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Chemical Structure| 114873-01-7 Chemical Structure| 114873-01-7
Chemical Structure| 114873-01-7

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Boc-Phe(3-F)-OH is a derivative of phenylalanine. Phenylalanine is essential for protein structure and neurotransmitter synthesis. This derivative is valuable in medicinal chemistry and protein engineering and can be used in developing new anti-inflammatory and neurological drugs.

Synonyms: (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3-fluorophenyl)propionic acid; (S)-2-[(tert-Butoxycarbonyl)amino]-3-(3-fluorophenyl)propionic acid; tert-Butoxycarbonyl-L-3-fluorophenylalanine

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Product Details of Boc-Phe(3-F)-OH

CAS No. :114873-01-7
Formula : C14H18FNO4
M.W : 283.30
SMILES Code : O=C(O)[C@H](CC1=CC=CC(F)=C1)NC(OC(C)(C)C)=O
Synonyms :
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3-fluorophenyl)propionic acid; (S)-2-[(tert-Butoxycarbonyl)amino]-3-(3-fluorophenyl)propionic acid; tert-Butoxycarbonyl-L-3-fluorophenylalanine
MDL No. :MFCD00672522
InChI Key :FPCCREICRYPTTL-NSHDSACASA-N
Pubchem ID :2734492

Safety of Boc-Phe(3-F)-OH

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of Boc-Phe(3-F)-OH

* 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.

  • Downstream synthetic route of [ 114873-01-7 ]

[ 114873-01-7 ] Synthesis Path-Downstream   1~35

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YieldReaction ConditionsOperation in experiment
100% To a well stirred solution of Boc-3-fluoro-L-phenylalanine (1.5 g, 5.3 mmol) in chloroform (30 mL), at ambient temperature, was added N, JV-carbonyldiimidazole (1.5 g, 9.3 mmol) as a solid. Carbon dioxide evolution was observed and the mixture was stirred at ambient temperature for 1.5 hours. A solution of -10ml Ammonia in 30 ml THF was added and the mixture was stirred for 10 minutes. The reaction mixture was poured into 250 ml water, acidified with sulfuric acid (^ pH 2) and extracted with chloroform (100 mL). The organic phase was dried over sodium sulfate and concentrated to give 1.5g white (quant.) product.Following all steps of the previous example (19), a 1:1 mixture of amides was obtained, which were purified using flash chromatography with ethyl acetate as the mobile phase.The solvent was removed under vacuum to give the less polar isomer A as a white solid (570 mg) with the following properties: MP: 135-139 0C; 1H NMR (300 MHz, CDCl3) delta 8.44 (IH, s), 7.61 (IH, s), 7.15-6.76 (5H, m), 5.94 (IH, dd, J = 5.4 and 10.5 Hz), 5.69 (IH, NH), 5.47 (IH, t, J = 6.0 Hz), 3.92-3.51 (4H, m) and 2.55-1.92 ppm (4H, m). The more polar isomer B was crystallized from AcOEt/MTBE to give a white solid (585 mg) with the following properties: MP: degradation > 191 0C; 1H NMR (300 MHz, CDCl3) delta 8.70 (IH, s), 7.75 (IH, s), 7.20-6.81 (4H, m), 6.12 (IH, NH), 5.82 (IH, dd, J = 8.1 and 9.6 Hz), 5.60 (IH, t, J = 5.7 Hz), 5.60 (IH, NH), 3.95-3.62 (4H, m) and 2.56-1.96 ppm (4H, m).
74% With ammonium carbonate; 1-hydroxybenzotriazol-hydrate; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; To a solution of Int-1 (1.5 g, 5.29 mmol) and DMF (15 mL), DIPEA (2.77mL, 15.9 mmol), HATU (3.02 g, 7.94 mmol), HOBt monohydrate (715 mg, 5.29 mmol) and ammonium carbonate (4.19 g, 52.9 mmol) were added and was allowed to stir at room temperature overnight. After completion of the reaction, the mixture was diluted with ether and the organic layer was washed with water (x2) followed by brine, dried using sodium sulfate, filtered and concentrated under reduced pressure to afford 1.1 g (74% yield) an off-white solid of Int-2. LCMS (+ESI) M+H+(-Boc) = 183.1. 1H NMR (400 MHz, CHLOROFORM-d) d = 7.30 - 7.26 (m, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.02 (br s, 1H), 5.60 (br s, 1H), 5.11 (br d, J = 8.0 Hz, 1H), 4.39 (br d, J = 6.0 Hz, 1H), 3.07 (m, 2H), 1.41 (s, 9H).
