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Publication numberUS3759920 A
Publication typeGrant
Publication dateSep 18, 1973
Filing dateJun 24, 1971
Priority dateJun 24, 1971
Also published asCA976164A1, DE2230394A1
Publication numberUS 3759920 A, US 3759920A, US-A-3759920, US3759920 A, US3759920A
InventorsJ Linder, P Mattner, W Salmond
Original AssigneeSandoz Ag
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Process for the preparation of 1-substituted-phenyl-2(1h)-quinazolinones
US 3759920 A
Abstract
1-ALKYL-4-PHENYL-2(1H)-quinazolinones, e.g., 1-isopropyl-7-methyl-4-phenyl-2(1H)-quinazolinone, are prepared by the reaction of an alkyl-N-alkyl-N-(substituted or unsubstituted-2-benzoyl-phenyl)-carbamates with ammonium salts of aliphatic carboxylic acids. The compounds are useful as anti-inflammatory and analgesic agents.
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Description  (OCR text may contain errors)

United States Patent 1 Linder et al.

[111 3,759,920 Sept. 18, 1973 PROCESS FOR THE PREPARATION OF 1-SUBSIITUTED-PHENYL-2(1H)- QUINAZOLINONES [75] Inventors: Jerome Linder, Westfield, N.J.; Paul G. Mattner, Brooklyn, N.Y.; William G. Salmond, Mount Arlington, NJ.

[73] Assignee: Sandoz-Wander, Inc., Hanover, NJ.

[22] Filed: June 24, 1971 [21] Appl. No.: 156,460

[52] US. Cl. 260/251 QB, 260/471 C, 424/251 [51] Int. Cl C07d 51/48 [58] Field of Search 260/251, QB

[56] References Cited OTHER PUBLICATIONS Brown Fused Pyrimidines Pt. I Quinazolines Interscience Publishers i967 pp. 39-40, 70.

Primary Examiner-Alex Maze] Assistant Examiner-R. V. Rush Attorney-Gerald D. Sharkin et al.

[57] ABSTRACT 10-Claims, No Drawings PROCESS FOR THE PREPARATION OF l-SUBST1TUTED-PHENYL-2( III)- QUINAZOLINONES This invention relates to 1-substituted-4-phenyl 2(1H)-quinazolinones. More particularly, the invention concerns a process for preparing l-substituted-4- phenyl-2(lH)-quinazolinones which may be represented structurally as follows:

I R N wherein and rind pen e tly..rsptes ithy rossn; ha 7 having an atomic weight no greater than 80, i.e., fluoro, bromo and chloro; lower alkyl containing one to five carbon atoms; lower alkoxy containing one to five carbon atoms; or nitro, provided that only one of R and 11, is nitro; or one of R and R is trifluoromethyl and the other hydrogen; or R and 11, together form 6,7-methylenedioxy;

R represents lower alkyl containing from one to five carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl; allyl; methallyl; or propargyl; or cyclolower alkyl of three to six carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclohexyl or cyclolower alkyl alkyl of four to seven carbon atoms, cyclopropylmethyl, cyclohexylbutyl;

R represents phenyl or substituted phenyl of the formula:

wherein Y represents halo having anatomic weight no greater than 80; lower containing from one to four carbon atoms, e.g., methyl and ethyl; lower alkoxy containing from one to four carbon atoms, e.g., methoxy and ethoxy; or trifluoromethyl; and

Y represents hydrogen; halo having an atomic weight no greater than 80; lower alkyl containing from one to four carbon atoms, e.g., methyl and ethyl; or lower alkoxy containing from one to four carbon atoms, e.g., methoxy and ethoxy.

