EXAMPLE 12 This example illustrates the synthesis of sulpiride with using as the condensation reagent N-succinimidyl diphenylphosphate (SDPP) which is prepared from N-hydroxysuccinimide (HOSu) and diphenylphospholy chloride. A solution of 462 mg (0.002 mol) of 2-methoxy-5-aminosulfonylbenzoic acid and 256 mg (0.002 mol) of N-ethyl-2-aminomethylpyrrole in 10 ml of acetonitrile was admixed with 694 mg (0.002 mol) of SDPP and 202 mg (0.002 mol) of triethylamine, and the admixture was stirred overnight at room temperature. The crystalline material deposited was collected by filtration and washed with acetonitrile and then with ethanol to give sulpiride, that is, 5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-2-methoxybenzamide. mp. 182°~185° C. Yield 24percent.
Reference：
[1] Patent: US4341707, 1982, A,
2
[ 6066-82-6 ]
[ 15761-38-3 ]
[ 3392-05-0 ]
Reference：
[1] Journal of Pharmaceutical Sciences, 1987, vol. 76, # 2, p. 134 - 140
[2] Chemical and pharmaceutical bulletin, 2002, vol. 50, # 2, p. 239 - 252
[3] Journal of the Chemical Society, Chemical Communications, 1985, # 8, p. 473
[4] Carbohydrate Research, 1984, vol. 132, p. 275 - 286
[5] Journal of the American Chemical Society, 1992, vol. 114, # 17, p. 6653 - 6661
[6] Journal of the American Chemical Society, 1996, vol. 118, # 29, p. 6975 - 6985
[7] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2386 - 2397
[8] Chemistry of Natural Compounds, 1997, vol. 33, # 5, p. 568 - 570
[9] Chemistry of Natural Compounds, 1998, vol. 34, # 1, p. 78 - 79
[10] Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4543 - 4551
[11] Patent: EP2123283, 2009, A1, . Location in patent: Page/Page column 17-18
[12] Patent: US2009/325894, 2009, A1, . Location in patent: Page/Page column 11-12
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3220 - 3224
[14] Biomacromolecules, 2010, vol. 11, # 2, p. 496 - 504
[15] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4182 - 4187
[16] Synlett, 2012, # 1, p. 142 - 144
[17] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1443 - 1446
[18] Biochimie, 2013, vol. 95, # 6, p. 1120 - 1126
[19] Chinese Chemical Letters, 2016, vol. 27, # 3, p. 357 - 360
[20] Patent: EP2612857, 2017, B1, . Location in patent: Paragraph 0137
[21] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
3
[ 6066-82-6 ]
[ 3744-87-4 ]
[ 3392-05-0 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 2005, vol. 70, # 10, p. 1615 - 1641
4
[ 30364-57-9 ]
[ 56-40-6 ]
[ 6066-82-6 ]
[ 13214-64-7 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3583 - 3586
5
[ 6066-82-6 ]
[ 501-53-1 ]
[ 13139-17-8 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1987, vol. 96, # 10, p. 775 - 782
[2] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 7, p. 2409 - 2418
[3] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1489 - 1490
[4] Organic Preparations and Procedures International, 2002, vol. 34, # 5, p. 531 - 537
[5] Patent: US3974137, 1976, A,
6
[ 6066-82-6 ]
[ 3303-84-2 ]
[ 32703-87-0 ]
Yield
Reaction Conditions
Operation in experiment
62%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane at 20℃; Inert atmosphere
In a dry flask containing a magnetic stir bar, 0.50 g of 1 (2.64 mmol) and 0.31 g of N-hydroxysuccinimide (SuOH) (2.72 mmol, 1.03 equivalent) were dissolved in 3mL of distilled dioxane. Subsequently, 1.25 equivalent of 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-l-amine in hydrogen chloride form (EDC) (0.63 g, 3.3 mmol) was added into the flask. The solution was cloudy, and 2mL of freshly distilled dioxane was added into the reaction mixture. The reaction mixture was stirred under nitrogen for 30 minutes and then left for stirring overnight at room temperature. Dioxane was removed under vacuum. The residue was dissolved in chloroform and washed with water (3x). The organic layer was dried of over Na2S04 and concentrated under vacuum. The desire product was precipitated in ethanol and dried in a desiccator, yielding 0.47g of product (62percent). The 1H NMR spectral data matched the previously reported values for the compound.
Reference：
[1] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 6, p. 557 - 561
[2] Patent: WO2017/53486, 2017, A1, . Location in patent: Page/Page column 11
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 529 - 537
[4] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 24, p. 3603 - 3608
[5] Chemical Communications, 2010, vol. 46, # 20, p. 3553 - 3555
[6] Patent: WO2011/133875, 2011, A2, . Location in patent: Page/Page column 46-47
[7] Patent: WO2013/110002, 2013, A1, . Location in patent: Page/Page column 45-46
[8] Patent: WO2013/109998, 2013, A1, . Location in patent: Page/Page column 45
[9] Bioconjugate Chemistry, 2018, vol. 29, # 4, p. 1454 - 1465
7
[ 6066-82-6 ]
[ 624-83-9 ]
[ 18342-66-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With triethylamine In ethyl acetate at 0 - 20℃; for 24 h;
A dried round-bottom flask was charged with N-hydroxysuccinimide (5.83 g, 50.7 mmol), ethyl acetate (20 mL) as a solvent and cooled at 0 °C. To the mixture were slowly added triethylamine (4.76 g) and methylisocyanate (6.39 g, 0.112 mmol) at the same temperature. The reaction temperature was slowly raised to rt, and the mixture was stirred for 24 h at rt. After the volatile materials were removed under reduced pressure the crude residue was re-crystallized from ethyl acetate/diethyl ether to give 51a (86 percent). Colorless needles, mp 148.0–149.0 °C (lit [19]. 148.0–152.0°C); 1H NMR (300 MHz, CDCl3): δ 8.15 (1H, br, NH), 2.76 (4H, s, CH2CH2), 2.67 (3H, s-like, CH3); 13C NMR (22.5 MHz, CDCl3): δ 170.66, 151.98, 27.98, 25.47; MS (FAB+) m/z 173 (M+H).
