| 95% |
In dichloromethane; at 0 - 25℃; for 4.25h;Inert atmosphere; |
To a solution of 2-(piperidin-4-yl)ethanol (2.42 g, 18.7 mmol) in dichloromethane (24 mL) was added under nitrogen at 0 C di-tert-butyl dicarbonate (4.09 g, 4.35 mL, 18.7 mmol). There was a strong gas evolution The solution was stirred at 0 C for 15 min and at room temperature for 4 h. The reaction mixture was washed with water (50 mL), potassium hydrogen sulfate (10% aqueous solution, 50 mL) and brine (50 mL). The aqueous layers were back-extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate to yield colorless oil (4.1 g, 95 %). MS: m/z = 230.5 (M+H)+ |
| 95% |
In methanol; at 20℃; for 2h; |
2-(N-tert-Butoxycarbonyl-4-piperidinyl)ethanol 2-(4-Piperidinyl)ethanol (1.0 g, 7.7 mmol) was dissolved in methanol (50 ml). To this solution, di-tert-butyl carbonate (2.0 g, 9.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was confirmed by TLC to be complete, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:acetone=9:1) to obtain N-tert-butoxycarbonyl-2-(4-piperidinyl)ethanol (1.68 g, yield: 95%). |
| 91.83% |
In dichloromethane; at 15 - 20℃; for 20h; |
2-(Piperidin-4-yl)ethan-1-ol (3.00 g, 23.22 mmol) was dissolved in 30 mL dichloromethane. Di-tert-butyl dicarbonate (5.22 g, 23.92 mmol) was slowly added portionwise at 15 to 20 C. After that, the reaction mixture was stirred for 20 h at room temperature. The reaction mixture was slowly poured into 50 mL water after the reaction was complete as monitored by TLC. Then, the mixture was extracted with dichloromethane (50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (Height: 250 mm, Diameter, 20 mm, 100-200 slica gel, petroleum/ethyl acetate=3:1, 1:1) to afford 2-(1-tert-butoxycarbonyl-4-piperidyl)ethanol (4.89 g, 91.83% yield) as a colorless liquid. |
| 91% |
In dichloromethane; at 0 - 20℃; |
To an ice-cold solution of 4-(2-hydroxyethyI) piperidine (4.25 g, 33 mmol) in CH2CI2 (5 ml_) was added a solution of di-te/t-butyl dicarbonate (7.2 g, 33 mmol) in CH2CI2 (30 ml.) over 1 h. The mixture was stirred at r.t. overnight. The solvent was removed. The residue was dissolved in Et2O (5OmL), washed with 1 M aq. NaH2PO4, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 6.9 g (91%) of the title compound.13C NMR (CDCI3) delta 154.9, 79.3, 60.1, 44.0, 39.3, 32.5, 32.1, 28.5 |
| 88% |
In DMF (N,N-dimethyl-formamide); at 20℃; |
To A solution of 2- (4-PIPERIDYL) ETHANOL (9. 63 G, 74. 5 MMOL) IN DMF (100 ML) AT 0 C, DI-TERT-BUTYL DICARBONATE (16. 26 g, 5 mol) was added slowly. The mixture was stirred overnight at room temperature. The solvent was concentrated and the residue was dissolved in A mixture of ETOAC and water. The phases were separated. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 15.09 g of the desired product : 88%). |
| 88% |
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 3h; |
To a stirred solution of 2-(piperidin-4-yl)ethanol (LXX, lg, 7.72 mmol) in tetrahydrofuran and water mixture (40 mL, 1 : 1) was added sodium bicarbonate (1.62 g, 19.32 mmol) and Boc anhydride (2.6 mL, 11.6 mmol) at room temperature and stirred for 3 h. The reaction mixture was diluted with ethyl acetate and the organic portion was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure to get the crude product which was purified by flash column chromatography using ethylacetate-hexane gradient to afford the titled product as gummy solid (LXXI, 1.6 g, 88 %). LC-MS m/z calcd for C12H23NO3, 229.2; found 130.2 [M-Boc]+. |
| 87% |
In tetrahydrofuran; at 20℃; |
