* 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] Chemistry Letters, 1988, p. 1125 - 1128
5
[ 1145-80-8 ]
[ 100-39-0 ]
[ 21209-51-8 ]
Reference：
[1] Tetrahedron Letters, 2003, vol. 44, # 28, p. 5251 - 5253
[2] Tetrahedron Asymmetry, 2007, vol. 18, # 18, p. 2121 - 2124
[3] Organic and Biomolecular Chemistry, 2018, vol. 16, # 8, p. 1343 - 1350
[4] Amino Acids, 2010, vol. 39, # 2, p. 367 - 373
[5] Tetrahedron Letters, 1968, p. 6323 - 6326
[6] Synthesis, 1979, p. 957 - 961
6
[ 1145-80-8 ]
[ 2978-10-1 ]
[ 21209-51-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 17, p. 2907 - 2915
7
[ 1145-80-8 ]
[ 21209-51-8 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 2166,2168
8
[ 1145-80-8 ]
[ 100-44-7 ]
[ 21209-51-8 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 1, p. 87 - 93
9
[ 1145-80-8 ]
[ 104-15-4 ]
[ 100-51-6 ]
[ 21209-51-8 ]
Reference：
[1] Journal of the Chemical Society, 1959, p. 941,945
[2] Acta Chemica Scandinavica (1947-1973), 1957, vol. 11, p. 1232,1235
10
[ 2016-04-8 ]
[ 1145-80-8 ]
[ 21209-51-8 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1974, vol. 39, p. 634 - 646
11
[ 1145-80-8 ]
[ 74-88-4 ]
[ 1676-81-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h;
Adapting the procedure of Chhabra et al.,4 to aflame-dried 250 mL round bottom flask containing Cbz-Serine-OH 8 (12.0 g, 50.0 mmol, 1.00 equiv) and K2CO3(7.60 g, 55.0 mmol, 1.10 equiv) in DMF (85 mL, 0.60 M) at 0 °C was added methyl iodide (6.20 mL, 100 mmol,2.00 equiv) over 30 minutes. The reaction was allowed to warm slowly to room temperature and stirred overnightThe reaction mixture was diluted with EtOAc (500 mL) and washed with a 1:4 mixture of saturated aqueousNaCl:H2O (2 x 100 mL). The combined aqueous washes were back extracted with EtOAc (2 x 150 mL). Thecombined organic extracts were washed sequentially with H2O (2 x 200 mL), saturated aqueous NaCl (2 x 200 mL),5percent aqueous (w/v) LiCl (2 x 200 mL), and again saturated aqueous NaCl (1 x 200 mL). The combined aqueouswashes were further back-extracted with Et2O (1 x 200 mL), and the combined organics were dried over Na2SO4,filtered, and concentrated in vacuo to afford the title compound as a viscous, colorless oil (13.0 g, 99percent) that wasused without further purification (Note: The crude material contained residual DMF). TLC: Rf = 0.17 (40percentEtOAc/hexanes; UV/KMnO4); 1H NMR (600 MHz, CDCl3) δ 7.40–7.30 (m, 5H), 5.79–5.49 (m, 1H), 5.13 (s, 2H),4.50–4.40 (m, 1H), 4.05–3.98 (m, 1H), 3.96–3.90 (m, 1H), 3.79 (s, 3H), 2.07 (t, J = 6.2 Hz, 1H); 13C NMR (151MHz, CDCl3) δ 171.0, 156.3, 136.2, 128.7, 128.4, 128.3, 67.4, 63.6, 56.2, 53.0. The spectra were in close agreementwith the literature.4 IR (FT-ATR, neat, cm-1): 3362, 2654, 1699, 1519, 1454, 1438, 1209, 1057, 976, 911, 750, 697;HRMS (ESI) m/z for [M+Na]+ C12H15NO5Na requires 276.0848, observed 276.0850; [α]D20 +8.3 (c = 1.0, CHCl3).
50%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: A solution of N-benzyloxycarbonyl-L-amino acid S5 (7.9 mmol) in DMF (20 ml) was added methyliodide (1.1 g, 7.9 mmol) and potassium carbonate (1.2 g, 8.7 mmol). The reaction mixture waskept at room temperature for 3 hours. The methylated products were purified by column chromatographyin the yields of 50percent (1.0 g, colorless-oil) for serine and 92percent (1.9 g, white-solid) for threonine.The methylated amino acid (4.0 mmol) in DMF (10 ml) was mixed with TBDPSCl (2.2 g, 7.9mmol), imidazole (810 mg, 11.9 mmol) and catalytic amount of DMAP. The reaction was processedat 45 °C for 7 hours. The desired products were purified by column chromatography in theyields of 90percent (1.7 g, colorless-oil) for serine and 90percent (1.8 g, white-solid) for threonine. The silylproduct (500 mg, 1.0 mmol) in DMF (1 ml) was reacted with 15percent NaOH (5 ml) for 2 hours. Thereaction mixture was quenching by 1 N HCl(aq) and 6 was extracted by ethyl acetate. The desiredamino acid 6 was obtained after removal of ethyl acetate in the quantitative yields (470 mg,white-solid for serine; 486 mg, colorless-oil for threonine).
Reference：
[1] Chemistry Letters, 2001, # 2, p. 102 - 103
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 20, p. 4871 - 4874
[3] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1264 - 1271
[4] Journal of Organic Chemistry, 2002, vol. 67, # 12, p. 4017 - 4029
[5] Journal of Organic Chemistry, 1999, vol. 64, # 2, p. 498 - 506
[6] Synlett, 2018, vol. 29, # 11, p. 1430 - 1436
[7] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 7, p. 1160 - 1164
[8] Journal of Organic Chemistry, 2013, vol. 78, # 21, p. 10853 - 10859
12
[ 67-56-1 ]
[ 1145-80-8 ]
[ 1676-81-9 ]
Yield
Reaction Conditions
Operation in experiment
16.8 g
at 0 - 20℃; Inert atmosphere
To a slurry of L-serine (10.5 g, 100 mmol) in H2O (100 mL), NaHCO3 (21.0 g, 250 mmol), and THF (50 mL) were added successively at 0 °C with cooling of the reaction vessel in an ice-water bath. The mixture was stirred for 30 min, benzyl chloroformate (15.5 mL, 110 mmol) was added dropwise at 0 °C. The ice-water bath was then removed, and the mixture was stirred for 4 h at r.t. The resulting mixture was washed with Et2O (2 × 50 mL) and acidified to pH 2 with aq 3 M HCl. The obtained solution was extractedwith EtOAc (1 × 100 mL and 3 × 50 mL). The combined organicphase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (150 mL), and SOCl2 (8.5 mL, 117 mmol) was then added dropwise to the solution at 0 °C under an N2 atmosphere. The mixture wasstirred for 10 min at 0 °C, the ice-water bath was then removed, and the mixture was stirred overnight at r.t. The resulting solution wasthen concentrated under reduced pressure, dissolved in Et2O (150mL), washed with cold sat. NaHCO3, dried (Na2SO4), filtered, and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (silica gel, hexane–EtOAc, 1:1 to 1:3) to give the product (16.8 g, 66 mmol, 66percent, 2 steps).
