Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems

Definitions

• the invention belongs to the technical field of medicines, and in particular relates to a method for preparing an amorphous form of darunavir. Background technique
• Damnavir trade name Prezista, is a first-generation non-peptide H developed by Tibotec, a Johnson & Johnson company.
• Daalunavir selectively inhibits the HIV-encoded Gag-Pol polyprotein in infected cells and prevents the formation of mature virions. Both in vivo and in vitro experiments have demonstrated that darunavir has a strong antiviral activity against HIV-resistant HIV and that the virus has a lower propensity to develop resistance to darunavir.
• WO03/106461 has reported various polymorphs of darunavir and preparation methods thereof: type A crystal (ethanol solvate), type B crystal (hydrate), type C crystal (methanol) Solvate), Form D crystal (acetone solvate), Form E crystal (dichloromethane solvate), Form F crystal (ethyl acetate solvate), Form G crystal (1-methoxy- 2-propanol solvate), H-form crystal (anisole solvate), Form I crystal (tetrahydrofuran solvate), J-type crystal (isopropanol solvate), K-type crystal (methanesulfonic acid) Solvate)
• an amorphous substance is also disclosed, the preparation method of the amorphous substance is not reported.
• WO2011048604 reports the following five methods for preparing amorphous darunavir using darunavir ethanol solvate as a raw material:
• the darunavir ethanol solvate is dissolved in 5000 times of dichloromethane (or n-heptyl or isopropyl ether), and then the solvent is distilled off under reduced pressure to obtain amorphous darunavir. This method requires a large amount of solvent, which is environmentally polluting and high in production cost. 3.
• the darunavir ethanol solvate is dissolved in 5 times the amount of ethyl acetate, and then ethyl acetate is distilled off, and then 5 times the amount of n-heptane is added to separate the amorphous darunavir. It has been found by the inventors that the amorphous material obtained by the method is usually an oil and is not easy to form a solid, which is disadvantageous for subsequent operations and use.
• the darunavir ethanol solvate is heated to 1 10-120 ° C to melt it, and then cooled to 25-35 ° C to obtain amorphous darunavir.
• the darunavir ethanol solvate is suspended in glycerin, heated to 1 10-120 ° C, then cooled to 25-35 ° C, and then added with water to separate the amorphous darunavir.
• the above fourth and fifth methods are too high in temperature, inconvenient to operate, high in cost, and easy to produce impurities during crystallization, which is not conducive to industrial production.
• the object of the present invention is to provide a process for preparing an amorphous form of darunavir which is simple in operation, environmentally friendly, low in production cost, and suitable for industrial production.
• a method for preparing an amorphous form of darunavir comprising the steps of: (1) dissolving darunavir or a solvate thereof in a first solvent to form a ruthenium a first solution of Nawei, the first solvent is methanol or a mixed solvent containing methanol;
• the second solvent It is water or a mixed solvent of water and methanol.
• the volume content of the water is >90%; preferably ⁇ 95%; more preferably ⁇ 98%.
• the second solvent is water.
• a process for the preparation of darunavir amorphous comprising the steps of: (i) providing a first solution comprising darunavir, said first solution comprising: daruna Or a solvate thereof, and a first solvent, wherein the first solvent is methanol or a mixed solvent containing methanol;
• the second solvent It is water or a mixed solvent of water and methanol.
• the volume content of the water is
• the second solvent is water.
• the methanol-containing mixed solvent further contains other organic solvents, and the other organic solvent is an organic solvent having a solubility in water of ⁇ 5% at 20 ° C;
• the other organic solvent is an organic solvent having a solubility in water at 20 ° C ⁇ 20%; more preferably selected from the group consisting of C 2 _ 3 alcohol, acetone, tetrahydrofuran, dioxane, N'N-dimethylformamide, dimethyl sulfoxide, or a combination thereof.
• the volume ratio of methanol to other organic solvents is ⁇ 1:1; preferably, the volume ratio is ⁇ 2:1; more preferably, the volume ratio is ⁇ 5: 1.
