* 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.
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - -55℃; for 0.5 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;
Example 3; 4-Formyl-piperidine-1-carboxylic acid benzyl ester (3); Oxalyl chloride (59.1 ml_, 674 mmol) was dissolved in dichloromethane (500 ml_) and cooled to -78°C. Dimethylsulfoxide (68.3 ml_, 963 mmol) was added and the mixture was stirred for 15 min. 4-Hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (2) (120 g, 481 mmol) dissolved in dichloromethane (500 ml_) was added. The mixture was allowed to warm to -55°C for 15 min. The mixture was again cooled to -78°C and triethylamine (205 ml_, 1443 mmol) in dichloromethane (250 ml_) was added. The suspension was allowed to warm to room temperature and quenched with glacial acetic acid (100 ml_). The solution was washed with water and the aqueous phase extracted with dichloromethane (2 x 200 ml_). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to give 4- formyl-piperidine-1-carboxylic acid benzyl ester (119 g, 100percent).
93%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.5 h;
To oxalyl chloride (10.3 mL, 0.120 mol) in 150 mL of DCM and at -78 °C, a solution of DMSO (17.1 mL, 0.241 mol) in DCM (25 mL) was added dropwisely. After 30 min, benzyl 4- (hydroxymethyl)-piperidine-l-carboxylate (20 g, 0.080 mol) in DCM (25 mL) was added dropwisely. After 30 min, Et3N (44.7 mL, 0.321 mol) was added. The resulting solution was stirred for 30 min at -78 °C. The reaction was diluted with water, extracted with DCM (3 x). Combined organic layers were washed with water (3 x 500 mL), dried over Na2S04, filtered and concentrated to give Intermediate 6C (18.5 g, 93.0percent). MS (ESI) m/z 247 (M+H)+.
75%
With pyridinium chlorochromate In dichloromethane at 20℃; for 3 h;
Example 25;. N-Benzyloxycarbonyl-4- (formyl)-piperidine (E-13).; A stirred suspension of N-(benzyloxycarbonyl)-4-hydroxymethyl)-piperidine (E-12,2 g, 8 mmol) and CeliteTM (4 g) in dry DCM (120 mL) at room temperature was treated with pyridinium chlorochromate (3.5 g, 16.0 mmol), stirred for 3 hours, and filtered on Celte. The filtrate was evaporated to a dark residue which was purified by column chromatography using a gradient of 25 to 50 percent EtOAc in hexane as eluant to give 1.5 g (75 percent) of aldehyde E-13 as a clear oil which was immediately used in the next step : 1H NMR (CDC13) 8 1.43 (dd, 2H, J=10), 1.78 (m, 2H), 2.31 (m, 1H), 2.91 (t, 2H, J=10. 6), 3.96 (m, 2H), 5.05 (s, 2H), 7.24 (m, 5H), 9.52 (s, 1H).
6.2 g
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 12 h;
Reaction Step 2 Synthesis of benzyl 4-formylpiperidine-1-carboxylate To a stirred solution of benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (10.0 g, 40.2 mmol, 1.0 eq) in dichloromethane (150 ml), Dess-Martin periodinane (20.4 g, 48.2 mmol, 1.2 eq) was added at 0° C. and stirring was continued at room temperature for 12 h. After completion of the reaction (monitored by TLC, 30percent ethyl acetate-hexane, Rf=0.45), the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, followed by brine. The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh), eluting with a 30-40percent gradient of ethyl acetate in hexanes to obtain benzyl 4-formylpiperidine-1-carboxylate (6.2 g, 62.5percent). LCMS Purity: 78.54percent (ES+): m/z 248.27 (M+H+); tr=3.01 min.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2663 - 2666
[2] Patent: WO2007/93603, 2007, A1, . Location in patent: Page/Page column 15
[3] Patent: WO2014/22349, 2014, A1, . Location in patent: Paragraph 00158
[4] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
[5] Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9830 - 9836
[6] Patent: WO2005/80394, 2005, A1, . Location in patent: Page/Page column 131-132
[7] European Journal of Organic Chemistry, 2008, # 25, p. 4277 - 4295
[8] Tetrahedron Letters, 2007, vol. 48, # 2, p. 199 - 202
[9] Patent: WO2014/70976, 2014, A1, . Location in patent: Page/Page column 20; 21
[10] Patent: US2015/252022, 2015, A1, . Location in patent: Paragraph 0375
[11] Patent: US2016/24056, 2016, A1, . Location in patent: Paragraph 0244
4
[ 138163-07-2 ]
[ 138163-08-3 ]
Yield
Reaction Conditions
Operation in experiment
49%
With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere
Stage (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78° C. DIBAL-H (60.9 ml) subsequently was added dropwise at -78° C., and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3*75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20percent ethyl acetate/hexane). Yield: 4.3 g (49percent)
49%
With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere
Stage (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of 1-benzyl 4-methylpiperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78° C. DIBAL-H (60.9 ml) was then added dropwise at -78° C., and the mixture was stirred for one hour at that temperature (TLC monitoring). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H were added and stirring was carried out for a further 30 minutes (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by saturated sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3*75 ml), dried (Na2SO4) and concentrated in vacuo. The crude product so obtained was purified by column chromatography (silica gel, 20percent ethyl acetate/hexane). Yield: 4.3 g (49percent)
49%
With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere
