Preparation method of 1, 1, 3-tribromoacetone compound

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a preparation method of a 1, 1, 3-tribromoacetone compound. According to the present invention, the composite catalyst system using tetrabutylammonium bromide as the phase transfer catalyst and using 1, 3-dibromoacetone and 1, 1, 3, 3-tetrabromoacetone as the selective catalyst is adopted, and 1, 3-dibromoacetone and 1, 1, 3, 3-tetrabromoacetone are used to improve the conversion rate of 1, 1, 3-tribromoacetone so as to achieve the purpose of catalytic effect improving, and the method is suitable for large-scale industrial application. According to the liquid composite catalyst, the reaction rate is increased, the product yield and purity are improved, rapid separation of the catalyst is achieved, the product stability is effectively improved, the catalyst can be recycled and reused, the inactivation problem is avoided, the production cost is reduced, and waste is avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and more specifically relates to a method for preparing a 1,1,3-tribromoacetone compound. Background Art

[0002] 1,1,3-Tribromoacetone is an organic raw material and ketone compound, mainly used for the synthesis of pteroic acid, methotrexate, (Z)-3-bromoacrylic acid, and 4-[N-(2,4-diamino-6-pteroylmethyl)-N-methylamino]benzoic acid hemihydrochloride. For example, the one-pot synthesis of methotrexate is a one-step synthesis using p-methylaminobenzoylglutamic acid, tetraaminopyrimidine sulfate or hydrochloride and 1,1,3-tribromoacetone. Methotrexate is an anti-tumor drug that interferes with folic acid metabolism. It can inhibit dihydrofolate reductase and prevent dihydrofolate from being reduced to physiologically active tetrahydrofolate, thereby hindering the transfer of one-carbon groups of purine nucleotides and pyrimidine nucleotides in their biosynthesis, thereby hindering the synthesis of DNA, RNA and some proteins to exert its efficacy. At present, methotrexate is widely used in clinical practice to treat osteosarcoma, acute lymphoblastic leukemia and malignant lymphoma. In addition, small doses of methotrexate are also commonly used to treat rheumatoid arthritis and inflammatory bowel disease.

[0003] However, the preparation method of 1,1,3-tribromoacetone disclosed in the prior art is single, wherein the raw materials include acetone, bromine, and hydrobromic acid, and it needs to be prepared through a long reaction and a multi-step post-treatment process. The yield and purity of the reaction product are low, and the process has more three wastes, greater pollution, and higher treatment costs.

[0004] Therefore, how to provide a method for preparing 1,1,3-tribromoacetone compound is a problem that those skilled in the art need to solve urgently. Summary of the invention

[0005] In order to overcome the shortcomings and deficiencies in the prior art, the present invention provides a method for preparing a 1,1,3-tribromoacetone compound, which utilizes the efficient catalysis of a liquid composite catalyst to accelerate the reaction rate, improve the product yield and purity, and realize rapid separation of the catalyst, thereby effectively improving the stability of the product.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] A method for preparing a 1,1,3-tribromoacetone compound comprises the following steps:

[0008] (1) In a reaction kettle, acetone and a liquid composite catalyst are added to hydrobromic acid and stirred to form a clear liquid as a reaction substrate;

[0009] (2) controlling the temperature of the reactor, continuously adding bromine, opening the falling film absorber to recover the by-product hydrobromic acid, and after the addition is completed, carrying out a heat preservation reaction;

[0010] (3) Cooling the reactor, standing it, separating the liquids, transferring the lower layer of liquid to a crystallization reactor, cooling it for crystallization, and centrifuging it to obtain the product 1,1,3-tribromoacetone and a mother liquor containing a liquid composite catalyst. The mother liquor is cooled and crystallized to recover the liquid composite catalyst.

[0011] Preferably, the liquid composite catalyst is a mixture of 1,3-dibromoacetone, 1,1,3,3-tetrabromoacetone and tetrabutylammonium bromide.

[0012] Preferably, the preparation method of the liquid composite catalyst is: in a reaction kettle, tetrabutylammonium bromide and 1,1,3,3-tetrabromoacetone are added to 1,3-dibromoacetone and stirred for 2 hours to form a clear liquid;

[0013] The molar ratio of tetrabutylammonium bromide, 1,1,3,3-tetrabromoacetone and 1,3-dibromoacetone is 1:1:1.25.

