* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Natural Products, 2011, vol. 74, # 10, p. 2137 - 2142
2
[ 1342309-24-3 ]
[ 17407-56-6 ]
[ 17407-55-5 ]
[ 312-84-5 ]
[ 56-45-1 ]
[ 20312-37-2 ]
[ 13748-90-8 ]
[ 3060-46-6 ]
[ 63-91-2 ]
[ 31321-74-1 ]
[ 673-06-3 ]
Reference：
[1] Journal of Natural Products, 2011, vol. 74, # 10, p. 2137 - 2142
3
[ 312-84-5 ]
[ 501-53-1 ]
[ 6081-61-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With sodium hydrogencarbonate In water at 0 - 5℃; Stage #2: at 0 - 20℃;
A solution of NaHCO3 (605 g, 5.72 mol) in water(3 l) was cooled to 0–5°C on an ice bath, and D-serine (200 g, 1.90 mol) was added in portions (8–10 portions with 20–30 min interval). Then 50percent solution of benzyl chloroformate in toluene (780 g, 2.29 mol) at 0–5°C was added dropwise over a 1 h period. Reaction mixture was stirred for 2 h at 0–5°C, then warmed up to room temperature and stirred for 2 h more. Then EtOAc (400 ml) was added and pH adjusted to 2.0 with hydrochloric acid.Product was extracted with EtOAc (2×800 ml). Combined exstracts were concentrated under reduced pressure up to~640 ml affording a suspension. Cyclohexane (1200 ml) was added and resulting mixture slurried for 6 h. The purified product was isolated by filtration and dried under reduced pressure at 50°C to afford compound 2. Yield432.5 g (95percent), white solid, mp 119–120°C (mp 119°C27),[α]D25 –5.08 (c 2.7, AcOH). IR spectrum, ν, cm–1: 1689(C=O), 1749 (C=O), 3319 (NH), 3338 (OH). UV spectrum, λmax, nm: 208. 1H NMR spectrum (CD3OD), δ, ppm(J, Hz): 3.83–3.92 (2H, m, CH2); 4.30 (1H, t, J = 8.8,NCH); 5.13 (2H, s, CH2); 7.29–7.40 (5H, m, H Ph). 13C NMR spectrum (CD3OD), δ, ppm: 57.7; 63.1; 67.7;128.9 (2C); 129.0; 129.5 (2C); 138.1; 158.6; 173.8. Massspectrum, m/z (Irel,percent): 238 [M–H]– (100).
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 19, p. 3114 - 3116
[2] Chemistry of Heterocyclic Compounds, 2017, vol. 53, # 11, p. 1248 - 1253[3] Khim. Geterotsikl. Soedin., 2017, vol. 53, # 11, p. 1248 - 1253,6
[4] European Journal of Organic Chemistry, 2001, # 16, p. 3067 - 3074
[5] Asian Journal of Chemistry, 2011, vol. 23, # 11, p. 5169 - 5170
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[10] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4815 - 4830
[11] Journal of Organic Chemistry, 1985, vol. 50, # 19, p. 3676 - 3678
[12] Patent: WO2011/99033, 2011, A1, . Location in patent: Page/Page column 37-38
[13] Journal of Medicinal Chemistry, 2012, vol. 55, # 10, p. 4824 - 4836
[14] MedChemComm, 2013, vol. 4, # 5, p. 783 - 791
[15] Patent: WO2015/42397, 2015, A1, . Location in patent: Paragraph 000219
[16] Patent: WO2015/65937, 2015, A1, . Location in patent: Paragraph 000201
[17] Patent: WO2016/145153, 2016, A1, . Location in patent: Paragraph 000166
[18] Angewandte Chemie - International Edition, 2018, vol. 57, # 11, p. 2884 - 2888[19] Angew. Chem., 2018, vol. 130, # 11, p. 2934 - 2938,5
4
[ 312-84-5 ]
[ 6081-61-4 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2887,2890
[2] Journal of Biological Chemistry, 1955, vol. 212, p. 39,42
4.2.1.1 (R)-Methyl 2-isopropyl-4,5-dihydrooxazole-4-carboxylate At first, SOCl2 (7.60 mL, 104.2 mmol) was added to d-serine (10.0 g, 95.1 mmol) in MeOH and allowed to react at room temperature for 24 h. 9a Removal of the solvents left a white solid that upon washing with n-hexane (3 * 25 mL) provided the d-serine methylester HCl salt (14.4 g, 97percent) as a colourless solid. 1H NMR (300 MHz, D2O) δ 4.32-4.28 (1H, m, CH), 4.12 (1H, dd, J 4.2, 12.5 Hz, CHaHbOH), 4.02 (1H, dd, J 3.4, 12.5 Hz, CHaHbOH), 3.88 (3H, s, CH3).
96%
at 20℃; for 12 h; Inert atmosphere
Dichlorosulfoxide (18.68 g, 157.00 mmol) was slowly added dropwise to anhydrous salt-cooled anhydrous CH3OH (30 mL)under N2 protection. After the addition was completed, the reaction solution was warmed to room temperature and stirred for half an hour. Then, Compound 1 (5.00 g, 47.58 mmol) as described in the above reaction formula was added and reacted at room temperature for 12 hours, and the reaction solution became clear from turbidity. The reaction was concentrated and dried in vacuo to give a white solid: Compound 2 (7.10 g, 96percent).
96%
at 5 - 20℃; for 4 h;
10 g of D-serine and 40 ml of methanol were placed in a reaction flask, 10 ml of thionyl chloride was added dropwise at 5±2 ° C, and reacted at room temperature for 4 hours. After the reaction was completed, it was concentrated to dryness.The crude cycloserine ester hydrochloride salt was 14.00 g.
95%
at 0℃; for 2 h; Reflux
General procedure: Acetyl chloride (1.6 mL, 22 mmol) was added to MeOH (100 mL), and the solution was cooled to 0°C. The solution was stirred for 5 min. Amino acid (L-serine, D-serine, L-cysteine, D-cysteine, L-2,3-diaminopropionic acid, and D-2,3-diaminopropionic acid) (20 mmol) was then added to the acetyl chloride solution in methanol (MeOH), and the solution was heated to reflux for 2 h, then cooled to room temperature.The reaction was evaporated under reduced pressure and gavea colorless solid. The solid was washed with CH2Cl2 (20 mL)to give amino acid methyl ester hydrochloride (2d–f, 2d–f)as a white solid. The yields of 2d, d, e, e, f and f were 95percent,96percent, 94percent, 96percent, 95percent, 95percent, respectively.
93%
at -5 - 20℃; Inert atmosphere; Reflux; Green chemistry
Dissolve 105.09g D-serine in 1.5L dry methanol and cool down to -50°C.With nitrogen protection, 178.46 g of thionyl chloride was added dropwise, and after completion of the addition, the reaction was allowed to warm to room temperature and stirred for 2 hours.Then continue to heat up to reflux, stirring and refluxing overnight, after the reaction is complete, the solvent is evaporated under reduced pressure,Ethyl acetate was washed by washing with suction to obtain 219 g of white solid D-serine methyl ester hydrochloride in 93percent yield.
67.75%
at 0 - 20℃; for 16 h; Inert atmosphere
To a stirred solution of D-serine (10 g, 95.23 mmol) in MeOH (100 mL) under an argon atmosphere was added thionylchloride (56.65 g, 476.19 mmol) at 0 oC. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were concentrated in vacuo. The crude material was washed with ether (2 x 100 mL) and dried in vacuo to obtain the methyl D-serinate hydrochloride (10 g, 67.75percent) as an off-white solid.1H-NMR (DMSO-d6, 500 MHz): δ 8.60-8.55 (m, 3H), 5.61-5.59 (m, 1H), 4.10-4.08 (m, 1H), 3.83-3.79 (m, 2H), 3.74 (s, 3H); TLC: 10percent MeOH/ CH2Cl2 (Rf: 0.3).
67.75%
at 0 - 20℃; for 16 h; Inert atmosphere
Synthesis of methyl D-serinate hydrochloride To a stirred solution of D-serine (10 g, 95.23 mmol) in MeOH (100 mL) under an argon atmosphere was added thionylchloride (56.65 g, 476.19 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were concentrated in vacuo. The crude material was washed with ether (2*100 mL) and dried in vacuo to obtain the methyl D-serinate hydrochloride (10 g, 67.75percent) as an off-white solid. 1H-NMR (DMSO-d6, 500 MHz): δ 8.60-8.55 (m, 3H), 5.61-5.59 (m, 1H), 4.10-4.08 (m, 1H), 3.83-3.79 (m, 2H), 3.74 (s, 3H); TLC: 10percent MeOH/CH2Cl2 (Rf: 0.3).
