| 50.2% |
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran; hexane at 0℃; for 2h; |
1.1
Under an argon atmosphere, a solution of indene (2.00 g, 18.0 mmol) in tetrahydrofuran (15 mL) was added with a solution of lithium hexamethyldisilazide in hexane (1.0 M, 36 mL) at 0° C. The resultant was stirred at the same temperature for 1 hour. Then, a solution of N-t-butyloxycarbonylbis(2-chloroethyl)amine (4.24 g, 18.0 mmol) in tetrahydrofuran (10 mL) was added thereto, and the mixture was further stirred at the same temperature for 2 hours. The reaction solution was concentrated in vacuo, and the resultant residue was purified using silica-gel chromatography (diethylether) and t-butyl spiro(indene-1,4'-piperidine)-1'-carboxylate (2.58 g, 50.2%) was obtained as a yellow amorphous solid.1H-NMR (400 MHz, CDCl3) δ; 1.33 (d, J=12.7 Hz, 2H), 1.51 (s, 9H), 1.96-2.07 (m, 2H), 3.07-3.17 (m, 2H), 4.10-4.21 (m, 2H), 6.78 (d, J=5.7 Hz, 1H), 6.84 (d, J=5.7 Hz, 1H), 7.20-7.34 (m, 4H). |
| 47% |
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran at 10℃; for 0.5h; Inert atmosphere;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran at 10 - 20℃; Inert atmosphere; |
tert-butylspiro[indene-1,4'-piperidine]-1'-carboxylate (7)
To a well stirred solution of 1H-indene (2g, 17.22 mmol) dissolvedin THF (40 ml), lithium bis(trimethylsilyl)amide (36.2 ml, 36.16 mmol) wasadded slowly under N2 atmosphere. The temperature was maintainedbelow 10C during the course of addition. After stirring for additional 30 minbelow 10C, a solution of 6 (3.75 g,15.50 mmol) dissolved in THF (40 mL) was added drop-wise to the above mixture.The temperature was again maintained below 10oC during the course ofaddition. The reaction mixture was warmed to room temperature and stirring wascontinued overnight. Completion of the reaction was monitored by LCMS. After completion of the reaction, the crudemixture was diluted with ethyl acetate (100mL) and the organic layer waswashed with water, dried over Na2SO4 and evaporated underreduced pressure to give a crude product. Purification of the crude product byflash chromatography through pre-loaded silica gel columns usingdichloromethane-hexane gradient to give 2.3g of tert-butyl spiro[indene-1,4'-piperidine]-1'-carboxylate (7), in 47% yield. ESMS calcd. 285.4;Found: 230.1 (M- tBu). |
| 36% |
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran at -50℃; for 1h;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran at -50℃; for 1h; |
1.a Step a:
Amixture of Compound 1H-indene (11.62g, 0.lOmol) and LiHMDS (220mL, lmol/L in THF) in THF(l2OmL) was stirred at -50°C for 1 hour. Tert-butyl bis(2-chloroethyl)carbamate (24.21g, 0.lOmol) was added to the reaction mixture and stirred at -50°C for lhr. The reaction was quenched with brine (300mL). The organic extracts were dried with anhydrous Na2504, and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford Compound tert-butyl spiro [indene- 1 ,4’-piperidine] -1 ‘-carboxylate as a yellow solid (10.36g, 36%). MS: 286 (M+H). |
| 36% |
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran at -50℃; for 1h;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran at -50℃; for 1h; |
1.a Step a:
Compound 1H- indene (11.62g, 0.10mol)A mixture of LiHMDS (220 mL, 1 mol/L in THF) The mixture in THF (120 mL) was stirred at -50 °C for 1 h.tert-Butyl bis(2-chloroethyl)carbamate (24.21 g, 0.10 mol) was added to the reaction mixture and stirred at -50 ° C for 1 h.Quenched with brine (300 mL). Dry the organic phase with anhydrous Na2SO4.Filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography.The compound spiro[-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (10.36 g, 36%) was obtained as a yellow solid. |
| 28.6% |
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran; hexane at 0℃; for 2h; |
5.1 Step 1 tert-Butyl spiro[indene- 1 ,4’-piperidine] -1 ‘-carboxylate
A solution of lithium hexamethyldisilazide (8.61 mmol) in hexane was added to a solution of indene (4.3 mmol) in THF (5 mL) at 0 °C under an argon atmosphere. The resultant was stirred at the same temperature for 1 h. Then a solution of N-tbutyloxycarbonylbis(2-chloroethyl)amine (4.3 mmol) in THF (2 mL) was added and the reaction mixture was further stirred at the same temperature for 2 h. After completion of reaction, the reaction mixture was poured in ice-cold water, extracted with diethyl ether, dried over Na2504, concentrated and purified by flash column chromatography (silica gel column, 0-40% DCM/petroleum ether). Yield: 28.6 % 1H NMR (CDC13, 300 MHz): 7.341 (m, 4H),6.877 (d, J= 5.7, 1H), 6.817 (d, J= 5.7, 1H), 4.189 (bs, 2H), 3.179 (t, J= 12.3, 2H), 2.064 (m, 2H), 1.527 (s, 9H), 1.371 (d, J= 13.2, 2H); MS: (mlz) 308.3 (M+Na). |
| 26.4% |
With Etamon; sodium hydride In N,N-dimethyl-formamide at -20 - 20℃; for 3h; |
68
