* 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.
The crude (5)-methyl 2-amino-3-hydroxypropanoate hydrochloride (0.29 mol) was suspended in DCM (200 mL) and to this mixture was added triethylamine (79 mL, 0.57 mol) and Boc20 (68 g, 0.31 mol) at 0 °C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight and then diluted with MTBE (300 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford (5)-methyl 2- ((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (60 g, 94percent yield) as a colorless oil.
86%
With triethylamine In tetrahydrofuran at 20℃;
to a solution of L-serine methyl ester hydrochloride (10.00 g, 64.5 mmol) and Boc20 (28.12 g, 129 mmol) in THF (258 ml_) was slowly added Et3N (27 ml_, 194 mmol) at room temperature. The reaction was stirred overnight, then quenched with saturated NaHC03 and brine, concentrated under vacuum and diluted with CH2CI2 and brine. The mixtures were separated and the aqueous layers were extracted with CH2CI2 three times, the combined organic phases were washed with brine, dried andiconcentrated, the residue was purified by silica gel column chromatography which gave the title compound as colourless oil (14.147 g, 86 percent yield).
82%
With triethylamine In tetrahydrofuran at 25℃; for 5 h; Automated synthesizer
To a solution of methyl L-serinate hydrochloride (1, 2.00 g, 12.9 mmol, 1.00equiv., RF1) in THF (50.0 mL, RR2) were added Et3N (5.36 mL, 38.7 mmol,3.00 equiv, RR3) and Boc2O (3.38 g, 15.5 mmol, 1.20 equiv, RR1) in THF (11.0mL, RR1) diluted with THF (5.00 mL, RR4) and transferred to RF1 at 25 °C.After being stirred at the same temperature for 5 h, the reaction mixture (RF1)was quenched with 1 M HCl aq. (RS2) and the aqueous layer was extractedwith two portions of ethyl acetate (RS1). The combined organic layer waswashed with 10percent NaCl aq. (RS3), dried over Na2SO4 (DT1), filtered, andconcentrated in vacuo. The residue was purified by column chromatography on silica gel (50percent ethyl acetate in hexane) to give methyl (tert-butoxycarbonyl)-Lserinate (2.31 g, 10.5 mmol, 82percent) as a colorless oil.
51.1%
With sodium hydroxide; triethylamine In dichloromethane; water
(1) Synthesis of N-t-butoxycarbonyl-D,L-serine methyl ester (65) Triethylamine[1.78 ml(12.5 mmol.)] was added, under stirring at room temperatre, to a solution of DL-serine methyl ester hydrochloride[3.89 g(12.5 mmol.)] in methylene chloride(50 ml), and the mixture was stirred for 30 minutes, and there was added di-t-butyl dicarbonate[6.00 g(13.8 mmol.)]. The whole mixture was stirred for 20 hours at room temperature. The reaction mixture was washed with 1N aqueous solution of sodium hydroxide and water, successively, and dried, and then the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate(2:1), to obtain the desired product (65)[2.80 g(51.1percent)] as a colorless oily substance. IR(Neat)cm-1: 3370(br), 1740(br), 1700(br). NMR(90 MHz,CDCl3) δ: 1.45(9H,s), 3.77(3H,s), 3.90(2H,m), 4.35(1H,m), 5.50(1H,br.d,J=7 Hz).
51.1%
With sodium hydroxide; triethylamine In dichloromethane; water
1) Synthesis of N-t-butoxycarbonyl-D,L-serine methyl ester (65) Triethylamine [1.78 m (12.5 mmol.)] was added, under stirring at room temperature, to a solution of DL-serine methyl ester hydrochloride [3.89 g (12.5 mmol.)] in methylene chloride (50 m), and the mixture was stirred for 30 minutes, to which was added di-t-butyl dicarbonate [6.00 g (13.8 mmol.)]. The whole mixture was stirred for 20 hours at room temperature. The reaction mixture was washed with 1N aqueous solution of sodium hydroxide and water, successively, and dried, and then the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (2: 1), to obtain the desired product (65) [2.80 g (51.1percent)] as a colorless oily substance.
9.4 g
With triethylamine In acetonitrile at 0 - 20℃; for 6 h;
To a solution of L-serine (5 g,47.6 mmol) in ice-cold methanol (142 mL) was dropwise added acetyl chloride (5 mL, 71.4mmol). Then the reaction mixture was warmed to room temperature and stirred overnight. Solventwas evaporated to afford a white solid, which was used without further purification.The L-serine methyl ester hydrochloride salt (7.4 g, 47.6 mmol) and triethylamine (20.0 mL, 142.8mmol) was added to a solution of Boc-anhydride (11.0 g, 47.6 mmol) in acetonitrile (160 mL) at 0. The reaction mixture was warmed to room temperature and stirred for 6 h. DCM (200 mL)was added and washed with HCl (1 N, 3 x 80 mL) and brine (100 mL). The organic layer wasdried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography(ethyl acetate / petroleum ether = 1:1) to afford 5 as a thick oil (9.4 g, 90percent). [α]D20 = +7.79 (c =0.42, CHCl3) [lit.1 [α]D26 = +9.7 (c = 4.29, CHCl3)]. 1H NMR (400 MHz, CDCl3): δ 5.80 (d, J = 6.8Hz, 1H), 4.35 (br s, 1H), 3.97 (m, 1H), 3.86 (m, 1H), 3.77 (s, 3H), 1.45 (s, 9H). 13C NMR (100MHz, CDCl3): δ 171.2, 155.4, 76.5, 62.4, 55.3, 52.0, 27.8. HRMS (ESI): calcd. for C9H17NO5Na[M+Na]+ 242.0999; found 242.1004.
Reference：
[1] European Journal of Organic Chemistry, 2000, # 1, p. 115 - 124
[2] Organic Letters, 2003, vol. 5, # 24, p. 4599 - 4602
[3] Journal of Organic Chemistry, 2015, vol. 80, # 1, p. 40 - 51
[4] Journal of the American Chemical Society, 2016, vol. 138, # 43, p. 14218 - 14221
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 19, p. 3089 - 3093
[6] Journal of Organic Chemistry, 1994, vol. 59, # 14, p. 3890 - 3897
[7] Patent: WO2014/152127, 2014, A1, . Location in patent: Paragraph 00319; 00321
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 31, p. 8190 - 8194[9] Angew. Chem., 2014, vol. 126, # 31, p. 8329 - 8333,5
[10] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2519 - 2520
[11] Journal of Medicinal Chemistry, 2018,
[12] Synthesis, 1994, # 1, p. 31 - 33
[13] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4204 - 4219
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[15] Patent: WO2007/68474, 2007, A1, . Location in patent: Page/Page column 42; 43
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[18] Organic Letters, 2011, vol. 13, # 10, p. 2614 - 2617
[19] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 106 - 110
[20] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1661 - 1681
[21] Phosphorus, Sulfur and Silicon and Related Elements, 2000, vol. 164, p. 277 - 291
[22] Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12228 - 12239
[23] Patent: US4987130, 1991, A,
[24] Patent: EP278621, 1991, B1,
[25] Helvetica chimica acta, 1990, vol. 73, p. 1373 - 1390
[26] Synthetic Communications, 1992, vol. 22, # 7, p. 979 - 985
[27] Tetrahedron, 1998, vol. 54, # 22, p. 6051 - 6064
[28] Tetrahedron Letters, 1998, vol. 39, # 51, p. 9389 - 9392
[29] Synthetic Communications, 1999, vol. 29, # 14, p. 2377 - 2391
[30] Synlett, 2003, # 3, p. 349 - 352
[31] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3064 - 3067
[32] Organic and Biomolecular Chemistry, 2007, vol. 5, # 23, p. 3826 - 3833
[33] Patent: US2005/101674, 2005, A1, . Location in patent: Page/Page column 5; sheet 6
[34] Organic Letters, 2010, vol. 12, # 1, p. 4 - 7
[35] Dalton Transactions, 2012, vol. 41, # 17, p. 5225 - 5234
[36] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10460 - 10474
[37] Organic and Biomolecular Chemistry, 2013, vol. 11, # 18, p. 2943 - 2946
[38] Tetrahedron Letters, 2013, vol. 54, # 48, p. 6511 - 6513
[39] Patent: US2014/275590, 2014, A1, . Location in patent: Paragraph 0309
[40] Patent: WO2014/140787, 2014, A2, . Location in patent: Paragraph 00256
[41] Organic Letters, 2016, vol. 18, # 8, p. 1812 - 1815
[42] European Journal of Organic Chemistry, 2017, vol. 2017, # 6, p. 1045 - 1051
[43] Organic Syntheses, 2000, vol. 77, p. 64 - 64
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[46] Organic Letters, 2018, vol. 20, # 12, p. 3574 - 3578
[47] Organic Letters, 2018,
3
[ 3262-72-4 ]
[ 74-88-4 ]
[ 2766-43-0 ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4.5 h; Cooling with ice
To a solution of 4 (1.26 g, 6.1 mmol) and potassiumcarbonate (0.91 g, 6.6 mmol) in DMF (12 mL) cooled on an ice bath was added a solution of iodomethane (0.80mL, 12.8 mmol) in DMF (6 mL). After stirring for 30 min on an ice bath, the mixture was stirred for 4 h at rt.Precipitates were filtered off, and the filtrate was added with water and extracted with EtOAc. The organiclayer was washed with water and brine, dried over MgSO4, and evaporated. The obtained colorless oil waspurified by silica gel column chromatography (hexane:EtOAc = 1:1) to give 5 as a colorless oil (1.24 g, 93percent).The spectral data of 5 were identical to the literature,25 and the purity was confirmed by 1H NMR.
