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Chemical Structure| 214834-18-1 Chemical Structure| 214834-18-1

Structure of 214834-18-1

Chemical Structure| 214834-18-1

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Product Details of [ 214834-18-1 ]

CAS No. :214834-18-1
Formula : C11H20N2O2S
M.W : 244.35
SMILES Code : C(C)(C)(C)OC(=O)N1CCC(CC1)C(N)=S
MDL No. :MFCD02180954
InChI Key :SCGQNJHAAYUQOO-UHFFFAOYSA-N
Pubchem ID :2735648

Safety of [ 214834-18-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Application In Synthesis of [ 214834-18-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 214834-18-1 ]

[ 214834-18-1 ] Synthesis Path-Downstream   1~54

  • 1
  • [ 91419-48-6 ]
  • [ 214834-18-1 ]
YieldReaction ConditionsOperation in experiment
92% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; To a solution of ferf-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in a DME/DCM 2: 1 mixture (78 ml_), Lawesson reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at r.t. overnight. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K2CO3. The organic layer was separated, dried over Na2S04 and concentrated to dryness. The residue was triturated with diethyl ether and dried to give 2.65 g (92%) of the title compound as a white solid.HPLC: Rt: 5.06 min1H NMR (401 MHz, DMSO-d6) δ ppm 9.39 (br. s., 1 H), 9.09 (br. s., 1 H), 4.00 (d, J = 12.6 Hz, 2 H), 2.77 - 2.61 (m, 3 H), 1.71 - 1.51 (m, 4 H), 1.39 (br. s., 9 H)
92% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; tert-Butyl-4-carbamothioylpiperidine-1-carboxylate, cmpd. of formula 8 [R1=1-tert-butoxycarbonyl-piperidin-4-yl] To a solution of tert-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in a DME/DCM 2:1 mixture (78 mL), Lawesson reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at r.t. overnight. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K2CO3. The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The residue was triturated with diethyl ether and dried to give 2.65 g (92%) of the title compound as a white solid. HPLC: Rt: 5.06 min 1H NMR (401 MHz, DMSO-d6) δ ppm 9.39 (br. s., 1H), 9.09 (br. s., 1H), 4.00 (d, J=12.6 Hz, 2H), 2.77-2.61 (m, 3 H), 1.71-1.51 (m, 4H), 1.39 (br. s., 9H)
82% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; for 1.33333h; Example 2: 4-Thiocarbamoyl-piperidine-l-carboxylic acid tert-butyl ester(Thioamide)[0030] To a suspension of 4-Carbamoyl-piperidine-l-carboxylic acid tert-butyl ester (288 g, 1.26 mol) in dimethoxyethane (2000 mL) and methylene chloride (800 mL) in a 5-lite of three-neck flask was added Lawesson's Reagent (255 g, 0.63 mol). The mixture was stirred at room temperature for 80 min. TLC check there was no starting material left. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (1500 mL), and washed with half saturated potassium carbonate water solution (500 mL each, two times), 50%> of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dry. The obtained solid was dissolved in ethyl acetate (1000 mL) and filtered at hot to remove insoluble white stuff. To the solution was added heptane (300 mL). After removing most of ethyl acetate, the solid formed was filtrated, washed with hexane-ether (1 : 1), and dried to give 252 g (82%>) of product. TLC: dichloromethane -methanol 90: 10, Rf (product) = 0.37, UV and iodine positive; Rf (starting material) = 0.28, iodine positive.
82% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; for 1.33333h; To a suspension of 4-Carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (288 g, 1.26 mol) in dimethoxyethane (2000 mL) and methylene chloride (800 mL) in a 5-lite of three-neck flask was added Lawesson's Reagent (255 g, 0.63 mol). The mixture was stirred at room temperature for 80 min. TLC check there was no starting material left. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (1500 mL), and washed with half saturated potassium carbonate water solution (500 mL each, two times), 50% of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dry. The obtained solid was dissolved in ethyl acetate (1000 mL) and filtered at hot to remove insoluble white stuff. To the solution was added heptane (300 mL). After removing most of ethyl acetate, the solid formed was filtrated, washed with hexane-ether (1:1), and dried to give 252 g (82%) of product.TLC: dichloromethane-methanol 90:10, Rf (product)=0.37, UV and iodine positive; Rf (starting material)=0.28, iodine positive.
82.2% With Lawessons reagent; In tetrahydrofuran; at 20℃; for 12h; Dissolve N-Boc-4-piperidinecarboxamide 2 (1.00g, 4.38mmol) in 20mLTetrahydrofuran solution, then add Lawesson's reagent (LR) (1.06g, 2.63mmol),Mechanically stirred at room temperature for 12 hours, TLC monitored until the reaction was complete, and the solutionAdd 20mL ethyl acetate to redissolve, 15mL*2 10% citric acid wash the organic layer, 15mL*2 saturated sodium carbonate wash the organic layer, 15mL water wash the organic layer,The organic layer was dried with anhydrous magnesium sulfate, filtered and desolvated to obtain 0.88 g of white solid.The yield was 82.2%,
78% With Lawessons reagent; In tetrahydrofuran; at 20℃; for 22h;Reflux; To a stirred solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate (1.3 g, 5.7 mmol) in THF (16 mL,), Lawssen's reagent 2.53 g, 6.27 mmol) was added. The reaction mixture was refluxed for 6 h and then stirred at rt for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and was washed with 10% citric acid, 10% sodium bicarbonate, water and brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound. Yield: 78% (1.09 g, colorless oil). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.11 (s, 1H), 4.03-3.97 (m, 1H), 2.66-2.61 (m, 2H), 1.64-1.52 (m, 4H), 1.40 (s, 9H), 1.38-1.34 (m, 2H). LCMS: (Method A) 245.2 (M+H), Rt. 3.38 min, 93.5% (Max).
72% With Lawessons reagent; In 1,2-dimethoxyethane (DME); chloroform; at 20℃; 4-CARBAMOYL-PIPERIDINE-L-CARBOXYLIC acid TERT-BUTYL ester (2) (45.4 g, 0.199 mol), Lawesson's reagent (40.2 g, 0.099 mol, 0.5 equiv), 1,2-dimethoxyethane (DME) (500 mL) and chloroform (200 mL) were combined and stirred at room temperature. The course of the reaction was followed by tlc analysis (30% ethyl ACETATE/HEXANE) and on completion the reaction mixture was evaporated to dryness (glassy solid). The solid was dissolved in ethyl acetate and washed with half saturated potassium carbonate solution, dried (MGSO4), filtered and concentrated to yield the title compound as a colourless solid. The crude product was crystallised from ethyl acetate and hexane to give the title compound (3) (35 g, 0.14 mol, 72%).
62.5% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; Lawson's reagent (12.75 g, 0.032 mol) was added a solution of compound 1(14.4 g, 0.063 mol) in dichloromethane (40 mL) and ethylene glycol dimethyl ether (100 ml). The reaction was stirred at room temperature for 8 h, and monitored by TLC, then concentrated. The residue was diluted with CH2Cl2 (100 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2/MeOH = 100:1) to afford compound 2 (9 g, 62.5 % yield) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.55(s, 1H), 6.99(s, 1H), 4.23(s, 2H), 3.73(q, J = 7.0 Hz, 2H), 2.74-2.65(m, 1H), 1.90(dt, J =13.4 Hz, 2.6 Hz, 2H), 1.72(qd, J = 12.6 Hz, 4.4 Hz, 2H), 1.46(s, 9H).
55% With Lawessons reagent; In toluene; at 20℃; for 1h;Inert atmosphere; To a suspension of compound8(2.2 g, 9.7 mmol) in toluene (100 mL) in a reaction flask was added Lawesson’s reagent (1.9 g, 4.8 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solvents were removed under vacuum. The residue was dissolved in EtOAc and washed with aqueous 1N NaOH solution (2 x 100 mL), 50% of brine (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography using 30% acetone in hexanes as an eluent to afford compound9(1.3 g, 55%)1H-NMR (CDCl3,300 MHz) δ 7.44 (1H, s, NH2), 6.86 (1H, s, NH2), 4.24 (2H, d,J= 11.7 Hz, CH2), 2.78-2.63 (3H, m, CH+CH2), 1.93 (2H, d,J= 14.7 Hz, CH2), 1.73 (2H, dt,J= 15.0 Hz, 6.0 Hz, CH2), 1.46 (9H, s, C(CH3)3).
40.2% With Lawessons reagent; In 1,4-dioxane; at 70℃; for 4h; Dissolve compound 2 (10.2 g, 42.6 mmol) and Lawson's reagent (10.7 g, 26.4 mmol) in 1,4-dioxane (150 mL), heat at 70±5C and stir for 4 h. After the reaction was detected by TLC, the reaction system was cooled to room temperature. Adjust pH=9 with saturated aqueous NaHCO3 solution, extract with DCM (3X100 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain crude product, which is purified by silica gel column to obtain 4.1 g of white solid, with a yield of 40.2 %.
With Lawessons reagent; In 1,4-dioxane; at 60℃; for 2h; The amide (20 g, 76.3 mmol) was dissolved in 1,4-dioxane with heating and the clear solution placed in a 60 0C oil bath. Lawesson's Reagent was added (15.43 g, 38.15 mmol) and the solution stirred for 2 hours. The solution was cooled to RT, poured into 8:1 water : saturated NaHCO3, followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (1:4)) to give the titled compound.
With Lawessons reagent; In 1,4-dioxane; dichloromethane; at 20 - 50℃; for 4h; under room temperature, nitrogen protection, (27.36g, 0 . 12mol, 1eq), laurance reagent (24.26g, 0 . 06mol, 0 . 5eq), mixed, added into the 1,4-dioxane 250 ml, the mixing tabs 50 C, 4h. Quality monitoring, after the reaction is complete. The reaction system can be obtained direct turns on lathe does target product 51. 86g crude product (containing laurance reagent decay product), purity 50%. The crude product of viscosity is very high bombycinous oily liquid.
1 g With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; for 16h; To a stirred solution of tert-butyl 4-carbamoylpiperidine-1 -carboxylate (1 .0 g, 4.38 mmol) in a mixture of dimethoxyethane (16 mL) and dichloromethane (8 mL) was added 2,4-bis(4-methoxyphenyl)-,3,2,4-dithiadiphosphetane-2,4-disulfide (885 mg, 2.1 9 mmol). The mixture was stirred at 20 C for 16 h,then concentrated in vacuo. The residue dissolved in ethyl acetate and washed with saturated aqueous potassium carbonate (10 mL x 2). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 4-carbamothioylpiperidine-1 -carboxylate (1 .0 g) as a yellow solid. This was used directly without further purification. 1H NMR (400 MHz, DMSO-d6) O 9.45 (br. s., 1 H), 9.17 (br. s., 1H), 4.14-3.98 (m, 2H), 3.91 -3.79 (m, 1H), 2.80-2.66 (m, 2H), 1.74-1.55 (m, 4H), 1.46 (s, 9H).