The process of the present invention involves the re action of an ammonium salt of an aliphatic carboyxlic acid with an intermediate carbamate of the formula (111):

More particularly, compounds of formula I may be produced in accordance with the invention by reactively combining a compound 11 with an ammonium salt of a lower alkyl (C -C monoor dicarboxylic acid e.g., ammonium formate, ammonium acetate, ammonium oxalate and ammonium succinate. The production ofcornpound 1 may be carried out at elevated temperaturesftypically in the range ofto l SlFCQpI-eferably to 140C. However, the temperature is not critical andthe reaction may be carried out at lower temperatures, although there may be a reduction in the yield. The reaction may be carried out in the absence or presence of solvents. Solvents of conventional type may be used including the polar and nonpolar solvents such as ethanol, glyme, di-glyme, chloroform, tetrahydrofuran, benzene, toluene and the lower carboxylic acids, e.g., acetic acid. The mole ratioof the ammonium salt to compound III is not particularly critical and desirably such to provide one molar equivalent of ammonium ion per mole of compound III. In the preferred forms of practice a substantial excess of the ammonium salt up to a molar equivalent ratio of 15:1 is employed to obtain the more efficient reaction rates. The reaction time may vary widely and is usually in the range of 5 to hours. Recovery of the product of the formula l is.

effected in a conventional manner.

The process of the present invention in addition to producing the compounds of the formula I also results R, R,, R and R are as defined above.

It has been found that, in general, the amount of the compounds of the formula 11 produced will vary depending upon the manner in which the process is carried out. For example, when the process is carried out under preferred conditions employing ammonium acetate in the absence of an added solvent, it has been found that little of the compound of the formula 11 is obtained. On the other hand, increased amounts of the formula 11 may be obtained when the reaction is carried out employing ammonium formate in the absence of an added solvent. In general, the compounds of the formula 11 may be separated and recovered, if desired, from the process by employing conventional techniques. In addition, if desirable, the compound of the formula 11 may readily be converted to the compound of formula 1 with or without separation from the compounds of the formula 11 from the compound of the formula I by oxidizing the compound of the formula II in a known manner, e.g., by treatment with potassium permanganate in an inert solvent at a temperature of from 10 C 580 The compounds of formula III may be prepared from wherein R, R,, R and R are as defined above, by reacting said Z-aminobenzophenone with a lower alkyl chloroformate or bromoformate, preferably a chloroformate. Such reaction with alkyl haloformate may be carried out in the range of 30 to 180" preferably 50 to 100C. In the preferred forms of practice, there is employed a substantial excess of the haloformate which also serves as the preferred solvent for the reaction. Other suitable well-known inert organic solvents may also be employed, if desired. Reaction time is usually in the range of /i to ten hours. Recovery may be effected in a conventional manner. The 2-aminobenzophenone which are compounds IV and reacted with the alkylhaloformate to obtain compounds III are either known or can be prepared i from available materials by procedures known in the art.

The compounds of structural formula I are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as antiinflammatory agents as indicated by the Carrageenaninduced edema test on rats (oral administration). For such use, the compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions and the like or parenterally in the form of an injectable solution or suspension. The dosage administered will, of course, vary depending upon the compounds used and mode of administration. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 0.15 milligram to about 100 milligrams per kilogram of body weight, preferably. given in divided doses 2 to 4 times a day, or in a sustained release form. For larger mammals, the administration of from about milligrams to about 1,000 milligrams of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprises from about three milligrams to about 500 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

The compounds I of the invention are also administration). as analgesics uses, indicated by application of pressure to yeast-inflamed foot of the rat (oral administration). They are also useful as anti-pyretics as indicated by inhibition of bacterial lipoplysaccharideinduced fever (oral adminstration). For such uses; the compound may be administered to obtain satisfactory results at dosages and in modes similar to those employed in the treatment of inflammation.

The compounds of the structural formula II are also useful as anti-inflammatory agents as indicated by the Carragneenan-induced edema test on rats. The dosage administered will, of course, vary depending upon known factors such as the compounds used and mode of administration. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 2 milligrams to about 180 milligrams per kilogram of body weight, preferably given in divided does two to four times a day, or in sustained release form. For most mammals the administration of from about 140 milligrams to about 2,000 milligrams of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise from about milligrams to about l,000 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

EXAMPLE 1 Preparation of ethyl-N-isopropyl-N-(2-benzoyl-5- methyl phenyl)-carbamate 50 Grams of 2-N-isopropylamino-4-methyl benzophenone and 170 grams of ethyl chloroformate are heated at a temperature from to C. for 3 hours. The excess ethyl chloroformate is concentrated under vacuum and the residue crystallized from cyclohexane to obtain ethyl-N-isopropyl-N-(2-benzoyl-5-methyl i. 2 N isopropylamino-5 methox benzophenone h j. 2-N-isopropylamino-4-methyl-4 methoxybenzophenone;

k. 2-N-methylamino-3 '-trifluoromethylbenzophenone;

