CN107382833B - Preparation method of atazanavir bisulfate crystal form H1 - Google Patents
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- CN107382833B CN107382833B CN201710827550.4A CN201710827550A CN107382833B CN 107382833 B CN107382833 B CN 107382833B CN 201710827550 A CN201710827550 A CN 201710827550A CN 107382833 B CN107382833 B CN 107382833B
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of atazanavir bisulfate crystal form H1, which comprises the following steps: mixing the atazanavir bisulfate with the solvent, and stirring; the solvent is a mixed solvent of methanol, butanone and ethyl acetate. The preparation method of the atazanavir bisulfate crystal form H1 provided by the invention has the advantages of good repeatability, simple and convenient operation, high yield, high chromatographic purity and suitability for being used as a medicament, meets the medicinal requirement of the methanol content of the obtained product, is suitable for industrial production and has potential market value.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of atazanavir bisulfate crystal form H1.
Background
Atazanavir bisulfate (Atazanavir sulfate), which is sold under the trade name "Ruyataz", is a drug developed by Behcet-Mitsunobo corporation for the treatment of HIV-1 infection. The medicinal preparation is in the form of capsules, is marketed in the United states in 2003 and enters the Chinese market in 2011.
The traditional chemical name of atazanavir bisulfate is (3S,8S,9S,12S) -3, 12-bis (1, 1-dimethylethyl) -8-hydroxy-4, 11-dioxo-9- (phenylmethyl) -6- [ [4- (2-pyrimidine) phenyl ] methyl ] -2,5,6,10, 13-pentaazatetradecanedioic acid dimethyl bisulfate, and the structure is shown as follows:
several crystalline forms of atazanavir bisulfate are reported in the present stage: WO9936404 discloses atazanavir bisulfate in form I (form a) and form II for the first time; WO2005103849 discloses atazanavir bisulfate form C and form E; WO2011027324 discloses atazanavir bisulfate in crystal form B, in crystal form P and in amorphous form.
The atazanavir bisulfate crystal form H1 is similar to the atazanavir bisulfate crystal form A, belongs to an anhydrous and non-solvating crystal form, and has potential clinical value and market prospect. WO2010079497 discloses atazanavir bisulfate crystal form H1 and a preparation method thereof: dissolving the atazanavir bisulfate in methanol, then dropwise adding ethyl acetate into the solution, stirring for 30min at room temperature after the dropwise adding is finished, and filtering to obtain the required product. The product obtained by the method has low yield, and simultaneously, the content of methanol is far beyond the requirement of pharmacopoeia. Therefore, industrial production cannot be carried out.
Therefore, the development of a simple, convenient and efficient preparation method of the atazanavir bisulfate crystal form H1 which is suitable for industrial production is urgently needed in the field.
Disclosure of Invention
The invention aims to overcome the defects of low yield, high methanol content and the like of the existing preparation method of the atazanavir bisulfate crystal form H1, and provides a preparation method of the atazanavir bisulfate crystal form H1. The method has the advantages of good repeatability, simple operation, high yield, high chromatographic purity, and applicability to industrial production.
The invention provides a preparation method of atazanavir bisulfate crystal form H1, which comprises the following steps: mixing the atazanavir bisulfate with a solvent, and stirring; the solvent is a mixed solvent of methanol, butanone and ethyl acetate.
Wherein, the atazanavir bisulfate can be atazanavir bisulfate which is conventional in the field, preferably a crystal form and/or an amorphous crystal form of the atazanavir bisulfate except the atazanavir bisulfate crystal form H1, more preferably one or more of the atazanavir bisulfate crystal form A, the atazanavir bisulfate crystal form II, the atazanavir bisulfate crystal form C, the atazanavir bisulfate crystal form E3, the atazanavir bisulfate crystal form B, the atazanavir bisulfate crystal form P and the atazanavir bisulfate amorphous crystal form A, and most preferably the atazanavir bisulfate crystal form A.
In the mixed solvent, the mass ratio of methanol to butanone to ethyl acetate is preferably 1:1: 5-1: 1:15, more preferably 1:1: 8.
said crystalline form of atazanavir bisulfate can be prepared according to methods known in the art, preferably according to patents WO2011027324, CN101565398, CN 1283188.
The mixing temperature is preferably 10 ℃ to 30 ℃.
