CN1865218A - Method for making 6-bromocaproic acid - Google Patents

Abstract

The invention belongs to the technical field of organic compound preparation, in particular to a preparation method of 6-bromohexanoic acid. In the method, the dry hydrogen bromide gas is directly passed into the organic solvent containing ε-caprolactone, and the ε-caprolactone is easy to undergo a ring-opening reaction, and the corresponding 6-bromohexanoic acid is generated in a high yield. Since 6-bromohexanoic acid is hardly soluble in alkanes, naphthenes and aromatic hydrocarbon solvents, cooling to below 30°C, which is lower than the melting point of 6-bromohexanoic acid, causes 6-bromohexanoic acid to form crystals and precipitate. Then, a high-purity 6-bromohexanoic acid solid is obtained by separating through a filtration process. The method has simple process, is easy to form large-scale production, has wide application prospects and good economic benefits.

Description

The preparation method of 6-bromohexanoic acid

technical field

The invention belongs to the technical field of organic compounds, and in particular relates to a preparation method of 6-bromohexanoic acid.

Background of the invention

6-bromohexanoic acid is a very important pharmaceutical intermediate, widely used in the preparation of medicine and veterinary medicine. At present, there is no domestic manufacturer producing it. The reason is that it is difficult to obtain high-purity products due to insufficient technology. Since the melting point of 6-bromohexanoic acid is low, that is, the melting point is 33-35°C, it is not easy to form crystals, and 6-bromohexanoic acid is generally obtained by distillation. But its boiling point is higher (bp 165-170/20mmHg), so it is not easy to distill. When the distillation temperature is high, 6-bromohexanoic acid is easy to debrominate and decompose, so it is difficult to obtain high-purity 6-bromohexanoic acid products.

G.A Olah (Synthesis, 1982, Page 963) reported that boron tribromide and ε-caprolactone were reacted in dichloromethane solvent, and then further hydrolyzed to generate the corresponding 6-bromohexanoic acid with a yield of 86%.

People such as S.Sankaranaryanan (Tetrahedron, Asymmetry, 1988, 9, page 1345) reported using cyclohexanone as a raw material by hydrogen peroxide oxidation reaction, and then added hydrobromic acid aqueous solution to synthesize corresponding 6-bromohexanoic acid, and the total yield was 48%.

S.Nanda (Tetrahedron, Asymmetry, 2003, 14, page 1799) et al. report that dry hydrogen bromide gas is directly passed into 1,6-hexanediol to generate 6-bromo-n-hexanol. Chromium trioxide is then oxidized to give the corresponding 6-bromohexanoic acid.

S.Wolfe (Can.J.Chem., 2003, 81, page 937) et al. reported that the acetic acid solution of hydrobromic acid reacted with ε-caprolactone to generate the corresponding 6-bromohexanoic acid with a yield of 95%. .

Since Olah's synthetic method needs to use equimolar boron tribromide, it needs to consume a large amount of expensive boron tribromide raw materials, resulting in high production costs. And in the production process, a large amount of boron compounds are produced. In the production process, the post-treatment of a large amount of industrial waste boron compounds discharged is quite difficult, so this method has no industrial use value.

The method of Sankaranaryanan uses a large amount of hydrogen peroxide as an oxidizing agent, resulting in high production costs. Because a large amount of hydrogen peroxide is used as an oxidizing agent in the reaction process, organic peroxides tend to remain in the crude product. As we all know, organic peroxides are explosive and dangerous substances. In the crude product distillation process, if the peroxides remain, there is a danger of explosion. This method is difficult for industrial production.

The method of S.Nandan uses chromium trioxide as an oxidizing agent, which requires a large amount of expensive chromium trioxide to be consumed, resulting in high production costs. And in the production process, a large amount of waste of heavy metal chromium compounds is produced. However, the post-treatment of a large amount of industrial waste heavy metal chromium compounds discharged is quite difficult, so this method has no industrial use value.

