GB2187190A - Preparation of phenol ether derivatives - Google Patents

Abstract

Phenol ethers of formula: <IMAGE> wherein m is 2-5; n is 1-4; R is a C3-4 branched alkyl or C3-4 cycloalkyl, are prepared from p-hydroxyphenethyl alcohol by first reacting at the phenolic group, with epichlorohydrin followed by an appropriate amine,to prepare the required secondary amine-hydroxy side chain. Protection of the alcoholic group is not required during these steps. Then the secondary amine-alcohol group is protected by reaction with a suitable aldehyde such as benzaldehyde to form an oxazolidine ring protectant whilst the alcohol chain is elaborated. The oxazolidine ring protectant is removed by simple acid hydrolysis. The above ethers may be converted to any desired pharmaceutically acceptable salts. <IMAGE>

Description

SPECIFICATION Preparation of phenol ethers using cyclic intermediates This invention relates two organic chemical synthesis and more specifically to synthesis of pharmaceutical compounds.

The chemical compound 1 -[4-[2-(cyclopropylmethoxy)-ethyl]phenoxy]-3-[(1 -methylethyl)amino]-2-propanol, hereinafter referred to as betaxolol, has recently been introduced and proposed for pharmaceutical use in human and veterinary therapy, in the cardiovascularfield, mainly as a P-adrenergic biocking agent.It has the chemical formula:

The family of compounds, including betaxolol,ofthefollowing general formula 1:

where mis an integerfrom 2to 5, n is an integerfrom 1 to 4, and R is a branched alkyl of 3 or4carbonatoms, or cycloalkyl of 3 or 4 carbon atoms, racemic and optically active forms thereof, and pharmaceutically acceptable acid addition salts thereof, is described in Canadian Patent 1,072,981 Synthelabo, togetherwith methodsforthe preparation thereof.

The prior art synthesis of betaxolol starts with the readily available reagent p-hydroxyphenethyi alcohol, of formula:

and converts this to the hydrochloride addition salt of betaxolol using a five step sequential synthesis. The more acidic phenolic hydroxyl is chemically blocked with a benzyl moiety e.g. by reaction of the phenoxide with benzyl chloride. In a second step, the hydroxyethyl group is then etherified by reaction with cyclopropylcarbinyl halide to give the desired species for the final product atthis position.The phenolic position is then deprotected by hydrogenolysis and the phenolic position re-etherified with epihalohydrin to give a compound of formula:

This fourth step product is then reacted with 2-aminopropaneto yield betaxolol base. Thus, two ofthefive steps in the synthesis are the protection and de-protection of the phenolic hydroxyl. Each is a separate and necessary step.

It is an object of the present invention to provide a novel process for the preparation of betaxolol.

It is a further object two provide a process which avoidsthe costly and potentially hazardous hydrogenolysis of the prior art process described above and has the potential for a reduced number of synthetic steps.

It is a further object ofthe invention to provide novel chemical compounds useful as intermediates in the synthesis of betaxolol and similar compounds.

In the process of the present invention, p-hydroxyphenethyl alcohol is first elaborated at its phenolic terminus. The phenolic group thereof is so much more reactive than the primary alcohol group that the latter does not need protection while the phenolicterminus is elaborated. Firstly the p-hydroxyphenethyl alochol is converted to its phenoxide anion with base, and then reacted with epihalohydrin, to produce a compound of formula l,thus:

where x represents halogen, preferably chlorine, bromine or iodine.Next, the compound of formula I is reacted with a primary amine R.NH2, where P is branched alkyl of 3-4 carbon atoms or cycloalkyl of 3-4 carbon atoms, to produce a compound offormula lI,thus:

It is a significant advantageous feature of the process ofthe present invention that intermediate I does not need to be isolated or purified. One mayjusfilterthe inorganic by-products, remove solvent and excess alkylating agent and proceed to prepare intermediate II in the same reaction vessel.

Now to complete the elaboration of compound II into the desired phenol ether base, the secondary alcohol-amine grouping must be protected whilstthe primary alcohol is appropriately etherified. In accordance with the present invention,this is accomplished by reaction of compound II with an appropriate aldehyde,to obtain a compound of general formula III below, thus:

where R has the meaning given above and R' is aryl, su bstituted aryl, or C2-C11 straight chain or branched alkyl. It is not necessary to isolate compound II before its reaction to form intermediate III, so that once again the reaction may proceed in the same reaction vessel, after simple removal of solvents.The oxazolidine ring formed provides a stable but easily removable protecting group forthe secondary alcohol-amine grouping required in the final moleculewhilstthe primary alcohol function is elaborated to form the desired final product.

