Preparation method of alkoxy bromoethane

Abstract

The invention provides a preparation method of alkoxy bromoethane, which comprises the following steps: with alkoxy ethanol and phosphorus tribromide as raw materials, carrying out reaction in the presence of a catalyst and a solvent or without the solvent, and carrying out after-treatment to prepare the alkoxy bromoethane, the catalyst being selected from triethylamine, tripropylamine or pyridine. The preparation method disclosed by the invention is simple in process operation, can realize the total yield of 68-78% and the content of the obtained final product of 98% or above under optimal conditions, does not need special rectification for post-treatment of the product, has the advantages of high yield, low cost and easiness in industrial production, does not need hydrogen bromide gas, does not discharge high-concentration waste liquid and waste gas, is environment-friendly and more friendly, and is suitable for industrial production. And the method has a very high application prospect. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis and relates to a method for preparing an important intermediate alkoxy bromoethane for medicine or pesticide. Technical Background

[0002] Alkoxy ethyl bromide is an important pharmaceutical or pesticide intermediate, among which 2-bromoethyl methyl ether (or 2-methoxy ethyl bromide) is an important intermediate in the pharmaceutical industry, such as the intermediate of the anticancer drug erlotinib; 2-bromoethyl methyl ether, 2-bromoethyl ethyl ether, and 2-bromoethyl propyl ether are also important intermediates of herbicides such as pethodiamide, dimethochlor, and pretilachlor in the pesticide industry. Chinese invention patent CN 115925576B shows that alkoxy ethyl bromide is also an important intermediate of new pesticides.

[0003] The traditional preparation method of alkoxy bromoethane usually uses alkoxy ethanol to directly react with phosphorus tribromide. The preparation process is simple but the yield is low (generally only about 30%), there are many impurities, it is difficult to obtain a high-content finished product, and the cost is high. The reaction formula is as follows:

[0004]

[0005] Usually, R is a C1-C5 alkyl group, and methyl, ethyl, n-propyl, and isopropyl are used in relatively large amounts.

[0006] In the prior art, alkoxyethanol and liquid bromine are also used in the presence of triphenylphosphine or triphenyl phosphite to obtain alkoxybromoethane with a higher yield. However, triphenylphosphine or triphenyl phosphite cannot be recycled, so the preparation method is too costly and has no industrial prospects.

[0007] Chinese invention patent CN 101671238B discloses a method for preparing 2-bromoethyl methyl ether, wherein 2-methoxyethanol is used as a raw material, and firstly reacts with metaboric anhydride in the presence of a solvent to obtain tri-(2-methoxy-1-yl)-ethyl metaborate, and then the intermediate tri-(2-methoxy-1-yl)-ethyl metaborate is treated with hydrogen bromide to obtain the target product 2-bromoethyl methyl ether. The invention has few side reactions, and the content and yield of the product are improved. However, the disadvantage is that the process requires the use of hydrogen bromide gas, and the industrial preparation and operation are relatively troublesome, and the pollution and corrosion are serious. The main reaction formula is as follows:

[0008] Summary of the invention

[0009] In view of the shortcomings of the prior art, the present invention hopes to provide a method for preparing alkoxybromoethane with high content and high yield by optimizing the preparation process route and improving the reaction conditions. The method has the characteristics of simple operation and low process cost, and does not require the use of environmentally unfriendly raw materials such as hydrogen bromide gas, so it can meet the needs of modern industrial production.

[0010] The invention provides a method for preparing alkoxy bromoethane. Alkoxyethanol and phosphorus tribromide are used as raw materials, and alkoxy bromoethane is reacted in the presence of a catalyst and a solvent, or without the participation of a solvent, and the alkoxy bromoethane is obtained through post-treatment.

[0011] The reaction formula is as follows:

[0012]

[0013] Among them, R is a C1-C5 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, or an isopropyl group.

[0014] In the present invention, the main raw materials alkoxyethanol and phosphorus tribromide have been industrialized in the market, with sufficient market supply and low price. In the preparation method of the present invention, the main raw materials and auxiliary raw materials are usually industrial grade raw materials, and the content is generally ≥99%.