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 82, p. 16 - 35
[2] Journal of Medicinal Chemistry, 1982, vol. 25, # 2, p. 178 - 182
[3] Journal of the American Chemical Society, 1995, vol. 117, # 4, p. 1240 - 1245
8
[ 6066-82-6 ]
[ 79-04-9 ]
[ 27243-15-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
With triethylamine In chloroform at 0℃; for 0.416667 h;
To a solution of N-hydroxysuccinimide (640.3 mg, 5.56 mmol) in chloroform (8.5 mL) was added triethylamine (861.6 μ, 6.18 mmol) 0 C. Then, a-chloroacetyl chloride was added dropwise over a 5 minute period and stirred for an additional 20 minutes at 0°C. The reaction mixture was washed with ice-cold water (15 mL) and brine (15 mL), concentrated to a volume of 1.7 mL in vacuo, then dried with sodium sulfate and filtered. To the resulting solution were added ethyl acetate (170 μ) and hexanes (1.2 mL), and the mixture was cooled down to 0 °C stirred for 2 h, and a white solid was precipitated. It was filtered and washed first with ice-cold 10 mL portion of hexanes/ethyl acetate (4: 1), then with 10 mL hexanes/ethyl acetate (9: 1), and finally with hexanes (10 mL, twice). The resulting white solid was dried under house vacuum to yield 2,5-dioxopyrrolidin-l-yl 2-chloroacetate (563.9 mg, 53percent). NMR 400 MHz (CDC13) δ 4.37 (s, 2H), 2.87 (s, 4H).
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 1, p. 199 - 204[2] Angew. Chem., 2013, vol. 126, # 1, p. 203 - 208,6
[3] Patent: WO2014/160200, 2014, A1, . Location in patent: Paragraph 000273
[4] Polish Journal of Chemistry, 1992, vol. 66, # 1, p. 111 - 118
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2380 - 2392
9
[ 6066-82-6 ]
[ 79-11-8 ]
[ 27243-15-8 ]
Reference：
[1] Polish Journal of Chemistry, 2009, vol. 83, # 11, p. 1959 - 1966
[2] Helvetica Chimica Acta, 1996, vol. 79, p. 133 - 136
[3] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 24, p. 3671 - 3676
[4] Patent: US6335437, 2002, B1, . Location in patent: Page column 22
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 11, p. 6156 - 6166
[6] Organic and Biomolecular Chemistry, 2011, vol. 9, # 21, p. 7296 - 7299
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 16, p. 6516 - 6532
10
[ 6066-82-6 ]
[ 65-85-0 ]
[ 23405-15-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 48 h;
General procedure: benzoic acid (0.353 g, 2.89 mmol) was dissolved in 50 mL of dry THF, and N-hydroxysuccinimide (0.40 g, 3.47 mmol) and DCC (0.776 g, 3.76 mmol) were added. The mixture was stirred at room temperature for 2 days. The soluble portion was separated from the viscous residue and the solvent was removed under reduced pressure. The residue was dissolved in CHCl3separated and dried over anhydrous Na2SO4, the solvent was removed by evaporation to dryness. The crude product was purified by column chromatography with 40percent ethyl acetate in hexane to afford a white solid (0.586 g, 93percent). The white solid wasrecrystallized from 2-propanol.
78%
With triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: Benzoic acid (ring d-5, heavy isotope, d-Bz) (127 mg, 1.00 mmol) or benzoic acid (ring d-0, light isotope, Bz) (122 mg, 1.00 mmol), N-hydroxysuccinimide (230 mg, 2.00 mmol) and triethylamine (167 μL, 1.20 mmol) were dissolved in anhydrous dimethylformamide (DMF) (1 mL). After addition of dicyclohexylcarbodiimide (DCC) (206 mg, 1.20 mmol), the solution was stirred at room temperature for 3 h. The reaction mixture was filtered to remove the precipitate, and concentrated in vacuo. The resulting syrup was crystallized from isopropanol (5 mL) to yield benzoic acid N-succinimidyl ester (d-Bz labeling reagent, 184 mg, 82percent) (Bz labeling reagent, 170 mg, 78percent). Rf = 0.42 (toluene-EtOAc = 10:1); 1H-NMR (600 MHz, CDCl3): δ 2.91 (s, 4H) for the heavy isotope, δ 2.91 (s, 4H), 7.52 (dd, 2H), 7.69 (dd, 1H), 8.14 (dd, 2H) for the light isotope; 13C-NMR (125 MHz, CDCl3): δ 25.63, 124.88, 128.31, 130.13, 134.38, 161.82, 169.24 for the heavy isotope, δ 25.65, 125.08, 128.83, 130.55, 134.91, 161.84, 169.23 for the light isotope.
