IE20090899A1 - Manufacture of beta blockers - Google Patents
Manufacture of beta blockers Download PDFInfo
- Publication number
- IE20090899A1 IE20090899A1 IE20090899A IE20090899A IE20090899A1 IE 20090899 A1 IE20090899 A1 IE 20090899A1 IE 20090899 A IE20090899 A IE 20090899A IE 20090899 A IE20090899 A IE 20090899A IE 20090899 A1 IE20090899 A1 IE 20090899A1
- Authority
- IE
- Ireland
- Prior art keywords
- bisoprolol
- oxazolidinone
- benzaldehyde
- oxazolidone
- sulphonate
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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 benzaldehyde are novel intermediates.
Description
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-am ί no 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).
O'-'M h2n
OH
2-(isopropoxy)ethoxyn»fl»yt-phenol
Ύ0' side reaction
Kisuprohil fumarate
Drill' Siihslaiicc side reaction
OH
0., J , 0H
Λ k
H2N
Ox/'V''
HOjC !
Risoprolnl Fumarate Imp I
IKTCt, ibsg, C£?7C Ίν+Ι or) 3 / co
IE Ο 9 Ο 8 9 9
-2DOS3205457 describes a process wherein the 2-(isopropoxy)cthoxy methyl substituent is introduced in two stages. Initially the aromatic ring of 3-isopropyl5-phenoxymethyl-oxazolidin-2-one is chloro methylated using HC1 and paraformaldehyde followed by a Williamson ether synthesis employing metallic sodium. The resultant oxazolidine ring is cleaved by alkaline hydrolysis.
i * “ iCHjOk HCl
O ----
3ΊΐορτοργΙ-5· ptocnoAymethyl -oi udJmIln-2 · on· irtj* rtaelion 1
- COjH \ide iMetionZ
..1.
o
Biioprolol bum ura te
Drug Subsume
ttistprohl Furnarit* tmpC
Ci' o'
O'* y' 'H
HOiC ’ ftisoprulol Fumantc tltlp G
This synthetic route suffers from several disadvantages including the handling of metallic sodium which can undergo violent reactions on contact with water or alcohols. In addition the chloromethylation of 3-isopropyl-5-phenoxymethyloxazolidin-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 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;
forming oxazolidone benzylalcohol from oxazolidone benzaldehyde; and
IE Ο 9 0 δ
-3subsequently reacting oxazolidinone benzylalcohol with isopropyl oxilol 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 4hydroxy benzaldehyde.
In one embodiment methyl isobutyl ketone 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.
Alternatively, the reaction between the intermediate and benzencsulphonyl chloride is performed in an organic solvent such as methyl isobutylketone utilising bases soluble in organic solvents such as triethylamine.
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.
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.
The invention also provides bisoprolol prepared by a process as described herein.
IE Ο 9 0 8 9 9
-4The invention further provides bisoprolol fumarate prepared by a process as described herein.
The invention also provides a process for preparing oxazolidinone benzaldehyde 5 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:
The invention further provides oxazolidinone benzaldehyde having the formula:
I he process described in this invention is superior to the conventional processes as the process consistently produces material of high quality suitable lor 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.
Brief Description of the Drawings
I he 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: 25
Fig. 1 is an infra-red spectrum (kBr disc) of oxazolidinone sulphonate;
IE Ο 9 Ο 8 9 9
-5Fig. 2 is a ιΗ NMR spectrum (CDCI3, 300 MHz) of oxazolidinone benzaldehyde;
Fig. 3 is a l3H NMR spectrum (CDCI3, 75 MHz) of oxazolidinone 5 benzaldehyde;
Fig. 4 is an infra-red spectrum (kBr disc) of oxazolidinone benzaldehyde;
Fig. 5 is a *H NMR spectrum (CDCI3, 300 MHz) of oxazolidinone benzyl 10 alcohol;
Fig. 6 is a l3H NMR spectrum (CDCI3, 75 MHz) of oxazolidinone benzyl alcohol; and
Fig. 7 is an infra-red spectrum (kBr disc) of oxazolidinone benzyl alcohol.
Detailed Description
I’he process for preparing bisoprolol according to the invention can be 20 summarised as follows:
CHO x,
IE 0 9 0 8 9 9
-610
I xx. /x ο+ρΝχ ^“0
Oxazolidtnone Sulphonate
OH
H^drcx.'beiizaWttvd'r
Oxazotoixre Etenzylalcohoi (API Starting N*aten«i ι
0..
x'
Isc-propy! ccctol )H
OH
B«sc»pfo!O Base catde
Example 1 - Stage 1: Synthesis of Oxazolidinone Sulphonate (Step 1)
IE Ο 9 Ο 8 9 9
OH
Isopropylaminopropanediol M.W.: 133.2
Dimethylcarbonate
M.W 90.1 [Intermediate - not isolated]
The following details describe the manufacture of a typical batch 5
A reactor is charged with 392 kg of isopropylaminopropanediol, approximately 240 L of methanol, 6 to 7L of sodium methoxide (30%) and 270 L of dimethylcarbonate. The contents were heated up to allow reaction lo 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. Ί etrabutylammoniumhydrogensulphate (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-/e/7-butyl ether (MTBE).
Fig. I illustrates the infra red spectrum of oxazolidinone sulphate.
Purity HPLC >98%
IE Ο 90 8 99
-8Stationary phase: octadecylsilyl silica gel for chromatography
Mobile phase: a mixture of 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, Atprenolol, Atenolol, Betaxolol. Bisoprolol, Esmolol and Metoprolol.
