. 3-Oxa-9-azaspiro[5.5]undecane has broad application prospects in asymmetric catalysis, luminescent materials, pesticides and polymer adhesives, and has huge market potential. However, the existing preparation process of 3-oxa-9-azaspiro[5.5]undecane is complicated and has a low yield. Summary of the invention

[0003] In order to solve the above technical problems, the present invention provides a method for preparing 3-oxa-9-azaspiro[5.5]undecane.

[0004] The purpose of the present invention can be achieved through the following technical solutions: A method for preparing 3-oxa-9-azaspiro[5.5]undecane comprises the following steps: Step S1, adding 50-55g of tert-butyl 4,4-bis(2-hydroxyethyl)-1-piperidincarboxylate and 1000-1100mL of tetrahydrofuran into a three-necked flask, cooling to 5-10°C, adding 12-15g of a catalyst, heating to 25-30°C after the addition, keeping the temperature for reaction for 1h, slowly dropping a tetrahydrofuran solution of p-toluenesulfonyl chloride, controlling the temperature at 20-30°C during the dropping process, keeping the temperature for reaction at 25-30°C for 4h after the dropping is completed, filtering the obtained reaction solution and pouring it into ice water, extracting it twice with ethyl acetate, combining the organic phases, adding the organic phases to a saturated sodium chloride solution for extraction, adding anhydrous sodium sulfate for drying, concentrating under reduced pressure to remove ethyl acetate, and finally purifying it by column chromatography (eluting solvent, petroleum ether:ethyl acetate=5:1) to obtain tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate, with a yield of not less than 88%; The tetrahydrofuran solution of p-toluenesulfonyl chloride is prepared by the following steps: 33.85-35.32 g of p-toluenesulfonyl chloride is added to 500-550 mL of tetrahydrofuran, and the mixture is stirred uniformly to obtain the tetrahydrofuran solution of p-toluenesulfonyl chloride.

[0005] Step S2, adding 40-42 g of tert-butyl 3-oxo-9-azaspiro[5.5]undecane-9-carboxylate to 200-210 mL of ethyl acetate, adding 200-210 mL of 4 mol / L hydrochloric acid-ethyl acetate solution (HCl·EA) solution under an ice-water bath, controlling the dropping temperature to 10-20° C. during the dropping process, raising the temperature to 25-30° C. after the dropping is completed, and keeping the temperature for reaction for 4 hours. After the reaction is completed, the mixture is concentrated under reduced pressure to remove ethyl acetate, pulped, filtered, and the obtained filter cake is dried at 45° C. to obtain 3-oxo-9-azaspiro[5.5]undecane hydrochloride, with a yield of not less than 98%; Step S3, add 30-35g of 3-oxo-9-azaspiro[5.5]undecane hydrochloride into a three-necked flask, cool to 0-10°C while stirring, slowly drop 20mL of 50% sodium hydroxide aqueous solution, control the dropping temperature to 5-10°C during the dropping process, stir at a uniform speed and react until the system becomes a light yellow clear liquid, continue to keep warm and react for 30min, extract with ethyl acetate three times after the reaction, and then dry to obtain 3-oxa-9-azaspiro[5.5]undecane, with a yield of not less than 88%. 1H NMR (400NHz,CDCl3), δ: 3.66 (2H, t, J =4.0Hz), 3.66 (2H, t, J =5.6Hz), 1.53-1.48 (4H,m).

[0006] The reaction process of the present invention is as follows: Beneficial effects of the invention: The invention discloses a method for preparing 3-oxa-9-azaspiro[5.5]undecane, using 4,4-bis(2-hydroxyethyl)-1-piperidinic acid tert-butyl ester as a raw material to first react with p-toluenesulfonyl chloride to generate 3-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester, then performing a deprotection reaction with a hydrochloric acid ethyl acetate solution to generate 3-oxo-9-azaspiro[5.5]undecane hydrochloride, and finally reacting with sodium hydroxide to generate 3-oxa-9-azaspiro[5.5]undecane. The route of the invention has high reaction yield, mild conditions and high product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for describing the embodiments are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0008] Figure 1 The 3-oxa-9-azaspiro[5.5]undecane prepared in Example 1 of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION

