MXPA98010590A

MXPA98010590A - Procedure for the selective allocation of epoxy alcohols

Info

Publication number: MXPA98010590A
Application number: MXPA/A/1998/010590A
Authority: MX
Inventors: C Wang Xiu; V Bhatia Ashok; Liu Luping
Original assignee: Abbott Laboratories
Priority date: 1996-06-19
Filing date: 1998-12-11
Publication date: 1999-09-20

Abstract

The present invention relates to: The hydroxy group of an epoxy alcohol is selectively alkylated, without affecting the epoxy group, through the reaction with an alkylating agent in the presence of a solvent and a strong base. As for example, Betaxolol (4) can be prepared according to the scheme (

Description

PROCEDURE FOR THE SELECTIVE ALTERNATIVES OF EPOXY ALCOHOLS 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-propan-2-ol through the selective alkylation of an intermediate alkoxide with an alkylating agent and a base. 2. Background of the Invention The procedures typically used to produce 1-. { 4- [2- (cyclopropyl-ethoxy) ethyl] -fe-noxy} -3-isopropylamino-propan-2-ol (Betaxolol) involved the protection of the phenol functional group, so that the alcohol could be alkylated. This involves extra steps of protection and deprotection, which make the reaction complicated as well as providing low yields, which may also require chromatography to purify the product. The patent of E.U.A. No. 4,252,984 of Manoury et al., Describes the benzylation to phenolic alcohol of 4-hydrofenetanoic acid. The ethanoic acid group is then reduced to an alcohol and subsequently alkylated with (bromomethyl) cyclopropane. The reduction with H2 in the presence of a catalyst deprotects the compound back to a phenolic compound. In a final step, the addition of isopropylamine produces the final product, Betaxolol. A column of silica gel is used to purify the compound. The patent of E.U.A. 4,760,182, by Ippolito et al., Discloses a process for producing Betaxolol by converting 4-hydroxyphenetanol to a phenoxide anion with a base and then reacting the phenoxide anion with an 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 necessary to obtain the final product. The patent of E.U.A. No. 5,034,535 to Keding et al., Describes reacting 4- [2-methoxyethyl] phenol with (S) -5-hydroxymethyl-3-isopropyloxazolidin-2-one sulfonic acid ester to prepare an intermediate in the preparation of S-metoprol . The procedures typically used to produce Betaxolol involves extra steps of protection and deprotection, which make the reaction complicated. Specifically, the epoxide 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane is not stable towards the alkylating reagent since the usual alkylation condition will cause the polymerization of the epoxy alcohol. This is because the molecule has a nucleophilic as well as electrophilic center. The alkoxide of 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane can react with the alkylation reagent as well as the epoxide portion of 1- [4- (2-hydroxyethyl) phenoxy] -2, 3-epoxypropane, leading to the formation of multiple products / polymers. Therefore, it is advantageous and preferable to have a method in which the protection and deprotection steps can be eliminated. In addition, it can be an additional advantage to have a process which produces highly pure Betaxolol.

COMPENDIUM OF THE INVENTION The present invention relates to a process for the selective alkylation of an alcohol in an epoxy alcohol compound comprising the steps of reacting an epoxy alcohol compound in the presence of an alkylating reagent, a solvent and a strong base. The present invention also relates to a process for the production of Betaxolol.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing selective alkylations of hydroxy alcohol groups in compounds, which also contain an epoxide functional group. The hydroxy alcohol group of a compound can be reacted with an alkylating agent in the presence of a strong base without the polymerization of the compound due to the reactivity of the epoxide with the alkylating reagent. The present invention also relates to a novel process for producing Betaxolol intermediates. The synthetic process for producing Betaxolol intermediates with the novel alkylation process of the present invention is shown in Scheme 1. The phenolic alcohol of 4-hydroxyphenetanol (1) is usually more easily alkylated than the hydroxy portion of alcohol in the same compound. Typically, for the hydroxy portion of alcohol that will be rented, the phenolic alcohol had to be protected, thus adding the extra steps of protection and deprotection. Said protection and deprotection steps included benzylation of the phenol before alkylation of the ethanol portion and then subsequent hydrolysis back to the phenol. After hydrolysis, the epoxide can be added to the phenol and the synthesis of the Betaxolol is continued. However, with the method of the present invention, said protection and deprotection steps are eliminated. The method of the present invention in this way eliminates extra steps resulting also in superior productions of the product. The selective alkylation of the present invention utilizes an alkylation reagent and a strong base. The present invention relates to a process for producing selective alkylations of hydroxy alcohol groups in compounds, which also contain an epoxide functional group. As an example, in the production of Betaxolol, Betaxolol can be produced in three steps, only an isolation is necessary. In Scheme 1, the composition between the reaction of the hydroxy portion of ethanol of 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane (2) with an inlet alkylation reagent and with the epoxide of 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane (2) was optimized, so that self-polymerization with the epoxide was eliminated.

