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Chemical Structure| 51987-73-6
Chemical Structure| 51987-73-6
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Product Details of [ 51987-73-6 ]

CAS No. :51987-73-6 MDL No. :MFCD00076977
Formula : C15H21NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :SDSWSVBXRBXPRL-LBPRGKRZSA-N
M.W : 279.33 Pubchem ID :9882138
Synonyms :
N-Boc-L-phenylalanine methyl ester

Calculated chemistry of [ 51987-73-6 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.47
Num. rotatable bonds : 8
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 75.66
TPSA : 64.63 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.73
Log Po/w (XLOGP3) : 2.31
Log Po/w (WLOGP) : 2.3
Log Po/w (MLOGP) : 2.22
Log Po/w (SILICOS-IT) : 2.18
Consensus Log Po/w : 2.35

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.72
Solubility : 0.531 mg/ml ; 0.0019 mol/l
Class : Soluble
Log S (Ali) : -3.31
Solubility : 0.138 mg/ml ; 0.000495 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.88
Solubility : 0.0372 mg/ml ; 0.000133 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.88

Safety of [ 51987-73-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P305+P351+P338 UN#:N/A
Hazard Statements:H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 51987-73-6 ]

* 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 [ 51987-73-6 ]

[ 51987-73-6 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 24424-99-5 ]
  • [ 7524-50-7 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane for 24h; Ambient temperature;
100% With triethylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; 15 Synthesis of N-Boc-L-phenylalanine methyl ester (6) Example 15 Synthesis of N-Boc-L-phenylalanine methyl ester (6) Thionyl chloride (3.10 mL, 42.38 mmol, 1.4 eq) was added dropwise to a suspension of L-phenylalanine (5.0 g, 30.27 mmol, 1.0 eq) in dry MeOH (30 mL) at 0° C. The cold bath was, removed and the solution was stirred at room temperature for 24 h, then concentrated under vacuum. The residue was triturated with cold Et2O, filtered and wash with cold Et2O and the filtrate evaporated in vacuo to give the methyl ester hydrochloride as a white crystalline solid. To a suspension of the methyl ester hydrochloride in THF (30 mL) at 0° C. was added Et3N (5.50 mL, 39.45 mmol, 1.2 eq) and then followed by a solution of (Boc)2O (8.61 g, 39.45 mmol, 1.2 eq) in THF (30 mL). The resulting mixture was stirred at room temperature for 8 h. The solvent was reduced to half its original volume, addition of H2O (20 mL) and then extracted with EtOAc (3*30 mL). The organic extract was dried over anhydrous MgSO4 and evaporation of the solvent afforded the N-Boc-L-phenylalanine methyl ester 6 as a pale yellow oil in quantitative yield; Rf 0.41 (20% EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 3.05 (2H, m, -CH2-), 3.64 (3H, s, OMe), 4.53 (1H, q, J.=7.8 Hz, -CH-), 5.06 (1H, d, J=9.0 Hz, -NH-) and 7.06-7.26 (5H, m, Ar-H), which was used directly in the next step without further purification.
99% In tetrahydrofuran; methanol at 20℃; for 4h; Inert atmosphere;
98% With Sodium hydrogenocarbonate In 1,4-dioxane at 20℃; for 12h;
97%
97% Stage #1: (L)-phenylalanine methyl ester hydrochloride With potassium carbonate In water monomer for 1h; Stage #2: di-<i>tert</i>-butyl dicarbonate With guanidinium monohydrochloride In ethanol at 35 - 40℃; for 0.166667h; 2.5. General procedure for N-tert-butoxycarbonylation of aminoacid esters (Table 2, entries 13-15): General procedure: Amino acid ester hydrochlorides and K2CO3 were suspended in water and stirred for one hour. The free amino acid esters were extracted with CH2Cl2 and dried with MgSO4. Evaporation of CH2Cl2 under reduced pressure gives free amino acid ester which should be immediately used for N-Boc protection. The free amino acid esters (1 mmol) in 1mL ethanol was added to a solution of di-tert-butyl dicarbonate (1.2 mmol) and guanidine hydrochloride (15 mol%) in ethanol (1 mL) at 35-40 °C and stirred for appropriate time. The work up was similar to same procedure for amines.
96% With triethylamine In dichloromethane at 0 - 20℃;
96% With Sodium hydrogenocarbonate In tetrahydrofuran; water monomer at 20℃; for 18h; N-(tert-Butyloxycarbonyl)-L-phenylalanine methyl esterTo To a stirred solution of L-phenylalanine methyl ester hydrochloride (4 g, 18.4 mmol) in THF/H2Oand NaHCO3 (3 g, 36.8 mmol), di-tert-butyl dicarbonate (Boc2O, 4.8 g, 22 mmol) was added.After being stirred at room temperature for 18 h, the reaction mixture was extracted with EtOAc(2x200 mL). The combined organic phases were washed with brine solution and dried overNa2SO4. The solvent was removed under diminished vacuum to provide product N-(tertbutyloxycarbonyl)-L-phenylalanine methyl ester (4.92 g, 96%), as a colorless oil. Rf 0.47 (nhexane/EtOAc; 4/1). 1H NMR (500 MHz, CDCl3) δ: 7.31-7.22 (m, 3H), 7.12 (d, J = 7.1 Hz, 2H),4.98 (brs, 1H), 4.59 (d, J = 7.1 Hz, 1H), 3.71 (s, 3H), 3.13-3.02 (m, 2H), 1.41 (s, 9H). 13C NMR(125 MHz, CDCl3) δ: 172.3, 155.0, 136.0, 129.2, 128.5, 127.0, 79.9, 54.4, 52.1, 38.3, 28.3.
95% With Sodium hydrogenocarbonate In 1,4-dioxane; water monomer at 20℃; for 12h;
95% With anhydrous sodium carbonate In methanol; water monomer at 40℃; for 6h; 1 To a mixed solvent of methanol (50 ml) and water (100 ml) were added L-phenylalanine methyl ester hydrochloride (21.6 g), sodium carbonate (11.64 g), and a solution of di-tert-butoxydicarbonate (21.8 g) in methanol (100 ml). The resulting mixture was heated to 40 DEG C, followed by stirring for 6 hours. The reaction mixture was concentrated to remove the methanol. The concentrate was extracted by adding ethyl acetate and water. The resulting ethyl acetate layer was washed with 0.1 N hydrochloric acid, water, an aqueous sodium hydrogencarbonate solution and a saturated solution of sodium chloride. The ethyl acetate layer after washed was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. The solvent was distilled off under reduced pressure to give the target N-tert-butoxycarbonyl-L-phenylalanine methyl ester (26.4 g) in a yield of 95 %.<1>H-NMR (CDCl3, 300MHz) delta ppm: 1.39 (s, 9H), 2.98 - 3.16 (m, 2H), 3.69 (s, 3H), 4.54-4.65 (m, 1H), 4.93-5.03 (bd, 1H), 7.08-7.32 (m, 5H)
94% With Sodium hydrogenocarbonate In tetrahydrofuran at 0 - 20℃; for 48h; Boc protection of methyl carboxylate 4j To a suspension of methyl (S)-2-amino-3-phenylpropanoate hydrochloride (4j) (49.5 mg, 0.230 mmol) in THF (3.1 mL) was added saturated aqueous NaHCO3 (3.1 mL) and di-tert-butyl dicarbonate (200 mg, 0.918 mmol) at 0 °C. The reaction mixture was stirred for 48 h at room temperature and then diluted with water. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by preparative thin layer chromatography on silica (ethyl acetate/hexane = 1/2) to afford 5j (60.5 mg, 94% yield, >99.5% ee) as a colorless oil.
94% Stage #1: (L)-phenylalanine methyl ester hydrochloride With anhydrous sodium carbonate In water monomer for 0.25h; Stage #2: di-<i>tert</i>-butyl dicarbonate In water monomer; ethyl acetate at 20℃; for 24h;
91% With anhydrous sodium carbonate In ethanol at 20℃; for 48h; 4.5.12. (S)-5-Benzyl-6,6-dimethyl-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-2-ium tetrafluoroborate 52 To a suspension of l-phenylalanine methyl ester hydrochloride (20.0 g, 97.2 mmol) in EtOH (60 mL) was added Na2CO3 (30.1 g, 284 mmol) and Boc2O (24.5 g, 112 mmol). The suspension was stirred for 48 h at ambient temperature. The colourless suspension was filtered through Celite and the filtrate concentrated in vacuo to afford Boc-l-phenylalanine methyl ester as a clear yellow oil (27.2 g, 91%). inlMMLBox (c 1.0, CH2Cl2), lit.49 +46.9 (c 3.4, CH2Cl2); δH (400 MHz, CDCl3) 7.06-7.03 (5H, m, ArH), 5.37 (1H, br d, J 8.3, NH), 4.47 (1H, app q, J 7.2, CHNH), 3.52 (3H, s, OCH3), 3.01 (1H, ABX, JAB 13.7, JAX 5.6, PhCHAHB), 2.90 (1H, ABX, JBA 13.7, JBX 7.0, PhCHAHB) and 1.42-1.30 (9H, m, C(CH3)3). Data are in accordance with the literature.49
91% With Sodium hydrogenocarbonate In neat (no solvent) for 1.5h; Milling;
73% With triethylamine In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (S-35) At 0°C di-tert-butoxydicarbonate (662 mg, 3.03 mmol) was added dropwise under a nitrogen atmosphere to a solution of L-phenylalanine methyl ester hvdrochloride (500 mg, 2.32 mmol) and triethylamine (0.786 mL,5.67 mmol) in CH2Cl2, (15 mL). The resulting mixture was stirred at room temperature for 24 hrs. After solvent evaporation, EtOAc (15 ml) was added and the solution washed with diluted acid (10 mL), then with saturated NaHCO3, (10 mL) and finally with H2O (5 mL). The organic layer was dried over Na2SO4, and evaporated to give 35 as an oily residue (73 % yield) as confirmed by TLC (Silica/EtOAc/n-hexane 3:1 v/v, Rf = 0.61). White solid. M.p.. 90 - 91 °C. 1H NMR (500 MHz,CDCl3) δ 7.31- 7.14 (m, 5H), 4.58 (m, 1H),3.71 (s, 3H), 3.19 (dd, J = 13.8, 5.0 Hz, 1H), 2.88 (dd, J = 9.5, 5.0 Hz, 1H), 1.33 (s, 9H). ESI-MS (+) Calc. for [C15H21NO4] 279.33, found: 280.21 [M+H]+.
70% With triethylamine In tetrahydrofuran at 20℃; for 24h;
63% With triethylamine In tetrahydrofuran at 0 - 20℃; for 20h; According to E. Sturrock, A. Nichinda, K. Chibale, US 2009/0281169 A1, 2009 l-phenylalanine methylester hydrochloride (17 g, 93.58 mmol) was suspended in dry tetrahydrofurane (150 mL) at 0 °C. Triethylamine (16.96 mL, 121.65 mmol) and solution of di-tert-butyl dicarbonate (26.55 g, 121.65 mmol) in dry tetrahydrofurane (100 mL) were added separately. Reaction mixture wasstirred for 20 hours and slowly heated to RT. The volume of reaction mixture was reduced to half by distillation, water (80 mL) was added and the solution was washed with ethyl acetate (4 x 40 mL). Combined organic phase was washed with water (3 x 30 mL) and dried over Na2SO4. . The crude product was purified via two column chromatographies (silica gel 310 g and 150 g, n-hexane/ethyl acetate (3:1)). The product was obtained in yield 63 %. (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate 8b. Colourless oil; yield 63 %; Rf (hex/EtOAc - 3/1) = 0.44. 1H NMR (400 MHz, CDCl3-d1): δ 7.30-7.15 (5H, m, Ar-H), 5.05-4.95 (1H, m, NH), 4.63-4.52 (1H, m, NH-CH), 3.70 (3H, s, O-CH3), 3.15-2.98 (2H, m, NH-CH-CH2-Ph), 1.51 (9H, s, C(CH3)3). 13C NMR (100.79 MHz, CDCl3-d1): δ 172.6, 155.3, 146.9, 136.2, 129.7, 129.5, 128.7, 127.2, 85.4, 54.6, 52.4, 38.5, 28.5. CNH Analysis: Calc. for C15H21NO4 (279.33): C, 64.50; H, 7.58; N, 5.01. Found: C, 63.49±0.02; H 7.91±0.02; N, 4.45±0.01. HRMS: m/z calc. for C15H21NO4: 302.13628 [M+Na]+; found: 302.13659 [M+Na]+.
With Sodium hydrogenocarbonate In tetrahydrofuran; water monomer Ambient temperature;
With TEA In N,N-dimethyl-formamide at 60℃; for 0.5h; Yield given;
With Sodium hydrogenocarbonate In tetrahydrofuran; methanol for 20h; Ambient temperature;
With triethylamine In chloroform at 20℃;
With triethylamine In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; (S)-Methyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (23) At 0 °C di-tert-butylpyrocarbonate (7 mL, 30 mmol) was added drop wise under a nitrogen atmosphere to a solution of L-phenylalanine methyl ester hydrochloride 22 (5 g, 23 mmol) and triethylamine (5.5 mL, 56 mmol) in CH2Cl2, (120 mL). The resulting mixture was stirred at room temperature for 5 h. After completion of the reaction organic layer was washed with 5% citric acid (100 mL), then with 5% NaHCO3, (100 mL) and finally with H2O (50 mL). The organic layer was dried over Na2SO4, and evaporated to give an oily residue (Yield: quantitative). Compound was purified by column chromatography with 5% EtOAc/hexane. ESI-MS: m/z 280 (M+H+).
With triethylamine In tetrahydrofuran Inert atmosphere;
With Sodium hydrogenocarbonate In dichloromethane; water monomer at 20℃; for 2h; 5; 22 Example 22 Preparation of compound 25 Example 22 Preparation of compound 25 A mixture of L-phenylalanine methyl ester hydrochloride (7.90 g, 36.6 mmol), di- ie/ -butyl dicarbonate (12.9 g) in DCM (100 mL) and saturated aqueous NaHC03 solution (80 mL) was stirred at r.t. for 2 h. The organic phase was separated and the aqueous phase was extracted with DCM twice. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated to give a colorless oil (9.76 g, 95% yield). The crude product was used directly in the next step.
With triethylamine In dichloromethane at 20℃; for 3h;
With Sodium hydrogenocarbonate In tetrahydrofuran; water monomer at 22℃; for 16h;
With triethylamine; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 5h; Cooling with ice; 2.1; 3.21; 4.1 A method for synthesizing a bisoxazoline ligand includes the following steps: S1), dilute 5 g of L-phenylalanine methyl ester hydrochloride 1 into 100 mL of DCM, then add 8 mL of Et3N or iPr2Net, and then dropwise add 6 mL of Boc2O in an ice bath, then transfer to room temperature and stir for 5 h After TLC monitoring, the reaction of the raw materials was completed. After that, about 100 mL of a 5% citric acid aqueous solution was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was washed with 5% NaHCO3 (aqueous solution), washed with water, and dried with anhydrous Na2SO4. Filter, spin dry, and pass through the column to obtain (tert-butoxyphenyl) -L-phenylalanine methyl ester 2;
With Sodium hydrogenocarbonate In tetrahydrofuran; water monomer at 22℃; for 16h; Inert atmosphere;
With anhydrous sodium carbonate In ethyl acetate
With triethylamine

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  • 2
  • [ 51987-73-6 ]
  • [ 88463-18-7 ]
YieldReaction ConditionsOperation in experiment
100% With ammonium hydroxide In methanol; water at 20℃; Inert atmosphere;
99% With ammonium hydroxide In methanol (S)-tert-butyl (1-amino-1-oxo-3-phenylpropan-2-yl)carbamate (S-34) Method A: Boc-protected amino ester S-35 (1.0 equiv) was dissolved in 50% ammonium hydroxide and 50% methanol to a concentration of 0.1 M. The reaction mixture was stirred overnight and monitored by TLC upon completion. Upon completion, the solvent was concentrated in vacuo, and the amides were taken on to the next reaction without further purification (99% yield).
With ammonia In methanol
With sodium methylate; formamide at 100℃;

