NO157137B - INTERMEDIATE FOR THE PREPARATION OF 1- (3-BENZYLOXY-PHENYL) -1,1-DIMETHYLHEPHANE. - Google Patents

Abstract

1- (3-Benzyloxyphenyl) -1-chloro-1-methylheptane as an intermediate for the preparation of 1- (3-benzyloxyphenyl) -1,1-dimethylheptane. Preparation of the compound is described.

Description

This invention relates to a new and effective intermediate for the production of 1-(3-benzyloxyphenyl)-1,1-dimethylheptane, a valuable starting material in the synthesis of 2-(cyclic- and acyclic-substituted)-5-(1,1-dimethylheptyl) )phenols, which are valuable analgesics, as described in US patents 4,285,867 and 4,284,829, issued August 25, 1981 and August 18, 1981, respectively. This intermediate is 1-(3-benzyloxyphenyl)-1-chloro-1 -methylheptane, which is methylated using aluminum trimethyl. The aforementioned chloroheptane intermediate is produced by chlorination with hydrogen chloride of 1-(3-benzyloxyphenyl)-1-methylheptan-l-ol, which itself is produced by reaction between n-hexylmagnesium bromide and 3-benzyloxyphenylacetophenone, the latter in turn produced by benzylation of 3-Hydroxyacetophenone.

The reaction between aluminum trialkyls and hydrocarbon chlorides is described by Miller in J.Org.Chem. 31, 908-912 (1966), by Kennedy, J. Org. Chem. 3_5, 532 (1970) and in references cited therein. Miller notes that in the case of the reactions between hydrocarbon halides and aluminum alkyls, the preparation of alkylbenzenes by alkylation of (alpha- and beta-haloalkyl)benzenes is most promising from a synthetic standpoint.

Prior to the present invention, 1-(3-benzyloxyphenyl)-1,1-dimethylheptane was prepared from methyl-3-hydroxybenzoate, as described in U.S. Patent 4,285,867, issued August 25, 1981. The general sequence included benzylation of the phenol group to produce methyl 3-benzyloxybenzoate, followed by reaction between said ether ester and methyl magnesium iodide and formation of 3-benzyloxybenzene-2-propanol. Reaction with

lom the propanol derivative thus formed and hydrochloric acid gave 2-(3-benzyloxyphenyl)-2-chloropropane, which was then reacted with n-hexylmagnesium bromide to form 1-(3-benzyloxyphenyl)-1,1 -dimethylheptane.

It has now been discovered that 1-(3-benzyloxyphenyl)-1,1-dimethylheptane can be easily prepared with a much greater yield than was possible with previously known syntheses. The procedure,

a multistep reaction, involves benzylation of 3-hydroxyacetophenone, followed by reaction of the benzyl ether with n-hexyl magnesium bromide to form 1-(3-benzyloxyphenyl)-1-methylheptan-1-ol. The alcohol is then treated with hydrogen chloride to give the corresponding chlorine compound which there-

is then methylated by reaction with aluminum trimethyl and gives 1-(3-benzyloxyphenyl)-1,1-dimethylheptane. The resulting product is easier to clean than the product produced by the previous method.

The overall process described and exemplified here when it comes to preparing 1-(3-benzyloxyphenyl)

-1,1-dimethylheptane, comprises as a first step benzylation of 3-hydroxyacetophenone. The reaction is carried out by reacting 3-hydroxyacetophenone and benzyl chloride or benzyl bromide in a reaction-initiated solvent at a temperature from around 50°C to the reflux temperature of the solvent, in the presence of an acid acceptor. Generally, 3-hydroxyacetophenone and benzyl chloride, or bromide, are allowed to react in equimolar or approximately equimolar ratios, ie from 1:1 to 0.9:1. From an economic point of view, a slight excess of benzyl chloride or bromide is used to ensure better utilization of the more expensive 3-hydroxyacetophenone reactant. The acid acceptor is used in equimolar amounts, based on the amount of benzyl chloride or bromide used. Suitable acid acceptors are alkali metal carbonates, alkaline earth metal carbonates and anion exchange resins, such as those consisting of polystyrene beads having -N (C2H,-) 2~ groups attached to the polymers.

Suitable solvents for the reactions are acetone, methyl ethyl ketone, tetrahydrofuran, benzene, toluene and dioxane.

