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Structure of 50893-53-3 * Storage: {[proInfo.prStorage]}
* 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 triethylamine In tetrahydrofuran; methanol; ethyl acetate; 1,2-dichloro-ethane
8-Benzyl-8-Aza-Bicyclo[3.2.1]Octan-3-One To a stirred solution of 29.2 g (209 mmol) tropinone in 300 mL 1,2-dichloroethane was added 45.5 mL (419 mmol) 1-chloroethyl chloroformate, and the resulting solution was warmed to 80° C. The reaction was monitored by TLC on a SiO2 plate eluding with EtOAc/2M NH3:MeOH (5:1). After stirring for 18 h, the solvent was evaporated, 300 mL MeOH was added, and the reaction was heated to reflux. After 45 min, the solvent was evaporated, then 300 mL THF, 38.83 g (227 mmol) benzyl bromide, and 33 mL (24.0 g, 237 mmol) triethylamine was added, and the resulting mixture was stirred at 23° C. After 69 h, the mixture was transferred to a separatory funnel containing 200 mL sat. NaHCO3 solution. The aqueous layer was extracted with EtOAc (2*300 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4 filtered and evaporated to a brown oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2Cl2/ EtOAc (40:1 to 20:1 to 8:1 to 4:1). The appropriate fractions were combined and evaporated to afford 19.91 g (92 mmol, a 44percent yield) of the title compound as a yellow-orange oil. MS (ES) m/z: 216 (MH)+.
44%
With triethylamine In tetrahydrofuran; methanol; ethyl acetate; 1,2-dichloro-ethane
8-Benzyl-8-aza-bicyclo[3.2.1]octan-3-one To a stirred solution of 29.2 g (209 mmole) tropinone in 300 mL of 1,2-dichloroethane was added 45.5 mL (419 mmole) 1-chloroethyl chloroformate, and the resulting solution was warmed to 80° C. The reaction was monitored by thin layer chromatography on a silica gel plate eluding with EtOAc/2M NH3:MeOH (5:1). After stirring for 18 h, the solvent was evaporated, 300 mL MeOH was added, and the reaction was heated to reflux. After 45 min, the solvent was evaporated, then 300 mL THF, 38.83 g (227 mmol) benzyl bromide, and 33 mL (24.0 g, 237 mmol) triethylamine was added, and the resulting mixture was stirred at 23° C. After 69 h, the mixture was transferred to a separatory funnel containing 200 mL sat. NaHCO3 solution. The aqueous layer was extracted with EtOAc (2*300 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4 filtered and evaporated to a brown oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2Cl2/ EtOAc (40:1 to 20:1 to 8:1 to 4:1). The appropriate fractions were combined and evaporated to afford 19.91 g (92 mmol, a 44percent yield) of the title compound as a yellow-orange oil. MS (ES) m/z: 216 (MH)+.
To a solution of ethyl chloroformate (11.35 g, 104.6 mmol, 1.0 eq) and sulfuryl chloride (15.38 g, 114.0 mmol, 1.09 eq) benzoyl peroxide (0.034 g, 0.14 mmol, 0.001 eq) was added and the reaction mixture was refluxed for overnight and it was distilled at atmospheric pressure (boiling range 119-140 °C) to give 1-chloroethyl chloroformate (3.5 g, 24percent yield) as colorless liquid. 1H NMR (300 MHz, CDCl3): δ ppm 6.45 (q, 1H, J= 5.7 Hz), 1.88 (d, 3H, J= 5.7 Hz).
Reference：
[1] Patent: WO2013/160810, 2013, A2, . Location in patent: Paragraph 0167
[2] Justus Liebigs Annalen der Chemie, 1890, vol. 258, p. 51,61
[3] Farmaco, 2003, vol. 58, # 5, p. 363 - 369
[4] Patent: US5310929, 1994, A,
[5] Patent: US4611056, 1986, A,
[6] Patent: US4666907, 1987, A,
[7] Patent: US4755598, 1988, A,
[8] Patent: EP138481, 1991, B1,
4
[ 75-44-5 ]
[ 75-07-0 ]
[ 50893-53-3 ]
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 11, p. 2081 - 2082
[2] Patent: US4592872, 1986, A,
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1991, vol. 40, # 11.1, p. 2185 - 2189[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, # 11, p. 2508 - 2512
5
[ 75-07-0 ]
[ 503-38-8 ]
[ 50893-53-3 ]
Reference：
[1] Patent: US4614829, 1986, A,
6
[ 32315-10-9 ]
[ 75-07-0 ]
[ 50893-53-3 ]
Reference：
[1] Patent: WO2006/63578, 2006, A2, . Location in patent: Page/Page column 24
[2] Synthetic Communications, 2003, vol. 33, # 12, p. 2045 - 2052
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5748 - 5763
7
[ 75-07-0 ]
[ 503-38-8 ]
[ 50893-53-3 ]
Reference：
[1] Patent: US4614829, 1986, A,
8
[ 56-23-5 ]
[ 64-17-5 ]
[ 105-57-7 ]
[ 75-44-5 ]
[ 67-66-3 ]
[ 67-72-1 ]
[ 50893-53-3 ]
[ 541-41-3 ]
[ 75-07-0 ]
[ 141-78-6 ]
[ 105-58-8 ]
Reference：
[1] Journal of Catalysis, 2010, vol. 275, # 2, p. 243 - 249
9
[ 124-05-0 ]
[ 75-34-3 ]
[ 5130-24-5 ]
[ 50893-53-3 ]
[ 627-11-2 ]
Reference：
[1] Patent: US2377085, 1943, ,
10
[ 64-17-5 ]
[ 50893-53-3 ]
[ 50893-36-2 ]
Yield
Reaction Conditions
Operation in experiment
78.5 g
at 0 - 20℃; for 0.3 h;
In the cooling to 0 °C under the 71.5 g (0.5 μM) 1 - chloro ethyl formate ester drop to 40 g and 52.0 g triethylamine 250 ml in toluene solution, about 2 hr after the completion of the dropping, then the temperature to room Temperature the reaction system, the reaction 1 hr, filtered to remove the solid, distilling and getting the intermediate H - 1 is 78.5 g.
Reference：
[1] Synthesis, 1986, # 8, p. 627 - 632
[2] Patent: EP1437352, 2004, A1, . Location in patent: Page 17
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5748 - 5763
[4] Patent: WO2016/207216, 2016, A1, . Location in patent: Page/Page column 70
[5] Patent: CN107652239, 2018, A, . Location in patent: Paragraph 0098
[6] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1619 - 1621
[7] Patent: CN108570008, 2018, A, . Location in patent: Paragraph 0228; 0229; 0230
11
[ 50893-53-3 ]
[ 50893-36-2 ]
Reference：
[1] Patent: US5674468, 1997, A,
[2] Patent: US4426391, 1984, A,
a solution of 2-propanol (0.64 mL, 8.39 mmol) and pyridine (0.79 mL, 9.79 mmol) at -78°C was added 1-chloroethyl chlorofonnate (0.76 mL, 6.99 mmol) dropwise. The reaction mixture was allowed to slowly warm to room temperature and stir overnight. The reaction mixture became a solid white clump and was sonicated in dichloromethane. The resulting suspension was concentrated and the white solid was dissolved in ethyl acetate and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a colorless liquid, 1.29 g, 99percent.‘H NMR (300 MHz, CDCl3 ö: 1.35 (m, 6H); 1.84 (d, 3H); 4.96 (m, 1H); 4.44 (m, 1H).
97%
With pyridine In dichloromethane at -78 - 20℃;
PREPARATION 46; 1-Chloroethyl isopropyl carbonate; To a solution of isopropanol (1.09 g, 18.27 mmol) and pyridine (1.45 g, 18.35 mmol) in of dichloromethane (30 ml) at-78 °C was dropwise added (10 minutes) 1-chloroethyl chloroformate (2.66 g, 18.60 mmol) under argon. After the addition, the cooling bath was removed and the mixture was allowed to warm to rt and stirred at that temperature overnight. The reaction was diluted with additional dichloromethane (20 ml), washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as a colourless oil (3 g, 97percent yield). No. (CDCl3): 1.33 (d, 3H), 1.35 (d, 3H), 1.84 (d, 3H), 4.95 (m, 1H), 6.43 (q, 1H).
87.7%
With pyridine In diethyl ether at 0 - 20℃;
0.66 g of isopropanol was added to 1.43 g of 1-chloroethyl chloroformate, and the solution was cooled to 0° C. in an ice-water bath. The mixture of 0.84 g of pyridine and 10 ml ethyl ether was added dropwise into the solution. The solution was reacted for 1 hour at that temperature, following 4 hours at room temperature. The reaction was stopped and the mixture was filtered, and the filtrate was washed respectively with 10percent hydrochloric acid and water once. The organic phase was dried and concentrated to give 1.461 g of a light yellow liquid 1-chloroethyl isopropyl carbonate with a yield of 87.7percent. The crude was directly used in the next reaction without purification.
81%
Stage #1: at 0℃; for 0.25 h; Stage #2: With pyridine In dichloromethane at 20℃;
The compound 1-chloroethyl chloroformate (3 ml, 27.8 mmol) was diluted with DCM (25 ml)Cooled to 0 ° C,Isopropanol (2.1 ml, 27.8 mmol) diluted with DCM (25 ml) was slowly added with a constant pressure dropping funnel,Reaction about 15min,Pyridine (2.4 ml, 30.6 mmol) diluted with DCM (5 ml) was added slowly using a constant pressure dropping funnel,The process to keep the same low temperature,After adding,Reaction at room temperature overnight,Then diluted with water,Extracted with DCM,Organic phase dry,After concentration of 3.74g light yellow liquid,The yield was 81percent.
68%
With pyridine In dichloromethane at 0 - 20℃; for 0.75 h;
Preparation Example 1 : Preparation of 1 -iodoethyl isopropylcarbonate(1) ; Preparation of 1-chloroethyl isopropylcarbonate 1-Chloroethyl chloroformate (31.7 g, 0.22 mol) was dissolved in methylene chloride (200 ml), and isopropanol (39.7 ml, 0.52 mol) was added thereto while ice-cooling. Pyridine (23 ml, 0.28 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 30 minutes. The reaction mixture was sequentially washed with water, 5percent brine, and 5percent potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was distilled under a reduced pressure to obtain 25 g of 1-chloroethyl isopropylcarbonate (yield: 68percent). bpδδmmHg: 92-94 0C ; <n="19"/>1H-NMR(200MHz, CDCI3) δ 1.33(d, J=6.0Hz, 6H), 1.79(d, J=6.0Hz, 3H), 4.84(heptet, J=6.0Hz, 1 H), 6.37(q, J=6.0Hz, 1 H)
3.1 g
With pyridine In dichloromethane at 0℃; for 0.666667 h;
To a solution of 1-Chloroethyl chloroformate (step-1, 3.5 g, 24.4 mmol, 1.0 eq) in CH2C12 (40 ml) isopropanol (1.76 g, 29.3 mmol, 1.2 eq) was added at 0 °C then pyridine (1.25 g, 15.8 mmol, 0.65 eq) was added dropwise to the solution over a period of 10 minutes. Once the addition finished, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed successively with water (2x30 ml), 5percent potassium hydrogen sulfate (2x30 ml) and brine solution (2x30 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to obtain the title compound (3.1 g) as colorless liquid. 1H NMR (300 MHz, CDCl3): δ ppm 6.43 (q, 1H, J= 5.7 Hz), 5.0-4.89 (m, 1H), 1.83 (d, 3H, J= 5.7 Hz), 1.34 (d, 3H, J= 4.5 Hz), 1.32 (d, 3H, J= 4.5 Hz).
EXAMPLE 4 Synthesis of PGB-03 (3-Aminomethyl-5-methyl-hexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester) Procedure: Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH2Cl2 (15 mL) under the treatment in a nitrogen atmosphere (0-5° C.). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH2Cl2 (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22 g, 15.42 mmol) and CH2Cl2(2 mL) were added dropwise. After stirring overnight at room temperature, CH2Cl2 (20 mL) and water (20 mL) were added to the reaction solution. The product was extracted to the CH2Cl2 phase and washed with water (3*20 mL). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94percent). 1H-NMR (CDCl3, 500 MHz) δ 1.22-1.30 (m, 1H), 1.32-1.41 (m, 2H), 1.42-1.58 (m, 3H), 1.71-1.80 (m, 2H), 1.83 (d, J=6.0 Hz, 3H), 1.89-2.00 (m, 2H), 4.65-4.72 (m, 1H), 6.43 (q, J=6.0 Hz, 1H).
94%
With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere
Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH2CI2 (15 mL) under the treatment in a nitrogen atmosphere (0 -5°C). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH2CI2 (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22g, 15.42 mmol) and CH2CI2 (2 mL) were added dropwise. After stirring overnight at room temperature, CH2CI2 (20 mL) and water (20 mL) were added to the <n="19"/>reaction solution. The product was extracted to the CH2CI2 phase and washed with water (3 x 20 ml_). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94percent). 1HNMR(CDCI3, 500 MHz) δ 1.22-1.30(m, 1 H), 1.32-1.41 (m, 2H), 1.42-1.58(m, 3H), 1.71-1.80(m, 2H), 1.83(d, J=6.0 Hz, 3H), 1.89-2.00(m, 2H), 4.65-4.72(m, 1H), 6.43(q, J=6.0 Hz, 1H).
80%
With pyridine In dichloromethane at -78℃;
Cyclohexanol (0.50 g, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) were dissolved in 10 ml dichloromethane and the mixture cooled to -78 ºC. a solution of 1-chloroethyl carbonochloridate (0.54 ml, 5.0 mmol) dissolved in 2 ml dichloromethane was added drop-wise and with stirring. The mixture was stirred for 30 min at -78ºC and then overnight, warming to room temperature and forming a precipitate. The mixture was diluted with dichloromethane and was washed sequentially with twice with water, once with 0.1N hydrochloric acid, once with water and once with brine. The organics were dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.82 g (4.0 mmol, 80percent) of the title compound as a colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.43 (1 H, q, J=5.9 Hz), 4.69 (0 H, tt, J=9.0, 4.5 Hz), 1.89 - 2.01 (2 H, m), 1.83 (3 H, d, J=5.9 Hz), 1.70 - 1.81 (2 H, m), 1.45 - 1.58 (2 H, m), 1.22 - 1.44 (4 H, m).
70%
With pyridine In dichloromethane at 0 - 20℃; for 16.25 h;
Preparation Example 2: ; Preparation of 1 -iodoethyl cyclohexylcarbonate(1) Preparation of 1-chloroethyl cyclohexylcarbonateCyclohexanol (19 ml, 0.18 mol) was dissolved in methylene chloride (300 ml), and pyridine (14.8 ml, 0.18 mol) was added thereto while ice-cooling. 1-Chloroethyl chloroformate (20 ml, 0.185 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 16 hours. The reaction mixture was sequentially washed with water, brine, and 5percent sodium thiosulfate solution, dried over anhydrous magnesium, and then filtered. The filtrate was distilled under a reduced pressure to obtain 26.06 g of 1-chloroethyl cyclohexylcarbonate (yield: 70percent). <n="20"/>bpδδmmHg: 101 -103 °C ;1H-NMR(200MHz, CDCI3) δ 1.0-2.3(m, 10H), 1.38(d, J=5.8Hz, 3H), 4.60-4.80(m, 1 H), 6.40(q, J=5.8Hz, 1 H).
With pyridine In dichloromethane at 0 - 20℃; for 1.5 h;
To an ice cold reaction mixture containing p-nitrophenol (1.39 g, 10 mmol) and pyridine (0.81 g, 10 mmol) in dichloromethane (60 mL) was added 1-chloroethyl chloroformate (1.2 mL, 11 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 1 hour. After removing the solvent under reduced pressure, the residue was dissolved in ether, washed with water, 10percent citric acid and water. The ether layer was dried over Na2SO4 and evaporated under reduced pressure to give 2.4 g (97percent) of the title compound (57) as an off-white solid. 1H NMR (CDCl3): 1.93 (d, 3H), 6.55 (q, 1H), 7.42 (d, 2H), 8.28 (d, 2H).
92%
With pyridine In dichloromethane at 0 - 20℃; for 6 h;
Example 3: 1-iodoethyl 4-nitrophenyl carbonateSTEP A: 1-chloroethyl 4-nitrophenyl carbonate.To a solution of 4-nitrophenol (3.0 g, 21.6 mmol) and pyridine (1.9 mL, 24 mmol) in CH2C12 (48 mL) cooled to 0°C, 1-chloroethyl chloroformate (2.3 mL, 21.6 mmol) was added. The reaction was stirred at room temperature for 5-6 hours, then washed with NaH2PC>4 (5percent) and brine, dried over Na2SC>4 and concentrated affording the title compound (4.88 g, 92percent) as a pale yellow solid.
92%
at 0 - 20℃;
STEP A: 1-chloroethyl 4-nitrophenyl carbonateTo a solution of 4-nitrophenol (3.0 g, 21.6 mmol) and pyridine (1.9 mL, 24 mmol) cooled to 0°C, 1-chloroethyl chloroformate (2.3 mL, 21.6 mmol) was added. The reaction was stirred at room temperature for 5-6 hours, then washed with Na3/4P04 (5percent) and brine, dried over Na2 S C>4 and concentrated affording the title compound (4.88 g, 92percent) as a pale yellow solid.1H-NMR (CDC13) : 8.32 (2H,m); 7.44 (2H,m); 6.52 ( 1H, q, J=5.8 Hz); 1.94 (3H, d, J=5.5Hz) .
88%
With pyridine In chloroform at 0 - 20℃;
Step 1: 1-Chloroethylchloroformate (7.8 ml, 72 mmol, 1 eq.) was added to an ice-cold solution of p-nitrophenol (10 g, 72 mmol) in chloroform (100 mL), followed by drop wise addition of pyridine (8.8 ml, 108 mmol, 1.5 eq.) over a period of 20 min. The mixture was stirred in the ice-cold bath for 15 min, and then at room temperature overnight. The reaction mixture was sequentially washed with water, 1 N hydrochloric acid, water, 1 N sodium hydroxide, water, and brine. The organic phase was dried over Na2SO4, and concentrated to give yellow oil which, upon standing, crystallized to afford the corresponding chloroethyl carbonate (15.5 g, 88percent).
85%
With triethylamine In dichloromethane at 0 - 20℃;
To an ice-cold solution of 4-nitrophenol (2.0 g, 15 mmol) and triethylamine (1.6 g, 16 mmol) in dichloromethane (20 ml) was added a solution of 1-chloroethyl chloroformate (2.1 g, 19 mmol) in dichloromethane, and the mixture was stirred for 15 min at 0 °C and then overnight at room temperature. The mixture was extracted with dichloromethane (50 ml), washed successively with water (50 ml), 0.5 N sodium hydroxide (50 ml), saturated aqueous sodium chloride solution (50 ml), and water (3 x 50 ml), and dried over Na2SO4. The dichloromethane solution was filtered and evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with chloroform (100percent) as eluent to furnish pure 1-chloroethyl 4- nitrophenyl carbonate, as a white solid in 85percent yield.
1.67 g
Stage #1: With pyridine In dichloromethane at 0 - 4℃; for 0.166667 h; Stage #2: at 20℃;
First, place a 4-nitro phenol 10g on 250ml flask and dissolved in 100ml of methylene chloride. The reaction was cooled to 0 ~ 4 and slowly added 5.92ml of pyridine. After stirring for 10 minutes and added to 1-chloroethyl chloroformate 8.81ml slowly. Warm to room temperature and then stirred for 30 minutes and stirred overnight. After distillation under reduced pressure and the residue was dissolved in diethyl ether and washed with water, 10wtpercent citric acid solution, water order. Distilled under reduced pressure after dried over anhydrous sodium sulfate phenyl 1-chloro-ethyl-4-nitro-carbonate to give the 1.67g.
