* 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.
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 19, p. 6726 - 6735
[2] Tetrahedron Letters, 1995, vol. 36, # 8, p. 1223 - 1226
[3] Journal of Organic Chemistry, 1981, vol. 46, # 23, p. 4799 - 4800
[4] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 9, p. 1119 - 1122
[5] Journal of Organic Chemistry, 1981, vol. 46, # 23, p. 4797 - 4798
[6] Tetrahedron Letters, 1993, vol. 34, # 41, p. 6513 - 6516
[7] Journal of Organic Chemistry, 1996, vol. 61, # 20, p. 6994 - 6996
[8] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1799 - 1804
[9] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1486 - 1490
[10] Synthetic Communications, 1996, vol. 26, # 13, p. 2511 - 2522
[11] Synthesis, 1990, p. 299 - 301
[12] Patent: WO2011/69149, 2011, A2, . Location in patent: Page/Page column 26
[13] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 2, p. 702 - 713
[14] Tetrahedron Letters, 2012, vol. 53, # 26, p. 3225 - 3229
[15] Tetrahedron Letters, 2012, vol. 53, # 32, p. 4216 - 4220
[16] Synlett, 2013, vol. 24, # 6, p. 747 - 751
2
[ 66866-45-3 ]
[ 79069-15-1 ]
Yield
Reaction Conditions
Operation in experiment
8.47 g
With sodium tetrahydroborate In water at 0℃; for 0.5 h;
To a stirred solution of 28 (9.28 g, 31.7 mmol) and N-methyl morpholine (3.7 mL, 33.7 mmol) in DME (70 mL) was added isobutyl chloroformate (4.3 mL, 33.3 mmol) at -20 °C under argon atmosphere. After being stirred for 30 min at 0 °C, the reaction mixture was filtered to remove the resulting precipitates. To a cooled suspension of sodium borohydride (2.5 g, 66.5 mmol) in water (30 mL) was added the filtrate at 0 °C. Stirring was continued for additional 30 min at the same temperature. The reaction mixture was diluted with EtOAc, washed with hydrochloric acid, water, brine, and dried over Na2SO4. The organic layer was removed by evaporation to give an alcohol 29 as a colorless oil (8.47 g, 96percent). 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 3.60-3.83 (m, 6H), 4.54 (s, 2H), 5.17 (br s, 1H), 7.40-7.28 (m, 5H).
Reference：
[1] Synthetic Communications, 1996, vol. 26, # 13, p. 2511 - 2522
[2] Nucleosides and Nucleotides, 1999, vol. 18, # 8, p. 1845 - 1861
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 2, p. 702 - 713
With sodium tetrahydroborate; triethanolamine In tetrahydrofuran; water; ethyl acetate
N-(tert-Butyloxycarbonyl)-O-Benzyl-L-Serinol (3) N-(tert-butyloxycarbonyl)-O- benzyl-L-serine 2 (6.0 g, 20.34 mmol) was dissolved in dry THF and cooled to -20° C. under argon atmosphere. To this cold stirred solution was added TEA (2.32 g, 23 mmol) and isobutyl chloroformate (3.13 g, 23 mmol). The stirring was continued for 30 min at -20° C. under argon atmosphere. The reaction mixture was filtered immediately under a blanket of argon, the precipitate was washed with dry THF (50 ml). The combined filtrate was added slowly into a cold (0° C.) solution of NaBH4 (7.4 g, 200 mmol) in THF/water (80:20, 200 ml) during 10 min period. After the addition, the reaction mixture was stirred for 2 h at 0° C. and the pH adjusted to 7 with acetic acid. The solution was evaporated to dryness, partitioned between ethyl acetate/water (300:150 ml) and extracted in ethyl acetate. The organic extract was washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography over silica gel using CH2 Cl2 -->EtOAc as the eluent. The pure product was pooled together and evaporated to dryness to give 4.7 g (82percent) of the pure product as an oil. 1 H-NMR (CDCl3): δ1.41 (s, 9H, Boc), 3.60-3.70 (m, 4H), 3.82 (d, 2H), 4.53 (s, 2H, OCH2 Ph), 5.20 (bs, 1H, NH) and 7.30-7.40 (m, 5H, Ph).
