Preparation method of valaciclovir hydrochloride anhydrous crystal form I

Abstract

The invention discloses a preparation method of a valaciclovir hydrochloride anhydrous crystal form I, and belongs to the technical field of medicinal chemistry. The preparation method comprises the following steps: mixing a valaciclovir hydrochloride hydrate with 0.2-0.4 time of water, heating to 60-80 DEG C, carrying out closed crystal transformation for 2-5 hours, and then drying at 60-80 DEG C under reduced pressure to obtain the valaciclovir hydrochloride anhydrous crystal form I. Water is adopted as a crystal transformation solvent, other solvents are not used, and the hidden danger of solvent residues is basically avoided; water is used as a crystal transformation solvent, so that the method is safe, environment-friendly and low in cost; meanwhile, the granularity is controlled by adjusting the water proportion, and the market requirements of coarse particles and large bulk density are met.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a method for preparing anhydrous crystalline form I of valacyclovir hydrochloride. Background Art

[0002] Valacyclovir hydrochloride is acyclovir L-valine ester, a prodrug of acyclovir. It was first launched in the UK and Ireland in January 1995 and was approved by the FDA in June of the same year for the treatment of herpes zoster. It was later approved for genital herpes and herpes simplex virus (HSV) infections of the skin and mucous membranes. Compared with acyclovir, valacyclovir hydrochloride rapidly inhibits viral replication at a higher blood concentration, avoids side effects and expands clinical indications.

[0003] Valacyclovir hydrochloride is a complex polymorphic drug. Currently, the public crystal forms include Type I, II, III, IV, V, VI and VII. Among them, the crystal form of the valacyclovir hydrochloride raw material produced by the original research company is the anhydrous crystal form I.

[0004] U.S. Patent No. 6107302B discloses anhydrous crystalline form I of valacyclovir hydrochloride and a preparation method thereof, wherein the preparation method comprises the following steps: firstly obtaining a dry valacyclovir hydrochloride hydrate, then mixing it with 15-40% ethanol by weight of the hydrate, heating it to 50-70° C. in a sealed container, keeping it warm for a period of time in an ethanol vapor atmosphere, and then directly drying it under reduced pressure to obtain anhydrous valacyclovir hydrochloride crystalline form I. Since it is difficult for the dry valacyclovir hydrochloride hydrate to mix evenly with ethanol, and it is difficult for the ethanol vapor generated by heating to enter the interior of the solid in a short time, it is difficult for the valacyclovir hydrochloride hydrate to be completely converted into anhydrous valacyclovir hydrochloride crystalline form I. Summary of the invention

[0005] To overcome the problems existing in the prior art such as poor conversion efficiency, potential safety hazards, long time consumption, and unsuitability for large-scale production.

[0006] The invention provides a method for preparing anhydrous crystalline form I of valacyclovir hydrochloride, comprising the following steps: mixing valacyclovir hydrochloride hydrate (1.5 times water, the same below) with water, heating and sealing for crystallization, and then reducing pressure and drying to obtain anhydrous crystalline form I of valacyclovir hydrochloride.

[0007] Furthermore, in the above technical solution, the water is 0.2-0.4 times the weight of valacyclovir hydrochloride hydrate.

[0008] Furthermore, in the above technical solution, the temperature for heating and crystallization is 60-80°C, and the sealed insulation time is 2-5 hours.

[0009] Furthermore, in the above technical solution, the reduced pressure drying temperature is 60-80°C.

[0010] Furthermore, in the above technical scheme, the valacyclovir hydrochloride hydrate is prepared by the following method: Cbz-valacyclovir, aqueous hydrochloric acid solution, methanol and palladium carbon are mixed, and the hydrogen pressure is maintained at 0.20±0.05MPa and the temperature is 30±5°C to catalyze the hydrogenolysis reaction; after the reaction is completed, the palladium carbon is filtered out, the filtrate is concentrated under reduced pressure to a slightly turbid state, acetone is added to cool and crystallize, filtered, the filter cake is slurried with acetone at room temperature, filtered, and the wet product of valacyclovir hydrochloride hydrate is obtained, and the valacyclovir hydrochloride hydrate is dried under reduced pressure at 55-65°C to obtain valacyclovir hydrochloride hydrate.

[0011] Furthermore, in the above technical scheme, the Cbz-valacyclovir is prepared by the following method: acyclovir, Cbz-L-valine, 4-dimethylaminopyridine and N,N-dimethylformamide are mixed, cooled to 0-5°C, a mixed solution of dicyclohexylcarbodiimide and N,N-dimethylformamide is added dropwise, and the mixture is kept at 10-25°C for reaction after the addition is completed; after the reaction is completed, the mixture is filtered, the filtrate is concentrated under reduced pressure, methanol is added, the temperature is raised to dissolve, and then cooled and crystallized, filtered, and the obtained solid is recrystallized from methanol; then filtered again, the obtained solid is added to N,N-dimethylformamide and heated to dissolve, the dissolved liquid is added to 50-60°C water, stirred and filtered while hot, and the filter cake is dried to obtain Cbz-valacyclovir.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] 1. Water is used as the crystallization solvent, and no other solvents are used, so there is basically no hidden danger of solvent residue.