Reference：
[1] Journal of Antibiotics, 1999, vol. 52, # 7, p. 643 - 648
[2] Patent: US2006/229361, 2006, A1, . Location in patent: Page/Page column 37
[3] Journal of Pharmacology and Experimental Therapeutics, 2016, vol. 357, # 2, p. 240 - 247
[4] Journal of Medicinal Chemistry, 1988, vol. 31, # 2, p. 318 - 322
[5] Patent: WO2011/92065, 2011, A1, . Location in patent: Page/Page column 60
[6] Patent: WO2011/101245, 2011, A1, . Location in patent: Page/Page column 38
[7] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 14, p. 1811 - 1816
[8] Patent: US2008/146642, 2008, A1, . Location in patent: Page/Page column 45
[9] Patent: WO2007/27248, 2007, A2, . Location in patent: Page/Page column 22
[10] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 1, p. 191 - 198
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 14, p. 6658 - 6670
[12] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 21, p. 7593 - 7603
[13] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3994 - 4000
[14] Patent: US2002/19437, 2002, A1,
[15] Patent: US5602118, 1997, A,
[16] Patent: US2004/138108, 2004, A1,
[17] Patent: WO2008/79839, 2008, A1, . Location in patent: Page/Page column 40
[18] Patent: WO2010/63002, 2010, A2, . Location in patent: Page/Page column 26
[19] Patent: KR2015/106357, 2015, A, . Location in patent: Paragraph 0171-0175
[20] Patent: WO2018/81513, 2018, A1, . Location in patent: Page/Page column 112
22
[ 50893-53-3 ]
[ 24424-99-5 ]
[ 40110-55-2 ]
[ 135716-08-4 ]
Reference：
[1] Patent: US6518423, 2003, B1,
23
[ 50893-53-3 ]
[ 161357-89-7 ]
Reference：
[1] Patent: US2012/196824, 2012, A1,
24
[ 50893-53-3 ]
[ 24424-99-5 ]
[ 80845-58-5 ]
[ 184368-74-9 ]
Reference：
[1] Patent: US6518423, 2003, B1,
25
[ 50893-53-3 ]
[ 24424-99-5 ]
[ 532-24-1 ]
[ 185099-67-6 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: at 80℃; for 5 h; Stage #2: at 20 - 75℃; for 1.5 h;
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. A mixture of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (50.5 g, 359 mmol) and 1- chloroethyl chloroformate (117 mL, 1.08 mol) in CH2ClCH2Cl (500 mL) was heated to 80 0C for 5 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dried under high vacuum for 3 h, and was added in portions to MeOH (250 mL) over 30 min. The mixture was stirred at 75 0C for 1 h, and allowed to cool to rt. The solvents were removed under reduced pressure. The residue was diluted with Et2O (250 mL), and the mixture was sonicated for 15 min. The mixture was then stirred for 30 min, and filtered. The precipitate was washed with Et2O (125 mL), and dried under high vacuum. The residue was diluted with dioxane (400 mL), and the mixture was cooled to 0 0C. Aq. IM NaOH (400 mL) was added. BoC2O (82.3 g, 377 mmol) was added, and the mixture was stirred overnight while warming up to rt. The mixture was extracted with Et2O (2x). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 3:7) yielded the title compound (59.0 g, 73percent). LC-MS: tR = 0.83 min.
Stage #1: With diisopropylamine In dichloromethane at -13℃; for 2 h; Stage #2: With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at -7℃; for 2.16667 h;
h) Preparation of [N-methyl-N-3-((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridin-2-yl]carbamic acid 1-chloro-ethyl ester; [00317] 2-(N-methylamino)-3-hydroxymethylpyridine (22 g,0.159 mol) and diisopropylamine (36.1 mL, 0.207 mol, 1.3 eq.) were dissolved in dichloromethane(1L) and cooled in ethanol-ice bath(ca-13° C.). 1-Chloroethyl chloroformate(17.5 mL, 0.161 mol, 1.01 eq.) was added dropwise over a period of 1 h and the mixture was stirred for 1 h.Boc-sarcosine(39.2 g, 0.207 mol, 1.3 eq.) was added to the stirring mixture and WSC(39.7 g, 0.207 mol. 1.3 eq.) was added portionwise over a period of 10 min. To the mixture was added DMAP(5.8 g, 0.047 mol, 0.3 eq.) and the mixture was stirred for 2 h at -7° C. The reaction mixture was concentrated at 25° C. and the residue was dissolved in diethylether(1L). The solution was transferred to the separate funnel and washed with 0.1N-HCl(500 mL.x.3), water (500 mL), NaHCO3 aq.(500 mL) and brine(500 mL.x.2) successively, dried over MgSO4 and concentrated under reduced pressure. The obtained residue(48.2 g, ca 72.9percent yield) was used for the next step without purification. 1H-NMR (270 MHz,CDCl3): δ 1.42 (9H, d, J=24.1), 1.57 (1.5H, br.s), 1.88 (1.5H, br.s), 2.94 (3H, s), 3.37 (3H, s), 4.00 (2H, d, J=21.1), 5.18 (2H, d, J=13.5), 6.58 (1H, q, J=5.45, 11.0), 7.30 (1H, s), 7.82 (1H, d, J=6.9), 8.47 (1H, s); FAB-MS: m/z 416 (M+H)+.
64%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at -13℃; for 1 h; Stage #2: With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at -7℃; for 2 h;
2-(N-methylamino)-3-hydroxymethylpyridine (2.2 g, 16 mmol) and diisopropylamine (3.6 mL, 20.7 mmol) in 50 mL of methylene chloride, cooled to -13 ° C, and 10 mL of 1.75 mL (16.1 mmol) 1-chloroethyl chloroformate in dichloromethane solution was added and the reaction mixture was stirred for 1 h. To the stirred mixture was added 3. 9 g (20.7 mmol) of Boc-sarcosine,Then, 3. 9 g (20.7 mmol) of EDCI and 0. 58 g (4.7 mmol) of DMAP were added slowly and the mixture was stirred at -7 ° C for 2 h. The reaction was concentrated at 25 ° C. The residue was dissolved in 50 mL of ether and washed with 0.1 N HC1 (50 mL * 3), water (50 mL), and aqueous sodium hydrogencarbonate solution (50 mL) and brine (50 mL * 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily solid 4. 6 g, yield 64percent. The purity was 48.90percent by HPLC.
Reference：
[1] Patent: US6812238, 2004, B1, . Location in patent: Page/Page column 21-22; 36
[2] Patent: CN106032356, 2016, A, . Location in patent: Paragraph 0042; 0043
27
[ 50893-53-3 ]
[ 338990-31-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 40℃; for 2 h;
A mixture of 30. 9 g (0.10 mmol) of 3-((tert-butoxycarbonyl-N-methylamino)acetoxymethyl)-2-methylaminopyridine and(0.13 mol) of diisopropylethylamine was dissolved in 60 mL of dichloromethane, and 18.6 g (0.13 mol) of 1-chloroethyl chloroformate was added dropwise at room temperature. The mixture was warmed to 40 ° C, stirred for 2 h, The methylene chloride layer was washed with aqueous ammonium chloride solution, dried and concentrated to give a yellow oil which was dissolved in 5 volumes of ethyl acetate at -5 to 0 ° C and a solution of leq hydrogen chloride in acetic acid Ester solution, stirred for 30 minutes, and filtered to obtain 33.3 g of a white solid. Yield 80percent. The purity was 86.13percent by HPLC.
Reference：
[1] Patent: CN106032356, 2016, A, . Location in patent: Paragraph 0033; 0034
28
[ 50893-53-3 ]
[ 1170994-04-3 ]
[ 923590-95-8 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 7804 - 7815
With pyridine; In dichloromethane; at 0 - 20℃; for 1.5h;
To an ice cold reaction mixture containing p-nitrophenol (1.39 g, 10 mmol) and pyridine (0.81 g, 10 mmol) in dichloromethane (60 mL) was added 1-chloroethyl chloroformate (1.2 mL, 11 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 1 hour. After removing the solvent under reduced pressure, the residue was dissolved in ether, washed with water, 10percent citric acid and water. The ether layer was dried over Na2SO4 and evaporated under reduced pressure to give 2.4 g (97percent) of the title compound (57) as an off-white solid. 1H NMR (CDCl3): 1.93 (d, 3H), 6.55 (q, 1H), 7.42 (d, 2H), 8.28 (d, 2H).
92%
With pyridine; In dichloromethane; at 0 - 20℃; for 6h;
Example 3: 1-iodoethyl 4-nitrophenyl carbonateSTEP A: 1-chloroethyl 4-nitrophenyl carbonate.To a solution of 4-nitrophenol (3.0 g, 21.6 mmol) and pyridine (1.9 mL, 24 mmol) in CH2C12 (48 mL) cooled to 0°C, 1-chloroethyl chloroformate (2.3 mL, 21.6 mmol) was added. The reaction was stirred at room temperature for 5-6 hours, then washed with NaH2PC>4 (5percent) and brine, dried over Na2SC>4 and concentrated affording the title compound (4.88 g, 92percent) as a pale yellow solid.
92%
With pyridine; at 0 - 20℃;
STEP A: 1-chloroethyl 4-nitrophenyl carbonateTo a solution of 4-nitrophenol (3.0 g, 21.6 mmol) and pyridine (1.9 mL, 24 mmol) cooled to 0°C, 1-chloroethyl chloroformate (2.3 mL, 21.6 mmol) was added. The reaction was stirred at room temperature for 5-6 hours, then washed with Na3/4P04 (5percent) and brine, dried over Na2 S C>4 and concentrated affording the title compound (4.88 g, 92percent) as a pale yellow solid.1H-NMR (CDC13) : 8.32 (2H,m); 7.44 (2H,m); 6.52 ( 1H, q, J=5.8 Hz); 1.94 (3H, d, J=5.5Hz) .
88%
With pyridine; In chloroform; at 0 - 20℃;
Step 1: 1-Chloroethylchloroformate (7.8 ml, 72 mmol, 1 eq.) was added to an ice-cold solution of p-nitrophenol (10 g, 72 mmol) in chloroform (100 mL), followed by drop wise addition of pyridine (8.8 ml, 108 mmol, 1.5 eq.) over a period of 20 min. The mixture was stirred in the ice-cold bath for 15 min, and then at room temperature overnight. The reaction mixture was sequentially washed with water, 1 N hydrochloric acid, water, 1 N sodium hydroxide, water, and brine. The organic phase was dried over Na2SO4, and concentrated to give yellow oil which, upon standing, crystallized to afford the corresponding chloroethyl carbonate (15.5 g, 88percent).
85%
With triethylamine; In dichloromethane; at 0 - 20℃;
To an ice-cold solution of 4-nitrophenol (2.0 g, 15 mmol) and triethylamine (1.6 g, 16 mmol) in dichloromethane (20 ml) was added a solution of 1-chloroethyl chloroformate (2.1 g, 19 mmol) in dichloromethane, and the mixture was stirred for 15 min at 0 °C and then overnight at room temperature. The mixture was extracted with dichloromethane (50 ml), washed successively with water (50 ml), 0.5 N sodium hydroxide (50 ml), saturated aqueous sodium chloride solution (50 ml), and water (3 x 50 ml), and dried over Na2SO4. The dichloromethane solution was filtered and evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with chloroform (100percent) as eluent to furnish pure 1-chloroethyl 4- nitrophenyl carbonate, as a white solid in 85percent yield.
With triethylamine; In dichloromethane; chloroform; water;
Example 20 Synthesis of 1-chloroethyl-4-nitrophenylcarbonate (16) To an ice cold solution of 4-nitrophenol (2.0 g, 0.015 mol) and triethylamine (1.6 g, 0.016 mol) (or pyridine) in CH2Cl2 (20 mL) at 0-5° C. was added a solution of 1-chloroethylchloroformate (2.1 g, mmol) in CH2Cl2 (10 mL) and stirred for 15 min and then at room temperature overnight (16 h). The mixture was extracted with CH2Cl2 (50 mL), aq. NaOH (0.5 N, 50 mL), sat. NaCl solution (50 mL), water (3*50 mL) and dried (Na2SO4). The CH2Cl2 solution was filtered, evaporated in a rotavap and the residue was purified by silicagel column chromatography using chloroform (100percent) as eluent to furnish pure 16as a white solid: TLC (Rf) 0.75 (CHCl3); mp 70-71° C. (lit.22 69-70° C.); IR (KBr) 3116, 3084, 2999, 2932, 2864, 2364, 2330, 1779, 1626, 1525, 1355, 1245, 1101, 914, 863, 779, 677 cm-1; 1H NMR (CDCl3) delta 8.31 (dd, 2H, J=5.08, 2.07 Hz, Ar-CH), 7.43 (dd, 2H, J=4.76, 2.22 Hz, Ar-CH), 6.50 (q, 1H, J=11.67 Hz, CHClCH3), 1.93 (d, 3H, J=5.87 Hz); 13C NMR (CDCl3) delta 155.16, 150.65, 145.94, 125.63, 121.89, 85.44, 25.34; MS m/e (EI+, relative intensity) 210 (M+-HCl, 4), 139 (26), 122 (13),109 (8), 76 (13), 75 (11), 65 (27), 64 (17), 63 (100), 50 (10), 43 (13).
With pyridine; In chloroform;
1-Chloroethyl p-Nitrophenyl Carbonate The title compound is prepared by the procedure described in J. Med. Chem., 1988, vol. 31, No. 2, p.321. To a ice cooled mixture of 27.8 g of p-nitrophenol, 16.0 g of pyridine and 1 L of chloroform is added, dropwise, 34 g of alpha-chloroethyl chloroformate. After 1 hour, the ice bath is removed and the reaction is stirred for 16 hours at room temperature. The mixture is washed with water, 0.5percent sodium hydroxide and water. The organic layer is dried and concentrated in vacuo to give 47.85 g of the desired product. 1 H NMR(D2 O): delta8.26(d,2H,ArH); 7.40(d,2H,ArH); 6.53(q,1H,CHCl); 1.93(d,3H,ArH). Calculated for C9 H8 NO5 Cl: C=44.00; H=3.30; N=5.70; Cl=14.45 Found: C=44.04; H=3.40; N=5.80; Cl=14.45
With pyridine; sodium hydroxide; In chloroform;
1.1.1. Preparation of alpha-chloroethyl para-nitrophenyl Carbonate (1) 2.6 ml (23.7 mmol, 1.1 eq) of alpha-chloroethyl chloroformate are added, at 0° C., to a solution of 3 g (21.6 mmol, 1 eq) of p-nitrophenol and 1.7 ml (21.7 mmol, 1 eq) of pyridine in 108 ml of chloroform. The reaction mixture is stirred for 30 min at 0° C. and then for 16 h at ambient temperature. The reaction mixture is extracted with water, with a 0.5percent NaOH solution and then with water. The organic phase is dried over Na2SO4, filtered and evaporated under reduced vacuum, to give a yellow oil which gives a pure white solid (5.8 g) after crystallization from hexane. 1H-NMR (400 MHz, CDCl3); delta: 8.32 (d, 2H), 7.44 (d, 2H), 6.52 (q, 1H), 1.95 (s, 3H).
With pyridine; In chloroform; at 0 - 20℃; for 16.5h;
A solution of the purified alpha-chloroethyl 4-nitrophenyl carbonate (1 mmol) in glacial acetic acid (7 mL) is treated with mercuric acetate (1.2 mmol) and stirred at ambient temperature for 22 hours. After removal of acetic acid under vacuum at ambient temperature, the residue is dissolved in diethyl ether. The solution is washed successively to remove any remaining acid, evaporated, and purified by flash chromatography to provide alpha-acetoxyethyl 4-nitrophenyl carbonate.
With tributyl-amine; In toluene; at 20℃;Product distribution / selectivity;
Example 1 : Preparation of CEC-NP; [00175] Reactor (500 ml) was loaded with 4-Nitrophenol (10 g, 0.07 mol) dissolved in Toluene (150 ml) followed by dropwise addition of 1-chloroethyl chloroformate (13.25 g, 0.09 mol) and then Tributyl amine (17.3 g, 0.09 mol). The obtained solution was stirred at room temperature for additional 30 min. At this point according to HPLC no 4- Nitrophenol remained. The reaction was washed with IN HCl (150 ml), water (2*100 ml) and brine. The aqueous phase was removed from the reactor and to the remaining toluenic solution was evaporated.
1.67 g
First, place a 4-nitro phenol 10g on 250ml flask and dissolved in 100ml of methylene chloride. The reaction was cooled to 0 ~ 4 and slowly added 5.92ml of pyridine. After stirring for 10 minutes and added to 1-chloroethyl chloroformate 8.81ml slowly. Warm to room temperature and then stirred for 30 minutes and stirred overnight. After distillation under reduced pressure and the residue was dissolved in diethyl ether and washed with water, 10wtpercent citric acid solution, water order. Distilled under reduced pressure after dried over anhydrous sodium sulfate phenyl 1-chloro-ethyl-4-nitro-carbonate to give the 1.67g.
With pyridine; In dichloromethane; at 20℃;Cooling with ice;
To an ice-cold reaction mixture of 4-nitrophenol (23a) (5 g, 35.9 mmol) and pyridine (2.91 mL, 35.9 mmol) in DCM (300 mL) was added 1-chloroethyl chloroformate (23b) (5.65 g, 39.5 mmol). The reaction was allowed warm to room temperature overnight washed with water, 0.5percent aqueous NaOH and water. The organic layer was dried and concentrated to give 1-chloroethyl 4-nitrophenyl carbonate (23c) (7.6 g, 86 percent yield) as an off white solid, which was used in next step without further purification. NMR (300 MHz, DMSO-ife) delta 8.40 - 8.30 (m, 2H), 7.67 - 7.58 (m, 2H), 6.62 (q, J= 5.7 Hz, 1H), 1.87 (d, J= 5.7 Hz, 3H).
With pyridine In dichloromethane for 5h; Ambient temperature;
84%
With pyridine In dichloromethane; water
23.a (a)
(a) Synthesis of 1-chloroethyl 2,3-dihydro-2,2-dimethyl-7-benzofuranyl carbonate 21.5 g (0.15 mole) of 1-chloroethylchloroformate are added in a single portion to a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (24.6 g; 0.15 mole) in dichloromethane (150 ml). The mixture is cooled to between 0° and 5° C., and 12 g (0.15 mole) of pyridine are added dropwise. The mixture is stirred for 3 hours at 20° C. The organic phase is then washed with 2*50 ml of iced water. It is dried over magnesium sulphate and the solvent is evaporated. A yellow oil is obtained which is distilled. 34.1 g of the expected carbonate is then recovered (84% yield). B.p. 127° C./66.6 Pa (0.5 mm Hg).
With pyridine; In tetrahydrofuran; at -78 - 20℃; for 48h;
1-Chloroethyl chloroformate (7.14 g) was added dropwise to a solution (60 mL) of ethanol (2.30 g) and pyridine (3.95 g) in tetrahydrofuran at -78°C. The mixture was stirred at room temperature for 2 days, and the precipitated solid was filtered off and washed with diethyl ether. The filtrate and the washing solution were combined, and the mixture was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to give the title compound (7.01 g) as a colorless liquid.1H-NMR(CDCl3): 1.34(3H,t,J=7.2Hz), 1.83(3H,d,J=5.8Hz), 4.27(2H,q,J=7.2Hz), 6.44(1H,q,J=5.8Hz).
