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Chemical Structure| 2313528-38-8 Chemical Structure| 2313528-38-8

Structure of 2313528-38-8

Chemical Structure| 2313528-38-8

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Product Details of [ 2313528-38-8 ]

CAS No. :2313528-38-8
Formula : C22H29N3O4S
M.W : 431.55
SMILES Code : O=C(N1[C@H](C(N[C@H](C2=CC=C(C3=C(C)N=CS3)C=C2)C)=O)C[C@@H](O)C1)OC(C)(C)C
English Name :tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate
MDL No. :MFCD34603379
InChI Key :BEGACMXKHPNZQU-VHSSKADRSA-N
Pubchem ID :146179678

Safety of [ 2313528-38-8 ]

Application In Synthesis of [ 2313528-38-8 ]

* 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 [ 2313528-38-8 ]

[ 2313528-38-8 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 27298-97-1 ]
  • [ 2313528-38-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 12 h / 90 °C 3: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C 4: 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 4 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 2 h / 120 °C 3: hydrogenchloride / methanol / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h 2: palladium diacetate; potassium acetate / dimethyl amine / 12 h / 90 °C 3: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C 4: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 20 °C / Cooling with ice 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 7 h / 90 °C / Inert atmosphere 3: hydrogenchloride / water; 1,4-dioxane / 5 h / 20 °C 4: 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 / 1.5 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere 3: hydrogenchloride / methanol / 2 h / 20 °C 4: 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 / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 12 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 4 h / 100 °C / Inert atmosphere 3: hydrogenchloride / ethyl acetate / 12 h / 20 °C 4: 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 / 3 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 4: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2 h / 20 °C
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / ethyl acetate; water / 1 h / 20 °C 2.1: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 3.2: 20 °C
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 1 h / 25 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 16 h / 90 °C 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 4: 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 4 steps 1: triethylamine / tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 12 h / 90 °C 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 12 h / 25 °C 4: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 15 °C
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 12 h / 25 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 15 °C
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 16 h / 25 °C 2.1: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 6 h / 120 °C / Inert atmosphere 3.1: hydrogenchloride / methanol; 1,4-dioxane / 16 h / 25 °C 4.1: 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 / 15 min / 25 °C 4.2: 16 h / 25 °C
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 2 h / 20 °C / Cooling with ice 1.2: 12 h / 90 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C / Inert atmosphere 2.2: 12 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C 3: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 20 °C 4: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2 h / 20 °C
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water / 18 h / 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 4 h / 130 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 18 h / 0 - 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide; dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C 3: hydrogenchloride / ethyl acetate / 12 h / 20 °C 4: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °C 3: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 4: 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 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / -10 - 20 °C 2: potassium carbonate; Trimethylacetic acid; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride / N,N-dimethyl acetamide / 125 °C
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: 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 / 2 h / 20 °C
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 3 h / 20 °C / Cooling with ice 2.1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 150 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / Cooling with ice 3.2: 3 h / 20 °C
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water / 2 h / 0 °C / Inert atmosphere 1.2: 12 h / 90 °C / Inert atmosphere 2.1: hydrogenchloride / dichloromethane; water / 2 h / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C 3.2: 12 h / 0 - 20 °C

References: [1]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].
[2]Current Patent Assignee: YALE UNIVERSITY - WO2019/195609, 2019, A2.
[3]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1.
[4]Current Patent Assignee: MITSUBISHI TANABE PHARMA - WO2020/9176, 2020, A1.
[5]Current Patent Assignee: YALE UNIVERSITY - WO2021/207172, 2021, A1.
[6]Current Patent Assignee: JIANGSU YAHONG MEDITECH - WO2022/161166, 2022, A1.
[7]Liu, Xingui; Kalogeropulou, Alexia F.; Domingos, Sofia; Makukhin, Nikolai; Nirujogi, Raja S.; Singh, Francois; Shpiro, Natalia; Saalfrank, Anton; Sammler, Esther; Ganley, Ian G.; Moreira, Rui; Alessi, Dario R.; Ciulli, Alessio [Journal of the American Chemical Society, 2022, vol. 144, # 37, p. 16930 - 16952].
[8]Wang, Chao; Zheng, Cangxin; Wang, Han; Shui, Sufang; Jin, Hongwei; Liu, Guoquan; Xu, Fengrong; Liu, Zhenming; Zhang, Liangren; Sun, Dan; Xu, Ping [European Journal of Medicinal Chemistry, 2023, vol. 247].
[9]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1.
[10]Current Patent Assignee: ARVINAS OPERATIONS - WO2023/97031, 2023, A1.
[11]Current Patent Assignee: ARVINAS OPERATIONS - WO2023/96987, 2023, A1.
[12]Current Patent Assignee: JINGRUI BIOPHARMA CO LTD - WO2023/185864, 2023, A1.
[13]Du, Wenhao; Huang, Yuting; Chen, Xiaoai; Deng, Yue; Sun, Yaoliang; Yang, Hong; Shi, Qiongyu; Wu, Feifei; Liu, Guobin; Huang, He; Ding, Jian; Huang, Xun; Xu, Shilin [Cell Chemical Biology, 2024, vol. 31, # 1, p. 177 - 17,183].
[14]Wang, Xiaohua; Xin, Lilan; Deng, Xiaofei; Dong, Chune; Hu, Guoyuan; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2024, vol. 267].
[15]Current Patent Assignee: UNIVERSITY OF DUNDEE - EP4276097, 2023, A1.
[16]Desantis, Jenny; Bazzacco, Alessandro; Eleuteri, Michela; Tuci, Sara; Bianconi, Elisa; Macchiarulo, Antonio; Mercorelli, Beatrice; Loregian, Arianna; Goracci, Laura [European Journal of Medicinal Chemistry, 2024, vol. 268].
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[22]Gao, Yunyun; Ni, Dan; Li, Yueying; Zheng, Jia; Zhang, Ke; Xiao, Yijie; Tang, Xi; Li, Linfeng; Wang, Xing; Wei, Yue; He, Yi; Guo, Zufeng; Nie, Shenyou [Journal of Medicinal Chemistry, 2025, vol. 68, # 16, p. 17046 - 17064].
  • 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.

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[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.
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  • 3
  • [ 847728-89-6 ]
  • [ 2313528-38-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 12 h / 90 °C 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: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 2 h / 120 °C 2: hydrogenchloride / methanol / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / dimethyl amine / 12 h / 90 °C 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 3 steps 1: potassium acetate; palladium diacetate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane / 25 °C / Inert atmosphere 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 7 h / 90 °C / Inert atmosphere 2: hydrogenchloride / water; 1,4-dioxane / 5 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 / 1.5 h / 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere 2: hydrogenchloride / methanol / 2 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 / 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 4 h / 100 °C / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 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 / 3 h / 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere 2: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 3: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2 h / 20 °C
Multi-step reaction with 2 steps 1.1: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2.2: 20 °C
Multi-step reaction with 3 steps 1: potassium acetate; palladium diacetate / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 16 h / 20 °C 3: 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
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 16 h / 90 °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: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 12 h / 90 °C 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 12 h / 25 °C 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 15 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C 2: hydrogenchloride / dichloromethane; 1,4-dioxane / 12 h / 25 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 15 °C
Multi-step reaction with 3 steps 1.1: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 6 h / 120 °C / Inert atmosphere 2.1: hydrogenchloride / methanol; 1,4-dioxane / 16 h / 25 °C 3.1: 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 / 15 min / 25 °C 3.2: 16 h / 25 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C 2: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 20 °C 3: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2 h / 20 °C
Multi-step reaction with 3 steps 1: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 4 h / 130 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 18 h / 0 - 20 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide; dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C 2: hydrogenchloride / ethyl acetate / 12 h / 20 °C 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °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: potassium acetate; palladium diacetate / N,N-dimethyl-formamide / 3 h / 16 - 90 °C / Inert atmosphere 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 °C
Multi-step reaction with 3 steps 1.1: potassium acetate; palladium diacetate / 12 h / 95 °C / Inert atmosphere 2.1: hydrogenchloride / methanol; 1,4-dioxane / 2 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 min / Cooling with ice 3.2: 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °C 2: trifluoroacetic acid / dichloromethane / 1 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 / 2 h / 20 °C
Multi-step reaction with 2 steps 1.1: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 150 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / Cooling with ice 2.2: 3 h / 20 °C
Multi-step reaction with 3 steps 1: palladium diacetate / N,N-dimethyl acetamide / 4 h / 150 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 2 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 / 2 h / 20 °C

