A crystal form of remegipam intermediate hydrochloride and preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a crystal form of a remigipam intermediate hydrochloride and a preparation method thereof. The remigipam intermediate hydrochloride crystal form A of the present invention has the advantages of high purity, low moisture absorption, high chemical stability, etc., and can remain stable and non-degradable during the long-term storage of the product. The preparation method of the crystal form A has the advantages of simple process, short time consumption, and suitability for process production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical technology, and particularly relates to a crystal form of a remegipam intermediate hydrochloride and a preparation method thereof. Background Art

[0002] Migraine is a widely-affected neurological disease. In recent years, according to epidemiological statistics of migraine, the incidence of migraine in the world is 8.4% to 28%, with a higher incidence in women than in men, and has become the third most prevalent disease in the world. There are 36 million patients in the United States alone; the incidence of migraine in Japan is 8.4% to 12%, and the rate of consultation is 36% to 38%. Remigipam is a calcitonin-related gene peptide (CGRP) receptor antagonist with good market prospects.

[0003] Patent WO2012050764A1 reports the synthesis route of Remigipam, and the synthesis route is as follows:

[0004]

[0005] The method involves the preparation of a remegipam intermediate hydrochloride (I). According to the description of the patent specification, the method uses (6S,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridine-5-one as a raw material, first prepares the free base of the intermediate (I), which is an oily substance; the oily free base is dissolved in isopropanol, and hydrochloric acid is added to form a salt to prepare the remegipam intermediate hydrochloride (I). The applicant has found through research that the remegipam intermediate hydrochloride (I) prepared by the method is an amorphous substance, which has high hygroscopicity and poor chemical stability. Because the intermediate hydrochloride (I) is prone to cyclization and other side reactions after hygroscopic deliquescence, which degrades the intermediate hydrochloride (I), further resulting in its poor chemical stability. In addition, after the amorphous material is deliquesced, it is not easy to provide convenience for feeding in the next reaction, and the material is easy to stick in the bag, which has an adverse effect on the convenience of production.

[0006] In addition, the hydrochloride salt of the intermediate Remigipam (I) has many chiral sites, and many isomers are produced during its preparation process, especially diastereoisomers such as (5R,6S,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridine-5-amine. In the preparation method reported in the current patent, there are many impurities in the product, resulting in more impurities in the Remigipam obtained in the subsequent synthesis of Remigipam, which increases the difficulty of purification in the subsequent steps. Summary of the invention

[0007] The technical problem to be solved by the present invention is that the intermediate hydrochloride (I) of remegipam in the prior art is easy to absorb moisture, has poor chemical stability, low purity and is not conducive to production and feeding.

[0008] In order to solve the above technical problems, the present invention provides a crystalline form A of a remegipam intermediate hydrochloride (I):

[0009]

[0010] The remegipam intermediate hydrochloride (I) is a hydrate; its X-ray powder diffraction spectrum has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, and 19.9±0.2°.

[0011] Furthermore, the remegipam intermediate hydrochloride (I) is a dihydrate.

[0012] Furthermore, its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, 18.0±0.2°, 19.9±0.2°, and 22.2±0.2°.

[0013] The crystal form A of the intermediate hydrochloride (I) of Remigipam of the present invention has the data shown in Table 1 in terms of X-ray powder diffraction expressed in 2θ:

[0014] Table 1

[0015]

[0016] The crystal form A of the intermediate hydrochloride (I) of Remigipam of the present invention has an X-ray powder diffraction pattern as shown in Figure 1 shown.

[0017] The crystalline form A of the intermediate hydrochloride (I) of Remigipam of the present invention has a DSC endothermic peak at 140±10°C, such as Figure 2 The TG graph shows that it loses 6.3-6.8% of its weight at 20-110°C. Figure 3 As shown; TG spectrum analysis shows that Form A starts to lose weight at around 29°C, and loses about 6.7% at 100°C.

[0018] The crystalline form A of the intermediate hydrochloride of Remigipam (I) of the present invention has an infrared spectrum at 2946±2cm -1 、2868±2cm -1 、1625±2cm -1 、1489±2cm -1 、1390±2cm -1 、1270±2cm -1、1134±2cm -1 、883±2cm -1 、789±2cm -1 、690±2cm -1 There is an absorption peak at; the infrared spectrum is as Figure 4 shown.

[0019] Another aspect of the present invention provides a method for preparing the crystalline form A of the intermediate hydrochloride (I) of Remigipam:

[0020]

[0021] The intermediate free base (II) of Remegipam is mixed with ethanol and isopropyl acetate, and a hydrochloric acid ethanol solution is added to form a salt, and the mixture is filtered and the filter cake is dried to obtain the crystal form A of the intermediate hydrochloride (I) of Remegipam;

[0022] The remegipam intermediate hydrochloride (I) is a hydrate; its X-ray powder diffraction spectrum has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, and 19.9±0.2°.

