Home Cart 0 Sign in  

[ CAS No. 4530-20-5 ]

{[proInfo.proName]} ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 4530-20-5
Chemical Structure| 4530-20-5
Structure of 4530-20-5 * Storage: {[proInfo.prStorage]}

Quality Control of [ 4530-20-5 ]

Related Doc. of [ 4530-20-5 ]

SDS
Alternatived Products of [ 4530-20-5 ]
Alternatived Products of [ 4530-20-5 ]

Product Details of [ 4530-20-5 ]

CAS No. :4530-20-5 MDL No. :MFCD00002690
Formula : C7H13NO4 Boiling Point : 315.9°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :175.18 g/mol Pubchem ID :78288
Synonyms :

Safety of [ 4530-20-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4530-20-5 ]

  • Upstream synthesis route of [ 4530-20-5 ]
  • Downstream synthetic route of [ 4530-20-5 ]

[ 4530-20-5 ] Synthesis Path-Upstream   1~37

  • 1
  • [ 4530-20-5 ]
  • [ 95-54-5 ]
  • [ 5805-57-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 590 - 602
  • 2
  • [ 4530-20-5 ]
  • [ 22356-89-4 ]
Reference: [1] Tetrahedron, 1993, vol. 49, # 5, p. 1133 - 1150
  • 3
  • [ 4530-20-5 ]
  • [ 784-38-3 ]
  • [ 2886-65-9 ]
Reference: [1] New Journal of Chemistry, 2011, vol. 35, # 11, p. 2412 - 2415
  • 4
  • [ 4530-20-5 ]
  • [ 100-39-0 ]
  • [ 4530-18-1 ]
Reference: [1] Tetrahedron Letters, 1992, vol. 33, # 43, p. 6461 - 6464
  • 5
  • [ 4530-20-5 ]
  • [ 200731-31-3 ]
  • [ 214360-73-3 ]
  • [ 39968-33-7 ]
  • [ 880545-43-7 ]
Reference: [1] Patent: WO2008/32086, 2008, A1, . Location in patent: Page/Page column 120-121
[2] Patent: WO2008/32086, 2008, A1, . Location in patent: Page/Page column 120-121
  • 6
  • [ 4530-20-5 ]
  • [ 6066-82-6 ]
  • [ 3392-07-2 ]
YieldReaction ConditionsOperation in experiment
61.8% With dicyclohexyl-carbodiimide In dichloromethane at 15 - 20℃; Step2: 2,5-Dioxopyrrolidine-1-yl 2-(fert-butoxycarbonylamino)acetate. /V-Boc-glycine (7.31 g, 41 .7 mmol) was dissolved in 100 mL of DCM and to the cooled (15°C) solution /V-hydroxysuccinimide (5.28 g, 45.9 mmol) was added. Λ/,Λ/'-dicyclohexylcarbodiimide (9.47 g, 45.9 mmol) was added to the formed suspension under vigorous stirring. After a few seconds, a cloudy white suspension formed, the mixture was allowed to reach room temperature and stirred for 1 h. It was subsequently filtrated over celite, washed with 50m L saturated sodium - - bicarbonate, dried over sodium sulfate and concentrated in vacuo to yield a crystalline powder. Yield: 7.02 g, 61 .8percent 1 H NMR (400 MHz, DMSO -cfe) : δ 1 .38 (s, 9H), 2.80 (s, 4H), 4.07 (d, J = 6 Hz, 2H), 7.43 (br s, 1 H). MS (ESI) m/z 567.2 [2M + Na]+.
61.8% With dicyclohexyl-carbodiimide In dichloromethane at 15℃; N-Boc-glycine (7.31 g, 41.7 mmol) was dissolved in 100 mL of DCM and to the cooled (15° C.) solution N-hydroxysuccinimide (5.28 g, 45.9 mmol) was added. N,N'-dicyclohexylcarbodiimide (9.47 g, 45.9 mmol) was added to the formed suspension under vigorous stirring.
After a few seconds, a cloudy white suspension formed, the mixture was allowed to reach room temperature and stirred for 1 h.
It was subsequently filtrated over celite, washed with 50 mL saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to yield a crystalline powder. Yield: 7.02 g, 61.8percent
1H NMR (400 MHz, DMSO-d6): δ 1.38 (s, 9H), 2.80 (s, 4H), 4.07 (d, J=6 Hz, 2H), 7.43 (br s, 1H). MS (ESI) m/z 567.2 [2M+Na]+.
Reference: [1] Chemistry - A European Journal, 2016, vol. 22, # 52, p. 18865 - 18872
[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 15, p. 2443 - 2449
[3] Chemical communications (Cambridge, England), 2003, # 23, p. 2870 - 2871
[4] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 402 - 407
[5] Helvetica Chimica Acta, 2004, vol. 87, # 5, p. 1077 - 1089
[6] Bioconjugate Chemistry, 2010, vol. 21, # 9, p. 1642 - 1655
[7] Patent: WO2013/107820, 2013, A1, . Location in patent: Page/Page column 42; 43
[8] Patent: US2014/357650, 2014, A1, . Location in patent: Paragraph 0265; 0268; 0269
[9] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1984, p. 2305 - 2308
[10] Journal of the American Chemical Society, 1993, vol. 115, # 10, p. 4228 - 4245
[11] Pharmaceutical Chemistry Journal, 1992, vol. 26, # 9-10, p. 753 - 756[12] Khimiko-Farmatsevticheskii Zhurnal, 1992, vol. 26, # 9-10, p. 72 - 74
[13] Journal of the American Chemical Society, 1996, vol. 118, # 29, p. 6975 - 6985
[14] Nucleosides and Nucleotides, 1998, vol. 17, # 9-11, p. 2135 - 2141
[15] Chemistry - A European Journal, 2001, vol. 7, # 19, p. 4280 - 4295
[16] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3220 - 3224
[17] Organic and Biomolecular Chemistry, 2015, vol. 13, # 13, p. 3950 - 3962
