| 76% |
With sodium hydroxide In acetone at 20℃; for 3h; |
|
| 75% |
Stage #1: D-Prolin With sodium hydroxide at 5℃;
Stage #2: Methacryloyl chloride With sodium hydroxide In water; acetone at 5 - 20℃; |
2.2. (R)-1-Methacryloylpyrrolidine-2-carboxylic acid (2)
d-Proline (1) (11.51 g, 0.10 mol) was dissolved in 2 N NaOH (60 mL) and cooled in an ice bath, and resulting alkaline solution was diluted with acetone (60 mL). An acetone solution (60 mL) of methacryloyl chloride (15.68 g, 0.15 mol) and 2 N NaOH (80 mL) were simultaneously added over 50 min to the aqueous solution of d-proline with stirring in an ice bath. After the stirring was continued for 3 h at room temperature (RT), the mixture was evaporated in vacuo at 40 °C to remove acetone. The residual solution was washed with ether and acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and extracted with EtOAc (3 × 120 mL). The combined EtOAc extracts were dried over Na2SO4, concentrated by evaporation in vacuo, mixed with hexanes (with about 1:1 ratio), and further concentrated until the beginning of crystallization to give 2 (13.66 g, 75%) as a white solid, Rf = 0.38 (7% MeOH/CH2Cl2), m.p. 102-103 °C. 1H NMR (DMSO-d6) δ: 1.78 (s, 3H, CH3), 1.80-1.94 (m, 3H, aliphatic CH2 and CH), 2.18-2.29 (m, 1H, aliphatic CH), 3.40-3.56 (m, 2H, aliphatic CH2), 4.23-4.47 (2q, J = 4.0 Hz, 1H, tertiary CH), 5.04, 5.16 and 5.29 (3s, 2H, vinyl CH2), 12.52 (s, 1H, COOH). MS (ESI): 184 ([M+H]+, 100%). |
| 73.1% |
With sodium hydroxide In water; acetone at 0 - 20℃; for 3h; |
|
| 68% |
With sodium hydroxide In water; acetone at 0 - 20℃; for 3.66667h; |
1 Synthetic Procedures
(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid (R-129). D-Proline (R-128, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloly chloride 127 (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (CO), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D26+80.80° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
Stage #1: D-Prolin; Methacryloyl chloride With sodium hydroxide In water; acetone at 10 - 20℃; for 3.66667h;
Stage #2: With hydrogenchloride In water |
1.1
Step 1: Synthesis of (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid (Precursor Compound A); D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11° C. during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally I H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) 8 for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (CO), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61. |
| 68% |
Stage #1: D-Prolin; Methacryloyl chloride With sodium hydroxide In water; acetone at 0 - 20℃; for 3.66667h;
Stage #2: With hydrogenchloride In water |
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloly chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-110C during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45 0C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 0C (lit. [214] mp 102.5-103.5 0C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally IH for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (IH, CH), 1.97- 1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm"1; [α]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H7.19, N 7.61. |
| 68% |
Stage #1: D-Prolin; Methacryloyl chloride With sodium hydroxide In water; acetone at 0 - 20℃; for 3.66667h;
Stage #2: With hydrogenchloride In water; acetone |
14
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-110C during the addition of the metacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45 0C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 niL x 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 0C (lit. [214] mp 102.5-103.5 0C); the NMR spectrum of this compound demonstrated the existence of two rotamers of Hie title compound. 1H NMR (300 MHz, DMSOd6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally IH for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (IH, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSOd6) 8 for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]026 +80.8° (c = 1, MeOH); Anal. Calcd. for C9Hi3NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
Stage #1: D-Prolin; Methacryloyl chloride With sodium hydroxide In water; acetone at 0 - 20℃; for 4.66667h;
Stage #2: With hydrogenchloride In water |
1; I; III; V; VII
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloly chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D- proline in an ice bath. The pH of the mixture was kept at 10-1 10C during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45 °C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 ml_ x 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 0C (lit. [214] mp 102.5-103.5 0C); the NMR spectrum of this compound demonstrated the existence of two retainers of the title compound. 1H NMR (300 MHz, DMSOd6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally IH for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (IH, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSOd6) δ for major rotamer 173.3, 169.1 , 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 1 15.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm"1; [α]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
