MXPA00010538A - PREPARATION OF&bgr;-LACTAM ANTIBIOTICS IN THE PRESENCE OF UREA OR AMIDE - Google Patents
PREPARATION OF&bgr;-LACTAM ANTIBIOTICS IN THE PRESENCE OF UREA OR AMIDEInfo
- Publication number
- MXPA00010538A MXPA00010538A MXPA/A/2000/010538A MXPA00010538A MXPA00010538A MX PA00010538 A MXPA00010538 A MX PA00010538A MX PA00010538 A MXPA00010538 A MX PA00010538A MX PA00010538 A MXPA00010538 A MX PA00010538A
- Authority
- MX
- Mexico
- Prior art keywords
- acid
- lactam
- process according
- further characterized
- solution
- Prior art date
Links
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 239000004202 carbamide Substances 0.000 title claims abstract description 16
- 150000001408 amides Chemical class 0.000 title claims abstract description 13
- 239000003782 beta lactam antibiotic agent Substances 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title description 13
- 239000002253 acid Substances 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000007792 addition Methods 0.000 claims abstract description 21
- 239000000725 suspension Substances 0.000 claims abstract description 14
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-APA Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims abstract description 13
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7-ACA Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- QMWWAEFYIXXXQW-KVVVOXFISA-M potassium;2-[[(Z)-4-ethoxy-4-oxobut-2-en-2-yl]amino]-2-phenylacetate Chemical compound [K+].CCOC(=O)\C=C(\C)NC(C([O-])=O)C1=CC=CC=C1 QMWWAEFYIXXXQW-KVVVOXFISA-M 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 β-lactam compound Chemical class 0.000 claims description 36
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 22
- 238000002425 crystallisation Methods 0.000 claims description 19
- 230000005712 crystallization Effects 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000011780 sodium chloride Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 12
- MNFORVFSTILPAW-UHFFFAOYSA-N Β-Lactam Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000003952 β-lactams Chemical class 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- AVKUERGKIZMTKX-NJBDSQKTSA-N Ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 5
- 229960000723 ampicillin Drugs 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N Cefalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims description 4
- 229940106164 Cephalexin Drugs 0.000 claims description 4
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 4
- 229960003022 amoxicillin Drugs 0.000 claims description 4
- 229960003525 cefalexin Drugs 0.000 claims description 4
- 150000001780 cephalosporins Chemical class 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002960 penicillins Chemical class 0.000 claims description 4
- 229960005361 Cefaclor Drugs 0.000 claims description 3
- 229960004841 Cefadroxil Drugs 0.000 claims description 3
- 229960004261 Cefotaxime Drugs 0.000 claims description 3
- RDMOROXKXONCAL-UEKVPHQBSA-N Cefroxadine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)OC)C(O)=O)=CCC=CC1 RDMOROXKXONCAL-UEKVPHQBSA-N 0.000 claims description 3
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 claims description 3
- BOEGTKLJZSQCCD-UEKVPHQBSA-N cefadroxil Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 BOEGTKLJZSQCCD-UEKVPHQBSA-N 0.000 claims description 3
- GPRBEKHLDVQUJE-QSWIMTSFSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-QSWIMTSFSA-N 0.000 claims description 3
- 229960003844 cefroxadine Drugs 0.000 claims description 3
- 239000006184 cosolvent Substances 0.000 claims description 3
- 229960002457 epicillin Drugs 0.000 claims description 3
- RPBAFSBGYDKNRG-NJBDSQKTSA-N epicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CCC=CC1 RPBAFSBGYDKNRG-NJBDSQKTSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- RDLPVSKMFDYCOR-UEKVPHQBSA-N Cefradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 claims description 2
- 229960002588 Cefradine Drugs 0.000 claims description 2
