CN113698404A - Hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide compound with low solvent residue and preparation method thereof - Google Patents
Hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide compound with low solvent residue and preparation method thereof Download PDFInfo
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Abstract
The present disclosure relates to hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide compounds with low solvent residue and methods of making the same. In particular to (3aR,5s,6aS) -N- (3-methoxyl-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydro-cyclopenta [ c ] pyrrole-2 (1H) -formamide with low solvent residue and impurity content, a crystal form and a preparation method thereof.
Description
Technical Field
The disclosure belongs to the technical field of medicines, and particularly relates to a compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide with low solvent residue and impurity content and a preparation method thereof.
Background
The JAK inhibitor is mainly used for screening therapeutic drugs for diseases of the blood system, tumors, rheumatoid arthritis, psoriasis and the like in clinic. Currently, several JAK inhibitors are entering clinical research, such as lucolinib (Ruxolitinib) approved by the FDA for the treatment of hematological diseases and Tofacitinib (Tofacitinib) for rheumatoid arthritis.
WO2013091539 discloses a series of novel JAK kinase inhibitors, including the compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide. While WO2014194741 discloses hydrogen sulfates of the compounds. WO2016054959 and WO2016070697 disclose crystalline forms I and II, respectively, of the bisulfate salt of the compound. CN201780001376.6 discloses a pharmaceutical composition containing the compound bisulfate. In the prior art, the compound is mostly developed into clinical medicines in a salt form, and a preparation is developed by using a compound raw material medicine meeting the Chinese pharmacopoeia residual solvent standard.
Residual solvents in drugs, defined in ICH (international human drug registration and harmonization of pharmaceutical technology) as organic volatile compounds produced or used in the production of drug substances or excipients, and in the preparation of formulations, cannot be completely eliminated in the process. The guiding principle classifies the residual solvent according to the degree of harm and sets the acceptable amount of the residual solvent under the condition of ensuring the safety of human bodies, namely the limit, and provides some toxicologically acceptable levels of the residual solvent. According to the ICH guidelines, residual solvents are classified into three classes, namely first class solvents, second class solvents, and third class solvents. The first group of solvents refers to solvents known to be carcinogenic and strongly suspected of being harmful to humans and the environment, including benzene (2ppm), carbon tetrachloride (4ppm), 1, 2-dichloroethane (5ppm), 1-dichloroethane (8ppm), and the like. The second solvent is a solvent having no genotoxicity but causing carcinogenicity to animals, and includes chloroform (60ppm), 1, 4-dioxane (380ppm), dimethylacetamide (1090ppm), methanol (3000ppm), dichloromethane (600ppm), n-hexane (290ppm), and the like. The third kind of solvent is a solvent with low toxicity to human body, and comprises acetone, ethyl acetate, ethanol, pentane, dimethyl sulfoxide, isobutyl acetate and tributyl methyl ether.
In the preparation of the compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide, solvents such aS methanol, ethanol, acetone, dichloromethane, and dimethyl sulfoxide are usually used. However, the compound obtained by the conventional preparation method cannot meet the regulations of solvent residue in Chinese pharmacopoeia 2015 (methanol is less than or equal to 0.3%, ethanol is less than or equal to 0.5%, dichloromethane is less than or equal to 0.06%, N-hexane is less than or equal to 0.029%, tetrahydrofuran is less than or equal to 0.072%, dimethyl sulfoxide is less than or equal to 0.5%, and N, N-dimethylformamide is less than or equal to 0.088%), and particularly, the solvent similar to dimethyl sulfoxide has the characteristics of high boiling point and low volatility, and is easy to wrap in a solid. Therefore, the development of a method capable of effectively controlling the solvent residue in the product is urgently needed in industrial production so aS to develop a pharmaceutical raw material drug of the (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide compound which meets the requirement of medicine.
