* 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.
Stage #1: for 6 h; Reflux Stage #2: With hydrogenchloride In water for 3 h; Reflux
A mixture of (2S,4R)-4-hydroxypyrrolidine-2-carboxylicacid(50 mmol, 6550 mg) and Ac2O (250 mmol, 23.5 mL) in AcOH (100 mL) wasstirred at reflux for 6 h. The resulting mixture was concentrated to give thecrude intermediate. The solution of this crude intermediate in 2 N HCl (50 mL)was stirred at reflux for 3 h. Then activated charcoal (1 g) was added, the hotmixture was ltered immediately through a Celite layer. The filtrate was concentrated in vacuo to give the crude intermediate.The crude intermediate was dissolved in acetone and filtered. The residue was washed twice with ether anddried in vacuo to give 17 as a white solid (7.54 g, 90percent). 1H NMR (400 MHz, D2O) δ 4.57-4.37(m, 2H), 3.42-3.21 (m, 2H), 2.46-2.31 (m, 1H), 2.31-2.20 (m, 1H). 13C NMR (100 MHz, D2O) δ 172.3, 68.9, 58.4, 53.3, 36.8.
75%
Stage #1: at 50 - 90℃; for 5.5 h; Stage #2: for 3 h; Heating / reflux
PREPARATION 25 (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid, hydrochloride To a mixture of acetic anhydride (408 g) and acetic acid (1.2 L) at 50° C. add trans-4-hydroxy-L-proline (0.36 mol, 94 g) in a single portion. Heat the reaction mixture for 5.5 h at 90° C. and then concentrate it. Dissolve the residue in 2 N hydrochloric acid and reflux for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum until white needles form. Filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (90.0 g, 75percent). [α]D20+10.0 (c=1.0 in methanol). 1H NMR (400 MHz, D2O), δ 2.34-2.39 (m, 1H), 2.45-2.53 (m, 1H), 3.38 (dd, 1H), 3.45 (d, 1H), 4.50 (dd, 1H), 4.58 (br s, 1H).
65%
Stage #1: With acetic anhydride In acetic acid at 20 - 90℃; Stage #2: With hydrogenchloride In water for 3 h; Reflux
Following a procedure essentially as described in Tetrahedron: Asymmetry, 14, (2003) 3141-3152, to a mixture of acetic anhydride (1.437 kg, 5.65 eq) and acetic acid (4.225 L) at 500C add ?raws-4-hydroxy-L-proline (331 g, 2.49 mol) in portions over 30 min. Heat the reaction mixture for 5.5 h at 90 0C then allow to cool to room temperature. Stir the reaction at room temperature overnight and then concentrate. Dissolve the residue in 2 N hydrochloric acid (4.57 L) and reflux for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum at 70 0C to approximately 700 mL. Allow the material to cool to room temperature and let sit overnight. Dilute the resulting slurry with ether (IL), filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (340 g). Dissolve the solid in hot ethanol (2.5 L), cool, stir slowly at 35 0C, and add ether (2.5 L) slowly in portions over one hour. Stir for 2 h, filter the resulting white solid, and dry overnight in a vacuum oven to obtain the title compound (270.6 g, 65percent). [α]D20 + 12.0 (c = 1.0 in methanol). 1H NMR (400 MHz, D2O), δ 2.34-2.39 (m, IH), 2.45-2.53 (m, IH), 3.38 (dd, IH), 3.45 (d, IH), 4.50 (dd, IH), 4.58 (br s, IH).
