Preparation method of promethazine oxalate

Abstract

The invention relates to the technical field of medicine synthesis methods, and discloses a preparation method of promethazine oxalate. The method comprises the following steps: (1) in the presence of isopropanol, adding an oxalic acid solution into a promethazine stock solution, and carrying out a salt forming reaction to obtain a salt solution; relative to 1 mol of the promethazine stock solution, the adding speed of the oxalic acid solution is 0.02 to 0.04 mol / min; the promethazine stock solution contains 25 to 30 weight percent of promethazine isomer and the balance of promethazine; (2) carrying out stirring treatment on the salt solution; the stirring treatment conditions are as follows: the temperature is 15-30 DEG C, and the time is 1-5 hours. The yield of the target product obtained by the method provided by the invention is stabilized between 67.5 mol% and 74.5 mol%, and the content of isomer impurities is kept below 7.2 wt%; moreover, the method does not need to adjust the pH value, is low in oxalic acid consumption, and has a better effect compared with the prior art.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis methods, and in particular to a method for preparing promethazine oxalate. Background Art

[0002] The chemical name of promethazine hydrochloride is 10-(2-dimethylamino-1-propyl) phenothiazine hydrochloride, its English name is Promethazine hydrochloride, its structural formula is shown in formula (a), and its properties are white to off-white powder.

[0003]

[0004] Promethazine hydrochloride is a phenothiazine drug that can block H1 receptors in smooth muscle, capillary wall and other tissues, thereby competing with histamine for antagonism. It can also have a significant central nervous system sedative effect, can enhance the effects of anesthetics, hypnotics and analgesia, and can lower body temperature and relieve vomiting. It can treat the following diseases: ① Skin and mucous membrane allergies, suitable for long-term seasonal allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, urticaria, food allergies, skin scratches; ② Motion sickness, suitable for patients with motion sickness, seasickness, and airplane sickness; ③ Suitable for the treatment of nausea, vomiting and other symptoms.

[0005] The existing preparation process mainly uses phenothiazine and N, N-dimethylaminochloropropane to react, and the reaction equation is as follows:

[0006]

[0007] The above process will inevitably produce a small amount of isomeric impurities, and the isomeric impurities are generally removed by salt formation in the presence of methanol and high vacuum distillation. The salt formation in the presence of methanol involves salt formation with oxalic acid in methanol, and the target product promethazine oxalate is precipitated due to the different solubility of the isomers in methanol. The salt formation in the presence of methanol can avoid the purchase of expensive production equipment and reduce production costs.

[0008] However, there are several problems in the process of salt formation with oxalic acid in methanol:

[0009] ①The process has poor safety and unstable yield;

[0010] ② In this process, when oxalic acid is added during the reflux operation, the pH value of the solution needs to be adjusted to 3-4, and the reaction is difficult to control;

[0011] ③ When using this process, the amount of oxalic acid required far exceeds the theoretical amount, resulting in material waste and increased costs.

[0012] For example, CN115974813A mentions the use of methanol as a salt-forming solvent to react with oxalic acid solid at a temperature of about 60°C, wherein the same molar amount of oxalic acid solid as that of promethazine is used, and the pH value of the solution is adjusted to 3-4 to prepare oxalate. Since the pH is adjusted during salt formation, a large amount of solvent is easily volatilized at the reflux temperature, which is very dangerous; and the amount of oxalic acid used in each production is not fixed, which easily leads to excessive impurities and unstable yield. Summary of the invention

[0013] The purpose of the present invention is to establish a promethazine oxalate salification process, so as to solve the problems of poor safety and unstable yield in the existing promethazine salification process under the premise of controlling the isomer impurity content to meet the requirements.

[0014] In order to achieve the above object, the first aspect of the present invention provides a method for preparing promethazine oxalate, the method comprising:

[0015] (1) In the presence of isopropanol, an oxalic acid solution is added to a promethazine stock solution to carry out a salt-forming reaction to obtain a salt solution; the oxalic acid solution is added at a rate of 0.02-0.04 mol / min relative to 1 mol of the promethazine stock solution; the promethazine stock solution contains 25-30 wt % of the promethazine isomer represented by formula (I), and the remainder is the promethazine represented by formula (II);

[0016] (2) stirring the salt solution; the stirring conditions include: temperature of 15-30° C. and time of 1-5 h;

[0017]

[0018] Through the above technical solution, the present invention has at least the following advantages:

[0019] (1) The method provided by the present invention is easy to operate and does not require pH adjustment during the experimental process.

[0020] (2) The product yield obtained by the method provided by the present invention is stable and maintained between 67.5 and 74.5 mol%, while the isomer impurity content is maintained below 7.2 wt%; and the product particles are uniform, loose and of good quality.

