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CAS No. : | 609-36-9 | MDL No. : | MFCD00005250 |
Formula : | C5H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 115.13 | Pubchem ID : | - |
Synonyms : |
H-DL-Pro-OH
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 32.52 |
TPSA : | 49.33 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.78 cm/s |
Log Po/w (iLOGP) : | 0.84 |
Log Po/w (XLOGP3) : | -2.5 |
Log Po/w (WLOGP) : | -0.56 |
Log Po/w (MLOGP) : | -2.59 |
Log Po/w (SILICOS-IT) : | 0.22 |
Consensus Log Po/w : | -0.92 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.09 |
Solubility : | 1410.0 mg/ml ; 12.2 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 2.01 |
Solubility : | 11700.0 mg/ml ; 102.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.13 |
Solubility : | 85.7 mg/ml ; 0.745 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.54 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
65% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 70℃; Inert atmosphere | DL-Proline (6.0 g, 52.0 mmol) was added slowly and portion wise to a stirred suspension of LiAIH4 (3.0 g, 78.0 mmol) in THF (80 ml_) at 0 °C under nitrogen atmosphere carefully over a period of 30 minutes. The reaction mixture was warmed to room temperature and then heated to reflux for 3 h. The mixture was quenched with 20percent KOH solution at 0 °C slowly (18 - 20 mL). The mixture was filtered through a Celite™ pad and washed ith THF. The filtered precipitate was again refluxed with THF for 30 minutes and filtered. The combined filtrates were concentrated to give K1 as pale yellow liquid which is slowly converts to dark brown liquid (3.2 g, 65percent). Rf: 0.1 (10percent MeOH in DCM & 1 drop AcOH, ninhydrin active). |
18% | Stage #1: With thionyl chloride In methanol at 0 - 20℃; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 60℃; Stage #3: With potassium hydroxide In tetrahydrofuran |
To a solution of DL-proline (10Og, 869 mmol) in MeOH (1500 mL) was slowly added SOCl2 at 0 0C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the crude material that was dissolved in THF (1700 mL) again. To this mixture was added portionwise LiAlH4 (132 g, 3.47 mol) at 0 0C. The resulting mixture was heated at 60 0C overnight. The excess LiAlH4 was quenched with KOH. The reaction mixture was filtered and the solid was washed with MeOH (1000 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure to give the crude material that was purified by distillation to afford 15.8 g (18percent) of pyrrolidin-2-ylmethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | for 16 h; Reflux | To a stirred solution of pyrrolidine-2-carboxylic acid (1 g, 8.69 mmol) in MeOH (10 mL) thionyl chloride (0.75 mL, 10.43 mmol) was added and the reaction mixture was stirred at reflux temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated, the residue was diluted with DCM (15 mL), the excess of thionyl chloride was quenched with solid NaHC03, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (1 .1 g, 98percent yield) as pale yellow solid. |
90% | at 0 - 20℃; for 16 h; | Thionyl chloride (3 mL) was added dropwise at 0 °C to a stirred solution of [DL]-proline (1 g, 8.6 mmol) in methanol (15 mL). The reaction was stirred at room temperature for 16 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated and purified via standard methods to afford methyl prolinate as an off- white solid (1 g, 90percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 70℃;Inert atmosphere; | DL-Proline (6.0 g, 52.0 mmol) was added slowly and portion wise to a stirred suspension of LiAIH4 (3.0 g, 78.0 mmol) in THF (80 ml_) at 0 °C under nitrogen atmosphere carefully over a period of 30 minutes. The reaction mixture was warmed to room temperature and then heated to reflux for 3 h. The mixture was quenched with 20percent KOH solution at 0 °C slowly (18 - 20 mL). The mixture was filtered through a Celite? pad and washed ith THF. The filtered precipitate was again refluxed with THF for 30 minutes and filtered. The combined filtrates were concentrated to give K1 as pale yellow liquid which is slowly converts to dark brown liquid (3.2 g, 65percent). Rf: 0.1 (10percent MeOH in DCM & 1 drop AcOH, ninhydrin active). |
18% | To a solution of DL-proline (10Og, 869 mmol) in MeOH (1500 mL) was slowly added SOCl2 at 0 0C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the crude material that was dissolved in THF (1700 mL) again. To this mixture was added portionwise LiAlH4 (132 g, 3.47 mol) at 0 0C. The resulting mixture was heated at 60 0C overnight. The excess LiAlH4 was quenched with KOH. The reaction mixture was filtered and the solid was washed with MeOH (1000 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure to give the crude material that was purified by distillation to afford 15.8 g (18percent) of pyrrolidin-2-ylmethanol. | |
With borane-THF; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a solution of DL-proline (10.0 g, 86.9 mmol) in THF (20 mL) were added boron trifluoride etherate complex (12.9 g, 91.2 mmol) and borane-tetrahydrofuran (1.0 mol/L THF solution, 100 mL) at 0°C, and the mixture was stirred at room temperature for 16 hr. After completion of the reaction, the mixture was further heated under reflux for 1 hr and cooled to room temperature. THF-water (1:1, 2.5 mL) and 6N sodium hydroxide were successively added to the reaction solution, and the mixture was heated under reflux for 2 hr. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was washed with diethyl ether. The remaining residue, di-tert-butyl dicarbonate (19.9 g, 91.2 mmol) and potassium carbonate (36.0 g, 260 mmol) were dissolved in diethyl ether-water (100 mL-150 mL), and the mixture was stirred at room temperature for 16 hr. The diethyl ether layer was separated and washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 95:5 - 60:40 - 50:50) to give the title compound (13.6 g, 76percent) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 4.74 (d like, 1H), 3.96 (br s, 1H), 3.74-3.21 (m, 4H), 2.13-1.67 (m, 4H), 1.49 (s, 9H). |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 10h; | Using DL-proline as a starting material, dissolving in tetrahydrofuran, adding lithium aluminum hydride in portions, and reacting for 10 hours at room temperature.TLC detects the progress of the reaction, quenches the reaction, filters, concentrates, and recrystallizes the product to obtain intermediate 1, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With thionyl chloride; at 0 - 20℃; | EXAMPLE 1; 4-amino-N-((1-ethylpyrrolidin-2-yl)methyl)-5-(ethylsulfonyl)-2-methoxybenzamide; Step 1 Methyl pyrrolidine-2-carboxylate hydrochloride: At about 0 C., thionyl chloride (15.7 mL, 217.4 mmol) was added dropwise to a solution of D/L-proline (5.0 g, 43.47 mmol) and methanol (50 mL) over a period of about 15 mintues. The resulting mixture was stirred at ambient temperature for about 16 hours, and then concentrated in vacuo. The resulting gummy mass was triturated with n-pentane, decanted and dried to give the title compound as an off-white solid (6.25 g, yield=87%). 1H NMR (400 MHz, DMSO-d6) delta 1.87-2.04 (m, 3H), 2.21-2.28 (m, 1H), 3.22-3.26 (m, 2H), 3.75 (s, 3H), 4.34 (t, J=7.8 Hz, 1H); IR (film) upsilon 3513, 3130, 2597, 1740, 1632, 1452, 1402, 1245, 1178, 1046, 764 cm-1; MS 130 (M+1). |
With hydrogenchloride; at 0 - 20℃; for 4.5h; | Hydrogen chloride gas (4 g) was bubbled through methanol (120 mL) at 0 C. Proline (3.80 g) was then added and the mixture was stirred at room temperature for 4.5 h and then reduced in vacuo to give pyrrolidine-2-carboxylic acid methyl ester hydrochloride salt as a white solid (5.5 g). | |
