Synthesis of new fluorine-containing pyrazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]pyridinones as promising drug precursors

Methods for the synthesis of 4-R-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones (R = CF₂SAr and 4-CFHSAr) were developed. The derivatives with R = CF₂SAr were obtained by both heterocyclization of 1-substituted 5-aminopyrazoles with ethyl 4,4-difluoro-3-oxo-4-phenylsulfanylbutanoate and replacement of the Br atom in 4-bromodifluoromethyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones by sodium arenethiolates. The fragment 4-CF-HSAr was introduced by replacement of the Cl atom in 4-chlorofluoromethyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones by sodium arenethiolates. Oxidation of 4-CF₂SPh-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones gave the corresponding sulfoxides; their structures were confirmed by X-ray diffraction data.     

Selenium heterocycles. XXXII . Synthesis of [1]benzoxepino[3,4-d]-thiazole, [1]benzothiepino[3,4-d]thiazole, [1]benzoxepino[3,4-d]selenazole,and [1]benzothiepino[3,4-d]selenazole. four novel heterocycles

Starting from the readily available ethyl 2-phenyl-4-methyl-thiazole-5-carboxylate (III), 2-phenyl-4-chloromethyl-thiazole (VIII) and 2-aryl-4-chloromethylselenazole (XIV), 2-phenyl-4,10-dihydro-10-oxo-[1]benzoxepino[3,4-d]thiazole (Ia), 2-phenyl-4,10-dihydro-10-oxo[1]benzothiepino[3,4-d]thiazole (Ib), 2-aryl-4,10-dihydro-10-oxo[1]benzoxepino[3,4-d]selenazoles (IIa-IIe) and 2-aryl-4,10-dihydro-10-oxo[1]benzothiepino[3,4-d]selenazoles (IIf-IIj) were prepared.     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

Chemistry of 1,2,3-thiadiazole. IV. Synthesis of [1]benzoxepino-[3,4-d][1,2,3]thiadiazole, [1]benzothiepino-[3,4-d][1,2,3]thiadiazole, [1]benzoxepino[4,3-d][1,2,3]thiadiazole, [1]benzoxepino[4,3-d]oxazole and [1]benzoxepino[4,3-d]oxazole. Four novel heterocycles

Starting from the readily available 4-bromomethy-5-carbethoxy 1,2,3-thiadiazole (V), 5-bromomethy-4-carbethoxy-1,2,3-thiadiazole (IX) and ethyl 2-aryl-5-bromomethyloxazole-4-carboxylate (XIV), 4,10-dihydro-10-oxo[1]benzoxepino[3,4-d][1,2,3]thiadiazole (Ia), 4,10-dihydro-10-oxo[1]benzothiepino[3,4-d][1,2,3]thiadiazole (Ib), 4,10-dihydro-4-oxo[1]benzothiepino[4,3-d] [1,2,3]thiazole (II), 2-aryl-4,10-dihydro-4-oxo[1]benzoxepino[4,3-d]oxazoles (XIXa-XIXc) and 2-aryl-4,10-dihydro-4-oxo[1]benzothiepino[4,3-d]oxazoles (XIXd-XIXf) were prepared.     

The first example ot the benzo[b]pyrimido[4,5-f]azocine king system

Base catalyzed cyclization of ethyl 4-[2-(2-amino-4,5-dimethoxyphenyl)ethyl]-2-phenylpyrimidine-5-carboxylate, derived from ethyl 4-methyl-2-phenyl-5-pyrimidinecarboxylate and 3,4-dimethoxy-6-nitrobenz-aldehyde, gave 5,6-dihydro-8,9-dimethoxy-3-phenylbenzo[b]pyrimido[4,5-f]azocine-12(11H)-one, the first reported example of this ring system.     

The synthesis of a pyrido[3,4-d]pyrimidine analog of pteroic acid

A multistep synthesis of ethyl 5-amino-2-methyIpyridine-4-carboxylate (5a) starting from ethyl acetopyruvate and nitroacetamide is described. The condensation of 5a with benzoylcyanamide gave 2-amino-3-benzoyl-6-methylpyrido[3,4-d]pyrimidin-4(3H) one (10), which could be hydrolyzed in alkali to give 2-amino-4-hydroxy-6-methylpyrido[3,4-d]pyrimidine (9). Free radical bromination of 10 in bromotrichloromethane gave a mixture of the bromo- and chloromethyl- derivatives (11). Fusion of 11 with ethyl p-aminobenzoate, followed by alkaline hydrolysis gave the corresponding pteroic acid analog (12).     

