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[ CAS No. 10378-06-0 ] {[proInfo.proName]}

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Chemical Structure| 10378-06-0
Chemical Structure| 10378-06-0
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Product Details of [ 10378-06-0 ]

CAS No. :10378-06-0 MDL No. :N/A
Formula : C14H19NO8 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 329.30 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 10378-06-0 ]

Physicochemical Properties

Num. heavy atoms : 23
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.71
Num. rotatable bonds : 7
Num. H-bond acceptors : 9.0
Num. H-bond donors : 0.0
Molar Refractivity : 78.22
TPSA : 109.72 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) : -8.67 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.16
Log Po/w (XLOGP3) : -0.51
Log Po/w (WLOGP) : -0.43
Log Po/w (MLOGP) : 0.1
Log Po/w (SILICOS-IT) : 0.7
Consensus Log Po/w : 0.61

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.1
Solubility : 26.3 mg/ml ; 0.0797 mol/l
Class : Very soluble
Log S (Ali) : -1.33
Solubility : 15.5 mg/ml ; 0.0472 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.9
Solubility : 41.6 mg/ml ; 0.126 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 5.04

Safety of [ 10378-06-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338-P304+P340 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 10378-06-0 ]

* 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 [ 10378-06-0 ]

[ 10378-06-0 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 76375-60-5 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
90% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 50℃;
79% With iron(III) chloride In dichloromethane at 25℃; for 2h; Inert atmosphere; Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH- pyranor3,2-d1oxazole-6,7-diyl diacetate (7) Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3- acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500 mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). The resulting mixture was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 1000 mL of water/ice. The organic layer was washed with 1x1000 mL of sodium aq. bicarbonate and 1x1000 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (7, 20 g, 79%) as yellow oil. 1HNMR(CDCl3, 300MHz, ppm): 2.03(s, 9H), 2.12(s, 3H), 3.97-4.27(m, 4H), 4.90-4.93(m, J = 3.3Hz, 1H), 5.45-5.47(t, J= 3.0Hz, 1H), 5.98-6.00(d, J= 6.6Hz, 1H).
69% With aluminium(III) iodide; calcium; sodium iodide In acetonitrile at 45℃; for 5h;
65% With iron(III) chloride In dichloromethane at 25℃; for 2h; Inert atmosphere; Into a 50 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of G7-3 (220 g, 565 mmol, 1.00 equiv.) in dichloromethane (22 L). This was followed by the addition of ferric chloride (275 g), in portions at 25°C. The resulting solution was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 17 L of water/ice. The resulting solution was washed with water and saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in 121 g (65%) of G7-4.
64% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 50℃; for 16h; 1 Alternatively, the following procedures were used to provide 4 (eg, 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-D-galactopyrano)[1,2d]-1,3-oxazoline).galactosamine penta-acetate 15 (2Mg, 5.15 rnmol) was dissolved in dichioroethane (DCE) (2() mL), Then trirnethylsilyl trifluoromethanesufonate (TMSOTf (1 ml, 5.53 mmol) was added, and the mixture was stirred at 50°C for 9h. The mixture was then removed from the heat and stirred for 7h. Triethylarnine (2m1) was added to the mixture at room temperature. The mixture was then washed with a saturated so’ution of NaHCO3 and then dried with sodium sulfate. The organic phase was then filtered and the solvent was removed via rotary evaporation and the residue was loaded onto silica gel. The product was purified via column chromatography on silica gel with EtOAc (100) to yield 16 as a yellow viscus solid, (Yield:64%) IH NMR: (400 MHz, CDCI3-d6): ö (ppm), 5.97 (d, J=69 Hz, 1H, H-4); 5.45 (t, J=3,O Hz, 1H, H5); 4.92 (dd, J=7,6 Hz, 14 Hz, 1H, H-4); 4.26 (td, J=63 Hz, 2.8 Hz, 1W); 425- 4J3 (m, IH, H-3); 3.99 (s, IH); 2.13 (s, 3H); 2M7 (s, 6H); 2M5 (s, 3Ff). 13C NMR: (125 MHz, DMSOd6): ö (ppm), 170M; 169.55; [68.11; 165.21; 100.9; 70.66; 68.2; 65.02, 63.00, 61.8, 20.5, 20.44, 20.42, 13.91. MS miz: [M + H]± 330.12.
62% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 50℃; Inert atmosphere;
54% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 50℃; for 9h; Inert atmosphere;
With iron(III) chloride In dichloromethane at 25℃; for 2h; Inert atmosphere; 1-2 Synthesis of (3aR.5R.6R.7R.7aR)-5-(acetoxymethyl)-2-methyl-5,6.7.7a-tetrahvdro-3aH- pyrano|"3.2-d"|oxazole-6,7-diyl diacetate (Compound 7) Synthesis of (3aR.5R.6R.7R.7aR)-5-(acetoxymethyl)-2-methyl-5,6.7.7a-tetrahvdro-3aH- pyrano|"3.2-d"|oxazole-6,7-diyl diacetate (Compound 7) Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3-acetamido-6- (acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (Compound 6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500 mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). The resulting mixture was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 1000 mL of water/ice. The organic layer was washed with 1x1000 mL of sodium aq. bicarbonate and 1x1000 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in (3aR,5R,6R,7R,7aR)-5- (acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (Compound 7) as yellow oil. ^MR CDCb, 300MHz, ppm): 2.03(s, 9H), 2.12(s, 3H), 3.97-4.27(m, 4H), 4.90-4.93(m, J = 3.3Hz, 1H), 5.45-5.47(t, J= 3.0Hz, 1H), 5.98-6.00(d, J= 6.6Hz, 1H).
With iron(III) chloride In dichloromethane at 25℃; for 2h; Inert atmosphere; A.1-2 Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahvdro-3aH- pyranor3,2-d1oxazole-6,7-diyl diacetate (Compound A7) Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahvdro-3aH- pyranor3,2-d1oxazole-6,7-diyl diacetate (Compound A7) Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3-acetamido-6- (acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (A6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500 mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). The resulting mixture was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 1000 mL of water/ice. The organic layer was washed with 1x1000 mL of sodium aq. bicarbonate and 1x1000 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2- methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (Compound A7) as yellow oil. 1HNMR(CDC13, 300MHz, ppm): 2.03(s, 9H), 2.12(s, 3H), 3.97-4.27(m, 4H), 4.90-4.93(m, J = 3.3Hz, 1H), 5.45-5.47(t, J= 3.0Hz, 1H), 5.98-6.00(d, J= 6.6Hz, 1H).
With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20 - 55℃; Inert atmosphere; 1.NAG7 Preparation of benzyloxycarbonylbutyl 2-deoxy 2-A/-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method A. Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) was added to a solution of NAG2 (10.0 g, 25.6 mmol) in DCE (100 mL) at ambient temperature. The mixture was stirred at 55 °C for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured onto ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 andconcentrated in vacuo to give syrup NAG6. A solution NAG6 in DCE (60 ml_) was charged with alcohol NAG5 (8.00 g, 38.4 mmol) and molecular sieves. The mixture was placed under an inert atmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at rt. The mixture was poured over ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 and concentrated in vacuo to give syrup. This crude material was purified by Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). H NMR (CDCI3, 500 MHz): δ 7.35 (m, 5H), 5.98 (d, 1 H, J 7.0 Hz), 5.57 (m, 1 H), 5.34 (d, 1 H, J 3.0 Hz), 5.25 (dd, 1 H, J 3.0 Hz, 1 1 Hz), 5.10 (s, 2H), 4.63 (d, 1 H, J 8.5 Hz), 4.1 1 (m, 2H), 3.95 (m, 1 H), 3.88 (m, 2H), 3.49 (m, 1 H), 2.37 (m, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H), 1.70 (m, 2H), 1.61 (m, 2H).
With iron(III) chloride In dichloromethane at 25℃; for 2h; Inert atmosphere; Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH- pyrano[3.2-d]oxazole-6.7-diyl diacetate (Compound A7) Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH- pyrano[3.2-d]oxazole-6.7-diyl diacetate (Compound A7)Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (A6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500 mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). The resulting mixture was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 1000 mL of water/ice. The organic layer was washed with 1x1000 mL of sodium aq. bicarbonate and 1x1000 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in Compound A7 as an oil. 1H NMR (CDCl3, 300MHz, ppm): 2.03(s, 9H), 2.12(s, 3H), 3.97-4.27(m, 4H), 4.90-4.93(m, J= 3.3Hz, 1H), 5.45-5.47(t, J= 3.0Hz, 1H), 5.98-6.00(d, J= 6.6Hz, 1H).
With iron(III) chloride In dichloromethane at 25℃; for 2h; Inert atmosphere; Synthesis of (3 aR,5R,6R,7R,7aR)-5 -(acetoxymethyl)-2-methyl-5 ,6,7,7a-tetrahydro-3 aH20 pyrano 13 ,2-d] oxazole-6,7-diyl diacetate (Compound AT) Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3-acetamido-6- (acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (A6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500 mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). The25 resulting mixture was stirred for 2 h at 25°C. The reaction was then quenched by the addition of1000 mL of water/ice. The organic layer was washed with lx 1000 mL of sodium aq. bicarbonate and lxl000 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in Compound A7 as an oil.‘HNMR(CDC13, 300MHz, ppm): 2.03(s, 9H), 2.12(s, 3H), 3.97-4.27(m, 4H), 4.90-4.93(m, J= 30 3.3Hz, 1H), 5.45-5.47(t, J= 3.0Hz, 1H), 5.98-6.00(d, J= 6.6Hz, 1H).
With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 50℃; for 12h; Inert atmosphere;
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 40 - 45℃; for 21h; 1.2 Step 2 To suspension of peracetylated galactosamine (1 .63g, 4.17mmol) in 30mL DCM. TMSOTf (1 .90mL, 10.4mmol) was added and reaction mixture stirred at 40-45°C for 5 h. An additional portion of TMSOTf (0.30 mL 2.8 mmol) was added and the reaction mixture was stirred for additional 16 h. Then the reaction was quenched with NEt3 (0.90 mL) at 0 °C and diluted with DCM, extracted with cold sat. NaHC03 (2x100 mL), brine (50 mL), dried over Na2S04 and evaporated. Product 1 isolated as a yellow oil, 1 .40 g crude yield.
1.35 g With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 40℃; for 24h; 13 Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxym-ethyl)-2-methyl-5,6,7,7a-tetrahydro-3aR-pyrano[3,2-d]oxazole-6,7-diyl diacetate (2) The crude mixture of compound 1(2.0 g, 5.139 mmol) was dissolved in DCM (25 mE) and TMSOTf (1.85 mE, 10.27 mmol) was added and reaction mixture stirred at 40°C. for 24 hours. The reaction was quenched with Et3N (0.4 mE, pH 7.5), diluted in DCM and extracted with sat. NaRCO3 solution. The organic layer was washed with water, brine and dried over Na2504 before evaporation of solvents under reduced pressure and the residue purified by silica gel column chromatography using DCM:EA:MeOR (7.5:2.0:0.5) as an eluent to obtain compound 2 (1.35 g, 82% yield). ‘R-NMR (500 MHz, CDC13): ö 2.03 (s, 3R, H7), 2.064 (s, 3R, CR3, OAc), 2.067 (s, 3R, CR3, OAc), 2.08 (s, 3R, CR3, OAc), 4.12 (dd, 1R, J=6.5 & 12.0 Hz, H5), 4.18 (d, 1R, J=9.0 Hz, H3), 4.32 (dd, 1R, J=3.5 & 12.0Hz, H5), 4.52 (dd, 1R, J=1.5 & 5.5 Hz, H2), 5.00 (m, 1R, H5), 5.14 (s, 1R, H4), 6.12 (d, 1R, J=6.5 Hz, H1); ‘3C-NMR (125 MHz, CDC13): ö 14.30 (C7), 20.6, 20.7,20.75 (OAc, 3CR3), 62.8 (C5), 69.6 (C2), 76.4 (C3), 77.6 (C5), 84.3 (C4), 107.3 (C1), 167.05 (C8), 169.6, 169.8, 170.3 (OAc, CO). EI-MS: [M+R] C,4R2QN08 calcd 330.12, obsd 330.11, [M+Na] C,4R,9NNaO8 calcd 352.10, obsd 352.11.
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 24h; Reflux;
26.9 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Inert atmosphere; Cooling with ice; 1.1-1b (1-1b) Synthesis of GAL-3 Dissolve the GAL-2 (35.1g, 90.0mmol) obtained in step (1-1a) in 213ml of anhydrous 1,2-dichloroethane,Under ice-water bath and nitrogen protection, 24.0 g of TMSOTf (CAS No.: 27607-77-8, purchased from Macleans Company, 108.0 mmol) was added and reacted at room temperature overnight.Add 400ml of dichloromethane to the reaction solution to dilute, filter with diatomaceous earth,Then add 1L saturated sodium bicarbonate aqueous solution, stir evenly, separate the organic phase, and extract the aqueous phase with dichloroethane twice, 300ml each time,The organic phases were combined and washed with 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of saturated brine respectively. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 26.9 g of light yellow viscous sugar thin product GAL-3.
26.9 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; 1.1-1b (1-1b) Synthesis of GAL-3 The GAL-2 (35.1g, 90.0mmol) obtained in step (1-1a) was dissolved in 213ml of anhydrous 1,2-dichloroethane, and 24.0g of TMSOTf(CAS No.: 27607-77-8, purchased from Macleans Company, 108.0 mmol), reacted at room temperature overnight.Add 400ml of dichloromethane to the reaction solution to dilute, filter with diatomaceous earth, then add 1L of saturated sodium bicarbonate aqueous solution, stir evenly, separate the organic phase, and extract the aqueous phase with dichloroethane twice, 300ml each time, and combine The organic phase was washed with 300 ml of saturated sodium bicarbonate aqueous solution and 300 ml of saturated brine respectively, the organic phase was separated, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 26.9 g of light yellow viscous syrupy product GAL-3.
26.9 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Cooling with ice; Inert atmosphere; 1.1-1-1; 1.1-1-1b (1-1-1b) Synthesis of GAL-3 Dissolve the GAL-2 (35.1g, 90.0mmol) obtained in step (1-1-1a) in 213ml of anhydrous 1,2-dichloroethane, Under ice-water bath and nitrogen protection, 24.0g TMSOTf (CAS number: 27607-77-8, purchased from Macleans Company, 108.0 mmol) was added, and reacted at room temperature overnight. Add 400ml of dichloromethane to the reaction solution to dilute, filter with diatomaceous earth, then add 1L of saturated sodium bicarbonate aqueous solution, stir well, separate the organic phase, The aqueous phase was extracted twice with 300ml of dichloroethane each time, and the organic phases were combined and washed with 300ml of saturated aqueous sodium bicarbonate solution and 300ml of saturated brine, respectively. Separate the organic phase, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 26.9 g of light yellow viscous sugar thin product GAL-3.
With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0 - 50℃; for 3.16667h; 3.2 Step 2: To a solution of (3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran- 2,4,5-triyl triacetate (100 g, 0.257 mol) in 1 ,2-dichloroethane (500 mL) cooled to 0 °C was added TMSOTF (85.5 g, 0.385 mol), the mixture was stirred for 10 min, then heated to 50 °C and stirred for 3 hours. TLC showed the start material was completely consumed. After cooling, the resultant mixture was treated with sat. aqueous NaHCO3 (1000 mL) at 0 °C, extracted with DCM (500 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated. The residue was dried under high vacuum overnight to give (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a-tetrahydro-5H-pyrano[3,2- d]oxazole-6,7-diyl diacetatel. 1H NMR (400 MHz, CDCIa) δ ppm 6.00 (d, 1 H, J = 2.8Hz), 5.47- 5.46 (m, 1 H), 4.93-4.90 (m, 1 H), 4.27-4.18 (m, 2H), 4.13-4.09 (m, 1 H), 4.02-3.98 (m, 1 H), 2.13 (s, 3H) , 2.07 (s, 6H), 2.06 (s, 3H).

