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CAS No. : | 3006-60-8 | MDL No. : | MFCD00214297 |
Formula : | C16H23NO10 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OVPIZHVSWNOZMN-IBEHDNSVSA-N |
M.W : | 389.36 | Pubchem ID : | 6547253 |
Synonyms : |
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.69 |
Num. rotatable bonds : | 11 |
Num. H-bond acceptors : | 10.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 86.14 |
TPSA : | 143.53 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.64 cm/s |
Log Po/w (iLOGP) : | 2.71 |
Log Po/w (XLOGP3) : | 0.05 |
Log Po/w (WLOGP) : | -0.79 |
Log Po/w (MLOGP) : | -1.01 |
Log Po/w (SILICOS-IT) : | -0.29 |
Consensus Log Po/w : | 0.13 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 2.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.56 |
Solubility : | 10.7 mg/ml ; 0.0276 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.62 |
Solubility : | 0.94 mg/ml ; 0.00241 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.89 |
Solubility : | 50.6 mg/ml ; 0.13 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.64 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride; acetic anhydride In diethyl ether at 3℃; for 72h; | |
87% | With acetyl chloride | |
With chloroform; titanium tetrachloride |
With hydrogenchloride In acetic anhydride; acetic acid for 4h; | ||
With thionyl chloride; acetic acid In dichloromethane for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With trimethylsilyl bromide In dichloromethane at 0 - 20℃; Inert atmosphere; | 1 Preparation of 1 -bromo 2-deoxy-2-acetamido 3,4, 6-tri-O-acetyl-f3-D-galactopyranoside (NAG22) To a D-galactosamine pentaacetate (NAG2, 10.0 g, 1 eq, 25.8 mmol) suspension in DCM (90 mL) at 000 in an ice bath under an argon balloon was added bromotrimethylsilane (4.1 mL, 1 .2 eq, 31 mmol) dropwise with stirring. Ice bath was removed after 10 minutes and the reaction was allowed to stir at room temperature overnight. Reaction was checked by TLC (Hanessians Stain) in 75% hexanes:ethyl acetate. Reaction was concentrated in vacuo, azeotroped with cyclohexane (3x50 mL). Dried on high vacuum overnight and used as is. |
With hydrogen bromide; acetic acid | ||
With trimethylsilyl bromide In dichloromethane at 0 - 20℃; Inert atmosphere; | Preparation of 1-bromo 2-deoxy-2-acetamido 3,4,6-tri-0-acetyl^-D-galactopyranoside (NAG22) Preparation of 1-bromo 2-deoxy-2-acetamido 3,4,6-tri-0-acetyl^-D-galactopyranoside (NAG22)To a D-galactosamine pentaacetate (NAG2, 10.0 g, 1 eq, 25.8 mmol) suspension in DCM (90 ml) at 0°C in an ice bath under an argon balloon was added bromotrimethylsilane (4.1 ml, 1 .2 eq, 31 mmol) dropwise with stirring. Ice bath was removed after 10 minutes, and the reaction was allowed to stir at room temperature overnight. The reaction progress was checked by TLC (Hanessian's stain) in 75% hexanes:ethyl acetate. The reaction mixture was concentrated in vacuo, azeotroped with cyclohexane (3x50 m L), dried under high vacuum overnight, and the resulting product was used as is. |
With trimethylsilyl bromide In dichloromethane at 0 - 20℃; Cooling with ice; Inert atmosphere; | Preparation of 1 -bromo-2-deoxy-2-acetamido-3, 4, 6-tri-O-acetyl-13-D-galactopyranoside (NAG22). To a D-galactosamine pentaacetate (NAG2, 10.0 g, 1 equiv., 25.8 mmol) suspension in DCM (90 ml) at0°C in an ice bath under an argon balloon was added bromotrimethylsilane (4.1 mL, 1 .2 equiv., 31 mmol) drop wise with stirring. Ice bath was removed after 10 minutes, and the reaction was allowed to stir at room temperature overnight. The reaction progress was monitored by TLC (Hanessian’s Stain) using 75% hexanes/ethyl acetate mobile phase. The reaction mixture was concentrated in vacuo, azeotroped with cyclohexane (3x50 mL), dried under high vacuum overnight, and used as is. | |
With trimethylsilyl bromide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; zinc(II) chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.3 g | With pyridine; at 0 - 20℃; | <strong>[66-84-2]2-amino-2-deoxyglucose hydrochloride</strong> (2.2g, 10.2mmol)Suspended in pyridine (10 mL),Cool to 0 C, add acetic anhydride (9.4mL, 99.6mmol),After stirring at room temperature overnight, ethyl acetate (100 mL) was added.Wash with 5% dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution,Washed with saturated brine,Dried over anhydrous sodium sulfate,Rotate under reduced pressure to concentrate,The residue was recrystallized from dichloromethane / diethyl ether to obtain 3.3 g of a white solid product. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc(II) chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With Lawessons reagent In toluene at 80℃; for 1.5h; | |
With Lawessons reagent In toluene at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine at 0℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine at 20℃; for 0.216667h; sonication; | |
93% | With pyridine at 0℃; Inert atmosphere; | Preparation of D-galactosamine pentaacetate (NAG2) Preparation of D-galactosamine pentaacetate (NAG2)_: D-Galactosamine (25.0 g, 1 16 mmol) was suspended in anhydrous pyridine (250 m L) and cooled to 0 °C under an inert atmosphere. Acetic anhydride (120 mL, 1 160 mmol) was added over the course of 2 h. After stirring overnight, the reaction mixture was concentrated in vacuo. Upon addition of methanol, a white solid precipitated and was collected by filtration to provide the desired product (42.1 g, 93% yield). 1 H NMR (CDCI3, 500 MHz) : δ 5.69 (d, 1 H, J 9.0 Hz), 5.40 (m , 1 H), 5.37 (d, 1 H, J 3.0 Hz), 5.08 (dd, 1 H, J 3.0 Hz, 1 1 Hz), 4.44 (dt, 1 H, J 9.5 Hz, 1 1 Hz), 4.17 (dd, 1 H, J 7.0 Hz, 1 1 .5 Hz) , 4.1 1 (dd, 1 H, , J 7.0 Hz, 1 1 .5 Hz), 4.01 (t, 1 H, J 7.0 Hz), 2.17 (s, 3H), 2.13 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1 .94 (s, 3H), 1 .57 (s, 3H). |
91% | With sodium acetate at 140℃; for 3h; |
86% | With pyridine; dmap; triethylamine at 20℃; Cooling with ice; | 1 Compound 2: Dissolve 2.15 g (10.0 mmol) of compound 1 salt (D-(+)-galactosamine hydrochloride) in 20 mL of anhydrous pyridine, add 1 mL of anhydrous triethylamine and 122 mg (1.00 mmol) of DMAP respectively Add 5.67 mL (60.0 mmol) of acetic anhydride dropwise under ice water, warm to room temperature after dripping, and stir overnight. The white solid was filtered, washed with 10 mL of toluene, 50 mL of water, and dried to obtain 3.35 g of white solid compound 2 (yield 86%). |
86% | With pyridine; dmap; triethylamine at 20℃; Cooling with ice; | 1 Compound 2: Dissolve 2.15 g (10.0 mmol) of compound 1 salt, D-(+)-galactosamine hydrochloride in 20 mL of anhydrous pyridine, add 1 mL of anhydrous triethylamine and 122 mg (1.00 mmol) DMAP respectively, 5.67 mL (60.0 mmol) of acetic anhydride was added dropwise under ice water. After the dripping, the temperature was raised to room temperature and stirred overnight. The white solid was filtered, washed with 10 mL of toluene, 50 mL of water, and dried to obtain 3.35 g of white solid compound 2 (yield 86%). |
82% | With pyridine for 48h; | |
75% | With pyridine at 0 - 20℃; | |
75% | With pyridine; dmap at 0 - 20℃; | 1.10. 3-Acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyltriacetate, 10’. Glucosamine hydrochloride (10 g, 46.40 mmol ) and DMAP (230 mg, 1.9 mmol) were dissolved in Py (100mL). Acetic anhydride (44 mL, 463.8 mmol) was added to the reaction at 0°C. The mixture was stirred at room tempreture overnight. The resulting solution was poured into 400 mL cold water. Then the mixture was stirred for 30 min, and white solid was precipitated. After filtration and dryness, 10’ (13.47 g, 75%) was obtained as white solid. 1H NMR(CDCl3, 400 MHz): δ 5.70 (d, J = 8.8 Hz, 1H, H-1), 5.38-5.35 (m, 2H, H-4, NH), 5.08 (dd, J = 11.6, 3.6 Hz, 1H, H-3), 4.49-4.41(m, 1H, H-2), 4.20-4.09 (m, 2H, H-6a,b), 4.02 (t, J = 6.4 Hz, 1H, H-5), 2.17 (s, 3H, CH3-OAc),2.13 (s, 3H, CH3-OAc), 2.05 (s, 3H, CH3-OAc),2.02 (s, 3H,CH3-OAc), 1.94 (s, 3H, CH3-NHAc); 13C NMR(CDCl3,100 MHz) δ 170.87 (CO- NHAc), 170.54(CO-OAc), 170.41 (CO-OAc), 170.31 (CO-OAc), 169.70 (CO-OAc), 93.17 (C-1),71.99, 70.46, 66.50, 61.46 (C-6), 49.97 (C-2), 23.46 (CH3-NHAc),21.04 (CH3-OAc), 20.82 (CH3-OAc), 20.79 (CH3-OAc).ESI-HRMS m/z: 390.1400 (M + H)+,412.1198 [M+Na]+. Calcd. C16H24NO10 390.1400,C16H23NNaO10 412.1220. |
With pyridine at 5 - 20℃; Inert atmosphere; | 1 Acetylation of galactosamine hydrochlorideTo a- 3 -necked, 12 L flask fitted with N2 inlet, temperature probe, and addition funnel was added 1 (452 g, 2.10 mol) and pyridine (2035 ml 25.2 mol), and the~mixture was cooled witlran ice bath. Acetic anhydride- (1781 ml, 18.9 mol) was added s-iowly over 30 min maintaining the temperature below 5°C. After stirred overnight (17 hr) at-RT, the mixture was cooled with an ice bath and slowly added water (5.0 L) maintaining- the temperature below 2°C. After aging for Thr in the ice bath, the mixture was filtered to collect solid which was washed with water (10 L). The white solid thus obtained was dried in a -vacuum oven with N2.sweep until the water level was below 500 ppm. (674 g, 1730 mmol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With hydrogenchloride; acetic anhydride In diethyl ether at 3℃; for 72h; Stage #2: With water In diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tin(IV) chloride In dichloromethane at 20℃; for 168h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 28 percent / SnCl4 / CH2Cl2 / 168 h / 20 °C 2: 88 percent / NaOH / methanol / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 100 percent / 2,4-(4-MeOC6H4)2-1,3-dithia-2,4-diphosphetane-2,4-disulfide / toluene / 1.5 h / 80 °C 2: 100 percent / trifluoroacetic acid / methanol; H2O | ||
With Lawessons reagent In toluene for 2.5h; Reflux; | ||
Multi-step reaction with 2 steps 1: Lawessons reagent / toluene / 80 °C 2: trifluoroacetic acid / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 100 percent / 2,4-(4-MeOC6H4)2-1,3-dithia-2,4-diphosphetane-2,4-disulfide / toluene / 1.5 h / 80 °C 2: 100 percent / trifluoroacetic acid / methanol; H2O 3: 92 percent / azobis(isobutyronitrile) / CHCl3 / 1 h / Heating | ||
Multi-step reaction with 3 steps 1: Lawessons reagent / toluene / 80 °C 2: trifluoroacetic acid / methanol 3: 2,2'-azobis(isobutyronitrile) / chloroform | ||
