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CAS No. : | 4298-08-2 | MDL No. : | MFCD00216471 |
Formula : | C5H9NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BJBUEDPLEOHJGE-IMJSIDKUSA-N |
M.W : | 131.13 | Pubchem ID : | 440575 |
Synonyms : |
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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 |
---|---|---|
91% | Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; Stage #2: With hydrogenchloride In dichloromethane; water |
Method A: To a stirred solution of the carboxylic acid (20.3 mmol) in tetrahydrofuran (75 ml) was added di-tert-butyl dicarbonate (2.5 equivalents (eq.), 50.8 mmol) followed by the addition of sodium bicarbonate (6 eq., 122 mmol) in water (75 ml). The carboxylic acids are commercially available from vendors like Aldrich, Acros, Anaspec, CNH technologies, etc. The addition is typically carried out at low temperatures, e.g. 0° C., after which the reaction was brought to rt and let to stir for 16 h. The reaction was concentrated to remove all solvent, diluted with excess water and extracted with ether. The aqueous layer was acidified with 6N HCl and extracted with DCM (2.x.) and once with n-butanol. All organic extracts were combined, concentrated, and co-evaporated with toluene. The residue was then dried under high vacuum to give the desired Boc-protected carboxylic acid.Step 1: (2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid was prepared from (2S,3S)-3-Hydroxypyrrolidine-2-carboxylic acid following Method A (yield=91percent). The resulting product was used without purification. 1H NMR (DMSO-d6): 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.10 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H). HPLC: Rt=3.868 min following Method R. ES-MS: calcd. for C10H17NO5 (231.25); found: 230.2 [M-H]. |
90% | With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; | Trans-3-hydroxy-L-proline (2.62 g, 20.0 mmol) and sodium bicarbonate (5.04 <n="132"/>g, 60 mmol) were dissolved in water (20 ml). Dioxane was added (20 ml) followed by di- tert-butyl-dicarbonate (8.72 g, 40 mmol). Stirring was continued at room temperature overnight. The reaction was concentrated, and the residue was partitioned between ethyl ether (10 ml) and water (30 ml). The aqueous layer was washed once more with ether, and the organic layers were discarded. Gradual acidification of the aqueous phase with concentrated HCl caused the oily product to precipitate and this was extracted into ethyl acetate by repeated washings (3x10 ml) of the aqueous layer. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the title compound as a viscous oil (4.17 g, 90percent). |
90% | With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 2 h; | Preparation 8; (2S,3S)- 1 -(tert-butoxycarbonyl)-3 -hydroxypyrrolidine-2-carboxylic acid; A suspension of .pound.rαroe-3-hydroxy-L-proline (5 g, 37.56 mmol) in methanol (100 mL) is treated with diisopropylethylamine (6.55 mL, 37.56 mmol) and subsequently di-t- butyldicarbonate (8.87 g, 39.44 mmol) at room temperature. The resulting suspension is stirred for 2 h at room temperature while becoming a homogeneous solution. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate (120 mL). The organic solution is washed with 1 N aqueous hydrogen chloride. The aqueous layer is discarded and the organic layer is washed with brine, dried over sodium sulfate, concentrated, and dried under vacuum to give 8.0 g (90percent) of the title compound. 1H NMR (300 MHz, CDCl3) δ 12.60 (s, br, IH), 5.40 (s, br, IH), 4.20-4.12 (m, IH), 3.87 (d, J = 6.4 Hz, IH), 3.25-3.42 (m, 2H), 1.90-1.75 (s, br, IH), 1.74-1.65 (s, br, IH), 1.30 (d, J = 7.1 Hz, 9H). |
85% | With sodium carbonate In 1,4-dioxane; water at 20℃; for 1.5 h; | Boc anhydride (2.95 g, 13.5 mmol) was added to a stirred solution of the (2S, 3S)-3-HYDROXYPYRROLIDINE-2-CARBOXYLIC acid (1.61 g, 12.3 mmol) and sodium carbonate (1.3 g, 12.3 mmol) in a mixture of dioxane (25 ml) and water (12.3 ml). The mixture was stirred for 1.5 h at ambient temperature then evaporated under reduced pressure to afford a residue (-10 ml). The residue was diluted with water (30 ML) then extracted with ethyl acetate (40 ml). The aqueous phase was acidified (PH-2. 5) with dilute aqueous hydrochloric acid (0.1 M) then extracted with chloroform (4 x 50 ml). The combined organic layers were dried (NA2SO4) and evaporated under reduced pressure to afford (2S, 3S)-3-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-TERT-BUTYL ester as a white crystalline solid (2.39 G,-85percent), HPLC- MS (single main peak, 254.1 [M + Na] + and 485.2 [M + H] +). |
70% | With sodium hydroxide In tetrahydrofuran; water | EXAMPLE 18A (2S,3 S)-1-(tert-butoxycarbonyl)-3-hydroxy-2-pyrrolidinecarboxylic acid trans-3-Hydroxy (L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in water (34 mL) at ambient temperature. After 10 minutes of stirring, the mixture was treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure, acidified to pH 2-3 with saturated KHSO4 (aq), and extracted with ethyl acetate (2*200 mL). The organic extracts were combined, washed with brine (2*30 mL), and concentrated to provide the title compound as a white solid (12.3 g, 70percent, yield). mp 156-157° C. |
70% | Stage #1: With sodium hydroxide In tetrahydrofuran; water Stage #2: at 20℃; for 10 h; Stage #3: With CHO4(1-)*K(1+) In water |
trans-3-Hydroxy-(L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in H2O (34 mL) and then treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure to remove the THF. The residue was acidified to pH 2-3 with saturated KHSO4 and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with brine (2 x 30 mL) and concentrated to provide the title compound as a white solid (12.3 g, 70percent). mp 156-157 °C. |
0.91 g | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol) in CH2Cl2 (19 mL) at roomtemperature was added di-tert-butyl dicarbonate (0.96 mL, 4.2 mmol) and Hunig’s base (1.32 mL, 7.6 mmol) to give atan solution. The reaction was stirred overnight at room temperature and then diluted with CH2Cl2 and washed withsaturated sodium bicarbonate solution. The aqueous layer was concentrated under reduced pressure and then suspendedin methanol and filtered. The solvent was then removed under reduced pressure to prodive the title compound(0.91g, 103percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride In ethanol for 3h; Inert atmosphere; Reflux; | |
70% | With hydrogenchloride for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogen; trifluoroacetic acid In ethanol; water for 15h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Method A: To a stirred solution of the carboxylic acid (20.3 mmol) in tetrahydrofuran (75 ml) was added di-tert-butyl dicarbonate (2.5 equivalents (eq.), 50.8 mmol) followed by the addition of sodium bicarbonate (6 eq., 122 mmol) in water (75 ml). The carboxylic acids are commercially available from vendors like Aldrich, Acros, Anaspec, CNH technologies, etc. The addition is typically carried out at low temperatures, e.g. 0 C., after which the reaction was brought to rt and let to stir for 16 h. The reaction was concentrated to remove all solvent, diluted with excess water and extracted with ether. The aqueous layer was acidified with 6N HCl and extracted with DCM (2×) and once with n-butanol. All organic extracts were combined, concentrated, and co-evaporated with toluene. The residue was then dried under high vacuum to give the desired Boc-protected carboxylic acid.Step 1: (2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid was prepared from (2S,3S)-3-Hydroxypyrrolidine-2-carboxylic acid following Method A (yield=91%). The resulting product was used without purification. 1H NMR (DMSO-d6): 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.10 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H). HPLC: Rt=3.868 min following Method R. ES-MS: calcd. for C10H17NO5 (231.25); found: 230.2 [M-H]. | |
