* 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.
Example 1 : methyl ("2S,4R)-4-hvdroxy-2-pyrrolidinecarboxylate hydrochloride To a solution of (2S,4R)- 4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride (1.0 g, 7.6 mmol) in methanol (25 mL) at 0 °C was added thionyl chloride (0.83 mL, 1 1.4 mmol). The reaction was warmed to room temperature and heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness to give the title compound (1.2 g, 92percent) as a white solid. lH NMR (300 MHz, DMSO-<) δ 9.99 (br. s, 2H), 5.58 (br. s, 1H), 4.49-4.41 (m, 2H), 3.75 (s, 3H), 3.38 (dd, 1H), 3.07 (d, 1H), 2.23-2.04 (m, 2H)
92%
at 0℃; Reflux
To a solution of (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride (1.0 g, 7.6 mmol) in methanol (25 mL) at 0° C. was added thionyl chloride (0.83 mL, 11.4 mmol). The reaction was warmed to room temperature and heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness to give the title compound (1.2 g, 92percent) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.99 (br. s, 2H), 5.58 (br. s, 1H), 4.49-4.41 (m, 2H), 3.75 (s, 3H), 3.38 (dd, 1H), 3.07 (d, 1H), 2.23-2.04 (m, 2H).
To a stirred solution of (2S, 4i?)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooled to 0°C was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was triturated with ether several times to get methyl (25',4/?)-4-hydroxypyrrolidine-2- carboxylate hydrochloride salt as a white powder (14.5 g) in 100percent yield, m/z (M+l) 145; 1H NMR (DMSOd6) 300 MHz δ 5.7-5.5 (s (br), IH), 4.55-4.35 (m, 2H), 3.76 (s, 3H), 3.35 (d, J= 12 Hz IH), 3.10 (d, J= 12 Hz IH), 2.25-2.0 (m, 2H).
100%
With hydrogenchloride; thionyl chloride In water at 20℃; for 18 h; Reflux
A solution of trans-4-hydroxy-ι-proline (10.0 g, 76.3 mmol) in MeOH (80 mL) was cooled to 0 °C andthionyl chloride (11.1 mL, 152 mmol) was added dropwise. The mixture was allowed to stir at roomtemperature for 1 h before being heated under reflux for a further 17 h. The resulting solution wasconcentrated and the residue azeotroped with MeOH (3 × 200 mL) to give the desired compound14·HCl (13.6 g, 100percent) as a colourless solid; mp 169–171 °C;−21.6 (c 1.0, EtOH); νmax/cm-1 3317,2952, 2707, 1740, 1439, 1240, 1074, 1025, 956, 901, 625; δH (500 MHz; MeOD) 4.63–4.59 (2 H, m),3.86 (3 H, s), 3.46 (1 H, dd, J 3.2, 10.0 Hz), 3.34–3.30 (1 H, m), 2.45–2.41 (1 H, m), 2.21 (1 H, ddd, J2.4, 8.0, 11.2 Hz); δC (125 MHz; CDCl3) 170.6, 70.6, 59.4, 55.0, 54.0, 38.6; m/z (+ESI) 146 ([M - Cl],100).
100%
at 0 - 64℃; for 8 h;
At room temperature,Trans-4-hydroxy-L-proline 2A (20.0 g, 152.6 mmol) was dissolved in anhydrous methanol (200 mL)Cooling to 0 ,Dichloro sulfoxide (20.6g, 172.4mmol),The temperature was raised to 64 ° C and the reaction was refluxed for 8 hours.The reaction solution was lowered to -20 ° C, and a white solid was precipitated. Methyl tertiary butyl ether (50 mL) was added and the reaction was continued for 30 minutes.The filter cake was washed with methyl tertiary butyl ether (50 mL x 2) and dried to give white solid 4A (28 g, yield 100percent).
99%
at 0℃; for 8 h; Heating / reflux
Acetyl chloride (4.14 g, 52.8 mmol) is dropped into a three neck round bottom flask containing anhydrous methanol (33 ml) in ice bath and under N2 flux. [(2S,4R)-(-)-4-Hydroxypyrrolidine-2-carboxylic acid (1) (5.0 g, 37.7 mmol) is added and the so obtained reaction mixture is firstly brought to room temperature (r.t.) then refluxed for 8 hours. Afterwards, the reaction is brought to room temperature and diethyl ether is added till complete precipitation of the reaction product, which, after Buchner filtration, is (2S,4R)-4-hydroxy-2-(methoxy- carbonyl)pyrrolidine chloride (2). Yield 99percent; white solid m.p. 149-152 0C.1H NMR (DMSO, 500 MHz): δ 2.07 (ddd, IH, J = 4.5, 11.0, 13.0 Hz), 2.18 (m, IH), 3.05 (d, IH, J =12.0 Hz), 3.35 (m, IH), 3.74 (s, 3H, OMe), 4.40 (t, IH, J = 4,5 Hz), 4.44 (dd, IH, J = 6.5, 11.0 Hz), 4.68 (bs, OH), 9.32 (IH, NH), 10.44 (IH, NH).13C NMR (DMSO, 50 MHz): δ 37.0, 53.0, 57.4, 57.8, 68.4, 169.0.Elemental analysis. Calculated for C6Hi2ClNO3: C, 39.68; H, 6.66; Cl, 19.52; N, 7.71. Found: C, 39.66; H, 6.64; Cl, 19.50; N, 7.71. Theoretical mass for C6Hi2ClNO3: 181.05. Found: 181.00.
98%
Stage #1: for 0.166667 h; Inert atmosphere Stage #2: at 0℃; Inert atmosphere
4-Hydroxy proline (10.0 g, 76.33 m mol)dissolved in dry methanol (150 ml) and stirred for 10 minutes under nitrogen atmosphere.The reaction mixture cooled to 0°C by ice bath and thionyl chloride (152.6 mmol, 11.07 ml)added dropwise under nitrogen atmosphere .The ice bath removed and the reaction mixturerefluxed for six hours. The solvents were removed under reduced pressure to obtain a whitesolid which was dissolved in methanol and again evapourated to dryness to yield 13.54 g ofthe title compound in 98percent yield.
96%
With thionyl chloride In neat (no solvent) at 0 - 25℃; for 16 h;
To a stirred solution of (25,4R)-4-hydroxypyrrolidine-2-carboxylic acid (75.0 g, 572 mmol) in MeOH (800 mL), SOCI2 (75 mL) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was triturated with Et20 (500 mL x 2), filtered, dried to afford compound 1 (100.0 g, 96percent) as a white solid as a HCI salt of compound 1. LCMS (ESI): m/z 146.0 [M++l].
95%
at -78℃; for 4.16667 h; Heating / reflux
Step 1 : (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2). Thionyl chloride (11.6 ml, 160 mmol) was added to a stirred solution of (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (10.0 g, 76.26 mmol) (1) in methanol (150 ml) at - 780C for 10 min. The mixture was then stirred in an ice bath for 30 minutes followed by stirring at RT for 30 min. Finally the mixture was refluxed for three hours and concentrated in vacuo to give (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2) (17.90 g, 95percent) as a white solid. Used without further purification. MS m/z 146.2 (M+H)+; retention time = 0.19 min, method [I].
94%
at 0 - 45℃; for 4 h;
SOCl2 (5.2 mL,71.3 mmol) was dissolved in 35.0 mL of anhydrous MeOHat 0 oC.Then trans-4-OH-proline (5.0 g, 38.1 mmol) was added and the reactionmixture was kept refluxing at 45 oC for 4 h, then the solvent was evaporated undervacuum. The residue was dissolved with methanol and recrystallized with diethylether to afford 15 as a white solid (6.5 g, 94percent yield). mp:167.3-167.5 oC; 1H NMR (600 MHz, D2O) δ 4.57–4.65 (m, 2H), 3.76 (s, 3H), 3.44 (dd, J = 12.5, 3.7 Hz, 1H), 3.32 (d, J = 12.6 Hz, 1H), 2.40 (dd, J = 13.5, 7.5 Hz, 1H), 2.21 (ddd, J = 14.3, 10.6, 4.0 Hz, 1H). 13C NMR (150 MHz, D2O) δ 170.24, 69.42, 58.16, 53.84, 53.46,36.68; IR (KBr, cm-1): ν 3328.59, 2960.67, 2869.04, 2705.78, 2602.05, 2421.58,1742.53, 1592.75, 1444.85, 1335.67, 1288.54, 1248.41, 1184.02, 1074.38, 1036.12, 958.20,902.21, 863.95, 710.91, 639.52; HRMS (ESI): m/z calculated forC6H12NO2 (M+H)+: 146.0817, found:146.0813.
92%
at 10 - 45℃; for 5 h;
Absolute methanol (8.0 equiv) was poured into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and a drop funnel. L-hydroxyproline (1 equiv) was placed into the flask with stirring. To the suspension obtained was added dropwise at 10-15 0C distilled thionyl chloride (1.1 equiv). Then the mixture was stirred at 45 0C until TLC indicated completion (5 h) of the reaction. The suspension was cooled to 5-10 0C and then filtered and washed with dry diethyl ether. The mother liquor was evaporated in vacuo and the residue was recrystallized from dry methanol to give the title compound in 92-97percent yield.
90%
for 2 h; Reflux
26.2 g (200 mmol) trans-4-hydroxy-L-proline (1) in methanol(300 ml) was treated with dry hydrogen chloride until homogeneous.The solution was heated to the reflux temperature for 2 h and concentrated in vacuo. Upon cooling, the product was crystallizedfrom the solvent, collected by filtration, washed with acetoneand ether, and dried to yield trans-4-hydroxy-L-proline methylesterhydrochloride (2) as white crystal (32.7 g, 90percent), mp 159–162 C.
