IE59103B1 - Preparation of phenol ethers using cyclic intermediates - Google Patents

Description

This invention relates to organic chemical synthesis and more specifically to synthesis of pharmaceutical compounds.

The chemical compound 1-(4-(2-(cyclopropylmethoxy)ethyllphenoxy!-3-((1-rae thylethyl)aminoi-2-propanol» hereinafter « referred to as betaxolol, has recently been introduced and proposed for pharmaceutical use in human and veterinary therapy» in the cardiovascular field» mainly as a β-adrenerglc blocking agent. It has the chemical formulas The family of compounds„ including betaxolol, of the following general formula Is where as is an Integer from 2 to 5» a is an Integer from 1 to 4, and R Is a branched alkyl of 3 or 4 carbon atoms» or cycloalkyl of 3 or 4 carbon atoms» racemic and optically active forms thereof» ©nd pharmaceutically acceptable acid addition salts thereof» is described in Canadian Patent 1^072,581 Synthelabo, together with methods for the preparation thereof.

The prior art synthesis of betaxolol starts with the readily available reagent p-hydroxyphenethy1 alcohol, of formula HO OH and converts this to the hydrochloride addition salt of betaxolol using a five step sequential synthesis. The mote acidic phenolic hydroxyl is chemically blocked with & bensyl moiety e.g. by reaction of the phenoxide with bensyl chloride.

In a second step,, the hydroxyethy 1 group is then ether if ied by reaction with cyclopropylcarbinyl halide to give the desired species for the final product at this position. The phenolic position is then deprotected by hydrogenolysis and the phenolic position re-etherif ied with epihalohydrIn to give a compound of formula: This fourth step product is then reacted with 2-am£nopropane to yield betaxolol base. Thus, two of the five steps in the synthesis are the protection and de-protection ©£ 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 to provide a process which avoids the costly and potentially hazardous hydrogenolysis of the prior act process described above and has the potential for a reduced number of synthetic steps.

It is a further object of the 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-hydeotcyphenethyl 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 phenolic terminus is elaborated. Firstly the p-hydroxyphenethyl alcohol is converted to its phenoxide anion with base? and then reacted with epihalohydcin, to produce a compound of formula I, thus; CHVOH X-CH^CH-CM V (1) CH, c.Mloh where X represents halogen,, preferably chlorine, bromine oc iodine. Next, the compound of formula I is reacted with a primary amine where a is branched alkyl of 3-4 carbon atoms oc cycloalkyl of 3-4 carbon atoms,, to produce a compound of formula XX, thus: il OR HH CH, (I) O—CR — CH (n) CHt OH OvOH It is a significant advantageous feature of the process of the present invention that intermediate ϊ does not need to be isolated or purified. One may just filter the inorganic by-products, remove solvent and excess alkylating agent and proceed to prepare intermediate ll in the same reaction vessel.

Mow to complete the elaboration of compound IX into the desired phenol ether base, the secondary alcohol-amine grouping must be protected whilst the primary alcohol is appropriately etherified. Xn accordance with the present invention,» this is accomplished by reaction of compound 11 with an appropriate aldehyde, to obtain a compound of general formula 1X1 below, where R has the meaning given above and S' is aryl, substituted aryl, or straight chain or branched alkyl. It is not necessary to isolate compound ll 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 oxasolidine ring formed provides a stable but easily removable protecting group for the secondary alcohol-amine grouping required in the final molecule whilst the 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; — N~R h/X«' — 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 fhe work-up of the preceding etherification step.

The process of the present invention thus avoids the unwanted hydrogenolysis step of th® prior art process, with its attendant hazards and inconveniences. If provides a process scheme in which the overall number of synthetic steps is reduced to four (when deprofection is conducted during the work-up of the etherification of the'primary alcohol). The steps can be conducted in rapid succession on© after fhe other since there is no need to isolate and purify intermediate I# II, III ot probably IV. If 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 of the process, at least in the cases of preparation of intermediates I, XX, 1XX and IV. Xn practical terms, therefore, the process is conducted in two steps, the first being the multi-stage preparation of intermediate XV 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, th© 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, dimethyIsulphoxide benzene, toluene, etc. Reaction is suitably conducted under reflux. Khen the reaction is complete, the mixture is cooled, filtered, and excess solvent stripped off. Intermediate ί forms as a white solid.

