Preparation method of iopamidol chiral side chain
Through a new preparation method, the reaction using L-lactic acid, ethanol and other additives was successfully improved, and the purity and yield of iopamol chiral side chain (S)-2-acetoxypropionyl chloride was solved, the problem of poor synthesis in the prior art was achieved, and more efficient industrial production was achieved.
Patent Information
- Application Number
- CN202411804360.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-10
- Publication Date
- 2025-03-21
AI Technical Summary
The synthesis of existing iopadol chiral side chain (S)-2-acetoxypropionyl chloride has problems such as low purity and yield and harsh reaction conditions, which limits the synthesis and application value of iopadol.
After mixing L-lactic acid and ethanol, toluene, vinyl acetate, Pseudomonas onion lipase and 3A molecular sieve were added. After the reaction was carried out, the filtrate was filtered. The filtrate was concentrated under reduced pressure to obtain (S)-2-acetoxypropionic acid, and then added to the mixed solution of chlorinated and pyridine. After the reaction, the obtained reaction solution was concentrated under reduced pressure to obtain (S)-2-acetoxypropionyl chloride.
The (S)-2-acetoxypropionyl chloride prepared by this method has excellent purity and yield, mild reaction conditions, simple operation, which is conducive to industrial production, and thus improves the application value of iopamol.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of medicines, and in particular to a method for preparing an iopamidol chiral side chain. Background Art
[0002] Iopamidol can be used for angiography of peripheral arteries, renal arteries, cardiovascular, cerebrovascular and urinary systems. It has the advantages of low toxicity and good systemic and local tolerance. It is widely used in clinical practice and is a commonly used contrast agent. The structure of iopamidol is as follows:
[0003]
[0004] The safety and application value of iopamidol are closely related to the purity of iopamidol. Low-purity iopamidol not only leads to a decrease in the quality of iopamidol, but also easily leads to the occurrence of adverse reactions, thereby reducing the application value of iopamidol. In the existing iopamidol preparation method, the chiral side chain (S)-2-acetoxy propionyl chloride of iopamidol is an important intermediate for synthesizing iopamidol, and the purity of the chiral side chain (S)-2-acetoxy propionyl chloride of iopamidol has an important influence on the purity of the synthesized iopamidol. The structure of the chiral side chain (S)-2-acetoxy propionyl chloride of iopamidol is as follows:
[0005]
[0006] However, the existing synthesis of the chiral side chain (S)-2-acetoxypropionyl chloride of iopamidol still has many problems, such as the low purity and yield of the prepared chiral side chain (S)-2-acetoxypropionyl chloride of iopamidol, harsh reaction conditions and being unfavorable for industrial production, etc., which further restricts the synthesis of iopamidol and reduces the application value of iopamidol.
[0007] Therefore, there is a need in the art to develop a method for preparing the chiral side chain (S)-2-acetoxypropionyl chloride of iopamidol with excellent purity and yield and easy industrial production. Summary of the invention
[0008] The object of the present invention is to provide a method for preparing iopamidol chiral side chain (S)-2-acetoxypropionyl chloride which has excellent purity and yield and is easy for industrial production.
[0009] In a first aspect, the present invention provides a method for preparing (S)-2-acetoxypropionyl chloride, the method comprising:
[0010] (1) After mixing L-lactic acid and ethanol, toluene, vinyl acetate, Pseudomonas cepacia lipase and 3A molecular sieves are added, reacted, filtered, and the filtrate is concentrated under reduced pressure to obtain (S)-2-acetoxypropionic acid;
[0011]
[0012] (2) adding the (S)-2-acetoxypropionic acid prepared in step (1) to a mixture of thionyl chloride and pyridine, stirring for reaction, and then heating to reflux for reaction, and concentrating the obtained reaction solution under reduced pressure to obtain (S)-2-acetoxypropanoyl chloride;
[0013]
[0014] Preferably, in step (1), the mass ratio of L-lactic acid to ethanol is 1:(6-12), preferably 1:(8-10), more preferably 1:(8.5-9.5), more preferably 1:(8.8-9.2), and most preferably 1:9.
[0015] Preferably, in the step (1), the mass ratio of the L-lactic acid to the toluene is 1:(1-6), preferably 1:(2-5), more preferably 1:(3-4), more preferably 1:(3.2-3.8), and most preferably 1:3.5.
