CA1094068A - Process for preparing quinazolinone oxides - Google Patents
Process for preparing quinazolinone oxidesInfo
- Publication number
- CA1094068A CA1094068A CA305,471A CA305471A CA1094068A CA 1094068 A CA1094068 A CA 1094068A CA 305471 A CA305471 A CA 305471A CA 1094068 A CA1094068 A CA 1094068A
- Authority
- CA
- Canada
- Prior art keywords
- quinazolinone
- formula
- phenyl
- chloro
- mole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
- C07D239/82—Oxygen atoms with an aryl radical attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pretreatment Of Seeds And Plants (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
IMPROVED PROCESS FOR PREPARING QUINAZOLINONE OXIDES
ABSTRACT
Improved process for the preparation of 6-sub-stituted-4-phenylquinazolinone 3-oxides. Such compounds are useful as intermediates in the preparation of 3-fluorobenzodiazepines, which are useful as tranquilizers, muscle relaxants and sedatives.
ABSTRACT
Improved process for the preparation of 6-sub-stituted-4-phenylquinazolinone 3-oxides. Such compounds are useful as intermediates in the preparation of 3-fluorobenzodiazepines, which are useful as tranquilizers, muscle relaxants and sedatives.
Description
~0!~406B
BACKGROUND OF THE INVENTION
Copending Canadian Patent Application Serial Number 257 231, filed 1976 July 19 by Elena M. Bingham and William J. Middleton, discloses certain novel 3-fluorobenzodiazepines of the formula:
~ N
X ~ N
~Y
where X is Cl, Br, NO2 or CF3;
Y is H, Cl, Br or F;
D is H, hydrocarbyl of 1-4 carbons, -CH2CF3, ~ 10 -CONHR, -cH2cH2NR2~ or -CH2CH2NR2-A~
where R is alkyl of 1-4 carbons and A
is a pharmaceutically suitable acid;
B is O; or
BACKGROUND OF THE INVENTION
Copending Canadian Patent Application Serial Number 257 231, filed 1976 July 19 by Elena M. Bingham and William J. Middleton, discloses certain novel 3-fluorobenzodiazepines of the formula:
~ N
X ~ N
~Y
where X is Cl, Br, NO2 or CF3;
Y is H, Cl, Br or F;
D is H, hydrocarbyl of 1-4 carbons, -CH2CF3, ~ 10 -CONHR, -cH2cH2NR2~ or -CH2CH2NR2-A~
where R is alkyl of 1-4 carbons and A
is a pharmaceutically suitable acid;
B is O; or
2 ;
~J
. . I
Ofi8 B and D together is =N-N=C(R')-where R' is H or Cl-C4 alkyl, and the use of such compounds as tranquilizers, muscle relaxants and sedatives in mammals. In addition, Bingham and Middleton disclose a process for making such compounds by reaction of the corresponding 3-hydroxybenzodiazepine with a dialkylaminosulfur trifluoride as follows:
D D
B ' B
$ oH + 4 ~ N-sF3 >
X :5: X~
where R3 and R4 are a primary alkyl group of 1-4 carbons or taken together are -(CH2)4-or -(CH2)5.
An improved process for preparing such 3-fluoro-benzodiazepines has been proposed. That improved process can be summarized schematically by the following equations:
CH CH O
, 3 ~ 3 ~ 1 X ~ N-H O > X ~ - C-CHFZ
y ~ 1H y ~ OH
(a) (b) (c) . 3 ~0~ ;8 N__~O
(c) ~base _> ~ ~ F
(e.g. NaOH) X ~ ~
\0 (d) (e) (e) + reducing agent ~ ~
~e.g.P(OCH3)3~ > ~ N ~ F
Y~b (f) (g) where X is Cl, Br, NO2 or CF3;
Y is H, Cl, Br or F; and Z and z2 are Cl or Br.
Starting material (1) can be prepared by the process disclosed in U.S. Patent No. 3 398 139.
In addition, copending Canadian Patent Application Serial No. 305 447, filed simultaneously herewith by Elena M. Bingham and Arthur J. Elliott discloses an improved process for preparing the N-methylaminobenzophenone anti-oxime used as the starting material in the improved process discussed immediately above. The Bingham and Elliott process can be summarized schematically by the following e~uations:
~0~4068 H CH~
~0 ~0 Y~ Y~
(1) , (2) (~) C~
I
t3) base ~ ~~
y ~ O~I
(~) where X is Cl, Br, NO2 or CF3;
Y is H, Cl, Br or F; and Z is I, Br, CF3SO2O-, FSO2O, CC13SO2O- or CH3OSO2O-, Bingham and Elliott also disclose that the starting material quinazoiinone 3-oxides can be prepared by a process taught by Sulkowski and Childress, J. Org.
30Chem., 27, 4424 (1962).
SUMMARY OF THE INVENTION
.
The present invention relates to an improved process for making the quinazolinone 3-oxides of formula (1), a~ove, and an alternate process for making the 35quinazolinone 3-oxides of formula ~3), above.
-" 10!~ ;8 More specifically, the present invention re-lates to an improved process for preparing 6-substi-tuted-4-phenylquinazolinone 3-oxides by the treatment of 2-aminobenzophenone-isocyanate reaction products with hydroxylamine salts.
Organic isocyanates of formula RNCO (where R
is hydrocarbyl or halohydrocarbyl of 1-8 carbon atoms) react with 2-aminobenzophenones of formula I (X = Cl, Br, CF3 or NO2; Y = H, Br, Cl or F; R = H or CH3) to give either ureas of formula II or quinazolinones of formula III (X, Y and Rl as previously defined), depend-ing on the reaction conditions and the isocyanates used.
R~
1 1 ~ H
/\ ~H ~ ~J-C-NR ' ~ 0 ~ ~ RNCO ~ ~ ~nd/
I II
~
I
,~(X.~
~ ~ H
~\o~y III
10!~40fiB
These reaction products (either or both II and III) can then be converted to quinazolinone oxides of formula IV
by treating them with an acid salt of hydroxylamine.
R
I
II and/or IIT + NH20H; A ~(X~
\~o~y w~ere A is an or~anic or inor~anic acid with a pKa of less than 2.
DETAIL~D DESC~IPTION OF THE INVENTION
Process Conditions Quinazolinone oxides of formula IV can be pre-pared by heating a solution or mixture of 2-aminobenzo-phenoneisocyanate reaction products (of Formula II orIII) and an acid addition salt of hydroxylamine in an alcohol solvent. The reaction is conveniently carried out at the reflux temperature of the alcohol solvent, but temperatures from 40 to 200C are operable. Alco-25 hol solvents useful for this reaction include, but arenot limited to, ethanol, methanol, propanol, isopropa-nol, butanol, 2-methoxyethanol, ethylene glycol, and propylene glycol. Salts of hydroxylamine useful in this reaction include salts with organic or inorganic acids 30 having a pKa of less than 2, such as hydroxylamine hydrochloride, hydroxylamine hydrobromide and hydroxyl-amine sulfate. The time required for the reaction varies from a few minutes when more reactive isocyanate adducts or higher boiling alcohols are used, to a few 35 days or even weeks when less reactive isocyanate 10~40fi8 adducts or lower hoiling alcohols are used.
