Preparation method of carfilzomib intermediate

Abstract

The invention discloses a preparation method of a carfilzomib intermediate, which comprises the following steps: adding ASC007-I into a reaction container, adding a solvent at room temperature, starting stirring, reducing the temperature to 5-10 DEG C, dropwise adding an alkali metal hydroxide solution into a reaction bottle, slowly heating to maintain the temperature at 20-25 DEG C after dropwise adding, reacting, adjusting the pH value to 3-4 with glacial acetic acid after the reaction is completed, separating out a large amount of white solid, and filtering to obtain the carfilzomib intermediate. Washing the filter cake with purified water until the filtrate is neutral; and recrystallizing to obtain the product ASC007-II. Alkali metal hydroxide and ASC007-I react, no catalyst or hydrogen is needed, the reaction yield finally reaches 90% through improvement of a feeding mode and adjustment of a reaction solvent, and compared with a hydrogenation method, the method has the advantages that the requirement for equipment is low, the reaction condition is milder, the process controllability is higher, and the method is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a carfilzomib intermediate, and belongs to the technical field of organic synthesis. BACKGROUND

[0002] Carfilzomib is a proteasome inhibitor, which is suitable for treating multiple myeloma patients. The dosage form is a lyophilized powder for intravenous injection, which is produced by Onyx Pharmaceutical Company. FDA approved its marketing on July 20, 2012.

[0003] The synthesis of a key intermediate is as follows:

[0004]

[0005] Since the compound has multiple amide bonds and chiral centers, the preparation method disclosed by the original manufacturer in patent CN102286070A reports a method of passing hydrogen under the catalysis of palladium carbon, and the yield can reach 90%. Although this high-pressure hydrogenation method has high yield, the preparation process involves high pressure and hydrogenation. The reaction is relatively controllable in laboratory small test, and the reaction purity and yield are relatively high. However, it involves a dangerous reaction (hydrogenation reaction) that is under key control, and has certain danger in industrial production, which belongs to a dangerous reaction under key control.

[0006] Therefore, it is hoped to find a more convenient method without hydrogenation. CN102286070A also discloses:

[0007]

[0008] When it is a methyl ester, lithium hydroxide is used to react in the presence of methanol water, and the yield is only about 30%.

[0009] CN116262776A discloses that 2.00g of compound 3 and 1.28g of lithium hydroxide are added into a 100ml flask, 40ml of methanol is added, the temperature is raised to 40-60℃, and the reaction is kept for 4 hours. After filtering to remove palladium carbon, it is concentrated under reduced pressure to stop the flow, and n-butanol is added for recrystallization to obtain 0.63g of white solid, with a yield of 32.28% and a chromatographic purity of 98.87%. That is, lithium hydroxide is used to react in the presence of palladium carbon, but the yield is also low. SUMMARY

[0010] In view of the above problems, the purpose of the present application is to provide a preparation method of a carfilzomib intermediate, which does not need hydrogenation and does not use hydrogenation hydrolysis for reaction, is simpler to operate, has high reaction efficiency and high yield, does not need a catalyst, has low cost, is convenient to handle, and the like.

[0011] In order to achieve the above object, the technical scheme of the present application is as follows: a preparation method of a carfilzomib intermediate, the reaction formula is:

[0012]

[0013] The method is characterized in that: ASC007-I is added into a reaction container, a solvent is added at room temperature, stirring is started, the temperature is reduced to 5-10 DEG C, an alkali metal hydroxide solution is added dropwise into the reaction bottle, after the dropwise addition is completed, the temperature is slowly increased and maintained at 20-25 DEG C for reaction, after the reaction is completed, glacial acetic acid is used to adjust the pH to 3-4, a large amount of white solid is precipitated, the filter cake is washed with purified water until the filtrate is neutral, and the product ASC007-II is obtained through recrystallization.

