Synthesis of Some New 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone Derivatives

4,5-Dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone계 화합물의 합성 연구

Abstract

The present study describes the synthesis of 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone derivatives. The synthesis of the first target compound, 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (1), was achieved by Friedel-Crafts acylation of o-cresyl methyl ether with succinic anhydride and subsequent cyclization of the intermediary g-keto acid with hydrazine hydrate. Condensation of compound 1 with aromatic aldehydes in the presence of sodium ethoxide affords the corresponding 4-substituted benzyl pyridazinones (3a-d). The dihydropyridazinone 1 underwent dehydrogenation upon treatment with bromine/acetic acid mixture to give (4). Pyridazine (5) has been synthesized upon the reaction of pyridazinone (1) with 1,3-diphenyl-2-propen-1-one under the Michael addition reaction. N-dialkylaminomethyl derivatives 6a-b have been obtained from the reaction of pyridazinone 1 with formaldehyde and secondary amine, whereas reaction of 1 with formaldehyde gives N-hydroxymethyl derivative (7). This study also includes the synthesis of the 3-chloropyridazine derivative 8 in excellent yield by heating pyridazinone 3b in phosphorus oxychloride. The behaviour of the chloro derivative toward sodium azide, benzyl amine and anthranilic acid was also studied. The proposed structures of the products were confirmed by elemental analysis, spectral data and chemical evidence.

4,5-Dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone derivative계 화합물의 합성연구를 수행하였다. 첫 번째로, 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (1)은 o-cresyl methyl ether와 succinic anhydride를 Friedel-Crafts 아실화 반응을 통하여 얻은 다음에, 고리화 반응을 통하여 합성하였다. 얻어진 화합물 1을, NaOEt조건 하에서, 방향족 알데히드와 반응시켜서 4-substituted benzyl pyridazinones (3a-d)을 합성하였으며, 화합물 1을 탈수소화반응을 시켜서 화합물 4를 얻었다. 한편 pyridazine 5는 화합물 1과 1,3-diphenyl-2-propen-1-one을 Michael 첨가반응을 이용하여 합성하였다. N-Dialkylaminomethyl 화합물 6a-b는 pyridazinone 1과 formaldehyde 및 2차 amine을 바능시켜서 얻은 반면에, 화합물 7은 pyridazinone 1을 반응시켜서 얻었으며, 화합물 8은 pyridazinone 3b를 phosphorus oxychloride 와 반응시켜서 얻었다.

INTRODUCTION

The 3(2H)-pyridazinone derivatives, particularly those bearing an aryl group at position-6, have attracted considerable attention due to their characteristic pharmacological and biological activities. They are reported to exhibit antiplatelet,1-2 antihypertensive,3-4 antimicrobial 5 analgesic and anti-inflammatory activities, 6 in addition they are known for their cardiovascular effects.7-8 These activities promoted the synthesis of a large number of pyridazinone derivatives in order to explore the usefulness of this heterocyclic system. In the present study, various new pyridazinone derivatives have been synthesized.

 

RESULTS AND DISCUSSION

β-Aroyl propionic acids have been successfully used in the synthesis of 6-aryl-3(2H)-pyridazinone by the reactions with hydrazines.9-10 arious new pyridazinone derivatives have been synthesized according to the reaction sequences outlined in Schemes 1-2. The key compound, 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone 1, was synthesized in good yield by Friedel-Crafts acylation of o-cresyl methyl ether with succininc anhydride11 and subsequent cyclization of the intermediate, 4-(4-methoxy-3-methylphenyl)-4-oxo-butanoic acid, with hydrazine hydrate in boiling ethanol.

Schemes 1.

The reaction of dihydropyridazinone 1 with appropriate aromatic aldehydes in the presence of sodium ethoxide afforded the corresponding 4-substituted benzyl pyridazinones 3a-d,12 which are the tautomers of 4-arylidene derivatives 2a-d. The 1H NMR of 3c showed two singlets at δ 2.26 and 3.86 corresponding to methyl and methoxy groups, respectively. The singlet at δ 3.94 which attributed to the presence of methylene group at the position-4 of the pyridazine ring is an evidence of the formation of the tautomers 3. The multiplets at δ 6.84-7.51 are indicative of the aromatic protons. The mass spectrum of 3b exhibits two ion peaks at m/z = 340 and 342 corresponding to M.+ and M.++2, respectively.

