CN111620880A - PF-06651600 DL-tartrate, crystal form and preparation method thereof - Google Patents
PF-06651600 DL-tartrate, crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention provides PF-06651600 DL-tartrate, a crystal form and a preparation method thereof. The PF-06651600 DL-tartrate and the crystal form thereof have good stability, water solubility and hygroscopicity, are convenient to store and transport, and provide possibility for improving the drug property of PF-06651600 and better storage stability.
Description
Technical Field
The invention relates to the field of medicines, in particular to PF-06651600 DL-tartrate, a crystal form and a preparation method thereof.
Background
PF-06651600, the structural formula of which is shown in formula (II), is a highly selective oral organism developed by the company Peucedanum and utilizes Janus kinase 3(JAK3) inhibitor, and represents a potential immunomodulatory therapy. Due to its good therapeutic efficacy, safety and ADME properties, this JAK 3-specific covalent inhibitor has been used in the treatment of alopecia areata, rheumatoid arthritis, crohn's disease and ulcerative colitis. On day 5 of 2018, 9, FDA awards PF-06651600 as a "breakthrough therapy" for the treatment of alopecia areata, with the support of positive results from a second phase study.
Approximately half of the drug molecules are present and administered in the form of a salt. Salification can improve some undesirable physicochemical or biological pharmaceutical properties of the drug, such as changing the solubility or dissolution rate of the drug, reducing hygroscopicity, improving stability, changing melting point, improving grinding performance, facilitating preparation and purification, improving permeability and the like, and selection of a proper salt form for drug development is necessary. Also, a salt may exist in polymorphic form. Different crystal forms have different melting points, solubilities, dissolution properties, chemical stabilities, mechanical stabilities and the like, and the physical and chemical properties sometimes directly influence the effectiveness and the processing performance of the medicine. Therefore, comprehensive and systematic salt form screening and crystal form screening are performed in drug research and development, and the selection of the most suitable salt form and crystal form thereof is one of important research contents which cannot be ignored.
Patent WO2015083028A1 discloses PF-06651600 and derivatives thereof, and reports on salts and crystal forms thereof are not found.
Org, Process Res, Dev, 2019,23, 1872-: process Development and Scale Up of a Selective JAK3 valuable Inhibitor PF-06651600, patent WO2020084435A1, all report PF-06651600 free base is not suitable for synthetic drugs due to poor stability and poor solubility.
Org, Process Res, Dev, 2019,23, 1872-: a Process Development and Scale Up of a Selective JAK3 equivalent Inhibitor PF-06651600 reported accelerated stability test investigation of PF-06651600 for tosylate (standing for 7 days at 70% to 75% relative humidity), but no specific data are disclosed.
Patent WO2020084435A1 reports PF-06651600 malonate, phosphate and p-toluenesulfonate, data of a p-toluenesulfonate crystal form and data comparison of stability relative to malonate and phosphate (relative humidity is 70-75% for 7 days) are reported in detail, only preparation methods and data comparison of stability are reported for malonate and phosphate (relative humidity is 70-75% for 7 days), and characterization of the crystal form and other physicochemical properties are not reported.
Currently, PF-06651600 is a tablet in the United states and China for clinical trials. The salt form and the crystal form physicochemical properties of the drug have the greatest influence on solid formulations, particularly tablets.
Based on the background, more salt forms and crystal forms of PF-06651600 with excellent properties are screened, and the method has important significance for the pharmacy and the industrial production of the compound.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide PF-06651600 DL-tartrate and a crystal form thereof, which have the advantages of good stability, high water solubility and high dissolution rate.
The invention provides a salt shown in a formula (I) formed by a compound (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one (PF-06651600) and DL-tartaric acid,
the salt is in a crystalline form having diffraction peaks at about 4.6, 7.3, 9.9 degrees expressed in terms of 2 θ in an X-ray powder diffraction pattern of Cu ka radiation, and has a melting point: 195-197 deg.c.