In addition, in the process of drug development, the content of active ingredients and impurities of the drug directly affect the curative effect and toxic and side effects of the drug. In order to obtain a safe and effective medicine, the limit of related substances (impurities) of the medicine is strictly regulated by Chinese pharmacopoeia 2015 (the impurity formula D is less than or equal to 0.6 percent),
disclosure of Invention
The present disclosure provides a compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide, wherein the content of organic solvent is less than 2.0% by mass, including 2.0%, 1.90%, 1.80%, 1.70%, 1.60%, 1.50%, 1.40%, 1.30%, 1.20%, 1.10%, 1.00%, 0.90%, 0.80%, 0.70%, 0.60%, 0.50%, 0.40%, 0.30%, 0.20%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or less.
In some embodiments, the compound has less than 0.3%, 0.5%, 0.06%, 0.03%, 0.08%, 0.6%, 0.1% methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethylsulfoxide, N-dimethylformamide, respectively. In some embodiments, the compound contains less than 0.2%, 0.5%, 0.01%, 0.05%, 0.5%, 0.01% methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethylsulfoxide, N-dimethylformamide, respectively. In some embodiments, the compounds have less than 100ppm, 50ppm, 10ppm, and 10ppm methanol, dichloromethane, n-hexane, and tetrahydrofuran, respectively. In other embodiments, the amount of the other solvent than methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethylsulfoxide, and N, N-dimethylformamide in the compound complies with the chinese pharmacopoeia limits for residual solvents.
In another aspect, provided in some embodiments are compounds in which the content of process impurity phenyl 3-methoxy-5-carbamate-1, 2, 4-thiadiazole that is a compound of formula D is less than 1%, including 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less, preferably less than 0.6%,
in some embodiments, the compounds described in the present disclosure are present in an amount greater than 97.00%, in non-limiting examples, greater than 97.00%, 97.10%, 97.20%, 97.30%, 97.40%, 97.50%, 97.60%, 97.70%, 97.80%, 97.90%, 98.00%, 98.10%, 98.20%, 98.30%, 98.40%, 98.50%, 98.52%, 98.54%, 98.56%, 98.58%, 98.60%, 98.62%, 98.64%, 98.66%, 98.68%, 98.70%, 98.72%, 98.74%, 98.76%, 98.78%, 98.80%, 98.82%, 98.84%, 98.86%, 98.88%, 98.90%, 98.92%, 98.94%, 98.96%, 98.98%, 99.00%, 99.02%, 99.04%, 99.06%, 99.08%, 99.10%, 99.12%, 99.14%, 99.16%, 99.18%, 99.22%, 99.24%, 99.30%, 99.99.99.30%, 99.99.99.99.42%, 99.99.99.42%, 99.30%, 99.99.30%, 99.30%, 99.64%, 99.60%, 99.70%, 40%, 99.70%, 98.80%, 98.72%, 98.80%, 98%, 95%, 98.80%, 95%, 99.80%, 99.90%, 99.98%, 99.90%, 99.98%, 99.30%, 99.99.99.99.50%, 99.99.99.50%, 99.99.50%, 99.50%, 99.99.99.99.50%, 99.50%, 99.99.50%, 99.50%, 99.99.99.99.99.50%, 99.99.99.50%, 99.50%, 99.99.99.99.99.99.99.50%, 99.99.30%, 99.30%, 99.50%, 99.99.50%, 99.50%, 99.30%, 99.50%, 99.99.30%, 99.50%, 99%, 99.50%, 99.99.99.50%, 99.50%, 99.99., 99.68%, 99.70%, 99.72%, 99.74%, 99.76%, 99.78%, 99.80%, 99.82%, 99.84%, 99.86%, 99.88%, 99.90%, 99.92%, 99.94%, 99.96%, 99.98%, any value between the two or higher, preferably greater than 99.00%.
In another aspect, the compounds of the present disclosure are of crystalline structure. In some embodiments, the compound has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 Θ, having characteristic peaks at 9.11, 12.43, 13.54, 15.54, 19.62, 25.85, and 26.99.