  • 2
  • [ 214834-18-1 ]
  • [ 814-75-5 ]
  • [ 1004527-71-2 ]
YieldReaction ConditionsOperation in experiment
13% With ethanol; at 200℃; for 0.0166667h;Microwave irradiation; -Bromobutan-2-one (124 mg, 0.8 mmol) and tert-butyl 4- carbamothioylpiperidine-1-carboxylate (200 mg, 0.8 mmol) in ethanol (1 iuL) were heated to 2000C for 1 minute under microwave irradiation. The black residue was purified by chromatography (DCM/MeOH/NH4OH 85/15/0.1) to yield 4,5- dimethyl-2- (piperidin-4-yl) thiazole as a brown solid (32 rag, 13%) : 1H NMR (400 MHz, DMSCHd6) δ 1.76-1.88 (m, 2H), 2.08-2.14 (m, 2H), 2.21 (s, 3H), 2.30 (s, 3H), 2.97-3.05 (m, 2H), 3.18- 3.24 (m, IH) , 3.30-3.35 (m, 2H); m/z (APCI pos) 197.1 (100%) [M+H] .
  • 3
  • [ 214834-18-1 ]
  • [ 70-23-5 ]
  • [ 365413-31-6 ]
YieldReaction ConditionsOperation in experiment
96.5% In methanol; for 4h;Reflux; Compound 3 (4.1 g, 16.8 mmol) and ethyl bromopyruvate (3.94 g, 20.2 mmol) were dissolved in anhydrous methanol (100 ml). The reaction system was heated under reflux and stirred for 4 h, until the reaction was detected by TLC. The reaction solution was concentrated and purified by a silica gel column to obtain 5.5 g of product 4 as a yellow powdery solid with a yield of 96.5%. Can be used directly in the next step.
82% 4-THIOCARBAMOYL-PIPERIDINE-L-CARBOXYLIC acid tert-butyl ester (3) (25 g, 102 mmol) was dissolved in anhydrous N, L9-DIMETHYLFORMAMIDE (DMF) (125 mL) and cooled to 0C in an ice-bath. A solution of ethyl bromopyruvate (22.2 g, 14.3 mL, 114 mmol, 1.1 equiv) in anhydrous DMF (125 mL) was added dropwise with stirring. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. Triethylamine (25 mL) was added dropwise with stirring at the rate of 1 mL/g of thioamide used. The DMF was removed in vacuo keeping the temperature below 60C. The resulting residue was partitioned between ethyl acetate (75 mL) and brine (100 mL). Sufficient water was added to ensure complete dissolution of the precipitated salts in the aqueous phase. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts washed successively with brine (x2), water (x2) and brine (x2). The organic phase was simultaneously dried with MGS04 and decolourised with finely divided charcoal. The mixture was filtered through Celite and concentrated in vacuo to give a yellow oil. Trituration with hexane yielded a yellow solid. This was diluted with an excess of hexane and cooled overnight to allow complete crystallisation of product. The product was collected by filtration, washed with hexane and dried in vacuo at room temperature. Recrystallisation from IPA/water gave the title compound (4) (28.33 g, 83 mmol, 82%).
74.2% To a suspension of tert-butyl 4-carbamothioylpiperidine- 1 -carboxylate (1.50 g, 6.14 mmol) in ethanol (6 mL) at 0 C was added dropwise a solution of ethyl 3-bromo- 2-oxopropanoate (0.788 mL, 6.26 mmol) in ethanol (6 mL). The ice bath was then removed and the reaction mixture was stirred at ambient temperature overnight. Triethylamine (1.5 mL, 10.76 mmol) was then added and the mixture was concentrated to near dryness and the concentrate was diluted with ethyl acetate, washed with brine, dried (MgS04) and evaporated to dryness. The residue was purified by flash chromatography using hexanes-ethyl acetate as eluent to give ethyl 2-(l-(tert-butoxycarbonyl)piperidin-4- yl)thiazole-4-carboxylate (1.55 g, 74.2%) as a nearly colorless oil that crystallized on standing to give a white solid. LC (Method A): 2.115 min. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.42 (s, 1H), 7.20 (br s, 2H), 4.29 (q, J= 7.0 Hz, 2H), 4.00 (m, 1H), 3.24 (m, 1H), 2.88 (br s, 1H), 2.03 (m, 2H), 1.54 (m, 2H), 1.29 (t, J= 7.2 Hz, 3H).
71% With triethylamine; In DMF (N,N-dimethyl-formamide); at 5℃; tert-Butyl 4-(AMINOCARBOTHIOYL) TETRAHYDROPYRIDINE-1 (2H)-CARBOXYLATE (May- bridge) (85 mmol ; 20. 8 g) is dissolved in 250 ml of DIMETHYLFORMAMIDE and placed at 5C. Ethyl bromopyruvate (1 EQ. ; 85 MMOL ; 16. 6 g) dissolved in 50 ml of dimethylformamide is added dropwise. The reaction medium is stirred overnight and excess triethylamine is then added dropwise. The reaction medium is evapo- rated and the residual brown oil is taken up in ethyl acetate and washed with water (twice) and then with saturated sodium chloride solution (twice). The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed on silica, eluting with DICHLOROMETHANE to DICHLOROMETHANE/3% methanol, to give 20. 5 g of the expected product in the form of oily crystals. TLC : 1/1 ethyl acetate/hexane : Rf = 0. 55 Yield = 71 %.
71% With triethylamine; In DMF (N,N-dimethyl-formamide); at 5℃; Tert-butyl-4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate (Maybridge) (85 mmol; 20.8 g) is dissolved in 250 ml of dimethylformamide and placed at 5 C. Ethyl bromopyruvate (1 eq.; 85 mmol; 16. 6 g) dissolved in 50 ml of dimethylformamide is added dropwise. The reaction medium is stirred overnight and excess triethylamine is then added dropwise. The reaction medium is evaporated and the residual brown oil is taken up in ethyl acetate and washed with water (twice) and then with saturated sodium chloride solution (twice). The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed on silica, eluting with dichloromethane to dichloromethane/3% methanol, to give 20.5 g of the expected product in the form of oily crystals. TLC: 1/1 ethyl acetate/hexane: Rf = 0.55 Yield = 71 %.
In ethanol; at 80℃; for 4h; (2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)amide 2-Piperidin-4yl-thiazole-4-carboxylic acid ethyl ester dihydrobromide salts A solution of tert-butyl-4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate (2.0 g, 8.2 mmol) and ethyl bromopyruvate (1.6 g, 8.2 mmol) in 30 mL of EtOH was stirred at 80 C. for 4h. Afterwards, the mixture cooled to room temperature and then charged with 48% HBr (1.0 mL, 14 mmol. The reaction mixture was allowed to stir an additional 1 h, and then concentrated to an oily solid. Trituration with diethyl ether afforded 3.0 g (91%) of a tan solid. 1H NMR (400 Liz, DMSO-d6) δ 9.02 (br s, 1 H), 8.77 (br s, 1 H), 8.46 (s, 1 H), 7.01 (br s, 1 H),4.29 (q, J=7.1 Hz,2 H), 3.44-3.33 (m, 3 H), 3.-2 (q, J=11.7 Hz 2 H), 2.19 (d, J=13.2 Hz, 2 H), 1.97-1.88 (m, 2 H), 1.29 (t, J=7.0 Hz, 3 H). MS calculated for C11H16N2O2S+H: 241, observed: 241.
Step A: Preparation of 1 , 1 -dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]- 1 - piperidinecarboxylate; To a suspension of 1,1 -dimethylethyl 4-(aminothioxomethyl)-l-tetrahydropyridine- carboxylate (30 g, 123 mmol) in ethanol (180 mL) cooled to 0 C in an ice bath, was added dropwise a solution of ethyl bromopyruvate (15.7 mL, 125 mmol) in ethanol (180 mL). The ice bath was removed, and the mixture was stirred at ambient temperature overnight. Triethylamine (30 mL) was added, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of a brown oil, which solidified on standing. A portion of this crude product (8.1 g) was heated with ether (200 mL), and the ether was then decanted. This was repeated a second time, and the combined ether solutions <n="53"/>were evaporated under reduced pressure to give 7.6 g of the title compound as a yellow solid.1H NMR (CDCl3) δ 1.40 (t, 3H), 1.46 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.25 (m, IH), 4.2 (m, 2H), 4.42 (q, 2H), 8.08 (s, IH).
In ethanol; at 0 - 20℃; To a suspension of 1,1-dimethylethyl 4-(aminothioxomethyl)-l-tetrahydropyridine- carboxylate (30 g, 123 mmol) in ethanol (180 mL), cooled to 0 C in an ice bath, was added dropwise a solution of ethyl bromopyruvate (15.7 mL, 125 mmol) in ethanol (180 mL). The <n="71"/>ice bath was removed, and the mixture was stirred at ambient temperature overnight. Triethylamine (30 mL) was added, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of a brown oil, which solidified on standing. A portion of this crude product (8.1 g) was heated with 200 mL of ether, and the ether was then decanted. This was repeated a second time, and the combined ether solutions were evaporated under reduced pressure to give 7.6 g of the title compound as a yellow solid. 1H NMR (CDCl3) 6 1.40 (t, 3H), 1.46 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.25 (m, IH), 4.2 (m, 2H), 4.42 (q, 2H), 8.08 (s, IH).
Synthesis of 4-(4-Carboxy-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (Intermediate 1-3.2)R9 m u R11 I-3.2Step 1: Synthesis of 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-l-carboxylic acid tert- butyl ester (Rl l)A solution of R9 (1.0 g, 4.09 mmol) in dimethylformamide (DMF) (5 ml) is cooled to 0C under nitrogen. To this mixture is added R10 (0.63 ml, 4.50 mmol) as a DMF solution (5 ml, drop wise addition). Upon complete addition, the reaction is allowed to gradually warm to ambient temperature and stirred over night. After this time the reaction is treated with triethylamine (1 ml, drop wise) and stirred for 10 minutes. The reaction is then poured into water and the product is extracted into EtO Ac (3x). The combined organics are dried (MgS04), filtered and concentrated. The remaining residue is purified via column chromatography (25g silica gel, 5-50% EtO Ac/heptane) to afford Rl l. (1.0 g)
EXAMPLE 1. Preparation of 2- [ 1 - [(2, 5-dimethylphenyl) acetyl] -4-piperidinyl] -N-methyl-N- [( 1R)- 1 - phenylpropyl]-4-thiazolecarboxamide (Compound 58). Step A: Preparation of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-l- piperidinecarboxylate. To a suspension of 1,1-dimethylethyl 4-(aminothioxomethyl)-1-tetrahydropyridine- carboxylate (30 g, 123 mmol) in ethanol (180 mL), cooled to 0 C in an ice bath, was added dropwise a solution of ethyl bromopyruvate (15.7 mL, 125 mmol) in ethanol (180 mL). The ice bath was removed, and the mixture was stirred at ambient temperature overnight. Triethylamine (30 mL) was added, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of a brown oil, which solidified on standing. A portion of this crude product (8.1 g) was heated with 200 mL of ether, and the ether was then decanted. This was repeated a second time, and the combined ether solutions were evaporated under reduced pressure to give 7.6 g of the title compound as a yellow solid. 1H NMR (CDCl3): 1.40 (t, 3H), 1.46 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.25 (m, 1H), 4.2 (m, 2H), 4.42 (q, 2H), 8.08 (s, 1H).

