US3446804A - 3,4-dihydroxybenzoxazinones and process for their production - Google Patents

Description

United States Patent Oflice ABSTRACT OF THE DISCLOSURE The present invention describes 3,4-dihydroxybenzoxazinones of the formula:

Ra Ra wherein R R R and R are described below.

These compounds are useful as anti-inflammatory agents.

This invention relates to compositions of matter. More particularly, this invention relates to new and novel 3,4- dihydroxybenzoxazinones and process for their production.

The new and novel 3, 4-dihydroxybenzoxazines may be represented by the formula:

wherein R may be straight or branched chain lower alkyl of 1 to 6 carbon atoms; lower alkenyl such as alkyl, methylallyl, dimethylallyl; cycloalkyl such as cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, and the like; R may be in which R, has the same significance as R Nasol is which R may be lower alkyl of 1 to 6 carbon atoms,

lower alkoxy of 1 to 6 carbon atoms, halogen, nitrogen, and the like; imides such as 3,446,804 Patented May 27, 1969 and the like; malonic esters such as (IS-002E;

p-keto esters such as 0 JL-C'Ha 0-0 Calls 1% aliphatic, aryl or aralkyl 1,3-diketones such as cycloaliphatic 1,3-diketones such as a 91: H3 H I)n in which n is from 1 to 4; 1,3-cyclohexanedione, 1,3-cyclopentanedione, cycloaliphatic ketones such as 0 cyclopentanone, cyclohexanone, cycloheptanone and methylcyclohexanone; aliphatic ketone such as Z-butanone, Z-pentanone, 2-hexanone and the like; aliphatic halo ketones such as o fi-ketonitriles,

C-CHa aryl ketones such as 0 CH2( --CqH5 aralkyl ketones such as amigm substituted phenols such as lower alkyl substituted phenols, nitro or halo substituted phenols and the like; aliphatic 1,2-diketones such as and cycloaliphatic 1,2-diketones such as 1,2-cyclohexanedione, 1,2-cycl0pentanedione, 1,2-cycloheptanedione, 1,2-

The symbols R R R R R R R and R used 10 hereinafter have the same meaning as defined above.

Exemplary of the compounds of this invention are tabulated below:

The compounds of this invention are useful as antiinflammatory agents. For example, in a test for determination of anti-inflammatory activity in warm-blooded mammals such as mice employing a procedure described by ODriscoll et al., Canadian Journal of Physiology and Pharmacology, volume 42 (1964), it was found that some of the compounds are capable of suppressing lung inflammation in albino mice to a marked degree and in some instances to an extent estimated to be up to 55.2% over untreated mice. Accordingly, these compounds are useful in treating the inflammatory process either systemically or locally. In use, the compounds of this invention are combined with an inert pharmaceutical diluent to form TABLE I N-R1 R R R2 R3 MLP C 1 CH3 CH NCONHCH H 156-157 2 CH --NHGOOC2H5 H 167-168 3 CH -N'HCOOC2H5 6-Cl 190-191 4.-.--- CH -NHCOOC2H5 7-OCONHCH3 I! 175-178 5 CH -NHCOOC-2H5 8-OCH3 166-167 6 CHzCH=CH2 NHCOOG2H5 H 113-114 7--. CH N(CH:;) COOCzHs H 49. 5-51 8 CH3 NHSO C5H5 1'1 5 203-204. 5

9 CH; N\ H 181-183. 2

on, 10..-... CH3 H l 196-197 CH COCHCO CH3 H 136-138 -CH3OOCHOOOC2H5 H 140,141 CH;COCHCOC5H5 H a 163,165 -CH:OO C O OH: H 143-144. 5

-CHCO ("JCN H 166-161 16".-- CH3 --CH2COCH3 H 95-965 17--- CH; --CH2COCH4C1 H 162,164

18..... CH: -GH2C 0-6-0113 H 153-154 f 20-..-. CH: 0 H 123-124 21..... CH: O H 130-131. 5

22..-" CH; S H 136-137 23 OH; -0H H 219-220 24..- CHaGH=CHa -NHCOO CaHr 6-01 3 156,158

I Melts with decomposition.

dosage forms such as tablets, capsules, elixirs, suspensions, suppositories, parentals and the like with the active ingredient being present in an amount from 1 mg. to 1000 mg. per dosage unit. The compounds of this invention may also be combined with other known therapeutic agents, for example, steroids such as Bmethasone, [3-methasone-17-valerate, prednisolone, cortisone and the like, analgesics such as aspirin, tranquilizers such as the 1,4-benzodiazepines, antibiotics such as neomycin, colymycin, anti-histamines such as chlorpheniramine and the like to enhance and broaden their therapeutic spectrum. The compounds of this invention are useful as intermediates for the production of other novel compounds as exemplified by the following reactions.

(1) Treatment with NaOR Treatment of compounds exemplified by Formula I with sodium hydroxide in an alcohol such as methanol causes ring opening to give compounds of type V:

R] R2 R3 /\'/\N R1 on. III-R1 R4 R4 000R.

(2) Reduction Compounds having a ketone group may be reduced to alcohols by sodium borohydride to give compounds of type VI:

CIH2COCH3 In turn compounds of type VI may be converted by reaction 1 to compounds of type V.

(3) Conversion to other heterocycles Compounds having 1,2 and 1,3-dicarbonyl groups may be converted to other heterocycles, for example:

These compounds will form the basis of further applications.

According to the process of this invention, the compounds are prepared by reacting compounds of the Formula II:

with any compound having an active hydrogen atom. Thus, they are reacted with a compound of the formula R H wherein said active hydrogen is attached to the bond of, for example, NH COOR or H NSO O H The reaction is conducted in an inert solvent such as benzene, toluene, chloroform or tetrahydrofuran in the presence of an acidic catalyst such as p-toluene sulfonic acid; the reaction is effected byheating together the reactants in a suitable vessel. It is preferable, in some instances, to include in the reaction vessel provision for effecting simultaneous azeotropic distillation of the solvent to remove the water formed thereby expediting the completion of the reaction. A suitable device for water removal is a Dean-Stark trap. The desired reaction products are recovered by simply evaporating the reaction mixture to dryness and recrystallizing the product from a suitable solvent such as ethyl acetate, methanol, ethanol, cyclohexane and the like.

The starting materials used in the above reaction are prepared in accordance with directions given by R. E. Strube et al., Recueil 83 No. 9-10, p. 1191 (1964).

It has also been found that in carrying out this reaction, Compound II itself reacts to form compounds of the Formula III:

III

Compounds corresponding to III are not within the scope of this invention but will form the basis of a further application.

In order to further illustrate the invention, the following examples are given. All temperatures are given in degrees centigrade and room temperature is at 20 to 30 C.

