IE20090901U1 - Manufacture of beta blockers - Google Patents

Manufacture of beta blockers

Info

Publication number
IE20090901U1
IE20090901U1 IE2009/0901A IE20090901A IE20090901U1 IE 20090901 U1 IE20090901 U1 IE 20090901U1 IE 2009/0901 A IE2009/0901 A IE 2009/0901A IE 20090901 A IE20090901 A IE 20090901A IE 20090901 U1 IE20090901 U1 IE 20090901U1
Authority
IE
Ireland
Prior art keywords
oxazolidinone
bisoprolol
benzaldehyde
oxazolidone
sulphonate
Prior art date
Application number
IE2009/0901A
Other versions
IES85565Y1 (en
Inventor
A. O'neill John
Jas Gerhard
Schickaneder Helmut
Nikolopoulos Aggelos
Original Assignee
Corden Pharma Ip Limited
Filing date
Publication date
Application filed by Corden Pharma Ip Limited filed Critical Corden Pharma Ip Limited
Publication of IE20090901U1 publication Critical patent/IE20090901U1/en
Publication of IES85565Y1 publication Critical patent/IES85565Y1/en

Links

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

Abstract

ABSTRACT Oxuzolidonc sulphonate and oxazolidone benzaldehyde are novel intermediates. They may be used in a process for preparaing bisoprolol comprises reacting oxazolidinonc sulphonale wi1h 4-hydroxybenzylaldehyde to form oxazolidinone benzaldchydc, fornring o,\a/.0|id0ne benzylalcohol from oxazolidone benzaldehyde and subsequently reacting oxazolidinone benzyalcohol with isopropyl oxitol to form bisoprolol base.

