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Then epichlorohydrin (1.2 equiv) was added. The reaction was carried out for 120C140 min at rt. chemistry, which might reduce the time required to generate compound libraries for biological testing or might make sure more efficient production of active pharmaceutical elements (APIs).1?4 Recently, mechanochemical synthesis has also been recognized as an innovative methodology, 5 with a wide range of practical applications in both academic and industrial study. In particular, mechanochemistry has been used to produce various families of compounds.6?10 The primary traveling force underlying the rediscovery of mechanochemistry is green chemistry,11?13 in particular, the need of chemical and pharmaceutical industries for the development of more sustainable synthetic protocols characterized by the energy efficiency of chemical transformations and reduction of solvent use. The use of such approaches gives additional advantages of mechanosynthesis over classical organic chemistry, in terms of superb selectivity and the possibility to perform previously unfamiliar reactions.14?16 Interestingly, an increasing quantity of mechanochemical methods for generating pharmaceutically relevant fragments and functionalities have been reported thus far.17?19 This novel mechanochemical application led to coining the term medicinal mechanochemistry.20,21 We have recently developed a novel class of a potent and selective 5-HT7 receptor (5-HT7R) antagonist, namely, an arylsulfonamide derivative of (aryloxy)alkyl alicyclic amine, and identified several lead structures that show significant antidepressant and pro-cognitive properties in rodents (Number ?Number11).22?26 Open in a separate window Number 1 Chemical structure of the potent and selective 5-HT7R antagonist PZ-1361 belonging to the class of arylsulfonamides of (aryloxy)alkyl alicyclic amines. The classical in batch synthetic pathway of this class of derivatives consists of four steps involving the alkylation of commercially available phenols in biphasic conditions, nucleophilic substitution of Boc-protected alicyclic amines, removal of the protecting group, and sulfonylation of the producing primary amine in an alkaline environment (Plan 1). The crucial step of the entire process is the alkylation of phenol, as this reaction should be performed in the presence of a large excess of halogeno-alkanes (from 3 to 6 equiv) to avoid undesirable dimerization or opening of the epoxide ring. Additionally, apart from the deprotection of amine function, column chromatography purification is required in all of the remaining steps together with the utilization of a large amount of organic solvents (in particular, the highly harmful dichloromethane).27,28 To overcome these issues and simultaneously lengthen the concept of medicinal mechanochemistry, we adapted the synthetic pathway by using a mechanochemical approach for the synthesis of the potent and selective 5-HT7R antagonist PZ-1361.29 To demonstrate the versatility of this method, we subsequently improved the diversity of building prevents by conducting experiments using 2-substituted phenols, different central amine cores (e.g., piperazine, 3-amino-tropane, 3-aminopyrrolidine), and in a different way substituted arylsulfonyl chlorides. This allowed proposing mechanochemistry like a encouraging synthetic strategy in medicinal chemistry, which would enable the preparation of lead compounds for preclinical development in a more sustainable and greener manner.30 Open in a separate window Plan 1 In-Solution Synthesis of the Compound PZ-1361 The optimization of the synthetic pathway started with the alkylation of commercially available 2-phenylphenol with racemic epichlorohydrin (1 equiv). The reaction was initially performed inside a 10 mL PTFE jar having a 1 cm diameter stainless steel ball by using a vibratory ball mill (vbm) managed at 30 Hz. A thorough study of the different guidelines was performed and is summarized in Table 1 (for more information, see Furniture S3C5). Table 1 Optimization of Milling Conditions for the Alkylation of 2-Phenylphenola Open in a separate window ideals are reported in hertz (Hz), and the splitting patterns are designated as follows: br s. (broad singlet), br d. (broad doublet), s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets), m (multiplet). Mass spectra were recorded on a UPLC-MS/MS system consisting of a Waters ACQUITY UPLC (Waters Corporation,.Data in agreement with lit.29 3-Chloro-= 6.3, 1.4 Hz, 1H), 7.47C7.52 (m, 4H), 7.33C7.39 (m, 2H), 7.26C7.32 (m, 3H), 7.03 (td, = 7.5, 1.0 Hz, 1H), 6.96 (dd, = 8.3, 0.9 Hz, 1H), 5.28 (s, 1H), 5.04 (br. circulation chemistry, which might reduce the time required to generate compound libraries for biological testing or might ensure more efficient production of active pharmaceutical