FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A NOVEL PROCESS FOR THE SYNTHESIS OF BISOPROLOL AND ITS INTERMEDIATE
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAIDESAI ROAD, MUMBAI-400 026.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR THE SYNTHESIS OF BISOPROLOL AND ITS INTERMEDIATE

FIELD OF INVENTION
This invention relates to a new method for preparing a pharmaceutically active
compound with antihypertensive properties.
BACKGROUND OF INVENTION
(±)-l-[4-[[2-(l-methylemoxy)ethoxy]methyl]phenoxy]-3-[(l-methyl-ethyl)amino]-2-propanol(£)-2-butenedioate having formula I and commonly known as bisoprolol fumarate, blocks the action of the sympathetic nervous system on the heart by blocking the heart's beta-adrenergic receptors. Beta-adrenergic blocking agents such as bisoprolol reduce the heart rate and are useful in treating abnormally rapid heart rhythms. It is also useful in treating angina

Bisoprolol can be prepared as described in US patent 4258062, US 4171370, or DE 2645710, by using p-hydroxybenzylalcohol and heating to 150° C with 2-isopropyl ethanol to give 4-[(2-isopropoxyethoxy)methyljphenol, which is further reacted with epichlorohydrin to give 2-[[4-(2-isopropoxyethoxy)methyl]-phenoxymethyl]oxirane. This is further reacted with isopropyl amine to give bisoprolol. The drawback of this process is that such a high temperature of 150° C is difficult to achieve on industrial scale and moreover p-hydroxybenzyl alcohol as well as 2-isopropyl alcohols get self-condensed and produces dimer impurities at this temperature.

F. H. C. Stewart in J. Org. Chem. 27, 2662, 1962, mention the selective etherification of p-hydroxybenzyl alcohol by treating its solution in alcohol with a strong acid cation-exchange (especially "Zeo-Karb 225") resin at room temperature. But the limitations of this process are that the yield is low (60% in methanol and 37% in ethanol) and rapid polymerization of p-hydroxybenzyl alcohol to form a resinous product.
Indian patent 178218 describes the preparation of bisoprolol and its pharmaceutically acceptable salt by reacting 4-[(2-isopropoxyethoxy)methyl]-phenol with 1,3-dichIoro2-hydroxy propane in the presence of phase transfer catalyst such as tri-n-butyl ammonium bromide to obtain l-[[p-(2-isopropoxyethoxy)methyl]phenoxy]-3-chloro-propan-2-ol, which is further reacted with isopropyl amine in methanol in an autoclave at 100° C to get bisoprolol. This process requires a pressure reactor (e.g. autoclave) and high temperature making the process industrially uneconomical. US patent 6087512 describes the preparation of 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyljoxirane by reacting epichlorohydrin with p-(2-isopropoxyethoxy)methyl phenol in the presence of alkali metal or alkaline earth metal fluoride.
US patent 6057476 describes one pot synthesis for the preparation of bisoprolol base by reacting isopropylamine with the reaction product of epichlorohydrin and p-(2-isopropoxyethoxy)methyl phenol in the presence of alkali metal or alkaline earth metal fluoride. We have observed that in this process 10-15% of l-[p-(2-isopropoxyethoxy)methyl]phenoxy]3-chloro-propane-2-ol remains unreacted in the reaction mixture. This reduces the overall yield of final product bisoprolol fumarate. These two process use fluoride salt of alkali metal or alkaline earth metal, which is environmentally hazardous also.
German patent 4434823 describes and claims a process for the preparation of 4-[(2-isopropoxyethoxy)m ethyl] -phenol. In this process the solution of 4-hydroxybenzylalcohol and 2-isopropoxy ethanol in THF is passed over a bed of Amberlyst 15 in a fixed bed reactor loaded with ion exchanger leads. The obtained product mixture is passed through a second fixed bed reactor filled with weekly basic ion exchanger the Amberlyst A-21. The yield achieved is 72%. This process requires a costly reactor loaded with ion exchanger leads and also the process is not feasible at industrial scale as it requires to be passed through two ion exchanger. Thus making the process commercially not viable. A reference example in the same patent
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mentions a process for the preparation of 4-[(2-isopropoxyethoxy)methyl]phenol without using the second ion exchanger but the yield is very low, only 52%. Thus there is a need to minimize the impurities e.g. dimmer impurities formed by self-condensation of p-hydroxybenzyl alcohol as well as 2-isopropyl alcohols, and l-[p-(2-isopropoxyethoxy)methyl]phenoxy]3-chloro-propane-2-ol, making the process economical and industrially viable.
We have found that the pure bisoprolol or its pharmaceutically acceptable salt can be prepared by our novel process easily and economically at industrial scale with all the individual impurity not more than 0.1% and the total impurity not more than 0.5%.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of bisoprolol and
its pharmaceutically acceptable salt, which is economical and easy to carry out at
industrial scale.
The present invention also provides a novel process for the preparation of pure 4-[(2-
isopropoxyethoxy)methyl]phenol, an intermediate of bisoprolol, which is economical
and easy to carry out at industrial scale.
One of the embodiments of the invention is to provide a process for the preparation of
pure 4-[(2-isopropoxyethoxy) methyl]phenol and to minimise the formation of
associated dimer impurities of starting materials.
Another embodiment of the invention is to provide a process for the preparation of
pure 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane and to check and
reduce the 10-15% l-[p-(2-isopropoxyethoxy)methyl]phenoxy]-3-chloro-propane-2-
ol left in the reaction mass as an impurity. Thus the objective is to improve the overall
yield of the product
Yet another embodiment of the invention is to provide a process for the preparation of
bisoprolol with the impurity 4-[2-hydroxy-3-[(l-
methylethyl)amino]propoxy]benzaldehyde

