CN106432197B - Ledipasvir intermediate mono-p-toluenesulfonate, crystal form and preparation method thereof - Google Patents
Ledipasvir intermediate mono-p-toluenesulfonate, crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention discloses ledipasvir intermediate mono-p-toluenesulfonate, a crystal form and a preparation method thereof. The crystal form A prepared by the preparation method provided by the invention has good chemical purity and product quality, and the preparation method is simple and rapid and is convenient for large-scale production. Meanwhile, the crystal form A has very high purity and is particularly suitable for being used as an intermediate for producing Ledipasvir, so that the quality of a final product Ledipasvir is improved, and impurities are reduced.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to mono-p-toluenesulfonate of a Ledipasvir intermediate, a crystal form and an amorphous substance thereof, and a preparation method and application thereof.
Background
Ledipasvir (LDV) is a hepatitis c therapeutic drug developed by Gilead and the FDA has granted a breakthrough therapy for LDV/sof (sofosbuvir) fixed dose combination drugs that is expected to cure genotype 1HCV patients in as little as 8 weeks without the need for interferon injection or Ribavirin (Ribavirin).
Chinese patent application (CN2015101179973) discloses a synthetic route of ledipasvir, a compound of formula II is a key intermediate, and the compound of formula II has great influence on the subsequent reaction and the quality of the final product, ledipasvir.
Due to the characteristics of a molecular structure, the compound shown in the formula II has poor crystallinity, and a crystal form needs to be obtained in a salifying mode, so that important means for improving the crystallization performance of the compound, removing impurities and improving the product quality can be realized.
Therefore, there is an urgent need in the art to develop a high purity intermediate useful as a synthetic route to ledipasvir, particularly a crystalline solid form thereof, in order to improve the purity and quality of the final product (ledipasvir).
Disclosure of Invention
the invention aims to provide a high-purity intermediate particularly suitable for producing Ledipasvir, and preparation and application thereof.
In a first aspect of the invention, there is provided a p-toluenesulfonate salt of a compound of formula II
in another preferred embodiment, the p-toluenesulfonate salt is according to formula I,
In another preferred embodiment, the p-toluenesulfonate salt is in crystalline form or amorphous form.
in another preferred embodiment, the purity of the p-toluenesulfonate salt is 99.0% or more, preferably 99.2% or more, more preferably 99.5% or more, most preferably 99.9% or more.
In another preferred embodiment, the crystalline form of the p-toluenesulfonic acid salt is form a, and the X-ray powder diffraction pattern of form a comprises 3 or more 2 θ values selected from the group consisting of: 4.9 +/-0.2 degrees, 8.2 +/-0.2 degrees, 10.0 +/-0.2 degrees, 13.7 +/-0.2 degrees, 13.9 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.6 +/-0.2 degrees, 21.9 +/-0.2 degrees and 24.2 +/-0.2 degrees.
In another preferred embodiment, the form a has an X-ray powder diffraction pattern comprising 3 or more 2 θ values selected from the group consisting of: 4.9 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 10.0 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees and 20.8 degrees +/-0.2 degrees.
In another preferred embodiment, the form a has one or more characteristics selected from the group consisting of:
(1) The form a has X-ray powder diffraction data selected from table 1;
(2) The form a has an X-ray powder diffraction pattern substantially as characterized in figure 1;
(3) The initial temperature of the differential scanning calorimetry analysis pattern of the crystal form A is 140.91 +/-3 ℃;
(4) The peak temperature of the differential scanning calorimetry analysis chart of the crystal form A is 157.65 +/-3 ℃;
(5) A differential scanning calorimetry analysis profile of form a substantially as characterized in figure 2;
(6) The thermogravimetric analysis profile of form a is substantially as characterized in figure 3; and/or
(7) The crystal form A is mono-p-toluenesulfonate.
In a second aspect of the present invention, there is provided a process for the preparation of a p-toluenesulfonate salt according to the first aspect of the present invention, which is an amorphous form, comprising the steps of:
(a) Reacting the compound of formula II with p-toluenesulfonic acid in a solvent at 0-50 ℃ to produce an amorphous form of the p-toluenesulfonic acid salt of the compound of formula II.
