CN102060842B - 3-(substituted xylylenimine-2-yl)-2,6-piperidine diketone polymorph and medical composition - Google Patents
3-(substituted xylylenimine-2-yl)-2,6-piperidine diketone polymorph and medical composition Download PDFInfo
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Abstract
The invention discloses a polymorph of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidine-2,6-diketone. In addition, the invention discloses a preparation method and a medical composition of the polymorph.
Description
The application is that the application number submitted on November 2nd, 2009 is 200910210392.3, denomination of invention is dividing an application that " 3-(substituted-dihydro isoindole-2-yl)-2,6-dioxopiperidine polymorphic form and medicinal compositions " applied for.
Technical field
The present invention relates to the polymorphic of medical compounds, more particularly, relate to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form of 6-diketone in addition, the invention still further relates to preparation method and the pharmaceutical composition thereof of this polymorphic form.
Background technology
Muller etc. are at " Amino-substituted thalidomide analogs:Potent inhibitors ofTNF-α production " (Bioorganic ﹠amp; Medicinal Chemistry Letters, Vol.9, Issue 11, on June 7th, 1999, pp1625-1630) and described a kind of 3-(substituted-dihydro isoindolone-2-yl)-2 in Chinese patent ZL97180299.8,6-dioxopiperidine, particularly 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone.In December, 2005,3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone, go through to go on the market in the U.S. as a kind of immunomodulator with antitumor character, be used for the treatment of myelodysplastic syndrome and multiple myeloma.
the example that 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone can be used for treating disease and symptom includes but not limited to: the treatment myeloproliferative disease, Myelodysplastic syndromes, vasculogenesis, cancer, pain, macular degeneration, Myelodysplastic syndromes, asbestosis, anemia, nervous system disorders, dyssomnia, tetter, pulmonary hypertension, immune deficiency disorder, management of parasitic diseases, central nervous system injury etc., i.e. Chinese patent application, application number is 97180299.8, 98805614.3, 03825761.0, 03825567.7, 03813733.X, 03816899.5, 200610150484.3, 200380107531.0, 200710103924.4, 200380108093.X, 200380108398.0, 200480043341.1, 200480038171.8, 200480035556.9, 200480020445.0, 200480043535.1, 200480040004.7, 200480041252.3, 200480042208.4, 200580017546.7, 200580016344.0, 200580020628.7, 200580037220.0, 200580047364.4, 200580046371.2, 200580047031.1 etc., introduce here as a reference fully.
U.S. Celgene Corp. has put down in writing 3-(4-amino-1-oxo-1 in Chinese patent application file CN 1871003A (publication number), 3-dihydro-2H-isoindole-2-yl) piperidines-2, eight kinds of polymorphic forms of 6-diketone and the preparation method who provides, its preparation method is with 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone joins 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, (as: hexane in the insoluble,practically water of 6-diketone or organic solvent, toluene, acetone, acetonitrile, methyl alcohol, ethyl acetate) after heating for dissolving the cooling crystallize out or in the pulp system of solid-liquid two-phase long-time the stirring turn brilliant and get.
Due to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone is the organic solvent such as water-soluble or hexane, toluene, acetone, acetonitrile, methyl alcohol, ethyl acetate hardly, even also need to use the solvent of a large amount of (more than 100 times) under heating state, be unfavorable for the industrially scalable preparation; In addition, this method of application documents CN 1871003A can not make the appearance luster of product make moderate progress by original light yellow white or the off-white color of becoming; And do not consider yet and to avoid using harmful (as toluene, acetonitrile etc.) two classes or the above organic solvent of two classes to reduce the detrimentally affect that in product, the residual organic solvent of meeting causes human body when the finished product synthesize as far as possible.
For the polymorphic of medicine, different polymorphics can have different chemistry and physical property, comprises fusing point, chemical stability, apparent solubility, dissolution rate, optics and mechanical properties, vapour pressure and density.These character can directly affect processing or the production of bulk drug and preparation, and can affect stability, solubleness and the bioavailability of preparation.Therefore, the polymorphic of medicine has great importance for quality, security and the validity of pharmaceutical preparation.For 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone, this area exists such demand: the novel polymorphic that is suitable for commercial scale production, physicochemical property excellence.
Summary of the invention
The present inventor is through a large amount of research, be surprisingly found out that new 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form, successfully solved the deficiency that prior art exists, it has physico-chemical property excellence, a good stability, be more suitable for the advantage such as industrially scalable preparation.
The purpose of this invention is to provide new 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form.
Another object of the present invention is to provide the preparation method of above-mentioned novel polymorphic thing.
The 3rd purpose of the present invention is to provide the medicinal compositions that contains above-mentioned novel polymorphic thing.
Specifically, the invention provides a kind of half molecular water and be substantially free of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2 of other solvent, 6-diketone polymorphic form I.
3-provided by the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form I of 6-diketone semihydrate, use the Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have diffraction peak 11.9 ± 0.2 and 22.0 ± 0.2, particularly, one or more (with arbitrary combination in addition 15.6 ± 0.2,22.5 ± 0.2,23.8 ± 0.2,26.4 ± 0.2,27.5 ± 0.2,29.1 ± 0.2, comprise more than two, perhaps whole) diffraction peak; See Fig. 1.
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form I of 6-diketone semihydrate
| The peak numbering | 2θ | The Flex width | The d-value | Intensity | L/ |
| 1 | 11.940 | 0.212 | 7.4060 | 17891 | 84 |
| 2 | 13.020 | 0.235 | 6.7940 | 5996 | 28 |
| 3 | 13.780 | 0.188 | 6.4210 | 6550 | 31 |
| 6 | 15.620 | 0.235 | 5.6685 | 9017 | 42 |
| 9 | 17.960 | 0.259 | 4.9349 | 5895 | 28 |
| 10 | 19.080 | 0.235 | 4.6476 | 8374 | 39 |
| 11 | 19.480 | 0.235 | 4.5531 | 6273 | 30 |
| 12 | 20.580 | 0.235 | 4.3121 | 6162 | 29 |
| 15 | 21.980 | 0.235 | 4.0405 | 21530 | 100 |
| 16 | 22.520 | 0.259 | 3.9449 | 13747 | 64 |
| 18 | 23.760 | 0.259 | 3.7417 | 15053 | 70 |
| 19 | 24.400 | 0.212 | 3.6450 | 5016 | 24 |
| 21 | 26.440 | 0.282 | 3.3682 | 15819 | 74 |
| 22 | 27.520 | 0.353 | 3.2384 | 11455 | 54 |
| 23 | 29.060 | 0.306 | 3.0702 | 11190 | 52 |
| 24 | 30.980 | 0.306 | 2.8842 | 6238 | 29 |
| 25 | 32.000 | 0.376 | 2.7945 | 4934 | 23 |
| 26 | 33.040 | 0.306 | 2.7089 | 5313 | 25 |
| 28 | 34.440 | 0.259 | 2.6019 | 5469 | 26 |
3-provided by the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form I of 6-diketone semihydrate, its DSC scanning should be between 140～180 ℃ in the scope of first endotherm(ic)peak, particularly 164.87 ℃ of left and right, endotherm(ic)peak is arranged, its second endotherm(ic)peak is that maximum endothermic transition is about 268.86 ℃.3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the DSC collection of illustrative plates of 6-diketone semihydrate polymorphic form I is seen Fig. 3-1, the TGA collection of illustrative plates is seen Fig. 3-2.