Reference：
[1] Tetrahedron Letters, 2003, vol. 44, # 28, p. 5251 - 5253
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 11, p. 3188 - 3191
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 23, p. 3397 - 3410
[4] Journal of Organic Chemistry, 1996, vol. 61, # 2, p. 581 - 586
[5] Organic Letters, 2005, vol. 7, # 22, p. 5047 - 5050
[6] Tetrahedron, 2007, vol. 63, # 35, p. 8645 - 8657
[7] Chemical Communications, 2014, vol. 50, # 88, p. 13608 - 13611
[8] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1264 - 1271
[9] European Journal of Organic Chemistry, 2001, # 16, p. 3067 - 3074
[10] Chemical Communications, 2005, # 2, p. 168 - 170
[11] Bulletin of the Chemical Society of Japan, 1978, vol. 51, # 6, p. 1897 - 1898
[12] Synthesis, 1995, # 9, p. 1155 - 1158
[13] Journal of Organic Chemistry, 2004, vol. 69, # 10, p. 3590 - 3592
[14] Synthesis (Germany), 2014, vol. 46, # 10, p. 1367 - 1373
13
[ 186581-53-3 ]
[ 1145-80-8 ]
[ 1676-81-9 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 1, p. 87 - 93
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 923 - 928
[3] Canadian Journal of Chemistry, 1986, vol. 64, p. 706 - 713
[4] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1264 - 1271
[5] Canadian Journal of Chemistry, 1956, vol. 34, p. 1182,1184
[6] Collection of Czechoslovak Chemical Communications, 1965, vol. 30, p. 1611,1615
[7] Helvetica chimica acta, 1975, vol. 58, # 5, p. 1471 - 1477
[8] Tetrahedron Letters, 1988, vol. 29, # 17, p. 2019 - 2022
[9] Journal of the Chemical Society, Chemical Communications, 1995, # 10, p. 1061 - 1062
[10] Tetrahedron, 1999, vol. 55, # 51, p. 14769 - 14776
14
[ 1145-80-8 ]
[ 77-78-1 ]
[ 1676-81-9 ]
Reference：
[1] Patent: US4622417, 1986, A,
15
[ 1145-80-8 ]
[ 100-39-0 ]
[ 20806-43-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 9, p. 2699 - 2706
[2] European Journal of Medicinal Chemistry, 1998, vol. 33, # 7-8, p. 635 - 645
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 17, p. 2907 - 2915
18
[ 1145-80-8 ]
[ 84713-20-2 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 706 - 713
19
[ 1145-80-8 ]
[ 19647-68-8 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 3702 - 3709
20
[ 1145-80-8 ]
[ 19647-68-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 7, p. 1160 - 1164
21
[ 1145-80-8 ]
[ 26054-60-4 ]
Yield
Reaction Conditions
Operation in experiment
72%
With dimethyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; acetonitrile at -55℃; for 2 h; Inert atmosphere
Example 4; Standard Procedure for the Synthesis of Ddz-Dap(Boc-Me)-OH (Ddz-AA4, FIG. 2); Step 4-1. Z-Serine-β-lactone (AA4-2).; This intermediate was prepared in an analogous fashion to that described previously for the Boc derivative AA3-1. In a dry 250 mL 3-neck flask equipped with a mechanical stirrer under nitrogen atmosphere was added triphenylphosphine (4.5 g, 17.1 mmol, 1.1 eq.), followed by 100 mL of an anhydrous THF:CH3CN (1:9) solvent mixture. The mixture was stirred until a solution was obtained and then cooled to -55° C. (bath temperature) and dimethylazodicarboxylate (DMAD, 1.9 mL, 17.1 mmol, 1.1 eq) was added dropwise over 10 min. After completion of the addition, the mixture was stirred for 20 min, then a solution of Z-Ser-OH (AA4-1, 3.7 g, 15.5 mmol, 1.0 eq) in 50 mL of anhydrous THF:CH3CN (1:9) was added dropwise over 30 min. The reaction mixture was stirred at -55° C. for 1.5 h, then the cooling bath removed and the solution allowed to warm slowly to room temperature. Once the mixture reached room temperature, the solvent was evaporated under reduced pressure. The resulting yellow oil was purified by flash chromatography [gradient, hexanes/EtOAc, (80:20) to (60:40)] to give 2.5 g of AA4-2 as a white solid in 72percent yield. Purification of the crude oil is preferentially performed the same day to avoid decomposition. DCM can be added to help solubilize the residue.TLC (hexanes/EtOAc (60/40): Rf=0.55 (UV, CMA)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2643 - 2646
[2] Patent: US2010/93720, 2010, A1, . Location in patent: Page/Page column 38
[3] Journal of the American Chemical Society, 1985, vol. 107, # 24, p. 7105 - 7109
[4] Organic and Biomolecular Chemistry, 2008, vol. 6, # 18, p. 3240 - 3243
[5] Organic Syntheses, 1992, vol. 70, p. 1 - 1
[6] Canadian Journal of Chemistry, 1986, vol. 64, p. 706 - 713
[7] Canadian Journal of Chemistry, 1986, vol. 64, p. 706 - 713
[8] Synthetic Communications, 1995, vol. 25, # 16, p. 2475 - 2482
[9] Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3979 - 3985
[10] Journal of Organic Chemistry, 2002, vol. 67, # 5, p. 1536 - 1547
[11] Chemistry Letters, 1982, p. 45 - 48
[12] Patent: US2010/22605, 2010, A1, . Location in patent: Page/Page column 49-50
22
[ 1145-80-8 ]
[ 1972-28-7 ]
[ 26054-60-4 ]
Yield
Reaction Conditions
Operation in experiment
45%
With triphenylphosphine In acetonitrile
a L-2-Amino-3-phenylaminoethylpropionic Acid 54.8 g (0.209 mol) of triphenylphosphine were suspended in 600 ml of acetonitrile and, with exclusion of moisture, cooled to -35° C. to -45° C. At this temperature, 36.4 g (0.209 mol) of diethyl azodicarboxylate were then added dropwise over a period of 50 min. The mixture was stirred at -35° C. for another 15 min. A solution of 50 g (0.209 mol) of N-benzyloxycarbonyl-L-serine in 500 ml of acetonitrile was added dropwise to this mixture, the temperature being kept below -35° C. The mixture was then allowed to react at 5° C. for another 12 h and warmed to RT. The reaction solution was freed from solvent under reduced pressure and the crude product was purified by medium pressure chromatography over silica gel (DCM/AcCN: 25/1). Removal of the solvent gave 20.8 g (yield 45percent) of pure N-benzyloxy-carbonyl-L-serine-β-lactone (see also Org. Synth. 1991 (70) 1ff.) in fine needles. Empirical formula C11H11NO4; M.W.=221.2; MS (M+H) 222.1.
With water; sodium hydrogencarbonate; sodium carbonate; In acetone; at 15 - 20℃;pH 8 - 10;
General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1.
< 69%
With sodium hydrogencarbonate; In water; toluene; at 20℃; for 4h;
Benzyl chloroformate (50 wt% solution, in toluene, 0.42 mL, 2.82 mmol, 1.48 eq)To a solution of L-serine (compound 11) (200 mg, 1.96 mmol, 1.0 eq) in saturated aqueous NaHCO3 (7.6 mg, 0.25 M).The mixture was stirred vigorously at room temperature for 4 hours and the aqueous layer was extracted with ether. Acidify the aqueous solution with 1M HCl and extract with ethyl acetate,The organic layer was dried over Na2SO4.Purification by silica gel column chromatography (CH2Cl2 / MeOH = 20: 1) gave the product, Compound 12, a colorless solid(249.6 mg, 1.03 mmol, <69%)
66%
To a solution of L-serine (SM-2) (60 g, 0.57 mol) in THE and 0 (750 mL, 1: 2) was added NaHC( (142 g, 1.71 mol) at 0 C and stirred for 10 minutes. CbzCl (127 mL, 0.74 mol) was added to the reaction mixture and stirred for 16 h. After completion of starting material (by TLC), the reaction mixture was acidified with 2N HC1 solution (pH to 2.0) and extracted with EtOAc (3 x 200 ml). The combined organic layer was washed with brine solution, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. Crude material was triturated with diethyl ether and dried under vacuum to afford Int-A (91 g, 66%) as a white solid. (0373) MHz, DMSO-ifc) d 12.66 - 12.48 (m, 1H), 7.41 - 7.26 (m, 6H), 5.04 (s, 2H), 4.12 - 3.98 (m, 2H), 3.70 - 3.63 (m, 2H). LCMS (ESI): m/z 240.2 [M++l]
65%
With sodium hydrogencarbonate; sodium carbonate; In water; acetone; at 20℃; for 3h;pH 8 - 10;
Sodium bicarbonate (1 eq., 3.36 g, 40 mmol) and sodium carbonate (2 eq., 8.48 g, 80 mmol) were dissolved in a mixture of water and acetone in a 15:2 ratio. Solvent was added until complete dissolution of the salts. After complete dissolution, 2(S)-amino-3-hydroxypropanoic acid (4.2036 g, 40 mmol) was added. To the reaction mixture was added benzyl chloroformate (1.25 eq., 7.1 mL 50 mmol), drop by drop, and the reaction was stirred for 3 h at room temperature. Strong stirring is required since 2 phases form with the addition of the benzyl. Precipitation may occur if the pH falls under 8 during the reaction, so 1N aqueous potassium hydroxide was added to give a pH of ~9. The resulting cloudy solution was washed 3 times with diethyl ether to give a clear aqueous layer and the organic phases were discarded. 1N aqueous hydrochloric acid was added to acidify the solution and cause a precipitation of the serine salt. The solution was then filtered and the filtrate was dried under vacuum to yield 6.18 g (16.7 mmol, 65 %) of a white salt. 1H NMR (400 MHz; DMSO-d6), delta = 3.60-3.61 (d, 2H, J = 4.8, CH2beta), 3.98-4.03 (m, 1H, CHalpha), 4.99 (s, 2H, Ph-CH2), 7.25-7.29 (m, 5H, Ph) 12.6 (bs, 1H, COOH). HRMS (ESI-TOF, m/z): calcd for C11H14NO5 (M+H)+ = 240.0872, found 240.0864, calcd for C11H13NO5Na (M+Na)+ = 262.0691, found 262.0684.
