* 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.
With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; for 18 h;
To a solution of L-4-hydroxyphenylglycine (1.00 g, 5.98 mmol) and sodium hydrogencarbonate (2.50 g, 29.11 mmol) in a mixture of 1,4-dioxane (20 mL) and water (20 mL) was added di-tert-butyl dicarbonate (1.40 g, 6.58 mmol) at 0 0C, followed by stirring at room temperature for 18 hours. The organic portion of the solvent was evaporated, and the reaction mixture was partitioned between ethyl acetate (300 mL) and 0.5M aqueous hydrochloric acid (50 mL). The organic layer was separated and washed with 0.5M aqueous hydrochloric acid, water and brine, dried over sodium sulfate, filtered and the solvent concentrated to give (S)-2-(tert- butoxycarbonylamino)-2-(4-hydroxyphenyl)acetic acid (1.6 g, quantitative). 1H NMR (400 MHz, CDCl3): 8.80 (bs, IH), 7.12 (d, 2H), 6.62 (d, 2H), 5.80 (d, IH), 5.00 (d, IH), 1.22 (s, 9H). MS (EI) for CnHi7NO5: 266 (M-H). [00989]
99%
at 20℃;
4-Hydroxy-L-phenylglycine (4.00 g, 23.93 mmol) and sodium bicarbonate (6.04 g, 71.80 mmol) was dissolved in water/tetrahydrofuran (70 mL/70 mL). The solution was cooled in an ice-bath and then di-tert-butyl dicarbonate (7.83 g, 35.90 mmol) was added into the solution. After stirring at room temperature overnight the mixture was washed with ether (50 mL). The aqueous portion was acidified to pH 4 with 2N HC1 and extracted with dichloromethane (3 x 100 mL). The organic portion was washed with saturated sodium chloride (60 mL) and dried over anhydrous sodium sulfate. The organic portion was filtered, concentrated, and dried under high vacuum to give 6.35 g product as a white solid (yield: 99percent). NMR (500 MHz, CD3OD): δ 7.22 (d, 2H), 6.77 (d, 2H), 5.07 (br, 1 H), 1.45 (s, 9H); MS (EI) for C,3Hi7N05: 266 (MH").
86%
With triethylamine In tetrahydrofuran; water at 0℃; for 18 h;
To a solution of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid (2.00 g, 11.96 mmol) and Et3N (1.67 mL, 11.96 mmol) in THF (30 mL) and H2O (30 mL) at 0° C. was added di-tert-butyl dicarbonate (2.61 g. 11.96 mmol). The solution was stirred at 0° C. for 18 hours and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 5percent H3PO4 aqueous solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (2.85 g, 86percent yield) MS (ESI+) m/z=290 (M+Na)+
Reference：
[1] Synlett, 2008, # 15, p. 2355 - 2359
[2] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 410
[3] Chemistry - A European Journal, 2010, vol. 16, # 34, p. 10523 - 10534
[4] Patent: WO2014/210436, 2014, A2, . Location in patent: Paragraph 00411; 00412
[5] Advanced Synthesis and Catalysis, 2017, vol. 359, # 17, p. 2897 - 2900
[6] Patent: WO2018/149419, 2018, A1, . Location in patent: Paragraph 00539
[7] Patent: US2010/29686, 2010, A1, . Location in patent: Page/Page column 73
[8] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6412 - 6426
[9] Heterocycles, 1994, vol. 39, # 2, p. 603 - 612
[10] Tetrahedron Letters, 2007, vol. 48, # 26, p. 4509 - 4513
[11] Journal of the American Chemical Society, 2007, vol. 129, # 51, p. 15830 - 15838
[12] Patent: WO2009/34388, 2009, A1, . Location in patent: Page/Page column 23
[13] Journal of the American Chemical Society, 2011, vol. 133, # 44, p. 17869 - 17877
[14] Patent: US9187524, 2015, B2, . Location in patent: Page/Page column 98; 99
[15] Patent: WO2017/84629, 2017, A1, . Location in patent: Paragraph 00254
[16] Patent: WO2017/84630, 2017, A1, . Location in patent: Paragraph 00377
[17] Patent: WO2008/134679, 2008, A1, . Location in patent: Page/Page column 98
2
[ 32462-30-9 ]
[ 69651-48-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With sodium bromide In acetonitrile for 2 h; Reflux Stage #2: at 65℃; for 20 h; Reflux
General procedure: (I) In a reaction vessel equipped with a stirrer, a condensing reflux device and a thermometer, a mass fraction of 65percentC eye solution200 ml,D- (a) -p-hydroxyphenylglycine 0.085mol, sodium bromide 0.08mol, stirring speed 190rpm, stirring time 120min, tert-butoxycarbonyl bromide 0.085mol, control solution temperature 65 , reaction time 20h, adding 500ml mass fraction 40 percent potassium bromide solution was diluted, ethylenediamine was extracted 8 times, the aqueous layer was washed with oxalic acid, and the pH value of the control solution was 6. After adding potassium bromide, the mass fraction was 96percent. The extract was extracted with calcium chloride, , 1.9kPa vacuum distillation, evaporation of the solvent, the residue added to the mass fraction of 95percent butanol solution, the solid crushing, filtration, D-α-tert-butoxycarbonylamino-α- (4-hydroxyphenyl) - acetic acid 14.62 g, yield 89percent.