In addition, 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone semihydrate polymorphic form I is with the infrared absorption pattern that the KBr compressing tablet records, and it is characterized by at about 3561.4cm
-1, 3507.4cm
-1, 3424.2cm
-1, 3345.8cm
-1, 3091.0cm
-1, 2912.5cm
-1, 1697.8cm
-1, 1658.8cm
-1, 1610.0cm
-1, 1494.3cm
-1, 1349.5cm
-1, 1201.4cm
-1There is absorption peak at the place; See Fig. 2.
3-of the present invention (4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone semihydrate polymorphic form I solid-state nuclear magnetic resonance carbon spectrogram, its characteristic displacement is at about δ (ppm): 22.25ppm, 30.18ppm, 43.63ppm, 45.98ppm, 50.45ppm, 110.19ppm, 111.24ppm, 114.25ppm, 115.06ppm, 117.25ppm, 118.18ppm, 124.22ppm, 125.20ppm, 125.91ppm, 126.88ppm, 128.87ppm, 129.93ppm, 132.96ppm, 133.88ppm, 140.62ppm, 143.27ppm, 168.67ppm, 170.13ppm, 171.38ppm, 173.44ppm, 174.67ppm, see Fig. 4.
In embodiments of the invention, the invention provides 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone semihydrate polymorphic form I, the method comprises the steps:
(1) with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone adds in the solution of dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) (DMSO), wherein: dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio usually should be greater than 1: 1; Preferably, be selected from: dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio were greater than 2: 1; Most preferably, be selected from: dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio are 3.5: 1 to 4: 1.Wherein: dimethyl sulfoxide (DMSO) and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio usually should be greater than 1: 1; Preferably, be selected from: dimethyl sulfoxide (DMSO) and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio were greater than 1.5: 1; Most preferably, be selected from: dimethyl sulfoxide (DMSO) and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio are 2.5: 1 to 3: 1.Under agitation heating makes its dissolving;
(2) drip the mixed solvent system of pure water or pure water and organic solvent; Wherein, the volume ratio of the volume of the mixed solvent body of pure water or pure water and organic solvent and dimethyl formamide and dimethyl sulfoxide (DMSO) usually should be greater than 1: 1; Preferably, be selected from: the volume of the mixed solvent body of pure water or pure water and organic solvent and the volume ratio of dimethyl formamide and dimethyl sulfoxide (DMSO) should be greater than 2: 1; Most preferably, be selected from: the volume of the mixed solvent body of pure water or pure water and organic solvent and the volume ratio of dimethyl formamide and dimethyl sulfoxide (DMSO) should be greater than 3: 1.wherein, described organic solvent is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and insoluble or sl. sol. one or more the mixed solvent of 6-diketone preferably, is selected from acetonitrile, trichloromethane, hexanaphthene, 1,2-dichloroethene, methylene dichloride, 1,2-glycol dimethyl ether, dioxane, cellosolvo, ethylene glycol, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, tetrahydrofuran (THF), toluene, 1,1,2-trieline, dimethylbenzene, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, the 3-methyl-1-butanol, butanone, methyl iso-butyl ketone (MIBK), isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1,1-di ethyl propyl ether, 1,1-Methylal(dimethoxymethane), 2,2-dimethoxypropane, octane-iso, isopropyl ether, methyl isopropyl Ketone, methyltetrahydrofuran, sherwood oil, most preferably, be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, the 3-methyl-1-butanol, butanone, methyl iso-butyl ketone (MIBK), isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1, the 1-di ethyl propyl ether, 1, the 1-Methylal(dimethoxymethane), 2, the 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, methyl isopropyl Ketone, methyltetrahydrofuran, one or more in sherwood oil etc., making mixed solvent system is binary or the above mixed system of binary that is comprised of water and organic solvent.Wherein the part by weight of water and above-mentioned organic solvent should greater than 10%, preferably, be selected from usually: the part by weight of water and above-mentioned organic solvent optimally, is selected from greater than 20%: the part by weight of water and above-mentioned organic solvent is greater than 30%;
(3) under agitation slowly cooling make and separate out solid;
(4) reclaim solid, reduced vacuum is dry.
in embodiments of the invention, the invention provides a kind of solvation 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic form II, use the Cu-Ka radiation, its X-ray diffracting spectrum, 2 θ that show with kilsyth basalt have diffraction peak 15.7 ± 0.2 and 25.2 ± 0.2, particularly, 7.8 ± 0.2, 8.6 ± 0.2, 14.2 ± 0.2, 17.1 ± 0.2, 17.9 ± 0.2, 18.8 ± 0.2, 21.4 ± 0.2, 21.9 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 24.2 ± 0.2, 27.1 ± 0.2, 29.3 ± 0.2 is one or more (with arbitrary combination in addition, comprise more than two, perhaps whole) diffraction peak, see Figure 13.
The 3-of solvation (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone
Polymorphic form II
| The peak numbering | 2θ | The Flex width | The d-value | Intensity | L/ |
| 1 | 7.780 | 0.212 | 11.3542 | 3887 | 35 |
| 2 | 8.580 | 0.259 | 10.2972 | 3889 | 35 |
| 4 | 14.180 | 0.259 | 6.2407 | 10819 | 95 |
| 5 | 14.600 | 0.188 | 6.0621 | 2759 | 25 |
| 6 | 15.040 | 0.235 | 5.8857 | 3457 | 31 |
| 7 | 15.680 | 0.212 | 5.6469 | 11410 | 100 |
| 8 | 16.360 | 0.212 | 5.4137 | 3413 | 30 |
| 9 | 17.060 | 0.212 | 5.1931 | 9678 | 85 |
| 10 | 17.920 | 0.259 | 4.9458 | 4770 | 42 |
| 11 | 18.760 | 0.235 | 4.7262 | 4035 | 36 |
| 12 | 19.520 | 0.212 | 4.5439 | 3733 | 33 |
| 13 | 19.920 | 0.235 | 4.4535 | 3350 | 30 |
| 14 | 21.400 | 0.212 | 4.1487 | 5096 | 45 |
| 15 | 21.940 | 0.259 | 4.0478 | 5065 | 45 |
| 16 | 22.580 | 0.235 | 3.9345 | 6307 | 56 |
| 17 | 23.380 | 0.376 | 3.8017 | 5613 | 50 |
| 18 | 24.160 | 0.235 | 3.6807 | 6624 | 59 |
| 19 | 24.540 | 0.235 | 3.6245 | 3649 | 32 |
| 20 | 25.160 | 0.235 | 3.5366 | 10617 | 94 |
| 21 | 26.800 | 0.188 | 3.3238 | 3634 | 32 |
| 22 | 27.060 | 0.188 | 3.2924 | 4818 | 43 |
| 24 | 29.300 | 0.259 | 3.0456 | 4521 | 40 |
| 26 | 30.480 | 0.212 | 2.9304 | 2319 | 21 |
| 27 | 30.860 | 0.235 | 2.8951 | 3105 | 28 |
(acetonitrile) provided by the present invention solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II, DSC scanning has the first endotherm(ic)peak at 140 to 170 ℃, preferably, located endotherm(ic)peak about 152.73 ℃, its second endotherm(ic)peak is that maximum endotherm(ic)peak is about 269.12 ℃; (acetonitrile) of the present invention solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the DSC collection of illustrative plates of 6-diketone polymorphic form II is seen Figure 15-1, the TGA collection of illustrative plates is seen Figure 15-2.