EXAMPLE 1 N-CHa I N BS024 4-benzenesulfonamido-3,4-dihydro-3-methyl- 2H-1,3-benzoxazin-2-one A solution of 6.0 g. of 3,4-dihydro-4-hydroxy-3- methyl-2H-1,3-benzoxazin-2-one and 5.25 g. of benzenesulfonamide in 300 ml. of anhydrous benzene is refluxed for two hours, whereas 0.60 ml. Water is collected in a Dean-Stark trap. After cooling, the white crystals are filtered olf to give 9.2 g. of 4-benzenesulfonamido-3,4-dihydro-3-methyl-2H-1,3 benzoxazin 2 one, M.P. 20l- 203. Concentration of the filtrate to about 15 ml. and cooling gives an additional crop of 1.1 g. of white crystals, M.P. 201-203"; yield 97%. Recrystallization from ethyl acetate gives analytically pure, white ciystals, M.P. 203-2045;

13.12? y (6) 215 14,500), 260 8.11. (1,250), 265 (1,680), 272 (1,450); 11%;? 721 (1118.), 750 (ms), 786 (111.), 995, (ms), 1045 (111.), 1150 (s.), 1242 (s.), 1310 (s.), 1360 (111.15.),1440 (s.), 1695 (V.S.), 3200 (111.) 616: vg jgP 1161 (s.), 1200 (111.), 1233 (s.), 1735 (v.s.), 2000 (111.), 3090 (111.), 3580 (w.) 01117 Analysis for C H N O S: Calcd: C, 56.59; H, 4.43; N, 8.80; S, 10.07; Found: C, 56.50; H, 4.39; N, 8.91; S, 10.16, 10.03.

EXAMPLE 2 N-CHa 4- (4,4-dimethyl-2,6-dioxo cyclohexyl) -3,4-dihydro-3 methyl-2H-1,3-benzoXazin-2-one A solution of 7.7 g. of 3,4-dihydro-4-hydroXy-3- methyl-2H-1,3-benzoxazin-2-one and 6.0 g. of dimedone in 250 m1. of anhydrous benzene is refluxed for one half hour, whereas 0.70 ml. of water is collected in the Dean- Stark trap. After cooling to room temperature and filtering 12.3 g. of 4-(4,-dimethyl-2,6-dioxocyclohexyl)-3,4- dihydro-3-methyl-2H-1,3-benzoxazin 2 one, M.P. 196- 196", decomp. are obtained. Concentration of the filtrate to a low volume and cooling gives 0.3 g. 01 an additional crop, M.P. 195-196, total yield: 97%. Recrystallization from ethyl-acetate-ethanol (1:1) gives analytically pure, white crystals, M.P. 196-197, dec.; 1222? my (6) 261 (13,900), k 233 (5,000); 11:34? 740 ms.) 733 (111.), 1038-1021 (split, s.), 1126 (s.), 1150 (s.), 1200 (s.), 1220 (V.S.), 1320 (s.), 1342 (s.), 1496 (111.), 1546 (1n.s.), 1600 (1:11.), 1626 (m.), 1722 (v.s.), 1920-1840 (wide band, 111.), 2600-2200 (wide band, In). GEL-1; 43, 1 7600-7380 (wide band, v.s.), 1128 (111.), 1202 (111.s.), 1236 (v.s.), 1272 (111.), 1372 (8.), 1460-1400 (wide band, s.), 1498 (111.), 1625 (vs), 1723-1708 (v.s.), 2500 (1115.), 2830 (1118.), 3000 s.h. (111.) 01117 Analysis for C H NO Calcd: C, 64.36, H, 5.79; N, 5.36. Found: C, 64.34; H, 5.91;N, 5.36.

EXAMPLE 3 4- (2,4-dioxo-3-pentyl) -3,4-dihydro-3-methyl- 2H-1,3-benzoxazin-2-one A solution of 9.0 g. of 3,4-dihydro-4-hydroxy-3-methyl- 2H-l,3-benzoxazin-2-one, 12 mil. of acetylacetone and 0.025 g. of p-toluenesulfonic acid monohydrate in 2 00 ml. of anhydrous benzene is refluxed with provision for azeotropical removal of water (0.9 ml.) for one and a half hours. Concentration of the reaction to about 25 ml. and tcooling gvies 10.6 g. of 4-(2,4-dioxo-3- pentyl)-3,4-dihydro-3-methyl-2H-1,3-benzoXazin-2-one as white crystals, M.P. 135-137". Further concentration of the mother liquor to about 8 ml. gives an additional crop of 1.3 g. of off-white crystals, M.P. 134-136", total yield: 92%. Recrystallization of the first crop from 8 ethyl acetate gives analytically pure, white crystals, M.P. 136-138 A312? 114 (e) 271 sh. (5,000), 277 (5,250), 272-276 plateau (4,800); kfi fif 273-276 plateau (8,000), 279 (8,050), 288 (7,800); 112352 770 (8.), 1032 (111.5.), 1138 (1115.), 1180 (s.), 1222 (s.), 1258 (s.), 1357 (111.s.), 1592 (111.), 1608(s.),1722 (v.s.),1740 5. 5,9 3,8 1028 (ms), 1089 (m.s.), 1132 (m.s.), 1180 (s.), 1230-1210 (wide band, v.s.), 1357 (s.), 1398 (m.s.), 1460 (v.s.), 1493 (ms), 1740-1710 (wide band, v.s.), 2995 (111.), 3600- 3400 (wide band, w.) emf Analysis for C H NO Calcd: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.34; H, 5.91; N, 5.27.

EXAMPLE 4 Ethyl 2- (3,4-dihydro-3-methyl-2-oxo-2H-1,3- b enzoxazin-4-yl) acetoacetate A solution of 8.0 g. of 3,4-dihydro-4-hydroxy-3methyl- 2H-1,3-benzoXazin-2-oue, 7.8 g. of ethyl acetoacetate and 0.05 g. of p-toluenesulfonic acid monohydrate in 200 ml. of dry benzene is refluxed for two hours while 0.7 ml. of Water is collected in the Dean-Stark trap. The solvent is removed in vacuo, the residue is triturated with hot cycloheXane-ethyl acetate and cooled to give 11.3 g. of white crystals, M.P. 139-140". Concentration of the mother liquor to a low volume gives an additional crop of 1.9 g. of white crystals, M.P. 138-140"; total yield: 88%. Recrystallization [from ethanol gives analytically pure, white crystals, M.P. 140-141"; 323? 11114 251 33 275 '23??? 759 (s.), 850 (1n.s.), 1011 (111.), 1027 (111.), 1060 (m.), 1095 (111.), 1202 (s.), 1260-1220 (wide band, 1 .8.), 1400 (s.), 1425 (s.), 1496 (111.), 1640-1595 (wide band, v.s.), 1725 (v.s.); 149 33 854 (wide band, m.), 1025 (mm), 1054 (m.), 1098 (ms), 1260-1195 (wide band, v.s.), 1290 (111.s.), 1402 (s.), 1426 (s.), 1460 (s.), 1610 (s.), 1640 (v.s.), 17301700 (wide band, v.s.), 3980 (111.) cm.

Analysis for G i-1 N0 1 Calcd: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.85; H, 6.02; N, 5.00.

