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Synthesis of pyrazolo[3,4-b]pyrazine starting with pyrazine moietyOnly 14 pages are availabe for public view
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Abstract
The starting material, 3-methyl-6-oxo-1-phenyl-6,7-dihydro-1H-pyrazolo[3,4-b] pyrazine-5-carbonitrile (71) was synthesized by the reaction of 5-amino-3-methyl-4-nitroso-1-phenyl pyrazole (48a) with ethyl cyanoacetate in the presence of anhydrous pyridine. Also, 6-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonitrile (306) was prepared by the reaction of compound 71 with phosphorus oxychloride.
Fig.1. The chemical structures of the synthetic compounds 48a, 71 & 306.
Reaction of compound 71 with some α-halocarbonyl compounds namely: diethyl 2-bromomalonate, phenacyl bromide and chloroacetone in the presence of acetone and anhydrous potassium carbonate afforded the o-alkylated derivatives 307a-c. The latter compounds underwent Thorpe-Zeigler cyclization upon heating in ethanolic sodium ethoxide solution to give 5-amino-6-substituted-furopyrazolopyrazine derivatives 308a-c. Compound 308a was also obtained from 307a by heating with an equimolar amount of hydrazine hydrate.
Fig. 2 . The chemical structures of the synthetic compounds 307a-c& 308a.
Cyclocondensation reaction of the aminobenzoyl 308b with diethyl malonate in ethanol afforded the oxopyridine carboxylate derivative 309. Moreover, the reaction of o-aminoester compound 308a with ethanolamine in refluxing ethanol yielded hydroxyethyl carboxamide derivative 310. Treatment of o-aminoester 308a with hydrazine hydrate in refluxing ethanol for a long time afforded the corresponding carbohydrazide 311. The amino carbohydrazide compound 311 was obtained by an alternative route through the reaction of diethyl oxymalonate ester 307a with excess hydrazine hydrate under solvent free conditions.
Fig. 3. The chemical structures of the synthetic compounds 309- 311.
Diazotization of amino carbohydrazide 311 with sodium nitrite solution in acetic acid at 0–5°C afforded the corresponding carbonyl azide 312. The produced carbonyl azide underwent Curtius rearrangement upon boiling in dry xylene to give the imidazofuropyrazolopyrazine 313. Furthermore, condensation of the aminocarbohydrazide 311 with acetyl acetone in ethanol under reflux yielded the corresponding amino dimethyl pyrazolyl compound 314. Also, condensation of the carbohydrazide 311 with triethyl orthoformate afforded the ethoxymethyleneamino pyrimidinone derivative 315.
Moreover, heating of the carbohydrazide 311 with formic acid led to the formation of N-formyl aminopyrimidinone compound 316. Similarly, when the carbohydrazide compound 311 was allowed to react with acetic anhydride, the methyl-N-diacetyl aminopyrimidinone derivative 317 was obtained. Furthermore, condensation of the carbohydrazide 311 with aromatic aldehydes yielded the corresponding Schiff’s bases 318a,b which were cyclized using triethyl orthoformate to afford the arylideneamino pyrimidinone derivatives 319a,b.
Fig. 4. The chemical structures of the synthetic compounds 312- 319a,b.
Chloroacetylation reaction of o-aminoester 308a with chloro acetyl chloride in dioxane afforded the corresponding chloroacetylamino derivative 320 which underwent nucleophilic substitution reaction with aniline to give the phenyl aminoacetamido compound 321. Also, the chloroacetylamino compound 320 was reacted with potassium thiocyanate to give pyrimidinylsulfanyl acetate derivative 322.
Fig. 5. The chemical structures of the synthetic compounds 320- 322.
The amino group of compounds 308a,c was converted to the pyrrolyl moiety via its reaction with 2,5-dimethoxytetrahydrofuran in boiling acetic acid to afford pyrrolyl derivatives 323a,c. Hydrazinolysis of 323a afforded the corresponding carbohydrazide 324. Consequently, the reaction of pyrrolyl carbohydrazide 324 with nitrous acid yielded the corresponding carbonyl azide 325. The latter compound underwent Curtius rearrangement followed by ring closure upon boiling in dry xylene to afford the pyrrolopyrazinone compound 326. Condensation of pyrrolyl carbonylazide 324 with acetyl acetone afforded the corresponding Schiff,s base 327 which underwent ring closure reaction upon boiling in acetic acid to give the dimethylpyrazolyl 328.
Fig. 6. The chemical structures of the synthetic compounds 323a,b- 328.
All attempts to convert the chloropyrazolopyrazine carbonitrile 306 to the mercaptopyrazolopyrazine carbonitrile 329 using thiourea in ethanol as the traditional method, failed affording the chloropyrazolopyrazine carbonitrile starting material 306. In the present work, we have reported a new and a facile method for synthesis of 5-amino-6-substituted-3-methyl-1-phenyl-1H-thieno[3,2-e]pyrazole[3,4-b]pyrazines 331a-e by the reaction of elemental sulfur with chloropyrazolopyrazine carbonitrile compound 306 in the presence of sodium borohydride afforded the non-isolated intermediate sulfanyl sodium salt A, which was used in situ for the next reactions with α-halogenated alkylating agents to afford the S-alkylated pyrazolopyrazine carbonitrile 330a–e. The latter compounds underwent Thorpe-Ziegler cyclization by heating in ethanolic sodium ethoxide solution to give the 5-amino-6-substituted thienopyrazolopyrazine compounds 331a–e
Fig.7. The chemical structures of the synthetic compounds 306 – 331a-e.