Xn the secorad step of the process, intermediate 1 Is reacted with a primary amine R-NH?. The choice of group 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. Xt is best to remove all residual amine from the mixture at the conclusion of this step of the process» e.g. by dissolving the compound in warm toluene» and removing it at reduced pressure» to minimise 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. Oxasolidine formation is a reversible reaction requiring the removal of water to drive the reaction to completion. Thus» the preferred aldehydes are those of general formula R-CHOf where R is aryl» substituted aryl» or C2~CX1 or branched alkyl group. Preferred are phenyl» lower alkyl substituted phenyl and C^-C^ straight chain alkyl groups. Host preferred» on account of its reaction efficiency and ready availability» is benzaldehyde» i.e. a 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 or toluene® under reflux® ©nd using a small molar (e.g. 1025¾) excess of benzaldehyde, larger excesses of benzaldehyde tend to lead to faster completion of the 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 III to elaborate the primary alcohol chain, it is necessary to 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 of formula X-(CHj) - CH an ® solvent. When the desired product is betaxolol, the reagent is cyclopropylearbinyl halide (preferably the chloride). Preferred solvents ©re selected from dimethylsulfoxide, dimethylformamide, N-methy1-2-pyrrolidinone, glyme, tetrahydrofuran etc. Host 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, intermediate IV is subjected to acid hydrolysis to effect deprotection and form the final product e.g. betaxolol. This may be effected by treatment with an appropriate aqueous inorganic or organic acid with a cosolvent such 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 -epoxypr ©pane .0 g p-hydroxyphenethyl alcohol, SO g of anhydrous potassium carbonate and 50.28 g of epichlorohydrin were refluxed in 250 mL of acetonitrile for 5 hrs. After cooling, filtering and removing acetonitrile at reduced pressure, 300 mL bf toluene were added and the toluene removed under reduced pressure. The r residual oil solidifies on standing and is used directly in th© next step. Yield® 43.2 g, c. 100% yield. This solid after · recrystallisation in water has a melting point of 56-58.5eC.

EXAMPLE 2 1- (4-( (2-hydroxyethy 1, Iphenoxy]-3( (1-methy lethy 1) amino]-2-propanol g of 1-(4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane produced in Example 1 was refluxed in 50 mL of isopropylamine for 16 hrs. The ©mine was 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 77-78®C.

EXAMPLE 3 2- Ph enyl-3-i sopr opyl-5-(4-((2-hydr oxyethy 1) phenoxy]me thyl] oxasolidine 26.2 g of 1-(4-(2-hydroxyethyl, phenoxy)-3-( (1-methyl ethyl)amino]-2-propanol from Example 2, 12.96 g of benzaldehyde and 200 mLs of toluene were refluxed for 24 hours with aseotropic removal of water. The solvent volume was reduced to 50 mLs during the final hour of reflux and the remaining solvent removed under reduced pressure. Yield® 33.75 g (9 6% of yellow oil) .

EXAMPLE 4 2-Pheny1-3“isopropyl-5“((4-(2-(cyclopropyImethoxy)ethyl] phenoxy]methyl]oxazolidine 2,0 g of 2-Phenyl~3-isopropyl-5-(4-( (2-hydroxyethyl) phenoxy]methyl)oxazolidine from Example 3 was dissolved in 15 mis of DMSO and added to 15 mis of DMSO containing 073 g t Βαθκ'. Th® solution ^as stirred for 1/2 hour and 0.64 g of chloromethylcyclopropane «as added. After stirring 16 hrs. an additional 0.20 g of chloromethylcyclopropane and 0.33 g :-3uOK' were added and the stirring continued for 16 hrs, a final increment of 010 g of t-3uO~K^ was added and the stirring continued for 8 hrs. The reaction mixture was quenched into 150 mis of water and the product extracted twice with 20 mis of toluene. 2.25 g of yellow oil was obtained upon removal of the solvent under reduced pressure. Yield is 96% of the theoretical.