  • 3
  • [ 51987-73-6 ]
  • [ 72155-45-4 ]
YieldReaction ConditionsOperation in experiment
100% With diisobutylaluminium hydride In toluene at -78℃; for 2h;
100% With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 5.25h; 73.A To a solution of N- (tert-butoxycarbonyl)-L-phenylalaine methyl ester (1.0 g, 3.58 mmol) in dichloromethane (10 ml) at -78°C, diisobutylaluminium (1.0 M in toluene) (7.87 ml, 7.87 mmol) is added dropwise over 15 minutes. The reaction mixture is stirred at -78°C for 5 hours, quenched with acetic acid /toluene (1 :5, 20 ml) at -78°C, warmed to room temperature, and poured into diluted hydrochloric acid (20 ml). The organic layer is separated. The aqueous layer is extracted with ethyl acetate (2x40 ml). The combined organic extracts are washed with brine, dried over νa2S04, filtered and concentrated to provide 891 mg (100%) of a white solid, which is identified as (5)-(l-formyl-2-phenyl-ethyl)- carbamic acid tert-butyl ester: MS (ESI) m/z 248.2, MS (ESI) m/z 294.2; HRMS (high- resolution MS): calculated for Ci4H19NO3+ Na+, 272.12571, found (ESI-FTMS, [M+Na]1+), 272.125.
96% With diisobutylaluminium hydride In hexane; dichloromethane at -95℃; for 1h; Inert atmosphere;
82% With diisobutylaluminium hydride In dichloromethane; hexae at -78℃; for 0.5h;
81% With diisobutylaluminium hydride In dichloromethane at -78℃; for 1h;
80% With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 2h;
With diisobutylaluminium hydride In toluene at -78℃; for 0.166667h;
With diisobutylaluminium hydride In hexane; toluene at -77℃;
With diisobutylaluminium hydride In hexane; toluene at -78℃; for 0.0833333h;
With diisobutylaluminium hydride In toluene at -78℃; for 0.0833333h;
With diisobutylaluminium hydride at -78℃;
With diisobutylaluminium hydride In toluene at -78℃; for 0.0833333h;
With diisobutylaluminium hydride In toluene at -78℃;
With diisobutylaluminium hydride In toluene at -78℃;
With diisobutylaluminium hydride
With diisobutylaluminium hydride In toluene at -78℃;
Multi-step reaction with 2 steps 1: CaCl2; NaBH4 / ethanol; tetrahydrofuran / 5 h / 0 °C 2: pyridine*SO3; triethylamine / CH2Cl2; dimethylsulfoxide / 0.5 h / 20 °C
Multi-step reaction with 2 steps 1: 89 percent / NaBH4; LiCl / tetrahydrofuran; ethanol / 12 h / 20 °C 2: pyridine - sulfur trioxide complex (1:1); triethylamine / dimethylsulfoxide / 1 h / -10 - 20 °C
Multi-step reaction with 2 steps 1: 90 percent / LiAlH4 / tetrahydrofuran / 1 h / 0 °C 2: (COCl)2; DMSO; Et3N / CH2Cl2 / -78 °C
Multi-step reaction with 2 steps 1: NaBH4, LiCl / ethanol; tetrahydrofuran 2: SO3 / pyridine; dimethylsulfoxide; triethylamine / 0.33 h / Ambient temperature
With diisobutylaluminium hydride In hexane; toluene at -78℃; for 2h;
Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1.5h; Inert atmosphere; Stage #2: With water In hexane; dichloromethane at -78 - 25℃;
With diisobutylaluminium hydride In dichloromethane at -78℃;
With diisobutylaluminium hydride In hexane; dichloromethane Inert atmosphere;
Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 3h; Inert atmosphere; Stage #2: With acetic acid In hexane; dichloromethane; benzene at -78 - 20℃; Inert atmosphere;
With diisobutylaluminium hydride In methanol
With diisobutylaluminium hydride In hexane; dichloromethane at -90 - -85℃; for 0.75h; Inert atmosphere; Procedure for : Alkyne (5) Boc-Phe-OMe (4.00g, 14.3mmol) was dissolved in anh DCM (60mL) under an Ar atmosphere. The solution was stirred at -90oC and DIBAL (32.9mL, 1M in hexanes, 32.9mmol) was added dropwise over 25 min so that temperature remained under -85 oC. The reaction was stirred for 20 min, then quenched slowly afterwards with MeOH (10mL). The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel using EtOAc and hexanes (3:7). The isolated aldehyde (2.45g, 9.83mmol) was immediately dissolved in DCM (100 mL) and Bestman reagent (4.12g, 21.4mmol) were dissolved in MeOH at 0 oC. K2CO3 (4.00g, 28.6mmol) was added all at once. The reaction was allowed to warm to rt and stirred for 16 h. The solution was concentrated under vacuum and dissolved in EtOAc (100mL). The organic phase was washed using a NaHCO3 saturated solution (2 x 50mL) and brine (50mL). The organic phase was dried (MgSO4) and concentrated under vacuum. The crude oil was purified by flash chromatography on silica gel eluting with EtOAc and hexanes (1:9) to afford the title compound as a white solid (2.22g, 63%).
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 20 °C 2: DMP / dichloromethane / 0 - 20 °C
With diisobutylaluminium hydride In tetrahydrofuran; cyclohexane at -80 - -69℃; for 3.75h; (S)-tert-Butyl 1-oxo-3-phenylpropan-2-ylcarbamate (24) Protected ester (7.4 g, 26.5 mmol) obtained above was dissolved in dry THF (300 mL) and cooled to -80 °C. To this diisobutylaluminumhydride (52 mL, 1 M solution in cyclohexane, 0.052 mol) was added via needle over a period of 45 min while maintaining the internal temperature below -69 °C. The mixture was stirred for 3 h, and precooled (-75 °C) methanol (20 mL) was added. During the addition, the reaction mixture was maintained below -69 °C.The mixture was then allowed to warm to 5 °C, and 300 g of icewas added with heavy agitation, the mixture was filtered through sintered funnel and extracted with chloroform. Organic layer was washed with brine (100 mL), dried over MgSO4, and concentrated. The crude product thus obtained stored at -20 °C for next step.
With diisobutylaluminium hydride In dichloromethane at -78℃; Inert atmosphere; Schlenk technique;
With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane Inert atmosphere;
With diisobutylaluminium hydride In hexane; dichloromethane at -65℃; for 3h; 5; 23 Example 23 Preparation of compound 26 Example 23 Preparation of compound 26 A solution of Boc-L-phenylalanine methyl ester (9.76 g, 35.0 mmol) in DCM (60 mL) was cooled to -65 °C, DIBAL-H (1.0 M in hexanes, 70 mL) was added slowly over 1 h. After being stirring for 2 h, the reaction was quenched by MeOH (20 mL) and warmed to r.t. IN HCl (120 mL) was then added and the organic phase was separated. The aqueous phase was extracted with DCM twice. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated to give a colorless oil (7.0 g, 80% yield). The crude product was used directly in the next step.
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol; lithium chloride / 5 - 20 °C / Inert atmosphere 2: sodium hydrogencarbonate; sodium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite solution / dichloromethane; water / 5 °C
Multi-step reaction with 2 steps 1: calcium chloride; sodium tetrahydroborate / methanol / 20 h / 20 °C 2: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / ethyl acetate / 5 h / Reflux

Reference: [1]McNulty; Still [Synthetic Communications, 1992, vol. 22, # 7, p. 979 - 985]
[2]Current Patent Assignee: PFIZER INC - WO2008/109613, 2008, A1 Location in patent: Page/Page column 228
[3]Xu, Jingjing; Lin, Benguo; Jiang, Xiuqing; Jia, Zejun; Wu, Jinlong; Dai, Wei-Min [Organic Letters, 2019, vol. 21, # 3, p. 830 - 834]
[4]Location in patent: experimental part Ullrich, Angelika; Herrmann, Jennifer; Mueller, Rolf; Kazmaier, Uli [European Journal of Organic Chemistry, 2009, # 36, p. 6367 - 6378]
[5]Santarem, Marco; Fonvielle, Matthieu; Sakkas, Nicolas; Laisné, Guillaume; Chemama, Maryline; Herbeuval, Jean-Philippe; Braud, Emmanuelle; Arthur, Michel; Etheve-Quelquejeu, Mélanie [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3231 - 3233] Santarem, Marco; Fonvielle, Matthieu; Sakkas, Nicolas; Laisné, Guillaume; Chemama, Maryline; Herbeuval, Jean-Philippe; Braud, Emmanuelle; Arthur, Michel; Etheve-Quelquejeu, Mélanie [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3231 - 3233]
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[18]Shie, Jiun-Jie; Fang, Jim-Min; Kuo, Tun-Hsun; Kuo, Chih-Jung; Liang, Po-Huang; Huang, Hung-Jyun; Wu, Yin-Ta; Jan, Jia-Tsrong; Cheng, Yih-Shyun E.; Wong, Chi-Huey [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 17, p. 5240 - 5252]
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[21]Zhang, Zuhui; Zhang, Jintang; Tan, Jiajing; Wang, Zhiyong [Journal of Organic Chemistry, 2008, vol. 73, # 13, p. 5180 - 5182]
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[23]Location in patent: body text Ullrich, Angelika; Chai, Yi; Pistorius, Dominik; Elnakady, Yasser A.; Herrmann, Jennifer E.; et al. [Angewandte Chemie - International Edition, 2009, vol. 48, p. 4422 - 4425][Angew. Chem., Int. Ed., 2009, vol. 121, p. 4486 - 4489]
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[25]Location in patent: experimental part Gabriele, Bartolo; Veltri, Lucia; Mancuso, Raffaella; Salerno, Giuseppe; Maggi, Sabino; Aresta, Brunella Maria [Journal of Organic Chemistry, 2012, vol. 77, # 8, p. 4005 - 4016]
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[32]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/151079, 2015, A2 Location in patent: Page/Page column 6; 72
[33]Current Patent Assignee: ZHEJIANG YONGNING PHARMA - CN105198829, 2017, B
[34]Le, Hai Van; Tran, Loc Van; Tran, Anh Tuan; Tran, Thao Thi Phuong; Tran, Sung Van; Tran, Chien Van [Synlett, 2022, vol. 33, # 2, p. 187 - 195]
  • 4
  • [ 51987-73-6 ]
  • [ 66605-57-0 ]
YieldReaction ConditionsOperation in experiment
100% With sodium tetrahydroborate In tetrahydrofuran; methanol at 65℃; for 1h;
100% With sodium tetrahydroborate; calcium chloride In methanol at 20℃; for 20h; N-(tert-Butyloxycarbonyl)-L-phenylalaninol (2)2 A solution of methyl ester (4 g, 14.24 mmol) and CaCl2 (6.33 g, 57 mmol) in MeOH (200 mL)was treated in portions with NaBH4 (2.18 g, 57 mmol) and further stirred at room temperature 20h. The solvent was removed under reduced pressure and the residue was acidified with 5% HCl.The precipitate was filtered off and dried to obtain pure N-(tert-butyloxycarbonyl)-Lphenylalaninol2 (3.72 g, 100%), as a white foam. Rf 0.21 (n-hexane/EtOAc; 3/1). 1H NMR (500MHz, CDCl3) δ: 7.31-7.28 (m, 2H), 7.26-7.2 (m, 3H), 4.78 (brs, 1H), 3.86 (brs, 1H), 3.65 (dd, J =3.0 Hz, 11.0 Hz, 1H), 3.54 (dd, J = 3.0 Hz, 11.0 Hz, 1H), 2.83 (d, J = 7.0 Hz, 2H), 1.41 (s, 9H).
94% With sodium tetrahydroborate; lithium chloride In tetrahydrofuran at 20℃; Inert atmosphere;
94% With methanol; sodium tetrahydroborate; lithium chloride at 5 - 20℃; Inert atmosphere; 4 Synthesis of compound 7b Compound 8b (27.9 g, 0. eq.) and lithium chloride (8.5 g, 2.0 eq.) were added to methanol (500 ml) and dissolved with stirring under nitrogen. The mixture was cooled to below 5 ° C in an ice-water bath, sodium borohydride (7.5g, 2. Oeq.) was added in portions to the reaction solution, and the reaction mixture was incubated at room temperature. The reaction was monitored by TLC until the starting material disappeared. The reaction was placed in ice water The bath was cooled to below 5 ° C, 15 ml of water was added dropwise to the mixture, and 2N hydrochloric acid was added dropwise to a pH of 2-3. The majority of the solvent was evaporated off and the residue was adjusted to pH 9 with 2 mol / L NaOH solution. The aqueous layer was extracted with dichloromethane (30 ml x 3) and the combined organic layers were washed with water (30 ml) and saturated brine (30 ml) Sodium drying. Filtration and concentration of the filtrate under reduced pressure gave a crude yellow oil. The crude product was recrystallized from ethyl acetate n-heptane (2: 1 mixed solvent) to give compound 7b (23.6 g, yield 94%).
90% With sodium tetrahydroborate; acetic acid In 1,4-dioxane at 80℃;
90% With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1h;
89% With lithium borohydride In 1,2-dimethoxyethane
89% With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol at 20℃; for 12h;
85% With sodium tetrahydroborate; ethanol; cerium(III) chloride heptahydrate at 20℃; for 24h; chemospecific reaction;
82% With sodium tetrahydroborate; ethanol; lithium chloride In tetrahydrofuran at 0 - 20℃; for 12h;
82% With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol at 20℃; for 16h;
81% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With triethyl borane; sodium methylate In tetrahydrofuran; diethyl ether at 20℃; for 10h; Inert atmosphere; Stage #2: With sodium hydroxide In methanol; diethyl ether; toluene at 20℃; for 2h;
72% With sodium tetrahydroborate; lithium iodide In 1,2-dimethoxyethane at 40℃; for 2.5h;
70% With diisobutylaluminum hydride In hexane; toluene
With lithium borohydride In ethanol Yield given;
With lithium borohydride In tetrahydrofuran; ethanol
With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol
With sodium tetrahydroborate; calcium chloride In tetrahydrofuran; ethanol at 0℃; for 5h;
With sodium tetrahydroborate In ethanol at 0℃; for 24.1667h; Inert atmosphere; Reflux;
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃; for 4h; 3.5.3. General method for preparation of compounds (5) General procedure: To a dried methanol (50 mL) solution of 4 (3.3 g, 20 mmol), thionyl chloride (3.57 g, 30 mmol) was slowly added over 30 minat 0 °C, and then, the solution was maintained at room temperature for 18 h. The solvent was evaporated to obtain a solid in quantitative yield, which was dissolved in dichloromethane (120 mL), and triethylamine (12.1 g, 120 mL) and di-tert-butyldicarbonate (9.6 g, 40 mmol) were added to the dichloromethane solution. The reaction mixture was stirred at 25 °C for 24 h. Afterc ompletion of the reaction, the solution was washed with phosphoric acid (50 x 3 mL), saturated sodium bicarbonate (50 x 3 mL) and saturated sodium chloride (50 x 3 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford a solid to which lithium aluminum hydride (13 mmol) in the presence of dried tetrahydrofuran (25 mL) was added at 0 °C. The reaction mixture was maintained at room temperature for 4 h, and then water was added until the lithium aluminum hydride reacted completely. Next, the solution was filtered, and the residue was washed with tetrahydrofuran (20 x 2 mL).The combined organic solvent phase was evaporated under reduced pressure to yield the crude product, which was purified using column chromatography (petroleum ether/acetone) to afford 5a-5g.
With lithium aluminium tetrahydride at 0℃;
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1h;
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 18h;
With sodium tetrahydroborate
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;