With pyridine; In dichloromethane; at -78℃; for 3h;Inert atmosphere;
1 eq. of ethanol and 1.2 eq. pyridine were dissolved in dichloromethane (1.2 mL/mmol). 1.05 eq. l-chloroethyl chloro formate was slowly added at -78 °C under nitrogen and the reaction mixture was stirred at -78 °C for 3 hours. The cold mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.
With pyridine; In dichloromethane; for 2h;Cooling;
1.43 g of 1-chloroethyl chloroformate (CAS: 50893-53-3) was added to 30 mL of anhydrous methylene chloride, 0.65 g of anhydrous ethanol was added, and 1.6 g of pyridine was added dropwise under cooling with cold water, followed by stirring for 2 hours. Dichloromethane (50 mL) was added and the organic layer was washed twice with 2N hydrochloric acid. The organic layer was washed once and the organic layer was separated and dried over anhydrous sodium sulfate overnight. After filtration, the filtrate was evaporated to dryness to give 1.21 g of crude 1-chloroethyl ethyl carbonate, which was used directly in the next step.
With pyridine; In dichloromethane; at 20℃;Cooling with ice;
To 1.91 g (0.041 mole) of 200 proof ethyl alcohol dissolved in 50 mL of well-stirred dichloromethane cooled with an ice bath was added 3.30 g (0.042 mole) of pyridine. 1-Chlorethyl chloroformate (5.91 g, 0.041 mole) was added to the cooled, well-stirred solution over the space of several minutes. The reaction mixture was protected with a drying tube and allowed to warm to room temperature overnight with continuous stirring. The suspension that resulted was diluted to 100 mL with dichloromethane, quickly washed four times with 5 mL volumes of water and finally with 5 mL of brine. The organic phase was separated, dried over sodium sulfate for 1 hour then concentrated at 23°C in vacuo to give 6.27 g of the desired product, contaminated with 7percent dichloromethane, as a colorless oil for a theoretical yield of 93percent.
78.5 g
With triethylamine; at 0 - 20℃; for 0.3h;
In the cooling to 0 °C under the 71.5 g (0.5 muM) 1 - chloro ethyl formate ester drop to 40 g and 52.0 g triethylamine 250 ml in toluene solution, about 2 hr after the completion of the dropping, then the temperature to room Temperature the reaction system, the reaction 1 hr, filtered to remove the solid, distilling and getting the intermediate H - 1 is 78.5 g.
(3-hydroxymethyl-pyridin-2-yl)-methyl-carbamic acid 1-chloro-ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; for 1h;
To a stirred solution of <strong>[32399-12-5](2-(methylamino)pyridin-3-yl)methanol</strong> (1 g, 5.79 mmol) in anhydrous DCM (10 mL) at -10 C, were added, DIPEA (1.315 mL, 7.53 mmol) and 1- chloroethyl chloroformate (0.700 mL, 6.37 mmol). After being stirred for 1 h, were sequentially added 2-((/er/-butoxycarbonyl)(methyl)amino)acetic acid (1.424 g, 7.53 mmol), EDC (1.443 g, 7.53 mmol), and DMAP (0.212 g, 1.737 mmol). The reaction mixture was stirred for 2 h at -10 C. The reaction mixture was allowed to warm to room temperature, diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The organic layer was washed with LhO and saturated NaCl solution, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified using CombiFlash (silica gel 60-120 mesh; 50% ethyl acetate in pet. ether as eluent) to afford (2-(((l-chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-((lerl- butoxycarbonyl)(methyl)amino)acetate (800 mg, 1.462 mmol, 25.3%) as pale yellow oil. NMR (400 MHz, DMSO-i) S ppm 8.49 - 8.56 (m, 1H), 7.91 - 7.97 (m, 1H), 7.43 - 7.53 (m, 1H), 6.53 - 6.65 (m, 1H), 5.01 - 5.24 (m, 2H), 3.97 - 4.10 (m, 3H), 3.17 - 3.29 (m, 3H), 2.79 - 2.88 (m, 3H), 1.45 - 1.63 (m, 2H), 1.24 - 1.41 (m, 9H); LCMS (ES): m/z = 416.2 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - -15℃; for 15h;Inert atmosphere;
Example 1 Preparation of Compound (QR16001) and its Sulfate 1.1 Preparation of Compound (QR16001-001) Under a nitrogen atmosphere, 80 mL dichloromethane, <strong>[32399-12-5]2-methylamino-3-pyridinemethanol</strong> (2.0 g, 0.014 mol) and 1.87 g N,N-diisopropylethylamine were added, and the reaction system was cooled to -15 to -20 C. followed by addition of a solution of 2.0 g (0.014 mol) 1-chloroethyl chloroformate in dichloromethane (20 mL) drop by drop. The reaction mixture was kept at the temperature of -15 to -20 C. for 16 hours. To the above reaction mixture, Boc-glycine (2.8 g, 0.016 mol, CAS No.: 4530-20-5) and 0.24 g 4-dimethylaminopyridine (DMAP) were added, at a temperature of -15 to -20 OC, dissolved, and added with 2.48 g 1-ethyl-3-(3-dimethylaminopropyl) carbonyldiimide hydrochloride (CAS No.: 25952-53-8), and after the completion of addition, kept at the temperature of -15 to -20 OC for 8 h. The end of the reaction was judged by TLC. The reaction mixture was washed with 0.1 M hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography to give 2.8 g colorless oil of Compound (QR16001-001). 1.2 Preparation of Compound (QR16001-002) 70 mL acetonitrile and 2.7 g (QR16001-001) were added, stirred to dissolve, and then added with 1.75 g voriconazole, sodium iodide (0.10 g, 0.13 eq.). The reaction system was heated to 50-60 C. for 5 h, and the end of the reaction was judged by TLC. The reaction mixture was concentrated to give a crude oily material, which was purified by silica gel column chromatography to give 2.0 g Compound (QR16001-002). 1.3 Preparation of Compound (QR16001) 0.78 g Compound (QR16001-002) was dissolved in 10 mL dioxane at room temperature, cooled to 0 C., added with 10 mL 4 M HCl/dioxane solution dropwise. After the completion of addition, the reaction mixture was stirred at room temperature and the end of the reaction was judged by TLC. The reaction mixture was filtered to give 0.52 g onium hydrochloride salt of Compound (QR16001); ESI-MS: 615.2.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - -15℃; for 17h;Inert atmosphere;
Under nitrogen atmosphere, 2.0 g of <strong>[32399-12-5]2-methylamino-3-pyridinemethanol</strong>, 80 mL of dichloromethane, and N,N-diisopropylethylamine (1.87 g) were added to a 250 mL three-necked flask, stirred and cooled to -15 to -20C., and a solution of 2.0 g of 1-chloroethyl chloroformate in dichloromethane (20 mL) was added dropwise and the addition was completed over 1 hr. The reaction temperature was kept at -15 to -20C. to allow reacting for 16 hours to obtain a reaction solution. 2.8 g of BOC-glycine (CAS No.: 4530-20-5, wherein BOC represents tert-butyloxycarbonyl), 0.53 g of DMAP were added to the reaction solution, stirred, and 2.47 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added in batches over 10 minutes, and the reaction was kept at the temperature of -15 to -20C. for 8 hours. It was determined by TLC that the reaction was complete, the reaction solution was concentrated, methyl tert-butyl ether was added for dissolution, and successively washed with 0.1 M hydrochloric acid, saturated sodium bicarbonate, and brine, dried, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to give 3.0 g of a colorless oily compound (ST0002-002).
a solution of 2-propanol (0.64 mL, 8.39 mmol) and pyridine (0.79 mL, 9.79 mmol) at -78C was added 1-chloroethyl chlorofonnate (0.76 mL, 6.99 mmol) dropwise. The reaction mixture was allowed to slowly warm to room temperature and stir overnight. The reaction mixture became a solid white clump and was sonicated in dichloromethane. The resulting suspension was concentrated and the white solid was dissolved in ethyl acetate and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a colorless liquid, 1.29 g, 99%.?H NMR (300 MHz, CDCl3 oe: 1.35 (m, 6H); 1.84 (d, 3H); 4.96 (m, 1H); 4.44 (m, 1H).
97%
With pyridine; In dichloromethane; at -78 - 20℃;
PREPARATION 46; 1-Chloroethyl isopropyl carbonate; To a solution of isopropanol (1.09 g, 18.27 mmol) and pyridine (1.45 g, 18.35 mmol) in of dichloromethane (30 ml) at-78 C was dropwise added (10 minutes) 1-chloroethyl chloroformate (2.66 g, 18.60 mmol) under argon. After the addition, the cooling bath was removed and the mixture was allowed to warm to rt and stirred at that temperature overnight. The reaction was diluted with additional dichloromethane (20 ml), washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as a colourless oil (3 g, 97% yield). No. (CDCl3): 1.33 (d, 3H), 1.35 (d, 3H), 1.84 (d, 3H), 4.95 (m, 1H), 6.43 (q, 1H).
87.7%
With pyridine; In diethyl ether; at 0 - 20℃;
0.66 g of isopropanol was added to 1.43 g of 1-chloroethyl chloroformate, and the solution was cooled to 0 C. in an ice-water bath. The mixture of 0.84 g of pyridine and 10 ml ethyl ether was added dropwise into the solution. The solution was reacted for 1 hour at that temperature, following 4 hours at room temperature. The reaction was stopped and the mixture was filtered, and the filtrate was washed respectively with 10% hydrochloric acid and water once. The organic phase was dried and concentrated to give 1.461 g of a light yellow liquid 1-chloroethyl isopropyl carbonate with a yield of 87.7%. The crude was directly used in the next reaction without purification.
81%
The compound 1-chloroethyl chloroformate (3 ml, 27.8 mmol) was diluted with DCM (25 ml)Cooled to 0 C,Isopropanol (2.1 ml, 27.8 mmol) diluted with DCM (25 ml) was slowly added with a constant pressure dropping funnel,Reaction about 15min,Pyridine (2.4 ml, 30.6 mmol) diluted with DCM (5 ml) was added slowly using a constant pressure dropping funnel,The process to keep the same low temperature,After adding,Reaction at room temperature overnight,Then diluted with water,Extracted with DCM,Organic phase dry,After concentration of 3.74g light yellow liquid,The yield was 81%.
68%
With pyridine; In dichloromethane; at 0 - 20℃; for 0.75h;
Preparation Example 1 : Preparation of 1 -iodoethyl isopropylcarbonate(1) ; Preparation of 1-chloroethyl isopropylcarbonate 1-Chloroethyl chloroformate (31.7 g, 0.22 mol) was dissolved in methylene chloride (200 ml), and isopropanol (39.7 ml, 0.52 mol) was added thereto while ice-cooling. Pyridine (23 ml, 0.28 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 30 minutes. The reaction mixture was sequentially washed with water, 5% brine, and 5% potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was distilled under a reduced pressure to obtain 25 g of 1-chloroethyl isopropylcarbonate (yield: 68%). bpdeltadeltammHg: 92-94 0C ; <n="19"/>1H-NMR(200MHz, CDCI3) delta 1.33(d, J=6.0Hz, 6H), 1.79(d, J=6.0Hz, 3H), 4.84(heptet, J=6.0Hz, 1 H), 6.37(q, J=6.0Hz, 1 H)
52%
With pyridine; In hexane; at 0 - 20℃; for 3h;
To a solution of 1-chloroethyl carbonochloridate (5 g, 35.0 mmol) in hexane (30 ml.) at 0 C was added a solution of pyridine (6.9 g, 87.4 mmol) in hexane (10 ml.) dropwise. A white precipitate formed after complete addition. A solution of propan-2-ol (3.15 g, 52.5 mmol) in hexane (10 ml.) was added and the mixture was stirred at 0 C for 2 h then allowed to warm to room temperature and stirred for a further 1 h. The mixture was diluted with hexane and washed with a saturated aqueous NaHCCh solution followed by water. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (3.0 g, 52%) as a pale yellow oil. 1H NMR (400 MHz, DMSO -de) d 6.49 (q, J = 5.7 Hz, 1 H), 4.89 - 4.79 (m, 1 H), 1.75 (d, J = 5.7 Hz, 3H), 1.27 - 1.23 (m, 6H).
With pyridine; In diethyl ether; at 0 - 20℃; for 5h;
0.66g of isopropanol was added to 1.43g of 1-chloroethyl chloroformate, and the solution was cooled to 0C in an ice-water bath. The mixture of 0.84g of pyridine and 10ml ethyl ether was added dropwise into the solution. The solution was reacted for 1 hour at that temperature, following 4 hours at room temperature. The reaction was stopped and the mixture was filtered, and the filtrate was washed respectively with 10% hydrochloric acid and water once. The organic phase was dried and concentrated to give 1.461g of a light yellow liquid 1-chloroethyl isopropyl carbonate with a yield of 87.7%. The crude was directly used in the next reaction without purification.
With pyridine; In dichloromethane; at -78 - 20℃; for 72h;
To a mixture of 2-propanol (3.83 mL), pyridine (4.85 mL) and dichloromethane (100 mL) was added 1-chloroethyl chloroformate (5.40 mL) at -78C and the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, ethyl acetate (200 mL) was added to the reaction solution. The mixture was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-chloroethyl isopropyl carbonate (7.87 g) as a yellow orange oil.1H-NMR (CDCl3) : 1.33(3H,d,J=6.3Hz), 1.34(3H,d,J=6.3Hz), 1.83(3H,d,J=5.8Hz), 4.88-5.02(1H,m), 6.43(1H,q,J=5.8Hz).
With pyridine; at 0 - 5℃; for 0.533333h;
7.4.1 Synthesis of 1-chloroethyl isopropyl carbonate [0327] The title compound was synthesized from 1-chloroethyl carbonochloridate according to General Procedure 7.; B) Synthesis of 1-chloroethyl acyloxy ester derivatives[0285] To a solution of the 1-chloroethyl chloro formate (1.07 equiv) in dichloromethane was added tert-hvXy alcohol (1 equiv) at 0-5 C, followed by the addition of pyridine (1.07 equiv) dropwise over 2 min. The resulting mixture was stirred at 0 - 5 C for 30 min. The reaction mixture was then washed successively with water, brine, and 0.5M HCl solution. The organic layer was dried over anhydrous MgSO4. After filtration, the solvent was removed by distillation to yield the crude product, which was used directly for the next step without further purification.
With pyridine; In dichloromethane; at 0 - 5℃; for 0.533333h;
7.C) Synthesis of 1-chloromethyl Acyloxy Ester Derivatives To a solution of the chloromethyl carbonochloridate (e.g., chloro(methyl)methyl carbonochloridate) (1.07 equiv) in DCM was added the alcohol (e.g., tert-butyl alcohol) (1 equiv) at 0-5 C., followed by the addition of pyridine (1.07 equiv) dropwise over 2 min. The resulting mixture was stirred at 0-5 C. for 30 min. The reaction mixture was then washed successively with water, brine, and 0.5M HCl solution. The organic layer was dried over anhydrous MgSO4. After filtration, the solvent was removed by distillation to yield the crude product (e.g., tert-butyl 1-chloroethyl carbonate), which was used directly for the next step without further purification.7.4 Synthesis of 1-(isopropoxycarbonyloxy)ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (36) 7.4.1 Synthesis of 1-chloroethyl isopropyl carbonate The title compound was synthesized from 1-chloroethyl carbonochloridate according to General Procedure 7.C.
With pyridine; In diethyl ether; at 20℃; for 4h;Cooling with ice;
To 2-chloroethyl chloroformate (10 ml) were added isopropyl alcohol (8.6 ml), diethyl ether (200 ml), and thereto was added dropwise pyridine under ice-cooling. Then, the mixture was stirred under ice-cooling for one hour, and warmed to room temperature, and further stirrred for 3 hours. Aftre the reaction was completed, the precipitated salt was removed with a filter, and the obtained filtrate was concentrated to give the residue (11.7 g), which was used in the next reaction without purification. To the crude product, 1-chloroethyl isopropylcarbonate, were added sodium iodide (26.3 g), tetrabutylammonium bromide (456 mg), and toluene (150 ml), and the reaction mixture was refluxed for 7 hours. After the reaction was completed, water was added to the reaction solution, and extracted with ethyl acetate. This ethyl acetate solution was washed with water, 5 % aqueous sodium hydrogen carbonate solution and 1 % aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.04 g). The obtained crude product was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) delta 6.77-6.71 (q, J = 6.2 Hz, 1H), 4.96-4.88 (quint, J = 6.4 Hz, 1H), 2.22-2.20 (d, J = 6.2 Hz, 3H), 1.33-1.29 (t, J = 6.4 Hz, 6H)
With pyridine; In dichloromethane; at 20℃; for 4h;
Example 9 [0124] Rac-1-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate 2-propanol (785 mg, 1 mL, 13.0 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at room temperature for 4 h to give 1-chloroethyl isopropyl carbonate. A portion of 1-chloroethyl isopropyl carbonate (221.6 mg, 1.33 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 244 mumol) in the presence of cesium carbonate (478 mg, 1.47 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (134.4 mg, 73% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N3O7: [(M+H)+]: 746, found: 746
3.1 g
With pyridine; In dichloromethane; at 0℃; for 0.666667h;
To a solution of 1-Chloroethyl chloroformate (step-1, 3.5 g, 24.4 mmol, 1.0 eq) in CH2C12 (40 ml) isopropanol (1.76 g, 29.3 mmol, 1.2 eq) was added at 0 C then pyridine (1.25 g, 15.8 mmol, 0.65 eq) was added dropwise to the solution over a period of 10 minutes. Once the addition finished, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed successively with water (2x30 ml), 5% potassium hydrogen sulfate (2x30 ml) and brine solution (2x30 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to obtain the title compound (3.1 g) as colorless liquid. 1H NMR (300 MHz, CDCl3): delta ppm 6.43 (q, 1H, J= 5.7 Hz), 5.0-4.89 (m, 1H), 1.83 (d, 3H, J= 5.7 Hz), 1.34 (d, 3H, J= 4.5 Hz), 1.32 (d, 3H, J= 4.5 Hz).
With pyridine; at 25℃;Cooling with acetone-dry ice;
To a solution of 2-propanol (2.66 mL, 34.97 mmol) and pyridine (3.39 mL, 41.96 mmol), pre-cooled in a dry- ice/acetone bath was slowly added 1-chloroethyl chloroformate. The resulting mixture was allowed to slowly warm to 25 C overnight, with stirring. After concentration under reduced pressure the mixture was dissolved in ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-chloroethyl isopropyl carbonate as a pink/orange oil (5.11 g, 88% yield).
With pyridine; In dichloromethane; at -20 - 20℃; for 4h;
Step 1) 1-chloroethyl isopropyl carbonate To a solution of 1-chloroethyl carbonochloridate (10 g, 69.9 mmol) in DCM (200 mL) was added a solution of isopropanol (5.9 mL, 76.9 mmol) and pyridine (6.75 mL, 83.9 mmol) in DCM (50 mL) at -20 C. The reaction was stirred at 0 C. for 2 h, then at rt for another 2 h. The mixture was washed with 1N HCl solution (250 mL*2), followed by brine (250 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (9.6 g, 82.4%). The product was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below: 1H NMR (400 MHz, CDCl3) delta 1.31-1.34 (m, 6H), 1.81-1.82 (d, J=5.84 Hz, 3H), 4.88-4.98 (m, 1H), 6.41-6.45 (t, J=5.84 Hz, 1H).
