CN104016966A - Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof - Google Patents

Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof Download PDF

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CN104016966A
CN104016966A CN201410045275.7A CN201410045275A CN104016966A CN 104016966 A CN104016966 A CN 104016966A CN 201410045275 A CN201410045275 A CN 201410045275A CN 104016966 A CN104016966 A CN 104016966A
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dihydro
oxo
yl
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安晓霞
吕峰
李祯
祖远远
邓义
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上海创诺制药有限公司
大丰创诺制药股份有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal form and a preparation method thereof, and particularly to four novel crystal forms, namely, crystal form X, crystal form XI, crystal form XII and crystal form XIII, and the preparation method of the novel crystal forms. The four novel crystal forms are stable to store, good in flowability, small in static electricity, more applicable to medicine preparations, simple and efficient in preparation process, capable of achieving on-scale production and environmental friendly.

Description

3- (4-氨基-1 ' 3- 二氢-1 -氧代-2H-异吲哚-1-基)-2, 6-哌啶二酮新晶型及其制备方法技术领域 3- (4-amino-1 '3- dihydro-1 - oxo -2H- isoindol-1-yl) -2, 6-piperidinedione new crystalline form and method of preparing Technical Field

[0001 ] 本发明涉及有机化学和药物化合物的晶型,更具体地说,涉及3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮的四种新晶型X、X1、XII和XIII,以及新晶型的制备方法。 [0001] The present invention relates to crystalline forms of organic chemistry and pharmaceutical compounds, and more particularly, relates to 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl -2H-) piperidine-2,6-dione four new crystalline forms X, X1, XII and XIII, as well as a new method for preparing the crystalline form.

背景技术 Background technique

[0002] 3- (4-氨基-1, 3- 二氢-1-氧代-2H-异吲哚_2_基)_2,6_哌啶二酮,分子式:C13H13N3O3,分子量:259.26,CAS号:191732-72-6,其分子结构式如下: [0002] 3- (4-amino-1,3-dihydro-1-oxo-isoindol _2_ -2H- yl) piperidine _2,6_ dione, of the formula: C13H13N3O3, molecular weight: 259.26, CAS No: 191732-72-6, its molecular structure formula as follows:

[0003] [0003]

Figure CN104016966AD00041

[0004] 3- (4-氨基-1,3- 二氢-1-氧代-2Η-异吲哚_2_基)_2,6_哌啶二酮,中文名称来那度胺(Lenalidomide),商品名为Revlimid,是由美国Celgene公司研发的用于治疗致死性血液疾病以及癌症的药物,是目前治疗多发性骨髓瘤疗效最显著的药品,超过一半的病人服用该药后可以延长存活时间达到3年以上。 [0004] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ -2Η- yl) piperidine dione _2,6_, Chinese name lenalidomide (Lenalidomide) tradename Revlimid, Celgene was developed by the US company lethal drugs for the treatment of blood diseases and cancer, the most significant is the treatment of multiple myeloma efficacy of drugs, more than half of the patients taking the drug can prolong survival time more than 3 years. 另外它也是可以有效治疗骨髓增生异常综合症(MDS)唯一的药物,临床结果发现64%的MDS病人用来那度胺治疗后无需再用输血来治疗MDS。 In addition, it is also effective in the treatment myelodysplastic syndromes (MDS) the only drug, and found that 64% of the clinical patients with MDS lenalidomide treatment which eliminates the need for blood transfusion therapy MDS. 2005年12月27日,美国FDA批准同于5q缺失型低危和中危的骨髓增长异常综合症(MDS)输血依赖型患者,以及与地塞米松联合用于治疗至少接受过I次治疗复发或难治性多发性骨髓瘤(MM)。 December 27, 2005, the FDA approved with the 5q deletion in low-risk and moderate-risk growth of abnormal bone marrow syndrome (MDS) transfusion-dependent patients, and in combination with dexamethasone for the treatment I have received at least secondary treatment relapse or refractory multiple myeloma (MM). 欧盟EMEA于2007年6月批准联合地塞米松治疗MM适应症,同时,该品在欧洲获得了治疗骨髓增生异常综合症(MDS)的罕用药物和治疗多发性骨髓瘤的罕用药物的地位。 EMEA in the EU in June 2007 approved in combination with dexamethasone MM indications, at the same time, the product acquired the status of orphan drugs myelodysplastic syndromes (MDS) and the treatment of multiple myeloma orphan drugs in Europe .

[0005] CN1871003B中公开了来那度胺晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H等形式;指出晶型A为非溶剂化物,晶型B为半水物,晶型C为半丙酮化物,晶型D为一水物,晶型E为二水物,晶型F为无水物(由二水物晶型E脱水得到),晶型G为非溶剂化物,晶型H为部分水合物的结晶物质(由晶型E不完全脱水得到)。 [0005] CN1871003B disclosed lenalidomide Form A, Form B, form C, form D, form type E, crystalline F, form type G, Form H and other forms; indicated Form A is a non-solvate, Form B is a hemihydrate, Form C is semi-acetonide, Form D is a monohydrate, Form E is a dihydrate, Form F is an anhydrous composition (a dihydrate Form E dehydration), Form G non-solvate, Form H is a monohydrate crystalline material portion (incomplete dehydration of Form E). 其中,晶型A、晶型B及晶型E的制备工艺周期较长,不利于产能的提高;晶型C为丙酮化物,丙酮含量为10%左右,远大于人体可接受的限度(〈0.5%),会对人体造成不良影响,因此不能用于药用;晶型D、晶型F、晶型G及晶型H的制备工艺不稳定、重复性较差。 Wherein the preparation period Form A, Form B, and Form E is longer, it is not conducive to production capacity; Form C is acetonide, the acetone content of about 10%, much greater than the acceptable limits of human (<0.5 %), the body will cause adverse effects, and therefore can not be used for medicinal purposes; preparation unstable crystalline D, form F, form G and form H-type, and poor reproducibility.

[0006] CN102639522A公开了一种新晶型形式I,为含有1.533%溶剂的溶剂化物,将来那度胺溶于120倍甲醇,加热浓缩至甲醇的1/3后,加入约200倍水,进一步浓缩以除去甲醇,过滤、干燥。 [0006] CN102639522A disclosed a new polymorphic forms I, a solvate containing 1.533% of the solvent, lenalidomide was dissolved in methanol and 120 times, was heated and concentrated to 1/3 of the methanol, water was added about 200-fold, further concentrated to remove methanol, filtered and dried. 该制备工艺所需溶剂量大,能耗高,并产生大量污水,且工艺重复性差。 The large amount of solvent required for preparation process, high energy consumption, and a large amount of wastewater, and the process poor reproducibility.

[0007] CN102453021A公开了来那度胺晶型I,将来那度胺在加热的条件下溶于DMF、DMSO、DMAC等有机溶剂中,滴加甲醇等溶析剂析晶。 [0007] CN102453021A discloses a lenalidomide crystalline Form I, lenalidomide was dissolved in DMF, DMSO, DMAC, etc. organic solvent under heating, and dropwise addition of methanol eluent crystallization. 经证明,该专利公开的新晶型I实则为DMF、DMSO或DMAC的溶剂化物,不可用来药用。 Proved, the disclosure of which is a new crystalline Form I actually DMF, DMSO or DMAC solvate thereof, can not be used pharmaceutically.

[0008] CN101817813B公开了来那度胺晶型IV及其药用组合,将来那度胺在搅拌下溶于热的乙腈中,梯度降温至室温静置;在20°C左右将溶剂长时间挥发,直至晶体缓慢析出;过滤收集固体,收集得到的固体于室温下挥干。 [0008] CN101817813B discloses a lenalidomide crystalline form IV and pharmaceutical compositions, lenalidomide was dissolved in acetonitrile with stirring under heat, the gradient was allowed to stand to cool to room temperature; at about 20 ° C for a long time the solvent was volatilized until crystals slowly precipitated; the solid was collected by filtration, the solid was collected at room temperature and evaporated to dryness. 该方法的缺点是乙腈约为溶质150倍,溶剂量非常大,能耗和成本均很高,且周期长,产能低。 A disadvantage of this method is that the solute is about 150 times in acetonitrile, the solvent is very large, and energy costs are high, and long cycle, low productivity.

[0009] 因此本领域尚需研发新的晶型,能够稳定储存,可药用,且制备工艺简单高效,可规模化生产。 [0009] Thus, the present art still need to develop new crystalline form, storage stable, pharmaceutically acceptable, and the simple and efficient preparation process, may be large-scale production.

发明内容 SUMMARY

[0010] 本发明的目的是提供3-( 4-氨基-1,3- 二氢-1-氧代-2H-异吲哚_2_基)_2,6_哌啶二酮的新晶型X、晶型X1、晶型XII和晶型XIII,及其制备方法。 [0010] The object of the present invention is to provide a 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ -2H- yl) piperidine-dione _2,6_ new crystalline form X, Form X1, Form XII and Form XIII, their preparation.

[0011] 本发明的第一方面,提供3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮的晶型X,其DSC图谱显示存在两个吸热峰,第一个吸热峰的峰值在169±4°C,第二个吸热峰的峰值在269±2°C。 [0011] In a first aspect of the present invention, there is provided 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione Form X, having a DSC spectrum showed the presence of two endothermic peaks, a first peak in the endothermic peak of 169 ± 4 ° C, the second peak endothermic peak at 269 ± 2 ° C.

[0012] CN1871003B中的晶型B的DSC谱图显示,第一个吸热峰的峰值仅为146°C,远低于晶型X的吸热峰。 DSC spectrum of the Form B [0012] CN1871003B display, a first peak of the endothermic peak is only 146 ° C, far lower than the endothermic peak X Form.

[0013] 在另一优选例中,晶型X的X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ 值:13.2±0.2 °、14.2±0.2 °、15.4±0.2 °、17.3±0.2 °、19.2±0.2 °、19.6±0.2 °、20.8±0.2 °、23.3±0.2 °、23.9±0.2 °、27.7±0.2 °、29.3±0.2 °、31.2±0.2。 [0013] In another preferred embodiment, X-ray powder diffraction pattern of Form X comprises 3 3 2 Θ value or more selected from the group: 13.2 ± 0.2 °, 14.2 ± 0.2 °, 15.4 ± 0.2 °, 17.3 ± 0.2 °, 19.2 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 23.9 ± 0.2 °, 27.7 ± 0.2 °, 29.3 ± 0.2 °, 31.2 ± 0.2. 、34.6±0.2°。 , 34.6 ± 0.2 °.

[0014] 在另一优选例中,所述的晶型X具有基本如图1所示的XRD谱图。 [0014] In another preferred embodiment, the crystalline form has a X 1 XRD spectrum substantially as shown in FIG.

[0015] 在另一优选例中,所述的晶型X具有基本如图5所示的DSC谱图。 [0015] In another preferred embodiment, the crystalline form has a DSC spectrum X shown in FIG. 5 substantially.

[0016] 在另一优选例中,所述的晶型X的热重分析图谱(TGA图谱)显示在56~177°C有一个失重台阶,此处失重3.3-3.8%。 [0016] In another preferred embodiment, a thermal analysis spectrum of the crystalline form X (TGA spectrum) shows 56 ~ 177 ° C has a weight loss step, here 3.3-3.8% weight loss.

[0017] 在另一优选例中,所述的晶型X的热重分析图谱(TGA图谱)显示在56~177°C有一个失重台阶,此处失重3.6%。 [0017] In another preferred embodiment, a thermal analysis spectrum of the crystalline form X (TGA spectrum) shows 56 ~ 177 ° C has a weight loss step, where weight loss of 3.6%.

