| 98% |
With sodium carbonate In dichloromethane; water at 20℃; for 24h; Inert atmosphere; |
4.1.9. Synthesis of t-butyl 2-(2-bromoethyl)piperidine-1-carboxylate (11)
The 2-(piperidin-2-yl)ethanol 10 (1.55 mmol, 200 mg, 1 eq.) wasadded to 10 mL mixture (1:1) of CH2Cl2 and Na2CO3 aqueous solution(10 mL total) in a round bottomed flask. Di-t-butyl dicarbonate(1.70 mmol, 371 mg, 1.1 eq.) was added to the stirringsolution. The reaction mixture was stirred for 24 h at room temperature.Then, the reaction mixture was diluted with 10 mL ofwater and extracted once with 10 mL of CH2Cl2 and twice with20 mL of EtOAc. The combined organic layers were washed withbrine, dried over Na2SO4 and concentrated under reduced pressuregiving a yellow crude oil. The crude product was purified by chromatographyon silica gel, using hexane/EtOAc (3:2) as eluentaffording the N-Boc-protected amino alcohol. Yield: 98% (314 mg).1H NMR (400 MHz CDCl3) d 4.35-4.19 (m, 1H) 3.85-3.80 (m, 2H),3.48-3.42 (m, 1H), 3.27 (br s, 1H), 2.59-2.52 (m, 1H), 1.81 (t,J =12.0 Hz, 1H), 1.64-1.54 (m, 1H), 1.51-1.37 (m, 5H), 1.37 (s, 9H),1.29-1.25 (m, 1H) ppm. 13C NMR (100 MHz CDCl3) δ155.0, 80.2,58.7, 46.1, 39.4, 32.5, 28.5, 28.4, 25.6, 19.0 ppm. LRMS m/z (ES+) m/z: 230 [M+Na]+ To a solution of the above synthesised N-Boc-amino alcohol(0.43 mmol, 89 mg, 1eq.) in CH2Cl2 (10 mL) was added PPh3(0.47 mmol, 123 mg, 1.1 eq.) followed by a solution of CBr4(0.47 mmol, 156 mg, 1.1 eq.) in 20 mL of CH2Cl2 at r.t. and themixture was allowed to stir for 45 min. Then, the reaction mixturewas concentrated under reduced pressure giving a yellow crude oil.The obtained product was then immediately purified by chromatographyon silica gel, using hexane/EtOAc (9:1) as eluent. The pureproduct 11 was obtained as a yellow oil. Yield: 79% (99 mg). 1HNMR (400 MHz CDCl3) δ 4.35-4.31 (m, 1H) 4.02-3.84 (m, 1H),3.33-3.19 (m, 2H), 2.70-2.64 (t, J= 12.0 Hz, 1H), 2.33-2.23 (m, 1H),1.90-1.64 (m, 1H), 1.63-1.43 (m, 5H), 1.40 (s, 9H), 1.38-1.31 (m, 1H)ppm. 13C NMR (100 MHz CDCl3) δ 155.2, 79.6, 49.5, 38.7, 33.6, 30.3,28.7, 28.5, 25.5, 19.2 ppm. LRMS m/z (ES+) m/z: 293 [M+H]+ |
| 96% |
In dichloromethane at 22℃; for 4h; |
212.1
Step 1 : Preparation of 2-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert- butyl ester :; To a solution of 2-piperidin-2-yl-ethanol (8. 0 g, 61. 9 mmol) in CH2C12 (200 ML) was added BOC20 (13. 5 g, 61. 9 mmol) at 22°C, and the mixture was stirred for 4 h. The reaction mixture was then washed with 100 mL of a 0. 2 M aqueous HC1 solution, followed by 200 mL OF H20, and finally 200 ML of brine. The organic layer was dried over MGS04, filtered and concentrated to provide 13. 6 g (59. 2 mmol) of the title compound in 96% yield. LH WIMR 300 MHz (CDCIS) 8 4. 36-4. 50 (m, 1H), 3. 87-4. 03 (m, 1H), 3. 51-3. 66 (m, 1H), 3. 27-3. 45 (m, 1H), 2. 58-2. 74 (m, 1H), 1. 87-2. 01 (m, 1H), 1. 66-1. 80 (m, 1H), 1. 47 (s, 9H), 1. 28-1. 65 (m, 6H). |
| 95% |
In ethyl acetate |
|
| 95% |
With triethylamine In dichloromethane at 20℃; for 1h; |
77
Referential Example 77]; 2-(2-Hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester; [] 2-Piperidineethanol (1.292 g) and triethylamine (1.393 mL) were dissolved in methylene chloride (40 mL). To the resultant solution, di-tert-butyl dicarbonate (2.182 g) in methylene chloride (40 mL) was added at room temperature, followed by stirring for 1 hour. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was partitioned between water and ethyl acetate. The organic layer was sequentially washed with 5% aqueous citric acid, water, and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as an oily product (2.182 g, 95%) .1H-NMR(400MHz,CDCl3)δ: 1.33-1.81(7H,m), 1.49(9H,s), 1.88-2.00(1H,br m), 2.63-2.73(1H,m), 3.25-3.47(1H,br), 3.56-3.66(1H,br m), 3.75-4.08(2H,br), 4.35-4.54(1H,br). |
