A kind of preparation method of 8-bromophylline

Abstract

The invention discloses a method for preparing 8-bromophylline, and belongs to the technical field of chemical synthesis. The method for preparing 8-bromophylline of the invention does not use liquid bromine but uses N-bromosuccinimide as a bromination reagent, and at the same time relies on a special dispersion environment to significantly reduce the probability of generating an impurity such as 8-chlorophylline or other impurities in the reaction, and the product purity is high; the preparation method is efficient and simple, and the yield can reach more than 50%.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing 8-bromophylline. Background Art

[0002] Pamabrom, whose chemical name is 2-amino-2-methylpropanol 8-bromocholine, has a certain diuretic effect. Therefore, it is also used in combination with acetanilide antipyretic and analgesic acetaminophen to treat premenstrual syndrome or primary dysmenorrhea in women, and to relieve the swelling and water retention symptoms during menstruation and the headaches, breast swelling and pain and other discomforts caused by it.

[0003] 8-Bromophophylline is an important intermediate for the preparation of pamabrom, and its chemical structure is as follows:

[0004] ;

[0005] 8-bromophylline is mainly obtained by theophylline reaction, and its reaction formula is as follows:

[0006] ;

[0007] At present, the reaction process mostly uses liquid bromine as the bromination reagent, and the entire reaction is carried out in water. However, liquid bromine is highly toxic and corrosive, and is highly dangerous, making it unsuitable as the main reagent raw material in large-scale synthesis processes. Moreover, in the existing synthesis process, chlorine residues are inevitably present in the bromination reagent during industrial synthesis preparation. For example, chlorine is contained in the raw material brine of liquid bromine during the production process, which is the upstream raw material of liquid bromine. These residual chlorines will react with theophylline during the synthesis reaction of 8-bromotheophylline to undergo chlorination reaction and eventually generate the impurity 8-chlorotheophylline (impurity B), whose structural formula is as follows:

[0008] ;

[0009] 8-Chlorophylline and 8-bromophylline have similar structures and chemical properties, and are difficult to remove in the subsequent refining process, which ultimately affects the purity of 8-bromophylline and even the final product, pamabrom. Summary of the invention

[0010] Based on the defects of the prior art, the purpose of the present invention is to provide a method for preparing 8-bromotheophylline, which does not use liquid bromine but uses N-bromosuccinimide as a bromination reagent, and at the same time relies on a special dispersion environment to significantly reduce the probability of generating an impurity such as 8-chlorotheophylline or other impurities in the reaction, and the product purity is high; the preparation method is efficient and simple, and the yield can reach more than 50%.

[0011] In order to achieve the above object, the technical solution adopted by the present invention is:

[0012] A method for preparing 8-bromophylline comprises the following steps:

[0013] (1) Theophylline is placed in a dispersion and mixed evenly, and then N-bromosuccinimide is added to carry out a bromination reaction; the dispersion is a mixture of acetonitrile and N,N-dimethylformamide, and the volume ratio of the two is (4.5-5.5):1;

[0014] (2) After the bromination reaction in step (1) is completed, the obtained mixed solution A is cooled and diluted, the pH is adjusted to 4-6 and the reaction is continued with stirring to obtain a mixed solution B;

[0015] (3) The mixed solution B is filtered and the obtained solid is washed and dried to obtain 8-bromophylline.

[0016] In the preparation method of 8-bromotheophylline of the present invention, N-bromosuccinimide is used as a bromination reagent instead of traditional liquid bromine to react with theophylline for bromination. After the reaction is completed, the reaction system is diluted and adjusted to a weak acidity to effectively remove the remaining unreacted N-bromosuccinimide, and a high-yield and high-purity (low 8-chlorotheophylline content) product can be obtained through simple steps. At the same time, the inventors note that N-bromosuccinimide also has the problem of residual chlorine, mainly because chlorine is more active than bromine, so N-chlorosuccinimide will inevitably be carried during the synthesis, production, maintenance and even reaction of the raw materials; on the other hand, the reaction of theophylline and N-bromosuccinimide is a free radical reaction, and due to the difference in solubility of the two and impurity components in different dispersion environments, if the dispersion environment is not appropriate, the bromination reaction will be incomplete, and even more side reactions will occur. Based on the consideration of different impurity conditions, the invention uses a specific mixture of acetonitrile and N,N-dimethylformamide as the dispersion environment for the bromination reaction, and finds that under a specific ratio of the two, the reaction degree of the bromination reaction can be effectively controlled, so that the reaction degree is complete and effectively suppresses the generation of various impurities.

