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CAS No. : | 4457-32-3 | MDL No. : | MFCD00007375 |
Formula : | C8H6ClNO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MHSGOABISYIYKP-UHFFFAOYSA-N |
M.W : | 215.59 | Pubchem ID : | 78205 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 51.51 |
TPSA : | 72.12 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.63 cm/s |
Log Po/w (iLOGP) : | 1.8 |
Log Po/w (XLOGP3) : | 2.79 |
Log Po/w (WLOGP) : | 2.32 |
Log Po/w (MLOGP) : | 0.89 |
Log Po/w (SILICOS-IT) : | 0.09 |
Consensus Log Po/w : | 1.58 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.99 |
Solubility : | 0.222 mg/ml ; 0.00103 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.96 |
Solubility : | 0.0236 mg/ml ; 0.000109 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.5 |
Solubility : | 0.69 mg/ml ; 0.0032 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.71 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine In dichloromethane at 20℃; | /j-Nitrobenzyloxycarbonylbenzotriazole (32a):/-Nitrobenzyl chlorofbrmate (0.5 mmol) was dissolved in 5 mL OfCH2Cl2 and treated with benzotriazole (0.5 mmol) using Et3N (2 mmol) as base. The mixture was stirred overnight at room temperature, diluted with CH2Cl2 (20 mL) and washed with 3 x 5 mL of IN HCl, 2 x 5 mL of IN NaOH and 1 x 5 mL of brine. The organic phase was dried and filtered. The volatiles were removed and the product was triturated with diethyl ether to provide a pale yellow solid (59percent yield), mp 160 - 162 0C. 1H NMR (CDCl3) δ 8.27 (d, IH5 J= 8.9 Hz), 8.17 (m, 3H), 7.72 (d, IH, J= 8.9 Hz), 7.65 (td, IH, J= 8.3 Hz, 1.1 Hz), 7.53 (m, 2H), 5.26 (s, 2H). 13C NMR (CDCl3) δ 154.84, 146.17, 142.27, 141.30, 132.01, 130.82, 128.78, 126.37, 124.16, 120.86, 113.58, 68.66. HRMS (FAB) calcd for Ci4H11N4O4 ([M+H]+): 299.0775, found 297.0775. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In tetrahydrofuran at 0 - 20℃; | [0228] To a stirring solution of 4-nitrobenzyl chloroformate (27.40g) in THF (500 mL) at 0 was added N-hydroxy-5-norbornene-2,3-dicarboximide (22.76), followed by the dropwiseaddition of a solution of Et3N (17.72rnl) in THF (200 rnL) and the reaction was stirred for overnight with gradual warming to room temperature. The reaction vessel was then placed in the freezer (-5 °C) for 1 hour to induce precipitation of triethylamine hydrochloride, which was removed by filtration. The filtrate was concentrated to dryness to yield a residue, which was vigorously stirred in MeOH (400 mL) for lh and then filtered to yield (N-hydroxy-5- norbornene-2,3- dicarboxyl-imido)-4-nitro-benzoate as a white solid (42.03g, yield: 92percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Example 4: Synthesis of (4R,5S,6S)- 3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-3-rhoyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl- 7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (I)Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-thio-l-PNZ-pyrrolindine (XX)L-hydoxyproline (XXVI) (26.2 g, 0.20 mol) was added to a solution of sodium hydroxide (220 ml, 2N) and cooled to O0C to 50C. The solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> dissolved in <n="17"/>methylene chloride (40 ml) was added dropwise. After stirred at the same temperature for 1 h, the phase of methylene chloride was separated. The aqueous phase was washed with methylene chloride (70 ml) and acidified with concentrated sulfuric acid (36.6 g) at a temperature of O0C to 5 C . Substantive crystals were precipitated, collected by filtration under vacuum, washed with water, dried, and afford trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XXV) (57.8 g, yield 93%), m.p.: 134~135.5C. | |
93% | Example 6] Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-acetylthio-l-PNZ-pyrrolidine (XIX)1. Synthesis of trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XV) L-hydoxyproline (XXVI) (26.2 g, 0.20 mol) was added to a solution of sodium hydroxide(220 ml, 2N) and cooled to 0C to 5C. The solution, of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> dissolved in methylene chloride (40 ml) was added dropwise. After stirred at the same temperature for 1 h, the phase of methylene chloride was separated. The aqueous phase was washed with methylene chloride (70 ml) and acidified with concentrated sulfuric acid (36.6 g) at a temperature of 0C to 5 C . Substantive crystals were precipitated, collected by filtration under vacuum, washed with water, dried, and afford trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XXV) (57.8 g, yield 93%), m.p.: 134~135.5C. | |
Trans-4-hydroxy-L-proline (II) was added to a solution of sodium hydroxide in water at 0-5 C, and stirred to get a clear solution, followed by p- nitrobenzyloxycarbonyl chloride in dichloromethane (MDC) was added and stirred till completion of reaction. at 0-5 C. To this reaction mass sodium hydroxide solution was added and the layers were separated. To the aqueous layer methanol was added and pH was adjusted to acidic using sulphuric acid at 0-5 C. The solid obtained was filtered, washed with water and dried in vacuum at 50C to afford the title compound (III) as colorless crystals. |
31.95 kg | With sodium hydroxide; In dichloromethane; water; at 0 - 5℃; for 5h;Large scale; | 20L reactor water 12kg,1kg sodium hydroxide, stirred and dissolved, cooled to 25 ~ 30 ,Add L-hydroxyproline 15kg, stirring to dissolve,Cool to 0 ~ 5 ,The temperature was controlled at 0 ~ 5 2.7kg of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> and 3kg of dichloromethane were added dropwise.Dropping about 2 hours, dropping is completed,Keep stirring 0 ~ 5 for about 3 hours. Detection reaction is complete.The dichloromethane phase was separated, the aqueous phase was washed with 3 kg of dichloromethane, the aqueous phase was separated,Control temperature but 15 degrees,Concentrated sulfuric acid adjusted to pH 2, cooled to 0 filtration,Washed, dried in the product(5) To a solution of (2S, 4R) -4- hydroxy- 1 - (((4-nitrobenzoyl) oxy) carbonyl) pyrrolidine-31.95kg |
With sodium hydroxide; In water; toluene; at -5 - 0℃; for 1.25h;pH 9; | In a 500mL three-neck bottle added purified water 192g, add 15.3g of sodium hydroxide, stir and dissolve, and cool at 0 C; add 3g of 3-hydroxyproline, stir and dissolve; cool down at -5 C, added the drops of about 180g of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> toluene solution, after about 1 hour, the drop is completed and pEta=9; continue to stir for 15 minutes, and then let stand for 20 min, dispense, and obtained lower aqueous phase; in the lower aqueous phase added toluene 63mL X 3 and wash three times, stand still; control the internal temperature at 10 C, and add 6N hydrochloric acid to the aqueous phase, add dropwise until the water phase becomes turbid and stop adding, pH=4, add a small amount of seed crystals and stir until more crystals are precipitated, continue to add hydrochloric acid at pEta = 2 (a total of about 5g of 6N dilute hydrochloric acid is required), cool down at 0 C, heat 1h suction filtration, wash with pure water to pEta = 3, obtained compound I hydrate product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydrogencarbonate; hydrazine hydrate; In water; toluene; at 20℃; for 6h; | A solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (10.78 g, 50 mmol) in toluene (50 mL) was added to an aqueous solution (water 50 mL) of NaHCO3 (5 g, 60 mmol) and 80% hydrazine hydrate (1 g, 20 mmol) at room temperature. The mixture was stirred at room temperature for 6 h and then precipitated crystals were cropped by filtration, washed with toulene, and dried in vacuo at 25 C to give 2 (6.87 g, 88%) as white solid powder. Mp 172-173 C; IR (NaCl, neat) 3248, 2365, 1755, 1698 cm-1; 1H NMR (500 MHz, DMSO-d6) delta 5.25 (s, 4H), 7.62 (d, J=8.2 Hz 4H), 8.25 (d, J=8.2 Hz, 4H), 9.48 (mix of rotamers, 2H total); 13C NMR (500 MHz, DMSO-d6) delta 156.81, 148.09, 128.80, 120.99, 65.60; MS (ESI): m/z=391.3 (M+H+), 413.4 (M+Na+). Anal. Calcd for C16H14N4O8 (390.08): C, 49.24; H, 3.62; N, 14.35. Found: C, 49.18; H, 3.57; N, 14.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 1) (3R)-3-Hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine [1752] To a suspension of (3R)-3-hydroxypyrrolidine hydrochloride (7.00 g, 56.6 mmol) in methylene chloride (210 ml) were added chloroformic acid p-nitrobenzyl ester (13.4 g, 62.3 mmol) and triethylamine (17.4 ml, 125 mmol) in an ice bath. The mixture was stirred at room temperature for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)?ethyl acetate as the eluant to afford (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (13.6 g, yield 90%) as a pale yellow solid. [1753] 1H-NMR (400 MHz, CDCl3): delta (ppm) 8.22 (2H, d, J=8.1 Hz), 7.53 (2H, d, J=8.1 Hz), 5.24 (2H, s), 4.55-4.50 (1H, m), 3.63-3.53 (3H, m), 3.51-3.44 (1H, m), 2.09-1.93 (2H, m) | |
90% | With triethylamine; In dichloromethane; | (1) (3R)-3-Hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine To a suspension of (3R)-3-hydroxypyrrolidine hydrochloride (7.00 g, 56.6 mmol) in methylene chloride (210 ml) were added chloroformic acid p-nitrobenzyl ester (13.4 g, 62.3 mmol) and triethylamine (17.4 ml, 125 mmol) in an ice bath. The mixture was stirred at room temperature for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1: 1) ? ethyl acetate as the eluant to afford (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (13.6 g, yield 90%) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): delta (ppm) 8.22 (2H, d, J=8.1Hz), 7.53 (2H, d, J=8.1Hz), 5.24 (2H, s), 4.55 - 4.50 (1H, m), 3.63 - 3.53 (3H, m), 3.51 - 3.44 (1H, m), 2.09 - 1.93 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In dichloromethane; at 0 - 20℃; | Step I; tert-butyl 4-(allyl((4-nitrobenzyloxy)carbonyl)amino)piperidine-l-carboxylate <n="61"/>A solution of the <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.65 g, 3.0 mmol) in DCM (2 mL) was added dropwise to a mixture of the amine (0.60 g, 2.5 mmol) from step H and triethyl amine(1.04 mL, 7.5 mmol) in DCM (8 mL) at 0C. After being stirred at room temperature overnight, the resulting solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (10%-20% EA in PE) afforded the title compound as a colorless oil (0.90 g, 86%). 1H NMR (CDCl3, 300MHz) delta 8.23-8.21 (d, J = 8.4 Hz, 2H), 7.52-7.49(d, J = 8.4 Hz, 2H), 5.85-5.74 (m, IH), 5.24-5.19 (m, 4H)5 4.17-4.09 (m, 3H), 3.84 (br, 2H), 2.73-2.69 (m, 2H), 1.73-1.51 (m, 4H), 1.46 (s, 9H). |