[0014] The beneficial effects of the above technical solution are as follows: the invention adds 1,3-dibromoacetone and 1,1,3,3-tetrabromoacetone to the system, which can significantly reduce the occurrence of side reactions and increase the content of acetone converted into 1,1,3-tribromoacetone. Tetrabutylammonium bromide is used as a phase transfer catalyst to increase the two-phase reaction rate and improve the overall effect of the catalyst.

[0015] Preferably, in step (1), the mass ratio of hydrobromic acid to acetone is 8:1, and the mass ratio of the liquid composite catalyst to hydrobromic acid is 0.7-0.8:1.

[0016] Preferably, the stirring time in step (1) is 1 h.

[0017] Preferably, in step (2), the temperature of the reaction kettle is controlled to be 10-15°C.

[0018] Preferably, the molar ratio of bromine to acetone in step (2) is 3.1:1.

[0019] Preferably, the temperature of the insulation reaction in step (2) is 20° C. and the time is 3 hours.

[0020] Preferably, the reaction kettle in step (3) is cooled to 10° C. and allowed to stand for 1 hour.

[0021] Preferably, the temperature of the cooling and crystallization in step (3) is -10°C and the time is 12h.

[0022] It can be seen from the above technical solution that, compared with the prior art, the present invention provides a method for preparing 1,1,3-tribromoacetone compound, which has the following beneficial effects:

[0023] (1) The present invention solves the problem of low yield of 1,1,3-tribromoacetone, utilizes liquid composite catalyst for efficient catalysis, accelerates the reaction rate, improves product yield and purity, and realizes rapid separation of catalyst, effectively improves product stability, and is suitable for large-scale industrial application.

[0024] (2) The present invention adopts tetrabutylammonium bromide as a phase transfer catalyst, and 1,3-dibromoacetone and 1,1,3,3-tetrabromoacetone as a composite catalyst system of selective catalysts, and utilizes 1,3-dibromoacetone and 1,1,3,3-tetrabromoacetone to improve the conversion rate of 1,1,3-tribromoacetone, thereby achieving the purpose of improving the catalytic effect.

[0025] (3) The catalyst of the present invention can be recycled and reused without the problem of deactivation, which not only reduces production costs but also avoids the generation of waste. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0027] Figure 1 The gas chromatogram of the product obtained in Example 1 is shown in FIG.

[0028] Figure 2 The gas chromatogram of the product obtained in Example 2 is shown in FIG.

[0029] Figure 3 The gas chromatogram of the product obtained in Comparative Example 1 is shown in FIG. DETAILED DESCRIPTION

[0030] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] Example 1

[0032] A method for preparing a liquid composite catalyst comprises the following steps:

[0033] In a reaction kettle, tetrabutylammonium bromide and 1,1,3,3-tetrabromoacetone are added to 1,3-dibromoacetone and stirred for 2 hours to form a clear liquid; the amount of tetrabutylammonium bromide added is 1 mol, the amount of 1,1,3,3-tetrabromoacetone added is 1 mol, and the amount of 1,3-dibromoacetone added is 1.25 mol.

[0034] A method for preparing a 1,1,3-tribromoacetone compound comprises the following steps:

[0035] (1) In a reaction kettle, acetone and a liquid composite catalyst are added to hydrobromic acid and stirred for 1 hour to form a clear liquid; the amount of acetone added is 1 mol, the amount of hydrobromic acid added is 8 times the mass of acetone, and the amount of the liquid composite catalyst added is 0.7 times the mass of hydrobromic acid;

[0036] (2) Controlling the temperature of the reactor to 10-15° C., continuously adding bromine, opening the falling film absorber to recover the by-product hydrobromic acid, and after the addition is complete, keeping the temperature at 20° C. for 3 h; the amount of bromine added is 3.1 mol;

[0037] (3) The reaction kettle was cooled to 10°C, allowed to stand for 1 hour, and the liquid was separated. The lower layer of the liquid was transferred to a crystallization kettle. The crystallization kettle was cooled to -10°C, and crystallization was carried out at -10°C for 12 hours. The product 1,1,3-tribromoacetone and a mother liquor containing a liquid composite catalyst were obtained by centrifugation. The mother liquor was cooled and crystallized to recover the liquid composite catalyst.

