CN102633683B - Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile - Google Patents
Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile Download PDFInfo
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- CN102633683B CN102633683B CN201210098514.6A CN201210098514A CN102633683B CN 102633683 B CN102633683 B CN 102633683B CN 201210098514 A CN201210098514 A CN 201210098514A CN 102633683 B CN102633683 B CN 102633683B
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- compound
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- cyclopropyl acetonitrile
- methylol
- methylol cyclopropyl
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- 0 CCC1*=*C(C)CC1C Chemical compound CCC1*=*C(C)CC1C 0.000 description 2
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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
-
- 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 organic chemical synthesis technical field, particularly a kind of synthetic method of 1-methylol cyclopropyl acetonitrile.
Background technology
1-methylol cyclopropyl acetonitrile, chemistry 2-[(1-Hydroxymethyl-cyclopropyl by name]-
Acetonitrile, molecular formula is C
6h
9nO, molecular weight is 111.1418, and outward appearance is colourless or weak yellow liquid, and structure is as follows:
1-methylol cyclopropyl acetonitrile is the important medicine intermediate of synthetic Montelukast, Montelukast is for prevention and the long-term treatment of more than 15 years old and 15 years old Adults Asthma, comprise the symptoms of asthma at prevention daytime and night, treat the asthmatic patient to Asprin sensitivity and prevent the bronchoconstriction of exercise induced for alleviating the symptom that allergic rhinitis causes.
In prior art, the synthetic method of 1-methylol cyclopropyl acetonitrile is mainly first cyclization to 1, and 1 cyclopropane dimethanol, then adopts sulfonic acid esterification, then with cyano group replacement, is finally hydrolyzed and obtains this product, and concrete synthetic route reaction equation is as follows:
But, the synthetic method of 1-methylol cyclopropyl acetonitrile in prior art, synthesis yield is low, employing raw materials cost is high, complex process, preparation technology is perfect not, and the 1-methylol cyclopropyl acetonitrile operational path of therefore developing an applicable industrialization has very large social benefit and market efficiency.
Summary of the invention
The technical problem that the present invention mainly solves is to provide a kind of simple to operate, and yield is high, the synthetic 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 synthetic method of 1-methylol cyclopropyl acetonitrile is provided, in turn includes the following steps:
(1), take tribromoneoamyl alcohol compound 1 as starting raw material, in acetylation reagent, carry out acetylize and obtain compound 2:
(2) under the condition that compound 2 exists at zinc powder and catalyzer, reduce to obtain compound 3:
(3) compound 3 first carries out substitution reaction with sodium cyanide, then, in alcoholic solution, carries out ester and be hydrolyzed to obtain 1-methylol cyclopropyl acetonitrile 4 under alkaline condition:
In a preferred embodiment of the present invention, in step (1), described acetylation reagent is the one in acetic acid, diacetyl oxide, Acetyl Chloride 98Min., vinyl acetic monomer or acetic acid pentafluorophenyl esters.
In a preferred embodiment of the present invention, in step (2), the mass ratio of described compound 2, zinc powder and catalyzer is 360-380:60-100:1
In a preferred embodiment of the present invention, in step (2), described temperature of reaction is 60-70 ℃, and the reaction times is 4-6h.
In a preferred embodiment of the present invention, in step (3), described organic solvent is DMF or dimethyl sulfoxide (DMSO).
In a preferred embodiment of the present invention, in step (3), described alcoholic solution is the one in methyl alcohol, ethanol or Virahol.
In a preferred embodiment of the present invention, in step (3), described alkali is sodium carbonate or salt of wormwood.
Compared with prior art, 1-methylol cyclopropyl acetonitrile provided by the invention technological operation is simple, and raw material used is cheap and easy to get, the equal low toxicity of reagent, and labor protection requires low.Produce the three wastes that produce less, with low cost, yield is greatly improved than prior art, is applicable to industrialized production.