[0015] In the present invention, the solvent is an inert solvent, usually selected from dichloromethane, chloroform, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, etc.; toluene, ethylbenzene, p-xylene, m-xylene, o-xylene, mixed xylene, mesitylene, etc.; cyclohexane, methylcyclohexane, etc.; or selected from their mixtures. Among them, the preferred solvent is toluene, ethylbenzene, p-xylene, m-xylene, o-xylene, mixed xylene, mesitylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene, etc. When the reaction is carried out in the presence of a solvent, a mixture of the product (alkoxy bromoethane) and the solvent is obtained after the reaction is completed. In order to avoid the trouble of separating the product from the solvent, the above preparation method can also be carried out under solvent-free conditions, and the product is obtained after the reaction is completed, and a relatively satisfactory effect can also be obtained. In the presence of a solvent, the product yield is further improved compared with the solvent-free condition, so it is preferably carried out under the condition of solvent presence.

[0016] The amount of solvent used is usually 0.5-10 times the weight of the alkoxyethanol, preferably 0.5-5 times. Too little solvent will lead to a lower yield of the product, while excessive use of solvent will not bring more benefits and will cause waste.

[0017] In the present invention, the catalyst is selected from triethylamine, tripropylamine, tributylamine, pyridine, N-methylmorpholine, N-methylpyrrolidone, 4-dimethylaminopyridine or triethylenediamine, etc., and the preferred catalyst is triethylamine, tripropylamine or pyridine to obtain the best total molar yield. The amount of the catalyst is usually 0.1%-20% of the weight of the alkoxyethanol, preferably 0.1%-10%, and excessive use has no benefit and is uneconomical. Usually, in the presence of a solvent and when triethylamine, tripropylamine or pyridine is used as a catalyst, the total molar yield is usually not less than 76.5%. If in the presence of a solvent and when other catalysts are used, the total molar yield can also achieve 61.2% to 63.9%.

[0018] In the present invention, the molar amount of phosphorus tribromide is 30%-100% of the amount of alkoxyethanol, preferably 30%-50%. Phosphorus tribromide is added to alkoxyethanol by dripping to avoid rapid heat release of the reaction system. Those skilled in the art can control the phosphorus tribromide dripping rate according to the actual feed amount so that the temperature of the reaction system is controlled at 20-120°C, preferably 20-80°C. The dropping time is generally 1-5 hours. If the dripping speed is too fast, the heat release of the reaction system is obvious, so the phosphorus tribromide can be dripped in 1-3 hours by adjusting the dripping speed. In the present invention, the reaction temperature is 20-120°C, preferably 20-80°C. The total reaction time is 2-12 hours, preferably 2-8 hours.

[0019] In the present invention, the post-treatment after the reaction is completed refers to the separation of the solvent and the product (alkoxy bromoethane) by direct vacuum distillation. Wherein, if a low boiling point solvent is used (in the present invention, a low boiling point solvent is generally understood as a solvent with a boiling point lower than 150°C, such as toluene, xylene, etc.), the vacuum distillation temperature is controlled at 80-110°C; if a high boiling point solvent is used (in the present invention, a solvent with a boiling point higher than or equal to 150°C is understood as a high boiling point solvent, such as mesitylene, etc.), the distillation temperature and vacuum degree can be increased accordingly. Those skilled in the art can also select appropriate distillation conditions according to the specific solvent used in the reaction system. The target product or the mixture of the target product and the solvent obtained by direct distillation is then washed and layered, and dried to obtain the target product or the mixture of the target product and the solvent. At this time, the total yield can reach 68-78% based on the alkoxyethanol raw material. When the distillation results in a mixture of the target product and the solvent, the mixture can be directly applied to other synthetic reactions, or a high-boiling-point solvent can be further used to obtain a high-content alkoxyethyl bromide product through simple redistillation. In this case, the alkoxyethyl bromide content is greater than 98%, and the product can be directly applied to various other synthetic reactions.

[0020] The residue after distillation is mainly a mixture of phosphorous acid and some phosphite esters. It is neutralized with potassium hydroxide and de-volatile components are removed by vacuum distillation to obtain a high-content potassium phosphite byproduct. These byproducts can be diluted into various concentrations and directly used as crop fertilizers, which is an environmentally friendly fertilizer.

[0021] Under the preferred reaction conditions, the preparation method of the present invention can achieve a reaction conversion rate of up to 78%, and the post-processing steps of the obtained product are simple. Only ordinary distillation operation is required to obtain a product with a content of more than 98% or a mixture of the product and a solvent. No special distillation and purification are required, and the product can be directly applied to other subsequent synthetic reactions.

