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

(19) World Intellectual Property Organization WO 2010/061366 A1

International Bureau
ll W (10) International Publication Number
(43) International Publication Date N / _ _ T_ _ . .. ... , , , , .
3 Ju n e 2010 (03.06.2010) WO 2010/061366 A l

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, fo r every
C07C 217/32 (2006.01) C07D 263/14 (2006.01) kind o f national protection available): AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
(21) International Application Number:
CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
PCT/IE2009/000082
DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
(22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
26 November 2009 (26.11.2009) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
ME, MG, MK, MN, MW, MX, MY, MZ, NA, NO, NI,
(25) Filing Language: English NO, NZ, OM, PE, PO, PH, PL, PT, RO, RS, RU, SC, SD,
(26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT,
TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
(30) PriorityData:
2008/0949 28 November 2008 (28.11.2008) IE (84) Designated States (unless otherwise indicated, fo r every
kind o f regional protection available): ARIPO (BW, GH,
(71) Applicant fo r all designated States except US): COR- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
DEN PHARMA IP LIMITED [IE/IE]; 90 South Mall, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
Cork (IE). TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV,
(72) Inventors; and
MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,
(75) Inventors/Applicants (for US only): O'NEILL, John, A.
TR), OAPI (BF, BJ, CF, CO, Cl, CM, GA, GN, GQ, GW,
[IE/IE]; 11 Meadowbrook, Heronswood, Carrigaline, Co.
ML, MR, NE, SN, TD, TG).
Cork (IE). SCHICKANEDER, Helmut [DE/IE]; c/o 90
South mall, Cork (IE). NIKOLOPOULOS, Aggelos Published:
WO 2010/061366
[DE/IE];A1c/o 90 South Mall, Cork (IE). JAS, Gerhard
— with international search report (Art. 21(3))
[DE/DE]; Falkenhausenweg 15, 12249 Berlin (DE).
(74) Agent: O'BRIEN, John, A.; c/o John A. O'Brien & As­
sociates, Third Floor, Duncalm House, 14 Carysfort Av­
enue, Blackrock, County Dublin (IE).
WO 2010/061366 A l

(54) Title: MANUFACTURE OF BISOPROLOL AND INTERMEDIATES THEREFOR

(57) Abstract: A process for preparing bisoprolol comprises reacting oxazolidinone sulphonate with 4-hydroxybenzylaldehyde to
form oxazolidinone benzaldehyde, forming oxazolidone benzylalcohol from oxazolidone benzaldehyde, and subsequently reacting
oxazolidinone benzylalcohol with isopropyl oxitol to form bisoprolol base. Oxazolidone sulphonate and oxazolidone benzalde­
hyde are novel intermediates.
WO 2010/061366 PCT/IE2009/000082

-I-

“Manufacture o f Bisoprolol and intermediates therefor”

Introduction

This invention relates to the manufacture of Bisoprolol fumarate and

intermediates used in the process.

The process described in DOS 2 645 710, describes a process, wherein 2-

(isopropoxy)ethoxymethyl-phenol is reacted with epichlorhydrin and the β-amino
alcohol moiety is formed by the addition of iso-propylamine. This synthetic route
suffers from several disadvantages including the handling of epichlorohydrin
which is a known carcinogen and can undergo violent reactions or exothermic
polymerisation on contact with amines or alkoxides. In addition, the reaction
between the epoxy intermediate and isopropylamine has the potential to
undergoes side reactions leading to the formation of the known impurity F (as
described in the European Pharmacopeia 6.1).

. ^ sxCO2H

2-(isopropoxy)ethoxymethyl-phenol Bisoprolol Fumarate

side'reaction Drug Substance

OH
side reaction

,/^CO2H
Bisoprolol Fumarate
ImpF
 WO 2010/061366 PCT/IE2009/000082

-2 -

DOS3205457 describes a process wherein the 2-(isopropoxy)ethoxymethyl

substituent is introduced in two stages. Initially the aromatic ring of 3-isopropyl-
5-phenoxymethyl-oxazolidin-2-one is chloromethylated using HCl and
paraformaldehyde followed by a Williamson ether synthesis employing metallic
sodium. The resultant oxazolidine ring is cleaved by alkaline hydrolysis.