87.4%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.25 h; Cooling with ice Stage #2: for 24 h;
Under ice cooling, 18.7 g of N-Boc-L-serine was dissolved in 200 ml of DMF and 13.25 g of solid K2CO3 was added and for 15 minutes, and then 41.6 g (3.2 eq) of Mel was added, followed by stirring for 24 hours. After the reaction, the reaction solution was filtered through celite and concentrated. The residue was extracted by liquid separation using 400 ml of water and 150 ml x 4 of ethyl acetate and dried over sodium sulfate. The ethyl acetate layer was concentrated and subjected to silica gel column chromatography to obtain 17.1 g (87.4percent) of an N-Boc-L-serine methyl ester as a transparent oily product.
5.3 g
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 1.5 h;
To an ice-cold solution of L-serine (3.2 g, 30 mmol) in 1 M sodium hydroxide (60 mL) was added di-tert-butyl dicarbonate [(Boc)2O] (7.8 g, 36 mmol) in dioxane (25 mL). The mixture was stirred at 5 °C for 30 min, then allowed to warm to room temperature over 3.5 h. The reaction mixture was concentrated to half its original volume, quenched with 1 M potassium bisulfate (60 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (2 x 30 mL) and water (30 mL), dried over Na2SO4 and concentrated in vacuo. The crude product (5.8 g) was used to the next step. To an ice-cold solution of N-Boc-L-serine (5.8 g, 28 mmol) in DMF (40 mL) solid potassium carbonate (4.3 g, 31 mmol) was added. After stirring for 10 min methyl iodide (3.5 mL, 56 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. The reaction was allowed to reach room temperature and stirred for an additional hour. Then the reaction mixture was filtered to remove inorganic material, water (20 mL) was added and the filtrate was extracted with diethyl ether (3 x 20 mL). The combined extracts were washed with brine (2 x 20 mL) and water (10 mL), dried over Na2SO4. After concentration in vacuo 5.3 g (86percent yield) of N-Boc-L-serine methyl ester was obtained as a colorless oil. The product was sufficiently pure to be used in the next step without further purification. 1H and 13C NMR spectra were consistent with literature data.2 IR (ATR, cm-1) ν: 3433, 2978, 1743, 1710, 1368, 1163; 1H NMR (400 MHz, CDCl3) δ: 5.67 (br s, 1H, NH), 4.25 (br s, 1H, CH-N), 3.85-3.74 (m, 2H, CH2-O), 3.63 (s, 3H, OCH3), 1.35 (s, 9H, Boc); 13C NMR (400 MHz, CDCl3) δ: 171.4, 155.7, 79.9, 62.7, 55.5, 52.3, 28.0; MS (ESI) m/z: [M+Na]+ 242.
Reference：
[1] Organic Letters, 2003, vol. 5, # 23, p. 4253 - 4256
[2] Arkivoc, 2016, vol. 2017, # 2, p. 260 - 271
[3] Patent: EP2319850, 2011, A1, . Location in patent: Page/Page column 8
[4] Tetrahedron Letters, 2003, vol. 44, # 28, p. 5251 - 5253
[5] Journal of the American Chemical Society, 2006, vol. 128, # 51, p. 16684 - 16691
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4427 - 4431
[7] Organic and Biomolecular Chemistry, 2005, vol. 3, # 13, p. 2476 - 2481
[8] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 2, p. 179 - 182
[9] European Journal of Organic Chemistry, 1998, # 6, p. 945 - 959
[10] Tetrahedron Letters, 2001, vol. 42, # 34, p. 5953 - 5954
[11] Tetrahedron Letters, 2007, vol. 48, # 16, p. 2857 - 2859
[12] Chemistry - A European Journal, 2009, vol. 15, # 17, p. 4428 - 4436
[13] Nature Chemistry, 2010, vol. 2, # 4, p. 280 - 285
[14] Synthesis, 2010, # 18, p. 3063 - 3066
[15] Medicinal Chemistry, 2014, vol. 10, # 6, p. 609 - 618
[16] Patent: US2015/51183, 2015, A1, . Location in patent: Paragraph 0460
[17] Organic Syntheses, 1992, vol. 70, p. 18 - 18
[18] Tetrahedron, 2018, vol. 74, # 38, p. 5392 - 5398
[19] Journal of Organometallic Chemistry, 2018, vol. 876, p. 1 - 9
4
[ 5680-80-8 ]
[ 2766-43-0 ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine In dichloromethane at 38 - 40℃;
General procedure: 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 5percent 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 (92percent) Methyl (tert-butoxycarbonyl)-L-phenylalaninate as a colorless oil.
Reference：
[1] Synthesis, 2010, # 16, p. 2816 - 2822
[2] Tetrahedron Letters, 1995, vol. 36, # 1, p. 67 - 70
[3] New Journal of Chemistry, 2018, vol. 42, # 4, p. 2450 - 2458
[4] Tetrahedron, 1985, vol. 41, # 10, p. 1833 - 1845
[5] Tetrahedron Letters, 2008, vol. 49, # 16, p. 2527 - 2532
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 17, p. 4621 - 4628
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 6, p. 997 - 1000
[8] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 663 - 677
[9] Patent: US5969135, 1999, A,
[10] Patent: WO2005/41899, 2005, A2, . Location in patent: Page/Page column 130-131
[11] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8012 - 8018
[12] Synthesis, 2010, # 3, p. 443 - 446
[13] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6075 - 6087
[14] Monatshefte fur Chemie, 2014, vol. 145, # 3, p. 509 - 515
[15] Letters in Organic Chemistry, 2013, vol. 10, # 9, p. 626 - 631
[16] Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 3738 - 3745
[17] Patent: WO2005/41899, 2005, A2, . Location in patent: Page/Page column 130-131
6
[ 24424-99-5 ]
[ 5680-80-8 ]
[ 2766-43-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium hydroxide; triethylamine In tetrahydrofuran; methanol; ethyl acetate
SYNTHESIS EXAMPLE 1 (Synthesis of Boc-1-serine methylester 2) (The term "Boc" as used herein means a t-butoxycarbonyl group.) 6.6 g (0.1 mol) of potassium hydroxide (purity, 85percent) was dissolved in 150 ml of methanol. To this was added 15.6 g (0.1 mol) of 1-serine methylester hydrochloride and the mixture was stirred for 45 minutes. The resulting solution was mixed with 10.1 g (0.1 mol) of triethylamine and then with 21.8 g (0.1 mol) di-tert-butyl-dicarbonate which has been dissolved in 100 ml of tetrahydrofuran (THF) solution. After standing overnight, the THF in the mixture was distilled off under reduced pressure. A portion of ethyl acetate was added to the reside remaining after the distillation and the organic layer was washed with water. After drying with sodium sulfate, the solvent was distilled off. The resulting residue was then subjected to silica gel chromatography (hexane/ethyl acetate=7/3) to obtain 18.9 g (0.086 mol) of the Boc-1-series methylester 2 as a purified colorless liquid with the yield of 86percent.
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 17, p. 6599 - 6601
11
[ 24424-99-5 ]
[ 2104-89-4 ]
[ 2766-43-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 759 - 769
12
[ 24424-99-5 ]
[ 2766-43-0 ]
Yield
Reaction Conditions
Operation in experiment
7.16 g
With triethylamine In tetrahydrofuran at 0 - 20℃; for 12 h;
To a solution of (L)-serinemethyl ester HC1 (5.00 g, 32.1 mmol) in dry tetrahydrofuran (THF)(64.3 mL) was added triethylamine (TEA)(9.85 mL, 70.7 mmol) followed by a solution of (Boc)20 (7.46 mL, 32.1 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred for 12 hours at room temperature. After concentration of the resulting mixture in vacuo, the residue was partitioned betweenethyl acetate (EtOAc) and water. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound (7.16 g, >99percent) as colorless oil, which was used for the next reaction withOut further purification.
With t-butyl bromide In acetonitrile for 0.5 h; Reflux
General procedure: To asolution of the PMB ether (1 mmol) in acetonitrile (10 mL), t-BuBr (1.1 equiv)was added and stirred at reflux. After completion of the reaction (monitored byTLC), it was concentrated under reduced pressure and the resulting crude wasdissolved in ethyl acetate (50 mL) and washed with saturated sodiumhydrogenocarbonate (25 mL). The aqueous layer was extracted with ethylacetate (2 5 mL) and the combine organic layer was washed with brinesolution, dried (MgSO4), concentrated under reduced pressure and the residuewas purified by column chromatography (silica gel, EtOAc, cyclohexane) toafford the corresponding alcohol.
Reference：
[1] Journal of Organometallic Chemistry, 2018, vol. 876, p. 1 - 9
37
[ 2766-43-0 ]
[ 98-59-9 ]
[ 56926-94-4 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 0℃; for 8 h; Inert atmosphere
To a solution of 5 (0.67 g, 3.1 mmol)in pyridine (10 mL) cooled on an ice bath was added p‐toluenesulfonyl chloride (3.0 g, 15.7 mmol). Afterstirring for 8 h on an ice bath under nitrogen atmosphere, Et2O (10 mL) was added to the solution, and themixture was further stirred at rt for 14 h. The resulting yellow solution was washed with water, 10percent potassium hydrogen sulfate, saturated sodium bicarbonate, and brine. The ethereal layer was dried over MgSO4 andevaporated. The obtained colorless oil was purified by silica gel column chromatography (hexane:EtOAc = 2:1)to give 6 as a white solid (1.05 g, 91percent). The spectral data of 6 were identical to the literature.32 The purity wasconfirmed by 1H NMR.