61%
With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 6 h;
Benzoic acid (3 g, 24.6 mmol) and N-hydroxysuccinimide (4.24 g, 36.8 mmol, 1.5 eq) were dissolved in 50 mL CH2Cl2, and the mixture was cooled to 0 °C. To this solution was added 7.6 g of DCC (36.8 mmol, 1.5 eq) in 25 mL CH2Cl2. The reaction mixture was stirred vigorously for 6 h. After filtration, the solvent was evaporated, and the crude product was purified by column chromatography to afford 7 as a white solid with a yield 61percent. m.p.:134-136 °C.1H NMR (400 MHz, CDCl3): δ 8.14 (400 MHz, d, J = 7.8 Hz, 2H, Ar-H), 7.69 (t, J = 7.4 Hz, 1H, Ar-H), 7.52 (t, J = 7.7 Hz, 2H, Ar-H), 2.91 (s, 4H, CH2).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 1, p. 124 - 127
[2] Chemistry Letters, 1980, p. 1161 - 1164
[3] Bulletin of the Chemical Society of Japan, 1984, vol. 57, # 3, p. 781 - 786
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4629 - 4632
[5] Journal of the Chemical Society, Chemical Communications, 1985, # 8, p. 473
[6] ACS Catalysis, 2013, vol. 3, # 8, p. 1685 - 1692
[7] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 6, p. 1317 - 1329
[8] Molecules, 2014, vol. 19, # 7, p. 9944 - 9961
[9] Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 31 - 34
[10] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 949 - 954
[11] Angewandte Chemie - International Edition, 2014, vol. 53, # 40, p. 10718 - 10722[12] Angew. Chem., 2014, vol. 126, # 40, p. 10894 - 10898,5
[13] Angewandte Chemie - International Edition, 2008, vol. 47, # 14, p. 2700 - 2703
[14] Tetrahedron, 1991, vol. 47, # 39, p. 8407 - 8416
[15] Journal of Medicinal Chemistry, 1992, vol. 35, # 7, p. 1246 - 1259
[16] Tetrahedron Letters, 1998, vol. 39, # 11, p. 1321 - 1324
[17] Helvetica Chimica Acta, 2007, vol. 90, # 6, p. 1043 - 1068
[18] Patent: WO2007/42775, 2007, A2, . Location in patent: Page/Page column 45-46
[19] Patent: WO2007/2135, 2007, A2, . Location in patent: Page/Page column 12-13
[20] Patent: WO2012/17400, 2012, A1, . Location in patent: Page/Page column 18
[21] Carbohydrate Research, 2013, vol. 378, p. 45 - 55
[22] Organic Preparations and Procedures International, 2014, vol. 46, # 4, p. 370 - 375
[23] Journal of the American Chemical Society, 2015, vol. 137, # 9, p. 3271 - 3275
[24] Patent: US2015/335759, 2015, A1, . Location in patent: Sheet 13A
[25] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 13 - 25
[26] Patent: CN107963978, 2018, A, . Location in patent: Paragraph 0014
[27] Patent: WO2018/71879, 2018, A1, . Location in patent: Sheet 5
11
[ 6066-82-6 ]
[ 100-52-7 ]
[ 23405-15-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
With oxygen In acetonitrile at 80℃; for 10 h; Green chemistry
General procedure: p-Fluorobenzaldehyde 1a (124.0 mg, 1.0 mmol, 1.0 equiv.) and NHSI (2b) (62.5 mg, 0.5 mmol, 0.5 equiv.) were dissolved in DEC/CH3CN (1:1 3 mL) and stirred under 80oC for 10 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under vacuum. The residue was purified by ethanol recrystallization to give the 4a as a white solid, m. p. 100-102 °C.
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 50, p. 12538 - 12541[2] Angew. Chem., 2012, vol. 124, # 50, p. 12706 - 12709,4
[3] New Journal of Chemistry, 2018, vol. 42, # 2, p. 807 - 811
[4] Tetrahedron Letters, 2017, vol. 58, # 18, p. 1742 - 1746
[5] RSC Advances, 2015, vol. 5, # 56, p. 44928 - 44932
[6] Tetrahedron Letters, 2012, vol. 53, # 38, p. 5094 - 5098
[7] Organic and Biomolecular Chemistry, 2013, vol. 11, # 47, p. 8241 - 8246
[8] Advanced Synthesis and Catalysis, 2014, vol. 356, # 11-12, p. 2709 - 2713
12
[ 6066-82-6 ]
[ 94-36-0 ]
[ 23405-15-4 ]
Yield
Reaction Conditions
Operation in experiment
84%
With 1,4-diaza-bicyclo[2.2.2]octane In acetonitrile at 20℃; for 1 h;
General procedure: To a test tube charged with a stir bar, 0.20 mmol of1a and 0.20 mmol of BPO weresequentially added MeCN 1.0 mL and 0.20 mmol of DABCO. The resulting reactionmixture was stirred at room temperature for 3 h and diluted by addition of EtOAc,the organic layer was briefly washed by saturated aqueous sodium bicarbonatesolution, brine and dried over anhydrous sodium sulfate. The bulk solvent wasremoved in vacuo, and the residue waspurified by silica gel flash chromatography (hexane/EtOAc = 5:1) to affordproduct 2a 48.8 mg, 90percent yield.
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 3, p. 1920 - 1928
22
[ 143-07-7 ]
[ 6066-82-6 ]
[ 14565-47-0 ]
Yield
Reaction Conditions
Operation in experiment
95%
With dicyclohexyl-carbodiimide In ethyl acetate at 20℃; for 12 h;
Lauric acid (12.0 g, 60 mmol) dissolved in dry ethyl acetate (100 mL) was added to a solution of N-hydroxysuccinimide (NHS) (6.9 g, 60 mmol) and N,N’-dicyclohexylcarbodiimide (DCC) (12.4 g, 60 mmol) in dry ethyl acetate (300 mL). The reaction mixture was left overnight at room temperature. Dicyclohexylurea (DCU) was removed by filtration and the filtrate was evaporated under reduced pressure to yield white crystals (17.4 g, 95 percent yield). Recrystallization from ethanol yielded 16.6g of pure dodecanoic acid 2,5-dioxo-pyrrolidine-1-yl ester.
