Preparation method of lenalidomide compound

Abstract

The invention relates to a preparation method of a lenalidomide compound. The process comprises the following steps: in a N-methyl pyrrolidone or acetonitrile solvent, by using triethylamine or DIPEA (Diisopropylethylamine) as an acid binding agent, enabling 2-bromomethyl-3-nitrobenzoate to react with alpha-amino glutarimide hydrochloride, so as to obtain 3-(4-nitro-1-oxo-1, 3-dihydroisoindole-2-yl)-piperidine-2, 6-diketone; in the presence of hydrazine hydrate and Pd / C, nitryl of 3-(4-nitro-1-oxo-1, 3-dihydroisoindole-2-yl)-piperidine-2, 6-diketone is reduced, and lenalidomide is obtained. The process is easy and convenient to operate and mild in reaction condition, the purity of the obtained lenalidomide reaches 99.9% or above, the impurity content is extremely low, and the method is suitable for industrial production. The invention also provides high-purity lenalidomide prepared on the basis of the process and an industrial production method of the lenalidomide.

Description

Technical Field

[0001] The present invention relates to the field of chemical pharmacy, and in particular to a method for preparing a lenalidomide compound. The chemical name of lenalidomide is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and its structure is shown in Formula I.

[0002] Background Art

[0003] Lenalidomide is a thalidomide analog that was originally used to treat multiple myeloma and has also shown efficacy in myelodysplastic syndrome. Although its exact mechanism is unclear, lenalidomide and its analogs, such as thalidomide and CC-4047 / Actimid, have been found to interfere with the immune system and angiogenesis. Lenalidomide has shown significant efficacy in patients with myelodysplastic syndrome with 5q deletion cytogenetic abnormalities. Lenalidomide was approved by the US FDA on December 27, 2005 for the treatment of patients with low-risk or intermediate-1 risk MDS, with or without additional cytogenetic abnormalities. Celgene commercializes it under the brand name REVLIMID™ and provides capsule dosages of 5 mg, 10 mg, 15 mg and 25 mg.

[0004] Prior art U.S. Patent No. US5635517 discloses substituted 1-oxo-2-(2,6-dioxopiperidin-3-yl)isoindole derivatives and their use in cancer treatment, as well as a preparation method using palladium-carbon catalysis in 1,4-dioxane solvent to reduce a nitro group to an amino group.

[0005] Another method for preparing lenalidomide is disclosed in US Pat. No. US20060052609, which involves hydrogenating (S)- or racemic 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione using 10% palladium on carbon in methanol to form (S)- or racemic 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Indian application No. IN047CHE2006 discloses a method for hydrogenating 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione using 10% palladium on carbon in a mixed solvent of methanol and N,N-dimethylformamide.

[0006] The above process conditions may result in the presence of impurities such as unreacted starting materials and derivatives of lenalidomide in the final product. The presence of these impurities may depend on factors such as solvents and reaction conditions in the hydrogenation reaction. None of these documents mention appropriate conditions to avoid the formation of impurities or purification techniques to reduce these impurities. Therefore, there is a need in the field to improve the purity and yield of lenalidomide and make it suitable for industrial-scale production.

[0007] The present invention provides an improved process for the synthesis of lenalidomide, which can be used to prepare pure, substantially impurity-free lenalidomide compounds. In one aspect of the present invention, a process for preparing substantially pure lenalidomide is provided, and an embodiment thereof comprises the following steps: 1. In a reaction system in which the reaction solvent is N-methylpyrrolidone or acetonitrile and the acid-binding agent is triethylamine or DIPEA, 2-bromomethyl-3-nitrobenzoate (Formula II) is reacted with α-aminoglutarimide hydrochloride (Formula III) to obtain 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione (Formula IV).

[0008]

[0009] 2. Use dichloromethane or acetonitrile as solvent, NBS as bromination reagent, add benzoyl peroxide and 2-methyl-3-nitrobenzoate (Formula V) to prepare 2-bromomethyl-3-nitrobenzoate (Formula II).

[0010]

[0011] 3. In the presence of hydrazine hydrate and ferric chloride, the nitro group of (3S)-3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of formula IV is reduced to obtain lenalidomide of formula I.

[0012] In one embodiment of the present invention, the process for preparing substantially pure lenalidomide comprises the following steps: 1. reacting 2-bromomethyl-3-nitrobenzoate (Formula II) with α-aminoglutarimide hydrochloride (Formula III),

[0013] - The base used is triethylamine, tributylamine or DIPEA, preferably DIPEA - The solvent is N-methylpyrrolidone (NMP), N,N-dimethylformamide, N,N-dimethylacetamide or acetonitrile, preferably N,N-dimethylacetamide - Reaction temperature is 10°C-60°C, preferably 20°C-35°C.

[0014] 2. Preparation of 2-bromomethyl-3-nitrobenzoate (Formula II)

[0015] - The bromination reagent used is NBS (N-bromosuccinimide) - The solvent is dichloromethane, chloroform or acetonitrile, preferably acetonitrile - Reaction temperature is 10°C-90°C, preferably 60°C-70°C.

[0016] 3. Reducing the nitro group of (3S)-3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of formula IV to obtain lenalidomide of formula I.

