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[ CAS No. 40542-90-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 40542-90-3
Chemical Structure| 40542-90-3
Chemical Structure| 40542-90-3
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Product Details of [ 40542-90-3 ]

CAS No. :40542-90-3 MDL No. :MFCD00441728
Formula : C13H16O4 Boiling Point : -
Linear Structure Formula :- InChI Key :CQSWISNVQPOAEM-UHFFFAOYSA-N
M.W : 236.26 Pubchem ID :11075409
Synonyms :

Calculated chemistry of [ 40542-90-3 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.38
Num. rotatable bonds : 8
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 63.31
TPSA : 63.6 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.87
Log Po/w (XLOGP3) : 1.76
Log Po/w (WLOGP) : 2.22
Log Po/w (MLOGP) : 2.12
Log Po/w (SILICOS-IT) : 2.48
Consensus Log Po/w : 2.09

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -2.15
Solubility : 1.68 mg/ml ; 0.00713 mol/l
Class : Soluble
Log S (Ali) : -2.71
Solubility : 0.457 mg/ml ; 0.00194 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.49
Solubility : 0.0763 mg/ml ; 0.000323 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 1.86

Safety of [ 40542-90-3 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 40542-90-3 ]

* 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.

  • Downstream synthetic route of [ 40542-90-3 ]

[ 40542-90-3 ] Synthesis Path-Downstream   1~88

  • 1
  • [ 124-04-9 ]
  • [ 100-51-6 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
40% With toluene-4-sulfonic acid In toluene Heating;
40% With toluene-4-sulfonic acid In toluene Reflux;
34% With toluene-4-sulfonic acid Adipic acid monobenzyl ester (17) was produced from adipic acid and benzyl alcohol in the presence of p-TsOH to yield the desired product as a colourless oil in 34% yield.The protected adipic acid then underwent a DCC coupling with 3- hydroxyflavone (1) to form flavone-3-hemiadipate monobenzyl ester as a yellow/brown gum in 59% yield. Hydrogenation of this compound in the presence of Pd(OH)2 catalyst, using a THF-based solvent system (9:1 THFrEtOH + 0.05% acetic acid) resulted in hydrogenolysis of the monobenzyl ester, forming flavone-3-hemiadpate as a yellow solid in 89% yield.
33% With toluene-4-sulfonic acid In toluene Reflux; Dean-Stark; 4 Synthesis of side chain G-a1 A mixture of adipic acid (10.0 g, 68.4 mmol), BnOH (11.1 g, 100 mmol) and p-TsOH (129 mg, 0.68 mmol) in toluene (60 mL) was heated at reflux in a flask equipped with a Dean-Stark trap overnight. The mixture was cooled to RT, diluted with water and basified to pH>10 with a 6 M aqueous NaOH solution. The aqueous mixture was washed with EtOAc (100 mL x 2), acidified to pH<4 with a dilute aqueous HC1 solution and extracted with EtOAc (100 mL). The organic extract was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuo to give the product (5.4 g, 33%) as a colorless oil. TLC: Rf = 0.2 ( silica gel, Pet.ether/EtOAc=4/l,v/v); LCMS (negative mode):m/z 235.1 [M-H]"; 1HNMR: (400 MHz, DMSO-
29% Stage #1: Adipic acid With acetic anhydride for 2.5h; Reflux; Stage #2: benzyl alcohol With pyridine; dmap In dichloromethane at 0 - 20℃; for 1.5h;
at 180 - 200℃;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane for 12h;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h;

  • 2
  • [ 40542-90-3 ]
  • [ 144840-97-1 ]
  • C119H114O30 [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With dicyclohexyl-carbodiimide; 4-(dimethylamino)pyridinium tosylate In tetrahydrofuran for 24h; Ambient temperature;
  • 3
  • [ 124-04-9 ]
  • [ 100-44-7 ]
  • [ 2451-84-5 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In toluene for 4.5h; Heating;
  • 4
  • [ 40542-90-3 ]
  • [ 530-62-1 ]
  • [ 127847-29-4 ]
YieldReaction ConditionsOperation in experiment
77% In dichloromethane Ambient temperature;
  • 5
  • [ 40542-90-3 ]
  • 6-O-benzyloxycarbonyl-2-deoxy-2-(2,2-difluorotetradecanamido)-4-O-(diphenylphosphoryl)-3-O-<(R)-3-(tetradecanoyloxy)tetradecanoyl>-D-glucopyranose [ No CAS ]
  • 1-O-<5-(benzyloxycarbonyl)pentanoyl>-6-O-benzyloxycarbonyl-2-deoxy-2-(2,2-difluorotetradecanamido)-4-O-(diphenylphosphoryl)-3-O-<(R)-3-(tetradecanoyloxy)tetradecanoyl>-α-D-glucopyranose [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 24℃; for 1h;
  • 6
  • [ 40542-90-3 ]
  • [ 67852-86-2 ]
YieldReaction ConditionsOperation in experiment
With oxalyl dichloride for 120h; 0 deg C to rt; Yield given;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃;
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 15℃; for 0.5h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; 8.8.7 Example 8.7: Synthesis of benzyl 6-chloro-6-oxo-hexanoate (100) To a solution of 6-benzyloxy-6-oxo-hexanoic acid (99, 2.31 g, 9.77 mmol, 1.00 equiv.) in DCM (30 mL) were added oxalyl chloride (1.20 mL, 13.44 mmol, 1.37 equiv.) and a drop of DMF for catalytic acceleration of the reaction. The reaction mixture was stirred overnight at r.t. until LC/MS indicated full conversion of the starting material (an aliquot of the reaction mixture was added to methanol and the acid chloride was detected as its corresponding methyl ester). The solvent was removed in vacuo and the crude product benzyl 6-chloro-6-oxo-hexanoate (100) was used for the next step without purification.LC-MS (Method D):Rt[min] (UV- signal 220 nm): 1.39

