* 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.
With pyridine; ammonium bicarbonate In 1,4-dioxane at 20℃; for 6 h;
General procedure: A mixture of compound 1 (1.00 g, 4.65 mmol), (Boc)2O (1.52 g, 6.97 mmol), NH4HCO3 (0.55 g, 6.97 mmol) and pyridine (1.0 mL) in dioxane (20 mL) was stirred at room temperature for 6 h. the product was extracted with CH2Cl2, washed with 1 M HCl and saturated NaCl, dried, filtrated, and concentrated. n-Hexane (100 mL) was added and the product 2 (0.85 g, 85percent) began to precipitate using the ultrasound as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.37–4.34 (m, 1H), 3.47–3.36 (m, 2H), 2.07–1.85 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z 215 [M+H]+.
85%
With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 20℃; for 6 h;
A mixture of compound 8 (1.00 g, 4.65 mmol), (Boc)2O (1.52 g, 6.97 mmol), NH4HCO3 (0.55 g, 6.97 mmol) and pyridine (1.0 mL) indioxane (20 mL) was stirred at room temperature for 6 h. the product wasextracted with CH2Cl2, washed with 1M HCl and saturated NaCl, dried, filtrated,and concentrated. n-hexane (100 mL) was added and the product 9 (0.85 g, 85percent) began to precipitate using the ultrasoundas a white solid . 1H NMR (CDCl3, 300 MHz):δ4.37-4.34(m, 1H), 3.47-3.36 (m, 2H), 2.07-1.85 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z 215[M+H]+.
76%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.583333 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 4 h;
General procedure: The solution of Boc-L-proline 1 g, 4.6 mmol,) in THF (12 mL) at 0 °C was charged with N-Methylmorpholine (0.54 g, 5.38 mmol). Then isobutyl chloroformate (0.75 g, 5.52 mmol) was added dropwise over 5 minutes. After 30 minutes of stirring the reaction was treated with the 25percent aqueous solution of ammonia (0.53 g, 15.18 mmol). The mixture was allowed to warm to room temperature and stirred for 4 h. Then, the mixture was concentrated under reduced pressure. Product was crystallized from hexane to yield 0.76 g (76percent) of product 1 as colorless crystals.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1719 - 1729
[2] Canadian Journal of Chemistry, 2007, vol. 85, # 2, p. 85 - 95
[3] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 35, p. 8544 - 8551
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 228 - 247
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[6] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
[7] Tetrahedron Letters, 1995, vol. 36, # 39, p. 7115 - 7118
[8] Tetrahedron, 2008, vol. 64, # 12, p. 2801 - 2815
[9] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2647 - 2648
[10] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 202 - 211
[11] Tetrahedron, 2009, vol. 65, # 46, p. 9536 - 9541
[12] Polish Journal of Chemistry, 1986, vol. 60, # 1-3, p. 95 - 105
[13] Tetrahedron Letters, 1991, vol. 32, # 39, p. 5359 - 5362
[14] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[15] Patent: US2011/136799, 2011, A1, . Location in patent: Page/Page column 43
[16] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
[17] Journal of Antibiotics, 2013, vol. 66, # 5, p. 259 - 264
[18] Chemical Biology and Drug Design, 2015, vol. 85, # 4, p. 439 - 446
[19] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7698 - 7701[20] Angew. Chem., 2016, vol. 128, p. 7829 - 7832,4
[21] Journal of the American Chemical Society, 2017, vol. 139, # 48, p. 17500 - 17507
Stage #1: With benzotriazol-1-ol; 1,2-dichloro-ethane In tetrahydrofuran at 20℃; for 6 h;
71f[0529] (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (71a): To a solution of 1-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.2 g, 0.93 mmol) in THE (13 mL), HOBT (142 mg, 0.93 mmol) was added followed by EDC (205 mg, 1.07 mmol). After stirring at r.t. for 6 hours, concentrated ammonium hydroxide (0.3 mL, 6.50 mmol) was added and the reaction mixture was stirred for 16-60 hours. Once reaction showed by TLC to be at completion, the organic solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to afford final product 71a (87 mg, 43percent) as an oil. 1H NMR (500 MHz, CDCI3) 64.17 (d, i=62.9 Hz, 1H), 3.35 (d, i=67.9 Hz, 2H), 2.26-1.98 (m, 2H), 1.92-1.75 (m, 2H), 1.39 (s, 9H); 13C NMR (126 MHz, CDCI3) 6175.15, 154.61, 80.33, 59.67, 47.15, 31.12, 28.37, 24.52. HRMS (ESI+): Calcd for C10H19N203 [M+H]: 215.1395, Eound:215.1389.