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[2]Le, Hai Van; Tran, Loc Van; Tran, Anh Tuan; Tran, Thao Thi Phuong; Tran, Sung Van; Tran, Chien Van [Synlett, 2022, vol. 33, # 2, p. 187 - 195]
[3]Location in patent: experimental part Spaeth, Andreas; Gonschor, Janina; Koenig, Burkhard [Monatshefte fur Chemie, 2011, vol. 142, # 12, p. 1289 - 1308]
[4]Current Patent Assignee: ZHEJIANG YONGNING PHARMA - CN105198829, 2017, B Location in patent: Paragraph 0073-0075
[5]Soucek, Milan; Urban, Jan; Saman, David [Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 3, p. 761 - 765]
[6]Seo, Woo Duck; Curtis-Long, Marcus J.; Kim, Jin Hyo; Park, Jong Keun; Park, Ki Min; Park, Ki Hun [Synlett, 2005, # 15, p. 2289 - 2292]
[7]Van den Broek; Fennis; Arevalo; Lazaro; Ballesta; Lelieveld; Ottenheijm [European Journal of Medicinal Chemistry, 1989, vol. 24, # 5, p. 503 - 510]
[8]Shie, Jiun-Jie; Fang, Jim-Min; Kuo, Tun-Hsun; Kuo, Chih-Jung; Liang, Po-Huang; Huang, Hung-Jyun; Wu, Yin-Ta; Jan, Jia-Tsrong; Cheng, Yih-Shyun E.; Wong, Chi-Huey [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 17, p. 5240 - 5252]
[9]Location in patent: experimental part Xu, Yinan; Wei, Yunyang [Synthetic Communications, 2010, vol. 40, # 22, p. 3423 - 3429]
[10]Shashidhar Kumar; Haritha; Venkateswara Rao [Tetrahedron Letters, 2003, vol. 44, # 22, p. 4261 - 4263]
[11]Location in patent: scheme or table Ramu, Errabelli; Venkateswara Rao [Tetrahedron Asymmetry, 2009, vol. 20, # 19, p. 2201 - 2204]
[12]Peng, Dongjie; Zhang, Mintao; Huang, Zheng [Chemistry - A European Journal, 2015, vol. 21, # 42, p. 14737 - 14741]
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[16]Wyslouch, Aleksandra; Lisowski, Marek; Siemion, Ignacy Z. [Bulletin of the Polish Academy of Sciences: Chemistry, 1994, vol. 42, # 1, p. 117 - 130]
[17]Zygmunt, Jan; Gancarz, Roman; Lejczak, Barbara; Wieczorek, Piotr; Kafarski, Pawel [Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 24, p. 2989 - 2992]
[18]Fu, Yiqiu; Xu, Bo; Zou, Xiaomin; Ma, Chao; Yang, Xiaoming; Mou, Ke; Fu, Gang; Lue, Yang; Xu, Ping [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1102 - 1106]
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[21]Liu, Hongtao; Xu, Lianhong; Hui, Hon; Vivian, Randy; Callebaut, Christian; Murray, Bernard P.; Hong, Allen; Lee, Melody S.; Tsai, Luong K.; Chau, Jennifer K.; Stray, Kirsten M.; Cannizzaro, Carina; Choi, You-Chul; Rhodes, Gerry R.; Desai, Manoj C. [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 989 - 994]
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[24]Kondaparla, Srinivasarao; Debnath, Utsab; Dola, Vasantha Rao; Sinha, Manish; Katti, Seturam B.; Soni, Awakash; Srivastava, Kumkum; Puri, Sunil K. [Antimicrobial Agents and Chemotherapy, 2018, vol. 62, # 12]
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  • 5
  • [ 51987-73-6 ]
  • [ 98105-41-0 ]
YieldReaction ConditionsOperation in experiment
98.2% With hydrogen In methanol for 18h;
93% With 5% rhodium-on-charcoal; hydrogen In methanol; water at 60℃; for 16h;
  • 6
  • [ 51987-73-6 ]
  • [ 1594-58-7 ]
  • [ 154345-82-1 ]
  • 7
  • [ 51987-73-6 ]
  • [ 1594-57-6 ]
  • [ 154345-83-2 ]
  • 8
  • [ 63658-18-4 ]
  • [ 51987-73-6 ]
  • methyl (2R)-2-(t-butoxycarbonylamino)-3-phenylpropionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With phenyl 4,6-O-(R)-benzylidene-2,3-O-bis(diphenylphosphino)-β-D-glucopyranoside; Rh(cyclo-octa-1,5-diene)2; hydrogen; tetrafluoroborate ion In methanol at 25℃; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With S(+)-2,3-O,N-bis(diphenylphosphino)-1-(-naphthoxy)-2-hydroxy-3-isopropylaminopropane; Rh(cyclo-octa-1,5-diene)2; hydrogen; tetrafluoroborate ion In methanol at 25℃; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With (((1R,2R)-1,3-Me2-2-(3,5-Me2-phenylthio)BuO)PPh2)Rh(COD)SbF6; hydrogen In tetrahydrofuran at 20℃; for 18h; Title compound not separated from byproducts;
With (((1S,2S)-2-t-butylthio-cyclohexyloxy)PPh2)Rh(COD)SbF6; hydrogen In tetrahydrofuran at 20℃; Title compound not separated from byproducts;
76 % ee With bis(norbornadiene)rhodium(l)tetrafluoroborate; C24H32O2P2; hydrogen In methanol at 20℃; for 24h; Autoclave; enantioselective reaction;

  • 9
  • [ 154409-62-8 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
97% With magnesium(II) perchlorate In acetonitrile for 16h; Ambient temperature;
91% With cerium(III) chloride; sodium iodide In acetonitrile at 20℃; for 6h;
86% With bismuth(III) bromide; water In acetonitrile at 20℃; for 12h;
85% With indium In methanol for 23h; Heating;
85% With Selectfluor In acetonitrile at 50℃; for 24h; 1 General reaction steps General procedure: The 0.1 mmol reaction substrate was dissolved in 10 mL acetonitrile, 0.1 mmol selective reagent was added during the stirring, and the reaction was heated to 50° C. for 24 hours.Thin layer silica gel plate (TLC) tracking detection reaction, the disappearance of raw material points that the reaction is complete, add 10mL 10% sodium thiosulfate solution to quench the reaction, add 20mL of ethyl acetate diluted, washed twice with 5mL of saline, there areThe organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, the residue was purified by column chromatography (eluent: n-hexane and ethyl acetate were mixed in a volume ratio of 1:1 to 1:2). Selective removal of tert-butoxycarbonyl leaving the product of another acyl protecting group.

  • 10
  • [ 13734-34-4 ]
  • [ 74-88-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
99.5% With sodium hydrogencarbonate In N,N-dimethyl-formamide for 120h;
99% Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: methyl iodide In N,N-dimethyl-formamide for 24h;
97% With sodium hydrogencarbonate In N,N-dimethyl-formamide
96% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;
94% With potassium hydrogencarbonate at 20℃; for 8h;
69% With potassium hydrogencarbonate In N,N-dimethyl-formamide for 24h;
With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 18h;
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 5h;
In acetonitrile at 20℃; for 6h;
With sodium hydrogencarbonate In N,N-dimethyl-formamide
With potassium hydrogencarbonate
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: methyl iodide at 0 - 20℃;
4 g With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; 4.4a Step 4a: Synthesis of Compound 4b Potassium carbonate (3.12 g, 22.6 mmol) and methyl iodide (2.56 g, 18.1 mmol) were added to a solution of compound 4a (4.0 g, 15.0 mmol) in DMF (45 mL) and stirred at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to yield 4.0 g of compound 4b. LCMS: 280.2 [M+H]+.
3 g With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; 1.1a Step 1a Potassium carbonate (2.3 g, 16.9 mmol) and methyl iodide (0.8 ml, 13.6 mmol) were added to a solution of compound la (3.0 g, 11.3 mmol) in DMF (30 mL) and stined at room temperature for 3 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get 3.0 g ofcompound lb. LCMS: 280.1(M+H).
With potassium carbonate In N,N-dimethyl-formamide
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃;

Reference: [1]Boger, Joshua; Payne, Linda S.; Perlow, Debra S.; Lohr, Nancy S.; Poe, Martin; et al. [Journal of Medicinal Chemistry, 1985, vol. 28, # 12, p. 1779 - 1790]
[2]Fatás, Paola; Bachl, Jürgen; Oehm, Stefan; Jiménez, Ana I.; Cativiela, Carlos; Díaz Díaz, David [Chemistry - A European Journal, 2013, vol. 19, # 27, p. 8861 - 8874]
[3]Vaz, Esther; Fernandez-Suarez, Miryam; Munoz, Luis [Tetrahedron Asymmetry, 2003, vol. 14, # 13, p. 1935 - 1942]
[4]Meyer, Falco-Magnus; Liras, Spiros; Guzman-Perez, Angel; Perreault, Christian; Bian, Jianwei; James, Keith [Organic Letters, 2010, vol. 12, # 17, p. 3870 - 3873]
[5]Shie, Jiun-Jie; Fang, Jim-Min; Kuo, Tun-Hsun; Kuo, Chih-Jung; Liang, Po-Huang; Huang, Hung-Jyun; Wu, Yin-Ta; Jan, Jia-Tsrong; Cheng, Yih-Shyun E.; Wong, Chi-Huey [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 17, p. 5240 - 5252]
[6]Medina; Moyano; Pericas; Riera [Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8574 - 8578]
[7]Rodriguez, Ana Chiva; Ramos, Anna Pico; Hawkes, Geoffrey E.; Berti, Federico; Resmini, Marina [Tetrahedron Asymmetry, 2004, vol. 15, # 12, p. 1847 - 1855]
[8]Fu, Yiqiu; Xu, Bo; Zou, Xiaomin; Ma, Chao; Yang, Xiaoming; Mou, Ke; Fu, Gang; Lue, Yang; Xu, Ping [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1102 - 1106]
[9]Palomo, Claudio; Palomo, Antonio L; Palomo, Francisco; Mielgo, Antonia [Organic letters, 2002, vol. 4, # 23, p. 4005 - 4008]
[10]Viswanathan, Kishore; Hoover, Dennis J.; Hwang, Jeannie; Wisniewski, Meagan L.; Ikonne, Uzoma S.; Bahr, Ben A.; Wright, Dennis L. [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 11, p. 920 - 924]
[11]Liu, Hongtao; Xu, Lianhong; Hui, Hon; Vivian, Randy; Callebaut, Christian; Murray, Bernard P.; Hong, Allen; Lee, Melody S.; Tsai, Luong K.; Chau, Jennifer K.; Stray, Kirsten M.; Cannizzaro, Carina; Choi, You-Chul; Rhodes, Gerry R.; Desai, Manoj C. [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 989 - 994]
[12]Kondaparla, Srinivasarao; Soni, Awakash; Manhas, Ashan; Srivastava, Kumkum; Puri, Sunil K.; Katti [RSC Advances, 2016, vol. 6, # 107, p. 105676 - 105689]
[13]Current Patent Assignee: DR REDDY&amp;apos;S LABORATORIES LIMITED - WO2018/47139, 2018, A1 Location in patent: Page/Page column 84
[14]Current Patent Assignee: DR REDDY&amp;apos;S LABORATORIES LIMITED - WO2018/47143, 2018, A1 Location in patent: Page/Page column 69
[15]Kondaparla, Srinivasarao; Debnath, Utsab; Dola, Vasantha Rao; Sinha, Manish; Katti, Seturam B.; Soni, Awakash; Srivastava, Kumkum; Puri, Sunil K. [Antimicrobial Agents and Chemotherapy, 2018, vol. 62, # 12]
[16]Fu, Jian; Fu, Huixiao; Xia, Yufen; N'Go, Inès; Cao, Jun; Pan, Weidong; Vincent, Stéphane P. [Organic and Biomolecular Chemistry, 2021, vol. 19, # 8, p. 1818 - 1826]
  • 11
  • [ 51987-73-6 ]
  • [ 7524-50-7 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride In ethyl acetate at 0℃; for 2h;
With hydrogenchloride In 1,4-dioxane for 2h;
With hydrogenchloride In 1,4-dioxane at 21 - 23℃; for 1h;
With hydrogenchloride In 1,4-dioxane at 21 - 23℃; for 1h;

  • 12
  • [ 51987-73-6 ]
  • [ 30189-48-1 ]
YieldReaction ConditionsOperation in experiment
65% With hydrazine hydrate; In methanol; at 20℃;Inert atmosphere; To (5)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (Aldrich, 300 mg, 1.07 mmol) in MeOH (5.4 mL) was added hydrazine hydrate (170 mu,, 3.44 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated with hexanes (2x) and then from a minimal amount of 2:3 hexanes/MeOH (2x) to give the title compound (195 mg, 65%) as a white solid. XH NMR (CDC13) delta 7.41-7.25 (m, 3H), 7.20 (d, J= 6.8 Hz, 2H), 4.39-4.21 (m, 1H), 3.07 (d, J= 7.0 Hz, 2H), 1.42 (s, 9H); MS(ESI+) m/z 280.3 (M+H)+
3.8 g With hydrazine hydrate; In methanol; at 20℃; for 3.0h; Hydrazine hydrate (10.0 mL) was added to a solution of compound 4b (4.0 g, 14.3 mmol) in methanol (20 mL) and stirred at room temperature for 3 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and the residue obtained was partitioned between water and ethyl acetate. The organic layer was washed with water followed by brine solution. The separated organic layer was dried over Na2SO t, filtered and evaporated to yield 3.8 g of compound 4c. LCMS: 280.2 [M+H]+.
3 g With hydrazine hydrate; In methanol; at 20℃; for 3.0h; Hydrazine hydrate (4.3 mL, 85.7 mmol) was added to a solution of compound lb (3.0 g, 10.7 mmol) in methanol (30 mL) and stined at room temperature for 3 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, the residue obtained was partitioned between water and ethyl acetate. Organic layerwas washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get3.0 g of compound lc. LCMS: 280.2 (M+H).
  • 13
  • [ 51987-73-6 ]
  • [ 72155-45-4 ]
  • [ 66605-57-0 ]
YieldReaction ConditionsOperation in experiment
96% With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 0.1h;
  • 14
  • [ 24424-99-5 ]
  • [ 106018-94-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
96% With cesium fluoride In N,N-dimethyl-formamide at 50℃; for 6h;
  • 15
  • [ 51987-73-6 ]
  • [ 756-79-6 ]
  • [ 176504-90-8 ]
YieldReaction ConditionsOperation in experiment
95% With n-butyllithium In tetrahydrofuran
95% With n-butyllithium In tetrahydrofuran at -78 - 0℃;
86% With n-butyllithium In tetrahydrofuran; hexane 1.) -78 deg C, 5 min, 2.) -78 deg C, 1 h; -30 deg C, 1 h;
77% Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; hexane at -78 - -30℃; for 3h;
72% With lithium diisopropyl amide In tetrahydrofuran at -78℃;
59% Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran at -78 - 20℃; Inert atmosphere; 16 Synthesis of dimethyl [(3S)-4-phenyl-3-[(tert-butyloxycarbonyl)amino]-2-oxobutyl]phosphonate (7) Example 16 Synthesis of dimethyl [(3S)-4-phenyl-3-[(tert-butyloxycarbonyl)amino]-2-oxobutyl]phosphonate (7) A solution of dimethyl methylphosphonate (3.10 mL, 28.60 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to -78° C. and 2.5 N n-BuLi (2.70 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at -78° C. for 30 min and then a solution of compound 6 (1.00 g, 3.58 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at -78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3*50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded the compound dimethyl [(3S)-4-phenyl-3-[(tert-butyloxycarbonyl)amino]-2-oxobutyl]-phosphonate 7 as a clear oil (0.797 g, 59%), which crystallizes in hexane as a white solid; mp 78-81° C. (lit.1 mp 76-78° C.); Rf 0.38 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 1.38 (9H, s, (CH3)3), 2.84-3.32 (4H, m), 3.74 and 3.78 (6H, 2xs, 2xOMe), 4.55 (1H, q, J=8.4 Hz, -CH-), 5.28 (1H, d, J=8.4 Hz, -NH-), and 7.16-7.32 (5H, m, Ar-H).
54% Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; hexane at -78℃; for 1h; Further stages.;
With n-butyllithium 1.) THF, -78 deg C, 20 min, 2.) -78 deg C, 1 h; room temperature, 15 min; Yield given. Multistep reaction;
Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; hexane at -78℃; for 2h;
Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran at -78℃; for 0.333333h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran at -78℃; for 1h;
With n-butyllithium In tetrahydrofuran at -78℃;
Stage #1: dimethyl methane phosphonate In tetrahydrofuran at -78℃; for 0.666667h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran at -78℃; for 1h; 11.a a) Preparation of 6. 2 A solution of dimethyl methylphosphonate [6. 1] (34.1 g, 215.4 mmol) in THF (250 mL) in a nitrogen atmosphere was cooled to-78 C to which was added 2.0 M solution of butyl lithium (107 mL, 215.4 mmol) via canula in 20 min. The solution was stirred at-78 [C] for 20 min, and a THF [(150] mL) solution [OF N-BOC-L-PHENYLALANINE] methyl ester (10.0 g, 35.8 mmol) was slowly added via dropping funnel. The mixture was stirred [AT-78 C] for [LH.] The reaction was then quenched with 10% AcOH (250 mL) and warmed to room temperature. The solution was extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous [NAHC03] and brine, and dried over [MGS04.] Solvents were evaporated and excess dimethyl methylphosphonate was removed by rotary evaporator under high vacuum at [90 C] water bath. The resulted oily product containing 5-10% dimethyl methylphosphonate (as shown by 1H NMR) was used without purification. 1H NMR (400 MHz, [CDC13)] [6] ppm 1.29 (m, 6 H) 1.35 (s, 9 H) 2.92 [(DD,] [J=14.] 24,8. 39 Hz, [1] H) 3.03 [(DD,] [J=22.] 38,13. 73 Hz, 1 H) 3.22 (m, 2 H) 4.10 (m, 4 H) 4.55 (d, [J=5.] 59 Hz, 1 H) 5.38 (d, [J=7.] 88 Hz, [1 H)] 7.20 (m, 5 H); MS: 422 [(MNA+).]
Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran at -78℃; for 0.666667h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran at -78℃; for 1h; 11.a A solution of dimethyl methylphosphonate 6.1 (34.1 g, 215.4 mmol) in THF (250 mL) in a nitrogen atmosphere was cooled to ?78 C. and then was added 2.0 M solution of butyllithium (107 mL, 215.4 mmol) via canula in 20 minutes. The solution was stirred at ?78 C. for 20 minutes, and a THF (150 mL) solution of N-boc-L-phenylalanine methyl ester (10.0 g, 35.8 mmol) was slowly added via dropping funnel. The mixture was stirred at ?78 C. for 1 hour. The reaction was then quenched with 10% AcOH (250 mL) and warmed to room temperature. The solution was extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine and then dried over MgSO4. Solvents were evaporated and the excess dimethyl methylphosphonate was removed by rotary evaporator under high vacuum in a 90 C. water bath. The resulted oily product 6.2 containing 5-10% dimethyl methylphosphonate (shown by 1H NMR) was used without purification. 1H NMR (400 MHz, CDCl3) ? ppm 1.29 (m, 6H) 1.35 (s, 9H) 2.92 (dd, J=14.24, 8.39 Hz, 1H) 3.03 (dd, J=22.38, 13.73 Hz, 1H) 3.22 (m, 2H) 4.10 (m, 4H) 4.55 (d, J=5.59 Hz, 1H) 5.38 (d, J=7.88 Hz, 1H) 7.20 (m, 5H); MS: 422 (MNa+)