The amount of the mixed solvent may be an amount conventionally used in the art as long as the dissolution of atazanavir bisulfate is not affected. Preferably, the mass ratio of the atazanavir bisulfate to the atazanavir bisulfate is 5: 1-8: 1, more preferably 8: 1.
the stirring temperature can be the conventional temperature in the field, preferably 10-30 ℃, and more preferably 20-25 ℃.
The stirring time can be conventional stirring time in the field, and is preferably 11-13 h, such as 12 h.
The preparation method can further comprise post-treatment, and the post-treatment can be conventional post-treatment in the field, preferably filtration, and washing of the product with butanone. The butanone may be used in amounts conventional in the art for such procedures.
The post-treatment can further comprise drying the product, wherein the drying can be conventional drying in the field, preferably vacuum drying, and the temperature of the vacuum drying can be conventional temperature in the field, preferably 50-55 ℃.
The present invention also provides a composition of atazanavir bisulfate form H1 comprising atazanavir bisulfate form H1 and methanol, wherein the methanol content is less than 0.16%, such as: 0.09% -0.16%.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The content of methanol in the present invention means a mass fraction.
In the atazanavir bisulfate form H1 composition of the invention, the content of methanol is not zero.
The positive progress effects of the invention are as follows: the preparation method has the advantages of good repeatability, simple and convenient operation, high yield, high chromatographic purity, suitability for being used as a medicament, suitability for industrial production and potential market value, and the obtained product methanol content meets the medicinal requirement.
Drawings
Figure 1 is an XRPD pattern of atazanavir bisulfate form H1 as obtained in example 1.
Figure 2 is an XRPD pattern of atazanavir bisulfate form H1 as disclosed in patent WO 2010079497.
Figure 3 is a DSC chart of atazanavir bisulfate form H1 prepared in example and comparative example 1.
Figure 4 is a DSC diagram of atazanavir bisulfate form H1 as disclosed in patent WO 2010079497.
Figure 5 is an XRPD pattern of atazanavir bisulfate form H1 prepared according to comparative examples 2-4.
Figure 6 is an XRPD pattern of atazanavir bisulfate form H1 prepared in comparative example 5.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The preparation method used in comparative example 1 in the examples of the present invention is a preparation method of atazanavir crystal form H1 disclosed in patent WO 2010079497.
Figures 2 and 4 of the drawings of the present invention are XRPD and DSC diagrams of atazanavir bisulfate form H1 disclosed in the cited patent WO 2010079497.
The invention relates to a powder X-diffraction testing instrument, which comprises the following models: bruker D8 advance, germany; and (3) testing conditions are as follows: voltage, Current 40Kv,40mA, Stand-End Position 0-40 degrees 2 theta, Increment 0.02 degrees 2 theta, Time per step 0.5s, test environment: 26 ℃ and a humidity of 44% RH.
The differential scanning calorimeter model number that the invention relates to is: TA Q200; the test method comprises the following steps: equulibrate at 20 deg.C, Ramp at 10.0 deg.C/min to 250.0 deg.C, N2Flow 40mL/min, aluminum pan, cover. Detecting the environment: at 25 ℃ and a humidity of 55% RH.
The methanol detection method of the invention comprises the following steps: HPLC column DB-624, 30m × 0.53mm × 3.0 μm; a detector FID; carrier gas N2(ii) a The column flow rate was 2.0 mL/min; hydrogen is 30 mL/min; air 300 mL/min; the temperature of a sample inlet is 200 ℃; the temperature of the detector is 250 ℃; the split ratio is 5: 1; the sample injection amount is 1 mL; GC cycle time 42 min; the column temperature is kept at 35 ℃ for 15min, the temperature is increased to 60 ℃ at 5 ℃/min for 5min, and then the temperature is increased to 220 ℃ at 30 ℃/min for 5 min.
Example 1: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 30g of methanol, 450g of ethyl acetate and 30g of butanone, stirred at room temperature for 12 hours, filtered and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 96.5%, HPLC purity: 98.86%, methanol content: 0.13 percent. XRPD is shown in figure 1, and DSC is shown in figure 3.