143.9 g | With thionyl chloride; at 0℃; for 12h;Reflux; | To a stirring solution of pyrrolidine-2-carboxylic acid (SMI) (100 g, 0.87 mol) in methanol (800 mL) was added thionyl chloride (76.9 mL, 1.04 mol) slowly drop wise at 0C. The reaction mixture was heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under vacuum. Obtained residue was washed with n- Hexane and distilled off the solvent to afford 1 (143.9 g, HC1 salt). 1H-NMR: (400 MHz, CDC13) (Rotamers): delta 3.89 (s, 3H), 3.68-3.62 (m, 2H), 3.59-3.47 (m, 2H), 2.49-2.37 (m, 1H), 2.27-2.05 (m, 3H). LCMS (ESI): 166 [M++l] |
143.9 g | With thionyl chloride; at 0℃;Reflux; | To a stirred solution of pyrrolidine-2-carboxylic acid (SMI) (100 g, 0.87 mol) in methanol (800 mL) was added thionyl chloride (76.9 mL, 1.04 mol) slowly drop wise at 0C. The reaction mixture was heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under vacuum. The residue was washed with n- Hexane and distilled off the solvent to afford 1 (143.9 g, HC1 salt). 1H-NMR: (400 MHz, CDC13) (Rotamers): delta 3.89 (s, 3H), 3.68-3.62 (m, 2H), 3.59-3.47 (m, 2H), 2.49-2.37 (m, 1H), 2.27-2.05 (m, 3H). LCMS (m/z): 166 [M++l] |
With thionyl chloride; at 0 - 80℃; for 12.5h; | General procedure: To a solution of alpha-amino acid 1 (0.134 mmol) in methanol (50 ml) was slowly added dropwise thionyl chloride (0.200 mmol), which was stired at ice bath (0 C) for 30 min, and then the mixture was heated to 80 C for 12 h reaction, and monitored by TLC. After the completion of reaction, the reaction solution was concentrated, filtered and washed twice with CH2Cl2 to obtain the crude amino-acid ester hydrochlorides 2, which were used for the next reaction without further purification. | |
With chloro-trimethyl-silane; at 70℃; for 2h;Reflux; | DL-Proline (1Og, 87mmol), TMSCI (51ml, 430 mmol) and methanol (500ml) were refluxed together (at 7O0C) for 2 hours. The reaction mixture was evaporated to dryness and LCMS analysis indicated 100% conversion to desired product pyrrolidine- 2-carboxylic acid methyl ester, m/z 130 [M++H]+. | |
With hydrogenchloride; at 0℃; for 4.5h; | Example 20: N-(l-f2-(lH-IndoI-4-vI)-4-morphoIiri-4-vI-thienof3,2-d1pyrimidin- 6-ylmethyn-pyrrolidin-2-vImethyU-N-methvI-methanesulfonamide; <n="104"/>Hydrogen chloride gas (4 g) was bubbled through methanol (120 mL) at 0 0C. Proline (3.80 g) was then added and.stirred for 4.5 hours, reduced in vacuo to give pyrrolidine-2-carboxylic acid methyl ester hydrochloride salt (5.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With thionyl chloride; for 16h;Reflux; | To a stirred solution of pyrrolidine-2-carboxylic acid (1 g, 8.69 mmol) in MeOH (10 mL) thionyl chloride (0.75 mL, 10.43 mmol) was added and the reaction mixture was stirred at reflux temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated, the residue was diluted with DCM (15 mL), the excess of thionyl chloride was quenched with solid NaHC03, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (1 .1 g, 98% yield) as pale yellow solid. |
90% | With thionyl chloride; at 0 - 20℃; for 16h; | Thionyl chloride (3 mL) was added dropwise at 0 C to a stirred solution of [DL]-proline (1 g, 8.6 mmol) in methanol (15 mL). The reaction was stirred at room temperature for 16 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated and purified via standard methods to afford methyl prolinate as an off- white solid (1 g, 90%). |
With thionyl chloride; at 20℃; for 24h;Cooling with ice; | Step 1 Methyl pyrrolidine-2-carboxylate 7 mL of thionyl chloride was dissolved in 50 mL of methanol in an ice-water bath, followed by addition of pyrrolidine-2-carboxylic acid 10a (5 g, 43.40 mmol). The mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure to obtain methylpyrrolidine-2-carboxylate 10b (10 g) crude product as a white solid, which was directly used in the next step without purification. MS m/z (ESI): 130.1 [M+1] |
With thionyl chloride; at 30℃; for 24h;Cooling with ice; Inert atmosphere; | Under ice-cooling, 7 mL thionyl chloride was added dropwise to 50 mL methanol. Add pyrrolidine-2-carboxylic acid 10a (5 g, 43.40 mmol). Stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to give the crude 2-carboxylic acid methyl ester 10b (10 g, white solid) was used without purification in the next step directly. | |
With thionyl chloride; at 0 - 20℃; | Example 27 1-tert-butgammal 2-methyl pyrrolidine- 1 ,2-dicarboxylate (17)[00189] D,L-proline (8.7 mmols, 1 g) was dissolved in methanol (75 mL) and cooled to 0 0C. Thionyl chloride (17.4 mmols, 2.07 g) was then added dropwise to the solution. The reaction mixture was then allowed to warm slowly to room temperature and stirred for 15 hours. At this time the reaction mixture was evaporated to dryness. Three 15 mL portions of methanol were added and evaporated immediately followed by one 15 mL portion of diethyl ether. The intermediate was collected as a white crystalline solid. After drying under high vacuum for a few hours, the white solid was suspended in DCM (87 mL) and triethylamine (34.8 mmols, 3.52 g) was added followed by di-tert-butyl dicarbonate (9.57 mmol, 1.13 g). The reaction was monitored by TLC and when complete, the reaction mixture was evaporated to dryness. The crude material was then taken up in ethyl acetate and washed with three 15 mL portions of aqueous IN HCl followed by one 10 mL portion of brine. The organic layer was then dried with magnesium sulfate and evaporated to dryness. No further purification was carried out; 1.556g (6.8 mmol) was recovered after two steps. 1H NMR (500 MHz, CDCl3) delta 4.31 (d, J = 8.6, IH), 4.20 (dd, J = 4.2, 8.5, IH), 3.77 - 3.69 (m, 3H), 3.58 - 3.50 (m, IH), 3.45 (dd, J = 6.8, 10.6, IH), 3.37 (s, IH), 2.27 - 2.14 (m, IH), 2.02 - 1.90 (m, 2H), 1.90 - 1.81 (m, IH), 1.46 (d, J = 12.5, 4H), 1.43 - 1.36 (m, 6H). 13C NMR (126 MHz, CDCl3) delta 173.37, 153.80, 79.84, 59.09, 58.69, 52.09, 51.92, 46.53, 46.29, 30.85, 29.90, 28.40, 28.27, 24.32, 23.67, 18.38. | |
With thionyl chloride; at 0 - 70℃; for 3.33333h; | Take 40 g (0.35 mol) of proline and 250 mL of methanol in a 500 mL single-necked reaction flask, cool to 0 C, and take another 45 g (0.38 mol) of dichlorosulfoxide into a 250 mL constant pressure dropping funnel, and slowly add to the above In the solution system, with the exothermic addition of the system, the internal temperature is controlled to be less than 5 C, and the addition is completed in about 20 minutes. The temperature was raised to 70 C to obtain a clear solution, which was refluxed for 3 hours. After reducing the temperature to room temperature, the solvent was distilled off under reduced pressure to obtain 43 g of a light yellow oily liquid, and the crude product was directly used in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With [NO(1+)*18-crown-6*H(NO3)2(1-)] In dichloromethane at 20℃; for 0.0833333h; | |
74% | With bismuth(III) chloride; sodium nitrite In dichloromethane at 20℃; for 0.833333h; chemoselective reaction; | |
54% | With hydrogenchloride; sodium nitrite In water at -5 - 5℃; for 1.5h; | Intermediate 65A Intermediate 65 A: l-Nitrosopyrrolidine-2-carboxylic acid To the stirred solution of pyrrolidine-2-carboxylic acid (10 g, 87 mmol) in HCl (6.6 ml, 217 mmol) and water (34 mL) at -5 °C was added sodium nitrite (8.2 g, 119 mmol) in water (10 mL) and stirring was continued for 1.5 h at 5 °C. The reaction mixture was extracted with ethyl acetate (5 x 100 mL) and the combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product recrystallized from benzene (20 mL) to afford pure Intermediate 65A (6.8 g, 54%) as brown solid. MS(ES): m/z = 145 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ ppm 6.56 - 7.2 (br, m, 1H), 5.33 (dd, J= 8.03, 3.51 Hz, 1H), 4.22 - 4.61 (m, 2H), 3.62 - 3.74 (m, 1H), 2.06-2.42 (m, 4H) |
