Manufacture of lacto-n-tetraose
A general formula and compound technology, applied in the field of lactose-N-tetrasaccharide manufacturing, can solve the problems of not being able to provide attractive technology, poor yield, etc.
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Embodiment 1
[0441] Phenyl 2-deoxy-3,4,6-tri-O-acetyl-2-trichloroacetylamino-1-thio-β-D-glucopyranoside
[0442] D-Glucosamine hydrochloride (100.0 g, 464.0 mmol) was added to a stirred solution of NaOMe in methanol (300 mL, 2.6 equiv of NaOMe) in MeOH (200 mL) at -5 °C. Trichloroacetyl chloride (1.4 equiv) was added dropwise. After 10 minutes, the mixture was carefully neutralized by adding aqueous HCl. The reaction solution was evaporated to ~300 mL, after which water (200 mL) was added and the remaining methanol was evaporated. Another portion of water (200 mL) was added for crystallization. After overnight stirring in a cold room, the crystals were filtered and washed with 300 mL iPr 2 O washed twice and dried overnight to yield the N-trichloroacetamide protected compound (95.5 g, 63%) as an off-white solid.
[0443] Pyridine (75 mL, 6 equiv) was cooled to 0 °C and 2-deoxy-2-trichloroacetamido-D-glucopyranose (50 g) was added during stirring. Add Ac dropwise within 3h 2 O (5 equi...
Embodiment 2
[0448] Example 2 Benzyl 2,3,6,2',6'-penta-O-(4-chlorobenzoyl)-β-D-lactoside
[0449] A suspension of 10 g benzyl β-D-lactoside in acetone (50 ml), dimethoxypropane (3.5 ml) and TMSCl (7 ml) was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate (50ml), filtered and the filter cake washed with ethyl acetate (2x30ml). The wet filter cake was dissolved in pyridine (36ml) and dry DCM (50ml) and 4-chlorobenzoyl chloride (22ml) was slowly added to maintain the temperature between 40-45°C. After stirring overnight, methanol (10ml) and DCM (10ml) were added and an extractive workup (2x1M HCl, 1x water, 1x saturated NaHCO 3 ). The combined organic phases were concentrated and a thick slurry was poured into 50 ml isopropanol with vigorous stirring. The solid was filtered, washed with isopropanol and dried to yield 20.0 g of benzyl 2,3,6,2',6'-penta-O-(4-chlorobenzoyl)-3',4'-di- O-isopropylidene-β-D-lactoside (72%). [α] D =+58.4° (c=1 DCM), Mp: 184°C. ...
Embodiment 3
[0452] Example 3 Benzyl 4'-O-benzoyl-2,3,6,2',6'-penta-O-(4-chlorobenzoyl)-β-D-lactoside
[0453] To a mixture of 116.6 g of benzyl 2,3,6,2',6'-penta-O-(4-chlorobenzoyl)-β-D-lactoside in toluene (600 ml) was added orthobenzene Trimethyl formate (120ml) and camphenesulfonic acid (4g). The mixture was stirred vigorously at room temperature for 3h, then 80% acetic acid (160ml) was added. After stirring for another hour, the obtained biphasic mixture was separated, the organic phase was diluted with toluene (600 ml), water (800 ml) and saturated NaHCO 3 (2x600ml) washed, dried, filtered and evaporated. The resulting oil was dropped into 600 ml of heptane and seeded. The white crystalline compound was filtered, washed and dried to yield 110.3 g of product.
[0454] [α] D =+17.13° (c=1 DCM), M.p.: 156-157°C.
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