88%
Stage #1: for 0.5 h; Cooling with ice Stage #2: for 4 h; Reflux
Acetyl chloride (14 mL, 198 mmol) was slowly added into the anhydrous methanol (100 mL) in an ice bath. After stirred for 30 min, compound 2 (7.87 g, 60.0 mmol) was added to the solution. Then the reaction was refluxed for 4 h in an oil bath. After the methanol was removed under reduced pressure, about 10 mL acetone was added into the residue and filtered to give 8.67 g of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride as a white powder. Yield: 88percent, mp: 160-164 °C. Di-tert-butyl dicarbonate (11.42 g, 52.3 mmol) in 50 mL dichloromethane was slowly added to the solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.64 g, 47.6 mmol), triethylamine (13.5 mL, 96.0 mmol) in 150 mL dichloromethane. After stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure and dissolved with EtOAc. The EtOAc layer was washed two times by 1 M citric acid, saturated sodium bicarbonate and brine, respectively. Finally, the organic layer was dried over anhydrous MgSO4 and concentrated to obtain compound 3 as a white powder. Yield: 88percent, mp: 93-94 °C. 1H NMR (CDCl3, 300 MHz), δ 1.41 (s, 9H), 2.06-2.09 (m, 1H), 2.27-2.34 (m, 1H), 3.43-3.64 (m, 2H), 3.73 (s, 3H), 4.37-4.48 (m, 2H), ESI-MS m/z: 246.3 (M+H)+.
87%
at 0 - 20℃;
Trans-4-hydroxy-L-proline (15.0 g, 114.3 mmol) in dry methanol (250 mL) at 0 - 4 °C, was added dropwise thionyl chloride (17 ml .. 231 mmol). The resulting mixture was sl irrcd for at RT overnight, concentrated, crystallized with EtOH/hexane to provide the title compound (18.0 g, 87percent yield), ESI MS m//+ 168.2 (M + Na).
87%
at 0 - 20℃;
To a solution of trans-4-hydroxy-L-proline (15.0 g, 114.3 mmol) in dry methanol (250 mL) was added thionyl chloride (17 mL, 231 mmol) dropwise at 0 to 4 °C. The resulting mixture was stirred for at r.t. overnight, concentrated, crystallized with EtOH/hexane to provide the title compound (18.0 g, 87percent yield). ESI MS m/z 168.2 ([M+Na]+).
20.5 g
at 0 - 20℃;
Step-1: Synthesis of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate To a suspension of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (15 g, 114.5 mmol) in MeOH (150 mL) was added SOCl2 (17 mL, 229 mmol) dropwise at 0° C. The resultant mixture was allowed to stir at RT overnight. The reaction mixture was concentrated under vacuum, azeotroped with toluene and dried to afford (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate as the HCl salt (20.5 g).
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5
[ 51-35-4 ]
[ 75-36-5 ]
[ 40216-83-9 ]
Yield
Reaction Conditions
Operation in experiment
88%
With thionyl chloride In methanol
Step C-1. Preparation of an ester compound To a suspension of trans-4-hydroxy-L-proline (200 g: 1.525 mole) in methanol (800 ml), acetylchloride (163 ml: 2.288 mole) is added dropwise under ice cooling in a nitrogen atmosphere. The mixture is warmed to room temperature, mixed with thionyl chloride (55.7 ml: 0.763 mole), and stirred for 4 hours at 40° C. to give (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (244.27 g). Yield: 88percent. Colorless crystals. NMR δ(D2 O) ppm: 1.8 to 2.0(m, 1H), 2.0 to 2.2(m, 1H), 2.9 to 3.1(m, 1H), 3.17(dd, J=12.6 Hz, J=3.6 Hz, 1H), 3.49(s, 3H), 4.2 to 4.4(m, 2H). IR ν (KBr) cm-1: 3380, 3330, 2695, 2960, 1742.
Reference：
[1] Patent: US5317016, 1994, A,
6
[ 67-56-1 ]
[ 13726-69-7 ]
[ 40216-83-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 20℃; for 12 h;
Compound 20r (2 g, 8.6 mmol) was taken up with a solution of HC1 (g) in methanol (4 M, 40 mL). The mixture was stirred at ambient temperature for 12 hrs. After that, the reaction mixture was concentrated under reduced pressure to afford compound 20s (1.6 g, yield 99percent) as a white solid.
Reference：
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[2] Synthesis, 1990, vol. 1, # 10, p. 925 - 930
[3] Tetrahedron Letters, 2013, vol. 54, # 39, p. 5345 - 5347
[4] Patent: US2014/179680, 2014, A1,
11
[ 24424-99-5 ]
[ 40216-83-9 ]
[ 61478-26-0 ]
Reference：
[1] Patent: WO2015/6740, 2015, A2,
12
[ 24424-99-5 ]
[ 40216-83-9 ]
[ 74844-91-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In dichloromethane at 0 - 20℃; for 2 h;
To a stirred suspension of the hydrochloride salt obtained in step I (14.5 g, 0.1 mol) in CH2Cl2 (400 mL) cooled to 0°C was added Et3N (28 mL, 0.2 mol), DMAP (0.61 g,5 mmol), and Boc anhydride (27.5 mL, 0.12 mol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The solvent was then removed under vacuum and ether was added to the residual solid. The solid was filtered through a sintered funnel and washed thoroughly with ether. The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with sat. NaCl and sat.NaHCO3 followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain light yellow oil which solidified under high vacuum. The resulting solid was triturated several times with hexanes. The solid was dried under high vacuum yielding l-ter/-butyl 2-methyl (2S, 4i?)-4-hydroxypyrrolidine-l,2-dicarboxylate as a white solid (24.5 g) in 100percent yield. (M+l) 245; 1H NMR (CDCl3) 300 MHz δ 4.54-4.37 <n="62"/>(m, 2H), 3.75 (s, 3H), 3.70-3.40 (m, 2H), 2.48-2.21 (m, 2H), 2.13-2.0 (m, IH), 1.46 (s, 3H), 1.41 (s, 6H).
100%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: at 20℃; for 12 h;
At room temperature,4A (27.7 g, 152.6 mmol) was dissolved in dichloromethane (150 mL)After cooling to 0 ° C, triethylamine (38.6 g, 381.5 mmol) was added and stirred for 10 minutes.A mixture of two or three terephthalate (39.9 g, 183.1 mmol)In dichloromethane (50 mL) was added dropwise to the reaction mixture, and the reaction was stirred at room temperature for 12 hours.The organic phase was washed successively with hydrochloric acid (0.5 mol / L, 150 mL x 1), sodium bicarbonate solution (100 mL x 1), saturated brine solution (100 mL x 1).Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give pale yellow liquid 4B (28.0 g, yield 100percent).
99%
With triethylamine In dichloromethane at 0 - 20℃;
Methyl (2S,4R)-N-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate. L-trans-4-Hydroxyproline methyl ester hydrochloride (25.00 g, 138.0 mmol) was dissolved in dichloromethane (300 mL) and triethylamine (58.0 mL, 413 mmol). The solution was cooled to 0° C. and then di-tert-butyldicarbonate (33.00 g, 151.0 mmol) was added in small portions. After stirring at room temperature overnight, the mixture was concentrated to a thick white sludge. The residue was dissolved in ethyl acetate and the organic layer was washed successively with NH4Cl/H2O, NaHCO3/H2O and brine. The organic extracts were dried over MgSO4, filtered, and concentrated to give 33.0 g (99percent) of desired product as a colorless oil. LC/MS (M+Na)+ m/z=267.9. 1H NMR (CDCl3) δ 4.50 (m, 1H), 4.40 (m, 1H), 3.75 (s, 3H), 3.43-3.68 (m, 2H), 2.30 (m, 1H), 1.95-2.15 (m, 2H), 1.42 and 1.45 (s, 9H).
99%
With triethylamine In dichloromethane at 0 - 20℃;
Step AMethyl (2S,4f?)-N-iert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate. L-trans-A- Hydroxyproline methyl ester hydrochloride (25.00 g, 138.0 mmol) was dissolved in dichloromethane (300 mL) and triethylamine (58.0 mL, 413 mmol). The solution was cooled to 0 °C and then di-terf-butyldicarbonate (33.00 g, 151.0 mmol) was added in small portions. After stirring at room temperature overnight, the mixture was concentrated to a thick white sludge. The residue was dissolved in ethyl acetate and the organic layer was washed successively with NH4CI/H20, NaHC03/H20 and brine. The organic extracts were dried over MgS04, filtered, and concentrated to give 33.0 g (99percent) of desired product as a colorless oil. LC/MS (M+Na)+ m/z = 267.9. 1H NMR (CDCI3) δ 4.50 (m, 1 H), 4.40 (m, 1 H), 3.75 (s, 3H), 3.43-3.68 (m, 2H), 2.30 (m, 1 H), 1.95-2.15 (m, 2H), 1 .42 and 1 .45 (s, 9H).