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
12
[ 15761-39-4 ]
[ 35150-07-3 ]
[ 70138-72-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 13, p. 2531 - 2536
13
[ 24424-99-5 ]
[ 147-85-3 ]
[ 35150-07-3 ]
Reference：
[1] Chemical Biology and Drug Design, 2015, vol. 85, # 4, p. 439 - 446
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7698 - 7701[3] Angew. Chem., 2016, vol. 128, p. 7829 - 7832,4
[4] Journal of the American Chemical Society, 2017, vol. 139, # 48, p. 17500 - 17507
14
[ 15761-39-4 ]
[ 24424-99-5 ]
[ 35150-07-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5257 - 5261
15
[ 84890-94-8 ]
[ 35150-07-3 ]
Reference：
[1] Polish Journal of Chemistry, 1986, vol. 60, # 1-3, p. 95 - 105
16
[ 344-25-2 ]
[ 35150-07-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
17
[ 15761-39-4 ]
[ 35150-07-3 ]
[ 70138-72-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 13, p. 2531 - 2536
18
[ 35150-07-3 ]
[ 228244-04-0 ]
Yield
Reaction Conditions
Operation in experiment
76%
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 1 h;
General procedure: A mixture of compound 2 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at room temperature for 1 h (monitored by TLC). After the reaction completed, the solution was extracted with EtOAc, washed, dried, concentrated, and purified by flash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v), to afford 3 (3.48 g, 76percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.76 (s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90–1.87 (m, 1H), 1.49 (s, 9H). MS (ESI) m/z 197 [M+H]+.
76%
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 1 h;
A mixture of compound 9 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at roomtemperature for 1 h (monitored by TLC). After the reaction completed, thesolution was extracted with EtOAc, washed, dried, concentrated, and purified byflash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v)to afford 10 (3.48 g, 76percent) as a white solid. 1H NMR (CDCl3,300 MHz): δ4.76(s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H),1.49 (s, 9H). MS (ESI) m/z 197[M+H]+.
55 g
With triethylamine; trifluoroacetic anhydride In dichloromethane at -15℃; for 3 h;
step 1:The first reaction solution containing the compound represented by Formula II was cooled to -15.0 ° C., 30.0 g of triethylamine,A dichloromethane solution containing 0.357 mol of trifluoroacetic anhydride (TFAA) was added dropwise,Dropping time 2h, after the addition was completed, incubated for 1h,Insulation temperature was -15.0 , TLC monitoring showed that the reaction was completed;Step 2: To the solution in Step 1 was added purified water 100mL, washed and stratified;The pH was adjusted to 1 with 1 M hydrochloric acid, the temperature was controlled below 0 ° C,Stirring for 30-45min, standing stratification;Step 3: The mass concentration of 5percent -10percent dilute salt water 100mL wash phase;The organic layer was dried over sodium sulfate, filtered and the methylene chloride removed under reduced pressure.55.0 g (0.280 mol) of an oil was obtained as a compound of the formula III.