elements (APIs).1?4 Recently, mechanochemical synthesis has also been recognized as an innovative methodology,5 with a wide range of practical applications in both academic and industrial study. In particular, mechanochemistry has been used to produce various families of compounds.6?10 The primary traveling force underlying the rediscovery of mechanochemistry is green chemistry,11?13 in particular, the need of chemical and pharmaceutical industries for the development of more sustainable synthetic protocols characterized by the energy effectiveness of chemical transformations and reduction of solvent use. The use of such approaches gives additional advantages of mechanosynthesis over classical organic chemistry, in terms of superb selectivity and the possibility to perform previously unfamiliar reactions.14?16 Interestingly, an increasing quantity of mechanochemical methods for generating pharmaceutically relevant fragments and functionalities have been reported thus far.17?19 This novel mechanochemical application led to coining the term medicinal mechanochemistry.20,21 We have recently developed a novel class of a potent and selective 5-HT7 receptor (5-HT7R) antagonist, namely, an arylsulfonamide derivative of (aryloxy)alkyl alicyclic amine, and identified several lead structures that show significant antidepressant and pro-cognitive properties in rodents (Number ?Number11).22?26 Open in a separate window Number 1 Chemical structure of the potent and selective 5-HT7R antagonist PZ-1361 belonging to the class of arylsulfonamides of (aryloxy)alkyl alicyclic amines. The classical in batch synthetic pathway of this class of derivatives consists of four steps involving the alkylation of commercially available phenols in biphasic conditions, nucleophilic substitution of Boc-protected alicyclic amines, removal of the protecting group, and sulfonylation of the producing primary amine in an alkaline environment (Plan 1). The crucial step of the entire process is the alkylation of phenol, as this reaction should be performed in the presence of a large excess of halogeno-alkanes (from 3 to 6 GSK256066 2,2,2-trifluoroacetic acid equiv) to avoid undesirable dimerization or opening of the epoxide ring. Additionally, apart from the deprotection of amine function, column chromatography purification is required in all of the remaining steps together with the utilization of a large amount of organic solvents (in particular, the highly harmful dichloromethane).27,28 To overcome these issues and simultaneously lengthen the concept of medicinal mechanochemistry, we adapted the synthetic pathway by using a mechanochemical approach for the synthesis of the potent and selective 5-HT7R antagonist PZ-1361.29 To demonstrate SLIT1 the versatility of this method, we subsequently increased the diversity of building blocks by conducting experiments using 2-substituted phenols, different central amine cores (e.g., piperazine, 3-amino-tropane, 3-aminopyrrolidine), and differently substituted arylsulfonyl chlorides. This allowed proposing mechanochemistry as a promising synthetic strategy in medicinal chemistry, which would enable the preparation of lead compounds for preclinical development in a more sustainable and greener manner.30 Open in a separate window Scheme 1 In-Solution Synthesis of the Compound PZ-1361 The optimization of the synthetic pathway started with the alkylation of commercially available 2-phenylphenol with racemic epichlorohydrin (1 equiv). The reaction was initially performed in a 10 mL PTFE jar with a 1 cm diameter stainless steel ball by using a vibratory ball mill (vbm) operated at 30 Hz. A thorough study of the different parameters was performed and is summarized in Table 1 (for more information, see Tables S3C5). Table 1 Optimization of Milling Conditions for the Alkylation of 2-Phenylphenola Open in a separate window values are reported in GSK256066 2,2,2-trifluoroacetic acid hertz (Hz), and the splitting patterns are designated as follows: br s. (broad singlet), br d. (broad doublet), s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets), m (multiplet). Mass spectra were recorded on a UPLC-MS/MS system consisting of a Waters ACQUITY UPLC (Waters Corporation, Milford, MA, USA) coupled to a Waters TQD mass spectrometer (electrospray ionization mode ESI-tandem quadrupole). Chromatographic separations were carried out using the.13C1H NMR (126 MHz, CDCl3): 155.8, 137.4, 126.7, 126.4, 121.4, 111.7, 68.9, 50.5, 44.7, 27.0, 22.9. microwave-assisted organic chemistry and flow chemistry, which might reduce the time required to generate compound libraries for biological screening or might make sure more efficient production of active pharmaceutical ingredients (APIs).1?4 Recently, mechanochemical synthesis has also been recognized as an innovative methodology,5 with a wide range of practical