CN105646345A - Novel crystal forms of bosutinib and preparation method thereof - Google Patents
Novel crystal forms of bosutinib and preparation method thereof Download PDFInfo
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- CN105646345A CN105646345A CN201610153746.5A CN201610153746A CN105646345A CN 105646345 A CN105646345 A CN 105646345A CN 201610153746 A CN201610153746 A CN 201610153746A CN 105646345 A CN105646345 A CN 105646345A
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- crystal form
- quinolinecarbonitriles
- methoxyphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to novel crystal forms of bosutinib and a preparation method thereof. The novel crystal forms respectively are a crystal form A, a crystal form B and a crystal form C. The crystal form products disclosed by the invention are high in purity, excellent in physical and chemical properties and high in stability; by a crystallization method, product quality can be effectively improved; the crystallization method can be effectively applied to preparation and large-scale production of medicine.
Description
Technical field
The present invention relates to pharmaceutical field. More particularly, it relates to bosutinib novel crystal forms and preparation method thereof.
Technical background
Bosutinib chemistry is called: 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles, its structural formula:
Bosutinib is a kind of potent kinases inhibitor, can suppress the autonomous phosphorylation of Src albumen in various human tumor cell, also can suppress the Phosphorylation events of Src and Ab1 substrate. This medicine is developed by the Wyeth Pharmaceuticals under Pfizer, in JIUYUE in 2012 4 days in U.S.'s Initial Public Offering, it is approved for the treatment of chronic myelocytic leukemia (CML) adult patients that chronic phase, accelerated period or acute transformation phase Philadelphia chromosome are positive. Major part CML patient suffers from the gene mutation being referred to as Philadelphia chromosome, and this causes that bone marrow produces tyrosine kinase. This enzyme triggers bone marrow and produces the too much unsound leukocyte of deformity and granulocyte. Granulocyte can to infection. Bosutinib stimulates the bone marrow acceleration generation unsound granulocytic signal of deformity to play a role by blocking tyrosine kinase.
The synthetic method of bosutinib disclosed in patent CN101792416, and five kinds of crystal formations of bosutinib disclosed in patent CN10248047. But for polymorph medicine, different crystal formations can have different physicochemical properties, including fusing point, chemical stability, apparent solubility, rate of dissolution, optically and mechanically character, vapour pressure and density. These character directly influence the process of crude drug and preparation, and can affect the stability of preparation, dissolubility and bioavailability. Therefore, for pharmaceutical preparation, the novel crystal forms that exploitation has good stability, excellent solubility and dissolution is very necessary as the harsh demand of medicine to meet.
Summary of the invention
The present invention relates to the three of bosutinib kind novel crystal forms, respectively crystal form A, crystal form B and crystal C, and the preparation method of three kinds of novel crystal forms. Wherein, described crystal form A to be alcohol solvent compound, crystal form B be pentahydrate, crystal C are n-butanol solvent compound.
An object of the present invention is in that to provide a kind of bosutinib crystal form A
The X-ray powder diffraction of a kind of bosutinib crystal form A provided by the present invention in 2 �� (��) values is: 5.6 �� 0.2,11.8 �� 0.2,16.8 �� 0.2,23.3 �� 0.2,23.9 �� 0.2,24.9 �� 0.2,27.0 �� 0.2 places have characteristic peak.
In one aspect, the X-ray powder diffraction of bosutinib crystal form A provided by the present invention in 2 �� (��) values is: 10.5 �� 0.2,15.3 �� 0.2,18.1 �� 0.2,19.5 �� 0.2,21.3 �� 0.2,21.8 �� 0.2 places also have characteristic peak.
Further, the X-ray powder diffraction of bosutinib crystal form A provided by the present invention have 2 �� as shown in table 1 below,And Relative intensity data:
Table 1
Without limitation, the bosutinib crystal form A of the present invention has X-ray powder diffractogram as shown in Figure 1.
Additionally, the bosutinib crystal form A of the present invention, it is possible to the infrared absorption pattern recorded with KBr tabletting characterizes, at about 3383.27cm-1��2cm-1��1461.04cm-1��2cm-1��1425.59cm-1��2cm-1��1371.58cm-1��2cm-1��1134.61cm-1��2cm-1There is absworption peak at place.
