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A method for pipeline synthesis of key intermediates of Shakubiqu

A technology of sacubitol and chemical synthesis, applied in the direction of organic chemistry and the like, can solve the problems of hidden danger of explosion of raw material azodicarboxylate, reaction of a large number of refrigerants, low yield, etc., to eliminate hidden danger of explosion, simple production process, The effect of large specific surface area

Active Publication Date: 2021-03-30
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(R)-1-(1–([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5-dione was synthesized by Mitsunobu reaction , In the traditional batch synthesis process, the exothermic force is severe, and azodicarboxylate needs to be slowly added dropwise at 0°C. When amplifying, a large amount of refrigerant is required and the reaction is slow, and the yield is low; and the raw material azodicarboxylate is heated There is an explosion hazard when stirring vigorously

Method used

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  • A method for pipeline synthesis of key intermediates of Shakubiqu
  • A method for pipeline synthesis of key intermediates of Shakubiqu
  • A method for pipeline synthesis of key intermediates of Shakubiqu

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1. A pipeline synthesis of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-yl)pyrrolidine-2,5- The diketone method, using figure 1 device shown.

[0029] 1) Accurately weigh 200g (S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol and 212g triphenylphosphine, dissolve in 1000mL tetrahydrofuran to prepare solution A ; Weigh again 144g diethyl azodicarboxylate and 92g succinimide, dissolve with 1000mL tetrahydrofuran to form solution B.

[0030] 2) Turn on the constant temperature tank 5, set the reaction temperature to 0°C, and control the temperature of the pipelined reactor 4 (coiled tube with a volume of 4 to 50 mL) through the constant temperature tank 5 to be 0°C;

[0031] 3) The first constant flow pump 1 sets the delivery flow rate of solution A to 10mL / min, the second constant flow pump 2 sets the delivery flow rate of solution B to 10mL / min, and transports solution A and solution B into the T-type mixer 3 for mixing , the mixed solution continuously enter...

Embodiment 2

[0036] Example 2. A pipeline synthesis of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloroprop-2-yl)pyrrolidine-2,5- The diketone approach:

[0037] Reaction conditions repeat Example 1, but different from Example 1: the reaction temperature is replaced by 15°C, under the different coil volumes (volumes) of the pipelined reactor 4, the reaction yield is as shown in Table 2, and the reaction raw material mole The ratio is: n((S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol):n(succinimide):n(azo Diethyl dicarboxylate): n(triphenylphosphine)=1.0:1.0:1.0:1.0.

[0038] Table 2

[0039]

Embodiment 3

[0040] Example 3, a pipeline synthesis of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5- The diketone approach:

[0041]Reaction conditions repeat Example 1, but different from Example 1: the reaction temperature is replaced by 25 ° C, under the different coil volumes (volumes) of the pipeline reactor 4, the reaction yield is as shown in Table 3, and the reaction raw material mole The ratio is: n((S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol):n(succinimide):n(azo Diethyl dicarboxylate): n(triphenylphosphine)=1.0:1.0:1.0:1.0.

[0042] table 3

[0043]

[0044]

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Abstract

The invention discloses a channelization synthesis method for a key intermediate of sacubitril. The method comprises the following steps: (S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol, succinimide,triphenylphosphine, ethyl azodicarboxylate and an organic solvent are mixed, the mixed solution is fed continuously into a channelization reactor for reaction, a feed liquid obtained after the reaction is fed into a quenching kettle containing an quenching liquid, a quenching reaction is performed with the quenching liquid, (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidin-2,5-dioneis prepared, and the key intermediate of sacubitril is obtained. According to the reaction process, reaction temperature, time and material proportion can be controlled precisely; the reactor has theadvantages of large specific surface area and high mass and heat transfer efficiency, precise proportion moment of the materials can be determined, heat transfer efficiency is high, and safety of a production process is guaranteed.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a key intermediate of Shakubiqu through pipeline. Background technique [0002] (R)-1-(1–([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5-dione (CAS: 1573000-36- 8), its molecular structural formula is as follows: [0003] [0004] (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5-dione is a synthetic sacubitril (Sacubitril Qu) key intermediates. (R)-1-(1–([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5-dione was synthesized by Mitsunobu reaction , In the traditional batch synthesis process, the exothermic force is severe, and azodicarboxylate needs to be slowly added dropwise at 0°C. When amplifying, a large amount of refrigerant is required and the reaction is slow, and the yield is low; and the raw material azodicarboxylate is heated There is an explosion hazard when stirred vigorously...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/404
CPCC07D207/404
Inventor 叶青曹金松张文成胡圆圆高建荣
Owner ZHEJIANG UNIV OF TECH
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