CN105131026A - Method for synthesizing N, O-bis(trimethylsilyl) acetamide by virtue of two-component catalyst - Google Patents

Abstract

The invention provides a method for synthesizing N,O-bis(trimethylsilyl)acetamide with a two-component catalyst. The synthesis kettle is charged, and acetamide, triethylamine, catalyst dimethylaniline and catalyst imidazole are added to the synthesis kettle; the weight ratio of the acetamide and triethylamine is 1:3.60-3.94; the catalyst dimethylaniline The consumption is 0.1-0.5% of the weight of acetamide; the consumption of the catalyst imidazole is 0.08-0.6% of the weight of acetamide; the addition of trimethylchlorosilane, the weight ratio of the addition of trimethylchlorosilane to acetamide is 3.77-4.03:1. The finished product prepared by the invention has a purity of 99.51-99.62% and a single-pass yield of 91.33-93.66%.

Description

Method for synthesizing N,O-bis(trimethylsilyl)acetamide with a two-component catalyst

technical field

The invention relates to a method for synthesizing N,O-bis(trimethylsilyl)acetamide with a two-component catalyst, belonging to the technical field of organic synthesis.

Background technique

N,O-bis(trimethylsilyl)acetamide (hereinafter referred to as BSA) is an important organosilicon protective agent. Silicone protective agent refers to an organosilylating agent used to protect various organic functional groups in organic synthesis. In organic synthesis, if several parts or functional groups in the molecule may react, if only a certain part or functional group is expected to react, and no selective reaction conditions or reagents can be found, the reaction may not be expected to occur at this time. The parts are protected, and the original functional groups are restored after the purpose is achieved. Silicone protective agents can generally be divided into four categories: trimethylsilane type, monofunctional steric hindrance type, bifunctional steric hindrance type and special type. BSA is the most commonly used trimethylsilyl protective agent. It is mainly used for the silanization protection of amino acids, carboxyl acids, alcohols and amides. It is a neutral silylation protective agent with low toxicity, easy reaction, and easy removal. Applications in chemistry, organic synthesis, medicine and modification of natural substances have been increasingly valued.

As an important pharmaceutical intermediate, BSA products are used in the preparation of cephalosporins and their intermediates, such as the synthesis of cefpiramic acid, the synthesis of propylene glycol ceftriaxone, the synthesis of 7-αmethoxy-7-amino-3-methyltetra Amazolium thiomethyl cephalosporanic acid dimethyl ester, synthesis of 7β-amino-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephalosporin Diphenylmethyl-ene-4-carboxylate, etc.; synthesis of selective cholesterol absorption inhibitor raw material ezetimibe; as passivation of chromatographic carrier and modifier of sample polar groups, for a variety of conventional chromatographic Analysis of compounds that cannot be qualitatively or quantitatively analyzed to obtain satisfactory results. In recent years, with the rapid improvement and development of organosilicon chemical technology in our country, the correlation research of organosilicon compounds as drug synthesis reagents and intermediates has been widely valued. BSA is increasingly widely used in organic synthesis, especially for the protection of unsaturated bonds, hydroxyl, carbonyl, carboxyl, amino and other functional groups in the compound structure, BSA has played a more important role.

Existing BSA synthesis method mainly contains:

Chinese patent (Application No.: 200410044929.0) proposes a BSA production process, the main operation of which is: put triethylamine and acetamide into the reactor during synthesis, stir for 1 hour, and then drip into the reactor under the protection of _N2 gas Add trimethylchlorosilane, control the temperature within the range of <50°C, complete the injection within 2-6 hours, then protect the reaction at 40-65°C for 8-16 hours, and cool down to below 35°C after the reaction is over. material; add the reacted material to a closed centrifuge for solid-liquid separation, and send the mother liquor to the concentration tank for concentration. The concentrated mother liquor is at 60-100°C, the pressure is -0.2 to -0.998 atmospheres, and the tower height is 6-15 It is a colorless transparent liquid obtained by rectification under rice conditions. The main disadvantages of this process are: (1) the reaction time is long, and the reaction time exceeds 10 hours; (2) the reaction is carried out under normal pressure, although the protection of _N2 gas is used, the reaction system will inevitably enter the air and bring in moisture, which will cause Other side reactions; (3) Rectification is carried out under the conditions of a vacuum of 0.2 to 0.998 atmospheres and a tower height of 6-15 meters, which consumes a lot of power and energy, especially when the vacuum is 0.998 atmospheres. big.

Chinese patent (application number: 200810120760.0) proposes a method of synthesizing BSA by reactive distillation using trimethylsilimidazole and acetamide as raw materials and mercapto compounds as catalysts. Add 33.6g (0.24mol) trimethylsilyl imidazole and 1.5g (0.01mol) 2-mercaptobenzo Thiazole, and a mixture of 12g (0.2mol) acetamide and 33.6g (0.24mol) trimethylsilyl imidazole was added to a constant pressure dropping funnel. Then heat, turn on magnetic stirring, depressurize, control the reaction pressure to a vacuum of 0.08MPa, control the temperature of the reactor at about 160°C, slowly add the mixed solution dropwise from the constant pressure funnel, rectify while reacting, and collect the The fraction is the crude BSA product, and the reaction time is controlled to be 5 hours. Then, the crude product was rectified to obtain a pure BSA product with a high content, with a yield of 85% and a content of 99.2%. The main disadvantages of this process are: (1) Acetonitrile and silicon ether are produced as by-products, and other side reactions will occur; (2) The reaction temperature is high, and the temperature of the reactor is controlled at about 160°C, which consumes a lot of energy and easily causes BSA loss. (3) Even under the condition of vacuum degree of 0.08MPa, the reaction time is as long as 5 hours; (4) The production cost is high, and the quality requirement for the raw material trimethylsilimidazole is high.

