IE85808B1 - Manufacture of beta blockers - Google Patents
Manufacture of beta blockers Download PDFInfo
- Publication number
- IE85808B1 IE85808B1 IE2009/0899A IE20090899A IE85808B1 IE 85808 B1 IE85808 B1 IE 85808B1 IE 2009/0899 A IE2009/0899 A IE 2009/0899A IE 20090899 A IE20090899 A IE 20090899A IE 85808 B1 IE85808 B1 IE 85808B1
- Authority
- IE
- Ireland
- Prior art keywords
- oxazolidinone
- bisoprolol
- formula
- oxazolidone
- benzaldehyde
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 239000002876 beta blocker Substances 0.000 title 1
- 229960002781 Bisoprolol Drugs 0.000 claims abstract description 34
- VHYCDWMUTMEGQY-UHFFFAOYSA-N Bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 claims abstract description 34
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims abstract description 26
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims abstract description 22
- -1 oxazolidone benzylalcohol Chemical compound 0.000 claims abstract description 20
- DGURWEAHLDSUHU-UHFFFAOYSA-N benzaldehyde;1,3-oxazolidin-2-one Chemical compound O=C1NCCO1.O=CC1=CC=CC=C1 DGURWEAHLDSUHU-UHFFFAOYSA-N 0.000 claims abstract description 17
- HCGFUIQPSOCUHI-UHFFFAOYSA-N 2-propan-2-yloxyethanol Chemical compound CC(C)OCCO HCGFUIQPSOCUHI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-Hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 10
- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 10
- 229960005400 Bisoprolol Fumarate Drugs 0.000 claims description 9
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 9
- VMDFASMUILANOL-WXXKFALUSA-N bisoprolol fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1.CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VMDFASMUILANOL-WXXKFALUSA-N 0.000 claims description 9
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 9
- IEJIGPNLZYLLBP-UHFFFAOYSA-N Dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 7
- FNYJUSZPPHSXJA-UHFFFAOYSA-N 1-(propan-2-ylamino)propane-1,1-diol Chemical compound CCC(O)(O)NC(C)C FNYJUSZPPHSXJA-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000005712 crystallization Effects 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 238000007792 addition Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- LXJCXWKBRRFMEJ-UHFFFAOYSA-N 1,3-oxazolidin-2-one;phenylmethanol Chemical compound O=C1NCCO1.OCC1=CC=CC=C1 LXJCXWKBRRFMEJ-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 101700068694 mfpA Proteins 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 5
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 5
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 5
- 235000019797 dipotassium phosphate Nutrition 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960004217 benzyl alcohol Drugs 0.000 description 4
- 235000019445 benzyl alcohol Nutrition 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N Isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- ZOHMWSMZPRSYPJ-UHFFFAOYSA-N 1,3-oxazolidin-2-one;sulfuric acid Chemical compound OS(O)(=O)=O.O=C1NCCO1 ZOHMWSMZPRSYPJ-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- INSWRFZAYZOYRW-UHFFFAOYSA-N 2-(2-propan-2-yloxyethoxymethyl)phenol Chemical compound CC(C)OCCOCC1=CC=CC=C1O INSWRFZAYZOYRW-UHFFFAOYSA-N 0.000 description 1
- 229960002122 Acebutolol Drugs 0.000 description 1
- GOEMGAFJFRBGGG-UHFFFAOYSA-N Acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N Alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- 229960002274 Atenolol Drugs 0.000 description 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N Betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 1
- 101700067048 CDC13 Proteins 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229960002237 Metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N Metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- RVXXBPUFJQELHG-UHFFFAOYSA-N O1C(NCC1)=O.C(C)N(CC)CC Chemical compound O1C(NCC1)=O.C(C)N(CC)CC RVXXBPUFJQELHG-UHFFFAOYSA-N 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940095076 benzaldehyde Drugs 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 229960003745 esmolol Drugs 0.000 description 1
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 1
- WTDFFADXONGQOM-UHFFFAOYSA-N formaldehyde;hydrochloride Chemical compound Cl.O=C WTDFFADXONGQOM-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- MZSDGDXXBZSFTG-UHFFFAOYSA-M sodium;benzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC=C1 MZSDGDXXBZSFTG-UHFFFAOYSA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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 A process for preparing bisoprolol comprises reacting oxazolidinonc sulphonate with 4-hydroxybcnzylaldehyde to form oxazolidinone benzaldehyde, forming oxazolidone benzylalcohol from oxazolidone benzaldehyde. and subsequently reacting 0x21’/.o|idi11unc bcnzylalcohol with isopropyl oxitol to form bisoprolol base. ()xaz,olido|1c sulphonate and oxazolidone benzaldchyde are novel interrnediatcs.