- 229940106192 Cephradine Drugs 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- MIHIJWOEDDPOLG-UHFFFAOYSA-N 2-methoxyiminoacetic acid Chemical compound CON=CC(O)=O MIHIJWOEDDPOLG-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 26
- HNIOAUGOSZOAGN-UHFFFAOYSA-N NC=1SC=C(N=1)N=C(C(=O)O)OC Chemical compound NC=1SC=C(N=1)N=C(C(=O)O)OC HNIOAUGOSZOAGN-UHFFFAOYSA-N 0.000 abstract description 2
- JBJJTCGQCRGNOL-SSDOTTSWSA-N (2R)-2-amino-2-cyclohexa-1,4-dien-1-ylacetic acid Chemical compound OC(=O)[C@H](N)C1=CCC=CC1 JBJJTCGQCRGNOL-SSDOTTSWSA-N 0.000 abstract 1
- 239000003929 acidic solution Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000003115 biocidal Effects 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 3
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 3
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 3
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 3
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 3
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229940079866 intestinal antibiotics Drugs 0.000 description 3
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 229960004920 Amoxicillin Trihydrate Drugs 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- FUBBGQLTSCSAON-PBFPGSCMSA-N Cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 2
- 229950004030 Cefaloglycin Drugs 0.000 description 2
- MQLRYUCJDNBWMV-GHXIOONMSA-N Cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- MQXQVCLAUDMCEF-CWLIKTDRSA-N amoxicillin trihydrate Chemical compound O.O.O.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 MQXQVCLAUDMCEF-CWLIKTDRSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229960004041 cefetamet Drugs 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- DRLJIPQOBJCEET-YWUHCJSESA-N (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrochloride Chemical compound Cl.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DRLJIPQOBJCEET-YWUHCJSESA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- LJCWONGJFPCTTL-UHFFFAOYSA-M 2-amino-2-(4-hydroxyphenyl)acetate Chemical compound [O-]C(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-M 0.000 description 1
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7β-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 1
- 229960003311 Ampicillin Trihydrate Drugs 0.000 description 1
- VUYQLIBQJSATAS-UHFFFAOYSA-N Cl.C1(=CC=CC=C1)C(C1CO1)Cl Chemical compound Cl.C1(=CC=CC=C1)C(C1CO1)Cl VUYQLIBQJSATAS-UHFFFAOYSA-N 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine zwitterion Chemical class [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- RXDALBZNGVATNY-CWLIKTDRSA-N ampicillin trihydrate Chemical compound O.O.O.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 RXDALBZNGVATNY-CWLIKTDRSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 235000012970 cakes Nutrition 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UXIPJZUVTLMZBG-UHFFFAOYSA-M potassium;2-hydroxy-2-phenylacetate Chemical compound [K+].[O-]C(=O)C(O)C1=CC=CC=C1 UXIPJZUVTLMZBG-UHFFFAOYSA-M 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Abstract
A process to prepare a crystalline&bgr;-lactam compound by the addition of a base to an acidic solution of a&bgr;-lactam compound obtained by the addition of an acid to a solution or suspension of a&bgr;-lactam compound obtained by (a) an acylation reaction of 6-amino-penicillanic acid, 7-amino-cephalosporanic acid, 7-amino-3'-desacetoxycephalosporanic acid or 3-chloro-7-aminodesacetoxydesmethylcephalosporanic acid or derivatives thereof with a mixed-anhydride of the Dane salt of any one of the compound comprising D-phenyl-glycine, D-p-hydroxyphenyl-glycine, D-2(1,4-cyclohexadien-1-yl)glycine or (2-aminothiazol-4-yl)-(2-methoxy-imino-acetic acid) in one or more organic solvents, or (b) dissolving or suspending a crude&bgr;-lactam compound in a solution comprising water and/or one or more organic solvents, wherein, to the solution or suspension of a&bgr;-lactam compound, urea or derivatives thereof and/or amide or derivatives thereof are added.
