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Chemical Structure| 6066-82-6
Chemical Structure| 6066-82-6
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Product Details of [ 6066-82-6 ]

CAS No. :6066-82-6 MDL No. :MFCD00005516
Formula : C4H5NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :NQTADLQHYWFPDB-UHFFFAOYSA-N
M.W : 115.09 Pubchem ID :80170
Synonyms :

Calculated chemistry of [ 6066-82-6 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.5
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 27.17
TPSA : 57.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.02 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.33
Log Po/w (XLOGP3) : -1.44
Log Po/w (WLOGP) : -0.86
Log Po/w (MLOGP) : -0.53
Log Po/w (SILICOS-IT) : -0.31
Consensus Log Po/w : -0.56

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.35
Solubility : 260.0 mg/ml ; 2.26 mol/l
Class : Highly soluble
Log S (Ali) : 0.73
Solubility : 623.0 mg/ml ; 5.41 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.53
Solubility : 388.0 mg/ml ; 3.37 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.21

Safety of [ 6066-82-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P261-P280-P271-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 6066-82-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 6066-82-6 ]
  • Downstream synthetic route of [ 6066-82-6 ]

[ 6066-82-6 ] Synthesis Path-Upstream   1~98

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YieldReaction ConditionsOperation in experiment
24% With triethylamine In acetonitrile 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
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  • [ 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
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  • [ 13734-34-4 ]
  • [ 3674-06-4 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 16, p. 3372 - 3378
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 4.1, p. 720 - 726[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 4, p. 811 - 818
[4] Tetrahedron, 2007, vol. 63, # 43, p. 10637 - 10645
[5] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 15, p. 2443 - 2449
[6] Journal of Medicinal Chemistry, 2007, vol. 50, # 24, p. 6080 - 6094
[7] Angewandte Chemie - International Edition, 2018, vol. 57, # 22, p. 6475 - 6479[8] Angew. Chem., 2018, vol. 130, p. 6585 - 6589,5
[9] Organic and Biomolecular Chemistry, 2016, vol. 14, # 46, p. 10894 - 10905
[10] Chemistry Letters, 1981, p. 1331 - 1332
[11] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 24, p. 2925 - 2930
[12] Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4543 - 4551
[13] Synlett, 2005, # 18, p. 2802 - 2804
[14] Chemistry - A European Journal, 2001, vol. 7, # 19, p. 4280 - 4295
[15] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 3, p. 1071 - 1078
[16] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3220 - 3224
[17] Chemistry - A European Journal, 2014, vol. 20, # 6, p. 1530 - 1538
[18] Chinese Chemical Letters, 2016, vol. 27, # 3, p. 357 - 360
[19] Research on Chemical Intermediates, 2017, vol. 43, # 10, p. 5305 - 5320
[20] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
[21] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 8, p. 803 - 808
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  • [ 1142-20-7 ]
  • [ 3401-36-3 ]
Reference: [1] Polish Journal of Chemistry, 2005, vol. 79, # 12, p. 1909 - 1917
[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 15, p. 2443 - 2449
[3] Liebigs Annales, 1996, # 3, p. 335 - 348
[4] Journal of Pharmaceutical Sciences, 1993, vol. 82, # 1, p. 1 - 10
[5] Chemische Berichte, 1980, vol. 113, # 11, p. 3511 - 3516
[6] Dalton Transactions, 2006, # 1, p. 137 - 148
[7] Chemistry Letters, 1985, p. 123 - 126
[8] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 7, p. 2409 - 2418
[9] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 7, p. 989 - 998
[10] Journal of Medicinal Chemistry, 1994, vol. 37, # 18, p. 2841 - 2845
[11] Bioorganic & Medicinal Chemistry Letters, 1998, vol. 8, # 23, p. 3343 - 3346
[12] Chemistry - A European Journal, 2004, vol. 10, # 16, p. 3879 - 3890
[13] Tetrahedron Letters, 2008, vol. 49, # 48, p. 6885 - 6888
[14] Biochimie, 2013, vol. 95, # 6, p. 1120 - 1126
[15] Tetrahedron, 2013, vol. 69, # 2, p. 551 - 558
[16] Chemistry - A European Journal, 2013, vol. 19, # 48, p. 16256 - 16262
[17] Organic Preparations and Procedures International, 2014, vol. 46, # 4, p. 370 - 375
[18] Organic and Biomolecular Chemistry, 2016, vol. 14, # 47, p. 11125 - 11136
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Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3583 - 3586
  • 7
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  • [ 64-69-7 ]
  • [ 39028-27-8 ]
YieldReaction ConditionsOperation in experiment
30% at 0 - 20℃; for 4 h; On a solution of N-hydroxysuccinimide (12.6 mmol) and dicyclohexylcarbodiimide (20.3 mmol) at 0° C., corresponding acid (6 mmol) was added and allowed to react for 4 hours at room temperature. In the case of compound VIa, a solution of maleic anhydride (10 mmol) and β-alanine was added in N,N-dimethylformamide, which has been previously made react for 1 hour. After 4 hours, mixture was evaporated at reduced pressure and the crude was dissolved in dichloromethane and washed with water. Organic extracts were dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. Resulting residue was recrystallized to give desired compound. [0112] Using this methodology, and corresponding acid, the following compounds were prepared: Succinimidyl iodoacetate (VIb, 30percent yield). 1H NMR (CDCl3) δ ppm: 2.87 (2H, s), 3.96 (1H, s); 13C NMR (CDCl3) δ ppm: −12.47 (1C, s) 25.85 (2C, s) 164.78 (1C, s) 168.78 (2C, s).
Reference: [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 32, p. 7777 - 7791
[2] Patent: US2013/273581, 2013, A1, . Location in patent: Page/Page column 0092; 0111-0112; 0114
[3] Farmaco, 1992, vol. 47, # 11, p. 1367 - 1383
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  • [ 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,
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YieldReaction ConditionsOperation in experiment
80%
Stage #1: at 70℃; Inert atmosphere
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0 - 70℃;
EXAMPLE 1N-Maleimidopropionic acid NHS ester[0083] Maleic anhydride, β-alanine (1 mol eq.), and acetonitrile (ACN, 25 volumes) were charged to a vessel. The slurry was stirred under nitrogen and heated to 70 0C. The temperature was maintained at 70 0C for a further 5 to 8 hours. After cooling to 5 0C, NHS (1 mol eq.) was charged, followed by Λ/-(3-dimethylaminopropyl)-Λf'-ethylcarbodiimide hydrochloride (EDCI, 1 mol eq.). The temperature was maintained at 0 - 5 0C for 1 hour before adding a further charge of EDCI (1 mol eq.). The mixture was heated to 70 0C and maintained at this temperature for 7 hours. The reaction mixture was cooled to 200C and concentrated under vacuum at a maximum temperature of 45°C until the rate of solvent distillation was negligible. Dichloromethane (DCM, 40 volumes) was added to the residue, which was stirred until a solution was formed. This solution was washed with aqueous ammonium chloride (12 percent w/w, 25 wt eq.) then with aqueous sodium chloride (24 percent w/w, 25 wt eq.). The organic solution was dried by stirring with magnesium sulphate (1 wt eq.) at ambient temperature for 1 to 2 hours. The inorganics were filtered off under vacuum and the filter cake was washed with DCM (4 volumes). The filtrates were concentrated under vacuum, whilst gradually replacing DCM with isopropylacetate (IPAC). The residual slurry was cooled and stirred at ambient temperature for 1 hour before filtering under vacuum. The product filter cake was washed with IPAC (4 volumes) and then dried to constant mass under vacuum with slow rotation at 40 0C to yield the desired compound as an off white solid. The typical yield is 60 to 80 percent of the maximum theoretical yield.[0084] The product was characerised by NMR as follows: 1H NMR (400MHz, d6-DMSO): δ 2.80 (4H, br s), δ 3.05 (2H, t, J ~ 7Hz), δ 3.75 (2H, t J ~ 7Hz), δ 7.05 (2H, s).
