| 89% |
With cis-nitrous acid |
|
| 82% |
With sulfuric acid; sodium nitrite In water at 0℃; for 4h; |
|
| 79% |
With sulfuric acid; sodium nitrite |
|
| 79% |
With sulfuric acid; sodium nitrite In water at 0℃; for 2h; |
|
| 76% |
Stage #1: L-isoleucine With sulfuric acid; sodium nitrite In water at 0℃; for 1.16667h;
Stage #2: In water at 20℃; for 70h; |
|
| 71% |
With sulfuric acid; sodium nitrite In water at 0 - 20℃; |
|
| 65% |
With sulfuric acid; water; sodium nitrite at 0 - 20℃; for 17h; |
4.3. Preparation of (S)-2-hydroxy-4-methylpentanoic acid 2c and (2S,3S)-2-hydroxy-3-methylpentanoic acid 2d
General procedure: To a stirred and cooled to 0 °C, solution of l-leucine or l-iso-leucine (24.92 g, 0.189 mol) in 1.25 M H2SO4 (125 mL), a solution of sodium nitrite (19.73 g, 0.286 mol) in H2O (100 mL) was added dropwise. Next the mixture was stirred at 0 °C for 2 h and then at room temperature for 15 h. After this time, the contents of the flask were extracted with ethyl ether (6 × 75 mL). The organic layer was dried over MgSO4 and diethyl ether evaporated to yield the appropriate crude α-hydroxycarboxylic acid 2c or 2d, which was purified by recrystallization from hexane-ethyl ether mixture. |
| 60% |
With sulfuric acid; sodium nitrite In water for 12h; |
|
| 59% |
With sulfuric acid; sodium nitrite 0 deg C, 2 h, room temperature, 16 h; |
|
| 57% |
With sulfuric acid; sodium nitrite In water at 0 - 20℃; for 168h; |
65 Compound 65a
To L-isoleucine (2 g, 15.2 mmol) in 1 M H2SO4(aq) (30 mL, 0.5 M) at 0°C was added 2 MNaNO2(aq) (11.5 mL, 22.9 mmol) slowly and the reaction was allowed to warm to rt slowly. Afterdays, the reaction was saturated with (NH4)2S04, extracted with EtOAc (3 x 50 mL), dried overNa2SO4 and concentrated in vacuo to afford 65a (1.25 g, 57%) as a white solid. 1H NMR (400MHz, d6-DMSO): 53.77(d, J=4.9 Hz, 1H), 1.66(m, 1H), 1.40(m, 1H), 1.15 (1 H), 0.84(dd, J15.0, 7.2 Hz, 6H). |
| 57% |
With sulfuric acid; sodium nitrite In water at 0 - 20℃; for 18h; Cooling with ice; |
2-3 Synthesis of Compound 4
7.87 g (60 mmol) of l-Ile was dissolved in ice-cold H2S04 (40 mL, 2.5 mol/L). 6.21 g (90 mmol) of NaNC was dissolved in 30 mL of H20, and was added to the above solution dropwise. The mixture was kept at 0 °C for 2 h, then warmed to rt and stirred for another 16 h. After extraction with EtOAc (200 mL x 1, 100 mL x 3), the combined organic phase was washed with brine (50 mL x 1), dried over Na2S04, and concentrated in vacuo, giving the a-hydroxy acid (4.50 g, 57%) as a colorless oil, which was used for next step without further purification. |
| 52% |
With sulfuric acid; sodium nitrite In water at 0 - 20℃; |
|
| 43% |
With sulfuric acid; sodium nitrite In water |
|
| 43% |
With sulfuric acid; sodium nitrite In water stereoselective reaction; |
|
| 40% |
With sulfuric acid; water; sodium nitrite for 13h; |
|
| 21% |
With tert.-butylnitrite In 1,4-dioxane; water at 20℃; for 1h; Inert atmosphere; |
α-Hydroxy carboxylic acids
General procedure: The Boc-protected amino acid (1 mmol) was treated with TFA (3 mL) for 15 minutes. Afterevaporation the residue was dissolved in dioxane-water (1:1, 4 mL) and the flask wasplaced in an ice bath. tert-Butylnitrite (0.13 mL, 1.1 mmol) was added and stirring wasmaintained under nitrogen at room temperature for one hour. After pouring the reactionmixture onto celite and evaporation (50 Pa, 30 °C) into a dry free-floating powder,separation was performed utilizing a CombiFlash Rf (Teledyne ISCO) automated flashchromatography apparatus by means of AcOH-MeOH-EtOAc (1:9:90) on a normal phasesilica column affording the pure a-hydroxy carboxylic acid in the yield specified in Table 1.HO-His(Bom)-OH and HO-Arg(Tos)-OH were isolated by adding water (30 mL) to thereaction mixture followed by freeze drying and HPLC purification. |
|
Diazotization; |
|
|
With hydrogenchloride; acetic acid; sodium nitrite |
|
|
With hydrogenchloride; sodium nitrite In water; acetic acid Ambient temperature; |