Ring transformation of 6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine. IV (1). Reduction and reaction of 5a-acetyl-6a-ethoxycarbonyl-5a,6a-dihydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine-3-carbonitriles with primary amines

The reaction of 5a-acetyl-6-ethoxycarbonyl-5a,6a-dihydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine-3-carbonitrile ( 1a ) with benzylamine gave ethyl l-benzyl-5-cyano-8a,9-dihydro-2-methyl-1H-pyrrolo[3,4-e]-pyrazolo[1,5-a]pyrimidine-8a-carboxylate ( 2a ), in addition to 5-acetyl-3-benzylamino-1-(4-cyanopyrazol-3-yl)- 2-pyridone ( 3 ). Reaction of 1a with aniline gave ethyl 6-acetyl-8-anilino-3-cyano-7,8-dihydro-4H-pyrazolo-[1,5-a][1,3]diazepine-8-carboxylate ( 4 ), in addition to ethyl 3-cyano-7-methyl-6-pyrazolo[1,5-a]pyrimidine-acrylate ( 5 ). On the other hand, the same reactions of 1b with benzylamine or aniline gave 2b or 8b , respectively. Though catalytic hydrogenation of 1a over 5% palladium-carbon proceeded by ring fission of cyclopropane ring to give 9 , 1a (or 1b ) afforded 4,5-dihydro derivatives ( 13 or 15 ) by catalytic hydrogenation over platinum oxide. The reactivity of 5-methoxy-4,5,5a,6a-tetrahydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine ( 16 ), which are related analogs of 1a,b , is also described.     

Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

Inhibitors of platelet aggregation. 4. [1,2,5]Thiadiazolo[3,4-c]acridines, 7,8,9,10-Tetrahydro[1,2,5] thiadiazolo[3,4-c]acridities,and 8,9-Dihydro-7H-cyclopenta[b][1,2,5] thiadiazolo[3,4-H]quinolines

The condensation of 4-amino-2,1,3-benzothiadiazole (IV) with diphenyliodonium-2-earboxylate gave N-(2,1,3-benzothiadiazoI-4-yl)anthranilic acid (V) (28%), which was cyclized with phosphorus oxychloride to 6-chloro[1,2,5]thiadiazolo[3,4-c]acridine (VI) (84%). Treatment of VI with 3-(dimethylamino)-1-propanethiol hydrochloride in phenol afforded 6-[ [3-(dimethylamino)-propyl]thio] [1,2,5]thiadiazolo[3,4-c]acridine (VII) (65%). The reaction of IV with a mixture of methyl and ethyl 2-oxocyclohexanecarboxylate gave the adduct, which was ring closed in Dowtherm to 7,9,10,1 1-tetrahydro[1,2,5] thiadiazolo[3,4-c]acridin-6(8H)one (VIII) (70%). Chlorination of VIII with phosphorus oxychloride gave 6-chloro-7,8,9,10-tetrahydro[1,2,5]thiadiazolo[3,4-c]acridine (IX) (84%), which was condensed with 3-(dimethylamino)-1-propanethiol hydrochloride in phenol yielding 6-[ [3-(dimethylamino)propyl]thio]-7,8,9,10-tetrahydrof 1,2,5]-thiadiazolo[3,4-c]acridine (X) (27%). 6-[ [3(1)imethylamino)propyl]thio]-8,9-dihydro-7H-cyclopenta[b] [1,2,5]thiadiazolo[3,4-h]quinoline (XIII) (25%) was prepared similarly from IV and a mixture of methyl and ethyl 2-oxocyclopentanecarboxylate via 7,8,9,10-tetrahydro-6H-cyclopenta[b][1,2,5]thiadiazolo[3,4-h]quinolin-6-one (XI) (85%) and 6-chloro-8,9-dihydro-7H-cyclopenta[b][1,2,5]thiadiazolof3,4-h]quinoline (XII) (56%). The effects of compounds VII-XIII as inhibitors of platelet aggregation are discussed.     

Synthesis of 2-Aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2<Emphasis Type="Italic">H</Emphasis>-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyridazin-7-ones

Bromination of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates gave ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazol-3-carboxylates which were used to alkylate benzenethiol and heterocyclic thiones at the sulfur atom. Reactions of the resulting S-alkylation products with hydrazine or methylhydrazine involved closure of pyridazine ring to afford 2-aryl-3-methyl-4-[phenyl(or hetaryl)sulfanylmethyl]-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.     

Synthesis of 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acids and the reinvestigation of the thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate

Diethyl [2-(3- or 4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonates 5 prepared by the reaction between 2-(3- or 4-pyridinyl)-4-pyrimidinamines 3 and diethyl ethoxymethylenemalonate ( 4 ) were thermally cyclized to afford ethyl 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylates 6 . The later were alkylated with ethyl iodide and then saponified to give 5,8-dihydro-8-ethyl-5-oxo-2-(3- or 4-pyridinyl)pyrido-[2,3-d]pyrimidine-6-carboxylic acids 2 . Thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate ( 8 ) gave ethyl 1,6-dihydro-4,6-dioxo-4H-pyrimido[1,6-a]pyrimidine-3-carboxylate ( 10 ) instead of ethyl 5,8-dihydro-2-hydroxy-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate ( 9 ) as previously claimed.     