90% | With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; | Trans-3-hydroxy-L-proline (2.62 g, 20.0 mmol) and sodium bicarbonate (5.04 <n="132"/>g, 60 mmol) were dissolved in water (20 ml). Dioxane was added (20 ml) followed by di- tert-butyl-dicarbonate (8.72 g, 40 mmol). Stirring was continued at room temperature overnight. The reaction was concentrated, and the residue was partitioned between ethyl ether (10 ml) and water (30 ml). The aqueous layer was washed once more with ether, and the organic layers were discarded. Gradual acidification of the aqueous phase with concentrated HCl caused the oily product to precipitate and this was extracted into ethyl acetate by repeated washings (3x10 ml) of the aqueous layer. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the title compound as a viscous oil (4.17 g, 90%). |
90% | With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃; for 2h; | Preparation 8; (2S,3S)- 1 -(tert-butoxycarbonyl)-3 -hydroxypyrrolidine-2-carboxylic acid; A suspension of £ralphar°-3-hydroxy-L-proline (5 g, 37.56 mmol) in methanol (100 mL) is treated with diisopropylethylamine (6.55 mL, 37.56 mmol) and subsequently di-t- butyldicarbonate (8.87 g, 39.44 mmol) at room temperature. The resulting suspension is stirred for 2 h at room temperature while becoming a homogeneous solution. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate (120 mL). The organic solution is washed with 1 N aqueous hydrogen chloride. The aqueous layer is discarded and the organic layer is washed with brine, dried over sodium sulfate, concentrated, and dried under vacuum to give 8.0 g (90%) of the title compound. 1H NMR (300 MHz, CDCl3) delta 12.60 (s, br, IH), 5.40 (s, br, IH), 4.20-4.12 (m, IH), 3.87 (d, J = 6.4 Hz, IH), 3.25-3.42 (m, 2H), 1.90-1.75 (s, br, IH), 1.74-1.65 (s, br, IH), 1.30 (d, J = 7.1 Hz, 9H). |
~ 85% | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 1.5h; | Boc anhydride (2.95 g, 13.5 mmol) was added to a stirred solution of the (2S, 3S)-3-HYDROXYPYRROLIDINE-2-CARBOXYLIC acid (1.61 g, 12.3 mmol) and sodium carbonate (1.3 g, 12.3 mmol) in a mixture of dioxane (25 ml) and water (12.3 ml). The mixture was stirred for 1.5 h at ambient temperature then evaporated under reduced pressure to afford a residue (-10 ml). The residue was diluted with water (30 ML) then extracted with ethyl acetate (40 ml). The aqueous phase was acidified (PH-2. 5) with dilute aqueous hydrochloric acid (0.1 M) then extracted with chloroform (4 x 50 ml). The combined organic layers were dried (NA2SO4) and evaporated under reduced pressure to afford (2S, 3S)-3-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-TERT-BUTYL ester as a white crystalline solid (2.39 G,-85%), HPLC- MS (single main peak, 254.1 [M + Na] + and 485.2 [M + H] +). |
70% | With sodium hydroxide; In tetrahydrofuran; water; | EXAMPLE 18A (2S,3 S)-1-(tert-butoxycarbonyl)-3-hydroxy-2-pyrrolidinecarboxylic acid trans-3-Hydroxy (L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in water (34 mL) at ambient temperature. After 10 minutes of stirring, the mixture was treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure, acidified to pH 2-3 with saturated KHSO4 (aq), and extracted with ethyl acetate (2*200 mL). The organic extracts were combined, washed with brine (2*30 mL), and concentrated to provide the title compound as a white solid (12.3 g, 70%, yield). mp 156-157 C. |
70% | trans-3-Hydroxy-(L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in H2O (34 mL) and then treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure to remove the THF. The residue was acidified to pH 2-3 with saturated KHSO4 and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with brine (2 x 30 mL) and concentrated to provide the title compound as a white solid (12.3 g, 70%). mp 156-157 C. | |
With sodium hydroxide; In 1,4-dioxane; water; at 5 - 20℃; for 16.5h; | A mixture of trans-3-hydroxy-L-proline (5 g), di-tert-butyl dicarbonate (9.15 g), sodium hydroxide (1.52 g), water (78 ml) and dioxan (80 ml) was stirred at 5 C. for 30 mins. and then at ambient temperature for 16 hours. The mixture was evaporated to a smaller volume (30 ml) and diluted with water (150 ml). The pH was adjusted to 2-3 with aqueous sodium bisulphate and saturated with sodium chloride. It was then extracted with ethyl acetate (3*100 ml), the extracts dried and the solution evaporated to dryness to give (2S,3S)-1-(tert-butoxycarbonyl)-2-carboxy-3-hydroxypyrrolidine (compound 64) as a white solid (8.42 g). Compound 64: NMR (DMSOd6) delta: 1.27 (2s, 9H), 1.64-1.76 (m, 2H), 3.24-3.45 (m, 2H), 3.92 (d, 1H), 4.20 (br, 1H), 5.40 (br, 1H), 12.6 (br, 1H). | |
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 16h; | To a cold (0 C) mixture of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid 26a (6.37g, 48.6 mmol) in tetrahydrofuran (180 mL) is added di-tert-butyl dicarbonate (26.4 g, 0.121 mmol) followed by addition of solution of NaHCO3 (24.5 g, 0.292 mmol) in water (180 mL). The cooling bath is removed and the mixture is stirred 16 hours at room temperature. The solvent is evaporated in vacuo, the residue is diluted with water and extracted with ether. The ethereal layer is discarded. The aqueous layer is cooled to 0 C, acidified to pH 1 with 6 N hydrochloric acid, extracted with dichloromethane (3x) and n-butanol (2x). The combined organic phase is concentrated in vacuo. The oily residue is co-evaporated twice with toluene anddried on a high vacuum pump to give (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid B16b: ESI-MS calcd. for C10H17NNaO5 ([M+Na]+) 254.1, found 254.1. The product is used without further purification. | |
0.91 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol) in CH2Cl2 (19 mL) at roomtemperature was added di-tert-butyl dicarbonate (0.96 mL, 4.2 mmol) and Hunig?s base (1.32 mL, 7.6 mmol) to give atan solution. The reaction was stirred overnight at room temperature and then diluted with CH2Cl2 and washed withsaturated sodium bicarbonate solution. The aqueous layer was concentrated under reduced pressure and then suspendedin methanol and filtered. The solvent was then removed under reduced pressure to prodive the title compound(0.91g, 103% yield). |
With water; sodium hydroxide; In 1,4-dioxane; at 20℃; for 2h; | Step 1 : (2S,3S)-l-(tert-Butoxycarbonyl)-3-hvdroxypyrrolidine-2-carboxylic acid.To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (3.0 g, 23 mmol) in dioxane/H20 (40 mL/20 mL) was added sodium hydroxide (1.83 g, 46 mmol), followed by the dropwise addition of di-tert-butyl dicarbonate (9.49 g, 43 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature (rt) for 2 h. The reaction mixture was extracted with EtOAc (50 mL) and the organic layer was washed with 10% aq. NaOH (30 mL). The combined aqueous layers were acidified with cone. HC1 to pH 2 and extracted with CH2C12. The organic phases were dried (Na2S04) and concentrated to give the crude product, which was used without further purification (5.01 g, 95%). 1H NMR (CD3OD, 400 MHz) delta 4.40- 4.30 (m, 1H), 4.15-4.00 (m, 1H), 3.50-3.40 (m, 2H), 2.00-1.95 (m, 1H), 1.85 (m, 1H), 1.45- 1.35 (m, 9H). | |
With sodium hydrogencarbonate; In 1,4-dioxane; water; | (2S,3S)-1-(Tert.-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (15) was prepared by Boc protection of the secondary amino group of 13 by di-tert. -butyl dicarbonate in dioxane in the presence of aq. Na2CC>3 soln applying standard conditions. Data of 15: Ci0Hi7NO5 (231 .2). FI-MS: 230.1 ([M-H]-). 1H-NMR (DMSO-d6): 5.43 (br. s, 1 H); 4.23 (br. m, 1 H); 3.92 (d, J = 12.4, 1 H); 3.46 - 3.29 (m, 2 H); 1 .85 (m, 1 H); 1 .72 (m, 1 H); 1 .40, 1.34 (2 s, 9 H). | |
