KR102147068B1 - Novel crystal form of lenalidomide and preparation of the same - Google Patents

Abstract

(b) 상기 화학식 1의 화합물의 니트로기를 환원하고 결정화하여 하기 화학식 2의 화합물인 3-(4-아미노-1- 옥소이소인돌린-2-일)피페리딘-2,6-디온 염산염을 제조하는 단계;
[화학식 2]

(c) 상기 화학식 2의 화합물을 중화 및 정제하여, X-선 분말 회절 스펙트럼 피크가 회절각 2θ에서 11.9, 13.8, 18.3, 및 27.4 ± 0.2°의 주요 피크를 특징으로 하는 제1 결정형의 하기 화학식 3의 화합물인 3-(4-아미노-1-옥소 1,3-다이하이드로-2H-아이소인돌-2-일)피페리딘-2,6-다이온을 제조하는 단계; 및
[화학식 3]

(d) 상기 화학식 3의 화합물을 제1 유기용매 하에 용해시키고, 제2 유기용매를 혼합하여 결정화하여, X-선 분말 회절 스펙트럼 피크가 회절각 2θ에서 10.1, 12.4, 21.5, 22.9, 32.4 ± 0.2°의 주요 피크를 특징으로 하는 제2 결정형의 레날리도마이드를 제조하는 단계를 포함할 수 있다.
본 발명의 다양한 실시예에 따른 신규 결정형 레날리도마이드는, X-선 분말 회절 스펙트럼 피크가 회절각 2θ에서 10.1, 12.4, 21.5, 22.9, 및 32.4 ± 0.2 °의 주요 피크를 특징으로 한다.A method for preparing a novel crystalline lenalidomide according to various embodiments of the present invention,
(a) preparing 3-(4-nitro-1-oxoisoindolin-2-yl)piperidin-2,6-dione, which is a compound of the following formula 1;
[Formula 1]

(b) Reduction and crystallization of the nitro group of the compound of Formula 1 to prepare 3-(4-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione hydrochloride, which is a compound of Formula 2 Step to do;
[Formula 2]

(c) Neutralizing and purifying the compound of Formula 2, wherein the X-ray powder diffraction spectrum peaks are 11.9, 13.8, 18.3, and 27.4 ± 0.2° at the diffraction angle 2θ. Preparing 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione which is the compound of 3; And
[Formula 3]

(d) The compound of Formula 3 was dissolved in a first organic solvent and crystallized by mixing a second organic solvent, and the peaks of the X-ray powder diffraction spectrum were 10.1, 12.4, 21.5, 22.9, 32.4 ± 0.2 at diffraction angles 2θ. It may comprise preparing a second crystalline form of lenalidomide characterized by a major peak of °.
In the novel crystalline lenalidomide according to various embodiments of the present invention, the X-ray powder diffraction spectrum peaks are characterized by main peaks of 10.1, 12.4, 21.5, 22.9, and 32.4 ± 0.2 ° at diffraction angles 2θ.

Description

Novel crystal form of lenalidomide and its manufacturing method {NOVEL CRYSTAL FORM OF LENALIDOMIDE AND PREPARATION OF THE SAME}

Various embodiments of the present invention relate to a novel crystalline lenalidomide and a method for preparing the same.

The chemical name of lenalidomide is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and the following It is structurally represented by the formula.

Lenalidomide is used as a therapeutic agent for a wide range of diseases including multiple myeloma, autoimmune diseases and cancer.

Lenalidomide can be formulated for oral administration in a variety of forms, requiring pure and crystalline form of lenalidomide that can be formulated to meet exact pharmaceutical requirements and specifications. Accordingly, there is a demand in the art for a more stable and easy crystalline form for mass production.

However, according to the conventional method for producing lenalidomide, there is a problem that the process process is complicated, the yield of the final material is lowered, and the process efficiency is lowered. Accordingly, there is a need for an improved method suitable for producing lenalidomide with improved purity and yield and suitable for use on an industrial scale.

In various embodiments of the present invention, in order to compensate for the above problems, a novel crystalline lenalidomide (new KI crystalline lenalidomide, a new KII crystalline lenalidomide and a new KIII crystalline form of lenalidomide) can be provided. In addition, it is possible to provide a method for producing a novel crystalline lenalidomide with a simple process and improved efficiency.

