MXPA99002754A - Selective alkylation of an alcohol substituted phenol compound - Google Patents

Abstract

The present invention relates to a process for the selective alkylation of intermediates of betaxolol.

Description

SELECTIVE ALLOCATION OF A PHENOL COMPOSITE SUBSTITUTED WITH ALCOHOL 1. Field of the Invention The present invention relates to a novel process for the preparation of 1- hydrochloride. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy] -3-isopropylamino-propane-2-ol by selective alkylation of a phenol substituted with alcohol. 2- Background of the Invention The process normally used to produce 1-. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy] -3-isopropylamino-propane-2-ol (Betaxolol) involved protecting the phenol functional group so that the alcohol functionality can be alkylated. The resulting steps of protection and deprotection extend the length of the synthesis. In addition, a chromatographic purification is required, resulting in a lower overall yield. US Pat. No. 4,252,984 to Manoury et al. Describes the benzylation of the phenolic alcohol of 4-hydroxyphenetanoic acid. The ester group is then reduced to an alcohol and subsequently alkylated with (bromomethyl) cyclopropane. The debenzylation with H in the presence of a catalyst deprotects the compound back to a phenolic intermediate. In a final step, the addition of isopropylamine produces the final product, Betaxolol. A column of silica gel is used to purify the compound. This process involves the protection of the phenolic hydroxy group and the subsequent deprotection.

US 4,760,182 to Ippolito et al., Describes a process for producing Betaxolol by converting 4-hydroxyphenetanol to a phenoxide anion with a base and then reacting the phenoxide anion with epichlorohydrin to produce 1- [4- (2-hydroxyethyl) phenoxy] ] -2,3-epoxypropane. The 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane is reacted with a primary amine to produce an intermediate of Betaxolol. The protection and deprotection steps are also necessary to obtain the final product. US 5,034,535 to Keding et al. Describes reacting 4- [2-methoxyeti!] Phenol with the ester of (S) -5-hydroxymethyl-3-isopropyloxazolidin-2-one sulfonic acid to prepare an intermediate in the preparation of S-metoprolol. The processes normally used to produce Betaxolol involve steps of protection and extra deprotection, which makes the reaction complicated. Therefore, it is advantageous and preferable to have a process from which the protection and deprotection steps have been eliminated. In addition, it could be an additional advantage to have a process which produces highly pure betaxolol. SUMMARY OF THE INVENTION The present invention relates to the selective alkylation of a phenol compound substituted with alcohol to form an ether product by the addition of an alkylating agent in the presence of a strong base and a solvent.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the selective alkylation of a phenol compound substituted with alcohol where an ether is obtained. The present invention provides the selective alkylation of the unprotected alcohol substituent and subsequent deprotection of the phenolic hydroxy portion. In one embodiment of the present invention, a phenol compound containing an alcohol substituent can be selectively alkylated at the position of the alcohol substituent. In the present invention, as depicted in Scheme 1, a phenol compound containing an alcohol substituent, such as 4-hydroxyphenetanol (1), can be selectively alkylated via an oxygen dianion (2). The formation of the oxygen dianion (2) avoids the need to protect the phenolic hydroxy. The reaction of 4-hydroxyphenetanol (1) in a solvent with a strong base produces a dianion of oxygen (2) which is selectively alkylated to form a 4 - [(2-cyclopropylmethoxy) -ethyl] phenol (3) in the presence of suitable alkylating agents. SCHEME 1 - ^ \ < In another embodiment of the present invention, selective alkylation processes can be used in the synthesis of betaxolol intermediates or their salts, as shown in Scheme 2. For example 4 - [(2-cyclopropylmethoxy) -ethyl] phenol (3) can be further reacted with a halide compound, such as, but not intended to be limited to, epichlorohydrin , in the presence of base to give an epoxide, 1 -. { 4- [2- (Cyclopropylmethoxy) -ethyl] phenoxy] -2,3-epoxypropane (4). The subsequent addition of isopropylamine produces 1 -. { 4- [2- (Cyclopropylmethoxy) ethyl] phenoxy] -S-isopropylamino-propane-2-ol (free base of Betaxolol) which can then be converted to the hydrochloride salt (5) by addition of HCl. SCHEME 2 Suitable alkylating agents used in the selective alkylation of the present invention include substituted haloalkyls, haloalubstituted cycloalkyls, haloalubstituted cycloalkylalkyls, haloalubstituted arylalkyls, haloalubstituted aryls, haloalubstituted alkoxides, haloalubstituted arylalkoxides, haloalubstituted cycloalkoxides, haloalubstituted cycloalkylalkoxides, halo substituted heterocyclics, or heterocyclic) halosubstituted alkyls. In addition, the sulfonated substituted alkylation agents can be used in place of the halosubstituted alkylating agents. Alkyl groups include alkyl groups of straight or branched chain alkyl radicals of 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-ethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. Preferred haloalkyls include but are not intended to be limited to alkyl chloride, alkyl bromide and alkyl iodide. Suitable strong bases used in the selective alkylation of the present invention include, but are not intended to be limited to, potassium terbutoxide, alkyllithium including, but not limited to, butyl lithium (BuLi), and lithium diisopropylamide. (LDA, for its acronym in English) and methyl-2-piperidone, 1-methyl-2-pyrrolidone, and 1,3-dimetll-2-imidazolidinone. The reaction temperature is usually operated from about -10 ° C to about 70 ° C. A more preferred temperature scale is from about 0 ° C to about 50 ° C. An even more preferred temperature scale is from about 20 ° C to about 50 ° C. The process of the present invention can be used to form betaxolol salts. The salt forms of betaxolol can be derived from inorganic or organic acids. The salts can be prepared in situ during the isolation and final purification of betaxolol or separately by reacting the free base of betaxolol with a suitable organic acid. These salts include, but are not limited to the following: acetate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydoryodide, lactate, maleate, methanesulfonate, oxalate, propionate, succinate, tartrate and thiocyanate.