To a stirred solution of (2 S, 3S)-3-hydroxypyrrolidine-2-carboxylic acid (3.00 g, 22.88 mmol) in THF (150 mL) was added water (150 ml_) and NaHCCb (7.70 g, 92 mmol) at 0 C. The reaction mixture was stirred at room temperature for 15 minutes. After B0C2O (7.50 g, 34.4 mmol) was added, the reaction mixture was stirred at 25 C for 16 h. The resulting mixture was added sat'd aqueous NaHCC>3 (50 mL) and washed with ethyl ether (2 x 100 mL). The separated organic phases were deserted. The pH value of the aqueous phase was adjusted to 3 with aqueous HCI (1 M). The aqueous solution was extracted with EA (6 x 200 mL). The organic layers were combined and concentrated under reduced pressure to afford 5.00 g (90% yield) of 123 as an off-white solid. LCMS (ESI) calc?d for C10H17NO5 [M + Na]+: 254.1 , found 253.9. 1H NMR (300 MHz, CDsOD) d 4.47-4.33 (m, 1 H), 4.19-4.08 (m, 1 H), 3.69-3.44 (m, 2H), 2.16-1.97 (m, 1 H), 1.94-1.81 (m, 1 H), 1.45 (d, J = 13.3 Hz, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium hydroxide In methanol; water Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride | |
With thionyl chloride | ||
With hydrogenchloride |
0.7 g | With hydrogenchloride at 20℃; for 2h; | |
With thionyl chloride at 0 - 20℃; for 48h; Inert atmosphere; | ||
With boron trifluoride diethyl etherate for 48h; Reflux; | a a) (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate General procedure: a) (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate To a stirred solution of trans-3-hydroxy-L-proline (15 g, 0.1 14 moles) in methanol (200 mL) was added borontrifluoride diethyl ether (42 mL, 0.343 moles) and the reaction mixture was refluxed for 48 h. Once the starting material had disappeared (monitored by TLC) the reaction mixture was concentrated to get the title compound which was used in the next step without further purification.Wt of the crude product: 16.6 g (99%) MS (ES): m/z 146 (M + 1 ) | |
With thionyl chloride at 0 - 60℃; for 6h; Inert atmosphere; | ||
With boron trifluoride diethyl etherate for 48h; Reflux; | B1.a a) (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate To a stirred solution of trans-3-hydroxy-L-proline (15 g, 0.114 moles) in methanol (200 mL) was added borontrifluoride diethyl ether (42 mL, 0.343 moles) and the reaction mixture was refluxed for 48 h. Once the starting material had disappeared (monitored by TLC) the reaction mixture was concentrated to get the title compound which was used in the next step without further purification. Wt of the crude product: 16.6 g (99%) MS (ES): m/z 146 (M+1) | |
With hydrogenchloride for 4h; Cooling with ice; | 2.1 Step 1 Synthesis of Methyl (2S,3S)-1-[3-[[4-(4,5-Difluorobenzofuran-7-yl)phenoxy]methyl]benzoyl]-3-hydroxy-pyrrolidine-2-carboxylate (0147) To (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (19.6 mg, 0.15 mmol), hydrochloric acid/methanol prepared from acetyl chloride (0.103 mL) and methanol (3.0 mL) was added under ice cooling, followed by stirring for 4 hours. Then, the solvent was evaporated under reduced pressure. To the obtained residue, dichloromethane (1.5 mL), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (hereinafter, WSC) hydrochloride (56.4 mg, 0.300 mmol), Intermediate 1-A (57.0 mg, 0.150 mmol), 1-hydroxybenzotriazole (hereinafter, HOBt) monohydrate (41.1 mg, 0.300 mmol), and triethylamine (0.0626 mL, 0.450 mmol) were added, followed by stirring at room temperature overnight. The mixture was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound. (0148) Yield: 38.5 mg (0.0759 mmol) (0149) MS (ESI) m/z 508 [M+H]+ | |
With acetyl chloride at 0 - 65℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydrogencarbonate In 1,4-dioxane at 0 - 20℃; for 9h; | |
98% | With sodium hydrogencarbonate In 1,4-dioxane at 0 - 20℃; for 9h; | |
59% | With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 3h; |
59.2% | With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 3h; | 1.1 (1) PREPARATION OF (2S, 3S) 3-HYDROXYPYRROLIDINE-1, 2-DICARBOXYLIC ACID 1- (9H- fluoren-9-ylmethyl) ester. Trans-3-hydroxy-L-proline (LO. OG, 76.3mmole) was added to a vigorously stirred, ice-cooled solution of sodium carbonate (16.90g, 160.2mmole) in water (lOOmL). 1,4-Dioxan (75mL) was added providing an opaque but mobile mixture. 9-Fluorenylmethyl CHLOROFORMATE (20. 31g, 80mmole) in 1,4-dioxan (75mL) was added over lhr, then the ice-cooling removed and the mixture stirred at RT for an additional 2hr. Additional water (300mL) was added, the reaction mixture washed with chloroform (2 x 250mL) and the combined organic layers discarded. The aqueous phase was acidified with IN HC1 to-pH 2, providing a thick opaque mixture. The acidified aqueous mixture was extracted with chloroform (2 x 500ML) and the now clear aqueous phase discarded. The opaque combined chloroform layers were dried (NA2S04), filtered and reduced in vacuo to provide batch 1 (5.70g). The residual precipitate (a mixture of product and drying agent) was triturated with hot methanol (2 x 250mL) and the combined methanol solutions reduced in vacuo to provide batch 2 (10.25g). Batch 1 and 2 were individually analysed by TLC (single UV spot, RF= 0. 15, 20% MEOH in CHC13), and HPLC-MS (single main UV peak with Rt = 7.069mins, 354.2 [M + H] +, 376.2 [M + Na] +) and found to be identical, giving a combined yield of 15.95g (45.2mmole, 59.2%). Analysis BY H and 13C NMR showed the presence of cis and trans geometrical isomers around the 3 AMIDE bond. δH (DMSO-d6 at 298K); 1.80-2. 02 (2HY, m), 3.49-3. 62 (2HO, m), 4.12-4. 38 (HA, HP, Fmoc H-9 and CH2, m), 5.55/5. 62 (OH), 7.30-7. 31 (2H aromatic, Fmoc H-2 and H-7), 7.35-7. 37 (2H aromatic, Fmoc H-3 and H- 6), 7.43-7. 45 (2H aromatic, Fmoc H-1 and H-8), 7.63-7. 65 (2H aromatic, Fmoc H-4 and H-5), 12.8-13. 0 (COOH) ;δC (DMSO-d6 at 298K); 31.70/32. 70 (d, CY), 44.68/45. 32 (d, CL), 46.94/46. 97 (u, Fmoc C-9), 67.04/67. 33 (d, Fmoc CH2), 68.24/68. 51 (u, CA), 73. 12/74. 23 (u, Cp), 120.49/120. 52 (u, Fmoc C-4 and C-5), 125.49/125. 58 (u, Fmoc C-1 and C- 8), 127.50 (u, Fmoc C-2 and C-7), 128.04 (u, Fmoc C-3 and C-6), 140.99/141. 09 (q, Fmoc C-4'and C-5'), 144.02/144. 16 (Q, Fmoc C-l'and C-8'), 154.33/154. 54 (q, OCON), 172.10/172. 39 (COOH). |
58% | With sodium hydrogencarbonate In 1,4-dioxane; water at 4 - 20℃; for 10h; | Fmoc-trans-3-hydroxy-(E)-proline To a stirred and cooled suspension of trans-3-hydroxy-(L)-proline (2.00 g, 15.3 mmol, 1.00 eq.) in 1,4-dioxane (110 mL) and aq. NaHCO3 (5% w/v, 55 mL) was added slowly a solution of Fmoc-Cl (4.02 g, 15.56 mmol, 1.02 eq.) in dioxane (50 mL). The reaction mixture was kept at 4° C. for 4 h, allowed to warm to room temperature, and stirred for another 6 h to afford a clear, colorless solution. Most of the dioxane was evaporated in vacuo (45° C. bath temperature), and the resultant solution was extracted with diethyl ether (2*100 mL) to remove excess Fmoc-Cl. The aqueous layer was acidified to pH 2-3 with 1 M HCl to afford a cloudy solution, which was extracted with EtOAc (4*100 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo and co-evaporated twice with CH2Cl2. Drying under vacuum afforded the product as an off-white, microcrystalline solid (3.10 g, expected 5.39 g, yield 58%). Spectroscopic data were in agreement with the literature (Taylor, Hardre et al. 2005). Fmoc-cis-4-hydroxy-(L)-proline Prepared as described (Taylor, Hardre et al. 2005). From 270 mg starting material, the product was obtained as a light pink powder (514 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δH 1.88 (dt, J=13.0, 4.0 Hz, 1H), 1.94-2.04 (m, 1H), 2.26-2.44 (m, 1H), 3.21 (ddd, J=10.5, 7.0, 3.0 Hz, 1H), 3.37 (brs, 1H), 3.48-3.62 (m, 1H), 4.12-4.40 (m, 5H), 7.28-7.38 (m, 2H), 7.38-7.48 (m, 2H), 7.59-7.73 (m, 2H), 7.89 (t, J=7.0 Hz, 2H), 12.52 (brs, 1H); |