The French patent (patent number: FR2574079) proposes a route to synthesize BSA, which uses hexamethyldisilazane as a raw material, first reacts with acetic anhydride, and then reacts with trimethylchlorosilane and triethylamine to generate BSA. The main disadvantages of this process are: (1) although this reaction only produces triethylamine hydrochloride in half the amount of acetamide and trimethylchlorosilane reaction, it produces trimethylsilylated acetate again, which is extremely It is easy to block the pipeline, which seriously affects the progress of the reaction; (2) the increase of side reactions and by-products increases the production cost; (3) the purity of the finished product is low, and the number and content of impurities are relatively high.

US Patent (Patent No.: US4276423) proposes a method for preparing BSA using trimethylsilyl imidazole and N-trimethylsilyl acetamide. The temperature of the reaction system is adjusted at 120-170°C, the vacuum degree is 65mmHg column, and distillation is carried out while reacting. The reaction yield is over 90%. The main disadvantages of this process are: (1) trimethylsilyl imidazole and N-trimethylsilyl acetamide will undergo a reversible reaction, and the reaction temperature is high; (2) due to many side reactions, the number and content of impurities in the product are large : (3) adopting reaction while distillation process, industrialized production implementation difficulty is big.

In recent years, with the development of the third-generation new cephalosporin antibiotics and the success of clinical use, the requirements for the purity of BSA in drug synthesis are getting higher and higher, and the conventional purity of 99.0 (GC)% can no longer meet the requirements; in addition, using MEMS ( MEMS cell capture chips used to separate and detect cancer cells based on microelectromechanical systems) must use BSA with a purity of more than 99.5 (GC)% in use, otherwise the test results are meaningless; several other cephalosporin antibiotics for injection BSA with a purity of more than 99.5 (GC)% must be used for synthesis, otherwise, side effects, especially severe side effects, may occur frequently or even cause death after intracorporeal injection. Most of the existing BSA production processes at home and abroad have long reaction time, high production cost, product purity of about 99.0 (GC)%, and poor product stability (the product will turn yellow and have flocs after a period of time). Therefore, developing a production method that simultaneously improves the purity and yield of BSA has important economic significance and social benefits for promoting the development of the industry.

Contents of the invention

Aiming at problems such as high reaction temperature, long reaction time, low product purity and high impurity content in the existing domestic BSA production, increased yield and increased cost, the invention provides a two-component catalyst for synthesizing N,O—bis( The method of trimethylsilyl) acetamide, using trimethylchlorosilane, triethylamine and acetamide which are easily available in China as raw materials, adding another organic base as an acid-binding agent to play a catalytic role at the same time, and reacting under low vacuum In addition to promoting the reaction, the forced circulation of the circulating pump removes the hydrochloride generated by the reaction from the reaction system in time, which greatly speeds up the reaction speed; rectification under vacuum conditions ensures stable product quality and long storage time.

The purpose of the invention that the present invention realizes is:

(1) shorten the reaction time;

(2) Reduce the reaction temperature to below 40°C;

(3) Increase the purity of the product BSA to above 99.5% (GC);

(4) Reduce the number of impurities, reduce the content of impurities, especially reduce the content of complex structural compounds such as polysilane and polyoxysilane in the product;

(5) Reduce the amine content in the product;

(6) While increasing yield, reduce production cost;

(7) The product has good storage stability.

The reaction principle of the present invention is as follows:

In the BSA synthesis reaction, trimethylchlorosilane and acetamide are reacted as direct raw materials, and triethylamine is used as an acid-binding agent to neutralize the HCl generated by trimethylchlorosilane and acetamide, so that the medium remains neutral or weakly alkaline property, to improve the yield of the acylation reaction, the reaction equation is briefly shown as follows:

In order to solve the above technical problems, the technical scheme adopted in the present invention is as follows:

A method for synthesizing N,O-bis(trimethylsilyl)acetamide with a two-component catalyst comprises the steps of feeding trimethylchlorosilane, feeding a synthesis kettle, adjusting the dropping speed and temperature of trimethylchlorosilane, and reacting.

Following is the further improvement to above-mentioned technical scheme:

The synthesis kettle is fed, and acetamide, triethylamine, catalyst dimethylaniline and catalyst imidazole are added to the synthesis kettle; the weight ratio of acetamide to triethylamine is 1:3.60-3.94.

The dosage of the catalyst dimethylaniline is 0.1-0.5% of the weight of acetamide.

The dosage of the catalyst imidazole is 0.08-0.6% of the weight of acetamide.

For the addition of trimethylchlorosilane, the weight ratio of the added amount of trimethylchlorosilane to acetamide is 3.77-4.03:1.

The synthesis kettle is fed. After the raw materials are added, the stirring is started, and the rotation speed of the agitator is set at 85-100 RPM. After stirring for 45-55 minutes, the vacuum degree of the synthesis kettle is adjusted to 0.01-0.025MPa.