Further, the infrared absorption pattern of described bosutinib crystal form A is at about 3383.27cm-1��2cm-1��2940.11cm-1��2cm-1��2820.28cm-1��2cm-1��2212.25cm-1��2cm-1��1620.54cm-1��2cm-1��1595.19cm-1��2cm-1��1570.57cm-1��2cm-1��1503.87cm-1��2cm-1��1461.04cm-1��2cm-1��1425.59cm-1��2cm-1��1371.58cm-1��2cm-1��1286.69cm-1��2cm-1��1245.41cm-1��2cm-1��1221.21cm-1��2cm-1��1163.98cm-1��2cm-1��1134.61cm-1��2cm-1��1091.40cm-1��2cm-1��1050.16cm-1��2cm-1��1011.55cm-1��2cm-1��967.33cm-1��2cm-1��925.81cm-1��2cm-1��848.87cm-1��2cm-1��819.76cm-1��2cm-1��727.40cm-1��2cm-1��598.94cm-1��2cm-1There is absworption peak at place.
The infrared spectrum of the bosutinib crystal form A of the present invention is as shown in Figure 2.
Means of differential scanning calorimetry (DSC) collection of illustrative plates of bosutinib crystal form A of the present invention has maximum absorption band in the scope of 92.5��105.6 DEG C.
The DSC collection of illustrative plates of the bosutinib crystal form A of the present invention is as shown in Figure 3.
The TGA collection of illustrative plates of the bosutinib crystal form A of the present invention is as shown in Figure 4.
An object of the present invention there are provided the X-ray powder diffraction of a kind of bosutinib crystal form B a kind of bosutinib crystal form B provided by the present invention: 6.5 �� 0.2,12.8 �� 0.2,22.8 �� 0.2,25.4 �� 0.2,28.2 �� 0.2,29.6 �� 0.2 places have characteristic peak.
In one aspect, the X-ray powder diffraction of bosutinib crystal form B provided by the present invention in 2 �� (��) values is: 8.8 �� 0.2,15.6 �� 0.2,17.8 �� 0.2,20.8 �� 0.2,27.1 �� 0.2 places also have characteristic peak.
Further, the X-ray powder diffraction of bosutinib crystal form B provided by the present invention have 2 �� as shown in table 2 below,And Relative intensity data:
Table 2
Without limitation, the bosutinib crystal form B of the present invention has X-ray powder diffractogram as shown in Figure 5.
The bosutinib crystal form B of the present invention, it is possible to the infrared absorption pattern recorded with KBr tabletting characterizes, at about 1502.58cm-1��2cm-1��1463.92cm-1��2cm-1��1426.64cm-1��2cm-1��1355.14cm-1��2cm-1��1246.02cm-1��2cm-1��1221.41cm-1��2cm-1��1050.45cm-1��2cm-1��1092.71cm-1��2cm-1There is absworption peak at place.
Further, the infrared absorption pattern of described bosutinib crystal form B is at about 3407.08cm-1��2cm-1��2942.16cm-1��2cm-1��2818.39cm-1��2cm-1��2211.23cm-1��2cm-1��1620.57cm-1��2cm-1��1595.32cm-1��2cm-1��1569.93cm-1��2cm-1��1502.58cm-1��2cm-1��1463.92cm-1��2cm-1��1426.64cm-1��2cm-1��1373.13cm-1��2cm-1��1355.14cm-1��2cm-1��1286.91cm-1��2cm-1��1246.02cm-1��2cm-1��1221.41cm-1��2cm-1��1166.34cm-1��2cm-1��1092.71cm-1��2cm-1��1050.45cm-1��2cm-1��1010.34cm-1��2cm-1��987.86cm-1��2cm-1��927.67cm-1��2cm-1��849.29cm-1��2cm-1��814.97cm-1��2cm-1��729.14cm-1��2cm-1��601.77cm-1��2cm-1There is absworption peak at place.
The infrared spectrum of the bosutinib crystal form B of the present invention is as shown in Figure 6.
Means of differential scanning calorimetry (DSC) collection of illustrative plates of bosutinib crystal form B of the present invention has maximum absorption band in the scope of 60.2��105.1 DEG C.
The DSC collection of illustrative plates of the bosutinib crystal form B of the present invention is as shown in Figure 7.
The TGA collection of illustrative plates of the bosutinib crystal form B of the present invention is as shown in Figure 8.
