WO2005019229A1

WO2005019229A1 - Process for purification of boronic acid and its derivatives

Info

Publication number: WO2005019229A1
Application number: PCT/IN2003/000284
Authority: WO
Inventors: Shashidhara Bhat; Shridhar Punachithaya; Sambasivam Ganesh
Original assignee: Biocon Ltd
Current assignee: Biocon Ltd
Priority date: 2003-08-26
Filing date: 2003-08-26
Publication date: 2005-03-03
Anticipated expiration: 2006-02-26
Also published as: AU2003269474A1

Abstract

A process for purification of boronic acid or its derivatives of the formula (I): R-B(OH)2 wherein R is any unsubstituted or substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or derivatives thereof. The process comprises (a) treating crude compound of the formula (I) with a base to afford a salt of boronic acid, (b) isolating the substantially pure salt of compound of formula (I) from other compounds (such as impurities etc) by solvent extraction etc, (c) treating the substantially pure salt with an acid to afford substantially pure boronic acid and (d) isolating the substantially pure compound of formula (I).

Description

PROCESS FOR PURIFICATION OF BORONIC ACID AND ITS

DERIVATIVES

FIELD OF THE INVENTION The present invention relates to a novel process for purification of boronic acid and its derivatives. BACKGROUND OF THE INVENTION Boronic acid derivatives of organic compounds are of particular interest, not only as intermediary means for forming covalent carbon-carbon bonds between organic compounds, but as a starting point for further chemical manipulations and transformations or in conferring or increasing biological activity to otherwise biologically inactive compounds. Whilst these boronic acid derivatives may be obtained by conventional hydrolysis or hydrogenolysis procedures applied to boronic ester compounds, many conventional conditions employed in the preparation of boronic ester compounds are incompatible with compounds bearing sensitive functionality. Furthermore, there are practical and commercial advantages in reducing the number of chemical manipulations employed in a synthetic procedure and it is therefore desirable to obtain the boronic acid derivatives directly. Prior art methods per se suffer from certain drawbacks like the boronic acid will have varying amount of anhydride and very difficult to obtain with purity more than 97%. The process of the present invention alleviates the drawbacks of the prior art as the present method results in very high purity of the boronic acid. The process in simple and does not require further purification steps. SUMMARY OF THE INVENTION The present invention relates to a novel process for purification of boronic acid and its derivatives of formula I. The boronic acid and its derivatives (FORMULA I) can be purified by employing one or more in any order of the following steps: a) treating crude compound of formula I with a base to afford a salt of boronic acid, b) isolating substantially pure salt of compound of formula I, c) treating the substantially pure salt with an acid to afford substantially pure boronic acid, d) isolating the substantially pure boronic acid (FORMULA I). In particular, the process of present invention comprises, a) treating crude compound of formula I with compounds of sodium or potassium to afford a sodium or potassium salt of boronic acid, b) isolating substantially pure salt of compound of formula I, c) treating the salt with a suitable acid to afford substantially pure boronic acid or its derivative, d) isolating the substantially pure boronic acid (FORMULA I). The process of present invention has following advantages:

1. High purity of the product

2. Simple reaction 3. Economic

4. Industrially scalable 5. Use of non-hazardous reagent and reaction conditions DETAILED DESCRIPTION OF THE INVENTION The first aspect of the invention is to provide a method for purification of boronic acid or its derivatives. The second aspect of the invention is to provide a simple, economic non-hazardous and industrially scalable process for the purification of boronic acid or its derivatives. As mentioned earlier, the boronic acid or its derivatives of formula I can be purified by employing a novel process comprising: a) treating crude compound of formula I with a base to afford a salt of boronic acid, b) isolating substantially pure salt of compound of formula I, c) treating the salt with an acid to afford substantially pure boronic acid, d) isolating the substantially pure boronic acid (FORMULA I)

HO OH B R

FORMULA I wherien R is any unsubstituted or substituted alkyl, cycloalkyl, aryl, hetereoaryl, heterocycloalkyl or derivatives thereof, The boronic acid or its derivatives can be treated with a base to afford a salt of boronic acid. The base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate or any other suitable base to form salt. The salt of boronic acid or its derivatives can be separated from the reaction mixture by addition of an organic solvent or mixture of organic solvents. Preferably, the solvents can be selected from diethylether or diisopropylether. The reaction can be carried out at a temperature between 0°C to 40°C. The salt of boronic acid can be dissolved in aqueous solvent and treated with an acid to afford substantially pure boronic acid derivatives. Preferably, the acid is a mineral acid. Most preferably, the mineral acid is selected from hydrochloric acid or sulphuric acid. The reaction can be carried out at a temperature between 0°C to 40°C. The substantially pure boronic acid thus obtained after hydrolysis with acid can be extracted into a water immiscible solvent. Preferably, the solvent is ethyl acetate. The substantially pure boronic acid in the organic solvent can be isolated by either evaporation of the organic solvent or by addition of an anti-solvent. The evaporation of the organic solvent can be effected by distillation without or with reduced pressure. The anti-solvent can be a water immiscible solvent. The water immiscible solvent can be hydrocarbon. Preferably, the hydrocarbon can be selected from pentane, hexane, heptane or cylohexane. The important aspect of the present invention is the conversion of crude boronic acid or its derivatives to salt of boronic acid or its derivatives which results in the purification of the boronic acid by leaving other impurities like anhydride into the mother liquor. The pure salt of boronic acid can be used directly for Suzuki coupling or other reactions to prepare industrially important molecules. The process of the present invention is described in scheme I. The following examples are provided to illustrate some preferred embodiments of the invention. However it is to be understood that the following description is not to supersede the generality of the invention previously described. EXAMPLES EXAMPLE 1: 4-cyclobutyl benzene boronic acid To crude 4-cyclobutyl benzene boronic acid (lOg) sodium hydroxide solution (50%, 8ml) was added and mixed. To this mixture diethyl ether (50 ml) was added and stirred. The solid separated was filtered, washed with diethyl ether and dried to obtain pure sodium salt of 4-cyclobutyl benzene boronic acid with yield of llg. The pure sodium salt thus obtained was dissolved in 30ml water and acidified to pH 3 with 15ml of 1.5N HCI to afford pure 4- cyclobutyl benzene boronic acid. The reaction mixture was extracted ethyl acetate (25ml, twice). The combined organic phase was washed with 35ml water, 35ml brine and concentrated. The pure compound was crystallized with hexane. Yield: 8g Purity by HPLC: 99.6% EXAMPLE 2: 4-n-butyl benzene boronic acid To crude 4-n-butyl benzene boronic acid (lOg) sodium hydroxide solution (50%, 8ml) was added and mixed. To this mixture diethyl ether (50 ml) was added and stirred. The solid separated was filtered, washed with diethyl ether and dried to obtain pure sodium salt of 4-n-butyl benzene boronic acid with yield of 10.7g. The pure sodium salt thus obtained was dissolved in 30ml water and acidified to pH 3 with 15ml of 1.5N HCI to afford pure 4- n-butyl benzene boronic acid. The reaction mixture was extracted ethyl acetate (25ml, twice). The combined organic phase was washed with 35ml water, 35ml brine and concentrated. The pure compound was crystallized with hexane. Yield: 7.9g Purity by HPLC: 99.8% I