[0038] The yield of 1,1,3-tribromoacetone in Example 1 was 53.98%. The purity of the prepared 1,1,3-tribromoacetone was tested by high performance gas chromatography, and the purity was 94.64%.

[0039] Example 2

[0040] A method for preparing a liquid composite catalyst comprises the following steps:

[0041] In a reaction kettle, tetrabutylammonium bromide and 1,1,3,3-tetrabromoacetone are added to 1,3-dibromoacetone and stirred for 2 hours to form a clear liquid; the amount of tetrabutylammonium bromide added is 1 mol, the amount of 1,1,3,3-tetrabromoacetone added is 1 mol, and the amount of 1,3-dibromoacetone added is 1.25 mol.

[0042] A method for preparing a 1,1,3-tribromoacetone compound comprises the following steps:

[0043] (1) In a reaction kettle, acetone and a liquid composite catalyst are added to hydrobromic acid and stirred for 1 hour to form a clear liquid; the amount of acetone added is 1 mol, the amount of hydrobromic acid added is 8 times the mass of acetone, and the amount of the liquid composite catalyst added is 0.8 times the mass of hydrobromic acid;

[0044] (2) Controlling the temperature of the reactor to 10-15° C., continuously adding bromine, opening the falling film absorber to recover the by-product hydrobromic acid, and after the addition is complete, keeping the temperature at 20° C. for 3 h; the amount of bromine added is 3.1 mol;

[0045] (3) The reaction kettle was cooled to 10°C, allowed to stand for 1 hour, and the liquid was separated. The lower layer of the liquid was transferred to a crystallization kettle. The crystallization kettle was cooled to -10°C, and crystallization was carried out at -10°C for 12 hours. The product 1,1,3-tribromoacetone and a mother liquor containing a liquid composite catalyst were obtained by centrifugation. The mother liquor was cooled and crystallized to recover the liquid composite catalyst.

[0046] The yield of 1,1,3-tribromoacetone in Example 2 was 55.29%. The purity of the prepared 1,1,3-tribromoacetone was tested by high performance gas chromatography, and the purity was 93.63%.

[0047] Comparative Example 1

[0048] A method for preparing a 1,1,3-tribromoacetone compound comprises the following steps:

[0049] (1) In a reaction kettle, acetone is added to hydrobromic acid and stirred for 1 hour to form a clear liquid; the amount of acetone added is 1 mol, and the amount of hydrobromic acid added is 8 times the mass of acetone;

[0050] (2) Controlling the temperature of the reactor to 10-15° C., continuously adding bromine, opening the falling film absorber to recover the by-product hydrobromic acid, and after the addition is complete, keeping the temperature at 20° C. for 3 h; the amount of bromine added is 3.1 mol;

[0051] (3) The reaction kettle was cooled to 10°C, left to stand for 1 hour, and the liquid was separated. The lower layer of liquid was transferred to a crystallization kettle, and the crystallization kettle was cooled to -10°C. Crystallization was carried out at -10°C for 12 hours, and the product 1,1,3-tribromoacetone was obtained by centrifugation.

[0052] The yield of 1,1,3-tribromoacetone in Comparative Example 1 was 27.9%. The purity of the prepared 1,1,3-tribromoacetone was tested by high performance gas chromatography, and the purity was 84.78%.

[0053] The specific detection steps of high performance gas chromatography are as follows:

[0054] Instrument: Shimadzu GC-2010 gas chromatograph.

[0055] Chromatographic column: SE-54, 30m*0.53mm*1.0μm.

[0056] Chromatographic conditions: detector: FID; carrier gas: N2; air: 360 ml / min; carrier gas flow rate: 1.0 mL / min; split ratio: 30:1: column temperature: 200°C: vaporizer temperature: 250°C: detector temperature: 250°C; injection volume: 0.2 μL.

[0057] Detection method: Melt the test sample with warm water, take a sample, inject 0.2μL, and analyze and measure it in a gas chromatograph. Press the stop button after 10 minutes.

[0058] Calculation method: area normalization method.

[0059] Tables 1-2 are the peak tables of Examples 1-2 respectively. Table 3 is the peak table of Comparative Example 1.

