* 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: at 20℃; Molecular sieve Stage #2: at -10 - 20℃; for 16 h;
Preparation 63 Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A) To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 Å. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10° C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3*100 mL). The combined aqueous solution was cooled to 0° C., basified with sat. NaHCO3 and extracted with CHCl3 (3*100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30.
92%
Stage #1: at 20℃; molecular sieve 3Å Stage #2: at -10 - 20℃; for 16.5 h;
Example 34: Synthesis of N-((S)-l-{2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino}-butyl)-malonamic acid (Compound KC-4)Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
92%
Stage #1: at 20℃; Molecular sieve 3 Å Stage #2: With sodium tetrahydroborate In methanol at -10 - 20℃; for 16.5 h; Cooling with ice
Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
92%
Stage #1: at 20℃; Molecular sieve Stage #2: at -10 - 20℃; for 16.5 h;
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL), Benzaldehyde (4.7 g, 44.0 mmol)And molecular sieves 3 Å were added.After stirring overnight at ambient temperature, the mixture was cooled to about -10 ° C. (ice / salt bath) and treated in portions with NaBH 4 (9.1 g, 240.0 mmol) for 30 minutes. After all addition, the bathtub was removed and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was taken up in EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3 × 100 mL). The combined aqueous solution was cooled to 0 ° C., basified with saturated NaHCO 3 and extracted with CHCl 3 (3 × 100 mL). The combined organic layers were washed with brine (200 mL). After drying and filtering over MgSO 4, the solvent was evaporated under reduced pressure to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil.
51%
Stage #1: at 20℃; for 2 h; Stage #2: at 0 - 20℃;
Example 3Atert-butyl [2-(benzylamino)ethyl]carbamate; 2.0 g (18.4 mmol) benzaldehyde and 3.32 g (20.7 mmol) N-Boc-ethylendiamine are dissolved in 25 ml methanol. The mixture is stirred 2 h at rt before cooled to 00C and 3.57 g (94.2 mmol) sodium borohydride and water are added to generate a solution, which is stirred over night at rt. Solvents are removed in vacuo and the residue is dissolved in dichloromethane and washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC (water / acetonitrile) to afford 2.4 g (51percent of th.) of the title compound.HPLC (method 1): R, = 3.70 min; MS (ESIpos): m/z = 251 (M+H)+1H-NMR (400 MHz, DMSOd6): δ = 7.30 (m, 4H), 7.21 (m, IH), 6.72 (m, IH), 3.68 (s, 2H), 3.02 (m, 2H), 2.53 (m, 2H), 2.08 (bs, IH), 1.37 (s, 9H).
23%
Stage #1: With sodium tris(acetoxy)borohydride; magnesium sulfate; triethylamine In 1,2-dichloro-ethane at 20℃; for 16 h; Stage #2: With water; sodium hydrogencarbonate In 1,2-dichloro-ethane
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10percent) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23percent). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3.
Reference：
[1] Patent: US2011/262355, 2011, A1, . Location in patent: Page/Page column 135
[2] Patent: WO2011/133149, 2011, A1, . Location in patent: Page/Page column 297-298
[3] Patent: WO2011/133150, 2011, A1, . Location in patent: Page/Page column 299-300
[4] Patent: JP2016/41698, 2016, A, . Location in patent: Paragraph 0364; 0375
[5] Chemical Communications, 2016, vol. 52, # 63, p. 9837 - 9840
[6] Journal of Medicinal Chemistry, 2005, vol. 48, # 22, p. 7024 - 7039
[7] Patent: WO2007/17092, 2007, A1, . Location in patent: Page/Page column 22
[8] Patent: US2010/41748, 2010, A1, . Location in patent: Page/Page column 120
[9] Journal of Organic Chemistry, 1997, vol. 62, # 2, p. 411 - 416
[10] Organic Letters, 2014, vol. 16, # 24, p. 6366 - 6369
[11] Synthesis (Germany), 2015, vol. 47, # 16, p. 2391 - 2406
[12] Patent: US2016/168138, 2016, A1, . Location in patent: Paragraph 0120-0121
[13] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 8696 - 8709
4
[ 58632-95-4 ]
[ 4152-09-4 ]
[ 174799-52-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 20℃; for 72 h;
55 (15.861 g, 105.58 mmol) was dissolved in eOH at rt. To this stirred solution was added 2-(tert- butoxycarbonyloxyimino)-2-phenylacetonitrile (26.00g, 105.58 mmol, 1 eq), in portions, allowing dissolution before next addition. The resulting yellow solution was stirred at rt for 3 days (over weekend) before removal of all volatiles under reduced pressure. The crude residue was dissolved in EtOAc (300 mL) before washing with aq. 1 NaOH (2 x 100 mL). The combined aqueous layers were again washed with EtOAc (100 mL). Combining and concentrating the organic portions gave 29.8g of crude product. This was further purified by FCC (eluent DCIWPE 1 :1 to load column, continued until impurities wash off, then 100percent DC , followed eOH/DC 1 :1 0). This gave 25.3g (96percent) of pale yellow oil.
