CN101209953B - Applied synthesis method for bromocyclobutane - Google Patents
Applied synthesis method for bromocyclobutane Download PDFInfo
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- CN101209953B CN101209953B CN2006101487941A CN200610148794A CN101209953B CN 101209953 B CN101209953 B CN 101209953B CN 2006101487941 A CN2006101487941 A CN 2006101487941A CN 200610148794 A CN200610148794 A CN 200610148794A CN 101209953 B CN101209953 B CN 101209953B
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Abstract
The invention relates to a practical synthesis method of bromomethyl cyclobutane. The method solves the problems of complicated operation and high cost of rectification and refined production in purification separation of the existing technology. The technical proposal is that: the invention adopts cyclopropyl carbinol and hydrobromic acidand, which are easy to be obtained at low-price, as reaction materials; after reaction, a compound comprising bromomethyl cyclobutane, 4-bromo-1-butene and cyclopropylmetyl bromide is obtained, wherein, the bromomethyl cyclobutane is the main product. The compound is mixed one of imine compounds such as bromo-succinimide, chlorosuccinimide, etc.; the reaction materials are stirred under room temperature for 1-2 days to remove 4-bromo-1-butene; then the separated organic layer is distilled at atmospheric pressure or reduced pressure to obtain crude product which is heated to 50-100 DEG C by mixing with high boiling point amines such as dibenzyl amine, N-Benzylmethylamine, benzylamine, benzylamine, etc. and is stirred for 1-5 days to remove the cyclopropylmetyl bromide; then the bromomethyl cyclobutane with high purity is obtained after distilled under normal pressure or reduced pressure.
Description
Technical field: the present invention relates to a kind of method for practical synthesizing of cyclobutyl bromine, obtain the cyclobutyl bromine by rational separation method.
Background technology: in medicine and material field, the cyclobutyl compound all has comparatively widely to be used.The cyclobutyl bromine then is a kind of important source material of synthetic cyclobutyl compound.Existing cyclobutyl bromine synthetic method mainly is the synthetic cyclobutyl bromine of mode that is heated to certain temperature by cyclopropyl-carbinol and hydrogen bromide.In above-mentioned building-up reactions, two by products can appear usually: Cyclopropylmetyl bromide and 4-bromo-1-butylene.At present, mainly be to rely on rectifying [Shaowo Liang, US Patent5905176,1999] remove this two kinds of by products, but, make existing rectificating method exist and separate very difficulty because cyclobutyl bromine (b.p.:108 ℃) and 4-bromo-1-butylene (b.p.:98-100 ℃) and Cyclopropylmetyl bromide (b.p.:105-107 ℃) boiling point are more or less the same, the last handling process complexity, operation is loaded down with trivial details, and the separation costs height is difficult to realize shortcomings such as scale operation.
Summary of the invention: a kind of succinctly cyclobutyl bromine synthesis technique easily of purpose of the present invention exploitation mainly solves existing synthetic method and generates the technical problem that by product is difficult to separate, separation costs is high.
Technical scheme of the present invention: obtain one with cyclopropyl-carbinol and Hydrogen bromide reaction and comprise the cyclobutyl bromine, the mixture of 4-bromo-1-butylene and Cyclopropylmetyl bromide, be primary product wherein with the cyclobutyl bromine, the mix products that reaction obtains mixes with bromo-succinimide or chlorosuccinimide, remove 4-bromo-1-butylene, isolated then organic layer obtains crude product by normal pressure or underpressure distillation, the gained crude product by with the mixed reacting by heating of high boiling point aminated compounds, to remove Cyclopropylmetyl bromide, normal pressure or underpressure distillation obtain purified cyclobutyl bromine then, and the reaction formula of above-mentioned reaction is:
In the synthesis technique of above-mentioned cyclobutyl bromine, cyclopropyl-carbinol and hydrobromic mol ratio are 1 in the first step reaction: (1～2).In above-mentioned reaction, used hydrobromic concentration range is 20%～80%, and the concentration range of optimization is 30%～60%; Temperature of reaction is controlled at 35～120 ℃, and the temperature of reaction of optimization is 40～85 ℃; Reaction times is 2～8 hours, and the reaction times of optimization is 3-6 hour.The product that above-mentioned reaction generates is mixture (a thick product 1), comprises cyclobutyl bromine, 4-bromo-1-butylene and Cyclopropylmetyl bromide, is primary product with the cyclobutyl bromine wherein.
Thick product 1 by with imine compounds such as bromo-succinimide or chlorosuccinimide in a kind of the mixing, stirring at room 1-2 days, isolate organic layer then, organic layer obtains thick product 2 by normal pressure or underpressure distillation, purity can reach 85%～92%, and yield can reach 53%～71%.
Thick product 2 again by with high boiling point aminated compoundss such as dibenzylamine, N-methylbenzylamine, benzylamine, aniline in a kind of the mixing.Thick product 2 and high boiling point aminated compounds mixing post-heating stirred 1-5 days to 50-100 ℃, obtained purified cyclobutyl bromine by normal pressure or underpressure distillation then, and purity can reach 98.5%～100%, and yield can reach 36%～62%.
