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Chemical Structure| 1948273-00-4 Chemical Structure| 1948273-00-4

Structure of 1948273-00-4

Chemical Structure| 1948273-00-4

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Product Details of [ 1948273-00-4 ]

CAS No. :1948273-00-4
Formula : C12H14N2S
M.W : 218.32
SMILES Code : C[C@H](N)C1=CC=C(C2=C(C)N=CS2)C=C1
English Name :(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine
MDL No. :MFCD30803692

Safety of [ 1948273-00-4 ]

Application In Synthesis of [ 1948273-00-4 ]

* 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.

  • Downstream synthetic route of [ 1948273-00-4 ]

[ 1948273-00-4 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 1948273-00-4 ]
  • [ 1997302-16-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 2: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dimethyl sulfoxide / 24 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 2.2: 24 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 16 h / 20 °C 2: dichloromethane / 18 h / 20 °C 3: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C 2: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 12 h / 20 °C 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 30 min / 20 °C 2: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 30 min / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 16 °C 2: hydrogenchloride / 1,4-dioxane / 1 h / 16 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 16 - 20 °C

  • 2
  • [ 1948273-00-4 ]
  • [ 13726-69-7 ]
  • [ 2313528-38-8 ]
YieldReaction ConditionsOperation in experiment
70% With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 20℃; for 24h;
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;
10.98 g With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere; 1 [0191] HATU (14.51 g, 38.2 mmol, 1.2 eq) was added to a solution of the intermediate (0324) (55) obtained as described above (6.95 g, 31.8 mmol, 1.0 eq), (2S,4R)-l-(fert- butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carboxylic acid (7.36 g, 31.8 mmol, 1.0 eq), and DIPEA (11.08 mL, 63.6 mmol, 2.0 eq) in DMF (36 mL) at 0 °C under N2. The mixture was stirred at ambient temperature for 12 h when TLC showed that the reaction was complete. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (150mL>4. The organic solution was filtered and concentrated and the residue was purified by silica gel flash column chromatography with hexane :EtO Ac (100:1-1:100), then DCM:MeOH (10:1) to afford the intermediate (56) as white solid (10.98 g, 80% yield). 'H NMR (CD3OD, 400 MHz) d (ppm) 8.84 (s, 1H), 7.43-7.37 (m, 4H), 5.11-5.07 (m, 1H), 4.44-4.37 (m, 2H), 3.60-3.46 (m, 2H), 2.44 (s, 3H), 2.27-2.22 (m, 1H), 1.98-1.91 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 1.46 (s, 9H); UPLC-MS (ESL) calc, for C22H30N3O4S [M+l]+: 432.20, found 432.20.
11 g With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; 3 The third step Synthesis of tert-butyl (2S,4R)-4-hydroxyl-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)formyl)pyrroline-1-carboxylate (TV-6) At room temperature, to compound TV-4 (10.0g, 30.09mmol, 1.0eq.) and TV-5 (6.96g, 30.09mmol, 1.0eq.)Triethylamine (16.02mL, 90.27mmol, 3.0eq.) and HATU (17.15g, 45.13mmol, 1.5eq.) were added to a solution of DCM (500mL).The mixture was stirred at room temperature until the reaction was complete. Then concentrated, the residue was subjected to silica gel column chromatography to obtain the target compound TV-6 (11.0 g, 25.49 mmol, 84.7% yield).
6.8 g With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 20℃; D Step D: Add compounds N-Boc-trans-4-hydroxy-D-proline (4.2 g, 18.2 mmol), compounds INT-5-3 (7 g), 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.9 g, 18.2 mmol) and N,N-Diisopropylethylamine (11.7 g, 90.7 mmol) to tetrahydrofuran (100 ml) and stir at 20 degrees Celsius for 18 h. LCMS monitoring shows that raw materials are gone. The reaction solution was quenched with purified water (200 ml) and extracted with ethyl acetate (100 ml×3). The organic phase was combined and dried with anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain 6.8 g of compound INT-5-4.
52 g Stage #1: (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; Stage #2: (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine In N,N-dimethyl-formamide at 25℃;
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;
