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CAS No. : | 43041-12-9 | MDL No. : | MFCD06656665 |
Formula : | C6H11NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BLWYXBNNBYXPPL-RXMQYKEDSA-N |
M.W : | 129.16 | Pubchem ID : | 853476 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.84 |
TPSA : | 38.33 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) : | -7.01 cm/s |
Log Po/w (iLOGP) : | 1.89 |
Log Po/w (XLOGP3) : | 0.11 |
Log Po/w (WLOGP) : | -0.47 |
Log Po/w (MLOGP) : | 0.0 |
Log Po/w (SILICOS-IT) : | 0.63 |
Consensus Log Po/w : | 0.43 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.58 |
Solubility : | 34.1 mg/ml ; 0.264 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.47 |
Solubility : | 43.7 mg/ml ; 0.339 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.85 |
Solubility : | 18.3 mg/ml ; 0.142 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
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 |
---|---|---|
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 |
---|---|---|
96% | With ammonium cerium (IV) nitrate; water; acetic acid In dichloromethane at 20℃; for 0.133333 h; Inert atmosphere | The substrate (1 equiv) was added to a solution of CAN (20 mol percent) in minimum amount of water (roughly 15 equiv). The reaction mixture was dissolved in dichloromethane and stirred magnetically. Acetic acid (10 equiv) was added to the solution and left to stir at rt for the required time mentioned in Table 2. Upon completion of the reaction, the solvent was evaporated under reduced pressure and worked up in the following methods. Method A: The solid residue was washed twice with petroleum ether to remove the by product trityl alcohol. The residue was then dissolved in methanol and filtered through a short pad of celite. Removal of the solvent under reduced pressure yielded the free amine. Method B: Water and acetic acid were removed from the reaction mixture in vacuo. The residue was dissolved in dry dichloromethane, followed by the addition of triethylamine (2.5 equiv) and acetic anhydride or benzoyl chloride (1.5 equiv). After the completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate twice. The combined organic layer was washed with water and brine and finally dried (Na2SO4). Solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to afford the acylated amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: at -5 - 25℃; for 2 h; Stage #2: With potassium carbonate In water at 0℃; |
A solution of L-proline (2.23 g) in dry methanol (15 ml) was cooled to -5° C. and thionyl chloride (4.52 g) was added dropwise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction was continued at 25° C. for 2 h. The solvent was distilled and the residue stored in ice-chest for 12 h. The solid mass was added to aqueous solution of potassium carbonate (50percent, 20 ml) at 0° C. and the separated oily layer was extracted into ether (15 ml.x.3). The ethereal layer was dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine (85percent), [MS (m/z) M+129 (1percent), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. It was taken in dry diethyl ether (15 ml), cooled to 0° C. and t-butylhypochlorite (2.16 g) added dropwise. The reaction was monitored on silica gel thin layer using chloroform as the eluant. After completion of the reaction (15 min.), potassium t-butoxide (2.24 g) was added gradually over 10 min. and the reactants stirred at 25° C. for 5 h. The solution was filtered and the solvent distilled under reduced pressure to afford 2-(carbomethoxy)-1-pyrrroline (2 g), [MS (m/z) M+ 127(1percent), 112(0.5), 97 (15), 69 (100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry ether, iodine (0.01 g) was added followed by dropwise addition of a solution of methyl iodide (3.08 g) in ether (5 ml) at 35° C. The mixture was stirred until the disappearance of magnesium turnings (15 min), then cooled to 0° C. To it, a solution of 2-(carbomethoxy)-1-pyrrroline (2 g) in dry ether (5 ml) was added over 5 min. and the mixture was stirred at room temperature. On completion of the reaction (2 h) the product was worked up by the addition of dilute hydrochloric acid (5percent, 10 ml) and the organic layer separated. The aqueous layer was further extracted with ether (10 ml.x.2) and the combined organic layers dried over anhydrous sodium sulphate and distilled to afford pure 2-acetyl-1-pyrroline [1.3g, 95percent purity, [MS (m/z) M+ 111 (5percent), 96 (0.1), 83 (15), 69(8), 68 (10), 55 (2), 52 (0.2), 43 (100),42 (25), 41 (50)].To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to -5° C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction mixture was allowed to attain room temperature (25° C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50percent, 20 ml) at 0° C. and the separated oily layer extracted into ether (15 ml.x.3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85percent, MS (m/z) M+129 (1percent), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25° C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1percent), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35° C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0° C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5percent, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml.x.2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95percent purity, MS (m/z) M+ 111 (5percent), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 0 - 20℃; for 16 h; | 1002721 To a stirring solution of proline methyl ester (70 g, 422 mmol) in CH2C12 (700 mL) were added Et3 (183 mL, 1.26 mol) at 0 °C and stirred for 10 min. After added Boc- anhydride (184 mL, 845 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with (( (2 x 200 mL). The combined organic layer was washed with citric acid (1 x 150 mL), brine (1 x 200 mL). The organic layer was dried over a2S04 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting 50percent EtOAc/w-hexane to obtain 6S-N (80 g, 83percent) as thick syrup. 1H-NMR: (400 MHz, DMSO-d6): δ 4.15-4.13 (m, 1H), 3.65 (s, 3H), 3.35-3.30 (m, 2H), 2.23- 2.15 (m, 1H), 1.86-1.78 (m, 3H), 1.41 (s, 9H); LCMS (m/z): 129 [(M++l)-Boc] |
73% | With triethylamine In dichloromethane at 0 - 20℃; for 16 h; | To a stirred solution of methyl pyrrolidine-2-carboxylate (lntermediate-8) (1 g, 7.74 mmol) in DCM (10 mL) TEA (2.7 mL) was added, followed by di-ie/f-butyl dicarbonate (Boc anhydride, (Boc)20) (1 .86 g, 8.51 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with chloroform (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh) to afford the title compound (1.3 g, 73percent yield) as pale yellow liquid. |
66% | With triethylamine In acetonitrile at 0 - 20℃; for 16.1667 h; | To stirred solution of methyl prolinate (300 mg, 2.32mmol) in acetonitrile (5 mL) was added triethyl amine (0.55 g, 4.65mmol) and the reaction was stirred for 10 min. Di-t-butyl dicarbonate (0.43 g, 2.78 mmol) was added dropwise to the reaction mixture at 0 °C and stirred for 16 h at ambient temperature. The reaction mixture was concentrated and purified via standard methods to afford 1-(tert-butyl) 2-methyl pyrrolidine-1 ,2-dicarboxylate (0.35 g, 66percent) as pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With diphenylphosphoranyl azide; triethylamine In N,N-dimethyl-formamide at -4℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With [(nBu3Sn)2WO4]; dihydrogen peroxide; In methanol; water; at 20℃; for 10h;Catalytic behavior; | General procedure: Four mol% (33 mg) of organometallic coordinationpolymer [(nBu3Sn)2WO4], was added to a stirred solutionof methanol (2 mL) and amine (1.0 mmol) and theresultant suspension was stirred for 2 min. To this, 3-4 mmol aqueous hydrogen peroxide (30 wt%) was added,after which the reaction mixture was stirred at r.t., untilcompletion of the reaction as indicated by thin-layerchromatography (TLC). The catalyst was filtered andwashed with acetone several times. Excess hydrogenperoxide was decomposed by adding small portions ofsodium hydrogen sulphite. The solution was extractedwith dichloromethane. The combined organic extractswere dried over anhydrous sodium sulfate. The mixturewas filtered and the solvent was removed by a rotaryevaporator and the crude residue was purified bypreparative thin-layer chromatography using ethyl acetateand n-hexane (1:4) as eluents to give correspondingnitrone or oxime derivatives. All the products are knowncompounds (except 7b) and were characterized bycomparison of their IR, 1H NMR and 13C NMR spectroscopicdata and respective melting points with the reportedvalues. |