[18] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1257 - 1262
[19] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
  • 7
  • [ 4530-20-5 ]
  • [ 3392-07-2 ]
Reference: [1] Patent: WO2006/17352, 2006, A1, . Location in patent: Page/Page column 38
[2] Patent: US4782164, 1988, A,
  • 8
  • [ 4530-20-5 ]
  • [ 6066-82-6 ]
  • [ 3392-07-2 ]
Reference: [1] Patent: US5635158, 1997, A,
[2] Patent: EP659764, 1995, A2,
  • 9
  • [ 4530-20-5 ]
  • [ 3392-07-2 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 9, p. 1661 - 1664
  • 10
  • [ 4530-20-5 ]
  • [ 90704-86-2 ]
  • [ 3392-07-2 ]
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1984, vol. 54, # 8, p. 1696 - 1698[2] Zhurnal Obshchei Khimii, 1984, vol. 54, # 8, p. 1904 - 1907
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1984, vol. 33, p. 1067 - 1070[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1984, # 5, p. 1163 - 1165
  • 11
  • [ 4530-20-5 ]
  • [ 107960-02-1 ]
  • [ 3392-07-2 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 12, p. 2364 - 2367
  • 12
  • [ 4530-20-5 ]
  • [ 96935-01-2 ]
  • [ 3392-07-2 ]
Reference: [1] Tetrahedron Letters, 1985, vol. 26, # 14, p. 1721 - 1722
  • 13
  • [ 4530-20-5 ]
  • [ 116-52-9 ]
  • [ 3392-07-2 ]
Reference: [1] Patent: US8153759, 2012, B2,
  • 14
  • [ 4530-20-5 ]
  • [ 74-88-4 ]
  • [ 13734-36-6 ]
YieldReaction ConditionsOperation in experiment
94% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 26 h; Inert atmosphere General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)
91% With sodium hydride In tetrahydrofuran at 0 - 20℃; Sodium hydride (6.85 g, 171 mmol) was added to a mixture of (fer/-butoxycarbonyl)glycine (10 g, 57.1 mmol) and methyl iodide (75 g, 528 mmol) in THF (600 mL) at 0 °C. The mixture was slowly allowed to warm to rt overnight. Water (300 mL) was added and extracted into ethyl acetate (2 x 500 mL). The aqueous layer was acidified to pH 3 with 1 M Hci extracted with ethyl acetate (2 x 500 mL). The combined organic layer was extracted with saturated aqueous sodium chloride (500 mL), dried (MgSO^, filtration and concentrated to give the title compound as an oil (10 g, 91 percent).
91% With sodium hydride In tetrahydrofuran at 0 - 20℃; Sodium hydride (6.85 g, 171 mmol) was added to a mixture of (tert-butoxycarbonyl) glycine (10 g, 57.1 mmol) and methyl iodide (75 g, 528 mmol) in THF (600 mL) at 0 . The mixture was slowly allowed to warm to rt overnight. Water (300 mL) was added and extracted into ethyl acetate (2 x 500 mL). The aqueous layer was acidified to pH 3 with 1 M HCl extracted with ethyl acetate (2 x 500 mL). The combined organic layer was extracted with saturated aqueous sodium chloride (500 mL), dried (MgSO 4), filtration and concentrated to give the title compound as an oil (10 g, 91 percent).
Reference: [1] Tetrahedron, 2002, vol. 58, # 9, p. 1719 - 1737
[2] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[3] Tetrahedron Letters, 2005, vol. 46, # 25, p. 4377 - 4379
[4] Tetrahedron Letters, 2009, vol. 50, # 6, p. 611 - 613
[5] Patent: WO2017/100668, 2017, A1, . Location in patent: Page/Page column 155
[6] Patent: WO2018/103058, 2018, A1, . Location in patent: Page/Page column 155
[7] Journal of the American Chemical Society, 2009, vol. 131, # 50, p. 18072 - 18074
[8] Molecules, 2005, vol. 10, # 1, p. 259 - 264
  • 15
  • [ 4530-20-5 ]
  • [ 64-17-5 ]
  • [ 14719-37-0 ]
Reference: [1] Combinatorial Chemistry and High Throughput Screening, 2011, vol. 14, # 2, p. 132 - 137
[2] Tetrahedron, 1987, vol. 43, # 8, p. 1823 - 1826
[3] Journal of Organic Chemistry, 1995, vol. 60, # 10, p. 3112 - 3120
[4] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 14, p. 1511 - 1514
[5] The Journal of organic chemistry, 2002, vol. 67, # 24, p. 8291 - 8298
  • 16
  • [ 4530-20-5 ]
  • [ 541-41-3 ]
  • [ 14719-37-0 ]
Reference: [1] Tetrahedron, 2003, vol. 59, # 51, p. 10173 - 10179
[2] Tetrahedron Letters, 2016, vol. 57, # 9, p. 990 - 992
  • 17
  • [ 4530-20-5 ]
  • [ 31972-52-8 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1986, vol. 59, p. 3553 - 3558
[2] Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 8, p. 2433 - 2438
[3] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1985, p. 535 - 540
[4] Journal of Medicinal Chemistry, 1980, vol. 23, # 10, p. 1113 - 1122
[5] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 12, p. 4448 - 4456
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 803 - 808
[7] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 11B, p. 2787 - 2790
[8] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 9, p. 2357 - 2359