Multi-step reaction with 3 steps 1: Lawessons reagent / toluene / 80 °C 2: trifluoroacetic acid / methanol 3: 2,2'-azobis(isobutyronitrile) / chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.04 g (92%) | In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; chloroform; acetone; | 1-S-Acetyl-2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranose (11). After a mixture of <strong>[7512-17-6]2-acetamido-2-deoxy-D-glucose</strong> 10 (2.0 g, 9.04 mmol) and acetyl chloride (3 mL) was stirred overnight, 30 mL of chloroform was added, and the solution was poured into 20 mL of ice water. The mixture was rapidly shaken, the organic layer was run into saturated sodium bicarbonate solution containing cracked ice, and the mixture was stirred at first, then shaken until the acid was neutralized. The chloroform layer was separated and dried over anhydrous Na2SO4. The solution was concentrated in vacuo to afford 2.88 g of a yellow solid, which was used in the next step without purification. A mixture of the above crude product (2.0 g, 5.46 mmol), potassium thioacetate (0.624 g, 5.5 mmol), and dry acetone (20 mL) was shaken for 6 hours. The solution was filtered to remove inorganic material, and the combined filtrate and chloroform washings were concentrated. The residue was purified by chromatography on silica gel (elution with 5% EtOH/CHCl3) to afford 2.04 g (92%) of product 11. 1H NMR (300 MHz, CDCl3):delta6.01(d, J=9.9 Hz, 1H, NH), 5.18-5.06 (m, 3H), 5.35 (q, 1H), 4.23 (dd, J=4.4, 12.5 Hz, 1H), 4.05 (dd, J=2.2, 12.4 Hz, 1H), 3.77 (m, 1H), 2.35 (s, 3H, SAc), 2.05 (s, 3H, OAc), 2.02 (s, 6H, OAc), 1.90 (s, 3H, NAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine | |
94% | With pyridine at 0℃; Inert atmosphere; | 1 Preparation of D-galactosamine pentaacetate (NAG2) D-Galactosamine (25.0 g, 116 mmol) was suspended in anhydrous pyridine (250 mL) and cooled to 0 00 under an inert atmosphere. Acetic anhydride (120 mL, 1160 mmol) was added over the course of 2 h. After stirring overnight, the reaction mixture was concentrated in vacuo. Upon addition of methanol, a white solid precipitated and wascollected via filtration to provide the desired product (42.1 g, 93% yield). 1H NMR (ODd3, 500 MHz): O5.69 (d, 1H, J9.0 Hz), 5.40 (m, 1H), 5.37 (d, 1H, J3.0 Hz), 5.08 (dd, 1H, J3.0 Hz, 11 Hz), 4.44(dt, 1H, J9.5 Hz, 11 Hz), 4.17 (dd, 1H, J7.0 Hz, 11.5 Hz), 4.11 (dd, 1H, , J7.0 Hz, 11.5 Hz), 4.01 (t, 1H, J7.0 Hz),2.17 (s, 3H), 2.13 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H), 1.57 (s, 3H). |
89% | With pyridine |
82% | With pyridine at 20℃; | 2-Acetamido-1,3,4,6-tetra-O-acetyl-β-D-Galactopyranoside (5) D-(+)-Galactosaminehydrochloride (2.00 g, 9.28 mmol) was dissolved in anhydrous pyridine (20 mL), andacetic anhydride (10.5 mL, 111.3 mmol, 12 eq) was added. The reaction mixture wasstirred at room temperature until disappearance of starting material, and poured in abeaker with ice-cold water (200 mL). A white solid precipitated was collected by vacuumfiltration, washed with ice-cold water and co-evaporated with toluene (3×20 mL) toremove residual water to yield 5 (2.96 g, 82%) as a powdery solid: 1H NMR (300 MHz,CDCl3) δ 5.73 (d, J = 8.8 Hz, 1 H), 5.46 (d, J = 9.5 Hz, 1 H), 5.40 (d, J = 2.8 Hz, 1 H),5.12 (dd, J = 3.3, 11.3 Hz, 1 H), 4.52-4.43 (m, 1 H), 4.24-4.11 (m, 2 H), 4.07-4.02 (m, 1H), 2.20 (s, 3 H), 2.16 (s, 3 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 1.97 (s, 3 H). |
82% | With pyridine | 2; 1.3 Step 3. Preparation of peracetylated galactosamine 6 D-Galactosamine hydrochloride 5 (250 g, 1.16 mol) in pyridine (1.5 L) was treated with acetic anhydride (1.25 L, 13.2 mol) over 45 minutes. After stirring overnight the reaction mixture was divided into three 1 L portions. Each 1 L portion was poured into 3 L of ice water and mixed for one hour. After mixing the solids were filtered off, combined, frozen over liquid nitrogen and then lyophilized for five days to yield peracetylated galactosamine 6 (369.4 g, 82%) as a white solid. Rf (0.58, 10% MeOH-CH2Cl2). |
82% | With pyridine | 1.3 Step 3. Preparation of peracetylated galactosamine 6 D-Galactosamine hydrochloride 5 (250 g, 1.16 mol) in pyridine (1.5 L) was treated with acetic anhydride (1.25 L, 13.2 mol) over 45 minutes. After stirring overnight the reaction mixture was divided into three 1 L portions. Each 1 L portion was poured into 3 L of ice water and mixed for one hour. After mixing the solids were filtered off, combined, frozen over liquid nitrogen and then lyophilized for five days to yield peracetylated galactosamine 6 (369.4 g, 82%) as a white solid. Rf (0.58, 10% MeOH-CH2Cl2). |
82% | With pyridine | 1.3; 25; 26 Step 3. Preparation of peracetylated galactosamine 6 D-Galactosamine hydrochloride 5 (250 g, 1.16 mol) in pyridine (1.5 L) was treated with acetic anhydride (1.25 L, 13.2 mol) over 45 minutes. After stirring overnight the reaction mixture was divided into three 1 L portions. Each 1 L portion was poured into 3 L of ice water and mixed for one hour. After mixing the solids were filtered off, combined, frozen over liquid nitrogen and then lyophilized for five days to yield peracetylated galactosamine 6 (369.4 g, 82%) as a white solid. Rf (0.58, 10% MeOH-CH2Cl2). |
80% | In pyridine at 0 - 20℃; for 48h; | 4.4-1 To D-galactosamine hydrochloride salt (5.0 g, 23.2 mmol), pyridine (48 mL) was added and suspended, the suspension was cooled to 0°C, and acetic anhydride (60 mL) was added dropwise thereto. After the 48 hours stirring at room temperature, the reaction solution was cooled to 0°C and poured into distilled water (700 mL). After stirring vigorously at 4°C, thus obtained white precipitate was separated by filtration. The obtained white solid was dried under reduced pressure to obtain Compound (12) (7.2 g, 80% yield) having the structure below. |
76.7% | With pyridine at 20℃; for 16h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With scandium tris(trifluoromethanesulfonate) In dichloromethane for 67h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With scandium tris(trifluoromethanesulfonate) In dichloromethane for 2h; Reflux; | |
82% | With silica-gel-supported sulfuric acid In 1,2-dichloro-ethane at 110℃; for 0.25h; Microwave irradiation; stereoselective reaction; | |
81% | With scandium tris(trifluoromethanesulfonate) In 1,1-dichloroethane at 90℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tin(IV) chloride In dichloromethane Reflux; | |
at 50℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose In dichloromethane for 1h; Molecular sieve; Stage #2: With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; Stage #3: 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol In dichloromethane at 20℃; | 4.4-2 The Compound (12) (3.9 g, 10.0 mmol) was dissolved in methylene chloride (60 mL), then molecular sieves 4Å were added, stirred for 1 hour, and thoroughly dried. Thereafter, the reaction solution was cooled to 0°C, and boron trifluoride diethylether complex (4.3 g, 30.0 mmol) was added dropwise thereto. After the overnight stirring at room temperature, the reaction solution was added with 1-Azido-3.6.9-trioxaundecan-11-ol (4.38 g, 20.0 mmol), and further stirred at room temperature for 48 hours. The reaction solution was cooled to 4°C and poured into 5% aqueous sodium carbonate solution (200 mL). After separating the molecular sieve 4Å by filtration, chloroform was added to isolate the organic layer. The organic layer was washed with brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol = 10/1) to obtain Compound (13) (3.7 g, 66% yield) having the structure below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluorormethanesulfonic acid; In dichloromethane; at 20℃;Inert atmosphere; Reflux; | In a 12 L flask was placed 2 (440 g, 1130 mmol), 4 (297 g, 1243 mmol, LI eq.), and anhydrous DCM (4.4 L, 10 vols) under nitrogen atmosphere. The mixture was added trifluoromethanesulfonic acid (TfOH, 17.3 g, 1 .2 mL, 113 mmol, 0.1 eq.) via a syringe at RT, and then the resulting mixture was warmed to a gentle reflux. After 18 hr, LC showed the reaction was not complete. Additional TfOH (5.1 mL, 0.05 eq.) was introduced via a syringe, and the mixture was refluxed further. After 9 hr, the reflux condenser was replaced with a distillation head, and the mixture was concentrated to about half of the original volume under vacuum-. The resulting DCM- solution was washed successively with aqueous solution of 2CO3 (10 wt%, 780 mL), water (1.0 L), andNaCl solution (20 wt%5 0.75-L), and then dried over anhydrous MgS04. After filtration, the filtrate -was placed" in a 12 L flask, and the solvent was switched to 2-Me-THF by distillation of DCM with addition of 2-Me-THF until the final volume was ca. 2.64 L, and the residual DCM was below 5% judged ?y 1H-NMR. White solid" precipitated slowly during the solvent switch. The resulting slurry was added heptane (Gamma320 mL, 3 vols) slowly over 1 hr maintaining the internal temperature at 35C. After the addition was completed, the -slurry was stirred at the same temperature for 1 hr then allowed to cool to RT slowly. The solid was collected by filtration, washed with 2-Me-THE/heptane (5/3, v/v, 2.0 L, 4.5 vols), and -dried under vacuum with N2 sweep affording 5 as a white microcrystalline solid (514 g, 1130 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: trifluorormethanesulfonic acid / dichloromethane / 20 °C / Inert atmosphere; Reflux 2.1: potassium carbonate; methanol / 7 h / 20 °C / Inert atmosphere 2.2: Amberlyst 15 acidic resin / 0.5 h / 20 °C 3.1: hydrogen / palladium-on-charcoal / 2,2,2-trifluoroethanol / 5 h / 20 °C | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 4 h / 20 °C 3: palladium on activated charcoal; hydrogen / methanol / 24 h / 20 °C / 15001.5 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine; acetic anhydride at 20℃; for 16h; | {Synthesis of GalNAc(OAc)4 (β-N-Acetylgalactosamine per-O-acetate)} {Synthesis of GalNAc(OAc)4 (β-N-Acetylgalactosamine per-O-acetate)} Take D-(+)-Galactosamine hydrochloride [GalN.HCl] (15 g, 69.9 mmol) in a 250 ml round-bottom flask and suspend GalN.HCl in 60 ml anhydrous pyridine and 90 ml, 10.5M acetic anhydride. Stir the solution at room temperature overnight (about 16 hours). Filter the suspension and wash solid with acetic acid and water alternatively. White solid is obtained after being dried. Add 15 ml ether and pump dry to get white solid product GalNAc(OAc)4(20.4 g, 75%). Compound Data Of The Product [0051] IR(neat) vN-H=3230 cm-1, vC═O=1750 cm-1, 1730 cm-1. [0052] 1H-NMR(CDCl3) δ 5.68 (d, 1H, C1-H), 5.38 (s, 1H, NH), 5.36 (dd, 1H, C4-H), 5.06 (dd, 1H, C3-H), 4.43 (dd, 1H, C2-H), 4.15 (dd, 1H, C6-Hb), 4.07 (dd, 1H, C6-Ha), 4.00 (td, 1H, C5-H), 2.15 (s, 3 H, C8-H3), 2.11 (s, 3 H, C14-H3), 2.05 (s, 3H, C12-H3), 2.03 (s, 3H, C10-H3) and 2.00 (s, 3 H, C16-H3). [0053] 13C-NMR(CDCl3): δ 170 (C7, C9, C11 and C13), 169 (C15), 93 (C1), 71 (C5), 70 (C3), 66 (C4), 61 (C6), 49 (C2), 23 (C8) and 20 (C10, C12, C14 and C16). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl trifluoromethanesulfonate In dichloromethane; 1,2-dichloro-ethane; N,N-dimethyl-formamide at 50℃; | {synthesis of Z-G-ah-GalNAc (6-(Benzyloxycarbonyl-glycylamino)hexyl β-N-acetyl-galactosamine)} Put GalNAc(OAc)4 (1.2 g, 3.1 mmol) and Z-G-ah (1.14 g, 3.7 mmol) into a 250 ml round-bottom flask and pump to create vacuum for 2 hours. Add 1, 2-ethylene dichloride (100 ml), dichloromethane (20 ml) and anhydrous N, N-dimethylformamide (DMF, 4 ml) into the solution. Then add trimethylsilyl trifluoromethane sulfonate (TMSOTf, 0.7 ml) to form a brick red solution that is delivered to a drying tube, heated to 50 degrees Celsius and stir the solution overnight. After being cooled down to room temperature, the solution is added with 1 ml triethylamine and is stirred for 5 min. Add 5 g NaHCO3 and 50 ml deionized water into the solution and stir the mixture for 5 min. Then wash with saturated sodium bicarbonate solution (100 ml×4) and ice 1N sodium chloride solution (100 ml) in turn. Next the organic layer is added with dichloromethane, concentrated under reduced pressure, put in a vacuum system and pump overnight. Use 300 ml methanol to wash the residue in batches in a 500 ml round-bottom flask. Then add 0.572 ml, 5.4M NaOMe/MeOH into the solution, cover a glass cap, stir the solution at room temperature for 2 hours. Add certain amount of DOWEX 50W×8 (H+ form) for adjusting pH value of the solution to 6 (detected by litmus paper) and stir the solution at room temperature for 30 min. Concentrate the solution under reduced pressure and vacuum dry at 25° C. Put the concentrated solution in a vacuum system and pump overnight. With an ice bath, add 150 ml dichloromethane into the solution and stir the solution for 30 min. Suction filter by using a ceramic funnel and take the solid. Put the solid in a vacuum system and pump overnight to get light brown solid product Z-G-ah-GalNAc (1.18 g, 75%). | |
With boron trifluoride diethyl etherate | 3 See FIG. 2 for the preparation process. Tri-galactosamine is labeled as product 5. First, perform glycosidation reaction on galactose amine acetylated in advance and 6-(benzyloxycarbonyl glycine amino) hexanol under the catalysis by caBF3OEt2. Next, the acetal protection group of the hydroxyl on galactose amine is removed using sodium methoxide to obtain compound 1. The two-step synthesis yield is 46%. The central configuration of mutarotation and isomerism of the product is confirmed through hydrogen nuclear magnetic resonance spectroscopy, and through the signals on the spectrogram, the chemical offset is at the position of 4.37 ppm, the coupling constant is J1.2=8.4 Hz, it can be confirmed that the configuration of compound 1 is β-type. Perform hydrogenolysis reaction on compound 1 to remove the benzyloxycarbonyl protection group easily to obtain compound 2. Subsequently, compound 2 is introduced, through amine bonds, into the tri-lactose backbone of nitrilotriacetic acid protected by benzyloxycarbonyl amino to obtain compound 4, and the yield is 89%. Next, similarly, Perform hydrogenolysis reaction in the air under the condition of Pd/C and hydrogen balloon to remove the benzyloxycarbonyl protection group to obtain compound 5 whose amine groups are exposed. Its analysis report is as follows: IR (KBr) 3410, 3196, 1654, 1547 cm-1; 1H NMR (D2O, 300 MHz) 4.28 (d, J=8.1 Hz, 3H), 3.81-2.62 (m, 43H), 1.86 (s, 9H), 1.60-1.01 (m, 30H); 13C NMR (D2O, 75 MHz) 175.16, 174.52, 171.01, 101.76, 75.20, 71.17, 70.39, 67.94, 65.30, 61.09, 55.66, 52.60, 42.44, 39.70, 39.56, 28.67, 28.53, 25.84, 24.91, 22.81, 22.42; and ESI-MS (m/z) 671.10 [M+2H]2+ and 1340.69 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C / Molecular sieve; Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 2.2: 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 2.2: 20 °C |
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 3 h / Molecular sieve |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C / Molecular sieve; Inert atmosphere 3: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 12 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2.1: dichloromethane / 0.5 h / Molecular sieve; Inert atmosphere 2.2: 20 °C 3.1: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 12 h / 20 °C |
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 16 h / 20 °C / Molecular sieve 3: hydrogen; palladium on activated charcoal / methanol; ethyl acetate / 3 h | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 12 h / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane 3: palladium 10% on activated carbon; hydrogen / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 - 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve |
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 13.5 h / 20 - 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / Molecular sieve | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere 3: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 8 h | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere 3: hydrogen; 10 wt% Pd(OH)2 on carbon / methanol; ethyl acetate / 8 h | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 14 h / Molecular sieve; Inert atmosphere 3: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol; ethyl acetate / 8 h |
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 13.5 h / 20 - 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / Molecular sieve 3: water; triphenylphosphine / tetrahydrofuran / 36 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 3: triphenylphosphine / tetrahydrofuran; water | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane 3: triphenylphosphine / tetrahydrofuran; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 - 55 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve; Inert atmosphere |
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 - 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 2 h / 55 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C / Inert atmosphere; Molecular sieve | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 2 h / 20 - 55 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C / Inert atmosphere; Molecular sieve | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 3: hydrogen; palladium(0) / methanol | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 3: palladium(0); hydrogen / methanol | ||
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoropmethanesulfonate; hydrogen; palladium on activated charcoal |
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane 3: palladium(0); hydrogen / methanol | ||
Multi-step reaction with 2 steps 1: scandium trifluoromethanesulphonate / 1,2-dichloro-ethane / 3 h / Inert atmosphere; Reflux 2: palladium 10% on activated carbon / ethanol; cyclohexane / 6 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 - 55 °C / Inert atmosphere 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve; Inert atmosphere 3: palladium 10% on activated carbon / ethanol; cyclohexane / 6 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 - 50 °C 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C / Molecular sieve 3: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 23.08 h / 20 - 50 °C / Inert atmosphere 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 24.5 h / 20 °C / Molecular sieve; Inert atmosphere 3: 5%-palladium/activated carbon; hydrogen / methanol / 18 h / 20 °C / 2482.38 Torr | ||
Multi-step reaction with 2 steps 1: scandium trifluoromethanesulphonate / 1,2-dichloro-ethane / 3 h / Inert atmosphere; Reflux 2: palladium 10% on activated carbon / ethanol; cyclohexane / 6 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 2 h / 55 °C / Inert atmosphere 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C / Inert atmosphere; Molecular sieve 3: palladium 10% on activated carbon / ethanol; cyclohexane / 6 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / dichloromethane / 2 h / 20 - 55 °C / Inert atmosphere 2: trimethylsilyl trifluoropmethanesulfonate / dichloromethane / 20 °C / Inert atmosphere; Molecular sieve 3: palladium 10% on activated carbon; cis-cyclohexene / ethanol / 6 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 50 °C 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / dichloromethane / 20 °C 2: trimethylsilyl trifluoropmethanesulfonate / 1,2-dichloro-ethane / 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate / 20 °C | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / dichloromethane / 2 h / 20 - 30 °C / Inert atmosphere 2: trimethylsilyl trifluoropmethanesulfonate / dichloromethane / 2.5 h / 0 - 30 °C / Inert atmosphere 3: sodium (meta)periodate; ruthenium(III) trichloride monohydrate / dichloromethane; acetonitrile; lithium hydroxide monohydrate / 0 - 5 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: trimethylsilyl trifluoropmethanesulfonate / dichloromethane 2: dichloromethane / Molecular sieve 3: ruthenium(III) trichloride monohydrate; sodium (meta)periodate / dichloromethane; lithium hydroxide monohydrate; acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With H2SO4-silica In 1,2-dichloro-ethane at 110℃; for 0.25h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetyl chloride 2: sodium azide; tetrabutylammonium hydrogen sulfate | ||
Multi-step reaction with 2 steps 1: trimethylsilyl bromide / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide; tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 1 h | ||
Multi-step reaction with 2 steps 1: trimethylsilyl bromide / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide; tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 1 h |