Another object of the present invention is to provide a kind of bosutinib crystal C.
The X-ray powder diffraction of a kind of bosutinib crystal C provided by the present invention in 2 �� (��) values is: 9.2 �� 0.2,12.1 �� 0.2,13.4 �� 0.2,14.1 �� 0.2,19.2 �� 0.2,21.0 �� 0.2,25.2 �� 0.2,26.5 �� 0.2,27.7 �� 0.2 places have characteristic peak.
In one aspect, the X-ray powder diffraction of bosutinib crystal C provided by the present invention in 2 �� (��) values is: 14.6 �� 0.2,17.6 �� 0.2,21.7 �� 0.2,22.3 �� 0.2,24.7 �� 0.2,27.4 �� 0.2,29.5 �� 0.2,30.6 �� 0.2 places also have characteristic peak.
Further, the X-ray powder diffraction of bosutinib crystal C provided by the invention have 2 �� as shown in table 3 below,And Relative intensity data:
Table 3
Without limitation, the bosutinib crystal C of the present invention has X-ray powder diffractogram as shown in Figure 9.
Additionally, the bosutinib crystal C of the present invention, it is possible to the infrared absorption pattern recorded with KBr tabletting characterizes, at about 1825.25cm-1��2cm-1��1352.86cm-1��2cm-1��1325.04cm-1��2cm-1��1148.95cm-1��2cm-1��1025.39cm-1��2cm-1��963.51cm-1��2cm-1��846.52cm-1��2cm-1There is absworption peak at place.
3303.62cm-1��2cm-1��2957.41cm-1��2cm-1��2930.15cm-1��2cm-1��2810.06cm-1��2cm-1��2206.27cm-1��2cm-1��1621.57cm-1��2cm-1��1593.08cm-1��2cm-1��1569.00cm-1��2cm-1��1528.25cm-1��2cm-1��1501.79cm-1��2cm-1��1422.90cm-1��2cm-1��1372.27cm-1��2cm-1��1352.85cm-1��2cm-1��1325.04cm-1��2cm-1��1283.72cm-1��2cm-1��1242.13cm-1��2cm-1��1221.13cm-1��2cm-1��1163.73cm-1��2cm-1��1148.95cm-1��2cm-1��1133.16cm-1��2cm-1��1111.49cm-1��2cm-1��1091.32cm-1��2cm-1��1051.57cm-1��2cm-1��1025.39cm-1��2cm-1��1011.03cm-1��2cm-1��963.51cm-1��2cm-1��910.00cm-1��2cm-1��846.52cm-1��2cm-1��769.90cm-1��2cm-1��725.77cm-1��2cm-1��634.73cm-1��2cm-1��598.28cm-1��2cm-1There is absworption peak at place.
The infrared spectrum of the bosutinib crystal C of the present invention is as shown in Figure 10.
Means of differential scanning calorimetry (DSC) collection of illustrative plates of bosutinib crystal C of the present invention has maximum absorption band in the scope of 102��111.6 DEG C.
The DSC collection of illustrative plates of the bosutinib crystal C of the present invention is as shown in figure 11.
The TGA collection of illustrative plates of the bosutinib crystal C of the present invention is as shown in figure 12.
One object of the present invention also resides in and provides a kind of method preparing bosutinib crystal form A, and the method includes:
(1) 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is dissolved in ethanol;
(2) it is warming up to 60-65 DEG C, and after continuing stirring until dissolving, place stirring and crystallizing 7-10h under room temperature, filter, obtain the crystal form A of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles.
In described step (1), the w/v of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles and ethanol is 1:15��25 (g/ml). In described step (2), its mixing speed can be not especially limited.
One object of the present invention also resides in and provides a kind of method preparing bosutinib crystal form B, and the method includes:
(1) 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is dissolved in acetone;
(2) it is warming up to 50-55 DEG C, and continues stirring until dissolving;
(3) step (2) gained solution is added in the water of 5-10 DEG C;
(4) stirring and crystallizing at 5-10 DEG C, filters, obtains the crystal form B of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles.
In described step (1), 4-[(2, the chloro-5-methoxyphenyl of 4-bis-) amino] w/v of-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles and acetone is 1:15��25g/ml, the volume ratio of water and acetone is 4:1��10:1. The stirring and crystallizing time in described step (4) can be not especially limited, as long as stirring is to no longer crystallization, it is preferred that the time of stirring and crystallizing is 2 hours. Described mixing speed can be not especially limited.
