Preparation method of polycyclic compound crystal form I containing nitrogen heterocycle

Abstract

The present invention discloses a method for preparing Form I of a polycyclic compound containing a nitrogen heterocycle. Specifically, a method for preparing Form I of a compound of Formula (I) is disclosed. The preparation method comprises the following steps: 1) mixing the compound of Formula (I) with a good solvent; 2) dropwise adding a poor solvent; and 3) lowering the system temperature to crystallize to obtain Form I of the compound of Formula (I). This method can produce high-purity Form I of the compound of Formula (I), has a high yield, is easy to operate and control, and is suitable for large-scale production. #imgabs0#.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a method for preparing a crystalline form of a polycyclic compound containing a nitrogen heterocycle. Background Art

[0002] Orexin is a neuropeptide naturally produced by the hypothalamus and primarily active in the central nervous system. It plays a wide range of roles in regulating food intake, energy metabolism, sleep-wake cycles, and blood pressure. Orexin receptors are neuropeptides synthesized and secreted by orexin neurons in the lateral hypothalamus (LH). They are named for their strong orexigenic effects. Orexins are divided into orexin A (Orexin A) and orexin B (Orexin B). Orexin A and Orexin B both act on the G protein-coupled receptors orexin receptor OX1R and orexin receptor OX2R. OX1R and OX2R are widely expressed throughout the central nervous system. OX1R binds more strongly to orexin A than to orexin B, while OX2R binds equally well to both orexin A and B. Orexin has a complex relationship with other neuropeptides that influence feeding. It plays a wide range of roles, including increasing food intake and drinking, regulating sleep-wake cycles, reproduction, body temperature, blood pressure, and sensation. For example, it regulates wakefulness and arousal by modulating two different G protein-coupled receptors, OX1R and OX2R. Orexin receptor antagonists have potential therapeutic advantages in the treatment of neurological diseases, including insomnia, depression, anxiety, and drug addiction.

[0003] With increasing stress, the incidence of insomnia is increasing year by year. Benzodiazepine receptor agonists (BZDs) are currently commonly used, but they are addictive and prone to withdrawal symptoms. Non-benzodiazepines (non-BZDs), such as zolpidem and zopiclone, while less prone to adverse reactions than traditional BZDs, can cause temporary insomnia upon discontinuation. Orexin receptor blockers, however, have become a new target for the treatment of insomnia due to their non-addictive nature and minimal second-day residual effects.

[0004] Currently, there are several OX1 / 2R target drugs in the clinical stage or on the market, such as Merck's Suvoraxant and Eisai's Lemborexant. However, as orexin 1 / 2 antagonists, they have antagonistic effects on both OX1R and OX2R receptors. Acting on OX1R will change rapid eye movement sleep (NEM, brain activity is the same as when awake) and non-rapid eye movement sleep (NEREM, deep sleep), that is, sacrificing NREM time and prolonging REM time, thereby increasing the risk of sleepiness. In addition, OX1R cannot have an antidepressant effect.

[0005] OX2R antagonists can have antidepressant effects, and single-receptor OX2R antagonists can also be sufficiently effective for insomnia. Therefore, selective OX2R antagonists can avoid the various side effects such as drowsiness caused by the effects on OX1R. Currently, the only OX2R antagonist in clinical trials is Seltorexant, developed by Janssen, with primary indications for major depressive disorder (MDD) and primary and secondary insomnia.

[0006] Selective OX2R antagonists have the potential to treat neurological disorders such as insomnia, depression, and anxiety, and have a huge clinical demand. As drugs, selective OX2R antagonists have promising application prospects in the pharmaceutical industry.

[0007] This product exists in two crystalline forms: Form I and Form II. Conventional methods for preparing Form I are prone to producing Form II, which can affect product quality and increase the risk of pharmaceutical use. This application aims to provide a method for preparing Form I with high yield and high purity. Summary of the Invention

[0008] The compound of formula (I) exists in polymorphic forms, including Form I and Form II.