85%
With pyridine In dichloromethane at 0 - 20℃; for 16 h;
To a solution of N-t-butoxycarbonyl-L-serine methyl ester (6.57 g, 30 mmol) in CH2Cl2 (30 mL) at 0° C. was added pyridine (10 mL). Then, p-toluenesulfonyl chloride (6.84 g, 36 mmol) was added portionwise. The mixture was allowed to warm to rt and was stirred for 16 h. The mixture was then poured into EtOAc/H2O (150 mL/100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), and filtered. After removal of solvent, the mixture was purified by silica gel chromatography using EtOAc/hexane (1/9 to 7/13) as the eluent to give 9.5 g of the desired compound (85percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=6.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 5.34 (d, J=6.0 Hz, 1H), 4.52-4.49 (m, 1H), 4.39 (dd, J=12.0, 3.0 Hz, 1H), 4.29 (dd, J=9.0, 3.0 Hz, 1H), 3.69 (s, 3H), 2.45 (s, 3H), 1.42 (s, 9H).
Reference：
[1] Arkivoc, 2016, vol. 2017, # 2, p. 260 - 271
[2] Tetrahedron Letters, 1987, vol. 28, # 48, p. 6069 - 6072
[3] Journal of the American Chemical Society, 2006, vol. 128, # 51, p. 16684 - 16691
[4] Patent: US2008/103129, 2008, A1, . Location in patent: Page/Page column 57
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 405 - 408
[6] Chemical Communications, 2014, vol. 50, # 41, p. 5487 - 5489
[7] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 16, p. 2443 - 2447
[8] Organic Syntheses, 2005, vol. 81, p. 77 - 88
[9] Tetrahedron, 1985, vol. 41, # 10, p. 1833 - 1845
[10] Synlett, 2016, vol. 27, # 19, p. 2685 - 2688
[11] Journal of Organic Chemistry, 1990, vol. 55, # 13, p. 3998 - 4006
[12] Tetrahedron Letters, 1994, vol. 35, # 4, p. 551 - 554
[13] Phosphorus, Sulfur and Silicon and the Related Elements, 1998, vol. 136, p. 611 - 616
[14] Tetrahedron Letters, 2003, vol. 44, # 28, p. 5251 - 5253
[15] Organic and Biomolecular Chemistry, 2005, vol. 3, # 13, p. 2476 - 2481
[16] Organic Letters, 2001, vol. 3, # 9, p. 1331 - 1334
[17] Patent: US4795815, 1989, A,
[18] Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12228 - 12239
38
[ 2766-43-0 ]
[ 93267-04-0 ]
Yield
Reaction Conditions
Operation in experiment
68%
at 0 - 20℃; for 1.5 h;
A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50 mol) in DCM (600 mL) was cooled to 0 °C and iodide (127 g, 0.50 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0 °C, a solution of (5)-methyl 2-((tert- butoxycarbonyl)amino)-3-hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel to afford (i?)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (74.0 g, 68percent yield) as a colorless solid.
67%
Stage #1: With methyltriphenoxyphosphonium iodide In N,N-dimethyl-formamide at 0℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water; N,N-dimethyl-formamide for 0.25 h;
Triphenylphosphite methiodide (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 4, p557; 34Og, 753 mmol, 1.4 equiv.) was added in one portion to a solution of (S)-2- rert-butyloxycarbonylamino-3-hydroxypropionic acid methyl ester (118g, 538 mmol) in dry N,N-dimethylformamide (1.1 L) at 0°C. After 30 minutes at O0C solid sodium bicarbonate (27Og) was added followed by water (1. IL). The resulting mixture was stirred vigorously for 15 minutes and then extracted with 1:1 diethylether/hexanes (3 x 80OmL). The combined organic extracts were washed with 0.5M sodium hydroxide (5 x IL) and brine (2 x IL), dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting orange oil was loaded onto a SiO2 plug (2" x 7") and eluted with 5percent EtOAc/hexanes to afford (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate as a pinkish oil, which solidified (118.5g, 67percent) 1H NMR (CDC13; 400MHz): δppm 5.32 (m, IH), 4.51 (m, IH), 3.81 (s, 3H), 3.58 (m, 2H), 1.45 (s, 9H).
65%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere
Triphenylphosphine (66.0 g, 0.250 mol) and imidazole (17.1 g, 0.250 mol) were dissolved in methylene chloride (900 ml). After cooling to 0° C., iodine (64.0 g, 0.250 mol) was added thereto, and the temperature was gradually raised from 0° C. to room temperature in the presence of nitrogen gas, followed by stirring for 10 minutes. After cooling to 0° C., a methylene chloride solution (100 of methyl N-(tert-butoxycarbonyl)-L-serinate (45.0 g, 0.200 mol) was slowly added dropwise over one hour, followed by stirring at room temperature for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 1:2) to obtain the title compound (43.8 g, 65percent). [0585] 1H NMR (CDCl3, 400 MHz): δ 5.36-5.34 (m, 1H), 4.53-4.51 (m, 1H), 3.80 (s, 3H), 3.61-3.53 (m, 2H), 1.46 (s, 9H)
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 17, p. 6792 - 6796
[2] Organic Letters, 2003, vol. 5, # 24, p. 4599 - 4602
[3] Organic Letters, 2011, vol. 13, # 10, p. 2614 - 2617
[4] Tetrahedron, 2017, vol. 73, # 42, p. 6085 - 6091
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39
[ 2766-43-0 ]
[ 55477-80-0 ]
[ 93267-04-0 ]
Reference：
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With potassium hydrogen sulphate; triethylamine; In tetrahydrofuran; DMF(100 ml each); water; ethyl acetate;
N-Boc-<strong>[2788-84-3]L-Serine methyl ester</strong> (2) <strong>[2788-84-3]L-Serine methyl ester</strong> (15.6 g, 100 mmol) was suspended in THF/DMF(100 ml each) mixture at room temperature. To this stirred mixture was added triethylamine (11.13 g, 110 mmol) followed by di-tert-butyl dicarbonate (24.0 g, 110 mmol) and the stirring continued at room temperature for 30 minutes. Water (20 ml) was added and the solution was stirred at room temperature for 8 h. The solution was evaporated to dryness. The residue was suspended in ethyl acetate (250 ml) and treated with potassium hydrogen sulfate (0.25N solution, 100 ml). The product was extracted immediately with ethyl acetate solution. The organic extract was washed with water (100 ml), brine (100 ml) and dried over anhydrous sodium sulfate. Evaporation of the organic solvent provided an oily residue of 26 g (90%).
With triethylamine; In dichloromethane; at 20℃; for 4h;
To a solution of the crude methyl ester serine (33) in CH2C12 (100 mL), stirring under N2 (g), was added di-tert-butyl pyrocarbonate (11.420 g, 52. 34 mmol) and triethyl amine (16.6 mL, 118.95 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours, and then poured over NH4Cl at 0C. The organic layer was extracted with 10% HC1 (2x), then NaHCO3 and brine. The organic layer was then dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was again carried on to the following step
With triethylamine; In dichloromethane; at 20℃; for 16h;
iii) Preparation of methyl L-2- (tert-butoxycarbonyl) amino-3-iodopropionate:L-serine methyl ester 30mmol (Gill Biochemical Shanghai Co., Ltd.),60 mmol of di-tert-butyl dicarbonate (Sarn Chemical Technology Co., Ltd.) and 60 mmol of triethylamine (Sinopharm) were stirred in 100 mL of dichloromethane,React for 16 hours at room temperature,After the reaction,Extract with dichloromethane and water, keep the organic phase,Dry, spin dry to get L-tert-butoxycarbonyl-serine methyl ester. Then, make iodine 15mmol (national medicine),Triphenylphosphine 15mmol (national medicine), imidazole 15mmol (national medicine) were stirred in 40mL dichloromethane at 0 for 10min,10 mmol of L-tert-butoxycarbonyl-serine methyl ester 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,Sodium thiosulfate was added to quench the reaction until the solution was colorless, extracted with dichloromethane and water, and the organic phase was retained.Dry, spin dry, and use n-hexane / ethyl acetate ten to one to separate the crude silica gel (100-200 mesh) column (Rf = 0.5) to obtain the product L-2- (tert-butoxycarbonyl) amino-3-iodopropyl Methyl acid ester is liquid,Place the product at minus 20 degrees Celsius and freeze for 24 hours to obtain a solid product.The yield was 70%.
With triethylamine; In dichloromethane; at 0 - 20℃;
The crude (5)-methyl 2-amino-3-hydroxypropanoate hydrochloride (0.29 mol) was suspended in DCM (200 mL) and to this mixture was added triethylamine (79 mL, 0.57 mol) and Boc20 (68 g, 0.31 mol) at 0 C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight and then diluted with MTBE (300 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford (5)-methyl 2- ((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (60 g, 94% yield) as a colorless oil.
88%
With tert.-butyl lithium; triethylamine; In acetonitrile; at 20℃; for 14h;Inert atmosphere;
l-Serine (11.1g, 106mmol, 1.0eq.) was added in portions to a solution of 60 thionyl chloride (63.1g, 38.4mL, 530mmol, 5.0eq.) in 23 methanol (200mL) at 0C. The cooling bath was removed and the reaction mixture was stirred for 24h at ambient temperature. All volatiles were removed under reduced pressure to obtain l-serine methyl ester hydrochloride in quantitative yield which was directly used for the next transformation. For this, a mixture of 61 l-serine methyl ester hydrochloride (16.5g, 106mmol, 1.0eq.), Boc2O (23.1g, 106mmol, 1.0eq.) and 62 Et3N (44.1mL, 318mmol, 3.0eq.) were stirred in anhydrous 63 MeCN (330mL) at ambient temperature for 14h. The reaction mixture was diluted with CH2Cl2 and washed with 1n HCl. The layers were separated and the organic layer was washed one additional time with sat. aq. K2CO3. The organic layer was dried (MgSO4) and all volatiles were removed under reduced pressure to obtain title compound 64 22 as white solid (20.5g, 93.6mmol, 88% yield over two steps) which was used directly for the next transformation without further purification. 1H NMR (400MHz, CDCl3) delta 5.50 (br s, 1H), 4.36 (br s, 1H), 3.94 (dd, J=11.2, 3.9Hz, 1H), 3.88 (dd, J=11.2, 3.6Hz, 1H), 3.77 (s, 3H), 2.64 (br s, 1H), 1.44 (s, 9H). 13C NMR (101MHz, CDCl3) delta 171.5, 155.9, 80.4, 63.6, 55.8, 52.8, 28.4.