In another preferred embodiment, in the step (a), the solvent is selected from the group consisting of: toluene, acetone, ethanol, tetrahydrofuran, acetonitrile, or combinations thereof.
In another preferred embodiment, the molar ratio of the compound of formula II to p-toluenesulfonic acid is from 1:0.5 to 1:1.5, preferably 1: 1-1: 1.2.
In another preferred embodiment, in the step (a), the reaction temperature is 4 to 35 ℃, more preferably 10 to 25 ℃.
In another preferred embodiment, in the step (a), the reaction time is 0.1 to 24 hours, preferably 0.2 to 20 hours, and more preferably 0.5 to 10 hours.
In a third aspect of the present invention, there is provided a process for the preparation of the p-toluenesulfonate salt of the first aspect of the present invention which is form a comprising the steps of:
(1) Dissolving the amorphous material prepared by the method of the second aspect of the present invention in a solvent at a temperature of 4-30 ℃, wherein the weight/volume ratio of the amorphous material to the solvent is 10-1000mg/ml (preferably 50-800mg/ml, more preferably 80-600mg/ml, most preferably 120-400 mg/ml);
(2) and (3) standing the solution obtained in the previous step for 1-72 hours (preferably 5-36 hours), and filtering and crystallizing to obtain the crystal form A of the p-toluenesulfonic acid salt.
in another preferred embodiment, in the step (1), the solvent is selected from the group consisting of: toluene, acetone, ethanol, tetrahydrofuran, acetonitrile, or combinations thereof.
In another preferred example, between the step (1) and the step (2), the method further comprises a step (2-1):
Adding seed crystals to the solution obtained in the step (1), wherein the weight percentage of the seed crystals to the compound of the formula I is 0.1-10%.
In another preferred example, in the step (2-1), the preparation method of the seed crystal includes the steps of:
(1) Dissolving the amorphous substance prepared by the method of the second aspect of the present invention in a solvent at 4-30 ℃, wherein the weight/volume ratio of the compound of formula I to the solvent is 10-1000mg/ml (preferably 50-800mg/ml, more preferably 80-600mg/ml, most preferably 120-400 mg/ml);
(2) standing the solution obtained in the step (1) for 1 to 72 hours (preferably 5 to 36 hours), and filtering the crystals to obtain the p-toluenesulfonate seeds.
in a fourth aspect of the present invention, there is provided the use of a compound of formula I as described in the first aspect of the present invention for the manufacture of a medicament for the prophylaxis and/or treatment of Hepatitis C (HCV).
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows an X-ray powder diffraction pattern (XRPD) of form A of the p-toluenesulfonate salt of the present invention.
FIG. 2 shows a Differential Scanning Calorimetry (DSC) spectrum of form A of the p-toluenesulfonate salt of the present invention.
figure 3 shows a thermogravimetric analysis (TGA) of crystalline form a of the p-toluenesulfonate of the present invention.
Detailed Description
The inventor of the invention unexpectedly discovers a salt-type amorphous substance and a crystal form A of an important intermediate for producing Ledipasvir, particularly the crystal form A is easy to prepare, contributes to reducing impurities and is more beneficial to improving the quality of the product Ledipasvir, through extensive and intensive research. The present invention has been completed based on this finding.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
A compound of formula I
As used herein, the terms "compound of formula I", "p-toluenesulfonate" are used interchangeably, i.e. the p-toluenesulfonate salt of the compound of formula II, including its amorphous or crystalline forms.
As used herein, the terms "crystal of the present invention", "crystal form of the compound of formula I", "crystal form of p-toluenesulfonate", used interchangeably, all refer to p-toluenesulfonate of the compound of formula II, i.e. crystal form a of the compound of formula I.
Preparation method
The invention provides a preparation method of amorphous or crystal form of a compound shown in formula I.
the crystal form is preferably prepared in the invention because the crystal form has higher purity (such as more than or equal to 99 percent), and the crystal form is used as a raw material of Ledipasvir.
In another preferred embodiment, the crystalline form is prepared by preparing an amorphous form of the compound of formula I, for example, one skilled in the art can refer to the teachings of the present invention to prepare an amorphous form of the compound of formula I, and then using the amorphous form as a starting material for preparing the crystalline form of the compound of formula I, thereby obtaining a crystalline product, such as form a.
in another preferred embodiment, the crystalline form is prepared by reacting a compound of formula II with an appropriate amount of p-toluenesulfonic acid to form a compound of formula I in crystalline form directly during or after the reaction.
