JPS60237055A - N-arylphthalamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 and R3 are lower alkyl; R2 is straight chain or branched alkoxycarbonyl; R4-R6 are H, halogen, alkyl, alkoxyl, CF3, NO2, dialkylamino or R4 and R5 together may represent methylenedioxy). EXAMPLE:4-Ethoxycarbonyl-3,5-dimethyl-2-[N-( alpha,alpha,alpha-trifluoro-o-tolyl )carbamoyl] benzamide. USE:An intermediate for preparing compounds useful as a vasodilator, ameliorant of blood stream, hypotensive agent or antiarteriosclerotic agent. PREPARATION:A phthalisoimide derivative having the corresponding group of formulaII, e.g. 5-methoxycarbonyl-4,6-dimethyl-3-(alpha,alpha,alpha-trifluoro-o, m- or p- tolylimino)phthalide, is ammonolyzed to give the aimed compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the formula (wherein R4 and R5 are lower alkyl groups, R2 is a linear or branched alkoxylic M-nyl group, and R
4, R5 and R6 are each a hydrogen atom, a halogen atom,
Alkyl group, alkoxyl group, trifluoromethyl group,
means a nitro group and a dialkylamino group, provided that R4
and R5 may together represent a methylenedioxy group).

The compound of formula (1) provided by the present invention is a compound useful as a vasodilator, a blood flow improving agent, an antihypertensive agent, or an antiarteriosclerotic agent.
p-fluorophenyl) -5,? -dimethyl-2.4
(IH,3H)-quinazolinedione, 3-(O-riprophenyl)-6-nitoxycaryl-5,7-nomethyl-1-(2-py<lidinoethyl)-2,4
, 3H)-quinazolinedione, 6-ethoxycarbonyl-5,7-di, Ifyl-1-[3-(4-phenethyl-1-piperazinyl)propyl)-3-(α, α, α-
trifluoro-)lyl)-2,4(],H,3H)
Quinazolinedione and 6-ethoxycarbonyl-1-
[3-[:4-(p-fluorophenethyl)-1-piveranonyl]propyl]-5,7-simethyl-3-(α,
α,α-trifluoro-tolyl)-2,4(LH
,3H)-quinazolinedione etc.
) Quinazolinedione derivative (!Jf!f
1375, JP-A-56-164172, JP-A-57-7
471, JP-A-57-14580, JP-A-57-280
67, JP 57-28068, JP 57-3167
0, JP-A-57-197269, JP-A-57-2066
65 and JP-A-57-212178).

That is, the compound of formula (1) provided by the present invention can be prepared by reacting with a halogen in the presence of an alkali to form 2.4 (IH, 3H) as described in the above-cited patent specification.
)-quinazolinedione without substitution at the 1-position (It) can be easily produced. Furthermore, it goes without saying that a substituent can be appropriately introduced into the 1-position of the compound of formula (It) according to the content described in the above-cited patent specification, as desired by Koran's six months. .

The above reaction is represented by the following general formula (in the formula R4
. The derivative has a general formula (in the formula R4,
It can be produced by ring-closing condensation of a urea derivative obtained by reacting a phenyl isocyanate derivative represented by
161375 and JP-A-57-28067), the compound of formula (2) used as a starting material is 4'-alkoxycaromyl-3,5-dialkyl phthalate (5) limide. Hofmann rearrangement reaction (written by Fuguchi and Ishiyuki, Tokyo Medical and Dental University, Medical Instruments Research Institute Report, vol. 11, p. 55, 1)
977) or 2,4-dialkoxycarbonyl-
It is obtained by Curchis rearrangement reaction of acid azide of 3,5-dialkylbenzoic acid (Japanese Patent Application Laid-Open No. 83738/1983). However, in the production method using the Hofmann rearrangement reaction, isomers are the main products, and the yield of the desired compound of formula (to) is only 14%, and the separation and purification of 1% is also complicated. In addition, the production method using the Kurtis rearrangement reaction presents the greatest difficulty in handling because the intermediate acid azide compound is an explosive substance. Furthermore, the compound of formula (1) used as the other starting material is conventionally obtained by reacting the aniline derivative with phosgene, but phosgene is highly toxic to the human body, so its availability is extremely limited and it is not commonly used. It is difficult to find a suitable manufacturing method. However, according to the production method using the compound of formula (1) according to the present invention, formula (
A compound II) can be obtained.