[0021] (3) The method provided by the present invention can ensure that the target product promethazine oxalate has a high purity while maintaining a high yield, which is significantly superior to the prior art.

[0022] (4) The method provided by the present invention uses a low amount of oxalic acid, which greatly reduces material costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1is the HPLC spectrum of the promethazine stock solution in the example of the present invention;

[0024] Figure 2 is the HPLC spectrum of promethazine oxalate after salification in Example 1 of the present invention;

[0025] Figure 3 It is the HPLC spectrum of promethazine oxalate after salification in Comparative Example 1 of the present invention;

[0026] Figure 4 It is the HPLC spectrum of promethazine oxalate after salification in Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0027] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0028] As mentioned above, the present invention provides a method for preparing promethazine oxalate, the method comprising:

[0029] (1) In the presence of isopropanol, an oxalic acid solution is added to a promethazine stock solution to carry out a salt-forming reaction to obtain a salt solution; the oxalic acid solution is added at a rate of 0.02-0.04 mol / min relative to 1 mol of the promethazine stock solution; the promethazine stock solution contains 25-30 wt % of the promethazine isomer represented by formula (I), and the remainder is the promethazine represented by formula (II);

[0030] (2) stirring the salt solution; the stirring conditions include: temperature of 15-30° C. and time of 1-5 h;

[0031]

[0032] The inventors of the present invention have found that, referring to CN115974813A, methanol is used as a solvent for salt-forming reaction. When the temperature is raised to 60°C and solid oxalic acid with a molar amount of 1 times the original amount of promethazine is added, the reaction is violent, violent reflux occurs, a large amount of methanol overflows, the acidity varies between 2 and 5, and the yield is about 60 mol%; when oxalic acid is dissolved in methanol and added dropwise, the acidity is controlled to 3 to 4, the yield is sometimes high and sometimes low, the lowest is reduced to 42.5 mol%, and the highest is 67.5wt%; the isomer impurity content in the product is in the range of about 3wt%; when solid oxalic acid is added when the reaction temperature is lowered to room temperature, the pH value is well controlled, and basically no methanol overflows, but as oxalic acid is added to the product, solids are immediately precipitated, resulting in isomer impurities being sandwiched, fine particles, and sticky, and the isomer impurity content is in the range of more than 10wt%.

[0033] The inventor tried to change the salt-forming process and unexpectedly found that when isopropanol was used as the salt-forming solvent, the temperature was raised to 80°C, and an oxalic acid solution dissolved in isopropanol was added to 1 times the molar amount of the isopropanol stock solution, the product yield reached 81.8 mol%, and the isomeric impurities accounted for 13.15 wt%; when the amount of isopropanol was increased to 8 times the molar amount of the isopropanol stock solution, the yield still reached 79.3 mol%, and the isomeric impurities accounted for 10.40 wt%. By studying the changes in the isomer content before and after salt formation, it was found that almost all of the isopropanol hydrochloride was precipitated when isopropanol was used as a solvent. Because the content of the target product in the reaction solution is about 70 wt%. In view of this, the inventor obtained the following scheme: using multiple volumes of isopropanol as the salt-forming solvent, adding the oxalic acid solution to the isopropanol stock solution at a certain speed, and stirring under specific conditions, the target product, isopropanol oxalate, can be crystallized to obtain. The promethazine oxalate is light yellow, has uniform and loose particles, has a low impurity content, a stable yield between 67.5 and 74.5 mol%, and a stable isomer impurity level below 7.2 wt%. The salt-forming reaction of the promethazine stock solution and the oxalic acid is as follows:

[0034]

[0035] Preferably, in step (1), the addition rate of the oxalic acid solution is 0.025-0.028 mol / min relative to 1 mol of the promethazine stock solution. In this preferred embodiment, the yield of promethazine oxalate prepared by the present invention is higher, and the content of promethazine isomer impurities is lower.

[0036] Preferably, in step (1), the weight ratio of the promethazine stock solution to the isopropanol is 1:6-8. In this preferred embodiment, the yield of promethazine oxalate prepared by the present invention is higher, and the content of promethazine isomer impurities is lower.

[0037] Preferably, in step (1), the solvent in the oxalic acid solution is isopropanol.

[0038] It should be noted that, in the weight ratio of the isopropyl alcohol used in the promethazine stock solution and the isopropyl alcohol used, the amount of isopropyl alcohol used does not include the amount of isopropyl alcohol used in the oxalic acid solution.

[0039] Preferably, in step (1), the concentration of oxalic acid in the oxalic acid solution is 20-30 wt %.