The drop rate and temperature of the trimethylchlorosilane are adjusted, and the dropping temperature is controlled to be 33-39° C., and the addition of the trimethylchlorosilane is controlled within 90-110 minutes.

In the reaction, the trimethylchlorosilane is added dropwise, and the reaction temperature is kept at 33-39° C., the vacuum degree of the synthesis tank is kept at 0.01-0.025 MPa, and the circulation pump continues to circulate for 120-150 minutes, and the reaction is completed.

The finished product prepared by the invention has a purity of 99.51-99.62% and a single-pass yield of 91.33-93.66%.

The present invention selects a suitable catalyst, mainly uses Lewis base, accelerates the reaction speed of trimethylchlorosilane and acetamide, enhances the carbonyl activity of acetamide, thereby improving its reactivity, and reduces the contact chance of BSA and hydrogen chloride.

The present invention removes the generated triethylamine hydrochloride from the reaction system while reacting, so that the reaction is basically maintained under homogeneous conditions, and the generated triethylamine hydrochloride is removed in time, which is also beneficial to speed up the reaction speed and reduce the production of finished products. BSA reacts deeply with hydrogen chloride to form other compounds.

The selection of the catalyst of the present invention, through many tests, determined to use dimethylaniline as the main catalyst, wherein 2,6-dimethylaniline is the preferred use, other such as 2,5-dimethylaniline, 3,4- Dimethylaniline and 2,3-dimethylaniline can also be used; at the same time, imidazole is selected as the auxiliary catalyst, and imidazole has a higher boiling point, and the separation of the finished product has a large difference in boiling point from BSA, so it is easy to separate.

The beneficial effects of the present invention are:

(1) In the synthesis reaction of trimethylchlorosilane and acetamide, the two-component catalyst catalyst dimethylaniline and imidazole are used to react under low vacuum conditions, and the reaction speed is accelerated.

The reaction time of the present invention (from the start of feeding to the completion of the reaction) is 4-4.5 hours, and the industrial production process in the prior art is generally 8-18 hours.

(2) The reaction temperature is reduced from the current 40-65°C to 33-39°C; the rectification temperature and the temperature of the condensate receiving the finished product are reduced from 90°C to 73°C, which significantly reduces the decomposition, polymerization and other side reactions of the finished BSA .

(3) The product BSA prepared by the present invention is operated under vacuum conditions at the beginning of distillation, and the post-distillation adopts high vacuum and low temperature operation, and the product purity is increased to 99.51-99.62%.

(4) The product BSA prepared by the present invention has less impurity quantity and impurity content, and the content of complex structural compounds such as polysilane and polyoxysilane in the product is low, and the polysilane content in the control product is ≤0.1%, and the polyoxysilane content is ≤0.1%.

(5) In the product prepared by the present invention, the amine content is low, and the amine content is 0.21-0.35%.

(6) The method of the present invention reduces the production cost while increasing the yield. The single-pass yield of BSA reaches 93.66%, and the existing domestic yield does not exceed 90%, and the product cost is reduced by more than 2%.

(7) Solve the problem of poor product storage stability;

The product prepared by the invention has good storage stability, and after one year of storage, the product purity is 99.40-99.53% (GC), and the appearance is a colorless transparent liquid without floc. The storage stability of similar domestic products is poor, and the purity drops by 3% after one year of storage, and the product is light yellow to light yellow, and even flocs appear.

(8) When trimethylchlorosilane is added dropwise to the kettle, the feeding port of trimethylchlorosilane is submerged below the liquid level of the synthesis kettle; when the circulating liquid of the circulating pump enters the synthesis kettle, the feed port of the circulation pipeline must be submerged in the synthesis kettle below the liquid level. In addition, under the negative pressure of the synthesis kettle, the raw material trimethylchlorosilane is hardly in contact with the air, the influence of moisture on the hydrolysis of trimethylchlorosilane is greatly weakened, and the conversion rate of the raw material trimethylchlorosilane is improved, and the conversion rate is improved More than 3%.

(9) A circulation pump is connected to the outlet at the bottom of the reactor, and the circulation pump is turned on after the dripping of trimethylchlorosilane, which cooperates with the reactor agitator to strengthen the degree of material mixing and promote heat and mass transfer; Two filters are connected after the circulating pump, one is used for coarse filtration (filter fineness 100-200 mesh), and the other is used for fine filtration (filter fineness 300-400 mesh), to filter out the triethylamine hydrochloride formed, The system reacts under homogeneous conditions, the material contact is more sufficient, and the reaction effect is good.

Description of drawings

The process flow and equipment of the present invention will be further described below in conjunction with the accompanying drawings and implementation methods.

Fig. 1 is the schematic diagram of BSA synthetic process flow;

In the figure: 1-Trimethylchlorosilane high tank; 2-First pipeline sight cup; 3-Synthesis kettle; 4-Circulation pump; 5-First filter; 6-Second filter; 7-Still still ;8-Packed tower; 9-Condenser; 10-Front fraction receiving tank; 11-Product receiving tank; 12-Hydraulic jet vacuum pump; 13-Oil-sealed mechanical vacuum pump; 14-First pressure (vacuum degree) local indicating device ; 15-the first temperature on-site indicating device; 16-the second temperature on-site indicating device; 17-the second pipeline as the cup. 18-the second pressure (vacuum degree) local indicating device; 19-the third pressure (vacuum degree) local indicating device.