Preparation 63 Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A) To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3*100 mL). The combined aqueous solution was cooled to 0 C., basified with sat. NaHCO3 and extracted with CHCl3 (3*100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30.
92%
Example 34: Synthesis of N-((S)-l-{2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino}-butyl)-malonamic acid (Compound KC-4)Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
92%
Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
92%
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL), Benzaldehyde (4.7 g, 44.0 mmol)And molecular sieves 3 A were added.After stirring overnight at ambient temperature, the mixture was cooled to about -10 C. (ice / salt bath) and treated in portions with NaBH 4 (9.1 g, 240.0 mmol) for 30 minutes. After all addition, the bathtub was removed and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was taken up in EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3 × 100 mL). The combined aqueous solution was cooled to 0 C., basified with saturated NaHCO 3 and extracted with CHCl 3 (3 × 100 mL). The combined organic layers were washed with brine (200 mL). After drying and filtering over MgSO 4, the solvent was evaporated under reduced pressure to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil.
51%
Example 3Atert-butyl [2-(benzylamino)ethyl]carbamate; 2.0 g (18.4 mmol) benzaldehyde and 3.32 g (20.7 mmol) N-Boc-ethylendiamine are dissolved in 25 ml methanol. The mixture is stirred 2 h at rt before cooled to 00C and 3.57 g (94.2 mmol) sodium borohydride and water are added to generate a solution, which is stirred over night at rt. Solvents are removed in vacuo and the residue is dissolved in dichloromethane and washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC (water / acetonitrile) to afford 2.4 g (51% of th.) of the title compound.HPLC (method 1): R, = 3.70 min; MS (ESIpos): m/z = 251 (M+H)+1H-NMR (400 MHz, DMSOd6): delta = 7.30 (m, 4H), 7.21 (m, IH), 6.72 (m, IH), 3.68 (s, 2H), 3.02 (m, 2H), 2.53 (m, 2H), 2.08 (bs, IH), 1.37 (s, 9H).
23%
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10%) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3.
Benzaldehyde (2.30 mL, 22.6 mmol) was added dropwise to a stirredsuspension of N-Boc-ethylenediamine (3.29 g, 20.5 mmol) and 4A MS(3.0 g) in CH2Cl2 (30 mL) at r.t. under N2. The resulting solution wasstirred at r.t. for 16 h, filtered through Celite, washed with CH2Cl2 (50mL), and concentrated under reduced pressure. The residue was takenup in MeOH (30 mL) and cooled to 0 C. NaBH4 (1.55 g, 41.1 mmol)was added portionwise over 10 min and the resulting solution wasallowed to warm to r.t. and stirred at r.t. for 2 h, then concentratedunder reduced pressure. H2O (20 mL), aq 1 M HCl (20 mL) and EtOAc(30 mL) were added and the layers were separated. The aqueous layerwas extracted with EtOAc (2 × 20 mL), then basified with aq 2 MNaOH (20 mL) and extracted with EtOAc (3 × 20 mL). The combinedorganic layers were dried (MgSO4) and evaporated under reducedpressure to give the crude secondary amine 7 (3.91 g, 76%) as a paleyellow oil that was used without further purification.