and 4-[2-hydroxy-3-[(l-methylethyl)amino]propoxy] benzenemethanol

below 0.1% as required by ICH guidelines. DETAIL DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of bisoprolol and its pharmaceutically acceptable salts especially fumarate salt. This invention further provides a process for the preparation of its intermediates. According to this invention bisoprolol fumarate is prepared as given below in scheme.

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4-[(2-isopropoxyethoxy)methyl]phenol is prepared from 4-hydroxy benzyl alcohol. 2-Isopropoxy ethanol is charged in a reactor and cooled to 0°C and added Amberlyst-15 resin in one lot. Then 4-hydroxy benzyl alcohol is added in small lots at temperature below 30° C, preferably 0-5 °C. The reaction mixture is stirred at 0-5 °C for about 2 hrs. The temperature is raised to 15-20° C and stirred for another 10 hrs. The Amberlyst-15 resin is filtered and washed with 2-Isopropoxy ethanol. The reaction mixture is treated with an alkali metal carbonate. The alkali metal carbonate may be selected from the group comprising sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate preferably potassium carbonate. The alkali metal carbonate is filtered and the reaction mixture is taken for distillation to recover excess of 2-Isopropoxy ethanol to obtain pure 4-[(2-isopropoxyethoxy)methyl]phenol in quantitative yield.
To remove the dimer of 4-hydroxy benzyl alcohol and 2-Isopropoxy ethanol formed as an impurity (2-3% by HPLC), 4-[(2-Isopropoxyethoxy)methyl]phenol obtained after distillation of 2-isopropoxy ethanol is taken in toluene and washed three times with water. Then the toluene layer is extracted with aqueous sodium hydroxide solution resulting in a sodium salt. The aqueous layer containing the sodium salt of the 4-[(2-Isopropoxyethoxy)methyl]-phenol is treated with acid and the free phenol liberated is extracted in chloroform. After removal of solvents 4-[(2-Isopropoxyethoxy)methyl]phenol is isolated with high purity. Alternatively, the aqueous layer containing the sodium salt of the phenol is cooled to 5-10° C. Acetic anhydride is added to it and stirred for 2 hrs. and re-extracted with toluene, the toluene layer is further washed with water and distilled out the toluene to obtain acetyl derivative which is further subjected to high vacuum distillation. The distilled compound is further hydrolysed by dissolving in sodium hydroxide solution
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and heating it to 45-50 C and extracting in toluene to obtain the highly pure 4-[(2-
Isopropoxyethoxy)methyl]phenol.
The aqueous solution of sodium salt of 4-[(2-Isopropoxyethoxy) methyljphenol is reacted with epichlorohydrin at 60-65 °C for 1 hr. The reaction mixture is then extracted twice with toluene. The combined toluene extract is stirred with solid sodium hydroxide to convert the l-[p-(2-isopropoxyethoxy)methyl]phenoxy]3-chloro-propane-2-ol to the 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane ring. Thus solid sodium hydroxide takes the reaction to the completion. Otherwise approximately 10-15% of l-[p-(2-isopropoxyethoxy)methyl]phenoxy]3-chloro-propane-2-ol remains unreacted in the reaction mass. The reaction mixture is washed with water three times and the toluene layer is taken for distillation. 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane is isolated as an oil after the removal of solvent. The product is further purified by high vacuum distillation at 0.5 mm at 160-200 °C to obtain purified 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane.
2-[[4-(2-Isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane is mixed with methanol and cooled to 15 °C . Catalytic amount of sodium borohydride is added to it in small lots at 15-20 °C. Sodium borohydride is added to remove the aldehydic impurity i.e. 4-[2-hydroxy-3-[(l-methylethyl)amino]propoxy]benzaldehyde. The reaction mixture is digested for 1 hr at 15 - 20 °C and added to cooled isopropyl amine at 15 - 20 °C in about 1 hr. The reaction mixture is stirred for 3 hrs and heated to reflux for 3 hrs. The excess of Isopropyl amine and methanol is removed by distillation. The residual oil is taken in organic solvent selecting from chloroform, dichloromethane and dichloroethane preferably, chloroform and washed thrice with water. The organic layer is then passed over a bed of neutral alumina and washed the neutral alumina with same solvent. Bisoprolol base is obtained as an oil after removal of solvent by distillation. The bed of neutral alumina traps the impurity 4-[2-hydroxy-3-[(l-methylethyl)amino]propoxy] benzenemethanol formed and makes the product free of this impurity.
