BACKGROUND OF THE INVENTION
[0001] Copending U.S. Patent Application Serial Number 687,318, filed May 26, 1976 by Elena
M. Bingham and William Joseph Middleton, which is a continuation-in- part of U.S.
Patent Application Serial Number 597,502, now abandoned, discloses certain novel 3-fluorobenzodiazepines
of the formula:
where
X is Cl, Br, N02 or CF3;
Y is H, Cl, Br or F;
D is H, hydrocarbyl of 1-4 carbons, -CH2CF3, -CONHR, - CH2CH2NR2, or -CH2CH2NR2 A, where R is alkyl of 1-4 carbons and A is a pharmaceutically suitable acid;
B is 0; or
B and D together is =N-N=C(R')-where RI is H or C1-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-hydroxy- benzodiazepine with a dialkylaminosulfur
trifluoride as follows:
where
R3 and
R4 are a primary alkyl group of 1-4 carbons or taken together are -(CH
2)
4- or -(CH
2)
5.
[0002] Copending U.S. Patent Application Serial Number , filed simultaneously with the present
application by William Joseph Middleton (attorney' docket number CR-7796) discloses
an improved process for preparing such 3-fluorobenzodiazepines, which improved process
can be summarized schematically by the following equations:
where
X is Cl, Br, N02 or CF3;
Y is H, Cl, Br or F; and
Z1 and Z2 are Cl or Br.
Middleton also discloses that starting material (1) can be prepared by the process
disclosed in U.S. Patent No. 3,398,139.
[0003] In addition, copending U.S. Patent Application Serial No. , filed simultaneously
herewith by Elena M. Bingham and Arthur J. Elliott (attorney's docket number CR-7795)
discloses an improved process for preparing the N-methylaminobenzophenone anti-oxime
used as the starting material in Middleton's improved process discussed immediately
above. The Bingham and Elliott process.can be summarized schematically by the following
equations:
where
X is Cl, Br, N02 or CF3;
Y is H, Cl, Br or F; and
Z is I, Br, CF3SO2O-, FS020, CCl3SO2O- or CH3OSO2O-.
[0004] Bingham and Elliott also disclose that the starting material quinazolinone 3-oxides
can be prepared by a process taught by Sulkowski and Childress, J. Org. Chem., 27,
4424 (1962).
SUMMARY OF THE INVENTION
[0005] The present invention relates to an improved process for making the quinazolinone
3-oxides of formula (1), above, and an alternate process for making the quinazolinone
3-oxides of formula (3), above.
[0006] More specifically, the present invention relates to an improved process for preparing
6-substituted-4-phenylquinazolinone 3-oxides by the treatment of 2-aminobenzophenone-isocyanate
reaction products with hydroxylamine salts.
[0007] 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, CF
3 or NO
2; Y = H, Br, Cl or F; R
1 = H or CH
3) to give either ureas of.formula II or quinazolinones of formula III (X, Y and R
1 as previously defined), depending on the reaction conditions and the isocyanates
used.
and/or
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.
where A is an organic or inorganic acid with a pKa of less than 2.
DETAILED DESCRIPTION OF THE INVENTION
Process Conditions
[0008] Quinazolinone oxides of formula IV can be prepared by heating a solution or mixture
of 2-aminobenzo- phenoneisocyanate reaction products (of Formula II or III) 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 200°C are operable. Alcohol solvents useful for this reaction include, but
are not limited to, ethanol, methanol, propanol, isopropanol, butanol, 2-methoxyethanol,
ethylene glycol, and propylene glycol. Salts of hydroxylamine useful in this reaction
include salts with organic or inorganic acids having a pKa of less than 2, such as
hydroxylamine hydrochloride, hydroxylamine hydrobromide and hydroxylamine 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 days or even weeks when less
reactive isocyanate adducts or lower boiling alcohols are used.