Multi-step reaction with 2 steps 1: trimethylsilyl bromide / dichloromethane / 0 - 20 °C / Cooling with ice; Inert atmosphere 2: sodium azide; tetra(n-butyl)ammonium hydrogensulfate / water; dichloromethane / 1 h | ||
Multi-step reaction with 2 steps 1: trimethylsilyl bromide / dichloromethane / 20 °C 2: tetra(n-butyl)ammonium hydrogensulfate; sodium azide / dichloromethane; water / 20 °C | ||
With iron(III) chloride; trimethylsilylazide stereospecific reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: acetyl chloride 2: sodium azide; tetrabutylammonium hydrogen sulfate 3: hydrogen; platinum(IV) oxide | ||
Multi-step reaction with 3 steps 1: trimethylsilyl bromide / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide; tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 1 h 3: hydrogen; palladium on activated charcoal / ethyl acetate / 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1: trimethylsilyl bromide / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide; tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 1 h 3: palladium on activated charcoal; hydrogen / ethyl acetate / 1 h / 20 °C |
Multi-step reaction with 3 steps 1: trimethylsilyl bromide / dichloromethane / 0 - 20 °C / Cooling with ice; Inert atmosphere 2: sodium azide; tetra(n-butyl)ammonium hydrogensulfate / water; dichloromethane / 1 h 3: palladium 10% on activated carbon; hydrogen / ethyl acetate / 20 °C | ||
Multi-step reaction with 3 steps 1: trimethylsilyl bromide / dichloromethane / 20 °C 2: tetra(n-butyl)ammonium hydrogensulfate; sodium azide / dichloromethane; water / 20 °C 3: palladium on activated charcoal; hydrogen / ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.70 g | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose In dichloromethane at 25℃; for 0.166667h; Stage #2: 2-(2-isothiocyano-ethoxy)-ethanol With iron(III) chloride In dichloromethane at 25℃; for 24h; | 1-O-(5-Isothiocyanato-3-oxopentyl)-2,3,4,6-tetra-O-acetyl-β-D-galactosaminopyranoside (3) 0.94 g of 1,3,4,6-penta-O-acetyl-β-D-N-acetyl-galactaminopyranoside (2.4 mmol) was dissolved in 15 mL of methylene chloride, 1.4 g of dririte was added, the slurry stirred for 10 min and 1.4 g of FeCl3 (10.2mmol) and 0.83 g of 2-(2-isothiocyantoethoxy)ethanol (5.7 mmol) were added. The reaction was stirred 24 h, then 1 g of NaHCO3 was added. The mixture was filtered over celite and solvent was removed in vacuo. The residue was purified via column chromatography with a 9:1 ethyl acetate-hexane eluant (Rf 0.4), yielding 0.70 grams of pure material. 1H-NMR (500 MHz DMSO-d6) δ 7.83 (1H, d,J = 9.2 Hz, NHAc), 5.21 (1H, d, J = 3.0 Hz, H4), 4.97 (1H, dd, J = 3.0, 11.2 Hz, H3), 4.55 (1H, d,J = 9.5 Hz, H1), 4.02 (3H, m, H5, OCH2CH2O), 3.87 (1H, app q, J = 9.2 (NHAc), 9.5, 11.2 Hz, H2),3.80 (2H, t, J = 4.9 Hz, OCH2CH2NCS), 3.59 (6H, m, H6, CH2CH2OCH2CH2), 2.11 (3H, s), 2.04 (3H, s),1.89 (3H, s), 1.78 (3H, s) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 % de | Stage #1: isopropyl alcohol; 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose at 65℃; for 1h; Stage #2: acetic anhydride With pyridine at 20℃; for 48h; Overall yield = 57 %; Overall yield = 28.6 mg; | Isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-α-D-galactopyranoside (17) Asolution of 5 (50.0 mg, 0.128 mmol) in a 5% HCl solution in 2-propanol (3.8 mL) wasstirred at 65 C for 1 h. The reaction mixture was evaporated to dryness, and the residuewas dissolved in pyridine (0.50 mL) and treated with acetic anhydride (0.146 mL, 1.54mmol). This mixture was stirred at room temperature for 2 d and then co-evaporated withtoluene to give a brown oil that was a 3:1 mixture of α:β-isomers by NMR analysis.Purification by chromatography on SiO2 (75% EtOAc/hexanes) gave 17 (28.6 mg, 0.0737mmol, 57%) as a foaming colorless solid: IR (ATR) 3310, 2973, 2930, 1745, 1732, 1653,1534, 1372, 1284, 1240, 1217, 1124, 1083, 1034, 992, 936, 878 cm-1; 1H NMR (400MHz, CDCl3) δ 5.54 (d, J = 9.6 Hz, 1 H), 5.35 (app. d, J = 2.8 Hz, 1 H), 5.13 (dd, J = 3.2,11.2 Hz, 1 H), 4.95 (d, J = 4.0 Hz, 1 H), 4.56-4.50 (m, 1 H), 4.23 (app. t, J = 6.8 Hz, 1 H),4.12-4.02 (m, 2 H), 3.88 (sept, J = 6.0 Hz, 1 H), 2.15 (s, 3 H), 2.03 (s, 3 H), 1.98 (s, 3 H),1.95 (s, 3 H), 1.22 (d, J = 6.0 Hz, 3 H), 1.13 (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz,CDCl3) δ 171.0, 170.4 (2 C), 169.9, 96.3, 71.0, 68.5, 67.5, 66.7, 62.0, 47.8, 23.3, 23.1,21.7, 20.8, 20.7, 20.6; HRMS (ESI) m/z calcd for C17H28NO9 [M+H]+ 390.1764, found390.1776. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane for 3h; Inert atmosphere; Reflux; | Preparation of benzyloxycarbonylbutyl 2-deoxy 2-/V-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method B Preparation of benzyloxycarbonylbutyl 2-deoxy 2-/V-acetyl -3,4,6-tri-0-acetyl^-D- galactopyranoside (NAG7) - Method BTo a solution of NAG2 (5.00 g, 12.8 mmol) and alcohol NAG5 (5.33 g, 25.6 mmol) in DCE (50 mL) was added Sc(OTf)3 (0.44 g, 0.90 mmol) in one portion. The mixture was placed under an inert atmosphere and refluxed for 3 h. Upon cooling the mixture was diluted with CH2CI2, washed with sat. NaHC03 (aq.), dried over MgS04, and concentrated in vacuo. Purification via Si02 gel chromatography afforded glycoside NAG7 (5.53 g, 80% yield). |
80% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane for 3h; Inert atmosphere; Reflux; | 1.B Preparation of benzyloxycarbonylbutyl 2-deoxy 2-N-acetyl -3,4, 6-tri-O-acetyl-β-D-galactopyranoside (NAG7) Method B. To a solution of NAG2 (5.00 g, 12.8 mmol) and alcohol NAG5 (5.33 g, 25.6 mmol) in DOE (50 mL) was added Sc(OTf)3 (0.44 g, 0.90 mmol) in one portion. The mixturewas placed under an inert atmosphere and refluxed for 3 h. Upon cooling, the mixture was diluted with0H2012, washed with sat NaHOO3 (aq.), dried over MgSO4, and concentrated in vacuo. Purification by Si02 gel chromatography afforded glycoside NAG7 (5.53 g, 80% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20 - 50℃; | 1 Preparation of 101 Galactosamine pentaacetate 100 (52.00 g, 133.63 mmol) was taken in dichloroethane (300 mL) at ambient temperature. TMSOTf (44.55 g, 200.44 mmol) was added that and the mixture stirred at 50 C for 90 minutes in a water bath, heating stopped and the mixture stirred overnight at room temperature. It was poured in to an ice cold sodium bicarbonate solution; extracted with dichloromethane, washed with water and dried over sodium sulfate. Solvents were removed the residue dried under high vacuum overnight to get the compound as dark gum (44.50 g, quantitative). It was used for next reaction with out any further purification. 1H NMR and MALDI confirmed the product formation. MS: Calculated for C14H19NO8, 329.11. Found 352.1 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 4-methoxy-phenol; 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; Stage #2: With hydrazinium monoacetate In N,N-dimethyl-formamide at 20℃; for 3.5h; | 1.11. 5-Acetamido-2-(acetoxymethyl)-6-(4-methoxyphenoxy)tetrahydro-2H-pyran-3,4-diyldiacetate 10’ (10 g, 25.70 mmol) and 4-methoxyphenol (9.57 g, 77.1 mmol) were dissolved in anhyd CH2Cl2 (180mL). BF3.Et2O (5.6 mL, 43.7 mmol) was added into thesolution at 0°C. The system was warmed to room tempreture and stirred overnight. The reaction was quenched with sat. NaHCO3 aq., and the aqueous layer was extracted with CH2Cl2(3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. In this reaction, it was hard to seprate product from byproduct, and to make the purification possible, a followed experiment was conducted to reduce the Rf value of byproduct in TLC: this crude material was dissolved in DMF, and N2H4-HOAc (2.36g, 25.62 mmol) was added to the reaction. The reaction was stirred at room tempreture for 3.5 h. Then the reaction was poured into cold water, and extracted with CH2Cl2 (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Column chromatography (20:1 CH2Cl2/MeOH) gave11’ (5.23 g, 45%) as white solid.1H NMR(CDCl3, 400 MHz): δ 6.88 (d, J = 8.8 Hz,2H, ArH-OMP), 6.71-6.67 (m, 3H, ArH-OMP, NH), 5.37-5.33 (m, 2H, H-3, H-4), 5.10(d, J = 8.4 Hz, 1H, H-1), 4.21-4.05(m, 3H, H-2, H-6a,b), 3.99 (t, J= 6.4 Hz, 1H, H-5), 3.68 (s, 3H, OCH3-OMP), 2.07 (s, 3H, CH3-OAc),1.97 (s, 3H, CH3-OAc), 1.92 (s, 3H, CH3-OAc), 1.86 (s,3H, CH3-NHAc); 13C NMR (CDCl3, 100MHz): δ 170.68 (CO-NHAc), 170.58(CO-OAc), 170.54 (CO-OAc), 170.43 (CO-OAc), 155.71 (ArC-OMP), 151.31 (ArC-OMP),118.67 (ArC-OMP), 114.65 (ArC-OMP), 100.50 (C-1), 70.97, 69.80, 66.81, 61.66(C-6), 55.78 (OCH3-OMP), 51.89 (C-2), 23.58 (CH3-NHAc),20.83 (CH3-OAc), 20.81 (CH3-OAc). ESI-HRMS m/z: 454.1697 (M + H)+,476.1514 [M+Na]+. Calcd. C21H28NO10454.1713, C21H27NNaO10 476.1533 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 18h; Inert atmosphere; Reflux; Stage #2: With triethylamine In dichloromethane at 0 - 20℃; for 0.5h; Stage #3: N-(tert-butyloxycarbonyl)-5-aminopentanol; trifluoroacetic acid Further stages; | 4 [271] 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 NaHC03 (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 NaHC03 solution (100 mL) and solid NaHC03 in an open flask at room temperature to quench remaining Ac2Oand 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 NaHC03 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 Compound 3. To a 100 mL round bottom flask was added Compound 2 (3.14 g, 5.9 mmol) followed by trifluoro acetic acid (10 mL, TFA). The mixture was stirred until all of the carbohydrate was completely dissolved, then the TFA was evaporated under vacuum to yield light yellow oil. To the oily residue was added diethyl ether (10 mL), the mixture was sonicated for 2-5 min, and the supernatant was decanted. The trituration process was repeated (3 x 10 mL Et20), and the crude product was dried under vacuum to yield a white foam (3.2 g), which was used as described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 18h; Inert atmosphere; Reflux; Stage #2: With triethylamine In dichloromethane at 0 - 20℃; for 0.5h; Stage #3: N-(tert-butyloxycarbonyl)-5-aminopentanol Further stages; | 4 [271] 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 NaHC03 (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 NaHC03 solution (100 mL) and solid NaHC03 in an open flask at room temperature to quench remaining Ac2Oand 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 