Embodiment
A synthetic method for 1-methylol cyclopropyl acetonitrile, in turn includes the following steps:
(1), take tribromoneoamyl alcohol compound 1 as starting raw material, in acetylation reagent, carry out acetylize and obtain compound 2:
(2) under the condition that compound 2 exists at zinc powder and catalyzer, reduce to obtain compound 3:
(3) compound 3 first carries out substitution reaction with sodium cyanide, then, in alcoholic solution, carries out ester and be hydrolyzed to obtain 1-methylol cyclopropyl acetonitrile 4 under alkaline condition:
In the present invention, in step (1), acetylation reagent is the one in acetic acid, diacetyl oxide, Acetyl Chloride 98Min., vinyl acetic monomer or acetic acid pentafluorophenyl esters; In 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 step (3), organic solvent is DMF or dimethyl sulfoxide (DMSO), and alcoholic solution is methyl alcohol, ethanol or Virahol one, and alkali is sodium carbonate or salt of wormwood.
Further explain and describe by the following examples content of the present invention, but the examples of implementation that provide should not be construed as protection domain of the present invention is construed as limiting.Wherein compound 1(tribromoneoamyl alcohol) raw material has commercially available.
Embodiment 1
?tribromo neo-pentyl acetic ester (compound 2)
Aceticanhydride 300g will be added in 1000ml reaction flask, start and stir, drop into again 650g tribromoneoamyl alcohol, open steam and be warming up to 90-110 ℃, stir insulation 2 hours, sampling, detection level reaches 99%, is cooled to 15-30 ℃, is filtered dry, obtain finished product tribromo neo-pentyl acetic ester (compound 2) 754 g, yield 116%.
Embodiment 2
1-(brooethyl) cyclopropyl methyl acetate (compound 3)
Methyl alcohol 460g will be added in 1000ml reaction flask, under stirring, add tribromo neo-pentyl acetic ester 362G, be heated to micro-backflow, temperature 40-70 ℃, then add zinc powder 60g, catalyzer 1g (organic acid and mineral acid), temperature can rise to backflow, maintain back flow reaction at 65-75 ℃, after in 3h, reaction finishes, cool at 20 ℃, suction filtration, 60g methyl alcohol and the washing of 140g ethyl acetate for filter cake, suction filtration liquid, be cooled to below 15 ℃, then splash into ammoniacal liquor 600g, dropwise, add Industrial Salt 50g, stir 0.5h, leave standstill 30min, layering, the very slight color of liquid, note liquid level, ethyl acetate 200ml extracting twice time for water layer, merge organic layer, with twice of 250 grams of salt washing, organic layer reclaims solvent, in 70 ℃, sampling detects, obtain 1-(brooethyl) cyclopropyl methyl acetate (compound 3) 180g, content 82%(GC detects).
Embodiment 3
1-(brooethyl) cyclopropyl methyl acetate (compound 3)
Methyl alcohol 460g will be added in 1000ml reaction flask, under stirring, add tribromo neo-pentyl acetic ester 380g, be heated to micro-backflow, temperature 50-65 ℃, then add 90 zinc powders, catalyzer 1g (organic acid and mineral acid), temperature can rise to backflow, , maintain back flow reaction at 65-75 ℃, after in 3h, reaction finishes, cool at 20 ℃, suction filtration, 60g methyl alcohol and the washing of 140g ethyl acetate for filter cake, suction filtration liquid, be cooled to below 15 ℃, then splash into ammoniacal liquor 600g, dropwise, add Industrial Salt 50g, stir 0.5h, leave standstill 30min, layering, the very slight color of liquid, note liquid level, ethyl acetate 200ml extracting twice time for water layer, merge organic layer, with twice of 250 grams of salt washing, organic layer reclaims solvent, in 70 ℃, sampling detects, obtain 1-(brooethyl) cyclopropyl methyl acetate (compound 3) 180g, content 82%.
Embodiment 4
1-methylol cyclopropyl acetonitrile (compound 4)
In 2000ml reaction flask, add 350g1-(brooethyl) cyclopropyl methyl acetate (compound 3), 330g
30% NaCN, 700gDMF, sodium carbonate 53g, slowly be warming up to 25 ℃, stir 0.5h, rear continue to be heated to 75-80 ℃ insulation 2 hours, detect, after reacting completely, reclaim DMF, reclaim under reduced pressure DMF, controlling 90 ℃ does not have solvent to go out, after add methyl alcohol 940g, sodium carbonate 27g, reflux insulation 6h, detection reaction is complete, rear recovery methyl alcohol (can apply mechanically).Steam to 60 ℃ solvent-free go out, add ethyl acetate 250ml, water 300ml, layering, water layer is extracted with ethyl acetate 2,50m,l*2 twice, reclaim solvent, obtain crude product 210g, content 85 % (GC detection), yield 62%.