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 2, p. 372 - 376
[2] Heterocyclic Communications, 2005, vol. 11, # 3-4, p. 343 - 346
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5716 - 5726
[4] Chemical Communications, 2016, vol. 52, # 55, p. 8612 - 8614
[5] Journal of Organic Chemistry, 2003, vol. 68, # 26, p. 10162 - 10165
[6] Organic Letters, 2013, vol. 15, # 10, p. 2474 - 2477
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4204 - 4219
[8] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 12, p. 1837 - 1841
[9] Tetrahedron Letters, 2012, vol. 53, # 32, p. 4090 - 4092
[10] Tetrahedron: Asymmetry, 2012, vol. 23, # 18-19, p. 1350 - 1359,10
[11] Tetrahedron Asymmetry, 2012, vol. 23, # 18-19, p. 1350 - 1359
[12] Patent: CN107973830, 2018, A, . Location in patent: Paragraph 0033; 0047; 0049; 0051
[13] Patent: CN108558690, 2018, A, . Location in patent: Paragraph 0055; 0056; 0080; 0081
[14] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 1, p. 33 - 37
[15] Patent: CN107641087, 2018, A, . Location in patent: Paragraph 0018-0020; 0027
[16] Synthesis, 1993, # 2, p. 250 - 262
[17] Agricultural and Biological Chemistry, 1986, vol. 50, # 3, p. 615 - 624
[18] Tetrahedron Letters, 2014, vol. 55, # 19, p. 3114 - 3116
[19] Journal of the American Chemical Society, 2008, vol. 130, # 31, p. 10072 - 10073
[20] Patent: WO2015/109109, 2015, A1, . Location in patent: Paragraph 0775
[21] Patent: US2017/44182, 2017, A1, . Location in patent: Paragraph 1067
[22] Tetrahedron, 1990, vol. 46, # 20, p. 7263 - 7282
[23] Journal of Organic Chemistry, 1986, vol. 51, # 14, p. 2728 - 2735
[24] Journal of Organic Chemistry, 1985, vol. 50, # 17, p. 3133 - 3137
[25] Archiv der Pharmazie, 1993, vol. 326, # 2, p. 101 - 113
[26] Heterocycles, 1995, vol. 40, # 1, p. 261 - 270
[27] Journal of Medicinal Chemistry, 1996, vol. 39, # 9, p. 1907 - 1916
[28] Synthesis, 2002, # 17, p. 2616 - 2626
[29] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 12, p. 3259 - 3267
[30] Tetrahedron Letters, 2006, vol. 47, # 20, p. 3337 - 3339
[31] Organic letters, 2001, vol. 3, # 21, p. 3273 - 3275
[32] Tetrahedron Letters, 2010, vol. 51, # 49, p. 6381 - 6383
[33] Patent: WO2011/99033, 2011, A1, . Location in patent: Page/Page column 34-35
[34] Tetrahedron, 2011, vol. 67, # 48, p. 9426 - 9432
[35] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10460 - 10474
[36] Angewandte Chemie - International Edition, 2015, vol. 54, # 5, p. 1537 - 1541[37] Angew. Chem., 2015, vol. 127, # 5, p. 1557 - 1561,5
[38] Organic Letters, 2018, vol. 20, # 12, p. 3574 - 3578
7
[ 312-84-5 ]
[ 75-36-5 ]
[ 5874-57-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
for 15.5 h; Reflux
Example-1 Preparation of D-Serine Methyl Ester Hydrochloride D-serine (100 g, 0.9515 mole) was suspended in 600 ml methanol at room temperature. Acetyl chloride (224.0 g, 2.8545 mole) was added drop wise at -5° C. to 0° C. and stirred for 30 minutes. The reaction mixture was refluxed for 15 hours. Evaporation of the reaction mixture under reduced pressure followed by crystallization of the resulting residue from methanol and methyl tert-butyl ether, resulted in colorless solid of D-serine methyl ester hydrochloride (134.7 g, Yield: 91percent, HPLC: 99.6percent) M.R: 165−167° C. (Lit.: 163−165° C., Tetrahedron Letters, 2012, 53, 1668-1670,)[α]D20=3.7 (C=4 in EtOH); IR(KBr): 3361, 2921, 2660, 2732, 2550, 2488, 2134, 2079, 1922, 1747, 1592, 1505, 1471, 1444, 1431, 1382, 1343, 1297, 1258, 1187, 1158, 1128, 1094, 1038, 969, 900, 793, 844, 580, 469 Cm−1; H1NMR: (300 MHz, DMSO), δ3.745 (s, 3H), 3.82 (s, 2H), 4.11 (s, 1H), 5.63 (s, 1H), 8.58 (s, 2H); 13CNMR: (300 MHz, DMSO), δ 52.66, 54.37, 59.38, 161.39.
Stage #1: for 0.0833333 h; Cooling with ice Stage #2: for 2 h; Reflux
Acetyl chloride (4.06 mL, 57.14 mmol) was added to MeOH (100 mL) cooled in ice. The solution was stirred for 5 min. d-Serine (2 g, 19.04 ml) was added in one portion to a solution of d-serine in MeOH, and the solution was heated to reflux. The mixture was stirred for 2 h at reflux and cooled to room temperature. The reaction was evaporated under reduced pressure and gave a colorless solid. The solid was filtered and washed with CH2Cl2 (100 ml) to give d-serine methyl ester hydrochloride 2 (2.86 g, 97percent) as a white solid. mp 164-166 °C; -4 (c = 4.0, EtOH); 1H NMR (CD3OD, 300 MHz) δ 4.03 (m, 1H), 3.90 (dd, J = 6.6 Hz, J = 18.6 Hz, 1H), 3.82 (dd, J = 4.8 Hz, J = 17.4 Hz, 1H), 3.81 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 168.5, 59.5, 54.4, 52.8; HRMS (ESI) m/z (M+H)+ calculated for C4H10ClNO3 = 155.5801, found 155.4573.
Stage #1: serin at 37℃; for 42h; Microbiological reaction; aq. phosphate buffer; Inert atmosphere;
Stage #2: aq. phosphate buffer;
Stage #3: With ammonia In water enantioselective reaction;
4.6. Preparation of d-serine by cell suspensions
F. nucleatum resuspended in a phosphate buffer (5 g damp cells/100 mL) containing dl-serine (8.4 g, 800 mM) was incubated anaerobically with gentle magnetic stirring for 42 h at 37 °C and centrifuged (8200g, 15 min). The supernatant was applied to Amberlite IR-120 (2.5 × 50 cm column, H+ form) at a flow rate of 5.0 mL/min. The column was washed with water (500 mL) and eluted with 0.5 M aqueous ammonia (3 L). Fractions (200 mL) containing amino acid (ninhydrin spot test) were combined and evaporated to dryness in vacuo. The residue (approximately 3.5 g) was dissolved in hot water (100 mL), treated with decolorizing charcoal (2 g), and filtered through Celite. Concentration of the filtrate in vacuo and the addition of ethanol yielded d-serine (3.47 g, 83% recovery), mp 213-215 °C, (c 1, 1 M HCl), 98% chemical purity by HPLC, >99% ee by HPLC, Ref. 55 mp 217-219 °C, Ref. 56 [α]D25 = -15.0 (c 4, 1 M HCl). 1H NMR δ 3.98-3.86 (overlapping AB quartets of ABX, JAB = 12.2 Hz, 2H), 3.80 (X of ABX, apparent t, splittings of 4.9 and 4.3 Hz, 1H). 13C NMR δ 175.1, 62.8, 59.0; ESI+MS (MeOH-H2O, 1:1, 20 μL/min) m/z 106 [M+H]+; CID of m/z 106: m/z 89 (2), 88 (26), 60 (100).
92 % ee
Stage #1: serin With tetraphenyl phosphonium chloride In 1,2-dichloro-ethane for 2h; Resolution of racemate; Flow reactor;
Stage #2: With sodium hydroxide In water
Stage #3: With hydrogenchloride; water for 1h; enantioselective reaction;
Separation of D-AA from Racemic D/L-AA by Adsorption
General procedure: Organic compounds containing 1.0 eq. (S)-ARCA (Aminologics Co., > 98%, 3 g), 1.4 eq. of TPPC (Aldrich, > 98%) (or OTPPBr (synthesized in our lab.), CTAB (Aldrich,> 98%)) in 10 mL ethylene dichloride (EDC; Duksan Pure Chem., > 98%) were mixed and stirred until the ARCA was fully dissolved. TPPC, OTPPBr and CTAB were used as PTR for the rapid diffusion of AA into an organic layer, allowing contact with ARCA. The organic solution mixture was coated on MMC, and EDC solvent was then partially evaporated. After packing the final product into a tube-type reactor, pure water was circulated by pump until the solution became clear. For the adsorptive separation reaction, the aqueous basic solution of racemic D/L-AAs (Aldrich, > 98%) was prepared by dissolving D/L-AAs and a base in distilled water. Typically, 2.0 eq. of NaOH (DaeJung, > 98%), trimethylamine (TEA; DaeJung, > 98%) or diisopropylamine (DIPA; DaeJung, 99%) were used to investigate the effect of base type. The total volume of aqueous solution was fixed at 300 ml. The basic solution of D/L-AAs was injected at various speeds, and was circulated through the reactor, which was packed with (S)-ARCA/carbon support for the adsorption of D-AA. After adsorption was carried out for 1 h, the packed bed was washed with pure distilled water, after which the circulating solution was changed to 3 M HCl solution for the hydrolysis of adsorbed AAs for an additional 1 h. The AAs, which were adsorbed on ARCA through imine formation reaction between aldehydes of ARCA and NH2 in AAs, were hydrolyzed in the acidic solution. The hydrolyzed AA was diffused into acidified water during the circulation by pump via. back-extraction. The concentration of amino acid which remained in the aqueous solution was determined using HPLC with a prolonged adsorption time. For the repeated use of ARCA/support in the separation of chiral AA from racemic D/L-AAs, a fresh basic solution of D/LAA was prepared, after which the same procedure for adsorption/desorption treatment was performed as described above. D-AA in acidic solution was isolated as a crystallized powder in methanol solvent with 3 h stirring. The structures of AAs, ionic liquids and ARCA are listed in Scheme 3. In addition, the diagram of the fixed bed type reactor adopted in this work is shown in Figure 1.
