A preparation method of lisinopril intermediate

Abstract

The invention discloses a method for preparing a lisinopril anhydride intermediate. The method innovatively introduces an acid-binding agent in the use of triphosgene, thereby avoiding the overflow of highly toxic phosgene in the synthesis process and shortening the reaction time, which is very beneficial to industrial production.

Description

Technical field:

[0001] The invention relates to a preparation method of a lisinopril intermediate and belongs to the field of pharmaceutical chemical industry. Background technology:

[0002] Lisinopril is a third-generation angiotensin-converting enzyme inhibitor developed by Merck, and its structural formula is shown in Formula I:

[0003]

[0004] CN109422702 discloses a method for preparing a lisinopril anhydride intermediate shown in formula III, comprising reacting a lisinopril hydride shown in formula II with triphosgene in dichloromethane and refluxing for 20±4 hours to obtain a target product. The synthetic route is as follows:

[0005]

[0006] In the process of preparing the above-mentioned acid anhydride intermediate, the by-product of highly toxic phosgene will be produced, and the reaction time is relatively long. The reaction is carried out by refluxing in a solvent such as dichloromethane. After the reaction is completed, the excess phosgene needs to be removed by reduced pressure distillation. The obtained acid anhydride intermediate will inevitably have a large amount of residual phosgene, which will pose many safety and environmental risks in industrial production. Summary of the invention:

[0007] The present invention provides a method for preparing a lisinopril anhydride intermediate shown in formula III, comprising reacting a lisinopril hydride shown in formula II in a mixed solvent of an organic solvent and water with triphosgene in the presence of an acid binding agent to obtain the lisinopril anhydride intermediate shown in formula III. The synthesis route is as follows:

[0008]

[0009] In the method for preparing the lisinopril anhydride intermediate represented by the above formula III, the following steps are preferably used:

[0010] (a) adding triphosgene and an organic solvent to the compound represented by formula II; adding water and an acid binding agent to the above mixture to react;

[0011] (b) After the reaction is completed, the organic layer is separated, washed, dried, and concentrated to dryness to obtain the target compound.

[0012] In the method for preparing the lisinopril anhydride intermediate represented by the above formula III, the organic solvent is preferably selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, toluene, and xylene, and more preferably dichloromethane, chloroform, and toluene.

[0013] In the preparation method of the lisinopril anhydride intermediate represented by the above formula III, the acid binding agent is preferably selected from: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, pyridine, etc., and more preferably: sodium carbonate, pyridine, sodium bicarbonate, ammonium carbonate.

[0014] In the method for preparing the lisinopril anhydride intermediate represented by the above formula III, the amount of triphosgene required per mole of the compound of formula II is 0.4 to 1.0 mole, preferably 0.4 to 0.6 mole, and more preferably 0.5 to 0.55 mole.

[0015] In the preparation method of the lisinopril anhydride intermediate represented by the above formula III, the weight of the solvent required per gram of the compound of formula II is 1 to 100 ml, preferably 1 to 40 ml, and more preferably 1 to 2.5 ml.

[0016] In the preparation method of the lisinopril anhydride intermediate represented by the above formula III, the amount of the acid binding agent required per mole of the compound of formula II is 0.1 to 3 moles, preferably 1 to 2.5 moles, and more preferably 1.5 to 2.2 moles.

[0017] In the preparation method of the lisinopril anhydride intermediate represented by the above formula III, the weight of water required per gram of the compound of formula II is 0.5-10 ml, preferably 0.5-4 ml, more preferably 0.5-2.5 ml.

[0018] In the method for preparing the lisinopril anhydride intermediate represented by the above formula III, the reaction temperature is 0 to 40°C, preferably 15 to 35°C, and more preferably 20 to 28°C.

[0019] The synthesis method of the lisinopril anhydride intermediate shown in formula III provided by the present invention, on the one hand, avoids the generation of highly toxic phosgene during the reaction, eliminates the residual phosgene in the anhydride intermediate, and reduces the safety risk during the synthesis process; on the other hand, the reaction time is shortened, the reaction conditions are relatively mild, and a product with high purity can be obtained without further purification. It has strong practical significance in industrial production. Specific implementation method:

[0020] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. Based on the examples in the present invention, any changes and modifications of the present invention by those skilled in the art without creative work shall fall within the protection scope of the present invention.

[0021] Example 1:

[0022] Take N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6-13g of trifluoroacetyl-L-lysine, 6g of triphosgene, 26ml of dichloromethane were added, and the mixture was stirred for 5 minutes to dissolve. Then, 13ml of water and 6.6g of sodium carbonate were added, and the mixture was kept warm at 20°C for 40 minutes. After the heat preservation was completed, 0.2ml of pyridine was slowly added, and the mixture was kept warm for 20 minutes. The water layer was separated and the organic layer was taken. After washing with 20ml of water, 2g of anhydrous sodium sulfate was added and dried for 10 minutes. After filtering, the filtrate was concentrated to obtain a white solid, which was the target product. The HPLC purity was 99.8% and the yield was 99%.

[0023] Example 2:

[0024] Take N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -13g of trifluoroacetyl-L-lysine, 5g of triphosgene, 40ml of toluene were added, and after stirring for 5 minutes, 20ml of water and 6g of potassium carbonate were added, and the mixture was kept warm at 20°C for 2 hours. After the heat preservation was completed, 0.1ml of pyridine was slowly added, and the heat preservation was continued for 20 minutes. The water layer was separated and the organic layer was taken. After washing with 20ml of water, 2.5g of anhydrous sodium sulfate was added and dried for 10 minutes, and then filtered. The filtrate was concentrated to obtain a white solid, which was the target product. The HPLC purity was 99.0% and the yield was 98%.