In another preferred embodiment, the process for preparing a crystalline form of the compound of formula I comprises the steps of:
(i) Reacting the compound of formula II with p-toluenesulfonic acid in an inert solvent (such as toluene, acetone, ethanol, tetrahydrofuran, acetonitrile, or a combination thereof) to produce an amorphous form of the p-toluenesulfonic acid salt of the compound of formula II;
(ii) Optionally allowing the amorphous material to stand for a period of time (e.g., 1-72 hours, preferably 5-36 hours); and/or optionally seeding the amorphous material;
(iii) separating (e.g., centrifuging) the reaction mixture to obtain form a of the p-toluenesulfonate salt.
crystallization of
In the present invention, production scale crystallization can be accomplished by manipulating the solution such that the compound of interest is brought to supersaturation. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. In a preferred embodiment, the compound of interest is dissolved in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
The main advantages of the invention are:
(1) The preparation method of the p-toluenesulfonate (crystal form or amorphous form) is simple and quick, and is convenient for large-scale production.
(2) The p-toluenesulfonate salt of the present invention has particularly low solubility in some solvents, and thus forms a precipitate or a crystal in a short time, and thus is very convenient and rapid for purification and isolation.
(3) The crystal form A has very high purity (such as more than or equal to 99 percent), and is particularly suitable for being used as an intermediate for producing Ledipasvir, so that the quality of a final product Ledipasvir is improved, and impurities are reduced.
(4) The crystal form A has good crystallinity and impurity removal effect, and is favorable for preparing high-quality Ledipasvir bulk drug.
(5) the crystal form A has better thermodynamics and illumination stability, and is beneficial to stable quality control and industrial application.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Feedstock, apparatus and general methods
XRD (X-ray diffraction) spectrum determination method
x-ray powder diffraction instrument (XRPD): bruker D8 Advance X-ray powder diffractometer, Cu target, Ka wavelength, tube voltage 40KV, tube current 40 mA. Scanning range: 3-40 ° 2-Theta; step by step: 0.02 degree; scanning speed: 1 step/second.
Differential Scanning Calorimetry (DSC)
Differential Scanning Calorimetry (DSC) instrument: TA Q2000 differential scanning calorimeter; temperature range: 45-200 ℃; heating rate: 10 deg.C/min.
TGA (TGA-specific molecular weight analysis) spectrum determination method
NETZSCH TG 209F3 thermogravimetric analyzer; temperature range: 30-400 ℃; heating rate: 10 deg.C/min.
High Performance Liquid Chromatography (HPLC):
Agilent 1260; a chromatographic column: xbridge C18, 4.6X 150 mm; mobile phase: trifluoroacetic acid, acetonitrile and water; detection wavelength: 220 nm.
A compound of formula II
See the method of Chinese invention patent CN2015101179973 for preparation.
EXAMPLE 1 preparation of amorphous form of Compound I
600mg of the compound of formula II is placed in a 25mL round bottom flask, 5mL of ethanol are added and the mixture is sonicated until dissolved. 1mL of a solution of 1M p-toluenesulfonic acid in acetonitrile was added and the resulting solution was placed on a rotary evaporator and dried by spinning.
the solid obtained was identified by polarizing microscope and was confirmed to be amorphous.
EXAMPLE 2 preparation of form A of the Compound of formula I
(1) 40mg of the compound of the formula II are placed in a 1.5ml centrifuge tube, 0.2ml of ethanol are added, and then an equimolar amount of 0.5M ethanol solution of p-toluenesulfonic acid is added, and the reaction mixture is slowly evaporated at room temperature, with a solid precipitating out. The crystal was identified by a polarizing microscope.
(2) the tube was placed in a centrifuge and centrifuged at 12000 rpm for 5 minutes, the supernatant removed and the separated solid dried at room temperature for 1 hour.
(3) The dried solid was tested for p-toluenesulfonate content by HPLC and characterized for solid form by XRPD, DSC, TGA, and the like.