With hydrogenchloride; sodium nitrite In water | ||
25 mg | With hydrogenchloride; sodium nitrite In water at 0 - 15℃; | 1-Nitrosopyrrolidine-2-carboxylic acid To a solution of pyrrolidine-2-carboxylic acid (30.0 g, 260.6 mmol, 1.0 eq) in H2O (250 mL) at 0° C. was added NaNO2 (26.97 g, 390.9 mmol, 21.2 mL, 1.5 eq) followed by aqueous HCl (12 M, 26.06 mL, 1.20 eq), and the mixture was allowed to warm slowly to 15° C. and stirred for a further 12 hr. The reaction mixture was diluted with EtOAc (500 mL), the aqueous layer was separated. The organic layer was washed with brine (100 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (25 g) as a white solid. The product was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With trifluoroacetic anhydride In acetonitrile at 80℃; for 5h; Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: benzyl chloroformate; rac-Pro-OH With sodium hydroxide In water at 0 - 20℃; Stage #2: With hydrogenchloride In water | 89.1 Benzyl chloroformate (29.7 g, 174 mmol) was added dropwise to a 0° C. solution of Pyrrolidine-2-carboxylic acid (20.0 g, 174 mmol) dissolved in 1N NaOH (350 mL). The solution was stirred at 0° C. for 30 mins. The solution was allowed to equilibrate to room temperature while stirring overnight. The solution was acidified to pH=3 by addition of 1M HCl. The resulting solution was extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuo to afford 40.4 g (89%) of the crude product, pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, as a colorless oil. |
88% | With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; | |
88% | Stage #1: benzyl chloroformate; rac-Pro-OH With sodium hydroxide at 0 - 20℃; Stage #2: With hydrogenchloride In water | 46.1 Intermediate 46. Synthesis of 3-(hexahydropyrrolo[l,2-a]pyrazin-2(li/)-yl)-l//- pyrrolo [3,2-b] pyridine.CbzCICO2H -CO2HNaOH ICbz1. Synthesis of l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acidBenzyl chloro formate (174 mmol) was added dropwise to a solution of pyrrolidine-2- carboxylic acid (174 mmol) in 2 M sodium hydroxide (88 mL) at 0 0C. Additional 2 M sodium hydroxide (88 mL) was added and the reaction mixture was allowed to warm to rt and was maintained for 3 h. The resulting solution was extracted with ether (50 mL) and the pH of the aqueous layers was adjusted to 4-5 with 2 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid in 88% yield as a colorless liquid. |
88% | With sodium hydroxide In water at 0℃; for 0.5h; | |
27% | With sodium hydroxide at 20℃; for 6h; | lntermediate-22: 1 -(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid A mixture of pyrrolidine-2-carboxylic acid (2.5 g, 21.7 mmol), NaOH (2 M solution, 10 mL) and carbobenzoxy chloride (3.7 g, 21.7 mmol) were stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was acidified with 2N HCI and extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (1 .5 g, 27% yield) as colourless liquid. |
With sodium hydroxide at 20℃; for 15h; | ||
With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 6h; | ||
Stage #1: benzyl chloroformate; rac-Pro-OH With sodium hydrate In water at 0℃; Stage #2: With hydrogenchloride; water | 150.A Example 150 A1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid; To the solution of pyrrolidine-2-carboxylic acid (1.15 g, 10 mmol) of water (20 ml) was added sodium hydrate (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added drop wise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.0 g of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In neat (no solvent) at 80℃; for 0.166667h; Green chemistry; chemoselective reaction; | General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80°C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions. |
98.36% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 8.1 Step 1: Preparation of 2 To DCM (189 mL, c = 0.46) was added Included 1 (10 g, 86.9 mmol, 1 eq)TEA (35.2 g, 347.6 mmol, 4 eq) was added to the mixture and then (Boc) 2 O (12.57 g, 99.03 mmol, 1.2 eq) was dropped at 0 ° C. After the addition, the reaction mixture was stirred for 3 hours while slowly heating to room temperature. The reaction mixture was immediately concentrated in vacuo to give a residue (18 g, 98.36% yield) of a white oil without further purification. |
98% | With sodium hydrogencarbonate In tetrahydrofuran at 0 - 20℃; for 16h; | 53.1 Step 1: To a solution of DL-Proline (0.3 g, 2.60 mmol, 1 equiv) in a saturated solution ofaqueous NaHCO3 (3.9 mL) was added di-tert-butyl dicarbonate (0.65 mL, 2.86 mmol, 1.1equiv) with THF (3.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for16 h at which time the starting materials were completely consumed. After this time, thereaction mixture was concentrated under vacuum and the crude material was redissolvedin water (5 mL). The aqueous layerwas then acidified with 3 N HCI (to pH = 2) and extractedwith ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and evaporated under vacuum to afford (tert-butoxycarbonyl)proline (0.55 g, 98 %yield) as colorless oil. LCMS (ES) m/z = 214 [M-H]-. 1H NMR (400 MHz, DMSO-d6) O ppm1.49 (5, 9 H), 1.90 - 1.95 (m, 2 H), 2.26 - 2.44 (m, 2 H), 3.35 - 3.42 (m, 2 H), 4.34 (bs, 1H). |
96% | With amberlyst-15 at 20℃; for 0.166667h; Neat (no solvent); | |
96.2% | With sodium hydrogencarbonate In tetrahydrofuran at 0 - 20℃; for 16h; | 135.1 Step 1: 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid To a solution of compound 135-la (1 g, 8.69 mmol, 1 eq) in NaHC03 (1 M, 8.7 mL, 1 eq ) was added Boc20 (2.1 g, 9.55 mmol, 2.2 mL, 1.1 eq) in THF (5 mL) at 0°C. Then the mixture was stirred at 20°C for 16 hr. The reaction mixture was concentrated in vacuum to remove THF, then the aqueous phase was adjusted pH = 2 with 1M. aq. HC1. The aqueous phase was extracted with EA (20 mL*3), washed with brine (10 mL), dried over Na2S04, filtered and concentrated in vacuum. The crude product was used for the next step directly. 1HNMR confirmed that compound 135-lb (1.8 g, 8.36 mmol, 96.2% yield) was obtained. 1H NMR (400 MHz, CDCl3) d 9.87 - 7.76 (m, 1H), 4.42 - 4.21 (m, 1H), 3.63 - 3.29 (m, 2H), 2.35 - 2.06 (m, 2H), 2.01 - 1.85 (m, 2H), 1.51 - 1.38 (m, 9H). |
95% | at 20℃; for 0.25h; Ionic liquid; | General procedure for preparation of N-tert-butylcarbamates To the ionic liquid [TPA][Pro] (1 mL) was added amine (1-14; Table-1) (1 mmol) and di-tert-butyl dicarbonate (1.2 mmol). The reaction was stirred at room temperature for an appropriate time (Table-1). After completion of the reaction as monitored by TLC, water was added to the reaction mixture and the product was extracted into ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine solution and concentrated under reduced pressure to give crude product, which was purified over silica gel column to afford corresponding N-tert-butylcarbamate. The ionic liquid [TPA][Pro] in aqueous solution was recovered by removing water under reduced pressure and dried. The recovered ionic liquid was reused for five times without loss of its activity. Finally, all the compounds confirmed by their m.p.’s, IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis wherever needed. |
84% | With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; | |