72.6 % With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; 4.1.19. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidine-1-carboxylate (P12) Compound P11 was synthesized using the reported procedure [35],was dissolved in 2 M HCl in EA (40 mL, 80 mmol), and the mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,and the residue was dried under vacuum to afford the intermediate,which was used in next step without further purification (2.45 g, 88.0%). HATU (6.90 g, 18.2 mmol, 1.2 equiv) was added to a solution of the intermediate obtained above (3.3 g, 15.1 mmol, 1.0 equiv), (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(3.49 g, 15.1 mmol, 1.0 equiv), and DIPEA (8.1 mL, 45.4 mmol, 3.0equiv) in DMF (30 mL) at 0 C under nitrogen. The mixture was stirred atambient temperature for 2 h. TLC showed that the reaction was complete.The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (150 mL × 2). The combined organic layer waswashed with brine (200 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 10:1) to afford the intermediate(P12) as white solid (4.02 g, 72.6 %).
72.6 % With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; 4.1.19. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidine-1-carboxylate (P12) Compound P11 was synthesized using the reported procedure [35],was dissolved in 2 M HCl in EA (40 mL, 80 mmol), and the mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,and the residue was dried under vacuum to afford the intermediate,which was used in next step without further purification (2.45 g, 88.0%). HATU (6.90 g, 18.2 mmol, 1.2 equiv) was added to a solution of the intermediate obtained above (3.3 g, 15.1 mmol, 1.0 equiv), (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(3.49 g, 15.1 mmol, 1.0 equiv), and DIPEA (8.1 mL, 45.4 mmol, 3.0equiv) in DMF (30 mL) at 0 C under nitrogen. The mixture was stirred atambient temperature for 2 h. TLC showed that the reaction was complete.The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (150 mL × 2). The combined organic layer waswashed with brine (200 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 10:1) to afford the intermediate(P12) as white solid (4.02 g, 72.6 %).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; Step 1tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl)pyrrolidine-1-carboxylate A mixture of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (2480.mg, 11.36 mmol) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2889.57 mg, 12.5 mmol), HATU (5183.19mg, 13.63mmol) and TEA (7.92mL, 56.8mmol) in DCM (25 mL) was stirred at 25 for 2 h. The mixture was diluted with water and extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give the title compound.
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; 47.1 Step 1: tert-Butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]-carbamoyl]pyrrolidine-1-carboxylate To a stirred solution of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (2.48g, 11.36 mmol, 1.00 eq.) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2.9 g, 12.5 mmol, 1.10 eq.) in DCM (25 mL) was added HATU (5.132 g, 13.63 mmol, 1.20 eq.) and triethylamine (7.92 mL, 56.8 mmol, 5.00 eq.), and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with water, extracted with DCM, and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel flash chromatography to afford the title compound.
22 g With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Step 1: Synthesis of compound M29-1 (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylamine (12.7 g), Boc-L-hydroxyproline (13.5 g) and HATU (23.2 g) were dissolved in DMF (100 mL), DIPEA (38.5 mL) was added, and the mixture was reacted at room temperature for 10 minutes. The reaction was monitored by LCMS until completion. EA (100 mL) and saturated brine (100 mL) were added to the reaction solution, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 22.0 g of a white solid, namely compound M29-1.
51 % With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 16℃; 6.d Synthesis of Int. 26 Into a 100 mL round-bottom flask were added (1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethanamine (3.3 g, 15.115 mmol, 1.2 equiv), (2S,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (2.91 g, 12.596 mmol, 1 equiv), DMF (30 mL), HATU (7.18 g, 18.894 mmol, 1.5 equiv), and DIEA (4.88 g, 37.788 mmol, 3 equiv) and the resulting mixture was stirred for 1 h at 16 °C. The reaction was quenched with water at 16 °C and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (1:1) to afford tert-butyl (2S,4R)-4-hydroxy-2-[(1S)-1- [4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-carboxylate (2.8 g, 51% yield) as a light yellow solid. LCMS: (ES, m/z): [M-H]- = 430 (LCMS condition: Column: Shim-pack Scepter C18-120; Mobile phase A: Water/5 mM NH4HCO3; Mobile phase B: Acetonitrile; Flow rate: 1.5 mL/min; RT: 0.801 min)