SCHEME 1 1. Isopropylamine; • HCl Suitable alkylating agents used in the selective alkylation of the present invention include substituted haloalkyls, halo-substituted cycloalkyls, halo-substituted cycloalkylalkyl, halo-substituted arylalkyl, halo-substituted aryl, halo-substituted alkoxy, halo-substituted arylalkoxy, cycloalkoxy halo-substituted, halo-substituted cycloalkylalkoxy, halo-substituted heterocyclic or halo-substituted (heterocyclic) alkyl.

In addition, sulfonated substituted alkylation agents can be used in place of halo-substituted alkylating agents. Alkyl groups include straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl , n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. Suitable strong bases used in the selective alkylation of the present invention include, but are not limited to, potassium tert-butoxide, 1,8-diazabicyclo [5.4.0] undec-ene (DBU), including lithium alkyls, but or limited to, butyl lithium (BuLi), and lithium diisopropylamide (LDA) and phenyllithium. The most preferred base is potassium tert-butoxide. Solvents that can be used in the present invention include, but are not limited to, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (D F), N, N-dimethylacetamide (DMA), acetonitrile, dichloromethane, ethyl acetate and tetrahydrofuran (THF).

The reaction temperature typically operates from about -10 ° C to about 25 ° C. A very preferred temperature scale is from about -10 ° C to about 10 ° C. A highly preferred temperature scale is from about -5 ° C to about 5 ° C. According to the teaching of the present invention, the selective alkylation of 1 - [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane (2) in the presence of a strong base produces the intermediate, 1-. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy} -2,3-epoxypropane (3). The 1-. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy} -2,3-epoxypropane can then be reacted with isopropylamine followed by an acid including, but not limited to, hydrochloric acid to produce Betaxolol (4). The following example is merely an example of the process of the present invention utilizing the process of selective alkylation in the presence of a base.

EXAMPLE 1 A reaction flask was charged with 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane (140 g, 0.72 mol), bromomethylcyclopropane (90 ml, 125 g, 0.92 mmol) and N.N'- dimethylacetamide (700 ml). A blanket of nitrogen was placed in the mixture and stirred at room temperature for 10 minutes and then cooled to 0 ° C. Potassium tert-butoxide (120 g, 1.1 mole) was slowly added. After the addition was complete, the reaction mixture was kept at 0 ° C for 3 hours. The reaction mixture was diluted with aqueous hydrochloric acid (7 normal, 500 ml). The reaction mixture was extracted three times with 500 ml portions of heptane. The combined organic extracts were washed twice with 500 ml portions of water and concentrated to an oil through vacuum distillation to give 179 g (100% yield) of 1 -. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy} - 2,3-epoxypropane, which was used for the preparation of Betaxolol without further purification.

EXAMPLE 2 The oil obtained in Example 1 (179 g) was dissolved in 400 ml of isopropylamine. After the reaction, the solution was brought to reflux for 2 days, the isopropylamine was distilled off and the residue was dissolved in 200 ml of toluene. The toluene was removed by vacuum distillation to give 222 grams of 1-. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy} 3-isopropylamino-propan-2-ol (free base of Betaxolol), which was used for the preparation of the hydrochloride salt without further purification. The free base Betaxolol was dissolved in 300 ml of toluene containing 20 ml of isopropanol. A stream of hydrogen chloride gas was passed through the above solution at 0 ° C until the pH of the reaction mixture was less than 3.0. The solvent was removed by vacuum distillation, and the residue was crystallized from 400 ml of acetone to give 102 grams (99% pure) of Betaxolol hydrochloride.

