CN102633683A - Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile - Google Patents
Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile Download PDFInfo
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- CN102633683A CN102633683A CN2012100985146A CN201210098514A CN102633683A CN 102633683 A CN102633683 A CN 102633683A CN 2012100985146 A CN2012100985146 A CN 2012100985146A CN 201210098514 A CN201210098514 A CN 201210098514A CN 102633683 A CN102633683 A CN 102633683A
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- cyclopropyl acetonitrile
- methylol
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- methylol cyclopropyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 1-hydroxymethyl cyclopropylacetonitrile, which comprises the steps of: firstly, taking a tribromoneopentyl alcohol compound 1 as a starting material, and carrying out acetylation in a acetylation reagent to obtain tribromoneopentyl acetate; reducing the tribromoneopentyl acetate in the presence of zinc powder and catalyst, to obtain 1-(brooethyl) cyclopropyl methyl acetate; carrying out substitution reaction on the 1-(brooethyl) cyclopropyl methyl acetate in an organic solvent by cyanide; and then, carrying out esterolysis under the alkaline condition to obtain the 1-hydroxymethyl cyclopropylacetonitrile. The synthesis method is simple in technological operation, all raw materials used by the synthesis method are cheap and easy to obtain, and the synthesis method is low in cost and high in yield, so that the method is suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to the organic chemistry synthesis technical field, particularly a kind of compound method of 1-methylol cyclopropyl acetonitrile.
Background technology
1-methylol cyclopropyl acetonitrile, chemistry 2-by name [(1-Hydroxymethyl-cyclopropyl]-
Acetonitrile, molecular formula is C
6H
9NO, molecular weight are 111.1418, and outward appearance is colourless or weak yellow liquid, and structure is following:
1-methylol cyclopropyl acetonitrile is the important medicine intermediate that synthesizes Rust in the Meng; The Meng, Rust was used for the prevention and the long-term treatment of adult's asthma more than 15 years old and 15 years old; The SOA that comprises prevention daytime and night, treatment is used to alleviate the symptom that allergic rhinitis causes to the asthmatic patient of Asprin sensitivity and the bronchoconstriction of prevention exercise induced.
In the prior art, the compound method of 1-methylol cyclopropyl acetonitrile mainly is first cyclization to 1, and 1 Trimetylene dimethanol adopts the sulfonic acid esterification then, replaces with cyanic acid again, and last hydrolysis obtains this product, and concrete synthetic route reaction equation is following:
But, the compound method of 1-methylol cyclopropyl acetonitrile in the prior art, synthesis yield is low; The employing raw materials cost is high; Complex process, preparation technology are perfect inadequately, and the 1-methylol cyclopropyl acetonitrile operational path of therefore developing a suitable industrialization has very big social benefit and market efficiency.
Summary of the invention
The technical problem that the present invention mainly solves provides a kind of simple to operate, and yield is high, the compound method of lower-cost 1-methylol cyclopropyl acetonitrile.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: a kind of compound method of 1-methylol cyclopropyl acetonitrile is provided, in turn includes the following steps:
(1) be starting raw material with tribromoneoamyl alcohol compound 1, in acetylation reagent, carry out acetylize and get compound 2:
(2) compound 2 under the condition that zinc powder and catalyzer exist, reduce compound 3:
(3) compound 3 carries out substitution reaction with sodium cyanide earlier, in alcoholic solution, carries out the ester hydrolysis under the alkaline condition and gets 1-methylol cyclopropyl acetonitrile 4 then:
In preferred embodiment of the present invention, in the step (1), described acetylation reagent is a kind of in acetic acid, diacetyl oxide, Acetyl Chloride 98Min., vinyl acetic monomer or the acetic acid pentafluorophenyl esters.
In preferred embodiment of the present invention, in the step (2), the mass ratio of described compound 2, zinc powder and catalyzer is 360-380:60-100:1
In preferred embodiment of the present invention, in the step (2), described temperature of reaction is 60-70 ℃, and the reaction times is 4-6h.
In preferred embodiment of the present invention, in the step (3), described organic solvent is N, dinethylformamide or DMSO 99.8MIN..