  • 7
  • [ 78277-26-6 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
85% With glacial acetic acid; NaNO2 In dimethyl sulfoxide at 35℃;
45% With glacial acetic acid; NaNO2 In dimethyl sulfoxide at 40℃; for 48h; 8.8.6 Example 8.6: Synthesis of 6-benzyloxy-6-oxo-hexanoic acid (99) To a solution of benzyl 6-bromohexanoate (98, 5.73 g, 20.09 mmol, 1.00 equiv.) in DMSO (40 mL) were added NaNO2(5.54 g, 80.30 mmol, 4.00 equiv.) and acetic acid (12 mL). The reaction mixture was stirred for 2 d at 40°C. EtOAc (300 mL) and aqueous 1 N HC1 (100 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl-solution (3 x 50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica, 1-50% EtOAc in n-heptane) to yield 6-benzyloxy-6- oxo-hexanoic acid (99, 2.12 g, 8.97 mmol, 45%) as a colorless oil.LC-MS (Method D):Rt[min] (UV- signal 220 nm): 1.14M[g/mol]: 237.1 [M+H+]
  • 8
  • 6-Nitro-hexanoic acid benzyl ester [ No CAS ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
96% With acetic acid; sodium nitrite In dimethyl sulfoxide at 35℃;
  • 9
  • [ 7205-91-6 ]
  • [ 40542-90-3 ]
  • [ 201210-69-7 ]
YieldReaction ConditionsOperation in experiment
94% With caesium carbonate In N,N-dimethyl-formamide 1.) room temperature, 30 min; 70 deg C, 15 min, 2.) room temperature, 3 h; 70 deg C, 15 min;
  • 10
  • [ 40542-90-3 ]
  • [ 1053419-40-1 ]
  • [ 209270-25-7 ]
YieldReaction ConditionsOperation in experiment
75% With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In N,N-dimethyl-formamide Ambient temperature;
  • 11
  • [ 40542-90-3 ]
  • {(S)-6-Amino-2-[(S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-hexanoylamino}-acetic acid (benzhydryl-carbamoyl)-methyl ester [ No CAS ]
  • [ 209270-18-8 ]
YieldReaction ConditionsOperation in experiment
84% With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In N,N-dimethyl-formamide Ambient temperature;
  • 12
  • [ 40542-90-3 ]
  • [ 104615-18-1 ]
  • 5-(9-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]quinazolin-5-ylcarbamoyl)-pentanoic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide for 48h;
  • 13
  • [ 40542-90-3 ]
  • [ 156055-46-8 ]
  • [ 209617-78-7 ]
YieldReaction ConditionsOperation in experiment
67.5% With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 48h; Ambient temperature;
  • 14
  • [ 40542-90-3 ]
  • [ 359014-93-0 ]
  • 5-[6-(4-trityl-phenoxy)-hexylcarbamoyl]-pentanoic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.20 g In dichloromethane at 20℃; for 1h;
  • 15
  • [ 40542-90-3 ]
  • [ 3282-30-2 ]
  • C18H24O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 1h;
  • 16
  • [ 111-50-2 ]
  • [ 100-51-6 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
6.6 g With triethylamine In dichloromethane at 20℃; for 2h;
  • 17
  • [ 40542-90-3 ]
  • 3-[(2R,3S,4S,5R,6R)-6-Amino-4,5-bis-(2-cyano-ethoxy)-2-(2-cyano-ethoxymethyl)-tetrahydro-pyran-3-yloxy]-propionitrile [ No CAS ]
  • [ 394245-96-6 ]
YieldReaction ConditionsOperation in experiment
0.98 g With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran
  • 18
  • [ 124-04-9 ]
  • [ 100-51-6 ]
  • [ 2451-84-5 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
With Candida antarctica lipase immobilized on polyacrylic resin In 1,4-dioxane for 3h; microwave irradiation; Title compound not separated from byproducts;
With Candida antarctica lipase immobilized on polyacrylic resin In 1,4-dioxane at 60℃; for 3h; Title compound not separated from byproducts;
  • 19
  • [ 873576-78-4 ]
  • [ 40542-90-3 ]
  • [ 873576-79-5 ]
YieldReaction ConditionsOperation in experiment
62% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran
  • 20
  • [ 124-04-9 ]
  • [ 104-57-4 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
87% With DOWEX 50W-X2; In octane; at 100℃; for 4h;Heating / reflux; DOWEX 50W-X2 (2 g), <strong>[104-57-4]benzyl formate</strong> (10 mL, mol), and adipic acid (2 g, mol) were added to octane (10 mL). The mixture was refluxed for 4 hours at 100 C., and the crude product was purified via silica chromatography to yield a clear, colorless liquid (87% yield). 1H NMR (CDCl3) 1.59-1.78 (m, 4H, CH2CH2), 2.33-2.39 (m, 4H, CH2COOH), 5.09 (s, 2H, PhCH2), 7.25-7.30 (m, 5H, aromatic).
87% With DOWEX 50W-X2; In octane; at 100℃; for 4h; Synthesis of hexanedioic acid monobenzyl ester10475] DOWEX 50W-X2 (2 g), <strong>[104-57-4]benzyl formate</strong> (10 mE, mol), and adipic acid (2 g, mol) were added to octane (10 mE). The mixture was refluxed for 4 hours at 100 C., and the crude product was purified via silica chromatography to yield a clear, colorless liquid (87% yield). ?H NMR (CDC13) 1.59- 1.78(m, 4H, CH2CH2), 2.33-2.39(m, 4H, Ci2.COOH), 5.09 (s, 2H, PhCH2), 7.25-7.30 (m, 5H, aromatic).
  • 21
  • [ 124-04-9 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: SOCl2; DMF / 2 h / Heating 2: 6.6 g / NEt3 / CH2Cl2 / 2 h / 20 °C
  • 22
  • [ 40542-90-3 ]
  • [ 359014-84-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 2.20 g / CH2Cl2 / 1 h / 20 °C 2: 88 percent / H2 / 5 percent Pd/C / ethyl acetate; methanol / 1 h
  • 23
  • [ 40542-90-3 ]
  • C42H49NO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 2.20 g / CH2Cl2 / 1 h / 20 °C 2: 88 percent / H2 / 5 percent Pd/C / ethyl acetate; methanol / 1 h 3: NEt3 / CH2Cl2 / 1 h / 20 °C
  • 24
  • [ 40542-90-3 ]
  • Hexane-1.6-dioic acid [2-(2-{2-[4-(2-methoxyethoxy)phenoxy]ethoxy}ethoxy)ethyl]amide [6-(4-tritylphenoxy)hexyl]amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 2.20 g / CH2Cl2 / 1 h / 20 °C 2: 88 percent / H2 / 5 percent Pd/C / ethyl acetate; methanol / 1 h 3: NEt3 / CH2Cl2 / 1 h / 20 °C 4: 0.13 g / CH2Cl2 / 2 h / 20 °C
  • 25
  • [ 40542-90-3 ]
  • Hexane-1,6-dioic acid [2-(2-{2-[5-(2-methoxyethoxy)naphthalen-1-yloxy]ethoxy}ethoxy)ethyl]amide [6-(4-tritylphenoxy)hexyl]amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 2.20 g / CH2Cl2 / 1 h / 20 °C 2: 88 percent / H2 / 5 percent Pd/C / ethyl acetate; methanol / 1 h 3: NEt3 / CH2Cl2 / 1 h / 20 °C 4: CH2Cl2 / 2 h / 20 °C
  • 26
  • [ 40542-90-3 ]
  • 1-[(2-Dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-(5-carboxypentanoyloxy)-6H-pyrido[4,3-b]carbazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 67.5 percent / 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / dimethylformamide / 48 h / Ambient temperature 2: cyclohexene / 5 percent Pd/C / various solvent(s) / 0.5 h / 80 °C
  • 27
  • [ 40542-90-3 ]
  • [ 87343-30-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 94 percent / Cs2CO3 / dimethylformamide / 1.) room temperature, 30 min; 70 deg C, 15 min, 2.) room temperature, 3 h; 70 deg C, 15 min 2: 1.) SO2Cl2, 2.) cis-4-cyclohexene-1,2-dicarboxylic acid / 1.) CH2Cl2, room temperature, 1 h, 2.) 1 h
  • 28
  • [ 40542-90-3 ]
  • [ 201210-73-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 94 percent / Cs2CO3 / dimethylformamide / 1.) room temperature, 30 min; 70 deg C, 15 min, 2.) room temperature, 3 h; 70 deg C, 15 min 2: 1.) SO2Cl2, 2.) cis-4-cyclohexene-1,2-dicarboxylic acid / 1.) CH2Cl2, room temperature, 1 h, 2.) 1 h 3: 63 percent / Et3N / dimethylformamide / 16 h / Ambient temperature 4: 60 percent / 1,4-cyclohexadiene / Pd/C / acetic acid / 1 h / Ambient temperature
  • 29
  • [ 40542-90-3 ]
  • [ 201210-71-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 94 percent / Cs2CO3 / dimethylformamide / 1.) room temperature, 30 min; 70 deg C, 15 min, 2.) room temperature, 3 h; 70 deg C, 15 min 2: 1.) SO2Cl2, 2.) cis-4-cyclohexene-1,2-dicarboxylic acid / 1.) CH2Cl2, room temperature, 1 h, 2.) 1 h 3: 63 percent / Et3N / dimethylformamide / 16 h / Ambient temperature
  • 30
  • [ 40542-90-3 ]
  • [ 201210-75-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 94 percent / Cs2CO3 / dimethylformamide / 1.) room temperature, 30 min; 70 deg C, 15 min, 2.) room temperature, 3 h; 70 deg C, 15 min 2: 1.) SO2Cl2, 2.) cis-4-cyclohexene-1,2-dicarboxylic acid / 1.) CH2Cl2, room temperature, 1 h, 2.) 1 h 3: 63 percent / Et3N / dimethylformamide / 16 h / Ambient temperature 4: 60 percent / 1,4-cyclohexadiene / Pd/C / acetic acid / 1 h / Ambient temperature 5: 77 percent / EDCI*HCl / dimethylformamide / 2 h / Ambient temperature
  • 31
  • [ 40542-90-3 ]
  • [ 201210-77-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 94 percent / Cs2CO3 / dimethylformamide / 1.) room temperature, 30 min; 70 deg C, 15 min, 2.) room temperature, 3 h; 70 deg C, 15 min 2: 1.) SO2Cl2, 2.) cis-4-cyclohexene-1,2-dicarboxylic acid / 1.) CH2Cl2, room temperature, 1 h, 2.) 1 h 3: 63 percent / Et3N / dimethylformamide / 16 h / Ambient temperature 4: 60 percent / 1,4-cyclohexadiene / Pd/C / acetic acid / 1 h / Ambient temperature 5: 77 percent / EDCI*HCl / dimethylformamide / 2 h / Ambient temperature 6: 66 percent / dimethylformamide / 96 h / Ambient temperature
  • 32
  • [ 40542-90-3 ]
  • 5-{(S)-4-[(Benzhydryl-carbamoyl)-methoxycarbonylmethyl]-carbamoyl}-4-[(S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-butylcarbamoyl}-pentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 75 percent / (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate, N-methylmorpholine / dimethylformamide / Ambient temperature 2: 79 percent / H2 / 10percent Pd/C / dimethylformamide / Ambient temperature
  • 33
  • [ 40542-90-3 ]
  • 5-{(S)-5-[(Benzhydryl-carbamoyl)-methoxycarbonylmethyl]-carbamoyl}-5-[(S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-pentylcarbamoyl}-pentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 84 percent / (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate, N-methylmorpholine / dimethylformamide / Ambient temperature 2: 99 percent / H2 / 10percent Pd/C / dimethylformamide / Ambient temperature
  • 34
  • [ 40542-90-3 ]
  • Hexanedioic acid mono-[(2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl] ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: oxalyl chloride / 120 h / 0 deg C to rt 2: 2.) NaBH4 / 1.) Py, 0 deg C to rt, 24 h, 2.) THF, H2O, rt, 15 min 3: 43 percent / H2 / Pd-C / ethanol; acetic acid / 24 h / 760 Torr / Ambient temperature
Multi-step reaction with 3 steps 1: oxalyl chloride / 120 h / 0 deg C to rt 2: 45 percent / pyridine; CH2Cl2 / 2.5 h 3: 43 percent / H2 / Pd-C / ethanol; acetic acid / 24 h / 760 Torr / Ambient temperature
  • 35
  • [ 40542-90-3 ]
  • Hexanedioic acid mono-[(2R,3S,5R)-5-(2,4-dioxo-5-thiophen-2-yl-3,4-dihydro-2H-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethyl] ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: oxalyl chloride / 120 h / 0 deg C to rt 2: 50 percent / pyridine; CH2Cl2 / 2.5 h 3: 13 percent / H2 / Pd-C / ethanol; acetic acid / 72 h / 3800 Torr / Ambient temperature
Multi-step reaction with 3 steps 1: oxalyl chloride / 120 h / 0 deg C to rt 2: 2.) NaBH4 / 1.) Py, 0 deg C to rt, 24 h, 2.) THF, H2O, rt, 15 min 3: 13 percent / H2 / Pd-C / ethanol; acetic acid / 72 h / 3800 Torr / Ambient temperature
  • 36
  • [ 2035-75-8 ]