References: [1]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].
[2]Current Patent Assignee: YALE UNIVERSITY - WO2019/195609, 2019, A2.
[3]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1.
[4]Current Patent Assignee: KYMERA THERAPEUTICS - WO2020/206424, 2020, A1.
[5]Current Patent Assignee: MITSUBISHI TANABE PHARMA - WO2020/9176, 2020, A1.
[6]Current Patent Assignee: YALE UNIVERSITY - WO2021/207172, 2021, A1.
[7]Current Patent Assignee: JIANGSU YAHONG MEDITECH - WO2022/161166, 2022, A1.
[8]Liu, Xingui; Kalogeropulou, Alexia F.; Domingos, Sofia; Makukhin, Nikolai; Nirujogi, Raja S.; Singh, Francois; Shpiro, Natalia; Saalfrank, Anton; Sammler, Esther; Ganley, Ian G.; Moreira, Rui; Alessi, Dario R.; Ciulli, Alessio [Journal of the American Chemical Society, 2022, vol. 144, # 37, p. 16930 - 16952].
[9]Wang, Chao; Zheng, Cangxin; Wang, Han; Shui, Sufang; Jin, Hongwei; Liu, Guoquan; Xu, Fengrong; Liu, Zhenming; Zhang, Liangren; Sun, Dan; Xu, Ping [European Journal of Medicinal Chemistry, 2023, vol. 247].
[10]Current Patent Assignee: HINOVA PHARMACEUTICALS - WO2023/280237, 2023, A1.
[11]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1.
[12]Current Patent Assignee: ARVINAS OPERATIONS - WO2023/97031, 2023, A1.
[13]Current Patent Assignee: ARVINAS OPERATIONS - WO2023/96987, 2023, A1.
[14]Current Patent Assignee: JINGRUI BIOPHARMA CO LTD - WO2023/185864, 2023, A1.
[15]Wang, Xiaohua; Xin, Lilan; Deng, Xiaofei; Dong, Chune; Hu, Guoyuan; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2024, vol. 267].
[16]Current Patent Assignee: UNIVERSITY OF DUNDEE - EP4276097, 2023, A1.
[17]Desantis, Jenny; Bazzacco, Alessandro; Eleuteri, Michela; Tuci, Sara; Bianconi, Elisa; Macchiarulo, Antonio; Mercorelli, Beatrice; Loregian, Arianna; Goracci, Laura [European Journal of Medicinal Chemistry, 2024, vol. 268].
[18]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[19]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].
[20]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1.
[21]Current Patent Assignee: SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY - WO2024/179529, 2024, A1.
[22]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].
[23]Current Patent Assignee: WUHAN UNIVERSITY - CN120247870, 2025, A.
[24]Current Patent Assignee: SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY - WO2025/131111, 2025, A1.
  • 4
  • [ 1973408-97-7 ]
  • [ 2313528-38-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C 2: 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 2 steps 1: hydrogenchloride / methanol / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 25 °C / Inert atmosphere 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: hydrogenchloride / water; 1,4-dioxane / 5 h / 20 °C 2: 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 / 1.5 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol / 2 h / 20 °C 2: 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 / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 12 h / 20 °C 2: 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 / 3 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 2: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2 h / 20 °C
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 16 h / 20 °C 2: 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
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 2: 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 2 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 12 h / 25 °C 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 15 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane / 12 h / 25 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 15 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / methanol; 1,4-dioxane / 16 h / 25 °C 2.1: 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 / 15 min / 25 °C 2.2: 16 h / 25 °C
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 20 °C 2: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 18 h / 0 - 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide; dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 12 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: 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 2 steps 1: hydrogenchloride / 1,4-dioxane / 1 h / 16 °C 2: 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
Multi-step reaction with 2 steps 1.1: hydrogenchloride / methanol; 1,4-dioxane / 2 h / 0 - 20 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 min / Cooling with ice 2.2: 20 °C
8.02 g Stage #1: tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate With trifluoroacetic acid In dichloromethane for 1h; Cooling with ice; Stage #2: With (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid; 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 dichloromethane at 20℃; for 3h; Further, step S8 can specifically be: take a 100mL single-necked flask and add DCM (20mL), then add the reaction mixture.(7)The prepared raw material (compound 11, 7.00 g, 21.98 mmol) was slowly added dropwise with TFA (trifluoroacetic acid, 10.03 g, 87.93 mmol) under ice bath conditions. After the addition was completed, stirring was continued for 1 h. The reaction was monitored by TLC. After the starting material disappeared, DCM and TFA in the system were removed by rotary evaporation. The residue was then dissolved in DCM. The pH was adjusted to alkaline using ammonia. DCM was extracted, and most of the DCM was removed by rotary evaporation. An appropriate amount of anhydrous DCM (30 mL) was added. Then, DIPEA (N,N-diisopropylethylamine, 11.41 g, 87.93 mmol), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 9.20 g, 24.18 mmol), and Boc-Hyp-OH (Boc-L-hydroxyproline, 5.59 g, 24.18 mmol) were added sequentially. After the addition was complete, the mixture was stirred at room temperature for 3 h. After the starting material was completely eliminated by TLC monitoring, it was extracted with DCM, dried by rotary evaporation, and then purified by column chromatography with petroleum ether/ethyl acetate (V/V=3/1) as the mobile phase, yielding a white solid product (compound 12, 8.02 g, 18.59 mmol).
Multi-step reaction with 2 steps 1.1: hydrogenchloride / dichloromethane; water / 2 h / 0 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 12 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 2 h / 20 °C 2: 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 / 2 h / 20 °C

