A method for the synthesis of Biolimus A9

Abstract

The present application provides a kind of synthesis method of Biolimus A9, the method steps as follows: rapamycin and monohalogen ether are dissolved in polar aprotic solvent, then silver oxide is added, avoid light processing, stirring is carried out at room temperature to 60 DEG C or below, after reaction, remove insoluble solid by filtration, after extraction purification of filtrate, product Biolimus A9 is obtained;The halogen of the monohalogen ether is chlorine, bromine or iodine.The present application has the characteristics of mild reaction condition and low reaction temperature, high product yield, less reaction byproduct, especially the byproduct of lactone ring opening is effectively controlled;And also has the advantage of low reaction cost.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthetic method of Biolimus A9. BACKGROUND

[0002] Biolimus (also known as BA9) as a derivative of rapamycin (also known as sirolimus, CAS [53123-88-9]), like other members of the "mTOR" family including everolimus (CAS [159351-69-6]), zotarolimus (CAS [221877-54-9]) and temsirolimus (CAS [162635-04-03]), binds to the intracellular immunophilin FKBP12, the resulting macrolide / FKBP12 complex then binds to mTOR (a key protein in cell cycle progression) in a similar manner to sirolimus, which in turn inhibits the mTOR signaling pathway and causes cell cycle arrest at the G1 to S phase, thus having immunosuppressive, antifungal, antitumor and / or anti-inflammatory activity in vivo, and is used to treat transplant rejection, infectious diseases, autoimmune diseases and conditions characterized by cell overproliferation. BA9 is currently being developed as an active pharmaceutical ingredient for drug coating of coronary stents to prevent smooth muscle cell proliferation and restenosis.

[0003]

[0004] The chemical structure of BA9 is composed of a 31-membered triene macrocyclic lactone that retains the core rapamycin ring structure, and only a side chain is added at position 40, in which the hydroxyl group of rapamycin is alkylated by an ethoxyethyl group. Due to the therapeutic value of BA9 and other rapamycin derivatives, patents such as US2005 / 192311, US2009 / 292118, WO2014 / 116611, etc. report their synthetic methods, and the synthetic route is as follows:

[0005]

[0006] This route prepares 2-ethoxyethyl triflate from 2-ethoxyethanol, and performs etherification reaction with rapamycin under the condition of the same amount of organic base with more than 10 times the amount of the use. The target product Biolimus is obtained. This synthetic method has two obvious shortcomings: ① The intermediate 2-ethoxyethyl triflate is not stable and cannot be stored for a long time, and needs to be prepared on demand, and the amount is greatly excessive, which causes the reaction to be not economical. ② The etherification conversion rate is not high, the substrate rapamycin cannot be completely reacted, and the overall yield is only about 45%. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a synthesis method of Biolimus A9, which has the characteristics of mild reaction condition, low reaction temperature, high product yield, few reaction by-products, especially effective control of lactone ring-opening by-products, and low reaction cost.

[0008] The present application is implemented as follows:

[0009] A synthesis method of Biolimus A9, the steps of which are as follows: dissolving rapamycin and a monohalo ether in a polar aprotic solvent, then adding silver oxide, avoiding light, stirring at room temperature to below 60 DEG C, after the reaction is completed, removing the insoluble solid by filtration, and then purifying the filtrate by extraction to obtain the product Biolimus A9.

[0010] The halogen of the monohalo ether is chlorine, bromine or iodine.

[0011] Further, the halogen of the monohalo ether is bromine or iodine.

[0012] Further, the amount of silver oxide is between 1.0 and 1.5 equivalents.

[0013] The synthesis route of Biolimus A9 is as follows:

[0014]

[0015] Further, the amount of silver oxide is 1.2 equivalents.

[0016] Further, the amount of the monohalo ether is between 1.5 and 3.0 equivalents.

[0017] Further, the amount of the monohalo ether is 2.0 equivalents.

[0018] Further, when the monohalo ether is 2-iodoethyl ethyl ether or 2-bromoethyl ethyl ether, the reaction temperature is room temperature.

[0019] Further, the polar aprotic solvent is N,N-dimethylformamide, dimethyl sulfoxide, dioxane, acetone or tetrahydrofuran.