2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indoles. II. Reversible transformation of 1-alkyl-2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)cyclohexanol into 1-alkylidene-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles

Treatment of 2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-1-methylcyclohexanol ( 2a ) with acetic anhydride or methyl isocyanate gave 2-acetyl-2,3,4,9-tetrahydro-1-(6-oxoheptylidene)-1H-pyrido[3,4-b]indole ( 3 ) or 1,3,4,9-tetrahydro-N-methyl-1-(6-oxoheptylidene)-2H-pyrido[3,4-b]indole-2-carboxamide ( 4 ), respectively. Simpler analogues, 1-alkyl-4,9-dihydro-3H-pyrido[3,4-b]indoles, 7 , subjected to identical reaction conditions, gave 2-acetyl-1-alkylidene-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles 8 and 1,3,4,9-tetrahydro-N-methyl-1-alkyli-dene-2H-pyrido[3,4-b]indole-2-carboxamides 9 , respectively. A limited lanthanide shift reagent study to determine stereochemical assignments was also performed.     

New heterocyclic ring systems. XI. Azadithiasteroid analogues

Synthesis of the title compounds has been achieved starting from 4-oxo-3,4-dihydro-2H,5H-thiopyrano[3,2-c][1]benzothiopyran 6,6-dioxide (III), which was converted to glyoxylate (IV), β-ketoester (V), difluoride complex (VII) and β-diketone (XII) gave with hydrazine, hydroxyl-amine and glycine ethyl ester several azadithiasteroid analogues.     

Synthesis of 10-thia-5-deazafolic acid and 2-desamino-2-oxo-10-thia-5-deazafolic acid

The folate analogue, 10-thia-5-deazafolic acid, was obtained via a multistep synthetic sequence beginning with the known intermediate, 2,4-diaminopyrido[2,3-d]pyrirnidine-6-carboxaldehyde. Reduction of this aldehyde with sodium borohydride gave 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine, which when heated in base gave 2-amino-3,4-dihydro-6-(hydroxymethyl)-4-oxopyrido[2,3-d]pyrimidine. Treatment of the latter compound with phosphorus tribromide in tetrahydrofuran afforded 2-amino-6-(bromomethyl)-3,4-dihydro-4-oxopyrido[2,3-d]pyrimidine, thus constituting the first successful synthesis of this elusive intermediate. The aforementioned bromomethyl compound reacted smoothly with the sodium salt of ethyl 4-mercaptobenzoate, and the resulting ester was saponified to give 10-thia-5-deazapteroic acid. Conventional peptide bond coupling to di-tert-butyl L-glutamate followed by treatment with trifluoroacetic acid afforded the target compound in respectable yield. Attempts to prepare its 5,6,7,8-tetrahydro derivative by catalytic hydrogenation were unsuccessful.     

A convenient synthesis of 3-aryl-4H- Benzopyrano[3,4-d]isoxazol-4-ones

Regioselective 1,3-dipolar cycloaddition of nitrile oxides 5a-c to ethyl o-hydroxycinnamate (3) gave the corresponding ethyl trans-3-aryl-4,5-dihydro-5-(2-hydroxyphenyl)-4-isoxazolecarboxylates 6a-c . Their structure was confirmed by reductive cleavage to 1 and compounds 9a-c . Compounds 6a-c afforded upon heating in the presence of pyridine the 3-aryl-4H-[1]benzopyrano[3,4-d]isoxazol-4-ones 11a-c . Compound 10c was also isolated from 6c and transformed thermally into 11c .     

Synthesis of Some amino-4,5-dihydropyrazolo[3,4-a]acridines as potential cholinesterase inhibitors

A synthesis of the 4,5-dihydro derivatives of the previously known pyrazolo[3,4-a]acridine ring system is described. The reaction of a 3,4-dihydroacridin-1(2H)-one with N,N-dimethylformamide dimethyl acetal gave a reactive enamino ketone, which yielded the desired heterocycle upon reaction with hydrazine. Using this chemistry, 11-amino-4,5-dihydro-2H-pyrazolo[3,4-a)acridine ( 3 ) and a number of its 2-substituted derivatives 4a-k were synthesized and evaluated as acetylcholinesterase inhibitors, based on their relationship to 1,2,3,4-tetrahydro-9-acridinamine (THA). 1-Amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine ( 11a ) and 2-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine ( 11b ) were also synthesized and investigated as potential cholinesterase inhibitors.     