59% | With triethylamine In dichloromethane for 2.5h; Reflux; | 2.1 4.2.1 N-Boc-proline (1)16 A solution of proline (8.70 mmol, 1.0 g) and ditertbutyl dicarbonate (12.85 mmol, 2.8 g) were refluxed for 2.5 h at room temperature in 20 mL of CH2Cl2 solution, which containing 1.4 mL of triethylamine. When it was turned colorless, the mixture was diluted with CH2Cl2. The organic phase was washed with 3 mL saturation citric acid aqueous solution, saturation brine (4mL×2), water, and dried over MgSO4. After the solvent was removed in vacuum, the residue wash with a small amount hexanes and dried. When it was cooled down, the colorless oil was turned a large white solid to give a large white powder (1.22 g, 59%). 1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 4.31 (m, 1H), 3.42 (m, 2H), 2.26 (m, 1H), 2.06 (m, 1H), 1.98 (m, 2H), 1.47 (s, 9H). |
58% | Stage #1: di-<i>tert</i>-butyl dicarbonate; rac-Pro-OH With sodium hydroxide In water at 0 - 20℃; Stage #2: With hydrogenchloride In water at 10℃; | E Synthesis of 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid Into a 2000 mL 3-necked round-bottom flask was placed a solution of pyrrolidine-2-carboxylic acid (100 g, 869.57 mmol) in THE (400 mL). This was followed by the addition of a solution of NaOH (69.56 g, 1.74 mol) in H2O (870 mL). This was followed by the addition of a solution of (Boc)2O (208.5 g, 956.42 mmol) in THE (300 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (CH2Cl2/MeOH=5;1). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was extracted two times with 500 mL of ethyl ether and the organic layers combined. Then adjustment of the pH to 3 was accomplished by the addition of HCl (20%) while the temperature was maintained below 10° C. A filtration was performed. The filtrate was extracted 2 times with 500 mL ethyl acetate and the organic layers combined and dried over MgSO4 and concentrated by evaporation using a rotary evaporator. This resulted in 120 g (58%) of 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid as a white solid. |
22% | With potassium carbonate In water | 19 Example 19; Pirrolidine-1,2-dicarboxylic acid-1-tert-butyl ester PYRROLIDINE-1,] 2-dicarboxylic acid [1-TERT-BUTYL] ester (4.16 g, 22%) was obtained from pyrrolidine-2-carboxylic acid (10.0 g, [85.] 2 mmol) with di-tert-butyl dicarbonate (19 g, 87 mmol) and potassium carbonate (25.5 g, 185 mmol) in water (250 mL). Work up was carried out as in Example 18 and the product was used without further purification. |
With sodium hydroxide In acetonitrile at 20℃; for 3h; | 13.a Example 13: 3,4, 5-TRIMETHOXY-N- (2-METHYL-3-PHENYL-ALLYL)-N- (2-PYRROLIDIN- 2-YL-ETHYL)-BENZAMIDE Example 13: 3,4, 5-TRIMETHOXY-N- (2-METHYL-3-PHENYL-ALLYL)-N- (2-PYRROLIDIN- 2-YL-ETHYL)-BENZAMIDE a: BOC-anhydride, NAOH, acetonitrile, 3 h, RT b: Borane DIMETHYLSULFIDE, THF, 14 H, RT c: Methanesulfonylchloride, triethylamine, dichloromethane, 4 h, RT d: Sodium cyanide, DIMETHYLFORMAMIDE, 5 h, RT e: Raney nickel, ammonia gas in methanol, H2 2.5 kg pressure, 14 h F : 1/1-METHYL CINNAMALDEHYDE, DICHLOROMETHANE, 16 h, RT, N2 2/Sodium borohydride, methanol, 30 minutes at 0°C Scheme 1: Preparation OF 2-[2-(2-METHYL-3-PHENYL-ALLYLAMINO)-ETHYL-PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester [00128] To a solution of the compound 2- [2- (2-Methyl-3-phenyl- ALLYLAMINO)-ETHYL-PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester (prepared from racemic proline according to the scheme1), 0.6 g (2 MMOL) and 3,4, 5- trimethoxy benzoic acid 0.513 g (2. 4MMOL) in dry dichloromethane 10MI, triethyl amine 0.2 ml was added and stirred at room temperature for 20 min. Then was added O-(BENZOTRIAZOLE-1-YL)-N, N, N', N'-tetramethyl uranium tetrafluoroborate 1.3 g (4 MMOL) at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and was washed with 10% NAHCO3 solution, water and brine, dried, concentrated and subjected to column chromatography silica gel using CHCI3/MeOH as eluent to obtain-1 g of 2- {2- [ (2-METHYL-3-PHENYL-ALLYL)-3, 4, 5-TRIMETHOXY- BENZOYL)-AMINO]-ETHYL}-PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester. [00129] This compound was dissolved in 10ML of dioxane and 6N HCI 10 ML was added to it. The reaction mixture was stirred at room temperature for 14 hr, basified with 10% NAOH solution and was extracted twice with ethyl acetate (15 ML). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography over silica gel to obtain the free amine 0.35 g. The free amine 100 mg was converted to its hydrochloride salt using dry HCI in ether to yield 88 mg as a white solid. Yield : 39%. [00130] LC-MSD, m/z for C26H34N204 [M+H] +: 439.3 [00131] 1H NMR (300 MHz, MeOD/D20): 8 1. 6-1.8 (m, 4 H), 1.9-2. 1 (m, 4H), 2.25 (m, 1H), 3.2 (m, 3H), 3.5-3. 8 (m, 12H), 4.1 (s, 2H), 6.5 (s, 1H), 6.7- 6.9 (m, 2H), 7.2-7. 5 (m, 5H) | |
With sodium hydroxide In tetrahydrofuran; water | 2.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), and 87 mL of a 2M NaOH solution was added, followed by Boc2O (24.6 g, 113 mmol). The reaction mixture was stirred at ambient temperature overnight. The THF was removed in vacuo. The remaining aqueous mixture was acidified to pH 3 with aqueous citric acid, extracted twice with EtOAc. The combined organinc layers were washed with water, brine, dried with MgSO4, filtered and concentrated to yield the title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 11.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 12.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), and 87 mL of a 2M NaOH solution was added to the resulting mixture, followed by Boc2O (24.6 g, 113 mmol). The mixture was stirred at ambient temperature overnight. THF was removed in vacuo, and the remaining water was acidified to pH 3 with citric acid, then extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 13.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 14.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 15.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 16.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 18.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 19.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 20.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 27.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 3.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 4.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With sodium hydroxide In tetrahydrofuran; water | 5.1 Step 1 Step 1 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H2O (2:1), added 87 mL of a 2M NaOH solution followed by Boc2O (24.6 g, 113 mmol). Stirred at ambient temperature overnight. Removed THF in vacuo, acidified water to pH 3 with citric acid, extracted twice with EtOAc, washed organics with water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (18.7 g, quant.) APCI (AP-): 214.1 (M-H)-. | |
With triethylamine In dichloromethane at 20℃; for 2.5h; | ||
With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; | 21 Example 21 : 4-amino-2-pyridin-2-yl-6-pyrrolidin-2-ylpyrimidine- 5-carbonitrile [00338] Step 1: Preparation of 1- (tert-butoxycarbonyl) proline [00340] To a suspension of proline (10.0 g, 86.9 mmol) in DMF (200 mL) was added di-tert-butyl dicarbonate (37.98 g, 174 mmol) followed by triethylamine (17.6 g, 174 mmol). The reaction mixture was stirred overnight at room temperature. The solution was diluted with water (200 mL) and extracted first with EtOAc (2 x 400 mL) followed by CH2CI2 (3 x 400 mL). The combined organic phase was dried (Na2SO4) and concentrated. The crude product was carried forth to the next step.'H NMR (300 MHz, CDCI3) 6 4.37-4. 22 (m, 1 H), 3.57-3. 39 (m, 2H), 2.70-1. 89 (m, 4H), 1. 48-1. 40 (m, 9H). | |
In ethanol at 45℃; for 0.166667h; | ||
With sodium hydroxide In 1,4-dioxane; water for 1h; | N-Boc-protected amino acids 2a-2f (general procedure). General procedure: Amino acid (4.3 g, 37.4 mmol) wasdissolved in dioxane (75 mL) and after 30 min 1 MNaOH (38 mL) and H2O (38 mL) were added followedby (Boc)2O (9 g, 41.4 mmol). The reaction mixture wasstirred for 1 h and concentrated under reduced pressureto about 30-40 mL, after which ice and a little of ethylacetate. A dilute KHSO4 solution was then added verycarefully to the reaction mixture to adjust its pH to 2-3.The solution was then washed with brine and the productwas extracted with ethyl acetate and dried over MgSO4.The solvent was evaporated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
