(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date (10) International Publication Number

2 1 June 2007 (21.06.2007)
(51) International Patent Classification:
C07C 209/60 (2006.01) C07C 41/01 (2006.01)
C07C 41/16 (2006.01)
(21) International Application Number:
PCT/IN2006/000358
(22) International Filing Date:
12 September 2006 (12.09.2006)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
1533/MUM/2005
12 December 2005 (12.12.2005)
(71) Applicant (for all designated States except US):
UNICHEM LABORATORIES LIMITED [IN/IN];
Unichem Bhavan, Prabhat Estate, S.V. Road, logeshwari
(West), Mumbai 400 102, Maharashtra (IN).
(72) Inventors; and
(75) Inventors/Applicants (for US only): RAMAKRISH-
NAN, Arul [IN/IN]; Unichem Laboratories Limited,
Unichem Bhavan, Prabhat Estate, S.V. Road, Jogeshwari
(West), Mumbai 400 102, Maharashtra (IN). AJAY, Day-
alji, Chauhan [IN/IN]; Unichem Laboratories Limited,
Unichem Bhavan, Prabhat Estate, S.V. Road, Jogeshwari
(West), Mumbai 400 102, Maharashtra (IN). RAJESH,
Harshnath, Pathak [IN/IN]; Unichem Laboratories
Limited, Unichem Bhavan, Prabhat Estate, S.V. Road,
Jogeshwari (West), Mumbai 400 102, Maharashtra
(IN). RUCHI, Agarwal [IN/IN]; Unichem Laboratories
PCT WO 2007/069266 A2
Limited, Unichem Bhavan, Prabhat Estate, S.V. Road,
Jogeshwari (West), Mumbai 400 102, Maharashtra (IN).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DK, DM, DZ, EC, EE, EG, ES, FI, GB,
GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KN, KP, KZ, LA, LC, LK, LR, LS, LT, LU, LV,
LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG,
NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, SC, SD, SE,
SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
UG, US, UZ, VC, VN, ZA, ZM, ZW
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
IN ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT,
RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
GN, GQ, GW, ML, MR, NE, SN, TD, TG).
Declarations under Rule 4.17:
— as to applicant's entitlement to apply for and be granted a
patent (Rule 4.17(U))
— as to the applicant's entitlement to claim the priority of the
earlier application (Rule 4 . 1 7(Hi))
— of inventor ship (Rule 4.17 (iv))
Published:
— without international search report and to be republished
upon receipt of that report
For two-letter codes and other abbreviations, refer to the "G uid
ance Notes on Codes and Abbreviations" appearing at the beg in
ning of each regular issue of the PCT Gazette.

(54) Title: A NOVEL PROCESS FOR THE SYNTHESIS OF BISODPROLOL AND ITS INTERMEDIATE

(57) Abstract: This invention relates to a manufacturing process for the preparation of bisoprolol and its pharmaceutically accept -
able salt as well as its intermediates. The intermediate 4-[(2-isopropoxyethoxy)methyl]phenol is prepared by reaction of 4-hydrox-
ybenzyl alcohol with 2-isopropoxy ethanol in presence of Amberlyst 15 in high yield with high purity.
 TITLE-A NOVEL PROCESS FOR THE SYNTHESIS
OF
BISDPROLOL AND ITS INTERMEDIATE

FIELD OF INVENTION

This invention relates to a new method for preparing a pharmaceutically active

compound with antihypertensive properties.

BACKGROUND O F INVENTION

(±)-l-[4-[[2-(l-methyletho?^)e1hoxy]methyl]phenoxy]-3-[(l-methyl-e1hyl)amino]-2-
propanol(iT)-2-butenedioate having formula I and commonly known as bisoprolol
fumarate, blocks i 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
in rhythms. It is also useful in treating angina.

Formula I

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)methyl]phenol, which is further reacted with
epichlorohydrin to give 2-[[4-(2-isopropoxyethoxy)methyl]-phenoxymethyl]oxirane.
i 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

0 acceptable salt ,by reacting 4-[(2-isopropoxyethoxy)methyl]-phenol with 1,3-

dichloro2-hydroxy propane in the presence of phase transfer catalyst such as tri-n-
butyl ammonium bromide to obtain l-[[p-(2-isopropoxyethoxy)methyJ]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.
l autoclave) and high temperature making the process industrially uneconomical.