Claims

1. A process for the selective alkylation of a hydroxy alcohol in an epoxy alcohol compound, comprising the steps of reacting the epoxy alcohol compound in the presence of an alkylating reagent, a solvent and a strong base.

2. A process according to claim 1, wherein the alkylating agent is selected from the group consisting of: substituted haloalkyls, halo-substituted cycloalkyls, halo-substituted cycloalkylalkyl, halo-substituted arylalkyl, halo-substituted aryl, alkoxy halo-substituted, halo-substituted arylalkoxy, halo-substituted cycloalkoxy, halo-substituted cycloalkylalkoxy, halo-substituted heterocyclic and halo-substituted (heterocyclic) alkyl.

3. A process according to claim 1, wherein the alkylating agent is selected from the group consisting of: alkyls substituted with sulfonate, cycloalkyls, cycloalkylalkyl, arylalkyl, alkoxy, arylalkoxy, cycloalkoxy, cycloalkylalkoxy, heterocyclic and alkyl (heterocyclic ) halo-substituted.

4. A process according to claim 1, wherein the strong base is selected from the group consisting of: potassium terbutoxide, 1,8-diazabicyclo [5.4.0] undec-ene, alkyllithium, lithium diisopropylamide , and phenyl-lithium.

5. - A process according to claim 1, wherein the temperature of the reaction is carried out at a temperature below -10 ° C to about 25 ° C.

6. A process according to claim 1, wherein the temperature of the reaction is carried out at a temperature below -10 ° C to about 10 ° C.

7. A process according to claim 1, wherein the temperature of the reaction is carried out at a temperature below -5 ° C to about 5 ° C.

8. A process according to claim 1, wherein the solvent is selected from the group consisting of: dimethyl sulfoxide, NN-dimethylformamide, N, -dimethylacetamide, acetonitrile, tetrahydrofuran, 1-methyl-2-piperidone, and -methyl-2-pyrrolidone.

9. A process for the selective alkylation of the hydroxy ethanol portion of 1- [4- (hydroxyethyl) phenoxy] -2,3-epoxypropane, comprising the steps of reacting 1- [4- (hydroxyethyl) phenoxy) 2,3-epoxypropane in the presence of an alkylating agent, a solvent and a strong base.

10. A process according to claim 9, wherein the alkylating agent is selected from the group consisting of: substituted haloalkyls, halo-substituted cycloalkyls, halo-substituted cycloalkylalkyl, halo-substituted arylalkyl, halo-substituted aryl, alkoxy halo-substituted, halo-substituted arylalkoxy, halo-substituted cycloalkoxy, halo-substituted cycloalkylalkoxy, halo-substituted heterocyclic and alkyl (heterocyclic) halo-substituted.

11. A process according to claim 9, wherein the alkylating agent is selected from the group consisting of: alkyls substituted with sulfonate, cycloalkyls, cycloalkylalkyl, arylalkyl, alkoxy, arylalkoxy, cycloalkoxy, cycloalkylalkoxy, heterocyclic and alkyl (heterocyclic) ) halo-substituted.

12. A process according to claim 9, wherein the temperature of the reaction is carried out at a temperature below -10 ° C to about 25 ° C.

13. A process according to claim 9, wherein the temperature of the reaction is carried out at a temperature below -10 ° C to about 10 ° C.

14. A process according to claim 9, wherein the temperature of the reaction is carried out at a temperature below -5 ° C to about 5 ° C.

15. A process according to claim 9, wherein the strong base is selected from the group consisting of: potassium tert-butoxide, 1,8-diazabicyclo [5.4.0] undec-ene, alkyllithium, diisopropylamide of lithium, and phenyllithium.

16. A method according to claim 9, wherein the solvent is selected from the group consisting of: dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 1-methyl-2-piperidone and 1-methyl-2-pyrrolidone.

17. A process for the production of Betaxolol comprising the steps of: a) reacting 1 - [4- (hydroxyethyl) phenoxy] -2,3-epoxypropane with a strong base to produce 1-. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy} -2,3-epoxypropane; and b) reacting 1-. { 4- [2- (cyclopropylmethoxy) ethyl] phenoxy} -2,3-epoxypropane with isopropylamine to produce Betaxolol.