Reference: [1]Tossi, Alessandro; Benedetti, Fabio; Norbedo, Stefano; Skrbec, Damiano; Berti, Federico; Romeo, Domenico [Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 22, p. 4719 - 4727]
[2]Hu, Zilun; Wang, Cailan; Han, Wei; Rossi, Karen A.; Bozarth, Jeffrey M.; Wu, Yiming; Sheriff, Steven; Myers, Joseph E.; Luettgen, Joseph M.; Seiffert, Dietmar A.; Wexler, Ruth R.; Quan, Mimi L. [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 6, p. 987 - 992]
[3]Litera, Jaroslav; Budesinsky, Milos; Urban, Jan; Soucek, Milan [Collection of Czechoslovak Chemical Communications, 1998, vol. 63, # 2, p. 231 - 244]
[4]Kobayashi, Kazuya; Narumi, Tetsuo; Oishi, Shinya; Ohno, Hiroaki; Fujii, Nobutaka [Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4626 - 4629]
[5]Chun, Jiong; Yin, Ye Ingrid; Yang, Guangli; Tarassishin, Leonid; Li, Yue-Ming [Journal of Organic Chemistry, 2004, vol. 69, # 21, p. 7344 - 7347]
[6]Current Patent Assignee: ANGIODESIGN UK - US2009/281160, 2009, A1 Location in patent: Page/Page column 9
[7]Vabeno, Jon; Brisander, Magnus; Lejon, Tore; Luthman, Kristina [Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9186 - 9191]
[8]Déziel, Robert; Plante, Raymond; Caron, Valérie; Grenier, Louis; Llinas-Brunet, Montse; Duceppe, Jean-Simon; Malenfant, Eric; Moss, Neil [Journal of Organic Chemistry, 1996, vol. 61, # 8, p. 2901 - 2903]
[9]Rodriguez, Ana Chiva; Ramos, Anna Pico; Hawkes, Geoffrey E.; Berti, Federico; Resmini, Marina [Tetrahedron Asymmetry, 2004, vol. 15, # 12, p. 1847 - 1855]
[10]Yang, Wenjin; Lu, Wanli; Lu, Yafan; Zhong, Min; Sun, Jian; Thomas, Anila E.; Wilkinson, Jennifer M.; Fucini, Raymond V.; Lam, Melissa; Randal, Mike; Shi, Xiao-Ping; Jacobs, Jeffrey W.; McDowell, Robert S.; Gordon, Eric M.; Ballinger, Marcus D. [Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 839 - 842]
[11]Nchinda, Aloysius T.; Chibale, Kelly; Redelinghuys, Pierre; Sturrock, Edward D. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4612 - 4615]
[12]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - WO2003/106405, 2003, A1 Location in patent: Page column 147,148
[13]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - US2004/147454, 2004, A1 Location in patent: Page 49-50
  • 16
  • [ 51987-73-6 ]
  • [ 2577-90-4 ]
YieldReaction ConditionsOperation in experiment
90% With phosphoric acid In dichloromethane at 20℃; for 3h;
70% With 3-butyl-l-methyl-1H-imidazol-3-iumtrifloroacetate In 1,4-dioxane; water at 80 - 82℃; for 3h;
With molecular sieve; boron trifluoride diethyl etherate In dichloromethane for 20h; Ambient temperature;
Multi-step reaction with 2 steps 1: 173.5 percent / 2,6-lutidine / CH2Cl2 / 0.25 h / Ambient temperature 2: 93 percent / n-Bu4NF / tetrahydrofuran / 1 h / Ambient temperature
Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With trifluoroacetic acid In dichloromethane at 20℃; for 2h; Cooling with ice; Stage #2: With 4-methyl-morpholine In dichloromethane at 0℃;
With trifluoroacetic acid In dichloromethane at 20℃; for 2h; Inert atmosphere; General procedure: A mixture of S10 (0.20g, 0.69 mmol) in TFA : DCM (1:1, 5 mL) was stirred at room temprature for 2 h (TLC control, 100% EtOAc). After completion of the reaction, the solvent was evaporated in vacuo. The residue was repeatedly washed with diethyl ether (5 x 5 mL) and the intermediate obtained was used for the next step without purification.

  • 17
  • [ 51987-73-6 ]
  • [ 74-88-4 ]
  • [ 37553-64-3 ]
YieldReaction ConditionsOperation in experiment
99% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0333333h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 2h;
97% With sodium hydride In N,N-dimethyl-formamide at 25℃; for 15h;
93% With silver(l) oxide In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere; (S)-Methyl-2-((tert-butoxycarbonyl)(methyl)amino)-3-phenylpropanoate (34) To a stirred solution of amino acid derivative (0.5 g, 1.79 mmol) in dry DMF (15 mL) were added methyl iodide (4.06 g, 28.8 mmol) followed by silver(I) oxide (1.66 g, 7.15 mmol). The mixture was stirred at room temperature for 4 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the solids were filtered off and the filtrate was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with saturated NaCl solution (70 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 9:1) to afford N-methyl amino acid derivative (0.49 g, 93%) as a colorless liquid. [α]D26 -51.8 (c= 0.1, CHCl3); IR (neat): 3567, 2976, 1745, 1698, 1454, 1392, 1367, 1329, 1254, 1222, 1170, 1144, 1080, 1030 cm-1; 1H NMR(500 MHz, CDCl3): δ 7.33-7.26 (m, 2H), 7.25-7.11 (m, 3H), 4.94 (dd, J = 10.5, 5.3 Hz , 0.5 H), 4.54 (dd, J =10.6, 4.4 Hz, 0.5 H ), 3.74 (s, 3H), 3.35-3.25 (m, 1H), 3.05-2.98 (m, 1H), 2.71(s, 3H), 1.31 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 172.3, 155.0, 135.9, 129.2, 128.5, 126.9, 79.9, 54.3, 52.1, 38.3, 29.6, 28.2 ppm; HRMS (ESI): m/z cald. for C16H23NO4Na [M+ Na]+: 316.1525, found: 316.1520.
With sodium hydride

  • 18
  • [ 591-50-4 ]
  • [ 93267-04-0 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #2: iodobenzene With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
With chloro-trimethyl-silane; tris(dibenzylideneacetone)dipalladium (0); ethylene dibromide; tris-(o-tolyl)phosphine; zinc 1) DMF, rt; 2) DMF, rt; further conditions; Yield given. Multistep reaction;
  • 19
  • [ 63-91-2 ]
  • [ 51987-73-6 ]
  • [ 13122-90-2 ]
  • 20
  • [ 51987-73-6 ]
  • [ 79-11-8 ]
  • [ 102123-74-0 ]
  • 21
  • (2S) 1-naphthylmethyl 2-[N-(1,1-dimethylethyl)oxycarbonyl]amino-3-phenylpropanoate [ No CAS ]
  • [ 74-88-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: (2S) 1-naphthylmethyl 2-[N-(1,1-dimethylethyl)oxycarbonyl]amino-3-phenylpropanoate With ammonium formate; 1,2-bis-(diphenylphosphino)ethane In dimethyl sulfoxide at 50℃; for 12h; Stage #2: methyl iodide With sodium carbonate In water; dimethyl sulfoxide at 20℃; for 12h;
  • 22
  • [ 24424-99-5 ]
  • [ 2577-90-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine
99% at 30 - 35℃; for 0.166667h;
99% With sodium hydrogencarbonate In 1,4-dioxane; water at 0℃; for 1h;
97% With perchloric acid at 30 - 35℃; for 0.25h;
96% With 1-butyl-3-methylimidazolium trifluoromethanesulfonimide at 30 - 35℃; for 0.0333333h; neat (no solvent); chemoselective reaction;
96% In water at 110℃; for 0.0833333h; Microwave irradiation; Green chemistry; chemoselective reaction;
96% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; 2 Synthesis of compound 8b Compound 9a (20 g, 1.0 eq.), Boc-anhydride (26.8 g, 1. 1eq.) were added to dichloromethane (240 ml) and stirred at room temperature under nitrogen to give a clear solution. Diisopropylethylamine (5.4 g, 1.2 eq.) Was added dropwise to the mixture, and the dropwise addition was completed. The reaction was incubated until the consumption of the starting material 9a was completed. The reaction mixture was washed successively with 1N hydrochloric acid (80 ml), saturated sodium bicarbonate (80 ml) and saturated brine (80 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate evaporated to remove the organic solvent under reduced pressure. The resulting crude solid was beaten for half an hour with t-butyl methyl ether (MTABE) (70 ml) and filtered. The resulting precipitate was dried to give compound 8b (30.1 g, yield 96%).
94% With sulfated polyborate In neat (no solvent) at 20℃; for 0.166667h; Sonication; Green chemistry; chemoselective reaction; 1.2. Representative procedure for the synthesis of N-tert-butyl carbamate under ultrasonic irradiation. General procedure: A mixture of amine (2 mmol) and Boc2O (2 mmol), and sulfated polyborate (10 wt%) was sonicated using 20 kHz frequency and 35W power at room temperature in 25mL round bottom flask for stipulated time (progress was monitored by TLC). After complete consumption of the starting materials (TLC), the reaction mixture was cooled to room temperature. The crude mixture was dissolved in the ethyl acetate and the insoluble catalyst was separated using simple filtration then dried and reused. The filtrate was washed with water, dried over sodium sulfate, and concentrated in vacuo to furnish the corresponding N-tert-butyl carbamate derivatives of amines in excellent (87-99%) yields.
93% With indium(III) bromide at 30 - 35℃; for 0.25h;
92% With sodium hydroxide In 1,4-dioxane for 6h;
92% With nanocerium oxide In neat (no solvent) at 20℃; for 0.166667h; 2. General procedure for N-Boc protection of amines General procedure: To a mixture of amines (1mmol) and Boc2O (1mmol), 10mol% nanocerium oxidewas added wit h vigorous stirring at room temperature for stipulated time. Aftercompletion of reaction as monitored by TLC, diethyl ether was added and the catalyst wasremoved by simple filtration. After removal of the solvent, the pure products wereobtained and no recrystallization or column chromatography was needed.
91% With PEG-400 at 20℃; for 0.666667h; Neat (no solvent);
91% With sulfated tungstate 10 wt % In neat (no solvent) at 20℃; for 0.25h; chemoselective reaction; 2. General procedure for N-Boc protection of amines General procedure: A mixture of amine (1mmol), (Boc)2O (1mmol) and sulfated tungstate (10wt%) was vigorously stirred at room temperature for appropriate time until complete disappearance of amines was observed in the TLC monitoring. After the completion of reactions, the reaction mixture was diluted with diethyl ether and the catalyst was isolated by simple filtration. After drying catalyst, it is reused for N-Boc protection of amines. The product was isolated in purified form by evaporating the diethyl ether at room temperature. After the evaporation of diethyl ether solvent, the pure products were obtained and no recrystallization or column chromatography was needed for the purification of products.
90% In water at 30 - 35℃; for 1h;
90% With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 12.33h; Cooling with ice; 1 (2S) - 2 - (tert-butoxycarbonylamino) - 3-phenyl-propionic acid methyl ester (3a) The L-phenylalanine (1.65g, 10mmol) dissolved in 25 ml methanol, and the protection of nitrogen cooling ice bath next drips into SOCl 2 (1 ml, 14mmol), the drop finishes, to continue stirring 15 minutes, removed ice-bath, stirring the mixture at room temperature for overnight. Reaction 12 hours later, the reaction end. Reducing pressure and evaporating the solvent the crude phenylalanine methyl ester obtained, without purification directly used for the next step reaction. Crude phenylalanine methyl ester is added to 50 ml aqueous solution of sodium bicarbonate, cooling and stirring ice (Boc) 2 O (2.53mml, 1 . 1mmol) dioxane solution of 50 ml, then continue to stir 20 minutes, then removed ice-bath, stir at room temperature overnight, the reaction 12 hours after the reaction end. Distilling the reaction liquid, after removing half of the solvent, by adding ethyl acetate extraction (50 ml × 3), combined with the organic layer, first washing water and salt (100 ml × 3) and anhydrous sodium sulfate concentrated after drying, to obtain colorless oily liquid 2.51g, yield 90%.
89% With 1-butyl-3-methylimidazolium trifluoroacetate In neat (no solvent) at 20℃; for 1h;
85% With iodine at 20℃; for 3h;
82% With fipronilβ-cyclodextrin In methanol; acetone at 20℃; for 0.416667h;
With triethylamine In tetrahydrofuran at 0 - 20℃; for 8h;
With sodium hydrogencarbonate In tetrahydrofuran; water 3 Method C: Example 3 Method C: Preparation of N-t-Butyloxycarbonyl-AHPA (3-Amino-2-Hydroxy-4-Phenylbutanoic Acid) Methyl Ester (Scheme 1) To a stirred solution of L-phenylalanine methyl ester (10.8 g, 50 mmol, hydrochloride salt) in 150 mL of 20 percent THF in water was added sodium bicarbonate (8.4 g, 100 mmol) at room temperature, followed by di-t-butyl dicarbonate (10.9 g, 50 mmol). The mixture was stirred at room temperature overnight (about 18 hours). The reaction mixture was extracted with ether (2*100 mL), and the ether layers were combined and dried over MgSO4. Boc-phenylalanine methyl ester was obtained as a pale yellow oil. The oil was dissolved in 70 mL dry toluene and cooled to -77° C. under nitrogen and 125 mmol diisobutylaluminum hydride (1.0M in hexane, 125 mL, 2.25 equivalent) were added in 15 minutes. Methanol (10 mL) was added immediately to quench the reaction.
With triethylamine In tetrahydrofuran at 20℃; for 7h;
In methanol at 20℃; for 12h;
With triethylamine In dichloromethane at 22 - 24℃; for 2h; Inert atmosphere;
With triethylamine In dichloromethane at 25℃; for 24h; General procedure: To a dried methanol (50 mL) solution of 4 (3.3 g, 20 mmol), thionyl chloride (3.57 g, 30 mmol) was slowly added over 30 minat 0 °C, and then, the solution was maintained at room temperature for 18 h. The solvent was evaporated to obtain a solid in quantitative yield, which was dissolved in dichloromethane (120 mL), and triethylamine (12.1 g, 120 mL) and di-tert-butyldicarbonate (9.6 g, 40 mmol) were added to the dichloromethane solution. The reaction mixture was stirred at 25 °C for 24 h. Afterc ompletion of the reaction, the solution was washed with phosphoric acid (50 x 3 mL), saturated sodium bicarbonate (50 x 3 mL) and saturated sodium chloride (50 x 3 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford a solid to which lithium aluminum hydride (13 mmol) in the presence of dried tetrahydrofuran (25 mL) was added at 0 °C. The reaction mixture was maintained at room temperature for 4 h, and then water was added until the lithium aluminum hydride reacted completely. Next, the solution was filtered, and the residue was washed with tetrahydrofuran (20 x 2 mL).The combined organic solvent phase was evaporated under reduced pressure to yield the crude product, which was purified using column chromatography (petroleum ether/acetone) to afford 5a-5g.
147.8 mg at 20℃; Ionic liquid;
With sodium hydrogencarbonate In ethanol at 0 - 20℃;
With triethylamine In dichloromethane at 0 - 20℃; for 12h; Procedure b General procedure: To a solution of compounds 15, 16 or 17 (1 equiv)in dry CH2Cl2, TEA (1.5 equiv) and (Boc)2O (1.2 equiv) were added.The reaction mixture was stirred for 12 h at rt and the solvent wasthen removed in vacuo. The mixture was diluted with EtOAc,washed with a 3 N solution of HCl, dried over Na2SO4 and concentratedin vacuo. The resulting residue was purified by flash columnchromatography to remove the excess of (Boc)2O, using as eluent amixture of light petroleum/EtOAc (6:4) to afford pure carbamates
137 mg With sodium hydroxide In water; acetonitrile for 0.5h; Inert atmosphere;
With triethylamine In dichloromethane at 0 - 20℃; for 12h;

