Description:Field of Invention: This invention describes the synthesis of (E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one by refluxing the substituted 1-carbothiamide with different phenacyl bromides in ethanol yielded target compounds, where aryl group may be C6H5, p-F-C6H4, p-Cl-C6H4, p-Br-C6H4, p-CH3-C6H4, p-OCH3-C6H4, p-NO2-C6H4, p-CF3-C6H4, p-OCF3-C6H4, p-C6H5-C6H4, p-CN-C6H4, 2-Naphthyl, 3-acetylcoumarin.
Background: A hybrid-structure of two or more heterocyclic scaffolds is a promising tool in drug discovery. It is evident from literature that synthesis of compounds containing thiazole and azole rings are the lead candidates as novel biologically potent molecules (J. Med. Chem. 2017, 60, 7108-7122). Thiazol-2-yl-1H-pyrazol-5(4H)-one, mainly thiazole clubbed pyrazolone nucleus, seeks attention due to their promising biological activity like antitubercular, anti-inflammatory, anti-mycobacterial, anti-microbial, anticancer activity (BMC Chem. 2019, 13, 116). Pyrazolone and its derivatives represent a class of compounds which have significant results in medicinal chemistry (BMC Chem. 2020, 53, 356-376). Various FDA approved drugs and natural products bearing thiazole nucleus were reported for their pharmacological potential such as antimalarial, antiviral, antitumor, and antimycobacterial (BMCL 2019, 29, 1199–2012; Mol. 2021, 26, 3166). Moreover, thiazole derivatives have a wide range of biological activities such as anticancer, antiviral, anti-inflammatory, anti-mycobacterial, CNS active agents, and antimicrobial activities (J. Saudi Chem. Soc. 2023, 27, 101669; Med. Chem. Res. 2016, 25, 2237-2249). On the other hand, pyrazole condensed with other key heterocyclic active motifs exhibit various pharmacological activities such as anticancer, anti-tubercular, antipyretic, and anti-inflammatory (Med. Chem. Res. 2015, 24, 3863-3875; Eur. J. Med. Chem. 2014, 81, 267-276). In addition to it, modification or incorporation of pyrazole nucleus in different structure leads to various applications in different fields like agriculture, medicine and technology (Sci. Rep. 2023, 13, 19170). Moreover, structure-activity relationship revealed that substitution of 4-phenylthiazole at position-1 instead of position-4 of pyrazole ring is responsible to show remarkable biological potential. Literature survey revealed the biological and structural significance of pyrazole and thiazole motifs which make them suitable candidates for synthesis. Keeping in mind the aforementioned facts, pharmacological importance of thiazolyl-pyrazolone and in continuation of our ongoing work to synthesize new biologically active heterocyclic scaffolds, it was planned to synthesize new thiazole linked pyrazolone derivatives with an expectation to develop new potential bioactive scaffolds.

Detailed Description of the Invention:
In view of the biological potential of thiazolyl-pyrazoles and in continuation of our research work to synthesize essential heterocyclic active motifs, thirteen new hybrid heterocycles (5a-m) were synthesized and characterized (Scheme 1). To achieve the targeted compound, (E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-ones (5a), the reactant (3) was treated with different derivative of phenacyl bromides (4a-m) at 80 °C temperature in ethanol. Initially, substituted Aniline (1) was diazotized which upon treatment with ethylacetoacetate gave ester derivative (3a) followed by reaction with thiosemicarbazide which resulted in formation of 1-carbothioamide (4) a key intermediate for targeted compounds. All compounds were synthesized by adopting the similar procedure and physical data of the synthesized compounds were mentioned in Table-1.

Scheme-1: Synthesis of (E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-arylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-ones (5a-m)
Table-1: Reaction times and percentage yields and observed melting points of the synthesized compounds (5a-m)
Sr. No. Compd. Ar T1 (h) Yield (%) Color
Observed M.pt.
(?)
