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Reaction of N-(2-hydroxyphenyi)anthranilic acids (I) with acetic anhydride was investigated further. Treatment of Ia with refluxing acetic anhydride for 3 hours afforded two minor products, IIIa and IV, in addition to the previously reported IIa. Under similar conditions, the reaction of Ib with acetic anhydride afforded IIb as reported previously, and IIIb and IXb in small quantities. Treatment of IIIb with hydrazine gave X, and treatment of IXb with methoxyethylamine gave XI. When Ic was allowed to react with refluxing acetic anhydride, there were obtained three minor products, IIIc, IXc and XIII, in addition to IIc. Reaction of Id with acetic anhydride gave IId, and two minor products IXc and XIV. The formation of these minor products in the reaction of Ia-d with acetic anhydride are discussed based on the reation mechanism proposed previously for the formation of II.

1,2,3,4,8,9,10,11-Octahydro[1,4]diazepino[6,5,4-jk]earbazole (VIa) was synthesized from 2,3,4,5-tetrahydro-1H-benzodiazepine (la) via the route shown in Scheme 1. Other compounds which were prepared similarly are 3-acetyl-6-chloro-1,2,3,4,8,9,10,11-octahydro[1,4]diazepino-[6,5,4-jk]carbazole(Vb) and 3-methyl-1,2,3,4,8,9,10,11-octahydro[1,4]diazepino[6,5,4-jk]carb-azole (VIII). Chemical transformations which were carried out with VI and 3-acetyl-1,2,3,4,8,9, 10,11-octahydro[1,4]diazepino[6,5,4-jk]carbazole (Va) are also described.

Treatment of N-(2-hydroxyphenyl)anthranilic acid with acetic anhydride, under refluxing conditions provided a simple method for the synthesis of 5H-henzoxazolo[3,2-a] quinolin-5-one (IVa), a heretofore unreported ring system. When propionic anhydride was used in the above reaction, 6-methyl-5H-benzoxazolo[3,2-a]quinolin-5-one (Va) was obtained. Other examples prepared in this fashion were IVb, IVc and Vb. Treatment of IVa with methoxyethylamine afforded 1,2-dihydro-1-(2-hydroxyphenyl)-2-(methoxyethylimino)-4-quinolinol (VII). A possible mechanism for the cyclization reaction is discussed.

The usefulness of 5H-benzoxazolo[3,2-a]quinolin-5-ones (I) as synthons for the preparation of otherwise difficulty obtainable quinolin-5-ones is demonstrated. Nucleophilic reagents cleaved the oxazole ring of I at the 7-position, resulting in 1-(2-hydroxyphenyl)-2-substituted 4-(1H)quinolinones. Treatment of 5H-benzoxazolo-[3,2-a]quinolin-5-one (Ia) with ethanoiic potassium hydroxide gave 1-(2-hydroxyphenyl)-2-ethoxy-4-(1H)quinolinone (IIIa), and attempted formylation of Ia with the Vilsmeier-Haak reagent instead gave 2-chloro-1-(2-hydroxyphenyl)-4-(1H)quinolinone (II). Likewise, 10-chloro-5H-benzoxazolo[3,2-a]quinolin-5-ones (Ib) afforded 2-ethoxy- and 2-methoxy-1-(5-chloro-2-hydroxyphenyl)-4-(1H)quinolinone (IIIb and IIId) upon treatment with ethanol and methanol, respectively. Reaction of Ib with 1-phenylpiperazine yielded 1-(5-chloro-2-hydroxyphenyl)-2-(4-phenyl-1-piperazinyl)-4-(1H)quinolinone (IV). Alkaline hydrolysis of IIIb gave 1-(2-hydroxy-5-chlorophenyl)-2-(1H)quinolinone (V). Treatment of IIId with epichlorohvdrin gave 1-[5-chloro-2-(2-oxiranylmethoxy)phenyl]-2-methoxy-4-(1H)quinolinone (VIa) which in turn upon treatment with isopropylamine gave 1-[5-chloro-2-[2-hydroxy-3-(1-methylethylamino)propoxy]phenyl]-2-methoxy-4-(1H)quinolinone (VIIa). Similarly, the ethoxy analog (VIIb) was prepared. Reaction of Ib with sodium cyanide in dimethylsulfoxide produced 1-(5-chloro-2-hydroxyphenyl)-1,4-dihydro-4-oxo-2-quinolinecarbonitrile (X) which was hydrolized to give the corresponding carboxamide (XIV) and carboxylic acid (XI) depending on the reaction conditions. The latter yielded 2-chloroquino[2,1-c][1,4]benzoxazine-6,8-dione (XII) when heated with an excess of acetic anhydride. Treatment of XII with methoxyethylamine gave 1-(5-chloro-2-hydroyphenyl)-1,4-dihydro-N-2(methoxyethyl)-4-oxo-2-quinolinecarboxamide (XV). 1-(5-chloro-2-hydroxyphenyl)-2-(1H-tetrazoyl-5-y1)-4-(1H)qutnolinone (XIII) was prepared from X. When Ib was allowed to react with sodium diethylmalonate, there was obtained [1-(5-chloro-2-hydroxyphenyl)-1,4-dihydro-4-oxo-2-quinolinyl]-propanedioic acid diethyl ester (XVI) which was transformed to 1-(5-chloro-2-hydroxyphenyl)-1,4-dihydro-4-oxo-2-quinolinacetic acid ethyl ester (XVII) upon heating in hexamethylphosphoramide.