Description

This invention relates to the manufacture of Bisoprolol fumaratc and intennediates used in the process.
The process described in DOS 2 645 710. describes a process wherein Z- (isopropoxy)ethoxymethyl-phenol is reacted with epichlorhydrin and the B-amino alcohol moiety is formed by the addition ofiso-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 intenncdiate 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).
DOS3205457 describes a process wherein the 2-(isopropoxy)E:th0x)'methyl substituent is introduced in two stages. Initially the aromatic ring ol" 3-isopropyl- -phenoxymethyl—oxazolidinone is chloromethylated using IICI and paraformaldehyde followed by a Williamson ether synthesis employing metallic sodium. The resultant oxazolidine ring is cleaved by alkaline hydrolysis.
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-isopropyIphenoxymethyh oxazolidinone with paraformaldehyde in the presence of HCl undergoes side reactions leading to the formation of the knovm impurities C and G. This process generates material of inferior quality as exemplified by a limit for impurity (J of .5% {as described in the European Pliarmacopeia 6.1).
Statements of lnvention According to the invention there is provided a process for preparing bisoprolol comprising the steps of:- reacting oxazolidinone sulphonate with 4-hydroxybemylaldehyde to form oxazolidinone benzaldehyde; forming oxazolidone benzylalcohol from oxazolidone benzaldehydc: and lE09090t subsequently reacting oxazolidinone benzylalcohol with isopropyl oxitol to form bisoprolol base.
In one embodiment the oxazolidone sulphonate is formed by reacting isopropylaminopropanediol with dimethylcarbonate and reacting the intermediate product thus formed with benzcnesulphonylchioride.
In one case oxazolidinone sulphonate is not isolated prior to reaction with 4- h yd rox ybenzaldehyde.
In one embodiment methylisobutylketone is added to the intermediate product prior to the addition of benzencsulphortylchloride. 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 bcnzenesulphonyl chloride is performed in an organic solvent such as methylisobutylketonc 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 convening bisoprolol fumarate to bisoprolol base.
The invention also provides bisoprolol prepared by a process as described herein. lE0909 The invention further provides bisoprolol fumarate prepared by a process as described herein.
The invention also provides a process for preparing oxazolidinone benzaldehydc 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: one CH3 / CH3kN/w/\O >—o 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 [C11 guidance Q3A(R2) for impurities in new drug substances.
Brief Description ofthe Drawings The invention will be more clearly understood from the following description oi‘ an embodiment thereofi given by way of example only, with reference to the accompanying drawings, in which: - Fig. I is an infra-red spectrum (l-;Br disc) of oxazolidinone sulphonate; IEo9o9o1 Fig. 2 is a ‘H NMR spectrum (CDCI3. 300 MHz) of oxzizolidinone henzaldehyde; Fig. 3 is a “H NMR spectrum (CDCI3, 75 MHz) ol’ oxazolidinone benzaldehyde; Fig. 4 is an infra-red spectrum (kBr disc) ofoxazolidinone benzaldchydc; Fig. 5 is a ‘H NMR spectrum (CDCI3, 300 MHz) of oxazolidinone benzyl alcohol; Fig. 6 is a '-‘H NMR spectrum (‘CDCl_z. 75 MHZ) ofoxazolidinone bcnzyl 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: !Eo9o9o1 //\“‘ ’ CH0 CH? 0 i\ U L V V; \ CH3 CI,/.\\\O />-5 r / C’ OH Oxazdidmone Sulphonaie \ 4-}‘+ydrox~,benz.:i|delmie é ..
CH3 ./‘\ /1'”) CH.» ‘N’!\'}/A“ O 01aD.)|I:;l\I‘-Lave Béfilzaldeffy-IfE i CH OP 3 \ H I ’ E /x /\ X /K, ‘ (H CH3 r~ ‘y’ ‘'3’ \ + I /}—t') O’ is:.p{:p.r1 Oxs’. .1 Omzoimuxane BeuLz~,13Icr»hot (AP! Stamng D.-‘at-:-ma‘: CH, »//"\. /‘:1’“‘wOT r/\ \ L:~~ CH3 N L» ‘V UH Bxsoprc-iol Bass crude Example I — Stage 1: Svnthesis 0fOxaz0lidinone Sulphonate (Step I ) lEo9o9o1 CH3 CH3, /]\ ‘O O\ MeOH J\ C \ CH3 N/YOH + CH3 Y H3 p} CH3 N/ Y\OH H 0 OH Isoptopylam-nopropanediol Dtmethylcarbonate M.W.Z133.Z M W '90 1 [Intermediate - not Isolated] MIBK/DIW N60!-I rCH3rCH:)d4Nt'HSO.) was / CH3 0\ \ k \ cH£\N/\//\o’$\\v0 : so,ct M.W..176.6 Oxazolidinone Sulphonate T he following details describe the manufacture ofa typical batch A reactor is charged with 392 kg of isopropylaminopropanedioI. approximately 340 l, of methanol, 6 to 7L of sodium methoxide (30%) and 270 L of dimetltylcarbonate. The contents were heated up to allow reaction to occur.
Solvent is removed by distillation.
L water and ca 450 L of methylisobutylketone (MIBK) are then charged to the reactor. The reactor contents are then cooled down to <25"(‘.
Tetrabutylammoniumhydrogensulphate (ca 25kg) and 520 kg of bcnzcnesulphonylchloride 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-tert-butylether (MTBE).
F ig. 1 illustrates the infra red spectrum ofoxazolidinone sulphate.