With N-ethyl-N,N-diisopropylamine; sodium hydroxide In water; 1,2-dichloro-ethane for 1h; Enzymatic reaction; enantioselective reaction;
2.2. Separation of D-AA from Racemic AA
General procedure: Organic solution of 10 g of (S)-ARCA, 1.4 eq. of IonicLiquid, 20 ml of EDC solvent was mixed until ARCA was fully dissolved. This solution was impregnated on MMCsupport and then it was packed in the tubular type reactor.The aqueous solution of 2.0 eq. D/L-phenylalanine,2.0 eq. NaOH and 1.8 eq. DIPA dissolved in 200 ml of distilledwater was pumped and circulated through the reactorpacked with (S)-ARCA/carbon support for adrsorptionof D-AA. The adsorption analysis was performed for onehour, and after changing the circulating solution as 3 MHCl,the hydrolysis and back-extraction of adsopted AAinto the acidified water was performed for additional 1 hwith circulation by pump.
[00102] Acetyl chloride (AcCI, 96.0 mL, 1.35 mol) was added dropwise over 15 min to pre-cooled methanol (650 mL) at 0C. The solution was stirred for an additional 5 min, and then solid D-serine (51.0 g, 0.49 mol) was added in portions. The resulting mixture was heated under reflux for 2 h, then cooled to room temperature and the solvent was removed under reduced pressure. The solid obtained was triturated with 3:1 hexane/ether (300 mL) to give compound 1_5_2 as an off-white solid, which was thoroughly dried overnight in an oven under vacuum to give compound 1_5_2 (87.0 g, 99 %) as a white solid. [00103] NMR (400 MHz, Methanol-^): delta = 3.72 (s, 3H), 3.81 (br. s, 2H), 4.07 (s, 1H), 5.6 (br. s, 1H), 8.78 (br. s, 2H).
97.0%
With hydrogenchloride; at 20℃; for 16h;
An HCl gas was vigorously bubbled in a dry MeOH solution of <strong>[312-84-5](R)-serine</strong> (9) (25 g, 238 mmols) until the solution became very hot (spontaneous reflux). The solution was allowed to stand for 16 hours at room temperature, and then MeOH was removed under vacuum. The residue was triturated with ether (50 ml). The resulting <strong>[312-84-5](R)-serine</strong> Me ester (10) in solid form was recovered on a filter paper, washed with ether (50 ml), and dried in a vacuum. Recrystallization from MeOH-ether (1:3) gave 35.9 g (97.0%) of <strong>[312-84-5](R)-serine</strong> Me ester (10).
90%
With thionyl chloride; at -20 - 20℃; for 2h;
Step 1[00245] Methanol (5 mL/mmol) was cooled -20C before (1.2 eq) of thionyl chloride was added dropwise while maintaining the temperature below -10C. The cooling bath was removed and D-Ser-OH (1 eq) (LXXXVII) was added. The flask was tightly stoppered and the reaction was stirred at room temperature for 2 hours. The methanol was removed in vacuo and the crystalline residue was evaporated twice with toluene. It was then slurred with diethyl ether, filtered and dried in open air at room temperature to give pure D-Ser-OMe (LXXXVIII) (90% yield).
With acetyl chloride; at -5℃; for 25h;Reflux;
To the suspension of D-serine (105.09 g, 1 .0 moL) in methanol (630 mL) was added acetyl chloride (1 17.75 g, 1.5 moL) slowly and under constant stirring over a 1 hour period at -5C. The reaction mixture was heated to reflux and stirred for 24 hours. The reaction mixture was cooled at 0-5C and charged with sodium bicarbonate (298.20 g, 3.55 moL), sodium iodide (37.47 g, 0.25 moL) and benzyl chloride (259.50 g, 2.05 moL). The reaction mixture was heated to reflux and stirred for 12 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad and the filter cake was washed with methanol (157 mL). The filtered methanolic solution was added dropwise, to a cooled solution of KOH (224.44 g 4.0 moL) in water (525 mL) at below 5C. The reaction mixture was stirred 0-5C for 20 hours. Water (174 mL) was charged and the pH adjusted to 6.5 to 7.0 by dropwise addition of 30% HCI. The reaction mixture was heated to 20-25C and the pH was adjusted to 3.0 to 3.4 by dropwise addition of 30% HCI. The reaction mixture was stirred at 20-25C for 30 minutes, cooled to 15C and stirred for 30 min. The reaction mixture was filtered and the filter cake was washed three times with water (315 mL).The resulting solid was dried under vacuum at 45-50C for about 12 hours to provide (R)-2-(dibenzylamino)-3- hydroxypropanoic acid as a white solid (228.04 g, yield 80.0%, HPLC purity >99.6%). 1 H NMR (300 MHz, DMSO-d6) delta 12.52 (1 H, brs), 7.47-7.25 (10H, m), 4.76 (bs, 1 H), 3.89-3.82 (2H, m), 3.71-67 (2H, m). 13C NMR (75 MHz, DMSO-d6) delta 172.5, 139.4, 129.3, 129.0, 128.6, 128.3, 127.6, 127.1 , 62.9, 60.3, 54.8.
With thionyl chloride; at 0 - 20℃; for 12h;
One hundred milliliters of a methanol solution containing D-serine(4.5 g, 43 mmol, 19) was cooled in a salt-ice bath at 0 C, andSOCl2 (18.6 mL, 258 mmol) was added dropwise. The resulting mixturewas stirred for 12 h at ambient temperature and then concentratedin vacuo. After coevaporating the solvent with diethyl ethermultiple times to remove excess SOCl2, the residue was dissolved in100 mL of CH2Cl2, to which Et3N (15.7 mL, 113 mmol) was added at0 C. To this solution was added di-tert-butyl dicarbonate (11.3 g,52 mmol) under stirring, and the resulting mixture was refluxeduntil the starting material was consumed, as determined by TLC(methanol). The reaction mixture was concentrated in vacuo, andthe residue was dissolved in ethyl acetate (100 mL) and thenwashed with saturated NaHCO3 followed by washing with brine(3). The organic layer was dried over Na2SO4, filtered, andconcentrated to afford N-tert-butoxycarbonylserine methyl ester(Boc-NH-Ser-OMe) as the intermediate as an oil, which was used in the subsequent reaction without further purification. The crudeBoc-NH-Ser-OMe was dissolved in a mixture of acetone (100 mL)and 2,2-dimethoxypropane (81.0 mL, 659 mmol). To the resultingmixture was added BF3-Et2O complex (1.1 mL, 9 mmol) at ambienttemperature, and the reaction mixture was stirred for 12 h. Afterdetermining that the reaction was complete by TLC, 1.1 mL ofEt3N was added to the mixture to quench the reaction, and the solventwas removed in vacuo. The brown oil was then partitionedbetween Et2O and saturated NaHCO3 (aq). The aqueous layer wasextracted with Et2O (5), and the organic layers were combined,dried over Na2SO4, and concentrated. The resulting brown oil waspurified by column chromatography (hexane/ethyl acetate = 10:1)to afford 20 as a yellow oil (9.6 g, 85%).
