CN109251165B - Atazanavir darby 4-aminobenzenesulfonate and preparation method thereof - Google Patents
Atazanavir darby 4-aminobenzenesulfonate and preparation method thereof Download PDFInfo
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- 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
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- 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 atazanavir darby 4-aminobenzenesulfonic acid salt and a preparation method thereof, wherein the molar ratio of atazanavir to 4-aminobenzenesulfonic acid in the atazanavir di 4-aminobenzenesulfonic acid salt is 1:2, and the atazanavir darby 4-aminobenzenesulfonic acid salt has the advantage of improving the solubility.
Description
Technical Field
The invention relates to atazanavir darby 4-aminobenzenesulfonate and a preparation method thereof.
Background
Atazanavir sulfate, marketed as ryastaz, was first marketed in the united states in 6 months in 2003, primarily in combination with other antiretroviral drugs for the treatment of HIV infection. Atazanavir sulfate is a novel azapeptide Protease Inhibitor (PI), which is a highly selective and efficient inhibitor of HIV-1 protease, and inhibits the production of viral structural proteins, reverse transcriptase, integrase and protease by blocking the cleavage of the viral gap and gap-pol precursor polyprotein, resulting in the release of non-infectious immature viral particles from HIV-1 infected cells.
It was found that atazanavir sulfate is practically insoluble in water.
Disclosure of Invention
The first purpose of the invention is to provide atazanavir di-4-aminobenzenesulfonate which has the advantage of improving the solubility.
The technical purpose of the invention is realized by the following technical scheme:
atazanavir di-4-aminobenzenesulfonate having the following structural formula:
by adopting the technical scheme, the solubility is improved, and the absorption is facilitated.
More preferably: the atazanavir di-4-aminobenzenesulfonate is of an A crystal form; the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at diffraction angles 2 theta of 5.5 +/-0.2 degrees, 7.5 +/-0.2 degrees, 10.2 +/-0.2 degrees, 13.4 +/-0.2 degrees and 15.3 +/-0.2 degrees by using Cu-Kalpha radiation.
By adopting the technical scheme, the crystal form and the salt form are stable.
More preferably: by using Cu-Kalpha radiation, an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at diffraction angles 2 theta of 3.6 +/-0.2 degrees, 5.5 +/-0.2 degrees, 7.5 +/-0.2 degrees, 10.2 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.4 +/-0.2 degrees, 15.3 +/-0.2 degrees and 20.1 +/-0.2 degrees.
More preferably: using Cu-ka radiation, the diffraction angles 2 θ and their relative intensities of the X-ray powder diffraction patterns of form a are as follows:
the second purpose of the invention is to provide a preparation method of atazanavir di-4-aminobenzenesulfonate.
The technical purpose of the invention is realized by the following technical scheme:
the preparation method of atazanavir di-4-aminobenzenesulfonate comprises the following steps:
(1) pretreatment of atazanavir
Taking an atazanavir raw material, adding ethanol and water, heating to 50-55 ℃ under stirring, preserving heat for 1-3 hours, putting into an ice water bath, cooling for 10-20 min, filtering to obtain a solid, and drying at 35-45 ℃; the mass of the atazanavir raw material, the volume of the ethanol and the volume of the water are in a ratio of 10mg: 2-4 ml;
(2) salt formation
Preparation of atazanavir aqueous suspension
Adding water into the atazanavir treated in the step (1), and uniformly stirring to obtain an atazanavir water suspension; the mass of the atazanavir and the volume ratio of water are 1mg: 2-4 ml;
preparation of aqueous solution of 4-aminobenzenesulfonic acid
Adding water into 4-aminobenzenesulfonic acid, and uniformly stirring to obtain a 4-aminobenzenesulfonic acid aqueous solution; the mass ratio of the 4-aminobenzenesulfonic acid to the water is 1mg: 2-4 ml;