With pyridine; at 25℃;Cooling with acetone-dry ice;
To a solution of 2-propanol (2.66 mL, 34.97 mmol) and pyridine (3.39 mL, 41.96 mmol), pre-cooled in a dry-ice/acetone bath was slowly added 1 -chloroethyl chloro formate. The resulting mixture was allowed to slowly warm to 25 C overnight, with stirring. After concentration under reduced pressure the mixture was dissolved in ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1 -chloroethyl isopropyl carbonate as a pink/orange oil (5.11 g, 88% yield).
With pyridine; In dichloromethane; for 2h;Cooling;
1.43 g of 1-chloroethyl chloroformate (CAS: 50893-53-3) was added to 30 mL of anhydrous methylene chloride, 0.65 g of isopropanol was added, and 1.6 g of pyridine was added dropwise under cooling with cold water, followed by stirring for 2 hours. Dichloromethane (50 mL) was added and the organic layer was washed twice with 2N hydrochloric acid. The organic layer was washed once and the organic layer was separated and dried over anhydrous sodium sulfate overnight. After filtration, the filtrate was evaporated to dryness to give 1.44 g of crude 1-chloroethyl isopropyl ester, which was used directly in the next step.
With pyridine; In dichloromethane; at -20 - 20℃; for 4h;
1-chloroethyl carbonate acid chloride(10 g, 69.9 mmol) was dissolved in dichloromethane (200 mL).The temperature was lowered to -20 C, and isopropyl alcohol (5.9 mL, 76.9 mmol) and pyridine (6.75 mL, 83.9 mmol) were added thereto. A solution of DCM (50 mL).After the reaction solution was reacted at 0 C for 2 hours, it was returned to room temperature, and stirring was continued for 2 hours.After the reaction, the mixture was sequentially treated with 1N aqueous HCl.(250mLx2) and saline (250mL), dry with anhydrous Na2SO4 and concentrate under reduced pressure.The title compound was obtained as a colorless oil (9.6 g, 82.4%). The compound was used directly in the next reaction without purification.
diethyl 3-[[(2-chloroethoxy)carbonyl]oxy]pentanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In tetrahydrofuran; at 0 - 20℃; for 24h;
A solution of 1-chloroethyl chloroformate (3.92 mL) in tetrahydrofuran (20 mL) was added dropwise to a solution of <strong>[32328-03-3]diethyl 3-hydroxyglutarate</strong> (6.24 mL) and pyridine (5.46 mL) in tetrahydrofuran (100 mL) at 0C. The mixture was stirred at room temperature for 24 hrs. and the precipitated solid was filtered off. Ethyl acetate (100 mL) was added to the filtrate and the mixture was washed with water (100 mL), 1N hydrochloric acid (100 mL) and saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to give the title compound (9.68 g) as a colorless oil.1H-NMR (CDCl3) : 1.26(3H,t,J=7.0Hz), 1.27(3H,t,J=7.0Hz), 1.83(3H,d,J=6.0Hz), 2.78(4H,d,J=6.6Hz), 4.16(2H,q,J=7.0Hz), 4.17(2H,q,J=7.0Hz), 5.48(1H,quintet,J=6.6Hz), 6.42(1H,q,J=6.0Hz).
carbonic acid 1-chloro-ethyl ester 4-trifluoromethoxy-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
Scheme 1. A solution of 1-chloroethyl CHLOROFORMATE (1.03 g; 7.20 MMOL) in CH2CI2 (10 mL) was cooled to 0 C, TRIFLUOROMETHOXYPHENOL (1.09 g; 6.0 MMOL) and triethylamine were added, and the resulting solution was warmed to RT. After stirred for3 h, the reaction was quenched with saturated NAHC03, and extracted with EtOAc (3 times). The combined organic extracts were washed with water, brine, dried over NA2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with Hexane-EtOAc (10: 1) to provide 1.54 g (90%) of carbonic acid 1- chloro-ethyl ester 4-trifluoromethoxy-phenyl ester as a colorless oil. 1H NMR (400 MHz, CDCI3) : 8 7.26 (m, 4 H), 6.49 (q, 1H), 1.91 (d, 3H)
EXAMPLE 4 Synthesis of PGB-03 (3-Aminomethyl-5-methyl-hexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester) Procedure: Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH2Cl2 (15 mL) under the treatment in a nitrogen atmosphere (0-5 C.). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH2Cl2 (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22 g, 15.42 mmol) and CH2Cl2(2 mL) were added dropwise. After stirring overnight at room temperature, CH2Cl2 (20 mL) and water (20 mL) were added to the reaction solution. The product was extracted to the CH2Cl2 phase and washed with water (3*20 mL). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94%). 1H-NMR (CDCl3, 500 MHz) delta 1.22-1.30 (m, 1H), 1.32-1.41 (m, 2H), 1.42-1.58 (m, 3H), 1.71-1.80 (m, 2H), 1.83 (d, J=6.0 Hz, 3H), 1.89-2.00 (m, 2H), 4.65-4.72 (m, 1H), 6.43 (q, J=6.0 Hz, 1H).
94%
With pyridine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH2CI2 (15 mL) under the treatment in a nitrogen atmosphere (0 -5C). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH2CI2 (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22g, 15.42 mmol) and CH2CI2 (2 mL) were added dropwise. After stirring overnight at room temperature, CH2CI2 (20 mL) and water (20 mL) were added to the <n="19"/>reaction solution. The product was extracted to the CH2CI2 phase and washed with water (3 x 20 ml_). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94%). 1HNMR(CDCI3, 500 MHz) delta 1.22-1.30(m, 1 H), 1.32-1.41 (m, 2H), 1.42-1.58(m, 3H), 1.71-1.80(m, 2H), 1.83(d, J=6.0 Hz, 3H), 1.89-2.00(m, 2H), 4.65-4.72(m, 1H), 6.43(q, J=6.0 Hz, 1H).
80%
With pyridine; In dichloromethane; at -78℃;
Cyclohexanol (0.50 g, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) were dissolved in 10 ml dichloromethane and the mixture cooled to -78 ºC. a solution of 1-chloroethyl carbonochloridate (0.54 ml, 5.0 mmol) dissolved in 2 ml dichloromethane was added drop-wise and with stirring. The mixture was stirred for 30 min at -78ºC and then overnight, warming to room temperature and forming a precipitate. The mixture was diluted with dichloromethane and was washed sequentially with twice with water, once with 0.1N hydrochloric acid, once with water and once with brine. The organics were dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.82 g (4.0 mmol, 80%) of the title compound as a colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 6.43 (1 H, q, J=5.9 Hz), 4.69 (0 H, tt, J=9.0, 4.5 Hz), 1.89 - 2.01 (2 H, m), 1.83 (3 H, d, J=5.9 Hz), 1.70 - 1.81 (2 H, m), 1.45 - 1.58 (2 H, m), 1.22 - 1.44 (4 H, m).
70%
With pyridine; In dichloromethane; at 0 - 20℃; for 16.25h;
Preparation Example 2: ; Preparation of 1 -iodoethyl cyclohexylcarbonate(1) Preparation of 1-chloroethyl cyclohexylcarbonateCyclohexanol (19 ml, 0.18 mol) was dissolved in methylene chloride (300 ml), and pyridine (14.8 ml, 0.18 mol) was added thereto while ice-cooling. 1-Chloroethyl chloroformate (20 ml, 0.185 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 16 hours. The reaction mixture was sequentially washed with water, brine, and 5% sodium thiosulfate solution, dried over anhydrous magnesium, and then filtered. The filtrate was distilled under a reduced pressure to obtain 26.06 g of 1-chloroethyl cyclohexylcarbonate (yield: 70%). <n="20"/>bpdeltadeltammHg: 101 -103 C ;1H-NMR(200MHz, CDCI3) delta 1.0-2.3(m, 10H), 1.38(d, J=5.8Hz, 3H), 4.60-4.80(m, 1 H), 6.40(q, J=5.8Hz, 1 H).
With pyridine; In dichloromethane; at -78 - 20℃; for 15h;
Chloroethyl chloroformate (4 ml) was added to a solution of cyclohexyl alcohol (4.3 ml) and pyridine (3.3 ml) in dichloromethane (60 ml) at -78C, and they were stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to obtain crude 1-chloroethylcyclohexyl carbonate (7.5 g). Sodium iodide (1.6 g) and acetonitrile (16 ml) were added to the obtained crude product (7.5 g), and they were stirred at 60C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated to obtain a mixture (420 mg) of 1-chloroethylcyclohexyl carbonate and 1-iodoethylcyclohexyl carbonate. The compound obtained in Referential Example 108 (50 mg), triethylamine (26 ul) and dichloromethane (750 ul) were added to the obtained mixture (54 mg), and they were stirred at room temperature for 16 hours. After the evaporation of the reaction mixture followed by the purification by the reversed-phase high-performance liquid chromatography (reversed-phase HPLC) [water - acetonitrile each containing 0.1 % trifluoroacetic acid (TFA)], the title compound (25 mg) was obtained. MS(ESI MH+) : 725 CHNO : C36H38Cl2N4O8
With pyridine; In chloroform; at -78 - 20℃; for 24h;
Step 1 1-chloroethyl cyclohexyl carbonate Cyclohexanol (4.58 g) was dissolved in chloroform (75 ml), pyridine (3.63 g) was added, and the mixture was cooled to -78C. 1-Chloroethyl chlorocarbonate (5.0 ml) was added. The reaction mixture was gradually returned to room temperature and stirred for one day. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (8.85 g).
With pyridine; In dichloromethane; at 20℃; for 1h;
[00388] To a mixture of cyclohexanol (10.9 G, 10.9 MMOL), pyridine (8.62 g, 10.9 mmol) in dichloromethane was added 1-CHLOROETHYL CHLOROFORMATE (15.59, 10. 9 mmol) AT C. The resulting mixture was stirred at room temperature for 60 min. The mixture was partitioned between hexane and 10% citric acid. The organic phase was separated and dried over MGS04. Removal of the solvent gave the title compound, which was used in the next reaction without further purification.
With pyridine; In dichloromethane; at 0 - 20℃; for 2h;
(1) 9.15 g of cyclohexanol was dissolved in 150 ML of methylene chloride, to which 7.4 ML of pyridine was added followed by dropwise addition of 10 ML of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature.. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom.. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
With pyridine; In dichloromethane; at -78℃; for 3h;
Example 8 1-(Cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate [0122] cyclohexanol (Alfa Aesar, 1.33 g, 1.4 mL, 13.3 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at -78 C. for 3 h to give 1-chloroethyl cyclohexyl carbonate. A portion of 1-chloroethyl cyclohexyl carbonate (253 mg, 1.22 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 0.244 mmol) in the presence of cesium carbonate (487.4 mg, 1.5 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (135.4 mg, 70% yield). MS (ES+) m/z calcd. for C40H44Cl2F2N3O7: [(M+H)+]: 786, found: 786
2-(Acetylamino)ethyl 1-chloroethyl carbonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In tetrahydrofuran; at 0 - 20℃; for 24h;
A solution of 1-chloroethyl chloroformate (3.92 mL) in tetrahydrofuran (20 mL) was added dropwise to a solution of N-acetylethanolamine (3.10 mL) and pyridine (5.46 mL) in tetrahydrofuran (100 mL) at 0C. The mixture was stirred at room temperature for 24 hrs. and the precipitated solid was filtered off. Ethyl acetate (100 mL) was added to the filtrate and the mixture was washed with 1N hydrochloric acid (100 mL) and saturated brine (100mL×2) and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to give the title compound (6.05 g) as a colorless oil.1H-NMR (CDCl3) : 1.84(3H,d,J-5.8Hz), 2.02(3H,s), 3.60(2H,q,J=5.6Hz), 4.18-4.39(2H,m), 6.27(1H,brs), 6.86(1H,q,J=5.8Hz).
With pyridine; In tetrahydrofuran; at 0 - 20℃; for 24.0h;
A solution of 1-chloroethyl chloroformate (3.84 mL) in tetrahydrofuran (20 mL) was added dropwise to a solution of <strong>[4740-78-7]glycerol formal</strong> (2.92 mL) and pyridine (5.46 mL) in tetrahydrofuran (100 mL) at 0C. The mixture was stirred at room temperature for 24 hrs. and the precipitated solid was filtered off. Ethyl acetate (100 mL) was added to the filtrate and the mixture was washed with water (100 mL), 1N hydrochloric acid (100 mL) and saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (eluted with ethyl acetate:hexane=1:40-1:10) to give the title compound (2.95 g) as a colorless oil.1H-NMR(CDCl3): 1.85(3H,d,J=6.0Hz), 4.04(4H,t,J=3.0Hz), 4.66(1H,quintet,J=3.0Hz), 4.81(1H,d,J=6.0Hz), 4.95(1H,d,J=6.0Hz), 6.42(1H,q,J=6.0Hz).
In 1,2-dichloro-ethane; at 0℃; for 16h;Heating / reflux;
To a stirring solution OF TROPINONE (LOG, 72MMOL) into 350ML DCE at 0°C was added 1-chloroethyl chloroformate (11. 6ML, 108MMOL). The reaction mixture was then heated to reflux and stirred for 16 hours. Upon completion (TLC), volatiles were removed in vacuo and the dark brown residue was washed with ether and filtered. The filtrate was concentrated under reduced pressure and the product formed a brown oil (Yield: 12.65g, 54. 7MMOL). The brown oil was dissolved in 100mL MEOH and set to reflux for 2 hours. Upon completion (TLC), the methanol was removed in vacuo and the residue was dissolved in ether. Solid particulates were filtered, and the ether was removed under reduced pressure and 8-aza-bicyclo [3.2. 1] octan-3-one hydrochloride formed as a beige solid (Yield: 5. 0g, 40mmol). The product was used without any further purification.
5. 2 Example 2: O-(l-Chloroethyl) S-Ethvl Thiocarbonate (2) A solution of 1-chloroethyl chloroformate (71.5 g, 0.5 mol) in diethyl ether (600 mL) was cooled to 0-4C in an ice-water bath and a solution of ethanethiol (37 mL, 0.5 mol) and triethylamine (69.3 mL, 0.5 mol) in diethyl ether (200 mL) was added dropwise over 1 h. The reaction mixture was removed from the ice bath and stirred at ambient temperature for 4 h. Triethylamine hydrochloride was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by vacuum distillation (67-68 C at 240 mTorr) to afford the title compound (2) as a colorless liquid (75 g, 89%). 1H NMR (CDC13, 400 MHz) : 8 1.35 (t, 3H), 1.8 (d, 3H), 2.9 (dq, 2H), 6.6 (q, 1H).
C
Preparation C; Synthesis of benzyl 3-oxo-8-azabicycIo[3.2.1]octane-8-carboxylate; [00202] Tropinone (10.0 g; 71.84 mmol) was dissolved in DCE (60 mL) and treated drop- wise with 1-chloroethyl chloroformate ACE-Cl (14.5 mL; 19.11 g; 133.7 mmol). The reaction was allowed to stir at room temperature overnight and was then diluted with Et2O (400 mL) and filtered. The filtrate was concentrated under reduced pressure to provide the crude chloroethyl carbamate. This compound was taken in MeOH (200 mL) and stirred at room temperature for 1 h, then concentrated under reduced pressure (at 55 C) to provide the crude des-methyltropinone as the HCl salt (tan solid, 11.4 g, 98% yield). The crude material was recrystallized from acetonitrile to furnish the pure product as a white crystalline solid (5 g).
In 1,2-dichloro-ethane for 3h; Heating / reflux;
A mixture of tropinone (100 g, 718 mmol), and 1-chloroethyl chloroformate (308 g, 2.16 mol) in CH2ClCH2Cl (1.00 L) was heated to reflux for 5 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dried under high vacuum for 15 min, and was dissolved in MeOH (500 mL). The mixture was stirred at 75 °C for 1 h, and allowed to cool to rt. The residue was triturated with Et2O (500 mL), and put in an ultrasound bath for 15 min. The EPO mixture was stirred then for 30 min, and was filtered. The precipitate was washed with Et2O (250 mL), and dried under reduced pressure. The precipitate was diluted with dioxane (800 mL), and the mixture was cooled to 0 °C. Aq. IM NaOH (800 mL, 800 mmol), and Boc2O (165 g, 754 mmol) were added. The mixture was stirred overnight while warming up to it The mixture was extracted with Et2O (2x). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The pure title compound (109 g, 67%) crystallized spontaneously, and was dried under high vacuum.
In methanol; dichloromethane; at 20 - 60℃; for 6h;
Dissolve <strong>[84761-04-6]4-benzyl-2,2-dimethyl-morpholine</strong> (5.67 g, 27.6 mmol) in CH2Cl2 (50 mL) and add 1-chloroethyl chloroformate (4.60 mL, 42.2 mmol) while stirring at room temperature. After 4 h, concentrate the solution and treat the residue with MeOH (60 mL). Heat the mixture at 60 C for 2 h, then concentrate again. Dissolve the residue in water (125 mL) and wash with tert-butyl methyl ether (125 mL). Concentrate the aqueous EPO <DP n="134"/>layer and dry the resulting residue at 80 C under vacuum to give the title compound (3.91 g, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) delta 9.52 (2H, br s), 3.75 (2H, m), 2.89-2.96 (4H, m), 1.25 (6H, s).
With triethylamine; In tetrahydrofuran; methanol; ethyl acetate; 1,2-dichloro-ethane;
8-Benzyl-8-Aza-Bicyclo[3.2.1]Octan-3-One To a stirred solution of 29.2 g (209 mmol) tropinone in 300 mL 1,2-dichloroethane was added 45.5 mL (419 mmol) 1-chloroethyl chloroformate, and the resulting solution was warmed to 80 C. The reaction was monitored by TLC on a SiO2 plate eluding with EtOAc/2M NH3:MeOH (5:1). After stirring for 18 h, the solvent was evaporated, 300 mL MeOH was added, and the reaction was heated to reflux. After 45 min, the solvent was evaporated, then 300 mL THF, 38.83 g (227 mmol) benzyl bromide, and 33 mL (24.0 g, 237 mmol) triethylamine was added, and the resulting mixture was stirred at 23 C. After 69 h, the mixture was transferred to a separatory funnel containing 200 mL sat. NaHCO3 solution. The aqueous layer was extracted with EtOAc (2*300 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4 filtered and evaporated to a brown oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2Cl2/ EtOAc (40:1 to 20:1 to 8:1 to 4:1). The appropriate fractions were combined and evaporated to afford 19.91 g (92 mmol, a 44% yield) of the title compound as a yellow-orange oil. MS (ES) m/z: 216 (MH)+.
44%
With triethylamine; In tetrahydrofuran; methanol; ethyl acetate; 1,2-dichloro-ethane;
8-Benzyl-8-aza-bicyclo[3.2.1]octan-3-one To a stirred solution of 29.2 g (209 mmole) tropinone in 300 mL of 1,2-dichloroethane was added 45.5 mL (419 mmole) 1-chloroethyl chloroformate, and the resulting solution was warmed to 80 C. The reaction was monitored by thin layer chromatography on a silica gel plate eluding with EtOAc/2M NH3:MeOH (5:1). After stirring for 18 h, the solvent was evaporated, 300 mL MeOH was added, and the reaction was heated to reflux. After 45 min, the solvent was evaporated, then 300 mL THF, 38.83 g (227 mmol) benzyl bromide, and 33 mL (24.0 g, 237 mmol) triethylamine was added, and the resulting mixture was stirred at 23 C. After 69 h, the mixture was transferred to a separatory funnel containing 200 mL sat. NaHCO3 solution. The aqueous layer was extracted with EtOAc (2*300 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4 filtered and evaporated to a brown oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2Cl2/ EtOAc (40:1 to 20:1 to 8:1 to 4:1). The appropriate fractions were combined and evaporated to afford 19.91 g (92 mmol, a 44% yield) of the title compound as a yellow-orange oil. MS (ES) m/z: 216 (MH)+.