65% | General procedure: The secondary amine(1 mmol) was added to a mixture of catalyst (0.01 g, 1.1 mol %) and methanol(2 mL). The mixture was stirred for 5 min, under an argon atmosphere, andthen H2O2 (3 equiv) was added in two or three portions. The mixture wasstirred at room temperature until completion of the reaction [monitored byTLC (CH2Cl2/MeOH, 95:5)]. After complete disappearance of the amine, thecatalyst was separated from the reaction mixture using an external magnet,washed with MeOH three times to remove all residual products, and then driedfor reuse in a subsequent run. Evaporation of the solvent gave the crudeproduct, which was purified by recrystallization (CH2Cl2/n-hexane) or bypreparative thin-layer chromatography. All isolated products gave satisfactoryphysical and spectral data (melting points, FT-IR, and 1H and 13C NMR)compared with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of L-proline (2.23 g) in dry methanol (15 ml) was cooled to -5 C. and thionyl chloride (4.52 g) was added dropwise, while stirring and maintaining the temperature of the reactants below 0 C. The reaction was continued at 25 C. for 2 h. The solvent was distilled and the residue stored in ice-chest for 12 h. The solid mass was added to aqueous solution of potassium carbonate (50%, 20 ml) at 0 C. and the separated oily layer was extracted into ether (15 ml×3). The ethereal layer was dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine (85%), [MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. It was taken in dry diethyl ether (15 ml), cooled to 0 C. and t-butylhypochlorite (2.16 g) added dropwise. The reaction was monitored on silica gel thin layer using chloroform as the eluant. After completion of the reaction (15 min.), potassium t-butoxide (2.24 g) was added gradually over 10 min. and the reactants stirred at 25 C. for 5 h. The solution was filtered and the solvent distilled under reduced pressure to afford 2-(carbomethoxy)-1-pyrrroline (2 g), [MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69 (100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry ether, iodine (0.01 g) was added followed by dropwise addition of a solution of methyl iodide (3.08 g) in ether (5 ml) at 35 C. The mixture was stirred until the disappearance of magnesium turnings (15 min), then cooled to 0 C. To it, a solution of 2-(carbomethoxy)-1-pyrrroline (2 g) in dry ether (5 ml) was added over 5 min. and the mixture was stirred at room temperature. On completion of the reaction (2 h) the product was worked up by the addition of dilute hydrochloric acid (5%, 10 ml) and the organic layer separated. The aqueous layer was further extracted with ether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate and distilled to afford pure 2-acetyl-1-pyrroline [1.3g, 95% purity, [MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55 (2), 52 (0.2), 43 (100),42 (25), 41 (50)]. | ||
To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to -5 C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0 C. The reaction mixture was allowed to attain room temperature (25 C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50%, 20 ml) at 0 C. and the separated oily layer extracted into ether (15 ml×3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85%, MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25 C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35 C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0 C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5%, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)]. |
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 |
---|---|---|
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In chloroform | ||
5.10 g | With WSC*HCl; benzotriazol-1-ol In chloroform at 20℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride for 1h; Heating; | ||
With thionyl chloride for 1h; Heating; | ||
With thionyl chloride at 20℃; for 12h; |
Stage #1: methanol; D-Prolin With thionyl chloride Stage #2: With triethylamine In tetrahydrofuran | ||
Stage #1: methanol; D-Prolin With sulfuric acid for 18h; Heating / reflux; Stage #2: With potassium carbonate In water at 0℃; | 2.C Method C To a solution of sulfuric acid (3.5 mi, 65.3 mmol) in methanol (45 ml) was added D- proline (10.0 g, 86.9 mmol). The mixture was refluxed with stirring for 18 h. The solution was then cooled to 0°C and neutralised by addition of aqueous potassium carbonate (2. 5 M; 10 ml). Formaldehyde (37% solution in water; 11 ml, 136 mmol) was added and the mixture stirred at 0°C for 15 minutes. Sodium borohydride (1.6 g, 42.3 mmol) was added at 0°C and the mixture was stirred at room temperature for 3 h. The precipitate was filtered off and the filtrate was partitioned between dichloro- methane and water. The isolated aqueous layer was adjusted to pH 10 using solid sodium carbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford crude (R)-1- methylpyrrolidine-2-carboxylic acid methyl ester (13.13 g). A portion of this crude product (5. 0 g) was purified by flash column chromatography eluting with 0-2% (v/v) methanol in dichloromethane to afford (R)-1-methylpyrrolidine- 2-carboxylic acid methyl ester (1. 30 g). | |
Stage #1: methanol; D-Prolin With sulfuric acid at 20℃; for 16.16h; Stage #2: With potassium carbonate In methanol; water at 0℃; | 48.A Section E-Other HeterocyclesPreparation of Pyrimidines:; Example 48; Step A; (R)-1-tert-Butyl 2-methyl pyrrolidine-1,2-dicarboxylate:; To a solution of D-proline (10 g, 46.4 mmol) in MeOH (80 ml) was added 20 ml of concentrated H2SO4 over 10 min at rt. An exothermic reaction resulted. The resulting solution was stirred at rt for 16 h and then poured into 200 g of crushed ice and made basic with the careful addition of solid K2CO3. The mixture was extracted with CH2Cl2 (2×50 ml). The combined organic layers were dried over K2CO3 and concentrated on a rotary evaporator to give the crude amino ester. The proline ester was dissolved in MeOH (140 ml) and H2O (140 ml) and treated with 12.0 g of NaHCO3 followed by the addition of 17.4 g of Boc anhydride. The resulting mixture was stirred at rt for 16 h and the methanol was removed on a rotary evaporator. The aqueous layer was cooled to 0° C. and acidified with careful addition of 0.5 N HCl (360 ml) and extracted with EtOAc (3×140 ml). The combined organic layers were washed with 20% NaHCO3 (160 ml) and brine (180 ml), dried over MgSO4 and concentrated on a rotary evaporator to give the product (10.4 g, 96% yield) as a clear syrup. | |
With thionyl chloride | ||
With chloro-trimethyl-silane at 80℃; for 8h; | ||
With hydrogenchloride at 95℃; for 6h; | Acid hydrolysis of psychrophilin E General procedure: The compound (0.5 mg) was refluxed at 95°C for 6 h with 6N methanolic HCl. After cooling, the sample was evaporated under reduced pressure to dryness. Then, the remaining residue was dissolved in 1.0 mL of methylene chloride and 100 mL of TFAA and then it was refluxed at 60°C for 20 min. The sample was then cooled and the remaining liquid was evaporated at room temperature. The residue obtained was dissolved in methylene chloride for chiral gas GC analysis. The same procedure was conducted for an unequal known mixture of D- and L-proline standards. The configuration of proline was determined by an isothermic GC analysis using CP chirasil Dex CB column at 120°C over 15 min. Retention times (in min) for the standards were proline, R, 7.12 min, and S, 7.24 min. Analysis of the derivative gave a retention time of 7.24 min, determining an S configuration for the proline residue. | |
With thionyl chloride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | ||
With thionyl chloride at 0 - 20℃; | ||
With thionyl chloride at 0℃; for 1h; Reflux; | ||