EXAMPLE 5 fiy 3,4-dihydro-3-methyl-4- (2,5 -dioxo-1-1pyrrolidinyl) -2H-1, 3 -ben zoXazin-2- one A solution of 5.37 g. of 3,4-dihydro-4-hydroxy-3- methyl-21H-1,3-benzoxazin-2-one, 3.0 g. of succinimide, and 0.03 g. of p-toluenesulfonic acid monohydrate is refluxed for one hour, while 0.50 ml. of water is collected in the Dean-Stark trap. The solution is filtered when hot and, after standing at room temperature for two days, 2.5 g. of 3,4-dihydro-3-methyl-4=(2,5-dioxo 1-pyrrolidinyl)-2.H-1,3-benzoxazin-2-one as analytically pure, white crystals are obtained, M.P. 182-183". Evaporation of the filtrate to dryness and recrystallization of the residue from ethyl acetate gives an additional crop of 3.3 g. of white crystals, M.P. 181-182".

152,2? m (e) 213 inflection (8,400), 267 (1,200), 274.5 (1,200) 11252 742 (m.), 1042 (m.), 1097 (m.), 1128 (m.), 1178 (m.s.), 1208 (m.s.), 1238 (s.), 1350 (m.s.), 1707 (s.), 1723 (v.s.), 1774 111. 3560 (w.) GEL-1. 1255 1040 (m.), 1130 (m.s.), 1176 (5.), 1245-1200 (wide band, v.s.), 1302 (s.), 1313 (m.s.), 1346 (5.), 1400-1373 (split, 1115.), 1466 (s.), 1603 (m.), 1740-1700 (Wide band, v.s.), 1780 (m.), 3990 (m.), 3500 (w.) emf.

Analysis for C H N O Calcd: C, 59.99; H, 4.6 5; N, 10.77. Found: C, 59.70; H, 4.92 N, 10.68.

EXAMPLE 6 3,4-dihydro-3-rnethyl-2-oxo-2H-il,3-benzoxazin- 4-(cyclohexanone) A solution of 15.0 g. of 3,4-dihydro-4-hydroxy-3- methyl-2H-benzoxazin-Z-one, 25 ml. of cyclohexanone, and 0.05 g. of p-toluenesulfonic acid monohydrate in 250 ml. dry benzene is refluxed for 40 minutes during which time 1.5 ml. of water is collected in the Dean-Stark trap. The solution is evaporated to dryness in vacuo, the residue is dissolved in 450 ml. of ether-Skelly B (1:1), and concentrated to about 200 ml. On standing at room temperature for five days, 15.7 g. of 3,4-dihydro- 3-methyl-2-oxo-2H-1,3-benzoxazir1-4 (Zacyclohexanone) as white crystals are obtained, M.P. 1 50415 2". Concentration of the filtrate to about 50 ml. and cooling gives an additional crop of 2.9 g. of white crystals, M.P. 149- 152", yield 86%. Recrystallization from ethanol gives analytically pure, white crystals, M.P. 151.5-153";

15,32? m (6) 266.5 (1,020), 272.5 (960); 1 532 760 (s.), 1027 (m.) 1120 (m.s.), 1196-1186 (split, ms), 1232- 1221 (split, 8.), 1429 (m.s.), 1490 (111. 1705 (V.S.) 6111- 11 1022 (m.s.), 1093 111. 1124 (m.s.),

1232-1185 (wide band, 3.), 1402 (m.), 1430 (m.s.), 1459 (v.s.), 1490 (111.), 1730-1695 (Wide band, v.s.), 2820 (m.), 2900 (m.), 3420 (w.), 0111?.

Analysis for C H NO Calcd: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.56; H, 6.81; N, 5.16.

EXAMPLE 7 3,4-dihydro-4 -methyl-2-furyl -3-methyl- 2H-1,3-b enzoxazin-Z-one A solution of 20.0 g. of 3,4-dihydro-4-hydroxy-3- methyl- 2H-1,3-benzoxazin-2-one, 30 ml. of 2-methyl furan, and 0.2 g. of p-toluenesulfonic acid monohydrate is refluxed for one hour, while 2.0 ml. of Water are collected in the Dean-Stark trap. The solvent is removed in vacuo and the residue is recrystallized from ethanol to give 19.0 g. of 3,4-dihydr0-4(S-methyl-Z-furyl)3-rnethyl- 2H1,3-benzoXazin-2-one as analytically pure, white, shiny needles, M.P. 130-1315". Concentration of the mother 10 liquor to a low volume gives 5.4 g. of an additional white product, M.P. 129-131 total yield:

EXAMPLE 8 3,4-dihydro-4-(2-furyl)-3-methyl-2H-1,3- henzoxazin-2-one The reaction is carried out in the same way as with Z-methyl furan (Example 7) except that the ethyl acetate is used as a recrystallization solvent. Thus, the mixture 0f 15 g. of 3,4-dihydro -4-hydroxy-S-methyl-ZH-1,3-benzoxazin-Z-one, 25 ml. of furan, and 0.025 g. of p-toluenesulfonic acid monohydrate in 250 ml. of dry benzene gives 18.0 g. (94% yield) of 3,4-dihydro-4-(2-furyl)-3- methyl-2H-1,3-benzoxazin-2-one as white crystals, M.P. 123-'l24;

15.12? 11111 (1) 213 (15,600), 267 (1,000 1 331? 739 (s.), 757 (s.), 934 (m.), 1150 (m.s.), 1240-1221 (triplet, s.), 1394 (m.s.), 1430 (m.s.), 1495 (m.), 1506 (m.), 1602 (m.s.), 1668 (m.), 1703 (V.S.) CID-1; 15 55 932 (111. 1006 (m.s.), 1025 (m.), 1095 (m.s.), 1185 (m.s.), 1235-1195 (Wide band, v.s.), 1396 (s.), 1429 (s.), 1460 (v.s.), 1494 (m.), 1602 (m.), 1710 (v.s.), 2980 (111.) omf Analysis for C H NO Calcd: C, 68.11; H, 4.84; N,

6.11. Found: C, 68.38; H, 5.02; N, 6.16.

EXAMPLE 9 4-( l-acetonyl -3,4-dihydro-3-methyl-2H- 1,3-benzoxazin-2-one A solution of 6.0 g. of 3,4-dihydro-4-hydroxy-3-methyl- 2H-1,3-benzoxazin-2-one, 25 ml. of acetone, and 0.02 g. of p-toluenesulfonic acid monohydrate in 250 ml. of dry benzene is refluxed for two hours, while 0.6 m1. of water separates in the Dean-Stark trap. The solvent is evaporated and the residue is recrystallized from ethyl acetate to give 6.0 g. of 4-( l-acetonyl)-3,4-dihydro-3-methyl-2H- 1,3-benzoxazin-2-one as pure, white crystals, M.P. 95- 96.5 Concentration of the mother liquor to a low volume gives an additional crop of 1.1 g. of white crystals (total yield: 86%), M.P. 94 96;

122.2? 11111 (4) 267 (1,040); vggi? 746 (111.), 746 (111.), 754 (m.s.), 1130 (m.), 1240 (s.), 1398 (m.), 1442 (s.), 1500 (m.), 1600 111. 1707 (v.s.) GILL-1; 1,9 5,3 1096 (m.), 1160 (m.), 1235-1190 (wide band, v.s.), 1362 (m.), 1402 (m.s.), 1435 (m.s.), 1402 (s.), 1712 (v.s.), 1725 (v.s.), 2990 (m.), cmf

Analysis for C H NO Calcd: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.72; H, 6.02; N, 6.47.

