A process for preparing dutasteride crystalline form I

Abstract

The application belongs to the technical field of chemical pharmacy, and particularly relates to a method for preparing dutasteride crystal form I. The method specifically comprises the following steps: S1, dissolving crude dutasteride in methanol; S2, adding small-molecule saturated alkane, and distilling under stirring until no methanol is distilled out; S3, cooling and standing the mixture to precipitate crystals; and S4, filtering, and drying the filter cake to obtain dutasteride crystal form I. The method uses a methanol-small-molecule saturated alkane double-solvent distillation recrystallization method, and dutasteride crystal form I can be obtained through simple dissolving, distilling, filtering and drying operations. The method overcomes the problems in the prior art, such as difficult control of the reaction process, easy occurrence of mixed crystals, poor repeatability, excessive solvent residue and the like, has the characteristics of simple controllability, high crystal purity, good repeatability and low solvent residue, is suitable for large-scale production, and has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical pharmacy, and particularly relates to a method for preparing dutasteride crystal form I. BACKGROUND

[0002] Dutasteride, chemical name N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide, is developed by GlaxoSmithKline, and belongs to 5alpha-reductase inhibitors. It can inhibit type I and type II 5alpha-reductase isozymes by forming enzyme complexes, inhibit the conversion of testosterone into dihydrotestosterone (DHT), and then inhibit the generation of androgen dihydrotestosterone, thereby inhibiting the growth of the prostate of a benign prostatic hyperplasia (BPH) patient.

[0003] Currently reported crystal forms of dutasteride include crystal form I, crystal form II, crystal form III and amorphous, wherein the crystal form I is the most stable and most suitable for pharmaceutical preparation production. However, the method for preparing the crystal form I of dutasteride in the prior art has problems such as difficult control of the reaction process, easy occurrence of mixed crystal phenomenon, poor repeatability, and solvent residue exceeding the standard, which is not conducive to large-scale industrial production and drug safety. For example, US7022854 discloses a method for preparing the crystal form I of dutasteride using a “halogenated hydrocarbon-low molecular aliphatic hydrocarbon” system, but in the implementation process, there is a serious solvent inclusion problem, the solvent residue is seriously excessive, and the solvent cannot be removed by high-temperature drying, and thus the method cannot be used for pharmaceutical production. CN 103724397 uses the heat stability of the crystal form I of dutasteride, and uses the crystal seeds of the crystal form I to induce the preparation of the crystal form I of dutasteride, but the operation conditions such as the amount of the crystal seeds, the critical point of crystallization and temperature adjustment are not easy to control in the production process, and thus the method is not suitable for industrial production. CN 103570796A uses ethyl acetate to convert the amorphous dutasteride into the crystal form I of dutasteride, but in the actual production process, it is found that if the beating time of ethyl acetate is slightly long or the temperature is slightly high, the compound of the crystal form II will appear, and mixed crystals will be formed. SUMMARY

[0004] In view of the above problems in the prior art, the present application improves the prior art, and provides a method for preparing the crystal form I of dutasteride. The crystal form I of dutasteride is obtained through simple dissolution, distillation, filtration and drying operations by using a methanol-small molecule saturated alkane double-solvent distillation recrystallization method, and the method has the advantages of simple operation, stable production, solvent residue meeting the ICH standard, and no other crystal compounds appearing.

[0005] The method for preparing the crystal form I of dutasteride provided by the present application specifically comprises the following steps:

[0006] S1, dissolving the crude dutasteride in methanol;

[0007] S2, add small molecule saturated alkane, distill under stirring until methanol is distilled out;

[0008] S3, cool the mixture and stand to precipitate crystals;

[0009] S4, filter, dry the filter cake, and obtain dutasteride crystal form I.

[0010] Further, the small molecule saturated alkane is any one of cyclohexane, n-heptane, n-hexane, and methylcyclohexane.

[0011] In the present application, the ratio of the crude dutasteride and methanol is not limited, as long as the crude dutasteride can be completely dissolved in methanol.