Example 2 - Synthesis of Oxazolidinone benzaldehyde (Step 2)
Oxazolidinone Sulphonate 4-Hydroxybenzaidehyde Oxazolidinone Benzaldehyde
MW/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 of 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
IE Ο 9 Ο 8 9 9
-9Mobile phase: a mixture of methanol water buffered with potassium hydrogen phosphate and triethylamine
Example 3 - Alternative Synthesis of Oxazolidinone benzaldehvde (Step 2)
I sop ropyla m ι nopropa nediot MW. 133.2
o
MeOH
Dimelhylcarbonate MW. 90 1
CH.0N3
[Intermediate - not isolated]
MW 176.6
MIBK/DW. NaOH f&ijCHMiN/HSO:)
CH,
X
CH} N
CHO
DMF
CHO l·0
K£O3
OxazoiKiinone Benzaldehyde Mol. Wt: 263 29
OH
4-Hydroxybenzaldehyde MW: 122.1
Oxazolidinone Sulphonate (intermediate not isolated]
Λ 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 (o the reaction. The reaction mixture is then cooled down to <25°C. Tetrabutylammoniumhydrogensulphate (ca 0.5g) and I45g 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.
IE 0 9 Ο 8 9 9
-10Το the reaction vessel is charged 55 g of potassium carbonate and 85 g of 4hydroxybenzaldehyde. 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 of 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 of 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)
I sopro py la mi nop ropa ned 10I M W :133 2
o
Ms OH
CHjONa
(Intermediate - nol isolated]
Di me
- H ydrox y be nz a I dehy de MW 122.1
Oxazolidinone Benzaldehyde Mol Wt : 263 29
Oxazolidinone Sulphonate [ntermediaie not isolated]
IE 0 9 Ο 8 9 9
- 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 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 dissolved in 380 ml dimethylforamide.
To the reaction vessel is charged 55 g of potassium carbonate and 85 g of 4hydroxybenzaldehyde. 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 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 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.
ΙΕ ο 9 ο
899
-12Example 5 - Step 3 - Conversion of Benzaldehyde to Benzylalcohol
Oxazolidinone Benzaldehyde M W: 263.3
Oxazolidinone Benzylalcohol M.W. 265 3
Sodium borohydride (11 Kg) in a mixture of water (71L) and sodium hydroxide (0.31,), 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 100°C, 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
IE 0 9 0 8 9 9
-13Ihe purified bisoprolol base is converted to Pharmacopoeia grade bisoprolol funiarate by addition of fumaric acid to bisoprolol base in acetone.
Example 8: Bisoprolol Base for use as a drug substance
Charge bisoprolol fumarate (30Kg) in a mixture of water (301L) and sodium methyl-ft?r/-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.
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 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 reference to the accompanying drawings, which may be varied in and detail.
IE 0 908 9 9
Claims (19)
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 1 wherein the oxazolidone sulphonate is formed by reacting isopropylaminopropanediol with dimethylcarbonate and reacting the intermediate product thus formed with benzenesulphonylchloride. A process as claimed in claim I or 2 wherein oxazolidinone sulphonate is not isolated prior to reaction with 4-hydroxybenzaldehyde.
3. 4. A process as claimed in claim 2 or 3 wherein methylisobutylketonc is added to the intermediate product prior to the addition of benzenesulphonylchloride.
4. 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.
5. 6. A process as claimed in claim 4 wherein the reaction between the intermediate and benzenesulphonyl chloride is performed in an organic IE 0 9 0 -15solvent such as methylisobutylketone utilising bases soluble in organic solvents such as triethylamine.
6. 7. A process as claimed in any of claims 1 to 6 comprising purifying bisoprolol base.
7. 8. A process as claimed in claim 7 wherein the bisoprolol base is purified by distillation.
8. 9. A process as claimed in claim 7 wherein the bisoprolol base is purified hy crystallisation.
9. 10. A process as claimed in any of claims 1 to 9 comprising forming bisoprolol fumarate by reacting bisoprolol base with fumaric acid.
10. 11. A process as claimed in claim 10 comprising converting bisoprolol fumarate to bisoprolol base and isolating the bisoprolol base.
11. 12. A process substantially as hereinbefore described.
12. 13. Bisoprolol prepared by a process as claimed in any of claims 1 to 9.
13. 14. Bisoprolol fumarate prepared by a process as claimed in claim 10.
14. 15. Bisoprolol prepared by a process as claimed in claim 11.
15. 16. A process for preparing oxazolidinone benzaldehyde by reacting oxazolidinone sulphonate with 4-hydroxy benzyl aldehyde.
16. 17. A process for preparing oxazolidone benzylalcohol comprising converting oxazolidone benzaldehyde to oxazolidone benzylalcohol.
17. 18. Oxazolidinone sulphonate having the formula: IE 0 9 Ο 8 9 9
18.
19. Oxazolidinone Benzaldehyde having the formula: IE 0 9 0 8 9 9 PERKIN ELMER 4000 3500 3000 2500 2000 1500 1000 cm’ 1 500
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE2009/0899A IE85808B1 (en) | 2009-11-26 | Manufacture of beta blockers |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IEIRELAND28/11/20082008/0949 | |||
| IE20080949 | 2008-11-28 | ||
| IE2009/0899A IE85808B1 (en) | 2009-11-26 | Manufacture of beta blockers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE20090899A1 true IE20090899A1 (en) | 2010-07-07 |
| IE85808B1 IE85808B1 (en) | 2011-07-06 |
Family
ID=
Also Published As
| Publication number | Publication date |
|---|---|
| IES20090902A2 (en) | 2010-07-07 |
| WO2010061366A1 (en) | 2010-06-03 |
| IES20090901A2 (en) | 2010-07-07 |
| IES20090900A2 (en) | 2010-07-07 |
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| MM4A | Patent lapsed |