* 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.
To a solution of Compound 3A (1.00 g, 10.0 mmol) in tetrahydrofuran (10mL), di-tert-butyl dicarbonate (3.48 mL, 15.0 mmol) was added under ice-cooling and stirred at room temperature for 2 hours. The solution was concentrated and subjected to silica gel column chromatography. The fraction containing the desired compound was concentrated and dried under reduced pressure to yield Compound 3B (2.15 g, quantitative). 1H-NMR (CDCl3) δ: 3.44 (4H, t, J = 5.0 Hz), 2.34 (4H, t, J = 5.0 Hz), 2.29 (3H, s), 1.46 (9H, s).
100%
at 20℃; for 0.333333 h; Ionic liquid
To the ionic liquid [TPA][Pro] (1 mL) was added amine (1-14; Table-1) (1 mmol) and di-tert-butyl dicarbonate (1.2 mmol). The reaction was stirred at room temperature for an appropriate time (Table-1). After completion of the reaction as monitored by TLC, water was added to the reaction mixture and the product was extracted into ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine solution and concentrated under reduced pressure to give crude product, which was purified over silica gel column to afford corresponding N-tert-butylcarbamate. The ionic liquid [TPA][Pro] in aqueous solution was recovered by removing water under reduced pressure and dried. The recovered ionic liquid was reused for five times without loss of its activity. Finally, all the compounds confirmed by their m.p.’s, IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis wherever needed.
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 16, p. 2527 - 2532
[2] Patent: EP2703406, 2014, A1, . Location in patent: Paragraph 0392
[3] Asian Journal of Chemistry, 2017, vol. 29, # 6, p. 1313 - 1316
[4] Tetrahedron Letters, 2009, vol. 50, # 46, p. 6244 - 6246
[5] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286
[6] Journal of Organic Chemistry, 2011, vol. 76, # 17, p. 7132 - 7140
[7] Advanced Synthesis and Catalysis, 2008, vol. 350, # 7-8, p. 1081 - 1089
[8] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 7023 - 7031
[9] Patent: US2009/163508, 2009, A1, . Location in patent: Page/Page column 20
[10] Patent: EP2540728, 2013, A1, . Location in patent: Page/Page column 69
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 452 - 458
6
[ 870-46-2 ]
[ 53788-49-1 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, p. 657 - 661
7
[ 57260-71-6 ]
[ 53788-49-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 452 - 458
8
[ 109-01-3 ]
[ 1070-19-5 ]
[ 53788-49-1 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, p. 657 - 661
9
[ 3934-20-1 ]
[ 53788-49-1 ]
[ 479691-42-4 ]
Yield
Reaction Conditions
Operation in experiment
73%
at 110℃;
A mixture of 2,4-dichloropyrimidine (50g, 336mmol), tert-butyl 4-methylpiperazine-1-carboxylate (67.2g, 336mmol), and toluene (500mL) was stirred at 110 °C overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane–EtOAc) to give 10 (109g, 73percent) as a colorless powder. 1H NMR (300MHz, CDCl3) δ: 1.49 (9H, s), 3.44–3.53 (4H, m), 3.75–3.84 (4H, m), 6.53 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.1Hz). MS (ESI): m/z 299 [M+H]+.
62%
at 110℃;
(2) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate A mixture of 4-methyltert-butyl piperazine-1-carboxylate (2.0 g, 9.98 mmol), 2,4-dichloropyrimidine (1.49 g, 9.98 mmol) and toluene (20 ml) was stirred at 110° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (1.83 g, 62percent) as a solid. 1H NMR (CDCl3) δ: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.1 Hz).
In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;
To a solution of Compound 3A (1.00 g, 10.0 mmol) in tetrahydrofuran (10mL), di-tert-butyl dicarbonate (3.48 mL, 15.0 mmol) was added under ice-cooling and stirred at room temperature for 2 hours. The solution was concentrated and subjected to silica gel column chromatography. The fraction containing the desired compound was concentrated and dried under reduced pressure to yield Compound 3B (2.15 g, quantitative). 1H-NMR (CDCl3) delta: 3.44 (4H, t, J = 5.0 Hz), 2.34 (4H, t, J = 5.0 Hz), 2.29 (3H, s), 1.46 (9H, s).