Reference：
[1] Patent: CN105585510, 2016, A, . Location in patent: Paragraph 0014; 0015; 0006
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h;
To a solution of L-4-hydroxyphenylglycine (1.00 g, 5.98 mmol) and sodium hydrogencarbonate (2.50 g, 29.11 mmol) in a mixture of 1,4-dioxane (20 mL) and water (20 mL) was added di-tert-butyl dicarbonate (1.40 g, 6.58 mmol) at 0 0C, followed by stirring at room temperature for 18 hours. The organic portion of the solvent was evaporated, and the reaction mixture was partitioned between ethyl acetate (300 mL) and 0.5M aqueous hydrochloric acid (50 mL). The organic layer was separated and washed with 0.5M aqueous hydrochloric acid, water and brine, dried over sodium sulfate, filtered and the solvent concentrated to give (S)-2-(tert- butoxycarbonylamino)-2-(4-hydroxyphenyl)acetic acid (1.6 g, quantitative). 1H NMR (400 MHz, CDCl3): 8.80 (bs, IH), 7.12 (d, 2H), 6.62 (d, 2H), 5.80 (d, IH), 5.00 (d, IH), 1.22 (s, 9H). MS (EI) for CnHi7NO5: 266 (M-H). [00989]
99%
In tetrahydrofuran; water; at 20℃;
4-Hydroxy-L-phenylglycine (4.00 g, 23.93 mmol) and sodium bicarbonate (6.04 g, 71.80 mmol) was dissolved in water/tetrahydrofuran (70 mL/70 mL). The solution was cooled in an ice-bath and then di-tert-butyl dicarbonate (7.83 g, 35.90 mmol) was added into the solution. After stirring at room temperature overnight the mixture was washed with ether (50 mL). The aqueous portion was acidified to pH 4 with 2N HC1 and extracted with dichloromethane (3 x 100 mL). The organic portion was washed with saturated sodium chloride (60 mL) and dried over anhydrous sodium sulfate. The organic portion was filtered, concentrated, and dried under high vacuum to give 6.35 g product as a white solid (yield: 99%). NMR (500 MHz, CD3OD): delta 7.22 (d, 2H), 6.77 (d, 2H), 5.07 (br, 1 H), 1.45 (s, 9H); MS (EI) for C,3Hi7N05: 266 (MH").
86%
With triethylamine; In tetrahydrofuran; water; at 0℃; for 18h;
To a solution of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid (2.00 g, 11.96 mmol) and Et3N (1.67 mL, 11.96 mmol) in THF (30 mL) and H2O (30 mL) at 0 C. was added di-tert-butyl dicarbonate (2.61 g. 11.96 mmol). The solution was stirred at 0 C. for 18 hours and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 5% H3PO4 aqueous solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (2.85 g, 86% yield) MS (ESI+) m/z=290 (M+Na)+
With potassium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 16h;
Preparation 14: (.S)-ferf-Butoxycarbonylamino-(4-hydroxyphenyl)acetic acid; (5)-4-Hydroxyphenylglycine (10.00 g, 59.8 mmol) was added to H2O (50 mL) and THF (50 mL) at O0C under argon. K2CO3 (16.40 g, 119.8 mmol) and di-ferf-butyl dicarbonate (14.4 g, 66.0 mmol) were added and the reaction was stirred at ambient temperature for 16 h. The THF was removed in vacuo, then the aqueous layer was extracted with EtOAc (50 mL), acidified to pH 4 with citric acid and further extracted with EtOAc (2 X 50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo, azeotroping several times with DCM to afford the title compound: RT = 2.55 min, m/z (ES+) = 268.1 [M + H]+.
