Process for the synthesis of quinazolinones

Details Process for the synthesis of quinazolinones Process for the synthesis of quinazolinones

1999-11-08

2001-02-13

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...

C544S287000

Reexamination Certificate

active

06187923

ABSTRACT:

FIELD OF INVENTION
The present invention relates to a process for the synthesis of Quinazolinones having potential biological activity.
BACKGROUND OF THE INVENTION
A variety of substituted quinazolinones have been reported in the literature These Quinazolinones are known to be biologically active. One such class of Quinazolinones is 2,3-dihydro-4(1 H)-quinazolinones. It has been reported that these Quinazolinone compounds were studied for their pharmacodynamic, insecticidal, and antifungal activity.
Other studies, for example as reported by Yale and Kalkstein in J. Med. Chem. 10(3), 334-336, suggest that the 2,3-Dihydro-4(1 H)-Quinazolinones were effective inhibitors of multiplication of the Earle's L cell line. Quinazolinone derivatives were also shown to act as cholerectic agents useful in the treatment of cholelthiasis and jaundice, as reported by Okuura et. al. in J. Med. Chem., 1972, Vol. 15, No. 5, 518-532. It has also been reported by Ozaki et. al. in J. Med. Chem., 1985, 28, 568-576, that the 4(1 H)-Quinazolinones were studied as potent antiinflammatory agents.
Given the wide spread utility of the Quinazolinone compounds, there is a continuing need to synthesize Quinazolinone compounds. Traditional synthetic methods are time consuming and can only make these compounds on an individual basis. There is thus a need for a synthetic process which will produce a large number (library) of such Quinazolinone compounds in a rapid manner.
SUMMARY OF THE INVENTION
The present invention provides a process for synthesizing a compound or a library of compounds represented by Formula 1A and 1B:
wherein:
R
1
is selected from a group consisting of —C
1-10
alkyl, —OC
1-4
alkyl, —C
4-10
saturated or partially unsaturated cyclo alkyl, heteroaryl, aryl substituted with R
3
, R
4
, and R
5
, and —C
1-4
, alkyl substituted with one or more of aryl or heteroaryl;
R
2
is selected from H, —C
1-4
alkyl, —COOH, —COOC
1-4
alkyl, —NO
2
, —NH
2
, —C
4-8
alkyl-C(O)—NH
2
, —NHC
1-6
alkyl, aryl-C(O)—NH
2
, —CN, —O—C
1-4
alkyl, and halogen;
X represents —(CH
2
)
1-4
-;
Y represents —C
1-6
alkyl, —C
4-10
cycloalkyl, or aryl substituted with R
6
, R
7
, and R
8
; R
3
, R
4
, and R
5
independently at each occurrence represent H, —CF
3
, —OCF
3
, halogen, —OC
1-4
alkyl or —C
1-6
alkyl;
R
6
, R
7
, and R
8
independently at each occurrence represent H, —O—C
1-4
alkyl, alkyl, —O—Ph—O-alkyl, —O—Ph-alkyl, —Ph, halogen, or —CN; alternatively when R
6
and R
7
along with the phenyl ring to which they are attached represent
R
8
is H; and
R
10
represents H, C
1
-C
4
alkyl, benzyl, substituted benzyl, C
2
-C
6
alkelene, substituted alkyl, or —(CH
2
)
1-3
-COOC
1-4
alkyl; said process comprising the steps of:
(i) reacting an aldehyde of Formula A
Y—CHO   Formula A,
with an amine of Formula B
R
2
-X—NH
2
  Formula B,
wherein R
2
, X, and Y are as defined above, to yield a compound of Formula C
(ii) reacting the compound of Formula C with a compound of Formula D
to yield a compound of Formula 1A
where R
1
, R
2
, R
10
and Y are as defined above; and
(iii) optionally oxidizing a compound of Formula 1A, when R
10
is H, followed by treating with an aminomethyl polystyrene resin, to yield a compound of Formula 1B.
Another aspect of the present invention provides a process for synthesizing a compound or a library of compounds represented by Formula 1A:
wherein X, Y, R
1
, R
2
and R
10
are as defined above, said process comprising:
reacting a compound of Formula C
with a compound of Formula D
followed by optional treatment with an aminoalkyl, preferably aminomethyl, polystyrene resin to yield a compound of Formula 1A.
In yet another aspect of the present invention is provided a process for synthesizing of a compound or a library of compounds of Formula 1B
wherein:
R
1
, R
2
, X, Y, are as defined above, and R
10
represents H, said process comprising:
oxidizing a compound of Formula 1A,