With methanol; sodium tetrahydroborate; sodium sulfate; at 0 - 20℃; for 4.5h;
Tert-butyl 2-aminoethylcarbamate (100 g, 0.625 moles) and methanol (500 ml) were charged into round bottom flask at room temperature and stirred to get pale yellow colored clear solution. Reaction mixture was cooled to 0 C.-10 C. and sodium sulphate (25 g, 0.187 moles) was added to the reaction mixture. Benzaldehyde (53 g, 0.5 moles) was added to the reaction mixture portion wise over a period of 20-30 min at 0 C.-10 C. and stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0 C.-10 C. then sodium borohydride was added portion wise over a period of 20-30 min at the same temperature and stirred at RT for 4 h. After completion of the reaction, the reaction mixture was cooled to 0 C.-10 C., quenched with 30% Citric acid aqueous solution (300 ml) and stirred for 20-30 min at room temperature. The reaction mixture was concentrated under reduced pressure at 40-45 C. to obtain pale yellow turbid solution, diluted with ethyl acetate (250 ml) and stirred for 30 min at room temperature. Both aqueous and organic layers were separated and aqueous layer was again extracted with ethyl acetate (250 ml). The aqueous layer was basified with saturated sodium bicarbonate solution and again extracted with ethyl acetate (2*300 ml). The organic extracts were combined, washed with brine solution (200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure at 45-50 C. to obtain tert-butyl (2-(benzylamino)ethyl)carbamate (Formula II, 110 g, yield 70.69%, HPLC purity of 93.38%) as a pale yellow color liquid.
Starting from commercially available, literature or readily available protected amino acids. Amino acid 17.2 is treated with benzyl amine and a coupling reagent such as HATU, to give 17.3. Compound 17.3 is reduced by a reducing reagent such as LAH to give amine 17.4. 17.4 is treated with acid to afford diamine 17.5, which follow by condensation with an oxalic acid derivative give the dioxopiperazine 17.6. Treatment of 17.6 with NaH and alkyl halide gives compound 17.7. Removal of benzyl group by hydrogenation to give 17.8, which is [ALKYLATED] with an a-halo alkyl ester to give compound 17.9. Hydrolysis of 17.9 affords acid [17.] 1.
With lithium aluminium tetrahydride;
This example describes the synthesis of compounds of the formula wherein RI, RJ, and RL are each independently substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 12 and the procedure below. Amino acid 12.2 is treated with benzyl amine and a coupling reagent such as HATU, to give 12.3. Compound 12.3 is reduced by a reducing reagent such as LAH to give amine 12.4. Compound 12.4 is treated with acid to afford diamine 12.5, which follow by condensation with an oxalic acid derivative gives the dioxopiperazine 12.6. Treatment of 12.6 with NaH and alkyl halide gives compound 12.7. Removal of benzyl group by hydrogenation to give 12.8, which is alkylated with an a-halo alkyl ester to give compound 12.9. Hydrolysis of 12.9 affords acid 12.1.
Starting from commercially available, literature or readily available protected amino acids. Amino acid 17.2 is treated with benzyl amine and a coupling reagent such as HATU, to give 17.3. Compound 17.3 is reduced by a reducing reagent such as LAH to give amine 17.4. 17.4 is treated with acid to afford diamine 17.5, which follow by condensation with an oxalic acid derivative give the dioxopiperazine 17.6. Treatment of 17.6 with NaH and alkyl halide gives compound 17.7. Removal of benzyl group by hydrogenation to give 17.8, which is [ALKYLATED] with an a-halo alkyl ester to give compound 17.9. Hydrolysis of 17.9 affords acid [17.] 1.
With trifluoroacetic acid; In dichloromethane; at 20℃;
General procedure: To a stirred solution of compounds 11, 12 in acetonitrile was added potassium carbonate and benzyl bromides 10a, b. The mixture was refluxed for 3h, cooled to room temperature and concentrated. The residue was treated with EtOAc, washed with water and saturated brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel column (DCM: MeOH=50: 1) to yield oils. To a solution of above oils in DCM was added TFA at room temperature. The mixture was concentrated to afford the crude compounds 13a-b, 14a-b which were not further purified and used directly for the next step.
