Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein

1. Process for preparing the compounds of general formula III,

wherein

R 1 denotes cyclobutyl, cyclopentyl, cyclohexyl, R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or tetrahydropyran-4-yl; and

R 2 independently of one another denote hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl, aryl-C 1-3 -alkyl, allyl,

R a R b R c Si, CR a R b OR c , wherein two adjacent groups R 2 may be linked with each other to form a bridging group SiR a R b , CR a R b or CR a OR b —CR a OR b ; and

R′ denotes hydrogen, C 1-6 -alkyl, (C 1-4 -alkyl)carbonyl, (C 1-4 -alkyl)oxycarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl;

R a , R b , R c independently of one another denote C 1-4 -alkyl, aryl or aryl-C 1-3 -alkyl, while the alkyl groups may be mono- or polysubstituted by halogen;

L1 independently of one another are selected from among fluorine, chlorine, bromine, C 1-3 -alkyl, C 1-4 -alkoxy and nitro;

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, which may be mono- or polysubstituted with L1;

said method comprised of the step of adding an organometallic compound of the formula VI

wherein R 1 is defined as hereinbefore and M denotes Li or MgHal, wherein Hal denotes Cl, Br or I;

or a derivative thereof obtained by transmetallation;

which compound of the formula VI may be obtained by halogen-metal exchange or by the insertion of a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of general formula V

wherein R 1 is defined as hereinbefore and X denotes Br or I;

and optionally subsequent transmetallation, to a gluconolactone of general formula IV

wherein R 2 is as hereinbefore defined,

and reacting the adduct obtained with water or an alcohol R′—OH, where R′ denotes C 1-6 -alkyl, in the presence of an acid and optionally the product obtained in the reaction with water wherein R′ denotes H is converted in a subsequent reaction with an acylating agent into the product of formula III wherein R′ denotes (C 1-4 -alkyl)carbonyl, (C 1-4 -alkyl)oxycarbonyl, arylcarbonyl, or aryl-(C 1-3 -alkyl)-carbonyl, wherein the term aryl is defined as hereinbefore.

2. Process for preparing a compound of general formula II,

wherein

R 1 denotes cyclobutyl, cyclopentyl, cyclohexyl, R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or tetrahydropyran-4-yl; and

R 2 independently of one another denote hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl, aryl-C 1-3 -alkyl, allyl, R a R b R c Si, CR a R b OR c , wherein two adjacent groups R 2 may be linked with each other to form a bridging group SiR a R b , CR a R b or CR a OR b —CR a OR b ;

R a R b , R c independently of one another denote C 1-4 -alkyl, aryl or aryl-C 1-3 -alkyl, while the alkyl groups may be mono- or polysubstituted by halogen;

wherein an aglycon of the formula V

wherein

R 1 denotes cyclobutyl, cyclopentyl, cyclohexyl, R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or tetrahydropyran-4-yl; and

X denotes a bromine atom or a iodine atom;

is obtained by a method comprised of the steps of reacting a benzoyl chloride derivative of the formula XII

wherein X is defined as above; or a derivative thereof such as a benzoyl anhydride, an ester or a benzonitrile;

with a halobenzene of the formula XXVII

wherein Z 5 denotes a fluorine, chlorine or iodine atom;

in the presence of a catalyst to obtain an intermediate compound of the formula XXVI

wherein X and Z 5 are defined as hereinbefore; and

reacting the intermediate compound of the formula XXVI with R 1 —OH, wherein R 1 is defined as hereinbefore, or an anion thereof, in the presence of a base to yield a benzophenone derivative of the formula VII

wherein X and R 1 are defined as hereinbefore; and

the benzophenone derivative of the formula VII is reacted with a reducing agent in the presence of a Lewis acid to furnish the compound of the formula V as defined above,

and said compound of general formula V is transformed into an organometallic compound of the formula VI

wherein R 1 is defined as hereinbefore and M denotes Li or MgHal, wherein Hal denotes Cl, Br or I;

by an halogen-metal exchange or by the insertion of a metal in the carbon-halogen bond of the compound of general formula V, and optionally subsequent transmetallation; and

said organometallic compound of the formula VI is reacted with a gluconolactone of general formula IV

wherein R 2 is as hereinbefore defined, in accordance with the process according to claim 1 to obtain an intermediate of the formula III,

wherein R 2 , R′ and R 1 are defined as in claim 1 , and

reacting said intermediate of the formula III with a reducing agent to obtain the compound of the formula II.

3. Process according to claim 2 wherein in formula lithe substituent R 2 denotes hydrogen, and in the formulae IV the substituent R 2 denotes a protecting group as defined in claim 1 , and in the formula III the substituent R 2 has the same meaning as in formula IV or denotes hydrogen.

4. Process according to claim 1 , in which R 1 denotes R-tetrahydrofuran-3-yl or S-tetrahydrofuran-3-yl.

5. Process according to claim 2 , in which R 1 denotes R-tetrahydrofuran-3-yl or S-tetrahydrofuran-3-yl.

6. Process according to claim 3 , in which R 1 denotes R-tetrahydrofuran-3-yl or S-tetrahydrofuran-3-yl.

7. Process according to claim 2 , wherein in formula lithe substituent R 2 denotes hydrogen, and in the formulae IV the substituent R 2 denotes trimethylsilyl, and in the formula III the substituent R 2 has the same meaning as in formula IV or denotes hydrogen.

8. Process according to claim 2 , wherein the group X denotes iodine.

9. Process according to claim 2 , wherein the group R′ denotes hydrogen, methyl or ethyl.

10. Process according to claim 2 , wherein the group Z 5 denotes fluorine.

11. Process according to claim 2 , wherein the compound of the formula V is transformed into the organometallic compound of the formula VI by a halogen-metal exchange with C 3-4 -alkylmagnesium chloride or bromide without or in the presence of lithium chloride whereby the halogen-metal exchange is carried out between −80° C. and 10° C.

12. Process according to claim 2 , wherein the compound of the formula V is transformed into the organometallic compound of the formula VI by a halogen-metal exchange with isopropylmagnesium chloride in the presence of lithium chloride whereby the halogen-metal exchange is carried out between −80° C. and 10° C.

13. Process according to claim 2 , wherein the intermediate of the formula III is reacted with a silane as a reducing agent in the presence of or without a Lewis acid to obtain the compound of the formula II.

14. Process according to claim 2 , wherein the intermediate of the formula III is reacted with triethylsilane as a reducing agent in the presence of a Lewis acid to obtain the compound of the formula II.