With sodium hydroxide In water; acetone at 20℃; for 3.66667h; |
1 Synthetic Procedures; (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid (R-129).
D-Proline (R-128, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloly chloride 127 (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (CO), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
Stage #1: D-Prolin With sodium hydroxide In water at 0℃;
Stage #2: Methacryloyl chloride In water; acetone at 0 - 20℃; for 3.66667h;
Stage #3: With hydrogenchloride In water |
(2R)-l-Methacryloylpyrrolidin-2-carboxylic Acid. D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacrylolyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-110C during the addition of the methacrylolyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45 0C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 0C (lit. [214] mp 102.5-103.5 0C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSOd6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24- 4.20 (m) for the second rotamer (totally IH for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (IH, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO- d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm"1; [α]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
Stage #1: D-Prolin; Methacryloyl chloride With sodium hydroxide In water; acetone at 0 - 20℃; for 3.66667h;
Stage #2: With hydrogenchloride In water; acetone |
2
(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid (R-129). D-Proline (R-128, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloly chloride 127 (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4 filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (CO), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C, 59.13; H, 7.19; N, 7.61. |
| 68% |
Stage #1: D-Prolin With sodium hydroxide In water Cooling with ice;
Stage #2: Methacryloyl chloride In water; acetone at 20℃; for 3.66667h; Cooling with ice;
Stage #3: With hydrogenchloride In water |
1A; 1B
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 niL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 rnL). An acetone solution (71 rnL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 rnL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11°C during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45 0C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 0C (lit. [214] mp 102.5-103.5 0C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-J6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally IH for both rotamers, CH at the chiral center), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (IH, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-J6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm"1; [α]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9Hi3NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
Stage #1: D-Prolin With sodium hydroxide at 0 - 5℃;
Stage #2: Methacryloyl chloride In acetone at 20℃; for 3h; |
1 Step 1: (2fl)-l-Methacryloylpyrrolidin-2-carboxylic Acid
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11°C during the addition of the methacryloyl chloride. After stirring (3 h, room temperature (it)), the mixture was evaporated in vacuo at a temperature at 35-45 °C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HC1. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried P-75003-PC over Na2S04, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102-103 °C; the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-i¾ δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-i¾ δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=0), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm"1 ; [a]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13N03: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. 335] |
| 68% |
With sodium hydroxide In water; acetone at 20℃; for 3.67h; Cooling with ice; |
10 (2fl)-l-Methacryloylpyrrolidin-2-carboxylic Acid
(2fl)-l-Methacryloylpyrrolidin-2-carboxylic Acid. D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11°C during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45 °C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2S04, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102-103 °C; the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. *H NMR (300 MHz, DMSO-i δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-i δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=0), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm"1 ; [a]D26 +80.8° (c = 1 , MeOH); Anal. Calcd. for C9H13N03: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
With sodium hydroxide In acetone at 10 - 20℃; for 3h; Cooling with ice; |
4 (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11°° during the addition of the methacryloyl chloride. After stirring (3 h, RT), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102-103° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral center), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2; CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61. |
| 68% |
With sodium hydroxide In acetone at 10 - 11℃; for 3.66667h; Cooling with ice; |
1 (2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2).
