Vennetola impurity as well as preparation method and application thereof
A synthesis method for high-purity compound I addresses the challenge of impurity control in Venetoclax production by employing specific base ratios and chromatography, enhancing Venetoclax purity through effective quality control.
Patent Information
- Application Number
- CN202410026953.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-01-08
- Publication Date
- 2025-07-15
AI Technical Summary
The prior art is difficult to effectively obtain the impurity compound I produced during the synthesis of Venettola with high purity, which affects the purity of Venettola. The lack of corresponding references makes it difficult to conduct qualitative and quantitative detection.
A method for preparing impurity compound I is provided, by reacting compound II with triethylamine, N,N-diisopropylethylamine or sodium hydroxide in a specific solvent and temperature, and then purifying by column chromatography to obtain high purity compound I as a reference for the impurity of Venetora intermediate.
The high-purity impurity compound I was achieved efficiently, and used as a reference for impurity control of Venetora to ensure the quality of the drug.
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Figure CN120309565A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a venetoclax impurity, a preparation method thereof and an application thereof. Background Art
[0002] Venetoclax ( ) was jointly developed by AbbVie and Roche, and was granted breakthrough therapy by the FDA in 2015 and approved for marketing by the FDA in 2016 for the treatment of patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is the only Bcl-2 selective inhibitor approved for marketing globally at present, which can play a targeted role, selectively bind to and inhibit the B-cell lymphoma factor-2 protein, and contribute to the restoration of apoptosis of tumor cells.
[0003] On December 2, 2020, venetoclax tablets were approved for marketing in China, and its indication is to be combined with azacitidine for the treatment of newly diagnosed adult patients with acute myeloid leukemia (AML) who are not suitable for receiving intensive induction chemotherapy due to comorbidities or are 75 years of age or older.
[0004] Currently, the synthetic route of the original research of venetoclax is as follows:
[0005]
[0006] In the process of synthesizing the compound venetoclax, compound II will react with the reaction solvent dimethyl sulfoxide to generate impurity compound I, and impurity compound I will remain in compound III, thereby affecting the purity of venetoclax. It is necessary to monitor and detect impurity compound I during the synthesis process of venetoclax to control the quality of venetoclax. As one of the main impurities generated during the synthesis of venetoclax, impurity compound I is difficult to enrich and separate during the synthesis process of venetoclax, and there is no synthesis report of this impurity compound I in the prior art. It is difficult for people to obtain a large amount of impurity compound I with high purity, lack of corresponding reference substances, and it is difficult to qualitatively and quantitatively detect this impurity during the synthesis of venetoclax.
[0007] Therefore, we synthesize impurity I and develop a preparation method for effectively obtaining impurity compound I with high purity, which can be used as an impurity reference substance for impurity localization and impurity control in compound III, and further control the quality of venetoclax raw materials. Summary of the Invention
[0008] Object of the Invention: The object of the present invention is to provide a preparation method and an application of a venetoclax impurity, namely a compound of formula I.
[0009] To achieve the above object, the technical solution provided by the present invention is as follows:
[0010] The compound of the present invention having the structure shown in Formula I:
[0011]
[0012] The preparation method of the compound of the present invention having the structure shown in Formula I has the following reaction route:
[0013]
[0014] Among them, in the step of preparing Compound I, the molar ratio of Compound II to base ranges from 1:2 to 3; the base is triethylamine, N,N-diisopropylethylamine or sodium hydroxide; this preparation method includes the following steps: adding Compound II, base, and organic solvent, carrying out a heat preservation reaction, and then performing post-treatment and purification to obtain Compound I; the reaction temperature range is 90 - 100 °C; the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide; the heat preservation reaction time is 16 - 24 h; the steps of post-treatment and purification are as follows: adding water and ethyl acetate to the reaction solution, stirring at room temperature, standing, separating layers, and concentrating the organic phase; subjecting the organic phase to column chromatography to obtain Compound I; the eluent for column chromatography is gradient elution with petroleum ether and ethyl acetate, and the ratio of petroleum ether to ethyl acetate is 5:1 to 2:1 to remove small-polarity impurities first; then changing to gradient elution with ethyl acetate and methanol, and the ratio of ethyl acetate to methanol is 30:1 to 20:1 to obtain Compound I; Compound I is used as a reference substance for detecting related substances of the venetoclax intermediate and for controlling the purity of the venetoclax bulk drug.
[0015] Beneficial effects:
[0016] The present invention provides venetoclax impurities and a preparation method thereof. Using Compound II as a raw material, Compound I is obtained in one step. This method has cheap and easily available raw materials, simple operation, mild reaction conditions, and can effectively obtain Compound I with high purity. Compound I will remain in the venetoclax intermediate Compound III, thereby affecting the purity of venetoclax. Compound I can be used as an impurity reference substance for the entire process research of venetoclax. Description of the Drawings
[0017] Figure 1 It is the detection spectrogram of the content of Compound I in Compound III in Example 1. Detailed Embodiments
[0018] The following combines specific embodiments to further clarify the present invention. These embodiments are implemented on the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.
[0019] Example 1
[0020] Synthesis of Compound I
[0021]
[0022] Add 20 g (0.063 mol, 1.0 eq) of Compound II, N,N-dimethylformamide (100 mL), and 24.3 g (0.19 mol, 3.0 eq) of N,N-diisopropylethylamine to a 250 mL four-necked flask. Start stirring and heat up to 90 - 100 °C for heat preservation reaction for 16 h. Cool to room temperature, add ethyl acetate (100 mL) and water (100 mL), stir for 5 min, separate the aqueous phase, and concentrate the organic phase to dryness under reduced pressure at 50 °C to obtain the crude product of Compound I. Perform sand column chromatography separation (column chromatography conditions: packed column with 20 w / w silica gel (200 - 300 mesh)), and use a petroleum ether∶ethyl acetate ratio of 5∶1 as the eluent to remove small-polarity impurities. Adjust the eluent and ratio to ethyl acetate∶methanol of 30∶1 for column chromatography to obtain 19.6 g of Compound I, with a yield of 90% and a purity of 98.67%.