[0018] 在另一优选例中,所述的晶型X的TGA图谱基本如图9所示。 [0018] In another preferred embodiment, the TGA spectrum of Form X is substantially as shown in FIG.

[0019] 在另一优选例中,所述的晶型X的FTIR谱图显示,在3422011-^3344011^2848011'1701cm \ 1602cm \ 1542cm \ 1236cm \ 1043cm \988cm \934cm \910cm \848cm \795cm \748cm \671cm \597cm \552cm \519cm \462cm 1 左右有特征峰。 [0019] In another preferred embodiment, the FTIR spectrum of Form X show that in 3422011- ^ 3344011 ^ 2848011'1701cm \ 1602cm \ 1542cm \ 1236cm \ 1043cm \ 988cm \ 934cm \ 910cm \ 848cm \ 795cm ​​\ 748cm \ 671cm \ 597cm \ 552cm \ 519cm \ about 462cm 1 characteristic peaks.

[0020] 在另一优选例中,所述的晶型X的FTIR图谱基本如图13所示。 [0020] In another preferred embodiment, the FTIR spectra of crystalline form X substantially as shown in Fig.

[0021] 本发明第二方面,提供了第一方面所述的晶型X的制备方法,包括如下步骤: [0021] The second aspect of the present invention, there is provided a process for preparing a crystalline form of the first aspect X, comprising the steps of:

[0022] (I)将3- (4-氨基-1,3- 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐在室温条件下溶解于溶剂中,重量体积比为约1:10~1:30克/毫升; [0022] (I) 3- (4-amino-oxo-1,3-dihydro _1_ _2_ _2H_ isoindol-yl) piperidine-dione _2,6_ salt dissolves at room temperature in a solvent, the weight to volume ratio of about 1:10 to 1: 30 g / ml;

[0023] (2)在步骤(1)得到的溶液中,加入碳酸氢钠水溶液,调pH至7.0~9.0 ; [0023] (2) in step (1) to give a solution, aqueous sodium bicarbonate was added to adjust pH to 7.0 to 9.0;

[0024] (3)升温至60~90°C,保温24~48小时; [0024] (3) was warmed to 60 ~ 90 ° C, for 24 to 48 hours;

[0025] (4)降温至40~60°C,析晶,从而得到所述的晶型X。 [0025] (4) cooling to 40 ~ 60 ° C, crystallization, to obtain the crystalline form X.

[0026] 本发明的上下文中,所述室温是指10~30°C。 [0026] In the context of the present invention, the room temperature means 10 ~ 30 ° C. [0027] 步骤(1)所述的3- (4-氨基-1,3- 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐选自:3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐、盐酸盐、对甲苯磺酸盐。 [0027] Step (1) 3- (4-oxo-1,3-dihydro _1_ _2_ _2H_ isoindol-yl) piperidine-dione salt selected _2,6_ : 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione mesylate, hydrochloride, p-toluenesulfonate sulfonate.

[0028] 步骤(1)所述的溶剂选自:去离子水、甲醇、乙醇、甲醇-水混合溶剂、乙醇-水混合溶剂。 [0028] Step (1) the solvent is selected from: deionized water, methanol, ethanol, methanol - water mixed solvent of ethanol - water mixed solvent.

[0029] 步骤(1)中所述的3-(4-氨基-1,3- 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐与溶解溶剂的比例约10~30倍,优选10~25倍,更优选15~20倍,更优选15~18倍。 [0029] Step (1) of the 3- (4-amino-oxo-1,3-dihydro _1_ _2_ _2H_ isoindol-yl) piperidine-dione salt with _2,6_ the proportion of solvent for dissolving about 10 to 30 times, preferably 10 to 25 times, more preferably 15 to 20 times, more preferably 15 to 18 times.

[0030] 所述的步骤⑵中调pH至7.0~9.5,优选7.5~9,更优选8.0~8.5。 [0030] In the step ⑵ pH adjusted to 7.0 to 9.5, preferably from 7.5 to 9, more preferably 8.0 to 8.5.

[0031] 所述的步骤(3)中升高体系温度至60~90°C,优选70~85°C,更优选80~85°C ;保温24~48小时,优选24~36小时,更优选30~36小时; [0031] The step (3) the temperature of the system was elevated to 60 ~ 90 ° C, preferably 70 ~ 85 ° C, more preferably 80 ~ 85 ° C; for 24 to 48 hours, preferably 24 to 36 hours, more preferably 30 to 36 hours;

[0032] 所述的步骤(4)中降低体系温度至40~60°C,优选45~55°C,更优选50~55°C。 Said step (4) [0032] reduction in temperature of the system to 40 ~ 60 ° C, preferably 45 ~ 55 ° C, more preferably 50 ~ 55 ° C. 真空过滤,用去离子水滤饼2~3次,析晶,从而得到所述的晶型X。 Vacuum filtration, the filter cake with deionized water 2 to 3 times, crystallization, thereby obtaining the Form X.

[0033] 本发明的第三方面,提供3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚-2-基)-2,6-哌啶二酮的晶型XI其X射线粉末衍射图谱包括3个或3个以上选自下组的2Θ 值:12.0±0.2°、14.3±0.2°、14.8±0.2°、16.2±0.2°、17.6±0.2°、21.5±0.2 °、22.6±0.2 °、23.8±0.2 °、24.0±0.2 °、26.0±0.2 °、28.3±0.2 °、29.8±0.2°、31.9±0.2°、32.6±0.2° 和33.5±0.2°。 [0033] The third aspect of the present invention, there is provided 3- (4-amino-1,3-dihydro-1-oxo _2H_ isoindol-2-yl) piperidine-2,6-dione Form XI which has an X-ray powder diffraction pattern comprising three or more than three selected from the group 2Θ values: 12.0 ± 0.2 °, 14.3 ± 0.2 °, 14.8 ± 0.2 °, 16.2 ± 0.2 °, 17.6 ± 0.2 °, 21.5 ± 0.2 °, 22.6 ± 0.2 °, 23.8 ± 0.2 °, 24.0 ± 0.2 °, 26.0 ± 0.2 °, 28.3 ± 0.2 °, 29.8 ± 0.2 °, 31.9 ± 0.2 °, 32.6 ± 0.2 ° and 33.5 ± 0.2 °.

[0034] 在另一优选例中, 所述的晶型XI的X射线粉末衍射图谱基本如图2所示。 [0034] In another preferred embodiment, the X-ray powder diffraction pattern of Form XI substantially as shown in FIG.

[0035] 在另一优选例中,所述的晶型XI的差示扫描量热法分析图谱(DSC图谱)显示第一个吸热峰在90±5°C及107 ± 5°C,第二个吸热峰在269±3°C。 [0035] In another preferred embodiment, Form XI according to the differential scanning calorimetry spectrum analysis (DSC spectrum) shows a first endothermic peak at 90 ± 5 ° C and 107 ± 5 ° C, of two endothermic peak at 269 ± 3 ° C.

[0036] 在另一优选例中,所述的晶型XI的差示扫描量热法分析图谱(DSC图谱)基本如图6所示。 [0036] In another preferred embodiment, the differential scanning calorimetry analysis of the pattern of crystalline form XI (DSC spectrum) substantially as shown in Figure 6.

[0037] 在另一优选例中,所述的晶型XI的TGA谱图显示在62~96°C有一个失重台阶,此处失重4.5%~5.5%ο [0037] In another preferred embodiment, the crystalline form XI is shown in the TGA spectrum of 62 ~ 96 ° C there is a step weight loss, where weight loss of 4.5% ~ 5.5% ο

[0038] 在另一优选例中,所述的晶型XI的TGA谱图基本如图10所示。 [0038] In another preferred embodiment, the TGA spectrum of Form XI is substantially as shown in FIG.

[0039] 在另一优选例中,所述的晶型XI的含水量为4.5wt%~5.5wt%,用卡氏水分测定仪测得晶型的含水量。 [0039] In another preferred embodiment, the water content of Form XI was 4.5wt% ~ 5.5wt%, the meter measured moisture content measured by Form Karl Fischer.

[0040] 在另一优选例中,所述的晶型XI的卡氏水分测定仪测得其含有4.8%的水份,因此可判断晶型XI为含0.75分子水的水合物。 [0040] In another preferred embodiment, Form XI according to the Karl Fischer moisture meter measured obtaining water containing 4.8% of Form XI thus can be judged as a hydrate containing 0.75 molecules of water.

[0041] 在另一优选例中,所述晶型XI的FTIR谱图显示,在3408011^3196(^^3087011'2875cm \ 1681cm \ 1490cm \1459cm \141Icm \1343cm \ 1299cm \ 1240cm \879cm \744cm \610cm \546cm 1左右出有特征峰。 [0041] In another preferred embodiment, the FTIR spectrum of Form XI shows the 3408011 ^ 3196 (^^ 3087011'2875cm \ 1681cm \ 1490cm \ 1459cm \ 141Icm \ 1343cm \ 1299cm \ 1240cm \ 879cm \ 744cm \ 610cm \ about 546cm 1 Chu characteristic peaks.

[0042] 在另一优选例中,所述的晶型XI的FTIR谱图基本如图14所示。 [0042] In another preferred embodiment, the crystalline form XI, the FTIR spectrum substantially as shown in FIG.

[0043] 本发明的第四方面,提供第三方面所述的晶型XI的制备方法,包括如下步骤: [0043] The fourth aspect of the present invention, there is provided a third aspect of the methods of preparation of Form XI comprising the steps of:

[0044] a)将3- (4-氨基_1,3_ 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐在室温条件下溶解于去离子水/有机溶剂的混合溶剂中; [0044] a) 3- (4-amino-oxo _2H_ _1_ _1,3_ dihydro-isoindol _2_ yl) piperidine-dione _2,6_ salt is dissolved in at room temperature to a mixed solvent of deionized water / organic solvent;

[0045] b)在步骤a)得到的溶液中,加入碱调pH至7.0~9.0 ; [0045] b) step a) to give a solution, adding a base to adjust pH to 7.0 to 9.0;

[0046] c) (TC~回流温度下搅拌0.5~4小时,析晶,从而得到所述的晶型XI。[0047] 在另一优选例中,所述制备方法,包括如下步骤: In another preferred embodiment, the preparation method comprising the steps of [0046] c) under stirring (the TC ~ reflux temperature for 0.5 to 4 hours, crystallization, thereby obtaining the Form XI [0047].:

[0048] (I)将3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐在室温条件下溶解于去离子水/有机溶剂的混合溶剂中得到混合溶液; The [0048] (I) 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione salt room temperature It was dissolved in a mixed solvent of deionized water / organic solvent to give a mixed solution;

[0049] (2)在所述混合溶液中,搅拌下滴加入碱调节pH至7.0~9.0 ; [0049] (2) in the mixed solution, a base is added dropwise with stirring to adjust the pH from 7.0 to 9.0;

[0050] (3)滴毕,氮气保护,(TC至回流温度条件下搅拌0.5~4小时,真空过滤,用去离子水淋洗滤饼2~3次; [0050] (3) dropwise, nitrogen, (TC was stirred to reflux temperature for 0.5 to 4 hours, vacuum filtered, the filter cake was rinsed with deionized water 2 to 3 times;

[0051] (4)滤饼在室温至45°C条件下真空干燥12~36小时,析晶,从而得到所述的晶型XI。 [0051] (4) filter cake was dried at room temperature to 45 ° C under vacuum conditions for 12 to 36 hours, crystallization, thereby obtaining the Form XI.