Preparation of novel heterocyclic systems from isatoic anhydrides

Isatoic anhydride ( 1a ) and 5-chloroisatoic anhydride ( 1b ) were treated with 2-(1-methylhydrazino)ethanol ( 2 ) to produce 2-aminobenzoic acid 2-(2-hydroxyethyl)-2-methylhydrazide ( 3a ) and its 5-chloro analog 3b , respectively. Treatment of 3a and 3b with carbon disulfide gave, respectively, 2,3-dihydro-3-[(2-hydroxyethyl)methylamino]-2-thioxo-4-(1H)quinazolinone ( 4a ) and its 6-chloro analog 4b . Compounds 4a and 4b afforded 5,6-dihydro-5-methyl-2-thioxo-4H,8H-[1,3,5,6]oxathiadiazocino[4,5-b]quinazolin-8-one ( 5a ) and its 10-chloro analog 5b , respectively, upon treatment with thiophosgene. Compound 5a could be produced directly from 3a and thiophosgene. Treatment of 4a and 4b with trifluoroacetic anhydride followed by potassium carbonate gave 3,4-dihydro-4-methyl-2H,6H-[1,3,4]thiadiazino[2,3-b]quinazolin-6-one ( 7a ) and its 8-chloro analog 7b , respectively. Treatment of 4a with thionyl chloride also gave 7a , but 4b and thionyl chloride afforded a mixture of 7b and 8-chloro-3,4-dihydro-4-methyl-2H,6H-[1,3,4]oxadiazino[2,3-b]quinazolin-6-one ( 10 ). The dimethyl analogs of 4a and 4b ( 13a and 13b ) upon treatment with thiophosgene afforded 3,4-dihydro-2,2,4-trimethyl-2H,6H-[1,3,4]oxadiazino[2,3-b]quinazolin-6-one ( 14a ) and its 8-chloro analog 14b , respectively.     

Etude de la décomposition thermique d'azido dithiényl-1,2 éthènes et éthanes

Thermal decomposition of azido-1,2-dithienylethenes 1 gave thienyl 4H-thieno[3,2-b]pyrroles 3 . For the 3,4-disubstituted thiophene derivatives 2 , the same reaction led to the amino-1,2-dithienylethenes 4 . In contrast, only azido-1,2-dithienylethanes 7 led to thienyl-5,6-dihydro-4H-thieno[3,4-b]pyrroles 8 . The structure of the obtained derivatives was established on the basis of ¹H nmr, ir, and mass spectral data.     

Synthesis of 1H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazines, 8H-pyrazolo[3,4-e]tetrazolo[5,1-c]-as-triazine and 1,7-dihydro-8H-pyrazolo[3,4-e]-as-triazine derivatives

3-Hydrazino-7-methyl-5-phenyl-5H-pyrazolo[3,4-c]-as-triazine 1 underwent ring closure and/or condensation reaction with formic acid, acetic acid, acetic anhydride and benzoyl chloride to afford 1H-pyrazolo-[3,4-d]-s-triazolo[3,4-c]-as-triazines 2, 5 and 7a and/or N-acyl derivatives 3, 4 and 6 . N-Acyl derivatives 3 and 6 underwent cyclisation reaction on treatment with phosphoryl chloride to give 5 and 7a . 3-Methyl-1-phenyl-8-aryl-1H-pyrazolo[3,4-e]-s-triazolo[34,-c]-as-triazines 7 were also prepared by the reaction of the hydrazono derivatives 8 wit thionyl chloride. On treatment of 1 with nitrous acid gave the 8H-pyrazolo[3,4-e]tetrazolo-[5,1-c]-as-triazine 9 . Compound 1 underwent ring closure with carbon disulphide or ethyl chloroformate to 1,7-dihydro-8H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazine derivatives 10 and 12 . Reaction of 1 with ethyl acetoacetate or acetylacetone gave 3-pyrazolo derivatives 13 and 14 .     

N-ethoxycarbonylamidines as starting materials and intermediates in the synthesis of heterocyclic compounds

Treatment of N-ethoxycarbonylthioamides ( 1 ) with primary aromatic amines yields N-aryl-N′-ethoxy-carbonylamidines ( 2 ), which thermally cyclize to 2-aryl-4(3H)-quinazolinones ( 6 ). Analogous reactions of 1 with ethyl 3-aminocrotonate and with 2-amino-2-thiazoline lead respectively to ethyl 2-aryl-3,4-dihydro-6-methyl-4-oxo-5-pyrimidinecarboxylates ( 10 ) and to 2-aryl-6,7-dihydro-4H-thiazolo[3,2-a]-1,3,5-triazin-4-ones ( 14 ), presumably through the corresponding N-ethoxycarbonylamidines.