[0009] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0010] Example 1: A method for preparing 3-oxa-9-azaspiro[5.5]undecane, comprising the following steps: Step S1, adding 50g of tert-butyl 4,4-bis(2-hydroxyethyl)-1-piperidincarboxylate and 1000mL of tetrahydrofuran into a three-necked flask, cooling to 5°C, adding 12g of a catalyst, heating to 25°C after the addition, keeping the temperature for reaction for 1h, slowly dropping a tetrahydrofuran solution of p-toluenesulfonyl chloride, controlling the temperature at 20°C during the dropping process, keeping the temperature for reaction at 25°C for 4h after the dropping is completed, filtering the obtained reaction solution and pouring it into ice water, extracting it twice with ethyl acetate, combining the organic phases, adding the organic phases to a saturated sodium chloride solution for extraction, adding anhydrous sodium sulfate for drying, concentrating under reduced pressure to remove ethyl acetate, and finally purifying it by column chromatography (eluting solvent, petroleum ether:ethyl acetate=5:1) to obtain tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate, with a yield of 88%; The catalyst is prepared by the following steps: Step S11, adding polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer to a 37% hydrochloric acid aqueous solution, stirring at a uniform speed and adding tetraethyl orthosilicate, stirring at a uniform speed and reacting at 30-35°C for 24 hours, transferring the obtained mixture to a reactor after the reaction is completed, crystallizing at 100°C for 24 hours, filtering, washing three times with deionized water, and calcining at 580°C for 4 hours to obtain a porous carrier, and controlling the amount ratio of polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer, tetraethyl orthosilicate and hydrochloric acid aqueous solution to be 3g:8.2g:100mL; Step S12, adding the porous carrier to toluene, ultrasonically dispersing for 30 minutes, adding 3-aminopropyltriethoxysilane, reflux reacting for 12 hours under a nitrogen atmosphere, filtering after the reaction, washing three times with anhydrous toluene and drying to obtain an amino carrier, wherein the amount ratio of the porous carrier, 3-aminopropyltriethoxysilane and toluene is controlled to be 1 g: 1.5 mL: 50 mL; Step S13, adding the amino carrier to anhydrous methanol, ultrasonically dispersing for 30 minutes, adding sodium methoxide, stirring at a uniform speed and reacting for 6 hours, filtering after the reaction, washing the filter cake three times with anhydrous methanol and drying to obtain a catalyst, and controlling the dosage ratio of the amino carrier, sodium methoxide and anhydrous methanol to be 1g:0.5g:20mL.

[0011] In step S11, a porous carrier is prepared by a template method, which is a mesoporous silica; in step S12, the porous carrier is modified by a silane coupling agent to introduce amino groups on the surface of the porous carrier; in step S13, the amino groups on the amination carrier form coordination bonds with the sodium ions in the sodium methoxide, and then the sodium methoxide is loaded on the surface of the carrier to prepare a catalyst. When used in the reaction in step S1, the catalyst can catalyze the reaction of toluenesulfonyl chloride and hydroxyl groups to increase the reaction rate, and the high specific surface area of ​​the carrier can provide more reaction catalytic sites, and the ordered mesoporous structure is conducive to the diffusion of reactants, further increasing the reaction rate. The hydrogen chloride produced by the reaction can also be neutralized by the sodium methoxide. In addition, the catalyst is a solid catalyst, which is also convenient for subsequent separation and treatment, and convenient for recovery.

[0012] The tetrahydrofuran solution of p-toluenesulfonyl chloride is prepared by the following steps: 33.85 g of p-toluenesulfonyl chloride is added to 500 mL of tetrahydrofuran, and the mixture is stirred uniformly to obtain the tetrahydrofuran solution of p-toluenesulfonyl chloride.