[0012] Further, the dissolution temperature in step S1 is 60-65℃.

[0013] Further, the distillation in step S2 is atmospheric distillation or reduced pressure distillation.

[0014] In the present application, the pressure, temperature, and time of distillation are not limited, as long as the distillation is until methanol is distilled out.

[0015] Further, the temperature of crystallization in step S3 is 0-25℃, and the time of crystallization is 2-16h.

[0016] Further, the temperature of drying in step S4 is 60-90℃, and the time of drying is 12-24h.

[0017] Compared with the prior art, the present application has the following advantages:

[0018] The present application uses a methanol-small molecule saturated alkane double solvent distillation recrystallization method, and the dutasteride crystal form I can be obtained through simple dissolution, distillation, filtration, and drying operations, which overcomes the problems in the prior art, such as difficult control of the reaction process, easy occurrence of mixed crystals, poor repeatability, and excessive solvent residue, and has the characteristics of simple controllability, high crystal purity, good repeatability, and low solvent residue, and is suitable for large-scale production and has good industrial application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 XRPD pattern of the dutasteride crystal form I prepared in Example 1;

[0020] Figure 2 IR pattern of the dutasteride crystal form I prepared in Example 1;

[0021] Figure 3 XRPD pattern of the dutasteride crystal form II prepared in Comparative Example 3;

[0022] Figure 4XRPD patterns of crystalline form I and form II of dutasteride prepared for Comparative Example 4. DETAILED DESCRIPTION

[0023] The application will be further described in the following specific examples. It should be understood that these examples are intended to be illustrative only and should not be construed as limiting the scope of the application. The materials used in the experiments were ordinary commercially available products or prepared according to the prior art. The crystalline form obtained in Examples 1-5 and Comparative Example 1 was tested by powder X-ray diffraction and was determined to be crystalline form I of dutasteride. The crystalline form obtained in Comparative Example 3 was tested by powder X-ray diffraction and was determined to be crystalline form II of dutasteride. The crystalline form obtained in Comparative Example 4 was tested by powder X-ray diffraction and was determined to be a mixture of crystalline form I and form II of dutasteride.

[0024] Example 1

[0025] A method for preparing crystalline form I of dutasteride, the steps of which are as follows: 10 g of dutasteride is added to 69 g of methanol, dissolved at 65°C, 100 g of cyclohexane is added, and the mixture is stirred at an external temperature of 90°C under normal pressure until the rate of solvent distillation decreases significantly (almost no methanol distills), the mixture is allowed to stand at 0-5°C for 16 h, filtered, and the filter cake is dried at 90°C for 16 h to obtain 9.72 g of white powder, with a yield of 97.2%, a methanol residue of 480 ppm (ICH solvent residue qualification standard is 3000 ppm or less), and a cyclohexane residue of 1440 ppm (ICH solvent residue qualification standard is 3880 ppm or less).

[0026] The dutasteride prepared in this example is crystalline form I, which has an X-ray diffraction pattern as shown in Figure 1 The characteristic peaks of the X-ray diffraction correspond to the following 2θ angle parameters: 5.20, 10.25, 11.83, 12.70, 14.00, 14.82, 15.65, 15.83, 16.59, 17.75, 18.04, 18.50, 19.68, 20.49, 21.57, 21.89, 22.93, 23.72, 24.65, 25.63, 26.88, 28.03, 30.14, 32.42, 33.59, 37.45, 40.15. The characteristic peaks of the X-ray diffraction correspond to the following interplanar spacing parameters: 16.97, 8.62, 7.47, 6.96, 6.32, 5.97, 5.66, 5.59, 5.34, 4.99, 4.91, 4.79, 4.51, 4.33, 4.12, 4.06, 3.88, 3.75, 3.61, 3.47, 3.31, 3.18, 2.96, 2.76, 2.67, 2.40, 2.24. The crystal data are consistent with the data in US 7022854.

