Preparation method of 1-(1-piperidyl) cyclohexene

Abstract

The invention discloses a preparation method of 1-(1-piperidyl) cyclohexene. The preparation method of the 1-(1-piperidyl) cyclohexene comprises the following steps: dissolving cyclohexanone and piperidine in an organic solvent, adding a solid acid catalyst to carry out reflux reaction, separating and removing water generated in the reaction process; after the reaction is finished, filtering and separating to obtain solid which is the solid acid catalyst, and reserving filtrate for later use; adding inorganic acid into the filtrate, filtering and separating to obtain a filter cake and filtrate, and washing the filter cake to obtain piperidine salt; collecting the washing liquid and the filtrate, and carrying out rotary evaporation to obtain a crude product; and carrying out reduced pressure distillation on the crude product to obtain the 1-(1-piperidyl) cyclohexene. The solid acid catalyst is adopted, after the reaction is finished, the solid acid catalyst is recycled through filtration and directly applied mechanically, and the problem that a traditional catalyst cannot be recycled is solved; excessive piperidine is removed through an acid precipitation method, and the separation problem caused by approximate boiling points in a traditional process is avoided.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a preparation method of 1-(1-piperidyl)cyclohexene. BACKGROUND

[0002] 1-(1-piperidyl)cyclohexene is an important pharmaceutical synthesis intermediate. At present, the mainstream synthesis method is to use cyclohexanone and piperidine as raw materials, to be heated and refluxed in toluene solvent under the catalysis of liquid proton acid such as p-toluenesulfonic acid, and to be dehydrated to obtain 1-(1-piperidyl)cyclohexene. The synthesis method has the following obvious defects: (1) the catalyst cannot be recovered: the soluble strong acid catalyst remains in the system after the reaction, and needs to be neutralized and removed through alkaline washing, water washing and other steps, which produces a large amount of salt-containing organic wastewater, causes serious environmental pollution, and the catalyst cannot be recycled, so the cost is high; (2) the raw material recovery is difficult: in order to improve the conversion rate, the piperidine is usually excessive, after the reaction is completed, the excessive piperidine is difficult to be effectively separated from the product through conventional distillation because the boiling points of the two are similar, so the raw material is wasted or the product purity is not high; (3) the equipment is corroded: the liquid strong acid has strong corrosiveness to the reaction equipment, and the equipment material has high requirements.

[0003] In summary, it is urgent to develop an environmentally friendly, economically feasible and catalyst and raw material recycling synthesis method. SUMMARY

[0004] In view of the defects of the prior art, the purpose of the present application is to provide a preparation method of 1-(1-piperidyl)cyclohexene.

[0005] The purpose of the present application is achieved by the following technical solutions. A preparation method of 1-(1-piperidyl)cyclohexene, comprising the following steps: S1, dissolving cyclohexanone and piperidine in an organic solvent, adding a solid acid catalyst for refluxing reaction, separating and removing water generated in the reaction process; after the reaction is completed, filtering and separating, the obtained solid is a solid acid catalyst, and the filtrate is reserved for use; The molar ratio of the cyclohexanone to the piperidine is 1:1.05-1.20; and the solid acid catalyst is a strong acid cation exchange resin. S2, adding an inorganic acid to the filtrate in step S1, filtering and separating to obtain a filter cake and a filtrate, washing the filter cake to obtain a piperidine salt; collecting the washing liquid and the filtrate, and rotary evaporating to obtain a crude product; S3, performing vacuum distillation on the crude product to obtain 1-(1-piperidyl)cyclohexene.

[0006] The preparation process route of the 1-(1-piperidyl)cyclohexene is as follows: .

