Preparation method of escitalopram pamoate crystal form A

Abstract

The invention relates to a novel preparation method of escitalopram pamoate ((S)-(+)-1-(3-(dimethylamino) propyl)-1-(4-fluorophenyl)-1, 3-dihydro-5-cyano isobenzofuran pamoate) crystal form A. The method is environment-friendly and pollution-free, and the escitalopram pamoate crystal form A prepared by adopting the method is high in purity, high in purity, high in purity, high in purity, high in purity, high in purity and high in purity. The repeatability is good.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a preparation method of escitalopram pamoate ((S)-(+)-1-〔3-(dimethylamino)propyl〕-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzofuran pamoate) crystal form A. BACKGROUND

[0002] Escitalopram, chemical name: (S)-(+)-1-〔3-(dimethylamino)propyl〕-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzofuran. Escitalopram oxalate is jointly developed by Forest Laboratories and Lundbeck, and was first marketed in Switzerland and other European and American countries in March 2002, and was approved by FDA in August. Escitalopram is a serotonin reuptake inhibitor (SSRI) with a unique serotonin isomer site binding mechanism, and has high selectivity for serotonin receptors, and is used for the treatment of major depression and the maintenance treatment of depression.

[0003] Patients with major depression are often non-compliant, and it is difficult to evaluate whether the patient has received the accurate dose of the drug. Therefore, it is necessary to prepare escitalopram oxalate into a salt type with low solubility and sustained release effect by replacing the acid radical.

[0004] Patent document EP0347066 discloses escitalopram pamoate crystal form A and a preparation method thereof, and the solvent used is methanol, and the starting material is escitalopram free base and pamoic acid.

[0005] The solvent methanol used in the above preparation method of escitalopram pamoate has a certain toxicity. Therefore, it is a technical problem to be solved by the skilled person to prepare escitalopram pamoate by using a solvent with lower or even no toxicity. SUMMARY

[0006] The inventors of the present application have found, through continuous research, a new preparation method of escitalopram pamoate crystal form A, which uses water and ethanol as solvents, and the preparation method is environmentally friendly and has no pollution, and overcomes the solvent toxicity problem existing in the prior art. Further, the escitalopram pamoate crystal form A prepared by the method has a purity of more than 99.5%.

[0007] The specific scheme is as follows:

[0008] The application provides a preparation method of eslicarbazepine acetate pamoate (a compound of formula I) crystal form A, which comprises the following steps: dissolving eslicarbazepine acetate in a reaction solvent to obtain an eslicarbazepine acetate solution; and adding a pamoate solution dropwise into the eslicarbazepine acetate solution to precipitate eslicarbazepine acetate pamoate crystal form A.

[0009]

[0010] In some embodiments of the application, the X-ray powder diffraction pattern of the compound of formula I crystal form A has characteristic peaks at 8.9±0.2°, 11.3±0.2°, 13.2±0.2°, 18.4±0.2°, 20.6±0.2° and 21.9±0.2°.

[0011] In some embodiments of the application, the reaction solvent is water.

[0012] In some embodiments of the application, the temperature for dissolving is 0-70°C.

[0013] In some embodiments of the application, the temperature for dissolving is 25-35°C.

[0014] In some embodiments of the application, the pamoate is a disodium pamoate.

[0015] In some embodiments of the application, the solvent of the pamoate solution is a mixed solvent of water and ethanol; preferably, the mixing ratio of water and ethanol in the mixed solvent is 7:3-3:7, preferably 1.2:1-1:1.2, and more preferably 1:1.

[0016] In some embodiments of the application, the temperature of the eslicarbazepine acetate solution is 25-35°C during the process of adding the pamoate solution dropwise.

[0017] In some embodiments of the application, the temperature of the eslicarbazepine acetate solution is 30°C during the process of adding the pamoate solution dropwise.

[0018] In some embodiments of the application, the mass ratio of eslicarbazepine acetate and pamoate is 1:0.9-1:1.2. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the application and the prior art, the drawings needed in the embodiments and the prior art are briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the application, and other drawings can be obtained by those skilled in the art without any creative effort on the basis of these drawings.

[0020] Figure 1XRPD pattern of escitalopram embonate Form A prepared in Example 1.

[0021] Figure 2 HPLC pattern of escitalopram embonate Form A prepared in Example 1.