97%
With triethylamine In dichloromethane at 0℃; for 17 h;
A solution of 14·HCl (13.3 g, 73.9 mmol) and NEt3 (26.0 mL, 192 mmol) in CH2Cl2 (160 mL) was cooledto 0 °C and di-tert-butyl dicarbonate (17.7 g, 81.3 mmol) was added portion-wise. The ice bath wasallowed to expire and stirring was continued for 17 h. The reaction mixture was diluted with CH2Cl2(100 mL) and washed with hydrochloric acid (1M; 100 mL). The organic extract was further washedwith H2O (100 mL), saturated aqueous sodium hydrogencarbonate (100 mL), brine (100 mL) andthen dried (MgSO4) and the solvent removed under reduced pressure to yield the desired alcohol(17.8 g, 72.9 mmol, 97percent) as a yellow oil (and as a mixture of conformers);−60.4 (0.98, CHCl3);νmax/cm-1 3431, 2978, 1748, 1677, 1411, 1367, 1158, 894, 733, 551; δH (500 MHz; CDCl3) 4.38–4.46 (2H, m), 3.71 (3 H, s), 3.42–3.59 (2 H, m), 2.24–2.47 (2 H, m), 2.04–2.10 (1 H, m), 1.39–1.43 (9 H, m) δC(125 MHz; CDCl3) 173.8, 154.1, 80.4, 69.9, 69.2, 58.0, 54.7, 52.0, 39.1, 38.4, 28.4, 28.3; m/z (+ESI)289 ([M + Na], 100).
96%
With triethylamine In chloroform at 25 - 50℃; for 3.5 - 4 h;
Chloroform (1.4 L) and compound methyl (2S,4f?)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (544.8 g) were mixed under stirring. Triethylamine (464 mL, 3.3 mol) was added under cooling to the mixture and the precipitate dissolved almost completely. A solution of BoC2O (687.5 g, 3.15 mol) in chloroform (1 L) was added dropwise at the temperature less than 25 0C for 1.5-2 h. Then the reaction mixture was heated to 45-50 0C and kept at this temperature for 2 h under stirring. The course of the reaction was monitored by TLC (chloroform/methanol 10:3). Then the reaction mixture was washed sequentially with water (50O mL, 20O mL and 10O mL), a solution of citric acid (28.8 g, 0.15 mol) in water (100 mL), a solution of sodium hydroxide (12 g) in water (100 mL) and water. The solution was dried with potassium carbonate for 2-3 h and then evaporated to give a viscous light-yellow liquid. The liquid was treated with diethyl ether (400 mL), stirred and cooled for 1 h. The product was washed with diethyl ether (3 x 300 mL) and dried to constant weight to give 615-620 g of 3 as white crystals. The mother solution of ether was evaporated and cooled to room temperature. Ether (50 mL) and a small amount of the product were added to the solution. The precipitate formed was filtered, washed with ether and dried to give 50 g of the title compound. The total yield was 96percent.
91%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.5 h; Stage #2: With dmap In dichloromethane at 20℃; for 18 h;
Add triethylamine (1.56 mol, 157.5 g) to a solution of methyl ester hydrochloride in dry dichloromethane (2 L) at 0° C. and stir for 30 min. Then add N,N-dimethylaminopyridine (0.10 mol, 13 g) and di-tert-butyl dicarbonate (0.85 mol, 185.7 g) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Quench the reaction mixture with water, separate the organic layer, and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (160 g, 91percent) as viscous oil. ES-MS m/z 246.1 [M+1]+.
91%
With sodium hydrogencarbonate In 1,4-dioxane at 20℃; for 24 h;
A solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (10) (0.5g, 2.75mmol) in dioxane (15mL) was added (Boc)2O (721mg, 3.3mmol) and saturated NaHCO3 (10.5mL). The reaction was stirred at room temperature overnight. The solvent was then removed in vacuo and CH2Cl2 was added. The organics were washed with H2O twice and saturated NaCl once, then dried, filtered and concentrated. The residue was purified by flas h chromatography on silica gel, eluted with a mixture of EA/PE (1:5, v/v), to afford 11 (611mg, 91percent) as a white solid. 1H NMR (CDCl3, 300MHz): δ 4.35–4.48 (m, 2H), 3.72 (s, 3H), 3.46–3.65 (m, 2H), 2.03–2.29 (m, 2H), 1.39 (s, 9H). MS (ESI) m/z 246 [M+H]+.
91%
With triethylamine In dichloromethane at 0 - 25℃; for 16.5 h;
To a stirred solution of compound 1 (100.0 g, 552 mol) in DCM (1 L), Et3N (230 mL, 1.65 mol) was added at 0 °C and stirred for 15 min. B0C2O (152 mL, 662 mmol) was added drop wise to the reaction mixture at 0 °C over 30 min and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (500 mL) and extracted with DCM (3 x 300 mL). The combined organic layer was washed with brine (150 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 2 (123.0 g, 91percent) as a colorless solid. H NMR (400 MHz, DMSO-cfe): δ 5.09 (d, / = 3.6 Hz, 1H), 4.29 - 4.15 (m, 2H), 3.64 (m, 3H), 3.45 - 3.21 (m, 2H), 2.14 - 2.09 (m, 1H), 1.95 - 1.82 (m, 1H), 1.39 - 1.32 (m, 9H).
90.1%
With triethylamine In 1,4-dioxane; water at 0 - 20℃;
Methyl 4-trans-hydroxy-prolinate hydrochloride (1.45 g, 8 mmol) was dissolved in a mixture of dioxane and water (2:1, v/v, 20 mL) at 0 °C. To the solution was added triethylamine (1.7 mL, 12 mmol) and Boc anhydride (2.0 g, 8.8 mmol). The reaction mixture was then stirred at room temperature for 5 h and evaporated in vacuo. The resulting residue was washed with ethyl acetate (20 mL) and water (15 mL). The aqueous layer was successively extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with HCl (0.5 M, 5 mL), water (5 mL x 2), sodium carbonate (5percent, 5 mL), water (5 mL x 2), and brine (10 mL) and finally was dried overnight by anhydrous MgSO4. The product was obtained as a white solid. Yield, 1.76 g, 90.1percent, mp 92-94 °C, [α]25D -64.0 (c 1.0, CHCl3).
90%
With triethylamine In dichloromethane at 0 - 20℃; for 4 h;
Boc2O (94.0 g, 428 mmol) was added into a solution of H-2 (65.0 g, 357.0 mmol) and Et3N (124.0 mL, 892 mmol) in DCM (300 mL) at 0 °C. The resulting mixture was stirred at r.t. for 4 hours before the reaction solution was washed with 1 N HCI (300 mL), brine (300 mL) and dried over Na2SO4, filtered and concentrated to dryness to give H-3 (79.0 g, 90percent) as a white solid.
89%
With triethylamine In dichloromethane at 20℃;
(a) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester HCl (10 g, 55.1 mmol) in DCM (100 mL) was added triethylamine (16.73 g, 165.3 mmol) and di-tert-butyl dicarbonate (14.41 g, 66.1 mmol). The reaction mixture was stirred at RT overnight, concentrated, and purified by column chromatography (3:1 petroleum ether:EtOAc) to give the title intermediate (12 g, 89percent yield) 1H NMR (400 MHz, CDCl3): δ(ppm) 4.48 (m, 1H), 4.38 (m, 1H), 3.72 (s, 3H), 3.63 (m, 1H), 3.45 (m, 1H), 2.29 (m, 1H), 2.06 (m, 2H), 1.39 (s, 9H).
88%
With triethylamine In dichloromethane at 20℃;
Acetyl chloride (14 mL, 198 mmol) was slowly added into the anhydrous methanol (100 mL) in an ice bath. After stirred for30 min, compound 2 (7.87 g, 60.0 mmol) was added to the solution.Then the reaction was refluxed for 4 h in an oil bath. After the methanol was removed under reduced pressure, about 10 mLacetone was added into the residue and filtered to give 8.67 g of(2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochlorideas a white powder. Yield: 88percent, mp: 160–164 °C. Di-tert-butyl dicarbonate (11.42 g, 52.3 mmol) in 50 mL dichloromethane was slowly added to the solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.64 g, 47.6 mmol), triethylamine(13.5 mL, 96.0 mmol) in 150 mL dichloromethane. After stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure and dissolved with EtOAc. The EtOAc layer was washed two times by 1 M citric acid, saturated sodium bicarbonate and brine, respectively. Finally, the organic layer was dried over anhydrous MgSO4 and concentrated to obtain compound 3 as a white powder.
86%
With sodium hydrogencarbonate In methanol
To a solution of trans-4-hydroxy-l .-proline methyl ester (18.0 g, 107.0 mmol) in the mixture of MeOH (150 ml) and sodium bicarbonate solution (2.0 M, 350 ml) was added (BOQ2O (30.0 g, 137.6 mmol) in three portions in 4 h. After stirring for an additional 4 h, the reaction was concentrated to -350 ml and extracted with EtOAc (4 x 80 mL). The combined organic layers were washed with brine (100 mL), dried ( MgS( ).t ). filtered, concentrated and purified by SiO.-> chromatography (1 : 1 hexanes/EtOAc) to give the title compound (22.54 g, 86percent yield). LSI MS m/z+ 268.2 (M + Na).
86%
With sodium hydrogencarbonate In methanol; water for 8 h;
To a solution of trans-4-hydroxy-L-proline methyl ester (18.0 g, 107.0 mmol) in the mixture of MeOH (150 ml) and sodium bicarbonate solution (2.0 M, 350 ml) was added Boc2O (30.0 g, 137.6 mmol) in three portions in 4 h. After stirring for an additional 4 h, the reaction was concentrated to ~350 ml and extracted with EtOAc (4 × 80 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered, concentrated and purified by SiO2 column chromatography (1:1 hexanes/EtOAc) to give the title compound (22.54 g, 86percent yield). ESI MS m/z 268.2 ([M+Na]+).
