Synthesis method of tetrabutylammonium bromide

Abstract

The invention belongs to the technical field of synthesis of chemical intermediates, and particularly relates to a synthesis method of tetrabutylammonium bromide, which comprises the following steps: filling a tubular fixed bed reactor with a molecular sieve as a catalyst; 1-bromobutane and tri-n-butylamine are mixed to serve as a raw material solution, the raw material solution enters a tubular fixed bed reactor, and a reaction is carried out under the action of a catalyst; carrying out reduced pressure distillation on a reaction product to recover 1-bromobutane, so as to obtain a tetrabutylammonium bromide crude product; and recrystallizing the crude tetrabutylammonium bromide product to obtain the tetrabutylammonium bromide. By adopting the method disclosed by the invention, the use of solvents can be reduced, the generation of byproducts is reduced, and the reaction yield is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical intermediate synthesis, and particularly relates to a method for synthesizing tetrabutylammonium bromide. Background Art

[0002] Tetrabutylammonium bromide, with the molecular formula of C16H36BrN, is a white crystal or powder in its pure form. It is a common organic salt used in the synthesis of drug intermediates such as anti-infective drugs bacampicillin, sultamicillin, ethyl cinnamate and pseudoionone; or as a catalyst in the synthesis of anti-diabetic drugs such as dapagliflozin; or as a phase transfer catalyst in the synthesis of liver function improving and metabolic detoxifying agent tiopronin; or as a brominating agent in the synthesis of the muscle relaxant reversal agent sugammadex sodium.

[0003] At present, the preparation method of tetrabutylammonium bromide is to use tri-n-butylamine and 1-bromobutane as raw materials and synthesize it through a traditional tank reactor. This method has the disadvantages of long reaction time, difficult to control side reactions and low yield.

[0004] Application No. 202210413857.0 discloses a method for preparing tetrabutylammonium bromide by a microreactor, comprising the following steps:

[0005] Step a, mixing butyl bromide, a reaction solvent and a solid acid catalyst uniformly to obtain a reaction liquid; continuously introducing the reaction liquid and tributylamine into a microchannel reactor respectively, reacting, and separating the solid and the liquid to obtain a tetrabutylammonium bromide reaction liquid;

[0006] The solid acid catalyst is a SiO2-Al2O3 catalyst, a SiO2-MgO catalyst or a SiO2-ZnO catalyst, and the reaction solvent is methanol, ethanol, ether or ethylene glycol;

[0007] Step b, distilling the tetrabutylammonium bromide reaction solution to obtain a crude tetrabutylammonium bromide product;

[0008] Step c, adding a refined solvent to the crude tetrabutylammonium bromide, heating to dissolve, distilling to remove the refined solvent, cooling to crystallize, and separating the solid from the liquid to obtain the tetrabutylammonium bromide product. The yield can reach 95% (up to 97.8%).

[0009] Although this method reduces the reaction time, it still has the following disadvantages: the solid acid catalyst cannot be recycled, which poses a certain economic and environmental burden; the heterogeneous solid acid catalyst is introduced into the microreactor along with the reaction liquid, which easily causes microreactor blockage and causes production accidents; the reaction state cannot be detected online, and the product quality fluctuates greatly. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a synthesis method capable of efficiently synthesizing tetrabutylammonium bromide.

[0011] In order to solve the above technical problems, the present invention provides a method for synthesizing tetrabutylammonium bromide, comprising the following steps:

[0012] 1) Using molecular sieve as catalyst, filling into a tubular fixed bed reactor;

[0013] 2) 1-bromobutane and tri-n-butylamine are mixed in a mass ratio of 4 to 20:1 (preferably 5 to 10:1, more preferably 5 to 6:1) as a raw material liquid, and the raw material liquid enters a tubular fixed bed reactor, and reacts under the action of a catalyst at a set reaction temperature and reaction pressure;

[0014] The reaction temperature in the fixed bed reactor is 60-90°C (preferably 70-85°C, more preferably 80°C), and the reaction pressure is 0.1-0.3 MPa (preferably 0.1-0.2 MPa);

[0015] 3) The reaction product is subjected to reduced pressure distillation to recover 1-bromobutane to obtain crude tetrabutylammonium bromide;

[0016] The crude tetrabutylammonium bromide is recrystallized to obtain tetrabutylammonium bromide.

