| 85% |
With hydrogen bromide; sodium nitrite In water at 0℃; for 2.5h; Inert atmosphere; |
|
| 83% |
With potassium bromide; sodium nitrite In water |
1.A Preparation of (2R) 2-Bromo-4-Methylpentanoic Acid
1A. Formula 2 Where X Is Bromo and R3 Is 2-Methylpropyl A solution of 3.00 g of D-Leu, 9.53 g of KBr in 15 mL of water and 4.5 mL of conc. H2 SO4 was formed and stirred at -4° C. To this solution was added 2.09 g of NaNO2 in 10 mL of water over a period of 1 h. Stirring was continued for 1 h at the same temperature, then the reaction mixture was extracted with CH2 Cl2. The organic layer was washed with water, dried over Na2 SO4 and evaporated under vacuum to give 3.72 g of (2R)-2-bromo-4-methylpentanoic acid at 83% yield as a colorless oil. Characteristic analytical data are as follows: 1 H NMR (300 MHz, CDCl3) d 4.31 (t, J=8 Hz, 1H), 1.94 (t, J=7 Hz, 2H), 1.82 (m, 1H), 0.98 (d, J=7 Hz, 3 H), 0.93 (d, J=7 Hz, 3H); [α]D25 +39.0° (c=2.02, MeOH). |
| 77.6% |
With potassium bromide; sodium nitrite In sulfuric acid; water 2 h, 0 deg C; r.t., overnight; |
|
| 65% |
With hydrogen bromide; sodium nitrite In water at 0 - 20℃; |
|
| 62% |
With nitrosyl bromide |
|
| 57% |
With sodium nitrate; hydrogen bromide at 4℃; for 14h; |
|
|
With nitrosyl bromide |
|
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With potassium bromide; sodium nitrite In sulfuric acid at 0℃; for 1h; |
|
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With hydrogen bromide; potassium bromide; sodium nitrite |
|
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With hydrogen bromide; sodium nitrite In water at 0 - 2℃; for 3h; |
|
|
With hydrogen bromide; sodium nitrite In water |
|
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With sodium nitrite In chloroform; water; hydrogen bromide |
15 Compound of Formula (R)
EXAMPLE 15 Compound of Formula (R) To a solution of D-leucine (50 g, 0.381 mol) in 570 mL of 3N HBr (aq) at 0° C. was added sodium nitrite (42 g, 1.6 eq) portion-wise over 1 hour and 15 minutes. The reaction was further stirred for 3 hrs at 0° C. then it was extracted with ether (1000 mL). After washing the ether layer with water (2*500 mL) it was dried over MgSO4 and concentrated. The red syrup was then co-evaporated with chloroform (3*200 mL) to remove the color and then it was pumped to give (2R)-2-bromo-4-methylpentanoic acid, as a colorless oil with a constant weight of 71.3 g. |
|
With potassium bromide; sodium nitrite In sulfuric acid |
13.a a
a (R)-2-Bromo-4-methylpentanoic acid Potassium bromide (9.5 g., 80 mmol) was added to a stirred solution of D-leucine (3.0 g., 23 mmol) in 2.5N sulfuric acid (47 ml) at room temperature. The reaction mixture was cooled to -10° C. and solid sodium nitrite (2.4 g., 34 mmol) was added portionwise, maintaining the temperature between -10° and -5° C. After addition was complete, the reaction was stirred for 1 hour and then warmed to room temperature and stirred for another hour. The reaction mixture was then extracted twice with ether, the ether extracts were washed once with water, dried (magnesium sulfate), filtered and evaporated to give 2.7 g of crude title product. |
|
With sodium nitrite In chloroform; water; hydrogen bromide |
17 Compound of formula (R)
EXAMPLE 17 Compound of formula (R) To a solution of D-leucine (50 g, 0.381 mol) in 570 mL of 3N HBr (aq) at 0° C. was added sodium nitrite (42 g, 1.6 eq) portion-wise over 1 hour and 15 minutes. The reaction was further stirred for 3 hrs at 0° C. then it was extracted with ether (1000 mL). After washing the ether layer with water (2*500 mL) it was dried over MgSO4 and concentrated. The red syrup was then co-evaporated with chloroform (3*200 mL) to remove the color and then it was pumped to give (2R)-2-bromo-4-methylpentanoic acid, as a colorless oil with a constant weight of 71.3 g. |
|
With hydrogen bromide; sodium nitrite In water at 0℃; |
4
Preparation 4. (S)-2-Acetylsulfanyl-4-methylpentanoic Acid. D-Leucine (8.2 g, 62.7 mmol) was dissolved in 3.0M HBr in water (99 mL, 0.3 mol) and cooled to 0° C. A solution of NaNO2 (6.9 g, 100 mmol) in water (11.3 mL, 627 mmol) was slowly added over 20 minutes. The mixture was stirred at 0° C. for 3 hours and then extracted twice with ethyl ether, washed with water then saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to afford (R)-2-bromo-4-methylpentanoic acid (11.5 g) as an off-yellow oil. This was taken on to the next step without further purification.Thioacetic acid (4.2 g, 54.4 mmol) and DMF (100 mL, 1.0 mol) were combined, and the mixture cooled in an ice bath. Sodium carbonate (5.8 g, 54.4 mmol) was added. After 30 minutes, (R)-2-bromo-4-methylpentanoic acid (10.1 g, 51.8 mmol) in DMF (20 mL) was added dropwise and the mixture was stirred at 0° C. to room temperature over 6 hours. The mixture was diluted with 100 mL EtOAc and extracted with 100 mL of a 1:1 1N HCl: saturated aqueous NaCl solution. The layers were separated and the aqueous phase was extracted with additional EtOAc (100 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was dissolved into diisopropyl ether (45 mL, 320 mmol) and chilled at 0° C. Dicyclohexylamine (10.1 mL, 50.7 mmol) was added dropwise and the solid was allowed to crash out of solution. After stirring for an additional 30 minutes the material was filtered and washed with 75 mL cold diisopropyl ether. The recovered solid (14 g) was suspended in 100 mL EtOAc. 150 mL of 5% KHSO4 was added and the layers were separated. The organic was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was then azeotroped (3×25 mL toluene) to yield the title compound (6.1 g) as a dicyclohexylamine salt. |
