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Processes for producing 3-amino crotonic acid cinnamyl ester and cilnidipine in large scale

A large-scale, crotonic acid technology, applied in the preparation of ketene/polyketene, the preparation of organic compounds, organic chemistry, etc., to achieve the effect of reducing industrial costs, ensuring yield and purity, and ensuring purity and yield

Active Publication Date: 2018-12-21
董小林
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the reported literature, the synthesis of cinnamyl 3-amino-2-butenoate is limited to the laboratory to open up the process route, and it cannot be used when the feasibility of the process is verified through scale-up production.

Method used

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  • Processes for producing 3-amino crotonic acid cinnamyl ester and cilnidipine in large scale
  • Processes for producing 3-amino crotonic acid cinnamyl ester and cilnidipine in large scale

Examples

Experimental program
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Embodiment 1

[0038] The present embodiment provides a kind of technique of large-scale production of cinnamyl 3-amino-2-butenoate, comprising the following steps:

[0039] S1, preparing crude cinnamyl acetoacetate;

[0040] 100 kg of cinnamyl alcohol was dropped into a 200L reaction kettle, triethylamine was added, and the temperature was raised. When the temperature in the kettle reached 75° C., a total amount of 68 kg of diketene was added dropwise.

[0041] Take every 10kg of diketene as a dropping unit, and make it drop into the glass high tank at the production site for dropping.

[0042] It is advisable to add 10kg every 40 minutes for the dropping speed, and the dropping temperature shall not exceed 85°C.

[0043] After all the diketene was added dropwise, the reaction was kept at 85° C. for 5 hours.

[0044] After the heat preservation reaction is finished, the content of the produced substance is detected by high-performance liquid phase analysis on-line. The column temperature ...

Embodiment 2-3

[0055] The technique for the large-scale production of 3-amino-2-butenoic acid cinnamyl ester provided by embodiment 2-3 is consistent with the steps of the large-scale production of 3-amino-2-butenoic acid cinnamyl ester provided by embodiment 1, The difference is that the operating conditions change.

Embodiment 2

[0057] The temperature in the reaction kettle was 85° C., the rate of dropping diketene was 10 kg in 30 minutes, and the temperature was kept for 6 hours. The temperature of the amination reaction is 2-8° C., the time of the amination reaction is 36-37 hours, and 25% methanol is used for bleaching.

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Abstract

The invention relates to the field of pharmaceutical synthesis and particularly, relates to processes for producing 3-amino crotonic acid cinnamyl ester and cilnidipine in a large scale. The process for producing 3-amino crotonic acid cinnamyl ester in a large scale comprises the following steps of: dropwise adding diketene in batches at a rate of dropwise adding 10kg of diketene in 30 to 40 minutes, wherein the amount of diketene added in each batch is not greater than 10kg; after detecting online that content of cinnamyl acetoacetate obtained by the reaction in each batch accords with the requirement, directly performing an amination reaction. Safety of a production workshop is ensured by adding diketene in batches; meanwhile, the reaction is guaranteed to be sufficiently performed by controlling the adding rate of diketene so as to ensure purity and yield of prepared 3-amino crotonic acid cinnamyl ester; moreover, by detecting purity of cinnamyl acetoacetate on line, use of distillation is avoided, so that industrial cost is further reduced.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a process for large-scale production of cinnamyl 3-amino-2-butenoate and cilnidipine. Background technique [0002] Cinnamyl 3-amino-2-butenoate, also known as cinnamyl 3-amino-crotonate, is one of the key intermediates for the synthesis of the fourth-generation antihypertensive drug cilnidipine. The chemical reaction route is completed in two steps: the first step is the esterification reaction of diketene and cinnamyl alcohol to generate cinnamyl acetoacetate; the second step is the amination reaction of cinnamyl acetoacetate and liquid ammonia to obtain 3-amino-2-butyl Cinnamyl enoate. Since cinnamyl 3-amino-2-butenoate has a low melting point and high solubility, its large-scale production is difficult and the yield is low. It is known that the color of the product reported in the literature is light yellow to off-white, the content is low, the quality is not high, and it is d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/04C07C229/30C07D211/90
CPCC07C67/46C07C227/04C07D211/90C07C69/738C07C229/30
Inventor 董小林董婉琰王景景
Owner 董小林
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