[0052] 所述的3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐选自:3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐、盐酸盐、对甲苯磺酸盐。 [0052] The 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ salt is selected from: 3- ( 4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione mesylate, hydrochloride, p-toluenesulfonate.

[0053] 所述的有机溶剂为醇类溶剂,选自:甲醇、乙醇、异丙醇。 [0053] The organic solvent is an alcohol solvent selected from: methanol, ethanol, isopropanol.

[0054] 所述的去离子水/有机溶剂的混合溶剂中醇类溶剂的含量约为70~95% (v/v),优选75~90%,更优选80~90%。 A mixed solvent of deionized water [0054] the / an organic solvent content of the alcoholic solvent is about 70 ~ 95% (v / v), preferably 75 to 90%, more preferably 80 to 90%.

[0055] 所述的碱选自:二乙胺、三乙胺、苯胺、碳酸氢钠、氢氧化钠、碳酸钠等,优选三乙 [0055] The base is selected from: diethylamine, triethylamine, aniline, sodium bicarbonate, sodium hydroxide, sodium carbonate, preferably triethylamine

胺、二乙胺。 Diethylamine.

[0056] 步骤(3)或步骤c)中的温度优选20~40°C;搅拌时间0.5~4小时,优选I~5小时,更优选2~4小时。 [0056] Step (3) or step c) the temperature is preferably 20 ~ 40 ° C; stirring time of 0.5 to 4 hours, preferably from I ~ 5 hours, more preferably 2 to 4 hours.

[0057] 步骤(4)所述的干燥温度,优选室温至35°C,更优选室温条件下,时间12~36小时,优选12~24小时,更优选18~22小时。 [0057] Step (4) the drying temperature, preferably room temperature to 35 ° C, more preferably room temperature, time 12 to 36 hours, preferably 12 to 24 hours, more preferably 18 to 22 hours.

[0058] 在另一优选例中,步骤(3)或步骤c)中搅拌时间优选2~4小时,更优选3~4小时。 [0058] In another preferred embodiment, step (3) or step c) stirring time is preferably 2 to 4 hours, more preferably 3 to 4 hours.

[0059] 本发明的第五方面,提供3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚-2-基)-2,6-哌啶二酮的晶型XII,其X射线粉末衍射图谱包括3个或3个以上选自下组的2Θ 值:13.1±0.2°、14.1±0.2°、15.7±0.2°、16.4±0.2°、17.2±0.2°、17.4±0.2 °、19.1±0.2 °、19.5±0.2 °、20.9±0.2 °、21.3±0.2 °、26.6±0.2 °、27.4±0.2°、28.6±0.2°、29.2±0.2°、32.0±0.2° 和33.2±0.2°。 [0059] A fifth aspect of the present invention, there is provided 3- (4-amino-1,3-dihydro-1-oxo _2H_ isoindol-2-yl) piperidine-2,6-dione Form XII, which is an X-ray powder diffraction pattern comprising three or more than three selected from the group 2Θ values: 13.1 ± 0.2 °, 14.1 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, 20.9 ± 0.2 °, 21.3 ± 0.2 °, 26.6 ± 0.2 °, 27.4 ± 0.2 °, 28.6 ± 0.2 °, 29.2 ± 0.2 °, 32.0 ± 0.2 ° and 33.2 ± 0.2 °.

[0060] 在另一优选例中,所述的晶型XII的XRD图谱基本如图3所示。 [0060] In another preferred embodiment, the crystalline form XII XRD pattern substantially as shown in FIG.

[0061] 在另一优选例中,所述的晶型XII的差示扫描量热法分析图谱(DSC图谱)显示第一个吸热峰在89±4°C,第二个吸热峰在124±4°C,第三个吸热峰在269±3°C。 [0061] In another preferred embodiment, the crystalline form XII, differential scanning calorimetry spectrum analysis (DSC spectrum) shows a first endothermic peak at 89 ± 4 ° C, the second endothermic peak 124 ± 4 ° C, the third endothermic peak at 269 ± 3 ° C.

[0062] 在另一优选例中,所述的晶型XII的DSC图谱基本如图7所示。 [0062] In another preferred embodiment, the crystalline form XII, DSC thermogram substantially as shown in FIG.

[0063] 在另一优选例中,所述的晶型XII的TGA谱图显示在75~130°C有明显的两个失重台阶,其中,75~95°C之间失重为3.4~4.2%,110~130°C之间失重为2.1~2.9%。 [0063] In another preferred embodiment, the crystalline form XII, the TGA spectrum showed 75 ~ 130 ° C a significant weight loss two steps, wherein, the weight loss between 75 ~ 95 ° C 3.4 to 4.2% , between 110 ~ 130 ° C a weight loss of 2.1 to 2.9%. 在另一优选例中,所述的晶型XII的TGA谱图显示在75~95°C有一个失重为3.8%的失重台阶,在110~130°C有一个失重为2.5%的失重台阶。 In another preferred embodiment, the crystalline form XII, the TGA spectrum showed 75 ~ 95 ° C has a weight loss of 3.8% weight loss step at 110 ~ 130 ° C has a weight loss of 2.5% weight loss steps.

[0064] 在另一优选例中,晶型XII的含水量为6.0~7.0%,用卡氏水分测定仪测得。 [0064] In another preferred embodiment, the water content of Form XII is 6.0 to 7.0%, measured by Karl Fischer moisture meter was measured.

[0065] 在另一优选例中,卡氏水分测定仪测得所述的晶型XII含有6.3%的水份,因此可判断新晶型XII为含I分子水的水合物。 [0065] In another preferred embodiment, the Karl Fischer moisture meter as measured according to Form XII containing 6.3% moisture, and therefore can judge whether the new Form XII I is a hydrate containing water molecules.

[0066] 在另一优选例中,所述的晶型XII的TGA谱图基本如图11所示。 [0066] In another preferred embodiment, the TGA spectrum of Form XII, substantially as shown in FIG. [0067] 在另一优选例中,所述的晶型XII的FTIR谱图显示,在3559011^3502011'3425cm \3224cm \3085cm \1954cm \ 1491cm \ 1419cm \ 1351cm \ 1048cm \994cm \935CHT1、850CHT1、796cm_1 左右有特征峰。 [0067] In another preferred embodiment, the crystalline form of the FTIR spectrum showed XII in 3559011 ^ 3502011'3425cm \ 3224cm \ 3085cm \ 1954cm \ 1491cm \ 1419cm \ 1351cm \ 1048cm \ 994cm \ 935CHT1,850CHT1,796cm_1 there are left and right peaks.

[0068] 在另一优选例中,所述的晶型XII的FTIR谱图基本如图15所示。 [0068] In another preferred embodiment, the crystalline form of the FTIR spectrum substantially XII shown in Figure 15.

[0069] 本发明的第六方面,提供第五方面所述的晶型XII的制备方法,包括如下步骤: A sixth aspect [0069] of the present invention, there is provided a fifth aspect of the method of preparing Form XII comprising the steps of:

[0070] a)将3- (4-氨基_1,3_ 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐在室温下溶解于去离子水Il醇类溶剂的混合溶剂中; [0070] a) 3- (4-amino-oxo _2H_ _1_ _1,3_ dihydro-isoindol _2_ yl) piperidine-dione _2,6_ salt is dissolved at room temperature in deionized a mixed solvent of water in an alcoholic solvent Il;

[0071] b)在步骤a)得到的溶液中,加入碱调pH至7.0~9.0 ; [0071] b) step a) to give a solution, adding a base to adjust pH to 7.0 to 9.0;

[0072] c) (TC~回流温度条件下搅拌5~8小时;析晶,从而得到所述的晶型XII。 [0072] was stirred under c) (TC ~ reflux conditions for 5 to 8 hours; crystallization, thereby obtaining the Form XII.

[0073] 在另一优选例中,所述制备方法包括以下步骤: [0073] In another preferred embodiment, the manufacturing method comprising the steps of:

[0074] (I)将3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐在室温条件下溶解于去离子水/有机溶剂的混合溶剂中; The [0074] (I) 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione salt room temperature It was dissolved in deionized water / organic solvent mixed solvent;

[0075] (2)在以上混合溶液中,搅拌下滴加入合适的碱调节体系调pH至7.0~9.0 ; [0075] (2) In the above mixed solution was added dropwise with stirring under a suitable base to adjust the system pH was adjusted to 9.0 7.0;

[0076] (3)滴毕,氮气保护,(TC~回流温度条件下搅拌5~8小时,真空过滤,用去离子水淋洗滤饼2~3次; It was stirred at [0076] (3) dropwise, nitrogen, (~ the reflux temperature of the TC conditions 5 to 8 hours, vacuum filtered, the filter cake was rinsed with deionized water 2 to 3 times;

[0077] (4)滤饼在室温至45°C条件下真空干燥12~36小时。 [0077] (4) filter cake was dried in vacuo for 12 to 36 hours at room temperature to 45 ° C conditions.

[0078] 所述的3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐选自:3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐、盐酸盐、对甲苯磺酸盐。 [0078] The 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ salt is selected from: 3- ( 4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione mesylate, hydrochloride, p-toluenesulfonate.

[0079] 所述的去离子水/有机溶剂的混合溶剂中醇类溶剂的含量约为65~80% (v/v),优选70~80%,更优选70~75%。 A mixed solvent of deionized water [0079] the / an organic solvent content of the alcoholic solvent is about 65 ~ 80% (v / v), preferably 70 to 80%, more preferably 70 to 75%.

[0080] 所述的有机溶剂为醇类溶剂,选自:甲醇、乙醇、异丙醇。 [0080] The organic solvent is an alcohol solvent selected from: methanol, ethanol, isopropanol.

[0081] 所述的碱选自:二乙胺、三乙胺、苯胺、碳酸氢钠、氢氧化钠、碳酸钠,优选三乙胺、 Base [0081] selected according to: diethylamine, triethylamine, aniline, sodium bicarbonate, sodium hydroxide, sodium carbonate, preferably triethylamine,

二乙胺。 Diethylamine.

[0082] 步骤(3)或步骤c)中的温度优选室温~35 V ;搅拌时间5~8小时,优选5~7小时,更优选5~6小时; Preferably room temperature [0082] Step (3) or step c) in ~ 35 V; stirring time of 5 to 8 hours, preferably 5-7 hours, more preferably 5 to 6 hours;

[0083] 步骤(4)所述的干燥温度,优选室温至35°C,更优选室温条件下,时间12~36小时,优选12~24小时,更优选18~22小时。 [0083] Step (4) the drying temperature, preferably room temperature to 35 ° C, more preferably room temperature, time 12 to 36 hours, preferably 12 to 24 hours, more preferably 18 to 22 hours.

[0084] 发明的第七方面,提供3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚-2-基)-2,6-哌啶二酮的晶型XIII,其X射线粉末衍射图谱包括3个或3个以上选自下组的2Θ 值:13.3±0.2°、13.4±0.2°、14.2±0.2°、16.6±0.2°、19.6±0.2°、20.8±0.2°、21.4±0.2°、29.3±0.2°。 A seventh aspect of the [0084] invention, there is provided 3- (4-amino-1,3-dihydro-1-oxo _2H_ isoindol-2-yl) -2,6-piperidinedione crystalline type XIII, an X-ray powder diffraction pattern comprising three or more than three substituents selected from the group 2Θ values: 13.3 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 16.6 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 29.3 ± 0.2 °.

[0085] 在另一优选例中,所述晶型XIII的X射线粉末衍射图谱还包括选自下组的2 Θ值:11.4±0.2°、17.3±0.2°、21.0±0.2°、30.6±0.2°。 [0085] In another preferred embodiment, X-ray powder diffraction pattern of the Form XIII comprising a 2 Θ value further selected from the group: 11.4 ± 0.2 °, 17.3 ± 0.2 °, 21.0 ± 0.2 °, 30.6 ± 0.2 °.

