GB2176477A - Manufacture of diphenhydramine - Google Patents

Abstract

A process for the manufacture of diphenhydramine comprises reacting approximately equimolar amounts of benzhydrol and beta -dimethylaminoethanol in the presence of a slight molar excess of p-toluenesulfonic acid at the boiling point of toluene.

Description

SPECIFICATION Manufacture of diphenhydramine Diphenhydramine is a well-known antihistamine described in US Patents 2,427,878 and 2,421,714.

The compound was synthesized by using classical Williamson synthetic means for preparing esters using alkoxides prepared from sodium or potassium metals and alkyl halides. An alternate method of synthesis is described in US Patent 2,397,799.

The present invention employs two commercially available and easy to handle alcohols, an acid catalyst, and a safe to handle aromatic solvent to form an ether by elimination and removal of water from the reaction mixture in excellent yields and in one simple step.

A similar reaction has been described in Chemical Communications, 1971, p 170-171, where a tertiary alcohol is coupled with a primary aliphatic alcohol using p-toluenesulfonic acid and benzene as solvent. The tertiary alcohol provides an easily available carbonium ion for coupling with a simple aliphatic alcohol. On the other hand, attempts to prepare diphenylhydramine by coupling of two alcohols with use of p-toluenesulfonic acid and in benzene have resulted in poor yields.

US Patents 3,407,258 and 3,666,811 describe coupling of secondary benzhydrvl alcohols with (3- amino-alcohols employing acid while heating under reduced pressure.

Accordingly, it has been unexpectedly found that diphenhydramine can be conveniently manufactured by coupling benhydrol and (3-dimethylamino- ethanol with a slight molar excess of p-toluenesulfonic acid at the boiling point of toluene.

Since toluene is an azeotroping solvent, water formed during the reaction is removed through a trap. The amount of heating at reflux, boiling point of toluene, ranges from 12 to 36 hours.

The resulting free base may then be converted by known means to a corresponding pharmaceutically acceptable acid addition salt with an inorganic or organic acid. Examples of such salts are the hydro-chloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, citrate, oxalate, succinate, benzoate, tartrate, phthalate, maleate, oleate, and the like.

The alcohols are used in approximate equimolar amounts. The amount of p-toluenesulfonic acid required is a slight excess over an equimolar amount in order to tie-up the amino group and to provide an additionai catalytic amount for helping the reaction proceed to completion.

The invention is illustrated further by the following example.

Example A mixture of 57.8 g of para-toluenesulfonic acid, 26.7 g of (3-dimethylaminoethanol, 57.5 g of benzhydrol, and 150 ml of toluene is heated to reflux using a condensor equipped with a Dean Stark trap. The mixture is refluxed for 12-36 hours and then cooled to room temperature. It is poured into 250 ml of water, and the pH adjusted to 11.0 with sodium hydroxide. The aqueous layer is discarded and the organic layer is washed with water, charcoaled, and dried.

After filtration, the organic layer is converted to its hydrochloride by gassing with 8 g of anhydrous hydrogen chloride. The product melts at 168-169 C after crystallization from isopropyl alcohol. Yield 67%.

1. A process for the manufacture of diphenhydramine which comprises reacting approximately equimolar amounts of benzhydrol and ss-dimethyl- aminoethanol in the presence of a slight molar excess of p-toluenesulfonic acid at the boiling point of toluene.

2. A process according to Claim 1 in which the free base diphenhydramine is converted to a pharmaceutically acceptable acid addition salt.

3. A process substantially as herein described with reference to the Example.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (3)

**WARNING** start of CLMS field may overlap end of DESC **. SPECIFICATION Manufacture of diphenhydramine Diphenhydramine is a well-known antihistamine described in US Patents 2,427,878 and 2,421,714. The compound was synthesized by using classical Williamson synthetic means for preparing esters using alkoxides prepared from sodium or potassium metals and alkyl halides. An alternate method of synthesis is described in US Patent 2,397,799. The present invention employs two commercially available and easy to handle alcohols, an acid catalyst, and a safe to handle aromatic solvent to form an ether by elimination and removal of water from the reaction mixture in excellent yields and in one simple step. A similar reaction has been described in Chemical Communications, 1971, p 170-171, where a tertiary alcohol is coupled with a primary aliphatic alcohol using p-toluenesulfonic acid and benzene as solvent. The tertiary alcohol provides an easily available carbonium ion for coupling with a simple aliphatic alcohol. On the other hand, attempts to prepare diphenylhydramine by coupling of two alcohols with use of p-toluenesulfonic acid and in benzene have resulted in poor yields. US Patents 3,407,258 and 3,666,811 describe coupling of secondary benzhydrvl alcohols with (3- amino-alcohols employing acid while heating under reduced pressure. Accordingly, it has been unexpectedly found that diphenhydramine can be conveniently manufactured by coupling benhydrol and (3-dimethylamino- ethanol with a slight molar excess of p-toluenesulfonic acid at the boiling point of toluene. Since toluene is an azeotroping solvent, water formed during the reaction is removed through a trap. The amount of heating at reflux, boiling point of toluene, ranges from 12 to 36 hours. The resulting free base may then be converted by known means to a corresponding pharmaceutically acceptable acid addition salt with an inorganic or organic acid. Examples of such salts are the hydro-chloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, citrate, oxalate, succinate, benzoate, tartrate, phthalate, maleate, oleate, and the like. The alcohols are used in approximate equimolar amounts. The amount of p-toluenesulfonic acid required is a slight excess over an equimolar amount in order to tie-up the amino group and to provide an additionai catalytic amount for helping the reaction proceed to completion. The invention is illustrated further by the following example. Example A mixture of 57.8 g of para-toluenesulfonic acid, 26.7 g of (3-dimethylaminoethanol, 57.5 g of benzhydrol, and 150 ml of toluene is heated to reflux using a condensor equipped with a Dean Stark trap. The mixture is refluxed for 12-36 hours and then cooled to room temperature. It is poured into 250 ml of water, and the pH adjusted to 11.0 with sodium hydroxide. The aqueous layer is discarded and the organic layer is washed with water, charcoaled, and dried. After filtration, the organic layer is converted to its hydrochloride by gassing with 8 g of anhydrous hydrogen chloride. The product melts at 168-169 C after crystallization from isopropyl alcohol. Yield 67%. CLAIMS

1. A process for the manufacture of diphenhydramine which comprises reacting approximately equimolar amounts of benzhydrol and ss-dimethyl- aminoethanol in the presence of a slight molar excess of p-toluenesulfonic acid at the boiling point of toluene.

2. A process according to Claim 1 in which the free base diphenhydramine is converted to a pharmaceutically acceptable acid addition salt.

3. A process substantially as herein described with reference to the Example.