In producing the compound of formula (1) according to the present invention (6
) can be obtained by ammonia decomposition of a phthalisoimide derivative having the substituent represented by the following general formula (wherein R1, R2, R,, R4, R5 and R6 have the above meanings) For example, the compound of the formula (2) is obtained by adding the aniline derivative 0 to the 7-talic anhydride derivative (2) having the substituent.
) to form a 7-thalimide derivative (■) (see specification (A) filed on the same day), which was then hydrolyzed to obtain a phthalanilide acid derivative (Do (see specification (B) filed on the same day), and It is produced by dehydration condensation (filed on the same day (see specification 0)).

(7) M (a) 0 (lx) (8) (In the formula, R,, R2, R3, R4, R5 and R6 have the above-mentioned meanings) Examples of the compound of formula (V) include 5-methoxycarbonyl -4,6-nomethyl-3-(α,α,α-trifluoro-, m- or p-1 lylimino)phthalide, 5-
Ethoxycarbonyl-4,6-nomethyl-3-(α, α
, α-trifluoro o-, m- or p-tolylimino)phthalide, 4,6-trifluoro-5-propoxycarbonyl-3-(α, α, α-trifluoro o-, m-
or p-)lylimino)phthalide, 5-impropoxycarbonyl-4,6-dimethyl-3-(α,α,α-trifluoro-, m- or p-tolylimino)phthalide, 5-butoxycarbonyl-4,6 -cymethyl-3-
(α, α, α-trifluoro-, m- or p-)
lylimino)phthalide, 5-isobutoxycarbonyl-
4,6-dimethyl-3-(α,α,α-trifluoro-, nl- or p-tolylimino)phthalide, 5-tert-butoxycarbonyl-4,6-nomethyl-3-
(α, α, α-Trifluoro-o-, m- or p-tolylimino) (9) Phthalide, 5-ethoxycarbonyl-4,6-dimethyl-3-phenyliminophthalide, 3-(o-.

m- or p-chlorophenylimino)-5-ethoxycarbonyl-4,6-dimethylphthalide, 3-(o-, m
- or p-bromophenylimino)-5-ethoxycarbonyl-4,6-nomethylphthalide, 5-ethoxycarbonyl-3-(o-, m- or p-fluorophenylimino)-4,6-nomethylphthalide, 5-ethoxy Carbonyl-4,6-dimethyl-3-(o-, m- or p
-) lylimino) 7thalide, 5-ethoxycarbonyl-
3-(o-.

m- or p-isopropylphenylimino)-4,6-
dimethylphthalide, 5-ethoxycarbonyl-3-(,
o-, m- or p-methoxyphenylimino) -4,
6-nomethylphthalide, 5-ethoxycarbonyl-4,
6-nomethyl-3-(o-, m-.