Purity H PLC >98"/o phosphate and triethylamine Oxazolidinone sulphonate is a novel intermediate and may used for the manufacture of [3-blockers such as Acebutolol. Alprenolol, Atenolol. Belaxolol.
Bisoprolol. Esmolol and Metoprolol.
Example 2 — Svnthesis of Oxazolidinone benzaldehyde (Step 2) CH0 CH3 0 .040 L \\S\ DMF CH3 / I ~ / \ T» J\ , CH3 N/Y\D O + K2603 CH3 N/ 7/\O \ re i ci on O O oxazoiidinoi-.3 suiphoi-me 4-Hydroxybenzaldehyde Oxazolidinone Benzalclehyde M.W:299.3 MW..122.1 Moi Wt 253 29 A reaction vessel is charged with l54.5kg of 4-hydroxybenzaldehyde, 600 L of dimethylfomiamide (DMFL I00 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.
Ni‘vlR 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 398%, 51% 4-hydroxybenzaldhyde Stationary phase: octadecylsilyl silica gel for chromatography lEo9o9o1 _ 9 - Mobile phase: a mixture of methanol water buffered with potassium hydrogen phosphate and triethylamine Example 3 — Alternative Synthesis ot‘Oxazolidinone benzaldehvde (Step 2) CH3 CH) «O 0 M o CH':I\N OH CH; Y ‘CH3 Li’; CH/[\N/‘\ /\OH ” + 0 ca owe I / OH 1 )—t_‘) Isopropytaminopropanedtol Dirnethytcarbonate O M W-W332 M W 90 1 [Intermediate - not isolated] \ S09 M:'Br J / t'CH;{CH.~)tI4/VrH5'C‘4/ MW .176 6 CH0 A DMF 3 O_\ \ L” O at 0 /\ \\ ' CH; N\ 7/\o W303 cng\~/\f\o”S\\.O /)—O )——O / O 0 OH O><&Z0lldi'l0"|8 Benzaldehvde 4-Hydroxybenzaldehyde Oxazoludunone Sulphonate M01 W‘ 263 29 M W 122 1 [Intermediate not isotated] A vessel is charged with I00 g of isopropylaminopropanediol. methanol. 3-4 g of sodium methoxide 30% and 70 ml ofdimethylcarbonate. The vessel contents are heated up to allow reaction to occur. Solvent is removed by distillation.
I00 ml water and methylisobutylltetone are then charged to the reaction. The reaction mixture is then cooled down to <'35°C. 'l‘etrabutylammoniumhydrogensulphate (ca 0.5g) and 145;; of benxenesulphonylchloride are then added to the reaction mixture under cooling. % 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 d imethyl foramicie. lEo9o9o1 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 393%. 51% 4-hydroxybenzaldhyde Stationary phase: octadeeylsilyl 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 henzaldehyde intennediate may also be prepared in a “telescoped“ process described in this example 3, this process is more efficient as the use ofMTBE for the isolation of oxazolidinone siilphonate is eliminated. This results in reduced waste disposal costs and a 50% reduction in the requirement for solids separations equipment.
Fzxanmle 4 — Alternative Synthesis ofOxazolidinone benzaldehyde (Step 2) CH: CH; 40. .0.
/J\ /\ /\ CH3 \CH3 MQOH \ ,/\ /\\ CH3 N OH + Tb CH3 N 7/ OH H 0 CHJONC on /r—o / Isopropylarninopropanediol Dirnethylcarbonate M W «133 2 M W 90 1 [Intermediate - not isolated] \ sr>_ci / MIBK E i ,rv MW 1766 CH0 CH0 C H; ;/’E/ DMF i H; o _ J \ \ c H; u /YE K \/| ' i X \.._ K3503 >110 / /F0 // 0' U OH O7«aIOlIdlflOl|O Benzaldohydo 4'HyL|lOXYD€f‘|ZEIld9hydG O-cazolidinone SulPh0"3'9 MoI\Nl.2‘6329 MW 1221 [intermediate not ISOIBIBU] IE090901 - 11 _ A vessel is charged with 100 g ofisopropylaminopropanediol, 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 cooled mixture is then and 80g of triethylamine and 145g ol‘ benzenesulphony[chloride 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 dimethylforaniide.
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 398%, 51% 4-hydroxybenzaldhyde Stationary phase: octadeeylsilyl 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 oxazolidinonc hen‘/aldehyde 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. lEo9o9o1 Example 5 — Step 3 — Conversion of Benzaldehyde to Benzylalcohol CHO Na8H4 It-Buranol -0 xzcog. D/W )—o O O Oxazolidinone Benzaldehyde 0X3Z°"d’“0“9 B9"ZY'3lC0h0l M W.‘ 263.3 M W‘ 255 3 Sodium borohydride (1 lKg) in a mixture of water (71LV) and sodium hydroxide (0.3Ll. (300L'). (1501,) oxazolidinone benzaldehyde (271 Kg‘) are charged to a vessel. to n-butanol Water potassium carbonate and The vessel contents are heated up to lO0°C. cooled and ethyl acetate tl0OL) 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 oxazoliclinone benzaldehyde are illustrated in Figs. 5 and 6. An infra-red spectrum for the product is illustrated in Fig. 7.
Purity HPLC 399°/o Stationary phase: octadecylsilyl silica gel for chromatography Mobile phase: a mixture of methanol water buffered with potassium hydrogen phosphate and triethylamine Example 6: Purification ofBisoprolol 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 / CHQOH U ,£090901 The purified bisoprolol base is converted to Pharmacopoeia grade bisoprolol lumarate by addition of fumaric acid to bisoprolol base in acetone.
Exaniple 8: Bisoprolol Base for use as a drug substance Cliarge bisoprolol fumarate (30l\'g) in a mixture of water (301 L‘) and sodium methyl-(er!-butylether (l05L}, 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.