[0013] Step S2, adding 40g of tert-butyl 3-oxo-9-azaspiro[5.5]undecane-9-carboxylate to 200mL of ethyl acetate, adding 200mL of 4mol / L hydrochloric acid-ethyl acetate solution under an ice-water bath, controlling the dropping temperature to 10°C during the addition process, raising the temperature to 25°C after the addition is completed, and keeping the temperature for 4h. After the reaction is completed, the ethyl acetate is removed by concentrating under reduced pressure, beating, filtering, and drying the obtained filter cake at 45°C to obtain 3-oxo-9-azaspiro[5.5]undecane hydrochloride, with a yield of 98%; Step S3, adding 30g of 3-oxo-9-azaspiro[5.5]undecane hydrochloride into a three-necked flask, cooling to 5°C while stirring, slowly dropping 20mL of 50% by mass sodium hydroxide aqueous solution, controlling the dropping temperature to 5°C during the dropping process, stirring at a uniform speed and reacting until the system becomes a light yellow clear liquid, continuing to keep warm and react for 30min, extracting with ethyl acetate three times after the reaction is completed and drying to obtain 3-oxa-9-azaspiro[5.5]undecane, with a yield of 88%, 1H NMR (400NHz,CDCl3), δ: 3.66 (2H, t, J =4.0Hz), 3.66 (2H, t, J =5.6Hz), 1.53-1.48 (4H, m).

[0014] Example 2: A method for preparing 3-oxa-9-azaspiro[5.5]undecane, comprising the following steps: Step S1, adding 52g of tert-butyl 4,4-bis(2-hydroxyethyl)-1-piperidincarboxylate and 1000mL of tetrahydrofuran into a three-necked flask, cooling to 8°C, adding 14g of a catalyst, heating to 28°C after the addition, keeping the temperature for reaction for 1h, slowly dropping a tetrahydrofuran solution of p-toluenesulfonyl chloride, controlling the temperature at 25°C during the dropping process, keeping the temperature for reaction at 28°C for 4h after the dropping is completed, filtering the obtained reaction solution and pouring it into ice water, extracting it twice with ethyl acetate, combining the organic phases, adding the organic phases to a saturated sodium chloride solution for extraction, adding anhydrous sodium sulfate for drying, concentrating under reduced pressure to remove ethyl acetate, and finally purifying it by column chromatography (eluting solvent, petroleum ether:ethyl acetate=5:1) to obtain tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate, with a yield of 89%; The catalyst is prepared by the following steps: Step S11, adding polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer to a 37% by mass aqueous solution of hydrochloric acid, stirring at a uniform speed and adding tetraethyl orthosilicate, stirring at a uniform speed and reacting at 32° C. for 24 hours, transferring the obtained mixture to a reactor after the reaction is completed, crystallizing at 100° C. for 24 hours, filtering, washing three times with deionized water, and calcining at 580° C. for 4 hours to obtain a porous carrier, and controlling the amount ratio of polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer, tetraethyl orthosilicate and hydrochloric acid aqueous solution to be 3.5 g:8.4 g:100 mL; Step S12, adding the porous carrier to toluene, ultrasonically dispersing for 30 minutes, adding 3-aminopropyltriethoxysilane, reflux reacting for 12 hours under a nitrogen atmosphere, filtering after the reaction, washing three times with anhydrous toluene and drying to obtain an amino carrier, wherein the amount ratio of the porous carrier, 3-aminopropyltriethoxysilane and toluene is controlled to be 1.1 g: 1.8 mL: 50 mL; Step S13, adding the aminated carrier to anhydrous methanol, ultrasonically dispersing for 30 minutes, adding sodium methoxide, stirring at a uniform speed and reacting for 6 hours, filtering after the reaction, washing the filter cake three times with anhydrous methanol and drying to obtain a catalyst, and controlling the amount ratio of the aminated carrier, sodium methoxide and anhydrous methanol to be 1.1g:0.6g:20mL.

[0015] The tetrahydrofuran solution of p-toluenesulfonyl chloride is prepared by the following steps: 34.32 g of p-toluenesulfonyl chloride is added to 550 mL of tetrahydrofuran, and the mixture is stirred uniformly to obtain the tetrahydrofuran solution of p-toluenesulfonyl chloride.