Reference：
[1] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 35, p. 8544 - 8551
[2] Canadian Journal of Chemistry, 2007, vol. 85, # 2, p. 85 - 95
[3] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[5] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
[6] Tetrahedron, 2009, vol. 65, # 46, p. 9536 - 9541
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5257 - 5261
[8] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6672 - 6684
[9] Tetrahedron, 2010, vol. 66, # 34, p. 6718 - 6724
[10] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
[11] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[12] Patent: WO2014/20462, 2014, A1, . Location in patent: Page/Page column 9
[13] Patent: CN107033054, 2017, A, . Location in patent: Paragraph 0070; 0071; 0075; 0076-0082; 0111; 0115-0118
19
[ 79-37-8 ]
[ 35150-07-3 ]
[ 228244-04-0 ]
Yield
Reaction Conditions
Operation in experiment
66%
With pyridine In ethyl acetate; N,N-dimethyl-formamide; acetonitrile
Preparation 116 tert-butyl (2S)-2-cyano-1-pyrrolidinecarboxylate A solution of oxalyl chloride (11.0 ml, 0.126 mol) and DMF (11.4 ml, 0.138 mol) in MeCN (170 ml) was treated dropwise with a solution of N-Boc-L-proline amide (12.3 g, 0.57mol) and pyridine (20.4 ml, 0.253 mol) in MeCN (30 ml) at 0° C. and stirred at this temperature for 15 minutes. The reaction mixture was diluted with EtOAc and washed with H2O (*3). The organic extract was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluding with a solvent gradient of pentane:EtOAc (80:20) gradually changing to (60:40) to afford the title compound (7.40 g, 66percent). 1H nmr: (d6DMSO) 1.40 (9H, s), 1.88 (2H, brs), 2.05-2.30 (2H, m), 3.21 (1H, m), 3.35 (1H, brs), 4.60 (1H, d). MS: 214 (MNH4+)
Reference：
[1] Patent: US2002/151535, 2002, A1,
20
[ 108-77-0 ]
[ 35150-07-3 ]
[ 228244-04-0 ]
Yield
Reaction Conditions
Operation in experiment
71%
at 0℃; for 1 h;
[0530] (S)-tert-butyl 2-cyanopyrrolidine-1-carboxylate (71b): To a solution of (S)-tert-butyl 2- carbamoylpyrrolidine-1-carboxylate 71a (86 mg, 0.40 mmol) in DME (2 mL) at 0 °C, 2,4,6-trichloro-1,3,5- triazine (104 mg, 0.56 mmol) was added. After stirring for one hour at 0°C, the reaction mixture was quenched with a cold 0.5 M NaOH solution. The mixture was then extracted with ethyl acetate. Organic layers were combined and washed with water and brine twice, dried over Na2SO4, and concentrated via vacuum. The crude reside was purified by silica gel column chromatography (15percent ethyl acetate hexane to yield 71b (56 mg, 71percent) as an oil. 1H NMR (500 MHz, CDCI3) 6 4.56-4.39 (m, 1H), 3.58-3.22 (m, 2H),2.28-1.94 (m, 4H), 1.47 (d, i=16.4 Hz, 9H); 13C NMR (126 MHz, CDCI3) 6 153.09, 119.23, 81.50, 47.27,45.79, 31.74, 28.39, 23.89; HRMS (ESI+): Calcd for C10H17N2O2 [M+H]: 197.1290, Found: 197.1287.
With pyridine; ammonium bicarbonate; In 1,4-dioxane; at 20℃; for 6h;
General procedure: A mixture of compound 1 (1.00 g, 4.65 mmol), (Boc)2O (1.52 g, 6.97 mmol), NH4HCO3 (0.55 g, 6.97 mmol) and pyridine (1.0 mL) in dioxane (20 mL) was stirred at room temperature for 6 h. the product was extracted with CH2Cl2, washed with 1 M HCl and saturated NaCl, dried, filtrated, and concentrated. n-Hexane (100 mL) was added and the product 2 (0.85 g, 85%) began to precipitate using the ultrasound as a white solid. 1H NMR (300 MHz, CDCl3) delta 4.37-4.34 (m, 1H), 3.47-3.36 (m, 2H), 2.07-1.85 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z 215 [M+H]+.
85%
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; at 20℃; for 6h;
A mixture of compound 8 (1.00 g, 4.65 mmol), (Boc)2O (1.52 g, 6.97 mmol), NH4HCO3 (0.55 g, 6.97 mmol) and pyridine (1.0 mL) indioxane (20 mL) was stirred at room temperature for 6 h. the product wasextracted with CH2Cl2, washed with 1M HCl and saturated NaCl, dried, filtrated,and concentrated. n-hexane (100 mL) was added and the product 9 (0.85 g, 85%) began to precipitate using the ultrasoundas a white solid . 1H NMR (CDCl3, 300 MHz):delta4.37-4.34(m, 1H), 3.47-3.36 (m, 2H), 2.07-1.85 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z 215[M+H]+.
76%
General procedure: The solution of Boc-L-proline 1 g, 4.6 mmol,) in THF (12 mL) at 0 C was charged with N-Methylmorpholine (0.54 g, 5.38 mmol). Then isobutyl chloroformate (0.75 g, 5.52 mmol) was added dropwise over 5 minutes. After 30 minutes of stirring the reaction was treated with the 25% aqueous solution of ammonia (0.53 g, 15.18 mmol). The mixture was allowed to warm to room temperature and stirred for 4 h. Then, the mixture was concentrated under reduced pressure. Product was crystallized from hexane to yield 0.76 g (76%) of product 1 as colorless crystals.