100%
at 20℃; for 0.333333h;Ionic liquid;
To the ionic liquid [TPA][Pro] (1 mL) was added amine (1-14; Table-1) (1 mmol) and di-tert-butyl dicarbonate (1.2 mmol). The reaction was stirred at room temperature for an appropriate time (Table-1). After completion of the reaction as monitored by TLC, water was added to the reaction mixture and the product was extracted into ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine solution and concentrated under reduced pressure to give crude product, which was purified over silica gel column to afford corresponding N-tert-butylcarbamate. The ionic liquid [TPA][Pro] in aqueous solution was recovered by removing water under reduced pressure and dried. The recovered ionic liquid was reused for five times without loss of its activity. Finally, all the compounds confirmed by their m.p.?s, IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis wherever needed.
With triethylamine; In tetrahydrofuran; at 20℃; for 8h;
(1) Tert-butyl 4-methyl piperazine-1-carboxylate To a solution of 1-methylpiperazine (1.0 g, 9.98 mmol) and triethylamine (1.53 ml, 11.0 mmol) in tetrahydrofuran (20 ml) was added di-tert-butyl dicarbonate (2.40 g, 11.0 mmol) at room temperature, and the mixture was stirred at room temperature for 8 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as an oily material. The resulting crude product was used for the subsequent reaction as such.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 3h;
A) Production of tert-butyl 4-methylpiperazine-1-carboxylate A mixture of 1-methylpiperazine (15 g), triethylamine (22.7 mL) and tetrahydrofuran (300 mL) was cooled to 0C, and di-tert-butyl dicarbonate (22 g) was added with stirring. Thereafter, the reaction system was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, 4M aqueous sodium hydroxide solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (300 mL). The extract was washed with water (200 mL) and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (25.5 g) as a yellow oil. 1H-NMR(CDCl3) delta 1.40(9H,s), 2.25(3H,s), 2.31(4H,t,J=4.8Hz), 3.40(4H,t,J=4.8Hz).
Example 8Synthesis of [F- 18]- 1 -methyl- l-(4-fluorophenyl)piperazinium saltt-BOC-Protected methylpiperizine was heated in the presence of l-fluoro-4- nitrobenzene under pressure in benzene to give 4-t-BOC-protected 1 -methyl- 1 -(4- nitrophenyl)piperazinium salt. The piperazinium salt was heated in the presence of potassium [18F]fluoride and Krytofx at 2000C for 10 minutes. The oil was treated with aq. 3 M HCl for 20 minutes to give [F-18]- 1 -methyl- l-(4-fluorophenyl)piperazinium chloride.
t-BOC-Protected methylpiperizine was heated in the presence of l-fluoro-4- nitrobenzene under pressure in benzene to give 4-t-BOC-protected 1-methyl-1- (4- nitrophenyl) piperazinium salt. The piperazinium salt was heated in the presence of potassium [F] fluoride and Krytofix at 200C for 10 minutes. The oil was treated with aq. 3 M HC1 for 20 minutes to give [F-18]-1-methyl-1-(4-fluorophenyl) piperazinium chloride
Example 8Synthesis of [F- 18]- 1 -methyl- l-(4-fluorophenyl)piperazinium saltt-BOC-Protected methylpiperizine was heated in the presence of l-fluoro-4- nitrobenzene under pressure in benzene to give 4-t-BOC-protected 1 -methyl- 1 -(4- nitrophenyl)piperazinium salt. The piperazinium salt was heated in the presence of potassium [18F]fluoride and Krytofx at 2000C for 10 minutes. The oil was treated with aq. 3 M HCl for 20 minutes to give [F-18]- 1 -methyl- l-(4-fluorophenyl)piperazinium chloride.