3.2 g Stage #1: (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide Cooling with ice; Stage #2: (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Step 3: (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.2g, 14.1mmol) and HATU (7.3g, 19.2mmol), DMF (100mL) were stirred in an ice bath for 20 minutes, then DIEA (13g, 102.5mmol), 2-b (2.8g, crude product) were added. The reaction solution was stirred overnight at room temperature, then water (50mL) was added, ethyl acetate was extracted, anhydrous sodium sulfate was dried, and silica gel column chromatography purified to obtain 2-c (3.2g, light yellow solid).
1.06 g With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 2h; Step 1. tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate Ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (2.7 g, 11 mmol) was added to a stirred solution of (1S)- 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine (2 g, 9.2 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.2 mmol) in DCM (20 mL). The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with DCM (100 mL), washed with water (50 mL x 2) and brine (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1.06 g, 2.5 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 432.2.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Synthesis of (2S,4R)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2 -carboxamide, 7. To a solution of 4 (2.00 g, 9.16 mmol, 1.0 eq), 5 (2.12 g, 9.16 mmol, 1.0 eq), HATU (5.22 g, 13.74 mmol, 1.5 eq) in DMF (50 mL) was added DIPEA (3.55 g, 27.48 mmol, 3.0 eq). The mixture was stirred for 30 minutes. The reaction was quenched by adding water. The mixture was extracted by ethyl acetate (80*2 mL) twice. Combined organic phases were washed by water twice. After dried by anhydrous Na2SO4and concentrated. The received residue was dissolved into DCM (40 mL), TFA (20 mL) was added, the mixture stirred for 30 minutes. After reaction, the solution was concentrated. The residue was purified by C-18 reversal column chromatography (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get target product 7 (1.6 g, 53%) as a slight yellow solid. ESI MS m/z: 332.13 [M+H]+.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h;
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 2h; 59.1 Step 1 : tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate A mixture of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (2480.mg, 11.3610 mmol) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2889.57 mg,12.5 mmol), HATU (5183.19mg, 13.63mmol) and TEA (7.92mL, 56.8mmol) in DCM (25mL) was stirred at 25 for 2 h. The mixture was diluted with water and extracted with DCM,and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash column chromatography to give the title compound.
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 2h; Step 1 : tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl)pyrrolidine-1-carboxylate A mixture of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (2480.mg, 11.36 mmol) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2889.57 mg,12.5 mmol), HATU (5183.19mg, 13.63mmol) and TEA (7.92mL, 56.8mmol) in DCM (25 mL) was stirred at 25 for 2 h. The mixture was diluted with water and extracted with DCM,and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give the title compound.
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 2h; 1 Step 1: tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl]pyrrolidine-1-carboxylate A mixture of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (2480.mg, 11.3610 mmol) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2889.57 mg,12.5 mmol), HATU (5183.19mg, 13.63mmol) and TEA (7.92mL, 56.8mmol) in DCM (25mL) was stirred at 25 for 2 h. The mixture was diluted with water and extracted with DCM,and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash column chromatography to give the title compound.
1.06 g With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 2h; 6.1 Step 1. tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5 yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate Ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (2.7 g, 11 mmol) was added to a stirred solution of (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine (2 g, 9.2 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.2 mmol) in DCM (20 mL). The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with DCM (100 mL), washed with water (50 mL x 2) and brine (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1.06 g, 2.5 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 432.2.