References: [1]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].
[2]Current Patent Assignee: YALE UNIVERSITY - WO2019/195609, 2019, A2.
[3]Current Patent Assignee: KYMERA THERAPEUTICS - WO2020/206424, 2020, A1.
[4]Current Patent Assignee: MITSUBISHI TANABE PHARMA - WO2020/9176, 2020, A1.
[5]Current Patent Assignee: YALE UNIVERSITY - WO2021/207172, 2021, A1.
[6]Current Patent Assignee: JIANGSU YAHONG MEDITECH - WO2022/161166, 2022, A1.
[7]Liu, Xingui; Kalogeropulou, Alexia F.; Domingos, Sofia; Makukhin, Nikolai; Nirujogi, Raja S.; Singh, Francois; Shpiro, Natalia; Saalfrank, Anton; Sammler, Esther; Ganley, Ian G.; Moreira, Rui; Alessi, Dario R.; Ciulli, Alessio [Journal of the American Chemical Society, 2022, vol. 144, # 37, p. 16930 - 16952].
[8]Current Patent Assignee: HINOVA PHARMACEUTICALS - WO2023/280237, 2023, A1.
[9]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1.
[10]Current Patent Assignee: ARVINAS OPERATIONS - WO2023/97031, 2023, A1.
[11]Current Patent Assignee: ARVINAS OPERATIONS - WO2023/96987, 2023, A1.
[12]Current Patent Assignee: JINGRUI BIOPHARMA CO LTD - WO2023/185864, 2023, A1.
[13]Wang, Xiaohua; Xin, Lilan; Deng, Xiaofei; Dong, Chune; Hu, Guoyuan; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2024, vol. 267].
[14]Current Patent Assignee: UNIVERSITY OF DUNDEE - EP4276097, 2023, A1.
[15]Desantis, Jenny; Bazzacco, Alessandro; Eleuteri, Michela; Tuci, Sara; Bianconi, Elisa; Macchiarulo, Antonio; Mercorelli, Beatrice; Loregian, Arianna; Goracci, Laura [European Journal of Medicinal Chemistry, 2024, vol. 268].
[16]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[17]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].
[18]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1.
[19]Current Patent Assignee: SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY - WO2024/179529, 2024, A1.
[20]Current Patent Assignee: WUHAN UNIVERSITY - CN120247870, 2025, A Location in patent: Paragraph 0048-0050.
[21]Gao, Yunyun; Ni, Dan; Li, Yueying; Zheng, Jia; Zhang, Ke; Xiao, Yijie; Tang, Xi; Li, Linfeng; Wang, Xing; Wei, Yue; He, Yi; Guo, Zufeng; Nie, Shenyou [Journal of Medicinal Chemistry, 2025, vol. 68, # 16, p. 17046 - 17064].
[22]Current Patent Assignee: SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY - WO2025/131111, 2025, A1.
  • 5
  • [ 2313528-38-8 ]
  • [ 2086301-12-2 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 12h;
With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 12h; 1 tert- Butyl ((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carb-amoyl)pyrrolidin- 1 -yl)-3 ,3 -dimethyl- 1 -oxobutan-2-yl)carbamate (57) This solid (56), obtained as described above was dissolved in 4N HC1 in dioxane (0327) (25 mL, 100 mmol) and MeOH (25 mL) and the mixture was stirred at ambient temperature for 12 h. The mixture was then concentrated and the residue was dried under vacuum to afford an intermediate, which was used in next step without further purification. UPLC-MS (ESL) calc, for C17H22N3O2S [M+l]+: 332.14, found 332.11. HATU (1.37 g, 3.6 mmol, 1.2 eq) was added to a solution of this intermediate (994 mg, 3.0 mmol, 1.0 eq), (S)-2-((/er/-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (694 mg, 3.0 mmol, 1.0 eq), and DIPEA (1.57 mL, 9.0 mmol, 3.0 eq) in DMF (10 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 (100 mL) and extracted with EtOAc (75mLx2). The combined organic layer was washed with brine (100 mL) and dried over Na2S04. The organic solution was filtered and concentrated. The residue was purified by silica gel flash column chromatography with hexane :EtO Ac then DCM: MeOH to afford the desired compound (57) as a white solid (1.31 g, 80% yield). NMR (CDCI3, 400 MHz) d (ppm) 8.65 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.35- 7.31 (m, 4H), 5.29 (d, J= 9.2 Hz, 1H), 5.06-5.01 (m, 1H), 4.67 (t, J= 8.0 Hz, 1H), 4.46- 4.44 (m, 1H), 4.22-4.19 (m, 1H), 3.91 (d, J = 17.2 Hz, 1H), 3.61-3.58 (m, 1H), 2.46 (s, 3H), 2.37-2.30 (m, 1H), 2.04-1.99 (m, 1H), 1.44 (d, J= 7.2 Hz, 3H), 1.35 (s, 9H), 0.96 (s, 9H); 13C NMR (CDCI3, 100 MHz) d (ppm) 172.22, 170.13, 156.15, 150.56, 148.21, 143.43, 131.74, 130.59, 129.49, 126.46, 80.18, 69.91, 58.86, 56.58, 48.74, 38.60, 36.02, 35.48, 28.34, 26.39, 22.17, 15.95; UPLC-MS (ESF) calc for C28H41N4O5S [M+l]+: 545.28, found 545.35.
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 1h;
420 mg With hydrogenchloride In 1,4-dioxane; dichloromethane at 25℃; E Step E: Add 1,4-dioxane solution (4 M, 4 ml) of hydrochloric acid with compound INT-5-4 (350 mg, 0.8 mmol) to dichloromethane (4 ml). The reaction mixture is stirred at 25 degrees Celsius for 1 h. LCMS monitoring shows that raw materials are gone. The reaction mixture was concentrated to remove the solvent to obtain 420 mg of INT-5-5.
40 g With hydrogenchloride In 1,4-dioxane at 25℃;
With trifluoroacetic acid In dichloromethane at 20℃;
With hydrogenchloride In ethyl acetate at 20℃; 4.1.20. tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) carbamate (P13) This solid material (P12), obtained as described above was dissolvedin 2 M HCl in EA (20 mL, 40 mmol), and the mixture was stirred atambient temperature for 12 h. The mixture was then concentrated, andthe residue was dried under vacuum to afford intermediate, which wasused in next step without further purification. HATU (8.50 g, 22.5 mmol,1.4 equiv) was added to a solution of this intermediate (5.80 g, 16.0mmol, 1.0 equiv), (S)-2-((tert-butoxycarbonyl) amino)-3,3- dimethylbutanoicacid (3.46 g, 16.0 mmol, 1.0 equiv), and DIPEA (8.8 mL,48.0 mmol, 3.0 equiv) in DMF (30 mL) at 0 C. The mixture was stirredat ambient temperature for 12 h when TLC showed that the reaction wascomplete. The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (75 mL × 2). The combined organic layer waswashed with brine (100 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 30:1) to afford the desiredcompound.
With hydrogenchloride In ethyl acetate at 20℃; 4.1.20. tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) carbamate (P13) This solid material (P12), obtained as described above was dissolvedin 2 M HCl in EA (20 mL, 40 mmol), and the mixture was stirred atambient temperature for 12 h. The mixture was then concentrated, andthe residue was dried under vacuum to afford intermediate, which wasused in next step without further purification. HATU (8.50 g, 22.5 mmol,1.4 equiv) was added to a solution of this intermediate (5.80 g, 16.0mmol, 1.0 equiv), (S)-2-((tert-butoxycarbonyl) amino)-3,3- dimethylbutanoicacid (3.46 g, 16.0 mmol, 1.0 equiv), and DIPEA (8.8 mL,48.0 mmol, 3.0 equiv) in DMF (30 mL) at 0 C. The mixture was stirredat ambient temperature for 12 h when TLC showed that the reaction wascomplete. The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (75 mL × 2). The combined organic layer waswashed with brine (100 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 30:1) to afford the desiredcompound.
With hydrogenchloride In 1,4-dioxane; dichloromethane; water at 20℃; Step 2: (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)-phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.77 g, 8.74 mmol) in DCM (20 mL) was added 4M HCl-dioxane (20 mL, 80 mmol) and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to afford the title compound.
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol / 2 h / 4 °C 2: sodium hydroxide / methanol; dichloromethane; water / 4 °C / pH 12.5 - 13
With hydrogenchloride In 1,4-dioxane 39.3 (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 39c Compound 1a (4.00 g, 9.27 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (50 mL, 4.0 M), stirred for 1 hour, and concentrated to obtain a crude product. The crude product was adjusted to neutrality with triethylamine and concentrated under reduced pressure to obtain the crude title compound 39c (5.06 g). The product was used directly in the next step without purification.
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; 47.2 Step 2: (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl) phenyl)ethyl) pyrrolidine-2-carboxamide To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.77 g, 8.74 mmol, 1.00 eq.) in DCM (20 mL) was added HCl-dioxane (4.0 M, 20.0 mL). The resulting mixture was stirred at RT for 1 h and concentrated to afford the title compound.
16.8 g With hydrogenchloride In 1,4-dioxane at 20℃; Step 2: Synthesis of compound M29-2 M29-1 (22.0 g) was added to DCM (100 mL), and a hydrochloric acid dioxane solution (100 mL) was added under an ice-water bath. The reaction was reacted at room temperature for 60 minutes, and the reaction was completed by LCMS monitoring. The reaction solution was directly concentrated, and 1M NaOH solution was added until the pH of the reaction solution was 8. DCM (100 mL) was added to the reaction solution, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 16.8 g of a white solid, namely compound M29-2.
98 % With hydrogenchloride In 1,4-dioxane at 16℃; 6.e Synthesis of Int. 27 Into a 100 mL round-bottom flask were added 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, 6.488 mmol, 1 equiv), 1,4-dioxane (10 mL) and HCl in 1,4-dioxane (0.79 mL, 4 M). The mixture was stirred for 1 h at 16 °C and was concentrated under reduced pressure. This afforded (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (2.1 g, 98% yield) as a yellow green solid. LCMS: (ES, m/z): [M+H]+ = 332 (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)
With trifluoroacetic acid In dichloromethane at 20℃; for 1h; TFA (2 mL) was added to a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (1 g, 2.3 mmol) in DCM (8 mL). The reaction mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product that was purified by reverse phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (682 mg, 2.1 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 332.1.
1.6 g With trifluoroacetic acid In dichloromethane 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 trifluoroacetic acid In dichloromethane at 20℃; for 1h;
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 1h; 59.2 Step 2: (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[(1S)-1-[4-(4-methylthiazol-5-yl)-phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.77 g, 8.74 mmol) in DCM (20 mL) wasadded 4M HCl-dioxane (20 mL, 80 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. The solvent was evaporated under reduced pressure to afford the titlecompound.
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 1h; 2 Step 2: (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)-phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.77 g, 8.74 mmol) in DCM (20 mL) wasadded 4M HCl-dioxane (20 mL, 80 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. The solvent was evaporated under reduced pressure to afford the titlecompound.
682 mg With trifluoroacetic acid In dichloromethane at 20℃; for 1h; 6.2 Step 2. (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TFA (2 mL) was added to a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5 yl)phenyl)ethyl) carbamoyl)pyrrolidine-1-carboxylate (1 g, 2.3 mmol) in DCM (8 mL). The reaction mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product that was purified by reverse phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (682 mg, 2.1 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 332.1.