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  • 3
  • [ 10378-06-0 ]
  • [ 100-51-6 ]
  • [ 41355-94-6 ]
YieldReaction ConditionsOperation in experiment
60% With aluminium(III) iodide In acetonitrile at 40℃;
  • 4
  • [ 3006-60-8 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
100% With trimethylsilyl trifluoropmethanesulfonate In chloroform at 40℃; for 1.5h; 2; 1.4 Step 4. Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyI-3a,6,7,7a- tetrahydro-5H-pyrano[3,2-d]oxazoIe-6,7-diyI diacetate 7 A solution of per-acetylated galactosamine 6 (8.45 g, 21.7 mmol) in CHC13 (320 mL) was treated dropwise with TMSOTf (4.32 mL, 23.9 mmol). After stirring (1.5 hr, 40°C) the reaction was quenched by the addition of triethylamine (5 mL) and concentrated to dryness to afford compound 7 as a pale yellow glass (7.2 g, Quant.). The product was used without further purification. Rf (0.59, 10% MeOH-CH2Cl2).
100% With trimethylsilyl trifluoropmethanesulfonate In chloroform at 40℃; for 1.5h; 1.4 Step 4. Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a- tetrahydro-5H-pyrano[3,2-d]oxazole-6,7-diyl diacetate 7 A solution of per-acetylated galactosamine 6 (8.45 g, 21.7 mmol) in CHCb (320 mL) was treated dropwise with TMSOTf (4.32 mL, 23.9 mmol). After stirring (1.5 hr, 40°C) the reaction was quenched by the addition of triethylamine (5 mL) and concentrated to dryness to afford compound 7 as a pale yellow glass (7.2 g, Quant.). The product was used without further purification. Rf (0.59, 10% MeOH-CH2Cl2).
100% With trimethylsilyl trifluoropmethanesulfonate In chloroform at 40℃; for 1.5h; 1.4 Step 4. Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a- tetrahydro-5H-pyrano[3,2-d]oxazole-6,7-diyl diacetate 7 A solution of per-acetylated galactosamine 6 (8.45 g, 21.7 mmol) in CHCb (320 mL) was treated dropwise with TMSOTf (4.32 mL, 23.9 mmol). After stirring (1.5 hr, 40°C) the reaction was quenched by the addition of triethylamine (5 mL) and concentrated to dryness to afford compound 7 as a pale yellow glass (7.2 g, Quant.). The product was used without further purification. Rf (0.59, 10% MeOH-CH2Cl2
100% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane 1 Compound 3: Dissolve 1.95 g (5.00 mmol) of compound 2 in 20 mL of anhydrous 1,2-dichloroethane, add 1.08 mL (6.00 mmol) TMSOTf dropwise, and stir overnight after dropping. Dissolve 840 mg (10.0 mmol) of NaHCO3 in 50 mL of ice water, pour the reaction solution into it under vigorous stirring, and continue stirring for 30 min. It was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.65 g of a pale yellow viscous liquid (namely compound 3), with a quantitative yield. Go to the next step without separation.
99% Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 50℃; for 10h; Stage #2: With triethylamine In dichloromethane 5; VI The scheme is shown in FIG. 5. Galactosamine hydrochloride is treated with acetic anhydride and pyridine at room temperature for 16 hr. The white precipitate is the per-o-acetyl GalNAc with a yield 76.7%. Formation of oxazoline derivative from per-o-acetyl GalNAc and subsequent glycoside formation were done according to the published method of Wu and Gao (Bioconjug Chem 17, 1537-44, 2006) with minor modification. To a solution of per-o-acetyl GalNAc in dichloroethane was added trimethylsilyl trifluoromethane sulfonate (TMSOTf) and the mixture was heated at 50° C. for 10 hr. Triethylamine was added to quench the acid. The reaction mixture was evaporated, the residue was dissolved in chloroform, and the chloroform solution was washed with cold saturated sodium bicarbonate (twice) and with 1M NaCl (once). The chloroform layer was dried with anhydrous sodium sulfate, filtered and evaporated. The dark red syrup was oxazoline derivative with yield 99%. This compound is unstable and it is better to proceed to the next step immediately. The oxazoline derivative obtained above and TFA-ah were dissolved in methylene chloride. Molecular sieve (4 {acute()}) was added and the mixture was flushed with nitrogen gas, and stirred at room temperature for 1 hr. Concentrated sulfuric acid was then added, and the mixture was stirred overnight. The reaction mixture was filtered through a pad of Celite on a sintered-glass filter. The filtrate was diluted with methylene chloride and the solution was washed with cold saturated sodium bicarbonate (twice) and 1M NaCl (once). The residue was dissolved in 95% ethanol and fractionated on a Sephadex LH20 column using 95% ethanol as eluant. Only the product TFA-ah-GalNAc(OAc)3 were combined and evaporated.
98% Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 60℃; for 4h; Stage #2: With triethylamine In 1,2-dichloro-ethane at 20℃; for 0.25h; 2-Methyl-3,4,6-tri-O-acetyl-1,2-deoxy-α-D-glucopyrano[2,1,d]-2-oxazoline (17) TMSOTf (1.0 mL, 5.40 mmol) was added at r.t. to a solution of peracetylated sugar 16 (2 g, 5.15 mmol) in anhydrous 1,2-dichloroethane (15 mL). The mixture was stirred for 4 h at 60 °C and allowed to cool to r.t. To this solution, triethylamine (2.9 mL) was added dropwise and, after 15 min at r.t., the reaction mixture was diluted with CH2Cl2(50 mL) and washed with a NaHCO3 sat. aq. soln (2 × 50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatographyon silica gel (CH2Cl2/MeOH, 50:1 → 30:1) to afford 18 (1.60 g, 98%) as a yellow oil. Spectroscopic and physical data matched those reported.19
98% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃; 1 Preparation of Compound 2 Compound 1 (2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose or galactosamine pentaacetate) is commercially available. Following a published procedure, Compound 2 was obtained in a 93% yield (Rensen et al., J. Med. Chem., 2004, 47, 5798-5808; Nakabayashi et al., Carbohyrate Res., 1986, 150, C7).
92% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane
92% With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 20℃; 4.4 (4) Synthesis of Compound 6 (0139) In a 250 mL round-bottomed flask, compound 5 (10 g, 25.7 mmol) and 100 mL of anhydrous dichloromethane were added, and stirred for 10 min, then added with trimethylsilyl trifluoromethanesulfonate (7 mL, 38.7 mmol), and allowed to overnight at room temperature; the reaction solution was slowly poured into an aqueous solution (200 mL) of sodium bicarbonate (7 g, 79.5 mmol), and stirred for 0.5 hours; the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 7.78 g of a light yellow gum with a yield of 92%.
90% Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃; for 1h; Stage #2: With triethylamine at 20℃; for 0.166667h; 2,3-Dihydrooxazole-3,4,6-tri-O-acetyl-α-D-galactopyranoside A solution of 5 (400mg, 1.03 mmol) in dichloroethane (28.6 mL) was treated with TMSOTf (0.200 mL, 1.08mmol) at room temperature, heated at 50 C for 1 h, cooled, and treated with NEt3 (0.440mL, 3.08 mmol). The mixture was stirred at room temperature for 10 min, passed througha short plug of SiO2 and washed with ethyl acetate (25 mL) and dichloromethane (30 mL).The solvent was evaporated under reduced pressure and the crude oil was purified bychromatography on SiO2 (100% EtOAc, SiO2 was base-washed with 1% NEt3 prior touse) to yield 5 as a clear slightly orange oil (304 mg, 0.923 mmol, 90%): 1H NMR (400MHz, CDCl3) δ 5.98 (d, J = 6.8 Hz, 1 H), 5.45 (d, J = 2.8 Hz, 1 H), 4.90 (dd, J = 3.2, 7.2Hz, 1 H), 4.26-4.16 (m, 2 H), 4.10 (dd, J = 5.6, 11.2 Hz, 1 H), 3.98 (td, J = 1.2, 7.6 Hz, 1H), 2.11 (s, 3 H), 2.06 (s, 6 H), 2.04 (d, J = 1.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ170.5, 170.2, 169.8, 166.4, 101.5, 71.8, 69.5, 65.3, 63.6, 61.6, 20.8, 20.7, 20.6, 14.4;HRMS (ESI) m/z calcd for C14H20NO8 [M+H]+ 330.1189, found 330.1187.
84% With iron(III) chloride In dichloromethane for 1h; Ambient temperature;
82% With iron(III) trifluoride In dichloromethane at 20℃; for 1h; Inert atmosphere;
Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoropmethanesulfonate In dichloromethane; lithium hydroxide monohydrate Reflux; Inert atmosphere; Stage #2: With triethylamine at 0 - 20℃; for 0.5h; Inert atmosphere; 2.1 Compound 2. Compound 2 was prepared by a procedure adopted from the literature (Westerlind, U. et al. Glycoconj. J. 2004, 21, 227-241). To a 500-mL one-neck round-bottom flask was added 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D- galactopyranose 1 (12.8 g, 32.8 mmol) followed by anhydrous CH2CI2 (150 mL) and trimethylsilyl trifluoromethanesulfonate (14.3 mL, 79.2 mmol). This mixture was stirred at reflux overnight (ca. 18 h) under a flow of argon gas. The reaction mixture was cooled to 0° C and treated with triethylamine (6.4 mL, 45.9 mmol) for 30 min before being warmed to room temperature, then washed with saturated aqueous NaHCC>3 (100 mL). The organic layer was separated and dried over Na2S04, filtered and evaporated providing crude oxazoline intermediate. To the crude oxazoline product was added anhydrous CH2CI2 (200 mL), N-t-Boc-5-amino-l-pentanol (10.0 g, 49.2 mmol) and 3 A molecular sieves (18.0 g, dried at 150°C for >24h). This mixture was stirred at room temperature for 30 min under a blanket of argon gas. Trimethylsilyl trifluoromethanesulfonate (2.97 mL, 16.4 mmol) was added to the reaction mixture, and the solution was stirred at room temperature overnight . The solution was cooled to 0°C and treated with triethylamine (3.2 mL, 23.07 mmol) for 30 min before being warmed to room temperature. After the reaction reached room temperature the mixture was filtered, and the mother liquor was evaporated providing the crude product as brown oil which was dissolved in anhydrous pyridine (100 mL) and treated with acetic anhydride (36 mL, 38.2 mmol). This mixture was stirred under an argon atmosphere at room temperature overnight , then evaporated under vacuum yielding a brown liquid, which was dissolved in CH2CI2 (200 mL). The solution was vigorously stirred with a saturated aqueous NaHCC>3 solution (100 mL) and solid NaHCC>3 in an open flask at room temperature to quench remaining Ac20and the organic layer was separated. The aqueous layer was extracted with CH2CI2 (1 x 200 mL) and all organic layers were combined. The organic layers were washed with saturated aqueous NaHCC>3 solution (1 x 100 mL), separated, dried over Na2S04, filtered and evaporated providing the crude product as a brown oil which was then dissolved in CH2CI2 (15 mL) and purified using column chromatography (S1O2, column size 7.5 cm ID x 16.0 cm length, EtOAc: Hexanes 1 :3 v/v for 500 mL, EtOAc : Hexanes 4: 1 v/v for 500 mL, 100% EtOAc for 1.0 L, 10 % MeOH in EtOAc v/v for 3.0 L). Product-containing fractions were pooled and evaporated under vacuum to a white solid which was further purified by trituration with ether to yield the desired product as a white solid (5 g, 29%). ESI MS [M+H]+ m/z 533.4.
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane 21; 38 Compound 1 (15.6 g, 40.1 mmol) was treated with TMSOTf (7.98 mL, 44.1 mmol) in DCE to give compound 2. Molecular weight for C14H20N08 (M+H) Calc. 330.12, Found 330.0.
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 20 - 55℃; Inert atmosphere; Preparation of benzyloxycarbonylbutyl 2-deoxy 2-/V-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method A.Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) was added to a solution of NAG2 (10.0 g, 25.6 mmol) in DCE (100 mL) at ambient temperature. The mixture was stirred at 55 °C for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured onto ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 and concentrated in vacuo to give syrup NAG6. A solution NAG6 in DCE (60 m L) was charged with alcohol NAG5 (8.00 g, 38.4 mmol) and molecular sieves. The mixture was placed under an inert atmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at rt. The mixture was poured over ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 and concentrated in vacuo to give syrup. This crude material was purified via Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). 1 H NMR (CDCI3, 500 MHz) : δ 7.35 (m , 5H), 5.98 (d, 1 H, J 7.0 Hz), 5.57 (m, 1 H), 5.34 (d, 1 H, J 3.0 Hz), 5.25 (dd, 1 H, J 3.0 Hz, 1 1 Hz), 5.10 (s, 2H), 4.63 (d, 1 H, J 8.5 Hz), 4.1 1 (m, 2H), 3.95 (m, 1 H), 3.88 (m, 2H), 3.49 (m, 1 H), 2.37 (m , 2H), 2.13 (s, 3H), 2.03 (s, 3H), 1 .99 (s, 3H), 1 .90 (s, 3H), 1 .70 (m , 2H), 1 .61 (m, 2H).
10.3 g Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 45℃; Stage #2: With triethylamine In dichloromethane at 0℃; 13.B B. Acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester. Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45°C. After cooling to 0°C, triethylamine (4.88 ml, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step. MS (ISP): 330.0 [M+H]+.
10.3 g Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 45℃; Stage #2: With triethylamine In dichloromethane at 0℃; 7.B Example 7
Synthesis of GalNAc Cluster
B.
Acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester Example 7 Synthesis of GalNAc Cluster B. Acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 mL, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step, MS (ISP): 330.0 [M+H]+.
Ca.3.7 g With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 20 - 50℃; for 23.08h; Inert atmosphere; 8.b Synthesis of G1' An oven-dried flask was charged with the GalNAc (Gl) (4.360 g, 11.20 mmol, 1.00 equivalents) and a stir bar. 1,2-Dichloroethane (Aldrich . anhydrous, 26 mL) was added to give a milky suspension. To this mixture was added Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (Alfa, 2.8 mL over 1 minute) via syringe at room temperature under N2. This mixture was stirred at room temperature for 30 minutes, but remained heterogeneous. The flask was placed in an oil-bath pre-heated to 50 °C. Within a few minutes the reaction mixture became homogeneous. After heating for 95 minutes, the power to the oil bath was turned off, and the flask was allowed to cool to room temperature overnight. After 21 hours an aliquot was removed, diluted with CH3CN, and checked by Mass spectroscopy (MS) CI POS: 362.1 (10), 330.1 (100), 210.1 (20), 168.1 (12), 150.1 (28) . [00552] The reaction solution (amber color) was poured into a 500-mL separately funnel containing 130 mL of ice-cold saturated aqueous NaHC03, and the reaction flask was rinsed with DCM (100 mL). After gas evolution had subsided, the phases were separated (the lower organic phase was cloudy yellow, and the upper aqueous phase was milky with a bit of color). The aqueous phase was extracted with DCM (1 x 50 mL). The combined DCM phases were washed with H20 (120 mL) and saturated aqueous NaCl (120 mL). The DCM phase (clear, light yellow) was dried over Na2SO4, filtered (Na2SO4 rinsed with about 100 mL of DCM), and concentrated by rotavap to give an amber oil. This was dried at room temperature under full vacuum overnight (about 3.7 g), and then stored in the freezer. This material was used without further purification in the next step.
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 55℃; for 2h; Inert atmosphere; 1.A Method A. Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) wasadded to a solution of NAG2 (10.0 g, 25.6 mmol) in DOE (100 mL) at ambient temperature. The mixture was stirred at 55 00 for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured onto ice cold sat. NaHCO3 (aq.) and extracted with CH2CI2. The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give syrup NAG6. A solution NAG6 in DOE (60 mL) was charged with alcohol NAG5 (8.00 g, 38.4 mmol) and molecular sieves. The mixture was placed under an inertatmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at room temperature. The mixture was poured over ice cold sat. NaHOO3 (aq.) and extracted with 0H2012. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude material as syrup. This crude material was purified by Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). 1H NMR (ODd3, 500 MHz): O 7.35 (m, 5H), 5.98 (d, 1H, J7.0 Hz), 5.57 (m, 1H), 5.34 (d, 1H, J3.0 Hz), 5.25 (dd, 1H, J3.0 Hz,11 Hz), 5.10 (s, 2H), 4.63 (d, 1H, J8.5 Hz), 4.11 (m, 2H), 3.95 (m, 1 H), 3.88 (m, 2H), 3.49 (m, 1H), 2.37 (m, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H), 1.70 (m, 2H), 1.61 (m, 2H).
16.64 g With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 45℃; Inert atmosphere; 12 00509] Compound (101) - Compound 100 (20g, 51.4mmol) was suspended in anhydrous dichloroethane (DCE) (200mL). The reaction flash was evacuated and purged with argon. Trimethylsilyl trifluoromethanesulfonate (11.16ml, 61.7mmol) was added dropwise via syringe. Reaction was heated to 45oC utilizing water bath and stirred overnight resulting in a clear solution. Reaction was checked by TLC (5% MeOH/DCM) and developed using Hanessian stain. Reaction was complete and cooled reaction with ice bath. Took sodium bicarbonate (12.95g, 154.2ml) and dissolved in 100ml of water. Sodium bicarbonate solution was SLOWLY to reaction mixture and effervescence occurred. Reaction was left to stir for 20 minutes to completely neutralize. The mixture was added to separation funnel and organic layer was separated and aqueous layer was washed with dichloromethane. The organic layers were combined and washed with a brine solution. The organic layer was separated and dried with sodium sulfate. The solid was filtered off and the mother liquor was concentrated and put on hi vacuum to yield (16.64g) of 101. NMR (400 MHz, DMSO-d6) δ 6.04 (d, J = 7.0 Hz, 1H), 5.23 (dd, J = 3.9, 2.8 Hz, 1H), 4.87 (dd, J = 6.9, 3.9 Hz, 1H), 4.25 (ddd, J = 7.5, 5.0, 2.8 Hz, 1H), 4.10 (dd, J = 11.6, 7.2 Hz, 1H), 4.02 (dd, J = 11.5, 5.0 Hz, 1H), 3.94 (tq, J = 6.9, 1.4 Hz, 1H), 3.89 (s, 1H), 2.06 (s, 3H), 2.00 (d, J = 3.6 Hz, 6H), 1.94 (d, J = 1.4 Hz, 3H). Mass calc. for C14H19N08: 329.31, found: 330.1 (M+H)
With trimethylsilyl trifluoropmethanesulfonate; triethylamine In acetonitrile at 0 - 65℃; Molecular sieve; 1 Synthesis of oxazoline [3] See, e.g., Guo, et. al. Bioconjug. Chem. 2006, 17, 1537-1544; Manoharan, et.al. J. Am. Chem. Soc. 2014, 136, 16958-16961. Compound 2 (17 g, 43.7 mmol) was dissolved in anhydrous acetonitrile (100 mL). 4 A molecular sieves were added in to the reaction mixture to keep it under complete anhydrous condition. Reaction mixture was cooled to zero degree and TMSOTf (11.84 mL, 65.5 mmol) was added in it. Reaction was then slowly warmed up to room temperature and then heated to 65 °C over night. After completion of reaction, triethylamine (-17 mL) was added to quench the reaction. Molecular sieves were filtered off and the reaction mixture was evaporated off to dryness. It was then diluted with ethyl acetate (-250 mL). Organic layer was washed with sodium bicarbonate (3x100 mL) and with brine solution (2 x 100 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated off to obtain a crude product (12.6 g) as brown color foam. MS analysis confirmed the formation of desired oxazoline derivative 3. The crude mixture was taken into the next step without further purification. Results: ESI-MS analysis: Calculated C14H19NO8, [M+H+] = 329.10, Observed = 329.0.
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 30 - 50℃; for 2h; C.1.69 69: [(3aR,5R,6R, 7R, 7aR)-6,7-diacetoxy-2-methyl-5, 6, 7, 7a-tetrahydro-3aH-pyrano[3, 2- d] oxazol- 5 -yl]methyl acetate To a solution of 20,0 g (51,4 mmol) D-galactosamine pentaacetate (68) in 200 ml DCE was added 17,1 g (77,1 mmol) TMSOTf dropwise at 30°C. The mixture was heated to 50°C for 2 h. After standing overnight at room temperature, complete conversion was detected. The mixture was quenched by a solution of NaHC03 (8,63 g, 102,8 mmol) in 1 1 water and extracted with 2 x 500 ml DCM. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated in vacuo, yielding 19,0 g of the title compound 69 (crude), which were used without further purification. LCMS-Method A: ELSD: Rt[min] = 0,90 Ionization method: ES+: [M+H]+ = 330,1
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
1.65 g With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane 1 Compound 3: Dissolve 1.95 g (5.00 mmol) of compound 2 in 20 mL of anhydrous 1,2-dichloroethane, and add 1.08 mL (6.00 mmol) of trimethylsilyl trifluoromethanesulfonate (TMSOTf) dropwise. , Stir overnight. Dissolve 840 mg (10.0 mmol) of NaHCO3 in 50 mL of ice water, pour the reaction solution into it under vigorous stirring, and continue stirring for 30 min. Extracted with dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate,The compound 3 was concentrated to obtain 1.65 g of a light yellow viscous liquid with a quantitative yield.
With trimethylsilyl trifluoropmethanesulfonate In dichloromethane