[0040] Preferably, in step (1), the conditions for the salt-forming reaction include: a temperature of 75-80° C. and a time of 10-30 min.

[0041] It should be noted that the time of the salt-forming reaction is equal to the time it takes for the oxalic acid solution to be added to the promethazine stock solution.

[0042] According to a preferred embodiment, in step (1), the method further comprises: stirring the product obtained by the salt-forming reaction for 0.5-1 h to obtain the salt solution.

[0043] Preferably, in step (2), the stirring speed is 60-100 rpm.

[0044] Preferably, in step (2), the stirring treatment conditions include: temperature of 20-27° C., and time of 1-4 h.

[0045] Preferably, in step (2), the method further comprises: removing impurities from the mixed material obtained after the stirring treatment.

[0046] Preferably, in step (2), the impurity removal process comprises: centrifuging and washing the mixture in sequence.

[0047] Preferably, the yield of the promethazine oxalate is 67-75 mol%, and the isomer impurity content in the promethazine oxalate is ≯7.2 wt%.

[0048] The aforementioned promethazine oxalate provided by the present invention can be used as an intermediate for preparing promethazine hydrochloride.

[0049] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, the instruments, reagents, materials, etc. involved are all conventional instruments, reagents, materials, etc., which can be obtained through conventional commercial channels. Among them, unless otherwise specified, the reagents used are all commercially available analytically pure products.

[0050] In the following examples, the promethazine stock solution contains 27 wt % of the promethazine isomer represented by formula (I), and the remainder is promethazine represented by formula (II);

[0051]

[0052] In the following examples, the calculation formula for the yield of promethazine oxalate is: (weight of promethazine oxalate obtained in each example / molecular weight of promethazine oxalate) / molar amount of promethazine stock solution used in the corresponding example × 100%;

[0053] The formula for calculating the isomeric impurity content in promethazine oxalate is: peak area of ​​promethazine isomers in the HPLC spectrum / sum of all peak areas × 100%.

[0054] Example 1

[0055] (1) isopropanol was added to a 300 L reactor (the weight ratio of the isopropanol added here to the weight of the promethazine stock solution was 8:1), and a 27.6 wt% oxalic acid solution (dissolved in isopropanol) was added to the 100 mol promethazine stock solution by pumping to perform a salt-forming reaction, and then stirring was continued for 0.5 h to obtain a salt solution;

[0056] Wherein, relative to 1 mol of promethazine stock solution, the addition rate of oxalic acid solution is 0.025 mol / min;

[0057] The conditions for the salt-forming reaction are: temperature 80°C, time 30 min;

[0058] (2) The salt solution is stirred (temperature is 20°C, time is 2 hours, rotation speed is 80 rpm), the mixture obtained after stirring is centrifuged, the filter cake is washed with isopropanol, and placed in a 65°C forced air drying oven for 3 hours to obtain promethazine oxalate (containing isomeric impurities, the same below).

[0059] Example 2

[0060] (1) isopropanol was added to a 3 L reaction bottle (the weight ratio of the isopropanol added here to the weight of the promethazine stock solution below was 6:1), and a 26.0 wt% oxalic acid solution (dissolved in isopropanol) was added to 1 mol of the promethazine stock solution by pumping to perform a salt-forming reaction, and then stirring was continued for 0.5 h to obtain a salt solution;

[0061] Wherein, relative to 1 mol of promethazine stock solution, the addition rate of oxalic acid solution is 0.025 mol / min;

[0062] The conditions for the salt-forming reaction are: temperature 78°C, time 30 min;

[0063] (2) The salt solution is stirred (temperature is 27° C., time is 4 h, rotation speed is 100 rpm), the mixture obtained after the stirring treatment is centrifuged, the filter cake is washed with isopropanol, and placed in a 65° C. forced air drying oven to obtain promethazine oxalate.

[0064] Example 3

[0065] This example is carried out in a similar manner to Example 1, except that the amount of the promethazine stock solution in this example is kept unchanged, and the weight ratio of the promethazine stock solution to isopropanol is adjusted to 1:3.5;

[0066] The rest are the same, and promethazine oxalate is obtained.

[0067] Comparative Example 1

[0068] (1) Methanol was added to a 2L reaction bottle (the weight of the methanol added here was in a ratio of 4:1 to the weight of the promethazine stock solution below), and a 27.6wt% oxalic acid solution (dissolved in methanol) was added to the 1.5mol promethazine stock solution by pumping to perform a salt-forming reaction, and then stirring was continued for 0.5h to obtain a salt solution;

[0069] Wherein, relative to 1 mol of promethazine stock solution, the addition rate of oxalic acid solution is 0.1 mol / min;

[0070] The conditions for the salt-forming reaction are: temperature 80°C, time 10 min;

[0071] (2) The salt solution is stirred (temperature is 20° C., time is 2 h, rotation speed is 80 rpm), the mixture obtained after the stirring treatment is centrifuged, the filter cake is washed with methanol, and placed in a 65° C. forced air drying oven for 3 h to obtain promethazine oxalate.

