Preparation method of lenalidomide impurity A

Abstract

The invention relates to the technical field of drug impurity synthesis, in particular to a preparation method of a lenalidomide impurity A. The preparation method comprises the following steps: (1) heating lenalidomide and a compound 1 in an alkali and solvent system, carrying out cyclization reaction, and carrying out column purification to obtain a compound 2, the compound 1 being 2-bromomethyl-3-nitrobenzoic acid methyl ester; and (2) reducing the compound 2 in an alcohol solvent and water system by using an inorganic metal reducing agent and a lewis acid system, and then concentrating, crystallizing, filtering and drying to obtain the lenalidomide impurity A. The invention provides a simple and efficient directional synthesis method of the lenalidomide impurity A. The method is low in cost, mild in condition, and suitable for industrial production. The lenalidomide impurity A is prepared by cyclizing lenalidomide and a compound 1 (lenalidomide intermediate, 2-bromomethyl-3-nitrobenzoic acid methyl ester) and then reducing, and the prepared lenalidomide impurity A is high in purity and can be used as an impurity reference substance for quality research of lenalidomide.

Description

Technical Field

[0001] The present invention relates to the technical field of drug impurity synthesis, and in particular to a method for preparing lenalidomide impurity A. Background Art

[0002] Lenalidomide is an anti-tumor and anti-tumor cell proliferation immunomodulatory agent that can be used to treat multiple myeloma, mantle cell lymphoma, and myelodysplastic syndrome. Its chemical name is: 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and its chemical structure is as follows:

[0003] Lenalidomide Lenalidomide impurity A is one of the important process impurities produced in the production process of lenalidomide, and plays an important role in the drug quality control of lenalidomide. The directional preparation of lenalidomide impurity A is an important task in the drug development process. The present invention provides a method for directional synthesis of lenalidomide impurity A, which is efficient and convenient. The chemical structure of lenalidomide impurity A is shown below: Summary of the invention

[0004] The object of the present invention is to provide a method for preparing lenalidomide impurity A.

[0005] The present invention discloses a method for preparing lenalidomide impurity A, comprising the following steps: (1) Lenalidomide and compound 1 (methyl 2-bromomethyl-3-nitrobenzoate) are heated in a certain base / solvent system to produce a cyclization reaction, which is then purified by a column to obtain compound 2; (2) Compound 2 is reduced in an alcohol solvent / water system using an inorganic metal reducing agent / Lewis acid system, and then concentrated, crystallized, filtered, and dried to obtain lenalidomide impurity A.

[0006] Preferably, the solvent in step (1) is one or a combination of acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0007] More preferably, the solvent used in step (1) is selected from N,N-dimethylacetamide and N-methylpyrrolidone.

[0008] Preferably, the base in step (1) is one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, and tributylamine.

[0009] Preferably, in the method described in step (1), the molar feed ratio of compound 1 to lenalidomide is 1 to 2:1.

[0010] Preferably, in the method described in step (1), the reaction temperature is 50 to 80°C.

[0011] Preferably, the alcohol solvent used in step (2) is selected from methanol, ethanol, isopropanol, n-butanol, 2-butanol, n-propanol or a combination of several thereof.

[0012] More preferably, the solvent used in step (2) is selected from methanol and ethanol.

[0013] Preferably, the inorganic metal reducing agent used in step (2) is one of reducing iron powder and zinc powder, and the Lewis acid is one of ammonium chloride, hydrochloric acid, acetic acid, ammonium acetate and ammonium sulfate.

[0014] Preferably, in the method described in step (2), the molar feed ratio of the inorganic metal reducing agent to the compound 2 is 2 to 6:1, and the molar feed ratio of the Lewis acid to the compound 2 is 1 to 6:1.

[0015] Preferably, in the method described in step (2), the reaction temperature is 70-90°C.

[0016] The present invention provides a simple and efficient directional synthesis method for lenalidomide impurity A, which has low cost and mild conditions. The method is prepared by cyclization of lenalidomide and compound 1 (lenalidomide intermediate, methyl 2-bromomethyl-3-nitrobenzoate) followed by reduction. The lenalidomide impurity A prepared by the present invention has high purity and can be used as an impurity reference substance for quality research of lenalidomide. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Attached Figure 1 For lenalidomide impurity A 1 H-NMR detection spectrum; Attached Figure 2 For lenalidomide impurity A 13 C-NMR detection spectrum; Attached Figure 3 This is the MS detection spectrum of lenalidomide impurity A. DETAILED DESCRIPTION

[0018] The present invention will be further explained and illustrated below in conjunction with specific embodiments.