82%
With triethylamine In dichloromethane
Step C-2. Preparation of a Boc compound To a suspension of (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (12.71 g: 70 mmole) in dichloromethane (70 ml), triethylamine (10.7 ml: 77 mmole) is added dropwise under ice cooling in a nitrogen atmosphere. The mixture is stirred for 5 min. at room temperature. A solution of di-t-butyl dicarbonate (19.10 g: 87.5 mmole) in dichloromethane (72 ml) is added dropwise thereto, and the mixture is stirred for 45 minutes at room temperature to give (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (14.06 g). Yield: 82percent. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=9.6 Hz, 9H), 1.9 to 2.4(m, 3H), 3.4 to 3.7(m, 2H), 3.74 (s, 3H), 4.3 to 4.6(m, 2H).
64%
With triethylamine In dichloromethane at 20℃; for 5 h;
To a stirred solution of V (3.0 g, 12.24 mmol) in DCM (30 mL) was added Et3N(1.85 g, 18.31 mmol) and Boc anhydride (2.92 g, 13.46 mmol). Stirring was continued at rt for 5 h after which the reaction was quenched with water. The organic layer was separated, dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, 100percent ethyl acetate) to give 3' (3.2 g, 64percent) as a white solid.
91 %Spectr.
Stage #1: With triethylamine In dichloromethane at 0℃; Stage #2: With triethylamine In dichloromethane at 0℃; for 12 h;
Triethylamine (10.1 g, 100 mmol), then di-ter-butyl-dicarbonate (8.3 g, 38.0 mmol) are added to the suspension of (2S,4R)-4-hydroxy-2-(methoxycarbonyl)- pyrrolidine chloride (2) (6.32 g, 34.8 mmol) in 45 ml of anhydrous CH2Cl2 at 00C. The reaction is carried out in ice/salt bath for 12 hours under N2 flux. Then, the reaction mixture is treated with a 1 M H3PO4 solution (158 ml), then with a Na- HCO3 saturated solution (3x45 ml). The obtained organic phase is dried over sodium sulfate, evaporated to dryness and l-ter-butyl-2-methyl-(2S,4R)-4-hydroxy- pyrrolidine-l,2-dicarboxylate (3) is obtained. Pale yellow oil, yield 91percent (calcu- lated by 1H NMR).1H NMR (CDCl3, 500 MHz): δ 1.37 (s, 6H), 1.43 (s, 3H), 2.03 (m, IH), 2.26 (m, IH), 2.97 (m, IH), 3.46 (m, IH), 3.59 (m, IH), 3.69 (s, 3H), 4.36 (m, IH), 4.44 (m, IH).13C NMR (CDCl3, 50 MHz): δ 27.9, 37.1, 54.0, 57.9, 61.3, 72.0, 83.4, 160.1, 168.4.Elemental analysis. Calculated for CHHI9NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.84; H, 7.77; N, 5.69. Theoretical mass for CHHI9NO5: 245.27. Found: 245.25.
27 g
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 3 h;
Step-2: Synthesis of (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine To a suspension of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (20.5 g, 113.25 mmol) in DCM was added triethylamine (31.4 mL, 226.5 mmol), DMAP (690 mg, 5.66 mmol) and di-tert-butyl dicarbonate (29.6 g, 135.9 mmol) at 0° C. The reaction mixture was allowed to stir at RT for 3 h. the reaction mixture was washed with water (3*150 mL) followed by saturated NaHCO3 (150 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine as oil (27 g).
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13
[ 1070-19-5 ]
[ 40216-83-9 ]
[ 74844-91-0 ]
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30
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With triethylamine In dichloromethane at 0 - 20℃; for 2h;
5.II
To a stirred suspension of the hydrochloride salt obtained in step I (14.5 g, 0.1 mol) in CH2Cl2 (400 mL) cooled to 0°C was added Et3N (28 mL, 0.2 mol), DMAP (0.61 g,5 mmol), and Boc anhydride (27.5 mL, 0.12 mol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The solvent was then removed under vacuum and ether was added to the residual solid. The solid was filtered through a sintered funnel and washed thoroughly with ether. The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with sat. NaCl and sat.NaHCO3 followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain light yellow oil which solidified under high vacuum. The resulting solid was triturated several times with hexanes. The solid was dried under high vacuum yielding l-ter/-butyl 2-methyl (2S, 4i?)-4-hydroxypyrrolidine-l,2-dicarboxylate as a white solid (24.5 g) in 100% yield. (M+l) 245; 1H NMR (CDCl3) 300 MHz δ 4.54-4.37 (m, 2H), 3.75 (s, 3H), 3.70-3.40 (m, 2H), 2.48-2.21 (m, 2H), 2.13-2.0 (m, IH), 1.46 (s, 3H), 1.41 (s, 6H).
100%
With triethylamine
100%
With triethylamine In dichloromethane
100%
With triethylamine
100%
Stage #1: (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride With triethylamine In dichloromethane at 0℃; for 0.166667h;
Stage #2: di-<i>tert</i>-butyl dicarbonate In dichloromethane at 20℃; for 12h;
2 (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate
At room temperature,4A (27.7 g, 152.6 mmol) was dissolved in dichloromethane (150 mL)After cooling to 0 ° C, triethylamine (38.6 g, 381.5 mmol) was added and stirred for 10 minutes.A mixture of two or three terephthalate (39.9 g, 183.1 mmol)In dichloromethane (50 mL) was added dropwise to the reaction mixture, and the reaction was stirred at room temperature for 12 hours.The organic phase was washed successively with hydrochloric acid (0.5 mol / L, 150 mL x 1), sodium bicarbonate solution (100 mL x 1), saturated brine solution (100 mL x 1).Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give pale yellow liquid 4B (28.0 g, yield 100%).
99%
With triethylamine In dichloromethane at 0 - 20℃;
59.A
Methyl (2S,4R)-N-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate. L-trans-4-Hydroxyproline methyl ester hydrochloride (25.00 g, 138.0 mmol) was dissolved in dichloromethane (300 mL) and triethylamine (58.0 mL, 413 mmol). The solution was cooled to 0° C. and then di-tert-butyldicarbonate (33.00 g, 151.0 mmol) was added in small portions. After stirring at room temperature overnight, the mixture was concentrated to a thick white sludge. The residue was dissolved in ethyl acetate and the organic layer was washed successively with NH4Cl/H2O, NaHCO3/H2O and brine. The organic extracts were dried over MgSO4, filtered, and concentrated to give 33.0 g (99%) of desired product as a colorless oil. LC/MS (M+Na)+ m/z=267.9. 1H NMR (CDCl3) δ 4.50 (m, 1H), 4.40 (m, 1H), 3.75 (s, 3H), 3.43-3.68 (m, 2H), 2.30 (m, 1H), 1.95-2.15 (m, 2H), 1.42 and 1.45 (s, 9H).
99%
With triethylamine In dichloromethane at 0 - 20℃;
59.A
Step AMethyl (2S,4f?)-N-iert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate. L-trans-A- Hydroxyproline methyl ester hydrochloride (25.00 g, 138.0 mmol) was dissolved in dichloromethane (300 mL) and triethylamine (58.0 mL, 413 mmol). The solution was cooled to 0 °C and then di-terf-butyldicarbonate (33.00 g, 151.0 mmol) was added in small portions. After stirring at room temperature overnight, the mixture was concentrated to a thick white sludge. The residue was dissolved in ethyl acetate and the organic layer was washed successively with NH4CI/H20, NaHC03/H20 and brine. The organic extracts were dried over MgS04, filtered, and concentrated to give 33.0 g (99%) of desired product as a colorless oil. LC/MS (M+Na)+ m/z = 267.9. 1H NMR (CDCI3) δ 4.50 (m, 1 H), 4.40 (m, 1 H), 3.75 (s, 3H), 3.43-3.68 (m, 2H), 2.30 (m, 1 H), 1.95-2.15 (m, 2H), 1 .42 and 1 .45 (s, 9H).
99%
With triethylamine In acetonitrile at 0 - 20℃; Inert atmosphere;
7 (2S, 4R)-l-to/-Butyl 2-methyl 4-hydroxypyrrolidine-l, 2-dicarboxylate (30)
Under argon, at 0 °C, to a suspension of (29) (27.6 g, 0.15 mol) in acetonitrile (200 mL) was successively added triethylamine (63.6 mL, 0.47 mol) and di-tot-butyl dicarbonate (33.2 g, 0.15 mol). The resulting mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated under reduced pressure and the residue poured into CH2CI2 (300 mL). The organic layer was washed with IN aqueous NaHSCC solution (4 x 100 mL), dried over Na2SC>4 , and concentrated under reduced pressure to give the (2S, 4R)-methyl 1 -(tot-butyloxycarbonyl)-4- hydroxypyrrolidine-2-carboxylate (30) (36.7 g, 99%) as light yellow oil. 1 H NMR (250 MHz, CDCI3, rotamers) d 4.49-4.36 (m, 2H), 3.72 (s, 3H), 3.60-3.43 (m, 2H), 2.24-2.17 (m, 1H), 2.11-2.01 (m, 2H), 1.45 and 1.40 (2 x s, 9H); LCMS C11H19NO5 Rt = 5.101 min, ESI+ m/z = 146.1 (M+2H-Boc).