[0086] 在另一优选例中,所述的晶型XIII的XRD图谱基本如图4所示。 [0086] In another preferred embodiment, the XRD pattern of Form XIII, substantially as shown in FIG.

[0087] 在另一优选例中,所述的晶型XIII的DSC图谱显示DSC谱图显示第一个吸热峰在86±4 °C,第二个吸热峰在123±5 °C,第三个吸热峰在154±3 °C,第四个吸热峰在269±3°C。 [0087] In another preferred embodiment, the DSC of Form XIII shows the DSC spectrum exhibiting a first endothermic peak at 86 ± 4 ° C, the second endothermic peak at 123 ± 5 ° C, a third endothermic peak at 154 ± 3 ° C, endothermic peak at a fourth 269 ± 3 ° C.

[0088] 在另一优选例中,所述的晶型XIII的DSC图谱基本如图8所示。 [0088] In another preferred embodiment, Form XIII according to the DSC thermogram substantially as shown in FIG. [0089] 在另一优选例中,所述的晶型XIII的TGA谱图显示在75~130°C有明显的两个失重台阶,其中,75~95°C之间失重为6.8~7.6%, 110~160°C之间失重为1.7~2.5%。 [0089] In another preferred embodiment, the TGA of Form XIII spectrum showed 75 ~ 130 ° C in a significant weight loss in two steps, wherein, the weight loss between 75 ~ 95 ° C is 6.8 to 7.6% , between 110 ~ 160 ° C a weight loss of 1.7 to 2.5%.

[0090] 在另一优选例中,所述的晶型XIII的TGA谱图显示有两个失重台阶,在75~95°C有一个失重为7.2%的失重台阶,在110~160°C有一个失重为2.1%的失重台阶。 [0090] In another preferred embodiment, the TGA of Form XIII spectrum showed two weight loss steps, at 75 ~ 95 ° C has a weight loss of 7.2% weight loss steps in the 110 ~ 160 ° C with a a weight loss of 2.1% weight loss level.

[0091] 另一优选例中,用卡氏水分测定仪测得的含水量,晶型XIII的含水为8.9~10.2%。 [0091] In another preferred embodiment, measured by the Karl Fischer water content meter was measured, Form XIII aqueous 8.9 to 10.2%.

[0092] 另一优选例中,卡氏水分测定仪测得所述的晶型XIII含有9.5%的水份,因此可判断新晶型XIII为含1.5分子水的水合物。 [0092] In another preferred embodiment, Karl Fischer moisture meter as measured according to Form XIII containing 9.5% moisture, and therefore judge whether the new Form XIII may be a hydrate containing 1.5 molecules of water.

[0093] 在另一优选例中,所述的晶型XIII的TGA谱图基本如图12所示。 [0093] In another preferred embodiment, the TGA of Form XIII spectrum substantially as shown in Fig.

[0094] 在另一优选例中,所述新晶型XIII的FTIR谱图显示,在3428(^^3241(^'3065cm \ 1742cm \ 1634cm \ 1447cm \ 1359cm \987cm 1 左右有特征峰。 [0094] In another preferred embodiment, the new Form XIII show the FTIR spectrum, at 3428 (^^ 3241 (^ '3065cm \ 1742cm \ 1634cm \ 1447cm \ 1359cm \ characteristic peaks around 987cm 1.

[0095] 在另一优选例中,所述的晶型XIII的FTIR谱图基本如图16所示。 [0095] In another preferred embodiment, the crystalline form of the FTIR spectrum substantially XIII shown in Figure 16.

[0096] 本发明的第八方面,提供第七方面所述的晶型XIII的制备方法,包括如下步骤: The eighth aspect of the [0096] present invention, there is provided a seventh aspect of the methods of preparation of Form XIII comprising the steps of:

[0097] a)将3- (4-氨基_1,3_ 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮盐在室温条件下溶解于去离子水/醇类溶剂的混合溶剂中; [0097] a) 3- (4-amino-oxo _2H_ _1_ _1,3_ dihydro-isoindol _2_ yl) piperidine-dione _2,6_ salt is dissolved in at room temperature to a mixed solvent of deionized water / alcohol solvent;

[0098] b)在步骤a)得到的溶液中,加入碱调pH至7.0~9.0 ; [0099] c ) (TC~回流温度下搅拌9~24小时; [0098] b) step a) to give a solution, adding a base to adjust pH to 7.0 ~ 9.0; [0099] c) (TC ~ was stirred at reflux temperature for 9 to 24 hours;

[0100] d)干燥析晶,从而得到所述的晶型XIII。 [0100] d) crystallization dried to obtain Form XIII according to.

[0101] 在另一优选例中,所述制备方法包括如下步骤: [0101] In another preferred embodiment, the manufacturing method comprising the steps of:

[0102] (I)将3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐在室温条件下溶解于去离子水/有机溶剂的混合溶剂中; The [0102] (I) 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione salt room temperature It was dissolved in deionized water / organic solvent mixed solvent;

[0103] (2)在步骤(1)得到的溶液中,搅拌下滴加入合适的碱调节体系调pH至7.0~9 ; [0103] (2) in step (1) the resulting solution, was added dropwise with stirring under a suitable base to adjust the system pH was adjusted to 9, 7.0;

[0104] (3)滴毕,氮气保护,(TC~回流温度条件下搅拌9~24小时,真空过滤,用去离子水淋洗滤饼2~3次; [0104] (3) dropwise, nitrogen, (the TC was stirred at reflux temperature conditions ~ 9 to 24 hours, vacuum filtered, the filter cake was rinsed with deionized water 2 to 3 times;

[0105] (4)滤饼在室温至45°C条件下真空干燥12~36小时。 [0105] (4) filter cake was dried in vacuo for 12 to 36 hours at room temperature to 45 ° C conditions.

[0106] 所述的3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚_2_基)_2,6_哌啶二酮盐选自:3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐、盐酸盐、对甲苯磺酸盐等; [0106] The 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ -2H- yl) piperidine-dione _2,6_ salt is selected from: 3- ( 4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione mesylate, hydrochloride, p-toluenesulfonate and the like ;

[0107] 所述的去离子水/有机溶剂的混合溶剂中醇类溶剂的含量约为50~75% (v/v),优选60 ~65% (v/v) ο A mixed solvent of deionized water [0107] the / an organic solvent content of the alcoholic solvent is about 50 ~ 75% (v / v), preferably 60 ~ 65% (v / v) ο

[0108] 所述的有机溶剂为醇类溶剂,选自:甲醇、乙醇、异丙醇。 [0108] The organic solvent is an alcohol solvent selected from: methanol, ethanol, isopropanol.

[0109] 所述的碱选自:二乙胺、三乙胺、苯胺、碳酸氢钠、氢氧化钠、碳酸钠等,优选三乙胺、二乙胺; [0109] The base is selected from: diethylamine, triethylamine, aniline, sodium bicarbonate, sodium hydroxide, sodium carbonate, preferably triethylamine, diethylamine;

[0110] 步骤(3)或步骤c)中的温度优选室温~40°C ;搅拌时间9~24小时,优选9~14小时,更优选9~11小时,甚至9~10小时。 Preferably room temperature [0110] Step (3) or step c) of ~ 40 ° C; stirring time of 9 to 24 hours, preferably 9 to 14 hours, more preferably 9 to 11 hours, or even 9 to 10 hours.

[0111] 步骤(4)所述的干燥温度,优选室温至35°C,更优选室温条件下,时间12~36小时,优选12~24小时,更优选18~22小时。 [0111] Step (4) the drying temperature, preferably room temperature to 35 ° C, more preferably room temperature, time 12 to 36 hours, preferably 12 to 24 hours, more preferably 18 to 22 hours.

[0112] 本发明的第九方面,提供一种药物组合物,包含药学上可接受的载体以及选自下组中的一种或两种以上的晶体组合:[0113] (a)第一方面所述晶型X ; [0112] The ninth aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one selected from the group of a crystal or a combination of two or more: [0113] (a) a first aspect of the the X-type crystal;

[0114] (b)第三方面所述的晶型XI ; [0114] (b) a third aspect of the Form XI;

[0115] (c)第五方面所述的晶型XII ; [0115] (c) Form XII fifth aspect;

[0116] (d)第七方面所述的晶型XIII。 [0116] (d) a seventh aspect of the Form XIII.

[0117] 本发明的第十方面,提供一种3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮组合物或混合物,包括至少95%的晶型X、至少95%的晶型X1、95%的晶型XI1、或至少95%的晶型XIII。 [0117] A tenth aspect of the present invention, there is provided a 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-isobutyl-yl) -2,6-piperidinediyl one composition or mixture comprising at least 95% Form X, at least 95% polymorph crystalline form xi1 X1,95%, or at least 95% of the Form XIII.

[0118] 本发明的第十一方面,提供(a)第一方面所述晶型X;(b)第三方面所述的晶型XI ; (c)第五方面所述的晶型XII ;或(d)第七方面所述的晶型XIII的用途,用于制备预防和/或治疗致死性血液疾病或肿瘤的药物。 An eleventh aspect of [0118] the present invention, there is provided (a) a first aspect of Form X; (b) a third aspect of the Form XI; (c) a fifth aspect of the Form XII; or (d) a seventh aspect of the use of Form XIII, used for the prophylaxis and / or treatment of a disease or fatal blood cancer drug.

[0119] 本发明提供的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮四种新晶型X、晶型X1、晶型XII和晶型XIII,储存稳定(在高温、高湿、光照、研磨、压片等加速试验中均未转晶),且流动性好、静电小,更适合药物制剂。 [0119] The present invention provides 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione four new polymorphs X, Form X1, Form XII and Form XIII, storage-stable (in the acceleration test temperature, humidity, light, grinding, tabletting crystals were not transfected), and good flowability, a small electrostatic more suitable pharmaceutical preparation.

[0120] 与现有技术相比,本发明所述的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型X、晶型X1、晶型XII及晶型XIII的制备工艺简单高效,可以实现规模化生产,并对环境友好。 [0120] Compared with the prior art, the present invention is 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperazine piperidine dione new crystal X, preparation of crystal X1, crystal form XII and Form XIII is simple and efficient, large-scale production can be achieved, and a friendly environment.

[0121] 应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。 [0121] It should be understood, in the range of the present invention, can be combined with each other between the technical features of the invention and in the following technical features (as described in Example) specifically described, thereby constituting a new or preferred technique Program. 限于篇幅,在 Due to space limitations, in

此不再一一累述。 This not going to be described herein.