[0009] Form I has a characteristic XRD pattern with characteristic peaks including: 8.5±0.2 o , 9.1±0.2 o , 10.2±0.2 o , 10.7±0.2 o , 12.0±0.2 o , 12.7±0.2 o , 13.6±0.2 o , 14.1±0.2 o , 14.5±0.2 o , 15.4±0.2 o , 16.5±0.2 o , 17.2±0.2 o , 18.3±0.2 o , 19.0±0.2 o , 19.4±0.2 o , 20.4±0.2 o , 21.2±0.2 o , 21.9±0.2 o , 23.1±0.2 o , 24.2±0.2 o , 25.1±0.2 o , 26.3±0.2 o , 27.6±0.2 o , 28.4±0.2 o , 29.0±0.2o , 29.3±0.2 o , 31.3±0.2 o , 32.0±0.2 o .

[0010] Form II has a characteristic XRD pattern, with characteristic peaks including: 9.0±0.2 o , 9.9±0.2 o , 10.9±0.2 o , 13.3±0.2 o , 14.7±0.2 o , 15.0±0.2 o , 16.0±0.2 o , 16.4±0.2 o , 17.2±0.2 o , 17.9±0.2 o , 19.4±0.2 o , 19.8±0.2 o , 20.3±0.2 o , 20.5±0.2 o , 21.1±0.2 o , 22.0±0.2 o , 23.0±0.2 o , 24.1±0.2 o , 25.0±0.2 o , 25.8±0.2 o , 26.5±0.2 o , 27.0±0.2 o , 27.6±0.2 o , 33.9±0.2 o .

[0011] Methods for determining the crystalline purity of raw materials include X-ray diffraction (XRD), differential scanning calorimetry (DSC), Raman, infrared, solid-state nuclear magnetic resonance, etc. This application adopts the XRD method.

[0012] In the XRD pattern of the sample of the crystal form I of the compound of formula (I), when the 2θ value has the following data: 9.9±0.2 o , 15.0±0.2 o , 15.9±0.2 o , 17.9±0.2 o If one or more of the above is found, it means that the sample is mixed with Form II sample.

[0013] The above XRD pattern data of Form I show that the preparation method of Form I of the present invention can obtain pure Form I.

[0014] The present invention provides a method for preparing the crystalline form I of the compound of formula (I), comprising the following steps:

[0015] 1) mixing the compound of formula (I) and a good solvent;

[0016] 2) Add poor solvent;

[0017] 3) lowering the system temperature and crystallizing to obtain Form I of the compound of formula (I);

[0018]

[0019] Wherein, the good solvent is ethanol or isopropanol; the poor solvent is an ether solvent or an alkane solvent, wherein the ether solvent is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, anisole, ethylene glycol methyl ether or ethylene glycol ethyl ether; the alkane solvent is selected from n-pentane, n-hexane, cyclohexane or n-heptane.

[0020] In certain embodiments of the present invention, in step 1), the temperature is 60-85 o C, preferably 60~80 o C, more preferably 70-80°C, further preferably 75-80°C.

[0021] In certain embodiments of the present invention, in step 1), the good solvent is isopropyl alcohol.

[0022] In certain embodiments of the present invention, in step 2), the ether solvent is selected from diethyl ether, isopropyl ether or methyl tert-butyl ether; and the alkane solvent is cyclohexane or n-heptane.

[0023] In certain embodiments of the present invention, in step 2), the ether solvent is isopropyl ether or methyl tert-butyl ether;

[0024] The alkane solvent is n-heptane.

[0025] In certain embodiments of the present invention, in step 1), the mass volume ratio of the compound of formula (I) to the good solvent is 1:2 to 1:30, preferably 1:3 to 1:20, more preferably 1:3 to 1:10, further preferably 1:4 to 1:8, further 1:4 to 1:6, and even more preferably 1:4 to 1:5.

[0026] In certain embodiments of the present invention, in step 2), the mass volume ratio of the compound of formula (I) to the poor solvent is 1:5-1:40, preferably 1:10-1:30, more preferably 1:10-1:20, and even more preferably 1:10-1:15.

[0027] In certain embodiments of the present invention, step 1) further comprises stirring. Preferably, the stirring time is 0.5 hour to 2 hours, more preferably 0.5 hour to 1 hour.

[0028] In certain embodiments of the present invention, in step 2), the poor solvent is added dropwise for 5 minutes to 6 hours; preferably, the poor solvent is added dropwise for 30 minutes to 3 hours; more preferably, the poor solvent is added dropwise for 1 hour to 3 hours; further preferably, the stirring time after the poor solvent is added dropwise is 2 to 3 hours.