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[9]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/42447, 2015, A1 Location in patent: Page/Page column 111
[10]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168589, 2015, A2 Location in patent: Page/Page column 179
[11]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2018/67900, 2018, A1 Location in patent: Page/Page column 31; 39; 40
[12]Current Patent Assignee: IONIS PHARMACEUTICALS - US10098959, 2018, B2 Location in patent: Page/Page column 70; 80; 81
[13]Ivanenkov, Yan A.; Majouga, Alexander G.; Petrov, Rostislav A.; Petrov, Stanislav A.; Kovalev, Sergey V.; Maklakova, Svetlana Yu.; Yamansarov, Emil Yu.; Saltykova, Irina V.; Deyneka, Ekaterina V.; Filkov, Gleb I.; Kotelianski, Victor E.; Zatsepin, Timofey S.; Beloglazkina, Elena K. [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 3, p. 503 - 508]
[14]Current Patent Assignee: GUANGZHOU RIBOBIO - US2020/369703, 2020, A1 Location in patent: Paragraph 0135; 0139
[15]Wipf, Peter; Eyer, Benjamin R.; Yamaguchi, Yukihiro; Zhang, Feng; Neal, Matthew D.; Sodhi, Chhinder P.; Good, Misty; Branca, Maria; Prindle, Thomas; Lu, Peng; Brodsky, Jeffrey L.; Hackam, David J. [Tetrahedron Letters, 2015, vol. 56, # 23, p. 3097 - 3100]
[16]Yamazaki, Tatsumi; Warren, Christopher D.; Herscovics, Annette; Jeanloz, Roger W. [Canadian Journal of Chemistry, 1981, vol. 59, p. 2247 - 2252]
[17]Bernardes, Gonalo J. L.; Kikkeri, Raghavendra; Maglinao, Maha; Laurino, Paola; Collot, Mayeul; Hong, Sung You; Lepenies, Bernd; Seeberger, Peter H. [Organic and Biomolecular Chemistry, 2010, vol. 8, # 21, p. 4987 - 4996]
[18]Current Patent Assignee: ARBUTUS BIOPHARMA CORP; ROIVANT SCIENCES GMBH - WO2015/17519, 2015, A1 Location in patent: Paragraph 000223
[19]Current Patent Assignee: ALNYLAM PHARMACEUTICALS INC - WO2015/6740, 2015, A2 Location in patent: Page/Page column 136; 137; 142; 188; 189
[20]Current Patent Assignee: SOLSTICE BIOLOGICS LLC - WO2015/188197, 2015, A2 Location in patent: Page/Page column 157; 157
[21]Current Patent Assignee: ARROWHEAD RESEARCH CORP - EP2539451, 2016, B1 Location in patent: Paragraph 0151; 0152
[22]Current Patent Assignee: ARROWHEAD RESEARCH CORP - US9249179, 2016, B2 Location in patent: Page/Page column 40; 41
[23]Current Patent Assignee: NOVO NORDISK A/S - WO2016/100401, 2016, A1 Location in patent: Paragraph 00551-00552
[24]Current Patent Assignee: SOLSTICE BIOLOGICS LLC - WO2017/100461, 2017, A1 Location in patent: Page/Page column 60; 61
[25]Current Patent Assignee: ALNYLAM PHARMACEUTICALS INC - WO2018/136620, 2018, A2 Location in patent: Paragraph 00509
[26]Current Patent Assignee: SANOFI; Translate Bio (in: Sanofi) - WO2019/140102, 2019, A1 Location in patent: Page/Page column 82
[27]Current Patent Assignee: SANOFI - WO2019/170731, 2019, A1 Location in patent: Page/Page column 218
[28]Bhingardeve, Pramod; Madhanagopal, Bharath Raj; Naick, Hemanth; Jain, Prashant; Manoharan, Muthiah; Ganesh, Krishna [Journal of Organic Chemistry, 2020, vol. 85, # 14, p. 8812 - 8824]
[29]Current Patent Assignee: HEBEI UNIVERSITY - CN111748003, 2020, A Location in patent: Paragraph 0041-0043
[30]Current Patent Assignee: SAPREME TECHNOLOGIES B.V. - WO2021/261998, 2021, A1 Location in patent: Page/Page column 10; 41
  • 5
  • [ 53765-90-5 ]
  • [ 171973-79-8 ]
  • [ 10378-06-0 ]
  • Acetic acid (2R,3R,4R,5R,6R)-3-acetoxy-2-acetoxymethyl-5-diacetylamino-6-((2R,3S,4S,5R,6S)-3,4,5,6-tetrakis-benzyloxy-tetrahydro-pyran-2-ylmethoxy)-tetrahydro-pyran-4-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With dimethyl-(methylthio)-sulphonium trifluoromethanesulphonate In dichloromethane at 5℃;
  • 6
  • [ 147129-68-8 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
95% With iron(III) chloride at 50℃; for 1.5h;
  • 7
  • [ 10378-06-0 ]
  • [ 194728-54-6 ]
  • [ 194728-55-7 ]
YieldReaction ConditionsOperation in experiment
61% With pyridinium p-toluenesulfonate In dichloromethane for 24h; Heating;
  • 8
  • [ 10378-06-0 ]
  • [ 110253-00-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In acetone
  • 9
  • [ 10378-06-0 ]
  • 4-(9<i>H</i>-fluoren-9-ylmethoxycarbonylamino)-4-(6-hydroxy-hexylcarbamoyl)-butyric acid <i>tert</i>-butyl ester [ No CAS ]
  • 4-[6-((2R,3R,4R,5R,6R)-4,5-Diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-hexylcarbamoyl]-4-(9H-fluoren-9-ylmethoxycarbonylamino)-butyric acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With calcium sulfate; tin(IV) chloride In dichloromethane at 20℃; for 16h;
  • 10
  • [ 10385-50-9 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
99% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 55℃; for 1h; Darkness;
99% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 55℃; for 2h; 10 Preparation of (3aR,5R,6R, 7R, 7aR)-5-(acetoxymethyl)-2-methyl-5,6, 7, 7a-tetrahydro- 3aH-pyrano[3,2-d]oxazole-6, 7 -diyl diacetate (J12) To a solution of compound Jll (1557 mg, 4.0 mmol, 1.0 equiv) in DCE (5 mL) was added TMSOTf (1333 mg, 6.0 mmol, 1.5 equiv) and stirred at 55°C for 2hrs, then the mixture was stirred at r.t for overnight. The mixture was poured into the ice cold Sat.NaHCOs, extracted with DCM, washed with water and brine, dried over Na2SO4, concentrated to give compound J12 as a dark gum, which was used for the next step without any further purification (1.3g, yield: 99 %).
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
93% With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 50℃;
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 45℃; for 16h;
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 20 - 50℃; C 71: [(3aR,5R,6R,7R,7aR)-6,7-diacetoxy-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxa- zol-5-yl]methyl acetate To a solution of 20,0 g (51,4 mmol) D-galactosamine pentaacetate (70) in 200 ml DCE was added 17,1 g (77,1 mmol) TMSOTf dropwise at 30°C. The mixture was heated to 50°C for 2 h. After standing overnight at room temperature, complete conversion was detected. The mixture was quenched by a solution of NaHCO3 (8,63 g, 102,8 mmol) in 1 l water and extracted with 2 x 500 ml DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo, yielding 19,0 g of the title compound 71 (crude), which were used without further purification. LCMS-Method A: ELSD: Rt[min] = 0,90 Ionization method: ES+: [M+H]+ = 330,1

  • 11
  • [ 86520-52-7 ]
  • [ 10378-06-0 ]
  • [ 153253-46-4 ]
YieldReaction ConditionsOperation in experiment
91% With trimethylsilyl trifluoromethanesulfonate; 4 A molecular sieve In dichloromethane
85% With trimethylsilyl trifluoromethanesulfonate; 4 A molecular sieve In 1,2-dichloro-ethane
85% Stage #1: 2-[2-(2-azidoethoxy)ethoxy]ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.333333h; Molecular sieve; Inert atmosphere; Stage #2: With (1S)-10-camphorsulfonic acid In dichloromethane at 20 - 45℃; for 32h; 13 This protocol was modified to synthesis 513 exclusively.Briefly, compound 2 (1.0 g, 3.03 mmol) and alcohol 4 (1.60 g,9.11 mmol) were dissolved in anhydrous DCM (20 mE), followed by addition of dried 4 A° MS (0.4 g) and reaction mixture stirred at room temperature for 20 minutes under N2. CSA (camphor sulphonic acid, 0.6 15 g, 9.0 mE, 9.1 mmol)was added at room temperature and 8 hours, followed by heating to 45° C. for 24 hours. The reaction mixture was cooled to room temperature, neutralized with Et3N (0.2 mE, pH 7.5), diluted with DCM (100 mE) and extracted using saturated NaRCO3 solution. The organic layer was washedwith water, brine and dried over Na2504. Solvents were evaporated under reduced pressure and the residue purified by silica gel column chromatography using DCM:EtOAc:MeOH (8.0:1.5:0.5) to obtain compound (1.15 g, 85%). Tbe spectral data matched with above compound
72% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Inert atmosphere; Molecular sieve;
61% Stage #1: 2-[2-(2-azidoethoxy)ethoxy]ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 27h; Inert atmosphere; Molecular sieve;
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 14h; Molecular sieve; Inert atmosphere; 76 Example 76: Preparation of oligomeric compound 230 comprising GalNAc3-23 Compound 222 is commercially available. 44.48 ml (0.33 mol) of compound 222 was treated with tosyl chloride (25.39 g, 0.13 mol) in pyridine (500mL) for 16 hours. The reaction was then evaporated to an oil, dissolved in EtOAc and washed with water, sat. NaHC03, brine, and dried over Na2S04. The ethyl acetate was concentrated to dryness and purified by column chromatography, eluted with EtOAc/hexanes (1 : 1) followed by 10% methanol in CH2CI2 to give compound 223 as a colorless oil. LCMS and NMR were consistent with the structure. 10 g (32.86 mmol) of 1 -Tosyltriethylene glycol (compound 223) was treated with sodium azide (10.68 g, 164.28 mmol) in DMSO (l OOmL) at room temperature for 17 hours. The reaction mixture was then poured onto water, and extracted with EtOAc. The organic layer was washed with water three times and dried over Na2S04. The organic layer was concentrated to dryness to give 5.3g of compound 224 (92%). LCMS and NMR were consistent with the structure. 1 -Azidotriethylene glycol (compound 224, 5.53 g, 23.69 mmol) and compound 4 (6 g, 18.22 mmol) were treated with 4A molecular sieves (5g), and TMSOTf (1.65 ml, 9.1 1 mmol) in dichloromethane (l OOmL) under an inert atmosphere. After 14 hours, the reaction was filtered to remove the sieves, and the organic layer was washed with sat. NaHC03, water, brine, and dried over Na2S04. The organic layer was concentrated to dryness and purified by column chromatography, eluted with a gradient of 2 to 4%> methanol in dichloromethane to give compound 225. LCMS and NMR were consistent with the structure. Compound 225 (1 1.9 g, 23.59 mmol) was hydrogenated in EtOAc/Methanol (4: 1 , 250mL) over Pearlman's catalyst. After 8 hours, the catalyst wasremoved by filtration and the solvents removed to dryness to give compound 226. LCMS and NMR were consistent with the structure. In order to generate compound 227, a solution of nitromethanetrispropionic acid (4.17 g, 15.04 mmol) and Hunig's base (10.3 ml, 60.17 mmol) in DMF (lOOmL) were treated dropwise with pentaflourotrifluoro acetate (9.05 ml, 52.65 mmol). After 30 minutes, the reaction was poured onto ice water and extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na2S04. The organic layer was concentrated to dryness and then recrystallized from heptane to give compound 227 as a white solid. LCMS and NMR were consistent with the structure. Compound 227 (1.5 g, 1.93 mmol) and compound 226 (3.7 g, 7.74 mmol) were stirred at room temperature in acetonitrile (15 mL) for 2 hours. The reaction was then evaporated to dryness and purified by column chromatography, eluting with a gradient of 2 tol0% methanol in dichloromethane to give compound 228. LCMS and NMR were consistent with the structure. Compound 228 (1.7 g, 1.02 mmol) was treated with Raney Nickel (about 2g wet) in ethanol (lOOmL) in an atmosphere of hydrogen. After 12 hours, the catalyst was removed by filtration and the organic layer was evaporated to a solid that was used directly in the next step. LCMS and NMR were consistent with the structure. This solid (0.87 g, 0.53 mmol) was treated with benzylglutaric acid (0.18 g, 0.8 mmol), HBTU (0.3 g, 0.8 mmol) and DIEA (273.7 μ, 1.6 mmol) in DMF (5mL). After 16 hours, the DMF was removed under reduced pressure at 65°C to an oil, and the oil was dissolved in dichloromethane. The organic layer was washed with sat. NaHC03, brine, and dried over Na2S04. After evaporation of the organic layer, the compound was purified by column chromatography and eluted with a gradient of 2 to 20% methanol in dichloromethane to give the coupled product. LCMS and NMR were consistent with the structure. The benzyl ester was deprotected with Pearlman's catalyst under a hydrogen atmosphere for 1 hour. The catalyst was them removed by filtration and the solvents removed to dryness to give the acid. LCMS and NMR were consistent with the structure. The acid (486 mg, 0.27 mmol) was dissolved in dry DMF (3 mL). Pyridine (53.61 μ, 0.66 mmol) was added and the reaction was purged with argon. Pentaflourotriflouro acetate (46.39 μ, 0.4 mmol) was slowly added to the reaction mixture. The color of the reaction changed from pale yellow to burgundy, and gave off a light smoke which was blown away with a stream of argon. The reaction was allowed to stir at room temperature for one hour (completion of reaction was confirmed by LCMS). The solvent was removed under reduced pressure (rotovap) at 70 °C. The residue was diluted with DCM and washed with IN NaHSC^, brine, saturated sodium bicarbonate and brine again. The organics were dried over Na2S04, filtered, and were concentrated to dryness to give 225 mg of compound 229 as a brittle yellow foam. LCMS and NMR were consistent with the structure.
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 14h; Molecular sieve; Inert atmosphere; 52 Compound 222 is commercially available. 44.48 ml (0.33 mol) of compound 222 was treated withtosyl chloride (25.39 g, 0.13 mol) in pyridine (500mL) for 16 hours. The reaction was then evaporated to anoil, dissolved in EtOAc and washed with water, sat. NaHC03, brine, and dried over Na2S04. The ethyl5 acetate was concentrated to dryness and purified by column chromatography, eluted with EtOAc/hexanes(1: 1) followed by 10% methanol in CH2Cb to give compound 223 as a colorless oil. LCMS and NMR wereconsistent with the structure. 10 g (32.86 mmol) of 1-Tosyltriethylene glycol (compound 223) was treatedwith sodium azide (10.68 g, 164.28 mmol) in DMSO (lOOmL) at room temperature for 17 hours. Thereaction mixture was then poured onto water, and extracted with EtOAc. The organic layer was washed with10 water three times and dried over Na2S04. The organic layer was concentrated to dryness to give 5.3g ofcompound 224 (92%). LCMS and NMR were consistent with the structure. 1-Azidotriethylene glycol(compound 224, 5.53 g, 23.69 mmol) and compound 4 (6 g, 18.22 mmol) were treated with 4A molecularsieves (5g), and TMSOTf (1.65 ml, 9.11 mmol) in dichloromethane (lOOmL) under an inert atmosphere.After 14 hours, the reaction was filtered to remove the sieves, and the organic layer was washed with sat.15 NaHC03, water, brine, and dried over Na2S04. The organic layer was concentrated to dryness and purifiedby column chromatography, eluted with a gradient of 2 to 4% methanol in dichloromethane to givecompound 225. LCMS and NMR were consistent with the structure. Compound 225 (11.9 g, 23.59 mmol)was hydrogenated in EtOAc/Methanol (4:1, 250mL) over Pearlman's catalyst. After 8 hours, the catalyst wasremoved by filtration and the solvents removed to dryness to give compound 226. LCMS and NMR were20 consistent with the structure.
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 14h; Molecular sieve; Inert atmosphere; 76 1-Azidotriethylene glycol (compound 224, 5.53 g, 23.69 mmol) and compound 4 (6 g, 18.22 mmol) were treated with 4A molecular sieves (5g), and TMSOTf (1.65 ml, 9.11 mmol) in dichloromethane (100mL) under an inert atmosphere. After 14 hours, the reaction was filtered to remove the sieves, and the organic layer was washed with sat. NaHCO3, water, brine, and dried over Na2SO4. The organic layer was concentrated to dryness and purified by column chromatography, eluted with a gradient of 2 to 4% methanol in dichloromethane to give compound 225. LCMS and NMR were consistent with the structure.
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 14h; Molecular sieve; Inert atmosphere; 76 1-Azidotriethylene glycol (compound 224, 5.53 g, 23.69 mmol) and compound 4 (6 g, 18.22 mmol) were treated with 4A molecular sieves (5g), and TMSOTf (1.65 ml, 9.11 mmol) in dichloromethane (100mL) under an inert atmosphere. After 14 hours, the reaction was filtered to remove the sieves, and the organic layer was washed with sat. NaHCO3, water, brine, and dried over Na2SO4. The organic layer was concentrated to dryness and purified by column chromatography, eluted with a gradient of 2 to 4% methanol in dichloromethane to give compound 225. LCMS and NMR were consistent with the structure.
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 14h; Molecular sieve; Inert atmosphere; 76 Compound 222 is commercially available. 44.48 ml (0.33 mol) of compound 222 was treated withtosyl chloride (25.39 g, 0.13 mol) in pyridine (500mL) for 16 hours. The reaction was then evaporated to anoil, dissolved in EtOAc and washed with water, sat. NaHCO3, brine, and dried over Na2SO4. The ethyl acetate was concentrated to dryness and purified by column chromatography, eluted with EtOAc/hexanes (1:1) followed by 10% methanol in CH2C12 to give compound 223 as a colorless oil. LCMS and NMR were consistent with the structure. 10 g (32.86 mmol) of 1-Tosyltriethylene glycol (compound 223) was treatedwith sodium azide (10.68 g, 164.28 mmol) in DMSO (lOOmL) at room temperature for 17 hours. The reaction mixture was then poured onto water, and extracted with EtOAc. The organic layer was washed with water three times and dried over Na2SO4. The organic layer was concentrated to dryness to give 5.3g of compound 224 (92%). LCMS and NMR were consistent with the structure. 1-Azidotriethylene glycol (compound 224, 5.53 g, 23.69 mmol) and compound 4 (6 g, 18.22 mmol) were treated with 4A molecularsieves (5g), and TMSOTf (1.65 ml, 9.11 mmol) in dichloromethane (lOOmL) under an inert atmosphere. After 14 hours, the reaction was filtered to remove the sieves, and the organic layer was washed with sat. NaHCO3, water, brine, and dried over Na2SO4. The organic layer was concentrated to dryness and purified by column chromatography, eluted with a gradient of 2 to 4% methanol in dichloromethane to give compound 225. LCMS and NMR were consistent with the structure. Compound 225 (11.9 g, 23.59 mmol)was hydrogenated in EtOAc/Methanol (4:1, 250mL) over Pearlman’s catalyst. After 8 hours, the catalyst was removed by filtration and the solvents removed to dryness to give compound 226. LCMS and NMR were consistent with the structure.
With camphor-10-sulfonic acid In dimethyl sulfoxide at 40℃; for 72h;
With trimethylsilyl trifluoromethanesulfonate 1.d Synthesis and Testing of Cu(gtsm) and Gal-Cu(gtsm) Gal-Cu(gtsm) was synthesized using a convergent synthetic approach where the ionophore and targeting group fragments were synthesized independently and then linked together through a transamination reaction in the penultimate step (Klayman, D. L.; Lin, A. J. Org. Prep. Proced. Int. 1984, 16, 79; Brett, M. P.; John, A. K.; Denis, B. S.; Jonathan, M. W.; Donnelly, P. S. Inorg. Chem. 2010, 49, 1884). Oxazoline 5 (see e.g., Wang et al., Chem. Commun. 2011, 47, 11240) was reacted with azidotriethylene glycol in the presence of trimethylsilyl trifluoromethanesulfonate to access the azide-protected peracetylated GalNAc 6.