In some embodiments, the X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 Θ angles, has characteristic peaks at 9.11, 10.66, 12.43, 13.54, 15.54, 19.62, 21.04, 25.55, 25.85, and 26.99.
In alternative embodiments, the compounds have characteristic peaks in the X-ray powder diffraction pattern expressed in degrees 2 θ at diffraction angles of 9.11, 10.66, 12.43, 12.71, 13.54, 15.54, 16.52, 19.62, 21.04, 21.39, 25.55, 25.85, and 26.99.
Further, in alternative embodiments, the compounds have characteristic peaks at 9.11, 10.66, 12.43, 12.71, 13.54, 15.54, 16.52, 19.34, 19.62, 21.04, 21.39, 22.88, 25.55, 25.85, and 26.99.
In other embodiments, the compound has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 θ, as shown in FIG. 1.
In other embodiments, the 2 θ angle error ranges from ± 0.20.
In another aspect of the present disclosure, there is provided a process for preparing the aforementioned compound, comprising at least one step of crystallization from an organic solvent containing water.
In some embodiments, the foregoing methodsThe organic solution contains a solvent (I) and a solvent (II), the solvent (I) is dimethyl sulfoxide, and the solvent (II) is selected from C1-6At least one of alkyl alcohol, ethyl acetate, water, n-hexane, acetone, isopropyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, 1, 4-dioxane or dichloromethane, wherein C is1-6The alkyl alcohol is preferably selected from methanol, ethanol, isopropanol.
In some embodiments, a method of making the foregoing compounds comprises:
a) mixing a crude compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydro-cyclopenta [ c ] pyrrole-2 (1H) -formamide with a solvent (I), and stirring for dissolving or heating for dissolving;
b) then adding a solvent (II), preferably at least one of methanol, ethanol, isopropanol and water, more preferably ethanol, for crystallization;
c) adding the solid obtained in the step b) into a solvent (III), stirring for dissolving or heating for dissolving, wherein the solvent (III) is dimethyl sulfoxide;
d) and then adding a solvent (IV), preferably a mixed solution of at least one of methanol, ethanol or isopropanol and water, for crystallization.
In some embodiments, a method of making the foregoing compounds comprises:
a) mixing a compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide with dimethyl sulfoxide, and stirring or heating to dissolve the mixture;
b) then adding ethanol for crystallization;
c) adding the solid obtained in the step b) into dimethyl sulfoxide, and stirring for dissolving or heating for dissolving;
d) then adding a mixed solution of ethanol and water for crystallization.
In other embodiments, the process for preparing the aforementioned compounds preferably comprises a step of slurry purification.
In other embodiments, the methods of making the foregoing compounds further comprise the steps of filtering, washing, or drying, preferably under reduced pressure, at a pressure < -0.08 MPa.
In some embodiments, the volume (ml) of the solvent (I) used in the method is 1 to 50 times of the weight (g) of the compound, and may be 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
In other embodiments, the ratio of the volume (ml) of solvent (I) to the volume (ml) of solvent (II) used in the present process is from 10:1 to 1:10, and may be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1: 10; preferably 1:1 to 1: 10. .
In other embodiments, the ratio of the volume (ml) of solvent (III) to the volume (ml) of solvent (IV) used in the present process is from 10:1 to 1:10, and may be from 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1: 10; preferably 1:1 to 1: 10.
In another aspect, the present disclosure also provides a compound prepared by the foregoing preparation method, wherein the content of the organic solvent is less than 2% by mass, and further wherein the content of methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethyl sulfoxide, and N, N-dimethylformamide is less than 0.3%, 0.5%, 0.06%, 0.03%, 0.08%, 0.6%, and 0.1%, respectively.
The present disclosure also provides a pharmaceutical composition comprising the aforementioned compound or a compound prepared by the aforementioned method, and optionally a pharmaceutical excipient from pharmaceutically acceptable excipients.