[0023] Furthermore, the remegipam intermediate hydrochloride (I) is a dihydrate.

[0024] Furthermore, its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, 18.0±0.2°, 19.9±0.2°, and 22.2±0.2°; its X-ray powder diffraction pattern is substantially as follows: Figure 1 shown.

[0025] The crystalline form A of the intermediate hydrochloride of Remigipam (I) has a DSC endothermic peak at 140±10°C, such as Figure 2 The TG graph shows that it loses 6.3-6.8% of its weight at 20-110°C. Figure 3 TG spectrum analysis shows that Form A starts to lose weight at about 29°C and loses about 6.7% at 100°C.

[0026] The crystalline form A of the intermediate hydrochloride of Remigipam (I) has an infrared spectrum at 2946±2cm -1 、2868±2cm -1 、1625±2cm -1 、1489±2cm -1 、1390±2cm -1 、1270±2cm -1 、1134±2cm -1 、883±2cm -1 、789±2cm-1 、690±2cm -1 There is an absorption peak at; the infrared spectrum is as Figure 4 shown.

[0027] The weight ratio of the intermediate free base of Remegipam (II) to ethanol is 1:2-10; the weight ratio of ethanol to isopropyl acetate is 1:1-10; the weight ratio of the intermediate free base of Remegipam (II) to the hydrochloric acid in the hydrochloric acid ethanol solution is 1.0:0.14-0.30.

[0028] Furthermore, the weight ratio of the intermediate free base of Remigipam (II) to ethanol is 1:2-3; the weight ratio of ethanol to isopropyl acetate is 1:1-6; the weight ratio of the intermediate free base of Remigipam (II) to the hydrochloric acid in the hydrochloric acid ethanol solution is 1.0:0.14-0.22.

[0029] Furthermore, the filter cake is preferably dried under reduced pressure, with the conditions of vacuum degree ≥ 0.09 mPa and drying temperature of 0 to 20°C.

[0030] The intermediate free base (II) of Remigipam described in the present invention can be a crude product or a refined product, preferably with a purity of ≥95%. The specific preparation method thereof can refer to documents such as WO201205076A1.

[0031] Beneficial effects: The crystal form A of the intermediate hydrochloride (I) of Remegipam of the present invention has the advantages of high purity, low moisture absorption, high chemical stability, etc., and can remain stable and not degraded during the long-term storage of the product. The preparation method of the crystal form A of the intermediate hydrochloride (I) of Remegipam of the present invention has the advantages of simple process, short time consumption, and suitability for process production, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 , X-ray powder diffraction pattern of Form A of Remigipam intermediate hydrochloride (I).

[0033] Figure 2 , DSC graph of Form A of Remigipam intermediate hydrochloride (I).

[0034] Figure 3 , TG graph of Form A of Remigipam intermediate hydrochloride (I).

[0035] Figure 4 , infrared spectrum of the crystalline form A of the intermediate hydrochloride of Remigipam (I).

[0036] Figure 5 , liquid chromatogram of Form A of Remigipam intermediate hydrochloride (I).

[0037] Figure 6, X-ray powder diffraction pattern of the amorphous form of the intermediate hydrochloride of Remigipam (I).

[0038] Figure 7 , liquid chromatogram of the amorphous form of the intermediate hydrochloride of Remigipam (I). DETAILED DESCRIPTION

[0039] Example 1. Preparation of Remegipam Intermediate Free Base (II)

[0040]

[0041] Preparation of Remigipam Intermediate Free Base (II) Reference Patent WO2012050764A1 Example 1 disclosed method: (6S,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (III, 5.00 g, 11.22 mmol), 1,4-dioxane (50 mL) and titanium tetra(isopropoxide) (8.33 mL, 28.11 mmol) were added to a 100 mL Hastelloy autoclave. The reactor was purged three times with nitrogen and then three times with ammonia. After the purge cycle was completed, the reactor was pressurized to 100 psi with ammonia. The reaction mixture was heated to 50°C and stirred at a certain rate to ensure adequate mixing. The reaction mixture was reacted with ammonia at 100 psi and 50°C for 20 h. The mixture was then cooled to 20°C, and then 5% Pd / alumina (1.0 g, 20 wt%) was loaded into the autoclave reactor. The reactor was purged three times with nitrogen and three times with hydrogen. After the purge cycle was completed, the reactor was pressurized to 100 psi with hydrogen, and the mixture was heated to 50°C and stirred at a certain rate to ensure adequate mixing. The reaction mixture was heated at 100 psi H2 and 50°C for 23 h. The mixture was then cooled to 20°C, filtered, and then transferred to a 100 mL three-necked flask. Water (0.55 mL) was added dropwise to the mixture, stirred for 30 min, and then filtered. The filter cake was washed with 1,4-dioxane (30 mL), and the filtrate was combined and concentrated to obtain the free base of the intermediate of Remigipam (II) as an oil.