With thionyl chloride at 20℃; for 2h; | 2.1 The first step: methyl D-prolinate(2B) 2A (2g, 17.4mmol) was dissolved in 15ml of methanol, thionyl chloride (2mL) was added at room temperature and the reaction was stirred for 2h. The reaction solution was adjusted to pH about 9 with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, and the organic phase was washed with water (20 mL×2), dried with anhydrous sodium sulfate, and concentrated. The obtained methyl D-prolinate(2B) was directly used in the next reaction. | |
With thionyl chloride at 0 - 40℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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Treatment of the 5-nitro-isophthalic acid monomethyl ester (1) with an amine alcohol results in the formation of a 5-nitro-N-alkylisophthalamic acid (2). Reduction of the nitro group, by catalytic hydrogenation, yields the corresponding 5-amino-N-hydroxylalkylisophthalamic acid (3). Catalytic hydrogenation of the 5-nitro-N-hydroxylalkylisophthalamic acid is carried out on the free acid, dissolved in ethanol. The 5-amino-N-hydroxylalkylisophthalamic acid (3) is converted to the corresponding triiodo compound (4) by iodination with iodine monochloride. Treatment of the iodinated amino compound (4) with acyl halide alcohol in the presence of sulfuric, results in the formation of a 5-alkanamido-2,4,6-triiodo-N-hydroxylalkylisophthalamic acid (36). Conversion of this acid to an acid halide (37) is accomplished with thionyl chloride. (Hoey, U.S. Pat. No. 3,145,197). The enamino ketone (43) is transformed with hydrazine hydrate into the tetrahydroindazole (44), which after acid hydrolysis provides 4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine (45). Masic, et al., Tetrahedron Lett 2000; 41 :5589-92. Boc-D-cyclohexylglycine-proline (48) is prepared by standard amino acid coupling of Boc-D-cyclohexylglycine (46) with proline methyl ester (47), followed by ester hydrolysis. Standard amino acid coupling of Boc-D-cyclohexylglycine-proline with the amine (45), followed by removal of the Boc protecting group, produces the free amine (49). Tucker et al., J Med Chem 1998; 41:3210-19. The acid chloride (37) is condensed with the amine (49), followed by the removal of hydroxyl protecting groups results in the formation of Compound VI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; sodium hydrogencarbonate; | 2-Pyrrolidinemethanol was made from proline methyl ester as described in Method B1b |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | A solution of L-proline (2.23 g) in dry methanol (15 ml) was cooled to -5 C. and thionyl chloride (4.52 g) was added dropwise, while stirring and maintaining the temperature of the reactants below 0 C. The reaction was continued at 25 C. for 2 h. The solvent was distilled and the residue stored in ice-chest for 12 h. The solid mass was added to aqueous solution of potassium carbonate (50%, 20 ml) at 0 C. and the separated oily layer was extracted into ether (15 ml×3). The ethereal layer was dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine (85%), [MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. It was taken in dry diethyl ether (15 ml), cooled to 0 C. and t-butylhypochlorite (2.16 g) added dropwise. The reaction was monitored on silica gel thin layer using chloroform as the eluant. After completion of the reaction (15 min.), potassium t-butoxide (2.24 g) was added gradually over 10 min. and the reactants stirred at 25 C. for 5 h. The solution was filtered and the solvent distilled under reduced pressure to afford 2-(carbomethoxy)-1-pyrrroline (2 g), [MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69 (100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry ether, iodine (0.01 g) was added followed by dropwise addition of a solution of methyl iodide (3.08 g) in ether (5 ml) at 35 C. The mixture was stirred until the disappearance of magnesium turnings (15 min), then cooled to 0 C. To it, a solution of 2-(carbomethoxy)-1-pyrrroline (2 g) in dry ether (5 ml) was added over 5 min. and the mixture was stirred at room temperature. On completion of the reaction (2 h) the product was worked up by the addition of dilute hydrochloric acid (5%, 10 ml) and the organic layer separated. The aqueous layer was further extracted with ether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate and distilled to afford pure 2-acetyl-1-pyrroline [1.3g, 95% purity, [MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55 (2), 52 (0.2), 43 (100),42 (25), 41 (50)].To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to -5 C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0 C. The reaction mixture was allowed to attain room temperature (25 C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50%, 20 ml) at 0 C. and the separated oily layer extracted into ether (15 ml×3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85%, MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25 C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35 C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0 C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5%, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)]. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: formaldehyd; methyl (2R)-pyrrolidine-2-carboxylate With sodium tris(acetoxy)borohydride In DMF (N,N-dimethyl-formamide); water for 12h; Stage #2: With sodium hydrogencarbonate In water | 53.A Intermediate 53: (2R)-N-Methyl-prolinecarboxyaldehyde Step A: (2R) -N-Methyl-proline methyl ester To a solution of (2R)-Proline methylester (1.20 g, 10.0 mmol) and formalin (37 % in H2O, 1.12 mL, 15.0 mmol) in DMF (30 mL) was added NaBH (OAc) 3 (4.20 g, 20.0 mmol). After being stirred for 12h, the reaction mixture was concentrated in vacuo, and the residue was diluted with NaHC03 (30 mL). The organic material was extracted with EtOAc, and the extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 4/1) to give the title compound. MS [M+H] = 144 (M+1) | |
Stage #1: formaldehyd; methyl (2R)-pyrrolidine-2-carboxylate In water at 0℃; for 0.25h; Stage #2: With sodium tetrahydroborate In water at 0 - 20℃; for 3h; Stage #3: With sodium carbonate In water | 2.C Method C To a solution of sulfuric acid (3.5 mi, 65.3 mmol) in methanol (45 ml) was added D- proline (10.0 g, 86.9 mmol). The mixture was refluxed with stirring for 18 h. The solution was then cooled to 0°C and neutralised by addition of aqueous potassium carbonate (2. 5 M; 10 ml). Formaldehyde (37% solution in water; 11 ml, 136 mmol) was added and the mixture stirred at 0°C for 15 minutes. Sodium borohydride (1.6 g, 42.3 mmol) was added at 0°C and the mixture was stirred at room temperature for 3 h. The precipitate was filtered off and the filtrate was partitioned between dichloro- methane and water. The isolated aqueous layer was adjusted to pH 10 using solid sodium carbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford crude (R)-1- methylpyrrolidine-2-carboxylic acid methyl ester (13.13 g). A portion of this crude product (5. 0 g) was purified by flash column chromatography eluting with 0-2% (v/v) methanol in dichloromethane to afford (R)-1-methylpyrrolidine- 2-carboxylic acid methyl ester (1. 30 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hydroxide; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In methanol; N,N-dimethyl-formamide; | Step 1 To 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid C-1 (prepared in four steps from dimethyl malate; see Example 21 for details) in DMF was added proline O-methyl ester, DIEA and HATU and the solution stirred 4 hours. Standard aqueous workup afforded the desired amide, which was dissolved in methanol and treated with lithium hydroxide to yield 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-carboxypyrrolidin-1-ylcarbonyl)pentane C-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In hexane; dichloromethane; ethyl acetate; | N-(4-Nitrobenzoyl)-2-carbomethoxypyrrolidine To 2-carbomethoxypyrrolidine (d,1-proline methylester, 1.64 g, 12.7 mmol) with pyridine (10.1 g, 12.7 mmol) in CH2 Cl2 (100 mL) at 0 C. was added 4-nitrobenzoyl chloride (2.36 g, 12.7 mmol) in CH2 Cl2 (25 mL) dropwise. The reaction was allowed to warm to ambient temperature and stirred 18 h. The reaction was evaporated and applied to a silica gel flash column and eluted with a gradient of 2:1 Hexane:EtOAc to 1:2 Hexane:EtOAc. There was isolated 1.3 g of the title compound; LRMS (M+H)+ m/z=279. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