[0007] In the present application, cyclohexanone and excess piperidine are used as raw materials, a solid acid catalyst is used for catalytic reaction in an organic solvent, and water generated during the reaction is removed; after the reaction is completed, the solid acid catalyst is recovered by filtration and directly reused; then inorganic acid is added to the filtrate to convert the excess piperidine into piperidine salt crystals, and high-efficiency separation of piperidine and the product is achieved by filtration. It should be noted that piperidine is a strong organic base, and 1-(1-piperidinyl)cyclohexene is a very weak base. The significant difference in basicity will cause the inorganic acid to react with the excess piperidine to generate a salt and precipitate under controlled acid addition conditions, without affecting the structure of the product 1-(1-piperidinyl)cyclohexene.

[0008] The piperidine salt can be further alkalized to regenerate free piperidine for production; finally, high-purity 1-(1-piperidinyl)cyclohexene product is obtained by concentrating the organic phase after separation of the piperidine salt. The present application realizes the double circulation of the catalyst and the raw material piperidine, has the advantages of high atom economy, less waste, good product purity, and low production cost, and is suitable for industrial green production.

[0009] Preferably, the strong acid cation exchange resin in step S1 is a hydrogen type cation exchange resin. More preferably, the hydrogen type cation exchange resin is Amberlyst-15 resin.

[0010] Preferably, the organic solvent in step S1 is at least one of toluene, xylene, benzene, and cyclohexane.

[0011] Preferably, in step S1, a water separator is used to separate and remove the water generated during the reaction.

[0012] Preferably, the amount of the solid acid catalyst added in step S1 is 8-15 wt% of the total amount of cyclohexanone and piperidine.

[0013] Preferably, in step S2, the filtrate in step S1 is placed in an ice bath, inorganic acid is added dropwise to pH=2-4, and then the ice bath is continued for aging for 0.5-2 h, and the filter cake and filtrate are separated by filtration.

[0014] Preferably, in step S2, the filter cake is washed with toluene pre-cooled to 0-10°C to obtain the piperidine salt. In the present application, toluene pre-cooled to 0-10°C is used for washing in order to reduce the solubility of the piperidine salt. If toluene at room temperature or higher temperature is used, part of the product may be dissolved and taken away.

[0015] Preferably, step S2 further comprises dissolving the separated piperidine salt in water, neutralizing to alkaline with lye, separating the free piperidine oil layer, and drying the piperidine oil layer for reuse in step S1.

[0016] Preferably, the inorganic acid in step S2 is at least one of hydrochloric acid, sulfuric acid and phosphoric acid. More preferably, it is concentrated hydrochloric acid.

[0017] Preferably, step S2 further comprises collecting the organic solvent obtained by rotary evaporation and recycling it to step S1.

[0018] Preferably, the reduced pressure distillation in step S3 is carried out at 2 mmHg, 125-130℃.

[0019] Compared with the prior art, the present application has the following advantages: (1) Green and environmentally friendly: the present application completely eliminates the salt-containing wastewater generated by neutralizing soluble strong acid, greatly reducing the discharge of three wastes.

[0020] (2) High atomic economy: the present application realizes efficient recovery and recycling of solid acid catalyst and excess piperidine, greatly reducing raw material consumption and production cost.

[0021] (3) High product purity and stable quality: the present application removes excess piperidine by acid precipitation, avoiding the separation problem caused by close boiling points in traditional processes, thereby ensuring high purity of the final product 1-(1-piperidinyl)cyclohexene.

[0022] (4) High process integration: the present application organically integrates multiple unit operations such as reaction, catalyst recovery, raw material recovery and product purification, forming a closed and efficient cyclic production process, which is very suitable for industrial large-scale production.

[0023] (5) Small equipment corrosion: the present application uses solid acid, avoiding strong acid corrosion to the reaction equipment. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below with examples. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application.