With pyridine; di-tert-butyl dicarbonate; ammonium carbonate; In 1,4-dioxane; rac-Pro-OH; at 20℃; for 19h;
Example 8 Synthesis of (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (10a) N-Boc- L -proline (5.0 g, 23.2 mmol) was dissolved in 1,4-dioxane (110 ml) at room temperature. To the proline solution were added pyridine (1.1 mL, 13.9 mmol), di-tert-butyl dicarbonate (6.6 g, 30.2 mmol), and ammonium carbonate (2.9 g, 30.2 mmol). The reaction mixture was then stirred at room temperature for 19 hours. The resulting mixture was evaporated under reduced pressure to remove volatile components. To the residue, ethyl acetate (50 ml), 20% aqueous citric acid (100 ml), and brine (50 ml) were added. The mixture was stirred at room temperature for 5 min. The aqueous layer was extracted with ethyl acetate and the organic layer was combined, dried over MgSO4, and filtered. The filtrate was concentrated to yield crude product. And then purified with column chromatography (dichloromethane:methanol=9:1) to give 10a (4.5 g).
22.0 g
To a mixture of (tert-butoxycarbonyl)-L-proline (20.3 g, 94.20 mmol) and triethylamine (16 ml) in tetrahydrofuran (80 ml) was added a solution of methyl 2-chloroacetate (30.0 g, 245.9 mmol) in tetrahydrofuran (40 ml) was at -lOC. After stirring for 30 minutes, to the reaction mixture was added ammonium hydroxide (30 ml) at -l0C. The resulting mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure to a residue which was taken up with ethyl acetate (100 ml), wash with aqueous solution of sodium bicarbonate (sat 40 ml), then brine (40 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a tert-butyl (S)-2-carbamoylpyrrolidine-l- carboxylate (22.0 g) as colorless oil.
With Lawessons reagent; In tetrahydrofuran; at 20℃; for 3.5h;Inert atmosphere;
A solution of (S)-1-(tert-butoxycarbonyl)prolinamide (9.0 g, 42.0 mmol) and Lawesson?s reagent (8.5 g, 21.0 mmol) in dry THF (55 mL) was stirred at rt under N2 for 3.5 h. The solvent was removed under reduced pressure, saturated aq. NaHCO3 (100 mL) was added and the mixture stirred for 1 h. The aqueous suspension was extracted with EtOAc/CH2Cl2 (1:1) (400 mL), the organic fraction was washed with saturated aq NaHCO3 (2 × 100 mL) and the combined aqueous fractions were extracted with EtOAc/CH2Cl2 (200 mL). The combined organics extracts were dried over Na2SO4 and then concentrated in vacuo to obtain the title compound as a white solid (8.74 g, 90%), mp (EtOAc) 190-192 C. [alpha]D -103.4 (c 1.00, CHCl3). IR (KBr) 3380, 3202, 2981, 2881, 1671, 1411, 1166 cm-1.1H NMR (400 MHz, CDCl3) delta = 1.41-1.50 (m, 9 H), 1.65-2.75 (m, 4 H), 3.22-3.74 (m, 2 H), 4.67 (dd, J = 8.0 and 3.6 Hz, 1 H) ppm. HRMS(ESI) m/z calcd for C10H19N2O2S (M+H) 231.1162, found 231.1161.
89%
With Lawessons reagent; In tetrahydrofuran; at 23℃; for 5h;
Step 1: Thioamdie (1)Lawesson's Reagent (13.9 g, 34 mmol, 0.70 equiv.) is added portionwise (3×4.6 g) over 20 minutes to a solution of Boc-L-Pro (10.5 g, 49 mmol, 1 equiv.) in 70 mL of THF at 23 C. The resulting cloudy yellow mixture is stirred vigorously for 5 hours, then is concentrated to a light yellow solid. This residue is partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (500 mL). The organic phase is separated and the aqueous phase is further extracted with ethyl acetate (2×500 mL). The organic phases are combined, washed with brine (500 mL), and dried over anhydrous sodium sulfate. The dried solution is filtered and concentrated to a light yellow solid. This solid is triturated with dichloromethane (2×20 mL) affording the desired thioamide 1 as a fluffy white solid (10 g, 89%).