With sodium tetrahydroborate; benzaldehyde;molecular sieve; In methanol; ethyl acetate;
Preparation 63 Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A) To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3*100 mL). The combined aqueous solution was cooled to 0 C., basified with sat. NaHCO3 and extracted with CHCl3 (3*100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30.
With triethylamine; In chloroform; at 5 - 20℃; for 16h;Sealed tube;
Preparation 64 Synthesis of tert-butyl 2-(N-benzyl-N-methylamino)ethylcarbamate (B) To a cooled (~5 C.) solution of compound A (6.2 g, 25.0 mmol) and TEA (3.0 g, 29.7 mmol, 4.13 mL) in chloroform (50 mL) was added iodomethane (4.2 g, 29.7 mmol, 1.85 mL). The pressure tube was sealed, and the mixture stirred at ambient temperature for 20 h. The mixture was then precipitated with ether (300 mL); the white solid was filtered off and washed with ether (50 mL). The filtrate was concentrated and the residual yellow oil (5.2 g) was purified by silica gel column chromatography (2-10% MeOH gradient in DCM) to give compound B (3.3 g, 12.5 mmol, 50%) as a colorless oil. TLC Rf (DCM/MeOH 9:1): 0.55. LC-MS [M+H] 264.3 (C15H24N2O2+H, calc: 264.4).
50%
With triethylamine; In chloroform; at 5 - 20℃; for 20h;
Preparation 64: Synthesis of tert-butyl 2-(N-benzyl-N-methylamino)ethylcarbamate (B)To a cooled (~5 C) solution of compound A (6.2 g, 25.0 mmol) and TEA (3.0 g, 29.7 mmol, 4.13 mL) in chloroform (50 mL) was added iodomethane (4.2 g, 29.7 mmol, 1.85 mL). The pressure tube was sealed, and the mixture stirred at ambient temperature for 20 h. The mixture was then precipitated with ether (300 mL); the white solid was filtered off and washed with ether (50 mL). The filtrate was concentrated and the residual yellow oil (5.2 g) was purified by silica gel column chromatography (2-10% MeOH gradient in DCM) to give compound B (3.3 g, 12.5 mmol, 50%) as a colorless oil. TLC Rf (DCM/MeOH 9:1): 0.55. LC-MS [M+H] 264.3 (C15H24N2O2 +H, calc: 264.4).
50%
With triethylamine; In chloroform; at 5 - 20℃; for 20h;Sealed tube;
Preparation 64: Synthesis of tert-butyl 2-(N-benzyl-N-methylamino)ethylcarbamate (B)To a cooled (~5 C) solution of compound A (6.2 g, 25.0 mmol) and TEA (3.0 g, 29.7 mmol, 4.13 mL) in chloroform (50 mL) was added iodomethane (4.2 g, 29.7 mmol, 1.85 mL). The pressure tube was sealed, and the mixture stirred at ambient temperature for 20 h. The mixture was then precipitated with ether (300 mL); the white solid was filtered off and washed with ether (50 mL). The filtrate was concentrated and the residual yellow oil (5.2 g) was purified by silica gel column chromatography (2-10% MeOH gradient in DCM) to give compound B (3.3 g, 12.5 mmol, 50%) as a colorless oil. TLC Rf (DCM/MeOH 9:1): 0.55. LC-MS [M+H] 264.3 (C15H24N2O2 +H, calc: 264.4).