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 2, p. 513 - 519
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2434 - 2437
[3] Journal of the American Chemical Society, 2013, vol. 135, # 11, p. 4333 - 4363
[4] Patent: US2009/163472, 2009, A1, . Location in patent: Page/Page column 21
[5] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1132 - 1139
[6] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1620 - 1629
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4099 - 4101
[8] Patent: WO2010/104721, 2010, A1, . Location in patent: Page/Page column 21
[9] Journal of Organic Chemistry, 1981, vol. 46, # 14, p. 2954 - 2960
[10] Journal of Organic Chemistry, 1994, vol. 59, # 13, p. 3616 - 3625
[11] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 4, p. 539 - 546
[12] Patent: WO2014/32, 2014, A1,
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 21 - 26
4
[ 24424-99-5 ]
[ 77449-94-6 ]
[ 135042-12-5 ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium hydroxide In tetrahydrofuran; water at 20℃;
cis-4-Hydroxy-l-proline hydrochloride 14 (0.50 g, 3.0 mmol) was dissolved in 6 mL of THF/H2O (2:1) and then treated with 10percent aqueous NaOH (1.25 mL) followed by the addition of di-tert-butyldicarbonate (0.95 g, 4.42 mmol). The reaction mixture was stirred at room temperature overnight and then THF was removed by rotavapor. The residue was adjusted to pH 2 by the addition of 10percent aqueous KHSO4. The acidic solution was extracted several times with ethyl acetate. The combined organic extracts were washed with H2O and brine, and dried over anhydrous Na2SO4. The solvent was removed by a rotary evaporator to afford compound 15 as a syrup (542 mg, 78percent), which was used without purification for the next step. [α]D25 = 15.3 (c 1.02, MeOH). IR (film): ν = 3462, 2976, 2934, 1740, 1639 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.22 (br s, 1H), 5.11-5.09 (m, 2H), 4.94-4.93 (m, 1H), 4.40 (s, 1H), 3.64-3.62 (m, 1H), 3.49-3.44 (m, 2H), 2.27-1.90 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 172.47, 151.74, 75.81, 67.15, 55.24, 52.27, 35.97, 25.63 ppm. HRMS (ESI): m/z [M+H]+ calcd for C10H18NO5: 232.1185; found: 232.1171.
70.1%
With sodium hydroxide In tetrahydrofuran; water at 20℃;
At room temperature,A solution of sodium hydroxide (4.73 g, 118.14 mmol) in water (41 mL) was added dropwise to a solution of 3A (9.0 g, 53.70 mmol) in tetrahydrofuran (90 mL)A mixture of di-tricarbonate (17.58 g, 80.55 mmol)Was added to the reaction solution, and the reaction was stirred at room temperature overnight.(2.15 g, 53.70 mmol), di-n-tri-n-butyl ester (9.38 g, 42.96 mmol) was added and stirring was continued at room temperature for 5 hours.Tetrahydrofuran was removed by distillation under reduced pressure, and the impurities were extracted with ethyl acetate (50 mL x 2).The aqueous phase was adjusted to pH 3 with 3 mol / L hydrochloric acid solution and extracted with ethyl acetate (50 mL x 3)The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give colorless liquid 15a (8.7 g, yield 70.1percent).
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 681 - 694
[2] Journal of the American Chemical Society, 2013, vol. 135, # 11, p. 4333 - 4363
[3] Tetrahedron Asymmetry, 2015, vol. 26, # 20, p. 1156 - 1166
[4] Patent: TW2017/8221, 2017, A, . Location in patent: Page/Page column 92; 93
5
[ 67-56-1 ]
[ 77449-94-6 ]
[ 114676-59-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0 - 75℃; for 4.5 h;
Cis-4-hydroxy-D-proline hydrochloride 3A (12.8 g, 76.38 mmol) was dissolved in anhydrous methanol (120 mL) at room temperature,Cooled to 0 , dichloro sulfoxide (10.27g, 86.31mmol),Heated to 75 ° C, refluxed for 4.5 hours, and allowed to react overnight at room temperature.The solvent was taken off in vacuo to give a white solid 3B (13.83 g, yield 100percent).
