Preparation method of 1-chloroethyl cyclohexyl carbonate

Abstract

The invention relates to a preparation method of 1-chloroethyl cyclohexyl carbonate, and belongs to the technical field of synthesis of drug intermediates. In order to solve the problems of long route and high toxicity in the prior art, the invention provides a preparation method of 1-chloroethyl cyclohexyl carbonate, which comprises the following steps: mixing cyclohexanol and 1-chloroethanol under the action of organic alkali with a nitrogen-containing cyclic structure, and introducing carbon dioxide for reaction to obtain the 1-chloroethyl cyclohexyl carbonate. According to the method, high-toxicity phosgene does not need to be adopted as a raw material, the characteristic of one-pot reaction is achieved, the method further has the advantage of being short in reaction route, conversion loss of intermediate steps and loss of intermediate operation are better reduced, the obtained product has the effect of being high in product yield and quality, the yield reaches 98% or above, and the purity reaches 99% or above.

Description

Technical Field

[0001] This invention relates to a method for preparing 1-chloroethylcyclohexyl carbonate, belonging to the field of pharmaceutical intermediate synthesis technology. Background Technology

[0002] Candesartan medoxomil is an antihypertensive drug for essential hypertension. It is rapidly hydrolyzed in the body into the active metabolite candesartan. Candesartan is a selective angiotensin II receptor (AT1) antagonist. It antagonizes the vasoconstrictive effect of angiotensin II by binding to AT1 receptors in vascular smooth muscle, thereby reducing peripheral vascular resistance and achieving the effect of lowering blood pressure. It has broad market application prospects.

[0003] 1-Chloroethylcyclohexyl carbonate is a key intermediate in the synthesis of candesartan cilexetil, CAS: 99464-83-2, and its structural formula is shown below:

[0004]

[0005] Currently, the main methods for synthesizing 1-chloroethylcyclohexylpropyl carbonate include the following:

[0006] For example, the existing literature disclosed in Chinese patent application (publication number: CN 108358787A) describes a synthesis reaction using dichloroethane, cyclohexanol, and 1-chloroethyl chloroformate as raw materials, and triethylamine as an acid-binding agent. After the reaction, 1-chloroethylcyclohexyl carbonate is obtained through processes such as pressure filtration, distillation, water washing, and oil distillation. This method uses triethylamine as an acid-binding agent, and the amount used is relatively large. A large amount of ammonium hydrochloride is formed during the reaction. Although it can be recycled after treatment, the reaction route is long, the operation is difficult, it is not conducive to large-scale production, and the yield of the product is also poor. For example, existing literature discloses the synthesis of 1-chloroethyl chloroformate using acetaldehyde, triphosgene, and dichloromethane as raw materials, followed by reaction with cyclohexanol to synthesize the target compound 1-chloroethylcyclohexylpropyl carbonate. The above synthesis method is achieved through microchannel reaction. However, considering that the reaction involves triphosgene, a highly toxic and polluting reagent, and that the microchannel reactor equipment is expensive, has a long reaction process, and is difficult to operate, it is not conducive to large-scale production.

[0007] Another method involves reacting chloroethyl chloroformate in dichloromethane solvent with cyclohexanol and pyridine, followed by stirring at room temperature to obtain the corresponding 1-chloroethylcyclohexyl carbonate. However, this reaction yields a low product, only around 56%. Summary of the Invention

[0008] To address the problems existing in the prior art, this invention provides a method for preparing 1-chloroethylcyclohexyl carbonate, which simplifies the synthetic route, eliminates the need for highly toxic substances, and achieves a high product yield.

[0009] The objective of this invention is achieved through the following technical solution: a method for preparing 1-chloroethylcyclohexyl carbonate, which includes mixing cyclohexanol and 1-chloroethanol under the action of an organic base having a nitrogen-containing cyclic structure, and then reacting the mixture with carbon dioxide to obtain 1-chloroethylcyclohexyl carbonate.