Reference: [1]Murahashi, Naokazu; Ishihara, Hiroshi; Sakagami, Masahiro; Sasaki, Atsushi [Biological and Pharmaceutical Bulletin, 1997, vol. 20, # 6, p. 704 - 707]
[2]Rensen, Patrick C. N.; Van Leeuwen, Steven H.; Sliedregt, Leo A. J. M.; Van Berkel, Theo J. C.; Biessen, Erik A. L. [Journal of Medicinal Chemistry, 2004, vol. 47, # 23, p. 5798 - 5808]
[3]Current Patent Assignee: UNIVERSITY OF MICHIGAN - US9345781, 2016, B2 Location in patent: Page/Page column 70; 71
[4]Su, Timothy A.; Shihadih, Diyala S.; Cao, Wendy; Detomasi, Tyler C.; Heffern, Marie C.; Jia, Shang; Stahl, Andreas; Chang, Christopher J. [Journal of the American Chemical Society, 2018, vol. 140, # 42, p. 13764 - 13774]
[5]Saneyoshi, Hisao; Yamamoto, Yuta; Kondo, Kazuhiko; Hiyoshi, Yuki; Ono, Akira [Journal of Organic Chemistry, 2017, vol. 82, # 3, p. 1796 - 1802]
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC; IONIS PHARMACEUTICALS - WO2014/179620, 2014, A1 Location in patent: Page/Page column 645-647
[7]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/42447, 2015, A1 Location in patent: Page/Page column 202; 203
[8]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168635, 2015, A2 Location in patent: Page/Page column 296-300
[9]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168618, 2015, A2 Location in patent: Page/Page column 279-283
[10]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168589, 2015, A2 Location in patent: Page/Page column 308; 309; 310
[11]Kuruvilla, Sibu P.; Tiruchinapally, Gopinath; Kaushal, Neha; ElSayed, Mohamed E.H. [International Journal of Pharmaceutics, 2018, vol. 545, # 1-2, p. 27 - 36]
[12]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - US2020/113937, 2020, A1 Location in patent: Paragraph 0272-0273
  • 12
  • [ 10378-06-0 ]
  • Acetic acid (2R,3R,4R,6R)-4,6-diacetoxy-2-acetoxymethyl-5-[(Z)-hydroxyimino]-tetrahydro-pyran-3-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester With 3-chloro-benzenecarboperoxoic acid In acetonitrile at 20℃; for 48h; Stage #2: In acetonitrile at 50℃; for 15h;
  • 13
  • [ 10378-06-0 ]
  • [ 4064-06-6 ]
  • [ 20072-88-2 ]
YieldReaction ConditionsOperation in experiment
83% With ytterbium(III) triflate In dichloromethane for 24h; Heating;
  • 14
  • [ 6240-11-5 ]
  • [ 10378-06-0 ]
  • [ 913816-31-6 ]
  • 15
  • [ 37729-18-3 ]
  • [ 10378-06-0 ]
  • [ 913816-33-8 ]
  • 16
  • [ 10378-06-0 ]
  • [ 19128-75-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: m-chloroperbenzoic acid / acetonitrile / 48 h / 20 °C 1.2: 50 percent / acetonitrile / 15 h / 50 °C 2.1: 61 percent / Dess-Martin periodinane
  • 17
  • [ 10378-06-0 ]
  • Acetic acid (2R,3R,4R,5R,6R)-3-acetoxy-2-acetoxymethyl-5-acetylamino-6-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-tetrahydro-pyran-4-yl ester; compound with toluene-4-sulfonic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 91 percent / TMSOTf; 4 Angstroem molecular sieves / CH2Cl2 2: H2 / Lindlar catalyst / methanol
  • 18
  • [ 10378-06-0 ]
  • 8-(2-hexadecyloctadecanoylamido)-3,6-dioxaoctyl-2-acetamido-2-deoxy-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 91 percent / TMSOTf; 4 Angstroem molecular sieves / CH2Cl2 2: H2 / Lindlar catalyst / methanol 3: Et3N / CH2Cl2 4: NaOMe / methanol
  • 19
  • [ 10378-06-0 ]
  • [ 153253-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 91 percent / TMSOTf; 4 Angstroem molecular sieves / CH2Cl2 2: H2 / Lindlar catalyst / methanol 3: Et3N / CH2Cl2
  • 20
  • [ 10378-06-0 ]
  • 4-[6-((2R,3R,4R,5R,6R)-4,5-Diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-hexylcarbamoyl]-4-(9H-fluoren-9-ylmethoxycarbonylamino)-butyric acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: SnCl4; Drierite / CH2Cl2 / 16 h / 20 °C 2: HCOOH; TFA / 6 h / 20 °C
  • 21
  • [ 10378-06-0 ]
  • dipotassium of 2-acetamido-2-deoxy-α-D-galactopyranosyl phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: benzene / Ambient temperature 2: H2 / 10 percent Pd/C / benzene; methanol / 1 h / 760 Torr / Ambient temperature 3: 92 percent / NaOMe / methanol
  • 22
  • [ 10378-06-0 ]
  • [ 79769-40-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: benzene / Ambient temperature 2: H2 / 10 percent Pd/C / benzene; methanol / 1 h / 760 Torr / Ambient temperature 3: 80 percent / tributylamine / pyridine / 10 h / Ambient temperature
  • 23
  • [ 10378-06-0 ]
  • dilithium uridine 5'-(2-acetamido-2-deoxy-α-D-galactopyranosyl diphosphate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: benzene / Ambient temperature 2: H2 / 10 percent Pd/C / benzene; methanol / 1 h / 760 Torr / Ambient temperature 3: 80 percent / tributylamine / pyridine / 10 h / Ambient temperature 4: 82 percent / 1 M NaOH / H2O / 1 h / Ambient temperature
  • 24
  • [ 10378-06-0 ]
  • [ 79744-05-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: benzene / Ambient temperature 2: H2 / 10 percent Pd/C / benzene; methanol / 1 h / 760 Torr / Ambient temperature
  • 25
  • [ 40248-34-8 ]
  • [ 10378-06-0 ]
  • [ 70337-72-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 6-trifluoroacetamido-1-hexanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane at 20℃; for 1h; Molecular sieve; Inert atmosphere; Stage #2: With sulfuric acid In dichloromethane Stage #3: With sodium hydrogencarbonate In dichloromethane Cooling; 5; VI The scheme is shown in FIG. 5. Galactosamine hydrochloride is treated with acetic anhydride and pyridine at room temperature for 16 hr. The white precipitate is the per-o-acetyl GalNAc with a yield 76.7%. Formation of oxazoline derivative from per-o-acetyl GalNAc and subsequent glycoside formation were done according to the published method of Wu and Gao (Bioconjug Chem 17, 1537-44, 2006) with minor modification. To a solution of per-o-acetyl GalNAc in dichloroethane was added trimethylsilyl trifluoromethane sulfonate (TMSOTf) and the mixture was heated at 50° C. for 10 hr. Triethylamine was added to quench the acid. The reaction mixture was evaporated, the residue was dissolved in chloroform, and the chloroform solution was washed with cold saturated sodium bicarbonate (twice) and with 1M NaCl (once). The chloroform layer was dried with anhydrous sodium sulfate, filtered and evaporated. The dark red syrup was oxazoline derivative with yield 99%. This compound is unstable and it is better to proceed to the next step immediately. The oxazoline derivative obtained above and TFA-ah were dissolved in methylene chloride. Molecular sieve (4 {acute()}) was added and the mixture was flushed with nitrogen gas, and stirred at room temperature for 1 hr. Concentrated sulfuric acid was then added, and the mixture was stirred overnight. The reaction mixture was filtered through a pad of Celite on a sintered-glass filter. The filtrate was diluted with methylene chloride and the solution was washed with cold saturated sodium bicarbonate (twice) and 1M NaCl (once). The residue was dissolved in 95% ethanol and fractionated on a Sephadex LH20 column using 95% ethanol as eluant. Only the product TFA-ah-GalNAc(OAc)3 were combined and evaporated.
  • 26
  • [ 14257-79-5 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: pyridine / 16 h / 20 °C 2: trimethyl((trifluoromethyl)sulfonyl)silane / dichloromethane / 10 h / 50 °C
Multi-step reaction with 2 steps 1.1: pyridine / 20 °C 2.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 1 h / 50 °C 2.2: 0.17 h / 20 °C
Multi-step reaction with 2 steps 1: pyridine / 0 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 2 h / 55 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: pyridine 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane
Multi-step reaction with 2 steps 1: pyridine 2: trimethylsilyl trifluoromethanesulfonate / chloroform / 1.5 h / 40 °C

  • 27
  • [ 10378-06-0 ]
  • (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine; trimethylsilyl trifluoromethanesulfonate / dichloromethane 2: H2 / palladium-carbon / ethyl acetate
  • 28
  • [ 142504-42-5 ]
  • [ 10378-06-0 ]
  • (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With trimethylsilyl trifluoromethanesulfonate; triethylamine In dichloromethane 13.C C. C. (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-Diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester The above prepared acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester (10.3 g, 26 mmol) and {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-acetic acid benzyl ester (8.62 g, 29 mmol) were mixed in 520 mL of CH2Cl2 and treated with 63 g of 4 Angstrom molecular sieves. After 1 h trimethylsilyl triflate (6.13 g, 28 mmol) was added. The reaction mixture was stirred over the weekend at ambient temperature. Triethylamine (5.21 ml, 37 mmol) was added, the molecular sieves filtered off, the filtrate diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent followed by flash chromatography (SiO2, ethyl acetate/AcOH/MeOH/water=60/3/3/2) afforded 15.7 g of the title compound as a brownish oil. MS (ISP): 626.6 [M-H]-.
  • 29
  • [ 582318-96-5 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
With trimethylsilyl trifluoromethanesulfonate; triethylamine 13.B B. B. Acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 ml, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step. MS (ISP): 330.0 [M+H]+.
With trimethylsilyl trifluoromethanesulfonate; triethylamine 7.B B. B. Acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 mL, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step, MS (ISP): 330.0 [M+H]+.
  • 30
  • [ 139115-90-5 ]
  • [ 10378-06-0 ]
  • [ 1268342-13-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(2-azidoethoxy)ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 25℃; for 1h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 25℃; 1-2 Synthesis of (2R.3R.4R.5R.6RV5-acetamido-2-(acetoxymethylV6-r2-(2- azidoethoxy)ethoxy1tetrahydro-2H-pyran-3,4-diyl diacetate (Compound 8) Synthesis of (2R.3R.4R.5R.6RV5-acetamido-2-(acetoxymethylV6-r2-(2- azidoethoxy)ethoxy1tetrahydro-2H-pyran-3,4-diyl diacetate (Compound 8) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2- methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (Compound 7, 40 g, 121.47 mmol, 1.00 equiv) in 1 ,2-dichloroethane (200 mL), 2-(2-azidoethoxy)ethan-l-ol (Compound 4, 23.89 g, 182.18 mmol, 1.50 equiv). To the above several 4A zeolite was added. The resulting mixture was stirred for 1 h at 25°C. Then trimethylsilyl trifluoromethanesulfonate (10.8 mL, 0.50 equiv) was added. After stirred overnight at 25°C, the reaction mixture was diluted with 500 mL of dichloromethane and washed with 1x500 mL of water, 1x500 mL of aq. sodium bicarbonate and 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2- azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyl diacetate (Compound 8) as a colorless oil. MS(m/z): 461.1, [M+H]+ 1HNMR(CDCl3, 500MHz, ppm) 5.78 (d, J= 8.90 Hz, 1H), 5.36 (d, J = 2.9 Hz, 1H), 5.22 (dd, J = 11.2, 3.6 Hz, 1H), 4.77 (d, J= 8.3 Hz, 1H), 4.19-4.12 (m, 2H), 4.11-4.05 (m, 1H), 3.98-3.92 (m, 2H), 3.82-3.78 (m, 1H), 3.71-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H).
Stage #1: 2-(2-azidoethoxy)ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 25℃; for 1h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 25℃; A.1-2 Synthesis of R^R^R^R^RVS-acetamido^-facetoxymethviye- -^- azidoethoxy^thoxyltetrahydro^H-pyran-S.^-diyl diacetate (Compound A8) Synthesis of R^R^R^R^RVS-acetamido^-facetoxymethviye- -^- azidoethoxy^thoxyltetrahydro^H-pyran-S.^-diyl diacetate (Compound A8) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2- methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (A7, 40 g, 121.47 mmol, 1.00 equiv) in 1 ,2-dichloroethane (200 mL), 2-(2-azidoethoxy)ethan-l-ol (A4, 23.89 g, 182.18 mmol, 1.50 equiv). To the above several 4A zeolite was added. The resulting mixture was stirred for 1 h at 25°C. Then trimethylsilyl trifluoromethanesulfonate (10.8 mL, 0.50 equiv) was added. After stirred overnight at 25°C, the reaction mixture was diluted with 500 mL of dichloromethane and washed with 1x500 mL of water, 1x500 mL of aq. sodium bicarbonate and 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in (2R,3R,4R,5R,6R)-5- acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyl diacetate (A8) as a colorless oil. MS(m z): 461.1, [M+H]+ 1HNMR(CDC13, 500MHz, ppm) 5.78 (d, J= 8.90 Hz, 1H), 5.36 (d, J= 2.9 Hz, 1H), 5.22 (dd, J= 11.2, 3.6 Hz, 1H), 4.77 (d, J= 8.3 Hz, 1H), 4.19-4.12 (m, 2H), 4.11-4.05 (m, 1H), 3.98- 3.92 (m, 2H), 3.82-3.78 (m, 1H), 3.71-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H).
Stage #1: 2-(2-azidoethoxy)ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester at 25℃; for 1h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate at 25℃; Synthesis of (2R R.4R.5R.6R)-5-acetamido-2-(acetoxymethyl)-6-r2-(2- azidoethoxy)ethoxyltetrahydro-2H-pyran-3,4-diyl diacetate (8) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]oxazole-6,7-diyl diacetate (7, 40 g, 121.47 mmol, 1.00 equiv) in 1 ,2-dichloroethane (200 mL), 2-(2-azidoethoxy)ethan-l-ol (4, 23.89 g, 182.18 mmol, 1.50 equiv). To the above several 4A zeolite was added. The resulting mixture was stirred for 1 h at 25°C. Then trimethylsilyl trifluoromethanesulfonate (10.8 mL, 0.50 equiv) was added. After stirred overnight at 25 °C, the reaction mixture was diluted with 500 mL of dichloromethane and washed with 1x500 mL of water, 1x500 mL of aq. sodium bicarbonate and 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H- pyran-3,4-diyl diacetate (8) as a colorless oil. MS(m/z): 461.1, [M+H]+ 1HNMR(CDCl3, 500MHz, ppm) 5.78 (d, J= 8.90 Hz, 1H), 5.36 (d, J= 2.9 Hz, 1H), 5.22 (dd, J = 11.2, 3.6 Hz, 1H), 4.77 (d, J= 8.3 Hz, 1H), 4.19-4.12 (m, 2H), 4.11-4.05 (m, 1H), 3.98-3.92 (m, 2H), 3.82-3.78 (m, 1H), 3.71-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H).
Stage #1: 2-(2-azidoethoxy)ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 25℃; for 1h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 25℃; Synthesis of (2R.3R.4R.5R.6R)-5-acetamido-2-(acetoxymethyl)-6-r2-(2- azidoethoxy)ethoxyltetrahydro-2H-pyran-3.4-diyl diacetate (Compound A8) Synthesis of (2R.3R.4R.5R.6R)-5-acetamido-2-(acetoxymethyl)-6-r2-(2- azidoethoxy)ethoxyltetrahydro-2H-pyran-3.4-diyl diacetate (Compound A8)Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2- methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (A7, 40 g, 121.47 mmol, 1.00 equiv) in 1,2-dichloroethane (200 mL), 2-(2-azidoethoxy)ethan-l-ol (A4, 23.89 g, 182.18 mmol, 1.50 equiv). To the above several 4A zeolite was added. The resulting mixture was stirred for 1 h at 25°C. Then trimethylsilyl trifluoromethanesulfonate (10.8 mL, 0.50 equiv) was added. After stirred overnight at 25°C, the reaction mixture was diluted with 500 mL of dichloromethane and washed with 1x500 mL of water, 1x500 mL of aq. sodium bicarbonate and 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in Compound A8 as an oil.MS(m/z): 461.1, [M+H]+ 1HNMR(CDCl3, 500MHz, ppm) 5.78 (d, J= 8.90 Hz, 1H), 5.36 (d, J= 2.9 Hz, 1H), 5.22 (dd, J = 11.2, 3.6 Hz, 1H), 4.77 (d, J= 8.3 Hz, 1H), 4.19-4.12 (m, 2H), 4.1 1-4.05 (m, 1H), 3.98-3.92 (m, 2H), 3.82-3.78 (m, 1H), 3.71-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H).
Stage #1: 2-(2-azidoethoxy)ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In cis-1,2-Dichloroethylene at 25℃; for 1h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In cis-1,2-Dichloroethylene at 25℃; Inert atmosphere; Synthesis of (2R,3 R,4R,5R,6R)-5 -acetamido-2-(acetoxymethyl)-6- 12-(2- azidoethoxy)ethoxy]tetrahydro-2H-pyran-3 ,4-diyl diacetate (Compound A8) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3 aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2- methyl-5 ,6,7,7a-tetrahydro-3 aH-pyrano [3 ,2-d] oxazole-6,7-diyl diacetate (A7, 40 g, 121.47 mmol, 1.00 equiv) in 1,2-dichloroethane (200 mL), 2-(2-azidoethoxy)ethan-1-ol (A4, 23.89 g,5 182.18 mmol, 1.50 equiv). To the above several 4A zeolite was added. The resulting mixture was stirred for 1 h at 25°C. Then trimethylsilyl trifluoromethanesulfonate (10.8 mL, 0.50 equiv) was added. After stirred overnight at 25°C, the reaction mixture was diluted with 500 mL of dichloromethane and washed with 1x500 mL of water, 1x500 mL of aq. sodium bicarbonate and 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and10 concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in Compound A8 as an oil. MS(m/z): 461.1, [M+H]‘HNMR(CDC13, 500MHz, ppm) 5.78 (d, J= 8.90 Hz, 1H), 5.36 (d, J= 2.9 Hz, 1H), 5.22 (dd, J = 11.2, 3.6 Hz, 1H), 4.77 (d,J= 8.3 Hz, 1H), 4.19-4.12 (m, 2H), 4.11-4.05 (m, 1H), 3.98-3.92(m, 2H), 3.82-3.78 (m, 1H), 3.7 1-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H),2.01 (s, 3H), 1.97 (s, 3H).
1.84 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 4h; 1 Compound 4: Dissolve 1.65 g (5.00 mmol) of compound 3 in 20 mL of anhydrous 1,2-dichloroethane, add 786 mg (6.00 mmol) of 2-(2-azidoethoxy) ethanol, and add 181 μL ( 1.00 mmol) TMSOTf. Stir at room temperature for 4 h. The reaction solution was slowly poured into a cold aqueous NaHCO3 solution, and stirring was continued for 0.5 h. It was extracted with dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain 1.84 g of a pale yellow viscous liquid (namely compound 4), with a two-step yield of 80%.
1.84 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 4h; 1 Compound 4: Dissolve 1.65 g (5.00 mmol) of compound 3 in 20 mL of anhydrous 1,2-dichloroethane, and add 786 mg (6.00 mmol)2-(2-azidoethoxy)ethanol,Add 181 μL (1.00 mmol) TMSOTf dropwise. Stir at room temperature for 4 h.The reaction solution was slowly poured into a cold NaHCO3 aqueous solution, and stirring was continued for 0.5 h. After extraction with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, and concentration, 1.84 g of compound 4 was obtained as a pale yellow viscous liquid, with a two-step yield of 80%.