[0025] Example 1 A method for preparing 1-(1-piperidinyl)cyclohexene, the specific steps are as follows: S1, in a 1000 mL three-neck flask equipped with a water trap, a condenser and a mechanical stirrer, cyclohexanone (98.1 g, 1.0 mol), piperidine (93.6 g, 1.1 mol), toluene (500 mL) and strong acidic cation exchange resin (Amberlyst-15 resin, 24 g) were added; the reaction was carried out under reflux by stirring and heating, the water generated was separated by the water trap and recorded, when the water amount in the water trap reached 9 mL and no longer increased (the reaction was 8 h), the heating was stopped, and the reaction mixture was cooled to room temperature; the solid acid catalyst was separated by filtration through a Buchner funnel, washed with a small amount of toluene (20 mL x 2), and the filtrate and washing liquid were collected (combined as the organic phase); S2, the combined organic phase was transferred to a 1000 mL beaker equipped with a stirrer, cooled in an ice water bath, and concentrated hydrochloric acid (8.5 mL) was slowly added dropwise under stirring, after the addition was completed, a large amount of white solid was precipitated, and the stirring and aging in the ice bath was continued for 1 h; the filter cake and filtrate were separated by filtration, the filter cake was washed with pre-cooled toluene (20 mL x 2) at 0°C to obtain 11.5 g of piperidine hydrochloride solid. The filtrate and washing liquid were collected (recorded as the product liquid); the product liquid was transferred to a rotary evaporator, and the toluene solvent was distilled off under reduced pressure at 50°C water bath; the crude product was obtained; S3, the crude product was subjected to vacuum distillation, and the fraction at 2 mmHg, 125-130°C was collected to obtain colorless transparent 1-(1-piperidinyl)cyclohexene product.

[0026] Example 1 obtained 168.5 g of 1-(1-piperidinyl)cyclohexene, and the GC analysis showed that the purity was 99.1%, and the yield was 93% based on the molar amount of cyclohexanone.

[0027] Example 2 The regeneration and reuse of piperidine were carried out according to the following steps: (1) 11.5 g of piperidine hydrochloride solid obtained in step S2 of Example 1 was dissolved in 100 mL of purified water, and under ice bath cooling and stirring, 30% sodium hydroxide solution was slowly added to pH>12, the mixture was transferred to a separatory funnel, and the upper oily substance (i.e. recovered piperidine) was separated by layering, and the oily substance was dried with anhydrous magnesium sulfate and weighed to obtain 7.6 g of piperidine.

[0028] (2) The recovered 7.6 g of piperidine was mixed with 86.0 g of additional piperidine to obtain a total of 93.6 g of piperidine, which was used to prepare 1-(1-piperidinyl)cyclohexene according to the method of Example 1. The results showed that the product obtained using the recovered piperidine was 167.8 g, the yield was 92.6%, and the purity was 98.5%, which was comparable to the first batch, indicating that the recovered piperidine could be effectively reused in subsequent reactions and had good recycling feasibility.

[0029] Comparative Example 1 A traditional strong acid catalytic preparation of 1-(1-piperidinyl)cyclohexene was carried out according to the following steps: (1) A 1000 mL three-necked flask equipped with a water separator, a condenser and a mechanical stirrer was charged with cyclohexanone (98.1 g, 1.0 mol), piperidine (93.6 g, 1.1 mol), toluene (500 mL) and p-toluenesulfonic acid (3.5 g, 0.02 mol). The stirring was started and the reaction was carried out under reflux. The water produced was separated by the water separator and recorded. When the water in the water separator reached 9 mL and did not increase any more (the reaction was 8 h), the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was transferred to a separatory funnel and washed with a 5% sodium hydroxide solution (50 mL x 3) to neutralize the catalyst, and then washed once with saturated brine (50 mL); (2) The organic phase was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was transferred to a rotary evaporator and the toluene solvent was evaporated under reduced pressure at 50°C water bath; the crude product was obtained; (3) The crude product was distilled under reduced pressure. The fraction collected at 2 mmHg, 125-130°C was 1-(1-piperidinyl)cyclohexene product in colorless transparent state.

[0030] Comparative Example 1 produced 158.0 g of 1-(1-piperidinyl)cyclohexene. GC analysis showed that the purity was 95.5% and contained 3.2% of unseparated piperidine. The yield was 86.8% based on the molar amount of cyclohexanone. 150 mL of alkaline wastewater was produced.