60%
Stage #1: at 20℃; for 2.5 h;
Stage #2: With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃;
To a solution of maleic anhydride (2.00 g, 20.4 mmol) in 24 mL of DMF was added β-alanine (1.82 g, 20.4 mmol)and the mixture was stirred for 2.5 h at room temperature in which the solid was gradually dissolved to afford clear solution. The reaction was cooled in an ice bath and N-hydroxysuccinimide (HOSu) (2.88 g, 25 mmol) andN,N'-dicyclohexylcarbodiimide (8.24 g. 40.0 mmol) were successively added to the solution. After 30 min, the reaction was warmed to room temperature and stirred for 14 h. The reaction mixture was filtered through a cottonplug and the residue was washed with DCM and water. The filtrates were gathered and the organic layer was washed with satd NaHCO3 (three times) and brine, dried over Na2SO4 and concentrated to afford 1 (3.20 g, 60percent) as a white solid. 1H NMR (400 MHz, d6-DMSO): 2.78 (s, 4H), 3.03 (t, J = 6.9 Hz, 2H), 3.73 (t, J = 6.9 Hz, 2H),7.02 (s, 2H); 13C NMR (100 MHz, d6-DMSO): 25.4, 29.0, 32.7, 134.6, 166.7, 169.9, 170.5.
25% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 1 h; On a solution of N-hydroxysuccinimide (12.6 mmol) and dicyclohexylcarbodiimide (20.3 mmol) at 0° C., corresponding acid (6 mmol) was added and allowed to react for 4 hours at room temperature. In the case of compound VIa, a solution of maleic anhydride (10 mmol) and β-alanine was added in N,N-dimethylformamide, which has been previously made react for 1 hour. After 4 hours, mixture was evaporated at reduced pressure and the crude was dissolved in dichloromethane and washed with water. Organic extracts were dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. Resulting residue was recrystallized to give desired compound. [0112] Using this methodology, and corresponding acid, the following compounds were prepared: [0113] 3-succinimidyl maleimidopropionate (VIa, 25percent yield). 1H NMR (CDCl3) δ ppm: 2.82 (4H, s), 3.02 (2H, t, J=7.07 Hz), 3.94 (2H, t, J=7.07 Hz), 6.74 (2H, s); 13C NMR (CDCl3) δ ppm: 25.5 (2C, s), 29.7 (1C, s), 32.9 (1C, s), 134.3 (2C, s), 166.0 (1C, s), 168.7 (2C, s), 170.1 (2C, s).
Reference: [1] Patent: WO2011/23680, 2011, A2, . Location in patent: Page/Page column 13-14
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10198 - 10201[3] Angew. Chem., 2015, vol. 127, p. 10336 - 10339
[4] Journal of the American Chemical Society, 2013, vol. 135, # 29, p. 10582 - 10585
[5] Journal of the American Chemical Society, 2004, vol. 126, # 3, p. 734 - 735
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1721 - 1728
[7] Macromolecular Bioscience, 2012, vol. 12, # 9, p. 1209 - 1219
[8] Patent: US2013/273581, 2013, A1, . Location in patent: Paragraph 0111-0113
[9] Synthesis, 1991, # 10, p. 819 - 821
[10] Patent: WO2011/9047, 2011, A2, . Location in patent: Page/Page column 13
[11] Patent: US2013/157375, 2013, A1, . Location in patent: Paragraph 0103; 0104
[12] Chemical Communications, 2014, vol. 50, # 26, p. 3473 - 3475
[13] Patent: WO2014/100762, 2014, A1, . Location in patent: Paragraph 248
[14] Chemical Communications, 2015, vol. 51, # 53, p. 10758 - 10761
[15] Angewandte Chemie - International Edition, 2017, vol. 56, # 9, p. 2356 - 2360[16] Angew. Chem., 2017, vol. 129, # 9, p. 2396 - 2400,5
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Reference: [1] Analytical Chemistry, 2016, vol. 88, # 22, p. 10837 - 10841
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 40, p. 12243 - 12247[3] Angew. Chem., 2016, vol. 128, # 40, p. 12431 - 12435,5
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[5] Tetrahedron Letters, 1998, vol. 39, # 11, p. 1321 - 1324
[6] Organic Letters, 2004, vol. 6, # 20, p. 3561 - 3564
[7] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6400 - 6407
[8] Chemical Communications, 2011, vol. 47, # 25, p. 7068 - 7070
[9] Chemistry - A European Journal, 2011, vol. 17, # 46, p. 13059 - 13067
[10] Patent: US2014/56810, 2014, A1, . Location in patent: Paragraph 0181
[11] Organic and Biomolecular Chemistry, 2014, vol. 12, # 34, p. 6624 - 6633
[12] Journal of Controlled Release, 2015, vol. 220, p. 660 - 670
[13] Patent: WO2015/196167, 2015, A1, . Location in patent: Paragraph 0269; 0277
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YieldReaction ConditionsOperation in experiment
64%
Stage #1: at 60℃; for 3 h;
Stage #2: With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 22℃; for 18.5 h;
To a solution of maleic anhydride (8; 86.0 g, 877 mmol) in DMF(1.03 L) was added β-alanine (9; 78.14 g, 877 mmol). The resultingsuspension was heated to 60 °C and, after 1 h, a solution was obtained.After 2 h, the mixture was cooled to 0–5 °C and N-hydroxysuccinimide(29; 126.17 g, 1.09 mol) was added followed by DCC(361.9 g, 1.75 mol) over 30 min in several portions while the internaltemperature was held below 22 °C. The thick, white slurry wasthen stirred at 20 °C for 18 h. The slurry was filtered and the solid(dicyclohexyl urea) was washed with H2O (1 L) and CH2Cl2 (1 L)and discarded. To the filtrates was added CH2Cl2 (1 L) and the phaseswere separated. The aqueous layer was extracted with CH2Cl2(2 × 300 mL) and the combined organic extracts were washed withH2O [500 mL; a small amount of brine (50 mL) was added to facilitatephase separation], sat. aq NaHCO3 (2 × 300 mL), and dried(MgSO4). The solvent was removed to give an oily, light tan solidthat was slurried in EtOH (520 mL) for 2 h at 20 °C. The solid wasfiltered, washed with EtOH (2 × 75 mL) and dried under vacuum at30 °C for 72 h to give 186.35 g (64percent) of NHS ester 30 as a whitesolid;32 HPLC purity: 96.6percent (areapercent); mp 169–171 °C.IR (ATR cell): 3088, 2954, 1825, 1783, 1705, 1583, 1446, 1433,1382, 1325, 1298, 1250, 1211, 1149, 1070, 1049, 998, 956, 901,836, 813, 786, 767, 756, 696, 651, 634, 596, 561, 544, 528 cm–1.1H NMR (400 MHz, DMSO-d6): δ = 2.80 (s, 4 H), 3.05 (t, J = 6.90Hz, 2 H), 3.75 (t, J = 6.78 Hz, 2 H), 7.05 (s, 2 H).13C NMR (100 MHz, DMSO-d6): δ = 25.38, 29.00, 32.67, 134.63,166.72, 169.93, 170.52.HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O6: 267.06116;found: 267.06147.