|
With hydrogen bromide; sodium nitrite In water at 0℃; for 3.33333h; |
3
D-Leucine (8.2 g, 62.7 mmol) was dissolved in 3.0M HBr in water (99 mL, 0.3 mol) and cooled to 0° C. A solution of NaNO2 (6.9 g, 100 mmol) in water (11.3 mL, 627 mmol) was slowly added over 20 minutes. The mixture was stirred at 0° C. for 3 hours and then extracted twice with ethyl ether, washed with water then saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to afford (R)-2-bromo-4-methylpentanoic acid (11.5 g) as an off- yellow oil. This was taken on to the next step without further purification. |
|
With hydrogen bromide; sodium nitrite In water at 0℃; for 3.33333h; |
4
D-Leucine (8.2 g, 62.7 mmol) was dissolved in 3.0M HBr in water (99 mL, 0.3 mol) and cooled to 0° C. A solution of NaNO2 (6.9 g, 100 mmol) in water (11.3 mL, 627 mmol) was slowly added over 20 minutes. The mixture was stirred at 0° C. for 3 hours and then extracted twice with ethyl ether, washed with water then saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to afford (R)-2-bromo-4-methylpentanoic acid (11.5 g) as an off-yellow oil. This was taken on to the next step without further purification. |
|
With hydrogen bromide; sodium nitrite In water at 0℃; for 3.33333h; |
1
D-leucine (23.3 g, 177.3 mmol, 1.0 eq) was dissolved into 3.0M HBr in water (280 mL, 840 mmol) and cooled to 0° C. A solution of NaNO2 (19.6 g, 284 mmol) in water (31.9 mL, 1.8 mol) was slowly added over 20 minutes and the mixture was stirred at 0° C. for 3 hours. The mixture was extracted with ethyl ether (2*500 mL), washed with water (100 mL) and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated, to yield (R)-2-bromo-4-methylpentanoic acid as an off-yellow yellow oil (33.4 g). |
|
With hydrogen bromide; potassium bromide; sodium nitrite In water at -15 - 20℃; for 3h; Inert atmosphere; |
|
| 3.56 g |
With hydrogen bromide; sodium nitrite In water at 0 - 20℃; for 4h; |
1.B B.Preparation of (R)-2-bromo-4-methylpentanoic acid
The (R)-2-amino-4-methylpentanoic acid (H-D-Leu-OH, 4 g, 30.5 mmol) was dissolved in a mixture of HBr 48% (9.6 mL, 84 mmol) and H2O (30 mL). At 0° C., a solution of NaNO2 (2.62 g, 38 mmol) in H2O (15 mL) was added over a period of 60 min. The reaction was stirred for 1.5 hours at 0° C. and 1.5 hours at room temperature. The reaction mixture was degassed in vacuo and extracted with ethyl acetate (EtOAc) (3*50 mL). The extract was washed with water (50 mL), dried (Na2SO4), filtered and evaporated to give 4.52 g crude as oil. The oil was distillated at high vacuum to obtain 3.56 g of (R)-2-bromo-4-methylpentanoic acid as oil. |
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With sulfuric acid; potassium bromide; sodium nitrite In water |
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Stage #1: (R)-leucine With hydrogen bromide In water at 0℃; for 0.166667h;
Stage #2: With sodium nitrite In water at 0 - 20℃; for 3.5h; |
4.1.2.1. 2-Bromo-4-(methylthio)butanoic acid (35c).
General procedure: To a solution ofDL-methionine (3.0 g, 20.1 mmol) in H2O (50 mL) was added 30% HBr (20 mL). The reaction mixture was stirred at 0 C for 10 min. A solution of sodium nitrite (1.7 g, 24 mmol) in H2O (50 mL) was added. The reaction mixture was stirred at 0 C for 30 min and thenwarmed to rt for 3 h. The reaction mixture was extracted withEtOAc (100 mL 3). The organic layer was washed with brine and dried over Na2SO4. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give 3.6 g of intermediate 35c (83% yield). |
|
With hydrogen bromide; sodium nitrite In water at 0 - 20℃; for 14h; |
2 (R)-2-bromo-4-methylpentanoic acid
A solution of NaNO2 (62.7 g, 909 mmol) in H2O (200 mL) was added to compound D-leucine (75.0 g, 572 mmol) in HBr (6.0 M, 850 mL) at 0° C. The reaction was stirred at 20° C. for 14 hours. Two batches reaction were combined, and then the reaction mixture was extracted with ethyl acetate (1.5 L*2), washed with saturated aqueous NaCl (1.0 L*2), dried over MgSO4, filtered and concentrated under reduced pressure to give compound (R)-2-bromo-4-methylpentanoic acid (230 g, crude) as a red oil. NMR (400 MHz CDCl3) 11.18 (br, 1H), 4.30 (t, J=7.6 Hz, 1H), 1.94 (t, J=7.2 Hz, 2H), 1.80-1.87 (m, 1H), 0.93-0.99 (m, 6H). |
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