The fumarate salt of bisoprolol is prepared from bisoprolol base by the addition of fumaric acid to a hot solution of bisoprolol base in acetone or ethyl acetate. The reaction mixture is stirred for 30 minutes at reflux and after that it is cooled to 0-5° C.
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The separated product is centrifuged and washed with chilled acetone or ethyl acetate and dried.
The obtained bisoprolol fumarate is purified with organic solvent like acetone, ethyl acetate etc.
The starting compound 4-Hydroxy benzyl alcohol can be prepared by any conventional method or by adding 4-Hydroxy benzaldehyde in aqueous sodium hydroxide. The reaction mixture is stirred to get a clear solution and cooled to 15 °C. Sodium borohydride dissolved in water at 15 - 20 °C is added to it. The reaction mixture further stirred for 3 hrs. After charcoal treatment the reaction mixture is filtered over celite bed. The collected reaction mixture is chilled to 0 - 5 °C and added diluted solution of acetic acid to it. The separated product is filtered and washed with water and dried.
For better understanding, the invention can be illustrated by the following non-limiting examples.
Example 1
Preparation of 4-Hydroxy benzyl alcohol
In a 250 1 reactor 8.33 kg of sodium hydroxide was dissolved in water and 25.0 kg of 4-Hydroxy benzaldehyde was added. The reaction mixture was stirred to obtain a clear solution. The reaction mixture was cooled to 15 °C and added a solution of 3.0 kg Sodium borohydride dissolved in 15 1 of water at 15 - 20 °C in about 3 hrs. The reaction mixture was further stirred for 3 hrs. 1.0 kg Charcoal slurry prepared in 15 1 water was added to reaction mixture and stirred further for 30 minutes and filtered over celite bed. The reaction mixture was collected in 400 1 reactor and chilled to 0 -5 °C. Dilute solution of acetic acid (20 kg diluted with 20 1 water) was slowly added to the reaction mixture at 0 -5 °C in a period of 3 - 5 hrs to get the product separated. The separated product was filtered and washed with 40 1 water, spin dried and dried under vacuum to obtain 21 - 23 kg 4-Hydroxy benzyl alcohol.
Example 2
Preparation of 4-[(2-isopropoxyethoxy)methyl]-phenol
In a 400 1 reactor, 280 1 of 2-Isopropoxy ethanol was charged and cooled to 0 °C. Amberlyst-15 (22.5 kg) resin was added to it in one lot 4-Hydroxy benzyl alcohol (22.5 kg) was added to it in small lots of 2 kg each at 0 -5 °C in about 5 hrs. The
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reaction mixture was stirred at 0 - 5 °C for 2 hrs. The temperature was raised to 157
20° C and maintained for 10 hrs. The Amberlyst-15 resin was filtered and washed
with 2-Isopropoxy ethanol. The reaction mixture was collected in a 400 I vessel and
basified with 1.0kg of potassium carbonate. The potassium carbonate was filtered and
the reaction mixture was taken for distillation of 2-Isopropoxy ethanol to get 36 - 38
kg of 4-[(2-isopropoxyethoxy)methyl]-phenol. The 4-[(2-
isopropoxyethoxy)methyl]phenol obtained was taken in 144 1 toluene and washed three times with 144 1 water. Then the toluene layer was extracted with aqueous Sodium hydroxide solution (prepared by dissolving 7.2 kg in 108 1 water) and used directly in example 3.
Example 3
Preparation of 2-[[4-{2-isopropoxyethoxy)-methyl]phenosymethyl]oxirane The aqueous solution of sodium salt of 4-[(2-Isopropoxyethoxy) methyl]-phenol was reacted with 90 kg of Epichlorohydrin at 60-65 °C for 1 hr. The reaction mixture was then extracted twice with 90 1 toluene. The toluene extracts was stirred with 7.2 kg solid Sodium hydroxide. The reaction mixture was washed with water three times and the toluene layer was taken for distillation. 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyljoxirane was obtained as an oil after the removal of solvent. The product was further purified by high vacuum distillation at 0.5 mm at 160-200 °C to get purified 2-[[4-(2-isopropoxyethoxy)-methyl]phenoxymethyl]oxirane.
Example 4
Preparation of bisoprolol base
In a 160 1 vessel, 60 1 methanol was charged and 30 kg of 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane was added. The reaction mixture was cooled to 15 °C and 0.3 kg of Sodium borohydride was added in small lots of 30 gm each to the reaction mixture at 15 - 20 °C. The reaction mixture was stirred for 1 hr at 15 - 20 °C and was added to a cooled solution of isopropyl amine at 15 - 20 °C in about 1 hr. The reaction mixture was stirred for 3 hrs and heated to reflux for 3hrs. The excess of Isopropyl amine and methanol was distilled out of the reaction mixture. The residual oil was taken in 60 1 chloroform and washed three times with water. The chloroform layer was then passed over a bed of 30 kg neutral allumina in about 4-6 hrs and washed with another 30 1 chloroform. Chloroform was distilled out and degassed to obtain 34 - 37 kg bisoprolol base as oil.