50%
With triethylamine; In chloroform; at 5 - 20℃; for 20h;
Chloroform (50 mL)Compound A (6.2 g, 25.0 mmol)And iodomethane (4.2 g, 29.7 mmol, 1.85 mL) was added to a cooled (~ 5 C) solution of TEA (3.0 g, 29.7 mmol, 4.13 mL). The pressure tube was sealed and the mixture was stirred at ambient temperature for 20 hours. The mixture was then precipitated with ether (300 mL); the white solid was filtered off and washed with ether (50 mL). The filtrate was added toConcentrate and purify the residual yellow oil (5.2 g) by silica gel column chromatography (2-10% MeOH gradient in DCM) to give compound B (3.3 g, 12.5 mmol, 50%).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 72h;
Example 16-1; (1); To a solution of Compound 1 (57.3 mg) and Compound 2 (95.9 mg) in DMF (2 ml) were added HOBt (37.7 mg) and WSC (69.6 mg) at room temperature, and the mixture was stirred for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extracted layer was washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (eluent chloroform-methanol 100:0 to 85:15 gradient) to give Compound 3 (110.6 mg) as a colorless oily substance.MS (APCI) 452 [M+H]+
55 (15.861 g, 105.58 mmol) was dissolved in eOH at rt. To this stirred solution was added 2-(tert- butoxycarbonyloxyimino)-2-phenylacetonitrile (26.00g, 105.58 mmol, 1 eq), in portions, allowing dissolution before next addition. The resulting yellow solution was stirred at rt for 3 days (over weekend) before removal of all volatiles under reduced pressure. The crude residue was dissolved in EtOAc (300 mL) before washing with aq. 1 NaOH (2 x 100 mL). The combined aqueous layers were again washed with EtOAc (100 mL). Combining and concentrating the organic portions gave 29.8g of crude product. This was further purified by FCC (eluent DCIWPE 1 :1 to load column, continued until impurities wash off, then 100% DC , followed eOH/DC 1 :1 0). This gave 25.3g (96%) of pale yellow oil.
In ethanol; at 100℃; under 12929.0 Torr; for 0.5h;MW reactor;
41 c (5.00g, 17.96 mmol) and 56 (4.497g, 17.96 mmol, 1 eq) were dissolved in EtOH (30 mL) and a few drops of water added, before splitting the mixture into 2 x 30 mL W vessels. Each mixture was heated at 100 C for 30 mins in the MW reactor (dynamic program with maximum pressure 250 psi, maximum power 300W). Concentration of the reaction mixture gave approximately 10 g of crude residue. This was purified by FCC (eluent PE/DCM 1 :1 to prime/load the column, with the gradient increasing to 100% DCM over 5CV, 1 00% DCM for a further 3 CV and then raise to DCM/MeOH 99:1 over 1 CV, then to 95:5 over 3 CV, holding at this concentration to elute the desired product). This gave 7.30 (77%) g of white crystalline solid.
With sodium tris(acetoxy)borohydride; In dichloromethane; at -78℃;Molecular sieve;
Representative experimental for the synthesis of enantioenriched C2-functionalized orthogonally N,N'-protected piperazines: To a solution of aldehyde (1 mmol, 1 equiv) and (2R,5R)-2,5-diphenylpyrrolidine (22.3 mg, 0.1 mmol, 0.1 equiv) in DCM (2.0 mL) was added N-chlorosuccinimide (173 mg, 1.3 mmol, 1.3 equiv) at 0 C. The reaction was kept at 0 C for 1 h at which point it was allowed to warm to ambient temperature. It was then stirred until the aldehyde was completely consumed as determined by 1H NMR spectroscopy of the reaction mixture. Pentane was added to the reaction mixture at -78 C and the precipitated NCS, succinimide, and catalyst were filtered off. After removal of the solvent at 0 C, the filtration process was repeated one time. The crude oil was redissolved in DCM (3 mL) and 4 A molecular sieves (500 mg) were added. The reaction was cooled to -78 C and a solution of amine (1.5 mmol, 1.5 equiv) in DCM (2 mL) was added followed by the addition of NaBH(OAc)3 (339 mg, 1.6 mmol, 1.6 equiv). The reaction vessel was purged and left to stir at -78 C for greater than 16 h at which time it was filtered through a pad of celite eluting with ethyl acetate. It was extracted with ethyl acetate and washed with saturated NaHCO3 and brine, and the organic layer was dried over MgSO4 followed by concentration in vacuo resulting in a crude oil, which was then redissolved in DMF (50 mL). The solution was cooled to -20 C followed by the addition of KOtBu (560 mg, 5 mmol, 5 equiv). It was then stirred until the beta-chlorodiamine was completely consumed as determined by thin layer chromatography. The reaction was extracted with diethyl ether (3 × ) and washed with brine. The crude oil was concentrated and purified by flash column chromatography (9:1 Hexanes/Ethyl Acetate) to afford the product. Enantiomeric Excess was determined via chiral SFC analysis.The product was prepared according to the above description and was purified by silica chromatography (9:1 Hexanes/EtOAc) to afford the product as a clear oil (208 mg, 50%).