References: [1]Xu, Chenxi; Meng, Fanye; Park, Kwang-Su; Storey, Aaron J.; Gong, Weida; Tsai, Yi-Hsuan; Gibson, Elisa; Byrum, Stephanie D.; Li, Dongxu; Edmondson, Rick D.; Mackintosh, Samuel G.; Vedadi, Masoud; Cai, Ling; Tackett, Alan J.; Kaniskan, H. Ümit; Jin, Jian; Wang, Gang Greg [Cell Chemical Biology, 2022, vol. 29, # 3, p. 386 - 9,397].
[2]Hu, Jiantao; Hu, Biao; Wang, Mingliang; Xu, Fuming; Miao, Bukeyan; Yang, Chao-Yie; Wang, Mi; Liu, Zhaomin; Hayes, Daniel F.; Chinnaswamy, Krishnapriya; Delproposto, James; Stuckey, Jeanne; Wang, Shaomeng [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1420 - 1442].
[3]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1 Location in patent: Paragraph 0191.
[4]Current Patent Assignee: HINOVA PHARMACEUTICALS - WO2023/280237, 2023, A1 Location in patent: Page/Page column 52; 53.
[5]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1 Location in patent: Page/Page column 32-33.
[6]Current Patent Assignee: JINGRUI BIOPHARMA CO LTD - WO2023/185864, 2023, A1 Location in patent: Paragraph 0270; 0275; 0279.
[7]Wang, Xiaohua; Xin, Lilan; Deng, Xiaofei; Dong, Chune; Hu, Guoyuan; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2024, vol. 267].
[8]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[9]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[10]Xin, Lilan; Wang, Chao; Cheng, Yan; Wang, Hongli; Guo, Xinyi; Deng, Xiaofei; Deng, Xiangping; Xie, Baohua; Hu, Hankun; Min, Chang; Dong, Chune; Zhou, Hai-Bing [Journal of Medicinal Chemistry, 2024, vol. 67, # 11, p. 8913 - 8931].
[11]Current Patent Assignee: NIKANG THERAPEUTICS - WO2024/102849, 2024, A1 Location in patent: Page/Page column 329.
[12]Current Patent Assignee: NIKANG THERAPEUTICS - WO2023/249970, 2023, A1 Location in patent: Page/Page column 235.
[13]Current Patent Assignee: BETTA PHARMACEUTICALS - WO2024/120424, 2024, A1 Location in patent: Page/Page column 57.
[14]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1 Location in patent: Page/Page column 37-38.
[15]Current Patent Assignee: SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY - WO2024/179529, 2024, A1 Location in patent: Page/Page column 60.
[16]Current Patent Assignee: FOGHORN THERAPEUTICS - WO2024/220946, 2024, A1 Location in patent: Page/Page column 156.
[17]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2024/64328, 2024, A1 Location in patent: Paragraph 0542-0544.
[18]Wang, Dandan; Wu, Yihe; Zhao, Yijin; Ma, Xiaoyu; Shi, Jiahao; Ni, Jian; Gao, Yang; Cai, Hongbing; Dong, Chune; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2026, vol. 302].
[19]Current Patent Assignee: NIKANG THERAPEUTICS - WO2025/235298, 2025, A1 Location in patent: Page/Page column 200.
[20]Current Patent Assignee: NIKANG THERAPEUTICS - WO2025/235261, 2025, A1 Location in patent: Page/Page column 214-215.
[21]Current Patent Assignee: NIKANG THERAPEUTICS - WO2025/235331, 2025, A1 Location in patent: Page/Page column 205.
[22]Current Patent Assignee: FOGHORN THERAPEUTICS - WO2025/222187, 2025, A1 Location in patent: Page/Page column 450-451.
  • 3
  • [ 1973408-97-7 ]
  • [ 1948273-00-4 ]
YieldReaction ConditionsOperation in experiment
42% With hydrogenchloride In water; ethyl acetate at 20℃; for 4h;
With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 12h;
With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 4h;