2 N-rnethallylamino-benzophenone;

m. 2 -N-isopropylamino-4,5-dichlorobenzophenone n. 2-N-isopropylamino-4-fluorophenyl-4,5- methylenedioxybenxophenone;

o. 2-N-isopropylamino-4,S-methylenedioxyphenone 2-N-isopropylamino-4-methyl-4'- fluorobenzophenone in place of the 2-N-isopropylamino-4-methyl-2- benzophenone used therein, there is obtained:

a. ethyl-N-methyl-N-( 2 4-chlorobenzoyl 1 -phen yl carbamate;

b. ethyl-N-isopropyl-N-( 2-benzoyl-3 ,5 -dimethylphenyl)-carbamate; c. ethyl-N-isopropyl-N-(2-[4- methylbenzoyl1-phenyl)-carbamate;

d. ethyl- N-propergyl-N 2-benzoyl-4,5-dimethylphenyl)-carbamate;

e. ethyl-N-ethyl-N-(2-benzoyl-4-trifluoromethylphenyl)-carba'mate;

f. ethyl-N-ethyl-N-(2-benzoyl-4-nitrophenyl)- carbamate;

g. ethy1-N-isopropyl-N-(2-benzoyl-4-bromophenyl)- carbamate;

h. ethyl-N-allyl-N-( 2-benzoyl-5-chlorophenyl carbam ate;

i. ethyl-N-isopropyl-N-(2-benzoyl-4-methoxy- EXAMPLE 3 l-lsopropyl-7-methyl-4-phenyl-2 lH)-quinazolinone grams of ethy1-N-isopropyl-N-(2-benzoyl-5- methyl phenyl)-carbamate is added to 30 grams of ammonium acetate and heated to a temperature from 120 to 130C. for 66 hours. At the end of this period the resulting product is cooled to room temperature and dissolved in chloroform and extracted four times with ml. of water for each extraction. The chloroform is then concentrated under vacuum and the residue crystallized from ethylacetate to obtain l-isopropyl-7- methyl-4-phenyl-2(1H)-quinazoline; m.p. 139-141C.

EXAMPLE 4 lisopropyl-7-methyl-4-phenyl-2( 1H )-quinazolinone 10 Grams of ethyl-N-isopropyl-N-(Z-benzoyl-S- methylphenyl)-carbamate and 90 grams of ammonium acetate are added to 132 ml. of blacial acetic acid and heated to reflux for 90 hours. The reaction mixture is cooled to 40C. and concentrated under vacuum. The resulting solution is then dissolved in 100 ml. of toluene and extracted four times with 20 ml. of water for each extraction. The toluene layer is concentrated under vacuum and the residue is crystallized from 20 ml. of ethylacetate to obtain l-isopropyl'7-methyl- 1 -phenyl dhiq uinazolinone; m.p. 139 to 141C.

EXAMPLE 5 1-isopropyl-7-methyl-4-phenyl-2( 1H)-quinazolinone l0 Grams of methyl-N-isopropyl-N-(2-benzoy1-5- methylphenyl)-carbamate and 62 grams of ammonium acetate are added to 95 cc. of glacial acetic acid and heated to reflux for 20 hours. The reaction mixture is concentrated under vacuum and dissolved in 100 cc. of toluene. The resulting solution is then extracted four times with 20 ml. of water for each extraction. The toluene layer is concentrated under vacuum and the residue is crystallized from 20 ml. of ethylacetate to obtain l-isopropyl-7-methyl- 4-phenyl-2( 1 H)-quinazolinone; m.p. 139 to 141C.