[0029] In certain embodiments of the present invention, in step 3), the cooling rate is 2 to 150 ℃ / hour, preferably 5~40℃ / hour, more preferably 5~10℃ / hour;

[0030] In certain embodiments of the present invention, in step 3), the system temperature is slowly lowered to 10-30°C, preferably 10-20°C.

[0031] In certain embodiments of the present invention, in step 3), the crystallization step further includes filtering, washing and drying processes to obtain the crystal form I of the compound of formula (I).

[0032] In a further preferred embodiment of the present invention, the solvent used for washing is preferably an ether solvent or an alkane solvent; the ether solvent is preferably one or both of isopropyl ether and methyl tert-butyl ether; the alkane solvent is preferably one or both of n-hexane and n-heptane.

[0033] In a further preferred embodiment of the present invention, the drying method is preferably air drying or vacuum drying. The drying temperature is preferably 50-70 ℃, and the drying time is preferably 6 to 20 hours.

[0034] The crystal form I obtained by the preparation method of the present invention has high purity, high yield, low cost, stable quality, mature process, easy operation and control, and is suitable for process-based large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The XRPD diagram of the free base form I of the compound of formula (I) is shown in FIG.

[0036] Figure 2 The XRPD diagram of the free base form II of the compound of formula (I) is shown in FIG.

[0037] Figure 3 This is an XRPD diagram of the free base crystal form and the mixed crystal form I and II of the compound of formula (I). DETAILED DESCRIPTION

[0038] The following embodiments of the present invention are described in further detail with reference to the accompanying drawings and examples. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0039] The base in the following examples is the compound of formula (I), and its preparation method can refer to patent WO2022223025.

[0040]

[0041] Example 1: 5.0 g of the compound of formula (I) was placed in a reaction flask, 20 ml of ethanol was added, the internal temperature was raised to 75°C, and stirring was carried out for 30 minutes. The temperature was then cooled at 20°C / hour to 55°C. 60 ml of n-heptane was added dropwise over 6 hours, then cooled to 20°C at 10°C / hour, and stirring was continued for 10 hours. The mixture was filtered and rinsed with 20 ml of n-heptane twice. The resulting filter cake was placed in a drying oven and air-dried at 60°C for 8 hours. The resulting product was 4.41 g, with a mass yield of 88.2% and a purity of 99.4%.

[0042] Example 2: 5.0 g of the compound of formula (I) was placed in a reaction flask, 25 ml of isopropyl alcohol was added, the internal temperature was raised to 80°C, and stirred for 30 minutes. The temperature was lowered to 55°C, and 75 ml of isopropyl ether was added dropwise over 3 hours. ℃ / hour to room temperature, stir for 12 hours. Filter, rinse with 30 ml of isopropyl ether twice, and place the resulting filter cake in a vacuum drying oven at 60 The product was dried under vacuum at ℃ for 10 hours, yielding 4.65 g with a mass yield of 93% and a purity of 99.8%.

[0043] Example 3: 2.0 g of the compound of formula (I) was placed in a reaction flask, 10 ml of isopropanol was added, and the internal temperature was raised to 80 ℃, stir for 30 minutes. Rapidly cool to 50 ℃, add 20 ml of methyl tert-butyl ether dropwise over 1 hour, and reduce the temperature to 20℃ at 10℃ / hour. The mixture was stirred at 400 °C for 10 hours. Filtered, rinsed with 10 ml of methyl tert-butyl ether twice, and the filter cake was placed in a drying oven and dried with forced air at 60 °C for 6 hours. The product yield was 1.73 g, with a mass yield of 86.5% and a purity of 99.6%.

[0044] Example 4: 5.0 g of the compound of formula (I) was placed in a reaction flask, 30 ml of isopropanol was added, and the internal temperature was raised to 70 ℃, stir for 30 minutes. Cool to 57℃, keep warm for 2 hours, add 75 ml of n-heptane dropwise for 2 hours, 30 The mixture was cooled to room temperature at 40 °C / hour and stirred for 12 hours. Filtered and rinsed with 20 ml of n-heptane twice. The filter cake was dried in a vacuum oven at 60 °C for 10 hours to obtain 4.63 g of product, with a mass yield of 92.6% and a purity of 99.2%.