86%
With triethylamine; In tetrahydrofuran; at 20℃;
to a solution of L-serine methyl ester hydrochloride (10.00 g, 64.5 mmol) and Boc20 (28.12 g, 129 mmol) in THF (258 ml_) was slowly added Et3N (27 ml_, 194 mmol) at room temperature. The reaction was stirred overnight, then quenched with saturated NaHC03 and brine, concentrated under vacuum and diluted with CH2CI2 and brine. The mixtures were separated and the aqueous layers were extracted with CH2CI2 three times, the combined organic phases were washed with brine, dried andiconcentrated, the residue was purified by silica gel column chromatography which gave the title compound as colourless oil (14.147 g, 86 % yield).
82%
With triethylamine; In tetrahydrofuran; at 25℃; for 5h;Automated synthesizer;
To a solution of methyl L-serinate hydrochloride (1, 2.00 g, 12.9 mmol, 1.00equiv., RF1) in THF (50.0 mL, RR2) were added Et3N (5.36 mL, 38.7 mmol,3.00 equiv, RR3) and Boc2O (3.38 g, 15.5 mmol, 1.20 equiv, RR1) in THF (11.0mL, RR1) diluted with THF (5.00 mL, RR4) and transferred to RF1 at 25 C.After being stirred at the same temperature for 5 h, the reaction mixture (RF1)was quenched with 1 M HCl aq. (RS2) and the aqueous layer was extractedwith two portions of ethyl acetate (RS1). The combined organic layer waswashed with 10% NaCl aq. (RS3), dried over Na2SO4 (DT1), filtered, andconcentrated in vacuo. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to give methyl (tert-butoxycarbonyl)-Lserinate (2.31 g, 10.5 mmol, 82%) as a colorless oil.
Multi-step reaction with 2 steps
1: Et3N / CH2Cl2 / 0 °C
2: 87 percent / Et3N / tetrahydrofuran
Multi-step reaction with 5 steps
1: pyridine / 4 °C
2: CsCO3 / dimethylformamide
3: NaOMe / methanol
4: triethylbenzylammonium chloride, KOH
5: 1. NaH 2. NaI / 1. dimethoxyethane, -10 deg C -> room temp.
With methanesulfonyl chloride; triethylamine In dichloromethane at -15 - -5℃; for 0.5h;
Multi-step reaction with 2 steps
1.1: pyridine / dichloromethane / 0.25 h / -50 °C
1.2: 20 h / -50 - 20 °C
2.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 65 °C
Multi-step reaction with 2 steps
1: dmap / acetonitrile / 8 h / 22 °C / Inert atmosphere
2: 1,1,3,3-tetramethylguanidine / acetonitrile / 8 h / 22 °C / Inert atmosphere; Darkness
With N-ethyl-N,N-diisopropylamine In acetonitrile at 45℃; for 2h;
A716.1 Synthesis of (3S)-1-acryloyl-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-21,22,23,26,61,62,63,64,65,66-decahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(5,1)-pyridinacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N-methylpyrrolidine-3-carboxamide
Step 1. To a solution of methyl (tert-butoxycarbonyl)-L-serinate (10 g, 45 mmol) in anhydrous MeCN (150 mL), was added DIPEA (17 g, 137 mmol). The reaction mixture was stirred at 45° C. for 2 h to give methyl 2-((tert-butoxycarbonyl)amino)acrylate in solution. LCMS (ESI): m/z [M+Na] calc'd for C9H15NO4 201.1; found 224.1.
To a solution of 5 (0.67 g, 3.1 mmol)in pyridine (10 mL) cooled on an ice bath was added p-toluenesulfonyl chloride (3.0 g, 15.7 mmol). Afterstirring for 8 h on an ice bath under nitrogen atmosphere, Et2O (10 mL) was added to the solution, and themixture was further stirred at rt for 14 h. The resulting yellow solution was washed with water, 10% potassium hydrogen sulfate, saturated sodium bicarbonate, and brine. The ethereal layer was dried over MgSO4 andevaporated. The obtained colorless oil was purified by silica gel column chromatography (hexane:EtOAc = 2:1)to give 6 as a white solid (1.05 g, 91%). The spectral data of 6 were identical to the literature.32 The purity wasconfirmed by 1H NMR.
85%
With pyridine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of N-t-butoxycarbonyl-L-serine methyl ester (6.57 g, 30 mmol) in CH2Cl2 (30 mL) at 0 C. was added pyridine (10 mL). Then, p-toluenesulfonyl chloride (6.84 g, 36 mmol) was added portionwise. The mixture was allowed to warm to rt and was stirred for 16 h. The mixture was then poured into EtOAc/H2O (150 mL/100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), and filtered. After removal of solvent, the mixture was purified by silica gel chromatography using EtOAc/hexane (1/9 to 7/13) as the eluent to give 9.5 g of the desired compound (85%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 7.76 (d, J=6.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 5.34 (d, J=6.0 Hz, 1H), 4.52-4.49 (m, 1H), 4.39 (dd, J=12.0, 3.0 Hz, 1H), 4.29 (dd, J=9.0, 3.0 Hz, 1H), 3.69 (s, 3H), 2.45 (s, 3H), 1.42 (s, 9H).
82%
With pyridine; In dichloromethane; at 20℃;Inert atmosphere;
[0598] A homogeneous solution of Boc-L-serine methyl ester (5.0 g, 22.8 mmol) in DCM (30 mL) at room temperature under N2 atmosphere was treated with pyridine (8 mL), P-toluene sulfonyl chloride (5.22 g, 27.4 mmol, 1.2 eq.) and stirred overnight. The reaction was quenched by addition of water (50 mL) and extract with EA (100 mL3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex:EA=9:1 to 2:1) to obtain compound L-11-1 (7.0 g, 82%) as white solid. [0599] 1H NMR (600 MHz, CDCl3) delta 7.76 (d, J=8.4 Hz, 2H), 7.35 (d, J=7.8 Hz, 2H), 5.29 (S, 1H), 4.53-4.47 (m, 1H), 4.39 (dd, J=2.4, 7.8 Hz, 1H), 4.29 (d, J=7.2, 2.4 Hz, 1H), 3.69 (s, 3H), 2.45 (s, 3H).
82%
With pyridine; In dichloromethane; at 20℃;
A homogeneous solution of Boc-L-serine methyl ester (5.0 g, 22.8 mmol) in DCM (30 mL) at room temperature under N2 atmosphere was treated with pyridine (8mL), para-toluene sulfonyl chloride (5.22 g, 27.4 mmol) and stirred overnight. The reaction was quenched by addition of water (50 mL) and extracted with EA (100 mL x 3). The combined organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex: EA = 9: 1 to 2: 1) to obtain compound L-9-1 (7.0 g, 82 %) as white solid. NMR (600 MHz, CDCb) d 7.76 (d, J= 8.4 Hz, 2H), 7.35 (d, J= 7.8 Hz, 2H), 5.29 (S, 1H), 4.53 - 4.47 (m, 1H), 4.39 (dd, J= 2.4, 7.8 Hz, 1H), 4.29 (d, J= 7.2 , 2.4 Hz, 1H), 3.69 (s, 3H), 2.45 (s, 3H).
With pyridine; dmap; In dichloromethane; Petroleum ether;
Preparation 1 Methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate Methyl (3-hydroxy)-2-(S)-(t-butoxycarbonylamino)propionate (58 g, 196 mmol), dry methylene chloride (150 ml), p-toluenesulfonyl chloride (43.35 g, 227.4 mmol), 4-(dimethylamino)pyridine (2.4 g, 19.6 mmol) and pyridine (30 ml, 371 mmol) were combined and stirred at room temperature overnight. The reaction solution was concentrated in vacuo to a pale yellow oil. The oil was stored in vacuo overnight, then the white solid that formed was isolated to give 75.33 g of crude product. The product was triturated in petroleum ether (approximately 200 ml) to yield methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate: n.m.r.: (CDCl3, 90 MHz): delta7.72, 7.31 (2x dd, 4, aromatic protons), 5.26 (m, 1, nitrogen proton), 4.48 (m, 1, C-2 proton), 4.32 (m, 2, C-3 protons), 3.68 (s, 3, methyl protons of methyl ester), 2.44 (s, 3, methyl protons of toluene moiety), 1.40 (s, 9,
With boron trifluoride diethyl etherate; In dichloromethane; at 25℃; for 3h;Automated synthesizer;
To a solution of methyl (tert-butoxycarbonyl)-L-serinate (2a, 1.94 g, 8.85 mmol,1.00 equiv, RF1) in CH2Cl2 (20.0 mL, RF1) were added 2,2-dimethoxylpropane(3.25 mL, 26.6 mmol, 3.00 equiv, RR1) in CH2Cl2 (15.0 mL, RR1) diluted withCH2Cl2 (10.0 mL, RR4) and boron trifluoride·ethyl ether complex (0.0553 mL,0.443 mmol, 0.500 equiv, RR3) in CH2Cl2 (15.0 mL, RR3) diluted with CH2Cl2(10.0 mL, RR6) and transferred to RF1 at 25 C. After being stirred at the same temperature for 3 h, the reaction mixture (RF1) was quenched with saturatedNaOH aq. (RR2) and the aqueous layer was extracted with two portions of ethylacetate (RS1). The combined organic layer was washed with 10% NaCl aq.(RS3), dried over Na2SO4 (DT2), filtered, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (16% ethyl acetatein hexane) to give 3-(tert-butyl) 4-methyl (S)-2,2-dimethyloxazolidine-3,4-dicarboxylate (2.28 g, 8.79 mmol, 99%) as a colorless oil.
