CN101993393B - Method for artificially synthesizing cyclopropanecarbonitrile - Google Patents
Method for artificially synthesizing cyclopropanecarbonitrile Download PDFInfo
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- CN101993393B CN101993393B CN2009101706764A CN200910170676A CN101993393B CN 101993393 B CN101993393 B CN 101993393B CN 2009101706764 A CN2009101706764 A CN 2009101706764A CN 200910170676 A CN200910170676 A CN 200910170676A CN 101993393 B CN101993393 B CN 101993393B
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- cyclopropanecarbonitrile
- chlorobutyronitrile
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Abstract
The invention relates to a method for artificially synthesizing cyclopropanecarbonitrile, which comprises the following steps of: reacting anhydrous sulfates or anhydrous calcium chloride used as mass transfer acclerants and alkali metal alkali used as acid-binding agents with 4-chlorobutyronitrile at 60 to 90 DEG C in the existence of aprotic solvents to obtain the cyclopropanecarbonitrile. The method belongs to the synthesizing method with the advantages of high yield, safety, economy, easy operation, no explosive heat release and temperature rise and simple separation and purification, and is applicable to large-scale industrial production.
Description
(1) technical field
The present invention relates to a kind of preparation method of cyclopropanecarbonitrile, belong to pharmaceutical chemistry technical field.
(2) background technology
Cyclopropanecarbonitrile is as synthesizing thiourea class weedicide and anticoagulant--and the raw material of prasugrel, its synthetic method receives much attention.US.Pat.No.8843709 has reported that take the 4-chlorobutyronitrile is starting raw material, sodium hydroxide is acid binding agent, the method of synthetic cyclopropanecarbonitrile in non-proton dipole solvent, the method advantage is yield high (98.3%), yet defect is: in reaction process, the indissoluble thing that there will be sticky shape, hinder and stir, reduce mass transfer velocity, controlled poor to temperature, be accompanied by the intensification of explosive type, can cause the destruction of equipment and the reduction of yield (approximately 56%), also can cause increasing of by product simultaneously; There is in addition the separation problem of product.
US.Pat.No.5380911 is improved the synthetic method of above-mentioned patent: the water of introducing sodium-chlor and catalytic amount in reaction process has improved mass transfer effect, but can not eliminate the intensification of explosive type fully; And yield relatively the former decrease (86%); Yet aspect the separating-purifying of product, but obtaining larger breakthrough: first use concentrated hydrochloric acid neutralization reaction liquid, then adopt azeotropic distn, utilize water-and-oil separator to separate and obtain a part of product, finally the water layer after separating is carried out to the purification of secondary component distillation again, the product water content after merging is low and purity is higher (99.9%).
With prior art, it seems, the problem that need to overcome at present is to eliminate the intensification of explosive type, when improving yield, reduces the loss to equipment, further this reaction system of Improvement and perfection.The present application people adopts the further mass transfer system of improving, and abandons using the water of catalytic amount, adopts more simple temperature control method, eliminates the intensification of explosive type fully, obtains a mild reaction process; Then adopting the azeotropic distn process profit to be carried out to after continuous circulation separates repeatedly disposablely obtaining product (water-and-oil separator of former process using routine need to carry out to product the intermittent purification of secondary); By improving, the present invention can reach higher yield and higher purity (although US.Pat.No.5380911 technique product purity is higher, yield is than low 14 percentage points of the technique of US.Pat.No.3843709 report) simultaneously when overcoming prior art to have defect.
(3) summary of the invention
The technical solution used in the present invention is: the methyl-sulphoxide of take is solvent, adopting anhydrous sulfate or Calcium Chloride Powder Anhydrous is mass transfer promotor, sodium hydroxide is acid binding agent, in 65 ℃～80 ℃, drip the 4-chlorobutyronitrile, dropwise, then, in 80 ℃ of reactions 5 hours, then use concentrated hydrochloric acid neutralization reaction liquid, finally adopt azeotropic distn, utilize constant pressure funnel to carry out continuous circulation to profit and repeatedly separate the rear disposable product cyclopropanecarbonitrile that obtains.The product yield that the method obtains reaches more than 90.0%, more than purity to 99%.Reaction formula is as follows:
The method for preparing cyclopropanecarbonitrile as above, mass transfer promotor used are anhydrous magnesium sulfate or anhydrous sodium sulphate or calcium chloride.The consumption of mass transfer promotor be 0.05～0.5 times to the quality of 4-chlorobutyronitrile, preferable amount is 0.15 times.
Experiment finds that water is not necessary catalyzer, need in reaction process, remove on the contrary the water of free state.Adopt anhydrous sulfate or Calcium Chloride Powder Anhydrous as mass transfer promotor, mainly based on the reason of two aspects: utilize the water-absorbent of anhydrous sulfate to form crystalline hydrate (being a kind of inorganic salt hydrate that does not cohere and be conducive to stir mass transfer), thereby the water that prevents the free state that sodium hydroxide and neutralization produce is combined the indissoluble thing that produces sticky shape and is hindered the stirring mass transfer; Utilize the extremely dispersiveness of hydrate of anhydrous sulfate, promote to stir mass transfer.