Reference：
[1] Patent: TW2017/8221, 2017, A, . Location in patent: Page/Page column 41
[2] Journal of Organic Chemistry, 2009, vol. 74, # 2, p. 513 - 519
[3] Patent: US2009/163472, 2009, A1, . Location in patent: Page/Page column 21
[4] Patent: WO2014/32, 2014, A1, . Location in patent: Page/Page column 64
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2434 - 2437
A mixture of (2S,4R)-4-hydroxypyrrolidine-2-carboxylicacid(50 mmol, 6550 mg) and Ac2O (250 mmol, 23.5 mL) in AcOH (100 mL) wasstirred at reflux for 6 h. The resulting mixture was concentrated to give thecrude intermediate. The solution of this crude intermediate in 2 N HCl (50 mL)was stirred at reflux for 3 h. Then activated charcoal (1 g) was added, the hotmixture was ltered immediately through a Celite layer. The filtrate was concentrated in vacuo to give the crude intermediate.The crude intermediate was dissolved in acetone and filtered. The residue was washed twice with ether anddried in vacuo to give 17 as a white solid (7.54 g, 90%). 1H NMR (400 MHz, D2O) delta 4.57-4.37(m, 2H), 3.42-3.21 (m, 2H), 2.46-2.31 (m, 1H), 2.31-2.20 (m, 1H). 13C NMR (100 MHz, D2O) delta 172.3, 68.9, 58.4, 53.3, 36.8.
75%
PREPARATION 25 (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid, hydrochloride To a mixture of acetic anhydride (408 g) and acetic acid (1.2 L) at 50 C. add trans-4-hydroxy-L-proline (0.36 mol, 94 g) in a single portion. Heat the reaction mixture for 5.5 h at 90 C. and then concentrate it. Dissolve the residue in 2 N hydrochloric acid and reflux for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum until white needles form. Filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (90.0 g, 75%). [alpha]D20+10.0 (c=1.0 in methanol). 1H NMR (400 MHz, D2O), delta 2.34-2.39 (m, 1H), 2.45-2.53 (m, 1H), 3.38 (dd, 1H), 3.45 (d, 1H), 4.50 (dd, 1H), 4.58 (br s, 1H).
65%
Following a procedure essentially as described in Tetrahedron: Asymmetry, 14, (2003) 3141-3152, to a mixture of acetic anhydride (1.437 kg, 5.65 eq) and acetic acid (4.225 L) at 500C add ?raws-4-hydroxy-L-proline (331 g, 2.49 mol) in portions over 30 min. Heat the reaction mixture for 5.5 h at 90 0C then allow to cool to room temperature. Stir the reaction at room temperature overnight and then concentrate. Dissolve the residue in 2 N hydrochloric acid (4.57 L) and reflux for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum at 70 0C to approximately 700 mL. Allow the material to cool to room temperature and let sit overnight. Dilute the resulting slurry with ether (IL), filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (340 g). Dissolve the solid in hot ethanol (2.5 L), cool, stir slowly at 35 0C, and add ether (2.5 L) slowly in portions over one hour. Stir for 2 h, filter the resulting white solid, and dry overnight in a vacuum oven to obtain the title compound (270.6 g, 65%). [alpha]D20 + 12.0 (c = 1.0 in methanol). 1H NMR (400 MHz, D2O), delta 2.34-2.39 (m, IH), 2.45-2.53 (m, IH), 3.38 (dd, IH), 3.45 (d, IH), 4.50 (dd, IH), 4.58 (br s, IH).
N-<(2R,4S)-4-<1-(Benzyloxycarbonyl)-2-(tert-butoxycarbonyl)pyrrolidinyl>>-N-<(2S,4S)-4-<2-(tert-butoxycarbonyl)-1-<(tert-butoxycarbonyl)methyl>pyrrolidinyl>>amine[ No CAS ]
N-<(2R,4R)-4-<1-(Benzyloxycarbonyl)-2-(tert-butoxycarbonyl)pyrrolidinyl>>-N-<(2S,4S)-4-<2-(tert-butoxycarbonyl)-1-<(tert-butoxycarbonyl)methyl>pyrrolidinyl>>amine[ No CAS ]
Cis-4-hydroxy-D-proline hydrochloride 3A (12.8 g, 76.38 mmol) was dissolved in anhydrous methanol (120 mL) at room temperature,Cooled to 0 , dichloro sulfoxide (10.27g, 86.31mmol),Heated to 75 C, refluxed for 4.5 hours, and allowed to react overnight at room temperature.The solvent was taken off in vacuo to give a white solid 3B (13.83 g, yield 100%).