With sodium tris(acetoxy)borohydride; In dichloromethane; at -78℃;Molecular sieve;
Representative experimental for the synthesis of enantioenriched C2-functionalized orthogonally N,N'-protected piperazines: To a solution of aldehyde (1 mmol, 1 equiv) and (2R,5R)-2,5-diphenylpyrrolidine (22.3 mg, 0.1 mmol, 0.1 equiv) in DCM (2.0 mL) was added N-chlorosuccinimide (173 mg, 1.3 mmol, 1.3 equiv) at 0 C. The reaction was kept at 0 C for 1 h at which point it was allowed to warm to ambient temperature. It was then stirred until the aldehyde was completely consumed as determined by 1H NMR spectroscopy of the reaction mixture. Pentane was added to the reaction mixture at -78 C and the precipitated NCS, succinimide, and catalyst were filtered off. After removal of the solvent at 0 C, the filtration process was repeated one time. The crude oil was redissolved in DCM (3 mL) and 4 A molecular sieves (500 mg) were added. The reaction was cooled to -78 C and a solution of amine (1.5 mmol, 1.5 equiv) in DCM (2 mL) was added followed by the addition of NaBH(OAc)3 (339 mg, 1.6 mmol, 1.6 equiv). The reaction vessel was purged and left to stir at -78 C for greater than 16 h at which time it was filtered through a pad of celite eluting with ethyl acetate. It was extracted with ethyl acetate and washed with saturated NaHCO3 and brine, and the organic layer was dried over MgSO4 followed by concentration in vacuo resulting in a crude oil, which was then redissolved in DMF (50 mL). The solution was cooled to -20 C followed by the addition of KOtBu (560 mg, 5 mmol, 5 equiv). It was then stirred until the beta-chlorodiamine was completely consumed as determined by thin layer chromatography. The reaction was extracted with diethyl ether (3 × ) and washed with brine. The crude oil was concentrated and purified by flash column chromatography (9:1 Hexanes/Ethyl Acetate) to afford the product. Enantiomeric Excess was determined via chiral SFC analysis.The product was prepared according to the above description and was purified by silica chromatography (9:1 Hexanes/EtOAc) to afford the product as a clear oil (208 mg, 50%).
With sodium tris(acetoxy)borohydride; In dichloromethane; at -78℃;Molecular sieve;
Representative experimental for the synthesis of enantioenriched C2-functionalized orthogonally N,N'-protected piperazines: To a solution of aldehyde (1 mmol, 1 equiv) and (2R,5R)-2,5-diphenylpyrrolidine (22.3 mg, 0.1 mmol, 0.1 equiv) in DCM (2.0 mL) was added N-chlorosuccinimide (173 mg, 1.3 mmol, 1.3 equiv) at 0 C. The reaction was kept at 0 C for 1 h at which point it was allowed to warm to ambient temperature. It was then stirred until the aldehyde was completely consumed as determined by 1H NMR spectroscopy of the reaction mixture. Pentane was added to the reaction mixture at -78 C and the precipitated NCS, succinimide, and catalyst were filtered off. After removal of the solvent at 0 C, the filtration process was repeated one time. The crude oil was redissolved in DCM (3 mL) and 4 A molecular sieves (500 mg) were added. The reaction was cooled to -78 C and a solution of amine (1.5 mmol, 1.5 equiv) in DCM (2 mL) was added followed by the addition of NaBH(OAc)3 (339 mg, 1.6 mmol, 1.6 equiv). The reaction vessel was purged and left to stir at -78 C for greater than 16 h at which time it was filtered through a pad of celite eluting with ethyl acetate. It was extracted with ethyl acetate and washed with saturated NaHCO3 and brine, and the organic layer was dried over MgSO4 followed by concentration in vacuo resulting in a crude oil, which was then redissolved in DMF (50 mL). The solution was cooled to -20 C followed by the addition of KOtBu (560 mg, 5 mmol, 5 equiv). It was then stirred until the beta-chlorodiamine was completely consumed as determined by thin layer chromatography. The reaction was extracted with diethyl ether (3 × ) and washed with brine. The crude oil was concentrated and purified by flash column chromatography (9:1 Hexanes/Ethyl Acetate) to afford the product. Enantiomeric Excess was determined via chiral SFC analysis.The product was prepared according to the above description and was purified by silica chromatography (9:1 Hexanes/EtOAc) to afford the product as a clear oil (208 mg, 50%).