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YieldReaction ConditionsOperation in experiment
100% A mixture of L-2-AMINO-3- (3-FLUORO- phenyl)-propionic acid (20.0 g, 110 MMOL, 1 eq) in H20 (100 mL) was treated with NA2CO3 (16.2 g, 153 mmol, 1.4 eq) in H20 (40 mL) followed by 1,4-dioxane (100 mL) and cooled to 0 C. The BOZO was added and the reaction mixture was stirred at ambient temperature for 5 h after which the- dioxane was evaporated. H2O (125 mL) was then added and the mixture then washed with Et2O (2 x 100 mL). The aqueous phase was acidified with 10% citric acid followed by extraction with EtOAc (2 x 300 mL). The combined EtOAc layers were washed with H20 (2 x 150 mL), brine (150 mL), dried (Na2SO4) and concentrated to give the acid as a colorless, viscous oil which slowly solidified upon standing (31 G, QUANT). H NMR (CDC13) 7.33-7. 26 (m, 1H), 7.00-6. 91 (m, 3H), 4.96 (s, 1H), 4.62 (bs, 1H), 3.23 (dd, J=14, 5.3, 2H), 1. 44 (s, 9H) ; Anal CALCD for C14HL8NO4F : C, 59.36 ; H, 6.40 ; N, 4.94. Found: C, 59.29 ; H, 6.34 ; N, 4.90.
100% With sodium carbonate; In 1,4-dioxane; water; at 0 - 25℃; for 5h; A mixture of BOC-L-3-fluorophenylalanine 1 (20 g, 109 MMOL) in water was treated with sodium carbonate (16.2 g, 15.3 MMOL) in H20 (40 mL). 1,4-Dioxane (100 mL) was added, and the mixture cooled to 0 C. The BOC20 (28. 6 g, 120 MMOL) was added in one portion, and the mixture was maintained for 5 h at 25 C. The solvent was evaporated and H2O (125 mL) was added. The aqueous layer was washed with diethyl ether (2 x 100 mL). The ether layers were discarded, and the aqueous layer was acidified with a 10% citric acid solution. The mixture was then extracted with EtOAc (2 x 150 mL). The organic layers were combined, washed with H20 (2 x 150 mL), Brine (150 mL), dried (NA2SO4), filtered and evaporated to give the desire crude product 2 as a clear viscous oil. 30.9 9, 100%, ) which slowly solidified to a white solid at rt. 1H NMR (300 MHz, CDCl3) 8 7.33-7. 26 (M, 1H), 7.00-6. 91 (m, 3H), 4.96 (s, 1H), 4.62 (bs, 1H), 3.23 (dd, J= 14,5. 3 Hz, 2H), 1.44 (s, 9H) ppm; Anal CALCD for CR4HR8NO4F : C, 59.36 ; H, 6.40 ; N, 4.94. Found: C, 59.29 ; H, 6.34 ; N, 4.90.
97% With sodium hydrogencarbonate; In tetrahydrofuran; water;pH 9.0; 3-Fluoro-L-Phenylalanine (1 g, 5.46 mmol, Combi-blocks, Cat SS-0819, Lot L78093) was dissolved in THF (15 mL) and water (15 mL) and the pH of the solution was adjusted to 9 using saturated sodium bicarbonate solution. Di -tert- butyl -di carbonate (1.31 g, 6 mmol) was added to the solution slowly and was stirred overnight. After completion of the reaction, the pH of the solution was adjusted to 4 using 0.1 M HC1 and the aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with water (x2) followed by brine, dried using sodium sulfate, filtered and concentrated under reduced pressure to afford 1.5 g (97% yield) off-white solid of the title product (Int-1). LCMS (+ESI) M+H+(-Boc)=l 84.1.
