CN116135854A - Preparation method of 2-acylaminothiazole derivative maleate crystal form - Google Patents
Preparation method of 2-acylaminothiazole derivative maleate crystal form Download PDFInfo
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- CN116135854A CN116135854A CN202111353518.XA CN202111353518A CN116135854A CN 116135854 A CN116135854 A CN 116135854A CN 202111353518 A CN202111353518 A CN 202111353518A CN 116135854 A CN116135854 A CN 116135854A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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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- 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
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Abstract
The invention relates to a preparation method of a 2-acylaminothiazole derivative crystal form, which comprises the following steps: 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazine-1-yl) -1, 3-thiazole-2-yl ] carbamoyl } pyridine-2-yl) piperidine-4-carboxylic acid, and after being mixed with a solvent and maleic acid, the mixture reacts at the reaction temperature of 20-60 ℃, and is filtered and dried, the crystal form C of the compound of the formula I is obtained; wherein the solvent is selected from acetone or acetonitrile. The method has the advantages of simple operation, high yield and small risk of solvent residue, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a 2-acylaminothiazole derivative crystal form, and particularly relates to a preparation method of a C crystal form of a compound shown in a formula I.
Background
Thrombocytopenia is a clinically common disease, and is commonly found in radiotherapy and chemotherapy injury, myelopathy diseases, idiopathic thrombocytopenic purpura, chronic liver diseases and the like.
Patent WO2004029049A1 discloses compounds of formula I which act as orally available small molecule Thrombopoietin (TPO) receptor agonists, stimulating megakaryocyte proliferation and differentiation in myeloid progenitor cells, thereby increasing platelet production. The incidence of adverse reactions is similar in the similar drugs, but the administration time and the preoperative waiting time of patients are shortened compared with the similar drugs. Patent WO2013018362A1 discloses three crystalline forms of a compound of formula I, wherein form a of the compound of formula I has good oral absorbability, but is unstable and may be converted to form B as the production scale increases; the compound of the formula I has good stability of the B crystal form, can not generate crystal transformation along with the expansion of the production scale, but has poor oral absorbability; the C crystal form of the compound of the formula I is the only crystal form with both crystal form stability and good oral absorbability.
Patent WO2013018362A1 discloses that the compound C form of formula I can be obtained by recrystallization from a three-phase mixed solvent of water, acetone and DMSO, but in lower yields and with a high risk of DMSO residue.
Disclosure of Invention
The invention aims to provide a preparation method which has simple process, high yield and small risk of solvent residue and is beneficial to industrial scale-up production of a compound C crystal form of a formula I.
The invention provides a preparation method of a C crystal form of a compound shown in a formula I, which comprises the following steps:
1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazine-1-yl) -1, 3-thiazole-2-yl ] carbamoyl } pyridine-2-yl) piperidine-4-carboxylic acid, and after being mixed with a solvent and maleic acid, the mixture reacts at the reaction temperature of 20-60 ℃, and is filtered and dried, the crystal form C of the compound of the formula I is obtained;
wherein the solvent is selected from acetone or acetonitrile.
In some embodiments of the invention, the molar ratio of 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid to maleic acid is 1:1.1 to 2.0, for example 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.8 or 1:2.0.
In some embodiments of the invention, the mass to volume ratio of 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid to solvent, in g/mL, is 1:10 to 30, for example 1:10, 1:15, 1:20, 1:25 or 1:30.
In some embodiments of the invention, the reaction time is at least 0.5h, preferably no more than 5h, for example 0.5h, 1h, 2h, 3h, 4h or 5h.
In some embodiments of the invention, the reaction temperature is 20 to 50 ℃, such as 20 to 30 ℃,30 to 40 ℃, or 40 to 50 ℃.
In some embodiments of the invention, the reaction solution is filtered after cooling to room temperature when the reaction temperature is 30 to 60 ℃.
Compared with the prior art, the invention has the following effective effects:
the method is simple and convenient to operate, high in yield, low in risk of solvent residue, and suitable for industrial production, and the adopted solvent is easy to remove by drying.
Detailed Description
The above-described aspects of the present invention will be described in further detail below with reference to the following embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. All technical schemes realized based on the above content of the invention belong to the scope of the invention.
The crystalline forms prepared in the examples were characterized by X-ray powder diffraction (XRPD).
An XRPD pattern is acquired by adopting a Japan Smartlab (9 Kw) X-ray powder diffraction analyzer, wherein the mode is a reflection mode, and the detector is a full-energy matrix one-dimensional detector. Scanning 2 theta range from 3 deg. to 40 deg. (Cu ka emitter, wavelength is
) The tube current is 150mA, the tube voltage is 40KV, the scanning speed is 15 DEG/min, the scanning mode is continuous scanning theta/theta, the emitting slit is 10mm, and the receiving slit is 10mm.
The HPLC purity of the compound of formula I was measured by high performance liquid chromatography under the following conditions: octadecylsilane chemically bonded silica is used as filler (Agilent Zorbax Bonus-RP C18, 250 mm. Times.4.6 mm,3.5 μm or column with comparable performance); taking 0.3% trifluoroacetic acid aqueous solution as a mobile phase A,0.3% trifluoroacetic acid acetonitrile solution as a mobile phase B, and 0.3% trifluoroacetic acid methanol solution as a mobile phase C; the detection wavelength is 330nm; column temperature 15 ℃; the flow rate is 1.0ml per minute; the sample volume was 20. Mu.l.