°Λ
(C H 2O )n i HCl

----------- CO A γ τ ίΛ
ό Ο
Η
Y HO2C-^c0*"
3 - |s o p ro p y l-5 -
p h e n o x y m e th y l-o x a z o ! id I n - 2 -
one .t
Y B iso p ro lo l F u m a r a te
, sic(e rea ctio n 1
D rug Substance

ΛN-^O- Y
/-ο ο-Λο h HO
^ . C O 2H
H O 2C '

side reaction 2 B iso p ro lo l F u m a r a te

Im p C

1 οΛ
Λ
όT 0Η0
Η
20Η
·^^η
cr
B iso p ro lo l F u m a r a te
Im p G

This synthetic route suffers from several disadvantages including the handling of
10 metallic sodium which can undergo violent reactions on contact with water or
alcohols. In addition the chloromethylation of 3-isopropyl-5-phenoxymethyl-
oxazolidin-2-one with paraformaldehyde in the presence of HCl undergoes side
reactions leading to the formation of the known impurities C and G. This process
generates material of inferior quality as exemplified by a limit for impurity G of
15 0.5% (as described in the European Pharmacopeia 6.1).

Statements of Invention

According to the invention there is provided a process for preparing bisoprolol

20 comprising the steps of:-

reacting oxazolidinone sulphonate with 4-hydroxybenzylaldehyde to form

oxazolidinone benzaldehyde;

25 forming oxazolidone benzylalcohol from oxazolidone benzaldehyde; and

 WO 2010/061366 PCT/IE2009/000082

-3-
subsequently reacting oxazolidinone benzylalcohol with isopropyl oxitol
to form bisoprolol base.

In one embodiment the oxazolidone sulphonate is formed by reacting

5 isopropylaminopropanediol with dimethylcarbonate and reacting the intermediate
product thus formed with benzenesulphonylchloride.

In one case oxazolidinone sulphonate is not isolated prior to reaction with 4-

hydroxybenzaldehyde.
10
In one embodiment methylisobutylketone is added to the intermediate product
prior to the addition of benzenesulphonylchloride. In this case the reaction
between the intermediate and benzenesuphonyl chloride may be performed under
phase transfer conditions utilising water soluble bases such as sodium hydroxide.
15
Alternatively, the reaction between the intermediate and benzenesulphonyl
chloride is performed in an organic solvent such as methylisobutylketone
utilising bases soluble in organic solvents such as triethylamine.

20
The process may comprise the step of purifying bisoprolol base. The bisoprolol
base may be purified by distillation. The bisoprolol base may be purified by
crystallisation.

25 The process may comprise the step of forming bisoprolol fumarate by reacting
bisoprolol base with fumaric acid.

In one embodiment the process comprises converting bisoprolol fumarate to

bisoprolol base.
30
The invention also provides bisoprolol prepared by a process as described herein.
WO 2010/061366 PCT/IE2009/000082

-4-

The invention further provides bisoprolol fumarate prepared by a process as

described herein.

The invention also provides a process for preparing oxazolidinone benzaldehyde

by reacting oxazolidinone sulphonate with 4-hydroxybenzylaldehyde.

The process for preparing oxazolidone benzylalcohol may comprise converting

oxazolidone benzaldehyde to oxazolidone benzylalcohol.

The invention also provides oxazolidinone sulphonate having the formula:

OH·

The invention further provides oxazolidinone benzaldehyde having the formula:

.CHO

ch.

The process described in this invention is superior to the conventional processes

as the process consistently produces material of high quality suitable for use as a
drug substance. Specifically product purity of greater than 99.5% is achieved
with no single impurity present above a threshold of 0.10%, as described in ICH
guidance Q3A(R2) for impurities in new drug substances.

