FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION
"A cost effective process for production of (benzhydryloxy)-dimethylethylamine and salts."
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi-Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to a cost effective process for synthesis of 2-Diphenylmethoxy-NN-dimethylethanamine (diphenhydramine) of formula (I) and its salts.

Background of invention:
Diphenhydramine is an antihistamine with anticholinergic (drying) and sedative properties that is used to treat allergic reactions. Histamine is released by the body during several types of allergic reactions and to a lesser extent—during some viral infections; such as the common cold. When histamine binds to its receptors on cells, it causes changes within the cells that lead to sneezing, itching, and increased mucus production. Antihistamines compete with histamine for cell receptors; however, when they bind to the receptors they do not stimulate the cells. In addition, they prevent histamine from binding and stimulating the cells. Diphenhydramine was originally approved by the FDA in 1946.
Synthesis of diphenhydramine is 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.
The US patent 2,421,714 describes the preparation of benzhydryl bromide (II) from diphenylmethane (I) by addition of bromine at 130°C. Overall yield is around 35% of theoretical. An alternate method of synthesis is described in US Patent 2,397,799. The patent describes use of sodium amide and benzene or sodium metal. The disadvantage in this process is use of sodium amide as it dangerously reactive towards water.
2

Chemical Communications, 1971, p 170-171 describes coupling of tertiary alcohol 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. 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 benzhydryl alcohols
with 3-amino-alcohols employing acid.
Accordingly, diphenhydramine can be conveniently manufactured by coupling
benzhydrol and 3-dimethylamino- ethanol in toluene but the same is not commercially
feasible.
Summary of the invention:
The present invention discloses a cost effective process for production of diphenhydramine. The process involves preparation of benzhydryl bromide with purity not less than 97 % and percentage yield not less than 95 %. Condensation of benzhydryl bromide with dimethyl aminoethanol to get diphenhydramine hydrobromide of 99.5 % purity. Diphenhydramine is prepared by the treatment with sodium hydroxide and converted to its hydrochloride and citrate salts by treatment with IPA-HC1 and Citric acid in water respectively.
Detailed description of the invention:
The present invention describes a cost effective preparation of diphenhydramine and preparation of citrate salt. The process of the present invention comprises the steps of;
i) Bromination of diphenylmethane to get benzhydryl bromide with an yield of
more than 95% and purity of more than 97%.
ii) Condensation of Benzhydryl bromide with Dimethyl amino ethanol is carried out in monochlorobenzene to get diphenhydramine hydrobromide with an yield of 91% and purity not less than 99.5%.
3

iii) Diphenhydramine is prepared from diphenhydramine hydrobromide by
treatment with caustic lye with a yield of 91% and purity not less than 99.5
%.
iv) Diphenhydramine is treated with citric acid in water to produce
diphenhydramine citrate,
v) Crude diphenhydramine citrate is purified in water to get pure
diphenhydramine citrate,
vi) Diphenhydramine is treated with alcoholic HC1 to get diphenhydramine
hydrochloride. The present invention is further illustrated with the following examples.
Examples:
Example 1 [Bromo(phenyl)methyl]benzene(Stage-I)
Charged 80 g. of diphenylmethane in flask. Heated the content to 110-115°C. Added bromine maintaining temperature between 110-115°C in 5-6 hrs. Maintained at 110-115°C till completion of reaction. Cooled the content room temperature to yield 117 g. (96.5 % of theoretical) as light yellow liquid. Purity: Not less than 97 %.
Example 2
Diphenhydramine hydrobromide. (Stage-II)
Charged 117 g. (0.473 moles), monochlorobenzene 240 ml in flask. Heated the content
to 110-115°C. Charged mixture of 45.6 kg dimethylaminoethanol in 14 ml.
monochlorobenzene in 3-4 hrs at 110-115°C. Batch was cooled to 0-5°C slowly. Stirred
at 0-5°C for 5-6 hrs. Filter the material and washed with monochlorobenzene and water
separately to obtain 145 g. diphenhydramine hydrobromide (91.1.0% of theoretical).
Purity: Not less than 99.5 %
4