A mixture of 4-piperidin ethanol (2. 0 g, 15 mmol, 1.0 eq. ) and t-butyl dicarbonate (3. 87 ML, 18.5 MMOL,). 2 eq. ) in anhydrous THF (80 mL) is kept under stirring at room temperature for one night. The solvent is then removed by evaporation under reduced pressure and the raw product obtained purified by flash chromatography using AcOEt : petroleum ether 60 : 40 as eluent mixture. 4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (37) is obtained as a colourless oil (3.1 G, 13.4 mmol, yield = 87%) HPLC (method A) : Rt = 7.92 min. H1 NMR (No., CDCL3-D3, 300 MHz) : 1.14 (DQ, 2H, Hf, J=6. 3,13. 5 Hz); 1.47 (S, 9H, C (CH3) 3) : 1. 55 (pt, 2H, Hc, J= 6.3 HZ) ; 1. 50-1.65 (m, 1H, Hc); 1.69 (d, 2H, Hd, J=13. 2 Hz); 1.89 (s, 1H, OH) ; 2.71 (LAD, 2H, Hb, J= 2. 1, 12.9 Hz) ; 3.73 (t, 2H, Hg, J= 6.3 Hz) ; 4.10 (m, 2H, Ha). |
| 85.2% |
With triethylamine; In dichloromethane; at 0 - 25℃; |
(0.01 mol) of 4-piperidineethanol, 2.4 ml (0.02 mol) of triethylamine and 30 ml of dichloromethane were charged into a 150 ml three-necked flask. After cooling to 0 C, 2.54 g (0.01 mol) of di-t-butyl dicarbonate was slowly added dropwise. After completion of the reaction, the reaction was carried out at 25 C overnight. The reaction was terminated by the disappearance of the starting material by TLC (PE: EA = 2: 1). Dichloromethane was distilled off under reduced pressure, 40 ml of ethyl acetate was added thereto, and the mixture was washed with saturated brine, neutralized and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2.27 g (85.2%) of a clear oil. |
|
|
Using the general method of Part A of Example 1, 4-piperidineethanol (10 g, 77.4 mmol) was reacted with di-tert-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tert-butyl <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>-1-carboxylate as a clear oil. |
|
With sodium hydroxide; In tetrahydrofuran; for 12h; |
Step A: <strong>[622-26-4]4-(2-Hydroxyethyl)piperidine</strong>-1-carboxylic acid tert-butyl ester To a solution OF 2- (PIPERIDIN-4-YL) ETHANOL (5.0 g, 39 MMOL) in THF (60 mL) was added 1 N NaOH (60 mL). DI-TERT-BUTYL DICARBONATE (9.5 g, 44 MMOL) was added and the mixture was stirred vigorously overnight. Ethyl acetate (100 mL) was added and the mixture was stirred vigorously. The phases were separated and the organic phase was washed with water and then dried (MGS04). The mixture was filtered and the solvent was evaporated to give 9.5 g of 4- (2-HYDROXYETHYL) PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ester. OH NMR (400 MHz, CDCL3) # 1. 05-1.18 (m, 2H), 1.45 (s, 9H), 1.53 (q, 2H), 1.57-1. 63 (m, 1H), 1.65-1. 72 (m, 2H), 1.74 (t, 1H), 2.63-2. 76 (m, 2H), 3.70 (q, 2H), 4.02-4. 12 (m, 2H). HPLC: Rt = 15.31 min. |
|
With sodium hydroxide; In 1,4-dioxane; water; |
Part A. 2-(1-BOC-piperidin-4-yl)ethanol: To a mixture of 4-piperidineethanol and di-t-butyl dicarbonate in Dioxane (15 ml) was added 1N NaOH (30 ml).The reaction was stirred at room temperature for 18 hr. Solvent was evaporated in vacuo and water (100 ml) was added, followed by extraction with ethyl acetate (3*). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo provided the product (3.62 g). LRMS(ESI) (M+Na)+252.2 (100); 1H-NMR(CDCl3) d: 4.05(brd, 2H); 3.74(m, 2H); 2.69(m, 2H); 1.65(m, 2H); 1.55(m, 3H); 1.45(s, 9H); 1.26(m, 1H); 0.60(m, 2H) ppm. |
|
In tert-butyl alcohol; |
a) 1-(tert-Butoxycarbonyl)-<strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong> A solution of 87 g of di-tert-butyl dicarbonate in 100 ml of tert-butanol is added dropwise at RT to a solution of 51 g of <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong> in 20 ml of tert-butanol and the mixture is stirred overnight at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2 and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 91.5 g of the expected product, which is used as such. |
|
With triethylamine; In acetonitrile; at 20℃; for 22h; |