The present disclosure also provides a pharmaceutical composition prepared from the aforementioned compound and optionally a pharmaceutically acceptable excipient.
The present disclosure also provides a method of preparing a pharmaceutical composition comprising the step of mixing the aforementioned compound or a compound prepared by the aforementioned method with a pharmaceutically acceptable excipient.
The disclosure also provides the use of the aforementioned compound or a compound prepared by the aforementioned method or a composition from the aforementioned in the manufacture of a medicament for treating or preventing a disease associated with a JAK kinase.
The present disclosure also provides the use of the aforementioned compound or a compound prepared by the aforementioned method or the aforementioned composition for the manufacture of a medicament for the treatment or prevention of rheumatic and rheumatoid arthritis.
The "2 theta or 2 theta angle" referred to in this disclosure means the diffraction angle, theta being the bragg angle in degrees or degrees; the error range of each characteristic peak 2 theta is + -0.20, and may be-0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
In the present disclosure, "differential scanning calorimetry or DSC" refers to measuring the temperature difference and heat flow difference between a sample and a reference substance during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemical changes related to the thermal effect, and obtain the phase change information of the sample.
In the present disclosure, the drying temperature is generally 25 ℃ to 100 ℃, preferably 40 ℃ to 70 ℃, more preferably 45 ℃ to 55 ℃, and the drying can be carried out under normal pressure or reduced pressure, the pressure is less than-0.08 MPa, and the drying time is 5 h to 10h, preferably 7h to 8 h.
In the present disclosure, the numerical values such as the related substance content are data calculated by measurement, and certain errors are inevitable. Generally speaking, ± 10% are within reasonable error. There is a degree of variation in the error which is not more than + -10%, which may be + -9%, + -8%, + -7%, + -6%, + -5%, + -4%, + -3%, + -2% or + -1%, preferably + -5%, depending on the context in which it is used.
Drawings
FIG. 1: an XRPD pattern of a crystalline form of the compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide I.
Detailed Description
The present disclosure will be explained in more detail with reference to examples or experimental examples, which are only used to illustrate the technical solutions in the present disclosure, and do not limit the spirit and scope of the present disclosure.
The reagents used in the present disclosure are commercially available.
The test conditions of the instruments used in the experiments in this disclosure:
1. gas Chromatography (Gas Chromatography, GC)
The instrument model is as follows: agilent 7890B
Detection object and corresponding detection conditions: residual solvents such as methanol, ethanol, acetone, dichloromethane, methyl tert-butyl ether, n-hexane, ethyl acetate, tetrahydrofuran, ethylene glycol dimethyl ether, and toluene. A capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as a stationary liquid is used as a chromatographic column (30m is multiplied by 0.53mm is multiplied by 3.0 m); the temperature of a sample inlet is 160 ℃; FID detector temperature 260 ℃; temperature rising procedure: starting the column temperature at 40 ℃, keeping for 6min, heating to 180 ℃ at 20 ℃/min, and keeping for 6 min; the carrier gas is nitrogen, the flow rate is 4.0ml/min, and the split ratio is 10: 1. Headspace column incubator: 80 ℃; and (3) quantitative ring: 90 ℃; transmission line: 100 ℃; sample balancing: 20min, GC cycle time: 26 min; dimethyl sulfoxide (DMSO) is used as solvent.
Detection object and corresponding detection conditions: dimethylsulfoxide (DMSO) residual solvent. Capillary column using polyethylene glycol (or similar polarity) as stationary liquid as chromatographic column
The temperature of a sample inlet is 120 ℃; FID detector temperature 260 ℃; temperature rising procedure: the initial column temperature is 80 ℃, the temperature is increased to 180 ℃ at the speed of 10 ℃/min, and the temperature is kept for 6 min; the carrier gas is nitrogen, the flow rate is 3.0ml/min, and the split ratio is 10: 1; sample introduction amount: 1 mul; 1, 3-dimethyl-2-imidazolidinone (DMI) is used as a solvent.