The dihydropyridazinone 1 underwent dehydrogenation upon treatment with bromine/acetic acid mixture to give 4. The 1H NMR of compound 4 showed two singlets at δ 2.28 and 3.89 corresponding to methyl and methoxy groups attached to benzene ring, respectively and the two doublets at δ 7.03 (J=9.85) and 7.73 (J=9.75) assigned to pyridazine protons H-5 and H-4, respectively. However, the singlet at δ 7.26 and the two doublets at δ 6.89 (J= 8.23) and 7.57 (J=9.80) are corresponding to aromatic protons and finally the singlet at 10.9 is due to NH proton.

The reaction of dihydropyridazinone 1 with 1,3-diphenyl- 2-propen-1-one under the Michael reaction condition caused the addition of the methylene group at position-4 of pyridazinone 1 to the double bond of the chalcone with the formation of pyridazinone 5.

The Mannich-reaction of the dihydropyridazinone 1 occurred at position-2 and not at position-4. Thus, in the reaction of pyridazinone 1 with formaldehyde and secondary amine in methanol, the N-dialkylaminomethyl group attaches itself to the ring nitrogen with the formation of 6a-b.

The N-hydroxymethyl derivative 7 was obtained via the interaction of pyrdazinone 1 with formaldehyde.13

Schemes 2.

On the other hand, the chloropyridazine derivative 8 has also been used as the key starting material for the synthesis of some new heterocyclic compounds. The 3-chloropyridazine 8 was prepared in excellent yield by heating pyridazinone 3b in phosphorus oxychloride. The IR spectrum of compound 8 showed the absence of absorption bands corresponding to NH and C=O groups. The tetrazole derivative 9 was prepared from 8 by refluxing with excess sodium azide in boiling dimethylformamide solution. Nucleophilic substitution of the chloro function in 8 with amines requires relatively harsh conditions by heating in a high boiling amine in solvent free condition. By this method, the benzylamino compound 10 could be obtained in good yield.

Also, compound 8 was reacted with anthranilic acid, in DMF affording pyridazino[3,2-b]quinazolinone 11. Our attempts to convert the chloropyridaznone 8 to hydrazino derivative were failed under different conditions.

 

EXPERIMENTAL

All melting points reported are uncorrected and determined by the open capillary tube method using Gallen Kamp melting point apparatus. Microanalyses were carried out by the Micro Analytical Center at Cairo University. The IR spectra were recorded on FT/IR-460 plus spectrophotometers using KBr pellets. The 1H NMR spectra were measured on Varian Gemini 300 MHz instrument with chemical shifts (d) in ppm downfield from TMS. Mass spectra were recorded on Shomadzu GC-MS (QP-1000EX) instrument operating at 70eV. Homogeneity of all synthesized compounds was established by TLC Silica gel 60 F254.

Synthesis of 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (1)

To a solution of 4-(4-methoxy-3-methylphenyl)-4-oxobutanoic acid (0.01 mole) in 20 ml ethanol, 1 ml of (80%) hydrazine hydrate was added. The reaction mixture was heated under reflux for 3 hrs. The solid product obtained after cooling was filtered off and crystallized from ethanol to give (1) as a white crystals. Yield: 73%; m.p.152-153℃; IR (KBr) õmax (cm-1): 3200 (NH), 2923 (CH, aliphatic), 1659 (C=O). 1H NMR (CDCl3) ä (ppm): 2.15 (s, 3H, CH3), 2.47-2.54 (t, 2H, H-5 pyridazine), 2.86-2.88 (t, 2H, H-4 pyridazine), 3.89 (s, 3H, CH3O), 6.78-7.59 (m, 3H, Ar-H). Anal. Calc. for C12H14N2O2 (218): C: 66.04, H: 6.47, N: 12.84. Found: C: 66.15, H: 6.41, N: 12.79.

Condensation of 4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (1) with aromatic aldehydes

To a solution of sodium ethoxide (prepared from 0.23 gm sodium and 30 ml absolute ethanol), pyridazinone (1) (0.01 mole) was added. The appropriate aldehyde (0.01 mole), namely benzaldehyde, p-chloro benzaldehyde, p-bromo benzaldehyde, and/ or p-anisaldehyde, was added with stirring. The reaction mixture was kept overnight; the solid product obtained was filtered off and crystallized from the proper solvent.