In benzene;Heating / reflux;
t-BOC-Protected methylpiperizine was heated in the presence of l-fluoro-4- nitrobenzene under pressure in benzene to give 4-t-BOC-protected 1-methyl-1- (4- nitrophenyl) piperazinium salt. The piperazinium salt was heated in the presence of potassium [F] fluoride and Krytofix at 200C for 10 minutes. The oil was treated with aq. 3 M HC1 for 20 minutes to give [F-18]-1-methyl-1-(4-fluorophenyl) piperazinium chloride
N-methyl piperazine di-trifluoroacetic acid salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With water; In dichloromethane; for 0.5h;Product distribution / selectivity;
Deprotection; A solution of 1:1 TFA, DCM with 0.5% water was prepared. This solution was added to the material isolated from the reduction, above (10 mL/g starting material). The reaction was stirred for 30 minutes then the solvent was removed with a rotoevaporator. Solvent evaporation was terminated when no more solvent was observed to be collecting on the condenser. TFA was added to the product residue (2 mL/g starting material) to form a free flowing solution. The TFA solution was transferred to a centrifuge tube and diethyl ether was added to precipitate the product salt. The solution was mixed using a vortex. The solution was then centrifuged and the supernatant decanted to collect the precipitate. The filtrate was then washed 1 time with ether by resuspending the product, vortexing, and re-centrifugation. Product was dried under low vacuum to remove residual ether.
With water; In dichloromethane;Product distribution / selectivity;
Deprotection: A solution of 1:1 TFA, DCM with 0.5% water was prepared. This solution was added to the material isolated from the reduction, above (10 mL/g starting material). The reaction was stirred for 30 minutes then the solvent was removed with a rotoevaporator. Solvent evaporation was terminated when no more solvent was observed to be collecting on the condenser. TFA was added to the product residue (2 mL/g starting material) to form a free flowing solution. The TFA solution was transferred to a centrifuge tube and diethyl ether was added to precipitate the product salt. The solution was mixed using a vortex. The solution was then centrifuged and the supernatant decanted to collect the precipitate. The filtrate was then washed 1 time with ether by resuspending the product, vortexing, and re-centrifugation. Product was dried under low vacuum to remove residual ether.
Example 3; General Procedure for the Synthesis of N-Methyl Piperazine (Route A; FIG. 1); A saturated solution of sodium sulfate was prepared. Tetrahydrofuran (THF) (4 mL per mmol starting material based upon the material used in Example 2) was added to the diketopiperazine formed using the procedure of Example 2. The reaction flask was fit with a reflux condenser and three equivalents of 1M LiAlH4 in THF (LAH solution; it may be possible to substitute Red-Al or other reducing reagent for LAH but this has not been attempted) was added to the solution through a dropping funnel. There was vigorous hydrogen evolution at the initiation of the addition but this subsided as the addition continued. The reaction was heated to reflux for 4 hours. After the reaction was complete, the solution was cooled to room temperature and the remaining LAH was quenched with the very slow addition of saturated aqueous sodium sulfate (¼ the volume of the LAH solution added). The reaction appeared as a gray suspension. DCM was added to this suspension (½ volume of the THF) and the gray gel-like solid was removed by filtration. The flask and filtered solids were then thoroughly washed 2× with DCM (¼ volume of the THF). The combined organic solution (DCM/THF) was then dried with Na2SO4 (solid-anhydrous) and filtered. (In some early experiments the N-methyl piperazine was isolated as an oil (free base and not as a TFA or HCl salt) but the product was determined to be a volatile oil and therefore not be isolated in high yield). Di-tert-butyl-dicarbonate (3 equivalents) was added to this solution that was stirred and vented overnight. TLC was used to monitor the reaction. Once complete, the solvent was removed by rotary evaporation to yield a liquid. This liquid is slightly volatile, so low vacuum evaporation of solvent is recommended (high vacuum conditions should be avoided). The product was dissolved in DCM and loaded onto a silica-gel column packed with 8% methanol in ethyl acetate. Product was eluted with the 8% methanol in ethyl acetate solution. Product containing fractions were determined by TLC, pooled, and evaporated to a liquid. This liquid was taken directly to the deprotection reaction. Note: the t-boc deprotection was performed only as a means to isolate the crude N-methyl piperazine product but this requires subsequent deprotection. TLC-N-methyl Piperazine (Develop with Ninhydrin) 4:1:1 Ethanol:Water:Ammonium hydroxide Product Rf=0.6 TLC-N1-t-Boc-N2-methyl Piperazine (Develop with Ninhydrin) 4:1 DCM-MeOH Product Rf=0.5