Results
(1) The ion chromatographic analysis result shows that the content of the p-toluenesulfonate in the crystal form A is 21.8 wt%, which is basically consistent with the theoretical content (22.3 wt%) of the p-toluenesulfonate in the compound of the formula I. The molar ratio of p-toluenesulfonic acid to compound of formula II during salt formation (1:1) was combined, indicating that the crystals were mono-p-toluenesulfonic acid salt.
(2) XRPD pattern
The XRPD pattern of form a is substantially as shown in figure 1. The main diffraction peaks and relative intensities are shown in table 1.
table 1 XRPD data for form a
(3) Results of DSC analysis
The DSC analysis of form a is substantially as shown in figure 2. The results show that the heat flow curve of form a has an endothermic peak between 50 and 220 ℃, with an onset temperature of 140.91 ℃ and a peak temperature (peak) of 157.65 ℃.
(4) TGA analysis results
The TGA analysis of form a is substantially as shown in figure 3. The results show that the weight loss of 3.38% between 40 ℃ and 140 ℃ is caused by solvent volatilization; the weight loss of 8.36% between 220 ℃ and 300 ℃ is due to decomposition of the compound.
(5) Purity analysis
HPLC analysis shows that after the compound of the formula II reacts to generate the crystal form A of the mono-p-toluenesulfonate, the HPLC purity is improved to be more than or equal to 99.0 percent (the compound of the formula I) from 85.6 percent (the compound of the formula II). The result shows that the impurities can be obviously removed after salifying crystallization, thereby being beneficial to improving the quality of the final product ledipasvir.
EXAMPLE 3 crystallization of amorphous form of Compound I
1g of amorphous form I compound (prepared as in example 1) was added to a 25mL round bottom flask, 4mL of acetonitrile was added to form a clear solution, and then about 5mg of form A compound of formula I compound (prepared as in example 2) was seeded.
The suspension is stirred for 2 hours at room temperature for crystallization, a solid is separated by filtration, and the crystal is identified as a crystal form A by XRPD identification.
EXAMPLE 4 salt screening of Compounds of formula I
40mg of the compound of formula II was added to a series of 1.5ml centrifuge tubes and 100. mu.L of ethanol was added separately. And (4) carrying out ultrasonic treatment to dissolve.
Ethanol or acetonitrile solutions of different acids (see table 2) were prepared.
And dropwise adding an acid solution with an equimolar ratio into the compound II solution. If a precipitate was formed, it was confirmed by a polarizing microscope whether the precipitate was crystalline. If a clear solution forms, the solvent is slowly evaporated by leaving open to room temperature.
TABLE 2 Compound I salt screening
| Acid(s) | phenomenon(s) | results |
| Hydrochloric acid | clear solution | oil is precipitated |
| Sulfuric acid | Clear solution | Oil is precipitated |
| Phosphoric acid | Clear solution | Oil is precipitated |
| oxalic acid | clear solution | oil is precipitated |
| Fumaric acid | Clear solution | Oil is precipitated |
| P-toluenesulfonic acid | Solid precipitation out | mono-p-toluenesulfonate salt |
taken together, the above results indicate that the crystalline form of the compound of formula I (i.e. the mono-p-toluenesulfonate salt of the compound of formula II) is particularly suitable for use as an intermediate in the preparation of ledipasvir.
all documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (11)
1. A crystalline form a of p-toluenesulfonate salt of a compound of formula II,
The form a has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 4.9 +/-0.2 degrees, 8.2 +/-0.2 degrees, 10.0 +/-0.2 degrees, 13.7 +/-0.2 degrees, 13.9 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.6 +/-0.2 degrees, 21.9 +/-0.2 degrees and 24.2 +/-0.2 degrees.
2. The crystalline form a of p-toluenesulfonate according to claim 1, wherein said form a has one or more characteristics selected from the group consisting of:
(1) The form a has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 4.9 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 10.0 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees and 20.8 degrees +/-0.2 degrees;
(2) The form a has X-ray powder diffraction data selected from table 1;
(3) The form a has an X-ray powder diffraction pattern substantially as characterized in figure 1;
(4) The initial temperature of the differential scanning calorimetry analysis pattern of the crystal form A is 140.91 +/-3 ℃;
(5) The peak temperature of the differential scanning calorimetry analysis chart of the crystal form A is 157.65 +/-3 ℃;
(6) A differential scanning calorimetry analysis profile of form a substantially as characterized in figure 2;
(7) The thermogravimetric analysis profile of form a is substantially as characterized in figure 3; and/or
(8) the crystal form A is mono-p-toluenesulfonate.