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 24, p. 7692 - 7705
[2] Journal of the American Chemical Society, 2003, vol. 125, # 40, p. 12110 - 12111
[3] RSC Advances, 2015, vol. 5, # 81, p. 66339 - 66354
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1763 - 1767
[5] Synthetic Communications, 2009, vol. 39, # 24, p. 4467 - 4472
[6] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5381 - 5390
[7] Liebigs Annalen der Chemie, 1990, # 2, p. 145 - 150
[8] Journal of Mass Spectrometry, 1995, vol. 30, # 6, p. 900 - 910
[9] Tetrahedron Letters, 2008, vol. 49, # 48, p. 6838 - 6840
[10] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 14, p. 2351 - 2353
[11] New Journal of Chemistry, 2013, vol. 37, # 4, p. 961 - 964
[12] Agricultural and Biological Chemistry, 1982, vol. 46, # 2, p. 597 - 600
[13] Journal of the American Chemical Society, 2008, vol. 130, # 41, p. 13555 - 13557
[14] Chemistry - A European Journal, 2014, vol. 20, # 4, p. 941 - 945
[15] Journal of the American Chemical Society, 1990, vol. 112, # 7, p. 2498 - 2506
[16] Journal of Molecular Structure, 1992, vol. 273, # 1, p. 215 - 226
[17] Agricultural and Biological Chemistry, 1986, vol. 50, # 10, p. 2561 - 2572
[18] Russian Journal of Bioorganic Chemistry, 2006, vol. 32, # 5, p. 413 - 419
[19] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 10, p. 3117 - 3121
[20] Molecules, 2009, vol. 14, # 10, p. 4051 - 4064
[21] Australian Journal of Chemistry, 2009, vol. 62, # 7, p. 653 - 656
[22] Chemical Communications, 2012, vol. 48, # 58, p. 7265 - 7267
[23] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 6121 - 6129
[24] International Journal of Pharmaceutics, 2013, vol. 457, # 1, p. 124 - 135
[25] Organic Preparations and Procedures International, 2014, vol. 46, # 4, p. 370 - 375
[26] Journal of Drug Targeting, 2016, vol. 24, # 1, p. 68 - 79
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
Stage #1: With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 20℃; for 0.333333 h; Stage #2: for 48 h;
To a solution of Gly-Gly (1.00 g, 7.57 mmol) in dioxane:water (30:5 mL) at room temperature was added triethylamine (1.15 g,11.4 mmol) and di-tert-butyl-dicarbonate (1.84 g, 8.33 mmol) consecutively. The mixture was stirred at room temperature overnight, then diluted with water, acidified to approximately pH 2via the addition of solid KHSO4, extracted with EtOAc, dried(Na2SO4), and concentrated in vacuo to afford (tert-butoxycarbonyl)glycylglycine [8] as a white solid. To a solution of crude (tertbutoxycarbonyl)glycylglycine (0.106 g, 0.451 mmol) in anhydrous dichloromethane (5.00 mL) was added triethylamine (45.6 mg,0.451 mmol) and propylphosphonic anhydride solution (T3P®) [9] (0.344 g, 0.541 mmol) at room temperature. The mixture was stirred for 20 min, followed by the addition of N-hydroxy succinimide (51.9 mg, 0.451 mmol). The reaction was stirred for 48 h and upon completion, the organic layer was washed with brine (3),dried (Na2SO4), and concentrated in vacuo to afford the product as a white solid. The crude solid was triturated from diethyl ether toafford 65.4 mg (44percent) of the product as a white solid: 1H NMR(400 MHz, CDCl3) d 6.76 (brs, 1 H), 5.15 (brs, 1 H), 4.43 (d, 2 H,J 5.7 Hz), 3.87 (d, 2 H, J 5.3 Hz), 2.85 (s, 4 H), 1.45 (s, 9 H); ESIMSm/z 330 [MH]. Direct infusion ESI-MS on a high resolution accurate mass measurements (Exactive Plus, Thermo Fisher Scientific) in the negative ion mode yielded an elemental composition of the expected product within 5 ppm (see Fig. 1).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 22, p. 5973 - 5982
[2] Journal of Pharmaceutical Sciences, 1984, vol. 73, # 2, p. 275 - 277
[3] Analytical Biochemistry, 2016, vol. 512, p. 114 - 119
36
[ 6066-82-6 ]
[ 110-15-6 ]
[ 30364-60-4 ]
Yield
Reaction Conditions
Operation in experiment
27%
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃;
To succinic acid (3 0 g, 25 42 mmol, 1 OO equiv) m THF (50 mL) was added a solution of 1- hydroxypyrrohdine-2,5-dione (64 g, 55 65 mmol, 2 20 eqmv) This was followed by the addition of a solution of DCC (11 5 g, 55 83 mmol, 2 20 equiv) in THF (50 mL) dropwise with stirring at O0C The resulting solution was stirred overnight at room temperature The reaction progress was monitored by LCMS The solids were collected by filtration and the filtrate was concentrated to give the crude product The resulting solids were washed with THF and ethanol This resulted in 2 4 g (27percent) of bis(2,5- dioxopyrrohdin-1-yl) succinate as a white solid.