The product quinazolinone oxides can be iso-lated from the reaction mixture by conventional means.
In most cases, the quinazolinone oxides are consider-ably less soluble than the reactants, and will precipi-tate during the course of the reaction. When this occurs, the product quinazolinone oxides can be iso-lated ~y simply filtering the reaction mixture.
The 2-aminobenzophenone-isocyanate adducts used as starting materials can be prepared by the reac-tion of 2-aminobenzophenones with organic isocyanates as illustrated in the following Examples or as described by Sulkowski et al~ J, Org~ Chem., 27 4424 (1962) or by Metlesics et al., J. Org~ Chem., 31 1007 (1966).
Alternatively, the compounds of formula IV can ~e prepared ~y heatin~ a compound of formula II in a suitable alcohol followed by treatment with a suitable acid addition salt of hydroxylamine.
2Q Rl 0 H R
-C-NR ~ N-~
(II) (V) R
(V) + NH2OH-A ~ ~ N
X
8 (IV) lO!~ ~Ofi8 w~ere R20H is lower aliphat;c alcohol of 1-6 carbon atoms, prefera~ly met~anol or ethanol.
` EX~P~ 1 Part A. 6-C~loro-3,4-di~ydro-4-hydroxy-3-methyl-4-phenyl-2~lH)-quinazolinone H
I
NC
'~'~ =o 3 ` ~ ~ -C
0~ bH
A solution of lQQ g ~Q~43 molel o~ 2~amino-5-chlorobenzophenone and 40 g (0 7 mole~ of methyl iso-cyanate in 300 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 119.8 g (96% yield) of 2Q 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone as a white crystalline powder: mp 296-298 (dec); H nmr (~MSO-d6), ~ 2.66 ppm (s, 3H), 6.8-7.6 ppm (m, 8H) and 10.0 ppm (s, NH); C nmr (DMSO-d6) ~ 86.6 ppm (for COH) and 151.4 ppm (for NHCO).
Anal. Calcd for C15H13ClN202: C, 62.39; H, 4.54;
N, 9.70 Found: C, 62.10; H, 4.67; N, g.53 Part B. 6-Chloro-4-phenyl-2(lH)-quinazolinone 3-Oxide ~ ~ C~3 ~ NH20~-HCl ---~
~ H
10~940fi8 1~
S ~ 0 ~ ~ + CH3NH2 HCl A stirred mixture of 86.6 g (0.3 mole) of 6-chloro-
~J
. . I
Ofi8 B and D together is =N-N=C(R')-where R' is H or Cl-C4 alkyl, and the use of such compounds as tranquilizers, muscle relaxants and sedatives in mammals. In addition, Bingham and Middleton disclose a process for making such compounds by reaction of the corresponding 3-hydroxybenzodiazepine with a dialkylaminosulfur trifluoride as follows:
D D
B ' B
$ oH + 4 ~ N-sF3 >
X :5: X~
where R3 and R4 are a primary alkyl group of 1-4 carbons or taken together are -(CH2)4-or -(CH2)5.
An improved process for preparing such 3-fluoro-benzodiazepines has been proposed. That improved process can be summarized schematically by the following equations:
CH CH O
, 3 ~ 3 ~ 1 X ~ N-H O > X ~ - C-CHFZ
y ~ 1H y ~ OH
(a) (b) (c) . 3 ~0~ ;8 N__~O
(c) ~base _> ~ ~ F
(e.g. NaOH) X ~ ~
\0 (d) (e) (e) + reducing agent ~ ~
~e.g.P(OCH3)3~ > ~ N ~ F
Y~b (f) (g) where X is Cl, Br, NO2 or CF3;
Y is H, Cl, Br or F; and Z and z2 are Cl or Br.
Starting material (1) can be prepared by the process disclosed in U.S. Patent No. 3 398 139.
In addition, copending Canadian Patent Application Serial No. 305 447, filed simultaneously herewith by Elena M. Bingham and Arthur J. Elliott discloses an improved process for preparing the N-methylaminobenzophenone anti-oxime used as the starting material in the improved process discussed immediately above. The Bingham and Elliott process can be summarized schematically by the following e~uations:
~0~4068 H CH~
~0 ~0 Y~ Y~
(1) , (2) (~) C~
I
t3) base ~ ~~
y ~ O~I
(~) where X is Cl, Br, NO2 or CF3;
Y is H, Cl, Br or F; and Z is I, Br, CF3SO2O-, FSO2O, CC13SO2O- or CH3OSO2O-, Bingham and Elliott also disclose that the starting material quinazoiinone 3-oxides can be prepared by a process taught by Sulkowski and Childress, J. Org.
30Chem., 27, 4424 (1962).
SUMMARY OF THE INVENTION
.
The present invention relates to an improved process for making the quinazolinone 3-oxides of formula (1), a~ove, and an alternate process for making the 35quinazolinone 3-oxides of formula ~3), above.
-" 10!~ ;8 More specifically, the present invention re-lates to an improved process for preparing 6-substi-tuted-4-phenylquinazolinone 3-oxides by the treatment of 2-aminobenzophenone-isocyanate reaction products with hydroxylamine salts.
Organic isocyanates of formula RNCO (where R
is hydrocarbyl or halohydrocarbyl of 1-8 carbon atoms) react with 2-aminobenzophenones of formula I (X = Cl, Br, CF3 or NO2; Y = H, Br, Cl or F; R = H or CH3) to give either ureas of formula II or quinazolinones of formula III (X, Y and Rl as previously defined), depend-ing on the reaction conditions and the isocyanates used.
R~
1 1 ~ H
/\ ~H ~ ~J-C-NR ' ~ 0 ~ ~ RNCO ~ ~ ~nd/
I II
~
I
,~(X.~
~ ~ H
~\o~y III
10!~40fiB
These reaction products (either or both II and III) can then be converted to quinazolinone oxides of formula IV
by treating them with an acid salt of hydroxylamine.
R
I
II and/or IIT + NH20H; A ~(X~
\~o~y w~ere A is an or~anic or inor~anic acid with a pKa of less than 2.