With thionyl chloride; at 0 - 70℃; for 2h;
To a solution of (R)-2-amino-3-hydroxypropanoic acid (3 g, 28.55 mmol) in MeOH (40 mL) was slowly added thionyl chloride (2.082 mL, 28.55 mmol) at 0C. The mixture was heatedTo a solution of (R)-2-amino-3-hydroxypropanoic acid (3 g, 28.55 mmol) in MeOH (40 mL) was slowly added thionyl chloride (2.082 mL, 28.55 mmol) at 0C. The mixture was heated
To a flask containing MeOH (20 mL) was added dropwise AcCl (2.00mL, 28.2 mmol) at 0 C under Ar. After stirring for 15 min at ambient temperature, D-serine (1.03 g, 9.81mmol) was added to the mixture, and the whole was stirred for further 2 h at the same temperature. The volatile solvent was removed in vacuo, and the residue was used for the next step without further purification. To a solution of the obtained D-serine methyl ester in CHCl3 (20 mL) were added Et3N (6.64mL, 47.7 mmol) and TsCl (2.13 g, 11.2 mmol) at 0 C. After stirring for 20 h at ambient temperature, the reaction was quenched by addition of sat. aqueous NaHCO3 solution, and the mixture was extracted with CHCl3 (x2). The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel using AcOEt-CHCl3 (6:4, v/v) as eluent togive N-tosyl-D-serine methyl ester (2.19 g, 82%) as a white solid. 1H-NMR (CDCl3; 400 MHz) delta 7.75(2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 5.39 (1H, d, J = 9.2 Hz), 4.05 (1H, ddd, J = 9.2, 3.4, 2.9 Hz),3.97 (1H, dd, J = 9.9, 2.9 Hz), 3.79 (1H, dd, J = 9.9, 3.4 Hz), 3.57 (3H, s), 2.44 (3H, s), 0.84 (9H, s), 0.02(3H, s), 0.01 (3H, s).
22 g
With thionyl chloride;Inert atmosphere;
In Step 1, 20 g of S-l is reacted with thionyl chloride in methanol to provide 22 g of S- 2
With chloro-trimethyl-silane;
Methyl esters of d-Ile and O-benzyl-Ser derivatives were prepared as described in Li and Sha [38]using 2 mmol of amino acid, 0.5 mL of trimethylsilyl chloride (TMSCl), and 10 mL of methanol. Thereaction mixture was evaporated to dryness and stored in a desiccator.
With thionyl chloride; at 20℃; for 24h;Inert atmosphere;
4.2.1.1 (R)-Methyl 2-isopropyl-4,5-dihydrooxazole-4-carboxylate At first, SOCl2 (7.60 mL, 104.2 mmol) was added to d-serine (10.0 g, 95.1 mmol) in MeOH and allowed to react at room temperature for 24 h. 9a Removal of the solvents left a white solid that upon washing with n-hexane (3 * 25 mL) provided the d-serine methylester HCl salt (14.4 g, 97%) as a colourless solid. 1H NMR (300 MHz, D2O) delta 4.32-4.28 (1H, m, CH), 4.12 (1H, dd, J 4.2, 12.5 Hz, CHaHbOH), 4.02 (1H, dd, J 3.4, 12.5 Hz, CHaHbOH), 3.88 (3H, s, CH3).
96%
With thionyl chloride; at 20℃; for 12h;Inert atmosphere;
Dichlorosulfoxide (18.68 g, 157.00 mmol) was slowly added dropwise to anhydrous salt-cooled anhydrous CH3OH (30 mL)under N2 protection. After the addition was completed, the reaction solution was warmed to room temperature and stirred for half an hour. Then, Compound 1 (5.00 g, 47.58 mmol) as described in the above reaction formula was added and reacted at room temperature for 12 hours, and the reaction solution became clear from turbidity. The reaction was concentrated and dried in vacuo to give a white solid: Compound 2 (7.10 g, 96%).
96%
With thionyl chloride; at 5 - 20℃; for 4h;
10 g of D-serine and 40 ml of methanol were placed in a reaction flask, 10 ml of thionyl chloride was added dropwise at 5±2 C, and reacted at room temperature for 4 hours. After the reaction was completed, it was concentrated to dryness.The crude cycloserine ester hydrochloride salt was 14.00 g.
95%
With acetyl chloride; at 0℃; for 2h;Reflux;
General procedure: Acetyl chloride (1.6 mL, 22 mmol) was added to MeOH (100 mL), and the solution was cooled to 0C. The solution was stirred for 5 min. Amino acid (L-serine, D-serine, L-cysteine, D-cysteine, L-2,3-diaminopropionic acid, and D-2,3-diaminopropionic acid) (20 mmol) was then added to the acetyl chloride solution in methanol (MeOH), and the solution was heated to reflux for 2 h, then cooled to room temperature.The reaction was evaporated under reduced pressure and gavea colorless solid. The solid was washed with CH2Cl2 (20 mL)to give amino acid methyl ester hydrochloride (2d-f, 2d-f)as a white solid. The yields of 2d, d, e, e, f and f were 95%,96%, 94%, 96%, 95%, 95%, respectively.
93%
With thionyl chloride; at -5 - 20℃;Inert atmosphere; Reflux; Green chemistry;
Dissolve 105.09g D-serine in 1.5L dry methanol and cool down to -50C.With nitrogen protection, 178.46 g of thionyl chloride was added dropwise, and after completion of the addition, the reaction was allowed to warm to room temperature and stirred for 2 hours.Then continue to heat up to reflux, stirring and refluxing overnight, after the reaction is complete, the solvent is evaporated under reduced pressure,Ethyl acetate was washed by washing with suction to obtain 219 g of white solid D-serine methyl ester hydrochloride in 93% yield.
67.75%
With thionyl chloride; at 0 - 20℃; for 16h;Inert atmosphere;
To a stirred solution of D-serine (10 g, 95.23 mmol) in MeOH (100 mL) under an argon atmosphere was added thionylchloride (56.65 g, 476.19 mmol) at 0 oC. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were concentrated in vacuo. The crude material was washed with ether (2 x 100 mL) and dried in vacuo to obtain the methyl D-serinate hydrochloride (10 g, 67.75%) as an off-white solid.1H-NMR (DMSO-d6, 500 MHz): delta 8.60-8.55 (m, 3H), 5.61-5.59 (m, 1H), 4.10-4.08 (m, 1H), 3.83-3.79 (m, 2H), 3.74 (s, 3H); TLC: 10% MeOH/ CH2Cl2 (Rf: 0.3).
With sodium hydroxide; In water; at -5 - 35℃; for 20h;
The sodium hydroxide (8.4g, 0 . 210mol) dissolved in water at room temperature (53 ml) in, cooling to 5-10C, and in ? 10 C D-serine added under (10.5g, 0 . 100mol) and di-tert-butyl dicarbonate (26.2g, 0 . 120mol), heating to 30-35 C reaction 20 hours, obtains the type aqueous solution of compound I (yield according to the 100% meter, HPLC purity 99.1%, chiral purity 99.4%). Compound of formula I without separation, reaction solution directly used for the next step synthesis.
98%
With sodium hydroxide; In water; tert-butyl alcohol; at 0 - 20℃; for 14h;
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):
94%
<strong>[312-84-5]D-Serine</strong> (0.47 mol) was dissolved in water and cooled to 20-30 C. Sodium hydroxide (1.0 mol) solution was added to the reaction mixture at 20-30 C. and stirred for 45 min at the same temperature. Boc-anhydride (0.75 mol) was added to reaction mixture at 20-30 C. for 60 min. The temperature of the reaction mixture was raised up to 25-30 C. and maintained the reaction for 8 hrs. The reaction mass was filtered and separated the aqueous layer. The aqueous layer pH was adjusted to 1.0-2.0 with dilute hydrochloric acid and extracted the compound with ethyl acetate. The ethyl acetate layer was washed with sodium chloride solution, evaporated the solvent under reduced pressure to get title compound. Yield: 94%
92.57%
With sodium hydroxide; In water; at 20℃; for 14h;
Water (5L) was charged at room temperature, sodium hydroxide (1.03 kg), D-serine (1 kg) with Di-tert-butyl dicarbonate (3.32 kg) into a reaction kettle, stir for 14 hours. Apply potassium bicarbonate solution 1 to adjust the pH to 2.5. filter, the filtrate was extracted with ethyl acetate, concentrated under reduced pressure, and toluene was charged to the reaction mass at 50 C and stirred at 45 C for 10 minutes. After cooling to room temperature, 0.01 kg stage I seed crystals were put in, stirred for 3 hours, centrifuged, and dried, to obtain lacosamide stage I. The yield was 92.57%.
91%
With triethylamine; In water;
(A) Manufacture of (2R)-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-tert-butoxycarbonylaminopropionic acid D-serine (25 g, 238 mmol) and triethylamine (35 mL, 250 mmol) were dissolved in water (400 mL), and Boc2O (50 g, 230 mmol) was added thereto and stirred at room temperature for 20 hours. The reaction mixture was washed with ethyl acetate (200 mL*2). The aqueous layer was acidified with 2 mol/L HCl to pH 2 and extracted with ethyl acetate (200 mL*5). The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give Boc-D-Ser (44.4 g, 91%) as a colorless oil.
