Structure of 1973408-97-7
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| CAS No. : | 1973408-97-7 |
| Formula : | C17H22N2O2S |
| M.W : | 318.43 |
| SMILES Code : | O=C(OC(C)(C)C)N[C@H](C1=CC=C(C2=C(C)N=CS2)C=C1)C |
| English Name : | (S)-tert-Butyl (1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate |
| MDL No. : | MFCD30741909 |
* 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.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; for 2h; Inert atmosphere; | 65.2 Step 2: 7er/-butyl N-r(TSVl-r4-(4-methylthiazol-5-v0phenyl1ethyl1carbamate. A mixture of /er/-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (15.0 g, 50.0 mmol), potassium acetate (9.81 g, 100 mmol) and Pd(OAc)2 (112 mg, 0.50 mmol) in DMA (100 mL) at it, was added 4-methylthiazole (9.10 mL, 100 mmol). The mixture was purged with nitrogen and put under vacuum (3 x cycle) and then stirred at 120 °C for 2 h. The mixture was cooled to rt and diluted with water (250 mL). The resulting solid was filtered and washed with water (500 mL). The solid was dried in a vacuum oven at 65 °C for 18 h to afford the title compound 15.6 g, 98%). MS (ESI) [M+H]+ 319.2. |
| 98.04% | With palladium diacetate In N,N-dimethyl acetamide at 150℃; for 4h; Inert atmosphere; | 1 Under argon, tert-butyl (S)-(1-(4-bromophenyl)ethyl)carbamate (5 g, 16.66 mmol), 4-methylthiazole (3.30 g, 33.31 mmol), palladium acetate (37.39 mg, 166.56 μmol), potassium acetate (3.27 g, 33.31 mmol), and DMA (10 mL) were mixed and heated at 150°C for 4 hours. The reaction mixture was filtered, and the filtrate was added to ice water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 75:%:25%) to obtain H64-c (5.2 g, 16.33 mmol, 98.04% yield) as a yellow solid. |
| 85% | With palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 18h; Inert atmosphere; |
| 82.3% | With palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 18h; Inert atmosphere; | 2 Preparation of (5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride A mixture of (S)-tert-b ty -l-(4-bromophenyl)-ethyl carbamate (4.0 g, 13.3 mmol), 4- methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF(10 mL) was stirred at 90°C under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H20 (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50°C to afford (S)-tert-b ty l-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. HNMR (400 MHz, DMSO-d6): δ 1.33 (d, / = 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J = 8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+l]+: 319.5 [00205] This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3h then concentrated and triturated with ether. The mixture was filtered and the solid was collected and dried in oven at 60°C to afford (5)-l-(4-(4- methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g , 85%) as a light green solid. HNMR (400 MHz, DMSO-d6): 5 1.56 (d, = 6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, = 8.4Hz, 2H), 7.67 (d, / = 8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+l]+: 219.2 |
| 82.3% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 18h; Inert atmosphere; | 2 Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (3) A mixture of compound 2 (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 90° C. under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H2O (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50° C. to afford (S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1]+: 319.5 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 h. the mixture was filtered and the solid was collected and dried in oven at 60° C. to afford (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as a light green solid. 1HNMR (400 MHz, DMSO-d6): δ 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1]+: 219.2 |
| 82.3% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; for 18h; | 2 Step 2: Preparation of (5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (3) A mixture of intermediate compound 2 (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 90°C under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H20 (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50°C to afford (S)-ieri-butyl 1- (4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): δ 1.33 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J = 8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC- MS [M+l]+: 319.5 |
| 82.3% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; for 18h; Inert atmosphere; | 2 Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride A mixture of (S)-tert-butyl-1-(4-bromophenyl)-ethyl carbamate (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF (10 mL) was stirred at 90° C. under N2 for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H2O (50 mL) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50° C. to afford (S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1]+: 319.5 |
| 82.3% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; for 18h; Inert atmosphere; | 2 Step 2: Preparation of (ri)-l-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride A mixture of (S)-tert- butyl -l-(4-bromophenyl)-ethyl carbamate (4.0 g, 13.3 mmol), 4- methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF(10 mL) was stirred at 90°C under N2 for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H2O (50 mL) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50°C to afford (S)- /c/T-butyl l-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid.1HNMR (400 MHz, DMSO-de): d 1.33 (d, J= 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64- 4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J = 8 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+l]+: 319.5 |
| 74% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 18h; | Tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (AL) The titled compound can be prepared according to the process described by Raina K. et al. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129. Under nitrogen atmosphere, a mixture of compound tert-butyl (S)-1-(4-bromophenyl)ethyl)carbamate (AK) (5.00 g, 16.65 mmol), 4-methylthiazole (commercially available from, for example, Fluorochem) (3.30 g, 33.31 mmol), palladium (11) acetate (0.037 g, 0.166 mmol), and potassium acetate (3.27 g, 33.31 mmol) in DMA (12.5 mL) was stirred at 90° C. for 18 h. After cooling, the reaction mixture was filtered. Water (60 mL) was added to the filtrate, and the resulting mixture was stirred at rt for 4 h. The solid was collected by filtration and dried in an oven at 50° C. to afford the titled compound (3.14 g, 74% yield) as a gray solid. 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.44-7.40 (m, 2H), 7.41-7.35 (m, 2H), 4.86 (bs, 2H), 2.56 (s, 3H), 1.50 (d, J=6.5 Hz, 3H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 155.06, 150.20, 148.48, 131.65, 130.72, 129.48 (2C), 127.60, 126.20 (2C), 79.60, 49.91, 28.39 (3C), 22.71, 16.11. |
| 68% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 100℃; for 4h; Inert atmosphere; | 1.1.3 4-Methylthiazole (Compound C-4) (19.82g, 0.2mol), palladium acetate (4.49g, 0.2mol), potassium acetate (19.61g, 0.2mol), successively added to (S)-1-((4-bromophenyl)ethyl) carbamate (compound C-3) (30.00g, 0.1mol) of N, N-dimethylformamide (150mL) solution, stirred evenly. After the nitrogen gas is displaced, the reaction solution is stirred at 100 °C for 4 hours. After the reaction is complete, the reaction liquid is filtered, ethyl acetate (200mL×2) is extracted, the filtrate is concentrated to 50mL, water (375mL) is added, and the gray solid product is gradually precipitated. After stirring for 4 hours, it was filtered and dried to give a gray solid product (S)-(1-(4-(4-methylthiazole-5-yl)phenyl)) ethyl) tert-butyl carbamate (compound C-5) (21.65g, yield 68%). |
| 66% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 120℃; for 16h; | Step-b: Synthesis of tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (17b) To a stirred solution of tert-butyl (S)-(1-(4-bromophenyl)ethyl)carbamate (20.0 g, 66.66 mmol) and 4-methylthiazole (13.11 g, 133.32 mmol) in DMF (250 mL) was added KOAc (19.66 g, 99.98 mmol) and Pd(OAC)2 (0.75 g, 33.33 mmol). The reaction mixture was heated at 120 °C for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture was allowed to cool to RT and poured into ice cold water. The resulting mixture was extracted with ethyl acetate (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 residue which was purified by combi flash column chomatography using 15 % ethyl acetate in hexane as eluent to afford the title compound (14.0 g, 66 %). 1H NMR (400 MHz, DMSO-d6): d 8.97 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38-7.35 (m, 3H), 4.63 (d, J = 6.8 Hz, 1H), 2.45 (s, 3H), 1.35 (s, 9H), 1.25 (d, / = 7.3 Hz, 3H), LC-MS: m/z 319.1 (M+l)+. |