84%
With Lawessons reagent; In toluene; at 50℃; for 1h;
A particular procedure: A mixture of Boc-proline-amide c (8.4 g, 39.2 mmol), Lawesson's reagent (8.25 g, 20.4 mmol) and toluene was heated at 50 0C for 1 h (use of higher temperatures results in loss of enantiopurity). The mixture was then adsorbed onto Celite, and purified by chromatography (ISCO, 12O g silica column, gradient elution 10-70% EtOAc-hexanes) to afford 7.6 g (84%) of the thioamide d as a colorless solid.
50%
With Lawessons reagent; In 1,2-dimethoxyethane; at 20 - 80℃; for 2.5h;Heating / reflux;
E-1 (1.Og, 4.7 mol) is dissolved in 20 ml anhydrous DME and added to another round bottom flask containing a slurry of Lawesson's reagent (1.89g, 4.7 mol) in anhydrous DME (5 ml) under Argon at room temp. The reaction mixture is refluxed at 8O0C for about 2.5hr and the reaction completion is monitored by LCMS. The excess solvent is evaporated under reduced pressure and the crude residue obtained is kept at low temp away from direct light. The crude material is purified by liquid column chromatography to yield the desired product J-1 (50%).
38%
With Lawessons reagent; In tetrahydrofuran; at 70℃; for 2h;
A mixture of (S)-2-carbamoylpyrrolidine-l-carboxylate (22.0 g) in tetrahydrofuran (80 ml) and Lawesson reagent (41.8 g, 103.40 mmol) was stirred at 70C for 2 hours. The mixture was partitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was collected, washed with brine (300 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude residue which was purified by silica gel flash chromatography (eluted with 20% ethyl acetate in hexane) to afford tert-butyl (S)-2- carbamothioylpyrrolidine-l-carboxylate (8.3 g, 38% yield) as white solid. LC/MS (ESI) in/z: 231.0 [M+l] +.
22%
With Lawessons reagent; In toluene; at 50℃; for 2h;
Into a 250-mL round-bottom flask, was placed tert-butyl (2S)-2-carbamoylpyrrolidine-1-carboxylate (4.2 g, 19.60 mmol, 1.00 equiv) in toluene (50 mL). Lawesson's reagent (4.1 g, 0.50 equiv) was added. The resulting solution was stirred for 2 h at 50C. The reaction mixture was cooled. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1 :2). This resulted in 1 g (22%) of tert-butyl (2S)-2-carbamothioylpyrrolidine-1-carboxylate as a yellow solid.
With Lawessons reagent; In tetrahydrofuran; at 70℃; for 8h;Inert atmosphere;
Example 9 Preparation of (S)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (11a) A round-bottomed flask with (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (compound 10a, 3.0 g, 14.0 mmol) and Lawesson's reagent (6.8 g, 16.8 mmol) was flushed with nitrogen. Dry THF (40 ml) was added as the solvent. The reaction mixture was stirred at 70 C. under nitrogen for 8 hours. After cooled to room temperature, the resulting mixture was evaporated under reduced pressure and purified by column chromatography (ethyl acetate:n-hexane=1:2) to yield pure product 11a (2.7 g).
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 0.5h;Inert atmosphere;
General procedure: To the Boc N-protected amino acid, or peptide compound, in dichloromethane (0.1 M) is added TFA (25-55% v/v) slowly at 0 oC and the reaction left at room temperature for 30 min. After completion,solvents and excess TFA are removed in vacuo and the residue is triturated with diethylether until ahomogenous precipitate forms. The supernatant diethylether layer is removed and the solid redissolvedin dichloromethane followed by the addition of the amido-carboxylic acid. At 0 oC, DIPEA(2.0 equiv), HATU (1.2 equiv) and HOAt (1.0 equiv) are then added sequentially, followed by acatalytic amount of DMAP (0.1 equiv). The reaction is left stirring at room temperature. Aftercompletion, typically within 3-8 hours, the reaction mixture is evaporated in vacuo. The residueobtained is dissolved in ethyl acetate. The organic layer is washed with sat. sodium bicarbonatesolution and then with brine solution. The organic layer is finally dried over sodium sulphate andevaporated in vacuo. The residue is purified by silica gel flash column chromatography typicallyusing ethyl acetate/hexane mixtures
With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h;
General procedure: TFA (8 mL) was added to the solution of (S)-tert-butyl 2-(piperidine-1-carbonyl)pyrrolidine-1-carboxylate 3 (0.82 g, 2.9 mmol), in DCM (2 mL) and stirred for 2 h at room temperature. The excess reagent and solvent were removed under reduced pressure and left under vacuum overnight. Then the residue was dissolved in DCM (15 ml). and cooled to 0 C. TEA (1.9 g, 18.85 mmol) was added followed by dropwise addition of 5-bromopentanoyl chloride (0.74 g, 3.73 mmol,), dissolved in DCM (8 ml). The stirring was continued for 12 h. Solvent was evaporated under reduced pressure and the N-acylated product 13 was purified by column chromatography using silica gel and a mixture of DCM/MeOH = 9/0.7 (v/v) as an eluting system to yield 0.74 g (74%) of product 13 as colorless oil.