One purpose of the present invention also resides in the method providing another kind to prepare bosutinib crystal form B, and the method includes:
(1) the crystal form A of 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is mixed with water; Preferably, wherein said crystal form A is 1:30��50g/ml with the w/v of water;
(2), at being positioned over 20-40 DEG C, pull an oar 4-12h;
(3) filter, obtain 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles crystal form B.
Having it is also an object of the present invention to provide a kind of method preparing bosutinib crystal C, the method includes:
(1) 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is dissolved in n-butyl alcohol;
(2) it is warming up to 60-70 DEG C, and continues stirring until dissolving;
(3) place stirring and crystallizing 10-20h under room temperature, filter, obtain the crystal C of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles;
In described step (1), the w/v of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles and n-butyl alcohol is 1:20��30 (g/ml). Described mixing speed can be not especially limited.
The bosutinib raw material used in the inventive method can be commercially available, or prepares according to known methods. Solvent used in the present invention has no particular limits, and can adopt the Conventional solvents being purchased.
In the present invention, as do not indicated temperature, then referring to and at room temperature operate, described room temperature refers to ambient temperature, is generally 10 DEG C-30 DEG C.
X-ray powder diffractometer device involved in the present invention and test condition be: X-diffraction apparatus model RigakuD/max-2200Cu target; Operational approach: 4 ��/min of scanning speed, scans step width 0.01 ��.
Infrared spectrophotometer involved in the present invention and test condition be: infrared spectrophotometer model: BRWKERVECTOR22; Operational approach: adopt KBr pressed disc method, sweep limits 400��4000cm-1��
The DSC test condition that the present invention relates to is: DSC detector model is: NETZSCHDSC200F3Maia; Operational approach: 10 DEG C/min of heating rate, temperature range: 30 DEG C��250 DEG C.
The TGA test condition that the present invention relates to is: TGA model: PerkinElmerTGA400; Operational approach: 10 DEG C/min of heating rate, temperature range: 30 DEG C��300 DEG C.
The liquid phase test condition that the present invention relates to is: chromatographic column is PurospherRSTARRP-18endcapped(5��m)HibarRRT250-4.6; Mobile phase A: acetonitrile, Mobile phase B: 10% acetonitrile (0.01N ammonium dihydrogen phosphate);
Detection wavelength: 250nm; Flow velocity: 1ml/min; Sample size: 10 �� l.
Table 4 liquid-phase condition
| t(min) | A (%) | B (%) |
| 0 | 30 | 70 |
| 10 | 55 | 45 |
| 20 | 66 | 45 |
| 21 | 30 | 70 |
| 25 | 30 | 70 |
It should be emphasized that; numerical value involved in technical solution of the present invention or numerical end point; its implication or desired protection domain are not limited to this numeral itself; skilled artisans appreciate that; that they include those by this area is well accepted can allowable error scope; such as experimental error, measurement error, statistical error and random error etc., and these range of error are all contained within the scope of the present invention.
The present inventor has extensively studied and found that novel crystal forms A, B and the C of bosutinib, its favorable solubility and possess product purity height, physicochemical property is excellent, chemical stability is good, processing (filter, dry) reproducible advantage; Simultaneously the crystal form A of bosutinib of the present invention, B and C crystallization processes simple, it is simple to operation, industrialized production can be realized; It addition, the crystal form A of the bosutinib of the present invention, B and C have good dissolution.
Accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction of embodiment 1 gained bosutinib crystal form A.
Fig. 2 is the infrared absorption spectroscopy of embodiment 1 gained bosutinib crystal form A.
Fig. 3 is the DSC collection of illustrative plates of embodiment 1 gained bosutinib crystal form A.
Fig. 4 is the TGA collection of illustrative plates of embodiment 1 gained bosutinib crystal form A.
Fig. 5 is the X-ray powder diffraction of embodiment 7 gained bosutinib crystal form B.
Fig. 6 is the infrared absorption spectroscopy of embodiment 7 gained bosutinib crystal form B.
Fig. 7 is the DSC collection of illustrative plates of embodiment 7 gained bosutinib crystal form B.
Fig. 8 is the TGA collection of illustrative plates of embodiment 7 gained bosutinib crystal form B.