Reference：
[1] Patent: WO2010/78449, 2010, A2, . Location in patent: Page/Page column 291
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 785 - 789[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1078 - 1081
[4] Chemical Papers, 2016, vol. 70, # 4, p. 505 - 514
[5] Patent: WO2016/205488, 2016, A1, . Location in patent: Paragraph 0264
37
[ 6066-82-6 ]
[ 543-20-4 ]
[ 30364-60-4 ]
Reference：
[1] Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2011, vol. 69, # 1-2, p. 75 - 84
[2] Patent: WO2015/155231, 2015, A1, . Location in patent: Page/Page column 67; 68
38
[ 6066-82-6 ]
[ 29022-11-5 ]
[ 113484-74-5 ]
Reference：
[1] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 7, p. 999 - 1005
[2] Journal of the American Chemical Society, 2003, vol. 125, # 45, p. 13680 - 13681
[3] Tetrahedron, 2009, vol. 65, # 19, p. 3871 - 3877
[4] Patent: WO2015/21092, 2015, A1, . Location in patent: Page/Page column 36
39
[ 6066-82-6 ]
[ 68858-20-8 ]
[ 130878-68-1 ]
Yield
Reaction Conditions
Operation in experiment
89%
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3 h;
Dicyclocarbodiimide (1 .55 g, 7.52 mmol) and N-hydroxysuccinimide (762 mg, 6.63 mmol) are added at room temperature to a stirrer solution of Fmoc-Val-OH [9] (1 .5 g, 4.42 mmol) in anhydrous dichloromethane (25 ml_). The mixture is kept at room temperature for 3 hours. The white solid formed in this reaction is filtrated with dichloromethane to remove the dicyclohexylurea, the organic phase is washed with HCI 0.1 N and water, then dried over anhydrous sodium sulfate and the solvent removed by rotatory evaporation. The residue is subjected to a flash column chromatography in 1 percent methanol in dichloromethane to afford product [10] as a white solid, 1 .7 g (89percent yield). MS: m/z 459 [M+Na]+.1H NMR (400 MHz, CDCIs) δ 7.80 (d, J = 7.5 Hz, 2H), 7.68 - 7.55 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (dd, J = 15.9, 8.5 Hz, 2H), 4.70 (d, J = 4.6 Hz, 1 H), 4.56 - 4.40 (m, 3H), 4.28 (t, J = 6.6 Hz, 1 H), 2.85 (s, 4H), 2.37 (dd, J = 12.3, 6.5 Hz, 1 H), 1 .08 (dd, J = 1 1 .0, 6.9 Hz, 6H).
65%
With dicyclohexyl-carbodiimide In 1,2-dimethoxyethane at 20℃; for 23 h; Cooling with ice; Inert atmosphere
Fmoc-Valine (1.02 g, 3 mmol) and N-hydroxysuccinimide (0.345 g, 3 mmol) were dissolved in dimethoxy ethane (35 ml) and cooled in an ice bath, then DCC (0.681 g, 3.3 mmol) was added. The resulting mixture was stirred in the ice bath for 3 hours, then at room temperature for 20 hours. The precipitate formed was filtered off and the filtrate concentrated under vacuo. The crude product was further purified by flash chromatography (ethyl acetate/hexane, v:v, 4:6) to afford SI20B as a white solid. Isolated yield: 65percent. TLC (EtOAc:Hexane 3:2). Rf=0.57, irradiated by a UV lamp. HPLC: 0.1percent TFA (v/v) in water (solvent A):acetonitrile (solvent B); gradient 45-85percent in 30 min, flow rate=0.5 mL/min. Retention time (Rt)=15.77 min. 1H NMR (FIG. 26A): (400 MHz, CDCl3) δ 7.76-7.78 (d, J=7.20 Hz, 2H), 7.59-7.60 (d, J=7.20 Hz, 2H), 7.38-7.42 (t, J=7.20 Hz, 2H), 7.30-7.34 (m, 2H), 5.26-5.28 (d, J=9.20 Hz, 1H), 4.67-4.71 (dd, J=4.8, 5.2 Hz, 1H), 4.42-4.46 (dd, J=6.8, 6.4 Hz, 2H), 4.23-4.26 (t, J=6.8 Hz, 1H), 2.84 (s, 4H), 2.04-2.36 (m, 1H), 0.83-088 (m, 6H). 13C NMR (FIG. 26B): (101 MHz, CDCl3) δ 168.7, 141.5, 127.9, 127.3, 127.3, 125.3, 120.2, 120.2, 67.5, 57.7, 47.4, 31.9, 25.8, 18.9, 17.5.
26.51 g
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 6 h; Inert atmosphere
[00125] This compound is prepared according to R. A. Firestone et al, US 6,214,345. Fmoc-Val-OH (20.24 g; 59.64 mmol) and N-hydroxysuccinimide (6.86 g =1 .0 eq.) in tetrahydrofuran (200 ml) at 000 were treated with N,N’dicyclohexylcarbodiimide (12.30 g; 1.0 eq.). The mixture was stirred at RT under argon atmosphere for 6 h and then the solid dicyclohexyl urea (DCU) by-product was filtered off and washed with THF and the solvent was removed by rotavap. The residue was dissolved in 300 ml dichloromethane, cooled in an ice bath for 1 h and filtered again to remove additional DCU. The dichloromethane was evaporated and the solid foam (26.51 g) was used in the next step without further purification.