With 1,3,5-trichloro-2,4,6-triazine; In N,N-dimethyl-formamide; at 20℃; for 1h;
General procedure: A mixture of compound 2 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at room temperature for 1 h (monitored by TLC). After the reaction completed, the solution was extracted with EtOAc, washed, dried, concentrated, and purified by flash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v), to afford 3 (3.48 g, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 4.76 (s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H), 1.49 (s, 9H). MS (ESI) m/z 197 [M+H]+.
76%
With 1,3,5-trichloro-2,4,6-triazine; In N,N-dimethyl-formamide; at 20℃; for 1h;
A mixture of compound 9 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at roomtemperature for 1 h (monitored by TLC). After the reaction completed, thesolution was extracted with EtOAc, washed, dried, concentrated, and purified byflash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v)to afford 10 (3.48 g, 76%) as a white solid. 1H NMR (CDCl3,300 MHz): delta4.76(s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H),1.49 (s, 9H). MS (ESI) m/z 197[M+H]+.
With 1,3,5-trichloro-2,4,6-triazine; N,N-dimethyl-formamide; In dichloromethane; at 20 - 40℃;Inert atmosphere;
Dichloromethane (500 ml), L-Prolinamide (100 g), potassium carbonate (60.50 g) were mixed and stirred under nitrogen atmosphere in round bottom flask The reaction mass was cooled to 10-15C and then Di-tert-butyl dicarbonate (210.30 g) was added. Reaction mixture was stirred till completion of the reaction. After completion water (500m1) was added and product was extracted in dichloromethane. Dichloro methane was removed and then dimethyl formamide (140 ml) and dichloromethane (700 ml) were added under nitrogen atmosphere. Cyanuric chloride (72.70 g) was charged in 2-3 equal lots to the reaction mass at 20-25C under nitrogen atmosphere. The reaction mass was maintained at 35-40C for 4-5 hrs. After completion of the reaction solid was filtered and washed with MDC. Methane sulfonic acid (252.60 g) was added to the filtrate and heated the reaction mass to 40-45C for 3-4 hrs. After completion of the reaction the reaction mass was cooled at 0-5C and Triethyl amine (88.65 g) and Chloroacetyl chloride (118.70 g) were added. The reaction mass was maintained at 20-30C for 1-2 hrs under nitrogen atmosphere. After completion of the reaction water was charged and product was extracted in dichloromethane. Organic layer was washed first with dilute HC1 solution and then with ammonia solution. Organic solvent was removed and product was crystallized using isopropyl alcohol. Yield: 75.0gm
55 g
With triethylamine; trifluoroacetic anhydride; In dichloromethane; at -15℃; for 3h;
step 1:The first reaction solution containing the compound represented by Formula II was cooled to -15.0 C., 30.0 g of triethylamine,A dichloromethane solution containing 0.357 mol of trifluoroacetic anhydride (TFAA) was added dropwise,Dropping time 2h, after the addition was completed, incubated for 1h,Insulation temperature was -15.0 , TLC monitoring showed that the reaction was completed;Step 2: To the solution in Step 1 was added purified water 100mL, washed and stratified;The pH was adjusted to 1 with 1 M hydrochloric acid, the temperature was controlled below 0 C,Stirring for 30-45min, standing stratification;Step 3: The mass concentration of 5% -10% dilute salt water 100mL wash phase;The organic layer was dried over sodium sulfate, filtered and the methylene chloride removed under reduced pressure.55.0 g (0.280 mol) of an oil was obtained as a compound of the formula III.