(a) 8-Azabicyclo[3.2.1]octane Hydrochloride. To an oven-dried, 100-mL, round-bottomed flask was added tropane (2.5 g, 19.96 mmol) followed by toluene (20 mL), and a-chloro-ethyl chloroformate (3.2 mL, 30 mmol). The flask was purged with N2 and the mixture was heated at 120 C. for 16 h. The reaction was allowed to cool to room temperature and the solvent was evaporated in vacuo. The resulting residue was dissolved in MeOH (20 mL) and heated to reflux at 85 C. for 3 h. The solvent was evaporated in vacuo and the product dried under vacuum to give 2.90 g (98% yield) of a light brown solid. MS m/z: 112.0 (M+1). 1H NMR (DMSO-d6; 400 MHz): d 1.64 (m, 4), 1.95 (m, 6), 3.92 (s,2), 9.24 (br d, 2, J=7.3).
In methanol; toluene;
a 8-Azabicyclo[3.2.1]octane hydrochloride A mixture of tropane (900 mg), 1-chloroethyl chloroformate (1 ml), and toluene (20 ml) was heated and refluxed for 6 hours. After that, methanol (10 ml) was added to the reaction solution, and further refluxed for 4 hours. The solvent was distilled to yield the title compound (850 mg).
With hydrogenchloride; potassium hydroxide; In methanol; dichloromethane;
Example 21 (+)-4beta-(4-Chlorophenyl)-3alpha-n-propylpiperidine (50) To a solution of the compound of Example 15 (158 mg, 0.63 mmol) in dichloromethane (16 mL) were added 1,8-bis-(dimethylamino)naphthalene (proton sponge, 74 mg, 0.43 mmol) and alpha-chloroethyl chloroformate (0.53 mL, 4.9 mmol). This mixture was heated under reflux for 1.5 h. After cooling to room temperature, 232 mL of 1 M anhydrous hydrogen chloride in ether solution was added, and the mixture was passed through a silica gel plug using CH2Cl2 as the eluent. The combined eluents were concentrated, the residue was taken up in MeOH (14 mL), and the resulting mixture was stirred at reflux for 1 h. After evaporation, 0.5 M KOH was added, the mixture was extracted with EtOAc, and the organic extracts were washed with brine, dried and concentrated. Flash chromatography afforded the title compound (145 mg, 97%): [alpha]D +43.4 ((c 0.32, CHCl3); 1H NMR (CDCl3) d 0.73 (t, 3H, J=6.9 Hz), 0.82-0.94 (m, 1H), 0.96-1.13 (m, 2H), 1.20-1.35 (m, 1H), 1.60-1.78 (m, 3H), 2.24 (dt, 1H, J=4.2, 11.7 Hz), 2.34 (t, 1H, J=11.1 Hz), 2.54 (s, 1H), 2.69 (dt, 1H, J=2.7, 11.7 Hz), 3.15 (d, 1H, J=12.0 Hz), 3.29 (dd, 1H, J=3.6, 12.0 Hz), 7.10 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.1 Hz); 13C NMR (CDCl3) d 14.4, 19.8, 34.0, 36.0, 41.8, 47.2, 49.3, 52.2, 128.7, 129.1, 131.8, 144.1; MS m/z 44 (69), 57 (100), 194 (40), 237 (M+, 29); Anal. (C14H20ClN) Calcd: C 70.72, H 8.48, N 5.89; Found: C 70.39, H 8.14, N 6.22.
With hydrogenchloride; potassium hydroxide; In methanol; dichloromethane;
Example 16 (-)-Methyl 4beta-(4-Chlorophenyl)-piperidine-3beta-carboxylate (45) To a solution of the compound of Example 3 (300 mg, 1.18 mmol) in dichloromethane (30 mL) was added 1,8-bis-(dimethylamino)-naphthalene (proton sponge, 140 mg, 0.66 mmol) and a-chloroethyl chloroformate (1 mL, 9.26 mmol). This mixture was heated under reflux for 1.5 h. After cooling to room temperature, 437 mL of 1 M anhydrous hydrogen chloride in ether solution was added, and the mixture was passed through a silica gel plug and eluted with CH2Cl2. The combined eluents were evaporated. Methanol (26 mL) was added to the residue, and the mixture was stirred at reflux for 1 h. After evaporation 0.5 M KOH was added, and the mixture-was extracted with EtOAc, washed with brine, dried, and concentrated. PTLC afforded the title compound (209 mg, 73.5%): [alpha]D -143.0 ((c 1.30, CHCl3); 1H NMR (CDCl3) d 1.62-1.73 (m, 1H), 2.34 (dq, 1H, J=3.9, 12.6 Hz), 2.68-2.84 (m, 2H), 2.93-3.16 (m, 3H), 3.34 (t, 2H, J=13.5 Hz), 3.45 (s, 3H), 7.12 (d, 2H, J=8.4 Hz), 7.26 (d, 2H, J=8.4 Hz); 13C NMR (CDCl3) d 26.7, 42.9, 45.7, 46.4, 48.9, 51.3, 128.6, 128.7, 132.5, 141.8, 174.0; MS m/z 43 (25), 57 (100), 194 (41), 253 (M+, 20).
73.5%
In methanol; dichloromethane;
Example 75 (-)-Methyl 4beta-(4-Chlorophenyl)-piperidine-3beta-carboxylate (26) A suspension of (-)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3beta-carboxylate (300 mg, 1.18 mmol), 1,8-bis-(dimethylamino)-naphthalene (proton sponge, 140 mg, 0.66 mmol) and alpha-chloroethyl chloroformate (1.0 mL, 9.26 mmol) in CH2Cl2 (30 mL) was stirred at reflux for 2 h. After cooling to rt, the reaction mixture was diluted with HCl/ether (1M, 20 mL) and the mixture was passed through a silica gel plug and chased with CH2Cl2 The combined eluents were evaporated to give an oil. This oil was dissolved in MeOH (20 mL) and stirred at reflux for 3 h. The solvent was removed in vacuo, diluted with CH2Cl2 (20 mL) and washed with NaHCO3 (20 mL). The solvent was dried over Na2SO4 and evaporated in vacuo to give the title compound as an oil (209 mg, 73.5%): [alpha]D -143.0 (c 1.30, CHCl3); 1H NMR (CDCl3)d 1.62-1.73 (m, 1H), 2.34 (dq, J=3.9, 12.6 Hz, 1H), 2.68-2.84 (m, 2H), 2.93-3.16 (m, 3H), 3.34 (t, J=13.5 Hz, 2H), 3.45 (s, 3H), 7.12 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H); MS m/z 43 (25), 57 (100), 194 (41), 253 (M+, 20).
With sodium chloride; triethylamine; In methanol; dichloromethane;
Methyl 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylate 4.62 g of <strong>[80845-58-5]methyl 1-benzyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate</strong> was dissolved in 30 ml of dichloromethane. Under ice-cooling, 4.29 g of 1-chloroethyl chloroformate was added thereto and the resulting mixture was heated under reflux for 2 hours. After adding 50 ml of methanol, the mixture was stirred at 70 C. for 1 hour and 20 minutes. Then triethylamine was added to the reaction mixture under ice-cooling until the pH value of the mixture exceeded 7. After further adding 4.37 g of tert-butyl dicarbonate, the resulting mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.46 g of the title compound as a yellow oily substance. 1H-NMR(CDCl3) delta ppm: 1.47(s, 9H), 2.40(br.s, 2H), 3.51(t, J=5.6 Hz, 2H), 3.76(s, 3H), 4.07(d, J=2.4 Hz, 2H), 6.88(br.s, 1H)
To a solution of 3-aminophenethyl alcohol (2.0 g, 14.6 mmol) in dioxane (50 ml) and water (25 ml) was added an aqueous solution of sodium hydroxide (0.64 g in 14.4 ml of water, 16.1 mmol), followed by chloroethyl chloroformate (2.19 g, 15.3 mmol). The mixture was stirred for 0.25 h at room temperature and then NaOH solution added to pH11 and stirring continued for 0.25 h. Further chloroethyl chloroformate (1.1 g, 7.7 mmol) was added followed, after 10 minutes, by NaOH solution to pH11. The mixture was stirred for 0.25 h and the solvents removed in vacuo. The residue was partitioned between ethyl acetate (2*100 ml) and water (50 ml) and the organic extracts combined, dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel with 50% ethyl acetate/hexane to give the chloroethyl carbamate (3.6 g, 100%).
With sodium hydrogencarbonate; In 1,2-dichloro-ethane; for 2h;Heating / reflux;
Et2O (800 mL) and Et3N (22.0 mL, 0.158 mol) were added to <strong>[552-70-5]pseudopelletierine</strong> hydrochloride (30.00 g, 0.158 mol). The suspension was stirred for 15 min, filtered and the filtrate reduced in vacuo to yield the free amine (23.00 g, 150.1 mmol). To a suspension of the free amine (23.00 g, 150.1 mmol) and NaHCO3 (22.0 g, 0.263 mol) in 1,2-dichloroethane (800 mL) was added dropwise 1-chloroethyl chloroformate (82 mL, 0.750 mol). The mixture was heated to reflux. After 2 h, the reaction mixture was allowed to cool to rt, filtered, and the solvents were thoroughly removed in vacuo. MeOH (800 mL) was added and the mixture was stirred at 50 C for 60 min. The sol. was allowed to cool to rt, and the solvents were removed in vacuo. The residue was dissolved in CH2Cl2 (400 mL), DIPEA (64 mL, 0.375 mol) was added followed by BoC2O (39.0 g, 0.180 mol), and the mixture was stirred at rt overnight. The mixture was washed with aq. IM HCl (Ix), and aq. sat. NaHCO3 (Ix). The org. phase was dried over MgSO4, filtered, and the solvents were removed in vacuo. Recrystallization from EtOAc yielded the title compound (31.7 g, 88%). LC-MS: tR = 0.86 min, ES+ = 240.29.
In 1,2-dichloro-ethane; at 20 - 90℃; for 3.5h;
The pseudo-pelletierine (3.35 g, 21.9 mmol) was dissolved in 1 ,2-dichloroethane (18 mL) and 1-chloroethyl chloroformate (4.7 g, 33 mmol) is added all at once with good stirring. After stirring 30 min at RT, the stirred mixture is heated in a 90 0C bath for 3 h and evaporated under a stream of nitrogen. The residue is taken up in dry MeOH (25 mL) and slowly heated to reflux for 2 h and evaporated under a stream of nitrogen. The solids are taken up in additional dry MeOH and heated in a 90 0C bath and evaporated again to yield 3.8 g the hydrochloride salt. MS (ES) m/e 140.0 (M+H)+. The amine hydrochloride (2.98 g, 16.9 mmol) was dissolved in dichloromethane (20 mL) and 4 M aq NaOH (11 mL). The 4-chlorobenzenesulfonyl chloride (5.07 g, 24 mmol) is added all at once to the reaction mixture with good stirring. After stirring at RT for 16 h, N, N- diethyl-ethylenediamine (1.39 g, 12 mmol) is added and stirred for 1 h. The reaction mixture was diluted with dichloromethane and acidified to pH 4 using aq NaHSO4. The aqueous phase was separated and extracted once with dichloromethane. The combined organic phases were washed with 5% NaHSO4 (three times), water, brine, and then dried (Na2SO4) and evaporated to yield 5.03 g of the product upon evaporation. Further purification was optionally performed by applying the product in dichloromethane to a silica gel column and elution (0-10% EtOAc in dichloromethane) to yield the purified product upon evaporation. MS (ES) m/e 314.0- (M+H)+.
With chloro-trimethyl-silane In methanol; diethyl ether; ethanol; dichloromethane; water; benzene
1 3-acetyl-1,2,5,6,-tetrahydropyridine-oxime and its hydrochloride
EXAMPLE 1 3-acetyl-1,2,5,6,-tetrahydropyridine-oxime and its hydrochloride Stage A: 1-benzyl-3-acetyl-pyridine-oxime bromide. 7.4 g of 3-acetylpyridine oxime is dissolved in 80 cm3 of ethanol, 8 cm3 of benzyl bromide is added to it, with heating at reflux for 6 hours. The solvent is eliminated followed by crystallization from an ether/methanol mixture. 14.21 g of the expected product is obtained. m.p.=200°-201° C. Stage B: 1-benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-oxime. 13.76 g of the product obtained at stage A in solution in 100 cm3 of methanol is cooled to 0° C., 2.54 g of sodium hydroboride is added, the whole is allowed to return to ambient temperature and agitated for 45 minutes. After concentrating under reduced pressure, water is added and extraction is done with chloroform. The organic phase is dried, the solvent is eliminated, and the residue is chromatographed on silica (eluent: ethyl acetate-toluene 8-2). After crystallization of the residue from ethyl acetate, 7.8 g of the expected product is obtained. m.p. 103°-105° C. Stage C: 1-benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-trimethylsilyl oxime. 3.6 g of the product obtained at stage B is dissolved in 60 cm3 of benzene and 1.86 g of 1,4-diazabicyclo [2.2.2.] octane, and over 5 minutes, under an inert atmosphere, 2.07 cm3 of trimethylchlorosilane is added. The suspension is heated to reflux for 3 hours, then cooled, filtered and concentrated to dryness. The residue is taken up in ethyl ether, filtered, the solvent is eliminated under reduced pressure, and 4.5 g of the expected product is obtained. (b.p. 150° C., under 0.05 mbar) Stage D: 3-acetyl-1,2,5,6-tetrahydropyridine-oxime and its hydrochloride. Under an inert atmosphere, 20 g of the product obtained as at stage C in solution in 20 cm3 of methylene chloride is cooled to 0° C., 21.6 g of alpha-chloroethyl chloroformate is added, followed by heating to reflux for two-and-a-half hours. After cooling, filtering and eliminating the solvent, the residue is taken up in ethyl ether, triturated and filtered. The solvent is evaporated off, the residue is taken up in methanol, heated to reflux for 30 minutes, then concentrated to dryness. The residue is taken up in methanol and ethyl ether, filtered, crystallized from ethanol, and 2.1 g of the expected product is collected. m.p. 237° C. (with decomposition).
In methanol; sodium hydroxide; 1,2-dichloro-ethane; acetone;
EXAMPLE 34 1,2,5,6-Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine oxalate To a solution of <strong>[131986-45-3]3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine</strong> (0.70 g, 2.4 mmol) in 1,2-dichloroethane (20 mi) was added a solution of 1-chloroethyl-chloroformate (0.35 g, 2.4 mmol) in 1,2-dichloroethane at 0 C. The reaction mixture was heated to 40 C. for 2 h and evaporated. The residue was dissolved in methanol and heated to reflux for 1 h and evaporated. The residue was dissolved in diluted sodium hydroxide and extracted with ether. The combined ether phases were dried and evaporated. Crystallization as the oxalate salt from acetone gave the title compound in 72% (620 mg) yield. (M.p. 157-159 C.; M+: 267; Compound 37).
72%
In methanol; sodium hydroxide; 1,2-dichloro-ethane; acetone;
EXAMPLE 34 1,2,5,6-Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine oxalate To a solution of <strong>[131986-45-3]3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine</strong> (0.70 g, 2.4 mmol) in 1,2-dichloroethane (20 ml) was added a solution of 1-chloroethyl-chloroformate (0.35 g, 2.4 mmol) in 1,2-dichloroethane at 0 C. The reaction mixture was heated to 40 C. for 2 h and evaporated. The residue was dissolved in methanol and heated to reflux for 1 h and evaporated. The residue was dissolved in diluted sodium hydroxide and extracted with ether. The combined ether phases were dried and evaporated. Crystallization as the oxalate salt from acetone gave the title compound in 72% (620 mg) yield. (M.p. 157-159 C.; M+: 267; Compound 37).
72%
In methanol; sodium hydroxide; 1,2-dichloro-ethane; acetone;
EXAMPLE 34 1,2,5,6-Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine oxalate To a solution of <strong>[131986-45-3]3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine</strong> (0.70 g, 2.4 mmol) in 1,2-dichloroethane (20 ml) was added a solution of 1-chloroethyl-chloroformate (0.35 g, 2.4 mmol) in 1,2-dichloroethane at 0 C. The reaction mixture was heated to 40 C. for 2 h and evaporated. The residue was dissolved in methanol and heated to reflux for 1 h and evaporated. The residue was dissolved in diluted sodium hydroxide and extracted with ether. The combined ether phases were dried and evaporated. Crystallization as the oxalate salt from acetone gave the title compound in 72% (620 mg) yield. (M.p. 157-159 C.; M+: 267; Compound 37).
4-{2-[N-(1-benzylpiperid-4-yl)amino]-1,3-thiazol-4-yl}benzonitrile[ No CAS ]
4-{2-[N-(piperid-4-yl)amino]-1,3-thiazol-4-yl }-benzonitrile dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In methanol; diethyl ether; 1,2-dichloro-ethane;
PREPARATION V 4-{2-[N-(piperid-4-yl)amino]-1,3-thiazol-4-yl }-benzonitrile dihydrochloride (Compound 5.1, (III) with R1 =H) This compound is obtained by the action of chloroformares as described in Tetrahedron Letters, 1983, 24, 31, 3233-3236 and more particularly by the action of 1-chloroethyl chloroformate according to J. Org. Chem., 1984, 49, 2081-2082. 6.2 g of 1,8-bis-dimethylaminonaphthalene are added to 18 g of 4-{2-[N-(1-benzylpiperid-4-yl)amino]-1,3-thiazol-4-yl}benzonitrile in 250 ml of 1,2-dichloroethane and then the reaction mixture is cooled to 0 C., 10.4 ml of 1-chloroethyl chloroformate are added and then the reaction mixture is stirred for 30 minutes at this temperature and then heated under reflux for 3 hours. The mixture is evaporated to dryness and the residue is taken up in 250 ml of methanol and-then the mixture is heated under reflux for 2 hours. The reaction mixture is allowed to cool and then, successively, 250 ml of diethyl ether are added, the mixture is filtered, washed with diethyl ether and dried in order to obtain beige crystals which melt at 266 C.; yield 87%.
With calcium carbonate; In 1,4-dioxane; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Step 2 2-chloroethyl-N-[(4-fluoro-2-methyl-5-nitro)phenyl]-carbamate 5 g (29 mmol) of <strong>[446-18-4]2-amino-5-fluoro-4-nitrotoluene</strong> was heated with 2.5 g calcium carbonate in 200 ml dioxan at 70 C., reacted with 3.1 ml of chloroformic acid chloroethyl ester and heated for 3 hours at 100 C. The resultant solution was filtered hot and the filtrate is introduced into 500 ml of ice water. The ocher colored precipitate was filtered with suction and recrystallized from an ethanol-water mixture. The resulting 6.6 g (81% of theoretical) of 2-chloroethyl-N-[(4-fluoro-2-methyl-5-nitro)phenyl]-carbamate had a melting point of 113 C. 1 H-NMR(D6 -DMSO): delta=2.33 (s; 3H, --CH3) 3.88 (t; 2H, --CH2 Cl) 4.38 (t; 2H, --CH2 CH2 Cl) 7.49 (d, J=12.3 Hz; 1H, 6-H) 8.22 (d, J=7.3 Hz; 1H, 3-H) 9.44 (br.s; 2H, --NH, exchange with D2 O) MS(70ev): m/e=276(M+.)