Detailed ways

Preferred embodiments of the present invention are described below, and it should be understood that the preferred embodiments described here are only used to illustrate and explain the present invention, and are not intended to limit the present invention.

Embodiment 1 A kind of two-component catalyst synthesis N, the method of O-bis (trimethylsilyl) acetamide

The reaction is carried out in a 1000L kettle, and the synthesis steps are as follows:

(1) Adding trimethylchlorosilane

Use a vacuum to pump 350kg of trimethylchlorosilane into the trimethylchlorosilane head tank 1, and maintain a slight negative pressure in the trimethyl chlorosilane head tank 1 before starting to feed, and maintain a vacuum degree of 0.001-0.005

MPa.

(2) Synthetic kettle 3 feeding

Add 90kg of acetamide, 345kg of triethylamine, 0.15kg of 2,6-dimethylaniline and 0.25kg of imidazole into synthesis kettle 3, start stirring, set the speed of the stirrer at 85RPM, and after stirring for 45 minutes, adjust the vacuum degree of synthesis kettle 3 0.01-0.015MPa.

(3) Start adding trimethylchlorosilane dropwise

Adjust the trimethylchlorosilane head tank 1 to normal pressure, drop trimethylchlorosilane into the kettle, the trimethylchlorosilane feeding port must be submerged 20-35mm below the liquid level of the synthesis kettle 3, and start to feed the synthesis kettle 3 Add trimethylchlorosilane dropwise to start the circulation pump 4, and the material passes through the circulation pump 4, the first filter 5, and the second filter 6 in turn and enters the synthesis kettle 3, and then passes through the first filter 5 and the second filter 6. The generated triethylamine hydrochloride is filtered off; the feed inlet of the circulation line of the synthesis kettle 3 must be submerged 20-35 mm below the liquid level of the synthesis kettle 3 when the circulating liquid enters.

(4) Adjust the drop rate and temperature of trimethylchlorosilane

Adjust the dropping rate of trimethylchlorosilane, control the dropping temperature to 33-35° C., and control the addition of trimethylchlorosilane within 90 minutes.

(5) Reaction

After the trimethylchlorosilane is added dropwise, keep the reaction temperature at 33-35° C., keep the vacuum degree of the synthesis kettle 3 at 0.01-0.015 MPa, and continue the circulation with the circulation pump 4 for 120 minutes, and the reaction ends.

(6) The material is sent into the distillation kettle 7

Close the material valve leading to the synthesis kettle 3, open the valve leading to the distillation kettle 7, open the circulation pump 4, and send the materials in the synthesis kettle 3 to the distillation kettle 7 for distillation.

(7) Distillation to obtain the former fraction

The distillation tower used for distillation is a packed tower 8 with a tower height of 4 meters and PTFE packing inside.

A. Collection of the first preceding fraction

First turn on the hydraulic jet pump 12, and when the vacuum reaches 0.082-0.086MPa, feed steam into the jacket of the still 3 to heat the material in the still, pass through the second pipeline sight cup 17, and carefully observe the steaming of the material. When the vacuum displayed by the second pressure (vacuum degree) on-site indicator device 18 is stable, the condensate before 68°C (that is, the temperature <68°C) is used as the front fraction, and the front fraction is connected to the front fraction receiving tank 10, Get the first preceding fraction;

B. Collection of the second front fraction

When the gas phase temperature gradually increases to 68.1°C, first close the steam valve, then switch the vacuum system, and switch the hydraulic jet vacuum pump 12 to the oil-sealed mechanical vacuum pump 13; after the oil-sealed mechanical vacuum pump 13 runs stably and the vacuum degree is stable, observe the second temperature On-site indicator device 16 gas phase temperature change, keep the vacuum degree and cut off the vacuum degree to 0.096-0.099MPa, after opening the steam valve again, the obtained condensate at 68.1-70°C is also put into the former fraction receiving tank 10 as the former fraction, Obtain the second front fraction.

(8) Distilled products

When the gas phase temperature is gradually increased to 70.1°C, close the valve of the front fraction receiving tank 10 and open the valve of the finished product receiving tank 11, intercept 70.1-73°C, and the obtained condensate is used as a finished product and connected to the finished product receiving tank 11.

(9) Close the distillation system, pack and store finished products, and store at low temperature

When observing the temperature increase shown by the second temperature on-site indicating device 16 and observing that the condensate flow out from the condenser 9 decreases by the second pipeline sight glass 17, first close the distillation kettle 7 heating steam, when it is observed When the second pipeline sees the cup 17 liquid almost without dripping, close the oil-sealed mechanical vacuum pump 13, and the finished product is packaged and put into storage, and stored at low temperature under nitrogen-tight conditions.

The prepared BSA product has a one-way yield of 91.33% and a purity (GC) of 99.51%. see table 1

The BSA product quality index that table 1 makes

After the product is stored for one year, the purity of the product is 99.42% (GC), and the appearance is a colorless transparent liquid without floc.

Embodiment 2 A kind of two-component catalyst synthesis N, the method of O-bis (trimethylsilyl) acetamide

The reaction was carried out in a 1000L kettle. The synthesis steps are as follows:

(1) Adding trimethylchlorosilane

Use vacuum to pump 380kg of trimethylchlorosilane into the trimethylchlorosilane header tank 1, and maintain a slight negative pressure in the trimethylchlorosilane header tank 1 before starting to feed, and maintain a vacuum degree of 0.001-0.005MPa.