NaHC03 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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap In pyridine at 0 - 20℃; for 25h; | 13 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 (2) D-Gal-NH2.HCl (5.0 g, 23.24 mmol) was dissolved in pyridine (28.15 mL, 348.74 mmol) and acetic anhydride (26.35 mL, 278.88 mmol) was added slowly, followed by addition of DMAP (2.0 g) and reaction mixture stirred at 0° C. for 1 hour, then at room temperature for 24 hours. The reaction was then quenched with sat. NaHCO3 solution and extracted into ethyl acetate, followed by washing with 1N HCl solution, water, brine and dried over Na2SO4. Solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using DCM:EA:MeOH (7.5:2.0:0.5) as an eluent to obtain compound 1 (7.25 g, 80% yield). ‘R-NMR (500 MHz, CDC13): 1:0.33 13:a ratio. ö 1.82 (s, 3H, CR3, OAc, (13)), 1.85 (s, 3R, CR3, OAc, (a)), 1.88 (s, 3R, CR3, OAc, (13)), 1.90 (s, 3R, CR3, OAc, (13)), 1.92 (s, 3R, CR3, OAc, (a)), 1.94 (s, 3R, CR3, OAc, (a)), 1.98 (s, 3R, CR3, OAc, (a)), 2.00 (s, 3R, CR3, OAc, (a)), 2.03 (s, 3R, CR3, OAc, (13)), 2.04 (s, 3R, CR3, OAc, (13)), 3.90-4.04 (m, 3R, H3 and 2xR6), 4.06 (m, 3R, H6, 2xR3), 4.55 (dt, 1R, J=3.5 & 9.0 Hz, H5), 4.61 (dt, 1R, J=4.5 & 9.0 Hz, H5), 5.04-5.12 (m, 2R, 2xR2), 5.22 (d, 1R, J=1.5 Hz, H4), 5.30 (d, 1R, J=2.0 Hz, H4), 6.10 (d, 1R, J=3.5 Hz, (a), H1), 6.28 (d, 1R, J=8.5 Hz, (13), Rj; ‘3C-NMR (125 MHz, CDC13): ö20.30 (OAc, 3CR3, (13)), 20.33 (OAc, 3CR3, (13)), 20.35 (OAc, 3CR3, (13)), 20.40 (OAc, 3CR3, (a)), 20.42 (OAc, 3 CR3, (a)), 20.52 (OAc, 3CR3, (13)), 20.70 (OAc, 3CR3, (a)), 20.75 (OAc, 3CR3, (a)), 23.51 (OAc, 3CR3, (a)), 23.53 (OAc, 3CR3, (13)), 46.52(13’ C2), 55.90 (a, C2), 61.03 (13 C6), 61.78 (a, C5), 66.41 (13, C3), 67.36 (13, C4), 68.14 (13, C5),70.01 (a, C3), 73.45 (a, C4), 78.47 (a, C5), 90.80 (13 C,),93.63 (a, C1), 168.80 (13, Q), 169.01 (a, Q), 169.65 (a, p), 169.98Q3,CO), 170.14 (13,CO), 170.20(a,p), 170.53 (a, Q), 170.56 (13, CO), 170.58 (13, CO), 173.87 (a, Q).EI-MS: [M+R] C,6R24N0,Q calcd 390.13, obsd 390.12, [M+Na] C,6R23NNaO,0 calcd 412.12, obsd 412.11 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With trifluorormethanesulfonic acid In dichloromethane for 4.5h; Reflux; Dean-Stark; | 6 Example 6 Benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate Example 6 Benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate 268.0 g Benzyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (900 mol) were dissolved in 2.4 L dichloromethane. 385.0 g (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro- 2H-pyran-2,4,5-triyl triacetate (990 mmol, 1.1 eq) and 12.0 ml trifluoromethanesulfonic acid (135 mmol, 0.15 eq)were added. The suspension was heated to reflux with a dean-stark separator (50 ml, to remove AcOH). After lh, 4.50 ml trifluoromethanesulfonic acid (50.7 mmol, 0.05 eq) and 50 ml dichloromethane were added to the orange suspension, the solvent (50 ml) from the dean- stark separator was discharged. Every half hour this procedure was repeated, total 6 times (3h). After a total of 4.5h, the red solution was cooled to 10-15°C and added within 30 min at 20-25°C to a solution of 1.8 L 1M sodium hydrogen carbonate (1.8 mol, 2.0 eq) (C02 evolution, pH 7-8). The yellow organic layer was separated and evaporated at 40°C/600-10mbar/3h to obtain 585.4 g of crude benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate as yellow oil (HPLC purity: 87%). The crude product was dissolved in 700 ml acetone and charged to a preloaded silica column (3.0 kg silica 60; 0.063-0.2 mm). The chromatography was conducted using n- heptane/acetone as mobile phase (gradient from 5: 1 to 1:2). , The combined collected fractions were evaporated at 40°C/600-10mbar and dried at 20-25°C/0.3mbar/3h to obtain 465.0 g benzyl 2- [2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-pyran-2- yl]oxyethoxy]ethoxy]ethoxy] acetate as yellow oil in 83% yield and 100% purity (HPLC area-%). MS: m/z = 628.2627 (M+H)+. |
83% | With trifluorormethanesulfonic acid In dichloromethane Dean-Stark; Reflux; | 6 Example 6 Benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate 268.0 g Benzyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (900 mol) were dissolved in 2.4 L dichloromethane. 385.0 g (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H- pyran-2,4,5-triyl triacetate (990 mmol, 1.1 eq) and 12.0 ml trifluoromethanesulfonic acid (135 mmol, 0.15 eq)were added. The suspension was heated to reflux with a dean-stark separator (50 ml, to remove AcOH). After lh, 4.50 ml trifluoromethanesulfonic acid (50.7 mmol, 0.05 eq) and 50 ml dichloromethane were added to the orange suspension, the solvent (50 ml) from the dean- stark separator was discharged. Every half hour this procedure was repeated, total 6 times (3h). After a total of 4.5h, the red solution was cooled to 10-15°C and added within 30 min at 20-25°C to a solution of 1.8 L 1M sodium hydrogen carbonate (1.8 mol, 2.0 eq) (C02 evolution, pH 7-8). The yellow organic layer was separated and evaporated at 40°C/600-10mbar/3h to obtain 585.4 g of crude benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate as yellow oil (HPLC purity: 87%). The crude product was dissolved in 700 ml acetone and charged to a preloaded silica column (3.0 kg silica 60; 0.063-0.2 mm). The chromatography was conducted using n- heptane/acetone as mobile phase (gradient from 5: 1 to 1:2). , The combined collected fractions were evaporated at 40°C/600-10mbar and dried at 20-25°C/0.3mbar/3h to obtain 465.0 g benzyl 2- [2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-pyran-2- yl]oxyethoxy]ethoxy]ethoxy] acetate as yellow oil in 83% yield and 100% purity (HPLC area- MS: m/z = 628.2627 (M+H)+. |
83% | With trifluorormethanesulfonic acid In dichloromethane for 4.5h; Reflux; Dean-Stark; | B2 Example B2 Benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate 268.0 g Benzyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (900 mol) were dissolved in 2.4 L dichloromethane. 385.0 g (2S,3R,4R,5R,6R)-3-acetamido-6- (acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (990 mmol, 1.1 eq) and 12.0 ml trif uoromethanesulfonic acid (135 mmol, 0.15 eq)were added. The suspension was heated to reflux with a dean-stark separator (50 ml, to remove AcOH). After lh, 4.50 mltrifluoromethanesulfonic acid (50.7 mmol, 0.05 eq) and 50 ml dichloromethane were added to the orange suspension, the solvent (50 ml) from the dean-stark separator was discharged. Every half hour this procedure was repeated, total 6 times (3h). After a total of 4.5h, the red solution was cooled to 10-15°C and added within 30 min at 20-25°C to a solution of 1.8 L 1M sodium hydrogen carbonate (1.8 mol, 2.0 eq) (C02evolution, pH 7-8). The yellow organic layer was separated and evaporated at 40°C/600-10mbar/3h to obtain 585.4 g of crude benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate as yellow oil (HPLC purity: 87%). The crude product was dissolved in 700 ml acetone and charged to a preloaded silica column (3.0 kg silica 60; 0.063-0.2 mm). The chromatography was conducted using n- heptane/acetone as mobile phase (gradient from 5: 1 to 1:2). , The combined collected fractions were evaporated at 40°C/600-10mbar and dried at 20-25°C/0.3mbar/3h to obtain 465.0 g benzyl 2-[2-[2-[2-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydro-pyran-2-yl]oxyethoxy]ethoxy]ethoxy] acetate as yellow oil in 83% yield and 100% purity (HPLC area-%). MS: m/z = 628.2627 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / chloroform / 1.5 h / 40 °C 2: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 5 °C | ||
Multi-step reaction with 2 steps 1.1: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 0 - 65 °C / Molecular sieve 2.1: 1,2-dichloro-ethane / 0.5 h / 20 °C / Molecular sieve 2.2: 45 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine; trimethylsilyl trifluoromethanesulfonate / acetonitrile / 0 - 65 °C / Molecular sieve 2.1: 1,2-dichloro-ethane / 0.5 h / 20 °C / Molecular sieve 2.2: 45 °C / Molecular sieve |
Multi-step reaction with 2 steps 1: chloroform / 1.5 h / 40 °C 2: trimethylsilyl trifluoromethanesulfonate / toluene; 1,2-dichloro-ethane / 5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine at 20℃; for 2h; | |
82% | With pyridine at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 50℃; for 12h; | |
92% | With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20 - 50℃; for 13.5h; | 3 Galactosamine pentaacetate (100 mg, .257 mmol) was dissolved in dichloroethane (1 mL) and stirred at room temperature before the addition of TMSOTf (70 uL, 86.0 mg, .387 mmol, 1.5 eq). The reaction was stirred at 50° for 90 minutes, then allowed to cool to room temperature and stirred for a further 12 hours. The reaction was poured into ice cold saturated sodium bicarbonate and extracted into DCM. The organic layer was washed with water (2x), dried over sodium sulfate, and evaporated to give compound 66 (.236 mmol, 77.7 mmol, 92%) as a dark gum, which was used without further purification. (0655) HNMR (0656) 'HNMR (400 MHz, Chloroform -if) 65.98 (d, .7 = 6.8 Hz, 1H), 5.45 (t, J= 3.0 Hz, 1H), 4.90 (dd, J= 7.4, 3.3 Hz, 1H), 4,29 - 4.20 (m, 1H), 4.17 (d, J= 6.9 Hz, 1H), 4.10 (dd, J= 11.1, (0657) 5.7 Hz, 1H), 3.99 (td, J= 7.1, 1.4 Hz, 1H), 2.11 (s, 3H), 2.05 (m, J= 7.6 Hz, 6H). (0658) CNMR (0659) l3C NMR (101 MHz, cdcl3) d 170.46, 170.13, 169.78, 166.35, 121.82, 118.64, 101.41,71.76, 69.44, 65.25, 63.53, 61.56, 46.82, 20.77, 20.68, 20.54, 14,41, 8.64, -0.06. |
With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 0 - 65℃; Molecular sieve; | 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). 4A 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 sulf ate 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 C14H19N08, [M+Hj = 329.10, Observed = 329.0. |
With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 41h; Molecular sieve; Inert atmosphere; Reflux; | 1.1; 2.1; 3.1 Step 1: Preparation of intermediate NB-08 Add SM1 (50g, 0.1284mol),500 mL of dichloromethane and 50 g of molecular sieves. It was then stirred under nitrogen for 1 h.Trimethylsilyl triflate (30 ml, 0.1658 mol) was slowly added dropwise to the reaction solution in an ice water bath. After the dropwise addition was completed, the reaction was refluxed for 40 hours. The reaction solution was brown-black.After the reaction was monitored by TLC, the temperature was lowered to room temperature, and triethylamine was added dropwise to neutrality. filter,The filtrate was washed with ice water (3 × 300 ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate,Stir for 1 h and filter. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. filter,The dichloromethane solution of NB-08 was obtained and directly used in the next reaction. | |