[0009] The product quinazolinone oxides can be isolated from the reaction mixture by conventional
means. In most cases, the quinazolinone oxides are considerably less soluble than
the'reactants, and will precipitate during the course of the reaction. When this occurs,
the product quinazolinone oxides can be isolated by simply filtering the reaction
mixture.
[0010] The 2-aminobenzophenone-isocyanate adducts used as starting materials can be prepared
by the reaction of 2-aminobenzophenones with organic isocyanates as illustrated in
the following Examples cr as described by Sulkowski et al. J. Org. Chem., 27 4424
(1962) or by Metlesics et al., J. Org. Chem., 31 1007 (1966).
[0011] Alternatively, the compounds of formula IV can be prepared by heating a compound
of formula II in a suitable alcohol followed by treatment with a suitable acid addition
salt of hydroxylamine.
where
R20
H is lower aliphatic alcohol of 1-6 carbon atoms, preferably methanol or ethanol.
EXAMPLE 1
Part A. 6-Chloro-3',4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone
[0012]
[0013] A solution of 100 g (0.43 mole) of 2-amino-5-chlorobenzophenone and 40 g (0.7 mole)
of methyl isocyanate 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 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)-quinazolinone
as a white crystalline powder: mp 296-298° (dec);
1H nmr (DMSO-d
6) , δ 2.66 ppm (s, 3H), 6.8-7.6 ppm (m, 8H) and 10.0 ppm (s, NH);
13C nmr (DMSO-d
6) δ 86.6 ppm (for COH) and 151.4 ppm (for NHCO).
[0014] Anal. Calcd for C
15H
13ClN
2O
2: C, 62.39; H, 4.54; N, 9.70 Found: C, 62.10; H, 4.67; N, 9.53
Part B. 6-Chloro-4-phenyl-2(1H)-quinazolinone 3-Oxide
[0015]
[0016] A stirred mixture of 86.6 g (0.3 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)quinazolinone
and 62.5 g (0.9 mole) of hydroxylami.ne hydrochloride in 1500 ml ethanol was refluxed
for 187 hours, and then cooled. The solid portion of the reaction'mixture was 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°.
EXAMPLE 2
Part A. 6-Chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone
[0017]
[0018] 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-chlorobenzophenone 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 methylene chloride to give 50.72 g (84%) of 6-chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone
as colorless crystals: m.p. 182-184°; 13C nmr (DMSO-d
6) δ 86.9 ppm (for COH) and 6 151.0 ppm (for NHCO) .
[0019] Anal. Calc'd. for C
16H
15ClN
2O
2: C,
63.47; H, 4.99; N, 9.25 Found: C, 63.29; H, 4.83, N, 9.46
Part B. 6-Chloro-4-phenyl-2(1H)quinazolinone 3-Oxide
[0020]
[0021] A stirred mixture of 12.11 g (0.04 mole) of 6-chloro 3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(lH)quinazolinone
and 8.34 g (0.12 mole) of hydrdxylamine hydrochloride in 200 ml ethanol was refluxed
for 3 days and then cooled. 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-phertyl-2(1H)quinazolinone
3-oxide as yellow crystals, m.p. 267-269°.
EXAMPLE 3
Part A. 6-Chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(lH)quinazolinone
[0022]
[0023] 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 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-l,3-dimethyl-4-phenyl-2(lH)-quinazolinone
as light yellow crystals; m.p. 174-175°;
1H nmr (DMSO-d
6) δ 2.67 ppm (s, 3H), 3.38 ppm (s, 3H), 6.8-7.7 ppm (m, 9H).
[0024] Anal. Calc'd. for C
16H
15C1N
20
2:
C, 63.47; H, 4.99; N, 9.25 Found: C, 63.44; H, 4.96; N, 8.84
Part B. 6-Chloro-l-methyl-4-phenyl-2(lH)quinazolinone 3-Oxide
[0025]
[0026] A stirred mixture of 3.03 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-l,3-dimethyl-4-phenyl-2(lH)quinazolinone
and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of ethanol was refluxed
for 5 days. The reaction mixture was cooled, and the solid portion was collected on
a filter, washed with ethanol, and dried in air to give 1.75 g (61%) of 6-chloro-l-methyl-4-phenyl-2(l
H)quinazolinone 3-oxide as yellow crystals: m.p. 289-291°;
1H nmr (TFA) δ 4.22 ppm (s, 3H) and 7.6-8.