[0017]

[0018] - The reducing agent of the nitro group is Pd / C, formic acid or hydrazine hydrate-ferric chloride system, preferably hydrazine hydrate-ferric chloride system - The solvent is methanol, ethanol or isopropanol, preferably methanol - The reaction temperature is 10°C-90°C, preferably 20°C-30°C. Specific embodiments

[0020] Example 1: Preparation of 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione (Formula IV) In a 50L glass reactor, add 22kg acetonitrile and 2.2kg 2-bromomethyl-3-nitrobenzoate and stir at 20℃-30℃. Gradually add 1.3kg α-aminoglutarimide hydrochloride, stir evenly and then drop 0.48kg triethylamine. Warm the reaction mixture to 50℃-60℃, stir for 10 hours, and then detect the completion of the reaction by TLC (PE:EA=3:1). After the reaction is completed, cool the mixture to 10℃-30℃, add 10kg water and stir for 2 hours. Filter the reaction solution to obtain a crude wet product, dry it with air at 40℃-65℃ for 10 hours, and obtain 2kg 3-(4-nitro-1-oxy-1,3-dihydroisoindole-2-yl)-piperidine-2,6-dione (Formula IV), with an HPLC purity of 99.14%.

[0021] Example 2: Preparation of 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride In a 50L glass reactor, add 23.5kg isopropanol, 2.3kg 3-(4-nitro-1-oxy-1,3-dihydroisoindole-2-yl)-piperidine-2,6-dione (Formula IV) and 0.14kg Pd / C (10% wet palladium carbon), stir at 70-75°C for 1.5 hours, add 1.6kg hydrazine hydrate dropwise, continue stirring for 60 minutes, and then heat to reflux for reaction. After 1 hour, HPLC detected that the raw material was less than 0.5%, and the reaction was stopped. The reaction solution was cooled to 10-25°C, the palladium carbon was filtered, the mother liquor was concentrated to basically dry, 5.0kg ethyl acetate was added to reflux and pulped for 1 hour, cooled to 15-25°C, filtered and centrifuged to obtain the product, LC-99.5%. The mother liquor was further concentrated to dryness, 23kg ethyl acetate was added to pulp, filtered and centrifuged at 0-5°C, LC-99.1%. Dry in a forced air oven at 50℃-60℃ for 6 hours, yield: 83%.

[0022] Salt-forming process: The wet product was added to 10 kg of ethanol, stirred and heated to 40-50 ° C. After the solid was completely dissolved, 1.0 kg of 36% hydrochloric acid was added dropwise to precipitate a white solid. The temperature was lowered to 0-5 ° C. After keeping warm for 1 hour, the mixture was filtered and centrifuged, and rinsed with a small amount of ethanol. The wet product was dried at 40-60 ° C for 14-18 hours to obtain 1.9 kg of light brown solid. The yield was 80.5%. The HPLC purity was 99.87%. Impurity A was 0.02%, impurity B was 0.02%, impurity C was 0.03%, and impurity D was not detected.

[0023] Example 3: Preparation of Lenalidomide In a 20L glass reactor, 6kg of isopropanol and 1kg of lenalidomide hydrochloride were added, and 0.4kg of triethylamine was added at a uniform rate at room temperature. After stirring for 30 minutes, the reaction solution was filtered, and the filtered solid was rinsed twice with a small amount of isopropanol and dried in a vacuum oven at 40℃-50℃ for 5 hours to obtain 0.62kg of pure lenalidomide with a yield of 93% and a HPLC purity of 99.92%.

Claims

1. A process for preparing pure, substantially impurity-free lenalidomide, characterized in that: The following steps are involved: 1.1 In a reaction system in which the reaction solvent is N-methylpyrrolidone or acetonitrile and the acid-binding agent is triethylamine or DIPEA, 2-bromomethyl-3-nitrobenzoate (Formula II) is reacted with α-aminoglutarimide hydrochloride (Formula III) to obtain 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione (Formula IV). 2.1.2 Use dichloromethane or acetonitrile as solvent, NBS as bromination reagent, add benzoyl peroxide and 2-methyl-3-nitrobenzoate (Formula V) to prepare 2-bromomethyl-3-nitrobenzoate (Formula II). 3.1.3 In the presence of hydrazine hydrate and ferric chloride, the nitro group of (3S)-3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of formula IV is reduced to obtain lenalidomide of formula I.

4. The process according to claim 1, characterized in that The acid-binding agent in step 1.1 is preferably DIPEA, the reaction solvent is preferably N,N-dimethylacetamide, and the reaction temperature is 10°C-60°C, preferably 20°C-35°C.

5. The process according to claim 1, characterized in that The bromination reagent in step 1.2 is NBS, the solvent is preferably acetonitrile, and the reaction temperature is 10°C-90°C, preferably 60°C-70°C.

6. The process according to claim 1, characterized in that The nitro reducing agent in step 1.3 is a hydrazine hydrate-ferric chloride system, the solvent is preferably methanol, and the reaction temperature is 10°C-90°C, preferably 20°C-30°C.

7. The process according to any one of claims 1 to 4, characterized in that The reaction in step 1.1 is carried out in N-methylpyrrolidone, the acid-binding agent is triethylamine, and the reaction temperature is 20°C-35°C.

8. The process according to any one of claims 1 to 4, characterized in that The nitro reduction reaction in step 1.3 is carried out in methanol solvent at a temperature controlled at 20°C-30°C.

9. The process according to any one of claims 1 to 4, characterized in that The product obtained in step 1.3 is dissolved in ethanol, and hydrochloric acid is added to form a salt to obtain lenalidomide hydrochloride.

10. The process according to claim 7, characterized in that The salt-forming step is carried out at 40° C.-50° C., and the generated lenalidomide hydrochloride is kept at 0-5° C., rinsed with ethanol and dried.

11. An industrial production method of a lenalidomide compound, characterized in that: The process according to any one of claims 1 to 9 is used.

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