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Crystalline form of N-[4-[(3-Chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3- furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide and salts thereof

IP.com Disclosure Number: IPCOM000240150D
Publication Date: 2015-Jan-07
Document File: 5 page(s) / 312K

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The IP.com Prior Art Database

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Crystalline form of N-[4-[(3-Chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3- furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide and salts thereof

Disclosed hereinafter are crystalline forms of N-[4-[(3-Chloro-4-fluorophenyl) amino]- 7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide (referred herein as compound I) and salts thereof, e.g. N-[4-[(3-Chloro-4- fluorophenyl) amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]- 4(dimethylamino)-2-butenamide dimaleate (referred herein as compound II).

Figure 1: a powder XRPD pattern of crystalline compound II:

Intensity (counts)

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2Theta (°)

Peak at 28.46°2 theta belongs to Si.

XRPD peaks: 4.1, 5.0, 7.0, 8.1, 13.9, 17.5, 18.4, 21.7, 20.5 and 26.2 degrees two theta ± 0.2 degrees two theta.

Figure 2: a DSC thermogram of crystalline compound II:


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Sample: AFT-TM-3168-59 Size: 2.9500 mg

DSC

File: C:...\TAPI\Afatinib\AFT-TM-3168-59.001 Operator: Maja
Run Date: 08-Dec-2014 14:09
Instrument: DSC Q1000 V9.9 Build 303


4.5


2.5

Heat Flow (W/g)


0.5

-1.5

25

75

125

175

225

Exo Up

Temperature (°C)

Universal V4.5A TA Instruments

Example 1: Preparation of crystalline form of Compound II


0.25 g of compound I was dissolved in 5 ml of system 2-Me-THF/2-propanol 19:1 (v/v). Solution of 0.113 g of maleic acid in 1.3 ml of system 2-Me-THF/2-propanol 19:1 (v/v) was added slowly. Obtained suspension was stirred at 20°C for about 2 hours, cooled at 0-5°C and stirred for additional 1.5 hour. Crystals were filtered, washed with system 2-Me-THF/2-propanol 19:1 (v/v) and dried at 50°C under reduced pressure to obtain 0.27 g of the crystalline compound II.

Figure 3: a powder XRPD pattern of crystalline form I of compound I:

Intensity (counts)

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2Theta (°)


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XRPD peaks: 5.8, 7.9, 8.4, 9.8, 11.5, 13.0, 18.6, 19.8, 21.0 and 25.8 degrees two theta ± 0.2 degrees two theta.

Figure 4: a DSC thermogram of crystalline form I of compound I:

File: C:...\Afatinib\AFT-Baza-ZM-3106-139.001 Operator: Dalibor
Run Date: 17-Nov-2014 15:47
Instrument: DSC Q1000 V9.9 Build 303

Example 2: Preparation of crystalline form I of Compound I


5.0 g of compound I was dissolved in 36 ml of ethanol, 96% at 20-25°C. Solution was cooled down at 0-5°C and 68 ml of water was added dropwise. Suspension was stirred at the same temperature for 30 minutes and filtered. Crystals were washed with ethanol/water 1:2 mixture and dried at 60°C under reduced pressure. 4.38 g of crystalline form I of compound I was obtained.

Figure 5: a powder XRPD pattern of crystalline form II of compound I:

Sample: AFT-Baza-ZM-3106-139 Size: 2.8000 mg


1.0


0.5


0.0

Exo Up

DSC

Heat Flow (W/g)

25 75

125 175

Temperature (°C)

Universal V4.5A TA Instruments


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Intensity (counts)

22500

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2Theta (°)

XRPD peaks: 6.6, 7.2, 12.7, 14.5, 16.5, 19.3, 19.7, 20.1, 2...