[0027] The dutasteride crystal form I prepared in this example has an infrared spectrum as shown in Figure 2

[0028] Example 2

[0029] A method for preparing the dutasteride crystal form I, the steps of which are as follows: 10 g of dutasteride is added to 69 g of methanol, dissolved at 65°C, 100 g of cyclohexane is added, and distilled at a reduced pressure under stirring at an external temperature of 35 to 40°C until the solvent distillation rate is obviously reduced (almost no methanol distillation), and then the temperature is lowered to 0 to 5°C, and the crystal is precipitated for 16 h, filtered, and the filter cake is dried at 90°C for 16 h to obtain 9.68 g of white powder, with a yield of 96.8%, methanol residue of 450 ppm (ICH solvent residue qualification standard of 3000 ppm or less), and cyclohexane residue of 290 ppm (ICH solvent residue qualification standard of 3880 ppm or less).

[0030] It can be seen from the test data of Example 1 and Example 2 that the crystal form I can be stably obtained whether atmospheric distillation or reduced pressure distillation is used.

[0031] Example 3

[0032] A method for preparing the dutasteride crystal form I, the steps of which are as follows: 10 g of dutasteride is added to 69.00 g of methanol, dissolved at 65°C, 100 g of n-heptane is added, and distilled at a reduced pressure under stirring at an external temperature of 35 to 40°C until the solvent distillation rate is obviously reduced (almost no methanol distillation), and then the temperature is lowered to 20 to 25°C, and the crystal is precipitated for 2 h, filtered, and the filter cake is dried at 90°C for 16 h to obtain 9.84 g of white powder, with a yield of 98.4%, methanol residue of 510 ppm (ICH solvent residue qualification standard of 3000 ppm or less), and n-heptane residue of 480 ppm (ICH solvent residue qualification standard of 5000 ppm or less).

[0033] Example 4

[0034] A method for preparing the dutasteride crystal form I, the steps of which are as follows: 10 g of dutasteride is added to 69 g of methanol, dissolved at 65°C, 100 g of n-hexane is added, and distilled at a reduced pressure under stirring at an external temperature of 35 to 40°C until the solvent distillation rate is obviously reduced (almost no methanol distillation), and then the temperature is lowered to 0 to 5°C, and the crystal is precipitated for 16 h, filtered, and the filter cake is dried at 90°C for 16 h to obtain 9.02 g of white powder, with a yield of 90.2%, methanol residue of 360 ppm (ICH solvent residue qualification standard of 3000 ppm or less), and n-hexane residue of 280 ppm (ICH solvent residue qualification standard of 290 ppm or less).

[0035] Example 5

[0036] ​A method for preparing dutasteride crystal form I comprises the following steps: adding 10g of dutasteride to 69g of methanol, dissolving at 65℃, adding 100g of methylcyclohexane, and distilling at 100℃ under atmospheric pressure with stirring until the solvent distillation rate decreases significantly (almost no methanol distilled out), cooling to 0-5℃ and allowing to stand for crystallization for 16h, filtering, and drying the filter cake at 90℃ for 16h to obtain 9.46g of white powder with a yield of 94.6%, methanol residue of 540ppm (ICH solvent residue acceptable standard below 3000ppm), and methylcyclohexane residue of 310ppm (ICH solvent residue acceptable standard below 1180ppm).

[0037] Comparative Example 1

[0038] A method for preparing dutasteride crystal form I comprises the following steps: adding 10.00 g of dutasteride to 66.30 g of dichloromethane, stirring until dissolved, adding 100 g of cyclohexane, and distilling at 90 °C under ambient pressure with stirring until the solvent distillation rate decreases significantly (almost no dichloromethane distilled out), cooling to 0–5 °C to crystallize for 16 hours, filtering, and drying the filter cake at 90 °C for 16 hours to obtain 9.65 g of white powder with a yield of 96.5%, a dichloromethane residue of 3360 ppm (ICH solvent residue acceptable standard below 600 ppm), and a cyclohexane residue of 5440 ppm (ICH solvent residue acceptable standard below 3880 ppm).