The primary alcohol group is next etherified appropriately, e.g. with base and a cycloalkyl carbinyl halide, to produce protected phenol ether compound of formula IV, thus:

Then in a final step, compound IV is subjected to acid hydrolysis, to effect deprotection and produce the final phenol ether base. This acid hydrolysis step can be performed as a separate step but is preferably conducted during the work-up of the preceding etherification step.

The process of the present invention thus avoids the unwanted hydrogenolysis step of the prior art process, with its attendant hazards and inconveniences. It provides a process scheme in which the overall number of synthetic steps is reduced to four (when deprotection is conducted during the work-up ofthe etherification ofthe primary alcohol). The steps can be conducted in rapid succession one after the other since there is no need to isolate and purify intermediate I, II, III or probably IV.It is merely necessary to filter the reaction mixture to remove solvents and reaction products dissolved therein, possibly to remove excess reagents by distillation from higher boiling solvents, and then proceed directly to the next stage ofthe process, at least in the cases of preparation of intermediates 1,11, III and IV. In practicalterms,therefore,the process is conducted in two steps,thefirst being the multi-stage preparation of intermediate IV from p-hydroxyphenethyl alcohol, and the second being the preparation and recovery of betaxolol or its analogues therefrom. Additionally, all steps provide high yield of desired product.

In the first step of the process, the p-hydroxyphenethyl alcohol is first converted to its phenoxide anion with base, in an appropriate solvent. The base can be chosen from among a wide variety, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride etc. being most preferred. Examples of suitable solvents include acetonitrile, lower aliphatic alcohols (straight or branched chain), acetone, 2-butanone, tetrahydrofuran, dimethylformamide, dimethylsulphoxide benzene, toluene, etc. Reaction is suitably conducted under reflux. When the reaction is complete, the mixture is cooled, filtered, and excess solvent stripped off. Intermediate I forms as a white solid.

In the second step ofthe process, intermediate I is reacted with a primary amine R.NH2. The choice ofgroup R is dictated by the desired final product. In the preferred case of betaxolol preparation, R is isopropyl, and the amine reactant is isopropylamine. The process may be conducted without additional solvent, the reactant I being dissolved in the isopropylamine, and the reaction suitably being conducted under reflux. It is best to remove all residual amine from the mixture at the conclusion ofthis step ofthe process, e.g. by dissolving the compound in warm toluene, and removing it at reduced pressure, to minimize side reactions in subsequent steps of the process.

Intermediate II is protected by reaction with a suitable aldehyde, to form a compound having an oxazolidine ring, intermediate III. Oxazolidine formation is a reversible reaction requiring the removal of water to drive the reaction to completion. Thus, the preferred aldehydes are those ofgeneral formula R'-CHO, where R' is aryl, substituted aryl, or C2-C11 straight or branched alkyl group. Preferred are phenyl,lower aikyl substituted phenyl and C4-C8 straight chain alkyl groups. Most preferred, on account of its reaction efficiency and ready availability, is benzaldehyde, i.e. R' is phenyl. The reaction with benzaldehyde is clean, efficient, relatively fast, and yields an intermediate of satisfactory stability, but is in fact readily reversible under appropriate conditions.The reaction is conducted preferably in the presence of an inert solvent e.g. benzene ortoluene, under reflux, and using a small molar (e.g. 10-25%) excess of benzaldehyde. Larger excesses of benzaldehyde tend to lead to faster completion ofthe reaction but lead to greater problems of subsequent removal of the excess benzaldehyde. Intermediate III thus formed need not be isolated and purified. The reaction mixture at the end of the reaction can be merely stripped under reduced pressure and pumped under vacuum to remove excess benzaldehyde.