[0017] In addition, it should be noted that, since the synthesis scheme described in the present invention adopts a preferred dispersion liquid and a bromination reagent, the raw materials selected can be commercial products purchased on the market, or homemade products with similar quality. The raw materials can be products that have not been specially treated and have trace amounts of chlorine residues, or they can be pure products that have undergone secondary impurity removal treatment. As long as they do not affect the expected effect of the final product and are of an acceptable type in industrial synthesis, they can all be used.

[0018] Preferably, the bromination reaction time in step (1) is 4 to 6 hours.

[0019] Preferably, in step (1), the mass ratio of theophylline to the volume of the dispersion is 1 g: (5-10) mL;

[0020] More preferably, in step (1), the ratio of the mass of theophylline to the volume of the dispersion is 1 g: (6-8) mL.

[0021] Preferably, in step (1), the molar ratio of theophylline to N-bromosuccinimide is 1:(1.4-2).

[0022] The solubility of theophylline and N-bromosuccinimide in acetonitrile and N,N-dimethylformamide is not the same, and the generated impurities also have this situation. The bromination reaction is a free radical reaction. Therefore, if the solubility of the reaction raw materials in the dispersion is poor, the free radicals of the raw materials are likely to react with each other, and the target reaction degree of the product is low and there are many impurities. However, if the solubility of the reaction raw materials in the dispersion is high, it will lead to more side reactions and the purity of the product is also difficult to meet the standard. Therefore, whether it is the amount of reaction raw materials or dispersion added, it needs to be maintained within a specific range to ensure that the product raw materials can react completely without producing too many by-products (especially 8-chlorotheophylline).

[0023] Preferably, the temperature of the mixed solution A after cooling in step (2) is 20-30°C.

[0024] Preferably, the stirring reaction time in step (2) is 30 to 60 minutes.

[0025] By stirring the reaction for a period of time, the unreacted N,N-dimethylformamide in the reaction system can be effectively eliminated to avoid affecting the purity of the product.

[0026] The beneficial effects of the present invention are that the present invention provides a method for preparing 8-bromotheophylline, wherein the method does not use liquid bromine but uses N-bromosuccinimide as a bromination reagent, and simultaneously relies on a special dispersion environment to significantly reduce the probability of generating an impurity such as 8-chlorotheophylline or other impurities in the reaction, and the product purity is high; the preparation method is efficient and simple, and the yield can reach more than 50%, wherein when the best dispersion liquid ratio is selected, the purity of the obtained product can reach more than 99% at the highest, and the purity of the further prepared pamabrom is as high as 99.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a liquid chromatography test result diagram of sample No. 1 among the three batches of 8-bromophylline samples prepared in Example 2 of the present invention.

[0028] Figure 2 This is a liquid chromatography test result diagram of sample No. 2 among the three batches of 8-bromophylline samples prepared in Example 2 of the present invention.

[0029] Figure 3 This is a liquid chromatography test result diagram of sample No. 3 among the three batches of 8-bromophylline samples prepared in Example 2 of the present invention.

[0030] Figure 4 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Example 3 of the present invention.

[0031] Figure 5 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Example 4 of the present invention.

[0032] Figure 6 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Example 5 of the present invention.

[0033] Figure 7 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Example 6 of the present invention.

[0034] Figure 8 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Example 7 of the present invention.

[0035] Fig. 9 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Comparative Example 1 of the present invention.

