Process for the preparation of quinazolinones

Details Process for the preparation of quinazolinones Process for the preparation of quinazolinones

1999-11-18

2001-01-16

Shah, Mukund J. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S286000

Reexamination Certificate

active

06175009

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to an asymmetric synthesis of 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones, and intermediates thereof. The target compounds are useful for the treatment of human immunodeficiency virus (HIV) as an inhibitor of reverse transcriptase.
BACKGROUND
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
An extremely promising and active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors. Commonly assigned U.S. patent application Ser. No. 09/056,820(PCT Application WO98/45276) discloses novel quinazolinones of formula (I) as active non-nucleoside HIV reverse transcriptase inhibitors.
Due to the importance of this structural class, methods to synthesize the quinazolinone core which are amenable to industrial manufacture are needed.
Previous methods to prepare quinazolinones have employed dehydration of a quinazolinone, followed by 1,4 nucleophilic addition. Sternbach et al., Journal of Organic Chemistry, 1966, 31, 1007. International publication WO 93/04047 discloses the application of this methodology to the preparation of quinazolinone derivatives which are inhibitors of HIV reverse transcriptase (Scheme 1).
In this methodology, however, the 1,4 addition of R
2
occurs without stereoselectivity. A manufacturing process which attempts to exploit this teaching would require tedious separation of the undesired enantiomer, making this approach unfeasible for reasons related to both cost and scale. Moreover, the dehydration protocol teaches thermal conditions, which may prove hazardous on an industrial scale.
The present invention finds utility in the asymmetric preparation of quinazolinone derivatives. By dehydrating a quinazolinone containing a chiral R
8
, the subsequent 1,4 nucleophilic addition is directed to afford the desired stereochemistry (Scheme 2). Removal of the directing group then affords the target compound.
The dehydration of the hemiaminal preferably occurs through the use of a dehydrating agent. This discovery allows for the safe preparation of electron deficient quinazolinones which are known to be resistant to dehydration. Additionally, convenient conditions for the preparation of the desired hemiaminal from an &agr;-ketoaniline and a chiral isocyanate are disclosed. As a result, these important compounds can be prepared safely and efficiently.
SUMMARY OF THE INVENTION
The present invention relates generally to processes for the efficient production of 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones (I):
and intermediates thereof;
wherein R
1
, R
2
, R
3a
, R
3b
, R
3c
, and R
3d
are defined below, which has been achieved by the inventors' discovery that a compound of formula (I) or a pharmaceutically acceptable salt form thereof, is formed by a high yielding and chiral process, comprising:
step (1), contacting a compound of formula (II):
 or a salt form or a hydrate of the salt form thereof;
with an isocyanate of formula (III):
 wherein R
8
and R
8a
are defined below;
to form a compound of formula (II-a):
 or a salt form thereof;
step (1-i), cyclizing the compound of formula (II-a) to form a compound of formula (IV):
step (2), dehydrating the compound of formula (IV) to form a compound of formula (V):
step (2-i), contacting the compound of formula (V) with a nucleophile of formula (VI):
 wherein M is a metal counterion;
to form a compound of formula (VII):
 or a salt form thereof; and
step (3), ionizing the compound of formula (VII) to form a compound of formula (I), or a pharmaceutically acceptable salt form thereof.
DETAILED DESCRIPTION OF THE INVENTION
[1] Thus, in a first embodiment, the present invention describes a novel process for the preparation of a compound of formula (I):
wherein:
R
1
is C
1-3
alkyl substituted with 1-7 halogen;
R
2
is selected from C
1-5
alkyl substituted with 1-2 R
4
, C
2-5
alkenyl substituted with 1-2 R
4
, C
2-5
alkynyl substituted with 1 R
4
, and OR
2a
;
R
2a
is C
1-4
alkyl;
R
3a
is H;
R
3b
is selected from H, C
1-4
alkyl, C
1-4
alkoxy, F, Cl, Br, I, and NR
5
R
5a
;
R
3c
is selected from H, C
1-4
alkyl, C
1-4
alkoxy, F, Cl, Br, I, and NR
5
R
5a
;
R
3d
is selected from H, C
1-4
alkyl, C
1-4
alkoxy, F, Cl, Br, I, and NR
5
R
5a
;
alternatively, R
3a
and R
3b
combine to form —OCH
2
O—;
R
4
is selected from C
3-5
cycloalkyl substituted with 0-2 R
4a
, phenyl substituted with 0-5 R
4a
, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R
4a
;
R
4a
is selected from C
1-3
alkyl, Cl, Br, F, I, OCH
3
, SCH
3
, and NR
5
R
5a
; and
R
5
and R
5a
are independently selected from H and C
1-3
alkyl;
the process comprising:
step (1), contacting a compound of formula (II):
 or a salt form or a hydrate of the salt form thereof;
with an isocyanate of formula (III):
wherein:
R
8a
is selected from methyl, ethyl, propyl, and isopropyl;
R
8
is selected from phenyl substituted with 0-3 R
9
, and naphthyl substituted with 0-3 R
9
; and
R
9
is selected from C
1-4
alkyl, C
1-4
alkoxy, F, Cl, Br, and I;
to form a compound of formula (II-a):
 or a salt form thereof;
step (1-i), cyclizing the compound of formula (II-a) to form a compound of formula (IV):
step (2), dehydrating the compound of formula (IV) to form a compound of formula (V):
step (2-i), contacting the compound of formula (V) with a nucleophile of formula (VI):
 wherein M is a metal counterion;
to form a compound of formula (VII):
 or a salt form thereof; and
step (3), ionizing the compound of formula (VII) to form a compound of formula (I), or a pharmaceutically acceptable salt form thereof.
[2] In a preferred embodiment, R
1
is CF
3
;
R
2
is selected from ethene substituted with cyclopropyl and ethyne substituted with cyclopropyl;
R
3a
is H;
R
3b
is Cl;
R
3c
and R
3d
are H;
R
8a
is CH
3
;
R
8
is phenyl;
M is a counter ion selected from Li
+
, Na
+
, K
+
, CuCl
+
, CuBr
+
, MgCl
+
, MgI
+
, and MgBr
+
; and wherein:
step (1) comprises contacting the compound of formula (II) with the isocyanate of formula (III) in the presence of a first strong acid;
step (1-i) comprises cyclizing the compound of formula (II-a) by heating the compound of formula (II-a) to a temperature in the range of about 50° C. to about 70° C.;
step (2) comprises dehydrating the compound of formula (IV) by contacting the compound of formula (IV) with at least one equivalent of a dehydrating agent in the presence of suitable amount of a base;
step (2-i) comprises contacting the compound of formula (V) with the nucleophile of formula (VI) by adding the nucleophile of formula (VI) to the compound of formula (V) at a suitable temperature to form the compound of formula (VII); and
step (3) comprises ionizing the compound of formula (VII) by contacting the compound of formula (VII) with a second strong acid to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
[3] In a more preferred embodiment,
the first strong acid is selected from trifluoroacetic acid, formic acid, methanesulfonic acid, nitric acid, sulfuric acid, hydrochloric acid; trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethyl silyl cyanide, triisopropylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl chloride, and trimethylsilyl trifluoromethanesulfonate;
the dehydrating agent is selected from methanesulfonyl chloride, thionyl chloride, acetyl chloride, and triphenylphosphine;
the amount of base in step (2) is in the range of about 2 to about

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