(2) Synthetic kettle 3 feeding

Add 100kg of acetamide, 365kg of triethylamine, 0.2kg of 2,6-dimethylaniline and 0.2kg of imidazole into synthesis kettle 3, start stirring, set the stirrer speed at 85RPM, and after stirring for 50 minutes, adjust the vacuum degree of synthesis kettle 3 0.01-0.015MPa.

(3) Start adding trimethylchlorosilane dropwise

Adjust the trimethylchlorosilane head tank 1 to normal pressure, drop trimethylchlorosilane into the kettle, the trimethylchlorosilane feeding port must be submerged 20-35cm below the liquid level of the synthesis kettle 3; Adding trimethylchlorosilane dropwise starts the circulation pump 4, and the material passes through the circulation pump 4, the first filter 5, and the second filter 6 successively and enters the synthesis kettle 3, and is filtered in the first filter 5 and the second filter 6. In addition to the generated triethylamine hydrochloride; the feed port of the circulation line of the synthesis kettle 3 must be submerged 20-35cm below the liquid level of the synthesis kettle 3 when the circulating liquid enters.

(4) Adjust the drop rate and temperature of trimethylchlorosilane

Adjust the dropping rate of trimethylchlorosilane, control the dropping temperature to 33-35° C., and control the addition of trimethylchlorosilane within 100 minutes.

(5) Reaction

After the trimethylchlorosilane is added dropwise, keep the reaction temperature at 33-35° C., keep the vacuum degree of the synthesis kettle 3 at 0.01-0.015 MPa, and continue the circulation with the circulation pump 4 for 130 minutes, and the reaction ends.

(6) The material is sent into the distillation kettle 7

Close the material valve leading to the synthesis kettle 3, open the valve leading to the distillation kettle 7; open the circulation pump 4, send the material in the synthesis kettle 3 to the distillation kettle 7, and add the front fraction of Example 1.

(7) Distillation to obtain the former fraction

The distillation tower used for distillation is a packed tower 8 with a tower height of 4 meters and PTFE packing inside.

A. Collection of the first preceding fraction

First turn on the hydraulic jet pump 12, and when the vacuum degree reaches 0.082-0.086MPa, feed steam into the jacket of the distillation kettle 7 to heat the materials in the kettle, and carefully observe the steaming of the materials through the second pipeline sight cup 17. When the vacuum degree displayed by the second pressure (vacuum degree) on-site indicator device 18 is stable, the obtained condensate before 68°C (<68°C) is used as the front fraction, and the front fraction is connected to the front fraction receiving tank 10 to obtain first fore fraction;

B. Collection of the second front fraction

When the gas phase temperature gradually increases to 68.1°C, first close the steam valve, then switch the vacuum system, and switch the hydraulic jet vacuum pump 12 to the oil-sealed mechanical vacuum pump 13. After the oil-sealed mechanical vacuum pump 13 runs stably and the vacuum degree is stable, observe the change of the gas phase temperature of the second temperature local indicator device 16, keep the vacuum degree and intercept the vacuum degree to be 0.096-0.099MPa; after opening the steam valve again, the obtained 68.1-70 The condensate at ° C. is also used as the front cut to enter the front cut receiving tank 10 to obtain the second front cut.

(8) Distilled products

When the gas phase temperature is gradually increased to 70.1°C, close the valve of the front fraction receiving tank 10 and open the valve of the finished product receiving tank 11, intercept 70.1-73°C, and the obtained condensate is used as a finished product and connected to the finished product receiving tank 11.

(9) Close the distillation system, pack and store finished products, and store at low temperature

When observing the temperature increase shown by the second temperature on-site indicating device 16 and observing that the condensate flow out from the condenser 9 decreases by the second pipeline sight glass 17, first close the distillation kettle 7 heating steam, when it is observed When the second pipeline sees the cup 17 liquid almost without dripping, close the oil-sealed mechanical vacuum pump 13, and the finished product is packaged and put into storage, and stored at low temperature under nitrogen-tight conditions. The prepared product: the yield per pass is 92.46%, and the purity (GC) is 99.55%. see table 2

The product quality index that table 2 makes

After the product is stored for one year, the purity of the product is 99.43% (GC), and the appearance is a colorless transparent liquid without floc.

Embodiment 3 A kind of two-component catalyst synthesis N, the method of O-bis (trimethylsilyl) acetamide

The reaction is carried out in a 1000L kettle, and the synthesis steps are as follows:

(1) Adding trimethylchlorosilane

Use vacuum to pump 420 kg of trimethylchlorosilane into the trimethylchlorosilane head tank 1, and maintain a slight negative pressure in the trimethylchlorosilane head tank 1 before starting feeding, and maintain a vacuum degree of 0.001-0.005 MPa.

(2) Synthetic kettle 3 feeding

Add 110kg of acetamide, 400kg of triethylamine, 0.3kg of 2,6-dimethylaniline and 0.2kg of imidazole into synthesis kettle 3, start stirring, and set the speed of the stirrer at 90RPM. After stirring for 50 minutes, adjust the vacuum degree of the synthesis kettle 3 to 0.01-0.015 MPa.

