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Example 14B [(1R)-1-phenylethyl]amino}acetic Acid The product from Example 14A (4.5 g; 15.6 mmol) in water (100 mL) was heated to reflux for 18 hours. The mixture was cooled to 30° C. and concentrated under reduced pressure to provide the title compounds as a white solid (2.7 g; 80percent yield). MS (DCl/NH3) m/z 180 (M+H)+.
The product from Example 14B (27.5 g, 154 mmol) and <strong>[128740-03-4]ethyl allyl(2-oxoethyl)carbamate</strong> (26.3 g, 154 mmol), prepared as described in (U.S. Pat. No. 5,071,999), in toluene (500 mL) were heated at reflux for 17 hours. The solvent was evaporated under reduced pressure to provide the crude product (45 g) as a nearly 1:1 mixture of diastereomers. These were separated by flash chromatography on silica gel, eluting with 30% ethyl acetate in pentane. The more mobile diastereomer was obtained as a thick syrup (Rf=0.42, pentane:ethyl acetate (3:7) 17 g, 38% yield). The stereocenters were determined to be (R,R) using X-Ray diffraction as described in Example 14E. MS (DCl/NH3) m/z 289 (M+H)+. The less mobile diastereomer was obtained as a thick syrup (Rf=0.21, pentane:ethyl acetate (3:7) 17.8 g, 40% yield). The stereocenters were determined to be (S,S) using X-Ray diffraction as described in Example 15B. MS (DCl/NH3) m/z 289 (M+H)+.
EXAMPLE 14B [(1R)-1-phenylethyl]amino}acetic acid The product from Example 14A (4.5 g; 15.6 mmol) in water (100 mL) was heated to reflux for 18 hours. The mixture was cooled to 30 C. and concentrated under reduced pressure to provide the title compounds as a white solid (2.7 g; 80% yield). MS (DCI/NH3) m/z 180 (M+H)+.
80%
With water; for 18.0h;Heating / reflux;
Example 14B [(1R)-1-phenylethyl]amino}acetic Acid The product from Example 14A (4.5 g; 15.6 mmol) in water (100 mL) was heated to reflux for 18 hours. The mixture was cooled to 30 C. and concentrated under reduced pressure to provide the title compounds as a white solid (2.7 g; 80% yield). MS (DCl/NH3) m/z 180 (M+H)+.
methyl 2-[(1R)-1-phenylethyl]amino}acetate[ No CAS ]
[ 78397-15-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium hydroxide; In water;Reflux;
Methyl 2-[(1R)-1-phenylethyl]amino}acetate (Intermediate 44, 587.0 g, 3.0 mol) was refluxed in aqueous KOH (3.36 g, 0.06 mol dissolved in 2.5 L water) overnight. The phases were then separated and the aqueous solution was washed with EtOAc (3 x 1 L). The combined organic solutions were concentrated in vacuo to give the title compound (490 g, 90%) as white solid; 1H NMR: 1.48 (3H, d), 2.89 (1H, d), 3.00 (1H, d), 4.20 (1H, m), 7.37-7.43 (5H, m).
83%
In ethanol; water;
Intermediate 2: R-(1-Phenyl-ethylamino)-acetic acid A mixture of R-(1-phenyl-ethylamino) acetic acid methyl ester (12.3 g, 64 mmol) and water (30 ml) was stirred vigorously and heated at reflux for 24 hours. The mixture was allowed to cool, then washed with ethyl acetate. The aqueous was then evaporated (using ethanol to azeotrope to dryness) to yield the title acid (9.5 g, 83%) as a colourless solid; delta (250 MHz, d6 -DMSO+D2 O) 1.55 (3H, d, J=6.9 Hz, CHCH3), 2.94 (1H, d, J=15.6 Hz, 1 of NCH2 CO2 Me), 3.11 (1H, d, J=15.6 Hz, 1 of NCH2 CO2 Me), 4.31 (1H, q, J=6.8 Hz, CHCH3), 7.42-7.54 (5H, m, Ar-H).
With water; for 13.0h;Heating / reflux;
A solution of (1 -(R)-phenyl-ethylamino)-acetic acid methyl ester (21.7 g of a solution in EtOAc) was concentrated, and the residue was taken up in 24 ml_ of water and heated at reflux for 13 hours. Upon completion, the mixture was concentrated under reduced pressure and 30 ml_ of isopropanol was added. The resulting precipitate was filtered and rinsed with 10 ml_ of isopropanol then dried under reduced pressure to provide 2.4 g of the title compound.