  • 31
  • D-(+)-galactosamine hydrochloride [ No CAS ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: pyridine / 0 - 25 °C / Inert atmosphere 2: iron(III) chloride / dichloromethane / 2 h / 25 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: pyridine / 0 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 - 55 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: pyridine / 0 - 25 °C / Inert atmosphere 2: iron(III) chloride / dichloromethane / 2 h / 25 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: pyridine / 0 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: pyridine / 0 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 - 55 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: triethylamine; pyridine; dmap / 16 h / 0 - 20 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 16 h / 50 °C
Multi-step reaction with 2 steps 1: pyridine / 16 h / 25 °C / Inert atmosphere 2: iron(III) chloride / dichloromethane / 2 h / 25 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: pyridine / 1.5 h / 20 °C / Inert atmosphere; Cooling with ice 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Inert atmosphere; Cooling with ice
Multi-step reaction with 2 steps 1: pyridine / 20 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 1 h / 55 °C / Darkness
Multi-step reaction with 2 steps 1: pyridine / 1.5 h / 20 °C / Cooling with ice 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C
Multi-step reaction with 2 steps 1: triethylamine; dmap; pyridine / 20 °C / Cooling with ice 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane
Multi-step reaction with 2 steps 1: pyridine; dmap; triethylamine / 20 °C / Cooling with ice 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane
Multi-step reaction with 2 steps 1: pyridine / 1.5 h / 20 °C / Cooling with ice 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Cooling with ice; Inert atmosphere

  • 32
  • [ 1536199-57-1 ]
  • [ 10378-06-0 ]
  • [ 1536202-03-5 ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: C8H9NO5S2; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 25h; 1.96 Synthesis of Com ound 96 Compounds 9 (1.81 g, 5.50 mmol) and 54 (2.17 g, 8.25 mmol) were combined and dried by co-evaporation with anhydrous toluene (3 x 2 mL) . The mixture was dissolved in dry 1 ,2-dichloroethane (16.5 mL). 4 A molecular sieves were added to the solution and the mixture was stirred 30 min at r.t. Trimethylsilyltriflate (497 L, 2.75 mmol) was added to the stirred solution. The solution was stirred for 9 h at r.t., then additional 54 (0.723 g, 2.75 mmol) was added to the stirred solution. After stirring 16 h at r.t., the solution was diluted with DCM (100 mL) and washed with sat. NaHCC>3 (1 x 100 mL). The aqueous layer was extracted with DCM (1 x 50 mL). The combined organic layers were dried with Na2S04, filtered and concentrated by rotary evaporation. The resulting crude was subjected to column chromatography and was eluted with an EtOAc/hexane gradient to give compound 96 (2.21 g, 3.73 mmol, 68 % yield). 1H NMR (399 MHz, CDCI3) δ 8.42 - 8.36 (d, 2H), 8.12 8.06 (d, 2H), 6.07 - 6.00 (d, 1H), 5.33 - 5.30 (d, 1H), 5.23 - 5.15 (dd, 1H), 4.69 - 4.63 (d, 1H), 4.15 - 4.04 (m, 3H), 4.04-3.87 (m, 2H), 3.84-3.73 (m, 1H), 3.22-3.12 (t, 2H), 2.12-1.92 (m, 12H); 13C NMR (100 MHz, CDC13)179.95, 170.74, 170.48, 150.77, 149.59, 128.47, 125.03, 101.40, 71.08, 70.02, 67.39, 66.92, 61.76, 51.12, 36.51, 23.72, 20.92; R = 0.25 (1 :9 MeOH/DCM).
  • 33
  • [ 14273-92-8 ]
  • [ 10378-06-0 ]
  • C14H25NO8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% Stage #1: methyl 5-hydroxypentanoate; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 3h; Inert atmosphere; Large scale; Stage #2: With methanol; triethylamine at 50℃; for 48h; Inert atmosphere; Large scale; Synthesis of compound 24 Step (iii)[l]: The reaction was performed in a 20 L reactor fitted with a cooling jacket under Aratmosphere. TMSOTf (250 mL, 1.38 mol) was added to a stirred and cooled (12 °C) solution ofcrude 21 (2.14 kg, ~6.49 mol) and hydroxyester 23 (0.94 L, 7.14 mol) in anhyd. DCE (6.5 L).Immediate exothermic effect (up to 23 °C) observed, the cooler was turned off, and the mixturewas stirred at rt for 3 h and transferred to a 22 L open flask with a vigorously stirred mixture ofNaHC03 (168 g, 2.0 mol), water (3 L), and some ice. The organic phase was separated, driedover anhyd. Na2S04 , the solvent was evaporated, and oily residue was dried on rotary evaporatorat 12 mbar/30 °C to afford 3.09 kg of crude product that was used in the next step without furtherpurification. Step (iii)[2]: The reaction was performed in a 20 L filtration reactor fitted with a heating/coolingjacket. Crude product obtained from previous step (3.09 kg, ~ 6.49 mol) was dissolved inanhydrous methanol (10 L) under Ar atmosphere, and triethylamine (0.90 L, 6.49 mol) wasadded. The mixture was heated at 50 °C for 2 days, and toluene (4 L) was added and the solutionwas allowed to cool to rt overnight during which time bulk crystallization occurred. The slurrywas cooled to 0 °C, stirred overnight, filtered, and the solid was washed with 10% methanol intoluene (8.8 L) and dried on air at 65 °C over a hot plate to afford 0.97 kg of 24. Filtrate wasconcentrated in vacuum till bulk crystallization, and dry ethyl alcohol (4.0 L) was added. Theslurry was triturated on rotary evaporator at rt overnight, filtered, and the solid was washed withtoluene-ethanol mixture (1: 1, -2 L) to afford additional 191 g of 24 after drying on air at 65 °Cover a hot plate. Total yield: 1.16 kg, 54% based on 9, -95% purity.
  • 34
  • [ 14273-92-8 ]
  • [ 10378-06-0 ]
  • C20H31NO11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In 1,2-dichloro-ethane Inert atmosphere; Peracetylated GalNAc glycoside 12A (crude) The reaction was pelformed in a 20 L reactor fitted with a cooling jacket under Ar atm. TMSOTf(250 mL, 1.38 mol) was added to a stirred and cooled (12 °C) solution of crude 10 (2.14 kg,.::::;6.49 mol) and the methyl 5-hydroxypentanoate (llA, 0.94 L, 7.14 mol) in anhyd. DCE (6.5 L).Immediate exothermic effect (up to 23 °C) observed, the cooler was turned off, and the mixturewas stirred at rt for 3 h and transferred to a 22 L open flask with a vigorously stirred mixture ofNaHC03 (168 g, 2.0 mol), water (3 L), and some ice. The organic phase was separated, driedover anhyd. Na2S04 ; solvent was evaporated, and the oily residue was dried on the rotaryevaporator at 12 mbar/30 oc to afford 3.09 kg of crude 12A that was used in the next stepwithout further purification. 1H NMR (400 MHz, CDCb): 8 5.73 (d, J = 8.6 Hz, 1H), 5.35 (d, J =3.1 Hz, 1H), 5.26 (dd, J = 11.2, 3.3 Hz, 1H), 4.68 (d, J = 8.4 Hz, 1H), 4.34 (t, J = 5.6 Hz, 1H),4.21- 4.04 (m, 3H), 3.93 (tdd, J = 17.7, 11.1, 7.0 Hz, 3H), 3.72 (s, 3H), 3.70- 3.62 (m, 4H),3.57-3.41 (m, 2H), 2.55 (t, J = 6.9 Hz, 1H), 2.32 (dt, J = 23.8, 11.7 Hz, 3H), 2.18-2.11 (m,4H), 2.11- 1.78 (m, 14H), 1.78- 1.44 (m, 5H).
  • 35
  • [ 23739-93-7 ]
  • [ 10378-06-0 ]
YieldReaction ConditionsOperation in experiment
With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Inert atmosphere; Cooling with ice; 4 Synthesis of compound 21 Step (i)[2]: The reaction was performed in a 20 L reactor under Ar atmosphere. TMSOTf (1.40L, 7.74 mol) was added slowly (10 min) to a stirred suspension of the peracetylated sugarintermediate (2.52 kg, 6.49 mol) in anhyd. DCE ( 4.0 L) under Ar atmosphere. The mixture wasstirred at rt overnight and transferred via transfer line to a vigorously stirred mixture of NaHC03(1.64 kg, 19.4 mol), ice (5.5 L) and water (5.5 L) in an open 40 L reactor. The stirring wascontinued for 40 min, the organic layer was separated, the water layer was washed with DCM(x2), and the combined organic extracts were dried over anhyd. Na2S04 . The mixture wasfiltered, the solvent was evaporated, oily residue was dried on rotary evaporator (15 mbar at 30°C), redissolved in anhyd. DCE ( 4.0 L), and the solvent was evaporated again, and dried onrotary evaporator (3 mbar at 30 °C bath temperature) to afford 2.14 kg of crude 21. The crudecompound in the rotary evaporator was redissolved in anhyd. DCE ( 4.0 L) and the resultingsolution was used in the next step.
  • 36
  • [ 10378-06-0 ]
  • [ 146292-90-2 ]
  • C20H32N4O9 [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; Molecular sieve; 31 Compound 4 (9.5g, 28.8 mmoles) was treated with compound 103a or 103b (38 mmoles),individually, and TMSOTf (0.5 eq.) and molecular sieves in dichloromethane (200 mL), and stirred for 16hours at room temperature. At that time, the organic layer was filtered thru celite, then washed with sodiumbicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filteredand reduced under reduced pressure. The resultant oil was purified by silica gel chromatography (2%--> 10%10 methanoVdichloromethane) to give compounds 104a and 104b in >80% yield. LCMS and proton NMR wasconsistent with the structure.
80% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; Molecular sieve; 45 Compound 4 (9.5g, 28.8 mmoles) was treated with compound 103a or 103b (38 mmoles), individually, and TMSOTf (0.5 eq.) and molecular sieves in dichloromethane (200 mL), and stirred for 16 hours at room temperature. At that time, the organic layer was filtered thru celite, then washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced under reduced pressure. The resultant oil was purified by silica gel chromatography (2%- >10% methanol/dichloromethane) to give compounds 104a and 104b in >80% yield. LCMS and proton NMR was consistent with the structure.
80% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; Molecular sieve; 45 Compound 4 (9.5g, 28.8 mmoles) was treated with compound 103a or 103b (38 mmoles), individually, and TMSOTf (0.5 eq.) and molecular sieves in dichloromethane (200 mL), and stirred for 16 hours at room temperature. At that time, the organic layer was filtered thru celite, then washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced under reduced pressure. The resultant oil was purified by silica gel chromatography (2%-->10% methanol/dichloromethane) to give compounds 104a and 104b in >80% yield. LCMS and proton NMR was consistent with the structure.
80% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; Molecular sieve; 45 Compound 4 (9.5g, 28.8 mmoles) was treated with compound 103a or 103b (38 mmoles), individually, and TMSOTf (0.5 eq.) and molecular sieves in dichloromethane (200 mL), and stirred for 16hours at room temperature. At that time, the organic layer was filtered thru celite, then washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced under reduced pressure. The resultant oil was purified by silica gel chromatography (2%-->10% methanolldichloromethane) to give compounds 104a and 104b in >80% yield. LCMS and proton NMR was consistent with the structure.
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; Molecular sieve; 45 Example 45: Preparation of PFP Ester, Compound 110a Compound 4 (9.5g, 28.8 mmoles) was treated with compound 103a or 103b (38 mmoles), individually, and TMSOTf (0.5 eq.) and molecular sieves in dichloromethane (200 mL), and stirred for 16 hours at room temperature. At that time, the organic layer was filtered thru celite, then washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced under reduced pressure. The resultant oil was purified by silica gel chromatography (2%->10% methanol/dichloromethane) to give compounds 104a and 104b in >80% yield. LCMS and proton NMR was consistent with the structure.

  • 37
  • [ 17996-12-2 ]
  • [ 10378-06-0 ]
  • 6'-(N-benzyloxycarbonyl)aminohexyl-2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
65.4% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 12h; Molecular sieve;
63% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; Molecular sieve; Inert atmosphere; 51 Example 51: Preparation of Oligonucleotide 155 Comprising GalNAc3-6 Compound 4 (15 g, 45.55 mmol) and compound 35b (14.3 grams, 57 mmol) were dissolved in CH2CI2(200 ml). Activated molecular sieves (4 A. 2 g, powdered) were added, and the reaction was allowed to stir for 30 minutes under nitrogen atmosphere. TMS-OTf was added (4.1 ml, 22.77 mmol) and the reaction was allowed to stir at room temp overnight. Upon completion, the reaction was quenched by pouring into solution of saturated aqueous NaHCOs (500 ml) and crushed ice (~ 150 g). The organic layer was separated, washed with brine, dried over MgS04, filtered, and was concentrated to an orange oil under reduced pressure. The crude material was purified by silica gel column chromatography and eluted with 2-10 % MeOH in CH2Cl2to yield Compound 112(16.53 g, 63 %). LCMS andlB NMR were consistent with the expected compound.
63% Stage #1: N-benzyloxycarbonyl-6-amino-1-hexanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; Inert atmosphere; 37 Compound 4 (15 g, 45.55 mmol) and compound 35b (14.3 grams, 57 mmol) were dissolved inCH2Cb (200 ml). Activated molecular sieves ( 4 A. 2 g, powdered) was added, and the reaction was allowedto stir for 30 minutes under nitrogen atmosphere. TMS-OTf was added ( 4.1 ml, 22.77 mmol) and the5 reaction was allowed to stir at room temp overnight. Upon completion, the reaction was quenched bypouring into solution of saturated aqueous NaHC03 (500 ml) and crushed ice (~ 150 g). The organic layerwas separated, washed with brine, dried over MgS04, filtered, and was concentrated to an orange oil underreduced pressure. The crude material was purified by silica gel column chromatography and eluted with 2-10% MeOH in CH2Cbto yield Compound 112 c16.53 g, 63 %). LCMS and 1H NMR were consistent with the10 expected compound.
63% Stage #1: N-benzyloxycarbonyl-6-amino-1-hexanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; 51 Compound 4 (15 g, 45.55 mmol) and compound 35b (14.3 grams, 57 mmol) were dissolved in CH2Cl2 (200 ml). Activated molecular sieves (4 Å. 2 g, powdered) were added, and the reaction was allowed to stir for 30 minutes under nitrogen atmosphere. TMS-OTf was added (4.1 ml, 22.77 mmol) and the reaction was allowed to stir at room temp overnight. Upon completion, the reaction was quenched by pouring into solution of saturated aqueous NaHCO3 (500 ml) and crushed ice (~ 150 g). The organic layer was separated, washed with brine, dried over MgSO4, filtered, and was concentrated to an orange oil under reduced pressure. The crude material was purified by silica gel column chromatography and eluted with 2-10 % MeOH in CH2Cl2 to yield Compound 112 (16.53 g, 63 %). LCMS and 1H NMR were consistent with the expected compound.
63% Stage #1: N-benzyloxycarbonyl-6-amino-1-hexanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; 51 Compound 4 (15 g, 45.55 mmol) and compound 35b (14.3 grams, 57 mmol) were dissolved in CH2Cl2 (200 ml). Activated molecular sieves (4 Å. 2 g, powdered) were added, and the reaction was allowed to stir for 30 minutes under nitrogen atmosphere. TMS-OTf was added (4.1 ml, 22.77 mmol) and the reaction was allowed to stir at room temp overnight. Upon completion, the reaction was quenched by pouring into solution of saturated aqueous NaHCO3 (500 ml) and crushed ice (~ 150 g). The organic layer was separated, washed with brine, dried over MgSO4, filtered, and was concentrated to an orange oil under reduced pressure. The crude material was purified by silica gel column chromatography and eluted with 2-10 % MeOH in CH2Cl2 to yield Compound 112 (16.53 g, 63 %). LCMS and 1H NMR were consistent with the expected compound.
63% Stage #1: N-benzyloxycarbonyl-6-amino-1-hexanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; 51 Compound 4 (15 g, 45.55 mmol) and compound 35b (14.3 grams, 57 mmol) were dissolved in CH2C12 (200 ml). Activated molecular sieves (4 A. 2 g, powdered) were added, and the reaction was allowed to stir for 30 minutes under nitrogen atmosphere. TMS-OTf was added (4.1 ml, 22.77 mmol) and thereaction was allowed to stir at room temp overnight. Upon completion, the reaction was quenched by pouring into solution of saturated aqueous NaHCO3 (500 ml) and crushed ice ( 150 g). The organic layer was separated, washed with brine, dried over MgSO4, filtered, and was concentrated to an orange oil under reduced pressure. The crude material was purified by silica gel column chromatography and eluted with 2-10 % MeOH in CH2C12 to yield Compound 112 (16.53 g, 63 %). LCMS and ‘H NMR were consistent with theexpected compound.
With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
155.14 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane for 3h; Molecular sieve; 6 Compounds 1 and 10 were dried over P205 overnight under high vacuum at 35 °C in separate flasks. Compound 1 (150 g, 0.385 mol) was dissolved in anhydrous dichloroethane (500.0 mL) with stirring under nitrogen at room temperature. To the resulting clear solution was added TMSOTf (119.87g, 0.539 mol, 1.5 eq.) with stirring for two hours to form Compound 2 in Solution 1. Compound 10 (106.51 g, 0.424 mol, 1.1 eq.) was dissolved in anhydrous dichloroethane (1.0 L) and molecular sieves were added (powder molecular sieves ~30g, dried at 275 °C overnight and subsequently cooled to room temperature under high vacuum) with stirring maintained for 40 minutes. To the resulting mixture was added Solution 1 by cannula dropwise slowly over a period of 1 hour with stirring for an additional 2 hours. The reaction mixture was filtered and the filtrate dripped onto an ice cold saturated solution of NaHC03 (300 mL). The organic phase was separated and washed with DI water (500 mL), brine (500 mL), dried over Na2S04, filtered and evaporated to dryness to provide the crude material as a white solid. The crude material was suspended in EtOAc/hexanes (800 mL) and filtered to provide pure white crystalline product, Compound 11 (111.44 g). The filtrate was concentrated and the residue purified by silica gel chromatography eluted with DCM/MeOH (97/3) and the collected fractions concentrated and suspended in EtOAc/hexane (400 mL) and filtered to provide additional Compound 11 (44.0 g, for a combined yield of 70%, 155.14 g). The structure of Compound 11 was confirmed by LCMS and NMR.
155.14 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane for 3h; Molecular sieve; 6 Compounds 1 and 10 were dried over P2O5 overnight under high vacuum at 35° C. in separate flasks. Compound 1 (150 g, 0.385 mol) was dissolved in anhydrous dichloroethane (500.0 mL) with stirring under nitrogen at room temperature. To the resulting clear solution was added TMSOTf (119.87 g, 0.539 mol, 1.5 eq.) with stirring for two hours to form Compound 2 in Solution 1. Compound 10 (106.51 g, 0.424 mol, 1.1 eq.) was dissolved in anhydrous dichloroethane (1.0 L) and molecular sieves were added (powder molecular sieves 30 g, dried at 275° C. overnight and subsequently cooled to room temperature under high vacuum) with stirring maintained for 40 minutes. To the resulting mixture was added Solution 1 by cannula dropwise slowly over a period of 1 hour with stirring for an additional 2 hours. The reaction mixture was filtered and the filtrate dripped onto an ice cold saturated solution of NaHCO3 (300 mL). The organic phase was separated and washed with DI water (500 mL), brine (500 mL), dried over Na2SO4, filtered and evaporated to dryness to provide the crude material as a white solid. The crude material was suspended in EtOAc/hexanes (800 mL) and filtered to provide pure white crystalline product, Compound 11 (111.44 g). The filtrate was concentrated and the residue purified by silica gel chromatography eluted with DCM/MeOH (97/3) and the collected fractions concentrated and suspended in EtOAc/hexane (400 mL) and filtered to provide additional Compound 11 (44.0 g, for a combined yield of 70%, 155.14 g). The structure of Compound 11 was confirmed by LCMS and 1H NMR.

  • 39
  • benzyl (3-(5-hydroxypentanamido)propyl)carbamate [ No CAS ]
  • [ 10378-06-0 ]
  • C30H43N3O12 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 12h; Molecular sieve; 2 Compound 2 (17.2 g, 52.2 mmol), Compound 3 (16.11 g, 52.2 mmol) and pre-dried molecular sieves (20 g) were suspended in dry dichloromethane (120 mL). The mixture was stirred at room temperature for 30 minutes and TMSOTf (4.7 mL) was added. The reaction was stirred at room temperature for 12 hours and then analyzed by LCMS. The reaction mixture was poured into icy NaHC03 and extracted with dichloromethane. The dichloromethane extract was washed with brine and concentrated to dryness. The crude product was purified via Biotage silica gel column that was eluted with 2%, (5 column volumes "CV"), 3% (3 CV), 5% (4 CV) and 8% (3 CV) MeOH in dichloromethane to provide Compound 4 as a white foam (22.8 g, 68%).
68% Stage #1: benzyl (3-(5-hydroxypentanamido)propyl)carbamate; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 12h; Molecular sieve; 2 Compound 2 (17.2 g, 52.2 mmol), Compound 3 (16.11 g, 52.2 mmol) and pre-dried molecular sieves (20 g) were suspended in dry dichloromethane (120 mL). The mixture was stirred at room temperature for 30 minutes and TMSOTf (4.7 mL) was added. The reaction was stirred at room temperature for 12 hours and then analyzed by LCMS. The reaction mixture was poured into icy NaHCO3 and extracted with dichloromethane. The dichloromethane extract was washed with brine and concentrated to dryness. The crude product was purified via Biotage silica gel column that was eluted with 2%, (5 column volumes “CV”), 3% (3CV), 5% (4CV) and 8% (3CV) MeOH in dichloromethane to provide Compound 4 as a white foam (22.8 g, 68%). The structure of Compound 4 was confirmed by LCMS and 1H NMR.
With trimethylsilyl trifluoromethanesulfonate
With trimethylsilyl trifluoromethanesulfonate
With trimethylsilyl trifluoromethanesulfonate
With trimethylsilyl trifluoromethanesulfonate 53 Lactone 161 was reacted with diamino propane (3-5 eq) or Mono-Boc protected diamino propane (1eq) to provide alcohol 162a or 162b. When unprotected propanediamine was used for the above reaction, theexcess diamine was removed by evaporation under high vacuum and the free amino group in 162a was protected using CbzCl to provide 1 62b as a white solid after purification by column chromatography. Alcohol 162b was further reacted with compound 4 in the presence of TMSOTf to provide 163a which was converted to 1 63b by removal of the Cbz group using catalytic hydrogenation. The pentafluorophenyl (PFP)ester 164 was prepared by reacting triacid 113 (see Example 48) with PFPTFA (3.5 eq) and pyridine (3.5 eq) in DMF (0.1 to 0.5 M). The triester 164 was directly reacted with the amine 163b (3-4 eq) and DIPEA (3-4 eq) to provide Compound 18. The above method greatly facilitates purification of intermediates and minimizes the formation of byproducts which are formed using the procedure described in Example 4.

