CN112300139A - Crystalline form of sitagliptin hydrate and preparation method thereof - Google Patents
Crystalline form of sitagliptin hydrate and preparation method thereof Download PDFInfo
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- CN112300139A CN112300139A CN202011594574.8A CN202011594574A CN112300139A CN 112300139 A CN112300139 A CN 112300139A CN 202011594574 A CN202011594574 A CN 202011594574A CN 112300139 A CN112300139 A CN 112300139A
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- sitagliptin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a crystal form I of a sitagliptin hydrate and a preparation method thereof, wherein the crystal form I is about 6.35 in an X-ray powder diffraction pattern expressed by a 2 theta angle°、8.68°、9.89°、10.36°、10.75°、11.40°、12.63°、13.06°、14.45°、15.28°、16.47°、17.14°、17.88°、18.70°、19.44°、20.18°、20.96°、21.90°、22.37°、22.75°、23.66°、24.49°、24.89°、25.74°、26.37°、27.12°、28.54°、29.57°、29.95°、30.41°、30.84°、33.01°、33.35°Diffraction peaks exist, and the crystal form has the advantages of high purity and good stability.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a (S) -2- [2- (benzofuran-6-carbonyl) -5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-formamido ] -3- (3-methylsulfonylphenyl) propionic acid crystal form and a preparation method thereof.
Background
The ritastemide is developed by SARcodebioscience and is a first small-molecule integrin inhibitor for treating dry eye in the world, and the ritastemide takes effect by antagonizing the combination of ICAM-1 and LFA-1, so that the T cell mediated inflammatory reaction is blocked, the curative effect of treating the dry eye is obvious, the incidence rate of adverse reactions is low, and the symptoms are slight. Rittas eye drops (Xiidra) were approved by the FDA in 2016 for marketing for the treatment of ocular sicca syndrome. The English name of the compound of the product is: lifitegrast, chemical name: (S) -2- [2- (benzofuran-6-carbonyl) -5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxamido ] -3- (3-carboxamidophenyl) propionic acid, the structural formula is:
at present, the existing literature reports that crystal forms of sitagliptin are that patents US2019300512 disclose sitagliptin crystal forms S1 and S2 and preparation methods thereof, CN104797574 reports that crystal form II of sitagliptin monohydrate, WO2009/139817 reports five crystal forms of the sitagliptin crystal form A, B, C, D, E and amorphous preparation methods, and WO2019043724 discloses the sitagliptin crystal form M, S, N, L and a preparation method thereof. In the preparation process of the sitagliptin, the prior art has the factors of non-ideal impurity control and higher solvent residue.
Disclosure of Invention
The inventor unexpectedly discovered a new hydrate crystal form of sitagliptin during the process of preparing optimized sitagliptin.
The invention provides a crystalline form I of sitagliptin using Cu-Kalpha radiation at an angle of 2 theta (b°) The ray diffraction pattern represented is: at 6.35 +/-0.2°、8.68±0.2°、9.89±0.2°、10.36±0.2°、10.75±0.2°、11.40±0.2°、12.63±0.2°、13.06±0.2°、13.67±0.2°、14.45±0.2°、15.28±0.2°、16.47±0.2°、17.14±0.2°、17.88±0.2°、18.70±0.2°、19.44±0.2°、20.18±0.2°、20.49±0.2°、20.96±0.2°、21.90±0.2°、22.37±0.2°、22.75±0.2°、23.66±0.2°、24.49±0.2°、24.89±0.2°、25.74±0.2°、26.37±0.2°、27.12±0.2°、27.59±0.2°、28.54±0.2°、29.57±0.2°、29.95±0.2°、30.41±0.2°、30.84±0.2°、32.17±0.2°、33.01±0.2°、33.35±0.2°、34.45±0.2°Has diffraction peaks.
Further, the crystal form I of the sitagliptin, which uses Cu-Kalpha radiation, has a powder X-ray diffraction pattern shown in figure 1 of the attached drawing of the specification.
Further, the crystal form I of the sitagliptin is dried at 105 ℃ to constant weight, and the water content of a crystal is 1.3-1.7% by a Karl Fischer method.
Further, the crystal form I of the sitagliptin has a melting point of 195-201 ℃.
The preparation method of the crystal form I of the sitagliptin comprises the following steps: dissolving the crude product of the sitagliptin in an alkaline solution, adding DMF, adding acid to adjust the pH value to form a turbid liquid, decompressing and concentrating until the total volume of the solvent is half, then precipitating a large amount of solid, cooling and crystallizing to obtain the crystal of the sitagliptin.
Further, the alkaline solution is any one of sodium hydroxide, lithium hydroxide and potassium hydroxide, and lithium hydroxide is preferable.