(acetonitrile) provided by the present invention solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II with the infrared absorption pattern that the KBr compressing tablet records, is characterized by at about 3466.9cm
-1, 3366.5cm
-1, 3223.8cm
-1, 3078.0cm
-1, 2957.2cm
-1, 2871.0cm
-1, 1687.2cm
-1, 1666.7cm
-1, 1346.5cm
-1, 1199.1cm
-1There is absorption peak at the place; See Figure 14.
In embodiments of the invention, the invention provides solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the preparation method of 6-diketone polymorphic form II, the method comprises the steps:
(1) with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone adds in anhydrous dimethyl formamide (DMF), wherein: anhydrous dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio are generally greater than 1: 1; Preferably, be selected from: anhydrous dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and weight ratio are greater than 2: 1; Most preferably, be selected from: anhydrous dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and weight ratio are greater than 3.5: 1 to 4: 1.Make its dissolving in stirring heating;
(2) drip 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2 be several times as much as the dimethyl formamide volume, the insoluble or sl. sol. anhydrous organic solvent of 6-diketone.Here, organic solvent and dimethyl formamide volume ratio usually should be greater than 1: 1; Preferably, be selected from organic solvent and dimethyl formamide volume ratio greater than 2: 1, most preferably, be selected from organic solvent and dimethyl formamide volume ratio greater than 3: 1.here, described organic solvent is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and one or more mixed solvents that the 6-diketone is insoluble preferably, are selected from acetonitrile, trichloromethane, hexanaphthene, 1,2-dichloroethene, methylene dichloride, 1,2-glycol dimethyl ether, dioxane, cellosolvo, ethylene glycol, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, tetrahydrofuran (THF), toluene, 1,1,2-trieline, dimethylbenzene, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, the 3-methyl-1-butanol, butanone, methyl iso-butyl ketone (MIBK), isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1,1-di ethyl propyl ether, 1,1-Methylal(dimethoxymethane), 2,2-dimethoxypropane, octane-iso, isopropyl ether, methyl isopropyl Ketone, methyltetrahydrofuran, sherwood oil, most preferably, be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, the 3-methyl-1-butanol, butanone, methyl iso-butyl ketone (MIBK), isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1, the 1-di ethyl propyl ether, 1, the 1-Methylal(dimethoxymethane), 2, the 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, methyl isopropyl Ketone, methyltetrahydrofuran, a kind of solvent of sherwood oil etc. or two or more mixed solvents,
(3) stir under slowly cooling make and separate out solid;
(4) reclaim solid, reduced vacuum is dry.
in embodiments of the invention, the invention provides solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form III of 6-diketone, use the Cu-Ka radiation, its X-ray diffracting spectrum, 2 θ that show with kilsyth basalt have diffraction peak 17.4 ± 0.2 and 24.5 ± 0.2, particularly, 14.5 ± 0.2,15.5 ± 0.2,18.7 ± 0.2,21.0 ± 0.2,21.9 ± 0.2,22.1 ± 0.2,24.0 ± 0.2,25.3 ± 0.2,27.8 ± 0.2 is one or more (with arbitrary combination in addition, comprise more than two, perhaps whole) peak, see Figure 24.
The 3-of solvation (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone
Polymorphic form III
| The peak numbering | 2θ | The Flex width | The d-value | Intensity | L/ |
| 1 | 7.660 | 0.165 | 11.5318 | 911 | 12 |
| 2 | 8.700 | 0.212 | 10.1555 | 970 | 13 |
| 3 | 13.980 | 0.212 | 6.3295 | 1777 | 24 |
| 4 | 14.480 | 0.212 | 6.1121 | 3334 | 44 |
| 6 | 15.440 | 0.212 | 5.7342 | 3384 | 45 |
| 7 | 15.720 | 0.165 | 5.6326 | 2108 | 28 |
| 8 | 16.300 | 0.212 | 5.4335 | 1679 | 23 |
| 9 | 17.340 | 0.235 | 5.1099 | 4285 | 57 |
| 10 | 17.780 | 0.235 | 4.9844 | 1551 | 21 |
| 11 | 18.140 | 0.212 | 4.8863 | 1585 | 21 |
| 12 | 18.640 | 0.212 | 4.7563 | 3080 | 41 |
| 13 | 19.380 | 0.188 | 4.5764 | 2319 | 31 |
| 14 | 20.200 | 0.329 | 4.3924 | 2199 | 29 |
| 15 | 20.920 | 0.235 | 4.2428 | 4001 | 53 |
| 16 | 21.820 | 0.188 | 4.0698 | 2919 | 39 |
| 17 | 22.120 | 0.188 | 4.0153 | 4094 | 54 |
| 18 | 22.740 | 0.235 | 3.9072 | 1962 | 26 |
| 19 | 23.540 | 0.235 | 3.7762 | 2590 | 35 |
| 20 | 24.020 | 0.282 | 3.7018 | 4122 | 55 |
| 21 | 24.520 | 0.282 | 3.6274 | 7608 | 100 |
| 22 | 25.240 | 0.235 | 3.5256 | 4272 | 57 |
| 23 | 27.760 | 0.235 | 3.2110 | 4234 | 56 |
| 24 | 29.540 | 0.212 | 3.0214 | 1965 | 26 |
| 25 | 30.040 | 0.235 | 2.9723 | 2254 | 30 |
| 26 | 30.300 | 0.212 | 2.9474 | 2162 | 29 |
| 30 | 35.700 | 0.306 | 2.5129 | 2036 | 27 |
3-(4-amino-1-oxo-1 of (acetone) provided by the present invention solvation, 3-dihydro-2H-isoindole-2-yl) piperidines-2, the DSC collection of illustrative plates of 6-diketone polymorphic form III, it has the first endotherm(ic)peak at 150 to 200 ℃, preferably, preferably, approximately 188.96 ℃ located the first endothermic transition, the second endotherm(ic)peak is that maximum endotherm(ic)peak is about 268.19 ℃; (acetone) of the present invention solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the DSC collection of illustrative plates of 6-diketone polymorphic form III is seen Figure 26-1, the TGA collection of illustrative plates is seen Figure 26-2.
(acetone) of the present invention solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III sees Figure 25 with the infrared absorption pattern that the KBr compressing tablet records, and it is characterized by at about 3466.7cm
-1, 3363.3cm
-1, 3228.2cm
-1, 3081.7cm
-1, 2958.5cm
-1, 2877.2cm
-1, 1688.5cm
-1, 1666.2cm
-1, 1609.1cm
-1, 1491.7cm
-1, 1347.3cm
-1, 1199.5cm
-1There is absorption peak at the place.
