CN102942470B - Production technology of pharmaceutical grade valeryl chloride - Google Patents
Production technology of pharmaceutical grade valeryl chloride Download PDFInfo
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- CN102942470B CN102942470B CN201210432079.6A CN201210432079A CN102942470B CN 102942470 B CN102942470 B CN 102942470B CN 201210432079 A CN201210432079 A CN 201210432079A CN 102942470 B CN102942470 B CN 102942470B
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- valeric acid
- storage tank
- chloride
- rectifying still
- sulfur oxychloride
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Abstract
The invention discloses a production technology of pharmaceutical grade valeryl chloride, relating to the field of chemical industry production. The production technology disclosed herein comprises the following steps: respectively pumping n-valeric acid and thionyl chloride into an enamel reaction kettle from storage tanks by using a metering pump, wherein the ratio of n(n-valeric acid) to n(thionyl chloride) is 1.0:1.2-1.0:1.5; then measured as n-valeric acid, adding 1-5wt% of DMF, heating up to 50-90 DEG C to react until no gas is generated; sucking the chlorination reaction liquid into a rectifying still under vacuum condition, measured as n-valeric acid, adding 1-5wt% of stabilizer, conducting rectification under vacuum, controlling the temperature of the rectifying still being no higher than 90 DEG C, collecting the front cut fraction thionyl chloride into a receiving storage tank, and collecting valeryl chloride into a finished product storage tank. According to the invention, by adding the electron-rich stabilizer to allow acyl cations to preferentially be combined with the stabilizer, thus the generation of valeric anhydride is avoided; simultaneously the temperature of the rectifying still is reduced, the equilibrium constant of valeryl chloride dissociation is reduced, and the stability of distillation separation is raised.
Description
Technical field
The present invention relates to chemical production field, be specifically related to a kind of production technique of pharmaceutical grade n-amyl chloride.
Background technology
N-amyl chloride is a kind of Chemicals with extensive use, as can be used for the own azoles alcohol of synthetic pesticide sterilant; Nematic Santosol 360 liquid crystal material; Depressor perindopril, valsartan, irbesartan; And for the radical protection etc. in organic synthesis field.Wherein the attached value of the product of pharmaceutical grade n-amyl chloride is high, and quality index is also strict, requires n-amyl chloride content >=99.5%, positive valeric anhydride content≤0.2%, positive valeric acid content≤0.25%, without phosphoric remnants etc.
The production method of n-amyl chloride is with positive valeric acid for raw material, and through chlorination reagent chlorination synthesis, optional chlorination reagent has phosgene, sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride etc.From raw material sources and cost consideration, being most widely used of sulfur oxychloride and phosphorus trichloride.Because pharmaceutical grade n-amyl chloride requires without phosphoric remaining, and the phosphoric acid generated in phosphorus trichloride chlorination process and valeryl chloride boiling point close, aftertreatment is difficult, thus sulfur oxychloride to be chlorination reagent comparatively suitable.
Usually adding DMF in chlorination production process is catalyzer, to improve reaction kinetics and chlorination selectivity, avoids the n-amyl chloride of generation and unreacted positive valeric acid condensation to form positive valeric anhydride.Its catalytic mechanism is: DMF and sulfur oxychloride, through condensation, rearrangement, slough SO
2form Vilsmeier reagent, its chlorization activity is stronger than sulfur oxychloride, and make preferential and its generation chlorination reaction of carboxylic acid, mechanism is as follows.
But, the 126-127 DEG C of cut that this system rectifying is collected, purity >=98% (GC), wherein positive valeric anhydride content is about 1%, only meets agricultural chemicals level product index, and remnants 5 ~ 10% black tars at the bottom of rectifying still.
Summary of the invention
Have problems for above-mentioned production, the object of the present invention is to provide a kind of production technique of high-content pharmaceutical grade n-amyl chloride, the present invention implements by following technical scheme:
1. positive valeric acid, sulfur oxychloride are squeezed in enamel reaction still by storage tank through volume pump respectively, n (positive valeric acid): n (sulfur oxychloride)=1.0:1.2 ~ 1.0:1.5, add 1 ~ 5wt ‰ DMF in positive valeric acid again, be warming up to 50 ~ 90 DEG C, until reaction is to releasing without gas;
2. above-mentioned chlorination reaction liquid vacuum sucked in rectifying still, add 1 ~ 5wt ‰ stablizer, rectification under vacuum in positive valeric acid, control rectifying still temperature≤90 DEG C, front-end volatiles sulfur oxychloride is collected into reception storage tank, and n-amyl chloride is collected into finished product storage tank.
Stablizer structure wherein described in step (2) is shown in following formula:
Wherein R
1, R
2, R
3be abundant electron substituents, such as, phenyl, one or more in alkyl or alkoxyl group.
beneficial effect of the present invention
Even if the general rectification working process later stage keeps higher reflux ratio etc., in discharging cut, positive valeric anhydride content progressively raises.As can be seen here, although boiling point differs comparatively large, there is azeotropism with valeric anhydride (228 ~ 230 DEG C) in valeryl chloride (125 ~ 127 DEG C).Wherein the possible formation mechanism of positive valeric anhydride is as follows.