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  • Boc-βAla-benzhydrylamine resin [ No CAS ]
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  • S-p-MeBzl-Nα-Boc-D-Pen Merrifield [ No CAS ]
  • Tyr-D-Cys-m-FPhe-D-Pen-OH [ No CAS ]
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  • 2-<i>tert</i>-butoxycarbonylamino-3-(3-fluoro-phenyl)-propionic acid benzotriazol-1-yl ester [ No CAS ]
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  • [1-(cyanomethyl-carbamoyl)-2-(3-fluoro-phenyl)-ethyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
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  • (R)-N-{(S)-2-(3-Fluoro-phenyl)-1-[(S)-4-guanidino-1-(thiazole-2-carbonyl)-butylcarbamoyl]-ethyl}-3-phenyl-2-phenylmethanesulfonylamino-propionamide [ No CAS ]
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  • (S)-2-Amino-N-benzyl-3-(3-fluoro-phenyl)-N-methyl-propionamide; hydrochloride [ No CAS ]
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  • <(1-methyl-1H-indol-3-yl)carbonyl>-(2S,4R)Hyp-Phe(3-F)-NMeBzl [ No CAS ]
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  • (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid [(S)-1-(benzyl-methyl-carbamoyl)-2-(3-fluoro-phenyl)-ethyl]-amide; hydrochloride [ No CAS ]
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  • (S)-2-amino-3-(3-fluorophenyl)propenamide hydrochloride [ No CAS ]
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  • (S)-2-[(2-Amino-acetyl)-ethyl-amino]-3-(3-fluoro-phenyl)-propionamide; hydrochloride [ No CAS ]
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  • (R)-2-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-5-guanidino-pentanoic acid ([(S)-1-carbamoyl-2-(3-fluoro-phenyl)-ethyl]-ethyl-carbamoyl}-methyl)-amide; compound with acetic acid [ No CAS ]
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YieldReaction ConditionsOperation in experiment
90 - 92% N'-Methoxy-N'-methyl (S)-N-BOC- (3-fluorophenvl) alanine amide (VII-3) : In a 1 L 4N-flask equipped with addition funnel, cold temperature thermometer, under nitrogen gas and mechanical stirrer, combined BOC- (3-fluorophenyl) alanine (VIII-3) (56.6 g, 0.2 moles) and methylene chloride. This was stirred to give a solution and N-methylmorpholine (23.05 ml, 0.21 moles) was added with a slight exotherm of 18C to 24C. The solution was cooled to-25C and isobutyl chloroformate (25.27 mi, 0.195 moles) was added over a 2 to3 minute period while keeping the temperature from-25C to-20C. A precipitate formed as the reaction mixture was stirred at-20C to-10C for one hour. In a separate flask, a slurry of N, O- dimethylhydroxylamine hydrochloride (21.45 g, 0.22 moles) was treated with N- methylmorpholine (24.15 ml, 0.22 moles) at room temperature. The reaction remained a slurry throughout as the N-methylmorpholine hydrochloride formed. After one hour, the hydroxylamine suspension was added over 30 minutes to the mixed anhydride with the temperature rising to 5C. The mixture was stirred at room temperature over the weekend. The reaction was quenched with a solution of citric acid (50 g) in water (200 ml). The organic layer was separated and washed with water, saturated sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate filtered and evaporated to an oil, which was pumped at high vacuum to remove residual solvents. The crude yield was 61.7 g, 97% by weight and 90-92% corrected for HPLC purity assay. The NMR showed the presence of an impurity which was thought to be the N, O-dimethylhydroxylamine sec-butyl carbamate. This was suitable for use in the next step without purification. HPLC: 97.33% desired amide; 1.57% enantiomer. (Starting BOC-AA was 1.7% enantiomer. [a] o : 21.8 (c = 1.0, methylene chloride). 1H NMR (CDCI3, 400 MHz) : 57. 22 (q, 1), 6.93-6. 85 (m, 3), 5.24 (m, 1), 4.91 (m, 1), 3.66 (s, 3), 3.15 (s, 3), 3.02 (abx, 1), 2.84 (abx, 1), 1.36 (s, 9). 13C NMR (CDCI3, 100 MHz): 172.1, 164.1, 155.3, 129.985, 129.903, 125.345, 125.323, 116.663, 116.454, 113.963. 113.754, 79.9, 61.8, 51.6, 38.7, 32.3, 28.5. LCMS exact mass measurement: C6H23N204F+Na+ ; Calcd : 349.1540 ; Measured: 349.1548.