A method for preparing a novel crystalline lenalidomide according to various embodiments of the present invention,

(a) preparing 3-(4-nitro-1-oxoisoindolin-2-yl)piperidin-2,6-dione, which is a compound of the following formula 1;

[Formula 1]

(b) Reduction and crystallization of the nitro group of the compound of Formula 1 to prepare 3-(4-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione hydrochloride, which is a compound of Formula 2 Step to do;

[Formula 2]

(c) Neutralizing and purifying the compound of Formula 2, wherein the X-ray powder diffraction spectrum peaks are 11.9, 13.8, 18.3, and 27.4 ± 0.2° at the diffraction angle 2θ. Preparing 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione which is the compound of 3; And

[Formula 3]

(d) The compound of Formula 3 was dissolved in a first organic solvent and crystallized by mixing a second organic solvent, and the peaks of the X-ray powder diffraction spectrum were 10.1, 12.4, 21.5, 22.9, 32.4 ± 0.2 at diffraction angles 2θ. It may comprise preparing a second crystalline form of lenalidomide characterized by a major peak of °.

In the novel crystalline lenalidomide according to various embodiments of the present invention, X-ray powder diffraction spectrum peaks are characterized by main peaks of 10.1, 12.4, 21.5, 22.9, and 32.4 ± 0.2 ° at diffraction angles 2θ.

In various embodiments of the present invention, a novel crystalline lenalidomide (new KI crystalline lenalidomide, a new KII crystalline lenalidomide, and a new KIII crystalline lenalidomide) that is stable and easy to mass-produce. ) Can be provided. In addition, it is possible to provide a method of manufacturing lenalidomide with a simple process and improved efficiency.

1 is an XRD pattern of lenalidomide in a first crystalline form according to various embodiments of the present disclosure.
2 is an XRD pattern of a second crystalline form of lenalidomide (new KI crystalline form of lenalidomide) according to various embodiments of the present disclosure.
3 is an XRD pattern of a second crystalline form of lenalidomide (new KII crystalline form of lenalidomide) according to various embodiments of the present disclosure.
4 is an XRD pattern of a second crystalline form of lenalidomide (new KIII crystalline form of lenalidomide) according to various embodiments of the present disclosure.

Justice

The term "nitrolenalidomide" as used herein refers to 3-(4-nitro-1-oxoisoindolin-2-yl)piperidin-2,6-dione, which is a compound represented by the following Formula 1 .

[Formula 1]

The term "renalidomide hydrochloride" as used herein refers to 3-(4-amino-1-oxoisoindolin-2-yl)piperidin-2,6-dione hydrochloride, which is a compound represented by the following Chemical Formula 2.

[Formula 2]

The term “renalidomide” as used herein refers to 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidin-2, which is a compound represented by the following Formula 3 ,6-dione.

[Formula 3]

Method for producing new crystalline lenalidomide

Hereinafter, various embodiments of the present specification will be described with reference to the accompanying drawings. The examples and terms used therein are not intended to limit the technology described in this document to a specific embodiment, and should be understood to include various modifications, equivalents, and/or substitutes of the corresponding embodiments.

Hereinafter, an embodiment of the present invention will be described in detail.

The present invention has the following steps:

(a) preparing nitrolenalidomide;

(b) reducing and crystallizing the nitro group of nitro lenalidomide to prepare lenalidomide hydrochloride;

(c) Lenalidomide hydrochloride is neutralized and purified, so that the X-ray powder diffraction spectrum peaks are 11.9, 13.8, 18.3, and 27.4 ± 0.2° at diffraction angles of 2θ. Preparing domide; And

(d) The first crystalline form of lenalidomide was dissolved in a first organic solvent, and a second organic solvent was mixed to crystallize, so that the X-ray powder diffraction spectrum peaks were 10.1, 12.4, 21.5, 22.9, and It provides a method for preparing a novel crystalline lenalidomide comprising the step of preparing a second crystalline form of lenalidomide characterized by a main peak of 32.4 ± 0.2°.

Preferably, in step (b), hydrochloric acid and a metal chloride can be used to reduce the nitro group of nitrolenalidomide. In this case, the metal chloride is a metal chloride having a reducing power, and may be at least one of cobalt chloride, iron chloride, nickel chloride, and tin chloride. More preferably, in step (b), hydrochloric acid and tin chloride (SnCl ₂ ) may be used to reduce the nitro group of nitro lenalidomide. In the present invention, when reducing the nitro group of nitrolenalidomide, metal chlorides such as tin chloride, which are inexpensive, are used, which is industrially and industrially useful.