or p-nitrophenylimino)phthalide, 3-(o-
, m- or p-methylaminophenylimino)-5-
Ethoxycarbonyl-4,6-dimethylphthalide, 5-
Ethoxycarbonyl-4,6-di(10) Methyl-3-(3,4-methylenedioxyphenylimino)phthalide, 3-(2,4-13,4- or 2,6
-dichlorophenylimino) -5-ethoxycarbonyl-4,6-tumethylphthalide, 5-ethoxycarbonyl-3-(2,4-12,5-12,6-father is 3,4-difluorophenylimino) -4 , 6-tmethylphthalide, 3-(3-chloro-4-fluorophenylimino)
-5-ethoxycarbonyl-4,6-trimethylphthalide, 5-ethoxycarbonyl-4,6-trimethyl-3-
(2,6-xylylimino)phthalide, 3-(2-chloro-4- or 6-methylphenylimino)-5-ethoxycarbonyl-4,6-tmethylphthalide, 5-ethoxycarbonyl-3-(4-fluoro-3 -methylphenylimino)-4,6-tmethylphthalide, 3-(2,4
-12,5-1j: 3,4-dimethoxyphenylimino)-5-ethoxycarbonyl-4,6-tmethylphthalide, 3-(4-chloro-2-)! J Fluoromethylphenylimino)-5-ethoxycarbonyl-4,6-dimethylphthalide, 3-(2,4-dinitrophenylimino)-5-ethoxycar? Ni-4,6-dimethylphthalide, 5-ethoxycarbonyl-3-(4-fluoro-2
-nitrophenylimi/ ) -4,6-tmethylphthalide, 5-ethoxycarbonyl = 4,6-nomethyl-3
-(4-Nitro-2- or 3-trifluoromethylphenylimino)phthalide, 3-(3-10-4-noethylaminophenylimino)-5-ethoxycarbonyl-
4,6-trimethylphthalide, 5-ethoxycarbonyl-
4,6-trimethyl-3-(2,4,6-)dichlorophenylimino)phthalide, 5-ethoxycar? Nilu 4
,6-dimethyl-3- (2,4,5- or 2,4.6
'-)lifluorophenylimino)phthalide, 5-ethoxycarbonyl-4,6-nomethyl-3- (3,4
, 5-)dimethoxyphenylimino)phthalide, and the like.

When the compound of formula (V) is subjected to ammonia decomposition, it is preferable to carry out the decomposition in the presence of a suitable solvent.

Examples of solvents include water, alcohols (e.g. methanol, ethanol, isozolopanol, etc.), ethers (e.g. tetrahydrofuran, dioxane, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, etc.), and other dimethyl Various solvents such as formamide are used, and these solvents may be used alone or as a mixed solvent. In addition to the gaseous ammonia, ammonia water may be used, and any salts such as ammonium carbonate and ammonium chloride may be used, or a mixture thereof may be used.

The reaction conditions are not necessarily limited, but it is generally appropriate to carry out the reaction within the following ranges.

Molar ratio of the compound of formula (7) and ammonia: 1:0.8~
20, preferably 1:1-5; reaction temperature knee 10-20
0°C, preferably 0-100°C; reaction time = 0.1-5
0 hour, preferably 0.5 to 24 hours: Reaction pressure: normal pressure to 10 atm, preferably normal pressure to 3 atm; under stirring or non-stirring, with many special requirements for post-reaction post-treatment and purification of the target product. It is carried out as appropriate using a commonly used method.

(13) As described above, the compound of formula (1) of the present invention is 6-nidoxycardenyl-5,7-dimethyl-1-(3-(4-phenethyl-1-piperazinyl)propyl)-3-(α, α ,
α-trifluoroo-)lyl)-2,4(IH, 3
Although it is a useful compound as an intermediate for the synthesis of H)-quinazolinedione, etc., representative examples of the synthesis method of the compound of the present invention from a known compound and the synthesis method of the compound of the present invention to the known compound are described below. and will be explained more specifically. However, it goes without saying that these are merely examples for explanation and the present invention is not limited thereto.

Example 1 5-ethoxycarbonyl-4,6-cymethyk" 3-(
α,α,α-Trifluoro-0-tolylimino)phthalide To a solution of 4.265 m in 64 ml of dry dichloromethane is added, under water cooling, a solution of 371 ml of dry ammonia in 18 ml of dry dichloromethane.

The reaction mixture was stirred for 3 hours under water cooling, and then further stirred at room temperature for 15 hours. The resulting dull precipitate was filtered, washed with a small amount of ether, and then recrystallized from tet(14) dihydrofuran-n-hexane, with a melting point of 2.
4-ethoxycarginyl-3,5-tmethyl-2-('N-(α,α,α-trifluoro0
-)Ryl)carbamoyl)benzoic acid amide 3.68y
(Yield 82.8%) is obtained as white crystals.