EXAMPLE 5 (4-( 2- (cyclopropyImethoxy) ethyl] phenoxy] 3( (1-methylethyl) amino]-2-propanol 2.25 g of 2-Pheny1-3-isopropy1-5-([4-[2-(cyclopropy1 methoxy)ethyl]phenoxy]methyl]oxazolidine from Example 4 was dissolved in a mixture of 10 inis isopropanol, 10 mis 5% aqueous hydrochloric acid. It was stirred at room temperature for 16 hrs. The isopropanol was removed under reduced pressure and 30 mis 1% hydrochloric acid was added. The aqueous phase was washed with 15 sals of toluene then basified and extracted twice with 10 mL portions of toluene. After removal of the 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 the toluene solution the hydrochloride salt of betaxolol was obtained. This solid is recrystallised twice from acetone, 4 mL/g, the second time with charcoal treatment to give a white crystalline solid with a melting point of 111.5-112.,,5°C.

Claims (16)

1. A process for preparing phenol ethers of the general formula : OH R - NH. C H 2 „ <[ H „ C H 2 „ 0- -CHj.CHj-O (CS 2 ) n -CH (CH 2 ) wherein m is an integer from 2 to 5, n is an integer from 1 to 4, and R is branched alkyl of 3 or 4 carbon atoms or cyclo-alkyl of 3 or 4 carbon atoms or a pharmaceutically acceptable salt thereof, which comprises subjecting to acid hydrolysis a compound of the general formula IV; H R* \ / c / \ R-N 0 / -CH_.CH,.O„ (CSS-J -CH CCS,*

2. 2 ' 2 tt 2 bU (IV) CH 2 -CH-CH 7 -O- where R e is aryl, substituted aryl, straight chain or branched C 2” C 11 en< ^ n ra have the meanings given above, and if necessary subsequently preparing the desired pharmaceutically acceptable salt therefrom. - 13 2„ The process of claim 1 wherein R represents 2-oropyi m is 2® n is 1 and R' is phenyl® ' alkyl substituted phenyl, r or straight chain or branched C^-C^ alkyl,

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

4. The process of claim 1 wherein the compound of formula XV is prepared by reacting a compound of formula Ills H R’ \/ (III) with a eyeloaIkylearbinyl halide of general formulas X-(CH-) ί ns. > & m where X is under basic conditions. chlorine® bromine or iodine

5. The process of claim 4 wherein R represents 2-propyl# m is 2» a is 1 and R' is phenyl® alkyl substituted phenyl® or straight chain or branched C^Cj 1 alkyl.

6. The process of claim 5 wherein R is phenyl.

7. „ The process of claim 4 wherein the compound of formula Ill is prepared by reacting a compound -of formula Ils (IIS with aa aldehyde of formula RZ-GBO in which R 0 is aryl, substituted aryl, or straight chain or branched alkyl.

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

9. The process of claim 8 wherein R® is phenyl. XO„ The process of claim 7 wherein the compound of formula ΪΙ is prepared by reacting a compound of formula ϊ with a primary amine R.NH_ where R is a branched alkyl of 3-4 25 carbon atoms or a cycloalkyl of 3-4 carbon atoms.

10. 11. The process of claim 10 wherein R is 2-propyl.

11. 12. The process of claim 10 wherein the compound of formula I is prepared by reaction of p.hydroxyphenethyl alcohol with an • epihalohydrin under basic conditions. 35

12. 13. A process according to claim 1 substantially as herein described 6» by way of Example.

13. 14. Phenol ethers of the formula stated in claim 1 whenever prepared by a process according to any of the previous claims. TOMKIHS & CO. - 15 15. The process of claim )3 wherein R is 2-propyl,. R’ is phenyl n is 1 and m is 2. An oxasoiidine phenol alcohol compound of the formula: / CH 3

14. 17. a process for preparing phenol ethers of the formula stated in Claim 1, substantially as hereinbefore described with reference to the Examples. l©w Phenol ethers of the formula stated in Claim 1, whenever prepared by a process as claimed in any of Claims 1 to 12 or 21.

15. 19. Compounds of the general formula IV as stated in Claim 13, whenever prepared by a process as claimed in Claim 13 or 15.

16. 20. A compound of the general formula III as stated in Claim 17, whenever prepared by a process as claimed in Claim 17.