In preferred embodiment of the present invention, in the step (3), described alcoholic solution is a kind of in methyl alcohol, ethanol or the Virahol.
In preferred embodiment of the present invention, in the step (3), described alkali is yellow soda ash or salt of wormwood.
Compared with prior art, 1-methylol cyclopropyl acetonitrile provided by the invention technological operation is simple, and used low in raw material cost is easy to get, the equal low toxicity of reagent, and labor protection requires low.It is less, with low cost to produce the three wastes that produce, and yield is greatly improved than prior art, is applicable to industrialized production.
Embodiment
A kind of compound method of 1-methylol cyclopropyl acetonitrile in turn includes the following steps:
(1) be starting raw material with tribromoneoamyl alcohol compound 1, in acetylation reagent, carry out acetylize and get compound 2:
(2) compound 2 under the condition that zinc powder and catalyzer exist, reduce compound 3:
(3) compound 3 carries out substitution reaction with sodium cyanide earlier, in alcoholic solution, carries out the ester hydrolysis under the alkaline condition and gets 1-methylol cyclopropyl acetonitrile 4 then:
。
In the present invention, in the step (1), acetylation reagent is a kind of in acetic acid, diacetyl oxide, Acetyl Chloride 98Min., vinyl acetic monomer or the acetic acid pentafluorophenyl esters; In the step (2), the mass ratio of compound 2, zinc powder and catalyzer is 360-380:60-100:1, and answering temperature is 60-70 ℃, and the reaction times is 4-6h; In the step (3), organic solvent is N, and dinethylformamide or DMSO 99.8MIN., alcoholic solution are that methyl alcohol, ethanol or Virahol are a kind of, and alkali is yellow soda ash or salt of wormwood.
Below come further to explain or explanation content of the present invention that but the examples of implementation that provided should not be construed as protection domain of the present invention is constituted restriction through embodiment.Wherein compound 1 (tribromoneoamyl alcohol) raw material has commercially available.
Embodiment 1
Tribromo neo-pentyl acetic ester (compound 2)
Stir adding aceticanhydride 300g in the 1000ml reaction flask, starting, drop into the 650g tribromoneoamyl alcohol again; Open steam and be warming up to 90-110 ℃, stir insulation 2 hours, sampling; Detection level reaches 99%, is cooled to 15-30 ℃, filters dried; Get finished product tribromo neo-pentyl acetic ester (compound 2) 754 g, yield 116%.
Embodiment 2
1-(brooethyl) cyclopropyl methyl acetate (compound 3)
With adding methyl alcohol 460g in the 1000ml reaction flask, stir adding tribromo neo-pentyl acetic ester 362G down, be heated to little backflow, temperature 40-70 ℃, add zinc powder 60g then; Catalyzer 1g (organic acid and mineral acid), temperature can rise to backflow, maintains 65-75 ℃ of refluxed reaction, and the 3h internal reaction cools under 20 ℃ after finishing; Suction filtration, filter cake are with 60g methyl alcohol and the washing of 140g ETHYLE ACETATE, and suction filtration liquid is cooled to below 15 ℃; Splash into ammoniacal liquor 600g then, dropwise, add Industrial Salt 50g, stir 0.5h; Leave standstill 30min, layering, the very slight color of liquid will be noted liquid level; Water layer is inferior with ETHYLE ACETATE 200ml extracted twice, merges organic layer, and with 250 gram salt washings twice, organic layer reclaims solvent; In 70 ℃, sampling detects, and obtains 1-(brooethyl) cyclopropyl methyl acetate (compound 3) 180g, content 82% (GC detection).