The benzyl ether is separated from the reaction mixture by usual methods and purified by vacuum distillation.

The benzyl group's function is to protect the phenol's hydroxy group. Suitable protecting groups are those which do not affect subsequent reactions with the aforementioned 3-(protected hydroxy)acetophenone and which can be easily removed to restore the hydroxy group. Representative protecting groups, in addition to benzyl, are methyl, ethyl, and substituted benzyl where the substituent is, for example, alkyl with from 1 to 4 carbon atoms, halogen (Cl, Br, F, I), and alkoxy with from one to four carbon atoms. The exact chemical structure of the protecting group is not important to this invention, as its importance lies in its ability to act in the manner described above.

Selection and determination of suitable protective groups is easily carried out by someone skilled in the art. Whether a group is suitable and effective as a hydroxy-protecting group is determined by using such a group in the reaction sequence described above. There should therefore be a group that can be easily removed so that the hydroxy group is restored. The benzyl group, a preferred protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.

The next step in the method involves extending the acetyl side chain to the desired length, and simultaneously transferring the keto group in this side chain to hydroxy. This is conveniently achieved by a Grignard reaction with 1-n-hexyl-magnesium bromide in a reaction-inert solvent at a temperature from about -10°C to 50°C. Suitable solvents are tetrahydrofuran, dioxane or diethyl ether. An excess, up to 5% excess magnesium is usually used to ensure more complete utilization of the n-hexyl bromide reactant. The Grignard reagent and the acetophenone derivative are allowed to react in approximately equimolar ratios, ie from about 1.0:1.0 to about 1.10 to 1.0. The reaction mixture is then hydrolysed by treatment with water so that an alcohol is formed.

1-(3-Benzyloxyphenyl)-1-methylheptan-1-ol which is prepared in this way is then transferred by reaction with an excess of aqueous hydrogen chloride to the corresponding 1-(3-benzyloxyphenyl)-1-chloro-1-methylheptane. The tertiary alcohol group is easily replaced by a chlorine atom, simply by shaking with an excess of aqueous hydrochloric acid at room temperature. Molar ratios of up to 10 mol HC1 per mole hydroxy derivative are particularly useful. Larger ratios can be used, but do not give any advantage. Temperatures above or below room temperature can be used, but are usually avoided to reduce the need for heating or cooling the reaction mixture. Alternatively, the hydroxy group can be replaced by bromine or iodine by using hydrogen bromide or hydrogen iodide instead of hydrogen chloride. However, aqueous hydrochloric acid is preferable to the use of other halogenating agents because it is simpler and more economical. The chlorine derivative is collected by extraction with a solvent that is not miscible with water.

The chlorine derivative is then methylated by reaction with aluminum trimethyl in a reaction-inert solvent. Typical solvents for the reaction are dichloromethane, hexane, xylene, toluene, diethyl ether, cyclopentane and methyl chloride. The reaction takes place from around -50°C to 10°C over a period of 15 to 25 hours. The chlorine derivative and aluminum trimethyl are allowed to react in molar ratios from 1:1 to 1:3. The methylated product is recovered by careful hydrolysis of the reaction mixture, for example by adding it to ice at the same time as concentrated hydrochloric acid is added. The product is isolated by separating the organic phase from the hydrolysis mixture and removing the organic solvent.

The 1-(3-benzyloxyphenyl)-1,1-dimethylheptane produced in this way is a valuable starting material, particularly for the synthesis of painkillers. It is transferred by bromination with bromine according to known techniques to 1-(3-benzyloxy-4-bromophenyl)-1,1-dimethylheptane, also known as 2-benzyloxy-1-bromo-4- (1,1-dimethylheptyl)-benzene.

EXAMPLE 1

3- benzyloxyacetophenone

A mechanically stirred mixture of 1 kg (7.35 mol) of 3-hydroxyacetophenone, 1.035 kg (7.5 mol) of anhydrous potassium carbonate, and 0.945 kg (7.5 mol) of benzyl chloride in 4 L of acetone was refluxed for 24 hours, and then a 0.1035 kg (0.75 mole) portion of potassium carbonate and a 0.0945 kg (0.75 mole) portion of benzyl chloride were added and reflux continued. This addition was repeated after 72 hours of reflux, and the reflux was continued for 96 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated in a rotary evaporator. The filtrate was then treated with 0.202 kg (2.0 mol) of triethylamine and stirred overnight. The reaction mixture was diluted with 1 liter of ether and filtered. The filtrate was evaporated and the residue was distilled to yield 1.429 kg (86%) of the title compound as an oil.

