A process for the preparation of a lucotinib intermediate

Abstract

The application provides a preparation method of a luspaterin intermediate. Specifically, by selecting a solvent and optimizing a reaction condition, the chiral purity and yield of the intermediate are improved, the number of refining times is reduced, the method is more green and environment-friendly, and is more suitable for industrialization.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and in particular, the present application relates to a lucedastine intermediate and a preparation method of lucedastine. BACKGROUND

[0002] Lucedastine, the chemical name of which is "(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile", has the following chemical structure:

[0003]

[0004] The structure contains a chiral center, and it is difficult to construct the chiral center. How to obtain a product with high chiral purity is an important work in the process research of lucedastine. At present, there are mainly the following ways to introduce the chiral center of lucedastine:

[0005] According to patent CN201080012029, a high-chiral-purity intermediate can be obtained by chiral preparation liquid phase, and a high-chiral lucedastine product can be further obtained, and the production process is as follows:

[0006]

[0007] This method needs to use a special preparation HPLC device, and the required device is expensive, which is not conducive to production scale-up.

[0008] Patent CN201080012029 reports a method for selectively obtaining an intermediate with a certain chiral purity by using asymmetric synthesis, and further preparing lucedastine, and the production process is as follows:

[0009]

[0010] This method needs to use a chiral catalyst, and the preparation of the catalyst is difficult, which is not conducive to industrial production.

[0011] In patent CN201080012029, a chiral reagent is used for chiral resolution of the related intermediate, but the resolution effect is not ideal, and the chiral purity of the obtained intermediate (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl neopentanoate (2S,3S)-dibenzoyl tartarate is about 74%-87%, which needs to be refined multiple times, and the production cost is too high, which is not conducive to industrialization. SUMMARY

[0012] The present application provides a preparation method of a lucedastine intermediate of formula I, comprising the following steps:

[0013]

[0014] (2S, 3S)-dibenzoyl tartaric acid salt of the compound of formula I, which is prepared by reacting the compound of formula II with (2S, 3S)-dibenzoyl tartaric acid in an organic solvent,

[0015] wherein the organic solvent is a mixture of 2-butanone and one or more polar aprotic organic solvents.

[0016] wherein the polar aprotic organic solvent is one or more of acetonitrile, tetrahydrofuran, acetone, dimethylformamide or dimethylsulfoxide, and wherein acetonitrile or tetrahydrofuran is preferred.

[0017] Further, the organic solvent is a mixture of 2-butanone and two polar aprotic organic solvents.

[0018] Further, the organic solvent is a mixture of 2-butanone, acetonitrile and tetrahydrofuran.

[0019] Further, the volume ratio of the organic solvent 2-butanone, acetonitrile and tetrahydrofuran is 1:10 to 20:1.

[0020] Further, the volume ratio of the organic solvent 2-butanone, acetonitrile and tetrahydrofuran is 1:15:1.

[0021] Further, the process for preparing the intermediate of the compound of formula I, Lucitanib, comprises the following steps:

[0022]

[0023] The compound of formula II is added to a mixture of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warmed, stirred, (2S, 3S)-dibenzoyl tartaric acid is added, again warmed and stirred, cooled, seeded and crystallized to obtain the target compound.

[0024] Further, the temperature for the cooling and crystallization is 20 to 55°C, preferably 20 to 30°C, and more preferably 25 to 30°C.

[0025] Further, in some embodiments of the present application, the compound of formula II is added to a mixture of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warmed, stirred, (2S, 3S)-dibenzoyl tartaric acid is added, again warmed and stirred, cooled, seeded and crystallized to obtain the target compound.

[0026] Further, the seed crystal is (R)-(4-(l-(2-cyano-l-cyclopentylethyl)-lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (2S,3S)-dibenzoyltartrate with a chiral purity of 99%.

[0027] Further, in some embodiments of the present application, the compound of formula II is added to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warmed to 50°C, stirred, (2S,3S)-dibenzoyltartrate acid is added, then warmed to 80°C and stirred, cooled to 40-50°C, seed crystal is added, cooled to 20-30°C, crystallized, washed, dried, and recrystallized to obtain the compound of formula I.

[0028] Further, the mass molar ratio of the compound of formula II to (2S,3S)-dibenzoyltartrate acid is 1:0.5-0.7, preferably 1:0.55.

[0029] Further, in some embodiments of the present application, the compound of formula II is added to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warmed to 50°C, stirred, (2S,3S)-dibenzoyltartrate acid is added, then warmed to 80°C and stirred, cooled to 40-50°C, seed crystal is added, cooled to 20-30°C, crystallized, washed, dried, and recrystallized to obtain the compound of formula I.

[0030] Further, in some embodiments of the present application, the compound of formula II is added to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warmed to 50°C, stirred, (2S,3S)-dibenzoyltartrate acid is added, then warmed to 80°C and stirred, cooled to 40-50°C, seed crystal is added, cooled to 20-30°C, crystallized, washed, dried, and recrystallized to obtain the compound of formula I.