preparation of sodium bicarbonate aqueous solution
Adding water into sodium bicarbonate, and stirring and uniformly mixing to obtain a sodium bicarbonate aqueous solution; the mass ratio of the sodium bicarbonate to the water is 1: 0.5-1.0 ml;
fourthly, salifying reaction
Adding the aqueous solution of sodium bicarbonate prepared in the third step into the aqueous suspension of atazanavir prepared in the first step, stirring and uniformly mixing, heating to 40-45 ℃ under stirring, slowly adding the aqueous solution of 4-aminobenzene sulfonic acid prepared in the second step, cooling to room temperature after complete reaction, preserving heat at room temperature for 1-3 hours, filtering to obtain filtrate, concentrating at 0-40 ℃ to remove the solvent completely, and obtaining atazanavir di-4-aminobenzene sulfonate; the molar ratio of the atazanavir to the 4-aminobenzenesulfonic acid to the sodium bicarbonate is 1.5-2.5: 1: 0.05-0.08;
after-treatment
Adding ethanol into the atazanavir di-4-aminobenzenesulfonate obtained in the step (iv), stirring, filtering to obtain filtrate, concentrating at 0-40 ℃ to remove the solvent completely, and obtaining atazanavir di-4-aminobenzenesulfonate; the mass ratio of the atazanavir di-4-aminobenzenesulfonate to the volume of the ethanol is 1mg: 6-10 ml;
the steps are carried out at room temperature except for special notes, and the room temperature is 20-30 ℃.
By adopting the technical scheme, the technical problem that the atazanavir and the 4-aminobenzenesulfonic acid salt are difficult to form salt in ethanol is solved, the salt is formed in the ethanol, the introduction of other organic solvents is reduced, and the safety is improved.
More preferably: in the fourth step, the 4-aminobenzene sulfonic acid aqueous solution is slowly added into the reaction system through a peristaltic pump, and the adding speed is 45-55 mul/min.
In conclusion, the invention has the following beneficial effects: the solubility in water and simulated gastric juice is greatly improved, and the absorption by a human body is facilitated; the stability in a high-temperature test, a high-humidity test or a strong illumination test is equivalent to that of the prior art; the salt forming process is changed, the technical problem that the atazanavir and the 4-aminobenzenesulfonic acid salt are difficult to form the salt in the ethanol is solved, the salt is formed in the ethanol, the introduction of other organic solvents is reduced, and the safety is improved.
Drawings
Figure 1 is an XPRD pattern of atazanavir bis 4-aminobenzenesulfonate form a.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
The present embodiment is only for explaining the present invention, and it is not limited to the present invention, and those skilled in the art can make modifications without inventive contribution to the present embodiment as needed after reading the present specification, but all of them are protected by patent law within the scope of the present invention.
The detection instrument and the method comprise the following steps:
the instrument used for X-ray powder diffraction (XPRD) was a Bruker D8Advance diffractometer, using Kalpha X-rays with a copper target wavelength of 1.54nm, under operating conditions of 40kV and 40mA, a theta-2 theta goniometer, a Mo monochromator, a Lynxeye detector. The instrument was examined with corundum prior to use. The acquisition software was a Diffrac Plus XRD Commander. The sample is tested at room temperature, and the sample to be tested is placed on a silicon phosphide sheet. The detailed detection conditions are as follows, the angle ranges: 3-40 ° 2 θ, step size: 0.02 ° 2 θ, speed: step-1, 0.2s. Unless otherwise specified, the samples were not ground prior to testing.
Preparation example: atazanavir starting material, prepared according to example 3 of CN107021919A, with a purity of 98.3%.