Reference: [1] Synthesis (Germany), 2014, vol. 46, # 10, p. 1399 - 1406
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1985, vol. 327, # 5, p. 789 - 798
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  • [ 57079-11-5 ]
  • [ 55750-62-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 20, p. 5032 - 5038
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  • [ 25021-08-3 ]
  • [ 55750-61-3 ]
Reference: [1] Bioconjugate Chemistry, 2012, vol. 23, # 12, p. 2417 - 2433
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 10, p. 1325 - 1335
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YieldReaction ConditionsOperation in experiment
116 g With triethylamine In dichloromethane at 20℃; for 2 h; To a 500 ml three-necked flask, N-maleimidyl acetic acid (94 g, 0.6 mol)And dichloromethane 300ml,Oxalyl chloride (90 g, 0.72 mol) was then added,The reaction was warmed to reflux, a large amount of gas was released.After 2h the reaction became clear,Concentrate to remove methylene chloride and excess oxalyl chloride,Addition of 200 ml of methylene chloride to remove the residual acid in one pass afforded crude N-maleimidoacetyl chloride.The crude product was dissolved in 200 ml of dichloromethane,Was added dropwise to N-hydroxysuccinimide (69 g, 0.6 mol)Triethylamine (80.8 g, 0.8 mol)Dissolved in 300 ml of dichloromethane,Ice water cooling control temperature does not exceed 20 , drip finished room temperature 2h.The reaction solution was washed with 200 ml of water to remove triethylamine hydrochloride,1N hydrochloric acid 100ml washing to remove excess triethylamine,200ml saturated salt water, washed and dried,Concentrated to dry off like white solid 137g,After recrystallization from a mixed solvent of ethyl acetate and petroleum ether, 116 g of a white solid was obtained,HPLC purity 98.7percent, 76.7percent yield.
Reference: [1] Patent: CN105037237, 2017, B, . Location in patent: Paragraph 0071-0074
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1985, vol. 327, # 5, p. 789 - 798
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  • [ 32703-87-0 ]
YieldReaction ConditionsOperation 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
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  • [ 102774-86-7 ]
YieldReaction ConditionsOperation in experiment
95 kg With tributyl-amine In tetrahydrofuran at -2 - 5℃; Large scale From the reactor solid feed port one - time investment HosuL43. 8Kg (l. 25KmOl),With stirring,So that the kettle liquid at -2 ° C ~ 0 ° C.The tributylamine300Kg (l. 62 kP)And tetrahydrofuran450Kg into the high slot,After mixing,In 10 ~ llhr slowly added to the reactor in the reaction,The amount of added per hour for the 50 ~ 57Kg;And keep the kettle temperature not to exceed 5 ° C,Because of the exothermic reaction,After adding tributylamine in tetrahydrofuran solution,The reaction vessel was allowed to warm to room temperature and the reaction was continued for 7.5 h.A large amount of white solid crystals were observed to be precipitated by DSC from the reaction vessel.(3) filtered DSC crude: the reactor material in lhr evenly introduced into a fully enclosed centrifuge in N2Under the protection of throwing dry, and then twice the introduction of about 0 ° C tetrahydrofuran solvent 100Kg in the centrifuge rinse, throw dry,The DSC wet goods 120Kg. The wet goods in a vacuum oven at 40 ~ 45 ° C drying 7 ~ 8hr to constant weight, get out of the white crystalline powder 95Kg; HPLC analysis of 99. 1percent. The resulting filtrate was centrifuged to proceed to the next step. (3) filtered to obtain DSC crude: the reactor material in 1hr evenly introduced into a fully enclosed centrifuge, in the N2Under the protection of throwing dry, and then twice the introduction of about 0 ° C tetrahydrofuran solvent 100Kg in the centrifuge rinse, throw dry, get DSC wet goods 120Kg.The wet product in a vacuum oven at 40 ~ 45 dry 7 ~ 8hr to constant weight, get out of the white crystalline powder 95Kg; HPLC analysis of 99.1percent.The resulting filtrate was centrifuged to proceed to the next step.(4) The centrifugal filtrate in step (3) is combined with two washing solvents and introduced into a 2000L distilling apparatus. The tetrahydrofuran solvent is removed at a vacuum control temperature of 0 to 5 DEG C, and the inside temperature of the kettle is kept at 40 to 42 DEG C .After the tetrahydrofuran was removed, 230 kg of dichloroethane was introduced, stirred at 40-50 ° C for 0.5 hr, and washed with 160 kg of water 3 times. The phases were separated and the dichloromethane was introduced into a 500 L autoclave.
Reference: [1] Patent: CN104030962, 2016, B, . Location in patent: Paragraph 0036-0041
  • 19
  • [ 6066-82-6 ]
  • [ 32315-10-9 ]
  • [ 74124-79-1 ]
Reference: [1] Synthesis, 1993, # 1, p. 103 - 106
[2] Synthetic Communications, 1998, vol. 28, # 21, p. 4019 - 4024
[3] Synthetic Communications, 2005, vol. 35, # 24, p. 3119 - 3121
  • 20
  • [ 6066-82-6 ]
  • [ 503-38-8 ]
  • [ 74124-79-1 ]
Reference: [1] Patent: US4341707, 1982, A,
  • 21
  • [ 6066-82-6 ]
  • [ 55750-53-3 ]
  • [ 55750-63-5 ]
YieldReaction ConditionsOperation in experiment
95% With dicyclohexyl-carbodiimide In acetonitrile at 0 - 20℃; Inert atmosphere Under nitrogen protection, 4.7 g (22 mmol) of MC and 25 g (22 mmol) of HOSu were added to 50 ml of acetonitrile.Another 4.5 g (22 mmol) of DCC was dissolved in 25 ml of acetonitrile,Keeping the internal temperature around 0°C,It was slowly dropped into the reaction solution.The reaction solution was reacted at 0°C for 2 hours and then reacted overnight at room temperature.filter,The filter cake was washed with acetonitrile 10ml×3.The filtrate was concentrated to dryness under reduced pressure.The resulting oil was dried under reduced pressure at room temperature for 6 h to give 6.4 g of light brown solid.Yield 95percent.
70% With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3 h; Dicyclohexyl-carbodiimide (2.68 g, 13.02 mmol) and N-hydroxysuccinimide (1 .36 g, 1 1 .84 mmol) are added at room temperature to a stirrer solution of compound [4] (2.5 g, 1 1 .84 mmol) in anhydrous dichloromethane (15 mL) and the mixture stirred at room temperature for 3 hours. The white solid is filtered 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 resulting residue is subjected to flash column chromatography with a medium pressure system Sepacore® Buchi (silica gel; gradient A: petroleum ether/B: ethyl acetate; Bpercent 0-80 in 15 minutes) to give the activated acid [5] as a white solid, 2.4 g (70percent). MS: m/z 309 [M+H]+.1H NMR (400 MHz, MeOD) δ 6.78 (s, 2H), 3.49 - 3.46 (m, 2H), 2.82 (s, 4H), 2.62 - 2.59 (m, 2H), 1 .78 - 1 .65 (m, 2H), 1 .64 - 1 .50 (m, 2H), 1 .46 - 1 .26 (m, 2H).13C NMR (100 MHz, MeOD) δ 169.8, 169.0, 167.3, 132.5, 35.4, 28.6, 26.1 , 23.8, 23.6, 22.3.
48% With dicyclohexyl-carbodiimide In ethyl acetate at 0 - 20℃; for 20 h; To a stirred solution of 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoate (3.08 g, 14.6 mmol, 1.0 eq) and N-hydroxysuccinimide (1.76 g, 15.3 mmol, 1.05 eq) in EtOAc (30 mL) at 0 °C, was added dicyclohexylcarbodiimide (3.16 g, 15.3 mmol, 1.05 eq). The reaction was then allowed to warm to rt. After 20 h, the reaction was filtered and washed with EtOAc and the filtrate concentrated. The residue was purified by flash chromatography to yield the title compound (2.16 g, 48percent) as a clear oil that solidified slowly to a waxy white solid. NMR (400 MHz, Chloroform-i/) δ 6.71 (s, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.86 (s, 4H), 2.63 (t, J = 7.4 Hz, 2H), 1.80 (p, J= 7.4 Hz, 2H), 1.73 - 1.57 (m, 2H), 1.50 - 1.35 (m, 2H). m/z calcd. for C14H16N206 = 308.10. Found [M+H]+ = 309.13. Rf = 0.28 (50percent EtOAc/Hex).