References: [1]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].
[2]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1 Location in patent: Paragraph 0192-0193.
[3]Liu, Xingui; Kalogeropulou, Alexia F.; Domingos, Sofia; Makukhin, Nikolai; Nirujogi, Raja S.; Singh, Francois; Shpiro, Natalia; Saalfrank, Anton; Sammler, Esther; Ganley, Ian G.; Moreira, Rui; Alessi, Dario R.; Ciulli, Alessio [Journal of the American Chemical Society, 2022, vol. 144, # 37, p. 16930 - 16952].
[4]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1 Location in patent: Page/Page column 32-33.
[5]Current Patent Assignee: JINGRUI BIOPHARMA CO LTD - WO2023/185864, 2023, A1 Location in patent: Paragraph 0270; 0275; 0280.
[6]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].
[7]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[8]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[9]Current Patent Assignee: NIKANG THERAPEUTICS - WO2024/102849, 2024, A1 Location in patent: Page/Page column 329.
[10]Soto-Martínez, Diana M.; Clements, Garrett D.; Díaz, John E.; Becher, Joy; Reynolds, Robert C.; Ochsenbauer, Christina; Snowden, Timothy S. [RSC Advances, 2024, vol. 14, # 24, p. 17077 - 17090].
[11]Current Patent Assignee: SHANGHAI HENGRUI MEDICINE - WO2024/67818, 2024, A1 Location in patent: Page/Page column 304-306.
[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 57-58.
[14]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1 Location in patent: Page/Page column 37; 39.
[15]Current Patent Assignee: FOGHORN THERAPEUTICS - WO2024/220946, 2024, A1 Location in patent: Page/Page column 156-157.
[16]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2024/64328, 2024, A1 Location in patent: Paragraph 0542-0544.
[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].
[18]Current Patent Assignee: NIKANG THERAPEUTICS - WO2025/235298, 2025, A1 Location in patent: Page/Page column 200.
[19]Current Patent Assignee: NIKANG THERAPEUTICS - WO2025/235331, 2025, A1 Location in patent: Page/Page column 205.
[20]Current Patent Assignee: FOGHORN THERAPEUTICS - WO2025/222187, 2025, A1 Location in patent: Page/Page column 450-451.
  • 6
  • [ 2313528-38-8 ]
  • [ 1997302-16-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C 2: 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 2 steps 1: hydrogenchloride / methanol / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 2: triethylamine; HATU / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol / 2 h / 20 °C 2: 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 / 20 °C
Multi-step reaction with 2 steps 1: methanol; hydrogenchloride / ethyl acetate / 20 °C 2: 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 / 3 h / 20 °C
Multi-step reaction with 2 steps 1: dichloromethane / 18 h / 20 °C 2: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 2: 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 2 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 0 - 20 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / 1,4-dioxane / 18 h / 0 - 20 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C / Inert atmosphere 2.2: 18 h / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 12 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: 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: hydrogenchloride / methanol / 2 h / 4 °C 2: sodium hydroxide / methanol; dichloromethane; water / 4 °C / pH 12.5 - 13 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / -10 - 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 1 h / 16 °C 2: 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
8.06 g Stage #1: tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate With trifluoroacetic acid for 1h; Cooling with ice; Stage #2: With N-tert-butyloxycarbonyl-L-tert-leucine; 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 dichloromethane at 20℃; for 3h; Further, step S9 can specifically be: take a 50mL single-necked flask and add DCM (50mL), then add the reaction mixture.(8)The prepared raw material (compound 12, 7.80 g, 18.07 mmol) was slowly added dropwise with TFA (8.24 g, 72.30 mmol) under ice bath conditions. After the addition was complete, the mixture was stirred for 1 h. The reaction was monitored by TLC. After the raw material disappeared, DCM and TFA in the system were removed by rotary evaporation. The residue was dissolved in an appropriate amount of DCM, and the pH was adjusted to alkaline with ammonia. The mixture was extracted with DCM, dried, and most of the DCM was removed by rotary evaporation. An appropriate amount of anhydrous DCM (30 mL) was added, followed by DIPEA (0.09 g, 72.30 mmol), HATU (7.56 g, 19.88 mmol), and Boc-Tle-OH (4.60 g, 19.88 mmol). After the addition was complete, the mixture was stirred at room temperature for 3 h. After the raw material was completely eliminated by TLC monitoring, it was extracted with DCM, dried by rotary evaporation, and then purified by column chromatography with dichloromethane/methanol (V/V=30:1) as the mobile phase, yielding a white solid product Boc-VHL (8.06 g, 14.79 mmol).

References: [1]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].
[2]Current Patent Assignee: YALE UNIVERSITY - WO2019/195609, 2019, A2.
[3]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1.
[4]Current Patent Assignee: KYMERA THERAPEUTICS - WO2020/206424, 2020, A1.
[5]Current Patent Assignee: YALE UNIVERSITY - WO2021/207172, 2021, A1.
[6]Current Patent Assignee: JIANGSU YAHONG MEDITECH - WO2022/161166, 2022, A1.
[7]Current Patent Assignee: HINOVA PHARMACEUTICALS - WO2023/280237, 2023, A1.
[8]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1.
[9]Wang, Xiaohua; Xin, Lilan; Deng, Xiaofei; Dong, Chune; Hu, Guoyuan; Zhou, Hai-Bing [European Journal of Medicinal Chemistry, 2024, vol. 267].
[10]Desantis, Jenny; Bazzacco, Alessandro; Eleuteri, Michela; Tuci, Sara; Bianconi, Elisa; Macchiarulo, Antonio; Mercorelli, Beatrice; Loregian, Arianna; Goracci, Laura [European Journal of Medicinal Chemistry, 2024, vol. 268].
[11]Yao, Xiaoxuan; Mao, Jianping; Zhang, Haoyu; Xiao, Yi; Wang, Yongjun; Liu, Hongzhuo [European Journal of Medicinal Chemistry, 2024, vol. 272].
[12]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]Soto-Martínez, Diana M.; Clements, Garrett D.; Díaz, John E.; Becher, Joy; Reynolds, Robert C.; Ochsenbauer, Christina; Snowden, Timothy S. [RSC Advances, 2024, vol. 14, # 24, p. 17077 - 17090].
[14]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1.
[15]Current Patent Assignee: WUHAN UNIVERSITY - CN120247870, 2025, A Location in patent: Paragraph 0051-0053.
  • 7
  • [ 2313528-38-8 ]
  • [ 1948273-02-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C 2: 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 3: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 24 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 1.2: 20 °C 2.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C 2: 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 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C / Inert atmosphere 1.2: 12 h / 0 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 0 - 20 °C 3: trifluoroacetic acid / dichloromethane / 30 min / 20 °C
Multi-step reaction with 3 steps 1: hydrogenchloride / ethyl acetate / 12 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C 3: hydrogenchloride / ethyl acetate / 12 h / 20 °C
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: 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 3: trifluoroacetic acid / dichloromethane / 30 min / 20 °C
Multi-step reaction with 5 steps 1: hydrogenchloride / methanol / 2 h / 4 °C 2: sodium hydroxide / methanol; dichloromethane; water / 4 °C / pH 12.5 - 13 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / -10 - 20 °C 4: hydrogenchloride / methanol / 2 h / 4 °C 5: sodium hydroxide / methanol; dichloromethane; water / 4 °C / pH 12.5 - 13
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane / 1 h / 16 °C 2: 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 3: hydrogenchloride / 1,4-dioxane / 1 h / 16 °C
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 2: 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 / 2 h / 20 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / 1 h / Cooling with ice 1.2: 3 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / Cooling with ice