97%
With triethylamine In dichloromethane
97%
With triethylamine In dichloromethane at 0℃; for 17h;
A solution of 14·HCl (13.3 g, 73.9 mmol) and NEt3 (26.0 mL, 192 mmol) in CH2Cl2 (160 mL) was cooledto 0 °C and di-tert-butyl dicarbonate (17.7 g, 81.3 mmol) was added portion-wise. The ice bath wasallowed to expire and stirring was continued for 17 h. The reaction mixture was diluted with CH2Cl2(100 mL) and washed with hydrochloric acid (1M; 100 mL). The organic extract was further washedwith H2O (100 mL), saturated aqueous sodium hydrogencarbonate (100 mL), brine (100 mL) andthen dried (MgSO4) and the solvent removed under reduced pressure to yield the desired alcohol(17.8 g, 72.9 mmol, 97%) as a yellow oil (and as a mixture of conformers);-60.4 (0.98, CHCl3);νmax/cm-1 3431, 2978, 1748, 1677, 1411, 1367, 1158, 894, 733, 551; δH (500 MHz; CDCl3) 4.38-4.46 (2H, m), 3.71 (3 H, s), 3.42-3.59 (2 H, m), 2.24-2.47 (2 H, m), 2.04-2.10 (1 H, m), 1.39-1.43 (9 H, m) δC(125 MHz; CDCl3) 173.8, 154.1, 80.4, 69.9, 69.2, 58.0, 54.7, 52.0, 39.1, 38.4, 28.4, 28.3; m/z (+ESI)289 ([M + Na], 100).
96%
With N,N-dimethyl-4-aminopyridine; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃;
96%
With triethylamine In chloroform at 25 - 50℃; for 3.5 - 4h;
21.b
Chloroform (1.4 L) and compound methyl (2S,4f?)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (544.8 g) were mixed under stirring. Triethylamine (464 mL, 3.3 mol) was added under cooling to the mixture and the precipitate dissolved almost completely. A solution of BoC2O (687.5 g, 3.15 mol) in chloroform (1 L) was added dropwise at the temperature less than 25 0C for 1.5-2 h. Then the reaction mixture was heated to 45-50 0C and kept at this temperature for 2 h under stirring. The course of the reaction was monitored by TLC (chloroform/methanol 10:3). Then the reaction mixture was washed sequentially with water (50O mL, 20O mL and 10O mL), a solution of citric acid (28.8 g, 0.15 mol) in water (100 mL), a solution of sodium hydroxide (12 g) in water (100 mL) and water. The solution was dried with potassium carbonate for 2-3 h and then evaporated to give a viscous light-yellow liquid. The liquid was treated with diethyl ether (400 mL), stirred and cooled for 1 h. The product was washed with diethyl ether (3 x 300 mL) and dried to constant weight to give 615-620 g of 3 as white crystals. The mother solution of ether was evaporated and cooled to room temperature. Ether (50 mL) and a small amount of the product were added to the solution. The precipitate formed was filtered, washed with ether and dried to give 50 g of the title compound. The total yield was 96%.
96%
With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; Cooling with ice;
52 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (89)
To a solution of 2.50 g (88) (13.8 mmol) and 1.73 g NaHCO3 (20.6 mmol) in a mixture of THF/water (20ml each) were added 3.16 ml Boc2O (13.8 mmol) via syringe under icecooling. After gas evolution ceased, the cooling bath was removed and stirring was continued overnight at ambient temperature. The reaction was diluted with EtOAc and transferred to a separatory funnel. The phases were separated and the aqueous phase was further extracted with EtOAc (4x50ml). The combined extracts were washed with 2N NaHSO4 and brine, prior to drying over Na2SO4 and evaporation. The title compound was yielded as 3.25 g (96%) of a slightly yellowish oil. 1H NMR (200 MHz, CDCl3) δ 4.56 - 4.28 (m, 2H), 3.72 (s, 3H), 3.68 - 3.36 (m, 2H), 2.38 - 2.18 (m, 1H), 2.17 - 1.97 (m, 2H), 1.49 - 1.30 (m, 9H). ESI-MS m/z: 267.8 [M+Na]+
96%
With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; Cooling with ice;
52 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (89)
To a solution of 2.50 g (88) (13.8 mmol) and 1.73 g NaHCO3 (20.6 mmol) in a mixture of THF/water (20ml each) were added 3.16 ml Boc2O (13.8 mmol) via syringe under icecooling. After gas evolution ceased, the cooling bath was removed and stirring was continued overnight at ambient temperature. The reaction was diluted with EtOAc and transferred to a separatory funnel. The phases were separated and the aqueous phase was further extracted with EtOAc (4x50ml). The combined extracts were washed with 2N NaHSO4 and brine, prior to drying over Na2SO4 and evaporation. The title compound was yielded as 3.25 g (96%) of a slightly yellowish oil. 1H NMR (200 MHz, CDCl3) δ 4.56 - 4.28 (m, 2H), 3.72 (s, 3H), 3.68 - 3.36 (m, 2H), 2.38 - 2.18 (m, 1H), 2.17 - 1.97 (m, 2H), 1.49 - 1.30 (m, 9H). ESI-MS m/z: 267.8 [M+Na]+
95%
With triethylamine In dichloromethane Ambient temperature;
95%
With triethylamine In dichloromethane at 0 - 20℃; for 2h;
94%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane for 2h; Ambient temperature;
92%
With Sodium hydrogenocarbonate In tetrahydrofuran for 2h;
92%
With triethylamine In dichloromethane
91%
With triethylamine In dichloromethane for 8h; Ambient temperature;
91%
Stage #1: (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride With triethylamine In dichloromethane at 0℃; for 0.5h;
Stage #2: di-<i>tert</i>-butyl dicarbonate With N,N-dimethyl-4-aminopyridine In dichloromethane at 20℃; for 18h;
24
Add triethylamine (1.56 mol, 157.5 g) to a solution of methyl ester hydrochloride in dry dichloromethane (2 L) at 0° C. and stir for 30 min. Then add N,N-dimethylaminopyridine (0.10 mol, 13 g) and di-tert-butyl dicarbonate (0.85 mol, 185.7 g) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Quench the reaction mixture with water, separate the organic layer, and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (160 g, 91%) as viscous oil. ES-MS m/z 246.1 [M+1]+.
91%
With Sodium hydrogenocarbonate In 1,4-dioxane at 20℃; for 24h;
4.1.1 1-tert-Butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (11)
A solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (10) (0.5g, 2.75mmol) in dioxane (15mL) was added (Boc)2O (721mg, 3.3mmol) and saturated NaHCO3 (10.5mL). The reaction was stirred at room temperature overnight. The solvent was then removed in vacuo and CH2Cl2 was added. The organics were washed with H2O twice and saturated NaCl once, then dried, filtered and concentrated. The residue was purified by flas h chromatography on silica gel, eluted with a mixture of EA/PE (1:5, v/v), to afford 11 (611mg, 91%) as a white solid. 1H NMR (CDCl3, 300MHz): δ 4.35-4.48 (m, 2H), 3.72 (s, 3H), 3.46-3.65 (m, 2H), 2.03-2.29 (m, 2H), 1.39 (s, 9H). MS (ESI) m/z 246 [M+H]+.
91%
With triethylamine In dichloromethane at 0 - 25℃; for 16.5h;
Synthesis of l-(tert-butyl) 2-methyl (2S,4/?)-4-hydroxypyrrolidine-l,2-dicarboxylate (2):
To a stirred solution of compound 1 (100.0 g, 552 mol) in DCM (1 L), Et3N (230 mL, 1.65 mol) was added at 0 °C and stirred for 15 min. B0C2O (152 mL, 662 mmol) was added drop wise to the reaction mixture at 0 °C over 30 min and stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (500 mL) and extracted with DCM (3 x 300 mL). The combined organic layer was washed with brine (150 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 2 (123.0 g, 91%) as a colorless solid. H NMR (400 MHz, DMSO-cfe): δ 5.09 (d, / = 3.6 Hz, 1H), 4.29 - 4.15 (m, 2H), 3.64 (m, 3H), 3.45 - 3.21 (m, 2H), 2.14 - 2.09 (m, 1H), 1.95 - 1.82 (m, 1H), 1.39 - 1.32 (m, 9H).
90.1%
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃;
Methyl N-Boc-4-trans-hydroxy-prolinate (3)
Methyl 4-trans-hydroxy-prolinate hydrochloride (1.45 g, 8 mmol) was dissolved in a mixture of dioxane and water (2:1, v/v, 20 mL) at 0 °C. To the solution was added triethylamine (1.7 mL, 12 mmol) and Boc anhydride (2.0 g, 8.8 mmol). The reaction mixture was then stirred at room temperature for 5 h and evaporated in vacuo. The resulting residue was washed with ethyl acetate (20 mL) and water (15 mL). The aqueous layer was successively extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with HCl (0.5 M, 5 mL), water (5 mL x 2), sodium carbonate (5%, 5 mL), water (5 mL x 2), and brine (10 mL) and finally was dried overnight by anhydrous MgSO4. The product was obtained as a white solid. Yield, 1.76 g, 90.1%, mp 92-94 °C, [α]25D -64.0 (c 1.0, CHCl3).
90%
With triethylamine In dichloromethane at 0 - 20℃; for 4h;
Boc2O (94.0 g, 428 mmol) was added into a solution of H-2 (65.0 g, 357.0 mmol) and Et3N (124.0 mL, 892 mmol) in DCM (300 mL) at 0 °C. The resulting mixture was stirred at r.t. for 4 hours before the reaction solution was washed with 1 N HCI (300 mL), brine (300 mL) and dried over Na2SO4, filtered and concentrated to dryness to give H-3 (79.0 g, 90%) as a white solid.