Reference：
[1] Patent: US5969135, 1999, A,
10
[ 24424-99-5 ]
[ 79069-15-1 ]
Reference：
[1] Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278
[2] Synthesis, 1997, # 10, p. 1146 - 1150
[3] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1799 - 1804
[4] Tetrahedron Letters, 2012, vol. 53, # 26, p. 3225 - 3229
11
[ 4726-96-9 ]
[ 79069-15-1 ]
Reference：
[1] Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278
[2] Nucleosides and Nucleotides, 1999, vol. 18, # 8, p. 1845 - 1861
[3] Synthesis, 1997, # 10, p. 1146 - 1150
[4] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1799 - 1804
(25)-3-(benzyloxy)-2-[(ter?-butoxycarbonyl)amino]propanoic acid (7.2 g, 24.4 mmole) was dissolved in ethylene glycol dimethyl ether (50 mL). N- Methylmorpholine (2.7 ml, 24.4 mmole) was added, and the resulting clear solution was cooled to -20C. Isobutyl chloroformate (3.19 ml, 24.4 mmole) was added dropwise to cause N-methylmorpholine HCl salt precipitation. Stirring was continued for 15 min and the supernatant was then transferred via a filter-tipped funnel into a rapidly stirred solution of NaBH4 (2.93 g, 73.2 mmole) in ice water and washed with dry DME. After the mixture was stirred for 30 min, it was extracted with EtOAc and washed with H20. The organic layers were combined, dried over Na2S04, and concentrated in vacuo. Purification by chromatography (silica, 4/1 : Hexane/EtOAc, Rf= 0.2) afforded tert-butyl N-[(lR)-2-(benzyloxy)-l- (hydroxymethyl)ethyl]carbamate as a white solid (6.3 g, 92 %).
With borane-THF; In tetrahydrofuran; at 0 - 23℃;
To solution of (L)-N-Boc Ser(OBn)-OH 28 (1 g, 3.38 mmol) in anhydrous THF (6 mL) was added 1 M Borane-THF complex (7.5 mL, 7.5 mmol) at 0 C. After stirring at 0 C for 1 h, the reaction mixture was slowly warmed to 23 C and stirred for 3 h. The reaction mixture was cooled to 0 C, quenched by MeOH, concentrated, diluted with MeOH, and concentrated again. The concentrated oil was then subjected to flash column chromatography (EtOAc/ hexane) on silica gel to afford the alcohol 29 (0.87 g, 91%) as an oil.
tert-Butyl N-[(lR)-2- (benzyloxy)-l-(hydroxymethyl)ethyl]carbamate (1.2 g, 4.3 mmole) was dissolved in CH2C12 (40 mL). Dess-Martin periodinane (2.4 g, 5.5 mmole) was added. The solution was stirred for 2 h at room temperature and then quenched with Na2S2(¾ and saturated bicarbonate solution. After extracting with CH2C12, the organic layer was dried over MgS04, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 4/1 : Hexane /EtOAc, R{= 0.4) afforded (S)-tert-butyl l-(benzyloxy)-3-oxopropan-2-ylcarbamate as a white solid (1.1 g, 96%).
With sodium hydrogencarbonate; Dess-Martin periodane; In dichloromethane; at 0℃; for 1h;
General procedure: The primary alcohol (890 mg, 1.98 mmol) was dissolved in 30 mL of anhydrous dichloromethane and the solution was cooled to 0 C. After adding 166 mg of sodium carbonate, Dess-Martin Periodinane (0.92 g, 2.18 mmol) was added and the mixture stirred for 1 h at 0 C. As soon as the TLC showed full conversion of the starting material, the reaction was quenched with saturated NaHCO3 solution and 10% sodium thiosulfate solution. The organic layer was then w ashed with brine, dried over sodium sulfate, concentrated in vacuo at low temperature. The crude aldehyde 11a was subjected to the next reaction without further purification.
(S)-2-{(S)-3-Allyloxycarbonyl-2-[(R)-2-tert-butoxycarbonylamino-3-(4-heptyloxy-phenoxy)-propionylamino]-propionylamino}-pentanedioic acid dibenzyl ester[ No CAS ]
[((R)-1-Benzyloxymethyl-2-[2-(bis-tert-butoxycarbonylmethyl-amino)-ethyl]-tert-butoxycarbonylmethyl-amino}-ethyl)-tert-butoxycarbonylmethyl-amino]-acetic acid tert-butyl ester[ No CAS ]
(2R)-2-amino-3-(benzyloxy)propan-1-ol hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With hydrogenchloride; In ethyl acetate; at 0℃; for 3h;Inert atmosphere;
To a stirred solution of 29 (8.56 g, 30.3 mmol) in EtOAc (10 ml) was added 4 N hydrogen chloride/EtOAc (30 mL) at 0 C under argon atmosphere, and the stirring was continued for 3 h. The reaction mixture was evaporated. The remaining organic solvent was further removed by repeated evaporation with toluene. To the resulting residue was added EtOAc/hexane (1:5, 10 mL) and the resulting mixture was stirred for 1 h. The resulting precipitates were removed by filtration to afford an amino alcohol hydrochloride as a white powder (5.23 g, 79%). 1H NMR (300 MHz, DMSO-d6): delta 8.15 (m, 3H), 7.38-7.25 (m, 5H), 5.32 (m, 1H), 4.55 (s, 2H), 3.65-3.52 (m, 4H).