The method of S.Wolfe uses the acetic acid solution of expensive hydrobromic acid, which causes the production cost to be too high. Therefore, there are also technical difficulties in this method.

Contents of the invention

The purpose of the present invention is to propose a kind of technique simple, the preparation method of the high-purity 6-bromohexanoic acid that is easy to large-scale production.

The preparation method of the high-purity 6-bromohexanoic acid that the present invention proposes, its steps are as follows: the hydrogen bromide gas that is dried is passed directly in the organic solvent containing ε-caprolactone, and the usage amount of the hydrogen bromide gas that is dried is ε - Caprolactone 1.0-2.0 times (molar ratio); stirring, a ring-opening reaction occurs, the reaction temperature is 0 ° C ~ 100 ° C, and high-purity 6-bromohexanoic acid is generated.

The organic solvents used are alkanes, cycloalkanes, halogenated alkanes, halogenated cycloalkanes, aromatic hydrocarbons or halogenated aromatic hydrocarbon compounds, or other organic solvents, such as butane, pentane, hexane , heptane, octane, nonane, decane, undecane, dodecane and other alkane compounds; cyclopentane, cyclohexane, cycloheptane, cyclooctane and other alkane compounds; benzene, Toluene, ethylbenzene, cumene, tert-butylbenzene, xylene and other aromatic hydrocarbons; fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, methylene chloride, three Chloromethane, carbon tetrachloride and other halogenated alkanes, carbon disulfide, diethyl ether, propyl ether, butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, anisole, diphenyl ether Ether compounds such as cyanide, cyanide, cyanide, cyanide, nitrobenzene, dimethyl sulfoxide, etc.

In the present invention, when the organic solvent used is alkanes, cycloalkanes or aromatic hydrocarbons, because 6-bromohexanoic acid is insoluble in alkanes, cycloalkanes and aromatic hydrocarbons solvents, after the reaction finishes, cool to 30 Below °C, 6-bromohexanoic acid crystallized and precipitated. Then, it is separated by filtration process to obtain high-purity 6-bromohexanoic acid solid.

In the present invention, when the organic solvent used is halogenated cycloalkane and halogenated aromatic hydrocarbon solvent, because 6-bromohexanoic acid is insoluble in alkane, cycloalkane and aromatic hydrocarbon solvent, after the reaction finishes, Through the distillation process, distill off the used solvent, then add alkanes, cycloalkanes and aromatic hydrocarbons, cool to below 30°C, and make 6-bromohexanoic acid form crystal precipitation; then, separate and obtain high-purity 6- Bromohexanoic Acid Solid.

The method of the invention has simple process, is easy to form large-scale production, and has wide application prospects.

Detailed ways

The present invention is further specifically described below by way of examples.

Embodiment 1: in the three-necked bottle of 500 milliliters, install thermometer, stirrer, add raw material ε-caprolactone (1 mole, 114 grams), normal hexane (200 milliliters), start to stir then. Dry hydrogen bromide gas (1.1 mol, 89 g) was introduced, and the reaction temperature was controlled at 20°C to 30°C. After completion of the hydrogen bromide gas sparging, the mixture was stirred at this temperature for an additional 6 hours. Then cool to 0~10°C and stir for 3 hours, a large amount of crystals are formed. After filtration, a light yellow solid of 6-bromohexanoic acid was obtained, weighing 183 g, with a yield of 95% and a purity of 99.2% (gas chromatography analysis).

Embodiment 2: in the three-necked bottle of 500 milliliters, install thermometer, stirrer, add raw material ε-caprolactone (1 mole, 114 grams), hexanaphthene (150 milliliters), start to stir then. Dry hydrogen bromide gas (1.2 mol, 97 g) was introduced, and the reaction temperature was controlled at 30°C~40°C. After completion of the hydrogen bromide gas sparging, the mixture was stirred at this temperature for an additional 5 hours. Then cool to 5~15°C and stir for 2 hours, a large amount of crystals are formed. After filtration, a light yellow solid of 6-bromohexanoic acid was obtained, weighing 180 g, with a yield of 92% and a purity of 99.4% (gas chromatography analysis).