| 55% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 110℃; Inert atmosphere; | |
| 47% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 20 - 120℃; for 2h; Inert atmosphere; | 2 tep 2: Synthesis of tert-butyl N-[(lS)-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl] ethyl] carbamate (P) tep 2: Synthesis of tert-butyl N-[(lS)-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl] ethyl] carbamate (P)[0421] To a stirred solution of tert-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (O,15.0 g, 49.97 mmol) in DMA (100 mL), under an atmosphere of nitrogen, was added 4-methyl- 1,3-thiazole (9.9 g, 99.84 mmol), potassium acetate (9.8 g, 99.86 mmol) and Pd(OAc)2(112.5 mg, 0.50 mmol) at rt. The resulting mixture was then stirred at 120°C for 2h. The reaction mixture was then cooled to rt, diluted by water (120mL), and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:5) to give P (yield: 47%) as a white solid. LC-MS (ES+): m/z 319.13 [MH+], tR= 0.97 min (2.0 minute run). |
| 47% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; for 2h; Inert atmosphere; | 2 Step 2: Synthesis of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (P) To a stirred solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (0, 15.0 g, 49.97 mmol) in DMA (100 mL), under an atmosphere of nitrogen, was added 4-methyl-1,3-thiazole (9.9 g, 99.84 mmol), potassium acetate (9.8 g, 99.86 mmol) and Pd(OAc)2 (112.5 mg, 0.50 mmol) at rt. The resulting mixture was then stirred at 120° C. for 2 h. The reaction mixture was then cooled to rt, diluted by water (120 mL), and extracted with ethyl acetate (200 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v:v=1:5) to give P (yield: 47%) as a white solid. LC-MS (ES+): m/z 319.13 [MH+], tR=0.97 min (2.0 minute run). |
| 47% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; for 2h; | 2 Step 2: Preparation of //77-butyl (S)-(l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamate Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (15.0 g, 49.97 mmol, 1.00 equiv) in N,N-Dimethylaeetamide (100 mL), 4-methyl- l,3-thiazole (9.9 g, 99.84 mmol, 2.00 equiv), potassium acetate (9.8 g, 99.86 mmol, 2.00 equiv), palladium(II) acetate (112.5 mg, 0.50 mmol, 0.01 equiv). The resulting solution was stirred for 2 hours at l20°C. The reaction mixture was quenched by the addition of water (500 mL). The resulting solution was extracted with ethyl acetate (200 mL x 3) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.5 g (47%) of tert-butyl N-[(lS)-l-[4-(4-methyl- l,3-thiazol-5-yl)phenyl]ethyl]carbamate as a white solid. LC/MS (ESI) in/z: 319.13 [M+Na] +. |
| 47% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; for 2h; Inert atmosphere; | 2 Step 2: Preparation of tert-butyl (S)-(1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamate Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (15.0 g, 49.97 mmol, 1.00 equiv) in N,N-Dimethylacetamide (100 mL), 4-methyl-1,3-thiazole (9.9 g, 99.84 mmol, 2.00 equiv), potassium acetate (9.8 g, 99.86 mmol, 2.00 equiv), palladium(II) acetate (112.5 mg, 0.50 mmol, 0.01 equiv). The resulting solution was stirred for 2 h at 120C. The reaction mixture was quenched by the addition of water (500 mL). The resulting solution was extracted with ethyl acetate (200 mL x 3) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.5 g (47%) of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl]carbamate as a white solid. LC/MS (ESI) m/z: 319.13 [M+Na] +. |
| 47% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; | 9.1.b b. Synthesis of Intermediate V2 Dissolve V1 (1.67g, 5.56mmol) with 20mL dry DMF, add 4-methylthiazole (1.10g, 11.13mmol) and Pd(OAc)2 in sequence(13mg, 0.056mmol) and potassium acetate (1.09g, 11.13mmol), reacted at 90°C for 2h under argon protection.After the reaction is over, cool to room temperature, add water, extract three times with ethyl acetate, combine the organic phases, wash with saturated NaCl solution and then with anhydrous Na2SO4dry.Column separation (P/E=15/1) gave white solid V2 (0.60 g, 47%). |
| 47% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; for 2h; Inert atmosphere; | 2 Step 2: Preparation of tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (15.0 g, 49.97 mmol, 1.00 equiv) in N,N-Dimethylacetamide (100 mL), 4-methyl-1,3-thiazole (9.9 g, 99.84 mmol, 2.00 equiv), potassium acetate (9.8 g, 99.86 mmol, 2.00 equiv), palladium(II) acetate (112.5 mg, 0.50 mmol, 0.01 equiv). The resulting solution was stirred for 2 hours at 120°C. The reaction mixture was quenched by the addition of water (500 mL). The resulting solution was extracted with ethyl acetate (200 mL x 3) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 7.5 g (47%) of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate as a white solid. LC/MS (ESI) m/z: 319.13 [M+Na] + |
| 38% | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 80℃; for 16h; Inert atmosphere; | 1 Step 1: Tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate. To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (70.0 g, 233 mmol) and 4- methylthiazole (25.5 g, 257 mmol) in DMF (500 mL) were added AcOK (45.8 g, 466 mmol) and Pd(OAc)2 (5.24 g, 23.3 mmol). After being stirred for 16 h at 80 °C under nitrogen atmosphere. The reaction was cooled down to room temperature and was quenched by the addition of water (200 mL). The resulting mixture was extracted with EtOAc (3 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 8:1) to afford the title compound as a light yellow solid (30.0 g, 38%): 1H NMR (400 MHz, CD3OD) d 8.86 (s, 1H), 7.48-7.36 (m, 4H), 4.82-4.63 (m, 1H), 2.48 (s, 3H), 1.43 (s, 9H), 1.42 (d, J = 6.9 Hz, 3H); |
| 32% | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 18h; Inert atmosphere; | |
| With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; | ||
| With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; for 12h; | ||
| With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 12h; | ||
| With potassium acetate; palladium diacetate In dimethyl amine at 90℃; for 12h; | ||
| 23.4 g | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 7h; Inert atmosphere; | 5.5-2 (5-2) t-Butyl {(1S) -1-[4-(4-methyl-1,3-thiazole-5-yl) phenyl] ethyl} carbamate (Reference Example Compound 5-2) A mixture of Reference Example compound 5-1 (32.2 g), dimethylacetamide (80 mL), 4-methylthiazole (21.3 g), palladium acetate (482 mg) and potassium acetate (21.0 g) was added to a mixture at 90 ° C. under a nitrogen atmosphere. Was stirred for 7 hours.Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give the title compound (23.4 g) as a colorless solid. |
| Stage #1: 4-Methylthiazole; (S)-tert-butyl (1-(4-bromophenyl)ethyl)carbamate With potassium acetate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: With palladium diacetate In N,N-dimethyl-formamide at 20 - 90℃; for 16.0833h; Inert atmosphere; | ||
| 19 g | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 12h; Inert atmosphere; | |
| With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; for 18h; | 7 Scheme 7. Synthesis of VHL-based E3LB-3 moiety and linker connection: | |
| 84 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 130℃; Inert atmosphere; | |
| With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | Synthesis of VHL ligand VIII The synthetic route of VHL ligand VIII is shown in the following reaction formula: first, under alkaline conditions,Use di-tert-butyl dicarbonate (1.0 equiv.) to (S)-(-)-1-(4-bromophenyl)ethylamine I (1.2 equiv.)The amino group carries out Boc protection to obtain intermediate compound IV, then compound IV (1.0equiv.)and tetramethylthiazole (1.2equiv.) at 90°C by palladium acetate (0.3equiv.)The catalytic reaction produces intermediate V. After V was deprotected by TFA (1.1equiv.),Intermediate VI was obtained by amide condensation with Boc-Hyp-OH (1.0 equiv.) at room temperature. After VI was deprotected by TFA, intermediate VII was obtained by amide condensation with Boc-L-tert-Leu (1.05 equiv.) at room temperature. VII was deprotected by TFA (1.0 equiv.) to generate compound VIII. | |
| 47 % | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; | 4.1.2. Tert-butyl-(S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (V2) To a solution of V1 (1.67 g, 5.56 mmol) in dry DMF (20 mL) wasadded 4-methylthiazole (1.10 g, 11.13 mmol), Pd(OAc)2 (13 mg, 0.056)2mmol) and AcOK (1.09 g, 11.13 mmol) successively, followed by reactionat 90 .C under argon for 2 h. The reaction mixture was cooled toroom temperature and concentrated in vacuo. Then the residue wasextracted with 15 mL ethyl acetate and 10 mL H2O, and organic phasewas separated, washed with brine and dried with Na2SO4 followed byconcentration to give the crude product. The compound was purified bydry-loaded silica gel chromatography (petroleum ether/ethyl acetate=1H15/1) to give a white solid V2 (0.60 g, 47%).NMR (400 MHz, CDCl3)8.70 (s, 1H, Ar-Ha), 7.37-7.43 (m, 4H, Ar-H × 4), 4.84-4.89 (m, 2H,×13CCH & NH), 2.55 (s, 3H, CH3), 1.45-1.50 (m, 12H, CH3 & CH3 × 3);&×NMR (100 MHz, CDCl3)155.07, 150.22, 150.22, 148.30, 131.76,130.59, 129.46, 126.22, 79.59, 49.86, 28.39, 22.70, 16.02. |