[0031] Comparative Example 2 A method for preparing 1-(1-piperidinyl)cyclohexene was carried out according to the following steps: S1, A 1000 mL three-necked flask equipped with a water separator, a condenser and a mechanical stirrer was charged with cyclohexanone (98.1 g, 1.0 mol), piperidine (93.6 g, 1.1 mol), toluene (500 mL) and strong acid cation exchange resin (Amberlyst-15 resin, 24 g). The stirring was started and the reaction was carried out under reflux. The water produced was separated by the water separator and recorded. When the water in the water separator reached 9 mL and did not increase any more (the reaction was 8 h), the heating was stopped and the reaction mixture was cooled to room temperature. The solid acid catalyst was separated by filtration through a Buchner funnel and washed with a small amount of toluene (20 mL x 2). The filtrate was collected; S2, The filtrate collected in step S1 was transferred to a rotary evaporator and the toluene solvent was evaporated under reduced pressure at 50°C water bath; the crude product was obtained; S3, the crude product was subjected to vacuum distillation, and the fraction at 2 mmHg, 125-130°C was collected to obtain colorless transparent 1-(1-piperidinyl)cyclohexene product.

[0032] In the comparative example 2, during the distillation, the excessive piperidine was close to the boiling point of the product, which resulted in the difficulty in separation of the target product. Finally, 162.5 g of 1-(1-piperidinyl)cyclohexene was obtained, which had a purity of only 96.2% by GC analysis, contained 2.5% of piperidine, and had a yield of 89.6% based on the molar amount of cyclohexanone.

[0033] The specific embodiments of the application described above do not constitute a limitation of the protection scope of the application. Any various other corresponding changes and modifications made according to the technical concept of the application shall be included in the protection scope of the claims of the application.

Claims

1. A process for the preparation of 1-(1-piperidinyl)cyclohexene, characterized in that, The method comprises the following steps: S1, dissolving cyclohexanone and piperidine in an organic solvent, adding a solid acid catalyst for refluxing reaction, separating and removing water generated in the reaction process; after the reaction is completed, filtering and separating, the obtained solid is a solid acid catalyst, and the filtrate is reserved for use; The molar ratio of the cyclohexanone to the piperidine is 1:1.05-1.20; and the solid acid catalyst is a strong acid cation exchange resin. S2, adding an inorganic acid to the filtrate in step S1, filtering and separating to obtain a filter cake and a filtrate, washing the filter cake to obtain a piperidine salt; collecting the washing liquid and the filtrate, and performing rotary evaporation to obtain a crude product; S3, performing vacuum distillation on the crude product to obtain 1-(1-piperidyl)cyclohexene.

2. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, The amount of the solid acid catalyst added in step S1 is 8-15 wt% of the total amount of the cyclohexanone and the piperidine.

3. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, The strong acid cation exchange resin in step S1 is a hydrogen type cation exchange resin; and / or The organic solvent in step S1 is at least one of toluene, xylene, benzene and cyclohexane.

4. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, In step S1, a water segregator is used to separate and remove water generated in the reaction process.

5. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, In step S2, the filtrate in step S1 is placed in an ice bath, an inorganic acid is added dropwise until the pH is 2-4, and then the ice bath is continued to age for 0.5-2 hours, and filtering and separating are performed to obtain a filter cake and a filtrate.

6. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 5, characterized in that, In step S2, the filter cake is washed with toluene pre-cooled to 0-10 DEG C to obtain a piperidine salt.

7. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, Step S2 further comprises dissolving the separated piperidine salt in water, neutralizing to alkaline with a lye, separating an oil layer of free piperidine, and drying the oil layer for reuse in step S1.

8. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, The inorganic acid in step S2 is at least one of hydrochloric acid, sulfuric acid and phosphoric acid.

9. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, Step S2 further comprises collecting the organic solvent obtained by rotary evaporation and reusing it in step S1.

10. The process for the preparation of 1 -(1 -piperidinyl)cyclohexene according to claim 1, characterized in that, The vacuum distillation in step S3 is performed at 2 mmHg and 125-130 DEG C.