150 2-(lH-Indazol-4-yl)-6-r4-('2-methoxy-ethyl)-piperidin-l-ylmethyll-4- morpholin-4-yl-thienor3,2-d]pyrimidine.Via 2-Chloro-6-[4-(2-methoxy-ethyl)-piperidin- 1 -ylmethyl]-4-morpholin- 4-yl-thieno[3,2-d]pyrimidine, prepared from 4-(2-methoxy-ethyl)-piperidine.Amine preparation: To a solution of 4-piperidine ethanol (540 mg) in MeCN (8mL) was added triethylamine (0.7OmL) followed by tert-butyl dicarbonate (1.00 g). The mixture was stirred at room temperature for 22 h and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated to give 4-(2-hydroxy-ethyl)-piperidine-l- carboxylic acid tert-butyl ester (897 mg). This was dissolved in THF (14mL) and sodium hydride added (172 mg; 60% dispersion in mineral oil) at 0 0C. After 30 min iodomethane (0.97mL) was added and the mixture stirred for 22 h. The mixture was diluted with ethyl acetate and washed with water, brine and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4- (2-methoxy-ethyl)-piperidine-l-carboxylic acid tert-butyl ester (724 mg). To a solution of 4-(2-methoxy-ethyl)-piperidine-l-carboxylic acid tert-butyl ester (284 mg) in DCM (5mL) was added 2M hydrogen chloride in diethyl ether (5.OmL) and the mixture stirred for 21 h. The solvent was evaporated to give the desired amine as a white solid.1H NMR (400MHz, CDCl3) 1.45-1.25 (m, 5H), 1.71 (m, 2H), 2.10 (m, 2H), 2.98 (m, 2H), 3.33 (s, 3H), 3.42 (t, J=6.5Hz, 2H), 3.83 (s, 2H), 3.92 (t, J=4.8Hz, 4H), 4.09 (t, J=4.8Hz, 4H), 7.36 (s, IH), 7.51 (t, J=7.7Hz, IH), 7.59 (d, J=8.3Hz, IH), 8.28 (d, J=6.7Hz, IH), 9.02 (s, IH), 10.05 (br s, IH); MS (ESl+) 493.27 (MH+). |
|
With sodium carbonate; triethylamine; In dichloromethane; |
PREPARATION 21 STR77 Di-t-butyldicarbonate (52.2 g) was added dropwise at 0 to a stirred solution of 4-(2-hydroxyethyl)-piperidine (30 g) and triethylamine (50 cm3) in dichloromethane (400 cm3). After 3 hours sodium carbonate solution was added, the mixture was separated and the dried (MgSO4) organic phase was evaporated in vacuo to give an oil which was distilled to afford 1-(t-butyloxycarbonyl)-<strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>, b.p. 245-250/0.3 mm (Kugelrohr) (33.5 g). |
|
With triethylamine; In hexane; dichloromethane; ethyl acetate; |
Step A 1-t-Butyloxycarbonyl-<strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong> A mixture of 4-(2-hydroxyethyl) piperidine (5.0 g, 40 mmol), di-t-butyl dicarbonate (10.9 g, 50 mmol), and triethylamine (7 mL, 50 mmol) in 100 mL of anhydrous CH2Cl2 was stirred overnight at room temperature. Volatiles were removed in vacuo and the resulting oil was purified on a silica gel column using 20% EtOAc in hexane as eluant to give 7.9 g of the desired product as a colorless oil. |
|
In dichloromethane; at 20℃; for 4h; |
Part C To a mixture of 2-piperidin-4-yl ethanol (10 g, 77 mmol) and dichloromethane (190 mL) at 0 0C was added di-(tert-butyl) dicarbonate (17.7 g, 81.3 mmol). The reaction was warmed to ambient temperature and stirred 4 hours. The reaction was washed with water, EPO <DP n="57"/>10% aqueous potassium hydrosulfate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to 20 g of tert-butyl <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>-l- carboxylate as a clear oil. This clear oil was dissolved in dichloromethane (90 mL) and added dropwise over 20 minutes at 0 C to a suspension of triphenylphosphine (20 g, 77 mmol), imidazole (5.3 g, 77 mmol), iodine (22 g, 85 mmol), and dichloromethane (300 mL). The reaction was stirred 5 hours at ambient temperature. The reaction was filtered and the filtrate was quenched with sodium bisulfite and diluted with water. The layers were separated. The aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a brown oil. This oil was purified by chromatography (SiO2, 20% hexanes/ethyl acetate) to obtain 22 g of tert-butyl 4-(2-iodoethyl)piperidine-l-carboxylate as a colorless oil. |
|
|
Part A Using the general method of Part A of Examples 6-26, 4-piperidineethanol (10 g, 77.4 mmol) was reacted with di-tert-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tert-butyl <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>-1-carboxylate as a clear oil. |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; |