In conversion of intermediate Ill to elaborate the primary alcohol chain, it is necessaryto operate under basic conditions. Thus a base, such as lithium, potassium or sodium hydride or potassium t-butoxide etc. is added, followed by the appropriate compound offormula X-(CH2) - CH (CH2)m and a solvent. When the desired product is betaxolol, the reagent is cyclopropylcarbinyl halide (preferably the chloride). Preferred solvents are selected from dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrlidinone, glyme, tetrahydrofuran etc. Most preferred are polar aprotic solvents. The reaction proceeds satisfactorily at room temperature.The product, intermediate IV, may be isolated e.g. by pouring the reaction mixture into water, extracting with toluene, drying and evaporating but such isolation is not essential.

Finally, intemediate IV is subjected to acid hydrolysis to effect deprotection and form the final producte.g.

betaxolol. This may be effected by treatment with an appropriate aqueous inorganic or organic acid with a cosolventsuch as isopropanol. The product may be isolated and purified according to standard procedure.

The invention is further described and illustrated in the following non-limiting examples.

Example 1 1 -[4-(2-hydroxyethyl )phenoxy]-2,3-epoxypropane 30.0 g p-hydroxyphenethyl alcohol, 60 g of an hydros potassium carbonate and 50.28 g of epichlorohydrin were refluxed in 250 mL of acetonitrilefor 5 hrs. After cooling, filtering and removing acetonitrile at reduced pressure, 300 mL oftoluene were added and the toluene removed under reduced pressure. The residual oil solidifies on standing and is used directly in the next step. Yield= 43.2 g, c. 100% yield. This solid after recrystallization in water has a melting point of 56-58.5"C.

Example2 1-[4-[(2-hydroxyethyl)]phenoxy]-3[(1-methylethyl)amino]-2-propanol 10 g of 1 -[4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane produced in Example 1 was refluxed in 50 mLof isopropylamine for 16 hours. The aminewas removed under reduced pressure,the residue dissolved in warm toluene and the toluene removed under reduced pressure. On standing the oil solidified. Yield = 12.8 g (98%) After recrystallization in petroleum ether this solid had a melting point of 77-78C.

Example 3 2-Phenyl-3-isopropyl-5-[4-[(2-hyd roxyethyl)phenoxy]methyl]oxazol idine 26.2 g of 1 -[4-(2-hydroxyethyl)phenoxyl-3-[(1 -methylethyl)amino]-2-propanol from Example 2,12.96 g of benzaldehyde and 200 mLs oftoluene were refluxed for 24 hours with azeotropic removal of water. The solventvolu me was reduced to 50 mLs during the final hour of reflux and the remaining solvent removed under reduced pressure. Yield = 33.75 g (96% ofyellowoil).

Example 4 2-Phenyl-3-isopropyl-5-[[4-[2-(cyclopropylmethoxy)ethyl]phenoxylmethyl]oxazolidine 2.0 g of 2-Phenyl-3-isopropyl-5-[4-[(2-hydroxyethyl)phenoxy]methyl]oxazolidine from Example 3 was dissolved in 15 mLs of DMSO and added to 15 mLs of DMSO containing 0.78g t BuO-K+. The solution was stirred for 1/2 hour and 0.64 g of chloromethylcyclopropane was added. After stirring 16 hrs. an additional 0.20 g of chloromethylcyclopropane and 0.33 g t-BuO-K+ were added and the stirring continued for 16 hrs, a final increment of 0.10 g oft-BuO-K+ was added and the stirring continued for8 hrs.The reaction mixture was quenched into 150 mLs of water and the product extracted twice with 20 mLs oftoluene. 2.25 g of yellow oil was obtained upon removal of the solvent under reduced pressure. Yield is 96% of the theoretical.

Example 5 1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-[(1 -methylethyl)amino]-2-propanol 2.25 g of 2-Phenyl-3-isopropyl-5-[[4-[2-(cyclopropyl methoxy)ethyl]phenoxyjmethyljoxazolidine from Example 4was dissolved in a mixture of 10 mLs isopropanol, 10 mLs 5% aqueous hydrochloric acid. Itwas stirred at room temperaturefor 16 hrs. The isopropanol was removed under reduced pressure and 30 mLs 1% hydrochloric acid was added. The aqueous phase was washed with 15 mLs oftoluene then basified and extracted twice with 10 mL portions oftoluene. After removal ofthe solvent under reduced pressure 1.3 g of white solid was obtained (74% crude yield of betaxolol base). Betaxolol base was converted into its hydrochloride salt by dissolution in toluene and treatment with 1 equivalent of hydrochloric acid in isopropanol. Upon removal of isopropanol under reduced pressure and cooling of thetoluene solutionthe hydrochloride salt of betaxolol was obtained. This solid is recrystallized twice from acetone, 4 mug, the second time with charcoal treatment to give a white crystalline solid with a melting point of 111.5-11 2.50C.