  • 5
  • [ 214834-18-1 ]
  • [ 20099-90-5 ]
  • [ 860344-62-3 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 20 - 80℃; for 2.08333h; 4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.47 mmol) and 4- (2- Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80 C for 2 hours. The volume was reduced to 5 mL and diethylether (5 mL) was added. The mixture was then cooled to-20 C and filtered. The solid was washed with a small amount of diethylether and dried. m/z = 289.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
  • 6
  • [ 214834-18-1 ]
  • [ 62423-73-8 ]
  • [ 860344-60-1 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 20 - 80℃; for 2.08333h; 4-Methyl-piperazine-1-carbothioic acid amide (2.47 mmol) and 3- (2-Bromo-acetyl)- benzoic acid (2.47 mmo () were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80 C for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z = 304.1 in MS ES+, which was characterized by hpic and MS and used in the next step without any further purification.
  • 7
  • [ 214834-18-1 ]
  • [ 20656-61-5 ]
  • [ 867066-22-6 ]
YieldReaction ConditionsOperation in experiment
In toluene; at 80 - 90℃; for 2.75h; A mixture of tertiary butyl 4-(aminocarbothioyl)tetrahydropyridne-1(2H)carboxylate 25.1 (1 g) and methyl chloro(formyl)acetate (1.3 g) in toluene (20 mL) was heated in an 80-90 C. oil bath for 1.75 hours. Another spatula full of the chloro(formyl)acetate was added and the heating continued another hour. The reaction was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with water and brine. Drying and evaporation of the solvent gave an oily residue that was purified by flash chromatography eluting with 30% ethyl acetate hexane to give the thiazole 25.2 as a yellow oil (0.6 g). A solution of 25.2 (0.55 g) in methylene chloride (3 mL) was treated with trifluoroacetic acid (1 mL). After three hours, another portion of trifluoroacetic acid (1 mL) was added and stirring continued for three hours. The solvent was evaporated and the residue partitioned between water and ether. The aqueous phase was made basic with 1 N sodium hydroxide and extracted with chloroform. The chloroform solution was dried and the solvent evaporated to give 25.3 as a dark gum (0.187 g). A solution of the gum in methylene chloride (5 mL) and diisopropylethylamine (0.3 mL) was cooled in ice-water and treated with 4-biphenylsulphonyl chloride (0.21 g) in methylene chloride (2 mL). The cooling was removed and the reaction stirred one hour. A crystal of 4-dimethylaminopyridine was added and stirring was continued overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organics were washed with 1 N hydrochloric acid, aqueous saturated sodium bicarbonate, and brine. The solvent was dried and evaporated to give a tan solid. The solid was purified by flash chromatography eluting with 60-80% ethyl acetate-hexane to give 25.3 as a tan powder (91 mg) with the expected m/e of 443 (M+H+). A mixture of methyl 2-[1-(1,1'-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylate 25.3 (9 mg), 50% hydroxylamine in water (0.05 mL), and dioxane (1 mL) were cooled in ice-water. To the reaction was added 1N sodium hydroxide (0.053 mL) followed by removal of the cooling bath. After stirring overnight, the reaction was neutralized with 1 N hydrochloric acid (0.053 mL) and the solvent evaporated. The residue was purified by preparative hplc to give Example 25 as a floculant white solid (3.5 mg). 1H NMR (DMSO) δ: 2.75 (m, 2H), 2.15 (m, 2H), 2.5 (m, 2H), 3.1 (m, 1H), 3.75 (m, 2H), 7.45-7.55 (m, 3H), 7.72-7.96 (m, 6H), 8.08 (s, 1H), 11.3 (s, 1H); m/e=444 (M+H+).
  • 8
  • [ 214834-18-1 ]
  • [ 864958-50-9 ]
  • [ 864958-53-2 ]
YieldReaction ConditionsOperation in experiment
89% In ethanol; for 2h;Heating / reflux; Example 7; 2- (4-Piperidine)-4- [3- (3-bromophenyl)-5-methylisoxazolyl] thiazole Hydrobromide; A mixture of 3- (3-bromophenyl)-5-methyl-4- (bromoacetyl) isoxazole (1.50 g, 4.18 mmol) of Example 3 and 4-thiocarbamoyl-piperidine-1-carboxylic acid-tert-butyl ester (1.3 equiv) in EtOH (14.0 mL) was heated to reflux. After 2 h, the reaction mixture was cooled to room temperature and poured into Et2O. The product precipitated out and was filtered and dried in vacuo to give the title compound (1.48 g, 89%) as an off-white solid (HBr salt). LCMS only : 404, 406 (M+H).
  • 9
  • [ 214834-18-1 ]
  • C8H9BrF3NO2 [ No CAS ]
  • [ 767263-46-7 ]
YieldReaction ConditionsOperation in experiment
1-(Trifluoroacetyl)hexahydro-4H-azepin-4-one (may be prepared as described in Description 3) (L00g, 4.78mmol) was dissolved in acetic acid (10ml) and the mixture EPO <DP n="32"/>heated at 60 0C. Bromine (0.25ml, 4.78mmol) in acetic acid (10ml) was then added dropwise at such a rate that the solution decolourised between drops. The mixture was left stirring at 60 0C for 30 minutes. The acetic acid was evaporated and azeotroped with toluene. The mixture was re-dissolved in ethanol, treated with 1 ,1-dimethylethyl A- (aminocarbonothioyO-i-piperidinecarboxylate (2.34g, 9.57mmol) and heated at reflux for 4 hours and then overnight. The mixture was diluted with methanol and passed down an ion exchange cartridge (SCX), washed with methanol and then a 2M ammonia in methanol solution. The basic fractions were then combined and evaporated to afford the crude product which was purified using column chromatography eluting with a mixture of 2M ammonia in methanol and dichloromethane (10%) to afford the product (D27); MS (ES+) m/e 334 [M+H]+.
  • 10
  • [ 908094-01-9 ]
  • [ 214834-18-1 ]
  • [ 20772-12-7 ]
  • [ 301220-64-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogen bromide; In ethanol; hexane; Step B 4-(5-Benzyl-thiazol-2-yl)-1-t-butyloxycarbonyl-piperidine To a solution of 65 mg of 1-bromo-3-phenyl-2-propanone (from reacting the acid chloride with diazomethane followed by hydrogen bromide) in 4 ml EtOH was added 74 mg of 1-boc-isonipecot-thioamide (from Step A). The reaction was stirred for 2 hours at 80 C. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane to give 37 mg of the title compound.
  • 11
  • phosphorous pentasulfide [ No CAS ]
  • [ 91419-48-6 ]
  • [ 214834-18-1 ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; hexane; Step A 1-t-Butyloxycarbonyl-isonipecot-thioamide To a solution of 500 mg of 1-Boc-isonipecotamide in 5 ml of 1,4-dioxane was added 243 mg of phosphorous pentasulfide. The reaction was stirred at 100 C. for 1 hour. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 30% EtOAc in hexane to give 74 mg of the title compound.
  • 12
  • [ 214834-18-1 ]
  • [ 403-29-2 ]
  • [ 887625-38-9 ]
  • [ 887625-34-5 ]
YieldReaction ConditionsOperation in experiment
α-Bromo-4-fluoroacetophenone (2.0 g, 9.0 mmol) was dissolved in ethanol (20 mL) , N-tert- butoxycarbonylpiperidine-4-thioamide (2.0 g, 8.2 mmol) was added thereto, and the mixture was refluxed 1 hour. The reaction mixture was cooled to room temperature and concentrated. Saturated sodium bicarbonate (50 mL) was EPO <DP n="136"/>added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was dissolved in N,N-diraethylformamide (15 mL) , di-tert- butyldicarbonate (1.4 g, 6.1 mmol) and triethylamine (0.7 g, β.l mmol) were added thereto, and the mixture was stirred at 50 C for 2 hours. The reaction mixture was cooled to room temperature, water (150 mL) was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:3) to give the title compound (1.7 g, 4.7 mmol, yield 53%).
  • 13
  • [ 214834-18-1 ]
  • [ 70-11-1 ]
  • [ 926891-48-7 ]
YieldReaction ConditionsOperation in experiment
96% In methanol; at 70℃; for 22h; Example 1 Isopropyl-4-(4-phenyl-thiazol-2-yl)-piperidine Step 1: 4-(4-Phenyl-thiazol-2-yl)-piperidine hydrobromide (Intermediate 1) A mixture of 1 g (4.1 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 0.816 g (4.1 mmol) 2-bromo-1-phenyl-ethanone (commercially available) in 10 ml methanol was stirred at 70 C. for 22 h. After evaporation to dryness the residue was suspended in diethyl ether and filtered. The residue washed with diethyl ether and dried under vacuum to yield 1.279 g (96%) of the title compound in white crystalline form. (m/e): 245.2 (MH+(-HBr); 100%).
  • 14
  • [ 214834-18-1 ]
  • [ 70-23-5 ]
  • [ 721963-02-6 ]
YieldReaction ConditionsOperation in experiment
74% Step 1: 2-Piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester A mixture of 10 g (41 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 7.98 g (41 mmol) ethyl bromopyruvate (commercially available) in 120 ml ethanol was stirred at 70 C. for 90 min. The mixture was evaporated to dryness, Na2CO3 aq. was added and the residue was extracted with ethyl acetate. The organic phases were washed with NaCl aq., dried with MgSO4 and evaporated to dryness. The residue was purified on silica eluding with DCM/MeOH/25% NH3 in water 100/20/1 to yield after evaporation of the product fractions 7.28 g (74%) of the title compound as light brown solid.
  • 15
  • [ 214834-18-1 ]
  • [ 875639-57-9 ]
  • [ 1046793-76-3 ]
YieldReaction ConditionsOperation in experiment