|
|
With sulfuric acid; sodium nitrite at 0℃; |
|
|
With hydrogenchloride; sulfuric acid; sodium nitrite 2.) EtOH; Yield given. Multistep reaction; |
|
|
With sulfuric acid; sodium nitrite In water 1.) 0 deg C, 1 h, 2.) room temperature, 12 h; |
|
| 133 mg |
With sulfuric acid; sodium nitrite at 0 - 20℃; |
|
|
With sulfuric acid; sodium nitrite In water at 0℃; for 24h; |
|
|
Stage #1: L-isoleucine With acetic acid; sodium nitrite In water
Stage #2: With potassium carbonate In methanol; water |
|
|
With hydrogenchloride; sodium nitrite at 0℃; for 6h; |
|
|
Stage #1: L-isoleucine With acetic acid; sodium nitrite In water at -5 - 0℃; for 3h; Inert atmosphere;
Stage #2: With hydrogenchloride; water; methylamine Inert atmosphere; |
|
|
With perchloric acid; sodium nitrite In water at 0℃; Heating; |
|
| 17.3 mg |
With perchloric acid; sodium nitrite In water at 0℃; Reflux; |
|
|
With perchloric acid; water; sodium sulfite at 0 - 100℃; |
|
|
Stage #1: L-isoleucine With perchloric acid; sodium nitrite In water at 0 - 20℃; for 1h;
Stage #2: In water for 0.05h; Reflux; |
|
|
With perchloric acid; water; sodium nitrite at 0℃; Reflux; |
|
|
With perchloric acid; sodium nitrite In water at 0 - 20℃; for 0.5h; |
4.6. Preparation of isomers of 2-hydroxyisoleucic acid (Hila)
General procedure: L-Isoleucine (100 mg, 0.75 mmol) was dissolved in 50 mL of 0.2 N perchloric acid (0 °C). To this was added a cold (0 °C) solution of NaNO2 (1.4 g, 20 mmol) in 20 mL of H2O with rapid stirring. With continued stirring the reaction mixture was allowed to reach r.t. until evolution of N2 subsided (about 30 min). The solution was then brought to boil for 3 min, cooled to r.t., and saturated with NaCl. The mixture was then extracted with Et2O and dried under vacuum to give 2S, 3S-Hila (L-Hila). The three other stereoisomers 2R,3R-Hila (D-Hila), 2R, 3S-Hila (D-allo-Hila), and 2S, 3R-Hila (L-allo- Hila) were synthesized in a similar manner from D-Ile, D-allo-Ile, and L-allo-Ile, respectively (Mamer, 2000; Mamer and Reimer, 1992). |
|
With sulfuric acid; water; sodium nitrite at 0 - 20℃; |
|
|
With sulfuric acid; sodium nitrite at 0℃; for 24h; |
|
|
With sulfuric acid; sodium nitrite In water at 0 - 20℃; |
|
|
With sulfuric acid; sodium nitrite at 0 - 20℃; for 17h; |
|
|
With sulfuric acid; sodium nitrite In water at 5 - 20℃; for 26h; |
|
|
With sulfuric acid; sodium nitrite In water at 5℃; |
|
|
With perchloric acid; sodium nitrite at 0 - 20℃; for 0.05h; |
3.5. Preparation of 2-Hydroxy-3-methylpentanoic Acid (Hmpa)
To a stirring solution of L-Ile (10 mg, 0.076 mmol) in 0.2 M perchloric acid (5 mL) was added acold (0 °C) solution of 1 M NaNO2 (2 mL) at 0 °C. With continued rapid stirring, the reaction mixturewas allowed to reach room temperature until evolution of N2 subsided (about 30 min). The solutionwas then boiled for 3 min, cooled to room temperature, and saturated with NaCl before extraction withEt2O and drying under vacuum to give (2S,3S)-Hmpa (L-Hmpa). The three other stereoisomers(2S,3R)-Hmpa (L-allo-Hmpa), (2R,3R)-Hmpa (D-Hmpa), and (2R,3S)-Hmpa (D-allo-Hmpa) weresynthesized in a similar manner from L-allo-Ile, D-Ile, and D-allo-Ile, respectively. |
|
With sulfuric acid; sodium nitrite at 0 - 20℃; |
The (/yrij-HMP and (i?,i?)-HMP standards were prepared by treating L-isoleucine and D-isoleucine, respectively, with 1 M H2SO4 (0.8 mL) and NaNCh (55 mg) at 0°C. The reactants were stirred for 3 h at 0°C and then stirred overnight at room temperature. Extraction with Et20 provided the crude (L'.L)-HMR and (i?,i?)-HMP products, which were separately stirred overnight with 2-bromo-2'-acetonaphthone (100 mg) and Et3N (50 pL) in 3 mL MeCN. Purification of the products by preparative HPLC (Gemini 5 pm C18 column 250*21.2 mm, 65% MeCN in H2O containing 0.1% TFA) yielded the 2-naphthacyl esters (S.S)- 14a (37 mg) and (i?^?)-14b (39 mg). |
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