Claims (28)

1. A process for preparing phenol ethers of the general formula:

wherein m is an integer from 2 to 5, n is an integerfrom 1 to 4, and R is branched alkyl of 3 or4 carbon atoms orcyclo-alkyl of 3 or 4carbon atoms our a pharmaceutically acceptable saltthereof, which comprises subjecting to acid hydrolysis a compound of the general formula IV:

where R' is aryl, substituted aryl, straight chain or branched C2-C11 alkyl, and R, n and m have the meanings given above, and if necessary subsequently preparing the desired pharmaceutically acceptable salt therefrom.

2. The process of claim 1 wherein R represents 2-propyl, mis 2, n is 1 and R' is phenyl, loweralkyl substituted phenyl, or straight chain or branched C2-C11 alkyl.

3. The process of claim 2 wherein R' is phenyl.

4. The process of claim 1 wherein the compound of formula IV is prepared by reacting a compound of formula III:

with a cycloalkylcarbinyl halide of general formula:

where Xis a halogen, preferably chlorine, bromine or iodine under basic conditions.

5. The process of claim 4wherein R represents 2-propyl, m is 2, n is 1 and R' is phenyl, loweralkyl substituted phenyl, or straight chain or branched C2-C11 alkyl.

6. The process of claim Swherein R' is phenyl.

7. The process of claim 4wherein the compound of formula lil is prepared by reacting a compound of formula II:

with an aldehyde offormula R'-CHO in which R' is aryl, su bstituted aryl, or straight chain or branched C2-C11 alkyl.

8. The process of claim 7 wherein R represents 2-propyl.

9. The process of claim 8 wherein R' is phenyl.

10. The process of claim 7 wherein the compound offormula II is prepared by reacting a compound of formula I

with a primary amine R.NH2where R is a branched alkyl of3-4carbon atoms or a cycloalkyl of3-4carbon atoms.

11. The process of claim 10 wherein R is2-propyl.

12. The process of claim 10 wherein the compound offormula I is prepared by reaction of p.hydroxyphenethyl alcohol with an epihalohydrin under basic conditions.

13. A process of preparing an oxazolidine phenol ether compound of general formula IV

where R is branched alkyl of 3-4 carbon atoms or cycloalkyl of 3-4 carbon atoms, R' is aryl, substituted aryl, or straight chain or branched C2-C11 alkyl, m is an integerfrom 2-5 and n is an integer from 1-4, which comprises reacting a compound of general formula III:

with a cycloalkyl carbinyl halide of general formula

where is chlorine, bromine or iodine, under basic conditions.

14. An oxazolidine phenol ether of general formula IV:

wherein R, R', m and n have the meanings given in claim 13.

15. The process of claim 13 wherein R is 2-propyl, R' is phenyl, n is 1 and m is2.

16. An oxazolidine phenol etherofformula

17. A process of preparing an oxazolidine phenol alcohol compound of general formula III:

wherein R is branched alkyl of 3-4 carbon atoms or cycloalkyl of 3-4 carbon atoms, R' is aryl, substituted aryl, or straight chain or branched C2-C11 alkyl which comprises reacting a compound offormula ll:

with an aldehyde offormula R'-CHO.

18. An oxazolidine phenol alcohol compound of general formula III:

19. The process of claim 17 wherein R is 2-propyl and R' is phenyl.

20. An oxazolidine phenol alcohol compound oftheformula:

21. A process according to claim 1 and substantially as herein described.

22. A process for preparing phenol ethers substantially as described in any of the specific Examples.

23. A process according to claim 13 and substantially as herein described.

24. A process for preparing an oxazolidine phenol ether substantially as described in any of the specific Examples.

25. an oxazolidine phenol ether according to claim 14 and substantially as described herein.

26. A process according to claim 17 and substantially as described herein.

27. A process for preparing an oxazolidine phenol alcohol substantially as described in any of the specific Examples.

28. An oxazolidine phenol alcohol compound according to claim 18 and substantially as described herein.