References: [1]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].
[2]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2020/142227, 2020, A1.
[3]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].
[4]Wang, Chao; Zheng, Cangxin; Wang, Han; Shui, Sufang; Jin, Hongwei; Liu, Guoquan; Xu, Fengrong; Liu, Zhenming; Zhang, Liangren; Sun, Dan; Xu, Ping [European Journal of Medicinal Chemistry, 2023, vol. 247].
[5]Current Patent Assignee: SHANGHAI QILU PHARMACEUTICAL RES AND DEVELOPMENT CENTRE - WO2023/143249, 2023, A1.
[6]Du, Wenhao; Huang, Yuting; Chen, Xiaoai; Deng, Yue; Sun, Yaoliang; Yang, Hong; Shi, Qiongyu; Wu, Feifei; Liu, Guobin; Huang, He; Ding, Jian; Huang, Xun; Xu, Shilin [Cell Chemical Biology, 2024, vol. 31, # 1, p. 177 - 17,183].
[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]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].
[10]Soto-Martínez, Diana M.; Clements, Garrett D.; Díaz, John E.; Becher, Joy; Reynolds, Robert C.; Ochsenbauer, Christina; Snowden, Timothy S. [RSC Advances, 2024, vol. 14, # 24, p. 17077 - 17090].
[11]Current Patent Assignee: KESMALEA THERAPEUTICS LTD - WO2024/175905, 2024, A1.
[12]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].
[13]Current Patent Assignee: WUHAN UNIVERSITY - CN120247870, 2025, A.
  • 8
  • [ 1948273-01-5 ]
  • [ 13726-69-7 ]
  • [ 2313528-38-8 ]
YieldReaction ConditionsOperation in experiment
53% 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 dichloromethane at 0 - 20℃; for 16h; Step-d: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (17d) To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (11.0 g, 43.30 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (9.97 g, 43.30 mmol) in DCM (150 mL) at 0°C was added HATU (19.6 g, 51.96 mmol) followed by dropwise addition of DIPEA (39.78 mL, 216.5 mmol) and stirred for 16 h at RT. After completion of the reaction (monitored by TLC) the reaction mixture poured into ice cold water. The resulting mixture was extracted with DCM (2 X 500 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give the crude product which was purified by combi flash column chomatography using 6% MeOH in DCM as eluent to afford the title compound (10.0 g, 53 %). 1H NMR (400 MHz, DMSO-d6): d 8.98 (s, 1H), 8.38-8.80 (m, 1H), 7.45-7.36 (m, 4H), 4.99-4.18 (m, 2H), 4.21-4.18 (m, 2H), 3.39-3.35 (m, 1H), 3.26-3.16 (m, 1H), 2.45 (s, 3H), 2.06-2.03 (m, 1H), 1.80-1.17 (m, 1H), 1.40-1.37 (m, 6H), 1.33 (s, 6H); LC-MS: m/z 432.2 (M+l)+ .
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℃; for 2h;
1.2 g With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 15℃; [00464] To a solution of (2S,4R)-l-/er/-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (998 mg, 4.32 mmol, 1.1 eq) and O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.79 g, 4.71 mmol, 1.2 eq) in dimethylformamide (10 mL) were added (lS)-l-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (1 g, 3.92 mmol, 1 eq) and diisopropylethyl amine (1.52 g, 11.77 mmol, 2.05 mL, 3 eq). The reaction mixture was stirred at 15°C for 0.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate from 100:1 to 30:1). terZ-Butyl (2S,4R)-4-hydroxy-2- [[(1 S)- 1 - [4-(4-methylthiazol-5-yl)phenyl] ethyl] carbamoyl] pyrrolidine- 1 -carboxylate (1.2 g, 2.78 mmol, 70% yield) was obtained as a white solid.
1.2 g With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 15℃; 8 [00417] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (998 mg, 4.32 mmol, 1.1 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.79 g, 4.71 mmol, 1.2 eq) in dimethylformamide (10 mL) were added (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (1 g, 3.92 mmol, 1 eq) and diisopropylethyl amine (1.52 g, 11.77 mmol, 2.05 mL, 3 eq). The reaction mixture was stirred at 15°C for 0.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate from 100:1 to 30:1). tert-Butyl (2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl] pyrrolidine-1-carboxylate (1.2 g, 2.78 mmol, 70% yield) was obtained as a white solid.
1.2 g With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 15℃; 8 [00417] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (998 mg, 4.32 mmol, 1.1 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.79 g, 4.71 mmol, 1.2 eq) in dimethylformamide (10 mL) were added (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (1 g, 3.92 mmol, 1 eq) and diisopropylethyl amine (1.52 g, 11.77 mmol, 2.05 mL, 3 eq). The reaction mixture was stirred at 15°C for 0.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate from 100:1 to 30:1). tert-Butyl (2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl] pyrrolidine-1-carboxylate (1.2 g, 2.78 mmol, 70% yield) was obtained as a white solid.
1.2 g With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 15℃; [00464] To a solution of (2S,4R)-l-/er/-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (998 mg, 4.32 mmol, 1.1 eq) and O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.79 g, 4.71 mmol, 1.2 eq) in dimethylformamide (10 mL) were added (lS)-l-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (1 g, 3.92 mmol, 1 eq) and diisopropylethyl amine (1.52 g, 11.77 mmol, 2.05 mL, 3 eq). The reaction mixture was stirred at 15°C for 0.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate from 100:1 to 30:1). terZ-Butyl (2S,4R)-4-hydroxy-2- [[(1 S)- 1 - [4-(4-methylthiazol-5-yl)phenyl] ethyl] carbamoyl] pyrrolidine- 1 -carboxylate (1.2 g, 2.78 mmol, 70% yield) was obtained as a white solid.
98 % With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; 1.9 Step 9: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate. To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0 °C was added HATU (8.98 g, 23.5 mmol) followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, and dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (MeOH/DCM) to afford tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (8.33 g, 98%). LCMS (ESI) m/z: [M+H]+ = 432.38.