[0020] Further, when the monohalo ether is 2-bromoethyl ethyl ether, the reaction system further comprises 0.1-0.5 equivalents of potassium iodide, sodium iodide or tetrabutylammonium iodide.

[0021] Further, the extraction and purification of the filtrate are specifically as follows:

[0022] The filtrate was diluted with water and extracted with ethyl acetate for several times. The obtained extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered to remove the solid. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain a white solid.

[0023] The present application has the following advantages:

[0024] The present application uses an etherification reaction system of halogenated ethyl ether and silver oxide to increase the yield of Biolimus from the existing 45% to 65%. The bromoethyl ether or iodoethyl ether used in the present application is easy to obtain, and does not need to be used in large excess. In particular, the cheap bromoethyl ether and potassium iodide can replace the relatively expensive iodoethyl ether, so that the reaction cost is greatly reduced. At the same time, the reaction system of the present application has the characteristics of mild reaction conditions and low reaction temperature, so that the by-products are less, especially the by-products of lactone ring opening are effectively controlled.

DETAILED DESCRIPTION

[0025] The present application relates to a synthesis method of Biolimus A9, and the steps of the method are as follows: rapamycin and monohalogenated ether are dissolved in a polar aprotic solvent, silver oxide is added, and stirring is carried out at room temperature to below 60℃ in the dark. After the reaction is completed, the insoluble solid is removed by filtration, and the filtrate is extracted and purified to obtain the product Biolimus A9.

[0026] The halogen of the monohalogenated ether is chlorine, bromine or iodine.

[0027] Preferably, the halogen in the monohalogenated ether is bromine or iodine.

[0028] The amount of silver oxide used is between 1.0 and 1.5 equivalents.

[0029] The synthesis route of Biolimus A9 is as follows:

[0030]

[0031] Preferably, the amount of silver oxide used is 1.2 equivalents.

[0032] The amount of monohalogenated ether used is between 1.5 and 3.0 equivalents.

[0033] Preferably, the amount of monohalogenated ether used is 2.0 equivalents.

[0034] When the monohalogenated ether is 2-iodoethyl ether or 2-bromoethyl ether, the reaction temperature is room temperature.

[0035] The polar aprotic solvent is N,N-dimethylformamide, dimethyl sulfoxide, dioxane, acetone or tetrahydrofuran.

[0036] When the monohalo ether is 2-bromoethyl ethyl ether, the reaction system further comprises 0.1-0.5 equivalent of potassium iodide, sodium iodide or tetrabutylammonium iodide.

[0037] The extraction purification of the filtrate is specifically as follows:

[0038] The filtrate is diluted with water, extracted with ethyl acetate for multiple times, the obtained extract is washed with saturated brine, dried over anhydrous sodium sulfate, the solid is removed by filtration, the filtrate is concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a white solid.

[0039] The technical solutions of the present application will be clearly and completely described below in combination with specific embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application. The specific conditions not mentioned in the embodiments are carried out according to the conventional conditions or the conditions recommended by the manufacturers. The reagents or instruments not mentioned by the manufacturers are all conventional products that can be purchased on the market.

[0040] Example 1: 2.00 g of rapamycin (2.19 mmol) and 670 mg of 2-bromoethyl ethyl ether (4.38 mmol) are dissolved in 10 ml of N,N-dimethylformamide, 610 mg of silver oxide (2.63 mmol) is added, and the mixture is stirred at 40°C for 48 hours in the dark. The insoluble solid is removed by filtration. The filtrate is diluted with 100 ml of water, extracted with ethyl acetate (20 ml*3), the obtained extract is washed with saturated brine (15 ml*3), dried over 5 g of anhydrous sodium sulfate, the solid is removed by filtration, the filtrate is concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain 1.40 g of a white solid, with a yield of 65%.