EXAMPLE CH2CCCH3 1 1 1-(3,4-dihydro-3-methyl-2-oxo-2H-1,3-benzoxazin- 4-yl) -2,3-butanedione A solution of 5.0 g. of 3,4-dihydro-4-hydroxy-3-methyl- 2H-1,3benzoxazin-2-one, 10.0 ml. of diacetyl, and 0.02 g. of p-toluenesultonic acid monohydrate in 150 ml. of anhydrous benzene is refluxed for three hours, whereas 0.45 ml. of water is collected in the Dean-Stark trap. The solvent is removed in vacuo and the yellow-orange solid residue is crystallized from ethanol to give 3.1 g. of 1- (3,4 dihydro 3-methyl-2-oxo-2H-1,3-benzoXazin-4-yl)- 2,3-butanedione as yellow crystals, M.P. 141-143. Recrystallization from ethanol gives 1.7 g. of analytically pure yellow crystals, M.P. l43144.5; 15.135 me (e) 267 (1,400); 1123? 745 (111.), 760 (m.) 1210 (m.), 1232 (m.s.), 1229 (s.), 1708 (v.s.), 1727 (s.) 5111- 12, 5,5 1210-1100 (wide band, s.), 1250 (m.s.), 1405 (m.), 1435 (111.), 1462 (3.), 1730-1710 (wide band, s.), 2990 (W.) emf Analysis for C H NO Calcd: C, 63.15; H, 5.30; N, 5.67. Found: C, 63.21; H, 5.59; N, 5.57.

N-OHa 4-(3-chloro-1-acetonyl)-3,4-dihydro-3-methyl-2H- 1,3-benz0xazin-2-one A solution of 15.0 g. of 3,4-dihydro-4-hydroxy-3- methyl-2H-1,3-benzoxazin-2-one, 10.0 g. of 2-chloropropanone, and 0.06 g. of p-toluenesulfonic acid monohydrate in 300 ml. of anhydrous benzene is heated for three hours, whereas 1.3 ml. of water is collected in the Dean-Stark trap. The solvent is removed in vacuo, and the residual yellow oil is triturated with ml. of ethanol to give 4.9 g. of 4-(3-chloro-1-acetonyl)-3,4-dihydro-3- methyl-2H-1,3-benzoxazin-2-one as white crystals, M.P. 155-160". Two recrystallizations from ethanol gives an alytcially pure, white crystals, M.P. 162164, decomp.;

A532? m (6) 268 (1,040); 1131353 757 (m.s.), 1233 (111.), 1251 (m.s.), 1440 (m.s.), 1714 (vs), 1742 (5.) 01115 19,33 1230-1133 (5., wide band), 1401 (m.s.), 14.34 (m.s.), 1461 (s.), 1740-1710 (v.s., wide band), 2980 (w.) cm.-

Analysis for C H ClNO Calcd: C, 56.82; H, 4.77; N, 5.52; Cl, 13.98. Found: C, 57.09; H, 4.92; N, 5.52; Cl, 13.95, 13.68.

EXAMPLE 12 NCH3 12 3,4-dihydro-3-methyl-4- (2-phenylacetonitril-2-yl) 2H-1,3-benzoxazin-2-one A solution of 10. 0 g. of 3,4-dihydro-4-hydroxy-3- methyl-2H-1,3-benzoXazin-2-one, 8.9 g. of 2-phenylacetoacetonitrile, and 0.02 g. of p-toluenesulfonic acid monohydrate in 200 ml. benzene is refluxed for 2 hours, while 1.0 1111. of water is collected in the Dean-Stark trap. The solvent is removed in vacuo. The semi-solid residue is refluxed with 200 ml. of ether of one hour and, on cooling, 14.2 g. of 3,4-dihydro-3-methyl-4-(Z-phenylacetonitril- 2-yl)2H-1,3-benzoxazin-2-one as white crystals is obtained, M.P. 159-160. Concentration of the mother liquor to a low volume gives an additional crop of 2.1 g. of White crystals, M.P. 157-159; yield: 91%. Recrystallization from ether-ethanol (2:1) gives analytically pure product, M.P. -161";

1253 m (6) 265.5 (15,050); 131 1 690 (115.), 735 (111. 752 (s.), 1038 (111.), 1226 (s.), 1494 (111.), 1713 (v.s.) dmr 1339 690 51. 1035 (m.), 1195 (111.), 1133 (s.), 1230-1200 (s., wide band), 1395 (m.s.), 1450 (m.s.), 1465 (m.s.), 1494 (m.s.), 1740-1708 (v.s., wide band), 3000 (m.) emf.

Analysis for C H N O Calcd: C, 71.24; H, 5.03; N, 8.75. Found: C, 70.95; H, 5.32; N, 8.50.

EXAMPLE 13 3,4-dihydro-3-methyl-4-(p-methylphenacy1)-2H 1,3-benzoxazin-2-one A solution of 10.0 g. of 3,4-dihydro-4-hydroxy-3- methyl-2H-1,3-benzoxazin-2-one, 9.0 g. of p-methylacetophenone, and 0.02 g. of p-toluenesulfonic acid monohydrate in 250 ml. of dry benzene is refluxed for one and a half hours with the azeotropical removal of water (1.0 ml.). Concentration of the mother liquor to about 50 ml. and cooling gives 9.1 g. of 3,4-dihydro-3-methyl-4-(pmethylphenacyl)-2H-1,3-benzoXazin-2-one as White crystals, M.P. 152-153". The mother liquor is evaporated to dryness, taken up with 40 m1. of hot methanol and cooled to give 4.6 g. of white crystals, M.P. 15l-152, total yield 88%. Recrystallization from methanol gives analytically pure product, M.P. 153-154;

13. 3 m (6) 255.5 (15,700 12 5 75 1 (m.s.), 790 (m.), 1234 (m.s.), 1430 (m), 1609 (111.), 1577 (s.), 1712 (v.s.) 01117 1135,? 1228 (s.), 1403 (m.s.), 1430 (m.s.),

1451 (s.), 1009 (m.s.), 1532 (5.), 1730-1710 (v.s., wide band), 2980 (170.) 01117 Analysis for C18H17NO3Z Calcd: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.35; H, 5.91; N, 4.61.