[0042] Example 2: Preparation of Remegipam Intermediate Hydrochloride (I) Amorphous

[0043] The preparation of the amorphous intermediate hydrochloride (I) of Remegipam refers to the method disclosed in Example 1 of patent WO2012050764A1: 5 g of the intermediate free base (II) of Remegipam was dissolved in isopropanol, 9 mL of hydrogen chloride (5N) isopropanol solution was added under stirring, and then 60 mL of isopropyl acetate was added, and the mixture was heated to 45°C and maintained for 10 min, and then cooled to 22°C after 3 h, filtered, and the filter cake was dried to obtain 3 g of the amorphous intermediate hydrochloride (I) of Remegipam, with a yield of 51.5% and a purity of 98.88%.

[0044] Example 3. Preparation of Remegipam Intermediate Hydrochloride (I) Crystalline Form A

[0045] Batch 1: Add 146.2 g of free base (II) of the intermediate of Remigipam, 438.6 g of ethanol, and 2631 g of isopropyl acetate to a four-necked flask, replace with nitrogen three times, stir to dissolve, control the temperature to -10±10°C, add hydrochloric acid ethanol solution (30.7 g in terms of hydrogen chloride), and after the addition, keep warm and stir at -5°C to -10°C for 1 hour to precipitate a large amount of white solid. Centrifuge, rinse with isopropyl acetate; add 731 g of isopropyl acetate and 731 g of n-heptane to the filter cake for pulping and purification, filter, and dry the filter cake under reduced pressure (vacuum degree: 0.095 mPa, drying temperature: 20-25°C) to obtain 123 g of the intermediate of Remigipam hydrochloride (I), with a yield of 67.63% and a purity of 99.59%. X-ray powder diffraction of the sample shows diffraction peaks at 5.0°, 10.0°, 13.8°, 18.0°, 19.9°, and 22.2°.

[0046] Batch 2: Add 146.2 g of free base (II) of the intermediate of Remigipam, 438.6 g of ethanol, and 2631 g of isopropyl acetate to a four-necked bottle, replace with nitrogen three times, stir to dissolve, control the temperature to -10±10°C, add hydrochloric acid ethanol solution (32 g in terms of hydrogen chloride), add dropwise, keep warm and stir at -5°C to -10°C for 1 hour, and a large amount of white solid precipitates. Filter by suction, and dry the filter cake under reduced pressure (vacuum degree: 0.090 mPa, drying temperature: 40-45°C) to obtain 125 g of the intermediate of Remigipam hydrochloride (I), with a yield of 68.73% and a purity of 99.69%. The sample X-ray powder diffraction shows diffraction peaks at 5.0°, 10.0°, 13.7°, 18.0°, 19.9°, and 22.2°.

[0047] Batch 3: Add 150 g of Remigipam intermediate free base (II), 300 g of ethanol, and 300 g of isopropyl acetate to a four-necked flask, stir to dissolve, add hydrochloric acid ethanol solution (21 g in terms of hydrogen chloride), and a large amount of white solid precipitates. Filter and dry the filter cake under reduced pressure (vacuum degree: 0.095 mPa, drying temperature: 20-25°C) to obtain 112 g of Remigipam intermediate hydrochloride (I), with a yield of 60.02% and a purity of 99.57%. X-ray powder diffraction of the sample showed diffraction peaks at 5.1°, 10.0°, 13.8°, 18.1°, 19.9°, and 22.2°.

[0048] Batch 4: Add 150 g of Remigipam intermediate free base (II), 1500 g of ethanol, and 5000 g of isopropyl acetate to a four-necked flask, stir to dissolve, add hydrochloric acid ethanol solution (45 g in terms of hydrogen chloride), and a large amount of white solid precipitates. Filter and dry the filter cake under reduced pressure (vacuum degree: 0.095 mPa, drying temperature: 45-50°C) to obtain 86 g of Remigipam intermediate hydrochloride (I), with a yield of 46.09% and a purity of 99.77%. The sample X-ray powder diffraction showed diffraction peaks at 4.9°, 9.9°, 13.6°, 17.9°, 19.8°, and 22.1°.