  • [ 100-51-6 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; at 20℃; for 2h; Anhydride 1 (49.05 g, 0.38 moles) was added to a solution of benzyl alcohol (41.4 g, 0.38 moles) in dichloromethane (380 mL). No temperature change was noted during the addition. The mixture was stirred at room temperature, refluxed for 2 hours and then returned to room temperature, where it was maintained overnight. Compound 2 was isolated by distillation on a Kugelrohr apparatus. The fraction coming over at 160-175 C. at 0.1 mm was collected (45.1 g, 50%).
  • 37
  • [ 40542-90-3 ]
  • [ 6305-38-0 ]
  • C17H21NO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
48.3% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; dichloromethane; at 0℃; for 18h; Under a N2 atmosphere, <strong>[6305-38-0]L-homoserine lactone hydrobromide</strong> (10 g, 55 mmol), mono-benzyladipate (2), pyridine (50 mL) and EDC hydrochloride (11.5 g, 60 mmol) were combined in dichloromethane (100 mL) in a 500 mL round-bottomed flask with cooling (0 C.). The resulting mixture was stirred for 18 hours. The mixture was cooled to 0 C. and ice cold 15% citric acid solution was added. The citric acid layer was separated and extracted with dichloromethane (1100 mL). The extract was combined with the remaining dichloromethane reaction solution and the combined dichloromethane solutions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum, yielding 17.4 g (98.8%) of the crude product, which was slurried in isopropyl acetate to produce an off-white solid. The solid was collected and dried under high vacuum at 30 C., to produce 8.5 g (48.3%) of the desired product.
  • 38
  • [ 40542-90-3 ]
  • [ 307521-00-2 ]
  • 3',4'-dibenzyloxy-3-(benzyloxycarbonylbutylcarbonyIoxy)flavone [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h; Adipic acid monobenzyl ester (1.91 g, 5.04 mmol) followed by EDC hydrochloride (0.764 g, 3.98 mmol) and DMAP (0.324 g, 2.65 mmol) were added to a stirring solution of 3',4'-dibenzyloxyflavonol (1.21 g, 2.68 mmol) in dry dichloromethane (100 mL) and the resultant mixture was stirred at room temperature under N2 for 3 h. The reaction mixture was concentrated under reduced pressure and resuspended in ethyl acetate (100 mL). The suspension was then washed with water (3 x 50 mL), 1M HCl (3 x 50 mL), saturated NaHCO3 (3 x 50 mL) and brine (3 x 50 mL). The organic extract was dried (MgSO4), filtered, concentrated under reduced pressure and the yellow residue crystallized from EtOAc/ petroleum spirits to yield the benzyl EPO ester as a fluffy yellow solid (1.58 g, 88%); mp = 84-85 °C; 1H NMR (399.8 MHz, CDCl3); δ 1.70- 1.80 (m, 4H, CH2CH2); 2,38 (t, 2H, J = 6.8 Hz, CH2CO); 2.55 (m, 2H, CH2CO); 5.10 (s, 2H, CH2Ph); 5.20 (s, 2H, CH2Ph); 5.24 (s, 2H, CH2Ph); 7.01 (d, 1H, J7,8 = 8.4 Hz, H8); 7.26 - 7.49 (m, 19H, Ar, H6, 2', 5 6'); 7.62 (ddd, 1H, J5,7 = 1.2 Hz, J6,7 = 7.2 Hz, J7,8 = 8.4 Hz, H7); 8.22 (dd, 1H, J5,5 = 7.6 Hz, J5,7 = 1.2 Hz, H5). 13C NMR (100.5 MHz, CDCl3) 6 25.33 (2C, CH2CH2CO2); 34.59, 34,93 (2C, CH2CO2); 67.30, 71,91, 72.59 (2C, CH2Ph); 114.77, 115.84, 119.06, 123.76, 123.84, 124.60, 126.19, 127.12, 128.25, 128.36, 129.15, 129.29, 129-64, 129.73, 130.12, 134.23, 134.89, 137.05, 137.54, 137.85, 149.61, 152.64, 156.53, 157.00 (32C, Ar); 171.49, 173.12, 174.18 3C, C=O). Anal. Found: C, 75.39; H, 5.47; C42H36O8 requires C, 75.43; H, 5.43%. HRMS (ESI+) m/z 691.2303, C42H36NaO8 [M + Na]+ requires 691.2308.
59% With pyridine; dmap; dicyclohexyl-carbodiimide The scheme for the synthesis of 3',4'-dihydroxyflavone-3- hemiadipate (21) is illustrated in Figure 5. Following the methodology established above, 3',4'- dibenzyloxγ-3-hydroxyflavone (6) and adipic acid moribenzyl ester (17) underwent aDCC coupling to produce the hemiadipate monobenzyl ester as a brown gum in 59% yield. EPO Deprotection by hydrogenolysis on a small scale (100-500 mg) proceeded smoothly to completion in 3-5 hours to give the 3',4'-dihydroxyflavone-3-hemiadipate (21) in 33% yield
  • 39
  • [ 40542-90-3 ]
  • [ 102468-65-5 ]
  • 4'-(benzyloxy)-3-(benzyloxycarbonylbutylcarbonyloxy)flavone [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Ethylene dichloride (EDC) (843 mg, 4,40 mmol) was added to a solution of 4'- benzyloxy-3-hydroxyflavone (1.00 g, 2.90 mmol), adipic acid monobenzyl ester (1.30 g, 5.50 mmol) and DMAP (354 mg, 2.89 mmol) in dichloromethane (110 mL) and the mixture was stirred at rt overnight. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic-phase was washed with water (x 3), 1 M HCl (κ 3), sat NaHCO3 (x 3), brine (x 3), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (50% EtOAc/petrol) to give the benzyl ester as a brown oil, which was crystallized from EtOAc/petrol to give a colourless solid (900 mg, 55%); mp 93 °C; 1H NMR (500 MHz, CDCl3) δ 1.77-1.83 (m , 4H, CH2CH2), 2.42 (t, 2H, J = 7.5 Hz, CH2CO), 2,67 (t, 2H, J = 6.5 Hz, CH2CO), 5.13 (s, 2H, CH2Ph), 5.15 (s, 2H, CH2Ph), 7.09 (d, 1H, J7,8 = 8.5 Hz, H8), 7.35 (app. d, 2H, J = 8.5 Hz, H2',6'), 7.40-7.46 (m, IIH, 2 X Ph, H6). 7.69 (ddd, 1H, J5,7 = 1-5, J6,7 = 7-0, J7,8 = 8.5 Hz, H7), 7.85 (app. d, 2H, J = 8-5 Hz, H3',5'), 8.25 (4 1H, % = 8 Hz, H5); 13C NMR (125 MHz, CDCl3) δ 24.2 (x 2), 33.6, 33.8 (4C, CH2), 66.2, 70.1 (2C, CH2Ph), 115.0, 117,9, 122.4, 123.5, 125.0, 126.0, 127.4, 128.1, 12S.2, 128.5, 128.7, 130.0, 133.0. 133.7, 135.9, 136.2, 155.5, 156.1, 161.1 (AT), 170.4, 172,0- 173.0 (3C, C=O); IR (thin film) 2937, 1760, 1730, 1646, 1602, 1507, 1468, 899 cm-1; Anal. Found C, 74,67; H, 5.29, C35H30O7 requires C, 74.72; H, 5.37%.
  • 40
  • [ 14919-49-4 ]
  • [ 40542-90-3 ]
  • 3,4'-di-(benzyloxycarhonylbutylcarbonyloxy)flavone [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.833333h; Ethylene dichloride (1.13 g, 5.91 mmol) was added to a solution of 3,4'- dihydroxyflavone (500 rag, 1.97 mmol), adipic acid monobenzyl ester (1.86 g, 7,88 mmol) and DMAP (481 mg, 3.94 mmol) in dichloromethane (30 mL) and the mixture stirred at rt for 50 min. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic phase washed with water (x 3), 1 M HCl (x 3), sat NaHCO3 (x 3), brine (x 3), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (50% EtOAc/petrol) to give the diester as a colourless oil, which was crystallized from EtO Ac/petrol to afford a colourless solid (850 mg, 62%); mp 79°C; 1H NMR (500 MHz, CDCl3) δ 1.76-1.82 (m, 8H, 2 x CH2CH2), 2.42 (t, 2H. J = 7.0 Hz, CH2CO), 2.45 (t, 2H, J = 7-0 Hz, CH2CO), 2.62 (t, 2H, J = 7.0 Hz, CH2CO), 2.65 (t, 2H, J = 7.0 Hz, CH2CO), 5.12 (s, 2H, CH2Ph), 5.14 (S, 2H, CH2Ph), 7.25 (d, 2H, J = 8.5 Hz, H2',6'), 7.31-7.37 (m, 10H, 2 x Ph), 7.44 (t, 1H, J5,6 = J6,7 = 8.5 Hz, H6), 7.55 (d, 1H, J7,8 = 8.5 Hz, H8), 7.72 (td, 1H, J6,7 = J7,8 = 8.5, J7,5 = 1.5 Hz, HT). 7.89 (d, 2H, J = 8.5 Hz, H3',5'), 8.25 (dd, 1H, J5,6 = 8.5, J5,7 = 1.5 Hz, H8); 13C NMR (125 MHz, CDCl3) 6 24.16, 24.17, 24.21, 33.5, 33,8, 33.9, 66.1, 66.3 (CH2), 118.0, 121.9, 123.5, 125.2, 126.1, 127.4, 128.-1, 128.18, 128.22. 128.49, 128.53, 129.7, 133.7, 134.0, 135.9, 136.0, 152.8, 155.4, 155.5 (Ar), 170.3, 171.2, 172.1, 173.97, 173.0 (5C, C=O); IR 2943, 1765, 1732, 1652, 1501, 1465, 902 cm-1; Anal. Found C, 71.30; H, 5.56, C41H38O10 requires C, 71.29; H, 5.55%.
  • 41
  • [ 492-00-2 ]
  • [ 40542-90-3 ]
  • 3,7-di-(benzyloxycarbonylbutylcarbonyloxy)flavone [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Ethylene dichloride (EDC) (517 mg, 2.7 mmol) was added to a solution of 3,7- dihydroxyflavone (250 mg, 0.983 mmol), adipic acid monobenzyl ester (921 mg, 3.90 mmol) and DMAP (220 mg, 1.80 mmol) in dichlororoethane (25 mL) and the mixture was stirred at rt for 1 h. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic phase was washed with water (x 2), 1 M HCI (x 2), sat NaHCO3 (x 2), brine (x 2), dried (MgSO4) and concentrated. The residue was filtered through a pad of silica eluting with 50% EtOAc/petrol to give a solid, which was recrystallized from EtOAc/petrol to give the diester as a colourless solid (565 mg, 91%); mp 58 °C; 1H NMR (500 MHz, CDC13) δ 1.74-1.82 (m, 8H, CH2CH2 x 2), 2.39 (t, 2H, J = 7.0 Hz, CH2CO), 2.45 (t, 2H, J = 7.0 Hz, CH2CO), 2,62-2.64 (m, 4H, CH2CO x 2), 7.15-7.17 (m, 2H, H2', 6 ') ,7.30-7.36 (m, 10H, 2 x Ph), 7.39 (d, 1H, J6,8 = 1.6 Hz, H8), 7.48-7.51 (m, 2H, H3', 5'), 7.81-7.83 (m, 2H, 4' H6) 8.25 (d, 1H, J5,6 =9, H5); 13C NMR (125 MHz, CDCl3) δ 24.1, 24.20, 24.21, 33.5, 33,80, 33.82. 34.0, 44.7, 66.2, 66.3, (CH2), 111.0, 119.5, 121.5, 172.5. 128.19, 128.22, 128.3, 128.5, 128.6, 128.7, 129.8, 131.3, 133.7, 135.9, 136.0, 154.8, 156.1, 156.6 (Ar), 170.3, 170.8, 171.5, 172.96, 173,0 (5C, C=O) IR 3071, 3035, 2944, 2876, 1760, 1726, 1615, 848 cm-1; Anal. Found C, 71.34; H, 5.60%, C41H38O10 requires C, 71.29; H, 5.55%.
  • 42
  • [ 577-85-5 ]
  • [ 40542-90-3 ]
  • 3-(benzyloxycarbonylbutylcarbonyloxy)flavone [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 19h;Product distribution / selectivity; 3-Hydroxyflavone (0.105 g, 0.442 mmol), dicyclohexylcarbodiimide (0.193 g, 0.933 mmol) and 4-dimethylaminopyridine (9.80 tag, 0.0802 mmol) was added to a solution of adipic acid monobenzyl ester (0.168 g, 0,754 mmol) in dichloromethane (10 mL) and the mixture was stirred under N2 at room temperature for 19 h. Water (50 muL) was added and the resultant mixture was stirred for 10 rain, then diethyl ethex (10 mL) was added. The mixture was filtered, the filtrate concentrated and purified by flash chromatography (15-40% EtOAc in toluene) to yield the monobenzyl ester as a yellow gum (0.16 g, 80%). A small portion was recrystallized from EtQ Ac/petroleum spirits to give a colourless powder; mp = 74-76C; 1H NMR (399.7 MHz, CDCl3) delta 1.60 - 1.75 (m, 4H, CO2CH2CH2); 2.31 (t, J = 6.8 Hz, 2H, CO2CH2); 2.55 (t, J = 6.8 Hz, 2H, CO2CH2); 5.02 (s, 2H, CH2Ph); 7.20 - 7.28, 7.39 - 7.45 (2m, H, PhCH2, H3', 4', 5'); 7.34 (dd, 1H, J5,6 = 8.0 Hz, J6,7 - 7.6 Hz, H6); 7.46 (d, 1H, J7,8 = 8.0 Hz, H8); 7.62 (ddd, 1H, J5,7 = 1.6 Hz, J6,7 = 7.6 Hz, J7,8 = 8.0 Hz, H7); 7.73 - 7.77 (m, 2H, H2', 6'); 8.16 (dd, 1H- J5,7 = 1.6 Hz, H5). 13C KMR (100.5 MHz, CDCl3) delta 25.29 (2C, CO2CHiCH2); 34.62, 34.91 (2C, CO2CH2); 67.30 (1C, CH2Ph); 119,21, 124.68, 126-29, 127.17, 129.29, 129.40, 129.63, 129.75, 131.05, 132.36, 134.72, 135.06. 137.03, 156.7I, 157.45 (20C, Ar); 171.54, 173.27, 174.16 (3C, C-O). Anal. Found: C, 73.54; H, 5.27; C42H36O8 requires C, 73.67; H, 5.30%. HRMS (ESI+) ra/z 479.1469, C28H24NaO6 [M + Na]+ requires 479.1471.
59% With pyridine; dmap; dicyclohexyl-carbodiimide;Product distribution / selectivity; Adipic acid monobenzyl ester (17) was produced from adipic acid and benzyl alcohol in the presence of p-TsOH to yield the desired product as a colourless oil in 34% yield.The protected adipic acid then underwent a DCC coupling with 3- hydroxyflavone (1) to form flavone-3-hemiadipate monobenzyl ester as a yellow/brown gum in 59% yield. Hydrogenation of this compound in the presence of Pd(OH)2 catalyst, using a THF-based solvent system (9:1 THFrEtOH + 0.05% acetic acid) resulted in hydrogenolysis of the monobenzyl ester, forming flavone-3-hemiadpate as a yellow solid in 89% yield.
  • 43
  • [ 915389-76-3 ]
  • [ 40542-90-3 ]
  • [ 915390-07-7 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 14h;
  • 44
  • [ 1135829-47-8 ]
  • [ 40542-90-3 ]
  • [ 1015045-05-2 ]
YieldReaction ConditionsOperation in experiment