| 47 % | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; | 4.1.2. Tert-butyl-(S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (V2) To a solution of V1 (1.67 g, 5.56 mmol) in dry DMF (20 mL) wasadded 4-methylthiazole (1.10 g, 11.13 mmol), Pd(OAc)2 (13 mg, 0.056)2mmol) and AcOK (1.09 g, 11.13 mmol) successively, followed by reactionat 90 .C under argon for 2 h. The reaction mixture was cooled toroom temperature and concentrated in vacuo. Then the residue wasextracted with 15 mL ethyl acetate and 10 mL H2O, and organic phasewas separated, washed with brine and dried with Na2SO4 followed byconcentration to give the crude product. The compound was purified bydry-loaded silica gel chromatography (petroleum ether/ethyl acetate=1H15/1) to give a white solid V2 (0.60 g, 47%).NMR (400 MHz, CDCl3)8.70 (s, 1H, Ar-Ha), 7.37-7.43 (m, 4H, Ar-H × 4), 4.84-4.89 (m, 2H,×13CCH & NH), 2.55 (s, 3H, CH3), 1.45-1.50 (m, 12H, CH3 & CH3 × 3);&×NMR (100 MHz, CDCl3)155.07, 150.22, 150.22, 148.30, 131.76,130.59, 129.46, 126.22, 79.59, 49.86, 28.39, 22.70, 16.02. |
| 94.3 % | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 120℃; Inert atmosphere; | 1 The first step is the synthesis of intermediate tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamide (TV-3) Add compound TV-1 (6.61g, 66.62mmol, 2.0eq.) in the DMF (150mL) solution of compound TV-2 (10.0g, 33.31mmol, 1.0eq.),KOAc (6.53g, 66.62mmol, 2.0eq.) and Pd(OAc)2 (305.05mg, 0.33mmol, 0.01eq.).The reactant was reacted at about 120°C under the protection of nitrogen. After the reaction was completed, it was concentrated, and the residue was purified by silica gel column chromatography to obtain the target product TV-3 (10g, 31.40mmol, 94.3% yield) |
| 74 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; Inert atmosphere; | Tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (G). Under nitrogen atmosphere, a mixture of compound tert-butyl (S)-1-(4- bromophenyl)ethyl)carbamate (F) (5.00 g, 16.65 mmol), 4-methylthiazole (3.30 g, 33.31 mmol), palladium (II) acetate (0.037 g, 0.166 mmol), and potassium acetate (3.27 g, 33.31 mmol) in DMA (12.5 mL) is stirred at 90 °C for 18 h. After cooling, the reaction mixture is filtered. Water (60 mL) is added to the filtrate, and the resulting mixture is stirred at rt for 4 h. The solid is collected by filtration and dried in an oven at 50 °C to afford the titled compound (3.14 g, 74% yield) as a gray solid.1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.44-7.40 (m, 2H), 7.41-7.35 (m, 2H), 4.86 (bs, 2 ), 2.56 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H), 1.46 (s, 9H);13C NMR (101 MHz, CDCl3): δ 155.06, 150.20, 148.48, 131.65, 130.72, 129.48 (2C), 127.60, 126.20 (2C), 79.60, 49.91, 28.39 (3C), 22.71, 16.11. |
| With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | Synthesis of VHL ligand VIII The synthetic route of VHL ligand VIII is shown in the following reaction formula: first, under alkaline conditions,Use di-tert-butyl dicarbonate (1.0 equiv.) to (S)-(-)-1-(4-bromophenyl)ethylamine I (1.2 equiv.)The amino group carries out Boc protection to obtain intermediate compound IV, then compound IV (1.0equiv.)and tetramethylthiazole (1.2equiv.) at 90°C by palladium acetate (0.3equiv.)The catalytic reaction produces intermediate V. After V was deprotected by TFA (1.1equiv.),Intermediate VI was obtained by amide condensation with Boc-Hyp-OH (1.0 equiv.) at room temperature. After VI was deprotected by TFA, intermediate VII was obtained by amide condensation with Boc-L-tert-Leu (1.05 equiv.) at room temperature. VII was deprotected by TFA (1.0 equiv.) to generate compound VIII. | |
| 74 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; Inert atmosphere; | Tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (G). Under nitrogen atmosphere, a mixture of compound tert-butyl (S)-1-(4- bromophenyl)ethyl)carbamate (F) (5.00 g, 16.65 mmol), 4-methylthiazole (3.30 g, 33.31 mmol), palladium (II) acetate (0.037 g, 0.166 mmol), and potassium acetate (3.27 g, 33.31 mmol) in DMA (12.5 mL) is stirred at 90 °C for 18 h. After cooling, the reaction mixture is filtered. Water (60 mL) is added to the filtrate, and the resulting mixture is stirred at rt for 4 h. The solid is collected by filtration and dried in an oven at 50 °C to afford the titled compound (3.14 g, 74% yield) as a gray solid.1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.44-7.40 (m, 2H), 7.41-7.35 (m, 2H), 4.86 (bs, 2 ), 2.56 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H), 1.46 (s, 9H);13C NMR (101 MHz, CDCl3): δ 155.06, 150.20, 148.48, 131.65, 130.72, 129.48 (2C), 127.60, 126.20 (2C), 79.60, 49.91, 28.39 (3C), 22.71, 16.11. |
| With potassium acetate; palladium diacetate at 90℃; | ||
| 71.1 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; Inert atmosphere; | 17 tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate Add (S)-tert-butyl(1-(4-bromophenyl)ethyl)carbamate (30.0g, 100mmoL), 4-methylthiazole (19.8g, 200mmoL), palladium acetate (226mg, 1.0mmoL) and potassium acetate (19.6g, 20mmol) into a 500mL three-necked flask, add N,N-dimethylacetamide (200mL), and replace the nitrogen Three times, react at 120°C for 5h. TLC monitored that the reaction was complete, cooled to room temperature, and filtered. Ethyl acetate (800mL) was added to the filtrate, washed with water (500mL) three times, separated, the organic phase was evaporated under reduced pressure to remove the solvent, the residue was separated by flash column chromatography, the eluent was ethyl acetate:petroleum ether=1:5, and 22.6g of the product was obtained, with a yield of 71.1%. |
| 74 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; Inert atmosphere; | Tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (G). The titled compound can be prepared according to the process described by Raina K. et al., Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.[00139] Under nitrogen atmosphere, a mixture of compound tert-butyl (S)-1-(4-bromophenyl)ethyl)carbamate (F) (5.00 g, 16.65 mmol), 4-methylthiazole (3.30 g, 33.31 mmol),palladium (II) acetate (0.037 g, 0.166 mmol), and potassium acetate (3.27 g, 33.31 mmol) in DMA (12.5 mL) is stirred at 90 °C for 18 h. After cooling, the reaction mixture is filtered. Water (60 mL) is added to the filtrate, and the resulting mixture is stirred at rt for 4 h. The solid is collected by filtration and dried in an oven at 50 °C to afford the titled compound (3.14 g, 74% yield) as a gray solid.1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.44-7.40 (m, 2H), 7.41-7.35 (m, 2H), 4.86 (bs, 2H), 2.56 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H), 1.46 (s, 9H);13C NMR (101 MHz, CDCl3): δ 155.06, 150.20, 148.48, 131.65, 130.72, 129.48 (2C), 127.60, 126.20 (2C), 79.60, 49.91, 28.39 (3C), 22.71, 16.11. |
| 71.1 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 120℃; Inert atmosphere; | 17 tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate Add (S)-tert-butyl(1-(4-bromophenyl)ethyl)carbamate (30.0g, 100mmoL), 4-methylthiazole (19.8g, 200mmoL), palladium acetate (226mg, 1.0mmoL) and potassium acetate (19.6g, 20mmol) into a 500mL three-necked flask, add N,N-dimethylacetamide (200mL), and replace the nitrogen Three times, react at 120°C for 5h. TLC monitored that the reaction was complete, cooled to room temperature, and filtered. Ethyl acetate (800mL) was added to the filtrate, washed with water (500mL) three times, separated, the organic phase was evaporated under reduced pressure to remove the solvent, the residue was separated by flash column chromatography, the eluent was ethyl acetate:petroleum ether=1:5, and 22.6g of the product was obtained, with a yield of 71.1%. |
| 74 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; Inert atmosphere; | Tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (G). The titled compound can be prepared according to the process described by Raina K. et al., Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.[00139] Under nitrogen atmosphere, a mixture of compound tert-butyl (S)-1-(4-bromophenyl)ethyl)carbamate (F) (5.00 g, 16.65 mmol), 4-methylthiazole (3.30 g, 33.31 mmol),palladium (II) acetate (0.037 g, 0.166 mmol), and potassium acetate (3.27 g, 33.31 mmol) in DMA (12.5 mL) is stirred at 90 °C for 18 h. After cooling, the reaction mixture is filtered. Water (60 mL) is added to the filtrate, and the resulting mixture is stirred at rt for 4 h. The solid is collected by filtration and dried in an oven at 50 °C to afford the titled compound (3.14 g, 74% yield) as a gray solid.1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.44-7.40 (m, 2H), 7.41-7.35 (m, 2H), 4.86 (bs, 2H), 2.56 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H), 1.46 (s, 9H);13C NMR (101 MHz, CDCl3): δ 155.06, 150.20, 148.48, 131.65, 130.72, 129.48 (2C), 127.60, 126.20 (2C), 79.60, 49.91, 28.39 (3C), 22.71, 16.11. |
