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CRYSTALLINE FORMS OF N-(2,4-DI-TERT-BUTYL-5-HYDROXYPHENYL)-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE

IP.com Disclosure Number: IPCOM000234586D
Publication Date: 2014-Jan-21
Document File: 5 page(s) / 64K

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The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 52% of the total text.

Page 01 of 5

CR

HYD

NE FORM

ENYL)-1,4

-5-

E-3-

YSTALLI

ROXYPH

utyl-5-hyd ompound 1

are crysta

m R1 of co

Form R1of

droquinoli

ed by addi

re was coo

reaction w

1h. 5-Amin

50 oC and m

and MeCN

eTHF (80

e filtrate w

was consec

hed organi

tion iBu-ac

. This proc

at -10 oC f

ed at 50 oC

as analyzed

XRD of fo

CAR

S OF N-(2

-DIHYDR

BOXAM

)-1,4-dihyd

llowing ch

,4-DI-TER

O-4-OXOQ

IDE

ro-4-oxoqu

emical struc

1

43, R61, R

T-BUTYL

UINOLIN

inoline-3-c ture and :

32 and R72

was suspen

e (DIPEA, ride (65.27

stirred at th

asadded a

ht. Then th

The obtain e obtained

by phase s

water, satu

ated to app

mixture w

slurry was ake was wa

g of offwh

R1 of comp

N-(2

refe

Prov


1.

Cry

Prep

4-O

(800

reac

drop

for was

coo susp

filte

orga

wat ml. to h

slur

acet

yiel

1 pr

,4-di-tert-b

rred to as C

roxyphenyl

, has the fo

C

carboxamide

of compou

ded in M

140.15 g).

  g) was ad this tempera

nd the reac

e reaction

ned residue precipitate separation. rated NaHC

roximately

as concentr

obtained. shed with ite solid ( ound 1. Fi

,

ompound

R1, R13, R

1:
ylic acid

-Diisoprop

oC and piv

 to reach R rtbutylpheno

is temperat

ved by ev

water (800 d to reacto

shed with 0

s filtered an

ml) was ad

repeated t

nd then filt

um oven

and found

nd

eCN

The ded

ture tion was was was The

O3,

500 ated

This iBu-

70% gure

lline forms

mpound 1

compound ne-3-carbox

tion of N,N

led to 10 as allowed

o-2,4-ditert

ixed at th

was remo

0 ml) and w

as returne

utively wa

c phase wa

etate (500 edure was

or 2 days a

in a vacu

by PXRD rm R1.

ided herein

stalline for

aration of

xo-1,4-dihy

ml) follow

tion mixtu

wise. The additional

heated to led to RT

ended in M

red out. Th

nic phase er. The was

To this solu

alf volume

ry was kept

ate and dri


d) which w

esents the P

[102.56 g] ylethylamin

aloyl chlo T and was

l[80 g] w

ure overnig

aporation. ml) and th

r followed .5N HCl, d concentr

ded and the

wice until ered. The c to give 100

to be form


Page 02 of 5

Figure 1:PXRD pattern of form R1 of compound 1

Crystalline form R1 of Compound 1 may be characterized by PXRD peaks at : 5.6,


5.9, 6.6, 7.7, 8.2, 8.8, 9.5, 9.9, 10.4, 11.0, 11.3, 11.8, 12.2, 13.4, 13.6 13.9, 14.7, 15.4,


16.4, 16.8, 17.3, 17.6, 18.1, 18.4, 18.8, 19.3, 19.7, 20.5, 20.8, 21.6, 22.4, 22.8, 23.4,


25.3, 25.9, 26.7 and 27.5 ± 0.2 degrees 2-theta.

Crystalline form R13 of compound 1

Preparation of crystalline form R13:

Form R1 of compound 1 (40 g) was dissolved in Methyl ethyl ketone (MEK, 650 ml) at 89 oC followed by addition of water (72 ml) to the obtained solution. The final solution was evaporated to dryness and the obtained solid material was dried in an oven at 50 oC overnight. The obtained material was analyzed by PXRD and found to be form R13 of compound 1. Figure 2 presents the PXRD of form R13.

Figure 2:PXRD pattern of form R13 of compound 1


Page 03 of 5

Crystalline form R13 of Compound 1 may be characterized by PXRD peaks at: 4.4,


6.0, 6.6, 7.8, 8.7, 9.6, 10.7, 11.8, 13.0, 14.4, 15.6, 16.1, 16.8, 17.9, 18.8, 19.3, 19.9,


20.4, 21.5, and 22.6± 0...