Crosslinked nucleoside intermediate crystal and method for producing same, and method for producing crosslinked nucleoside amidite

1. A crystal of a compound represented by the following formula 5:

in which R 1 represents a protecting group for a hydroxyl group, and R 2 represents a leaving group.

2. The crystal according to claim 1 , wherein the crystal shows peaks at 5.9±0.3, 11.4±0.6, 11.8±0.6, 13.2±0.7, 16.2±0.8, 17.2±0.9, 18.5±0.9, 19.5±1.0, 19.7±1.0, 20.1±1.0, 20.4±1.0, 21.4±1.1, 22.0±1.1, 23.0±1.2, 24.1±1.2, 24.3±1.2, 26.4±1.3, and 29.9±1.5(°) as a diffraction angle (2θ) in powder X-ray analysis.

3. The crystal according to claim 1 , wherein the crystal shows an endothermic peak at 124° C. as measured by a thermogravimetry/differential thermal analysis (TG/DTA) apparatus.

4. The crystal according to claim 1 , wherein the compound represented by the formula 5 is a crosslinked nucleoside intermediate.

5. A method for producing a crystal of a compound represented by formula 5, the method comprising the following steps 1 to 5:

step 1: protecting hydroxyl groups of a compound represented by formula 1 to obtain a compound represented by formula 2;

step 2: converting a dimethyldioxolanyl group at position 4 of a compound represented by formula 2 to an aldehyde group to obtain a compound represented by formula 3;

step 3: reducing the compound represented by the formula 3 to convert the aldehyde group at the position 4 to a hydroxyl group to obtain a compound represented by formula 4;

step 4: converting the hydroxyl group at the position 4 of the compound represented by the formula 4 to a leaving group to obtain a compound represented by formula 5; and

step 5: crystallizing the compound represented by the formula 5 from a crystallization solvent to obtain the crystal of the compound represented by the formula 5;

in which R 1 represents a protecting group for a hydroxyl group, and R 2 represents a leaving group.

6. The method for producing the crystal according to claim 5 , further comprising a crystallization step between the step 2 and the step 3.

7. The method for producing the crystal according to claim 5 , wherein the compound represented by the formula 5 is a crosslinked nucleoside intermediate.

8. A method for producing a crosslinked nucleoside amidite, the method comprising the following steps:

step 6: suspending the crystal of the compound represented by the formula 5 obtained by the method according to claim 5 in a solvent, and then converting isopropylidene groups of the compound to acetyl groups to obtain a compound represented by formula 6;

step 7: condensing the compound represented by the formula 6 with a silylated base to obtain a compound represented by formula 7;

step 8: removing protecting groups of the compound represented by the formula 7 while at the same time performing a cyclization reaction to obtain a compound represented by formula 8;

step 9: removing the protecting groups for the hydroxyl groups of the compound represented by the formula 8 to obtain a compound represented by formula 9; and

step 10: optionally introducing a protecting group into the amino group on the base moiety of the compound represented by the formula 9 to obtain a compound represented by formula 10;

in which R 1 represents a protecting group for the hydroxyl group, R 2 represents a leaving group, and R 3 represents a hydrogen atom or an amino-protecting group.