Embodiment 3: in the three-necked flask of 500 milliliters, install thermometer, stirrer, add raw material epsilon-caprolactone (1 mole, 114 grams), toluene (200 milliliters), start to stir then. Dry hydrogen bromide gas (1.3 mol, 105 g) was introduced, and the reaction temperature was controlled at 40°C~50°C. After completion of the hydrogen bromide gas sparging, it was stirred at this temperature for an additional 4 hours. Then cool to 10~20°C and stir for 4 hours, a large amount of crystals are formed. After filtration, a light yellow solid of 6-bromohexanoic acid was obtained, weighing 185 g, with a yield of 95% and a purity of 99.1% (gas chromatography analysis).

Embodiment 4: in the three-necked flask of 500 milliliters, install thermometer, stirrer, add raw material ε-caprolactone (1 mole, 114 grams), methylene dichloride (200 milliliters), start to stir then. Dry hydrogen bromide gas (1.8 mol, 146 g) was introduced, and the reaction temperature was controlled at 0°C~20°C. After completion of the hydrogen bromide gas sparging, stirring was continued at this temperature for 7 hours. Then dichloromethane was distilled off under normal pressure, then n-hexane (200 ml) was added, cooled to -5~10°C, stirred for 5 hours, a large amount of crystals were formed. After filtration, a light yellow solid of 6-bromohexanoic acid was obtained, weighing 181 g, with a yield of 93% and a purity of 99.2% (gas chromatography analysis).

Claims (5)

1, a kind of preparation method of 6-bromocaproic acid is characterized in that direct feeding of exsiccant bromize hydrogen gas contained in the organic solvent of 6-caprolactone, and exsiccant bromize hydrogen gas and 6-caprolactone mol ratio are 1.1-2.0 times; Stir, ring-opening reaction takes place, temperature of reaction is 0 ℃ ~ 100 ℃, generates high purity 6-bromocaproic acid.

2, preparation method according to claim 1 is characterized in that employed organic solvent is alkanes, cycloalkane, haloalkane hydro carbons, halo cycloalkane, arene, halo arene, ethers or other organic solvents.

3, preparation method according to claim 2 is characterized in that alkane derivative is butane, pentane, hexane, heptane, octane, nonane, certain herbaceous plants with big flowers alkane, 11 charcoal alkane or 12 charcoal alkane; The cycloalkane compound is pentamethylene, hexanaphthene, suberane or cyclooctane; Compound fragrant hydrocarbon is benzene, toluene, ethylbenzene, isopropyl benzene, trimethylphenylmethane or dimethylbenzene; The halo compound fragrant hydrocarbon is fluorobenzene, chlorobenzene, bromobenzene, iodobenzene or dichlorobenzene; The halogenated alkane compounds is methylene dichloride, trichloromethane or tetrachloro charcoal; Ether compound is curing charcoal, ether, propyl ether, butyl ether, methyl tertiary butyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl-phenoxide or phenyl ether; Other organic solvent is second cyanogen, third cyanogen, fourth cyanogen, phenethyl cyanogen, oil of mirbane or methyl-sulphoxide.

4, preparation method according to claim 1 is characterized in that reaction is cooled to below 30 ℃ after finishing, and makes the 6-bromocaproic acid form crystal, obtains precipitation when the organic solvent that uses during as alkanes, cycloalkane and arene; Then, obtain high purity 6-bromocaproic acid solid by the filtration process separation.

5, preparation method according to claim 1, it is characterized in that when the organic solvent that uses during as halo cycloalkane and halogenated aromatic varsol, after reaction finishes, pass through distil process, distill out employed solvent, add alkanes then, cycloalkane and arene, be cooled to below 30 ℃, make the 6-bromocaproic acid form crystal settling; Then, obtain high purity 6-bromocaproic acid solid by the filtration process separation.