[0022] Compared with the prior art, the preparation method of the present invention is simple to operate, has mild chemical reaction conditions, is simple to post-process, does not require special distillation, can achieve a total yield of 68-78% under the conditions of the presence of a solvent and the use of a preferred catalyst, and obtains a final product (alkoxy bromoethane) with a content of more than 98%, or obtains a mixture of the final product and a small amount of solvent. The preparation method of the present invention has low cost, is easy to industrialize, and does not require the use of hydrogen bromide gas, does not require the discharge of high-concentration waste liquid (for example, no hydrogen bromide gas is generated), is environmentally friendly and economical, and has a high application prospect.

[0023] In the present invention, operations such as distillation, vacuum distillation, and layering involved in the preparation method are conventional operations and are basic unit operations for general chemists, and are not described in detail in the present invention. For details, see the synthesis examples. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described below through specific implementation methods. Those skilled in the art should understand that the embodiments are only used to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0025] The raw materials described in the synthesis examples of the present invention are generally purchased from the market unless otherwise specified, and the usual content specifications are industrial specifications or reagent grade specifications; the content specification of common solvents is ≥99%, and the above contents are not precisely calibrated.

[0026] Unless otherwise specified, the percentage concentrations described in the synthesis examples are weight percentage concentrations, and the GC content data are area-normalized contents without precise calibration.

[0027] Synthesis Example 1

[0028] In a 500ml four-mouth glass reaction bottle, ethylene glycol monomethyl ether 100g (1.31 moles) and triethylamine 5.0g were added, the temperature was controlled at 25 ℃-35 ℃, phosphorus tribromide 120g (0.44 mole) was added in 2 hours, and the reaction was kept at 45 ℃-55 ℃ for 3 hours. After the insulation was completed, the material was transferred to a 1000ml rotary evaporator for rotary distillation, and the product was distilled out under reduced pressure of 0.095Mpa, and the temperature was distilled to 105 ℃ to finish, and a crude product 130g was obtained. The crude product 130g was washed twice with 50ml water, and the oil layer was obtained by layering. After MgSO4 drying and filtering, 2-bromoethyl methyl ether (or 2-methoxy bromoethane) product 125g was obtained, GC content 98%, and molar total yield was 68.7% with ethylene glycol monomethyl ether.

[0029] Confirmed by H NMR spectrum and mass spectrum, H NMR spectrum uses BrukerAV-400spectrometer (400MHz), TMS is used as internal standard, and the solvent is CDCl3 (unless otherwise specified, the same below); mass spectrum is measured using Shimadzu QP2010 UTRAL gas chromatography-mass spectrometer (unless otherwise specified, the same below). Add 50ml of water to the distillation residue, neutralize with potassium hydroxide to pH 7.5-8.0, remove water under reduced pressure, and cool to obtain about 87g of potassium phosphite as a white solid. H NMR spectrum and mass spectrum data of 2-bromoethyl methyl ether are as follows:

[0030] 1 H NMR (400MHz, CDCl3) δ (ppm): 3.64 (t, J = 8.0 Hz, 2H, OCH2), 3.40 (t, J = 8.0 Hz, 2H, BrCH2), 3.33 (s, 3H, OCH3).

[0031] MS138(M + ),140(M+2).

[0032] Synthesis Example 2

[0033] In the four-mouth glass reaction bottle of 500ml, drop into ethylene glycol monomethyl ether 100g (1.31 moles), triethylamine 5.0g and toluene 350g, temperature is controlled at 25 ℃-35 ℃, in 2 hours, drip into phosphorus tribromide 120g (0.44 mole), drip off and be warming up to 45 ℃-55 ℃ and insulation reaction 3 hours.After insulation is finished, material transfer is to 1000ml rotary evaporator and revolves to evaporate, and under reduced pressure 0.095Mpa condition, product is distilled out, and temperature is distilled to 105 ℃ and finishes, and obtains the mixture 500g of toluene of crude product.Through 50ml water washing twice, again through MgSO4 after drying and filtering, obtain the toluene solution of 489g 2-bromoethyl methyl ether, GC content about 29.1%, and molar total yield is converted 78.1% in ethylene glycol monomethyl ether.

[0034] As can be seen here, in the presence of solvent toluene, reaction obtains the toluene solution of 2-bromoethyl methyl ether, these toluene can be removed by conventional distillation operation, and 2-bromoethyl methyl ether and toluene can also be used as the raw material of other building-up reactions in downstream together.Compared with solvent-free, the molar total yield (in ethylene glycol monomethyl ether) of the present embodiment obtains further improvement.