5 ppm (m, 8H).
EXAMPLE 4
Part A. 1-(2-Benzoyl-4-chlorophenyl)-3-isopropylurea
[0027]
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 filter and recrystallized from ethanol to give
12.0 g (63%) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea as colorless needles:
m.p. 190-192°;
1H nmr (CDC1
3) 6 1.19 ppm (d, J = 6 Hz, 6H), 3.98 ppm (m, 1H), 4.95 ppm (m, NH), 7.2-7.8 ppm (m,
7
H), 8.5 ppm (d,
J =
10 Hz, 1
H) and 10.1 ppm (NH); 13C nmr (DMSO-d
6) δ 195.4 ppm (C=O) and 153.9 ppm (NHCO).
[0028] Anal. Calc'd. for C
17H
17C1N
20
2: C, 6
4.
45; H, 5.41; N, 8.85 Found: C, 64.21; H, 5.40; N, 8.78
Part B. 6-Chloro-4-phenyl-2(lH)quinazolinone 3-Oxide
[0029]
[0030] 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 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
Part A. 1-(2-Benzoyl-4-chlorophenyl)-3-phenylurea
[0031]
A solution of 13.1 g (0.11 mole) of phenyl isocyanate and 23.17 g (0.1 mole) of 2-amino-5-chlorobenzophenone
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 l-(2-benzoyl-4-chlorophenyl)-3-phenylurea as colorless crystals: m.p. 145-147°;
1H nmr (DMSO-d
6) 6 6.7-8.3 ppm (m, 13H), 9.43 ppm (d, J = 7 Hz, 1H, exD
20) and 10.25 ppm (s, 1H, exD
20);
13C nmr (DMSO-d
6) 6 152.2 ppm (NHCO) and 195.5 ppm (C=O).
[0032] Anal.
Calc'd. for C
20H
15ClN
2O
2: C, 68.21; H, 4.50; N, 8.02
[0033] Found: C, 68.21; H, 4.50; N, 8.02
Part B. 6-Chloro-4-phenyl-2(lH)quinazolinone 3-Oxide
[0034]
[0035] 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. 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°.
EXAMPLE 6
Part A. 1-(2-Benzoyl-4-chlorophenyl)-1-methyl-3-phenyl- urea
[0036]
[0037] 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 until it crystallized. The crystals were collected on a filter
and washed with ether to give 12.06 g (66%) of 1-(2-benzoyl-4-chlorophenyl)-1-methyl-3-phenylurea
as light yellow crystals. A'sample was recrystallized from ethanol to give colorless
crystals: m.p. 158-160°;
1H nmr (DMSO-d
6) 6 3.41 ppm (s, 3H), 6.7-7.5 ppm (m, 13H) .
[0038] Anal. Calc'd. for C
21H
17ClN
2O
2: C, 69.13; H, 4.70; N, 7.68
[0039] Found: C, 68.82; H, 4.73; N, 7.48
Part B. 6-Chloro-l-methyl-4-phenyl-2(lH)quinazolinone 3-Oxide
[0040]
[0041] 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 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-l-methyl-4-phenyl-2(lH)quinazolinone as yellow crystals, m.p. 289-291°.
EXAMPLE 7
Part A. 6-Chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(lH)-quinazolinone
[0042]
[0043] A solution of 10.0 g (0.285 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylruea in
50 ml ethanol was refluxed 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)quinazolinone
as colorless crystals: m.p. 209-211°. The
1H nmr spectrum shows the presence of an ethyl group in addition to aromatic hydrogens.