With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 12h; 1 [0191] HATU (14.51 g, 38.2 mmol, 1.2 eq) was added to a solution of the intermediate (0324) (55) obtained as described above (6.95 g, 31.8 mmol, 1.0 eq), (2S,4R)-l-(fert- butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carboxylic acid (7.36 g, 31.8 mmol, 1.0 eq), and DIPEA (11.08 mL, 63.6 mmol, 2.0 eq) in DMF (36 mL) at 0 °C under N2. The mixture was stirred at ambient temperature for 12 h when TLC showed that the reaction was complete. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (150mL>4. The organic solution was filtered and concentrated and the residue was purified by silica gel flash column chromatography with hexane :EtO Ac (100:1-1:100), then DCM:MeOH (10:1) to afford the intermediate (56) as white solid (10.98 g, 80% yield). 'H NMR (CD3OD, 400 MHz) d (ppm) 8.84 (s, 1H), 7.43-7.37 (m, 4H), 5.11-5.07 (m, 1H), 4.44-4.37 (m, 2H), 3.60-3.46 (m, 2H), 2.44 (s, 3H), 2.27-2.22 (m, 1H), 1.98-1.91 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 1.46 (s, 9H); UPLC-MS (ESL) calc, for C22H30N3O4S [M+l]+: 432.20, found 432.20.
With trifluoroacetic acid In dichloromethane at 20℃; for 8h;
With trifluoroacetic acid In dichloromethane at 20℃;
With trifluoroacetic acid at 20℃; Synthesis of VHL ligand VIII The synthetic route of VHL ligand VIII is shown in the following reaction formula: first, under alkaline conditions,Use di-tert-butyl dicarbonate (1.0 equiv.) to (S)-(-)-1-(4-bromophenyl)ethylamine I (1.2 equiv.)The amino group carries out Boc protection to obtain intermediate compound IV, then compound IV (1.0equiv.)and tetramethylthiazole (1.2equiv.) at 90°C by palladium acetate (0.3equiv.)The catalytic reaction produces intermediate V. After V was deprotected by TFA (1.1equiv.),Intermediate VI was obtained by amide condensation with Boc-Hyp-OH (1.0 equiv.) at room temperature. After VI was deprotected by TFA, intermediate VII was obtained by amide condensation with Boc-L-tert-Leu (1.05 equiv.) at room temperature. VII was deprotected by TFA (1.0 equiv.) to generate compound VIII.
With trifluoroacetic acid In dichloromethane at 20℃; 2 Second step synthesis of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl-1-amine (TV-4) Compound TV-3 (10.0g, 31.40mmol, 1.0eq.) and TFA (20.0mL, 261.36mmol, 8.3eq.)Stir in DCM (20 mL) until the reaction is complete. Concentration affords the trifluoroacetate salt of TV-4 (10.7 g, 31.40 mmol, crude, ca. 100%), which is used directly in the next step
With trifluoroacetic acid at 20℃; Synthesis of VHL ligand VIII The synthetic route of VHL ligand VIII is shown in the following reaction formula: first, under alkaline conditions,Use di-tert-butyl dicarbonate (1.0 equiv.) to (S)-(-)-1-(4-bromophenyl)ethylamine I (1.2 equiv.)The amino group carries out Boc protection to obtain intermediate compound IV, then compound IV (1.0equiv.)and tetramethylthiazole (1.2equiv.) at 90°C by palladium acetate (0.3equiv.)The catalytic reaction produces intermediate V. After V was deprotected by TFA (1.1equiv.),Intermediate VI was obtained by amide condensation with Boc-Hyp-OH (1.0 equiv.) at room temperature. After VI was deprotected by TFA, intermediate VII was obtained by amide condensation with Boc-L-tert-Leu (1.05 equiv.) at room temperature. VII was deprotected by TFA (1.0 equiv.) to generate compound VIII.
With hydrogenchloride In 1,4-dioxane; dichloromethane at 25℃; C Step C: Add 20 ml of 1,4-dioxane solution of hydrochloric acid to a mixed solution of compound INT-5-2 (5.8 g, 18.2 mmol) and dichloromethane (40 ml). Stir the reaction mixture at 25 degrees Celsius for 1 h. LCMS monitoring shows that raw materials are gone. Concentrate the reaction solution under reduced pressure, The result is 7 g of compound INT-5-3, which is used directly for the next step without purification.