Further, the pH value is adjusted to 5.5-6.5, preferably 6.0 by acid.
Further, the acid is any one of hydrochloric acid, phosphoric acid and acetic acid, preferably acetic acid.
Further, the mass-to-volume ratio of the crude product of the sitagliptin to the alkaline solution is 1: 5-25, and the preferred mass-to-volume ratio is 1: 12.
Furthermore, the mass-to-volume ratio of the crude product of the sitagliptin to DMF is 1: 2.5-5, and the preferred mass-to-volume ratio is 1: 3.
Further, the crystallization temperature is-10 to 30 ℃, and 0 ℃ is preferred.
The crystal form I of the sitagliptin provided by the invention can be used for preparing a pharmaceutical composition for treating chronic inflammation of eyes.
Compared with the prior art, the invention has the following beneficial effects because the technology is adopted:
the crystal form I of the sitagliptin disclosed by the invention is higher in product purity, better in quality and better in stability.
Drawings
FIG. 1 is an X-ray diffraction pattern of crystalline form I of sitagliptin.
Figure 2 is a liquid chromatography (HPLC) plot of sitagliptin hydrate form I.
Detailed Description
Description of the atlas data:
it is noted that in the X-ray powder diffraction spectrum, the diffraction pattern obtained from a crystalline compound tends to be characteristic for a specific crystal, wherein the relative intensities of the bands may vary due to the dominant orientation resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal aimed at. To judge whether or not to coincide with the known crystalline phase, it is more important to note the relative positions of the peaks rather than their relative intensities. In addition, there may be slight errors in the position of the peaks for any given crystal, which are also well known in the crystallography art. For example, the position of the peak may shift due to temperature change when analyzing the sample, sample movement, calibration of the instrument, or the like, and the measurement error of the 2 θ value is sometimes about ± 0.2°. Therefore, this error should be taken into account when determining each crystalline structure. For the same crystal of the same compound, the peak positions of the XPRD spectrum have similarity as a whole, and the relative intensity error may be large. It should also be noted that in the identification of mixtures, the content may decrease due to such factors asResulting in the loss of a portion of the diffraction lines, in which case it is not necessary to rely on all the bands observed in the high purity sample, and even one band may be characteristic of a given crystal.
PXRD detection conditions are as follows:
the scanning angle range of the powder X-ray diffractometer can reach 0°～80°The correlation of the powder X-ray diffraction data collection range in the pharmacopoeia of the people's republic of China 2015 edition of four 0451X-ray diffraction method was stipulated that the range (2 theta) of diffraction data collection should be generally at least 3 when the copper Cu target experiment is used°～60°Sometimes it can be collected to 1°～80°. This is due to the instrument being at a scan angle of 1°A large blank diffraction peak is generated, the intensity of the blank diffraction peak exceeds that of the sample diffraction peak, and the analysis of the sample data is influenced, so that the blank diffraction peak is generally not from 0°The recording of data is started. The range of the strong diffraction peak generated by the organic crystal is generally 2°～40°. The experimental conditions selected were CuK alpha radiation, tube pressure 40kV, tube flow 30mA, graphite curved crystal monochromator, scanning speed 2°·min-1Step interval 0.02°Scanning Range 3°～35°。
Example 1: preparation of crystalline form I of sitagliptin:
adding 2g of crude sitaxel and 14mL of LiOH solution with the mass concentration of 10% into a 50mL reaction bottle, stirring for dissolving, adding DMF6mL, adjusting the pH value to 6.0 with acetic acid to form suspension, concentrating under reduced pressure until the volume of the solvent is half of the volume of the solvent, separating out a large amount of solid, continuously cooling to 0 ℃ for crystallization, filtering after 2 hours, and drying the filter cake at 50 ℃ in vacuum to obtain 1.6g of white solid, wherein the yield is 80%, and the HPLC purity is 99.83%.
Grinding the prepared white solid crystal form I sample, preparing a sheet, using a CuK alpha radiation graphite monochromator, performing tube pressure of 40kV, performing tube flow of 30mA, using a graphite curved crystal monochromator, and performing scanning at a speed of 2°·min-1Step interval 0.02°Scanning Range 3°～35°And obtaining the X-ray diffraction pattern of the crystal form I of the sitagliptin, wherein the data result is shown in figure 1.
Example 2: preparation of crystal form I of sitagliptin
Adding 2g of crude sitaxel and 24mL of NaOH solution with the mass concentration of 10% into a 100mL reaction bottle, stirring for dissolving, adding DMF5mL, adjusting the pH value to 5.5 by hydrochloric acid to form suspension, concentrating under reduced pressure until half of the volume of the solvent is dissolved, separating out solid, continuously cooling to 10 ℃ for crystallization, filtering after 2h, and drying the filter cake at 50 ℃ in vacuum to obtain 1.3g of white solid with the yield of 65% and the HPLC purity of 99.87%.
