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Chemical Structure| 365413-31-6 Chemical Structure| 365413-31-6

Structure of 365413-31-6

Chemical Structure| 365413-31-6

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Product Details of [ 365413-31-6 ]

CAS No. :365413-31-6
Formula : C16H24N2O4S
M.W : 340.44
SMILES Code : O=C(C1=CSC(C2CCN(C(OC(C)(C)C)=O)CC2)=N1)OCC
MDL No. :MFCD06659069

Safety of [ 365413-31-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 365413-31-6 ]

* 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 [ 365413-31-6 ]

[ 365413-31-6 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 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).

 

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