CN104402868B - Deuterated Crizotinib crystal formation and preparation method thereof - Google Patents

Deuterated Crizotinib crystal formation and preparation method thereof Download PDF

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Publication number
CN104402868B
CN104402868B CN201410614766.9A CN201410614766A CN104402868B CN 104402868 B CN104402868 B CN 104402868B CN 201410614766 A CN201410614766 A CN 201410614766A CN 104402868 B CN104402868 B CN 104402868B
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crystal formation
deuterated
preparation
crizotinib
deuterated crizotinib
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CN104402868A (en
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吴豫生
牛成山
邹大鹏
耿阳
郭瑞云
李敬亚
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BEIJING KYNING BIOSCIENCE CO., LTD.
TETRANOV PHARMACY STOCK INC.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/14—Heterocyclic 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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

The invention discloses a kind of deuterated Crizotinib crystal formation and preparation method thereof, described crystal formation includes the deuterated Crizotinib crystal formation as shown in structure formula (I) or structure formula (II), and gives this diffraction maximum that two kinds of crystal formations represent in X ray powder diffraction pattern with 2 θ angles.The preparation method of the deuterated Crizotinib crystal formation of the present invention, it is that deuterated Crizotinib is dissolved in organic solvent, by adding water and staged cooling after intensification, it is achieved that the preparation of the crystal formation of the deuterated Crizotinib as shown in structure formula (I) or structure formula (II)；This preparation method gained crystal formation has higher structural homogeneity and crystal form purity, and yield is high；This preparation method technique is simple, easy to operate, low cost, it is easy to Automated condtrol, is suitable for popularization and application.