In a certain embodiment, the resulting salt is in crystalline form and has diffraction peaks at the following angles, expressed in terms of 2 θ, in the X-ray powder diffraction pattern of Cu ka radiation.
| |
2 theta angle | d value | Strength (%) |
| 1 | 4.632 | 19.061 | 100.0 |
| 2 | 7.307 | 12.089 | 5.3 |
| 3 | 9.910 | 8.918 | 5.3 |
The intensity of the peak can be varied within the crystallographic range, but the diffraction peak position of the crystalline form cannot be varied. The position of the peak may be slightly deviated, thereby causing an error in the 2 θ value to fluctuate by about ± 0.2 degrees, which error range should be considered by those skilled in the art when confirming the crystal structure.
In another aspect of the present invention, there is provided a method for preparing the salt comprising the steps of: respectively dissolving PF-06651600 and DL-tartaric acid in a solvent at room temperature, dropwise adding the obtained DL-tartaric acid solution into the PF-06651600 solution under the stirring condition, stirring for 2-5 hours, separating out a white solid, continuously stirring for 8 hours, filtering the solid, and drying in vacuum to obtain PF-06651600 DL-tartrate shown in formula (I).
Preferably, the solvent is an alcohol, and more preferably, the solvent is selected from one or more of ethanol, methanol and isopropanol.
Preferably, the solvent is a ketone, and more preferably, the solvent is one or a mixture of more than one selected from acetone, butanone and methyl ethyl ketone.
Preferably, the solvent is a mixture of an alcohol or a ketone and water, the alcohol is selected from one or more of ethanol, methanol and isopropanol, and the ketone is selected from one or more of acetone, butanone and methyl ethyl ketone.
Preferably, the volume of the solvent in which PF-06651600 is dissolved is 5.0 to 10.0v/w (v is the volume of the solvent used, in ml, w is the mass of PF-06651600, in g); the volume of the solvent for dissolving the DL-tartaric acid is 15.0-20.0 v/w (v is the volume of the solvent used, unit ml, w is the mass of the DL-tartaric acid, unit g);
preferably, the dosage of the DL-tartaric acid is 0.5-3.0 molar equivalents of PF-06651600.
The salt of formula (I) of the invention can be prepared into solid preparations for treating alopecia areata, rheumatoid arthritis, Crohn's disease and ulcerative colitis.
Drawings
FIG. 1 is an X-ray powder diffraction (XRD) pattern of the crystalline form of PF-06651600 mono DL-tartrate of the present invention.
Detailed Description
For better understanding of the contents of the present invention, the following embodiments are further described, but the specific embodiments are not meant to limit the present invention.
Detection apparatus and method:
the instruments used for X-ray powder diffraction (XRD) were: bruker D8Advance X-ray Diffractometer (XRD)
PF-06651600 malonate, phosphate, p-toluenesulfonate used in the examples was prepared with reference to WO2020084435A 1.
EXAMPLE 1 preparation of PF-06651600 Crystal form of MonoDL-tartrate
PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml of ethanol and DL-tartaric acid (1.05g, 7.01mmol, 1.0 molar equivalent) was dissolved in 16ml of ethanol at room temperature, the resulting solution of DL-tartaric acid was added dropwise to the PF-06651600 solution under stirring, after stirring for 2 hours, a white solid precipitated, stirring was continued for 8 hours, the solid was filtered, and vacuum-dried at 50 ℃ overnight to give 2.66g of a white crystalline powder, yield 87.2%, melting point: 195-197 deg.c, DL-tartaric acid content of 34.48% detected by HPLC, and PF-06651600 mono DL-tartrate.