Boiling point 160°C (0.3 torr).

IR (CHC13) 1695, 1605, 1595, 1493 and 1443 cm"<1>.

PMR (CDCl 3 ) 62.52 (s.CH 2 ), 5.03 (s,CH 2 ) and 7.0-7.7 (m,Ph).

EXAMPLE 2

1-(3-Benzyloxyphenyl)-1-methylheptan-1-ol

To a slurry of 186 g (7.65 mol) of magnesium in 3.5 1 of tetrahydrofuran, 1.023 1 (7.29 mol) of 1-bromohexane was added over the course of 2 hours. The resulting Grignard solution was allowed to cool to 25°C. A solution of 1.098 kg (4.86 moles) of 3-benzyloxyacetophenone in 1 liter of tetrahydrofuran was added to the Grignard solution over a period of 3 hours. The reaction temperature was maintained at 12°-18°C by means of an ice bath. When the addition was finished, the reaction mixture was allowed to stand with stirring overnight at 25°C. A solution of 61.5 g (3.42 mol) of water in 120 mL of tetrahydrofuran was added to the reaction over 15 minutes, and after stirring 20 minutes longer, 0.440 1 (1.1 mol) of 2.5 M hexylmagnesium bromide in ether added. The reaction mixture was stirred for another 20 hours and the reaction was then stopped by slow addition to a mixture of 6 L of water and ice and 750 g (14.2 mol) of ammonium chloride. The organic extract was removed and the aqueous extract was extracted with 1 liter of ether. The combined organic extracts were washed with 1 liter of saturated sodium chloride solution, dried over magnesium sulfate and evaporated, yielding 1.424 kg (94%) of the title compound as an oil.

PMR (CDC13) 60.83 (m, CH3), 1.20 (m, CH2), 1.51 (s, CH3), 1.72 (s, OH), 1.80 (m, CH2), 5 .02 (s, CH2) and 6.7-7.6 (m, PhH).

EXAMPLE 3

1-(3-benzyloxyphenyl)-1,1-dimethylheptane

A mixture of 660 g (2.11 mol) of 1-(3-benzyloxyphenyl)-1-methylheptan-1-ol and 1.70 L of concentrated hydrochloric acid was stirred vigorously for 40 minutes. The reaction mixture was diluted with 600 ml of hexane and the layers were separated. The organic extract was washed with 500 ml saturated sodium bicarbonate solution,

500 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield 664 g (2.0 M) of the intermediate product 1-(3-benzyloxyphenyl)-1-chloro-1-methylheptane.

A solution of the above chloride in 660 ml of dichloromethane was added to a solution of 947 ml of 25% aluminum trimethyl

(3.28 M) in hexane, dissolved in 1.9 L of dichloromethane. The addition was carried out over a period of 1.5 hours while the reaction temperature was maintained at -18 to -20°C. The reaction mixture was stirred for 1 hour longer at -15°C, and overnight at -3°C.

The reaction was then stopped by slowly adding 2 L of ice while adding 540 ml of concentrated hydrochloric acid. The organic layer was separated and the aqueous layer extracted with 500 ml of dichloromethane. The combined organic extracts were washed with 500 ml saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The crude product was distilled to give 525 g (80%) of the title compound as an oil.

Boiling point 168°-176°C (0.3 torr).

IR (CHC13) 1604 and 1581 cm<-1.>

HRMS (m/e) 310.2351 (M+, Calculated for C22H3Q<0:> 310.2289

225.1304 (M+ -CgH13, Calculated for C16H17<0: >225.1275).

PMR (CDCl 3 ) 60, 82 (m, CH-j), 1.17 (m, CH 2 ), 1.23 (s, CH 3 ),

1.5 (m, CH ), 5.00 (s, CH 2 ) and 6.6-7.5 (m, PhH).

Claims (1)

Intermediate for the preparation of 1-(3-benzyloxyphenyl) -1,1-dimethylheptane, characterized in that it is 1-(3-benzyloxy-phenyl)-1-chloro-1-methylheptane.