• the solvate comprises: a methanolate, an ethanolate, a hydrate, an acetone, a dichloromethane, an ethyl acetate, and a 1-methoxy-2. a propanolate, anisole, tetrahydrofuran, isopropanolate, methanesulfonate, or a combination thereof;
• it comprises: a methanolate, an ethanolate, a hydrate, or a combination thereof.
• step (1) or step (i) the ratio of the mass (W) of the darunavir or its solvate to the volume (V) of the first solvent (g/ The mL) is 1: 2-50; preferably 1: 5-15.
• step (2) or step (ii) the volume ratio of the second solvent to the first solution is 1-100:1; preferably 1-50:1; Preferably 1-20: 1.
• the volume ratio of the second solvent to methanol in the first solvent is 1-100:1, preferably 1-60:1, more preferably 1-30:1.
• a separation step is further included.
• the separating step comprises: filtering.
• the mixing is carried out at a temperature of 0 to 30 ° C; preferably 0 to 20 ° C; more preferably 0 -15 ° C.
• the invention solves the defects of the amorphous darunavir in the prior art, such as low purity, unstable product, and difficult operation control.
• the amorphous darunavir obtained by the invention has high purity, good stability, simple preparation method, low production cost and is suitable for industrial production.
• Figure 1 shows an amorphous Danavir XRPD pattern of the present invention
• Figure 2 shows the IR map of amorphous darunavir of the present invention
• Figure 3 shows an amorphous Darfuravir DSC map of the present invention.
• Figure 4 shows the hygroscopic weight gain of the amorphous darunavir of the present invention at different relative humidities.
• Figure 5 shows the XRPD comparison of the amorphous darunavir of the present invention after 0 days, 5 days, and 10 days of high humidity (93% RH); the top to bottom curve is 10 days in sequence. , 0 days and 5 days. detailed description
• the inventors have unexpectedly discovered a preparation method of amorphous darunavir by a long-term and in-depth study, which obtains a solution containing darunavir from a first solvent as a solvent, and the solution and the second solvent Mixing to obtain precipitated amorphous darunavir.
• the method does not require high-temperature heating, requires no special equipment, does not require the use of a large amount of solvent, and adopts a simple separation process to obtain an amorphous darunavir with high stability and high purity.
• the inventors have completed the present invention.
• the "organic solvent having a solubility in water of ⁇ 5 wt% at 20 ° C" as used in the present invention means that the maximum weight of the organic solvent which can be dissolved in 100 g of water at 20 ° C is ⁇ 5 g.
• a "solvate” is a solvate of darunavir, a compound formed from darunavir and different solvent molecules, including but not limited to: methanol, ethanol, iso Propanol, water, acetone, chloroform, ethyl acetate, 1-methoxy-2-propanol, anisole, tetrahydrofuran, and the like.
• First solvent methanol, ethanol, iso Propanol, water, acetone, chloroform, ethyl acetate, 1-methoxy-2-propanol, anisole, tetrahydrofuran, and the like.
• the "first solvent” described in the present invention is a mixed solvent of methanol or methanol.
• the methanol-containing mixed solvent further contains other organic solvents, and the other organic solvent is an organic solvent having a solubility in water of ⁇ 5% at 20 ° C; preferably, the solubility in water at 20 ° C is ⁇ 20%.
• Organic solvent more preferably from the group consisting of: C 2 _ 3 alcohol (including ethanol, n-propanol or isopropanol), acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), or a combination thereof.
• the volume ratio of methanol to other organic solvents is ⁇ 1:1, preferably the volume ratio is ⁇ 5:1.
• the "second solvent” described in the present invention is water or a mixed solvent of water and methanol.
• the content of methanol should be such that the amount of precipitation of amorphous darunavir is not affected.
• the volume content of water is ⁇ 90%; more preferably ⁇ 95%; more preferably ⁇ 98%.
• the water used in the present invention is preferably purified water such as distilled water or deionized water; preferably water which is subjected to primary distillation or secondary distillation.