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20 - 30℃; for 2h; Inert atmosphere; | 1.2 Step 2: (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(hex-5-en-1- yloxy)tetrahydro-2H-pyran-3,4-diyl diacetate. DCM (6.0V) and (2S,3R,4R,5R,6R)-3-acetamido- 6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.0eq) were charged to a reactor. Water content was analyzed and if water content was0.1%, the mixture was repeatedly concentrated under vacuum and diluted with DCM (3.0V) until the system was £ 3.0V until the water content was £ 0.1%. TMSOTf (1.5eq) was then added dropwise to the mixture at 20-30°C and the system was stirred for at least 2 hours at 20-30oC. Reaction progress was monitored by TLC. Afterward the system was quenched by the dropwise addition to a 5% NaHCO3 solution (10.0V). The mixture was then stirred for at least 30 min, separated, and the organic phase was collected. The aqueous was extracted with DCM (3.0V) aqueous phase, and after stirring for 30 min was filtered and the filter cake rinsed with DCM (2.0V). The filtrate was then separated and the organic phase collected. The organic phases were combined and concentrated under vacuum below 40oC until the system was £ 3.0V. DCM (3.0V) was then charged to the mixture and water content was analyzed and if water content was0.05%, the mixture was repeatedly concentrated under vacuum and diluted with DCM (3.0V) until the system was £ 3.0V until the water content was £ 0.05%. Thereafter, 5-hexen-1-ol was charged into the mixture and the mixture was cooled to 0-5oC. TMSOTf (0.5eq) was then added dropwise to the mixture at 0-5oC and the mixture was stirred for 0.5h at 0-5oC, warmed to 20-30oC, and stirred for at least 2h. The reaction mixture was then quenched with soften water (10.0V), stirred for at least 0.5h, separated and the organic phase collected. The organic phase was washed with 8% NaCl solution (10.0V x 1) and concentrated under vacuum below 45oC until the system was 1.0V-1.5V. The organic phase was then filtered was concentrated below 45oC under vacuum to £ 3.0V. DCM (3.0V) was charged to the mixture and concentrated until the system was £ 3.0V, twice. MTBE (3.0V) was charged to the mixture and concentrated until the system was £ 3.0V, thrice. n-Heptane (1.0V) was then added dropwise into the mixture at a controlled temperature of 20±5oC. The mixture was then cooled to 0-5oC and stir for at least 2h. The mixture was centrifuged and the cake was rinsed with n-Heptane (1.0V) and collected. The filter cake was then slurried in n-Heptane (3.0V) for at least 2h at 15±5oC. The mixture was again centrifuged and the cake was rinsed with n-Heptane (1.0V) and collected. The filter cake was then dried under vacuum for at least 12 hours at 30±5oC until LOD £ 3% and packaged in double LDPE bags and stored at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 % de | With pyridine; dmap at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine; dmap at 20℃; for 3h; | Synthesis of acetylated Ga1NAc [2] See, e.g., Guo, et. al. Bioconjug. Chem. 2006, 17, 1537-1544. Ga1NAc (10 g, 45.2 mmol) was dissolved in pyridine (100 mL). DMAP (1.4 g, 11.3 mmol) was added in it. Acetic anhydride (46.2 mL, 452 mmol) was added into the reaction mixture and stirred for next three hours. Reaction was completed within three hours based on TLC. After completion of reaction the crude mixture was evaporated off to dryness and purified via column chromatography (0-100 % Ethyl acetate in Pet ether). The product comes at 100% Ethyl acetate. Pure product (17 g, 97%) was isolated as white foam and characterized based on Mass analysis. Results: ESI-MS analysis: Calculated C16H23N010. Na, [M+Naj = 412.13, Observed = 412.12. |
97% | With pyridine; dmap for 3h; | 1 Synthesis of acetylated GalNAc [2] See, e.g., Guo, et. al. Bioconjug. Chem. 2006, 17, 1537-1544. GalNAc (10 g, 45.2 mmol) was dissolved in pyridine (100 mL). DMAP (1.4 g, 11.3 mmol) was added in it. Acetic anhydride (46.2 mL, 452 mmol) was added into the reaction mixture and stirred for next three hours. Reaction was completed within three hours based on TLC. After completion of reaction the crude mixture was evaporated off to dryness and purified via column chromatography (0-100 % Ethyl acetate in Pet ether). The product comes at 100% Ethyl acetate. Pure product (17 g, 97%) was isolated as white foam and characterized based on Mass analysis. Results: ESI-MS analysis: Calculated C16H23NO10. Na+, [M+Na+] = 412.13, Observed = 412.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; | 1 Preparation of compound 3: compound 1 was dissolved in DCM with compound 2 (0.9 equiv. ). TMSOTf (1.0 equiv.) was added dropwise at room temperature, and the resulting mixture was stirred for 16 hours. Then, the reaction mixture was washed with 5% aqueous NaHC03, stirred for 30 minutes, and separated, and the organic phase was collected. The organic phase was then extracted with dichloromethane (DCM) and concentrated to dryness. The product was recrystallized from 2:1 EtOAc/hexane to yield a white solid (83% yield). |
83% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 16h; | 5 Preparation of compound 3: compound 1 was dissolved in DCM with compound 2 (0.9 equiv.). TMSOTf (1.0 equiv.) was added dropwise at room temperature, and the resulting mixture was stirred for 16 hours. Then, the reaction mixture was washed with 5% aqueous NaHC03, stirred for 30 minutes, and separated, and the organic phase was collected. The organic phase was then extracted with dichloromethane (DCM) and concentrated to dryness. The product was recrystallized from 2: 1 EtOAc/hexane to yield a white solid (83% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48 % de | With palladium on activated charcoal; hydrogen for 16h; Overall yield = 52 %; Overall yield = 108 mg; | 2-Acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-D-galactopyranose (2a) 8a (200 mg, 0.54 mmol, 1 equiv) was dissolved in 3 mL acetic anhydride. 20 mg Pd/C was added and a H2-ballon attached to the flask. The mixture was stirred for 16 h before acetic anhydride was removed under reduced pressure. The mixture was dissolved in warm EtOH/H2O (1:1) and filtered through a Celite pad. The solvents were removed under reduced pressure and the crude product purified by flash chromatography (DCM/ethyl acetate/MeOH7/2.5/0.5) to receive compound 2a (108 mg, 52%, α-pyr/β-pyr 26:74) as a colorless solid: 1H NMR (600 MHz, CDCl3) δ α: 6.21 (d, J = 3.6 Hz, 1 H, H-1), 5.44 (d, J = 9.0 Hz, 1 H, NH),5.42 (dd, J = 3.1, 1.2 Hz, 1 H, H-4), 5.22 (dd, J = 11.6, 3.1 Hz, 1 H, H-3), 4.72 (ddd, J = 11.6,9.2, 3.6 Hz, 1 H, H-2), 4.25 - 4.22 (m, 1 H, H-5), 4.12 - 4.04 (m, 2 H, H-6), 2.17 (s, 6 H, Ac),2.03 (s, 6 H, Ac), 1.95 (s, 3 H, Ac); β: 5.69 (d, J = 8.9 Hz, 1 H, H-1), 5.49 (d, J = 9.6 Hz, 1 H,NH), 5.37 (dd, J = 3.4, 1.2 Hz, 1 H, H-4), 5.08 (dd, J = 11.3, 3.4 Hz, 1 H, H-3), 4.44 (dt, J =11.3, 9.3 Hz, 1 H, H-2), 4.18 - 4.08 (m, 2 H, H-6), 4.01 (td, J = 6.5, 1.2 Hz, 1 H, H-5), 2.16 (s,3 H, Ac), 2.12 (s, 3 H, Ac), 2.04 (s, 3 H, Ac), 2.01 (s, 3 H, Ac), 1.93 (s, 3 H, Ac); 13C NMR(150 MHz, CDCl3) δ α: 171.38 (Cq, Ac), 170.56 (Cq, Ac), 170.38 (Cq, Ac), 170.21 (Cq, Ac),168.94 (Cq, Ac), 91.49 (CH, C-1), 68.70 (CH, C-5), 67.97 (CH, C-3), 66.84 (CH, C-4), 61.45(CH2, C-6), 47.14 (CH, C-2), 23.34 (CH3, Ac), 21.12 (CH3, Ac), 20.91 (CH3, Ac), 20.84 (CH3,Ac), 20.82 (CH3, Ac); β: 170.90 (Cq, Ac), 170.56 (Cq, Ac), 170.43 (Cq, Ac), 170.32 (Cq, Ac),169.72 (Cq, Ac), 93.18 (CH, C-1), 72.00 (CH, C-5), 70.46 (CH, C-3), 66.48 (CH,C-4), 61.45(CH2, C-6), 49.93 (CH, C-2), 23.46 (CH3, Ac), 21.05 (CH3, Ac), 20.82 (2 x CH3, Ac), 20.80(CH3, Ac); HRMS (ESI) m/z [M + Na]+ calcd for C16H23NO10Na 412.1220; found 412.1223. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine In acetic anhydride at 0℃; for 2h; Inert atmosphere; | Preparation of d-galactosamine pentaacetate (NAG2). D-Galactosamine (25.0 g, 116 mmol) wassuspended in anhydrous pyridine (250 ml) and cooled to 0 oc under an inert atmosphere. Aceticanhydride (120 ml, 1160 mmol) was added over the course of 2 h. After stirring overnight, the reactionmixture was concentrated in vacuo. Upon addition of methanol, a white solid precipitated and was collected via filtration to provide the desired product (42.1 g, 93% yield). 1H NMR (CDCl3, 500 MHz): δ5.69 (d, 1 H, J 9.0 Hz), 5.40 (m, 1 H), 5.37 (d, 1 H, J 3.0 Hz), 5.08 (dd, 1 H, J 3.0 Hz, 11 Hz), 4.44 (dt, 1 H, J9.5 Hz, 11 Hz), 4.17 (dd, 1 H, J 7.0 Hz, 11.5 Hz), 4.11 (dd, 1 H, , J 7.0 Hz, 11.5 Hz), 4.01 (t, 1 H, J 7.0 Hz),2.17 (s, 3H), 2.13 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H), 1.57 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20 - 55℃; for 2h; Inert atmosphere; | Preparation of benzyloxycarbonylbutyl 2-deoxy-2-N-acetyl-3,4, 6-tri-O-acetyl-{3-0-galactopyranoside (NAG7)- Method A. Under an inert atmosphere, TMSOTf (8.56 g, 38.4 mmol) was25 added to a solution of NAG2 (1 0.0 g, 25.6 mmol) in 1 ,2-dichloroethane (1 00 ml) at ambient temperature.The mixture was stirred at 55 oc for 2 h, removed from heat, and stirred overnight. The reaction mixture was poured over ice cold sat NaHC03 (aq.) and extracted with CH2CI2. The organic layer was dried overNa2S04 and concentrated in vacuo to give NAG6 as a syrup. A solution of NAG6 in 1 ,2-dichloroethane(60 ml) was charged with alcohol NAGS (8.00 g, 38.4 mmol) and molecular sieves. The mixture wasplaced under an inert atmosphere, treated with TMSOTf (2.85 g, 12.8 mmol), and stirred overnight at room temperature. The mixture was poured over ice cold sat NaHC03 (aq.) and extracted with CH2Cl2.The organic layer was dried over Na2S04 and concentrated in vacuo to give a syrup. This crude materialwas purified by Si02 gel chromatography to afford glycoside NAG7 (3.3 g, 24% yield). 1H NMR (CDCb,500 MHz): δ7.35 (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 3.0Hz, 11 Hz), 5.10 (s, 2H), 4.63 (d, 1 H, J 8.5 Hz), 4.11 (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) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 85℃; for 2h; | 15.3 Step 3. Preparation of compound 84 A solution of GalNAc 6 (12.2g, 31.4mmol) and HO-PEG-N3 83 (9.2g, 35mmol) in 1,2- dichloroethane (150mL) was treated with Sc(OTf)3 (771 mg, 1.6mmol). After stirring (85°C, 2hr) the reaction was cooled (RT), quenched by the addition of TEA (40mL) and concentrated. The crude material was subjected to chromatography to yield 84 (11.16g, 60%) as a pale yellow foam. Rf 0.7 (10% CH3OH-CH2CI2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 85℃; for 2h; | 26.2 Step 2 Preparation of compound 310 A solution of 7 (2.76g, 7.1mmol) and 309 (1.37g, 7.8mmol) in 1,2-dichloroethane (40mL) was treated with Sc(OTf)3 (174 mg, 0.36mmol) and heated (85°C). After stirring (2 hours) the mixture was cooled (RT) and quenched by the addition of TEA (4mL) and concentrated. The crude material was subjected to chromatography to yield 310 (3.03g, 85%) as a pale yellow foam. |
85% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 85℃; for 2h; | 52.2; 58.2 Step 2 Preparation of compound 310 A solution of 7 (2.76g, 7.1mmol) and 309 (1.37g, 7.8mmol) in 1,2-dichloroethane (40mL) was treated with Sc(OTf)3 (174 mg, 0.36mmol) and heated (85°C). After stirring (2 hours) the mixture was cooled (RT) and quenched by the addition of TEA (4mL) and concentrated. The crude material was subjected to chromatography to yield 310 (3.03g, 85%) as a pale yellow foam. |
85% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 85℃; for 2h; | 26.2 Step 2 Preparation of compound 510 A solution of 507 (2.76g, 7.1mmol) and 509 (1.37g, 7.8mmol) in 1,2-dichloroethane (40mL) is treated with Sc(OTf)3 (174mg, 0.36mmol) and heated (85C). After stirring (2 hours) the mixture is cooled (RT) and quenched by the addition of TEA (4mL) and concentrated. The crude material is subjected to chromatography to yield 510 (3.03g, 85%) as a pale yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ytterbium(III) triflate In 1,2-dichloro-ethane at 70℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; woollins’ reagent In toluene for 14h; Reflux; | |
With pyridine; woollins’ reagent In toluene Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine; dmap; triethylamine at 20℃; Cooling with ice; | 4.3 (3) Synthesis of Compound 5 (0138) In a 1 L round bottom flask, D-galactose hydrochloride (100 g, 0.46 mol) and 450 mL of anhydrous pyridine were added, and 325 mL of acetic anhydride, triethylamine (64.5 mL, 0.46 mol) and DMAP (2 g, 0.016 mol) were slowly added under are ice bath. After overnight reaction at room temperature, a large amount of solid was precipitated, which was filtered by suction and the filter cake was rinsed with 200 mL of 0.5 N HCl solution to obtain 162.5 g of a white solid with a yield of 90%. 1HNMR (400 MHz, DMSO-d6) δ: 7.88 (d, J=9.2 Hz, 1H), 5.63 (d, J=8.8 Hz, 1H), 5.26 (d, J=3.1 Hz, 1H), 5.05 (d, J=11.3, 3.3 Hz, 1H), 4.36 (m, 4H), 2.11 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H) 1.78 (s, 3H). |
82% | In pyridine | 1.3; 51; 57 Step 3. Preparation of peracetylated galactosamine 6 D-Galactosamine hydrochloride 5 (250 g, 1.16 mol) in pyridine (1.5 L) was treated with acetic anhydride (1.25 L, 13.2 mol) over 45 minutes. After stirring overnight the reaction mixture was divided into three 1 L portions. Each 1 L portion was poured into 3 L of ice water and mixed for one hour After mixing the solids were filtered off, combined, frozen over liquid nitrogen and then lyophilized for five days to yield peracetylated galactosamine 6 (369.4 g, 82%) as a white solid. Rf (0.58, 10% MeOH-CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With indium(III) bromide In diethyl ether; chloroform for 3h; Reflux; | 4 Example 4. Synthesis of Na-Fluoren-9-ylmethoxycarbonyl-S-(3,4,6-tetra-0-acetyl-2- acetamido-2-deoxy)-P-D-galactopyranosyl)-L-cysteine 13-D-galactosamine pentaacetate (850 mg, 2.18 mmol, 1.5 eq), InBr3 (232 mg, 0.65 mmol,0.3 eq), and N-fluoren-9-y1methoxycarbony1-L-cysteine (500 mg, 1.47 mmol, 1 eq) were suspended in 1:1 CHC13: ethyl ether (30 mL). The reaction mixture was stirred at reflux for 3hours. The solvent was evaporated and ether was added to the crude solid. The mixture was stirred for lhr at 0°C, filtered and washed with cold ether, Again the crude product was slurred with dichloromethane for 30 mm and filtered and washed with cold DCM to afford 5 as an off-white powder (725 mg, 74 %). Rf 0.4 (CH2C12/methanol, 9:1 v/v with 0.5 % Acetic acid)‘H NMR (500 MHz, Methanol-d4) ö 7.81 (d, J = 7.5 Hz, 2H), 7.71 (dd, J = 18.5, 7.5 Hz,2H), 7.45 -7.39 (m, 2H), 7.38 - 7.31 (m, 2H), 5.37 (d, J = 3.3 Hz, 1H), 5.07 (dd, J = 10.8,3.2 Hz, 1H), 4.72 (d, J = 10.4 Hz, 1H), 4.47 (dd, J = 9.4, 4.0 Hz, 1H), 4.43 - 4.32 (m, 2H),4.32 -4.24 (m, 2H), 4.17 -4.07 (m, 2H), 3.98 (t, J = 6.5 Hz, 1H), 3.45 (dd, J = 14.4, 4.0 Hz,1H), 2.88 (dd, J = 14.4, 9.4 Hz, 1H), 2.12 (s, 3H), 1.98 (s, 2H), 1.97 (s, 3H), 1.88 (s, 2H).‘3C NMR (126 MHz, Methanol-d4) ö 172.19, 170.80, 170.66, 170.24, 157.03, 143.90,143.75, 141.16, 127.42, 126.87, 126.83, 124.98, 124.85, 119.55, 119.53, 83.76, 74.34, 71.61,66.99, 66.76, 61.74, 54.22, 48.48, 46.91, 31.04, 21.34, 19.16, 19.14, 19.13.HRMS-ESI-TOF (mlz): Calcd. for [(C32H37N2012S+1 673.2067 (M+H), Found 673.2060(100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 90℃; for 16h; | C.2.78a 78a: benzyl 2-[(2R,3R,4R,5R, 6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl] oxyacetate To a mixture of starting compound 68 (16 g, 41,1 mmol) and benzyl 2 -hydroxy-acetate 77a (13,6 g, 82,2 mmol) in 160 ml DCE was added Sc(OTf)3 (1,41 g, 2,88 mmol). The solution was stirred at 90°C for 16 h to achieve complete conversion. The reaction mixture was poured into 200 ml sat. NaHC03 and extracted with 3 x 100 ml DCM. The combined organic phases were dried over anhydrous Na2S04, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc 1:1) and then reverse flash chromatography (neutral), yielding 12,0 g (60 %) of the title compound 78a as yellow oil. MS [M+H]+ (m/z) = 496,0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 15 - 50℃; Stage #2: benzyl 5-hydroxy pentanoate In 1,2-dichloro-ethane at 15℃; Molecular sieve; | C.2.78d 78d: benzyl 5-[(2R,3R,4R, 5R, 6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl] oxypentanoate To a solution of (D)-2-desoxy-2-amino-galactosyl-pentaacetate 68 (387 g, 0,968 mol) in 4 1 DCE, was added TMSOTf (322 g, 1,452 mol) dropwise at l5°C. The mixture was heated at 50°C for 1,5 h and then stirred at 30°C overnight. The reaction mixture was poured into 4 1 sat. NaHC03-solution and extracted twice with 1 1 DCM. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was dissolved in 4 1 DCE, benzyl-5-hydroxypentanoate 77d (302 g, 1,452 mol) and 300 g powdered molecular sieves (4A) were added at l5°C. After stirring for 1 h, TMSOTf (107,4 g, 0,484 mol) was added dropwise at l5°C. The suspension was stirred at l5°C overnight, to achieve complete conversion. The reaction mixture was poured into 4 1 sat. NaHC03-solution, filtered and extracted twice with 1 1 DCM. The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc 3:1) to give the desired product (240 g, 46 %) as colorless oil. 1H-NMR (CDCl3, 400 MHz) 5[ppm]: 7.47-7.30 (m, 5 H), 5.74 (br d, =8.5 Hz, 1H), 5.36 (d, =2.8 Hz, 1H), 5.30-5.23 (m, 1H), 5.17-5.07 (m, 2 H), 4.65 (d, =8.4 Hz, 1H), 4.20-4.08 (m, 3 H), 4.02-3.94 (m, 1H), 3.94-3.85 (m, 2 H), 3.50 (td, =6.l, 9.9 Hz, 1H), 2.49-2.32 (m, 2 H), 2.15 (s, 3 H), 2.05 (s, 3 H), 2.01 (s, 3 H), 1.92 (s, 3 H), 1.78-1.56 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With boron trifluoride diethyl etherate In dichloromethane at 0℃; Inert atmosphere; | Compound 272: A mixture of //-D-galactosamine pentaacetate 271 (0.30 g, 0.77 mmol) and compound A1 (0.23 g, 0.84 mmol) in CH2CI2 (5 mL) was cooled to 0 °C. Boron trifluoride diethyl etherate (0.4 mL, 3.24 mmol) was added. The solution was gradually warmed to room temperature and stirred for overnight. The reaction was treated with sat. aq. NaHCCL (10 mL) and CH2CI2 (10 mL). The organic phase was separated; washed with 1N aq. HC1 and brine; dried over Na2S04; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with 5% MeOH in CH2CI2) to give compound 272 (0.070 g, 15% yield) as a white foam solid m/z = 603 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With tin(IV) chloride In 1,2-dichloro-ethane at 80℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tin(IV) chloride In dichloromethane at 60℃; for 18h; | 1 3-(((2S,3R,4R,5R,6R)-3-Acetamide-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)thio) propionic Acid (Compound 2) 3-Mercaptopropionic acid (158 mg, 129 μL) and tin(IV) chloride (336 mg, 149 μL) were added to a dichloromethane (10 mL) solution of Compound 1 (386 mg, 0.99 mmol) that had been synthesized by a known method (Wang et al., Journal of Bacteriology, (2014), 196, 3122), and the obtained mixture was then heated to reflux at 60° C. for 18 hours. Thereafter, the solvent was distilled away under reduced pressure, 0.1 N hydrochloric acid was then added to the residue, and the obtained mixture was then extracted with ethyl acetate twice. The extract was dried over sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained crude product was purified by silica gel chromatography (dichloromethane/methanol=15:1, acetic acid 0.5%) to obtain Compound 2 (300 mg; yield: 70%; a white amorphous substance). (0087) 1H NMR (500 MHz, CDCl3) δ: 1.97 (s, 3H), 2.00 (s, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 2.77 (ddd, 2H, J=6.9, 6.9, 2.3 Hz), 2.98 (ddd, 2H, J=6.9, 6.9, 2.3 Hz), 3.89 (t, 1H, J=5.8 Hz), 4.06 (dd, 1H, J=11.5, 6.9 Hz), 4.19-4.25 (m, 2H), 4.74 (d, 1H, J=10.3 Hz), 5.13 (dd, 1H, J=10.9, 3.5 Hz), 5.39 (d, 1H, J=3.5 Hz), 5.51 (d, 1H, J=9.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With scandium tris(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 85℃; for 2h; | 15.3 Step 3. Preparation of compound 84 A solution of GalNAc 6 (12.2g, 31.4mmol) and HO-PEG-N383 (9.2g, 35mmol) in 1,2- dichloroethane (150mL) was treated with Sc(OTf)3 (771mg, 1.6mmol). After stirring (85C, 2hr) the reaction was cooled (RT), quenched by the addition of TEA (40mL) and concentrated. The crude material was subjected to chromatography to yield 84 (11.16g, 60%) as a pale yellow foam. Rf 0.7 (10% CH3OH-CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 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 CHCl3 (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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 5 - 15℃; for 2h; Stage #2: C17H26N2O4 In dichloromethane at 30 - 40℃; for 16h; | 1 Preparation of compound 9: compound 1 (1.1 equiv.) was dissolved in DCM, and the resulting solution was cooled to 5-15 °C. TMSOTf (1.2 equiv.) was added, and the resulting mixture was stirred for 2 hours at 5-15 °C. Compound 8 (1.0 equiv.) was added to the reaction mixture, and the resulting mixture was stirred for 16 hours as 30-40 °C. The reaction mixture was then cooled to 15-25 °C. Water was added, and the mixture was stirred for 10 minutes. Layers were separated, and the organic phase was washed with water twice. The organic layer was concentrated to dryness. The product was recrystallized from 2: 1 EtOAc/hexane and filtered, and the filter cake was dried in vacuo to product the white solid (65% yield). |
65% | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 5 - 15℃; for 2h; Stage #2: C17H26N2O4 In dichloromethane at 30 - 40℃; for 16h; | 5 Preparation of compound 9: compound 1 (1.1 equiv.) was dissolved in DCM, and the resulting solution was cooled to 5-15 °C. TMSOTf (1.2 equiv.) was added, and the resulting mixture was stirred for 2 hours at 5-15 °C. Compound 8 (1.0 equiv.) was added to the reaction mixture, and the resulting mixture was stirred for 16 hours as 30-40 °C. The reaction mixture was then cooled to 15-25 °C. Water was added, and the mixture was stirred for 10 minutes. Layers were separated, and the organic phase was washed with water twice. The organic layer was concentrated to dryness. The product was recrystallized from 2: 1 EtOAc/hexane and filtered, and the filter cake was dried in vacuo to product the white solid (65% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0 - 20℃; Stage #2: 2-(2-azidoethoxy)ethanol With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0 - 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0 - 20℃; for 40h; Inert atmosphere; | 2; 5 Preparation of Compound 2 To a solution of compound 1 (25.0 g, 64.2 mmol) in DCE (250 mL) was added TMSOTf (17.1 g, 77.1 mmol, 13.9 mL) dropwise at 0 °C under N2 atmosphere. The mixture was stirred at 20 °C for 40 hr. TLC indicated little compound 1 remaining and one new spot formed (dichloromethane: methyl alcohol = 10: 1, Rf= 0.51). The reaction was quenched by the addition of NaHCCb (1000 mL), extracted with DCM (1000 mL*3). The organic phase was dried with anhydrous Na2SC>4 and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 60/1) to give compound 2. This reaction was repeated 3 more times and final products from these 4 runs were combined to give total 45.0 gram of compound 2 (137 mmol, 53.2% yield) as a pale yellow oil. NMR (400 MHz, CDCb): d ppm 5.97 (d, J=7.03 Hz, 1 H), 5.43 (t, J=3.01 Hz, 1 H), 4.89 (dd, J=7.40, 3.39 Hz, 1 H), 4.18 - 4.24 (m, 1 H), 4.14 - 4.18 (m, 1 H), 4.05 - 4.11 (m, 1 H), 3.97 (td, J=7.15, 1.25 Hz, 1 H), 2.08 - 2.11 (m, 3 H), 2.04 (s, 6 H), 2.03 (d, J=1.25 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In 1,2-dichloro-ethane | 6 Example 6. Synthesis of Compound 10 To a solution of compound 9 (10 g, 35.3 mmol) in DCE (100 mL) was added compound 7 (16.5 g, 42.4 mmol) and TMSOTf (0.6 mL, 3.5 mmol). The mixture was agitated at 60 to 65 °C for not less than 3 hours until completion of reaction as confirmed by UPLC. The mixture was allowed to cool to 20 °C to 25 °C and sequentially washed with 8 wt% aq. NaHCO3 (2 x 60 mL), 1N HCl (120 mL), brine (120 mL), dried over Na2SO4 (120 g) and evaporated to dryness to give compound 10 (22.7 g, quantitative yield) as a light-yellow syrup. m/z 613.3 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.78 (d, J = 9.2 Hz, 1H), 7.38 - 7.26 (m, 5H), 7.29 - 7.22 (m, 1H), 5.20 (d, J = 3.4 Hz, 1H), 5.01 - 4.93 (m, 3H), 4.54 (d, J = 8.5 Hz, 1H), 4.01 (m, 3H), 3.86 (m, 1H), 3.76 (m, 1H), 3.60 - 3.51 (m, 1H), 3.54 - 3.43 (m, 6H), 3.39 (t, J = 6.0 Hz, 2H), 3.13 (q, J = 6.0 Hz, 2H), 2.08 (s, 3H), 1.98 (s, 3H), 1.87 (s, 3H), 1.75 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3-Butyn-1-ol; 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With triethylamine In dichloromethane at 20℃; for 0.166667h; Molecular sieve; Reflux; Stage #2: With boron trifluoride diethyl etherate In dichloromethane at 0 - 51℃; for 5h; | 105 [001161] To an activated 4Å molecular sieves (5.0 g) and [(2R,3R,4R,5R,6S)-3,4,6- tris(acetyloxy)-5-acetamidooxan-2-yl]methyl acetate (A-1) (5.0 g, 12.8 mmol), was added dichloromethane (50 mL) and stirred at room temperature for 5 min followed by addition of but-3-yn-1-ol (2.92 mL, 3.0 eq., 38.5 mmol). Stirred the reaction mixture for 10 min at room temperature and then cooled to 0 °C. Diethyl trifluoroborinate (4.75 mL, 38.5 mmol) added dropwise to above reaction mixture and again stirred for 10 min at room temperature followed by 5 h refluxing at 51 °C. TLC checked for the completion of reaction and triethylamine added to quench the diethyl trifluoroborinate (upto neutral pH) and filtered through celite bed followed by concentration on rotary evaporator. Obtained thick residue was purified by silica gel column purification with 60-75% ethyl acetate in dichloromethane as eluent that afforded Intermediate A-2 as an off white foam. Yield: 4.50 g, 87 %; Rf = 0.45 (7.5 % methanol in dichloromethane); LC-MS m/z 400.0 [M+1]+; 1H NMR (400 MHz, CDCl3) δ 5.44 (d, J = 8.6 Hz, 1H), 5.35 (d, J = 7.0 Hz, 1H), 5.30 (dd, J = 11.2, 3.0 Hz, 1H), 4.79 (d, J = 8.2 Hz, 1H), 4.14 - 4.09 (m, 2H), 3.99 - 3.90 (m, 3H), 3.71 - 3.65 (m, 1H), 2.49 - 2.47 (m, 2H), 2.14 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 16h; Molecular sieve; Reflux; | 119 [001202] ASGPR Example 119: Synthesis of Intermediate C [001203] To activated 4Å molecular sieves and [(2R,3R,4R,5R,6S)-3,4,6-tris(acetyloxy)-5-acetamidooxan-2-yl]methyl acetate (C-1) (1 eq.) is added dichloromethane. To the reaction solution is added but-3-yn-1-amine (3 eq). The reaction mixture is allowed to cool to 0 °C prior to the addition of diethyl trifluoroborinate (2 eq). The reaction is stirred at room temperature and then heated to refluxing for 16h. Aqueous NaHCO3 is added to quench the diethyl trifluoroborinate and the DCM layer is partitioned and dried over MgSO4. The solution is filtered and concentrated on a rotary evaporator. Silica gel column purification with 60-75% ethyl acetate in dichloromethane as eluent is used to obtain Intermediate C-2. [001204] Intermediate C-2 (1 eq.) is dissolved in methanol and cooled to 0 °C. Sodium methoxide 25%w/v (10 eq) in methanol is added dropwise to this solution. The reaction is maintained at room temperature for 3 h. After completion of reaction 1N HCl is added dropwise to quench the sodium methoxide. Methanol is evaporated and the obtained residue is washed with diethyl ether. The crude residue obtained is purified with prep-HPLC (5-20 % acetonitrile in water with 0.1% TFAH) to afford Intermediate C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.12% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20 - 40℃; for 5h; | 122 [001209] ASGPR Example 122: Synthesis of Compound I-122 [001210] To the solution of Compound A-1 (1.0 eq, 5.05 g, 13.0 mmol) and benzyl N-[3-(5-hydroxypentanamido) prop yl]carbamate (Compound 18A) (1.0 eq, 4.00 g, 13.0 mmol) in dichloromethane (50.0 mL), trimethylsilyl trifluoromethanesulfonate (1.1 eq, 2.52 mL, 14.3 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 40 °C for 5 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under high vacuum to get crude. The crude was purified by reverse phase chromatography using 0-30% acetonitrile in water to afford Compound 18B as yellow viscous liquid, Yield: (5.80 g, 70.12%); LCMS m/z 638.2 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With titanium(IV) tetrachloride In dichloromethane at 0 - 50℃; Inert atmosphere; | 5.5-64.1 Step 1: To a mixture of (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H- pyran-2,4,5-triyl triacetate (A92-1, 20.0 g, 51.4 mmol) in DCM (200 mL) was added TiCh (61.6 mL,1 M in DCM) at 0°C under N2. After refluxing at 50°C overnight, the mixture was concentrated and purified by chromatography (0-80% ethyl acetate in petroleum) to give (2R,3R,4R,5R)-5-acetamido-2-(acetoxymethyl)-6-chlorotetrahydro-2H-pyran-3,4-diyl diacetate (A92-2, 8.5 g, 45% yield) as white solid. LC-MS (ESI) found: 366 [M+l]+. |
45% | With titanium(IV) tetrachloride In dichloromethane at 0 - 50℃; Inert atmosphere; | 5.5-64.1 Step 1: To a mixture of (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H- pyran-2,4,5-triyl triacetate (A92-1, 20.0 g, 51.4 mmol) in DCM (200 mL) was added TiCh (61.6 mL,1 M in DCM) at 0°C under N2. After refluxing at 50°C overnight, the mixture was concentrated and purified by chromatography (0-80% ethyl acetate in petroleum) to give (2R,3R,4R,5R)-5-acetamido-2-(acetoxymethyl)-6-chlorotetrahydro-2H-pyran-3,4-diyl diacetate (A92-2, 8.5 g, 45% yield) as white solid. LC-MS (ESI) found: 366 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ytterbium(III) tris(trifluoromethanesulfonate) In dichloromethane for 24h; Reflux; | Preparation of N-acetyl galactosamine To a stirred solution of tetra-O-acetate -GalNAc (0.60 g,1.54 mmol) in dry DCM (50 mL) was added propargyl alcoahol (182 μL, 3.08 mmol) and Yb (OTf)3(0.286 g, 0.46 mmol) before the temperature was raised to cause reflux. [4] The reaction wasmaintained at this temperature for 24 hours before it was washed with H2O (20 mL), the organiclayer dried (MgSO4), and concentrated. Column chromatographic purification (silica, AcOEt) gavethe desired - glycoside (516 mg, 87%) as a colourless solid. NaOMe (63 μL, 0.06 mmol) was addedto a solution of the above solution (222 mg, 0.58 mmol) in MeOH (10 mL) at room temperature.After 4 h, the reaction mixture was neutralized with Dowex50W-X8 (H+) resin. |
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H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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