Following the above procedure but using an equivalent amount of; a. ethyl-N-methyl-N-(2-[4- chlorobenzoyl1-phenyl)-carbamate;

b. ethyl-N-isopropyl-N-(2-benzoyl-3,5-dimethylphenyl)-carbarnate; c. ethyl-N-isopropyl-N-(2[4- methylbenxoyl]-phenyl-carbamate;

d. ethyl-N-propargy1-N-(2-benzoyl-4,5-dimethylpheny1)-carbamate:

e. ethyl-N-ethyl-N-( 2-benzoyl'4-trifluoromethylphenyl)-carbamate;

f. ethyl-N-ethy1-N-( 2-benzoyl-4-nitrophen yl carbamate;

g. ethyl-N-isopropyl-N-(2-benzoyl-4-bromophenyl)- carbamate;

h. ethyl-N-a1lyl-N-(Z-benzoyl-S-chlorophenyl)- carbamate;

i. ethyl-N-isopropyl-N-( 2-benzoyl-4-methoxyphenyl)-carba.mate;

j. ethyl-N-isopropyl-N-( 2-[4-methoxybenzoyl1-5- methylphenyl)-carbamate;

k. ethyl-N-methyl-N-( 2- 3-trifluoromethylbenzoyl1- phenyl)-carhamate;

l. ethyl-N-methallyl-N( 2-benzoylphenyl)- carbamate;

m. ethyl-N-isopropyl-N-(2-benzoyl-4,S-dichlorophenyl)-carbamate;

n. ethyl-N-isopropyl-N-( 2-[fluorobenzoyl]-4,5- methylenedioxyphenyl)-carbamate;

o. ethyl-N-isopropy1-N-( 2-benzoy1-4,5- methylenedioxyphenyl)-carbamate;

p. ethyl-N-isopropyl-N-(2-[4-fluorobenzoyl1-5- methylphenyl)-carbamate in place of the ethyl-N- isopropyl-N-( 2-benzoyl-5-methy1phenyl)-carbamate therein, there is obtained:

a. 1-methyl4-(4-choropheny1)-2( 1H)- quinazolinone; m.p. l22-l23C.

b. 5,7-dimethyl- 1 -isopropyl-4-pheny1-2( 1H quinazolinone; m.p. l45-147C.

c. l-isopropyl-4-( 4-methylphenyl 2 (l H quinazolinone; m.p. 138 to 140C.

(:1. 6,7-dimethyl-4-phenyll -propargyl-2( 1H)- quinazolinone; m.p. l-180C.

e. l-ethyl-6-trifluoromethyl-4-phenyl-2( l H quinazolinone; m.p. 2l4-215C.

f. 1-ethyl-6-nitro-4-phenyl-2( 1H )-quinazolinone; m.p. 214- C.

g. 6-bromo-1-isopropyl4-phenyl-2(1H)- quinazolinone; m.p. 142-l43C.

h. 1-allyl-7-chloro-4-phenyl-2( ll-l )-quinazolinone; m.p. l73-l74C.

i. l-isopropyl-6-methoxy-4-phenyl-2( 1H quinazolinane; m.p. l48-150C.

j. 1-isopropyl-7-methyl-4-(4-methoxyphenyl )-2( 1H quinazolinone; m.p. 163-165C.

k. l-methyl-4-3-trifluoromethylphenyl )-2( 1H quinazolinone l. l-methal1yl-4-phenyl-2(ll-lyquinazolinone; m.p. l42-143C.

m. 6,7-dichloro-l-isopropyl-4-phenyl-2(1H)- quinazolinone; m.p. 191-194C.

n. l-isopropyl-4-(4fluorophenyl )-6,7-methylenedioxy-2( ll-l)-quinazolene; m.p. l69-170C.

o i-isopropyl-4-phenyl-6,7-methylenedioxy-2( l H quinazolinone; m.p. 215-2l8C.

p. l-isopropyl-7-methyl-4-(4-f1uorophenyl)-2( 1H uinazolinone; m.p. l76-l78C.

EXAMPLE 6 o. 1-isopropyl-7-methyl4-phenyl-2( l H)-quinazolinone and 3,4-dihydro-l-isopropyl-7-methyl-4-phenyl- 2(1H)-quinazolinone 20 Grams of ethyl-N-isopropyl-N-(2-benzoyl-5- methylphenyl)-carbamate and 43.5 grams of ammonium formate is heated at a temperature of to C. for 1 16 hours. The reaction mixture is dissolved in 200 ml. chloroform and washed twice with 50 ml. of water for each washing. The chloroform layer is then washed twice with 25 ml. of percent sodium bicarbonate and concentrated under vacuum to obtain a yellow oil. The yellow oil is then dissolved in 60 ml. of cyclohexane and cooled to obtain 3,4-dihydro-1- isopropyl-7-methyl-4-phenyl-2( 1H )-quinazolinone contaminated with ethyl-N-isopropyl-N-(2-benzoyl-5- methylphenyl)- carbamate.