According to the present invention, after reducing the nitro group of nitrolenalidomide in step (b), a filtration process and/or a complete concentration process are not additionally required, so that process time and process efficiency can be greatly improved. That is, since the nitro group of the nitro lenalidomide is reduced and crystallized immediately in step (b), the process can be simplified, and the yield of the new crystalline form of lenalidomide, which is the final product, can be improved.

Further, preferably, step (c) is:

(c-1) neutralizing and crystallizing lenalidomide hydrochloride in an organic solvent containing dimethylacetamide (hereinafter “DMAC”) to prepare a crude compound of lenalidomide; And

(c-2) dissolving the crude compound of lenalidomide in an organic solvent containing at least any one of DMAC and carboxylic acid, and purifying with an alcoholic solvent to make the lenalidomide highly purified. .

Specifically, in the step of preparing a crude compound of lenalidomide, after dissolving lenalidomide hydrochloride in an organic solvent containing DMAC, triethylamine (hereinafter “TEA”) is injected, stirred, and then filtered. I can. Thereafter, it is washed with DMAC, and acetic acid (AcOH) and isopropyl alcohol (isopropyl alcohol, hereinafter “IPA”) are injected into the filtrate, followed by stirring to crystallize. Thereafter, the product can be filtered and washed with IPA to obtain a crude compound of lenalidomide. At this time, the purity of the crude compound of lenalidomide may be 99.5% or more.

In the step of purifying lenalidomide, a crude compound of lenalidomide may be dissolved in DMAC, and then a carboxylic acid may be injected. Preferably, the carboxylic acid may be acetic acid. At this time, the volume ratio of DMAC and acetic acid may be mixed in 5 vol: 2 vol to 10 vol: 8 vol. In addition, the melting temperature may be dissolved in a temperature range of 20 ℃ to 50 ℃.

Thereafter, at least one alcohol solvent of 2-butanol (hereinafter “2-BuOH”) or isopropyl alcohol is added dropwise and stirred, and the product may be filtered. In this case, 50 vol to 100 vol of 2-BuOH may be used. In addition, purified lenalidomide may be precipitated in a temperature range of 30°C to 60°C. The filtered product can be washed with 2-BuOH to obtain purified lenalidomide. At this time, the purity of the purified lenalidomide may be 99.9% or more. Here, the purified lenalidomide is a novel first crystalline form of lenalidomide, wherein the X-ray powder diffraction spectrum peaks are characterized by main peaks of 11.9, 13.8, 18.3, and 27.4 ± 0.2° at diffraction angles 2θ. I can.

Thereafter, in step (d), lenalidomide of the first crystalline form is dissolved in a first organic solvent, and the first organic solvent may preferably be at least one of a ketone solvent and a carboxylic acid. The ketone solvent may be, for example, acetone (hereinafter, "Acetone"). The carboxylic acid may be, for example, acetic acid (hereinafter "AcOH").

In addition, in step (d), the second organic solvent is mixed and crystallized, and the second organic solvent may be preferably at least one of an alcoholic solvent and an ether solvent containing carbon atoms. More preferably, the alcohol solvent may be an alcohol having 2 to 9 carbon atoms. For example, the alcohol solvent may be 2-BuOH or heptanol. In addition, the ether solvent may be at least one of methyl tertiary butyl ether and isopropyl ether (hereinafter "IPE").

Preferably, in step (d), the first organic solvent may be AcOH and acetone, and the second organic solvent may be 2-BuOH and IPE.

Preferably, in step (d), the volume ratio of AcOH:acetone:2-BuOH:IPE may be 27:6:125:60 to 20:10:150:100.

Preferably, step (d) may be performed at 20° C. to 55° C. for 4 hours to 18 hours.