[0045] Example 5: 3.0 g of the compound of formula (I) was placed in a reaction flask, 15 ml of ethanol was added, the internal temperature was raised to 70°C, and stirred for 30 minutes. The temperature was lowered to 50°C, kept warm for 0.5 hours, and 45 ml of isopropyl ether was added dropwise over 2 hours. ℃ / hour to room temperature, stirred for 9 hours. Filter, rinse with 10 ml of isopropyl ether twice, and place the resulting filter cake in a vacuum drying oven at 60 The product was dried under vacuum at ℃ for 12 hours, yielding 2.68 g with a mass yield of 89.3% and a purity of 99.3%.

[0046] Example 6: 4.0 g of the compound of formula (I) was placed in a reaction flask, 32 ml of isopropanol was added, and the internal temperature was raised to 75 ℃, stir for 30 minutes. Rapidly cool to 60 ℃, add 40 ml of n-heptane dropwise over 3 hours, and reduce the temperature to 20℃ at 10℃ / hour. The mixture was stirred at 400 °C for 10 hours. Filtered, rinsed with 20 ml of n-heptane twice, and the filter cake was placed in a drying oven and dried with forced air at 60 °C for 6 hours. The product yield was 3.28 g, with a mass yield of 82% and a purity of 99.7%.

[0047] Example 7: 5.0 g of the compound of formula (I) was placed in a reaction flask, 30 ml of ethanol was added, the internal temperature was raised to 75°C, and stirring was carried out for 30 minutes. The temperature was rapidly cooled to 55°C, 100 ml of methyl tert-butyl ether was added dropwise over 2.5 hours, and the temperature was lowered to 20°C at 10°C / hour. Stirring was continued for 8 hours. The mixture was filtered and rinsed with 20 ml of methyl tert-butyl ether twice. The resulting filter cake was placed in a drying oven and air-dried at 60°C for 8 hours. The product yield was 4.53 g, with a mass yield of 90.6% and a purity of 99.4%.

[0048] Example 8: 3.0 g of the compound of formula (I) was placed in a reaction flask, 60 ml of isopropanol was added, and the internal temperature was raised to 60 ℃, stir for 30 minutes. o C / hour to 60℃, add 90 ml of cyclohexane dropwise over 3 hours, 10 ℃ / hour down to 20 The mixture was stirred at 400 °C for 10 hours, filtered, rinsed with 20 ml of cyclohexane twice, and the filter cake was placed in a drying oven and dried with forced air at 60 °C for 14 hours. The product yield was 2.61 g, with a mass yield of 87% and a purity of 99.6%.

[0049] Example 9: 3.0 g of the compound of formula (I) was placed in a reaction flask, 30 ml of isopropanol was added, and the internal temperature was raised to 70 ℃, stir for 30 minutes. ℃ / hour cooling to 50 o ℃, add 60 ml of n-heptane dropwise over 2 hours, and reduce the temperature to 20℃ at 10℃ / hour. ℃, stirred for 13 hours. Filter, rinse with 20 ml of n-heptane × 2, put the filter cake into the drying oven, 60 The product was dried at ℃ for 12 hours, yielding 2.73 g with a mass yield of 91% and a purity of 99.7%.

[0050] Example 10: 4.0 g of the compound of formula (I) was placed in a reaction flask, 20 ml of isopropanol was added, and the internal temperature was raised to 80 ℃, stir for 30 minutes. ℃ / hour cooling to 60 ℃, add 60 ml of n-heptane dropwise over 1 hour, continue stirring for 2 hours, 120 ℃ / hour down to 20 ℃, filter, rinse with 20 ml of n-heptane × 2, put the filter cake into a drying oven, and The product was dried at ℃ for 10 hours, yielding 3.61 g with a mass yield of 90.25% and a purity of 99.6%.