With sodium tris(acetoxy)borohydride; In dichloromethane; at -78℃;Molecular sieve;
Representative experimental for the synthesis of enantioenriched C2-functionalized orthogonally N,N'-protected piperazines: To a solution of aldehyde (1 mmol, 1 equiv) and (2R,5R)-2,5-diphenylpyrrolidine (22.3 mg, 0.1 mmol, 0.1 equiv) in DCM (2.0 mL) was added N-chlorosuccinimide (173 mg, 1.3 mmol, 1.3 equiv) at 0 C. The reaction was kept at 0 C for 1 h at which point it was allowed to warm to ambient temperature. It was then stirred until the aldehyde was completely consumed as determined by 1H NMR spectroscopy of the reaction mixture. Pentane was added to the reaction mixture at -78 C and the precipitated NCS, succinimide, and catalyst were filtered off. After removal of the solvent at 0 C, the filtration process was repeated one time. The crude oil was redissolved in DCM (3 mL) and 4 A molecular sieves (500 mg) were added. The reaction was cooled to -78 C and a solution of amine (1.5 mmol, 1.5 equiv) in DCM (2 mL) was added followed by the addition of NaBH(OAc)3 (339 mg, 1.6 mmol, 1.6 equiv). The reaction vessel was purged and left to stir at -78 C for greater than 16 h at which time it was filtered through a pad of celite eluting with ethyl acetate. It was extracted with ethyl acetate and washed with saturated NaHCO3 and brine, and the organic layer was dried over MgSO4 followed by concentration in vacuo resulting in a crude oil, which was then redissolved in DMF (50 mL). The solution was cooled to -20 C followed by the addition of KOtBu (560 mg, 5 mmol, 5 equiv). It was then stirred until the beta-chlorodiamine was completely consumed as determined by thin layer chromatography. The reaction was extracted with diethyl ether (3 × ) and washed with brine. The crude oil was concentrated and purified by flash column chromatography (9:1 Hexanes/Ethyl Acetate) to afford the product. Enantiomeric Excess was determined via chiral SFC analysis.The product was prepared according to the above description and was purified by silica chromatography (9:1 Hexanes/EtOAc) to afford the product as a clear oil (208 mg, 50%).
tert-butyl N-{2-[benzyl(3-oxobutyl)amino]ethyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.33 g
In ethanol; at 20℃; for 2h;Inert atmosphere;
The crude secondary amine 7 was dissolved in EtOH (30 mL) andmethyl vinyl ketone (2.51 mL, 31.0 mmol) was added dropwise underN2. The resulting solution was stirred at r.t. for 2 h and concentratedunder reduced pressure to give the crude product, which was purifiedby column chromatography (SiO2, 60:40 to 40:60 hexane-EtOAc) togive the amino ketone 8 (4.33 g, 87%, 66% over 2 steps) as a pale yellowoil; Rf = 0.25 (50:50 PE-EtOAc). IR (ATR): 3367, 2975, 2931, 2813, 1702, 1495, 1452, 1390, 1363, 1246,1165, 1049, 964, 734, 698 cm-1.1H NMR (500 MHz, CDCl3): delta = 7.35-7.30 (m, 2 H, C6H5), 7.30-7.24 (m,3 H, C6H5), 4.95 (br s, 1 H, NH), 3.58 (s, 2 H, CH2Ph), 3.20 (app d, J = 5.5Hz, 2 H, 1?-CH2), 2.80 (t, J = 6.9 Hz, 2 H, 1-CH2), 2.60 (t, J = 6.9 Hz, 2 H,2-CH2), 2.55 (t, J = 5.5 Hz, 2 H, 2?-CH2), 2.10 (s, 3 H, 4-CH3), 1.46 (s, 9 H,t-C4H9).13C NMR (126 MHz, CDCl3): delta = 208.1, 156.0, 138.9, 128.8, 128.3,127.1, 78.9, 58.6, 53.3, 48.5, 41.5, 38.1, 30.0, 28.4.HRMS (ESI): m/z [M + H]+ calcd for C18H29N2O3: 321.2178; found:321.2187, 2.8 ppm error.