Reference: [1]Location in patent: scheme or table Kobayashi, Kazuya; Narumi, Tetsuo; Oishi, Shinya; Ohno, Hiroaki; Fujii, Nobutaka [Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4626 - 4629]
[2]Chankeshwara, Sunay V.; Chakraborti, Asit K. [Tetrahedron Letters, 2006, vol. 47, # 7, p. 1087 - 1091]
[3]Current Patent Assignee: NAGASE &amp; CO LTD; TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY - WO2007/13681, 2007, A1 Location in patent: Page/Page column 85-87
[4]Chakraborti, Asit K.; Chankeshwara, Sunay V. [Organic and Biomolecular Chemistry, 2006, vol. 4, # 14, p. 2769 - 2771]
[5]Location in patent: experimental part Sarkar, Anirban; Roy, Sudipta Raha; Parikh, Naisargee; Chakraborti, Asit K. [Journal of Organic Chemistry, 2011, vol. 76, # 17, p. 7132 - 7140]
[6]Nardi; Cano, N. Herrera; Costanzo; Oliverio; Sindona; Procopio [RSC Advances, 2015, vol. 5, # 24, p. 18751 - 18760]
[7]Current Patent Assignee: ZHEJIANG YONGNING PHARMA - CN105198829, 2017, B Location in patent: Paragraph 0067-0069
[8]Pise, Ashok S.; Ingale, Ajit P.; Dalvi, Navnath R. [Synthetic Communications, 2021, vol. 51, # 24, p. 3768 - 3780]
[9]Chankeshwara, Sunay V.; Chakraborti, Asit K. [Synthesis, 2006, # 16, p. 2784 - 2788]
[10]Brouwer, Arwin J.; Mulders, Suzanne J. E.; Liskamp, Rob M. J. [European Journal of Organic Chemistry, 2001, # 10, p. 1903 - 1915]
[11]Garad, Dnyaneshwar N.; Ingale, Ajit P.; Shinde, Sandeep V.; Ukale, Dattatraya [Synthetic Communications, 2021, vol. 51, # 11, p. 1656 - 1668]
[12]Location in patent: experimental part Zeng, Hongyao; Li, Yongjia; Shao, Huawu [Synthetic Communications, 2012, vol. 42, # 1, p. 25 - 32]
[13]Ingale, Ajit P.; Shinde, Sandeep V.; Thorat, Nitin M. [Synthetic Communications, 2021, vol. 51, # 16, p. 2528 - 2543]
[14]Chankeshwara, Sunay V.; Chakraborti, Asit K. [Organic Letters, 2006, vol. 8, # 15, p. 3259 - 3262]
[15]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105622458, 2016, A Location in patent: Paragraph 0023; 0024
[16]Majumdar, Swapan; De, Jhinuk; Chakraborty, Ankita; Maiti, Dilip K. [RSC Advances, 2014, vol. 4, # 47, p. 24544 - 24550]
[17]Varala, Ravi; Nuvula, Sreelatha; Adapa, Srinivas R. [Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286]
[18]Somi Reddy; Narender; Nageswar; Rama Rao [Synlett, 2006, # 7, p. 1110 - 1112]
[19]Shashidhar Kumar; Haritha; Venkateswara Rao [Tetrahedron Letters, 2003, vol. 44, # 22, p. 4261 - 4263]
[20]Current Patent Assignee: SCRIPPS RESEARCH - US5455271, 1995, A
[21]Location in patent: scheme or table Ramu, Errabelli; Venkateswara Rao [Tetrahedron Asymmetry, 2009, vol. 20, # 19, p. 2201 - 2204]
[22]Location in patent: experimental part Choi, Jin Kyu; Jeon, Byung Sun; Cho, Jong Hyun; Kim, B. Moon [Bulletin of the Korean Chemical Society, 2010, vol. 31, # 3, p. 735 - 738]
[23]Herrmann, Aaron T.; Smith, Lindsay L.; Zakarian, Armen [Journal of the American Chemical Society, 2012, vol. 134, # 16, p. 6976 - 6979]
[24]Yang, Dezhi; Wang, Peng; Liu, Jianzhen; Xing, Hualu; Liu, Yang; Xie, Wencheng; Zhao, Guisen [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 366 - 373]
[25]Di Gioia; Barattucci; Bonaccorsi; Leggio; Minuti; Romio; Temperini; Siciliano [RSC Advances, 2014, vol. 4, # 6, p. 2678 - 2686]
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[27]Ettari, Roberta; Pinto, Andrea; Previti, Santo; Tamborini, Lucia; Angelo, Ilenia C.; La Pietra, Valeria; Marinelli, Luciana; Novellino, Ettore; Schirmeister, Tanja; Zappalà, Maria; Grasso, Silvana; De Micheli, Carlo; Conti, Paola [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 7053 - 7060]
[28]Speckmeier, Elisabeth; Klimkait, Michael; Zeitler, Kirsten [Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 3738 - 3745]
[29]Debia, Natalí P.; Rodríguez, Juan J.P.; da Silveira, Carolina H.; Chaves, Otavio A.; Iglesias, Bernardo A.; Rodembusch, Fabiano S.; Lüdtke, Diogo S. [Journal of Molecular Liquids, 2020, vol. 309]
  • 23
  • [ 75-09-2 ]
  • [ 51987-73-6 ]
  • [ 290836-37-2 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: dichloromethane With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.166667h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1h; 2 After cooling dehydrated tetrahydrofuran (15 ml) to-78 DEG C, a 2M solution (5.75 ml) of lithium diisopropylamide in heptane, tetrahydrofuran and ethyl benzene was added thereto. Then, a solution of methylene chloride (0.74 ml) in dehydrated tetrahydrofuran (5 ml) was added thereto. The mixture was stirred for 10 minutes. A solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (1.4 g) in dehydrated tetrahydrofuran (7 ml) was then added thereto, followed by stirring for 1 hour. The reaction was terminated by the addition of 1N hydrochloric acid (25 ml) to the reaction mixture. After heating to room temperature, the reaction mixture was added with ethyl acetate and water for extracting. The ethyl acetate solution thus obtained was analyzed by HPLC. As a result, it was confirmed that the target (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (1.31 g) had been formed in a yield of 79%. As a result of analysis of the (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone existent in the ethyl acetate solution by HPLC using an optically active column, it was confirmed that the optical purity thereof was greater than 99.5 %e.e. The ethyl acetate solution was then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. From the filtrate, the solvent was distilled off under reduced pressure. By the addition of ethyl acetate, the resulting residue was made into a slurry. The crystals were then separated from the slurry and dried, whereby the target (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (1.12 g) was obtained in a yield of 67%. As a result of analysis of the crystals thus separated of the (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone by HPLC using an optically active column, it was confirmed that the optical purity thereof was greater than 99.5 %e.e..<1>H-NMR (CDCl3, 300MHz) delta ppm: 1.40 (s, 9H), 3.01 (dd, J=7.9, 13.8Hz, 1H), 3.22 (dd, J=5.7, 13.8HZ, 1H), 4.62-5.00 (m, 2H), 6.08 (s, 1H), 7.17-7.22 (m, 2H), 7.22-7.36 (m, 3H). [ alpha ]D<20>= -52.7 DEG (c=2.25, CH2Cl2).
67% With lithium diisopropyl amide In tetrahydrofuran; ethylbenzene; pentane at -78℃; for 1h;
  • 24
  • [ 7524-50-7 ]
  • [ 404586-94-3 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
97% In 1,2-dimethoxyethane at 20℃;
  • 25
  • [ 63658-18-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
98% With bis(norbornadiene)rhodium(l)tetrafluoroborate; (3S,3'S)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-4,4'-bibenzo[d][1,3]oxaphosphole; hydrogen In methanol at 20℃; for 24h; Autoclave; enantioselective reaction;
91% With bis(norbornadiene)rhodium(l)tetrafluoroborate; (3S,3'S)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-4,4'-bibenzo[d][1,3]oxaphosphole; hydrogen In methanol at 20℃; for 24h; Inert atmosphere; Autoclave; 25 Application of Ia: A solution of Rh(NBD)2BF4 (1.1 mg, 0.003 mmol) and (3S,3'S)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-4,4'-bibenzo[d][1,3]oxaphosphole (Ia, 1.2 mg, 0.003 mmol) in 1.5 mL of N2-purged methanol was stirred for 20 min under nitrogen. Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-phenylacrylate 22 (83 mg, 0.3 mmol) was then added. The reaction vessel was transferred into an autoclave and pressurized with hydrogen to 100 psi. The reaction mixture was stirred at this pressure and 20° C. for 24 h. After release of the hydrogen and purging with nitrogen, the reaction mixture was concentrated under reduced pressure, and the product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in hexanes) to afford the acetamide 23 (76 mg, 91%, 99.3:0.7 er). The enantiomeric excess of the hydrogenation products was determined by chiral HPLC with a Kromasil 3-Amicoat (4.6*250 mm) column (heptane/denatured ethanol =95:5, 1.3 mL/min, 25° C., rt (major) =7.56 min, rt (minor) =9.45 min). The absolute configurations of products were determined by comparison with authentic sample. 1H NMR (500 MHz, CDCl3) δ7.32-7.22 (m, 3H), 7.66-7.10 (m, 2H), 5.00 (d, J=7.1 Hz, 1H), 4.62-4.55 (m, 1H), 3.70 (s, 3H), 3.15-3.00 (m, 2H), 1.41 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3) δ172.3, 155.1, 136.0, 129.3, 128.5, 127.0, 79.9, 54.4, 52.2, 38.4, 28.3 ppm.
With (R)-N-diphenylphosphino-N-methyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine; hydrogen In tetrahydrofuran at 25℃; for 1h;
With hydrogen In tetrahydrofuran at 20℃; for 1h;

  • 26
  • [ 4530-18-1 ]
  • resin-CH2N=C(OCH3)NH-cHex [ No CAS ]
  • [ 51987-73-6 ]
  • 27
  • [ 540-88-5 ]
  • [ 51987-73-6 ]
  • [ 191226-88-7 ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: acetic acid tert-butyl ester With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -45℃; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; n-heptane; ethylbenzene at -50℃;
  • 28
  • [ 51987-73-6 ]
  • methyl 2-(N-tert-butoxycarbonyl-N-chloroamino)-3-phenylpropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With aluminum oxide; calcium hypochlorite In dichloromethane at 35℃; for 22h;
99% With trichloroisocyanuric acid In dichloromethane at 20℃; for 3h;
  • 29
  • [ 67-56-1 ]
  • [ 13734-34-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
100% With thionyl chloride at 0 - 20℃; for 24h;
96% With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In water for 3h;
95% With cyano-hydroxyimino-acetic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester; sodium hydrogencarbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; acetonitrile
92% With cross-linked enzyme aggregates of Alcalase Enzymatic reaction;
76% With ammonium cerium(IV) nitrate at 25℃;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 21 - 23℃; for 3h;
With thionyl chloride at 0℃; for 16h; Inert atmosphere; Reflux;

  • 31
  • [ 593-71-5 ]
  • [ 51987-73-6 ]
  • [ 102123-74-0 ]
  • 32
  • [ 51987-73-6 ]
  • [ 98045-03-5 ]
  • 33
  • [ 949574-90-7 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
76% With sodium tetrahydroborate; nickel dichloride In methanol at 0℃; for 0.166667h;
  • 34
  • [ 24424-99-5 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
97% N-(tert.-butyloxycarbonyl)-L-phenylalanine methyl ester (4d) N-(tert.-butyloxycarbonyl)-L-phenylalanine methyl ester (4d) This compound was prepared in 97% yield from the hydrochloride of L-phenylalanine methyl ester (32.4 g, 0.15 mol) by treatment with di-tert.-butyl pyrocarbonate following the procedure that has been described earlier 1,2. TLC Rf0.85 (eluent MeOH/CHCl3, 3/97). 1H NMR (CDCl3) δ 1.40 (s, 9H, t-Bu), 3.04 and 3.11 (d, AB part of ABX spectrum, 2H, CHCH2), 3.70 (s, 3H, CO2CH3), 4.36-4.73 (m, 1H, CHCO2CH3), 4.75-5.10 (m, 1H, NH), 7.04-7.34 (m, 5H, Ph).
97% N-(tert.-butyloxycarbonyl)-L-phenylalanine methyl ester (4d) N-(tert.-butyloxycarbonyl)-L-phenylalanine methyl ester (4d) This compound was prepared in 97% yield from the hydrochloride of L-phenylalanine methyl ester (32.4 g, 0.15 mol) by treatment with di-tert.-butyl pyrocarbonate following the procedure that has been described earlier1,2. TLC Rf 0.85 (eluent MeOH/CHCl3, 3/97). 1 H NMR (CDCl3) δ 1.40 (s, 9H, t-Bu), 3.04 and 3.11 (d, AB part of ABX spectrum, 2H, CHCH2), 3.70 (s, 3H, CO2 CH3), 4.36-4.73 (m, 1H, CHCO2 CH3), 4.75-5.10 (m, 1H, NH), 7.04-7.34 (m, 5H, Ph).
Multi-step reaction with 2 steps 1: aq. NaOH / dioxane / 0.5 h / 0 °C 2: 100 percent / thionyl chloride / 24 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: 99 percent / Et3N / tetrahydrofuran; H2O 2: 97 percent / NaHCO3 / dimethylformamide
Multi-step reaction with 2 steps 1: tBuN=P(NMe2)3 / acetonitrile / 16 h / 20 °C 2: acetonitrile / 6 h / 20 °C
Multi-step reaction with 2 steps 1: tetrahydrofuran / 144 h / -15 °C 2: 10 percent (DHQD)2AQN; 4 Angstroem molecular sieves / diethyl ether / 15 h / -40 °C
Multi-step reaction with 2 steps 1.1: K2CO3 / H2O / 1.5 h / 130 °C 1.2: dioxane / 24 h / 20 °C 2.1: diethyl ether
Multi-step reaction with 3 steps 2: 76 percent / DBU 3: H2, Rh(COD)2/BF4, (S)-PROPRAPHOS / methanol / 25 °C / 750.06 Torr
Multi-step reaction with 4 steps 1: 82 percent 2: 68 percent 3: 76 percent / I(1-) / acetone 4: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -10 deg C, 5 h
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 1,4-dioxane; water / 0.25 h / 0 °C 1.2: 0.75 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.25 h / 0 °C 2.2: 0 - 20 °C
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 5 h / 0 - 30 °C 2: triethylamine / dichloromethane / 38 - 40 °C