Here, the finally produced lenalidomide is a new second crystalline form of lenalidom, characterized by the main peaks of 10.1, 12.4, 21.5, 22.9, 32.4 ± 0.2° at the diffraction angle of 2θ in the X-ray powder diffraction spectrum peak. It can be Maid. For example, when the volume ratio of AcOH:acetone:2-BuOH:IPE is 27:6:125:60, the second crystalline form of lenalidomide (new KI crystalline form of lenalidomide) is X-ray powder diffraction. Spectral peaks can be characterized by major peaks of 10.1, 12.4, 21.5, 22.9, 32.4 ± 0.2° at diffraction angles 2θ. Alternatively, when the volume ratio of AcOH:acetone:2-BuOH:IPE is 27:6:125:80, the second crystalline form of lenalidomide (new KII crystalline form of lenalidomide) has an X-ray powder diffraction spectrum peak Can be characterized by major peaks of 10.1, 12.4, 17.1, 18.4, 19.6, 21.5, 22.9, 27.8 and 32.4 ± 0.2° at diffraction angles of 2θ. Alternatively, when the volume ratio of AcOH:acetone:2-BuOH:IPE is 27:6:125:100, the second crystalline form of lenalidomide (new KIII crystalline form of lenalidomide) has an X-ray powder diffraction spectrum peak Can be characterized by major peaks of 10.0, 10.4, 11.6, 12.3, 13.7, 14.8, 17.1, 18.4, 19.6, 21.5, 22.9, 27.8 and 32.4± 0.2° at diffraction angles 2θ.

In addition, the purity of the novel second crystalline form of lenalidomide may range from 99.95% to 99.97%.

The novel second crystalline form of lenalidomide according to the present invention is a pure form and a crystalline form that can be formulated to satisfy precise pharmaceutical requirements and specifications when formulated into various forms. In addition, it is stable and easy to mass-produce.

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are for illustrative purposes only, and the present invention is not limited thereto.

Example 1-Novel KI Crystal Form Manufacturing Method

(a) preparing nitrolenalidomide

Dissolve 250.0 g of methyl 2-(bromomethyl)-3-nitrobenzoate (hereinafter “MBN”) in 1000 ml of dimethylformamide (“DMF”), and 3-aminopiperidine-2,6-dione hydrochloride (hereinafter, “PDD”) 180.0 g and 315.2 g of K ₂ CO ₃ are added, followed by washing and injection with 250 ml of DMF.

After stirring for 2 hours at 25 ℃ outside, the mixture was stirred for 8 hours while maintaining 40 ℃ to 45 ℃. After stirring for an additional 12 hours at room temperature, 1250 ml of purified water was added and stirred for 2 hours.

After injecting 250 ml of acetone, it crystallizes for 2 hours. The product was filtered and then washed with 1000.0 ml of purified water to obtain 244.5 g of nitrolenalidomide. Purity 95% or more.

(b) preparing lenalidomide hydrochloride

After adding 1022.0 ml of purified water, 611.2 ml of HCl, and 978.0 g of SnCl ₂ to the reaction section, the mixture is stirred and dissolved.

2445.0 ml of ethanol (hereinafter, "EtOH") is injected, and 244.5 g of nitrolenalidomide synthesized in step (a) is added. After injecting an additional 2445.0 ml of EtOH, the reaction was performed at 35°C to 40°C for 12 hours.

After cooling to 20° C. to 25° C., 2445.0 ml of absolute ethanol was injected and stirred for 2 hours to proceed with crystallization. After cooling to 0 ℃ to 5 ℃ stirred for 3 hours to filter the product. Washed with 1222.5 ml of acetone to give 190.7 g of lenalidomide hydrochloride.

(c-1) preparing a crude compound of lenalidomide

In 190.7 g of lenalidomide hydrochloride, 1907.0 ml of DMAC is injected and stirred to dissolve. Inject 85.82 ml of triethylamine (hereinafter “TEA”), stir for 30 minutes, and filter. After washing with 190.90 ml of DMAC, 381.4 ml of acetic acid and 19070.0 ml of IPA were injected into the filtrate, followed by stirring for 12 hours to crystallize. The product was filtered, and then washed with 900.0 ml of IPA to obtain 135.4 g of crude lenalidomide. More than 99.5% Purity

(c-2) step of purifying lenalidomide

After dissolving 135.4 g of crude lenalidomide in 850.0 ml of DMAC, 677.0 ml of AcOH is injected. 10155.0 ml of 2-BuOH was added dropwise, and after stirring for 1 hour, the product was filtered. The filtered product was washed with 338.5 ml of 2-BuOH to obtain 104.2 g of purified first crystalline lenalidomide. More than 99.9% Purity

Here, the first crystalline form of lenalidomide is characterized by main peaks of 11.9, 13.8, 18.3, and 27.4 ± 0.2° at diffraction angles of 2θ in the X-ray powder diffraction spectrum, as shown in FIG. 1.