With water; for 13.0h;Heating / reflux;
Example A2(1 -(R)-Phenyl-ethylamino)-acetic acid <n="76"/>A solution of ( 1-{R)-phenyl-ethylamino)-acetic acid methyl ester (21.7 g of a solution in EtOAc) was concentrated, and the residue was taken up in 24 ml_ of water and heated at reflux for 13 hours. Upon completion, the mixture was concentrated under reduced pressure and 30 mL of isopropanol was added. The resulting precipitate was filtered and rinsed with 10 mL of isopropanol then dried under reduced pressure to provide 2 4 g of the title compound.
A solution of (1 -(R)-phenyl-ethylamino)-acetic acid (25.6 g) in 384 ml_ of toluene was heated to 900C. To this 170 g (1.1 equivalents) of a 15.84 wt.% solution of allyl-(2-oxo-ethyl)-carbamic acid ethyl ester (U.S. Pat. No. 5,071 ,999) in toluene, was added over 20 minutes and the mixture was stirred at 900C for 14 hours then at 95C for 12 hours. After cooling, the product was extracted with 2 x 115 g of 20% citric acid solution. The citric acid solution was diluted with 205 ml_ of isopropyl acetate, and the mixture was neutralized with a solution of 51.2 g K2CO3 in 12O g water, and thoroughly shaken. The layers were separated, and the aqueous layer was extracted again with 102 ml_ of isopropyl acetate. The organic extracts were combined and distilled under reduced pressure to provide an oil which was then diluted with 125 ml_ of MeOH to provide 140 g (100% yield) of the title compound as a 30% by weight solution in MeOH.
100%
In toluene; at 90 - 95℃; for 26.3333h;
Example A3 Ethyl 1-((R)-1-phenylethyl)hexahvdropyrrolof2,3-cipyrroie~5(1 H)-carboxy[ate A solution of (1-(R)-phenyl-ethylamino)-acetic acid (25.6 g) in 384 mL of toluene was heated to 90 C To this 170 g (1 1 equivalents) of a 15.84 wt % solution of allyl~(2-oxo-ethyl)-carbamic acid ethy. ester (U.S. Pat. No. 5,071 ,999) in toluene, was added over 20 minutes and the mixture was stirred at 90 0C for 14 hours then at 95 DC for 12 hours After cooling, the product was extracted with 2 x 1 15 g of 20% citric acid solution. The citric acid solution was diluted with 205 mL of isopropyl acetate, and the mixture was neutralized with a solution of 51.2 g K2CO3 in 12O g water, and thoroughly shaken. The layers were separated, and the aqueous layer was extracted again with 102 mL of isopropyl acetate. The organic extracts were combined and distilled under reduced pressure to provide an oil which was then diluted with 125 mL of methanol to provide 14O g (100% yield) of the title compound as a 30% by weight solution in methanol.
A mixture of <strong>[128740-03-4]ethyl N-(2-oxoethyl)-N-prop-2-enylcarbamate</strong> (Intermediate 41, 466 g, 2.7 mol) and 2-[(1R)-1-phenylethyl]amino}acetic acid (Intermediate 43A, 490 g, 2.7 mol) in toluene (4 L) was refluxed overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. Purification by FCC, eluting with 10:1 petrol-EtOAc, gave the title compound (300 g, 38%) as red oil; 1H NMR: (CDCl3) 1.10-1.40 (8H, m), 1.55 (1H, m), 1.90 (1H, m), 2.45 (1H, m), 2.77 (1H, m), 3.20-3.65 (5H, m), 4.10-4.20 (2H, m), 7.25-7.38 (5H, m).
(R)-1-phenylethylaminoacetic acid (25 g, 0.14 mol) was dissolved in toluene (0.34 L). Heated to 90 C, <strong>[128740-03-4]N-allyl-N-(2-oxoethyl)carbamic acid ethyl ester</strong> (26 g, 0.15 mol) was added dropwise the toluene solution was then heated to 110 C for 26 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 15 / 1] purified, The title compound was obtained (19 g, yield 47%). It is a yellow oil.
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