Beneficial effect of the present invention:
Synthesis technique of the present invention is succinct, and method for purifying and separating is easy.Reduce the separating difficulty that needs rectifying to bring in the document, thereby reduced cost effectively.The present invention can apply to synthetic a large amount of cyclobutyl bromine.
Embodiment:
Embodiment one
With cyclopropyl-carbinol (725g, 10mol) be dissolved in 48% Hydrogen bromide (1.26L, 10.6mol) in.Being heated to 40-50 ℃ stirred 4 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (800g, productive rate: 59%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 69%: 23%: 8%.
With thick product 1 (160g 1.2mol) is dissolved in the 250mL water, add again bromo-succinimide (105g, 0.6mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (108g, productive rate: 68%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 90%: 10%.
(100g, 0.74mol) (40g 0.2mol) mixedly is heated to 65-80 ℃ to will be above thick product 2, stirs 3 days with dibenzylamine.Distill out cyclobutyl bromine (62g, productive rate: 62%) subsequently.The purity of cyclobutyl bromine reaches 99%, and the nucleus magnetic hydrogen spectrum demonstration wherein contains 1% cyclopropyl monobromomethane.
Calculate the overall yield of cyclobutyl bromine: 25% by cyclopropyl-carbinol.
Embodiment two
With cyclopropyl-carbinol (144g, 2mol) be dissolved in 30% Hydrogen bromide (400mL, 2.1mol) in.Being heated to 35-45 ℃ stirred 6 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (153g, productive rate: 56%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 64%: 25%: 11%.
Will be above thick product 1 (160g 1.2mol) is dissolved in the 250mL water, add again chlorosuccinimide (80g, 0.6mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (85g, productive rate: 53%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 92%: 8%.
(57g, 0.42mol) (25g 0.13mol) mixedly is heated to 65-80 ℃ to will be above thick product 2, stirs 2 days with dibenzylamine.Distill out cyclobutyl bromine (26g, productive rate: 46%) subsequently.The purity of cyclobutyl bromine reaches 100%.
Calculate the overall yield of cyclobutyl bromine: 13% by cyclopropyl-carbinol.
Embodiment three
With cyclopropyl-carbinol (216g, 3mol) be dissolved in 60% Hydrogen bromide (320mL, 3.6mol) in.Being heated to 60-80 ℃ stirred 5 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (247g, productive rate: 61%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 54%: 39%: 7%.
Will be above thick product 1 (80g 0.6mol) is dissolved in the 250mL water, add again bromo-succinimide (NBS, 53g, 0.3mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (52g, productive rate: 65%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 88%: 12%.
(50g, 0.37mol) (13g 0.11mol) mixedly is heated to 80-95 ℃ to will be above thick product 2, stirs 2 days with the N-methylbenzylamine.Distill out cyclobutyl bromine (22g, productive rate: 44%) subsequently.The purity of cyclobutyl bromine reaches 98%., the nucleus magnetic hydrogen spectrum demonstration wherein contains 2% cyclopropyl monobromomethane.
Calculate the overall yield of cyclobutyl bromine: 17% by cyclopropyl-carbinol.
Embodiment four
With cyclopropyl-carbinol (217g, 3mol) be dissolved in 40% Hydrogen bromide (420mL, 3.3mol) in.Being heated to 60-70 ℃ stirred 7 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (275g, productive rate: 68%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 59%: 33%: 8%.
Will be above thick product 1 (80g 0.6mol) is dissolved in the 250mL water, add again chlorosuccinimide (40g, 0.3mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (57g, productive rate: 71%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 85%: 15%.
(55g, 0.41mol) (15g 0.13mol) mixedly is heated to 55-70 ℃ to will be above thick product 2, stirs 5 days with the N-methylbenzylamine.Distill out cyclobutyl bromine (20g, productive rate: 36%) subsequently.The purity of cyclobutyl bromine reaches 99%., the nucleus magnetic hydrogen spectrum demonstration wherein contains 1% cyclopropyl monobromomethane.Calculate the overall yield of cyclobutyl bromine: 17% by cyclopropyl-carbinol.
Embodiment five
With cyclopropyl-carbinol (360g, 5mol) be dissolved in 80% Hydrogen bromide (400mL, 5.5mol) in.Being heated to 50-60 ℃ stirred 6 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (410g, productive rate: 60%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 71%: 20%: 9%.
Will be above thick product 1 (80g 0.6mol) is dissolved in the 250mL water, add again bromo-succinimide (NBS, 53g, 0.3mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (46g, productive rate: 58%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 91%: 9%.
(35g, 0.26mol) (8g 0.07mol) mixedly is heated to 60-75 ℃ to will be above thick product 2, stirs 4 days with benzylamine.Distill out cyclobutyl bromine (15g, productive rate: 42%) subsequently.The purity of cyclobutyl bromine reaches 100%.
Calculate the overall yield of cyclobutyl bromine: 15% by cyclopropyl-carbinol.
Embodiment six
With cyclopropyl-carbinol (72g, 1mol) be dissolved in 43% Hydrogen bromide (130mL, 11mol) in.Being heated to 90-100 ℃ stirred 3 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (95g, productive rate: 70%%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 60%: 35%: 5%.