EXAMPLE 3: 4-{8-(l,4-dϊoxaspiro[4.5]decane)}benzene boronic acid To crude 4-{8-(l,4-dioxaspiro[4.5]decane)}benzene boronic acid (lOg) sodium hydroxide solution (50%, 8ml) was added and mixed. To this mixture diethyl ether (50 ml) was added and stirred. The solid separated was filtered, washed with diethyl ether and dried to obtain pure sodium salt of 4-{8-(l,4- dioxaspiro[4.5]decane)}benzene boronic acid with yield of 10.5g. The pure sodium salt thus obtained was dissolved in 30ml water and acidified to pH 3 with 15ml of 1.5N HCI to afford pure 4-{8- (l,4-dioxaspiro[4.5]decane)}benzene boronic acid. The reaction mixture was extracted ethyl acetate (25ml, twice). The combined organic phase was washed with 35ml water, 35ml brine and concentrated. The pure compound was crystallized with hexane. Yield: 7.5g Purity by HPLC: 99.7% EXAMPLE 4: Benzene boronic acid To crude benzene boronic acid (lOg) sodium hydroxide solution (50%, 8ml) was added and mixed. To this mixture diethyl ether (50 ml) was added and stirred. The solid separated was filtered, washed with diethyl ether and dried to obtain pure sodium salt of benzene boronic acid with yield of 11.2g. The pure sodium salt thus obtained was dissolved in 30ml water and acidified to pH 3 with 15ml of 1.5N HCI to afford pure benzene boronic acid. The reaction mixture was extracted ethyl acetate (25ml, twice). The combined organic phase was washed with 35ml water, 35ml brine and concentrated. The pure compound was crystallized with hexane. Yield: 8.8g Purity by HPLC: 100% Scheme

R is any unsubstituted or substituted alkyl, cycloalkyl, aryl, hetereoaryl, heterocycloalkyl or derivatives thereof.

Claims

We claim:

1. A process for the purification of boronic acid or its derivatives of formula I HO OH B I R

FORMULA I wherien R is any unsubstituted or substituted alkyl, cycloalkyl, aryl, hetereoaryl, heterocycloalkyl or derivatives thereof, which comprises in any order one or more of the steps as follows: a) treating crude compound of formula I with a base to afford a salt of boronic acid, b) isolating the substantially pure salt of compound of formula I, c) treating the substantially pure salt with an acid to afford substantially pure boronic acid, d) isolating the substantially pure compound of formula I.

2. A process as in claim 1, wherein the crude boronic acid or its derivative of formula I is in any state selected from solid, liquid or semisolid.

3. A process as in claim 1, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate or any other suitable base capable of forming salt with the boronic acid.

4. A process as in claim 1, wherein the salt of boronic acid or its derivative is treated with a solvent to separate from the impurities.

5. A process as in claim 4, wherein the solvent is preferably selected from diethyl ether or diisopropylether.

6. A process as in claim 1, wherein the isolation of the salt and impurities is done by filtration.

7. A process as in claim 1, wherein the substantially pure salt is dissolved in water.

8. A process as in claim 1, wherein the substantially pure salt is treated with an acid in aqueous solution.

9. A process as in claim 1, wherein the acid is preferably a mineral acid or any acid capable of hydrolyzing the salt to afford free boronic acid.

10. A process as in claim 9, wherein the acid is hydrochloric acid or sulphuric acid.

11. A process as in claim 1, wherein the substantially pure compound of formula I is treated with a water immiscible solvent.

12. A process as in claim 11, wherein the solvent is ethyl acetate.

13. A process as in claim 1, wherein the substantially pure compound of formula I is isolated by vaporization of the solvent.

14. A process as in claim 1, wherein the substantially pure compound of formula I is isolated by treatment with an anti- solvent.

15. A process as in claim 14, wherein the anti-solvent is a hydrocarbon.

16. A process as in claim 15, wherein the hydrocarbon is selected from pentane, hexane, heptane or cyclohexane.