EXAMPLE 14 3,4-dihydro-3-methyl-4- Z-thienyl) -2H- 1,3-benzoxazin-2-one 1710-1690 (wide band, v.5. 5111- 1,255,9 12354133 (wide band, s.), 1395 (m.s.), 1428 (m.s.), 1456 (s.),

1490 (m.), 1599 (ms), 1619 (w.), (v.s.), 2960 (m.) cm."

Analysis for C H NO S: Calcd: C, 63.65; H, 4.52; N, 5.71; S, 13.07. Found: C, 63.91; H, 4.57; N, 5.83; S, 13.16, 13.05.

EXAMPLE 3,4-dihydro-4-(p-hydroxyphenyl)-3-methyl-2H- 1,3-benzoXazin-2-0ne A solution of 8.0 g. of 3,4-dihydro-4-hydroxy-3-methyl-2H-1,3-benzoxazin-2-one, 4.2 g. of phenol, and 0.02 g. of p-toluene-sulfonic acid monohydrate in 200 ml. of dry chloroform is refluxed for two hours, while 0.8 m1. of water is collected in the Dean-Stark trap. Concentration of the solution to about 25 ml. and cooling gives 7.6 g. of 3,4-dihydro-4-(p-hydroxyphenyl)-3-methyl 2H-1,3- benzoxazin-Z-one as white crystals, M.P. 213215. Recrystallization from methanol gives analytically pure, shiny crystals, M.P. 219-220;

15.22. mg (6) 231 (13,450), 269 (2,320), 276 (2,520), 234 5.11. (1,440); 15, ,3 733 (1115.), 313 (111.), 1222 (5. 1513 (111.), 1596 (1115.), 1615 (111.), 1680 (v.s.), 3120 (111.) 5111- 1333 754 (1115.), 325 111. 1196 (1115. 1220 (v.s.), 1510 (ms), 1594 (m.s.), 1010 (m.), 1720 (v.s.), 31002750 (wide band, 111.), 3420 (m.s.) cmf Analysis for C H NO Calcd: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.88; H, 5.34; N, 5.21.

EXAMPLE 16 4-(1-acetylphenacyl)-3,4-dihydro-3-methyl-2H- 1,3-benzoxazin-2-one A solution of 7.0 g. of 3,4-dihydro-4-hydroxy-3-methyl-2H-1,3-benzoxazin-2-one, 6.3 g. of 1-phenyl-1,3-butanedione, and 0.02 g. of p-toluenesulfonic acid monohydrate in 180 ml. of chloroform is refluxed for one and a half hours, while 0.65 ml. of Water is collected in the Dean- Stark trap. The solvent is removed in vacuo. The colorless semi-solid residue is crystallized from methanol to give 5.3 g. of 4-(I-acetylphenacyl)-3,4-dihydro-3-methyl- 2H-1,3-benzoxazin-2-one as analytically pure white crystals, M.P. 163-165 decomp. Concentration of the mother liquor to a low volume and cooling gives an ad- 14 ditional crop of 2.3 g. of white crystals, M.P. 163165, decomp.; 1 11111 (6) 253 (12,300 290 5.11. 2,000) 1959 1462 max.

(m.), 1596 (W.), 1678 (111.), 1725 (v.s.) cmf Analysis for C H NO Calcd: C, 70.57; H, 5.30; N, 4.33. Found: C, 70.44; H, 5.40; N, 4.55.

EXAMPLE 17 (METHOD A) N-CHa CHaN-(f-NHCHB 1- (3,4-dihydro-3-methyl-2-oxo-2H-1,3-benzoxazin-4-yl 1,3-dimethylurea A solution of 8.0 g. of 3,4-dihydro-4-hydroxy-3-methyl- 2H-1,3-benzoxazin-2-one, 4.3 g. of 1,3-dimethylurea, and 0.01 g. of p-toluenesulfonic acid monohydrate in 180 ml. of anhydrous benzene is refluxed for one half hour, while 0.8 ml. of water separates in the Dean-Stark trap. The solution is concentrated to about ml. and, on cooling, 8.7 g. (83%) of 1-(3,4-dihydro-3-methyl-2-oxo-2H-1,3- benzoxazin-4-yl)-1,3-dimethylurea as White crystals is obtained, M.P. 154156. Recrystallization from ethyl acetate gives an analytically pure product, M.P. 156157;

A223? m (5) 267 (1,190), 274 (1,150); 1 ,132 1230 (s.), 1308 (s.), 1540 (s.), 1626 (v.s.), 1730 (v.s.), 1736 (v.s.), 3320 111. 551: 13, 3,5 1240-1200 (wide band, v.s.), 1298 (v.s.), 1396 (s.), 1455 (v.s.), 1526 (v.s.), 1660- 1632 (wide band, v.s.), 1734-1710 (wide band, v.s.), 2990 (111.), 3330 (w), 3420 (11.) 5111- Analysis for C H N O Calcd: C, 57.82; H, 6.19; N, 16.86. Found: C, 58.14; H, 6.19; N, 16.61.

EXAMPLE 17 (METHOD B) A solution of 4.0 g. of 3,4-dihydro-4-hydroxy-3-methyl- 2H-l,3-benzoxazin-2-one, 3.54 g. of methyl isocyanate and 5 drops of triethylamine in 30 ml. of tetrahydrofuran is allowed to stand at room temperature. After a period of three days, 1.8 g. of 1-(3,4-dihydro-3-methyl-2-oxo- 2H-1,3-benzoXazin-4-yl)-1,3-dimethylurea as White crystals is obtained, M.P. 153-155". The solvent is removed in vacuo at 30, and the greenish residue is triturated with ethyl acetate to give an additional crop of 0.6 g. of White crystals, M.P. 152-155. Recrystallization from ethyl acetate gives pure product, M.P. 156-157". A mixed melting point with the analytical material obtained by method A is not depressed.

EXAMPLE 13 NHCOOEt Ethyl 3,4-dihydro-2-oXo-2H-1,3-benzoxazine-4-carbamate A solution of 1.0 g. of 3,4-dihydro-4-hydroxy-3-methyl- 2H-1,3-benzoxazin-2-one, 0.5 g. of ethyl carbamate, and 0.025 g. of p-toluenesulfonic acid monohydrate in 50 ml. of dry benzene is refluxed for one half hour, whereas 0.1 m1. of water is collected in the Dean-Stark trap. After the solvent is removed in vacuo, the residue is recrystallized from ethyl acetate to give 0.7 g. of ethyl 3,4-dihydro-2- oxo-2H-1,3-benzoXazine-4-carbamate as analytically pure, White, flufly crystals, M.P. 167-168;

713 ,12? 11114 (6) 267.5 (1,010), 274.5 (970); 1:33 761 (In. s.), 1035 (ms), 1236 (s.), 1525 (n1.s.), 1708 (v.s.), 1720 5. 3290 111. 1,9 5,3 1034 5. 1240-1200 (wide band, v.s.), 1466 (s.), 1502 (v.s.), 1740-1700 (wide band, v.s.), 2990 (m.), 3300 (W.), 3440 (m.) (NIL-1.