3. A process for preparing the p-toluenesulfonate form a of claim 1, wherein the p-toluenesulfonate is form a, comprising the steps of:
(1) Dissolving a p-toluenesulfonate amorphous substance in a solvent at 4-30 ℃, wherein the weight-volume ratio of the p-toluenesulfonate amorphous substance to the solvent is 10-1000 mg/ml;
(2) standing the solution obtained in the previous step for 1-72 hours, and filtering and crystallizing to obtain a crystal form A of the p-toluenesulfonate;
The p-toluenesulfonate amorphous substance is prepared by a method comprising the steps of:
(a) reacting the compound of formula II with p-toluenesulfonic acid in a solvent at 0-50 ℃ to produce an amorphous form of the p-toluenesulfonic acid salt of the compound of formula II.
4. The method of claim 3, wherein in step (1), the solvent is selected from the group consisting of: toluene, acetone, ethanol, tetrahydrofuran, acetonitrile, or combinations thereof.
5. the method of claim 3, wherein between the step (1) and the step (2), further comprising the step (2-1):
Adding seed crystals into the solution obtained in the step (1), wherein the weight percentage of the seed crystals to the compound of the formula I is 0.1-10%;
The compounds of formula I are:
6. The method as set forth in claim 5, wherein in the step (2-1), the seed crystal is prepared by a method comprising the steps of:
(1) Dissolving the p-toluenesulfonate amorphous substance in a solvent at 4-30 ℃, wherein the weight-volume ratio of the compound of the formula I to the solvent is 10-1000 mg/ml;
(2) Standing the solution obtained in the step (1) for 1-72 hours, and filtering and crystallizing to obtain the p-toluenesulfonate seed crystal;
The p-toluenesulfonate amorphous substance is prepared by a method comprising the steps of:
(a) Reacting the compound of formula II with p-toluenesulfonic acid in a solvent at 0-50 ℃ to produce an amorphous form of the p-toluenesulfonic acid salt of the compound of formula II.
7. The method of claim 6, wherein in step (1), the weight to volume ratio of the compound of formula I to the solvent is from 50 to 800 mg/ml.
8. the method of claim 6, wherein in step (1), the weight to volume ratio of the compound of formula I to the solvent is from 80 to 600 mg/ml.
9. the method as claimed in claim 6, wherein the weight/volume ratio of the compound of formula I to the solvent in step (1) is 120-400 mg/ml.
10. The method of claim 6, wherein in step (2), the solution obtained in step (1) is allowed to stand for 5 to 36 hours.
11. Use of crystalline form a of tosylate salt according to claim 1 for the synthesis of ledipasvir.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011156757A1 (en) * | 2010-06-10 | 2011-12-15 | Gilead Sciences, Inc. | Combination of anti-hcv compounds with ribavirin for the treatment of hcv |
| WO2012068234A2 (en) * | 2010-11-17 | 2012-05-24 | Gilead Sciences, Inc. | Antiviral compounds |
| WO2012087596A1 (en) * | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CN104244945A (en) * | 2011-09-16 | 2014-12-24 | 吉利德法莫赛特有限责任公司 | Methods for treating hcv |
| CN104829599A (en) * | 2015-03-17 | 2015-08-12 | 上海众强药业有限公司 | Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir |
-
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- 2016-09-07 CN CN201610808216.XA patent/CN106432197B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011156757A1 (en) * | 2010-06-10 | 2011-12-15 | Gilead Sciences, Inc. | Combination of anti-hcv compounds with ribavirin for the treatment of hcv |
| WO2012068234A2 (en) * | 2010-11-17 | 2012-05-24 | Gilead Sciences, Inc. | Antiviral compounds |
| WO2012087596A1 (en) * | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CN104244945A (en) * | 2011-09-16 | 2014-12-24 | 吉利德法莫赛特有限责任公司 | Methods for treating hcv |
| CN104829599A (en) * | 2015-03-17 | 2015-08-12 | 上海众强药业有限公司 | Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir |
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