100% 4-[4-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-piperidine-l- carboxylic acid tert-butyl ester (XXIII-f); (XXI-a) (XXIII-f)To a solution of (XXI-a) (1.71 g, 5.38 mmol) in THF (20 mL) was added 1- Boc-4-aminothiocarbonyl piperidine (1.31 g, 5.36 mmol) and the solution was allowed to stir at RT for 3 h. The reaction mixture was then poured onto saturated aqueous NaHCO3 (50 mL) and extracted with AcOEt (2 x 50 mL).The combined organic extracts were then evaporated to afford (XXIII-f) (2.58 g, 5.41 mmol, 100%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.64-1.84 (m, 4H), 2.07-2.17 (m, 2H), 2.81-2.94 (m, 2H), 3.13-3.24 (m,IH), 7.17 (s, IH), 7.74 (d, J = 2.4 Hz, 1 H), 8.32 (d, J = 2.1 Hz, IH), 8.48 (d, J= 2.1 Hz, IH), 8.97 (br s, IH).
100% 4-[4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (71) To a solution of 70 (1.71 g, 5.38 mmol) in THF (20 mL) was added 1-Boc-4-aminothiocarbonyl piperidine (1.31 g, 5.36 mmol) and the solution was allowed to stir at r.t. for 3 h. The reaction mixture was then poured onto saturated aqueous NaHCO3 (50 mL) and extracted with AcOEt (2 x 50 mL). The combined organic portions were then evaporated to afford 71 (2.58 g, 5.41 mmol, 100%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.64-1.84 (m, 4H), 2.07-2.17 (m, 2H), 2.81-2.94 (m, 2H), 3.13-3.24 (m, 1H), 7.17 (s, 1H), 7.74 (d, J = 2.4 Hz, 1 H), 8.32 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.97 (br s, 1H).
100% In tetrahydrofuran; at 20℃; for 3h; 4-[4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (71) To a solution of 70 (1.71 g, 5.38 mmol) in THF (20 mL) was added 1-Boc-4-aminothiocarbonyl piperidine (1.31 g, 5.36 mmol) and the solution was allowed to stir at r.t. for 3 h. The reaction mixture was then poured onto saturated aqueous NaHCO3 (50 mL) and extracted with AcOEt (2*50 mL). The combined organic portions were then evaporated to afford 71 (2.58 g, 5.41 mmol, 100%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.64-1.84 (m, 4H), 2.07-2.17 (m, 2H), 2.81-2.94 (m, 2H), 3.13-3.24 (m, 1H), 7.17 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.97 (br s, 1H).
  • 16
  • [ 214834-18-1 ]
  • [ 717915-17-8 ]
  • [ 1070176-35-0 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethanol; at 20℃; The bromoketone (See Example 20 Step 2, 0.67 g, 2.2 mmol) was dissolved in 1 : 1 ethyl alcohol/THF (22 mL), the thioamide (See Example 1 Step 9, 0.52 g, 2.2 mmol)) added, and the mixture stirred at room temperature overnight. The solution was diluted with aqueous NaOH (IN, 300 mL), followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc: hexanes (1 :9)) to afford the titled compound.
  • 17
  • [ 214834-18-1 ]
  • [ 14386-64-2 ]
  • C27H40N2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
The bromoketone (1.3 g, 4.0 mmol) was dissolved in 1:1 ethyl alcohol/THF (20 mL), the thioamide (SeeExample 1 Step 9 (0.97 g, 4.0 mmol) added, and the mixture stirred at room temperature overnight. The volatiles were removed in. vac. and the residue dissolved in DMF (6 mL). Et3N (0.48 g, 4.8 mmol) and di-Λ»rr-butyl dicarbonate (0.26 g, 1.2 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with water, followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (1 :9)) to afford the titled compound.
  • 18
  • [ 214834-18-1 ]
  • [ 131805-94-2 ]
  • C21H22F6N2O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethanol; at 20℃; The bromoketone (0.25 g, 0.75 mmol) was dissolved in 1 :4 ethyl alcohol/THF (20 mL), the thioamide (SeeExample 1 Step 9 (0.20 g, 0.82 mmol) added, and the mixture stirred at room temperature overnight. The mixture was diluted with 4: t water / saturated NaHCO3 followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (1:4)) to afford the titled compound.
  • 19
  • [ 214834-18-1 ]
  • [ 937047-12-6 ]
  • [ 937047-66-0 ]
YieldReaction ConditionsOperation in experiment
96% In ethanol; at 20 - 78℃; To a mixture of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-chloroethanone (500 mg, 2.37 mmol) in EtOH (12.5 mL) was added ferf-butyl 4-aminocarbothioyl)tetrahydropyridine-1 (2 H)-carboxylate (580 mg, 2.37 mmol). The mixture was stirred at 78 9C for 4.5 h, then allowed to cool to rt and stir overnight. The mixture was partitioned between saturated, aqueous NaHCO3 (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness to provide 914 mg (96%) <n="120"/>of the desired product, which contained trace impurities. ES-MS m/z 400.94 [M+H]+, HPLC RT (min) 3.12.
  • 20
  • [ 214834-18-1 ]
  • C10H4Br2F6O2 [ No CAS ]
  • C21H21BrF6N2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
The ketone (See Example 15 Step 2, 0.16 g, 0.46 mmol) was dissolved at RT in diethyl ether (2.3 mL), and aluminum chloride (3.0 mg, 0.02 mmol) added. Bromine (80 mg, 0.50 mmol) was added dropwise to the solution and the mixture stirred at RT for 10 minutes. The mixture was diluted with a solution of concentrated HCl /ice water (1:10, 40 mL), followed by aqueous/EtOAc work-up. The resulting material was dissolved in 1:1 ethyl alcohol/THF (2.3 mL), the thioamide (See Example 1 Step 9 (0. H g, 0.46 mmol) added, and the mixture stirred at 45 0C for 3 hours. The volatiles were removed in. vac. and the residue dissolved DMF (3.0 mL). Et3N (0.46 g, 4.6 mmol) and i-ert-butyl dicarbonate (100 mg, 0.46 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with 4:1 water/ saturated NaHCO3, followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether : hexanes (3:7)) to afford the titled compound.
  • 21
  • [ 214834-18-1 ]
  • [ 1124140-87-9 ]
  • [ 1124141-11-2 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethanol; at 20℃; for 1h; The bromoketone (See Example 17 Step 2, (0.50 g, 0.1.38 mmol) was dissolved in 1: 1 ethyl alcohol/THF (7.0 mL), the thioamide (See Example 1 Step 9, 0.34 g, 1.4 mmol) added, and the mixture stirred at room temperature for 1 hour. The solution was diluted with aqueous NaOH (IN, 150 mL), followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (3:7)) to afford the titled compound.
  • 22
  • [ 214834-18-1 ]
  • [ 1124142-20-6 ]
  • [ 1124142-45-5 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethanol; at 20℃; The bromoketone (See Example 18 Step 3, 0.13 g, 0.39 mmol) was dissolved in 1:1 ethyl alcohol/THF (4.0 mL), the thioamide (See Example 1 Step 13, 0.094 g, 0.39 mmol) added, and the solution stirred at room temperature overnight. The mixture was diluted with aqueous NaOH (IN5 40 mL), followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (3:17)) to afford the titled compound.
  • 23
  • [ 214834-18-1 ]
  • [ 1124143-07-2 ]
  • [ 1124143-24-3 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 19 Step 3, (0.078 g, 0.23 mmol) was dissolved in 1 :1 ethyl alcohol/THF (1.1 mL), the thioamide (See Example 1 Step 9, 0.056 g, 0.23 mmol) added, and the mixture stirred at room temperature overnight. The volatiles were removed in. vac. and the residue dissolved in DMF (1.0 mL). Et3N (0.23 g, 2.3 mmol) and di-tert-butyl dicarbonate (50 mg, 0.23 mmol) were added and the solution stirred at RT for 1 hour. The solution was diluted with aqueous NaOH (IN, 40 mL), followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (3:17)6) to afford the titled compound .
  • 24
  • [ 214834-18-1 ]
  • [ 1124144-10-0 ]
  • [ 1124144-28-0 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethanol; at 20℃; The bromoketone (See Example 21 Step 4, 0.074 g, 0.18 mmol) was dissolved in 1:1 ethyl alcohoI/THF (1.0 mL), the thioamide (See Example 1 Step 9, 0.044 g, 0.18 mmol)) added and the mixture stirred at room temperature overnight. The solution was diluted with aqueous NaOH (IN, 40 mL) followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (3:7)) to afford the titled compound.
  • 25
  • [ 214834-18-1 ]
  • [ 1005515-07-0 ]
  • [ 1124145-06-7 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 22 Step 4, 0.19 g, 51 mmol) was dissolved in 1 : 1 ethyl alcohol/THF (1.3 mL), the thioamide (See Example 1 Step 9, 0.12 g, 0.51 mmol)) added and the solution stirred overnight. The volatiles were removed in. vac. and the residue dissolved DMF (2.5 mL). Et3N (0.15 g, 1.5 mmol) and di-ffer/-butyl dicarbonate (110 mg, 0.51 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with 4: 1 water / saturated NaHCO3 followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (3:7)) to afford the titled compound.
  • 26
  • [ 214834-18-1 ]
  • [ 1124145-36-3 ]
  • [ 1124145-48-7 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 20℃; The bromoketone (See Example 23 Step 1, (0.043 g, 0.13 mmol) was dissolved in 1 :1 ethyl alcohol/THF (1.5 mL), the thioamide (See Example 1 Step 9, 0.036 g, 0.15 mmol) and NaHCO3 (12 mg, 0.15 mmol) added and the solution stirred at RT overnight. The mixture was poured into 4:1 water / saturated NaHCO3 (40 mL) followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (1 :9)) to afford the titled compound.
  • 27
  • [ 214834-18-1 ]
  • [ 1124146-33-3 ]
  • [ 1124146-46-8 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 24 Step 4, (0.073 g, 0.20 mmol) was dissolved in 1:1 ethyl alcohol/THF (1.0 mL), the thioamide (See Example 1 Step 9, 0.050 g, 0.20 mmol) added and the solution stirred at RT overnight. Et3N (0.20 g, 2.0 mmol) and di-tert-butyl dicarbonate (0.044 g, 0.20 mmol) were added and the solution stirred for 1 hour. The mixture was diluted with 4:1 water / saturated NaHCO3 followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (3 :7)) to afford the titled compound.
  • 28
  • [ 214834-18-1 ]
  • [ 1124146-93-5 ]