| 93% |
In diethyl ether for 24h; |
|
| 91% |
In dichloromethane |
|
| 87% |
With triethylamine In dichloromethane at 0 - 20℃; for 13h; |
|
| 85% |
With triethylamine In dichloromethane at 0 - 20℃; |
|
| 83% |
|
|
| 78% |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 25℃; |
B.2.1
piperidin-2-yl)butanoic acid (ACI-CC-08); Parallel synthesis acid building block ACI-CC-08 is identical to acid structural unit (S8) employed in single compound syntheses. Step-1: To a dichloromethane solution (5 ml/mmol) of piperidine-2-ethanol (1 eq.) was added DIPEA (1.5 eq.) and boc-anhydride (1.2 eq.) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 12 h. Reaction mixture was diluted with dichloromethane; organic layer was washed successively with water and brine and finally dried over sodium sulfate. Organic layer was evaporated under reduced pressure to get the crude product that was purified by column chromatography. Yield: 78% |
| 74% |
In ethyl acetate at 23℃; for 1.5h; |
|
| 74% |
In hexane; ethyl acetate |
53 N-t-Butoxycarbonyl-2(R,S)-(2-hydroxyethyl)piperidine
PREPARATION 53 N-t-Butoxycarbonyl-2(R,S)-(2-hydroxyethyl)piperidine A solution of di-t-butyl dicarbonate (10.91 g, 50 mmol) in ethyl acetate (15 ml) was added to a stirred, ice-cooled solution of 2(R,S)-(2-hydroxyethyl)piperidine (5.06 g, 50 mmol) in ethyl acetate (25 ml), then the cooling bath was removed. After a further 1.5 hours the reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel, using hexane:ether (1:1) as eluant, to provide the title compound (8.46 g, 74%) as a clear oil. Rf 0.25 (SS 14). |
| 70% |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 25℃; |
1
Preparation of 4- (1- (4-Methoxy-2, 6- dimethylphenylsulfonyl) piperidin-2-yl) butanoic acid S7.OH DCM / DIPEA(BOC)2O RT / 12 hrs 70% Step-1THF Procedure for step-1 : To a dichloromethane solution (5ml / mmol) of piperidine-2- ethanol (leqv) was added DIPEA (1.5 eqv) and boc-anhydride (1.2 eqv) at 0°C and the resulting reaction mixture was allowed to stir at 25°C for 12 hrs . Reaction mixture was diluted with dichloromethane, organic layer was washed successively with water and brine and finally dried over sodium sulfate. Organic layer was evaporated under reduced pressure to get the crude product which was purified by column chromatography. Yield : 70 % |
|
In ethyl acetate for 16h; Ambient temperature; |
|
|
With triethylamine In dichloromethane |
|
|
With triethylamine In tetrahydrofuran at 23℃; for 3h; |
|
|
With triethylamine In chloroform at 20℃; for 2h; |
50
2-Piperidine ethanol (starting compound A) (1.93 g, 15 mmol) and triethylamine (5 ml) were dissolved in chloroform (25 ml). Di-tert-butyl dicarbonate (3.3 g, 15 mmol) was dissolved in chloroform (5 ml), the solution was added to the mixed solution, and the mixture was stirred at room temperature for 2 hr. The solvent was removed by distillation, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate. The reaction solution was concentrated. The compound (1.5 g) thus obtained, triphenylphosphine (1.5 g, 5.7 mmol), and 1-{2-chloro-4-[7-hydroxy-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea (starting compound B) (1.12 g, 2.5 mmol) were dissolved in tetrahydrofuran (30 ml), and the solution was cooled to 0°C. 40% diethylazodicarboxylate (8 ml) was added thereto, and the temperature was returned to room temperature before the mixture was stirred for 3 days. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and was dried over sodium sulfate. The reaction solution was concentrated, and the concentrate was loaded on a chromatographic silica gel column and developed with chloroform/methanol (15/1) to give tert-butyl 2-[({4-[3-chloro-4-([(3,3-dimethylbutyl)amino]carbonyl}amino)phenoxy]-6-methoxy-7-quinolyl}oxy)methyl]-1-piperidine carboxylate. Next, 25% trifluoromethylacetic acid was added to tart-butyl 2-[({4-[3-chloro-4-([(3,3-dimethylbutyl)amino]carbonyl}amino)phenoxy]-6-methoxy-7-quinolyl}oxy)methyl]-1-piperidine carboxylate, and the mixture was stirred at room temperature for one hr. The solvent was removed by distillation, and the residue was loaded on a chromatographic silica gel column and developed with chloroform/methanol to give the title compound (yield 50%, 694 mg). Mass spectrometric value (ESI-MS, m/z): 556 (M++1) |
|
In tetrahydrofuran at 20℃; for 24h; |
20
Reference Example 20; To a solution of 2-piperidineethanol (10.0 g) in THF (100 ml) was added dropwise di-tert-butyl dicarbonate (16.9 g) at room temperature. After stirring the resulting mixture at room temperature for 24 hours, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate : hexane 1 : 3) to give tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate (17.92 g) as a colorless oily material. 1H-NMR (200MHz, CDCl3) δ 1.22-1.79 (15H, m), 1.85-2.04 (1H, m), 2.60-2.76 (1H, m), 3.23-3.47 (1H, m), 3.52-4.04 (3H, m), 4.35-4.52 (1H, m). IR (neat) 3443, 1689, 1667, 1418, 1366, 1275, 1165, 1142, 1053 cm-1 |
|
In dichloromethane at 0 - 20℃; for 16h; |
15.A
A. 2-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester. To an ice-cold solution of 2-piperidineethanol (3.0 g, 23 mmol) in CH2Cl2 (20 mL) was slowly added a solution of di-tert-butyl-dicarbonate (5.3 mL, 23 mmol) in CH2Cl2 (25 mL). After stirring at rt for 16 h, the solution was washed with 1 N NaOH (1*), H2O (2*) and brine (1*). Drying over Na2SO4 and concentration gave the crude product as a pale yellow oil that was used without further purification. 1H NMR (400 MHz, CD3OD): 4.32-4.29 (m, 1H), 3.93-3.88 (m, 1H), 3.49-3.46 (m, 2H), 2.83-2.75 (m, 1H), 1.98-1.92 (m, 1H), 1.65-1.56 (m, 5H), 1.42 (s, 9H), 1.35-1.30 (m, 1H). |
|
With triethylamine In dichloromethane at 0 - 20℃; for 16h; |
37.A
A. 2-(2-Hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (compound 42) To a stirred solution of piperidine-2-ethanol (5 g, 38.69 mmol) in DCM (80 m:) was added TEA (6.5 mL, 46.43 mmol), followed by BOC anhydride (9.8 mL, 42.56 mmol) at 0° C. and the reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and brine solution then dried over anhydrous Na2SO4, filtered and concentrated to get crude compound 42. Yield: 10 g (crude); 1H-NMR (400 MHz, DMSO-d6): δ 4.33 (t, J=5 Hz, 1H), 4.20-4.18 (m, 1H), 3.82-3.79 (m, 2H), 3.37-3.34 (m, 1H), 2.73 (t, J=13 Hz, 1H), 1.79-1.72 (m, 1H), 1.61-1.47 (m, 7H), 1.38 (s, 9H), 1.26-1.22 (m, 1H);LCMS [M+H]=230.2, RT=2.95 minutes, (Program P1, Column Y). |
|
With triethylamine In dichloromethane at 0 - 20℃; for 16h; |
37.A A. 2-(2-Hydroxyethyl)piperidine-l-carboxylic acid tert-buty\ ester (compound 42)
A. 2-(2-Hydroxyethyl)piperidine-l-carboxylic acid tert-buty ester (compound 42) To a stirred solution of piperidine-2-ethanol (5 g, 38.69 mmol) in DCM (80 m:) was added TEA (6.5 mL, 46.43 mmol), followed by BOC anhydride (9.8 mL, 42.56 mmol) at 0°C and the reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and brine solution then dried over anhydrous Na2S04, filtered and concentrated to get crude compound 42. Yield: 10 g (crude); 1H-NMR (400 MHz, DMSO- |
|
In methanol |
1
The hydrochloride of 2-(methylsulfanyl)-1O-[2-(piperi-din-2-yl)ethyl]-1OH-phenothiazine was prepared in accordance with Synthetic Scheme 1. This compound had a pale blue color, a molecular weight of 365.55 g/mol, the positive ion mass [M+H] has an mlz of 357.15 and a purity of 98%. |
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