BriefDescrintion o f the Drawings

The invention will be more clearly understood from the following description of
an embodiment thereof, given by way of example only, with reference to the
accompanying drawings, in which: -

Fig. I is an infra-red spectrum (kBr disc) of oxazolidinone sulphonate;

WO 2010/061366 PCT/IE2009/000082

-5 -
Fig. 2 is a 1H NMR spectrum (CDCI3, 300 MHz) of oxazolidinone
benzaldehyde;

Fig. 3 is a 13H NMR spectrum (CDCl3, 75 MHz) of oxazolidinone

benzaldehyde;

Fig. 4 is an infra-red spectrum (kBr disc) of oxazolidinone benzaldehyde;

Fig. 5 is a 1H NMR spectrum (CDCl3, 300 MHz) of oxazolidinone benzyl

alcohol;

Fig. 6 is a 13H NMR spectrum (CDCl3, 75 MHz) of oxazolidinone benzyl

alcohol; and

Fig. 7 is an infra-red spectrum (kBr disc) of oxazolidinone benzyl alcohol.

Detailed Description
The process for preparing bisoprolol according to the invention can be
summarised as follows:
 WO 2010/061366 PCT/IE2009/000082

β­

CH:

OxazdicSnone SuIjAonate 44dydr«Qtenzaldehyde

,CHO

ίο

Oxazsslidraie Baizalefehyrfe

15
Ύ °χ χ ^ ·Ο Η

Isopropyl exited

O xazdiriltors Benzylsloohoi (API Starting Material)

20

CH

Bisoprolol B ase crude

25

Example I - Stage I: Synthesis of Oxazolidinone Sulphonate TStep I)

WO 2010/061366 PCT/IE2009/000082

-7 -

CH3
M eO H
CH3 N ΌΗ
H C H 3O N a
OH

lsopropylaminopropanediol Dimethylcarbonate
M.W..-133.2 M.W..-90.1 [Intermediate - not isolated]

M IBK/D IW , N a O H

[CH 3 (C H 2) 3I4N (H S O 4)

M TBE

Oy °
Oxazolidinone Sulphonate

The following details describe the manufacture of a typical batch

A reactor is charged with 392 kg of isopropylaminopropanediol, approximately

240 L o f methanol, 6 to 7L of sodium methoxide (30%) and 270 L of
dimethylcarbonate. The contents were heated up to allow reaction to occur.
Solvent is removed by distillation.

200 L water and ca 450 L of methylisobutylketone (MIBK) are then charged to

the reactor. The reactor contents are then cooled down to <25°C.
Tetrabutylammoniumhydrogensulphate (ca 2.5kg) and 520 kg of
benzenesulphonylchloride are then added to the vessel under cooling. 30%
sodium hydroxide is added to the reactor

The reactor contents are heated and phase separation performed, removing the
aqueous layer. Solvent is distilled and the product oxazolidone sulphonate is
isolated from methyl-/er/-butylether (MTBE).

Fig. I illustrates the infra red spectrum of oxazolidinone sulphate.

Purity HPLC >98%

WO 2010/061366 PCT/IE2009/000082

-8 -

Stationary phase: octadecylsilyl silica gel for chromatography

Mobile phase: a mixture o f methanol water buffered with potassium hydrogen
phosphate and triethylamine

Oxazolidinone sulphonate is a novel intermediate and may used for the

manufacture of β-blockers such as Acebutolol, Alprenolol, Atenolol, Betaxolol,
Bisoprolol, Esmolol and Metoprolol.

Example 2 - Synthesis of Oxazolidinone benzaldehyde ISten 21

Oxazolidinone Sulphonate 4-Hydroxybenzaldehyde Oxazolidinone Benzaldehyde

M.W.:299.3 M.W.: 122.1 Mol. Wt.: 263.29

A reaction vessel is charged with 154.5kg of 4-hydroxybenzaldehyde, 600 L of

dimethylformamide (DMF), 100 kg of potassium carbonate and 475 kg of
oxazolidinone sulphonate. The mixture is agitated and heated and held until
reaction completion.

The reactor contents are then cooled down and vacuum is applied, solvent is
distilled off and discarded. Water is added to the reactor to facilitate
crystallisation and product isolation.

NMR spectra o f oxazolidinone benzaldehyde are illustrated in Figs. 2 and 3. An

infra-red spectrum for the product is illustrated in Fig. 4.