[0031] The crude product is added to a mixture of organic solvents, warmed, stirred, cooled, and crystallized to obtain the target product.

[0032] The organic solvent is a mixture of 2-butanone and one or more polar aprotic organic solvents.

[0033] The polar aprotic organic solvent is one or more of acetonitrile, tetrahydrofuran, acetone, dimethylformamide or dimethyl sulfoxide, with acetonitrile or tetrahydrofuran being preferred.

[0034] Further, the organic solvent is a mixture of 2-butanone and two polar aprotic organic solvents.

[0035] Further, the organic solvent is a mixture of 2-butanone, acetonitrile and tetrahydrofuran.

[0036] Furthermore, the volume ratio of the organic solvent 2-butanone, acetonitrile, and tetrahydrofuran is 1:10 to 20:1, preferably 1:15:1.

[0037] Furthermore, in some embodiments of this application, compound II is added to a mixed solvent composed of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, heated to 50°C, stirred, (2S,3S)-dibenzoyl tartaric acid is added, heated to 80°C and stirred, cooled to 40-50°C, seed crystals are added, cooled to 25-30°C, crystals are precipitated, washed and dried to obtain crude product of compound I;

[0038] The crude product was added to a mixture of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, heated to 80°C, stirred, cooled to 25-30°C, and crystallized to obtain the target compound.

[0039] The above preparation method can yield a compound of formula I with high optical purity, which can be used in the synthesis of ruxolitinib, reducing purification steps, making it more environmentally friendly, and suitable for industrial production. Attached Figure Description

[0040] Figure 1 Chiral HPLC chromatogram of Example 4. Specific Implementation

[0041] The specific embodiments of the concentration analysis method of the present invention will be further described in detail below with reference to examples. These embodiments are only for illustrating the present invention and are not intended to limit the present invention.

[0042] The HPLC method for determining chiral purity is as follows:

[0043] Chromatographic column: CHIRALCEL OD-H (250 mm × 4.6 mm × 5 μm);

[0044] Mobile phase: n-hexane-isopropanol-n-butanol (85:10:5);

[0045] Column temperature 30℃;

[0046] Flow rate 1.0 ml / min;

[0047] Isocratic elution;

[0048] Detection wavelength: 225nm.

[0049] Example 1

[0050] Methyl neopentanoate (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)neopentate was obtained by chiral preparative HPLC separation.

[0051] HPLC conditions for chiral preparation: Instrument: Thar 350 preparative SFC (SFC-6), preparative column: Chiral Pak AD, 300×50mm ID, 10μm, mobile phase: phase A is supercritical CO2, phase B is isopropanol containing 0.1% ammonia, volume ratio of mobile phase A to mobile phase B is 6:4, flow rate: 200mL / min, back pressure: 100bar, column temperature: 38℃, detection wavelength: 220nm.

[0052] 10g of methyl (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)neopentate was taken and separated under the above HPLC conditions to obtain 4.8g of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)neopentate product.

[0053] Example 2

[0054] Preparation of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl neopentanoate (2S,3S)-dibenzoyl tartrate (I)

[0055]

[0056] 2 g of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)neopentate methyl ester and 1.7 g of (2S,3S)-dibenzoyl tartaric acid from Example 1 were added to 20 mL of acetonitrile. The mixture was heated to 80 °C and stirred for 30 minutes. The temperature was then lowered to 20–30 °C, resulting in the precipitation of a large amount of white solid. The solid was filtered and dried to constant weight to obtain 2.5 g of white solid, which was the target compound. Yield: 67.8%. Chiral purity: 99.0%.

[0057] 1HNMR (DMSO, 500M): 13.89 (s, 2H), 8.84 (s, 1H), 8.79 (s, 1H), 8.40 (s, 2H), 8.02 (d, J=5.0Hz, 4H), 7.73-7.75 (m, 3H), 7.60-7.63 (m, 4H), 7.11-7.12 (m, 1H), 6.25 (s, 2H), 5.88 (s, 2H), 3.21-3.27 (m, 3H), 2.42-2.44 (m, 1H), 1.81-1.84 (m, 1H), 1.52-1.62(m, 3H), 1.44-1.46(m, 1H), 1.29-1.33(m, 2H), 1.18-1.22(m, 1H), 1.09(m, 8H);

[0058] 13 CNMR (DMSO, 125M): 117.50, 167.62, 165.13, 152.09, 151.96, 151.09, 139.81, 134.60, 131.76, 130.40, 129.88, 129.53, 128.96, 120.47, 118.60, 113.68, 101.54, 71.93, 67.00, 63.05, 44.77, 38.76, 29.55, 29.52, 27.03, 25.42, 24.80, 22.97.