Reference：
[1] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 7, p. 999 - 1005
[2] Langmuir, 2010, vol. 26, # 7, p. 4990 - 4998
[3] Patent: WO2018/178060, 2018, A1, . Location in patent: Page/Page column 64-66
[4] Journal of the American Chemical Society, 2015, vol. 137, # 21, p. 6932 - 6940
[5] Patent: US2017/247324, 2017, A1, . Location in patent: Paragraph 0284; 0285
[6] Tetrahedron, 2009, vol. 65, # 19, p. 3871 - 3877
[7] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4182 - 4187
[8] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[9] Patent: WO2013/67597, 2013, A1, . Location in patent: Page/Page column 80
[10] Patent: WO2014/80251, 2014, A1, . Location in patent: Sheet 16/23
[11] Patent: WO2015/21092, 2015, A1, . Location in patent: Page/Page column 36
[12] Bioconjugate Chemistry, 2015, vol. 26, # 11, p. 2261 - 2278
[13] Patent: WO2017/149077, 2017, A1, . Location in patent: Paragraph 00128-00129
[14] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0067; 0068; 0069
[15] Patent: WO2018/115466, 2018, A1, . Location in patent: Paragraph 00103; 00124; 00125
40
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[ 133081-25-1 ]
[ 133081-26-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4764 - 4767
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[4] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
41
[ 6066-82-6 ]
[ 253265-97-3 ]
Yield
Reaction Conditions
Operation in experiment
99.6%
With triethylamine In tetrahydrofuran for 2 h; Reflux
The compounds of formula 1 obtained in Example 3 (3.8g, 0.02mol) was dissolved in 30ml of tetrahydrofuran, was added dropwise to N- hydroxyalkylSuccinimide (2.3g, 0.02mol) in 45ml of tetrahydrofuran was added triethylamine (2.02g, 0.02mol), the addition was complete, reflux, 2 hours reaction, TLC detection material disappeared, water was added to brine and extracted , take the upper concentrated to give 5.4g compound of formula 6-1 in a yield of 99.6percent.
With dicyclohexyl-carbodiimide; In 1,4-dioxane; at 5 - 20℃; for 20h;
2.2 ml (25 mmol) DCCD was added at 5C to a solution of 1.43 ml (25 mmol) acetic acid and 2.2 ml (0.25 mmol)N-hydroxysuccinimide in 50 ml dioxane. The reaction mixture was stirred at 20C for 20 h. The resulting precipitate wasfiltered off and washed with dry dioxane. The filtrates were combined and evaporated to yield 3.65 g (93%) of the productas white crystals. Rf 0.41 (C), Rf 0.75 (I); m.p. 103-105C. 1H NMR (DMSO-d6): 2.34 (3H, s, -CH3CO-), 2.80 (4H, m, -CH2CH2- OSu).
With 1,2-dichloro-ethane; In dichloromethane; for 3h;
General procedure: To a stirred solution of appropriate acid 44a-f (1.96mmol) in CH2Cl2 (3mL) were added NHS (0.361g, 3.14mmol) and EDC (0.601g, 3.14mmol). After 3h, the mixture was diluted with CH2Cl2 (40mL). The organic layer was washed with brine (2×40mL), saturated aqueous NaHCO3 (40mL) and brine (2×40mL), dried over Na2SO4, filtered and concentrated to give NHS activated esters (80-100% yield) that were used immediately without further purification.
With dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃;Inert atmosphere;
The syntheses of GlcNAc and GlcNGc from glucosamine were based on the method described by Lapidot [31]. The procedure for the synthesis of GlcNAc was performed as follows: acetic acid (0.286 mL, 5 mmol) was added to a solution of N-hydroxysuccinimide (0.575 g, 5 mmol) in dry ethyl acetate (23 mL). A solution of dicyclohexylcarbodiimide (1.03 g, 5 mmol) in ethyl acetate (2 mL)was then added. The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. Then, the precipitate of the reaction mixture was removed by centrifugation at 13,400 g for 10 min. The supernatant contained an NHS-ester of acetic acid was dried by rotary evaporation under reduced pressure and re-dissolved in dry 17 mL of methanol. D-Glucosamine hydrochloride(0.862 g, 4 mmol) and triethylamine (0.56 mL) were then added and dissolved by placing the sample ina heated sonication bath (50 C for 1 h). The reaction mixture was then stirred at room temperature for 16 h. The sample was again dried using rotary evaporation and washed three times with ethyl acetate(1 mL) to remove the unreacted starting material. After vacuum drying of the sample using centrifugal evaporation, the product was dissolved in 8 mL of 10% methanol in water (v/v). The supernatant was collected and concentrated using a rotary evaporator under reduced pressure. For the synthesisof GlcNGc, glycolic acid (0.3 mL, 5 mmol) was used instead of acetic acid. As judged by TLC analysis, the conversion of D-glucosamine to the reaction products 4a or 4b reached approximately 70%. These amidated reaction products were then used directly as starting material for the enzymatic sialylation reactions.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;
To a round bottom flask were added acid 33 (640 mg, 2.43 mmol), N- hydroxysuccinimide (419 mg, 3.64 mmol), DMAP (30 mg, 0.25 mmol), and 10 mL CH2CI2 under N2. The mixture was cooled down to 0 C and then a solution of DCC (752 mg, 3.64 mmol) in 10 mL CH2CI2 was added dropwise. The mixture was allowed to warm up to room temperature slowly overnight (16 h). Lots of white precipitates formed during the reaction. The precipitates were filtered off and the filtrate was washed with 20 mL 0.05 N HCl(aq) twice. The organic layer was dried with Na2S04 and concentrated under vacuum. The residue was dispersed in 20 mL EtOAc, and the insoluble precipitates were filtered off. The filtrate was concentrated to give T2 as a colorless oil (840 mg, 96%). NMR (400 MHz, CDCL): d 4.99 (s, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 4H), 3.54 (t, J= 5.2 Hz, 2H), 3.32 (br q, J= 5.2 Hz, 2H), 2.86 (s, 4H), 1.44 (m, 9H).