[0044] Anal. Calc'd. for C
22H
19ClN
2O
2: C, 69.74; H, 5.05; N, 7.40
[0045] Found: C, 70.12; H, 5.05; N, 7.35
Part B. 6-Chloro-4-phenyl-2(1H)quinazolinone 3-Oxide
[0046]
[0047] A mixture of 3.51 g (0.0093 mole) of 6-chloro-4
- ethoxy-3,4-dihydro-3,4-diphenyl-2(1H)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 ethanol, and dried in air to give
1.82 g (72%) of 6-chloro-4-phenyl-2(lH)quinazolinone 3-oxide as yellow crystals, m.p.
267-269°.
EXAMPLE 8
6-Chloro-4-phenyl-2(1H)quinazolinone 3-Oxide
[0048]
[0049] 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 hydroxylamirie 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 as yellow crystals, m.p. 267-269°.
EXAMPLE 9
6-Chloro-4-phenyl-2(1H)quinazolinone 3-Oxide
[0050]
[0051] A stirred mixture of 2.89 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone
and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of 2-methoxyethanol
(ethylene glycol monoethyl ether) was refluxed for 2 hours, and then cooled to 0°.
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)quinazolinone 3-oxide as yellow
crystals, m.p. 267-269°.
EXAMPLE 10
Part A. 6-Bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(lH)quinazolinone
[0052]
[0053] A solution of 14.70 g (.053 mole) of 2-amino-5-bromobenzophenone and 6.0 g (0.21
mol) of methyl 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)-quinazolinone
as a white crystalline powder: m.p. 293-294° (dec.) .
[0054] 1H nmr (DMSO-d
6) δ 2.66 ppm (s, 3H), 6.5-7.5 ppm (m, 8H).
[0055] Anal. Calc'd. for C
15H
13BrN
2O
2: C, 54.07; H, 3.93 N, 8.41
[0056] Found: C, 54.24; H, 3.89; N, 8.12
Part B. 6-Bromo-4-phenyl-2(1H)quinazolinone 3-Oxide
[0057]
A stirred mixture of 28.28 g (.085 mol) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-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 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°.
EXAMPLE 11
Part A. 6-Chloro-3-ethyl-4-(2-fluorophenyl)-3,4-di- hydro-4-hydroxy-2(lH)quinazolinone
[0058]
[0059] A mixture of 25 g (0.1 mble) of 2-amino-5-chloro-2'-fluorobenzophenone and 35.5 g
(0.5 mole) of ethyl isocyanate was refluxed for 20 hours, and then cooled. The solid
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 powder: m.p. 176-178° (dec.);
19F nmr (DMSO-d
6) -114.0 ppm; ir (KBr) at 6.24 p for C=O.
[0060] Anal. Calc'd. for C
16H
14ClFN
2O
2: C, 59.92; H, 4.40; N, 8.73
[0061] Found: C, 60.11;
H, 4.44; N, 8.83
Part B. 6-Chloro-4-(2-fluorophenyl)-2(lH)quinazolinone 3-Oxide
[0062]
[0063] A stirred mixture of 18.0 g (0.056 mole) of 6-chloro-3-ethyl-4-(2-fluorophenyl)-3,4-dihydro-4-hydroxy-2(lH)quinazoline,
11.8 g (0.17 mole) of hydroxylamine hydrochloride, and 280 ml of ethanol was refluxed
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-fluorophenyl)-2(lH)quinazoline 3-oxide as a yellow crystalline powder; m.p. 268-270°
(dec.);
19F nmr (DMSO-d
6) 6 111.1 ppm.
[0064] Anal. Calc'd. for C
14H
8ClFN
2O
2: C, 57.85; H, 2.77; N, 9.64
[0065] Found: C, 58.01; H, 2.83; N, 9.59
[0066] Table I shows additional ureas and hydroxyquinazo- linones which can be prepared
by the process disclosed and exemplified above using the appropriate aminobenzophenone
and a suitable organic isocyanate.
[0067] 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.