Process for the preparation of (2,3-dihydro-benzo[b][1,4]dioxin-2-yl) methanol derivatives

A process for the preparation of compounds of formula (I)

• wherein
• b is an integer from 0 to 4;
• each R5 is independently selected from the group consisting of halogen and C1-4alkyl;
• and pharmaceutically acceptable salts thereof;
• comprising
• reacting a mixture of a compound of formula (V) and a compound of formula (VI), wherein R1 is selected from the group consisting of C1-4alkyl, C2-4alkenyl, substituted aryl, aralkyl, heteroaryl, —O—C1-4alkyl, —O—C2-4alkenyl, —O— (substituted aryl), —O-aralkyl and —O-heteroaryl, with a phosphate;
• in an organic solvent or mixture of solvents;
• at about room temperature;
• to yield a mixture of the corresponding compound of formula (VII-a) and the corresponding compound of formula (VII-b), wherein Cation+ is the corresponding phosphate cation;
• reacting the mixture of the compound of formula (VII-a) and the compound of formula (VII-b) with a compound of formula (IX), an (R)-glycidyl-(substituted aryl)sulfonate wherein R2 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, nitro, cyano and dichloro;
• to yield a mixture of the corresponding compound of formula (VIII-a) and the corresponding compound of formula (VIII-b);
• reacting the mixture of the compound of formula (VIII-a) and the compound of formula (VIII-b) with an aqueous base or a mixture of an aqueous base and an alcohol;
• in an organic solvent or mixture of organic solvents;
• at a temperature in the range of from about −10° C. to about 25° C.;
• to yield the corresponding compound of formula (I).

A process for the preparation of a compound of formula (I-S)

• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a mixture of a compound of formula (V-S) and a compound of formula (VI-S), wherein R1 is selected from the group consisting of C1-4alkyl, C2-4alkenyl, substituted aryl, aralkyl, heteroaryl, —O—C1-4alkyl, —O—C2-4alkenyl, —O— (substituted aryl), —O-aralkyl and —O-heteroaryl, with a base;
• in an organic solvent or mixture of solvents;
• at a temperature in the range of from about −10° C. to about 25° C.;
• to yield a mixture of the corresponding compound of formula (VI-Sa) and the corresponding compound of formula (VII-Sb), wherein Cation+ is the corresponding base cation;
• reacting the mixture of the compound of formula (VII-Sa) and the compound of formula (VII-Sb) with a compound of formula (IX), an (R)-glycidyl-(substituted aryl)sulfonate wherein R2 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, nitro, cyano and dichloro;
• to yield a mixture of the corresponding compound of formula (VIII-Sa) and the corresponding compound of formula (VIII-Sb);
• reacting the mixture of the compound of formula (VIII-Sa) and the compound of formula (VIII-Sb) with an aqueous base or a mixture of an aqueous base and an alcohol;
• in an organic solvent or mixture of organic solvents;
• at a temperature in the range of from about −10° C. to about 25° C.;
• to yield the corresponding compound of formula (I-S).

A process for the preparation of a compound of formula (I-S)

• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a mixture of a compound of formula (V-S) and a compound of formula (VI-S), wherein R1 is selected from the group consisting of C1-4alkyl, C2-4alkenyl, substituted aryl, aralkyl, heteroaryl, —O—C1-4alkyl, —O—C2-4alkenyl, —O— (substituted aryl), —O-aralkyl and —O-heteroaryl, with a phosphate;
• at about room temperature;
• to yield a mixture of the corresponding compound of formula (VI-Sa) and the corresponding compound of formula (VII-Sb), wherein Cation+ is the corresponding phosphate cation;
• reacting the mixture of the compound of formula (VII-Sa) and the compound of formula (VII-Sb) with a compound of formula (IX), an (R)-glycidyl-(substituted aryl)sulfonate wherein R2 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, nitro, cyano and dichloro;
• to yield a mixture of the corresponding compound of formula (VIII-Sa) and the corresponding compound of formula (VIII-Sb);
• reacting the mixture of the compound of formula (VIII-Sa) and the compound of formula (VIII-Sb) with an aqueous base or a mixture of an aqueous base and an alcohol;
• in an organic solvent or mixture of organic solvents;
• at a temperature in the range of from about −10° C. to about 25° C.;
• to yield the corresponding compound of formula (I-S).