Example 1: atazanavir di-4-aminobenzenesulfonate prepared by the following method:
(1) pretreatment of atazanavir
Adding ethanol and water into atazanavir, heating to 52 deg.C under stirring, holding for 2hr, cooling in ice water bath for 15min, filtering to obtain solid, and oven drying at 40 deg.C (air drying); the mass of the atazanavir raw material, the volume of the ethanol and the volume of the water are in a ratio of 10mg to 3 ml;
(2) salt formation
Preparation of atazanavir aqueous suspension
Adding water into the atazanavir treated in the step (1), and uniformly stirring to obtain an atazanavir water suspension; the mass of atazanavir and the volume ratio of water are 1mg: 3 ml;
preparation of aqueous solution of 4-aminobenzenesulfonic acid
Adding water into 4-aminobenzenesulfonic acid, and uniformly stirring to obtain a 4-aminobenzenesulfonic acid aqueous solution; the mass ratio of the 4-aminobenzenesulfonic acid to the water is 1mg: 3 ml;
preparation of sodium bicarbonate aqueous solution
Adding water into sodium bicarbonate, and stirring and uniformly mixing to obtain a sodium bicarbonate aqueous solution; the mass ratio of the sodium bicarbonate to the water is 1: 0.8 ml;
fourthly, salifying reaction
Adding the aqueous solution of sodium bicarbonate prepared in the third step into the aqueous suspension of atazanavir prepared in the first step, uniformly stirring, heating to 42 ℃ under stirring, slowly adding the aqueous solution of 4-aminobenzenesulfonic acid prepared in the second step through a peristaltic pump (the adding speed is 50 mu l/min), cooling to room temperature after complete reaction, preserving heat at room temperature for 2 hours, filtering to obtain filtrate, concentrating (nitrogen blowing method) at 25 ℃ to remove the solvent to obtain atazanavir di-4-aminobenzenesulfonic acid salt; the molar ratio of the atazanavir, the 4-aminobenzenesulfonic acid and the sodium bicarbonate is 2.0: 1: 0.06;
fifthly, after-treatment
Adding ethanol into the atazanavir di-4-aminobenzenesulfonate obtained in the step (IV), stirring, filtering to obtain filtrate, concentrating (nitrogen blowing method) at 25 ℃ to remove the solvent to obtain atazanavir di-4-aminobenzenesulfonate; the mass ratio of the atazanavir di-4-aminobenzenesulfonate to the volume of the ethanol is 1mg: 8 ml;
the above steps are carried out at room temperature, 25 ℃ unless otherwise noted.
The XRPD pattern of atazanavir bis 4-aminobenzenesulfonate of example 1 is shown in figure 1 as form a; determining salification through nuclear magnetic identification, wherein the molar ratio of the atazanavir to the 4-aminobenzenesulfonic acid in the atazanavir di-4-aminobenzenesulfonic acid salt is 1: 2; the purity by HPLC analysis was 99.5%, and no organic solvent residue was detected.
Example 2: atazanavir di-4-aminobenzenesulfonate prepared by the following method:
(1) pretreatment of atazanavir
Adding ethanol and water into atazanavir, heating to 50 deg.C under stirring, maintaining the temperature for 3hr, cooling in ice water bath for 20min, filtering to obtain solid, and oven drying at 35 deg.C (air blast drying); the mass of the atazanavir raw material, the volume of the ethanol and the volume of the water are in a ratio of 10mg to 2 ml;
(2) salt formation
Preparation of atazanavir aqueous suspension
Adding water into the atazanavir treated in the step (1), and uniformly stirring to obtain an atazanavir water suspension; the mass of the atazanavir and the volume ratio of water are 1mg:2 ml;
preparation of aqueous solution of 4-aminobenzenesulfonic acid
Adding water into 4-aminobenzenesulfonic acid, and uniformly stirring to obtain a 4-aminobenzenesulfonic acid aqueous solution; the mass ratio of the 4-aminobenzenesulfonic acid to the water is 1mg:2 ml;
preparation of sodium bicarbonate aqueous solution
Adding water into sodium bicarbonate, and stirring and uniformly mixing to obtain a sodium bicarbonate aqueous solution; the mass ratio of the sodium bicarbonate to the water is 1:0.5 ml;