Examples of acids that can be employed to form acceptable salts of the compound of the present invention include such inorganic acids such as hydrochloric, sulfuric and phosphoric acids and said organic acids such as acetic, oxalic, maleic, succinic and citric acids. Someone skilled in the art knows well how to prepare the betaxolol salts. It is intended that the following examples be illustrative of the present invention and not be considered as limiting. Example 1 4 - [(2-Cyclopropylmethoxy) -ethyl] phenol One reaction flask was charged with 4-hydroxyphenethyl alcohol (1) (100 g, 0.72 mol), potassium terbutoxide (240 g, 2.17 mol), and 500 ml of DMSO. The mixture was stirred under nitrogen at 50 ° C for 30 minutes. A solution of (Chloromethyl) cyclopropane (100 g, 1.10 moles) in 500 ml of DMSO was added dropwise to the reaction mixture. The mixture was then stirred at 50 ° C for one hour and then cooled to room temperature. The reaction mixture was subsequently cooled with 1 l of water. The aqueous mixture was washed twice with 600 ml portions of toluene to remove impurities. The desired product was extracted from the aqueous mixture neutralized with toluene. The toluene extract was then washed with water and concentrated in vacuo to give 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol (3) (70.5 g, 51%). Example 2 1- Hydrochloride. { 4- [2- (cyclopropylmethoxy) -ethyl] -phenoxy] -3-isopropylamino-2-ol (betaxolol hydrochloride) To a solution of 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol (3) (63.02 grams) , 0.328 mmoles) in 600 ml of acetonitrile were added 173 grams (1.25 mmoles) of potassium carbonate and 142 grams (1.53 mmoles) of eipiclorohydrin. After reflux for eight hours, the solids were filtered. The filtrate was concentrated by vacuum distillation. The residue was dissolved in 200 ml of toluene and the solvent was removed by vacuum distillation. The resulting residue was dissolved in 300 ml of isopropylamine and stirred at 29-33 ° C for two days. Excess isopropylamine was removed under reduced pressure and 300 ml of toluene was added to the residue. The product solution was extracted with 400 ml of 5% aqueous hydrochloric acid, followed by a separation of the layers. After another wash with 300 ml of toluene, the aqueous layer was adjusted to pH 9-10 and the product was extracted with 3x300 ml of toluene. The combined toluene layers were washed twice with 300 ml portions of water. After toluene was removed by vacuum distillation, the residue was redissolved in 150 ml of toluene. To the above toluene solution, 38 ml of 36% aqueous hydrochloric acid was added and stirred at room temperature for 10 minutes. The solvent was removed by vacuum distillation, the residue was crystallized with 200 ml of acetonitrile and then recrystallized with 350 ml of isopropanol to give 52.6 grams (47% yield) of 1 - hydrochloride. { 4- [2- (cyclopropylmethoxy) -ethyl] -phenoxy} -3-isopropylamino-2-ol (Betaxolol) with >99% purity

Claims (17)