A solution of 1-benzyl 4-methylpiperidine-1,4-dicarboxylate (10 g) in toluene (100 ml), under nitrogen, was cooled to -78° C. Then DIBAL-H (60.9 ml) was added dropwise at -78° C., and the mixture was stirred for 1 h at that temperature (TLC monitoring). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and stirring was carried out for a further 30 min (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78° C. The mixture was filtered over celite, and the solvent was removed under vacuum. The residue was extracted with ethyl acetate (3.x.75 ml), dried (Na2SO4) and concentrated under vacuum. The crude product so obtained was purified by column chromatography (silica gel, 20percent ethyl acetate/hexane). Yield: 4.3 g (49percent)
49%
With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere
A solution of 1-benzyl-4-methyl piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78° C. DIBAL-H (60.9 ml) was then added dropwise at -78° C. and the mixture was stirred for 1 h at that temperature (TLC monitoring). Because the conversion was incomplete, a further 0.2 eq. of DIBAL-H was added and stirring was carried out for a further 30 min. (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3.x.75 ml), dried (Na2SO4) and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 20percent ethyl acetate/hexane). Yield: 4.3 g (49percent)
49%
Stage #1: With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere Stage #2: With methanol; water; sodium chloride In toluene at -78℃; Inert atmosphere
Step (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78° C. DIBAL-H (60.9 ml) was then added dropwise at -78° C. and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3*75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20percent ethyl acetate/hexane). Yield: 4.3 g (49percent)
49%
Stage #1: With diisobutylaluminium hydride In toluene at -78℃; for 1.5 h; Inert atmosphere Stage #2: With methanol In toluene at -78℃;
Stage (iii): Benzyl 4-formylpiperidine-1-carboxylate; A solution of 1 -benzyl 4-methyl piperidine-1 ,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78 0C. DIBAL-H (60.9 ml) was then added dropwise at -78 0C and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 0C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3 x 75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20percent ethyl acetate / hexane). Yield: 4.3 g (49 percent)
With diisobutylaluminium hydride In dichloromethane at -78℃; for 0.5 h;
Add diisobutyl aluminum hydride (1 M in toluene, 30 [ML,] 30 mmol) over 5 minutes to a solution of 1- (benzyloxycarbonyl)-4- (ethoxycarbonyl) piperidine (7 g, 24 mmol) in anhydrous dichloromethane (150 mL) at-78°C under a nitrogen atmosphere. Stir the reaction mixture at this temperature for 30 minutes and then add 10percent aqueous sodium tartarate (100 [ML)] followed by dichloromethane. Stir the reaction mixture at room temperature overnight. Separate the phases and extract the aqueous phase with dichloromethane. Wash the combined organic phases sequentially with 10percent aqueous sodium tartarate, water, and saturated aqueous sodium chloride. Dry over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 3: 1 hexanes: ethyl acetate to provide 3.15 g [(53percent)] of the title compound.
Reference：
[1] Patent: WO2004/14900, 2004, A1, . Location in patent: Page 48-49
[2] Tetrahedron Letters, 2007, vol. 48, # 2, p. 199 - 202
[3] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2663 - 2666
6
[ 148148-48-5 ]
[ 138163-08-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With lithium aluminium tetrahydride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0℃; for 1 h;
To a solution of isonipecotic acid (1.29g, 10 mmol) in a mixture of CH3CN/H2O (2:3, 0.1M), NaHCO3 (1.5eq) and Na2CO3 (1.5 eq) were added (pH~ 10-11). Once the mixture was cooled to 0 °C, Cbz-Cl (1.42 mL,1.7 g, 10 mmol). was slowly added The resulting solution was stirred for 2 h at rt. After completion ofthe reaction, the mixture was acidified by dropwise addition of a 1 N HCl aqueous solution. Then, CH3CNwas removed by evaporation, followed by the extraction with EtOAc (3x). Finally the combined organicphase was washed with brine, dried over Na2SO4, and concentrated to afford the desired product inquantitative yield, which was used in the next reaction without further purification.
With triethylamine In dichloromethane; dimethyl sulfoxide
26c. Phenylmethyl 4-formylpiperidinecarboxylate To a stirred solution of oxalyl chloride (2M solution in dichloromethane, 10.9 mL, 21.9 mmol) was added DMSO (3.1 mL, 3.4 g, 43.8 mmol) in dichloromethane (6 mL) over a period of 15 minutes. The product of Example 26b (4.4 g, 17.5 mmol) in dichloromethane (7 mL) was then added at -78° C. over a period of 15 minutes. The resultant solution was stirred at -78° C. for 1 hour and then triethylamine (12.2 mL, 8.86 g, 87.5 mmol) was added, dropwise, over a period of 15minutes. The mixture was further stirred at -78° C. for 30 min and then at 0° C. for 15 min. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic phase was washed with 1percent HCl, water, dried over sodium sulfate, filtered and evaporated to give the title compound (4.4 g, 100percent) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ9.65 (s, 1H), 7.28-7.38 (m, 5H), 5.12 (s, 2H), 4.04 (br d, J=13.1 Hz, 2H), 2.97-3.06 (m, 2H), 2.38-2.45 (m, 1H), 1.88-1.92 (m,2H), 1.52-1.64 (m, 2H). 13C NMR (75 MHz, CDCl3) δ202.7, 155.2, 136.7, 128.5, 128.6, 127.9, 67.2, 47.8, 43.0, 25.1. LRMS (APIMS) m/z 248 (MH+).
