CN111732591B

CN111732591B - PF-06651600L-tartrate, crystal form and preparation method thereof

Info

Publication number: CN111732591B
Application number: CN202010545609.2A
Authority: CN
Inventors: 吴心宇; 陈磊; 陆平波; 丁杰
Original assignee: Jiangsu Ailikang Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Ailikang Pharmaceutical Technology Co ltd
Priority date: 2020-06-15
Filing date: 2020-06-15
Publication date: 2022-06-10
Anticipated expiration: 2040-06-15
Also published as: CN111732591A

Abstract

The invention provides PF-06651600L-tartrate, a crystal form and a preparation method thereof. The obtained PF-06651600L-tartrate and the crystal form thereof have good stability, water solubility and difficult hygroscopicity, are convenient to store and transport, and provide possibility for improving the drug property of PF-06651600 and better storage stability.

Description

PF-06651600L-tartrate, crystal form and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to PF-06651600L-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 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, details of data of p-toluenesulfonate crystal forms and data comparison of stability relative to malonate and phosphate (relative humidity is 70-75% for 7 days), reports only preparation methods and data comparison of stability for malonate and phosphate (relative humidity is 70-75% for 7 days), and does not report crystal form characterization and other physicochemical properties.

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-06651600L-tartrate and a crystal form thereof with 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 L-tartaric acid,

the salt is in a crystalline form and has diffraction peaks expressed in terms of 2 theta angles at about 6.8, 7.5, 9.2, 14.4, 20.7 degrees in an X-ray powder diffraction pattern of Cu Ka radiation. (ii) a The melting point is: 176 ℃ to 178 ℃.

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.

Peak numbering	2 theta angle	d value	Strength (%)
				1	3.370	26.194	1.8
2	6.155	14.349	1.7
				3	6.807	12.974	100.0
4	7.489	11.795	7.0
				5	9.170	9.636	4.4
6	10.663	8.290	1.7
				7	11.637	7.598	0.8
8	13.500	6.554	2.0
				9	14.388	6.151	5.4
10	15.385	5.754	2.9
				11	16.440	5.388	1.6
12	17.600	5.035	3.5
				13	18.079	4.903	2.7
14	18.834	4.708	2.5
				15	20.691	4.289	6.3
16	22.600	3.931	2.4
				17	23.896	3.721	3.0
18	26.390	3.375	2.7
				19	26.907	3.311	2.2
20	27.631	3.226	1.7

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 L-tartaric acid in a solvent at room temperature, dropwise adding the obtained L-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-06651600L-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 water and an alcohol or a ketone, the alcohol is selected from one or more than one of ethanol, methanol and isopropanol, and the ketone is selected from one or more than one 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 L-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 L-tartaric acid, unit g);

preferably, the L-tartaric acid is used in an amount of 0.5 to 3.0 molar equivalents of PF-06651600.

The salt of formula (I) of the present invention can be made into solid preparations for the treatment of 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 L-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 D8 Advance X-ray Diffractometer (XRD)

PF-06651600 malonate, phosphate, p-toluenesulfonate used in the examples was prepared by referring to WO2020084435A 1.

EXAMPLE 1 preparation of PF-06651600 crystalline form of mono L-tartrate

PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml ethanol and L-tartaric acid (1.05g, 7.01mmol, 1.0 molar equivalent) was dissolved in 16ml ethanol at room temperature, the resulting L-tartaric acid solution was added dropwise to the PF-06651600 solution under stirring for 2 hours, a white solid precipitated, the mixture was further stirred for 8 hours, the solid was filtered and dried overnight under vacuum at 50 ℃ to obtain 2.78g of a white crystalline powder, with a yield of 91.1%, a melting point of 176-178 ℃ and a L-tartaric acid content of 34.48% by HPLC, which was PF-06651600 mono L-tartrate.

Example 2 preparation of PF-06651600L-tartrate crystal form

PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml ethanol and L-tartaric acid (0.55g, 3.66mmol, 0.52 molar equivalent) was dissolved in 10ml ethanol at room temperature, the resulting L-tartaric acid solution 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 overnight under vacuum at 50 ℃ to obtain 1.67g of white crystalline powder with a yield of 65.5%, a melting point of 177-178 ℃ and an L-tartaric acid content of 34.46% as detected by HPLC, which was PF-06651600 mono-L-tartrate.

EXAMPLE 3 preparation of PF-06651600L-tartrate

PF-06651600(2.00g, 7.01mmol) was dissolved in 10ml of ethanol at room temperature, L-tartaric acid (0.55g, 3.66mmol, 0.52 molar equivalent) was dissolved in an ethanol/water mixed solution (10 ml of ethanol, 1ml of water), the resulting L-tartaric acid solution was added dropwise to the PF-06651600 solution under stirring, after stirring for 5 hours, a white solid was precipitated, stirring was continued for 8 hours, the solid was filtered, and vacuum-dried at 50 ℃ overnight to obtain 1.33g of white crystalline powder, yield 52.2%, melting point 176 ℃ -178 ℃, L-tartaric acid content was 34.49% by HPLC, which was PF-06651600 mono L-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-L-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 PF-06651600 crystalline salts

The results show that the hygroscopicity of the mono-L-tartrate of PF-06651600 of the present invention is significantly lower than that of PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate. The PF-06651600 mono L-tartrate salt 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-L-tartrate salt of the present invention was not changed and PF-06651600 p-toluenesulfonate, PF-06651600 malonate, and PF-06651600 phosphate were decreased in 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-L-tartrate is superior to PF-06651600 p-toluenesulfonate, PF-06651600 malonate and PF-06651600 phosphate under the condition of high humidity (70% relative humidity) for 14 days at room temperature.

Claims

1. A crystalline form of the L-tartrate 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 according to formula 1, wherein the diffraction angle 2 θ of the X-ray powder diffraction main peak of the crystalline form is shown in FIG. 1,

2. the crystalline form of L-tartrate of claim 1, having diffraction peaks, expressed in degrees 2 Θ, at about 6.8, 7.5, 9.2, 14.4, 20.7 in an X-ray powder diffraction pattern of Cu ka radiation.

3. A crystalline form of the L-tartrate salt as claimed in claim 1 or claim 2, characterized by a melting point of: 176 ℃ to 178 ℃.

4. A process for preparing the crystalline form of L-tartrate salt as claimed in 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-en-1-one and L-tartaric acid in an alcohol solvent or a mixture of alcohol and water at room temperature, dropwise adding the obtained L-tartaric acid solution into the (-)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, stirring for 2-5 hours, and precipitating white solids, stirring for 8 hours, filtering the solid, and drying in vacuum; the alcohol is selected from one or more of ethanol, methanol and isopropanol.

5. A process for the preparation of a crystalline form of the L-tartrate salt as claimed in claim 4, characterized in that (-)1- ((2S,5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) propan-2-en-1-one is dissolved in a solvent volume of 5.0 to 10.0v/w, v is the volume of solvent used in ml, w is 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, the unit g; the volume of the solvent for dissolving the L-tartaric acid is 15.0-20.0 v/w, v is the volume of the solvent used and the unit is ml, and w is the mass of the L-tartaric acid and the unit is g.

6. A process for preparing a crystalline form of the salt of L-tartaric acid according to claim 4, wherein the L-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.

7. Use of a crystalline form of the L-tartrate salt as claimed in claim 3, in the manufacture of a medicament for the treatment of alopecia areata, rheumatoid arthritis, Crohn's disease and ulcerative colitis.