4-piperidine ethanol (20-A) (5.0 g, 39.7 mmol) is dissolved in THF (120 mL). Triethylamine (5.6 mL, 40 mmol) is added, and the solution is cooled to 0 C. Boc2O (9.59 g, 44 mmol) is added, and the reaction is stirred overnight at room temperature. Solvent is removed in-vacuo; the crude residue dissolved in ethyl acetate (120 mL) is added; the solution is washed with 0.1 N HCl (3×100 mL) and brine (1×100 mL); dried with MgSO4; and filtered and solvent evaporated in vacuo to give compound 20-B as a clear oil. |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; |
1-B: 4-piperidine ethanol (1-A) (5 g, 39.7 mmol) is dissolved in THF (120 mL). Triethylamine (5.6 mL, 40 mmol) is added and the solution is cooled to 0 C. Boc2O (9.59 g, 44 mmol) is added, and the reaction is stirred overnight at room temperature. Solvent is removed in vacuo, and the crude residue is dissolved in ethyl acetate (120 mL). The solution is washed with 0.1 N HCl (3*100 mL) and brine (1*100 mL), dried with MgSO4, filtered and solvent evaporated in vacuo to give 1-B as a clear oil. |
|
|
Using the general method of Part A of Examples 7-21, 4-piperidine ethanol (10 g, 77.4 mmol) was reacted with di-tert-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tert-butyl <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>-1-carboxylate as a clear oil. |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; |
4-piperidine ethanol (4-A) (5 g, 39.7 mmol) is dissolved in THF (120 niL). Triethylamine (5.6 mL, 40 mmol) is added and the solution is cooled to 0 0C. BoC2O (9.59 g, 44 mmol) is added and the reaction is stirred overnight at room temperature. Solvent is removed in vacuo, the crude residue dissolved in ethyl acetate (120 mL) is added, and the solution is washed with 0.1 N HCl (3x100 mL) and brine (1 x 100 mL), dried with MgSO4, filtered and solvent evaporated in vacuo to give compound 4-B as a clear oil. |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; |
4-piperidine ethanol (8-A) (5g, 39.7 mmol) is dissolved in THF (120 mL). Triethylamine (5.6 mL, 40 mmol) is added and the solution is cooled to 00C. BoC2O (9.59g, 44 mmol) is added and the reaction is stirred overnight at room temperature. Solvent is removed in vacuo, and the crude residue is dissolved in ethyl acetate (120 mL). The solution is washed with 0.1 N HCl (3x100 mL) and brine (1 x 100 mL); dried with MgSO4; filtered and solvent evaporated in vacuo to give compound 8-B as a clear oil. |
|
With sodium hydroxide; In tetrahydrofuran; water; |
To a solution of 2-(piperidin-4-yl)ethanol (5.0 g, 39 mmol) in THF (60 mL) was added 1 N NaOH (60 mL). Di-tert-butyl dicarbonate (9.5 g, 44 mmol) was added and the mixture was stirred vigorously overnight. Ethyl acetate (100 mL) was added and the mixture was stirred vigorously. The phases were separated and the organic phase was washed with water and then dried (MgSO4). The mixture was filtered and the solvent was evaporated to give 9.5 g of <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) delta 1.05-1.18 (m, 2H), 1.45 (s, 9H), 1.53 (q, 2H), 1.57-1.63 (m, 1H), 1.65-1.72 (m, 2H), 1.74 (t, 1H), 2.63-2.76 (m, 2H), 3.70 (q, 2H), 4.02-4.12 (m, 2H). HPLC: Rt=15.31 min. |
|
In tetrahydrofuran; at 20℃; for 0.5h; |
Reference Example 21 8.60 ml of di-tert-butyl dicarbonate was added to a solution of 5.00 g of 2-<strong>[622-26-4]piperidin-4-ylethanol</strong> in 50 ml of tetrahydrofuran, followed by stirring at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 8.80 g of an oil. The oil was dissolved in 60 ml of dimethylsulfoxide, and the resulting solution was added 20.5 ml of triethylamine and 12.2 g of sulfur trioxide-pyridine complex, followed by stirring at ambient temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6.40 g of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate. _ |
|