[0014] 2. Using water as the crystallization solvent is safe, environmentally friendly and low-cost.

[0015] 3. Using water as the crystallization solvent, the particle size can be controlled by adjusting the water ratio to meet the market demand for coarse particles and high bulk density. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 It is the X-ray powder diffraction pattern of the anhydrous crystalline form I in patent CN1179159A;

[0017] Figure 2 The X-ray powder diffraction pattern of valacyclovir hydrochloride hydrate obtained in Example 2;

[0018] Figure 3 The X-ray powder diffraction pattern of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 3;

[0019] Figure 4 The particle size distribution diagram of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 3;

[0020] Figure 5The X-ray powder diffraction pattern of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 4;

[0021] Figure 6 The particle size distribution diagram of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 4;

[0022] Figure 7 The X-ray powder diffraction pattern of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 5;

[0023] Figure 8 The particle size distribution diagram of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 5;

[0024] Fig. 9 The X-ray powder diffraction pattern of valacyclovir hydrochloride anhydrous crystalline form I obtained in Example 6;

[0025] Fig.10 The particle size distribution diagram of valacyclovir hydrochloride anhydrous crystalline Form I obtained for Example 6. DETAILED DESCRIPTION

[0026] The present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0027] Example 1

[0028] Preparation of Cbz-valacyclovir: 200g of acyclovir, 360g of Cbz-L-valine, 10g of DMAP and 1000g of N,N-dimethylformamide were added to a reaction bottle, stirred and cooled to below 5°C, and a mixed solution of 300g of dicyclohexylcarbodiimide and 600g of N,N-dimethylformamide was added dropwise. After the addition, the mixture was kept at 10-25°C for 10 hours and the plate was spotted until the acyclovir spots were basically invisible. Dicyclohexylurea was removed by filtration. After the filtrate is concentrated under reduced pressure, 3000 g of methanol is added, the temperature is raised to dissolve, and then cooled to crystallize and filter. 3000 g of methanol is added to the filter cake, the temperature is raised to dissolve, and then cooled to crystallize and filter. An appropriate amount of N, N-dimethylformamide is added to the filter cake and heated to 50-60 ° C to dissolve. The dissolved liquid is added to 5000 g of 50-60 ° C water, stirred and filtered while hot, and the filter cake is dried to obtain 381 g of Cbz-valacyclovir.

[0029] Example 2

[0030] 340g of Cbz-valacyclovir prepared by the method of Example 1, 6800g of methanol, 100g of hydrochloric acid, 1200g of water, and 10g of 5% wet palladium carbon were put into a hydrogenolysis reactor. After sealing, nitrogen was replaced three times, and then hydrogen was replaced three times. Then, the hydrogen pressure was maintained at 0.20±0.05MPa, and the reaction was stirred at 30±5°C for 15 hours before the plate was spotted. When the Cbz-valacyclovir spots were basically invisible, the hydrogenolysis reaction was terminated. After the reaction was completed, the palladium carbon was removed by filtration, and the filtrate was concentrated to a slightly turbid state under reduced pressure. The distillation was stopped, 1700g of acetone was added dropwise, cooled and crystallized, filtered, the filter cake was returned, 1000g of acetone was added to pulp at room temperature, filtered, and 342g of wet valacyclovir hydrochloride hydrate was obtained. The valacyclovir hydrochloride hydrate was dried under reduced pressure at 60°C to obtain 221g of valacyclovir hydrochloride hydrate (1.5 times water). Its X-ray powder diffraction pattern is shown in Figure 2 , 2θ has characteristic peaks at 3.7, 8.6, 9.5, 10.6, 13.4, 16.5, 20.2, 21.4, 24.0, 26.9, and 27.3.

[0031] Example 3

[0032] Take 200 g of valacyclovir hydrochloride hydrate obtained in Example 2, put it into a reaction bottle, add 60 g of water, stir and mix, heat to 80°C, seal and keep warm for 2 hours, and dry under reduced pressure at 80°C to obtain 185 g of material. X-ray powder diffraction pattern see Figure 3 , 2θ has characteristic peaks at 8.6, 10.9, 12.1, 14.5, 15.1, 16.4, 16.9, 18.1, 20.0, 21.8, 23.9, 26.2, 26.8, 30.6, and 32.2, which is consistent with the anorthite type I in patent CN1179159A. The water content is 0.2%, no other solvents remain, the bulk density is 0.60g / mL, and the compactness is 0.80g / mL. See the particle size distribution diagram Figure 4 , d(0.1) is 6um, d(0.5) is 57um, and d(0.9) is 434um.