4-benzyl-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (3a): Yield: 61%; m.p. 200-202 ℃; IR (KBr) υmax (cm-1): 3133 (NH), 2965 (CH, aliphatic), 1652 (C=O), 1604 (C=N). 1H NMR (CDCl3) δ (ppm): 2.11 (s, 3H, CH3), 3.81 (s, 3H, CH3O), 3.92 (s, 2H, CH2), 6.80-7.74 (m, 9H, Ar-H), 10.7 (s, 1H, N-H pyridazine). Anal. Calc. for C19H18N2O2 (306): C: 74.49, H: 5.92, N: 9.14. Found: C: 74.60, H: 6.70, N: 9.20.

4-(4-chlorobenzyl-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (3b): Yield: 76%; m.p. 210-212 ℃; IR (KBr) υmax (cm-1): 3134 (NH), 2966 (CH, aliphatic), 1653 (C=O), 1606 (C=N). MS (m/z): 340- 342 (M+- M+2). 1H NMR (CDCl3) δ (ppm): 2.29 (s, 3H, CH3), 3.87 (s, 3H, CH3O), 3.96 (s, 2H, CH2), 6.89-7.65 (m, 8H, Ar-H), 11.31 (s broad, 1H, N-H pyridazine). Anal. Calc. for C19H17ClN2O2 (340): C: 66.96, H: 5.03, N: 8.22. Found: C: 66.99, H: 5.08, N: 8.50.

4-(4-bromobenzyl-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (3c): Yield: 67%; m.p. 231-233 ℃; IR (KBr) υmax (cm-1): 3117 (NH), 2956 (CH, aliphatic), 1659 (C=O), 1602 (C=N). 1H NMR (CDCl3) δ (ppm): 2.26 (s, 3H, CH3), 3.86 (s, 3H, CH3O), 3.94 (s, 2H, CH2), 6.84-7.51 (m, 8H, Ar-H), 10.9-11 (s broad, 1H, N-H pyridazine). Anal. Calc. for C19H17BrN2O2 (385): C: 59.24, H: 4.45, N: 7.27. Found: C: 59.33, H: 4.50, N: 7.30.

4-(4-methoxybenzyl-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (3d): Yield: 60%; m.p. 184-185 ℃;IR (KBr) υmax (cm-1): 3133 (N-H), 2957 (CH aliphatic), 1651 (C=O), 1604 (C=N). 1H NMR (CDCl3) δ (ppm): 2.17 (s, 3H, CH3), 3.82 (s, 3H, CH3O), 3.83 (s, 3H, CH3O), 3.94 (s, 2H, CH2), 6.82-7.89 (m, 8H, Ar-H), 11.44 (s, 1H, N-H pyridazine). Anal. Calc. for C20H20N2O3 (336): C: 71.41, H: 5.99, N: 8.33. Found: C: 71.70, H: 6.05, N: 8.43.

Synthesis of 6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (4)

A stirred solution of pyridazinone (1) (0.01 mol) in glacial acetic acid (20 ml) was treated dropwise with bromine solution (0.012 mol in glacial acetic acid (10 ml)) at room temperature during 30 min. The solution was further stirred for 2 hrs, and then kept overnight. The precipitated product was filtered off, washed with ether and crystallized from ethanol to give (4). Yield: 56%; m.p. 240-242 ℃; IR (KBr) υmax (cm-1): 2924 (CH, aliphatic), 1670 (C=O), 1588 (C=N). 1H NMR (CDCl3) δ (ppm): 2.28 (s, 3H, CH3), 3.89 (s, 3H, CH3O), 6.89 (d, 1H, H-5 pyridazinone, J=8.23), 7.15 (d, 1H, H-6 benzene ring, J=9.85), 7.27 (s, 1H, H-2 benzene ring), 7.57 (d, 1H, H-5 benzene ring J=9.80), 7.73 (d, 1H, H-4 pyridazinone J=9.75), 10.9 (s (broad), 1H, N-H pyridazine). Anal. Calc. for C12H12N2O2 (216): C: 66.65, H: 5.59, N: 12.95. Found: C: 66.87, H: 5.70, N: 13.89.