  • 40
  • [ 629-11-8 ]
  • [ 10378-06-0 ]
  • C20H33NO10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
86.2% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; 33.1 (1) Synthesis of Compound 44 (0241) In a 250 mL round bottom flask, compound 6 (5 g, 15.2 mmol) and 1,6-hexanediol (9 g, 76 mmol) were dissolved in 100 mL of anhydrous 1,2-dichloroethane, stirred for 30 min, and added with trimethylsilyl trifluoromethanesulfonate (0.55 mL, 3 mmol); the reaction was reacted overnight at room temperature; the reaction solution was extracted with dichloromethane, and the organic phase was washed twice with 80 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and passed through a silica gel column (petroleum ether:ethyl acetate V:V=3:2) to isolate 5.86 g of a clear oily liquid with a yield of 86.2%. MS (ESI), m/z: 470.2 ([M+Na]+).
With trimethylsilyl trifluoromethanesulfonate
  • 41
  • [ 86520-52-7 ]
  • [ 10378-06-0 ]
  • [ 153253-47-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere 2: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 8 h
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere 2: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 8 h
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere 2: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 8 h
  • 42
  • [ 10378-06-0 ]
  • C20H31NO11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene / water; acetonitrile
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene / water; acetonitrile
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 5 - 20 °C / Molecular sieve 2: hydrogen; palladium 10% on activated carbon / methanol; ethyl acetate / 16 h
  • 43
  • [ 10378-06-0 ]
  • [ 153252-07-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C / Molecular sieve; Inert atmosphere 2: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C
Multi-step reaction with 2 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol
Multi-step reaction with 2 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C
Multi-step reaction with 2 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 12 h / 20 °C
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 16 h / 20 °C / Molecular sieve 2: hydrogen; palladium on activated charcoal / methanol; ethyl acetate / 3 h
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 12 h / 20 °C / Molecular sieve 2: palladium hydroxide, 20 wt% on carbon; hydrogen / water; methanol; ethyl acetate / 0.5 h / 20 °C

  • 44
  • [ 10378-06-0 ]
  • C30H43N3O12 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C / Molecular sieve; Inert atmosphere 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere
Multi-step reaction with 3 steps 1.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 16 h / 20 °C / Molecular sieve 2.1: hydrogen; palladium on activated charcoal / methanol; ethyl acetate / 3 h 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere
Multi-step reaction with 3 steps 1.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 12 h / 20 °C / Molecular sieve 2.1: palladium hydroxide, 20 wt% on carbon; hydrogen / water; methanol; ethyl acetate / 0.5 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere

  • 45
  • [ 10378-06-0 ]
  • C22H37N3O10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C / Molecular sieve; Inert atmosphere 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere 4.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 0.5 h
Multi-step reaction with 4 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere 4.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 0.75 h
Multi-step reaction with 4 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere 4.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 0.5 h
Multi-step reaction with 4 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere 4.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 0.5 h
Multi-step reaction with 4 steps 1.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 16 h / 20 °C / Molecular sieve 2.1: hydrogen; palladium on activated charcoal / methanol; ethyl acetate / 3 h 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere 4.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 0.5 h
Multi-step reaction with 4 steps 1.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 1.2: 20 °C 2.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / Inert atmosphere 3.2: 2 h / Inert atmosphere 4.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 0.5 h

  • 46
  • [ 10378-06-0 ]
  • 12-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxydodecanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium on activated charcoal / methanol / 18 h / 20 °C
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 18 h / 20 °C / Molecular sieve 2: hydrogen; palladium 10% on activated carbon / water; methanol / 18 h / 20 °C
  • 47
  • [ 10378-06-0 ]
  • C26H30F5NO11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene / water; acetonitrile 3: pyridine / N,N-dimethyl-formamide
Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene / water; acetonitrile 4: pyridine / N,N-dimethyl-formamide
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 5 - 20 °C / Molecular sieve 2: hydrogen; palladium 10% on activated carbon / methanol; ethyl acetate / 16 h 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.5 h / 20 °C
  • 48
  • [ 10378-06-0 ]
  • C30H52N2O11Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate; hydrogen; palladium on activated charcoal 2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium; hydrogen / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide

  • 49
  • [ 10378-06-0 ]
  • C24H46N2O8Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4: ammonia / methanol
Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide 4: ammonia / methanol
Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide 4: ammonia / methanol
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate; hydrogen; palladium on activated charcoal 2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 3: ammonia / methanol
Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium; hydrogen / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4: ammonia / methanol

  • 50
  • [ 10378-06-0 ]
  • C45H58N2O11Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap
Multi-step reaction with 5 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap
Multi-step reaction with 5 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap
Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate; hydrogen; palladium on activated charcoal 2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 3: ammonia / methanol 4: dmap
Multi-step reaction with 5 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium; hydrogen / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap

  • 51
  • [ 10378-06-0 ]
  • C39H44N2O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap 6: triethylamine hydrofluoride
Multi-step reaction with 6 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap 6: triethylamine hydrofluoride
Multi-step reaction with 6 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap 6: triethylamine hydrofluoride
Multi-step reaction with 5 steps 1: trimethylsilyl trifluoromethanesulfonate; hydrogen; palladium on activated charcoal 2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 3: ammonia / methanol 4: dmap 5: triethylamine hydrogen fluoride
Multi-step reaction with 6 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium; hydrogen / methanol 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4: ammonia / methanol 5: dmap 6: triethylamine hydrogen fluoride

  • 52
  • [ 10378-06-0 ]
  • C26H46N2O9 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol
  • 53
  • [ 10378-06-0 ]
  • (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-hydroxyhexyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium; hydrogen / methanol
  • 54
  • [ 10378-06-0 ]
  • (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-(((2-cyanoethoxy)(diisopropylamino)phosphino)oxy)hexyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate 2: N-ethyl-N,N-diisopropylamine / dichloromethane
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium / methanol 3: N-ethyl-N,N-diisopropylamine / dichloromethane
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: palladium; hydrogen / methanol 3: N-ethyl-N,N-diisopropylamine / dichloromethane
  • 55
  • [ 10378-06-0 ]
  • 5-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium(0) / methanol
Multi-step reaction with 2 steps 1.1: trimethylsilyl trifluoropmethanesulfonate / 2.58 h / 20 °C / Molecular sieve 2.1: sodium (meta)periodate / dichloromethane; acetonitrile; lithium hydroxide monohydrate / 0.25 h / 10 °C 2.2: 1 h / 20 - 35 °C
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 2: palladium(0); hydrogen / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / Inert atmosphere 2: hydrogen; palladium(0) / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 2: hydrogen; palladium(0) / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 2: palladium(0); hydrogen / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve; Inert atmosphere 2: palladium 10% on activated carbon / ethanol; cyclohexane / 6 h / Inert atmosphere; Reflux
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 24.5 h / 20 °C / Molecular sieve; Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / methanol / 18 h / 20 °C / 2482.38 Torr
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C / Inert atmosphere; Molecular sieve 2: palladium 10% on activated carbon / ethanol; cyclohexane / 6 h / Inert atmosphere; Reflux
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 15 h / 25 °C / Inert atmosphere; Molecular sieve 2: hydrogen; palladium 10% on activated carbon / ethyl acetate / 3 h / 25 °C
Multi-step reaction with 2 steps 1.1: 1,2-dichloro-ethane / 0.5 h / 20 °C / Molecular sieve 1.2: 20 °C / Inert atmosphere; Cooling with ice 2.1: sodium (meta)periodate / dichloromethane; acetonitrile; lithium hydroxide monohydrate / 0.17 h / Cooling with ice 2.2: 20 °C
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve; Inert atmosphere 2: ruthenium (III) chloride; sodium (meta)periodate / dichloromethane; acetonitrile; lithium hydroxide monohydrate / 20 °C / Cooling with ice
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate / 20 °C
Multi-step reaction with 2 steps 1.1: 1,2-dichloro-ethane / 0.5 h / 20 °C / Molecular sieve 1.2: 20 °C / Molecular sieve; Cooling with ice; Inert atmosphere 2.1: sodium (meta)periodate / dichloromethane; acetonitrile; lithium hydroxide monohydrate / 0.17 h / Cooling with ice 2.2: 20 °C
Multi-step reaction with 2 steps 1.1: dichloromethane / 0.5 h / Molecular sieve 1.2: 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate
Multi-step reaction with 2 steps 1: dichloromethane / Molecular sieve 2: ruthenium(III) trichloride monohydrate; sodium (meta)periodate / dichloromethane; lithium hydroxide monohydrate; acetonitrile

Reference: [1]Current Patent Assignee: GLAXOSMITHKLINE PLC; IONIS PHARMACEUTICALS - WO2014/179620, 2014, A1
[2]Nair, Jayaprakash K.; Willoughby, Jennifer L. S.; Chan, Amy; Charisse, Klaus; Alam, Md. Rowshon; Wang, Qianfan; Hoekstra, Menno; Kandasamy, Pachamuthu; Kelin, Alexander V.; Milstein, Stuart; Taneja, Nate; Oshea, Jonathan; Shaikh, Sarfraz; Zhang, Ligang; Van Der Sluis, Ronald J.; Jung, Michael E.; Akinc, Akin; Hutabarat, Renta; Kuchimanchi, Satya; Fitzgerald, Kevin; Zimmermann, Tracy; Van Berkel, Theo J. C.; Maier, Martin A.; Rajeev, Kallanthottathil G.; Manoharan, Muthiah [Journal of the American Chemical Society, 2014, vol. 136, # 49, p. 16958 - 16961]
[3]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/42447, 2015, A1
[4]Yamamoto, Tsuyoshi; Sawamura, Motoki; Wada, Fumito; Harada-Shiba, Mariko; Obika, Satoshi [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 1, p. 26 - 32]
[5]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168635, 2015, A2 Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168618, 2015, A2
[6]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168589, 2015, A2
[7]Current Patent Assignee: SOLSTICE BIOLOGICS LLC - WO2015/188197, 2015, A2
[8]Current Patent Assignee: NOVO NORDISK A/S - WO2016/100401, 2016, A1
[9]Current Patent Assignee: SOLSTICE BIOLOGICS LLC - WO2017/100461, 2017, A1
[10]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/53661, 2019, A2
[11]Current Patent Assignee: SUZHOU RIBO LIFE SCIENCE CO LTD - CN111377984, 2020, A
[12]Bhingardeve, Pramod; Madhanagopal, Bharath Raj; Naick, Hemanth; Jain, Prashant; Manoharan, Muthiah; Ganesh, Krishna [Journal of Organic Chemistry, 2020, vol. 85, # 14, p. 8812 - 8824]
[13]Current Patent Assignee: SUZHOU RIBO LIFE SCIENCE CO LTD - CN111377985, 2020, A
[14]Current Patent Assignee: GUANGZHOU RIBOBIO - US2020/369703, 2020, A1
[15]Current Patent Assignee: SUZHOU RIBO LIFE SCIENCE CO LTD - CN112007040, 2020, A
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  • 57
  • [ 134848-96-7 ]
  • [ 10378-06-0 ]
  • 4-benzyloxycarbonylbutyl-2-deoxy-2-N-acetyl-3,4,6-tri-O-acetyl-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; 4.5 (5) Synthesis of Compound 7 (0140) In a 100 mL round bottom flask, compound 6 (5 g, 15.2 mmol) and compound 4 (3.8 g, 18.25 mmol) were dissolved in 50 mL of anhydrous 1,2-dichloroethane, stirred for 10 min, and trimethylsilyl trifluoromethanesulfonate (0.55 mL, 3 mmol) was added, reacted overnight at room temperature; the reaction solution was extracted with dichloromethane, and the organic phase was washed twice with 50 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and passed through a silica gel column (petroleum ether:ethyl acetate V:V=3:2) to isolate 6.94 g of a dear oily liquid with a yield of 85% 1HNMR (400 MHz, DMSO-d6) δ: 7.69 (d, J=9.3 Hz, 1H), 7.33-7.16 (m, 5H), 5.28 (d, J=5.3Hz, 1H), 4.95 (s, 2H), 4.93 (q, J=4.2 Hz, 1H), 4.40 (d, J=8.6 Hz, 1H), 4.00-3.86 (m, 3H), 3.73-3.56 (m, 2H), 3.36-3.21 (m, 1H), 2.53 (t, J=8.2 Hz, 2H), 2.11 (s, 3H), 1.89 (s, 3H), 1.83 (s, 3H), 1.65 (s, 3H), 1.59-1.36 (m, 4H). MS (ESI), m/z: 560.2 ([M+Na]+).
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
65% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃;
62% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane Inert atmosphere;
57% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 25℃; for 15h; Inert atmosphere; Molecular sieve; Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of G7-4 (111 g, 337.1 mmol, 1.00 equiv.) and benzyl 5- hydroxypentanoate (70.2 g, 438.2 mmol, 1.3 equiv.) in 1 ,2-dichloroethane (1100 rriL) and 22 g molecule sieves type 4A. The resulting solution was stirred 30 min at 25°C. This was followed by the addition of trimethylsilyl trifluoromethanesulfonate (22.48 g, 101.12 mmol, 0.3 equiv.) dropwise with stirring in 10 min. The resulting solution was stirred for 15 h at 25°C. The resulting solution was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Flash. This resulted in 110 g (57%) of G7-5.
24% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Molecular sieve; Inert atmosphere; Preparation of benzyloxycarbonylbutyl 2-deoxy 2-/V-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method A. Preparation of benzyloxycarbonylbutyl 2-deoxy 2-/V-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method A.Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) was added to a solution of NAG2 (10.0 g, 25.6 mmol) in DCE (100 mL) at ambient temperature. The mixture was stirred at 55 °C for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured onto ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 and concentrated in vacuo to give syrup NAG6. A solution NAG6 in DCE (60 m L) was charged with alcohol NAG5 (8.00 g, 38.4 mmol) and molecular sieves. The mixture was placed under an inert atmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at rt. The mixture was poured over ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 and concentrated in vacuo to give syrup. This crude material was purified via Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). 1 H NMR (CDCI3, 500 MHz) : δ 7.35 (m , 5H), 5.98 (d, 1 H, J 7.0 Hz), 5.57 (m, 1 H), 5.34 (d, 1 H, J 3.0 Hz), 5.25 (dd, 1 H, J 3.0 Hz, 1 1 Hz), 5.10 (s, 2H), 4.63 (d, 1 H, J 8.5 Hz), 4.1 1 (m, 2H), 3.95 (m, 1 H), 3.88 (m, 2H), 3.49 (m, 1 H), 2.37 (m , 2H), 2.13 (s, 3H), 2.03 (s, 3H), 1 .99 (s, 3H), 1 .90 (s, 3H), 1 .70 (m , 2H), 1 .61 (m, 2H).
3.3 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Molecular sieve; Inert atmosphere; 1.NAG7 Preparation of benzyloxycarbonylbutyl 2-deoxy 2-A/-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method A. Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) was added to a solution of NAG2 (10.0 g, 25.6 mmol) in DCE (100 mL) at ambient temperature. The mixture was stirred at 55 °C for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured onto ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 andconcentrated in vacuo to give syrup NAG6. A solution NAG6 in DCE (60 ml_) was charged with alcohol NAG5 (8.00 g, 38.4 mmol) and molecular sieves. The mixture was placed under an inert atmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at rt. The mixture was poured over ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried over Na2S04 and concentrated in vacuo to give syrup. This crude material was purified by Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). H NMR (CDCI3, 500 MHz): δ 7.35 (m, 5H), 5.98 (d, 1 H, J 7.0 Hz), 5.57 (m, 1 H), 5.34 (d, 1 H, J 3.0 Hz), 5.25 (dd, 1 H, J 3.0 Hz, 1 1 Hz), 5.10 (s, 2H), 4.63 (d, 1 H, J 8.5 Hz), 4.1 1 (m, 2H), 3.95 (m, 1 H), 3.88 (m, 2H), 3.49 (m, 1 H), 2.37 (m, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H), 1.70 (m, 2H), 1.61 (m, 2H).
3.3 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Inert atmosphere; Molecular sieve; 1.A Preparation of benzyloxycarbonylbutyl 2-deoxy 2-N-acetyl -3,4, 6-tri-O-acetyl-β-D-galactopyranoside (NAG7) Method A. Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) wasadded to a solution of NAG2 (10.0 g, 25.6 mmol) in DOE (100 mL) at ambient temperature. The mixture was stirred at 55 00 for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured onto ice cold sat. NaHCO3 (aq.) and extracted with CH2CI2. The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give syrup NAG6. A solution NAG6 in DOE (60 mL) was charged with alcohol NAG5 (8.00 g, 38.4 mmol) and molecular sieves. The mixture was placed under an inertatmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at room temperature. The mixture was poured over ice cold sat. NaHOO3 (aq.) and extracted with 0H2012. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude material as syrup. This crude material was purified by Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). 1H NMR (ODd3, 500 MHz): O 7.35 (m, 5H), 5.98 (d, 1H, J7.0 Hz), 5.57 (m, 1H), 5.34 (d, 1H, J3.0 Hz), 5.25 (dd, 1H, J3.0 Hz,11 Hz), 5.10 (s, 2H), 4.63 (d, 1H, J8.5 Hz), 4.11 (m, 2H), 3.95 (m, 1 H), 3.88 (m, 2H), 3.49 (m, 1H), 2.37 (m, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H), 1.70 (m, 2H), 1.61 (m, 2H).
Stage #1: benzyl 5-hydroxy pentanoate; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; 3.3 Step 3: (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a-tetrahydro-5H- pyrano[3,2-d]oxazole-6,7-diyl diacetate (65 g, 197.4 mmol) and benzyl 5-hydroxypentanoate (lnt-AA1) (41 g, 197.4 mmol) were dissolved in DCM (600 mL). Molecular sieves (50 g) were added, the reaction was stirred for 30 min, and TMSOTF (6.5 g, 29.6 mmol) was added. The reaction mixture was then stirred at room temperature overnight. TLC showed the starting material was completely consumed. The reaction mixture was filtered to remove the molecular sieves. The filtrate was treated with saturated aqueous NaHCO3 (500 ml) and extracted with DCM (500 mL x2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (elute: PE: EA=2:1-1 :2) to obtain (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((5- (benzyloxy)-5-oxopentyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate. 1H NMR (400 MHz, CDCIa) δ ppm 7.37-7.32 (m, 5H), 5.60 (d, 1 H, J = 8.4Hz), 5.35 (d, 1 H, J = 2.4Hz), 5.25 (dd, 1 H, J1 = 11.6Hz, J2 = 3.6Hz), 5.11 (s, 2H), 4.63 (d, 1 H, J1 = 8.4Hz), 4.15-4.11 (m, 2H), 3.98- 3.86 (m, 3H), 3.55-3.45 (m, 1 H), 2.41 -2.36 (m, 2H), 2.14 (s, 3H) , 2.03 (s, 3H), 2.00 (s, 3H), 1.91 (s, 3H), 1.72-1.55 (m, 4H).