89% To a solution of L-2-TERF-BUTOXYCARBONYLAMINO-3- (3-FLUORO-PHENYL)-PROPIONIC acid (30.9 g, 109 MMOL) in THF (180 mL) was added CARBONYIDIIMIDAZOLE (21.2 G, 131 mmol, 1.2 eq). After stirring the solution at ambient temperature for 45 min was added DMF (64 mL), N, O-dimethylhydroxylamine hydrochloride (11.7 g, 120 mmol, 1.1 eq) and diisopropylethylamine (20 mL, 113 mmol, 1.04 eq). After stirring for a total time of 2 h, the solvents were evaporated IN VACUO and the oily residue dissolved in EtOAc (300 mL). The organic phase was washed with H2O (500 mL), 10% citric acid (2 x 150 mL), H20 (500 mL), sat'd Na2CO3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated to give the product suitable for further use (31.6 g, 89%). H NMR (CDCl3) 7.29-7. 22 (m, 1H), 6.98-6. 89 (m, 3H), 5.20 (bs, 1H), 4.96 (bs, 1H), 3.72 (s, 3H), 3.19 (s, 3H), 3.07 (dd, J= 13.6, 5.9, 2H), 1.41 (s, 9H). ANAL CALCD for C, 6H23N204F : C, 58.88 ; H, 7.10 ; N, 8.58. Found: C, 58.89 ; H, 7.19 ; N, 8.71.
89% Amino acid 2 (30.9 g, 109 MMOL) was added THF (180 mL) and stirred until the solution was homogeneous. CARBONYL DIIMIDAZOLE (21.2 g, 131 MMOL) was added slowly. Gas evolution was observed and the solution became a yellow color. This solution was maintained at 25 C for 45 min and DMF (64 mL), N, O-dimethylhydroxylamine hydrochloride (11.7 g, 120 MMOL) and Hunig base (19.8 mL, 120 MMOL) were added. The solution was left to stir at 25 C for 2 h 15 min and the solvents were evaporated under vacuum. The oily residue was partitioned in EtOAc (300 mL) and washed with H2O (500 mL), 10% aqueous citric acid (2 x 150 mL), H2O (500 mL), saturated aqueous NA2CO3 (200 mL), and Brine (200 mL) followed by drying (NA2SO4). Filtration and evaporation of the organic solution provided the Weinreb amide intermediate 3 (31.6 G, 89%) which was taken on to the next step without further PURIFICATION. H NMR (300 MHz, CDCI3) a 7. 29-7.22 (m, 1H), 6.98-6. 89 (m, 3H), 5.20 (bs, 1H), 4.96 (bs, 1H), 3. 72 (s, 3H), 3.19 (s, 3H), 3.07 (dd, J= 13. 6,5. 9 Hz, 2H, ), 1.41 (s, 9H) ppm; Anal Calcd FOR C16H23N204F : C, 58.88 ; H, 7.10 ; N, 8.58. Found: C, 58.89 ; H, 7.19 ; N, 8.71.
INTERMEDIATE 34 <n="56"/>(lS)-l-(3-FIuorobenzyl)prop-2-vnylamine hydrochloride; To a well stirred solution of Boc-3-fluoro-L-phenylalanine (2.00 g, 7.06 mmol in dichloromethane (10 ml), at ambient temperature under nitrogen, was added N,N- carbonyldiimidazole (1.32 g, 8.14 mmol) as a solid. Carbon dioxide evolution was observed and the mixture was stirred at ambient temperature for 3 hour. Solid N,O- dimethylhydroxylamine hydrochloride (0.878 g, 8.82 mmol) was added followed by the slow addition of triethylamine (1.23 ml, 8.82 mmol) via syringe. The cloudy slurry was diluted with dichloromethane (5ml) to give a clear solution that was stirred at ambient temperature for 1 hour. The reaction mixture was poured into 10% citric acid (20 ml) and extracted with dichloromethane (4x20 ml). The organic phases were combined, dried over sodium sulfate and concentrated to give the crude product as a solid. This material was subjected to chromatography on silica gel (Merck Kieselgel 60, 230-400mesh, 90 g, elution with 25% EtOAc/hexane) to give (5)-[2-(3-fluorophenyl)-l-(methoxymethyl-carbamoyl)-ethyl]- carbamic acid tert-butyl ester as a white crystalline solid: 1H NMR (400 MHz, CDCl3) delta 1.41 (9 H, s), 2.87 (1 H, dd, J=13.58, 7.36 Hz), 3.07 (1 H, dd, J=13.6, 5.70 Hz), 3.20 (3 H, s), 3.71 (3 H, s), 4.94 (1 H, m), 5.20 (1 H, d, J=8.71 Hz), 6.93 (3 H, m), 7.26 ppm (1 H, m). MS (ESI+) for