48% With dicyclohexyl-carbodiimide In ethyl acetate at 0 - 20℃; for 20 h; To a stirred solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl)hexanoate (3.08 g, 14.6 mmol, 1.0 eq) and N-hydroxysuccinimide (1.76 g, 15.3 mmol, 1.05 eq) in EtOAc (30 mL) at 0 °C,was added dicyclohexylcarbodiimide (3.16 g, 15.3 mmol, 1.05 eq). The reaction was then allowed towarm to rt. After 20 h, the reaction was filtered and washed with EtOAc and the filtrate concentrated. The residue was purified by flash chromatography to yield the title compound (2.16 g, 48percent) as a clear oil that solidified slowly to a waxy white solid. ‘H NMR (400 MHz, Chloroform-d) ö 6.71 (s, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.86 (s, 4H), 2.63 (t, J = 7.4 Hz, 2H), 1.80 (p, J = 7.4 Hz, 2H), 1.73 — 1.57 (m,2H), 1.50 1.35 (m, 2H). m/z calcd. for C,4H,6N206 = 308.10. Found [M+H] = 309.13. Rf= 0.28 (50percent EtOAc/Hex)

Reference: [1] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0064; 0065; 0066
[2] Patent: WO2018/178060, 2018, A1, . Location in patent: Page/Page column 58; 60; 61
[3] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[4] Patent: WO2015/95953, 2015, A1, . Location in patent: Page/Page column 118
[5] Patent: WO2016/41082, 2016, A1, . Location in patent: Page/Page column 97; 98
[6] Organic and Biomolecular Chemistry, 2014, vol. 12, # 34, p. 6624 - 6633
[7] Patent: CN108743968, 2018, A, . Location in patent: Paragraph 0007; 0008; 0009
  • 22
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  • [ 6066-82-6 ]
  • [ 60-32-2 ]
  • [ 55750-63-5 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 41, p. 13091 - 13096
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4516 - 4520
[3] Synthesis (Germany), 2014, vol. 46, # 22, p. 3085 - 3096
  • 23
  • [ 6066-82-6 ]
  • [ 57079-14-8 ]
  • [ 55750-63-5 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1985, vol. 327, # 5, p. 789 - 798
[2] Journal of Organic Chemistry, 2011, vol. 76, # 21, p. 9169 - 9174
  • 24
  • [ 6066-82-6 ]
  • [ 55750-53-3 ]
  • [ 55750-63-5 ]
  • [ 57-13-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 17, p. 3400 - 3406
  • 25
  • [ 6066-82-6 ]
  • [ 57079-14-8 ]
  • [ 55750-63-5 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 21, p. 9169 - 9174
  • 26
  • [ 6066-82-6 ]
  • [ 1119-62-6 ]
  • [ 57757-57-0 ]
YieldReaction ConditionsOperation in experiment
85% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2 h; To the solution of 3,3'-dithioldipropionic acid (1 g, 4.75 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (2.16 g, 10.5 mmol) and N-hydroxysuccinimide (1.21 g, 10.5 mmol) were added. The mixture was stirred for 2 h at room temperature. The solution was concentrated in vacuo, and the obtained residue was subjected to silica column chromatography (ethyl acetate/hexane = 1:5) to give the NHS ester 2 (1.63 g, 85percent). 1H NMR (DMSO-d6, 400 MHz) δ 3.16 (m, 8H), 2.82 (s, 8H). FAB (DMSO-d6) [(M+H)+] calcd 405, found 405.
70% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; One kind of bis(succinimidyl) 3,3'-dithiodipropionate synthesis, the following steps: -; Weigh 3,3'-thiodipropionic acid (6.0g, 0.028mol), N-hydroxysuccinimide (8.0g, 0.06mol), EDC hydrochloride (13g, 0.06 mol), into a 100mL round bottom flask, 40mL of methylene chloride was added, stirred at room temperature, the solid gradually dissolved overnight reaction, there is generated a white solid. Filtered and dried to give the product (8.05g, white solid), yield 70percent.
49% With dicyclohexyl-carbodiimide In dichloromethane; acetone at 20℃; for 24 h; .
3,3'-Dithiobis(propanoic acid) (9.5 g, 45.2 mmol) was dissolved in a mixture of acetone (600 mL) and dichloromethane (600 mL) with stirring at room temperature. N-Hydroxysuccinimide (12.68 g, 110.2 mmol, 2.44 eq) was dissolved in the solution, then 1,3-dicyclohexylcarbodiimide (25.9 g, 125.5 mmol, 2.78 eq) was cautiously added.
The mixture was allowed to stir at room temperature for 24 hours, after which time the solution was vacuum filtered and the residual solid discarded.
The solvent was removed from the filtrate under vacuum, and the oily residue was redissolved in dichloromethane (ca 200 mL).
The solution was reduced in volume (ca. 50 mL) and cooled, giving the product as a colourless, crystalline solid (8.90 g, 49percent yield).
1H-NMR (d6-DMSO): δ 2.80 (s, 8H), 3.05 (m, 8H).
13C-NMR (d6-DMSO): δ 25.8, 30.7, 32.3, 167.9, 170.4 ppm.
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 96 - 100
[2] Organic and Biomolecular Chemistry, 2005, vol. 3, # 12, p. 2255 - 2261
[3] Patent: CN105315191, 2016, A, . Location in patent: Paragraph 0021; 0022; 0023
[4] Patent: US7074766, 2006, B1, . Location in patent: Page/Page column 44
[5] Angewandte Chemie - International Edition, 2010, vol. 49, # 26, p. 4405 - 4408
[6] Organic Letters, 2007, vol. 9, # 6, p. 1009 - 1012
[7] Rapid Communications in Mass Spectrometry, 2013, vol. 27, # 1, p. 238 - 248
[8] Patent: CN104667297, 2017, B, . Location in patent: Paragraph 0056-0058
[9] Nanomedicine: Nanotechnology, Biology, and Medicine, 2018, vol. 14, # 4, p. 1123 - 1136
  • 27
  • [ 6066-82-6 ]
  • [ 107-96-0 ]
  • [ 57757-57-0 ]
Reference: [1] Chemistry - A European Journal, 2014, vol. 21, # 10, p. 3956 - 3967
  • 28
  • [ 6066-82-6 ]
  • [ 814-68-6 ]
  • [ 38862-24-7 ]
YieldReaction ConditionsOperation in experiment
70% With triethylamine In chloroform at 0℃; for 2.5 h; N-hydroxysuccinimide (10 g, 0.086 mol) and triethylamine (13.2 g, 0.129 mol) were dissolved in chloroform (130 mL) at 0 °C. Acryloyl chloride (8.6 g, 0.094 mol) was added dropwise over a period of 2 hours to the stirred reaction mixture.
The reaction is described in Scheme 1, .
After being stirred an additional 30 minutes at 0 °C, the solution was washed twice with 60 mL saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated so as to get a residual volume of 30 mL. An ethyl acetate/pentane mixture (14 mL, 1:3 v/v) was added and the temperature was maintained at 0 °C to induce NAS crystallization overnight (70percent yield).