DETAIL~D DESC~IPTION OF THE INVENTION
Process Conditions Quinazolinone oxides of formula IV can be pre-pared by heating a solution or mixture of 2-aminobenzo-phenoneisocyanate reaction products (of Formula II orIII) and an acid addition salt of hydroxylamine in an alcohol solvent. The reaction is conveniently carried out at the reflux temperature of the alcohol solvent, but temperatures from 40 to 200C are operable. Alco-25 hol solvents useful for this reaction include, but arenot limited to, ethanol, methanol, propanol, isopropa-nol, butanol, 2-methoxyethanol, ethylene glycol, and propylene glycol. Salts of hydroxylamine useful in this reaction include salts with organic or inorganic acids 30 having a pKa of less than 2, such as hydroxylamine hydrochloride, hydroxylamine hydrobromide and hydroxyl-amine sulfate. The time required for the reaction varies from a few minutes when more reactive isocyanate adducts or higher boiling alcohols are used, to a few 35 days or even weeks when less reactive isocyanate 10~40fi8 adducts or lower hoiling alcohols are used.
The product quinazolinone oxides can be iso-lated from the reaction mixture by conventional means.
In most cases, the quinazolinone oxides are consider-ably less soluble than the reactants, and will precipi-tate during the course of the reaction. When this occurs, the product quinazolinone oxides can be iso-lated ~y simply filtering the reaction mixture.
The 2-aminobenzophenone-isocyanate adducts used as starting materials can be prepared by the reac-tion of 2-aminobenzophenones with organic isocyanates as illustrated in the following Examples or as described by Sulkowski et al~ J, Org~ Chem., 27 4424 (1962) or by Metlesics et al., J. Org~ Chem., 31 1007 (1966).
Alternatively, the compounds of formula IV can ~e prepared ~y heatin~ a compound of formula II in a suitable alcohol followed by treatment with a suitable acid addition salt of hydroxylamine.
2Q Rl 0 H R
-C-NR ~ N-~
(II) (V) R
(V) + NH2OH-A ~ ~ N
X
8 (IV) lO!~ ~Ofi8 w~ere R20H is lower aliphat;c alcohol of 1-6 carbon atoms, prefera~ly met~anol or ethanol.
` EX~P~ 1 Part A. 6-C~loro-3,4-di~ydro-4-hydroxy-3-methyl-4-phenyl-2~lH)-quinazolinone H
I
NC
'~'~ =o 3 ` ~ ~ -C
0~ bH
A solution of lQQ g ~Q~43 molel o~ 2~amino-5-chlorobenzophenone and 40 g (0 7 mole~ of methyl iso-cyanate in 300 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 119.8 g (96% yield) of 2Q 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone as a white crystalline powder: mp 296-298 (dec); H nmr (~MSO-d6), ~ 2.66 ppm (s, 3H), 6.8-7.6 ppm (m, 8H) and 10.0 ppm (s, NH); C nmr (DMSO-d6) ~ 86.6 ppm (for COH) and 151.4 ppm (for NHCO).
Anal. Calcd for C15H13ClN202: C, 62.39; H, 4.54;
N, 9.70 Found: C, 62.10; H, 4.67; N, g.53 Part B. 6-Chloro-4-phenyl-2(lH)-quinazolinone 3-Oxide ~ ~ C~3 ~ NH20~-HCl ---~
~ H
10~940fi8 1~
S ~ 0 ~ ~ + CH3NH2 HCl A stirred mixture of 86.6 g (0.3 mole) of 6-chloro-
3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)quinazoli-none and 62.5 g (0.9 mole) of hydroxylamine hydrochloride in 1500 ml ethanol was refluxed for 187 hours, and then cooled. The solid portion of the reaction mixture was lS collected on a filter, washed with ethanol, and dried in air to give 67.9 g (83%) of 6-chloro-4-phenyl-2(lH)-quinazolinone 3-oxide as yellow crystals: m.p. 267-269.
2Q Part A. 6-Chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone H
I
~ ~ ~ C~3~H2NCO ~ ~ 2H5 ¦ ~ H
A solution of 28.4 g (31.7 ml, 0.4 mole) of ethyl isocyanate and 46.3 g (0.2 mole) of 2-amino-5-chlorobenzo-phenone in 100 ml of methylene chloride was refluxed for 20 hours. The reaction mixture was cooled, and the solid portion was collected on a filter and washed with methyl-35 ene chloride to gi~e 50.72 g (~4~) of 6-chloro-3-ethyl-10940fiB
3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone as colorless crystals: m.p. 182-184; 13C nmr (DMSO-d6) 86.9 ppm (for COH) and ~ 151.0 ppm (for NHCO).
1. Calc d- for C16H15ClN22 C~ 63-47;
5 H, 4.99; N, 9.25 Found: C, 63.29;
H, 4.83, N, 9.46 Part B. 6-Chloro-4-phenyl-2(lH)quinazolinone 3-Oxide .
lC I H
~ 2HS e~
A stirred mixture of 12.11 g (0.04 mole) of 6-chloro 3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(1H)quinazolinone and 8.34 g tO.12 mole) of hydroxylamine hydrochloride in 200 ml ethanol was refluxed for 3 days and then cooled.
20 The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried to give 9.27 g (85~) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide as yellow crystals, m.p. 267-269.
25 Part A. 6-Chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(1H)quinazolinone CH3 ~3 I
~ O ~ ~ CH3NCO ~ ~O~H3 ¦ ~ H
lO~Qfi8 A solution of 12.3 g (0.05 mole) of 5-chloro-2-methylaminobenzophenone and 6 ml (0.1 mole) of methyl isocyanate in 50 ml of methylene chloride was refluxed for 3 days, and then cooled. The solid portion of the 5 reaction mixture was collected on a filter and washed with methylene chloride to give 7.05 g (47%) of 6-chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(lH)-quinazolinone as light yellow crystals; m.p. 174-175;
H nmr (DMSO-d6) ~ 2.67 ppm (s, 3H), 3.38 ppm (s, 3H), 10 6.8-7.7 ppm (m, 9H).
16 15ClN22: C, 63.47;
H, 4.99; N, 9.25 Found: C, 63.44;
H, 4.96; N, 8.84 15 Part B. 6-Chloro-l-methyl-4-phenyl-2(lH)quinazolinone 3-Oxide C
1~ f~3 ~ O ~ 2 ~ ~ O ~ ~
\~ 0 A stirred mixture of 3.03 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(lH)quina-zolinone and 2.09 g (0.03 mole) of hydroxylamine hydro-chloride in 50 ml of ethanol was refluxed for 5 days.
The reaction mixture was cooled, and the solid portion 30 was collected on a filter, washed with ethanol, and dried in air to give 1.75 g (61%) of 6-chloro-1-methyl-4-phenyl-2(lH)quinazolinone 3-oxide as yPllvw crystals: m.p.
289-291; lH nmr (TFA) ~ 4.22 ppm (s, 3H) and 7.6-8.5 ppm (m, ~H).