Example 2: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 50g of methanol, 500g of ethyl acetate and 50g of butanone, stirred at room temperature for 12 hours, filtered and the solid washed with 3.0g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.3%, HPLC purity: 99.13%, methanol content: 0.15 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 3: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered, and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.1%, HPLC purity: 99.92%, methanol content: 0.16 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 4: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 100g of methanol, 500g of ethyl acetate and 100g of butanone, stirred at room temperature for 12 hours, filtered and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 93.7%, HPLC purity: 99.93%, methanol content: 0.16 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 5: preparation of atazanavir bisulfate crystal form H1
To 10.0Kg of atazanavir bisulfate form A was added a mixed solution of 8.0Kg of methanol, 64.0Kg of ethyl acetate and 8.0Kg of butanone, stirred at room temperature for 12 hours, filtered, and the solid was washed with 3.0K butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.3%, HPLC purity: 99.93%, methanol content: 0.15 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 6: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form II was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 94.6%, HPLC purity: 99.89%, methanol content: 0.10 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 7: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form C was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered and the solid washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 94.8%, HPLC purity: 99.91%, methanol content: 0.11 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 8: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form E3 was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12h, filtered and the solid washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.2%, HPLC purity: 99.92%, methanol content: 0.10 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 9: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form B was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered and the solid washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.1%, HPLC purity: 99.92%, methanol content: 0.14 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 10: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form P was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered and the solid washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.3%, HPLC purity: 99.90%, methanol content: 0.09 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Example 11: preparation of atazanavir bisulfate crystal form H1
To 100g of amorphous form of atazanavir bisulfate was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12h, filtered and the solid washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 93.9%, HPLC purity: 99.88%, methanol content: 0.16 percent. XRPD is the same as that in FIG. 1, and DSC is the same as that in FIG. 3.
Comparative example 1: preparation of atazanavir bisulfate crystal form H1
Adding 500g methanol into 100g atazanavir bisulfate, stirring at room temperature for 20min to dissolve, maintaining at room temperature, dropwise adding 3000g ethyl acetate, stirring at room temperature for 30min after dropwise adding, filtering, and washing the solid with 300g ethyl acetate. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain 695g of white-like solid. Yield 29.1%, HPLC purity: 99.94%, methanol content: 1.13 percent. XRPD is shown in figure 1, and DSC is shown in figure 3.
Comparative example 2: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of acetone, stirred at room temperature for 12 hours, filtered, and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 95.9%, HPLC purity: 99.76%, methanol content: 0.15 percent. The XRPD is the same as that in figure 5, and the obtained product has incorrect crystal form.
Comparative example 3: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 80g of methanol, 640g of ethyl acetate and 80g of methyl butyl ketone, stirred at room temperature for 12 hours, filtered, and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 91.3%, HPLC purity: 99.79%, methanol content: 0.17 percent. The XRPD is the same as that in figure 5, and the obtained crystal form of the product is different from the H1 crystal form.
Comparative example 4: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 80g of methanol, 640g of methyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered, and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 90.2%, HPLC purity: 99.83%, methanol content: 0.39 percent. The XRPD is the same as that in figure 5, and the obtained crystal form of the product is different from the H1 crystal form.
Comparative example 5: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 80g of methanol, 640g of isopropyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered and the solid washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 83.6%, HPLC purity: 99.89%, methanol content: 0.23 percent. The XRPD is the same as that in figure 5, and the obtained crystal form of the product is different from the H1 crystal form.
Comparative example 6: preparation of atazanavir bisulfate crystal form H1
To 100g of atazanavir bisulfate form A was added a mixed solution of 80g of ethanol, 640g of ethyl acetate and 80g of butanone, stirred at room temperature for 12 hours, filtered, and the solid was washed with 30g of butanone. And (3) drying the obtained product at 50-55 ℃ for 8.0h in vacuum to obtain a white-like solid. Yield 89.3%, HPLC purity: 99.86 percent. The XRPD is the same as that in figure 6, and the obtained crystal form of the product is different from the H1 crystal form.