Description
Manufacture of 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 B-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).
H2~J\ jafik Bisoprolol Fumarate Imp F W - 85808 DOS3205457 describes a process wherein the 2-(isopropoxy)ethoxymethyl substituent is introduced in two stages. Initially the aromatic ring of 3-isopropyl—5-phenoxyrnethyl-oxazolidin- -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.
C H 3-lsopropyl C H020/\’ 02 phenoxymethyl-oxazolidin-z ' one . - side reacfion 1 Blsopralol Fumarate \ Drug Substance H HO OH H H020/~\/COEH side macfion 2 Bisoprolol Fumarate Imp C Bisoprolol Fumarate Imp 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-isopropylphenoxymethyl-oxazolidinone 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 comprising the steps of:— reacting oxazolidinone sulphonate with 4-hydroxybenzylaldehyde to form oxazolidinone benzaldehydeg forming oxazolidone benzylalcohol from oxazolidone benzaldehyde; and subsequently reacting oxazolidinone benzylalcohol with isopropyl oxitol to form bisoprolol base. formed the by isopropylaminopropanediol with dimethylcarbonate and reacting the intermediate product thus In one embodiment oxazolidone sulphonate is reacting formed with benzenesulphonylchloride.
In one case oxazolidinone sulphonate is not isolated prior to reaction with 4- hydroxybenzaldehyde.
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.
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.
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 fiimaric 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.
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: The invention further provides oxazolidinone benzaldehyde having the formula: CH0 CH3 / CH3 N/Y\0 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 dnlg substances.
Brief Description of the Drawiggs 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. 1 is an infra-red spectrum (kBr disc) of oxazolidinone sulphonate; Fig. 2 is a 1H NMR spectrum (CDCI3, 300 MHZ) of oxazolidinone benzaldehyde; Fig. 3 is a “H NMR spectrum (CDCI3, 75 MHZ) of oxazolidinone benzaldehyde; Fig. 4 is an infra-red spectrum (kBr disc) of oxazolidinone benzaldehyde; Fig. 5 is a ‘H NMR spectrum (CDC13, 300 MHZ) of oxazolidinone benzyl alcohol; Fig. 6 is a 13 H 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 The process for preparing bisoprolol according to the invention can be summarised as follows: % JMOAW CH3 CH3 lsopropylamlnopropanedIol Dimethylcarbonate M-W2 M.W.:90.1 [Intermediate — not isolated] [CH3(CH2)3I4N(HSO4) MTBE Oxazolidinone Sulphonate The following details describe the manufacture of a typical batch 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 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°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-tern butylether (MTBE).
Fig. 1 illustrates the infra red spectrum of oxazolidinone sulphate.
Purity HPLC >98% Stationary 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 B- blockers such as Acebutolol, Alprenolol, Atenolol, Betaxolol, Bisoprolol, Esmolol and Metoprolol.
Examnle 2 — Synthesis of Oxazolidinone benzaldehyde (Step 2) Oxazoiidinone Sulphonate 4"HYd|’°XYb9nZ3'dehYde 0"3Z°lidl“°“e Benzaldehyde M.W.:299.3 M.VV.: 122.1 Mot w1_;263_29 A reaction vessel is charged with l54.5kg 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 398%, 51% 4-hydroxybenzaldhyde Stationary phase: octadecylsilyl silica gel for chromatography Mobile phase: a mixture of methanol water buffered with potassium hydrogen phosphate and triethylamine Example 3 — Alternative Synthesis of Oxazolidinone benzaldehvde ( Step 2) Jsopropylaminopropanediol M.W.:133.2 Dimethylcarbonate M_W.:90.1 [Intermediate not isolated] 0X82-Olidinone Benlaldehyde 4-Hydroxybenzaldehyde Oxazolidinone Sulphonate intermediate not isolated] 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. 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 dimethylforarnide.