[0039] The results from Example 1 and Comparative Example 1 show that replacing dichloromethane with methanol significantly reduces the residual solvent in the product, and is far below the ICH compliance standard, thus meeting the requirements for dutasteride pharmaceutical preparations.

[0040] Comparative Example 2

[0041] 10g dutasteride was added to 69g methanol and dissolved at 65℃. 100g ethyl acetate was added and the mixture was concentrated to a small volume by atmospheric distillation at 65-70℃. Crystallization was carried out at 0-5℃, filtered, and the filter cake was dried at 90℃ for 16h to obtain 6.42g of white solid, with a yield of 64.2%.

[0042] The results of this comparative example show that, due to the miscibility of methanol and ethyl acetate, the crystallization effect is not obvious under azeotropic distillation, resulting in a low product yield.

[0043] Comparative Example 3

[0044] 10g dutasteride was added to 69g methanol and dissolved at 65℃. 100g ethyl acetate was added and the mixture was concentrated to a small volume by atmospheric distillation at 65-70℃. Another 180g ethyl acetate was added and the mixture was concentrated to a small volume by atmospheric distillation at 65-70℃. The mixture was cooled to 0-5℃ to crystallize. The crystals were filtered, and the filter cake was dried at 90℃ for 16 hours to obtain 9.48g of white solid, with a yield of 94.8%.

[0045] The dutasteride prepared in the present comparative example is crystal form II, having an X-ray diffraction pattern as shown in Figure 3 which has an obvious characteristic peak of crystal form II at crystal face spacing d = 4.6.

[0046] From the results of the present comparative example, it can be seen that the crystal obtained by adding ethyl acetate to the methanol-ethyl acetate double solvent distillation concentrate of dutasteride, and then recrystallizing by distillation and cooling crystallization is crystal form II of dutasteride.

[0047] Comparative Example 4

[0048] 10 g of dutasteride was added to 69 g of methanol, and dissolved at 65°C. The solution was filtered, and the filtrate was distilled under reduced pressure until the solution was distilled dry. The residue was scraped off, and the residue was dried at 50°C for 16 h. The residue was added to 20 ml of ethyl acetate, and stirred at 70-75°C for 40 min. After the temperature was lowered to room temperature, the solution was filtered, and the filter cake was dried at 75°C for 16 h to obtain 9.25 g of white solid, with a yield of 93%.

[0049] The dutasteride prepared in the present example is a mixed crystal of crystal form I and crystal form II, having an X-ray diffraction pattern as shown in Figure 4 which has an obvious characteristic peak of crystal form I at crystal face spacing d = 4.9, and an obvious characteristic peak of crystal form II at crystal face spacing d = 4.6.

[0050] From the results of the present comparative example, it can be seen that the crystal obtained by adding ethyl acetate to the methanol solution of dutasteride, and then recrystallizing by distillation and cooling crystallization is a mixed crystal of crystal form I and crystal form II of dutasteride.

[0051] Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can make modifications to the technical solutions described in the foregoing embodiments, or make equivalent replacements to some of the technical features, and any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing dutasteride crystal form I, characterized in that, Includes the following steps: S1. Dissolve crude dutasteride in methanol; S2. Add a small molecule saturated alkane and distill under stirring until no methanol is distilled off; the small molecule saturated alkane is any one of cyclohexane, n-heptane, n-hexane, and methylcyclohexane; S3. Cool the mixture and allow it to stand to precipitate crystals; S4. Filter and dry the filter cake to obtain dutasteride crystal form I.

2. The method for preparing dutasteride crystal form I according to claim 1, characterized in that, The dissolution temperature in step S1 is 55–65°C.

3. The method for preparing dutasteride crystal form I according to claim 1, characterized in that, In step S2, the distillation is either atmospheric distillation or vacuum distillation.

4. The method for preparing dutasteride crystal form I according to claim 1, characterized in that, In step S3, the crystallization temperature is 0–25°C, and the crystallization time is 2–16 h.

5. The method for preparing dutasteride crystal form I according to claim 1, characterized in that, In step S4, the drying temperature is 60–90°C, and the drying time is 12–24 hours.

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