86% | With triethylamine; In dichloromethane; at 0 - 20℃; | A solution of the <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.65 g, 3.0 mmol) in DCM (2 mL) was added dropwise to a mixture of the amine (0.60 g, 2.5 mmol) from step H and triethyl amine(1.04 mL, 7.5 mmol) in DCM (8 mL) at O0C. After being stirred at room temperature overnight, the resulting solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (10%-20% EA in PE) afforded the title compound as a colorless oil (0.90 g, 86%). 1H NMR (CDCl3, 300MHz) delta 8.23-8.21 (d, J = 8.4 Hz, 2H), 7.52-7.49 (d, J = 8.4 Hz, 2H), 5.85-5.74 (m, IH), 5.24-5.19 (m, 4H)5 4.17-4.09 (m, 3H), 3.84 (br, 2H), 2.73-2.69 (m, 2H), 1.73-1.51 (m, 4H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium bicarbonate; In tetrahydrofuran; 1,4-dioxane; water; | Step 1 4-Formyl-2-phenyl-imidazole-1-carboxylic acid 4-nitro-benzyl ester 4-Formyl-2-phenylimidazole (624 mg) and sodium hydrogen carbonate (791 mg) were dissolved in dioxane (3.6 mL), THF (3.6 mL) and water (7.2 mL). The 48.7% solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (PNZCl) in dioxane (2.08 mL) was added to the mixture at room temperature and stirred for 2.5 h. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and n-hexane to give the title compound (956 mg, 75%). 1H NMR (delta, CDCl3) 5.41 (s, 2H), 7.32 (d, 2H, J=8.6 Hz), 7.40-7.51 (m, 3H), 7.56-7.58 (m, 2H), 8.17-8.20 (m, 2H), 8.22 (s, 1H), 9.97 (s, 1H). |
75% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,4-dioxane; water; at 20℃; for 2.5h; | Example 6; Step 1 : 4-Formyl-2-phenyl-imidazole-1-carboxylic acid 4-nitro-benzyl ester 4-Formyl-2-phenylimidazole (624 mg) and sodium hydrogen carbonate (791 mg) were dissolved in dioxane (3.6 mL), THF (3.6 mL) and water (7.2 mL). The 48.7% solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (PNZCI) in dioxane (2.08 mL) was added to the mixture at room temperature and stirred for 2.5 h. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (MgS04) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and n-hexane to give the title compound (956 mg, 75%).'H NMR (8, CDCI3) 5.41 (s, 2H), 7.32 (d, 2H, J= 8.6 Hz), 7.40-7. 51 (m, 3H), 7.56-7. 58 (m, 2H), 8.17-8. 20 (m, 2H), 8.22 (s, 1H), 9.97 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium bicarbonate; In 1,4-dioxane; water; | Step 2 2-Benzyl-4-formyl-imidazole-1-carboxylic acid 4-nitro-benzyl ester 2-Benzyl-1H-imidazole-4-carbaldehyde (1 g) and sodium hydrogen carbonate (1.13 g) were dissolved in dioxane (30 mL) and water (30 mL). The 48.7% solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (PNZCl) in dioxane (2.62 g) was added to the solution at 0 C. and stirred for 2.5 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with chloroform-acetone (9/1). The title compound was obtained as pale brown oil (1.97 g, 100%). 1H NMR (delta, CDCl3) 4.46 (s, 2H), 5.42 (s, 2H), 7.19-7.30 (m, 5H), 7.44-7.47 (m, 2H), 8.06 (s, 1H), 8.21-8.25 (m, 2H), 9.91 (s, 1H). |
100% | With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0℃; for 2.5h; | Step 2: 2-Benzyl-4-formyl-imidazole-1-carboxylic acid 4-nitro-benzyl ester 2-Benzyl-1H-imidazole-4-carbaldehyde (1 g) and sodium hydrogen carbonate (1.13 g) were dissolved in dioxane (30 mL) and water (30 mL). The 48.7% solution of p- nitrobenzyl chloroformate (PNZCI) in dioxane (2.62 g) was added to the solution at 0 C and stirred for 2.5 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried (MgS04) and concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with chloroform-acetone (9/1). The title compound was obtained as pale brown oil (1.97 g, 100%). 1H NMR (8, CDCI3) 4.46 (s, 2H), 5.42 (s, 2H), 7.19-7. 30 (m, 5H), 7.44-7. 47 (m, 2H), 8.06 (s, 1H), 8.21-8. 25 (m, 2H), 9.91 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In 1,4-dioxane; dichloromethane; | Step 1 4-Formyl-2-thiazol-2-yl-imidazol-1-carboxylic acid 4-nitro-benzyl ester 2-Thiazol-2-yl-1H-imidazol-4-carbaldehyde (570 mg) was dissolved in dry CH2Cl2 (35 mL). N,N'-Diisopropylethylamine and 48.7% solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (PNZCl) in dioxane (1.69 mL) were added successively to the solution at 0 C. and stirred for 2 h. The reaction mixture was diluted with CHCl3 and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and n-hexane to give the title compound (1.05 g, 92%). 1H NMR (delta, CDCl3) 5.49 (s, 2H), 7.50 (d, 2H, J=8.8 Hz), 7.55 (d, 1H, J=3.4 Hz), 7.89 (d, 1H, J=3.1 Hz), 8.19 (s, 1H), 8.24 (dq, 2H, J=8.8, 2.0 Hz), 9.97 (s, 1H). |
92% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; at 0℃; for 2h; | Example 4; Step 1: 4-Formyl-2-thiazol-2-yl-imidazol-1-carboxylic acid 4-nitro-benzyl ester 2-Thiazol-2-yl-1 H-imidazol-4-carbaldehyde (570 mg) was dissolved in dry CH2CI2 (35 mL). N, N'-Diisopropylethylamine and 48.7% solution of <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (PNZCI) in dioxane (1.69 mL) were added successively to the solution at 0 C and stirred for 2 h. The reaction mixture was diluted with CHCI3 and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried (MgS04) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and n-hexane to give the title compound (1.05 g, 92%).'H NMR (5, CDCI3) 5.49 (s, 2H), 7.50 (d, 2H, J = 8.8 Hz), 7.55 (d, 1 H, J = 3.4 Hz), 7.89 (d, 1 H, J = 3.1 Hz), 8.19 (s, 1H), 8.24 (dq, 2H, J= 8.8, 2. 0 Hz), 9.97 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium hydroxide In tetrahydrofuran; water at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | CuCO3.Cu(OH)2.H2O (15.8 g) was added to the H2O (275 mL) solution of piperazine-2-carboxylic acid, dihydrochloride (22.3 g), then the mixture was refluxed and stirred for 10 min. The insoluble material was filtered off and was washed with hot H2O (165 mL). The filtrate was cooled to room temperature, and NaHCO3 (9.2 g) and 1,4-dioxane (220 mL) was added to the dark blue solution. The mixture was cooled to 0 C. and NaHCO3 (18.5 g) and 50% solution of 4-nitrobenzyl chloroformate in 1,4-dioxane (61.7 g) was added to the mixture for 0.5 h. After stirring for additional 1.5 h at 0 C., the precipitate was filtered and washed with cold H2O (140 mL), EtOH (100 mL), acetone (200 mL) and Et2O (100 mL), then it was allowed to dry under reduced pressure to obtain the pale blue crystals. The crystals were added to the 1 mol/L HCl (330 mL) solution of EDTA.2Na (20.5 g) for 30 min, and stirred for 2 h at room temperature. The suspension was filtered and the filtered material was diluted with EtOH-H2O (7:3, 550 mL) and refluxed for 10 min. The reaction mixture was filtered to obtain the colorless crystals. The recrystallization from the filtrate was carried out 3 times to obtain additional crystals. The combined crystals were dried under reduced pressure to obtain the titled compound (26.25 g, 77%) as colorless crystals. 1H NMR (D2O) delta 2.54-2.61 (m, 1H), 2.89 (dt, 2H, J=12.7, 3.4 Hz), 2.97 (br, 1H), 3.13 (br, 1H), 3.62-4.04 (m, 2H), 5.16 (s, 2H), 7.49 (d, 2H, J=8.6 Hz), 8.14 (d, 2H, J=8.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Step 3 [0211] To a stirred solution of N-Boc-N-methyl ethylenediamine (1.39 g, 8.0 mmol) and DIEA (1.05 g, 8.1 mmol) in dry DCM (50 mL) at 0C was added a solution ofp- nitrobenzylchloroformate (1.75 g, 8.1 mmol) in dry DCM (10 mL) dropwise over 5- 10 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature, and stirred overnight (monitored by TLC). The reaction mixture was then washed with 1M aq. NaHC03 solution, water, and brine. The organic layer was dried over Na2S04, concentrated , and the remaining residue was purified by flash chromatography to give the desired N-Boc-N'-PNB protected intermediate in 73% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 23.7h; | Dry triethylamine (0.045 mL, 0.322 mmol) was added to 4-(2-chloroethyl)-3-[5-(5-benzofuran-2-carboxanmdo)indole-2-carboxamido]phenol (74.1 mg, 0.156 mmol) and dissolved in distilled CH2Cl2 (20 mL), while under N2, then placed in an ice bath. 4-Nitrobenzyl chloroformate (0.087 g, 0.4025 mmol) was added to the solution and stirred in an ice bath under N2. Dry THF (2 mL) was added, and the contents were sonicated to completely dissolved the mixture. The solution was stirred in the ice bath for 40 minutes then at room temperature for 20 hours. After 20 hours the reaction was not completed by TLC and more <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.087 g) was added to the mixture and stirred for three hours. The mixture was diluted with chloroform (50 mL) and extracted with saturated NaCl and 5% sodium bicarbonate. The aqueous wash was extracted with ethyl acetate. The organic layers were combined and dried with sodium sulfate, gravity filtered, and concentrated under reduced pressure to a yellow-brown solid. The product was purified on a silica gel column run in 1% methanol, 99% chloroform. 4-(2-Chloroethyl)-O-(4-nitrobenzylcarbonato)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol was obtained as an off-white solid (85.7 mg, 0.131 mmol, 84%). Mp=192-195 C; TLC (5% MeOH/CHCl3) Rf=0.50; 1H-NMR (CDCl3, 500 MHz) 9.25 (s br, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.26 (d, 8.5, 1H), 7.91 (d, 2.0, 1H), 7.72 (d, 8.0, 1H), 7.614 (s, 1H), 7.612 (d, 8.5, 1H), 7.58 (d, 8.0, 1H), 7.47 (m, 3H), 7.34 (dt, 1.0, 8.0, 1H), 7.29 (d, 8.5, 1H), 7.08 (dd, 2.5, 8.5, 1H), 5.37 (s, 2H), 3.89 (t, 6.0, 2H), 3.20 (t, 6.0, 2H); IR (neat) 3401, 3281, 2959, 2871, 1758, 1660, 1643, 1594, 1523, 1442, 1344,1229, 1169, 1055, 804, 739; FAB-MS (NBA) m/z (relative intensity) 653 (M+H+, 3). Accurate mass for C34H26N4O8 35Cl: calcd. 653.1439, obsd. 653.1428. |
With triethylamine; In tetrahydrofuran; methanol; dichloromethane; chloroform; | obsd. 474.1219. Dry triethylamine (0.045 mL, 0.322 mmol) was added to 4-(2-chloroethyl)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol (74.1 mg, 0.156 mmol) and dissolved in distilled CH2Cl2 (20 mL), while under N2, then placed in an ice bath. 4-Nitrobenzyl chloroformate (0.087 g, 0.4025 mmol) was added to the solution and stirred in an ice bath under N2. Dry THF (2 mL) was added, and the contents were sonicated to completely dissolved the mixture. The solution was stirred in the ice bath for 40 minutes then at room temperature for 20 hours. After 20 hours the reaction was not completed by TLC and more <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.087 g) was added to the mixture and stirred for three hours. The mixture was diluted with chloroform (50 mL) and extracted with saturated NaCl and 5% sodium bicarbonate. The aqueous wash was extracted with ethyl acetate. The organic layers were combined and dried with sodium sulfate, gravity filtered, and concentrated under reduced pressure to a yellow-brown solid. The product was purified on a silica gel column run in 1% methanol, 99% chloroform. 4-(2-Chloroethyl)-O-(4-nitrobenzylcarbonato)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol was obtained as an off-white solid (85.7 mg, 0.131 mmol, 84%). Mp=192-195 C.; TLC (5% MeOH/CHCl3) Rf=0.50; 1H-NMR (CDCl3, 500 MHz) 9.25 (s br, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.26 (d, 8.5, 1H), 7.91 (d, 2.0, 1H), 7.72 (d, 8.0, 1H), 7.614 (s, 1H), 7.612 (d, 8.5, 1H), 7.58 (d, 8.0, 1H), 7.47 (m, 3H), 7.34 (dt, 1.0, 8.0, 1H), 7.29 (d, 8.5, 1H), 7.08 (dd, 2.5, 8.5, 1H), 5.37 (s, 2H), 3.89 (t, 6.0, 2H), 3.20 (t, 6.0, 2H); IR (neat) 3401, 3281, 2959, 2871, 1758, 1660, 1643, 1594, 1523, 1442, 1344,1229, 1169, 1055, 804, 739; FAB-MS (NBA) m/z (relative intensity) 653 (M+H+, 3). Accurate mass for C34H26N4O835Cl: calcd. 653.1439, obsd. 653.1428. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In dichloromethane; at 20℃; for 3h; | Eine Losung von 50 mg (0,125 mmol) der Verbindung (8), 27 mg (0,125 mmol) 4-Nitrobenzylchlorformiat und 52 ul (0,375 mmol) Triethylamin in 1 ml Methylenchlorid wurde fur 3 h bei Raumtemperatur geruhrt. Nach Abdampfen des Losungsmittels wurde der Ruckstand in 30 ml Ethylacetat aufgelost und dreimal mit 0,5 N wassriger HCl gewaschen. Nach Abdampfen des Ethylacetats wurde der Ruckstand in 95% Trifluoressigsaure gelost und fur 1 h geruhrt. Nach Abdampfen des Losungsmittel wurde das Produkt aus Ethanol/Diisopropylether umkristallisiert.Ausbeute:35 mg (60%); HPLC: tR 8,1 min; MS 344 (M+H)+, berechnet 343 (M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 18 - 25℃; for 20h; | 2-chloro-N- 2R)-1-{ [2-(TETRAHYDRO-2H-PYRAN-2-YLOXY) ETHYL] AMINO}-2, 3-DIHYDRO-LH- inden-2-yl)-6H-thieno [2, 3-B] PYRROLE-5-CARBOXAMIDE (INTERMEDIATE 3; 460 mg, 1.0 mmol) and DIPEA (342 muL, 2.0 mmol) were dissolved in DCM (15 mL), 4-nitrobenzyl CHLOROFORMATE (236 mg, 1.1 mmol) in DCM (5 mL) added and the reaction stirred at ambient temperature for 20 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (40 ML), washed water (10 mL) then brine (10 ML) and dried (MGS04). The volatiles were removed by evaporation under reduced pressure and the residue purified by silica gel chromatography (EtOAc : iso-hexane, 1: 1) to give the title compound (530 mg, 83%) as a foam. MS m/z 637,639 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.3% | With triethylamine; In tetrahydrofuran; at 20℃; for 2h; | Example 27; The synthesis of {2-[4-(furan-2-yl)-6-(hydroxymethyl) pyridine-2- carbonyl] amino} ethyl} carbamic acid 4-nitrobenzyl ester 27; Compound 25 (0.42 g; 1.7 mmol) was dissolved in ethylenediamine (10 ml). The mixture was stirred at RT for 3 hours and evaporated to dryness. The residue was reevaporated twice from toluene and then dissolved in THF (20ML). TEA (0.24 ml; 1. 7 mmol) was added and 4-NITROBENZYLCHLOROFORMATE (0.76 g; 3.4 mmol) in 10 ml THF was added dropwise. The mixture was stirred at RT for 2 hours. The precipitation was filtered off and the filtrate was evaporated o dryness. The residue was suspended to CH2CL2 and product was filtered. Purification on silica gel (eluent: 3% MEOH/CH2C12). Yield was 0.46 g (61.3 %). 1H-NMR (CDCL3) : 8.21 (2H, d, J 8. 8H), 8.13 (1H, s), 7.94 (1H, s), 7.87 (1H, s), 7.60 (2H, d, J8. 8), 7.42 (1H, d, J 3.4), 6.72 (1H, dd, J 1.7 and 3.4), 5.18 (2H, s), 4.66 (2H, d, J 5. 6 Hz), 3.42 (2H, m), 3.23 (2H, m). ESI-TOF-MS mass for C21H21N407 (M+H) + : calcd, 441.14 ; found: 441.14 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In dichloromethane; at 0 - 20℃; for 22h; | Example H. 4 (E)-4- (5, 6-dimethoxy-2-oxo-1, 2-dihydro-indol-3- ylidenemethyl)phenyl, 4-nitrobenzyl carbonate.; A suspension of (E)-3- (4-hydroxybenzylidene)-5, 6-dimethoxy-1, 3- dihydro-indol-2-one (1 g, 3.36 mmole), kept under N2 flow at 0C, and TEA (0.7 ml, 5.04 mmole) in DCM (50 ml), was dropwise added with a solution of 4-nitrobenzyl-chloroformate (1.08, 5.04 mmole) in DCM (300 ml). The mixture was stirred for 22 h at room temperature. The solid precipitate was recovered by filtration and resuspended in Et2O (4 ml), then filtered again to afford the desired product as a red solid (1.06 g, yield 69%). M. p. : 225-227C. lH NMR (DMSO-d6+AcOH-d4): 8 3. 55 (3H, s), 8 3.78 (3H, s), 6 5.45 (2H, s), 8 6.51 (1H, s), 8 7.06 (1H, s), 8 7.43 (2H, d, J=9.5 Hz), 8 7.44 (1H, s), 8 7.73-7. 78 (4H, m), 8 8. 28 (2H, d, J=9.5 Hz), 10.31 (1H, s). HPLC purity: 94.6%. Elemental analysis found C (62.43%), H (4.25%), N (5. 81%)- calculated C (63.028%), H (4.23%), N (5. 88%). (C24H27NO6). |
69% | With triethylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 20℃; for 22h; | Example H.4 (E)-4-(5,6-dimethoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)phenyl, 4-nitrobenzyl carbonate A suspension of (E)-3-(4-hydroxybenzylidene)-5,6-dimethoxy-1,3-dihydro-indol-2-one (1 g, 3.36 mmole), kept under N2 flow at 0 C., and TEA (0.7 ml, 5.04 mmole) in DCM (50 ml), was dropwise added with a solution of 4-nitrobenzyl-chloroformate (1.08, 5.04 mmole) in DCM (300 ml). The mixture was stirred for 22 h at room temperature. The solid precipitate was recovered by filtration and resuspended in Et2O (4 ml), then filtered again to afford the desired product as a red solid (1.06 g, yield 69%). M.p.: 225-227 C. 1H NMR (DMSO-d6+AcOH-d4): delta 3.55 (3H, s), delta 3.78 (3H, s), delta 5.45 (2H, s), delta 6.51 (1H, s), delta 7.06 (1H, s), delta 7.43 (2H, d, J=9.5 Hz), delta 7.44 (1H, s), delta 7.73-7.78 (4H, m), delta 8.28 (2H, d, J=9.5 Hz), 10.31 (1H, s). HPLC purity: 94.6%. Elemental analysis found C (62.43%), H, (4.25%), N, (5.81%)-calculated C (63.028%), H, (4.23%), N, (5.88%).(C24H27NO6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Step 1: Piperazine-1. 3-dicarboxylic acid 1- (4-nitrobenzvl) ester; CuCO3 Cu (OH) 2-H20 (15.8 g) was added to the H20 (275 mL) solution of piperazine-2-carboxylic acid, dihydrochloride (22.3 g), then the mixture was refluxed and stirred for 10 min. The insoluble material was filtered off and was washed with hot H20 (165 mL). The filtrate was cooled to room temperature, and NaHCO3 (9. 2 g) and 1,4-dioxane (220 mL) was added to the dark blue solution. The mixture was cooled to 0 C and NaHCO3 (18.5 g) and 50% solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> in 1,4-dioxane (61.7 g) was added to the mixture for 0.5 h. After stirring for additional 1.5 h at 0 C, the precipitate was filtered and washed with cold H20 (140 mL), EtOH (100 mL), acetone (200 mL) and Et2O (100 mL), then it was allowed to dry under reduced pressure to obtain the pale blue crystals. The crystals were added to the 1 mol/L HCI (330 mL) solution of EDTA-2Na (20.5 g) for 30 min, and stirred for 2 h at room temperature. The suspension was filtered and the filtered material was diluted with EtOH-H2O (7 : 3,550 mL) and refluxed for 10 min. The reaction mixture was filtered to obtain the colorless crystals. The recrystallization from the filtrate was carried out 3 times to obtain additional crystals. The combined crystals were dried under reduced pressure to obtain the titled compound (26.25 g, 77%) as colorless crystals. 1H NMR (D2O) 8 2.54-2. 61 (m, 1H), 2.89 (dt, 2H, J= 12.7, 3.4 Hz), 2.97 (br, 1H), 3.13 (br, 1H), 3.62-4. 04 (m, 2H), 5.16 (s, 2H), 7.49 (d, 2H, J= 8.6 Hz), 8.14 (d, 2H, J= 8. 6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; at 0℃; for 0.5h; | Step 1: 4-p-Nitrobenzyloxycarbonyl-2-ketopiperazine; The 48.7% solution of p-nitrobenzyloxycarbonyl chloride in 1,4-Dioxane (10.7 mL) was added to the dichloromethane (110 mL) solution of 2-Ketopiperazine (2.21 g) and diisopropylethylamine (4.6 mL) at 0C and stirred for 0.5 h at 0 C. Water (300 mL) was added to the reaction mixture, and extracted with dichloromethane (3 x 100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography, eluted with CHCI3-methanol (30: 1), and the title compound was obtained as white solid (7.1 g, quant.). 1H NMR (d, CDCl3)No. 3.42-3. 45 (m, 2H), 3.74 (t, 2H, J = 5.4 Hz), 4.19 (s, 2H), 5.26 (s, 2H), 6.39 (brs, 1 H), 7.52 (d, 2H, J = 8. 6 Hz), 8.24 (d, 2H, J = 8. 6 Hz). |
100% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; at 0℃; for 0.5h; | Example 10; Preparation of (5R). (6Z)-7-Oxo-6-(56, 7, 8-tetrahvdroimidazofl. 2-alPvrazin-2- ytmethylene)-4-thia-1-azabicyclor3. 2. 0lhept-2-ene-2-carboxyiic acid, sodium salt 2-Ketopiperazine 2-Ketopiperazine was prepared in the method of Merck group (USP 5,629, 322). Step 1 : 4-p-Nitrobenzyloxycarbonyl-2-ketopiperazine The 48.7% solution of p-nitrobenzyloxycarbonyl chloride in 1,4-Dioxane (10.7 mL) was added to the dichloromethane (110 mL) solution of 2-Ketopiperazine (2.21 g) and diisopropylethylamine (4.6 mL) at 0C and stirred for 0.5 h at 0 C. Water (300 mL) was added to the reaction mixture, and extracted with dichloromethane (3 x 100 mL). The organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography, eluted with CHCI3-methanol (30: 1), and the title compound was obtained as white solid (7.1 g, quant.). 'H NMR (d, CDCI3) 3.42-3. 45 (m, 2H), 3.74 (t, 2H, J = 5.4 Hz), 4.19 (s, 2H), 5.26 (s, 2H), 6.39 (brs, 1H), 7.52 (d, 2H, J = 8. 6 Hz), 8.24 (d, 2H, J = 8. 6 Hz). |
100% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; at 0℃; for 0.5h; | The 48.7% solution of p-nitrobenzyloxycarbonyl chloride in 1,4-Dioxane (10.7 mL) was added to the dichloromethane (110 mL) solution of 2-Ketopiperazine (2.21 g) and diisopropylethylamine (4.6 mL) at 0 C. and stirred for 0.5 h at 0 C. Water (300 mL) was added to the reaction mixture, and extracted with dichloromethane (3*100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography, eluted with CHCl3-methanol (30:1), and the title compound was obtained as white solid (7.1 g, quant.). 1H NMR (d, CDCl3)delta 3.42-3.45 (m, 2H), 3.74 (t, 2H, J=5.4 Hz), 4.19 (s, 2H), 5.26 (s, 2H), 6.39 (brs, 1H), 7.52 (d, 2H, J=8.6 Hz), 8.24 (d, 2H, J=8.6 Hz). |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; water; | Step 1 4-p-Nitrobenzyloxycarbonyl-2-ketopiperazine The 48.7% solution of p-nitrobenzyloxycarbonyl chloride in 1,4-Dioxane (10.7 mL) was added to the dichloromethane (110 mL) solution of 2-Ketopiperazine (2.21 g) and diisopropylethylamine (4.6 mL) at 0 C. and stirred for 0.5 h at 0 C. Water (300 mL) was added to the reaction mixture, and extracted with dichloromethane (3*100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography, eluted with CHCl3-methanol (30:1), and the title compound was obtained as white solid (7.1 g, quant.). 1H NMR (d, CDCl3) 3.42-3.45 (m, 2H), 3.74 (t, 2H, J=5.4 Hz), 4.19 (s, 2H), 5.26 (s, 2H), 6.39 (brs, 1H), 7.52 (d, 2H, J=8.6 Hz), 8.24 (d, 2H, J=8.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydroxide; dihydrogen peroxide; In dichloromethane; acetone; | Thus, to an ice-cold solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (10.11 g, 4.7 mmol) in acetone (20 mL) was added dropwise over 30 min an ice-cold mixture of 30% H2O2 (2.7 mL, 24 mmol) and 2.35 N NaOH (20 mL, 47 mmol). The mixture was vigorously stirred for 15 min and then it was filtered and the filter-cake was washed with water and then with hexane. The resulting damp solid was taken up in dichloromethane, the solution was dried (Na2SO4) and then it was diluted with an equal volume of hexane. Concentration of this solution at 20 C. on a rotary evaporator gave a crystalline precipitate which was filtered, washed with hexane and dried in vacuo to give compound III (6.82 g, 74%) as pale yellow microcrystals, mp 104 C. (dec). Di-4-nitrobenzyl peroxydicarbonate was found to be a relatively stable material which decomposed as its melting point with slow gas evolution. In comparison, dibenzyl peroxydicarbonate2 decomposed with a sudden vigorous expulsion of material from the melting point capillary. |