[0049] Batch 5: Add 150 g of Remegipam intermediate free base (II), 300 g of ethanol, and 3000 g of isopropyl acetate to a four-necked bottle, stir to dissolve, add hydrochloric acid ethanol solution (22 g in terms of hydrogen chloride), and a large amount of white solid precipitates. Filter the wet cake by suction, and boil and dry to obtain 95 g of Remegipam intermediate hydrochloride (I), with a yield of 50.91% and a purity of 99.71%. The sample X-ray powder diffraction shows diffraction peaks at 5.0°, 9.9°, 13.6°, 18.0°, 19.9°, and 22.2°.

[0050] Example 4: Preparation of other salt forms of Remigipam intermediates

[0051] Phosphate: Add 3.03 g of the intermediate free base (II) of Remegipam and 30 mL of anhydrous ethanol to the reaction flask. After heating to dissolve, add 220.3 mg of phosphoric acid. Cool to room temperature and stir for 17-18 h. Cool to room temperature and stir for 2-3 h. Filter by suction, and dry the filter cake under reduced pressure at 35-45°C for 2-4 h to obtain 2.2 g of the intermediate phosphate of Remegipam.

[0052] Tartaric acid salt: Add 3.05 g of the intermediate free base (II) of Remegipam and 30 mL of ethyl acetate to the reaction flask. After heating to dissolve, add 343.3 mg of L-tartaric acid. Cool to room temperature and stir for 2 to 3 h. Filter by suction, and dry the filter cake under reduced pressure at 35 to 45 °C for 15 to 18 h to obtain 2.5 g of the intermediate tartrate of Remegipam.

[0053] Oxalate: Add 3.22 g of the intermediate free base (II) of Remegipam and 30 mL of ethyl acetate to the reaction flask. After heating to dissolve, add 334.1 mg of oxalic acid. Cool to room temperature and stir for 17 to 18 h. Add 3 mL of n-heptane, cool to -5 to -10 °C and stir for 10 h. Filter by suction, and dry the filter cake under reduced pressure at 35 to 45 °C for 10 to 14 h to obtain 2.6 g of the intermediate oxalate of Remegipam.

[0054] Maleate: Add 3.10 g of the intermediate free base (II) of Remigipam and 30 mL of acetone to the reaction flask. After heating to dissolve, add 265.7 mg of maleic acid. Cool to room temperature and stir for 17-18 h. Add 3 mL of n-heptane and seed crystals, cool to 4±5°C and stir for 4-5 h. Filter by suction, and dry the filter cake under reduced pressure at 35-45°C for 2-4 h to obtain 2.3 g of the intermediate maleate of Remigipam.

[0055] Sulfate: Add 3.10 g of the intermediate free base (II) of Remigipam and 30 mL of acetone to the reaction flask. After heating to dissolve, add 245.6 mg of sulfuric acid. Cool to room temperature and stir for 17 to 18 hours. Add 3 mL of n-heptane and seed crystals, cool to 4±5°C and stir for 4 to 5 hours. Filter by suction, and dry the filter cake under reduced pressure at 35 to 45°C for 2 to 4 hours to obtain 2.3 g of the intermediate sulfate of Remigipam.

[0056] Example 5: Crystal stability experiment

[0057] The stability of batches 1 to 5 of the Remigipam intermediate hydrochloride crystal form A prepared in Example 3 was studied, sealed and placed at room temperature for 6 months, and the crystal form was detected by X-ray powder diffraction. The measurement conditions were: X-ray powder diffractometer D8ADVANCE, current intensity 10 mA, voltage 30 kV, step size 0.012°, Cu target, and the measurement error of the diffraction angle 2θ was ±0.2°. The test data are shown in Table 2.

[0058] Table 2

[0059]

[0060] Experimental conclusion: The Remigipam intermediate hydrochloride crystal form A prepared by the present invention has good stability. After being sealed and placed at room temperature for 6 months, the crystal form does not change.

[0061] Example 6: Comparative experiment on hygroscopicity and stability

[0062] The purity and water stability of batches 1 to 5 of the Remigipam intermediate hydrochloride crystal form A prepared in Example 3 and each salt form prepared in Example 4 were tested. Water content determination method: Karl Fischer method, solvent DMSO, aldehyde and ketone special titration solution. Purity detection was performed by high performance liquid chromatography, and the chromatographic conditions were as follows:

[0063] Chromatographic column: Agilent Infinity Lab Poroshell 120 EC-C18 4.6×100mm 4um or equivalent

[0064] Flow rate: 1.0 mL / min

[0065] Wavelength: 260 nm

[0066] Column temperature: 35°C

[0067] Injection volume: 10 µL

[0068] Mobile phase A is acetonitrile: methanol = 7:3 (V / V) (precisely measure 700 mL acetonitrile and 300 mL methanol, mix well, and ultrasonicate for later use)

[0069] Mobile phase B is 30 mMol / L ammonium acetate (precisely weigh 2.31 g of ammonium acetate and place it in a beaker filled with 1000 mL ultrapure water, dissolve it by ultrasonication, and set aside)

[0070] Elution method: Gradient elution according to the following ratio

[0071]

[0072] The moisture test results are shown in Table 3, and the purity test results are shown in Table 4.