  • C25H38N4O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 25 Step 4, 0.025 g, 0.080 mmol) was dissolved in 1:1 ethyl alcohol/THF (1.0 mL), the thioamide (See Example 1 Step 9, 0.020 g, 0.080 mmol) added and the solution stirred at RT overnight. The solvent was removed in vac. and the residue dissolved in DMF (1.0 mL). Et3N (0.024 g, 0.24 mmol) and di-tert-butyl dicarbonate (0.018 g, 0.080 mmol) were added and the solution stirred at RT for 1 hour. The mixture was poured into saturated NaHCO3 (50 mL) followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (3:7)) to afford the titled compound.
  • 29
  • [ 214834-18-1 ]
  • [ 1124147-60-9 ]
  • [ 1124147-72-3 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 26 Step 4, 0.24 g, 0.74 mmol) was dissolved in 1 : 1 ethyl alcohol/THF (3.7 mL), the thioamide (See Example 1 Step 9, 0.18 g, 0.74 mmol) added and the solution stirred at RT overnight. The solvent was removed in vac. and the residue dissolved in DMF (3.7 mL). Et3N (0.75 g, 7.4 mmol) and di~ter/-butyl dicarbonate (0.16 g, 0.74 mmol) were added and the solution stirred for 1 hour. The mixture was diluted with saturated NaHCC>3 (100 mL) followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (1:7)) to afford the titled compound.
  • 30
  • [ 214834-18-1 ]
  • [ 1124148-31-7 ]
  • [ 1124148-49-7 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 27 Step 4, 0.20 g, 0.51 mmol) was dissolved in 1: 1 ethyl alcohol/THF (2.6 mL), the thioamide (See Example 1 Step 9, 0.13 g, 0.51 mmol)) added and the solution stirred at RT overnight. The solvent was removed in vac. and the residue dissolved in DMF (2.6 mL). Et3N (0.52 g, 5.1 mmol) and di-ter/-butyl dicarbonate (0.11 g, 0.51 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with 4:1 water / saturated NaHCO3 (100 mL) followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (1 :4)) to afford the titled compound.
  • 31
  • [ 214834-18-1 ]
  • [ 1124136-01-1 ]
  • C24H31F3N2O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
The bromoketone (SeeExampIe 1 Step 8, (2.41 g, 5.4 mmol) was dissolved in 1:1 EtOH /THF (34 mL), the thioamide (SeeExampIe 1 Step 9 (1.66 g, 6.8 mmol) added, and the mixture stirred overnight at room temperature. The volatiles were removed in vac and the residue dissolved DMF (13.5 mL). Et3N (6.87 g, 68 mmol) and di-Λ?r*-butyl dicarbonate (888 mg, 4.07 mmol) were added and the solution stirred for 1 hour. The mixture was poured into 4:1 water / saturated NaHCO3 followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether : hexanes (1 :4)) to afford the titled compound.
  • 32
  • [ 214834-18-1 ]
  • [ 1124149-52-5 ]
  • [ 1124149-65-0 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 29 Step 6, 0.050 g, 0.15 mmol) was dissolved in 1: 1 ethyl alcohol/THF (0.75 mL), the thioamide (See Example 1 Step 9, 0.037 g, 0.15 mmol)) added and the solution stirred at RT overnight. The solvent was removed in vac. and the residue dissolved in DMF (0.75 mL). Et3N (0.15 g, 1.5 mmol) and di-tert-buty dicarbonate (0.033 g, 0.15 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with 4:1 water / saturated NaHCO3, followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc: hexanes (1:9)) to afford the titled compound.
  • 33
  • [ 214834-18-1 ]
  • [ 1124149-98-9 ]
  • [ 1124150-06-6 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 30 Step 5, 0.28 g, 0.91 mmol) was dissolved in 1 : 1 ethyl alcohol/THF (5.0 mL), the thioamide (See Example 1 Step 9, 0.22 g, 0.91 mmol)) added and the solution stirred at RT overnight. The solvent was removed in vac. and the residue dissolved in DMF (4.5 mL). Et3N (0.91 g, 9.1 mmol) and di-tert-butyl dicarbonate (0.20 g, 0.91 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with saturated NaHCO3 (100 mL), followed by <n="86"/>aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (1 :4)) to afford the titled compound.
  • 34
  • [ 214834-18-1 ]
  • [ 132392-28-0 ]
  • [ 1124150-29-3 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 20℃; for 2.5h; A vessel was charged with 2-bromo-l -(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-l-one (0.70 g, 2.3 mmol), thioamide (See Example 1 Step 9, 0.83 g, 3.4 mmol), and NaHCO3 (0.21 g, 2.5 mmol), the materials dissolved in 1:1 ethyl alcohol/THP (15 mL). The resulting solution was stirred at RT for 2.5 hours, diluted with water(50 mL), followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether: hexanes (1:4)) to afford the titled compound.
  • 35
  • [ 214834-18-1 ]
  • [ 1124153-36-1 ]
  • [ 1124153-40-7 ]
YieldReaction ConditionsOperation in experiment
The bromoketone (See Example 40 Step 6, 0.064 g, 0.17 mmol) was dissolved in 1:1 ethyl alcohoI/THF (1.7 mL), the thioamide (See Example 1 Step 9, 0.041 g, 0.17 mmol) added, and the mixture stirred at RT overnight. The volatiles were removed in. vac. and the residue dissolved DMF (1.0 mL). Et3N (0.17 g, 1.7 mmol) and -tert-butyl dicarbonate (36 mg, 0.17 mmol) were added and the solution stirred at RT for 1 hour. The mixture was diluted with 4: 1 water / saturated NaHCO3 followed by aqueous/EtOAc work-up and silica gel chromatography (diethyl ether : hexanes (1 :7)) to afford the titled compound.
  • 36
  • [ 214834-18-1 ]
  • [ 1124137-11-6 ]
  • C24H31F3N2O4S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
The bromoketone (SeeExampIe 3 Step 3, (0.28 g, 0.71 mmol) was dissolved in 1 :1 ethyl alcohol/THF (1.7 mL), the thioamide (SeeExampIe 1 Step 9 (0.17 g, 0.71 mmol) added, and the mixture stirred at room temperature overnight. The volatiles were removed in vac and the residue dissolved DMF (3.5 mL). Et3N (0.72 g, 7.1 mmol) and di-tert-butyl dicarbonate (78 mg, 0.36 mmol) were added and the solution stirred at RT for 1 hour. The mixture was poured into 4:1 water / saturated NaHCO3 followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (1 :4)) to afford the titled compound.
  • 37
  • [ 214834-18-1 ]
  • [ 1124138-91-5 ]
  • C23H31BrN2O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
The bromoketone (SeeExample 11 Step 3, (0.30 g, 0.90 mmol) was dissolved in 1:1 ethyl alcohoI/THF (4.5 mL), the thioamide (SeeExample 1 Step 9 (0.22 g, 0.9 mmol) added, and the mixture stirred at room temperature overnight. The volatiles were removed in. vac. and the residue dissolved in DMF (4.5 mL). Et3N (0.91 g, 9.0 mmol) and i-tert-butyl dicarbonate (0.20 g, 0.90 mmol) were added and the solution stirred for 1 hour. The mixture was diluted with 4:1 water / saturated NaHCC>3 (300 mL) followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc: hexanes (1:9)) to afford the titled compound.
  • 38
  • [ 214834-18-1 ]
  • [ 70-11-1 ]
  • [ 887624-95-5 ]
YieldReaction ConditionsOperation in experiment
93.2% With sodium hydrogencarbonate; In ethanol; for 3h;Reflux; To a solution of 1c (0.30 g, 1.23 mmol) and NaHCO3 (0.21 g,2.46 mmol) in ethanol (5 mL) was added a-bromoacetophenone(0.26 g, 1.29 mmol). The mixture was heated to reflux for 3 h. Afterevaporated under reduced pressure, the residue was purified bysilica gel flash column chromatography (CH2Cl2/EtOAc 40:1, V/V)to give a light-brown oil (0.40 g, 93.2% yield). 1H NMR (400 MHz,CDCl3) d: 7.90 (m, 2H), 7.42 (m, 2H), 7.38 (s, 1H), 7.34 (m, 1H), 4.21(m, 2H), 3.33 (m, 1H), 2.93 (m, 2H), 2.17 (m, 2H),1.77 (m, 2H),1.48 (s,9H). MS (ESI) m/z 345.18 [MH].
55.2% With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1.5h; Example 188; N-1,2-Benzisoxazol-3-yl-4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxamide; (1) tert-Butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate; A mixture of <strong>[214834-18-1]tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate</strong> (1.00 g, 7,24 mmol), 2-bromoacetophenone (1.58 g, 7.96 mmol), potassium carbonate (1.00 g, 7.24 mmol) and N,N-dimethylformamide (30 ml) was stirred at 110C for 1.5 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 1) to obtain the desired product (1.38 g, 55.2%) as an oil. 1H-NMR (CDCl3) δ; 1.46 (9H, s), 1. 69 - 1.86 (2H, m), 2.13 - 2.18 (2H, m), 2.88 - 2.96 (2H, m), 3.17 - 3.27 (1H, m), 4.19 (2H, br s), 7.29 - 7.51 (4H, m), 7.86 - 7.89 (2H, m).
55% With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1.5h; A mixture of <strong>[214834-18-1]tert-butyl 4-carbamothioylpiperidine-1-carboxylate</strong> (1.0 g, 7.24 mmol), 2-bromo-1-phenylethanone (1.58 g, 7.96 mmol), potassium carbonate (1.0 g, 7.24 mmol), and DMF (30 mL) was stirred at 110 C for 1.5 h, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue purified by silica gel column chromatography (hexane-EtOAc) to give 50 (1.38 g, 55%) as a colorless oil. 1H NMR (300 MHz, CDCl3) d: 1.46 (9H, s), 1.69-1.86 (2H, m), 2.13-2.18 (2H, m), 2.88-2.96 (2H, m), 3.17-3.27 (1H, m), 4.19 (2H, br s), 7.29-7.51 (4H, m), 7.86-7.89 (2H, m).
  • 39
  • [ 214834-18-1 ]
  • 2-(2-aminopyridin-4-yl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide [ No CAS ]
  • [ 144-55-8 ]
  • [ 365430-38-2 ]
YieldReaction ConditionsOperation in experiment
50% In N,N-dimethyl-formamide; Reference Example H 80 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide (2.74 g, 8.36 mmol) and 1-tert-butoxycarbonylpiperidine-4-carbothioamide in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and then purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate). The obtained crude crystalline was recrystallized from ethyl acetate-hexane to give the title compound (1.94 g, yield 50%). m.p.: 143-145C
50% In N,N-dimethyl-formamide; Example 80 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide (2.74 g, 8.36 mmol) and 1-tert-butoxycarbonylpiperidine-4-carbothioamide in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and then purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate). The obtained crude crystalline was recrystallized from ethyl acetate-hexane to give a title compound (1.94 g, yield 50%). m.p. 143-145 C.