93%
With boron trifluoride diethyl etherate; In acetone; at 20℃; for 12h;
Step 2: Preparation of (8)-3-tert-butyl-4-methyl 2,2-dimethyloxazolidine-3,4- dicarboxylate (Intermediate 3) To a solution of (5)-methyl 2-((tert-butoxycarbonyl)amino)-3- hydroxypropanoate (6.16 g, 28.1 mmol) and 2,2-dimethoxypropane (34.4 mL, 281 mmol) in dry acetone (55 mL) was added boron trifluoride diethyl ether (BF3OEt2)(0.2l4 mL, 1.68 mmol) at room temperature. The reaction mixture wasstirred for 12 hours at room temperature. After concentration of the resulting mixture in vacuo, the residue was diluted with dichloromethane (DCM), and washed with 50% aq. NaHCO3 solution and water twice. The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on Si02 (Hex:EtOAc=10:1) to obtain the title compound (6.75 g,93%) as a yellow oil.?H-NMR (400 MHz, CDC13): (two sets from rotamers) 4.38 (dd, J 6.8,2.8 Hz, 1H), 4.15 (ddd, J= 9.2, 9.2, 7.2 Hz, 2H), 3.76 (s, 3H), 1.83 (s, 3H), 1.54 (s,3H), 1.42 (s, 9H) oe 4.49 (dd, J = 6.8, 2.8 Hz, 1H), 4.05 (ddd, J= 9.2, 9.2, 3.2 Hz, 2H), 3.76 (s,3H), 1.64 (s, 3H), 1.50 (s, 12H).
90%
With boron trifluoride diethyl etherate; In acetone; at 20℃; for 2.5h;
2,2-Dimethyl-oxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester (35a). 2,2-Dimethoxypropane (50 ml, 400 mmol) and boron trifluoride etherate (0.35 ml, 2.8 mmol) was added to a solution of N-Boc serine methyl ester (1, 10.0 g, 45.6 mmol) in acetone (165 ml). The resulting orange solution was stirred at room temperature for 2.5 h until disappearance of starting material. 0.9 ml triethylamine was then added to the reaction mixture whereafter the solvent was removed under reduced pressure. The residue was partitioned between diethyl ether and sat. NaHCOs, the organics extracts were combined, dried and concentrated which gave the title compound (10.5 g, 90%) which was used without further purification.
With 1H-imidazole; bromine; triphenylphosphine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
To a pre-cooled mixture of triphenylphosphine (4.40 g, 16.8 mmol) in dry DCM (50 mL) was dropwisely added a solution of Br2 (0.86 mL, 16.8 mmol) in DCM (20 mL) at 0 C under nitrogen protection. After 20 min, a mixture of N-Boc-L-serine methyl ester (1.84 g, 8.4 mmol) and imidazole (1.14 g, 16.8 mmol) in DCM (50 mL) was slowly added to the above pale yellow solution and the mixture was stirred for another two hours at 0 C. Subsequently, the solids were filtered off and the solvent was evaporated. The resulting solid was re-dissolved in DCM (10 mL) and purified by column chromatography (hexanes/EtOAc, 6:1) to give the bromide intermediate in 86 % yield (2.03 g, 7.2 mmol).
86%
With 1H-imidazole; bromine; triphenylphosphine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
To a pre-cooled mixture of triphenylphosphine (4.40 g, 16.8 mmol) in dry DCM (50 mL) was dropwisely added a solution of Br2 (0.86 mL, 16.8 mmol) in DCM (20 mL) at 0 C under nitrogen protection. After 20 min, a mixture of N-Boc-L-serine methyl ester (1.84 g, 8.4 mmol) and imidazole (1.14 g, 16.8 mmol) in DCM (50 mL) was slowly added to the above pale yellow solution and the mixture was stirred for another two hours at 0 C. Subsequently, the solids were filtered off and the solvent was evaporated. The resulting solid was re-dissolved in DCM (10 mL) and purified by column chromatography (hexanes / EtOAc, 6:1) to give the bromide intermediate in 86% yield (2.03 g, 7.2 mmol).
65%
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h;Cooling with ice;
The obtained N-Boc-L-serine methyl ester (6.0 g) and 10.5 g (1.2 eq) of carbon tetrabromide were dissolved in 100 ml of dry THF and a solution prepared by dissolving 8.29 g (1.2 eq) of Ph3P in 50 ml of dry THF was added dropwise under ice cooling, followed by stirring at room temperature for 24 hours. After the reaction, the reaction solution was filtered and purified by silica gel column chromatography to obtain 4.9 g (65%) of methyl (S)-2-tert-butoxycarbonylaminopropanate as a white crystal.
Stage #1: methanol; L-serin With acetyl chloride
Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine
94%
Stage #1: methanol; L-serin With thionyl chloride at 20℃; for 10h; Reflux; Large scale;
Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In dichloromethane at 20℃; for 8h; Cooling with ice; Large scale;
1.1; 2.1 Example 1
1,Dissolve 3.1 kg of L-serine in 30 L of methanol.Add 2.2L of thionyl chloride at room temperature,After the addition was completed, the mixture was stirred for 2 hours and then heated to reflux for 8 hours.The reaction solution was concentrated and dried,The concentrate was dissolved in 30 L of dichloromethane, and 9.2 L of triethylamine and 7.25 kg of di-tert-butyl dicarbonate were added, and the mixture was cooled with ice water, and the temperature was controlled to not exceed 20 ° C. After the addition, the mixture was stirred at room temperature for 8 hours, and the reaction solution was treated with 1 N sulfuric acid. The organic phase was washed with anhydrous sodium sulfate and the solvent was evaporated to give the compound I 6.38 kg, yield 94%;
89%
Stage #1: methanol; L-serin With thionyl chloride at 0 - 20℃; for 6h;
Stage #2: di-<i>tert</i>-butyl dicarbonate With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 12h;
Stage #1: methanol; L-serin With hydrogenchloride
Stage #2: di-<i>tert</i>-butyl dicarbonate With sodium hydrogencarbonate In 1,4-dioxane; water Further stages.;
Stage #1: methanol; L-serin With thionyl chloride
Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 24h;
95%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 20h;
93%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4.5h; Cooling with ice;
N-(tert-Butoxycarbonyl)-L-serine methyl ester (5)
To a solution of 4 (1.26 g, 6.1 mmol) and potassiumcarbonate (0.91 g, 6.6 mmol) in DMF (12 mL) cooled on an ice bath was added a solution of iodomethane (0.80mL, 12.8 mmol) in DMF (6 mL). After stirring for 30 min on an ice bath, the mixture was stirred for 4 h at rt.Precipitates were filtered off, and the filtrate was added with water and extracted with EtOAc. The organiclayer was washed with water and brine, dried over MgSO4, and evaporated. The obtained colorless oil waspurified by silica gel column chromatography (hexane:EtOAc = 1:1) to give 5 as a colorless oil (1.24 g, 93%).The spectral data of 5 were identical to the literature,25 and the purity was confirmed by 1H NMR.
90%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 4.5h;
89%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃; for 4.5h;
1-3
N-Boc serine (1.23 g, 6 mmol) and potassium carbonate (0.90 g, 6.5 mmol) were dissolved in 12 mL of DMF, and after cooling to 0 ° C, 6 mL of a solution of methyl iodide in DMF was slowly added dropwise. The concentration of methyl iodide was 2.1 M And stir the reaction for 30min, and then return to 25 ° C to continue the reaction for 4h; filter the resulting reaction solution and collect the filtrate; add excess water to the filtrate and extract 3 times with ethyl acetate; use the combined organic phase with saturated chlorine The solution was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. The obtained residue was purified by column chromatography with n-hexane and ethyl acetate at a volume ratio of 1: 1. The collected eluate was evaporated to dryness under reduced pressure to obtain the product N-Boc serine methyl ester (a colorless oily liquid 1.17 g, yield 89%).
87.4%
Stage #1: (S)-N-(tert-butoxycarbonyl)serine With potassium carbonate In N,N-dimethyl-formamide for 0.25h; Cooling with ice;
Stage #2: methyl iodide In N,N-dimethyl-formamide for 24h;
b
Under ice cooling, 18.7 g of N-Boc-L-serine was dissolved in 200 ml of DMF and 13.25 g of solid K2CO3 was added and for 15 minutes, and then 41.6 g (3.2 eq) of Mel was added, followed by stirring for 24 hours. After the reaction, the reaction solution was filtered through celite and concentrated. The residue was extracted by liquid separation using 400 ml of water and 150 ml x 4 of ethyl acetate and dried over sodium sulfate. The ethyl acetate layer was concentrated and subjected to silica gel column chromatography to obtain 17.1 g (87.4%) of an N-Boc-L-serine methyl ester as a transparent oily product.