(d) preparing a second crystalline form of lenalidomide

100.0 g of the first crystalline form of lenalidomide was dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone, and 12500.0 ml of 2-BuOH and 10000.0 ml of IPE were added dropwise to the lenalidomide solution, followed by a temperature of 20° C. to 55° C. Crystallize by stirring for 8 to 16 hours in the range.

The product was filtered, washed with 200.0 ml of IPE, and dried to give 75.0 g (75% yield) of new anhydrous crystalline form of lenalidomide. Purity: 99.95 ~ 99.97%

According to Example 1, the second crystalline form of lenalidomide (new KI crystalline form of lenalidomide) has an X-ray powder diffraction spectrum peak of 10.1, 12.4, 21.5 at diffraction angles 2θ as shown in FIG. , 22.9, and 32.4 ± 0.2 °.

Example 2- Novel KII crystal form manufacturing method

In the step (d), 100.0 g of lenalidomide in the first crystalline form was dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone, and 12500.0 ml of 2-BuOH and 8000.0 ml of IPE were added dropwise to the lenalidomide solution. Except in the same method as in Example 1, a new anhydrous crystalline form of lenalidomide was obtained.

Here, in the second crystalline form of lenalidomide (new KII crystalline form of lenalidomide) according to Example 2, the X-ray powder diffraction spectrum peaks at diffraction angles 2θ of 10.1, 12.4, It is characterized by major peaks of 21.5, 22.9, and 32.4 ± 0.2 °. In more detail, in the second crystalline form of lenalidomide according to Example 2 (new KII crystalline form of lenalidomide), the X-ray powder diffraction spectrum peaks at diffraction angles of 2θ 10.1, 12.4, 17.1, 18.4, 19.6, 21.5 , 22.9, 27.8 and 32.4 ± 0.2 °.

Example 3- Novel KIII crystal form manufacturing method

In the step (d), 100.0 g of lenalidomide in the first crystalline form was dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone, and 12500.0 ml of 2-BuOH and 10000.0 ml of IPE were added dropwise to the lenalidomide solution. Except in the same method as in Example 1, a new anhydrous crystalline form of lenalidomide was obtained.

Here, in the second crystalline form of lenalidomide (new KIII crystalline form of lenalidomide) according to Example 3, the X-ray powder diffraction spectrum peaks at diffraction angles 2θ of 10.1, 12.4, It is characterized by major peaks of 21.5, 22.9, and 32.4 ± 0.2°. In more detail, the second crystalline form of lenalidomide (new KIII crystalline form of lenalidomide) according to Example 3 had an X-ray powder diffraction spectrum peak of 10.0, 10.4, 11.6, 12.3, 13.7, at diffraction angle 2θ. It is characterized by major peaks of 14.8, 17.1, 18.4, 19.6, 21.5, 22.9, 27.8 and 32.4±0.2°.

Comparative example Of step 1-(b) Lenalidomide In the manufacture of hydrochloride Tin chloride Example of nitro group reduction using Fe instead

Purified water 8.6 ml and NH ₄ Cl 1.48 g were added to the reaction unit, and nitrolenalidomide 1.0 g was added while stirring, and ethanol 49 ml was added, followed by heating to 60°C. Add 0.77 g of Fe (powder) and heat at 80 °C for 2 hours. After completion of the reaction, celite filtration was performed while maintaining at 60°C, and about 240 ml of a mixture of purified water and ethanol (1/3 ratio) was washed and injected. The resulting solution was completely concentrated, 200 ml of purified water was added, stirred for 30 minutes, 300 ml of ethanol was added, stirred at 80° C. for 2.5 hours, activated carbon was added, stirred for 1 hour, and then filtered. It crystallized by cooling to 5° C. to obtain 0.82 g of a yellow solid. (Yield 65%, purity: 94%)

According to Comparative Example 1, there is a problem in that the process time is increased and the yield is decreased because an additional filtration process is required after the reaction is completed compared to the Example. In addition, there is a problem that the process time is increased because a complete concentration process is additionally required, and impurities may be generated during complete concentration. In addition, according to Comparative Example 1, the purity is 94%, and it can be seen that the purity is significantly reduced compared to the purity of the lenalidomide 99% according to the Example.

