Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives

Patent metadata

Field	Value
Publication number	US-9873714-B2
Application number	US-201514680318-A
Country	US
Kind code	B2
Filing date	Apr 7, 2015
Priority date	Sep 30, 2009
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The present invention relates to processes for preparing a glucopyranosyl-substituted benzyl-benzene derivative of general formula III,

wherein R 1 is defined according to claim 1.

First claim

The invention claimed is:

1. Process for preparing a glucopyranosyl-substituted benzyl-benzene derivative of general formula III,

wherein
R 1 denotes (R)-tetrahydrofuran-3-yl or (S)-tetrahydrofuran-3-yl; and
R 2 denotes trimethylsilyl; and
R′ denotes hydrogen or C 1-6 -alkyl;
comprising the steps (S2), (S3) and (S4):
(S2): reacting the organometallic compound of the formula VI

wherein R 1 is defined as hereinbefore and M denotes Li, Mg or MgQ, wherein Q denotes Cl, Br, I or an organic moiety;
with a gluconolactone of general formula IV

wherein R 2 is as hereinbefore defined,
in an organic solvent or a mixture of two or more organic solvents; and
(S3): adding an aqueous solution comprising tartaric acid such that the reaction mixture forms an aqueous phase and an organic phase whereby the organic phase has a pH in the range from about 1 to 4; and
(S4): separating the organic phase comprising the adduct obtained in the step (S2) from the aqueous phase; and
(S5): reacting the obtained adduct with water or an alcohol R′—OH, where R′ denotes C 1-6 -alkyl, or a mixture thereof in the presence of one or more acids.

2. The process according to the claim 1 additionally comprising the step (S1):
(S1): reacting a compound of the formula V

wherein R 1 is defined as in claim 1 and X denotes Br, I or triflate;
with magnesium, lithium, a magnesium Grignard reagent or a lithium organic compound in an organic solvent or a mixture of two or more organic solvents yielding an organometallic compound of the formula VI

wherein R 1 is defined as hereinbefore and M denotes Li, Mg or MgQ, wherein Q denotes Cl, Br, I or an organic moiety.

3. The process according to the claim 2 wherein in the step (S1) the compound of the formula V is reacted with a C 3-4 -alkyl-magnesium chloride or bromide.

4. The process according to the claim 3 wherein at the beginning of, during or at the end of the step (S1) and/or at the beginning or during the step (S2) lithium bromide and/or lithium chloride is added to the reaction mixture whereby the molar ratio of the C 3-4 -alkyl-magnesium chloride or bromide to the lithium bromide and/or lithium chloride is in the range from 1:10 to 10:1.

5. The process according to claim 1 wherein the aqueous solution comprises 2 to 30 weight-% of tartaric acid.

6. The process according to claim 1 wherein the organic phase of the reaction mixture in the step (S3) comprises 2-methyltetrahydrofurane in an amount in the range from about 2 to 60 weight-% relative to the total amount of the organic phase of the reaction mixture.

7. The process according to claim 1
additionally comprising the step (S6):
(S6) reacting the glucopyranosyl-substituted benzyl-benzene derivative of general formula III with a reducing agent.

8. The process according to claim 1 , wherein the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, tert.-butyl-methylether, diethylether, heptane, toluene, benzene, dioxane, methylcyclohexane, hexane, dimethyl sulfoxide, dichloromethane and chloroform.

9. The process according to claim 1 , wherein the amount of the gluconolactone relative to the organometallic compound of the formula VI is in the range from about 0.8 to 3 mol.

10. The process according to claim 1 , wherein R′ denotes hydrogen, methyl or ethyl.

11. The process according to claim 1 , wherein in the step (S5) the obtained adduct is reacted with an alcohol R′—OH, wherein the alcohol R′—OH is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, tert-butanol or mixtures thereof.

12. The process according to claim 1 , wherein in the step (S5) with the addition of the one or more acids a pH is to be obtained in a pH range from about 0 to 7.

13. The process according to claim 1 , wherein in the step (S5) the one or more acids are selected from the group consisting of hydrochloric acid, sulphuric acid, nitric acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, oxalic acid and succinic acid.

14. The process according to claim 1 , wherein in the step (S5) the reaction temperature is in the range from about −50 to 50° C.

15. The process according to claim 2 , wherein the amount of the magnesium, lithium, a magnesium Grignard reagent or a lithium organic compound relative to the compound of the formula V is in the range from about 0.5 to 2 mol.

16. The process according to claim 2 , wherein the reaction in step (S1) and/or step (S2) is carried out in a temperature range from −70 to 10° C.

17. The process according to claim 5 , wherein the aqueous solution comprises 5 to 20 weight % of tartaric acid.

18. The process according to claim 6 , wherein the amount of 2-methyltetrahydrofurane is in the range from about 10 to 40 weight-% relative to the total amount of the organic phase of the reaction mixture.

19. The process according to claim 1 , wherein the organic phase in step (S3) has a pH in the range from about 2 to 3.

Assignees

• Boehringer Ingelheim Int

Inventors

• Weber Dirk
• Fiedler Tobias
• Filser Christian
• Hamm Rainer
• Orlich Simone
• Post Matthias
• Renner Svenja
• Wang Xiao-Jun
• Wirth Thomas

Classifications

• C07D309/10

  Oxygen atoms · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H7/04

  Carbocyclic radicals · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H1/06

  Separation; Purification · CPC title