氨基甲基丁三酸酯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and (S)-2-methoxymethyl-pyrrolidin-1-yl amine as starting materials (CAN 59983-39-0); MS (ESI) 396.4 (M+Na)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and (S)-2-methoxymethyl-pyrrolidin-1-yl amine as starting materials (CAN 59983-39-0); MS (ESI) 396.4 (M+Na)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 416.2159 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 416.2159 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; MS (EI) 402.3 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; MS (EI) 402.3 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 9-(2',3'-Di-O-acetyl-5'-O-methyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.3 g, 3.1 mmol), (S)-N-amino-2-(methoxymethyl)pyrrolidine (0.81 g, 6.2 mmol) and triethylamine (0.63 g, 6.2 mmol) were dissolved in dioxan. After stirring for 20 h the reaction mixture was diluted with dichloromethane (150 ml) and washed with water (2×75 ml). The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a mixture of dichloromethane and 10% ammonia in ethanol (97:3) to afford (S)-2',3'-di-O-acetyl-2-chloro-5'-O-methyl-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine (0.28 g, 18%) as a foam. 1H-NMR (400 MHz, CDCl3) δ1.70-2.10 (4H, m, pyrrolidine C--H), 2.05 (3H, s, --OCOCH3), 2.18 (3H, S, --OCOCH3), 2.85 (1H, m, pyrrolidine C--H), 3.10 (1H, br, pyrrolidine C--H), 3.22 (3H, s, --OCH3), 3.35-3.70 (8H, m, H-5'a and H-5'b, --OCH3, pyrrolidine, --CH2 --), 4.32 (1H, s, H-4'), 5.55 (1H, d, H-3'), 5.75 (1H, t, H-3'), 6.32 (1H, d, H-1'), 8.17 (1H, s, H-8). HPLC retention time 15.57 min. (gradient elution over 25 min.; 20-80% acetonitrile/0.1% TFA in water). washed with water (2×75 ml) The organic phase was dried (MgSO4) concentrated in vacuo The resultant residue was purified by flash chromatography eluting with a mixture of dichloromethane and 10% ammonia in ethanol (97:3)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (I-8A, 20.90 g, 77 mmol), p-toluenesulfonic acid monohydrate (0.584 g, 3.07 mmol), and cyclohexane (40 mL) was added (S)-2-(methoxymethyl)pyrrolidin-1-amine (10 g, 77 mmol) dropwise at room temperature under nitrogen. The mixture was heated with azeotropic removal of water for 5 h. The reaction mixture was diluted with ethyl acetate (20 mL) and mixed with saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 0% to 20% EtOAc in hexanes) afforded (S)—N-(6-iodo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-(methoxymethyl)pyrrolidin-1-amine (29.1 g, 76 mmol) as a yellow liquid. LC/MS M+1=385. The aqueous layer was separated extracted with ethyl acetate (2×30 mL) The combined organic solutions were dried over anhydrous sodium sulfate concentrated under reduced pressure Flash chromatography purification (330 g silica gel column, gradient elution from 0% to 20% EtOAc in hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (I-8A, 20.90 g, 77 mmol), p-toluenesulfonic acid monohydrate (0.584 g, 3.07 mmol), and cyclohexane (40 mL) was added (S)-2-(methoxymethyl)pyrrolidin-1-amine (10 g, 77 mmol) dropwise at room temperature under nitrogen. The mixture was heated with azeotropic removal of water for 5 h. The reaction mixture was diluted with ethyl acetate (20 mL) and mixed with saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 0% to 20% EtOAc in hexanes) afforded (S)—N-(6-iodo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-(methoxymethyl)pyrrolidin-1-amine (29.1 g, 76 mmol) as a yellow liquid. LC/MS M+1=385. The aqueous layer was separated extracted with ethyl acetate (2×30 mL) The combined organic solutions were dried over anhydrous sodium sulfate concentrated under reduced pressure Flash chromatography purification (330 g silica gel column, gradient elution from 0% to 20% EtOAc in hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and (S)-2-methoxymethyl-pyrrolidin-1-yl amine as starting materials (CAN 59983-39-0); MS (ESI) 396.4 (M+Na)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 416.2159 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; MS (EI) 402.3 (M+H)+.