[0016] Preferably, in the step (1), the mass ratio of the L-lactic acid to the vinyl acetate is 1:(1-5), preferably 1:(2.0-3.5), more preferably 1:(2.5-3.2), more preferably 1:(2.6-3.0), and most preferably 1:2.8.
[0017] Preferably, in step (1), the mass ratio of L-lactic acid to Pseudomonas cepacia lipase is (3-10):1, preferably (5-8):1, more preferably (6.0-7.5):1, more preferably (6.5-7.0):1, and optimally 6.7:1.
[0018] Preferably, in the step (1), the mass ratio of the L-lactic acid to the 3A molecular sieve is (3-10):1, preferably (5-8):1, more preferably (6.0-7.5):1, more preferably (6.5-7.0):1, and optimally 6.7:1.
[0019] Preferably, in step (1), the L-lactic acid is 0.5-2.0 parts by weight, preferably 1-1.5 parts by weight, more preferably 1.2-1.4 parts by weight, and most preferably 1.3 parts by weight.
[0020] Preferably, in step (1), the ethanol is 8-18 parts by weight, preferably 10-14 parts by weight, more preferably 11-13 parts by weight, and most preferably 11.7 parts by weight.
[0021] Preferably, in step (1), the toluene is 3-7 parts by weight, preferably 4-5 parts by weight, more preferably 4.3-4.7 parts by weight, and most preferably 4.5 parts by weight.
[0022] Preferably, in step (1), the vinyl acetate is 2-6 parts by weight, preferably 3-5 parts by weight, more preferably 3.3-4.0 parts by weight, and most preferably 3.7 parts by weight.
[0023] Preferably, in step (1), the amount of the Pseudomonas cepacia lipase is 0.1-0.3 parts by weight, preferably 0.15-0.25 parts by weight, more preferably 0.18-0.22 parts by weight, and most preferably 0.195 parts by weight.
[0024] Preferably, in step (1), the 3A molecular sieve is 0.1-0.3 parts by weight, preferably 0.15-0.25 parts by weight, more preferably 0.18-0.22 parts by weight, and most preferably 0.195 parts by weight.
[0025] Preferably, in step (1), the ethanol includes anhydrous ethanol.
[0026] Preferably, in step (1), the reaction temperature is 15-35°C, preferably 20-30°C, more preferably 23-27°C, and most preferably 25°C.
[0027] Preferably, in step (1), the reaction time is 10-30 h, preferably 15-25 h, more preferably 18-22 h, and most preferably 20 h.
[0028] Preferably, in step (1), L-lactic acid and ethanol are mixed, stirred and mixed at 25°C (preferably 15-35°C, more preferably 20-30°C, more preferably 23-27°C), and then toluene, vinyl acetate, Pseudomonas cepacia lipase and 3A molecular sieve are added.
[0029] Preferably, in step (1), the temperature of the reduced pressure concentration is 50-70°C, preferably 55-65°C, more preferably 58-62°C, and more preferably 60°C.
[0030] Preferably, in step (1), the filtrate is concentrated under reduced pressure until no liquid drips out.
[0031] Preferably, the weight volume ratio (kg:L) of L-lactic acid in step (1) to thionyl chloride in step (2) is 1:(1-3), preferably 1:(1.5-2.5), more preferably 1:(1.8-2.2), and most preferably 1:2.
[0032] Preferably, the weight volume ratio (kg:ml) of L-lactic acid in step (1) to pyridine in step (2) is 1:(5-25), preferably 1:(10-20), more preferably 1:(13-17), more preferably 1:(15-16), and most preferably 1:15.4.
[0033] Preferably, in the step (2), the volume ratio of the thionyl chloride to the pyridine is (90-160):1, preferably (110-150):1, more preferably (120-140):1, more preferably (125-135):1, and most preferably 130:1.
[0034] Preferably, in step (2), the amount of thionyl chloride is 1.5-3.5 parts by weight, preferably 2.0-3.0 parts by weight, more preferably 2.4-2.8 parts by weight, and most preferably 2.6 parts by weight.