58 g With hydrogenchloride In 1,4-dioxane; methanol at 25℃;
With trifluoroacetic acid In dichloromethane at 20℃;
88 % With hydrogenchloride In ethyl acetate at 20℃; 4.1.19. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidine-1-carboxylate (P12) Compound P11 was synthesized using the reported procedure [35],was dissolved in 2 M HCl in EA (40 mL, 80 mmol), and the mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,and the residue was dried under vacuum to afford the intermediate,which was used in next step without further purification (2.45 g, 88.0%). HATU (6.90 g, 18.2 mmol, 1.2 equiv) was added to a solution of the intermediate obtained above (3.3 g, 15.1 mmol, 1.0 equiv), (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(3.49 g, 15.1 mmol, 1.0 equiv), and DIPEA (8.1 mL, 45.4 mmol, 3.0equiv) in DMF (30 mL) at 0 C under nitrogen. The mixture was stirred atambient temperature for 2 h. TLC showed that the reaction was complete.The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (150 mL × 2). The combined organic layer waswashed with brine (200 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 10:1) to afford the intermediate(P12) as white solid (4.02 g, 72.6 %).
88 % With hydrogenchloride In ethyl acetate at 20℃; 4.1.19. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidine-1-carboxylate (P12) Compound P11 was synthesized using the reported procedure [35],was dissolved in 2 M HCl in EA (40 mL, 80 mmol), and the mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,and the residue was dried under vacuum to afford the intermediate,which was used in next step without further purification (2.45 g, 88.0%). HATU (6.90 g, 18.2 mmol, 1.2 equiv) was added to a solution of the intermediate obtained above (3.3 g, 15.1 mmol, 1.0 equiv), (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(3.49 g, 15.1 mmol, 1.0 equiv), and DIPEA (8.1 mL, 45.4 mmol, 3.0equiv) in DMF (30 mL) at 0 C under nitrogen. The mixture was stirred atambient temperature for 2 h. TLC showed that the reaction was complete.The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (150 mL × 2). The combined organic layer waswashed with brine (200 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 10:1) to afford the intermediate(P12) as white solid (4.02 g, 72.6 %).
93 % With hydrogenchloride In 1,4-dioxane at 16℃; 6.c; 9.h Synthesis of Int. 25 Into a 100 mL round-bottom flask were added tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl]carbamate (4.5 g, 14.131 mmol, 1 equiv), 1,4-dioxane (10 mL), and HCl in 1,4-dioxane (50 mL, 4 M) at 16 °C. The resulting mixture was stirred for 1 h at 16 °C. The resulting mixture was concentrated under reduced pressure to give 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethanamine (3.3 g, 93% yield) as a yellow solid. LCMS: (ES, m/z): [M+H-17]+ = 202 (LCMS condition: Column: Shim-pack Scepter C18-120; Mobile phase A: Water/5 mM NH4HCO3; Mobile phase B: Acetonitrile; Flow rate: 1.5 mL/min; RT: 0.634 min)
With hydrogenchloride In 1,4-dioxane; methanol at 0 - 20℃; Step 2: Dissolve 2-a (3.1g, 9.7mmol) in methanol (30mL), add HCl/dioxane solution (30mL, 4M) at 0 °C, raise the reaction solution to room temperature and stir for 2 hours. The reaction solution was concentrated to obtain 2-b (2.8g, light yellow, crude product).
With trifluoroacetic acid In dichloromethane at 20℃; for 1h;