followed by treating with an aminomethyl polystyrene resin, to yield a compound of Formula 1B.
DETAILED DESCRIPTION OF THE INVENTION
Step (i) of the process of the present invention may be performed successfully using either solutions or suspensions of the aldehyde of Formula A or the amine of Formula B. However preferred embodiments of the present invention provide a process wherein step (i) comprises using solutions of the aldehyde of Formula A, and the amine of Formula B. Illustrative examples of solvents which may be used to prepare the solutions of the aldehyde of Formula A and the amines of Formula B are acids, protic solvents, and polar solvents. Preferred acid solvents are acetic acid, and propionic acid. Preferred protic solvents are methanol and ethanol. Preferred polar solvents are DMF, DMSO, and dioxane. A further preferred embodiment provides a process wherein step (i) comprises using at least one of an acetic acid, or a propionic acid solution of the aldehyde of Formula A and the amine of Formula B. The foregoing signifies that the process of the preferred embodiment comprises at least a solution of the aldehyde and the amine in acetic acid or propionic acid, but can comprise a mixture of the two with or without additional solvents.
Another preferred embodiment provides a process wherein step (ii) comprises reacting an acetic acid solution of a compound of Formula C with a solution of a compound of Formula D. Preferably the solution of a compound of Formula D is prepared using at least one solvent selected from the group consisting of DMF, DMSO, dioxane, methylene chloride, acetic acid, chloroform, THF, and propionic acid. Particularly preferred solvents for preparing the solution of a compound of Formula D are at least one of acetic acid, methylene chloride, THF, and DMF.
Yet another preferred embodiment provides a process wherein step (iii) comprises oxidizing a compound of Formula 1A using iodine, KMnO
4
, or DDQ/CHCl
3
suspension. Also provided in another preferred embodiment of the present invention is a process wherein R
1
is selected from a group consisting of —C
1-6
alkyl, —OC
1-4
alkyl, —C
4-6
saturated or partially unsaturated cyclo alkyl, heteroaryl, aryl substituted with R
3
, R
4
, and R
5
, or —C
1-4
alkyl substituted with one or more of aryl or heteroaryl; R
2
is selected from H, —C
1-4
alkyl, —O—C
1-4
alkyl, and halogen; Y represents —C
1-4
alkyl, or aryl substituted with R
6
, R
7
, and R
8
; R
3
, R
4
, and R
5
independently at each occurrence represent H, —O—C
1-4
alkyl, —CF
3
, halogen, or —C
1-4
alkyl; R
6
, R
7
, and R
8
independently at each occurrence represent H, —O—C
1-4
alkyl, —C
1-4
alkyl, —O—Ph— O—C
1-4
alkyl, —Ph, or halogen; or when R
6
and R
7
along with the phenyl ring to which they are attached represent
R
8
is H; and R
10
represents —C
1-2
alkyl, —C
1-2
-Ph or —CH
2
-COO—C
2
H
5
.
A further preferred embodiment of the present invention provides a process wherein R
1
represents
Y represents
wherein R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are as defined in the summary of the invention.
Another aspect of the present invention provides a library of compounds synthesized by the processes of the present invention.
EXPERIMENTAL DETAILS
General Comments
Both the amines (compounds of Formula B) and aldehydes (compounds of Formula A) are dissolved in acetic acid at a concentration of 0.40 molar and mixed for 1.5-2 hours to allow for imine formation. Next a 0.10 molar solution or suspension of the isatoic anhydride (Formula D) in THF is added and the mixture is heated to about 95°-100°C. in a block heater for 4 hours. Several oxidation conditions are validated for the final oxidation step, e.g., KMnO
4
/acetone/RT, I
2
/CHCl
3
/RT, DDQ/dioxane/RT, etc., but the preferred conditions are DDQ/CHCl
3
/RT. It was surprisingly found that purification with aminomethyl polystyrene resin removes any unreacted isatoic anhydride, aldehyde, DDQ by-products along with colored impurities, to yield a purer Formula 1B compound.
Amines (Compounds of Formula B), and aldehydes (Compounds of Formula A) are commercially available. DDQ rea

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