90%
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃;
90%
With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 20℃; for 16h; Inert atmosphere;
89%
With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane for 3h; Ambient temperature;
89%
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 2h;
89%
With triethylamine In dichloromethane at 20℃;
(a) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
(a) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester HCl (10 g, 55.1 mmol) in DCM (100 mL) was added triethylamine (16.73 g, 165.3 mmol) and di-tert-butyl dicarbonate (14.41 g, 66.1 mmol). The reaction mixture was stirred at RT overnight, concentrated, and purified by column chromatography (3:1 petroleum ether:EtOAc) to give the title intermediate (12 g, 89% yield) 1H NMR (400 MHz, CDCl3): δ(ppm) 4.48 (m, 1H), 4.38 (m, 1H), 3.72 (s, 3H), 3.63 (m, 1H), 3.45 (m, 1H), 2.29 (m, 1H), 2.06 (m, 2H), 1.39 (s, 9H).
88%
With triethylamine In dichloromethane at 20℃;
5.1.1. (2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (3)
Acetyl chloride (14 mL, 198 mmol) was slowly added into the anhydrous methanol (100 mL) in an ice bath. After stirred for30 min, compound 2 (7.87 g, 60.0 mmol) was added to the solution.Then the reaction was refluxed for 4 h in an oil bath. After the methanol was removed under reduced pressure, about 10 mLacetone was added into the residue and filtered to give 8.67 g of(2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochlorideas a white powder. Yield: 88%, mp: 160-164 °C. Di-tert-butyl dicarbonate (11.42 g, 52.3 mmol) in 50 mL dichloromethane was slowly added to the solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.64 g, 47.6 mmol), triethylamine(13.5 mL, 96.0 mmol) in 150 mL dichloromethane. After stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure and dissolved with EtOAc. The EtOAc layer was washed two times by 1 M citric acid, saturated sodium bicarbonate and brine, respectively. Finally, the organic layer was dried over anhydrous MgSO4 and concentrated to obtain compound 3 as a white powder.
86%
With Sodium hydrogenocarbonate In methanol
22 Example 22 -l-tert-butyl 2-methyl 4-hydroxypyrrolidine~l ,2-dicarboxylate
To a solution of trans-4-hydroxy-l .-proline methyl ester (18.0 g, 107.0 mmol) in the mixture of MeOH (150 ml) and sodium bicarbonate solution (2.0 M, 350 ml) was added (BOQ2O (30.0 g, 137.6 mmol) in three portions in 4 h. After stirring for an additional 4 h, the reaction was concentrated to -350 ml and extracted with EtOAc (4 x 80 mL). The combined organic layers were washed with brine (100 mL), dried ( MgS( ).t ). filtered, concentrated and purified by SiO.-> chromatography (1 : 1 hexanes/EtOAc) to give the title compound (22.54 g, 86% yield). LSI MS m/z+ 268.2 (M + Na).
86%
With Sodium hydrogenocarbonate In methanol; lithium hydroxide monohydrate for 8h;
87 Example 87. Synthesis of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine- 1,2- dicarboxylate (233).
To a solution of trans-4-hydroxy-L-proline methyl ester (18.0 g, 107.0 mmol) in the mixture of MeOH (150 ml) and sodium bicarbonate solution (2.0 M, 350 ml) was added Boc2O (30.0 g, 137.6 mmol) in three portions in 4 h. After stirring for an additional 4 h, the reaction was concentrated to ~350 ml and extracted with EtOAc (4 × 80 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered, concentrated and purified by SiO2 column chromatography (1:1 hexanes/EtOAc) to give the title compound (22.54 g, 86% yield). ESI MS m/z 268.2 ([M+Na]+).
86%
With Sodium hydrogenocarbonate In methanol for 8h;
74 Example 74. Synthesis of (2S, 4R) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate.
To a solution of trans-4-hydroxy-L-proline methyl ester (18.0 g, 107.0 mmol) in the mixture of MeOH (150 ml) and sodium bicarbonate solution (2.0 M, 350 ml) was added Boc 2O (30.0 g, 137.6 mmol) in three portions in 4 h. After stirring for an additional 4 h, the reaction was concentrated to 350 ml and extracted with EtOAc (4 × 80 mL) . The combined organic layers were washed with brine (100 mL) , dried (MgSO 4) , filtered, concentrated and purified by SiO 2 column chromatography (1: 1 hexanes/EtOAc) to give the title compound (22.54 g, 86%yield) . ESI MS m/z 268.2 ( [M+Na] +) .
83%
With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 19h;
82%
With triethylamine In dichloromethane
P.7.C.2 Step C-2.
Step C-2. Preparation of a Boc compound To a suspension of (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (12.71 g: 70 mmole) in dichloromethane (70 ml), triethylamine (10.7 ml: 77 mmole) is added dropwise under ice cooling in a nitrogen atmosphere. The mixture is stirred for 5 min. at room temperature. A solution of di-t-butyl dicarbonate (19.10 g: 87.5 mmole) in dichloromethane (72 ml) is added dropwise thereto, and the mixture is stirred for 45 minutes at room temperature to give (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (14.06 g). Yield: 82%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=9.6 Hz, 9H), 1.9 to 2.4(m, 3H), 3.4 to 3.7(m, 2H), 3.74 (s, 3H), 4.3 to 4.6(m, 2H).
79%
With 4-methyl-morpholine In tetrahydrofuran 1.) 1 h, 2.) 18 h;
79%
With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 20℃;
79.6%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;
64%
With triethylamine In dichloromethane at 20℃; for 5h;
244.2
To a stirred solution of V (3.0 g, 12.24 mmol) in DCM (30 mL) was added Et3N(1.85 g, 18.31 mmol) and Boc anhydride (2.92 g, 13.46 mmol). Stirring was continued at rt for 5 h after which the reaction was quenched with water. The organic layer was separated, dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, 100% ethyl acetate) to give 3' (3.2 g, 64%) as a white solid.
27%
With triethylamine In dichloromethane at 20℃; for 18h;
53.4 g
With triethylamine In dichloromethane at 0 - 5℃; for 4h;
17.7 g
With triethylamine In N,N-dimethyl-formamide at 55℃; for 1.5h;
3.7 g
With anhydrous sodium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 16h;
1.74 g
Stage #1: (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride With triethylamine In dichloromethane at 0℃; for 0.5h;
Stage #2: di-<i>tert</i>-butyl dicarbonate With N,N-dimethyl-4-aminopyridine In dichloromethane at 20℃; for 18h; Further stages.;
With triethylamine In dichloromethane at 0 - 20℃; for 2.33333h;
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 3h;
7.5
Example 7-5 1-tert-Butyl 2-methyl (2S, 4R)-4-hydroxy-1, 2- pyrrolidinedicarboxylate To a solution of methyl (2S, 4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride obtained in Example 7-4 (215g) in water/dioxane (800/500mL) with cooling on an ice bath, was added a solution of di-tert-butyl dicarbonate (271g) in dioxane (150mL) and 6N NaOH (400mL) dropwise. The reaction mixture was stirred at room temperature for 3hrs and quenched by adding with 1N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with hexane to give the target compound as a white powder (200g). 1H NMR (in CDC13). 8 1. 51-1.32 (9H, m), 2.39-1. 82 (2H, m), 3. 79-3. 38 (5H, m), 4.58-4. 31 (2H, m).
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 4h;
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 3h;
1-2 Preparation 1-2; 1-tert-Butyl 2-methyl (2S, 4R)-4-hydroxy-1, 2-pyrrolidinedicarboxylate
To a solution of methyl (2S, 4R)-4-HYDROXY-2-PYRROLIDINECARBOXYLATE hydrochloride obtained in Preparation 1-1 (215g) in water/dioxane (800/500ML) with cooling on an ice bath, was added a solution of di-tert-butyl dicarbonate (271g) in dioxane (150ML) and 6N NAOH (400mL) dropwise. The reaction mixture was stirred at room temperature for 3hrs and quenched by adding with 1N HC1. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl solution, dried over MGS04, and concentrated in vacuo. The resulting residue was triturated with n-hexane to give the target compound as a white powder (200G). 1H-NMR (IN CDCL3) : No. 1.51-1. 32 (9H, m), 2.39-1. 82 (2H, M), 3.79-3. 38 (5H, m), 4.58-4. 31 (2H, m).
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0℃; for 2.5h;
NaHCO3 (3.9 g, 27.7 mmol) was dissolved in a mixture solution of dioxane and water 1:1 (40 mL)and then 15 was add to the solution. The resultant mixture waskept stirring for 30 min at 0 oC followed by addition of PhCH2OCOCl (5.9 mL,41.5 mmol). The reaction mixture was allowed to stir at 0 oC for additional 2 h. The reaction solventwas evaporated under vacuum and then CH2Cl2 (30 mL) was added, washed with 1N HCl, driedover Na2SO4, filtered and concentrated under reducedpressure. The residue was purified by flash-chromatography on silica gel(Petroleum ether/ethyl acetate = 1:1) to afford 16 as a colorless viscous liquid (5.6 g, 95% yield).
79%
With sodium carbonate; In 1,4-dioxane; water; at 0℃; for 2.5h;
A solution of (2S, 4R) -methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (5.5 g, 30 mmol) in 1, 4-dioxane (17 mL) was cooled to 0 , and then a solution of sodium carbonate (3.5 g, 33 mmol) in H 2O (17 mL) was added in portions, after that, CbzCl (4.8 mL, 34 mmol) was added over 30 min. The obtaining reaction mixture was stirred at 0 for 2 hours. The mixture was concentrated in vacuo to remove 1, 4-dioxane, the residue was extracted with ethyl acetate (3 x 100 mL) . The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatograph (PE/EtOAc (V/V) = 1/1) to give the title compound as a colorless oil (6.7 g, 79%) .
