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A kind of preparation method of 7a-double condensed pyrrolidine-acetonitrile

A technology of pyrrolidine and acetonitrile, which is applied in the field of synthesizing high-purity 7A-double-condensed pyrrolidine-acetonitrile, can solve the problems of poor industrialization prospects, reduced safety, difficult purification, etc., and achieves convenient purification and separation, improved stability, Effects of avoiding freezing conditions

Active Publication Date: 2017-01-04
SUZHOU CANIMBLE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2-Amino-2-methylpropionitrile is produced by the reaction of acetone and highly toxic sodium cyanide, and its safety is greatly reduced
This method is widely used in current literature reports, and the starting materials are cheap and easy to obtain, but the intermediate 1,7-dichloro-4-heptanone is relatively unstable and difficult to purify
And commercially available 1,7-dichloro-4-heptanone is expensive, making the industrialization prospect of this route relatively poor

Method used

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  • A kind of preparation method of 7a-double condensed pyrrolidine-acetonitrile
  • A kind of preparation method of 7a-double condensed pyrrolidine-acetonitrile
  • A kind of preparation method of 7a-double condensed pyrrolidine-acetonitrile

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] first step:

[0035] Pump 400kg of γ-butyrolactone and 320kg of anhydrous methanol into a 2000L reactor, stir, turn on and cool to below 25°C, then pump in 420kg of 30% sodium methoxide solution (28%-30%), and control the temperature below 35°C. After the addition, the water bath was heated to 65°C and kept for 4h. Begin to concentrate and distill to recover the solvent under reduced pressure (most of the solvents are recovered at an internal temperature lower than 45-55°C, keeping at 60°C for a long time may affect the yield). The solvent was concentrated as much as possible (vacuum -0.092 or more, until no obvious solvent dripping out). Add 300Kg of ethanol to dissolve, press filter after stirring to obtain about 235kg of crude product, the GC purity is about 80%.

[0036] Step two:

[0037] Add 400kg of formic acid and 110kg of ammonium formate to a 5000L reactor, cool to 0-5°C, and add 450kg of CMP-1. After the addition, the reaction was heated to reflux for 48 ...

Embodiment 2

[0041] first step:

[0042]Inject 400kg of γ-butyrolactone and 320kg of anhydrous methanol into the 2000L reactor, stir, turn on and cool to below 25°C, then pump in 420kg of 30% sodium methoxide solution (28%-30%), and control the temperature below 35°C. After the addition, the water bath was heated to 65°C and kept for 4h. Begin to concentrate and distill to recover the solvent under reduced pressure (most of the solvents are recovered at an internal temperature lower than 45-55°C, keeping at 60°C for a long time may affect the yield). The solvent was concentrated as much as possible (vacuum -0.092 or more, until no obvious solvent dripping out). Add 500Kg of methanol to dissolve, stir and freeze to precipitate crystals to obtain about 250kg (245-275kg) of crude product, with a GC purity of about 94%.

[0043] Step two:

[0044] Add 400kg of formic acid and 110kg of ammonium formate to a 5000L reactor, cool to 0-5°C, and add 450kg of CMP-1. After the addition, the reacti...

Embodiment 3

[0048] first step:

[0049] Pump 400kg of γ-butyrolactone and 320kg of anhydrous methanol into the 2000L reactor, stir, turn on and cool to below 25°C, then pump in 420kg of 30% sodium methoxide solution, and control the temperature below 35°C. After the addition, the water bath was heated to 65°C and kept for 4h. Begin to concentrate and distill to recover the solvent under reduced pressure (most of the solvents are recovered at an internal temperature lower than 45-55°C, keeping at 60°C for a long time may affect the yield). The solvent was concentrated as much as possible (vacuum -0.092 or more, until no obvious solvent dripping out). Add 500 Kg of methanol / isopropanol mixed solvent to dissolve, stir and freeze to precipitate crystals to obtain about 265 kg of crude product with a GC purity of about 96%.

[0050] Step two:

[0051] Add 400kg of formic acid and 110kg of ammonium formate to a 5000L reactor, cool to 0-5°C, and add 450kg of CMP-1. After the addition, the re...

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Abstract

The present invention relates to a preparation method of 7A-double-condensed pyrrolidin-acetonitrile, which uses gamma-butyrolactone raw material to prepare 7A-double-condensed pyrrole through affinity substitution reaction, acidolysis ring-closure reaction and affinity addition decarboxylation reaction Pyridine-acetonitrile, which is characterized in that the transition intermediate CMP-1 is separated and purified to replace 1,7-dichloro-4-heptanone to provide the carbon chain constructed by the mother nucleus. The purification is simple, the yield is high, and the intermediate is stable and easy to store and transfer . The inorganic ammonium salt ammonium acetate is used as the ammonia source to replace the large-scale ammonia gas used in the traditional process, and a high-purity (GC>99%) product is produced under relatively mild conditions. It avoids the shortcomings of the traditional process such as high energy consumption (low temperature freezing reaction), long time consumption, and low product quality (rectification is required, and the product purity is between 98‑99%). The raw materials of each step in the production process are cheap and easy to obtain, no toxic organic solvents are used, the post-treatment is simple, the "three wastes" are less in the production process, and it is green and environmentally friendly.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a new method for synthesizing high-purity 7A-double-condensed pyrrolidine-acetonitrile. Background technique [0002] 7A-double-condensed pyrrolidine-acetonitrile (CAS: 78449-75-9), also known as CMP-3, is a key intermediate of the new antiarrhythmic drug pilsicainide. Pisicanib is the main fist product of Daiichi Pharmaceutical Co., Ltd., and it is a new class Ic antiarrhythmic drug, which can be used for the treatment of atrial arrhythmia and ventricular arrhythmia. Pisicarib is a sodium channel blocker, which can block the extra-stimulus conduction of the action potential, prolong the refractory period, inhibit the depolarization during the refractory period, and fundamentally inhibit the role of reentry and triggering. At present, there is a clinical application for new indications of Pixicarib in China, which is in the clinical research stage. 7A-biscondensed pyrrolidine-a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 陆超曾鹏程孙明顾晓春
Owner SUZHOU CANIMBLE BIOTECH
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