  • 35
  • [ 51987-73-6 ]
  • [ 165727-45-7 ]
  • 36
  • [ 51987-73-6 ]
  • [ 162536-40-5 ]
  • 37
  • [ 51987-73-6 ]
  • [ 102123-74-0 ]
  • 38
  • [ 51987-73-6 ]
  • [ 38017-65-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 100 percent / HCl / ethyl acetate / 2 h / 0 °C 2: 92 percent / Et3N, DCC / CH2Cl2 / 0 - 20 °C 3: 100 percent / HCl / ethyl acetate / 2 h / 0 °C
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 16 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 16 h / 20 °C
  • 40
  • [ 13734-34-4 ]
  • [ 3945-69-5 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
93% With 4-methyl-morpholine; hydrogenchloride; sodium hydroxide; In methanol; diethyl ether; water; Example 263 Into the 100-ml eggplant-type flask, there were introduced 2.65 g (0.01 mol) of an N-tert-butoxycarbonyl-L-phenylalanine, 1.01 g (0.01 mol) of an N-methylmorpholine and 45 ml of a methanol (water content of 100 ppm), which were, then, stirred for 10 minutes, followed by the addition of 2.77 g (0.01 mol) of a <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> to conduct the reaction at room temperature for 4 hours. After the reaction, the methanol was distilled off. To the residue was added 50 ml of a diethyl ether, and the mixture was washed with 30 ml of water, 30 ml of 1N hydrochloric acid and 30 ml of an 1N sodium hydroxide aqueous solution. Thereafter, the diethyl ether was distilled off under a reduced pressure, and the residue was isolated and refined through the silica gel column chromatography to obtain 2.60 g of an N-tert-butoxycarbonyl-L-phenylalaninemethyl ester (yield, 93%).
With 4-methyl-morpholine; hydrogenchloride; In methanol; dichloromethane; water; Example 84 Into a 100-ml egg plant-type flask were added 5.30 g (0.02 mols) of an N-tert-butoxycarbonyl-L-phenylalanine as a carboxylic acid compound, 2.42 g (0.024 mols) of a 4-methylmorpholine as a tertiary amine compound and 100 ml of methanol as an alcohol compound, which were then stirred at room temperature for 10 minutes. Then, 6.85 g (0.02 mols) of the same <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> having a water content of 19.1% by weight as the one prepared in Example 5 was added thereto as a condensing agent to effect the reaction at room temperature for 3 hours. After the reaction, methanol was distilled off, 100 ml of water was added thereto, and the extraction operation was conducted twice with 30 ml of a methylene chloride. The separated methylene chloride solution was collected, and the organic layer was washed with 20 ml of a saturated sodium carbonate aqueous solution, 20 ml of a 1N hydrochloric acid and 20 ml of water. The obtained organic layer was dried on magnesium sulfate, condensed and the residue was isolated and refined by using a silica gel column chromatography to obtain 5.36 g of an N-tert-butoxycarbonyl-L-phenylalaninemethyl ester (yield, 96%).
  • 41
  • di-tert-butoxydicarbonate [ No CAS ]
  • [ 7524-50-7 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
95% With sodium chloride; sodium carbonate In methanol; water; ethyl acetate R.1 Production Process of N-tert-butoxycarbonyl-L-phenylalanine Methyl Ester REFERENTIAL EXAMPLE 1 Production Process of N-tert-butoxycarbonyl-L-phenylalanine Methyl Ester To a mixed solvent of methanol (50 ml) and water (100 ml) were added L-phenylalanine methyl ester hydrochloride (21.6 g), sodium carbonate (11.64 g), and a solution of di-tert-butoxydicarbonate (21.8 g) in methanol (100 ml). The resulting mixture was heated to 40° C., followed by stirring for 6 hours. The reaction mixture was concentrated to remove the methanol. The concentrate was extracted by adding ethyl acetate and water. The resulting ethyl acetate layer was washed with 0.1 N hydrochloric acid, water, an aqueous sodium hydrogencarbonate solution and a saturated solution of sodium chloride. The ethyl acetate layer after washed was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. The solvent was distilled off under reduced pressure to give the target N-tert-butoxycarbonyl-L-phenylalanine methyl ester (26.4 g) in a yield of 95%. 1H-NMR (CDCl3, 300 MHz) δppm: 1.39 (s, 9H), 2.98-3.16 (m, 2H), 3.69 (s, 3H), 4.54-4.65 (m, 1H), 4.93-5.03 (bd, 1H), 7.08-7.32 (m, 5H)
  • 42
  • [ 51987-73-6 ]
  • [ 693-04-9 ]
  • [ 74-95-3 ]
  • [ 290836-34-9 ]
YieldReaction ConditionsOperation in experiment
55% With hydrogenchloride In tetrahydrofuran; hexane; water; ethyl acetate 2 Production of tert-butyl (S)-(1-benzyl-3.3-dibromo-2-oxopropyl)carbamate EXAMPLE 2 Production of tert-butyl (S)-(1-benzyl-3.3-dibromo-2-oxopropyl)carbamate Under nitrogen gas, diisopropylamine (17.4 g, 157.5 mmol) was added to n-butylmagnesium chloride (1.8 mol/kg, 79.6 g, 143.2 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8 mmol), dibromomethane (12.45 g, 71.6 mmol) and THF (20 mL) (liquor B). To this liquor B was added said liquor A over 1 hour at an internal temperature of about 5° C., and the reaction was further conducted for 1 hour. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (34.5 g), water (50 g) and ethyl acetate (100 mL) over 15 minutes for hydrolysis. After phase separation, the organic layer was washed with 2 portions of water (50 mL) and partially concentrated and the residue was precipitated from hexane to provide white crystals of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (8.709 g, 95.5 area %, yield 55%).
  • 43
  • [ 74-97-5 ]
  • [ 51987-73-6 ]
  • [ 693-04-9 ]
  • tert-butyl (S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% With hydrogenchloride In tetrahydrofuran; water; ethyl acetate 5 Production of tert-butyl (S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate EXAMPLE 5 Production of tert-butyl (S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate Under nitrogen gas, diisopropylamine (19.92 g, 196.9 mmol) was added to n-butylmagnesium chloride (1.8 mol/kg, 99.4 g, 179 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8 mmol), bromochloromethane (9.27 g, 71.6 mmol) and THF (20 g) (liquor B). To this liquor B was added said liquor A over 1.5 hours at an internal temperature of about 5° C., and the reaction was conducted at 5° C. for 1 hour and at 20° C. for 16 hours. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (43.12 g), water (100 g) and ethyl acetate (50 mL) over 10 minutes for hydrolysis. After phase separation, the organic layer was washed serially with water (100 mL) and saturated NaCl/H2O, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 20.08 g of a reddish brown solid. This solid was recrystallized from ethyl acetate/hexane to provide yellow crystals of tert-butyl (S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate (4.409 mg, 90.7 area %, yield 30%, diastereomer ratio=42/58) as a mixture of diastereomers. 1H-NMR (400 MHz, CDCl3) δ: 1.39 (s, 9H), 1.41 (s, 9H), 2.92-3.30 (m, 2H+2H), 4.75-5.08 (m, 2H+2H), 5.89 (S, 1H), 6.29 (s, 1H), 7.17-7.42 (m, 5H+5H)
  • 44
  • [ 51987-73-6 ]
  • [ 693-04-9 ]
  • [ 290836-37-2 ]
YieldReaction ConditionsOperation in experiment
32% With hydrogenchloride In tetrahydrofuran; dichloromethane; water; ethyl acetate 6 Production of tert-butyl (S)-(1-benzyl-3,3-dichloro-2-oxopropyl)carbamate EXAMPLE 6 Production of tert-butyl (S)-(1-benzyl-3,3-dichloro-2-oxopropyl)carbamate Under nitrogen gas, diisopropylamine (19.92 g, 196.9 mmol) was added to n-butylmagnesium chloride (1.8 mol/kg, 99.4 g, 179 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8 mmol), dichloromethane (6.09 g, 71.6 mmol) and THF (20 g) (liquor B). To this liquor B was added said liquor A over 1.5 hours at an internal temperature of about 5° C., and the reaction was conducted at 5° C. for 6 hours and at 20° C. for 16 hours. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (43.12 g), water (100 g) and ethyl acetate (50 mL) over 10 minutes for hydrolysis. After phase separation, the organic layer was washed serially with water (100 mL) and saturated sodium hydrogencarbonate/H2O, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 20.22 g of a reddish brown solid. This solid was recrystallized from ethyl acetate/hexane to provide yellow crystals of tert-butyl (S)-(1-benzyl-3,3-dichloro-2-oxopropyl)carbamate (3.921 g, 98.1 area %, yield 32%). 1H-NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 3.02 (dd, 1H), 3.21 (dd, 1H), 4.82-4.91 (m, 1H), 4.92-5.01 (m, 1H), 6.09 (s, 1H), 7.18-7.35 (m, 5H)
  • 45
  • [ 51987-73-6 ]
  • [ 74-95-3 ]
  • [ 290836-34-9 ]
YieldReaction ConditionsOperation in experiment
53% With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1.16667h; 3 After cooling dehydrated tetrahydrofuran (15 ml) to-78 DEG C, a 2M solution (6.25 ml) of lithium diisopropylamide in heptane, tetrahydrofuran and ethyl benzene was added thereto. Then, a solution of dibromomethane (0.88 ml) in dehydrated tetrahydrofuran (5 ml) was added. The mixture was stirred for 10 minutes. A solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (1.4 g) in dehydrated tetrahydrofuran (7 ml) was added thereto, followed by stirring for 1 hour. The reaction was terminated by the addition of 1N hydrochloric acid (25 ml) to the reaction mixture. After heating to room temperature, the reaction mixture was added with ethyl acetate for extracting. The ethyl acetate solution thus obtained was analyzed by HPLC. As a result, it was confirmed that the target (3S)-1,1-dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butanone (1.14 g) had been formed in a yield of 53%. The ethyl acetate solution was then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. From the filtrate, the solvent was distilled off under reduced pressure. By the addition of ethyl acetate, the resulting residue was made into a slurry. The crystals were then separated from the slurry and dried, whereby the target (3S)-1,1-dibromo-3-tert-butoxycarbonylamino-4-phenyl-2-butanone (1.04 g) was obtained in a yield of 46%.<1>H-NMR (CDCl3, 300MHz) delta ppm: 1.41 (s, 9H), 3.04 (dd, J=7.3, 13.8Hz, 1H), 3.20 (dd, J=6.2, 13.8Hz, 1H), 4.64-5.05 (m, 2H), 6.00 (s, 1H), 7.17-7.37 (m, 5H).[ alpha ]D<30>= -40.6 DEG (c=2.0, CH2Cl2).
19% With n-butyllithium; diisopropylamine In tetrahydrofuran; of2N-HCl; hexane 1 Production of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate EXAMPLE 1 Production of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate Under nitrogen gas, a solution of diisopropylamine (2.4 g, 21.6 mmol) in tetrahydrofuran (10 mL) was added to n-butyllithium (in 1.6 M hexane, 13.5 mL, 21.6 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (2.0 g, 7.2 mmol), dibromomethane (2.5 g, 14.4 mmol) and tetrahydrofuran (10 mL) and cooled to -70° C. (liquor B). To this liquor B was added said liquor A over 30 minutes at -70° C., and the mixture was stirred for 30 minutes at the same temperature and then warmed to 20° C. This reaction mixture was poured in 25 mL of2N-HCl for hydrolysis and, then, extracted with 10 mL of ethyl acetate. The organic layer was washed with 20 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 2.670 g of black solid. This solid was recrystallized from ethyl acetate/hexane to provide brown crystals of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (630 mg, 92.2 area %, yield 19%). 1H-NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 3.05 (dd, 1H), 3.17 (dd, 1H), 4.91 (m, 1H), 4.98 (m, 1H), 6.00 (s, 1H), 7.13-7.36 (m, 5H).
  • 46
  • [ 4530-18-1 ]
  • [ 74-88-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
13.6 g (96%) With potassium hydrogencarbonate; In water; N,N-dimethyl-formamide; (1) To a mixture of N-tert-butoxycarbonylphenylalanine (13.3 g, 50.0 mmol), potassium hydrogencarbonate (10.0 g, 100 mmol) and N,N-dimethylformamide (80 mL) was added methyl iodide (5 mL, 80 mmol). The resulting mixture was stirred at room temperature for 5 h, and water (200 mL) was added. The mixture was extracted with ethyl acetate-benzene (1:1), and the organic layer was washed successively with water, 5% aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 90:10) to give 13.6 g (96%) of N-tert-butoxycarbonylphenylalanine methyl ester as a colorless oil.
  • 47
  • [ 4530-18-1 ]
  • [ 30566-31-5 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In dichloromethane; 14-1) Preparation of N-t-butoxycarbonyl-L-phenylalanine methyl ester To a solution of 8.8 g(0.0344 mol) of N-t-butoxycarbonylphenylalanine in 50 ml of dichloromethane were successively added 5.25 ml of triethylamine solution, and 3 ml of chloromethylformate at 0 C. 50 mg of 4-dimethylaminopyridine was added to catalyze the reaction. After the reaction was completed the reaction mixture was extracted with dichloromethane and distilled under a reduced pressure to give the title compound quantitatively. 1 H NMR(CDCl3) delta1.4(9H, s), 3.1(2H, m), 3.7(3H, s), 4.6(1H, m), 5.0(1H, d), 7.1-7.3(5H, m)
With dmap; triethylamine; In dichloromethane; 14-1) Preparation of N- t -butoxycarbonyl-L-phenylalanine methyl ester To a solution of 8.8g(0.0344mol) of N- t -butoxycarbonylphenylalanine in 50ml of dichloromethane were successively added 5.25ml of triethylamine solution, and 3ml of chloromethylformate at 0C. 50mg of 4-dimethylaminopyridine was added to catalyze the reaction. After the reaction was completed the reaction mixture was extracted with dichloromethane and distilled under a reduced pressure to give the title compound quantitatively. 1H NMR(CDCl3) delta 1.4(9H, s), 3.1(2H, m), 3.7(3H, s), 4.6(1H, m), 5.0(1H, d), 7.1-7.3(5H, m)
  • 48
  • [ 51987-73-6 ]
  • [ 618-87-1 ]
  • [ 167992-89-4 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In ethyl acetate; 1,2-dichloro-ethane 43.a a. a. N-tert-butyloxycarbonyl-1S-(3,5-dinitrophenylamino-carbonyl)-2-phenylethylamine 3,5-Dinitroaniline (3.44 g, 18.7 mmol) and BOC-L-phenylalanine methyl ester (5.24 g, 18.7 mmol) were dissolved in 1,2-dichloroethane (50 ml) and cooled to -10°. Trimethylaluminium (3.6 ml, 37.4 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 10 d. 2M sodium hydroxide solution (20 ml) was added and the reaction mixture filtered through celite, washed with brine and treated with three aliquots of magnesium sulphate, charcoal and celite. After evaporation, the residual material was chromatographed (silica gradient 5-10% ethyl acetate and dichloromethane) and recrystallized from a mixture of dichloromethane and hexane to leave the title compound as a pale yellow solid (2.99 g).
  • 49
  • [ 40203-94-9 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
99.5% In <i>tert</i>-butyl alcohol 4 EXAMPLE 4 To 60.9 g of the N-carbonyl-L-phenylalanine methyl ester, 66.0 g of t-butanol was added and the reaction was conducted under reflux for eight hours. Then, the unreacted t-butanol was distilled off at 65° C. under reduced pressure from the reaction solution to obtain 82.5 g of an oily N-t-butoxycarbonyl-L-phenylalanine methyl ester preparation. The reaction yield was 99.5%. The optical purity of the N-carbonyl-L-phenylalanine methyl ester preparation was 97.5%ee. The N-carbonyl-L-phenylalanine methyl ester preparation having an optical purity of 97.5%ee was purified by the procedure of Example 1 to obtain a preparation containing its optically active form having an optical purity of 99.5%ee.
  • 50
  • [ 51987-73-6 ]
  • [ 13734-34-4 ]
YieldReaction ConditionsOperation in experiment
99% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With dimethylsulfoxonium methylide In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With potassium hydrogensulfate; water In ethyl acetate Inert atmosphere;
98% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1h; Stage #2: With sodium hydroxide; water In tetrahydrofuran
With sodium hydroxide In methanol
Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With lithium iodide In ethyl acetate for 24h; Reflux; Stage #2: With potassium hydrogensulfate; sodium carbonate In ethyl acetate
With lithium hydroxide In methanol; water at 0 - 20℃; for 8h; Step 2 General procedure: To a solution of the carbamates obtained in the previous step(1 equiv) in a mixture methanol/water (1:1), LiOH (2 equiv) wasadded at 0 C. The reaction mixture was then stirred at rt, until disappearanceof the starting material (TLC monitoring). The solventwas then concentrated in vacuo and the reaction mixture was treatedwith 10% citric acid, extracted with EtOAc, dried over Na2SO4and concentrated to afford the pure carboxylic acids
With lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; for 0.5h; 79.1 Step 1: Synthesis of (ieri-butoxycarbonyl)phenylalanine. To methyl (fert-butoxycarbonyl)phenylalaninate 1.5 g (5.37 mmol) in tetrahydrofuran (18 mL)/water (18 mL) was added lithium hydroxide monohydrate 0.68 g (16.1 mmol, 3eq) and the reaction was stirred at rt for 30 min. Acidified mixture drop wise with 2N hydrochloric acid to pH 2, extracted with dichloromethane, washed organic layer with water/brine, dried over sodium sulfate, and concentrated to give the desired compound. ESI-MS m/z 266 (MH)+.

