FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF DESMETHYL DIPHEN-HYDRAMINE HYDROCHLORIDE"
2. APPLICANT:
(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 invention relates to an improved process for the preparation of Desmethyl diphenhydramine hydrochloride with high purity.
Background and Prior art:
Diphenhydramine, chemically known as 2-(diphenyl methoxy)-N. N dimethyl ethanamine is widely used as an over-the-counter antihistamine. However, this is known to show adverse effects on the central nervous system such as sedation, impairment of cognitive function and psychomotor performance.
Desmethyl diphenyhydramine, 2-(diphenyl methoxy)-N-methyl ethanamine, a naturally occurring metabolite of diphenhydramine is used for treating allergies, inflammations, cholinergic activities, asthma or other diseases that are mediated through histamine receptors of various types with no detectable sedative effects.
An article titled "Identification of Human Cytochrome P450 Isozymes Involved in Diphenhydramine N-Demethylation" by Tomoko Akutsu et al, DOI: 10.1124, identifies the involvement of P450 isozymes in the metabolic pathways of diphenhydramine wherein, diphenhydramine is extensively metabolized by demethylation to N-demethyl diphenhydramine, followed by rapid demethylation to N, N-didemethyl diphenhydramine.
Methods described in the art useful for the N-demethylation of tertiary amines include oxidation with potassium permanganate, Ber. 29, 1575 (1896), Liebigs Ann. Chem. 708, 210 (1967); or potassium ferricyanide, J. Amer. Chem. Soc. 74, 5566 (1952); treatment with ethyl or phenyl chloroformates followed by hydrolysis, Tet. Lett. 1971 57—58; J. Med. Chem. 15, 208 (1972); and formation of an alkylazodicarboxylate reaction product followed by hydrolysis, U.S. Pat. 3,213,128. The oxidative demethylation procedures suffer from the defect that large volumes of solvents are required and the yields of product are low. In addition, the hydrolysis of carbamates produced by the above chloroformate procedures is difficult and in some cases none of the desired secondary amine can be obtained. The di alky lazodicarboxy late method gives varying yields of the secondary amine product contaminated with small quantities of the tertiary amine. The following prior art discloses the formation of N-substituted metabolites of diphenhydramine.

US 6372799 discloses preparation of N-substituted metabolites of diphenhydramine and its pharmaceutically acceptable salts as antihistaminic agents, wherein 2-diphenylmethyloxy-ethyl chloride is treated with methyl-amine in methanol at 100°C for 15hrs.
GB1363986 describes in an embodiment, a process for the preparation of diphenylmethoxyethylamines (having dopaminergic activity) of formula 1;

in which R5 represents a fluorine, bromine or chlorine atom, R6 represents a hydrogen or fluorine atom and R7 represents a hydrogen, fluorine or chlorine atom, with the proviso that R7 is a hydrogen atom when R6 is a fluorine atom and R5 is a fluorine atom when R7 is a chlorine atom, by reacting an ether of formula;

where Hal is halogen atom, with excess of ammonia.
In another embodiment of the said patent, diphenylmethoxyethylamines is prepared by treating a phthalimide derivative

with hydroxylamine or an acid addition salt thereof.
In yet another embodiment of the said patent, diphenylmethoxyethylamines is prepared by hydrolysis of the amide;


wherein R5, R6 and R7, are as defined above, R8 represents a hydrogen atom or an alky], aryl or aralkyl group, with lower alcohol in the presence of base; and/or reduction of a nitrile,

with lithium aluminium hydride followed by decomposition with water.
US36668U discloses preparation of diphenylmethoxyethanamine and its acid addition salt of formula I;

where Rl, R2, R3 and R4 are the same or different and each represents a hydrogen or halogen atom or a lower alkyl group, R5 represents a hydrogen atom or a lower alkyl group and R6 represents a phenyl-lower alkyl group or phenyl-lower alkenyl group in which the phenyl group may be substituted by one or more lower alkyl groups, and acid addition and quaternary ammonium salts thereof, wherein benzhydrol of formula II,

is reacted with an amino alcohol (Formula 111) in presence of p-toluene sulphonic acid under reduced pressure.

In yet another process variant, diphenylmethoxyethanamine is prepared by reacting a compound of formula IX.