| 2.5 g | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | B Step B: The compound INT-5-1 (5 g, 16 mmol), palladium acetate (35.8 mg, 0.16 mmol) is dissolved in N,N-dimethylacetamide (80 ml), and potassium acetate (3.1 g, 32 mmol) and 4-methylthiazole (3.2 g, 32 mmol) are added to this solution. The resulting reaction mixture is stirred at 90 degrees Celsius for 16 h. LCMS monitoring showed that after the raw material disappeared, the reaction solution was quenched with purified water (50 ml) and extracted with dichloromethane (50 ml×3). The organic phase was combined and dried with anhydrous sodium sulfate and filtered and concentrated. The resulting mixture was purified twice by silica gel column chromatography to obtain 2.5 g of compound INT-5-2. |
| 98 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 20 - 120℃; Inert atmosphere; | 6 Synthesis of tert-butyl N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate (HB7g) 7e) (15.0 g, 50.0 mmol), potassium acetate (9.81 g, 100 mmol), and Pd(OAc)2 (112 mg, 0.50 mmol) in DMA (100 mL) at rt was added 4-methylthiazole (9.10 mL, 100 mmol). The mixture was purged with nitrogen and then put under vacuum (3 x cycle) and then stirred at 120 °C for 2 h. The mixture was cooled to rt and diluted with water (250 mL). The resulting solid was filtered and washed with water (500 mL). The solid was dried in a vacuum oven at 65 °C for 18 h to afford the title compound HB7g (15.6 g, 98%). MS (ESI) [M+H]+ 319.2. |
| 61 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | [00462] To a solution of tert-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (14.5 g, 48.30 mmol, 1 eq) and 4-methylthiazole (7.18 g, 72.45 mmol, 1.5 eq) in dimethylacetamide (15 mL) was added palladium(II) acetate (542 mg, 2.42 mmol, 0.05 eq) and potassium acetate (9.48 g, 96.61 mmol, 2 eq). The mixture was stirred at 90 °C for 12 h. Water (300 mL) was added, and the mixture was stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse phase C18 column chromatography [ACN7 H2O (0.5% FA) from 5% to 50%]. /er/-Butyl N-[(lS)-l-[4- (4-methylthiazol-5-yl)phenyl]ethyl]carbamate (9.8 g, 29.85 mmol, 61% yield) was obtained as a gray solid. |
| 61 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | 6 [00415] To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (14.5 g, 48.30 mmol, 1 eq) and 4-methylthiazole (7.18 g, 72.45 mmol, 1.5 eq) in dimethylacetamide (15 mL) was added palladium(II) acetate (542 mg, 2.42 mmol, 0.05 eq) and potassium acetate (9.48 g, 96.61 mmol, 2 eq). The mixture was stirred at 90°C for 12 hours. Water (300 mL) was added, and the mixture was stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse phase C18 column chromatography [ACN/ H2O (0.5% FA) from 5% to 50%]. tert-Butyl N-[(1S)-1-[4- (4-methylthiazol-5-yl)phenyl]ethyl]carbamate (9.8 g, 29.85 mmol, 61% yield) was obtained as a gray solid. |
| 61 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | 6 [00415] To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (14.5 g, 48.30 mmol, 1 eq) and 4-methylthiazole (7.18 g, 72.45 mmol, 1.5 eq) in dimethylacetamide (15 mL) was added palladium(II) acetate (542 mg, 2.42 mmol, 0.05 eq) and potassium acetate (9.48 g, 96.61 mmol, 2 eq). The mixture was stirred at 90°C for 12 hours. Water (300 mL) was added, and the mixture was stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse phase C18 column chromatography [ACN/ H2O (0.5% FA) from 5% to 50%]. tert-Butyl N-[(1S)-1-[4- (4-methylthiazol-5-yl)phenyl]ethyl]carbamate (9.8 g, 29.85 mmol, 61% yield) was obtained as a gray solid. |
| 61 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; | [00462] To a solution of tert-butyl N-[(lS)-l-(4-bromophenyl)ethyl]carbamate (14.5 g, 48.30 mmol, 1 eq) and 4-methylthiazole (7.18 g, 72.45 mmol, 1.5 eq) in dimethylacetamide (15 mL) was added palladium(II) acetate (542 mg, 2.42 mmol, 0.05 eq) and potassium acetate (9.48 g, 96.61 mmol, 2 eq). The mixture was stirred at 90 °C for 12 h. Water (300 mL) was added, and the mixture was stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse phase C18 column chromatography [ACN7 H2O (0.5% FA) from 5% to 50%]. /er/-Butyl N-[(lS)-l-[4- (4-methylthiazol-5-yl)phenyl]ethyl]carbamate (9.8 g, 29.85 mmol, 61% yield) was obtained as a gray solid. |
| 73 g | With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 120℃; Inert atmosphere; | |
| 98 % | With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 20 - 120℃; Inert atmosphere; | 6 Synthesis of tert-butyl N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate (HB7g) 7e) (15.0 g, 50.0 mmol), potassium acetate (9.81 g, 100 mmol), and Pd(OAc)2 (112 mg, 0.50 mmol) in DMA (100 mL) at rt was added 4-methylthiazole (9.10 mL, 100 mmol). The mixture was purged with nitrogen and then put under vacuum (3 x cycle) and then stirred at 120 °C for 2 h. The mixture was cooled to rt and diluted with water (250 mL). The resulting solid was filtered and washed with water (500 mL). The solid was dried in a vacuum oven at 65 °C for 18 h to afford the title compound HB7g (15.6 g, 98%). MS (ESI) [M+H]+ 319.2. |
| With potassium acetate; palladium diacetate In N,N-dimethyl acetamide at 90℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; for 3h; | 65.3 Step 3: -l-r4-(4-methylthiazol-5-vDphenyl1ethanamine hydrochloride [Intermediate 11. To a solution of /tvV-butyl N-[(lS)-l-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamate (17.4 g, 54.6 mmol) in DCM (200 mL) at 0 °C, was added HC1 (4M in dioxane, 200 mL, 800 mmol) and the mixture was warmed to rt and stirred for 3 h. The mixture was diluted with ether (50 mL) and the resulting solid was filtered. The solid was washed with ether (500 mL) and dried to afford the title compound as a solid (15.0 g, quant). NMR (400 MHz, DMSO) 5 9.11 (s, 1H), 8.69 (br s, 3H), 7.67 - 7.62 (m, 2H), 7.58 - 7.53 (m, 2H), 4.44 (dt, J = 11.9, 5.9 Hz, 1H), 2.47 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H). MS (ESI) [M+H]+ 202.2. |
| 100% | With hydrogenchloride In ethyl acetate at 20℃; for 12h; | 1.1.3 The solution of ethyl acetate (65 mL) of (S)-(1-(4-(4-methylthiazole-5-yl)phenyl)carbamic acid tert-butyl ester (compound C-5) (21.65 g, 68 mmol) was slowly added dropwise to the ethyl acetate solution (2 M, 85 mL, 160 mmol) of hydrogen chloride, and the reaction was 12 hours at room temperature. Filtration reaction solution, filter cake with ethyl acetate leaching 2-3 times, filter cake dried to give orange solid product (S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl-1-amine hydrochloride (compound C-6) (17.32g, yield 100%). |
| 99% | With hydrogenchloride In 1,4-dioxane; water at 20℃; for 3h; | (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine Hydrochloride (AM) (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine Hydrochloride (AM) The titled compound can be prepared according to the process described by Raina K. et al. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129. A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (AL) (3.00 g, 9.42 mmol). The reaction mixture was stirred at rt for 3 h. The solvent was evaporated to dryness, and the residue was triturated with DEE, filtered, and dried in an oven at 60° C. to afford the titled product (2.37 g, 99% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.78 (bs, 3H), 7.68 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 4.52-4.38 (m, 1H), 2.48 (s, 3H), 1.56 (d, J=6.8 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): δ 152.95, 147.68, 139.93, 131.97, 131.49, 129.64 (2C), 128.09 (2C), 50.11, 21.16, 16.03. |
| 97% | With hydrogenchloride In 1,4-dioxane at 25℃; Inert atmosphere; | 2 Step 2: (1S)-1-[4-(4-methyl-1, 3-thiazol-5-yl)phenyl]ethanamine hydrochloride. To a stirred solution of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (30.0 g, 94.2 mmol) in dioxane (150 mL) was added a solution of HCl (gas) in 1,4-dioxane (4 M, 100 mL) dropwise at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 25 °C under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with EtOAc (2 x 50.0 mL) and dried to give the title compound as a yellow solid (29.0 g, 97%): 1H NMR (400 MHz, CD3OD) d 10.11 (s, 1H), 7.75 (s, 4H), 4.63 (q, J = 6.9 Hz, 1H), 2.67 (s, 3H), 1.73 (d, J = 6.9 Hz, 3H); LC/MS (ESI, m/z): [(M + H)]+ = 219.10. |