In acetonitrile at 30℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; at 0℃; for 12h; | To a solution of commerically available trans-3-hydroxyproline is added 1.1 equivalents BOC-ON (Aldrich) in a 1:1 v/v solution water/dioxanes and NaOH (1N solution) and stirred at 0 C. for 12 hours. The combined organic phases are then washed with water (2×5 mL), 1 N HCl (aq.) (5 mL), saturated sodium bicarbonate solution (aq.) (50 mL), water (5 mL), brine (5 mL) and dried (MgSO4) before concentration in vacuo to give the crude product. Flash chromatography, eluting with 1:1 ethyl acetate/hexane gives the desired protected product. Step 2) As illustrated in FIG. 27 the substrate (70 mg, 0.213 mmol; vida supra), is dissolved in dry methylene chloride (3 mL). EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, (43 mg, 0.224 mmol) is added and the mixture is stirred for 30 minutes at room temperature. tert-butyl amine (73 mg, 0.255 mmol) is added and the reaction stirred for 18 hours. The reaction mixture is diluted with ethyl acetate (20 mL) and added to saturated ammonium chloride (30 mL). The aqueous phase is extracted with ethyl acetate (3×10 mL). The combined organic phases are then washed with water (2×5 mL), 1 N HCl (aq.) (5 mL), saturated sodium bicarbonate solution (aq.) (50 mL), water (5 mL), brine (5 mL) and dried (MgSO4) before concentration in vacuo to give the crude product. Flash chromatography, eluting with 1:1 ethyl acetate/hexane gives the desired product 1050A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In dichloromethane at -78 - 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogen In methanol at 20℃; for 13h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: N-Fmoc L-Phe With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h; Stage #2: trans-3-hydroxy-L-proline With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With α-ketoglutaric acid; iron(II) sulfate; ascorbic acid In water at 25℃; for 24h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride at 0 - 20℃; | 34.1 Example 34Step 1: To a stirred 0° C. suspension of (2S, 3S)-3-hydroxypyrrolidine-2-carboxylic acid (5.1 g, 38.9 mmol, Acros) in anhydrous MeOH (100 mL) was added dropwise SOCl2 (5.6 mL, 77.2 mmol) after 1 h dissolution of starting material was complete. The reaction mixture was stirred at rt 24 h then evaporated under reduced pressure. The resulting residue was triturated with anhydrous Et2O, filtered, washed with additional Et2O and dried in vacuo to furnish the product (7.1 g, quantitative yield). ES+MS: calcd. for C6H11NO3 (145.07); found: 146.0 [M +H]. |
99% | With hydrogenchloride at 0 - 20℃; | |
99% | With thionyl chloride at 0℃; for 16h; | (2S,3S)-Methyl 3-hydroxypyrrolidine-2-carboxylate hydrochloride (14 HCI): (2S,3S)-Methyl 3-hydroxypyrrolidine-2-carboxylate hydrochloride (14 HCI): At 0°C, SOCI2 (1 .0 mL) was slowly added to a suspension of 13 (1 .12 g, 8.5 mmol) in MeOH (20 mL). The resulting solution was stirred for 16 h and concentrated. The resulting solid was washed (Et20) to give 14 HCI (1.54 g, 99%). Data of 14 HCI: C6HnN03 HCI (145.1 + 36.5). 1H-NMR (DMSO-de): 9.58 (very br. s, NH2+); 5.98 (br. s, 1 H); 4.49 (br. s, 1 H); 4.16 (d, J = 2.5, 1 H); 3.77 (s, 3 H); ca 3.30 (2 H; superimposed by H20 signal); 2.03 - 1.83 (m, 2 H). |
98% | With thionyl chloride at 0 - 20℃; | |
94% | With hydrogenchloride at 0℃; for 0.5h; | 68 Hydrogen chloride gas was bubbled through a suspension of frans-3-hydroxy-L- proline (1.5 g, 11.4 mmol) in 20 ml of freshly distilled MeOH at 00C for 30 min. The resulting clear solution was stirred overnight, then concentrated under reduced pressure to afford the title compound as a white solid (1.96 g). Yield 94%. Reference: U.S. Pat. Appl. 2004 19,063. |
93.7% | With hydrogenchloride at 0 - 20℃; for 6.16667h; | 3.A Example 3 5-CHLORO-THIOPHENE-2-CARBOXYLIC ACID { (7R, 7AR)-3-OXO-2- [4- (2-OXO-2H-PYRIDIN-1-YL)-PHENYL]-HEXAHYDRO-PYRROLO [1, 2-C] IMIDAZOL-7-YL}-AMIDE [00630] Part A. Hydrogen chloride gas was bubbled into a stirred suspension of TRA7ZS-3-HYDROXY-L-PROLINE (25 g, 190 mmol) in MEOH (250 mL) at 0°C for 10 min. The resulting clear solution was capped and stirred at room temperature for 6 h. It was concentrated under reduced pressure. The resulting white solids were triturated with either, filtered, and dried under vacuum to give (2S, 3S)-3-HYDROXY-PYRROLIDINE-2- carboxylic acid methyl ester hydrochloride salt (32.5 g, yield: 93.7%). |
91% | With thionyl chloride at 0 - 20℃; for 16h; | 11 Example 11: Methyl (2S,3S)-3-hydroxypyrrolidine-2-carboxylate hydrochloride (33) To a stirred suspension of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 15.2 mmol) in anhydrous methanol (40 mL) at 0 °C, thionyl chloride (2.2 mL, 30.4 mmol)was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was triturated in anhycirous cliethyl ether, filtered, washed with extra diethyl ether and concentrated to give the title compound (2.5 g, 91%) as a beige solid. The obtained material was carried through to the next step without any further purification.1H NMR (400 MHz, MeOD) 64.66 (br s, 1H) 4.30 (s, 1H) 3.82-3.91 (m, 3H) 3.46-3.59(m, 2H) 2.07 (br 5, 2H); 13C NMR (100 MHz, MeOD) 6 169.1, 74.5, 68.6, 54.5, 45.8,33.2. |
91% | With thionyl chloride at 20℃; | R.B.9.1 Synthesis of (3S)-3-hydroxy-L-proline methyl ester hydrochloride To a solution of (3S)-3-hydroxy-L-proline (1.5 g, 12 mmol) in methanol (20 mL) was added thionyl chloride (1.4 g, 0.12 mol) at 000, and the mixture was stirred at room temperature overnight. The resulting insoluble material was collected by filtration, and washed with diethyl ether to give the title compound (1.9 g, 10 mmol, 91%). MS (ESI) m/z 146 (M+H)+ 1H NMR (CDCl3, 300 MHz): δ6.01-5.99 (m, 1H), 4.49-4.46 (m, 1H), 4.13 (d, J=2.7 Hz, 1H), 3.76 (s, 3H), 3.38-3.28 (m, 2H), 2.01-1.84 (m, 2H). |
91% | With acetyl chloride at 0 - 65℃; Cooling with ice bath; Inert atmosphere; | 16 Methyl-(3,Sl-3 -hydroxy- L-prolinate hydrochloride (2)(35)-3-Hydroxy-L-proline (1) (10.0 g, 76.3 mmol) was added, in one portion, to a stirred solution (at 0 °C / ice- water bath) of acetyl chloride (7.6 mL, 110 mmol) in methanol (70 mL). After the addition, the ice-water bath was removed and the reaction warmed to ambient temperature and then heated at 65 °C for 5-6 hr. After this period of time, the reaction was complete based on TLC (20% MeOH/CHCl3) and was cooled to ambient temperature. The cooled reaction mixture was diluted with ether (150 mL) and a white precipitate formed. The white precipitate was collected by filtration and the solid washed x2 with 25-mL of cold diethyl ether and then dried overnight under high vacuum to afford 12.6 g of (2) in 91% yield as a white crystalline solid. 1H NMR is consistent; 1H NMR (400 MHz, DMSO-d6 with CDCl3 added) δ ppm 9.67 (br. s., 2 H), 5.93 (br. s., 1 H), 4.50 (br. s., 1 H), 4.18 (d, J = 2.07 Hz, 1 H), 3.77 (s, 3 H), 3.35 (m, 2 H), 1.94 (m, 2 H). |
91% | With thionyl chloride In dichloromethane at 20℃; | B.5.1 (step 1) Synthesis of (3S)-3-hydroxy-L-proline methyl ester hydrochloride To 45 (3S)-3-hydroxy-L-proline (1.5 g, 12 mmol) were added 6 dichloromethane (20 mL) and 48 thionyl chloride (1.4 g, 0.12 mol), and the mixture was stirred at room temperature overnight. The resulting insoluble material was collected by filtration, and washed with diethyl ether to give the 49 title compound (1.9 g, 10 mmol, 91%). MS (ESI) m/z 146 (M+H)+ 1H NMR (CDCl3, 300 MHz): δ 6.01-5.99 (m, 1H), 4.49-4.46 (m, 1H), 4.13 (d, J = 2.7 Hz, 1H), 3.76 (s, 3H), 3.38-3.28 (m, 2H), 2.01-1.84 (m, 2H). |
With hydrogenchloride at 0 - 20℃; for 4.16667h; | 1.1A Hydrogen chloride gas was bubbled through a suspension of trans-3-hydroxy-L-proline (50.0 g, 0.380 mol) in MeOH (600 mL) cooled to 0° C. for 10 min. The resulting clear solution was stirred at rt for 4 h, then concentrated carefully under reduced pressure (white precipitates formed during the concentration). The resulting white solid was dried under vacuum overnight to afford the title compound (68.3 g) as a white solid. | |
With thionyl chloride at 0℃; Inert atmosphere; Reflux; | ||
With thionyl chloride at 0 - 20℃; for 2h; | 36 5.36 Methyl 1-benzyloxycarbonyl-(3S)-hydroxy-(2S)-pyrrolidinecarboxylate (9) To a cooled (0 °C), stirred solution of SOCl2 (27.0 mL, 0.37 mol) in MeOH (200 mL) was added trans-3-hydroxy-l-proline (8) (16.2 g, 0.12 mol) and the reaction mixture was stirred at 0 °C to room temperature for 2 h. After removal of the solvent, the crude solid was triturated with Et2O to give methyl (3S)-hydroxy-(2S)-pyrrolidinecarboxylate hydrochloride (22.4 g) as a colorless solid. | |
With thionyl chloride at -10 - 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C | ||
Multi-step reaction with 3 steps 1: acetyl chloride / 6 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 3.5 h | ||