74% | With sodium hydroxide; dihydrogen peroxide; In dichloromethane; acetone; | Thus, to an ice-cold solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (10.11 g, 4.7 mmol) in acetone (20 mL) was added dropwise over 30 min an ice-cold mixture of 30% H2O2 (2.7 mL, 24 mmol) and 2.35 N NaOH (20 mL, 47 mmol). The mixture was vigorously stirred for 15 min and then it was filtered and the filter-cake was washed with water and then with hexane. The resulting damp solid was taken up in dichloromethane, the solution was dried (Na2SO4) and then it was diluted with an equal volume of hexane. Concentration of this solution at 20 C. on a rotary evaptor gave a crystalline precipitate which was filtered, washed with hexane and dried in vacuo to give compound III (6.82 g, 74%) as pale yellow microcrystals, mp 104 C.(dec). Di-4-nitrobenzyl peroxydicarbonate was found to be a relatively stable material which decomposed as its melting point with slow gas evolution. In comparison, dibenzyl peroxydicarbonate2 decomposed with a sudden vigorous expulsion of material from the melting point capillary. |
With sodium hydroxide; dihydrogen peroxide; In dichloromethane; acetone; | A. Di-4-nitrobenzyl Peroxydicarbonate (V) Di-4-nitrobenzyl peroxydicarbonate was prepared using a modification of the literature procedure1. Thus, to an ice-cold solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (10.11 g, 4.7 mmol) in acetone (20 mL) was added dropwide over 30 min an ice-cold mixture of 30% H2O2 (2.7 mL, 24 mmol) and 2.35 N NaOH (20 mL, 47 mmol). The mixture was vigorously stirred for 15 min and then it was filtered and the filter-cake was washed with water and then with hexane. The resulting damp solid was taken up in dichloromethane, the solution was dried (Na2SO4) and then it was diluted with an equal volume of hexane. Concentration of this solution at 20 C. on a rotary evaptor gave a crystalline precipitate which was filtered, washed with hexane and dried in vacuo to give compound III (6.82 g, 74%) as pale yellow microcrystals, mp 104 C. (dec). Di-4-nitrobenzyl peroxydicarbonate was found to be a relatively stable material which decomposed as its melting point with slow gas evolution. In comparison, dibenzyl peroxydicarbonate2 decomposed with a sudden vigorous expulsion of material from the melting point capillary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In dichloromethane; | Step A 4-(N-((4-Nitrobenzyl)oxycarbonyl)-N-(prop-1-yl)amino)-piperidine trifluoroacetate The title compound was prepared by the reaction of <strong>[301225-58-1]4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine</strong> (from Example 17, Step A) with (4-nitrobenzyl)chloroformate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 322.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.6% | With sodium chloride; potassium carbonate; triethylamine; trifluoroacetic acid; In tetrahydrofuran; dichloromethane; ethyl acetate; | Production Example 25 (2S,4R)-4-Hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidine-4-ylhydroxymethyl)-pyrrolidine STR63 Under ice-cooling, trifluoroacetic acid (20 ml) was added to a solution of crude (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[N-(p-nitrobenzyloxycarbonyl)piperidine-4-ylhydroxymethyl]-pyrrolidine (3.89 g. 6.56 mmol) in methylene chloride (20 ml) and the obtained mixture was stirred at the same temperature for 40 minutes and then at room temperature for additional 40 minutes. Next, the solvent and trifluoro-acetic acid were distilled off under a reduced pressure. A 10% aqueous solution of potassium carbonate (30 ml) was added to the residue followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue thus obtained was dissolved in tetrahydrofuran (30 ml). To the solution thus obtained was added, under ice-cooling, a solution of triethylamine (0.94 ml, 6.7 mmol) and p-nitrobenzyl chloroformate (1.39 g, 6.45 mmol) in tetrahydrofuran (15 ml) and the resulting mixture was stirred at the same temperature for 10 minutes and then at room temperature for an additional 2.5 hours. After adding ethyl acetate (120 ml) to the reaction mixture, the organic layer was washed successively with water, 1 N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen-carbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The residue was dissolved in tetrahydrofuran (40 ml). To the obtained solution was added, under ice-cooling, a 1 M solution of tetrabutyl-ammonium fluoride in tetrahydrofuran (8.9 ml, 8.9 mmol) and the mixture was stirred at the same temperature for 15 minutes and then at room temperature for an additional 2 hours. After distilling off the solvent under a reduced pressure, ethyl acetate (80 ml) was added to the residue. The organic layer was washed successively with water, 1 N hydrochloric acid, a 50%-saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogen-carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The residue was subjected to silica gel chromatography (Wakogel C-200, 35 g, ethyl acetate) to thereby give the target compound (2.00 g, 54.6%). NMR(CDCl3) delta: 1.45~1.76(5H, m), 1.77~1.95(1H, m), 2.06~2.16(1H, m), 2.60~2.90(2H, m), 3.30~3.50(2H, m), 3.82(1H, d, J=12 Hz), 4.15~4.35(3H, m), 4.46(1H, brs), 4.65~4.86(1H, m), 5.15~5.28(4H, m), 7.50(2H, d, J=8 Hz), 7.51(2H, d, J=8 Hz), 8.22(4H, d, J=8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In dichloromethane; | N-(para-Nitrobenzyloxycarbonyl)-5-fluorotryptamine To a stirred solution of 3.0 g (18.5 mmol) of 5-fluorotryptamine and 2.06 g (20.4 mmol) of ns methylmorpholine in 100 mL of methylene chloride at 0 C. was added dropwise a solution of 4.31 g (20.4 mmol) of p-nitrobenzylchloroformate in 20 mL of methylene chloride. The reaction mixture was stirred at 0 C. under argon, for 1.5 hours and then overnight at room temperature. The reaction mixture was filtered to remove the morpholine hydrochloride salt. The methylene chloride solution was washed with 5*100 mL 5% HCl and 3*100 mL water, dried over anhydrous Na2 SO4. After the removal of the solvent under vacuum, a yellow solid was obtained which was crystallized from hot toluene (3.5 g, 53% yield). mp 93-94 C. 1 H NMR (CDCl3) delta8.3 (d, 2H), 7.8-6.9 (m, 7H), 5.2 (s, 2H), 3.3 (q, 2H), 2.9 (t, 2H). IR (KBr) 3380, 3300, 2890, 2820, 1700, 1520, 1480, 1450, 1330, 1250 Cm-1. Analysis calculated for C18 H15 FN3 O3: C, 60.67; H, 4.24; N, 11.79 Found: C) 60.58; H, 4.60; N, 11.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In sodium hydroxide; aqueous-acetonitrile | 6 [Reference Example 6] [Reference Example 6] (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(4-(2-((2S)-2-(p-nitrobenzyloxycarbonyl) -2-(p-nitrobenzyloxycarbonylamino) ethylthio)acetyl)piperazine-1-yl)carbonyl-4-mercaptopyrrolidine STR13 1) To 5.05 g of D-cysteine hydrochloride dissolved in 4N sodium hydroxide and cooled on an ice bath was added dropwise 9.39 ml of p-methoxybenzyl chloride, followed by 2 hours of stirring at room temperature. The resulting reaction solution was washed with ether and acidified with concentrated hydrochloric acid, and a crystal was collected by filtration to yield 7.78 g of S-p-methoxybenzyl-D-cysteine in the form of pale yellow crystals. A 7.025 g portion of the thus obtained S-p-methoxybenzyl compound was dissolved in an aqueous-acetonitrile, and, with cooling on an ice bath, to this were added 12.75 g of sodium bicarbonate and 7.09 g of p-nitrobenzyloxycarbonyl chloride, and the mixture was stirred for 1.5 hours at room temperature. The reaction solution was washed with ether, acidified with concentrated sulfuric acid and extracted with ethyl acetate, the resulting organic layer was washed with water and dried over sodium sulfate and then the solvent was removed by evaporation under a reduced pressure, thereby yielding 6.47 g of S-p-methoxybenzyl-N-p-nitrobenzyloxycarbonylcysteine as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In water; | N-PNZ^-amino-ZO^-hydroxy-butyric acid; To a stirring solution of 4-amino-2(5)-hydroxybutyric acid (5.0 g, 0.041 mol) in dioxane: H2O (200 mL, 1 :1 v/v) was added K2CO3 (11.6 g, 0.084 mol), followed by jo-nitrobenzyl chloroformate (9.23 g, 0.043 mol) and the reaction mixture was stirred overnight. The resulting precipitate was removed by filtration and the organic solvent was removed by rotary evaporation. The resulting aqueous solution was acidified to pH 1 by the addition of 1 M HCl (100 mL). Upon the addition of ethyl acetate (100 mL) to the aqueous layer, the product precipitated and was collected by filtration. The filtrate was added to a separatory funnel and the organic layer was <n="54"/>separated. Upon addition of ethyl acetate (100 mL) to the aqueous layer, a second precipitation occurred, the product was collected by filtration and this process was repeated once more. The combined organic layers were then placed at -5 C overnight, to induce precipitation of the product, which was collected by filtration. The desired N- PNZ-4-amino-2(5)-hydroxy-butyric acid (9.3 g, 0.031 mol, 75% yield, 90 % purity) was carried through to the next step without further purification. MS m/e [M+H]+ calcd 299.1, found 298.9. |
In sodium hydroxide; | 1) A 2.82 g portion of (2S)-4-amino-2-hydroxybutyric acid was dissolved in 15 ml of 2N sodium hydroxide, and to the solution cooled on an ice bath were simultaneously added dropwise 6.13 g of p-nitrobenzyloxycarbonyl chloride dissolved in ether and 7.5 ml of 4N sodium hydroxide. After 2 hours of stirring at the same temperature, the solution was washed with ether, an aqueous layer was adjusted to acidic with concentrated hydrochloric acid, and a precipitated solid material was collected by filtration, washed with water and then dried to yield 4.48 g of (2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyric acid. NMR (DMSO-d6) delta: 1.5-2.1 (2H, m), 2.9-3.4 (2H, m), 3.99 (1H, dd), 5.16 (2H, s), 7.59 (2H, d), 8.23 (2H, d) | |
With potassium carbonate; In 1,4-dioxane; water; | N-PNZ-4-amino-2(S)-hydroxy-butyric acidTo a stirring solution of 4-amino-2(,S)-hydroxybutyric acid (5.0 g, 0.041 mol) in dioxane: H2O (200 mL, 1:1 v/v) was added K2CO3 (11.6 g, 0.084 mol), followed by <strong>[4457-32-3]p-nitrobenzyl chloroformate</strong> (9.23 g, 0.043 mol) and the reaction mixture was stirred overnight. The resulting precipitate was removed by filtration and the organic solvent was removed by rotary evaporation. The resulting aqueous solution was acidified to pH 1 by the addition of 1 M HCl (100 mL). Upon the addition of ethyl acetate (100 mL) to the aqueous layer, the product precipitated and was collected by filtration. The filtrate was added to a separatory funnel and the organic layer was separated. Upon addition of ethyl acetate (100 mL) to the aqueous layer, a second precipitation occurred, the product was collected by filtration and this process was repeated once more. The combined organic layers were then placed at -5 C overnight, to induce precipitation of the product, which was collected by filtration. The desired N- PNZ-4-amino-2(1S)-hydroxy-butyric acid (9.3 g, 0.031 mol, 75% yield, 90 % purity) was carried through to the next step without further purification. MS m/e [M+H]+ calcd 299.1, found 298.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydrogencarbonate; In diethyl ether; water; 2-mercaptoethylamine hydrochloride; | STEP B Preparation of p-Nitrobenzyloxycarbonylaminoethanethiol STR32 To 600 ml diethyl ether(Et2 O)-75 ml H2 O in an ice bath with stirring is added 3.2 g cysteamine hydrochloride (mw=114; 28.1 mmole). A solution of 7.14 g NaHCO3 (mw=84; 85 mmole) in 75 ml H2 O is added. The ice bath is removed, and at room temperature a solution of 6.75 g p-nitrobenzylchloroformate (mw=216; 31.3 mmole) in 270 ml Et2 O is added dropwise over a period of one hour. After 10 additional minutes, the layers are separated. The ether layer is extracted with 150 ml 0.25 N HCl, and then with 200 ml brine. Each aqueous layer is then backwashed successively with 100 ml Et2 O. The combined Et2 O layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream. The crystalline residue is slurried in a small amount of ether, filtered, and the pale yellow crystals are dried under high vacuum to give 4.7 g p-nitrobenzloxycarbonylaminoethanethiol (65% yield). NMR (CDCl3): 8.18 (d, J=8 Hz, aromatic protons ortho to nitro), 7.47 (d, J=8 Hz, aromatic protons meta to nitro), 5.27 (--NH--), 5.20 (s, --CH2 --phi--pNO2), 3.40 (m, --CH2 --NH--), 2.67 (m, --CH2 --SH), 1.35 (t, J=8.5 Hz, --SH) in ppm downfield from TMS. IR (CHCl3 solution) carbonyl--~1725 cm-1 |