Ci6H23FN2O4 m/z 349.1 (M+Na)+.To a cold (-45 C; ACN - dry ice bath) well stirred slurry of 0S)-[2-(3 -fluorophenyl)- 1- (methoxymethylcarbamoyl)ethyl]carbamic acid tert-butyl ester (11.46 g, 35.1 mmol) in dry diethyl ether (300 ml) was added LiAlH4 (1.0 M in diethyl ether, 43.9 mmol) slowly via syringe. This mixture was stirred at -45 C for 1 hour and slowly, carefully quenched with a solution of potassium bisulfate (8.37 g, 61.4 mmol) in water (80 ml). This slurry was allowed to warm to ambient temperature, diluted with ethyl acetate (200 ml) and filtered through a Celite plug. The solids were washed with ethyl acetate and the filtrates combined and separated. The organic phases were washed with 10% citric acid, saturated sodium bicarbonate, and brine, dried over sodium sulfate and concentrated. This provided (iS)-[l-(3- fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid: 1H NMR (400 <n="57"/>MHz, CDCl3) delta 1.45 (9 H, s), 3.14 (2 H, m), 4.43 (1 H, m), 5.08 (1 H, m), 6.96 (3 H, m), 7.28 (1 H, m), 9.65 ppm (1 H, s). MS (ESI-) for C14H18FNO3 m/z 266.2 (M-H)'To a cold (-33 C; FTS Flexicool) well-stirred mixture of carbon tetrabromide (23.3 g, 70.2 mmol), triphenylphosphine (36.8 g, 0.140 mol) and dichloromethane (500 ml) under nitrogen was dropwise added a solution of (S)-[l-(3-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert- butyl ester (9.38 g, 35.1 mmol) in dichloromethane (100 ml). Stirring was continued for 1 hour, the reaction was quenched with saturated sodium bicarbonate (100 ml) and extracted with methylene chloride (3 x 100ml). The organic phases were combined, dried over sodium sulfate, and passed through a silica gel plug (~100 g). This plug was washed with additional dichloromethane (200 ml), the filtrates were combined and concentrated. The residue was chromatographed on silica gel (Merck Kieselgel 60, 230-400 mesh, 350 g, elution with dichloromethane) and the mixed fractions re-chromatographed similarly. The pure fractions from both columns were combined to give 10.05 g of (5)-[3,3-dibromo-l-(3-fluorobenzyl)- allyl]-carbamic acid tert-butyl ester as a white solid. The product was re-crystallized from 1 :1 hexane/ether to provide enantiomerically pure product: 1H NMR (400 MHz, CDCl3) delta 1.43 (9 H, s), 2.91 (2 H, m), 4.49 (1 H, m), 4.57 (1 H, m), 6.41 (1 H, m), 6.95 (3 H, m), 7.31 ppm (1 H, m). MS (ESI+) for C15Hi8Br2FNO2 m/z 445.9 (M+Na)+To a cold (-78 0C), well stirred solution of (S)-[3,3-dibromo-l-(3-fluorobenzyl)allyl]carbamic acid tert-butyl ester (4.25 g, 10.0 mmol) in dry tetrahydrofuran (50 mL) was added 1.35 M of n-butyllitliium in hexane (23.8 ml) over a period of 15 min. After 2.5 hr at -78 C, the reaction was quenched with saturated ammonium chloride (30 ml) and diluted with diethyl ether (100 ml). This mixture was allowed to warm to ambient temperature and extracted with diethyl ether (4x100 ml). The organic phases were combined, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (Merck Kieselgel 60, 230-400 mesh, 150 g, elution with 20% ethyl acetate/hexane) to give (S)-[I -(3-fluorobenzyl)-prop-2- ynyl]-carbamic acid tert-butyl ester which solidified under vacuum: 1H NMR (400 MHz, CDCl3) delta 1.45 (9 H, s), 2.32 (1 H, s), 2.97 (2 H, m), 4.70 (2 H, m), 7.01 (3 H, m), 7.30 ppm (1 H, m); 13C NMR (CDCl3) delta 162.67 (d, J = 246 Hz), 154.52, 138.84 (d, J = 7.3 Hz), 129.68 (d, J = 8.1 Hz), 125.43 (d, J = 2.9 Hz), 116.68 (d, J = 21.2 Hz), 113.81 (d, J = 20.5 Hz), 82.38, 80.15, 72.50, 43.70, 41.42, 28.29 ppm (3C). MS (ESI+) for C15Hi8FNO2 m/z 286.1 (...