(3) Start adding trimethylchlorosilane dropwise

Adjust trimethylchlorosilane header tank 1 to normal pressure. Add trimethylchlorosilane dropwise into the kettle, and the feeding port of trimethylchlorosilane must be submerged 20-35cm below the liquid level of the synthesis kettle 3; start to drop trimethylchlorosilane into the synthesis kettle 3 to start the circulation pump 4, and the material Enter the synthetic kettle 3 through the circulating pump 4, the first filter 5 and the second filter 6 successively, and filter out the triethylamine hydrochloride generated in the first filter 5 and the second filter 6; The feeding port of the circulation pipeline of synthesis kettle 3 must be submerged 20-35cm below the liquid level of synthesis kettle 3.

(4) Adjust the drop rate and temperature of trimethylchlorosilane

Adjust the dropping rate of trimethylchlorosilane, control the dropping temperature to 33-35° C., and control the addition of trimethylchlorosilane within 100 minutes.

(5) Reaction

After the trimethylchlorosilane is added dropwise, keep the reaction temperature at 33-35° C., keep the vacuum degree of the synthesis kettle 3 at 0.01-0.015 MPa, and continue the circulation with the circulation pump 4 for 130 minutes, and the reaction ends.

(6) The material is sent to the distillation kettle

Close the material valve leading to the synthesis kettle 3, open the valve leading to the distillation kettle 7, open the circulation pump 4, send the material in the synthesis kettle 3 to the distillation kettle 7, and add the front fraction of Example 2.

(7) Distillation to obtain the former fraction

The distillation tower used for distillation is a packed tower 8 with a tower height of 4 meters and PTFE packing inside.

A. Collection of the first preceding fraction

First turn on the hydraulic jet pump 12, and when the vacuum reaches 0.082-0.086 MPa, feed steam into the jacket of the still 7 to heat the material in the still, and carefully observe the steaming of the material through the second pipeline sight cup 17; when the second pressure (Vacuum degree) After the vacuum degree displayed by the local indicating device 18 is stable, the obtained condensate before 68°C (<68°C) is used as the front fraction, and the front fraction is connected to the front fraction receiving tank 10 to obtain the first front fraction ;

B. Collection of the second front fraction

When the gas phase temperature gradually increases to 68.1°C, first close the steam valve, then switch the vacuum system, and switch the hydraulic jet vacuum pump 12 to the oil-sealed mechanical vacuum pump 13. After the oil-sealed mechanical vacuum pump 13 runs stably and the vacuum degree is stable, observe the change of the gas phase temperature of the second temperature local indicator device 16, keep the vacuum degree and intercept the vacuum degree to be 0.096-0.099MPa; after opening the steam valve again, the obtained 68.1-70 The condensate at ° C. is also used as the front cut to enter the front cut receiving tank 10 to obtain the second front cut.

(8) Distilled products

When the gas phase temperature is gradually increased to 70.1°C, close the valve of the front fraction receiving tank 10 and open the valve of the finished product receiving tank 11, intercept 70.1-73°C, and the obtained condensate is used as a finished product and connected to the finished product receiving tank 11.

(9) Close the distillation system, pack and store finished products, and store at low temperature

When observing the temperature increase shown by the second temperature on-site indicating device 16 and observing that the condensate flow out from the condenser 9 decreases by the second pipeline sight glass 17, first close the distillation kettle 7 heating steam, when it is observed When the second pipeline sees the cup 17 liquid almost without dripping, close the oil-sealed mechanical vacuum pump 13, and the finished product is packaged and put into storage, and stored at low temperature under nitrogen-tight conditions. The prepared product has a one-way yield of 92.96% and a purity (GC) of 99.52%. see table 3

The product quality index that table 3 makes

After the product is stored for one year, the purity of the product is 99.40% (GC), and the appearance is a colorless transparent liquid without floc.

Embodiment 4 A kind of two-component catalyst synthesis N, the method of O-bis (trimethylsilyl) acetamide

The reaction is carried out in a 1000L kettle, and the synthesis steps are as follows:

(1) Adding trimethylchlorosilane

Use vacuum to pump 460kg of trimethylchlorosilane into the trimethylchlorosilane header tank 1, and maintain a slight negative pressure in the trimethylchlorosilane header tank 1 before starting to feed, and maintain a vacuum degree of 0.001-0.005MPa.

(2) Synthetic kettle 3 feeding

Add 120kg of acetamide, 440kg of triethylamine, 0.3kg of 2,6-dimethylaniline and 0.3kg of imidazole into synthesis kettle 3, start stirring, and set the speed of the stirrer at 90RPM. After stirring for 50 minutes, adjust the vacuum degree of the synthesis kettle 3 to 0.015-0.02MPa.

(3) Start adding trimethylchlorosilane dropwise

Adjust trimethylchlorosilane header tank 1 to normal pressure. Add trimethylchlorosilane dropwise into the kettle, and the feeding port of trimethylchlorosilane must be submerged 20-35cm below the liquid level of the synthesis kettle 3; start to drop trimethylchlorosilane into the synthesis kettle 3 to start the circulation pump 4, and the material Enter the synthetic kettle 3 through the circulating pump 4, the first filter 5 and the second filter 6 successively, and filter out the triethylamine hydrochloride generated in the first filter 5 and the second filter 6; The feeding port of the circulation pipeline of synthesis kettle 3 must be submerged 20-35cm below the liquid level of synthesis kettle 3.