[0014] In the above scheme, the alkali metal hydroxide solution is one of lithium hydroxide, potassium hydroxide and sodium hydroxide.

[0015] In the above scheme, the molar ratio of the alkali metal hydroxide to ASC007-I is 1.1-1.5:1.

[0016] In the above scheme, the solvent is one of methanol, ethanol, acetonitrile and tetrahydrofuran.

[0017] In the above scheme, the volume ratio of the addition amount of the solvent to the water in the alkali metal hydroxide solution is 2:1.

[0018] In the above scheme, the glacial acetic acid is glacial acetic acid with a mass concentration of 10%-15%.

[0019] In the above scheme, the refining solvent is one of methanol, ethanol, n-butanol and acetonitrile, and a small amount of water is added during recrystallization.

[0020] In the above scheme, the volume ratio of the refining solvent to water is 12:1.

[0021] In the above scheme, the reaction time is 2-3 h, and the reaction time is short.

[0022] Beneficial effects: the alkali metal hydroxide is used to react with ASC007-I without a catalyst and hydrogen, through improvement of the feeding mode and adjustment of the reaction solvent, the yield can finally reach 90%, compared with the hydrogenation method, the present application has low requirements on equipment, the reaction condition is more mild, the process controllability is stronger, and the present application is more suitable for industrial production. DETAILED DESCRIPTION

[0023] The present application is further described below through examples:

[0024] Example 1

[0025]

[0026] Into a reaction flask, ASC007-I 10.0 g was added, and placed in a constant temperature water bath. 200 ml of methanol was added at room temperature, and stirring was started. The temperature was lowered to 5-10 °C, and a solution of lithium hydroxide 0.44 g (1.2 eq, dissolved in 100 ml of purified water) was added dropwise to the reaction flask. After the dropwise addition was completed, the temperature was maintained at 20-25 °C for 2 h. The pH was adjusted to 3-4 with 10% glacial acetic acid, and a large amount of white solid was precipitated. The solid was filtered, and the filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250 ml reaction flask, 120 ml of anhydrous ethanol was added, and then 10 ml of purified water was added. The solution was dissolved by heating under reflux, and the temperature was slowly lowered to induce crystallization. The temperature was maintained at 0-5 °C for 1 h to induce crystallization, and then the product was filtered. The filter cake was dried at 50 °C under reduced pressure until the weight was constant, and white solid ASC007-II was obtained. The yield was 90.4%, and the liquid phase purity was 99.63%.

[0027] Example 2

[0028] Into a reaction flask, ASC007-I 10.0 g was added, and placed in a constant temperature water bath. 200 ml of methanol was added at room temperature, and stirring was started. The temperature was lowered to 5-10 °C, and a solution of lithium hydroxide 0.44 g (1.2 eq, dissolved in 100 ml of purified water) was added dropwise to the reaction flask. After the dropwise addition was completed, the temperature was maintained at 20-25 °C for 2 h. The pH was adjusted to 3-4 with 10% glacial acetic acid, and a large amount of white solid was precipitated. The solid was filtered, and the filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250 ml reaction flask, 120 ml of anhydrous ethanol was added, and then 10 ml of purified water was added. The solution was dissolved by heating under reflux, and the temperature was slowly lowered to induce crystallization. The temperature was maintained at 0-5 °C for 1 h to induce crystallization, and then the product was filtered. The filter cake was dried at 50 °C under reduced pressure until the weight was constant, and white solid ASC007-II was obtained. The yield was 90.4%, and the liquid phase purity was 99.63%.