Embodiment 3
1-(brooethyl) cyclopropyl methyl acetate (compound 3)
With adding methyl alcohol 460g in the 1000ml reaction flask, stir adding tribromo neo-pentyl acetic ester 380g down, be heated to little backflow, temperature 50-65 ℃, add 90 zinc powders then, catalyzer 1g (organic acid and mineral acid); Temperature can rise to backflow,, maintain 65-75 ℃ of refluxed reaction, the 3h internal reaction cools under 20 ℃ after finishing; Suction filtration, filter cake are with 60g methyl alcohol and the washing of 140g ETHYLE ACETATE, and suction filtration liquid is cooled to below 15 ℃, splashes into ammoniacal liquor 600g then; Dropwise, add Industrial Salt 50g, stir 0.5h, leave standstill 30min, layering; The very slight color of liquid will be noted liquid level, and water layer is inferior with ETHYLE ACETATE 200ml extracted twice, merges organic layer, with twice of 250 gram salt washing; Organic layer reclaims solvent, and in 70 ℃, sampling detects, and obtains 1-(brooethyl) cyclopropyl methyl acetate (compound 3) 180g, content 82%.
Embodiment 4
1-methylol cyclopropyl acetonitrile (compound 4)
Add 350g1-(brooethyl) cyclopropyl methyl acetate (compound 3) in the 2000ml reaction flask, 330g
30% NaCN, 700gDMF, yellow soda ash 53g slowly is warming up to 25 ℃; Stir 0.5h, continued is heated to 75-80 ℃ of insulation 2 hours, detects, and DMF is reclaimed in the back that reacts completely; Reclaim under reduced pressure DMF, controlling 90 ℃ does not have solvent to go out, and the back adds methyl alcohol 940g, yellow soda ash 27g; Refluxing is incubated 6h, and detection reaction is complete, and methyl alcohol (can apply mechanically) is reclaimed in the back.Steaming to 60 is ℃ solvent-free to go out, and adds ETHYLE ACETATE 250ml, water 300ml, and layering, water layer is with twice 250ml*2 of ethyl acetate extraction, and the recovery solvent obtains crude product 210g, content 85 % (GC detection), yield 62%.
Embodiment 5
1-methylol cyclopropyl acetonitrile (compound 4)
Add 350g1-(brooethyl) cyclopropyl methyl acetate (compound 3) in the 2000ml reaction flask, 330g
30% NaCN, the 700g DMSO 99.8MIN., salt of wormwood 60g slowly is warming up to 25 ℃; Stir 0.5h, continued is heated to 75-80 ℃ of insulation 2 hours, detects, and DMSO 99.8MIN. is reclaimed in the back that reacts completely; The reclaim under reduced pressure DMSO 99.8MIN., controlling 90 ℃ does not have solvent to go out, and the back adds ethanol 1000g, salt of wormwood 27g; Refluxing is incubated 6h, and detection reaction is complete, and methyl alcohol (can apply mechanically) is reclaimed in the back.Steaming to 60 is ℃ solvent-free to go out, and adds ETHYLE ACETATE 250ml, water 300ml, and layering, water layer is with twice 250ml*2 of ethyl acetate extraction, and the recovery solvent must obtain crude product 250g, content 90 % (GC detection), yield 70%.
The above is merely embodiments of the invention; Be not so limit claim of the present invention; Every equivalent structure or equivalent flow process conversion that utilizes description of the present invention to do; Or directly or indirectly be used in other relevant technical fields, all in like manner be included in the scope of patent protection of the present invention.
Claims (6)
1.1-the compound method of methylol cyclopropyl acetonitrile is characterized in that, in turn includes the following steps:
(1) be starting raw material with tribromoneoamyl alcohol compound 1, in acetylation reagent, carry out acetylize and get compound 2:
(2) compound 2 under the condition that zinc powder and catalyzer exist, reduce compound 3:
(3) compound 3 carries out substitution reaction with prussiate at organic solvent earlier, under alkaline condition, carries out the ester hydrolysis then and gets 1-methylol cyclopropyl acetonitrile 4:
2. the compound method of 1-methylol cyclopropyl acetonitrile according to claim 1 is characterized in that, in the step (1), described acetylation reagent is a kind of in acetic acid, diacetyl oxide, Acetyl Chloride 98Min., vinyl acetic monomer or the acetic acid pentafluorophenyl esters.