Example 3
Diphenhydramine (Stage-Ill)
Charge 145 g Diphenhydramine hydrobromide and 100 ml. water. Heat the content to 50-
55°C. Charge caustic lye at 50-55°C to get pH 9-11. Stirred for 1 hr. Allow the two layers
to settle for 60 mins. Separate the two layers. The organic layer was filtered to obtain
l0lg. (0.396 moles) diphenhydramine. (91.8% of theoretical). Purity: Not less than 99.5
%.
Example 4.
Diphenhydramine citrate.
Charge 303 ml water, 68.83 g. citric acid and heat the content to 55-60°C. Add dropwise diphenhydramine at 55-60°C. Stirred the material at same temperature and cool the content to 0-5°C. Filter the content and wash with water to yield 162.4 g. of pure Diphenhydramine citrate (92 % of theoretical) Percentage Purity: NLT 99.5 %. Contents of benzhydryl bromide are observed below detection limit. Other impurity profiles are very low.
Example 5.
Diphenhydramine Citrate.
Charge 325 ml. water, 81.2 g. Diphenhydramine citrate. Heat the content to 70-80°C.
Add charcoal and stir for 60 mins at 70-80°C. Filter the content and wash with water.
Cool the filtrate to 0-5°C. Stirred the content to 0-5°C for 3-4 hrs. The material was
filtered to yield 74.5 g. of pure diphenhydramine citrate (91.74 % of theoretical)
Percentage Purity: NLT 99.7 %.
Example 6.
Diphenhydramine HC1.
Charge 105 ml. IPA and Diphenhydramine free base, and heat the content to 50-55°C.
IPA.HCl (25%) and adjust the pH to 2-2.5. Stirred the material at same temperature for
30 mins. and cool the content to 0-5°C. Filter the content and wash with water to yield
5

103.5 g. of pure Diphenhydramine HCl (90 % of theoretical) Percentage Purity: NLT 99.5 %. Contents of benzhydryl bromide are observed below detection limit.
Example 7
Diphenhydramine HCl.
Charge 105 ml. IPA, diphenhydramine and heat the content to 55-60°C. Charge 68.83 g.
citric acid dissolved in 150 ml of IPA at 55-60°C. Stirred the material at same
temperature and cool the content to 0-5°C. Filter the content and wash with water to yield
162.4 g. of pure Diphenhydramine citrate (92 % of theoretical) Percentage Purity: NLT
99.5 %. Contents of benzhydryl bromide are observed below detection limit.
6

We claim,
1. A cost effective process for preparation of highly pure salts of diphenhydramine
substantially free from impurities, comprising the steps of;
i) Bromination of Diphenylmethane to get highy pure Benzhydril
bromide free from other brominated impurities,
ii) Condensation of benzhydryl bromide and dimethyl amino ethanol
to isolate diphenhydramine hydrobromide of purity. 99.5%.
iii) Free base of purity 99.5% is prepared by treating diphenhydramine
hydrobromide with sodium hydroxide,
iv) Preparation and purification of citrate salt in water.
2. The process as claimed in claim 1, wherein, preparation of citrate salt is prepared with the use of citric acid.
3. The process as claimed in claim 1, wherein, purification of citrate salt is carried out in water.
4. The process as claimed in claim 1, wherein, purification of citrate salt is carried out in IPA.
5. The process as claimed in claim 1, wherein, quantity of the citric acid used is 1:1 molar ratio of the substrate.
6. The process as claimed in claim 1, wherein, the yield of citrate salt prepared in water is not less than 95 % of theoretical.

Dr. Gopakumar G. Nair Agent for the Applicant
7
Dated this 22nd day of June, 2007

ABSRACT:
A cost effective process for preparation of highly pure diphenhydramine substantially free from impurities is described herein; bromination of diphenyl methane is carried out at 110-115°C. Diphenhydramine HBr salt is isolated in pure form after the condensation. Diphenhydramine is prepared in high purity with the use of caustic lye. Diphenhydramine citrate salt is prepared and purified in water to obtain pure Diphenhydramine citrate.
8