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 16h;
1.51 g With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;
  • 45
  • poly(5-hydroxy-1,3-dioxan-2-one-co-ε-caprolactone) [ No CAS ]
  • [ 40542-90-3 ]
  • poly(mono-benzyloxy-hexanedioic acid 2-oxo-1,3-dioxan-5-yl ester-co-ε-caprolactone) [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 18h; 12 Hexanedioic acid monobenzyl ester (0.184 g, 0.78 mmol), poly(5-hydroxy-1,3-dioxan-2-one-co-ε-caprolactone) (1.5 g, 2.6 mmol, 22 mol % carbonate), DCC (0.129 g, 0.63 mmol), and DMAP (0.032 g, 0.26 mmol) were dissolved in dichloromethane (20 mL). The solution was stirred at RT for 18 h. The DCU was filtered and the solvent evaporated. The product was dissolved in dichloromethane (10 mL) and precipitated in cold methanol. The solvent was decanted and subsequently dried by evaporation (83% yield). Addition of the carboxylic acid side chain was determined by the presence of the benzyl protecting group, with peaks in the 1H NMR spectrum at 5.06 (s, 2H, PhCH2), 7.27-7.33 (m, 5H, aromatic).
  • 46
  • [ 40542-90-3 ]
  • 5-fluoro-1-(hydroxymethyl) pyrimidine-2,4-(1H,3H)-dione [ No CAS ]
  • [ 201210-71-1 ]
YieldReaction ConditionsOperation in experiment
1.1 g With dmap; dicyclohexyl-carbodiimide In acetonitrile at 0 - 20℃; for 25h;
  • 47
  • [ 908094-01-9 ]
  • [ 40542-90-3 ]
  • [ 137195-65-4 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 0℃; for 0.5h;
  • 48
  • C14H17O4Pol [ No CAS ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic acid In dichloromethane for 1h; solid phase reaction;
  • 49
  • [ 40542-90-3 ]
  • [ 153086-78-3 ]
  • C24H38N2O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 20h; 4.2.13. General procedure for the synthesis of carboxylic acids 23 and 24 General procedure: N-Boc-3,6-dioxaoctane-1,8-diamine (22) (1 equiv) and the pertinent alkanedioic acid monobenzyl ester (1 equiv) were dissolved in anhydrous DCM. EDC (1.2 equiv) was added and the mixture was kept under stirring at rt for 20 h. The intermediate was purified by column chromatography (eluent: EtOAc/MeOH 10:1-5:1) prior to hydrogenation at rt and atmospheric pressure in MeOH using hydrogen and a 10% Pd/C catalyst.
  • 50
  • [ 870-46-2 ]
  • [ 40542-90-3 ]
  • [ 1321803-56-8 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: adipic acid monobenzyl ester With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.25h; Stage #2: t-butoxycarbonylhydrazine In N,N-dimethyl-formamide at 0 - 20℃; for 2h;
  • 51
  • [ 40542-90-3 ]
  • [ 28780-46-3 ]
  • C116H210O52 [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h; 2 A solution of PEG 2000 (2a) (11.0 g, 5.5 mmol) and benzyl adipate half-ester (4.8 g, 20.6 mmol) in DCM (90.0 mL) was cooled to 0°C. Dicyclohexylcarbodiimide (4.47 g, 21.7 mmol) was added followed by a catalytic amount of DMAP (5 mg) and the solution was stirred and allowed to reach room temperature overnight (12 h). The flask was stored at +4°C for 5 h. The solid was filtered and the solvent completely removed by distillation in vacuo. The residue was dissolved in 1000 mL 1/1 (v/v) diethyl ether/ethyl acetate and stored at RT for 2 hours while a small amount of a flaky solid was formed. The solid was removed by filtration through a pad of Celite. The solution was stored in a tightly closed flask at -30°C in the freezer for 12 h until crystallisation was complete. The crystalline product was filtered through a glass frit and washed with cooled diethyl ether (-30°C). The filter cake was dried in vacuo. Yield: 11.6 g (86 %) 2b as a colorless solid. The product was used without further purification in the next step. MS: m/z 813.1 = [M+3H]3+ (calculated = 813.3)
  • 52
  • [ 40542-90-3 ]
  • [ 1599469-65-4 ]
  • [ 1599469-66-5 ]
YieldReaction ConditionsOperation in experiment
73% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 48h; 4 Synthesis of G-e To a solution of intermediate G-d (1.50 g, 3.71 mmol) and intermediate G-al (1.67 g, 7.05 mmol) in DCM (60 mL) was added EDCI (1.06 g, 5.56 mmol) followed by DMAP (0.45 g, 3.71 mmol) and the mixture was stirred at RT for 48 h. The solvent was removed in vacuo and the residue was diluted with water and extracted with EtOAc (100 mL). The organic extract was washed with a saturated aqueous K2CO3 solution, a dilute aqueous HC1 solution, brine and dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/Pet. Ether, 0-100%, v/v) to give the product (1.70 g, 73%) as a yellow oil. TLC: Rf = 0.30 (silica gel, Pet.ether/EtOAc=4/l,v/v); LCMS: m/z 623.2 [M+H]+, 645.2 [M+Na]+; 1HNMR: (400 MHz, DMSO^) δ ppm 8.07 (dd, J= 8.0, 1.4 Hz, 1H), 7.88 (m, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.51 (m, 4H), 7.41 (m, 2H), 7.34- 7.26 (m, 7H), 5.29 (s, 2H), 5.20 (s, 2H), 5.07 (s, 2H), 3.39 (s, 3H), 2.58 (m, 2H), 2.37 (m, 2H), 1.61 (m, 4H).
  • 53
  • [ 40542-90-3 ]
  • [ 1599469-70-1 ]
  • [ 1599469-71-2 ]
YieldReaction ConditionsOperation in experiment
73% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 4 Synthesis of G2-e To a solution of intermediate G2-d (1.50 g, 3.71 mmol) and intermediate G-al (1.67 g, 7.05 mmol) in DCM (60 niL) was added EDCI (1.06 g, 5.56 mmol) followed by DMAP (0.45 g, 3.71 mmol) and the mixture was stirred at RT overnight, TLC analysis (Pet. Ether/EtOAc, 3/1, v/v) showed that some starting material remained. More EDCI (0.5 g, 2.61 mmol) and DMAP (0.2 g, 1.64 mmol) were added and stirring was continued for a further 1 h, TLC analysis (Pet. Ether/EtOAc, 3/1, v/v) showed that the starting material was consumed. The solvent was removed in vacuo and the residue was diluted with water and extracted with EtOAc (100 mL). The organic extract was washed with a 1 M aqueous HC1 solution, a saturated aqueous Na2C03 solution, brine, dried over Na2S04, filtered and concentrated in vacuo. Purification by column chromatography (DCM/Pet. Ether, 0-100%, v/v) gave the product (1.70 g, 73%) as a yellow oil. TLC: Rf = 0.40(silica gel, Pet.ether/EtOAc=3/l,v/v) LCMS: m/z 623.3 [M+H]+, 645.2 [M+Na]+; 1HNMR: (400 MHz, DMSO-
  • 54
  • [ 40542-90-3 ]
  • [ 105832-38-0 ]
  • benzyl 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; 24.1 Step 1 Benzyl(2,5-dioxopyrrolidin-l-yl) adipate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (5g, 21.16 mmol) in DMF (10 mL) at 0 °C was added N-ethyl-N-isopropylpropan-2-amine (4.44 mL, 25.4 mmol) followed by TSTU (7.0 lg, 23.28 mmol). The reaction was stirred at 0 °C for 1 hour and room temperature for 1 hour. The mixture was poured to ice-water/ethyl ether mixture (1/1, 100 mL). The mixture was extracted with ethyl ether (3 x 50 mL), washed with water (2x 10 mL) and brine (10 mL). The organic layer was dried over MgS04, filtered through a pad of celite and concentrate to give the titled compound as colorless syrup (5.2 g, 15.6 mmol, 74%). LC-MS 2min: Rt = 1.05 min, m/z = 334.1 [M+l].
74% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; 24.1 Step 1 Benzyl(2,5-dioxopyrrolidin-1-yl) adipate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (5g, 21.16 mmol) in DMF (10 mL) at 0 °C was added A/-ethyl-A/-isopropylpropan-2-amine (4.44 mL, 25.4 mmol) followed by TSTU (7.01 g, 23.28 mmol). The reaction was stirred at 0 °C for 1 hour and room temperature for 1 hour. The mixture was poured to ice-water/ethyl ether mixture (1/1 , 100 mL). The mixture was extracted with ethyl ether (3 x 50 mL), washed with water (2x 10 mL) and brine (10 mL). The organic layer was dried over MgS04, filtered through a pad of celite and concentrate to give the titled compound as colorless syrup (5.2 g, 15.6 mmol, 74%). LC-MS 2min: Rt = 1.05 min, m/z = 334.1 [M+1].
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; 1.A benzyl 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (3.3 g, 13.97 mmol) in DMF (50 mL) at 0° C. was added TSTU (4.3 g, 14.28 mmol) and DIPEA (2.5 mL, 14.31 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was partitioned between Et2O and water. The organic layer was separated and the aqueous layer was further extracted with ether (2*150 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. UPLC Method B: calculated for C17H19NO6 333.12, observed m/e: 334.10 [M+1]; Rt=3.75 min. 1H NMR (CDCl3) δ 7.40-7.30 (5H, m), 5.10 (2H, s), 2.80 (4H, s), 2.62-2.58 (2H, m), 2.41-2.37 (2H, m), 1.80-1.72 (4H, m).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; 1.A Step A: benzyl 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (3.3 g, 13.97 mmol) in DMF (50 mL) at 0 °C was added TSTU (4.3 g, 14.28 mmol) and DIPEA (2.5 mL, 14.31 mmol). After stirring at 0 °C for 1 hour, the reaction mixture was partitioned between Et2O and water. The organic layer was separated and the aqueous layer was further extracted with ether (2x150 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. UPLC Method B: calculated for C17H19NO6 333.12, observed m/e: 334.10 [M+1]; Rt = 3.75 min.1H NMR (CDCl3) δ 7.40-7.30 (5H, m), 5.10 (2H, s), 2.80 (4H, s), 2.62-2.58 (2H, m), 2.41- 2.37 (2H, m), 1.80-1.72 (4H, m).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; 19.1 Step 1 Benzyl(2,5-dioxopyrrolidin-l-yl) adipate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (5g, 21.16 mmol) in DMF (10 mL) at 0 °C was added DIPEA (4.44 mL, 25.4 mmol) followed by TSTU (7.01g, 23.28 mmol). The reaction was stirred at 0°C for 1 hour and room temperature for 1 hour. The mixture was poured to ice-water/ethyl ether mixture (1/1, 100 mL). The mixture was extracted with ethyl ether (3 x 50 mL), washed with water (2x 10 mL) and brine (10 mL). The organic layer was dried over MgSC>4, filtered through a pad of celite and concentrate to give the titled compound. UPLC-MS Method A: tR = 1.05 min, m/z = 334 (z = 1).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; 1.A Step A. benzyl 6-[(2,5-dioxopyrrolidin-l-yl)oxy]-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (3.3 g, 13.97 mmol) in DMF (50 mL) at 0 °C was added TSTU (4.3 g, 14.28 mmol) and DIPEA (2.5 mL, 14.31 mmol). After stirring at 0 °C for 1 hr, the reaction mixture was partitioned between Et20 and water. The organic layer was separated and the aqueous layer was further extracted with ether (2x150 mL). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated to afford the title compound. UPLC-MS Method B: calculated for C17H19NO6 333.12, observed m/z: 334.10 (z = l); tR = 3.75 min. 1H NMR (CDCI3) d 7.40-7.30 (5H, m), 5.10 (2H, s), 2.80 (4H, s), 2.62-2.58 (0451) (2H, m), 2.41- 2.37 (2H, m), 1.80-1.72 (4H, m).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; 1.1 Step 1: benzyl 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (3.3g, 13.97mmol) in DMF (50mL) at 0°C was added TSTU (4.3g, 14.28mmol) and DIPEA (2.5mL, 14.31mmol). After stirring at 0°C for 1h, the reaction mixture was partitioned between Et2O and water. The organic layer was separated, and the aqueous layer was further extracted with Et2O (2x150 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. UPLC Method B: calculated for C17H19NO6333.12, observed m/e: 334.10 [M+1]; tR=3.75min. 1H NMR (CDCl3) d 7.40-7.30 (5H, m), 5.10 (2H, s), 2.80 (4H, s), 2.62-2.58 (2H, m), 2.41- 2.37 (2H, m), 1.80-1.72 (4H, m).

