Novel process for the preparation of Dipivefrin hydrochloride
The invention relates to a process for the preparation of sympathomimetic amine derivatives, more particularly, a novel process for the preparation of Dipivefrin Hydrochloride (I) which acts as an antiglaucoma and broncholytic agent.

US patent No. 3809714 discloses the process for the preparation of Dipivefrin hydrochloride starting from 4-chloroacetyl catechol which was condensed with methylamine followed by esterification using pivaloyl chloride in the presence of perchloric acid and hydrogenation using platinum oxide as a catalyst yielded Dipivefrin hydrochloride (I).
US Patent 4275219 describes the process for the synthesis of both racemic and optically active forms of Dipivefrin hydrochloride (I). US patent No.4085270 discloses a process for the preparation of acyl derivatives of sympaticomimetic phenolethanolamines.(I) The method involves hydrogenation and debenzylation of the compound (IV) using palladium on charcoal in aqueous medium to reduce the carbonyl group.
Finland patent number FI 810700 used Sodium borohydride in acetic acid for the reduction of carbonyl group in compound (IV). JP 50130729 discloses the preparation of 4-chloroacetyl catechol using chloroacetic acid and phosphorous oxychloride. Colombini,etal, ( J.Proc. Int. Conf. Methods Prep. Stor. Label Compounds (1968), 237-

46) disclosed a method for the preparation of 4-chloroacetyl catechol using phosphorous oxychloride and catechol under stream of sulphur dioxide. Grinstein et.al in Inst.org.sin9USSR discloses a method for the acylation of catechol using chloroacetyl chloride and phosphorous oxychloride in benzene medium.
The object of the present invention is to provide industrially viable process for the production of very pure Dipivefrin hydrochloride (I) in high yields.
Summary
Accordingly, the present invention provides a novel process for the preparation of dipivefrin hydrochloride (I) as discussed in the Scheme (I)

Catechol was treated with chloroacetyl chloride in dichloromethane at reflux temperature to get 4-Chloroacetylcatechol, Reaction of the later (III) with N-methylbenzyl amine in acetone at reflux temperature yield l-(354-dihydroxyphenyl)-2-(N-benzylaminomethyl)-ethan-l-one(IV). Esterification with pivaloyl chloride in acetone at reflux temperature yields 1 -(3 \ 4'-dipivaloxyphenyl)"2-(N-benzylaminomethyl)-ethan-1 -one (V). Debenzylation of the later was carried out using palladium on carbon in 2-methoxyethanol at atmospheric pressure. Reduction of the debenzylated compound with sodium borohydride at a temperature between 10°to 15°C,followed by treatment with dry hydrochloric acid to yield dipivefrin hydrochloride (I), in an overall yield of 80%w/w.

Detailed description of present invention:
According to this invention a novel process for the preparation of dipivefrin hydrochloride (I) (Scheme I) involved:

a) treating catechol(II) with chloroacetyl chloride in dichloromethane at reflux
temperature to get 4-chloroacetylcatechol(III)
b) condensing the 4-chlorocaetylcatechol with N-benzylmethylamine in acetone
at reflux temperature to yielded 1 -(3,4-dihydroxyphenyl)-2-(N-
benzylaminomethyl)-ethan-l -one (IV)
c) etherification of the compound (IV) with pivaloyl chloride in acetone at reflux temperature to get 1 -(3'54,,-dipivaloxyphenyl)-2-(N-benzylaminomethyl)-ethan-l-one(V)
d) debenzylation of the compound (V) using palladium on carbon in 2-methoxyethanol at room temperature,followed by the reduction of ketone with using sodiumborohydride at 10° and 15 °C giving dipivefrin base (VI)
e) Conversion of Dipivefrin base to Dipivefrine hydrochloride is carried with dry
hydrochloride

Example I
Preparation of 4-chloroacetyl catechol
To a mixture of catechol (1.25Kg) and chloroacetylchloride (1.625L) in 20L of dichloromethane was slowly added anhydrous aluminium chloride (5.23Kg) with stirring. After the addition, the mixture was heated under reflux for 3 hrs with stirring. The contents were cooled to room temperature and poured slowly with stirring into ice cold aq. hydrochloric acid. The product obtained was collected by filtration and washed with water to give the crude product.
The crude product was dissolved in hot water (30L) and charcoalised and filtered. The filtrate on cooling to 10 °C yielded crystals of pure 4-chloroacetylcatechol (1.3Kg) (III), Yield: 104%w/w
Example II
Preparation of l-(3,4,-dihydroxyphenyl)-2-(N-benzylaminomethyl)-ethane-l-one
A mixture of N-benzylmethylamine (1430ml) and potassium carbonate (2.25Kg)
in dry acetone (3.5L) was heated under reflux for 3 hrs with stirring. The contents were
cooled to room temperature. A solution of 4-chloroacetylcatechol (1.3Kg) in acetone
(5.5L) was added to the reaction mixture slowly with stirring. The mixture was then
heated under reflux for 3 hrs. The cooled reaction mixture was filtered and the filtrate
was evaporated to dryness. The gummy material thus obtained was dissolved in hot
methanol (2L) and the solution was poured into ice cold aq. hydrochloric acid. The solid
obtained was collected by filtration and washed with water to yield l-(3, 4,-
dihydroxyphenyl)-2-(N-benzylaminomethyl)-ethan-l-one (1.6Kg) (IV). Yield:
123%w/w