[0023] 1 HNMR(CDCl3,400MHz): δδ7.98(s,1H), 7.32 - 7.24(m,2H), 7.00 - 6.92(m,2H), 3.50(m,2H), 3.36 - 3.28(m,2H), 2.82(m,2H), 2.22(m,6H), 2.02(m,2H), 1.47(m,2H), 0.99(m,6H).m / z[M]+: 347.28.
[0024] The detection results of the content of impurity Compound I in Compound III are shown in Table 1 and Figure 1 as follows:
[0025]
[0026] Example 2
[0027] Synthesis of Compound I:
[0028]
[0029] Add 20 g (0.063 mol, 1.0 eq) of Compound II, dimethyl sulfoxide (100 mL), and 19.2 g (0.19 mol, 3.0 eq) of triethylamine to a 250 mL four-necked flask. Start stirring and heat to 90 - 100 °C for heat preservation reaction for 20 h. Cool to room temperature, add ethyl acetate (100 mL) and water (100 mL), stir for 5 min, separate the aqueous phase, and concentrate the organic phase to dryness under reduced pressure at 50 °C to obtain the crude product of Compound I. Perform sand column chromatography separation (column chromatography conditions: packed with 20 w / w silica gel (200 - 300 mesh)), and use a petroleum ether:ethyl acetate ratio of 2:1 as the eluent to remove small-polarity impurities. Adjust the eluent and ratio to ethyl acetate:methanol of 20:1 for column chromatography to obtain 20.5 g of Compound I, with a yield of 94% and a purity of 98.59%.
[0030] 1 HNMR (CDCl3, 400 MHz): δ 7.98 (s, 1H), 7.32 - 7.24 (m, 2H), 7.00 - 6.92 (m, 2H), 3.50 (m, 2H), 3.36 - 3.28 (m, 2H), 2.82 (m, 2H), 2.22 (m, 6H), 2.02 (m, 2H), 1.47 (m, 2H), 0.99 (m, 6H). m / z [M]+: 347.28.
[0031] Example 3
[0032] Synthesis of Compound I:
[0033]
[0034] Add 20 g (0.063 mol, 1.0 eq) of Compound II, N,N-dimethylformamide (100 mL), and 5.2 g (0.13 mol, 2.0 eq) of sodium hydroxide to a 250 mL four-necked flask. Start stirring and heat to 90 - 100 °C for heat preservation reaction for 24 h. Cool to room temperature, add ethyl acetate (100 mL) and water (100 mL), stir for 5 min, separate the aqueous phase, and concentrate the organic phase to dryness under reduced pressure at 50 °C to obtain the crude product of Compound I. Perform sand column chromatography separation (column chromatography conditions: packed with 20 w / w silica gel (200 - 300 mesh)), and use a petroleum ether:ethyl acetate ratio of 3:1 as the eluent to remove small-polarity impurities. Adjust the eluent and ratio to ethyl acetate:methanol of 25:1 for column chromatography to obtain Compound I, and obtain 20 g of Compound I, with a yield of 92% and a purity of 98.62%.
[0035] 1HNMR(CDCl3, 400 MHz): δ 7.98 (s, 1H), 7.32 - 7.24 (m, 2H), 7.00 - 6.92 (m, 2H), 3.50 (m, 2H), 3.36 - 3.28 (m, 2H), 2.82 (m, 2H), 2.22 (m, 6H), 2.02 (m, 2H), 1.47 (m, 2H), 0.99 (m, 6H). m / z [M]+: 347.28.
[0036] The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.
Claims
1. Compounds of structural formula (I):
2. A method for preparing compound I according to claim 1, characterized in that: Wherein: the molar ratio of compound II to base ranges from 1:2 to 3.
3. The preparation method of Compound I according to claim 2, characterized in that: In the step of preparing compound I, the base used is triethylamine, N,N-diisopropylethylamine or sodium hydroxide.
4. The preparation method of compound I according to claim 2, characterized in that, It includes the following steps: Adding compound II, base, and organic solvent, carrying out a heat-preserving reaction, and performing post-treatment and purification to obtain compound I.
5. The preparation method of Compound I according to claim 4, wherein: In the step of preparing compound I, the temperature range of the heat-preserving reaction is 90-100°C.
6. The preparation method of compound I according to claim 4, characterized in that: In the step of preparing compound I, the organic solvent used is N,N-dimethylformamide or dimethyl sulfoxide.
7. The preparation method of compound I according to claim 4, characterized in that, In the step of preparing compound I, the time of the heat-preserving reaction is 16-24 h.
8. The preparation method of Compound I according to claim 4, characterized in that, The step of post-treatment and purification is to add water and ethyl acetate to the reaction solution, stir at room temperature, stand still, separate the layers, and concentrate the organic phase; the organic phase is subjected to column chromatography to obtain compound I.
9. The preparation method of Compound I according to Claim 8, characterized in that, The eluent for the column chromatography is gradient elution with petroleum ether and ethyl acetate, and the ratio of petroleum ether to ethyl acetate is 5:1 to 2:1 to remove small-polarity impurities first; then gradient elution is carried out with ethyl acetate and methanol, and the ratio of ethyl acetate to methanol is 30:1 to 20:1 to obtain compound I.
10. Use of the compound I according to claim 1, characterized in that, For use as a reference substance for the detection of related substances of venetoclax intermediates and for the purity control of venetoclax bulk drug.