Multi-step reaction with 3 steps 1: acetyl chloride / 20 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran / 10 h / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 4 h / 20 °C |
Multi-step reaction with 3 steps 1: acetyl chloride / 0 - 65 °C / Cooling with ice bath; Inert atmosphere 2: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C / Inert atmosphere; Cooling with ice bath 3: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: hydrogenchloride / 6.17 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: 1H-imidazole / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C | ||
Multi-step reaction with 5 steps 1: acetyl chloride / 6 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 3.5 h 4: lithium borohydride / tetrahydrofuran / 18 h / 0 - 20 °C 5: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.33 h / -78 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1: acetyl chloride / 20 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran / 10 h / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 4 h / 20 °C 4: lithium borohydride / tetrahydrofuran / 18 h / 0 - 20 °C 5: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.33 h / -78 - -65 °C |
Multi-step reaction with 5 steps 1.1: acetyl chloride / 0 - 65 °C / Cooling with ice bath; Inert atmosphere 2.1: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C / Inert atmosphere; Cooling with ice bath 3.1: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 4.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C / Cooling with ice bath 4.2: Ice 5.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / -78 - -65 °C / Inert atmosphere; Cooling with acetone-dry ice 5.2: -65 °C / Inert atmosphere; Cooling with acetone-dry ice | ||
Multi-step reaction with 5 steps 1: hydrogenchloride / 6.17 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: 1H-imidazole / dichloromethane / 20 °C 4: lithium triethylborohydride / tetrahydrofuran / 3.67 h / -78 - 20 °C 5: Dess-Martin periodane / 2 - 4 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 28 percent / tetrahydrofuran / -60 - 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h 10: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h 10: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 11: TFA / CH2Cl2 / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h 10: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 11: TFA / CH2Cl2 / 3 h / 20 °C 12: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h 10: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 11: TFA / CH2Cl2 / 3 h / 20 °C 12: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 13: Bu4NF / tetrahydrofuran / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h 10: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 11: TFA / CH2Cl2 / 3 h / 20 °C 12: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 13: Bu4NF / tetrahydrofuran / 1 h / 20 °C 14: PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 15 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: 29 percent / tetrahydrofuran / -60 - 0 °C 7: 78 percent / i-Pr2NEt / DMAP / CH2Cl2 / 3.33 h / 0 - 20 °C 8: 77 percent / NaN3 / dimethylformamide / 80 °C 9: 98 percent / H2 / Pd/C / methanol / 3 h 10: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 11: TFA / CH2Cl2 / 3 h / 20 °C 12: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 13: Bu4NF / tetrahydrofuran / 1 h / 20 °C 14: PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 15: KOH / tetrahydrofuran; methanol / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 51 percent / CsF / 29 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 8 percent / CsF / 29 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 51 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 51 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: 93 percent / i-Pr2NEt / CH2Cl2 / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 51 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: 93 percent / i-Pr2NEt / CH2Cl2 / -78 - 20 °C 11: 69 percent / t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 51 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: 93 percent / i-Pr2NEt / CH2Cl2 / -78 - 20 °C 11: 69 percent / t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 12: 86 percent / Bu4NF / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C 8: i-Pr2NEt / CH2Cl2 / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C 8: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 9: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C 8: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 9: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 10: Bu4NF / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C 8: i-Pr2NEt / CH2Cl2 / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C 8: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 9: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C 5: 89 percent / 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 6: CsF / 29 h / 20 - 50 °C 7: TFA / CH2Cl2 / 0.5 h / 20 °C 8: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 9: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 10: Bu4NF / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 8 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 8 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: i-Pr2NEt / CH2Cl2 / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 8 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 11: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: 8 percent / CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 11: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 12: Bu4NF / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: CsF / 29 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: CsF / 29 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: i-Pr2NEt / CH2Cl2 / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 11: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C 8: CsF / 29 h / 20 - 50 °C 9: TFA / CH2Cl2 / 0.5 h / 20 °C 10: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 11: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 12: Bu4NF / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C | ||
Multi-step reaction with 6 steps 1.1: thionyl chloride / 16 h / 0 - 20 °C / Cooling with ice bath; Inert atmosphere; Heating; Reflux 2.1: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C / Cooling with ice bath; Inert atmosphere 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Cooling with ice bath 4.1: methanol; potassium hydroxide / 1 h / 0 °C / Cooling with ice bath; Inert atmosphere 4.2: Inert atmosphere 5.1: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6.1: lithium borohydride / tetrahydrofuran / 24 h / 0 °C / Inert atmosphere; Cooling with ice bath; Heating; Reflux 6.2: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C 4: 72 percent / KOH / methanol / 2.42 h / 0 °C 5: i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 6: LiBHEt3 / tetrahydrofuran / -78 - 20 °C 7: 4-methylmorpholine N-oxide / n-Pr4NRuO4 / acetonitrile; CH2Cl2 / 4 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: thionyl chloride / 16 h / 0 - 20 °C / Cooling with ice bath; Inert atmosphere; Heating; Reflux 2.1: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C / Cooling with ice bath; Inert atmosphere 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Cooling with ice bath 4.1: methanol; potassium hydroxide / 1 h / 0 °C / Cooling with ice bath; Inert atmosphere 4.2: Inert atmosphere 5.1: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6.1: lithium borohydride / tetrahydrofuran / 24 h / 0 °C / Inert atmosphere; Cooling with ice bath; Heating; Reflux 6.2: Inert atmosphere 7.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.83 h / -78 - -35 °C / Inert atmosphere; Cooling with acetone-dry ice 7.2: -78 - -20 °C / Inert atmosphere; Cooling with acetone-dry ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C 4: 83 percent / LiBHEt3 / tetrahydrofuran / -78 - 20 °C | ||