Synthesis of 4,5-dihydro-6-(4-methoxy-3-methylphenyl)- 4-[3-oxo-1,3-diphenylpropyl]-3(2H)-pyridazinone (5)

To a solution of 0.01 mol pyridazinone (1) and potassium ethoxide (0.01 mol) in 30 mL absolute ethanol, 1,3-diphenyl propanone (0.01 mol) was added. The reaction mixture was heated under reflux for 4 hrs then left overnight at room temperature. The reaction mixture was acidified with dil. HCl. The solid product obtained was filtered off, washed with H2O and crystallized from ethanol to give (5). Yield: 66%; m.p. 190-191 ℃; IR (KBr) υmax (cm-1): 3208 (NH), 2916 (CH aliphatic), 1674 (C=O), 1603 (C=N). 1H NMR (CDCl3) δ (ppm): 2.21 (s, 3H, CH3), 2.64 (m, 1H, H-5 pyridazin), 2.84 (m, 1H, Ph-CH), 3.47 and 3.81 (2m, 2H, CO-CH2), 3.67 (m, 1H, H-4, pyridazine) 3.86 (s, 3H, CH3O), 6.75-7.89 (m, 13H, Ar-H), 8.66 (s, 1H, N-H pyridazine). Anal. Calc. for C27H26N2O3 (426): C: 76.03, H: 6.14, N: 6.57. Found: C: 76.24, H: 6.18, N: 6.68.

Synthesis of 2-[dialkylaminomethyl]-4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (6a-b)

An aqueous solution of formaldehyde (3 ml, 35%) was added to a mixture of pyridazinone (1) (0.01 mole) and the appropriate secondary amine (0.02 mole) in ethanol, the reaction mixture was kept overnight at room temperature. The solid product obtained after dilution with water was filtered off and crystallized from the proper solvent to give 6a-b.

2-[piperidinomethyl]-4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (6a): Yield: 67%; m.p. 82-83 ℃; IR (KBr) υmax (cm-1): 2927 (CH, aliphatic), 1678 (C=O), 1604 (C=N). 1H NMR (CDCl3) δ (ppm): 2.26(s, 3H, CH3), 2.51-2.54(t, 2H, H-5 pyridazine), 2.55-2.72 (m, 10H, piperidine), 2.91-2.96 (t, 2H, H-4 pyridazine), 3.87 (s, 3H, CH3O), 4.79 (s, 2H, N-CH2-N) 6.84-7.57(m, 3H, Ar-H). Anal. Calc. for C18H25N3O2 (315): C: 68.54, H: 7.99, N: 13.32. Found: C: 68.64, H: 8.09, N: 13.36.

2-[morpholinomethyl]-4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (6b): Yield: 53%; m.p. 152-154 ℃; IR (KBr) υmax (cm-1): 2925 (CH, aliphatic), 1675 (C=O), 1605 (C=N). 1H NMR (CDCl3) δ (ppm): 2.18 (s, 3H, CH3), 2.57-2.59 (t, 2H, H-5 pyridazine), 2.91-2.96 (t, 2H, H-4 pyridazine), 3.15-3.23 (m, 4H, -N(CH2)2- morpholine), 3.87(s, 3H, CH3O), 3.92-3.97 (m, 4H, -O(CH2)2- morpholine), 4.86 (s, 2H, N-CH2-N) 6.81- 7.39(m, 3H, Ar-H). Anal. Calc. for C17H23N3O3 (317): C: 64.33, H: 7.30, N: 13.24. Found: C: 65.03, H: 7.35, N: 13.30.

Synthesis of 2-[hydroxymethyl]-4,5-dihydro-6-(4-methoxy-3-methylphenyl)-3(2H)-pyridazinone (7)

A mixture of (0.01 mole) pyridazinone 1, aqueous formaldehyde (10 ml, 35%) and 20 ml water was refluxed for 4hrs. The solid product obtained after cooling was filtered off and crystallized from ethanol to give 7 as a white crystals. Yield: 81%; m.p. 171-173 ℃; IR (KBr) υmax (cm-1): 3315 (OH), 2963 (CH aliphatic), 1642 (C=O). 1H NMR (CDCl3) δ (ppm): 2.25 (s, 3H, CH3), 2.56-2.63 (t, 2H, H-5 pyridazine), 2.92-2.95 (t, 2H, H-4 pyridazine), 3.86 (s, 3H, CH3O), 5.29 (s, 2H, N-CH2-O), 6.82-7.61(m, 3H, Ar-H). Anal. Calc. for C13H16N2O3 (248): C: 62.89, H: 6.50, N: 11.28. Found: C: 62.86, H: 6.48, N: 11.20.

Synthesis of 3-chloro-4-(4-chlorobenzyl)-6-(4-methoxy-3-methylphenyl)-pyridazine (8)

A suspension of 3b (2 gm) in phosphorus oxychloride (20 ml) was refluxed for 4 hrs on a water bath at 70 ℃. The reaction mixture, after cooling, was poured gradually into a mixture of crushed ice and sodium bicarbonate. The solid product obtained was collected by filtration and crystallized from ethanol to give 8 as colorless crystals, yield: 93%; m.p. 122- 124 ℃; IR (KBr) υmax (cm-1): 2923 (CH aliphatic), 1603 (C=N). 1H NMR (CDCl3) δ (ppm): 2.28 (s, 3H, CH3), 3.89 (s, 3H, CH3O), 4.11 (s, 2H, CH2), 6.90-7.80 (m, 8H, Ar-H). Anal. Calcd. for C19H16Cl2N2O (359): C: 63.52, H: 4.49, N: 7.80. Found: C: 63.50, H: 4.40, N: 7.78.

Synthesis of 8-(4-Chlorobenzyl)-6-(4-methoxy-3-methylphenyl)-tetrazolo[1,5-b]pyridazine (9)

To a solution of the chloro compound 8 (1 mmole) in DMF (10 mL) was added sodium azide (3 mmol), and the mixture was refluxed for 24 hrs. the product was collected by filtration and recystallized from DMF to give 9 as colorless crystals, yield: 53%; m.p. 190-192 ℃ (decomp); IR (KBr) υmax: 2923 (CH aliphatic), 1603 (C=N). 1H NMR (CDCl3) δ (ppm): 2.30 (s, 3H, CH3), 3.91 (s, 3H, CH3O), 4.49 (s, 2H, CH2), 6.92-7.89 (m, 8H, Ar-H). Anal. Calc. for C19H16ClN5O (365): C: 62.38, H: 4.41, N: 19.14. Found: C: 62.30, H: 4.41, N: 19.10.

Synthesis of 3-benzylamino-4-(4-chlorobenzyl)-6-(4-methoxy-3-methylphenyl)-pyridazine (10)

A mixture of the chloro compound 8 (1 mmol) and benzylamine (2 mmol) was heated on oil bath for 6 hrs and the residue was triturated with diethyl ether, followed by crystallization from ethanol to give 10 as buff powder, yield: 53%; m.p. 169-170 ℃; IR (KBr) υmax (cm-1): 3426 (NH), 2950 (CH aliphatic), 1604 (C=N). 1H NMR (CDCl3) δ (ppm): 2.30 (s, 3H, CH3), 3.91 (s, 3H, CH3O), 4.49 (s, 2H, CH2), 6.92-7.89 (m, 8H, Ar-H). Anal. Calc. for C25H22ClN3O (415): C: 72.19, H: 5.33, N: 10.10. Found: C: 72.13, H: 5.30, N: 10.10.

Synthesis of 4-(4-chlorobenzyl)-2-(4-methoxy-3-methylphenyl)-10-oxo-pyridazino[3,2-b]quinazoline (11)

A mixture of the chloro compound 8 (1 mmol) and anthranilic acid (2 mmol) was heated in an oil bath for 4 hrs, the solid product was collected and crystallized from ethanol to give compound 11 as colorless crystals, yield: 66%; m.p. 202-204 ℃; IR (KBr) υmax (cm-1): 2902 (CH aliphatic), 1651 (C=O) 1606 (C=N). 1H NMR (CDCl3) δ (ppm): 2.24 (s, 3H, CH3), 3.86 (s, 3H, CH3O), 3.99 (s, 2H, CH2), 6.84-7.50 (m, 12H, Ar-H). Anal. Calc. for C26H20ClN3O2 (441): C: 70.67, H: 4.56, N: 9.51. Found: C: 70.49, H: 4.50, N: 9.47.