(i) Ethyl chloroethyl carbonate. To a solution of chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in methylene chloride (200 ml), pyridine (12.82 g, 0.162 mol) was added at 0° C. After 10 min at 0° C. and 21 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4), giving 18.5 g (74percent) of the intermediate ethyl chloroethyl carbonate as a crude product. 1 H NMR (60 MHz, CDCl3): delta1.30 (t, 3H, CH3), 1.85 (d, 3H, CH3 CH), 4.25 (q, 2H, CH2), 6.45 (q, 1H, CH).
With pyridine; In ethanol; dichloromethane;
1-Chloroethyl ethyl carbonate Ethanol (2.3 g) was dissolved in dichloromethane (50 ml) and pyridine (4.0 g) was added. It was reacted with 1-chloroethyl chloroformate (7.5 g) as described above. On work up it gave 7.5 g of a pale mobile liquid (desired product). NMR (CDCl3) delta1.36 (3H, t, J=7 Hz, OCH2 CH3), 1.88 (3H, d, J=7 Hz, ClCH2 CH3), 4.36 (2H, q, J=7 Hz, OCH2 CH3) and 6.41 (1H, q, J=7 Hz, CH3 CHCl).
The isopropyl (1-chloroethyl) carbonate used as starting material was prepared as follows. 1-chloroethyl chloroformate (28.5 g; 0.2 mol) was mixed with isopropyl alcohol (13.2 g; 0.22 mol) and heated to 90 C. After cooling to room temperature the product was washed with water and sodium bicarbonate solution and dried. 30 g was obtained. NMR spectrum (CDCl3) 1.40 (CH3)2 C; delta1.85 CH3 C; delta5.10 C--CH--C; delta6.45 OCH(C)Cl.
With N-ethyl-N,N-diisopropylamine; In dicholoroethane; ethyl acetate; at -78 - 20℃; for 1.08333h;
To a stirring mixture of <strong>[841290-80-0]N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine</strong> (250 mg, 0.53 mmol) and i-Pr2NEt (0.14 mL, 102 mg, 0.78 mmol) in dicholoroethane (10 mL) at -78 0C, 1-chloroethyl chloroformate (0.07 mL, 90 mg, 0.638 mmol) was added dropwise under nitrogen atmosphere over 5 min. After 1 h, the reaction mixture was diluted with EtOAc (10 mL) at -78 0C. Reaction mixture was allowed to warm to room temperature while stirring. Solid precipitated from pale brown transparent reaction mixture after stirring the contents at room temperature for 1 h. Reaction mixture was concentrated and diluted with water (15 mL). The precipitated solid was filtered and dried to provide (+/-)-N2-(1-chloroethoxycarbonyl)-<strong>[841290-80-0]N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine</strong> (250 mg, 81%). 1H NMR (DMSO-d6): delta 11.04 (s, 1H), 9.78 (s, 1H), 8.37 (d, 1H, J=3.2 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.17 (d, 1H, J=8.5 Hz), 6.64 (qt, 1H, J=5.7 Hz), 6.57 (s, 2H), 3.69 (s, 6H), 3.65 (s, 3H), 1.65 (d, 3H, J=5.7 Hz), 1.39 (s, 6H). LCMS: ret. time: 10.35 min.; purity: 95%; MS (m/e): 578 (MH+).
tris-dibenzylideneacetone-dipalladium(0)[ No CAS ]
[ 740806-53-5 ]
[ 50893-53-3 ]
[ 16817-43-9 ]
[ 255723-98-9 ]
[ 740807-97-0 ]
Yield
Reaction Conditions
Operation in experiment
With sodium t-butanolate; In methanol; dichloromethane; toluene;
Synthesis of 2-(R)-Benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine Following protocol A, 818 mg (3.70 mmol) of <strong>[16817-43-9]5-Bromo-2-chloroanisole</strong>, 1.15 g (3.88 mmol) of 1-Benzyl-3-(R)-benzyloxymethyl-piperazine, 0.50 g (5.18 mmol) of sodium tert-butoxide, 33 mg (0.037 mmol) of tris-dibenzylideneacetone-dipalladium(0), and 66 mg (0.11 mmol) of rac-Binap in 2 mL of dry toluene were heated at 85 C. for 6 hours. The mixture was cooled to ambient temperature, and was partitioned between ethyl acetate and water. The phases were separated, and the ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed to give 4-Benzyl-2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine. 1.05 g (2.40 mmol) of 4-Benzyl-2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine in 50 mL of dichloromethane was cooled to 0 C., and 406 mg (2.88 mmol) of 1-Chloroethyl chloroformate was added. The mixture was allowed to warm to ambient temperature after 30 minutes, then was heated at 75 C. in a sealed vessel for 3 hours. The solution was then concentrated in vacuo, the residue was dissolved in 30 mL of methanol, and the solution was heated at 60 C. for 2 hours. The solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give 2-(R)-Benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine.
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; In chloroform; at 20℃; for 5h;
1-Chloroethyl chloroformate (0.27 mL, 2.478 mmol) was added to a solution of <strong>[151096-09-2]moxifloxacin</strong> 3 (994.5 mg, 2.477 mmol) and 547.9 mg (2.557 mmol) of proton sponge in 25 mL chloroform. The clear yellow solution was stirred at room temperature for 5 h before being washed with water (3×) and dried over anhydrous sodium sulfate. Removal of the solvent yielded product 34 as a yellow foam (1.228 g, 98%). In the cases where proton sponge was still present after the water wash, the crude product was passed through a short silica gel column with the elution of 19:1 dichloromethane/methanol. 1H NMR (400 MHz, CDCl3): 0.78-0.86 (m, 1H), 1.03-1.17 (m, 2H), 1.25-1.35 (m, 1H), 1.47-1.64 (m, 1H), 1.78-1.90 (m, 5H), 2.32 (bs, 1H), 2.95-3.05 (m, 1H), 3.24-3.64 (m, 2H), 3.58 (s, 3H), 3.86-4.03 (m, 2H), 4.04-4.22 (m, 2H), 4.70-4.98 (m, 1H), 6.63 (q, J=5.9, 1H), 7.82 (dd, J=1.6, 13.7, 1H), 8.79 (s, 1H).
In accordance with the general Scheme 2C, the following is the preparation of a compound of Structure 4C, wherein each of p, q, r and s=1; and Y is benzyl. triethylamine (16.2 g, 0.16 mol) was added to a suspension of N-benzylmaleimide (25.0 g, 0.13 mol), <strong>[7689-50-1]N-benzylglycine hydrochloride</strong> (32.3 g, 0.16 mol) and paraformaldehyde (25.2 g, 0.84 mol) in benzene (1 L) in a mechanically stirred flask, under a nitrogen atmosphere.. The resulting solution was refluxed (3.5 h), cooled to room temperature, dried over anhydrous magnesium sulfate, treated with decolorizing charcoal, filtered through Celite and evaporated under reduced pressure.. The residue (52.9 g) was dissolved in 1,2-dichloroethane, and under a nitrogen atmosphere, sodium bicarbonate (22.4 g, 0.26 mol) was added followed by dropwise addition of 1-chloroethylchloroformate (38.18 g, 0.26 mol).. The resulting mixture was refluxed overnight before cooling to room temperature.. The solution was dried over anhydrous magnesium sulfate, treated with decolorizing charcoal, filtered through Celite and evaporated under reduced pressure.. The residue was dissolved in anhydrous methanol (500 ML) and heated at 50 C. for 3 h.. On cooling to room temperature the solution was concentrated to approximately half its volume yielding a precipitate.. The solid was collected by filtration, washed on the filter with diethyl ether and dried under vacuum yielding a white crystalline solid (26.0 g). A solution of the above mentioned solid (25.9 g) in tetrahydrofuran (250 ML) was added dropwise under a nitrogen atmosphere (over 1 h) to a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 300 ML, 300 mmol) in tetrahydrofuran (200 ML) cooled to 0 C. The resulting slurry was warmed slowly, refluxed for 15 min, cooled and stirred overnight at room temperature.. water (11.3 ML) was added very carefully with stirring followed by 15% aqueous NaOH (11.3 ML).. Additional water (34.1 ML) was added followed by anhydrous magnesium sulfate, and the mixture was stirred at room temperature, filtered through Celite and evaporated under reduced pressure to yield the desired product as a yellow oil 198 (18.7 g).. 1H NMR: (CDCl3) delta7.36-7.19 (m, 5H), 3.51 (s, 2H), 2.89-2.57 (m, 8H), 2.35-2.27 (m, 2H), 2.01 (br. s,1H, exch. D2O).
[0165] To a stirred solution of the benzyl amine (32) (10 g, 1 equiv.) in dichloroethane (220 mL) was added, dropwise, 1-chloroethylchloroformate (5.91 mL, 1.2 equiv.). The reaction was stirred at rt for 30 min followed by concentration of the mixture under reduced pressure. The residue was dissolved in MeOH (100 mL), refluxed for 20 min and then concentrated under reduced pressure. The residue was then dissolved in CHCl3 (80 mL) and Et3N (19.1 mL, 3 equiv.) and cooled to 0 C. To this mixture was added Boc2O (9.95 g, 1 equiv.) in CHCl3 (20 mL) and the reaction was stirred at rt for 16 h. This mixture was then concentrated under reduced pressure, dissolved in EtOAc and washed with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 20% EtOAc in hexane to 33% EtOAc in hexane) to afford the Boc-protected amine. To a solution of the Boc-protected amine (2.29 g, 1 equiv.) in MeOH (24 mL) was added 1 N NaOH (12 mL, 1.2 equiv.). The mixture was stirred at rt for 3 days and then concentrated under reduced pressure. The residue was poured into a solution of 1 N HCl (10 mL) and 10% citric acid (20 mL). The mixture was extracted with EtOAc (3×) and the combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated under reduced pressure to yield the acid (33).
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. A mixture of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (50.5 g, 359 mmol) and 1- chloroethyl chloroformate (117 mL, 1.08 mol) in CH2ClCH2Cl (500 mL) was heated to 80 0C for 5 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dried under high vacuum for 3 h, and was added in portions to MeOH (250 mL) over 30 min. The mixture was stirred at 75 0C for 1 h, and allowed to cool to rt. The solvents were removed under reduced pressure. The residue was diluted with Et2O (250 mL), and the mixture was sonicated for 15 min. The mixture was then stirred for 30 min, and filtered. The precipitate was washed with Et2O (125 mL), and dried under high vacuum. The residue was diluted with dioxane (400 mL), and the mixture was cooled to 0 0C. Aq. IM NaOH (400 mL) was added. BoC2O (82.3 g, 377 mmol) was added, and the mixture was stirred overnight while warming up to rt. The mixture was extracted with Et2O (2x). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 3:7) yielded the title compound (59.0 g, 73%). LC-MS: tR = 0.83 min.
h) Preparation of [N-methyl-N-3-((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridin-2-yl]carbamic acid 1-chloro-ethyl ester; [00317] <strong>[32399-12-5]2-(N-methylamino)-3-hydroxymethylpyridine</strong> (22 g,0.159 mol) and diisopropylamine (36.1 mL, 0.207 mol, 1.3 eq.) were dissolved in dichloromethane(1L) and cooled in ethanol-ice bath(ca-13 C.). 1-Chloroethyl chloroformate(17.5 mL, 0.161 mol, 1.01 eq.) was added dropwise over a period of 1 h and the mixture was stirred for 1 h.Boc-sarcosine(39.2 g, 0.207 mol, 1.3 eq.) was added to the stirring mixture and WSC(39.7 g, 0.207 mol. 1.3 eq.) was added portionwise over a period of 10 min. To the mixture was added DMAP(5.8 g, 0.047 mol, 0.3 eq.) and the mixture was stirred for 2 h at -7 C. The reaction mixture was concentrated at 25 C. and the residue was dissolved in diethylether(1L). The solution was transferred to the separate funnel and washed with 0.1N-HCl(500 mL×3), water (500 mL), NaHCO3 aq.(500 mL) and brine(500 mL×2) successively, dried over MgSO4 and concentrated under reduced pressure. The obtained residue(48.2 g, ca 72.9% yield) was used for the next step without purification. 1H-NMR (270 MHz,CDCl3): delta 1.42 (9H, d, J=24.1), 1.57 (1.5H, br.s), 1.88 (1.5H, br.s), 2.94 (3H, s), 3.37 (3H, s), 4.00 (2H, d, J=21.1), 5.18 (2H, d, J=13.5), 6.58 (1H, q, J=5.45, 11.0), 7.30 (1H, s), 7.82 (1H, d, J=6.9), 8.47 (1H, s); FAB-MS: m/z 416 (M+H)+.
64%
<strong>[32399-12-5]2-(N-methylamino)-3-hydroxymethylpyridine</strong> (2.2 g, 16 mmol) and diisopropylamine (3.6 mL, 20.7 mmol) in 50 mL of methylene chloride, cooled to -13 C, and 10 mL of 1.75 mL (16.1 mmol) 1-chloroethyl chloroformate in dichloromethane solution was added and the reaction mixture was stirred for 1 h. To the stirred mixture was added 3. 9 g (20.7 mmol) of Boc-sarcosine,Then, 3. 9 g (20.7 mmol) of EDCI and 0. 58 g (4.7 mmol) of DMAP were added slowly and the mixture was stirred at -7 C for 2 h. The reaction was concentrated at 25 C. The residue was dissolved in 50 mL of ether and washed with 0.1 N HC1 (50 mL * 3), water (50 mL), and aqueous sodium hydrogencarbonate solution (50 mL) and brine (50 mL * 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily solid 4. 6 g, yield 64%. The purity was 48.90% by HPLC.
Example 2: One -pot process for preparation of AEC-NP; [00176] Reactor (500 ml) was loaded with 4-Nitrophenol (10 g, 0.07 mol) dissolved in Toluene (150 ml) followed by dropwise addition of 1-chloroethyl chloroformate (13.25 g, 0.09 mol) and then Tributyl amine (17.3 g, 0.09 mol). The obtained solution was stirred at room temperature for additional 30 min. At this point according to HPLC no 4- Nitrophenol remained. The reaction was washed with IN HCl (150 ml), water (2*100 ml) and brine. The aqueous phase was removed from the reactor and to the remained toluenic solution was added Zinc oxide (17 g, 0.21 mol), Sodium iodide (10.5 g, 0.07 mol) and Isobutyric acid (50 ml). The obtained mixture was heated at 75 0C monitored by HPLC. The reaction was stopped approximately after 1Oh. The reaction was washed with NaHCO3 solution and then with brine. The solvent was evaporated to give the product in 60% yield.
A solution of <strong>[105601-04-5]3-[1-(dimethylamino)ethyl]phenol</strong> (0.41 g, 2.5 mmoL) and triethylamine (0.8 g, 7.9 mmoL) in dichloromethane (10 mL) was stirred under nitrogen and cooled using an ice-bath. 1-Chloroethyl chloroformate (0.43 g, 3 mmoL) was added to the solution and the mixture was stirred for 1 h whereupon N-ethylmethylamine (0.24 g, 4 mmoL) was added and the solution was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water (10 mL) and the pH of the aqueous layer was adjusted to >10 by the addition of aqueous NaOH solution. The organic layer was separated and the aqueous layer was extracted with additional dichloromethane. The combined organic extracts were washed with water and evaporated to dryness. The residue was dissolved in diethyl ether and extracted with dilute HCl solution. The pH of the aqueous solution was adjusted to >10 by the addition of aqueous NaOH solution and extracted with diethyl ether. The ethereal layers were washed with water and then evaporated to dryness to give racemic Rivastigime (0.5 g) as a liquid.
In methanol; N-benzyl-N'-methanesulphonylpiperazine; dichloromethane;
Step B 1-(methylsulfonyl)piperazine hydrochloride To dichloromethane (70 ml) was added the compound (9.58 g, 37.66 mmol) obtained in step A and 1-chloroethyl chloroformate (4.53 ml, 41.43 mmol) was added under ice-cooling with stirring, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (70 ml), and the mixture was heated under reflux for 30 min. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered and washed with a small amount of methanol. The filtrate was concentrated under reduced pressure, and the precipitated solid was filtered, and washed with a small amount of methanol. The obtained solid was combined, and the mixture was washed with diethyl ether to give the title compound (6.65 g, yield 88%) as a colorless solid. 1H-NMR (300 MHz, DMSO-d6); delta(ppm) 2.99 (s, 3H), 3.16 (t, J=5.4, 4H), 3.38 (t, J=5.7, 4H), 9.59 (brs, 1H), 9.90 (brs, 1H).
(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut 3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide[ No CAS ]
[ 154598-52-4 ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut 3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide With triethylamine In dichloromethane at 0 - 5℃; for 0.333333h;
Stage #2: carbonochloridic acid 1-chloro-ethyl ester In dichloromethane at 5 - 10℃; for 1h;
Stage #3: With potassium carbonate In dichloromethane; N,N-dimethyl-formamide at 20℃;
13
Example 13; Preparation of (S)-6-chloro-4-(cyclo propylethynyl)-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-one (Efavirenz, 1): A solution of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 30 g, 63.9 mmol), dichloromethane (150 mL) and triethylamine (7.11 g, 70.2 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethyl chloroformate (10.0 g, 70.2 mmol) was added dropwise. The mixture was stirred at 5-10° C. for 1 hour. Then N,N-dimethylformamide (150 mL) was added and further evaporated to 220 mL, then K2CO3 (13.3 g, 95.8 mmol) was added. The reaction mixture was stirred at room temperature overnight. Methyl t-butyl ether (300 mL) and water (200 mL) were added to the mixture, and the resulting layers were separated. The organic layer was washed with brine, and concentrated to 60 mL whereupon petroleum ether (200 mL) was added and stirred. The resulting precipitate was filtered and rinsed with petroleum ether to provide 18.4 g (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-ben zoxazin-2-one (Efavirenz, 1) as an off-white solid.
With potassium carbonate; In dichloromethane;Cooling with ice;
Example 7 synthesis (3R)-dihydroarteannuin B acid, 1-chloroethyl mixed carbonate 3.02 g (0.021 mol) of 1-chloroethyl chloroformate are added dropwise within 5 min. to a stirred solution of 5.03 g (0.021 mol) of DHAA and 3.44 g (0.025 mol) of K2CO3 in 25 mL of dichloromethane in an ice bath. After addition, stirring is continued for 20-30 min. The mixture is then washed twice with water (2 x 100 mL) and dried over MgSO4. The solution is then concentrated to dryness at reduced pressure and 5.84 g of an oily residue are obtained (crude yield = 80.5 %). The product can be used as such.
With potassium carbonate; In dichloromethane;Cooling with ice;
3.02 g (0.021 mol) of 1 -chloroethyl chloroformate are added dropwise within 5 min. to a stirred solution of 5.03 g (0.021 mol) of DHAA and 3.44 g (0.025 mol) of K2CO3 in 25 mL of dichloromethane in an ice bath. After addition, stirring is continued for 20-30 min.The mixture is then washed twice with water (2 x 100 mL) and dried over MgSO4. The solution is then concentrated to dryness at reduced pressure and 5.84 g of an oily residue are obtained (crude yield = 80.5 %). The product can be used as such.