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%, 31% 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 benzaldehvde (Step 2) /K «O °\ Me0H CH CH CH3 M/Y\OH + 3 T 3 -———-—> CH3 N/Y\OH OH 0 CH3ONa O , , o Isopropylammopropanediol Dimethylcarbonate M-WA133-2 M.W.:90.1 [intermediate - not isolated] sozci Ej MIBK,Et3N M.W.:176.6 CH0 CH0 DMF a 0% <=~ O CH: N/w/\° K2CO_-,- CH3 N o’S\\o o o 0 OH O Oxazolidinone Benzaldehyde Mol. VVt.: 263.29 —Hydroxybenzaidehyde M.W.: 122.1 Oxazolidinone Sulphonate [intermediate not isolated] 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 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: 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.
Example 5 — Step 3 — Conversion of Benzaldehvde to Benzvlalcohol CHO CH-20H CH3 CH3 J\ Nag;-/4 n-Butane! J\ CH3 N/w/\0 CH3 N/W/\o o KZCO3, D/W o O O Oxazofidinone Benzakjehyde Oxazolidinone Benzylalcohol M.W.: 263.3 M.W.: 265.3 Sodium borohydride (l1Kg) in a mixture of water (7lL) and sodium hydroxide (0.3L), to n- butanol (300L). Water (l50L) potassium carbonate and oxazolidinone benzaldehyde (271Kg) are charged to a vessel.
The vessel contents are heated up to 100°C, cooled and ethyl acetate (IOOL) 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 F ig. 7.
Purity HPLC 399% Stationary phase: octadecylsilyl silica gel for chromatography Mobile phase: a mixture of methanol water buffered with potassium hydrogen phosphate and triethylamine Examnle 6: Purification of Bisoprolol Base Bisoprolol base is formed fiom 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 The purified bisoprolol base is converted to Pharmacopoeia grade bisoprolol fiimarate by addition of fumaric acid to bisoprolol base in acetone.
Example 8: Bisoprolol Base for use as a drug substance Charge bisoprolol fiimarate (3OKg) in a mixture of water (30lL) and sodium methyI-z‘ert- 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 fiimarate 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 (3)
1. A process for preparing bisoprolol comprising the steps of:- wtfil CH3 N o’ *0 2-0 0 5 reacting oxazolidinone sulphonate of the formula with 4-hydroxybenzylaldehyde to form oxazolidinone benzaldehyde of the formula CH0 CH3 0/ CH3 N/Y\O o o 10 forming oxazolidone benzylalcohol of the formula fi*om the oxazolidone benzaldehyde; and subsequently reacting oxazolidinone benzylalcohol with isopropyl oxitol to form 15 bisoprolol base.
2. A process as claimed in claim 1 wherein the oxazolidone sulphonate is formed by reacting isopropylaminopropanediol with dimethylcarbonate and reacting the 20 intermediate product thus formed with benzenesulphonylchloride.
3. A process as claimed in claim 1 or 2 wherein the oxazolidinone sulphonate is not isolated prior to reaction with 4-hydroxybenzaldehyde. A process as claimed in claim 2 or 3 wherein methylisobutylketone is added to the intermediate product prior to the addition of benzenesulphonylchloride. 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. A process as claimed in claim 4 wherein 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. A process as claimed in any of claims 1 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 1 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 for preparing oxazolidinone benzaldehyde of the formula CH0 CH3 / CH3J\N/w/\O 0 O . by reacting oxazolidinone sulphonate of the formula CH3 0 KS with 4-hydroxybenzylaldehyde. A process for preparing oxazolidone benzylalcohol of the formula mfpA«©/ comprising converting oxazolidone benzaldehyde of the formula CH0 CH3 0/ CH3J\N/w/\0 O O to oxazolidone benzylalcohol. Oxazolidinone sulphonate having the formula: CH3 0 cHg\N/w/\o’\s\0 o o Oxazolidinone Benzaldehyde having the formula:
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 |
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| Publication Number | Publication Date |
|---|---|
| IE20090899A1 IE20090899A1 (en) | 2010-07-07 |
| IE85808B1 true IE85808B1 (en) | 2011-07-06 |
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