Description

Deuterated Crizotinib crystal formation and preparation method thereof
Technical field
The invention belongs to compound crystal form technical field, be specifically related to a kind of deuterated Crizotinib crystal formation, the most also relate to And the preparation method of a kind of deuterated Crizotinib crystal formation.
Background technology
Crizotinib is that the one developed by Pfizer is administered orally tyrosine kinase receptor inhibitor, according to clinical verification can Effectively reduce the malignant tumour of late gene saltant type non-small cell lung cancer (NSCLC) patient, advanced Non-small cell lung is suffered from Person has significant result for the treatment of, is this maximally effective medicine of type lung cancer current.
Deuterated Crizotinib is that the part hydrogen atom in Crizotinib structure is replaced with D-atom thus prepares New compound, deuterated achirality Crizotinib and derivative thereof as disclosed in patent CN10207944B, this patent also simultaneously Disclose the preparation method of deuterated Crizotinib.Owing to deuterium shape in drug molecule and volume are essentially identical with hydrogen, deuterium Typically can retain biologically active and the selectivity of original medicine for medicine, there is a possibility that some character of medicine is improved simultaneously. Deuterated medicine has that search time is short, cost is few, security and the advantage such as success rate is high, subject is few, by widely Pay close attention to.
The crystal formation of medicine has important impact, the crystal formation of current deuterated Crizotinib to validity and the security of medication Yet there are no report.
Summary of the invention
It is an object of the invention to provide a kind of deuterated Crizotinib crystal formation.
Second object of the present invention is to provide the preparation method of a kind of deuterated Crizotinib crystal formation.
In order to realize object above, the technical solution adopted in the present invention is:
Deuterated Crizotinib crystal formation, brilliant including the deuterated Crizotinib as shown in structure formula (I) or structure formula (II) Type:
Deuterated Crizotinib crystal formation as shown in structure formula (I), represents with 2 θ angles in X-ray powder diagram, 6.389 °, 10.480 °, 11.731 °, 12.340 °, 12.830 °, 15.710 °, 17.340 °, 18.520 °, 19.710 °, 21.030、21.340°、21.700°、22.890°、23.350°、24.450°、24.790°、25.290°、26.340°、 26.830 have diffraction maximum at °；
Deuterated Crizotinib crystal formation as shown in structure formula (II), with 2 θ angle tables in X-ray powder diagram Show, 6.380 °, 10.410 °, 11.610 °, 12.270 °, 12.770 °, 15.670 °, 17.300 °, 19.640 °, 21.000 °, 21.660°、22.880°、23.300°、24.400°、24.720°、25.240°、26.310°、26.780°、35.149°、 35.740 have diffraction maximum at °.
Described X-ray powder diagram is to use CuK α radiation.
The preparation method of a kind of above-mentioned deuterated Crizotinib crystal formation, comprises the following steps:
1) take deuterated Crizotinib to disperse in organic solvent, obtain mixture A；
2) by step 1) gained mixture A is warming up to 50～80 DEG C, adds water, and stirring makes solid all dissolve, and obtains solution；
3) by step 2) gained solution is cooled to 30～50 DEG C, and add water, obtain mixture B；
4) by step 3) gained mixture B is cooled to room temperature, continuously stirred, and filter, wash, be dried, to obtain final product.
Step 1) in, described organic solvent be in acetone, oxolane, methyl alcohol, ethanol, isopropanol any one or many Kind.
Preferably, described organic solvent is acetonitrile.
Step 1) in, every 1g deuterated Crizotinib correspondence uses 10～40ml organic solvents.
Step 2) in gained solution, organic solvent is 1～10:1～5 with the volume ratio of water.
Preferably, step 2) in mixture A be warming up to 72 DEG C.
Preferably, step 2) organic solvent is 2:1 with the volume ratio of water in gained solution.
Step 2) in, the time of described stirring is 1.5～3h.
Step 3) in, the amount added water is that to make the volume ratio of organic solvent and water in mixture B be 1:1～5.
Preferably, in mixture B, the volume ratio of organic solvent and water is 1:2.
Step 4) in, the described continuously stirred time is 2～10h.
Step 4) in, described washing is that the organic solvent using temperature to be 0～10 DEG C washs.
Step 4) in, described being dried is to dry under the conditions of 25～50 DEG C.
The deuterated Crizotinib crystal formation of the present invention, for the first crystal formation of the deuterated Crizotinib of report, this crystal formation Being mainly used in medicinal usage, compare without crystal formation medicine, it is excellent that this fixing crystal formation medicine has that medicine stability is good, curative effect is stable etc. Gesture.
The preparation method of the deuterated Crizotinib crystal formation of the present invention, is that deuterated Crizotinib is dissolved in organic solvent In, by adding water and staged cooling after intensification, it is achieved that the azoles base of a fruit in deuterated gram as shown in structure formula (I) or structure formula (II) The preparation of the crystal formation of Buddhist nun；This preparation method gained crystal formation has higher structural homogeneity and crystal form purity, and yield is high；This is prepared Method technique is simple, easy to operate, low cost, it is easy to Automated condtrol, is suitable for popularization and application.
Accompanying drawing explanation
Fig. 1 is the XRD spectra of the Crizotinib crystal formation shown in structure formula (I) in embodiment 1；
Fig. 2 is the XRD spectra of the Crizotinib crystal formation shown in structure formula (II) in embodiment 2.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further illustrated.