Fig. 9 is the X-ray powder diffraction of embodiment 10 gained bosutinib crystal C.
Figure 10 is the infrared absorption spectroscopy of embodiment 10 gained bosutinib crystal C.
Figure 11 is the DSC collection of illustrative plates of embodiment 10 gained bosutinib crystal C.
Figure 12 is the TGA collection of illustrative plates of embodiment 10 gained bosutinib crystal C.
Specific embodiment
The following example is explained further the explanation present invention, but, the present invention is not intended that restriction or limits.
The bosutinib crude product used in the inventive method can prepare according to the method disclosed in patent CN101792416.
Embodiment 1
Being dissolved in 15ml ethanol by bosutinib crude product 1g (HPLC purity > 99%), be warming up to 65 DEG C, continuously stirred 30min dissolves; Filtering, filtrate places stirring and crystallizing 7h under room temperature, and mixing speed is 200rpm/min, filters, vacuum drying at 40 DEG C, obtains 0.82g crystal, and it is 99.7% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form A.
Embodiment 2
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 25ml ethanol, it is warming up to 60 DEG C, continuously stirred 40min dissolves, filtering, filtrate places room temperature stirring and crystallizing 10h, and mixing speed is 200rpm/min, filter, vacuum drying at 40 DEG C, obtains 0.78g crystal, and it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form A.
Embodiment 3
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 20ml ethanol, it is warming up to 63 DEG C, continuously stirred 30min dissolves, filtering, filtrate places room temperature stirring and crystallizing 8h, and mixing speed is 200rpm/min, filter, vacuum drying at 40 DEG C, obtains 0.80g crystal, and it is 99.7% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form A.
The X-ray powder diffractogram of embodiment 2-3 products therefrom is identical with embodiment 1, is not repeated at this to illustrate.
Embodiment 4
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 15ml acetone, it is warming up to 55 DEG C, continuously stirred 20min dissolves, and filters, filtrate is added in the 60ml water of 5 DEG C, mixing speed is 200rpm/min, stirring and crystallizing 2h at 5 DEG C, filters, and normal-temperature vacuum dries, obtaining 0.86g crystal, it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form B.
Embodiment 5
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 25ml acetone, it is warming up to 50 DEG C, continuously stirred 30min dissolves, and filters, filtrate is added in the 250ml water of 10 DEG C, mixing speed is 200rpm/min, stirring and crystallizing 2h at 10 DEG C, filters, and normal-temperature vacuum dries, obtaining 0.83g crystal, it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form B.
Embodiment 6
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 20ml acetone, it is warming up to 52 DEG C, continuously stirred 40min dissolves, and filters, filtrate is added in the 120ml water of 8 DEG C, mixing speed is 200rpm/min, stirring and crystallizing 2h at 8 DEG C, filters, and normal-temperature vacuum dries, obtaining 0.81g crystal, it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form B.
Embodiment 7
By bosutinib crystal form A 1g (HPLC purity > 99%), add water 30ml, and under 40 DEG C of water-baths, pull an oar 4h, and mixing speed is 200rpm/min, filters, and normal-temperature vacuum dries, and obtains 0.94g crystal, and it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form B.
Embodiment 8
By bosutinib crystal form A 1g (HPLC purity > 99%), add water 50ml, and under 20 DEG C of water-baths, pull an oar 12h, and mixing speed is 200rpm/min, filters, and normal-temperature vacuum dries, and obtains 0.91g crystal, and it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form B.
Embodiment 9
By bosutinib crystal form A 1g (HPLC purity > 99%), add water 40ml, and under 30 DEG C of water-baths, pull an oar 8h, and mixing speed is 200rpm/min, filters, and normal-temperature vacuum dries, and obtains 0.91g crystal, and it is 99.6% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal form B.
The X-ray powder diffractogram of embodiment 4-6 and embodiment 8-9 products therefrom is identical with embodiment 7, is not repeated at this to illustrate.
Embodiment 10
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 20ml n-butyl alcohol, it is warming up to 70 DEG C, continuously stirred 30min dissolves, filtering, filtrate places room temperature stirring and crystallizing 10h, and mixing speed is 200rpm/min, filter, vacuum drying at 40 DEG C, obtains 0.84g crystal, and it is 99.7% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal C.