85%
With potassium carbonate In N,N-dimethyl-formamide
76%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
72.3%
With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 20h;
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
With potassium carbonate In N,N-dimethyl-formamide 1.) 0 deg C, 40 min; 2.) RT, 2 h; Yield given;
With potassium carbonate In N,N-dimethyl-formamide
With potassium hydrogencarbonate In N,N-dimethyl-formamide
20.9 g
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
With potassium carbonate In N,N-dimethyl-formamide
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
General procedure: To an ice-cold solution of D-serine (5.0 g, 47.6 mmol) and NaOH (2.11 g, 52.9 mmol) in a mixture of water (110mL) and t-BuOH (110 mL) was added di-tert-butyl dicarbonate(11.38 g, 52.1 mmol) with stirring. After 1 h at 0 °C, the mixture was warmed to room temperature and stirred for 13h. The mixture was concentrated to one third its original volume using reduced pressure and water (110 mL) was added.The aqueous layer was extracted with hexanes (3 X 100 mL)and acidified to pH 1-2 by slow addition of cold 1 M KHSO4(55 mL). The resulting mixture was extracted with EtOAc (4X 150 mL). The combined organic layers were washed with water (150 mL), dried over Na2SO4, filtered and concentrated to give the crude product 3 as colorless oil (9.6 g, 98%yield) which was used without further purification.To a white suspension of 3 (9.6 g, 46.8 mmol) and potassium carbonate (7.19 g, 52 mmol) in anhydrous DMF (50mL) was added methyl iodide (6.01 mL, 96.5 mmol). The mixture was stirred at room temperature for 1.5 h. To the resulting solution was added water (100 mL). The aqueouslayer was extracted with EtOAc (4 X 100 mL). The combined organic layers were washed with brine (2 X 175 mL),dried over Na2SO4, filtered and concentrated to give 4 as colorless oil (8.2 g, 80% yield): []D21 +17.2 (c 5.0, MeOH),lit: []D +18.9 (c 5.0, MeOH) [15]; IR v 3388, 2978, 2936,2886, 1740, 1691, 1456, 1437 cm-1; 1H NMR (200 MHz,acetone-d6) (ppm): 6.00 (bs, 1H, NHCO), 4.3-3.76 (m, 4H,CH2OH, OH, CHNH), 3.69 (s, 3H, OCH3), 1.41 (s, 9H,C(CH3)3); 13C NMR (50 MHz, acetone-d6) (ppm): 171.70(COOCH3), 155.89 (NHC=O), 79.05 (C(CH3)3), 62.65(CH2OH), 56.53 (CHNH), 51.84 (COOCH3), 28.08(C(CH3)3).
Stage #1: (S)-N-(tert-butoxycarbonyl)serine With sodium hydrogencarbonate In N,N-dimethyl-formamide at 0℃; for 0.25h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 19h;
10460] A soln of l3oc-serine (126; 14.0 g, 68.2 mmol) in DMF (143 mE) was cooled to 00 C. NaHCO3 (17.2 g 205 mmol) was added and the mixture was stirred for 15 mm. lodomethane (8.5 mE, 136 mmol) was added dropwise. The mixture was stirred at 00 C. to it for 16 hand again cooled to 00 C. More iodomethane (4.2 mE, 67 mmol) was slowly added and stirring was continued for 3 h. The mixture was diluted with H20 and extracted with EtOAc. The organic phase was washed (sat. aq. NaC1 soln), dried (Na2504), filtered and concentrated to give crude 127 (14.2 g).
Stage #1: (S)-N-(tert-butoxycarbonyl)serine With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.166667h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h;
5.3 g
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h;
N-Tert-butyloxycarbonyl-L-serine methyl ester (N-Boc-L-serine methyl ester)1
To an ice-cold solution of L-serine (3.2 g, 30 mmol) in 1 M sodium hydroxide (60 mL) was added di-tert-butyl dicarbonate [(Boc)2O] (7.8 g, 36 mmol) in dioxane (25 mL). The mixture was stirred at 5 °C for 30 min, then allowed to warm to room temperature over 3.5 h. The reaction mixture was concentrated to half its original volume, quenched with 1 M potassium bisulfate (60 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (2 x 30 mL) and water (30 mL), dried over Na2SO4 and concentrated in vacuo. The crude product (5.8 g) was used to the next step. To an ice-cold solution of N-Boc-L-serine (5.8 g, 28 mmol) in DMF (40 mL) solid potassium carbonate (4.3 g, 31 mmol) was added. After stirring for 10 min methyl iodide (3.5 mL, 56 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. The reaction was allowed to reach room temperature and stirred for an additional hour. Then the reaction mixture was filtered to remove inorganic material, water (20 mL) was added and the filtrate was extracted with diethyl ether (3 x 20 mL). The combined extracts were washed with brine (2 x 20 mL) and water (10 mL), dried over Na2SO4. After concentration in vacuo 5.3 g (86% yield) of N-Boc-L-serine methyl ester was obtained as a colorless oil. The product was sufficiently pure to be used in the next step without further purification. 1H and 13C NMR spectra were consistent with literature data.2 IR (ATR, cm-1) ν: 3433, 2978, 1743, 1710, 1368, 1163; 1H NMR (400 MHz, CDCl3) δ: 5.67 (br s, 1H, NH), 4.25 (br s, 1H, CH-N), 3.85-3.74 (m, 2H, CH2-O), 3.63 (s, 3H, OCH3), 1.35 (s, 9H, Boc); 13C NMR (400 MHz, CDCl3) δ: 171.4, 155.7, 79.9, 62.7, 55.5, 52.3, 28.0; MS (ESI) m/z: [M+Na]+ 242.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 1.5h;Inert atmosphere;
Triphenylphosphine (30.7g, 117mmol, 1.25eq.) was dissolved in anhydrous CH2Cl2 (390mL), cooled to 0C and imidazole (7.96g, 117mmol, 1.25eq.) was added. Iodine (29.7g, 117mmol, 1.25eq.) was added in portions and the resulting reaction mixture was stirred 5min at 0C and additional 10min at ambient temperature. The reaction was cooled to 0C and a solution of alcohol 64 22 (20.5g, 93.6mmol, 1.0eq.) in anhydrous 69 CH2Cl2 (90mL) was added over 10min. The reaction mixture was stirred 90min at 0C (monitored by TLC), then filtered over a plug of Celite. The filtride was washed with pentane-ether 1:1 (500mL). The filtrate was concentrated in vacuo and dissolved in CH2Cl2, silica was added and all volatiles were removed in vacuo to complete dryness. The residue was subjected to flash column chromatography (pentane-ether, 100:3?6:1) to obtain iodide as pale yellow solid (25.8g, 78.4mmol, 84% yield) which was stored at -20C. Rf=0.19 (pentane-ether, 20:1), stains dark blue with vanillin. 1H NMR (400MHz, CDCl3) delta 5.35 (d, J=7.8Hz, 1H), 4.52 (dt, J=7.9, 3.9Hz, 1H), 3.80 (s, 3H), 3.64-3.50 (m, 2H), 1.46 (s, 9H). 13C NMR (101MHz, CDCl3) delta 170.1, 154.8, 80.5, 53.7, 53.0, 28.3, 7.9. HRMS (ESI): calcd. for C9H16INO4 [M+Na]+ 352.0022, found 352.0022. [alpha]25D [alpha]D25 +40.3 (c 1.07, CHCl3).
68%
With 1H-imidazole; iodine; triphenylphosphine; at 0 - 20℃; for 1.5h;
A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50 mol) in DCM (600 mL) was cooled to 0 C and iodide (127 g, 0.50 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0 C, a solution of (5)-methyl 2-((tert- butoxycarbonyl)amino)-3-hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel to afford (i?)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (74.0 g, 68% yield) as a colorless solid.
67%
Triphenylphosphite methiodide (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 4, p557; 34Og, 753 mmol, 1.4 equiv.) was added in one portion to a solution of (S)-2- rert-butyloxycarbonylamino-3-hydroxypropionic acid methyl ester (118g, 538 mmol) in dry N,N-dimethylformamide (1.1 L) at 0C. After 30 minutes at O0C solid sodium bicarbonate (27Og) was added followed by water (1. IL). The resulting mixture was stirred vigorously for 15 minutes and then extracted with 1:1 diethylether/hexanes (3 x 80OmL). The combined organic extracts were washed with 0.5M sodium hydroxide (5 x IL) and brine (2 x IL), dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting orange oil was loaded onto a SiO2 plug (2" x 7") and eluted with 5% EtOAc/hexanes to afford (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate as a pinkish oil, which solidified (118.5g, 67%) 1H NMR (CDC13; 400MHz): deltappm 5.32 (m, IH), 4.51 (m, IH), 3.81 (s, 3H), 3.58 (m, 2H), 1.45 (s, 9H).
