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PROCESSES FOR PREPARING INTERMEDIATES OF N-(2-(4-(4- FLUOROBENZYLCARBAMOYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDRO PYRIMIDIN-2-YL)PROPAN-2-YL)-5-METHYL-1,3,4-OXADIAZOLE-2- CARBOXAMIDE POTASSIUM SALT

IP.com Disclosure Number: IPCOM000237645D
Publication Date: 2014-Jul-01
Document File: 4 page(s) / 121K

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     PROCESSES FOR PREPARING INTERMEDIATES OF N-(2-(4-(4- FLUOROBENZYLCARBAMOYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDRO

PYRIMIDIN-2-YL)PROPAN-2-YL)-5-METHYL-1,3,4-OXADIAZOLE-2- CARBOXAMIDE POTASSIUM SALT

    Ethyl-2-acetamido-2-oxoacetate (referred to as "Compound 2") has the following chemical structure:

O

O

HN

NH

O

O

                    Compound 2 5-methyl-1,3,4-oxadiazole-2-carboxylate (referred to as "Compound 3") and having the following chemical structure:

EtOOC

O

                    Compound 3 5-Methyl-1,3,4-oxadiazole-2-carboxylic acid potassium salt (referred to as "Compound 4"), has the following chemical structure:

CO2K

N

N

O

CH3

Compound 4

 


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    The above described compounds may be intermediates in the synthesis of N-(2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl) propan-2-yl)-5- methyl-1,3,4-oxadiazole-2-carboxamide potassium salt (referred to as "Compound 1"), which has the fallowing chemical structure

Compound 1

    
Samples of Compound 2, 3 and 4 were prepared by the process described in the examples below. Compound 4 was analyzed by X-ray powder diffraction ("XRPD") to provide a crystalline form. Figure 1 presents the XRPD of the obtained form

Figure 1: XRPD pattern of crystalline form of Compound 4

Main PXRD peaks:


6.6; 13.3; 16.5; 20.1; 25.2; 26.9 and 33.8 degrees two theta ± 0.2 degrees 2-theta

 


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X-ray Powder Diffraction (XRPD) method

X-ray powder diffraction was performed on X-Ray powder diffractometer:
Bruker D8 Advance; CuK_ radiation (λ = 1.5418 Å); Lynx eye detector; laboratory temperature 22- 25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass. Measurement parameters:
Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.05 degrees;

Time per step: 0.5 s;

Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring.

Divergence slit: V20

Examples

Example 1: Procedure for the preparation of ethyl-2-acetamido-2-oxoacetate ("compound 2")

Acetyl hydrazine (1.0 kg), MDC (2.0 ltr) ,Diis...