[9] Tetrahedron Letters, 1976, p. 2119 - 2120
[10] Molecular Pharmaceutics, 2011, vol. 8, # 4, p. 1224 - 1232
[11] Polymer, 2012, vol. 53, # 8, p. 1694 - 1702
[12] Science China Chemistry, 2013, vol. 56, # 2, p. 159 - 168
[13] International Journal of Pharmaceutics, 2014, vol. 468, # 1-2, p. 133 - 141
[14] Organic Letters, 2015, vol. 17, # 16, p. 4106 - 4109
[15] Chemical Biology and Drug Design, 2016, vol. 88, # 6, p. 884 - 888
[16] Patent: CN106749223, 2017, A,
[17] Chemistry - An Asian Journal, 2018, vol. 13, # 4, p. 400 - 403
[18] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1112 - 1119
  • 18
  • [ 4530-20-5 ]
  • [ 74-88-4 ]
  • [ 42492-57-9 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 39, p. 11954 - 11962
[2] Journal of Natural Products, 2003, vol. 66, # 2, p. 183 - 199
  • 19
  • [ 4530-20-5 ]
  • [ 35150-09-5 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere
Stage #2: With 2,2,2-Trichloroethyl chloroformate In tetrahydrofuran for 0.5 h; Inert atmosphere
Stage #3: With ammonium hydroxide In tetrahydrofuran at 20℃; for 16 h; Inert atmosphere
To a solution of Boc-Gly-OH (1.00 g, 5.70 mmol) in dry THF (16.0 mL) was added DIPEA (1.2 mL, 6.84 mmol) under N2 at 0 C. The reaction mixture was stirred at 0 C for 30 minutes before 2,2,2-trichloroethyl chloroformate (0.94 mL, 6.84 mmol) was added rapidly and continued stirring for 30 minutes. Then aqueous NH3 solution (2.0 mL) in THF (2.0 mL) was added. The resulting reaction mixture was allowed to reach room temperature and stirred for additionally 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc (40 mL) and H2O (40 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (30 mL), water (30 mL), brine (30 mL); dried with MgSO4 and concentrated in vacuo. The crude was purified by column chromatography on silica gel to obtain glycineamide (798 mg, 80 percent) as colorless oil.
24% With dmap; ammonium hydroxide; benzotriazol-1-ol In dichloromethane (1)
(Carbamoylmethyl)carbamic acid t-butyl ester
To a solution of N-(t-butoxycarbonyl)glycine (3.01 g, 17.2 mmol) in anhydrous methylene chloride (150 ml) were added 1-hydroxybenzotriazole (4.63 g, 34.3 mmol), WSC (6.60 g, 34.4 mmol) and 4-dimethylaminopyridine (210 mg, 1.72 mmol) in an ice bath.
The mixture was stirred at room temperature under an atmosphere of nitrogen overnight.
After checking the completion of the reaction, 28percent aqueous ammonia solution was added thereto and resulting mixture was stirred for 15 minutes.
After checking the completion of the reaction, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution.
The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (10: 1) as the eluant to afford (carbamoylmethyl)carbamic acid t-butyl ester (717.7 mg, yield 24percent) as a colorless and transparent syrup.
1H-NMR (400 MHz, CDCl3): δ(ppm) 6.202 (1H, br s), 5.763 (1H, br s), 5.267 (1H, br t, J-5.1 Hz), 3.820 (2H, d, J=5.1Hz), 1.456 (9H, s).
20% With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16 h; To a stirring solution of 2S-M (10 g, 57.14 mmol) in CH2C12 (100 mL) were added HOBt (15.43 g, 114 mmol), EDCI.HC1 (21.8 g, 1 14 mmol) followed by NH4C1 (4.54 g, 85.71 mmol) and DIPEA (30.7 mL, 171 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (2 x 100 mL). Organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography eluting with 2percent MeOH/CH2Cl2. After compound was triturated with ether (25 mL) and the precipitated solid was filtered to afford 2S-N (2 g, 20percent) as white solid. H-NMR: (500 MHz, DMSO-i/6): δ 7.52 (br s, 1H), 7.17 (br s, 1H), 3.46 (d, J = 6.5 Hz, 2H), 1.38 (s, 9H);
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 834 - 864
[2] Tetrahedron, 2018, vol. 74, # 15, p. 1951 - 1956
[3] Tetrahedron Letters, 2005, vol. 46, # 40, p. 6879 - 6882
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4994 - 4997
[5] Tetrahedron Letters, 2003, vol. 44, # 39, p. 7325 - 7328
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 2007, vol. 182, # 3, p. 657 - 666
[7] Patent: EP1340757, 2003, A1,
[8] Patent: WO2014/120783, 2014, A1, . Location in patent: Paragraph 00132
[9] Monatshefte fuer Chemie, 1974, vol. 105, p. 1110 - 1135
[10] Synthesis, 1988, # 3, p. 259 - 261
[11] Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11272 - 11273
[12] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 3, p. 601 - 607
[13] Synthesis, 1989, # 1, p. 37 - 38
[14] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[15] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[16] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6828 - 6831,4