Reference：
[1] Patent: US2003/203915, 2003, A1,
9
[ 10314-98-4 ]
[ 138163-08-3 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 32, p. 10983 - 10992
[2] European Journal of Medicinal Chemistry, 1991, vol. 26, # 6, p. 625 - 631
[3] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 7
[4] Synlett, 2017, vol. 28, # 3, p. 376 - 380
[5] Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9830 - 9836
10
[ 87413-09-0 ]
[ 122860-33-7 ]
[ 138163-08-3 ]
Reference：
[1] Patent: US6265434, 2001, B1,
11
[ 498-94-2 ]
[ 138163-08-3 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 32, p. 10983 - 10992
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
[3] Synlett, 2017, vol. 28, # 3, p. 376 - 380
12
[ 1126-09-6 ]
[ 138163-08-3 ]
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 2, p. 199 - 202
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2663 - 2666
13
[ 501-53-1 ]
[ 138163-08-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2663 - 2666
[2] Synlett, 2017, vol. 28, # 3, p. 376 - 380
14
[ 6457-49-4 ]
[ 138163-08-3 ]
Reference：
[1] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
With diisobutylaluminium hydride; In toluene; at -78℃;Inert atmosphere;
Stage (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of <strong>[138163-07-2]1-benzyl 4-methyl piperidine-1,4-dicarboxylate</strong> (10 g) in toluene (100 ml) under nitrogen was cooled to -78 C. DIBAL-H (60.9 ml) subsequently was added dropwise at -78 C., and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3*75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
49%
With diisobutylaluminium hydride; In toluene; at -78℃;Inert atmosphere;
Stage (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of <strong>[138163-07-2]1-benzyl 4-methylpiperidine-1,4-dicarboxylate</strong> (10 g) in toluene (100 ml) under nitrogen was cooled to -78 C. DIBAL-H (60.9 ml) was then added dropwise at -78 C., and the mixture was stirred for one hour at that temperature (TLC monitoring). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H were added and stirring was carried out for a further 30 minutes (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by saturated sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3*75 ml), dried (Na2SO4) and concentrated in vacuo. The crude product so obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
49%
With diisobutylaluminium hydride; In toluene; at -78℃;Inert atmosphere;
A solution of <strong>[138163-07-2]1-benzyl 4-methylpiperidine-1,4-dicarboxylate</strong> (10 g) in toluene (100 ml), under nitrogen, was cooled to -78 C. Then DIBAL-H (60.9 ml) was added dropwise at -78 C., and the mixture was stirred for 1 h at that temperature (TLC monitoring). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and stirring was carried out for a further 30 min (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 C. The mixture was filtered over celite, and the solvent was removed under vacuum. The residue was extracted with ethyl acetate (3×75 ml), dried (Na2SO4) and concentrated under vacuum. The crude product so obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
49%
With diisobutylaluminium hydride; In toluene; at -78℃;Inert atmosphere;
A solution of 1-benzyl-4-methyl piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78 C. DIBAL-H (60.9 ml) was then added dropwise at -78 C. and the mixture was stirred for 1 h at that temperature (TLC monitoring). Because the conversion was incomplete, a further 0.2 eq. of DIBAL-H was added and stirring was carried out for a further 30 min. (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3×75 ml), dried (Na2SO4) and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
49%
Step (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of <strong>[138163-07-2]1-benzyl 4-methyl piperidine-1,4-dicarboxylate</strong> (10 g) in toluene (100 ml) under nitrogen was cooled to -78 C. DIBAL-H (60.9 ml) was then added dropwise at -78 C. and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3*75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
49%
Stage (iii): Benzyl 4-formylpiperidine-1-carboxylate; A solution of 1 -benzyl 4-methyl piperidine-1 ,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78 0C. DIBAL-H (60.9 ml) was then added dropwise at -78 0C and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at -78 0C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3 x 75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20% ethyl acetate / hexane). Yield: 4.3 g (49 %)
With hydrogenchloride; diisobutylaluminium hydride; In hexane; toluene;
To a solution of <strong>[138163-07-2]1-benzyloxycarbonyl-piperidine-4-carboxylic acid methyl ester</strong> (2.0 g, 7.2 mmol) in anhydrous toluene (20 mL) at -78 C. was added DIBAL-H (15.2 mL of a 1 M solution in hexane, 15.2 mmol, 2 eq.) in a drop-wise fashion. The mixture was stirred at -60 C. for 2 h then quenched by addition of 1 N HCl. The resulting mixture was extracted with EtOAc (3*50 mL) and the combined organic extracts were washed with saturated brine (50 mL) then dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude residue was purified by flash column chromatography by eluding 9:1 toluene/EtOAc to give 1-benzyloxycarbonyl-piperidine-4-carboxaldehyde as a colorless gum (0.49 g, 2.09 mmol, 28%). 1H NMR (300 MHz, CDCl3): delta9.75 (s, 1H), 7.46 (m, 5H), 5.24 (s, 2H), 4.15 (m, 2H), 3.12 (t, 2H), 2.54 (m, 1H), 2.02 (m, 2H), 1.68 (m, 2H).
Example 3; 4-Formyl-piperidine-1-carboxylic acid benzyl ester (3); Oxalyl chloride (59.1 ml_, 674 mmol) was dissolved in dichloromethane (500 ml_) and cooled to -78C. Dimethylsulfoxide (68.3 ml_, 963 mmol) was added and the mixture was stirred for 15 min. 4-Hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (2) (120 g, 481 mmol) dissolved in dichloromethane (500 ml_) was added. The mixture was allowed to warm to -55C for 15 min. The mixture was again cooled to -78C and triethylamine (205 ml_, 1443 mmol) in dichloromethane (250 ml_) was added. The suspension was allowed to warm to room temperature and quenched with glacial acetic acid (100 ml_). The solution was washed with water and the aqueous phase extracted with dichloromethane (2 x 200 ml_). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to give 4- formyl-piperidine-1-carboxylic acid benzyl ester (119 g, 100%).
93.0%
To oxalyl chloride (10.3 mL, 0.120 mol) in 150 mL of DCM and at -78 C, a solution of DMSO (17.1 mL, 0.241 mol) in DCM (25 mL) was added dropwisely. After 30 min, benzyl 4- (hydroxymethyl)-piperidine-l-carboxylate (20 g, 0.080 mol) in DCM (25 mL) was added dropwisely. After 30 min, Et3N (44.7 mL, 0.321 mol) was added. The resulting solution was stirred for 30 min at -78 C. The reaction was diluted with water, extracted with DCM (3 x). Combined organic layers were washed with water (3 x 500 mL), dried over Na2S04, filtered and concentrated to give Intermediate 6C (18.5 g, 93.0%). MS (ESI) m/z 247 (M+H)+.
75%
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 3h;
Example 25;. N-Benzyloxycarbonyl-4- (formyl)-piperidine (E-13).; A stirred suspension of N-(benzyloxycarbonyl)-4-hydroxymethyl)-piperidine (E-12,2 g, 8 mmol) and CeliteTM (4 g) in dry DCM (120 mL) at room temperature was treated with pyridinium chlorochromate (3.5 g, 16.0 mmol), stirred for 3 hours, and filtered on Celte. The filtrate was evaporated to a dark residue which was purified by column chromatography using a gradient of 25 to 50 % EtOAc in hexane as eluant to give 1.5 g (75 %) of aldehyde E-13 as a clear oil which was immediately used in the next step : 1H NMR (CDC13) 8 1.43 (dd, 2H, J=10), 1.78 (m, 2H), 2.31 (m, 1H), 2.91 (t, 2H, J=10. 6), 3.96 (m, 2H), 5.05 (s, 2H), 7.24 (m, 5H), 9.52 (s, 1H).