(4) Adjust the drop rate and temperature of trimethylchlorosilane

Adjust the drop rate of trimethylchlorosilane, control the dropping temperature to 36-39° C., and control the addition of trimethylchlorosilane within 110 minutes.

(5) Reaction

After the trimethylchlorosilane is added dropwise, keep the reaction temperature at 36-39° C., keep the vacuum degree of the synthesis kettle 3 at 0.015-0.02 MPa, and continue the circulation with the circulation pump 4 for 150 minutes, and the reaction ends.

(6) The material is sent into the distillation kettle 7

Close the material valve leading to the synthesis kettle 3, and open the valve leading to the still kettle 7. Open the circulation pump 4, the material in the synthesis kettle 3 is sent to the distillation kettle 7, and add the front fraction of Example 3.

(7) Distillation to obtain the former fraction

The distillation tower used for distillation is a packed tower 8 with a tower height of 4 meters and PTFE packing inside.

A. Collection of the first preceding fraction

First turn on the hydraulic jet pump 12, and when the vacuum degree reaches 0.082-0.086MPa, feed steam into the jacket of the distillation kettle 7 to heat the materials in the kettle, and carefully observe the steaming of the materials through the second pipeline sight cup 17. When the vacuum degree displayed by the second pressure (vacuum degree) on-site indicator device 18 is stable, the obtained condensate before 68°C (<68°C) is used as the former fraction, and the former fraction is connected to the former fraction receiving tank 10;

B. Collection of the second front fraction

When the gas phase temperature gradually increases to 68.1°C, first close the steam valve, then switch the vacuum system, and switch the hydraulic jet vacuum pump 12 to the oil-sealed mechanical vacuum pump 13. After the oil-sealed mechanical vacuum pump 13 runs stably and the vacuum degree is stable, observe the change of the gas phase temperature of the second temperature on-site indicating device 16, maintain the vacuum degree and intercept the vacuum degree to be 0.096-0.099 MPa. After the steam valve is opened again, the obtained condensate at 68.1-70° C. is also put into the front fraction receiving tank 10 as the front fraction.

(8) Distilled products

When the gas phase temperature gradually increases to 70.1°C, close the valve of the front distillate receiving tank 10 and open the valve of the finished product receiving tank 11, and the obtained condensate is intercepted at 70.1-73°C as a finished product and connected to the finished product receiving tank 11.

(9) Close the distillation system, pack and store finished products, and store at low temperature

When observing the temperature increase shown by the second temperature on-site indicating device 16 and observing that the condensate flow out from the condenser 9 decreases by the second pipeline sight glass 17, first close the distillation kettle 7 heating steam, when it is observed When the second pipeline sees the cup 17 liquid almost without dripping, close the oil-sealed mechanical vacuum pump 13, and the finished product is packaged and put into storage, and stored at low temperature under nitrogen-tight conditions. The prepared product has a one-way yield of 93.28% and a purity (GC) of 99.60%. see table 4

The product quality index that table 4 makes

After the product is stored for one year, the purity of the product is 99.50% (GC), and the appearance is a colorless transparent liquid without floc.

Embodiment 5 A kind of two-component catalyst synthesis N, the method of O-bis (trimethylsilyl) acetamide

The reaction is carried out in a 1000L kettle, and the synthesis steps are as follows:

(1) Adding trimethylchlorosilane

Use vacuum to pump 470kg of trimethylchlorosilane into the trimethylchlorosilane head tank 1, and maintain a slight negative pressure in the trimethylchlorosilane head tank 1 before starting to feed, and maintain a vacuum degree of 0.001-0.005MPa.

(2) Synthetic kettle 3 feeding

Add 120kg of acetamide, 460kg of triethylamine, 0.45kg of 2,6-dimethylaniline and 0.4kg of imidazole into synthesis kettle 3, start stirring, and set the speed of the stirrer at 100RPM. After stirring for 55 minutes, adjust the vacuum degree of the synthesis kettle 3 to 0.02-0.025 MPa.

(3) Start adding trimethylchlorosilane dropwise

Adjust the trimethylchlorosilane head tank 1 to normal pressure, drop trimethylchlorosilane into the kettle, the trimethylchlorosilane feeding port must be submerged 20-35cm below the liquid level of the synthesis kettle 3; Adding trimethylchlorosilane dropwise starts the circulation pump 4, and the material passes through the circulation pump 4, the first filter 5, and the second filter 6 successively and enters the synthesis kettle 3, and is filtered in the first filter 5 and the second filter 6. In addition to the generated triethylamine hydrochloride; the feed port of the circulation line of the synthesis kettle 3 must be submerged 20-35cm below the liquid level of the synthesis kettle 3 when the circulating liquid enters.

(4) Adjust the drop rate and temperature of trimethylchlorosilane

Adjust the drop rate of trimethylchlorosilane, control the dropping temperature to 36-39° C., and control the addition of trimethylchlorosilane within 110 minutes.

(5) Reaction

After the trimethylchlorosilane is added dropwise, keep the reaction temperature at 36-39° C., keep the vacuum degree of the synthesis kettle 3 at 0.02-0.025 MPa, and continue the circulation with the circulation pump 4 for 150 minutes, and the reaction ends.

(6) The material is sent into the distillation kettle 7

Close the material valve leading to the synthesis kettle 3, and open the valve leading to the still kettle 7. Open the circulation pump 4, the material in the synthesis kettle 3 is sent to the distillation kettle 7, and add the front fraction of Example 4.