  • 30
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  • (S)-[2-(3-fluorophenyl)-1-(methoxymethyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a well stirred solution of Boc-3-fluoro-L-phenylalanine (2.00 g, 7.06 mmol in dichloromethane (10 mL), at ambient temperature under nitrogen, was added N5N- carbonyldiimidazole (1.32 g, 8.14 mmol) as a solid. Carbon dioxide evolution was observed and the mixture was stirred at ambient temperature for 3 hour. Solid N5O- dimethylhydroxylamine hydrochloride (0.878 g, 8.82 mmol) was added followed by the slow addition of triethylamine (1.23 mL, 8.82 mmol) via syringe. The cloudy slurry was diluted with dichloromethane (5mL) to give a clear solution that was stirred at ambient temperature for 1 hour. The reaction mixture was poured into 10% citric acid (20 mL) and extracted with dichloromethane (4chi20mL). The organic phases were combined, dried over sodium sulfate and concentrated to give the crude product as a solid. This material was subjected to chromatography on silica gel (Merck Kieselgel 60, 230-400mesh, 90 g, elution with 25% EtOAc/hexane) to give 2.25 g of (S)-[2-(3-fluorophenyl)-l-(methoxymethyl-carbamoyl)- ethyl]-carbamic acid tert-butyl ester as a white crystalline solid. 1H NMR (400 MHz, CDCl3) delta 1.41 (9 H, s), 2.87 (1 H, dd, J=13.58, 7.36 Hz)5 3.07 (1 H, dd, J=13.6, 5.70 Hz), 3.20 (3 H, s), 3.71 (3 H5 s), 4.94 (1 H, m), 5.20 (1 H5 d, J=8.71 Hz), 6.93 (3 H5 m), 7.26 ppm (1 H5 m). MS (ESI+) for Ci6H23FN2O4 m/z 349.1 (M+Na)+
  • 31
  • [ 114873-01-7 ]
  • [ 74-89-5 ]
  • [ 1039454-05-1 ]
YieldReaction ConditionsOperation in experiment
100% To a well stirred solution of Boc-3-fluoro-L-phenylalanine (1.41 g, 5.0 mmol, Peptech) in chloroform (30 mL), at ambient temperature, was added N,iV-carbonyldiimidazole (1.3 g, 8.0 mmol) as a solid. Carbon dioxide evolution was observed and the mixture was stirred at ambient temperature for 1.5 hours. A solution of ~5ml Methylamine inlO ml THF was added and the mixture was stirred for 10 minutes. The reaction mixture was poured into 100 ml water, acidified with sulfuric acid (^ pH 2) and extracted with chloroform (2x 75mL). The organic phases were combined, dried over sodium sulfate and concentrated to give the crude product. This material was subjected to chromatography on silica gel (Merck Kieselgel 60, 230-400mesh, 50 g, elution with EtOAc/Chloroform 1/1) to give 1.48 g (quant.) of (5)-[2-(3- fluorophenyl)]-loxo-l-(methyamino)-carbamic acid tert-butyl ester as a white crystalline solid.The amide from the previous step (1.0 g, 3.3 mmol) was dissolved in chloroform (40 mL) and trifluoroacetic acid (5 mL) was added. After 35 minutes the solvent was evaporated by vacuum and methylene chloride (80 mL, saturated with HCl gas) was added, then removed by high vacuum. The last step was repeated once to give a solid which was dissolved in DMF (60 mL), the nitro acid derivative from Example 1 (977 mg, 3.5 mmol) was added, followed by DMAP (416 mg, 3.4 mmol), HOBT (460 mg, 3.4 mmol), triethylamine (2 mL, 14.4 mmol), and EDCI (2.0 g, 10.6 mmol). The mixture was stirred at 45 0C for 18 hr. The DMF was removed under vacuum, water (100 mL) was added and the pH was adjusted to 2 using 2M sulfuric acid. The product was extracted with ethyl acetate (100 mL) and washed with <n="58"/>sodium bicarbonate solution (100 mL). The acidic phase was extracted a second time with ethyl acetate (100 mL) and the product was washed with sodium bicarbonate solution (100 