Nuclear magnetic resonance spectrum: δ (ppm, d6-D
Measured in MSO) 1.32 (3H, triplet), 2.24
(3H, single line) 2.29 (3H, single line), 4.3
4 (2H, quartet) 7.0 to 8.8 (8I (, multiplet) Infrared absorption spectrum: ν(crn-', KB
r) 1720.1665, 1635, 1580, 151
0°1450.1400,1360,1310,129
0°1240.1190.1165,1120,105
5゜1030.950,905,890,850,76
5 Mass spectrum: r11//e 408 (M”), 391.37j, 362,346,3
42゜247.161 Examples 2 to 10 In place of 5-ethoxycarvinyl-4,6-nomethyl-3-(α,α,α-trifluoro-tolylimino)phthalide in Example 1, as shown in Table 1 was used. By performing the same operation using the compound of formula (V), the compound of formula (1) as shown in the table therein was obtained in a theoretical amount of 60 to 9, respectively.
Obtained with a yield of 0%.

(Example 11) To a solution of 500 m9 of 5-ethoxycarbonyl-3-(p-fluorophenylimino)-4,6-tmethylphthalide in 2 oml of tetrahydrone puran is added a solution of 28 mg of dry ammonia in 2 ml of methanol Q. The reaction mixture is stirred at 60°C for 6 Heat and stir for an hour.

The residue obtained by distilling off the solvent was diluted with tetrahydrofuran.
Recrystallization from n-hexane yields 368 m9 of 4-ethoxycarbonyl-2-[N-(p-fluorophenyl)carbamoyl]-3,5-tmethylbenzoic acid amide (yield 702%) with a melting point of 203-205°C. Obtained as white crystals.

Nuclear magnetic resonance spectrum: δ (ppm, d6-DMSO
)], 32 (3H, triple line), 2.22 (
3H, single line), 2.30 (3H1 single line), 4.35
(2) (, quartet), 68-8.4 (7H, multiplet)
, 10.3 (1-H, single line) infrared absorption spectrum (υ-1, KBr) 1720.1650,1,63
0,1505,1440°1400.1360,1,2
50,1230,1210゜1190.1,155,1
1.10,1,090,1030°1015.955,
895,860,830.810 mass spectrum: r
n/e 358 (M+), 341, 31.2, 296, 247
, 111 Example 12 5-ethoxycarbonyl-4,6-thumef-3-(p
-Nitrophenylimino)phthalide To a solution of 500 mg in 10 ml of tetrahydrofuran are added 260 m9 of 25% aqueous ammonia. After stirring the reaction mixture at room temperature for 3 hours, n-hexane is added. When the precipitated crystals were collected and washed with a small amount of ether, the melting point was 19.
4-ethoxycarbonyl-3,5-tumethyl-2CN-(p-nitrophenyl)cal-gumoyl] benzoin $7mide at 1-193°C 400 μm (yield 76.4%) is obtained as white crystals. .

Nuclear magnetic resonance spectrum; δ (ppm, d6-DMSO
(measured inside) 1.30 (3H, triple line), 2.20 (3H
, single line), 2.30 (3H, single line), 4,37 (
2H, quartet), 7.2 to 8.4 (7H, multiple weight),
10.86 (I H, single line) infrared absorption spectrum (Crn-1, KBr) 1720.1670,15
90,1,530,1500゜1400.1335,1
300,1250,1190゜1105.1,035,
900,850 mass spectrum = rrI/e 368(M+-17), 338, 323, 24
7, 218.202°38 Example 13 3-(2-chloro-4-methylphenylimino)-5-
Ethoxycarbonyl-4,6-tmethylphthalide 37
To a solution of 2 m9 in 5 ml of dimethylformamide add 136 ~ of 25% aqueous ammonia.

