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Intermediate of synthesis of (2-[4-[2-(4-amino-2-oxo-3,5,7-triaza-bicyclo[4.3.0]nona-3,8,10-trien-9-yl)ethyl]benzoyl]aminopentanedioic acid

IP.com Disclosure Number: IPCOM000179746D
Publication Date: 2009-Feb-25
Document File: 9 page(s) / 153K

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   Intermediate of synthesis of (2-[4-[2-(4-amino-2-oxo-3,5,7-triaza- bicyclo[4.3.0]nona-3,8,10-trien-9-yl)ethyl]benzoyl]aminopentanedioic acid.

    (2-[4-[2-(4-amino-2-oxo-3,5,7-triaza-bicyclo[4.3.0]nona-3,8,10-trien-9- yl)ethyl]benzoyl]aminopentanedioic acid ("PMX") and salt thereof is a multitargeted antifolate drug approved for treatment of mesothelioma and for second-line treatment of non small cell lung cancer.

PMX disodium salt of formula I.

HN

N

O CO

Na

O

7H O

N

H

H N

CO Na

N

H

I

is marketed by Eli Lilly and Company under the trade name ALIMTA ® as a sterile lyophilized powder for intravenous administration.

    Herein it will be described crystalline forms of intermediates in the synthesis of PMX.
(4-[2-(4-amino-2-oxo-3, 5, 7-triazabicyclo[4.3.0] nona-3,8,10-trien-9- yl)ethyl]benzonitrile:

Crystalline (4-[2-(4-amino-2-oxo-3,5,7-triazabicyclo[4.3.0] nona-3,8,10-trien-9- yl)ethyl]benzonitrile ("DPMX3") of the following chemical structure:

N

N

H

CN

O

N

H2

N

H

is characterized by data selected from a group consisting of a PXRD pattern having peaks at about 6.9, 12.0, 13.8, 16.0, 17.7, 19.2, 21.1, 23.2, 23.6 and 27.7 ± 0.2 degrees two-theta, and a PXRD pattern described in Figure 1.

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Fig.1: PXRD pattern of DPMX3 crystalline form.

The crystalline form of DPMX3 is further characterized by data selected from
a group consisting of a FT-IR spectrum having peaks at about 3485, 3368, 2235, 1670, 1633, 1609, 1594, 1515, 1353, 1311, 1261, 1228, 1098, 1069, 859, 820, 788, 691, 669 and 614 cm-1, and a FT-IR spectrum described in Figure 2.

Fig.2: FT-IR spectrum of DPMX3 crystalline form.

4-[2-(4-amino-2-oxo-3,5,7-triazabicyclo[4.3.0]nona-3,8,10-trien-9-yl)ethyl] benzoic:

Several crystalline forms of 4-[2-(4-amino-2-oxo-3,5,7-triazabicyclo[4.3.0]nona- 3,8,10-trien-9-yl)ethyl] benzoic ("DPMX4") of the following chemical structure:

2

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OOH

O

N

N

H

H2

N

N

H

have been obtained.

Crystalline Form alpha of DPMX4:

    The crystalline form of DPMX4, designated Form alpha, is characterized by data selected from a group consisting of a PXRD pattern having peaks at about 7.3,
10.2, 11.0, 13.1, 14.0, 15.2, 15.8, 19.4, 24.1, 27.2 and 29.8 ± 0.2 degrees two-theta, and a PXRD pattern described in Figure 1.

Fig.1: PXRD pattern of DPMX4 crystalline Form alpha.

The crystalline Form alpha of DPMX4 is further characterized by data selected from a group consisting of a FT-IR spectrum having peaks at about 1590, 1539, 1246, 1227, 1098, 1077, 1022, 789, 733, 722 and 670 cm-1, and a FT-IR spectrum described in Figure 2.

Fig.2: FT-IR spectrum of DPMX4 crystalline Form alpha.

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Crystalline Form beta of DPMX4 :

    The crystalline form, designated Form beta, is characterized by data selected from a group consisting of a...