Step 2:Oxalyl chloride (9.4 g; 74 mmol) is dissolved in DCM (55 ml) and cooled to -78C. DMSO (7.5ml; 106 mmol) is added dropwise and the mixture is stirred for 15 min at -78C. In a separateflask, 4a3 (13 g; 53 mmol) is dissolved in DCM (55 ml) and added dropwise to the first flask viacannula. Once the addition is finished, the mixture is stirred at -55C for 15 min. The reactionmixture is cooled to -78C and a solution of triethylamine (22 ml; 158 mmol) in DCM (28 ml) isadded dropwise to the reation mixture via cannula. The mixture is stirred for 1 hat -78C then15 min at ooc and 30 min at RT. The reaction is neutralized with 11 ml of AcOH and dilutedwith 100 ml of DCM and 100 ml of water. The layers are separated and the aqueous layer isextracted with DCM (2 x 100 ml). The combined organic layers are washed with brine, driedover MgS04, filtered and concentrated. Purification by Combiflash (120 g column, 0-50%EtOAc/Hex) gives 4a4.
With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 12h;
Reaction step 2: Synthesis of benzyl 4-formylpiperidine-1-carboxylate To a stirred solution of <strong>[122860-33-7]benzyl 4-(hydroxymethyl)piperidine-1-carboxylate</strong> (10.0 g, 40.2 mmol, 1.0 eq) in dichloromethane (150 ml), Dess-Martin periodinane (20.4 g, 48.2 mmol, 1.2 eq) was added at at 0 C. and stirring was continued at room temperature for 12 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane, Rf=0.45), the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, followed by brine. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh), eluting with a 30-40% gradient of ethyl acetate in hexanes to obtain benzyl 4-formylpiperidine-1-carboxylate (6.2 g, 62.5%). LCMS Purity: 78.54% (ES+): m/z 248.27 (M+H+); tr=3.01 min.
6.2 g
With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 12h;
Reaction Step 2 Synthesis of benzyl 4-formylpiperidine-1-carboxylate To a stirred solution of <strong>[122860-33-7]benzyl 4-(hydroxymethyl)piperidine-1-carboxylate</strong> (10.0 g, 40.2 mmol, 1.0 eq) in dichloromethane (150 ml), Dess-Martin periodinane (20.4 g, 48.2 mmol, 1.2 eq) was added at 0 C. and stirring was continued at room temperature for 12 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane, Rf=0.45), the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, followed by brine. The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh), eluting with a 30-40% gradient of ethyl acetate in hexanes to obtain benzyl 4-formylpiperidine-1-carboxylate (6.2 g, 62.5%). LCMS Purity: 78.54% (ES+): m/z 248.27 (M+H+); tr=3.01 min.
With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 0.5h;
Add diisobutyl aluminum hydride (1 M in toluene, 30 [ML,] 30 mmol) over 5 minutes to a solution of 1- (benzyloxycarbonyl)-4- (ethoxycarbonyl) piperidine (7 g, 24 mmol) in anhydrous dichloromethane (150 mL) at-78C under a nitrogen atmosphere. Stir the reaction mixture at this temperature for 30 minutes and then add 10% aqueous sodium tartarate (100 [ML)] followed by dichloromethane. Stir the reaction mixture at room temperature overnight. Separate the phases and extract the aqueous phase with dichloromethane. Wash the combined organic phases sequentially with 10% aqueous sodium tartarate, water, and saturated aqueous sodium chloride. Dry over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 3: 1 hexanes: ethyl acetate to provide 3.15 g [(53%)] of the title compound.
Preparation 1; Benzyl spiro[in line-3,4'-piperidine]- 1 '-carboxylateA solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49/1 solution of toluene/acetonitrile (50 mL) is heated at 35 C. 4-Formyl- piperidine- l -carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49/1 solution of toluene/acetonitrile (10 mL) and added dropwise to the mixture(WO2005046682). The mixture is stirred at 35 C overnight. The resulting solution is cooled to 0 C, and methanol (5 mL) is added. NaBFLt (0.619 g, 16.38 mmol) is added slowly to the solution and the mixture is stirred for 45 min. The mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a pale yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by flash chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2n crop) with a total yield (2.4 g, 84%). ESI/MS m/z 323 (M+H)+.
76%
Preparation 1Benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate A solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49:1 solution of toluene:acetonitrile (50 mL) is heated at 35 C. 4-Formyl-piperidine-1-carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49:1 solution of toluene:acetonitrile (10 mL) and added dropwise to the mixture (WO2005046682). The mixture is stirred at 35 C. overnight. The resulting solution is cooled to 0 C., and methanol (5 mL) is added. NaBH4 (0.619 g, 16.38 mmol) is added portion wise to the solution and the mixture is stirred for 45 min. The reaction mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by silica gel chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2nd crop) with a total yield of (2.4 g, 76%). ESI/MS m/z 323 (M+H)+.
75%
A solution of phenylhydrazine (2.38 g, 22 mmol) and trifluoroacetic acid (5 mL) in Toluene/acetonitrile (49/1) (100 mL) was heated at 35C. N-benzyloxycarbonyl 4- formylpiperidine (4.94 g, 20 mmol) was dissolved in 20 mL of toluene/acetonitrile (49/1) and added dropwise to the mixture, which was stirred at 35C overnight. The resulting solution was then cooled to 0C, and methanol (10 mL) was added. NaBH4 (1.13 g, 30 mmol) was added very slowly to the solution which was stirred for a further 45 min. The reaction mixture was washed with aqueous NH40H 6% (40 mL). Methanol (2 mL) was added and the organic layer was washed with brine (40 mL) then dried over Na2S04 and evaporated. The crude material was purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (1/1) to give 4.85 g (75%) of A as a pale yellow solid.