[0016] Step S2, adding 42g of tert-butyl 3-oxo-9-azaspiro[5.5]undecane-9-carboxylate to 200mL of ethyl acetate, adding 200mL of 4mol / L hydrochloric acid-ethyl acetate solution under an ice-water bath, controlling the dropping temperature to 15°C during the addition process, raising the temperature to 30°C after the addition is completed, and keeping the temperature for 4h. After the reaction is completed, the ethyl acetate is removed by concentrating under reduced pressure, beating, filtering, and drying the obtained filter cake at 45°C to obtain 3-oxo-9-azaspiro[5.5]undecane hydrochloride, with a yield of 99%; Step S3, 32g of 3-oxo-9-azaspiro [5.5] undecane hydrochloride was added to a three-necked flask, the temperature was lowered to 8°C while stirring, and 20mL of a 50% sodium hydroxide aqueous solution was slowly added dropwise. The dropping temperature was controlled to 8°C during the dropping process. The system was stirred and reacted at a uniform speed until the system became a light yellow clear liquid. The reaction was continued at this temperature for 30min. After the reaction was completed, the system was extracted with ethyl acetate three times and then dried to obtain 3-oxa-9-azaspiro [5.5] undecane with a yield of 88%.

[0017] Example 3: A method for preparing 3-oxa-9-azaspiro[5.5]undecane, comprising the following steps: Step S1, add 55g of tert-butyl 4,4-bis(2-hydroxyethyl)-1-piperidincarboxylate and 1100mL of tetrahydrofuran into a three-necked flask, cool to 10°C, add 15g of a catalyst, heat to 30°C after addition, keep warm for 1h, slowly drop a tetrahydrofuran solution of p-toluenesulfonyl chloride, control the temperature at 30°C during the dropwise addition, keep warm for 4h at 30°C after the dropwise addition, filter the obtained reaction solution and pour it into ice water, extract twice with ethyl acetate, combine the organic phases, add the organic phases into a saturated sodium chloride solution for extraction, add anhydrous sodium sulfate for drying, concentrate under reduced pressure to remove ethyl acetate, and finally purify by column chromatography (elution solvent, petroleum ether: ethyl acetate = 5:1) to obtain tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate, with a yield of 88%; The catalyst is prepared by the following steps: Step S11, adding polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer to a 37% by mass aqueous solution of hydrochloric acid, stirring at a uniform speed and adding tetraethyl orthosilicate, stirring at a uniform speed and reacting at 35°C for 24 hours, transferring the obtained mixture to a reactor after the reaction is completed, crystallizing at 100°C for 24 hours, filtering, washing three times with deionized water, and calcining at 580°C for 4 hours to obtain a porous carrier, and controlling the amount ratio of polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer, tetraethyl orthosilicate and hydrochloric acid aqueous solution to be 4g:8.5g:100mL; Step S12, adding the porous carrier to toluene, ultrasonically dispersing for 30 minutes, adding 3-aminopropyltriethoxysilane, reflux reacting for 12 hours under a nitrogen atmosphere, filtering after the reaction, washing three times with anhydrous toluene and drying to obtain an amino carrier, wherein the amount ratio of the porous carrier, 3-aminopropyltriethoxysilane and toluene is controlled to be 1.2 g: 2 mL: 50 mL; Step S13, adding the amino carrier to anhydrous methanol, ultrasonically dispersing for 30 minutes, adding sodium methoxide, stirring at a uniform speed and reacting for 6 hours, filtering after the reaction, washing the filter cake three times with anhydrous methanol and drying to obtain a catalyst, and controlling the dosage ratio of the amino carrier, sodium methoxide and anhydrous methanol to be 1.2g:0.8g:20mL.

[0018] The tetrahydrofuran solution of p-toluenesulfonyl chloride is prepared by the following steps: 35.32 g of p-toluenesulfonyl chloride is added to 550 mL of tetrahydrofuran, and the mixture is stirred uniformly to obtain the tetrahydrofuran solution of p-toluenesulfonyl chloride.