15 Analysis for CHI-114N204: Calcd: C, H, N, 11.20. Found: C, 57.63; H, 5.69; N, 11.16.

EXAMPLE 19 C 1 i N-CHa NHC O OEt Ethyl 6-chloro-3,4-dihydro-3-methyl-2-o0(o-2H-1,3- benzoxazine-4-carbamate FE mu (e) 224 (10,460), 276 (1,450), 284 (1,300);

1 ,13 740 (m.s.), 832 (m.s.), 1031 (s.), 1238 (s.), 1513 (s.), 1535 (v.s.), 1732 (v.s.), 3230 (m.s.) 5111- VCHCIS m X. 314 (m.), 1023 (s.), 1240-1195 (wide band, v.s.), 1145 (s.), 1488 (v.s.), 1708 (v.s.), 1720 (v.s.), 2940 (m.), 3250 (w.), 338 (m.) cmf Analysis for C H ClNO Calcd: C, 50.63; H, 4.60; N, 9.84; Cl, 12.45. Found: C, 50.61; H, 4.75; N, 9.97; Cl, 12.51, 12.71.

EXAMPLE Z0 0 CH3-NH=C 0 oo N-GHa NHC o o E 1 Ethyl 3,4-dihydro-3-methyl-7-[ (methylcarb amoyl oxy] 2-oxo-2H-1,3-benzoxazine-4-carbamate A solution of 12.6 g. of 3,4 dihydro 4 hydroxy 7- [(methylcarbamoyl)oxy] 3-methyl 2H-l,3-benzoxazin- 2-one, 4.5 g. of ethyl carbamate and 0.02 g. of p-toluenesulfonic acid monohydrate in 250 ml. of chloroform is refluxed for two hours, while 0.9 ml. of water is collected in the Dean-Stark trap. The solvent is removed in vacuo and the residue is triturated with ethylene dichloride to give 8.5 g. of ethyl 3,4-dihydro-3-rnethy1-7- [(methylcarbamoyl)oxy] 2 oxo 2H 1,3 benzoxazine-4-carbamate as white crystals, M.P. 175-478". To the filtrate is added 25 ml. of ether, heated briefly and cooled, to yield 2.7 g. of an additional crop, M.P. 146- 147. Recrystallization of the first crop from isopropanol gives 4.9 g. of analytically pure, white crystals, M.P. 182-183;

it? m (e) 215 sh. (10,000), 268 (1,300), 275 (1,240); 55 1035 (m.s.), 1074 (m.s.), 1253 (s.), 1530 (m.s.), 1033 (s.), 1725 (v.s.), 3230 (m.), 3330 (m.) cmr Vggg 1027 (m.s.), 1154 (v.s.), 1240-1200 (wide band, v.s.), 1434 (s.), 1500 (v.s.), 1610 (m.), 17501700 (wide band, v.s.), 2970 (m.), 3300 (77.), 3440 (m.), 01117 Analysis for C14H1qN305: Calcd: C, 52.01; H, 5.30; N, 13.00. Found: C, 52.00; H, 5.34; N, 13.20.

EXAMPLE 21 16 Ethyl 3,4-dihydro-8-methoxy-3-methyl-2-oxo-2H- benzoxazine-4-carbarnate A solution of 10.0 g. of 3,4-dihydro-4-hydroxy-8-methoxy-3-rnethyl-2H-1,3-benzoxazin 2 one, 4.5 g. of ethyl carbamate, and 0.02 g. of p-toluenesulfonic acid monohydrate in 200 ml. of anhydrous chloroform is refluxed for two hours with the azeotropical removal of water. After the solvent is removed in vacuo, the crystalline residue is recrystallized from isopropanol to give 9.3 g. of ethyl 3,4 dihydro 8 methoXy-3-methyl-2-ox0 2H- benzoxazine-4-carbamate as analytically pure, White crystals, M.P. 166167. Concentration of the mother liquor to a low volume and cooling yields 3.1 g. of an additional product, M.P. 165-166 (total yield: 92%); A312? m (6) 222 (8,950), 274 (2,250), 280 (2,230); 11 E31? 1132 (m.s.), 1210 (m.s.), 1234 (m.s.), 1250 (m.s.), 1493 (m.s.), 1510 (m.), 1706 (s.), 1720 (m.s.), 3280 (m.) cmr 5235 1023 (s.), 1130 (m.s.), 1210-1200 (wide band, v.s.), 1270 (s.), 1332 (m.s.), 1405 (m.s.), 1440 (s.), 1493 (v.s.), 1630 (W), 1711 (v.s.), 1728 (v.s.), 2980 (m.) 2280 (w.), 3420 (m.) GEL-1.

Analysis for C H N O Calcd: C, 55.71; H, 5.75; N, 10.00. Found: C, 55.75; H, 5.80; N, 9.72.

EXAMPLE 22 N-on,0n=o1n NHCOOEt Ethyl 3-allyl-3,4-dihydro-2-oXo-2H-1,3-benzoxazine- 4-carbarnate A solution of 10.0 g. of 3-allyl-3,4-dihydro-4-hydroxy- 2H-l,3-benzoxazin-2-one, 4.35 g. of ethyl carbarnate, and 0.02 g. p-toluenesulfonic acid monohydrate in 200 ml. of chloroform is refluxed for one hour, while 0.95 ml. of water is collected in the Dean-Stark trap. After the solvent is removed in vacuo, the residue is recrystallized from cyclohexane-ethyl acetate (3:1) to give 8.1 g. of analytically pure, white crystals, M.P. 113-114. Concentration of the mother liquor to a low volume gives 27 g. of additional product, M.P. 1l3114 (total yield:

352.2? me (e) 277 (1,050), 274. (1,000); 11: 5. 744 (m.), 751 (m.s.), 1032 (m.s.), 1235 (s.), 1340 (m.s.), 1503 (m.s.), 1520 (s.), 1689 (v.s.), 1716 (v.s.), 3310 (m.) 515: vggg 1060 (m.s.), 1225 (s.), 1331 (m.s.), 14.15 (m.s.), 1152 (s.), 1500 (s.), 1000 (m.), 1643 (W), 2970 (w.), 3410 (w.), 3530 (w.) emf.

Analysis for C14H15N2O2: Calcd: C, 60.86; H, 5.84; N, 10.14. Found: c, 60.97; H, 5.84; N, 10.36.