[17] Amino Acids, 2013, vol. 44, # 3, p. 977 - 982
[18] Journal of Chemical Research, 2016, vol. 40, # 2, p. 101 - 106
[19] Patent: CN103601742, 2016, B, . Location in patent: Paragraph 0117-0119
[20] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 401 - 406
  • 20
  • [ 4530-20-5 ]
  • [ 6148-64-7 ]
  • [ 67706-68-7 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20 - 30℃; for 2 h;
Stage #2: With magnesium chloride In tetrahydrofuran at 60℃; for 1 h;
(1)
Carbonyldiimidazole (10.2 g, 63.1 mmol) was added to a suspension of 2-(tert-butoxycarbonylamino)acetic acid (10 g, 57.1 mmol) in THF (100 ml) and the mixture was stirred at room temperature for 2 hours.
To the reaction solution were added magnesium chloride (5.4 g, 57.1 mmol) and potassium monoethylmalonate (9.7 g, 57.1 mmol) and the mixture was stirred at 60°C for 1 hour.
The mixture was filtered to remove insoluble substances.
The filtrate was diluted with ethyl acetate (200 ml), washed with 1N hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography [developing solvent: hexane-ethyl acetate (2:1)] to obtain ethyl 4-(tert-butoxycarbonylamino)-3-oxobutanoate (11.9 g, 48.5 mmol, 85percent) as a colorless oil.
1H-NMR (CDCl3) δ: 1.29 (3H, t, J = 7.4 Hz), 1.45 (2H, s), 3.87 (2H, s), 3.96 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 7.08 (1H, d, J = 8.7 Hz), 7.39 (9H, s), 3.49 (2H, s), 4.14 (2H, d, J = 5.8 Hz), 4.21 (2H, q, J = 7.4 Hz), 5.15-5.24 (1H, br).
75%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 30℃; for 4 h;
Stage #2: With triethylamine; magnesium chloride In tetrahydrofuran at 30℃; for 76 h;
To a solution of [(fert-butoxycarbonyl)amino]acetic acid (47 g, 268 mmol) in THF (470 mL) was added CDI (47.6 g, 294 mmol), and the resulting solution was allowed to stir at 30°C for 4 h. Treatment of potassium 3-ethoxy-3-oxopropanoate (54.6 g, 321 mmol) with magnesium chloride (35.7 g, 375 mmol) and TEA (40.6 g, 402 mmol) in THF (540 mL) at 30°C for 4 h generated the dianion as its magnesium chelate. To this solution was added the imidazolide solution, and a gummy precipitate began to form immediately. After stirring at 30°C for 72 h, the reaction was poured into ice-cold 1 M HCl aqueous solution (1000 mL) and extracted with EtOAc (800 mL χ 2). The combined organic layers was washed with saturated NaHC03 aqueous solution (800 mL) and brine (800 mL), was dried over Na2S04, filtered and concentrated to give crude product. Purification by column chromatography gave ethyl 4-[(tert- butoxycarbonyl)amino]-3-oxobutanoate (49 g, 75percent yield) as a red oil. 1H NMR (400 MHz, CDC13) δ 5.18 (br s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.11-4.14 (m, 2H), 3.48 (s, 2H), 1.45 (s, 9H), 1.29 (t, J = 6.8 Hz, 3H).
Reference: [1] Organic Letters, 2005, vol. 7, # 2, p. 215 - 218
[2] Patent: EP1650201, 2006, A1, . Location in patent: Page/Page column 23-24
[3] Patent: WO2016/118565, 2016, A1, . Location in patent: Paragraph 00399
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 487 - 501
  • 21
  • [ 4530-20-5 ]
  • [ 67706-68-7 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 20, p. 4531 - 4536
[2] Journal of Organic Chemistry, 2011, vol. 76, # 22, p. 9444 - 9451
[3] Patent: US2010/152206, 2010, A1,
  • 22
  • [ 4530-20-5 ]
  • [ 35116-15-5 ]
  • [ 67706-68-7 ]
Reference: [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1978, vol. 32, p. 187 - 192
  • 23
  • [ 4530-20-5 ]
  • [ 45121-22-0 ]
Reference: [1] Journal of the American Chemical Society, 1997, vol. 119, # 4, p. 656 - 673
  • 24
  • [ 4530-20-5 ]
  • [ 75-03-6 ]
  • [ 149794-10-5 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h;
Stage #2: at 0℃;
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton- Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was EPO <DP n="134"/>added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With citric acid In water
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 <n="72"/>min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 °C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate -hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With citric acid In water
Example 10 N-Boc-N-methyl-L-glycine; Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pert, M.; Xu, J. Tetrahedron, 2002, 55, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 °C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes.This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100% With sodium hydride In tetrahydrofuran at 0 - 20℃; Example 29a b c Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.