[0036] Fig.10 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Comparative Example 2 of the present invention.

[0037] Fig.11 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Comparative Example 3 of the present invention.

[0038] Fig.12 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Comparative Example 4 of the present invention.

[0039] Fig.13 This is a liquid chromatography test result diagram of 8-bromophylline prepared in Comparative Example 5 of the present invention. DETAILED DESCRIPTION

[0040] In order to better illustrate the purpose, technical scheme and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments and comparative examples, the purpose of which is to understand the content of the present invention in detail, rather than to limit the present invention. All other embodiments obtained by those of ordinary skill in the art without making creative work premise belong to the protection scope of the present invention. The experimental reagents, raw materials and instruments designed for the implementation of the present invention and comparative examples are all commonly used ordinary reagents, raw materials and instruments unless otherwise specified.

[0041] Example 1

[0042] An embodiment of the preparation method of 8-bromophylline of the present invention comprises the following steps:

[0043] (1) 10 g (0.056 mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81 g (0.083 mol) of N-bromosuccinimide was slowly added in batches to carry out a bromination reaction, and the temperature during the addition was controlled to be below 40°C; the dispersion was a mixture of 50 mL of acetonitrile and 10 mL of N,N-dimethylformamide;

[0044] (2) After the bromination reaction in step (1) is completed for 5 hours, the obtained mixed solution A is cooled to 30°C and diluted with 90 mL of water, and the pH is adjusted to 4-6 with a 20% sodium hydroxide aqueous solution and the reaction is continued with stirring for 1 hour to obtain a mixed solution B;

[0045] (3) The mixed solution B is filtered and the obtained solid is washed and dried to obtain 8-bromophylline. The yield of the obtained product is calculated to be 55.14%.

[0046] Example 2

[0047] An embodiment of the preparation method of 8-bromophylline of the present invention comprises the following steps:

[0048] (1) 100 g (0.56 mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 1481 g (0.83 mol) of N-bromosuccinimide was slowly added in batches to carry out a bromination reaction, and the temperature during the addition was controlled to be below 40°C; the dispersion was a mixture of 500 mL of acetonitrile and 100 mL of N,N-dimethylformamide;

[0049] (2) After the bromination reaction in step (1) is completed for 5 hours, the obtained mixed solution A is cooled to 30°C and diluted with 900 mL of water, and the pH is adjusted to 4-6 with a 20% sodium hydroxide aqueous solution and the reaction is continued by stirring for 1 hour to obtain a mixed solution B;

[0050] (3) The mixed solution B is filtered, and the obtained solid is washed and dried to obtain 8-bromophylline, which is designated as sample No. 1;

[0051] (4) Two additional batches of products were prepared in parallel with the same steps as steps (1) to (3), and were named sample No. 2 and No. 3. The three batches of samples were subjected to liquid chromatography. The results are shown in Tables 1 and Figures 1 to 3 shown.

[0052] Table 1

[0053]

[0054] As can be seen from Table 1, the 8-bromophylline prepared in this embodiment has a high purity, all higher than 99%, and the content of the impurity 8-chlorophylline in the product is negligible or undetected, indicating that the method of the present invention can effectively avoid impurities generated by the traditional preparation process, and the yield reaches a maximum of more than 55%.

[0055] Further, the same method as above is used to prepare 8-bromophylline and used for preparing pamabrom, comprising the following steps:

[0056] In a reaction bottle equipped with a reflux tube and a thermometer, 75.0 g (0.29 mol) of 8-bromotheoline, 300 mL of anhydrous ethanol and 33.5 g (0.38 mol) of 2-amino-2-methylpropanol were added in sequence, the temperature was raised with stirring and refluxed to start the reaction until the reaction solution was clear, and the reaction was stopped after the insulation reaction for 1 hour. The obtained product was cooled and crystallized at 0±5°C for 2 hours, filtered, dried, and further recrystallized with anhydrous ethanol to obtain pharmaceutical grade Pamabrom. The above scheme was repeated twice to prepare a total of three batches of Pamabrom in parallel. The three batches of Pamabrom products were named No. 1-1, No. 2-1 and No. 3-1. The three batches of Pamabrom products were respectively subjected to liquid chromatography detection, and the results are shown in Table 2.