0225| Step -3: Synthesis of Com pound 6:0 2261 T a solution of eis-5,8; U J J 7-Eicosapentaenoic acid 4 ( 1.0 mmol} in dryDCM (..8 1.) was added N. N-diisopropylethylamine (2.0 mmol) at -10C, foliovved by drop wise addition of 1 -chloroemyichloroformaie (1 .2 mmol) for 30 min. at the same temperature and the reaction mixture was aliowed to stir for 1 h at 0"C. On completion of the reaction (monitored by TLC), the reaction mixture intermediate 5 was directly used for the next step without further isolation and purification.[002271 In another RB flask the Compound-3 (.1.2 mmol) and anhydrous K3CO? (3.0 mmol) was taken in dry- DMF (10 vol) stir at room temperature for 2 h and then cooled to -10''C, intermediate 5 was added slowly drop wise over 30 min. & then was allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether {2 x I L). The combined organic layers were washed with water (2 x .500 mL) followed by brine solution (100 mL), dried over anhydrous ' a2SO« and evaporated under reduced pressure. The erode was purifted by column chromatography over 100-200 mesh silica gel by using 0 to 20% ethyl acetate in pet ether as an elitent to yield 40% of compound 6 as a pale colorless liquid.
Example 20 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxycarbonyloxy]-ethyl ester [0146] [0147] In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with <strong>[23778-52-1]pentaethylene glycol monomethyl ether</strong> (TCI) and pyridine in methylene chloride at -78 C. for 3 h to give 1-chloroethyl 2,5,8,11,14-pentaoxahexadecan-16-yl carbonate. This was then reacted with 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxycarbonyloxy]-ethyl ester as a white solid. LCMS (ES+) m/z calcd. for C45H56Cl2F2N3O12 [(M+H)+]: 938, found: 938.
With pyridine; In dichloromethane; at -78℃; for 3h;
Example 41 [0183] 24-Oxo-2,5,8,11,14,17,20,23,25-nonaoxaheptacosan-26-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate [0184] In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Aldrich) was reacted with <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> (TCI) and pyridine in methylene chloride at -78 C. for 3 h to give 1-chloroethyl 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 24-oxo-2,5,8,11,14,17,20,23,25-nonaoxaheptacosan-26-yl-4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C51H68Cl2F2N3O15: [(M+H)+]: 1026, found: 1026.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10 - 0℃; for 1.5h;
00104J To a solution of compound 3 (1.0 rnmol) in dry DCM (1.8 ml) was added N, N- diisopropylethylamine (2.0 ramo) at 0C, followed by drop wise addition of 1- chloroethylchloroforniate 4(1 .2 mmol) for 30 rain at the same temperature and the reaction mixture was allowed to stir for 1 h at i C. On completion, of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get chio.ro compound 5.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10 - 0℃; for 1.5h;
Step-2: Synthesis of Compound 5: [0142] To a solution of compound 3 (1.0 mmol) in dry DCM (1.8 ml) was added N, N-diisopropylethylamine (2.0 mmol) at -10 C., followed by drop wise addition of 1-chloroethylchloroformate 4 (1.2 mmol) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 h at 0 C. On completion of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get chloro compound 5.
With triethylamine; In acetonitrile; at 0 - 22℃; for 1.08h;
Description 1-15 1-Chloroethyl 3,4-ethylenedioxyphenyl carbonate (D1-15) [0248] [0249] 3,4-Ethylenedioxyphenol (25 mmol) and chloroethyl chloroformate (3.0 ml) are mixed in acetonitrile (25 ml) at 0 C. Triethylamine (3.9 ml) is slowly charged while keeping the reaction temperature ?10 C. The reaction mixture is stirred for approximately 5 minutes at ?10 C., then warmed up to room temperature (22 C.). The reaction is stirred at 22 C. for one hour. The solid in the reaction is filtered and the filtrate is distilled to remove acetonitrile. The reaction mixture is then extracted with tert-butyl methyl ether (50 ml) and water (20 ml) to remove triethylamine hydrochloride salt. Distillation to remove solvents yields the title compound.
An isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoatehydrochloride solution was prepared by adding isopropyl (S)-2-amino-3-(3,4- dihydroxyphenyl)propanoate hydrochloride (28 g) into acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added into the dopamineHCl solution to provide a 3rd mixture. Then Na-(benzyloxycarbonyloxy)succinimide (25 g) was added to the 3rd mixture to provide a 4th mixture. The 4th mixture was stirred at RT overnight, and added ethyl acetate (R0061, 500 mL) for extraction. The organic layer was separated, and washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 5th solution. Then the sodium sulfate was filtered and washed with ethyl acetate to provide a 6th solution. The 5th solution and the 6th mixture were combined, and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved inacetone (300 mL) to provide a 7th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added into the 7th mixture to provide an 8th mixture. The 8th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500 ml) was added into the residue to provide a 9th mixture, which was washed with water (2 x 100 mL), 5% sodium bucarbonate(3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 10th solution. The sodium sulfate was filterred and washed with ethyl acetate to provide an 11th solution. The 10th solution and the 11th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to provide a 12th mixture. To the 12th mixture was added first palladium on activated charcoal (10 g, 10%) under nitrogen, and then bubbled with hydrogen gas to remove benzyloxycarbonyl group at RT. The obtained mixture (13th mixture) was filtered to remove the palladium on activated charcoal, and evaporated to dryness. [00169] The residue was suspended in DCM (200 mL) to provide a 14th mixture. Sodium bicarbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added into the 14th mixture to provide a 15th mixture. Then 1-chloroethyl chloroformate (16 g) was added into the 15th mixture to provide a 16th mixture. The 16th mixture was stirred at RT overnight. Then the organic layer of the 16th mixture was collected and washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to provide a 17th solution. The sodium sulfate was removed by filtration and washed with DCM to provide a 18th solution. The 17th solution and the 18th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to provide a 19th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared first and then added into the 19th mixture to provide a 20th mixture. The 20th mixture was stirred at 55 C for 48 hours, and added ethyl acetate (500 mL) with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to provide a 21st solution. The sodium sulfate was filtered and washed with ethyl acetate to provide a 22nd solution. The 21st solution and the 22nd solution were combined and concentrated to 300 mL. Into the concentrated solution was added anisole (20 g) and then bubbled HBr gas (30 g) to provide precipitation. The precipitated solid was collected and washed with ethyl acetate to yield (25)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]dioxocin-8-yl)- 2-(((1 -(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide and (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]dioxocin-8-yI)-2-(((1 - (isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide.
An isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoatehydrochloride solution was prepared by adding isopropyl (S)-2-amino-3-(3,4- dihydroxyphenyl)propanoate hydrochloride (28 g) into acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added into the dopamineHCl solution to provide a 3rd mixture. Then Na-(benzyloxycarbonyloxy)succinimide (25 g) was added to the 3rd mixture to provide a 4th mixture. The 4th mixture was stirred at RT overnight, and added ethyl acetate (R0061, 500 mL) for extraction. The organic layer was separated, and washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 5th solution. Then the sodium sulfate was filtered and washed with ethyl acetate to provide a 6th solution. The 5th solution and the 6th mixture were combined, and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved inacetone (300 mL) to provide a 7th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added into the 7th mixture to provide an 8th mixture. The 8th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500 ml) was added into the residue to provide a 9th mixture, which was washed with water (2 x 100 mL), 5% sodium bucarbonate(3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 10th solution. The sodium sulfate was filterred and washed with ethyl acetate to provide an 11th solution. The 10th solution and the 11th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to provide a 12th mixture. To the 12th mixture was added first palladium on activated charcoal (10 g, 10%) under nitrogen, and then bubbled with hydrogen gas to remove benzyloxycarbonyl group at RT. The obtained mixture (13th mixture) was filtered to remove the palladium on activated charcoal, and evaporated to dryness. [00169] The residue was suspended in DCM (200 mL) to provide a 14th mixture. Sodium bicarbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added into the 14th mixture to provide a 15th mixture. Then 1-chloroethyl chloroformate (16 g) was added into the 15th mixture to provide a 16th mixture. The 16th mixture was stirred at RT overnight. Then the organic layer of the 16th mixture was collected and washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to provide a 17th solution. The sodium sulfate was removed by filtration and washed with DCM to provide a 18th solution. The 17th solution and the 18th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to provide a 19th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared first and then added into the 19th mixture to provide a 20th mixture. The 20th mixture was stirred at 55 C for 48 hours, and added ethyl acetate (500 mL) with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to provide a 21st solution. The sodium sulfate was filtered and washed with ethyl acetate to provide a 22nd solution. The 21st solution and the 22nd solution were combined and concentrated to 300 mL. Into the concentrated solution was added anisole (20 g) and then bubbled HBr gas (30 g) to provide precipitation. The precipitated solid was collected and washed with ethyl acetate to yield (25)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]dioxocin-8-yl)- 2-(((1 -(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide and (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]dioxocin-8-yI)-2-(((1 - (isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide.
(2S)-isopropyl-3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]-dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide[ No CAS ]
(2S)-isopropyl-3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]-dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
An isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoatehydrochloride solution was prepared by adding isopropyl (S)-2-amino-3-(3,4- dihydroxyphenyl)propanoate hydrochloride (28 g) into acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added into the dopamineHCl solution to provide a 3rd mixture. Then Na-(benzyloxycarbonyloxy)succinimide (25 g) was added to the 3rd mixture to provide a 4th mixture. The 4th mixture was stirred at RT overnight, and added ethyl acetate (R0061, 500 mL) for extraction. The organic layer was separated, and washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 5th solution. Then the sodium sulfate was filtered and washed with ethyl acetate to provide a 6th solution. The 5th solution and the 6th mixture were combined, and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved inacetone (300 mL) to provide a 7th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added into the 7th mixture to provide an 8th mixture. The 8th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500 ml) was added into the residue to provide a 9th mixture, which was washed with water (2 x 100 mL), 5% sodium bucarbonate(3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 10th solution. The sodium sulfate was filterred and washed with ethyl acetate to provide an 11th solution. The 10th solution and the 11th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to provide a 12th mixture. To the 12th mixture was added first palladium on activated charcoal (10 g, 10%) under nitrogen, and then bubbled with hydrogen gas to remove benzyloxycarbonyl group at RT. The obtained mixture (13th mixture) was filtered to remove the palladium on activated charcoal, and evaporated to dryness. [00169] The residue was suspended in DCM (200 mL) to provide a 14th mixture. Sodium bicarbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added into the 14th mixture to provide a 15th mixture. Then 1-chloroethyl chloroformate (16 g) was added into the 15th mixture to provide a 16th mixture. The 16th mixture was stirred at RT overnight. Then the organic layer of the 16th mixture was collected and washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to provide a 17th solution. The sodium sulfate was removed by filtration and washed with DCM to provide a 18th solution. The 17th solution and the 18th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to provide a 19th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared first and then added into the 19th mixture to provide a 20th mixture. The 20th mixture was stirred at 55 C for 48 hours, and added ethyl acetate (500 mL) with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to provide a 21st solution. The sodium sulfate was filtered and washed with ethyl acetate to provide a 22nd solution. The 21st solution and the 22nd solution were combined and concentrated to 300 mL. Into the concentrated solution was added anisole (20 g) and then bubbled HBr gas (30 g) to provide precipitation. The precipitated solid was collected and washed with ethyl acetate to yield (25)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]dioxocin-8-yl)- 2-(((1 -(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide and (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1 ,4]dioxocin-8-yI)-2-(((1 - (isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide.
In this example, a dopamineHCl solution was prepared by adding dopamineHCl (19 g) into acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added into the dopamineHCl solution to provide a 1st mixture. Then Na-(benzyloxycarbonyloxy)succinimide (25 g) was added to the 1st mixture to provide a 2nd mixture. The 2nd mixture was stirred at RT overnight, and added ethyl acetate (R0061, 500 mL) for extraction. The organic layer was separated, and washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 3rd solution. Then the sodium sulfate was filtered and washed with ethyl acetate to provide a 4th mixture. The 3rd solution and the 4th mixture were combined, and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to provide a 5th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4- dimethylaminopyridine (22 g) were added into the 5th mixture to provide a 6th mixture. The 6th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500 ml) was added into the residue to provide a 7th mixture, which was washed with water (2 x 100 mL), 5% sodium bucarbonate(3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 8th solution. The sodium sulfate was filterred and washed with ethyl acetate to provide a 9th solution. The 8th solution and the 9th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to provide a 10th mixture. To the 10th mixture was added first palladium on activated charcoal (10 g, 10%) under nitrogen, and then bubbled with hydrogen gas to remove benzyloxycarbonyl group at RT. The obtained mixture (11th mixture) was filtered to remove the palladium on activated charcoal, and evaporated to dryness. [00132] The residue was suspended in DCM (200 mL) to provide a 12th mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added into the 12th mixture to provide a 13th mixture. Then 1-chloroethyl chloroformate (16 g) was added into the 13th mixture to provide an 14th mixture. The 14th mixture was stirred at RT overnight. Then the organic layer of the 14th mixture was collected and washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to provide a 15th solution. The sodium sulfate was removed by filtration and washed with DCM to provide a 16th solution. The 15th solution and the 16th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to provide a 17th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared first and then added into the 17th mixture to provide a 18th mixture. The 18th mixture was stirred at 55 C for 48 hours, and added ethyl acetate (500 mL) with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to provide a 19th solution. The sodium sulfate was filtered and washed with ethyl acetate to provide a 20th solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Into the concentrated solution was added anisole (20 g) and then bubbled HF gas (20 g) to provide precipitation. The precipitated solid was collected and washed with ethyl acetate to yield 1-(((2-(4-amino- 2, 5-d ioxo-2 ,3,4, 5-tetrahyd robenzo[b][1 ,4]d ioxoci n-8-yl )ethyl )carbamoyl )oxy)ethylisobutyrate hydrofluoride and I -(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahyd robenzo[b][1 ,4]d ioxoci n-8-yl )ethyl )carbamoyl )oxy)ethyl isobutyrate hyd rofluoride.
1-(((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride[ No CAS ]
1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In this example, a dopamineHCl solution was prepared by adding dopamineHCl (19 g) into acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added into the dopamineHCl solution to provide a 1st mixture. Then Na-(benzyloxycarbonyloxy)succinimide (25 g) was added to the 1st mixture to provide a 2nd mixture. The 2nd mixture was stirred at RT overnight, and added ethyl acetate (R0061, 500 mL) for extraction. The organic layer was separated, and washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 3rd solution. Then the sodium sulfate was filtered and washed with ethyl acetate to provide a 4th mixture. The 3rd solution and the 4th mixture were combined, and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to provide a 5th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4- dimethylaminopyridine (22 g) were added into the 5th mixture to provide a 6th mixture. The 6th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500 ml) was added into the residue to provide a 7th mixture, which was washed with water (2 x 100 mL), 5% sodium bucarbonate(3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 8th solution. The sodium sulfate was filterred and washed with ethyl acetate to provide a 9th solution. The 8th solution and the 9th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to provide a 10th mixture. To the 10th mixture was added first palladium on activated charcoal (10 g, 10%) under nitrogen, and then bubbled with hydrogen gas to remove benzyloxycarbonyl group at RT. The obtained mixture (11th mixture) was filtered to remove the palladium on activated charcoal, and evaporated to dryness. [00132] The residue was suspended in DCM (200 mL) to provide a 12th mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added into the 12th mixture to provide a 13th mixture. Then 1-chloroethyl chloroformate (16 g) was added into the 13th mixture to provide an 14th mixture. The 14th mixture was stirred at RT overnight. Then the organic layer of the 14th mixture was collected and washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to provide a 15th solution. The sodium sulfate was removed by filtration and washed with DCM to provide a 16th solution. The 15th solution and the 16th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to provide a 17th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared first and then added into the 17th mixture to provide a 18th mixture. The 18th mixture was stirred at 55 C for 48 hours, and added ethyl acetate (500 mL) with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to provide a 19th solution. The sodium sulfate was filtered and washed with ethyl acetate to provide a 20th solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Into the concentrated solution was added anisole (20 g) and then bubbled HF gas (20 g) to provide precipitation. The precipitated solid was collected and washed with ethyl acetate to yield 1-(((2-(4-amino- 2, 5-d ioxo-2 ,3,4, 5-tetrahyd robenzo[b][1 ,4]d ioxoci n-8-yl )ethyl )carbamoyl )oxy)ethylisobutyrate hydrofluoride and I -(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahyd robenzo[b][1 ,4]d ioxoci n-8-yl )ethyl )carbamoyl )oxy)ethyl isobutyrate hyd rofluoride.
In this example, a dopamineHCl solution was prepared by adding dopamineHCl (19 g) into acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added into the dopamineHCl solution to provide a 1st mixture. Then Na-(benzyloxycarbonyloxy)succinimide (25 g) was added to the 1st mixture to provide a 2nd mixture. The 2nd mixture was stirred at RT overnight, and added ethyl acetate (R0061, 500 mL) for extraction. The organic layer was separated, and washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 3rd solution. Then the sodium sulfate was filtered and washed with ethyl acetate to provide a 4th mixture. The 3rd solution and the 4th mixture were combined, and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to provide a 5th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4- dimethylaminopyridine (22 g) were added into the 5th mixture to provide a 6th mixture. The 6th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500 ml) was added into the residue to provide a 7th mixture, which was washed with water (2 x 100 mL), 5% sodium bucarbonate(3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to provide a 8th solution. The sodium sulfate was filterred and washed with ethyl acetate to provide a 9th solution. The 8th solution and the 9th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to provide a 10th mixture. To the 10th mixture was added first palladium on activated charcoal (10 g, 10%) under nitrogen, and then bubbled with hydrogen gas to remove benzyloxycarbonyl group at RT. The obtained mixture (11th mixture) was filtered to remove the palladium on activated charcoal, and evaporated to dryness. [00132] The residue was suspended in DCM (200 mL) to provide a 12th mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added into the 12th mixture to provide a 13th mixture. Then 1-chloroethyl chloroformate (16 g) was added into the 13th mixture to provide an 14th mixture. The 14th mixture was stirred at RT overnight. Then the organic layer of the 14th mixture was collected and washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to provide a 15th solution. The sodium sulfate was removed by filtration and washed with DCM to provide a 16th solution. The 15th solution and the 16th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to provide a 17th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared first and then added into the 17th mixture to provide a 18th mixture. The 18th mixture was stirred at 55 C for 48 hours, and added ethyl acetate (500 mL) with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to provide a 19th solution. The sodium sulfate was filtered and washed with ethyl acetate to provide a 20th solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Into the concentrated solution was added anisole (20 g) and then bubbled HF gas (20 g) to provide precipitation. The precipitated solid was collected and washed with ethyl acetate to yield 1-(((2-(4-amino- 2, 5-d ioxo-2 ,3,4, 5-tetrahyd robenzo[b][1 ,4]d ioxoci n-8-yl )ethyl )carbamoyl )oxy)ethylisobutyrate hydrofluoride and I -(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahyd robenzo[b][1 ,4]d ioxoci n-8-yl )ethyl )carbamoyl )oxy)ethyl isobutyrate hyd rofluoride.
