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Crystalline forms of intermediates of (2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-(2-propan-2-yl)-nonanamide hemifumarate.

IP.com Disclosure Number: IPCOM000202191D
Publication Date: 2010-Dec-08
Document File: 5 page(s) / 90K

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Crystalline forms of intermediates of (2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)- 4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-(2-propan-2-yl)- nonanamide hemifumarate.

tert-Butyl-(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-4-methylpentylcarbamate Form A


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Procedure A:

tert-Butyl-(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-4-methylpentylcarbamat (3 g) was dissolved in a mixture of MTBE/Heptane=1:3 (12 ml) under heating to provide clear solution. The solution was cooled slowly to room temperature and was maintained at this temperature for 16h. The obtained solid was filtered, dried in oven at 35 oC and analyzed by XRD & DSC and found to be Form A. Yield of the experiment: 96%.

Procedure B: tert-Butyl-(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-4-methylpentylcarbamat (3 g) was dissolved in a mixture of MeOH/H2O=2:1 (45 ml) under heating to provide clear solution. The solution was cooled slowly to room temperature and was maintained at this temperature for 16h. The obtained solid was filtered, dried in oven at 35 oC and analyzed by XRD & DSC and found to be Form A. Yield of the experiment: 90%.


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Procedure C:

tert-Butyl-(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-4-methylpentylcarbamat (10 g) was dissolved in a mixture of MeOH/Diisopropyl ether=1:3 (40 ml) under heating to provide clear solution. The solution was cooled slowly to 5 oC and was maintained at this temperature for 16h. The obtained solid was filtered, dried in oven at 35 oC and analyzed by XRD & DSC and found to be Form A. Yield of the experiment: 36%.

Form A of tert-Butyl-(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-4-methylpentylcarbamate was analyzed by XRPD.

The XRD pattern of form A prepared according to procedure A is presented in the following representative X-ray diffractogram (the peak at about 28.5° belongs to silicon powder added as an internal standard):

Range: 2.000 - 40.000° Cont. Scan Rate: 3.000 [°/min]

5000

4000

3000

2000

1000

0

Horz. Scale Unit: [deg]

2.0 6.0 10.0 14.0 18.0 22.0 26.0 30.0 34.0 38.0


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The XRD pattern of form A prepared according to procedure B i...