10'3^~0~8 Part A. 1-(2-Benzoyl-4-chlorophenyl)-3-isopropylurea O C~
2 IH3 ~ C-N-CH
) ~ Hc-NcO ~~~~ ~ U~ CH
0 ~. 0 A mixture of 14 g (0.06 mole) of 2-amino-5-chlorobenzophenone and 40 ml of isopropyl isocyanate was refluxed for 3 hours. The solid that formed was suspended in 25 ml of hexane, and then collected on a 15 filter and recrystallized from ethanol to give 12.0 g (63%) of 1-(2-~enzoyl-4-chlorophenyl)-3-isopropylurea as colorless needles: m.p. 190-192; lH nmr (CDC13) ~ 1.19 ppm (d, J = 6 Hz, 6H), 3.98 ppm (m, lH), 4.95 ppm (m, NH), 7.2-7.8 ppm (m, 7H), 8.5 ppm (d, J = 10 Hz, lH) and 10.1 20 ppm (NH); 13C nmr (DMSO-d6) 6 195.4 ppm (C=O) and 153.9 ppm (NHCO).
Anal. Calc'd. for C17~17ClN2O2:
H, 5.41; N, 8.85 Found: C, 64.21;
25 H, 5.40; N, 8.78 Part B. 6-Chloro-4-phenyl-2(1H)quinazolinone 3-Oxide O CH
~~b CH3 ~~~~~~~~~~ O ~
10!~-~0fi8 A stirred mixture of 6.34 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 48 hours, and then cooled. The 5 suspended crystals were collected on a filter, washed with alcohol, and then dried in air to give 4.60 g (84%) of 6-chloro-4-phenyl-2(lH)quinazolinone 3-oxide as yellow crystals, m.p. 267-269 (dec.).
EXAMPLE 5 0 Part A. 1-(2-Benzoyl-4-chlorophenyl)-3-phenylurea O
~ ~ + 0NCO ~ ~
A solution of 13.1 g (0.11 mole) of phenyl isocya-20 nate and 23.17 g (0.1 mole) of 2-amino-5-chlorobenzo-phenone in 70 ml of methylene chloride was refluxed for 20 hours, and then evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 31.71 g (90%) of 1-(2-~enzoyl-4-chlorophenyl)-25 3-phenylurea as colorless crystals: m.p. 145-147;
H nmr (DMSO-d6) ~ 6.7-8.3 ppm (m, 13H), 9.43 ppm (d, J = 7 Hz, lH, exD2O) and 10.25 ppm (s, lH, exD2O);
C nmr (DMSO-d6) ~ 152.2 ppm (NHCO) and 195.5 ppm (C=O) .
Anal. Calc'd. for C20H15ClN2O2: C, 68.21; H, 4.50;
N, 8.02 Found: C, 68.21; H, 4.50;
N, 8.02
2Q Part A. 6-Chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone H
I
~ ~ ~ C~3~H2NCO ~ ~ 2H5 ¦ ~ H
A solution of 28.4 g (31.7 ml, 0.4 mole) of ethyl isocyanate and 46.3 g (0.2 mole) of 2-amino-5-chlorobenzo-phenone in 100 ml of methylene chloride was refluxed for 20 hours. The reaction mixture was cooled, and the solid portion was collected on a filter and washed with methyl-35 ene chloride to gi~e 50.72 g (~4~) of 6-chloro-3-ethyl-10940fiB
3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone as colorless crystals: m.p. 182-184; 13C nmr (DMSO-d6) 86.9 ppm (for COH) and ~ 151.0 ppm (for NHCO).
1. Calc d- for C16H15ClN22 C~ 63-47;
5 H, 4.99; N, 9.25 Found: C, 63.29;
H, 4.83, N, 9.46 Part B. 6-Chloro-4-phenyl-2(lH)quinazolinone 3-Oxide .
lC I H
~ 2HS e~
A stirred mixture of 12.11 g (0.04 mole) of 6-chloro 3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(1H)quinazolinone and 8.34 g tO.12 mole) of hydroxylamine hydrochloride in 200 ml ethanol was refluxed for 3 days and then cooled.
20 The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried to give 9.27 g (85~) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide as yellow crystals, m.p. 267-269.
25 Part A. 6-Chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(1H)quinazolinone CH3 ~3 I
~ O ~ ~ CH3NCO ~ ~O~H3 ¦ ~ H
lO~Qfi8 A solution of 12.3 g (0.05 mole) of 5-chloro-2-methylaminobenzophenone and 6 ml (0.1 mole) of methyl isocyanate in 50 ml of methylene chloride was refluxed for 3 days, and then cooled. The solid portion of the 5 reaction mixture was collected on a filter and washed with methylene chloride to give 7.05 g (47%) of 6-chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(lH)-quinazolinone as light yellow crystals; m.p. 174-175;
H nmr (DMSO-d6) ~ 2.67 ppm (s, 3H), 3.38 ppm (s, 3H), 10 6.8-7.7 ppm (m, 9H).
16 15ClN22: C, 63.47;
H, 4.99; N, 9.25 Found: C, 63.44;
H, 4.96; N, 8.84 15 Part B. 6-Chloro-l-methyl-4-phenyl-2(lH)quinazolinone 3-Oxide C
1~ f~3 ~ O ~ 2 ~ ~ O ~ ~
\~ 0 A stirred mixture of 3.03 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(lH)quina-zolinone and 2.09 g (0.03 mole) of hydroxylamine hydro-chloride in 50 ml of ethanol was refluxed for 5 days.
The reaction mixture was cooled, and the solid portion 30 was collected on a filter, washed with ethanol, and dried in air to give 1.75 g (61%) of 6-chloro-1-methyl-4-phenyl-2(lH)quinazolinone 3-oxide as yPllvw crystals: m.p.
289-291; lH nmr (TFA) ~ 4.22 ppm (s, 3H) and 7.6-8.5 ppm (m, ~H).
10'3^~0~8 Part A. 1-(2-Benzoyl-4-chlorophenyl)-3-isopropylurea O C~
2 IH3 ~ C-N-CH
) ~ Hc-NcO ~~~~ ~ U~ CH
0 ~. 0 A mixture of 14 g (0.06 mole) of 2-amino-5-chlorobenzophenone and 40 ml of isopropyl isocyanate was refluxed for 3 hours. The solid that formed was suspended in 25 ml of hexane, and then collected on a 15 filter and recrystallized from ethanol to give 12.0 g (63%) of 1-(2-~enzoyl-4-chlorophenyl)-3-isopropylurea as colorless needles: m.p. 190-192; lH nmr (CDC13) ~ 1.19 ppm (d, J = 6 Hz, 6H), 3.98 ppm (m, lH), 4.95 ppm (m, NH), 7.2-7.8 ppm (m, 7H), 8.5 ppm (d, J = 10 Hz, lH) and 10.1 20 ppm (NH); 13C nmr (DMSO-d6) 6 195.4 ppm (C=O) and 153.9 ppm (NHCO).