65%
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;
Triphenylphosphine (66.0 g, 0.250 mol) and imidazole (17.1 g, 0.250 mol) were dissolved in methylene chloride (900 ml). After cooling to 0 C., iodine (64.0 g, 0.250 mol) was added thereto, and the temperature was gradually raised from 0 C. to room temperature in the presence of nitrogen gas, followed by stirring for 10 minutes. After cooling to 0 C., a methylene chloride solution (100 of methyl N-(tert-butoxycarbonyl)-L-serinate (45.0 g, 0.200 mol) was slowly added dropwise over one hour, followed by stirring at room temperature for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 1:2) to obtain the title compound (43.8 g, 65%). [0585] 1H NMR (CDCl3, 400 MHz): delta 5.36-5.34 (m, 1H), 4.53-4.51 (m, 1H), 3.80 (s, 3H), 3.61-3.53 (m, 2H), 1.46 (s, 9H)
With pyridine; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;
Boc-homoallyl glycine (9b) was synthesized using a three-step protocol from commercially available Boc-Ser-OMe (S2). In a typical procedure, a flask was charged with Boc-Ser-OMe (2.0 g, 9.1 mmol) and triphenylphosphine (3.6 g, 13.7 mmol, 1.5 eq.) under Ar(g). To this was added THF (20 mL) and the solution cooled to 0 C. by immersion in an ice bath. Pyridine (1.5 mL, 18.2 mmol, 2 eq.) was added dropwise, followed by solid iodine (3.5 g, 13.7 mmol, 1.5 eq.) in three portions at 0 C. The ice bath was removed and stirring was continued for 4 h at room temperature. The mixture was extracted with Et2O (3*20 mL). The combined organic layers were washed with 1M HCl (3*20 mL), 1M Na2S2O3 (2*20 mL), brine (2*20 mL) and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was of sufficient purity to be used in the next step without further purification. The iodopropanoate S3 was dissolved in DMF (5 mL) and added dropwise to a flask containing activated zinc (2.4 g, 36.4 mmol, 4 eq.) at 0 C. under Ar(g). The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 3 h, upon which TLC (4:1 petroleum ether: EtOAc) indicated loss of starting material and formation of a lower Rf spot. At this point, the reaction mixture was stopped to let the solid settle to the bottom. The supernatant was then carefully transferred by syringe to a suspension of copper (I) bromide (0.26 g, 1.8 mmol) in DMF (mL) at -15 C. that also contained allyl chloride (1.3 mL, 15.5 mmol, 1.7 eq.). After complete addition, the cooling bath was removed and stirring was continued overnight. At this point, EtOAc (20 mL) was added to the reaction mixture and stirring was continued for 15 min. To the mixture was added H2O (20 mL), the organic layer was removed and successively washed with 1M Na2S2O3 (2*20 mL), H2O (2*20 mL), brine (2*20 mL), and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 8:1 petroleum ether:EtOAc) to afford 2.0 g (90%) of (9b) as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 5.72 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.18-5.07 (m, 1H), 5.01-4.90 (m, 2H), 4.26-4.23 (m, 1H), 3.67 (s, 3H), 2.08-2.01 (m, 2H), 1.88-1.79 (m, 1H), 1.70-1.61 (m, 1H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3) delta 173.11, 155.23, 136.87, 115.50, 79.64, 52.09, 51.99, 31.85, 29.39, 28.21 (3C). HRMS (ESI) m/z calcd for C12H21NO4 [M+H]+: 244.1471. found 244.1474.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
Under nitrogen atmosphere, triphenyl phosphine (911 mg, 3.5 mmol) andimidazole (237 mg, 3.5 mmol) were dissolved in dry dichloromethane (12 mL). To this solution cooled on an icebath was added iodine (899 mg, 3.5 mmol). The mixture was stirred at rt for 10 min and then cooled on an icebath again. To the resulting yellow suspension was added a solution of 5 (507 mg, 2.3 mmol) in drydichloromethane (8 mL). After stirring for 2 h on an ice bath, the reaction mixture (a yellow suspension) waspassed through a short silica gel column (hexane:Et2O = 1:1) to remove the precipitates. The eluent wasevaporated to give crude 8 as an orange oil. Obtained 8 and bis-(p-methylbenzyl) diselenide (385 mg, 1.1mmol) were dissolved in a mixture of MeOH (8 mL) and Et2O (12 mL). The solution was cooled on an ice bathand then added with sodium borohydride until the solution color disappeared. After stirring for 1 h, water wasadded to the resulting solution, and the mixture was extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO4, and evaporated. The obtained crude product (a yellow oil) was purified by silica gelcolumn chromatography (hexane:EtOAc = 4:1) to give 7 as a pale yellow oil (741 mg, 83% from 5). When crude8 was purified by silica gel column chromatography, the yield of 7 was decreased to 75% from 5. Identity andpurity of 831 were confirmed by 1H NMR.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 2.33333h;
lambda/-(terf-butoxycarbonyl)-3-iodo-L-alanine methyl ester; Iodine (1.25 eq., 70.70 mmol, 17.94 g) was added portionwise to a mixture of PPh3 (1.25 eq., 70.70 mmol, 18.54 g) and imidazole (1.25 eq., 70.70 mmol, 4.81 g) in DCM (250 ml) at 0 deg C over 15 minutes. The cooling bath was removed and the mixture was stirred for 20 minutes. A solution of Boc-Ser-OMe (1 eq., 56.6 mmol, 12.40 g) in DCM (50 ml) was then added dropwise over 45 minutes at 0 deg C. The mixture was stirred at this temperature for a further 1 hour then warmed to room temperature. The mixture was filtered through silica (50% tBuOMe in ihexane eluant) then concentrated. 50% tBuOMe in ihexane was added and the precipitate formed was filtered off. The solution was concentrated and the residue purified by column <n="36"/>(silica, 15% -> 50% tBuOMe in ihexane) to give the product as a pale yellow oil which solidified on standing. The compound was stored in the dark until ready for use.1H NMR (400 MHz, CDCI3) delta; 5.38 (brd, 1 H), 4.50-4.56 (m, 1 H), 3.79 (s, 3H), 3.50-3.60 (m, 2H), 1.43 (s, 9H).
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane;
Starting from Boc-Ser-OMe, 6a was synthesized in 3 steps following the similar procedure reported for the synthesis of Boc-Sec(MPM)-OH.[S1] In brief, Boc-Ser-OMe was iodized with iodine, triphenylphosphine, and imidazole in DCM. The obtained crude product was reacted with di(benzhydryl) diselenide and sodium borohydride in a mixture solvent of MeOH and Et2O (2:3). The product was purified by silica gel column chromatography (EtOA-hexane 1:3). Obtained Boc-Sec(Bzh)-OMe was then saponified under a basic condition to give 6a as colorless crystals in 90% total yield. Product 6a was used for subsequent reactions after recrystallization from Et2O-hexane.
Stage #1: 6-methoxy-1-hydroxymethyl-3-oxo-3H-benzopyran; N-tert-butyloxycarbonyl-L-serine methyl ester; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 66h;
Stage #2: With triethylamine In N,N-dimethyl-formamide for 6h;
With silver(I) oxide In acetonitrile at 20℃; Inert atmosphere;
74%
With silver(I) oxide In acetonitrile at 20℃; for 12h;
Synthesis of methyl N-(tert-butoxycarbonyl)-O-methyl-L-serinate (22) [2]
To a mixture of commercially available methyl (tert-butoxycarbonyl)-L-serinate (3.3 g, 15.0mmol) in Acetonitrile (30 mL) was added Ag2O (2.51 g, 36.5 mmol) then was added MeI.The resulting suspension was stirred at room temperature for 12 h. The mixture wasfiltered through a pad of Celite and the solvent was evaporated. The residue was purifiedby column chromatography to give 22 (2.6 g, 74%) as clear oil; Rf = 0.57 (n-hexane/EtOAc1/1); 1H NMR (CDCl3, 400 MHz) δ 5.38-5.40 (m, 1H), 4.42-4.45 (m, 1H), 3.79-3.81 (m, 4H),3.60-3.63 (m, 1H), 3.36 (s, OCH3), 1.49 (s, C(CH3)3.
67%
With silver(I) oxide In propan-2-one Darkness; Reflux;
(S)-methyl 2-(tert-butoxycarbonyl)-3-methoxypropanoate (6)
To a solution of (S)-methyl2-(tert-butoxycarbonyl)-3-hydroxypropanoate 5 (4.60 g, 21.0 mmol) in acetone (100 mL) wasadded Ag2O (7.29 g, 31.5 mmol) and MeI (21.8 mL, 35.0 mmol) successively. The flask wasprotected from light and refluxed over night. The mixture was filtered through a pad of Celite andthe solvent was evaporated. The residue was purified by flash chromatography (ethyl acetate /petroleum ether = 1:20) to afford 6 as a pale yellow oil (3.3 g, 67%). [α]D20 = +8.28 (c = 0.40,CHCl3) [lit.2 [α]D20 = +9.4 (c = 1.28, CH2Cl2)]. 1H NMR (400 MHz, CDCl3): δ 5.45 (d, J = 7.6 Hz,1H), 4.42 (t, J = 4.0 Hz, 1H), 3.81(m, 1H), 3.76 (s, 3H), 3.60 (dd, J = 8.8, 2.8 Hz, 1H), 3.34 (s,3H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.1, 155.4, 79.8, 72.4, 59.1, 53.8, 52.4, 28.2.HRMS (ESI): calcd. for C10H19NO5Na [M+Na]+ 256.1155; found 256.1156.
55%
With silver(I) oxide In acetonitrile at 20℃;
54%
With silver(I) oxide In propan-2-one Heating;
47%
With silver(I) oxide In acetonitrile at 20℃; for 24h; Inert atmosphere; Darkness;
83 Synthesis of (S)-(2-chloro-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl) methanol
Synthesis of (S)-(2-chloro-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl) methanol To a stirred solution of methyl (tert-butoxycarbonyl)-L-serinate (5 g, 22.80 mmol) in CH3CN (200 mL) under an argon atmosphere were added silver oxide (26 g, 114.15 mmol) and methyl iodide (32 g, 228.10 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h in the absence of light. After consumption of the starting material (monitored by TLC), the reaction was filtered and the filtrate concentrated in vacuo. The crude material was purified by column chromatography using 10% EtOAc:hexanes to afford (S)-(2-chloro-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl)methanol (2.5 g, 47%) as a colorless liquid. 1H-NMR (CDCl3, 400 MHz): δ 5.40-5.31 (m, 1H), 4.44-4.38 (m, 1H), 3.80-3.78 (m, 1H), 3.77 (s, 3H), 3.60-3.56 (m, 1H), 3.33 (s, 3H), 1.44 (s, 9H); TLC: 30% EtOAc:hexane (Rf: 0.5).