2-((S)-1-{(S)-2-[(2S,3S)-2-((2S,3S)-2-Amino-3-methyl-pentanoylamino)-3-hydroxy-butyrylamino]-3-phenyl-propionyl}-pyrrolidin-2-yl)-thiazole-4-carboxylic acid ethyl ester; hydrochloride[ No CAS ]
2-((S)-1-{(S)-2-[(2S,3S)-2-((2S,3S)-2-[(S)-1-((S)-2-Amino-3-phenyl-propionyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-pentanoylamino)-3-hydroxy-butyrylamino]-3-phenyl-propionyl}-pyrrolidin-2-yl)-thiazole-4-carboxylic acid ethyl ester; hydrochloride[ No CAS ]
2-((S)-1-{(S)-2-[(2S,3S)-2-((2S,3S)-2-[(S)-1-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-pentanoylamino)-3-hydroxy-butyrylamino]-3-phenyl-propionyl}-pyrrolidin-2-yl)-thiazole-4-carboxylic acid[ No CAS ]
With pyridine; In ethyl acetate; N,N-dimethyl-formamide; acetonitrile;
Preparation 116 tert-butyl (2S)-2-cyano-1-pyrrolidinecarboxylate A solution of oxalyl chloride (11.0 ml, 0.126 mol) and DMF (11.4 ml, 0.138 mol) in MeCN (170 ml) was treated dropwise with a solution of N-Boc-L-proline amide (12.3 g, 0.57mol) and pyridine (20.4 ml, 0.253 mol) in MeCN (30 ml) at 0 C. and stirred at this temperature for 15 minutes. The reaction mixture was diluted with EtOAc and washed with H2O (*3). The organic extract was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluding with a solvent gradient of pentane:EtOAc (80:20) gradually changing to (60:40) to afford the title compound (7.40 g, 66%). 1H nmr: (d6DMSO) 1.40 (9H, s), 1.88 (2H, brs), 2.05-2.30 (2H, m), 3.21 (1H, m), 3.35 (1H, brs), 4.60 (1H, d). MS: 214 (MNH4+)
With triethylamine; In dichloromethane; at 0 - 20℃; for 6h;
Example-5: Preparation of BOC protected L-prolinamide:To a solution of L-prolinamide (50 grams) of in 300 ml of dichloromethane triethyl amine (121.5 ml) was added and cooled the mixture to 0-5C. Di-tert-butyl dicarbonate (154.5 ml dissolved in 200 ml of dichloromethane) was added slowly to the reaction mixture. The reaction mixture was stirred for 6 hrs at room temperature. The solvent was distilled off completely from the reaction mixture. Dichloromethane was added to the residue, stirred for 30 min and distilled off to get the title compound.Yield: 85 grams.
With potassium carbonate; In dichloromethane; at 10 - 15℃;Inert atmosphere;
Dichloromethane (500 ml), L-Prolinamide (100 g), potassium carbonate (60.50 g) were mixed and stirred under nitrogen atmosphere in round bottom flask The reaction mass was cooled to 10-15C and then Di-tert-butyl dicarbonate (210.30 g) was added. Reaction mixture was stirred till completion of the reaction. After completion water (500m1) was added and product was extracted in dichloromethane. Dichloro methane was removed and then dimethyl formamide (140 ml) and dichloromethane (700 ml) were added under nitrogen atmosphere. Cyanuric chloride (72.70 g) was charged in 2-3 equal lots to the reaction mass at 20-25C under nitrogen atmosphere. The reaction mass was maintained at 35-40C for 4-5 hrs. After completion of the reaction solid was filtered and washed with MDC. Methane sulfonic acid (252.60 g) was added to the filtrate and heated the reaction mass to 40-45C for 3-4 hrs. After completion of the reaction the reaction mass was cooled at 0-5C and Triethyl amine (88.65 g) and Chloroacetyl chloride (118.70 g) were added. The reaction mass was maintained at 20-30C for 1-2 hrs under nitrogen atmosphere. After completion of the reaction water was charged and product was extracted in dichloromethane. Organic layer was washed first with dilute HC1 solution and then with ammonia solution. Organic solvent was removed and product was crystallized using isopropyl alcohol. Yield: 75.0gm
With triethylamine; In dichloromethane; at -15℃; for 12h;
To a clean and dry four-necked flask, L-prolinamide 22.3g (0.195ml), dichloromethane 90mL, triethylamine 30.0g (0.297mol), cooled to -15 C Stirring the reaction; dropping a solution of Boc anhydride dichloromethane solution, the Boc anhydride 0.234mol, dropwise addition time 2h, incubated for 10h, TLC was monitored until the end of the reaction to obtain a solution containing the formula shown in Formula II Compound first reaction solution.