  • 55
  • [ 40542-90-3 ]
  • N,N'-bis{2-[(α-L-fucopyranosyl)oxy]ethyl}piperidine-cis-3,5-dicarboxamide [ No CAS ]
  • benzyl 6-[cis-3,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}carbamoyl)piperidin-1-yl]-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; 17.C benzyl 6-[cis-3,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}carbamoyl)piperidin-1-yl]-6-oxohexanoate
To a stirred solution of 6-(benzyloxy)-6-oxohexanoic acid (125 mg, 0.529 mmol) in DMF (3 mL) at room temperature was added DMAP (64.6 mg, 0.529 mmol), EDC (203 mg, 1.058 mmol) and a solution of N,N'-bis{2-[(α-L-fucopyranosyl)oxy]ethyl}piperidine-cis-3,5-dicarboxamide (438 mg, 0.794 mmol) in DMF (2 mL). After stirring at rt for overnight, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel, eluting with 0-50% AcCN in water, to afford the title compound. UPLC Method F: m/e=770.48 [M+1]; Rt=1.38 min.
  • 56
  • [ 40542-90-3 ]
  • 2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside [ No CAS ]
  • benzyl 6-(bis{2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; for 16h; 34.I benzyl 6-(bis{2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (40 mg, 0.169 mmol), EDC (114 mg, 0.593 mmol) and HOBt (2.59 mg, 0.017 mmol) in DMF (5 mL) at rt was added 2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside (190 mg, 0.478 mmol). After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (50 g), eluting with 5-40% AcCN in water to give the title compound. UPLC Method B: m/e=616.2923 [M+1]; Rt=3.114 min. 1H NMR (CD3OD) δ 1.24 (6H, d, J=6.58), 1.72-1.64 (4H, m), 2.45 (2H, t, J=7.11), 2.53 (2H, t, J=7.32), 3.91-3.55 (17H, m), 4.78-4.75 (2H, m), 5.14 (2H, s), 7.38-7.37 (5H, m).
With benzotriazol-1-ol; 1,2-dichloro-ethane In N,N-dimethyl-formamide for 16h; 34.I Step I: benzyl 6-(bis{2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (40 mg, 0.169 mmol), EDC (114 mg, 0.593 mmol) and HOBt (2.59 mg, 0.017 mmol) in DMF (5 mL) at rt was added 2-({2-[(α-L- fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside (190 mg, 0.478 mmol). After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (50 g), eluting with 5-40% AcCN in water to give the title compound. UPLC Method B: m/e = 616.2923 [M+1]; Rt = 3.114 min. 1H NMR (CD3OD) δ 1.24 (6H, d, J = 6.58), 1.72-1.64 (4H, m), 2.45 (2H, t, J = 7.11), 2.53 (2H, t, J = 7.32), 3.91-3.55 (17H, m), 4.78-4.75 (2H, m), 5.14 (2H, s), 7.38-7.37 (5H, m).
  • 57
  • [ 40542-90-3 ]
  • [ 85916-13-8 ]
  • benzyl 6-[bis(2-tert-butoxy-2-oxoethyl)amino]-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; To a stirred solution of 6-(benzyloxy)-6-oxohexanoic acid (1.5 g, 6.35 mmol) in DMF (50 mL) at room temperature was added DIPEA (2.218 mL, 12.70 mmol), HOBt (1.945 g, 12.7 mmol), EDC (2.434 g, 12.7 mmol) and di-tert-butyl 2,2'-iminodiacetate (2.34 g, 9.52 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2*30 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-40% EtOAc in hexane, to give the title compound. LC-MS Method A: m/e=464.04 [M+1]; Rt=2.47 min. 1H NMR (CDCl3) delta 7.32 (m, 5H), 5.07 (s, 2H), 4.02 (s, 2H), 3.96 (s, 2H), 2.35 (s, 2H), 2.26 (s, 2H), 1.66 (s, 4H), 1.42-1.44 (bs, 18H).
With benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; To a stirred solution of 6-(benzyloxy)-6-oxohexanoic acid (1.5 g, 6.35 mmol) in DMF (50 mL) at room temperature was added DIPEA (2.218 mL, 12.70 mmol), HOBt (1.945 g, 12.7 mmol), EDC (2.434 g, 12.7 mmol) and di-tert-butyl 2,2?-iminodiacetate (2.34 g, 9.52 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2x 30 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-40% EtOAc in hexane, to give the title compound. LC-MS Method A: m/e = 464.04 [M+1]; Rt = 2.47 min. 1H NMR (CDCl3) delta 7.32 (m, 5H), 5.07 (s, 2H), 4.02 (s, 2H), 3.96 (s, 2H), 2.35 (s, 2H), 2.26 (s, 2H), 1.66 (s, 4H), 1.42-1.44 (bs, 18H).
  • 58
  • [ 40542-90-3 ]
  • 2-[(N-{2-[(α-L-fucopyranosyl)oxy]ethyl}-L-α-glutaminyl)amino]ethyl α-L-fucopyranoside [ No CAS ]
  • benzyl [(2S)-1,5-dioxo-1,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentan-2-yl]amino}-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: adipic acid monobenzyl ester With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 2-[(N-{2-[(α-L-fucopyranosyl)oxy]ethyl}-L-α-glutaminyl)amino]ethyl α-L-fucopyranoside With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; 18.C benzyl [(2S)-1,5-dioxo-1,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentan-2-yl]amino}-6-oxohexanoate
To a solution of 6-(benzyloxy)-6-oxohexanoic acid (260 mg, 1.1 mmol) in DMF (10 mL) at 0° C. was added TSTU (348 mg, 1.155 mmol) followed by DIPEA (202 μL, 1.155 mmol). After stirring at 0° C. for 1 hr, the reaction mixture was partitioned between Et2O (100 mL) and brine (100 mL). The organic phase was separated, further washed with brine (2*100 mL), dried over MgSO4, and concentrated. The residue was redissolved in DMF (5 mL), added to a solution of 2-[(N-{2-[(α-L-fucopyranosyl)oxy]ethyl}-L-α-glutaminyl)amino]ethyl α-L-fucopyranoside (368 mg, 1.103 mmol) in DMF (10 mL) at 0° C. followed by adding Et3N (154 μL, 1.103 mmol). After stirring at 0° C. for 30 min, the reaction mixture was allowed to gradually warm up to rt and stir for 2 h. The reaction mixture was diluted with CH3OH (10 mL) and purified by HPLC (gradient 6-30% 0.1% TFA in water over 34 min, 50*250 mm C4 15 um, 300 A, 100 mL/min flow rate). 1H NMR (CD3OD) δ 8.18 (m, 1H), 7.35-7.30 (m, 5H), 5.11 (s, 2H), 4.76 (d, J=3.6, 2H), 4.30 (dd, J=5.5, 8.6, 1H), 3.93 (dd, J=6.5, 13.1, 2H), 3.74-3.71 (m, 4H), 3.65 (s, 2H), 3.54-3.25 (m, 6H), 2.40 (t, J=6.7, 2H), 2.29-2.26 (m, 4H), 2.07-2.03 (m, 2H), 1.93-1.88 (m, 2H), 1.65-1.64 (m, 4H), 1.19 (d, J=6.5, 6H).
Stage #1: adipic acid monobenzyl ester With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 2-[(N-{2-[(α-L-fucopyranosyl)oxy]ethyl}-L-α-glutaminyl)amino]ethyl α-L-fucopyranoside With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; 18.C Step C: benzyl [(2S)-1,5-dioxo-1,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentan-2- yl]amino}-6-oxohexanoate To a solution of 6-(benzyloxy)-6-oxohexanoic acid (260 mg, 1.1 mmol) in DMF (10 mL) at 0 °C was added TSTU (348 mg, 1.155 mmol) followed by DIPEA (202 μL, 1.155 mmol). After stirring at 0 °C for 1 hr, the reaction mixture was partitioned between Et2O (100 mL) and brine (100 mL). The organic phase was separated, further washed with brine (2x100 mL), dried over MgSO4, and concentrated. The residue was redissolved in DMF (5 mL), added to a solution of 2-[(N-{2-[(α-L-fucopyranosyl)oxy]ethyl}-L-α-glutaminyl)amino]ethyl α-L-fucopyranoside (368 mg, 1.103 mmol) in DMF (10 mL) at 0 °C followed by adding Et3N (154 μL, 1.103 mmol). After stirring at 0 °C for 30 min, the reaction mixture was allowed to gradually warm up to rt and stir for 2 h. The reaction mixture was diluted with CH3OH (10 mL) and purified by HPLC (gradient 6-30 % 0.1%TFA in water over 34 min, 50x250 mm C4 15 um, 300A, 100 mL/min flow rate). 1H NMR (CD3OD) δ 8.18 (m, 1H), 7.35-7.30 (m, 5H), 5.11 (s, 2H), 4.76 (d, J = 3.6, 2H), 4.30 (dd, J = 5.5, 8.6, 1H), 3.93 (dd, J = 6.5, 13.1, 2H), 3.74-3.71 (m, 4H), 3.65 (s, 2H), 3.54-3.25 (m, 6H), 2.40 (t, J = 6.7, 2H), 2.29-2.26 (m, 4H), 2.07-2.03 (m, 2H), 1.93-1.88 (m, 2H), 1.65-1.64 (m, 4H), 1.19 (d, J = 6.5, 6H).
  • 59
  • [ 40542-90-3 ]
  • benzyl 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere
  • 60
  • [ 40542-90-3 ]
  • 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 3: palladium on activated charcoal; hydrogen / water / 16 h / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 3: hydrogen; palladium on activated charcoal / water / 16 h / 20 °C
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: hydrogen; palladium on activated charcoal / water / 16 h / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 3: hydrogen; palladium on activated charcoal / water / 16 h / 20 °C