1. CLAIMS 1. A process for the selective alkylation of an alcohol-substituted phenol compound on the alcohol functionality to form an ether product by the addition of an alkylating agent in the presence of a strong base and a solvent.
2. 2. A process of claim 1, wherein the alkylating agent is selected from the group consisting of: haloalkyls, haloalubstituted cycloalkyls, haloalubstituted cycloalkylalkys, haloalubstituted arylalkyls, haloalubstituted aryls, haloalubstituted alkoxys, haloalubyxes halosubstituted, haloalubstituted cycloalkoxys, haloalicylated cycloalkylalkoxy, heterocyclics halosubstituted and (heterocyclic) alkyls substituted.
3. 3. A process of claim 1, wherein the alkylating agent is selected from the group consisting of alkyls substituted with sulfonates, cycloalkyls, cycloalkylalkys, arylalkys, alkoxys, arylalkoxys, cycloalkoxys, cycloalkylalkoxys, heterocyclics, and haloesubstituted (heterocyclic) alkyls.
4. 4. A process of claim 1, wherein the strong base is selected from the group consisting of a potassium terbutoxide, alkyllithium, lithium diisopropylamide, phenyllithium and Grignard reagents.
5. 5. A process of claim 1, wherein the temperature of the reaction is carried out at a temperature of about -10 ° C to about 70 ° C.
6. 6. A process of claim 1, wherein! A. The reaction temperature was carried out at a temperature from about 0 ° C to about 50 ° C.
7. 7. A process of claim 1, wherein the temperature of the reaction is carried out at a temperature of about 20 ° C to about 50 ° C.
8. 8. A process of claim 1, wherein said solvent is selected from the group consisting of: dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-piperidone, 1-methyl-2 -pyrrolidone and 1,3-dimethyl-2-imidazolidone.
9. 9. A process for the production of 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol comprising reacting 4-hydroxyphenetanol with an alkylating agent in the presence of a strong base and a solvent to produce 4 - [(2- cyclopropylmethoxy) -ethyl] -phenol.
10. 10. A process of claim 9, wherein the alkylating agent is selected from the group consisting of: haloalkyls, haloalubstituted cycloalkyls, haloalubstituted cycloalkylalkys, haloalubstituted arylalkyls, haloalubstituted aryls, haloalubstituted alkoxys, haloalubstituted haloalkoxys, haloalubstituted cycloalkoxys, haloalicylated cycloalkylalkoxys, heterocyclics halosubstituted and (heterocyclic) alkyls substituted.
11. 11. A process of claim 9, wherein the alkylating agent is selected from the group consisting of alkyls substituted with sulfonates, cycloalkyls, cycloalkylalkys, arylalkys, alkoxys, arylalkoxys, cycloalkoxys, cycloalkylalkoxys, heterocyclics, and haloesubstituted (heterocyclic) alkyls.
12. 12. A process of claim 9, wherein the strong base is selected from the group consisting of a potassium terbutoxide, alkyllithium, lithium diisopropylamide, phenyllithium and Grignard reagents.
13. 13. A process of claim 9, wherein the temperature of the reaction is carried out at a temperature of about -10 ° C to about 70 ° C.
14. 14. A process of claim 9, wherein the temperature of the reaction is carried out at a temperature from about 0 ° C to about 50 ° C.
15. 15. A process of claim 9, wherein the temperature of the reaction is carried out at a temperature of about 20 ° C to about 50 ° C.
16. 16. A process of claim 9, wherein said solvent is selected from the group consisting of: dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-piperidone, 1-methyl-2 -pyrrolidone and 1,3-dimethyl-2-imidazolidinone.
17. 17. A process of claim 9, wherein the alkylating agent is selected from the group of (chloromethyl) cyclopropane or (bromomethyl) cyclopropane. 18 A process for the production of Betaxolol comprising the steps of: a) reacting 4-hydroxyphenetanol with (chloromethyl) cyclopropane or (bromomethyl) cyclopropane in the presence of a strong base and a solvent to produce 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol; b) reacting 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol with epichlorohydrin in the presence of a base to form 1-. { 4- [2- (cyclopropylmethoxy) -ethyl] -phenoxy} -2,3-epoxypropane; and c) reacting 1-. { 4- [2- (cyclopropylmethoxy) ethyl] -phenoxy} -2,3-epoxypropane with isopropylamine to produce Betaxolol. 19. A process of claim 18, wherein the strong base is selected from the group consisting of: potassium tert-butoxide, alkyl lithium, lithium di-isopropylamide, phenyllithium and Grignard reagents. 20. A process of claim 18, wherein the temperature of the reaction is carried out at a temperature of about -10 ° C to about 70 ° C. 21. A process of claim 18, wherein the solvent is selected from the group consisting of: dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide 1-methyl-2-piperidone, 1-methyl-2- pyrrolidone and 1,3-dimethyl-2-imidazolidinone. 22. A process for the production of Betaxolol hydrochloride comprising the steps of: a) reacting 4-hydroxyphenetanol with (chloromethyl) cyclopropane or (bromomethyl) cyclopropane in the presence of a strong base and a solvent to produce 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol; b) reacting 4 - [(2-cyclopropylmethoxy) -ethyl] -phenol with epichlorohydrin in the presence of a base to form 1-. { 4- [2- (cyclopropylmethoxy) -ethyl] -phenoxy} -2,3-epoxypropane; and c) reacting 1-. { 4- [2- (cyclopropylmethoxy) ethyl] -phenoxy} -2,3-epoxypropane with isopropylamine to produce Betaxolol; d) form the salt form of betaxolol hydrochloride by the addition of HCl. 23. A process of claim 22, wherein the strong base is selected from the group consisting of: potassium tert-butoxide, alkyl lithium, lithium di-isopropylamide, phenyllithium and Grignard reagents. 24. A process of claim 22, wherein the temperature of the reaction is carried out at a temperature of about -10 ° C to about 70 ° C. 25. A process of claim 22, wherein the solvent is selected from the group consisting of: dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide 1-methyl-2-piperidone, 1-methyl-2- pyrrolidone and 1,3-dimethyl-2-imidazolidinone.