[0035] Preferably, in step (2), the pyridine is 0.01-0.03 parts by weight, preferably 0.015-0.025 parts by weight, more preferably 0.018-0.022 parts by weight, and most preferably 0.02 parts by weight.
[0036] Preferably, in step (2), the stirring reaction temperature is 30-50°C, preferably 35-45°C, more preferably 38-42°C, and more preferably 40°C.
[0037] Preferably, in step (2), the stirring reaction time is 0.5-2.5 h, preferably 1-2 h, more preferably 1.3-1.7 h, more preferably 1.5 h.
[0038] Preferably, in step (2), the heating to reflux reaction time is 0.5-2 h, preferably 0.5-1.5 h, more preferably 0.8-1.2 h, more preferably 1 h.
[0039] Preferably, in step (2), the temperature of the reduced pressure concentration is 35-50°C, preferably 40-50°C, more preferably 45°C.
[0040] Preferably, in step (2), the obtained reaction solution is concentrated under reduced pressure until no liquid drips out.
[0041] Preferably, the purity of the (S)-2-acetoxypropionyl chloride prepared in step (2) is 99.5-99.9%, preferably 99.5-99.7%.
[0042] Preferably, the yield of (S)-2-acetoxypropionyl chloride prepared in step (2) is 90-99%, preferably 99.2-99.4%.
[0043] Preferably, the preparation method of the (S)-2-acetoxypropionyl chloride comprises:
[0044] (1) Add 1.3 kg of L-lactic acid and 11.7 kg of anhydrous ethanol to a reactor, stir and mix at 25° C., then add 4.5 kg of toluene, 3.7 kg of vinyl acetate, 0.195 kg of Pseudomonas cepacia lipase and 0.195 kg of 3A molecular sieves, stir and react at 25° C. for 20 hours, filter, and concentrate the filtrate under reduced pressure at 60° C. until no liquid drips out, to obtain (S)-2-acetoxypropionic acid;
[0045] (2) The (S)-2-acetoxypropionic acid prepared in step (1) was added to a mixture of 2.6 L of thionyl chloride and 20 ml of pyridine, stirred at 40° C. for 1.5 h, then heated to reflux for 1.0 h, and concentrated under reduced pressure at 45° C. until no liquid dripped out to obtain (S)-2-acetoxypropanoyl chloride.
[0046] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. DETAILED DESCRIPTION
[0047] The present invention develops a preparation method of (S)-2-acetoxypropionyl chloride, wherein the method comprises mixing L-lactic acid and ethanol, adding toluene, vinyl acetate, Pseudomonas cepacia lipase and 3A molecular sieve, reacting, filtering, concentrating the filtrate under reduced pressure to obtain (S)-2-acetoxypropionic acid, and then adding the (S)-2-acetoxypropionic acid to a mixed solution of thionyl chloride and pyridine, reacting, and concentrating the obtained reaction solution under reduced pressure to obtain (S)-2-acetoxypropionyl chloride. The (S)-2-acetoxypropionyl chloride prepared by the method of the present invention has excellent purity and yield, mild reaction conditions, simple operation, is conducive to industrial production, and is further conducive to being used as an intermediate for preparing high-purity and high-yield iopamidol, thereby improving the application value of iopamidol.
[0048] the term
[0049] As used herein, the terms "include", "comprises", and "comprising" are used interchangeably, and include not only open definitions, but also semi-closed and closed definitions. In other words, the terms include "consisting of", "consisting essentially of".
[0050] As used herein, the structure of iopamidol is as follows:
[0051]
[0052] As used herein, the structure of (S)-2-acetoxypropanoyl chloride is as follows:
[0053]
[0054] As used herein, the structure of vinyl acetate is as follows:
[0055]
[0056] As used herein, 3A molecular sieve has the CAS Registry Number: 308080-99-1.
[0057] method
[0058] The present invention provides a method for preparing (S)-2-acetoxypropionyl chloride, the method comprising:
[0059] (1) After mixing L-lactic acid and ethanol, toluene, vinyl acetate, Pseudomonas cepacia lipase and 3A molecular sieves are added, reacted, filtered, and the filtrate is concentrated under reduced pressure to obtain (S)-2-acetoxypropionic acid;
[0060]
[0061] (2) adding the (S)-2-acetoxypropionic acid prepared in step (1) to a mixture of thionyl chloride and pyridine, stirring for reaction, and then heating to reflux for reaction, and concentrating the obtained reaction solution under reduced pressure to obtain (S)-2-acetoxypropanoyl chloride;
[0062]
[0063] Specifically, the preparation method of (S)-2-acetoxypropionyl chloride described in the present invention is as described above in the first aspect of the present invention.