[0033] Example 4

[0034] Take 200g of valacyclovir hydrochloride hydrate obtained in Example 2, put it into a reaction bottle, add 80g of water, stir and mix, heat to 70°C, seal and keep warm for 4 hours, and dry under reduced pressure at 70°C to obtain 186g of material. X-ray powder diffraction pattern see Figure 5, 2θ has characteristic peaks at 8.6, 10.9, 12.1, 14.5, 15.2, 16.5, 16.9, 18.1, 20.1, 21.9, 23.9, 26.2, 26.8, 30.6, and 32.2, which is consistent with the anorthite type I in patent CN1179159A. The water content is 0.2%, no other solvents remain, the bulk density is 0.62g / mL, and the compactness is 0.82g / mL. See the particle size distribution diagram Figure 6 , d(0.1) is 9um, d(0.5) is 135um, and d(0.9) is 568um.

[0035] Example 5

[0036] Take 200g of valacyclovir hydrochloride hydrate obtained in Example 2, put it into a reaction bottle, add 40g of water, stir and mix, heat to 60°C, seal and keep warm for 5 hours, and dry under reduced pressure at 60°C to obtain 187g of material. X-ray powder diffraction pattern see Figure 7 , 2θ has characteristic peaks at 8.6, 10.9, 12.1, 14.5, 15.2, 16.5, 16.9, 18.1, 20.1, 21.9, 23.9, 26.2, 26.8, 30.6, and 32.2, which is consistent with the anorthite type I in patent CN1179159A. The water content is 0.3%, no other solvents remain, the bulk density is 0.58g / mL, and the compactness is 0.78g / mL. See the particle size distribution diagram Figure 8 , d(0.1) is 7um, d(0.5) is 62um, and d(0.9) is 358um.

[0037] Example 6

[0038] Take 200g of valacyclovir hydrochloride hydrate obtained in Example 2, put it into a reaction bottle, add 80g of 75% ethanol (60g of anhydrous ethanol, 20g of water), stir and mix, heat to 60°C, seal and keep warm for 8 hours, and dry under reduced pressure at 60°C to obtain 185g of material. X-ray powder diffraction pattern see Fig. 9 , 2θ has characteristic peaks at 8.6, 10.8, 12.1, 14.5, 15.1, 16.4, 16.9, 18.1, 20.0, 21.8, 23.9, 26.2, 26.8, 30.6, and 32.2, which is consistent with the anhydrous crystalline form I in patent CN1179159A. The bulk density is 0.36g / mL and the compactness is 0.54g / mL. See the particle size distribution diagram Fig.10 , d(0.1) is 2um, d(0.5) is 39um, and d(0.9) is 154um.

[0039] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing anhydrous valacyclovir hydrochloride crystalline form I, comprising the following steps: The valacyclovir hydrochloride hydrate is mixed with water, the temperature is raised and the crystal is sealed, and then the valacyclovir hydrochloride anhydrous crystal form I is obtained by drying under reduced pressure.

2. The method for preparing anhydrous valacyclovir hydrochloride crystalline form I according to claim 1, wherein: The water is 0.2-0.4 times the weight of valacyclovir hydrochloride hydrate.

3. The method for preparing valacyclovir hydrochloride anhydrous crystalline form I according to claim 1, characterized in that: The temperature for heating and crystallization is 60-80° C., and the sealed insulation time is 2-5 hours.

4. The method for preparing anhydrous valacyclovir hydrochloride crystalline form I according to claim 1, characterized in that: The reduced pressure drying temperature is 60-80℃.

5. The method for preparing valacyclovir hydrochloride anhydrous crystalline form I according to claim 1, characterized in that: The preparation method of valacyclovir hydrochloride hydrate comprises the following steps: mixing Cbz-valacyclovir, hydrochloric acid aqueous solution, methanol and palladium carbon, maintaining a hydrogen pressure of 0.20±0.05MPa and a temperature of 30±5°C to carry out a catalytic hydrogenolysis reaction; after the reaction is completed, filtering to remove the palladium carbon, concentrating the filtrate under reduced pressure to a slightly turbid state, adding acetone to cool and crystallize, filtering, adding acetone to the filter cake to pulp at room temperature, filtering to obtain a wet product of valacyclovir hydrochloride hydrate, and drying the valacyclovir hydrochloride hydrate under reduced pressure at 55-65°C to obtain valacyclovir hydrochloride hydrate.

6. The method for preparing valacyclovir hydrochloride anhydrous crystalline form I according to claim 5, characterized in that: The preparation method of Cbz-valacyclovir comprises the following steps: mixing acyclovir, Cbz-L-valine, 4-dimethylaminopyridine and N,N-dimethylformamide, cooling to 0-5°C, dripping a mixed solution of dicyclohexylcarbodiimide and N,N-dimethylformamide, and reacting at 10-25°C after the dripping is completed; filtering after the reaction is completed, concentrating the filtrate under reduced pressure, adding methanol, heating to dissolve, cooling to crystallize, filtering, and re-crystallizing the obtained solid with methanol; then filtering again, adding N,N-dimethylformamide to the obtained solid and heating to dissolve it, adding the dissolved liquid into water at 50-60°C, stirring and filtering while hot, and drying the filter cake to obtain Cbz-valacyclovir.

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