Example 2 preparation of PF-06651600 DL-tartrate crystalline form
PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml of ethanol and DL-tartaric acid (0.55g, 3.66mmol, 0.52 molar equivalent) was dissolved in 10ml of ethanol at room temperature, the resulting solution of DL-tartaric acid was added dropwise to the PF-06651600 solution under stirring, after 3 hours of stirring, a white solid precipitated, which was further stirred for 8 hours, the solid was filtered and dried under vacuum at 50 ℃ overnight to give 1.58g of a white crystalline powder, with a yield of 62.0%, melting point: 196 ℃ to 197 ℃, the DL-tartaric acid content is 34.46 percent by HPLC detection, and the DL-tartaric acid is PF-06651600 mono DL-tartrate.
EXAMPLE 3 preparation of PF-06651600 DL-tartrate
PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml of ethanol and DL-tartaric acid (0.55g, 3.66mmol, 0.52 molar equivalent) was dissolved in an ethanol/water mixture (10 ml of ethanol, 1ml of water) at room temperature, the resulting solution of DL-tartaric acid was added dropwise to the PF-06651600 solution under stirring, after 5 hours of stirring, a white solid precipitated, which was further stirred for 8 hours, the solid was filtered and dried under vacuum at 50 ℃ overnight to give 1.29g of white crystalline powder with a yield of 50.6% and a melting point: 195-197 deg.c, DL-tartaric acid content of 34.49% as detected by HPLC, and PF-06651600 mono DL-tartrate.
Example 4 determination of solubility in Water
Water solubility (according to the requirements of Chinese pharmacopoeia), and the specific operation is as follows: weighing a test sample ground into fine powder, placing the test sample in a solvent with a certain volume at 25 ℃, shaking strongly for 30s every 5min, observing the dissolution condition within 30min, and if no visible solute particles exist, determining that the test sample is completely dissolved, wherein the measurement result is shown in table 1.
TABLE 1 solubility of salts of each crystal modification PF-06651600
Solubility tests show that the solubility of the PF-06651600 mono DL-tartrate in water is remarkably improved compared with PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate.
Example 5 moisture absorption test
Respectively placing the test articles in a clean crucible, placing in an open and flat manner, checking the mass increase percentage under the conditions of 25 ℃ and 20% relative humidity, and if the weight increase is less than 0.01% within 15min, continuing to increase by 10% and the maximum humidity reaches 80%; if the weight gain is more than 0.01 percent within continuous 15min, the humidity is continuously kept for 90min, and the measurement result is shown in table 2.
TABLE 2 hygroscopicity of salts of PF-06651600 in each crystalline form
The results show that the hygroscopicity of the PF-06651600 mono DL-tartrate of the present invention is significantly less than that of PF-06651600 p-toluenesulfonate, PF-06651600 malonate, and PF-06651600 phosphate. The PF-06651600 mono DL-tartrate of the present invention therefore represents a significant advance.
Example 6 crystalline form stability investigation test
Each salt crystal form of PF-06651600 was left to stand under dry and high humidity (70% relative humidity) conditions at room temperature for 14 days, and samples were taken for 1 day, 7 days, and 14 days to examine the crystal form, and the examination results are shown in table 3.
TABLE 3 stability study of salt crystal form of PF-06651600
The results show that the crystallinity of the PF-06651600 mono DL-tartrate was not changed and PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate were all decreased to various degrees under high humidity (70% relative humidity) conditions at room temperature for 14 days.
Example 7 chemical stability investigation test
The respective salt forms of PF-06651600 were left to stand at high humidity (70% relative humidity) at room temperature for 14 days, and the relevant substances were sampled and detected for 1 day, 7 days, and 14 days, respectively, and the detection results are shown in Table 4.
TABLE 4 chemical stability examination of salts of each crystal form PF-06651600
The results show that the chemical stability of PF-06651600 mono DL-tartrate is superior to PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate under the condition of room temperature and high humidity (70% relative humidity) for 14 days.
Claims (10)
1. A salt shown in formula 1 formed by a compound (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-ene-1-one and DL-tartaric acid,
2. the salt of claim 1, characterized by a crystalline form having diffraction peaks, expressed in terms of 2 Θ angles, at about 4.6, 7.3, 9.9 degrees in an X-ray powder diffraction pattern of Cu ka radiation.