With sodium hydrogencarbonate; In water; acetone;
To a solution of 4-hydroxyphenylglycine (12 g, 71.860 mmol) in a 1:1 mixture of acetone and water was addeddi-tert-butyldicarbonate (16.5 mL, 71.8 mmol, 1 eq) andsodium bicarbonate (6.03 g, 0.11 mol, 1.5 eq). The solutionwas allowed to stir overnight, and then was quenched with theaddition of citric acid (pH 3) to pH 4. The aqueous layer was65 then extracted 2x with EtOAc and the combined organiclayers were washed with brine, dried over Na2S04 and concentratedto a white foam. The crude material (18.43 g, 69mmol (assumed)) was used without further purification bydissolving it in anhydrous DMF and treating sequentiallywith triethylamine (12.6 mL, 75.9 mmol, 1.3 eq), HOBT(9.32 g, 69 mmol, 1 eq) andAla-OMe HCl (9.63 g, 69 mmol,1 eq). The solution was then cooled to oo C. and EDC (19.55 5g, 0.1 mol, 1.5 eq) was added in one portion. The reaction wasallowed to warm to room temperature and stirred overnight.Water and EtOAc were added, the aqueous layer wasextracted 3x, and the combined organic layers were washedwith brine, dried over Na2S04 and concentrated. The residue 10was purified by flash chromatography (6% MeOH, 0.6%AcOH in DCM) to give a clear residue (17.82 g, 71% yield).Rf=0.39 (7% MeOH in DCM). 1H NMR (CDC13 , 600 MHz)o (ppm) 7.11 (d, 1=8.4 Hz, 2H), 6.64 (d, 1=8.4 Hz, 2H), 6.51 15(brd, 1=6.6 Hz, lH), 5.71 (brs, lH), 5.07 (brs, lH), 4.57-4.52(m, 1H),3.69(s,3H), 1.42-1.40(m, 12H). 13CNMR(CDC13 ,600 MHz) o (ppm) 173.2, 170.5, 156.6, 155.4, 129.0, 128.7(2C), 116.1 (2C), 80.5, 58.2, 52.7, 48.5, 28.4 (3C), 18.4. IR(film)vmax=1655, 1512,1450,1365,1215,1157,1049 cm-1. 20ESI HRMS calcd for [(M+NatJ C17H24N20 6 : 375.1526.found: 375.1532.
With sodium hydrogencarbonate; In water; acetone; at 25℃;
To a stirred mixture of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid (100 g, 0.6 mol, 1 eq) in a mixture of acetone (400 mL) and water (400 mL) was added di-tert-butyl dicarbonate (130.5 g, 0.6 mol, 1 eq) and NaHCO3 (75.4 g, 0.9 mol, 1.5 eq). The mixture wasallowed to stir at 25 C overnight. After HPLC showed the reaction was complete, the mixture was acidified with 5% citric acid (pH 3). The mixture was filtered and the filter cake was washed with water, then dried to give (S)-2-((tert-butoxycarbonyl)amino)-2-(4- hydroxyphenyl)acetic acid (140 g, 87.5%). The crude product was used directly without further purification.
With sodium hydrogencarbonate; In water; acetone; at 25℃;
To a stirred mixture of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid (100 g, 0.6 mol, 1 eq) in a mixture of acetone (400 mL) and water (400 mL) was added di-tert-butyl dicarbonate (130.5 g, 0.6 mol, 1 eq) and NaHCO3 (75.4 g, 0.9 mol, 1.5 eq). The mixture wasallowed to stir at 25C overnight. After HPLC showed the reaction was complete, the mixture was acidified with 5% citric acid (pH 3). The mixture was filtered and the filter cake was washed with water, then dried to give (S)-2-((tert-butoxycarbonyl)amino)-2-(4- hydroxyphenyl)acetic acid (140 g, 87.5%). The crude product was used directly without further purification.