Reference: [1]Current Patent Assignee: GUANGZHOU RIBOBIO - US2020/369703, 2020, A1 Location in patent: Paragraph 0135; 0140
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC; IONIS PHARMACEUTICALS - WO2014/179620, 2014, A1 Location in patent: Page/Page column 510
[3]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/42447, 2015, A1 Location in patent: Page/Page column 111
[4]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168635, 2015, A2 Location in patent: Page/Page column 154
[5]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168618, 2015, A2 Location in patent: Page/Page column 145-146
[6]Current Patent Assignee: IONIS PHARMACEUTICALS - WO2015/168589, 2015, A2 Location in patent: Page/Page column 179
[7]Bhingardeve, Pramod; Madhanagopal, Bharath Raj; Naick, Hemanth; Jain, Prashant; Manoharan, Muthiah; Ganesh, Krishna [Journal of Organic Chemistry, 2020, vol. 85, # 14, p. 8812 - 8824]
[8]Yamamoto, Tsuyoshi; Sawamura, Motoki; Wada, Fumito; Harada-Shiba, Mariko; Obika, Satoshi [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 1, p. 26 - 32]
[9]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/53661, 2019, A2 Location in patent: Paragraph 0115; 0134
[10]Current Patent Assignee: SOLSTICE BIOLOGICS LLC - WO2015/188197, 2015, A2 Location in patent: Page/Page column 157; 157
[11]Current Patent Assignee: LIE DINGGUO; SOLSTICE BIOLOGICS LLC; LIE BIN - WO2015/69932, 2015, A1 Location in patent: Page/Page column 157; 158
[12]Current Patent Assignee: SOLSTICE BIOLOGICS LLC - WO2017/100461, 2017, A1 Location in patent: Page/Page column 60; 61
[13]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2021/156792, 2021, A1 Location in patent: Page/Page column 172-174
  • 58
  • [ 71126-73-3 ]
  • [ 10378-06-0 ]
  • (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-(benzyloxy)hexyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
71% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
71% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane
71% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane

  • 59
  • [ 821-41-0 ]
  • [ 10378-06-0 ]
  • (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(hex-5-en-1-yloxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With trimethylsilyl trifluoropmethanesulfonate at 20℃; for 2.58333h; Molecular sieve;
Stage #1: hex-5-en-1-ol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 20℃; Inert atmosphere; Cooling with ice; 1.1-1c (1-1c) Synthesis of GAL-4 GAL-3 (26.9 g, 81.7 mmol) obtained in step (1-1b)Dissolve in 136ml of anhydrous 1,2-dichloroethane, add 30g of dry molecular sieve powder,Then add 9.0g 5-hexen-1-ol (CAS number: 821-41-0, purchased from Adamas-beta company, 89.9mmol),Stir at room temperature for 30 minutes, add 9.08 g TMSOTf (40.9 mmol) under the protection of ice bath and nitrogen, and stir and react overnight at room temperature.Filter to remove molecular sieve powder, add 300ml dichloroethane to dilute the filtrate, filter with diatomaceous earth,Then add 500ml saturated sodium bicarbonate aqueous solution and stir for 10 minutes to wash, separate the organic phase, and extract the water phase once with 300ml dichloroethane.The organic phases were combined and washed with 300ml saturated sodium bicarbonate aqueous solution and 300ml saturated brine respectively. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain yellow sugar thin product GAL-441.3g, which was directly without purification. Proceed to the next oxidation reaction.
With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 20℃; Molecular sieve; Inert atmosphere; 1.1-1c (1-1c) Synthesis of GAL-4 Dissolve the GAL-3 (26.9g, 81.7mmol) obtained in step (1-1b) in 136ml of anhydrous 1,2-dichloroethane, add 30g of dry molecular sieve powder, and then add 9.0g of 5-hexene -1-ol (CAS number: 821-41-0, purchased from Adamas-beta company, 89.9mmol), stirred at room temperature for 30 minutes, added 9.08g TMSOTf (40.9mmol) under ice bath and nitrogen protection, and stirred at room temperature for reaction overnight. The molecular sieve powder was removed by filtration. The filtrate was diluted with 300ml of dichloroethane, filtered with diatomaceous earth, and then added with 500ml of saturated sodium bicarbonate aqueous solution and stirred for 10 minutes to wash, and the organic phase was separated. The aqueous phase was extracted once with 300ml of dichloroethane. The organic phases were combined and washed with 300ml saturated sodium bicarbonate aqueous solution and 300ml saturated brine respectively. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain yellow sugar thin product GAL-441.3g. It was directly without purification. Proceed to the next oxidation reaction.
Stage #1: hex-5-en-1-ol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In 1,2-dichloro-ethane at 20℃; Molecular sieve; Cooling with ice; Inert atmosphere; 1.1-1-1; 1.1-1-1c (1-1-1c) Synthesis of GAL-4 Dissolve the GAL-3 (26.9g, 81.7mmol) obtained in step (1-1-1b) in 136ml of anhydrous 1,2-dichloroethane, Add 30 g of dry molecular sieve powder, and then add 9.0 g of 5-hexen-1-ol (CAS No. 821-41-0, purchased from Adamas-beta, 89.9 mmol), and stir at room temperature for 30 minutes, Add 9.08 g TMSOTf (40.9 mmol) under ice bath and nitrogen protection, and stir and react overnight at room temperature. Filter to remove molecular sieve powder, add 300ml of dichloromethane to the filtrate to dilute, filter with diatomaceous earth, then add 500ml of saturated sodium bicarbonate aqueous solution and stir for 10 minutes to wash. Separate the organic phase, extract the aqueous phase with 300ml of dichloroethane once, combine the organic phases and wash with 300ml of saturated aqueous sodium bicarbonate solution and 300ml of saturated brine, respectively. Separate the organic phase, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain a yellow sugar thin product GAL-441.3g, and proceed directly to the next oxidation reaction without purification.
In dichloromethane Molecular sieve;