  • 61
  • [ 40542-90-3 ]
  • 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-N-(2-[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)-6-oxohexanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 3: palladium on activated charcoal; hydrogen / water / 16 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 3: hydrogen; palladium on activated charcoal / water / 16 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C
Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: hydrogen; palladium on activated charcoal / water / 16 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 2: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 3: hydrogen; palladium on activated charcoal / water / 16 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere

  • 62
  • [ 40542-90-3 ]
  • C76H122N10O33 [ No CAS ]
  • C89H136N10O36 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: adipic acid monobenzyl ester With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.25h; Stage #2: C76H122N10O33 at 20℃; for 16h; 47 Compound 99 (0.17g, 0.76 mmoles) was treated with HBTU (0.29 g, 0.76 mmoles) and N,N- Diisopropylethylamine (0.35 mL, 2.0 mmoles) in DMF (50mL) for 15 minutes. To this was added compounds 97a-d (0.51 mmoles), individually, and allowed to stir at room temperature for 16 hours. At that time, the DMF was reduced by >75%> under reduced pressure, and then the mixture was dissolved in dichloromethane. The organic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil was purified by silica gel chromatography (5%- >20% methanol/ dichloromethane) to give compounds lOOa-d in 40-60% yield. LCMS and proton NMR was consistent with the structure.
Stage #1: adipic acid monobenzyl ester With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.25h; Stage #2: C76H122N10O33 In N,N-dimethyl-formamide at 20℃; for 16h; 47 Compound 99 (0.17g, 0.76 mmoles) was treated with HBTU (0.29 g, 0.76 mmoles) and N,N- Diisopropylethylamine (0.35 mL, 2.0 mmoles) in DMF (50mL) for 15 minutes. To this was added compounds 97a-d (0.51 mmoles), individually, and allowed to stir at room temperature for 16 hours. At that time, the DMF was reduced by >75% under reduced pressure, and then the mixture was dissolved in dichloromethane. The organic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil was purified by silica gel chromatography (5%-->20% methanol/ dichloromethane) to give compounds 100a-d in 40-60% yield. LCMS and proton NMR was consistent with the structure.
  • 63
  • [ 40542-90-3 ]
  • [ 5557-81-3 ]
  • C23H27NO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;Inert atmosphere; General procedure: Typical Procedure for Amide-Bond Formation of Carboxylic Acid with L-Alanine Benzyl Ester To a mixture of the corresponding carboxylic acid (1.2 mmol) and <strong>[5557-81-3]L-alanine benzyl ester hydrochloride</strong> (1.0 mmol) in CH2Cl2(4.4 mL), Et3N (3.0 mmol), DMAP (0.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.44 mmol) were added successively at r.t. The mixture was stirred for several hours to few days at r.t. until the starting material was consumed on TLC. Water was added and the mixture was extracted with ether. The extract was washed with water, brine and dried over MgSO4. Solvent was removed and the crude product was purified by column chromatography on silica gel eluted with an appropriate ratio of ethyl acetate and hexane. In the case of 10?and 11?EtOAc was used for the extraction instead of ether.
  • 64
  • [ 40542-90-3 ]
  • 2,5-dioxopyrrolidin-1-yl 6-((6-((2,5-dioxopyrrolidin-1-yl)oxy)-6-oxohexyl)amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 2: 20 weight% Pd(OH)2/C; hydrogen / methanol / 20 °C / 2585.81 Torr 3: triethylamine / N,N-dimethyl-formamide / 0.75 h / 0 °C
Multi-step reaction with 3 steps 1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide 2: palladium hydroxide on carbon; hydrogen / methanol / 2585.81 Torr 3: triethylamine / N,N-dimethyl-formamide / 0.75 h / 0 °C
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 2: palladium hydroxide on carbon; hydrogen / methanol / 2585.81 Torr 3: triethylamine / N,N-dimethyl-formamide / 0.75 h / 0 °C
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / N,N-dimethyl-formamide 2: palladium hydroxide on carbon; hydrogen / methanol / 2585.81 Torr 3: triethylamine / N,N-dimethyl-formamide / 0.75 h / 0 °C