[0064] The main excellent technical effects of the present invention include:
[0065] The invention develops a method for preparing iopamidol chiral side chain (S)-2-acetoxypropionyl chloride. The (S)-2-acetoxypropionyl chloride prepared by the method has excellent purity and yield, mild reaction conditions, simple operation, is conducive to industrial production, and is further conducive to being used as an intermediate for preparing high-purity and high-yield iopamidol, thereby improving the application value of iopamidol.
[0066] The present invention is further described below in conjunction with specific examples. It should be understood that the following specific examples are based on the technical solution and provide detailed implementation methods and specific operation processes, but the protection scope of the present invention is not limited to these examples.
[0067] Example 1
[0068] This embodiment 1 provides a preparation of (S)-2-acetoxypropionyl chloride, and the preparation method is as follows:
[0069]
[0070] (1) Preparation of (S)-2-acetoxypropionic acid:
[0071] 1.3 kg of L-lactic acid and 11.7 kg of anhydrous ethanol were added to a 50 L reactor, and after stirring and mixing at 25 ° C, 4.5 kg of toluene, 3.7 kg of vinyl acetate, 0.195 kg of Pseudomonas cepacia lipase and 0.195 kg of 3A molecular sieves were added. After stirring and reacting at 25 ° C for 20 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure at 60 ° C until no liquid dripped out to obtain 1.88 kg of (S)-2-acetoxypropionic acid.
[0072] (2) Preparation of (S)-2-acetoxypropionyl chloride:
[0073] 1.88 kg of (S)-2-acetoxypropionic acid prepared in step (1) was added to a mixture of 2.6 L of thionyl chloride and 20 ml of pyridine, and the mixture was stirred for reaction at 40° C. for 1.5 h, and then heated to reflux for reaction for 1.0 h. The mixture was concentrated under reduced pressure at 45° C. until no liquid dripped out, to obtain 2.01 kg of (S)-2-acetoxypropanoyl chloride. The purity of (S)-2-acetoxypropanoyl chloride was 99.56% as determined by high performance liquid chromatography (HPLC), and the yield was 92.7%.
[0074] Comparative Example 1
[0075] This comparative example 1 provides a preparation of (S)-2-acetoxypropionyl chloride. The preparation method is the same as that of Example 1, except that Aminoacylase (acylating amino acid hydrolase) is used to replace Pseudomonas cepacia lipase. Other operations are the same as those of Example 1.
[0076] The purity of the prepared (S)-2-acetoxypropionyl chloride was 47.82% and the yield was 41.36% as determined by high performance liquid chromatography (HPLC).
[0077] Comparative Example 2
[0078] This comparative example 2 provides a preparation method of (S)-2-acetoxypropionyl chloride. The preparation method is the same as that of Example 1, except that acetic anhydride is used instead of vinyl acetate. Other operations are the same as those of Example 1.
[0079] The purity of the prepared (S)-2-acetoxypropionyl chloride was 70.68% and the yield was 62.53% as determined by high performance liquid chromatography (HPLC).
[0080] Comparative Example 3
[0081] This comparative example 3 provides a preparation of (S)-2-acetoxypropionyl chloride. The preparation method is the same as that of Example 1, except that toluene is replaced by methyl tert-butyl ether. Other operations are the same as those of Example 1.
[0082] The purity of the prepared (S)-2-acetoxypropionyl chloride was 81.71% and the yield was 69.24% as determined by high performance liquid chromatography (HPLC).