Reference: [1] Patent: WO2006/69063, 2006, A1, . Location in patent: Page/Page column 132-133
[2] Patent: WO2007/106192, 2007, A2, . Location in patent: Page/Page column 70; 71
[3] Patent: WO2008/79735, 2008, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2008/134679, 2008, A1, . Location in patent: Page/Page column 94
[5] Journal of the American Chemical Society, 1993, vol. 115, # 10, p. 4228 - 4245
[6] Patent: WO2010/21934, 2010, A2, . Location in patent: Page/Page column 44
[7] Patent: US2011/46066, 2011, A1,
  • 25
  • [ 4530-20-5 ]
  • [ 75-03-6 ]
  • [ 149794-10-5 ]
YieldReaction ConditionsOperation in experiment
39.9%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.166667 h;
Stage #2: at 60℃; for 10 h;
Stage #3: With citric acid In water; ethyl acetate
General procedure: A suspension of NaH in mineral oil (40 mmol) was added to a stirred solution of Nα-Boc-Nα-alkylamino acid (10 mmol) in anhydrous THF (30 mL), and the mixture was stirred at 20 °C for 10 min. Then alkyl iodide (100 mmol) was added, and the mixture was stirred at 60 °C for 10 h, and maintained at rt overnight. The solvent was removed under vacuum, the residue partitioned in a mixture of ethyl acetate (100 mL) and water (25 mL), and acidified with citric acid to pH 3. The organic phase was separated, washed with saturated aqueous NaCl, containing 1percent of Na2S2O3, and dried over anhydrous MgSO4. After evaporation of ethyl acetate, the residue was loaded on Al2O3 (30 g), and eluted consecutively with heptane (to remove mineral oil), eluent A (for Boc-Xaa-OAlk), and finally, with eluent L (for Boc-Xaa-OH). The fractions were evaporated under vacuum. The traces of acetic acid from eluent L were removed by the azeotrope distillation with toluene under reduced pressure. The products were dried in a desiccator under the residual pressure of 0.13-0.26 kPa.
Reference: [1] Tetrahedron, 2012, vol. 68, # 35, p. 7070 - 7076
  • 26
  • [ 4530-20-5 ]
  • [ 53267-93-9 ]
  • [ 37169-36-1 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 74, p. 60354 - 60364
  • 27
  • [ 4530-20-5 ]
  • [ 174799-52-1 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4131 - 4134
  • 28
  • [ 4530-20-5 ]
  • [ 142121-48-0 ]
Reference: [1] Tetrahedron Letters, 1988, vol. 29, # 11, p. 1265 - 1268
  • 29
  • [ 4530-20-5 ]
  • [ 1117-97-1 ]
  • [ 121505-93-9 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With triethylamine In dichloromethane at 20℃; for 12 h;
Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12 h;
To a stirred solution of (tert-butoxycarbonyl)glycine (HN, 5.0 g, 28.57 mmol) and triethylamine (4.1 mL, 31.42 mmol) in DCM (80 mL) was added N,0-dimethylhydroxylamine (3.0 g, 31.42 mmol) followed by DCC (6.5 g, 31.42 mmol) in DCM (20 mL) and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure to yield the crude compound which was purified by silica gel column chromatography using 10percent EtOAc/hexane to afford compound HO (6.0 g, 97.0percent) as an off-white solid. 1H NMR (400 MHz, CDC13): _ 5.27 (brs, 1H), 4.08 (brs, 2H), 3.72 (s, 3H), 3.21 (s, 3H), 1.46 (s, 9H).
91%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 0.5 h;
Stage #2: With triethylamine In dichloromethane at 20℃;
General procedure: This procedure has been carried out according to the following article: J. Am. Chem. Soc.,1999, 121 (13), pp 2974–2986.To a stirred solution of the corresponding Boc-protected amino acid (Boc-D-Ala-OH, Boc-LAla-OH or Boc-Gly-OH) (1.00 equiv) in anhydrous dichloromethane (0.3 M) at 0°C wasadded 1,1’-carbonyldiimidazole (1.40 equiv). After 30 min at 0°C, Et3N (1.40 equiv) and N,Odimethylhydroxylamine(1.40 equiv) were added. After 30 min, the reaction was stirred at r.tovernight. Et2O (for each 1.00 mmol of protected amino acid, add 6.70 mL of Et2O) wasadded and the organic layer was washed (x3) with a solution of HCl (1N) (for each 1.00mmol of protected amino acid, wash with 2.50 mL of HCl 1N), saturated solution of NaHCO3,brine and dried over MgSO4, filtered and concentrated to give the desired product ascolorless solid yield without further purification.
Reference: [1] Patent: WO2018/165520, 2018, A1, . Location in patent: Page/Page column 226-227
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 12, p. 2180 - 2183
[3] Journal of Organic Chemistry, 2006, vol. 71, # 17, p. 6678 - 6681
[4] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 1393 - 1397
[5] Arzneimittel-Forschung/Drug Research, 1989, vol. 39, # 4, p. 432 - 437
[6] Synthetic Communications, 1988, vol. 18, # 18, p. 2273 - 2280
[7] Tetrahedron Letters, 1999, vol. 40, # 45, p. 7925 - 7928
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 8, p. 1624 - 1632
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 23, p. 5790 - 5806
  • 30
  • [ 4530-20-5 ]
  • [ 6638-79-5 ]
  • [ 121505-93-9 ]
YieldReaction ConditionsOperation in experiment
96% With dmap; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0℃; for 24 h; N-Boc-Gly-OH (10.5 g, 60.0 mmol), N, O-dimethylhydroxylamine hydrochloride (11.1 g, 120 mmol) and DIEA (31.2 g, 240 mmol) were dissolved in 1:1 1 CH2C12/DMF (500 mL) and cooled to 0 °C. 1-Hydroxy-1H- benzotriazole (HOBt, 11.0 g, 72.0 mmol), DCC (14.9 g, 72.0 mmol) and DMAP (ca. 100 mg) were added and the reaction was stirred for 24 h. The reaction was filtered to remove dicyclohexylurea and concentrated. The resulting slurry was diluted with 500 mL ethyl acetate and washed with NH4C1 (2 x 100 mL), NaHC03 (2 x 100 mL) and brine (100 mL). The organic layer was dried on MgS04 and concentrated. Chromatography on silica with 20percent EtOAc in hexane gave 12.6 g (96percent) of 4 as a colorless plate-like crystal. m.p. 101-102 °C. 1H NMR 8 5.25 (br, s, 1H), 4.07 (d, J=3.7, 2H), 3.70 (s, 3H), 3.19 (s, 3H), 1.44 (s, 9H).
94%
Stage #1: With dmap; triethylamine In dichloromethane at 0℃; for 1.5 h; Large scale
Stage #2: at 0 - 24℃; for 25 h; Large scale
To a solution of Boc-Gly-OH (4250g, 24.26 mol), Ν,Ο-dimethylhydroxylamine- HCl(2839g, 29.10 mol) and DMAP(297g, 2.43 mol) in dichloromethane(36 L), is added triethylamine (5.54 L) at 0 °C over a period of 90 min followed by the addition of EDC hydrochloride (5674g, 29.60 mol). The mixture is stirred at 0 °C for lh then warmed to room temp for 24 h. The reaction mixture is cooled to 0 °C and quenched with 1.0M HC1 to pH 3 to 4, stirred at room temp for 20 min, then allowed to stand and separate. The organic phase is washed successively with 1.0M HC1 (15L), water (15.0 L) and brine (8.0 L), dried over Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure to provide the title compound (4985 g; 94percent yield) as a white solid
90% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Boc-glycine was coupled with N,O-dimethyl hydroxylamine hydrochloride, 1 equivalent, in DMF/CH2Cl2 (1:5) using HBTU reagent (1 eq.) and DIEA (2 eq.) at room temperature. The CH2Cl2 was evaporated in vacuo and the residue partitioned between diethyl ether and aq. NaHCO3. The aqueous layer was separated and the ether layer washed in turn with 1M HCl (.x.2), aq. NaHCO3, brine, and then dried over MgSO4. Filtration and removal of the solvent in vacuo left the product amide 69 as a viscous oil that slowly crystallised to a waxy solid and was further purified by chromatography on silica gel. Yield was >90percent. 1H NMR (300 MHz, CDCl3): δ 5.3, 1H, bs, NH; 4.09, 2H, bd, aH2; 3.72, 3H, s, OCH3; 3.20, 3H, s, NCH3; 1.46, 9H, s, Boc. 13C NMR (75 MHz, CDCl3): δ 79.6; 61.4; 41.7; 32.4; 28.3.
90% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 72.5 h; Step 1: To a suspension of /V-(ie f-butoxycarbonyl)glycine (4.0 g, 23 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and /V,/V-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2CI2 (100 ml.) was added /V-(3-dimethylaminopropyl)-/V'- ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0 °C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCI (1 M, 2 x 40 mL) followed by a saturated aqueous solution of NaHC03 (2 x 40 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to yield fe/f-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90percent). 1H-NMR (400 MHz, CDCI3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
82% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15 h; Inert atmosphere Preparation Example 15fe -Butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (45)To a mixture of N-Boc-glycine 44 (10.0 g, 57.1 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (6.68 g, 68.5 mmol), EDCI (13.1 g, 68.5 mmol), and HOBt (9.26 g, 68.5 mmol) in CH2C12 (200 mL) was added NMM (31.4 mL, 285 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 1.0 M HC1 solution, and extracted with EtOAc. The organic phase was washed with a saturated NaHC03 solution and brine, and then dried over anhydrous MgS04. After evaporation of solvent, the residue was triturated with hexanes (100 mL) to provide the Weinreb amide 45 (10.2 g, 82percent) as white solid.
80% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h; Example 54 - Synthesis of Compound 49 tert-butyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate (Boc-Gly Weinreb amide)49 tert-butyl 2-(methoxy(methyl)amino)- 2-oxoethylcarbamateTo a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 ml_, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 ml.) was added a pre-mixed solution of N,O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 ml_, 114.1 mmol) in DCM (20 ml.) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 ml_), H2O (3 x 120 ml_), saturated NaHCO3 aqueous solution (3 x 120 ml_) and brine (40 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to give 49 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min.
80% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h; To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N, O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 mL), H2O (3 x 120 mL), saturated NaHCO3 aqueous solution (3 x 120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 34 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min.
80% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h; To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature.
The resulting mixture was stirred for 16 h then washed with 1N HCl (3*120 mL), H2O (3*120 mL), saturated NaHCO3 aqueous solution (3*120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 49 as a white solid (20 g, 80percent), which was used in the next step without further purification.
MS (ESI) 219 (M+1); HPLC tR 4.12 min.
80%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -25℃; for 0.5 h;
Stage #2: at -25℃; for 5 h;
N-Boc-Gly-OH (20 mmol) was dissolved in CH2Cl2(100 mL) and cooled to 25 °C. NMM (44 mmol) and isobutyl chloroformate(22 mmol) were added. After stirring for 30 min, N,O-dimethylhydroxylaminehydrochloride (22 mmol) was added at 25 °C. After 5 h, the reaction mixturewas washed with 10percent KHSO4 (2 100 mL), sat. NaHCO3 (2 100 mL) and H2O(1 100 mL), dried over Na2SO4 and evaporated. The obtained yellowish solidwas purified by column chromatography using CH2Cl2/EtOAc (1+1) to give 1 asa white solid (80percent). mp 102–104 C (lit. 102–103 C);36 1H NMR (500 MHz,DMSO-d6) d 1.37 (s, 9H), 3.08 (s, 3H), 3.66 (s, 3H), 3.81 (d, 3J = 6.0 Hz, 2H), 6.79(t, 3J = 6.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) d 28.31, 32.23, 40.95, 61.21,78.05, 156.00, one carbon signal (CH2CO) is missing; LC-MS (ESI) (90percent H2O to100percent MeOH in 10 min, then 100percent MeOH for 10 min, DAD 200.0–400.0 nm): tr =8.16 min, 96percent purity, m/z= 219.2 ([M+H]+).
77%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.5 h;
Stage #2: at 20℃; for 12 h;
Example 33 (Compound 46) Step 1; N-tert-Butoxycarboxylglycine (10.0 g, 57.1 mmol) was dissolved in THF (100 mL). To the solution was added CDI (14.3 g, 59.0 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,O-dimethylhydroxylamine hydrochloride (6.2 g, 64.0 mmol), and the mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give [(methoxymethylcarbamoyl)methyl]carbamic acid tert-butyl ester (9.55 g, yield: 77percent). APCI-MS m/z: 218 [M+H]+.
72%
Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1 h; Inert atmosphere
Stage #2: With dmap; benzotriazol-1-ol In dichloromethane; N,N-dimethyl-formamide at 20 - 27℃; for 16 h;
Intermediate 83, [(teit-butoxycarbonyl)amino]acetic acid (5.00 g, 28.5 mmol), DIPEA (14.75 g, 104 mmol) and Intermediate 84, N-methoxymethanamine hydrochloride (5.60 g, 57.0 mmol)were dissolved in DCM (100 mL) and DMF (100 mL) and Intermediate 85, EDC hydrochloride (6.56 g, 34.0 mmol) was added. The reaction mixture was stirred under nitrogen at 0 °C for 1 h, then Intermediate 86, HOBt (4.63 g, 34.0 mmol) and DMAP (100 mg) were added portionwise and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between H20 (250 mL) and DCM (100 mL), and the aqueous layer was furtherextracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filteredand the solvent was removed in vacuo. The residue was purified by column chromatography(Normal-Phase Silica, 0 to 3 percent methanol in DCM) to give tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (4.50 g, 72 percent) as a solid.LCMS (Method F): mlz 219 (M+H) (ES), at 1 .77 mi UV active.
71% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 2-(tert-Butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol) and HOBt (740 mg, 5.48 mmol) were dissolved in DCM (25 mL), to which NMM (2.77 g, 27.42 mmol) was added at room temperature. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase preparative HPLC to provide the desired product (705 mg, 71percent) as a white solid1H NMR (400 MHz, CDCl3) δ 5.27 (br, 1H), 4.09 (d, J=4.6 Hz, 2H), 3.72 (s, 3H), 3.21 (s, 3H) 1.46 (s, 9H).MH+219.
6 g
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25 h; Cooling with ice
Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
A mixture of Boc-glycine (8.75g, 50mmol, 1 equiv), EDCI (11.5g, 60mmol) and HOBt (7.43g, 55mmol) in DCM (100ml) was stirred in an ice bath for 15min to give a clear solution. Then N,O-Dimethylhydroxylamine hydrochloride (5.1g, 52.5mmol) and triethylamine (5.85ml, 55mmol) were added and the mixture was stirred for 2h at room temperature. Water (100ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give F1 (6.0g) as a crystal.
6.0 g
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25 h;
Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
A mixture of l3oc-glycine (8.75 g, 50 mmol, 1 equiv), EDCI (11.5 g, 60 mmol) and HOSt (7.43 g, 55 mmol) in DCM (100 ml) was stirred in an ice bath for 15 mm to give a clear solution. Then N,O-Dimethylhydroxylamine hydrochloride (5.1 g, 52.5 mmol) and triethylamine (5.85 ml, 55 mmol) were added and the mixture was stirred for 2 h at room temperature. Water (100 ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2C12 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give Fl (6.0 g) as a crystal.

Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 65 - 77
[2] Tetrahedron, 2002, vol. 58, # 9, p. 1719 - 1737
[3] Patent: WO2005/105138, 2005, A2, . Location in patent: Page/Page column 15-16
[4] Patent: WO2014/66151, 2014, A1, . Location in patent: Page/Page column 12
[5] Patent: US2011/40087, 2011, A1, . Location in patent: Page/Page column 15
[6] Patent: WO2011/94823, 2011, A1, . Location in patent: Page/Page column 126-127
[7] Organic Letters, 2004, vol. 6, # 25, p. 4699 - 4702
[8] Journal of the American Chemical Society, 2006, vol. 128, # 51, p. 16456 - 16457
[9] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 4, p. 303 - 306
[10] Tetrahedron, 2009, vol. 65, # 20, p. 4025 - 4034
[11] Patent: WO2011/159067, 2011, A2, . Location in patent: Page/Page column 58
[12] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8963 - 8981
[13] Patent: WO2010/96853, 2010, A1, . Location in patent: Page/Page column 96
[14] Patent: WO2010/96854, 2010, A1, . Location in patent: Page/Page column 102
[15] Patent: US2012/141392, 2012, A1, . Location in patent: Page/Page column 53
[16] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2008 - 2012
[17] Journal of Medicinal Chemistry, 1995, vol. 38, # 2, p. 223 - 233
[18] Patent: EP1671957, 2006, A1, . Location in patent: Page/Page column 36-37
[19] Patent: WO2017/21730, 2017, A1, . Location in patent: Page/Page column 54
[20] Patent: US2008/207704, 2008, A1, . Location in patent: Page/Page column 19
[21] Journal of Medicinal Chemistry, 1996, vol. 39, # 2, p. 446 - 457
[22] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 10, p. 1501 - 1510
[23] Tetrahedron Letters, 1998, vol. 39, # 39, p. 6993 - 6996
[24] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 16, p. 2359 - 2364
[25] Tetrahedron, 2006, vol. 62, # 8, p. 1787 - 1798
[26] Organic Letters, 2002, vol. 4, # 16, p. 2665 - 2668
[27] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1932 - 1938
[28] Patent: US2009/221557, 2009, A1, . Location in patent: Page/Page column 116
[29] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5614 - 5617
[30] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 8119 - 8133
[31] Patent: US2013/289020, 2013, A1, . Location in patent: Paragraph 0195; 0196
[32] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 1254 - 1264
[33] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0552
[34] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0915
[35] European Journal of Organic Chemistry, 2014, vol. 2014, # 15, p. 3067 - 3071
  • 31
  • [ 4530-20-5 ]
  • [ 121505-93-9 ]
Reference: [1] European Journal of Medicinal Chemistry, 1991, vol. 26, # 9, p. 921 - 928
[2] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6209 - 6217
[3] Patent: US2013/53362, 2013, A1, . Location in patent: Paragraph 1013; 1014
  • 32
  • [ 4530-20-5 ]
  • [ 121505-93-9 ]
Reference: [1] Journal of the Chemical Society, Dalton Transactions, 2001, # 23, p. 3478 - 3488
  • 33
  • [ 4530-20-5 ]
  • [ 75-65-0 ]
  • [ 111652-20-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 13, p. 2770 - 2779
[2] Organic Syntheses, 2016, vol. 93, p. 37 - 49
  • 34
  • [ 4530-20-5 ]
  • [ 28334-73-8 ]
Reference: [1] Helvetica Chimica Acta, 1993, vol. 76, # 1, p. 563 - 595
[2] Tetrahedron Letters, 2012, vol. 53, # 45, p. 6148 - 6150,3
[3] Tetrahedron Letters, 2012, vol. 53, # 45, p. 6148 - 6150
[4] Supramolecular Chemistry, 2013, vol. 25, # 5, p. 269 - 275
[5] Patent: WO2016/65174, 2016, A1,
[6] Chemistry - An Asian Journal, 2018, vol. 13, # 4, p. 400 - 403
  • 35
  • [ 4530-20-5 ]
  • [ 170384-29-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 12, p. 2180 - 2183
  • 36
  • [ 4530-20-5 ]
  • [ 15761-38-3 ]
  • [ 13734-34-4 ]
  • [ 15260-10-3 ]
  • [ 23680-31-1 ]
  • [ 18942-46-6 ]
  • [ 54613-99-9 ]
  • [ 13139-14-5 ]
  • [ 65420-40-8 ]
  • [ 38916-34-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 17, p. 5981 - 5987
  • 37
  • [ 4530-20-5 ]
  • [ 120871-73-0 ]
Reference: [1] Patent: WO2012/58065, 2012, A1,
Historical Records