With sodium hydrogencarbonate; In diethyl ether; water; 2-mercaptoethylamine hydrochloride; | EXAMPLE 10 Preparation of p-Nitrobenzyloxycarbonylaminoethanethiol STR18 To 600 ml diethyl ether (Et2 O)-75 ml H2 O in an ice bath with stirring is added 3.2 g cysteamine hydrochloride (mw=114; 28.1 mmole). A solution of 7.14 g NaHCO3 (mw=84; 85 mmole) in 75 ml H2 O is added. The ice bath is removed, and at room temperature a solution of 6.75 g p-nitrobenzylchloroformate (mw=216; 31.3 mmole) in 270 ml Et2 O is added dropwise over a period of one hour. After 10 additional minutes, the layers are separated. The ether layer is extracted with 150 ml 0.25N HCl, and then with 200 ml brine. Each aqueous layer is then backwashed successively with 100 ml Et2 O. The combined Et2 O layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream. The crystalline residue is slurried in a small amount of ether, filtered, and the pale yellow crystals are dried under high vacuum to give 4.7 | |
With sodium hydrogencarbonate; In diethyl ether; water; | Step B Preparation of p-Nitrobenzyloxycarbonylaminoethanethiol STR24 To 600 ml diethyl ether (Et2 O)-75 ml H2 O in an ice bath with stirring is added 3.2 g cysteamine hydrochloride (mw=114; 28.1 mmole). A solution of 7.14 g NaHCO3 (mw=84; 85 mmole) in 75 ml H2 O is added. The ice bath is removed, and at room temperature a solution of 6.75 g p-nitrobenzylchloroformate (mw=216; 31.3 mmole) in 270 ml Et2 O is added dropwise over a period of one hour. After 10 additional minutes, the layers are separated. The ether layer is extracted with 150 ml 0.25 N HCl, and then with 200 ml brine. Each aqueous layer is then backwashed successively with 100 ml Et2 O. The combined Et2 O layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream. |
With sodium hydrogencarbonate; In diethyl ether; water; | Step B Preparation of p-Nitrobenzyloxycarbonylaminoethanethiol STR35 To 600 ml diethyl ether(Et2 O)-75 ml H2 O in an ice bath with stirring is added 3.2 g cysteamine hydrochloride (mw=114; 28.1 mmole). A solution of 7.14 g NaHCO3 (mw=84; 85 mmole) in 75 ml H2 O is added. The ice bath is removed, and at room temperature a solution of 6.75 g p-nitrobenzylchloroformate (mw=216; 31.3 mmole) in 270 ml Et2 O is added dropwise over a period of one hour. After 10 additional minutes, the layers are separated. The ether layer is extracted with 150 ml 0.25 N HCl, and then with 200 ml brine. Each aqueous layer is then backwashed successively with 100 ml Et2 O. The combined Et2 O layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream. The crystalline residue is slurried in a small amount of ether, filtered, and the pale yellow crystals are dried under high vacuum to give 4.7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; | EXAMPLE XII 7-(4-NO2 -Z-L-Arginamido)-3-phenylcoumarin The acylating reagent, 1-(4-nitrobenzyloxycarbonyl)-benzotriazole, was prepared from 4-nitrobenzyl chloroformate and 1-hydroxybenzotriazole using a procedure analogous to that described for 1-benzoyloxybenzotriazole [M. Ueda, K. Okada, and Y. Imai, J. Polym. Sci. Polym. Chem. Ed., 14, 2665 (1976)]: mp 184; IR (KBr) C=O=1745 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With pyridine; triethylamine; In dichloromethane; | (1) 4-Hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine To a solution of <strong>[5382-17-2]4-hydroxypiperidine hydrochloride</strong> (3.0 g, 21.8 mmol) in a mixture of methylene chloride (90 ml) and pyridine (15 ml) were added chloroformic acid p-nitrobenzyl ester (15.4 g, 72.0 mmol) and triethylamine (13.1 ml, 93.8 mmol) in an ice bath. The mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1: 1) --> ethyl acetate as the eluant to afford 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, yield 48percent) as pale yellow crystals. 1H-NMR (400 MHz, CDCl3): delta (ppm) 8.23 (2H, d, J=8.1Hz), 8.51 (2H, d, J=8.1Hz), 5.23 (2H, s), 3.98 - 3.87 (3H, m), 3.30 - 3.15 (2H, m), 1.96 - 1.85 (2H, m), 1.59 - 1.48 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | (1) 3-Hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine [1788] A solution of 1-benzhydryl-3-hydroxyazetidine (9.00 g, 37.6 mmol) in methanol (270 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (9.00 g) in a water bath (50 C.) for 5.5 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and distilled water. The organic layer was concentrated under reduced pressure and dried in vacuo to give a crude product. To a solution of the crude product in a mixture of methylene chloride (82 ml) and methanol (55 ml) were added chloroformic acid p-nitrobenzyl ester (8.90 g, 41.3 mmol) and triethylamine (5.79 ml, 41.3 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)?ethyl acetate as the eluant to afford 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine (3.52 g, yield 37%) as pale yellow crystals. [1789] 1H-NMR (400 MHz, CDCl3): delta (ppm) 8.22 (2H, d, J=8.8 Hz), 7.50 (2H, d, J=8.8 Hz), 5.19 (2H, s), 4.71-4.64 (1H, m), 4.27 (2H, dd, J=9.9, 7.0 Hz), 3.93 (2H, dd, J=9.9, 4.0 Hz), 2.20-2.16 (1H, brd, J=5.9 Hz). | |
37% | With triethylamine; In methanol; palladium on charcoal; dichloromethane; | (1) 3-Hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine A solution of 1-benzhydryl-3-hydroxyazetidine (9.00 g, 37.6 mmol) in methanol (270 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (9.00 g) in a water bath (50ØC) for 5.5 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and distilled water. The organic layer was concentrated under reduced pressure and dried in vacuo to give a crude product. To a solution of the crude product in a mixture of methylene chloride (82 ml) and methanol (55 ml) were added chloroformic acid p-nitrobenzyl ester (8.90 g, 41.3 mmol) and triethylamine (5.79 ml, 41.3 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1: 1) ? ethyl acetate as the eluant to afford 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine (3.52 g, yield 37%) as pale yellow crystals. 1H-NMR (400 MHz, CDCl3): delta (ppm) 8.22 (2H, d, J=8.8Hz), 7.50 (2H, d, J=8.8Hz), 5.19 (2H, s), 4.71 - 4.64 (1H, m), 4.27 (2H, dd, J=9.9, 7.0Hz), 3.93 (2H, dd, J=9.9, 4.0Hz), 2.20 - 2.16 (1H, br d, J=5.9Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 16h; | A solution of 6-chloro-2,4-dimethyl-JV-((i?)-3- {4-[(thiophen-3-ylmethyl)-amino]- piperidm-l-yl}-butyl)-nicotinamide (52 mg, 0.12 mmol), <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (50 mg, 0.23 mmol) and DIPEA (50 muL, 0.29 mmol) in THF (0.90 ml) was stirred at 60 0C for 16 hours. Once cooled, the reaction was diluted with saturated aqueous NaHCO3 (25 ml) and was extracted with CH2Cl2 (20 ml x 3). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2/Me0H, 29:1) gave COMPOUND 244 as an off-white foam (47.2 mg, 64%). 1H NMR (CDCl3) delta 0.85-1.30 (m, 2H), 0.97 (d, 3H, J= 7.0 Hz), 1.48-1.81 (m, 4H), 2.05-2.17 (m, IH), 2.31 (s, 3H), 2.43-2.57 (m, IH), 2.52 (s, 3H), 2.66-2.87 (m, 3H), 3.22-3.35 (m, IH), 3.77- 4.06 (m, 4H), 5.17 (s, 2H), 6.93-7.05 (m, 3H), 7.20-7.32 (m, 3H), 8.13 (d, 2H, J= 7.3 Hz), 8.60 (br s, IH); ES-MS m/z 614 (M+H), 616 (M+H+2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With hydrogenchloride; sodium hydrogencarbonate; In 1,4-dioxane; water; | Step 1 Piperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester CuCO3.Cu(OH)2.H2O (15.8 g) was added to the H2O (275 mL) solution of piperazine-2-carboxylic acid, dihydrochloride (22.3 g), then the mixture was refluxed and stirred for 10 min. The insoluble material was filtered off and was washed with hot H2O (165 mL). The filtrate was cooled to room temperature, and NaHCO3 (9.2 g) and 1,4-dioxane (220 mL) was added to the dark blue solution. The mixture was cooled to 0 C. and NaHCO3 (18.5 g) and 50% solution of 4-nitrobenzyl chloroformate in 1,4-dioxane (61.7 g) was added to the mixture for 0.5 h. After stirring for additional 1.5 h at 0 C., the precipitate was filtered and washed with cold H2O (140 mL), EtOH (100 mL), acetone (200 mL) and Et2O (100 mL), then it was allowed to dry under reduced pressure to obtain the pale blue crystals. The crystals were added to the 1 mol/L HCl (330 mL) solution of EDTA.2Na (20.5 g) for 30 min, and stirred for 2 h at room temperature. The suspension was filtered and the filtered material was diluted with EtOH-H2O (7:3, 550 mL) and refluxed for 10 min. The reaction mixture was filtered to obtain the colorless crystals. The recrystallization from the filtrate was carried out 3 times to obtain additional crystals. The combined crystals were dried under reduced pressure to obtain the titled compound (26.25 g, 77%) as colorless crystals. 1H NMR (D2O) delta 2.54-2.61 (m, 1H), 2.89 (dt, 2H, J=12.7, 3.4 Hz), 2.97 (br, 1H), 3.13 (br, 1H), 3.62-4.04 (m, 2H), 5.16 (s, 2H), 7.49 (d, 2H, J=8.6 Hz), 8.14 (d, 2H, J=8.