[0083] The above is an implementation scheme of the present invention designed for a case. It should be pointed out that for ordinary technicians in this technical field, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing (S)-2-acetoxypropionyl chloride, characterized in that: The method includes: (1) After mixing L-lactic acid and ethanol, toluene, vinyl acetate, Pseudomonas cepacia lipase and 3A molecular sieves are added, reacted, filtered, and the filtrate is concentrated under reduced pressure to obtain (S)-2-acetoxypropionic acid; (2) adding the (S)-2-acetoxypropionic acid prepared in step (1) to a mixture of thionyl chloride and pyridine, stirring for reaction, and then heating to reflux for reaction, and concentrating the obtained reaction solution under reduced pressure to obtain (S)-2-acetoxypropanoyl chloride; 2. The method according to claim 1, characterized in that In the step (1), the mass ratio of the L-lactic acid to the ethanol is 1:(6-12), preferably 1:(8-10), more preferably 1:(8.5-9.5), more preferably 1:(8.8-9.2), and most preferably 1:9; In the step (1), the mass ratio of the L-lactic acid to the toluene is 1:(1-6), preferably 1:(2-5), more preferably 1:(3-4), more preferably 1:(3.2-3.8), and most preferably 1:3.5; In the step (1), the mass ratio of the L-lactic acid to the vinyl acetate is 1:(1-5), preferably 1:(2.0-3.5), more preferably 1:(2.5-3.2), more preferably 1:(2.6-3.0), and most preferably 1:2.8; In the step (1), the mass ratio of the L-lactic acid to the Pseudomonas cepacia lipase is (3-10):1, preferably (5-8):1, more preferably (6.0-7.5):1, more preferably (6.5-7.0):1, and most preferably 6.7:1; and In the step (1), the mass ratio of the L-lactic acid to the 3A molecular sieve is (3-10):1, preferably (5-8):1, more preferably (6.0-7.5):1, more preferably (6.5-7.0):1, and optimally 6.7:
1.
3. The method according to claim 1, characterized in that In the step (1), the reaction temperature is 15-35°C, preferably 20-30°C, more preferably 23-27°C, and most preferably 25°C.
4. The method according to claim 1, characterized in that In the step (1), the reaction time is 10-30 h, preferably 15-25 h, more preferably 18-22 h, and most preferably 20 h.
5. The method according to claim 1, characterized in that The weight volume ratio (kg:L) of L-lactic acid in step (1) to thionyl chloride in step (2) is 1:(1-3), preferably 1:(1.5-2.5), more preferably 1:(1.8-2.2), and most preferably 1:2; and The weight-to-volume ratio (kg:ml) of L-lactic acid in step (1) to pyridine in step (2) is 1:(5-25), preferably 1:(10-20), more preferably 1:(13-17), more preferably 1:(15-16), and most preferably 1:15.
4.
6. The method according to claim 1, characterized in that In the step (2), the volume ratio of the thionyl chloride to the pyridine is (90-160):1, preferably (110-150):1, more preferably (120-140):1, more preferably (125-135):1, and most preferably 130:
1.
7. The method according to claim 1, characterized in that In the step (2), the stirring reaction temperature is 30-50°C, preferably 35-45°C, more preferably 38-42°C, and more preferably 40°C.
8. The method according to claim 1, characterized in that In the step (2), the stirring reaction time is 0.5-2.5 h, preferably 1-2 h, more preferably 1.3-1.7 h, and more preferably 1.5 h.
9. The method according to claim 1, characterized in that In the step (2), the heating to reflux reaction time is 0.5-2h, preferably 0.5-1.5h, more preferably 0.8-1.2h, and more preferably 1h.
10. The method according to claim 1, characterized in that The preparation method of the (S)-2-acetoxypropionyl chloride comprises: (1) Add 1.3 kg of L-lactic acid and 11.7 kg of anhydrous ethanol to a reactor, stir and mix at 25° C., then add 4.5 kg of toluene, 3.7 kg of vinyl acetate, 0.195 kg of Pseudomonas cepacia lipase and 0.195 kg of 3A molecular sieves, stir and react at 25° C. for 20 hours, filter, and concentrate the filtrate under reduced pressure at 60° C. until no liquid drips out, to obtain (S)-2-acetoxypropionic acid; (2) The (S)-2-acetoxypropionic acid prepared in step (1) was added to a mixture of 2.6 L of thionyl chloride and 20 ml of pyridine, stirred at 40° C. for 1.5 h, then heated to reflux for 1.0 h, and concentrated under reduced pressure at 45° C. until no liquid dripped out to obtain (S)-2-acetoxypropanoyl chloride.