34.5%
With silver(I) oxide In propan-2-one at 59℃; Darkness;
2.2.1 Preparation of BOC-L-O-methylserine methyl ester (IIIe-1)
BOC-L-serine methyl ester (5g, 22.8mmol) was dissolved in acetone (110mL), and methyl iodide (32mL, 524mmol) and silver oxide (8.2g, 35.4mmol) were added, and the mixture was refluxed at 59 ° C in the dark overnight. . The reaction was detected by TLC, filtered, and the solvent was distilled off under reduced pressure. 1.8 g of the target compound was obtained as an oil by column chromatography, with a yield of 34.5%
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h;
A solution of Boc-Ser-OMe S2 (2.0 g, 9.1 mmol) in anhydrous THF (40 mL) was degassed and treated with allylmethyl carbonate (1.4 mL, 12.7 mmol, 1.4 eq). Tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmol, 0.02 eq.) was added and the reaction mixture heated to 60 C. for 4 h upon which TLC (2:1 EtOAc:hexanes) indicated loss of starting material. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (30 mL) and washed with NaHCO3 (2*30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; 0% to 66% EtOAc in hexane) to afford 1.6 g (68%) of the product (9c) as a clear oil. 1H NMR (500 MHz, CDCl3) delta 5.79 (ddt, J=17.3, 10.4, 5.6 Hz, 1H), 5.41-5.31 (m, 1H), 5.25-5.10 (m, 2H), 4.40-4.37 (m, 1H), 3.95-3.92 (m, 2H), 3.80 (dd, J=9.5, 3.3 Hz, 1H), 3.71 (s, 3H), 3.61 (dd, J=9.5, 3.4 Hz, 1H), 1.41 (s, 9H); 13C NMR (126 MHz, CDCl3) delta 171.11, 155.42, 134.01, 117.29, 79.85, 72.14, 69.86, 53.92, 52.37, 28.25 (3C). HRMS (ESI) m/z calcd for C12H21N5O5 [M+H]+: 260.1420. found 260.1428.
58%
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h;Inert atmosphere;
[0595] To a solution of compound methyl (tert-butoxycarbonyl)-L-serinate (5.0 g, 23 mmol) in tetrahydrofuran (50 mL) was added allyl methyl carbonate (3.97 g, 34.2 mmol) at followed by Pd (PPli3)4 (527 mg, 456 muetaiotaomicron). The reaction mixture was degassed in vacuum and purged with nitrogen 3 times. The resulting mixture was stirred at 60C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate= 20: 1 to 10: 1) to afford compound 4-15-1 (4 g, 58% yield) as yellow oil.
55.2%
To a solution of <strong>[2766-43-0]N-(tert-butoxycarbonyl)-L-serine methyl ester</strong> (0.781 mL, 3.85 mmol) in THF (15 mL) was added allyl methyl carbonate (0.524 mL, 4.61 mmol). The solution was purged with N2, followed by the addition ofte?rafo's(triphenylphosphine)palladium(0) (444 mg, 0.385 mmol). The vessel was sealed and heated at 60 C overnight. The reaction mixture was diluted with ethyl acetate, washed with sat NaHCC^, and brine. The organic layer was concentrated. Purification by normal phase chromatography provided 52A (550 mg, 55.2 % yield) as a yellow oil. .H MR ^OO MHz, CDCl3) 5 ppm 5.75 - 5.94 (m, 1 H) 5.32 - 5.47 (m, 1 H) 5.1 1 - 5.29 (m, 2 H) 4.35 - 4.53 (m, 1 H) 3.92 - 4.03 (m, 2 H) 3.80 - 3.89 (m, 1 H) 3.76 (m, 3 H) 3.61 - 3.70 (m, 1 H) 1.46 (m, 9 H).
11.4 g
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 2h;Inert atmosphere;
A soln of crude 127 (14.2 g) and Pd(PPh3)4 (0.64 g) in THF (416 mE) was degassed. Carbonic acid allyl methyl ester (9.6 g, 82.8 mmol) was added and the mixture was heated to 60 C. for 2 h. The volatiles were evaporated. FC (hexane/EtOAc 9:1) afforded 128 (11.4 g, 79%)
In pyridine; ethyl acetate; N,N-dimethyl-formamide;
(3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic Acid Hydrochloride Step 413a. (S)-N-BOC-O-(t-butyldimethylsilyl)serine methyl ester A 7 g (31.96 mmol) sample of ((S)-N-BOC-serine methyl ester (obtained from Aldrich) was dissolved in pyridine and cooled in an ice bath. To this stirred solution was added dropwise 5.54 g (36.76 mmol) of t-butyldimethylsilyl chloride (TBDMSC) dissolved in 40 mL of pyridine. After all reagents were added the reaction was stirred for 4 hours at room temperature. An additional 0.5 g of TBDMSC was added and the reaction was stirred for an additional 2 hours. To the mixture was then added 2.5 equivalents of imidazole in 14 mL of DMF, and the reaction was stirred for 2 hours. The solvents were removed under reduced pressure, and the residue was dissolved in ethyl acetate, which was washed with water and brine.
Stage #1: di-<i>tert</i>-butyl dicarbonate; N-tert-butyloxycarbonyl-L-serine methyl ester With dmap In acetonitrile at 20℃;
Stage #2: With N,N,N',N'-tetramethylguanidine In acetonitrile Further stages.;
To a solution of 2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (0.400g, 1.82 [MMOL)] in dimethylformamide [(15ML)] was added sodium hydride [(65%)] (0.145g, 3.64 [MMOL)] at [0C.] after the evolution of hydrogen gas ceased, the freshly distilled benzyl bromide (0.449 g, 1. [82MMOL)] was added to the solution. The reaction mixture was stirred at 25-30 [C] for 5 hr to give a clear solution. The solvent was then removed under reduced pressure below [40C.] The residue was dissolved in water [(30MOI)] and the solution extracted with ethyl acetate (two 20 ml portions). The combined organic layers were further washed with brine and dried over anhydrous sodium sulfate. The ethyl acetate was then removed under reduced pressure to give the [3-(BIPHENYL-4-] [YLMETHOXY)- (2S)-TERT-BUTOXYCARBONYLAMINO-PROPIONIC] acid methyl ester as colorless oil [(0. 421 G,] 60%). LC/MS (m/z) : 386 (M+1). To [3- (BIPHENYL-4-YLMETHOXY)- (2S)-TERT-BUTOXYCARBONYLAMINO-PROPIONIC] acid methyl ester (0.421 gms, 1.1 mmol) was added [2ML] of 4M HCI in dioxane (8. 8mmol) and stirred for 30 min. The HCI was then removed under reduced pressure and the residue was then triturated with dichloromethane and hexane for [2-3] times and the solvents were removed under reduced pressure to yield the HCI salt of the compound (2S)-amino-3- (biphenyl-4- [YLMETHOXY)-PROPIONIC] acid methyl ester hydrochloride as a white solid (0.300g, 90%). LC/MS (m/z) : 286 (M+1). (2S) -Amino-3- (biphenyl-4-ylmethoxy)-propionic acid methyl ester hydrochloride (0.150g, 0. [483MMOL)] was reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic acid (0.136g, 0. [483MMOL)] as described in general procedure A yielding the 3- (biphenyl-4-ylmethoxy)- (2S)- [[ (4'-TRIFLUOROMETHYL-BIPHENYL-4-CARBONYL)-AMINO]-PROPIONIC] acid methyl ester. The resulting compound was then hydrolyzed by following the general procedure C to yield the title compound (0.200g, [80%).,] 'H-NMR (400 MHz, [CDC13)] : 4.2 (m, 2H), 4.9 (S, 2H), 5.1 (m, [1H),] 7.72 (m, [1H),] 7.74 (m, 4H), 7.94 (m, 4H), 8.17 (m, 4H), 8.28 (d, 2H), 8.34 (d, 2H), 8.62 (S, [1H),] 9.3 (d, 1H) ; LC/MS (m/z): 520.2 [(M+1) +.]
With triethylamine In dichloromethane at 20℃; for 3h;
Synthesis of methyl 2-(tert-butoxycarbonylamlno)acrylate (compound 1) At 0 °C, methylsulfonyl chloride (81.1 g, 0.71 mo.) was added to a solution of Boc-Ser-O e (77.5 g, 0.35 mol) and TEA (141.4 g, 1.4 mol) In dichloromethane (1 L). The reaction was stirred for 3 h at ambient temperature, then quenched with 5% NaHC03 solution (300 ml). The organic phase was collected, dried over anhydrous Na2504, and concentrated under vacuum. The residue was purified by HPFC (PE: EA » 10: 1) to afford methyl 2-(tert- butoxycarbonylamlno)acrylate (63.5 g, 90.3%). LC- S: 202.3 (M+l).
(S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl-4-iodobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With dmap; triethylamine In dichloromethane at 0 - 20℃;
3. Preparation of 4-iodoarenes 2
General procedure: General Procedure: The preparation of 2 is according to the literature.1 The corresponding alkylamine (5.0 mmol, 1.0 equiv) or alkyl alcohol (5.0 mmol, 1.0 equiv), triethylamine (1.5 mL, 11.0 mmol,2.2 equiv), DMAP (61 mg, 0.5 mmol, 0.1 equiv), and CH2Cl2 (10 mL) were added to a round-bottomedflask. The reaction mixture was cooled to 0 oC with an ice-water bath. 4-Iodobenzoyl chloride (2.0 g,7.5 mmol, 1.5 equiv) dissolved in CH2Cl2 (10 mL) was added dropwise to the reaction mixture withstirring. The reaction was slowly warmed to room temperature. The reaction was monitored by TLC.After the reaction was completed, the reaction mixture was diluted with EtOAc and washed withsaturated ammonium chloride, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated,the residue was purified with silica gel chromatography (petroleum) to afford compound 2.
(S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl-1-methyl-1H-imidazole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With dmap; In tetrahydrofuran; at 20℃;Inert atmosphere;
General procedure: To an oven-dried 20 mL vial equipped with a stir bar was added 2-trichloroacetyl-N-methylimidazole (5.0 mmol), DMAP (0.5 mmol), and the corresponding alcohol (10.0 mmol). The mixture was dissolved in THF (10 mL), then stirred overnight at room temperature. The unpurified reaction was concentrated and purified by column chromatography (ethyl acetate/hexanes) to afford imidazole ester.
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