75%
Synthesis of advanced intermediate E Synthesis of A:; A solution of phenylhydrazine (2.38 g, 22 mmol) and trifluoroacetic acid (5 mL) in Toluene/acetonitrile (49/1) (100 mL) was heated at 35C. N-benzyloxycarbonyl 4- formylpiperidine (4.94 g, 20 mmol) was dissolved in 20 mL of toluene/acetonitrile (49/1) and added dropwise to the mixture, which was stirred at 35C overnight. The resulting solution was then cooled to 0C, and methanol (10 mL) was added. NaBH4 (1.13 g, 30 mmol) was added very slowly to the solution which was stirred for a further 45 min. The reaction mixture was washed with aqueous NH40H 6% (40 mL). Methanol (2 mL) was added and the organic layer was washed with brine (40 mL) then dried over Na2S04 and evaporated. The crude material was purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (1/1) to give 4.85 g (75%) of A as a pale yellow solid.
74%
A solution of phenyl hydrazine (5.96 mmol) and trifluoroacetic acid (1.5 mL) in a solvent system of toluene: acetonitrile (49:1) (25 mL) was stirred at 35 C. To this reaction mixture, a solution of benzyl 4-formylpiperidine- 1 -carboxylate (5.46 mmol) in a solvent system of toluene: acetonitrile (49:1) (5 mL) was added drop wise. The reaction mixture was stirred overnight at 35 C. The reaction mixture was then cooled in ice bath and MeOH (2.5 mL) was added, followed by the addition of sodium borohydride (8.16 mmol) in portions. The reaction mixture was then stirred for 45 minutes. After the completion of reaction, the reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous ammonia, brine, dried over Na2504 and concentrated. The residue was purified by flash column chromatography (silica gel column, 10%-20% ethyl acetate/ petroleum ether). Yield: 74%; 1H NMR (CDC13, 300 MHz): 7.391 (m, 5H), 7.100 (m, 2H), 6.789 (t, J= 7.5, 1H), 6.686 (d, J = 7.5, 1H), 5.182 (s, 2H), 4.153 (bs, 2H), 3.501 (s, 2H), 3.067 (t, J = 14.1, 2H), 1.895 (m, 4H); MS (mlz): 323.1 (M+H) and 345.1 (M+Na).
49%
To a solution of phenylmethyl 4-formyl-1-piperidinecarboxylate (81 mmol) in 200 mL of DCM cooled in an ice bath was added phenylhydrazine (81 mmol). After stirring for approximately 15 min, TFA (202.5 mmol) was added over a period of 5 min. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was then cooled in and ice bath and NaBH4 (121.5 mmol) was added in small portions over 15 min. The resulting solution was allowed to warm to room temperature and stir for one hour, whereupon a 10% solution of NH4OH (~100 mL) was added. After stirring for 30 min, the mixture was separated, and the aqueous layer extracted with DCM. The combine organic solutions were dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluding with 0-10% MeOH in DCM. 12.72 g (39.4 mmol, 49% yield) of the desired product phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate was obtained. MS (ES) m/e 323 [M+H]+.
487 mg
(Reference Example 33) 1'-benzyloxycarbonyl-1-tert-butyloxycarbonylspiro[indoline-3,4'-piperidine] <Step 1> First, 1-benzyloxycarbonyl-4-formylpiperidine (514.5 mg) was dissolved in chloroform (10 mL), phenylhydrazine (0.245 mL) and trifluoroacetic acid (0.478 mL) were added thereto, and the mixture was stirred at 35C for 14 hours. After that, sodium triacetoxyborohydride (881.9 mg) was added thereto, and the mixture was further stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried with anhydrous magnesium sulfate and was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 50/50) to obtain 1'-benzyloxycarbonylspiro[indoline-3,4'-piperidine] (487.0 mg). MS (ESI)m/z:323[M+H]+.
Stage #1: 4-fluorophenyhydrazine hydrochloride; N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde With trifluoroacetic acid In toluene; acetonitrile at 20 - 50℃; for 23h;
Stage #2: With sodium tetrahydroborate In methanol; toluene; acetonitrile at 0 - 20℃; for 3h;
19.A
Example 19 3- [ (5-FLUORO-L-METHYL-1, 2-DIHYDRO-L H-SPIRO [INDOLE-3, 4 -PIPERIDIN]-L - yl) methyl]-1, 2,3, 4-tetrahydroisoquinolin-8-ol (A) Benzyl 5-fluoro-1-methyl-1, 2-DIHYDRO-1 H-SPIRO [INDOLE-3, 4 -PIPERIDINE]-1 - carboxylate To a stirred suspension of 4-fluorophenylhydrazine hydrochloride (1.66 g, 10.19 mmol) in trifluoroacetic acid (2.35 mL, 30.56 mmol) and mixed solvents of acetonitrile/toluene (49/1 : 20 mL) was added dropwise a solution of benzyl 4- FORMYLPIPERIDINE-1-CARBOXYLATE (2.29 g, 9.26 mmol) in mixed solvents of ACETONITRILE/TOLUENE (49/1: 5 mL) at room temperature. After 18 h stirring at 35 °C followed by 5 h stirring at 50 °C, the reaction mixture was diluted with methanol (2.5 mL) after cooling. To this reaction mixture was added NaBH4 (525 mg, 13. 89 mmol) at 0 °C. After 3 h stirring at room temperature, the reaction mixture was quenched with aqueous NAHCO3 solution (50 ML), extracted with ethyl acetate, dried (NA2S04), filtered, and concentrated to give brown syrup. This crude product was purified by silica gel column chromatography (HEXANE/ETHYL acetate: 2/1 to 1/1) to give 1.65 g (52 %) of the indoline derivative as pale orange color solid. To a stirred suspension of this solid (340 mg, 1 mmol), NaBH3CN (189 mg, 3 mmol), and 37 % aqueous solution of formaldehyde (151.5 mg, 5 mmol) in methanol (10 mL) was added acetic acid (300 mg, 5 mmol) at 0 °C. After 24 h stirring at room temperature, the reaction mixture was quenched with aqueous NAHCO3 solution and extracted with ethyl acetate. The extracts combined were washed with brine, dried (NA2S04), filtered, and concentrated to give an orange color syrup. This crude product was purified by silica gel column chromatography (HEXANE/ETHYL acetate: 2/1) to give 325 mg (92 %) of the title compound as pale yellow syrup. 1H NMR (300MHZ, CDC13) O 7.46-7. 29 (5H, m), 6.80 (1H, ddd, J = 2.6, 8. 6,9. 2 Hz), 6.71 (1H, dd, J = 2.6, 8.4 Hz), 6.38 (1H, dd, J = 4.2, 8.5 Hz), 5.16 (2H, s), 4.25-4. 05 (2H, m), 3.23 (2H, s), 3.10-2. 90 (2H, m), 2.74 (3H, s), 1. 85-1. 65 (9H, m). MS (ESI positive) m/z : 356.23 (M+H) +.