[003 13j D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath. The resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) weresimultaneously added over 40 mm to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11°C during the addition of the methacryloyl chloride. After stirring (3 h, room temperature (RT)), the mixture was evaporated in vacuo at a temperature at 35-45°C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HC1. The acidic mixture was saturated with NaC1 and was extracted withEtOAc (100 mL x 3). The combined extracts were dried over Na2504, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C (lit. mp 102.5-103.5 °C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound.[003 14j ‘H NMR (300 MHz, DMSO-d6) ö 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the firstrotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiralcenter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); ‘3C NMR(75 MHz, DMSO-d6) ö for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5:for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm’; [UjD26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H,3N03: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
With sodium hydroxide In acetone at 10 - 20℃; for 3.66667h; |
1 (2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2)
[00361] D-Proline (1, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath. The resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11C during the addition of the methacryloyl chloride. After stirring (3 hours (h), room temperature (RT)), the mixture was evaporated in vacuo at a temperature of 35-45°C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C (lit. mp 102.5-103.5°C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound.[00362] 1H NMR (300 MHz, DMSO-d6) d 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral center), 3.57- 3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) d for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [a] 26D +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 68% |
With sodium hydroxide In water; acetone at 10 - 20℃; for 3.66667h; |
1 (2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2)
D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath. The resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11C during the addition of the methacryloyl chloride. After stirring (3 h, room temperature (RT)), the mixture was evaporated in vacuo at a temperature at 35-45°C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL × 3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C (Marhefka, C. A.; Moore, B. M., 2nd; Bishop, T. C.; Kirkovsky, L.; Mukherjee, A.; Dalton, J. T.; Miller, D. D. Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands. J Med Chem 2001, 44, 1729-40: mp 102.5-103.5°C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound.1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral center), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me);13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]26D +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
| 45% |
With sodium hydroxide In water; acetone at 0 - 25℃; for 6h; |
|
|
With sodium hydroxide In acetone |
|
|
With sodium hydroxide In acetone |
|
|
In sodium hydroxide |
2 (a) N-methacryloyl-D-proline
(a) N-methacryloyl-D-proline D-Proline (50 g) was dissolved in 430 ml of 20% aqueous sodium hydroxide and the resultant solution was stirred with ice bath cooling as 217 ml ether was added followed by dropwise addition of 50 g of methacryloyl chloride in 400 ml ether over about 45 minutes. After another 30 minutes, the aqueous phase was removed and washed once with additional ether. The aqueous phase was then acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. These combined ethyl acetate extracts were evaporated in vacuo. The resultant residue was crystallized from a mixture of toluene and petroleum ether to yield the title compound, N-methacryloyl-D-proline, which was then recrystallized from acetone/petroleum ether to yield 51.5 g (53%) of purified material. |
|
With sodium hydroxide In acetone |
7
Pyrrolidine-2-carboxylic acid (56) was acylated by SchottenBaumann reaction to obtain methacryloyl pyrrolidine-2-carboxylic acid (57), which was subsequently lactonized in the presence of N-bromosuccinimide to obtain the bromolactone (58). Hydrolysis of the bromolactone (58) using a 24% HBr solution under reflux conditions for Ih and subsequent work up and recrystallization in ethyl acetate-hexane mixture gave 3-bromo-2-hydroxy-2- methylpropanoic acid (59) in high yields [59:White solid (Yield: 85%) Mp. 1080C [α]D25 = +10.5 0^2.5,1 O MeOH) NMR (1H1 SOOMHz1 DMSO): 1.35 (s, 3H, CH3), 3.5 (s, IH, CH), 3.6 (s, IH, CH), 4.0 (br, IH, OH) MS: 205 (M + Na+) C4H7BrO3 Calcd.: C, 26.25; H, 3.86 Found: C, 26.28; H, 3.75].