Purity HPLC >98%, <1% 4-hydroxybenzaldhyde

Stationary phase: octadecylsilyl silica gel for chromatography
WO 2010/061366 PCT/IE2009/000082

-9-
Mobile phase: a mixture of methanol water buffered with potassium hydrogen
phosphate and triethylamine

Example 3 - Alternative Synthesis of Oxazolidinone benzaldehyde (Step 2)

CH3 CH3
MeOH
, CH3 CH3
CH3 N
H
'Y '
I
OH T CH3ONa
CH3 N" Y " "O H

OH

Iso p ro p y la m in o p ro p a n e d io l D im e th y lc a rb o n a te
M .W .:133.2 M .W .:90.1 [In te rm e d ia te - n o t iso la ted ]

.SO2CI
MIBK/DIW, NaOH

[CH3(CH2) 3I4N(HSO4)

M .W .:176.i

CHO CHO
CH3
DMF CH3

CH^^N K2CO3 CH:

y~° OH
O x a z o lid in o n e B e n z a ld e h y d e 4 -H y d ro x y b e n z a ld e h y d e O x a z o lid in o n e S u lp h o n a te

Mol. W t.: 2 6 3 .2 9 M .W .. 122.1 [ in te rm e d ia te n o t iso la ted ]

A vessel is charged with 100 g of isopropylaminopropanediol, methanol, 3-4 g of

sodium methoxide 30% and 70 ml of dimethylcarbonate. The vessel contents are
heated up to allow reaction to occur. Solvent is removed by distillation.

100 ml water and methylisobutylketone are then charged to the reaction. The
reaction mixture is then cooled down to <25°C.
Tetrabutylammoniumhydrogensulphate (ca 0.5g) and 145g of
benzenesulphonylchloride are then added to the reaction mixture under cooling.
30% sodium hydroxide is added to the reaction mixture.

The reactor contents are heated and phase separation performed, removing the
aqueous layer. Solvent is distilled and the product dissolved in 380 ml
dimethylforamide.
WO 2010/061366 PCT/IE2009/000082

-10-
To the reaction vessel is charged 55 g of potassium carbonate and 85 g of 4-
hydroxybenzaldehyde. The mixture is agitated, heated, and held until reaction
completion.

The reactor contents are then cooled down and vacuum is applied, solvent is
distilled off and discarded. Water is added to the reaction mixture to facilitate
crystallisation and the product is isolated.

Purity HPLC >98%, <1% 4-hydroxybenzaldhyde

Stationary phase: octadecylsilyl silica gel for chromatography
Mobile phase: a mixture of methanol water buffered with potassium hydrogen
phosphate and triethylamine

In the specific case o f bisoprolol manufacture the key oxazolidinone

benzaldehyde intermediate may also be prepared in a “telescoped” process
described in this example 3, this process is more efficient as the use of MTBE for
the isolation o f oxazolidinone sulphonate is eliminated. This results in reduced
waste disposal costs and a 50% reduction in the requirement for solids
separations equipment.

Example 4 - Alternative Synthesis of Oxazolidinone benzaldehyde (Step 2)

CH3

CH3 N
C H f y 0^CH3 MeOH . Av N
CH3
O C H 3O N a

Is o p ro p y la m in o p ro p a n e d io l D im e th y lc a rb o n a te
M .W .:1 3 3 .2 M .W .:90.1 [In te rm e d ia te - n o t is o la te d ]

M .W .:1 7 6 .6

CHO
CH3
DMF

chT ^ n K 2C O 3
CH;

O x a z o lid in o n e B e n z a ld e h y d e 4 -H y d ro x y b e n z a ld e h y d e O x a z o lid in o n e S u lp h o n a te
M ol. W t.: 2 6 3 .2 9 M .W .: 122 .1 r. . ... , , , . ..
[in te rm e d ia te n o t is o la te d ]
 WO 2010/061366 PCT/IE2009/000082

-11-

A vessel is charged with 100 g of isopropylaminopropanediol, methanol, 3-4 g of

sodium methoxide 30% and 70 ml of dimethylcarbonate. The vessel contents are
heated up to allow reaction to occur. Solvent is removed by distillation and ca
400 ml methylisobutylketone is then charged to the reaction. The reaction
5 mixture is then cooled and 80g of triethylamine and 145g of
benzenesulphonylchloride are added.