1 H NMR (CDCl3) d (ppm): 2.95 (S, 4H, CH2CH2), 6.20 (m, 1 H, CH=CH2), 6.4 (m, 1H, CH=CH2) and 6.75 (m, 1 H, CH=CH2).
46% With triethylamine In chloroform at 12℃; for 2.5 h; Inert atmosphere 2,5-Dioxopyrrolidin-1 -yl acrylate (28)
To a cooled (ice-bath) solution of /V-hydroxysuccinimide (27) (6.41 g, 55.8 mmol) and NEt3 (8.5 ml_, 61.0 mmol) in CHCI3 (100 mL) was added acryloyl chloride (26) dropwise under argon. The temperature of the mixture was kept below 12°C during the addition. After stirring for 2.5 h, the reaction mixture was subsequently washed with ice-water (100 mL), water (100 mL), and brine (100 mL). The organic phase was dried over Na2S04, filtered, concentrated in vacuo to 15 mL, and filtered through a pad of celite. The celite was washed with CHCI3 (15 mL), the filtrate was diluted with EtOAc (2 mL) and petroleum ether (1 1 mL), and stored at -20 °C overnight. The formed precipitate was filtered off and dried in vacuo to yield 28 (4.30 g, 25.4 mmol, 46percent) as white needles.
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 10, p. 4528 - 4560
[2] Chemical Communications, 2014, vol. 50, # 95, p. 15045 - 15048
[3] Organic Letters, 2002, vol. 4, # 5, p. 737 - 740
[4] Chemical Communications, 2009, # 46, p. 7107 - 7109
[5] Journal of Medicinal Chemistry, 1995, vol. 38, # 21, p. 4179 - 4190
[6] Analytical Chemistry, 2003, vol. 75, # 7, p. 1658 - 1663
[7] Journal of Materials Chemistry, 2011, vol. 21, # 34, p. 12917 - 12926
[8] Patent: EP2960263, 2015, A1, . Location in patent: Paragraph 0098
[9] Angewandte Chemie - International Edition, 2018, vol. 57, # 6, p. 1557 - 1562[10] Angew. Chem., 2018, vol. 130, p. 1573 - 1578,6
[11] Organic Letters, 2014, vol. 16, # 15, p. 3974 - 3977
[12] Macromolecules, 2004, vol. 37, # 7, p. 2371 - 2382
[13] Patent: WO2015/136027, 2015, A1, . Location in patent: Page/Page column 48
[14] Journal of the American Chemical Society, 2003, vol. 125, # 2, p. 320 - 321
[15] Angewandte Chemie - International Edition, 2008, vol. 47, # 10, p. 1875 - 1878
[16] International Journal of Pharmaceutics, 2011, vol. 420, # 2, p. 333 - 340
[17] Angewandte Chemie - International Edition, 2017, vol. 56, # 14, p. 3880 - 3885[18] Angew. Chem., 2017, vol. 129, # 14, p. 3938 - 3943,6
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Reference: [1] Tetrahedron, 1998, vol. 54, # 14, p. 3489 - 3494
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 19, p. 6841 - 6850
[3] Journal of the American Chemical Society, 2010, vol. 132, # 2, p. 472 - 483
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  • [ 2524-64-3 ]
  • [ 38862-24-7 ]
Reference: [1] Patent: US5734064, 1998, A,
  • 31
  • [ 6066-82-6 ]
  • [ 624-83-9 ]
  • [ 18342-66-0 ]
YieldReaction ConditionsOperation 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
  • 32
  • [ 6066-82-6 ]
  • [ 79-04-9 ]
  • [ 27243-15-8 ]
YieldReaction ConditionsOperation 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
  • 33
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  • [ 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
  • 34
  • [ 6066-82-6 ]
  • [ 65-85-0 ]
  • [ 23405-15-4 ]
YieldReaction ConditionsOperation 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
  • 35
  • [ 6066-82-6 ]
  • [ 100-52-7 ]
  • [ 23405-15-4 ]
YieldReaction ConditionsOperation 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
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  • 36
  • [ 6066-82-6 ]
  • [ 94-36-0 ]
  • [ 23405-15-4 ]
YieldReaction ConditionsOperation 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.
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  • 46
  • [ 143-07-7 ]
  • [ 6066-82-6 ]
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YieldReaction ConditionsOperation 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.
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YieldReaction ConditionsOperation in experiment
72%
Stage #1: With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 0.166667 h;
Stage #2: at 20℃; for 22.5 h;
Tetradecanoic acid [3.00 g (13.1 mmol)] and 3.24 g of N,N′-dicyclohexylcarbodiimide (15.7 mmol) were dissolved in 26.2 ml of dry tetrahydrofuran and stirred at room temperature for 10 min. Then, 1.81 (15.7 mmol) of N-hydroxysuccinimide in 14.1 ml of the same solvent were added and the reaction mixture was stirred at room temperature for 22.5 h. TLC analysis [CHCl3/MeOH (50:1, v/v)] revealed a complete conversion of the educt. After this, the reaction mixture was filtrated by suction. The solvent was removed under reduced pressure and the residue was recrystallized from ethanol containing a trace of H2O (34). The product was obtained as a colorless solid (3.08 g, 72percent), 1H-NMR (300 MHz,CDCl3): [ppm] = 2.83 (s, 4H, H-3, 4), 2.60 (t, 2H,3 J H2 ′ -H3 ′ = 7.5 Hz, H-2 ′ ), 1.74 (tt, 2H, 3 J H3′-H4′ = 7.5 Hz, 3 JH3′-H2′ = 7.5Hz, H-3 ′ ), 1.46-1.18 (m, 20H), 0.88 (t, 3H, 3 J H14 ′ -H13 ′ = 6.7 Hz,H-14 ′ ), 13 C-NMR (75 MHz, CDCl3): [ppm] = 169.15 (R C ON,C-2, 5), 168.68 (R C O 2 R ′ , C-1 ′ ), 31.90 (CH 2 , C-2 ′ ), 30.93 (CH 2 ,C-12 ′ ), 29.63-28.77 (8 CH 2 ), 25.57 (CH 2 , C-3, 4), 24.56 (CH 2 ,C-3 ′ ), 22.67 (CH 2 , C-13 ′ ), 14.09 (CH 3 , C-14 ′ ), EI-MS: m/z 211.3[M+-C4H4NO3], 129.1 [C8H17O+ ], 98.2 [C7H14 ], 84.1 [C6H12 ], CHN analysis: calc.: C, 66.43; H, 9.60; N, 4.30, found: C, 66.03; H,9.63; N, 4.29.
67% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane Myristic acid (1.5 g, 6.6 mmol) was dissolved in dichloromethane (30 ml) and the mixture was stirred. To this solution were added N-hydroxysuccinimide (0.91 g, 1.2 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (1.5 g, 1.2 eq.), and the mixture was stirred overnight. After washing twice with water, the mixture was washed once with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the object product (1.4 g, yield 67percent). The NMR measurement results of the obtained myristic acid-N-hydroxysuccinimide ester (C14-NHS) are shown below. Myristic Acid-N-Hydroxysuccinimide Ester (C14-NHS) (0195) 1H-NMR (CDCl3) δ: 2.83 (4H, s), 2.60 (2H, t, J=7.6 Hz), 1.74 (2H, q, J=7.6 Hz), 1.44 (2H, q, J=6.9 Hz), 1.48-1.22 (18H, m), 0.88 (3H, t, J=6.8 Hz).
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  • 54
  • [ 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]+.