Will be above thick product 1 (80g 0.6mol) is dissolved in the 250mL water, add again chlorosuccinimide (40g, 0.3mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (51g, productive rate: 64%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 90%: 10%.
(30g, 0.22mol) (6g 0.07mol) mixedly is heated to 50-65 ℃ to will be above thick product 2, stirs 5 days with benzylamine.Distill out cyclobutyl bromine (13g, productive rate: 43%) subsequently.The purity of cyclobutyl bromine reaches 100%.
Calculate the overall yield of cyclobutyl bromine: 19% by cyclopropyl-carbinol.
Embodiment seven
With cyclopropyl-carbinol (72g, 1mol) be dissolved in 48% Hydrogen bromide (130L, 11mol) in.Being heated to 40-50 ℃ stirred 4 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (82g, productive rate: 60%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 70%: 23%: 7%.
Will be above thick product 1 (80g 0.6mol) is dissolved in the 250mL water, add again bromo-succinimide (NBS, 53g, 0.3mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (50g, productive rate: 63%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 91%: 9%.
(45g, 0.33mol) (8g 0.086mol) mixedly is heated to 65-80 ℃ to will be above thick product 2, stirs 2 days with aniline.Distill out cyclobutyl bromine (25g, productive rate: 55%) subsequently.The purity of cyclobutyl bromine reaches 98.5%, and the nucleus magnetic hydrogen spectrum demonstration wherein contains 1.5% cyclopropyl monobromomethane.
Calculate the overall yield of cyclobutyl bromine: 21% by cyclopropyl-carbinol.
Embodiment eight
With cyclopropyl-carbinol (144g, 2mol) be dissolved in 55% Hydrogen bromide (250L, 2.1mol) in.Being heated to 55-70 ℃ stirred 8 hours.Reaction finishes, cool to room temperature, and organic layer separates with water layer, and the organic phase distillation is obtained thick product 1 (113g, productive rate: 42%).Thick product 1 comprises the cyclobutyl bromine, and 4-bromo-1-butylene and cyclopropyl monobromomethane, nucleus magnetic hydrogen spectrum show that its content is 65%: 28%: 7%.
Will be above thick product 1 (80g 0.6mol) is dissolved in the 250mL water, add again chlorosuccinimide (40g, 0.3mol).Stirred overnight at room temperature.Subsequently water layer is separated with organic layer, organic layer is distilled out thick product 2 (55g, productive rate: 69%).Thick product 2 comprises cyclobutyl bromine and cyclopropyl monobromomethane, and nucleus magnetic hydrogen spectrum shows that its content is 88%: 12%.
(55g, 0.41mol) (10g 0.11mol) mixedly is heated to 65-80 ℃ to will be above thick product 2, stirs 2 days with aniline.Distill out cyclobutyl bromine (30g, productive rate: 55%) subsequently.The purity of cyclobutyl bromine reaches 98.5%, and the nucleus magnetic hydrogen spectrum demonstration wherein contains 1.5% cyclopropyl monobromomethane.
Calculate the overall yield of cyclobutyl bromine: 16% by cyclopropyl-carbinol.
Claims (3)
1. the synthetic method of a cyclobutyl bromine, obtain one with cyclopropyl-carbinol and Hydrogen bromide reaction and comprise the cyclobutyl bromine, the mixture of 4-bromo-1-butylene and Cyclopropylmetyl bromide, be primary product wherein with the cyclobutyl bromine, it is characterized in that, the mix products that reaction obtains mixes with bromo-succinimide or chlorosuccinimide, remove 4-bromo-1-butylene, isolated then organic layer obtains crude product by normal pressure or underpressure distillation, the gained crude product by with dibenzylamine, the N-methylbenzylamine, a kind of mixed reacting by heating in benzylamine or the aniline, to remove Cyclopropylmetyl bromide, normal pressure or underpressure distillation obtain purity and reach 98.5%～100% cyclobutyl bromine then, and the reaction formula of above-mentioned reaction is:
2. the synthetic method of a kind of cyclobutyl bromine according to claim 1 is characterized in that, the reaction of removing 4-bromo-1-butylene needs stirring at room 1～2 day.
3. the synthetic method of a kind of cyclobutyl bromine according to claim 1 and 2 is characterized in that, a kind of temperature of reaction in crude product and dibenzylamine, N-methylbenzylamine, benzylamine or the aniline is 50～100 ℃, stirs 1～5 day.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5905176A (en) * | 1998-08-28 | 1999-05-18 | Eastman Chemical Company | Process for the production of cyclobutyl halides |
| WO2000012453A1 (en) * | 1998-08-28 | 2000-03-09 | Eastman Chemical Company | Process for the production of cyclopropylmethyl halides |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5905176A (en) * | 1998-08-28 | 1999-05-18 | Eastman Chemical Company | Process for the production of cyclobutyl halides |
| WO2000012453A1 (en) * | 1998-08-28 | 2000-03-09 | Eastman Chemical Company | Process for the production of cyclopropylmethyl halides |
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