91%
With triethylamine; In water;
Example 1. Manufacture of (2R)-3-{3,5-bis(trifluoromethyl)benzyloxy}-2-tert-butoxycarbonylaminopropionic acid D-serine (25 g, 238 mmol) and triethylamine (35 mL, 250 mmol) were dissolved in water (400 mL), and Boc2O (50 g, 230mmol) was added thereto and stirred at room temperature for 20 hours. The reaction mixture was washed with ethyl acetate (200 mL x 2). The aqueous layer was acidified with 2 mol/L HCl to pH 2 and extracted with ethyl acetate (200 mL x 5). The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give Boc-D-Ser (44.4 g, 91%) as a colorless oil.
85%
With sodium hydroxide; In 1,4-dioxane; water; at 5 - 20℃; for 18h;pH 10;
Intermediate 1: Preparation of (2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acidTo a cold solution (5 C.) of 74.4 g (1.86 mol) of sodium hydroxide in 1800 mL of water was added 95.1 g (0.90 mol) of D-serine. Then, a solution of 274.5 g (1.26 mol) of di-tert-butyldicarbonate (BOC2O) in 840 mL of 1,4-dioxane was added dropwise maintaining the temperature below 10 C. The reaction was stirred during 1 hour at 10 C. and for 2 hours at room temperature. The pH was adjusted to 10 with 50% sodium hydroxide (19.0 mL) and the reaction mixture was stirred at room temperature for 15 hours. Half of the reaction volume was evaporated under vacuum and after cooling the residue to 5 C. the pH was adjusted to 2-3 using 1N NaHSO4. The mixture was extracted with ethyl acetate (5×1000 mL) and the combined organic phase was dried over sodium sulphate and concentrated under vacuum. The resulting oil was dissolved in methyl tert-butyl ether (200 mL), petroleum oil (800 mL) was added and the mixture was stirred for 1 hour. The solid was collected by filtration and dried yielding 158.3 g of the title compound as a white solid (Yield 85%).
53.2%
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 24h;
General procedure: To a stirred solution of l-serine and d-serine (5.2g, 50.0mmol) in 1M NaOH aqueous solution (50mL) and 1, 4-dioxane (100mL), di-tert-butyl dicarbonate (13.1g, 60.0mmol) was slowly added at 0C. The mixture was warmed to room temperature and stirred for 24h. After evaporation of 1, 4-dioxane, the aqueous layer was wash with Et2O (50mL). The aqueous layer was acidified with 1M H2SO4 aqueous solution to give pH 2-3 and extracted with ethyl acetate (3×50mL). The combined organic layer was dried over anhydrous Na2SO4, filtrated, and concentrated under reduced pressure to give the product N-Boc-l-serine.
With sodium hydroxide; In water; at 20 - 30℃;
Example 1:Preparation of N-Boc-O-methyl-D-serine: Into a 2L, four-necked RB flask was charged 90 ml of water and 40 g of sodium hydroxide. <strong>[312-84-5]D-Serine</strong> is added to the solution at 20-25 C. Boc anhydride (150 g) is slowly added to the reaction mass keeping the temperature below 20C. The reaction mass was allowed to reach 25-30C and maintained for 16 h. TLC of the reaction mass showed the presence of D-serine content at <1.0% level. The reaction mass is cooled to 0-5C and started the simultaneous addition of aqueous sodium hydroxide (104 g of sodium hydroxide dissolved in 100 ml of water) and dimethyl sulphate (300 g) through addition funnels keeping the temperature below 5C. The reaction mass was maintained at same temperature till the completion of reaction. The reaction mass is diluted with water and extracted the product into diisopropyl ether. Aqueous layer is neutralized with citric acid to get < 3.5 pH. The reaction mass is extracted with diisopropyl ether and distilled of solvent to get 87 g of title compound as an oil.
With sodium hydroxide; In water; at 20 - 25℃; for 10h;
ExampIe-30: Preparation of N-Boc-D-serine of Formula 16:; Di-tert.butyldicarbonate (124.5 grams) was added to solution of D-serine (50 grams) in aqueous sodium hydroxide (38.5 g of NaOH in 250 ml of water) at 20-25C and stirred for 10 hours at 20-25C. The reaction mixture containing N-Boc-D-serine has been used directly to next stage with out any purification.
To a stirred solution of sodium hydroxide 114 g (2.85 mole) in water (375 ml) was added (/?)-serine 250 g (2.37 mole). To the resulting clear solution of sodium salt of (i?)-serine were added t-butyloxycarbonic anhydride (Boc-anhydride), 571 g (2.61 mole) and a catalytic amount tetrabutylammonium bromidel2.0 g (0.036 mole). The mixture was stirred at ambient temperature for 16 hours. The resulting suspension was acidified to pH 3.5-4.0 with dilute HC1 (3N) and the product was extracted into dichloromethane to obtain a solution of (i?)-N-Boc-serine.
With dmap; sodium hydroxide; In water; tert-butyl alcohol; at 20℃; for 11h;
Preparation of N-Boc-D-serineSodium hydroxide (44 gm) was dissolved in water (300 ml) and stirred for 15 minutes. D-serine (105 gm) was added to the solution and then added dimethylaminopyridine (3 gm). Tert-butyl alcohol (180 gm) was added to the reaction mixture and then added di-tert-butyl dicarbonate (Boc anhydride, 230 gm) for 1 hour. The reaction mass was maintained for 10 hours at room temperature and then concentrated to obtain residual mass. The residual mass was then cooled to 5 to 10C and pH was adjusted to 2.9 with potassium bisulfate (IN). The reaction mass was extracted with ethyl acetate and the solvent was distilled off under vacuum at below 40C to obtain a residual solid of N-Boc-D-serine (190 gm).
With sodium hydroxide; In water; at 20 - 30℃; for 16h;
Into a 2 L, four-necked RB flask was charged 90 ml of water and 40 g of sodium hydroxide. <strong>[312-84-5]D-Serine</strong> is added to the solution at 20-25 C. Boc anhydride (150 g) is slowly added to the reaction mass keeping the temperature below 20 C. The reaction mass was allowed to reach 25-30 C. and maintained for 16 h. TLC of the reaction mass showed the presence of D-serine content at <1.0% level. The reaction mass is cooled to 0-5 C. and started the simultaneous addition of aqueous sodium hydroxide (104 g of sodium hydroxide dissolved in 100 ml of water) and dimethyl sulphate (300 g) through addition funnels keeping the temperature below 5 C. The reaction mass was maintained at same temperature till the completion of reaction. The reaction mass is diluted with water and extracted the product into diisopropyl ether. Aqueous layer is neutralized with citric acid to get <3.5 pH. The reaction mass is extracted with diisopropyl ether and distilled of solvent to get 87 g of title compound as an oil.
To a stirred solution of sodium hydroxide 114 g (2.85 mole) in water (375 ml) was added <strong>[312-84-5](R)-serine</strong> 250 g (2.37 mole). To the resulting clear solution of sodium salt of <strong>[312-84-5](R)-serine</strong> were added t-butyloxycarbonic anhydride (Boc-anhydride) 571 g (2.61 mole) and a catalytic amount tetrabutylammonium bromide 12.0 g (0.036 mole). The mixture was stirred at ambient temperature for 16 hours. The resulting suspension was acidified to pH 3.5-4.0 with dilute HCl (3N) and the product was extracted into dichloromethane to obtain a solution of (R)-N-Boc-serine.
With sodium hydroxide; In water; at 5 - 25℃; for 10.5h;
To a stirred aqueous solution of sodium hydroxide (23.1 g of NaOH in 150 ml of water) was added D-serine (30 g) lot wise at 2G-25C and BOC anhydride (74.7 g) at 10-15C. The traction mixture was stirred at 20-25 0C for 10 hours. Sodium hydroxide pellets (11.4g) was added to the reaction mixture at 5-10C and stirred for another 30 mins. To the resulting reaction mixture was slowly added dimethylsulphate (340 ml) and aqueous solution of sodium hydroxide (91.0 g NaOH in 1 10 mL of water) at 5-10C over 4 hours and then stirred for 10 hrs. The reaction mixture was acidified to pH -1 -2 with 2% hydrochloric acid solution at 0-5C and extracted with methylene chloride (300 ml). Separating organic layer, aqueous layer was extracted with methylene chloride (100 mL). The combined organic layer was concentrated under vacuum. The obtained residue was dissolved in methyl tert-butyl ether (83.25 mL) at 60-65C. To the resulting solution was added H-hexane (466.2 mL) at 20-25C and mixture was stirred for 10-12h. The solid was filtered and dried to provide the title compound as white solid. Weight: 34.5 g Yield: 55.29%.
With triethylamine; In methanol; at 20℃;
To a stirring solution of (Boc)20 (1.09 g, 5 mmol) in CH3OH (5 mL) was added the suspension of (R)-2-amino-3-hydroxypropanoic acid SM 1 (525 mg, 5 mmol) and Et3N (507 mg, 5 mmol) in CH3OH (5 mL) at RT and stirred overnight. The reaction mixture was concentrated and the residue was diluted with H20. Adjusted the pH to 9-10 and extracted with DCM. The water layer was adjusted the pH to 2 with 4N HC1 aq. and extracted with DCM. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound 1 (950 mg, 92%) as a white solid.