Formula IX with a compound of formula; R6-B where R6 represents a phenyl-lower alkyl group or phenyl-lower alkenyl group in which the phenyl group may be substituted by one or more lower alkyl groups, and wherein Rl, R2, R3, R4 are as hereinbefore defined, one of the symbols A and B represents a halogen atom and the other a group of the formula,

where R5 represents a hydrogen atom or a lower alkyl group, in an inert solvent and in presence of an acid binding agent such as sodium carbonate.
CA 655600 discloses the preparation of compound of formula I;

in which Rl represents a dimethylamino, diethylamino or piperidino radical, by reacting 4-chloro-a -methyl benzhydrol with a compound of the formula
HaI-CH.CH2.R, CH3

wherein Rl represents a member selected from the group consisting of dimethylamino, diethylamino, piperidino and morpholino radical and Hal represents a halogen atom, preferably chlorine in the presence of sodamide and an inert solvent.
Object of the invention:
The object of the invention is to provide an improved process for the preparation of Desmethyl diphenhydramine hydrochloride of Formula I;

Formula (I)
Another object of the invention is to prepare the compound of Formula I with the use of easily available and cost effective reagents resulting in high yield/purity of final product.
Summary of the invention:
The present invention provides a process for the preparation of desmethyl diphenyhydramine [2-(diphenyl methoxy)-N-methyl ethanamine] and its hydrochloride salt, comprising, reacting diphenhydramine carbamate (DPH. carbamate) with a basic compound to form desmethyl diphenyhydramine base.
In an aspect of the invention, diphenyhydramine base is reacted with phenyl chloroformate in presence of an inert solvent to obtain diphenhydramine carbamate (DPH. carbamate).
In another aspect of the invention, diphenhydramine base can be obtained by neutralization of diphenhydramine hydrochloride.
Brief description of the Drawings
Figures 1, 2 and 3 depict NMR spectra of DPH.carbamte Figures 4 and 5 depict Mass Spectra of DPH. Carbamate

Detailed Description:
The process of the present invention is described hereinafter in more details substantiating various embodiments and conditions of reaction for better understanding/appreciation of the invention.
The present invention provides an efficient process for preparing desmethyl diphenyhydramine hydrochloride comprising the steps of;
i. Reacting diphenhydramine carbamate (DPH. carbamate) with a basic
compound to form desmethyl diphenyhydramine base; and ii. reacting desmethyl diphenyhydramine base with hydrochloric acid to form desmethyl diphenyhydramine hydrochloride.
The basic compound used in step (i) is selected from organic/inorganic base such as methyl amine, trimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
The reaction of DPH.carbamate (IV) with the basic compound to obtain desmethyl base (V) is conducted in the solvent selected from C1-C6 alcohols, aromatic hydrocarbons such as toluene, xylene etc. at a temperature in the range of 50-120°C.
In one embodiment, diphenyhydramine base (III) is reacted with phenyl chloroformate in presence of an inert solvent to obtain diphenhydramine carbamate (DPH. carbamate) (IV). The inert solvent is selected from toluene, xylene etc. either alone or their mixtures thereof.
In another embodiment of the present invention, diphenhydramine base (III) can be obtained by neutralization of diphenhydramine hydrochloride(II).
The process steps of the invention are schematically depicted as below:


In an embodiment of the present invention, diphenyhydramine base(III) in toluene is treated with phenyl chloroformate at 55-60° C for 30 min and the temperature is further

raised and maintained at 105-110°C for 30min until TLC indicated completion of reaction. The reaction mass is then cooled to 55-60°C and triethyl amine is added at same temperature. The solution is further cooled to 25-30°C followed by addition of caustic solution, stirred and allowed the reaction mass to settle. The separated aqueous layer is extracted with toluene. Add water to the organic layer and pH of the mass is adjusted to 1-1.5 using conc. HCI, stirred and allowed the reaction mass to settle. Organic layer is washed with water. Organic layer is treated with sodium sulphate and toluene layer is then distilled off completely under vacuum to obtain DPH.carbamate (IV).
Diphenhydramine base can be obtained by neutralization of diphenhydramine hydrochloride.
Accordingly, in an embodiment, diphenhydramine hydrochloride (DPH.HC1)(I1) in water and toluene is treated with ammonia till pH 10-11 at 25 -30°C for 30min. After neutralization is complete, the combined toluene layer obtained after subsequent washings with water is collected in a R.B. flask. The combined toluene layer is then distilled off completely under vacuum. The reaction mass is cooled to obtain diphenhydramine base (111).
In yet another embodiment, DPH.carbamate (IV) obtained in step (i) is hydrolyzed using caustic solution in isopropyl alcohol at 80-82°C until TLC indicated complete reaction. The reaction mass is then cooled to 30-35°C and the aqueous layer is separated and repeatedly extracted with toluene. The pH of the toluene solution is adjusted to l-i.5 using conc. HCI. The aqueous layer is treated with solution of sodium hydroxide and extracted with toluene. Toluene is distilled off completely under vacuum. The reaction mass is cooled to yield desmethyl diphenhydramine base (V).
In an alternate embodiment, the carbamate (IV) obtained in step (i) is hydrolyzed using potassium hydroxide in toluene at reflux temperature until TLC indicated complete reaction. The reaction mass is then cooled to 40-45°C followed by addition of water. The aqueous layer is separated. Wash the organic layer with 5% sodium hydroxide solution repeatedly by maintaining the temperature to 40-45°C. The separated organic layer is repeatedly washed with water at 25-35°C. Toluene is then distilled off under vacuum, cooled the reaction mass to 30-35°C to yield desmethyl diphenhydramine base (V).