[0017] As an improvement of the synthetic method of tetrabutylammonium bromide of the present invention:

[0018] The reaction time is 0.5 to 5 h (preferably 0.5 to 3 h, more preferably 1 h).

[0019] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention: the feed volume space velocity of the raw material liquid is 0.03 to 0.15 min -1 .

[0020] The feed volume space velocity of the raw material liquid = the volumetric feed rate of the raw material liquid / the volume of the catalyst.

[0021] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention: in the step 1):

[0022] The molecular sieve catalyst is any one of the following: 13X, 3A, 4A, 5A, beta β and Mordenite (preferably 13X, beta β and Mordenite molecular sieves, more preferably Mordenite molecular sieve).

[0023] Mordenite, also known as mordenite molecular sieve (MOR-Mordenite).

[0024] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention: the molecular sieve catalyst after participating in the reaction can be activated by calcination, so as to achieve repeated utilization; the molecular sieve calcination activation temperature is 400-600°C (preferably 550°C), and the calcination activation time is 11-13h (preferably 12h).

[0025] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention, the reduced pressure distillation in step 3) has a distillation temperature of 45 to 90° C. (preferably 60 to 85° C., more preferably 75° C.) and a pressure of 0.01 to 0.03 MPa.

[0026] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention: in step 3), the solvent used for recrystallization is ethyl acetate, and the mass ratio of the solvent to the crude tetrabutylammonium bromide is 0.2-1:1 (preferably 0.3-0.4:1); the solvent is first added to the crude tetrabutylammonium bromide and then heated until the crude tetrabutylammonium bromide is dissolved, and then the temperature is lowered to 5-15°C for crystallization, and the crystallization time is 1-2h.

[0027] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention: when the total liquid holding capacity of the tubular fixed bed reactor is 120-180 mL (inner diameter is 10-15 mm), the flow rate of the raw material liquid composed of 1-bromobutane and tri-n-butylamine is 1-5 mL / min.

[0028] As a further improvement of the synthesis method of tetrabutylammonium bromide of the present invention: the molecular sieve used is Mordenite, the mass ratio of 1-bromobutane to tri-n-butylamine is 6:1, the reaction temperature is 80° C., the reaction pressure is 0.2 MPa, and the reaction time is 1 h.

[0029] In summary, the present invention discloses a method for synthesizing tetrabutylammonium bromide. The method uses tri-n-butylammonium and 1-bromobutane as raw materials, 1-bromobutane as a solvent, and a recyclable molecular sieve as a solid catalyst to synthesize tetrabutylammonium bromide through a tubular fixed bed reactor.

[0030] The present invention has the following technical advantages:

[0031] 1) Using 1-bromobutane as solvent, the use of acetonitrile as reaction solvent in the traditional autoclave synthesis process is omitted, and 1-bromobutane can be further used in the synthesis of 1-bromobutane after detection and recovery;

[0032] Reduce the use of solvents, reduce the generation of by-products, and improve the reaction yield;

[0033] 2) The traditional kettle reactor is replaced by a tubular fixed bed reactor, which effectively shortens the reaction time;

[0034] 3) Using molecular sieve as solid catalyst, its alkaline site can effectively inhibit the formation of by-products. During use, if the catalyst is found to be deactivated, the catalyst can be recycled by simple calcination;

[0035] 4) Online detection methods can effectively monitor the reaction status and adjust the reaction conditions in time to achieve stable and efficient synthesis of tetrabutylammonium bromide. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The specific implementation modes of the present invention are further described in detail below with reference to the accompanying drawings.