In detailed description of the invention, deuterated Crizotinib used is according to the preparation disclosed in patent CN102079744B Method prepares, and deuterated rate is 98%, ee value > 99%.
In detailed description of the invention, the X-ray powder diffractometer used is the X ' Pert that PANalytical company of Holland produces PRO type, incident light is CuK α spectral line, operating voltage 40KV, tube current 40mA, 10 °/min of surface sweeping speed.Testing conditions is: work Make voltage 35KV；Tube current 30mA；Angular range: 2-40 °；Step-length: 0.01 °/step；Wavelength 1.5406.
Embodiment 1
The deuterated Crizotinib crystal formation of the present embodiment, for the crystal formation of the deuterated Crizotinib shown in structure formula (I), its Preparation method comprises the following steps:
1) take the 1.2g deuterated Crizotinib as shown in structure formula (I), add in 20ml acetonitrile, obtain mixture A；
2) by step 1) gained mixture A is warming up to 72 DEG C, adds the water of 9ml, and stirring 2h makes solid all dissolve, obtains molten Liquid；
3) by step 2) gained solution is cooled to 40 DEG C, and stir 1h, have white solid to separate out, be slowly added to the water of 70ml, Obtain mixture B；
4) by step 3) gained mixture B is cooled to room temperature, continuously stirred 3h, filter, with the acetonitrile washing that temperature is 4 DEG C After, dry under the conditions of 30 DEG C, obtain white powdery solids 1g, be the azoles base of a fruit in described as shown in structure formula (I) deuterated gram Buddhist nun's crystal formation.
The gained deuterated Crizotinib crystal formation as shown in structure formula (I) is carried out X-ray diffraction mensuration, its XRD peak value As shown in table 1.
The XRD peak value of the deuterated Crizotinib crystal formation shown in table 1 structure formula (I)
2-Theta d(A) BG Height I% Area I% FWHM XS(A)
6.389 13.8221 66 112 2.6 4415 4.0 0.335 249
10.480 8.4342 73 332 7.8 8642 7.9 0.221 404
11.731 7.5377 85 262 6.2 7045 6.4 0.229 389
12.340 7.1667 64 183 4.3 7351 6.7 0.341 245
12.830 6.8941 45 490 11.6 12002 10.9 0.208 438
15.710 5.6362 63 1655 39.0 52510 47.9 0.270 320
17.340 5.1099 69 3090 72.9 66923 61.0 0.184 520
18.520 4.7869 75 152 3.6 4769 4.3 0.267 326
19.710 4.5005 87 4240 100.0 109694 100.0 0.220 412
21.030 4.2209 102 992 23.4 35602 32.5 0.305 280
21.340 4.1602 91 552 13.0 36530 33.3 0.563 146
21.700 4.0920 87 817 19.3 36739 33.5 0.382 219
22.890 3.8819 82 264 6.2 14944 13.6 0.481 172
23.350 3.8065 80 947 22.3 25468 23.2 0.229 395
24.450 3.6377 77 259 6.1 7508 6.8 0.246 361
24.790 3.5885 103 767 18.1 20352 18.6 0.226 402
25.290 3.5187 130 331 7.8 9204 8.4 0.236 380
26.340 3.3808 170 264 6.2 9531 8.7 0.307 281
26.830 3.3201 163 1418 33.4 38539 35.1 0.231 392
The deuterated Crizotinib that the gained deuterated Crizotinib crystal formation as shown in structure formula (I) is the present embodiment is brilliant Type, its X-ray diffraction spectrogram is as shown in Figure 1；Fig. 1 shows, this crystal formation represents with 2 θ angles in X-ray powder diagram, 6.389 °, 10.480 °, 11.731 °, 12.340 °, 12.830 °, 15.710 °, 17.340 °, 18.520 °, 19.710 °, 21.030、21.340°、21.700°、22.890°、23.350°、24.450°、24.790°、25.290°、26.340°、 26.830 have diffraction maximum at °.
Embodiment 2
The deuterated Crizotinib crystal formation of the present embodiment, for the crystal formation of the deuterated Crizotinib shown in structure formula (II), Its preparation method comprises the following steps:
1) take the 1.2g deuterated Crizotinib as shown in structure formula (II), add in 20ml acetonitrile, obtain mixture A；
2) by step 1) gained mixture A is warming up to 72 DEG C, adds the water of 9ml, and stirring 2h makes solid all dissolve, obtains molten Liquid；
3) by step 2) gained solution is cooled to 40 DEG C, and stir 1h, have white solid to separate out, be slowly added to the water of 70ml, Obtain mixture B；
4) by step 3) gained mixture B is cooled to room temperature, continuously stirred 3h, filter, with the acetonitrile washing that temperature is 4 DEG C After, dry under the conditions of 30 DEG C, obtain white powdery solids 1g, be the azoles base of a fruit in described as shown in structure formula (II) deuterated gram Buddhist nun's crystal formation.
The gained deuterated Crizotinib crystal formation as shown in structure formula (II) is carried out X-ray diffraction mensuration, its XRD peak Value is as shown in table 2.
The XRD peak value of the deuterated Crizotinib crystal formation shown in table 2 structure formula (II)
2-Theta d(A) BG Height I% Area I% FWHM XS(A)
6.380 13.8427 74 106 4.5 5299 6.9 0.425 193
10.410 8.4907 65 176 7.5 6238 8.1 0.301 281
11.610 7.6157 73 152 6.5 5935 7.7 0.332 252
12.270 7.2075 72 112 4.8 4410 5.7 0.335 250
12.770 6.9263 61 504 21.6 13439 17.5 0.227 393
15.670 5.6505 64 1147 49.2 45363 59.1 0.336 250
17.300 5.1216 59 1863 79.9 50239 65.5 0.229 390
19.640 4.5163 95 2333 100.0 76740 100.0 0.280 309
21.000 4.2269 104 596 25.5 30743 40.1 0.438 189
21.660 4.0996 83 428 18.3 35810 46.7 0.711 115
22.880 3.8836 84 292 12.5 17863 23.3 0.520 159
23.300 3.8145 93 620 26.6 18089 23.6 0.248 357
24.400 3.6450 117 332 14.2 8055 10.5 0.206 451
24.720 3.5985 109 438 18.8 15203 19.8 0.295 293
25.240 3.5256 152 207 8.9 4664 6.1 0.192 498
26.310 3.3846 227 163 7.0 5146 6.7 0.268 328
26.780 3.3262 171 960 41.1 34049 44.4 0.301 287
35.149 2.5510 73 160 6.9 9477 12.3 0.503 169
35.740 2.5102 80 178 7.6 9375 12.2 0.448 191
The gained deuterated Crizotinib crystal formation as shown in structure formula (II) is the deuterated Crizotinib of the present embodiment Crystal formation, its X-ray diffraction spectrogram is as shown in Figure 2；Fig. 2 shows, this crystal formation in X-ray powder diagram with 2 θ angle tables Show, 6.380 °, 10.410 °, 11.610 °, 12.270 °, 12.770 °, 15.670 °, 17.300 °, 19.640 °, 21.000 °, 21.660°、22.880°、23.300°、24.400°、24.720°、25.240°、26.310°、26.780°、35.149°、 35.740 have diffraction maximum at °.