Anal. Calc'd. for C17~17ClN2O2:
H, 5.41; N, 8.85 Found: C, 64.21;
25 H, 5.40; N, 8.78 Part B. 6-Chloro-4-phenyl-2(1H)quinazolinone 3-Oxide O CH
~~b CH3 ~~~~~~~~~~ O ~
10!~-~0fi8 A stirred mixture of 6.34 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 48 hours, and then cooled. The 5 suspended crystals were collected on a filter, washed with alcohol, and then dried in air to give 4.60 g (84%) of 6-chloro-4-phenyl-2(lH)quinazolinone 3-oxide as yellow crystals, m.p. 267-269 (dec.).
EXAMPLE 5 0 Part A. 1-(2-Benzoyl-4-chlorophenyl)-3-phenylurea O
~ ~ + 0NCO ~ ~
A solution of 13.1 g (0.11 mole) of phenyl isocya-20 nate and 23.17 g (0.1 mole) of 2-amino-5-chlorobenzo-phenone in 70 ml of methylene chloride was refluxed for 20 hours, and then evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 31.71 g (90%) of 1-(2-~enzoyl-4-chlorophenyl)-25 3-phenylurea as colorless crystals: m.p. 145-147;
H nmr (DMSO-d6) ~ 6.7-8.3 ppm (m, 13H), 9.43 ppm (d, J = 7 Hz, lH, exD2O) and 10.25 ppm (s, lH, exD2O);
C nmr (DMSO-d6) ~ 152.2 ppm (NHCO) and 195.5 ppm (C=O) .
Anal. Calc'd. for C20H15ClN2O2: C, 68.21; H, 4.50;
N, 8.02 Found: C, 68.21; H, 4.50;
N, 8.02
4~fi8 Part B. 6-Chloro-4-phenyl-2l1H)quinazolinone 3-Oxide
5 ~ ~; C N-0 NH OH~HCl ~ O ~
A stirred mixture of 7.02 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylruea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 22 hours, and then cooled.
15 The suspended solid was collected on a filter, washed with ethanol, and dried in air to give 3.82 g (70%) of 6-chloro-4-phenyl-2)lH)quinazolinone as yellow crystals; m.p. 267-269.
20 Part A. 1-(2-Benzoyl-4-chlorophenyl)-1-methyl-3-phenyl-urea fH~
~/0~ + 0r:co 3 ~0~
A solution of 12.3 g (0.05 mole) of 5-chloro-2-methylaminobenzophenone and 11.9 g (0.1 mole) of phenyl isocyanate in 50 ml of methylene chloride was refluxed for 3 days, and then evaporated to dryness under reduced pressure. The residual syrup was stirred with ether 35 until it crystallized. The crystals were collected on 10940fi8 a filter and washed with ether to give 12.06 g (66%) of l-(2-~enzoyl-4-chlorophenyl)-1-methyl-3-phenylurea as light yellow crystals. A sample was recrystallized from ethanol to give colorless crystals: m.p. 158-160;
5 lH nmr (DMSO-d6) ~ 3.41 ppm (s, 3H), 6.7-7.5 ppm (m, 13H).
Anal. Calc'd. for C21H17ClN2O2: C, 69.13; H, 4.70;
N, 7.68 Found: C, 68.82; H, 4.73;
10 N, 7.48 Part B. 6-Chloro-l-methyl-4-phenyl-2(lH)quinazolinone 3-Oxide CH
A mixture of 3.65 g (0.01 mole) of 1-(2-benzoyl-4-chlorophenyl)-1-methyl-3-phenylurea and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of ethanol was stirred and refluxed for 5 days. The reaction mixture 25 was cooled, and the suspended solid was collected on a filter, washed with alcohol, and dried in air to give 1.80 g (63%) of 6-chloro-1-methyl-4-phenyl-2(1H)quina-zolinone as yellow crystals, m.p. 289-291.
EXAMP~E 7 30 Part A. 6-Chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)-quinazolinone lO~ ~Ofi8 17 i o + EtOH
I OEt A solution of 10.0 g (0.285 mole) of 1-(2-benzoyl-10 4-chlorophenyl)-3-phenylruea in 50 ml ethanol was re-fluxed for 18 hours, and then cooled. The solid that formed was collected on a filter and washed with ethanol to give 9.46 g (88~) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)~uinazolinone as colorless 15 crystals: m.p. 209-211. The lH nmr spectrum shows the presence of an ethyl grvup in addition to aromatic hydrogens.
Anal. Calc'd. for C22HlgClN2O2: C, 69.74; H, 5.05;
N, 7.40 20Found: C, 70.12; H, 5.05;
N, 7.35 Part B. 6-~hloro-4-phenyl-2(lH)quinazolinone 3-Oxide H
~ ~ ~ 2 ~ ~ O
A mixture of 3 . 51 g (0.0093 mole) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)quinazolinone and 2.09 g (0.03 mole~ of hydroxylamine hydrochloride in 50 ml alcohol was refluxed for 4 days, and then cooled. The solid that formed was collected on a filter, washed with 35 ethanol, and dried in air to give 1.82 g (72%) of 6-- chloro-4-phenyl-2(1H)quinazolinone 3-oxide as yellow crystals, m.p. 267-269.
Qfi8
A stirred mixture of 7.02 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylruea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 22 hours, and then cooled.
15 The suspended solid was collected on a filter, washed with ethanol, and dried in air to give 3.82 g (70%) of 6-chloro-4-phenyl-2)lH)quinazolinone as yellow crystals; m.p. 267-269.
20 Part A. 1-(2-Benzoyl-4-chlorophenyl)-1-methyl-3-phenyl-urea fH~
~/0~ + 0r:co 3 ~0~
A solution of 12.3 g (0.05 mole) of 5-chloro-2-methylaminobenzophenone and 11.9 g (0.1 mole) of phenyl isocyanate in 50 ml of methylene chloride was refluxed for 3 days, and then evaporated to dryness under reduced pressure. The residual syrup was stirred with ether 35 until it crystallized. The crystals were collected on 10940fi8 a filter and washed with ether to give 12.06 g (66%) of l-(2-~enzoyl-4-chlorophenyl)-1-methyl-3-phenylurea as light yellow crystals. A sample was recrystallized from ethanol to give colorless crystals: m.p. 158-160;
5 lH nmr (DMSO-d6) ~ 3.41 ppm (s, 3H), 6.7-7.5 ppm (m, 13H).