In embodiments of the invention, the invention provides solvation 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the preparation method of 6-diketone polymorphic form III, the method comprises the steps:
(1) with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone adds anhydrous dimethyl sulfoxide (DMSO).Wherein: methyl-sulphoxide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and mass ratio are for usually should be greater than 1: 1; Preferably, be selected from: dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and weight ratio were greater than 2: 1; Most preferably, be selected from: anhydrous dimethyl formamide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the volume of 6-diketone and weight ratio were greater than 3: 1.Heating makes its dissolving stirring slowly;
(2) drip 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2 be several times as much as the methyl-sulphoxide volume, the insoluble or sl. sol. anhydrous organic solvent of 6-diketone.Here, organic solvent and methyl-sulphoxide volume ratio usually should be greater than 1: 1; Preferably, be selected from organic solvent and methyl-sulphoxide volume ratio greater than 2: 1; Most preferably, be selected from organic solvent and methyl-sulphoxide volume ratio greater than 3: 1.organic solvent described here is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and undissolved one or more mixed solvents of 6-diketone preferably, are selected from acetonitrile, trichloromethane, hexanaphthene, 1,2-dichloroethene, methylene dichloride, 1,2-glycol dimethyl ether, dioxane, cellosolvo, ethylene glycol, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, tetrahydrofuran (THF), toluene, 1,1,2-trieline, dimethylbenzene, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, the 3-methyl-1-butanol, butanone, methyl iso-butyl ketone (MIBK), isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1,1-di ethyl propyl ether, 1,1-Methylal(dimethoxymethane), 2,2-dimethoxypropane, octane-iso, isopropyl ether, methyl isopropyl Ketone, methyltetrahydrofuran, sherwood oil, most preferably, be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, the 3-methyl-1-butanol, butanone, methyl iso-butyl ketone (MIBK), isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1, the 1-di ethyl propyl ether, 1, the 1-Methylal(dimethoxymethane), 2, the 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, methyl isopropyl Ketone, methyltetrahydrofuran, one or more kinds of mixed solvents in sherwood oil etc.,
(3) stir under slowly cooling make and separate out solid;
(4) reclaim solid, reduced vacuum is dry.
In the present invention, X-powdery diffractometry testing tool involved in the present invention and test condition are: anode turns target x-ray diffractometer D/max-2500/PC type (Rigaku); It is 3～40 ° of 0.3mm, 5 °/min of sweep velocity, sweep limits that copper target, graphite monochromator, tube voltage 40kv, tube current 100mA, divergent slit and anti-scatter slit are 1 °, reception slit.
DSC testing tool and test condition involved in the present invention are: U.S. Perkin ElmerDiamond DSC; With the heating of 10 ℃/min speed, from 25 ℃ to 300 ℃.
TGA testing tool and test condition involved in the present invention are: U.S. Perkin ElmerThermal Analysis Pyris 1TGA; With the heating of 10 ℃/min speed, from 25 ℃ to 500 ℃.
Solid-state nuclear magnetic resonance testing tool and test condition involved in the present invention are: instrument: BRUKER AVANCE III 400MHz wide chamber solid-state nuclear magnetic resonance spectrometer.Test condition: CP-MAS; Mode: rotating speed 14000Hz; Scanning times 1404 times; Relaxation delay: 40s; Duration of contact: 2ms; 13C frequency: 100.6234936MHz; 1H frequency: 400.1413530MHz
Related substance testing conditions and method involved in the present invention are: measure according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; 0.01mol/L (with phosphorus acid for adjusting pH value to 3.5)-methyl alcohol-acetonitrile (80: 15: 5) is moving phase to potassium primary phosphate; Detect wavelength 240nm; Theoretical plate number is pressed 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and the peak calculating of 6-diketone should be not less than 2000.3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the resolution of 6-diketone peak and adjacent impurity peaks should meet the requirements.
The condition determination of dissolution rate and method: measure according to two appendix X C first methods of Chinese Pharmacopoeia version in 2005.
Get this product, according to dissolution method, take water 500ml (5mg specification) and 1000ml (10mg and 25mg specification) as solvent, rotating speed is that per minute 100 turns, and operation in accordance with the law is in the time of 45 minutes, get solution appropriate, filter, discard just filtrate, get subsequent filtrate as need testing solution (5mg and 10mg specification); Precision measures subsequent filtrate 10ml, is diluted with water to 25ml, as need testing solution (25mg specification).Another precision takes 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone reference substance is appropriate, water is made and is approximately contained 3-(4-amino-1-oxo-1 in every 1ml, 3-dihydro-2H-isoindole-2-yl) piperidines-2, the solution of 6-diketone 10 μ g, product solution in contrast.Get above-mentioned two kinds of solution, according to ultraviolet visible spectrophotometry (two appendix IV A of Chinese Pharmacopoeia version in 2005), the place measures absorbancy at the 240nm wavelength, calculates the stripping quantity of every (or sheet) with absorbancy by external standard method.
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the characteristic of 6-diketone (semihydrate) polymorphic form I
One, solvability: test with reference to two notes on the use of Chinese Pharmacopoeia version in 2000.Method: precision takes 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and I is appropriate for 6-diketone (semihydrate) polymorphic form, slowly add a certain amount of solvent, powerful jolting was 30 seconds every 5 minutes, observed the dissolving situation in 30 minutes, the results are shown in Table 1.
Table 1 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone (semihydrate) polymorphic form I solubility test
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone (semihydrate) polymorphic form I:N, easily molten in dinethylformamide; Dissolve in methyl-sulphoxide and Glacial acetic acid; Slightly molten in the 0.1mol/L sodium hydroxide solution; Slightly soluble in 0.1mol/L hydrochloric acid, acetonitrile, methyl alcohol and acetone soln; Soluble,very slightly in water, ethanol and ethyl acetate.
Two, stability
1, exposure experiments to light
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone (semihydrate) polymorphic form I evenly shares to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, respectively at 5, sampling in 10 days detects, and contrasts with the result of 0 day.The results are shown in Table 2.The x-ray diffraction pattern of 10 days is seen Fig. 5; 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone (semihydrate) the polymorphic form I strong illumination DSC figure of 10 days sees Fig. 6.
Table 2 exposure experiments to light (4500 ± 500lx)
Annotate: 23～26 ℃ of temperature variation; Relative humidity variations 56%～63%
2, high temperature test
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) in future piperidines-2,6-diketone (semihydrate) polymorphic form I raw material is positioned in the sealing clean vial, be placed in 60 ℃ of thermostatic drying chambers, detect respectively at sampling in 5,10 days, and contrast with the result of 0 day.The results are shown in Table 3.60 ℃ of x-ray diffraction patterns of investigating 10 days are seen Fig. 7; 60 ℃ of DSC figure that investigate 10 days see Fig. 8.
Table 3 high temperature test (60 ℃)
Annotate: relative humidity variations 54%～62%
3, high wet test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone (semihydrate) polymorphic form I raw material is evenly shared to uncovered culture dish, thickness≤5mm, be placed in room temperature (25 ℃ of left and right), relative humidity is in 75 ± 5% fixed temperature and humidity incubator, respectively at 5, sampling in 10 days is measured, and contrasts with the result of 0 day.The results are shown in Table 4.Relative humidity is that 75 ± 5% high humiditys x-ray diffraction pattern of 10 days is seen Fig. 9; The DSC scintigram is seen Figure 10-1; TGA figure sees 10-2.
