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Intermediates in the synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol Disclosure Number: IPCOM000234002D
Publication Date: 2014-Jan-07
Document File: 3 page(s) / 56K

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Intermediates in the synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

1-chloro-2-(4-fluorobenzyl)-4-iodobenzene, referred to as Compound I and (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran, referred to as Compound II, can be used as intermediates in the synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Compound I can be prepared by from (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone, referred to as compound Ia. Alternatively, Compound I can be prepared by reacting 2-chloro-5-iodobenzoyl chloride referred to as compound Ib, and fluorobenzene.

Compound I can then be reacted with (S)-tetrahydrofuran-3-ol to prepare Compound II, which can then be converted to (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Preparation of Compound I:

Method A:

To a solution of  (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (Compound Ia, 182.9 g) and aluminum chloride (81.5 g) in toluene (430 ml) at r.t. is added dropwise 1,1,3,3-tetramethyldisiloxane (82.5 g) .  After an additional  1 hour stirring, acetone (20 ml) is added and stirring continued for 1 hr at which time a solution of water (575 ml) and conc. HCl (34 g) is added while ensuring that the temperature does not rise above 50º.  The resulting mixture is stirred at 50º for an additional 30 min and allowed to stand for 20 min to allow the phases to separate.  The separated organic phase is concentrated to dryness under reduced pressure and toluene (60 ml) and ethanol (550 ml) are added to the residue (at ~65º). After cooling to 36º, seed crystals are added and stirring continued at this temperature of 30 min. followed by cooling to 0-5º and stirring for an additional 30 min.  The product is isolated by filtration and washed with ethanol to give 152 g (83%) of the title compound after drying.

Method B:

To a solution of  (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (Compound Ia, 95.6 g) and triethyl silane (101.5 ml)  in dichloromethane (75 ml)  and acetonitrile  (150 ml) at 10º is added with stirring boron trifluoride etherate (50.8 ml), maintaining the temperature below 20º.  After 14 hours stirring at rt, an additional triethyl silane (9 ml) and  boron trifluoride (4.4 ml) etherate are added.and the resulting solution is stirred for a further 3 hrs at 45-50º.  After cooling to rt, a solution of potassium hydroxide (“KOH”, 28 g)  in water (70 ml) is added and stirred for 2 hrs at which time the organic phase is separated off and the aqueous phas...