WO2015149727A1 - Nouvelles phases solides de 4- [(2,4-dichloro-5-méthoxyphényl)amino]-6-méthoxy-7-[3-4-méthyl-1-pipérazinyl)propoxy] -3-quinoléinecarbonitrile - Google Patents

Nouvelles phases solides de 4- [(2,4-dichloro-5-méthoxyphényl)amino]-6-méthoxy-7-[3-4-méthyl-1-pipérazinyl)propoxy] -3-quinoléinecarbonitrile Download PDF

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WO2015149727A1
WO2015149727A1 PCT/CZ2014/000033 CZ2014000033W WO2015149727A1 WO 2015149727 A1 WO2015149727 A1 WO 2015149727A1 CZ 2014000033 W CZ2014000033 W CZ 2014000033W WO 2015149727 A1 WO2015149727 A1 WO 2015149727A1
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piperazinyl
methoxyphenyl
propoxy
amino
methoxy
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PCT/CZ2014/000033
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English (en)
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Violetta Kiss
Ondrej Dammer
Ludek Ridvan
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Zentiva, K.S.
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Priority to PCT/CZ2014/000033 priority Critical patent/WO2015149727A1/fr
Publication of WO2015149727A1 publication Critical patent/WO2015149727A1/fr

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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

Definitions

  • the present invention relates to a novel modifications of 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile of Formula I
  • tyrosine kinase is a subclass of protein kinase and it plays an important role in the phosphate group transfer in form adenosine triphosphate (ATP) to a protein in the cell.
  • ATP adenosine triphosphate
  • the phosphate group is attached to the appropriate amino acid, tyrosine on the protein.
  • Tyrosine kinases act as an "on” and “off' switch, however, can be easily go under mutation by sticking in the "on” position resulting in uncontrolled growth of the cell that leads to the development of cancer. Consequently, tyrosine kinase inhibitors are often used as effective agents for cancer treatments.
  • WO03093241 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases.
  • One example of the compounds disclosed is 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile; preparation of the base is described.
  • Organic compound like 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile may exist in various crystal modifications having different crystal units and hence different physico-chemical properties including melting point, solubility, dissolution rate and finally, bioavailability.
  • solid state analytical techniques e.g. X- Ray Powder Diffraction, Raman spectroscopy and thermoanalytical methods.
  • the object of the present invention is to provide novel modifications of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile suitable for oral administration which meet the pharmaceutical requirements.
  • Figure 1 is an XRPD pattern of the Crystal modification 1 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 1;
  • Figure 2 is a Raman spectra of the Crystal modification 1 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 1;
  • Figure 3 is an XRPD pattern of the Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 2;
  • Figure 4 is a Raman spectra of the Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 2;
  • Figure 5 is an XRPD pattern of the Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 6;
  • Figure 6 is a Raman spectra of the Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 6;
  • Figure 7 is an XRPD pattern of the Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 9;
  • Figure 8 is a Raman spectra of the Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 9;
  • Figure 9 is an XRPD pattern of the Crystal modification 5 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 11;
  • Figure 10 is a Raman spectra of the Crystal modification 5 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 11;
  • Figure 11 is an XRPD pattern of the Crystal modification 6 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 12;
  • Figure 12 is a Raman spectra of the Crystal modification 6 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 12;
  • Figure 13 is an XRPD pattern of the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 14;
  • Figure 14 is a Raman spectra of the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 14.
  • the aim of the present invention is to provide novel modifications of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (bosutinib) of formula I with advantageous properties for pharmaceutical use regarding the physico- chemical properties and which can be produced in a reproducible manner even in industrial scale.
  • the invention relates to novel crystalline and amorphous modifications of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, which have not been described in the literature and no solid state analytical data (X-Ray Powder Diffraction patterns, Single-Crystal X-Ray Diffraction data etc.) serving to characterize the novel solid phases have been provided.
  • Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile has the characteristic XRPD pattern as shown in Figure 1.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • the Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7- [3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 1, below:
  • Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation.
  • Figure 2 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2939, 2820, 2214, 1622, 1594, 1508, 1464, 1428, 1328 and 703 cm 1 wavenumbers.
  • Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • the crystalline Modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 90°C- 99°C.
  • Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) suspending 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in water;
  • step b) stirring the suspension of the step a) for 10-15 min at a temperature of 95°C-100°C;
  • step c) keeping the suspension of the step c) at a temperature of 20°C-25°C for 12-16 hours;
  • Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 3.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 2, below:
  • Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation.
  • Figure 4 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3014, 2944, 2828, 2208, 1620, 1594, 1461, 1403, 1326 and 736 cm 1 wavenumbers.
  • Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • the crystalline Modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process with recrystallization phenomena between 100°C-110°C and final melting between 115 o C-120°C.
  • Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in methanol at 60°C-65°C;
  • step b) keeping the suspension of the step b) at a temperature of 20°C-25°C for 12-16 hours;
  • step b) cooling the solution of the step a) to 0°C-5°C by placing the vial containing the solution of 60°C-65°C into ice;
  • step b) keeping the suspension of the step b) at a temperature of 0°C-5°C for 12-16 hours;
  • Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 5.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoli exhibits the following diffraction peaks in XRPD pattern, see Table 3, below:
  • Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation.
  • Figure 6 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3017, 2939, 2833, 2209, 1595, 1407, 1463, 1404, 1328 and 738 cm 1 wavenumbers.
  • Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • the crystalline Modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 89°- 95°C.
  • Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in ethanol at 73°C-78°C;
  • step b) cooling the solution of the step a) to 0°C-5°C by placing the vial containing the solution of 73°C-78°C into ice;
  • step b) keeping the suspension of the step b) at a temperature of 0°C-5°C for 12-16 hours;
  • Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 7.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 4, below:
  • Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation.
  • Figure 8 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3075, 2942, 2976, 2215, 1620, 1590, 1466, 1404, 1381 and 740 cm "1 wavenumbers.
  • Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in 4-methyl-2-pentanone at 110°C-115°C;
  • Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 9.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Crystal modification 5 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 5, below:
  • Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation.
  • Figure 10 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3073, 3035, 2929, 2830, 2219, 1595, 1461, 1386, 1313 and 721 cm 1 wavenumbers.
  • Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • the crystalline Modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 136°C-145°C.
  • Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in butyl acetate at 120°C-125°C;
  • Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 11. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Crystal modification 6 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table6, below:
  • Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy.
  • Figure 12 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks 3041, 2945, 2792, 2214, 1623, 1596, 1405, 1329, 1248 and 741 cm 1 wavenumbers.
  • Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in dichloromethane at 35°C-40°C;
  • step b) cooling the solution of the step a) to 0°C-5°C by placing the vial containing the solution of 35°C-40°C into ice;
  • Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • the crystalline Modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a recrystallization phenomena between 85°C-88°c and final melting between 90°C-100°C.
  • the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 13.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation.
  • Figure 14 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2944, 2215, 1619, 1593, 1502, 1464, 1402, 1327, 1219 and 738 cm "1 wavenumbers.
  • the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera).
  • the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 108°C - 118°C.
  • the amorphous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in dichloromethane at 35°C-40°C;
  • Another process of preparation of the amorphous phase of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:
  • Another process of preparation of the amorphous phase of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:
  • Incident beam optics programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/4 9 anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122 9 . 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
  • FTIR spectra were recorded by FT-Raman Bruker RFS 100/S Spectrometer.
  • Melting process was determined by Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProgRes CT3 camera collecting the data by NIS-Elements AR software.