Example 3; General Procedure For The Synthesis Of N-Methyl Piperazine (Route A; FIG. 1); A saturated solution of sodium sulfate was prepared. Tetrahydrofuran (THF) (4 mL per mmol starting material based upon the material used in Example 2) was added to the diketopiperazine formed using the procedure of Example 2. The reaction flask was fit with a reflux condenser and three equivalents of 1M LiAlH4 in THF (LAH solution; it may be possible to substitute Red-Al or other reducing reagent for LAH but this has not been attempted) was added to the solution through a dropping funnel. There was vigorous hydrogen evolution at the initiation of the addition but this subsided as the addition continued. The reaction was heated to reflux for 4 hours. After the reaction was complete, the solution was cooled to room temperature and the remaining LAH was quenched with the very slow addition of saturated aqueous sodium sulfate (¼ the volume of the LAH solution added). The reaction appeared as a gray suspension. DCM was added to this suspension (½ volume of the THF) and the gray gel-like solid was removed by filtration. The flask and filtered solids were then thoroughly washed 2× with DCM (¼ volume of the THF). The combined organic solution (DCM/THF) was then dried with Na2SO4 (solid-anhydrous) and filtered. (In some early experiments the N-methyl piperazine was isolated as an oil (free base and not as a TFA or HCl salt) but the product was determined to be a volatile oil and therefore not be isolated in high yield). Di-tert-butyl-dicarbonate (3 equivalents) was added to this solution that was stirred and vented overnight. TLC was used to monitor the reaction. Once complete, the solvent was removed by rotary evaporation to yield a liquid. This liquid is slightly volatile, so low vacuum evaporation of solvent is recommended (high vacuum conditions should be avoided). The product was dissolved in DCM and loaded onto a silica-gel column packed with 8% methanol in ethyl acetate. Product was eluted with the 8% methanol in ethyl acetate solution. Product containing fractions were determined by TLC, pooled, and evaporated to a liquid. This liquid was taken directly to the deprotection reaction. Note: the t-boc deprotection was performed only as a means to isolate the crude N-methyl piperazine product but this requires subsequent deprotection. TLC-N-methyl piperazine (develop with ninhydrin) 4:1:1 Ethanol:Water:Ammonium hydroxide Product Rf=0.6 TLC-N1-t-Boc-N2-methyl piperazine (develop with ninhydrin) 4:1 DCM-MeOH Product Rf=0.5
Example 3; General Procedure for the Synthesis of N-Methyl Piperazine (Route A; FIG. 1); A saturated solution of sodium sulfate was prepared. Tetrahydrofuran (THF) (4 mL per mmol starting material based upon the material used in Example 2) was added to the diketopiperazine formed using the procedure of Example 2. The reaction flask was fit with a reflux condenser and three equivalents of 1M LiAlH4 in THF (LAH solution; it may be possible to substitute Red-Al or other reducing reagent for LAH but this has not been attempted) was added to the solution through a dropping funnel. There was vigorous hydrogen evolution at the initiation of the addition but this subsided as the addition continued. The reaction was heated to reflux for 4 hours. After the reaction was complete, the solution was cooled to room temperature and the remaining LAH was quenched with the very slow addition of saturated aqueous sodium sulfate (¼ the volume of the LAH solution added). The reaction appeared as a gray suspension. DCM was added to this suspension (½ volume of the THF) and the gray gel-like solid was removed by filtration. The flask and filtered solids were then thoroughly washed 2× with DCM (¼ volume of the THF). The combined organic solution (DCM/THF) was then dried with Na2SO4 (solid-anhydrous) and filtered. (In some early experiments the N-methyl piperazine was isolated as an oil (free base and not as a TFA or HCl