  • 40
  • [ 214834-18-1 ]
  • [ 4629-54-3 ]
  • [ 948041-00-7 ]
YieldReaction ConditionsOperation in experiment
68% In N,N-dimethyl-formamide; at 0 - 20℃; Example 1: Preparation of E-3-{4-[4-(3,4-ethylendioxphenyl)-thiazol-2-yl]-piperidin-1-yl}-1-(3,4-methylendioxyphenyl)-3-prop-1-ene (Compound I) [Show Image] A. Preparation of intermediate (7) [Show Image] To a solution of <strong>[214834-18-1]tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate</strong> (5) (1 eq.) in DMF (5 vol eq.) a solution of bromoketone (6) (1.05 eq.) in DMF (10 vol eq.) is added drop wise at 0C. The mixture is left to stir overnight gradually warming to room temperature. Triethylamine (2.2 eq.) is added portionwise to the resulting solution at room temperature, and then stirred for further 30 minutes. The reaction mixture is poured into water and extracted 3 times with ethyl acetate. The organic layers are combined, washed with waterand brine, dried overnight over MgSO4, and concentrated in vacuo. The desired product is obtained as a pale orange oily residue, collected and dried in a vacuum oven. Yield 68%.
68% A. Preparation of intermediate (7); To a solution of <strong>[214834-18-1]tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate</strong> (5) (1 eq.) in DMF (5 vol eq.) a solution of bromoketone (6) (1.05 eq.) in DMF (10 vol eq.) is added drop wise at 00C. The mixture is left to stir overnight gradually warming to room temperature. Triethylamine (2.2 eq.) is added portionwise to the resulting solution at room temperature, and then stirred for further 30 minutes. The reaction mixture is poured into water and extracted 3 times with ethyl acetate. The organic layers are combined, washed with waterand brine, dried overnight over MgSO4, and concentrated in vacuo. The desired <n="28"/>product is obtained as a pale orange oily residue, collected and dried in a vacuum oven. Yield 68%.
  • 41
  • [ 214834-18-1 ]
  • [ 887307-15-5 ]
  • [ 887307-16-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In isopropyl alcohol; at 70℃; for 2h; To a solution of the compound prepared in Example 7 (413 mg) and <strong>[214834-18-1]tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate</strong> (206 mg) in isopropanol (10 mL) was added potassium carbonate (350 mg) and the mixture was stirred at 70 C for 2 hours. The reaction mixture was filtrated and the filtrate was concentrated. The obtained residue was added by ethyl acetate and water, then the water layer was extracted with ethyl acetate. The obtained organic layer was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 1 : 1) to give the title compound (419 mg) having the following physical data. TLC : Rf 0.35 (hexane:ethyl acetate=2:3); NMR : δ 1.47 (s, 9H), 1.67-1.87 (m, 2H), 2.07-2.20 (m, J=6.00, 3.00Hz, 2H), 2.79-2.99 (m, 2H), 3.07-3.22 (m, 1H), 4.15-4.29 (m, 2H), 6.58 (d, J=9.70Hz, 1H), 6.98-7.09 (m, 1H), 7.19-7.40 (m, 4H), 7.41-7.49 (m, 3H).
  • 42
  • [ 214834-18-1 ]
  • [ 534-07-6 ]
  • [ 650579-82-1 ]
YieldReaction ConditionsOperation in experiment
92% With magnesium sulfate; magnesium carbonate; In acetone; for 12h;Reflux; Inert atmosphere; To a solution of compound9(1.3 g, 5.3 mmol) in acetone (50 mL) was added MgSO4(1.6 g, 13.2 mmol), MgCO3(534 mg, 6.3 mmol) and 1,3-dichloroacetone (1.1 g, 9.0 mmol). The resulting reaction mixture was heated under reflux overnight, cooled to room temperature and filtered through a celite. The solvent was removed by evaporation and the residue was dissolved with EtOAc. The resulting solution was washed with 5% NaHSO3(2 x 50 mL), saturated NaHCO3and brine. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and concentrated to afford compound10(1.5 g, 92%).1H-NMR (CDCl3,300 MHz) δ 7.19 (1H, s, thiazole), 4.66 (2H, s, CH2), 4.22 (2H, d,J= 12.0 Hz, CH2), 3.19 (1H, tt,J= 9.0 Hz, 3.0 Hz, CH), 2.91 (2H, t,J= 12.0 Hz, CH2), 1.70 (2H, dt,J= 12.0 Hz, 3.0 Hz, CH2), 1.47 (9H, s, C(CH3)3).
92.7% With magnesium sulfate; magnesium carbonate; In acetone; at 65℃; for 4h; Compound 2 (10 g, 0.04 mol) was added to a solution of 1,3-dichloroacetone(6.6 g, 0.052 mol), MgSO4 (7.2 g, 0.06 mol) and MgCO3 in acetone (60 mL). The resulting solution was heated to 65 C and stirred at this temperature for 4 h, and monitored by TLC, then concentrated. The residue was diluted with EA (80 mL), washed with brine, dried over Na2SO4, filtered and concentrated to afford compound 3 (12 g, 92.7% yield)as a yellow oily liquid. 1H NMR (400 MHz, CDCl3) δ 7.20(s, 1H), 4.67(s, 2H), 3.16(tt, J = 11.7 Hz, 3.8 Hz, 1H), 2.87(d, J = 3.2 Hz, 3H), 2.11-2.07(m, 2H), 1.71(qd, J = 12.5 Hz, 4.5 Hz, 3H), 1.47(s, 9H).
77.38% In toluene; for 10h;Reflux; 4-aminothiocarbonyl tetrahydropyridine-1(2H)-tert-butyl formate (3.00g, 12.28mmol)And 1,3-dichloroacetone (1.71g, 13.51mmol) dissolved in toluene,Heat up to reflux reaction, after 10h, TLC detects that the reaction is complete,Concentrate under reduced pressure to remove toluene, then add 100 mL of ethyl acetate for extraction,The organic layer was washed with water and saturated brine, and dried overnight with anhydrous Na2SO4.Filter out the desiccant, concentrate under reduced pressure to evaporate the solvent,The residue was purified by silica gel column chromatography,3.01g of the final product was obtained, and the yield was 77.38%.
With magnesium sulfate; magnesium carbonate; In acetone;Heating / reflux; Preparation of Intermediate 1: 4-(4-Chloromethyl-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester; To a solution of 4-thiocarbamoyl-piperidine-l-carboxylic acid tert-butyl ester (4.9 g, 20 mmol) in acetone (80 raL) was added 1 ,3-dichloroacetone (3.3 g, 26 mmol), MgSO4 (3.6 g, 30 mmol) and MgCO3 (1.68 g, 20 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (150 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product. 1H NMR (CDCl3): δ 7.20 (IH, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (IH, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
With magnesium sulfate; magnesium carbonate; In acetone;Reflux; Example 3b [0033] To a 500 mL flask under air, immersed in an oil bath and a condenser, was added 4-thiocarbamoyl-piperidine-l-carboxylic acid tert-butyl ester (29 g, 120mmol), acetone (300 mL) MgS04 (21.6g, 180 mmol) and MgC03 (10 g, 120 mmol), 1,3- dichloroacetone (19.8 g, 156 mmol). The resulting mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (500 mL). The resulting solution was washed successively with 5% NaHS03 (twice), saturated NaHC03 and brine. After drying (NaS04), the solvent was removed to afford 35 g of the title compound as light yellow oil. The oil became dark solid after standing at room temperature. The color could be removed by activated charcoal. The purity was improved from 92% to 96%.1H NMR (CDC13): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
With magnesium sulfate; magnesium carbonate; In acetone;Reflux; To a 500 mL flask under air, immersed in an oil bath and a condenser, was added 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (29 g, 120 mmol), acetone (300 mL) MgSO4 (21.6 g, 180 mmol) and MgCO3 (10 g, 120 mmol), 1,3-dichloroacetone (19.8 g, 156 mmol). The resulting mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (500 mL). The resulting solution was washed successively with 5% NaHSO3 (twice), saturated NaHCO3 and brine. After drying (NaSO4), the solvent was removed to afford 35 g of the title compound as light yellow oil. The oil became dark solid after standing at room temperature. The color could be removed by activated charcoal. The purity was improved from 92% to 96%. 1H NMR (CDCl3): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
Example 36 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-([2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine hydrochloride 1,1-Dimethylethyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.50 g, 6.14 mmol), NaHCO3 (0.570 g, 6.78 mmol) and 1,3-dichloroacetone (0.860 g, 6.77 mmol) were combined in 1,2-dichloroethane (4 mL) and the reaction mixture was stirred at room temperature for 12 h. The crude reaction mixture was filtered using CH2Cl2 and the filtrate was concentrated in vacuo until approximately 30 mL of solvent remained. To this solution was added pyridine (0.75 mL, 9.2 mmol), and the solution was cooled with an ice bath. Thionyl chloride (0.49 mL, 6.8 mmol) was added and the solution was allowed to warm slowly to room temperature. The solvent was removed in vacuo and the residue was taken up in 10% MeOH/ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo to yield 2.24 g (>100%) of crude 1,1-dimethylethyl 4-[4-(chloromethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, d6-DMSO): 7.62 (s, 1H), 4.60 (s, 2H), 3.98 (m, 1H), 3.63 (dd, 2H), 3.16 (m, 1H), 2.90 (broad s, 2H), 2.01 (dd, 1H), 1.51 (m, 2H), 1.40 (s, 9H). MS (EI) for C14H21N2O2SCl: 261 (M-tBu).
With magnesium sulfate; magnesium carbonate; In acetone;Reflux; To a solution of 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 20 mmol) in acetone (80 mL) was added 1,3-dichloroacetone (3.3 g, 26 mmol), MgSO4 (3.6 g, 30 mmol) and MgCO3 (1.68 g, 20 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (150 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product. ‘HNMR(CDC13): ö 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s)