[0010] By simultaneously catalyzing carbon dioxide activation under the action of an organic base with a nitrogen-containing cyclic group, the reaction with chloroethanol can be achieved directly in a one-pot process without separation, effectively forming the target product. This effectively avoids the separation of intermediates, improving product yield and quality, achieving the characteristics of a one-pot reaction, simplifying operation, and offering the advantage of a shorter reaction route. It also reduces conversion losses in intermediate steps, resulting in a high-yield product with a yield exceeding 98%. Furthermore, it eliminates the need for highly toxic phosgene as a raw material, reducing environmental pollution and aligning with green environmental protection principles. The raw materials used are readily available and relatively low-cost, making it more suitable for industrial production. The nitrogen-containing cyclic structure in the aforementioned organic base can be a nitrogen-containing five-membered ring or a nitrogen-containing six-membered ring.

[0011] In the above method for preparing 1-chloroethylcyclohexyl carbonate, an organic base containing a nitrogen-containing cyclic group can promote the activation of carbon dioxide and react with chloroethanol and cyclohexanol to form the target product. The specific nitrogen-containing five-membered ring structure organic base or the organic base with a nitrogen-containing six-membered ring structure can be a substituted or unsubstituted organic base. Simultaneously, using the above-mentioned organic base can suppress the side reaction of cyclohexanol self-condensation, thus better ensuring the purity and quality of the product. Preferably, the organic base is selected from one or more of pyridine, dimethylaminopyridine, piperidine, and pyrrole. More preferably, the organic base is dimethylaminopyridine. Using dimethylaminopyridine can better activate carbon dioxide simultaneously, exhibiting high reaction selectivity, resulting in a high product yield when reacting with 1-chloroethanol. It can also better suppress the self-condensation of cyclohexanol to produce byproducts, ensuring the purity and quality of the product, reaching over 99%.

[0012] In the above-mentioned method for preparing 1-chloroethylcyclohexyl carbonate, preferably, the reaction temperature is 20℃~50℃, and the reaction pressure is controlled below 1.6MPa. By carrying out the reaction under certain low-pressure conditions, the reaction can be better promoted, the yield and quality of the product can be better guaranteed, and the mild reaction conditions with low reaction temperature are beneficial for operation and avoid the generation of impurities due to excessively high temperatures, which would affect the purity and quality of the product. As a further preferred method, the reaction temperature is 25℃~35℃, and the reaction pressure is controlled between 1.0MPa~1.5MPa.

[0013] In the above-described method for preparing 1-chloroethylcyclohexyl carbonate, preferably, the reaction is carried out in a water-insoluble organic solvent, which is selected from one or more of haloalkanes, ester solvents, and aromatic solvents. This facilitates a gentle reaction and subsequent operations. Further preferably, the haloalkanes are selected from dichloromethane and / or chloroform; the ester solvents are selected from one or more of ethyl acetate, propyl acetate, and methyl ethyl ester; and the aromatic solvents are selected from toluene and / or xylene. Even more preferably, the water-insoluble organic solvent is selected from haloalkanes. The amount of water-insoluble organic solvent used can be any amount commonly used in chemical synthesis, but preferably, the amount of water-insoluble organic solvent is 8 to 12 times the mass of 1-chloroethanol.

[0014] In the above-mentioned method for preparing 1-chloroethylcyclohexyl carbonate, the molar ratio of cyclohexanol:1-chloroethanol:organic base is preferably 1:1.0-2.0:0.1-0.5.

[0015] The preparation method of the above-mentioned 1-chloroethylcyclohexyl carbonate can be represented by the following reaction equation:

[0016]

[0017] In summary, compared with the prior art, the present invention has the following advantages:

[0018] 1. This invention effectively avoids separating intermediates and can react with cyclohexanol in a one-pot process to form the target product. It achieves the one-pot reaction characteristic without the need for highly toxic phosgene as a raw material. It also has the advantage of a short reaction route, which better reduces the conversion loss and intermediate operation loss in intermediate steps, and makes the obtained product have a high product yield and quality, with a yield of over 98% and a purity of over 99%.