[0060] Table 1

[0061] SFID1

[0062] Peak Retention time area high concentration Concentration Unit area% 1 1.291 72205 17941 0.000 0.267 2 1.376 8749 4563 0.000 0.032 3 1.464 1057204 217765 0.000 3.907 4 1.715 25609623 5323990 0.000 94.641 5 2.179 275170 49005 0.000 1.017 6 2.404 1179 254 0.000 0.004 7 2.679 2530 401 0.000 0.009 8 3.394 6981 832 0.000 0.026 9 3.866 8808 762 0.000 0.033 10 4.164 4613 593 0.000 0.017 11 4.852 3517 497 0.000 0.013 12 5.171 1650 175 0.000 0.006 13 5.389 2727 341 0.000 0.010 14 5.780 2665 244 0.000 0.010 15 8.330 2273 262 0.000 0.008 total 27059894 5617625 100.000

[0063] Table 2

[0064] SFID1

[0065] Peak Retention time area high concentration area% 1 1.302 22264 5479 0.000 0.057 2 1.403 23862 8141 0.000 0.061 3 1.467 1690600 478006 0.000 4.339 4 1.721 36485096 10201328 0.000 93.634 5 2.171 729492 181926 0.000 1.872 6 3.357 13061 2575 0.000 0.034 7 4.188 1122 189 0.00o 0.003 total 38965497 10877645 100.000

[0066] Table 3 SFID1

[0067] Peak Retention time area high concentration Concentration Unit area% 1 1.283 91326 28639 0.000 0.333 2 1.380 68608 25859 0.000 0.250 3 1.447 2180471 653210 0.000 7.946 4 1.694 23264847 6848555 0.000 84.779 5 2.151 1671341 429862 0.000 6.090 6 2.670 4676 650 0.000 0.017 7 3.319 145306 31951 0.000 0.530 8 3.737 3737 650 0.000 0.014 9 4.128 11476 1537 0.000 0.042 total 27441787 8020912 100.000

[0068] In this specification, each embodiment is described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the embodiments can be referred to each other. For the scheme disclosed in the embodiment, since it corresponds to the method disclosed in the embodiment, the description is relatively simple, and the relevant parts can be referred to the method part.

[0069] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing 1,1,3-tribromoacetone compound, characterized in that: The steps include: (1) In a reaction kettle, acetone and a liquid composite catalyst are added to hydrobromic acid and stirred to form a clear liquid as a reaction substrate; (2) controlling the temperature of the reactor, continuously adding bromine, opening the falling film absorber to recover the by-product hydrobromic acid, and after the addition is completed, carrying out a heat preservation reaction; (3) Cooling the reactor, standing it, separating the liquids, transferring the lower layer of liquid to a crystallization reactor, cooling it for crystallization, and centrifuging it to obtain the product 1,1,3-tribromoacetone and a mother liquor containing a liquid composite catalyst. The mother liquor is cooled and crystallized to recover the liquid composite catalyst.

2. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: The liquid composite catalyst is a mixture of 1,3-dibromoacetone, 1,1,3,3-tetrabromoacetone and tetrabutylammonium bromide.

3. The method for preparing 1,1,3-tribromoacetone compound according to claim 2, characterized in that: The preparation method of the liquid composite catalyst is as follows: in a reaction kettle, tetrabutylammonium bromide and 1,1,3,3-tetrabromoacetone are added to 1,3-dibromoacetone and stirred for 2 hours to form a clear liquid; The molar ratio of tetrabutylammonium bromide, 1,1,3,3-tetrabromoacetone and 1,3-dibromoacetone is 1:1:1.

25.

4. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: In step (1), the mass ratio of hydrobromic acid to acetone is 8:1, and the mass ratio of the liquid composite catalyst to hydrobromic acid is 0.7-0.8:

1.

5. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: The stirring time in step (1) is 1 h.

6. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: In step (2), the temperature of the reaction kettle is controlled to be 10-15°C.

7. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: The molar ratio of bromine to acetone in step (2) is 3.1:

1.

8. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: The temperature of the insulation reaction in step (2) is 20° C. and the time is 3 hours.

9. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: The reaction kettle in step (3) was cooled to 10°C and allowed to stand for 1 hour.

10. The method for preparing 1,1,3-tribromoacetone compound according to claim 1, characterized in that: The temperature of the cooling and crystallization in step (3) is -10°C and the time is 12h.

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