Anal. Calc'd. for C21H17ClN2O2: C, 69.13; H, 4.70;
N, 7.68 Found: C, 68.82; H, 4.73;
10 N, 7.48 Part B. 6-Chloro-l-methyl-4-phenyl-2(lH)quinazolinone 3-Oxide CH
A mixture of 3.65 g (0.01 mole) of 1-(2-benzoyl-4-chlorophenyl)-1-methyl-3-phenylurea and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of ethanol was stirred and refluxed for 5 days. The reaction mixture 25 was cooled, and the suspended solid was collected on a filter, washed with alcohol, and dried in air to give 1.80 g (63%) of 6-chloro-1-methyl-4-phenyl-2(1H)quina-zolinone as yellow crystals, m.p. 289-291.
EXAMP~E 7 30 Part A. 6-Chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)-quinazolinone lO~ ~Ofi8 17 i o + EtOH
I OEt A solution of 10.0 g (0.285 mole) of 1-(2-benzoyl-10 4-chlorophenyl)-3-phenylruea in 50 ml ethanol was re-fluxed for 18 hours, and then cooled. The solid that formed was collected on a filter and washed with ethanol to give 9.46 g (88~) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)~uinazolinone as colorless 15 crystals: m.p. 209-211. The lH nmr spectrum shows the presence of an ethyl grvup in addition to aromatic hydrogens.
Anal. Calc'd. for C22HlgClN2O2: C, 69.74; H, 5.05;
N, 7.40 20Found: C, 70.12; H, 5.05;
N, 7.35 Part B. 6-~hloro-4-phenyl-2(lH)quinazolinone 3-Oxide H
~ ~ ~ 2 ~ ~ O
A mixture of 3 . 51 g (0.0093 mole) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)quinazolinone and 2.09 g (0.03 mole~ of hydroxylamine hydrochloride in 50 ml alcohol was refluxed for 4 days, and then cooled. The solid that formed was collected on a filter, washed with 35 ethanol, and dried in air to give 1.82 g (72%) of 6-- chloro-4-phenyl-2(1H)quinazolinone 3-oxide as yellow crystals, m.p. 267-269.
Qfi8
6-Chloro-4-phenyl-2(-lH)quinazolinone 3-Oxide H
e~(~ ~ 0NCO + NH20H - HC1 ~
o A mixture of 12.6 g (0.05 mole) of 2-amino-5-chlorobenzophenone and 6.55 g (0.055 mole) of phenyl isocyanate was heated on a steam-bath for 30 minutes, and then 250 ml ethanol and 10.43 g (0.15 mole) of 15 hydroxylamine hydrochloride were added and the mixture was refluxed for 2 days and then cooled. The solid precipitate that formed was collected on a filter, washed with ethanol, and dried in air to give 9.42 g (69~) of 6-chloro-4-phenyl-2(lH)quinazolinone 3-oxide 20 as yellow crystals, m.p. 267-269.
6-Chloro-4-phenyl-2(lH)quinazolinone 3-Oxide H X
-HCl ~`o~X C~3 CH30CH2C~I20H ~J~~
A stirred mixture of 2.89 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone and 2.09 g (0.03 mole) of hydroxylamine 35 hydrochloride in 50 ml of 2-methoxyethanol (ethylene 10~?40fi8 glycol monoethyl ether) was refluxed for 2 hours, and then cooled to O. The solid that formed was collected on a filter, washed with ethanol, and dried in air to give 1.40 g (51~) of 6-chloro-4-phenyl-2(lH)quinazoli-5 none 3-oxide as yellow crystals, m.p. 267-269.
Part A. 6-8romo-3,4--dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)quinazolinone H
~ ~ + CH3NCO t ~0~
15 ~ ~
A solution of 14.70 g (.053 mole) of 2-amino-5-bromobenzophenone and 6.0 g (0.21 mol) of methyl 20 isocyanate in 75 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 16.18 g (90% yield) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-25 quinazolinone as a white crystalline powder: m.p.293-294 (dec.).
H nmr (DMSO-d6) 5 2.66 ppm (s, 3H), 6.5-7.5 ppm (m, 8H).
- 15 13BrN22: C, 54.07; H, 3.93 30 N, 8.41 Found: C, 54.24; H, 3.89;
N, 8.12 lO~ ~Q~,~
Part B. 6-Bromo-4-phenyl-2(lH)quinazolinone 3-Oxide ~ ~ ~ 2 H
~ ~ ~ + CH3NH2 HCl / \
I~oJ
A stirred mixture of 28.28 g (.085 mol) of 6-20 bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone and 17.6 g (.25 mol) of hydroxylamine hydrochloride in 425 ml of ethanol was refluxed for 192 hours and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with 25 ethanol, and dried in air to give 20.92 g (.066 mol, 78~) of 6-bromo-4-phenyl-2(lH)quinazolinone 3-oxide as light yellow crystals: m.p. 275-276.
10~0~8 Part A. 6-Chloro-3-ethyl-4-(2-fluorophenyl)-3,4-di-hydro-4-hydroxy-2(1H)quinazolinone H
~ + C2H5NCO ' ~llc2H5 ~ y F ~
A mixture of 25 g (0.1 mole) of 2-amino-5-chloro-2'-fluorobenzophenone and 35.5 g (0.5 mole) of ethyl iso-15 cyanate was refluxed for 20 hours, and then cooled. Thesolid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 19.6 g (61~) of 6-chloro-3-ethyl-4-(2-fluorophenyl)-3,4-di-hydro-4-hydroxy-2(lH)quinazoline as a white crystalline 20 powder: m.p. 176-178 (dec.); l9F nmr (DMSO-d6) -114.0 ppm; ir (KBr) at 6.24 ~ for C~O.
Anal. Calc'd. for C16H14ClFN2O~: C, 59.92; H, 4.40;
N, 8.73 Found: C, 60.11; H, 4.44;
25 N, 8.83 Part B. 6-Chloro-4-(2-fluorophenyl)-2(lH)quinazolinone 3-Oxide H H
~ ~ H + NH2OH HC1 l ~ ~
~ F
lO~ iQ6~3 A stirred mixture of 18.0 g (0.056 mole) of 6-chloro-3-ethyl-4-(2-fluorophenyl)-3,4-dihydro-4-hydroxy-2(1H)quinazoline, 11.8 g (0.17 mole) of hydroxyl-amine hydrochloride, and 280 ml of ethanol was refluxed 5 for 3 days. The reaction mixture was cooled, and the precipitate was collected on a filter and washed with ethanol to give 6.67 g (47%) of 6-chloro-4-(2-fluoro-phenyl)-2(lH)quinazoline 3-oxide as a yellow crystalline powder; m.p. 268-270 (dec.); l9F nmr (DMSO-d6) 6 10 111.1 ppm.
Anal. Calc'd. for C14H8ClFN2O2: C, 57.85; H, 2.77;
N, 9.64 Found: C, 58.01; H, 2.83;
N, 9.59 Table I shows additional ureas and hydroxyquinazo-linones which can be prepared by the process disclosed and exemplified above using the appropriate aminobenzo-phenone and a suitable organic isocyanate.