fourthly, salifying reaction
Adding the aqueous solution of sodium bicarbonate prepared in the third step into the aqueous suspension of atazanavir prepared in the first step, uniformly stirring, heating to 40 ℃ under stirring, slowly adding the aqueous solution of 4-aminobenzenesulfonic acid prepared in the second step through a peristaltic pump (the adding speed is 45 mu l/min), cooling to room temperature after complete reaction, preserving heat at room temperature for 3 hours, filtering to obtain filtrate, concentrating (nitrogen blowing method) at 0 ℃ to remove the solvent to obtain atazanavir di-4-aminobenzenesulfonic acid salt; the molar ratio of the atazanavir, the 4-aminobenzenesulfonic acid and the sodium bicarbonate is 1.5: 1: 0.05;
after-treatment
Adding ethanol into the atazanavir di-4-aminobenzenesulfonate obtained in the step IV, stirring, filtering to obtain filtrate, concentrating at 0 ℃ (nitrogen blowing method) to remove the solvent to obtain atazanavir di-4-aminobenzenesulfonate; the mass ratio of the atazanavir di-4-aminobenzenesulfonate to the volume of the ethanol is 1mg:6 ml;
the above steps are carried out at room temperature of 20 ℃ except for special indications.
The XRPD assay of atazanavir bis 4-aminobenzenesulfonate of example 2 was identified as form a; determining salification through nuclear magnetic identification, wherein the molar ratio of the atazanavir to the 4-aminobenzenesulfonic acid in the atazanavir di-4-aminobenzenesulfonic acid salt is 1: 2; the purity by HPLC analysis was 99.2%, and no organic solvent residue was detected.
Example 3: atazanavir di-4-aminobenzenesulfonate prepared by the following method:
(1) pretreatment of atazanavir
Adding ethanol and water into atazanavir, heating to 55 deg.C under stirring, maintaining the temperature for 1hr, cooling in ice water bath for 10min, filtering to obtain solid, and oven drying at 45 deg.C (air blast drying); the mass of the atazanavir raw material, the volume of the ethanol and the volume of the water are in a ratio of 10mg to 4 ml;
(2) salt formation
Preparation of atazanavir aqueous suspension
Adding water into the atazanavir treated in the step (1), and uniformly stirring to obtain an atazanavir water suspension; the mass of the atazanavir and the volume ratio of water are 1mg: 4 ml;
preparation of aqueous solution of 4-aminobenzenesulfonic acid
Adding water into 4-aminobenzenesulfonic acid, and uniformly stirring to obtain a 4-aminobenzenesulfonic acid aqueous solution; the mass ratio of the 4-aminobenzenesulfonic acid to the water is 1mg: 4 ml;
preparation of sodium bicarbonate aqueous solution
Adding water into sodium bicarbonate, and stirring and uniformly mixing to obtain a sodium bicarbonate aqueous solution; the mass ratio of the sodium bicarbonate to the water is 1: 1.0 ml;
fourthly, salifying reaction
Adding the aqueous solution of sodium bicarbonate prepared in the third step into the aqueous suspension of atazanavir prepared in the first step, uniformly stirring, heating to 45 ℃ under stirring, slowly adding the aqueous solution of 4-aminobenzenesulfonic acid prepared in the second step through a peristaltic pump (the adding speed is 55 mu l/min), cooling to room temperature after complete reaction, preserving heat at room temperature for 3 hours, filtering to obtain filtrate, concentrating (rotary evaporation method) at 40 ℃ to remove the solvent to obtain atazanavir di-4-aminobenzenesulfonic acid salt; the molar ratio of the atazanavir, the 4-aminobenzenesulfonic acid and the sodium bicarbonate is 2.5:1: 0.08;
fifthly, after-treatment
Adding ethanol into the atazanavir di-4-aminobenzenesulfonate obtained in the step (IV), stirring, filtering to obtain filtrate, concentrating (rotary evaporation method) at 40 ℃ to remove the solvent to obtain the atazanavir di-4-aminobenzenesulfonate; the mass ratio of the atazanavir di-4-aminobenzenesulfonate to the volume of the ethanol is 1mg: 10 ml;
the above steps are carried out at room temperature of 30 ℃ except for special indications.