Boc anhydride (1.6 g, 7.2 mmol) in 10 ml THF was added dropwise to an ice-cooled stirring solution of 4-hydroxy-L-phenylglycine (1.0 g, 6 mmol) and NaHCtheta3 (1.0 g, 12 mmol) in 10 ml water. After complete addition, solution was warmed to room temp and stirred overnight. THF was evaporated off and 10 ml water was added. The aqueous layer was extracted twice with 20 ml ethyl acetate and the aqueous layer was acidified to pH 3 with aqueous citric acid. The aqueous layer was extracted twice with 25 ml ethyl acetate and organic layers combined. The organic layer was washed twice with brine and once with water, dried over MgStheta4 and concentrated to yield 1.5 g Boc-4-hydroxy-L-phenylglycine (Boc-Phg(4-OH)). The protected amino acid was a single peak with the correct mass by LCMS and was used without further purification. Calculated mass 267.3, found 268.5.
In a 50 mL round bottomed flask was added a 1:1 mixture of benzene:methanol and N-tert-butoxycarbonyl-(S)-4-hydroxyphenylglycine (2.8 g, 11 mmol). The solution was cooled to 0 C. and a 2 M solution of trimethylsilyldiazomethane (Aldrich Chemical Co.) in hexane was added with vigorous stirring until a slight yellow color persisted. Then the reaction mixture solvents were removed under reduced pressure and the crude product was purified by flash chromatography (80/20 hexane/ethyl acetate) to give N-tert-butyloxycarbonyl-(S)-4-hydroxyphenylglycine, methyl ester (2.05 g, 7.3 mmol) (66% yield). 300 MHz 1H NMR (CDCl3): delta1.43 (s, 9H), 3.71 (s, 3H), 5.22 (br d, 1H), 5.57 (1H, br d), 5.80 (br s, 1H), (6.7 (d, 2H, J=8 Hz), 7.17 (d, 2H, J=8 Hz).
With methanol; In toluene;
Preparation 15: (.S)-ferf-Butoxycarbonylamino-(4-hydroxyphenyl)acetic acid methyl ester; Trimethylsilyldiazomethane (5.40 mL, 7.62 mmol) was added dropwise to a solution of (5)-ferf-butoxycarbonylamino-(4-hydroxyphenyl)acetic acid (Preparation 14, 2.00 g, 7.48 mmol) in toluene:MeOH (4:1, 50 mL). The clear solution turned yellow and the MeOH was removed in vacuo. The remainder was diluted with EtOAc (100 mL), washed with H2O (50 mL), saturated NaHCO3 solution (50 mL) and brine (50 mL) before being dried (MgSO4), filtered and concentrated in vacuo, azeotroping several times with Et2O, to afford the title compound: RT = 2.98 min, m/z (ES+) = 282.1 [M + H]+.
STEP 2: To a solution of (S)-2-(tert-butoxycarbonylamino)-2-(4- hydroxyphenyl)acetic acid (1.60 g, 5.98 mmol) in dimethylformamide (20 mL) was added potassium carbonate (1.85 g, 13.42 mmol), and the mixture was stirred at room temperature for thirty minutes, followed by the addition of methyl iodide (0.76 mL, 12.20 mmol). The reaction mixture was then stirred at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate (250 mL) and water (50 mL). The organic layer was separated and washed with saturated aqueous sodium hydrogencarbonate, water and brine, dried over sodium sulfate, filtered and the solvent was concentrated to give (S)-methyl 2-(tert- butoxycarbonylamino)-2-(4-methoxyphenyl)acetate (1.8 g, quantitative). 1H NMR (400 MHz, CDCl3): 7.16 (d, 2H), 6.72 (d, 2H), 5.68 (d, IH), 5.14 (d, IH), 3.62 (s, 3H), 3.56 (s, 3H), 1.24 (s, 9H). MS (EI) for C15H21NO5: 294 (MH").
99%
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 18h;
The solution was stirred at 25 C. for 18 hours and then diluted with ethyl acetate and washed with 5% H3PO4 aqueous solution and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (1.06 g, 99% yield) MS (ESI+) m/z=318 (M+Na)+
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