Water is added and the reaction mixture is heated and phase separation
performed, removing the aqueous layer. Solvent is distilled and the product
10 dissolved in 380 ml dimethylforamide.

To the reaction vessel is charged 55 g of potassium carbonate and 85 g of 4-

hydroxybenzaldehyde. The mixture is agitated, heated, and held until reaction
completion.
15
The reactor contents are then cooled down and vacuum is applied, solvent is
distilled off and discarded. Water is added to the reaction mixture to facilitate
crystallisation and the product is isolated.

20 Purity HPLC >98%, <1% 4-hydroxybenzaldhyde

Stationary phase: octadecylsilyl silica gel for chromatography
Mobile phase: a mixture of methanol water buffered with potassium hydrogen
phosphate and triethylamine

25 In the specific case of bisoprolol manufacture the key oxazolidinone

benzaldehyde intermediate may also be prepared in a “telescoped” process
described in this example 4. This process is more efficient than the process
described in examples 2 and 3, as the use of triethylamine under non aqeous
reaction conditions for the coupling reaction between oxazolidinone sulphonate
30 and benzenesulphonyl chloride is more efficient. This results from a reduction in
side reactions under aqueous conditions which lead to the formation of sodium
benzenesulphonate as a by-product.
WO 2010/061366 PCT/IE2009/000082

-12-

Example 5 —Step 3 - Conversion of Benzaldehyde to Benzylalcohol

.CHO .CH2OH

n-B utanol
CH;

O xazolid in on e B e n za ld eh y d e O xazolidinon e B enzylalcohol

M.W.: 2 6 3 .3 M.W.: 2 6 5 .3

Sodium borohydride (IlK g) in a mixture of water (71L) and sodium hydroxide

(0.3L), to n-butanol (300L). Water (150L) potassium carbonate and
oxazolidinone benzaldehyde (271 Kg) are charged to a vessel.

The vessel contents are heated up to IOO0C, cooled and ethyl acetate (100L) is
charged to the vessel. Water or brine is used for washing and solvent is distilled
off and the product is isolated from ethyl acetate.

NMR spectra of oxazolidinone benzaldehyde are illustrated in Figs. 5 and 6. An

infra-red spectrum for the product is illustrated in Fig. 7.

Purity HPLC >99%

Stationary phase: octadecylsilyl silica gel for chromatography
Mobile phase: a mixture of methanol water buffered with potassium hydrogen
phosphate and triethylamine

Example 6: Purification of Bisoprolol Base

Bisoprolol base is formed from the oxazolidinone benzyl alcohol by an acid

catalysed coupling with isopropyl oxitol, followed by alkaline hydrolysis of the
oxazolidinone ring. The resultant bisoprolol base maybe further purified either
by distillation or crystallation.

Example 7: Salt Formation

 WO 2010/061366 PCT/IE2009/000082

-13-
The purified bisoprolol base is converted to Pharmacopoeia grade bisoprolol
fumarate by addition of fumaric acid to bisoprolol base in acetone.

Example 8: Bisoprolol Base for use as a drug substance

5
Charge bisoprolol fumarate (3OKg) in a mixture of water (3OIL) and sodium
methyl-/er/-butylether (105L), add aqueous sodium hydroxide to alkaline pH.
Split the lower aqeous layer to waste and wash the product layer with water.
Bisoprolol base is isolated following solvent removal by distillation.
10
Patches are routinely used for the controlled release of drugs via the trans dermal
route, the approach is advantageous over oral administration which can result in
irregular and unpredictable blood plasma levels. Bisoprolol is normally
administered in oral solid dose form as the fumarate salt, but is not suitable for
15 controlled release from transdermal patch formulations. It has been found that
Bisoprolol base prepared as described in this application is particularly suited to
controlled release from transdermal patch formulations.

The invention is not limited to the embodiment hereinbefore described, with

20 reference to the accompanying drawings, which may be varied in and detail.

25
WO 2010/061366 PCT/IE2009/000082

-14-

Claims

1. A process for preparing bisoprolol comprising the steps of:-

reacting oxazolidinone sulphonate with 4-hydroxybenzylaldehyde

to form oxazolidinone benzaldehyde;

forming oxazolidone benzylalcohol from oxazolidone

benzaldehyde; and

subsequently reacting oxazolidinone benzylalcohol with isopropyl

oxitol to form bisoprolol base.