Generalized case, yield improves gradually along with the raising of temperature of reaction in this reaction.When temperature of reaction during lower than 65 ℃, sluggish; When temperature of reaction surpasses 95 ℃, find that the amides by product increases; While surpassing 120 ℃, only obtain a small amount of cyclopropanecarbonitrile.
The solvent that reaction is adopted is generally non-proton dipole solvent.Take methyl-sulphoxide amine as solvent than N, N dimethyl formyl is the reaction system of solvent, product yield has obvious advantage.Methyl-sulphoxide is that this reacts preferably solvent selection.
This reaction is a reaction from heat release, adopts the mode dripped can effectively control temperature of reaction to the 4-chlorobutyronitrile.The initial reaction stage very exothermic, need to slowly drip, and thermal source need not be provided, and relies on reaction self liberated heat just can maintain reaction at 65 ℃～85 ℃.Along with the progress of reaction can suitably be accelerated rate of addition.If the 4-chlorobutyronitrile adopts the disposable mode fed intake, be difficult to avoid the outburst of temperature of reaction, cause reacting out of hand.After dropwising preferably temperature control method be: thermal source is not provided, and question response extinguishes naturally is down to room temperature, and then in 80 ℃ the reaction 5 hours.Now explanation reaction self liberated heat can't maintain the carrying out of reaction, needs external heat source to provide energy to maintain continuing of reaction.If too early external heat source may make temperature of reaction surpass the value that expection is set.
The constant pressure funnel of process using of the present invention is as a kind of reinforced instrument, but as a kind of special oily-water seperating equipment: the vapour passage to the side position constant voltage conduit parcel lagging material of constant pressure funnel during as component distillation; The dropping funnel part is as the profit separating device; After the profit layering, rely on the speed of the on-off control oily water separation of funnel to reach the balance of vapor condensation and oily water separation, thereby reach the separating-purifying repeatedly to the product continuous circulation.
With former technique, compared following advantage: use anhydrous magnesium sulfate or anhydrous sodium sulphate or Calcium Chloride Powder Anhydrous instead as mass transfer promotor, greatly improved mass transfer effect; Abandon using the water of catalytic amount; The 4-chlorobutyronitrile is used instead and is dripped the method fed intake, and temperature control method is simple to operation, and reaction process is mild, has eliminated the intensification of explosive type fully; Then adopt azeotropic distn, utilize constant pressure funnel repeatedly to separate the rear disposable product (water-and-oil separator of former process using routine need to carry out to product the intermittent purification of secondary) that obtains to the profit continuous circulation; Reach simultaneously higher yield (98%, former technique is 86%) and higher purity (99.7%) and lower water content.
The technique of technique of the present invention and US.Pat.No.3843709 and US.Pat.No.5380911 report compares that yield is higher, simple possible more, economy, and separating-purifying is more convenient, is applicable to large-scale industrial production.
(4) embodiment:
Below with specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited to this:
Embodiment 1:
The preparation of cyclopropanecarbonitrile
In the 250ml four-hole boiling flask of mechanical stirring, thermometer, reflux condensing tube, constant pressure funnel is housed, put into methyl-sulphoxide (45ml), anhydrous magnesium sulfate (9.0g), sodium hydroxide (26.4g), the control temperature is 60-85 ℃, adopt the mode dripped, in 1 hour, 4-chlorobutyronitrile (53.5g) is added drop-wise in reaction system and goes.Dropwise, naturally be down to room temperature, then in 80 ℃ of reactions 5 hours.Cooling, the slow injected water 100ml of room-temperature water bath condition, then slowly drip concentrated hydrochloric acid neutralization reaction liquid, regulate pH=6.5, finally adopt azeotropic distn, utilize constant pressure funnel repeatedly to separate the rear disposable colorless oil 34.0g that obtains, yield 98.0%, purity 99.7% to the profit continuous circulation.
Embodiment 2:
The preparation of cyclopropanecarbonitrile
In the 250ml four-hole boiling flask of mechanical stirring, thermometer, reflux condensing tube, constant pressure funnel is housed, put into methyl-sulphoxide (45ml), anhydrous sodium sulphate (8.9g), sodium hydroxide (26.4g), in 60-85 ℃ of condition, adopt the mode dripped, in 1 hour, 4-chlorobutyronitrile (53.5g) is added drop-wise in reaction system and goes.Dropwise, naturally be down to room temperature, then in 80 ℃ of reactions 5 hours.Cooling, the slow injected water 100ml of room-temperature water bath condition, then slowly drip concentrated hydrochloric acid neutralization reaction liquid, regulate pH=6.8, finally adopt azeotropic distn, utilize constant pressure funnel repeatedly to separate the rear disposable colorless oil 33.1g that obtains, yield 95.0%, purity 99.3% to the profit continuous circulation.