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 56.4 mg (0.4 mmol) ethyl methyl 5-amino-2- furancarboxylate in 5mL of anhydrous dichloromethane was added 84.5 mg (0.42 mmol) 4-nitrobezenechloroformate. The reaction mixture was stirred at room temperature for half an hour and concentrated. Diisopropylethylamine (0.14 mL, 0.8 mmol), DMHB resin bound 0-(1, 1-dimethylethyl)-N-{(3S)-1-[(2- nitrophenyl) sulfonyll-3-pyrrolidinyl}-L-tyrosinamide 4 (200 mg, 0.16 mmol) and dimethyl formamide (5 mL) were added to reaction mixture and shaked overnight.. The resin was washed with CH2CI2 (3 x 1 mL), CH2CI2/MeOH (1: 1, 3 x 1 mL), MeOH (3 x 1 mL) and CH2CI2 (3 x 10mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In chloroform; at 0 - 20℃; | 1.44 g (6.70 mmol) of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> in solution in 10 ml of chloroform is added dropwise and under stirring to a suspension of 1 g (3.27 mmol) of 1,12-bis(imidazolin-2-yl)dodecane and 0.87 ml (6.70 mmol) of triethylamine in 20 ml of chloroform cooled down by an ice bath. After which, stirring is maintained at ambient temperature overnight. The reaction mixture is then diluted with 30 ml of chloroform then washed successively with 120 ml of water, 120 ml of a saturated aqueous solution of sodium chloride and 2×120 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure. The residue, cooled down and taken up in a minimum of chloroform, is finally crystallized at -4 C. from hexane in order to produce 2.08 g (96%) of product in the form of a white powder. Melting point: 115-116 C. NMR 1H (CDCl3, 100 MHz), delta (ppm): 1.21 (s, 16H); 1.60 (m, 4H); 2.67 (t, 4H); 3.80 (s, 8H); 5.24 (s, 4H); 7.46 and 7.55 (dd, 4H); 8.17 and 8.25 (dd, 4H). FT-IR, nu (cm-1): 1005 and 1154 (C-O-C); 1343 and 1517 (NO2); 1645 (CN); 1724 (NCO). MS-ES+: [M+H]+: 665 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With soda solution; In 1,4-dioxane; water; at 0 - 20℃;pH 10 - 12; | To a solution of 1 g (3.06 mmol) of 1,12-bis(amidinyl)dodecane dihydrochloride in 60 ml of a dioxane/water (3:1) diphasic mixture and cooled down by an ice bath, 1.65 g (7.65 mmol) of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> in solution in 5 ml of dioxane is added dropwise and under vigorous stirring. The pH of the solution is maintained between 10 and 12 with a 4N aqueous soda solution. The mixture is then left under stirring and at ambient temperature overnight. After which, 100 ml of water is added. The precipitate formed is then separated, washed several times in water, then ether in order to produce, after drying in a desiccator, 1.37 g (74%) of product in the form of a white powder. Melting point: 87-88 C. NMR 1H (DMSO-d6, 100 MHz), delta (ppm): 1.22 (s, 16H); 1.51 (m, 4H); 2.18 (t, 4H); 5.15 (s, 4H); 7.59 (dd, 4H); 8.23 (dd, 4H); 8.69 (s, 4H). FT-IR, nu (cm-1): 1248 (C-O-C); 1344 and 1512 (NO2); 1621 (CN); 1658 (CO); 3316 (NHCO); 3406 (NH) MS-ES+: [M+H]+: 623 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In dichloromethane; at 20℃; | /j-Nitrobenzyloxycarbonylbenzotriazole (32a):/»-Nitrobenzyl chlorofbrmate (0.5 mmol) was dissolved in 5 mL OfCH2Cl2 and treated with benzotriazole (0.5 mmol) using Et3N (2 mmol) as base. The mixture was stirred overnight at room temperature, diluted with CH2Cl2 (20 mL) and washed with 3 x 5 mL of IN HCl, 2 x 5 mL of IN NaOH and 1 x 5 mL of brine. The organic phase was dried and filtered. The volatiles were removed and the product was triturated with diethyl ether to provide a pale yellow solid (59% yield), mp 160 - 162 0C. 1H NMR (CDCl3) delta 8.27 (d, IH5 J= 8.9 Hz), 8.17 (m, 3H), 7.72 (d, IH, J= 8.9 Hz), 7.65 (td, IH, J= 8.3 Hz, 1.1 Hz), 7.53 (m, 2H), 5.26 (s, 2H). 13C NMR (CDCl3) delta 154.84, 146.17, 142.27, 141.30, 132.01, 130.82, 128.78, 126.37, 124.16, 120.86, 113.58, 68.66. HRMS (FAB) calcd for Ci4H11N4O4 ([M+H]+): 299.0775, found 297.0775. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In tetrahydrofuran; for 4h; | (N-Hydroxy-5-norbornene-2,3-dicarboxyl-imido)-4-nitro-benzoate; <n="50"/>To a stirring solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (5.0 g, 0.023 mol) in THF (90 mL) at 0C was added N-hydroxy-5-norbornene-2,3-dicarboximide (4.16 g, 0.023 mol), followed by the dropwise addition of a solution Of Et3N (3.2 mL, 0.02 mol) in THF (50 mL) and the reaction was stirred for 4 hours with gradual warming to room temperature. The reaction vessel was then placed in the freezer (-50C) for 1 hour to induce precipitation of triethylamine hydrochloride, which was removed by filtration.The filtrate was concentrated to dryness to yield a residue, which was vigorously stirred in MeOH (80 mL) for Ih and then filtered to yield (N-hydroxy-5-norbornene-2,3- dicarboxyl-imido)-4-nitro-benzoate as a white solid (7.98 g, 0.022 mol, 96% yield):TLC (hexanes:EtOAc v/v 1 :1) R/= 0.35. |
87.9% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | 8.87 g HONB was dissolved in 80 mL THFAfter adding 6.29 g of triethylamine,The system was cooled to 0C.A solution of 60 mL of pNZ-Cl in THF was added dropwise.After dropping,Warmed to room temperature. After 2h the reaction,The THF was evaporated to dryness under reduced pressure.After adding 300 mL of 15% NaHSO4 solution,Another 400 mL of EA was added. After stirring for 5h at room temperature,Liquid separation. The organic phase is washed twice with saturated saline(300mL*2),Then dry with anhydrous calcium chloride.Distill the solvent under reduced pressureGet HONB-pNZ,White solid,Quality is15.6 grams,The yield is 87.9%. Rf = 0.85 (petroleum ether: ethyl acetate = 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In dichloromethane; at 0 - 20℃; | Step K; 4-Nitrobenzyl allyl(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-(4-methoxyphenyl)pyrrolidin-3-yl)methyl)piperidin-4-yl)carbamateA solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.034 g, 0.16 mmol) in DCM (1 mL) was added dropwise to a mixture of the amine from step J (0.057 g, 0.13 mmol) and triethyl amine (0.54 mL, 0.39 mmol) in DCM (2 mL) at 0 0C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (1 %-3 % MeOH in DCM) afforded the title compound as a white foam (0.060 g, 75 %). 1H NMR (CDCl3, 300 MHz) delta 7.51 -7.25 (m, 6H), 6.93-6.88 (d, J = 8.7 Hz, 2H), 5.88-5.74 (m, IH), 5.22-5.09 (m, 4H), 4.11-3.55 (m, 10H), 3.02-2.97 (m, IH), 2.85-2.66 (m, 3H), 2.65-2.39 (m, 2H), 2.22-2.03 (m, 2H), 1.92-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 621.5 (M+H)+, 643.5 (M+Na)+. |
75% | With triethylamine; In dichloromethane; at 0 - 20℃; | A solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.034 g, 0.16 mmol) in DCM (1 mL) was added dropwise to a mixture of the amine from step J (0.057 g, 0.13 mmol) and triethyl amine (0.54 mL, 0.39 mmol) in DCM (2 mL) at 0 0C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (1 %-3 % MeOH in DCM) afforded the title compound as a white foam (0.060 g, 75 %). 1H NMR <n="56"/>(CDCl3, 300 MHz) delta 7.51-7.25 (m, 6H), 6.93-6.88 (d, J = 8.7 Hz, 2H), 5.88-5.74 (m, IH), 5.22-5.09 (m, 4H), 4.11-3.55 (m, 10H), 3.02-2.97 (m, IH), 2.85-2.66 (m, 3H), 2.65-2.39 (m, 2H), 2.22-2.03 (m, 2H), 1.92-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 621.5 (M+H)+, 643.5 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In dichloromethane; at 0 - 20℃; | Step B; 4-Nitrobenzyl l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl(cyclopropylmethyl)carbamate; A solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.129 g, 0.60 mmol) in DCM (2 mL) was added dropwise to a mixture of the amine from step A (0.2 g, 0.54 mmol) and triethylamine (0.23 mL, 1.62 mmol) in DCM (4 mL) at 0 0C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined organinc extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-2% MeOH in DCM) afforded the title compound as a white foam (0.25 g, 77 %). 1H NMR (CDCl3, 300 MHz) delta 8.24-8.21 (d, J = 7.5 Hz, 2H), 7.52-7.27 (m, 7H), 5.23 (s, 2H), 3.87-3.66 (m, 5H), 3.10-2.83 (m, 3H), 2.83-2.65 (m, 3H), 2.65-2.44 (m, 2H), 2.20-2.09 (m, 2H), 1.86-1.54 (m, 12H), 0.95-0.94 (m, IH), 0.54-0.48 (m, 2H), 0.24 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 605.5 (M+H)+, 627.5 (M+Na)+. |
77% | With triethylamine; In dichloromethane; at 0 - 20℃; | A solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.129 g, 0.60 mmol) in DCM (2 mL) was added dropwise to a mixture of the amine from step A (0.2 g, 0.54 mmol) and triethylamine (0.23 mL, 1.62 mmol) in DCM (4 mL) at 0 0C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined organinc extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-2% MeOH in DCM) afforded the title compound as a white foam (0.25 g, 77 %). 1H NMR (CDCl3, 300 MHz) delta 8.24-8.21 (d, J = 7.5 Hz, 2H), 7.52-7.27 (m, 7H), 5.23 (s, 2H), 3.87-3.66 (m, 5H), 3.10-2.83 (m, 3H), 2.83-2.65 (m, 3H), 2.65-2.44 (m, 2H), 2.20-2.09 (m, <n="42"/>2H), 1.86-1.54 (m, 12H), 0.95-0.94 (m, IH), 0.54-0.48 (m, 2H), 0.24 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 605.5 (M+H)+, 627.5 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a stirring solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (5.0 g, 0.023 mol) in THF (90 mL) at 00C was added N-hydroxy-5-norbornene-2,3-dicarboximide (4.16 g, 0.023 mol), followed by the dropwise addition of a solution Of Et3N (3.2 mL, 0.02 mol) in THF (50 mL) and the reaction was stirred for 4 hours with gradual warming to room temperature. The reaction vessel was then placed in the freezer (-5C) for 1 hour to induce precipitation of triethylamine hydrochloride, which was removed by filtration. The filtrate was concentrated to dryness to yield a residue, which was vigorously stirred in MeOH (80 mL) for Ih and then filtered to yield (N-hydroxy-5-norbornene-2,3- dicarboxyl-imido)-4-nitro-benzoate as a white solid (7.98 g, 0.022 mol, 96% yield): TLC (hexanes:EtOAc v/v 1 :1) R/= 0.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4h; | (N-Hydroxy-5-norbornene-2,3-dicarboxyl-imido)-4-nitro-benzoateTo a stirring solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (5.0 g, 0.023 mol) in THF (90 mL) at 0C was added N-hydroxy-5-norbornene-2,3-dicarboximide (4.16 g, 0.023 mol), followed by the dropwise addition of a solution Of Et3N (3.2 mL, 0.02 mol) in THF (50 mL) and the reaction was stirred for 4 hours with gradual warming to room temperature. The reaction vessel was then placed in the freezer (-5C) for 1 hour to induce precipitation of triethylamine hydrochloride, which was removed by filtration. The filtrate was concentrated to dryness to yield a residue, which was vigorously stirred in MeOH (80 mL) for Ih and then filtered to yield (N-hydroxy-5-norbornene-2,3- dicarboxyl-imido)-4-nitro-benzoate as a white solid (7.98 g, 0.022 mol, 96% yield): TLC (hexanes:EtOAc v/v 1 : 1) R/= 0.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; at 20℃; for 1.5h;pH 8 - 9; | [0066] Boc-hAla(4-Pip-[Cbz-4-N02])-OMe; [0067] To a solution of compound 3.4 (1.5 g, 4.9 mmol) in THF (25 ml) was added 4-nitrobenzyloxycarbonyl-chloride (1.1 g, 4.9 mmol) and TEA (0.85 ml, 6 mmol) at room temperature and the mixture was stirred for 1.5 h while maintaining the pH of the reaction between 8-9 by addition of TEA. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate, washed with aqueous 5 % KHS04 and brine. The organic layer was dried (Na2S04) and evaporated in vacuo to afford the title compound.Yield: 2.35 g (100 , oil).Anal. HPLC: 76.7 % B; TLC: Rf = 0.89 (5: 1); MS calc: 479.2, found 480.0 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Step 1:1,4-Dioxane (10 mL) was added to a solution of guanidine hydrochloride (0.96 g, 10.0 mmol) and NaOH (0.80 g, 20.0 mmol) in H20 (10 mL), and the resulting mixture was cooled to 0 C. Next, a solution of 4- nitrobenzyl chloroformate (1.66 g, 7.7 mmol) in 1,4-dioxane (15 niL) was slowly added at 0-5 C under vigorous stirring. After stirring for an additional 10 h at room temperature, the mixture was concentrated under reduced pressure to one-third its original volume and extracted with EtOAc three times. The combined extracts were washed with brine and dried over a2S04. After filtering and a removal of the solvent under reduced pressure, the pure mono-protected guanidine 138 (1.56 g, 85%) was obtained.1H NMR (DMSO-d6, 400 MHz): delta 8.18 (d, J= 2.0 Hz, 2H), 7.57 (d, J= 2.0 Hz, 2H), 5.69 (br s, 4H), 4.62 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Step 3: General Procedures for de-hydroxylation & protectionA mixture of 180a (2.10 g, 10.5 mmol), acetic anhydride (1.98 mL, 21 mmol), Pd/C (5%, 210 mg) and acetic acid (0.5 mL) in ethanol (100 mL) was shaken under hydrogen (50 psi) on a Parr hydrogenator for 15h. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in a mixture of dry ethanol (50 mL) and toluene (50 mL), and evaporated to dryness. This process was repeated three times and the crude amidine residue was used without further purification.To a cooled (0 C) solution of amidine salt and sodium bicarbonate (1.93 g, 23.1 mmol) in dichloromethane / water (30 mL / 30 mL) was added <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (2.71 g, 12.6 mmol). After stirring at room temperature for 2 h, the layers were separated and the aqueous was extracted with CH2CI2 (3 X 25 mL). The combined organics were dried over NaS04 and concentrated to afford crude material. Flash column chromatography (EtOAc/Hexane 3: 1) provided title compound 181a (1.60 g, 41%) as white foam solid.1H NMR (CDCI3, 400 MHz) delta 8.85 (br s, 1H), 8.72 (br s, 1H), 8.22 (d, J= 7.2 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 5.08 (s, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 2.99 (m, 1H), 2.03 - 1.82 (m, 2H), 1.39 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In tetrahydrofuran; at 20℃; for 2h; | Example 2 Preparation of (1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-carbamic acid 4-nitro benzyl ester (Compound 2) 100 mg (0.28 mmol) of the compound obtained in Preparation Example <1-3> was dissolved in 3 mL of tetrahydrofuran, and then 78 mul (0.56 mmol, 2 eq) of triethylamine and 90 mul (0.42 mmol, 1.5 eq) of 4-nitro benzyl chloroformate were added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved again in 50 mL of ethyl acetate, and then the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica column chromatography (acetone:methylene chloride=1:4) to give 100 mg of a yellow foam solid compound (yield: 67%). 1H-NMR (300 MHz, CDCl3) delta=1.79-1.80 (m, 1H), 2.29-2.56 (m, 3H), 3.63 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 3.99 (s, 3H), 4.43-4.47 (m, 1H), 5.01 (d, 1H, J=13.5 Hz), 5.15 (d, 1H, J=13.2 Hz), 5.56 (d, 1H, J=7.2 Hz), 6.54 (s, 1H), 6.82 (d, 1H, J=10.8 Hz), 7.29 (d, 1H, J=10.8 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.51 (s, 1H), 8.18 (d, 2H, J=8.7 Hz) |
67% | With triethylamine; In tetrahydrofuran; at 20℃; for 2h; | Example 2 Preparation of (1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-carbamic acid 4-nitro benzyl ester (Compound 2) 100 mg (0.28 mmol) of the compound obtained in Preparation Example <1-3> was dissolved in 3 mL of tetrahydrofuran, and then 78 mul (0.56 mmol, 2 eq) of triethylamine and 90 mul (0.42 mmol, 1,5 eq) of 4-nitro benzyl chloroformate were added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved again in 50 mL of ethyl acetate, and then the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica column chromatography (acetone: methylene chloride=1:4) to give 100 mg of a yellow foam solid compound (yield: 67%). 1H-NMR(300MHz, CDCl3) delta = 1.79-1.80(m, 1H), 2.29-2.56(m, 3H), 3.63(s, 3H), 3.90(s, 3H), 3.93(s, 3H), 3.99(s, 3H), 4.43-4.47(m, 1H), 5.01(d, 1H, J = 13.5 Hz), 5.15(d, 1H, J = 13.2 Hz), 5.56(d, 1H, J = 7.2 Hz), 6.54(s, 1 H), 6.82(d, 1H, J = 10.8 Hz), 7.29(d, 1H, J = 10.8 Hz), 7.43(d, 2H, J = 8.7 Hz), 7.51(s, 1H), 8.18(d, 2H, J = 8.7 Hz)MS (m/e, M+): 536 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: 1-(p-Tosyl)-aziridine-2S-carboxylic acid methyl ester (2a). Trifluoroacetic acid (10 ml) was added dropwise over 10 min to asolution of 1a (2.0 g, 5.8 mmol) in dichloromethane (10 ml) and methanol (10 ml) at 0 oC and stirred for 30 min at 0 oC. Volatiles were removed by azeotropic removal with Et2O (3 x 10 ml). The residue was partitioned between Et2O (50 ml) and H2O (50 ml) and the ether layer was extracted with water (3 x10 ml). The combined aqueous layers were basified to pH 9 with solid NaHCO3 at 0 oC. Ethyl acetate (100 ml) was added to the aqueous solution followed by p-toluenesulfonyl chloride (1.11 g, 5.8 mmol) at 0 oC. The resulting immiscible layers were allowed to warm to room temperature and stirred vigorously for 24 h. After completion of the reaction, the two layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel in petroleum ether:ethyl acetate (4:1) to yield 2a as a clear oil (1.36 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: 1-(p-Tosyl)-aziridine-2S-carboxylic acid methyl ester (2a). Trifluoroacetic acid (10 ml) was added dropwise over 10 min to asolution of 1a (2.0 g, 5.8 mmol) in dichloromethane (10 ml) and methanol (10 ml) at 0 oC and stirred for 30 min at 0 oC. Volatiles were removed by azeotropic removal with Et2O (3 x 10 ml). The residue was partitioned between Et2O (50 ml) and H2O (50 ml) and the ether layer was extracted with water (3 x10 ml). The combined aqueous layers were basified to pH 9 with solid NaHCO3 at 0 oC. Ethyl acetate (100 ml) was added to the aqueous solution followed by p-toluenesulfonyl chloride (1.11 g, 5.8 mmol) at 0 oC. The resulting immiscible layers were allowed to warm to room temperature and stirred vigorously for 24 h. After completion of the reaction, the two layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel in petroleum ether:ethyl acetate (4:1) to yield 2a as a clear oil (1.36 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In a nitrogen atmosphere, at room temperature, in a 50 ml two-necked flask was 3-methylbenzofuran-2(3H)one (445 mg, 3.0 mmol) and 20 ml of dry THF. It was stirred to dissolve completely. The refined Et3N (0.56 ml, 4 mmol) was injected and stirred for 15min. <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (776.1 mg, 3.6 mmol) was injected. Monitored by TLC until the end of the reaction. Water was added. Extracted three times with EA. The organic phases were combined. The solvent was removed by rotary evaporation. Petroleum ether / ethyl acetate as the mobile phase for silica gel column chromatography separation of the product 2m, the yield was 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With pyridine; dmap; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: To a 2-dram vial equipped with magnetic stir bar and argon gas inlet needle was added 2C-dimer alcohol 12b (0.012 mmol, 1.0 equiv) in dichloromethane (200 muL). 4-Dimethylaminopyridine (0.012 mmol, 1.0 equiv), pyridine (0.036 mmol, 3.0 equiv), and the commercial chloroformate (0.036 mmol, 3.0 equiv) were added in that order to the stirring solution. The reaction was stirred at room temperature until evidence for product formation was observed by TLC analysis (typically 16-18 h).3,4 The reaction was quenched with water (ca. 0.5 mL) and extracted with dichloromethane (3 x 1 mL). The organic layers were pooled, dried with Na2SO4, vacuum filtered, and concentrated under rotary evaporation. The crude residue was purified directly on silica (CombiFlash Rf Isco) using a gradient mobile phase (0-30% EtOAc in hexanes), which afforded the desired carbonate as a colorless, amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; | [0228] To a stirring solution of 4-nitrobenzyl chloroformate (27.40g) in THF (500 mL) at 0 was added N-hydroxy-5-norbornene-2,3-dicarboximide (22.76), followed by the dropwiseaddition of a solution of Et3N (17.72rnl) in THF (200 rnL) and the reaction was stirred for overnight with gradual warming to room temperature. The reaction vessel was then placed in the freezer (-5 C) for 1 hour to induce precipitation of triethylamine hydrochloride, which was removed by filtration. The filtrate was concentrated to dryness to yield a residue, which was vigorously stirred in MeOH (400 mL) for lh and then filtered to yield (N-hydroxy-5- norbornene-2,3- dicarboxyl-imido)-4-nitro-benzoate as a white solid (42.03g, yield: 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: 1-(p-Tosyl)-aziridine-2S-carboxylic acid methyl ester (2a). Trifluoroacetic acid (10 ml) was added dropwise over 10 min to asolution of 1a (2.0 g, 5.8 mmol) in dichloromethane (10 ml) and methanol (10 ml) at 0 oC and stirred for 30 min at 0 oC. Volatiles were removed by azeotropic removal with Et2O (3 x 10 ml). The residue was partitioned between Et2O (50 ml) and H2O (50 ml) and the ether layer was extracted with water (3 x10 ml). The combined aqueous layers were basified to pH 9 with solid NaHCO3 at 0 oC. Ethyl acetate (100 ml) was added to the aqueous solution followed by p-toluenesulfonyl chloride (1.11 g, 5.8 mmol) at 0 oC. The resulting immiscible layers were allowed to warm to room temperature and stirred vigorously for 24 h. After completion of the reaction, the two layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel in petroleum ether:ethyl acetate (4:1) to yield 2a as a clear oil (1.36 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: 1-(p-Tosyl)-aziridine-2S-carboxylic acid methyl ester (2a). Trifluoroacetic acid (10 ml) was added dropwise over 10 min to asolution of 1a (2.0 g, 5.8 mmol) in dichloromethane (10 ml) and methanol (10 ml) at 0 oC and stirred for 30 min at 0 oC. Volatiles were removed by azeotropic removal with Et2O (3 x 10 ml). The residue was partitioned between Et2O (50 ml) and H2O (50 ml) and the ether layer was extracted with water (3 x10 ml). The combined aqueous layers were basified to pH 9 with solid NaHCO3 at 0 oC. Ethyl acetate (100 ml) was added to the aqueous solution followed by p-toluenesulfonyl chloride (1.11 g, 5.8 mmol) at 0 oC. The resulting immiscible layers were allowed to warm to room temperature and stirred vigorously for 24 h. After completion of the reaction, the two layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel in petroleum ether:ethyl acetate (4:1) to yield 2a as a clear oil (1.36 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dmap; In dichloromethane; at 20℃; | A solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (0.54 g, 2.5 mmol), DMAP (0.61 g, 5mmol), and 2-fluoroethanol (0.19 g, 3 mmol) in CH2Cl2 (10 mL) was stirred at room temperature overnight. After completion checked by TLC, the reaction mixture was diluted with CH2Cl2 (30 mL), and washed with HCl (0.5 N, 60 mL) and saturated NaHCO3(60 mL). The CH2Cl2 layer was dried with anhydrous MgSO4, concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate/Hexane 1:5) to provide the desired product 1 as a white solid (0.42 g, 69 %). 1H NMR (300 MHz,CDCl3) delta 8.24 (d, J = 8.7 Hz, 2H, Ar-H), 7.56 (d, J = 8.7 Hz, 2H, Ar-H), 5.28 (s, 2H, ArCH2),4.64 (ddd, J = 47.3, 4.7, 3.4 Hz, 2H, FCH2), 4.43 (ddd, J = 28.1, 4.8, 3.4 Hz, 2H, FCH2CH2).13C NMR (75MHz, CDCl3) delta 154.68, 147.92, 142.21, 128.43, 123.87, 82.04, 79.77,68.19, 67.28, 67.01. 19F NMR (282 MHz, CDCl3) delta -225.04. MS (ESI) calculated for C10H10FNO5 243.1,found [M]+ 243.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; triethylamine; In dichloromethane; at 20℃; for 5h; | To a solution of tert-butyl 4-((3 -(3 -cyanophenyl)-2-oxo-5 - ((phenethylamino)methyl)tetrahydropyrimidin- 1 (2H)-yl)methyl)piperidine- 1 -carboxylate (140 mg, 0.263 mmol) in CH2C12 (5266 tl) was added Et3N (147 tl, 1.053 mmol) and DMAP (32.2 mg, 0.263 mmol) followed by 4-nitrobenzyl carbonochloridate (171 mg, 0.789 mmol). This mixture was stirred at room temperature for 5 h. After the reaction was complete the solvent was evaporated and the product isolated by column chromatography (154 mg, 82% yield) as a viscous oil. LRMS: (M+H-Boc) = 611.3 mlz and (M+H-tBu) = 655.3 mlz. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | A flame-dried round bottom flask equipped with a Teflon-coated magnetic stir bar was charged with 3.77g (15mmol) of 7-tosyl-7-azabicyclo[4.1.0]heptane11 and 60mL of THF. The solution was cooled to -78C in a dry ice and acetone bath. The lithium naphthalenide reagent was added dropwise until the dark green endpoint was observed (?40mL of stock 1M solution). The reaction was quenched with 20mL of aqueous saturated sodium bicarbonate and slowly warmed to 0C. Solid <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (3.50g, 16.2mmol) was added all at once, and the suspension was stirred for a total of 2h at 0C. After this time, the mixture was diluted with 20mL of H2O and 30mL of ethyl acetate. The flask was warmed to room temperature and the organic layer was taken. The aqueous layer was extracted twice with 20mL of ethyl acetate. The combined organics layer was then washed with 30mL of brine and dried over MgSO4. The crude reaction mixture was concentrated and further purified with silica gel chromatography (4:1 hexanes/ethyl acetate) to yield 8 as a white solid in 66% yield (2.74 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: 7-Azaindole (6) (177 mg, 0.0015 mol) was dissolved in dry THF (10 mL) and cooled to 0 C in a salt-ice bath. To this was added sodium hydride (72 mg, 0.003 mol) and the temperature slowly raised to 40 C. The reaction mixture was stirred for 3 h under an inert atmosphere. After complete disappearance of the compound 6, the reaction mixture was cooled to room temperature and 4-iodophenylsulfonylchloride (8a) (302 mg, 0.001 mol) was added and then the reaction mixture was stirred at 40 C for 4 h. Reaction progress was monitored by TLC using n-hexane:ethyl acetate (3:7) as mobile phase. The reaction mixture was filtered to remove the NaCl salt and the filtrate was concentrated in a rota-evaporator. The crude product was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product thus obtained was purified by column chromatography using n-hexane:ethyl acetate (2:1). The product obtained was recrystallized from ethanol to give the pure product (9a). Similar procedures were adopted for the synthesis of the remaining compounds (9b-l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With dmap; triethylamine; In dichloromethane; at 25 - 30℃; | Into a 100ml three-necked round bottom flask was added 88% of the amount of crude ticagrelor (5.94g, 10.0mmol), triethylamine (1.21g, 12.0mmol), 4-(N,N-dimethylamino)pyridine (0.05 g of) and dichloromethane (50ml), stirred. Warmed to 25 ~ 30 deg. C, was added dropwise <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (2.82g, 12.0mmol) in methylene chloride, and the reaction was stirred at this temperature. After 3 to 4 hours, HPLC trace completion of the reaction, was added saturated ammonium chloride solution (50ml) to quench the reaction. The reaction mixture was extracted with dichloromethane (50ml) 3 times. The combined organic phase was washed with saturated ammonium chloride solution (50ml) and water (50ml) and twice each, dried over anhydrous sodium sulfate, methylene chloride was removed by concentrating under vacuum. To the residue was added ethyl acetate / n-heptane (1: 1, volume ratio) mixed solvent (60ml), was heated to 55 ~ 60 deg. C and incubated for 30 minutes, followed by 1 to 2 hours cooling to 20 ~ 25 deg. C , and incubated for 1 hour. The filter cake was dried under vacuum to give a white solid 5.63g namely Compound (II G) purified product, yield 80.2%, purity 99.8% (HPLC purity analysis, single impurity of not more than 0.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium carbonate; In water; acetone; at 0 - 25℃; for 0.25h; | The reaction flask was charged with 95.7 g (0.65 mol) of (2S, 4S) 2-carboxy-4-mercaptopyrrolidine (Formula V) prepared in Example 6 and 500 ML acetone was stirred at 20 C to 25 C for 15 minutes, 137.8 g (1.3 mol) of sodium carbonate dissolved in 700 mL of purified water was added, (1.17 mol) of p-nitrobenzyloxycarbonyl chloride dissolved in 350 mL of acetone was added dropwise at a temperature of 0 to 5 C, After completion of the reaction, the reaction was stirred at 40 to 50C for 5 hours, cooled to 10C to 15C, stirred for 2 hours, filtered, 100 mL of acetone and dried at 45C for 6 hours to give about 197.2 g of an off-white intermediate VI as a solid in 93.0% yield. HPLC purity 97.6%. Intermediate VI mass spectrometry data are as follows: C13H14N2O6S, molecular weight: 326.3, [M + Na] & lt; + & gt ;: 348.7. |
93% | With sodium carbonate; In water; acetone; at 0 - 50℃; for 5h; | The embodiment of the reaction flask to 4 preparation of 95.7g (0.65mol) (2S, 4S) 2-carboxy-4-mercapto-pyrrolidine (formula V) and 500 ml acetone in 20 C to the 25 C stirring 15 minutes, by adding dissolved in 700 ml of purified water 137.8g (1.3mol) sodium carbonate, cooling to 0 C to the 5 C, control the warm instillment dissolves in 350 ml of acetone 252.3g (1.17mol) P-nitro animal pen oxygen carbo- acid radical chlorine, after the drop finishes 40 C to the 50 C stirring reaction under 5 hours, cooling to 10 C to the 15 C, stirring 2 hours, filtering, with 100 ml acetone eluviation, for 45 C drying 6 hours, intermediate VI shall be of a kind of white solid about 197.2g, molar yield 93.0%, HPLC purity 97.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at 20℃; for 1h; | General procedure for preparing the activated, para-nitrobenzyl esters General procedure: To a flame dried round bottom flask was added commercially available carboxylic acid (1 eq) as a solutionin anhydrous THF (0.2 M), followed by para-nitrobenzyl chloroformate (1.1 eq) and NEt3 (1.2eq) at ambient temperature. After stirring for 1 h, the mixture was poured into a separatory funnel and extracted with EtOAc against NaHCO3. The organic layer was dried over MgSO4 and then concentrated to dryness to give the crude activated ester that was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: To a flame dried round bottom flask was added commercially available carboxylic acid (1 eq) as a solutionin anhydrous THF (0.2 M), followed by para-nitrobenzyl chloroformate (1.1 eq) and NEt3 (1.2eq) at ambient temperature. After stirring for 1 h, the mixture was poured into a separatory funnel and extracted with EtOAc against NaHCO3. The organic layer was dried over MgSO4 and then concentrated to dryness to give the crude activated ester that was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyridine; In dichloromethane; at 0 - 20℃; | Exam ple 96 : - Methyl 4 -(4 -(2 -(hvdroxym e thyl) pyrrolidine -l-carbonyl) -2- m eth oxy-5 -(( ((4 -nitro be nzyl) ox v) carbon yl)am ino)pheno xy) butanoate (73) (0980) Compound 5 (2.30 g, 1 equiv.) was dissolved in DCM (20 mL) and pyridine (1 equiv.). (0981) The reaction mixture was kept under magnetic stirrer at 0 C during the addition of 4- nitrobenzylchloroformiate (1 equiv.). The reaction mixture was then left at r.t. under magnetic stirrer overnight until TLC showed total consumption of the starting material (0982) The reaction mixture was then sequentially washed with saturated CuS04 solution (30 mL), saturated aqueous NaHC03 (30 mL) and brine (30 mL). The organic phase was dried over MgS04 and concentrated under reduced pressure using a rotary evaporator. The crude of reaction was subsequently purified by column chromatography (mobile phase: Diethyl ether/DCM, 50/50, v/v) giving pure 73 (2.67 g, 78%) as yellow oil. NMR (400 MHz, CHLOROFORM-d) delta 8.99 (NH), 8.15-8.18 (2H, m), 7.68 (s, lH), 7-48-7-51 (2H, m), 6.77 (lH, s), 5.19 (2H, d, J= 4 Hz), 4.18-4.40 (2H, m), 4.03 ( 2H, t, J= 8 Hz), 3.76 (3H, s), 3·63-3·67 (m, lH), 3.62 (s, 3H), 3-41-3-57 (2H, m), 2.46-2.49 (2H, m), 2.07-2.14 (m, 4H), 1.50-1.71 (2H, m). m/z (+EI) calc. C26H31N3O10 for (M)+ 545.2 found 546.0 ([M]+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 5.33333h;Inert atmosphere; | To a solution of compound 12 (20 mg, 0.06 mmol) in CH2Cl2 (4 mL) at 0 C was added a solution of iPrNEt2 (20.90 mg, 0.12 mmol) in CH2Cl2 (2 mL), followed by a solution of <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (15.52 mg, 0.07 mmol) in CH2Cl2 (2 mL), and the reaction mixture was stirred at 0 C for 20 min. The reaction mixture was allowed to warm to rt and stirred at rt for 5 h. The reaction was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel to afford 29 (27 mg, white crystalline powder) in 86% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6.33333h;Inert atmosphere; | To a solution of compound 18 (20 mg, 0.05 mmol) in anhydrous CH2Cl2 (2.5 mL) were added iPrNEt2 (12.9 mg, 0.1 mmol) and <strong>[4457-32-3]4-nitrobenzyl chloroformate</strong> (12.9 mg, 0.06 mmol), and the reaction mixture was stirred at 0 C for 20 min. The reaction mixture was allowed to warm to rt and stirred at rt for 6 h. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2CH2/EA = 9:1) to afford 30 (13 mg, yellow powder) in 47% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium carbonate; In tetrahydrofuran; water; at 0℃; for 2h; | Methyl acrylate (8.18 g, 45 mmol) was added to a solution of13 (33.5 g, 100 mmol) in methanol (100 mL) at room temperature.After stirring at room temperature for 24 h, thereaction mixture was concentrated in vacuo and the resultantresidue was purified by flash column chromatography onneutral silica gel (20-70% ethyl acetate in hexane) to producean amine compound (31.2 g, 74%) as a colorlessamorphous substance. p-Nitrobenzyloxycarbonyl chloride(15.6 g, 72.5 mmol) and sodium carbonate (7.68 g, 72.5mmol) were added to amine compound (29.08 g, 69.0 mmol)dissolved in tetrahydrofuran (200 mL) and water (200 mL) at0 C. After stirring at 0 C for 2 h, the reaction mixture wasquenched with water and ethyl acetate extraction was performedthree times. The combined organic phases werewashed with saturated aqueous sodium chloride solution,dried over sodium sulfate, and filtrated. The filtrate wasconcentrated in vacuo and the resultant residue was purifiedby flash column chromatography on silica gel (10-50%ethyl acetate in hexane) to produce a PNZ-protected compound(43.3 g, 94%) as a pale yellow amorphous substance.A solution of 1 N sodium hydroxide in water (180 mL) was added to the PNZ-protected compound (43.3 g, 72.2 mmol)dissolved in 1,4-dioxane (700 mL) and water (300 mL) at0 C. After stirring at room temperature for 20 min, thereaction mixture was quenched with aqueous potassiumhydrogen sulfate solution and ethyl acetate extraction wasperformed three times. The combined organic phases werewashed with saturated aqueous sodium chloride solution,dried over sodium sulfate, and filtrated. The filtrate wasconcentrated in vacuo to produce the title compound (39.9 g,94%) as a colorless solid. The resultant residue was used inthe next reaction without any further purification. |
Tags: 4457-32-3 synthesis path| 4457-32-3 SDS| 4457-32-3 COA| 4457-32-3 purity| 4457-32-3 application| 4457-32-3 NMR| 4457-32-3 COA| 4457-32-3 structure
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