附图说明 BRIEF DESCRIPTION

[0122] 图1为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型X的XRD谱图; [0122] FIG. 1 of the present invention 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XRD spectra of X;

[0123] 图2为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XI的XRD谱图; [0123] FIG. 2 of the present invention is 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XI of XRD spectra;

[0124] 图3为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XII的XRD谱图; 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-yl isobutyl) [0124] FIG. 3 is an 2,6-piperidinedione new crystalline form XII of XRD spectra;

[0125] 图4为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XIII的XRD谱图; 3- [0125] FIG. 4 of the present invention (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XIII of XRD spectra;

[0126] 图5为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型X的DSC谱图; 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-yl isobutyl) [0126] FIG. 5 of the present invention is 2,6-piperidinedione new crystalline form X, the DSC spectrum;

[0127] 图6为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XI的DSC谱图; 3- [0127] FIG. 6 of the present invention (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XI of the DSC spectrum;

[0128] 图7为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XII的DSC谱图; 3- [0128] FIG. 7 of the present invention (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XII of the DSC spectrum;

[0129] 图8为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XIII的DSC谱图; [0129] FIG. 8 of the present invention is 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XIII of DSC spectrum;

[0130] 图9为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型X的TGA谱图;[0131] 图10为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XI的TGA谱图; 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-yl isobutyl) [0130] FIG. 9 of the present invention is 2,6-piperidinedione new crystalline form TGA spectrum of X; [0131] FIG. 10 of the present invention 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperazine the new piperidine dione Form XI is a TGA spectrum;

[0132] 图11为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XII的TGA谱图; 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-yl isobutyl) [0132] FIG. 11 of the present invention is 2,6-piperidinedione new crystalline form XII of the TGA spectrum;

[0133] 图12为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XIII的TGA谱图; [0133] FIG. 12 of the present invention 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XIII of the TGA spectrum;

[0134] 图13为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型X的FTIR谱图; 3- [0134] FIG. 13 of the present invention (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form FTIR spectra of X;

[0135] 图14为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XI的FTIR谱图; 3- [0135] FIG. 14 of the present invention (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XI of FTIR spectra;

[0136] 图15为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XII的FTIR谱图; 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-yl isobutyl) [0136] FIG. 15 of the present invention is 2,6-piperidinedione new crystalline form XII of FTIR spectra;

[0137] 图16为本发明的3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮新晶型XIII的FTIR谱图; 3- [0137] FIG. 16 of the present invention (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2,6-piperidinedione new crystalline form XIII of FTIR spectra;

[0138] 图17为已知晶型B的DSC谱图。 [0138] FIG 17 is a DSC known Form B spectra.

具体实施方式 Detailed ways

[0139] 本申请的发明人经过广泛而深入地研究,首次研发出3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮的四种新晶型,储存稳定、流动性好、静电小,更适合药物制剂,且制备工艺简单高效,重复性好,且可以实现规模化生产,并对环境友好。 [0139] The inventors of the present application, through the extensive and intensive studies for the first time developed a 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) -2, 6- piperidinedione four new crystalline forms of storage stability, good fluidity, electrostatic, more suitable pharmaceutical formulations, and preparation process is simple and efficient, reproducible, and large-scale production can be achieved, and is friendly to the environment. 在此基础上,完成了本发明。 On this basis, we completed the present invention.

[0140] 晶型X、晶型X1、晶型XII和晶型XIII [0140] Form X, Form X1, Form XII and Form XIII

[0141] 本发明提供3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚_2_基)_2,6_哌啶二丽的四种新晶型,为晶型X、晶型X1、晶型XII和晶型XIII。 [0141] The present invention provides 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ -2H- yl) piperidine two Korea _2,6_ four new crystalline form, as Form X, Form X1, Form XII and Form XIII.

[0142] 晶型X的X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ值:13.2±0.2 °、14.2±0.2 °、15.4±0.2 °、17.3±0.2 °、19.2±0.2 °、19.6±0.2 °、20.8±0.2 °、23.3±0.2 °、23.9±0.2 °、27.7±0.2 °、29.3±0.2 °、31.2±0.2 °、34.6±0.2°。 [0142] X-ray powder diffraction pattern of Form X comprises 3 3 2 Θ value or more selected from the group: 13.2 ± 0.2 °, 14.2 ± 0.2 °, 15.4 ± 0.2 °, 17.3 ± 0.2 °, 19.2 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 23.9 ± 0.2 °, 27.7 ± 0.2 °, 29.3 ± 0.2 °, 31.2 ± 0.2 °, 34.6 ± 0.2 °.

[0143] 晶型X的DSC图谱显示存在两个吸热峰,第一个吸热峰的峰值在169 ±4°C,第二个吸热峰的峰值在269 ± 2 °C。 [0143] DSC pattern of Form X shows the presence of two endothermic peaks, a first peak in the endothermic peak of 169 ± 4 ° C, the second peak endothermic peak at 269 ± 2 ° C.

[0144] 所述的晶型X具有基本如图1所示的XRD谱图。 [0144] Form X has the XRD spectrum substantially as shown.

[0145] 所述的晶型X具有基本如图5所示的DSC谱图。 [0145] The crystalline form X has a DSC spectrum substantially as shown in FIG. 5.

[0146] 所述的晶型X的TGA图谱基本如图9所示。 [0146] The TGA of Form X pattern substantially as shown in FIG.

[0147] 所述的晶型X的FTIR图谱基本如图13所示。 According to [0147] FTIR spectra of Form X 13 substantially as shown in FIG.

[0148] 晶型XI的X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ值: [0148] X-ray powder diffraction pattern of Form XI include 3 3 2 Θ value or more selected from the group consisting of:

12.0±0.2 °、14.3±0.2 °、14.8±0.2 °、16.2±0.2 °、17.6±0.2 °、21.5±0.2 °、22.6±0.2 °、23.8±0.2 °、24.0±0.2 °、26.0±0.2 °、28.3±0.2 °、29.8±0.2 °、31.9±0.2°、32.6±0.2°和33.5±0.2°。 12.0 ± 0.2 °, 14.3 ± 0.2 °, 14.8 ± 0.2 °, 16.2 ± 0.2 °, 17.6 ± 0.2 °, 21.5 ± 0.2 °, 22.6 ± 0.2 °, 23.8 ± 0.2 °, 24.0 ± 0.2 °, 26.0 ± 0.2 °, 28.3 ± 0.2 °, 29.8 ± 0.2 °, 31.9 ± 0.2 °, 32.6 ± 0.2 ° and 33.5 ± 0.2 °. 所述的晶型XI的差示扫描量热法分析图谱(DSC图谱)显示第一个吸热峰在90±5°C及107±5°C,第二个吸热峰在269±3°C。 Form XI according to the differential scanning calorimetry spectrum analysis (DSC spectrum) shows a first endothermic peak at 90 ± 5 ° C and 107 ± 5 ° C, a second endothermic peak at 269 ± 3 ° C. [0149] 所述的晶型XI的X射线粉末衍射图谱基本如图2所示。 [0149] The X-ray powder diffraction pattern of Form XI substantially as shown in FIG.

[0150] 所述的晶型XI的差示扫描量热法分析图谱(DSC图谱)基本如图6所示。 As shown in [0150] Form XI according to the differential scanning calorimetry spectrum analysis (DSC spectrum) substantially as shown in FIG 6.

[0151] 所述的晶型XI的TGA谱图基本如图1O所示。 [0151] Form XI according to the TGA 1O spectrum substantially as shown in FIG.

[0152] 所述的晶型XI的FTIR谱图基本如图14所示。 [0152] Form XI according to the FTIR spectrum substantially as shown in FIG.

[0153] 晶型XII的X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ值:13.1±0.2 °、14.1±0.2 °、15.7±0.2 °、16.4±0.2 °、17.2±0.2 °、17.4±0.2 °、19.1±0.2 °、19.5±0.2 °、20.9±0.2 °、21.3±0.2 °、26.6±0.2 °、27.4±0.2 °、28.6±0.2°、29.2±0.2°、32.0±0.2° 和33.2±0.2°。 [0153] X-ray powder diffraction pattern of Form XII comprising three or 3 2 Θ value or more selected from the group: 13.1 ± 0.2 °, 14.1 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, 20.9 ± 0.2 °, 21.3 ± 0.2 °, 26.6 ± 0.2 °, 27.4 ± 0.2 °, 28.6 ± 0.2 °, 29.2 ± 0.2 °, 32.0 ± 0.2 ° and 33.2 ± 0.2 °.

[0154] 所述的晶型XII的XRD图谱基本如图3所示。 [0154] The crystalline form XII XRD pattern substantially as shown in FIG.

[0155] 所述的晶型XII的DSC图谱基本如图7所示。 [0155] The crystalline form XII, DSC thermogram substantially as shown in FIG.

[0156] 所述的晶型XII的TGA谱图基本如图11所示。 [0156] Form XII of claim TGA spectrum substantially as shown in FIG.

[0157] 所述的晶型XII的FTIR谱图基本如图15所示。 [0157] The crystalline form XII, the FTIR spectrum substantially as shown in FIG. 15.

[0158] 晶型XIII的X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ值: [0158] X-ray powder diffraction pattern of Form XIII comprising three or 3 2 Θ value or more selected from the group consisting of:

13.3±0.2 °、13.4±0.2 °、14.2±0.2 °、16.6±0.2 °、19.6±0.2 °、20.8±0.2 °、21.4±0.2°、29.3±0.2°。 13.3 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 16.6 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 29.3 ± 0.2 °. [0159] 所述的晶型XIII的XRD图谱基本如图4所示。 [0159] Form XIII according to the XRD pattern substantially as shown in FIG.

[0160] 所述的晶型XIII的DSC图谱基本如图8所示。 [0160] Form XIII according to the DSC thermogram substantially as shown in FIG.

[0161] 所述的晶型XIII的TGA谱图基本如图12所示。 [0161] Form XIII according to the TGA spectrum substantially as shown in Fig.

[0162] 所述的晶型XIII的FTIR谱图基本如图16所示。 [0162] Form XIII according to the FTIR spectrum substantially as shown in FIG. 16.

[0163] 药物组合物 [0163] The pharmaceutical compositions

[0164] 本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体。 [0164] The present invention further provides a pharmaceutical composition comprising an effective amount of the active ingredient within the safe range, and a pharmaceutically acceptable carrier.

[0165] 本发明所述的“活性成分”是指本发明所述的3- (4-氨基-1,3-二氢-1-氧代-2Η-异吲哚-2-基)-2,6-哌啶二酮的晶型X、晶型X1、晶型XII和/或晶型XIII。 [0165] "active ingredient" in the present invention means that the present invention is 3- (4-amino-1,3-dihydro-1-oxo -2Η- isoindol-2-yl) -2 , 6-piperidine-dione Form X, Form X1, Form XII and / or Form XIII.

[0166] 本发明所述的“活性成分”和药物组合物用于制备预防和/或治疗致死性血液疾病或肿瘤的药物。 The [0166] present invention, "active ingredient" and for the preparation of pharmaceutical compositions for the prevention and / or treatment of a blood disease or lethal tumors. 在另一优选例中,用于制备预防和/或治疗多发性骨髓瘤的药物。 In another preferred embodiment, for the preparation for the prevention and / or treatment of multiple myeloma. 在另一优选例中,用于制备预防和/或治疗骨髓增生异常综合症的药物。 In another preferred embodiment, a method of preventing and / or abnormal myeloproliferative syndrome medication.

[0167] “安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。 [0167] "safe and effective amount" refers to the: amount of active ingredient sufficient to significantly improve the condition, but will not have serious side effects. 通常,药物组合物含有l-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。 Typically, the pharmaceutical compositions containing l-2000mg of the active ingredient / agent, more preferably containing 10-200mg of active ingredient / agent. 较佳地,所述的“一剂”为一个药片。 Preferably, said "a" is a tablet.

[0168] “药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。 Means [0168] "pharmaceutically acceptable carrier" is: one or more compatible solid or liquid filler material or a gel, they are suitable for human use, and must have enough purity and sufficiently low toxicity. “相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。 "Compatible" herein means that the composition of each component and the active ingredient of the present invention can be well blended with each other between them, without significantly reducing the efficacy of the active ingredient. 药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温® )、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 Some examples of acceptable carriers are cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic pharmaceutically , magnesium stearate), calcium sulphate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), an emulsifier (e.g. Tween ®), Run humectants (e.g. sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water.