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under vacuum to yield a yellow foam. The product was further purified using flash chromatography with ethyl acetate as the mobile phase. The solvent was removed under vacuum to give 1046 mg of a 1 : 1 mixture of the two isomers.The product from the previous step (754 mg, 1.65 mmol) was dissolved in a mixture of THF (50 mL) and methanol (50 mL). The Zn/Cu reagent (1Og) was prepared according to the procedure in Example 3. The fresh Zn/Cu reagent was added to the above solution and stirred at ambient temperature. Formic acid (3 ml) was added and the mixture was stirred for an additional 15 min. The solids were filtered off, first washed with a mixture of THF (35 mL) and methanol (35 mL). The filtrate was concentrated to dryness under vacuum. The solid was dissolved in DMF (30 mL) and isoamyl nitrite (4 mL) was added. After 18 hr at ambient temperature, DMF was removed under vacuum, and the product was purified using flash chromatography with ethyl acetate as the mobile phase.The solvent was removed under vacuum to give the less polar Isomer A as a white solid (210 mg) with the following properties: MP: 147 - 150 0C; 1H NMR (300 MHz, CDCl3) delta 8.49 (IH, s), 7.63 (IH, s), 7.15-6.75 (4H, m), 6.71 (IH, m), 5.88 (IH, dd, J = 5.4 and 10.2 Hz), 5.49 (IH, t, J = 6.3 Hz), 3.92-3.50 (4H, m), 2.84 (3H, d, J = 4.8 Hz), 2.55-1.90 ppm (4H, m). The more polar isomer B was crystallized from methylenchloride/MTBE to give a white solid (125 mg) with the following properties: MP: 196 - 197 0C; 1H NMR (300 MHz, CDCl3) delta 8.72 (IH, s), 7.75 (IH, s), 7.19-6.81 (4H, m), 6.11 (IH, m), 5.77 (IH, dd, J = 6.5 and 9.0 Hz), 5.60 (IH, t, J = 5.7 Hz), 3.95-3.60 (4H, m), 2.81 (3H, d, J = 4.8 Hz), 2.60-1.96 ppm (4H, m).
  • 32
  • [ 114873-01-7 ]
  • [ 944470-56-8 ]
YieldReaction ConditionsOperation in experiment
74% To a solution of N-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (10 g, 35.3 mmol) in THF (200 ml.) at 0 0C stirred was added BH3-THF (88 ml_, 88 mmol-1 M in THF). After 12h, the reaction was quenched with AcOH:MeOH (8:50, 58 ml.) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were concentrated and the residue passed through a pad of silica gel (hexanes/EtOAc, 1 :1 ) to afford the product compound (7.0 g, 74%) as a white solid: LCMS (ES) m/e 270 (M+H)+.
74% To a solution of N-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (10 g, 35.3 mmol) in THF (200 mL) at 0 0C stirred was added BH3-THF (88 ml_, 88 mmoM M in THF). After 12h, the reaction was quenched with AcOH:MeOH (8:50, 58 mL) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then <n="31"/>extracted several times with DCM. The combined organic fractions were concentrated and the residue passed through a pad of silica gel (hexanes/EtOAc, 1 : 1 ) to afford the product compound (7.0 g, 74%) as a white solid: LCMS (ES) m/e 270 (M+H)+.
74% Preparation 1 Preparation of 2-r(2S)-2-amino-3-(3-fluorophenyl)propyll-1 /-/-isoindole-1 ,3(2/-/)-dione a) 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1-(hydroxymethyl)ethyl]carbamate To a solution of N-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (10 g, 35.3 mmol) in THF (200 ml.) at 0 0C stirred was added BH3-THF (88 ml_, 88 mmol-1 M in THF). After 12h, the reaction was quenched with AcOH:MeOH (8:50, 58 ml.) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were concentrated and the residue passed through a pad of silica gel (hexanes/EtOAc, 1 :1 ) to afford the product compound (7.0 g, 74%) as a white solid: LCMS (ES) m/e 270 (M+H)+.