The XRPD assay of atazanavir bis 4-aminobenzenesulfonate of example 3 was identified as form a; determining salification through nuclear magnetic identification, wherein the molar ratio of the atazanavir to the 4-aminobenzenesulfonic acid in the atazanavir di-4-aminobenzenesulfonic acid salt is 1: 2; the purity by HPLC analysis was 99.3%, and no organic solvent residue was detected.
Comparative example:
preparation of atazanavir aqueous suspension: taking an atazanavir raw material, adding water, and uniformly stirring to obtain an atazanavir water suspension; the mass of the atazanavir and the volume ratio of water are 1mg: 3 ml;
preparing an aqueous solution of 4-aminobenzene sulfonic acid: adding water into 4-aminobenzenesulfonic acid, and uniformly stirring to obtain a 4-aminobenzenesulfonic acid aqueous solution; the mass ratio of the 4-aminobenzenesulfonic acid to the water is 1mg: 3 ml;
③ salifying reaction: adding the aqueous solution of 4-aminobenzene sulfonic acid prepared in the step II into the aqueous suspension of atazanavir prepared in the step I, and stirring and reacting for 10 hours at the temperature of 40 ℃; the molar ratio of the atazanavir to the 4-aminobenzenesulfonic acid is 2.0: 1;
the salt is not formed by nuclear magnetic identification.
Solubility test
1. Test samples: atazanavir bis-4-aminobenzenesulfonate prepared in examples 1-3, atazanavir prepared in the preparation examples, and controls.
Control 1: atazanavir sulfate, prepared according to CN104163787A, example 6, was 98.3% pure.
Control 2: atazanavir fumarate, prepared as in example 1 of CN104250224A, purity 98.7%.
Control 3: atazanavir phosphate, prepared according to CN104250225A example 1, with a purity of 98.5%.
2. The test method comprises the following steps: placing m (generally 50mg) test samples into a glass bottle, gradually adding a solvent (the 1 st addition is 100 mu l, the 2 nd addition is 100 mu l, the 3 rd addition is 200 mu l, the Nth addition is the sum of the amounts of all the solvents, and if the solvent is not completely dissolved, the last addition is 5000ml), closing the glass bottle after each addition of the solvent, placing the glass bottle into constant-temperature ultrasonic waves for ultrasonic treatment for 60s or till the solvent is completely dissolved, recording the amount v of the solvent used for dissolving the solvent, and recording the solubility x in the solvent at the temperature as m/v.
The simulated gastric juice is prepared according to Chinese pharmacopoeia, namely: taking 16.4ml of dilute hydrochloric acid (equivalent to 3.84ml of hydrochloric acid), adding about 800ml of water and 10g of pepsin, shaking up, and adding water to dilute to 1000 ml.
3. And (3) testing results: as shown in table 1. Table 1 shows: the solubility of the preparation examples and the reference products 1-3 is less than 0.01mg/ml in 25 ℃/pure water, 37 ℃/pure water, 25 ℃/simulated gastric fluid or 37 ℃/simulated gastric fluid, while the solubility of the examples 1-3 is greatly improved.
TABLE 1 solubility test (unit: mg/ml)
Stability test
1. Test samples: atazanavir bis-4-aminobenzenesulfonate prepared in examples 1-3, atazanavir prepared in the preparation examples, and controls.
Control 3: atazanavir phosphate, prepared according to example 1 of CN104250225A, with a purity of 98.5%.