79%
With sodium carbonate; In 1,4-dioxane; water; at 0℃; for 2.5h;
(2S,4R)-4-Hydroxypyrrole-2-carboxylic acid methyl ester hydrochloride (5.5 g, 30 mmol) The 1,4-dioxane (17 mL) solution was cooled to 0 C. Then sodium carbonate (3.5 g, 33 mmol) was added in portions. H2O (17mL) solution, Then add CbzCl (4.8 mL, 34 mmol), After 30 minutes, the drop is completed. The resulting reaction solution was stirred at 0 C for 2 hours. The reaction mixture was concentrated to dryness The residue was purified with EtOAc EtOAc m. The title compound was obtained as a colorless oil ( 6.7 g, yield: 79%).
72%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 3h;
Example 2: 1 -benzyl 2-methyl (2S,4R)-4-hvdroxy-l,2-pyrrolidinedicarboxylate Chlorobenzylformate (1.0 mL, 7.9 mmol) was added to a mixture of the compound prepared in Example 1 (1.2 g, 6.6 mmol), NaHC03 (4.0 g) and saturated aqueous NaHC03 (5.0 mL) in THF (20 mL) at 0 C. After stirring at room temperature for 3 h, tris(hydroxymethyl)aminomethane (1.4 g) was added and the reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts were dried and concentrated and purified by flash chromatography (silica gel, 40 g, 20-80% ethyl acetate/hexanes) to give the title compound (1.3 g, 72%) as a pale yellow oil. NMR (300 MHz, CD3OD, rotamers present) 6 7.35-7.29 (m, 5H), 5.18-4.97 (m, 2H), 4.47-4.39 (m, 2H), 3.71 (s, 1.5H), 3.62-3.51 (m, 3.5H), 2.30-2.25 (m, 1H), 2.09-2.00 (m, 1H).
72%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 3h;
Chlorobenzylformate (1.0 mL, 7.9 mmol) was added to a mixture of the compound prepared in Example 1 (1.2 g, 6.6 mmol), NaHCO3 (4.0 g) and saturated aqueous NaHCO3 (5.0 mL) in THF (20 mL) at 0 C. After stirring at room temperature for 3 h, tris(hydroxymethyl)aminomethane (1.4 g) was added and the reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts were dried and concentrated and purified by flash chromatography (silica gel, 40 g, 20-80% ethyl acetate/hexanes) to give the title compound (1.3 g, 72%) as a pale yellow oil. 1H NMR (300 MHz, CD3OD, rotamers present) delta 7.35-7.29 (m, 5H), 5.18-4.97 (m, 2H), 4.47-4.39 (m, 2H), 3.71 (s, 1.5H), 3.62-3.51 (m, 3.5H), 2.30-2.25 (m, 1H), 2.09-2.00 (m, 1H).
With triethylamine In dichloromethane for 10h; cooling;
93%
With triethylamine In dichloromethane at 0 - 20℃; for 16h;
75%
With dmap; triethylamine In 1,4-dioxane; water at 20℃; for 24h;
75%
With triethylamine In 1,4-dioxane; water at 20℃; for 24h;
2.93 g
With triethylamine In dichloromethane at 20℃; for 10h;
With triethylamine In dichloromethane at 0 - 20℃; for 12h;
2.2 5.1.2. (2S,4R)-Methyl 4-hydroxy-1-sulfonylpyrrolidine-2-carboxylate (3a-d)
General procedure: 9.1 g (50 mmol) trans-4-hydroxy-L-proline methylester hydrochloride(2) was dissolved in DCM with Et3N (15 ml, 106 mmol),and added with various sulfonyl chloride (55 mmol) at 0 C. Themixture was stirred at room temperature for 12 h, washed with1 M citric acid, saturated NaHCO3 solution and brine, and driedover Na2SO4. Evaporation of DCM gave birth to white solid material(3a-d).
L-trans-4-Hydroxyproline methyl ester hydrochloride (9.70 g, 54.0 mmol) was dissolved in dry THF (180 mL) and triethylamine (7.53 mL, 54.0 mmol). N-(Benzyloxycarbonyloxy)succinimide (13.5 g, 54.0 mmol) dissolved in THF (70 mL) was slowly added to the solution. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate and the organic layer was washed successively with water and brine. The organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (30% to 70% ethyl acetate/hexane) to provide 12.8 g (85%) of desired product as a colorless oil. LC/MS (M+H)+ m/z=280.0; 1H NMR (CDCl3) delta 7.33 (m, 5H), 5.00-5.25 (m, 2H), 4.52 (m, 2H), 3.69 (m, 2H), 3.56 and 3.78 (s, 3H), 2.05-2.40 (m, 2H).
85%
With triethylamine; In tetrahydrofuran; at 20℃;
Step A1 -Benzyl 2-Methyl (2S,4f?)-4-hydroxypyrrolidine-1 ,2-dicarboxylate. L-trans-4- Hydroxyproline methyl ester hydrochloride (9.70 g, 54.0 mmol) was dissolved in dry THF (180 ml.) and triethylamine (7.53 ml_, 54.0 mmol). N-(Benzyloxycarbonyloxy)succinimide (13.5 g, 54.0 mmoles) dissolved in THF (70 ml.) was slowly added to the solution. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate and the organic layer was washed successively with water and brine. The organic extracts were dried over Na2S04, filtered, and concentrated. The residue was chromatographed on silica gel (30% to 70% ethyl acetate/hexane) to provide 12.8 g (85%) of desired product as a colorless oil. LC/MS (M+H)+ m/z = 280.0; 1H NMR (CDCI3) 57.33 (m, 5H), 5.00-5.25 (m, 2H), 4.52 (m, 2H), 3.69 (m, 2H), 3.56 and 3.78 (s, 3H), 2.05-2.40 (m, 2H).
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids) (3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50 (m, 8H), 1.46 (s, 9H), 1.57 (m, 1H), 1.72 (m, 1H) 2.08 (m, 2H), 2.28 (m, 1H), 3.72 (s, 3H,) 3.75-3.87 (m, 2H), 4.36 (m, 1H), 4.51 (bs, 1H), 4.57 (t, J=8.2 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 5.01 (m, 1H), 5.83 (m, 1H); MS m/z 399 (M++1).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;Inert atmosphere;
Step 1: Preparation of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmoL) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmoL), N-methyl morpholine (4.25 mL, 38.6 mmoL), and HATU (5.37 g, 14.1 mmoL). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50(m, 8H), 1.46 (s, 9H), 1.57 (m, 1H), 1.72 (m, 1H) 2.08 (m, 2H), 2.28 (m, 1H), 3.72 (s, 3H,) 3.75-3.87 (m, 2H), 4.36 (m, 1H), 4.51 (bs, 1H), 4.57 (t, J=8.2 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 5.01 (m, 1H), 5.83 (m, 1H). MS m/z 399 (M++1).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
Step 1: Preparation of l-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)- hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester; HOA solution of 2(,S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(5)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under nu2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (-100%) of l-(2(5)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy- pyrrolidine-2(5')-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50(m, 8 H), 1.46 (s, 9 H), 1.57 (m, 1 H), 1.72 (m, 1 H) 2.08 (m, 2 H), 2.28 (m, 1 H), 3.72 (s, 3 H,) 3.75-3.87 (m, 2 H), 4.36 (m, 1 H), 4.51 (bs, 1 H), 4.57 (t, J=8.2 Hz, 1 H), 4.95 (d, J=10.4 Hz, 1 H), 5.01 (m, 1 H), 5.83 (m, 1 H); MS m/z 399 (M++l).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (~100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50(m, 8 H), 1.46 (s, 9 H), 1.57 (m, 1 H), 1.72 (m, 1 H) 2.08 (m, 2 H), 2.28 (m, 1 H), 3.72 (s, 3 H,) 3.75-3.87 (m, 2 H), 4.36 (m, 1 H), 4.51 (bs, 1 H), 4.57 (t, J=8.2 Hz, 1 H), 4.95 (d, J=10.4 Hz, 1 H), 5.01 (m, 1 H), 5.83 (m, 1 H); MS H); MS m/z 399 (M++1).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
Step 1: Preparation of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (~100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50(m, 8 H), 1.46 (s, 9 H), 1.57 (m, 1 H), 1.72 (m, 1 H) 2.08 (m, 2 H), 2.28 (m, 1 H), 3.72 (s, 3 H,) 3.75-3.87 (m, 2 H), 4.36 (m, 1 H), 4.51 (bs, 1 H), 4.57 (t, J=8.2 Hz, 1 H), 4.95 (d, J=10.4 Hz, 1 H), 5.01 (m, 1 H), 5.83 (m, 1 H); MS m/z 399 (M++1).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids) (3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50 (m, 8H), 1.46 (s, 9H), 1.57 (m, 1H), 1.72 (m, 1H) 2.08 (m, 2H), 2.28 (m, 1H), 3.72 (s, 3H) 3.75-3.87 (m, 2H), 4.36 (m, 1H), 4.51 (bs, 1H), 4.57 (t, J=8.2 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 5.01 (m, 1H), 5.83 (m, 1H); MS m/z 399 (M++1).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50 (m, 8H), 1.46 (s, 9H), 1.57 (m, 1H), 1.72 (m, 1H) 2.08 (m, 2H), 2.28 (m, 1H), 3.72 (s, 3H,) 3.75-3.87 (m, 2H), 4.36 (m, 1H), 4.51 (bs, 1H), 4.57 (t, J=8.2 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 5.01 (m, 1H), 5.83 (m, 1H); MS m/z 399 (M++1).