[00447] The hydroxy and carboxyl groups of compound 59 were then protected with tribromoacetaldehyde by cooling to 00C under argon atmosphere and cone, sulfuric acid was added drop-wise with stirring. After 2h the solution turned dark; the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The solution was diluted with ice and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to obtain the compound 60, which appeared as white crystals upon recrystallization from ethyl acetate-hexane. [60: White solid (Yield: 89%) Mp. 97°C NMR (1H, 300MHz, CDCl3): 1.8 (s, 3H, CH3), 3.7 (s, 2H, CH2), 5.8 (s, 1 H, CH) C6H6Br4O3 Calcd.: C, 16.17; H, 1.36; Found: C, 16.08; H, 1.25][00448] Compound 60 was dissolved in a 1 : 1 mixture of 2-propanol and I M NaOH and was stirred at room temperature. After 3h, when no starting material was detectable by TLC, 4'- fluorobcnzenethiol was added and the reaction mixture was stirred overnight. The reaction mixture was then adjusted to pH 1 with cone. HCl, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain an oil. Flash column chromatography of the reaction mixture in hexane-ethyl acetate-acetic acid mixture followed by recrystallization in ethyl acetate-hexane afforded colorless needle shaped crystals. The compound was hydrolyzed to remove the protecting group, by acidifying the reaction mixture with cone. HCl which afforded the chiral hydroxy acid (55) as presented in Figure 2. [55: White solid (Yield: 65%) M.p. 54°C; [α]D25 = +24.85 (c=1.0, MeOH) NMR (1H, 300MHz, CDCl3): 1.5 (s, 3H, CH3), 3.2 (d, IH, CH), 3.4 (d, H, CH), 7.0 (m, 2H, Ar, J = 2.0 Hz, 8.9 Hz), 7.5 (m, 2H, Ar, 7 = 2.0 Hz, 8.9 Hz) MS: No parent ion peak C10H11FO3S Calcd.: C, 52.16; H, 4.82; Found: C, 52.05.59; H, 4.76].[00449] 4-Nitro-3-trifluoromethylaniline was converted to the corresponding isothiocyanate (66) by adding thiophosgene and sodium bicarbonate in chloroform medium at 00C, followed by overnight stirring at room temperature. The reaction mixture was concentrated, extracted into ethyl acetate dried and evaporated and purified by flash column chromatography using hexane-ethyl acetate mixture to afford 66 which appeared as a yellow solid. The hydroxy acid 55 and 4-nitro-3- trifluoromethylphenylisothocyanate (66), silver trifluoroacetate in acetonitrile and triethyl amine were added with stirring and the reaction mixture was heated to reflux for I h. Silver sulfide was removed by filtration and evaporation of the solvent under reduced pressure, the resulting residue was washed with water, extracted into ethyl acetate, dried, filtered and concentrated. The desired product, isolated by flash column chromatography using a hexane-ethyl acetate mixture appeared as yellow oil. The compound was identified as the oxazolidinedione (65), as presented in Figure 2.[65: Yellow colored oil (Yield : 52%) [α]D25 = +39.7 (c=1.0, MeOH) NMR (1H, 500MHz, CDC13): 1.8 (s, 3H, CH3), 3.2 (s, IH, 20 CH), 3.3 (s, IH, CH), 6.9 (m, 2H, Ar, J = 2.0 Hz, 8.9 Hz ), 7.2 (m, 2H, Ar, J = 2.0 Hz, 8.9 Hz), 7.9 (m, IH, Ar, J = 2.1 Hz, 9.0Hz), 8.0 (m, IH, Ar, J = 0.5Hz, 2.1 Hz) 8.1 (m, IH, Ar, J = 0.5Hz, 9.0Hz) NMR (13C, 500MHz, CDC13): 22.8, 43.4, 86.7, 1 17.0, 1 17.3, 124.4, 124.5, 124.6, 125.0, 126.8, 129.3, 134.2, 134.3, 135.3, 164.9, 172.8 MS: No parent ion peak C18Hi2F4N2O5S Calcd.: C, 48.65; H, 2.72; N, 6.30 Found: C, 48.59; H, 2.70; N, 6.31.HPLC analysis of this product (65) on a ϖ acceptor/donor (R,R)-Whelk-Ol chiral column exhibited two peaks in the ratio 70:30 corresponding to the two enantiomers, with an enantiomeric excess of 40%.The formation of oxazolidinedione must had occurred through the nucleophilic displacement of silver sulfide from the imino carbon by the hydroxy group followed by a concerted cyclic rearrangement as illustrated by intermediate structures (67a) and (67b); a mechanism identical to that established byShibuya et al. It is contemplated that the excellent separation of the enantiomers obtained in the aforesaid analytical chiral column may be extended to the corresponding preparative column in order to obtain quantitative yields of the enantiomers and thereby determine their absolute configurations with exciton coupled vibrational circular dichroism and infrared spectroscopy along with the aid of Gaussian empirical calculations. It is contemplated further that the oxygen atom of the heterocyclic ring system can be replaced by an amino group to obtain enantiomeric hydantoin analogs of bicalutamide which would then provide an additional site for hydrogen bonding interaction with the receptor. |
|
Stage #1: D-Prolin; Methacryloyl chloride With sodium hydroxide In water; acetone at 0 - 20℃; for 4h;
Stage #2: With hydrogenchloride In water |
3.B.a Example 3. (Method B); (2S)-3- (4-ACETYLAMINOPHENOXY)-2-HYDROXY-2-METHYL-N- (3-METHYL-4- nitrophenyl) propionamide; a) (2R)-L- (2-METHYLACRYLOYL) pyrrolidine-2-carboxylic acid
D-proline (5 g, 43.4 mmol) was dissolved in 2 M NAOH (26 ml) and cooled in an ice bath, and the solution was diluted with acetone (26 ml). An acetone solution (26 ml) of methacryloyl chloride (6.3 ml, 65.1 mmol) and a 2 M NAOH solution (34 ml) were simultaneously added over a period of lh to the solution of D-proline. After addition the resulting mixture was stirred for 3 h at room temperature. The mixture was evaporated at 40 °C, extracted with ether (2 x 40 ml) and acidified to pH 2 with concentrated HC1. The resulting mixture was extracted with ethyl acetate (3 x 50 ml), dried OVER NA2S04 and evaporated. The yield was 11.5 g (theoretical 8. 0 g), and it was used without further purifications. |
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With triethylamine In dichloromethane at 0℃; |