The high wet test of table 4 (room temperature, relative humidity, 75 ± 5%)
Annotate: 23～26 ℃ of temperature variation
4, accelerated test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the raw material of 6-diketone (semihydrate) polymorphic form I is packed with the polyethylene film plastic bag sealing, is placed in 40 ± 2 ℃, and relative humidity is in 75 ± 5% fixed temperature and humidity incubator, placed six months, respectively at 1,2,3,6 the end of month, sampling detected, and contrasted with the result of 0 month.The results are shown in Table 5.The x-ray diffraction pattern of 6 months is seen Figure 11; The DSC scintigram is seen Figure 12-1; TGA figure sees Figure 12-2.
Table 5 accelerated test (40 ℃, relative humidity 75%)
By the above results as can be known, the 3-that the present invention obtains (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone (semihydrate) polymorphic form I (60 ℃) in exposure experiments to light and high temperature test, outward appearance and content illustrate its stable in properties all without larger change; This product its outward appearance and content in high wet test all do not have considerable change, and water absorbability is very little.
This product is not observed crystal formation and is changed in long-term reserved sample observing test.So test shows that this polymorphous crystal habit is relatively stable.
In addition, weightless (water) process of polymorphic I occurs between 100 ℃ to 180 ℃, can differentiate for being that intermolecular form with the van der Waals interaction combination exists, according to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the TGA scintigram (Fig. 3-2) of 6-diketone polymorphic form I calculates weightless: 100.2825%-96.8165%=3.466%, result shows 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form I is semihydrate.
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the characteristic of 6-diketone polymorphic form II:
One, solvability: test with reference to two notes on the use of Chinese Pharmacopoeia version in 2000.Method: precision takes 3-(4-amino-1-oxo-1 of (acetonitrile) solvation, 3-dihydro-2H-isoindole-2-yl) piperidines-2, II is appropriate for 6-diketone polymorphic form, slowly add a certain amount of solvent, powerful jolting was 30 seconds every 5 minutes, observe the dissolving situation in 30 minutes, the results are shown in Table 6.
Table 6 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the solubility test of 6-diketone polymorphic form II
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II is easily molten in methyl-sulphoxide, DMF, and is slightly molten in Glacial acetic acid, 0.1mol/L hydrochloric acid soln; Slightly soluble in acetonitrile, acetone and 0.1mol/L sodium hydroxide solution; Soluble,very slightly in methyl alcohol, ethanol and ethyl acetate; Almost insoluble in water.
Two, stability
1, exposure experiments to light
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic II raw material is evenly shared to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, respectively at 5, sampling in 10 days detects, and contrasts with the result of 0 day.The results are shown in Table 7.The illumination X of 10 a days x ray diffration pattern x is seen Figure 16, and Figure 17 is seen in the illumination DSC of 10 days scanning.
Table 7 exposure experiments to light (4500 ± 500lx)
Annotate: 23～26 ℃ of temperature variation; Relative humidity variations 56%～63%
2, high temperature test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II raw material is positioned in the sealing clean vial, be placed in 60 ℃ of thermostatic drying chambers, detect respectively at sampling in 5,10 days, and contrast with the result of 0 day.The results are shown in Table 8.The high temperature x-ray diffraction pattern of 10 days is seen Figure 18; The high temperature DSC scintigram of 10 days is seen Figure 19.
Table 8 high temperature test (60 ℃)
Annotate: relative humidity variations 54%～62%
3, high wet test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II raw material is evenly shared to uncovered culture dish, thickness≤5mm, be placed in room temperature (25 ℃ of left and right), relative humidity is in 75 ± 5% fixed temperature and humidity incubator, respectively at 5, sampling in 10 days is measured, and contrasts with the result of 0 day.The results are shown in Table 9.The high humidity experiment x-ray diffraction pattern of 10 days is seen Figure 20, and the high humidity experiment DSC scintigram of 10 days is seen Figure 21-1, and the high humidity experiment TGA scintigram of 10 days is seen Figure 21-2.
The high wet test of table 9 (room temperature, relative humidity, 75 ± 5%)
Annotate: 23～26 ℃ of temperature variation
4, accelerated test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II raw material is packed with the polyethylene film plastic bag sealing, is placed in 40 ± 2 ℃, and relative humidity is in 75 ± 5% fixed temperature and humidity incubator, placed six months, respectively at 1,2,3,6 the end of month, sampling detected, and contrasted with the result of 0 month.The results are shown in Table 10.40 ℃ of x-ray diffraction patterns that accelerated 6 months are seen Figure 22, and 40 ℃ of DSC scintigrams that accelerated 6 months see that 0 ℃ of TGA scintigram that accelerated 6 months of Figure 23-Isosorbide-5-Nitrae sees Figure 23-2.
Table 10 accelerated test (40 ℃, relative humidity 75%)
By the above results as can be known, the 3-that the present invention obtains (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II is in exposure experiments to light and high temperature (60 ℃) test, outward appearance and content illustrate that all without larger change its character is relatively stable; This product its outward appearance and content in high wet test all do not have considerable change, but less water absorbability is arranged; Observe to scan by DSC in the test that keeps sample for a long time of high humidity and show small part polymorphic form II and begun to transform to polymorphic form I.
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the characteristic of 6-diketone polymorphic form III:
One, solvability: test with reference to two notes on the use of Chinese Pharmacopoeia version in 2000.Method: precision takes 3-(4-amino-1-oxo-1 of (acetone) solvation, 3-dihydro-2H-isoindole-2-yl) piperidines-2, III is appropriate for 6-diketone polymorphic form, slowly add a certain amount of solvent, powerful jolting was 30 seconds every 5 minutes, observe the dissolving situation in 30 minutes, the results are shown in Table 11.
Table 11 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the solubility test of 6-diketone polymorphic form III
-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic III raw material is evenly shared to uncovered training 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III dissolves in methyl-sulphoxide and DMF; Slightly molten in Glacial acetic acid, 0.1mol/L sodium hydroxide solution; Slightly soluble in 0.1mol/L hydrochloric acid, acetonitrile, methyl alcohol and acetone soln; Soluble,very slightly in water, ethanol and ethyl acetate.
Two, stability
1, exposure experiments to light
With 3-(4-amino-1 supports in ware, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects respectively at sampling in 5,10 days, and contrasts with the result of 0 day.The results are shown in Table 12.The illumination x-ray diffraction pattern of 10 days is seen Figure 27, and Figure 28 is seen in the illumination DSC of 10 days scanning.
Table 12 exposure experiments to light (4500 ± 500lx)
Annotate: 23～26 ℃ of temperature variation; Relative humidity variations 56%～63%
2, high temperature test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III raw material is positioned in the sealing clean vial, be placed in 60 ℃ of thermostatic drying chambers, detect respectively at sampling in 5,10 days, and contrast with the result of 0 day.The results are shown in Table 13.The high temperature x-ray diffraction pattern of 10 days is seen Figure 29, and the high temperature DSC scintigram of 10 days is seen Figure 30.