[0022] Figure 3 Related data of HPLC pattern of escitalopram embonate Form A prepared in Example 1. DETAILED DESCRIPTION

[0023] In order to make the technical problems, technical solutions and beneficial effects solved in the present application more clearly understood, the present application will be further described below in conjunction with specific examples. In the following examples, unless otherwise specified, the test method specific conditions described are generally carried out according to conventional conditions or manufacturer's recommended conditions; raw materials, reagents are obtained commercially or prepared using public information.

[0024] The X-ray powder diffraction data used in the present application is determined using BRUKER D8 Advance of Germany, using Cu-Ka radiation; voltage current: 40 kV, 40 mA; goniometer: vertical goniometer, radius 280 mm; slit: DS = 2°, SS = 1 / 2°, mask = 15 mm, RS = 5.0 mm; detector: LYNXEYE detector; scanning mode: continuous scanning; scanning range: 3-40°; counting time per step: 0.2 s; total scanning time: 390 s.

[0025] The HPLC detection conditions used in the present application are as follows:

[0026] Instrument: high performance liquid chromatograph equipped with ultraviolet detector

[0027] Chromatographic column: Waters Symmetry C18 100 x 4.6 mm, 3.5 μm

[0028] Mobile phase A 3.54 g / L aqueous disodium hydrogen phosphate solution, pH 7.0 adjusted with phosphoric acid

[0029] Mobile phase B methanol: acetonitrile = 1:1 (V / V)

[0030] Mobile phase Mobile phase A: mobile phase B = 55:45 (% V / V)

[0031] Detection wavelength: 230 nm

[0032] Flow rate: 1.2 mL / min

[0033] Injection volume: 10 μL

[0034] Column temperature: 40 °C

[0035] Run time: 25 min

[0036] Example 1: Preparation of escitalopram pamoate Form A

[0037] Escitalopram oxalate sample 35 g was weighed and added to 900 ml water, heated to 60 °C to completely dissolve; pamoic acid disodium salt 36.6 g was weighed and added to 500 ml water, completely dissolved at room temperature, then added 500 ml anhydrous ethanol, mixed well. The water / ethanol mixed solution of pamoic acid disodium salt was added dropwise to the escitalopram oxalate aqueous solution at 30 °C, solid appeared immediately, well dispersed. After 2 h of continuous stirring after the dropwise addition was completed, filtration was performed. The filter cake was washed with 500 ml water, suction filtered for 10 min, and vacuum dried. Escitalopram pamoate Form A sample 59.5 g was obtained. The XRPD spectrum thereof is shown in Figure 1 ; the HPLC spectrum thereof is shown in Figure 2 and Figure 3 ; the purity was 99.87% by HPLC detection.

[0038] Example 2: Preparation of escitalopram pamoate Form A

[0039] Escitalopram oxalate sample 500 mg was weighed and added to 25 ml water, heated to 30 °C to completely dissolve; pamoic acid disodium salt 520 mg was weighed and added to 12.5 ml water, completely dissolved at room temperature, then added 12.5 ml anhydrous ethanol, mixed well. The water / ethanol mixed solution of pamoic acid disodium salt was added dropwise to the escitalopram oxalate aqueous solution at 30 °C, solid appeared immediately, well dispersed. After 2 h of continuous stirring after the dropwise addition was completed, filtration was performed. The filter cake was washed with 50 ml water, suction filtered for 10 min, and vacuum dried. Escitalopram pamoate Form A sample 850 mg was obtained. The purity was 99.86% by HPLC detection.

[0040] Example 3: Preparation of escitalopram pamoate Form A

[0041] Escitalopram oxalate sample 5 g was weighed and added to 140 ml water, heated to 60 °C to completely dissolve; pamoic acid disodium salt 5.2 g was weighed and added to 25 ml water, completely dissolved at room temperature, then added 25 ml anhydrous ethanol, mixed well. The water / ethanol mixed solution of pamoic acid disodium salt was added dropwise to the escitalopram oxalate aqueous solution at 30 °C, solid appeared immediately, well dispersed. After 2 h of continuous stirring after the dropwise addition was completed, filtration was performed. The filter cake was washed with 50 ml water, suction filtered for 10 min, and vacuum dried. Escitalopram pamoate Form A sample 8.5 g was obtained. The purity was 99.81% by HPLC detection.