  • 51
  • [ 51987-73-6 ]
  • Nα-(tert-butoxycarbonyl)-N-hydroxy-L-phenylalaninamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With hydroxylamine; sodium methylate In methanol; water at 70℃;
70% With potassium hydroxide; hydroxylamine hydrochloride In methanol at 80℃; for 0.2h; microwave irradiation;
  • 52
  • [ 108-86-1 ]
  • [ 93267-04-0 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #2: bromobenzene With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In N,N-dimethyl-formamide at 50℃; for 3h; Inert atmosphere;
60% Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide for 0.0833333h; Stage #2: bromobenzene With tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 50℃; for 2h; Further stages.;
  • 53
  • [ 55477-80-0 ]
  • [ 934-56-5 ]
  • [ 51987-73-6 ]
  • methyl (2R)-2-(t-butoxycarbonylamino)-3-phenylpropionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.;
  • 54
  • [ 55477-80-0 ]
  • potassium phenyltrifluoborate [ No CAS ]
  • [ 51987-73-6 ]
  • methyl (2R)-2-(t-butoxycarbonylamino)-3-phenylpropionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.;
  • 55
  • [ 67-56-1 ]
  • [ 7535-56-0 ]
  • [ 100-02-7 ]
  • [ 51987-73-6 ]
  • [ 19901-50-9 ]
  • 56
  • [ 51987-73-6 ]
  • [ 5717-37-3 ]
  • [ 1174764-18-1 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With diisobutylaluminium hydride In dichloromethane at -78℃; for 0.75h; Stage #2: (carbethoxyethylidene)triphenylphosphorane With potassium <i>tert</i>-butylate In dichloromethane at -78 - 20℃; 64 Example 64. (S) -5-phenyl-4- (tert-butoxycarbonylamino) -2-methylpentenoate ethyl ester (327) Diisobutylaluminum hydride (40ml, 40mmol, 1.0M) was slowly added to (S) -3-phenyl-2- (tert-butoxycarbonylamino) -propanoic acid at -78 ° C. In a solution of ester 326 (5.60 g, 20.05 mmol) in CH2Cl2(80 ml), after reacting for 45 minutes, 1- (1-ethoxycarbonylethyl) triphenylphosphine bromide (18.0 g, 40.64mmol) and KOtBu (5.00g, 44.64mmol) in dichloromethane (80ml) solution. After the mixture was reacted at -78 ° C for 1 hour, it was stirred at room temperature overnight, and then added to the mixture. 1 liter of sodium dihydrogen phosphate solution, vigorously stirred, separated, the aqueous phase was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (ethyl acetate / n-hexane = 1: 7- 1: 5) to obtain the target product 327 (5.50g, 83%),
82% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With diisobutylaluminium hydride In dichloromethane at -78℃; Stage #2: (carbethoxyethylidene)triphenylphosphorane In dichloromethane
  • 57
  • [ 51987-73-6 ]
  • [ 1774-47-6 ]
  • [ 959761-70-7 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: trimethylsulfoxonium iodide With potassium 2-methylbutan-2-olate In tetrahydrofuran at 70℃; for 2h; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran at 1 - 20℃; for 1.33333h; 4 A one liter flask equipped with a large stir bar, a reflux condenser and an argon inlet was wrapped with aluminum foil to exclude light. The flask was charged with trimethylsulfoxonium iodide (35.3 g, 160 mmol) and tetrahydrofuran (200 mL). To this suspension was added with stirring a 25 wt % solution of potassium t-amylate in THF (88 mL, 176 mmol) and the mixture was stirred 2 h at 70° C. The reaction mixture was cooled to 1° C. and a solution of N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester (14.47 g, 51.8 mmol) in THF (80 mL) was added via cannula over 15 min so that the internal temperature remained between 1° and 5° C. After an additional 5 min at this temperature, the mixture was allowed to warm to room temperature over 30 min. After an additional 30 min, HPLC analysis of an aliquot diluted with 1 mL of acetonitrile and 5 drops of water showed complete consumption of the starting ester. The reaction was quenched with water (100 mL) and was stirred for 15 min after which the organic solvents were removed under vacuum. The concentrated mixture was further diluted with water (550 mL) and the product was extracted into dichloromethane (200 mL then 2×100 mL). The combined extracts were washed with water (2×200 mL), dried over magnesium sulfate, and concentrated under vacuum. Removal of residual solvents at high vacuum afforded the β-keto sulfur ylide (10.2 g, 59%) as a pale yellow solid. 1H NMR: δ 1.41 (s, 9H), 2.98 (m, 2H), 3.25 (s, 3H), 3.35 (s, 3H), 4.28 (s+m, 2H total), 5.22 (d, 1H), 7.15-7.31 (m, 5H). A broad resonance at δ 1.90 indicated the presence of water even after drying for 1 h at 0.5 torr. 13C NMR: δ 28.05, 39.48, 41.46, 41.76, 57.56, 69.39, 79.01, 126.15, 127.86, 129.23, 137.36, 154.90, 186.39.
  • 58
  • [ 51987-73-6 ]
  • [ 145149-48-0 ]
YieldReaction ConditionsOperation in experiment
19.3%Chromat. With potassium tert-butylate; hydrogen;[tris(mu-chloro)bis((triphos)ruthenium(II))] chloride; In methanol; at 100℃; under 30003.0 Torr; for 16h;Inert atmosphere; Autoclave; Example 21 Hydrogenation of N-Boc-phenylalanine methyl ester [Ru2(mu-Cl)3(triphos)2]Cl (3.0 mg), potassium tert-butoxide (5.5 mg), and 2.0 ml of methanol were added into a 20-ml Schlenk tube under an argon atmosphere, and the mixture was stirred for 30 minutes at room temperature. This solution, and N-Boc-phenylalanine methyl ester (0.34 g) suspended in 1.0 ml of methanol were added into a 100-ml autoclave having a stirrer placed inside, under an argon atmosphere. The autoclave was purged with hydrogen, and then hydrogen was further included in the autoclave up to 4.0 MPa. The contents of the autoclave were heated and stirred at 100C for 16 hours. After cooling, the reaction liquid was analyzed by high performance liquid chromatography, and it was found that N-Boc-phenylalaninol was produced at a yield of 19.3%.
  • 59
  • [ 112766-18-4 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
98% With dmap; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In 1,4-dioxane at 80℃; for 16 - 24h; Inert atmosphere;
0.333 g With palladium 10% on activated carbon; ammonium chloride; magnesium In methanol at 25℃; for 6h; Inert atmosphere;
  • 60
  • [ 3364-76-9 ]
  • [ 51987-73-6 ]
  • [ 1240521-20-3 ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: 4-chloromethylthiazole In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #3: With water; ammonium chloride In tetrahydrofuran; N,N-dimethyl-formamide 7.2 .A 2.B [0197] Methyl N-(((l,l-dimethylethyl)oxy)carbonyl)-N-(l,3-thiazol-4-ylmethyl)-L-phenylalaninate (2.B). To a solution of 2.A (available from Aldrich) (627 mg, 2.3 mmol) in THF at 0 0C under N2 atmosphere was added sodium hydride (88 mg, 60%, 2.3 mmol). When the gas formation ceased, to the mixture was added a solution of 4- (chloromethyl)thiazole (available from Combi-Blocks Inc.) (336 mg, 2.5 mmol) in DMF (1.0 mL). The reaction mixture was allowed to warm to rt over 30 mins and was then slowly poured into saturated aqueous NH4Cl (3.0 mL), diluted with water (15 mL), and extracted with EtOAc (3 x 10 mL). The combined organic solution was washed with brine (5 mL), and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-100% EtOAc/Hexanes for elution gave 2.B as colorless solid (523, 61%).
  • 61
  • [ 51987-73-6 ]
  • [ 100-51-6 ]
  • [ 66617-58-1 ]
YieldReaction ConditionsOperation in experiment
97% With lanthanum(III) isopropoxide; 2-(2-methoxyethoxy)ethyl alcohol In hexane at 50℃; Molecular sieve; optical yield given as %ee; chemoselective reaction;
84% With lanthanum (III) nitrate * water; 1,1,1-trioctyl-1-methylphosphonium methylcarbonate In hexane for 20h; Molecular sieve; Reflux;
  • 63
  • [ 51987-73-6 ]
  • [ 75-16-1 ]
  • (S)-(3-hydroxy-3-methyl-1-phenylbut-2-yl)carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester; methylmagnesium bromide In tetrahydrofuran; diethyl ether at 0 - 20℃; Stage #2: With water In tetrahydrofuran; diethyl ether Cooling with ice; 4.5.12. (S)-5-Benzyl-6,6-dimethyl-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-2-ium tetrafluoroborate 52 To a cooled (0 °C) solution of Boc-l-phenylalanine methyl ester (10.0 g, 35.8 mmol) in Et2O (100 mL) was added methylmagnesium bromide (37.0 mL of a 3.0 M solution in THF, 111 mmol) slowly via cannula. The mixture was stirred for 16 h at ambient temperature, quenched with ice-cold H2O (30 mL), then filtered through Celite. The (partially aqueous) filtrate was extracted with CH2Cl2 (50 mL × 2) and the combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the crude alcohol product as a pale yellow solid (7.32 g, 73%) which was used immediately without further purification. To a cooled (0 °C) solution of the crude alcohol (5.00 g, 17.9 mmol) in THF (50 mL) was added potassium tert-butoxide (2.21 g, 19.7 mmol). The mixture was stirred for 16 h at ambient temperature and then concentrated in vacuo to afford a viscous yellow oil. The oil was dissolved in EtOAc (100 mL) and washed with brine (100 mL) and the aqueous phase extracted with EtOAc (20 mL × 2). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give a clear yellow oil. Chromatographic purification (25% EtOAc:petrol) gave the oxazolidinone as a yellow oil (3.51 g, 79%); inlMMLBox (c 1.0, CHCl3), lit.50 -103.5 (c 0.6, CHCl3); δH (300 MHz, CDCl3) 7.37-7.15 (5H, m, ArH), 4.79 (1H, br s, NH), 3.74-3.65 (1H, m, CHNH2), 2.84 (1H, ABX, JAB 13.3, JAX 3.7, PhCHAHB), 2.67 (1H, ABX, JBA 13.3, JBX 10.8, PhCHAHB), 1.49 (3H, s, CH3) and 1.46 (3H, s, CH3). Data are in accordance with the literature.50
In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere;
In tetrahydrofuran; diethyl ether at 0 - 24℃; for 36h; Inert atmosphere;
In tetrahydrofuran at 0 - 20℃; 2.2; 4.2 S2), 2.6g of the prepared in step S1)(Tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 replacing 10 mL of THF,Then, 45 mL of a tetrahydrofuran solution of methylmagnesium bromide was slowly added dropwise under an ice bath or at room temperature, and then transferred to room temperature for stirring. TLC detected that the reaction of the raw materials was complete, and then added NH4Cl (aq., Sat.) To inactivate the reaction, EA extraction, Dry with anhydrous Na2SO4,Filtration, spin-drying, and column chromatography gave white(S)-(3-hydroxy-3-methyl-1-phenylbut-2-yl) sulfamic acid tert-butyl ester 3;