Example 5
Preparation of bisoprolol fumarate
100 1 of Acetone and 36 kg of bisoprolol base were taken in a 160 I vessel. The reaction mixture was heated to 40 °C and 6.54 kg fumaric acid was added. The reaction mixture was stirred at reflux for 30 minutes, cooled to 0 - 5 °C and maintained for 1 hr. The separated product was centrifuged and washed with 4x101 chilled acetone. The product was spin dried for 15 minutes to get 30 - 33 kg of bisoprolol fumarate. Example 6
Purification of bisoprolol fumarate
100 1 Acetone and 30 kg bisoprolol fumarate was taken in a 160 1 vessel and was heated to reflux and stirred for 30 minutes. The reaction mixture was filtered through micron filter and washed with 10 I acetone. The filtrate was cooled to 0-5 °C and maintained for 1 hr. The separated product was centrifuged and washed with 4x101 chilled acetone. The product was spin-dried for 15 minutes to get 27 - 30 kg of purified bisoprolol fumarate.
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We claim:
1. A process for preparation of 4-[(2-isopropoxyethoxy)methyl]-phenol
comprising:
a) addition of Amberlyst 15 to the cooled 2-isopropoxy ethanol;
b) lot wise addition of 4-hydroxy benzyl alcohol to above reaction mass;
c) basification of reaction mixture with alkali metal carbonate;
d) distillation of 2-isopropoxy ethanol.

2. A process according to claim 1, wherein isopropoxy ethanol in (a) is cooled below 30° C preferably 0-5° C and alkali metal carbonate in (c) is selected from the group comprising sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate preferably potassium carbonate
3. A process according to claim 2, further comprising:

a) making sodium salt or acetyl derivative of 4-[(2-isopropoxyethoxy)methyl]phenol; and
b) acidifying the sodium salt or hydrolyzing the acetyl derivative to get 4-[(2-isopropoxyethoxy)methyl]-phenol.
4. A process for preparation of 2-[[4-(2-isopropoxyethoxy)-methyl]-
phenoxymethyl]oxirane comprising:
a) treatment of 4-[(2-isopropoxyethoxy)methyl]-phenol with aqueous sodium hydroxide to get sodium phenolate salt;
b) reacting the sodium phenolate salt with epichlorohydrin in aqueous media;
c) extracting in a suitable organic solvent preferably toluene;
d) treating the organic layer with a suitable base preferably sodium hydroxide; and
e) removal of organic solvent.

A process for preparation of bisoprolol or its pharmaceutically acceptable salt comprising:
a) reaction of 2-[[4-(2-isopropoxyethoxy)-methyl]-phenoxymethyl]oxirane with catalytic quantity of sodium borohydride in presence of methanol and further reacting with isopropyl amine;
b) distillation of isopropyl amine and methanol and extraction in an organic solvent; and
c) passing the organic layer over bed of neutral alumina
6. A process according to claim 5, wherein organic solvent is selected from the
group consisting of chloroform, Dichloromethane and dichloroethane
preferably chloroform
7. A process of preparation of bisoprolol or its pharmaceutically acceptable salt
comprising a process as claimed in claim 1.
8. A process of preparation of bisoprolol or its pharmaceutically acceptable salt
comprising a process as claimed in claim 2.
9. A process of preparation of bisoprolol or its pharmaceutically acceptable salt
comprising a process as claimed in claim 4.
For Unichem Laboratorties Limited
Santosh Kumar Nair
G. M. - Legal & Company Secretary
Signature
Date : 12/12/05
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ABSTRACT
This invention relates to a manufacturing process for the preparation of bisoprolol and its pharmaceutically acceptable salt as well as its intermediates. The intermediate l-[(2-isopropoxyethoxy)methyl]phenol is prepared by reaction of 4-hydroxybenzyl alcohol with 2-isopropoxy ethanol in presence of Amberlyst 15 in high yield with high purity.