  • 9
  • [ 2313528-38-8 ]
  • [ 2086301-13-3 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; methanol In ethyl acetate at 20℃; 1.1.3 (2S,4R)-4-hydroxy-2-((S)-1-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (compound C-8) (16.60g, 39mmol) methanol (30mL) solution, stirred to dissolve. At room temperature, the solution of ethyl acetate (2M, 77mL, 154mmol) of hydrogen chloride was added to the system dropwise, and the stirring reaction was overnight. Concentrate the reaction liquid to give a yellow solid product (2S, 4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazole-5-yl) phenyl) carbamoyl) pyrrolidine hydrochloride (compound C-9) (14.15g, yield 100%).
96% With hydrogenchloride In 1,4-dioxane at 25℃; for 16h; Inert atmosphere; 4 Step 4: (2S, 4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1, 3-thiazol-5- yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride. To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine- 1-carboxylate (46.0 g, 107 mmol) in dioxane (300 mL) was added a solution of HCl (gas) in 1,4- dioxane (4 M, 150 mL) dropwise at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 25 °C under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with CH2Cl2 (3 x 50.0 mL) and dried to give the title compound as a light yellow solid (42.0 g, 96%): 1H NMR (400 MHz, CD3OD) d 10.11 (s, 1H), 7.66-7.60 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 5.13 (q, J = 7.0 Hz, 1H), 4.67-4.54 (m, 2H), 3.41 (dd, J = 12.1, 3.5 Hz, 1H), 3.37-3.29 (m, 1H), 2.65 (s, 3H), 2.56 (ddt, J = 13.5, 7.5, 1.7 Hz, 1H), 1.98 (ddd, J = 13.4, 10.6, 4.0 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H); LC/MS (ESI, m/z): [(M + H)]+ = 332.1.
83% With hydrogenchloride In methanol at 20℃; for 2h; 5 Step 5: Preparation of (2S,4R)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride Into a 500-mL round-bottom flask, was placed a solution of tert-butyl (2S,4R)-4- hydroxy-2- [ [( 1 S )- 1 - [4-(4-methyl- 1 ,3 -thiazol-5-yl)phenyl] ethyl] carbamoyl] pyrrolidine- 1 - carboxylate (5.0 g, 11.59 mmol, 1.00 equiv) in methanol (200 mL), then hydrogen chloride (gas) was bubbled into the reaction mixture for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3.2 g (83%) of (2S,4R)-4-hydroxy-N-[(lS)-l- [4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a red solid.
83% With hydrogenchloride In methanol at 20℃; for 2h; 5 Step 5: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride Into a 500-mL round-bottom flask, was placed a solution of tert-butyl (2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1- carboxylate (5.0 g, 11.59 mmol, 1.00 equiv) in methanol (200 mL), then hydrogen chloride (gas) was bubbled into the reaction mixture for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3.2 g (83%) of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a red solid.
83% With hydrogenchloride In methanol at 20℃; for 2h; 5 Step 5: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride Into a 500-mL round-bottom flask, was placed a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (5.0 g, 11.59 mmol, 1.00 equiv) in methanol (200 mL), then hydrogen chloride (gas) was bubbled into the reaction mixture for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3.2 g (83%) of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a red solid.
With hydrogenchloride In 1,4-dioxane at 0 - 20℃; for 16h; Step-e: Synthesis of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (17e) To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (10.0 g, 23.20 mmol) in l,4-dioxane (50 mL) at 0 °C was added 4M HC1 in l,4-dioxane (50 mL). The reaction mixture was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure and the residue was washed with diethyl ether to afford the title compound (8.5 g, 100 %) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): d 10.20 (bs, 1H), 9.22- 9.30 (m, 1H), 9.15 (s, 1H), 8.67 (bs, 1H), 7.46-7.42 (m, 3H), 5.01-4.95 (m, 1H) ,4.50-4.40 (m, 2H), 3.30-3.20 (m, 1H), 3.20-3.00 (m, 1H), 2.50 (s, 3H), 2.40-2.35 (m, 2H), 1.80-1.70 (m, 1H), 1.43 (d, / = 8.4 Hz, 3H), LC-MS: m/z 332.1 (M+l)+.
1.33 g With hydrogenchloride In 1,4-dioxane; methanol; dichloromethane; water at 20℃; for 6h; 210.210-2 (210-2) (2S, 4R) -4-hydroxy-N-{(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl} pyrrolidine-2- Carboxamide hydrochloride (Example compound 210-2) Example Compound 210-1 (2.02 g) was added to a mixed solution of dichloromethane (4.0 mL) and methanol (6.0 mL), and a 4M hydrogen chloride / dioxane solution (4.3 mL) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and then azeotroped with toluene. Hexane was added to the residue and concentrated under reduced pressure, and the obtained solid was suspended and washed with diethyl ether to give the title compound (1.33 g) as a light brown powder.
With hydrogenchloride In 1,4-dioxane; methanol; water at 0 - 20℃; for 2h; 1.10 Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide hydrochloride To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-l-carboxylate (8.33 g, 19.3 mmol) at 0 °C was added a solution of HCI in 1 ,4-dioxane (4 N, 50 mL, 200 mmol) resulting in a sticky yellow gum. 15 mL of MeOH was added to the mixture and the mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the residue was washed with diethyl ether to afford (2S,4R)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride which was used in the next step without further purification.
With hydrogenchloride In 1,4-dioxane; methanol; water at 0 - 20℃; for 2h; 1.10 Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide hydrochloride To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-l-carboxylate (8.33 g, 19.3 mmol) at 0 °C was added a solution of HCI in 1 ,4-dioxane (4 N, 50 mL, 200 mmol) resulting in a sticky yellow gum. 15 mL of MeOH was added to the mixture and the mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the residue was washed with diethyl ether to afford (2S,4R)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride which was used in the next step without further purification.
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; 3.2 Step 2: (25,4A)-4-Hydroxy-A-((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (hydrochloride salt) A solution of tert-butyl (2k,4/?)-4-hydroxy-2-((fS')- l -(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-l -carboxylate (6.89 g, 13.5 mmol) in 4 M HCl/dioxane (50 mL) and dichloromethane (100 mL) was stirred at room temperature for 1 hour. The solvent was concentrated under vacuum to yield 5.8 g (crude) of the title compound as a white solid. LC-MS: (ESI, m/z)'. [M+H]+= 332.