2. A process as claimed in claim I wherein the oxazolidone sulphonate is

formed by reacting isopropylaminopropanediol with dimethylcarbonate
and reacting the intermediate product thus formed with
benzenesulphonylchloride.

3. A process as claimed in claim I or 2 wherein oxazolidinone sulphonate is

not isolated prior to reaction with 4-hydroxybenzaldehyde.

4. A process as claimed in claim 2or 3 wherein methylisobutylketone is

added to the intermediate product prior to the addition of
benzenesulphonylchloride.

5. A process as claimed in claim 4 wherein the reaction between the

intermediate and benzenesuphonyl chloride is performed under phase
transfer conditions utilising water soluble bases such as sodium
hydroxide.

6. A process as claimed in claim 4 wherein the reaction between the

intermediate and benzenesulphonyl chloride is performed in an organic
 PCT/IE2009/000082

-15-

solvent such as methylisobutylketone utilising bases soluble in organic

solvents such as triethylamine.

A process as claimed in any of claims I to 6 comprising purifying

bisoprolol base.

A process as claimed in claim 7 wherein the bisoprolol base is purified by

distillation.

A process as claimed in claim 7 wherein the bisoprolol base is purified by

crystallisation.

A process as claimed in any of claims I to 9 comprising forming

bisoprolol fumarate by reacting bisoprolol base with fumaric acid.

A process as claimed in claim 10 comprising converting bisoprolol

fumarate to bisoprolol base and isolating the bisoprolol base.

A process substantially as hereinbefore described.

Bisoprolol prepared by a process as claimed in any of claims I to 9.

Bisoprolol fumarate prepared by a process as claimed in claim 10.

Bisoprolol prepared by a process as claimed in claim 11.

A process for preparing oxazolidinone benzaldehyde by reacting

oxazolidinone sulphonate with 4-hydroxybenzylaldehyde.

A process for preparing oxazolidone benzylalcohol comprising converting

oxazolidone benzaldehyde to oxazolidone benzylalcohol.

Oxazolidinone sulphonate having the formula:

 WO 2010/061366 PCT/IE2009/000082

-16-

CH-

19. Oxazolidinone Benzaldehyde having the formula:

-CHO

CH-

10

15

20

25

30

35
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WO 2010/061366
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 WO 2010/061366
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132.458
132.385
132.348
132.275
132.183
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131.596
131.486
130.808
130.661
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115.314
115.241
115.094
114.984
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114.507
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77.469
77.322
77.176
77.139
77.084
76.846
76.699
70.996
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Fig. 6

O -
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77.477
77.202
77.128
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76.633
76.523
71.169
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 INTERNATIONAL SEARCH REPORT
Internationa! a p plication No

P C T /IE 2 0 0 9 /0 0 0 0 8 2
A. CLASSIFICATION O F S U B J E C T MATTER
INV. C 0 7 C 2 1 7 /3 2 C 07D 263/14

A ccording to International P a te n t C lassification (IPC) o r to both natio n al classification a n d IPC

B. FIELDS SEARCHED
M inimum d o c u m en tatio n s e a r c h e d (classification sy ste m followed by classification sym bols)
C07C C07D

D o cum entation s e a rc h e d o th e r th a n m inim um do cu m en tatio n to th e ex ten t th a t s u c h d o c u m e n ts a r e in clu d ed in th e fields se a rc h e d

E lectronic d a ta b a s e c o n s u lte d during th e international s e a rc h (n am e of d a ta b a s e a n d , w h e re p ractical, s e a r c h te rm s u se d )

E P O - I n t e r n a l , CHEM ABS D a ta , WPI D a t a , BEILSTEIN Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

C ategory* C itation of d o c u m e n t, with indication, w h ere approp riate, of th e relev an t p a s s a g e s R elev an t to claim No.