With triethylamine; In dichloromethane; dimethyl sulfoxide;
26c. Phenylmethyl 4-formylpiperidinecarboxylate To a stirred solution of oxalyl chloride (2M solution in dichloromethane, 10.9 mL, 21.9 mmol) was added DMSO (3.1 mL, 3.4 g, 43.8 mmol) in dichloromethane (6 mL) over a period of 15 minutes. The product of Example 26b (4.4 g, 17.5 mmol) in dichloromethane (7 mL) was then added at -78 C. over a period of 15 minutes. The resultant solution was stirred at -78 C. for 1 hour and then triethylamine (12.2 mL, 8.86 g, 87.5 mmol) was added, dropwise, over a period of 15minutes. The mixture was further stirred at -78 C. for 30 min and then at 0 C. for 15 min. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic phase was washed with 1% HCl, water, dried over sodium sulfate, filtered and evaporated to give the title compound (4.4 g, 100%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) delta9.65 (s, 1H), 7.28-7.38 (m, 5H), 5.12 (s, 2H), 4.04 (br d, J=13.1 Hz, 2H), 2.97-3.06 (m, 2H), 2.38-2.45 (m, 1H), 1.88-1.92 (m,2H), 1.52-1.64 (m, 2H). 13C NMR (75 MHz, CDCl3) delta202.7, 155.2, 136.7, 128.5, 128.6, 127.9, 67.2, 47.8, 43.0, 25.1. LRMS (APIMS) m/z 248 (MH+).
With trifluoroacetic acid; In dichloromethane; at 0 - 40℃; for 18.25h;
1-(4-(Methylsulfonyl)phenyl)hydrazine hydrochloride (2.3Og, 10.3mmol) was slurried in dichloromethane(45 mL) in a dry flask under nitrogen. Benzyl 4-formylpiperidine-1- carboxylate( 2.03g, 10.3mmol) was charged to the pot and cooled to 0 0C. Trifluoroacetic acid (5 mL) was added to the flask over 15 minutes in a dropwise fashion and the pot was heated to 40 0C and held for 18 h. The reaction is checked by LC/MS and Was complete. The solvent was concentrated down to 10% original volume. The slurry was diluted with 40 mL of toluene, acetonitrile (1 mL) and methanol (2 mL). The solution was cooled down to -5 0C and sodium borohydride (0.456g, 12.1 mmol) was added portionwise over 30 minutes. The reaction is stirred for an additional hour at 0 0C. The reaction was complete by LC/MS and was neutralized with 6% NH4OH at O0C. The organic was collected and aqueous phase was extracted with 2 X 40 mL ethyl acetate. The combined EtOAc phases were washed with brine, dried (Na2SO4), and concentrated to dryness. The material was chromatographed using 1 :1 ethyl acetate - heptane to give 3.04 g of benzyl 5-t4-(methylsulfonyl)phenyl]-1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-11- carboxylate as a tan solid. % yield = 74% TR 2.4min. (HPLC conditions I); LRMS (M+): 401.2; 1H NMR (400 MHz, DMSO d6) delta 7.28 - 7.36 (5H, m), 6.63 (1H, s), 6.50 (1H, d, J = 8.3Hz), 5.08 (2H, s), 3.95 (2H, d, J = 12.9Hz), 3.49 ( 1 H, s), 3.02, (3H, s), 2.84 - 3.04(2H,m), 1.70 (2H, t, J = 13.1 Hz), 1.59 (2H, d, J = 13.3Hz).
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (1.92 g, 4.53 mmol) was added to a solution of <strong>[122860-33-7]1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine</strong> (1.00 g, 4.01 mmol) in CH2Cl2 (20 mL) and the mixture was stirred at RT for 45 min. Ether (75 mL) and 1.3 N NaOH (25 mL) were added and stirring was continued for 15 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N NaOH (20 mL). The organic layer was separated, washed with saturated aq. NaCl (20 mL, dried (Na2SO4), decanted,and evaporated to give 846 mg of 1-(benzyloxycarbonyl)-4-piperidine carboxaldehyde as a colorless syrup.
To a flask under N2 containing 4-^butylphenylhydrazine hydrochloride (1.0 g, 5 mmol) in degassed toluene/CH3CN (50/1, 22 mL) and TFA (1.5 g, 13 mmol) was added 1- ben2yloxycarbonyl-piperidine-4-carbaldehyde (1.2 g, 5 mmol) at room temperature. After stirring for 15 min, the reaction was heated to 400C and stirred overnight. The reaction was cooled to 50C, and MeOH (27 mL) was added and followed by NaBH4 (0.25 g, 6.7 mmol). The reaction was stirred for an additional 1 h, diluted with EtOAc (60 mL), and washed with IN NaOH (2x) and brine. The organic layer was dried with anhydrous MgSO4 and concentrated to afford solid residue, which was washed with hexane/ether (5/1) several times to give 1.0 g (51 percent) of 1'- (benzyloxycarbonyl)- 1 ,2-dihydro-5 -^-buryl-spiro [3H-indole-3 ,4 ' -piperidine] . LC-MS m/z 379 (M + H)+; 1H NMR (400 MHz, DMSO-fe) delta 7.39-7.31 (m, 5 H), 7.01 (s, 1 H), 6.93 (d, 1 H, J= 7.8 Hz), 6.41 (d, 1 H, J= 7.8 Hz), 5.34 (s, 1 H), 5.10 (s, 2 H), 3.98 (bd, 2 H, J= 13 Hz), 3.37 (s, 2 H), 2.98 (bm, 2 H), 1.71-1.55 (m, 4 H), 1.21 (s, 9 H).