3-[(1-chloroethoxycarbonyl)-methyl-amino]-propyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
3-[(1-Chloro-ethoxycarbonyl)-methyl-amino]-propyl acetate Under a nitrogen atmosphere, 3-methylamino-propan-1-ol (343.4 mg, 3.85 mmol) was dissolved in dichloromethane (5.0 mL), and triethylamine (588.2 muL, 4.24 mmol) was added. The mixture was cooled to 0 °C. While maintaining the reaction temperature at 0 °C, 1-chloroethyl chloroformate (415.7 muL, 3.85 mmol) was then added and the mixture was stirred for 1 hour. While maintaining the reaction temperature at 0 °C, acetic anhydride (400 muL, 4.24 mmol) and pyridine (314.4 muL, 3.85 mmol) were then added, and the mixture was stirred at room temperature for 15 hours. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with 1.0 M hydrochloric acid, water, and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The residue was then purified by silica gel column chromatography (n-hexane: ethyl acetate = 2:1, Rf = 0.6) to obtain 479.5 mg (52percent yield) of 3-[(1-chloro-ethoxycarbonyl)-methyl-amino]-propyl acetate. 1H-NMR (CDCl3, observed as rotermer mixture) delta: 1.80 (1.5H, d, J = 7.1 Hz), 1.82 (1.5H, d, J = 2.6 Hz), 1.84-1.96 (2H, m), 2.06 (1.5H, s), 2.07 (1.5H, s), 2.94 (1.5H, s), 2.96 (1.5H, s), 3.32-3.49 (2H, m), 4.08-4.11 (2H, m), 6.54-6.63 (1H, m). ESI (LC/MS positive mode) m/z 238 (M+H); Rt 1.70 min
With lithium tert-butoxide; In hexane; dichloromethane; acetonitrile; at 0 - 20℃; for 0.666667h;
Compound 5 (1 mmol) in 2.5 ml of DCM and 2.5 ml of CH3CN is cooled to 0 C. Lithium t-butoxide (1.0M in hexanes, 1.1 mmol) was added and the mixture was stirred at 0 C. for 15 min and then at room temperature for 10 min. The reaction mixture is re cooled to 0 C. and added 1-chloroethyl chloro formate 6 (1.2 mmol) dropwise. The reaction mixture is stirred at 0 C. for 15 min and then allowed to stir at room temperature overnight. After completion of reaction, the mixture is diluted with DCM and added water and the layers were separated. The organic layer is washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography afforded the compound 7.
Example 1 <strong>[132335-47-8](S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate</strong> (204g, 0.508mol) added to a flask, afterwhich 1L of toluene was added, followed by 1L of water, and stirred, then was added with 200g K2CO3, stirred for 30 min, until the solid was completely dissolved, the layers were then separated, toluene layer was washed once with 500mL water, 500mL brine, dried with MgSO4, and filtered, afterwhich the toluene layer was added with N,N-diisopropylethylamine (6.5g, 0.0508mol) and stirred, followed by dropwise addition of 1-chloroethyl chloroformate (87.2g, 0.61) while maintaining the reaction temperature at 35C-45C, stirred for 3 hrs, complete conversion of the reaction was monitored through TLC, then cooled to 20C, then washed with 500mL 5% NaOH aqueous solution, the toluene layer was washed with 5% hydrochloric acid and 500mL 5% NaHCO3 once, washed with 500mL brine once, concentrated under reduced pressure to 55 deg. C, toluene-free fraction was taken to give 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-yloxy)-3-(thiophen-2-yl)propyl)carbamate (184.7g, 0.46mol). 1L THF was then added, followed by addition of 1L of water with stirring, followed by addition of KOH (57g, 1.1mol) with stirring, warmed to 55C, heated for 4h, TLC monitored completion of the reaction, at 50C concentrated under reduced pressure to a non-flowing THF, cooled to 20C, then extracted with 1L of toluene. Duloxetine in toluene solution was added oxalic acid-ethanol solution (oxalate dihydrate 64g / 128g ethanol), stirred, filtered, and added to 1.2 L of ethyl acetate, water, 259g K2CO3, mixed and stirred. The ethyl acetate layer was separated and added with 29.5g of concentrated hydrochloric acid, stirred and filtered to give 100.7 g of duloxetine hydrochloride, from (S)-N,N-dimethyl-3- (1-naphthyloxy)-3-(2-thienyl)propanamine oxalate, total yield 59.4%, optical purity 99.9%, 99.8% purity.
With triethylamine; In dichloromethane; at 20℃; for 3h;
A solution of <strong>[226256-56-0]cinacalcet</strong> (about 360 mg, about 1.0 mmol, 12) in dichloromethane(About 173 mg, about 1.20 mmol) and triethylamine(TEA, about 0.21 mL, about 153 mg, about 1.50 mmol) was added and the solutionAnd the mixture was stirred for 3 hours at room temperature, and then the dichloromethane product mixture was added to 0.1 N HCl / NH4CL aqueous solution and once with Na2CO3 aqueous solution and the dichloromethane phase was washed with Na2After drying with SO 4 and evaporating the solvent, 1-chloroethyl-carbamate-<strong>[226256-56-0]cinacalcet</strong> (17)Was obtained as a colorless liquid (about 437 mg, about 94% isolated yield).
Stage #1: valproic acid With N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 0.5h;
Stage #2: carbonochloridic acid 1-chloro-ethyl ester In dichloromethane at -10 - 0℃; for 1h;
1.2 Synthesis of Compound 5
To a solution of compound 3 ( 1 .0 mmol) in dry DCM (1 .8 ml) was added N,N-diisopropylethylamine (2.0 mmol) at -10°C and stirred at same temperature for 30 min, followed by drop wise addition of 1-chloroethylchloroformate 4 (1.1 mmol) at the same temperature and the reaction mixture was allowed to stir for 1 h at 0°C. On completion of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get compound 5.
1-chloroethyl (2-(prop-2-yn-1-yl)pent-4-yn-1-yl) carbonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With dmap In dichloromethane at 20℃; for 18h;
9 I -Chioroethyl (2-(prop-2-yn- I -yi)pent-4-yn- 1-yl) carbonate
To an ice cold solution & 2-(prop-2-yn-1-yl)pent-4-yn-1-ol (2.0 g, 16.37 mmol) and DMAP (3.0 g, 24.55 mmol) in anhydrous dichloromethane (60 mL), was added 1-chloroethyl chloroformate (3.4 mL, 31.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18h. The solvent wasremoved under reduced pressure. The crude was slurried with ethyl acetate and passed through a plug & silica. The title compound was isolated as a dear amber coloured liquid (3.01 g, 80% yield). 1H NMR (400 MHz, CDCI3) 56.43 (q, J = 5.8 Hz, IH), 4.31 (d, J = 6.1 Hz, 2H), 2.48- 2.36 (m, 4H), 2.25-2.14 (m, IH), 2.03 (t, J=2.6Hz, 2H), 1.84(d, J=5.8 Hz, 3H).
With pyridine; In dichloromethane; at 20℃;Cooling with ice;
4-hydroxymethyl-5-methyl-1,3-dioxazol-2-one (2.6 g, 20 mmol) dissolved in 10 ml of dry dichloromethane, add 5 ml of pyridine,Ice water cooling under stirring, a solution of chloroethyl chloroformate (0.715 g, 5 mmol) the reaction was stirred overnight at room temperature, the reaction was quenched by the addition of 30 ml of saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography to give a pale yellow liquid (0.804 g)
0.804 g
With pyridine; In dichloromethane; at 20℃;
Compound 5 (2.6 g, 20 mmol) was dissolved in 10 ml dried dichloromethane. Afier adding 5 ml pyridine, themixture was stirred under the cooling condition with thedrops of Compound 6 (0.715 g, 5 mmol) and then beingincubated overnight with stirring at room temperature. The next day, 30 ml saturated sodium bicarbonate was added to quench the reaction. The organic phase was separated, dried by anhydrous sodium sulfate and then being filtered. Rotaryevaporators was used to treat the filtrate. The residue waspurified by column chromatography and finally got compound (111-4) (0.804 g, light yellow liquid).
1-(((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride[ No CAS ]
1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In this example, a dopamine · HCl solution was prepared by adding dopamine · HCl (19 g) to acetone (200 mL). Water (200 mL) and sodium hydrogencarbonate (R0090, 50 g) were added to the dopamine · HCl solution to obtain a first mixture. Next, Nalpha- (benzyloxycarbonyloxy) succinimide (25 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a third solution. Sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to obtain a fifth mixture. 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added to the fifth mixture to obtain a sixth mixture. The sixth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 ml) was added to the residue to give a seventh mixture and washed with water (2 × 100 ml), 5% sodium bicarbonate (3 × 100 ml), water (100 ml), 20% citric acid (2 × 200 ml) And washed with water (3 × 100 mL), respectively, and dried over sodium sulfate to obtain an eighth solution. The sodium sulfate was filtered and washed with ethyl acetate to give a ninth solution. The eighth solution and the ninth solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to obtain a tenth mixture. Palladium activated carbon (10 g, 10%) was first added to the tenth mixture under nitrogen and then bubbled with hydrogen gas to remove the benzyloxycarbonyl group at RT. The resulting mixture (eleventh mixture) was filtered to remove palladium activated carbon and evaporated to dryness.The residue was suspended in DCM (200 mL) to give a twelfth mixture. Sodium hydrogencarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the twelfth mixture to give a thirteenth mixture. 1-Chloroethyl chloroformate (16 g) was then added to the thirteenth mixture to give a fourteenth mixture. The 14th mixture was stirred at RT overnight. The organic layer of the 14th mixture was then collected, washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate to give a 15 th solution. The sodium sulfate was removed by filtration and washed with DCM to give a 16th solution. The 15th solution and the 16th solution were combined and evaporated to dryness. The residue was collected and dissolved in isobutyric acid (100 mL) to give a 17 th mixture. First, a mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared and then added to the 17 th mixture to obtain an 18 th mixture. The 18 th mixture was stirred at 55 C. for 48 h and ethyl acetate (500 mL) was added with stirring. The resulting organic layer was collected, washed with 5% sodium bicarbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to give a nineteenth solution. The sodium sulfate was filtered and washed with ethyl acetate to give a twentieth solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HF gas (20 g) was bubbled to cause precipitation. The precipitated solid was collected and washed with ethyl acetate to give 1 - (((2- (4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxo- 8 - yl) ethyl) carbamoyl) oxy) ethyl isobutyrate fluorohydrochloride and 1 - (((2- (3 - amino - 2,5 - dioxo - 2, 3, 4, 5 - tetrahydrobenzo [b] [ 1, 4] dioxocin-8-yl) ethyl) carbamoyl) oxy) ethylisobutyrate fluorohydrochloride.
isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride[ No CAS ]
(2S)-isopropyl-3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]-dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide[ No CAS ]
(2S)-isopropyl-3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]-dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20g) was added into isopropanol (200 mL)to provide a 1st mixture. HCl gas (20g) was bubbled into the1st mixture to provide a 2nd mixture. The 2nd mixture wasstirred for 2 days at 60 C., and then added with isopropylacetate (200 mL) to provide precipitation. The precipitatedSolid was collected and washed with isopropayl acetate toprovide isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride. An isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride solution was prepared by adding isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoatehydrochloride (28 g) into acetone (200 mL). Water (200 mL)and sodium bicarbonate (R0090, 50 g) were added into thedopamine.HCl solution to provide a 3rd mixture. ThenNC.-(benzyloxycarbonyloxy)succinimide (25 g) was addedto the 3rd mixture to provide a 4th mixture. The 4th mixturewas stirred at RT overnight, and added ethyl acetate (R0061,500 mL) for extraction. The organic layer was separated, andwashed with water (2x100 mL), 20% citric acid (2x200mL), and water (3x100 mL), respectively, and dried oversodium sulfate to provide a 5th solution. Then the sodiumsulfate was filtered and washed with ethyl acetate to providea 6th solution. The 5th solution and the 6th mixture werecombined, and evaporated to dryness. The obtained residueand Boc-L-aspartic acid (24 g) were dissolved in acetone(300 mL) to provide a 7th mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added into the 7th mixture toprovide an 8th mixture. The 8th mixture was stirred overnight at RT and evaporated to dryness. Ethyl acetate (500ml) was added into the residue to provide a 9th mixture,which was washed with water (2x100 mL), 5% sodium
1-chloroethyl ethyl(2-(Boc-amino)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.15 g
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
In a round bottom flask, Compound 1 (t-Boc-NHCH2CH2NHCH2CH3; 1.50 g) was dissolved in anhydrous dichloromethane (60 ml) and the solution was cooled to 0-5 C. Triethylamine (TEA, 1.2 ml) was added followed by 1-chloroethyl chloroformate (0.79 ml) and the mixture was stirred for three hours at room temperature. Next, the mixture was washed with 0.1M solution of NaH2PO4 (50 ml and 30 ml) and dried with anhydrous MgSO4. Then, the solvent was distilled under reduced pressure giving 2.15 g of the desired product.
With pyridine; In dichloromethane; at -78℃; for 3h;
To a cooled (-78 C) solution of <strong>[111-90-0]2-(2-ethoxyethoxy)ethanol</strong> (0.49 ml_, 3.5 mmol) and pyridine (0.32 ml_, 4.02 mmol) in DCM (5 mL) was slowly added 1-chloroethyl carbonochloridate (0.38 ml_, 3.5 mmol) and the reaction mixture was stirred at -78 C for 3 h. After warming to room temperature, the reaction mixture was filtered and the solid was washed with DCM. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered and the solvent was evaporated to yield the title compound (750 mg, 89%) as a colourless oil which was used in the next synthetic step without further purification.1 H-NMR d (400 MHz, CDC ): 1.21 (t, J=7 Hz, 3H), 1.83 (d, J=6 Hz, 3H), 3.53 (q, J=7 Hz, 2H), 3.61-3.57 (m, 2H), 3.67-3.63 (m, 2H), 3.77-3.73 (m, 2H), 4.39-4.31 (m, 2H), 6.42 (q, J=6 Hz, 1 H).
Add in 2L reaction bottle<strong>[54881-13-9]N-benzyl-3-hydroxyazetidine</strong> 100g (0.42mol), toluene 1000ml, stirred and dissolved, cooled to -5 C, 108 g of 1-chloroethyl chloroformate (0.76 mol) dissolved in 80 ml of toluene In the above solution, slowly add dropwise, the control temperature does not exceed 0 C during the dropwise addition, continue to maintain the temperature reaction for 10 minutes after the completion of the addition, and then slowly raise the temperature to 70 C, continue to react at this temperature for 2 hours, HPLC After the completion of the reaction, the temperature was lowered, and the mixture was concentrated to dryness under reduced pressure at 45 C to obtain 72.4 g of product. The purity of HPLC was 98.0%, and the yield was 96.5%.
4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-carboxylic acid 1-chloroethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With pyridine at 0 - 10℃; for 4h;
12 Synthesis of 4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-carboxylic acid 1-chloroethyl ester
Add 2,4-dihydroxy-6-methylpyrimidine (1.0g) and pyridine (5ml) to a 25mL flask and stir. Slowly add 1-chloroethyl chloroformate (1.1g) at 0°C10°C. After the dropwise addition, the reaction was incubated for 4 h, the reaction system was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE/EA=6:1) to yield product 1.58 g, yield 86%.
16031-SM (CAS 29167-28-0, preparation method referring to Burslem, G M, et al., ?Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups.?, Organic & Biomolecular Chemistry 14.15 (2016): 3782) was used as a starting material to obtain the product, referring to the preparation method of Compound (16026-001). (0278) 31.2 Preparation of Compound (16031-002) (0279) Using Compound (16031-001) as a reaction substrate, the target product was obtained referring to the preparation method of Compound (16026-002).
isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride[ No CAS ]
(2S)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide[ No CAS ]
(2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to add isopropyl (S) -2-amino-3- (3 A solution of 4,4-dihydroxyphenyl) propanoate hydrochloride was prepared.Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine / HCl solution to obtain a third mixture. Next, Nalpha- (benzyloxycarbonyloxy) succinimide (25 g) was added to the third mixture to obtain a fourth mixture.The fourth mixture was stirred at RT overnight and then ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to obtain a fifth solution. Next, sodium sulfate was filtered and washed with ethyl acetate to obtain a sixth solution. The fifth solution and the sixth mixture were combined and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to obtain a seventh mixture. 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added to the seventh mixture to give an eighth mixture. The eighth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 ml) was added to the residue to give a ninth mixture, water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 × 100 mL) and dried over sodium sulfate to give a tenth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a solution No. 11. The 10th solution and the 11th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to obtain a twelfth mixture. Palladium on activated carbon (10 g, 10%) was first added to the 12th mixture under nitrogen, and then hydrogen gas was bubbled at RT to remove the benzyloxycarbonyl group. The resulting mixture (13th mixture) was filtered to remove palladium on activated carbon and evaporated to dryness.The residue was suspended in DCM (200 mL) to give a 14th mixture. Sodium hydrogen carbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 14th mixture to obtain a 15th mixture. Then 1-chloroethyl chloroformate (16 g) was added to the 15th mixture to give a 16th mixture. The 16th mixture was stirred at RT overnight. The organic layer of the 16th mixture was then collected, washed with water (3 × 200 mL) and dried over anhydrous sodium sulfate to give a 17th solution. Sodium sulfate was removed by filtration and washed with DCM to give solution 18. The 17th and 18th solutions were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to obtain a 19th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was first prepared and then added to the 19th mixture to give a 20th mixture. The 20th mixture was stirred at 55 C. for 48 hours, and ethyl acetate (500 mL) was added with stirring. The resulting organic layers were collected, washed with 5% sodium hydrogen carbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain solution 21. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 22nd solution. The 21st and 22nd solutions were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and HBr gas (30 g) was bubbled in to cause precipitation. The precipitated solid was collected, washed with ethyl acetate and washed with (2S) -isopropyl 3- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin- 8-yl) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide and (2S) -isopropyl 3- (4-amino-2,5-dioxo -2,3,4,5-Tetrahydrobenzo [b] [1,4] dioxocin-8-yl) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate bromide The hydrogen salt was obtained.
In this example, a dopamine.HCl solution was prepared by adding dopamine.HCl (19 g) to acetone (200 mL). Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine / HCl solution to obtain a first mixture. Then Nalpha- (benzyloxycarbonyloxy) succinimide (25 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction.Separate the organic layer, water (2 x 100 mL), 20% citric acid (2 x 200 mL),And washed with water (3 x 100 mL) respectively and dried over sodium sulfate to give a third solution. Then sodium sulfate was filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and the fourth mixture were combined and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to obtain a fifth mixture. 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added to the fifth mixture to obtain a sixth mixture. The sixth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 ml) was added to the residue to give a seventh mixture, water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to give an eighth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a ninth solution. The eighth solution and the ninth solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to obtain a 10th mixture. Palladium on activated carbon (10 g, 10%) was first added to the 10th mixture under nitrogen and then bubbled with hydrogen gas to remove the benzyloxycarbonyl group at RT. The resulting mixture (11th mixture) was filtered to remove palladium on activated carbon and evaporated to dryness.The residue was suspended in DCM (200 mL) to give a twelfth mixture. Sodium hydrogen carbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the twelfth mixture to obtain a thirteenth mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the 13th mixture to obtain the 14th mixture. The 14th mixture was stirred at RT overnight. The organic layer of the 14th mixture was then collected, washed with water (3 × 200 mL) and dried over anhydrous sodium sulfate to give a 15th solution. Sodium sulfate was removed by filtration and washed with DCM to give a 16th solution. The 15th and 16th solutions were combined and evaporated to dryness. The residue was collected and dissolved in isobutyric acid (100 mL) to give a 17th mixture. First, a mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared and then added to the 17th mixture to obtain an 18th mixture. The 18th mixture was stirred at 55 C. for 48 hours, and ethyl acetate (500 mL) was added with stirring. The resulting organic layers were collected, washed with 5% sodium hydrogen carbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a nineteenth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a twentieth solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HF gas (20 g) was bubbled in to cause precipitation. The precipitated solid was collected, washed with ethyl acetate and washed with 1-(((2- (4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin- 8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate-hydrofluoric acid salt and 1-(((2- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [ 1,4] Dioxocin-8-yl) ethyl) carbamoyl) oxy) ethylisobutyrate hydrofluoride was obtained.
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