To a slurry of L-serine (10.5 g, 100 mmol) in H2O (100 mL), NaHCO3 (21.0 g, 250 mmol), and THF (50 mL) were added successively at 0 C with cooling of the reaction vessel in an ice-water bath. The mixture was stirred for 30 min, benzyl chloroformate (15.5 mL, 110 mmol) was added dropwise at 0 C. The ice-water bath was then removed, and the mixture was stirred for 4 h at r.t. The resulting mixture was washed with Et2O (2 × 50 mL) and acidified to pH 2 with aq 3 M HCl. The obtained solution was extractedwith EtOAc (1 × 100 mL and 3 × 50 mL). The combined organicphase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure.
With triethylamine; In 1,4-dioxane; water; at 20℃; for 12h;
iii) Preparation of benzyl L-2- (benzyloxycarbonyl) amino-3-iodopropionate: 30 mmol of L-serine (Gill Biochemical Shanghai Co., Ltd.), 60 mmol of benzyl chloroformate (Sarn Chemical Technology Co., Ltd.), Triethylamine 60 mmol (national medicine) was stirred in a mixed solvent of 45 mL of water / 10 mL of dioxane, and reacted at room temperature for 12 hours. After the reaction was completed, it was extracted with ethyl acetate and water, and the organic phase was retained, dried, and spin-dried to obtain L- (benzyloxycarbonyl) amino-serine. 20 mmol of L- (benzyloxycarbonyl) amino-serine, 60 mmol of benzyl bromide (national medicine), 40 mmol of cesium carbonate (Sarn Chemical Technology Co., Ltd.) were stirred in 40 mL of N, N-dimethylformamide, and reacted at room temperature for 6-8 After extraction with ethyl acetate and water for an hour, the organic phase was retained, dried, spin-dried, and recrystallized to obtain L- (benzyloxycarbonyl) amino-serine benzyl ester. Then, 15 mmol of iodine (national medicine), 15 mmol of triphenylphosphine (national medicine), and 15 mmol of imidazole (national medicine) were stirred in 40 mL of dichloromethane at 0 C. for 10 min, and L- (benzyloxycarbonyl) amino-serine benzyl ester 10 mmol It was dissolved in 5 mL of dichloromethane and added dropwise to the reaction solution. The reaction solution was stirred at 0 C for 2 hours and then reacted at room temperature for 2 hours. After the reaction was completed, sodium thiosulfate was added to quench the reaction until the solution was colorless, extracted with dichloromethane and water, the organic phase was retained, dried, spin-dried, and recrystallized with n-hexane / ethyl acetate ten to one to obtain the product L-2. -(Benzyloxycarbonyl) amino-3-iodopropionic acid benzyl ester, yield 85%.
With sodium carbonate; In acetone; at 30℃; for 10h;
The results of the multiple preparation experiments of IM2-1 are shown in Table 4. Taking Entry 1 in Table 4 as an example, the preparation method is as follows: Add L-Ser (1mmol),3mL of cooled saturated Na2CO3 solution, stirred in an ice bath; after dissolution, add 2 mL of Z-OSu (1.5 mmol) in acetone solution dropwise; The reaction was stirred at room temperature, and the progress of the reaction was monitored by TLC-ninhydrin colorimetry. After the reaction was completed, 15 mL of water was added, and extracted with EtOAc (10 mL × 2) at pH> 9. The aqueous phase was collected, and the pH was adjusted to 3 to 4 with 1.5N HCl. EtOAc (10 mL × 3) extraction, combined organic phases, washed with saturated NaCl solution (10 mL × 2),Dry with anhydrous Na2SO4,The purity was checked by TLC-ninhydrin chromogenic method, evaporated to dryness under reduced pressure, and dried under vacuum to obtain a white powdery solid IM2-1, m.p. 118-120 C, and stored at low temperature.
ZL-serine (Compound 12) (997.3 mg, 4.18 mmol, 1.0 eq), benzyltriethylammonium chloride(0.95 mg, 4.18 mmol, 1.0 eq) and potassium carbonate(3.8 g, 2 7.2 mmol, 6.5 eq) was stirred vigorously in MeCN (13 mL) at room temperature for 5 hours. And 2-bromo-2-methylpropane(5.0 mL, 42.6 mmol, 10.2 eq)The reaction mixture was warmed to 50 C. and stirred rapidly.The reaction mixture became very viscous after 2-3 hours.To this was further added MeCN (5 mL) to facilitate stirring,The resulting reaction mixture was stirred for 24 hours.The reaction mixture is then cooled to room temperature,Most of the MeCN was removed on a rotary evaporator.The reaction mixture was then partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc.The EtOAc layer was washed with brine, dried over Na2SO4,Filtration and concentration were performed.Silica gel column chromatographyPurification with (hexane / EtO Ac = 40: 1) gave the product compound 13 as a colorless solid (926.3 mg, 3.13 mmol, 75%).
63%
With potassium potassium methaneperoxoate; N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetonitrile; at 20℃; for 5h;
Into a 2-L round- bottom flask, was placed (25)-2-[ [(benzyloxy)carbonyl] amino] -3 -hydroxypropanoic acid (50 g, 209.01 mmol, 1.00 equiv), acetonitrile (400 mL), potassium potassium methaneperoxoate (180 g, 1.29 mol, 6.50 equiv), benzyltriethylazanium chloride (47 g, 206.35 mmol, 1.00 equiv). The resulting solution was stirred for 5h at r.t. Then 2-bromo-2-methylpropane (250 mL, 10.20 equiv) was added. The resulting solution was stirred overnight at 50C in an oil bath. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The residue was dissolved in 1.5 L of ethyl acetate. The resulting mixture was washed with 1x500 mL of H20. The organic layer was washed with 2x400 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 39 g (63%) of tertbutyl (2)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate as a white solid. MS (ES, m/z):296 (M+H).
63%
Into a 2-L round- bottom flask, was placed (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoic acid (50 g, 209.01 mmol, 1.00 equiv), acetonitrile (400 mL), potassium potassium methaneperoxoate (180 g, 1.29 mol, 6.50 equiv), benzyltriethylazanium chloride (47 g, 206.35 mmol, 1.00 equiv). The resulting solution was stirred for 5h at r.t. Then 2-bromo-2-methylpropane (250 mL, 10.20 equiv) was added. The resulting solution was stirred overnight at 50oC in an oil bath. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The residue was dissolved in 1.5 L of ethyl acetate. The resulting mixture was washed with 1x500 mL of H2O. The organic layer was washed with 2x400 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 39 g (63%) of tert- butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate as a white solid. MS (ES, m/z): 296 (M+H).
With dimethyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; acetonitrile; at -55℃; for 2h;Inert atmosphere;
Example 4; Standard Procedure for the Synthesis of Ddz-Dap(Boc-Me)-OH (Ddz-AA4, FIG. 2); Step 4-1. Z-Serine-beta-lactone (AA4-2).; This intermediate was prepared in an analogous fashion to that described previously for the Boc derivative AA3-1. In a dry 250 mL 3-neck flask equipped with a mechanical stirrer under nitrogen atmosphere was added triphenylphosphine (4.5 g, 17.1 mmol, 1.1 eq.), followed by 100 mL of an anhydrous THF:CH3CN (1:9) solvent mixture. The mixture was stirred until a solution was obtained and then cooled to -55 C. (bath temperature) and dimethylazodicarboxylate (DMAD, 1.9 mL, 17.1 mmol, 1.1 eq) was added dropwise over 10 min. After completion of the addition, the mixture was stirred for 20 min, then a solution of Z-Ser-OH (AA4-1, 3.7 g, 15.5 mmol, 1.0 eq) in 50 mL of anhydrous THF:CH3CN (1:9) was added dropwise over 30 min. The reaction mixture was stirred at -55 C. for 1.5 h, then the cooling bath removed and the solution allowed to warm slowly to room temperature. Once the mixture reached room temperature, the solvent was evaporated under reduced pressure. The resulting yellow oil was purified by flash chromatography [gradient, hexanes/EtOAc, (80:20) to (60:40)] to give 2.5 g of AA4-2 as a white solid in 72% yield. Purification of the crude oil is preferentially performed the same day to avoid decomposition. DCM can be added to help solubilize the residue.TLC (hexanes/EtOAc (60/40): Rf=0.55 (UV, CMA)
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -78 - 20℃;
Step 1: (Steps 1 and 2 are done similar to that described in Organic Syntheses, Coll. Vol. 9, p. 58-63) To a solution of triphenylphosphine (27.7 g, 106 mmol) in THF (500 mL) at -78 C., DIAD (20.8 mL, 106 mmol) was added dropwise. The mixture is stirred at -78 C. for 20 min. A solution of N-(benzyloxycarbonyl)-L-serine (25.3 g, 106 mmol) in THF (150 mL) is added to the reaction mixture. The reaction mixture is stirred for an additional 30 min at -78 C., warmed to rt, and stirred for an additional 3 h. The reaction mixture is concentrated in vacuo, dissolved in ether, and filtered. The filtrate was concentrated in vacuo, and the residue is purified by column chromatography (SiO2, gradient 10%-40% ethyl acetate in hexanes). This gave 8.0 g of N-(benzyloxycarbonyl)-L-serine p-lactone. 1H NMR (300 MHz, DMSO-d6) delta 7.73-7.43 (m, 5H), 5.80-5.66 (m, 1H), 5.48-5.28 (m, 3H), 4.77-4.89 (m, 2H).
benzyl N-[(1S)-1-(hydroxymethyl)-2-[(4-methoxyphenyl)amino]-2-oxoethyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16.5h;Inert atmosphere;
Under nitrogen atmosphere, to a cooled (0 C), vigorously stirred solution of commercially availablep-anisidine (141.5 g, 1.15 mol) in a 3:1 mixture of dry THF:CH2C12 (2.0L), commercially available carbobenzyloxy-L-serine (50.0 g, 0.21 mol) and commercially available EDCI (43.9 g, 0.23 mol) were sequentially added. The resulting mixture was stirred at 0 C for additional 0.5 h and then at r.t. for 16 h. After evaporation of the solvents, trituration with a 1:1 mixture Cy:EtOAc (3x0.4 L) mostly removed the excess ofp-anisidine, and the resulting gummy residue was taken up in EtOAc (0.5 L) and washed with a 0.1 M HC1 solution(iOxO.4 L). The organic layer was dried over Na2SO4, filtered and concentrated to dryness affording the pure title compound (58.6 g, 82%), as a white solid. R = 1.97 mm. MS (ESI) m/z:345 [M-H], 367 [M-Na], 383 [M-K]. ?H NMR (CDC13): oe 8.50-8.27 (bs, 1H), 7.44-7.29 (m, 6H), 6.90-6.81 (d, 2H, J= 9.1 Hz), 5.97-5.80 (bs, 1H), 5.17 (s, 2H), 4.37-4.21 (m, 2H), 3.80 (s, 3H), 3.77-3.66 (m, 1H), 2.92-2.75 (bs, 1H).
With dmap; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
Compound 2(S)-benzyloxycarbonylamino-3-hydroxypropanoic acid (1.20 g, 5 mmol), triethylamine (1.31 eq., 1 mL, 6.53 mmol) and DMAP (0.041 eq., 0.025 g, 0.20 mmol) were dissolved in 7 mL of dry CH2Cl2 under inert atmosphere at room temperature. Tert-butyldimethylsilyl chloride (1.10 eq., 0.83 g, 5,5 mmol) was quickly added and the reaction was stirred overnight. After quenching with water (5 mL), the organic layer was separated and evaporated under reduced pressure at 70 C. The oily residue was dissolved in tetrahydrofuran (7 mL) and potassium carbonate (10 % m/m, 5 mL) was added. The mixture was stirred for 8 h at room temperature then dried under reduced pressure at 70 C. The residue was dissolved in a mixture of dry CH2Cl2 and 10 % aqueous citric acid (14 mL). After separation, the organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum to yield 1.37 g (2.98 mmol, 78 %) of a white solid. 1H NMR (400 MHz; CDCl3), delta = 0.06 (s, 6H, Si-(CH3)2), 0.87 (s, 9H, Si-C-(CH3)3), 3.82-3.86 (dd, 1H, J = 10.0, 4.2, CH2beta), 4.13-4.16 (dd, 1H, J = 9.8, 2.3, CH2beta), 4.44-4.46 (t, 1H, J = 3.6, CHalpha), 5.14 (m, 2H, Ph-CH2), 5.57-5.59 (d, 1H, J = 8 Hz, NH), 7.33-7.38 (m, 5H, Ph). Tm = 82-83 C. HRMS (ESI-TOF, m/z): calcd for C17H28NO5Si (M+H)+ = 354.1737, found 354.1720, calcd for C17H27NO5SiNa (M+Na)+ = 376.1556, found 376.1538.
48%
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
To a mixture of (S)-2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoic acid (10.0 g, 42 mmol) and imidazole (5.7 g, 84 mmol) in DMF (500 mL), TBSC1 (6.3 g, 42 mmol) was added at 0C. The reaction mixture was warmed to room temperature slowly and stirred for another 16 hr. The volatiles were removed and the residue was taken up in EtOAc (1000 mL)and the EtOAc layer was washed sequentially with iN HC1, saturated NaHCO3 and brine (500 mL each). The EtOAc layer was dried over Na2504, concentrated and the resulting residue was purified by flash column chromatography to afford (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert- butyldimethylsilyl)oxy)propanoic acid (7.0 g, 48% yield) as colorless oil.