Stage #1: N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde; p-fluorophenylhydrazine With trifluoroacetic acid In toluene; acetonitrile at 35℃; for 16h;
Stage #2: With methanol; sodium tetrahydridoborate In tetrahydrofuran; acetonitrile at 0℃;
42.1 [0442] Step-1. Synthesis of benzyl 5-fluoro-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate :
[0443] A solution of (4-fluorophenyl)hydrazine (3 g, 23.7 mmol) and trifluoroacetic acid (6.0 mL) in a toluene/acetonitrile mixture (49/1, 100 mL) was heated to 35 °C, followed by addition dropwise of solution of 4-formyl-piperidine-l-carboxylic acid benzyl ester (5.31 g, 21.5 mmol) in toluene/acetonitrile mixture (49/1, 40 mL). The mixture was stirred at 35 °C for 16 h, then cooled to 0 °C and diluted with cold methanol (10 mL). NaBH4 (1.22 g, 32.3 mmol) was added slowly to the mixture, and it was stirred for additional 45 min. After, the reaction mixture was washed with aqueous NH4OH (6%, 50 mL) and brine (100 mL), then dried over sodium sulfate, filtered, and evaporated to dryness. The crude residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to give benzyl 5-fluoro-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate as yellow solid (1.75 g, 5.14 mmol, 95% purity, 23.9% yield).
Stage #1: N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde; p-fluorophenylhydrazine With trifluoroacetic acid In toluene; acetonitrile
Stage #2: With sodium tetrahydridoborate In methanol
Stage #1: N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde; N-4-chlorophenylhydrazine With trifluoroacetic acid In toluene; acetonitrile
Stage #2: With sodium tetrahydroborate In methanol
3-Chlorophenyl)hydrazine (1.3 g, 7.3 mmol, 1 eq.) was mixed with phenylmethyl 4-formyl-1-piperidinecarboxylate (1. 8 g, 7.3 mmol, 1 eq.) in DCM with trifluoroacetic acid (TFA, 8.3 g, 73 mmol, 10 eq.) and refluxed with stirring for 1/2 h. Sodium borohydride (0.831 g, 21.8 mmol, 3 eq.) was then added to the mixture and after 10 min the mixture was transferred to an ice water bath. Excess 28-30% ammonium hydroxide was then added portionwise followed by water. The mixture was shaken and the organic layer separated and dried over sodium sulfate followed by evaporation. The residue was loaded onto silica and purified by normal phase chromatography, eluding with 15, 20, 25% EtOAc/hexanes, eluding first the desired 6-Cl isomer followed by the 4-Cl isomer. The 6-Cl isomer was isolated for further use. MS (ES) m/e 357 [M+H]+.
To a mixture of 4-fluorophenylhydrazine hydrochloride (13.36 mmol,1.93 g), trifluoroacetic acid (40.06 mmol, 2.97 mL) in acetonitrile:toluene (49: 1, 25 mL), a solution of benzyl 4-formylpiperidine-l-carboxylate (12.14 mmol, 3 g) in acetonitrile:toluene (49:1, 10 mL) was added drop wise at room temperature. The reaction mixture was stirred at 35 C for 16 hr followed by 5 hr at 50 C. Then the reaction mixture cooled to 0 C, diluted with 3 mL MeOH, added NaBH4 (18.21 mmol, 688 mg) and continued stirring at room temperature for 3 hr. The reaction mixture was then diluted with sat. aq. NaHC03 solution, extracted with ethyl acetate, dried over anhydrous Na2S04, evaporated under reduced pressure and the residue was purified by flash column chromatography. The product eluted at 1 :2 hexane:ethyl acetate solvent mixture.
benzyl 2-cyclopropyl-4-fluoro-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate[ No CAS ]
benzyl 2-cyclopropyl-6-fluoro-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Intermediate B.2 and B.3benzyl 2-cyclopropyl-4-fluoro-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (B.2) and benzyl 2-cyclopropyl-6-fluoro-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (B.3)In analogy to the preparation of intermediate B.1 from A.2 the 4-fluoro isomer B.2 and the 6-fluoro isomer B.3 were obtained and separated by flash chromatography.To a stirred and degassed solution of indolenine A.1 (0.5 g, 1.25 mmol) in 4.5 ml THF boron trifluoride diethylether complex (0.15 ml, 1.25 mmol) was added dropwise at 0C. After 5 min of stirring, cyclopropylmagnesium bromide (7.5 ml of a 0.5 M solution in THF, 7.5 mmol) was added dropwise within approximately 1 h, keeping the temperature of the mixture at 5C. The mixture was further stirred at ooc until TLC and/or LCMS indicated complete consumption of the starting material. Then saturated aqueous ammonium chloride solution was added and the mixture partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried with magnesium sulfate, concentrated in vacuo and purified via flash chromatography (Si02- hexane/ethyl acetate) to give 374 mg (67%) of intermediate B.1.
benzyl 4-fluoro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate[ No CAS ]
benzyl 6-fluoro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In chloroform; at 20 - 50℃; for 4h;
General procedure: Intermediate A.2benzyl 4-fluoro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate and benzyl 6-fluoro-1'Hspiro[indole-3,4'-piperidine]-1'-carboxylateAs described for intermediate A.1 <strong>[2924-16-5](3-fluorophenyl)hydrazine hydrochloride</strong> was reacted with benzyl4-formylpiperidine-1-carboxylate to give a 1:1 mixture of benzyl4-fluoro-1'H spiro[indole-3,4'-piperidine]-1'-carboxylate and benzyl 6-fluoro-1'H-spiro[indole-3,4' piperidine]-1'-carboxylate. The product was used in the next step without further purification. UPLC-MS (ESI+): [M + Ht = 339 Rt in min 1.25To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (3 g, 13.4 mmol) and benzyl 4-formylpiperidine-1-carboxylate (3.5 g, 13.4 mmol) in 75 ml chloroform trifluoroacetic acid (3.4 ml, 44 mmol) was added dropwise at rt. The reaction mixture was heated to 50C for 4 h and then cooled to room temperature. An aqueous solution of ammonia (25%) was carefully added to reach a pH of- 10. The mixture was poured into water, the phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers were washed twice with water, dried with magnesium sulfate and the solvents removed in vacuo. The product (5.3 g) was used in the next step without further purification.
benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 3h;
Reaction step 3: Synthesis of benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate To a stirred solution of <strong>[22190-35-8]6-bromo-1,2,3,4-tetrahydroquinoline</strong> (4.7 g, 22.2 mmol, 1.0 eq) and benzyl 4-formylpiperidine-1-carboxylate (6.05 g, 24.5 mmol, 1.1 eq) in 1,2-dichloroethane (100 ml), sodium triacetoxy borohydride (15.5 g, 73.5 mmol, 3.0 eq) was added and stirring was continued at room temperature for 3 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane, Rf=0.40), the mixture was diluted with dichloromethane, and washed with saturated sodium bicarbonate solution followed by brine. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate (8.0 g, 81%) which was taken for next step without purification. LCMS purity: 70.29% (ES+): m/z 443.40 (M+H+); tr=2.77.
8 g
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 3h;
Reaction step 3 Synthesis of benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate To a stirred solution of <strong>[22190-35-8]6-bromo-1,2,3,4-tetrahydroquinoline</strong> (4.7 g, 22.2 mmol, 1.0 eq) and benzyl 4-formylpiperidine-1-carboxylate (6.05 g, 24.5 mmol, 1.1 eq) in 1,2-dichloroethane (100 ml), sodium triacetoxyborohydride (15.5 g, 73.5 mmol, 3.0 eq) was added and stirring was continued at room temperature for 3 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate-hexane, Rf=0.40), the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution followed by brine. The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude benzyl 4-((6-bromo-3,4-dihydroquinolin-1(2H)-yl)methyl)piperidine-1-carboxylate (8.0 g, 81%) which was taken for next step without purification. LCMS purity: 70.29% (ES+): m/z 443.40 (M+H+); tr=2.77.
Stage #1: methyl-triphenylphosphonium iodide With sodium t-butanolate In tetrahydrofuran at 20℃; for 1h;
Stage #2: N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde In tetrahydrofuran at 20℃;
16-1 benzyl 4-vinylpiperidine-1-carboxylate
To a solution of methyltriphenylphosphonium iodide (12.2 g, 30.3 mmol) in THF (50 mL) was added sodium tert-butoxide (2.9 g, 30.3 mmol) . The resulting mixture was stirred at rt for 1h and a solution of benzyl 4-formylpiperidine-1-carboxylate (5 g, 20.2 mmol) in THF (10 mL) was added. The reaction solution was stirred at rt overnight, diluted with aq NH4Cl (50 mL) and the organic phase was washed with water (100 mL × 3) , brine (10 mL × 3) and dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc 50/1 to 10/1) to get pure benzyl 4-vinylpiperidine-1-carboxylate (3.1 g, 62.6) . LRMS m/z (M+H) 246.0 found, 246.1 required
Multi-step reaction with 2 steps
1: sodium tris(acetoxy)borohydride / dichloromethane / 3.17 h / 25 °C
2: hydrogen; palladium on activated charcoal / ethanol / 16 h / 20 °C
Multi-step reaction with 2 steps
1: sodium tris(acetoxy)borohydride; glacial acetic acid / dichloromethane / 2 h / 20 °C
2: palladium hydroxide (10%) on carbon; hydrogen / ethanol / 90 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps
1.1: glacial acetic acid / 1,2-dichloro-ethane / 0.5 h / 20 °C
1.2: 20 °C
2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 50 °C
Multi-step reaction with 2 steps
1: dichloromethane / 3 h / 20 °C
2: Pearlman’s catalyst / ethanol / 20 °C
Stage #1: N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde; 3-bromophenylhydrazine With trifluoroacetic acid In dichloromethane at 0 - 40℃; for 18h;
Stage #2: With sodium tetrahydroborate In dichloromethane at 0℃; for 0.5h;
1.1-1 Step 1-1, preparation of benzyl 6-bromo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'- carboxylate:
Into a 250-mL round-bottom flask purged, were placed benzyl 4-formylpiperidine- 1-carboxylate (2.9 g, 12 mmol) and DCM (30 mL). The resulting solution was treated with (3- bromophenyl)hydrazine (2.0 g, 11 mmol) and then TFA (2.5 mL) at 0 C. The reaction mixture was stirred at 40 C for 18 h and cooled to rt. After cooling to 0 C, the reaction was treated with NaBH4 (0.82 g, 22 mmol) in several portions and stirred for 30 min. The resulting solution was diluted with water (20 mL) and added sat.-NaHCO3 to adjust the pH to 8~9. The solution was extracted with CH2Cl2 (2x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in the title compound (1.3 g, 30%) as yellow oil. LCMS (M+H)+ = 401.1.
benzyl 4-((4-(tert-butoxycarbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With anhydrous Sodium acetate; sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃;
14.1 Step 1: benzyl 4- ( (4- (tert-butoxycarbonyl) piperidin-1-yl) methyl) piperidine-1-carboxylate
To a stirred solution of benzyl 4-formylpiperidine-1-carboxylate (1.01 g, 4.044 mmol) , tert-butyl piperidine-4-carboxylate hydrochloride (897 mg, 4.044 mmol) , AcONa (3.31 g, 40.4 mmol, ) and DCM (20 mL) was added STAB (5.14 g, 24.263 mmol) in portions at 0 . The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (1.20 g) which was used in the next step directly without further purification. [M+H]+= 417.3.
With anhydrous Sodium acetate; sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃;
14.1 Step 1: benzyl 4- ( (4- (tert-butoxycarbonyl) piperidin-1-yl) methyl) piperidine-1-carboxylate
To a stirred solution of benzyl 4-formylpiperidine-1-carboxylate (1.01 g, 4.044 mmol) , tert-butyl piperidine-4-carboxylate hydrochloride (897 mg, 4.044 mmol) , AcONa (3.31 g, 40.4 mmol, ) and DCM (20 mL) was added STAB (5.14 g, 24.263 mmol) in portions at 0 . The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (1.20 g) which was used in the next step directly without further purification. [M+H]+= 417.3.
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