[0041] Example 2: 2.00 g of rapamycin (2.19 mmol) and 876 mg of 2-iodoethyl ethyl ether (4.38 mmol) are dissolved in 10 ml of N,N-dimethylformamide, 610 mg of silver oxide (2.63 mmol) is added, and the mixture is stirred at room temperature for 24 hours in the dark. The insoluble solid is removed by filtration. The filtrate is diluted with 100 ml of water, extracted with ethyl acetate (20 ml*3), the obtained extract is washed with saturated brine (15 ml*3), dried over 5 g of anhydrous sodium sulfate, the solid is removed by filtration, the filtrate is concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain 1.45 g of a white solid, with a yield of 67%.

[0042] Example 3: rapamycin 2.00 g (2.19 mmol), 2-bromoethyl ethyl ether 670 mg (4.38 mmol) and potassium iodide 33 mg (0.2 mmol) were dissolved in 10 ml of N, N-dimethylformamide, and then silver oxide 610 mg (2.63 mmol) was added. The mixture was stirred at room temperature for 36 hours in the dark, and then insoluble solids were removed by filtration. The filtrate was diluted with 100 ml of water, and extracted with ethyl acetate (20 ml*3). The obtained extract was washed with saturated brine (15 ml*3), dried with 5 g of anhydrous sodium sulfate, and then the solids were removed by filtration. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain 1.40 g of white solid, with a yield of 65%.

[0043] In summary, the etherification reaction system of the present application using halogenated ethyl ether and silver oxide can increase the yield of Biolimus from the existing 45% to 65%. The bromoethyl ether or iodoethyl ether used in the present application is easy to obtain, and does not need to be used in large excess. In particular, the inexpensive bromoethyl ether and potassium iodide can replace the relatively expensive iodoethyl ether, so that the reaction cost is greatly reduced. At the same time, the reaction system of the present application has the characteristics of mild reaction conditions and low reaction temperature, so that the reaction by-products are less, and especially the by-products of lactone ring opening are effectively controlled.

[0044] Although the specific embodiments of the present application are described above, it should be understood by those skilled in the art that the specific examples described are only illustrative, and are not intended to limit the scope of the present application. Equivalent modifications and variations made by those skilled in the art in accordance with the spirit of the present application should be covered within the scope of the claims of the present application.

Claims

1. A method of synthesis of Biolimus A9, characterized by: The method steps are as follows: rapamycin and monohalogen ether are dissolved in a polar aprotic solvent, silver oxide is added, the reaction is carried out at room temperature to below 60℃ under light protection, after the reaction is completed, insoluble solids are removed by filtration, and the filtrate is extracted and purified to obtain product Biolimus A9; The monohalogen ether is 2-iodoethyl ethyl ether or 2-bromoethyl ethyl ether.

2. The process for synthesis of Biolimus A9 as claimed in claim 1, wherein: The amount of silver oxide used is between 1.0 and 1.5 equivalents relative to rapamycin; The synthesis route of Biolimus A9 is as follows: 。 3. The process for synthesis of Biolimus A9 as claimed in claim 2, wherein: The amount of silver oxide used is 1.2 equivalents relative to rapamycin.

4. The process for synthesis of Biolimus A9 as claimed in claim 1, wherein: The amount of monohalogen ether used is between 1.5 and 3.0 equivalents relative to rapamycin.

5. The process for synthesis of Biolimus A9 as claimed in claim 4, wherein: The amount of monohalogen ether used is 2.0 equivalents relative to rapamycin.

6. The process for synthesis of Biolimus A9 as claimed in claim 1, wherein: The reaction temperature is room temperature.

7. The process for synthesis of Biolimus A9 as claimed in claim 1, wherein: The polar aprotic solvent is N,N-dimethylformamide, dimethyl sulfoxide, dioxane, acetone or tetrahydrofuran.

8. The process for synthesis of Biolimus A9 as claimed in claim 1, wherein: When the monohalogen ether is 2-bromoethyl ethyl ether, 0.1-0.5 equivalents of potassium iodide, sodium iodide or tetrabutylammonium iodide are also included in the reaction system relative to rapamycin.

9. The process for synthesis of Biolimus A9 as claimed in claim 1, wherein: The extraction and purification of the filtrate are as follows: The filtrate is diluted with water, extracted with ethyl acetate multiple times, the obtained extract is washed with saturated brine, dried with anhydrous sodium sulfate, the solids are removed by filtration, the filtrate is concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a white solid.

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