2. High Performance Liquid Chromatography (HPLC)
The instrument model is as follows: agilent 1260, column: XSelect HST 3 column (4.6X 150mm, 3.5 μm); detection wavelength: 218 nm; mobile phase: 0.01mol/L potassium dihydrogen phosphate solution is added with 0.1 percent triethylamine and acetonitrile to be used as a mobile phase.
3. X-ray Powder Diffraction Spectroscopy (XRPD)
(1) The instrument model is as follows: bruker D8 Focus X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 2-40 °
Voltage: 40KV, current: 40mA
Example 1:
a) 3-methoxy-1, 2, 4-thiadiazole-5-amine 34a (500mg,3.82mmol) and phenyl chloroformate 34b (600mg, 3.82mmol) were dissolved in 20mL of dichloromethane, and triethylamine (0.8mL, 5.73mmol) was added dropwise, and the reaction was completed dropwise. The reaction mixture was diluted with water, separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried, filtered, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the product, phenyl 3-methoxy-1, 2, 4-thiadiazol-5-ylcarbamate (200mg, white solid) in 20.8% yield.
MS m/z(ESI):252.0[M+l]
b) N-methyl-N- ((3aR,5s,6a) -octahydrocyclopenta [ c ] pyrrol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride 6a (120mg, 0.47mmol) was dissolved in 15mL of tetrahydrofuran, the 3-methoxy-1, 2, 4-thiadiazol-5-yl phenyl carbamate (117m g, 0.47mmol) prepared above was added dropwise, triethylamine (0.13mL, 0.94mmol) was added dropwise, and the reaction was completed at 60 ℃. To the reaction solution was added water, followed by extraction with dichloromethane, and the organic phases were combined, washed with saturated sodium chloride solution, dried, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give a crude compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide (50mg, white solid) (compound a) in 25.9% yield and 98.5% purity by HPLC.
MS m/z(ESI):412.9[M-l]
Example 2:
respectively taking 2g of a sample of the compound a in the example 1, refining according to 3 solvent systems in the table 1, namely respectively adding 16ml of dimethyl sulfoxide, heating to 45-55 ℃ to dissolve, respectively adding 40ml of acetone, 16ml of water and 32ml of ethanol while stirring, stirring to crystallize, filtering, and drying a filter cake in vacuum at 45-55 ℃ for 8 hours to respectively obtain 1.5g, 1.9g and 1.86g of solid samples, wherein the yield is 75.0%, 95.3% and 93.0%. The purity was 99.51%, 98.72% and 99.24% by HPLC, respectively.
TABLE 1
From the above experiments, it was found that the yield of compound a was low when purified with DMSO/acetone. The DMSO/water system has high refining yield but low purity. Only by DMSO/ethanol refining, the yield and purity can reach higher levels.
Example 3:
4L of tetrahydrofuran was charged in a reaction flask, and 373.7g (3.67mol, 4.32eq) of phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate 229.8g (0.91mol, 1.07eq) and 220.0g (0.85mol, 1.0eq) of N-methyl-N- ((3aR,5s,6aS) -octahydrocyclopenta [ c ] pyrrol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine were added with stirring, and heated under reflux, cooled, and filtered. Vacuum drying the filter cake at 45-55 ℃ to obtain 340.2g of a crude product of the compound a with the purity of 96.36%.