3. the compound method of 1-methylol cyclopropyl acetonitrile according to claim 1 is characterized in that, in the step (2), the mass ratio of described compound 2, zinc powder and catalyzer is 360-380:60-100:1
The compound method of 1-methylol cyclopropyl acetonitrile according to claim 1 is characterized in that, in the step (2), described temperature of reaction is 60-70 ℃, and the reaction times is 4-6h.
4. the compound method of 1-methylol cyclopropyl acetonitrile according to claim 1 is characterized in that, in the step (3), described organic solvent is N, dinethylformamide or DMSO 99.8MIN..
5. the compound method of 1-methylol cyclopropyl acetonitrile according to claim 1 is characterized in that, in the step (3), described alcoholic solution is a kind of in methyl alcohol, ethanol or the Virahol.
6. the compound method of 1-methylol cyclopropyl acetonitrile according to claim 1 is characterized in that, in the step (3), described alkali is yellow soda ash or salt of wormwood.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210098514.6A CN102633683B (en) | 2012-04-06 | 2012-04-06 | Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile |
| PCT/CN2012/000621 WO2013149364A1 (en) | 2012-04-06 | 2012-05-08 | Method for synthesizing 1-hydroxymethyl cyclopropyl acetonitrile |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210098514.6A CN102633683B (en) | 2012-04-06 | 2012-04-06 | Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile |
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| Publication Number | Publication Date |
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| CN102633683A true CN102633683A (en) | 2012-08-15 |
| CN102633683B CN102633683B (en) | 2014-05-21 |
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| CN201210098514.6A Expired - Fee Related CN102633683B (en) | 2012-04-06 | 2012-04-06 | Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile |
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| WO (1) | WO2013149364A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058884A (en) * | 2012-12-14 | 2013-04-24 | 武汉赛狮药物化学有限公司 | Method for synthesizing 1-hydroxymethyl cyclopropyl acetonitrile |
| CN113943231A (en) * | 2021-11-18 | 2022-01-18 | 能特科技有限公司 | Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101016227A (en) * | 2007-02-08 | 2007-08-15 | 宜兴市中正化工有限公司 | Synthetic method and refining for tribromoneoamyl alcohol |
| CN101200442A (en) * | 2007-12-06 | 2008-06-18 | 台耀化学股份有限公司 | Method for preparing [1-(mercapto methyl) cyclopropyl] acetate and derivatives thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW416948B (en) * | 1993-12-28 | 2001-01-01 | Merck & Co Inc | Process for the preparation of leukotriene antagonists |
| US7271268B1 (en) * | 2006-12-22 | 2007-09-18 | Formosa Laboratories Inc. | Process for preparation of [1-(mercaptomethyl)cyclopropyl]acetic acid and related derivatives |
-
2012
- 2012-04-06 CN CN201210098514.6A patent/CN102633683B/en not_active Expired - Fee Related
- 2012-05-08 WO PCT/CN2012/000621 patent/WO2013149364A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101016227A (en) * | 2007-02-08 | 2007-08-15 | 宜兴市中正化工有限公司 | Synthetic method and refining for tribromoneoamyl alcohol |
| CN101200442A (en) * | 2007-12-06 | 2008-06-18 | 台耀化学股份有限公司 | Method for preparing [1-(mercapto methyl) cyclopropyl] acetate and derivatives thereof |
Non-Patent Citations (1)
| Title |
|---|
| A.I.DYACHENKO: "MECHANISM OF THE GUSTAVSON REARRANGEMENT REACTION OF THE TETRAHALONEOPENTANES, ESTERS OF TRIBROMONEOPENTANOL AND THEIR CYCLOPROPYL ANALOGS WITH ZINC", 《TETRAHEDRON LETTERS》, no. 2, 31 December 1979 (1979-12-31) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058884A (en) * | 2012-12-14 | 2013-04-24 | 武汉赛狮药物化学有限公司 | Method for synthesizing 1-hydroxymethyl cyclopropyl acetonitrile |
| CN113943231A (en) * | 2021-11-18 | 2022-01-18 | 能特科技有限公司 | Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile |
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| Publication number | Publication date |
|---|---|
| WO2013149364A1 (en) | 2013-10-10 |
| CN102633683B (en) | 2014-05-21 |
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