h) l-(3,3-Dimethyl-butylideneamino)-<strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> M?[00179] The above 0.28 M solution of l-oxa-2-aza-spiro[2.5]octane in toluene(79 mL, 22 mmol) was added to <strong>[43041-12-9]DL-<strong>[43041-12-9]proline methyl ester</strong></strong> (1.42 g, 11 mmol) and stirred under an inert atmosphere at 80 C for 16 h. The mixture was cooled to 0 C and a 10% aqueous sulfuric acid solution (25 mL) was added. The toluene phase was separated and extracted with an ice-cold 10% aqueous sulfuric acid solution (3 x 10 mL). The combined cold aqueous layers were washed with diethyl ether (2 x 15 mL), and carefully concentrated in vacuo at 25 C to remove the remaining cyclohexanone. Crushed ice (70 g) was added and the stirred acidic solution was neutralized by dropwise addition of saturated aqueous sodium bicarbonate solution at 5-100C.[00180] This solution of methyl l-aminopyrrolidine-2-carboxylate was slowly poured into a stirred solution of 3,3-dimethyl-butyraldehyde (1.10 g, 11 mmol ) in methanol (100 mL) at 45 C. The mixture was allowed to cool to 25 C and stirred for 16 h. The product was extracted with chloroform (6 x 100 mL), the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Merck silica gel 60, 40-63 uM; 50% ethyl acetate in hexanes) to afford l-(3,3-dimethyl-butylideneamino)-<strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> (1.5 g, 6.63 mmol, 60.2% over two steps) as a light red oil. LC-MS (ESI) calcd for C12H22N2O2 226.17, found 227.3 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of L-proline (2.23 g) in dry methanol (15 ml) was cooled to -5 C. and thionyl chloride (4.52 g) was added dropwise, while stirring and maintaining the temperature of the reactants below 0 C. The reaction was continued at 25 C. for 2 h. The solvent was distilled and the residue stored in ice-chest for 12 h. The solid mass was added to aqueous solution of potassium carbonate (50%, 20 ml) at 0 C. and the separated oily layer was extracted into ether (15 ml×3). The ethereal layer was dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine (85%), [MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. It was taken in dry diethyl ether (15 ml), cooled to 0 C. and t-butylhypochlorite (2.16 g) added dropwise. The reaction was monitored on silica gel thin layer using chloroform as the eluant. After completion of the reaction (15 min.), potassium t-butoxide (2.24 g) was added gradually over 10 min. and the reactants stirred at 25 C. for 5 h. The solution was filtered and the solvent distilled under reduced pressure to afford 2-(carbomethoxy)-1-pyrrroline (2 g), [MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69 (100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry ether, iodine (0.01 g) was added followed by dropwise addition of a solution of methyl iodide (3.08 g) in ether (5 ml) at 35 C. The mixture was stirred until the disappearance of magnesium turnings (15 min), then cooled to 0 C. To it, a solution of 2-(carbomethoxy)-1-pyrrroline (2 g) in dry ether (5 ml) was added over 5 min. and the mixture was stirred at room temperature. On completion of the reaction (2 h) the product was worked up by the addition of dilute hydrochloric acid (5%, 10 ml) and the organic layer separated. The aqueous layer was further extracted with ether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate and distilled to afford pure 2-acetyl-1-pyrroline [1.3g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55 (2), 52 (0.2), 43 (100),42 (25), 41 (50)].To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to -5 C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0 C. The reaction mixture was allowed to attain room temperature (25 C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50%, 20 ml) at 0 C. and the separated oily layer extracted into ether (15 ml×3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85%, MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25 C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35 C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0 C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5%, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In methanol; water; at 20℃; for 16h; | Section E-Other HeterocyclesPreparation of Pyrimidines:; Example 48; Step A; (R)-1-tert-Butyl 2-methyl pyrrolidine-1,2-dicarboxylate:; To a solution of D-proline (10 g, 46.4 mmol) in MeOH (80 ml) was added 20 ml of concentrated H2SO4 over 10 min at rt. An exothermic reaction resulted. The resulting solution was stirred at rt for 16 h and then poured into 200 g of crushed ice and made basic with the careful addition of solid K2CO3. The mixture was extracted with CH2Cl2 (2×50 ml). The combined organic layers were dried over K2CO3 and concentrated on a rotary evaporator to give the crude amino ester. The proline ester was dissolved in MeOH (140 ml) and H2O (140 ml) and treated with 12.0 g of NaHCO3 followed by the addition of 17.4 g of Boc anhydride. The resulting mixture was stirred at rt for 16 h and the methanol was removed on a rotary evaporator. The aqueous layer was cooled to 0 C. and acidified with careful addition of 0.5 N HCl (360 ml) and extracted with EtOAc (3×140 ml). The combined organic layers were washed with 20% NaHCO3 (160 ml) and brine (180 ml), dried over MgSO4 and concentrated on a rotary evaporator to give the product (10.4 g, 96% yield) as a clear syrup. | |
With triethylamine; In tert-butyl alcohol; at 20℃;Inert atmosphere; | 1.1 The reaction is carried out under a nitrogen atmosphere.151 ml of triethylamine and subsequently 300 ml of tert-butanol are added to a solution of 83.77 g of (R)-proline methyl ester in 600 ml of tert-butanol. A solution of 96.03 g of di-tert-butyl dicarbonate [(BOC)2O] in 100 ml of tert-butanol is then added dropwise, and the mixture is stirred at room temperature for 20 hours. The deposited precipitate is separated off. The product is located in the filtrate. The solvent is removed, and the residue is taken up in 700 ml of diethyl ether. The solution is washed with 2×500 ml of 1 N HCl, 1× with 500 ml of saturated Na2CO3 solution and 1× with 500 ml of saturated NaCl solution. After drying over Na2SO4, the solvent is removed, giving 86.7 g of BOC-(R)-proline methyl ester (?1?) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N-ethyl-N,N-diisopropylamine; In 2-methyl-propan-1-ol; at 80℃; | A-045 Synthesis of 1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-pyrrolidine-3-carboxylic acid methyl ester A mixture of Int-29 (100 mg, 0.28 mmol), <strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> (70 mg, 0.42 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in 2-methyl-1-propanol (1 mL) was stirred at 80 C. overnight. The reaction was cooled, and the solvent removed under vacuum. The crude was purified twice by silica gel column chromatography (4:1 hexanes/ethyl acetate, 2:1 hexanes/ethyl acetate) to give A-045 (44.7 mg, 35% yield). 1H NMR (400 MHz, CHLOROFORM-d) delta=8.21 (s, 2H), 7.40-7.29 (m, 3H), 7.08 (t, J=8.6 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 3.88-3.74 (m, 3H), 3.76 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.63-3.53 (m, 1H), 3.19 (quin, J=7.4 Hz, 1H), 2.33-2.22 (m, 2H). LC/MS=94.7%, 456.1 (APCI+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; | 1002721 To a stirring solution of proline methyl ester (70 g, 422 mmol) in CH2C12 (700 mL) were added Et3 (183 mL, 1.26 mol) at 0 C and stirred for 10 min. After added Boc- anhydride (184 mL, 845 mmol) at 0 C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (200 mL) and extracted with (( (2 x 200 mL). The combined organic layer was washed with citric acid (1 x 150 mL), brine (1 x 200 mL). The organic layer was dried over a2S04 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting 50% EtOAc/w-hexane to obtain 6S-N (80 g, 83%) as thick syrup. 1H-NMR: (400 MHz, DMSO-d6): delta 4.15-4.13 (m, 1H), 3.65 (s, 3H), 3.35-3.30 (m, 2H), 2.23- 2.15 (m, 1H), 1.86-1.78 (m, 3H), 1.41 (s, 9H); LCMS (m/z): 129 [(M++l)-Boc] |