1 5a C6H5 2 85 Orange 232-235
2 5b p-F-C6H4 2.5 80 Orange 253-255
3 5c p-Cl-C6H4 3 79 Orange 241-243
4 5d p-Br-C6H4 3 67 Orange 227-229
5 5e p-CH3-C6H4 2 68 Orange 241-244
6 5f p-OCH3-C6H4 2.5 78 Orange 230-233
7 5g p-CF3-C6H4 2 78 Orange 245-247
8 5h p-OCF3-C6H4 2.5 81 Orange 180-182
9 5i p-NO2-C6H4 3 74 Orange 269-270
10 5j p-C6H5-C6H4 3.5 71 Orange 212-214
11 5k p-CN-C6H4 2 71 Orange 212-214
12 5l 2-Naphthyl 2.5 73 Orange 215-219
13 5m 3-coumarin 2.5 75 Orange 201-205

Structures of synthesized compounds were characterized by analysing their spectroscopic data. In the FT-IR spectrum of 2, stretching peaks at 1699-1702 cm-1 and 1647 cm-1 confirmed the presence of ester and carbonyl group respectively. Additionally, the presence of the ester group was confirmed by the presence of an intense peak at 1200 cm-1 due to C-O stretching frequency. The disappearance of C=O stretching peak at 1735 cm-1 corresponding to ester group and appearance of N-H stretching bands at 3140 cm-1 and 3387 cm-1 due to symmetric and asymmetric stretching respectively confirmed the formation of 4a. In 1H NMR spectrum of 5a-m, disappearance of quartet and triplet signals at d 4.41 ppm and 1.42 ppm and appearance of two signals at d 6.89 and 8.79 for NH2 also confirmed the formation of 4a. In contrast, disappearance of NH2 band of carbothioamide in FT-IR as well as disappearance of two signals corresponding to NH2 and appearance of singlet at d 7.21 ppm corresponding to 5-H proton of thiazole moiety, in 1H NMR spectrum, confirmed the formation of desired product (5a-m). Further, structure of 5a validated on the basis of 13C NMR spectral data in which signal corresponding to C-2, C-3, C-4 of thiazole system appear at d 160, 152 and 110 ppm, respectively. The mass spectra of synthesized compounds is in well agreement with formula weights of thiazolyl-pyrazoles, final targeted compounds.

Fig. 1. Lattice picture of Compound (5b) along a-c plane and representation of intramolecular weak interactions within the molecules.
Furthermore, structure of the compounds (5a-m) were established on the basis of the data of single crystal X-ray analysis of one of represented compound. Crystals of 5b were obtained through a straightforward slow evaporation technique utilising chloroform as the solvent. The crystallographic analysis unveiled that 5b crystallises in an orthorhombic space group Pccn. The C-S bond lengths (1.722 Å and 1.710 Å) and the angles within the newly formed thiazole ring matched existing values. The lattice structure of 5b represents the zig-zag packing of molecules in the a-c plane, as shown in (Fig. 1). A weak intramolecular interactions between S, O and N are present in molecules.
General procedure for the synthesis of (E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-arylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-ones (5a-m)
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothioamide 3 (0.03 moles, 1 eq) and different substituted phenacyl bromides (5a-m, 0.03 moles, 1eq) were dissolved in ethanol and the reaction mixture was refluxed for 2 h at 80 °C until complete precipitation. After completion of the reaction, solid obtained was filtered on suction, washed from cold ethanol to yield targeted compounds 5a-m in good yields and noted the melting points.