Experimental example 1: taking 220.0g of the crude product of the compound a, adding 1760ml of dimethyl sulfoxide, heating, dissolving, then performing suction filtration, collecting filtrate, slowly adding 3.5L of absolute ethyl alcohol while stirring, performing suction filtration, and performing vacuum drying on a filter cake for 8 hours at 45-55 ℃ under the pressure of less than-0.08 MPa to obtain 181.2g of a solid product with the purity of 98.69%. The content of impurity D was 0.71% by HPLC. Does not meet the standard that the impurity D is less than or equal to 0.6 percent specified in the Chinese pharmacopoeia 2015 edition. The residual solvent contents of methanol, ethanol, dichloromethane, n-hexane, tetrahydrofuran and dimethyl sulfoxide are respectively 0.0073%, 2.2145%, 0.0079%, 0.0003%, 0.0031% and 0.89% by GC detection. According to the specification of Chinese pharmacopoeia 2015 year edition, methanol is less than or equal to 0.3%, ethanol is less than or equal to 0.5%, dichloromethane is less than or equal to 0.06%, n-hexane is less than or equal to 0.029%, tetrahydrofuran is less than or equal to 0.072%, and dimethyl sulfoxide is less than or equal to 0.5%, wherein ethanol and dimethyl sulfoxide solvent residue do not meet the standard of Chinese pharmacopoeia.
Example 4:
experimental example 1: 40.0g of the solid sample purified in Experimental example 1 of example 3 was taken and put into a reaction flask, and 320ml of dimethyl sulfoxide was added, followed by heating, clearing, suction filtration, transfer of the filtrate into the reaction flask, stirring and heating, addition of 640ml of an anhydrous ethanol/purified water mixed solvent (volume ratio: 1), and stirred for crystallization. Suction filtration is carried out, and the filter cake is added into 400ml of absolute ethyl alcohol/purified water mixed solvent (volume ratio is 1: 1). And (4) carrying out suction filtration, and drying the filter cake for 8 hours in vacuum at the temperature of 45-55 ℃ and under the pressure of less than-0.08 MPa to obtain 38.8g of white-like solid with the purity of 99.38%. The HPLC and GC detection results are shown in Table 2, and the content of related substance impurity D and the solvent residue both accord with the specification of Chinese pharmacopoeia 2015 edition.
TABLE 2
Experimental example 2: 3000g of the crude compound a prepared in the example 3 is taken, dimethyl sulfoxide is added, heating, clearing and suction filtration are carried out, filtrate is collected, absolute ethyl alcohol/purified water mixed solvent (volume ratio is 1:1) is stirred and suction filtration is carried out, and a filter cake is dried in vacuum under the condition of 45-55 ℃ and pressure lower than-0.08 MPa to obtain a solid product. The content of related substance impurity D is detected to be 0.37%, and the content of residual solvent ethanol is 0.4721%.
Therefore, the purification method adopting two refining steps of dimethyl sulfoxide/ethanol and dimethyl sulfoxide/ethanol water solution has better effect.
Test example 1:
the XRPD pattern of the sample obtained in experimental example 1 was shown in fig. 1, and the characteristic peak positions are shown in table 3 below, when measured by an X-ray powder diffractometer:
TABLE 3
Test example 2:
firstly, the stability of the sample obtained in the experimental example 1 under grinding, tabletting and heating conditions is considered:
a. taking 1g of sample, grinding in a mortar for 10min under the protection of nitrogen, and scanning by X-ray powder diffraction and a differential scanning calorimeter;
b. taking 1g of sample, spreading, heating at 80 ℃ for 3h, and scanning by X-ray powder diffraction and differential scanning calorimeter;
c. samples were pressed into tablets and scanned by X-ray powder diffraction and differential scanning calorimetry;
the results show that: comparing the obtained X-ray powder diffraction and differential scanning calorimeter scanning map with the map before treatment, and investigating the change condition, the result shows that the sample is stable under the conditions of grinding, heating and tabletting.
Secondly, the stability of the sample is examined under the conditions of 25 ℃ and RH 90% + -5% for 0-30 days:
the experimental result shows that the X-ray powder diffraction pattern and the DSC pattern of the sample under the conditions are respectively consistent with the initial X-ray powder diffraction pattern and the initial DSC pattern, the physical stability is good, the maximum unknown single impurity and total impurity absolute value change amount is small, and the chemical stability is good.