(7) Distillation to obtain the former fraction

The distillation tower used for distillation is a packed tower 8 with a tower height of 4 meters and PTFE packing inside.

A. Collection of the first preceding fraction

First turn on the hydraulic jet pump 12, and when the vacuum degree reaches 0.082-0.086MPa, feed steam into the jacket of the distillation kettle 7 to heat the materials in the kettle, and carefully observe the steaming of the materials through the second pipeline sight cup 17. When the vacuum degree displayed by the second pressure (vacuum degree) on-site indicator device 18 is stable, the obtained condensate before 68°C (<68°C) is used as the former fraction, and the former fraction is connected to the former fraction receiving tank 10;

B. Collection of the second front fraction

When the gas phase temperature gradually increases to 68.1°C, first close the steam valve, then switch the vacuum system, and switch the hydraulic jet vacuum pump 12 to the oil-sealed mechanical vacuum pump 13. After the oil-sealed mechanical vacuum pump 13 runs stably and the vacuum degree is stable, observe the change of the gas phase temperature of the second temperature on-site indicating device 16, maintain the vacuum degree and intercept the vacuum degree to be 0.096-0.099 MPa. After the steam valve is opened again, the obtained condensate at 68.1-70° C. is also put into the front fraction receiving tank 10 as the front fraction.

(8) Distilled products

When the gas phase temperature gradually increases to 70.1°C, close the valve of the front distillate receiving tank 10 and open the valve of the finished product receiving tank 11, and the obtained condensate is intercepted at 70.1-73°C as a finished product and connected to the finished product receiving tank 11.

(9) Close the distillation system, pack and store finished products, and store at low temperature

When observing the temperature increase shown by the second temperature on-site indicating device 16 and observing that the condensate flow out from the condenser 9 decreases by the second pipeline sight glass 17, first close the distillation kettle 7 heating steam, when it is observed When the liquid in the second pipeline sight cup almost does not drip, the oil-sealed mechanical vacuum pump 13 is closed, and the finished product is packaged and put into storage, and stored at low temperature under nitrogen-tight conditions.

The prepared product has a one-way yield of 93.66% and a purity (GC) of 99.62%. see table 5

The product quality index that table 5 makes

After the product is stored for one year, the purity of the product is 99.53% (GC), and the appearance is a colorless transparent liquid without floc.

Unless otherwise specified, the percentages used in the present invention are all weight percentages, and the ratios described in the present invention are all mass ratios.

Finally, it should be noted that: the above is only a preferred embodiment of the present invention, and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, it still The technical solutions recorded in the foregoing embodiments may be modified, or some technical features thereof may be equivalently replaced. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (9)

1. the method for a dual-component catalyst synthesis N, O-bis-(trimethylsilyl) ethanamide, is characterized in that: comprise trimethylchlorosilane and feed in raw material, synthesis reactor feeds in raw material, and regulates trimethylchlorosilane rate of addition, temperature, reaction.

2. a kind of dual-component catalyst synthesis N according to claim 1, the method of O-bis-(trimethylsilyl) ethanamide, it is characterized in that: described synthesis reactor feeds in raw material, and ethanamide, triethylamine, catalyzer xylidine and catalyzer imidazoles are added synthesis reactor; Described ethanamide and triethylamine weight ratio are 1:3.60-3.94.

3. the method for a kind of dual-component catalyst synthesis N, O-bis-(trimethylsilyl) ethanamide according to claim 2, is characterized in that: described catalyzer xylidine consumption is the 0.1-0.5% of ethanamide weight.

4. the method for a kind of dual-component catalyst synthesis N, O-bis-(trimethylsilyl) ethanamide according to claim 2, is characterized in that: described catalyzer imidazoles consumption is the 0.08-0.6% of ethanamide weight.

5. a kind of dual-component catalyst synthesis N according to claim 1, the method of O-bis-(trimethylsilyl) ethanamide, it is characterized in that: described trimethylchlorosilane feeds in raw material, the add-on of trimethylchlorosilane and the weight ratio of ethanamide are 3.77-4.03:1.

6. a kind of dual-component catalyst synthesis N according to claim 2, the method of O-bis-(trimethylsilyl) ethanamide, it is characterized in that: described synthesis reactor feeds in raw material, after raw material adds, start to stir, agitator speed is set as 85-100RPM, stirs after 45-55 minute, and adjustment synthesis reactor vacuum tightness is 0.01-0.025MPa.

7. a kind of dual-component catalyst synthesis N according to claim 1, the method of O-bis-(trimethylsilyl) ethanamide, it is characterized in that: described adjustment trimethylchlorosilane rate of addition, temperature, control dropping temperature 33-39 DEG C, trimethylchlorosilane controls to add in 90-110 minute.

8. a kind of dual-component catalyst synthesis N according to claim 1, the method of O-bis-(trimethylsilyl) ethanamide, it is characterized in that: described reaction, trimethylchlorosilane dropwises, continue to keep temperature of reaction to be 33-39 DEG C, keep synthesis reactor vacuum tightness to be 0.01-0.025MPa, recycle pump continues circulation 120-150 minute, and reaction terminates.

9. the method for a kind of dual-component catalyst synthesis N, O-bis-(trimethylsilyl) ethanamide according to claim 1, it is characterized in that: finished product prepared by the present invention, purity is 99.51-99.62%, and once through yield is 91.33-93.66%.