Similar Product of
[ 4530-20-5 ]

Chemical Structure| 106665-75-2

A520943[ 106665-75-2 ]

Boc-[15n]gly-oh

Reason: Stable Isotope

Chemical Structure| 97352-64-2

A491114[ 97352-64-2 ]

N-(tert-butoxycarbonyl)glycine-1-13c

Reason: Stable Isotope

Chemical Structure| 145143-02-8

A158054[ 145143-02-8 ]

N-(tert-butoxycarbonyl)glycine-2-13c

Reason: Stable Isotope

Chemical Structure| 145143-01-7

A418158[ 145143-01-7 ]

N-(tert-butoxycarbonyl)glycine-2-13c-15n

Reason: Stable Isotope

Related Functional Groups of
[ 4530-20-5 ]

Amino Acid Derivatives

Chemical Structure| 31954-27-5

[ 31954-27-5 ]

Boc-Gly-OMe

Similarity: 0.95

Chemical Structure| 111652-20-1

[ 111652-20-1 ]

Boc-Gly-OtBu

Similarity: 0.93

Chemical Structure| 14719-37-0

[ 14719-37-0 ]

ethyl 2-((tert-Butoxycarbonyl)amino)acetate

Similarity: 0.93

Chemical Structure| 13734-36-6

[ 13734-36-6 ]

N-(tert-Butoxycarbonyl)-N-methylglycine

Similarity: 0.91

Chemical Structure| 3744-87-4

[ 3744-87-4 ]

Boc-DL-Ala-OH

Similarity: 0.89