With thionyl chloride; at 0 - 20℃; for 6h;
PREPARATION 26 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Add thionyl chloride (1.81 mol, 213.8 g, 1.5 eq) drop wise to a solution of (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid hydrochloride (1.19 mol, 200 g) in dry methanol (2 L) at 0 C. under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 6 h. Concentrate the reaction mixture under reduced pressure to obtain the corresponding methyl ester hydrochloride.
With thionyl chloride; for 3h;Reflux;
To a solution of A (16.56 g, 98.8 mmol) in CH3OH (150 mL) was added SOCI2 (35.26 g, 296.4 mmol) at room temperature and the mixture was heated to reflux for 3 h. The solvent was removed in vacuo and the off-white solid obtained was used in next step without further purification.
With thionyl chloride; at 0 - 60℃; for 4h;Inert atmosphere;
To a solution of17 (20 mmol, 3.36 g) in anhydrousMeOH (40 mL) was added dropwise thionyl chloride (24 mmol, 1.74 mL) at 0 Cunder N2 atmosphere. The mixture was stirred at 60 C for 4 h. After completion of thereaction (monitored by TLC), the resulting mixture was concentrated in vacuo to give the crude product 18 as a white solid, the crude productwas used directly without further purification. 1H NMR (400 MHz, D2O) delta4.66-4.61 (m, 2H), 3.82 (s, 3H), 3.47-3.40 (m, 2H), 2.52-2.33 (m, 2H). 13C NMR (100 MHz, D2O) delta 170.7,68.9, 58.4, 53.8, 53.4, 36.7.
With thionyl chloride; at 0 - 80℃; for 3.5h;
<strong>[77449-94-6]cis-4-Hydroxy-D-proline hydrochloride</strong> (200 g, 1.19 mol) was dissolved in MeOH (2 L) in four-neck flask (equipped with mechanical stirrer, reflux condenser, dropping funnel and septum) and was cooled to 0 C. Thionyl chloride (95.8 mL, 1.31 mol) was added dropwise to the reaction mixture for 1.5 h (maintain a temperature 0 C.). The reaction mixture was warmed to room temperature for 1 h and heated to reflux for 1 h. The reaction mixture was cooled to room temperature (overnight), transferred to round-bottom-flask and concentrated. The gel-like residue was evaporated with CHCl3 (3*1 L) and dried under high vacuum for 1 h at 50 C. (water bath). The residue was crumbled with spatula, suspended in Et2O (1 L) and placed in ultrasound bath for 40 minutes (2*20 minutes). The white solid was filtered, washed with Et2O (2*0.5 L) and dried under high vacuum for 4 h at 50 C. (water bath) to give 234.6 g of the crude product that was used in the next step without further purification. ESI+MS m/z=146 (M+1)+; 1H NMR (700 MHz, D2O) delta 4.75 (d, J=3.1 Hz, 1H), 4.74 (d, J=3.0 Hz, 1H), 4.70 (qt, J=4.2, 1.6 Hz, 2H), 3.92 (s, 7H), 3.57-3.50 (m, 5H), 2.59 (ddd, J=14.4, 10.1, 4.2 Hz, 3H), 2.51-2.47 (m, 2H).