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[2] Patent: EP659764, 1995, A2,
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YieldReaction ConditionsOperation in experiment
100% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72 h; Inert atmosphere; Sealed tube Step A: To a round-bottom flask was weighed Boc-L-valine (1.03 g, 4.74 mmol), N-hydroxysuccinimide (1.22 g, 10.6 mmol), and EDC (1.60 g, 8.35 mmol). The reagents were dissolved in dry DCM (30 mL), the flask sealed via rubber septum, purged with argon, and the reaction stirred at ambient temperature. After 3 days no Boc-valine remained by TLC (after staining with ninhydrin), so the reaction was washed with water and sat. aq. NaHCO3, the aqueous layer extracted with DCM, combined organic layers washed with brine, dried over Na2SO4, and filtered. The filtrate was then evaporated and dried in vacuo giving Boc-L-valine-succinate as a white solid (1.52 g, 100percent). 1H-NMR (300 MHz, CDCl3): ^ 4.98 (br d, 1H), 4.58 (dd, 1H), 2.82 (m, 4H), 2.27 (m, 1H), 1.44 (s, 9H), 1.03 (dd, 6H). Boc-L-valine-L-citrulline (3):
13.28 g
Stage #1: at 20℃; for 0.05 h;
Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 0 - 20℃; for 18 h;
[000701 A solution of N-Hydroxysuccinimide (5.0 g, 43.44 mmol) and Boc-Val-OH (la, 9.462 g, 43.44 mmol ) in THF (83 mL) was stirred in room temperature for 3.0 minutes. Then DCC (9.856 g, 45.57 mmol) in CH2C12 (83 mL) was slowly added to the solution at 0°C and then warmed to room temperature. The reaction mixture was stirred for further 18 hours. The solution was cooled to 0°C and the precipitate was filtered and washed with EA (100 mL), dried over reduced pressure to give Boc-Val-OSu (ib, 13.28 g). ‘H NMR (500 MHz, DMSO-d6): ö: 5.02 (d, 1H), 4.60 (d, 1H), 2.85 (s, 4H), 2.31 (m, 1H), 1.48 (m, 9H), 1.05 (m, 6H). MS (M+1 ): 314.8.
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YieldReaction ConditionsOperation in experiment
90% With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 16 h; Step 1.
To a stirred solution of compound 39-1 (1 g, 4 mmol), compound 39-2 (459 mg, 4 mmol) in THF (20 mL) was added DCC (908 mg, 4.4 mmol) at 0°C. The reaction mixture was stirred at r.t. for 16 h. The mixture was filtered and the filtrate was concentrated to give compound 39-3 (Yield: 90 percent).
85.5 g With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 5℃; for 20.75 h; 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoic acid (65g, 259mMol), tetrahydrofuran (450ml) were charged to a flask. N-hydroxy succinimide (33.3g 285mMol) was added to the reaction mass. Reaction mass was stirred for lOmins. Dimethyl amino pyridine (DMAP, lg) was added to the reaction mass. Reaction mass was stirred and temperature of reaction mass was decreased to 5°C. Solution of DCC in THF (42.5percent, 200ml) was added dropwise to the reaction mass over a period of 45 minutes at 5°C. Reaction mass was stirred for 20 hours. Obtained solid was filtered; solvent was stripped off under reduced pressure. Solid was washed with heptane (3x250ml ), to get crude material (2,5- dioxopyrrolidin-l-yl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate) with sufficient purity. Yield 85.5 g. (0091) JH NMR (DMSO-D6, 400 MHz): δ 1.02(d,6H), 2.24(m,lH), 2.82(s,4H), 4.37(q,lH), 5.09 (s,2H), 7.34-7.44 (m,5H), 8.09 (d,lH). (0092) 13C NMR (DMSO D6, 100MHz): δ 18.3, 19.3, 25.4, 30.1, 58.1, 65.9, 127.7, 128.4,136.7, 156.3, 168.0, 170.0, 172.8 (0093) FTIR (KBr): 3327, 2933, 2117, 1816, 1784, 1741, 1527, 1204, 893 cm"1 . (0094) MS (EI): Q7H20N2O6 Exact mass: 348.35, observed mass: 366.2 (+ H20).
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YieldReaction ConditionsOperation in experiment
91% at 20℃; To a solution of (+)-biotin (0.82 mmol, 200 mg) and N-hydroxysuccinimide (0.89 mmol, 102 mg) was added 3-(ethyliminomethylidenamino)-N,N-dimethylpropan-1-aminehydrochloride (0.96 mmol, 184 mg). The reaction mixture was stirred overnight at room temperature and concentrated to give a white solid. The crude solid was mixed with isopropanol, heated up to 70 °C and cooled down. The pure product was filtered off as white powder in 91percent yield (0.75 mmol, 255 mg).
90% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 12 h; Heating D-Biotin (5.00 g, 2.05 mmol) and N-hydroxysuccinimide (2.36 g, 2.05 mmol) were dissolved in hot DMF (150 mL). N,N′-Dicyclohexylcarbodiimide (5.50 g, 2.67 mmol) was added to the above reaction mixture, and was stirred overnight at room temperature. The dicyclohexyl urea was filtered, and the filtrate was evaporated and triturated with ether. The white precipitate was obtained and washed with ether to give a white powder in 90percent. (6.29 g) yield (1H NMR(400 MHz, CDCl3): 1.5–1.6 (m, 2H)), 1.6–1.9 (m, 4H) 2.58–2.70 (m, 2H),2.75 (d, 1H,) 2.86 (s, 4H), 2.87–2.97 (m, 1H), 3.16 (m, 1H), 4.33 (m, 1H), 4.52 (m, 1H), 4.96 (s, 1H), 5.23 (s, 1H). m/z (ESI) found 342 (M + H)+.C14H19N3O5S calculated 341.
79% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20 - 70℃; D-Biotin (0.819 mmol) and N-hydroxysuccinimide (0.819 mmol) were dissolved into anhydrous DMF (6 ml) at 70 00 while stirring. DCC (1.064 mmol) was added and the solution was stirred overnight at room temperature. The formed DCU was filtered off and the solvent was removed under reduced pressure. The residue was taken up into boiling isopropanol and the solution was allowed to cooldown to RT. The target compound precipitated and the product was filtered off as a white solid.Yield: 79percent, MS (ESI) m/z 364.1 [M ÷ Na]NMR (DMSO-d6, 400 MHz): 6 1.42-1.67 (m, 6H), 2.57-2.60 (d, J=12.4 Hz, 1H), 2.68 (t, J=7.3 Hz, 2H), 2.81-2.90(m, 5H), 3.11 (m, 1H), 4.14-4.17(m, 1H), 4.29-4.35 (m, 1H), 6.37(s, 1H), 6.42 (s, 1H)
70% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20 - 50℃; 1. Synthesis of Biotinyl-N-hydroxysuccinimide (Scheme I) . D-Biotin (0.49 g, 2.0 mmol, Sigma B4501) was added to N-hydroxysuccinimide (0.3 g, 2.7 mmol, Pierce HC102040) into 20 mL DMF (Sigma 227056), heated to 50°C until most of the material dissolved. A solution of Ν,Ν'- Dicyclohexylcarbodiimide (0.45g, 2.1 mmol, Sigma D80002) in 5 mL DMF was added dropwise to the aforementioned solution. The resulting solution was stirred overnight at room temperature during which time a white precipitate was formed. The reaction mixture was filtered through celite, and the filtrate was triturated with diethyl ether (Sigma 309966) . The white precipitate was vacuum filtered and then washed with diethyl ether to give a white powder. The yield was 0.52 g (~ 70 percent final efficiency) .