In yet another embodiment desmethyl diphenyhydramine base(V) obtained from step (ii) is dissolved in isopropyl alcohol and the reaction mass is stirred for 30 min. To the reaction mass isopropyl alcohol hydrochloride (IPA.HCI) is added at same temperature. The reaction mass is stirred for 30 min, cooled to 10-15°C. The reaction mass is maintained at 10-l5°C for about 60 min. It is then filtered, washed with IPA. and dried under vacuum till constant weight to give the hydrochloride salt.
In an embodiment of the present invention, desmethyl diphenyhydramine hydrochloride (I) having purity of 99.90% is achieved.
The advantage of the process of the present invention is that high yield and high purity is made possible by subjecting the intermediates formed to repeated water washings thus making the process economical and industrially viable.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and not restrictive to the invention.
Examples:
Example 1:
Preparation of Diphenhydramine base from Diphenhydramine hydrochloride
(DPH.HC1)
To a neat, clean, dry, four neck round bottom flask with reflux condenser and thermometer pocket, was charged water (500ml), diphenhydramine hydrochloride(II) (250g) and toluene (875ml). This was followed by addition of ammonia solution (18-20%) till pH 10-11 at 25-30°C. Stirred the reaction mass at 25-30°C for 30min and allowed to settle the two layers. Separated the layers, collected the toluene layer (A). Charged aqueous layer to a R.B. flask followed by addition of toluene (250ml), stirred the reaction mass for 30min at 25-30°C, settled and separated the layers. The organic layer separated was combined with the toluene layer (A). To the aqueous layer was further added toluene (250ml), stirred, separated and the organic layer was combined with the toluene layer (A). The combined toluene layer was washed with water (3 x 500ml), stirred the reaction mass for 30min at 25-30°C, settled and separated the layers. The washed

toluene layer was treated with sodium sulfate (25g), stirred for 30min at 25-30°C, and filtered. The sulfate bed was further washed with toluene (50ml) filtered and added to the main toluene layer. Toluene was then distilled off completely under vacuum at 55-60°C. The reaction mass is cooled to 25 - 30 °C to obtain 215g diphenhydramine base(III). Theoretical wt: 218.7g Yield: 98%
Example 2:
Preparation of Diphenyhydramine Carbamate (DPH. Carbamate) from Dipheny-
hydramine base
To a neat, clean, dry four neck round bottom flask with reflux condenser and thermometer pocket, was charged toluene (500ml) and diphenhydramine base(III) (l00g).The reaction mass was heated to 55-60°C. Phenyl chloroformate (73g) was added at 55-60 °C. The reaction mass was stirred at 55-60°C for 30min.The mass temperature was then raised tol05-110°C and maintained until TLC indicated complete reaction. Cooled the reaction mass to 55-60°C followed by addition of triethylamine (40g) at the same temperature and further maintained for 60minutes.The reaction mass was then cooled to 25-30°C, caustic solution (obtained by dissolving 5g of caustic flakes in 300ml water) was added, stirred for 30 minutes and allowed to settle. The organic layer was separated (A) and to the aqueous layer toluene (200ml) was added, stirred the reaction for 30 min and allowed to settle. The aqueous layer was removed and the toluene layer was collected (B). Combined organic layer (A+B) was washed with water (2 x 200 ml). To this toluene layer water (300ml) was added and pH of the solution was adjusted to 1-1.5 by adding cone. HCI, and stirred for 30min.Separated the layers. Toluene layers were washed with water (2 x 300ml). To the washed toluene layer was added 15g sodium sulphate, stirred for 30min and filtered. The sulphate bed was again washed with toluene (50ml), filtered and added to the main toluene layer. Combined Toluene was then distilled out completely under vacuum at 55-60°C. The reaction mass was cooled to 30-35°C to yield 135g diphenhydramine carbamate(lV).
Theoretical yield: I41.5g Yield-95.4%
Purity-98% by HPLC Example 3:

Preparation of Desmethyl Diphenhydramine base from diphenhydramine carbamate (DPH. carbamate)
Example 3a
To a neat, clean, dry four neck round bottom flask with reflux condenser and thermometer pocket, was charged isopropyl alcohol (1000ml) and DPH.carbamate(IV)(100gm) and heated to reflux, 80-82°C. Caustic solution (obtained by dissolving 140g of caustic flakes in 300ml of water) was further added to the reaction mixture at the same temperature and maintained at reflux for 6 hours until TLC indicated complete reaction. After completion of the reaction, the reaction mass was cooled to 30-35°C Water (500ml) and toluene (300 ml) was added to the reaction mixture, stirred for 30 fflin, separated. Toluene layer was washed with water (5 x 300ml). Water (200 ml) was added to the toluene layer and the pH of the mass adjusted to 1-1.5 by adding cone. HCI with constant stirring. The toluene layer was washed with water (2 x 200ml) and followed by addition sodium sulphate (25g). The reaction mixture was stirred for 30min and filtered through hyflo bed. The hyflo bed was further washed with toluene (25ml) and the combined toluene layer was distilled under vacuum at 700-720mm/Hg and at 55-60°C. The reaction mass was then cooled to 30-35°C to yield 50g desmethyl diphenyhydramine base(V). Theoretical yield: 66.76g Yield- 75% ■ Purity-90-95%byHPLC
Example3b
To a neat, clean, dry four neck round bottom flask with reflux condenser and thermometer pocket, was charged toluene (1500ml), DPH carbamate(IV) (100 gm) and potassium hydroxide flakes (94g). The reaction mass was heated to reflux until TLC indicated complete reaction. The reaction mass was then cooled to 40-45°C followed by addition of water (600ml). The reaction mass was further stirred for 15-20min at 40-45°C and then allowed to settle. Separated organic layer was washed with water (2 x 400ml) at 40-45°C. The separated organic layer was repeatedly washed with 5% sodium hydroxide solution (3x300 ml). The organic layer is further repeatedly washed with water (3 x 400ml) followed by distilled off toluene under vacuum (700-720mm/Hg) at 55-60°C. The

reaction mass was then cooled to 30-35°C to yield desmethyl diphenylhydramine base
(III).
Yield: 92-94%
Purity: 95-98% by HPLC
Example 4
Preparation of Desmethyl diphenhydramine hydrochloride
To a neat, clean, dry four neck round bottom flask with reflux condenser and thermometer pocket, was charged of isopropyl alcohol (40ml) and desmethyl diphenyhydramine base(III) (l0g). The reaction mass was stirred for 30 min followed by addition of IPA.HC1 (8ml), stirred for 30min. The reaction mixture was next cooled to a temperature in the range of 10-15°C for about 60 min. The reaction mass was filtered and further washed with a lPA (10ml), dried the cake under vacuum at 40-45 °C till constant weight to yield l0g of the hydrochloride salt of desmethyl diphenyhydramine(l). Theoretical yield: 11.51g Yield- 87% Purity-99.90% by HPLC

We claim,
1. A process for preparation of desmethyl diphenyhydramine hydrochloride
comprising the steps of;
i. reacting diphenhydramine carbamate (DPH. carbamate) with a basic
compound to form desmethyl diphenyhydramine base; and ii. reacting the said desmethyl diphenyhydramine base with hydrochloric acid to form desmethyl diphenyhydramine hydrochloride.
2. The process according to claim 1, wherein, the basic compound is selected from organic/inorganic base such as methyl amine, trimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
3. The process according to claim 1, wherein, the basic compound is sodium hydroxide or potassium hydroxide.
4. The process according to claim 1, wherein, the reaction of diphenhydramine carbamate (DPH. carbamate) with a basic compound is conducted in a solvent selected from C1-C6 alcohols, aromatic hydrocarbons such as toluene, xylene.
5. The process according to claim 1, wherein, the reaction of diphenhydramine carbamate (DPH. carbamate) with a basic compound is conducted in toluene.
6. The process according to claim 1, wherein, the reaction of desmethyl diphenyhydramine base with hydrochloric acid is conducted in IPA.
7. The compound of Formula IV;


8. A process for preparation of DPH carbamate of formula IV comprising a step of reacting diphenyhydramine base (III) with phenyl chloroformate in presence of an inert solvent to obtain diphenhydramine carbamate (DPH. carbamate) (IV).
9. The process according to claim 8, wherein, the inert solvent is selected from toluene or xylene.