EXAMPLE 23 NHCOOCzHs Ethyl 3-allyl-6-chloro-3,4-dihydro-2-oxo- 2H-1,3-benzoxazine-4-carbamate A solution of 10.0 g. of 3-allyl-6-chloro-3,4-dihydro- 4-hydroXy-4H-1,3-benzoxazin-2-one, 3.7 g. of ethyl carbamate and 0.01 g. of p-toluenesulfonic acid monohydrate in 200 ml. of dry benzene is refluxed for one hour, while 0.75 ml. of Water is collected in the Dean-Stark trap. Concentration of the solution to about 25 ml. and cooling gives 11. 5 g. (89%) of ethyl 3-ally1-6-chloro- 3,4-dihydro-2-oXo-2H-1,3-benzoxazine 4 carbamate as white crystals, M.P. -157. Recrystallization from droxy-ZH-l,3-benzoxazin-2-one 7-carbamate, 2.2 g. of ethyl carbamate, and 0.01 g. of p-toluenesulfonic acid monohydrate in 100 ml. of dry chloroform is refluxed for one hour with the azeotropical removal of 0.4 ml. of water. The solvent is evaporated in vacuo and the residue is crystallized from ether to give 7.1 g. (83%) of pinkish colored crystals, M.P. 153155. Recrystallization from ethyl acetate gives analytically pure, white crystals, M.P. 155.5157;

max.

(v.s.), 1713 (v.s.), 1740 (v.s.), 3290 (m.) BBL-1.

-i3* 218 (760), 276 (1,280), 284 (s.), 1686 (s.), 1508 (m.s.),

224.5 (9,840), 248-262 plateau (1,200); 1 233 3340 (w.), 1720 1232 (s.), 833 (m.) cmr Analysis for C H ClN O Calcd: C, 54.11; H, 4.87;

N, 9.01; Cl, 11.41. Found: C, 54.35; H, 4.97; N, 8.82; CI, 11.38, 11.48.

EXAMPLE 24 O 0 Ha NBC -0 02H.

ll Ethyl 3-allyl-3,4-dihydro-8-methoxy-2-oxo- 2H-1,3-benzoxazine-4-carbamate A solution of 10.0 g. of 3-allyl-3,4-dihydro-4-hydroxy-8- methoxy-ZH-1,3-benzoxazin-2-one, 3.8 g. of ethyl carbamate and 0.01 g. of p-toluenesulfonic acid monohydrate in 150 ml. of dry chloroform is refluxed for one and a half hours, while 0.75 ml. of water separates in the Dean- Stark trap. After the solvent is removed in vacuo, the semi-solid residue is recrystallized from ethyl acetate to give 4.8 g. of analytically pure, white crystals, M.P. 127.5-129. Concentration of the mother liquor to a low volume and addition of a small amount of hot cyclohexane gives 42 g. of an additional material, M.P. 127- 128.5 (total yield: 69%);

155,2? my (6) 221 (8,950), 272 (2,050), 279 (2,050); 1 1,135,? 1213 (s.), 1241 (s.), 1498 (s.), 1531 (m.s.), 1627 (w.), 1687 (v.s.), 1706 (m.s.), 1735 (s.), 3290 (m.) cmf N, 9.15. Found: C, 58.55; H, 5.96; N, 9.11.

EXAMPLE 25 NHOOOEt Ethyl 3-allyl-7-[ (allylcarbamoyl) oxy]-1,3-dihydro- 2-oxo-2H-l,3-benzoxazine-4-carbamate A solution of 7.0 g. of 3-allyl-3,4-dihydro-4,7-dihymy (6) vggi? 1155 (s.), 1240 (v.s.), 1534 (s.), 1681 Analysis for C H N O Calcd: C, 57.59; H, 5.64;

N, 10.20. Found: C, 57.88; H, 5.78; N, 10.35.

EXAMPLE 26 OCH;

NCH2CH=CH:

NHCOOCHzCHaCl fl-Chloroethyl-3-allyl-3,4-dihydro-8-methoxy- 2-oxo-2H-1,3-benzoxazine-4-carbamate A solution of 8.0 g. of 3-allyl-3,4-dihydro-4-hydroxy- 18 8-methoxy-2-oxo-2H-1,3-benzoxazin-2-one, 4.2 g. of B- chloroethyl carbamate, and 0.01 g. of p-toluenesulfonic acid monohydrate in "150 ml. of dry chloroform is refluxed for one hour, while 0.6 ml. of water is collected in the Dean-Stark trap. Evaporation of the solvent and trituration with ethyl acetate gives 9.3 g. of white crystals, M.P. 126-128". Recrystallization from ethyl acetate yields analytically pure product, M.P. 127128; A233? mu (6) 221 (9,200), 271 (2,200), 279 (2,200); 1215 (m.s.), 1254 (s.), 1494 (111.8.) 1535 (m.), 1688 III!- (v.s.), 1725 (s.), 3290 (m.) cmr Analysis for C15H17ClN2O5Z Calcd: C, 52.87; H, 5.03; N, 8.22; Cl, 10.40. Found: C, 53.16; H, 4.98; N, 8.06; CI,

' EXAMPLE 27 N-CHa o Hz-N-C o 0E1; Ethyl 6-chloro-3,4-dihydro-3,N-dimethyl- 2-oxo-2H-1,3-benzoxazine-4-carbarnate A solution of -6-chloro-3,4-dihydro-4-hydroxy-3-methyl- 1,3-benzoxazin-2-one, 2.4 g. of ethyl methylcarbamate, and 0.1 g. p-toluenesulfonic acid monohydrate in ml. of anhydrous benzene is refluxed for one and a half hours with the azeotropical removal of 0.37 ml. of water. The solvent is removed in vacuo. Trituration with 2.0 ml. of hot cyclohexane gives 4.8 g. of white crystals, M.P. 94-95 Recrystallization from cyclohexane yields 3.7 g. of analytically pure crystals, M.P. 9*697; 1232? 224 (21,800), 277 (2,800), 285 (2,450); 1 23i? 821 (m.), 1158 (m.s.), 1231 (s.), 1313 (s.), 1381 (m.s.), 1694 (v.s.), 1740 (.s.) cmr.

Analysis for C H ClN O Calcd: C, 52.27; H, 5.06; N, 9.38; CI, 11.87. Found: C, 52.45; H, 5.01; N, 9.40; C1, 1200, 11.73.

EXAMPLE 2s N-CH; 0 11:!) Hz CH NCONHCHa 1-(3-allyl-3,4-dihydro-2-oxo-2H-l,3-benzoxazin-4-yl)- 1,3-dimethylurea A solution of 7.5 g. of 3-allyl-6-chloro-3,4-dihydro-4- hydroxy-ZH-1,3-benzoxazin-2-one, 3.7 g. of 1,3-dimethylurea, and 0.01 g. of p-toluenesulfonic acid monohydrate in 15 0 ml. of dry benzene is refluxed for one hour, while 0.64 ml. of water is collected in the Dean-Stark trap. After the solvent is removed in vacuo, the residue is triturated with 8 ml. of ethyl acetate to give 8.5 g. of white crystalline product, M.P. 147-148. Recrystallization from ethyl acetate gives analytically pure white crystals, MP, 148 149;

A223? m (6) 267 (1,100), 273 (1,100); vfigl? 1206 (m.s.), 1310 (m.s.), 1460 (m.s.), 1546 (m.s.), 1625 (s.), 1726 (s.), 3320 (m.) cmr Analysis for C H N O Calcd: C, 61.08; H, 6.22; N, 15.26. Found: C, 61.18; H, 6.27; N, 15.20.