EP 0 0 8 6 4 0 3 A2 (MERCK PATENT GMBH [D E ]) 13-15

24 A u g u s t 1983 ( 1 9 8 3 - 0 8 - 2 4 )
e x a m p le s 1 - 6 1-19
p a g e 1 4 , l i n e 13 - l i n e 20

KITA0RI K ET AL: "CsF i n O r g a n ic 13-15

S y n t h e s i s . The F i r s t and C o n v e n i e n t
S y n t h e s i s o f E n a n t io p u r e B i s o p r o l o l by Use
o f G l y c i d y l N o sy l a te "
TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM,
NL1
v o l . 3 9 , n o . 2 0 , 14 May 1998 ( 1 9 9 8 - 0 5 - 1 4 ) ,
p a g e s 3 1 7 3 - 3 1 7 6 , XP004116223
ISSN: 0 0 4 0 - 4 0 3 9
p a g e 3 1 7 6 , l i n e 5 - l i n e 17

-I-

F u rth er d o c u m e n ts a r e listed in th e continuation of Box C. S e e p a te n t fam ily an n e x .

* S p ecial c a te g o rie s of cited d o c u m e n ts :

"T" I a te r d o c u m e n tp u b lis h e d a f te r th e international filing d a te
or priority d a te a n d n o t in conflict with th e application but
"A" d o c u m e n t defining th e g e n e ra l s ta te of th e a rt w hich is not
cited to u n d e rs ta n d th e principle o r theory underlying th e
co n sid e red to b e of p articu lar re lev an ce invention
Έ " earlier d o cu m en t but p u b lish e d o n o r afte r th e international "X" d o c u m e n t of p articu lar re le v a n c e ; th e claim ed invention
filing d a te ca n n o t b e c o n s id e re d novel o r ca n n o t be co n sid ered to
11L" d o c u m e n t w hich m ay throw d o u b ts on priority claim (s) or involve a n inventive s te p w h e n th e d o cu m en t is ta k en a lo n e
which is cited to e s ta b lis h th e publication d a te of an o th er
"Y" d o c u m e n t of p articu lar re le v a n c e ; th e claim ed invention
citation or o th e r sp ecial r e a s o n ( a s specified)
ca n n o t b e c o n s id e re d to involve a n inventive s te p w hen th e
"O" d o cu m en t referring to a n o ral d isc lo su re , u s e , exhibition or d o c u m e n t is c o m b in e d with o n e o r m ore o ther s u c h d o cu ­
o th e r m e a n s m en ts, s u c h co m b in atio n b ein g o b v io u s to a p erso n skilled
“P" d o c u m e n t pu b lish ed prior to th e international filing d a te but in th e art.
la ter th a n th e priority d a te claim ed d o c u m e n t m e m b e r of th e s a m e p a te n t family

D ate of th e actual com p letio n of th e international se a rc h D ate of m ailing of th e in tern atio n al s e a r c h report

9 February 2010 1 7 /0 2 /2 0 1 0
N am e a n d mailing a d d r e s s of th e ISA/ A uthorized officer
E u ro p e a n P a te n t Office, P.B . 5 8 1 8 P a te n tla a n 2
NL - 2 2 8 0 HV Rijswijk
Tel. (+ 3 1 -7 0 ) 3 4 0 - 2 0 4 0 ,
Fax: (+ 3 1 -7 0 ) 3 4 0 - 3 0 1 6 F it z , W o lfg a n g

F orm P C T /lS A /210 (s e c o n d s h e e t) (April 2 0 0 5 )

 INTERNATIONAL SEARCH REPORT
International a p p lica tio n N o

P C T /I E 2 0 0 9 /0 0 0 0 8 2
C (C on tin u ation ). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of d o cu m en t, with indication, w h e re ap p ro p riate, of th e re le v a n t p a s s a g e s R elev an t to claim No.