• the invention provides a preparation method of amorphous darunavir, comprising the steps of:
• the solvate may include: an ethanolate of darunavir, a hydrate, a methanolate, an acetone, a dichloromethane, an ethyl acetate, a 1-methoxy- 2-propanol, aniline, tetrahydrofuran, isopropanolate, methanesulfonate, etc.; preferably a methanolate, an ethanolate, a hydrate, or a combination thereof.
• the ratio (g/mL) of the mass (W) of the darunavir or its solvate to the volume (V) of the first solvent is 1: 2-50, preferably 1: 5 -15.
• the dissolution is carried out at a temperature of 20 to 50 ° C, preferably 25 to 40 ° C.
• the first solution containing darunavir is mixed with the second solvent of the present invention to form a second solution containing darunavir and precipitated darunavir, thereby obtaining amorphous darunavir.
• the volume ratio of the second solvent to the first solution is from 1 to 100:1, preferably from 1 to 50:1, more preferably from 1 to 20:1.
• the volume ratio of the second solvent to the methanol in the first solvent is
• 1 - 100 1, preferably 1 - 60: 1, more preferably 1 - 30: 1.
• the mixing is carried out at a temperature of 0 to 30 ° C, preferably 0 to 20 ° C; more preferably 0 to 15 ° C.
• the mixing step may be: adding (eg, dropping) the first solution containing darunavir to the second solvent, or adding (eg, dropping) the second solvent to the In the first solution of darunavir.
• the stirring speed is controlled at 50-1000 rpm (preferably 200-500 rpm or agitation time is 1-8 hours (preferably 1-5 hours).
• the separation step e.g., filtration, etc.
• the drying step may be included after the precipitation of darunavir.
• the preparation method of the invention does not require the use of special equipment or devices, does not require high temperature heating, does not require the use of a large amount of solvent, and therefore, is easy to operate, low in cost, and environmentally friendly.
• the amorphous darunavir obtained by the preparation method of the invention is not easy to absorb moisture, is not easy to deteriorate, and has good stability.
• the invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
• the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
• the starting materials used in the present invention are commercially available or are prepared according to the document WO2003106461.
• the hygroscopic or high temperature destruction test and high humidity destruction test of the present invention can be referred to the experimental method of influencing factors in the 2010 edition of the Chinese Pharmacopoeia. Test condition
• X-ray powder diffraction Brucker D8 advance X-ray powder diffractometer, scanning range:
• DSC Differential scanning calorimetry
• Example 2 Preparation of amorphous darunavir 200 g of darunavir methanolate was dissolved in a mixed solvent containing 1000 ml of methanol and 1000 ml of ethanol at room temperature, and the resulting solution was added dropwise to 4 L of cold water (water temperature of 5-10 ° C) with stirring. Stir for 1-2 hours. After filtration, the filter cake was washed with about 200 mL of water and dried to give 192 g of white solid. After testing, it was amorphous darunavir, and its XRPD pattern, FTIR chart and DSC chart were basically the same as those in Example 1.
• Example 3 Preparation of amorphous darunavir
• the sample was placed in a constant humidity sealed container, placed at different relative humidity conditions for 48 hours at 25 °C, and accurately weighed at 24 hours and 48 hours. The difference in sample weight before and after the test was compared to absorb moisture. The percentage is plotted against the relative humidity to obtain the hygroscopic weight gain curve of amorphous darunavir at different relative humidity (as shown in Figure 4).
• the sample was placed in a constant-humidity sealed container, placed at a relative humidity of 90 ⁇ 5% for 10 days at 25 °C, and sampled on the 5th and 10th days, and tested according to the stability investigation item. The weight of the test sample before and after the test was weighed to examine the moisture absorption and deliquescence properties of the test sample.
• the stability of the amorphous darunavir obtained by the present invention is shown in Fig. 5 and Table 1 under conditions of high temperature (60 ° C) or high humidity (about 93% of RH).

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• 2012
  • 2012-06-20 WO PCT/CN2012/077236 patent/WO2013189049A1/fr not_active Ceased

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