The reaction mixture was stirred at room temperature for 1 hour and then added to 30 ml of water. When the precipitated crystals were collected and washed with a small amount of water and ether, 2-CN-C2- with a melting point of 266-270°C was obtained.
Chloro-4-methylphenyl)carbamoyl)-4-ethoxycarbonyl-3,5-dimethylbenzoic acid amide
248 my (yield 640%) is obtained as white crystals.

Nuclear magnetic resonance spectrum: δ (ppm, d6-DMSO
(measured inside) (23) 1.33 (3H, triple line), 2.3 ], (9H,
single line), 4.38 (2H, quartet), 7.2-8.0
(6H, multiplet), 9.81 (i H, single line) Infrared absorption spectrum /l/: I/ (cfn”,
KBr) 1720.1,660,1635,1600,
1560°1510.1480,1440,1,385
．． 1290°1245.1235,1190,1110
,1030°955.880,865,850,820
Mass spectrum: m/e 371 (M"-17), 336, 326, 308, 24
7゜41 Example 13 3-(o-Bromophenylimino)-5-ethoxycarbonyl-4,6-trimethylphthalide Ammonium chloride 1.30 m9,) IJ ethylamine 250 m in solution in 500 Da of tetrahydro7 run 10rnl
9 and 1'ml of water. After stirring the reaction mixture at room temperature for 1 hour, n-hexane was added. When the precipitated crystals are stabilized and washed with a small amount of ether, the melting point is 218~2.
361 m9 (yield 69.2%) of 2-(N-(o-pro(24)mophenyl)carbamoyl)-4-ethoxycarbonyl-3,5-tmethylbenzoic acid amide at 20°C is obtained as white crystals.

Nuclear magnetic resonance spectrum: δ (ppm, measured in CDC13) 1.4.0 (3H, triplet), 2.38 (3H
, single line), 2.42 (3H, single line), 4.44 (
2H, quartet), 5.7 (IH, broad), 6.
3 (IH, broad), 69-8.4 (5H, multiplet) Infrared absorption spectrum (c!n-1, KBr) 17
20.1660, 1640, 1580, 1520°14
60.1435,1300,1,270,1245゜1
190.1130,1110,1025,900°85
0.755 Mass spectrum: m/e 401 (M-17), 356,322,294,24
7゜71 Reference Example 1 A solution of 4-ethoxycarbonyl-3,5-tumethyl phthalic anhydride 298y in 18 ml of acetic acid contains α, α, α.
-Trifluoro0-)Luidine Add 231 and 17
Heat to reflux for an hour. When the reaction mixture was cooled to room temperature and the precipitated solid was washed with 2 ml of toluene, the melting point was 1.
4-ethoxycarbonyl-3,5-dimethyl-N-(α,α,α-trifluoro-tolyl)phthalimide at 94-196°C is obtained as 407F (yield: 868%).

Nuclear magnetic resonance spectrum: δ (ppm, CDC), measured in ) 1, . 42 (3H, triple line), 2.48 (3
H, single line), 2.69 (3H, single line), 4.48
(2H, quartet), 7.3-8.0 (5H, multiplet) Infrared absorption spectrum (m-', KB r )
1770.1720,1600,1500,1455゜1.380,1315,1275,1260,1205
゜1180, l 1.60, 1130, 1060, 10
40°870.770.750 Mass spectrum: m/e 391 (M”), 37], 362,346,342
, 131 Reference Example 2 (4-ethoxycarbonyl-3,5-dimethyl-N-(α
To a solution of ,α,α-trifluoro0-)IJl)phthalimide 196F in 30 ml of tetrahydrofuran are added sodium hydroxide 2407/9 and 6 ml of water under water cooling, and the mixture is stirred for 5 hours. 2N to the reaction mixture
After adding hydrochloric acid to adjust the pH to 3, the solvent was distilled off, water was added to the resulting residue, and the mixture was extracted with dichloromethane.