| 86% | With hydrogenchloride In methanol at 20℃; for 2h; | 3 Step 3. Synthesis of (lS)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethan-l-amine hydrochloride (Q) Step 3. Synthesis of (lS)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethan-l-amine hydrochloride (Q)[0423] To a stirred solution of tert-butyl N-[(lS)-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl] ethyl] carbamate (P, 7.5 g, 23.55 mmol) in methanol (20 mL) was bubbled in hydrogen chloride (gas) at rt for 2 h. Then the resulting mixture was concentrated under vacuum to give Q (yield: 86%) as a white solid, which was used in the next step without any further purifications. |
| 86% | With hydrogenchloride In methanol at 20℃; for 2h; | 3 Step 3. Synthesis of (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-amine hydrochloride (Q) To a stirred solution of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (P, 7.5 g, 23.55 mmol) in methanol (20 mL) was bubbled in hydrogen chloride (gas) at rt for 2 h. Then the resulting mixture was concentrated under vacuum to give Q (yield: 86%) as a white solid, which was used in the next step without any further purifications. |
| 86% | With hydrogenchloride In methanol at 20℃; for 2h; | 3 Step 3: Preparation of (S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethan-l-amine hydrochloride Into a lOO-mL round-bottom flask, was placed a solution of tert-butyl N-[(lS)-l-[4- (4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]carbamate (7.5 g, 23.55 mmol, 1.00 equiv) in methanol (20 mL), hydrogen chloride (gas) was bubbled in at room temperature. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 4.4 g (86%) of (lS)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethan-l- amine as a white solid. |
| 86% | With hydrogenchloride In methanol at 20℃; for 2h; | 3 Step 3: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[(1S)-1-[4- (4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (7.5 g, 23.55 mmol, 1.00 equiv) in methanol (20 mL), hydrogen chloride (gas) was bubbled in at room temperature. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 4.4 g (86%) of (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-amine as a white solid |
| 86% | With hydrogenchloride In methanol at 20℃; for 2h; | 3 Step 3: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (7.5 g, 23.55 mmol, 1.00 equiv) in methanol (20 mL), hydrogen chloride (gas) was bubbled in at room temperature. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 4.4 g (86%) of (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-amine as a white solid. |
| 85% | With hydrogenchloride In methanol at 20℃; for 3h; | 2 Preparation of (5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride A mixture of (S)-tert-b ty -l-(4-bromophenyl)-ethyl carbamate (4.0 g, 13.3 mmol), 4- methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF(10 mL) was stirred at 90°C under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H20 (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50°C to afford (S)-tert-b ty l-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. HNMR (400 MHz, DMSO-d6): δ 1.33 (d, / = 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J = 8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+l]+: 319.5 [00205] This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3h then concentrated and triturated with ether. The mixture was filtered and the solid was collected and dried in oven at 60°C to afford (5)-l-(4-(4- methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g , 85%) as a light green solid. HNMR (400 MHz, DMSO-d6): 5 1.56 (d, = 6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, = 8.4Hz, 2H), 7.67 (d, / = 8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+l]+: 219.2 |
| 85% | With hydrogenchloride In methanol at 20℃; for 3h; | 2 Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (3) A mixture of compound 2 (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 90° C. under N2 for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H2O (50 mL) and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50° C. to afford (S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1]+: 319.5 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 h. the mixture was filtered and the solid was collected and dried in oven at 60° C. to afford (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as a light green solid. 1HNMR (400 MHz, DMSO-d6): δ 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1]+: 219.2 |
| 85% | With hydrogenchloride In methanol at 20℃; for 3h; | 2 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 h. the mixture was filtered and the solid was collected and dried in oven at 60°C to afford (S)- l-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g , 85%) as a light green solid. 1HNMR (400 MHz, DMSO-d6): δ 1.56 (d, J = 6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J = 8.4Hz, 2H), 7.67 (d, J = 8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+l]+: 219.2 |
| 85% | With hydrogenchloride In methanol; water at 20℃; for 3h; | 2 Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride A mixture of (S)-tert-butyl-1-(4-bromophenyl)-ethyl carbamate (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF (10 mL) was stirred at 90° C. under N2 for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added H2O (50 mL) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in oven at 50° C. to afford (S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as gray solid. 1HNMR (400 MHz, DMSO-d6): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1]+: 319.5 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3h then concentrated and triturated with ether. The mixture was filtered and the solid was collected and dried in oven at 60° C. to afford (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as a light green solid. 1HNMR (400 MHz, DMSO-d6): δ 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1]+: 219.2. |
| 85% | With hydrogenchloride In methanol; water at 20℃; for 3h; | 2 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3h then concentrated and triturated with ether. The mixture was filtered and the solid was collected and dried in oven at 60°C to afford (ri)-l-(4-(4-methylthiazol-5- yl)phenyl)ethanamine hydrochloride (1.3 g , 85%) as a light green solid.1HNMR (400 MHz, DMSO-d6): d 1.56 (d, J= 6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J= 8.4Hz, 2H), 7.67 (d, J= 8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+l]+: 219.2 |
| 20.5 g | With hydrogenchloride In 1,4-dioxane; water at 20℃; for 5h; | 5.5-3 (5-3) (1S) -1-[4-(4-Methyl-1,3-thiazole-5-yl) phenyl] ethane-1-amine hydrochloride (Reference Example Compound 5-3) In a mixture of Reference example compound 5-2 (24.3 g) and 1,4-dioxane, 4M hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and suspended and washed with isopropyl ether to give the title compound (20.5 g) as a yellow solid. |
| With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 16h; | ||
| With hydrogenchloride In methanol at 25℃; for 1h; | ||
| With hydrogenchloride In 1,4-dioxane at 20℃; for 3h; | 7 Scheme 7. Synthesis of VHL-based E3LB-3 moiety and linker connection: | |
| 99 % | With hydrogenchloride In 1,4-dioxane at 20℃; | (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (H). A solution of 4N HCl in dioxane (10 mL) is added to tert-butyl (S)-(1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamate (G) (3.00 g, 9.42 mmol). The reaction mixture is stirred at rt for 3 h. The solvent is evaporated to dryness, and the residue is triturated with DEE, filtered, and dried in an oven at 60 °C to afford the titled product (2.37 g, 99% yield) as a light- yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.78 (bs, 3H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 4.52-4.38 (m, 1H), 2.48 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d6): δ 152.95, 147.68, 139.93, 131.97, 131.49, 129.64 (2C), 128.09 (2C), 50.11, 21.16, 16.03 |
| 99 % | With hydrogenchloride In 1,4-dioxane at 20℃; | (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (H). A solution of 4N HCl in dioxane (10 mL) is added to tert-butyl (S)-(1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamate (G) (3.00 g, 9.42 mmol). The reaction mixture is stirred at rt for 3 h. The solvent is evaporated to dryness, and the residue is triturated with DEE, filtered, and dried in an oven at 60 °C to afford the titled product (2.37 g, 99% yield) as a light- yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.78 (bs, 3H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 4.52-4.38 (m, 1H), 2.48 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d6): δ 152.95, 147.68, 139.93, 131.97, 131.49, 129.64 (2C), 128.09 (2C), 50.11, 21.16, 16.03 |
| With hydrogenchloride In methanol | ||