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95% | With 10% Rh/C; hydrogen In isopropyl alcohol at 60℃; for 8h; | |
With phosphate buffer at 21℃; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
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76% | With dmap; sodium carbonate In water at 20℃; for 3.5h; | Synthesis of 1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxylic (2b) Compound 1b (5 g, 24 mmol) was added portion wise to a stirred aqueous solution of Na2CO3 and L-proline (2a) (2.8 g, 24 mmol) within 30 min. After complete addition, dimethylaminopyridine (DMAP) (50 mg, 0.41 mmol) was added as catalyst and stirred for another 3 h. The reaction was maintained at pH 9-10 by adding sodium carbonate. The solution was filtered, acidified to pH 2-3 with HCl, extracted with ethyl acetate and dried over anhydrous MgSO4 overnight. It was distilled under vacuum and purified by flash chromatography using ethyl acetate and benzene in 4:1 ratio followed by recrystallization using hydro-alcoholic solution to afford compound 2b as a white solid (Scheme-II) (76%, 5.3 g, 80-82 °C). Elemental analysis of C12H15NO5S calcd. (found) %: C,50.52 (50.27); H, 5.30 (5.43); N, 4.91 (4.79). 1H NMR: (500 MHz, CDCl3): δ 1.77 (1H, m, -SO2NCH2CHH-), 1.94 (2H, m, -SO2N-CH2-CHH-, -SO2NCHCHH-), 2.19 (1H, m, -SO2NCHCHH-), 3.25 (1H, q, J = 8.3 Hz, -NHCHHCH2-), 3.52 (1H, m, -NCHH-CH2-), 3.89 (3H, s, -OCH3), 4.25 (1H, m, -N-CH-CH2), 7.02 (2H, d, J = 9 Hz, Ar-H), 7.83 (2H, d, J = 9 Hz, Ar-H). 13C NMR: (125 MHz, CDCl3): δ 24.59, 30.64, 48.66, 55.59, 60.27, 114.31, 128.91, 129.63, 163.20, 176.84. ESI+MS (m/z): 170.94(C7H7O3S), 286.08 (M+H), 287.12 (M+2H) , 308.08 (M+Na); ESI-MS(m/z): 284.10 (M-H). |
With triethylamine In dichloromethane | 20 Ciompound 20 1-[(4-Methoxyphenyl)sulfonyl]-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)-2-pyrrolidine carboxamide Proline is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 1-[(4-methoxyphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid. | |
With triethylamine In dichloromethane at 20℃; | 1.1 Method for the synthesis of (2) General procedure: A mixture of L-proline (1mmol), different substituted sulfonyl chloride (1 mmol), and triethyl amine (1.2 mmol) was stirred over night at room temperature. The resulting mixture was concentrated under vaccuo and purified by column chromatography by using hexane and ethyl acetate as an eluent. |
With sodium hydroxide In diethyl ether at 20℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol; ethyl acetate; | Step B 5-[1,8]-Naphthyridin-2-yl-pentanoic Acid Methyl Ester (1-4) A mixture of 1-2 (1.4 g, 9.04 mmol), 1-3, 2-amino-3-formylpyridine (552 mg, 4.52 mmol) (for preparation, see: J. Org. Chem., 1983, 48, 3401), and proline (260 mg, 2.26 mmol) in absolute ethanol (23 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatog,raphed (silica gel, 80percent ethyl acetate/hexane, then ethyl acetate) to give ester 1-4 as a white solid. TLC Rf=0.38 (silica, EtOAc). 1H NMR (300 MHz, CDCl13) delta 8 9.08 (m, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.45 (m, 1H), 7.39 (d, J=8.3 Hz, 1H), 3.66 (s, 3H), 3.08 (t, J=7.6 Hz,2H), 2.39 (t, J=7.6 Hz, 2H), 1.94 (m,2H), 1.78 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; triethanolamine; In water; sodium carbonate; ethyl acetate; N,N-dimethyl-formamide; | Boc-Gly-Pro-OH Boc-Gly-ONp (50 g, 0.17 mol.) and proline (20.7 g, 0.175 mol.) were dissolved in 300 ml DMF. 20 ml TEA and 30 ml water were added while stirring the solution. The stirring was continued overnight and TLC analysis showed no more starting materials. The solvents were removed under reduced pressure and the resulting mixture was dissolved in 250 ml saturated Na2 CO3. The aqueous solution was extracted by 3*100 ml ethyl acetate to remove p-nitrophenol. Then, after chilling to 0 C., the aqueous solution was acidified to about pH=3 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase by 3*150 ml ethyl acetate. The organic phase was combined and washed by saturated NaCl (brine) 3*20 ml, and dried using Na2 SO4. TLC analysis showed there was still p-nitrophenol in the solution. The ethyl acetate was removed under reduced pressure and column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product Boc-Gly-Pro-OH (white solid, 41.2 g, 88%). TLC Rf=0.25 (CMA, 85:15:3). FAB-MS, observed (M+H)+ =273. 1 H-NMR (360 MHz, DMSO-d6, 20 C.) delta 12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 6.44 (s, NH-minor), 4.50 (dd, 0.25H, Pro-alpha-minor), 4.20 (dd, 0.71H, Pro-alpha-major), 3.81-3.62 (m, 1.7H, Gly-alpha-major), 3.47-3.33 (m, 2.5H, Pro-delta and Gly-alpha-minor), 2.25-2.00 (m, 1.2H, Pro-beta), 1.96-1.60 (m, 2.7H, Pro-beta and Pro-gamma), 1.36 (s, 9H, Boc-CH3)b. |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; In methanol; | Step A Methyl pyrrolidine-2-carboxylate hydrochloride 600 ml of technical-grade methanol are introduced into a multinecked flask equipped with dropping funnel and internal thermometer, with ice/sodium chloride cooling. 2.4 mol of thionyl chloride are added dropwise in such a way that the temperature of the reaction solution does not exceed -5 C. Then, 2.18 mol of proline are added in portions in the course of approximately 10 minutes. The mixture is stirred for approximately 4 hours at 40 C. and subsequently for three days at room temperature, and the solution is greatly concentrated, the residue is taken up several times in methanol to remove excess thionyl chloride, and the mixture is reconcentrated. After drying the product for several hours in a lukewarm water bath in an evacuated flask, the target compound is obtained in quantitative yield. Some of the oily crude product crystallises after being left to stand over several days. 1H NMR (d4 methanol): delta=1.81-2.69 (m, 4H, 3-CH2, 4-CH2), 3.23-3.59 (m. 2H, 5-CH2), 3.84 (s, 3H, CH3), 4.46 (t, J=7 Hz, 1H, 2-CH), 4.81 (s, 2H, NH, HCl) IR (oil film): 3390 (broad), 2959 (broad), 2740, 1745, 1570, 1445, 1245, 1050, 1000, 920 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
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In toluene; | a) Ethyl 1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate STR50 8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 5.8 g (50 mmol) of proline in 200 ml of toluene. The mixture is concentrated and the residue is distilled. Yield: 9.6 g (86% of theory). Boiling point: 102-112 C./0.13-0.15 mbar. |
Yield | Reaction Conditions | Operation in experiment |