  • 43
  • [ 214834-18-1 ]
  • [ 2065-75-0 ]
  • C14H20N2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 72h; a) Method of Synthesising B-3a:; tert.-Butyl-4-(aminocarbothioyl)-tetrahydropyridine-1-(2H)-carboxylate (3.03 g, 12.4 mmol) is placed in THF (30 mL) with Hünig base (2.1 mL, 12.3 mmol) and bromine malonaldehyde (1.853 g, 12.3 mmol) is added at RT. After 3 d stirring at RT the solvent is eliminated under reduced pressure, the residue remaining is taken up in DCM and washed with aqueous sodium hydrogen carbonate solution and water. The organic phase is dried on magnesium sulphate, filtered and the filtrate is evaporated down under reduced pressure. The crude product is then purified by chromatography using silica gel (cyclohexane/EE from 60:40 to 50:50). B-3a is obtained (HPLC-MS: tRet=1.91 min; MS (M+H-tBu)+=240).
  • 44
  • [ 214834-18-1 ]
  • 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate [ No CAS ]
  • 4-oxo-8-(2-piperidin-4-yl-thiazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% 55 mg (1.5 mmol) of 4-thiocarbamoyl-piperidine-1-tert-butyl carboxylate is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90 C. for 3 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added, then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol/triethylamine 8/2/1). After drying, 11 mg (17%) of 4-oxo-8-(2-piperidin-4-yl-thiazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.LCMS (IE, m/z): (M+1) 423.241H-NMR: δH ppm 400 MHz, DMSO11.76 (1H, bs, NH), 9.76 (1H, d, CHarom), 8.00 (1H, s, CHarom), 7.95 (1H, dd, CHarom), 7.74 (1H, s, CHarom), 7.44 (1H, d, CHarom), 4.35 (2H, q, CH2), 3.35-3.30 (1H, m, CHpiper), 3.16-3.10 (2H, m, 2×CHpiper), 2.80-2.72 (2H, m, 2×CHpiper), 2.13-2.06 (2H, m, 2×CHpiper), 1.77-1.68 (2H, m, 2×CHpiper), 1.36 (3H, t, CH3).
  • 45
  • [ 214834-18-1 ]
  • [ 1173693-31-6 ]
  • [ 1173693-32-7 ]
YieldReaction ConditionsOperation in experiment
With pyridine; In ethanol; at 20 - 77℃; To a solution of l-tert-butoxycarbonylpiperidine-4-carbothioamide (1 g, 4.10 mmol) in ethanol (10 niL) was added 2-chloro-l-[4,5-dihydro-5-(2-fluorophenyl)-3- isoxazolyl]ethanone (i.e. the product of Step A) (0.99 g) followed by pyridine (0.34 mL,4.10 mmol). The reaction mixture was heated at 77 0C for 3 h, and then stirred at room temperature overnight. Ethanol was removed from the reaction mixture, and the remaining residue was diluted with ethyl acetate (50 mL). The organic layer was separated, washed with water, saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel to provide the title compound as a pale yellow sticky oil (1.11 g).1H NMR (CDCl3) δ 1.46 (S, 9H), 1.65 (m, 2H), 2.04 (m, 2H), 2.82 (m, IH), 3.24 (m, IH), 3.40, (m, IH), 4.02 (m, 2H), 5.98 (m, IH), 7.08 (m, 2H), 7.27 (m, IH), 7. 35 (m, IH), 7.61 (s, 1 H). 19F NMR (CDCl3) δ 118.39 (1F).
  • 46
  • [ 214834-18-1 ]
  • [ 1173693-37-2 ]
  • [ 1148104-71-5 ]
YieldReaction ConditionsOperation in experiment
A mixture of l-tert-butoxycarbonylpiperidine-4-carbothioamide (7.33 g, 30 mmol) and 2-bromo-l-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step C) (9.12 g, 30 mmol) in acetone (100 mL) was heated at 45 0C for 3 h, and then stirred at room temperature overnight. The acetone solvent was evaporated, and the resulting residue was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (40 mL). The mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The resulting oil was dissolved in aqueous hydrochloric acid solution (0.5 N, 200 mL) and extracted with ethyl acetate. The organic layer was basified by adding aqueous sodium hydroxide solution (10% in water). The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated under reduced pressure to provide the title compound as a thick amber-colored oil (8.62 g, including residual ethyl acetate). The hydrochloric acid solution that had been extracted with ethyl acetate was subsequently basified by adding aqueous sodium hydroxide solution (50% in water) and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated under reduced pressure to provide more of the title product as an oil (1.33 g, including residual ethyl acetate). <n="139"/>1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.87 (br s, IH), 2.22 (m, 2H), 2.77 (m, 2H), 3.18 (m, 3H), 3.62 (m, IH), 3.80 (m, IH), 6.05 (m, IH), 6.92 (m, 2H), 7.30 (m, IH), 7.64 (s, IH).
  • 47
  • [ 214834-18-1 ]
  • [ 1171113-63-5 ]
  • [ 1171113-92-0 ]
  • 48
  • [ 214834-18-1 ]
  • [ 1195768-27-4 ]
  • [ 1195769-70-0 ]
YieldReaction ConditionsOperation in experiment
Example 321; 2,6-difluoro-N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide; Step A: 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate; To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-carbamate (1.43 g, 4.09 mmol) in N,N-dimethylacetamide (DMA) (15 mL) was added NBS (0.728 g, 4.09 mmol), and the reaction mixture was stirred for 1 h. 1,1-Dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (0.999 g, 4.09 mmol) was added and the reaction mixture was heated to 80 C. for 25 min. The mixture was cooled, quenched with water (30 mL) and extract with EtOAc (3×). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (hexane/EtOAc, 0 to 100%) to give 1.34 g of the title compound. MS (ESI): 574.2 [M+1]+.
  • 49
  • [ 214834-18-1 ]
  • 2-bromo-1-(4-chlorophenyl)-2-(4-methylphenyl)ethan-1-one [ No CAS ]
  • C26H29ClN2O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; for 4h;Heating / reflux; A solution of 1-tert-butoxycarbonyl-4-piperidine thioamide (500 mg, 2.05 mmol) and 2-bromo-1-(4-chlorophenyl)-2-(4-tolyl)ethanone (662 mg, 2.05 mmol) in methanol (15 ml) was heated under reflux for 4 hours and then cooled to room temperature. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved with the addition of 10% hydrochloric acid-methanol (10 ml), and the resultant was heated under reflux for 4 hours. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. Chloroform was added to the residue to filter the slurry, and a title compound (831 mg, 2.05 mmol, quant.) was obtained as a yellow powder. 1H-NMR (400 MHz, CDCl3) δ: 1.71-1.82 (3H, m), 2.14-2.18 (2H, m), 2.36 (3H, s), 2.74-2.82 (2H, m), 3.11-3.23 (3H, m), 7.13 (2H, d, J = 8.8 Hz), 7.18-7.26 (4H, m), 7.45 (2H, d, J = 8.8 Hz). IR (KBr, cm-1): 3426, 2921, 1736, 1637, 1491, 1445, 1318, 1244, 1089, 1014, 970, 835,812. ESI-MS: m/z = 369 (M+H+).
  • 50
  • [ 214834-18-1 ]
  • [ 27895-95-0 ]
  • [ 951745-06-5 ]
YieldReaction ConditionsOperation in experiment
47% In methanol; at 20℃; for 2 - 4h;Heating / reflux;Product distribution / selectivity; Reference Example 93 4-(4,5-Bis(4-methoxyphenyl)thiazol-2-yl)piperidine [Show Image] A solution of 1-tert-butoxycarbonyl-4-piperidine thioamide (350 mg, 1.4 mmol) and 2-bromo-1,2-bis(4-methoxyphenyl)ethanone (Reference Example 14) (480 mg, 1.4 mmol) in methanol (15 ml) was heated under reflux for 4 hours and then cooled to room temperature. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved with the addition of 10% hydrochloric acid-methanol (15 ml), and the resultant was heated under reflux for 14 hours. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by flash chromatography (amine silica gel, chloroform) to give a title compound (263mg, 0.69 mmol, 48%) as a colorless oil product. 1H-NMR (400 MHz, CDCl3) δ: 1.67 (1H, s), 1.71-1.81 (2H, m), 2.15-2.18 (2H, m), 2.74-2.81 (2H, m), 3.11-3.23 (3H, m), 3.80 (3H, s), 3.82 (3H, s), 6.82 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz). IR (neat, cm-1): 3341, 2937, 2836, 2736, 1736, 1608, 1575, 1538, 1514, 1496, 1464, 1372, 1319, 1293, 1250, 1176, 1141, 1106, 1034, 969, 880, 834, 795. ESI-MS: m/z = 381 (M+H+).; Reference Example 143 4-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)-1-tert-butoxycarbonylpiperidine [Show Image] To a solution of 1,2-bis(4-methoxyphenyl)-2-bromoethanone (Reference Example 14) (1.05 g, 3.29 mmol) in methanol (10 ml) was added 1-tert-butoxycarbonylpiperidine-4-thiocarboxamide (804 mg, 3.29 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under a reduced pressure, and an aqueous solution of 1M sodium hydroxide was added to the residue, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under a reduced pressure. The residue was purified by flash chromatography on silica gel (n-hexane/ethyl acetate) to give a title compound (745 mg, 1.55 mmol, 47%) as a light yellow oil product. 1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.72-1.83 (2H, m), 2.10-2.18 (2H, m), 2.85-2.95 (2H, m), 3.12-3.21 (1H, s), 3.80 (3H, s), 3.82 (3H, s), 4.16-4.27 (2H, m), 6.81 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz).