| 99 % | With hydrogenchloride In 1,4-dioxane at 20℃; | (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (H). The titled compound can be prepared according to the process described by Raina K. et al., Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.[00142] A solution of 4N HCl in dioxane (10 mL) is added to tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (G) (3.00 g, 9.42 mmol). The reaction mixture is stirred at rt for 3 h. The solvent is evaporated to dryness, and the residue is triturated with DEE, filtered, and dried in an oven at 60 °C to afford the titled product (2.37 g, 99% yield) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.78 (bs, 3H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 4.52-4.38 (m, 1H), 2.48 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d6): δ 152.95, 147.68, 139.93, 131.97, 131.49, 129.64 (2C), 128.09 (2C), 50.11, 21.16, 16.03. |
| 99 % | With hydrogenchloride In 1,4-dioxane at 20℃; | (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (H). The titled compound can be prepared according to the process described by Raina K. et al., Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7124-7129.[00142] A solution of 4N HCl in dioxane (10 mL) is added to tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (G) (3.00 g, 9.42 mmol). The reaction mixture is stirred at rt for 3 h. The solvent is evaporated to dryness, and the residue is triturated with DEE, filtered, and dried in an oven at 60 °C to afford the titled product (2.37 g, 99% yield) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.78 (bs, 3H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 4.52-4.38 (m, 1H), 2.48 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H);13C NMR (101 MHz, DMSO-d6): δ 152.95, 147.68, 139.93, 131.97, 131.49, 129.64 (2C), 128.09 (2C), 50.11, 21.16, 16.03. |
| 100 % | With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; | 6 Synthesis of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine;hydrochloride (HB7h) ethylthiazol-5- yl)phenyl]ethyl]carbamate (HB7g) (17.4 g, 54.6 mmol) in DCM (200 mL) at 0 °C was added HCl (4 M in dioxane, 200 mL, 800 mmol) and the mixture was warmed to rt and stirred for 3 h. The mixture was diluted with ether (50 mL) and the resulting solid was filtered. The solid was washed with ether (500 mL) and dried to afford the title compound HB7h as a solid (15.0 g, quant.).1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.69 (br s, 3H), 7.67 - 7.62 (m, 2H), 7.58 - 7.53 (m, 2H), 4.44 (dt, J = 11.9, 5.9 Hz, 1H), 2.47 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H). MS (ESI) [M+H]+ 202.2. |
| 100 % | With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; | 6 Synthesis of (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine;hydrochloride (HB7h) ethylthiazol-5- yl)phenyl]ethyl]carbamate (HB7g) (17.4 g, 54.6 mmol) in DCM (200 mL) at 0 °C was added HCl (4 M in dioxane, 200 mL, 800 mmol) and the mixture was warmed to rt and stirred for 3 h. The mixture was diluted with ether (50 mL) and the resulting solid was filtered. The solid was washed with ether (500 mL) and dried to afford the title compound HB7h as a solid (15.0 g, quant.).1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.69 (br s, 3H), 7.67 - 7.62 (m, 2H), 7.58 - 7.53 (m, 2H), 4.44 (dt, J = 11.9, 5.9 Hz, 1H), 2.47 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H). MS (ESI) [M+H]+ 202.2. |
| With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; | General procedure: 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). | |
| 99.8 % | With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; | 4.6.3. (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride(49) To the solution of 48 (0.655 g, 2.057 mmol) in dry DCM (1.5 mL),4.0 N HCl in dioxane (3.7 mL) was added dropwise at 0 C. The reactionwas stirred at room temperature for 18 h. Then, the solvent was evaporatedto dryness and the residue was tritured with DEE (10 mL),collected by filtration, and dried in vacuo to afford the titled compoundas a light brown solid (0.523 g, two-step yield 99.8 %). 1H NMR (400MHz, DMSO-d6) δ 9.09 (s, 1H), 8.67 (bs, 3H), 7.69-7.52 (m, 4H),4.52-4.36 (m, 1H), 2.47 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H). |
| 99.8 % | With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; | 4.6.3. (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride(49) To the solution of 48 (0.655 g, 2.057 mmol) in dry DCM (1.5 mL),4.0 N HCl in dioxane (3.7 mL) was added dropwise at 0 C. The reactionwas stirred at room temperature for 18 h. Then, the solvent was evaporatedto dryness and the residue was tritured with DEE (10 mL),collected by filtration, and dried in vacuo to afford the titled compoundas a light brown solid (0.523 g, two-step yield 99.8 %). 1H NMR (400MHz, DMSO-d6) δ 9.09 (s, 1H), 8.67 (bs, 3H), 7.69-7.52 (m, 4H),4.52-4.36 (m, 1H), 2.47 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H). |
| With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; | General procedure: 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). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 20 - 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: palladium diacetate; potassium carbonate / N,N-dimethyl-formamide / 18 h / 90 °C / Inert atmosphere |
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl-formamide / 18 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 6 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 16 h / 120 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 2 h / 120 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 18.25 h / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 2 h / 5 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h 2: palladium diacetate; potassium acetate / dimethyl amine / 12 h / 90 °C | ||
| Multi-step reaction with 2 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 | ||
| Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C 1.2: 16.25 h / 0 - 20 °C 2.1: potassium acetate / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 16.08 h / 20 - 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: ethyl acetate; water / 1 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane / 4 h / 20 °C 2: palladium diacetate; potassium carbonate / N,N-dimethyl-formamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / 2 h / 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 18 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 12 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 4 h / 100 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 2 h / 0 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 4 h / 130 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 1 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 2 h / 5 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate 2: palladium diacetate; potassium acetate / 90 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 5 - 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 1 h / 25 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 16 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 2 h / 20 - 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water / 18 h / 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 4 h / 130 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 1 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere |
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 16 h / 25 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 6 h / 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 3 h / 20 °C / Cooling with ice 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 150 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 1 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere |
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 5 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 18 h / 90 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 2 h / 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 110 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 12 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 16 h / 25 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 6 h / 120 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 18 h / 150 °C | ||
| Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 3 h / 20 °C / Cooling with ice 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 150 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: hydrogenchloride / methanol / 3 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 - 20 °C | ||
| Multi-step reaction with 2 steps 1: dichloromethane / 0.5 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 / 20 °C | ||
| Multi-step reaction with 4 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 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: hydrogenchloride / methanol / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °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 2 steps 1: hydrogenchloride / 1,4-dioxane; methanol / 4 h / 20 °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 / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: hydrogenchloride / water; 1,4-dioxane / 3 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 / tetrahydrofuran / 5 h / 0 - 20 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: hydrogenchloride / water; methanol / 3 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 / tetrahydrofuran / 2 h / 0 - 20 °C | ||