[0019] The present invention discloses a method for preparing lenalidomide impurity A, which adopts the following synthetic route: Example 1

[0020] The synthesis method of compound 2 is as follows: 10 g of lenalidomide (38.6 mmol), 10.6 g of compound 1 (methyl 2-bromomethyl-3-nitrobenzoate) (38.6 mmol), 300 ml of acetonitrile, and 9 g of sodium bicarbonate (107 mmol) are sequentially added into a 500 mL three-necked flask, the temperature is raised to 80° C. and the reaction is carried out for 48 hours. The solvent is evaporated, and the residue is directly purified by column purification using methanol / dichloromethane as the eluent. 9.5 g of white solid is obtained by column purification, which is compound 2 with a purity of >98% and a yield of 59%. Example 2

[0021] The synthesis method of compound 2 is as follows: 10 g of lenalidomide (38.6 mmol), 14 g of compound 1 (methyl 2-bromomethyl-3-nitrobenzoate) (50 mmol), 100 ml of N-methylpyrrolidone, and 7.8 g of triethylamine (77.2 mmol) are placed in a 250 mL three-necked flask in sequence, the temperature is raised to 50 ° C and reacted for 48 hours, the solvent is evaporated, and the residue is directly purified by column purification using methanol / dichloromethane as eluent to obtain 12.7 g of white solid, which is compound 2, with a purity of >98% and a yield of 79%. Example 3

[0022] The synthesis method of compound 2 is as follows: 5 g of lenalidomide (19.3 mmol), 10.6 g of compound 1 (methyl 2-bromomethyl-3-nitrobenzoate) (38.6 mmol), 50 ml of NN dimethylacetamide, and 4.0 g of potassium carbonate (29 mmol) are put into a 200 mL three-necked flask in sequence, the temperature is raised to 60 ° C and reacted for 36 hours, the solvent is evaporated, and the residue is directly purified by column purification using methanol / dichloromethane as eluent to obtain 7.1 g of white solid, which is compound 2, with a purity of >98% and a yield of 88%. Example 4

[0023] The synthesis method of compound 2 is as follows: 10 g of lenalidomide (38.6 mmol), 14 g of compound 1 (methyl 2-bromomethyl-3-nitrobenzoate) (50 mmol), 300 ml of acetonitrile, and 9 g of triethylamine (107 mmol) are placed in a 200 mL three-necked flask in sequence, the temperature is raised to 75°C and the reaction is carried out for 48 hours. The solvent is evaporated and the residue is directly purified by column purification using methanol / dichloromethane as the eluent to obtain 9.1 g of a white solid, which is compound 2, with a purity of >98% and a yield of 56%. Example 5

[0024] The preparation method of lenalidomide impurity A is as follows: 4.2 g of compound 2 (10 mmol), 3.2 g of ammonium chloride (60 mmol), 100 ml of ethanol and 20 ml of water are placed in a 250 ml three-necked flask in sequence, stirred, and then 2.3 g of reducing iron powder (41 mmol) is added, the temperature is raised to 75°C, reacted for 2 hours, filtered, the filtrate is concentrated to remove most of the solvent, and then 30 ml of water is added, stirred, filtered, and dried to obtain 3.0 g of light yellow solid, which is lenalidomide impurity A, with a purity of >98% and a yield of 77%; please refer to Figure 1-3 , come to that impurity A 1 H-NMR, 13 The data of C-NMR and MS (APCI) are as follows: 1 H-NMR (500MHz, DMSO-d6): δ10.98 (s, 1H); δ7.82 (d, J=7.75Hz, 1H); δ7.71 (d, J=7.3Hz, 1H); δ7.62-7.66 (m, 1H); δ7.22-7.26 (m, 1H); δ6.98 (d, J=7.35Hz, 1H); δ6.85 (d, J=7.9Hz, 1H); δ5.55 (s, 2H); δ5.12-5.17 (m, 1H); δ4.85 (d, J=16.8Hz, 1H); δ4.75 (d,J=16.8Hz, 1H); δ4.44-4.54(m,2H); δ2.86-2.94 (m,1H); δ2.55-2.59 (m,1H); δ2.36-2.45 (m,1H); δ1.96 -1.99 (m,1H).