  • 51
  • [ 214834-18-1 ]
  • [ 951744-04-0 ]
  • C26H29FN2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; at 20℃; for 4h; A solution of 2-bromo-2-(4-fluorophenyl)-1-(4-methoxyphenyl)ethanone (Reference Example 22) (199 mg, 0.616 mmol) and 1-tert-butoxycarbonylpiperidine-4-thiocarboxamide (153 mg, 0.613 mmol) in methanol (5.0 ml) was stirred at room temperature for 4 hours. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved with the addition of dichloromethane. Trifluoroacetic acid (1.0 ml) was added, the mixture was stirred at room temperature for 3 hours, and the resultant was then concentrated under a reduced pressure. The residue was neutralized with the addition of an aqueous solution of 1M sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried and then concentrated under a reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to give a title compound (177 mg, 0.480 mmol, 78 %) as a white amorphous product. 1H-NMR (400 MHz, CDCl3) δ: 1.71-1.83 (2H, m), 2.12-2.20 (2H, m), 2.75-2.82 (2H, m), 3.07-3.26 (3H, m), 3.80 (3H, s), 6.81 (2H, d, J = 8.8 Hz), 7.00 (2H, t, J = 8.8 Hz), 7.29 (2H, dd, J = 5.4, 3.4 Hz), 7.41 (2H, d, J = 8.8 Hz).
  • 52
  • [ 214834-18-1 ]
  • [ 31984-10-8 ]
  • [ 1220713-44-9 ]
  • [ 1374830-40-6 ]
YieldReaction ConditionsOperation in experiment
tert-Butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (IV-1) At 0 C., a solution of <strong>[214834-18-1]tert-butyl 4-carbamothioylpiperidine-1-carboxylate</strong> (1.95 g) is added dropwise to a solution of 1-bromo-4-phenylbutan-2-one (2.00 g) in ethanol (20 ml). Under argon, the reaction mixture is stirred at room temperature overnight. Triethylamine (1.7 ml) is added, and the mixture is diluted with ethyl acetate and washed with concentrated sodium chloride solution. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure, which gives a mixture of tert-butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate and tert-butyl 4-[4-hydroxy-4-(2-phenylethyl)-4,5-dihydro-1,3-thiazol-2-yl]piperidine-1-carboxylate. The two compounds are separated chromatographically. This gives tert-butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (800 mg) and tert-butyl 4-[4-hydroxy-4-(2-phenylethyl)-4,5-dihydro-1,3-thiazol-2-yl]piperidine-1-carboxylate (640 mg). Both compounds can be used for Process 1.2 since the latter compound is, under the reaction conditions, converted into the former. 1H NMR (DMSO-d6): δ 7.28-7.25 (m, 2H), 7.22-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.13 (s, 1H), 4.00 (bs, 2H), 3.35 (s, 2H), 3.16 (m, 1H), 2.95 (s, 4H), 2.00 (d, 2H), 1.52 (qd, 2H), 1.41 (s, 9H) ppm MS (ESI): 373 ([M+H]+)
  • 53
  • [ 214834-18-1 ]
  • [ 1173693-37-2 ]
  • tert-butyl 4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetone; at 20 - 45℃; Step D: Preparation of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2- thiazolyl]piperidineA mixture of l-fert-butoxycarbonylpiperidine-4-carbothioamide (7.33 g, 30 mmol) and 2-bromo-l-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step C) (9.12 g, 30 mmol) in acetone (100 mL) was heated at 45 0C for 3 h, and then stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (40 mL), stirred at room temperature for 3 h and then concentrated under reduced pressure. The resulting oil was dissolved in aqueous hydrochloric acid solution (0.5 N, 200 mL) and extracted with ethyl acetate. The organic layer was basified by adding aqueous sodium hydroxide solution (10% in water), then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a thick amber-colored oil (8.62 g, weight included residual ethyl acetate).More aqueous sodium hydroxide solution (50% in water) was added to the hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide more of the title product as an oil (1.33 g, weight included residual ethyl acetate). 1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.87 (br s, IH), 2.22 (m, 2H), 2.77 (m, 2H), 3.18 (m, 3H), 3.62 (m, IH), 3.80 (m, IH), 6.05 (m, IH), 6.92 (m, 2H), 7.30 (m, IH), 7.64 (s, IH).
In methanol; at 20 - 50℃; for 2h;Inert atmosphere; under the room temperature, the (42.53g, 0 . 14mol, 1eq), (34.602g, 0 . 141mol, 1eq) and 300 ml methanol are successively added into a 500 ml three-mouth bottle. 50 C stirring under nitrogen protection 2h, the reaction produces Quality monitoring, to be after the reaction is complete,
  • 54
  • [ 214834-18-1 ]
  • [ 70-23-5 ]
  • [ 1192878-45-7 ]
YieldReaction ConditionsOperation in experiment
75% With sodium acetate; In ethyl acetate; at 5℃; for 16h; General MethodTo 5.5 g (15.4 mmol) of 4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester in 50 ml of ethyl acetate was added 3.4 g (40.9 mmol, 2eq) of sodium acetate and 3.7 ml (26.6 mmol, 1.3 eq) of ethyl bromopyruvate at 5 C. The reaction was allowed to pursue for 16 hrs. After addition of water, the compound was extracted 3× CH2Cl2. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The compound was recristallized in diisopropyl oxyde to give 5.53 g (15.43 mmol, 75%) of a white solid.To 54.2 g (0.15 mol) of the above compound was added 300 ml of acetic acid and the reaction was heated to 100 C. for 1 h30. The mixture was concentrated, CH2Ck2 was the added and the organic layer washed with a solution of NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 45.7 g (0.13 mol, 89%) ofthe desired cyclized compound which was saponified by addition of Ethanol (300 ml) and 16.1 ml (1.16 mol, 1.2 eq) of a sodium hydroxyde solution (10N) for 16 h at room temperature. After concentration in vacuo and addition of water (300 ml), washing with CH2Cl2, the solution was then acidified with AcOH. The compound which precipitates is filtered and washed with water to give 34.63 g (0.11 mol, 83%) of a white solid.To 1.960 g (6.2 mmol) of the free carboxylic acid under N2 was added 20 ml DMF, and 0.974 g (6.2 mmol, 1 eq) of decahydroquinolin-4ol, 2.838 ml (21.9 mmol, 3.5 eq) of diisopropylamine and 2.4 g (6.2 mmol, 1 eq) of HBTU. The mixture was stirred at room temperature for 16 hrs and the reaction quenched with water (100 ml) and the compound extracted with AcOEt (3×) and washed with a solution of NaHCO3, citrique acid 15%, water, NaCl saturated solution, and finally dried over Na2SO4 and concentrated to give 2.42 g (5.3 mmol, 86%) of an oil.To 2.35 g (5.2 mmol) of the starting material in 20 ml CH2Cl2 was added at 5 C. was added 13 mi of a HCl/dioxanne solution (4M/L). The reaction was allowed to warm up at room temperature and stirred for 16 hrs. After concentration in vacuo, water was added, the compound washed with CH2Cl2, NaOH solution (10 N) was then added, and the compound was finally extracted with CH2Cl2, washed with a saturated solution of NaCl, dried over Na2SO4 and concentrated to give an oil (1.30 g, 3.7 mmol, 7%).
 

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Technical Information

Categories

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[ 214834-18-1 ]

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[ 214834-18-1 ]

Piperidines

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