38%
With 1H-imidazole; dmap; In dichloromethane; at 0 - 25℃; for 16h;
To a stirring solution of Int-A (10 g, 41.8 mmol) in CH2CI2 (100 mL) were added imidazole (8.5g, 125.5 mmol), DMAP (511 mg, 4.18 mmol) and TBDMSC1 (15.4 mL, 83.6 mmol) at 0 C. The reaction mixture was stirred at RT for 16 h. After completion of starting material (by TLC), diluted ice water (100 ml) and extracted with CH2CI2 (3 x 200 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to obtain crude material was purified by column chromatography eluting with 3% MeOH/ CH2CI2 to afford Int-B (5.7 g, 38%) as a white solid. (0376) MHz, DMSO-d6) d 12.75 (s, 1H), 7.35-7.28 ( m, 5H), 5.06-5.01 (m, 2H), 4.14- 4.10 (m, 1H), 3.82-3.79 (m, 2H), 0.83 (s, 9H), 0.01 (s, 6H). LCMS (ESI): m/z 354.3 [M++l]
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 12h;
Cbz-L-serine (1.0 mmol), TBDMS-Cl (1.2 mmol) and imidazole (2.0 mmol) were stirred in DMF at room temperature overnight. The crude product was extracted with CH2Cl2. After drying the organic layer over anhydrous Na2SO4 and evaporating the solvent under vacuum, the crude product was purified by flash chromatography with dichloromethane-methanol (20:1) as eluent. The crude product (0.50 mmol), EDCI (0.50 mmol) and DMAP (0.025 mmol) were dissolved in dry DCM, then compound 4 (0.25 mmol) was added and the reaction solution was stirred at room temperature overnight. The crude product was extracted with CH2Cl2. After drying the organic layer over anhydrous Na2SO4 and evaporating the solvent under vacuum, the crude product was purified by flash chromatography with dichloromethane-methanol (20:1) as eluent. The crude product and 1.5 equivalents of TBAF were stirred in THF for about 0.5 h in an ice-bath. The crude product was extracted with CH2Cl2. After drying the organic layer over anhydrous Na2SO4 and evaporating the solvent under vacuum, the crude product was purified by flash chromatography with dichloromethane-methanol (20:1) as eluent. The crude product and a little 10% Pd/C or Pd(OH)2/C were stirred in methanol under a hydrogen atmosphere overnight. The crude product was extracted with CH2Cl2. After drying the organic layerover anhydrous Na2SO4 and evaporating the solvent under vacuum, the crude product was purified by flash chromatography with dichloromethane-methanol (20:1) as eluent. The product was lyophilized.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;
In turn weighed 239.22mg (1.0mmol) Cbz-L- serine, 180.00mg (1.2mmol) TBDMS-Cl , 136.16mg (2.0mmol)imidazole placed in 50mL single-necked flask, add appropriate amount of DMF to dissolve, stirring at room temperature overnight. TLC [V (dichloromethane) :V (methanol) = 20] detection progress of the reaction, the reaction solution was extracted with ethyl acetate, the organic layer was collected, dried over anhydrous sodium sulfate and the right amount of water removal, and evaporated to dryness under reduced pressure, a silica gel column [V (dichloromethane) :V (methanol) = 20] was intermediate; take 83.35mg (0.38mmol) intermediate, 95.50mg (0.50mmol) EDCI, 3.05mg (0.025mmol) DMAPand 147.75mg ( 0.25mmol) TOA appropriate amount of methylene chloride was added and dissolved, and extracted with methylene chloride, the organic layer was collected, dried over anhydrous sodium sulfate and the right amount of water removal, and evaporated to dryness under reduced pressure, a silica gel column [the V (dichloromethane) :V ( methanol) = 20] as a white solid; which is dissolved in an appropriate amount of THF, was added 5 volumes of TBAF, ice-salt bath and stirred for 0.5h, TLC [V (dichloromethane) :V (methanol) = 20 1] detecting progress of the reaction, the reaction solution was extracted with methylene chloride, the organic layer was collected, dried over anhydrous sodium sulfate and the right amount of water removal, and evaporated to dryness under reduced pressure, a silica gel column [the V (dichloromethane) :V (methanol) = 20 ] as a white solid; which was dissolved containing 10% Pd / C in methanol was stirred overnight at room temperature under hydrogen protection; filtered, and the filtrate evaporated to dryness under reduced pressure, a silica gel column [the V (dichloromethane) :V (methanol) = 20:1] as a white solid
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;
Adapting the procedure of Chhabra et al.,4 to aflame-dried 250 mL round bottom flask containing Cbz-Serine-OH 8 (12.0 g, 50.0 mmol, 1.00 equiv) and K2CO3(7.60 g, 55.0 mmol, 1.10 equiv) in DMF (85 mL, 0.60 M) at 0 C was added methyl iodide (6.20 mL, 100 mmol,2.00 equiv) over 30 minutes. The reaction was allowed to warm slowly to room temperature and stirred overnightThe reaction mixture was diluted with EtOAc (500 mL) and washed with a 1:4 mixture of saturated aqueousNaCl:H2O (2 x 100 mL). The combined aqueous washes were back extracted with EtOAc (2 x 150 mL). Thecombined organic extracts were washed sequentially with H2O (2 x 200 mL), saturated aqueous NaCl (2 x 200 mL),5% aqueous (w/v) LiCl (2 x 200 mL), and again saturated aqueous NaCl (1 x 200 mL). The combined aqueouswashes were further back-extracted with Et2O (1 x 200 mL), and the combined organics were dried over Na2SO4,filtered, and concentrated in vacuo to afford the title compound as a viscous, colorless oil (13.0 g, 99%) that wasused without further purification (Note: The crude material contained residual DMF). TLC: Rf = 0.17 (40%EtOAc/hexanes; UV/KMnO4); 1H NMR (600 MHz, CDCl3) delta 7.40-7.30 (m, 5H), 5.79-5.49 (m, 1H), 5.13 (s, 2H),4.50-4.40 (m, 1H), 4.05-3.98 (m, 1H), 3.96-3.90 (m, 1H), 3.79 (s, 3H), 2.07 (t, J = 6.2 Hz, 1H); 13C NMR (151MHz, CDCl3) delta 171.0, 156.3, 136.2, 128.7, 128.4, 128.3, 67.4, 63.6, 56.2, 53.0. The spectra were in close agreementwith the literature.4 IR (FT-ATR, neat, cm-1): 3362, 2654, 1699, 1519, 1454, 1438, 1209, 1057, 976, 911, 750, 697;HRMS (ESI) m/z for [M+Na]+ C12H15NO5Na requires 276.0848, observed 276.0850; [alpha]D20 +8.3 (c = 1.0, CHCl3).
50%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
General procedure: A solution of N-benzyloxycarbonyl-L-amino acid S5 (7.9 mmol) in DMF (20 ml) was added methyliodide (1.1 g, 7.9 mmol) and potassium carbonate (1.2 g, 8.7 mmol). The reaction mixture waskept at room temperature for 3 hours. The methylated products were purified by column chromatographyin the yields of 50% (1.0 g, colorless-oil) for serine and 92% (1.9 g, white-solid) for threonine.The methylated amino acid (4.0 mmol) in DMF (10 ml) was mixed with TBDPSCl (2.2 g, 7.9mmol), imidazole (810 mg, 11.9 mmol) and catalytic amount of DMAP. The reaction was processedat 45 C for 7 hours. The desired products were purified by column chromatography in theyields of 90% (1.7 g, colorless-oil) for serine and 90% (1.8 g, white-solid) for threonine. The silylproduct (500 mg, 1.0 mmol) in DMF (1 ml) was reacted with 15% NaOH (5 ml) for 2 hours. Thereaction mixture was quenching by 1 N HCl(aq) and 6 was extracted by ethyl acetate. The desiredamino acid 6 was obtained after removal of ethyl acetate in the quantitative yields (470 mg,white-solid for serine; 486 mg, colorless-oil for threonine).