The maleic acid content in the compound of the formula I is detected by adopting a high performance liquid chromatography, and the sample diluent is 75% acetonitrile water solution-0.1 mol/L sodium hydroxide (96:4) (v/v); the chromatographic conditions were as follows: octadecylsilane chemically bonded silica is used as a filler (Inertsil ODS C18, 4.6X105 mm,5 μm or a column with equivalent performance); taking phosphoric acid aqueous solution (pH 3.0) as a mobile phase A and acetonitrile as a mobile phase B; the detection wavelength is 210nm; column temperature is 30 ℃; the flow rate is 1.0ml per minute; the sample volume was 10. Mu.l.
Room temperature means a temperature of 20-30 ℃.
Example 1:
to the reaction flask was added 100.0g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 1.5L of acetone and 21.8g of maleic acid, which were reacted at 20 to 30℃for 1 hour, filtered and dried to give 108.3g (yield 91.9%), which had an HPLC purity of 99.90% and a maleic acid content of 15.21%. The resulting product was detected by XRPD as form C of compound I.
Example 2:
to the reaction flask was added 100.0g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 2L of acetone and 29.0g of maleic acid, which were reacted for 3 hours at 30 to 40℃and cooled to room temperature, filtered and dried to obtain 107.8g (yield 91.5%) of a product having an HPLC purity of 99.93% and a maleic acid content of 15.20%. The resulting product was detected by XRPD as form C of compound I.
Example 3:
to the reaction flask was added 100.0g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 2.5L of acetone and 36.2g of maleic acid, which were reacted at 40 to 50℃for 5 hours, cooled to room temperature and filtered, dried to give 113.1g (yield 96.0%), HPLC purity 99.91% and maleic acid content 15.50%. The resulting product was detected by XRPD as form C of compound I.
Example 4:
to the reaction flask was added 20.0g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 500mL of acetonitrile and 7.1g of maleic acid, which were reacted for 3 hours at 40 to 50℃and cooled to room temperature, and then filtered, dried to obtain 19.3g (yield 81.9%) of a product having an HPLC purity of 99.75% and a maleic acid content of 15.45%. The resulting product was detected by XRPD as form C of compound I.
The residual acetone content of the C crystal form of the compound of formula I obtained in a similar manner to examples 1-4 is 0.02-0.04%.
Comparative example 1:
to the reaction flask was added 30.0g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 600mL of tetrahydrofuran and 10.7g of maleic acid, reacted at 65℃for 3 hours, cooled to room temperature, filtered and dried to give 33.5g (yield 94.7%) of a product having an HPLC purity of 99.69% and a maleic acid content of 14.99%. The resulting product was detected by XRPD as form B of compound I.
Comparative example 2:
to the reaction flask was added 8.0g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 80mL of water and 2.9g of maleic acid, reacted at 75℃for 3 hours, cooled to room temperature, filtered and dried to give 7.7g (yield 81.7%) of the compound of formula I, HPLC purity 99.70% and maleic acid content 5.00%.
Comparative example 3:
2.1g of 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 40mL of ethanol and 2.9g of maleic acid were added to a reaction flask and reacted for 5 hours at 50 to 60℃and cooled to room temperature, filtered and dried to give 1.8g (yield 72.7%) of the compound of formula I with an HPLC purity of 99.25% and a maleic acid content of 13.78%.
Comparative example 4:
to a 250mL bottle were added 7.9g of 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid, 120mL of ethanol, 30mL of water and 1.8g of maleic acid, reacted for 2 hours at 70-80℃and filtered after cooling to room temperature, 7.5g (yield 80.5%) of the compound of formula I after drying was obtained, HPLC purity 99.84% and maleic acid content 2.10%.
The maleic acid content in the compound of the formula I can be qualified when the maleic acid and 1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid are salified according to the proportion of 1:1 by mol, the 100% salification rate corresponds to 15.16% of the maleic acid content, and the salification rate is in the range of 95% -105%, namely, the maleic acid content is 14.4-15.9%. The compounds of formula I obtained in comparative examples 2 to 4 were found to have a poor maleic acid content.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the claims of the present invention. The scope of the patent of the invention should therefore be determined with reference to the appended claims, which are to be construed as in accordance with the doctrines of claim interpretation.
Claims (5)
1. A method for preparing a 2-acylaminothiazole derivative maleate crystal form, which is characterized by comprising the following steps:
1- (3-chloro-5- { [4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazine-1-yl) -1, 3-thiazole-2-yl ] carbamoyl } pyridine-2-yl) piperidine-4-carboxylic acid, and after being mixed with a solvent and maleic acid, the mixture reacts at the reaction temperature of 20-60 ℃, and is filtered and dried, the crystal form C of the compound of the formula I is obtained;
wherein the solvent is selected from acetone or acetonitrile.
2. The process according to claim 1, wherein the molar ratio of 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid to maleic acid is 1:1.1 to 2.0, for example 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.8 or 1:2.0.
3. The preparation process according to claim 1 or 2, characterized in that the mass to volume ratio of 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid to solvent, expressed in g/mL, is 1:10 to 30, for example 1:10, 1:15, 1:20, 1:25 or 1:30.
4. A method according to any one of claims 1 to 3, characterized in that the reaction time is at least 0.5h, preferably not more than 5h, such as 0.5h, 1h, 2h, 3h, 4h or 5h.
5. The process according to any one of claims 1 to 4, wherein the reaction temperature is 20 to 50 ℃, such as 20 to 30 ℃,30 to 40 ℃ or 40 to 50 ℃.
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