2. The test method comprises the following steps: a30 mg sample is placed in a glass bottle, the glass bottle is placed in a certain placing environment in an open mode, and the purity of the glass bottle is tested after the glass bottle is placed for a period of time. Groups of 3 were tested in parallel and the average was taken.
3. And (3) testing results: as shown in table 2. Table 2 shows: in the high temperature test, the high humidity test or the high light test, the purity of the reference substance 3 is reduced to a certain degree, while the purities of the preparation examples and the examples 1-3 are not changed basically (the change value is within the error range of HPLC), which shows that the examples 1-3 and the preparation examples are stable in the high temperature test, the high humidity test or the high light test, and the stability of the examples 1-3 is equivalent to that of the prior art.
TABLE 2 stability test
It should be understood, however, that the description herein of specific embodiments is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
Claims (1)
1. Atazanavir di-4-aminobenzenesulfonate has the following structural formula:
the atazanavir di-4-aminobenzenesulfonate is obtained by the following preparation method, and comprises the following steps:
(1) pretreatment of atazanavir
Taking an atazanavir raw material, adding ethanol and water, heating to 50-55 ℃ under stirring, preserving heat for 1-3 hours, putting into an ice water bath, cooling for 10-20 min, filtering to obtain a solid, and drying at 35-45 ℃; the mass of the atazanavir raw material, the volume of the ethanol and the volume ratio of the water are 10mg: 2-4 ml;
(2) salt formation
Preparation of atazanavir aqueous suspension
Adding water into the atazanavir treated in the step (1), and uniformly stirring to obtain an atazanavir water suspension; the mass of the atazanavir and the volume ratio of the water are 1mg: 2-4 ml;
preparation of aqueous solution of 4-aminobenzenesulfonic acid
Adding water into 4-aminobenzenesulfonic acid, and uniformly stirring to obtain a 4-aminobenzenesulfonic acid aqueous solution; the volume ratio of the mass of the 4-aminobenzenesulfonic acid to the volume of water is 1mg: 2-4 ml;
preparation of sodium bicarbonate aqueous solution
Adding water into sodium bicarbonate, and stirring and uniformly mixing to obtain a sodium bicarbonate aqueous solution; the mass ratio of the sodium bicarbonate to the water is 1: 0.5-1.0 ml;
fourthly, salifying reaction
Adding the aqueous solution of sodium bicarbonate prepared in the third step into the aqueous suspension of atazanavir prepared in the first step, stirring and uniformly mixing, heating to 40-45 ℃ under stirring, slowly adding the aqueous solution of 4-aminobenzenesulfonic acid prepared in the second step, cooling to room temperature after complete reaction, preserving heat at room temperature for 1-3 hours, filtering to obtain filtrate, concentrating at 0-40 ℃ to remove the solvent completely, and obtaining atazanavir di-4-aminobenzenesulfonic acid salt; the molar ratio of the atazanavir to the 4-aminobenzenesulfonic acid to the sodium bicarbonate is 1.5-2.5: 1: 0.05-0.08;
in the fourth step, slowly adding the 4-aminobenzene sulfonic acid aqueous solution into the reaction system by a peristaltic pump at the adding speed of 45-55 mul/min;
fifthly, after-treatment
Adding ethanol into the atazanavir di-4-aminobenzenesulfonate obtained in the step (iv), stirring, filtering to obtain filtrate, concentrating at 0-40 ℃ to remove the solvent completely, and obtaining atazanavir di-4-aminobenzenesulfonate; the mass ratio of the atazanavir di-4-aminobenzenesulfonate to the volume of the ethanol is 1mg: 6-10 ml;
the steps are carried out at room temperature except for special notes, and the room temperature is 20-30 ℃;
the atazanavir di-4-aminobenzenesulfonate is of an A crystal form;
using Cu-ka radiation, the diffraction angles 2 θ and their relative intensities for the X-ray powder diffraction pattern of form a are as follows:
。
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|---|---|
| CN109251165A (en) | 2019-01-22 |
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