Table 13 high temperature test (60 ℃)
Annotate: relative humidity variations 54%～62%
3, high wet test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III raw material is evenly shared to uncovered culture dish, thickness≤5mm, be placed in room temperature (25 ℃ of left and right), relative humidity is in 75 ± 5% fixed temperature and humidity incubator, respectively at 5, sampling in 10 days is measured, and contrasts with the result of 0 day.The results are shown in Table 14.The high humidity experiment x-ray diffraction pattern of 10 days is seen Figure 31, and the high humidity experiment DSC scintigram of 10 days is seen Figure 32-1, and the high humidity experiment TGA scintigram of 10 days is seen Figure 32-2.
The high wet test of table 14 (room temperature, relative humidity, 75 ± 5%)
Annotate: 23～26 ℃ of temperature variation
4, accelerated test
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III raw material is packed with the polyethylene film plastic bag sealing, is placed in 40 ± 2 ℃, and relative humidity is in 75 ± 5% fixed temperature and humidity incubator, placed six months, respectively at 1,2,3,6 the end of month, sampling detected, and contrasted with the result of 0 month.The results are shown in Table 15.40 ℃ of x-ray diffraction patterns that accelerated 6 months are seen Figure 33; 40 ℃ of DSC scintigrams that accelerated 6 months see that 0 ℃ of TGA scintigram that accelerated 6 months of Figure 34-Isosorbide-5-Nitrae sees Figure 34-2.
Table 15 accelerated test (40 ℃, relative humidity 75%)
By the above results as can be known, the 3-that the present invention obtains (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III is in exposure experiments to light and high temperature (60 ℃) test, outward appearance and content illustrate that all without larger change its character is relatively stable; This product its outward appearance and content in high wet test all do not have considerable change, but very little water absorbability is arranged.Observe to scan by DSC in the test that keeps sample for a long time of high humidity and show small part polymorphic form III and begun to transform to polymorphic form I.
in another embodiment of the invention, the invention provides and contain above-mentioned three kinds of 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic form I, II, the medicinal compositions of one or more of III and pharmaceutical excipient, preferably, this medicinal compositions contains 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic form 1-500mg, particularly preferably, contain 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone approximately 5, 10, 15, 25 milligrams of polymorphic forms.According to the instruction of state of the art, and the patent of quoting with reference to the present invention, medicinal compositions of the present invention can be made into various formulations, and selects suitable pharmaceutical excipient.For example, according to disease to be treated and object, medicinal compositions of the present invention, by oral, parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion), suction spraying, nose, vagina, rectum, hypogloeeis or topical administration, preferably, be oral solid formulation, for example tablet, granule or capsule.
The present invention comprises 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and the medicinal compositions of 6-diketone polymorphic form optionally also can contain other therapeutic component.
Medicinal compositions of the present invention is once a day or repeatedly per daily dose and administration, and per daily dose is about the 0.10-500 mg/day, more preferably about 1-250 mg/day.Perhaps, administration every other day, about 0.10-150 mg/day, or about 1-250 mg/day.
the example that 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone can be used for treating disease and symptom includes but not limited to: the treatment myeloproliferative disease, Myelodysplastic syndromes, vasculogenesis, cancer, pain, macular degeneration, Myelodysplastic syndromes, asbestosis, anemia, nervous system disorders, dyssomnia, tetter, pulmonary hypertension, immune deficiency disorder, management of parasitic diseases, central nervous system injury etc., concrete method and dosage can be with reference to Chinese patent application, and application number is 97180299.8, 98805614.3, 03825761.0, 03825567.7, 03813733.X, 03816899.5, 200610150484.3, 200380107531.0, 200710103924.4, 200380108093.X, 200380108398.0, 200480043341.1, 200480038171.8, 200480035556.9, 200480020445.0, 200480043535.1, 200480040004.7, 200480041252.3, 200480042208.4, 200580017546.7, 200580016344.0, 200580020628.7, 200580037220.0, 200580047364.4, 200580046371.2, 200580047031.1.
Useful technique effect of the present invention is embodied in: although the report of prior art CN 1871003A patent documentation eight kinds of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,8 kinds of polymorphic forms of 6-diketone and preparation method thereof.But; the preparation 3-that patent CN1871003A provides (4-amino-1-oxo-1; 3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form of 6-diketone learns that by test its polymorphic form A, B show that in the dilute hydrochloric acid of 0.1 mol/L and Oxidative demage experiment the rotating crystal method of its poor chemical stability and the instruction of this patent is not suitable for industrial scale production.
Prior art CN 1871003A patent documentation its preparation method is with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone joins 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, lower the temperature after (as: hexane, toluene, acetone, acetonitrile, methyl alcohol, ethyl acetate) heating for dissolving in the insoluble,practically water of 6-diketone or organic solvent crystallize out or long-time solid-liquid two-phase pulp stirring turn crystalline substance and make.
1, preparation target compound 3-(4-amino-1-oxo-1 in patent document US 5635517 and Chinese patent application CN 101080400A, 3-dihydro-2H-isoindole-2-yl) piperidines-2, the final step chemical reaction of 6-diketone is to make this target compound by palladium carbon hydrogenating reduction nitro, just because of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone is the solvability extreme difference in the solvent system of various reactions, very easily causes heavy metals exceeding standard in product that the method makes;
2, due to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone is hardly in water-soluble or above-described organic solvent, even need to use the solvent of a large amount of (more than 100 times) under heating state yet, and do not consider yet and to avoid using harmful (as toluene, acetonitrile etc.) two classes or the above organic solvent of two classes to reduce the detrimentally affect that in product, the residual organic solvent of meeting causes human body when the finished product synthesize as far as possible;
3, the rotating crystal method described in CN1871003A and CN 101080400A can not make the appearance luster of product make moderate progress, as by original light yellow white or the off-white color of becoming;
4, polymorphic form A, the B that makes with the method for preparing polymorphic form of instructing in patent document CN1871003A and CN 101080400A the hydrochloric acid of 0.1mol/L and in Oxidative demage within a short period of time just very easily destroy and decompose, chemical stability is very poor.
Turn brilliant technique length consuming time when 5, preparing polymorphic form in CN1871003A and CN 101080400A, poor controllability is not suitable for commercial scale production.
In a word: CN1871003A and CN 101080400A prepare polymorphous method and are unsuitable for industrial production.
Yet, the invention provides three kinds of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2 that are suitable for suitability for industrialized production, 6-diketone polymorphic form has overcome problems of the prior art.
The present invention is to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, three kinds of novel polymorphic things of 6-diketone, its crystallization condition fully takes into account 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone does not dissolve in the solvent of the overwhelming majority, and the characteristics that are difficult to purify have adopted simple and easy to do preparation method:
1, preparation technology of the present invention is simple, easy handling very, and suitability for industrialized production is convenient, and the quality controllable and polymorphic form good stability that makes is suitable for long-term seasoning;
2, turn brilliant scheme at an easy rate the place to go impurity of strong polarity make related substance significantly to reduce;
3, can reduce significantly that in product, heavy-metal residual exceeds standard or too high problem;
4, can significantly improve the appearance luster of product, make the appearance luster of product from light yellow white or the off-white color of becoming;
5, the stability of polymorphic I disclosed in this invention in the hydrochloric acid soln of water and 0.1mol/L and Oxidative demage experiment stablize of disclosed polymorphic A in the patent CN1871003A, substantially do not destroy decomposition or degree of decomposition and be significantly less than disclosed polymorphic form A in CN1871003A in mentioned solution.This makes polymorphic form of the present invention more be of value to the requirement of preparation;
6, the polymorphous method of preparation of the present invention can reduce organic solvent usage quantity when turning crystalline substance greatly, has fallen at the end cost;
7, method alternative of the present invention makes water or 3 low class organic solvents of toxicity prepare polymorphic form of the present invention, can avoid using in patent CN1871003A the residual toxic action to human body to organic solvents such as the larger toluene of human toxicity, methylethylketones.