Multi-step reaction with 4 steps 1: acetyl chloride / 6 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 3.5 h 4: lithium borohydride / tetrahydrofuran / 18 h / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1: acetyl chloride / 20 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran / 10 h / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 4 h / 20 °C 4: lithium borohydride / tetrahydrofuran / 18 h / 0 - 20 °C |
Multi-step reaction with 4 steps 1.1: acetyl chloride / 0 - 65 °C / Cooling with ice bath; Inert atmosphere 2.1: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C / Inert atmosphere; Cooling with ice bath 3.1: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 4.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C / Cooling with ice bath 4.2: Ice | ||
Multi-step reaction with 4 steps 1: hydrogenchloride / 6.17 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: 1H-imidazole / dichloromethane / 20 °C 4: lithium triethylborohydride / tetrahydrofuran / 3.67 h / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 100 percent / aq. NaOH / tetrahydrofuran / 20 °C 2.1: 4-methylmorpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / -15 °C 2.2: 100 percent / aq. NH3 / tetrahydrofuran / 1.5 h / -15 - 20 °C 3.1: 61 percent / diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 36 h / 20 °C 4.1: 100 percent / sodium azide; MeOH / 14 h / 40 °C 5.1: pyridine / cooling 6.1: 0.255 g / sodium azide / dimethylformamide / 21 h / 70 °C 7.1: H2 / Pd/C / methanol / 21 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 100 percent / aq. NaOH / tetrahydrofuran / 20 °C 2.1: 4-methylmorpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / -15 °C 2.2: 100 percent / aq. NH3 / tetrahydrofuran / 1.5 h / -15 - 20 °C 3.1: 61 percent / diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 36 h / 20 °C 4.1: 100 percent / sodium azide; MeOH / 14 h / 40 °C 5.1: pyridine / cooling 6.1: 0.255 g / sodium azide / dimethylformamide / 21 h / 70 °C 7.1: H2 / Pd/C / methanol / 21 h / 20 °C 8.1: N-methylmorpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / -15 °C 8.2: 0.43 g / tetrahydrofuran / 2 h / -15 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: 100 percent / aq. NaOH / tetrahydrofuran / 20 °C 2.1: 4-methylmorpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / -15 °C 2.2: 100 percent / aq. NH3 / tetrahydrofuran / 1.5 h / -15 - 20 °C 3.1: 61 percent / diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 36 h / 20 °C 4.1: 100 percent / sodium azide; MeOH / 14 h / 40 °C 5.1: pyridine / cooling 6.1: 0.255 g / sodium azide / dimethylformamide / 21 h / 70 °C 7.1: H2 / Pd/C / methanol / 21 h / 20 °C 8.1: N-methylmorpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / -15 °C 8.2: 0.43 g / tetrahydrofuran / 2 h / -15 - 20 °C 9.1: CH2Cl2 / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C 6.1: morph-DAST / tetrahydrofuran / -78 - 20 °C 7.1: H2 / Pd/C / methanol 8.1: HCl / dioxane / 1.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C 6.1: morph-DAST / tetrahydrofuran / -78 - 20 °C 7.1: H2 / Pd/C / methanol 8.1: HCl / dioxane / 1.5 h 9.1: 0.82 g / aq. NaHCO3 / dioxane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C 6.1: morph-DAST / tetrahydrofuran / -78 - 20 °C 7.1: H2 / Pd/C / methanol 8.1: HCl / dioxane / 1.5 h 9.1: 0.82 g / aq. NaHCO3 / dioxane 10.1: 77 percent / PyBroP; DIEA / CH2Cl2 / 21 h / 0 - 20 °C 11.1: 63 percent / H2 / Pd/C / methanol / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C 6.1: morph-DAST / tetrahydrofuran / -78 - 20 °C 7.1: H2 / Pd/C / methanol 8.1: HCl / dioxane / 1.5 h 9.1: 0.82 g / aq. NaHCO3 / dioxane 10.1: 77 percent / PyBroP; DIEA / CH2Cl2 / 21 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 80 percent / aq. NaOH / tetrahydrofuran 2: diethyl ether 3: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4: aq. NaOH / tetrahydrofuran / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C | ||
Multi-step reaction with 5 steps 1.1: NaOH / tetrahydrofuran 2.1: Cs2CO3 / dimethylformamide; H2O 3.1: 70 percent / CH2Cl2 4.1: PPh3; DEAD; PhCOOH / toluene 4.2: 71 percent / KOH / methanol 5.1: HCOOH / 1,2-dichloro-ethane 5.2: 82 percent / NEt3 / CH2Cl2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C 6.1: morph-DAST / tetrahydrofuran / -78 - 20 °C 7.1: H2 / Pd/C / methanol | ||
Multi-step reaction with 7 steps 1.1: NaOH / tetrahydrofuran 2.1: Cs2CO3 / dimethylformamide; H2O 3.1: 70 percent / CH2Cl2 4.1: PPh3; DEAD; PhCOOH / toluene 4.2: 71 percent / KOH / methanol 5.1: HCOOH / 1,2-dichloro-ethane 5.2: 82 percent / NEt3 / CH2Cl2 6.1: 38 percent / DAST / CH2Cl2 7.1: 96 percent / H2 / Pd/C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 80 percent / aq. NaOH / tetrahydrofuran 2.1: diethyl ether 3.1: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h 4.1: aq. NaOH / tetrahydrofuran / 1 h 5.1: Cs2CO3 / dimethylformamide / 0 °C 5.2: 5.3 g / dimethylformamide / 20 °C 6.1: morph-DAST / tetrahydrofuran / -78 - 20 °C | ||
Multi-step reaction with 6 steps 1.1: NaOH / tetrahydrofuran 2.1: Cs2CO3 / dimethylformamide; H2O 3.1: 70 percent / CH2Cl2 4.1: PPh3; DEAD; PhCOOH / toluene 4.2: 71 percent / KOH / methanol 5.1: HCOOH / 1,2-dichloro-ethane 5.2: 82 percent / NEt3 / CH2Cl2 6.1: 38 percent / DAST / CH2Cl2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 80 percent / aq. NaOH / tetrahydrofuran 2: diethyl ether 3: PPh3P; diisopropyl azodicarboxylate / tetrahydrofuran / 3 h | ||
Multi-step reaction with 3 steps 1: 88 percent / triethylamine / dioxane; H2O; methanol / 4 h / 20 °C 2: 99 percent / methanol; diethyl ether / 0.25 h / 20 °C 3: 90 percent / diethylazodicarboxylate; triphenylphosphine / tetrahydrofuran / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In methanol | 5 Synthesis of the pro3 Monomer Class; Example 5 trans-3-Hydroxy-(L)-proline 39 is commercially available from Acros at $19/gram (2000/2001 catalog) and is the starting point for two diastereomeric members of the pro3 monomer class.First the carboxylate of 39 will be converted to the methyl ester 40 via a Fischer esterification.Next, the amine will be protected using the 9-phenyl-fluorenyl (PhF) group [32] to obtain 41.The alcohol will then be oxidized to the ketone 42 using a TPAP oxidation.This sequence is similar to that used by Kamenecka and co-workers in their enantioselective synthesis of 3-substituted prolines [33].The N-PhF group will protect the a-carbon from epimerization.A Bucherer-Bergs reaction is then carried out to form the two diastereomeric hydantoins 43 and 44.In the event that only one diastereomer is formed selectively, the two step Strecker/Bucherer-Bergs sequence suggested by Edward [34] can be used to obtain the second diastereomer.In either case, access to both diastereomers 43 and 44 is obtained.The diastereomeric hydantoins can be separated by chromatography as in the pro4 monomer class or separated by selective crystallization.The two diastereomeric hydantoins will be carried through independently to form two diastereomeric building blocks.If the hydantoins cannot be separated at this stage, the synthesis can continue with the mixture, with separation of the diastereomers at a later stage. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetyl chloride at 100℃; for 16h; | Acetyl chloride (10.8 mL, 153 mmol) was slowly added to ice cold 100% Ethanol (100 mL). (3S)-3-hydroxy-L-proline (5 g, 38.2 mmol) was added and heated at 100°C for 16 hours. The ester was concentrated to a solid and used without purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (t, J=8.1 Hz, 3 H) 1.9 (m, 2 H) 3.3 (m, 2 H) 4.1 (m, 1 H) 4.2 (q, J=7.1 Hz, 2 H) 4.4 (m, 1 H) 9.0 (s, 1 H) 10.4 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-cyanobenzene sulfonyl chloride; trans-3-hydroxy-L-proline With sodium carbonate In water at 0 - 20℃; Stage #2: With hydrogenchloride Stage #3: diazomethyl-trimethyl-silane In methanol; dichloromethane at 0 - 20℃; for 0.25h; | 2.A EXAMPLE 2 N {N- [ (3-Cyanobenzene) sulfonyl]-3 (S)-tert-butylamino-(L)-prolyl}-4-[ (3', 5'-dichloroisonicotinoyl)- amino]-(L)-phenylalanine (Rl = H), ethyl ester (Rl = CH2CH3), pivaloyloxymethyl ester (Rl = -CH2OC (O) C (CH3) 3), and 1-(ethoxycarbonyloxy) ethyl ester (Rl =-CH (CH3) OC (O) OCH2CH3); Step A : To a solution of (3S)-hydroxy-(L)-proline (Acros, 20 g, 0. 15 mol) and sodium carbonate (26 g, 0. 25 mol) in 500 mL of water at 0°C was added powdered 3-cyanobenzenesulfonyl chloride (25 g, 0. 12 mol). After stirring at rt overnight, the reaction mixture was acidified with concentrated HC1 (pH=3), and the product was extracted with EtOAc (3 x 100 mL). The organic extracts were dried (MgSO4), filtered and concentrated to dryness. The residue was then dissolved in methylene chloride (100 mL) and MeOH (100 mL), and was added trimethylsilyldiazomethane (2 M in ether) at 0°C until a yellow color persisted. After stirring at rt for 15 min, the mixture was concentrated to dryness to give N-[(3- cyanobenzene) sulfonyl]-3 (S)-hydroxy-(L)-proline, methyl ester (31. 5 g) LC-MS : calculated for C13H14N205S 310, observed m/e 311 (M + H) + (2. 3 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydrogencarbonate In water for 20h; | |