[0072] Comparative Example 2

[0073] (1) adding isopropanol to a 2L reaction bottle (the weight ratio of the isopropanol added here to the weight of the promethazine stock solution is 4:1), and adding a 27.6wt% oxalic acid solution (dissolved in isopropanol) to the 0.15mol promethazine stock solution by pumping to perform a salt-forming reaction, and then continuing to stir for 0.5h to obtain a salt solution;

[0074] Wherein, relative to 1 mol of promethazine stock solution, the addition rate of oxalic acid solution is 0.1 mol / min;

[0075] The conditions for the salt-forming reaction are: temperature 80°C, time 10 min;

[0076] (2) The salt solution is stirred (temperature is 20° C., time is 2 h, rotation speed is 80 rpm), the mixture obtained after the stirring treatment is centrifuged, the filter cake is washed with isopropanol, and placed in a 65° C. forced air drying oven for 3 h to obtain promethazine oxalate.

[0077] Comparative Example 3

[0078] (1) isopropanol was added to a 0.5 L reaction bottle (the weight ratio of the isopropanol added here to the weight of the promethazine stock solution below was 8:1), and a 27.6 wt% oxalic acid solution (dissolved in isopropanol) was pumped into the 0.10 mol promethazine stock solution to perform a salt-forming reaction, and then the mixture was stirred for 0.5 h to obtain a salt solution;

[0079] Wherein, relative to 1 mol of promethazine stock solution, the addition rate of oxalic acid solution is 0.05 mol / min;

[0080] The conditions for the salt-forming reaction are: temperature 80°C, time 20 min;

[0081] (2) The salt solution is stirred (temperature is 20° C., time is 2 h, rotation speed is 80 rpm), the mixture obtained after the stirring treatment is centrifuged, the filter cake is washed with isopropanol, and placed in a 65° C. forced air drying oven for 3 h to obtain promethazine oxalate.

[0082] Comparative Example 4

[0083] This comparative example was carried out in a similar manner to Example 1, except that in this comparative example, the stirring conditions were: temperature of 10°C, time of 0.5h, and rotation speed of 50rpm;

[0084] The rest are the same, and promethazine oxalate is obtained.

[0085] Comparative Example 5

[0086] This example is carried out in a similar manner to Example 1, except that the amount of the promethazine stock solution in this example is kept unchanged, and the rate of addition of the oxalic acid solution is 0.06 mol / min relative to 1 mol of the promethazine stock solution;

[0087] The rest are the same, and promethazine oxalate is obtained.

[0088] The present invention Figure 1 The HPLC spectrum of the promethazine stock solution is provided in, and the corresponding peak spectrum information is shown in Table 1, in which "AU" represents the electrical signal; Figure 1 As can be seen from Table 1, before salt formation, the content of promethazine isomers in the promethazine stock solution was 27.187 wt%, and the content of promethazine was 69.060 wt%.

[0089] Table 1

[0090] Retention time (minutes) area Area percentage (%) Resolution (USP) Peak attribution 27.025 1412099 2.280 2.23 Impurity A (phenothiazine) 30.269 42769053 69.060 5.63 Promethazine 38.396 16837242 27.187 3.23 Promethazine isomers

[0091] The present invention is exemplarily Figure 2 The HPLC spectrum of promethazine oxalate after salification in Example 1 is provided, and the corresponding peak spectrum information is shown in Table 2; Figure 2 As can be seen from Table 2, after the promethazine stock solution is salified, the content of promethazine isomers in promethazine oxalate is 4.523wt%, and the content of promethazine is 95.259wt%.

[0092] Table 2

[0093] Retention time (minutes) area Area percentage (%) Resolution (USP) Peak attribution 25.561 25546 0.047 3.69 Impurity A (phenothiazine) 29.948 51913063 95.259 - Promethazine 37.385 2464707 4.523 - Promethazine isomers

[0094] The present invention is exemplarily Figure 3 The HPLC spectrum of the salified promethazine oxalate in Comparative Example 1 is provided in Table 3, and the corresponding peak spectrum information is shown in Table 3; Figure 3 As can be seen from Table 3, after the promethazine stock solution is salified, the content of promethazine isomers in promethazine oxalate is 2.162wt%, and the content of promethazine is 97.631wt%.