TABLE I
20 Preparatlon of Substituted Ureas and Hydroxyquinazo-linones Aminobenzophenone Organic Isocyanate Product / \ ~ 2 r~ ~ = ~ Cl ~ NCO
~ -C-N ~ ~ Cl ~ F
10~ 01`,8 Aminobenzophenone Organic Isocyanate Product ~_ + C2HSNC ' C~
~ 3 ~ ~3 ~c o G NCO
H O H
-C-N
~3 b=o ~, lO'~i~Ofi8 Table II shows additional quinazolinone oxides which can be prepared by the process disclosed and exemplified above using the appropriate isocyanate adduct and hydroxylamine or a suitable salt thereof.
TABLE II
Preparation of Selected Quinazolinone Oxides Quinazolinone Isocyanate Adduct Hydroxylamine Oxide o -C!N ~ ~ Cl H
NH20H~HCl CH3 f H3 ~ ~ -C2~1 ~ (NH30H)2S0~
25 ~ Cl ~ C1 ~X~; + NH2~
l~?~Ofi8 TABLE II (cont'd.) Quinazolinone Isocyanate Adduct Hydroxylamine Oxide H O H
I 111 ~\
10 G~ t NH20H-HBr ' ~3(0
e~(~ ~ 0NCO + NH20H - HC1 ~
o A mixture of 12.6 g (0.05 mole) of 2-amino-5-chlorobenzophenone and 6.55 g (0.055 mole) of phenyl isocyanate was heated on a steam-bath for 30 minutes, and then 250 ml ethanol and 10.43 g (0.15 mole) of 15 hydroxylamine hydrochloride were added and the mixture was refluxed for 2 days and then cooled. The solid precipitate that formed was collected on a filter, washed with ethanol, and dried in air to give 9.42 g (69~) of 6-chloro-4-phenyl-2(lH)quinazolinone 3-oxide 20 as yellow crystals, m.p. 267-269.
6-Chloro-4-phenyl-2(lH)quinazolinone 3-Oxide H X
-HCl ~`o~X C~3 CH30CH2C~I20H ~J~~
A stirred mixture of 2.89 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone and 2.09 g (0.03 mole) of hydroxylamine 35 hydrochloride in 50 ml of 2-methoxyethanol (ethylene 10~?40fi8 glycol monoethyl ether) was refluxed for 2 hours, and then cooled to O. The solid that formed was collected on a filter, washed with ethanol, and dried in air to give 1.40 g (51~) of 6-chloro-4-phenyl-2(lH)quinazoli-5 none 3-oxide as yellow crystals, m.p. 267-269.
Part A. 6-8romo-3,4--dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)quinazolinone H
~ ~ + CH3NCO t ~0~
15 ~ ~
A solution of 14.70 g (.053 mole) of 2-amino-5-bromobenzophenone and 6.0 g (0.21 mol) of methyl 20 isocyanate in 75 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 16.18 g (90% yield) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-25 quinazolinone as a white crystalline powder: m.p.293-294 (dec.).
H nmr (DMSO-d6) 5 2.66 ppm (s, 3H), 6.5-7.5 ppm (m, 8H).
- 15 13BrN22: C, 54.07; H, 3.93 30 N, 8.41 Found: C, 54.24; H, 3.89;
N, 8.12 lO~ ~Q~,~
Part B. 6-Bromo-4-phenyl-2(lH)quinazolinone 3-Oxide ~ ~ ~ 2 H
~ ~ ~ + CH3NH2 HCl / \
I~oJ
A stirred mixture of 28.28 g (.085 mol) of 6-20 bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone and 17.6 g (.25 mol) of hydroxylamine hydrochloride in 425 ml of ethanol was refluxed for 192 hours and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with 25 ethanol, and dried in air to give 20.92 g (.066 mol, 78~) of 6-bromo-4-phenyl-2(lH)quinazolinone 3-oxide as light yellow crystals: m.p. 275-276.
10~0~8 Part A. 6-Chloro-3-ethyl-4-(2-fluorophenyl)-3,4-di-hydro-4-hydroxy-2(1H)quinazolinone H
~ + C2H5NCO ' ~llc2H5 ~ y F ~
A mixture of 25 g (0.1 mole) of 2-amino-5-chloro-2'-fluorobenzophenone and 35.5 g (0.5 mole) of ethyl iso-15 cyanate was refluxed for 20 hours, and then cooled. Thesolid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 19.6 g (61~) of 6-chloro-3-ethyl-4-(2-fluorophenyl)-3,4-di-hydro-4-hydroxy-2(lH)quinazoline as a white crystalline 20 powder: m.p. 176-178 (dec.); l9F nmr (DMSO-d6) -114.0 ppm; ir (KBr) at 6.24 ~ for C~O.
Anal. Calc'd. for C16H14ClFN2O~: C, 59.92; H, 4.40;
N, 8.73 Found: C, 60.11; H, 4.44;
25 N, 8.83 Part B. 6-Chloro-4-(2-fluorophenyl)-2(lH)quinazolinone 3-Oxide H H
~ ~ H + NH2OH HC1 l ~ ~
~ F
lO~ iQ6~3 A stirred mixture of 18.0 g (0.056 mole) of 6-chloro-3-ethyl-4-(2-fluorophenyl)-3,4-dihydro-4-hydroxy-2(1H)quinazoline, 11.8 g (0.17 mole) of hydroxyl-amine hydrochloride, and 280 ml of ethanol was refluxed 5 for 3 days. The reaction mixture was cooled, and the precipitate was collected on a filter and washed with ethanol to give 6.67 g (47%) of 6-chloro-4-(2-fluoro-phenyl)-2(lH)quinazoline 3-oxide as a yellow crystalline powder; m.p. 268-270 (dec.); l9F nmr (DMSO-d6) 6 10 111.1 ppm.
Anal. Calc'd. for C14H8ClFN2O2: C, 57.85; H, 2.77;
N, 9.64 Found: C, 58.01; H, 2.83;
N, 9.59 Table I shows additional ureas and hydroxyquinazo-linones which can be prepared by the process disclosed and exemplified above using the appropriate aminobenzo-phenone and a suitable organic isocyanate.
TABLE I
20 Preparatlon of Substituted Ureas and Hydroxyquinazo-linones Aminobenzophenone Organic Isocyanate Product / \ ~ 2 r~ ~ = ~ Cl ~ NCO
~ -C-N ~ ~ Cl ~ F
10~ 01`,8 Aminobenzophenone Organic Isocyanate Product ~_ + C2HSNC ' C~
~ 3 ~ ~3 ~c o G NCO
H O H
-C-N
~3 b=o ~, lO'~i~Ofi8 Table II shows additional quinazolinone oxides which can be prepared by the process disclosed and exemplified above using the appropriate isocyanate adduct and hydroxylamine or a suitable salt thereof.