With sodium hydroxide; In water; at 50℃;
To a solution of D-serine (150 g, 1.427 mol) and NaOH (68.5 g, 1.712 mol) in water (225 mL) was added di-tert-butyl dicarbonate (393.5 g, 1.712 mol) with stirring. The reaction mixture was heated to 50 C for 1-2 h (the initial clear reaction mass turns turbid in 1-2 h). The mixture was cooled to room temperature and diluted with of water (900 ml). The reaction mixture was washed with ethyl acetate (2 X 300 mL) to get rid of the traces of unreacted D-serine and other minor impurities. The pH of the reaction mixture was adjusted to 3-4 by slow addition of cold 3N HC1 (200 mL). The aqueous layer was extracted with ethyl acetate (3 X 400 mL). The combined organic layers of Boc-D-serine were washed with brine solution (300 mL) and used for the next stage.
5 kg
With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 18h;Large scale;
Add 50L of water and 1.37kg of sodium hydroxide to the 50L reactor, and add 3kg of D-serine in batches. After the addition, cool down to 0-5 degrees, and dissolve 7kg of di-tert-butyl dicarbonate in 14L of tetrahydrofuran. Add the reaction solution, add room temperature to react for 18 hours, cool down to 0 C, add concentrated hydrochloric acid dropwise, adjust ph to 2-3.5, add 1.5 kg of ethyl acetate to extract three times, dry and spin dry to obtain 5 kg of colorless oil.
With sulfuric acid In methanol; water monomer at 25℃; Resolution of racemate;
With R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 coated C18 silica gel column at 25℃; Resolution of racemate;
With C9H20N(1+)*C5H8NO2(1-); copper (II) acetate In water monomer at 10℃; Resolution of racemate;
With capillary electrochromatography open-tubular column coated with 1-allylimidazolium-β-cyclodextrin In aq. acetate buffer at 20℃; Resolution of racemate;
With (R,R)-BINOL2-C/PDAN-based chiral covalent organic frameworks covered silica gel packed HPLC column In methanol; water monomer at 25℃; Resolution of racemate;
To a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2M NaOH (70 mL) was added benzaldehyde (14.6 g, 14.0 mL, 138.0 mmol). The reaction mixture was then stirred at r.t. for 1 h before cooling to 5C. NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of between 6 and 100C was maintained. After addition, the reaction mixture was allowed to stir at 5C for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5C and a further portion OfNaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of <10C was maintained. The ice bath was removed on completion of addition and the reaction <n="41"/>mixture stirred at r.t. for 16 h. The reaction mixture was then extracted with Et2O (3 x 100 mL) and the aqueous phase acidified to pH 5 with cone. HCl. The resultant white precipitate was filtered and washed with water. The product was dried in vacuo to give the title compound (24.0 g, 88%) as a white solid. deltaH (DMSOd6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (IH, t, J5.8 Hz).
88%
INTERMEDIATE 34JV-Benzyl-D-serineTo a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2M NaOH (70 mL) was added benzaldehyde (14.0 mL, 138.0 mmol). The reaction mixture was stirred at r.t. for 1 h before cooling to 5C. NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of between 6 and 100C was maintained. After addition, the reaction mixture was allowed to stir at 5C for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5C and further NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of < 100C was maintained. The ice bath was removed on completion of addition and the reaction mixture stirred at r.t. for 16 h. The reaction mixture was then extracted with ether (3 x 100 mL) and the aqueous phase acidified to pH 5 with cone. HCl. The resulting white precipitate was filtered off, washed with water and dried in vacuo to give the title compound (24.0 g, 88%) as a white solid. deltaH (DMSO-(I6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (IH, t, J 5.8 Hz).
88%
To a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2M NaOH (70 mL) was added benzaldehyde (14.6 g, 14.0 mL, 138.0 mmol). The reaction mixture was then stirred at r.t. for 1 h before cooling to 5 C. NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of between 6 and 10 C. was maintained. After addition, the reaction mixture was allowed to stir at 5 C. for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5 C. and a further portion of NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of <10 C. was maintained. The ice bath was removed on completion of addition and the reaction mixture stirred at r.t. for 16 h. The reaction mixture was then extracted with Et2O (3×100 mL) and the aqueous phase acidified to pH 5 with conc. HCl. The resultant white precipitate was filtered and washed with water. The product was dried in vacuo to give the title compound (24.0 g, 88%) as a white solid. deltaH (DMSO-d6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (1H, t, J 5.8 Hz).
46%
The title compound was made according to the procedure described G. R. Brown, J. Chem. Soc. Perkin Trans 1 , 1985, 2577. Benzaldehyde (10.16mL,0.1 mol) was added to a vigorously stirred solution of <strong>[312-84-5]D-Serine</strong> (10.47g, 0.1 mol) in 2N NaOH solution (5OmL), stirred for 30 minutes at RT. before cooling in an ice-salt bath to ~6C before adding Sodium Borohydride (1.06g, 27.90mmol) portionwise over 40 minutes. The reaction was stirred at RT. for 1 hour before adding more benzaldehyde (10.16ml_, 0.1 mol) and cooling down in an ice-salt bath to between 6-10C and then adding more sodium Borohydride (1.06g, 27.90mmol) portionwise over 45 minutes. The reaction mixture was stirred at RT. for 2 hours, washed with Et2O. Made sure all solid material in solution, hence diluted with water before washing with Et2O x2. Aqueous layer acidified to ~pH 6.5, using c.HCI solution. Solid precipitated out. Filtered, dried in the vacuum oven overnight at 400C to afford a white solid in 46% yield.NMR (DMSO-d6) delta 7.44-7.30 (5H, m), 3.98 (2H, q), 3.73- 3.61 (1 H, m), 3.14 (1 H, m).
With sodium carbonate; In water; acetonitrile; at 5 - 20℃; for 12.5h;
<strong>[312-84-5]D-Serine</strong> (10.5 g, 100 mmol) and sodium carbonate (11.1 g, 105 mmol) were dissolved in water (100 mL). Acetonitrile (50 mL) was added to this solution and the mixture was cooled in an ice bath to 5 C. Allyl chloroformate (11.7 mL, 13.3 g, 110 mmol) was added dropwise during period of 30 min. The reaction mixture was gradually allowed to warm to room temperature and stirred for 12 h. The mixture was concentrated under vacuum to approximately 100 mL to remove acetonitrile and the residue was cooled to 0-5 C. The pH of the solution was adjusted to 2.0 by adding concentrated aqueous HCl (approx. 10 mL). The product was extracted with ethyl acetate (5×40 mL), and the extract was dried over anhydrous magnesium sulfate. The solvent was removed on rotary evaporator under vacuum to yield N-(Alloc)-D-serine (16.9 g, 89%) which appeared as a pale yellow oil.
With sodium carbonate; In water; acetonitrile; at 20℃; for 30h;
d-Serine (1.00 g, 9.51 mmol) and Na2CO3(1.05 g, 9.90 mmol) were dissolved in water (10 mL) and acetonitrile (5 mL) was added followed by the dropwise addition of allyl chloroformate (1.05 mL, 1.19 g, 9.88 mmol) over 5 min. The mixture was stirred for 30 h, at room temperature, before being concentrated to drynessin vacuo. The residue was then dissolved in dry DMF (20 mL) and NaHCO3(0.82 g, 9.8 mmol) was added followed by the dropwise addition of allyl bromide (0.85 mL, 1.19 g, 9.8 mmol) over 5 min. The mixture was stirred for 45 h at room temperature and then concentratedin vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with a saturated aqueous NaHCO3solution (40 mL), water (3 x 40 mL), and brine (2 x 30 mL). The organic layer was dried over anhydrous MgSO4and concentratedin vacuoto afford a yellow oil. Purification by flash chromatography on silica in petroleum ether:ethyl acetate (3:2) gaveallyl (R)-1-[(allyloxy)carbonyl)]-N-(2-hydroxyethyl)carbamateas a pale yellow oil (1.52 g, 70%). [alpha]D20: +2.96 (c= 1.35 in CHCl3); Rf0.56, petroleum ether:ethyl acetate (2:1);1H NMR (CDCl3) delta/ppm; 6.21 (d, 1H,J =8.3 Hz), 5.94-5.86 (m, 2H), 5.25-5.19 (m, 4H), 4.67-4.64 (m, 4H), 4.44-4.41 (m, 1H), 3.98 (dd, 1HJ =11.5 and 3.7 Hz), 3.86 (dd, 1HJ =11.5 and 3.4 Hz);13C NMR(CDCl3) delta/ppm; 163.1, 156.2, 132.5, 131.5, 118.4, 117.6, 66.4, 65.8, 62.6, 56.1;IR(Thin Film, NaCl)/cm-1; 3404, 2949, 1722, 1689, 1645, 1320; HRMS:ES+for C10H15NO5, expected [M+H]+230.1028, observed [M+H]+230.1024.