WO 2 0 0 7 / 0 6 9 2 6 6 A2 (UNICHEM LAB LTD [ I N ] ; 1 3-15

RAMAKRISHNAN ARUL [ I N ] ; AJAY DAYALJI
CHAUHAN [ I N ) 21 Ju n e 2007 ( 2 0 0 7 - 0 6 - 2 1 )
p a g e 3 , l i n e 13 - l i n e 15
e x a m p le s 4 - 6

EP 0 339 006 Al (ASTRA PHARMA PROD [ S E ] ) 1-19

25 O c t o b e r 1 98 9 ( 1 9 8 9 - 1 0 - 2 5 )
p a g e 2 , l i n e 26 - p a g e 3 , l i n e 4 3
e x a m p le I

EP 0 605 729 Al (ΤΑΙΗ0 PHARMACEUTICAL CO 1-19

LTD [ J P ] ) 13 J u l y 1994 ( 1 9 9 4 - 0 7 - 1 3 )
p a g e 33 ; e x a m p le s 2 0 , 2 1

BALDWIN, JOHN J . ET AL: 1-19

" . b e t a . I - S e l e c t i v e ad ren ocep tor
a n ta g o n ists: e x a m p le s o f t h e
2 -[4 -[3 -(su b stitu ted -a m in o )-2 -h y d ro x y p ro p o
x y ]p h e n y l]im id a z o le c la ss"
JOURNAL OF MEDICINAL CHEMISTRY, 2 6 ( 7 ) ,
9 5 0 - 7 CODEN: JMCMAR; ISSN: 0 0 2 2 - 2 6 2 3 ,
1 9 8 3 , XP002562859
p a g e 9 5 6 , method D: colum n I , l a s t tw o
p a r a g r a p h s - colum n 2 f i r s t tw o p a r a g r a p h s

KASZYNSKI P ET AL: "A COMPREHENSIVE 1-19

APPROACH TO (S)-(-)-2 -M E T H Y L -l-B U T A N 0 L AS
A CONVENIENT PRECURSOR FOR SYNTHESIS OF
CHIRAL LIQUID CRYSTALS"
MOLECULAR CRYSTALS AND LIQUID CRYSTALS,
GORDON AND BREACH, LONDON, GB,
v o l . 1 7 4 , I J a n u a r y 1989 ( 1 9 8 9 - 0 1 - 0 1 ) ,
p a g e s 2 1 - 3 7 , XP001056715
ISSN: 0 0 2 6 - 8 9 4 1
p a g e 2 4 , schem e 4 , compounds 6 , 8

Form P C T /IS A /210 (co n tin u a tio n of s e c o n d s h e e t) (April 2005)

 INTERNATIONAL SEARCH REPORT
Intern ation al a p p lica tio n N o
Inform ation o n p aten t fam ily m em b ers
P C T /I E 2 0 0 9 /0 0 0 0 8 2
P a te n t docu m en t Publication P a te n t family Publication
cited in s e a rc h report d a te m em ber(s) d a te

EP 0 0 8 6 4 0 3 A2 24-08-1983 AU 553328 B2 10-07-1986

AU 1087683 A 25-08-1983
CA 1198116 Al 17-12-1985
DE 3205457 Al 25-08-1983
ES 8404338 Al 16-07-1984
HU 18 85 31 B 28-04-1986
IL 67907 A 31-10-1986
JP 58152872 A 10-09-1983
PT 76229 A 01-03-1983
ZA 8300993 A 30-11-1983

WO 2 0 0 7 0 6 9 2 6 6 A2 21-06-2007 NONE

EP 0 3 3 9 0 0 6 Al 25-10-1989 AU 607323 B2 28-02-1991

AU 3311589 A 26-10-1989
DE 68902001 Dl 13-08-1992
DE 68902001 T2 11-02-1993
ES 2043106 T3 16-12-1993
GR 3005827 T3 07-06-1993
HK 2 5 09 5 A 03-03-1995
JP 2022253 A 25-01-1990
JP 2550410 B2 06-11-1996
NZ 228780 A 25-10-1991
US 5034535 A 23-07-1991

EP 0 6 0 5 7 2 9 Al 13-07-1994 AT 19 4981 T 15-08-2000

AU 653896 B2 13-10-1994
AU 4271093 A 29-11-1993
CA 2112129 Al 11-11-1993
DE 69329106 Dl 31-08-2000
DE 69329106 T2 22-03-2001
FI 935920 A 29-12-1993
HU 70423 A2 30-10-1995
HU 9500726 A3 28-11-1995
WO 9322298 Al 11-11-1993
US 5480899 A 02-01-1996

Form P C T /IS A /210 (p a te n t fam ily an n e x ) (April 2 0 0 5 )