With N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 0 - 20℃; | 376 Example 376 (2S,3S)-2-[4-(4-Cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5376) (2S,3S)-3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid (254.5 mg, 1.9 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (500 μL, 2.9 mmol) was added followed by benzyl chloroformate (410 μL, 2.9 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product. | |
With sodium hydrogencarbonate |
In dichloromethane at 0℃; for 0.333333h; | i Compound 1031 (290 mg, 1.09 mmol; Aldrich) in methylene chloride (0.10 Molar) at 0° C. under argon was added CBZ-CL (1.1 equivalents; Aldrich) and the mixture was stirred at 0° C. for 20 min. and then quenched with a few drops of water. Saturated ammonium chloride solution was added (10 mL) and the aqueous layer was washed with ethyl ether. The aqueous layer was then neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×20 mL), dried over MgSO4, and concentrated to afford a yellow oil. The mother liquor is then chromatographed to give the product. Next, to a solution of substrate (0.5 mmol) in anhydrous DMF (5 mL) was added TBDMSCl (1.05 eq: Aldrich), Et3N (1.1 eq), and a catalytic amount of imidazole. The solution was stirred at ambient temperature for 15 hr and then was partitioned between EtOAc (60 mL) and H2O (30 mL). The organic layer was then washed with sat'd NH4Cl (aq.) solution (2×30 mL), water (30 mL), brine (30 mL), dried over MgSO4, and concentrated in vacuo to yield product. The mother liquor is then chromatographed to give the product 1032. | |
With sodium hydrogencarbonate In diethyl ether | 4 The C-ring precursor 6 may be prepared as shown in the reaction scheme above.Commercially available trans-3-hydroxy-L-proline (Sigma-Aldrich) is N-protected (69,84, 8) as the benzyl carbamate 2 and the carboxylic acid is then esterified and subsequently is reduced to the alcohol 4 (30). One of the alcohol groups may be protected with using TBDMS chloride and the N-protecting group may be removed to give the C-ring precursor 6 (84, 85). The following reagents and conditions mayused. | |
With sodium hydroxide In 1,4-dioxane at 0℃; for 5h; | 1.a Step A: Preparation of Intermediate compound 65 To a suspension of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (5.32 g, 40.6 mmol) in dioxane (100 ml) at 0°C was added sodium hydroxide (122 ml, 122 mmol), followed by addition of benzyl chloroformate (6.50 ml, 44.6 mmol) dropwise. The resulting suspension was stirred at 0 °C for 5h. After removing the volatile, the aqueous phase was acidified to pH 3, then partitioned between 30%IPA/DCM(200 ml_) and brine (50 ml_), the aqueous phase was further extracted with 30%IPA/DCM(2x1 OOmL). Combined organic phases were dried over Na2S04 and concentrated to give (2S,3S)-1 -((benzyloxy)carbonyl)-3- hydroxypyrrolidine-2 -carboxylic acid (65). LC/MS: (M+1 )+: 266.1. | |
With sodium hydroxide In 1,4-dioxane; water at 0℃; for 5h; | A Step A Synthesis of intermediate M-1 To a suspension of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (5.32 g, 40.6 mmol) in dioxane (100 ml) at 0°C was added 1N aqueous NaOH (122 ml, 122 mmol), followed by addition of benzyl chloroformate (6.50 ml, 44.6 mmol) dropwise then the resulting suspension was stirred at 0 °C for 5 h. The solution was concentrated, the aqueous layer was acidified to pH 3, partitioned between 30% IPA in DCM (200 mL) and brine (50 mL), and the aqueous phase was further extracted with 30% IPA in DCM (2x100mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give M-1. LC/MS: [M+H]+ = 266.1. | |
With sodium hydroxide In 1,4-dioxane; water at 0℃; for 5h; | A Step A - Synthesis of intermediate E-l To a suspension of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (5.32 g, 40.6 mmol) in dioxane (100 ml) at 0°C was added IN NaOH (122 ml, 122 mmol), followed by addition of benzyl chloroformate (6.50 ml, 44.6 mmol) dropwise then the resulting suspension was stirred at 0 °C for 5 h. The solution was concentrated, the aqueous layer was acidified to pH 3, partitioned between 30% IPA in DCM (200 mL) and brine (50 mL), and the aqueous phase was further extracted with 30% IPA in DCM (2xl00mL). The combined organic layers were dried over Na2SOt, filtered and the filtrate was concentrated to give E-l . LC/MS: [M+H]+ = 266.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In water at 0 - 20℃; | 3.A To a solution of (3S)-hydroxy-(L)-proline (Acros, 1.223 g, 9.324 mmol) and sodium carbonate (2.08 g, 19.63 mmol) in 30 mL of water at O0C was added powdered 3- methylsulfonylbenzenesulfonyl chloride (2.5 g, 9.815 mmol). After stirring at room temperature overnight, the reaction mixture was acidified with concentrated hydrochloric acid (pH=3), and the product was extracted with ethyl acetate (3 x 30 mL). The organic extracts were dried (MgSO-].), filtered and concentrated to dryness. The residue was then dissolved in methylene chloride (10 mL) and methanol (10 mL), and was added trimethylsilyldiazomethane (2 Min ether) at O0C until a yellow color EPO persisted. After stirring at room temperature for 15 min, the mixture was concentrated to dryness to give the title compound (2.6 g, 77%).LC-MS: calculated for C13H17NO7S2 363, observed m/e 364 (M + H)+(2.1 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trans-3-hydroxy-L-proline With hydrogenchloride In 1,4-dioxane; ethanol at 20℃; for 21h; Heating / reflux; Stage #2: With ammonia In methanol at 20℃; for 48h; | F A 4 M solution of HCl in 1,4-dioxan (3 ml) is added to a suspension of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (1 g) in ethanol (10 ml) at room temperature and the mixture heated at reflux for 21 hours. The reaction mixture is evaporated and a 7 M solution of ammonia in methanol (10.5 ml) added. The reaction mixture is stood at room temperature for 2 days then evaporated, the residue triturated with ethanol (2 ml) and filtered and washed cold mixture of 9:1 ethanol/methanol (2 ml) to give the title compound as a pale pink solid. 1H nmr (d6-DMSO, 400 MHz) 8.27 (s, 1H), 7.76 (s, 1H), 5.85 (d, J=4 Hz, 1H), 4.38-4.32 (m, 1H), 3.97 (d, J=2 Hz, 1H), 3.36-3.15 (m, 3H), 1.90-1.80 (m, 2H). | |