With sodium hydrogencarbonate In acetone at 40℃; for 1h;
With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;
With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;
With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;
With sodium hydrogencarbonate In acetone at 37℃; for 1h;
Stereochemistry of amino acids constituting verlamelin A and B
General procedure: One milligram of aliquots of 1 or 2 were hydrolyzed by heating at 115 1C for8 h in 10 ml of 6M HCl. After cooling to room temperature, theywere completely dried in vacuo and dissolved in 150 ml of water. Marfey’sreagent (300 ml of 10mgml1 solution in acetone) (Na-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan)was added, followed by the addition of 70 ml of 1M NaHCO3. The reactionsproceeded at 37 1C for 1h and were quenched by addition of 70ml of 1M HCl.The resulting mixture was dried in vacuo and then dissolved in 1ml of DMSOto be analyzed by HPLC. Marfey’s derivatives of amino acids as a standard wereprepared by reacting 50mM of amino acids in the same manner as describedabove. HPLC analysis was carried out on a Shiseido Capcell-Pak C18 column(4.6250mm) with a linear gradient of CH3CN from 10% to 50% in 0.05%aqueous TFA solution (60min from 10% to 50%, 5 min at 50%, 3 min from50% to 10%), at a flow rate of 1.0mlmin1, with detection at 340 nm. Theglutamine (Gln) residues of 1 and 2 should be converted by acid hydrolysis toglutamic acid (Glu). Retention times (min) of Marfey’s derivatives used asstandards were as follows: L-Ser (25.6), D-Ser (26.0), L-Thr (27.0), D-Thr(31.8), L-alloThr (27.5), D-alloThr (29.3), L-Glu (30.1), D-Glu (31.9), L-Pro(34.3), D-Pro (36.0), L-Ala (33.2), D-Ala (37.2), L-Val (42.1), D-Val (48.1),L-Tyr (57.9) and D-Tyr (40.4, 62.2).
With sodium hydrogencarbonate In water; acetone at 80℃; for 0.166667h;
2.4 Determination of the absolute configurations of the amino acid units in 1
A 0.5 mg quantity of 1 was hydrolyzed in 0.5 mL of 6N HCl at 110 °C for 5 h. The reaction solvent was evaporated in vacuo, and residual HCl was completely removed by adding 0.5 mL of water and removing the solvent three times. The hydrolysate was purified by column chromatography using a C18 Sepak column (0.5 g). The free amino acids were eluted with 10 % CH3CN in water. A solution of Marfey's reagent (20 μL, 10 mg/mL in acetone) was added to the purified hydrolysate containing the free amino acids, followed by 1N aqueous NaHCO3 (100 μL). The reaction was heated to 80 °C for 10 min, cooled to room temperature, and acidified with 2N HCl (50 μL). The reaction mixture was filtered and analyzed by LC-MS with a gradient solvent system from 20 % to 70 % CH3CN containing 0.1 % formic acid over 50 min (Agilent 1200 Series HPLC/6130 Series mass spectrometer, Hydrosphere C18, YMC column 5 μm, 4.6 mm×250 mm, 0.7 mL/min flow rate). Standards were prepared from the appropriate authentic D- or L-amino acids (0.2 mg) by derivatizing them with Marfey's reagent using the above procedure. The retention times for Marfey's derivatives were as follows: serine (L-Ser, 15.62 min and D-Ser, 15.98 min), proline (L-Pro, 21.87 min and D-Pro, 22.24 min), tyrosine (L-Tyr, 24.71 min and D-Tyr, 25.95 min), and leucine (L-Leu, 32.04 min and D-Leu, 33.82 min). Sample prepared from 1 was also co-injected with standards to confirm its assignment which proved that compound 1 contains D-serine (15.99 min), L-proline (21.85 min), D-tyrosine (25.90 min), and L-leucine (32.07 min).
With sodium hydrogencarbonate In water; acetone at 80℃; for 0.166667h;
With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;
With sodium hydrogencarbonate In water at 40℃; for 1.5h;
3.4. Hydrolysis of Compounds 1-2 and HPLC Analysis by Marfey’s Method
Compounds 1 (1.0 mg) and 2 (1.4 mg) were dissolved in 6 N HCl (1 mL), and heated at 110 °C for18 h. After cooling to room temperature, the hydrolysates were dried under reduced pressure and resuspended into 100 μL of H2O.Then they were treated with 1 M NaHCO3 (25 μL), and reacted with100 μL of 1% (w/v) FDAA in acetone at 40 °C for 1.5 h. After cooling to room temperature, the mixture was added with 1 M HCl (25 μL) to neutralize and terminate the reaction. MeOH was then added to the quenched reaction to afford a total volume of 500 μL; 10 μL of each hydrolysate derivatization reaction was used for HPLC analysis using an Agilent C18 column (150 × 4.6 mm,5 μM) with a solvent gradient from 15% to 45% solvent B (solvent A: CH3COOH/H2O, 0.05/99.95,solvent B: CH3CN) over the course of 30 min and UV detection at 340 nm at a flow rate of 1 mL/min.Similarly, 10 μL of the standard amino acids in H2O (4 μM) were added to 1 M NaHCO3 (20 μL) and each mixture was treated with 1% (w/v) FDAA (50 μL) for 1.5 h at 40 °C. Derivatization reactions were terminated with 1 M HCl (20 μL) and diluted to a total volume of 500 μL with MeOH. Of these standard amino acid derivatization reactions, 10 μL was subjected to HPLC analysis and used as structural standards in the elucidation of structures 1 and 2.
With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;
With sodium hydrogencarbonate In water at 40℃; for 1h;
With sodium hydrogencarbonate In water; acetone at 45℃; for 1h;
Stage #1: D-Serine With sodium hydrogencarbonate In water
Stage #2: N-(2,4-dinitro-5-fluorophenyl)-L-alaninamide In water; acetone at 60℃; for 1h;
With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;
Step 1 To a suspension of D-serine (6.95 g, 66.1 mmol) in acetonitrile (100 mL) was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resulting solution was heated to 80 C. After 1 h, <strong>[80745-07-9]4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride</strong> (17.3 g, 69.4 mmol) was added and the heating was continued. After 12 h, the reaction mixture was cooled to room temperature. Methanol (15 mL) was added, and the organics were removed in vacuo. The residue was diluted with diethyl ether (300 mL) and after cooling the reaction mixture to 0 C., the pH was adjusted to 8 with 6 N aqueous sodium hydroxide solution. The organic layer was collected and the aqueous layer was extracted with diethyl ether. The aqueous layer was adjusted to pH 4 and again extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzene-sulfonylamino)-3-hydroxypropionic acid (20.5 g) as a brown foam which was used without further purification.
18 Preparation of D-glyceric acid (Compound 18)
EXAMPLE 18 Preparation of D-glyceric acid (Compound 18) Portions of sulfuric acid (297 mL; 11.14 mol; 1.23 eq) was added to a large excess of water (7,300 mL) under stirring and cooling (0-5° C.). D-Serine (952 g;9.06 mol;1 eq) was added in one portion under vigorous stirring, followed by dropwise addition of aqueous sodium nitrite (769 g;11.14 mol; 1.23 eq in 3,060 mL water). Temperature was kept between 0-5° C. during the addition time (seven hours). The reaction vessel was stirred overnight at room temperature and the reaction monitored by TLC (ninhydrin). In order to complete the reaction, additional sulfuric acid (115 mL; 4.31 mol; 0.47 eq) and aqueous sodium nitrite (255 g; 3.69 mol; 0.4 eq in 1,100 mL water) was added, keeping the reaction vessel temperature between 0-5° C. The reaction vessel was then kept under stirring at room temperature for another 18 hours. Nitrogen was bubbled through the solution for one hour and the water removed by vacuum, keeping the reaction vessel temperature between 28-30° C. The residue (D-glyceric acid) was co-evaporated with toluene (3*1L)
With potassium carbonate In water; acetonitrile at 55℃; for 24h;
12.1
Example 12.1; Benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate; D-serine (10.5 g, 0.1 rαol) was stirred with potassium carbonate (69 g, 0.5 mol), benzyl bromide (64.8 g, 0.375 mol) and water (10 mL) in acetonitrile (250 mL) at 55°C for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20 % ethyl acetate in hexanes to give benzyl (2R)-2-(dibenzylamino)-3- hydroxypropanoate (33.36 g, 88 %) as a pale-yellow sticky oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.20-7.44 (m, 15H), 5.27(q, 2H), 3.91 (d, 2H), 3.80 (m, 2H), 3.67 (d, 2H), 3.63 (m, IH) and 2.52 (dd, IH).