In chloroform; at 20℃; for 3h; |
To a solution of 240 mg of piperidine-4-ethanol in 3 ml of chloroform, 446 mg of DIBOC (di-tert-butyldicarbonate) was added and stirred for 3 hours at room temperature. The reaction liquid was diluted with chloroform, and the chloroform layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue so obtained was purified on silica gel chromatography (chloroform / methanol = 30 / 1) to provide 456 mg of 1-(tert-butoxycarbonyl)piperidine-4-ethanol, which was then dissolved in 2 ml of chloroform. To the solution 205 mul of methanesulfonyl chloride and 1 ml of triethylamine, followed by 10 hours' stirring at room temperature. Saturated sodium hydrogencarbonate was added to the reaction liquid, which was then extracted with chloroform three times. This solution was dried over anhydrous sodium sulfate and concentrated. To the residue, 20 ml of dimetylformamide, 499 mg of 1-(piperidin-4-yl)-1,3-dihydro- 2H-benzimidazol-2-one, 477 mg of potassium carbonate and 38 mg of potassium iodide were added, followed by 10 hours' stirring at 80C. After cooling the reaction liquid, chloroform and saturated aqueous sodium hydrogencarbonate solution were added thereto, and the resulting mixture was shaken to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and removed of the solvent. The resulting residue purified on silica gel chromatography, to provide 275 mg of 1-[1-[2-[1-tert-butoxycarbonylpiperidin-4-yl]ethyl]piperidin-4-yl]-1,3-dihydro-2H- benzimidazol-2-one. To this compound, 10 ml of 10% hydrogen chloride / methanol was added, followed by 6 hours' stirring at room temperature. The reaction liquid was concentrated, to which methanol was added and distilled under reduced pressure to remove excess of hydrogen chloride and to provide the title compound. |
|
|
Di-tert-butyl dicarbonate (41.25g, 189 mmol) was added in one portion to a solution of 4- (2-hydroxyethyl) piperidine Compound 14a (24.42g, 189 mmol) in DMF (200 mL) at [0 C.] After 1 hour, the cooling bath was removed and the reaction mixture was allowed to stir for 20 h at RT. The reaction mixture was treated with Et2O (200 [ML)] and [H20] (500 mL). The organic layer was separated, washed with sat NH4C1 (200 mL) and brine (200 mL) and dried [MGS04).] After filtration and evaporation, Compound 14b was obtained as a transparent oil and used as such without further purification. A solution of DMSO (14g, 179 mmol) in DCM (80 mL) was added dropwise over a period of 1.5 h to a 2M solution of oxalyl chloride (62.8mL, 125.6 mmol) in dry DCM (200 mL) [AT-78 C,] such that the temperature did not [EXCEED-60 C.] A solution of Compound 14a in DCM (30 mL) was added dropwise at-78C over a 50 min period. After stirring 30 min [AT-78 C,] the cooling bath was removed and the temperature of the reaction mixture was allowed to rise to-30 C over a 30 min period. TEA (25.41 g, 251 mmol) was added and the reaction mixture was allowed to stir for lh at rt. The solid precipitate that had formed was removed by filtration and the filtrate was washed with 0.3N [HC1] (2 x [100] mL) and brine (200 mL). The organic phase was dried [(NA2SO4),] evaporated and the residue was purified via flash column chromatography (eluent gradient : hexane/EtOAc 100/0 to 70/30) to yield Compound 14c. A 1M solution [OF LIHMDS] (73 mL, 73 mmol) was added via syringe to a solution of trimethyl phosphonoacetate (13.29g, 73 mmol) in THF (200 mL) at-78C under argon. The reaction mixture was then stirred for 20 min at-78C and a solution of Compound 14c (8.3g, 36.5 mmol) in THF (50 mL) was added over a 30 min period. After stirring for 15 min [AT-78 C,] the cooling bath was removed and the reaction mixture was heated to reflux for 2. The reaction mixture was allowed to cool to room temperature and a saturated [NH4CL] solution (40 mL) was added. [ET20] (200 mL) was added, the organic layer was separated and washed with brine (140 mL) and dried [(NA2S04).] After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient : hexane/EtOAc: 100/0 to 85/15), yielding a mixture of [E-AND] Z- isomers of Compound 14d. Compound 14d, phenyl boronic acid [(1.] [55G,] 12.32 mmol), [RhCl (Cod) ] 2 [(0.] [LU ; 0.] 