[0095] Table 3

[0096] Retention time (minutes) area Area percentage (%) Resolution (USP) Peak attribution 27.034 82145 0.159 2.99 Impurity A (phenothiazine) 30.251 50446641 97.631 5.43 Promethazine 38.492 1117120 2.162 3.54 Promethazine isomers

[0097] The present invention is exemplarily Figure 4 The HPLC spectrum of the salified promethazine oxalate in Comparative Example 3 is provided, and the corresponding peak spectrum information is shown in Table 4; Figure 4 It can be seen from Table 4 that, under the same proportion of oxalic acid dosage, after the promethazine stock solution is salified, the content of promethazine isomers in the promethazine oxalate is 10.408wt%, and the content of promethazine is 88.989wt%.

[0098] Table 4

[0099] Retention time (minutes) area Area percentage (%) Resolution (USP) Peak attribution 25.905 117754 0.202 3.69 Impurity A (phenothiazine) 29.917 51972774 88.989 - Promethazine 37.936 6078522 10.408 - Promethazine isomers

[0100] The yield of promethazine oxalate obtained in each example of the present invention, the purity of the target product (promethazine oxalate) and the isomeric impurity content are shown in Table 5.

[0101] Table 5

[0102] Yield / mol% Purity of target product (promethazine oxalate) / wt% Isomer impurity content / wt% Example 1 67.5 95.5 4.523 Example 2 69.8 95.0 4.985 Example 3 74.4 92.8 7.145 Comparative Example 1 52.7 97.8 2.162 Comparative Example 2 81.8 86.8 13.15 Comparative Example 3 79.3 89.6 10.408 Comparative Example 4 76.5 89.8 10.18 Comparative Example 5 73.5 91.0 8.532

[0103] By comparing Example 1 and Example 2, it can be seen that the method for preparing promethazine oxalate provided by the present invention has a yield of 69.8 mol% under the production capacity of 3 L, a purity of the target product (promethazine oxalate) of 95.0 wt%, and an isomer impurity content of only 4.985 wt%. When the production capacity is expanded to 300 L, the yield can still reach 67.5 mol%, and the purity of the target product (promethazine oxalate) reaches 95.5 wt%, and the isomer impurity content is only 4.523 wt%. This shows that the method of the present invention can obtain a relatively stable yield.

[0104] From the above results, it can be seen that the yield of the target product obtained by the method for preparing promethazine oxalate provided by the present invention is stable between 67.5 and 74.5 mol%, and the isomer impurity content is kept below 7.2 wt%; and the method does not need to adjust the pH, and the amount of oxalic acid used is low. Therefore, the method can ensure that the target product has a high purity while maintaining a high yield, and has a significantly superior effect compared to the prior art.

[0105] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing promethazine oxalate, characterized in that: The method includes: (1) In the presence of isopropanol, an oxalic acid solution is added to a promethazine stock solution to carry out a salt-forming reaction to obtain a salt solution; the oxalic acid solution is added at a rate of 0.02-0.04 mol / min relative to 1 mol of the promethazine stock solution; the promethazine stock solution contains 25-30 wt % of the promethazine isomer represented by formula (I), and the remainder is the promethazine represented by formula (II); (2) stirring the salt solution; the stirring conditions include: temperature of 15-30° C. and time of 1-5 h; 2. The method according to claim 1, characterized in that In step (1), the addition rate of the oxalic acid solution is 0.025-0.028 mol / min relative to 1 mol of the promethazine stock solution.

3. The method according to claim 1, characterized in that In step (1), the weight ratio of the promethazine stock solution to the isopropanol is 1:6-8.

4. The method according to any one of claims 1 to 3, characterized in that: In step (1), the solvent in the oxalic acid solution is isopropanol.

5. The method according to any one of claims 1 to 3, characterized in that: In step (1), the concentration of oxalic acid in the oxalic acid solution is 20-30 wt %.

6. The method according to any one of claims 1 to 3, characterized in that: In step (1), the conditions for the salt-forming reaction include: temperature of 75-80° C. and time of 10-30 min.

7. The method according to any one of claims 1 to 3, characterized in that: In step (2), the stirring speed is 60-100 rpm.

8. The method according to any one of claims 1 to 3, characterized in that: In step (2), the stirring treatment conditions include: temperature of 20-27° C. and time of 1-4 h.

9. The method according to any one of claims 1 to 3, characterized in that: In step (2), the method further comprises: removing impurities from the mixed material obtained after the stirring treatment.

10. The method according to claim 9, characterized in that In step (2), the impurity removal process includes: centrifuging and washing the mixed material in sequence.

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