30 g
Tert-butyl(2-(benzylamino)ethyl)carbamate (Formula II, 50 g, 0.200 moles), 1,8-Diazabicycloundec-7-ene (61.12 ml, 0.401 moles) and DMF (300 ml) were charged in round bottom flask at RT and stirred to get heterogeneous solution. The reaction mixture was cooled to 0-5 C. and methyl vinyl ketone (75.3 ml, 0.903 moles) was added to the reaction mixture slowly over a period of 30 min. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to 0-5 C. and diluted with water (500 ml). The aqueous solution was extracted with ethyl acetate (250 ml*2). The organic layer was washed with 1N HCL (200 ml). The pH of aqueous layer was adjusted to 8 with saturated NaHCO3 solution (200 ml) and extracted with ethyl acetate (250 ml*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure at 45-50 C. to give tert-butyl(2-(benzyl(3-oxobutyl)amino)ethyl)carbamate (Formula III, 30 g, yield 46.87%) as a dark brown color liquid.
General procedure: To a 40 mL reaction vessel was added commercial tert-butyl (2-aminoethyl)carbamate (159 mg, 1 .00 mmol), MeOH (9.5 mL) and AcOH (0.50 mL). To the resulting solution was then added 3-fluorobenzaldehyde (250 mg, 2.00 mmol) and then after approximately 10 minutes was added sodium cyanoborohydride (250 mg, 2.00 mmol) portion-wise over 15 minutes. After8 hrs the reaction was partially concentrated to a volume of 5 mL and then directly purified by reverse phase chromatography using a 10 to 90 % water/acetonitrile gradient (0.05 % AcOH modified). The resulting product eluent was lyopholized to dryness to give 1-38. 1H NMR (400 MHz, Acetonitrile-D3) O 7.31-7.29 (m, 1H), 7.17-7.08(m, 2H), 6.88 (d, J=8.0 Hz, 1H), 3.98 (br s, 2H), 3.48 (t, J=7.8 Hz, 2H), 2.49 (t, J=7.8 Hz, 2H), 1.44 (s, 9H). MS (m/z) (M÷H), 269.1.
70
[ 57260-73-8 ]
[ 100-39-0 ]
[ 174799-52-1 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; for 3h;Reflux;
General procedure: To a stirred solution of compounds 11, 12 in acetonitrile was added potassium carbonate and benzyl bromides 10a, b. The mixture was refluxed for 3h, cooled to room temperature and concentrated. The residue was treated with EtOAc, washed with water and saturated brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel column (DCM: MeOH=50: 1) to yield oils. To a solution of above oils in DCM was added TFA at room temperature. The mixture was concentrated to afford the crude compounds 13a-b, 14a-b which were not further purified and used directly for the next step.
1-cyano-3-(isoquinolin-6-yl)-2-phenylisourea[ No CAS ]
[ 174799-52-1 ]
C25H28N6O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 18h;
86.63 mg diphenyl cyanocarbonimidate, 52.1 mg isoquinolin-6-amine, and 6 ml THF were added to a reaction bottle with thermal reflux for 3.5 hrs. After removing THF by vacuum, the residue was added to 10 ml EA. The precipitated solid was filtered to obtain 32.9 mg 1-cyano-3-(isoquinolin-6-yl)-2-phenylisourea. The intermediate was reacted with equivalent tert-butyl-2-(benzylamino)ethylcarbamate and 20 mg of DIPEA in 5 ml DMF at 110 C. for 18 hrs. After cooling, 1N NaOH was added and extracted twice with EA. After the combined EA layer was dried and concentrated by Na2SO4, 26.4 mg intermediate product was eluted out by a SiO2 column (EA/Hexane 4:1). The intermediate was added to 1.5 ml 6N HCl at room temperature with stirring overnight. After the reaction solution was evaporated under reduced pressure, 2 ml acetone/methanol (10:1) was added. The precipitate was filtered and washed with acetone, and then the solid was taken and evaporated in vacuum to give 18.7 mg of product.
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