Embodiment 11
Bosutinib crude product 1g (HPLC purity > 99%) is dissolved in 30ml n-butyl alcohol, it is warming up to 60 DEG C, continuously stirred 30min dissolves, filtering, filtrate places room temperature stirring and crystallizing 20h, and mixing speed is 200rpm/min, filter, vacuum drying at 40 DEG C, obtains 0.83g crystal, and it is 99.7% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal C.
Embodiment 12
Being dissolved in 25ml n-butyl alcohol by bosutinib crude product 1g (HPLC purity > 99%), be warming up to 65 DEG C, continuously stirred 30min dissolves; Filtering, filtrate places room temperature stirring and crystallizing 15h, and mixing speed is 200rpm/min, filters, vacuum drying at 40 DEG C, obtains 0.80g crystal, and it is 99.7% that HPLC records its purity.
Through X-ray powder diffraction, infrared, DSC and TGA mensuration, confirm as bosutinib crystal C.
The X-ray powder diffractogram of embodiment 11-12 products therefrom is identical with embodiment 10, is not repeated at this to illustrate.
Table 5 illustrates that three kinds of novel crystal forms prepared by the present invention and existing crystal formation I are 40 DEG C in temperature, when humidity 75%, and bimestrial stability of crystal form Liquid Detection result.
Choose the embodiment of the present invention 1, bosutinib crystal form A, crystal form B, crystal C and existing crystal formation I that embodiment 7, embodiment 10 prepare respectively carry out liquid phase test respectively.
Wherein crystal formation I is monohydrate, is the crystal formation disclosed in existing document (CN10248047A), and the document also reports that crystal formation I is crystal formation the most stable in crystal formation disclosed in it.
Table 5
| 0 month | 1 month | 2 months | |
| Crystal formation I | 99.6% | 99.6% | 98.8% |
| Crystal form A | 99.7% | 99.7% | 99.4% |
| Crystal form B | 99.6% | 99.6% | 99.4% |
| Crystal C | 99.7% | 99.7% | 99.3% |
Showing according to table 5, after 2 months, there is significantly degraded in existing crystal formation I, existing crystal formation I relative to crystal C is more stable for bosutinib crystal form A, crystal form B. Stably refer to by liquid phase, infrared and XRPD analysis, namely do not find degraded, be also not detected by the transformation to other crystal formations.
Table 6 illustrates at the different crystal forms prepared by the present invention and existing crystal formation I dissolubility data in different solvents.
Choose the embodiment of the present invention 1, bosutinib crystal form A, crystal form B, crystal C and existing crystal formation I that embodiment 7, embodiment 10 prepare respectively carry out dissolubility test, and dissolubility measures and measures according to EP method. Table 6
| Solvent | Crystal formation I | Crystal form A | Crystal C | Crystal form B |
| Methanol | Readily soluble | Slightly soluble | Slightly soluble | Slightly soluble |
| Ethanol | Dissolve | Slightly soluble | Slightly molten | Slightly molten |
| Isopropanol | Slightly soluble | Readily soluble | Insoluble | Readily soluble |
| N-butyl alcohol | Slightly soluble | Readily soluble | Slightly soluble | Readily soluble |
| Acetone | Slightly molten | Readily soluble | Readily soluble | Readily soluble |
| Acetonitrile | Slightly molten | Readily soluble | Dissolve | Dissolve |
| EA | Slightly soluble | Readily soluble | Slightly molten | Slightly molten |
| Methyl tertiary butyl ether(MTBE) | Insoluble | Insoluble | Insoluble | Insoluble |
| Water | Insoluble | Insoluble | Insoluble | Insoluble |
Claims (16)
1. a 4-[(2, the chloro-5-methoxyphenyl of 4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles crystal form A, it is characterized in that, its X-ray powder diffraction in 2 �� (��) values is: 5.6 �� 0.2,11.8 �� 0.2,16.8 �� 0.2,23.3 �� 0.2,23.9 �� 0.2,24.9 �� 0.2,27.0 �� 0.2 places have characteristic peak.
2. crystal form A according to claim 1, it is characterized in that, its X-ray powder diffraction in 2 �� (��) values is: 10.5 �� 0.2,15.3 �� 0.2,18.1 �� 0.2,19.5 �� 0.2,21.3 �� 0.2,21.8 �� 0.2 places have characteristic peak.