[0073] Table 3

[0074]

[0075] Table 4

[0076]

[0077] Experimental conclusion: The Remigipam intermediate hydrochloride crystal form A prepared in the present invention is non-hygroscopic and has excellent stability compared with the hydrochloride amorphous substance and other salt forms.

[0078] Example 7. Comparative experiment on the preparation of Remigipam

[0079] Using batches 1 to 5 of the Remigipam intermediate hydrochloride crystal form A prepared in Example 3 of the present invention and each salt form prepared in Example 4 as raw materials, Remigipam was prepared according to the method disclosed in Examples 2 and 3 of the specification of patent WO2012050764A1. The purity test results of each batch of the obtained Remigipam products are shown in Table 5.

[0080] Table 5

[0081]

[0082] Experimental conclusion: Compared with the amorphous hydrochloride and other salt forms, the Remigipam intermediate hydrochloride form A of the present invention has higher purity and lower impurities as a raw material for preparing the final product Remigipam, and has obvious advantages.

Claims

1. A crystalline form A of a remegipam intermediate hydrochloride (I), characterized in that: The remegipam intermediate hydrochloride (I) is a dihydrate; its X-ray powder diffraction spectrum has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, and 19.9±0.2°.

2. The crystalline form A of the intermediate hydrochloride of Remigipam (I) according to claim 1, characterized in that: Its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, 18.0±0.2°, 19.9±0.2°, and 22.2±0.2°.

3. The crystalline form A of the intermediate hydrochloride of Remigipam (I) according to claim 2, characterized in that: Its X-ray powder diffraction pattern is shown in Figure 1.

4. The crystalline form A of the Remigipam intermediate hydrochloride (I) according to any one of claims 1 to 3, characterized in that: Crystal form A has a DSC endothermic peak at 140±10°C; the TG graph shows that it loses 6.3-6.8% of its weight at 20-110°C.

5. The crystalline form A of the Remigipam intermediate hydrochloride (I) according to any one of claims 1 to 3, characterized in that: Infrared spectrum at 2946±2cm -1 、2868±2cm -1 、1625±2cm -1 、1489±2cm -1 、1390±2cm -1 、1270±2cm -1 、1134±2cm -1 、883±2cm -1 、789±2cm -1 、690±2cm -1 There is an absorption peak.

6. The crystalline form A of the intermediate hydrochloride of Remigipam (I) according to claim 5, characterized in that: Its infrared spectrum is shown in Figure 4.

7. A method for preparing the crystalline form A of the intermediate hydrochloride of Remigipam (I), characterized in that: The intermediate free base (II) of Remegipam is mixed with ethanol and isopropyl acetate, and a hydrochloric acid ethanol solution is added to form a salt, and the mixture is filtered and the filter cake is dried to obtain the crystal form A of the intermediate hydrochloride (I) of Remegipam; The remegipam intermediate hydrochloride (I) is a dihydrate; its X-ray powder diffraction spectrum has diffraction peaks at the following 2θ angles: 5.0±0.2°, 10.0±0.2°, 13.7±0.2°, and 19.9±0.2°.

8. The method for preparing the crystalline form A of the intermediate hydrochloride of Remigipam (I) according to claim 7, characterized in that: The weight ratio of the intermediate free base of Remegipam (II) to ethanol is 1:2-10; the weight ratio of ethanol to isopropyl acetate is 1:1-10; the weight ratio of the intermediate free base of Remegipam (II) to hydrochloric acid in the hydrochloric acid ethanol solution is 1.0:0.14-0.

30.

9. The method for preparing the crystalline form A of the intermediate hydrochloride of Remigipam (I) according to claim 8, characterized in that: The weight ratio of the intermediate free base of Remegipam (II) to ethanol is 1:2-3; the weight ratio of ethanol to isopropyl acetate is 1:1-6; the weight ratio of the intermediate free base of Remegipam (II) to the hydrochloric acid in the hydrochloric acid ethanol solution is 1.0:0.14-0.22.

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