References: [1]Dong, Guanyu; Chen, Mengfei; Jiang, Xiangyi; Shi, Jing; Meng, Xiangjiao; Zhan, Peng; Liu, Yuguo; Liu, Chuanfeng; Song, Yuning [Journal of Medicinal Chemistry, 2026, vol. 69, # 2, p. 982 - 1003].
[2]Hu, Jiantao; Hu, Biao; Wang, Mingliang; Xu, Fuming; Miao, Bukeyan; Yang, Chao-Yie; Wang, Mi; Liu, Zhaomin; Hayes, Daniel F.; Chinnaswamy, Krishnapriya; Delproposto, James; Stuckey, Jeanne; Wang, Shaomeng [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1420 - 1442].
[3]Wang, Mingliang; Lu, Jianfeng; Wang, Mi; Yang, Chao-Yie; Wang, Shaomeng [Journal of Medicinal Chemistry, 2020, vol. 63, # 14, p. 7510 - 7528].
[4]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1 Location in patent: Paragraph 0191.
[5]He, Shipeng; Gao, Fei; Ma, Junhui; Ma, Haoqian; Dong, Guoqiang; Sheng, Chunquan [Angewandte Chemie - International Edition, 2021, vol. 60, # 43, p. 23299 - 23305][Angew. Chem., 2021, vol. 133, # 43, p. 23487 - 23493].
[6]Keuler, Tim; König, Beate; Bückreiß, Nico; Kraft, Fabian B.; König, Philipp; Schäker-Hübner, Linda; Steinebach, Christian; Bendas, Gerd; Gütschow, Michael; Hansen, Finn K. [Chemical Communications, 2022, vol. 58, # 79, p. 11087 - 11090].
[7]Current Patent Assignee: WUHAN UNIVERSITY - CN115557965, 2023, A Location in patent: Paragraph 0054-0057.
[8]Current Patent Assignee: HINOVA PHARMACEUTICALS - WO2023/280237, 2023, A1 Location in patent: Page/Page column 52; 53.
[9]Current Patent Assignee: WUHAN UNIVERSITY - CN115557965, 2023, A Location in patent: Paragraph 0054-0057.
[10]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1 Location in patent: Page/Page column 32.
[11]Current Patent Assignee: JINGRUI BIOPHARMA CO LTD - WO2023/185864, 2023, A1 Location in patent: Paragraph 0270; 0275; 0278.
[12]Wang, Xiaohua; Xin, Lilan; Deng, Xiaofei; Dong, Chune; Hu, Guoyuan; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2024, vol. 267] Xin, Lilan; Wang, Chao; Cheng, Yan; Wang, Hongli; Guo, Xinyi; Deng, Xiaofei; Deng, Xiangping; Xie, Baohua; Hu, Hankun; Min, Chang; Dong, Chune; Zhou, Hai-Bing [Journal of Medicinal Chemistry, 2024, vol. 67, # 11, p. 8913 - 8931].
[13]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[14]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[15]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1 Location in patent: Page/Page column 37-38; 53; 56.
[16]Current Patent Assignee: SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY - WO2024/179529, 2024, A1 Location in patent: Page/Page column 60.
[17]Wang, Dandan; Wu, Yihe; Zhao, Yijin; Ma, Xiaoyu; Shi, Jiahao; Ni, Jian; Gao, Yang; Cai, Hongbing; Dong, Chune; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2026, vol. 302].
  • 4
  • [ 1948273-00-4 ]
  • [ 2458220-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 2: dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 4: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C
  • 5
  • [ 1948273-00-4 ]
  • [ 3037880-55-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 2: dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 4: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C
  • 6
  • [ 1948273-00-4 ]
  • [ 2458219-65-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 2: dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 4: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C / Inert atmosphere 6: trifluoroacetic acid / dichloromethane / 0 h / 0 - 20 °C
  • 7
  • [ 1948273-00-4 ]
  • [ 2458219-92-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 2: dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 4: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C
  • 8
  • [ 630421-46-4 ]
  • [ 1948273-00-4 ]
  • [ 1997302-16-5 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;
64 % With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
48.08 % With 1-methyl-1H-imidazole In acetonitrile at 20℃; Step 1: Dissolve (1S)-1-[4-(4-methyl-thiazol-5-yl)phenyl]ethyl-1-amine (500mg, 1.962mmol) in acetonitrile (8mL), and add (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyroyl)-4-hydroxypyrrolidine-2-carboxylic acid (675.90mg, 1.962mmol) and N-methylimidazole (805.70mg, 9.812mmol). ), stir for 5 minutes, add TCFH (715.82mg, 2.551mmol), stir the reaction at room temperature for 3 hours, and TLC monitors the reaction completely. The reaction solution was quenched with water (20mL), ethyl acetate (20mL×3) was added, the organic phase was washed with saturated saline water, anhydrous sodium sulfate was dried, concentrated, and purified by column chromatography (EA/PE=0-70%) to obtain 9-a (500mg, yellow solid), yield: 48.08%.
  • 9
  • [ 1948273-00-4 ]
  • [ 1948273-05-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dimethyl sulfoxide / 24 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 2.2: 24 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
  • 11
  • [ 1948273-00-4 ]
  • [ 2411422-49-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 4: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C
 

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