91%
With diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 2h;
Boc-AEEA-OH (26.4 g, 100 mmol) and HOSu (12.6 g, 110 mmol) were dissolved in 200 ml tetrahydrofuran. DIC (13.9 g, 110 mmol) was added dropwise under a condition of ice bath, and the reaction was continued at room temperature for 2 h after the dropwise addition. TLC showed that the reaction of the raw materials was completed. A vacuum concentration was performed, and the residue was recrystallized with EA to obtain 33.0 g of Boc-AEEA-OSu with yield: 91%, purity: 96.7%, MS: 361.4 (M+1).
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃; for 8h;
To 2-chloro-4-methylsulfonylbenzoic acid (20 g, 86 mmmol) and N-hydroxysuccinimide (11.5 g, 100 mmol) in 300 mL of dichloromethane was added EDC (19.8 g, 100 mmol) and the resulting mixture was stirred at room temperature for 8 h. The mixture was then quenched with 100 mL of saturated aqueous sodium bicarbonate solution then diluted with 200 mL of water. The mixture was then extracted with ethyl acetate (3 x 300 mL), and the organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated aqueous brine (100 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude ester. The ester was then dissolved into 200 mL of dioxane then treated with 100 mL of ammonium hydroxide. After stirring for 2 h, the reaction mixture was evaporated in vacuo, diluted with 700 mL of ethyl acetate and then washed with saturated aqueous brine (2 x 200 mL). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the primary amide, which was used without further purification.
With acetic acid; triethylamine; In ethanol; ethyl acetate; isopropyl alcohol;
EXAMPLE 12 1.27 g (0.011 mol) of N-hydroxysuccinimide were initially introduced into 10 ml of ethyl acetate, a solution of 3.22 g (0.012 mol) of diphenyl chlorophosphate in 10 ml of ethyl acetate was added and then a solution of 2.53 g (0.025 mol) of triethylamine in 10 ml of ethyl acetate was added dropwise in the course of 10 minutes, the temperature rising to 41° C. A thick, white suspension resulted, which was treated with a solution of 0.6 g (0.01 mol) of acetic acid in 10 ml of ethyl acetate and heated at 45°-55° C. for 16 hours. After ending of the reaction, the solid was filtered off and washed with 2*3 ml of ethyl acetate. The combined filtrates were evaporated in vacuo and the semicrystalline residue which remained was washed by stirring with 20 ml of ethanol for 30 minutes. The white solid thus obtained was filtered off, washed with 2*3 ml of ethanol, sucked dry and then washed by stirring with 10 ml of isopropanol. After filtering off, washing with 2*2 ml of isopropanol and drying in vacuo, 1.1 g (70percent) of white acetic acid succinimidyl ester were obtained. M.p.: 130°-134° C.
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
Into a 100- mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of <strong>[23351-91-9]5-bromoisophthalic acid</strong> (3 g, 11 76 mmol, 1 00 equiv, 96percent) in THF (20 mL) followed by NHS (3 g, 2609 mmol, 220 equiv) at 0-50C To this was added a solution of DCC (5 6 g, 27 18 mmol, 2 20 equiv) m THF (20 mL) dropwise with stirring at 0-50C The resulting solution was stirred overnight at room temperature The solids were filtered out and the filtrate was concentrated under vacuum The crude product was re-crystalhzed from DCM/ethanol in the ratio of 1 10 This resulted m 4 g (75percent) of the title compound as a white solid.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h;Inert atmosphere;
EXAMPLE 4 SYNTHESIS OF PROBE COMPOUND, DYn-Naph [0147] The DYn-Naph compound (FIG. 5) may be synthesized by the following method (FIG. 6A, Scheme 2). To a dry round bottom flask flushed with nitrogen was added 6-amino-2-napthoic acid (200 mg, 1.07 mmol), NHS (135.18 mg, 1.17 mmol), and dry DMF (2 mL). The reaction mixture was cooled in an ice-bath. EDC-HC1 (224.71 mg, 1.17 mmol) was added and the reaction mixture was allowed to react at 0 °C for 30 min, then the reaction was brought up to room temperature and allowed to mix for an additional 3 hrs. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated for the next step. To a dry round bottom flask flushed with nitrogen was added the NHS-ester of Intermediate Compound (1) (323 mg, 1.13 mmol), which was suspended in dry DMF (4 mL). 4-pentyneamine (292.5 mg, 3.52 mmol) and DIPEA (613 uL, 3.52 mmol) were subsequently added and the reaction mixture was allowed to mix at 75 °C overnight under nitrogen. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated. Flash column chromatography was used for purification (1 : 1 EtOAc:Hexanes, 10percent MeOH in EtOAc spiked with 1percent TEA) to yield 188.2 mg of Intermediate Compound (2) (70percent yield). To a dry round bottom flask flushed with nitrogen was added 3-methoxy-5-oxocyclohex-3-9-enecarboxylic acid (115.39 mg, 0.678 mmol), EDC-HC1 (194.48 mg, 1.02 mmol), and DMAP (99.4 mg, .813 mmol). The flask was sealed under nitrogen. Intermediate Compound (2) (188.2 mg, 0.746 mmol) was resuspended in dry DMF (2 mL) and added to the reaction mixture followed by the addition of TEA (95 mu, 0.678 mmol). The reaction mixture was brought up to 85 °C and allowed to mix overnight under nitrogen. The reaction was quenched with the addition of water and extracted with EtOAc. The organic phases were combined and dried over MgS04, filtered, and concentrated. Flash column chromatography was used for purification (1 : 1 Hexanes:EtOAc, 7:3 EtOAc:Hexanes, 5percent MeOH in EtOAc) to yield 138.1.6 mg of product (46percent yield). In a round bottom flask, Intermediate Compound (3) (138.1 mg, 0.34 mmol) was suspended in a 1 : 1 Acetonitrile:Water solution (5 mL). 