salt) but the product was determined to be a volatile oil and therefore not be isolated in high yield). Di-tert-butyl-dicarbonate (3 equivalents) was added to this solution that was stirred and vented overnight. TLC was used to monitor the reaction. Once complete, the solvent was removed by rotary evaporation to yield a liquid. This liquid is slightly volatile, so low vacuum evaporation of solvent is recommended (high vacuum conditions should be avoided). The product was dissolved in DCM and loaded onto a silica-gel column packed with 8% methanol in ethyl acetate. Product was eluted with the 8% methanol in ethyl acetate solution. Product containing fractions were determined by TLC, pooled, and evaporated to a liquid. This liquid was taken directly to the deprotection reaction. Note: the t-boc deprotection was performed only as a means to isolate the crude N-methyl piperazine product but this requires subsequent deprotection. TLC-N-methyl piperazine (develop with ninhydrin) 4:1:1 Ethanol:Water:Ammonium hydroxide Product Rf=0.6 TLC-N1-t-Boc-N2-methyl piperazine (develop with ninhydrin) 4:1 DCM-MeOH Product Rf=0.5
A mixture of 2,4-dichloropyrimidine (50g, 336mmol), tert-butyl 4-methylpiperazine-1-carboxylate (67.2g, 336mmol), and toluene (500mL) was stirred at 110 C overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 10 (109g, 73%) as a colorless powder. 1H NMR (300MHz, CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.1Hz). MS (ESI): m/z 299 [M+H]+.
62%
In toluene; at 110℃;Product distribution / selectivity;
(2) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate A mixture of 4-methyltert-butyl piperazine-1-carboxylate (2.0 g, 9.98 mmol), 2,4-dichloropyrimidine (1.49 g, 9.98 mmol) and toluene (20 ml) was stirred at 110 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (1.83 g, 62%) as a solid. 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.1 Hz).
In water; toluene;
Example 2 Preparation of Intermediate 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-2a): To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mL of toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 20 mL of water and extracted with ethyl acetate (2*40 mL). The combined organic layers were washed with brine (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to an off-white solid. Flash column chromatography (silica gel, gradient elution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes) yielded 1.14 g of the title compound (I-2a). 1H NMR (400 MHz, CDCl3) delta 8.15 (d, 1H); 6.52 (d, 1H); 3.80 (m, 4H); 3.48 (m, 4H); 1.47 (s, 9H). MS (APCI+) Calc: 298, Found: 299.1 (M+1).
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; ethyl acetate;
Example 45 (4-Hexyl-piperazin-1-yl)-(1H-indol-2-yl)-methanone Indole-2-carboxylic acid (5.2 g) in THF (200 mL) was treated with carbonyldiimidazole (4.8 g) and stirred at ambient temperature for 10 min whereupon <strong>[53788-49-1]4-methyl-piperazine-1-carboxylic acid tert-butyl ester</strong> (5.0 g) was added. The mixture was stirred at ambient temperature for 72 h and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was separated, dried over sodium sulfate and filtered, and solvent was evaporated to afford a solid. Recrystallization from hot ethanol afforded 4-(1H-Indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.2 g).
Indole-2-carboxylic acid (5.2 g) in THF (200 mL) was treated with [CARBONYIDIIMIDAZOLE] (4.8 g) and stirred at ambient temperature for 10 min whereupon [4-METHYL-PIPERAZINE-1-CARBOXYLIC] acid tert-butyl ester (5.0 g) was added. The mixture was stirred at ambient temperature for 72 h and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was separated, dried over sodium sulfate and filtered, and solvent was evaporated to afford a solid. Recrystallization from hot ethanol afforded [4- (1 H-] lndole-2-carbonyl)-piperazine-1-carboxylic acid ter-butyl ester (4. 2 g).
4.2 g
Indole-2-carboxylic acid (5.2 g) in THF (200 mL) was treated with carbonyldiimidazole (4.8 g) and stirred at ambient temperature for 10 min whereupon <strong>[53788-49-1]4-methyl-piperazine-1-carboxylic acid tert-butyl ester</strong> (5.0 g) was added. The mixture was stirred at ambient temperature for 72 h and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was separated, dried over sodium sulfate and filtered, and solvent was evaporated to afford a solid. Recrystallization from hot ethanol afforded 4-(1 H-Indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.2 g).