With 4-methyl-morpholine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;
Example 4General Method 4A solution of Z-protected-L-Serine (5g, 20.9 mmol), amine (25,1 mmol), WSC (6 g, 31.4 mmol), N-methylmorpholine (2.55 ml, 23 mmol) in DMF (150 ml) was stirred at room temperature for 16h under a nitrogen atmosphere.The reaction mixture was evaporated to dryness under vacuum and the residue was re- dissolved in EtOAc (100 ml). This solution was washed with 2M solution of HC1 (2x75 mL), sat. Solution of sodium bicarbonate (2x75mL), brine (2x75 mL) and dried (Na2S04). The solvent was evaporated to give the Z-protected serine amide as a white solid (64%). Example 4a(2-Hydroxy-l-octylcarbamoyl-ethyl)-carbamic-acid benzyl ester1H-NMR(CDC13, 300 MHz): 7.37 (m, 5H, ArH), 6.56 (m, 1H, NH), 5.83 (m, 1H, NH), 5.15 (s, 2H, ArCH2-), 4.16 (m, 2H, CH2OH), 3.67 (m, 1H, NHCHCO), 3.24 (m, 2H, CONHCH2- ), 1.49 (m, 2H, NHCH2-CH2-), 1.27 (m, 10H, -CH2-CH2-), 0.89 (m, 3H, -CH3)
64%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;
Example 4General Method 4 A solution of Z-protected-L-serine (5 g, 20.9 mmol), amine (25.1 mmol), WSC (6 g, 31.4 mmol), N-methylmorpholine (2.55 mL, 23 mmol) in DMF (150 mL) was stirred at room temperature for 16 h under a nitrogen atmosphere.The reaction mixture was evaporated to dryness under vacuum and the residue was re-dissolved in EtOAc (100 mL). This solution was washed with 2M solution of HCl (2×75 mL), sat. Solution of sodium bicarbonate (2×75 mL), brine (2×75 mL) and dried (Na2SO4). The solvent was evaporated to give the Z-protected serine amide as a white solid (64%).Example 4a(2-Hydroxy-1-octylcarbamoyl-ethyl)-carbamic-acid benzyl ester 1H-NMR (CDCl3, 300 MHz): 7.37 (m, 5H, ArH), 6.56 (m, 1H, NH), 5.83 (m, 1H, NH), 5.15 (s, 2H, ArCH2-), 4.16 (m, 2H, CH2OH), 3.67 (m, 1H, NHCHCO), 3.24 (m, 2H, CONHCH2-), 1.49 (m, 2H, NHCH2-CH2-), 1.27 (m, 10H, -CH2-CH2-), 0.89 (m, 3H, -CH3)
With sodium hydroxide; In water; at 0 - 20℃; for 0.5h;
5.2.1.6 (S)-2-Oxooxazolidine-4-carboxylic acid (8a) At 0 C, to (l)-carbobenzyloxyserine (25.34 g, 106 mmol) is added a NaOH solution (8.0 g, 1.9 equiv) in 40 mL of H2O. The solid quickly dissolves and the solution is stirred at rt for 30 min. The mixture is then washed with Et2O (3 * 40 mL), carefully acidified to pH 1 using 37% HCl (at 0 C), and extracted with EtOAc (12 * 50 mL). The organic layers are collected, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 8a (10.21 g, 73%) is obtained as a white waxy solid. Mp = 119-120 C; [alpha]D20 -21 (c 0.1, H2O); 1H NMR (500 MHz, DMSO): delta 13.2 (br s, 1H), 8.15 (br s, 1H), 4.48 (d, J = 8.8 Hz, 1H), 4.38-4.26 (m, 2H).
In water;
Step A: (S)-2-Oxooxazolidine-4-carboxylic acid To a solution of NaOH (0.8 g, 20 mmol) in water (4 mL) was added (S)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid (1 g, 4.2 mmol) portionwise at 0 C. over 3 min. The resulting solution was warmed to r.t and stirred for 2 h. After cooling to 0 C., the solution was adjusted to pH=1-2 with 2 N HCl. The mixture was extracted with EtOAc (4*10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 13.93-12.30 (m, 1H), 8.15 (s, 1H), 4.49 (t, J=8.6 Hz, 1H), 4.32 (m, 2H); MS: 130.0 (M-1)-.
With water; sodium hydroxide; at 0 - 20℃; for 2.05h;
Example 5. Preparation of (S)-N-((S)-l-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)- 2- oxoethyl)-N-(3-fluorophenyl)-3-hydroxy-2-(pyrimidin-2-ylamino)propanamide. Compound 9 was prepared according to the following scheme, using the following protocol. Step A: (S)-2-Oxooxazolidine-4-carbox lic acid. To a solution of NaOH (0.8 g, 20 mmol) in water (4 mL) was added (S)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid (1 g, 4.2 mmol) portionwise at 0 C over 3 min. The resulting solution was warmed to r.t and stirred for 2 h. After cooling to 0 C, the solution was adjusted to pH=l-2 with 2 N HC1. The mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to give the desired product as a white solid. FontWeight="Bold" FontSize="10" Eta NuMuKappa (400 MHz, DMSO-de): delta 13.93 - 12.30 (m, 1H), 8.15 (s, 1H), 4.49 (t, J= 8.6 Hz, 1H), 4.32 (m, 2H); MS: 130.0 (M-l)
With sodium hydroxide; In water; at 0 - 20℃; for 2.05h;
To a solution of NaOil (0.8 g, 20 mmol) inwater (4 mL) was added (S)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid (1 g, 4.2mmol) portionwise at 0C over 3 mm. The resulting solution was warmed to r.t and stirred for 2h. After cooling to 0C, the solution was adjusted to p11=1-2 with 2 NHC1. The mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the desired product as a white solid. ?H NMR (400 MHz, DMSO-d6): 13.93 -12.30 (m, 111), 8.15 (s, 111), 4.49 (t,J= 8.6 Hz, 1H), 4.32 (m, 2H); MS: 130.0 (M-1).
With sodium hydroxide; In water; at 20℃; for 2h;
Step A: (S)-2-Oxooxazolidine-4-carboxylic acid. To a solution of NaOH (0.8 g, 20 mmol) in water (4 mL) was added (S)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid ( 1 g, 4.2 mmol) portionwise at 0 C over 3 min. The resulting solution was warmed to r.t and stirred for 2 h. After cooling to 0 C, the solution was adjusted to pH= l -2 with 2 N HC1. The mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to give the desired product as a white solid. NMR (400 MHz, DMSO-d6): 6 13.93 - 12.30 (m, 1 H), 8. 15 (s, 1 H), 4.49 (t, J = 8.6 Hz, 1 H), 4.32 (m, 2H); MS: 130.0 (M-
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 3 - 24h;
Example; For example, (R1 = Cbz, Boc, or Fmoc, R2 = H) protected serine with L or D configuration are widely commercially available from Sigma-Aldrich, Acros and other major chemical companies.(formula II) (R1 = H, R2 = Cbz, R3 = phenyl)Procedure: Thiophenol (about 1 - 20 equiv.) was added to a THF solution of N- Cbz-L-Serine (about 10 mmol (1 equiv), about 4 ml/mmol) at about 0 - 300C, followed by HOBT (1 equiv) and l^-dicyclohexylcarbodiimide (1.1 equiv). The mixture was stirred for about 3 - 24 hours at room temperature and the reaction progress was monitored by TLC analysis. After completion of the reaction, a few drops of acetic acid were added to remove the excess 1,3-dicyclohexylcarbodiimide. About thirty minutes later, the reaction solution was filtered to remove the dicyclohexylurea and washed sequentially with about 0.1 M HCl, followed with saturated NaHCO3 and then brine solution. The combined organic layer was concentrated under vacuum and the residue was crystallized in ethyl acetate and hexane (1:1) to generate the thiophenyl ester (formula II) in about 75 - 94% yield (about 2.94 gram), Mp = 108-110 0C. TLC (Rf = 0.40, silica gel, ethyl acetate/hexanes - 1 :1). ee about 85 - 99% was determined by HPLC analysis using the corresponding racemic mixture for comparison. 1H NMR (400MHz, CDCl3) delta 7.43-7.31 (m, 10H), 5.87 (d, J= 8.8 Hz, IH), 5.20 (s, 2H), 4.64 (m, IH), 4.17 (dd, J= 11.2, 2.8 Hz, IH), 3.86 (dd, J= 11.6, 4.0 Hz, IH). 13C NMR (100 MHz, CDCl3) delta 198.9, 156.3, 136.1, 134.8, 129.9, 129.5, 128.8, 128.5, 128.4, 126.9, 67.7, 63.2, 62.4. IR (neat, cnT1) 3377 (br), 3065 (w), 2937 (w), 1698 (s), 1521 (s), 1254 (s), 1058 (s), 694 (m). HRMS (FAB) Calcd for C17H18NO4S ([M+H]+): 332.0951. Found: 332.0944.
Step 1. [Z-Ser-NH 2(XVI) Z-Ser-OH (2.39 g, 10 mmol) and Z-Ser-NH-NH2(2.90 g, 10 mmol) (J.S. Fruton, J. Biol. Chem. (1942) 146 , 463) were coupled as described in the Example 4, Step 1, but purified as reported in the Example 1, Step 1, to give 3.65 g (77% yield) of pure compound XVI from AcOEt; [alpha] [24/D] - 4.7; RfC.32.
2-amino-3-phenylaminoethyl-propionic acid[ No CAS ]
[ 26054-60-4 ]
Yield
Reaction Conditions
Operation in experiment
45%
With triphenylphosphine; In acetonitrile;
a L-2-Amino-3-phenylaminoethylpropionic Acid 54.8 g (0.209 mol) of triphenylphosphine were suspended in 600 ml of acetonitrile and, with exclusion of moisture, cooled to -35 C. to -45 C. At this temperature, 36.4 g (0.209 mol) of diethyl azodicarboxylate were then added dropwise over a period of 50 min. The mixture was stirred at -35 C. for another 15 min. A solution of 50 g (0.209 mol) of N-benzyloxycarbonyl-L-serine in 500 ml of acetonitrile was added dropwise to this mixture, the temperature being kept below -35 C. The mixture was then allowed to react at 5 C. for another 12 h and warmed to RT. The reaction solution was freed from solvent under reduced pressure and the crude product was purified by medium pressure chromatography over silica gel (DCM/AcCN: 25/1). Removal of the solvent gave 20.8 g (yield 45%) of pure N-benzyloxy-carbonyl-L-serine-beta-lactone (see also Org. Synth. 1991 (70) 1ff.) in fine needles. Empirical formula C11H11NO4; M.W.=221.2; MS (M+H) 222.1.
With 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.333333h;Cooling with ice; Inert atmosphere;
A suspension of 300 methyl D-alaninate hydrochloride (25 g, 179.11 mmol) and 301 N-[(benzyloxy)carbonyl]-L-serine (42.8 g, 179.11 mmol) in 302 dichloromethane (786 ml) was cooled in an ice-bath to 0 C. and 303 EDC (41.2 g, 214.93 mmol) was added. 56 DIPEA (109 ml, 626.89 mmol) was added dropwise over 20 minutes and then the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a colourless residue. The residue was dissolved in 57 ethyl acetate (500 ml) and washed with 1:1 water/aqueous saturated sodium hydrogen carbonate solution (600 ml). The organic portion was collected and the aqueous was washed with a further portion of ethyl acetate (500 ml). The combined organic extracts were washed with aqueous 2 M hydrochloric acid solution (300 ml), brine (300 ml), dried over magnesium sulphate, filtered and concentrated to give 304 methyl N-[(benzyloxy)carbonyl]-L-seryl-D-alaninate (44.9 g, 77%) as a colourless solid. 1H NMR (400 MHz, CD3OD, 30 C.): 1.38 (3H, d), 3.71 (3H, s), 3.76 (2H, d), 4.24 (1H, t), 4.37-4.48 (1H, m), 5.11 (2H, s), 7.21-7.47 (5H, m). m/z: ES+ [M+H]+=325.1.
172 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
Preparation 1: (R)-2-((S)-2-Benzyloxycarbonylami no-3-hydroxy-propionyl-ami no)propionic acid methyl esterDiisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino- propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDC (165 g, 0.86 mol), carbobenzyloxy-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture wasstirred under nitrogen at ambient temperature for 16 h. After removing solvent in vacuo at 40C, the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extracted with EtOAc (2 L, 2 x 1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and concentrated in vacuo at 40 C, to give the title compound (172 g) as a colourless solid. 1H NMR (Me-d3-OD):7.44-7.28 (6H, m), 5.13 (2H, 5), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m),1.39 (3H, d).
172 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
Preparation 1: (R)-2-((S)-2-Benzyloxycarbonylami no-3-hydroxy-propionyl-ami no)propionic acid methyl esterDiisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino- propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDC (165 g, 0.86 mol), carbobenzyloxy-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture wasstirred under nitrogen at ambient temperature for 16 h. After removing solvent in vacuo at 40C, the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extracted with EtOAc (2 L, 2 x 1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and concentrated in vacuo at 40 C, to give the title compound (172 g) as a colourless solid. 1H NMR (Me-d3-OD):7.44-7.28 (6H, m), 5.13 (2H, 5), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m), 1.39 (3H, d).
172 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
Preparation 1: (R)-2-((S)-2-Benzyloxycarbonylami no-3-hydroxy-propionyl-ami no)propionic acid methyl esterDiisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino- propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDC (165 g, 0.86 mol), carbobenzyloxy-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture wasstirred under nitrogen at ambient temperature for 16 h. After removing solvent in vacuo at 40C, the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extracted with EtOAc (2 L, 2 x 1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and concentrated in vacuo at 40 C, to give the title compound (172 g) as a colourless solid. 1H NMR (Me-d3-OD):7.44-7.28 (6H, m), 5.13 (2H, 5), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m),1.39 (3H, d).
172 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
Diisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino- propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDO (165 g, 0.86 mol), carbobenzyloxy-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture was stirred under nitrogen at ambient temperature for 16 h. After removing solvent in vacuo at 40C, the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extractedwith EtOAc (2 L, 2 x 1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and concentrated in vacuo at 40 C, to give the title compound (172 g) as a colourless solid. 1H NMR (Me-d3-OD):7.44-7.28 (6H, m), 5.13 (2H, 5), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m), 1.39 (3H, d).
1-((N,4-dimethylphenyl)sulfonamido)vinyl ((benzyloxy)carbonyl)-L-serinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
In dichloromethane at 25℃; for 0.583333h;
99%
In dichloromethane at 30℃; for 0.5h;
9 Example 9
In a clean 25 mL reaction tube N-methyl-N-ethynyl-p-toluenesulfonamide (0.20 mmol) was added, N-benzyloxycarbonyl-L-serine (0.2 mmol)Adding appropriate amount of dichloromethane as solvent,At 30 degrees Celsius for 30 minutes,TLC spot plate detection,After completion of the reaction, the solvent was concentrated and subjected to column chromatography to give pure product,solid,Yield 99%.
(S)-octadecyl 2-(benzyloxycarbonylamino)-3-hydroxypropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With hydrogenchloride In dichloromethane at 20℃; for 16h;
4.5. (S)-Octadecyl 2-(benzyloxycarbonylamino)-3-hydroxypropanoate (8)
A mixture of Z-L-Ser (100.0 mg, 0.42 mmol) and octadecan-1-ol(135.7 mg, 0.50 mmol) were dissolved in DCM (5 mL), The solutionwas saturated with dry hydrogen chloride and stirred at roomtemperature for 16 h. Then the solvent was evaporated. The residuewas purified by column chromatography (silica gel, hexane/EtOAc4:1) to give 143.8 mg (70%) of 8. 1H NMR (CDCl3, 400 MHz): δ 0.87(t, 3H, J =6.8 Hz, CH3), 1.24 (m, 30H, 15 CH2), 1.64 (m, 2H,OCH2CH2), 2.14 (br s, 1H, OH), 3.94-3.97 (m, 2H, CHCH2OH), 4.16 (t,2H, J =6.8 Hz, COOCH2), 4.42 (br s, 1H, NHCH), 5.12 (s, 2H, Cbz CH2),5.65 (br s, 1H, NH), 7.34-7.36 (m, 5H, Cbz Ar); 13C NMR (CDCl3,100 MHz): δ 12.63 (CH3), 21.20, 24.28, 26.98, 27.61, 27.72, 27.87,28.01, 28.21, 30.43, 54.72, 61.78, 64.52, 65.61, 126.56, 126.67, 127.00,127.22, 134.62 (Cbz PhCH2OOC), 154.81 (Cbz C=O), 169.15 (C=O);HR-ESIMS (m/z) for C29H50NO5 [M+H]+, calcd: 492.36835, found:492.36769.