[0037] Figure 1 It is a schematic diagram of the process of the present invention. DETAILED DESCRIPTION

[0038] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0039] The reaction process of the present invention is as follows Figure 1 Said:

[0040] A molecular sieve as a catalyst is loaded in a tubular fixed bed reactor; the flow rates of 1-bromobutane and tri-n-butylamine are controlled by respective flow controllers, so that 1-bromobutane and tri-n-butylamine are mixed according to a set mass ratio, and the obtained raw material liquid enters the tubular fixed bed reactor according to a set feed volume space velocity, and reacts under the action of the catalyst at a set reaction temperature and reaction pressure; and tetrabutylammonium bromide is synthesized under heating conditions.

[0041] An online detector is arranged at the outlet of the shell-and-tube fixed bed reactor. The online detector detects the component content of the obtained product by high performance liquid phase detection method. The online detector transmits the detected data to the control center, and the control center adjusts the flow ratio of 1-bromobutane and tri-n-butylamine through a flow controller, and adjusts the temperature heat exchanger accordingly through a temperature controller, thereby controlling the reaction temperature of the shell-and-tube fixed bed reactor.

[0042] The particle size of the molecular sieve catalyst used in the present invention is less than 1 mm.

[0043] Embodiment 1, a kind of synthesis method of tetrabutylammonium bromide, carries out the following steps in sequence:

[0044] 1) Take 30 ml (about 60 g) of Mordenite molecular sieve and put it into a tubular fixed bed reactor with an inner diameter of 15 mm and a length of about 1000 mm, with a liquid holding capacity of 180 mL.

[0045] 2) Use 600 g of 1-bromobutane and 100 g of tri-n-butylamine; control 1-bromobutane and tri-n-butylamine to be mixed in a mass ratio of 6:1 as a raw material liquid, and pass the raw material liquid into a tubular fixed bed reactor at a flow rate of 3 mL / min. The temperature in the reactor is stabilized at 80° C. by a temperature controller, the pressure is controlled to be 0.2 MPa, and the reaction time is 1 h (i.e., the residence time of the raw material liquid in the tubular fixed bed reactor is 1 h).

[0046] That is, the feed volume space velocity of the raw material liquid is 0.1min -1 .

[0047] 3) The reaction liquid discharged from the tubular fixed bed reactor was tested for reaction status by high performance liquid chromatography, and the conversion rate of tri-n-butylamine was 99.3%.

[0048] The reaction solution was distilled under reduced pressure (0.01 MPa, 75° C.) to recover 1-bromobutane to obtain crude tetrabutylammonium bromide.

[0049] The recovery rate of 1-bromobutane is 98.3%, and the recovery rate of 1-bromobutane=1-bromobutane recovery amount / (total amount of 1-bromobutane-reaction amount of 1-bromobutane).

[0050] The crude tetrabutylammonium bromide was obtained, and the purity of the crude product was 96.6%.

[0051] According to the mass ratio of crude tetrabutylammonium bromide:ethyl acetate=0.3:1, ethyl acetate was added to the crude tetrabutylammonium bromide and heated at 80°C to dissolve the crude tetrabutylammonium bromide, then cooled to 10°C, kept at 10°C for crystallization for 1h, and dried (dried to constant weight at 65°C) to obtain 170.5g of tetrabutylammonium bromide with a purity of 99.6%, and a molar yield of 98.0%.

[0052] Embodiment 2, a method for synthesizing tetrabutylammonium bromide, carrying out the following steps in sequence:

[0053] 1) Take 30 ml of 13X molecular sieve and load it into a tubular fixed bed reactor. The tubular fixed bed reactor is the same as that in Example 1.

[0054] 2) Use 500 g of 1-bromobutane and 100 g of tri-n-butylamine; control 1-bromobutane and tri-n-butylamine to be mixed in a mass ratio of 5:1 as a raw material liquid, and pass the raw material liquid into a tubular fixed bed reactor at a flow rate of 2 mL / min. The temperature in the reactor is stabilized at 80° C. by a temperature controller, the pressure is controlled to be 0.2 MPa, and the reaction time is 1.5 h.