Step 1: 4-tert-Butoxycarbonyl-(2R)-methylpiperazine. Glacial acetic acid (6.3 g, 105 mmol), followed by di-tert-butyldicarbonate (23.11 g, 106 mmol), were added to a stirred solution of (2R)-methylpiperazine (10.3 g, 103 mmol) in MeOH (200 mL) at 0 C., and the resulting mixture was stirred for 1 h. The reaction mixture was allowed to warm to room temperature and stirred for further 15 h. An excess of triethylamine (20 mL, 140 mmol) was added and the reaction mixture was concentrated under reduced pressure. The residue was suspended in CHCl3 and filtered through a fritted glass filter. The filtrate was concentrated, and the residue was purified by chromatography on silica gel using CHCl3/MeOH (85:15) as eluent to give 21 g (65%) of the title product as an oil that crystallized upon standing. The product was used in the next step without further characterization.
Step 3: (2R)-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine, Hydrochloride. KO-t-Bu (0.52 g, 4.66 mmol) was added to a solution of 2-phenoxyethanol (0.42 g, 3.0 mmol) in dioxane (15 mL) and the mixture was stirred at room temperature for 15 minutes. 4-tert-Butoxycarbonyl-(2R)-methylpiperazine (0.73 g, 2.33 mmol; from
(oily) t-butyl (4-methylpiperazin-1-yl)-carboxylate[ No CAS ]
1-Methyl-1-oxidopiperazine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In tetrahydrofuran; chloroform; water;
1-Methylpiperazine-1-oxide dihydrochloride employed as starting material can be obtained in the following way: Preparation of (oily) <strong>[53788-49-1]t-butyl (4-methylpiperazin-1-yl)-carboxylate</strong> (15.0 g.) by reacting t-butyl azidoformate (12.9 g.) with 1-methylpiperazine (9.5 g.) in water (30 cc.) and tetrahydrofuran (15 cc.), whilst gradually adding a 5N sodium hydroxide solution (19 cc.), at a temperature of about 20C. Preparation of 1-methyl-4-(t-butoxycarbonyl)piperazine-1-oxide hydrochloride (8.7 g.), m.p. 233C, by reacting 4-nitroperbenzoic acid (34.0 g.) with <strong>[53788-49-1]t-butyl (4-methylpiperazin-1-yl)-carboxylate</strong> (24.2 g.) in anhydrous chloroform (240 cc.) at a temperature not exceeding 40C. Preparation of 1-methylpiperazine-1-oxide dihydrochloride (5.5 g.), m.p. 205C, by reacting anhydrous hydrogen chloride gas (2.35 g.) with 1-methyl-4-(t-butoxycarbonyl)-piperazine-1-oxide hydrochloride (8.1 g.) in refluxing anhydrous ethanol (60 cc.) for half an hour.
1'-benzyl-7-methyltetrahydro-5H-spiro[1,3-oxazolo[3,4-a]pyrazine-1,4'-piperidin]-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
B) Production of 1'-benzyl-7-methyltetrahydro-5H-spiro[1,3-oxazolo[3,4-a]pyrazine-1,4'-piperidin]-3-one A mixture of <strong>[53788-49-1]tert-butyl 4-methylpiperazine-1-carboxylate</strong> (24.2 g), N,N,N',N'-tetramethylethane-1,2-diamine (21 g) and tetrahydrofuran (500 mL) was cooled to -78C under a nitrogen atmosphere, and sec-butyllithium (184 mL, 1.3M cyclohexane solution) was added dropwise over 1.5 hr while stirring. Furthermore, the mixture was stirred at the same temperature for 2 hr, the reaction system was heated to 30C, and the mixture was stirred for 1.5 hr. Thereafter, the reaction system was cooled again to -78C, and a solution of 1-benzylpiperidin-4-one (28.3 g) in tetrahydrofuran (50 mL) was added dropwise over 1 hr. The reaction system was stirred at room temperature overnight, and the mixture was cooled to 0C. Saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (300 mL), and the extract was washed with water (300 mL) and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (17.6 g) as a brown oil. 1H-NMR(CDCl3) delta 1.62-1.89(6H,m), 2.21(3H,s), 2.31-2.40(2H,m), 2.62(1H,m), 2.96(1H,m), 3.31(1H,m), 3.42(2H,m), 3.67(1H,m), 7.20-7.28(5H,m).