[0169] 本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。 No [0169] administration of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, typical modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) Wait.

[0170] 用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。 [0170] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0171] 在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(C)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。 [0171] In such solid dosage forms, the active ingredient is mixed with at least one conventional inert excipients (or carrier) such as sodium citrate or dicalcium phosphate, or mixed with the following components: (a) fillers or extenders , for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (C) humectants, e.g., glycerine; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvent, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (G) wetting agents such as cetyl alcohol and glycerol monostearate; (H) absorbents such as kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. 胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。 Capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0172] 所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。 [0172] The solid dosage form may also be prepared using a material and a shell material coatings, such as enteric coatings and others well known in the art. 它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。 They may contain opacifying agents, and such compositions release the active ingredient may be in a delayed manner in a certain part of the digestive tract. 可采用的包埋组分的实例是聚合物质和蜡类物质。 Examples of embedding compositions that can be employed are polymeric substances and waxes species.

[0173] 用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。 [0173] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. 除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。 Addition to the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example known, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 1,3-butanediol, dimethylformamide and oils, in particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. 除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。 Besides such inert diluents, compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0174] 除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。 [0174] In addition to the active ingredient suspension may comprise suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar or combinations of these substances mixtures.

[0175] 用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。 [0175] The compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and for non redissolved into sterile injectable solutions or dispersions of mushroom powder. 适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。 Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include mixtures of water, ethanol, polyol and suitable.

[0176] 本发明化合物可以单独给药,或者与其他治疗药物(如化疗药)联合给药。 Compound [0176] The present invention can be administered alone, or in combination with other therapeutic agents (e.g., chemotherapeutic agent) are administered in combination.

[0177] 使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为I~2000mg,优选20~500mg。 [0177] When using the pharmaceutical composition, is a safe and effective amount of a compound of the present invention is applicable to a mammal in need of such treatment (e.g., human), wherein the effective dose is the dose that is administered in a pharmaceutically acceptable, for a person weighing 60kg words, daily dose is generally I ~ 2000mg, preferably 20 ~ 500mg. 当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。 Of course, the specific dose factors should be considered the route of administration, patient health status, these are skilled physician within the skill range.

[0178] 下面结合具体实施例,进一步阐述本发明。 [0178] The following embodiments with reference to specific embodiments, further illustrate the present invention. 应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。 Experimental methods without specific conditions in the examples below, are performed under routine conditions, or according to conditions recommended by the manufacturer. 除非另外说明,否则百分比和份数按重量计算。 Unless otherwise indicated, percentages and parts are by weight.

[0179] 通用方法 [0179] General Procedure

[0180] XRD图谱测定方法 [0180] XRD pattern measurement method

[0181] 在Bruker AXS/D8Advance X-射线粉末衍射仪上进行,发射靶为Cu靶,电源设置为40kV、40mA,发射狭缝为1mm、接收狭缝为0.1mm,扫描速率为0.5° /min、步长为0.02°,2 Θ扫描范围为3~40°。 [0181] performed on a Bruker AXS / D8Advance X- ray powder diffractometer, Cu target as emission target, the power is set to 40kV, 40mA, emission slit of 1mm, receiving slit of 0.1mm, a scan rate of 0.5 ° / min a step size of 0.02 °, 2 Θ scan range 3 ~ 40 °.

[0182] DSC图谱测定方法 [0182] DSC spectrum measuring method

[0183] 在密闭的铝坩埚中,通入50ml/min氮气流,于25~300°C之间温度下,加热速率为10°c /min,在DSC Q2000 (美国TA公司)设备中测定差示扫描热量分析(DSC)图。 [0183] In a closed alumina crucible, into 50ml / min nitrogen stream at a temperature between 25 ~ 300 ° C, heating rate 10 ° c / min, measuring the difference in the DSC Q2000 (U.S. TA Instruments) apparatus scanning calorimetry (DSC) Fig.

[0184] TGA图谱测定方法 [0184] TGA spectrum measuring method

[0185] 在密闭容器中,通入lOOml/min的氮气流,于20~450°C之间温度下,加热速率为10C /min,在SDT Q600(美国TA公司)设备中的热重分析(TGA)图。 [0185] in a sealed container, a stream of nitrogen lOOml / min, and at a temperature between 20 ~ 450 ° C, heating rate of 10C / min, thermogravimetric analysis SDT Q600 (TA Instruments USA) apparatus ( TGA) diagram.

[0186] FTIR图谱测定方法 [0186] FTIR spectra measuring method

[0187] 在PerkinElmer Spectrum65型傅立叶变换红外光谱仪(FTIR)的PE仪器上进行红外光谱分析,扫描范围设定为4000(311^-450(^-1,扫描次数4次,分辨率为4cm—1,采用KBr压片。 [0187] IR spectroscopy on a PerkinElmer Spectrum65 Fourier Transform infrared spectrometer (FTIR) instrument of PE, the scanning range is set to 4000 (311 ^ -450 (^ - 1, the scan number 4, with a resolution of 4cm-1 , KBr tablet.

[0188] 堆密度测定方法 [0188] Determination of bulk density

[0189] 先称取一定重量的产品,倒入10ml具有刻度的振实密度量筒中,然后将其固定在FZS4-4B型振实密度测定仪上振动,直至固体体积无明显变化,读取体积,计算振实密度。 [0189] Weigh a certain weight to the product, having a tap density was poured into a 10ml graduated cylinder, then mounted on a vibration-type FZS4-4B tap density analyzer, until no significant change in solids volume, reading volume calculating the tap density.

[0190] HPLC测定方法 [0190] HPLC Determination

[0191] 取本品约10mg,加稀释剂(甲醇/0.01mol.L—1磷酸二氢钾,用H3PO4调pH为 [0191] To about 10mg, plus diluent (methanol /0.01mol.L-1 potassium dihydrogen phosphate, pH was adjusted with H3PO4

3.5=50/50)溶解并稀释至20ml,摇匀,作为供试品溶液。 3.5 = 50/50) was dissolved and diluted to 20ml, shake, as the test solution. 照高效液相色谱法实验,选用XTerra RP18色谱柱(4.6*250mm, 5 μ m),流动相B为乙腈,流动相C为甲醇,流动相D为 High performance liquid chromatography experiments, selection XTerra RP18 column (4.6 * 250mm, 5 μ m), mobile phase B was acetonitrile, methanol mobile phase C, phase D is the flow

0.01mol.L4磷酸二氢钾,用H3PO4调pH为3.50,按下表进行梯度洗脱,后运行时间15min,流速为1.0ml/min,柱温为30°C,样品室温度为10°C,波长为210nm。 0.01mol.L4 potassium dihydrogen phosphate, adjusted to pH 3.50 with H3PO4, gradient following table, run time 15min, flow rate of 1.0ml / min, column temperature was 30 ° C, the temperature of the sample chamber in 10 ° C a wavelength of 210nm.

[0192] [0192]

Figure CN104016966AD00141

[0193] 实施例1 [0193] Example 1

[0194] 3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型X的制备 Preparation of [0194] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ new crystalline form of X

[0195] 将43g3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐原料与690ml去离子水,加入一个IL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;将溶液减压过滤,所得澄清液转移入另一个2L三口烧瓶中。 [0195] The 43g3- (4- amino-1,3-dihydro-1-oxo -2H- isoindol-2-yl) piperidine-2,6-dione methanesulfonic acid salt to the raw material with 690ml deionized water, was added a IL three-necked flask, mixed at room temperature with stirring, until the solute was completely dissolved; the solution was filtered under reduced pressure, and the resulting supernatant was transferred to another 2L three-necked flask. 调节机械搅拌器,滴加浓度为0.525mol/L的碳酸氢钠水溶液400ml,开始反应结晶过程;滴毕,氮气保护下,升高体系温度至80~82°C保温30小时后,降低体系温度至53~56°C,将晶浆抽滤,滤饼用一定体积的55°C左右的去离子水洗涤3次;将滤饼在室温下真空干燥24小时,得到30.0g类白色晶体,质量收率为69.8%,摩尔收率为95.6%,堆密度为0.41g/ml,流动性好、静电小。 Adjusting a mechanical stirrer, dropping the concentration of 0.525mol / L aqueous sodium bicarbonate 400ml, reactive crystallization process begins; dropwise, under nitrogen, to a temperature of the system was elevated after holding 80 ~ 82 ° C for 30 hours to reduce the temperature of the system washed with deionized water of about 55 ° C to 53 ~ 56 ° C, the crystal slurry is suction filtered, the cake washed with a volume of 3 times; the filter cake was dried in vacuo at room temperature for 24 hours to obtain 30.0g white crystals, mass The yield was 69.8%, molar yield of 95.6%, a bulk density of 0.41g / ml, good flowability, a small electrostatic.

[0196] 其粉末X射线衍射图如图1所示,进行DSC分析所得到的差示扫描热量分析(DSC)图如图5所示,进行TGA分析所得到的的热重分析(TGA)图如图9所示,所得的红外光谱分析图如图13所示。 [0196] a powder X-ray diffraction pattern shown in Figure 1, differential scanning calorimetry (DSC) in FIG. 5, the thermal analysis of the resulting TGA analysis of the obtained DSC analysis (TGA) in FIG. 9, the infrared spectrum obtained is shown in Figure 13.

[0197] 图17为CN1871003B中的已知晶型B的DSC谱图,该图显示第一个吸热峰的峰值仅为146°C,远低于实施例1制备的晶型X的吸热峰。 [0197] FIG 17 is a DSC spectrum CN1871003B known in Form B, which shows a first peak of the endothermic peak is only 146 ° C, far lower than Example 1 Preparation of Form X endothermic embodiment peak. 新晶型X相对已知晶型B,具有颗粒完整、流动性好、静电小、更有利于制剂工艺等优点。 The new Form X Form B relative to known, having a particle integrity, good flowability, a small electrostatic, preparation process more conducive to advantages.

[0198] 实施例2 [0198] Example 2

[0199] 3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型X的制备 Preparation of [0199] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ new crystalline form of X

[0200] 将30g3- (4-氨基-1,3- 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮甲磺酸盐原料与750ml去离子水,加入一个IL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;将溶液减压过滤,所得澄清液转移入另一个2L三口烧瓶中。 [0200] The 30g3- (4- oxo-1,3-dihydro-_1_ _2_ _2H_ isoindol-yl) piperidine-dione mesylate _2,6_ feedstock with 750ml deionized of water, was added a IL three-necked flask, mixed at room temperature with stirring, until the solute was completely dissolved; the solution was filtered under reduced pressure, and the resulting supernatant was transferred to another 2L three-necked flask. 调节机械搅拌器,滴加浓度为0.525mol/L的碳酸氢钠水溶液300ml,开始反应结晶过程;滴毕,氮气保护下,升高体系温度至80~83°C保温28小时后,降低体系温度至55~58°C,将晶浆抽滤,滤饼用一定体积的55°C左右的去离子水洗涤2次;将滤饼在室温下真空干燥12小时,得到20.5g类白色晶体,质量收率为68.4%,摩尔收率为93.8%,堆密度为0.36g/ml,流动性好、静电小。 Adjusting a mechanical stirrer, dropping the concentration of 0.525mol / L aqueous sodium bicarbonate 300ml, reactive crystallization process begins; After dropwise, under nitrogen, the temperature of the system was elevated to 80 ~ 83 ° C incubation for 28 hours to reduce the temperature of the system to 55 ~ 58 ° C, the crystal slurry is suction filtered, the cake washed with a volume of about 55 ° C and washed twice with deionized water to; the filter cake was dried in vacuo for 12 hours to give 20.5g white crystals at room temperature, mass The yield was 68.4%, molar yield of 93.8%, a bulk density of 0.36g / ml, good flowability, a small electrostatic.