[0035] Synthesis Comparative Example 1

[0036] In a 500ml four-mouth glass reaction bottle, ethylene glycol monomethyl ether 100g (1.31 moles) was dropped, without any catalyst, the system temperature was controlled at 25 ℃-35 ℃, phosphorus tribromide 120g (0.44 mole) was dripped in 2 hours, and the reaction was incubated for 3 hours at 45 ℃-55 ℃ after dripping. After insulation was completed, the material was transferred to a 1000ml rotary evaporator for rotary evaporation, and the product was distilled out under a negative pressure of 0.095Mpa, and distilled to 105 ℃ to finish, and a crude product 71g was obtained. The crude product 71g was washed twice with 25ml water, and the oil layer was obtained by layering. After MgSO4 drying and filtration, 2-bromoethyl methyl ether product 55g was obtained, and GC content 92.2% was recorded, and the total molar yield was 27.8% in terms of ethylene glycol monomethyl ether.

[0037] It can be seen that in the absence of a catalyst, the total molar yield of the reaction decreases significantly.

[0038] Synthesis Example 3

[0039] In the four-mouth glass reaction bottle of 500ml, drop into ethylene glycol monomethyl ether 100g (1.31 moles), pyridine 5.0g and mesitylene 350g, system temperature is controlled at 25 ℃-35 ℃, in 2 hours, drip phosphorus tribromide 120g (0.44 mole), drip off and be warming up to 45 ℃-55 ℃ insulation reaction 3 hours.After insulation is completed, material transfer is to 1000ml rotary evaporator and revolves to evaporate, distills under negative pressure 0.085Mpa condition first, and then high vacuum distillation is divided into two sections to receive product fraction and solvent fraction.Obtain fore-cut crude product 170g, through 50ml water washing twice, then through MgSO4 drying and filtering, obtain 160g product containing a small amount of mesitylene, GC content 92.2% (all the other components are solvent), then through conventional distillation redistillation once, obtain 143g product, record GC content 98.3%, through nuclear magnetic hydrogen spectrum and mass spectrum confirmation, data are consistent with synthetic embodiment 1 sample data. The total molar yield is 77.1% based on ethylene glycol monomethyl ether. The rear fraction is mainly the solvent mesitylene.

[0040] Add 50 ml of water to the distillation residue, neutralize with potassium hydroxide to pH 7.5-8.0, remove water under reduced pressure, and cool to obtain 86 g of potassium phosphite as a white solid.

[0041] Synthesis Example 4

[0042] The procedure of Synthesis Example 3 was followed, except that 120 g (0.44 mole) of phosphorus tribromide was replaced by 145 g (0.54 mole) of phosphorus tribromide. Other operations were the same, and 142 g of 2-bromoethyl methyl ether was obtained. The GC content was 98.2%, and the total molar yield was 76.5% based on ethylene glycol monomethyl ether.

[0043] Synthesis Example 5

[0044] In a 500ml four-necked glass reaction bottle, 118g (1.31 mol) of ethylene glycol monoethyl ether, 6.0g of pyridine and 350g of mesitylene were added, the temperature of the reaction system was controlled at 25°C-35°C, 120g (0.44 mol) of phosphorus tribromide was added dropwise within 2 hours, and the temperature was raised to 45°C-55°C for 3 hours of insulation reaction. After insulation, the material was transferred to a 1000ml rotary evaporator for rotary evaporation, first distilled at a negative pressure of 0.085Mpa, and then distilled under high vacuum in two stages to receive the product fraction and the solvent fraction. 178 g of the crude product of the front fraction was obtained, which was washed twice with 50 ml of water, dried and filtered over MgSO4 to obtain 168 g of the product with a GC content of 93.3% (the remaining components were solvents), and then redistilled once by conventional distillation to obtain 158 g of the product 2-bromoethyl ethyl ether with a GC content of 98.2%. The total molar yield was 77.3% based on ethylene glycol monoethyl ether, as confirmed by H NMR and mass spectrometry.

[0045] The H NMR spectrum and mass spectrum data are as follows:

[0046] 1 HNMR (400MHz, CDCl3) δ (ppm): 3.70 (t, J = 8.0Hz, 2H, OCH2), 3.51 (q, J = 8.0Hz, 2H, CH3CH2), 3.42 (t, J = 8.0Hz, 2H, BrCH2), 1.18 (s, 3H, CH2CH3).