[0025] Example 3:

[0026] Take N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -13g of trifluoroacetyl-L-lysine, add 4.8g of triphosgene and 50ml of dichloromethane, stir for 5 minutes to dissolve, then add 25ml of water, add sodium carbonate aqueous solution (5g of sodium carbonate dissolved in 25ml of water) dropwise at 20°C, keep warm for 20 minutes after the addition is complete, slowly add 0.2ml of pyridine, continue to keep warm for 10 minutes, separate the water layer, take the organic layer, wash with 20ml of water, add 2g of anhydrous sodium sulfate, dry for 10 minutes, and filter, take the filtrate and concentrate to obtain a white solid as the target product, HPLC purity 99.9%, yield 100%.

[0027] Example 4:

[0028] Take N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6-13g of trifluoroacetyl-L-lysine, add 5.6g of triphosgene and 50ml of chloroform, stir for 5 minutes to dissolve, then add 50ml of water and 5.6g of ammonium carbonate, keep warm at 28°C for 1 hour, slowly add 0.2ml of pyridine, keep warm for 10 minutes, separate the water layer, take the organic layer, wash with 20ml of water, add 2g of anhydrous sodium sulfate, dry for 10 minutes, filter, and concentrate the filtrate to obtain a white solid as the target product, with HPLC purity of 99.3% and a yield of 97%.

[0029] Example 5:

[0030] Take N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -13g of trifluoroacetyl-L-lysine, 6.2g of triphosgene, 50ml of dichloromethane were added, and the mixture was stirred for 5 minutes to dissolve. Then, 20ml of water and 6.8g of sodium carbonate were added, and the mixture was kept warm at 25°C for 1.5 hours. After the heat preservation, the organic layer was taken, washed with 20ml of water, and 2g of anhydrous sodium sulfate was added, dried for 10 minutes, and filtered. The filtrate was concentrated to obtain a white solid, which was the target product. The HPLC purity was 99.6%, and the yield was 98%.

[0031] Comparative Example:

[0032] Take N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -13g of trifluoroacetyl-L-lysine, add 6.2g of triphosgene and 50ml of dichloromethane, stir for 5 minutes to dissolve, heat under reflux for 26 hours, take samples every 4 hours for detection, the data are shown in the table below, evaporate the phosgene under reduced pressure, and then drag twice with 50ml of dichloromethane to obtain a white solid, which is the target product, with HPLC purity of 95.4% and a yield of 97%.

[0033] Reaction time Purity of reactants 4 hours 32.5％ 8 hours 67.8％ 12 hours 79.5％ 16 hours 88.7％ 20 hours 93.5％ 24 hours 95.4％ 26 hours 95.2％

[0034] The data show that without adding an acid binding agent, the reaction requires reflux reaction for 24 hours to complete the reaction.

Claims

1. A method for preparing a lisinopril anhydride intermediate of formula III, comprising reacting a lisinopril hydride of formula II with triphosgene in a mixed solvent of an organic solvent and water in the presence of an acid binding agent to obtain a lisinopril anhydride intermediate of formula III. The synthetic route is as follows: The amount of the acid-binding agent required for each mole of the compound of formula II is 1 to 3 moles, and the acid-binding agent is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, and pyridine.

2. The method according to claim 1, characterized in that The following steps are involved: (a) adding triphosgene and an organic solvent to the compound represented by formula II to obtain a mixture; adding water and an acid binding agent to the mixture to react; (b) After the reaction is completed, the organic layer is separated, washed, dried, and concentrated to dryness to obtain the target compound.

3. The method according to claim 1 or 2, wherein the organic solvent is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, toluene or xylene.

4. The method according to claim 3, wherein the organic solvent is selected from the group consisting of dichloromethane, chloroform or toluene.

5. The method according to claim 1 or 2, wherein the amount of triphosgene required per mole of the compound of formula II is 0.4 to 1.0 mole.

6. The method according to claim 5, wherein 0.4 to 0.6 moles of triphosgene are required per mole of the compound of formula II.

7. The method according to claim 6, wherein the amount of triphosgene required per mole of the compound of formula II is 0.5 to 0.55 moles.

8. The method according to claim 1 or 2, wherein the weight of the organic solvent required per gram of the compound of formula II is 1 to 100 ml.

9. The method according to claim 8, wherein the weight of the organic solvent required per gram of the compound of formula II is 1 to 40 ml.

10. The method according to claim 9, wherein the weight of the organic solvent required per gram of the compound of formula II is 1 to 2.5 ml.

11. The method according to claim 1 or 2, wherein the amount of the acid binding agent required per mole of the compound of formula II is 1 to 2.5 moles.

12. The method according to claim 11, wherein the amount of the acid binding agent required per mole of the compound of formula II is 1.5 to 2.2 moles.

13. The method according to claim 1 or 2, wherein the weight of water required for each gram of the compound of formula II is 0.5 to 10 ml.

14. The method according to claim 13, wherein the weight of water required per gram of the compound of formula II is 0.5 to 4 ml.

15. The method according to claim 14, wherein the weight of water required per gram of the compound of formula II is 0.5 to 2.5 ml.

16. The method according to claim 1 or 2, wherein the reaction temperature is 0 to 40°C.

17. The method according to claim 16, wherein the reaction temperature is 15-35°C.

18. The method according to claim 17, wherein the reaction temperature is 20-28°C.

Images