[0019] Step S2, adding 42g of tert-butyl 3-oxo-9-azaspiro[5.5]undecane-9-carboxylate to 210mL of ethyl acetate, adding 210mL of 4mol / L hydrochloric acid-ethyl acetate solution under an ice-water bath, controlling the dropping temperature to 10-20°C during the dropping process, raising the temperature to 30°C after the addition is completed, and keeping the temperature for 4h. After the reaction is completed, the ethyl acetate is removed by concentrating under reduced pressure, beating, filtering, and drying the obtained filter cake at 45°C to obtain 3-oxo-9-azaspiro[5.5]undecane hydrochloride, with a yield of 98%; Step S3, 35g of 3-oxo-9-azaspiro [5.5] undecane hydrochloride was added to a three-necked flask, the temperature was lowered to 10°C while stirring, and 20mL of a 50% sodium hydroxide aqueous solution was slowly added dropwise. The dropping temperature was controlled to 10°C during the dropping process. The system was stirred and reacted at a uniform speed until the system became a light yellow clear liquid. The reaction was continued at this temperature for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate three times and then dried to obtain 3-oxa-9-azaspiro [5.5] undecane with a yield of 89%.

[0020] Comparative Example 1: Compared with Example 1, this comparative example uses 60% sodium hydride to replace the catalyst of the present invention, and the rest is the same as Example 1. The preparation method is as follows: Step S1, add 50g of tert-butyl 4,4-bis(2-hydroxyethyl)-1-piperidincarboxylate and 1000mL of tetrahydrofuran into a three-necked flask, cool to 5°C, add 12g of 60% sodium hydride, heat to 25°C after addition, keep warm for reaction for 1h, slowly drop a tetrahydrofuran solution of p-toluenesulfonyl chloride, control the temperature at 20°C during the dropwise addition, keep warm for reaction at 25°C for 4h after the dropwise addition, filter the obtained reaction solution and pour it into ice water, extract twice with ethyl acetate, combine the organic phases, add the organic phases into a saturated sodium chloride solution for extraction, add anhydrous sodium sulfate for drying, concentrate under reduced pressure to remove ethyl acetate, and finally purify by column chromatography (elution solvent, petroleum ether: ethyl acetate = 5:1) to obtain tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate with a yield of 82%.

[0021] The above contents are merely examples and explanations of the concept of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the concept of the invention or exceed the scope defined by the claims, they shall all fall within the protection scope of the present invention.

Claims

1. A method for preparing 3-oxa-9-azaspiro[5.5]undecane, characterized in that: The steps include: Step S1, adding tert-butyl 4,4-bis(2-hydroxyethyl)-1-piperidincarboxylate and tetrahydrofuran into a three-necked flask, adding a catalyst, and slowly dropping a tetrahydrofuran solution of p-toluenesulfonyl chloride to react to obtain tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate; Step S2, adding tert-butyl 3-oxo-9-azaspiro[5.5]undecane-9-carboxylate to ethyl acetate, adding hydrochloric acid-ethyl acetate solution under ice-water bath, and reacting to obtain 3-oxo-9-azaspiro[5.5]undecane hydrochloride; Step S3, adding 3-oxo-9-azaspiro[5.5]undecane hydrochloride into a three-necked flask, slowly adding a sodium hydroxide aqueous solution dropwise, and reacting to obtain 3-oxa-9-azaspiro[5.5]undecane.

2. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 1, characterized in that: In step S1, the temperature is controlled at 20-30° C. during the dropwise addition, and the reaction is kept at 25-30° C. for 4 hours after the dropwise addition is completed.

3. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 2, characterized in that: In step S2, the reaction temperature is 25-30° C. and the reaction time is 4 h.

4. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 3, characterized in that: In step S3, 3-oxo-9-azaspiro[5.5]undecane hydrochloride is added while being stirred and cooled to 0-10°C.

5. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 4, characterized in that: The tetrahydrofuran solution of p-toluenesulfonyl chloride in step S1 is prepared by mixing p-toluenesulfonyl chloride and tetrahydrofuran.

6. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 5, characterized in that: The catalyst in step S1 is a base catalyst.

7. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 6, characterized in that: During the dropping process in step S2, the dropping temperature is controlled to be 10-20°C.

8. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 7, characterized in that: The concentration of the hydrochloric acid-ethyl acetate solution in step S2 is 4 mol / L.

9. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 8, characterized in that: During the dropping process in step S3, the dropping temperature is controlled to be 5-10°C.

10. The method for preparing 3-oxa-9-azaspiro[5.5]undecane according to claim 9, characterized in that: The mass fraction of the sodium hydroxide aqueous solution in step S3 is 50%.

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