Example 3: preparation of crystal form I of sitagliptin
Adding 2g of crude sitaxel and 50mL of KOH solution with the mass concentration of 10% into a 100mL reaction bottle, stirring for dissolving, adding DMF10mL, adjusting the pH value to 6.5 with phosphoric acid to form suspension, concentrating under reduced pressure until half of the volume of the solvent is dissolved, separating out solid, continuously cooling to-10 ℃ for crystallization, filtering after 2h, and drying the filter cake at 50 ℃ in vacuum to obtain 1.1g of white solid, wherein the yield is 55% and the HPLC purity is 99.89%.
Example 4: preparation of crystal form D of sitagliptin
Adding 2g of crude sitaxel and 14mL of LiOH solution with the mass concentration of 10% into a 50mL reaction bottle, stirring for dissolving, adding DMF6mL, adjusting the pH value to 5.0 by using acetic acid to prevent suspension from forming, concentrating under reduced pressure to half of the volume of the solvent, separating out solid, continuously cooling to 0 ℃ for crystallization, filtering after 2 hours, and drying the filter cake at 50 ℃ in vacuum to obtain 1.3g of white solid with the yield of 65% and the HPLC purity of 99.53%. (the obtained crystal form is the crystal form D and the same as WO 2009/139817).
Example 5: preparation of crystal form D of sitagliptin
Adding 2g of crude sitaxel and 14mL of LiOH solution with the mass concentration of 10% into a 50mL reaction bottle, stirring for dissolving, adding DMF6mL, adjusting the pH value to 7.0 by using acetic acid to prevent suspension from forming, concentrating under reduced pressure to half of the volume of the solvent, separating out solid, continuously cooling to 0 ℃ for crystallization, filtering after 2 hours, and drying the filter cake at 50 ℃ in vacuum to obtain 1.4g of white solid with the yield of 70% and the HPLC purity of 99.63%. (the obtained crystal form is the crystal form D and the same as WO 2009/139817).
Example 6: chemical stability study of crystal form I of sitagliptin
According to the invention, the chemical stability of the crystal form I is researched, a sample prepared by the method in the example 1 is used, a reference substance of the crystal form A of the sitosta is prepared at the same time (refer to WO 2009/139817), the influence factor test investigation conditions are high temperature (60 ℃), high humidity (92.5%), and strong light irradiation (4500 +/-500 Lx), the content of related substances is determined in 0, 5 and 10 days, and the crystal form I is tested for a long time (25 +/-2 ℃, sealed and shaded) and the content of the related substances is determined in 0, 3, 6 and 12 months.
Table 1: influence factor test and stability test results
According to the test results, under a long-term condition, all indexes of the crystal form I sample have no obvious change, and the crystal form I has good stability. Meanwhile, the stability of the crystal form I compared with the original crystal form A is obviously superior to that of the existing crystal form A under the conditions of illumination and high temperature.
The above-mentioned embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention should be defined by the claims, and equivalents including technical features of the claims, i.e., equivalent modifications within the scope of the present invention.
Claims (10)
1. A crystalline form of sitagliptin hydrate, characterised in that it uses Cu-ka radiation in an X-ray diffraction pattern expressed in degrees 2 Θ: at 6.35 +/-0.2°、8.68±0.2°、9.89±0.2°、10.36±0.2°、10.75±0.2°、11.40±0.2°、12.63±0.2°、13.06±0.2°、13.67±0.2°、14.45±0.2°、15.28±0.2°、16.47±0.2°、17.14±0.2°、17.88±0.2°、18.70±0.2°、19.44±0.2°、20.18±0.2°、20.49±0.2°、20.96±0.2°、21.90±0.2°、22.37±0.2°、22.75±0.2°、23.66±0.2°、24.49±0.2°、24.89±0.2°、25.74±0.2°、26.37±0.2°、27.12±0.2°、27.59±0.2°、28.54±0.2°、29.57±0.2°、29.95±0.2°、30.41±0.2°、30.84±0.2°、32.17±0.2°、33.01±0.2°、33.35±0.2°、34.45±0.2°Has diffraction peaks.
2. The crystalline form of claim 1, characterized in that: which uses Cu-Ka radiation and has a powder X-ray diffraction pattern shown in figure 1 of the attached drawings of the specification.
3. The crystalline form of claim 1, characterized in that: after drying at 105 ℃ to constant weight, the water content of the crystal is 1.3-1.7% by Karl Fischer method.