[0047] MS152(M + ),154(M+2).

[0048] Synthesis Example 5

[0049] The operation of Synthesis Example 3 was followed, except that 350 g of mesitylene was replaced by 350 g of recycled mesitylene obtained by the operation of Synthesis Example 3. Other operations were similar, and finally 144 g of product was obtained with a GC content of 98% and a total molar yield of 77.5% based on ethylene glycol monomethyl ether.

[0050] Synthesis Example 6

[0051] The method of Synthesis Example 2 was followed, except that 5.0 g of the catalyst triethylamine was replaced by 5.0 g of tripropylamine, and other operations were the same, and similar results were obtained.

[0052] The synthesis of other alkoxyethyl bromides can be carried out by methods similar to those described in the synthesis examples.

[0053] Synthesis Example 7

[0054] The operation of Synthesis Example 3 was followed, except that 350 g of mesitylene was replaced by 350 g of o-dichlorobenzene. Other operations were similar, and similar results were obtained.

[0055] Synthesis Comparative Example 2

[0056] The operation of Synthesis Example 3 was followed, except that 5.0 g of catalyst pyridine was replaced by 5.0 g of N-methylmorpholine. Other operations were similar, and finally 120 g of product was obtained with a GC content of 97.1% and a total molar yield of 63.9% based on ethylene glycol monomethyl ether.

[0057] Synthesis Comparative Example 3

[0058] The operation of Synthesis Example 3 was followed, except that 5.0 g of the catalyst pyridine was replaced by 5.0 g of 4-dimethylaminopyridine. Other operations were similar, and finally 115 g of the product was obtained with a GC content of 97.2% and a total molar yield of 61.2% based on ethylene glycol monomethyl ether.

[0059] It can be seen that the use of other catalysts (including tributylamine, N-methylmorpholine, N-methylpyrrolidone, 4-dimethylaminopyridine or triethylenediamine) can also obtain a good yield, but it is lower than the effect obtained by using the preferred catalyst, but it will not reduce the content of the obtained product.

[0060] Application Synthesis Examples 1-6

[0061] The alkoxy bromoethane products obtained according to the methods of Synthesis Example 1, Synthesis Example 2 and Synthesis Example 3 were used to replace the synthesized product of the present invention in equal amounts according to the synthesis methods of Synthesis Example 10 and Synthesis Example 13 in Chinese Patent CN 115974717A, respectively, and the results obtained were the same, with no significant difference.

[0062] The above results show that under the catalyst and process conditions of the present invention, pyridine, triethylamine and tripropylamine catalysts have high reaction activity, and in the presence of a solvent, the total yield of the reaction is greatly improved, in order to reduce costs and reduce the three wastes. The process of the present invention is simple to operate and has high industrial application value.

[0063] The present invention illustrates a novel method for preparing alkoxy bromoethane through the above representative embodiments, but the present invention is not limited to the above embodiments, nor does it mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials in the process of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing alkoxy bromoethane, characterized in that Alkoxyethanol and phosphorus tribromide are used as raw materials, react in the presence of a catalyst and a solvent or without a solvent, and are prepared by post-treatment; the reaction formula is as follows: Wherein, R is methyl, ethyl, n-propyl or isopropyl; The solvent is one or more solvents selected from toluene, ethylbenzene, p-xylene, m-xylene, o-xylene, mixed xylenes, mesitylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and p-dichlorobenzene; The catalyst is selected from triethylamine, tripropylamine or pyridine.

2. The method for preparing alkoxy bromoethane according to claim 1, characterized in that The method is prepared by taking alkoxyethanol and phosphorus tribromide as raw materials, reacting in the presence of a catalyst and a solvent, and post-treating the reaction mixture; wherein R is methyl or ethyl.

3. The method for preparing alkoxy bromoethane according to claim 1, 2, characterized in that The reaction temperature is 20-120°C.

4. The method for preparing alkoxy bromoethane according to claim 1, characterized in that The amount of the solvent used is 0.5-10 times the weight of the alkoxyethanol.

5. The method for preparing alkoxy bromoethane according to claim 1 or 2, characterized in that The amount of the catalyst used is 0.1%-20% by weight of the alkoxyethanol.

6. The method for preparing alkoxy bromoethane according to claim 1 or 2, characterized in that The molar amount of phosphorus tribromide used is 30%-50% of the amount of alkoxyethanol used.

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