227 mmol) and Cod (0.557g, 5.15 mmol) were combined in [H20] [(15ML)] and heated to 100 [C] for 3 h under a nitrogen atmosphere. Phenylboronic acid [(L.] [OG,] 8. 2 mmol) was added again and the reaction mixture was heated to [100 C] for another 6 h. The reaction mixture was allowed to cool to rt, Et20 (100 mL) was added and the organic layer was separated. The aqueous layer was washed with [ET20] (2 x 100 mL) and the combined organic layers were dried [(NA2SO4),] filtered and evaporated. The residue was purified via flash column chromatography, yielding Compound 14e. TFA (6 mL) was added to a solution of Compound 14e (1.48 g, 4.09 mmol) in DCM (14 mL). The mixture was stirred at rt for 20 min, concentrated under vacuum and purified via RP-HPLC to yield Compound 14f as a trifluoroacetate salt. HOBt (0.333 g, 2.46 mmol), EDC (0.47 g, 2.46 mmol) and NMM (0.68 g, 5.28 mmol) were added to a solution of Compound 8a [(0. 64] g, 2.64 mmol) in DMF (30 mL) under argon. The mixture was stirred at rt for 1 h, then a solution of Compound 14f (0.66 g, 1.76 mmol) and NMM (0. [68] g, 5.28 mmol) in DMF (10 mL) was added. The resulting mixture was stirred overnight at rt. Water (2 mL) was added, followed by DCM (20 mL). The organic layer was separated, dried [(NA2SO4)] and concentrated. The resulting crude Compound 14g was used as such in the next reaction. To a solution of Compound 14g in dioxane (2 mL) and [H20] [(1] mL) was added [NAOH] (0.78g, 19. 5 mmol). The mixture was stirred at rt for 5 h and neutralized with 2N HCI. After the solvent was evaporated, the residue was purified by RP-HPLC to give Compound 13 after lyophilization |
|
With sodium hydrogencarbonate; |
Example 1; An exemplary method for preparation of the compound designated ATT-11T is demonstrated. However, modifications of this method (e.g., similar processes including additional or other steps known in the art such as alkylation, hydration, condensation, as well as other steps), which may result in similar compounds, are also included in embodiments of the invention.The synthetic scheme for ATT-11T according to one embodiment of the invention is illustrated below. As a first step, Boc protection is preformed on a piperidine derivative 1, followed by bromination to obtain compound 3, and condensation with diethyl-methyl malonate, which is produced by methylation of di-ethyl malonate 4. Said condensation results in compound 6A, which is then reduced, to obtain compound 6B. Subsequently, etherification is performed, in order to obtain compound 7. Compound 7 is then Boc-de-protected and condensed with SN-38 (compound 10), to result in compound 11, i.e., the desired product ATT-11T. This synthetic route is further illustrated in the following synthetic scheme: |
| 52 g |
In dichloromethane; at 20℃; |
[00482] To a stuffed solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in i,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g, 0.24 mmol) . The resultant mixture was stuffed at room temperature overnight. After confirming reaction completion by thin-layer chromatography, the reaction mixture was washed with water and concentrated to yield compound INT-1(52g). |
|
With triethylamine; In dichloromethane; at 25℃; for 1h; |
step 1: A mixture of 2-(piperidin-4-yl)ethanol (1.00 g, 7.74 mmol), di-tert-butyl dicarbonate (1.86 g, 8.51 mmol) and TEA (1.57 g, 15.48 mmol) in DCM (20 mL) was stirred at 25 C. for 1 h. The mixture was then diluted with DCM (20 mL) and washed with HCl (1 N, 2×20 mL) and brine (20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to afford the crude product tert-butyl <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>-1-carboxylate as a white solid (1.60 g, 90%), which was used in the next step without further purification. MS (ESI): 230.2 [M-55]+. |