[0042] Example 4

[0043] Take 15 g of escitalopram oxalate sample, add 400 ml of water, heat to 60 °C to completely dissolved; take 14.9 g of pamoate disodium salt, add 200 ml of water, and then add 120 ml of anhydrous ethanol, mix well. Completely dissolved at room temperature. The water / ethanol mixed solution of pamoate disodium salt is added dropwise to the escitalopram oxalate aqueous solution at 30 °C, and solid appears immediately, with a small amount of agglomeration. After the addition is complete, the agglomeration is serious. Continue stirring for 2 h and then filter. The filter cake is washed with 50 ml of water, suction filtered for 10 min, and vacuum dried. 25.5.5 g of escitalopram pamoate Form A sample is obtained. The purity is 99.74% by HPLC detection.

[0044] Example 5

[0045] Take 15 g of escitalopram oxalate sample, add 400 ml of water, heat to 60 °C to completely dissolved; take 14.9 g of pamoate disodium salt, add 200 ml of water, and then add 120 ml of anhydrous ethanol, mix well. Completely dissolved at room temperature. The water / ethanol mixed solution of pamoate disodium salt is added dropwise to the escitalopram oxalate aqueous solution at 30 °C, and solid appears immediately, with a small amount of agglomeration. After the addition is complete, the agglomeration is serious. Continue stirring for 2 h and then filter. The filter cake is washed with 50 ml of water, suction filtered for 10 min, and vacuum dried. 25.5.5 g of escitalopram pamoate Form A sample is obtained. The purity is 99.74% by HPLC detection.

[0046] Example 6

[0047] Take 15 g of escitalopram oxalate sample, add 400 ml of water, heat to 60 °C to completely dissolved; take 14.9 g of pamoate disodium salt, add 200 ml of water, and then add 120 ml of anhydrous ethanol, mix well. Completely dissolved at room temperature. The water / ethanol mixed solution of pamoate disodium salt is added dropwise to the escitalopram oxalate aqueous solution at 30 °C, and solid appears immediately, with a small amount of agglomeration. After the addition is complete, the agglomeration is serious. Continue stirring for 2 h and then filter. The filter cake is washed with 50 ml of water, suction filtered for 10 min, and vacuum dried. 25.5.5 g of escitalopram pamoate Form A sample is obtained. The purity is 99.74% by HPLC detection.

[0048] The above examples serve to illustrate the essential content of the present application, but do not limit the protection scope of the present application. Those of ordinary skill in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the essence and protection scope of the technical solutions of the present application.

Claims

1. A process for preparing a crystalline form A of a compound of formula I, characterized in that, The escitalopram oxalate is dissolved in a reaction solvent to obtain an escitalopram oxalate solution; a pamoate salt solution is added dropwise to the solution to precipitate the compound of formula I in form A, wherein the reaction solvent is water, and the solvent of the pamoate salt solution is a mixed solvent of water and ethanol.

2. The production method according to claim 1, wherein The temperature for dissolving is 0-70℃.

3. The production method according to claim 2, wherein The temperature for dissolving is 25-35℃.

4. The production method according to claim 1, wherein The pamoate salt is a disodium pamoate.

5. The production method according to claim 1, wherein The mixing ratio of water and ethanol in the mixed solvent is 1:

1.

6. The production method according to claim 1, wherein The mixing ratio of water and ethanol in the mixed solvent is 7:3-3:7 by volume, preferably 1.2:1-1:1.2 by volume, and the mixing ratio of water and ethanol is not 1:

1.

7. The production method according to any one of claims 1 to 6, wherein The temperature of the escitalopram oxalate solution during the dropwise addition of the pamoate salt solution is 25-35℃.

8. The production method according to claim 8, wherein The temperature of the escitalopram oxalate solution during the dropwise addition of the pamoate salt solution is 30℃.

9. The production method according to any one of claims 1 to 6, wherein The mass ratio of escitalopram oxalate to pamoate salt is 1:0.9-1:1.

2.

10. The production method according to any one of claims 1 to 6, wherein The X-ray powder diffraction pattern of the compound of formula I in form A has characteristic peaks at 8.9±0.2°, 11.3±0.2°, 13.2±0.2°, 18.4±0.2°, 20.6±0.2°, and 21.9±0.2°.

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