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63% | Heat a slurry of <strong>[796600-15-2]2-chloro-4-fluoro-3-methyl-benzonitrile</strong> (0.4 g, 2.36 mmol) and L-proline (2.11 g, 18.8 mmol) in N-methylmorpholine (1.6 mL) at 200 0C in a microwave for 30 min. Partition the reaction between 2N aqueous hydrochloric acid and ethyl acetate. Separate and extract the organic portion with 2N aqueous sodium hydroxide. Acidify the aqueous extract to pH 1 by adding concentrated EPO <DP n="71"/>hydrochloric acid and back extract into ethyl acetate. Extract the combined organic portions with brine, dry over magnesium sulphate, filter, and concentrate under reduced pressure to give the title compound. (0.395 g, 63%) mass spectrum (m/e): 263(M-I); 1H NMR (300 MHz, CDCl3): delta 8.66(bs,lH0, 7.31(d, IH), 6.75(d, IH), 4.38(t,lH), 3.67(m, IH), 3.10(m,lH), 2.43(m,lH), 2.29(s,3H), 2.20-1.90(m.3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: Diethyl vinylphosphonate; rac-Pro-OH With sodium hydroxide In water at 20℃; for 2h; Stage #2: With hydrogenchloride In water | N-[2-(Diethoxyphosphoryl)ethyl]- and N-[2-(diphenylphosphoryl)ethyl]-amino acids (2a-f, 5,6) (general procedure): General procedure: (a) Sodium salts: a mixture of diethyl vinylphosphonate 1 (0.41 g, 2.5 mmol) or diphenylvinylphosphine oxide 4 (0.57 g, 2.5 mmol), the corresponding amino acid (2.5 mmol), and NaOH (0.10 g, 2.5 mmol) in H2O (5 ml) was stirred either under ambient conditions (for the reaction of 1) or at reflux (in the case of 4). The reaction was completed in 2 h in the case of proline (both for 1 and 4), 10 h (reaction of l-methionine and 4), 72 h for the reaction of 1 and l-phenylalanine and 48 h for the reaction of vinylphosphonate 1 with other amino acids. The corresponding sodium salts were isolated as white hygroscopic powders by lyophilization of the crude reaction mixture. (b) Free acids: After completion of the reaction, the mixture was acidified with 5.4 N HCl (0.46 ml, 2.5 mmol) in H2O (2 ml) and then concentrated to dryness under reduced pressure. The residue was dissolved in EtOH (10 ml), precipitated NaCl was filtered, and the filtrate was concentrated in vacuo and dried over P2O5 to give the crude final products. If necessary, the products were additionally purified by recrystallization or precipitation. Otherwise, the reaction mixture was loaded onto a Dowex 50WX8-H+column and eluted with EtOH-NH4OH = 7:3. The fraction from the cation exchange column was evaporated to the dryness, dissolved in MeOH, and the final acid precipitated with Et2O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Stage #1: ethyl coumarin-3-carboxylate; benzaldehyde; rac-Pro-OH In toluene for 9h; Dean-Stark; Reflux; Stage #2: With acetyl chloride In isopropyl alcohol at 20℃; | 4.5. General procedure for the synthesis of 11-phenyloctahydrochromeno[3,4-a]pyrrolizines 16-17 General procedure: A mixture of the corresponding coumarin 4 (1.0mmol), benzaldehyde (0.04g, 0.4mmol) and finely ground proline (0.12g, 1.0mmol) was refluxed in dry toluene (8mL) with magnetic stirring and removal of the water formed by means of a Dean-Stark trap. After 3h, a second portion of benzaldehyde (0.04g, 0.4mmol) was added; after another 2h, a third portion of benzaldehyde (0.04g, 0.4mmol) was added. Reflux was continued for an additional 4h. Adducts 16 and 17 were isolated by column chromatography on silica gel using CH2Cl2:EtOAc as an eluent. Alternatively, for 17c: the crude yellow reaction mixture was cooled to room temperature and slowly filtered through a thin layer of silica gel, then washed with toluene. Isopropanol (0.07g, 1.2mmol) and acetyl chloride (0.09g, 1.1mmol) were added with stirring to the solution, the resulting mixture was allowed to stand overnight at room temperature. The formed dark-magenta precipitate was dissolved in hot acetone, diluted with EtOAcand then kept for 2 days in a refrigerator. The colourless crystals of the product were filtered and washed with an acetone-ethyl acetate mixture. The hydrochloride of adduct 17c was dried to a constant weight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In methanol; water; for 2h;Reflux;Mechanism; | General procedure: A mixture of isatin(1.0 mmol), alpha-amino acid (1.0 mmol) and acrylamide (1.0 mmol) in 4.0 mL aqueous methanol (1:3) was heated in an oil bath to reflux temperature for 40 min to 7 hours. The resulting precipitates were collected by filtration and washed with cold methanol to give the analyticallypure products 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 96h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 72h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 96h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 110℃; for 96h; Inert atmosphere; | General Procedure for the Preparation of 3 General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 °C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 90℃; for 96h; Inert atmosphere; | General Procedure for the Preparation of 3 General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 °C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
45% | With dicarbonyl-(2,4-bis(trimethylsilyl)bicyclo[3.3.0]nona-1,4-dien-3-one)[acetonitrile]iron In toluene at 120℃; for 24h; Schlenk technique; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 24h;Inert atmosphere;Catalytic behavior; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 110℃; for 96h; Inert atmosphere; | General Procedure for the Preparation of 3 General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 °C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 110℃; for 72h; Inert atmosphere; | General Procedure for the Preparation of 3 General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 °C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 72h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 72h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 72h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 110℃; for 48h; Inert atmosphere; | General Procedure for the Preparation of 3 General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 °C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 24.0h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate; In toluene; at 110℃; for 96h;Inert atmosphere; | General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water at 50℃; for 1h; Sonication; Combinatorial reaction / High throughput screening (HTS); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water at 50℃; for 1h; Sonication; Combinatorial reaction / High throughput screening (HTS); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water at 50℃; for 1h; Sonication; Combinatorial reaction / High throughput screening (HTS); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In methanol at 50℃; for 1h; Sonication; Combinatorial reaction / High throughput screening (HTS); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / Reflux 2: hydrazine hydrate; dimethyl sulfoxide; 1,2-bis(dimethylphosphanyl)ethane; potassium <i>tert</i>-butylate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / <i>tert</i>-butyl alcohol / 100 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In isopropyl alcohol; for 48h;Reflux; | General procedure: 4.2. General procedure for the preparation of spiro[indoline-3,20-pyrrolidin]-2-ones 3 and spiro[indoline-3,30-pyrrolizin]-2-ones 4 and 6 A mixture of corresponding isatin 2 (1.0 mmol) and sarcosine(0.13 g, 1.5 mmol) or proline (0.17 g, 1.5 mmol) was stirred in isopropanol (4 mL), and corresponding nitroalkene 1 (1.0 mmol)was added in one portion. The resulting mixture was stirred atreux for 48 h and the reaction progress was monitored by TLC.Upon completion, the mixture was diluted with brine (10 mL),resulting precipitate was ltered off and washed with water andhexane and vacuum dried. In some cases, additional recrystallisa-tion from the mixture hexane/CH2Cl2 (2:1) was necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In isopropyl alcohol; for 48h;Reflux; | General procedure: 4.2. General procedure for the preparation of spiro[indoline-3,20-pyrrolidin]-2-ones 3 and spiro[indoline-3,30-pyrrolizin]-2-ones 4 and 6 A mixture of corresponding isatin 2 (1.0 mmol) and sarcosine(0.13 g, 1.5 mmol) or proline (0.17 g, 1.5 mmol) was stirred in isopropanol (4 mL), and corresponding nitroalkene 1 (1.0 mmol)was added in one portion. The resulting mixture was stirred atreux for 48 h and the reaction progress was monitored by TLC.Upon completion, the mixture was diluted with brine (10 mL),resulting