Comparative example Of step 2--(b) Lenalidomide In the manufacture of hydrochloride Tin chloride Example of nitro group reduction using Zn instead

After adding 8.6 ml of purified water and 1.48 g of NH ₄ Cl to the reaction unit, 1 g of nitrolenalidomide was added while stirring, and 49 ml of ethanol was added, followed by heating to 60°C. 0.9 g of Zn was added and heated to reflux at 80°C. (After 4 hours, 6% of unreacted remains, by-products are generated)

According to Comparative Example 2, it can be seen that about 6% of unreacted nitrolenalidomide remained and the reaction was not terminated. In addition, it was found that about 50% of by-products were generated, so that the yield and purity would be significantly lowered compared to the examples.

Comparative example Of step 3--(b) Lenalidomide In the manufacture of hydrochloride Tin chloride Instead, an example of nitro group reduction using Zn and HCl gas

HCl gas was injected into 4000 ml of methanol in the reaction part to the level of 1.5%, 50 g of nitrolenalidomide, 50 g of zinc, and stirred for 12 hours while maintaining at 25°C, and then 100 ml of 6N HCl solution was slowly added. After the reaction was terminated, filtered, and the filtrate washed with 120 ml of methanol was completely concentrated. Then, 120 ml of purified water and 120 ml of NH ₄ OH solution were slowly added to crystallize the resulting wet body into 200 ml of DMAC, and for 1 hour. The slurry was filtered, washed with 100 ml of DMAC, and then 60 ml of acetic acid was added to the obtained solution, 1800 ml of IPA was injected, and then stirred for 2 hours to obtain 24.2 g of Kurd's lenalidomide. (Completion: 53%, purity 96.3%)

According to Comparative Example 3, since HCl gas is used, there is a problem that there is a high risk in actual industrial application. In addition, compared to the examples, a filtration process was additionally required, so that the process time was increased and the yield was decreased. In addition, there is a problem that the process time is increased because a complete concentration process is additionally required, and impurities may be generated during complete concentration.

Comparative example Of step 4--(b) Lenalidomide In the manufacture of hydrochloride Tin chloride Example of nitro group reduction using Zn instead

4000 ml of methanol was injected into the reaction part, 100 g of nitrolenalidomide was added, 600 ml of 6N HCl solution was slowly added, 150 g of Zn was added while maintaining at 25°C, and 400 ml of conc HCl solution was slowly added. After stirring for 5 hours, 75 g of Zn was added, and after 10 hours, 75 g of Zn was further added. After stirring for 24 hours, 75 g of Zn was added, followed by further stirring for 10 hours. When the reaction was completed, it was filtered and washed and injected with 400 ml of methanol. The obtained filtrate was completely dissolved, and 700 ml of NH ₄ OH solution was slowly added to adjust the pH to 7.3, cooled to 5 degrees, and the crystallized solid was filtered. The resulting solid was subjected to a slurry in 400 ml of DMAC for 1 hour, filtered, and washed and injected with 200 ml of methanol. 80 ml of AcOH was added to the obtained filtrate, 2000 ml of IPA was added, crystallized by stirring for 12 hours, filtered, and washed with 200 ml of IPA to obtain 19.7 g of lenalidomide Kurd. (21.9% of completion)

According to Comparative Example 4, Zn must be used in an excessive amount, and since the reaction proceeding time is lengthened, it is difficult to apply it to the actual industry. In addition, the yield is significantly inferior compared to the examples.

Comparative example Of the first crystalline form in step 5--(d) Lenalidomide Example of using methyl ethyl ketone (hereinafter “MEK”) instead of acetone when dissolved

100.0 g of lenalidomide prepared in Example (c) was dissolved in 2600.0 ml of AcOH and 2700.0 ml of MEK. After adding 12500.0 ml of 2-BuOH and 6000.0 ml of IPE dropwise to the lenalidomide solution, the mixture is stirred for 8 to 16 hours to crystallize. The product was filtered, washed with 200.0 ml of IPE, and dried to give 55.0 g (yield 55%) of a new anhydrous crystalline form of lenalidomide. Purity: 99.8%

According to Comparative Example 5, when using MEK, it can be seen that the purity is lowered compared to the Example due to impurity generation. In addition, it can be seen that the residual amount of AcOH remaining in the final product is 7000-10000 ppm, which is not suitable for the standard 5000 ppm or less, which makes it unsuitable for a product.