70% With borane; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; Boc-L-3-fluorophenylalanine (1.0g, 3.5 mmol)) was dissolved in dry THF (15ml) at 0 0C under N2. BH3 (1 M in THF, 9.6ml) was added dropwise. The reaction was stirred for 30 min before it was warmed up to rt. Methanol was added to quench the excess BH3. The mixture was washed with brine, dried over MgSO4. The solvent was removed under vacuum and the residue was purified on Biotage (30% EtOAc/hexane) to give 0.66g of white solid 1 b (70%).
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3h; Step A tert-butyl[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]carbamate To a solution of <strong>[114873-01-7](2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propanoic acid</strong> [Aldrich] (3.00 g, 10.6 mmol) in tetrahydrofuran (30 mL, 400 mmol) at 0 C. was added 1.0 M borane-THF complex in tetrahydrofuran (32 mL, 32 mmol). The reaction mixture was stirred at room temperature for 3 hrs, cooled with an ice bath, quenched with AcOH:MeOH (1:5, 10 mL and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure. The residue was used directly for the next reaction. LCMS (ES) m/e 270 (M+H)+.

  • 33
  • [ 885223-59-6 ]
  • [ 114873-01-7 ]
  • C24H25FN6O3S [ No CAS ]
  • 34
  • [ 114873-01-7 ]
  • [ 244152-11-2 ]
  • [ 1226790-30-2 ]
  • 35
  • [ 114873-01-7 ]
  • [ 74-88-4 ]
  • methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluorophenyl)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% [00271] Synthesis of N-2-heptenoyl-3-fluorophenylalanine-COOH (9):[00272] N-Boc-L-3-fluorophenyl-L-alanine (500 mg, 1.76 mmol) and NaHC03 (300 mg, 3.6 mmol) were dissolved in 10 mL DMF. Mel (1 mL, 16 mmol) was added dropwise and the mixture stirred for 24h. Reaction mixture was then partition in 25mL EtOAc 25 mL 0.1N HC1 and 25 mL brine, then dried over Na2S04 and concentrated in vacuo. Yield: 500 mg (1.68 mmol, 96%). N-Boc-L-3-fluorophenyl-L-alanine methyl ester product (500 mg, 1.7 mmol) was dissolved in 6.75 mL DCM and 4.3 mL 9: 1 TFA:H20 added at 0C. Reaction was allowed to warm up to room temperature and stirred for 2 h 2 x lOOmL toluene successively added and removed in vacuo. Yield: 510 mg of TFA salt of L-3-fluorophenyl-L- alanine methyl ester (1.63 mmol, 93%). The product (650 mg, 2.09 mmol) was dissolved in 25 mL dry DCM and 3 mL DIEA added and was added to a separate flask containing HATU (1.14 g, 3 mmol) and iraw5,-2-heptenoic acid (350 mu, 2.6 mmol) in 15mL DCM and the mixture stirred overnight. The reaction mixture was then washed with 30mL 0.1N HC1, dried over Na2S04 and concentrated under vacuum, then purified by flash Si gel chromatography with 1: 1 EtOAc:hexanes as eluent. Rf=0.95 (1: 1 EtOAc:hexanes). /V-2-heptenoyl-3- fluorophenylalanine methyl ester (400 mg, 1.3 mmol) was dissolved in 4 mL 1: 1 THF:H20, then LiOH.H20 (149 mg, 3.55 mmol) added and reaction stirred for 30 min. IN HC1 was added to adjust the pH to 1, THF removed under vacuum and the resulting aqueous layer extracted with 2x20mL EtOAc, which was then dried with Na2S04 and concentrated under vacuum. Yield: 400 mg (100%) of 9. 1H NMR (CDC13) 7.18 (1H, m), 6.88 (4H, m), 6.37 (1H, d, J = 8 Hz), 5.77 (1H, d, J = 16Hz), 4.91 (1 H, d, J = 8 Hz), 3.22 (1H, m) 3.12, (1H, m), 2.13 (2H, m), 1.33 (4H, m), 0.86, (3H, m). 13C NMR (CDC13, mixture of rotamers) 174.2, 167.0, 164.1, 161.7, 147.5, 138.5, 130.3, 125.4, 122.7, 116.6, 114.4, 53.7, 37.1, 32.0, 30.2, 22.3, 13.9. HRMS (FAB): calcd for C16H20NO3FNa [M+Na]+ 316.1325, obsd 316.1306 (Delta = 6.0 ppm).
 

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