  • 64
  • [ 853308-49-3 ]
  • [ 51987-73-6 ]
  • [ 1332305-25-5 ]
YieldReaction ConditionsOperation in experiment
96% With chloroauric acid In dichloromethane at 20℃; for 2h; Molecular sieve; Inert atmosphere;
  • 65
  • [ 953795-87-4 ]
  • [ 51987-73-6 ]
  • [ 1332305-33-5 ]
YieldReaction ConditionsOperation in experiment
98% With chloroauric acid In dichloromethane at 20℃; for 2h; Molecular sieve; Inert atmosphere;
  • 66
  • [ 953795-90-9 ]
  • [ 51987-73-6 ]
  • [ 1332305-31-3 ]
YieldReaction ConditionsOperation in experiment
97% With chloroauric acid In dichloromethane at 20℃; for 2h; Molecular sieve; Inert atmosphere;
  • 67
  • [ 1198083-94-1 ]
  • [ 51987-73-6 ]
  • [ 1332305-35-7 ]
YieldReaction ConditionsOperation in experiment
95% With chloroauric acid In dichloromethane at 20℃; for 2h; Molecular sieve; Inert atmosphere;
  • 68
  • [ 51987-73-6 ]
  • [ 30018-16-7 ]
  • [ 244033-72-5 ]
YieldReaction ConditionsOperation in experiment
83% L-t-l3oc-phenylalanine methyl ester 326 (5.60 g,20.05 mmol) in CH2C12 (80 ml) at -78 C. was added dropwise DIHAL (40 ml, 40 mmol, 1.0 M) in CH2C12. After stirred at -78 C. for 45 mm, the ylide solution prepared from 1 -(1 -ethoxycarbonyl ethyl)-triphenylphosphonium bromide (18.0 g, 40.64 mmol) and KOtHu (5.00 g, 44.64 mmol) in CH2C12 (80 ml) at RT was added at -78 C. After stirred at -78 C. for 1 h and RT over night, the mixture was poured into 1 L of NaH2PO4 (sat.) solution with vigorously stirring. Separated and the aqueous phase was extracted with CH2C12. The organic layers were dried over Na2504, concentrated and purified by 5i02 chromatography (EtOAc/ Hexane, 1:7.-1:5) to afford 5.50 g (83% yields) of the title compound. ESI: mlz: [M+Na], calcd for C19H27NNaO4, 356.19, Found, 356.20.
83% Example 64. (S, E)-Ethyl 5-phenyl-4-(tert-butoxy-carbonylamino)-2-methylpent-2-enoate (327) L-t-Boc-phenylalanine methyl ester 326 (5.60 g, 20.05 mmol) in CH2Cl2 (80 ml) at -78 C. was added dropwise DIBAL (40 ml, 40 mmol, 1.0 M) in CH2Cl2. After stirred at -78 C. for 45 min, the ylide solution prepared from <strong>[30018-16-7]1-(1-ethoxycarbonyl ethyl)-triphenylphosphonium bromide</strong> (18.0 g, 40.64 mmol) and KOtBu (5.00 g, 44.64 mmol) in CH2Cl2 (80 ml) at RT was added at -78 C. After stirred at -78 C. for 1 h and RT over night, the mixture was poured into 1 L of NaH2PO4 (sat.) solution with vigorously stirring. Separated and the aqueous phase was extracted with CH2Cl2. The organic layers were dried over Na2SO4, concentrated and purified by SiO2 chromatography (EtOAc/Hexane, 1:7?1:5) to afford 5.50 g (83% yields) of the title compound. ESI: m/z: [M+Na]+, calcd for C19H27NNaO4, 356.19, Found, 356.20.
82% 1.6. (4S,2E)-4-(tert.-Butoxycarbonylamino)-2-methyl-5-phenyl-2-pentenic acid ethyl ester (8): To a solution of 4.90 g of L-Boc-phenylalanine methyl ester (17.5 mmol, 1.0 eq.) in 50 ml of absolute dichloromethane, 35 ml of a 1 M DIBAlH solution (35 mmol, 2.0 eq.) is added slowly dropwise at -78 C. While the reaction mixture is stirred at -78 C. for 30 min, the ylide solution is prepared from 15.5 g of (1-ethoxycarbonyl-ethyl)-triphenylphosphonium bromide (35.0 mmol, 2.0 eq.) and 4.03 g of KOtBu (35.9 mmol, 2.1 eq.) in 40 ml of absolute dichloromethane at room temperature. The ylide is added dropwise to the aldehyde solution at -78 C., and after one hour, the cooling bath is removed, and stirring is performed over night at room temperature.The reaction mixture is poured into 800 ml of saturated potassium-sodium tartrate solution and stirred vigorously for 30 min. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried over Na2SO4. Purification by column chromatography (hexane:EE 95:5, then 9:1) yields 4.78 g of the Wittig product (8) (14.3 mmol, 82% of theory) as a colorless oil, which congeals over night to give a white solid.Rf(8)=0.31 (hexane:EE 8:2) 1H NMR (500 MHz, CDCl3): delta=1.26 (t, 3J15,14=7.3 Hz, 3H, 15-H), 1.38 (s, 9H, 13-H), 1.68 (d, 4J10,3=1.5 Hz, 3H, 10-H), 2.76 (dd, 2J5a,5b=13.3 Hz, 3J5a, 4=7.0 Hz, 1H, 5-Ha), 2.90 (m, 1H, 5-Hb), 4.16 (q, 3J14,15=7.3 Hz, 2H, 14-H), 4.55 (bs, 1H, NH), 4.64 (bs, 1H, 4-H), 6.49 (dd, 3J3,4=9.1 Hz, 4J3,10=1.5 Hz, 1H, 3-H), 7.15 (d, 3J7,8=7.0 Hz, 2H, 7-H), 7.20 (t, 3J9,8=7.3 Hz, 1H, 9-H), 7.26 (dd, 3J8,7?3J8,9=7.2 Hz, 2H, 8-H).13C NMR (100 MHz, CDCl3): delta=12.5 (q, C-10), 14.2 (q, C-15), 28.3 (q, C-13), 41.1 (t, C-5), 50.1 (d, C-4), 60.6 (t, C-14), 79.6 (s, C-12), 126.6 (d, C-9), 128.4 (d, C-8), 129.2 (s, C-2), 129.5 (d, C-7), 136.7 (s, C-6), 140.2 (d, C-3), 154.9 (s, C-11), 167.7 (s, C-1).Melting point: 68 C.
  • 69
  • [ 1355062-31-5 ]
  • [ 51987-73-6 ]
  • [ 1355062-34-8 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With trifluoroacetic acid In dichloromethane for 0.5h; Stage #2: (2S)-1-tert-butyloxycarbonylaminobicyclo[2.2.2]octane-2-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;
  • 70
  • [ 51987-73-6 ]
  • [ 7803-57-8 ]
  • [ 30189-48-1 ]
  • 71
  • [ 51987-73-6 ]
  • [ 100-46-9 ]
  • (S)-N-Boc-phenylalanine benzylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With 4-hydroxybenzotrifluoride; sodium methylate In toluene at 50℃; for 72h; Inert atmosphere; Molecular sieve; optical yield given as %ee;
55% With 4-hydroxybenzotrifluoride; potassium acetate In tetrahydrofuran at 90℃; for 22h; Schlenk technique; Sealed tube; Inert atmosphere;
48% With zirconocene dichloride In toluene at 110℃; for 4h; 20 4.1. General procedure General procedure: Carboxylic ester (5.0 mmol), amine (6.5 mmol), and Cp2ZrCl2 (146.7 mg, 0.5 mmol) were suspended in 1.2 mL of anhydrous toluene. The reaction was stirred at 110°C for 4-20 h. The solvent was then removed under reduced pressure. The crude product was purified on a Biotage Isolera One using a Biotage SNAP Ultra cartridge (12 g or 25 g, 10-60% EtOAc in n-heptane) to isolate the desired amide.
  • 72
  • [ 51987-73-6 ]
  • [ 67-68-5 ]
  • [ 184537-67-5 ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: dimethyl sulfoxide With sodium amide In tetrahydrofuran at 60 - 70℃; for 2h; Industry scale; Inert atmosphere; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; toluene at -5 - 5℃; for 1h; 1 Example 1 Preparation of 1,1-dimethylethyl N-[(1S)-3-(methylsulfinyl)-2-oxo-1-(phenylmethyl)propyl]carbamate 2a To a suitable reactor was added THF (7.8 L) and NaNH2 (0.77 kg, 4.0 equiv) at 20-30° C. under N2. The white slurry was heated to 60-70° C. DMSO (5.8 L, 17.7 equiv) in THF (7.8 L) solution was added at 60-70° C., and the mixture was stirred at this temperature for 2 hr. The mixture was cooled to -5-5° C. Ester 1a (1.00 kg, 1.00 equiv) in toluene solution was added at -5-5° C., and the mixture was stirred at this temperature for 1 hr. The reaction was deemed completed as determined by HPLC. 10% citric acid aqueous solution (15.6 L) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic layer was washed with 20% NaCl aqueous solution (13 L). The separated organic portion was concentrated at 35-45° C. under reduced pressure until the volume reached about 6 L. n-Heptane (12 L) was added at 20-30° C. over 1 hr, and the mixture was stirred at this temperature for 3 hr. The mixture was filtered, and the filtered cake was washed with n-heptane (5 L). After being dried at 40-50° C. under reduced pressure, a diastereomeric mixture of 2a (1.2 kg, 80% yield) with purity greater than 98% was obtained. 1H NMR (400 MHz, CDCl3) δ 7.23-7.11 (m, 5H), [5.90 (broad, minor isomer), 5.72 (m, major isomer), totaling 1H], 4.34-4.31 (m, 1H), 3.94 (d, J=15 Hz, 1H), 3.73 (d, J=15 Hz, 1H), 3.11-3.04 (m, 1H), 2.87-2.81 (m, 1H), [2.57 (s, major isomer), 2.55 (s, minor isomer), totaling 3H], 1.32 (s, 9H)
  • 73
  • [ 51987-73-6 ]
  • [ 17193-39-4 ]
  • 74
  • [ 96-50-4 ]
  • [ 51987-73-6 ]
  • (S)-tert-butyl {1-oxo-3-phenyl-1-(thiazol-2-ylamino)propan-2-yl}carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.6% With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Green chemistry; General experimental procedure General procedure: An oven dried 5 mL round bottom flask charged with a magnetic pellet and 2-aminothiazole 2 (2.0 equiv.) in THF (1 mL), 1.0 M t-butylmagnesiumchloride (t-BuMgCl) solution in THF (2.0 equiv.) added and stirred at the 0°C. Then Boc-L-α-phenylglycine ester 1a (1.0 equiv) in THF was added drop wise to the reaction mixture at the 0°C. Then, the reaction mixture was allowed to stir for 2 h at the room temperature. After completion of the reaction, followed by thin layer chromatography (TLC), the reaction mixture was quenched with saturated aqueous NH4Cl solution, and extract with EtOAc (3×10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on neutral alumina using hexanes/EtOAc as the eluent. The solvent was evaporated to dryness to get the pure product 3a. The same procedure was followed for the preparation of other substrates 1b-f also. For the substrates 1h-m, only 1.0 equiv. of 2-aminothizole, ester derivative and t-BuMgCl were required.
  • 75
  • [ 70557-99-2 ]
  • [ 51987-73-6 ]
  • methyl N-(tert-butoxycarbonyl)-N-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-L-phenylalaninate [ No CAS ]
  • 76
  • [ 51987-73-6 ]
  • [ 38574-62-8 ]
YieldReaction ConditionsOperation in experiment
95% In acetonitrile at 300℃;
  • 77
  • [ 3112-85-4 ]
  • [ 51987-73-6 ]
  • [ 169701-71-7 ]
YieldReaction ConditionsOperation in experiment
94% Stage #1: methylphenylsulfonate With n-butyllithium In tetrahydrofuran; hexane at -5℃; for 0.5h; Inert atmosphere; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; hexane at -78 - 25℃; Inert atmosphere; 3.1. General Procedure for the Synthesis of α-Ketosulfones 3 General procedure: 1.6 M n-BuLi in hexane (2.5 mL, 4 mmol for 3a-f,h; 1.25 mL, 2 mmol for 3g,i) was slowly addedat 5 °C, under Ar, to a solution of sulfone 2 (2.0 mmol) in 1.5 mL dry THF, and the mixture wasstirred at 5 °C for 30 min (4 h for reactions with sulfone 2b). The resulting yellow suspension wastransferred via a syringe to a three-necked flask, containing a 2.5 M solution of the N-Boc amino ester 1(1 mmol) in dry THF (1M for 3h,i), at 78 °C, under an Ar atmosphere, with stirring. The mixturewas stirred overnight while the temperature was allowed to reach 25 °C, and partitioned between 5%aqueous citric acid (water for 3f) and ethyl acetate. The organic phase was extracted with saturatedNaHCO3 and brine, dried over Na2SO4 and evaporated to give a solid that was purified by flashchromatography (eluent AcOEt/petroleum ether from 0%-15%).
  • 78
  • [ 599-70-2 ]
  • [ 51987-73-6 ]
  • (2S,4S)-2-(tert-butoxycarbonylamino)-1-phenyl-4-(phenylsulfonyl)-3-pentanone [ No CAS ]
  • (2S,4R)-2-(tert-butoxycarbonylamino)-1-phenyl-4-(phenylsulfonyl)-3-pentanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
20 % de Stage #1: ethyl phenyl sulfone With n-butyllithium In tetrahydrofuran; hexane at -5℃; for 4h; Inert atmosphere; Stage #2: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester In tetrahydrofuran; hexane at -78 - 25℃; Inert atmosphere; Overall yield = 77 %; 3.1. General Procedure for the Synthesis of α-Ketosulfones 3 General procedure: 1.6 M n-BuLi in hexane (2.5 mL, 4 mmol for 3a-f,h; 1.25 mL, 2 mmol for 3g,i) was slowly addedat 5 °C, under Ar, to a solution of sulfone 2 (2.0 mmol) in 1.5 mL dry THF, and the mixture wasstirred at 5 °C for 30 min (4 h for reactions with sulfone 2b). The resulting yellow suspension wastransferred via a syringe to a three-necked flask, containing a 2.5 M solution of the N-Boc amino ester 1(1 mmol) in dry THF (1M for 3h,i), at 78 °C, under an Ar atmosphere, with stirring. The mixturewas stirred overnight while the temperature was allowed to reach 25 °C, and partitioned between 5%aqueous citric acid (water for 3f) and ethyl acetate. The organic phase was extracted with saturatedNaHCO3 and brine, dried over Na2SO4 and evaporated to give a solid that was purified by flashchromatography (eluent AcOEt/petroleum ether from 0%-15%).
  • 79
  • [ 51987-73-6 ]
  • [ 75-65-0 ]
  • [ 116400-16-9 ]
YieldReaction ConditionsOperation in experiment
86% With Fe<SUP>III</SUP>-salen In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 24h; Reflux; 12 EXAMPLE 12 On the basis of the above-described results, in present Example, the substrate generality was verified by using a nonsubstituted iron(III)-salen complex (Table 11).When methyl 3-phenylpropionate was used, the reaction proceeded nearly quantitatively by increasing the catalyst amount to 10 mol % in terms of iron. Methyl esters of N-protected glycines also yielded the target products respectively in favorable yields. Further, an investigation was performed by using an optically active amino acid. When Boc-Phe-OMe was used, the target product was successfully obtained without impairing the optical purity. Also when a phenyl glycine tending to be racemized was used, the target product was obtained in a moderate yield although a slight degradation of the optical purity was found. The above-described results suggest that the present iron catalyst is useful for the synthesis of the tert-butyl esters of the various chiral amino acids and the like.
84% With (μ-oxo)bis[(1,2-ethanediamino-N,N'-bis(salicylidene))iron(III)] In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 24h; Inert atmosphere; Schlenk technique; stereoselective reaction;
  • 80
  • [ 78-38-6 ]
  • [ 51987-73-6 ]
  • ((2S)-4-(diethoxyphosphoryl)-3-oxo-1-phenylpentane-2-yl)carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; 2 ((2S) - 4 - (diethoxyphosphoryl) - 3-oxo-1-phenyl pentane-2-yl) carbamic acid T-butyl ester (4a) Ethylphosphonic acid diethyl ester (11.53 ml, 71.47 mmol) was dissolved in 100 ml THF at -78 C and into protection of nitrogen BuLi(44.67 ml, 71.47 mmol) was added under atmospheric pressure and the reaction was continued at -78 & lt; 0 & gt; C for 1 hAfter which a solution of compound 3a (6.65 g, 23.82 mmol) in THF was added and the reaction was allowed to proceed at -78 ° C until TLCAfter the disappearance of the raw material, the reaction was terminated. An appropriate amount of water was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml× 3), and the organic layers were combined and washed with saturated brine (100 ml × 3), dried over anhydrous sodium sulfate and concentratedThe crude product was purified by column chromatography to give 8.68 g of a colorless oil, m.p. 88%. Product can not be separated for a pairOf the diastereomers, and the mixture has a hydrogen spectrum
  • 81
  • [ 24424-99-5 ]
  • 3-phenyl-2-pyrrol-1-ylpropionic acid methyl ester [ No CAS ]
  • [ 51987-73-6 ]
  • methyl (2R)-2-(t-butoxycarbonylamino)-3-phenylpropionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-phenyl-2-pyrrol-1-ylpropionic acid methyl ester With ozone In methanol at -78℃; for 2h; Stage #2: With thiourea In methanol at -78 - 0℃; for 1.5h; Inert atmosphere; Stage #3: di-<i>tert</i>-butyl dicarbonate Optical yield = 87%ee; Further stages; 7.2 Ozonolysis and Protection with 13oc of CarboxylicAcid Methyl Ester 3s 10763] A solution prepared by dissolving the carboxylic acid methyl ester3s (85.6 mg, 0.373 mmol) in methanol (15 mE) was treated with ozone for 2 hours at -78° C. Argon gas was allowed to bubble in the reaction mixture for 1 minute, and a solution prepared by dissolving thiourea (34.1 mg, 0.448 mmol) in methanol (4 mE) was added thereto at -78° C. Subsequently, the reaction mixture was stirred for 30 minutes at -78° C. and for 1 hour at 0° C. and filtered through Celite. The filtrate was dried under reduced pressure, and the residue was dissolved in methanol (7.46 mE).10764] Subsequently, 1,4-dioxane (4.0 M, 7.46 mE, 29.8 mmol) containing hydrochloric acid was added to the mixture at 0° C., and the mixture thus obtained was stirred for 6 hours at room temperature. The liquid was dried under reduced pressure, and the residue was suspended in THF (5 mE).10765] Subsequently, a saturated aqueous solution of sodium hydrogen carbonate (5 mE) and di(tert-butyl) dicarbonate (325 mg, 1.49 mmol) were added to the mixture at 0° C. The reaction mixture was stirred for 60 hours at room temperature and then diluted with watet Subsequently, the mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was dried over sodium sulfate, then filtered, and concentrated under reduced pressure, thereby obtaining a crude product. The crude product was separated (developing solvent: ethyl acetate/hexane=6/14) by silica gel thin layer chromatography, thereby obtaining the colorless oily N-l3oc-phenylala- nine methyl ester 4s (72.9 mg, 70% yield, 87% cc). 10766] HPEC (CHIRAEPAK 113-3, i-PrOH/hexane=1/49, flow rate=0.75 mE/mm): tR=12.3 mm (6.6%), tR=14.4 mm (93.4%);10767] [a]D25+39.5 (c 1.13, CHC13).
  • 82
  • [ 51987-73-6 ]
  • [ 6638-79-5 ]
  • [ 87694-53-9 ]
YieldReaction ConditionsOperation in experiment
85% With isopropylmagnesium chloride; In tetrahydrofuran; at -40 - 0℃; for 3.25h;Inert atmosphere; General procedure: According to V. Druais, M.J. Hall, C. Corsi, S.V. Wendeborn, Ch. Meyer, J. Cossy, A convergent approach toward phoslactomycins and leustroducsins, Tetrahedron 66 (2010) 6358-6375 N-Boc-L-leucine methylester (1 g, 4.08 mmol) was dissolved in a secured three-neck round-bottom flask in the suspension of O,N-dimethylhydroxylamine hydrochloride (CH3ONHCH3HCl, 0.597 g, 6.12 mmol) in dry tetrahydrofurane (25 mL) under nitrogen atmosphere. The reaction mixture was cooled to -40 C and i-PrMgCl (2M in dry THF, 6.12 mL, 12.24 mmol) was added dropwise via syringe pump over 15 minutes. The mixture was stirred and over the period of 3 hours slowly heated from -30 C to 0 C, the quenched saturated solution of NH4Cl in H2O (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with H20 (2 x 10 mL) and dried over Na2SO4. The crude product was purified by column chromatography (silica gel 70 g, n-hexane/ethyl acetate (3:1)) to afford Weinreb amides in yield 53 % as colourless oil.
  • 83
  • tert-butyl (2,4-dioxo-3-azaspiro[5,5]undecan-3-yl) carbonate [ No CAS ]
  • [ 7524-50-7 ]
  • [ 51987-73-6 ]
YieldReaction ConditionsOperation in experiment
92% With triethylamine In dichloromethane at 38 - 40℃; Preparation of Methyl (tert-butoxycarbonyl)-L-phenylalaninate (Table 2, entry 1). L-Phenylalanine methyl ester hydrochloride (5.0 g, 23.2 mmol), triethyl amine (2.47 g, 24.4 mmol) and 2 (7.24 g, 24.4 mmol) were added to dichloromethane (50 mL) and stirred at reflux temp (38-40°C) for 5h. After completion of the reaction, filtered to remove salts and the filtrate was washed with 5% KHSO4 (20 mL), water (25 mL), brine (25 mL), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain a pale yellow oil. The oil was purified by column chromatography (silica gel, ethyl acetate/ hexane, 8:2) to afford 5.96 g (92%) Methyl (tert-butoxycarbonyl)-L-phenylalaninate as a colorless oil. Rf 0.5 (n-Hexane: EtOAc-4:1); [α]D 25 = -4.5° (c 1 in MeOH) {lit.5 [α]D 25 = -6.0° (c 2.5, MeOH)}; IR (neat, cm-1) : vmax 3437, 3020, 2980, 2954, 1735, 1719, 1604, 1507, 1492, 1454, 1444, 1437, 1391, 1364, 1250, 1177, 1154, 1079, 1053, 1015, 951, 932, 858, 817, 779, 739, 701, 668; 1H NMR (300 MHz, CDCl3): δ 7.32-7.11 (m, 5H), 4.98-4.95 (d, 1H), 4.62-4.55 (q, 1H), 3.71 (s, 3H), 3.15-3.01 (m, 2H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 172.33, 155.08, 136.05, 129.28, 128.53, 127.00, 79.86, 54.44, 52.15, 38.34, 28.28; MS: m/z 302.90 [M+Na]+.
  • 84
  • [ 6274-57-3 ]
  • [ 51987-73-6 ]
  • C32H43N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Magnesium strips (0.36 g, 15 mmol), a small amount of iodine, 4-bromo-N,N-dimethylbenzylamine (0.21 g, 1 mmol), tetrahydrofuran (25 mL) were added to a round bottom flask, and the mixture was heated to reflux. The reaction is initiated.A solution of 4-bromo-N,N-dimethylbenzylamine (2.98 g, 14 mmol) in THF (5 mL) was then added dropwise over 30 min.After the addition is completed, the reflux is continued for 2 hours.Then cooled to room temperature, and slowly added the compound a derived from amino acid within 30 min.(2-[(tert-Butoxycarbonyl)amino]-3-phenylpropanoic acid methyl ester) (1.40 g, 5 mmol) in THF (5 mL)The saturated ammonium chloride solution was quenched, extracted with ethyl acetate and washed with saturated brine.After drying over anhydrous sodium sulfate, a crude Boc-protected amino alcohol b was obtained, which was used directly in the next step.
  • 85
  • [ 25022-99-5 ]
  • [ 51987-73-6 ]
  • methyl (S)-3-phenyl-2-[(9-phenyl-9H-fluoren-9-yl)amino]propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: 9-chloro-9-phenyl-9H-fluorene With 4-methyl-morpholine; silver nitrate In acetonitrile at 0 - 20℃; for 2h;
Same Skeleton Products
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