88%
With potassium carbonate In water; acetonitrile at 55℃; for 24h;
12.1
D-serine (10.5 g, 0.1 mol) was stirred with potassium carbonate (69 g, 0.5 mol), benzyl bromide (64.8 g, 0.375 mol) and water (10 rnL) in acetonitrile (250 mL) at 550C for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20 % ethyl acetate in hexanes to give benzyl (2R)-2- (dibenzylamino)-3-hydroxypropanoate (33.36 g, 88 %) as a pale-yellow sticky oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.20-7.44 (m, 15H), 5.27(q, 2H), 3.91 (d, 2H), 3.80 (m, 2H), 3.67 (d, 2H), 3.63 (m, IH) and 2.52 (dd, IH).
Example 58; (R)-2-Chloro-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxyethylamino)-3-methylbenzonitrile; Intermediate 58a; (R)-2-(3-Chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoic acid K2CO3 (5.71 g, 41.28 mol) was added to a solution of <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (3.5 g, 20.64 mmol) and D-Serine (2.17 g, 20.096 mol) in DMSO (100 mL) at room temperature. The reaction mixture was heated to 75 C. and stirred for 19 h, then was allowed to cool to room temperature whereupon water (30 mL) was added followed by citric acid monohydrate (5g). After stirring for 10 min the mixture was partitioned between EtOAc (50 mL) and water. The organic phase was then washed with water (20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated to furnish a pale yellow solid (4.2 g). This crude product was then passed through a silica-plug [hexanes-EtOAc (95:5) as eluent] to furnish the title compound as a white solid (1.5 g, 29%) 1H NMR (500 MHz, acetone-d6, delta in ppm) 7.49 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.56 (d, J=8 Hz, 1H), 4.43-4.40 (m, 1H), 4.06 (dd, J=11, 18 Hz, 1H), 4.05 (dd, J=11, 18 Hz, 1H) and 2.31 (s, 3H).
Examples 11 and 12Example 11 Example 12 11a to l ib(R)-2-(3 -chloro-4-cyano-2-methylphenylamino)-3 -hydroxypropanoic acidTo a stirred solution of <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (1 la) (1.0 gm, 5.8 mmol) in DMSO (10 mL), D-Serine (1.4 gm, 13.3 mmol) was added followed by K2C03 (1.7 gm, 12.3 mmol) at room temperature. The resulting reaction mixture was heated to 90C for 12 h. After completion of reaction (by TLC), the reaction mixture was poured into ice-cold water (300 mL) and extracted with EtOAc (100 mL). The aqueous layer was acidified with citric acid (pH ~3) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04, and concentrated under reduced pressure to afford the acid 1 lb (0.3 gm, crude) as off- white solid. The crude material was taken for the next step without purification.TLC: 10% MeOH/DCM (Rf: 0.2)1H NMR (500MHz, DMSO-c¾, delta in ppm): 8.2-10.2 (br s, 1H), 7.54 (d, J= 8.5 Hz, 1H), 6.57 (d, J= 9.0 Hz, 1H), 5.79 (d, J= 7.5 Hz, 1H), 4.20 (t, J= 3.0 Hz, 1H), 3.86-3.79 (m, 2H), 3.22 (br s, 1H), 2.25 (s, 3H).
Examples 7 and 8Example 77a to 7b( )-2-(4-Cyano-3-(trifluoromethyl) phenyl amino)-3-hydroxypropanoic acidTo a solution of D-Serine (1) (3.65 gm, 34.8 mmol) in DMSO (30 mL),K2C03 (4.36 gm, 31.6 mmol) followed by 4-Fluoro-2-(trifluoromethyl) benzonitrile (7a) (3.0 gm, 15.8 mmol) was added and the reaction was heated to 80C for 4 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The aqueous layer was acidified with citric acid and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to afford the crude compound which was triturated with Hexane/EtOAc to afford the acid 7b (2.1 gm, 48%) as a crystalline solid.TLC: 30% MeOH/DCM (Rf: 0.3)1H NMR (500MHz, DMSO-c¾, delta in ppm): 7.72 (d, J= 9.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.20 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 4.28-4.25 (m, 1H), 3.81-3.74 (m, 2H).
Examples 9 and 109d9a to 9b( )-2-(3-chloro-4-cyanophenylamino)-3-hydroxypropanoic acidTo a stirred solution of D-Serine (2.98 gm, 28.4 mmol) in DMSO (30 mL), K2C03 (3.5 gm, 25.3 mmol) followed by <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (9a) (2.0 gm, 12.8 mmol) was added at room temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 80C and stirred for 12 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL). The aqueous layer was acidified with citric acid and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (2 x 30 mL) dried over Na2S04 and concentrated under reduced pressure to afford the acid 9b (1.7 gm, crude) as a white solid which was taken for the next step without purification.TLC: 10% MeOH/DCM (Rf: 0.4)1H NMR (200MHz, DMSO-c/6, delta in ppm): 7.54 (d, J= 8.4 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.86 (d, J= 1.8Hz, 1H), 6.69 (dd, J= 8.8, 2.2 Hz, 1H), 4.21-4.12 (m, 1H), 3.74 (dd, J= 4.6, 2.6 Hz, 2H).
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 3h;
55.1 Step 1
Step 1. To a mixture of compound 55-1 (1.55 g, 10 mmol), 55-la (2.51 g, 10 mmol) and Et3N (3.03 g, 30 mmol) in DMF (20 mL) was added HATU (3.8 g, 10 mmol). After the mixture was stirred at r.t. for 3 h, it was extracted with EtOAc (60 mL x 3). The organic layer was washed with brine (60 mL x 3), dried over NaSO i, concentrated in vacuo and purified by column (20% EtOAc in hexane) to give compound 55-2 (3.21 g, 91.2%). LCMS (ESI): m/z 353.1 [M+H+].
[Ru(4,4'bis(methoxycarbonyl)-2,2'-bipyridine)2(D-serine)]NO3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
General procedure: [RuCl2(p-cymene)]2 (0.12 g, 0.20 mmol), glycine (0.03 g,0.40 mmol) and potassium tert-butoxide (0.05 g, 0.40 mmol) wereadded to dry methanol (40 mL), and the resulting mixture wasrefluxed for 30 min under argon atmosphere. AgNO3 (0.14 g,0.80 mmol) and dcmb (0.23 g, 0.85 mmol) were then added andthe reaction mixture was refluxed for additional 14 h in the dark.The reaction mixture was cooled to room temperature and filteredthrough a fine porosity frit to remove precipitated AgCl andexceeding dcmb. The filtrate was evaporated to dryness, and theresidue was recrystallized from a mixture of chloroform and hexane(v/v = 2:1), and dried in a vacuum to afford complex 3 as deepblue powder in a yield of 0.16 g (50percent).
With potassium carbonate In ethanol; water at 100℃; for 10h;
1 General procedure for the preparation of 2a-f
General procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g,4.55 mmol), K2CO3 (0.78 g, 5.68 mmol) and different amino acid(5.45 mmol) in ethanol (5 ml) and water (4 ml) were refluxed at100 C for 10 h. After cooling to the room temperature, pH valuewas adjusted to 2 with 1 M HCl solution. The mixture was filteredand the precipitate was collected to afford 2a-g as golden yellowsolid.
With dmap; di(succinimido) carbonate In water; N,N-dimethyl-formamide at 20℃; for 15h;
Step 1. (R)-2-(4-Cyclohexylbutoxycarbonylamino)-3-hydroxy-propanoic acid (S19)
To a solution of commercially available D-serine (0.3 g, 2.86 mmol) and 4-cyclohexyl-1-butanol (0.494 mL, 2.86 mmol) in a DMF:H2O mixture (1:1, 12 mL), DMAP (0.07 g, 0.57 mmol) and N-N’-disuccinimidyl carbonate (DSC) (0.878 g, 3.43 mmol) were subsequently added. The reaction was vigorously stirred for 15 hours at room temperature. The solution was acidified till pH 3, then diluted with EtOAc (10 mL) and H2O (10 mL). The layers were separated and the aqueous one was extracted with EtOAc (3 x 10 mL). The organic phase was dried over Na2SO4, filtered and the solvent removed under vacuum to yield the title compound (0.537 g, 65%) as colorless oil, which was used in the next step without any further purification. MS (ESI) m/z: 288.2 [M-H]+, 286.2 [M-H]-. 1H NMR (DMSO-d6): δ 7.03 (d, J = 8.2 Hz, 1H), 4.01 (dt, J = 8.2, 5.1 Hz, 1H), 3.93 (t, J = 6.7 Hz, 2H), 3.64 (d, J = 5.1 Hz, 2H), 1.71-1.58 (m, 5H), 1.56-1.43 (m, 2H), 1.37-1.26 (m, 2H), 1.24-1.07 (m, 6H), 0.95-0.78 (m, 2H). ppm.
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