4. A method for producing the crystal according to any one of claims 1 to 3, characterized by comprising the steps of: dissolving the crude product of the sitagliptin in an alkaline solution, adding DMF, adding acid to adjust the pH value to 5.5-6.5 to form a turbid liquid, concentrating under reduced pressure until the total volume of the solvent is half, and cooling and crystallizing to obtain the crystal of the sitagliptin.
5. The method of claim 4, wherein: the alkaline solution is any one of sodium hydroxide, lithium hydroxide and potassium hydroxide.
6. The method of claim 4, wherein: the acid is any one of hydrochloric acid, phosphoric acid and acetic acid.
7. The method of claim 4, wherein: the mass-volume ratio of the crude product of the sitagliptin to the alkaline solution is 1: 5-25.
8. The method of claim 4, wherein: the mass-volume ratio of the crude product of the sitagliptin to the DMF is 1: 2.5-5.
9. The method of claim 4, wherein: the crystallization temperature is-10 to 30 ℃.
10. Use of the crystal according to any one of claims 1 to 3 for the preparation of a pharmaceutical combination for chronic inflammation of the eye.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024001995A1 (en) * | 2022-06-27 | 2024-01-04 | 浙江海翔药业股份有限公司 | Lifitegrast morpholine salt, method for preparing same, and use thereof |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011050175A1 (en) * | 2009-10-21 | 2011-04-28 | Sarcode Corporation | Crystalline pharmaceutical and methods of preparation and use thereof |
| CN104797574A (en) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | LFA-1 inhibitor and polymorph thereof |
| WO2019043724A1 (en) * | 2017-08-28 | 2019-03-07 | Msn Laboratories Private Limited, R&D Center | Processes for the preparation of (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid and polymorphs thereof |
| WO2019073325A1 (en) * | 2017-10-10 | 2019-04-18 | Mankind Pharma Ltd. | Novel process for the preparation of lifitegrast |
| WO2019097547A1 (en) * | 2017-11-15 | 2019-05-23 | Cipla Limited | An improved process for the preparation of lifitegrast or salts thereof |
| US20190300512A1 (en) * | 2018-03-30 | 2019-10-03 | Scinopharm Taiwan, Ltd. | Crystal forms of Lifitegrast |
| WO2019186520A1 (en) * | 2018-03-31 | 2019-10-03 | Aurobindo Pharma Limited | A process for the preparation of lifitegrast |
| CN110831938A (en) * | 2017-06-30 | 2020-02-21 | 台湾神隆股份有限公司 | Process for the preparation of sitagliptin and intermediates thereof |
| CN111205275A (en) * | 2020-04-22 | 2020-05-29 | 南京佰麦生物技术有限公司 | Crystal form of sitagliptin and preparation method thereof |
| CN111747941A (en) * | 2019-03-29 | 2020-10-09 | 成都惟邦药业有限公司 | Synthesis method of lifustat |
-
2020
- 2020-12-29 CN CN202011594574.8A patent/CN112300139A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011050175A1 (en) * | 2009-10-21 | 2011-04-28 | Sarcode Corporation | Crystalline pharmaceutical and methods of preparation and use thereof |
| CN104797574A (en) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | LFA-1 inhibitor and polymorph thereof |
| CN110831938A (en) * | 2017-06-30 | 2020-02-21 | 台湾神隆股份有限公司 | Process for the preparation of sitagliptin and intermediates thereof |
| WO2019043724A1 (en) * | 2017-08-28 | 2019-03-07 | Msn Laboratories Private Limited, R&D Center | Processes for the preparation of (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid and polymorphs thereof |
| WO2019073325A1 (en) * | 2017-10-10 | 2019-04-18 | Mankind Pharma Ltd. | Novel process for the preparation of lifitegrast |
| WO2019097547A1 (en) * | 2017-11-15 | 2019-05-23 | Cipla Limited | An improved process for the preparation of lifitegrast or salts thereof |
| US20190300512A1 (en) * | 2018-03-30 | 2019-10-03 | Scinopharm Taiwan, Ltd. | Crystal forms of Lifitegrast |
| WO2019186520A1 (en) * | 2018-03-31 | 2019-10-03 | Aurobindo Pharma Limited | A process for the preparation of lifitegrast |
| CN111747941A (en) * | 2019-03-29 | 2020-10-09 | 成都惟邦药业有限公司 | Synthesis method of lifustat |
| CN111205275A (en) * | 2020-04-22 | 2020-05-29 | 南京佰麦生物技术有限公司 | Crystal form of sitagliptin and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| ANON.: "Process for the preparation of (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl) propanoic acid", 《IP.COM》 * |
| 张利军，等: "Lifi tegrast合成路线图解", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024001995A1 (en) * | 2022-06-27 | 2024-01-04 | 浙江海翔药业股份有限公司 | Lifitegrast morpholine salt, method for preparing same, and use thereof |
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