  • 65
  • [ 40542-90-3 ]
  • [ 66060-81-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 3: hydrogen; palladium 10% on activated carbon / water / 18 h / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / water / 18 h / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 3: hydrogen; palladium 10% on activated carbon / water / 18 h / 20 °C
  • 66
  • [ 40542-90-3 ]
  • [ 22617-15-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 2: 20 weight% Pd(OH)2/C; hydrogen / methanol / 20 °C / 2585.81 Torr
Multi-step reaction with 2 steps 1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide 2: palladium hydroxide on carbon; hydrogen / methanol / 2585.81 Torr
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 2: palladium hydroxide on carbon; hydrogen / methanol / 2585.81 Torr
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / N,N-dimethyl-formamide 2: palladium hydroxide on carbon; hydrogen / methanol / 2585.81 Torr

  • 67
  • [ 40542-90-3 ]
  • [ 5514-99-8 ]
  • benzyl 6-((6-(benzyloxy)-6-oxohexyl)amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; 1 Step 1 Benzyl 6-((6-(benzyloxy)-6-oxohexyl)amino)-6-oxohexanoate To a mixture of adipic acid monobenzyl ester (600 mg, 2.54 mmol) and 6- (benzyloxy)-6-oxohexan-l-aminium 4-methylbenzenesulfonate (1.0 g, 2.54 mmol) in DMF (12.71 mL) was added HOBt (584 mg, 3.81 mmol), Hunig's base (888 μ, 5.08 mmol), and EDC (731 mg, 3.81 mmol). After stirring overnight, the reaction mixture was partitioned between sat. NaHC03 and EtOAc. The organic phase was separated, washed with 1.0 M HC1 and brine, dried over Na2SC"4, and concentrated to give the title compound as a semi-solid and used in the next step without further purification. UPLC-MS Method A: Rt = 1.26 min, m/z = 440.3 [M+l]
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide 1.1 Step 1 Benzyl 6-((6-(benzyloxy)-6-oxohexyl)amino)-6-oxohexanoate To a mixture of adipic acid monobenzyl ester (600 mg, 2.54 mmol) and 6- (benzyloxy)-6-oxohexan-1 -aminium 4-methylbenzenesulfonate (1.0 g, 2.54 mmol) in DMF (12.71 ml_) was added HOBt (584 mg, 3.81 mmol), Hunig's base (888 μΙ_, 5.08 mmol), and EDC (731 mg, 3.81 mmol). After stirring overnight, the reaction mixture was partitioned between sat. NaHCO3 and EtOAc. The organic phase was separated, washed with 1.0 M HCI and brine, dried over Na2SO4, and concentrated to give the title compound as a semi-solid and used in the next step without further purification. UPLC-MS Method A: Rt = 1.26 min, m/z = 440.3 [M+1]
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide 12.1 Step 1 Benzyl 6-((6-(benzyloxy)-6-oxohexyl)amino)-6-oxohexanoate To a mixture of adipic acid monobenzyl ester (600 mg, 2.54 mmol) and 6- (benzyloxy)-6-oxohexan-l-aminium 4-methylbenzenesulfonate (1.0 g, 2.54 mmol) in DMF (12.71 mL) was added HOBt (584 mg, 3.81 mmol), DIPEA (888 μ, 5.08 mmol), and EDC (731 mg, 3.81 mmol). After stirring overnight, the reaction mixture was partitioned between sat. NaHC03 and EtOAc. The organic phase was separated, washed with 1.0 M HC1 and brine, dried over Na2SO_i, and concentrated to give the title compound as a semi-solid and used in the next step without further purification. UPLC-MS Method A: tR= 1.26 min, m/z = 440 (z = 1).
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide 1.1 (Linking reagent 1 is described. o a m xture o a p c ac mono enzy ester ( mg, . mmo) an ( enzy oxy) oxohexan-1-aminium 4-methylbenzenesulfonate (1.0 g, 2.54 mmol) in DMF (12.71 mL) was added HOBt (584 mg, 3.81 mmol), Hunig's base (888 µL, 5.08 mmol), and EDC (731 mg, 3.81 mmol). After stirring overnight, the reaction mixture was partitioned between sat. NaHCO3 and EtOAc. The organic phase was separated, washed with 1.0 M HCl and brine, dried over Na2SO4, and concentrated to give the title compound as a semi-solid and used in the next step without further purification. UPLC-MS Method A: Rt = 1.26 min, m/z = 440.3 [M+1].