[0019] 2. By carrying out the reaction under certain low-pressure conditions, the reaction can be better promoted, the yield and quality of the product can be better guaranteed, and the mild reaction conditions with low reaction temperature are beneficial to operation and avoid product impurities caused by excessive temperature, which would affect the purity and quality of the product. Detailed Implementation

[0020] The technical solution of the present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments.

[0021] Example 1

[0022] At room temperature, 100 ml of dichloromethane, 10 g of cyclohexanol, and 12.05 g of 1-chloroethanol were added sequentially to a clean reaction flask, followed by 3.65 g of dimethylaminopyridine (DMAP). After mixing and stirring, carbon dioxide was bubbled through the mixture three times to replace the carbon dioxide, and the pressure of the reaction system was controlled at 1.0 MPa. The reaction was carried out at 35°C for 10 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 30 g of water, allowed to stand and separate into layers, and then dried with 10 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was then concentrated by vacuum distillation to remove the solvent, yielding 20.35 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.6% and a gas phase purity of 99.5%.

[0023] Example 2

[0024] At room temperature, 150 ml of dichloromethane, 15 g of cyclohexanol, 18.07 g of 1-chloroethanol, and 5.47 g of dimethylaminopyridine (DMAP) were added sequentially to a clean reaction flask. After mixing and stirring, carbon dioxide was bubbled through the mixture three times, and the carbon dioxide was continuously bubbled through while maintaining the pressure of the reaction system at 1.2 MPa and the temperature at 35°C for 11 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 45 g of water, allowed to stand and separate into layers, and then dried with 15 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was then concentrated by vacuum distillation to remove the solvent, yielding 30.49 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.5% and a gas phase purity of 99.6%.

[0025] Example 3

[0026] At room temperature, 200 ml of dichloromethane, 20 g of cyclohexanol, 24.10 g of 1-chloroethanol, and 7.3 g of dimethylaminopyridine (DMAP) were added sequentially to a clean reaction flask. After mixing and stirring, carbon dioxide was introduced three times to replace the carbon dioxide, and the reaction system pressure was controlled at 1.0 MPa. The temperature was maintained at 30 °C for 12 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 60 g of water, allowed to stand and separate into layers, and then dried with 15 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was concentrated by vacuum distillation to remove the solvent, yielding 40.73 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.7% and a gas phase purity of 99.5%.

[0027] Example 4

[0028] At room temperature, 300 ml of ethyl acetate, 20 g of cyclohexanol, 32.2 g of 1-chloroethanol, and 12.2 g of dimethylaminopyridine (DMAP) were added sequentially to a clean reaction flask. After mixing and stirring, carbon dioxide was bubbled through the mixture three times, and the carbon dioxide was continuously bubbled through the mixture. The pressure of the reaction system was controlled to be below 1.5 MPa, and then controlled between 1.3 MPa and 1.5 MPa. The temperature was 25 °C, and the reaction was maintained at this temperature for 13 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 60 g of water, allowed to stand and separate into layers, and then dried with 15 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was then concentrated by vacuum distillation to remove the solvent, yielding 40.6 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.3% and a gas phase purity of 99.6%.

[0029] Example 5

[0030] At room temperature, 300 ml of ethyl acetate, 20 g of cyclohexanol, 20.9 g of 1-chloroethanol, and 4.9 g of dimethylaminopyridine (DMAP) were added sequentially to a clean reaction flask. After mixing and stirring, carbon dioxide was bubbled through the mixture three times, and the carbon dioxide was continuously bubbled through the mixture. The pressure of the reaction system was controlled to be below 1.2 MPa, and then controlled between 1.0 MPa and 1.2 MPa. The temperature was 30 °C, and the reaction was maintained at this temperature for 11 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 55 g of water, allowed to stand and separate into layers, and then dried with 12 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was then concentrated by vacuum distillation to remove the solvent, yielding 40.65 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.5% and a gas phase purity of 99.7%.