The samples prepared according to the methods of examples 1-11 and comparative example were tested, and the results are shown in Table 1
Table 1: test results of samples obtained in examples 1 to 11 and comparative examples 1 to 6
| Sample source | Yield of | HPLC purity | Methanol content (%) | XRPD | DSC |
| Example 1 | 96.5％ | 98.86％ | 0.13％ | See FIG. 1 | See FIG. 3 |
| Example 2 | 95.3％ | 99.13％ | 0.15％ | See FIG. 1 | See FIG. 3 |
| Example 3 | 95.1％ | 99.92％ | 0.16％ | See FIG. 1 | See FIG. 3 |
| Example 4 | 93.7％ | 99.93％ | 0.16％ | See FIG. 1 | See FIG. 3 |
| Example 5 | 95.3％ | 99.93％ | 0.15％ | See FIG. 1 | See FIG. 3 |
| Example 6 | 94.6％ | 99.89％ | 0.10％ | See FIG. 1 | See FIG. 3 |
| Example 7 | 94.8％ | 99.91％ | 0.11％ | See FIG. 1 | See FIG. 3 |
| Example 8 | 95.2％ | 99.92％ | 0.10％ | See FIG. 1 | See FIG. 3 |
| Example 9 | 95.1％ | 99.92％ | 0.14％ | See FIG. 1 | See FIG. 3 |
| Example 10 | 95.3％ | 99.90％ | 0.09％ | See FIG. 1 | See FIG. 3 |
| Example 11 | 93.9％ | 99.88％ | 0.16％ | See FIG. 1 | See FIG. 3 |
| Comparative example 1 | 29.1％ | 99.94％ | 1.13％ | See FIG. 1 | See FIG. 3 |
| Comparative example 2 | 95.9％ | 99.76％ | 0.15％ | See FIG. 5 | N/A |
| Comparative example 3 | 91.3％ | 99.79％ | 0.17％ | See FIG. 5 | N/A |
| Comparative example 4 | 90.2％ | 99.83％ | 0.39％ | See FIG. 5 | N/A |
| Comparative example 5 | 83.6％ | 99.89％ | 0.23％ | See FIG. 5 | N/A |
| Comparative example 6 | 89.3％ | 99.86％ | N/A | See FIG. 6 | N/A |
Wherein N/A represents that the crystal form of the product is incorrect.
As can be seen from Table 1, the atazanavir bisulfate crystal form obtained by the two methods of the invention and the comparative example 1 has higher HPLC purity, and the results of XRPD pattern and DSC pattern show that the crystal form is consistent. However, the yield of the atazanavir bisulfate crystal form H1 prepared by the method is 93.7-96.5%, while the yield of the atazanavir bisulfate crystal form H1 prepared by the comparative example 1 is only about 29.1%, and the yield of the method is obviously higher than that of the comparative example 1 (the method disclosed by the patent WO 2010079497); the content of methanol in the atazanavir bisulfate crystal form H1 prepared by the method is 0.09-0.16 percent and is obviously lower than the pharmacopeia standard (0.30 percent), while the content of methanol in the atazanavir bisulfate crystal form H1 prepared by the comparative example 1 is 1.13 percent and is higher than the pharmacopeia standard, thus not meeting the medicinal requirements. In addition, as can be seen from examples 5 to 11, all of the atazanavir bisulfate crystal forms are suitable for the preparation process.
Meanwhile, according to comparative examples 2-6, the crystal form of the product is not correct after the mixed solvent is changed.
Claims (8)
1. A process for the preparation of atazanavir bisulfate form H1 comprising the steps of: mixing the atazanavir bisulfate with a solvent, and stirring; the solvent is a mixed solvent of methanol, butanone and ethyl acetate; the mass ratio of methanol to butanone to ethyl acetate in the mixed solvent is 1:1: 5-1: 1: 15; the mass ratio of the mixed solvent to the atazanavir bisulfate is 5: 1-8: 1.
2. The process of claim 1, wherein the atazanavir bisulfate is in a crystalline and/or amorphous form of atazanavir bisulfate other than atazanavir bisulfate form H1.
3. The process of claim 2, wherein the form of atazanavir bisulfate is one or more of form a of atazanavir bisulfate, form II of atazanavir bisulfate, form C of atazanavir bisulfate, form E3 of atazanavir bisulfate, form B of atazanavir bisulfate, form P of atazanavir bisulfate, and amorphous form of atazanavir bisulfate.
4. The process of claim 3, wherein the crystalline form of atazanavir bisulfate is atazanavir bisulfate form A.
5. The method of claim 1, wherein the mixing is at a temperature of 10 ℃ to 30 ℃.
6. The method according to claim 1, wherein the stirring temperature is 10 to 30 ℃.
7. The preparation method according to claim 1, wherein the stirring time is 11 to 13 hours.
8. The process of claim 1 further comprising a post-treatment, wherein the post-treatment is filtration and the product is washed with methyl ethyl ketone.
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