Stage #1: trans-3-hydroxy-L-proline With hydrogenchloride In 1,4-dioxane; ethanol at 20℃; for 21h; Heating / reflux; Stage #2: With ammonia In methanol at 20℃; for 48h; | E Intermediate E (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid amide; A 4 M solution of HCI in 1 ,4-dioxan (3 ml) is added to a suspension of (2S,3S)-3- hydroxylpyrrolidine-2-carboxylic acid (1 g) in ethanol (10 ml) at room temperature and the mixture heated at reflux for 21 hours. The reaction mixture is evaporated and a 7 M solution of ammonia in methanol (10.5 ml) added. The reaction mixture is stood at room temperature for 2 days then evaporated, the residue triturated with ethanol (2 ml) and filtered and washed cold mixture of 9:1 ethanol/methanol (2 ml) to give the title compound as a pale pink solid. 1H nmr (d6-DMSO, 400 MHz) 8.27 (s, 1 H), 7.76 (s, 1 H), 5.85 (d, J = 4 Hz, 1 H), 4.38-4.32 (m, 1 H), 3.97 (d, J = 2 Hz, 1 H), 3.36-3.15 (m, 3H), 1.90-1.80 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: trans-3-hydroxy-L-proline; isobutene With toluene-4-sulfonic acid In dichloromethane at -78 - 20℃; for 72h; Stage #2: With sodium hydroxide In dichloromethane; water at 0℃; for 4h; Stage #3: With hydrogenchloride In dichloromethane; water at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: di-<i>tert</i>-butyl dicarbonate; trans-3-hydroxy-L-proline With sodium hydroxide; water In tetrahydrofuran at 20℃; for 19h; Stage #2: With hydrogenchloride In tetrahydrofuran; water Stage #3: benzyl bromide With hydrogenchloride; potassium hydrogencarbonate more than 3 stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride at 0 - 20℃; for 16h; Cooling with ice bath; Inert atmosphere; Heating; Reflux; | 24 Ethyl-(3S)-3-hvdroxy-L-prolinate (2) and 1-tert-butyl 2-ethyl (2S3S)-3- hydroxypyrrolidine-1 ,2-dicarboxylate (3)Thionyl chloride (1.60 mL, 22.0 mmol) was added to a solution of (35)- 3 -hydroxy- L-proline (1) (2.62 g, 20.0 mmol) in ethanol (20.0 mL) that was cooled at 0 °C in an ice-water bath. After the addition was complete, the reaction was warmed to ambient temperature and then heated at reflux for 16 hr. When the reaction was complete (based on TLC analysis, 30% methanol/CHCl3), the reaction was concentrated in vacuo and excess thionyl chloride was removed by dissolving the thick oil several times in absolute ethanol and concentrating to dryness. The crude ester (2) was then dissolved in tetrahydrofuran (100 mL) and water (20 mL) and sodium bicarbonate (8.40 g, 100 mmol) was added. The reaction was cooled at 0 °C and then di-tert- butyldicarbonate (6.5 g, 30 mmol) in tetrahydrofuran (20 mL) was added dropwise via an addition funnel, the water bath was removed, and then the reaction was stirred for 4- 6 hr at ambient temperature. After this period of time, TLC (40% ethyl acetate in hexanes) shows complete consumption of the starting material and formation of a higher Rf product. The reaction was concentrated to remove the THF and then partitioned between ethyl acetate (200 mL) and water (50 mL). The water layer was extracted twice more with 5OmL ethyl acetate, the combined organic layers were washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated to afford the crude product. 1H NMR of the crude material is clean except for residual t-BuOH. The crude product was purified by silica gel chromatography (40 g), eluting with 0,5,10,15,20,25, and 30% ethyl acetate in hexanes to afford the desired product (3), 4.73 g in 91% yield for the two steps. 1H NMR confirms; 1H NMR (400 MHz, CDCl3) 5 ppm 4.46 (d, J= 1.66 Hz, 1 H), 4.21 (m, 3 H), 3.64 (m, 2 H), 2.13 (m, 2 H), 1.93 (m, 1 H), 1.49 (s, 4 H, t-Bu rotamer), 1.44 (s, 5 H, t-Bu rotamer), 1.29 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.27 g | Stage #1: trans-3-hydroxy-L-proline With thionyl chloride In methanol at 0 - 20℃; for 24h; Stage #2: trityl chloride With triethylamine In dichloromethane at 0 - 20℃; | Steps 1 and 2. Preparation of B2-1: Steps 1 and 2. Preparation of B2-1: trans-3-Hydroxy-L-proline (571 mg, 4.35 mmol, Chem-Impex International, Inc.) was suspended in MeOH and cooled to 0 00. Thionyl chloride (1 .6 mL, 22 mmol) was added over 5 mm and the solution was warmed to rt. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure to afford the methyl ester, which was carried on without further purification. The crude ester was suspended in DCM (22 mL) and treatedwith TEA (1 .3 mL, 9.57 mmol). The stirred mixture was cooled to 0 00 and trityl chloride (1 .21 g, 4.35 mmol) was added. The reaction mixture was allowed to gradually come to rt 0/n, and then poured into saturated aqueous NaHCO3. The aqueous layer was extracted three times with DOM. The combined organ ics were dried over Na2SO4, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica gel chromatography (25% to 50% EtOAc/Hex to afford alcohol B2-1 (1.27 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With acetyl chloride at 0 - 65℃; for 6h; | 9 Methyl (35)-3-hydroxy-L-prolinate hydrochloride (9.3) To a stirring solutionof acetyl chloride(7.6 mL, 110 mmol) in methanol (70 mL) at ooc was added (3S)-3-hydroxy-L-proline (9.2, 10.0 g, 76.3mmol) and the reaction was warmed to ambient temperature and was then heated at 65oc for 6 hr. Thereaction was20 cooled to ambienttemperature and was diluted with ether (150 mL) and a white precipitateformed. The white precipitatewas collected by filtration andthe solids were washedwith Et20 (2 x 25 mL) and dried overnightunder reducedpressure to afford compound 9.3 (12.6 g, 91%)as a white solid.1H NMR (400 MHz, DMSO-d6)oG 9.67 (br. s., 2 H), 5.93 (br. s., 1 H), 4.50 (br.s., 1 H), 4.18 (d, J = 2.07 Hz, 1 H), 3.77 (s, 3 H), 3.35 (m, 2 H), 1.94 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: methanol; trans-3-hydroxy-L-proline With thionyl chloride at 0 - 20℃; for 16h; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride In water at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogenchloride In water at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: methanol; trans-3-hydroxy-L-proline With thionyl chloride Stage #2: trityl chloride With triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16%Chromat. | With hydrogenchloride; α-ketoglutaric acid; ammonium iron (II) sulfate; L-proline trans-4-hydroxylase; sodium L-ascorbate In aq. buffer at 21℃; for 14h; Enzymatic reaction; | 1.4.5.1. LC/MS Assays General procedure: Analytical scale proline hydroxylase (PH) incubations were performed by sequential addition of the reagents in Table S1 to a 1.5 mL Eppendorf tube (100 μL final volume): The incubation mixture was kept at 21 °C for 14 h (unless otherwise stated). To quench the reaction, an equal volume of methanol was added and the mixture cooled on ice for 10 min before centrifugation (13,000g for 3 min); the quenching methanol contained 0.25 mM p-aminosalicylic acid (pASA) as an internal standard. The supernatant was decanted and analysed by an LC/MS. ‘Negative controls’ were performed in parallel, but with substitution of 50 mM MES-NaOH, pH 6.5 for the enzyme solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 8h; | A solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (73, 4.90 g, 37.4 mmol), 4 mol/L sodium hydroxide solution (10.5 mL, 37.4 mmol) and di-tert-butyl dicarbonate (13.01 g, 56.1 mol) in a mixed solution of tetrahydrofuran (40 mL) and water (20 mL) was stirred for 8 h at room temperature. After almost half of the solvent was removed under reduced pressure, the pH value of the aqueous layer was adjusted to 2.0 by using 10% potassium hydrogen sulfate solution. The mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over sodium sulfate then concentrated. The residue was washed with a mixed solution of hexane and diethyl ethyl (3/1) to give a colorless solid (7.85 g). To an ice-cooled solution of this solid in tetrahydrofuran (120 mL) was added borane-tetrahydrofuran complex (102 mL, 97.0 mmol). The mixture was stirred for 18 h at room temperature under argon atmosphere. 4 mol/L sodium hydroxide solution (80 mL) was added, and the mixture was stirred for 30 min at room temperature. After the pH value of the solution was adjusted using 2 mol/L hydrochloric acid, the mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over sodium sulfate then concentrated to give the corresponding diol as colorless oil (7.50 g). To an ice-cooled solution of the diol and triethylamine (24.1 mL, 173 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (13.5 mL, 173 mmol). The mixture was stirred for 18 h at room temperature. After water was added, the mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over sodium sulfate then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate; 80:20 to 60:40) to give 74 as colorless oil (11.0 g, 79% over 3 steps). |
Tags: 4298-08-2 synthesis path| 4298-08-2 SDS| 4298-08-2 COA| 4298-08-2 purity| 4298-08-2 application| 4298-08-2 NMR| 4298-08-2 COA| 4298-08-2 structure
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P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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