Abstract: A solid-state approach was used to synthesize compound PZ-1190, a multitarget ligand for serotonin and dopamine receptors with potential antipsychotic activity in rodents. Compared to the classical batch synthesis approach, the developed multistep mechanochem. protocol improved the overall yield (from 32% to 56%), reduced the reaction time (from 42 to 4 h), and decreased the use of toxic reagents and organic solvents. All synthesized intermediates and PZ-1190 were isolated in high purity by extraction without the requirement of chromatog. purification PZ-1190 was obtained in high enantiomeric purity (≥99% ee) with no impact of grinding processes on the integrity of stereocenter. The described procedures represent rare examples of mechanochem. reduction of a carboxylic function, which might open up the possibility to obtain crucial β- and γ-amino alcs. in a sustainable manner. The oxidation of an aliphatic alc. into an aldehyde using mechanochem. has also been reported for the first time. The obtained results confirmed the suitability of mechanochem. as a sustainable and efficient method of synthesizing candidates for preclin. development.
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With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 24h;
General procedure: According to a procedure of Choi et al.36 (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1equiv) was dissolved in 20mL anhydrous CH2Cl2 and at 0C the corresponding alcohol (1.0equiv), EDC·HCl (1.5equiv) and DMAP (0.2equiv) were added. After the reaction was completed (TLC control) the organic layer was washed twice with water and the solvent was evaporated in vacuo. The boc-protection group was cleaved with 2mL trifluoroacetic acid in 20mL CH2Cl2. After 24h the reaction was neutralized with saturated NaHCO3 extracted with 3×30mL CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was evaporated to yield compound 8a, b, n-y which was used in the next step without further purification. Compound 8a, b, n-y (1equiv) was dissolved in 40mL of anhydrous CH2Cl2, and NMM or DIPEA (3equiv) was added at 0C followed by corresponding sulfonyl chloride (1equiv), respectively. The mixture was stirred until completion (TLC) and subsequently the solvent removed in vacuo. After purification by means of flash-chromatography compounds S-5a, b, n-y were obtained.
(S)-tert-butyl2-((2,3,6-trimethylphenyl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With triethylamine; isobutyl chloroformate; In dichloromethane; at 20℃; for 6.0h;Cooling with ice;
To the reaction flask was added (S) -1-t-butoxycarbonylpiperidine-2-carboxylic acid (3.1 g, 13.3 mmol) and dichloromethane (20 mL)Ice bath cooling,Triethylamine (1.5 g, 14.7 mmol) was added,A solution of isobutyl chloroformate (2.0 g, 14.7 mmol)In dichloromethane (10 mL),After incubation for 1 hour dropwise,A solution of 2,3,6-trimethylaniline 9e (1.5 g, 11.1 mmol)In dichloromethane (10 mL),The reaction was stirred at room temperature for 5 hours.(30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the silica gel (10 mL) was added to the reaction mixture, and the reaction mixture was added with water and dichloromethane (50 mL).Column chromatography and purification (petroleum ether / ethyl acetate (v / v) = 20: 1-15: 1) gave a white solid (S) -tertButyl-2 - (2,3,6-trimethylphenyl) carbamoyl) piperidine-1-carbonate 9f (2.6 g, 68% yield).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 3h;
Compound 13-1 (3.96 g, 17.28 mmol) and compound 13-7-0 (5.82 g, 19.81 mmol) weredissolved in CH 3CN (60 mL) and DIPEA (3.4 mL, 20.67 mmol) was slowly added dropwise at0 C. At the end of the addition, the mixture was stirred at rt for 3.0 hours. Afterthe reaction was completed, the reaction was quenched with ice water (50 mL) and theaqueous layer was extracted with DCM (50 mL x 3). The organic phases were combined,washed with saturated brine and dried over anhydrous Na 2SO 4Dried and concentrated. Theresidue was purified by column chromatography (eluent: PE / EtOAc (v / v) = 5/1) to give4.67 g of a white solid. Yield: 61%.
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