Claims (1)

1. A process for preparing oxazolidinone benzaldehyde by reacting oxazolidinone sulphonate with 4-hydroxybenzylaldehyde. A process for preparing oxazolidone benzylalcohol comprising convening oxazolidone benzaldehyde to oxazolidone benzylalcohol. Oxazolidinone sulphonate having the fomiula: Oxazolidinone Benzaldehyde having the formula: Use of the compound of claim 3 or the compound of claim 4 as intennediates in a process for preparing bisoprolol or pharmaceutically acceptable salts thereof.
IE2009/0901A 2009-11-26 Manufacture of beta blockers IES85565Y1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IEIRELAND28/11/20082008/0949

Publications (2)

Publication Number Publication Date
IE20090901U1 true IE20090901U1 (en) 2010-07-07
IES85565Y1 IES85565Y1 (en) 2010-08-04

Family

ID=

Similar Documents

Publication Publication Date Title
AU2006331365B2 (en) Epoxide intermediate in the TAMIFLU synthesis
KR910003334B1 (en) Process for the preparation of unsaturated carboxylic acid amides
JP3794029B2 (en) Method for producing (meth) acrylate having epoxy group
JPH0662519B2 (en) Method for producing phenol ether using cyclic intermediate
WO2007069266A2 (en) A novel process for the synthesis of bisodprolol and its intermediate
IES20090900A2 (en) Manufacture of beta blockers
IE20090901U1 (en) Manufacture of beta blockers
KR20020010914A (en) Process for preparing (1r, 2s, 4r)-(-)-2-[(2&#39;-(n,n-dimethylamino)-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof
IES85566Y1 (en) Manufacture of beta blockers
IE85808B1 (en) Manufacture of beta blockers
CN1093355A (en) The preparation method of phenylacetic acid derivatives
IES85567Y1 (en) Manufacture of beta blockers
IES85565Y1 (en) Manufacture of beta blockers
EP1167365B1 (en) Method of producing sesamol formic acid ester and sesamol
SK29099A3 (en) Process for the preparation of fluoxetine
IE911015A1 (en) Production of 4-hydroxyphenethyl alcohol
US7417153B2 (en) Method for the production of 3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol derivatives
TWI828123B (en) Method for purification of terpenoid amino alcohol derivatives
JP2008222566A (en) New method for producing febrifugine and isofebrifugine
JP4371054B2 (en) Process for producing quinolinecarbaldehydes
JPH0637482B2 (en) Process for producing optically active atenolol and its intermediates
WO2004011451A1 (en) Process for industrially producing optically active 1,4-benzodioxane derivative
Kumar et al. Synthesis of racemic and chiral Carvedilol starting from corresponding 5-(chloromethyl) oxazolidin-2-one
KR950002832B1 (en) Process for the preparation of phenol ethers
JPH11217376A (en) Production of alpha-alkenyl-2-oxazoline