[0057] Table 2

[0058]

[0059] As can be seen from Table 2, when the 8-bromophylline prepared by the method of this embodiment is further used to prepare pamabrom, since the impurities contained in the raw materials are relatively small, the purity of the further prepared pamabrom product is also very high, and the content of 8-chlorophylline can still be controlled within a relatively low range.

[0060] Example 3

[0061] The difference between this embodiment and embodiment 1 is that the bromination reaction time of step (2) is 7 hours. The yield of 8-bromophylline is 52.4%. The obtained product is subjected to liquid chromatography detection. Figure 4 shown.

[0062] When the reaction time is extended from 5 h in Example 1 to 7 h, the content of impurity A in the product is lower. However, since the limit requirement for impurity A of the drug pamabrom is relatively wide in the United States Pharmacopoeia (not exceeding 0.5%) and it is easier to remove in the subsequent process, there is little significance in extending the reaction time.

[0063] Example 4

[0064] The difference between this embodiment and embodiment 1 is that the amount of water added in step (2) of embodiment 1 is increased to 1.5 times, i.e., 120 mL. The yield of 8-bromophylline obtained is 52.18%. The obtained product is subjected to liquid chromatography detection. Figure 5 shown.

[0065] The yield of the obtained product is between 50% and 55%, which is substantially unchanged compared with Example 1. Since among the numerous product impurities, only impurity B (8-chlorophylline) is difficult to remove, while the remaining impurities are relatively easy to remove, the contents of most of the remaining impurities in the product of this embodiment are below 0.1%, which can be considered to have substantially no effect.

[0066] Example 5

[0067] The difference between this embodiment and embodiment 1 is that step (1) is:

[0068] 10g (0.056mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81g (0.083mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled below 40°C; the dispersion was a mixture of 70mL of acetonitrile and 14mL of N,N-dimethylformamide. The yield of the obtained product was calculated to be 52.52%. The obtained product was subjected to liquid chromatography detection, as shown in FIG. Figure 6 shown.

[0069] Example 6

[0070] The difference between this embodiment and embodiment 1 is that step (1) is:

[0071] 10g (0.056mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81g (0.083mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled below 40°C; the dispersion was a mixture of 83mL of acetonitrile and 16.6mL of N,N-dimethylformamide. The yield of the obtained product was calculated to be 52.82%. The obtained product was tested by liquid chromatography, as shown in FIG. Figure 7 shown.

[0072] Compared with Example 1, the yield of the obtained product is between 50% and 55%, and the yield is basically unchanged. Since only impurity B (8-chlorophylline) is difficult to remove among the impurities generated in the product, while the remaining impurities are relatively easy to remove, the content of most of the impurities except impurity B in this embodiment is below 0.2%, which can be considered to have basically no effect.

[0073] Example 7

[0074] The difference between this embodiment and embodiment 1 is that step (1) is:

[0075] 10g (0.056mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 19.98g (0.112mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled below 40°C; the dispersion was a mixture of 50mL of acetonitrile and 10mL of N,N-dimethylformamide. The yield of the obtained product was calculated to be 52.85%, and the obtained product was subjected to liquid chromatography detection, as shown in FIG. Figure 8 shown.

[0076] Compared with Example 1, the yield of the obtained product is between 50% and 55%, and the yield is basically unchanged. Since only impurity B (8-chlorophylline) is difficult to remove among the impurities generated in the product, while the remaining impurities are relatively easy to remove, the content of most of the impurities except impurity B in this embodiment is below 0.2%, which can be considered to have basically no effect.

[0077] Comparative Example 1

[0078] The difference between this comparative example and Example 1 is that the step (1) is:

[0079] 10 g (0.056 mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81 g (0.083 mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled below 40°C; the dispersion was a mixture of 55 mL of acetonitrile and 5 mL of N,N-dimethylformamide.