70%
With hydrogenchloride In dichloromethane at 20℃;
Synthesis of Compound 8
100.0 mg of L-Z-Ser (0.42 mmol) and 135.7 (0.50 mmol) of octadecanol were dissolved150 ml of dry DCM solvent, and then through the reaction solution into the dry hydrogen chloride gas until saturated, stirring at room temperature overnight, after the completion of the reaction, vacuum distillation of DCM solvent, silica gel column chromatography V petroleum ether: V ethyl acetate = 4 : 1 was separated to give 143.8 mg of a white powder as a solid 8 with a yield of 70%.
benzyl N6-((benzyloxy)carbonyl)-N2-(((benzyloxy)carbonyl)-L-seryl)-L-lysinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
0253] A solution/suspension of H-Lys(Z)-OBzl hydrochloride (7.0 g, 17.2 mmol) and Z-(L)-Ser-OH (4.12 g, 17.2 mmol) in anhydrous dichloromethane (50 mL) under nitrogen was cooled on ice and treated with HOBT hydrate (3.49 g, 25.8 mmol) and triethylamine (7.22 mL, 52.0 mmol) and the clear solution was stirred for 15 min. EDC hydrochloride (4.12 g, 21.5 mmol) was added and the stirred mixture was allowed to warm to room temperature and stirred 20 h. The product mixture was diluted to 200 mL total volume with dichloromethane, then washed successively with 5% citric acid, water, saturated aqueous sodium bicarbonate and brine (100 mL each) and dried (Na2SO4). The solution was concentrated by half, added directly to a silica gel colunm and eluted with dichloromethane, then 2:1 dichloromethane/ethyl acetate to afford 9.67 g (95%) of subject material as a light yellow solid.
To a solution of (5)-2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoic acid (15 g, 62.7 mmol) and l-hydroxypyrrolidine-2,5-dione (7.50 g, 65.2 mmol) in anhydrous THF (90 mL) was added a solution of DCC (12.94 g, 62.7 mmol) in anhydrous tetrahydrofuran (THF) (90 mL) at 0 C dropwise over 5 min. The reaction mixture was stirred for 2 h at 0 C and an additional 1 h at room temperature. The resulting precipitate was removed by filtration. A solution of IH-pyrrol-l-amine (5.15 g, 62.7 mmol) in THF (20 mL) was added, and the mixture was stirred for 12 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in refluxing EtOAc (10 mL) and filtered immediately. The filtrate was cooled to 25 C, and the resulting solids were collected by filtration, washed with a minimum amount of EtOAc (5 mL) and pentane (100 mL), and dried under vacuum for 12 hr to afford (5)-benzyl (1- ((lH-pyrrol-l-yl) amino)-3-hydroxy-l-oxopropan-2-yl)carbamate (11 g, 57.8 % yield) as a white solid. LCMS (m/z) 304.2 [M+H]+.
(S)-2-(2-(benzyloxy)phenyl)-2-oxoethyl-2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
A mixture of l-(2-(benzyloxy)phenyl)-2-bromoethanone (1.80 g, 5.90 mmol), (S)-2- (((benzyloxy)carbonyl)amino)-3-hydroxypropanoic acid (1.60 g, 6.69 mmol), and cesium carbonate (1.40 g, 4.30 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 h. After this time, the mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, 5% lithium chloride, and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (80 g silica, 0-100% ethyl acetate/heptane) to provide (S)-2-(2- (benzyloxy)phenyl)-2-oxoethyl 2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoate (2.04 g, 75%): ESI MS m/z 464 [C26H25NO7 + H]+.
75%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
A mixture of l-(2-(benzyloxy)phenyl)-2-bromoethanone (1.80 g, 5.90 mmol), (S)-2- (((benzyloxy)carbonyl)amino)-3-hydroxypropanoic acid (1.60 g, 6.69 mmol), and cesium carbonate (1.40 g, 4.30 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 h. After this time, the mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, 5% lithium chloride, and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (80 g silica, 0-100% ethyl acetate/heptane) to provide (S)-2-(2- (benzyloxy)phenyl)-2-oxoethyl 2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoate (2.04 g, 75%): ESI MS m/z 464 [C26H25NO7 + H]+.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;
To a solution of N-Cbz-L-serine (6.00 g, 25.1 mmol) in DMF (60 mL) were added 1,1,1,3,3,3-hexafluoroisopropanol (5.21 mL, 50.2 mmol) and triethylamine (7.00 mL, 50.2 mmol) at room temperature under an argon atmosphere. 1H-Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (13.1 g, 25.1 mmol) was added, followed by stirring at room temperature for 1 h. Aqueous solutions of 1 N HCl (300 mL) and EtOAc (300 mL) were added, and the organic layer was washed with brine (300 mL). After drying with Na2SO4 and evaporation of the solvent, the residue was purified by flash silica gel column chromatography. Yield: 8.54 g, 21.9 mmol (87%); white solid; mp 75-77 C. FTIR (KBr): 3285, 1780, 1693, 1662, 1549, 1387, 1278, 1255, 1199,1106, 696 cm-1. 1H NMR (400 MHz, DMSO-d6, 80 C): delta = 7.53-7.27 (m, 6 H), 6.55 (sept, J = 6.3 Hz, 1 H), 5.08 (dd, J = 16.4, 12.6 Hz, 2 H), 4.89 (t, J = 5.4 Hz, 1 H), 4.41 (td, J = 7.5, 5.4 Hz, 1 H), 3.78 (t, J = 5.4 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6): delta = 168.36, 156.07, 136.76, 128.40, 127.96, 127.80, 124.82, 122.02, 119.21, 116.41, 67.32, 66.99, 65.98, 65.83, 65.65, 65.31, 60.81, 56.54. HRMS (ESI): m/z [M + Na]+ calcd for C14H13F6N1Na1O5: 412.0590; found: 412.0590.
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
4.iii
iii) Preparation of benzyl L-2- (benzyloxycarbonyl) amino-3-iodopropionate: 30 mmol of L-serine (Gill Biochemical Shanghai Co., Ltd.), 60 mmol of benzyl chloroformate (Sarn Chemical Technology Co., Ltd.), Triethylamine 60 mmol (national medicine) was stirred in a mixed solvent of 45 mL of water / 10 mL of dioxane, and reacted at room temperature for 12 hours. After the reaction was completed, it was extracted with ethyl acetate and water, and the organic phase was retained, dried, and spin-dried to obtain L- (benzyloxycarbonyl) amino-serine. 20 mmol of L- (benzyloxycarbonyl) amino-serine, 60 mmol of benzyl bromide (national medicine), 40 mmol of cesium carbonate (Sarn Chemical Technology Co., Ltd.) were stirred in 40 mL of N, N-dimethylformamide, and reacted at room temperature for 6-8 After extraction with ethyl acetate and water for an hour, the organic phase was retained, dried, spin-dried, and recrystallized to obtain L- (benzyloxycarbonyl) amino-serine benzyl ester. Then, 15 mmol of iodine (national medicine), 15 mmol of triphenylphosphine (national medicine), and 15 mmol of imidazole (national medicine) were stirred in 40 mL of dichloromethane at 0 ° C. for 10 min, and L- (benzyloxycarbonyl) amino-serine benzyl ester 10 mmol It was dissolved in 5 mL of dichloromethane and added dropwise to the reaction solution. The reaction solution was stirred at 0 ° C for 2 hours and then reacted at room temperature for 2 hours. After the reaction was completed, sodium thiosulfate was added to quench the reaction until the solution was colorless, extracted with dichloromethane and water, the organic phase was retained, dried, spin-dried, and recrystallized with n-hexane / ethyl acetate ten to one to obtain the product L-2. -(Benzyloxycarbonyl) amino-3-iodopropionic acid benzyl ester, yield 85%.
(S)-benzyl 1-((4-fluorophenyl)(methyl)amino)-3-hydroxy-1-oxopropan-2-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20℃; for 17h;
35.1 Step 1. Preparation of fV)-methyl 3-(benzyloxycarbonylamino)-4-((4-fluorophenyl)- (methyl)amino)-4-oxobutanoate
General procedure: To a solution of (2,S)-2-[[(benzyloxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid (1 g, 3.6 mmol) and 4-fluoro-/V-m ethyl aniline (0.44 g, 3.6 mmol) in THF (10 mL) was added propylphosphonic anhydride solution (3.4 g, 5.343 mmol, 50 wt % in EtOAc), and DIEA (0.92 g, 7.111 mmol) under nitrogen. The mixture was stirred for 4 h at 50 °C and then diluted with water and extracted with EtOAc. The mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography (eluent: 17% EtOAc in PE) to give 0.9 g of the title compound as a light-yellow oil.
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