precipitate was ltered off and washed with water andhexane and vacuum dried. In some cases, additional recrystallisa-tion from the mixture hexane/CH2Cl2 (2:1) was necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In isopropyl alcohol; for 48h;Reflux; | General procedure: 4.2. General procedure for the preparation of spiro[indoline-3,20-pyrrolidin]-2-ones 3 and spiro[indoline-3,30-pyrrolizin]-2-ones 4 and 6 A mixture of corresponding isatin 2 (1.0 mmol) and sarcosine(0.13 g, 1.5 mmol) or proline (0.17 g, 1.5 mmol) was stirred in isopropanol (4 mL), and corresponding nitroalkene 1 (1.0 mmol)was added in one portion. The resulting mixture was stirred atreux for 48 h and the reaction progress was monitored by TLC.Upon completion, the mixture was diluted with brine (10 mL),resulting precipitate was ltered off and washed with water andhexane and vacuum dried. In some cases, additional recrystallisa-tion from the mixture hexane/CH2Cl2 (2:1) was necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol for 48h; Reflux; | 4.2. General procedure for the preparation of spiro[indoline-3,20-pyrrolidin]-2-ones 3 and spiro[indoline-3,30-pyrrolizin]-2-ones 4 and 6 General procedure: 4.2. General procedure for the preparation of spiro[indoline-3,20-pyrrolidin]-2-ones 3 and spiro[indoline-3,30-pyrrolizin]-2-ones 4 and 6 A mixture of corresponding isatin 2 (1.0 mmol) and sarcosine(0.13 g, 1.5 mmol) or proline (0.17 g, 1.5 mmol) was stirred in isopropanol (4 mL), and corresponding nitroalkene 1 (1.0 mmol)was added in one portion. The resulting mixture was stirred atreux for 48 h and the reaction progress was monitored by TLC.Upon completion, the mixture was diluted with brine (10 mL),resulting precipitate was ltered off and washed with water andhexane and vacuum dried. In some cases, additional recrystallisa-tion from the mixture hexane/CH2Cl2 (2:1) was necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In acetonitrile at 80℃; for 24h; diastereoselective reaction; | 4.2. General experimental procedures for synthesis of compounds 3-5 General procedure: A solution of isatin derivatives 1 (0.4 mmol), 3-methyl-4-nitro-5-alkenyl-isoxazoles 2 (0.6 mmol) and proline or thioproline or sarcosine (0.8 mmol) in 10.0 mL of CH3CN at 80 °C for 24 h. After completion of the reaction, as indicated by TLC, the reaction mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/EtOAc5:1-3:1) to furnish the corresponding products 3-5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In isopropyl alcohol at 60℃; | Synthesis of compounds 6a-j (General method). General procedure: Theappropriate nitrostyrene 1a-e (1.0 mmol) was added to astirred solution of indenoquinoxalinone 5a or 5b(1.0 mmol) and proline (0.17 g, 1.5 mmol) in 2-PrOH (4 ml).NNO2Me7d3'4'NN N4'N 3'HHNN N7'dMe NO2HHH1HHo1HoFigure 4. The most important cross peaks observed in 1H-1HNOESY 2D NMR experiment for a mixture of isomers 7d and 7'd.Figure 5. A fragment of 1H-1H NOESY 2D NMR experiment fora mixture of isomers 7d and 7'd.The obtained mixture was stirred at 45°C (for the reactionwith compound 5) or at 60°C (for the reaction withcompound 5b) for 4-5 days (control by TLC method), thenthe precipitated product was filtered off. The filtrate wasdiluted with saturated NaCl solution (10 ml) and water (3 ml),the obtained precipitate was combined with the firstprecipitate, washed with hexane and H2O, dried, andrecrystallized, if necessary, from a 1:2 mixture of CH2Cl2and hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In isopropyl alcohol at 45℃; | Synthesis of compounds 6a-j (General method). General procedure: Theappropriate nitrostyrene 1a-e (1.0 mmol) was added to astirred solution of indenoquinoxalinone 5a or 5b(1.0 mmol) and proline (0.17 g, 1.5 mmol) in 2-PrOH (4 ml).NNO2Me7d3'4'NN N4'N 3'HHNN N7'dMe NO2HHH1HHo1HoFigure 4. The most important cross peaks observed in 1H-1HNOESY 2D NMR experiment for a mixture of isomers 7d and 7'd.Figure 5. A fragment of 1H-1H NOESY 2D NMR experiment fora mixture of isomers 7d and 7'd.The obtained mixture was stirred at 45°C (for the reactionwith compound 5) or at 60°C (for the reaction withcompound 5b) for 4-5 days (control by TLC method), thenthe precipitated product was filtered off. The filtrate wasdiluted with saturated NaCl solution (10 ml) and water (3 ml),the obtained precipitate was combined with the firstprecipitate, washed with hexane and H2O, dried, andrecrystallized, if necessary, from a 1:2 mixture of CH2Cl2and hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | In ethanol; acetic acid butyl ester; at 75℃; for 15h; | In a reaction vessel equipped with a reflux condenser and a stirrer, 100.0 parts by weight of <strong>[13402-02-3]hexadecyl acrylate</strong>, 38.8 parts by weight of pyrrolidine-2-carboxylic acid, 258.5 parts by weight of ethanol,50.0 parts by weight of butyl acetate was charged. After raising the temperature with stirring,The reaction was carried out at 75 C. for 15 hours. The end point of the reaction was judged by the disappearance of the material spot by thin layer chromatography. After the reaction, the solvent was removed by drying under reduced pressure and recrystallization was carried out with acetone. The obtained product was subjected to measurement by 1 H-NMR and elemental analysis in the same manner as in Example 1. The yield was 90.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | In ethanol at 75℃; for 15h; | 3 Example 3 A reaction vessel equipped with a reflux condenser and a stirrer was charged with 100.0 parts by weight of stearyl acrylate, 35.5 parts by weight of pyrrolidine-2-carboxylic acid, 307.1 parts by weight of ethanol, and 80.0 parts by weight of mesoisobutyl ketone . After raising the temperature with stirring, the reaction was carried out at 75 ° C. for 15 hours. The end point of the reaction was judged by the disappearance of the material spot by thin layer chromatography. After the reaction, the solvent was removed by drying under reduced pressure and recrystallization was carried out with acetone. The obtained product was subjected to 1 H-NMR and elemental analysis. The yield was 89.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 80℃; for 3h;Green chemistry; | General procedure: A solution of chromones 1 (0.2 mmol), isatins 2 (0.3 mmol) and proline, or thioproline (0.5 mmol) in the 4.0 mL of EtOH at 80 C in oil bath for 3 h. After completion of the reaction, as indicated by TLC, the reaction solvent was directly removed, and purification by flash column chromatography (petroleum ether/EtOAc = 5:1~10:1) was carried out to furnish the corresponding products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In methanol; water;Reflux; | General procedure: A solution of C3-beta-cholestrylcarboxylate (4) (1 mmol), proline (11)(1 mmol) and isatin (1a-f)/acenaphthenequinone (7)/ninhydrin (9)(1 mmol) was stirred in aqueous methanol for 1-2 h at reflux temperature.After the completion of reaction as indicated by TLC, methanolwas evaporated under reduced pressure. The crude product waspurified by column chromatography using hexane:EtOAc mixture (2:1)as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In methanol; water;Reflux; | General procedure: A solution of C3-β-cholestrylcarboxylate (4) (1 mmol), proline (11)(1 mmol) and isatin (1a-f)/acenaphthenequinone (7)/ninhydrin (9)(1 mmol) was stirred in aqueous methanol for 1-2 h at reflux temperature.After the completion of reaction as indicated by TLC, methanolwas evaporated under reduced pressure. The crude product waspurified by column chromatography using hexane:EtOAc mixture (2:1)as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.73% | With hydrogenchloride In isopropyl alcohol at 100℃; for 8h; | 10 Example 10 Synthesis of Compound (E)-N-[(2-ferrocenyl)vinyl]methylhistidine (1i) The reaction is carried out in a one-pot process:Weigh 0.46 g (2 μmol) of ferrocene ethanol,0.46 g (4 μmol) of proline,0.8 mL (8 μmol) aqueous formaldehyde solution was mixed in 5 mL of isopropanol.Stir well until clear liquid solution,Add 200 μL of concentrated hydrochloric acid to adjust the pH to 5.0, and heat to 100 ° C to reflux.The progress of the reaction was monitored by TLC (the ratio of the developing solvent was ethyl acetate: methanol = 10..1), and the reaction was carried out for 8 hours. Post processing:The reaction solution was adjusted to pH with saturated NaHCO3, extracted with dichloromethane for 2 to 3 times, then washed once with saturated NaCl and dried over anhydrous Na2SO4 overnight.Column chromatography and concentrated to give compound 1i (eluent, ethyl acetate ratio methanol = 101), a yield of 15.73%.