After n-amyl chloride is heated, molecular motion aggravation, is dissociated into acyl cation and chlorine negative ion.The enol tautomeric isomers of the electric attack n-amyl chloride of acyl cation parent, forms ester compound, release a part hydrogenchloride.This ester compound is subject to parent's electricity attack of acyl cation again, forms positive valeric anhydride and chloro-alkenes.This mechanism meets in production process the phenomenon that hydrogen chloride gas overflows and black tars generates.
The present invention, by adding the stablizer of electron rich structure, makes acyl cation preferentially be combined with stablizer, avoids the generation of positive valeric anhydride.Reduce rectifying still temperature simultaneously, reduce the equilibrium constant of n-amyl chloride dissociation, improve the stability of rectifying separation.
Specific embodiment
embodiment 1
By positive for 100kg valeric acid, 140kg sulfur oxychloride respectively by storage tank, squeeze in 500L enamel reaction still through volume pump, then add 0.1kg DMF, open steam valve, be warming up to 50 DEG C, the sour gas of generation is absorbed by device for absorbing tail gas, and reaction is until release without gas.Above-mentioned reaction solution vacuum is sucked in 200L rectifying still, adds 0.1kg DMA, rectification under vacuum, control still temperature≤90 DEG C, reclaim sulfur oxychloride 23kg, collect n-amyl chloride 115kg, purity 99.7% (GC), yield 98%.
embodiment 2
By positive for 100kg valeric acid, 175kg sulfur oxychloride respectively by storage tank, squeeze in 500L enamel reaction still through volume pump, then add 0.2kg DMF, open steam valve, be warming up to 70 DEG C, the sour gas of generation goes device for absorbing tail gas to absorb, and reaction is until release without gas.Above-mentioned reaction solution vacuum is sucked in 200L rectifying still, adds 0.5kg triphenylamine, rectification under vacuum, control still temperature≤90 DEG C, reclaim sulfur oxychloride 57kg, collect n-amyl chloride 113kg, purity 99.6% (GC), yield 96%.
embodiment 3
By positive for 100kg valeric acid, 152kg sulfur oxychloride respectively by storage tank, squeeze in 500L enamel reaction still through volume pump, then add 0.5kg DMF, open steam valve, be warming up to 90 DEG C, the sour gas of generation goes device for absorbing tail gas to absorb, and reaction is until release without gas.Above-mentioned reaction solution vacuum is sucked in 200L rectifying still, adds 0.3kg trolamine, rectification under vacuum, control still temperature≤90 DEG C, reclaim sulfur oxychloride 35kg, collect n-amyl chloride 114kg, purity 99.7% (GC), yield 97%.
Claims (1)
1. the production technique of pharmaceutical grade n-amyl chloride, it is characterized in that carrying out according to following step: positive valeric acid, sulfur oxychloride are squeezed in enamel reaction still by storage tank through volume pump by (1) respectively, n (positive valeric acid): n (sulfur oxychloride)=1.0:1.2 ~ 1.0:1.5, the DMF of quality meter 1 ~ 5w ‰ is added again in positive valeric acid, be warming up to 50 ~ 90 DEG C, until reaction is to releasing without gas;
(2) above-mentioned chlorination reaction liquid vacuum sucked in rectifying still, add quality meter 1 ~ 5 ‰ stablizer, rectification under vacuum in positive valeric acid, control rectifying still temperature≤90 DEG C, front-end volatiles sulfur oxychloride is collected into reception storage tank, and n-amyl chloride is collected into finished product storage tank;
Stablizer structure wherein described in step (2) is shown in following formula:
Wherein R1, R2, R3 are phenyl, one or more in alkyl or alkoxyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210432079.6A CN102942470B (en) | 2012-11-02 | 2012-11-02 | Production technology of pharmaceutical grade valeryl chloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210432079.6A CN102942470B (en) | 2012-11-02 | 2012-11-02 | Production technology of pharmaceutical grade valeryl chloride |
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| CN102942470A CN102942470A (en) | 2013-02-27 |
| CN102942470B true CN102942470B (en) | 2015-06-24 |
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| CN201210432079.6A Expired - Fee Related CN102942470B (en) | 2012-11-02 | 2012-11-02 | Production technology of pharmaceutical grade valeryl chloride |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103880646A (en) * | 2014-03-13 | 2014-06-25 | 东力（南通）化工有限公司 | Hydrolysis-resistant rectifying process of isovaleryl chloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1373742A (en) * | 1999-09-13 | 2002-10-09 | 巴斯福股份公司 | Method for producing acid chlorides |
| CN101007774A (en) * | 2007-01-29 | 2007-08-01 | 浙江大学 | Method for synthesizing D-norvaline using n-pentanoic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2128122B1 (en) * | 2007-03-01 | 2014-01-22 | Mitsui Chemicals, Inc. | Process for producing carboxylic acid chloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1373742A (en) * | 1999-09-13 | 2002-10-09 | 巴斯福股份公司 | Method for producing acid chlorides |
| CN101007774A (en) * | 2007-01-29 | 2007-08-01 | 浙江大学 | Method for synthesizing D-norvaline using n-pentanoic acid |
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