[0029] Example 3

[0030] Into a reaction flask, ASC007-I 10.0 g was added, and placed in a constant temperature water bath. 200 ml of methanol was added at room temperature, and stirring was started. The temperature was lowered to 5-10 °C, and a solution of lithium hydroxide 0.44 g (1.2 eq, dissolved in 100 ml of purified water) was added dropwise to the reaction flask. After the dropwise addition was completed, the temperature was maintained at 20-25 °C for 2 h. The pH was adjusted to 3-4 with 10% glacial acetic acid, and a large amount of white solid was precipitated. The solid was filtered, and the filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250 ml reaction flask, 120 ml of anhydrous ethanol was added, and then 10 ml of purified water was added. The solution was dissolved by heating under reflux, and the temperature was slowly lowered to induce crystallization. The temperature was maintained at 0-5 °C for 1 h to induce crystallization, and then the product was filtered. The filter cake was dried at 50 °C under reduced pressure until the weight was constant, and white solid ASC007-II was obtained. The yield was 90.4%, and the liquid phase purity was 99.63%.

[0031] Example 4

[0032] The rest is the same as example 1, except that the solvent is replaced by ethanol, the yield is 86.2%, and the liquid phase purity is 99.6%.

[0033] Example 5

[0034] The rest is the same as example 1, except that the solvent is replaced by acetonitrile and tetrahydrofuran respectively, when the solvent is acetonitrile, the yield is 85.8%, and when the solvent is tetrahydrofuran, the yield is 86.1%.

[0035] Example 6

[0036] The rest is the same as example 1, except that the recrystallization solvent is replaced by methanol, n-butanol and acetonitrile respectively, the yield of methanol is 88.4%, the yield of n-butanol is 87.8%, and the yield of acetonitrile is 87.9%.

[0037] Example 7

[0038]

[0039] Into the reaction bottle, ASC007-I 10.0g was added, and placed in a constant temperature water bath. 200ml of methanol was added at room temperature, and stirring was started. The temperature was reduced to 5-10℃, and a solution of sodium hydroxide 0.79g (1.3eq, dissolved in 100ml purified water) was added dropwise to the reaction bottle. After the dropwise addition was completed, the temperature was slowly increased to maintain 20-25℃ for 2h. 10% glacial acetic acid was used to adjust the pH to 3-4, and a large amount of white solid was precipitated. Filtration was performed, and the filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250ml reaction bottle, 120ml of anhydrous ethanol was added, and then 10ml of purified water was added. The solution was dissolved by heating to reflux, and then slowly cooled to crystallize. Crystallization was maintained at 0-5℃ for 1h, and then filtration was performed. The filter cake was dried at 50℃ under reduced pressure to constant weight, and white solid ASC007-II was obtained, with a yield of 75.14% and a liquid phase purity of 99.40%.

[0040] Example 8

[0041] Into the reaction bottle, ASC007-I 10.0g was added, and placed in a constant temperature water bath. 200ml of acetonitrile was added at room temperature, and stirring was started. The temperature was reduced to 5-10℃, and a solution of sodium hydroxide 0.91g (1.5eq, dissolved in 100ml purified water) was added dropwise to the reaction bottle. After the dropwise addition was completed, the temperature was slowly increased to maintain 20-25℃ for 2h. 10% glacial acetic acid was used to adjust the pH to 3-4, and a large amount of white solid was precipitated. Filtration was performed, and the filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250ml reaction bottle, 120ml of anhydrous ethanol was added, and then 10ml of purified water was added. The solution was dissolved by heating to reflux, and then slowly cooled to crystallize. Crystallization was maintained at 0-5℃ for 1h, and then filtration was performed. The filter cake was dried at 50℃ under reduced pressure to constant weight, and white solid ASC007-II was obtained, with a yield of 72.14% and a liquid phase purity of 99.42%.