Heating the o-aminocarbonitrile compound 331c with a slight excess of triethyl orthoformate in presence of catalytic amount of acetic anhydride yielded the ethoxymethyleneamino compound 332. Treatment of the ethoxymethyleneamino 332 with an equimolar amount of hydrazine hydrate in dioxane at room temperature produced the corresponding amino-iminopyrimidine derivative 333. Thus, the reaction of amino-iminopyrimidine compound 333 with carbon disulfide and phenyl isothiocyanate in pyridine furnished the corresponding triazolethione 334 and phenyl thiourea 335, respectively.
Fig. 8. The chemical structures of the synthetic compounds 332 – 335.
Reaction of the amino-imino 333 with triethyl orthoformate in acetic acid yielded the corresponding pyrazolopyrazinothienotriazolopyrimidine compound 336. Also, the reaction of 333 with acetyl acetone under neat conditions in absence of solvent afforded the corresponding methyltriazolo compound 337 instead of the expected dimethyl triazepine 338. Moreover, condensation of the amino-imino compound 333 with benzaldehyde afforded the dihydrophenyl triazole compound 339. Thus, condensation of the amino-imino 333 with diethyl malonate afforded the corresponding ethyl triazolopyrimidinyl acetate 340. Similarly, reaction of the amino-imino compound 6 with ethyl benzoylacetate afforded the expected phenyl triazepinone product 341. It’s interesting to note that the triazepinone compound 341 exists in two tautomeric forms 341A and 341B.
Fig. 9. The chemical structures of the synthetic compounds 336 – 341.
Consequently, the reaction of o-aminocarbonitrile 331c with 1,3-propanediamine in the presence of carbon disulfide afforded the amino tetrahydropyrimidinyl derivative 342. Thus, when the amino tetrahydropyrimidinyl 342 was allowed to react with triethyl orthoformate and benzaldehyde yielded the corresponding tetrahydropyrimido pyrimidine 343 and phenyl hexahydropyrimidopyrimidine 344, respectively rather than the expected Schiff,s base 345. Subsequently,the reaction of compound 342 with carbon disulfide in pyridine afforded the pyrimidine thione compound 346, which in turn was converted into the S-ethylsulfanyl acetate derivative 347 via the reaction with ethyl chloroacetate in DMF and anhydrous potassium carbonate.
Fig.10. The chemical structures of the synthetic compounds 342 – 347.
Chloroacetylation reaction of the o-aminocarbonitrile derivative 331c with chloroacetyl chloride in dioxane followed by neutralization with sodium carbonate solution furnished the chloroacetyl amino 348 which underwent nucleophilic substitution followed by Dimorth rearrangement upon reaction with aniline to give 6-phenyl aminomethyl-3-methyl-1-phenyl-1H-pyrazolo[4’’,3”:5’,6’]pyrazino[3’,2’:4,5]thieno[3,2-d] pyrimidine-8(7H)-one (349).
Fig.11. The chemical structures of the synthetic compounds 348 – 349.
The amino group of pyrazolothienopyrazine derivatives 331a,d were converted to the pyrrolyl moiety via its reaction with 2,5-dimethoxytetrahydrofuran in boiling acetic acid to afford the pyrrolyl derivatives 350a,d. Hydrazinolysis of o-amino-ester compound 331a afforded the corresponding carbohydrazide 351. When the amino carbohydrazide 351 was subjected to react with triethyl orthoformate in the presence of glacial acetic acid afforded the corresponding ethoxymethyleneaminopyrimidinone 352. The cyclocondensation of derivative 331d with diethyl malonate in refluxing ethanol afforded the ethyloxopyridine carboxylate derivative 353. Also, condensation of pyrroloacetyl compound 350d with N,N-dimethylformamide diethylacetal in dioxane afforded 6-(3-N,N-dimethylamino)acryloyl-3-methyl-5-(pyrrol-1-yl)-1-phenyl-1H-thieno[3,2-e]pyrazolo[3,4-b]pyrazine (354).
Fig.12. The chemical structures of the synthetic compounds 350a,d-354.
Alkaline hydrolysis of o-aminoester 331a with an ethanolic potassium hydroxide solution followed by acidification with diluted hydrochloric acid gave the o-amino carboxylic acid 355 .When the o-amino carboxylic acid 355 was heated with acetic anhydride, the oxazinone 356 was obtained upon ring closure reaction. Nucleophilic substitution reaction of oxazinone 356 with different amines namely: aniline, ammonium acetate and hydrazine hydrate led to the formation of N-substituted pyrimidi none 357-359, respectively.
Fig.13. The chemical structures of the synthetic compounds 355 – 359.
Treatment of o-amino carboxylic acid 355 with ethanolic sodium hydroxide solution led to the formation of sodium carboxylate salt 360. The latter compound was converted into the o-alkylated derivatives 361a,b upon reaction with α-haloketones namely: chloroacetone and phenacyl bromide in DMF and anhydrous potassium carbonate. Also, when chloroacetonitrile was used in the above reaction instead of α-haloketones, the 1,4-oxazepinone derivative 362 was obtained. On the other hand, heating of 361b with polyphosphoric acid on water bath at 60-70 °C afforded 7-hydroxy-3-methyl-1,6-diphenyl-1,5-dihydropyrido[2ʹ,3ʹ: 4,5]thieno[3,2-e]pyrazolo[3,4-b]pyrazin-8-one (363).
Fig.14. The chemical structures of the synthetic compounds 360 – 363.
The chemical structures of the newly synthesized compounds were confirmed by elemental and spectral analyses FT-IR, 1H NMR, 13C NMR and mass spectra. Also, the biological activities were evaluated in vitro anti-microbial and in vivo anti-inflammatory agents of some thienopyrazolopyrazines heterocycles in comparison with the standard drugs.