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Crystalline forms of intermediates used in the preparation of 4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid

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Publication Date: 2017-Feb-15
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Crystalline forms of intermediates used in the preparation of 4-{[(2S,4R)-1-(4-

Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid

4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic

acid

has the following structure:

(Compond I)

The following compounds can be used as intermediates in the preparation of compond I:

(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid)

(compound A)

(2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride

(compound B)

Crystalline form I of compound A:

List of XRD peaks: 6.8, 8.5, 10.0, 10.7, 11.6, 13.7, 16.7, 18.2, 22.0 degrees two theta ± 0.2

degrees.

Figure 1. PXRD pattern of compound A-form I

Figure 2. FTIR spectrum of compond A-form I

5 10 15 20 25 30 35 2Theta (°)

0

2000

4000

6000

8000

In te

n si

ty (

co u

n ts

)

of compound A: form IICrystalline

Main XRPD peaks: 7.9, 9.9, 12.1, 13.5, 14.8, 17.4, 18.6, 19.9, 21.4, 22.8 degrees two theta ±

0.2 degrees.

Figure 3. PXRD pattern of compound A- form II

Figure 4. FTIR spectrum of of compound A-form II

5 10 15 20 25 30 35 2Theta (°)

0

2000

4000

6000

8000

10000

12000

14000

In te

n si

ty (

co u

n ts

)

Crystalline form of compound B

Main XRPD peaks: 5.7, 6.2, 7.7, 12.5, 14.8, 16.2, 17.1, 17.9, 18.5, 19.9, 20.3, 22.4, 22.6,

22.9, 24.1 degrees two theta ± 0.2 degrees.

Figure 5. PXRD pattern of crystalline compound B

Figure 6. FTIR spectrum of crystalline compound B

5 10 15 20 25 30 35 2Theta (°)

0

1000

2000

3000

In te

n si

ty (

co u

n ts

)

Experimental:

PXRD method:

After being powdered using mortar and pestle, samples were applied directly on a silicon

plate holder. The X-ray powder diffraction pattern was measured with a Philips X'Pert PRO

X-ray powder diffractometer, equipped with a Cu irradiation source = 1.54184 Ǻ (Ǻngström),

X’Celerator (2.022º 2θ) detector. Scanning parameters: angle range: 3-40 deg., step size

0.0167, time per step 37 s, continuous scan. The accuracy of peak positions was defined as +/-

0.2 degrees due to experimental differences like instrumentations and sample preparations.

FTIR method:

Equipment

Instrument: Nicolet 6700 FT-IR spectrometer

Sample preparation: Sample was prepared as KBr pellet. Empty sample compartment was

used for background spectrum acquisition.

Scanning parameters

The spectra were scanned between: 4000-400 cm -1

All the spectra were measured in 16 scans

Resolution: 4.0 cm -1

Experimental part:

The crystalline intermediates can be further convert into compound I, by method known in the

prior art, for example, according to the process described in US8946481.

Compound I can be further used in the preparation of Trisodium [3-((1S,3R)-1-biphenyl-4-

ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-

(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate], as described in US8877938

Preparation of crystalline (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-

butoxycarbonyl)amino)-2-methylpentanoic...