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.

5H-Pyrido[1,2-a]pyrimido[5,4-e]pyrimidin-5-ones IVa,b and 5H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones Va,b were synthesized from ethyl 4-chloro-5-pyrimidinecarboxylate and 2-aminopyridine. The former compounds were obtained directly upon heating the reactants in ethanol, and the latter were prepared by the fusion of ethyl 4-(2-pyridylamino)-5-pyrimidinecarboxylates obtained as minor products from the above reaction. The angular fused cyclic compounds, IVa,b were rearranged to the linear tricycles, Vb-f upon heating with amines.

The reaction of 4-chloro-2-phenyl-5-pyrimidinecarbonitrile (III) with N-methylglycinonitrile gave 4-[(eyanomethyl)methylamino]-2-phenyl-5-pyrimidinecarbonitrile (VIa), which upon cycli-zation under Dieckmann conditions afforded 5-amino-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]-pyrimidine-6-carbonitrile (VIIa). Other examples (VIIb and VIIc) were prepared similarly from the reactions of III with glycinamide and ethyl glycinate, respectively. The preparation of simple 5-amino derivatives of the pyrrolo[2,3-d] pyrimidines thus synthesized is described. The alkyla-tion of VIIc with N-cyeloheptylchloroacetamide took place at the ring nitrogen, giving XII. The reaction of VIIa with formamide gave 4-amino-5-methyl-7-phenyl-5H-pyrrolo[2,3-d:4,5-d′ ]-dipyrimidine (XIII), the first member of a new ring system. Treatment of VIIa with carbon disulfide and pyridine afforded another example of this new ring system, 1,5-dihydro-5-methyl-7-phenyl-2H-pyrrolo[2,3-d:4,5-d′] dipyrimidine-2,4-(3H)dithione (XIV).

Eighteen novel pyrimido[4,5-e][1,4]oxazepin-5-ones were prepared directly via the reaction of either ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate (Ia) or ethyl 4-chloro-2-m-chlorophenyl-5-pyrimidinecarboxylate (Ib) with a variety of substituted 2-(alkylamino)ethanols. A typical example was the preparation of 8,9-dihydro-9-methyl-2-phenylpyrimido[4,5-e][1,4]-oxazepin-5(7H)-one (IIa) from the reaction of Ia with 2-(methylamino)ethanol. Hydrolytic cleavage of the lactone ring in IIa with sodium hydroxide solution, followed by acidification with hydrochloric acid afforded 4-[(2-hydroxyethyl)methylamino]-2-phenyl-5-pyrimidinecarboxylic acid (IV). Reactions of IIa with concentrated ammonium hydroxide or hydrazine also caused cleavage of the lactone ring, giving the corresponding amide (V) or hydrazide (VI), respectively. Structural assignments were supported by infrared and nuclear magnetic resonance spectra.

A novel method for the preparation of esters and amides of thieno[2,3-d]pyrimidine-6-carb-oxylic acids was described. A typical example was the direct formation of ethyl 5-amino-2-methylthiothieno[2,3-d]pyrimidine-6-earboxylate(IIIa) from 4-chloro-2-methylthio-5-pyrimidine-carbonitrile (Ia) and ethyl mercaptoacetate in refluxing ethanol containing sodium carbonate. Displacement of the methylthio group in IIIa by various amines gave the corresponding amino derivatives. The reactions of IIIa and related compounds with acetylating agents such as acetic anhydride or chloroacetyl chloride gave various products. Treatment of 5-carbethoxy-4-chloro-2-phenylpyrimidine(IV) with methyl mercaptoacetate afforded the dechloro intermediate diester Va, which cyclized on reaction with sodium ethoxide to form methyl 5-hydroxy-2-phenylthieno-[2,3-d]pyrimidine-6-carboxylate (Vla). The synthesis was expanded to include the preparation of various new 2,4,5-trisubstituted thieno[2,3-d]pyrimidine-6-carboxylic acid esters and amides (Charts I-V).

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one (16a) and analogs (16b,c, 22) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (7) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester (8a). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (9), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (12a) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid (15a). Reaction of 15a with acetic anhydride afforded 16a, the first member of a novel ring system, the pyrimido[5,4-c][1,5]-benzoxazepin. Additional examples (16b,c) were prepared similarly. The corresponding 11-ethyl derivative (22) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.

The treatment of N-(2-hydroxyphenyl)anthranilic acids with cyanogen bromide in the presence of triethylamine gave dibenz[b,e][1,4]oxazepin-11-(5H)ones in good yields.

Synthesis of (4S,9aS)-hexahydro-4-methyl-1H,5H-pyrrolo[2,1-c][1,4]thiazepine-1,5-dione, an orally active potent angiotensin converting enzyme inhibitor is described.

Treatment of 10-chloro-5H-benzoxazole[3,2-a]quinolin-5-one (I) with an excess of sodium diethyl malonate at 190° for 3 hours in hexamethylphosphoramide gave, in 38% yield, 9-chloro-8-ethoxy-12-hydroxy-5H-dibenz[c,f]quinolizin-5-one (IV) which, on heating with acetic anhydride, afforded monoacetylated product, V. A possible reaction mechanism for the novel ring expansion reaction is suggested.