[0025] 13 C-NMR (125MHz, DMSO-d6): δ172.81, 170.87, 167.53, 166.85, 143.61, 137.03, 134.59, 133.22, 131 .97, 129.06, 128.99, 127.74, 125.86, 121.02, 116.51, 110.59, 51.49, 50.40, 47.20, 31.15, 22.41.

[0026] MS (APCI): 391.7 (M+H). Example 6

[0027] The preparation method of lenalidomide impurity A is as follows: 4.2 g of compound 2 (10 mmol), 0.54 g of ammonium chloride (10 mmol), 100 ml of ethanol and 20 ml of water are placed in a 250 ml three-necked flask in sequence, stirred, and then 1.3 g of zinc powder (20 mmol) is added, the temperature is raised to 80°C and reacted for 2 hours, filtered, and the filtrate is concentrated to remove most of the solvent, and then 30 ml of water is added, stirred, filtered, and dried to obtain 2.6 g of a light yellow solid, which is lenalidomide impurity A, with a purity of >98% and a yield of 67%. Example 7

[0028] The preparation method of lenalidomide impurity A is as follows: 4.2 g of compound 2 (10 mmol), 2.0 g of ammonium sulfate (15.1 mmol), 100 ml of ethanol and 20 ml of water are placed in a 250 ml three-necked flask in sequence, stirred, and then 1.3 g of zinc powder (20 mmol) is added, the temperature is raised to 70°C and reacted for 2 hours, filtered, and the filtrate is concentrated to remove most of the solvent, and then 30 ml of water is added, stirred, filtered, and dried to obtain 2.3 g of light yellow solid, which is lenalidomide impurity A, with a purity of >98% and a yield of 59%. Example 8

[0029] The preparation method of lenalidomide impurity A is as follows: 4.2 g of compound 2 (10 mmol), 2.0 g of ammonium sulfate (15.1 mmol), 60 ml of n-butanol and 20 ml of water are placed in a 250 ml three-necked flask in sequence, stirred, and then 3.4 g (60 mmol) of reducing iron powder is added, the temperature is raised to 90°C, the reaction is performed for 4 hours, the filtrate is filtered, the filtrate is separated, and the organic phase is separated. The organic phase is directly concentrated and the solvent is evaporated to obtain 2.7 g of a yellow solid, which is lenalidomide impurity A, with a purity of >98% and a yield of 69%.

[0030] The above description is only an embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A method for preparing lenalidomide impurity A, characterized in that: The following steps are involved: (1) heating lenalidomide and compound 1 in a base and solvent system to cause a cyclization reaction, and then purifying the mixture by a column to obtain compound 2, wherein compound 1 is methyl 2-bromomethyl-3-nitrobenzoate; (2) reducing the compound 2 in an alcohol solvent and water system with an inorganic metal reducing agent and a Lewis acid system, and then concentrating, crystallizing, filtering and drying to obtain lenalidomide impurity A; The reaction formula of the method is as follows: 。 2. The preparation method according to claim 1, characterized in that: The base and solvent system in step (1) refers to adding a base to an organic solvent, wherein: the organic solvent is selected from one or more of acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, and tributylamine.

3. The preparation method according to claim 2, characterized in that: The organic solvent in step (1) is N,N-dimethylacetamide or N-methylpyrrolidone.

4. The preparation method according to claim 1, characterized in that: In the step (1), the molar ratio of methyl 2-bromomethyl-3-nitrobenzoate to lenalidomide is 1 to 2:

1.

5. The preparation method according to claim 1, characterized in that: The reaction temperature of step (1) is 50-80°C.

6. The preparation method according to claim 1, characterized in that: The alcohol solvent in step (2) is selected from one or more of methanol, ethanol, isopropanol, n-butanol, 2-butanol and n-propanol.

7. The preparation method according to claim 6, characterized in that: The alcohol solvent in step (2) is methanol or ethanol.

8. The preparation method according to claim 1, characterized in that: The inorganic metal reducing agent in step (2) is selected from one of reducing iron powder and zinc powder; the Lewis acid is selected from one of ammonium chloride, hydrochloric acid, acetic acid, ammonium acetate and ammonium sulfate.

9. The preparation method according to claim 1, characterized in that: In the step (2), the molar ratio of the inorganic metal reducing agent to the compound 2 is 2 to 6:1, and the molar ratio of the Lewis acid to the compound 2 is 1 to 6:

1.

10. The preparation method according to claim 1, characterized in that: The reaction temperature of step (2) is 70-90°C.

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