| 52 g |
In dichloromethane; at 20℃; |
To a stirred solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in 1,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g, 0.24 mmol) . The resultant mixture was stirred at room temperature overnight. After confirming reaction completion by thin-layer chromatography, the reaction mixture was washed with water and concentrated to yield compound INT-1 (52g). |
|
With triethylamine; In chloroform; at 0 - 20℃; for 9.5h; |
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate: 2-(piperidin-4-yl)ethanol (1.3091 g, 10.15 mmol), Et3N (4.20 mL, 30.19 mmol) and CHCl3 (10 mL) were mixed and stirred at 0 C., followed by dropwise addition of Di-tert-butyl-dicarbonate (2.5770 g, 11.81 mmol) in CHCl3 (4 mL) in 30 min. The reaction solution was then allowed to warm up to room temperature and stirred for 9 h. The reaction solution was poured into saturated NaHCO3 solution (30 mL) and extracted by CHCl3 (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the Boc protected 2-(piperidin-4-yl)ethanol which was used for next step without further purification. |
| 52 g |
In dichloromethane; at 20℃; |
Preparation of tert-butyl <strong>[622-26-4]4-(2-hydroxyethyl)piperidine</strong>- 1 -carboxylate (TNT-1):[00491] To a stirred solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in i,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g, 0.24 mmol) . The resultant mixture was stirred at room temperature overnight. After confirming reaction completion by thin-layer chromatography, the reaction mixture was washed with water and concentrated to yield compound INT-1 (52g). |
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In tetrahydrofuran; at 20℃; for 16h; |
To a solution of 2- (piperidin-4-yl)ethan-l-ol (5.0 g, 38.7 mmol) in THF (100 mL) at rt, was added Boc20 (8.45 g, 38.7 mmol). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified using silica gel chromatography (40 to 80%> EtOAc in hexanes) to afford the desired product as an oil. |
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In acetonitrile; at 20℃; for 22h; |
Reference Example 39; <n="82"/>2-Chloro-6-[4-(2-methoxy-ethyl)-piperidin-l-ylmethyI]-4-morpholm-4-yI- thieno[3,2-d]pyrimidine; To a solution of 4-piperidine ethanol (1.95 g) in acetonitrile (25 mL) was added triethylamine (2.53 mL) followed by tert-butyl dicarbonate (3.63 g). The mixture was stirred at room temperature for 22 hours and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated to give 4-(2-hydroxy-ethyl)-piperidine-l- carboxylic acid tert-butyl ester (3.46 g). This was dissolved in tetrahydrofuran (50 mL) and sodium hydride added (664 mg; 60% dispersion in mineral oil) at 0 0C. After 30 minutes iodomethane (3.76 mL) was added and the mixture stirred for 22 hours. The mixture was diluted with ethyl acetate and washed with water, brine and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethyl)- piperidine- 1 -carboxylic acid tert-butyl ester (3.12 g). |
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With sodium hydrogencarbonate; In tetrahydrofuran; water; |
Synthesis of tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate To a solution of 2-(4-piperidyl)ethanol (1 eq.) in a mixture THF/water is added di-tert-butyl dicarbonate (1.3 eq.) and sodium bicarbonate (2 eq.). The mixture is stirred at room temperature overnight. After aqueous work-up, the residue is purified by flash chromatography to yield the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3), delta (ppm): 4.08 (br d, 2H), 3.71 (t, 2H), 2.70 (br t, 2H), 1.73-1.47 (m, 6H), 1.46 (s, 9H), 1.21-1.04 (m, 2H) |
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