[0031] Example 6

[0032] At room temperature, 300 ml of dichloromethane, 20 g of cyclohexanol, 25.8 g of 1-chloroethanol, and 7.9 g of pyridine were added sequentially to a clean reaction flask. After mixing and stirring, carbon dioxide was bubbled through the mixture three times, and the carbon dioxide was continuously bubbled through the mixture. The pressure of the reaction system was controlled to be below 1.3 MPa, and the pressure was controlled between 1.0 MPa and 1.3 MPa. The temperature was 32 °C, and the reaction was maintained at this temperature for 10 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 55 g of water, allowed to stand and separate into layers, and then dried with 12 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was then concentrated by vacuum distillation to remove the solvent, yielding 40.52 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.2% and a gas phase purity of 99.2%.

[0033] Example 7

[0034] At room temperature, 280 ml of dichloromethane, 20 g of cyclohexanol, 25.76 g of 1-chloroethanol, and 7.9 g of piperidine were added sequentially to a clean reaction flask. After mixing and stirring, carbon dioxide was bubbled through the mixture three times, and the carbon dioxide was continuously bubbled through the mixture. The pressure of the reaction system was controlled at 1.0 MPa, and the temperature was 32 °C. The reaction was maintained at this temperature for 10 hours. After the reaction was completed and confirmed to be complete, the mixture was allowed to stand and separate into layers. The collected organic phase was washed once with 50 g of water, allowed to stand and separate into layers, and then dried with 15 g of anhydrous sodium sulfate. The mixture was stirred for 30 min and filtered. The filtrate was concentrated by vacuum distillation to remove the solvent, yielding 40.5 g of 1-chloroethylcyclohexyl carbonate, with a yield of 98.1% and a gas phase purity of 99.3%.

[0035] The specific embodiments described in this invention are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains can make various modifications or additions to the described specific embodiments or use similar methods to replace them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

[0036] Although the present invention has been described in detail and specific embodiments have been cited, it will be apparent to those skilled in the art that various changes or modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A method for preparing 1-chloroethylcyclohexyl carbonate, characterized in that, The method involves mixing cyclohexanol and 1-chloroethanol under the action of an organic base with a nitrogen-containing cyclic structure, and then reacting the mixture with carbon dioxide to obtain 1-chloroethylcyclohexyl carbonate.

2. The method for preparing 1-chloroethylcyclohexyl carbonate according to claim 1, characterized in that, The organic base having a nitrogen-containing cyclic structure is selected from one or more of pyridine, dimethylaminopyridine, piperidine, and pyrrole.

3. The method for preparing 1-chloroethylcyclohexyl carbonate according to claim 1, characterized in that, The reaction temperature is between 20°C and 50°C, and the reaction pressure is controlled within 1.6 MPa.

4. The method for preparing 1-chloroethylcyclohexyl carbonate according to claim 3, characterized in that, The reaction temperature is 25℃~35℃, and the reaction pressure is controlled at 1.0MPa~1.5MPa.

5. The method for preparing 1-chloroethylcyclohexyl carbonate according to any one of claims 1-4, characterized in that, The reaction is carried out in a non-water-soluble organic solvent, which is selected from one or more of haloalkanes, ester solvents and aromatic solvents.

6. The method for preparing 1-chloroethylcyclohexyl carbonate according to claim 5, characterized in that, The haloalkane is selected from dichloromethane and / or chloroform; the ester solvent is selected from one or more of ethyl acetate, propyl acetate and methyl ethyl acetate; the aromatic solvent is selected from toluene and / or xylene.

7. The method for preparing 1-chloroethylcyclohexyl carbonate according to any one of claims 1-4, characterized in that, The molar ratio of cyclohexanol:1-chloroethanol:organic base is 1:1.0-2.0:0.1-0.5.

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