68%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 78℃; Inert atmosphere
Stage #2: at 20℃;
Example 2. Biotin N-Hydroxysuccinimide Ester (5); [0157] To a solution containing 101 mg (0.41 mmol) of biotin in 2 rnL of DMF at 78 0C was added 67 mg (0.41 mmol) of l,l '-carbonyldiimidazole with continued heating until CO2 evolution ceased. The solution was equilibrated to room temperature and stirred for an additional 3 h. To the reaction mixture was added a solution of 47 mg (0.41 mmol) of N- hydroxysuccinimide in 2 mL of DMF. The solution was stirred overnight at room temperature. The solvent was removed under diminished pressure and the product was crystallized from 2-propanol and then DMF-ether to afford 5 as a fine white powder: yield 95 mg (68percent); 1H NMR (CDCl3) δ 1.43-1.66 (m, 7H), 2.58 (m, IH), 2.66 (t, 2H), 2.75 (s, 4H), 3.05 (m, IH), 4.11 (m, IH), 4.27 (m, IH), and 6.36 (d, 2H, J = 18.4 Hz); 13C NMR (CDCl3) δ 55.19, 60.68, 63.46, 65.43, 69.11, 70.08, 73.25, 75.85, 79.05, 101.35, 101.83, 126.32, 127.20, 127.81, 128.11, 128.16, 128.48, 128.72, 129.18, 137.81, and 138.24; mass spectrum (MALDI-TOF), m/z 342.1 (M + H)+.
65% With diisopropyl-carbodiimide In N,N-dimethyl-formamide at 45℃; [0074] To 2 grams of biotin was added 2 eq of N,N’-diisopropylcarbodiimide and 3 eq of Nhydroxysuccinimide in 0.2 M DMF at 45 °C to yield compound 6. One eq of t-Boc protected PEG amine (3) was then added in methylene chloride at room temperature to give compound 7 and deprotected using TFA to afford compound 8, followed be activation using 2 eq of N,N’-diisopropylcarbodiimide and 3 eq of N-hydroxysuccinimide to form its activated ester, compound 9. G3 dendrimer DNT-296 was added to compound 9 in methanol at room temperature to yield compound 10.
61% With CDI In N,N-dimethyl-formamide; isopropyl alcohol 1.
Preparation of Biotin-N-hydroxysuccinimide
Biotin (1.0 g, 4.1 mmole) was dissolved in 10 ml DMF (dry) with heating at 80° C. in oil bath. CDI (665 mg, 4.1 mmoles) was added and the mixture was heated at 80° C.
The reaction mixture was stirred at 80° C. for 30 minutes, then at room temperature for 2 hours; a white precipitate formed. N-hydroxysuccinimide (475 mg, 4.1 mmoles) was added and the reaction mixture was stirred at room temperature overnight.
DMF was removed under vacuum on rotary evaporator.
The solid residue was dissolved in 250 ml of refluxing isopropanol, filtered, and stored in the cold room overnight.
The precipitate was filtered, washed one time with cold isopropanol and dried in vacuo at 45° C. overnight to give 870 mg (61percent yield) of the desired product.
57% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere Biotin (498mg, 2mmol) was dissolved in anhydrous DMF (10mL) by heating to approximately 70°C for 10min or until fully dissolved. The reaction mixture was allowed to cool to room temperature before adding N-hydroxysuccinimide (240mg, 2.1mmol) with stirring at room temperature. A solution of N,N′-dicyclohexylcarbodiimide (438mg, 2.13mmol) in anhydrous DMF (2mL) was added dropwise to the stirred solution. The reaction was then stirred overnight at room temperature over which time a white precipitate formed (N,N′-dicyclohexylurea). The precipitate was removed by filtration and washed with DMF. The filtrate was diluted with EtO2 until a white precipitate formed. The precipitate was collected by filtration and rinsed with EtO2 then dried to give the crude product 26 as a white solid (395mg, 57percent): m.p. (decomp.) 178–190°C; IR (νmax, ATR): 3227, 2941, 2876, 1818, 1788, 1729, 1698, 1465, 1369, 1210, 1071, 861, 739, 656cm−1; 1H NMR (600MHz, DMSO-d6): δ=6.40 (1H, s, NH), 6.35 (1H, s, NH), 4.30 (1H, m, HNCHCHNH), 4.14 (1H, m, HNCHCHNH), 3.10 (1H, m, SCH), 2.84–2.78 (5H, contains NCOCH2CH2 and SCHAHB), 2.67 (2H, t, J=7.7Hz, CH2CH2CO2N), 2.57 (1H, d, J=12.4Hz, SCHAHB), 1.64 (3H, contains CHAHBCH2CH2CH2CO2N), 1.52–1.36 (3H, contains CHAHBCH2CH2CH2COON); 13C NMR (150MHz, DMSO-d6): δ=170.3, 169.0, 162.7, 61.0, 59.2, 55.3, 40.1 (overlaps with NMR solvent peak), 30.0, 27.9, 27.6, 25.5, 24.3; HRMS (ESI): M+H+, found 342.1128. C14H20N3O5S+ requires 342.1118.
30%
Stage #1: With pyridine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 0.5 h;
Stage #2: for 24 h;
Biotin (24.4mg, 0.1mmol) was dissolved to N, N- dimethylformamide (DMF) (10mL),Pyridine (Py) (2mL) and N, N'- dicyclohexylcarbodiimide imide (DCC) (41.2mg, 0.2mmol), after half an hour the reaction was added N- hydroxysuccinimide (N-Hydroxysuccinimide ) (13.8mg, 0.12mmol), the reaction is stopped after 24h the reaction, after removal of DMF by filtration and the filtrate evaporated under reduced pressure, then dissolved in hot isopropanol solvent and then filtered and the filtrate precipitated 2 days in a refrigerator at 4 finally filtered to give a white solid precipitated 10.2mg, yield 30percent.
1 g With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 50℃; for 24 h; Inert atmosphere Into a 50 mL reaction flask, 1.0 g of biotin [manufactured by Wako Pure Chemical Industries, Ltd.], 0.59 g of NHS, and 19 g of DMF were charged and the mixture was dissolved with stirring at 50° C. To this solution, 1.0 g of DCC was added and the resultant reaction liquid was stirred at 50° C. for 24 hours in a nitrogen atmosphere. Subsequently, insoluble substances were removed from the reaction liquid by filtration and then DMF was removed by distillation. The obtained residue was washed with 3 g of diethyl ether and then recrystallized with 15 g of IPA. The obtained white crystal was filtered under reduced pressure and dried under vacuum to obtain 1.0 g of biotin N-hydroxysuccinimide ester.

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[53] Analytical Biochemistry, 2011, vol. 413, # 1, p. 30 - 35
[54] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 586 - 590
[55] European Journal of Organic Chemistry, 2013, # 3, p. 465 - 473
[56] Chemistry and Physics of Lipids, 2015, vol. 188, p. 27 - 36
[57] Asian Journal of Chemistry, 2013, vol. 25, # 2, p. 811 - 816
[58] Bioconjugate Chemistry, 2016, vol. 27, # 11, p. 2780 - 2790
[59] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 219 - 228
[60] Organic and Biomolecular Chemistry, 2014, vol. 12, # 34, p. 6624 - 6633
[61] Patent: WO2014/203156, 2014, A2, . Location in patent: Paragraph 0001-0002
[62] Journal of Nanoscience and Nanotechnology, 2015, vol. 15, # 1, p. 176 - 180
[63] Journal of Polymer Science, Part A: Polymer Chemistry, 2015, vol. 53, # 17, p. 2036 - 2049
[64] Journal of Materials Chemistry B, 2015, vol. 3, # 41, p. 8170 - 8179
[65] Patent: US9284393, 2016, B2, . Location in patent: Page/Page column 15
[66] Organic and Biomolecular Chemistry, 2014, vol. 12, # 47, p. 9638 - 9643
[67] Molecules, 2016, vol. 21, # 5,
[68] Patent: US2016/272669, 2016, A1, . Location in patent: Paragraph 0056-0058
[69] Journal of the American Chemical Society, 2017, vol. 139, # 1, p. 156 - 170
[70] Chemical Communications, 2017, vol. 53, # 36, p. 5020 - 5023
[71] Patent: CN106866743, 2017, A, . Location in patent: Paragraph 0016; 0119
[72] Chemistry - A European Journal, 2017, vol. 23, # 49, p. 11945 - 11954
[73] Angewandte Chemie - International Edition, 2018, vol. 57, # 13, p. 3406 - 3410[74] Angew. Chem., 2018, vol. 130, p. 3464 - 3468,5
[75] Chemical Communications, 2018, vol. 54, # 68, p. 9506 - 9509
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[77] RSC Advances, 2018, vol. 8, # 57, p. 32775 - 32793
  • 81
  • [ 6066-82-6 ]
  • [ 35013-72-0 ]
YieldReaction ConditionsOperation in experiment
2.7 g With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; Heating Step 1: To a round bottom flask with a stirring bar, biotin (2.0 g, 8.2 mmol) and DMF (60 mL) were added. After the solid was dissolved with heat, N-hydroxysuccinimide (0.944 g, 8.2 mmol) and DCC (2.2 g, 10.7 mmol) were added. The reaction mixture was stirred at room temperature overnight. The white solid was filtered, and the DMF was evaporated under reduced pressure. The resulting residue was further purified by re-crystallization from isopropanol to give the desired product 2 (2.7 g, M+H+ = 342.5) as white crystals.