Thirdly, the stability of the sample is inspected under the conditions of 60 ℃ and RH 90% + -5%:
the experimental result shows that the X-ray powder diffraction pattern and the DSC pattern of the sample under the conditions are respectively consistent with the initial X-ray powder diffraction pattern and the initial DSC pattern, the physical stability is good, the maximum unknown single impurity and total impurity absolute value change amount is small, and the chemical stability is good.
Claims (16)
1. The compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide is characterized in that the mass percentage of the organic solvent is lower than 2.0%.
2. The compound of claim 1, wherein the methanol, ethanol, dichloromethane, hexane, tetrahydrofuran, dimethylsulfoxide, and N, N-dimethylformamide are present in an amount of less than 0.3%, 0.5%, 0.06%, 0.03%, 0.08%, 0.6%, 0.1%, respectively.
3. The compound of claim 1 or 2, wherein the contents of methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethylsulfoxide, and N, N-dimethylformamide are less than 0.2%, 0.5%, 0.01%, 0.05%, 0.5%, 0.01%, respectively.
4. The compound according to any one of claims 1 to 3, wherein the compound further comprises a solvent other than methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethylsulfoxide and N, N-dimethylformamide, and the content thereof is in accordance with the limit of the Chinese pharmacopoeia for residual solvents.
5. The compound according to any one of claims 1 to 4, which is a crystalline compound having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ having characteristic peaks at 9.11, 12.43, 13.54, 15.54, 19.62, 25.85 and 26.99.
6. The compound of any one of claims 1-4, wherein an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 θ, has characteristic peaks at 9.11, 10.66, 12.43, 13.54, 15.54, 19.62, 21.04, 25.55, 25.85, and 26.99.
7. The compound of any one of claims 1-6, wherein an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 θ, has characteristic peaks at 9.11, 10.66, 12.43, 12.71, 13.54, 15.54, 16.52, 19.62, 21.04, 21.39, 25.55, 25.85, and 26.99.
8. The compound of any one of claims 1-7, wherein an X-ray powder diffraction pattern, expressed in terms of diffraction angle, 2 Θ, is shown in figure 1.
9. The compound of any one of claims 5-8, wherein the 2 θ angle error is within ± 0.20.
10. A compound according to any one of claims 1 to 9, wherein the content of the compound of formula D is less than 1%, preferably less than 0.6%,
11. a process for the preparation of a compound according to any one of claims 1 to 10, comprising at least one step of crystallization from an organic solvent comprising water.
12. The method of claim 11, wherein the organic solvent comprises a solvent (I) and a solvent (II), wherein the solvent (I) is dimethyl sulfoxide and the solvent (II) is selected from C1-6At least one of alkyl alcohol, ethyl acetate, water, n-hexane, acetone, isopropyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, 1, 4-dioxane or dichloromethane, wherein C is1-6The alkyl alcohol is preferably selected from methanol, ethanol, isopropanol.
13. A method according to claim 11 or 12, characterized in that it comprises:
a) mixing a crude compound (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydro-cyclopenta [ c ] pyrrole-2 (1H) -formamide with a solvent (I), and stirring for dissolving or heating for dissolving;
b) then adding a solvent (II), preferably at least one of methanol, ethanol, isopropanol and water, more preferably ethanol, for crystallization;
c) adding the solid obtained in the step b) into a solvent (III), stirring for dissolving or heating for dissolving, wherein the solvent (III) is dimethyl sulfoxide;
d) and then adding a solvent (IV), preferably a mixed solution of at least one of methanol, ethanol or isopropanol and water, for crystallization.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a compound prepared by a process according to any one of claims 11 to 13, and optionally pharmaceutically acceptable excipients.
15. A pharmaceutical composition prepared from a compound according to any one of claims 1 to 10 and optionally a pharmaceutically acceptable excipient.
16. Use of a compound according to any one of claims 1 to 10 or a compound prepared according to any one of claims 11 to 13 or a composition according to claim 14 or 15 for the manufacture of a medicament for the treatment or prophylaxis of rheumatic and rheumatoid arthritis.
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