[0055] That is, the feed volume space velocity of the raw material liquid is 0.067min -1 .

[0056] 3) Same as step 3) of Example 1.

[0057] The conversion rate of tri-n-butylamine was 98.6%, the recovery rate of 1-bromobutane was 97.7%, and the purity of the crude product was 97.1%.

[0058] Finally, 169.3 g of tetrabutylammonium bromide with a purity of 99.4% was obtained, and the molar yield was 97.3%.

[0059] Embodiment 3, a method for synthesizing tetrabutylammonium bromide, carrying out the following steps in sequence:

[0060] 1) Take 30 ml of beta-β molecular sieve and put it into a tubular fixed bed reactor with an inner diameter of 12 mm and a length of about 1000 mm, with a liquid holding capacity of 120 mL.

[0061] 2) Using 600 g of 1-bromobutane and 100 g of tri-n-butylamine, 1-bromobutane and tri-n-butylamine were mixed in a mass ratio of 6:1 as a raw material liquid, and the raw material liquid was passed into a tubular fixed bed reactor at a flow rate of 2 mL / min. The temperature in the reactor was stabilized at 80° C. by a temperature controller, the pressure was 0.2 MPa, and the reaction time was 1 h.

[0062] That is, the feed volume space velocity of the raw material liquid is 0.067min -1 .

[0063] 3) The mass ratio of crude tetrabutylammonium bromide to ethyl acetate was set to 0.4:1, the crystallization time was 1.5 h, and the rest was the same as step 3) of Example 1.

[0064] The conversion rate of tri-n-butylamine was 98.6%, the recovery rate of 1-bromobutane was 97.5%, and the purity of the crude product was 97.3%.

[0065] Finally, 168.9 g of tetrabutylammonium bromide with a purity of 99.1% was obtained, and the molar yield was 97.1%.

[0066] Embodiment 4, a method for synthesizing tetrabutylammonium bromide, carrying out the following steps in sequence:

[0067] 1) Take 30 ml of 4A molecular sieve and load it into a tubular fixed bed reactor. The tubular fixed bed reactor is the same as that in Example 3.

[0068] 2) Using 600 g of 1-bromobutane and 100 g of tri-n-butylamine, 1-bromobutane and tri-n-butylamine were mixed in a mass ratio of 6:1 as a raw material liquid, and the raw material liquid was passed into a tubular fixed bed reactor at a flow rate of 4 mL / min. The temperature in the reactor was stabilized at 75° C. by a temperature controller, the pressure was 0.2 MPa, and the reaction time was 0.5 h.

[0069] That is, the feed volume space velocity of the raw material liquid is 0.133min -1 .

[0070] 3) Same as step 3) of Example 3.

[0071] The conversion rate of tri-n-butylamine was 98.4%, the recovery rate of 1-bromobutane was 97.4%, and the purity of the crude product was 97.5%.

[0072] Finally, 167.7 g of tetrabutylammonium bromide with a purity of 99.1% was obtained, and the molar yield was 96.4%.

[0073] Embodiment 5, with respect to embodiment 1, the following changes are made:

[0074] The amount of Mordenite molecular sieve was changed from 30 ml to 45 ml, so the feed volumetric space velocity of the raw material liquid was 0.067 min -1 ; The rest is the same as Example 1.

[0075] The conversion rate of tri-n-butylamine was 98.1%. The recovery rate of 1-bromobutane was 97.7%, and the purity of the crude product was 96.7%;

[0076] Finally, 169.8 g of tetrabutylammonium bromide with a purity of 99.2% was obtained, and the molar yield was 97.6%.

[0077] Embodiment 6: With respect to Embodiment 1, the following changes are made:

[0078] The amount of Mordenite molecular sieve was changed from 30 ml to 45 ml; the flow rate of the raw material solution was changed from 3 mL / min to 5 mL / min, and the reaction time was changed from 1 h to 0.6 h; that is, the feed volume space velocity of the raw material solution was 0.11 min -1 ; The rest is the same as Example 1.