Reference: [1] Patent: WO2015/6754, 2015, A2, . Location in patent: Paragraph 00274
  • 82
  • [ 6066-82-6 ]
  • [ 101187-31-9 ]
  • [ 35013-72-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 11, p. 1406 - 1410
[2] Journal of the American Chemical Society, 2009, vol. 131, # 7, p. 2438 - 2439
  • 83
  • [ 6066-82-6 ]
  • [ 20160-60-5 ]
  • [ 78269-85-9 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In acetonitrile at 0 - 20℃; for 16 h; Inert atmosphere TeocCl reagent S13 was dissolved in CH3CN (105 mL) at 0 °C. Then, NHS (5.22 g,45.4 mmol, 1.30 equiv) and Et3N (4.59 g, 45.4 mmol, 1.30 equiv; in 11.0 mL CH3CN) wereadded. The reaction mixture was stirred at 0 °C rt. After 16 h, the reaction mixture waspoured into H2O. The aqueous layer was extracted with Et2O (6×). The combined organiclayers were washed with H2O (2×), HCl (1.0 M), followed by H2O and subsequent dried overMgSO4, filtered a well as concentrated under reduced pressure. The desired TeocOSu S14(7.72 g, 29.8 mmol, 85percent over two steps) was collected as colourless solid.
Reference: [1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 564 - 570
[2] Synthesis, 1987, # 4, p. 346 - 349
[3] Patent: US6627660, 2003, B1,
[4] Patent: US2004/116391, 2004, A1,
  • 84
  • [ 6066-82-6 ]
  • [ 31972-52-8 ]
  • [ 29248-48-4 ]
YieldReaction ConditionsOperation in experiment
65.4 mg
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
  • 85
  • [ 6066-82-6 ]
  • [ 372-09-8 ]
  • [ 56657-76-2 ]
Reference: [1] Polish Journal of Chemistry, 1992, vol. 66, # 1, p. 111 - 118
[2] Farmaco, 1992, vol. 47, # 11, p. 1367 - 1383
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7781 - 7788
[4] Patent: WO2010/14930, 2010, A2, . Location in patent: Page/Page column 29-30
  • 86
  • [ 6066-82-6 ]
  • [ 35661-39-3 ]
  • [ 73724-40-0 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 7, p. 999 - 1005
[2] Helvetica Chimica Acta, 2018, vol. 101, # 1,
[3] Journal of the American Chemical Society, 2003, vol. 125, # 45, p. 13680 - 13681
[4] Chemical Communications, 2009, # 4, p. 407 - 409
[5] Tetrahedron, 2009, vol. 65, # 19, p. 3871 - 3877
[6] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4182 - 4187
[7] Patent: WO2015/21092, 2015, A1, . Location in patent: Page/Page column 36
[8] Bioconjugate Chemistry, 2015, vol. 26, # 11, p. 2261 - 2278
[9] Patent: WO2015/187540, 2015, A1, . Location in patent: Page/Page column 22; 23
  • 87
  • [ 6066-82-6 ]
  • [ 110-15-6 ]
  • [ 30364-60-4 ]
YieldReaction ConditionsOperation 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
  • 88
  • [ 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
  • 89
  • [ 6066-82-6 ]
  • [ 57078-98-5 ]
  • [ 80307-12-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 5, p. 901 - 919
[2] Patent: WO2013/162757, 2013, A1, . Location in patent: Sheet 7
[3] Organic and Biomolecular Chemistry, 2014, vol. 12, # 34, p. 6624 - 6633
[4] Patent: US2016/228572, 2016, A9, . Location in patent: Paragraph 0185
  • 90
  • [ 6066-82-6 ]
  • [ 116965-29-8 ]
  • [ 80307-12-6 ]
YieldReaction ConditionsOperation in experiment
104.2g With tributyl-amine In acetonitrile at 20℃; for 2 h; N-maleimidobutyric acid (99 g, 0.54 mol) and acetonitrile (300 ml) were placed in a500 ml three-necked flask andthionyl chloride (93.6 g, 0.82 mol) was added. The reaction was warmed to reflux and a large amount of gas was released .After the reaction was refluxed for 4h, the reaction became clear,acetonitrile and excess thionyl chloride were removed by concentration, and 200 ml of acetonitrile was added to remove the remaining acid in one pass to obtaincrudeN-maleimidobutyrylchloride.The crude product was dissolved in 200ml of acetonitrile was added dropwise to N- hydroxysuccinimide (69g, 0.6mol) and tri-n-butylamine (148g, 0.8mol) was dissolved in 300ml of acetonitrile, with ice water cooling to control the temperature does not exceed 20 , drip finished at room temperature for2h.The reaction solution was concentrated to remove acetonitrile, dissolved in 400 ml of methylene chloride, and dissolved in 200 ml of dichloromethane to remove tri-n-butylaminehydrochloride and 100 ml of 1N hydrochloric acid to remove excess tri-n-butylamine and 200 ml of saturated saline solution, Drywhite solid 139g, a mixed solvent of ethyl acetate and petroleum ether to give a white solid after recrystallization 104.2g, HPLC purity 98.9percent, 69.1percent yield.
Reference: [1] Patent: CN105037237, 2017, B, . Location in patent: Paragraph 0075-0078
  • 91
  • [ 6066-82-6 ]
  • [ 57078-98-5 ]
  • [ 57-13-6 ]
  • [ 80307-12-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 17, p. 3400 - 3406
  • 92
  • [ 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
  • 93
  • [ 6066-82-6 ]
  • [ 68858-20-8 ]
  • [ 130878-68-1 ]
YieldReaction ConditionsOperation 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
  • 94
  • [ 6066-82-6 ]
  • [ 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
  • 95
  • [ 6066-82-6 ]
  • [ 253265-97-3 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: CN102617586, 2016, B, . Location in patent: Paragraph 0066 - 0669
  • 96
  • [ 6066-82-6 ]
  • [ 133081-24-0 ]
  • [ 67-64-1 ]
  • [ 362522-50-7 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11392 - 11395
  • 97
  • [ 6066-82-6 ]
  • [ 1172623-98-1 ]
Reference: [1] Patent: WO2013/3249, 2013, A1, . Location in patent: Page/Page column 10; 11
  • 98
  • [ 6066-82-6 ]
  • [ 1137725-46-2 ]
  • [ 1195771-65-3 ]
Reference: [1] Molecular Pharmaceutics, 2010, vol. 7, # 2, p. 468 - 476
[2] Journal of Controlled Release, 2011, vol. 155, # 2, p. 167 - 174
[3] Advanced Functional Materials, 2013, vol. 23, # 24, p. 3040 - 3052
[4] Patent: WO2014/152451, 2014, A2, . Location in patent: Sheet 3
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