  • 68
  • [ 40542-90-3 ]
  • cis-N,N’-bis{2-[(α-L-fucopyranosyl)oxy]ethyl}piperidine-3,5-dicarboxamide [ No CAS ]
  • benzyl 6-[cis-3,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}carbamoyl)piperidin-1-yl]-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1,2-dichloro-ethane In N,N-dimethyl-formamide at 20℃; 17.C Step C: benzyl 6-[cis-3,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}carbamoyl)piperidin-1-yl]-6- oxohexanoate To a stirred solution of 6-(benzyloxy)-6-oxohexanoic acid (125 mg, 0.529 mmol) in DMF (3 mL) at room temperature was added DMAP (64.6 mg, 0.529 mmol), EDC (203 mg, 1.058 mmol) and a solution of N,N’-bis{2-[(α-L-fucopyranosyl)oxy]ethyl}piperidine-cis-3,5- dicarboxamide (438 mg, 0.794 mmol) in DMF (2 mL). After stirring at rt for overnight, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel, eluting with 0-50% AcCN in water, to afford the title compound. UPLC Method F: m/e = 770.48 [M+1]; Rt = 1.38 min.
  • 69
  • [ 219550-95-5 ]
  • [ 40542-90-3 ]
  • C63H82O10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.71 g Stage #1: adipic acid monobenzyl ester With oxalyl dichloride; N,N-dimethyl-formamide In acetonitrile at 0℃; for 0.5h; Stage #2: benzyl (3β,4α)-3,23-dihydroxy-olean-12-en-28-oate With pyridine In acetonitrile at -20℃; for 1h; 3.3.2.b Hederagenin diadipate (Method A) A similar procedure as for the manufacture of Hederagenin disuccinate was applied: To a solution of 1 .5 ml of dimethylformamide and 1 .5 ml of acetonitrile was added at -20°C a solution of 0.35 ml of oxalyl chloride (4 mmol) in 2 ml of acetonitrile. The slurry was stirred for 20 minutes at -20°C, followed by the addition of 1.68 g of adipic acid monobenzyl ester (4 mmol) in 2 ml of acetonitrile. The solution was stirred for 30 minutes at 0°C, followed by the addition of a solution of 0.58 g of hederagenin benzyl ester (1 mmol) in 2 ml of pyridine at -20°C. The slurry was stirred for 1 hour at -20°C. The mixture was diluted with diethyl ether and acidified with 0.5 mol/l hydrochloric acid. The organic phase was washed with water and evaporated. The residue was purified by chromatography on silica gel to ield 0.71 g of II as viscous oil.
  • 70
  • [ 40542-90-3 ]
  • [ 169527-49-5 ]
  • C17H25NO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: adipic acid monobenzyl ester With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.166667h; Stage #2: bis-[2-(tertbutyldimethylsilanyloxy)ethyl]amine In N,N-dimethyl-formamide General procedure for the synthesis of diols from functionalized carboxylic acids. (0080) Diol 3a: Mono benzyl adipate (3.07 g, 13 mmol) and EDC (2.68 g, 13 mmol) were taken in the RB flask. In this 15 mL dry DMF was added and stirred for 10 mins. To this activated carboxylic acid, compound 2a (3.33 g, 10 mmol) dissolved in 5 mL in DMF was added and reaction was stirred overnight. After completion of reaction, DMF was removed under reduced pressure and compound was extracted with 100 mL ethyl acetate (EtOAc). The organic layer was washed with 10% NaHCO3 solution and brine and dried over anhy. Na2SO4. The crude product was purified column chromatography with Hexane-EtOAc. Yield=3.4g (61%) (0081) 1H NMR(300 MHz, CDCl3): δ 1.66-1.71(m, 4H), 2.37-2.44(m, 4H), 3.47(dd, J1=4.98 Hz, J2=5.27 Hz, 2H), 3.54(dd J1=4.68, J2=4.98 Hz, 2H), 3.76(t, J1=4.98, J2=5.27 Hz, 2H), 3.84(t, J=4.68 Hz, 4.98 Hz, 2H), 5.11(s, 2H), 7.31-7.36(m, 5H). 13CNMR (75 MHz, CDCl3): δ 24.5, 33.1, 50.4, 52.1, 60.7, 61.5, 66.2, 128.2, 128.5, 135.9, 173.4, 174.9. (ESI-MS) Cal: 309.36, Obs.=311.2+Na+
  • 71
  • [ 40542-90-3 ]
  • [ 60984-63-6 ]
  • C57H90N2O37 [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: adipic acid monobenzyl ester With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.25h; Stage #2: mono-6-deoxy-6-(2-aminoethylamino)-β-cyclodextrin In N,N-dimethyl-formamide at 20℃; for 1h;
  • 72
  • [ 771-61-9 ]
  • [ 40542-90-3 ]
  • benzyl (perfluorophenyl) adipate [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With dicyclohexyl-carbodiimide In ethyl acetate at 0 - 20℃; 8.1 Step 1: Synthesis of benzyl (perfluorophenyl) adipate (8a) To a stirring solution of adipic acid monobenzyl ester (1.03 g, 4.3 mmol) and pentafluorophenol (0.87 g, 4.7 mmol) in EtOAc (18.7 mL) at 0° C. was added N,N′-dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). The mixture was allowed to warm to room temperature and then stirred overnight. The resulting solid was removed by vacuum filtration through a pad of Celite. The filter cake was washed with EtOAc. The filtrate was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/hexanes (0:1 to 4:6) as eluent, to give the product (8a) (1.59 g, 93%) as a solid. 1H NMR (300 MHz, CDCl3): δ 7.37-7.35 (m, 5H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.5 Hz, 2H), 1.82-1.78 (m, 4H).
93% With dicyclohexyl-carbodiimide In ethyl acetate at 0 - 20℃; 7.1; 49.1 Step 1: Synthesis of benzyl (perfluorophenyl) adipate (7a) To a stirring solution of 77 adipic acid monobenzyl ester (1.03 g, 4.3 mmol) and 78 pentafluorophenol (0.87 g, 4.7 mmol) in 21 EtOAc (18.7 mL) at 0° C. was added 79 N,N′-dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). The mixture was allowed to warm to room temperature and then stirred overnight. The resulting solid was removed by vacuum filtration through a pad of Celite. The filter cake was washed with EtOAc. The filtrate was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/hexanes (0:1 to 4:6) as eluent, to give the 80 product (7a) (1.59 g, 93%) as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.37-7.35 (m, 5H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.5 Hz, 2H), 1.82-1.78 (m, 4H).
93% With dicyclohexyl-carbodiimide In ethyl acetate at 0 - 20℃; 24.1 Step 1:
Synthesis of benzyl (perfluorophenyl) adipate (24a)
To a stirring solution of adipic acid monobenzyl ester (1.03 g, 4.3 mmol) and pentafluorophenol (0.87 g, 4.7 mmol) in EtOAc (18.7 mL) at 0° C. was added N,N'-dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). The mixture was allowed to warm to room temperature and then stirred overnight. The resulting solid was removed by vacuum filtration through a pad of Celite. The filter cake was washed with EtOAc. The filtrate was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/hexanes (0:1 to 4:6) as eluent, to give the product (24a) (1.59 g, 93%) as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.37-7.35 (m, 5H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.5 Hz, 2H), 1.82-1.78 (m, 4H).
  • 73
  • [ 40542-90-3 ]
  • 6-((3S,4S)-3-(([(1R)-1-(1-naphthyl)ethyl]amino)methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl)-6-oxohexanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 14 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 5 h / 20 °C 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -60 °C 3.2: 4.5 h / -78 - -50 °C 4.1: acetic acid; 1,2-dichloro-ethane / 0.33 h 4.2: 17 h / 20 °C 5.1: water / sodium hydroxide / tetrahydrofuran; methanol / 16 h / 20 °C 5.2: pH 2.0
  • 74
  • [ 40542-90-3 ]
  • 6-{(3S,4S)-3-([(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoic acid hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 14 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 5 h / 20 °C 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -60 °C 3.2: 4.5 h / -78 - -50 °C 4.1: acetic acid; 1,2-dichloro-ethane / 0.33 h 4.2: 17 h / 20 °C 5.1: water / sodium hydroxide / tetrahydrofuran; methanol / 16 h / 20 °C 5.2: pH 2.0 6.1: hydrogenchloride / 1,4-dioxane
  • 75
  • [ 2212-75-1 ]
  • [ 40542-90-3 ]
  • N6-[6-(benzyloxy)-6-oxohexanoyl]-N2-[(benzyloxy)carbonyl]-L-lysine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: adipic acid monobenzyl ester With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: N2-[(benzyloxy)carbonyl]-L-lysine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; 7.A Step A. N6-[6-(benzyloxy)-6-oxohexanoyl]-N2-[(benzyloxy)carbonyl]-L-lysine To a solution of 6-(benzyloxy)-6-oxohexanoic acid (3.20 g, 13.5 mmol) in DMF (30 mL) at 0°C was added TSTU (4.08 g, 13.5 mmol) and, after 5 min, DIPEA (2.36 mL, 13.5 mmol) dropwise. After stirring for 1 hr at 0°C, to the resulting mixture was added [(benzyloxy)carbonyl]-L-lysine (2.53 g, 9.03 mmol) as a solid and DIPEA (3.15 mL, 18.1 mmol). The suspension was allowed to stir overnight while the temperature gradually warmed up to rt. The reaction mixture was concentrated, and the title compound was isolated by chromatography on C-18 column (ISCO 130 g), flow rate 50 mL/min; gradient 0-50% AcCN in H2O over 40 min). UPLC Method A: m/z = 499.26 (z = 1); tR = 4.22 min.
  • 76
  • [ 40542-90-3 ]
  • Gly-γGlu(OtBu)-Glu [ No CAS ]
  • [(S)-4-{2-[ 6-(benzyloxy)-6-oxohexanamido]acetamido}-5-(tert-butoxy)-5-oxopentanoyl]-L-glutamic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: adipic acid monobenzyl ester; Gly-γGlu(OtBu)-Glu In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; 12.A Step A. [ (S)-4-{2-[ 6-(benzyloxy)-6-oxohexanamido]acetamido}-5-(tert-butoxy)-5- oxopentanoyl]-L-glutamic acid To a solution of Gly-yGlu(OtBu)-Glu (1.487 g, 3.82 mmol) in DMF (20 mL) at 0 °C was added 6-(benzyloxy)-6-oxohexanoic acid (1.337 g, 4.01 mmol) in DMF (4 mL) portionwise over a period of l5min and then TEA (1.064 mL, 7.64 mmol) dropwise over a period of 10 min. After stirring at rt overnight, the reaction mixture was concentrated. The residue was purified by flash chromatography on C18 reverse phase silica gel (150 g), eluting with 5-60% AcCN/H20 24 CV, to give the title compound. UPLC-MS Method B: tR = 4.71 min; m/z = 608.33 (z = 1).
  • 77
  • [ 872100-85-1 ]
  • [ 40542-90-3 ]
  • benzyl 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In N,N-dimethyl-formamide at 0℃; for 1h; 1.B Step B. benzyl 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoate To a solution of 2-aminoethyl a-D-mannopyranosyl-(l 3)-[a-D-mannopyranosyl- (0454) ( 1 6)] -a-D-mannopyranoside (1.23 g, 2.247 mmol, WO 2010/088294 Al) in DMF (20 mL) at 0 °C was added benzyl 6-[(2,5-dioxopyrrolidin-l-yl)oxy]-6-oxohexanoate (1.02 g, 3.06 mmol) and TEA (0.5 mL, 3.59 mmol). After stirring at 0 °C for 1 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on Cl 8 reverse phase silica gel column (275 g), eluting with 0-40% AcCN in H2O, to give the title compound. UPLC-MS Method A: calculated for (0455) C33H5iN019 765.31, observed m/z = 766.26 (z = 1); tR = 4.04 min. ifl NMR (D20) d 7.43-7.37 (5H, m), 5.14 (2H, s), 5.07-5.06 (1H, m), 4.82-4.81 (1H, m), 4.77-4.76 (1H, m), 4.06-4.01 (2H, m), 3.96-3.92 (2H, m), 3.87-3.81 (5H, m), 3.79-3.77 (1H, m), 3.74-3.67 (5H, m), 3.65-3.60 (4H, m), 3.53-3.49 (1H, m), 3.37-3.35 (2H, m), 2.43-2.40 (2H, m), 2.22-2.19 (2H, m), 1.62-1.52 (4H, m).
  • 78
  • [ 85342-65-0 ]
  • [ 40542-90-3 ]
  • C21H15Cl4NO6 [ No CAS ]
  • 79
  • [ 40542-90-3 ]
  • 6-((4-((2-((tert-butoxycarbonyl)amino)phenyl)carbamoyl)phenyl)amino)-6-oxohexanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 0 °C / Inert atmosphere 1.2: 20 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / Inert atmosphere; Schlenk technique
  • 80
  • [ 40542-90-3 ]
  • tert butyl(2-(4-(6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanamido)benzamido)phenyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 0 °C / Inert atmosphere 1.2: 20 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / Inert atmosphere; Schlenk technique 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 0 °C / Inert atmosphere 3.2: 16 h / 20 °C
  • 81
  • [ 40542-90-3 ]
  • N-1-(4-((2-aminophenyl)carbamoyl)phenyl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 0 °C / Inert atmosphere 1.2: 20 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / Inert atmosphere; Schlenk technique 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 0 °C / Inert atmosphere 3.2: 16 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 20 °C / Inert atmosphere
  • 82
  • tert-butyl (2-(4-aminobenzamido)phenyl)carbamate [ No CAS ]
  • [ 40542-90-3 ]
  • benzyl 6-((4-((2-((tert-butoxycarbonyl)amino)phenyl)carbamoyl)phenyl)amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: adipic acid monobenzyl ester With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate at 0℃; Inert atmosphere; Stage #2: tert-butyl (2-(4-aminobenzamido)phenyl)carbamate In N,N-dimethyl-formamide at 20℃;
  • 83
  • [ 124-04-9 ]
  • [ 100-39-0 ]
  • [ 40542-90-3 ]
YieldReaction ConditionsOperation in experiment
31% With sodium hydrogencarbonate In 1,4-dioxane; N,N-dimethyl-formamide at 90℃; for 16h; Inert atmosphere;
  • 84
  • C92H186O47 [ No CAS ]
  • [ 40542-90-3 ]
  • C118H214O53 [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h; 2 A solution of PEG2000 (2a) (11.0 g, 5.5 mmol) and benzyl adipate half-ester (4.8 g, 20.6 mmol) in dichloromethane(90.0 mL) was cooled to 0°C. Dicyclohexylcarbodiimide (4.47 g, 21.7 mmol) was added followed by a catalyticamount of DMAP (5 mg) and the solution was stirred and allowed to reach room temperature overnight (12 h). The flaskwas stored at +4°C for 5 h. The solid was filtered and the solvent completely removed by destination in vacuo. Theresidue was dissolved in 1000 mL 1/1(v/v) ether/ethyl acetate and stored at RT for 2 hours while a small amount of aflaky solid was formed. The solid was removed by filtration through a pad of Celite. The solution was stored in a tightlyclosed flask at -30°C in the freezer for 12 h until crystallisation was complete. The crystalline product was filtered througha glass frit and washed with cooled ether (-30°C). The filter cake was dried in vacuo. Yield: 11.6 g (86 %) 2b as a colorlesssolid.The product was used without further purification in the next step.MS: m/z 813.1 = [M+3H]3+ (calculated = 813.3)
  • 85
  • [ 40542-90-3 ]
  • (S)-2,2’-[6-amino-1-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-1-oxohexan-2-yl]azanediyl}bis(N-{2-[(α-L-fucopyranosyl)oxy]ethyl}acetamide) [ No CAS ]
  • benzyl (S)-6-[5-{bis[2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}-6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexyl]amino}-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide 42.3 Step 3. benzyl (S)-6-[5-(bis[2-({2-[(a-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}-6- ({2-[(a-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexyl]amino}-6-oxohexanoate To a solution of N-{2-[(a-L-fucopyranosyl)oxy]ethyl}-N2,N2-bis[2-({2-[(a-L- fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]-L-lysinamide (2.66g, 3.21mmol) and 6- (benzyloxy)-6-oxohexanoic acid (909mg, 3.85mmol) in DMF (16mL) was added sequentially DIPEA (1.679mL, 9.62mmol), HOBt (589mg, 3.85mmol) and EDC (737mg, 3.85mmol). After stirring overnight, the reaction mixture was concentrated, and the residue was purified on 120g SiCh column (flow rate lOOmL/min, gradient solvent A - solvent B of 0-100% solvent B in 30min followed by hold, where solvent A was EtOAc, and solvent B was EtOAc/MeOH/AcCN/ H2O (v/v/v/v = 6/1/1/1), to give the title compound. UPLC-MS Method A: m/z = 1048.6133 (z = 1); tR = 2.72.
  • 86
  • bis{2-[(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)oxy]ethyl} amine [ No CAS ]
  • [ 40542-90-3 ]
  • benzyl 6-(bis{2-[(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: bis{2-[(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)oxy]ethyl} amine; adipic acid monobenzyl ester With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; 28.1 Step 1. benzyl 6-(bis{2-[(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyl)oxy]ethyl}amino)-6- oxohexanoate To a solution of adipic acid monobenzyl ester (l.Og, 4.23mmol) and bis{2-[(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyl)oxy] ethyl} amine (3.24g, 4.23mmol) in DMF (3.0mL) was added DIPEA (2.22mL, 12.70mmol), HOBt (843 mg, 5.50mmol) and, after stirring for lOmin, EDC (1.055g, 5.50mmol). After stirring at rt overnight, the mixture was concentrated. The residue was dissolved in EtOAc (lOOmL) and washed with 1M HC1 (lOOmL), saturated NaElCCh (lOOmL) and brine (lOOmL). The organic layer was separated, dried over NaiSCE, and concentrated. The title material was isolated by chromatography (80g SiCh column, flow rate = 80mL/min, gradient 0-100% of EtOAc in Hexanes in 30min followed by 30min hold with 100% EtOAc). UPLC-MS Method D: m/z = 984.44 (z = 1); tR = 4.46min.
  • 87
  • [ 40542-90-3 ]
  • 3-amino-([2,3,4,6-penta-O-benzoyl-α-D-mannopyranosyl-(1→3)-[2,3,4,6-penta-O-benzoyl-α-D-mannopyranosyl-(1→6)]-2,4-di-O benzoyl-α-D-mannopyranosyl]propane) [ No CAS ]
  • benzyl N-(3-[2,3,4,6-penta-O-benzoyl-α-D-mannopyranosyl-(1→3)-[2,3,4,6-penta-O-benzoyl-α-D-mannopyranosyl-(1→6)]-2,4-di-O-benzoyl-α-D-mannopyranosyl]propyl)-6-oxohexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Inert atmosphere; 38.5 Step 5: benzyl N-(3-[2,3,4,6-penta-O-benzoyl-a-D-mannopyranosyl-(13)-[2,3,4,6- penta-O-benzoyl-a-D-mannopyranosyl-(16)]-2,4-di-O-benzoyl- a-D-mannopyranosyl]propyl)- 6-oxohexanoate To a solution of 3-amino-([2,3,4,6-penta-O-benzoyl-a-D-mannopyranosyl-(13)- [2,3,4,6-penta-O-benzoyl-a-D-mannopyranosyl-(16)]-2,4-di-O-benzoyl- a-D-mannopyranosyl] propane) (800mg, 0.504mmol) and 6-(benzyloxy)-6-oxohexanoic acid (143mg, 0.605mmol) in DCM (5ml) was added EDC (155mg, 0.807mmol) and HOBt (108mg, 0.706mmol), and the resulting mixture stirred at rt for 1h. The mixture was diluted with further DCM (5ml) and washed with water (10ml); the organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography using a 40g gold column) eluted with gradient 0-100% EtOAc in hexanes (8CV) to give the title compound. 1H NMR d (ppm) (CHCl3-d): 1.69 (2 H, s), 1.92-1.84 (2 H, m), 2.02-1.97 (3 H, m), 2.15 (2 H, t, J=7.28Hz), 3.30- 3.24 (1 H, m), 3.57-3.51 (1 H, m), 3.84 (1 H, d, J=10.29Hz), 4.26 (2 H, d, J=10.37Hz), 4.42-4.31 (3 H, m), 4.48 (1 H, dt, J=10.19, 3.19Hz), 4.53 (1 H, dd, J=12.25, 3.82Hz), 4.60 (1 H, dd, J=7.99, 3.54Hz), 4.64 (1 H, dt, J=10.16, 3.06Hz), 4.77 (1 H, dd, J=12.22, 2.50Hz), 5.07 (2 H, s), 5.20 (1 H, s), 5.44 (1 H, d, J=1.83Hz), 5.49 (1 H, s), 5.58 (1 H, t, J=3.67Hz), 5.62 (1 H, t, J=7.84Hz), 5.73 (1 H, dd, J=3.32, 1.82Hz), 5.77 (1 H, dd, J=10.07, 3.28Hz), 5.98 (1 H, dd, J=10.15, 3.29Hz), 6.03 (1 H, t, J=10.05Hz), 6.20 (1 H, t, J=10.12Hz), 6.54 (1 H, t, J=5.60Hz), 7.22 (2 H, t, J=7.76Hz), 7.39-7.33 (11 H, m), 7.46-7.39 (8 H, m), 7.55-7.50 (5 H, m), 7.63-7.57 (4 H, m), 7.78-7.76 (2 H, m), 7.80-7.78 (2 H, m), 7.84-7.82 (2 H, m), 7.91-7.89 (2 H, m), 7.97- 7.95 (2 H, m), 8.04 (2 H, dd, J=7.97, 1.40Hz), 8.10-8.08 (2 H, m), 8.13 (2 H, dd, J=4.64, 1.58Hz), 8.15-8.14 (2 H, m), 8.26-8.24 (2 H, m).
  • 88
  • [ 40542-90-3 ]
  • benzyl 5-isocyanatopentanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With diphenyl phosphoryl azide; triethylamine In chloroform at 65℃; for 2h; Inert atmosphere; 48.1 Step 1: Benzyl 5-(3-(2-(((2R,3S,4S,5R,6R)-3,5-dihydroxy-4-(((2R,3S,4S,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-((((2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2- yl)oxy)ethyl)ureido)pentanoate A mixture of diphenylphosphoryl azide (641mg, 2.328mmol), adipic acid monobenzyl ester (500mg, 2.116mmol), TEA (590 µl, 4.23mmol) using chloroform (2.116ml) as solvent is heated at 65°C for 2h, then removed heat and stirred overnight. The solvent was evaporated, and the crude was re-dissolved resulting crude benzyl 5-isocyanatopentanoate in 3.6ml of DMF. 2- aminoethyl a-D-mannopyranosyl-(13)-[a-D-mannopyranosyl-(16)]-b-D-mannopyranoside (100mg, 0.183mmol), Hünig’s base (63.8 µl, 0.365mmol) was added, and the mixture was heated at 70°C, overnight. The reaction mixture was concentrated on a rotary evaporator and purified by silica gel column flash chromatography with a 13g C18 column using gradient 0- 40% of B in 30min (flow 6ml/min, Solvent A=water-0.05%TFA, solvent B=AcN-0.05% TFA). The title compound was isolated after lyophilization. UPLC-MS: calculated for C33H52N2O19 780.31, observed m/z: 781.22 (M+H) (tR=1.31/2.00min).
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