  • 60
  • [ 75178-90-4 ]
  • [ 108-24-7 ]
  • [ 10378-06-0 ]
  • C24H40N2O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-(tert-butyloxycarbonyl)-5-aminopentanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester at 20℃; for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate at 20℃; Inert atmosphere; Stage #3: acetic anhydride Further stages; 2.1 Compound 2. Compound 2 was prepared by a procedure adopted from the literature (Westerlind, U. et al. Glycoconj. J. 2004, 21, 227-241). To a 500-mL one-neck round-bottom flask was added 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D- galactopyranose 1 (12.8 g, 32.8 mmol) followed by anhydrous CH2CI2 (150 mL) and trimethylsilyl trifluoromethanesulfonate (14.3 mL, 79.2 mmol). This mixture was stirred at reflux overnight (ca. 18 h) under a flow of argon gas. The reaction mixture was cooled to 0° C and treated with triethylamine (6.4 mL, 45.9 mmol) for 30 min before being warmed to room temperature, then washed with saturated aqueous NaHCC>3 (100 mL). The organic layer was separated and dried over Na2S04, filtered and evaporated providing crude oxazoline intermediate. To the crude oxazoline product was added anhydrous CH2CI2 (200 mL), N-t-Boc-5-amino-l-pentanol (10.0 g, 49.2 mmol) and 3 A molecular sieves (18.0 g, dried at 150°C for >24h). This mixture was stirred at room temperature for 30 min under a blanket of argon gas. Trimethylsilyl trifluoromethanesulfonate (2.97 mL, 16.4 mmol) was added to the reaction mixture, and the solution was stirred at room temperature overnight . The solution was cooled to 0°C and treated with triethylamine (3.2 mL, 23.07 mmol) for 30 min before being warmed to room temperature. After the reaction reached room temperature the mixture was filtered, and the mother liquor was evaporated providing the crude product as brown oil which was dissolved in anhydrous pyridine (100 mL) and treated with acetic anhydride (36 mL, 38.2 mmol). This mixture was stirred under an argon atmosphere at room temperature overnight , then evaporated under vacuum yielding a brown liquid, which was dissolved in CH2CI2 (200 mL). The solution was vigorously stirred with a saturated aqueous NaHCC>3 solution (100 mL) and solid NaHCC>3 in an open flask at room temperature to quench remaining Ac20and the organic layer was separated. The aqueous layer was extracted with CH2CI2 (1 x 200 mL) and all organic layers were combined. The organic layers were washed with saturated aqueous NaHCC>3 solution (1 x 100 mL), separated, dried over Na2S04, filtered and evaporated providing the crude product as a brown oil which was then dissolved in CH2CI2 (15 mL) and purified using column chromatography (S1O2, column size 7.5 cm ID x 16.0 cm length, EtOAc: Hexanes 1 :3 v/v for 500 mL, EtOAc : Hexanes 4: 1 v/v for 500 mL, 100% EtOAc for 1.0 L, 10 % MeOH in EtOAc v/v for 3.0 L). Product-containing fractions were pooled and evaporated under vacuum to a white solid which was further purified by trituration with ether to yield the desired product as a white solid (5 g, 29%). ESI MS [M+H]+ m/z 533.4.
  • 61
  • [ 14273-92-8 ]
  • [ 10378-06-0 ]
  • C20H31NO11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 3h;
  • 62
  • [ 134848-96-7 ]
  • [ 10378-06-0 ]
  • 5-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve; Inert atmosphere 2: palladium 10% on activated carbon / ethanol; cyclohexene / 6 h / Inert atmosphere; Reflux
With trimethylsilyl trifluoromethanesulfonate; palladium on activated charcoal; hydrogen
  • 63
  • [ 10378-06-0 ]
  • [ 67-63-0 ]
  • isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With copper dichloride In chloroform at 62℃; for 2h; Inert atmosphere; Sealed tube; Isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-galactopyranoside (7) solution of 6 (0.133 g, 0.404 mmol) and anhydrous CuCl2 in anhydrous CHCl3 (0.76 mL)in a 2-5 mL conical sealed vessel under an atmosphere of Ar was treated with anhydrous2-propanol (0.130 mL, 1.72 mmol). The reaction mixture was heated at 62 C for 2 h,cooled to room temperature, diluted with acetone (15 mL) and sat. NaHCO3 solution (7mL) filtered through a short plug of Celite, and concentrated. The residue was coevaporatedwith toluene to remove residual water and shaken in CHCl3 and weakly acidicion-exchange resin (Amberlite IRC-86, ca 1.5 g). The solution was filtered, the solventwas removed under vacuum, and the residue was purified by chromatography on SiO2(75% EtOAc/hexanes) to give 7 (119 mg, 0.305 mmol, 75%) as a colorless solid: [α]D -14.4 ( 1.0, CH2Cl2); Mp 188.5-189.5 C; IR (ATR) 3264, 2980, 1735, 1648, 1568, 1380,1256, 1232, 1215, 1124, 1072, 1053, 1023 cm-1; 1H NMR (600 MHz, CDCl3) δ 5.57 (d, J= 7.8 Hz, 1 H), 5.42 (dd, J = 3.0, 11.1 Hz, 1 H), 5.35 (app d, J = 3.6 Hz, 1 H), 4.86 (d, J =8.4 Hz, 1 H), 4.16 (dd, J = 6.6, 11.4 Hz, 1 H), 4.10 (dd, J = 7.2, 11.4 Hz, 1 H), 3.95-3.90(m, 2 H), 3.77-3.73 (m, 1 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H), 1.94 (s, 3 H), 1.23(d, J = 6.6 Hz, 3 H), 1.13 (d, J = 6.6 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δ 170.5,170.3, 99.4, 72.8, 70.4, 69.6, 66.8, 61.5, 52.4, 23.5, 23.3, 22.0, 20.7 (2 C); HRMS (ESI)m/z calcd for C17H28NO9 [M+H]+ 390.1764, found 390.1774.
  • 64
  • [ 10378-06-0 ]
  • [ 108-93-0 ]
  • cyclohexyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With copper dichloride In chloroform at 62℃; for 2h; Inert atmosphere; Sealed tube; Cyclohexyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-galactopyranoside (8) Asolution of 6 (0.135 g, 0.411 mmol) and anhydrous CuCl2 (55.0 mg, 0.411 mmol) inanhydrous CHCl3 (0.68 mL) in a 2-5 mL conical sealed vessel under an atmosphere of Arwas treated with cyclohexanol (0.170 mL, 1.66 mmol). The reaction mixture was heatedat 62 C for 2 h, cooled to room temperature, diluted with ethyl acetate (15 mL), washedwith 1 N HCl (2 × 9 mL), sat. NaHCO3 solution (1 × 10 mL), and brine (1 × 10 mL),dried (MgSO4), evaporated, and purified by chromatography on SiO2 (75%EtOAc/hexanes) to give 8 (141 mg, 0.328 mmol, 80%) as a colorless solid: [α]D -14.6 (1.0, CH2Cl2); Mp 164.3-165.3 C; IR (ATR) 3331, 2936, 2857, 1735, 1661, 1541, 1364,1251, 1219, 1079, 1031, 984 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.48 (d, J = 8.5 Hz, 1H), 5.41 (dd, J = 3.5, 11.5 Hz, 1 H), 5.35 (app. d, J = 3.5 Hz, 1 H), 4.89 (d, J = 8.5 Hz, 1H), 4.17 (dd, J = 6.5, 11.5 Hz, 1 H), 4.10 (dd, J = 7.0, 11.0 Hz, 1 H), 3.91 (app t, J = 10.5Hz, 1 H), 3.80-3.74 (m, 1 H), 3.64-3.59 (m, 1 H), 2.13 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3H), 1.94 (s, 3 H), 1.93-1.17 (m, 10 H); 13C NMR (125 MHz, CDCl3) δ 170.4, 170.3 (3 C),99.1, 78.0, 70.4, 69.6, 66.8, 61.4, 52.5, 33.3, 31.7, 25.5, 23.9, 23.8, 23.5, 20.7 (2 C);HRMS (ESI) m/z calcd for C20H32NO9 [M+H]+ 430.2077, found 430.2084.
  • 65
  • [ 106-24-1 ]
  • [ 10378-06-0 ]
  • geranyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With copper dichloride In chloroform at 62℃; for 2h; Inert atmosphere; Sealed tube; Geranyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-galactopyranoside (9). Asolution of 6 (0.120 g, 0.364 mmol) and anhydrous CuCl2 (49.0 mg, 0.364 mmol) inanhydrous CHCl3 (0.84 mL) in a 2-5 mL conical sealed vessel under an atmosphere of Arwas treated with geraniol (0.270 mL, 1.47 mmol). The reaction mixture was heated at 62C for 2 h, cooled to room temperature, diluted with ethyl acetate (15 mL), washed with 1N HCl (2 × 9 mL), sat. NaHCO3 solution (1 × 10 mL), and brine (1 × 10 mL), dried(MgSO4), evaporated, and purified by chromatography on SiO2 (75% EtOAc/hexanes) togive 9 (149 mg, 0.308 mmol, 65%) as a colorless solid: [α]D -17.0 ( 1.0, CH2Cl2); Mp117.5-118.9 C; IR (ATR) 3279, 2982, 2939, 1737, 1659, 1555, 1536, 1431, 1374, 1241,1226, 1131, 1064, 1053, 1036, 1012, 997, 958 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.41(d, J = 8.5 Hz, 1 H), 5.36-5.27 (m, 3 H), 5.09-5.06 (m, 1 H), 4.75 (d, J = 8.5 Hz, 1 H),4.29 (dd, J = 6.5, 12.0 Hz, 1 H), 4.23-4.11 (m, 3 H), 4.94-3.88 (m, 2 H), 2.13 (s, 3 H),2.12-2.00 (m, 4 H), 2.03 (s, 3 H), 1.99 (s, 3 H), 1.94 (s, 3 H), 1.68 (s, 3 H), 1.65 (s, 3 H),1.60 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 170.4 (2 C), 170.3, 170.2, 142.1, 131.8,123.8, 119.3, 99.0, 70.6, 69.9, 66.9, 65.2, 61.6, 51.8, 39.6, 26.3, 25.7, 23.5, 20.7 (2 C),17.7, 16.3; HRMS (ESI) m/z calcd for C24H37NO9Na [M+H]+ 506.2366, found 506.2384.
  • 67
  • [ 99837-97-5 ]
  • [ 10378-06-0 ]
  • C33H49NO11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane 52 Compound 156 was synthesized following the procedure described in the literature (J. Med. Chem. 2004, 47, 5798-5808).
66% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane 52 Compound 156 was synthesized following the procedure described in the literature (J. Med. Chem. 2004, 47, 5798-5808).
  • 68
  • [ 10378-06-0 ]
  • C54H65NO11Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate 2: ammonia / methanol
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate 2: ammonia / methanol
  • 69
  • [ 100-27-6 ]
  • [ 10378-06-0 ]
  • [(2R,3S,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-(4-nitrophenyl)ethoxy]tetrahydropyran-2-yl]methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With (R)-10-camphorsulfonic acid; In 1,2-dichloro-ethane; at 60℃; for 3h;Molecular sieve; (1-6A) Synthesis of [(2R,3S,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-(4-nitrophenyl)ethoxy]tetrahydropyran-2-yl]methyl acetate (compound 1-6A: compound of the following formula) (0161) (0162) 4,5-Dihydro-2-methyloxazolo[5',4':1,2]-3,4,6-tri-O-acetyl-1,2-dideoxy-alpha-glucopyranose (1.00 g, 3.04 mmol) produced according to the description of Bull. Chem. Soc. Jpn., 2003, 76, 485-500 was dissolved in dichloroethane (10 ml). To the solution, molecular sieve 4A (312 mg), 2-(4-nitrophenyl)-ethanol (2.54 g, 15.2 mmol), and (+)-camphorsulfonic acid (0.78 g, 3.34 mmol) were added at room temperature, and the mixture was stirred at 60C for 3 hours. The reaction solution was added to a saturated aqueous solution of sodium bicarbonate, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This product was purified by silica gel column chromatography (hexane:ethyl acetate = 67:33 - 0:100, v/v) to obtain the title compound 1-6A as a colorless solid (1.51 g, yield: 65%). 1H-NMR (CDCl3) delta: 8.14 (2H, d, J = 8.9 Hz), 7.38 (2H, d, J = 9.0 Hz), 5.32 (1H, d, J = 8.6 Hz), 5.21 (1H, dd, J = 10.6, 9.4 Hz), 5.07 (1H, t, J = 9.6 Hz), 4.63 (1H, d, J = 8.2 Hz), 4.25 (1H, dd, J = 12.1, 4.7 Hz), 4.20-4.12 (2H, m), 3.88 (1H, dt, J = 10.6, 8.6 Hz), 3.72-3.64 (2H, m), 3.06-2.93 (2H, m), 2.09 (3H, s), 2.03 (3H, s), 2.03 (3H, s), 1.84 (3H, s).
  • 70
  • [ 142504-42-5 ]
  • [ 10378-06-0 ]
  • (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
15.7 g Stage #1: benzyl <2-<2-(2-hydroxyethoxy)ethoxy>ethoxy>acetate; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; Molecular sieve; Stage #2: With triethylamine In dichloromethane 13.C C. (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-Diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester The above prepared acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester (10.3 g, 26 mmol) and {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-acetic acid benzyl ester (8.62 g, 29 mmol) were mixed in 520 mL of CH2Cl2 and treated with 63 g of 4 Angstrom molecular sieves. After 1 h, trimethylsilyl triflate (6.13 g, 28 mmol) was added. The reaction mixture was stirred over the weekend at ambient temperature. Triethylamine (5.21 ml, 37 mmol) was added, the molecular sieves filtered off, the filtrate diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent followed by flash chromatography (SiO2, ethyl acetate / AcOH / MeOH / water = 60 / 3 / 3 / 2) afforded 15.7 g of the title compound as a brownish oil. MS (ISP): 626.6 [M-H]-.
15.7 g Stage #1: benzyl <2-<2-(2-hydroxyethoxy)ethoxy>ethoxy>acetate; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In dichloromethane for 1h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; Molecular sieve; Stage #3: With triethylamine In dichloromethane 7.C Example 7
Synthesis of GalNAc Cluster
C. (2-{2-[2-(2R3R,4R,5R,6R)-4,5-Diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester. Example 7 Synthesis of GalNAc Cluster C. (2-{2-[2-(2R3R,4R,5R,6R)-4,5-Diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester. The above prepared acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-30-1-pyrano[3,2-d]oxazol-7-yl ester (10.3 g, 26 mmol) and {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-acetic acid benzyl ester (8.62 g, 29 mmol) were mixed in 520 mL of CH2Cl2 and treated with 63 g of molecular sieves 4 Angstrom. After 1 h, trimethylsilyl triflate (6.13 g, 28 mmol) was added. The reaction mixture was stirred over the weekend at ambient temperature. Triethylamine (5.21 mL, 37 mmol) was added, the molecular sieves filtered off, the filtrate diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent followed by flash chromatography (SiO2, ethyl acetate/AcOH/MeOH/water=60/3/3/2) afforded 15.7 g of the title compound as a brownish oil. MS (ISP): 626.6 [M-H]-.
  • 71
  • [ 5238-56-2 ]
  • [ 10378-06-0 ]
  • [ 1443446-15-8 ]
  • 72
  • [ 10378-06-0 ]
  • [ 111-46-6 ]
  • [(2R,3R,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-(2-hydroxy ethoxy) ethoxy]tetrahydropyran-2-yl]methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.4% With pyridinium p-toluenesulfonate at 80℃; for 18h; 40 1-O-(5-Hydroxy-3-oxapentyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7b) Example 40 1-O-(5-Hydroxy-3-oxapentyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7b) A mixture of compound 5 (13.17 g, 40.0 mmol, prepared as disclosed in Fukase, K.; Ueno, A.; Fukase, Y; et al., Bull. Chem. Soc. Japan 2003, 76, 485-500), anhydrous diethyleneglycol (42.5 g, 0.4 mol), and pyridiniump-toluenesulfonate (9.05 g, 36.0 mmol) was heated at 80° C. for 18 h, then distributed between DCM (300 mL) and a 1:1 mixture of brine and 5% aqueous NaHCO3 (100 mL). The organic phase was separated, dried over Na2SO4, and evaporated in vacuo. The product was isolated by column chromatography on silica gel eluted with a step gradient from DCM to a mixture of MeOH and DCM (8:92). Evaporation of the relevant fractions gave the title compound as an off-white solid (7.92 g, 45.4%). 1H NMR (CD3CN): δ 6.572 (1H, d, J=9.5 Hz); 5.278 (1H, d, J=3 Hz); 5.010 (1H, dd, J=11.5 Hz, J=3 Hz); 4.673 (1H, d, J=8.5 Hz); 4.109 (1H, dd, J=9 Hz, J=7 Hz); 4.066 (1H, dd, J=9 Hz, J=6 Hz); 3.951 (2H, m); 3.828 (1H, m); 3.703 (1H, m); 3.64-3.54 (4H, m); 3.54-3.45 (2H, m); 3.053 (1H, br. s); 2.098 (3H, s) 1.988 (3H, s); 1.910 (3H, s), 1.845 (3H, s). ES MS: 436.1 (MH+). Calculated for C18H29NO11.H+: 436.2.
  • 73
  • [ 10378-06-0 ]
  • [ 112-27-6 ]
  • [(2R,3R,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]tetrahydropyran-2-yl]methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48.4% With pyridinium p-toluenesulfonate at 80℃; for 18h; 48 1-O-(8-Hydroxy-3,6-dioxaoctyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7c) Example 48 1-O-(8-Hydroxy-3,6-dioxaoctyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7c) A mixture of compound 5 (3.29 g, 10.0 mmol), anhydrous triethyleneglycol (12.0 g, 80 mmol), and pyridiniump-toluenesulfonate (2.26 g, 9.0 mmol) was heated at 80° C. for 18 h, then distributed between DCM (70 mL) and a 1:1 mixture of brine and 5% aqueous NaHCO3 (100 mL). The organic phase was separated, dried over Na2SO4, and evaporated in vacuo. The product was isolated by column chromatography on silica gel eluted with a step gradient from DCM to a mixture of MeOH and DCM (8:92). Evaporation of the relevant fractions gave the title compound as an off-white solid (2.32 g, 48.4%). ES MS: 480.2 (MH+). Calculated for C18H29NO11.H+: 480.2.
  • 74
  • [ 112-60-7 ]
  • [ 10378-06-0 ]
  • [(2R,3R,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]tetrahydropyran-2-yl]methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42.7% With pyridinium p-toluenesulfonate at 80℃; for 18h; 56 1-O-(11-Hydroxy-3,6,9-trioxaundecyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7d) Example 56 1-O-(11-Hydroxy-3,6,9-trioxaundecyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7d) A mixture of compound 5 (7.25 g, 22.0 mmol), anhydrous tetraethyleneglycol (34.2 g, 176 mmol), and pyridiniump-toluenesulfonate (4.98 g, 19.8 mmol) was heated at 80° C. for 18 h, then distributed between DCM (50 mL) and a 1:1 mixture of brine and 5% aqueous NaHCO3 (100 mL). The organic phase was separated, dried over Na2SO4, and evaporated in vacuo. The product was isolated by column chromatography on silica gel eluted with a step gradient from DCM to a mixture of MeOH and DCM (8:92). Evaporation of the relevant fractions gave the title compound as an off-white solid (4.92 g, 42.7%). ES MS: 524.4 (MH+). Calculated for C18H29NO11H+: 524.2.
  • 75
  • [ 4792-15-8 ]
  • [ 10378-06-0 ]
  • [(2R,3R,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]tetrahydropyran-2-yl]methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
38.1% With pyridinium p-toluenesulfonate at 80℃; for 18h; 69 1-O-(14-Hydroxy-3,6,9,12-tetraoxatetradecyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7e) Example 69 1-O-(14-Hydroxy-3,6,9,12-tetraoxatetradecyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7e) A mixture of compound 5 (1.64 g, 5.0 mmol), anhydrous pentaethyleneglycol (7.15 g, 30.0 mol), and pyridinium p-toluenesulfonate (1.13 g, 4.5 mmol) was heated at 80° C. for 18 h, then distributed between DCM (50 mL) and a 1:1 mixture of brine and 5% aqueous NaHCO3 (25 mL). The organic phase was separated, dried over Na2SO4, and evaporated in vacuo. The product was isolated by column chromatography on silica gel eluted with a step gradient from DCM to a mixture of MeOH and DCM (8:92). Evaporation of the relevant fractions gave the title compound as an off-white solid (1.08 g, 38.1%). ES MS: 568.0 (MK). Calculated for C18H29NO11.H+: 568.2.
  • 79
  • [ 10378-06-0 ]
  • [ 147526-49-6 ]
  • C36H51NO12Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With camphor-10-sulfonic acid at 70 - 75℃; for 18h; 1.7 Step 7 To a mixture of 1 (app 7.4g, 20.6mmol) and TBDPS triethyleneglycol (6.68g, 17.2mmol) in DCE (130mL), camphor-sulfonic acid (CSA, 0.40, 1 .72mmol) was added and the reaction mixture was stirred at 70-75 °C for 18 h. NEt3 (0.48 mL) was added to the reaction mixture at room temperature, then diluted with DCM (80 mL), extracted with sat. NaHC03 (2x1 00 mL), water (100 ml), brine (100 mL), dried over Na2S04 and evaporated. Residues were purified by chromatography (eluent EtOAc in hexanes from 66% to 80%). 2 was isolated as slightly yellow oil 8.90 g, 1 H-NMR, MS [M+1 ]+ 718, HPLC purity 95 %, yield 69 %,
  • 80
  • [ 138499-16-8 ]
  • [ 10378-06-0 ]
  • C32H43NO10Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.59 g With camphor-10-sulfonic acid In 1,2-dichloro-ethane at 70 - 75℃; for 4h; 1.3 Step 3 1 (1 .40g, 4.17mmol) and TBDPS glycol (1 .08g, 1 .60mmol) was dissolved in 20mL DCE. Camphor-sulfonic acid (CSA) (84mg, 0.36mmol) was added and the reaction mixture was stirred at 70-75°C for 2 hours. Additional CSA (84mg, 0.36mmol) was added and the reaction mixture was stirred at 70-75°C for additional 2 hours. NEt3 (80 μΙ_) was added to the reaction mixture at room temperature and then it was diluted with DCM (20ml_). The mixture was washed with sat. NaHC03 (100 mL), water (100 ml), brine (50 mL), and the organic phase was dried over Na2S04 and evaporated. The resulting residue was purified by column chromatography (eluent: EtOAc in hexanes from 30% to 50%). The product was isolated as a white foam (1 .59g, yield 70%), 1 H-NMR and MS, HPLC 99 %
  • 81
  • [ 134848-96-7 ]
  • [ 10378-06-0 ]
  • [ 41355-94-6 ]
  • 4-benzyloxycarbonylbutyl-2-deoxy-2-N-acetyl-3,4,6-tri-O-acetyl-β-D-galactopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
13.52 g With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 24.5h; Molecular sieve; Inert atmosphere; 8.c Synthesis of G2 The 5-hydroxpentanoic acid benzyl ester D2 (12.44 g, 59.73 mmol, 1.75 equivalents) was dissolved in 1,2-dichloroethane (80 mL, Aldrich anhydrous), and this solution was added to the crude GalNAc derivative (Gl') (11.24 g, 34.13 mmol, 1.00 equivalents). Once this solution was homogeneous, to it was added dried 3 Å molecular sieves (10.5 g, beads). The mixture was stirred at room temperature under N2 for 30 minutes. TMSOTf (3.2 mL, 18 mmol, 0.52 equivalents) was added via syringe. The mixture was stirred at room temperature under N2 overnight. The reaction was monitored by MS (CI POS), and TLC (silica gel, 100% EtOAc, stained with PMA or H2SO4/MeOH). MS POS: 638.3 (15), 538.2 (100), 438.2 (10), 330.1 (40). After 24 hours at room temperature, the reaction was worked up. The amber solution was poured into a separately funnel containing 100 mL of saturated aqueous NaHCO3, and the flask and sieves were rinsed with 80 mL of DCM, which was also added to the separately funnel. The phases were separated, and the aqueous phase was extracted withl x 80 mL DCM. The combined organic phases were washed with H20 (100 mL) and saturated aqueous NaCl (100 mL). The amber organic phase was dried (Na2SO4), filtered (paper), and evaporated to give a viscous, amber liquid: 26.54 g (145%). The crude sample was purified directly by FC on silica gel (ISCO): 330-g column, compound injected onto the equilibrated column and rinsed with 8 mL DCM; eluted with 0% - 100% EtOAc/Hexanes, UV 254 nm, 280 nm. The desired fractions were combined and evaporated to give an almost colorless, viscous liquid: 13.52 g (74%). This material was contaminated by a small amount of GalNAc-OBn (M+l = 438) and minor amounts of "dimer" and "trimer" (homologs of pentanoic acid) derivatives (M+l = 738 and 638).
  • 82
  • [ 10378-06-0 ]
  • (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((5-((2,5-dioxopyrrolidin-1-yl)oxy)-5-oxopentyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 24.5 h / 20 °C / Molecular sieve; Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / methanol / 18 h / 20 °C / 2482.38 Torr 3: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / 20 °C
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.5 h / Molecular sieve 1.2: 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate 3.1: 4-dimethylaminopyridine; diisopropyl-carbodiimide / dichloromethane / 3 h / 20 °C
Multi-step reaction with 3 steps 1: dichloromethane / Molecular sieve 2: ruthenium(III) trichloride monohydrate; sodium (meta)periodate / dichloromethane; lithium hydroxide monohydrate; acetonitrile 3: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; 4-dimethylaminopyridine / dichloromethane / 20 °C
  • 83
  • [ 86520-52-7 ]
  • [ 10378-06-0 ]
  • (2R,3R,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ No CAS ]
  • [ 153253-46-4 ]
YieldReaction ConditionsOperation in experiment
1: 15% 2: 85% Stage #1: 2-[2-(2-azidoethoxy)ethoxy]ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.333333h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 50℃; for 24h; 13 Synthesis of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate (5α & β) Synthesis of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate (5α & β) (5α & 5β): Compound 2 (150 mg, 0.454 mmol) and alcohol 4 (95.5 mg, 0.545 mmol) was dissolved in 1,2-dichloroethane (3 mL), followed by the addition of 4 A° MS (0.3 g) and reaction mixture stirred at room temperature for 20 minutes under N2. TMSOTf (50.5 mg, 0.227 mmol) was then added via syringe and mixture stirred at 50° C. for 24 hours, followed by cooling to room temperature and quenching with Et3N (0.4 mL, pH 7.5). The reaction mixture was extracted twice with DCM (60 mL) and saturated NaHCO3 solution (20 mL), and organic layer washed with water, brine and dried over Na2SO4. Solvents were evaporated under reduced pressure and the residue purified by silica gel column chromatography using DCM:MeOH (9.5:0.5) as an eluent to obtain compound 5α (40 mg, 15% yield) as the first eluted. 5α 1H NMR (400 MHz, CDCl3): δ 1.97 (s, 3H, CH3, OAc), 1.98 (s, 3H, CH3, OAc), 2.03 (s, 3H, CH3, OAc), 2.14 (s, 3H, CH3, OAc), 3.46 (t, 2H, J=5.2 Hz, Ha), 3.62-3.76 (m, 8H, Hb,c,d,e), 3.81-3.92 (m, 2H, Hf), 4.09-4.25 (m, 3H, H5, H6), 4.76 (d, 1H, J=8.5 Hz, H3); 5.04 (dd, 1H, J=3.0, 11.0 Hz, H4), 5.29-5.31 (m, 2H, H2, H6), 6.18 (d, 1H, J=4.6 Hz, H1); EI-MS: [M+Na]+ C20H32N4NaO11 calcd 527.20, obsd 520.19. Second eluted was 5β: (1.15 g, 85% yield). 5β 1H NMR (500 MHz, CDCl3): δ 1.98 (s, 3H, CH3, OAc), 2.04 (s, 3H, CH3, OAc), 2.06 (s, 3H, CH3, OAc), 2.13 (s, 3H, CH3, OAc), 3.38 (t, 2H, J=5.0 Hz, Ha), 3.61-3.67 (m, 8H, Hb,c,d,e), 3.75-3.82 (m, 1H, Hf), 4.18-4.22 (m, 2H, Hf, H6), 4.32-4.38 (m, 2H, H2, H6'), 4.75 (dd, 1H, J=2.5 & 5.5 Hz, H3); 5.0 (s, 1H, H4), 5.34 (m, 1H, H5), 6.06 (d, 1H, J=8.0 Hz, H1), 4.52 (dd, 1H, J=1.5 & 5.5 Hz, H2), 5.00 (m, 1H, H5), 5.14 (s, 1H, H4), 6.12 (d, 1H, J=6.5 Hz, H1); 5β 13C NMR (125 MHz, CDCl3): δ 20.9 (OAc, CH3), 21.12 (2 OAc, CH3), 23.39 (OAc, CH3), 50.87 Ca), 60.54 (C2), 62.87 (C6), 67.21 (Cf), 70.13 (Cb), 70.23 (Cc), 70.55 (Cd), 70.88 (Ce), 70.91 (C5), 78.03 (C3), 80.04 (C4), 106.90 (C1), 169.72, 170.25, 170.77, 170.82 (4OAc, CO). EI-MS: [M+Na]+ C20H32N4NaO11 calcd 527.20, obsd 520.19.
  • 84
  • [ 86770-67-4 ]
  • [ 10378-06-0 ]
  • [ 879004-91-8 ]
YieldReaction ConditionsOperation in experiment
85% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 5℃; 2; 1.5 (2.65 g, 15.2 mmol) were azeotroped (3x) from toluene (150 mL) to remove traces of water. The dried material was dissolved in 1 ,2-dichloroethane (150 mL), cooled (~5°C) and treated with TMSOTf (784 μ, 4.34 mmol). After stirring overnight the reaction was quenched by the addition of triethylamine (5 mL) and concentrated. The residue was purified by chromatography (1%→ 5% MeOH-CH2Cl2) to afford 8 (7.12 g, 85%) as a brown oil. Rf (0.3, 10% MeOH- CH2C12).
85% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 5℃; 1.5 Step 5. Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-(2- azidoethoxy)ethoxy)ethox ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate 8 Compound 7 (7.2 g, 21.7 mmol) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-l-ol 4 (2.65 g, 15.2 mmol) were azeotroped (3x) from toluene (150 mL) to remove traces of water. The dried material was dissolved in 1,2-dichloroethane (150 mL), cooled (~5°C) and treated with TMSOTf (784 μL, 4.34 mmol). After stirring overnight the reaction was quenched by the addition of triethylamine (5 mL) and concentrated. The residue was purified by chromatography (1%→ 5% MeOH-CH2Cl2) to afford 8 (7.12 g, 85%) as a brown oil. Rf (0.3, 10% MeOH-CH2Cl2).
85% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 5℃; 1.5 Step 5. Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate 8 Compound 7 (7.2 g, 21.7 mmol) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-l-ol 4 (2.65 g, 15.2 mmol) were azeotroped (3x) from toluene (150 mL) to remove traces of water. The dried material was dissolved in 1,2-dichloroethane (150 mL), cooled (~5°C) and treated with TMSOTf (784 μ, 4.34 mmol). After stirring overnight the reaction was quenched by the addition of triethylamine (5 mL) and concentrated. The residue was purified by chromatography (1%→ 5% MeOH-CH2Cl2) to afford 8 (7.12 g, 85%) as a brown oil. Rf (0.3, 10% MeOH- CH2C12).
85% With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane; toluene at 5℃; 1.5 Step 5. Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate 8 Compound 7 (7.2 g, 21.7 mmol) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-ol 4 (2.65 g, 15.2 mmol) were azeotroped (3x) from toluene (150 mL) to remove traces of water. The dried material was dissolved in 1,2-dichloroethane (150 mL), cooled (~5°C) and treated with TMSOTf (784 mL, 4.34 mmol). After stirring overnight the reaction was quenched by the addition of triethylamine (5 mL) and concentrated. The residue was purified by chromatography (1% 5% MeOH-CH2Cl2) to afford 8 (7.12 g, 85%) as a brown oil. Rf (0.3, 10% MeOH-CH2Cl2).
70% Stage #1: 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester In 1,2-dichloro-ethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 45℃; Molecular sieve; 1 Synthesis of [4] See, e.g., Guo, et. al. Bioconjug. Chem. 2006, 17, 1537-1544; Manoharan, et.al. J. Am. Chem. Soc. 2014, 136, 16958-16961. Compound 3 (9.0 g, 27.3 mol) was co-evaporated with 1,2- dichloroethane (3 x 50 mL) and then re-dissolved in to the same solvent (250 mL). Reaction mixture was then stirred with 4A molecular sieves (2 g) for 5 min at room temperature. Azido-dPEG4-OH (6.59 g, 30.1 mmol) was added and stirring was continued for 30 min. TMS-triflate (2.5 mL, 13.7 mmol) was added drop-wise under constant stirring over 10 min. Stirring was continued over night at 45°C followed by quenching with saturated NaHC03 solution (100 mL). The organic layer was separated, diluted with dichloromethane 200 mL, and washed with water (2 x 100 mL) and brine (2 x 100 mL) solution. Linally, the organic layer was dried over anhydrous Na2S04, and evaporated to dryness under reduced pressure. The crude product was purified via column chromatography (1-2 % methanol in dichloromethane). Pure product 4 (10.5 g, 70%) was isolated as light yellow oil and characterized based on Mass and 'HNMR analysis. Results: ESI-MS analysis: Calculated C22H36N4O12. Na+, [M+Na+] = 571.22, Observed = 571.20.

  • 85
  • [ 86770-67-4 ]
  • [ 10378-06-0 ]
  • 2-(2-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-aminium 2,2,2-trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 5 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 5 °C 2: hydrogen; palladium 10% on activated carbon / ethyl acetate
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 5 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate
Same Skeleton Products
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