Comparative example 6--(d) of the first crystalline form Lenalidomide Example of increasing the amount of acetone used during dissolution

100.0 g of lenalidomide prepared in Example (c) was dissolved in 2700.0 ml of AcOH and 3000.0 ml of Acetone.

After adding 12500.0 ml of 2-BuOH and 6000.0 ml of IPE dropwise to the lenalidomide solution, the mixture is stirred for 8 to 16 hours to crystallize.

The product was filtered, washed with 200.0 ml of IPE, and dried to obtain 60.0 g of lenalidomide acetone solvate (yield 60%). Purity: 99.8%

According to Comparative Example 6, when the amount of acetone is increased and used, it can be seen that the crystalline form appears in the form of acetone solvate. That is, a new second crystal form according to the example was not prepared.

Comparative example 7--(d) of the second crystalline form Lenalidomide When precipitation 2- BuOH Unused example

100.0 g of lenalidomide prepared according to Example (c) was dissolved in 2700.0 ml of AcOH and 1000.0 ml of Acetone. After adding 10000.0 ml of IPE dropwise to the lenalidomide solution, it is stirred for 8 to 16 hours to crystallize.

The product was filtered, washed with 200.0 ml of IPE, and dried to obtain 60.0 g of lenalidomide acetone solvate (yield 60%). Purity: 99.8%

According to Comparative Example 7, when crystallization proceeds without 2-BuOH, it can be seen that the crystal form appears in the form of acetone solvate. That is, a new second crystal form according to the example was not prepared. In addition, it can be seen that the residual amount of AcOH exceeds 10000ppm and is not suitable as a product.

Comparative example 8--(d) of the second crystalline form Lenalidomide When precipitation 2- BuOH Example of using 3-methyl-1-butanol instead

100.0 g of lenalidomide prepared according to Example (c) is dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone. After adding 12500.0 ml of 3-methyl-1-butanol and 6000.0 ml of IPE dropwise to the lenalidomide solution, the mixture is stirred for 8 to 16 hours to crystallize.

The product was filtered, washed with 200.0 ml of IPE, and dried to give 50.0 g (yield 50%) of a new anhydrous crystalline form of lenalidomide. Purity: 99.8%

According to Comparative Example 8, it can be seen that the yield is significantly lowered compared to the Example. In addition, it can be seen that the residual amount of AcOH is 7000 ppm, which is not suitable for use as a product.

Comparative example 9--(d) of the second crystalline form Lenalidomide When precipitation 2- BuOH Instead of using ethyl acetate (“EA”)

100.0 g of lenalidomide prepared according to Example (c) is dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone. After adding 2000.0 ml of EA and 10000.0 ml of IPE dropwise to the lenalidomide solution, the mixture is stirred for 8 to 16 hours to crystallize.

The product was filtered, washed with 200.0 ml of IPE, and dried to obtain 63.5 g of lenalidomide A type (yield 63.5%). Purity: 99.8%

According to Comparative Example 9, it was confirmed that lenalidomide of the new second crystalline form according to the example was not prepared, but was transferred to form A.

Comparative example In step 10--(d), Lenalidomide When precipitation 2- BuOH Example of using MeOH instead

100.0 g of lenalidomide prepared according to Example (c) is dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone. After adding 12500.0 ml of MeOH and 6000.0 ml of IPE dropwise to the lenalidomide solution, the mixture is stirred for 8 to 16 hours to crystallize.

The product was filtered, washed with 200.0 ml of IPE, and dried to give 15.0 g (yield 15%) of lenalidomide. Purity: 99.9%

According to Comparative Example 10, the yield was significantly lower than that of the Example. Further, no novel second crystalline form of lenalidomide was produced, and crystalline form H1 was obtained.

Comparative example 11--(d) of the second crystalline form Lenalidomide When precipitation 2- BuOH Example using EtOH instead

100.0 g of lenalidomide prepared according to Example (c) is dissolved in 2700.0 ml of AcOH and 600.0 ml of Acetone. After adding EtOH 12500.0 ml and IPE 6000.0 ml dropwise to the lenalidomide solution, the mixture is stirred for 8 to 16 hours to crystallize.