73% | With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; | To a stirred solution of methyl pyrrolidine-2-carboxylate (lntermediate-8) (1 g, 7.74 mmol) in DCM (10 mL) TEA (2.7 mL) was added, followed by di-ie/f-butyl dicarbonate (Boc anhydride, (Boc)20) (1 .86 g, 8.51 mmol) at 0 C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with chloroform (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh) to afford the title compound (1.3 g, 73% yield) as pale yellow liquid. |
66% | With triethylamine; In acetonitrile; at 0 - 20℃; for 16.1667h; | To stirred solution of methyl prolinate (300 mg, 2.32mmol) in acetonitrile (5 mL) was added triethyl amine (0.55 g, 4.65mmol) and the reaction was stirred for 10 min. Di-t-butyl dicarbonate (0.43 g, 2.78 mmol) was added dropwise to the reaction mixture at 0 C and stirred for 16 h at ambient temperature. The reaction mixture was concentrated and purified via standard methods to afford 1-(tert-butyl) 2-methyl pyrrolidine-1 ,2-dicarboxylate (0.35 g, 66%) as pale yellow oil. |
With triethylamine; In dichloromethane; 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. | |
75 g | Take 43g (0.33mol) of methyl pyrrolidine-2-carboxylic acid and 400mL of dichloromethane in a 2L single-necked reaction flask, and add 88g (0.87mol) of triethylamine to obtain a white emulsion. Stir at room temperature for 15 minutes and cool to 0 C.Another 152 g (0.69 mol) of Boc anhydride was dissolved in 600 mL of dichloromethane in a constant-pressure funnel and added dropwise to the above system. A large number of bubbles were released with the dropwise addition, exotherm was controlled, and the drop rate was controlled to maintain the internal temperature of the system <10 C. After the dropwise addition, a white suspension was obtained, and the mixture was stirred at room temperature for 12 hours. Filter to remove the white precipitate. Evaporate the solvent under reduced pressure to obtain a white suspension. Add 300 mL of citric acid solution (0.5M) and wash with ether. Extract with ether (3 * 500 mL). Combine the organic layers and wash with saturated brine. It was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 5) to obtain 75 g of a clear, colorless oily liquid with a yield of 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | To a solution or suspension of the amine or amine hydrochloride salt (1 mmol) in dry DCMor DMF were added a solution of trityl chloride (1.1 mmol), Et3N (2 - 4 mmol) and DMAP(10 mol %) at 0 oC and the mixture was stirred at rt until the disappearance of startingmaterials. The reaction was then quenched with H2O and extracted with EtOAc. Thecombined organic phases were washed with brine and dried (Na2SO4). After evaporation ofthe solvent at reduced pressure, the resulting residue was purified by column chromatography(deactivated silica gel, pet ether-ethyl acetate) to afford the expected tritylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ammonium cerium (IV) nitrate; water; acetic acid; In dichloromethane; at 20℃; for 0.133333h;Inert atmosphere; | The substrate (1 equiv) was added to a solution of CAN (20 mol %) in minimum amount of water (roughly 15 equiv). The reaction mixture was dissolved in dichloromethane and stirred magnetically. Acetic acid (10 equiv) was added to the solution and left to stir at rt for the required time mentioned in Table 2. Upon completion of the reaction, the solvent was evaporated under reduced pressure and worked up in the following methods. Method A: The solid residue was washed twice with petroleum ether to remove the by product trityl alcohol. The residue was then dissolved in methanol and filtered through a short pad of celite. Removal of the solvent under reduced pressure yielded the free amine. Method B: Water and acetic acid were removed from the reaction mixture in vacuo. The residue was dissolved in dry dichloromethane, followed by the addition of triethylamine (2.5 equiv) and acetic anhydride or benzoyl chloride (1.5 equiv). After the completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate twice. The combined organic layer was washed with water and brine and finally dried (Na2SO4). Solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to afford the acylated amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetone; at 0 - 20℃; | General procedure: Propargyl bromide (0.5 mmol) was dropwise added to a mixture of Cs2CO3 (0.5 mmol), acetone (30 mL) and the corresponding secondary amine (0.5 mmol) at 0 C. The mixture was stirred overnight at room temperature and then filtered. The filtrates was evaporated to dryness to afford the target productes as an orange-brown oil. which was directly used for the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: (S)-p-toluenesulfinimide With potassium hydride In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; Stage #2: methyl (2R)-pyrrolidine-2-carboxylate In tetrahydrofuran for 2h; Inert atmosphere; Stage #3: With acetic acid In tetrahydrofuran for 0.333333h; Inert atmosphere; | Compound 13. THF (10 mL) was added to a flask containing (S)-toluenesulfinamide (0.388 g, 2.50 mmol) and KH (0.100 g, 2.50 mmol), resulting in the evolution of hydrogen gas as the sulfinamide was deprotonated. The reaction mixture was stirred for 1.5 h at rt. (d)-Proline methyl ester (3.0 mmol) was added via syringe. After 2 h, the reaction was quenched by addition of acetic acid (0.150 g, 2.50 mmol), and resulting mixture was stirred for 20 min. The crude mixture in THF was loaded onto a silica plug and side products were eluted with 100% EtOAc. The mobile phase was switched to 50:40:10 EtOAc:MeOH:NH4OH, resulting in rapid elution of the product. Fractions containing the desired product were concentrated several times from EtOAc, and then the white solid was dissolved in CH2Cl2 and filtered to remove a white solid byproduct. The filtrated was concentrated and then recrystallized from EtOAc. The solids were collected by vacuum filtration and rinsed with additional EtOAc, to yield 0.21 g (34%) of 13 as a white powder, mp 115.0-117.5 °C. 1H NMR (600 MHz, CDCl3): δ 1.70 (m, 2H), 1.99 (m, 1H), 2.20 (m, 1H), 2.43 (s, 3H), 2.79 (m, 1H), 2.98 (m, 1H), 3.88 (m, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H). 13C NMR (150 MHz, CDCl3): δ 21.4, 26.1, 30.7, 47.1, 61.0, 124.6, 130.0, 141.3, 142.2, 176.6. Exact mass calcd for C12H16N2O2SNa requires m/z 275.0825, found m/z 275.0836 (M+Na+, ESI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 0 - 25℃; | To a solution of niacin (0.4g 3.50 mmol) in DCM (10 mL) were added L-<strong>[43041-12-9]proline methyl ester</strong> (0.5g, 3.21 mmol), N-methyl morpholine (l.lmL, .10.5 mmol), EDC.HCl (1.2g, 6.4 mmol) and catalytic amount of DMAP at ice temperature (0C). The mixture was allowed to stir at room temperature (25 C) over a period of 2h. The resulting mixture diluted with DCM (lOOmL) washed with water (2X100mL) and dried over sodium sulphate. Solvent was evaporated under reduced pressure to obtain product as yellow gummy oil (1.3 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In N,N-dimethyl-formamide; for 24h;Reflux; | General procedure: Method A: A suspension of azaisatoic anhydride (0.48 g, 2.9 mmol) and alpha-amino acid methyl ester (3.5 mmol) in 10 mL of DMF and 2 mL of Et3N was heated under reflux for 24 h. The solvent was evaporated, and the crude product was purified by chromatography to give 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In dichloromethane; at 25℃; for 12h; | A mixture of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol), <strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> (55 mg, 0.33 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156 mg, 0.41 mmol) in dichloromethane (3 mL) and triethyl-amine (0.12 mL, 0.82 mmol) was prepared. The reaction mixture was stirred at 25 C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-[3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxyl]-<strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> (125 mg, 96%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C28H35N3O4 (M+H)+: 478.61, observed: 478.