[0042] Example 9

[0043]

[0044] Into a reaction flask, 10.0 g of ASC007-I was added, and placed in a constant temperature water bath. 200 ml of methanol was added at room temperature, and stirring was started. The temperature was lowered to 5-10°C, and a solution of 1.11 g of potassium hydroxide (1.3 eq, dissolved in 100 ml of purified water) was added dropwise to the reaction flask. After the dropwise addition was completed, the temperature was slowly increased and maintained at 20-25°C for 2 h. The PH was adjusted to 3-4 with 10% glacial acetic acid, and a large amount of white solid was precipitated. The filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250 ml reaction flask, 120 ml of anhydrous ethanol was added, and then 10 ml of purified water was added. The solution was dissolved by heating under reflux, and the temperature was slowly lowered to induce crystallization. The temperature was maintained at 0-5°C for 1 h to induce crystallization. The product was filtered, and the filter cake was dried at 50°C under reduced pressure until the weight was constant. White solid ASC007-II was obtained with a yield of 79.19% and a liquid phase purity of 98.67%.

[0045] Example 10

[0046] Into a reaction flask, 10.0 g of ASC007-I was added, and placed in a constant temperature water bath. 200 ml of tetrahydrofuran was added at room temperature, and stirring was started. The temperature was lowered to 5-10°C, and a solution of 1.11 g of potassium hydroxide (1.3 eq, dissolved in 100 ml of purified water) was added dropwise to the reaction flask. After the dropwise addition was completed, the temperature was slowly increased and maintained at 20-25°C for 2 h. The PH was adjusted to 3-4 with 10% glacial acetic acid, and a large amount of white solid was precipitated. The filter cake was washed with purified water until the filtrate was neutral. The wet product was added to a 250 ml reaction flask, 120 ml of anhydrous ethanol was added, and then 10 ml of purified water was added. The solution was dissolved by heating under reflux, and the temperature was slowly lowered to induce crystallization. The temperature was maintained at 0-5°C for 1 h to induce crystallization. The product was filtered, and the filter cake was dried at 50°C under reduced pressure until the weight was constant. White solid ASC007-II was obtained with a yield of 75.19% and a liquid phase purity of 98.64%.

[0047] The present application is not limited to the above-described embodiments, and those skilled in the art can understand that various changes, modifications, replacements, and variations can be made to these embodiments without departing from the principles and purposes of the present application. The scope of the present application is defined by the claims and their equivalents.

Claims

1. A method for preparing a carfilzomib intermediate, the reaction formula is: Its characteristics are: ASC007-I was added to the reaction vessel, and the solvent was added at room temperature. Stirring was started and the temperature was lowered to 5-10°C. An alkali metal hydroxide solution was added dropwise to the reaction flask. After the addition was complete, the temperature was raised and maintained at 20-25°C for reaction. After the reaction was completed, the pH was adjusted to 3-4 with glacial acetic acid to precipitate a large amount of white solid. The solid was filtered and the filter cake was washed with purified water until the filtrate was neutral. The product ASC007-II was obtained by recrystallization.

2. The method for preparing the carfilzomib intermediate according to claim 1, wherein: The alkali metal hydroxide solution is one of lithium hydroxide, potassium hydroxide and sodium hydroxide.

3. The method for preparing the carfilzomib intermediate according to claim 2, wherein: The molar ratio of the alkali metal hydroxide to ASC007-I is 1.1-1.5:

1.

4. The method for preparing the carfilzomib intermediate according to any one of claims 1 to 3, characterized in that: The solvent is one of methanol, ethanol, acetonitrile and tetrahydrofuran.

5. The method for preparing the carfilzomib intermediate according to claim 4, wherein: The volume ratio of the added amount of the solvent to the water in the alkali metal hydroxide solution is 2:

1.

6. The method for preparing the carfilzomib intermediate according to claim 5, wherein: The glacial acetic acid has a mass concentration of 10%-15%.

7. The method for preparing the carfilzomib intermediate according to claim 1, wherein: The refining solvent is one of methanol, ethanol, n-butanol and acetonitrile, and a small amount of water is added during recrystallization.

8. The method for preparing the carfilzomib intermediate according to claim 7, wherein: The volume ratio of the refined solvent to water is 12:

1.

9. The method for preparing the carfilzomib intermediate according to claim 1, wherein: Reaction time: 2-3h.

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