applications in both academic and industrial research. In particular, mechanochemistry has been used to produce various families of compounds.6?10 The primary driving force underlying the rediscovery of mechanochemistry is green chemistry,11?13 in particular, the need of chemical and pharmaceutical industries for the development of more sustainable synthetic protocols characterized by the energy efficiency of chemical transformations and reduction of solvent use. The use of such approaches offers additional advantages of mechanosynthesis over classical organic chemistry, in terms of excellent selectivity and the possibility to perform previously unknown reactions.14?16 Interestingly, an increasing number of mechanochemical procedures for generating pharmaceutically relevant fragments and functionalities have been reported thus far.17?19 This novel mechanochemical application led to coining the term medicinal mechanochemistry.20,21 We have recently developed a novel class of a potent and selective 5-HT7 receptor (5-HT7R) antagonist, namely, an arylsulfonamide derivative of (aryloxy)alkyl alicyclic amine, and identified several lead structures that exhibit significant antidepressant and pro-cognitive properties in rodents (Determine ?Physique11).22?26 Open in a separate window Determine 1 Chemical structure of the potent and selective 5-HT7R antagonist PZ-1361 belonging to the class of arylsulfonamides of (aryloxy)alkyl alicyclic amines. The classical in batch synthetic pathway of this class of derivatives consists of four steps involving the alkylation of commercially available phenols in biphasic conditions, nucleophilic substitution of Boc-protected alicyclic amines, removal of the protecting group, and sulfonylation of the resulting primary amine in an alkaline environment (Scheme 1). The crucial step of the entire process is the alkylation of phenol, as this reaction should be performed in the presence of a large excess of halogeno-alkanes (from 3 to 6 equiv) to avoid unwanted dimerization or opening of the epoxide ring. Additionally, apart from the deprotection of amine function, column chromatography purification is required in all of the remaining steps together with the use of a large amount of organic solvents (in particular, the highly toxic dichloromethane).27,28 To overcome these issues and simultaneously extend the concept of medicinal mechanochemistry, we adapted the synthetic pathway by using a mechanochemical approach for the synthesis of the potent and selective 5-HT7R antagonist PZ-1361.29 To demonstrate the versatility of this method, we subsequently increased the diversity of building blocks by conducting experiments using 2-substituted phenols, different central amine cores (e.g., piperazine, 3-amino-tropane, 3-aminopyrrolidine), and differently substituted arylsulfonyl chlorides. This allowed proposing mechanochemistry as a promising synthetic strategy in medicinal chemistry, which would enable the preparation of lead compounds for preclinical development in a more sustainable and greener manner.30 Open in a separate window Scheme 1 In-Solution Synthesis of the Compound PZ-1361 The optimization of the synthetic pathway started with the alkylation of commercially available 2-phenylphenol with racemic epichlorohydrin (1 equiv). The reaction was initially performed in a 10 mL PTFE jar with a 1 cm diameter stainless steel ball by using a vibratory ball mill (vbm) operated at 30 Hz. A thorough study of the different parameters was performed and is summarized in Table 1 (for more information, see Tables S3C5). Table 1 Optimization of Milling Conditions for the Alkylation of 2-Phenylphenola Open in a separate window values are reported in hertz (Hz), and the splitting patterns are designated as follows: br s. (broad singlet), br d. (broad doublet), s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets), m (multiplet). Mass spectra were recorded on a UPLC-MS/MS system consisting of a Waters ACQUITY UPLC (Waters Corporation, Milford, MA, USA) coupled to a Waters TQD mass spectrometer (electrospray ionization mode ESI-tandem quadrupole). Chromatographic separations were carried out using the Acquity UPLC BEH (bridged ethyl hybrid) C18 column; 2.1 mm 100 mm, and 1.7 m particle size, equipped with Acquity UPLC BEH C18 Van Guard precolumn; 2.1 mm 5 mm, and 1.7 m particle size. The column was maintained at 40 C and eluted under gradient conditions from 95% to 0% of eluent A over 10 min, at a flow rate of 0.3 mL minC1. Eluent A: GSK256066 2,2,2-trifluoroacetic acid water/formic acid (0.1%, v/v), Eluent B: acetonitrile/formic acid (0.1%, v/v). HRMS analyses were performed on an UPLC Acquity H-Class from Waters hyphenated to a Synapt G2-S mass spectrometer with a dual ESI source from Waters. Alkylation of 2-Phenylphenol in Ball Mill (General Procedure A) 2-Phenylphenol (24.5 mg, 0.144.