Physical and characterization data of the synthesized compounds are given below
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one 5a. IR (?max cm-1): 3120 (N-H str.), 1669 (C=O str.), 1560 (C=N str.), 1519 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.26 (s, 1H, NH, D2O exchangeable), 7.95 (m, 2H, 2'',6''-H), 7.77 (d, 1H, 2'''-H, J = 2.3 Hz), 7.57 (d, 1H, 5'''-H J = 8.7 Hz), 7.53 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.41 (m, 2H, 3'',5''-H), 7.32 (m, 1H, 4''-H), 7.29 (s, 1H, 5'-H), 2.47 (s, 3H, 3-CH3); MS: m/z 464.0458 (M)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-fluorophenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5b. IR (?max cm-1): 3110 (N-H str.), 1659 (C=O str.), 1556 (C=N str.), 1517 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.27 (s, 1H, NH, D2O exchangeable), 7.93 (m, 2H, 2'',6''-H), 7.78 (d, 1H, 2'''-H, J = 2.3 Hz), 7.58 (d, 1H, 5'''-H J = 8.7 Hz), 7.54 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.22 (s, 1H, 5'-H), 7.10 (m, 2H, 3'',5''-H), 2.47 (s, 3H, 3-CH3); MS: m/z 482.0395 (M)+
(E)-4-(2-(4-chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-chlorophenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5c. IR (?max cm-1): 3115 (N-H str.), 1656 (C=O str.), 1555 (C=N str.), 1519 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.26 (s, 1H, NH, D2O exchangeable), 7.89 (m, 2H, 2'',6''-H), 7.78 (d, 1H, 2'''-H, J = 2.3 Hz), 7.58 (d, 1H, 5'''-H J = 8.7 Hz), 7.54 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.28 (s, 1H, 5'-H), 7.39 (m, 2H, 3'',5''-H), 2.47 (s, 3H, 3-CH3); MS: m/z 498.0060 (M+1)+ and 500 (M+1+2)+ showing typical chlorine isotope profile in ratio (3:1)
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-bromophenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5d. IR (?max cm-1): 3112 (N-H str.), 1661 (C=O str.), 1555 (C=N str.), 1516 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.23 (s, 1H, NH, , D2O exchangeable), 7.81 (m, 2H, 2'',6''-H), 7.76 (d, 1H, 2'''-H, J = 2.3 Hz), 7.57 (d, 1H, 5'''-H J = 8.7 Hz), 7.53 (m, 3H, 3'',5'',6'''-H), 7.28 (s, 1H, 5'-H), 2.46 (s, 3H, 3-CH3); MS: m/z 543.9509 (M+1)+ and 545.8903 (M+1+2)+ showing typical chlorine isotope profile in ratio (1:1)
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-(p-tolyl)thiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one 5e. IR (?max cm-1): 3114 (N-H str.), 1659 (C=O str.), 1554 (C=N str.), 1517 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.26 (s, 1H, NH, D2O exchangeable), 7.84 (m, 2H, 2'',6''-H), 7.77 (d, 1H, 2'''-H, J = 2.3 Hz), 7.57 (d, 1H, 5'''-H J = 8.7 Hz), 7.52 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.24 (s, 1H, 5'-H), 7.22 (m, 2H, 3'',5''-H), 2.47 (s, 3H, 3-CH3), 2.38 (s, 3H, 4''-CH3); MS: m/z 478.0606 (M+1)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-methoxyphenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5f. IR (?max cm-1): 3112 (N-H str.), 1661 (C=O str), 1558 (C=N str.), 1516 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.22 (s, 1H, NH, D2O exchangeable), 7.85 (m, 2H, 2'',6''-H), 7.74 (d, 1H, 2'''-H, J = 2.3 Hz), 7.54 (d, 1H, 5'''-H J = 8.7 Hz), 7.49 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.13 (s, 1H, 5'-H), 6.91 (m, 2H, 3'',5''-H), 2.45 (s, 3H, 3-CH3), 3.83 (s, 3H, 4''-OCH3); MS: m/z 494.1010 (M+1)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-trifluoromethyl)phenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5g. IR (?max cm-1): 3112 (N-H str), 1673 (C=O str), 1612 (C=N str.), 1555 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.27 (s, 1H, NH, D2O exchangeable), 7.96 (m, 2H, 2'',6''-H), 7.77 (d, 1H, 2'''-H, J = 2.3 Hz), 7.57 (d, 1H, 5'''-H J = 8.7 Hz), 7.53 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.28 (s, 1H, 5'-H), 7.25 (m, 2H, 3'',5''-H), 2.49 (s, 3H, 3-CH3); MS: m/z 532.0347 (M)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-trifluoromethoxy)phenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5h. IR (?max cm-1): 3112 (N-H str.), 1661 (C=O str.), 1555 (C=N str.), 1516 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.23 (s, 1H, NH, D2O exchangeable), 8.07 (m, 2H, 2'',6''-H), 7.79 (d, 1H, 2'''-H, J = 2.3 Hz), 7.59 (d, 1H, 5'''-H J = 8.7 Hz), 7.55 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.41 (s, 1H, 5'-H), 7.67 (m, 2H, 3'',5''-H), 2.47 (s, 3H, 3-CH3); MS: m/z 548.0268 (M)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-nitrophenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5i. IR (?max cm-1): 3546 (N-H str.), 1665 (C=O str.), 1595 (C=N str.), 1524 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.26 (s, 1H, NH, D2O exchangeable), 8.29 (m, 2H, 2'',6''-H), 7.79 (d, 1H, 2'''-H, J = 2.3 Hz), 7.60 (d, 1H, 5'''-H J = 8.7 Hz), 7.56 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.51 (s, 1H, 5'-H), 8.13 (m, 2H, 3'',5''-H), 2.49 (s, 3H, 3-CH3); MS: m/z 509.0239 (M+1)+
(E)-2-(4-([1,1'-Biphenyl]-4-yl)thiazol-2-yl)-4-(2-(4-chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5j. IR (?max cm-1): 3112 (N-H str), 1670 (C=O str), 1557 (C=N str.), 1513 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.24 (s, 1H, NH, D2O exchangeable), 8.01 (d, 2H, 2'',6''-H), 7.76 (d, 1H, 2'''-H, J = 2.3 Hz), 7.64 (m, 4H, -H,), 7.55 (d, 1H, 5'''-H J = 8.7 Hz), 7.51 (dd, 1H, 6'''-H, JH-H = 8.7, 2.3 Hz), 7.45 (m, 2H, -H), 7.35 (m, 1H, -H) 7.32 (s, 1H, 5'-H), 2.47 (s, 3H, 3-CH3); MS: m/z 540.0808 (M)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-2-(4-(4-cyanophenyl)thiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 5k. IR (?max cm-1): 3112 (N-H str.), 1667 (C=O str.), 1605 (C=N str.), 1555 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.25 (s, 1H, NH, D2O exchangeable), 8.07 (m, 2H, 2'',6''-H), 7.79 (d, 1H, 2'''-H, J = 2.3 Hz), 7.60 (d, 1H, 5'''-H J = 8.7 Hz), 7.56 (dd, 1H, 6'''-H, JH-H = 8.7, 2.4 Hz), 7.45 (s, 1H, 5'-H), 7.71 (m, 2H, 3'',5''-H), 2.49 (s, 3H, 3-CH3); MS: m/z 489.0501 (M)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one 5l. IR (?max cm-1): 3112 (N-H str.), 1716 (C=O str.), 1671 (C=O str.), 1607 (C=N str.), 1537 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.25 (s, 1H, NH, D2O exchangeable), 7.66 (dd, 1H, 5''-H), 7.79 (d, 1H, 2'''-H, J = 2.3 Hz), 7.59 (d, 1H, 5'''-H J = 8.7 Hz), 7.54 (m, 2H, 7'',6'''-H), 8.82 (s, 1H, 5'-H), 8.35 (s, 1H, 4'-H), 7.34 (m, 2H, 6'',8''-H), 2.50 (s, 3H, 3-CH3); MS: m/z 532.0407 (M)+
(E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-(naphthalen-2-yl)thiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one 5m. IR (?max cm-1): 3112 (N-H str.), 1668 (C=O str.), 1564 (C=N str.), 1522 (C=C str.), 1223.95 (C-N str.); 1H NMR (400 MHz; CDCl3, dH) 13.25 (s, 1H, NH, D2O exchangeable), 8.53 (s, 1H, 1''-H), 7.77 (d, 1H, 2'''-H, J = 2.2 Hz), 7.47 (m, 4H, 3'',4'',6'',8''-H), 7.56 (d, 1H, 5'''-H J = 8.7 Hz), 7.52 (dd, 1H, 6'''-H, JH-H = 8.5, 2.1 Hz), 7.42 (s, 1H, 5'-H), 2.50 (s, 3H, 3-CH3); MS: m/z 514.0637 (M)+
, Claims:I/We claim:

1. The compounds with Formula-I where Ar may be C6H5, p-F-C6H4, p-Cl-C6H4, p-Br-C6H4, p-CH3-C6H4, p-OCH3-C6H4, p-NO2-C6H4, p-CF3-C6H4, p-OCF3-C6H4, p-C6H5-C6H4, p-CN-C6H4, 2-Naphthyl, 3-Acetylcoumarin and a process for the synthesis of (E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-5-methyl-2-(4-arylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one derivatives.

Formula I
2. Synthetic protocol for the compounds claimed in claim 1 comprising steps of reacting (E)-4-(2-(4-Chloro-3-(trifluoromethyl)phenyl)hydrazono)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothioamide (0.03 moles, 1 eq) and different substituted phenacyl bromides (4a-m) (0.03 moles, 1eq) at temperature 70-80 ? for 2 to 3h.
3. The process as claimed in claim 2, wherein the yields in the range 67-85% can be achieved.