3. crystal form A according to claim 1 and 2, it is characterised in that there is the diffraction maximum of X-ray powder diffraction substantially as shown in, it is preferable that in DSC collection of illustrative plates, have endothermic peak near 92.5��105.6 DEG C.
4. the preparation method of the crystal form A of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles, it is characterised in that the method includes:
(1) 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is dissolved in ethanol;
(2) it is warming up to 60-65 DEG C, and after continuing stirring until dissolving, place stirring and crystallizing 7-10h under room temperature, filter, obtain the crystal form A of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles.
5. preparation method according to claim 4, it is characterized in that, the w/v of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles and ethanol is 1:15��25g/ml.
6. a 4-[(2, the chloro-5-methoxyphenyl of 4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles crystal form B, it is characterized in that, its X-ray powder diffraction in 2 �� (��) values is: 6.5 �� 0.2,12.8 �� 0.2,22.8 �� 0.2,25.4 �� 0.2,28.2 �� 0.2,29.6 �� 0.2 places have characteristic peak.
7. crystal form B according to claim 6, it is characterised in that its X-ray powder diffraction in 2 �� (��) values is: 8.8 �� 0.2,15.6 �� 0.2,17.8 �� 0.2,20.8 �� 0.2,27.1 �� 0.2 places have characteristic peak.
8. the crystal form B according to claim 6 or 7, it is characterised in that there is the diffraction maximum of X-ray powder diffraction substantially as shown in Figure 5, it is preferable that in DSC collection of illustrative plates, have endothermic peak near 60.2��105.1 DEG C.
9. the preparation method of the crystal form B of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles, it is characterised in that the method includes:
(1) 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is dissolved in acetone;
(2) it is warming up to 50-55 DEG C, and continues stirring until dissolving;
(3) step (2) gained solution is added in the water of 5-10 DEG C;
(4) stirring and crystallizing at 5-10 DEG C, filters, obtains the crystal form B of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles.
10. preparation method according to claim 9, it is characterized in that, 4-[(2, the chloro-5-methoxyphenyl of 4-bis-) amino] w/v of-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles and acetone is 1:15��25g/ml, the volume ratio of water and acetone is 4:1��10:1.
11. the preparation method of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles crystal form B, it is characterised in that the method includes:
(1) the crystal form A of 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is mixed with water; Preferably, wherein said crystal form A is 1:30��50g/ml with the w/v of water;
(2), at being positioned over 20-40 DEG C, pull an oar 4-12h;
(3) filter, obtain the crystal form B of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles.
12. a 4-[(2, the chloro-5-methoxyphenyl of 4-bis-) amino] crystal C of-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles, it is characterized in that, its X-ray powder diffraction in 2 �� (��) values is: 9.2 �� 0.2,12.1 �� 0.2,13.4 �� 0.2,14.1 �� 0.2,19.2 �� 0.2,21.0 �� 0.2,25.2 �� 0.2,26.5 �� 0.2,27.7 �� 0.2 places have characteristic peak.
13. crystal C according to claim 12, it is characterized in that, its X-ray powder diffraction in 2 �� (��) values is: 14.6 �� 0.2,17.6 �� 0.2,21.7 �� 0.2,22.3 �� 0.2,24.7 �� 0.2,27.4 �� 0.2,29.5 �� 0.2,30.6 �� 0.2 places have characteristic peak.
14. the crystal C according to claim 12 or 13, it is characterised in that there is the diffraction maximum of X-ray powder diffraction substantially as shown in Figure 9, it is preferable that in DSC collection of illustrative plates, have endothermic peak near 102��111.6 DEG C.
15. the preparation method of the crystal C of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles, it is characterised in that the method includes:
(1) 4-[(the chloro-5-methoxyphenyl of 2,4-bis-) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles is dissolved in n-butyl alcohol;
(2) it is warming up to 60-70 DEG C, and continues stirring until dissolving;
(3) place stirring and crystallizing 10-20h under room temperature, filter, obtain the crystal C of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles.
16. preparation method according to claim 15, it is characterized in that, the w/v of 4-[(2,4-bis-chloro-5-methoxyphenyl) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxyl group]-3-quinolinecarbonitriles and n-butyl alcohol is 1:20��30g/ml.
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| CN110317168A (en) * | 2018-03-30 | 2019-10-11 | 正大天晴药业集团股份有限公司 | A kind of purification process of bosutinib |
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