The product was filtered, washed with 200.0 ml of IPE, and dried to give 15.0 g (yield 15%) of lenalidomide. Purity: 99.9%

According to Comparative Example 11, the yield was significantly lower than that of the Example. Further, no novel second crystalline form of lenalidomide was produced, and crystalline form H1 was obtained.

Table 1 below is a table comparing Examples and Comparative Examples 5 to 11. According to Table 1 below, it can be seen that the purity, yield, AcOH residual amount, and lenalidomide crystal form may be affected depending on the type of solvent and the composition of the solvent.

Solvent system yield
(%) water
(%) AcOH residual amount
(ppm) New
Whether the second crystalline form is generated Dissolved solvent
(Volume ratio) Precipitation solvent Example AcOH/ Acetone
(27:6) 2-BuOH/ IPE 75 99.95 ~ 99.97 - ○ Comparative Example 5 AcOH/ MEK 2-BuOH/ IPE 55 99.8 7000-10000 ○ Comparative Example 6 AcOH/ Acetone
(9:10) 2-BuOH/ IPE 60 99.8 - X Comparative Example 7 AcOH/ Acetone IPE 60 99.8 - X Comparative Example 8 AcOH/ Acetone 3-methyl-1-butanol/IPE 50 99.8 10000 ○ Comparative Example 9 AcOH/ Acetone EA/IPE 63.5 99.8 7000 X (transition to type A) Comparative Example 10 AcOH/ Acetone MeOH/IPE 15 99.9 - X(H1) Comparative Example 11 AcOH/ Acetone EtOH/IPE 15 99.9 - X(H1)

Features, structures, effects, and the like described in the above-described embodiments are included in at least one embodiment of the present invention, and are not necessarily limited to only one embodiment. Furthermore, the features, structures, effects, and the like illustrated in each embodiment may be combined or modified for other embodiments by a person having ordinary knowledge in the field to which the embodiments belong. Accordingly, contents related to such combinations and modifications should be interpreted as being included in the scope of the present invention.

In addition, although the embodiments have been described above, these are only examples and do not limit the present invention, and those of ordinary skill in the field to which the present invention pertains are illustrated above within the scope not departing from the essential characteristics of the present embodiment. It will be seen that various modifications and applications that are not available are possible. For example, each component specifically shown in the embodiments can be modified and implemented. And differences related to these modifications and applications should be construed as being included in the scope of the present invention defined in the appended claims.

Claims (19)

(a) preparing 3-(4-nitro-1-oxoisoindolin-2-yl)piperidin-2,6-dione, which is a compound of the following formula 1;
[Formula 1]

(b) 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6, which is a compound of the following formula 2 by reducing and crystallizing the compound of Formula 1 using hydrochloric acid and tin chloride -Preparing dione hydrochloride;
[Formula 2]

(c) neutralizing and crystallizing the compound of Formula 2 in an organic solvent containing dimethylacetamide to prepare a crude compound of Formula 3;
[Formula 3]

(d) The crude compound of Formula 3 was mixed in a volume ratio of dimethylacetamide and acetic acid in a volume ratio of 5 vol: 2 vol to 10 vol: 8 vol, dissolved at 20 to 50°C, and dissolved in 2-butanol at 30 to 60 Purified at °C, the X-ray powder diffraction spectrum peaks 11.9, 13.8, 18.3, and 27.4 ± 0.2° at a diffraction angle of 2θ. 3-(4-amino, which is a compound of Formula 3 in the first crystalline form. Preparing -1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione; And
(e) Dissolving the first crystalline compound of Formula 3 in a first organic solvent containing acetic acid and acetone, and mixing a second organic solvent containing 2-butanol and isopropyl ether, but acetic acid: acetone: 2-butanol : The volume ratio of isopropyl ether was mixed at 27:6:125:60 to 100 and crystallized at 20℃ to 55℃, and the peaks in the X-ray powder diffraction spectrum were 10.1, 12.4, 21.5, 22.9, 32.4 ± at diffraction angle 2θ. A method for producing a novel crystalline form of lenalidomide comprising the step of preparing a second crystalline form of lenalidomide, characterized in that having 0.2°. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

Images