CN114835715A - PF-06651600 maleate and preparation method thereof - Google Patents
PF-06651600 maleate and preparation method thereof Download PDFInfo
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- CN114835715A CN114835715A CN202210436725.XA CN202210436725A CN114835715A CN 114835715 A CN114835715 A CN 114835715A CN 202210436725 A CN202210436725 A CN 202210436725A CN 114835715 A CN114835715 A CN 114835715A
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- methylpiperidin
- pyrrolo
- maleic acid
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- CBRJPFGIXUFMTM-WDEREUQCSA-N 1-[(2S,5R)-2-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en-1-one Chemical compound N1=CN=C(C2=C1NC=C2)N[C@@H]2CC[C@@H](N(C2)C(C=C)=O)C CBRJPFGIXUFMTM-WDEREUQCSA-N 0.000 title claims abstract description 68
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 29
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 22
- 239000011976 maleic acid Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 208000004631 alopecia areata Diseases 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- JEBLBBIWVAQPNB-QGQFQQFLSA-N C(\C=C/C(=O)O)(=O)O.N1=CN=C(C2=C1NC=C2)N[C@@H]2CC[C@@H](N(C2)C(C=C)=O)C Chemical compound C(\C=C/C(=O)O)(=O)O.N1=CN=C(C2=C1NC=C2)N[C@@H]2CC[C@@H](N(C2)C(C=C)=O)C JEBLBBIWVAQPNB-QGQFQQFLSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 8
- 229910019142 PO4 Inorganic materials 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 8
- 239000010452 phosphate Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- QMPMPSGDPRHZCG-VZXYPILPSA-N 1-[(2S,5R)-2-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en-1-one propanedioic acid Chemical compound OC(=O)CC(O)=O.C[C@H]1CC[C@H](CN1C(=O)C=C)Nc1ncnc2[nH]ccc12 QMPMPSGDPRHZCG-VZXYPILPSA-N 0.000 description 6
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000011165 process development Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- -1 (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino Chemical group 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 108091082332 JAK family Proteins 0.000 description 1
- 108010019421 Janus Kinase 3 Proteins 0.000 description 1
- 241000244269 Peucedanum Species 0.000 description 1
- 229940125808 covalent inhibitor Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides PF-06651600 maleate and a preparation method thereof. Particularly, the obtained PF-06651600 maleate has good stability, water solubility and hygroscopicity, is convenient to store and transport, and provides possibility for improving the drug property of PF-06651600 and having better storage stability.
Description
Technical Field
The invention relates to the field of medicines, in particular to PF-06651600 maleate 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 medicament. 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.
PF-06651600 and its derivatives are disclosed in WO2015083028A1, and no report is made on the maleate.
Org, Process Res, Dev, 2019,23, 1872-: process Development and Scale Up of a Selective JAK3 equivalent Inhibitor PF-06651600, patent WO2020084435A1 all report PF-06651600 free base is not suitable for synthesizing 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 on 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, reports data of p-toluenesulfonate and data comparison of stability relative to malonate and phosphate in detail (relative humidity 70% -75% standing for 7 days), reports only preparation method and data comparison of stability for malonate and phosphate (relative humidity 70% -75% standing for 7 days), and does not report other physical and chemical properties.
Currently, PF-06651600 is a tablet in the United states and China for clinical trials. The salt form of the drug and its physicochemical properties have the greatest influence on solid formulations, particularly tablets.
Based on the background, more salt 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 maleate which has good stability, high water solubility, high dissolution rate and difficult moisture absorption and a preparation method thereof.
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 maleic acid,
wherein x is 0.5 or 1.
In another aspect, the invention provides a process for the preparation of said salt 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-en-1-one and maleic acid in an alcohol solvent or a mixture of a ketone and water at room temperature, dropwise adding the obtained solution of the maleic acid into a (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one solution under stirring, separating out a white solid after stirring for 1-5 hours, continuously stirring for 6-8 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 monomaleate or hemimaleate.
Preferably, the alcohol solvent is selected from one or more of ethanol, methanol and isopropanol.
Preferably, the volume of solvent in which (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-one is dissolved is from 5.0 to 10.0v/w, v being the volume of solvent used in ml, the mass of w (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one in g; the volume of the solvent for dissolving maleic acid is 15.0-20.0 v/w, v is the volume of the solvent used, unit ml, w is the mass of maleic acid, unit g.
Preferably, maleic 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.
The invention also provides the monohydrate of the hemimaleate salt of formula (I).
The invention also provides the use of said salts of formula (I) for the treatment of alopecia areata, rheumatoid arthritis, crohn's disease, and ulcerative colitis.
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.
PF-06651600 malonate, phosphate, p-toluenesulfonate used in the examples was prepared by referring to WO2020084435A 1.
EXAMPLE 1 preparation of PF-06651600 Monomaleate
PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml ethanol and maleic acid (0.81g, 7.01mmol, 1.0 molar equivalent) was dissolved in 15ml ethanol at room temperature, the resulting solution of maleic acid was added dropwise to PF-06651600 solution under stirring, after 1 hour of stirring, a white solid precipitated, stirring was continued for 6 hours, the solid was filtered and dried overnight under vacuum at 50 ℃ to give 2.60g of white crystalline powder with a yield of 92.6%, the measured melting point was: 159 ℃ to 161 ℃, and the maleic acid content is 28.93 percent by HPLC detection, and the maleic acid is PF-06651600 monomaleate.