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Abstract

Des modifications cristallines 1, 2, 3, 4, 5 et 6 et une forme amorphe de 4-[(2,4-dichloro -5-méthoxyphényl)amino]-6-méthoxy-7-[3- (4-méthyl-1-pipérazinyl)propoxy]-3-quinoléinecarbonitrile sont divulguées. (Formule (I))
PCT/CZ2014/000033 2014-04-02 2014-04-02 Nouvelles phases solides de 4- [(2,4-dichloro-5-méthoxyphényl)amino]-6-méthoxy-7-[3-4-méthyl-1-pipérazinyl)propoxy] -3-quinoléinecarbonitrile WO2015149727A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105646345A (zh) * 2016-03-16 2016-06-08 浙江海正药业股份有限公司 博舒替尼的新晶型及其制备方法
WO2017145089A1 (fr) * 2016-02-23 2017-08-31 Sun Pharmaceutical Industries Limited Forme cristalline x du bosutinib

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WO2003093241A1 (fr) 2002-04-30 2003-11-13 Wyeth Holdings Corporation Preparation de 3-quinoline et de 3-quinol- 4-one carbonitriles substitues en position 7
WO2007005462A1 (fr) 2005-07-01 2007-01-11 Wyeth Formes cristallines de 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile, et leurs procedes de preparation

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