Above advantage is of value to the present invention the quality of product is significantly improved and be more suitable for suitability for industrialized production.
Description of drawings
Fig. 1 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the XRPD figure of 6-diketone polymorphic form I
Fig. 2 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the IR infrared absorpting light spectra of 6-diketone polymorphic form I
Fig. 3-1 and Fig. 3-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, DSC scintigram and the TGA scintigram of 6-diketone polymorphic form I
Fig. 4 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the solid-state nuclear magnetic resonance carbon spectrogram of 6-diketone polymorphic form I
Fig. 5 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone polymorphic form I strong illumination XRPD of 10 days figure
Fig. 6 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,10 days DSC differential scanning figure of 6-diketone polymorphic form I strong illumination
Fig. 7 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, investigates 10 days XRPD figure for 60 ℃ of 6-diketone polymorphic form I
Fig. 8 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, investigates 10 days DSC differential scanning figure for 60 ℃ of 6-diketone polymorphic form I
Fig. 9 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and 6-diketone polymorphic form I high humidity is investigated the XRPD figure of 10 days
Figure 10-1 and Figure 10-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and 6-diketone polymorphic form I high humidity is investigated 10 days DSC scintigrams and TGA scintigram
Figure 11 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and 6-diketone polymorphic form I puts and investigates XRPD figure in June in 40 ℃ of environment
Figure 12-1 and Figure 12-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and 6-diketone polymorphic form I puts DSC scintigram and the TGA scintigram in 40 ℃ of June
Figure 13 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the XRPD figure of 6-diketone polymorphic form II
Figure 14 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the IR infrared absorpting light spectra of 6-diketone polymorphic form II
Figure 15-1 and Figure 15-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, DSC scintigram and the TGA scintigram of 6-diketone polymorphic form II
Figure 16 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone polymorphic form II rayed XRPD of 10 days figure
Figure 17 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,10 days DSC differential scanning figure of 6-diketone polymorphic form II rayed
Figure 18 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,60 ℃ of 10 days XRPD figure of 6-diketone polymorphic form II
Figure 19 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,60 ℃ of 10 days DSC differential scanning figure of 6-diketone polymorphic form II
Figure 20 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone polymorphic form II high humidity XRPD of 10 days figure
Figure 21-1 and Figure 21-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,10 days DSC scintigrams of 6-diketone polymorphic form II high humidity and TGA scintigram
Figure 22 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and 6-diketone polymorphic form II puts the XRPD figure that keeps sample 40 ℃ of June
Figure 23-1 and Figure 23-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, and 6-diketone polymorphic form II puts DSC scintigram and the TGA scintigram in 40 ℃ of June
Figure 24 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the XRPD figure of 6-diketone polymorphic form III
Figure 25 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the infrared IR abosrption spectrogram of 6-diketone polymorphic form III
Figure 26-1 and Figure 26-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, DSC scintigram and the TGA scintigram of 6-diketone polymorphic form III
Figure 27 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone polymorphic form III rayed XRPD of 10 days figure
Figure 28 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,10 days DSC differential scanning figure of 6-diketone polymorphic form III rayed
Figure 29 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,60 ℃ of 10 days XRPD figure of 6-diketone polymorphic form III
Figure 30 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,60 ℃ of 10 days DSC differential scanning figure of 6-diketone polymorphic form III
Figure 31 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone polymorphic form III high humidity XRPD of 10 days figure
Figure 32-1 and Figure 32-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,10 days DSC scintigrams of 6-diketone polymorphic form III high humidity and TGA scintigram
Figure 33 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III put 40 ℃ June XRPD figure
Figure 34-1 and Figure 34-2 are respectively 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form III put 40 ℃ June DSC scintigram and TGA scintigram
Figure 35 is 3-of the present invention (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the infrared comparison diagram of 6-diketone polymorphic form I, II, III
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the preparation of 6-diketone polymorphic form
The preparation of polymorphic form I:
with 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone 100 grams add in the solution of DMF400 milliliter (perhaps DMSO300 milliliter), stirring heating makes its dissolving, (or the mixed solvent system of 1000 milliliters of pure water and 600 milliliters of organic solvents is (as water and acetone to drip 1600 milliliters of pure water, acetonitrile, ethyl acetate, methylene dichloride, Virahol, methyl alcohol, the 3-such as ethanol (4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, binary or the above mixed system of binary that the insoluble organic solvent of 6-diketone forms), under agitation slowly cooling makes and separates out solid, reclaim solid, reduced vacuum is dry, make 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic I.
DMF/ aqueous systems: product 78 grams of weighing, yield 78%;
DMSO/ aqueous systems: product 90 grams of weighing, yield 90%.
The preparation of polymorphic form II:
With 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone 100 grams add 400 milliliters of dry DMF, and stirring heating makes its dissolving; Drip 1800 milliliters of anhydrous ethanol (or the single or mixed solvent 1600-2000 milliliter such as methyl alcohol, acetone, ethyl acetate, acetonitrile, methylene dichloride, acetonitrile), slowly lower the temperature to make under stirring and separate out solid, reclaim solid, reduced vacuum is dry, make 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form II.
Product 72 grams of weighing, yield 72%.
The preparation of polymorphic form III:
with 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone 100 grams add 300 milliliters of anhydrous DMSO, stirring slowly, heating makes its dissolving, (other available organic solvents are as methyl alcohol to drip 2000 milliliters of anhydrous ethanol, , acetone, ethyl acetate, acetonitrile, the 3-such as methylene dichloride (4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, the undissolved single or mixed solvent of 6-diketone), slowly lower the temperature to make under stirring and separate out solid, reclaim solid, reduced vacuum is dry, make 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic form III.
Product is weighed: 86 grams, yield 86%.
Embodiment 4
The prescription of tablet and preparation technology:
Use as follows several vehicle with above-mentioned 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the arbitrary proportion mixture of 6-diketone polymorphic form I or II or III or I, II, III is mixed with every tablet of tablet that contains 10mg.
contain 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic form I, II, the manufacture method of the tablet of the mixture of the arbitrary proportion of III or above-mentioned three kinds of polymorphic forms is with above-mentioned vehicle and 3-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-yl) piperidines-2, 6-diketone polymorphic form I, II, the mixture of the arbitrary proportion of III or above-mentioned three kinds of polymorphic forms mixes, add 10%PVP solution appropriate, make softwood, the granulation of sieving, the wet granular oven dry, whole grain sieves, add Magnesium Stearate and talcum powder to mix, compressing tablet.