[0080] The yield of the obtained product was 58.53%. The product was subjected to liquid chromatography detection. Fig. 9 As shown, the purity of the obtained product is 99.13%, wherein the content of impurity B 8-chlorophylline is 0.21%, and the impurity content is high.

[0081] Comparative Example 2

[0082] The difference between this comparative example and Example 1 is that the step (1) is:

[0083] 10 g (0.056 mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81 g (0.083 mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled below 40°C; the dispersion was a mixture of 52.5 mL of acetonitrile and 7.5 mL of N,N-dimethylformamide.

[0084] The yield of the obtained product was 55.18%. The product was subjected to liquid chromatography detection. Fig.10 As shown, the purity of the obtained product is 99.30%, wherein the content of impurity B 8-chlorophylline is 0.17%, and the impurity content is high.

[0085] Comparative Example 3

[0086] The difference between this comparative example and Example 1 is that the step (1) is:

[0087] 10 g (0.056 mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81 g (0.083 mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled below 40°C; the dispersion was a mixture of 40 mL of acetonitrile and 20 mL of N,N-dimethylformamide.

[0088] The yield of the obtained product was 47.15%. The product was subjected to liquid chromatography detection. Fig.11 As shown, the purity of the obtained product is 95.87%, wherein the content of the impurity 8-chlorotheophylline is 0.08%, and the impurity content is high.

[0089] Comparative Example 4

[0090] The difference between this comparative example and Example 1 is that the step (1) is:

[0091] 10 g (0.056 mol) of theophylline was placed in a reaction bottle containing a dispersion and mixed evenly, and then 14.81 g (0.083 mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled to be below 40° C.; the dispersion was 60 mL of acetonitrile.

[0092] The product was subjected to liquid chromatography test, such as Fig.12 As shown, the purity of the obtained product is 65.79%, wherein the content of the impurity 8-chlorotheophylline is 0.3%, and the impurity content is high.

[0093] Comparative Example 5

[0094] The difference between this comparative example and Example 1 is that the step (1) is:

[0095] 10 g (0.056 mol) of theophylline was placed in a reaction bottle containing the dispersion and mixed evenly, and then 14.81 g (0.083 mol) of N-bromosuccinimide was slowly added in batches to cause a bromination reaction, and the temperature during the addition was controlled to be below 40°C; the dispersion was 60 mL of N-bromosuccinimide.

[0096] The product was subjected to liquid chromatography test, such as Fig.13 As shown, the purity of the obtained product is 89.47%, and the product purity is low.

[0097] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 8-bromophylline, characterized in that: The following steps are involved: (1) Theophylline is placed in a dispersion and mixed evenly, and then N-bromosuccinimide is added to perform a bromination reaction; the dispersion is a mixture of acetonitrile and N,N-dimethylformamide, and the volume ratio of the two is (4.5-5.5):1; the mass ratio of theophylline to the volume of the dispersion is 1 g: (5-10) mL; the molar ratio of theophylline to N-bromosuccinimide is 1: (1.4-2); (2) After the bromination reaction in step (1) is completed, the obtained mixed solution A is cooled and diluted, the pH is adjusted to 4-6 and the reaction is continued with stirring to obtain a mixed solution B; (3) The mixed solution B is filtered and the obtained solid is washed and dried to obtain 8-bromophylline.

2. The method for preparing 8-bromophylline as claimed in claim 1, characterized in that: The bromination reaction time in step (1) is 4 to 6 hours.

3. The method for preparing 8-bromophylline as claimed in claim 1, characterized in that: In the step (1), the mass ratio of theophylline to the volume of the dispersion is 1 g: (6-8) mL.

4. The method for preparing 8-bromophylline as claimed in claim 1, characterized in that: The temperature of the mixed solution A after cooling in step (2) is 20-30°C.

5. The method for preparing 8-bromophylline as claimed in claim 1, characterized in that: The stirring reaction time in step (2) is 30 to 60 minutes.

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