~ 100%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 72h;
A solution of 2(5)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(5)-carboxylic acid methyl ester hydrochloride (2.15 g, <n="66"/>11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under nu2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCtheta3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (-100%) of l-(2(5)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy- pyrrolidine-2(5')-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) delta 1.33-1.50(m, 8 H), 1.46 (s, 9 H), 1.57 (m, 1 H), 1.72 (m, 1 H) 2.08 (m, 2 H), 2.28 (m, 1 H), 3.72 (s, 3 H,) 3.75-3.87 (m, 2 H), 4.36 (m, 1 H), 4.51 (bs, 1 H), 4.57 (t, J=8.2 Hz, 1 H), 4.95 (d, J=10.4 Hz, 1 H), 5.01 (m, 1 H), 5.83 (m, 1 H); MS m/z 399 (M++l).
Stage #1: L-4-hydroxyproline methyl ester hydrochloride With triethylamine In 1,2-dichloro-ethane
Stage #2: n-hexadecylaldehyde With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Inert atmosphere;
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 120℃; for 0.333333h;Irradiation with microwave;
trans-4-Hydroxy-L-proline methyl ester hydrochloride salt (0.272 g; 1.50 mmol), 5,6- dichloronicotinonitrile (Bionet, 0.173 g; 1.00 mmol) and DIEA (0.523 ml 3.00 mmol) were combined in a microwave vial with MeCN (4 ml_). The vial was heated under microwave irradiation at 120 0C for 20 minutes. The reaction mixture was diluted with DCM and water and then passed through a hydrophobic frit. The solvent was evaporated to afford the title compound (0.275 g; 98%). 1H NMR (CDCI3, 400 MHz) delta 8.25 (1 H, d, J = 1.6 Hz), 7.66 (1 H, d, J = 1.6 Hz), 4.95 (1 H, t, J = 8 Hz), 4.65 (1 H, br s), 4.29-4.25 (1 H, dd, J = 1 1.6, 4.4 Hz), 4.02- 3.99 (1 H, m), 3.72 (3H, s), 2.40-2.35 (1 H, m), 2.17-2.11 (1 H, m), 1.49 (1 H, br s).
Example 1 : methyl ("2S,4R)-4-hvdroxy-2-pyrrolidinecarboxylate hydrochloride To a solution of (2S,4R)- 4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride (1.0 g, 7.6 mmol) in methanol (25 mL) at 0 C was added thionyl chloride (0.83 mL, 1 1.4 mmol). The reaction was warmed to room temperature and heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness to give the title compound (1.2 g, 92%) as a white solid. lH NMR (300 MHz, DMSO-<) delta 9.99 (br. s, 2H), 5.58 (br. s, 1H), 4.49-4.41 (m, 2H), 3.75 (s, 3H), 3.38 (dd, 1H), 3.07 (d, 1H), 2.23-2.04 (m, 2H)
92%
With thionyl chloride; at 0℃;Reflux;
To a solution of <strong>[32968-78-8](2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride</strong> (1.0 g, 7.6 mmol) in methanol (25 mL) at 0 C. was added thionyl chloride (0.83 mL, 11.4 mmol). The reaction was warmed to room temperature and heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness to give the title compound (1.2 g, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 9.99 (br. s, 2H), 5.58 (br. s, 1H), 4.49-4.41 (m, 2H), 3.75 (s, 3H), 3.38 (dd, 1H), 3.07 (d, 1H), 2.23-2.04 (m, 2H).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 13h;
Synthesis of Cyclo(trans-4-hydroxy-L-Proline-L-Leucine) (4).
To a stirred solution of trans-4-hydroxy-L-prolinemethyl ester hydrochloride (216 mg, 1.19 mM) and triethylamine (200 mL, 1.43 mM) in CH2Cl2 (6.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (389 mg, 2.03 mM) and N-(tert-butoxycarbonyl)-L-leucine (128 mg, 1.20 mM) at 0 °C. The mixture was stirred at 0 °C for 3 h and then at room temperature for 10 h. CH2Cl2 and brine were added and the organic layer was washed with 0.2 M HCl, saturated sodium carbonate (NaHCO3) and brine. The separated CH2Cl2 layer was dried over anhydrous sodium sulphate (Na2SO4)and concentrated to give a crude product. This was subjected to CC with increasing polarities of CHCl3-MeOH to give the protected dipeptide (290 mg, 81%, eluted with CHCl3-MeOH 10:1) as colorless oil. 1H-NMR(CDCl3, 400 MHz) d0.95 (3H, d, J = 6.4 Hz), 0.98 (3H, d,J = 6.4 Hz), 1.41 (9H, s), 1.46 (1H,m), 1.55 (1H, m), 1.75 (1H, m), 2.00 (1H, m), 2.35 (1H, m), 3.19 (1H, br s, OH), 3.68 (1H, dd, J = 11.0, 3.6 Hz), 3.73 (3H, s, OCH3), 4.02 (1H, br d, J= 11.0 Hz), 4.41 (1H, m), 4.54 (1H, br s, NH), 4.67 (1H, t, J = 8.4Hz), 5.17 (1H, d, J = 8.4 Hz).
78%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2h;
45%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 16h;
2,5-Dioxorhoyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (2.5 g, 9.64 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate, HCl salt (2.10 g, 11.6 mmol) and triethylamine (4.0 mL, 28.9 mmol) in acetonitrile (20 mL) and stirred at room temperature overnight. The reaction was quenched with water and ether. The organic layer was washed with 1.0 M HCl (2x) followed by brine. It was then dried with MgSO4, filtered and concentrated to afford crude (2S,4R)-2-methyl l-(2- (trimethylsilyl)ethyl) 4-hydroxypyrrolidine-l ,2-dicarboxylate which was used directly in the next step.
tert-butyl 4-((2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-yl)-3-methylpiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; N-ethyl-N,N-diisopropylamine; at 20℃; for 16h;
General procedure: To a solution of 1-t-Butoxycarbonyl-3-methyl-4-piperidone (2.83 g, 13.3 mmol) in dichloroethane (30 mL) at room temperature was added piperidine (1.58 mL, 16 mmol), AcOH (1.14 mL, 20 mmol), and sodium triacetoxyborohydride (4.24 g, 20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured onto saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give the title compound as a mixture of diastereomers.
Stage #1: methyl (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylate hydrochloride With chloro-trimethyl-silane; triethylamine In methanol; dichloromethane at 0 - 20℃; for 2h;
Stage #2: 9-bromo-9-phenyl-9H-fluorene With lead(II) nitrate In methanol; dichloromethane at 20℃; for 96h;
Starting Material, Ketone 6
A solution of methyl (2S, 4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (3.0 g, 16.5 mmol) and chlorotrimethylsilane (5.2 mL, 41.3 mmol) in DCM (40 mL) at 0°C was treated with TEA under stirring (8.0 mL, 57.8 mmol) and allowed to reach r.t. The mixture was stirred at reflux for 1 h, cooled to 0°C,treated with MeOH (1.0 mL) in DCM (4.5 mL), allowed to warm to r.t. for 1 h and then treated with 9- bromo-9-phenylfluorene (6.9 g, 21.45 mmol) and Pb(N03)2 (4.9 g, 14.9 mmol). The mixture was stirred at r.t. for 96 h, filtered and evaporated. The remaining solid was dissolved in MeOH (54 mL) and citric acid (5.5 g) was added. The solution was vigorously stirred for 1 additional hour, solvent was evaporated under reduce pressure. EtOAc (50 mL) was added and the mixture was carefully washed with saturated NaHCO3solution.The organic phase was dried over anhydrous Mg504, then solvent was removed under reduced pressure. The cmde product was purified by flash chromatography (Heptane EtOAc 1:1) to give the Pf protected compound (5.7 g, 90%) as a white foam. ‘H NMR (400 MHz, CDC13) : 1.79 (ddd, 1H, J = 5.6, 8.9, 13.0 Hz), 1.98 (dt, 1H, J = 5.6, 12.6 Hz), 2.92 (dd, 1H, J = 4.8, 9.9 Hz), 3.24 (s, 3H), 3.29 (dd, 1H, J =5.3, 8.8 Hz), 3.57 (dd, 1H, J = 5.3, 10.0 Hz), 4.43-4.58 (m, 1H), 7.16 (td, 1H, J = 1.1, 7.5 Hz), 7.21-7.35 (m, 6H), 7.43 (td, 1H, J = 1.1, 7.5 Hz), 7.50-7.59 (m, 3 H), 7.65 (dd, 1H, J = 0.7, 6.8 Hz), 7.74 (dd, 1H, J =0.8, 6.8 Hz); 13CNMR(100MHz, CDC13) : 40.0, 51.3, 56.8, 59.3, 70.4, 76.1, 119.8, 120.1, 126.4, 127.1,127.2, 127.3 (x2), 127.4, 127.6, 128.3 (x2), 128.4, 128.8, 139.9, 141.5, 142.7, 146.1, 147.2, 175.8.
Stage #1: N-tert-butyloxycarbonyl-L-tert-leucine; L-4-hydroxyproline methyl ester hydrochloride With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;
Stage #2: With water; lithium hydroxide In tetrahydrofuran
1; 7
To a solution of the s5 (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (2.32 g, 10 mmol) and S6 methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrogen chloride (1.1 equiv) in DMF was added DIPEA (6 equiv) and HATU (1.2 equiv). Then the mixture was stirred at r.t. overnight. The mixture was quenched with water and extracted with EA three times. The organic layer was washed with 5% (v/v) citric acid, NaHCOs solution, brine and dried with Na2SC>4. The product was obtained by removing the solvent for the next step without further purification. Then, s7 can be obtained through the hydrolysis by LiOH in THF/H2O (85 % yield).
Stage #1: N-phthaloyl L-valine With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere;
Stage #2: L-4-hydroxyproline methyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Inert atmosphere;
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