[0201] 其XRD图、DSC图、TGA图与实施例1基本一致。 [0201] its XRD pattern, DSC FIG, TGA FIG basically the same as in Example 1.

[0202] 实施例3 [0202] Example 3

[0203] 3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XI的制备 Preparation of [0203] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ XI new crystalline form of

[0204] 将37g3- (4-氨基_1,3_ 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮甲磺酸盐原料与400ml体积比为20:80的去离子水/甲醇混合溶剂,加入一个IL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;将溶液减压过滤,所得澄清液转移入另一个IL三口烧瓶中。 [0204] The 37g3- (4- amino-oxo _2H_ _1_ _1,3_ dihydro-isoindol _2_ yl) piperidine-dione mesylate _2,6_ feedstock with 400ml volume ratio 20:80 deionized water / methanol mixed solvent, was added a IL three-necked flask, and stirred and mixed at room temperature until the solute was completely dissolved; the solution was filtered under reduced pressure, and the resulting supernatant was transferred to another IL three-necked flask. 充分搅拌,向溶液中缓慢加入三乙胺,开始反应结晶过程;滴加过程中,有大量类白色固体析出;当体系PH调至8.3后,氮气保护,室温下搅拌4小时,将晶浆过滤,滤饼用去离子水洗涤3次;将滤饼在室温下真空干燥20小时,得到23.9g类白色晶体,质量收率为64.6%,摩尔收率为88.5%,其堆密度为0.37g/ml,流动性好、静电小。 Sufficiently stirred, to which was slowly added triethylamine, the reaction was started crystallization process; the addition, a large number of white solid was precipitated; After 8.3, stirred for 4 hours under nitrogen at room temperature was adjusted to PH system, the crystal slurry was filtered and the filter cake was washed three times with de-ionized water; the filter cake was dried in vacuo at room temperature for 20 hours to obtain 23.9g white crystals in a yield of 64.6% by mass, molar yield of 88.5%, a bulk density of 0.37g / ml, good fluidity, electrostatic small.

[0205] 取本实施例所制得的3_(4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XI的结晶物样品,测定的X射线粉末衍射(XRD)谱图如图2所示,差示扫描热量分析(DSC)图如图6所示,热重分析(TGA)图如图10所示,红外光谱分析图如图14所 [0205] The present embodiment takes the obtained embodiment 3_ (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ new crystalline form XI crystalline samples, X-ray powder diffraction (XRD) measurement spectrum shown in FIG. 2, differential scanning calorimetry (DSC), is shown in Figure 6, thermogravimetric analysis (TGA) as shown in FIG. 10 , IR spectrum shown in Figure 14

/Jn ο / Jn ο

[0206] 实施例4 [0206] Example 4

[0207] 3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XI的制备 Preparation of [0207] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ XI new crystalline form of

[0208] 将43g3- (4-氨基_1,3_ 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮对甲苯磺酸盐与600ml体积比为85:15的乙醇/去离子水混合溶剂,加入一个IL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;将溶液减压过滤,所得澄清液转移入另一个IL三口烧瓶中,充分搅拌,向溶液中缓慢加入三乙胺,开始反应结晶过程;滴加过程中,有大量类白色固体析出;当体系PH调至8.1后,氮气保护,室温下搅拌3.5小时,将晶浆过滤,滤饼用去离子水洗涤3次;将滤饼在室温下真空干燥19小时,得到23.6g类白色晶体,质量收率为54.9%,摩尔收率为91.0%。 [0208] The 43g3- (4- amino-oxo _2H_ _1_ _1,3_ dihydro-isoindol _2_ yl) piperidine-dione _2,6_ toluenesulfonate and 600ml volume ratio 85:15 ethanol / deionized water mixed solvent was added a IL three-neck flask, and stirred and mixed at room temperature until the solute was completely dissolved; the solution was filtered under reduced pressure, and the resulting supernatant was transferred to another IL three-necked flask, sufficiently stirred to the solution was slowly added triethylamine, the reaction was started crystallization process; the addition, a large number of white solid was precipitated; the system when the PH was adjusted to 8.1, was stirred under nitrogen at room temperature for 3.5 hours and the crystal slurry was filtered, filtrate the cake was washed with de-ionized water three times; the filter cake was dried under vacuum at room temperature for 19 hours to give 23.6g white crystals, 54.9% mass yield, 91.0% molar yield. 其XRD图、DSC图、TGA图与实施例3基本一致。 Its XRD pattern, DSC FIG, TGA FIG consistent with Example 3. [0209] 实施例5 [0209] Example 5

[0210] 3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚_2_基)_2,6_哌啶二酮新晶型XII的制备 Preparation of [0210] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ -2H- yl) piperidine-dione _2,6_ XII new crystalline form of

[0211] 将52g3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐酸盐原料与800ml体积比为75:25的异丙醇/去离子水混合溶剂,加入一个IL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解,向溶液中缓慢加入三乙胺,开始反应结晶过程;滴加过程中,有大量类白色固体析出;当体系PH调至7.7后,氮气保护,35°C下搅拌5.5小时,将晶浆过滤,滤饼用异丙醇/去离子水混合溶剂洗涤2~3次;将滤饼在35°C下真空干燥17小时,得到41.7g类白色晶体,质量收率为80.2%,摩尔收率为91.4%,堆密度为0.35g/ml,流动性好、静电小。 [0211] The 52g3- (4- amino-1,3-dihydro-1-oxo -2H- isoindol-2-yl) piperidine-2,6-dione hydrochloride feedstock with 800ml volume ratio 75:25 isopropanol / deionized water mixed solvent was added a IL three-neck flask, and stirred and mixed at room temperature until the solute was completely dissolved, the solution was slowly added triethylamine, the reaction was started crystallization process; dropwise addition in a large number of white solid was precipitated; stirred for 5.5 hours when the system was adjusted to PH 7.7, nitrogen atmosphere, 35 ° C, the crystal slurry was filtered, the filter cake was washed with isopropanol / deionized water mixed solvent 2-3 times ; the filter cake was dried in vacuo at 35 ° C for 17 hours to give 41.7g white crystals in a yield of 80.2% by mass, molar yield of 91.4%, a bulk density of 0.35g / ml, good flowability, a small electrostatic. [0212] 取本实施例所制得的3_(4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XII的结晶物样品,进行XRD分析测定的X射线粉末衍射(XRD)谱图如图3所示,差示扫描热量分析(DSC)图如图8所示,热重分析(TGA)图如图13所示,红外光谱分析图如图17所示。 [0212] The present embodiment takes the obtained embodiment 3_ (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ new crystalline form XII is crystallized samples, the XRD analysis X-ray powder diffraction (XRD) spectrum shown in Figure 3, differential scanning calorimetry (DSC) in FIG. 8, thermogravimetric analysis (TGA) as shown in FIG. 13, the infrared spectrum shown in Figure 17. FIG.

[0213] 实施例6 [0213] Example 6

[0214] 3- (4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XII的制备 Preparation of [0214] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ XII new crystalline form of

[0215] 将15g3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐原料与180ml体积比为73:27的乙醇/去离子水混合溶剂,加入一个500mL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;向溶液中缓慢加入三乙胺,开始反应结晶过程;滴加过程中,有大量类白色固体析出;当体系PH调至7.8后,氮气保护,室温下搅拌5小时,将晶浆过滤,滤饼用乙醇/去离子水混合溶剂洗涤2次;将滤饼在35°C下真空干燥19小时,得到9.7g类白色晶体,质量收率为64.7%,摩尔收率为88.6%。 [0215] The 15g3- (4- amino-1,3-dihydro-1-oxo -2H- isoindol-2-yl) piperidine-2,6-dione mesylate feedstock with 180ml volume 73:27 ratio of ethanol / deionized water mixed solvent is added in a 500mL three-necked flask, and stirred and mixed at room temperature until the solute was completely dissolved; the solution was slowly added triethylamine, the reaction was started crystallization process; during the addition , a large number of white solid was precipitated; the system when the PH was adjusted to 7.8, nitrogen, stirred at room temperature for 5 hours, the crystal slurry was filtered, the filter cake was washed with ethanol / deionized water mixed solvent 2 times; the filter cake at 35 ° C and dried under vacuum for 19 hours to give 9.7g white crystals, 64.7% mass yield, 88.6% molar yield.

[0216] 其XRD图、DSC图、TGA图与实施例5基本一致。 [0216] its XRD pattern, DSC FIG, TGA FIG embodiment consistent with Example 5.

[0217] 实施例7 [0217] Example 7

[0218] 3-(4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XIII的制备 Preparation of [0218] 3- (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ XIII new crystalline form of

[0219] 将56g3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮甲磺酸盐原料与600ml体积比为65:35的甲醇/去离子水混合溶剂,加入一个IL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;向溶液中缓慢加入二乙胺,开始反应结晶过程;滴加过程中,有大量类白色固体析出;当体系PH调至8.2后,氮气保护,室温下搅拌9小时,将晶浆过滤,滤饼用甲醇/去离子水混合溶剂洗涤3次;将滤饼在室温下真空干燥33小时,得到38.5g类白色晶体,质量收率为68.8%,摩尔收率为94.0%,堆密度为0.35g/ml,流动性好、静电小。 [0219] The 56g3- (4- amino-1,3-dihydro-1-oxo -2H- isoindol-2-yl) piperidine-2,6-dione mesylate feedstock with 600ml volume ratio of 65:35 methanol / deionized water mixed solvent was added a IL three-neck flask, and stirred and mixed at room temperature until the solute was completely dissolved; was slowly added to the solution of diethylamine, the reaction was started crystallization process; during the addition , a large number of white solid was precipitated; the system when the PH was adjusted to 8.2, nitrogen, stirred at room temperature for 9 hours. the crystal slurry was filtered, the filter cake was washed with methanol / deionized water mixed solvent 3 times; the filter cake at room temperature dried in vacuo 33 hours to give 38.5g white crystals in a yield of 68.8% by mass, molar yield of 94.0%, a bulk density of 0.35g / ml, good flowability, a small electrostatic.

[0220] 取本实施例所制得的3_(4-氨基-1,3- 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XIII的结晶物样品,进行XRD分析测定的X射线粉末衍射(XRD)谱图如图4所示,差示扫描热量分析(DSC)图如图8所示,热重分析(TGA)图如图12所示,红外光谱分析图如图16所示。 [0220] The present embodiment takes the obtained embodiment 3_ (4-amino-1-oxo-1,3-dihydro-isoindol _2_ _2H_ yl) piperidine-dione _2,6_ new crystalline form XIII crystallized samples, the XRD analysis X-ray powder diffraction (XRD) spectrum shown in Figure 4, differential scanning calorimetry (DSC) in FIG. 8, thermogravimetric analysis (TGA) as shown in FIG. 12, the infrared spectrum shown in Figure 16. FIG.

