Crystalline sugar compositions and method of making
Described are novel crystalline pivaloyl furanoses and methods of crystallizing the pivaloyl furanoses. These compounds are useful as intermediates in the synthesis of compounds such as the deoxyjirimycins and nojirimycins and are particularly useful as intermediates for production on a multi-kg scale. Particular crystalline compounds include 1,2,3,6-tetrapivaloyl-α-D-galactofuranose, 1,2,3,6-tetrapivaloyl-α-L-altrofuranose, and 5-azido-5-deoxy-1,2,3,6-tetrapivaloyl-α-D-galactofuranose.
1 . A crystalline furanose of the formula:
wherein each R is independently H, acetyl, methylacetyl, dimethylacetyl, trimethylacetyl, or a protecting group, and at least two Rs are selected from the group consisting of methylacetyl, dimethylacetyl, and trimethylacetyl;
R 1 and R 2 are independently H, OH, OR 3 , N 3 , NH 2 , NHR 3 , NR 3 2 , SH, SR 3 , OS(═O) 2 R 3 , C(═O)R 3 , methylacetoxy, dimethylacetoxy, trimethylacetoxy, acetoxy, chloroacetoxy, dichloroacetoxy, trichloroacetoxy or an O-protecting group, wherein at least one of R 1 and R 2 is H; and
each R 3 is independently H or a substituted or unsubstituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 6 cycloalkyl, C 5 -C 12 cycloalkenyl, C 5 -C 12 aryl, C 4 -C 12 heteroaryl, C 6 -C 12 arylalkyl, C 4 -C 12 heterocycle, C 6 -C 12 heterocycloalkyl, C 5 -C 12 heteroarylalkyl, a C 2 -C 12 acyl, or a combination thereof; and
wherein the molecular weight of the furanose is between 300 g/mol and 1000 g/mol.
2 . The crystalline furanose of claim 1 , wherein the furanose has a molecular weight of at least 350 g/mol.
3 . The crystalline furanose of claim 2 , wherein the furanose has a molecular weight of at least 400 g/mol.
4 . The crystalline furanose of claim 3 , wherein furanose has a molecular weight of at least 450 g/mol.
5 . The crystalline furanose of claim 1 , wherein at least three R groups are trimethylacetyl.
6 . The crystalline furanose of claim 5 , wherein the furanose is a tetrapivaloyl furanose.
7 . The crystalline furanose of claim 1 , wherein R 1 is OH or N 3 and R 2 is H.
8 . The crystalline furanose of claim 1 , wherein the furanose is 1,2,3,6-tetrapivaloyl-α-D-galactofuranose or 1,2,3,6-tetrapivaloyl-α-L-altrofuranose.
9 . The crystalline furanose of claim 1 , wherein the furanose is 5-azido-5-deoxy-1,2,3,6-tetrapivaloyl-α-D-galactofuranose.
10 . A method for producing a crystalline furanose represented by the formula:
wherein each R is independently H, acetyl, methylacetyl, dimethylacetyl, trimethylacetyl, or a protecting group, and at least two Rs are selected from the group consisting of methylacetyl, dimethylacetyl, and trimethylacetyl;
R 1 and R 2 are H, OH, OR 3 , N 3 , NH 2 , NHR 3 , NR 3 2 , SH, SR 3 , OS(═O) 2 R 3 , C(═O)R 3 , methylacetoxy, dimethylacetoxy, trimethylacetoxy, acetoxy, chloroacetoxy, dichloroacetoxy, trichloroacetoxy or an O-protecting group, wherein at least one of R 1 and R 2 is H;
each R 3 is independently H or a substituted or unsubstituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 6 cycloalkyl, C 5 -C 12 cycloalkenyl, C 5 -C 12 aryl, C 4 -C 12 heteroaryl, C 6 -C 12 arylalkyl, C 4 -C 12 heterocycle, C 6 - C 12 heterocycloalkyl, C 5 -C 12 heteroarylalkyl, a C 2 -C 12 acyl, or a combination thereof; and
wherein the molecular weight of the furanose is between 300 g/mol and 1000 g/mol,
comprising adding the furanose to, or forming the furanose in a solvent; and crystallizing the furanose from the solvent.
11 . The method of claim 10 , wherein the furanose has a molecular weight of at least 350 g/mol.
12 . The method of claim 11 , wherein the furanose has a molecular weight of at least 400 g/mol.
13 . The method of claim 12 , wherein furanose has a molecular weight of at least 450 g/mol.
14 . The method of claim 10 , wherein at least three R groups are trimethylacetyl.
15 . The method of claim 16 , wherein furanose is a tetrapivaloyl furanose.
16 . The method of claim 15 , wherein at least one of monopivaloyl, dipivaloyl, tripivaloyl, or pentapivaloyl furanose is formed in addition to the tetrapivaloyl furanose, and the monopivaloyl, dipivaloyl, tripivaloyl, or pentapivaloyl furanose is not crystallized when the tetrapivaloyl furanose is crystallized.
17 . The method of claim 10 , wherein R 1 is OH and R 2 is H.
18 . The method of claim 17 , wherein the solvent comprises heptane.
19 . The method of claim 10 , wherein R 1 is N 3 and R 2 is H.
20 . The method of claim 19 , wherein the solvent comprises methanol.
21 . The method of claim 10 , wherein crystallizing comprises cooling the solvent system, allowing the solution to cool without an external cooling source, adding a seed crystal, adding an additional solvent or solvent system to cause the furanose to precipitate out of solution, or a combination thereof.
22 . The method of claim 21 , wherein crystallizing comprises first heating the furanose and the solvent to a temperature near the boiling point of the solvent, and then cooling to a temperature of between −20° C. and −10° C., and waiting for at least 36 hours.
23 . The method of claim 10 , wherein the method further comprises:
adding a second solvent, wherein the second solvent is miscible with the solvent and capable of dissolving the furanose; and
subjecting the solution to a crystallization treatment, to obtain said crystalline form of the furanose.