TABLE II
Preparation of Selected Quinazolinone Oxides Quinazolinone Isocyanate Adduct Hydroxylamine Oxide o -C!N ~ ~ Cl H
NH20H~HCl CH3 f H3 ~ ~ -C2~1 ~ (NH30H)2S0~
25 ~ Cl ~ C1 ~X~; + NH2~
l~?~Ofi8 TABLE II (cont'd.) Quinazolinone Isocyanate Adduct Hydroxylamine Oxide H O H
I 111 ~\
10 G~ t NH20H-HBr ' ~3(0
Claims (3)
1. A process for preparing a compound of the formula:
where X is Cl, Br, NO2 or CF3;
Y is H, Br, Cl, or F; and R1 is H or CH3;
which comprises treating either or both of compounds of the formulae:
with an acid salt of hydroxylamine, where R is hydrocarbyl or halohydrocarbyl of up to 8 carbon atoms, and R2 is H or alkyl of 1-6 carbon atoms.
where X is Cl, Br, NO2 or CF3;
Y is H, Br, Cl, or F; and R1 is H or CH3;
which comprises treating either or both of compounds of the formulae:
with an acid salt of hydroxylamine, where R is hydrocarbyl or halohydrocarbyl of up to 8 carbon atoms, and R2 is H or alkyl of 1-6 carbon atoms.
2. A process for preparing a compound of the formula:
where X is Cl, Br, NO2 or CF3;
Y is H, Br, Cl or F; and R1 is H or CH3;
which comprises the following steps in sequence:
(a) reacting a compound of the formula:
with an organic isocyanate of the formula RNCO to pro-duce a compound or compounds of one or both of the following formulae:
(b) treating the reaction product or products of step (a) with an acid salt of hydroxylamine, where R is hydrocarbyl or halohydrocarbyl of 1-8 carbon atoms.
where X is Cl, Br, NO2 or CF3;
Y is H, Br, Cl or F; and R1 is H or CH3;
which comprises the following steps in sequence:
(a) reacting a compound of the formula:
with an organic isocyanate of the formula RNCO to pro-duce a compound or compounds of one or both of the following formulae:
(b) treating the reaction product or products of step (a) with an acid salt of hydroxylamine, where R is hydrocarbyl or halohydrocarbyl of 1-8 carbon atoms.
3. A process for preparing a compound of the formula:
where X is Cl, Br, NO2 or CF3;
Y is H, Br, Cl or F; and R1 is H or CH3;
which comprises the following steps in sequence:
(a) reacting a compound of the formula:
with an organic isocyanate of the formula RNCO to produce a compound of the formula:
(b) heating the reaction product of step (a) in a lower aliphatic alcohol of the formula R2OH to produce a compound of the formula:
(c) treating the reaction product of step (b) with a suitable acid addition of hydroxylamine, where R2 is alkyl of 1-6 carbon atoms.
where X is Cl, Br, NO2 or CF3;
Y is H, Br, Cl or F; and R1 is H or CH3;
which comprises the following steps in sequence:
(a) reacting a compound of the formula:
with an organic isocyanate of the formula RNCO to produce a compound of the formula:
(b) heating the reaction product of step (a) in a lower aliphatic alcohol of the formula R2OH to produce a compound of the formula:
(c) treating the reaction product of step (b) with a suitable acid addition of hydroxylamine, where R2 is alkyl of 1-6 carbon atoms.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80707677A | 1977-06-16 | 1977-06-16 | |
| US807,076 | 1991-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1094068A true CA1094068A (en) | 1981-01-20 |
Family
ID=25195510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA305,471A Expired CA1094068A (en) | 1977-06-16 | 1978-06-14 | Process for preparing quinazolinone oxides |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0000149A1 (en) |
| JP (1) | JPS545988A (en) |
| AT (1) | ATA436678A (en) |
| AU (1) | AU3709278A (en) |
| CA (1) | CA1094068A (en) |
| DK (1) | DK176378A (en) |
| ES (1) | ES470828A1 (en) |
| FI (1) | FI781928A (en) |
| GR (1) | GR64944B (en) |
| IT (1) | IT1098341B (en) |
| NO (1) | NO782087L (en) |
| NZ (1) | NZ187581A (en) |
| PL (1) | PL113420B1 (en) |
| PT (1) | PT68174A (en) |
| SU (1) | SU797575A3 (en) |
| ZA (1) | ZA783438B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4946633B2 (en) * | 1971-08-17 | 1974-12-11 |
-
1978
- 1978-04-24 DK DK176378A patent/DK176378A/en unknown
- 1978-06-14 CA CA305,471A patent/CA1094068A/en not_active Expired
- 1978-06-14 AU AU37092/78A patent/AU3709278A/en active Pending
- 1978-06-15 PT PT68174A patent/PT68174A/en unknown
- 1978-06-15 NO NO782087A patent/NO782087L/en unknown
- 1978-06-15 IT IT24615/78A patent/IT1098341B/en active
- 1978-06-15 NZ NZ187581A patent/NZ187581A/en unknown
- 1978-06-15 AT AT436678A patent/ATA436678A/en not_active Application Discontinuation
- 1978-06-15 SU SU782627504A patent/SU797575A3/en active
- 1978-06-15 EP EP78100163A patent/EP0000149A1/en not_active Withdrawn
- 1978-06-15 ES ES470828A patent/ES470828A1/en not_active Expired
- 1978-06-15 ZA ZA00783438A patent/ZA783438B/en unknown
- 1978-06-16 PL PL1978207682A patent/PL113420B1/en not_active IP Right Cessation
- 1978-06-16 GR GR56539A patent/GR64944B/en unknown
- 1978-06-16 FI FI781928A patent/FI781928A/en not_active Application Discontinuation
- 1978-06-16 JP JP7367978A patent/JPS545988A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DK176378A (en) | 1978-12-17 |
| NO782087L (en) | 1978-12-19 |
| EP0000149A1 (en) | 1979-01-10 |
| SU797575A3 (en) | 1981-01-15 |
| ES470828A1 (en) | 1979-10-01 |
| NZ187581A (en) | 1980-11-28 |
| GR64944B (en) | 1980-06-10 |
| IT7824615A0 (en) | 1978-06-15 |
| ATA436678A (en) | 1981-01-15 |
| PL207682A1 (en) | 1979-05-07 |
| FI781928A (en) | 1978-12-17 |
| JPS545988A (en) | 1979-01-17 |
| PT68174A (en) | 1978-07-01 |
| IT1098341B (en) | 1985-09-07 |
| PL113420B1 (en) | 1980-12-31 |
| AU3709278A (en) | 1979-12-20 |
| ZA783438B (en) | 1979-06-27 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |