Synthesis of 3-(2-aminoethyl)-5-hydroxy-1 H -pyrazole derivatives

Treatment of β -keto ester 8 with hydrazines 9a–g gave 1'-substituted tert -butyl 2-(5-hydroxy-1 H - pyrazol-3-yl)ethylcarbamates 10a–e and 2-(5-oxo-2,5 - dihydro-1 H -pyrazol-3-yl)ethylcarbamates 11f,g . Acidolytic deprotection of 10b,c afforded the corresponding 3-(2-aminoethyl)-5-hydroxy- 1 H -pyrazoles 6b,c in good yields. Acylation of 6 gave either the N -acyl compounds 12b,c and 13c , or the N , O-diacyl derivative 14 . Next, three N , N-dialkyl analogues 15a,b and 26c were prepared from dimethyl acetone-1,3 -d icarboxylate 21 via condensation with hydrazines 9a and 9h followed by hydrolysis of the esters 22a,b , amidation of the carboxylic acids 23a,b , and reduction of the tertiary carboxamides 24a and 25b,c .


Introduction
Novel 2-(heteroaryl)ethylamine-containing molecules represent important targets in medicinal and synthetic organic chemistry because these compounds are synthetic analogs of histamine 1, tyramine, dopamine, tryptamine, serotonin, and melatonin, which are involved as chemical messengers in numerous biological processes. 1yrazoles 2 and imidazoles 3 are important classes of structurally closely related heterocyclic compounds.The ability of 1-unsubstituted derivatives to act as proton acceptor and donor simultaneously is probably the most important common feature of both systems.In contrast to We found pyrazolols 6 interesting because they are structurally closer analogues of histamine 1 than their known regioisomers 2. Like histamine 1, compounds 6 have the aminoethyl residue attached at the position adjacent to the ring nitrogen atom.Besides, 3-(2-aminophenyl)pyrazolols could also serve as useful building blocks for further transformations including combinatorial studies.As a result of our research efforts in this field, we now report two simple syntheses of title compounds 6 and their derivatives.

Scheme 3
Reagents and conditions: i: R The structures of novel compounds 6b,c, 10a-e, 11f,g, 12b,c, 13c, 14, 15a,b, 22b, 24a, 25b,c, and 26c were determined by spectroscopic methods (IR, 1 H and 13 C NMR, NOESY spectroscopy, and MS) and by elemental analyses for C, H, and N. Compounds 23a,b, 24a, and 25b,c were not obtained in analytically pure form.The identities of carboxamides 24a and 25b,c were confirmed by 1 H NMR, 13 C NMR and HRMS, while the intermediate carboxylic acids 23a,b were characterized only by 1 H NMR and HRMS.Physical and spectral data for known compounds 18a, 10a 18b, 10b,c 19a, 11a 19b, 11b and 22a 12a were in agreement with the literature data.

Conclusions
In summary, two synthetic methods for the preparation of a novel type of pyrazole analogues of histamine 6, 15, and 26 were developed.The first method starts from Boc-β-alanine 7, which is transformed in three steps into the title compounds, 1-substituted 3-(2-aminophenyl)-1H-pyrazol-5(4H)-ones 6.Further acylation of 6 in methanol produced the N-acyl derivatives 12 and 13, while acylation of 6c in dichloromethane led to the N,O-diacylated compound 14.The second method enables access to N,N-dialkyl analogues 15.It comprises cyclisation of dialkyl acetone-1,3dicarboxylate 21 with monosubstituted hydrazines 9 to give alkyl pyrazolone-3-acetates 22, followed by a three-step transformation into 3-(2-(dialkylamino)phenyl)-1H-pyrazol-5-ols 15 and 26.These synthetic methods enable easy access to a novel type of histamine analogues as interesting molecules for biological studies.

General procedure for the preparation of carboxamides (24a) and (25b,c)
A suspension of the ester 22 (10 mmol) in 1.5 M aq.NaOH (40 mL) was vigorously stirred at r.t. for 24 h.Reaction mixture was neutralized with 3 M aq.HCl (20 mL) and stirred for additional 15 min at r.t.The product was extracted with EtOAc (3×100 mL), the combined organic phase was dried over anh.Na2SO4, filtered, and the volatile components were evaporated in vacuo to give 23a,b as sticky resins, which were characterised by 1 H NMR and HRMS and then used for further amidation without purification.Under argon, the crude acid 23 (10 mmol) was dissolved in anh.THF (40 mL), 1,1'-carbonyldiimidazole (2.432 g, 15 mmol) was added, and the reaction mixture was stirred at r. t. for 2 h.Then, the corresponding amine 17 (40 mmol) was added and stirring at r.t. was continued for 3 h.Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with 1 M aq.NaHSO4 (100 mL).The organic phase was dried over anh.Na2SO4, filtered, and volatile components were evaporated in vacuo.The residue was purified by CC (EtOAc/hexanes).Fractions containing the product were combined and volatile components were evaporated in vacuo to give 24 or 25 as a viscous oil.

Table 1 .
Selected experimental data for compounds 6

Table 2 .
Selected experimental data for compounds