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; for 15.5h;Reflux; | To a solution of 3-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-(4- (methoxycarbonyl)phenyl)-5a,5b,8,8,l 1 a-pentamethyl- 1 -(prop- l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)propanoic acid (intermediate 8) (0.06 g, 0.093 mmol) in DCE (2 mL) was added DIEA (0.049 mL, 0.280 mmol), O-Benzotriazol-l-yl- Nu,Nu,Nu',Nu'-tetra-methyluronium tetrafluoroborate (0.045 g, 0.140 mmol), and <strong>[43041-12-9]methyl pyrrolidine-2-carboxylate</strong> (0.014 g, 0.112 mmol). The mixture was stirred at rt for 15.5h, then was diluted with 7 mL of water and was extracted with dichloromethane (3 x 7 mL). The combined organic layers were dried with Na2S04. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-75% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl l-(3-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9- (4-(methoxycarbonyl)phenyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)propanoyl)pyrrolidine-2-carboxylate (63 mg, 0.083 mmol, 90 % yield) as a white foam. LCMS: m/e 753.5 (M-H)~, 3.09 min (method 4)· |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; In methanol; at 0 - 20℃; for 26h; | Step 2 Methyl 1-<strong>[43041-12-9]methylpyrrolidine-2-carboxylate</strong> Methyl pyrrolidine-2-carboxylate 10b crude product (5 g) was dissolved in 100 mL of methanol. The solution was cooled to 0~5 C. in an ice-water bath, followed by addition of 13 mL of 40% formaldehyde. The reaction mixture was warmed up to room temperature and stirred for 2 hours, then cooled to 0~5 C. in an ice-water bath, and sodium cyanoborohydride (5.45 g, 87.20 mmol) was added in batches. The reaction mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and added with 5 mL of water, extracted with dichloromethane (5 mL*3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 1-<strong>[43041-12-9]methylpyrrolidine-2-carboxylate</strong> 10c (4.7 g, yield 70.1) crude product as a brown oil. MS m/z (ESI): 144.1 [M+1] | |
The crude <strong>[43041-12-9]methyl pyrrolidine-2-carboxylate</strong> 10b (5 g) was dissolved in a 100 mL of methanol. The reaction solution was cooled in an ice bath to 0 to 5 deg.C. Add 13 mL 40% formaldehyde solution. The reaction was warmed to room temperature and stirred for 2 hours. Ice bath continue cooling to 0 to 5 deg.C. Add portionwise sodium cyanoborohydride (5.45g, 87.20 mmol). Stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, add 5 mL of water, and extracted with methylene chloride (5 mL × 3), the combined organic phases were washed with dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude methyl 1- - <strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> 10c (4.7g, brown liquid), yield: 70.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; under 750.075 Torr; for 24h; | General procedure: In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3 (13.1 mg, 0.050 mmol), 5-iodo-2-methylpyridazin-3(2H)-one (236 mg, 1.0 mmol), 3 mmol of a (or the amount of amine given in Table 1) and triethylamine (0.5 mL) were dissolved in DMF (10 mL) under argon in a 100 mL three-necked flask equipped with a gas inlet and a reflux condenser with a balloon at the top. The atmosphere was changed to carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 50 C and analysed by GC-MS. The mixture was then concentrated and evaporated to dryness. The residue was dissolved in chloroform (20 mL) and washed with water (2×20 mL). The organic phase was dried over Na2SO4 and evaporated to a solid material or to a waxy residue. All compounds were subjected to column chromatography using the solvent mixture indicated for the Rf values in Section 4.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | A mixture of 27A (2.4 g, 13.9 mmol) and CDI (2.3 g, 13.9 mmol) in dry DCM (50 mL) was stirred at RT for 1 hr, then <strong>[43041-12-9]proline methyl ester</strong> (2.3g, 13.9 mmol) was added. The mixture was stirred at RT overnight. After ELSD showed the reaction was complete, the mixture was treated with water, then extracted with DCM (30 mL*3).The combined organic layers were washed with brine, dried over sodium sulfate. The solvent was removed to give 27B (3.8 g, yield: 97%), as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | A mixture of 14A (2 g, 11 mmol) and CDI (1.8 g, 10.8 mmol) in dry DCM (50 mL) was stirred at 20 C for 1 hr, then 14A1 (1.4 g, 10.8 mmol) was added. The mixture was stirred at 20 C overnight. After ELSD showed the reaction was complete, the reaction was quenched with water, and then extracted with DCM (30 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give 14B (3.1 g, yield: 94%), as an off-white solid without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; potassium iodide; In acetone; at 0 - 75℃; for 18h;Inert atmosphere; | General procedure: To a solution of 7 (30mg, 0.074mmol), KI (25mg, 0.15mmol) and K2CO3 (102mg, 0.74mmol) in acetone (5mL) was added piperidine (31mg, 0.37mmol) at 0C. The mixture was stirred at 75C for 18h. The solution was diluted with EtOAc (100mL), washed with 0.1N HCl (aq) (10mL) and brine (10mL). The organic layer was dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to give the desired product 14 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.3% | With dmap; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; | Example 22 Methyl 1-(5-(4-(benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinoyl)pyrrolidine-2-carboxylate To a stirred solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (80.0 mg, 0.190 mmol) (prepared as in Example 12) in DMF (2 mL), were added DMAP (35.0 mg, 0.285 mmol) and HATU (108 mg, 0.285 mmol) and the reaction mixture was stirred for 10 minutes. Methyl pyrrolidine-2-carboxylate (12.0 g, 0.0950 mmol) was added and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture concentrated under reduced pressure to remove DMF and to the resulting residue water (10 mL) was added. The aqueous mixture was extracted with CH2Cl2 (15*2 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-68 as described in general methods) to obtain methyl 1-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinoyl)pyrrolidine-2-carboxylate (30.0 mg, 59.3%). LCMS Condition B-14: retention time 2.31 min, [M-1]=531.2. HPLC Condition B-63: retention time 16.30 min, Purity 99.70%. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.87-1.98/2.30-2.35 (m, 4H), 3.44/3.70 (s, 3H), 3.55/3.67 (dd, J=6.0 Hz, J=6.8 Hz, 2H), 4.47-4.49/4.56-4.58 (m, 1H), 4.54/4.82 (d, J=5.6 Hz, 2H), 6.71/6.76 (t, J=5.6 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 7.23-7.56 (m, 10H), 7.91/7.94 (d, J=2.8 Hz, 1H), 8.44/8.58 (t, J=2.0 Hz, 1H), 8.65/8.81 (d, J=2.0 Hz, 1H), 9.39/9.44 (d, J=2.0 Hz, 1H). Molecule exists as two rotomers with ratio 70/30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In tetrahydrofuran; at 60℃; for 18h; | General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproductThe title compound was prepared following general procedure B, except <strong>[43041-12-9]methyl pyrrolidine-2-carboxylate</strong> was the amine reactant, 2 equivalents oftriethylamine was used, and the contents were heated to 60 C for 18 h as a solution in THF. Solvent was removed in vacuo, and contents were taken up in ethyl acetate. The organic layer was washed with iN hydrochloric acid solution, water, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography utilizing a 0-5% methanolldichloromethane gradient to deliver the desired compound, Compound 1-34 (10.6 mg, 57% yield).1H NMR (500 MHz, CDC13) oe 8.47 (m, 1H), 8.20 (m, 1H), 8.17.29 (s, 1H), 7.21 (m, 1H), 7.04 (m, 1H), 6.98 (m, 1H), 6.87 (m, 1H), 6.59 (dm, 1H), 5.98 (m, 2H), 4.76 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H), 3.73 (s, 3H), 2.35 (m, 1H), 2.17 (m, 3H).. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With palladium diacetate; triethylamine; triphenylphosphine; at 50℃; under 750.075 Torr; for 24h;Inert atmosphere; | General procedure: In a typical experiment Pd(OAc)2 (5.6mg, 0.025mmol), triphenylphosphine (13.1mg, 0.05mmol), 7-iodoindole (243mg, 1mmol) or 5-bromo-7-iodoindole (322mg, 1mmol), amine nucleophile (3mmol of a/2mmol of b/1.5mmol of c, d/1.1mmol of e, f, g, h) and triethylamine (0.5mL) were dissolved in DMF (10mL) under argon in a three-necked flask equipped with a gas inlet, reflux condenser with a ballon (filled with argon) at the top. The atmosphere was changed to carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 50C and analysed by GC-MS (internal standard: naphthalene). The mixture was then concentrated and evaporated to dryness. The residue was dissolved in chloroform (20mL) and washed with water (3×20mL). The organic phase was dried over Na2SO4, filtered and evaporated to a crystalline material or a waxy residue. All compounds were subjected to column chromatography (Silicagel 60 (Merck), 0.063-0.200mm), EtOAc/CHCl3, or EtOAc/toluene, or hexane/EtOAc/MeOH (the exact ratios are specified in Section Characterization (3.4) for each compound). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; under 30003.0 Torr; for 72h;Autoclave; | General procedure: In a typical experiment, Pd(OAc)2 (5.6mg, 0.025mmol), triphenylphosphine (13.1 mg, 0.05 mmol), 7-iodoindole (243 mg, 1 mmol) or 5-bromo-7-iodoindole (322 mg, 1 mmol), amine nucleophile (3 mmol of a/2 mmol of b/1.5 mmol of c, d/1.1 mmol of e, f, g, h) and triethylamine (0.5mL) were dissolved in DMF (10mL) under argon in a 100 mL autoclave. The atmosphere was changed to carbon monoxide and the autoclave was pressurized to the given pressure by carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 50C and analysed by GC-MS (internal standard: naphthalene). The mixture was then concentrated and evaporated to dryness and worked-up as described in Section 4.2. The analogous procedures (same molar ratios, identical reaction conditions, similar work-up) were used in the aminocarbonylation of 5-iodoindole and 5-bromo-7-iodoindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; under 30003.0 Torr; for 24h;Autoclave; | General procedure: In a typical experiment, Pd(OAc)2 (5.6mg, 0.025mmol), triphenylphosphine (13.1 mg, 0.05 mmol), 7-iodoindole (243 mg, 1 mmol) or 5-bromo-7-iodoindole (322 mg, 1 mmol), amine nucleophile (3 mmol of a/2 mmol of b/1.5 mmol of c, d/1.1 mmol of e, f, g, h) and triethylamine (0.5mL) were dissolved in DMF (10mL) under argon in a 100 mL autoclave. The atmosphere was changed to carbon monoxide and the autoclave was pressurized to the given pressure by carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 50C and analysed by GC-MS (internal standard: naphthalene). The mixture was then concentrated and evaporated to dryness and worked-up as described in Section 4.2. The analogous procedures (same molar ratios, identical reaction conditions, similar work-up) were used in the aminocarbonylation of 5-iodoindole and 5-bromo-7-iodoindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | To a solution of 3-(chloromethyl)-6-ethyl- 10-methoxy-9-(3-methoxypropoxy)-6,7-dihydrobenzo[a]quinolizin-2-one (78 mg) in dichloromethane (10 ml. ) was added methyl pyrro I iclinc-2 -carboxy late (38 mg) and triethylam ine (150 mu). The resulting solution was stirred at room temperature overnight and then quenched with water (20 mL). The aqueous solution was extracted with dichloromethane (2x 15 mL). The organic layers were combined and concentrated to give methyl l-[[6-ethyl- 10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizin-3-yl]methyl]pyrrolidine-2-carboxylate (97 mg ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; acetic acid; In dichloromethane; at 20℃; for 12h; | Step 5: (2R.5R)-tert-butyl 2-(l-bromo-8-((2^-dimethoxybenzyl)amino)imidazo[1.5-alpyrazin-3- yl -5- 2- methoxycarbonyl pyrrolidin-l-yl methyl mophiholine-4-carboxylate To a mixture of (2R,5S)-tert-butyl 2-(l-bromo-8-((2,4-dimethoxybenzyl)amino)imidazo[l,5- a]pyrazin-3-yl)-5-formylmo holine-4-carboxylate (200 mg, 0.347 mmol), methyl pyrrolidine-2- carboxylate (53.8 mg, 0.416 mmol) and sodium cyanoborohydride (65.4 mg, 1.041 mmol) in CH2CI2 (5 mL) was added AcOH (1.986 mu, 0.035 mmol). The mixture was stirred at 20 C for 12 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mLx4). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated to afford the crude product ,which was purified on silica gel column chromatograph (DCM/THF = 100% ~ 30 %) to afford the title compound. MS: 689.2/691.2 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: A 4-ml screw neck vial was charged with gem-fluorohalocyclopropane (0.50 mmol) and CuX (0.10 mmol). In a stream of argon MeCN (0.50 mL) was added. The vial was quickly sealed and the reaction mixture was stirred at 100 C for 5 h. GC analysis of a reaction aliquot showed the completion of the cyclopropane isomerization. Next, HNR2 or HNR2·HCl (0.60 mmol) and K2CO3 (1.5 mmol) were added and the reaction mixture was stirred at room temperature for additional 2 h. The desired product was isolated as written above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With platinum on carbon; hydrogen; toluene-4-sulfonic acid; at 120℃; under 30003.0 Torr; for 0.1h;Inert atmosphere; Autoclave; | General procedure: An autoclave was filled with catalyst (1 mol% based on the molar amount of amine), flushed with argon and topped up with a solution of amine (0.1 mol) and orthocarboxylic acid ester (0.11-0.3mol) in 10 ml of methanol (or ethanol) and 0.5 ml of a 0.2 M solution of anhydrous ptoluenesulphonic acid in methanol (or ethanol). The mixture was heated to 120C and hydrogen was injected to 40 bar and then the mixture was stirred at a constant pressure until hydrogen absorption could no longer be detected (0.2 - 6 h). After being filtered off from the catalyst, the filtrate was distilled. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In methanol; at 20℃; for 16h; | To a stirred solution of <strong>[43041-12-9]methyl pyrrolidine-2-carboxylate</strong> (lntermediate-8) (0618) (250 mg, 1 .937 mmol) in MeOH (2 mL), acrylonitrile (0.15 mL, 2.264 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to afford the title compound (200 mg, 56% yield) as colourless liquid. The crude compound was used in the next step without purification. 1H NMR (400 MHz, CDCI3) delta 3.75 (s, 3H), 3.35 (bs, 1 H), 3.22-3.20 (m, 1 H), 3.19-3.10 (m, 1 H), 2.86-2.81 (m, 1 H), 2.58-2.55 (m, 3H), 2.15-2.13 (m, 1 H), 2.00- 1 .85 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine; In dichloromethane; at 20℃; for 2h; | To a stirred solution of <strong>[43041-12-9]methyl pyrrolidine-2-carboxylate</strong> (200 mg, 1.74 mmol) in DCM (10 mL) TEA (0.72 mL, 5.27 mmol) was added, followed by dimethylcarbamic chloride (0.19 mL, 2.08 mmol) and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x15 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (180 mg, 51 % yield) as off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | With triethylamine; In dichloromethane; at 20℃; for 16h; | To a stirred solution of 1 -(4-(ie f-butoxycarbonyl)piperazine-1 -carbonyl)- (0633) 3-methyl-7H-imidazol-3-ium iodide (3 g, 10.16 mmol) in DCM (30 mL), TEA (1 .42 mL, 50.84 mmol) and <strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> (2.62 g, 20.35 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL), and extracted with DCM (2x50 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (1 g, 29% yield) as off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | With triethylamine; In dichloromethane; at 20℃; for 16h; | To a stirred solution of (3-methyl-1 -(morpholine-4-carbonyl)-1 H-imidazol- 3-ium iodide (2 g, 10.16 mmol) in DCM (30 mL) TEA (7.1 mL, 50.84 mmol) and <strong>[43041-12-9]pyrrolidine-2-carboxylic acid methyl ester</strong> (2.62 g, 20.35 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2x25 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (1 g, 41 % yield) as off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100%Chromat. | With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; under 750.075 Torr; for 120h;Inert atmosphere; Autoclave; | General procedure: In a typical experiment Pd(OAc)2 (5.6mg, 0.025mmol), triphenylphosphine (13.2mg, 0.05mmol), 5-iodouracil (1) or <strong>[40738-83-8]5-iodo-1,3-dimethyluracil</strong> (5) substrates (1mmol), amine nucleophiles (see above in tables) and triethylamine (0.5mL) were dissolved in DMF (10mL) under argon in a 100mL three-necked flask equipped with reflux condenser connected to a balloon filled with argon. The atmosphere was changed to carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 50 C and analysed by GC and GC-MS. The cooled reaction mixture was then concentrated and evaporated to dryness under reduced pressure. Method A. (2b, 3a, 3c-3g): Chloroform (10mL) was added to the residue and the insoluble material (product) was filtered, washed with absolute ethanol and dried. Method B. (6a-6g, 7a-3g): The residue was dissolved in chloroform (15mL) and washed twice with water (15mL). The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure to a solid material. All compounds were subjected to column chromatography (Silicagel 60 (Sigma), 0.063-0.200mm), CHCl3/EtOAc/MeOH or hexane/EtOAc/MeOH eluent mixtures (the exact ratios are specified in Characterisation (3.4) for each compound). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25%; 21% | With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; under 30003.0 Torr; for 24h;Inert atmosphere; Autoclave; | General procedure: In a typical experiment Pd(OAc)2, triphenylphosphine, iodouracil derivatives (1, 5), amine nucleophiles (a-g) and triethylamine were used in the same amount as above and were dissolved in 10mL of DMF under argon in a 100mL autoclave. The atmosphere was changed to carbon dioxide and the autoclave was pressurized to the given pressure with carbon monoxide. (Caution: High pressure carbon monoxide should only be used with adequate ventilation (hood) using CO sensors as well.) The reaction was conducted for the given reaction time upon stirring at 50C. After the given reaction time the reaction mixture was cooled to room temperature and the autoclave was carefully depressurized in a well-ventilated hood. The product mixture was analysed by GC and GC-MS. The work-up of the reaction mixture was identical to that discussed for the atmospheric experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; under 30003.0 Torr; for 68h;Inert atmosphere; Autoclave; | General procedure: In a typical experiment Pd(OAc)2, triphenylphosphine, iodouracil derivatives (1, 5), amine nucleophiles (a-g) and triethylamine were used in the same amount as above and were dissolved in 10mL of DMF under argon in a 100mL autoclave. The atmosphere was changed to carbon dioxide and the autoclave was pressurized to the given pressure with carbon monoxide. (Caution: High pressure carbon monoxide should only be used with adequate ventilation (hood) using CO sensors as well.) The reaction was conducted for the given reaction time upon stirring at 50C. After the given reaction time the reaction mixture was cooled to room temperature and the autoclave was carefully depressurized in a well-ventilated hood. The product mixture was analysed by GC and GC-MS. The work-up of the reaction mixture was identical to that discussed for the atmospheric experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 3h;Inert atmosphere; | General procedure: Compound 10: The phenylthionophosphonic dichloride (0.45 mL, 3 mmol) was dissolved in 3.5 mL anhydrous CH2Cl2. Tothe solution, 3-hydroxypropionitrile (0.2 mL, 3 mmol) and triethylamine (0.45 ml, 3 mmol) were added at 0 C under an atmosphereof Ar (g). The reaction was stirred at 0 C for 15 min and atroom temperature for 3 h. A solution of glycine methyl ester (0.414 g, 3.3 mmol), triethylamine (1.25 ml, 9 mmol), and 3.5 mL anhydrous CH2Cl2 was added and the reaction was stirred for an additional 3 h. The mixture was diluted with 10 ml CH2Cl2, washed with 10 mL of 2M H2SO4, dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography to afford yellow oil. Yield: 35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.51% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Sealed tube; | A mixture of methyl 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (1.5 g, 2.97 mmol, 1 equiv.), Pd2(dba)3(280 mg, 0.31 mmol, 0.103 equiv.), XantPhos (520 mg, 0.90 mmol, 0.303 equiv.), <strong>[43041-12-9]methyl pyrrolidine-2-carboxylate</strong> (800.0 mg, 6.19 mmol, 2.088 equiv.) and Cs2CO3 (4.9 g, 15.04 mmol, 5.070 equiv.) in dioxane (40 mL) was stirred at 100 C for 14 hours. The reaction mixture was filtered and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography, eluting with PE:EA (20:1 to 4:1) to afford methyl 1-[(4-chlorophenyl)methyl]-4-[2-(methoxycarbonyl)pyrrolidin-1-yl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (830 mg ,50.51%) as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 6h;Inert atmosphere; | [0314] No. Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (3A) (287 mg, 1.2 mmol), No.35 acetic acid (144 mg, 2.4 mmol), No.43 D-proline methyl ester (154 mg, 1.2 mmol), No.35 sodium triacetoxyborohydride (233 mg, 2.4 mmol) and No.2 dichloromethane (30 mL) were added sequentially in a 50 mL reaction flask. After the addition, the reaction was allowed to proceed at room temperature for 6 h. The reaction solution was suction-filtered, and the filtrate was washed with a saturated sodium bicarbonate solution (50 mL). After the liquid separation, the organic layer was dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-pyrrolidin-1-yl-7-azaspiro[3.5]nonane-7-carboxylate (No.43 26A)) as white powder (275 mg, yield 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | Stage #1: di-<i>tert</i>-butyl dicarbonate; methyl (2R)-pyrrolidine-2-carboxylate With potassium carbonate In methanol at 20℃; for 3h; Large scale; Stage #2: With sodium tetrahydroborate In 2-methyltetrahydrofuran at 0℃; for 5h; Large scale; Stage #3: methanesulfonyl chloride Large scale; Further stages; | 1-5 A production method of (R)-2-methylpyrrolidine hydrochloride includes the following steps: (a) 100KgMethyl pyrrolidine-(R)-2-carboxylate,70Kg potassium carbonate was added to 500Kg methanol, after stirring to dissolve,Start dripping 220Kg of di-tert-butyl carbonate (Boc anhydride), after the dripping is complete,Spontaneously warm up to room temperature and react for 3 hours. After the detection reaction is complete,Then add a certain amount of 1N hydrochloric acid to adjust the pH to about 5-6,Then centrifuge to obtain a white solid, which can be used after drying;(b) Add the white solid obtained in step (a) to 500KgIn 2-methyltetrahydrofuran, stir to dissolve, and then control to 0,Add 45Kg of sodium borohydride in batches, and keep the reaction for 5 hours after the addition.After the reaction is complete, filter, then add a certain amount of 6N hydrochloric acid to adjust the pH to about 5-6, evaporate 2-methyltetrahydrofuran, and then use500Kg chloroform is extracted for 2-3 times, after the chloroform is concentrated,Add 600Kg methyl tert-butyl ether and stir to obtain off-white solid;(c) The off-white solid obtained in step (b),65Kg of ethylenediamine was added to 500Kg of 2-methyltetrahydrofuran,After stirring, after cooling to -5°C, 90Kg of methanesulfonyl chloride was added dropwise,After the addition is complete, naturally warm to room temperature and continue to stir for 2 hours. After the detection is complete,First evaporate tetrahydrofuran, then add 400Kg petroleum ether and 400Kg water,After stirring for 1-2h, a large amount of solid precipitated;(d) Add the solid obtained in step (c) to 500Kg dimethyl sulfoxide,After all is dissolved, first add 45Kg of sodium borohydride in batches, then heat to 170°C, keep the reaction for 4 hours, and after the completion of the reaction is detected, cool down and filter.Add 1000Kg of water to the filtrate,Then it was extracted with 500Kg ethyl acetate for 2-3 times, and the ethyl acetate was evaporated to dryness to obtain an oil;(e) Add the oil obtained in step (d) to 400Kg ethyl acetate,Cool down to about 0°C, add 38Kg of hydrogen chloride and stir,A large amount of white solid precipitates, continue to pass hydrogen chloride for 30 minutes, filter,Then wash the filter cake with 80Kg ethyl acetate,After drying, the purity is over 98.6%,The target product is 69.8Kg of 2-methylpyrrolidine hydrochloride, with a total yield of 74.5%. |
Tags: 43041-12-9 synthesis path| 43041-12-9 SDS| 43041-12-9 COA| 43041-12-9 purity| 43041-12-9 application| 43041-12-9 NMR| 43041-12-9 COA| 43041-12-9 structure
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