Claims (8)

  1. The most deuterated Crizotinib crystal formation, it is characterised in that: include in deuterated gram as shown in structure formula (I) or structure formula (II) Azoles base of a fruit Buddhist nun's crystal formation:
    Deuterated Crizotinib crystal formation as shown in structure formula (I), represents with 2 θ angles in X-ray powder diagram, 6.389°、10.480°、11.731°、12.340°、12.830°、15.710°、17.340°、18.520°、19.710°、 21.030、21.340°、21.700°、22.890°、23.350°、24.450°、24.790°、25.290°、26.340°、 26.830 have diffraction maximum at °；
    Deuterated Crizotinib crystal formation as shown in structure formula (II), represents with 2 θ angles in X-ray powder diagram, 6.380°、10.410°、11.610°、12.270°、12.770°、15.670°、17.300°、19.640°、21.000°、 21.660°、22.880°、23.300°、24.400°、24.720°、25.240°、26.310°、26.780°、35.149°、 35.740 have diffraction maximum at °.
  2. 2. the preparation method of a deuterated Crizotinib crystal formation as claimed in claim 1, it is characterised in that: include following step Rapid:
    1) take deuterated Crizotinib to add in organic solvent, obtain mixture A；
    2) by step 1) gained mixture A is warming up to 50～80 DEG C, adds water, and stirring makes solid all dissolve, and obtains solution；
    3) by step 2) gained solution is cooled to 30～50 DEG C, and add water, obtain mixture B；
    4) by step 3) gained mixture B is cooled to room temperature, continuously stirred, and filter, wash, be dried, to obtain final product；
    Step 1) in, described organic solvent is any one or more in acetone, oxolane, methyl alcohol, ethanol, isopropanol； Step 2) in gained solution, organic solvent is 1～10:1～5 with the volume ratio of water.
  3. The preparation method of deuterated Crizotinib crystal formation the most according to claim 2, it is characterised in that: step 1) in, often 1g deuterated Crizotinib correspondence uses 10～40ml organic solvents.
  4. The preparation method of deuterated Crizotinib crystal formation the most according to claim 2, it is characterised in that: step 2) in, institute The time stating stirring is 1.5～3h.
  5. The preparation method of deuterated Crizotinib crystal formation the most according to claim 2, it is characterised in that: step 3) in, add The amount of water is that to make the volume ratio of organic solvent and water in mixture B be 1:1～5.
  6. The preparation method of deuterated Crizotinib crystal formation the most according to claim 2, it is characterised in that: step 4) in, institute Stating the continuously stirred time is 2～10h.
  7. The preparation method of deuterated Crizotinib crystal formation the most according to claim 2, it is characterised in that: step 4) in, institute Stating washing is that the organic solvent using temperature to be 0～10 DEG C washs.
  8. The preparation method of deuterated Crizotinib crystal formation the most according to claim 2, it is characterised in that: step 4) in, institute Stating dry is to dry under the conditions of 25～50 DEG C.
CN201410614766.9A 2014-11-04 2014-11-04 Deuterated Crizotinib crystal formation and preparation method thereof Active CN104402868B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ552946A (en) * 2004-08-26 2010-09-30 Pfizer Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
CN101967140A (en) * 2010-09-14 2011-02-09 郑州泰基鸿诺药物科技有限公司 Deuterated crizotinib as well as derivant, preparation method and application thereof

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