The tablet of polymorphic form I---accumulation dissolution rate %
| |
1# | 2# | 3# | 4# | 5# | Average % | SD | RSD％ | |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| 5 | 64.40 | 65.14 | 69.30 | 60.78 | 70.55 | 66.0 | 3.94 | 5.97 | |
| 10 | 97.72 | 96.74 | 99.01 | 97.49 | 99.00 | 98.0 | 0.99 | 1.01 | |
| 20 | 98.85 | 96.49 | 98.54 | 97.94 | 87.07 | 95.8 | 4.95 | 5.17 | |
| 30 | 97.98 | 96.99 | 100.27 | 98.03 | 97.55 | 98.2 | 1.25 | 1.27 | |
| 45 | 96.76 | 95.27 | 97.51 | 96.59 | 96.83 | 96.6 | 0.82 | 0.84 | |
| 60 | 97.08 | 94.62 | 96.16 | 96.59 | 96.73 | 96.2 | 0.96 | 1.00 |
The prescription of capsule and preparation technology:
Use as follows several vehicle with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the arbitrary proportion mixture of 6-diketone I or II or III or above-mentioned polymorphic form is mixed with every capsule that contains 10mg.
contain 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form I, II, the manufacture method of the capsule of the mixture of the arbitrary proportion of III or above-mentioned three kinds of polymorphic forms is with above-mentioned vehicle and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form I, II, the mixture of the arbitrary proportion of III or above-mentioned three kinds of polymorphic forms mixes, add 10%PVP solution, make wet granular, oven dry, whole grain sieves, add Magnesium Stearate, mix, the insertion capsule makes.Or do not granulate, with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone crystal and above-mentioned mixed with excipients are even, sieve, and directly insert capsule and make.
The accumulation dissolution rate % of polymorphic form I capsule
| |
1# | 2# | 3# | 4# | 5# | Average % | SD | RSD％ | |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| 5 | 60.86 | 59.90 | 35.00 | 50.84 | 22.77 | 45.9 | 16.57 | 36.12 | |
| 10 | 91.04 | 93.30 | 85.66 | 91.23 | 83.92 | 89.0 | 4.02 | 4.51 | |
| 20 | 94.08 | 96.78 | 92.84 | 95.18 | 93.02 | 94.4 | 1.64 | 1.73 | |
| 30 | 95.38 | 96.14 | 93.62 | 95.42 | 93.56 | 94.8 | 1.17 | 1.23 | |
| 45 | 93.02 | 95.66 | 93.91 | 94.11 | 93.00 | 93.9 | 1.09 | 1.16 | |
| 60 | 94.63 | 94.10 | 93.38 | 93.83 | 92.08 | 93.6 | 0.97 | 1.03 |
Simultaneous test:
Prepare 3-(4-amino-1-oxo-1 with the disclosed method of CN 1871003A, 3-dihydro-2H-isoindole-2-yl) piperidines-2,6-diketone polymorphic form A, B (being designated hereinafter simply as " polymorphic form A, B ") are representative, and study on the stability method and the result of polymorphic form I of the present invention (being designated hereinafter simply as " polymorphic form I ") contrast breaking test:
The breaking test study on the stability result of table 16 polymorphic form A, B and polymorphic form I
Experimental technique:
Acid destroys: sample thief 50mg, and accurately weighed, be placed in the 100ml measuring bottle, the hydrochloric acid soln 10ml that adds 0.1mol/L, room temperature was placed after 1 hour, added the sodium hydroxide solution neutralization of the 0.1mol/L of equivalent, be diluted to scale with moving phase again, shake up, high performance liquid chromatography detects.
Oxidative demage: sample thief 50mg, accurately weighed, be placed in the 100ml measuring bottle,, adding 30% hydrogen peroxide 10ml, room temperature was placed after 2 hours, was diluted to scale with moving phase, shook up, and high performance liquid chromatography detects.
Determination of related substances
The condition of high performance liquid chromatography and system suitability octadecylsilane chemically bonded silica are weighting agent; Take 0.01mol/L potassium primary phosphate (with phosphorus acid for adjusting pH value to 3.5)-methyl alcohol-acetonitrile (80: 15: 5) as moving phase; Detect wavelength 240nm; Theoretical plate number should be not less than 2000 by Revlimid peak calculating.3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the resolution of 6-diketone peak and adjacent impurity peaks should meet the requirements.
Assay method: sample thief, add moving phase and dissolve and make the solution that contains 0.5mg in every 1ml, measure 20 μ l, injection liquid chromatography respectively records color atlas to 4 times of principal constituent peak retention time.If any impurity peaks, press areas of peak normalization method and calculate total assorted and single impurity in the need testing solution color atlas.
Experimental result shows, no matter is under acidic conditions or under oxidizing condition, and polymorphic form I of the present invention is more stable than polymorphic form A, B, is more suitable for making medicine.
Claims (6)
1. a 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the polymorphic form of 6-diketone acetone solvate uses the Cu-Ka radiation, and its X-ray diffracting spectrum has following diffraction peak:
Described polymorphic form, its DSC collection of illustrative plates, endothermic transition have the first endotherm(ic)peak about 188.96 ℃, about 268.19 ℃, the second endotherm(ic)peak are arranged.
2. polymorphic form according to claim 1, its X-ray diffracting spectrum as shown in figure 24.
3. polymorphic form according to claim 1, the infrared absorption pattern that records with the KBr compressing tablet is at about 3466.7cm
-1, 3363.3cm
-1, 3228.2cm
-1, 3081.7cm
-1, 2958.5cm
-1, 2877.2cm
-1, 1688.5cm
-1, 1666.2cm
-1, 1609.1cm
-1, 1491.7cm
-1, 1347.3cm
-1, 1199.5cm
-1There is absorption peak at the place.
4. the preparation method of the described polymorphic form of arbitrary claim in claims 1 to 3, comprise the steps:
(1) with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2, the 6-diketone adds anhydrous dimethyl sulfoxide, and stirring slowly, heating makes its dissolving;
(2) drip anhydrous acetone;
(3) stir under slowly cooling make and separate out solid;
(4) reclaim solid, reduced vacuum is dry.
5. preparation method according to claim 4, wherein, anhydrous dimethyl sulfoxide and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidines-2 in step (1), the volume of 6-diketone and weight ratio are greater than 2: 1.
6. pharmaceutical composition that comprises the described polymorphic form of arbitrary claim in claims 1 to 3.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1871003A (en) * | 2003-09-04 | 2006-11-29 | 细胞基因公司 | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| CN101080400A (en) * | 2004-09-03 | 2007-11-28 | 细胞基因公司 | Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines |
| CN101531653A (en) * | 2008-03-13 | 2009-09-16 | 天津和美生物技术有限公司 | Salts of 3-(4-amino-1-oxo-1,3-dihydro-iso-indol-2-yl)piperdine-2,6-dione and derivatives thereof, polymorph of the salts, preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1871003A (en) * | 2003-09-04 | 2006-11-29 | 细胞基因公司 | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| CN101080400A (en) * | 2004-09-03 | 2007-11-28 | 细胞基因公司 | Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines |
| CN101531653A (en) * | 2008-03-13 | 2009-09-16 | 天津和美生物技术有限公司 | Salts of 3-(4-amino-1-oxo-1,3-dihydro-iso-indol-2-yl)piperdine-2,6-dione and derivatives thereof, polymorph of the salts, preparation and application thereof |
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