Example-6: Preparation of pyrroIidine-2-carbonitriIe:To the BOC protected L-prolinamide (50 grams) in tetrahydrofuran (500 ml), trifluoroacetic anhydride (98.15 grams) was added at 0-5C. The reaction mixture was stirred for 3 hours at room temperature. Ammonium bicarbonate solution was added to the reaction mixture at 0-5 C and stirred for one hour. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was concentrated and toluene was added to the residue stirred for one hour and filtered. The toluene layer was distilled off completely under reduced pressure to provide the title compound.Yield: 24 grams
(2S,2'S)-di-tert-butyl 2,2'-(((3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-3',6'-diyl)bis(azanediyl))bis-(carbonyl))bis(pyrrolidine-1-carboxylate)[ No CAS ]
Example 1 ((S)-1-{(S)-2-[3-(4'-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-ureidocarbonyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester A mixture of <strong>[35150-07-3](S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate</strong> (1.0 g, 4.67 mmol) and 1-bromo-4-isocyanatobenzene (924 mg, 4.67 mmol) in toluene (10 mL) was stirred at reflux for 3 h. Upon completion of the reaction the solid was removed by filtration and the filtrate concentrated. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (0% to 100% ethyl acetate/hexane) to afford, (S)-2-[3-(4-bromo-phenyl)-ureidocarbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid, (1.30 g, 68%): ESI-LRMS m/e calcd for C17H22BrN3O4 [M+] 412. found 413 [M+H+].
To a -78 C. solution of <strong>[35150-07-3](S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate</strong> (252 mg, 1.18 mmol) in THF (11.8 mL) was added phenyl chloroformate (163 muL, 1.29 mmol) followed by lithium bis(trimethylsilyl)amide (2.59 mL, 1 M in THF, 2.59 mmol) dropwise. The clear, orange solution was stirred at -78 C. for 2 h. The reaction was quenched by the addition of sat. aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo.The crude material was taken up in MeCN (6.81 mL) and 2-bromobenzo[d]thiazol-6-amine (156 mg, 681 mumol) and N,N-diisopropylethylamine (236 muL, 1.36 mmol) were added. The reaction was stirred at rt for 20 h. The reaction was concentrated in vacuo and the crude material was purified by flash chromatography (40 g RediSep Gold silica gel; 0-100% EtOAc-hexanes linear gradient) to provide (S)-tert-butyl 2-(2-bromobenzo[d]thiazol-6-ylcarbamoylcarbamoyl)pyrrolidine-1-carboxylate (251 mg, 79%) as an off-white solid. [alpha]-19 (c 0.065, MeOH); MS (ES+APCI+) m/z 469/471 [M+H]+; 1H NMR (300 MHz, DMSO-d6) delta 11.05-10.92 (m, 1H), 10.72, 10.63 (2×s, 1H), 8.44 (d, J=2.3 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.3 Hz, 1H), 4.36-4.25 (m, 1H), 3.46-3.29 (m, 2H), 2.29-2.11 (m, 1H), 1.99-1.75 (m, 3H), 1.40, 1.32 (2×s, 9H).
[0530] (S)-tert-butyl 2-cyanopyrrolidine-1-carboxylate (71b): To a solution of (S)-tert-butyl 2- carbamoylpyrrolidine-1-carboxylate 71a (86 mg, 0.40 mmol) in DME (2 mL) at 0 C, 2,4,6-trichloro-1,3,5- triazine (104 mg, 0.56 mmol) was added. After stirring for one hour at 0C, the reaction mixture was quenched with a cold 0.5 M NaOH solution. The mixture was then extracted with ethyl acetate. Organic layers were combined and washed with water and brine twice, dried over Na2SO4, and concentrated via vacuum. The crude reside was purified by silica gel column chromatography (15% ethyl acetate hexane to yield 71b (56 mg, 71%) as an oil. 1H NMR (500 MHz, CDCI3) 6 4.56-4.39 (m, 1H), 3.58-3.22 (m, 2H),2.28-1.94 (m, 4H), 1.47 (d, i=16.4 Hz, 9H); 13C NMR (126 MHz, CDCI3) 6 153.09, 119.23, 81.50, 47.27,45.79, 31.74, 28.39, 23.89; HRMS (ESI+): Calcd for C10H17N2O2 [M+H]: 197.1290, Found: 197.1287.
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