[0079] The conversion rate of tri-n-butylamine was 98.1%. The recovery rate of 1-bromobutane was 97.6%, and the purity of the crude product was 98.1%;

[0080] Finally, 168.9 g of tetrabutylammonium bromide with a purity of 99.2% was obtained, and the molar yield was 97.1%.

[0081] Example 7: The catalyst obtained in Example 6 was reused, and the rest was referred to Example 6. When the catalyst was reused for the fifth time, the results were compared with those of Example 6 and are shown in Table 1 below.

[0082] Table 1

[0083]

[0084]

[0085] According to Table 1, the following summary conclusions can be obtained: after 5 cycles, the inhibitory effect of the catalyst on the side reaction becomes significantly worse, and the by-product tri-n-butylamine bromate is generated, which affects the recrystallization yield and causes a decrease in the molar yield of pure tetrabutylammonium bromide.

[0086] Example 8: The molecular sieve catalyst after repeated cycles 4 times in Example 7 was calcined and activated, the calcination temperature was 550°C, and the calcination time was 12 hours. Then the calcined and activated molecular sieve catalyst was used to synthesize tetrabutylammonium bromide according to Example 6. The obtained results are compared with those in Example 6 as shown in Table 2 below.

[0087] Table 2

[0088]

[0089] It can be seen from Table 2 that the reaction result of Example 8 is very close to that of Example 6.

[0090] Embodiment 9, with respect to embodiment 1, the following changes are made:

[0091] The 1-bromobutane recovered in Example 1 was used as a raw material for the reaction, and the rest was the same as Example 1.

[0092] The result is:

[0093] The conversion rate of tri-n-butylamine was 97.8%, and the purity of crude product was 98.0%;

[0094] The final tetrabutylammonium bromide has a purity of 99.2% and a molar yield of 96.8%.

[0095] Embodiment 10: With respect to Embodiment 2, the following changes are made:

[0096] The flow rate of the raw material solution was changed from 2 mL / min to 1 mL / min, the reaction temperature was changed from 80° C. to 70° C., and the reaction time was correspondingly changed from 1.5 h to 3 h; the rest was the same as Example 2.

[0097] The result is:

[0098] The conversion rate of tri-n-butylamine was 97.7%. The recovery rate of 1-bromobutane was 97.7%, and the purity of the crude product was 99.1%;

[0099] Finally, 169.7 g of tetrabutylammonium bromide with a purity of 99.2% was obtained, and the molar yield was 97.6%.

[0100] Embodiment 11, with respect to embodiment 3, the following changes are made:

[0101] 700 g of 1-bromobutane was used, that is, the mass ratio of 1-bromobutane to tri-n-butylamine was changed from 6:1 to 7:1; the flow rate of the raw material liquid was changed from 2 mL / min to 1 mL / min, so the reaction time was 2 h.

[0102] The rest is the same as Example 3.

[0103] The results obtained were: the conversion rate of tri-n-butylamine was 98.5%, the recovery rate of 1-bromobutane was 97.3%, and the purity of the crude product was 97.2%;

[0104] After drying, 170.9 g of tetrabutylammonium bromide with a purity of 99.3% was obtained, and the molar yield was 98.3%.

[0105] Comparative Example 1-1, relative to Example 1, made the following changes:

[0106] 300 g of 1-bromobutane, that is, 1-bromobutane and tri-n-butylamine were mixed in a mass ratio of 3:1 as the raw material liquid, and the rest was the same as in Example 1.

[0107] The results obtained were that the conversion rate of tri-n-butylamine was 76.5%, the recovery rate of 1-bromobutane was 94.3%, and the purity of the crude product was 94.2%;

[0108] Finally, 129.2 g of tetrabutylammonium bromide with a purity of 98.2% was obtained, and the molar yield was 74.3%.