With hydrogenchloride In 1,4-dioxane at 20℃; 1.10 Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride. To tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate (8.33 g, 19.3 mmol) at 0 °C was added a solution of HCI in 1 ,4-dioxane (4 N, 50 mL, 200 mmol) resulting in a sticky yellow gum. 15 mL of MeOH were added to the mixture and the mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the residue was washed with diethyl ether to afford (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride which was used in the next step without further purification.
100 % With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; General procedure: (9H-fluoren-9-yl)methyl((R)-1-((2R,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo-3-(tritylthio)butan-2-yl)carbamatewas prepared following general procedure 4. 190 mg(9H-fluoren-9-yl)methyl ((R)-1-((2R,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo-3-(tritylthio)butan-2-yl)carbamatewas obtained from 118 mgtert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate,75% yield.1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.78 - 7.72 (m, 2H), 7.62 - 7.52 (m, 8H), 7.41 - 7.17 (m, 18H), 5.73 (d, J = 5.3 Hz, 1H), 5.00 (p, J = 7.0 Hz, 1H), 4.65 (t, J = 8.0 Hz, 1H), 4.42 - 4.15 (m, 4H), 3.56 (d, J = 5.3 Hz, 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.17 (dd,J= 11.6, 3.5 Hz, 1H), 2.83 (br, s, 1H), 2.51 (s, 3H), 2.44 - 2.32 (m, 1H), 2.08 - 1.96 (m, 1H), 1.39 - 1.31 (m, 6H), 1.17 (s, 3H).13C NMR (101 MHz, CDCl3) δ 170.91, 169.57, 156.61, 150.35, 148.68, 144.60, 144.02, 143.58, 143.26, 141.41, 130.99, 130.04, 129.68, 128.03, 127.94, 127.28, 127.08, 126.58, 125.29, 125.13, 120.18, 70.25, 67.79, 58.61, 58.38, 56.62, 48.92, 47.14, 35.86, 26.12, 26.05, 22.34, 16.23. LC-MS,ESI+,m/z927 [M+H]+.
With hydrogenchloride In 1,4-dioxane at 20℃; 1.10 Step 10: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride. To tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate (8.33 g, 19.3 mmol) at 0 °C was added a solution of HCI in 1 ,4-dioxane (4 N, 50 mL, 200 mmol) resulting in a sticky yellow gum. 15 mL of MeOH were added to the mixture and the mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the residue was washed with diethyl ether to afford (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride which was used in the next step without further purification.
100 % With hydrogenchloride In 1,4-dioxane at 0 - 20℃; 4.6.5. (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (52) To the solution of 50 (1.0 g, 2.317 mmol) in dioxane (3.2 mL) and EA(0.8 mL), 4.0 N HCl in dioxane (4.4 mL) was added dropwise at 0 C. Thereaction was stirred at room temperature for 18 h. Then, the solvent wasevaporated to dryness and the residue was tritured with DEE (10 mL),collected by filtration, and dried in vacuo to afford the titled compoundas a yellow solid (0.852 g, two-step yield 100 %). 1H NMR (400 MHz,DMSO-d6) δ 10.16 (bs, 1H), 9.28 (d, J = 7.5 Hz, 1H), 9.09 (s, 1H), 8.58(bs, 1H), 7.44 (dd, J = 25.3, 8.2 Hz, 4H), 5.06-4.93 (m, 1H), 4.45-4.36(m, 2H), 3.35-3.24 (m, 1H), 3.12-3.03 (m, 1H), 2.68 (s, 3H), 2.46 (s,3H), 2.40-2.31 (m, 1H), 1.84-1.75 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H).
100 % With hydrogenchloride In 1,4-dioxane at 0 - 20℃; 4.6.5. (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (52) To the solution of 50 (1.0 g, 2.317 mmol) in dioxane (3.2 mL) and EA(0.8 mL), 4.0 N HCl in dioxane (4.4 mL) was added dropwise at 0 C. Thereaction was stirred at room temperature for 18 h. Then, the solvent wasevaporated to dryness and the residue was tritured with DEE (10 mL),collected by filtration, and dried in vacuo to afford the titled compoundas a yellow solid (0.852 g, two-step yield 100 %). 1H NMR (400 MHz,DMSO-d6) δ 10.16 (bs, 1H), 9.28 (d, J = 7.5 Hz, 1H), 9.09 (s, 1H), 8.58(bs, 1H), 7.44 (dd, J = 25.3, 8.2 Hz, 4H), 5.06-4.93 (m, 1H), 4.45-4.36(m, 2H), 3.35-3.24 (m, 1H), 3.12-3.03 (m, 1H), 2.68 (s, 3H), 2.46 (s,3H), 2.40-2.31 (m, 1H), 1.84-1.75 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H).
100 % With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; General procedure: (9H-fluoren-9-yl)methyl((R)-1-((2R,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo-3-(tritylthio)butan-2-yl)carbamatewas prepared following general procedure 4. 190 mg(9H-fluoren-9-yl)methyl ((R)-1-((2R,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo-3-(tritylthio)butan-2-yl)carbamatewas obtained from 118 mgtert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate,75% yield.1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.78 - 7.72 (m, 2H), 7.62 - 7.52 (m, 8H), 7.41 - 7.17 (m, 18H), 5.73 (d, J = 5.3 Hz, 1H), 5.00 (p, J = 7.0 Hz, 1H), 4.65 (t, J = 8.0 Hz, 1H), 4.42 - 4.15 (m, 4H), 3.56 (d, J = 5.3 Hz, 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.17 (dd,J= 11.6, 3.5 Hz, 1H), 2.83 (br, s, 1H), 2.51 (s, 3H), 2.44 - 2.32 (m, 1H), 2.08 - 1.96 (m, 1H), 1.39 - 1.31 (m, 6H), 1.17 (s, 3H).13C NMR (101 MHz, CDCl3) δ 170.91, 169.57, 156.61, 150.35, 148.68, 144.60, 144.02, 143.58, 143.26, 141.41, 130.99, 130.04, 129.68, 128.03, 127.94, 127.28, 127.08, 126.58, 125.29, 125.13, 120.18, 70.25, 67.79, 58.61, 58.38, 56.62, 48.92, 47.14, 35.86, 26.12, 26.05, 22.34, 16.23. LC-MS,ESI+,m/z927 [M+H]+.
7.29 g With hydrogenchloride In methanol at 4℃;
With hydrogenchloride In 1,4-dioxane; methanol at 0 - 20℃; Step 4: Dissolve 2-c (3.2g, 7.4mmol) in MeOH (30mL), add HCl/dioxane solution (30mL, 4M) at 0°C, raise the reaction solution to room temperature and stir for 2 hours. The reaction is concentrated to obtain intermediate 2 (3.1g, brown solid, crude product).
5.4 g With hydrogenchloride In 1,4-dioxane; dichloromethane; water at 20℃; for 1h; Inert atmosphere; Step 2. (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1 ,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide A solution of tert-butyl (2S,4R)-4-hydroxy-2-[(1 S)-1 -[4-(4-methyl-1 ,3-thiazol-5- yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-carboxylate (11 .7 g, 27.11 mmol) in 4N HCI in 1 ,4-dioxane (70 mL) and DCM (70 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure, The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 0% to 100% gradient in 15 min; detector, UV 254 nm, to afford the title compound (5.4 g) as a brown solid. LCMS (ESI) m/z [M+H]+= 332.3. 1H NMR (300 MHz, DMSO-d6) 5 = 9.01 (s, 1 H), 8.22 - 8.06 (m, 1 H), 7.48 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 5.10 - 4.93 (m, 1 H), 4.47 - 4.25 (m, 3H), 3.11 (s, 1 H), 2.46 (s, 3H), 2.36 (dd, J = 13.2, 7.2 Hz, 3H), 1 .92 - 1 .75 (m, 1 H), 1 .43 (d, J = 7.0 Hz, 3H). LCMS (ESI) m/z [M+H]+= 332.2.
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 1h; Step 2: (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2 carboxamide To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl) phenyl]ethyl]carbamoy1]pyrrolidine-1-carboxylate (3.77 g, 8.74 mmol) in DCM (20 mL) was added 4M HCl-dioxane (20 mL, 80 mmol) and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to afford the title compound.
With hydrogenchloride In dichloromethane; water at 0 - 20℃; for 2h;