With hydrogenchloride; In 1,4-dioxane; toluene; at 60℃; for 2h;
To a solution of the compound prepared in Reference Example 21 (3.30 g) in toluene (20 mL) was added 4N hydrogen chloride dioxane solution (4 mL) and the mixture was stirred at room temperature for 2 hours and at 60C for 1 hour. After cooling, hexane was added to the reaction mixture, which was filtrated. The obtained residue was dried to give the title compound (2.18 g) having the following physical data. TLC: Rf 0.21 (chloroform:methanol=9:1); NMR (CDCl3): delta 2.31 (br. s., 4 H) 3.69 (m, 5 H) 4.55 (s, 2 H) 7.31 (m, 5 H).
With sodium tetrahydroborate; In tetrahydrofuran; at 0 - 20℃;
Under an atmosphere of argon, to a solution of 2,5-dioxopyrrolidin-1-yl O-benzyl-N-t-butoxycarbonyl-L-serinate (4.41 g) in tetrahydrofuran(30 mL) was added sodium borohydride (644 mg) in ice bath and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (3.30 g) having the following physical data. TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1); NMR (CDCl3): delta 1.45 (s, 9 H) 2.61 (br. s., 1H) 3.72 (m, 5 H) 4.53 (s, 2 H) 5.17 (br. s., 1 H) 7.34 (m, 5 H).
Example 15 N-{(1S)-2-(benzyloxy)-1-[(3-methylphenoxy)methyl]ethyl}-N'-1-naphthyl urea Step 1: t-butyl (1R)-2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate; O-benzyl-N-(t-butoxycarbonyl)-L-serine (2 g) was dissolved in tetrahydrofuran (20 ml), triethylamine (1.22 ml) was added, and ethyl chloroformate (713 mul) was further added dropwise at 0C. After stirring the reaction mixture at room temperature for 30 min, the reaction mixture was filtered, and one piece of ice was added to the filtrate. Sodium borohydride (515 mg) was further added, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl (1R)-2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate (1.7 g).
With sodium tetrahydroborate; triethanolamine; In tetrahydrofuran; water; ethyl acetate;
N-(tert-Butyloxycarbonyl)-O-Benzyl-L-Serinol (3) N-(tert-butyloxycarbonyl)-O- benzyl-L-serine 2 (6.0 g, 20.34 mmol) was dissolved in dry THF and cooled to -20 C. under argon atmosphere. To this cold stirred solution was added TEA (2.32 g, 23 mmol) and isobutyl chloroformate (3.13 g, 23 mmol). The stirring was continued for 30 min at -20 C. under argon atmosphere. The reaction mixture was filtered immediately under a blanket of argon, the precipitate was washed with dry THF (50 ml). The combined filtrate was added slowly into a cold (0 C.) solution of NaBH4 (7.4 g, 200 mmol) in THF/water (80:20, 200 ml) during 10 min period. After the addition, the reaction mixture was stirred for 2 h at 0 C. and the pH adjusted to 7 with acetic acid. The solution was evaporated to dryness, partitioned between ethyl acetate/water (300:150 ml) and extracted in ethyl acetate. The organic extract was washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography over silica gel using CH2 Cl2 ?EtOAc as the eluent. The pure product was pooled together and evaporated to dryness to give 4.7 g (82%) of the pure product as an oil. 1 H-NMR (CDCl3): delta1.41 (s, 9H, Boc), 3.60-3.70 (m, 4H), 3.82 (d, 2H), 4.53 (s, 2H, OCH2 Ph), 5.20 (bs, 1H, NH) and 7.30-7.40 (m, 5H, Ph).
With N-iodo-succinimide; In acetonitrile; at 20 - 60℃; for 2h;
{(S)-2-benzyloxy-1-[1-(2,2-dimethylpropoxy)-2-iodoethoxymethyl]-ethyl}-carbamic acid tert-butyl ester Add N-iodosuccinimide (14.19 g, 74.63 mmol) to ((R)-2-benzyloxy-1-hydroxymethylethyl)-carbamic acid tert-butyl ester (15.00 g, 53.30 mmol) and 2,2-dimethyl-1-vinyloxypropane (9.13 g, 79.96 mmol) in acetonitrile (267 mL) at room temperature. Heat to 60 C. under nitrogen for 2 hours. Cool to room temperature and dilute with ethyl acetate. Wash with water and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluding with 0:100 to 10:90 ethyl acetate:hexanes) to give the desired compound as an oil (23.4 g 84.2%). MS(ES)=544.2 [M+Na]
(3S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-1-[(2-ethoxy-2-oxoethyl)amino]carbonylpropyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoate[ No CAS ]
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