The mother liquor is concentrated under vacuum and dissolved in 25 ml. of cyclohexane and cooled to obtain ethyl-N-isopropyl-N-( 2-benzoyl-5-methylphenyl carbamate.

The mother liquor was once again concentrated under vacuum to obtain a yellow oil which is chromatographed with benzene in a silica-gel column to obtain 3,4-dihydro-l-isopropyl-7-methyl-4-phenyl- 2(1H)quinazolinone; m.p. l57-l59C. and isopropyl-7-methyl-4-phenyl-2( 1H )-quinazolinone; m.p. 138C. to 140C.

What is claimed is:

l. A process for the preparation of a compound of the formula:

wherein R and Rl represent, independently, hydrogen; halo having an atomic weight no greater than 80, alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms; nitro, provided that only one of R and R",, is nitro, or one of R and R is trifiuoromethyl and the other hydrogen, or R and R, together form 6,7-methylenedioxy;

R represents alkyl of one to five carbon atoms, allyl, methallyl, or propargyl, or cycloalkyl of three to six carbon atoms and cycloalkylalkyl of four to seven carbon atoms;

R represents phenyl, or substituted phenyl of the formula wherein R, R and R and R are as above defined and R is alkyl of one to four carbon atoms with an ammonium salt of an alkyl mono or dicarboxylic acid of one to four carbon atoms at a temperature in the range of from 70 to 180C.

2. The process of claim 1 where R" and R" is 6,7- methylenedioxy and R is cycloalkyl or cycloalkylalkyl.

3. The process of claim 1 in which the ammonium salt is ammonium formate.

4. The process of claim 1 in which the ammonium salt is ammonium acetate.

5. The process of claim 1 in which the ammonium salt is ammonium oxalate.

6. The process of claim 4 in which the reaction temperature is in the range of to C.

7. The process of claim 6 which is carried out substantially in the absence of added solvent.

8. The process of claim 6 which is carried out in the presence of acetic acid.

9. The process of claim 6 in which the carbamate is an alkyl-N-isopropyl-N-(2-benzoyl-5-methylphenyl)- carbamate.

10. The process of claim 7 in which the carbamate is the ethyl carbamate.

Non-Patent Citations
Reference
1 *Brown Fused Pyrimidines Pt. I Quinazolines Interscience Publishers 1967 pp. 39 40, 70.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3937705 *Jul 3, 1974Feb 10, 1976Sandoz, Inc.1-isopropyl-7-methyl-4-(p-fluorophenyl)-2(1h)-quinazolinone
US6465472Sep 1, 2000Oct 15, 2002Euro-Celtique S.A.Substituted quinazolines and analogs and use thereof
US6765006Aug 16, 2002Jul 20, 2004Euro-Celtique S.A.Antagonists of amino-3-hydroxy-5-methylisoxazole-4-propionic acid (ampa) ionotropic receptors; neurodegenerative, alzheimer's, and huntington's disease; amyotrophic lateral sclerosis; schizophrenia, excitatory amino acid deficiency
US7652006Feb 6, 2004Jan 26, 2010Euro-Celtique S.A.Substituted 1(2H)-phthalazinones and pharmaceutical compositions thereof
US8058469Dec 31, 2008Nov 15, 2011Sabic Innovative Plastics Ip B.V.Method for making carbamates, ureas and isocyanates
Classifications
U.S. Classification544/250, 560/27, 544/286, 560/21, 514/870
International ClassificationC07D317/68, C07D491/04, C07D239/82, C07D317/66, C07D491/056
Cooperative ClassificationC07D491/04, Y10S514/87, C07D317/66, C07D239/82, C07D317/68
European ClassificationC07D239/82, C07D317/68, C07D317/66, C07D491/04