Embodiment 4:
The preparation of cyclopropanecarbonitrile
In the 250ml four-hole boiling flask of mechanical stirring, thermometer, reflux condensing tube, constant pressure funnel is housed, put into N, N dimethyl formyl (45ml), anhydrous magnesium sulfate (9.0g), sodium hydroxide (26.4g), in 60-85 ℃ of condition, adopt the mode dripped, in 1 hour, 4-chlorobutyronitrile (53.5g) is added drop-wise in reaction system and goes.Dropwise, naturally be down to room temperature, then in 100 ℃ of reactions 5 hours.Cooling, the slow injected water 100ml of room-temperature water bath condition, then slowly drip concentrated hydrochloric acid neutralization reaction liquid, regulate pH=6.8, finally adopt azeotropic distn, utilize constant pressure funnel repeatedly to separate the rear disposable colorless oil 32g that obtains to the profit continuous circulation, yield 92%, purity 99.4%.
Embodiment 5:
The preparation of cyclopropanecarbonitrile
In the 250ml four-hole boiling flask of mechanical stirring, thermometer, reflux condensing tube, constant pressure funnel is housed, put into N, N dimethyl formyl (45ml), Calcium Chloride Powder Anhydrous (8.3g), sodium hydroxide (26.4g), in 60-85 ℃ of condition, adopt the mode dripped, in 1 hour, 4-chlorobutyronitrile (53.5g) is added drop-wise in reaction system and goes.Dropwise, naturally be down to room temperature, then in 100 ℃ of reactions 5 hours.Cooling, the slow injected water 100ml of room-temperature water bath condition, then slowly drip concentrated hydrochloric acid neutralization reaction liquid, regulate pH=7.0, finally adopt azeotropic distn, utilize constant pressure funnel repeatedly to separate the rear disposable colorless oil 31.4g that obtains, yield 90.0%, purity 99.1% to the profit continuous circulation.
Claims (2)
1. the synthetic method of a cyclopropanecarbonitrile, it is characterized in that it is mass transfer promotor that this method adopts anhydrous sulfate or Calcium Chloride Powder Anhydrous, the alkali metal base of take is acid binding agent, under aprotic solvent exists, with the 4-chlorobutyronitrile, react and obtain cyclopropanecarbonitrile in 65 ℃～80 ℃, the method fed intake that the 4-chlorobutyronitrile adopts is the dropping mode; Wherein said mass transfer promotor is anhydrous magnesium sulfate or anhydrous sodium sulphate or calcium chloride, the consumption of mass transfer promotor be 0.05～0.5 times to the quality of 4-chlorobutyronitrile; The mol ratio of described alkali metal base consumption and 4-chlorobutyronitrile consumption is 1: 1～2.
2. technique according to claim 1, is characterized in that described aprotic solvent can be methyl-sulphoxide or N, and N dimethyl formyl, described alkali metal base are sodium hydroxide.
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| CN2009101706764A CN101993393B (en) | 2009-08-26 | 2009-08-26 | Method for artificially synthesizing cyclopropanecarbonitrile |
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| CN101993393B true CN101993393B (en) | 2013-11-27 |
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| CN114989018A (en) * | 2022-08-05 | 2022-09-02 | 山东国邦药业有限公司 | Synthetic method of cyclopropylamine |
| CN115819276A (en) * | 2023-02-21 | 2023-03-21 | 山东国邦药业有限公司 | Synthesis method of cyclopropanecarbonitrile |
| CN116621730B (en) * | 2023-07-24 | 2023-12-15 | 山东国邦药业有限公司 | Synthesis method of cyclopropylnitrile |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1107143A (en) * | 1993-12-02 | 1995-08-23 | 美国氰胺公司 | Improved process for the manufacture of cyclopropylniitrile |
| CN1196047A (en) * | 1995-07-17 | 1998-10-14 | 伊斯曼化学公司 | Process for preparation and separation of cyclopropanecarbonitrile |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1107143A (en) * | 1993-12-02 | 1995-08-23 | 美国氰胺公司 | Improved process for the manufacture of cyclopropylniitrile |
| CN1196047A (en) * | 1995-07-17 | 1998-10-14 | 伊斯曼化学公司 | Process for preparation and separation of cyclopropanecarbonitrile |
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Effective date of registration: 20181130 Address after: 317024 Flood Bridge, Linhai City, Zhejiang Province Co-patentee after: Universal Bailey biological medicine research and development (Shanghai) Co., Ltd. Patentee after: Zhejiang Huahai Pharmaceutical Co., Ltd. Address before: 317024 Xunqiao Development Zone, Linhai City, Zhejiang Province Patentee before: Zhejiang Huahai Pharmaceutical Co., Ltd. |