[0221] 实施例8[0222] 3-(4-氨基-1,3- 二氢_1_氧代_2H_异吲哚_2_基)_2,6_哌啶二酮新晶型XIII的制备 [0221] Example 8 [0222] 3- (4-oxo-1,3-dihydro _1_ _2_ _2H_ isoindol-yl) piperidine-dione _2,6_ new Form XIII preparation

[0223] 将10g3- (4-氨基-1,3_ 二氢-1-氧代_2H_异吲哚_2_基)_2,6_哌啶二酮甲磺酸盐原料与100mL体积比为65:35的甲醇/去离子水混合溶剂,加入一个250mL三口烧瓶中,室温下搅拌充分混合,直至溶质完全溶解;向溶液中缓慢加入三乙胺,开始反应结晶过程;滴加过程中,有大量类白色固体析出;当体系PH调至8.8后,氮气保护,室温下搅拌9.5小时,将晶浆过滤,滤饼用去离子水洗涤2次;将滤饼在室温下真空干燥30小时,得到6.2g类白色晶体,质量收率为69.5%,摩尔收率为85.0%。 [0223] The 10g3- (4- amino-1-oxo _2H_ -1,3_ dihydro-isoindol _2_ yl) piperidine-dione mesylate _2,6_ feedstock with 100mL volume ratio 65:35 methanol / deionized water mixed solvent is added in a 250mL three-necked flask, and stirred and mixed at room temperature until the solute was completely dissolved; the solution was slowly added triethylamine, the reaction was started crystallization process; dropping, there a large number of white solid was precipitated; the system when the PH was adjusted to 8.8, nitrogen, stirred at room temperature for 9.5 hours, the crystal slurry was filtered, the filter cake was washed twice with de-ionized water; the filter cake was dried 30 hours under vacuum at room temperature to give 6.2g white crystals, 69.5% mass yield, 85.0% molar yield.

[0224] 其XRD图、DSC图、TGA图与实施例7基本一致。 [0224] its XRD pattern, DSC FIG, TGA embodiment consistent with FIG. 7.

[0225] 实施例9 [0225] Example 9

[0226] 稳定性试验 [0226] Stability Test

[0227] 取上述实施例所制得的3- (4-氨基-1,3- 二氢_1_氧代_2H_异吲哚-2-基)-2,6-哌啶二酮新晶型X、晶型X1、晶型XII及晶型XIII,分别在60°C、105°C常压放置10d,相对湿度为80%、92.5%常温25°C放置10d,光照10d,压片,研钵中强力研磨30min。 [0227] Take 3- (4-oxo-1,3-dihydro _1_ _2H_ isoindol-2-yl) prepared above in Example 2,6-dione new piperidine Form X, Form X1, Form XII and Form XIII, respectively, at 60 ° C, 105 ° C and pressure is placed 1Od, a relative humidity of 80%, 92.5% at room temperature 25 ° C is placed 1Od, light 1Od, tabletting , mortar powerful grinding 30min. 取上述七种不同条件处理后的样品,进行XRD、DSC和HPLC分析,发现以上条件放置10天后,产品的晶型均未发生变化,化学纯度几乎不变,说明所制得的3-(4-氨基-1,3- 二氢_1_氧代-2H-异Π引哚-2-基)-2, 6-哌唳二酮新晶型X、晶型X1、晶型XII及晶型XIII具有良好的物理稳定性和化学稳定性。 Samples were taken after the above treatment seven different conditions, for XRD, DSC and HPLC analysis found the above conditions for 10 days, no change in crystal form of the product occurs, chemical purity almost unchanged, indicating that the obtained 3- (4 - amino-oxo-1,3-dihydro -2H- _1_ isobutyl Π indol-yl) -2, 6-dione piperazine Li new Form X, Form X1, Form XII and Form XIII has good physical and chemical stability.

[0228]在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。 [0228] The present application are incorporated in all documents mentioned herein incorporated by reference, as if each reference were individually incorporated by reference above. 此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。 Furthermore, it should be understood that, after reading the above teachings of the present invention, those skilled in the art that various changes or modifications may be made to the present invention, and these equivalents also fall within the present application as defined in the appended claims scope.

Claims (10)

1.一种3-(4-氨基-1,3- 二氢-1-氧代-2H-异吲哚-2-基)_2,6-哌啶二酮的晶型X,其特征在于,所述晶型X的DSC谱图显示第一个吸热峰的峰值在169 ±4°C,第二个吸热峰的峰值在269±4°C。 A 3- (4-amino-1-oxo-1,3-dihydro -2H- indol-2-isobutyl-yl) piperidine-dione _2,6- crystalline form X, wherein the DSC spectrum of Form X show a first peak in the endothermic peak of 169 ± 4 ° C, the second peak endothermic peak at 269 ± 4 ° C.
2.根据权利要求1所述的晶型X,其特征在于,所述晶型X的红外吸收谱图的特征吸收峰在3422cm \3344cm \2848cm \ 1701cm \ 1602cm \ 1542cm \ 1236cm \ 1043cm \988cm \934cm \910cm \848cm \795cm \748cm \671cm \597cm \552cm \519cm \462cm 1O Polymorph according to claim 1 of the X, wherein the infrared absorption spectrum of Form X of the characteristic absorption peak at 3422cm \ 3344cm \ 2848cm \ 1701cm \ 1602cm \ 1542cm \ 1236cm \ 1043cm \ 988cm \ 934cm \ 910cm \ 848cm \ 795cm ​​\ 748cm \ 671cm \ 597cm \ 552cm \ 519cm \ 462cm 1O
3.根据权利要求1或2所述的晶型X的制备方法,其特征在于,包括以下步骤: a)在室温下,将3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚_2_基)_2,6-哌啶二酮盐溶解于溶剂中,重量体积比为约1:10~1:30克/毫升; b)在步骤a)得到的溶液中,加入碳酸氢钠水溶液,调pH至7.0~9 ; c)升温至60~90°C,保温24~48小时; d)降温至40~60°C,析晶,从而得到所述的晶型X。 3. Preparation method of claim 12 or Form X according to claim, characterized by comprising the steps of: a) A mixture of 3- (4-amino-1,3-dihydro-1-oxo Generation -2H- isoindol _2_ yl) piperidine-dione _2,6- salt dissolved in a solvent, the weight to volume ratio of about 1:10 to 1: 30 g / ml; b) is obtained in step a), solution, aqueous sodium bicarbonate was added to adjust pH to 7.0 ~ 9; c) was warmed to 60 ~ 90 ° C, for 24 to 48 hours; D) cooling to 40 ~ 60 ° C, crystallization, thereby obtaining the Form X.
4.一种3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮的晶型XI,其X射线粉末衍射图谱包括3个或3个以上选自下组的2Θ值:12.0° ±0.2°、14.3 ° ±0.2 °、14.8 ° ±0.2 °、16.2 ° ±0.2 °、17.6 ° ±0.2 °、21.5±0.2 °、22.6° ±0.2°、23.8° ±0.2°、24.0 ° ±0.2°、26.0 ° ±0.2°、28.3 ° ±0.2°、29.8±0.2°、31.9° ±0.2°、32.6° ±0.2° 和33.5° ±0.2°。 A 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione Form XI, X-ray powder diffraction pattern comprising three or more than three selected from the group 2Θ values: 12.0 ° ± 0.2 °, 14.3 ° ± 0.2 °, 14.8 ° ± 0.2 °, 16.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 21.5 ± 0.2 °, 22.6 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.0 ° ± 0.2 °, 26.0 ° ± 0.2 °, 28.3 ° ± 0.2 °, 29.8 ± 0.2 °, 31.9 ° ± 0.2 °, 32.6 ° ± 0.2 ° and 33.5 ° ± 0.2 °.
5.如权利要求4所述的晶型XI的制备方法,包括如下步骤: a)将3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐在室温条件下溶解于去离子水/有机溶剂的混合溶剂中; b)在步骤a)得到的溶液中,加入碱调pH至7.0~9 ; c) (TC~回流温度下搅拌0.5~4小时,析晶,从而得到所述的晶型XI。 5. The preparation method according to claim Form XI comprising the steps of: a) 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2 -2H- yl) -2,6-piperidinedione salt dissolves at room temperature in a mixed solvent of deionized water / organic solvent; b) step a) to give a solution, adding a base to adjust pH to 7.0 ~ 9; c ) with stirring (under the TC ~ reflux temperature for 0.5 to 4 hours, crystallization, thereby obtaining the Form XI.
6.一种3-(4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮的晶型XII,其X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ值:13.1±0.2°、14.1±0.2°、15.7±0.2 °、16.4±0.2 °、17.2±0.2 °、17.4±0.2 °、19.1±0.2 °、19.5±0.2 °、20.9±0.2 °、21.3±0.2 °、26.6±0.2 °、27.4±0.2 °、28.6±0.2 °、29.2±0.2 °、32.0±0.2° 和33.2±0.2°。 A 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione Form XII, X-ray powder diffraction pattern comprising three or 3 2 Θ value or more selected from the group: 13.1 ± 0.2 °, 14.1 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, 20.9 ± 0.2 °, 21.3 ± 0.2 °, 26.6 ± 0.2 °, 27.4 ± 0.2 °, 28.6 ± 0.2 °, 29.2 ± 0.2 °, 32.0 ± 0.2 ° and 33.2 ± 0.2 °.
7.如权利要求6所述的晶型XII的制备方法,包括如下步骤: a)将3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐在室温下溶解于去离子水/醇类溶剂的混合溶剂中; b)在步骤a)得到的溶液中,加入碱调pH至7.0~9 ; c) (TC~回流温度条件下搅拌5~8小时;析晶,从而得到所述的晶型XII。 7. The method of claim 6 for preparing crystalline form as claimed in claim XII, comprising the steps of: a) 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2 -2H- yl) piperidine-2,6-dione salt dissolved at room temperature in a mixed solvent of deionized water / alcohol solvent; b) step a) to give a solution, adding a base to adjust pH to 7.0 ~ 9; c ) under stirring (the TC ~ reflux temperature condition of 5 to 8 hours; crystallization, thereby obtaining the Form XII.
8.—种3- (4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮的晶型XIII,其X射线粉末衍射图谱包括3个或3个以上选自下组的2 Θ值:13.3±0.2°、13.4±0.2 °、14.2±0.2 °、16.6±0.2 °、19.6±0.2 °、20.8±0.2 °、21.4±0.2 °、29.3±0.2°。 8.- species 3- (4-amino-1-oxo-1,3-dihydro -2H- isoindol-2-yl) piperidine-2,6-dione Form XIII, X-ray powder diffraction pattern comprising three or 3 2 Θ value or more selected from the group: 13.3 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 16.6 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 29.3 ± 0.2 °.
9.如权利要求8所述的晶型XIII的制备方法,包括如下步骤: a)将3- (4-氨基-1,3- 二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮盐在室温条件下溶解于去离子水/醇类溶剂的混合溶剂中;b)在步骤a)得到的溶液中,加入碱调pH至7.0~9 ; c) (TC~回流温度下搅拌9~24小时; d)干燥析晶,从而得到所述的晶型XIII。 9. The method of preparing Form XIII according to claim 8, comprising the steps of: a) 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2 -2H- yl) piperidine-2,6-dione salt is dissolved at room temperature in a mixed solvent of deionized water / alcohol solvent; b) step a) to give a solution, adding a base to adjust pH to 7.0 to 9; c) under stirring (the TC ~ reflux temperature for 9 to 24 hours; D) crystallization dried to obtain Form XIII according to.
10.一种药物组合物,其特征在于,所述药物组合物包含药学上可接受的载体以及选自下组中的一种或两种以上的晶体组合: (a)权利要求1或2所述的晶型X ; (b)权利要求4所述的晶型XI ; (c)权利要求6所述的晶型XII ; (d)权利要求8所述的晶型XIII。 10. A pharmaceutical composition, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a combination of the above crystal selected from the group of one or both of: (a) as claimed in claim 1 or 2, Form X described later; the Form XI 4 (b) of claim 1; Form XII of claim 6 (c) of claim 1; Form XIII according to 8 (d) as claimed in claim.
CN201410045275.7A 2014-01-30 2014-01-30 Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof CN104016966A (en)

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