[0109] Comparative Example 1-2, relative to Example 1, makes the following changes:

[0110] 1000 g of 1-bromobutane, that is, 1-bromobutane and tri-n-butylamine were mixed in a mass ratio of 10:1 as the raw material liquid, and the rest was the same as in Example 1. The rest was the same as in Example 1.

[0111] The results obtained were that the conversion rate of tri-n-butylamine was 98.8%, the recovery rate of 1-bromobutane was 92.5%, and the purity of the crude product was 95.3%;

[0112] Finally, 170.8 g of tetrabutylammonium bromide with a purity of 98.6% was obtained, and the molar yield was 98.2%.

[0113] Comparative Example 2: The molecular sieve catalyst in Example 1 was changed from Mordenite molecular sieve to the one described in Table 2 below, the dosage remained unchanged (30 ml), and the rest was the same as Example 1.

[0114] The comparison of the obtained results with those of Example 1 is shown in Table 2 below.

[0115] Table 2

[0116]

[0117] Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by a person skilled in the art should be considered as the protection scope of the present invention.

Claims

1. A method for synthesizing tetrabutylammonium bromide, characterized in that The following steps are involved: 1) Using molecular sieve as catalyst, filling into a tubular fixed bed reactor; 2) 1-bromobutane and tri-n-butylamine are mixed in a mass ratio of 4 to 20:1 as a raw material liquid, and the raw material liquid enters a tubular fixed bed reactor, and reacts under the action of a catalyst at a set reaction temperature and reaction pressure; The reaction temperature in the fixed bed reactor is 60-90°C and the reaction pressure is 0.1-0.3Mpa; 3) The reaction product is subjected to reduced pressure distillation to recover 1-bromobutane to obtain crude tetrabutylammonium bromide; The crude tetrabutylammonium bromide is recrystallized to obtain tetrabutylammonium bromide.

2. The method for synthesizing tetrabutylammonium bromide according to claim 1, wherein: The reaction time is 0.5 to 5 hours.

3. The method for synthesizing tetrabutylammonium bromide according to claim 1, characterized in that: The raw material liquid enters the tube-type fixed bed reactor according to the set feed volume space velocity, and the feed volume space velocity of the raw material liquid is 0.03~0.15min -1 .

4. The method for synthesizing tetrabutylammonium bromide according to claim 2 or 3, characterized in that: In the step 1): The molecular sieve catalyst is any one of the following: 13X, 3A, 4A, 5A, beta β and Mordenite.

5. The method for synthesizing tetrabutylammonium bromide according to claim 4, characterized in that: The molecular sieve catalyst after the reaction can be activated by calcination, so as to achieve repeated use; the molecular sieve calcination activation temperature is 400-600°C (, and the calcination activation time is 11-13h.

6. The method for synthesizing tetrabutylammonium bromide according to any one of claims 1 to 5, characterized in that The reduced pressure distillation in step 3) has a distillation temperature of 45 to 90° C. and a pressure of 0.01 to 0.03 MPa.

7. The method for synthesizing tetrabutylammonium bromide according to any one of claims 1 to 5, characterized in that In the step 3), the solvent used for recrystallization is ethyl acetate, and the mass ratio of the solvent to the crude tetrabutylammonium bromide is 0.2-1:1; the solvent is first added to the crude tetrabutylammonium bromide and then heated until the crude tetrabutylammonium bromide is dissolved, and then the temperature is lowered to 5-15° C. for crystallization, and the crystallization time is 1-2 hours.

8. The method for synthesizing tetrabutylammonium bromide according to any one of claims 1 to 7, characterized in that: When the total liquid holding capacity of the tubular fixed bed reactor is 120-180 mL, the flow rate of the raw material liquid composed of 1-bromobutane and tri-n-butylamine is 1-5 mL / min.

9. The method for synthesizing tetrabutylammonium bromide according to any one of claims 1 to 7, characterized in that: The molecular sieve used was Mordenite, the mass ratio of 1-bromobutane to tri-n-butylamine was 6:1, the reaction temperature was 80°C, the reaction pressure was 0.2 MPa, and the reaction time was 1 h.

Images