Embodiment 5
1-methylol cyclopropyl acetonitrile (compound 4)
In 2000ml reaction flask, add 350g1-(brooethyl) cyclopropyl methyl acetate (compound 3), 330g
30% NaCN, 700g dimethyl sulfoxide (DMSO), salt of wormwood 60g, slowly be warming up to 25 ℃, stir 0.5h, rear continue to be heated to 75-80 ℃ insulation 2 hours, detect, after reacting completely, reclaim dimethyl sulfoxide (DMSO), reclaim under reduced pressure dimethyl sulfoxide (DMSO), controlling 90 ℃ does not have solvent to go out, after add ethanol 1000g, salt of wormwood 27g, reflux insulation 6h, detection reaction is complete, rear recovery methyl alcohol (can apply mechanically).Steam to 60 ℃ solvent-free go out, add ethyl acetate 250ml, water 300ml, layering, water layer is extracted with ethyl acetate 2,50m,l*2 twice, reclaim solvent, must obtain crude product 250g, content 90 % (GC detection), yield 70%.
The foregoing is only embodiments of the invention; not thereby limit the scope of the claims of the present invention; every equivalent structure or conversion of equivalent flow process that utilizes description of the present invention to do; or be directly or indirectly used in other relevant technical fields, be all in like manner included in scope of patent protection of the present invention.
Claims (7)
- The synthetic method of 1.1-methylol cyclopropyl acetonitrile, is characterized in that, in turn includes the following steps:(1), take tribromoneoamyl alcohol compound 1 as starting raw material, in acetylation reagent, carry out acetylize and obtain compound 2:(2) under the condition that compound 2 exists at zinc powder and catalyzer, reduce to obtain compound 3:(3) compound 3 first carries out substitution reaction with prussiate at organic solvent, then under alkaline condition, carries out ester and is hydrolyzed to obtain 1-methylol cyclopropyl acetonitrile 4:。
- 2. according to the synthetic method of the 1-methylol cyclopropyl acetonitrile described in claim 1, it is characterized in that, in step (1), described acetylation reagent is the one in acetic acid, diacetyl oxide, Acetyl Chloride 98Min., vinyl acetic monomer or acetic acid pentafluorophenyl esters.
- 3. according to the synthetic method of the 1-methylol cyclopropyl acetonitrile described in claim 1, it is characterized in that, in step (2), the mass ratio of described compound 2, zinc powder and catalyzer is 360-380:60-100:1.
- 4. according to the synthetic method of the 1-methylol cyclopropyl acetonitrile described in claim 1, it is characterized in that, in step (2), described temperature of reaction is 60-70 ℃, and the reaction times is 4-6h.
- 5. according to the synthetic method of the 1-methylol cyclopropyl acetonitrile described in claim 1, it is characterized in that, in step (3), described organic solvent is N, N-dimethyl formamide or dimethyl sulfoxide (DMSO).
- 6. according to the synthetic method of the 1-methylol cyclopropyl acetonitrile described in claim 1, it is characterized in that, in step (3), described alcoholic solution is the one in methyl alcohol, ethanol or Virahol.
- 7. according to the synthetic method of the 1-methylol cyclopropyl acetonitrile described in claim 1, it is characterized in that, in step (3), described alkali is sodium carbonate 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 |
Applications Claiming Priority (1)
| 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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| CN102633683A CN102633683A (en) | 2012-08-15 |
| CN102633683B true 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) |
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| CN103058884B (en) * | 2012-12-14 | 2014-10-29 | 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 |
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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 (2)
| Title |
|---|
| A.I.DYACHENKO.MECHANISMOFTHEGUSTAVSONREARRANGEMENTREACTIONOFTHETETRAHALONEOPENTANES ESTERS OF TRIBROMONEOPENTANOL AND THEIR CYCLOPROPYL ANALOGS WITH ZINC.《TETRAHEDRON LETTERS》.1979 |
| MECHANISM OF THE GUSTAVSON REARRANGEMENT REACTION OF THE TETRAHALONEOPENTANES, ESTERS OF TRIBROMONEOPENTANOL AND THEIR CYCLOPROPYL ANALOGS WITH ZINC;A.I.DYACHENKO;《TETRAHEDRON LETTERS》;19791231(第2期);全文 * |
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| WO2013149364A1 (en) | 2013-10-10 |
| CN102633683A (en) | 2012-08-15 |
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