The indene (2 g, 17.2 mmol) was dissolved in 150 mL of dimethylformamide, then tetraethylammonium bromide (636 mg,1.72 mmol, 0.1 eq.) was added, and sodium hydride (1.5 g) was added portionwise at -20 °C. 37.8 mmol, 2.2 eq.), then 68a(4.5 g, 18.92 mmol, 1.1 eq.) was added dropwise, and the mixture was reacted at room temperature for 3 h after completion of the dropwise addition.After the reaction is completed, the ice water is slowly added dropwise, and thepH is adjusted to neutralitywith hydrochloric acid, and thendiluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase is combined, dried andevaporated todryness.(1.3 g of, as a white solid), yield% 26.4. |
|
With lithium hexamethyldisilazane 1.) THF, 30 min, 2.) THF, a) 30 min, b) RT, 20 min; Yield given. Multistep reaction; |
|
|
With lithium hexamethyldisilazane 1.) THF, 0 deg C, 30 min, 2.) THF, 0 deg C, 2 h; Yield given. Multistep reaction; |
|
|
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; |
1.1a.2
1H-Indene (U6g, lO.Ommol), bis-(2-chloro-ettιyl)-carbamic acid tert-butyl ester (2.41g, lO.Ommol), and catalytic tetrabutylammonium iodide were combined in DMF and cooled to O0C. Sodium hydride (60% in mineral oil; 0.44Og, 11.Ommol) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with H2O and extracted with MTBE, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the desired product (2.17g). |
| 352.4 mg |
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran at 0 - 20℃; for 3h; |
40.1 Step 1
First, indene (3.42 g) was dissolved in tetrahydrofuran (8 mL), the mixture was cooled to 0 C, and lithium bis(trimethylsilyl) amide (1.0 M tetrahydrofuran solution) (60 mL) was added dropwise thereto. After 1 hour, a tetrahydrofuran solution (13 mL) of N-tert-butyloxycarbonylbis(2-chloroethyl)amine (6.44 g) was added dropwise to the reaction solution, and the mixture was stirred at 0 C for 30 minutes, and then was stirred at room temperature for 2 hours 30 minutes. Water was added to the reaction solution, followed by four times of extraction with chloroform. The organic layer was washed with saturated brine, then was dried with anhydrous sodium sulfate, and was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 0/100 to 15/85) to obtain 1’-tert-butyloxycarbonylspiro[indene-1,4’-piperidine] (3.74 g). 1H-NMR (270MHz, CDCl3) δ: 1.33 (br.d, J=12.9Hz, 2H), 1.51 (s, 9H), 1.90-2.11 (m, 2H), 3.12 (br.t , J=12.2Hz, 2H), 4.05-4.31 (m, 2H), 6.76-6.89 (m, 2H), 7.14-7.39 (m, 4 H). MS (ESI) m/z:230 [M- (tert-Bu) +H]+. |
|
Stage #1: 1-indene With 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran for 2h; Inert atmosphere; |
Preparation of Compound S13
Under the protection of argon, the Compound 13-1 was dissolved in THF, and HMDLi (2 eq) was added dropwise to the solution at 0°C, then reacted at 0°C for 1 hour. Then tert-butyl N, N-bis(2-chloroethyl)carbamate (1eq) was diluted with THF, and added dropwise to the reaction flask and the reaction was continued for 2 hours. The raw materials were completely reacted. The reaction was quenched with saturated ammonium chloride, and the reaction solution was concentrated, dissolved with ethyl acetate, and water was added for extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, dried by rotary evaporation, then Compound 13-2 was obtained by silica gel column chromatography (PE : EA = 40 : 1). |
|
Stage #1: 1-indene With 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran for 2h; Inert atmosphere; |
Preparation of Compound S13
Under the protection of argon, the Compound 13-1 was dissolved in THF, and HMDLi (2 eq) was added dropwise to the solution at 0°C, then reacted at 0°C for 1 hour. Then tert-butyl N, N-bis(2-chloroethyl)carbamate (1eq) was diluted with THF, and added dropwise to the reaction flask and the reaction was continued for 2 hours. The raw materials were completely reacted. The reaction was quenched with saturated ammonium chloride, and the reaction solution was concentrated, dissolved with ethyl acetate, and water was added for extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, dried by rotary evaporation, then Compound 13-2 was obtained by silica gel column chromatography (PE : EA = 40 : 1). |
|
Stage #1: 1-indene With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: N-(2,2'-bischloro)diethyl-N-(1,1-dimethylethoxy)carbonyl amine In tetrahydrofuran for 2h; |
Preparation of Compound S13
Under the protection of argon, the Compound 13-1 was dissolved in THF, and HMDLi (2 eq) was added dropwise to the solution at 0°C, then reacted at 0°C for 1 hour. Then tert-butyl N, N-bis(2-chloroethyl)carbamate (1eq) was diluted with THF, and added dropwise to the reaction flask and the reaction was continued for 2 hours. The raw materials were completely reacted. The reaction was quenched with saturated ammonium chloride, and the reaction solution was concentrated, dissolved with ethyl acetate, and water was added for extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, dried by rotary evaporation, then Compound 13-2 was obtained by silica gel column chromatography (PE : EA = 40 : 1). |
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