3. The salt of claim 1 or 2, characterized by a melting point of: 195-197 deg.c.
4. A method of preparing the salt of claim 3, comprising the steps of: respectively dissolving (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-ene-1-one and DL-tartaric acid in a solvent at room temperature, dropwise adding the obtained DL-tartaric acid solution into the (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-ene-1-one solution under stirring, stirring for 2-5 hours, precipitating a white solid, continuously stirring for 8 hours, the solid was filtered and dried in vacuo to give (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one DL-tartrate.
5. The method according to claim 4, wherein the solvent is an alcohol selected from the group consisting of ethanol, methanol and isopropanol.
6. The process according to claim 4, wherein the solvent is a ketone selected from acetone, methyl ethyl ketone and methyl ethyl ketone.
7. The method according to claim 4, wherein the solvent is a mixture of water and an alcohol selected from one or more of ethanol, methanol and isopropanol, or a ketone selected from one or more of acetone, methyl ethyl ketone and methyl ethyl ketone.
8. The method of claims 4-7, wherein: the volume of solvent in which (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) propan-2-en-1-one is dissolved is 5.0 to 10.0v/w (v ═ the volume of solvent used, unit ml, mass w ═ 1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) propan-2-en-1-one, unit g); the volume of the solvent in which the DL-tartaric acid is dissolved is 15.0 to 20.0v/w (v is the volume of the solvent used, in ml, and w is the mass of the DL-tartaric acid, in g).
9. The process according to claims 4-7, wherein DL-tartaric acid is used in an amount of 0.5 to 3.0 molar equivalents of (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one.
10. Use of a salt according to claim 3 in the manufacture of a medicament for the treatment of alopecia areata, rheumatoid arthritis, crohn's disease, and ulcerative colitis.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022012587A1 (en) * | 2020-07-14 | 2022-01-20 | 苏州晶云药物科技股份有限公司 | Malonate crystal form of propenone compound, and preparation method therefor |
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| WO2015083028A1 (en) * | 2013-12-05 | 2015-06-11 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| WO2019040706A1 (en) * | 2017-08-24 | 2019-02-28 | Aclaris Therapeutics, Inc. | Compositions and methods for treatment of vitiligo |
| WO2020067887A1 (en) * | 2018-09-24 | 2020-04-02 | Erasmus University Medical Center Rotterdam | Specific inhibition of janus kinase 3 (jak3) for modulating anti-tumor immune responses |
| WO2020084435A1 (en) * | 2018-10-22 | 2020-04-30 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine tosylate salt, crystalline form thereof and manufacturing process and intermediates thereto |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015083028A1 (en) * | 2013-12-05 | 2015-06-11 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| WO2019040706A1 (en) * | 2017-08-24 | 2019-02-28 | Aclaris Therapeutics, Inc. | Compositions and methods for treatment of vitiligo |
| WO2020067887A1 (en) * | 2018-09-24 | 2020-04-02 | Erasmus University Medical Center Rotterdam | Specific inhibition of janus kinase 3 (jak3) for modulating anti-tumor immune responses |
| WO2020084435A1 (en) * | 2018-10-22 | 2020-04-30 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine tosylate salt, crystalline form thereof and manufacturing process and intermediates thereto |
Non-Patent Citations (3)
| Title |
|---|
| ATLI THORARENSEN: "Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1‑((2S,5R)‑5-((7H‑Pyrrolo[2,3‑d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| TAO YONG: "Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 唐晓楠: "靶向 JAK 治疗自身免疫病的小分子药物研究进展", 《药学学报 ACTA PHARMACEUTICA SINICA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022012587A1 (en) * | 2020-07-14 | 2022-01-20 | 苏州晶云药物科技股份有限公司 | Malonate crystal form of propenone compound, and preparation method therefor |
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