|
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Stage #1: D-Prolin With sodium hydroxide In water; acetone Cooling with ice; Inert atmosphere;
Stage #2: Methacryloyl chloride With sodium hydroxide In water; acetone at 20℃; for 3.66667h; Cooling with ice; Inert atmosphere; |
1.1.5 Synthesis of (2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (37)vi
Compound 37 was synthesised according to literature: D-Proline (R-128, 14.93 g,0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; theresulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71mL) of metacryloly chloride 127 (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL)were simultaneously added over 40 min to the aqueous solution of D-proline in an icebath. The pH of the mixture was kept at 10-11° C. during the addition of themetacryloly chloride. After stirring (3 h, room temperatures) the mixture wasevaporated in vacuo (35-45 °C) to remove acetone. The resulting solution was washedwith ethyl ether and acidified to pH 2 with concentrated HCl. The mixture was thensaturated with NaCl and extracted with EtOAc (3x100 mL). The combined extractswere dried over Na2SO4, filtered and evaporated to give the crude product ascolourless oil. Compound was used in the next step without further purification. 1H[α]D26 +81.8° (c=1, MeOH); 1H-NMR (CDCl3): 5.37 (s, 1H, major rotamer), 5.28(s, 1H, major rotamer), 5.22 (s, 1H, minor rotamer), 5.10 (s, 1H, minor rotamer), 4.62(dd, J = 8.3 Hz, 4.7 Hz, 1H, major rotamer), 4.56 (dd, J = 9.0 Hz, 2.2 Hz, minorrotamer), 3.68-3.60 (m, 3H), 2.37-2.29 (m, 1H), 2.24-2.17 (m, 1H), 2.10-2.03 (m, 1H), 2.02 (dd, J = 1.4 Hz, 0.9 Hz, 3H), 1.98-1.90 (m, 2H). |
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Stage #1: D-Prolin With sodium hydroxide In water Cooling with ice;
Stage #2: Methacryloyl chloride In water; acetone at 10 - 20℃; for 3h; |
1 (2R)-1-Methacryloylpyrrolidin-2-carboxylic acid
(2 ?)-l-Methacryloylpyrrolidin-2-carboxylic acid (2) (0659) [00302] D-Proline (1, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath. The resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11°C during the addition of the methacryloyl chloride. After stirring (3 hours (h), room temperature (RT)), the mixture was evaporated in vacuo at a temperature of 35-45°C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HC1. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2S04, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102.1- 103.4°C (lit. mp 102.5- 103.5°C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. (0660) [00303] lH NMR (300 MHz, DMSO-i δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral center), 3.57- 3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-i δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=0), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm 1; [ ]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
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With sodium hydroxide; recorcinol In tert-butyl methyl ether at 10 - 20℃; Large scale; |
1.1; 2.1; 3.1 (1) Preparation of methacryloyl-D-proline:
D-proline, NaOH, MTBE and resorcinol were mixed and stirred at 10 ° C, and then methacryloyl chloride was added dropwise, and stirred at 20 ° C, and the layers were allowed to stand. The upper organic phase was taken. Having methacryloyl-D-proline;The lower aqueous phase was further added with HCl while stirring at 10-20 ° C, and then ethyl acetate was added thereto to separate the organic phase; the mass-to-volume ratio of D-proline, HCl and ethyl acetate was: 8kg: 8.8L: 40L; then add the resorcinol to the above organic phase, concentrate to 2.5 volume between 37 ° C, add the first toluene, concentrate to 2.5 volume between 37 ° C, then add the first The toluene was stirred uniformly, cooled to 12 ° C, and the filter cake was washed with toluene after filtration; the mass-to-volume ratio of D-proline, resorcin, first toluene, and second toluene was 8 kg: 0.8g: 16L: 24L.The mass to volume ratio of D-proline, NaOH, MTBE, resorcinol, methacryloyl chloride: 8kg: 6.39kg: 24L: 0.8g: 8.35kg; |
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With sodium hydroxide In water; acetone at 20℃; for 3.66667h; Cooling with ice; |
1 (2/?)-l-Methacryloylpyrrolidin-2-carboxylic Acid (3).
D-Prolinc (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (2, 13.56 g, 0.13 mol) and 2 /VNaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-1 l°C during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45°C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HC1. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2S04, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded the designed compound (3, 16.2 g, 68%) as colorless crystals: mp l02-l03°C (lit. mp 102.5-103.5°C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the titled compound. ' H NMR (300 MHz, DMSO-ife) d 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH CH, Me); 13C NMR (75 MHz, DMSO-ife) d for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=0), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm 1; [a]D26 +80.8° (c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. |
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