10percent> CAN (18.8 mg, 0.034 mmol) was added and the reaction mixture was refluxed at 95 °C for 3 hrs., resulting in the synthesis of DYn-Naph (FIG. 5). The reaction was then cooled and concentrated and directly purified by HPLC.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h;Inert atmosphere;
To a dry round bottom flask flushed with nitrogen was added 6-amino-2-napthoic acid (200 mg, 1.07 mmol), NHS (135.18 mg, 1.17 mmol), and dry DMF (2 mL). The reaction mixture was cooled in an ice-bath. EDC-HCl (224.71 mg, 1.17 mmol) was added and the reaction mixture was allowed to react at 0 °C for 30 min, then the reaction was brought up to rt and allowed to mix for an additional 3 hrs. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated for the next step without further purification. To a dry round bottom flask flushed with nitrogen was added the NHS-ester (323 mg, 1.13 mmol) which was suspended in dry DMF (4 mL). 4-pentyneamine (292.5 mg, 3.52 mmol) and DIPEA (613 uL, 3.52 mmol) were subsequently added and the reaction mixture was allowed to mix at 75 °C overnight under nitrogen. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. Flash column chromatography was used for purification (1:1 EtOAc:Hexanes, 10percent MeOH in EtOAc spiked with 1percent TEA) to yield 188.2 mg of (5) (70percent yield over 2 steps)
2,5-dioxopyrrolidin-1-yl 4-(2-methoxy-2-oxoethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3.5h;Inert atmosphere;
2,5-Dioxopyrrolidin-1-yl 4-(2-methoxy-2- oxoethyl)benzoate (13) To a solution of monoacid 12 (0.917 g, 4.72 mmol, 1 equiv.) in DMF (107 ml_), A/-hydroxysuccinimide (1.47 g, 12.8 mmol, 2.7 equiv.) and N-(3- dimethylamino-propyl)-/V-ethylcarbodiimide hydrochloride (2.44 g, 12.8 mmol, 2.7 equiv.) were added. The reaction mixture was stirred at room temperature for 3.5 h under an argon atmosphere. The colorless mixture was diluted with EtOAc and water. The solution was extracted three times with EtOAc. The combined organic layers were washed three times with water, dried over Na2S04 and concentrated under reduced pressure in order to get NHS-ester 13 (1.329 g, 97percent) as a pale yellow oil. NMR (CDCI3, 600 MHz) delta 8.10 (d, 2H, J = 8.1 Hz), 7.44 (d, 2H, J= 8.1 Hz), 3.72 (s, 2H), 3.71 (s, 3H), 2.90 (s, 4H); 13C NMR (CDCI3, 151 MHz) delta 169.9, 168.3, 160.8, 140.5, 130.0, 129.0, 123.2, 51.5, 40.4, 24.8; Ci4Hi4N06 [M+H]+ 292.0816, found 292.0824; C14H17N2O6 [M+NH4]+ 309.1081 , found 309.1084; Purity: 100percent, tR = 2.4 min.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 48h;
The commercial product 6-Biotinylamino-hexanoic acid (Biotin-Ahx-OH, 101 mg, 0.28 mmol) was dissolved in 4 ml of DMF (light suspension). N-hydroxy succinimide (NHS, 36 mg, 0.31 mmol) and N-(3-Dimethylaminopropyl)-N' ethyl-carbodiimide (EDC x HCI, 59 mg, 0.31 mmol.) were added to reaction mixture and stirred at room temperature for 2 days following disappearance of the acid on TLC analysis. Then, the organic solvent was evaporated under high vacuum and the obtained residue was dissolved in CH2CI2 (20 ml) and rapidly washed with 0.1 N HCI solution to remove excess reagents. The combined organic phase were washed with brine (20 ml), dried over anhydrous Na2S04, filtered and concentrated to give a white solid Biotin-OSu activated (91 mg, yield 71 percent), used immediately without further purification.
2,5-dioxopyrrolidin-1-yl 2-morpholinoacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 15℃; for 12h;
A mixture of the product of the previous step (150 g, 826 mmol), 67 1-hydroxypyrrolidine-2,5-dione (95 g, 826 mmol), 68 DCC (256 g, 1.24 mol) and 69 DIPEA (160 g, 1.24 mol) in 70 DCM (2 L) was stirred at 15° C. for 12 h and filtered. The filtrate was concentrated and washed with EtOAc (800 mL). The solid was collected by filtration and concentrated to give the 71 title compound (150 g, 75percent yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 3.68 (s, 2H), 3.58 (t, J=4.8 Hz, 4H), 2.82 (s, 4H), 2.57 (t, J=5.2 Hz, 4H).
(S)-N-boc-(3-hydroxyadamantan-1-yl)glycine succinimide ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; In dichloromethane; at 25℃; for 1h;
In 150 mL of dichloromethane, 8.14 g (25 mmol) of (S)-N-Boc-(3-hydroxyadamantan-1-yl)glycine and 3.45 g (30 mmol) of N-hydroxysuccinimide, 5.04 g ( 50 mmol) triethylamine, stirring at 25 ° C for 1 hour, adjusting the pH to 7.5 with hydrochloric acid, adding a water layer, concentrating the organic phase under reduced pressure, column chromatography,(S)-N-Boc-(3-hydroxyadamantan-1-yl)glycine succinimide ester 9.55 g (22.6 mmol) was obtained in a yield of 90percent.
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