| Multi-step reaction with 4 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 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: hydrogenchloride / 1,4-dioxane / 25 °C / Inert atmosphere 2: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 4: triethylamine; HATU / 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 / 20 °C / Cooling with ice | ||
| Multi-step reaction with 2 steps 1: hydrogenchloride / water; methanol / 3 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 / tetrahydrofuran / 2 h / 0 - 20 °C | ||
| Multi-step reaction with 4 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 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: 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 3: methanol; hydrogenchloride / ethyl acetate / 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 2 steps 1: trifluoroacetic acid / 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 / 18 h / 20 °C / Inert atmosphere | ||
| 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 2.2: 20 °C | ||
| Multi-step reaction with 4 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 3: dichloromethane / 18 h / 20 °C 4: 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 / methanol 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 / 12 h / 20 °C | ||
| Multi-step reaction with 4 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 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 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 2.2: 12 h / 0 - 20 °C / Inert atmosphere | ||
| Multi-step reaction with 4 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C 3: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 0 - 20 °C | ||
| Multi-step reaction with 4 steps 1.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 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; triethylamine / N,N-dimethyl-formamide; dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane / 18 h / 0 - 20 °C 4.1: 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 4.2: 18 h / 20 °C / Inert atmosphere | ||
| Multi-step reaction with 4 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 3: hydrogenchloride / ethyl acetate / 12 h / 20 °C 4: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C | ||
| Multi-step reaction with 4 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 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 4 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 3: hydrogenchloride / 1,4-dioxane / 1 h / 16 °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 h / 16 - 20 °C | ||
| Multi-step reaction with 2 steps 1: hydrogenchloride / methanol; 1,4-dioxane / 2 h / 0 - 20 °C 2: 1-methyl-1H-imidazole / acetonitrile / 3 h / 20 °C | ||
| Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / Cooling with ice 1.2: 3 h / 20 °C 2.1: trifluoroacetic acid / 1 h / Cooling with ice 2.2: 3 h / 20 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: hydrogenchloride / methanol / 3 h / 20 °C 2: HATU; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 - 20 °C 3: hydrogenchloride / methanol / 3 h / 20 °C | ||
| Multi-step reaction with 5 steps 1: hydrogenchloride / methanol / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C 3: hydrogenchloride / methanol / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C 5: hydrogenchloride / methanol / 2 h / 20 °C | ||
| Multi-step reaction with 3 steps 1: hydrogenchloride / water; 1,4-dioxane / 3 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 / tetrahydrofuran / 5 h / 0 - 20 °C / Inert atmosphere 3: hydrogenchloride / water; 1,4-dioxane / 3 h / 20 °C |
| Multi-step reaction with 3 steps 1: hydrogenchloride / water; methanol / 3 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 / tetrahydrofuran / 2 h / 0 - 20 °C 3: hydrogenchloride / water; methanol / 3 h / 20 °C | ||
| Multi-step reaction with 5 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 3: hydrogenchloride / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 4: triethylamine; HATU / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere | ||
| Multi-step reaction with 3 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 / 20 °C / Cooling with ice 3: hydrogenchloride / water; 1,4-dioxane; chloroform / 20 °C / Cooling with ice | ||
| Multi-step reaction with 3 steps 1: hydrogenchloride / water; methanol / 3 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 / tetrahydrofuran / 2 h / 0 - 20 °C 3: hydrogenchloride / water; methanol / 3 h / 20 °C | ||
| Multi-step reaction with 5 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 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 5: hydrogenchloride / methanol / 2 h / 20 °C | ||
| Multi-step reaction with 5 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 3: methanol; hydrogenchloride / ethyl acetate / 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 5: methanol; hydrogenchloride / ethyl acetate | ||
| Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane / 3 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 / tetrahydrofuran / 5 h / 0 - 20 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C | ||
| Multi-step reaction with 5 steps 1.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 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; triethylamine / N,N-dimethyl-formamide; dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane / 18 h / 0 - 20 °C 4.1: 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 4.2: 18 h / 20 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; 1,4-dioxane; dichloromethane / 0 - 20 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: dichloromethane / 0.5 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 / 20 °C 3: trifluoroacetic acid / dichloromethane / 20 °C | ||
| Multi-step reaction with 5 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 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 5: hydrogenchloride / methanol; 1,4-dioxane / 12 h / 20 °C | ||
| Multi-step reaction with 5 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 4: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C |
| Multi-step reaction with 3 steps 1: trifluoroacetic acid / 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 / 18 h / 20 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C | ||
| Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 1.2: 20 °C 2.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2.2: 20 °C 3.1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C | ||
| Multi-step reaction with 3 steps 1: hydrogenchloride / methanol 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 / 12 h / 20 °C 3: hydrogenchloride / methanol | ||
| Multi-step reaction with 5 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 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 5: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 25 °C | ||
| Multi-step reaction with 3 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 2.2: 12 h / 0 - 20 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane; methanol / 12 h / 20 °C / Inert atmosphere | ||
| Multi-step reaction with 5 steps 1: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C 3: trifluoroacetic acid / dichloromethane / 30 min / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 0 - 20 °C 5: trifluoroacetic acid / dichloromethane / 30 min / 20 °C | ||
| Multi-step reaction with 5 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 3: hydrogenchloride / ethyl acetate / 12 h / 20 °C 4: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 0 - 20 °C 5: hydrogenchloride / ethyl acetate / 12 h / 20 °C | ||
| Multi-step reaction with 5 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 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 5: trifluoroacetic acid / dichloromethane / 30 min / 20 °C | ||
| Multi-step reaction with 5 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 3: hydrogenchloride / 1,4-dioxane / 1 h / 16 °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 h / 16 - 20 °C 5: hydrogenchloride / 1,4-dioxane / 1 h / 16 °C | ||
| Multi-step reaction with 3 steps 1: hydrogenchloride / methanol; 1,4-dioxane / 2 h / 0 - 20 °C 2: 1-methyl-1H-imidazole / acetonitrile / 3 h / 20 °C 3: hydrogenchloride / ethyl acetate / 20 °C | ||
| Multi-step reaction with 5 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 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 5: trifluoroacetic acid / dichloromethane / 1 h / 20 °C | ||
| Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / Cooling with ice 1.2: 3 h / 20 °C 2.1: trifluoroacetic acid / 1 h / Cooling with ice 2.2: 3 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0.5 h / Cooling with ice | ||
| Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; ethyl acetate / 4 h / 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 / 0.5 h / 0 °C 2.2: 20 °C 3.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 42% | With hydrogenchloride In water; ethyl acetate at 20℃; for 4h; | |
| With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 12h; | ||
| With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 4h; |
| With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 12h; | 1 [0191] HATU (14.51 g, 38.2 mmol, 1.2 eq) was added to a solution of the intermediate (0324) (55) obtained as described above (6.95 g, 31.8 mmol, 1.0 eq), (2S,4R)-l-(fert- butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carboxylic acid (7.36 g, 31.8 mmol, 1.0 eq), and DIPEA (11.08 mL, 63.6 mmol, 2.0 eq) in DMF (36 mL) at 0 °C under N2. The mixture was stirred at ambient temperature for 12 h when TLC showed that the reaction was complete. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (150mL>4. The organic solution was filtered and concentrated and the residue was purified by silica gel flash column chromatography with hexane :EtO Ac (100:1-1:100), then DCM:MeOH (10:1) to afford the intermediate (56) as white solid (10.98 g, 80% yield). 'H NMR (CD3OD, 400 MHz) d (ppm) 8.84 (s, 1H), 7.43-7.37 (m, 4H), 5.11-5.07 (m, 1H), 4.44-4.37 (m, 2H), 3.60-3.46 (m, 2H), 2.44 (s, 3H), 2.27-2.22 (m, 1H), 1.98-1.91 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 1.46 (s, 9H); UPLC-MS (ESL) calc, for C22H30N3O4S [M+l]+: 432.20, found 432.20. | |
| With trifluoroacetic acid In dichloromethane at 20℃; for 8h; | ||
| With trifluoroacetic acid In dichloromethane at 20℃; | ||
| With trifluoroacetic acid at 20℃; | Synthesis of VHL ligand VIII The synthetic route of VHL ligand VIII is shown in the following reaction formula: first, under alkaline conditions,Use di-tert-butyl dicarbonate (1.0 equiv.) to (S)-(-)-1-(4-bromophenyl)ethylamine I (1.2 equiv.)The amino group carries out Boc protection to obtain intermediate compound IV, then compound IV (1.0equiv.)and tetramethylthiazole (1.2equiv.) at 90°C by palladium acetate (0.3equiv.)The catalytic reaction produces intermediate V. After V was deprotected by TFA (1.1equiv.),Intermediate VI was obtained by amide condensation with Boc-Hyp-OH (1.0 equiv.) at room temperature. After VI was deprotected by TFA, intermediate VII was obtained by amide condensation with Boc-L-tert-Leu (1.05 equiv.) at room temperature. VII was deprotected by TFA (1.0 equiv.) to generate compound VIII. | |
| With trifluoroacetic acid In dichloromethane at 20℃; | 2 Second step synthesis of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl-1-amine (TV-4) Compound TV-3 (10.0g, 31.40mmol, 1.0eq.) and TFA (20.0mL, 261.36mmol, 8.3eq.)Stir in DCM (20 mL) until the reaction is complete. Concentration affords the trifluoroacetate salt of TV-4 (10.7 g, 31.40 mmol, crude, ca. 100%), which is used directly in the next step | |
| With trifluoroacetic acid at 20℃; | Synthesis of VHL ligand VIII The synthetic route of VHL ligand VIII is shown in the following reaction formula: first, under alkaline conditions,Use di-tert-butyl dicarbonate (1.0 equiv.) to (S)-(-)-1-(4-bromophenyl)ethylamine I (1.2 equiv.)The amino group carries out Boc protection to obtain intermediate compound IV, then compound IV (1.0equiv.)and tetramethylthiazole (1.2equiv.) at 90°C by palladium acetate (0.3equiv.)The catalytic reaction produces intermediate V. After V was deprotected by TFA (1.1equiv.),Intermediate VI was obtained by amide condensation with Boc-Hyp-OH (1.0 equiv.) at room temperature. After VI was deprotected by TFA, intermediate VII was obtained by amide condensation with Boc-L-tert-Leu (1.05 equiv.) at room temperature. VII was deprotected by TFA (1.0 equiv.) to generate compound VIII. | |
| With hydrogenchloride In 1,4-dioxane; dichloromethane at 25℃; | C Step C: Add 20 ml of 1,4-dioxane solution of hydrochloric acid to a mixed solution of compound INT-5-2 (5.8 g, 18.2 mmol) and dichloromethane (40 ml). Stir the reaction mixture at 25 degrees Celsius for 1 h. LCMS monitoring shows that raw materials are gone. Concentrate the reaction solution under reduced pressure, The result is 7 g of compound INT-5-3, which is used directly for the next step without purification. | |
| 58 g | With hydrogenchloride In 1,4-dioxane; methanol at 25℃; | |
| With trifluoroacetic acid In dichloromethane at 20℃; | ||
| 88 % | With hydrogenchloride In ethyl acetate at 20℃; | 4.1.19. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidine-1-carboxylate (P12) Compound P11 was synthesized using the reported procedure [35],was dissolved in 2 M HCl in EA (40 mL, 80 mmol), and the mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,and the residue was dried under vacuum to afford the intermediate,which was used in next step without further purification (2.45 g, 88.0%). HATU (6.90 g, 18.2 mmol, 1.2 equiv) was added to a solution of the intermediate obtained above (3.3 g, 15.1 mmol, 1.0 equiv), (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(3.49 g, 15.1 mmol, 1.0 equiv), and DIPEA (8.1 mL, 45.4 mmol, 3.0equiv) in DMF (30 mL) at 0 C under nitrogen. The mixture was stirred atambient temperature for 2 h. TLC showed that the reaction was complete.The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (150 mL × 2). The combined organic layer waswashed with brine (200 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 10:1) to afford the intermediate(P12) as white solid (4.02 g, 72.6 %). |
| 88 % | With hydrogenchloride In ethyl acetate at 20℃; | 4.1.19. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl) pyrrolidine-1-carboxylate (P12) Compound P11 was synthesized using the reported procedure [35],was dissolved in 2 M HCl in EA (40 mL, 80 mmol), and the mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,and the residue was dried under vacuum to afford the intermediate,which was used in next step without further purification (2.45 g, 88.0%). HATU (6.90 g, 18.2 mmol, 1.2 equiv) was added to a solution of the intermediate obtained above (3.3 g, 15.1 mmol, 1.0 equiv), (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(3.49 g, 15.1 mmol, 1.0 equiv), and DIPEA (8.1 mL, 45.4 mmol, 3.0equiv) in DMF (30 mL) at 0 C under nitrogen. The mixture was stirred atambient temperature for 2 h. TLC showed that the reaction was complete.The reaction mixture was quenched with H2O (120 mL) andextracted with EtOAc (150 mL × 2). The combined organic layer waswashed with brine (200 mL) and dried over Na2SO4. The organic solutionwas filtered and concentrated. The residue was purified by silica gelflash column chromatography (DCM: MeOH 10:1) to afford the intermediate(P12) as white solid (4.02 g, 72.6 %). |
| 93 % | With hydrogenchloride In 1,4-dioxane at 16℃; | 6.c; 9.h Synthesis of Int. 25 Into a 100 mL round-bottom flask were added tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl]carbamate (4.5 g, 14.131 mmol, 1 equiv), 1,4-dioxane (10 mL), and HCl in 1,4-dioxane (50 mL, 4 M) at 16 °C. The resulting mixture was stirred for 1 h at 16 °C. The resulting mixture was concentrated under reduced pressure to give 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethanamine (3.3 g, 93% yield) as a yellow solid. LCMS: (ES, m/z): [M+H-17]+ = 202 (LCMS condition: Column: Shim-pack Scepter C18-120; Mobile phase A: Water/5 mM NH4HCO3; Mobile phase B: Acetonitrile; Flow rate: 1.5 mL/min; RT: 0.634 min) |
| With hydrogenchloride In 1,4-dioxane; methanol at 0 - 20℃; | Step 2: Dissolve 2-a (3.1g, 9.7mmol) in methanol (30mL), add HCl/dioxane solution (30mL, 4M) at 0 °C, raise the reaction solution to room temperature and stir for 2 hours. The reaction solution was concentrated to obtain 2-b (2.8g, light yellow, crude product). | |
| With trifluoroacetic acid In dichloromethane at 20℃; for 1h; |

| Yield | Reaction Conditions | Operation 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 3 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 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 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 3 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 3.1: hydrogenchloride / 1,4-dioxane / 2 h / 25 °C | ||
| 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 / 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 / 2 h / 0 - 20 °C / Inert atmosphere 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 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 °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 |

| Yield | Reaction Conditions | Operation 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 |