(The product is a brownish black oily liquid with fluorescence at 254 nm and ninhydrin color development). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 g | With 2,6-di-tert-butyl-4-methyl-phenol; In water; at 45 - 80℃; for 4h; | Suspend BHT (0.55g) in IPA (350 ml) at 20-30 C. Heat the suspension to 45-50 C and continue stirring at this temperature for 30 min. Took 200 ml of the IPA solution, under N2 atmosphere and Cangaliflozin (25gm) was added at 45-50 C. The obtained solution was treated with DL-proline (9.66 gm) which is dissolved in mixture of IPA solution (lOOml) and DM water (10 ml) at 70-80 C and stirred for 4 hours. Lowering the temperate of solution to 60-65 C and stir for 1 hour to precipitate out DL-proline co-crystal of <strong>[842133-18-0]Canagliflozin</strong> as slurry. Cool the obtained slurry slowly to 15-20 C and continue the stirring for 2 hours. Filter the obtained product at 15-20 C and washed with (50 ml, 20-30 C) IPA. Dried the product at 50-60C. (0069) Purity: 99.99 % (0070) Yield: 30 gm: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1-hydroxytetraphenyl-cyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II) In toluene at 120℃; for 24h; Schlenk technique; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; at 90℃; for 4.0h; | Synthesis was referred to the literature [48]. Amixture of proline (0.23 g, 2 mM) and 2-(methylthio)-4,5-dihydrothiazole (0.32 g, 2.4 mM) was dissolved in MeOH (8 mL)and H2O (4 mL), heated to 90 C and refluxed for 4 h. Then themixture was cooled down to room temperature and solvent wasevaporated at reduced pressure. The residue was recrystallized toget 26. 26 was dissolved in Ac2O (10 mL) and reacted under N2atmosphere for 2 h at 60 C. Methyl propionate (8.5 g, 87 mM) wasadded and the solution was heated for 3 h at 120 C. After solventevaporation, the residue was purified by column chromatographyeluting with PE/EA (1/4) to give 53% yield (245 mg) intermediate28. A mixture of 28 (0.2 g, 0.68 mM) and MeOH (10 mL) was addedRaney-Ni (20 mg). The reaction mixture was purged three timeswith hydrogen and stirred under hydrogen atmosphere (3.5 atm)overnight. The mixture was filtered, concentrated, and purified bycolumn chromatography with PE/EA (1/4) to get 29. After hydrolysisand condensation followed similar procedures as 10a, 31 wasafforded. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; for 0.75h;pH 8-9;Reflux; | General procedure: Solid vanadyl(II)-orotate-amino acid complexes with genaral formula NH4[(OAH)(VO)(AAn)]·H2O (1-6), where AAa is isoleucine, AAb is threonine,AAc is proline, AAd is phenylalanine, AAe is lysine, andAAf is glutamine) were prepared from the correspondingreagents (OAH3 : VOSO4 : AAn) applied in equal molarratio. The complexes were synthesized directly by mixing the appropriate amino acid (1.0 mmol) with 40 mL ofCH3OH-H2O solution of <strong>[65-86-1]orotic acid</strong> followed by additionof VOSO4·H2O salt. The mixture was treated by ammoniasolution (5%) to adjust pH 8.0-9.0 and refluxed for 45 mintill the precipitate settled down. The corresponding solidprecipitate was isolated, washed repeatedly by CH3OHand dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With phosphorus trichloride In acetonitrile Reflux; | 4.1.3 General procedure for the synthesis of compounds 5a-p General procedure: The 3-aminocoumarin 3 (1mmol) and appropriate carboxylic acid 4a-p (1.1mmol) were dissolved in 3mL CH3CN and the mixture was stirred at room temperature for half an hour. The PCl3 (1mmol) was added dropwise in the reaction mixture and the reaction mixture was again refluxed for 5-6h but in case of compounds 5c and 5p 8h refluxing was required. After completion the reaction was quenched by adding ice cold water (5mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (10mL) and washed twice with water (2×20mL) and then with saturated NaHCO3 solution (10mL) and finally with brine (20mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum. The solid products obtained in case of compounds 5a, 5b, 5d, 5f, 5h, and 5p were recrystallized from acetone while those in case of compounds 5c, 5i and 5l were recrystallized in acetone and DMSO mixture (3:1). The crude products obtained in case of compounds 5e, 5g, 5j, 5k and 5m-5o were purified by silica gel column using chloroform:methanol (9:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; | A. Proline Analog Un-Fixing Agent Preparation The proline analog un-fixing agent corresponding to compound (12) ((2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid) was purchased from Sigma-Aldrich and used without further purification (Cat. No. 51-35-4; Sigma-Aldrich Corp., St. Louis, Mo., USA). The proline analog un-fixing agent of compound (13) ((2S,4R)-4-aminopyrrolidine-2-carboxylic acid) was prepared from a Boc protected reagent using the following 1-step procedure. To a solid of <strong>[132622-69-6](2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid</strong> (150 mg, 0.7 mmol, 1 equiv) (Catalog#: 132622-69-6, Combi-Blocks) was added 4 mL of 4M HCl and stirred at RT. After stirring at RT for 2 h, the reaction mixture was conc. in vacuo to give the title compound in quantitative yield. 1H NMR (80 MHz, CD3OD): δ=2.53-2.13 (m, 2H), 3.12-2.91 (m, 1H), 3.66-3.12 (m, 2H), 4.13-3.67 (m, 1H). The proline analog un-fixing agent corresponding to compound (14) dihydrochloride ((2S,4S)-4-[(pyridin-4-yl)oxy]pyrrolidine-2-carboxylic acid dihydrochloride) was purchased from Enamine and used without further purification (Cat. No. EN300-7353434; Enamine, New Jersey, USA). The proline analog un-fixing agent of compound (15) ((2S,4S)-4-(Pyridin-3-yloxy)pyrrolidine-2-carboxylic acid) was prepared from a Boc-protected reagent using the following 1-step procedure To a solid of (2S,4S)-1-(tert-butoxycarbonyl)-4-(pyridin-3-yloxy)pyrrolidine-2-carboxylic acid (100 mg, 0.3 mmol, 1 equiv) (Catalog#: PH014404, Sigma Aldrich) was added 2 mL of 4M HCl and stirred at RT. After stirring at RT for 2 h, the reaction mixture was conc. in vacuo to give the title compound in quantitative yield. 1H NMR (80 MHz, CD3OD): δ=2.75-2.05 (m, 2H), 3.51 (br-s, 2H), 4.63-4.25 (m, 1H), 5.61-5.13 (m, 1H), 8.67-7.49 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With C15H12N4O3; potassium carbonate In ethanol; water at 20℃; for 24h; Irradiation; |
Tags: 609-36-9 synthesis path| 609-36-9 SDS| 609-36-9 COA| 609-36-9 purity| 609-36-9 application| 609-36-9 NMR| 609-36-9 COA| 609-36-9 structure
[ 68078-09-1 ]
1-Methylpyrrolidine-2-carboxylic acid
Similarity: 0.95
[ 58123-62-9 ]
(R)-1-Methylpyrrolidine-2-carboxylic acid
Similarity: 0.95
[ 3105-95-1 ]
(S)-Piperidine-2-carboxylic acid
Similarity: 0.95
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