US patent 6087512 describes the preparation of 2-[[4-(2-isopropoxyethoxy)-methyl]-

phenoxymethyl]oxirane by reacting epichlorohydrin with p-(2-
isopropoxyethoxy)methyl phenol in the presence of alkali metal or alkaline earth
metal fluoride.

US patent 60574/6 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)methyl]-phenol. In this process the solution of A-
I
hydroxybenzylalc hol 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
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 embodinient 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- ρropane-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

i 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. Formula I

4-[(2-isopropoxyethoxy)methyl]phenol is prepared from 4-hydroxy benzyl alcohol. 2-

Isopropoxy ethanol is charged in a reactor and cooled to O0C 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 0C . The reaction mixture is stirred at 0-5 0C 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

in 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

and heating it to 45-50° C and extracting in toluene to obtain the highly pure 4-[(2-

1 5 Isopropoxyethoxy)methyl]phenol.

The aqueous solution of sodium salt of 4-[(2-Isopropoxyethoxy) methyl]phenol is

reacted with epichlorohydrin at 60-65 0C 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-
20 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 16O-2 θ6 0C 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 0C . Catalytic amount of sodium borohydride is added to it in small
lots at 15 - 20 0C . 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 0C and added to cooled isopropyl

amine at 15 - 20 βC 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 .
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 0C.
. Sodium borohydride dissolved in water at 15 - 20 0C 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 0C 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 1reactor 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 0C and added a solution of 3.0
kg Sodium borohydride dissolved in 15 1 of water at 15 - 20 0C in about 3 hrs. The
reaction mixture was further stirred for 3 hrs. 1.0 kg Charcoal slurry prepared in 15 1
Ω 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 0C . Dilute solution of acetic acid (20 kg diluted with 20 1 water) was slowly added
to the reaction mixture at 0 - 5 0C in a period of 3 - 5 hrs to get the product separated.
The separated product was filtered and washed with 40 1water, spin dried and dried
I under vacuum to obtain 2 1 - 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 0C .

Amberlyst-15 (22.5 kg) resin was added to it in one lot. 4-Hydroxy benzyl alcohol
Ω (22.5 kg) was added to it in small lots of 2 kg each at 0 - 5 0C in about 5 hrs. The
reaction mixture was stirred at 0 - 5 0C for 2 hrs. The temperature was raised to 15 -
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 1 vessel and
basified with 1.0 kg 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)-methyI]phenoxymethyI]oxirane

The aqueous solution of sodium salt of 4-[(2-Isopropoxyethoxy) methyl]-phenol was

reacted with 90 kg of Epichlorohydrin at 60-65 0C 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]-
I
phenoxymethyl]ox%ane 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 0C to
get purified 2-[[4-(2-isopropoxyethoxy)-methyl]phenoxymethyl]oxirane.

Example 4

Preparation of bisoprolol base

I 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 0C and 0.3 kg of Sodium borohydride was added in small lots of 30
gm each to the reaction mixture at 15 - 20 0C . The reaction mixture was stirred for 1
hr at 15 - 20 0C and was added to a cooled solution of isopropyl amine at 15 - 20 0C
7.0 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 1chloroform 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
2 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 1 vessel. The
reaction mixture was heated to 40 0C and 6.54 kg fumaric acid was added. The
reaction mixture was stirred at reflux for 30 minutes, cooled to 0 - 5 0C and
maintained for 1 hr. The separated product was centrifuged and washed with 4 x 10 1
chilled acetone. The product was spin dried for 15 minutes to get 30 - 33 kg of
bisoprolol fumarate.

Example 6

Purification of bisoprolol fumarate

1 100 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 1 acetone. The filtrate was cooled to 0-5 0C and
maintained for 1 hr. The separated product was centrifuged and washed with 4 x 10 1
chilled acetone. The product was spin-dried for 15 minutes to get 27 - 30 kg of
purified bisoprolol fumarate.
 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) basifϊ cation 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

1Q 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

1 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]-

phenoxyrnethyl]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.

 5. A process for preparation of bisoprolol or its pharmaceutically acceptable salt

comprising:

a) reactioh 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

1 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 .