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  • [ 2313528-38-8 ]
YieldReaction ConditionsOperation in experiment
98% 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 dichloromethane at 0 - 20℃; for 16h; 1.9 To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxy pyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0 °C was added HATU (8.98 g, 23.5 mmol) followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, and dried over anhydrous Na2SC>4 and concentrated under vacuum. The resulting reidue was purified by silica gel flash chromatography (MeOH:DCM) to afford tert-butyl (2S,4R)- 4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl) pyrrolidine-1 -carboxylate (8.33 g, 98%). LCMS (ESI) m/z: [M+H]+ = 432.38.
98% 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 dichloromethane at 0 - 20℃; for 16h; 1.9 To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxy pyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0 °C was added HATU (8.98 g, 23.5 mmol) followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, and dried over anhydrous Na2SC>4 and concentrated under vacuum. The resulting reidue was purified by silica gel flash chromatography (MeOH:DCM) to afford tert-butyl (2S,4R)- 4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl) pyrrolidine-1 -carboxylate (8.33 g, 98%). LCMS (ESI) m/z: [M+H]+ = 432.38.
96% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 25℃; Inert atmosphere; 3 Step 3: Tert-butyl (2S, 4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1, 3-thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate. To a stirred mixture of (2S,4R)-1-(tert- butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (24.0 g, 104 mmol) and HATU (46.6 g, 123 mmol) in DMF (300 mL) were added (1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethanamine hydrochloride (24.0 g, 94.2 mmol) and DIEA (36.5 mL, 283 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 25 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (200 mL) at 0 °C. The resulting mixture was extracted with EtOAc (4 x 300 mL). The combined organic layers were washed with brine (4 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (10:1 to 1:10) to give the title compound as a light yellow solid (46.0 g, 96%): 1H NMR (400 MHz, CD3OD) d 8.89 (s, 1H), 7.50-7.41 (m, 4H), 5.08 (td, J = 7.7, 5.6 Hz, 1H), 4.44-4.27 (m, 2H), 3.57 (dt, J = 11.5, 3.7 Hz, 1H), 3.50 (dt, J = 11.4, 1.9 Hz, 1H), 2.50 (s, 3H), 2.30-2.18 (m, 1H), 1.95 (ddd, J = 13.1, 8.6, 4.6 Hz, 1H), 1.56-1.46 (m, 3H), 1.44 s, 9H); LC/MS (ESI, m/z): [(M + H)]+ = 432.15.
85.4% Stage #1: (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride; (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With HCTU; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Stage #2: With sodium hydroxide In N,N-dimethyl-formamide for 0.333333h; Synthesis of Compound 5 (2S,4R)-l-[(2S)-2-{4-[4-([(3S,6S, 7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ (lS)-l-[4- (4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (1.009 g, 3.96 mmol) was dissolved in DMF (8 mL) and treated with iPr2EtN (2.07 mL, 11.9 mmol), Boc- trans-4-hydroxy-L-proline (916mg, 3.96 mmol), and HCTU (1.80 g, 4.36 mmol) at 0 °C then allowed to warm to rt and stirred for Ihr. IM NaOH (50mL) was added and stirring for 20min then the mixture was diluted with water and extracted with EtOAc (x2) and the combined extract was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel rinsing with 5% MeOH in EtOAc, and concentrated to give Intermediate 15-1 (tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate; 1.46 g, 85.4%) as a white foam. LC/MS-ESI [M+H]+= 432.0 m/z.
57% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 12h; 4 Step 4: Preparation of tert- butyl (2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine- 1 -carboxylate Into a lOO-mL round-bottom flask, was placed (2S,4R)-l-[(tert-butoxy)carbonyl]-4- hydroxypyrrolidine-2-carboxylic acid (4.7 g, 20.32 mmol, 1.00 equiv) in N,N- dimethylformamide (20 mL), N-ethyl-N-isopropylpropan-2-amine (7.8 g, 60.35 mmol, 3.00 equiv), o-(7-Azabenzotriazol-l-yl)-N,N,N',N'-te-tramethyiuronium he afluorophosphate (11.5 g, 30.26 mmol, 1.50 equiv), (lS)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethan-l-amine (4.4 g, 20.15 mmol, 1.00 equiv). The resulting solution was stirred for 12 hours at room temperature. The reaction mixture was quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (100 mL x 3) and the organic layers combined and dried in an oven under reduced pressure, concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 5.0 g (57%) of tert-butyl (2S ,4R)-4-hydroxy-2- [ [( 1 S )- 1 - [4-(4-methyl- 1 ,3 -thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-l-carboxylate as a yellow solid. LC/MS (ESI) in/z: 432.15 [M+l] +.
57% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 12h; 4 Step 4: Preparation of tert- butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate Into a 100-mL round-bottom flask, was placed (2S,4R)-1-[(tert-butoxy)carbonyl]-4- hydroxypyrrolidine-2-carboxylic acid (4.7 g, 20.32 mmol, 1.00 equiv) in N,N- dimethylformamide (20 mL), N-ethyl-N-isopropylpropan-2-amine (7.8 g, 60.35 mmol, 3.00 equiv), o-(7-Azabenzotriazol-1-yl)-N,N,N',N'-te-tramethyluronium hexafluorophosphate (11.5 g, 30.26 mmol, 1.50 equiv), (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-amine (4.4 g, 20.15 mmol, 1.00 equiv). The resulting solution was stirred for 12 h at room temperature. The reaction mixture was quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (100 mL x 3) and the organic layers combined and dried in an oven under reduced pressure, concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 5.0 g (57%) of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate as a yellow solid. LC/MS (ESI) m/z: (2306) 432.15 [M+1] +.
57% 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 12h; 4 Step 4: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate Into a 100-mL round-bottom flask, was placed (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.7 g, 20.32 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), N-ethyl-N-isopropylpropan-2-amine (7.8 g, 60.35 mmol, 3.00 equiv), o-(7-Azabenzotriazol-1-yl)-N,N,N',N'-te-tramethyluronium hexafluorophosphate (11.5 g, 30.26 mmol, 1.50 equiv), (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-amine (4.4 g, 20.15 mmol, 1.00 equiv). The resulting solution was stirred for 12 hours at room temperature. The reaction mixture was quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (100 mL x 3) and the organic layers combined and dried in an oven under reduced pressure, concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 5.0 g (57%) of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate as a yellow solid. LC/MS (ESI) m/z: 432.15 [M+1] +
56.6% 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℃; for 3h; 1.1.3 The (S)-1-(4-(4-methylthiazole-5-yl)phenyl) ethyl-1-amine hydrochloride (compound C-6) (17.32g, 68mmol), (2S,4R)-1-(tert-butoxycarbonyl)-2-carboxy-4-hydroxypyrrolidine (Compound C-7) (17.29g, 0.75mmol), diisopropylethylamine (19.33g, 150mmol) was added to N, N-dimethylformamide (87mL), stirred and dissolved. At room temperature, HATU (31.02g, 1.2eq) was added to the system, and the reaction was stirred for 3 hours. To the reaction solution was added saturated lithium chloride and sodium chloride aqueous solution, diluted with ethyl acetate, separated, organic phase with saturated lithium chloride and sodium chloride aqueous solution washed (100mLx3), anhydrous sodium sulfate dried, filtered, concentrated filtrate, to obtain oily crude products. Silica gel column chromatography purification (petroleum ether: ethyl acetate = 1: 1 ~ 0:1) to give a white solid product (2S, 4R) -4-hydroxy-2- ((S)-1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-tert-butyl carboxylate (compound C-8) (16.60g, yield 56.6%).
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℃; for 1.5h; 210.210-1 (210-1) tert-butyl (2S, 4R) -4-hydroxy-2-({(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl} Carbamoyl) pyrrolidine-1-carboxylate (Example Compound 210-1) Reference Example Compound 5-3 (944 mg), (2S, 4R) -1-t-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (1.0 g) of N, N-dimethylformamide (22.0 mL) N, N-diisopropylethylamine (2.99 mL) and HATU (1.97 g) were added to the mixture, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 90:10)The title compound (2.02 g) was obtained as a crude brown oil.
83 % With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; 3.1 Step 1: te/7-Butyl (25,4A)-4-hydroxy-2-(((5)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine- 1 -carboxylate A solution of (5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethan-l-amine (hydrochloride salt) (10.0 g, 39.3 mmol), (2,S',4/?)- l-(/c77-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (9.07 g, 39.2 mmol), HATU (17.9 g, 47.0 mmol) and DIPEA (25.3 g, 195 mmol) in DMF (lOOmL) was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-packed Cl 8 column (solvent gradient: 0-100% ACN in water (0.05% NH4HCO3)) to yield 14.2 g (83% yield) of the title compound as an off-white solid. LC-MS: (ESI, m/z): [M+H]+= 432
83 % With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; 3.1 Step 1: te/7-Butyl (25,4A)-4-hydroxy-2-(((5)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine- 1 -carboxylate A solution of (5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethan-l-amine (hydrochloride salt) (10.0 g, 39.3 mmol), (2,S',4/?)- l-(/c77-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (9.07 g, 39.2 mmol), HATU (17.9 g, 47.0 mmol) and DIPEA (25.3 g, 195 mmol) in DMF (lOOmL) was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-packed Cl 8 column (solvent gradient: 0-100% ACN in water (0.05% NH4HCO3)) to yield 14.2 g (83% yield) of the title compound as an off-white solid. LC-MS: (ESI, m/z): [M+H]+= 432
98 % 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 dichloromethane at 0 - 20℃; 1.9 Step 9: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate. To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1 -amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0 °C was added HATU (8.98 g, 23.5 mmol) followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, and dried over anhydrous Na2SC>4 and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (MeOH/DCM) to afford tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate (8.33 g, 98%). LCMS (ESI) m/z: [M+H]+= 432.38.
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℃; tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylatewas prepared following general proceure 3. 380 mgtert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylatewas obtained from 337 mgtert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate,83% yield.1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.45 - 7.37 (m, 4H), 5.13 (s, 1H), 4.49 (d, J = 35.0 Hz, 2H), 3.75 - 3.35 (m, 2H), 2.55 (s, 3H), 1.94 (d, J = 3.8 Hz, 1H), 1.62 (s, 1H), 1.56 - 1.33 (m, 12H).
98 % 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 dichloromethane at 0 - 20℃; 1.9 Step 9: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate. To a solution of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1 -amine hydrochloride (5.0 g, 19.6 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (4.47 g, 20.5 mmol) in DCM (70 mL) at 0 °C was added HATU (8.98 g, 23.5 mmol) followed by dropwise addition of DIEA (16.4 mL, 98.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted several times with DCM. The combined organic layers were washed with water, brine, and dried over anhydrous Na2SC>4 and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (MeOH/DCM) to afford tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate (8.33 g, 98%). LCMS (ESI) m/z: [M+H]+= 432.38.
1.038 g With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; 4.6.4. (2S,4R)-tert-butyl 4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (50) Under nitrogen atmosphere, to a stirred solution of 49 (0.650 g,2.551 mmol) in dry DMF (3 mL) and dry DCM (3 mL), Et3N (1.08 mL,7.77 mmol), (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.601 g, 2.602 mmol) and HATU (1.181 g, 3.106 mmol)were added at 0 C. The mixture was stirred for 1 h at 0 C and then for17 h at room temperature. Then, DCM was evaporated in vacuo and tothe residue was added saturated NaHCO3 solution (60 mL). The reactionwas extracted with EA (40 mL x 3), washed with water (20 mL x 2), brine(20 mL), dried over anhydrous Na2SO4 and concentrated under reducedpressure to afford the desired compound as a yellow solid (1.038 g)which was used directly for the next step.
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℃; tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylatewas prepared following general proceure 3. 380 mgtert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylatewas obtained from 337 mgtert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate,83% yield.1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.45 - 7.37 (m, 4H), 5.13 (s, 1H), 4.49 (d, J = 35.0 Hz, 2H), 3.75 - 3.35 (m, 2H), 2.55 (s, 3H), 1.94 (d, J = 3.8 Hz, 1H), 1.62 (s, 1H), 1.56 - 1.33 (m, 12H).
62.3 % 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℃; 10.1 Step 1: Preparation of (2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine -1-Formic acidtert-butyl ester Combine (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (1.0g, 3.92mmol) and (2S,4R)-1-[( Tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (998 mg, 4.31 mmol) was dissolved in DMF (10 mL), and N, N-diisopropylethylamine (1.52 g, 11.76 mmol) was added and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.94g, 5.10mmol).Stir at 25°C for 3 hours.The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1, volume ratio) to obtain the title compound (1.23 g, yield: 62.3%).
13.9 g With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 2h; Inert atmosphere; Step 1. tert-Butyl (2S,4R)-4-hydroxy-2-[(1S)-1-[4-(4-methyl-1 ,3-thiazol-5- yl)phenyl]ethyl]carbamoyl}pyrrolidine-1 -carboxylate To a stirred solution of (1 S)-1-[4-(4-methyl-1 ,3-thiazol-5-yl)phenyl]ethanamine hydrochloride (10 g, 39.25 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (9.08 g, 39.25 mmol) in DCM (100 mL) was added EEDQ (9.7 g, 39.25 mmol). The mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % FA), 0% to 100% gradient in 30 min; detector, UV 254 nm, to afford the title compound (13.9 g) as a white solid. LCMS (ESI) m/z [M+H]+= 432.1 .

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