EXAMPLE 29 N-OHa OCHs 19 3,4-dihydro-4,8-dimethoxy-3-methyl-2H-1,3- benzoxazin-Z-one 2,4 dihydro 4 hydroxy-8-methoxy-3-methyl-2H-1,3- benzoxazin-Z-one (8.0 g.) in 80 ml. of absolute methanol is refluxed for seventy hours. Concentration to ca. 10 ml. and cooling gives 6.3 g. of white crystals, M.P 88-90". Recrystallization from ethanol gives analytically pure product, MP. 88-90";

A523? mu (e) 223 (5,850), 273 (1,730), 280 (1,680), 1123i? 1055 (m.s.), 1130 (me), 1211 (ms), 1492 (ms); 1712 (s.) cm."

Analysis for C H NO Calcd: C, 59.18; H, 5.87; N,

6.28. Found C, 59.49, 59.39; H, 5.89, 6.02; N, 6.41, 6.39.

EXAMPLE 30 N-OHa NH? NH:

l-( 3,4-dihydro-3-methyl-2-oxo-2H-benzoxazin) urea To a solution of 5.0 g. of 3,4-dihydro-4-hydroxy-3- methyI-ZH-l,3-benzoxazin-2-one and 2.5 g. of urea in 80 ml. of absolute ethanol is added five drops of ethanolic hydrogen chloride at room temperature. The white crystals begin to separate soon and, after five hours, 5.4 g. (88%) of product is filtered ofi, M.P. 202-203", decomp. Recrystallization from ethanol gives analytically pure crystals, M.P. 203-204", decomp.

Analysis for C H N O Calcd: C, 54.29; H, 5.01; N, 19.00. Found: C, 54.18; H, 5.28; N, 19.25.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made without departing from the spirit of the invention.

Having described our invention, what we desire to secure by Letters Patent is:

1. A compound of the formula:

Ra R4 wherein R is a member of the group consisting of lower alkyl, lower alkoxy, halogen, nitro,

U U U 3 0-011, C-GCHs H/ ---CH -0 (6-0 01H; fi Hr-C o o in whichn is from 1 to 4; 1,3-cyc1ohexanedione, 1,3-cyclopentanedione,

oyclopentanone, eyclohexanone, cycloheptanone, methylcyclohexanone;

Z-butanoue, 2-pentanone, 2-hexanone; 3-chloro-acetony1 lower alkyl substituted phenols, nitro or halo substituted phenols 1,2-cyclopentanedione, 1,2-cycloheptanedione, and 1,2- cyclooctanedione.

2. 4-benzenesulfonamido-3,4-dihydro-3-methyl-2H- 1,3-benzoxazin-2-one.

3. 4-(4,4-dimethyl-Z,6-dioxocyclohexyl)-3,4-dihydro- 3-methyl-2H-1,3-benzoxazin-2-one.

4. 4 (2,4-dioxo-3-pentyl) -3 ,4-dihydro-3-methyl-2H- 1,3-benzoxazin-2-one.

5. Ethyl 2-(3,4-dihydro-3-methy1-2-oxo-2H-1,3- benzoxazin-4-yl) acetoacetate.

6. 3,4-dihydro-3-methyl-4-(2,5-dioxo-1-pyrrolidinyl)- 2H-1,3-benzoxazin-2-one.

7. 3,4dihydro-3-methyl-2-oxo-2H-1,3-benzoxazin-4- (2-oyclohexan0ne) 8. 3,4-dihydro-4-(S-methyl-Z-furyl)-3-methyl-2H-l,3- benzoxazin-Z-one.

9. 3,4-dihydro-4-(2-furyl)-3-methyl-2H-1,3-benzoxazine-2one.

10. 4-(1-acetonyl)-3,4-dihydro-3-methyl-2H-1,3- benzoxazin-Z-one.

11. 1-(3,4-dihydro-3-methyl-2-oxo-2H-1,3-benzoxazin- 4-yl) -2,3 -butanedione.

12. 4-(3-chloro1-acetonyl)-3,4-dihydro-3-methyl- 2H-1,3-benzoXazin-2-one.

13. 3,4-dihydro-3-methyl-4-(2-phenylacetonitril-2- yl)-2H-1,3-benzoxazin-2-one.

14. 3,4-dihydro-3-methyl-4-(p-methylphenacyl)-2H- 1,3-benzoxazin-2-0ne.

15. 3,4-dihydro-3-methyl-4-(Z-thienyl)-2H-1,3- benzoxazin-Z-one.

16. 3,4-dihydro-4-(p-hydroxyphenyl)-3-methyl-2H- 1,3-benzoxazin-2-one.

17. 4-( l-acetylphenacyl) -3,4-dihydro-3-meth-yl-2H- 1,3-benzoxazin-2-one.

18. 1 (3,4-dihydro-3-methyl-2-oXo-2H-1,3-benzoxazin- 4-yl)-l,3-dimethylurea.

19. Ethyl 3 allyl-6-chloro-3,4-dihydro-2-oxo-2H-1,3- benzoxazine-4-carbamate.

20. Ethyl 3,4-dihydro-2-oxo-2H-1,3-benzoxazine-4-carbamate.

21. Ethyl 6-chloro-3,4-dihydro-3-methy12-oX0-2H-1,3- benzoxazine-4-carbamate.

22. Ethyl 3 allyl-3,4-dihydro-2-oxo-2H-1,3-benzoxazine-4-carbamate.

23. Ethyl 3,4 dihydro-3-methy1-7-[(methylcarbamoyl)1-2-oxo-2H-1,3-benzoxazine-4-carbamate.

R N-Rr R4 0 wherein R is a member of the group consisting of lower alkyl; allyl, methylqllyl, dimethylallyl and cycloalkyl; R and R are each a member of the group consisting of hydrogen, lower aIkOXY, lower alkyl and carbamoyloxy; R is a member of the group consisting of wherein R is a member of the group consisting of lower alkyl, lower alkoxy, halogen, nitro,

{ tin U til in which n is from 1 to 4; 1,3-cyclohexanedione, 1,3-cyclopentanedione,

cyclopentanone, cyclohexanone, cycloheptanone, methylcyclohexanone;

CHg(I:l-CH3 O Z-butanone, 2 pentanone, 2-hexanone; 3-chloro-1-acetonyl /CN 0 E) -o-c.H. CH: 3CaHa -orr=o@-om lower alkyl substituted phenols, nitro or halo substituted phenols 1,2-cyclopentanedione, 1,2-cycloheptanedione, and 1,2- cyclooctanedione, which comprises heating over an extended period of time a compound of the formula:

R: I Ill-R1 R4 with a compound of the formula R H.

References Cited UNITED STATES PATENTS 3,259,620 7/1966 Moffett 260-244 HENRY R. unis, Primary Examiner. R. T. BOND, Assistant Examiner.

US. Cl. X.R. 424248