Dry the dichloromethane extract with anhydrous sodium sulfate,
The solvent is distilled off. The residue was recrystallized from tetrahydrofuran-n-hexane to give 4-ethoxycarbonyl-3,5-methyl-2-[N-(α
, α, α-trifluoro-)IJl)carbamoyl]benzoic acid (yield: 824).

Nuclear magnetic resonance spectrum: δ (ppm, d6-DMSO
) 1.32 (3H1 triplet), 2.22 (3
H, single line), 2.31 (3H, single line), 4.38 (
2H, quartet), 73-8.2 (5H, multiplet), 10
．． 01 (LH, single line), 13.2 (IH, broad) Infrared absorption spectrum (m-1, KB r ) 17
25.1695, 1660, 1585, 1525°14
55.1,320,1295,1275,1255゜(
27) 1160.1125,1110,1060,1015°955.900.855.800.770 Mass spectrum: m/e 391 (M+-18), 371. ．． 362.346.
342.

248.1.61 Reference Example 3 4-ethoxycarbonyl-3,5-dimethyl-2-CN
-(α,α,α-trifluoro-o-)lyl)carbamoyl]benzoic acid 409F in dry dichloromethane 175
Add thionyl chloride to the solution in mlJ under water cooling.
Add a solution in 2 ml of dry dichloromethane. After stirring the reaction mixture at room temperature for 3 hours, 100ml of water was added.
1, then 168 g of sodium hydrogen carbonate and extraction with dichloromethane.

The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The yellow oily substance obtained by distilling off the solvent is dissolved in n-hexane and left to stand, resulting in a 5%
-ethoxycarbonyl-4,6-nomethyl-3-(α,
α,α-trifluoro-tolylimino)phthalide
3.34F (yield 85.4%) is obtained as (28) as pale yellow crystals.

Nuclear magnetic resonance spectrum: δ (ppm, CDC), measured in ) 1.44 (3H1 triplet), 2.48 (3H,
- double line), 2.76 (3H, - double line), 4.48 (
2H, quartet), 7.2 to 7.9 (5H, multiplet) Infrared absorption spectrum: l/(crn-1, KBr)
1800.1715, 1690, 1590, 1570°1480', 1445.1380.1360.1330
.

1305.1280,1270,1240,1200゜11.70,1160,1150,1120,1100
゜1085.1050,1030,990,950,9
20°890.860.835.820.790.78
0.

770.760 Mass spectrum: m/e 391 (M), 372,362,346,342,3
34°22 Reference Example 4 To a solution of potassium hydroxide at 8.96F in 7 ml of water, 6.2F of bromine is added dropwise while maintaining the temperature at -5 to 0°C.

Then, 4-ethoxycarbonyl-3,5-dimethyl-
2-('N-(α,α,α-trifluoro-o-)lyl)carbamoyl]benzoic acid amide 408y is added little by little. After stirring the reaction mixture at -5 to 0°C for 8 hours, hydrogen sulfite (6.9F) and water are added. Neutralize with acetic acid and extract with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. When the solid obtained by distilling off the solvent is recrystallized from ethanol, 6-nidoxycar? Nilu-5,7-nomethyl-3-
(α, α, α-trifluoro-tolyl) -'2.
4(If(,3H)-quinazolinedione 2.85F(
A yield of 70.2%) is obtained.

Infrared absorption spectrum ((7)-1, KBr) 17
15.1665, 1605, 1585, 1495°14
40.1370, 1310, 1265, 1205°11
70.1160, 1150.1125, 1075°10
55.1030,890,860,790,760 Agent Sei Kikuchi -

Claims (1)

[Claims] General formula (wherein R1 and Rs are lower alkyl groups, R2 is a linear or branched alkoxycarbonyl group, R4
, R, and R6 each represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxyl group, a trifluoromethyl group, a nido group, and a dialkyl group, provided that R4 and R5 together represent a methylenedioxy group. N-arylphthalamide derivatives represented by