[0051] Example 11: 8.0 g of the compound of formula (I) was placed in a reaction flask, 40 ml of ethanol was added, and the internal temperature was raised to 70 ℃, stir for 30 minutes. Cool down to 60 ℃, continue stirring for 0.5 hour, add 120 ml of isopropyl ether dropwise over 3 hours, continue stirring for 2 hours, reduce the temperature to 20℃ at 20℃ / hour, continue stirring for 3 hours, filter, rinse with 30 ml of isopropyl ether×2, put the filter cake into a drying oven, and dry it in vacuum at 60℃ for 12 hours, the yield is 7.44 g, the mass yield is 93%, and the purity is 99.5%.

[0052] Example 12: 10.0 g of the compound of formula (I) was placed in a reaction flask, 50 ml of ethanol was added, and the internal temperature was raised to 75 ℃, stir for 30 minutes. Cool to 55℃ in 1 hour, add 150 ml of n-heptane dropwise in 2 hours, continue stirring for 3 hours after the addition, and continue stirring for 5 minutes. The temperature was lowered to 20°C / hour, stirring was continued for 6 hours, and the mixture was filtered and rinsed with 50 ml of n-heptane × 2. The filter cake was placed in a drying oven and dried with forced air at 60°C for 15 hours to obtain 9.45 g of the product with a mass yield of 94.5% and a purity of 99.4%.

[0053] Example 13: 100.0 g of the compound of formula (I) was placed in a reaction flask, 500 ml of isopropanol was added, and the internal temperature was raised to 80 ℃, stir for 30 minutes. Cool down to 60 in 1 hour. ℃, add 1500 ml of n-heptane dropwise over 2.5 hours, continue stirring for 2 hours, 10 The temperature was lowered to 20°C / hour, stirring was continued for 9 hours, and the mixture was filtered and rinsed with 100 ml of n-heptane × 2. The filter cake was placed in a drying oven and dried with forced air at 60°C for 8 hours, yielding 96.41 g of the product with a mass yield of 96.41% and a purity of 99.3%.

[0054] The XRPD patterns of the crystals prepared in Examples 1-13 are basically the same as those in Figure 1 The results are consistent, indicating that the crystal form prepared in this application is crystal form I and does not contain mixed crystals.

[0055] During the crystal form research, it was found that mixed crystals of crystal form II were easily produced during the preparation of crystal form I. Figure 2 is the XRPD pattern of Form II, Figure 3 It is a mixed XRPD pattern of Form I and Form II. From the pattern, it can be seen that the crystal form prepared by the method of the present application is Form I and does not contain mixed crystals.

[0056] Test Example 1: 15.3 g of the compound of formula (I) was dissolved in 20 ml of methanol, 30 ml of water was added dropwise, and the mixture was stirred for 20 min. The solid precipitated, and 6 ml of water was added dropwise, stirred for 16 h, filtered, 4 mL of methanol + 12 mL of water was mixed, the filter cake was washed, and dried at 40 ° C to obtain 7.7 g of a light brown solid; then added to 23 mL of methanol, heated to an external temperature of 65 ° C, dissolved, cooled to 20 ° C and stirred for 0.5 h, a solid precipitated, 23 mL of water was added dropwise, and stirred for 4 h; filtered, 10 mL of methanol + 30 mL of water was mixed, the filter cake was washed, and dried at 40 ° C to obtain 7.3 g of a light brown solid; added to 22 mL (3V) EA, heated to reflux and stirred for 1 h, 22 mL (3V) of n-heptane was added dropwise, and stirring was continued for 0.5 h, cooled to 20-24 ° C and stirred for 16 h, filtered, 4 mL of EA + 8 ml of n-heptane was mixed, the filter cake was washed, and dried at 40 ° C to obtain 6.5 g, with a mass yield of 42.5% and a purity of 78%.

Claims

1. A method for preparing the crystalline form I of the compound of formula (I), characterized in that: The following steps are involved: 1) mixing the compound of formula (I) and a good solvent; 2) adding a poor solvent dropwise; 3) lowering the system temperature and crystallizing to obtain Form I of the compound of formula (I); in, The good solvent is isopropyl alcohol; The poor solvent is n-heptane; In step 1), the mass volume ratio of the compound of formula (I) to the good solvent is 1:5 to 1:10, and the reaction temperature is 70 to 80°C; In step 2), the mass volume ratio of the compound of formula (I) to the poor solvent is 1:10 to 1:20.

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