[0059] Example 3

[0060] 5 g of methyl neopentanoate (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)neopentate was added to 35 mL of a mixed solution of acetonitrile / 2-butanone / tetrahydrofuran (volume ratio: 15 / 1 / 1), heated to 50 °C, and stirred for 10 minutes; 2.6 g of (2S,3S)-dibenzoyl tartaric acid was added, heated to 80 °C, and stirred for 10 minutes until the reaction solution became clear; the temperature was lowered to 50 °C, and 0.05 g of the chiral seed crystals with a purity of 99% obtained in Example 1 was added; the temperature was lowered to 30 °C and kept warm overnight, then filtered. The filter cake was washed with 5 mL of acetonitrile and dried under vacuum at 40 °C to constant weight to obtain 2.8 g of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H- Pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanoate-(2S,3S)-dibenzoyl tartrate. Chiral purity 92%. Yield 60%.

[0061] Example 4

[0062] 2.8 g of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanoate-(2S,3S)-dibenzoyl tartrate with a chiral purity of 92% was added to 18 ml of a mixed solution of acetonitrile / 2-butanone / tetrahydrofuran (volume ratio: 15 / 1 / 1). The solution was heated to 80 °C and stirred for 30 minutes. After dissolving completely, the solution was allowed to cool naturally to 25 °C to crystallize. 2.1 g of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanoate-(2S,3S)-dibenzoyl tartrate, a white solid, was obtained. Chiral HPLC analysis showed a chiral purity of 99.75% (refer to the instruction manual). Figure 1 The yield was 74%.

[0063] Example 5 considers the effects of different solvents and different solvent ratios on chiral purity and final product yield.

[0064] Referring to the preparation method in Example 3, the acetonitrile / 2-butanone / tetrahydrofuran solvent combination was replaced accordingly, while other parameters remained unchanged. The purity and yield of the product are shown in the table below:

[0065] Table 1. Effects of different solvents on product purity

[0066]

[0067] As can be seen from the data in the table above, the chiral purity of the product is not very high when acetonitrile is combined with other solvents. Only when combined with 2-butanone and tetrahydrofuran can the chiral purity be higher than 80%.

[0068] Example 6 examines the effect of different crystallization temperatures.

[0069] Following the preparation method of Example 3, only the crystallization temperature was adjusted, and the results are detailed in the table below:

[0070] Table 2 Effect of different temperatures on yield and purity

[0071]

[0072] The data in the table above shows that the crystallization temperature does not have a significant impact on the purity of the product, and can ensure a chiral purity of over 90%. However, it has a significant impact on the product yield. When the crystallization temperature is between 20-30℃, the product yield is high.

Claims

1. A method for preparing a compound of formula I, comprising the steps of: reacting a compound of formula II with (2S, 3S)-dibenzoyl tartaric acid in an organic solvent to form a (2S, 3S)-dibenzoyl tartaric acid salt of the compound of formula I, wherein the organic solvent is a mixture of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:

1.

2. A process for the preparation of a compound of formula I according to claim 1, characterized in that, comprising the steps of: adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming and stirring, cooling and crystallization to form the target compound.

3. A process for the preparation of a compound of formula I according to claim 2, characterized in that, wherein the temperature for cooling and crystallization is 20-55°C.

4. A process for the preparation of a compound of formula I according to claim 2, characterized in that, wherein the temperature for cooling and crystallization is 20-30°C.

5. A process for the preparation of a compound of formula I according to claim 2, characterized in that, wherein the temperature for cooling and crystallization is 25-30°C.

6. A process for the preparation of a compound of formula I according to any one of claims 1 to 5, characterized in that, adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming and stirring, cooling, adding a seed crystal and crystallization to form the target compound.

7. A process for the preparation of a compound of formula I according to any one of claims 1 to 5, characterized in that adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming to 50°C, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming to 80°C and stirring, cooling to 40-50°C, adding a seed crystal, cooling to 25-30°C and crystallization to form the target compound.

8. A process for the preparation of a compound of formula I according to any one of claims 1 to 5, characterized in that, adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming to 50°C, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming to 80°C and stirring, cooling to 40-50°C, adding a seed crystal, cooling to 25-30°C and crystallization to form the target compound.

9. A process for the preparation of a compound of formula I according to any one of claims 1 to 5, characterized in that, adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming to 50°C, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming to 80°C and stirring, cooling to 40-50°C, adding a seed crystal, cooling to 25-30°C and crystallization to form the target compound. adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming to 50°C, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming to 80°C and stirring, cooling to 40-50°C, adding a seed crystal, cooling to 25-30°C and crystallization to form the target compound. adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming to 50°C, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming to 80°C and stirring, cooling to 40-50°C, adding a seed crystal, cooling to 25-30°C and crystallization to form the target compound. adding the compound of formula II to a mixed solvent of 2-butanone, acetonitrile and tetrahydrofuran in a volume ratio of 1:15:1, warming to 50°C, stirring, adding (2S, 3S)-dibenzoyl tartaric acid, further warming to 80°C and stirring, cooling to 40-50°C, adding a seed crystal, cooling to 25-30°C and crystallization to form the target compound.

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