With thionyl chloride; at 20℃; for 6h;Inert atmosphere;
Add thionyl chloride (233 mL, 3.10 mol) drop wise to a solution of (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid hydrochloride (355 g, 2.12 mol) in dry methanol (3.5 L) at 0 0C under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 6 h. Concentrate the reaction mixture under reduced pressure to obtain the corresponding methyl ester hydrochloride as a waxy solid. Suspend the solid in dry dichloromethane (3.5 L) at 00C and add triethylamine (640 mL, 4.66 mol) cautiously over 30 min and stir for an additional 30 min. Add N,N-dimethylaminopyridine (39 g, 0.32 mol) and di- tert-butyl dicarbonate (500 g, 2.25 mol) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Extract the solution with water (4 L), saturated sodium bicarbonate (4 L), and brine (4 L). Treat the organic layer with ethylenediamine (8 mL), stir for 15 min, and back-extract with 10% aqueous citric acid (4 L). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain a yellow oil (484 g), which solidifies overnight. Dissolve in methyl t-butyl ether (1 L) and concentrate to low volume. Add hexanes (2 L) and allow the mixture to stand for one hour. Filter the white solids and wash with hexanes. Dry the white solid (20 mm Hg/60C) overnight to obtain the title compound (354 g, 68%). [alpha]D20 + 56.3 (c = 1.0 in methanol). 1H NMR (400 MHz, CDCl3) delta 1.43 (s, 9H), 1.46 (s, 9 H), 2.05-2.10 (m, 2H), 2.26-2.35 (m, 2H), 3.48-3.56 (m, 2H), 3.58-3.61 (m, IH), 3.64-3.70 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 4.27-4.29 (m, IH), 4.34-4.38 (m, 2H). X- 18487
With sodium hydroxide; In tetrahydrofuran; water; at 20℃;
cis-4-Hydroxy-l-proline hydrochloride 14 (0.50 g, 3.0 mmol) was dissolved in 6 mL of THF/H2O (2:1) and then treated with 10% aqueous NaOH (1.25 mL) followed by the addition of di-tert-butyldicarbonate (0.95 g, 4.42 mmol). The reaction mixture was stirred at room temperature overnight and then THF was removed by rotavapor. The residue was adjusted to pH 2 by the addition of 10% aqueous KHSO4. The acidic solution was extracted several times with ethyl acetate. The combined organic extracts were washed with H2O and brine, and dried over anhydrous Na2SO4. The solvent was removed by a rotary evaporator to afford compound 15 as a syrup (542 mg, 78%), which was used without purification for the next step. [alpha]D25 = 15.3 (c 1.02, MeOH). IR (film): nu = 3462, 2976, 2934, 1740, 1639 cm-1. 1H NMR (400 MHz, CDCl3) delta 7.22 (br s, 1H), 5.11-5.09 (m, 2H), 4.94-4.93 (m, 1H), 4.40 (s, 1H), 3.64-3.62 (m, 1H), 3.49-3.44 (m, 2H), 2.27-1.90 (s, 9H). 13C NMR (100 MHz, CDCl3): delta 172.47, 151.74, 75.81, 67.15, 55.24, 52.27, 35.97, 25.63 ppm. HRMS (ESI): m/z [M+H]+ calcd for C10H18NO5: 232.1185; found: 232.1171.
70.1%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃;
At room temperature,A solution of sodium hydroxide (4.73 g, 118.14 mmol) in water (41 mL) was added dropwise to a solution of 3A (9.0 g, 53.70 mmol) in tetrahydrofuran (90 mL)A mixture of di-tricarbonate (17.58 g, 80.55 mmol)Was added to the reaction solution, and the reaction was stirred at room temperature overnight.(2.15 g, 53.70 mmol), di-n-tri-n-butyl ester (9.38 g, 42.96 mmol) was added and stirring was continued at room temperature for 5 hours.Tetrahydrofuran was removed by distillation under reduced pressure, and the impurities were extracted with ethyl acetate (50 mL x 2).The aqueous phase was adjusted to pH 3 with 3 mol / L hydrochloric acid solution and extracted with ethyl acetate (50 mL x 3)The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give colorless liquid 15a (8.7 g, yield 70.1%).
The mixture of B (14 g, 90.3 mmol) in 2N HCI (160 mL) was stirred overnight at 100 C , LCMS showed the reaction was complete, the solvent was removed in vacuo and the residue was recrystallized in EtOAc to give the desired product as a white solid. LC- S : 205.1 ([M+1]+ ).
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