(8aS)-7-methyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-a]pyrazin-3-one[ No CAS ]
(8aR)-7-methyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-a]pyrazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of N-Boc heterocycle(1.0-1.95 mmol, 1.0 eq.) and diamine (1.3 eq.) in Et2O (3.5-10.5 mL) at -78 C under Ar. The resultingsolution was stirred at -78 C for 1 h. Then, the electrophile (2.0 eq.) was added dropwise, as a solutionin Et2O (1 mL) if necessary. The reaction mixture was allowed to warm slowly to rt overnight. Then,saturated NH4Cl(aq) (10 mL), 20% NaOH(aq) (10 mL), and Et2O (10 mL) were added, and the two layerswere separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layerswere dried (MgSO4), filtered, and evaporated under reduced pressure to give the crude product
General procedure: s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of N-Boc heterocycle(1.0-1.95 mmol, 1.0 eq.) and diamine (1.3 eq.) in Et2O (3.5-10.5 mL) at -78 C under Ar. The resultingsolution was stirred at -78 C for 1 h. Then, the electrophile (2.0 eq.) was added dropwise, as a solutionin Et2O (1 mL) if necessary. The reaction mixture was allowed to warm slowly to rt overnight. Then,saturated NH4Cl(aq) (10 mL), 20% NaOH(aq) (10 mL), and Et2O (10 mL) were added, and the two layerswere separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layerswere dried (MgSO4), filtered, and evaporated under reduced pressure to give the crude product
(8aS)-7-methyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-a]pyrazin-3-one[ No CAS ]
(8aR)-7-methyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-a]pyrazin-3-one[ No CAS ]
C8H14N2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of N-Boc heterocycle(1.0-1.95 mmol, 1.0 eq.) and diamine (1.3 eq.) in Et2O (3.5-10.5 mL) at -78 C under Ar. The resultingsolution was stirred at -78 C for 1 h. Then, the electrophile (2.0 eq.) was added dropwise, as a solutionin Et2O (1 mL) if necessary. The reaction mixture was allowed to warm slowly to rt overnight. Then,saturated NH4Cl(aq) (10 mL), 20% NaOH(aq) (10 mL), and Et2O (10 mL) were added, and the two layerswere separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layerswere dried (MgSO4), filtered, and evaporated under reduced pressure to give the crude product
General procedure: s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of N-Boc heterocycle(1.0-1.95 mmol, 1.0 eq.) and diamine (1.3 eq.) in Et2O (3.5-10.5 mL) at -78 C under Ar. The resultingsolution was stirred at -78 C for 1 h. Then, the electrophile (2.0 eq.) was added dropwise, as a solutionin Et2O (1 mL) if necessary. The reaction mixture was allowed to warm slowly to rt overnight. Then,saturated NH4Cl(aq) (10 mL), 20% NaOH(aq) (10 mL), and Et2O (10 mL) were added, and the two layerswere separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layerswere dried (MgSO4), filtered, and evaporated under reduced pressure to give the crude product
With oxone; trifluoroacetic acid;Acidic conditions;
Compound 4- A is treated with Oxone (i.e., potassium peroxymonosulfate) and deprotected using acidic conditions ( e.g ., TFA). The deprotected product 4-B is then coupled with aldehyde 4-C via a reductive amination to afford the desired product 4-D. The compound 4-D is then deprotected to afford compound 4-1 as indicated above.In parallel, compound 4-F is reacted with 4-G using the conditions indicated above. Compound 4-H is then reacted with compound 4-1 prepared as described above to afford the desired product, Compound 5. Purification using standard techniques (e.g., silica gel chromatography or prep-HPLC) as needed.
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