Example III
Preparation of l-(3,4,-dipivaloxyphenyl)-2-(N-benzylaminomethyl)-ethane-l-one
A mixture of 1 -(3 ,4,-dihydroxyphenyl)-2-(N-benzylaminomethyl)-ethan-1 -one(I V) (1.6Kg) and potassium carbonate (1.28Kg) in dry acetone (12L) was heated under reflux for 3 hrs with stirring. The reaction mixture was cooled to room temperature and a solution of pivaloyl chloride (2.88L) in acetone (3.5L) was added to it and continued refluxing for 3 hrs with stirring. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness to give a gummy material to which petroleum ether (60-80°C) (13L)was added and refluxed to give the solid which was collected by filtration and washed with petroleum ether (60-80°C). Recrystallisation of the later from toluene yield pure 1 -(3' ,4'-dipivaloxyphenyl)-2-(N-benzylaminomethyl)-ethan-1 -one (2.0Kg) (V). Yield: 125%w/w
Example IV
Preparation of l-(3,,4%-dipivaloxyphenyl)-2-methylamino-l-ethanol
To a solution of l-(3', 4'-dipivaloxyphenyl)-2-(N-benzylaminomethyl)-ethan-l-one (V) (2.0 Kg) in 2-methoxyethanol (20L), palladium on carbon (0.2Kg) was added to and hydrogenation was carried out until 1 mol of hydrogen gas was absorbed. The catalyst was filtered, and the filtrate cooled to 10 °C and Sodium borohydride (55G) was added slowly with stirring. The mixture was further stirred for lHr and the pH was adjusted to 5.5 with acetic acid followed by distillation of solvent under vacuum. The gummy material thus obtained was dissolved in water, saturated with sodium chloride and extracted with ethyl acetate. The organic layer was washed once with brine and solvent was distilled out completely. The resulting gummy material was stirred with

diethyl ether (12L) to yield a solid which was filtered and dried to give l-(3\4'-dipivaloxyphenyl)-2-methylamino -1- ethanol (l.lKg)(VI),Yield : 55%w/w
Example V
Preparation of l-(3\ 4',-dipivaloxyphenyl)-2-methylamino -1-ethanol hydrochloride
l-(3', 4'-dipivaloxyphenyl)-2-methylamino -1- ethanol (1.1 Kg) was dissolved in hot methylisobutyl ketone (20L) and cooled to room temperature. An ethereal HCl solution (1.5 mol) was added into mixture with stirring. The content was cooled to 10 °C and the separated material was filtered and dried to give very pure 1 -(3' ,4'-dipivaloxyphenyl)-2-methylamino -1- ethanol hydrochloride (1.0Kg)(I),
Yield: 91%w/w and purity of 99.8% as per USP 28.

We claim
1. A novel process for the preparation of dipiverfin hydrochloride (I)

a) treating Catechol with chloroacetyl chloride in an organic solvent such as
dichloromethane, acetone preferably dichloromethane at reflux temperature
between 40 to 60°C preferably 40°C to get 4-chloroacetylcatechol;
b) condensing 4-chloroacetylcatechol with N- benzylmethyl amine using an organic
solvent such as acetone ,methyl isobutyl ketone ,ethyl methyl ketone or ethyl
acetate in between 60° to 120°C preferably preferably acetone at reflux
temperature to achieve l-(3,4-dihydroxyphenyl)-2-(N-benzylaminomethyl)-ethan-
1-one;
c) Esterfication of compound(IV) using pivaloyl chloride in an organic solvent such as acetone ,methyl isobutyl ketone ,ethyl methyl ketone or ethyl acetate in between 60° to 120°C preferably preferably acetone at reflux temperature to get 1 -(3' ,4' -dipivaloxypheny l)-2-(N-benzylaminomethyl)-ethan-1 -one;
d) debenzylating the compound(V) using palladium on carbon in an organic solvent such as ethanol,methanol,2-methoxyethanol at 5 and 40°C preferably 2-methoxyethanol and subsequently reduce the resulting compound using sodiumborohydride at temperature between 5 and 40°C
e) Conversion of the compound (VI) using hydrochloric acid gas to get
pharmaceutically acceptable salt of compound I.

2. The process as claimed in claim 1, debenzylation in step (d) of claim 1 is more preferably carried out at 25° to 30°C under atmospheric pressure.
3. The process as claimed in claim 1, reduction step (d) of claim 1 is carried out more preferably at 10° to 15°C.
4. The process for the preparation of compound I is substantially herein described and
exemplified.