EXAMPLE 2 preparation of PF-06651600 hemimaleate
PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml ethanol and maleic acid (0.45g, 3.85mmol, 0.55 molar equivalent) was dissolved in 8ml ethanol at room temperature, the resulting maleic acid solution was added dropwise to 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 overnight under vacuum at 50 ℃ to obtain 2.11g of white crystalline powder with a yield of 87.7%, and the maleic acid content was 16.90% by HPLC as PF-06651600 hemimaleate.
EXAMPLE 3 preparation of PF-06651600 hemimaleate salt 1 hydrate
Dissolving PF-06651600(2.00g, 7.01mmol) in 10ml of ethanol at room temperature, dissolving maleic acid (0.45g, 3.85mmol, 0.55 molar equivalent) in an ethanol/water mixed solution (8 ml of ethanol and 1ml of water), dropwise adding the obtained maleic acid solution into the PF-06651600 solution under the condition of stirring, precipitating white solid after stirring for 5 hours, continuing stirring for 8 hours, filtering the solid, and drying in vacuum at 50 ℃ overnight to obtain 2.30g of white crystalline powder, wherein the yield is 90.8%, and the content of the maleic acid is 16.06% by HPLC; the water content of Karl Fischer water content was 2.49%, and it was PF-06651600 hemimaleate 1 hydrate.
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 various salts of PF-06651600
Solubility tests show that the solubility of PF-06651600 monomaleate, PF-06651600 hemimaleate and PF-06651600 hemimaleate 1 hydrate in water is obviously 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 the salts PF-06651600
The results show that the hygroscopicity of PF-06651600 monomaleate, PF-06651600 hemimaleate and PF-06651600 hemimaleate 1 hydrate of the present invention is significantly lower than that of PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate. Therefore, the PF-06651600 monomaleate, the PF-06651600 hemimaleate and the PF-06651600 hemimaleate 1 hydrate have remarkable progress.
Example 6 physical stability investigation test
The salts of PF-06651600 were dried at room temperature and humidified at room temperature (70% relative humidity) for 14 days, and sampled for 1 day, 7 days, and 14 days, respectively, and the results are shown in Table 3.
TABLE 3 stability test of each salt PF-06651600
The results show that the crystallinity of the PF-06651600 monomaleate, PF-06651600 hemimaleate and PF-06651600 hemimaleate 1 hydrate of the present invention is not changed and PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate are reduced to different degrees under the condition of high humidity (70% relative humidity) at room temperature for 14 days.
Example 7 chemical stability investigation test
Each salt of PF-06651600 was left to stand at room temperature under high humidity (70% relative humidity) for 14 days, and samples were taken for 1 day, 7 days, and 14 days to examine the substances, and the examination results are shown in Table 4.
TABLE 4PF-06651600 salts chemical stability examination
The results show that the chemical stability of the PF-06651600 monomaleate, PF-06651600 hemimaleate and PF-06651600 hemimaleate 1 hydrate of the invention is better than that of 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 (8)
1. A salt of compound (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one with maleic acid as shown in formula 1,
wherein X is 0.5 or 1.
2. The salt of claim 1, having a melting point of: 159 to 161 ℃.
3. A method of preparing the salt of claim 1, 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-en-1-one and maleic acid in an alcohol solvent or a mixture of a ketone and water at room temperature, dropwise adding the obtained solution of the maleic acid into a (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one solution under stirring, separating out a white solid after stirring for 1-5 hours, continuously stirring for 6-8 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 monomaleate or hemimaleate.
4. The method according to claim 3, wherein the alcoholic solvent is selected from one or more of ethanol, methanol, and isopropanol.
5. The production method according to claim 3, characterized in that: (ii) 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 from 5.0 to 10.0v/w, v being the volume of solvent used in ml, w being the mass of (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) propan-2-en-1-one in g; the volume of the solvent for dissolving maleic acid is 15.0-20.0 v/w, v is the volume of the solvent used, unit ml, w is the mass of maleic acid, unit g.
6. The process according to claim 3 to 5, wherein the maleic acid is used in an amount of 0.5 to 3.0 molar equivalents to (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one.
7. The monohydrate of the hemimaleate salt of claim 1.
8. Use of a salt as claimed in claim 1 in the manufacture of a medicament for the treatment of alopecia areata, rheumatoid arthritis, crohn's disease, and ulcerative colitis.
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| CN106061973A (en) * | 2013-12-05 | 2016-10-26 | 辉瑞公司 | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| US20190060311A1 (en) * | 2017-08-24 | 2019-02-28 | Aclaris Therapeutics, Inc. | Compositions and methods for treatment of vitiligo |
| 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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2020
- 2020-06-15 CN CN202210436725.XA patent/CN114835715B/en active Active
- 2020-06-15 CN CN202010545606.9A patent/CN111620879B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106061973A (en) * | 2013-12-05 | 2016-10-26 | 辉瑞公司 | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| US20190060311A1 (en) * | 2017-08-24 | 2019-02-28 | Aclaris Therapeutics, Inc. | Compositions and methods for treatment of vitiligo |
| 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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| Title |
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| ATLI THORARENSEN, ET AL.: "Design of a Janus Kinase 3 (JAK3) Speci fi c 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", 《J. MED. CHEM.》, vol. 60, pages 1971 - 1993, XP055573346, DOI: 10.1021/acs.jmedchem.6b01694 * |
| YONG TAO, ET AL.: "Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600", 《ORG. PROCESS RES. DEV.》, vol. 23, pages 1872 - 1880 * |
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| CN111620879A (en) | 2020-09-04 |
| CN114835715B (en) | 2024-04-05 |
| CN111620879B (en) | 2022-06-10 |
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