Description
PREPARATION OF R-LACTAMAS ANTIBIOTICS IN THE PRESENCE OF UREA OR AMIDA
The present invention relates to a better process for the preparation of ß-lactam antibiotic compounds in the presence of urea or its derivatives and / or amide or its derivatives. It is commonly accepted that the most economical approach for the isolation of compounds, such as β-lactam antibiotics or their intermediate compounds, from their solutions comprising them, is crystallization. Various methods have been proposed for the preparation of the semi-synthetic β-lactam antibiotic compounds, such as penicillins and cephalosporins. These proposals generally involve the acylation of 6-aminopenicillanic acid (6-APA) or 7-aminocephalosporanic acid (7-ACA) or one of its protective derivatives using, for example, an acyl halide which serves to introduce the desired acyl group. For example, in European Patent Application EP 0011513, a method has been described for the preparation of polar ion antibiotics, for example, ampicillin, amoxycillin or cephalexin by acylation of silylated 6-aminopenicillanic acid or 7-aminocephalosporanic acid with a phenylglycyl halide or p-hydroxyphenylglycyl halide in the presence of N-alkyl pyrrolidone as an acid acceptor. Similarly, the U.S. Patent. No. 4,248,780 for example, describes the preparation of polar ion antibiotic ampicillin by acylation of silylated 6-aminopenicillanic acid with a phenylglycidylchloride hydrochloride using urea as a base. In addition, a number of patent and patent applications describe a method of preparing aminoacylpenicillanic acid derivatives by adding 6-APA with mixed anhydrides derived from modified Dane salts of D-2-amino- (p-hydroxyphenyl) acetic acid, as described in German patent applications Serial No. 1,302,847, No. 2,020,133 and No. 2,065,879 and British Patents No. 1, 327,270 and No. 1, 347,979 and European Patent Application No. 439,096. The patent of E.U.A. 4,358,588 describes a better process for the preparation of D-amino-p-hydroxyphenyl-acetamide-penicillanic acid and cephalosporanic acid derivatives by reacting an appropriate mixed anhydride of a Dame salt with a protected derivative, for example 6-APA or 7 -ACA in the presence of a tertiary amine. This type of acylation is called the Dane salt coupling reaction. Subsequently, the ß-lactam antibiotic compounds are isolated from an aqueous acid solution, obtained by acid hydrolysis of the reaction mixture after the Dane sai coupling reaction, by adding a base and followed by filtration. An important drawback of the procedures for the preparation of ß-lactam antibiotic compounds is the crystallization of unwanted by-products, among which, the hydrochloric acid salts of the antibiotic ß-lactam compounds are the most notorious. This unwanted crystallization of by-products can take place at any stage of the hydrolysis or crystallization process. The formation of acid salts of the ß-lactam antibiotic compounds is strongly dependent on the temperature, pH and time during the acid hydrolysis of the Dame salt coupling reaction. Lower temperatures, lower pH and prolonged time during the hydrolysis of the Dame salt coupling reaction result in the production of a greater amount of acid salt of the corresponding ß-lactam antibiotic compound. At higher temperatures, however, the formation of the corresponding acid salt of the β-lactam during the hydrolysis of the Dame salt coupling reaction is reduced but, on the other hand, the dissociation of the β-lactam increases. Also, the presence of seed crystals, which correspond to the acid salt of the ß-lactam compound, produced during the hydrolysis of the Damage salt coupling reaction., facilitates the formation of acid salts of the ß-lactam antibiotic compounds. Especially, the formation of the seed material during the hydrolysis of the Dane coupling reaction increases in an industrial scale process compared to a laboratory scale process. Thus, the crystalline products resulting from the Dane salt coupling reaction often comprise unacceptable levels of impurities. It was surprisingly discovered that ß-lactam antibiotic compounds free from acid salts of the corresponding ß-lactams can be prepared by the addition of urea or its derivatives and / or amide or its derivatives after the Dane salt coupling reaction at low temperature . Urea or its derivatives and / or amide or its derivatives can also be added during the purification of crude β-lactam antibiotic compounds, during the crystallization phase. In addition to the lower content of the hydrochloric acid salt of the β-lactam produced, these processes also result in a higher yield of the final product. So far, this method has not been described or suggested anywhere for β-lactam compounds.BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a better process for the preparation of ß-lactam antibiotic compounds in the presence of urea or its derivatives and / or amide or its derivatives. The β-lactam compounds are crystallized by the addition of a base to an acid solution of a β-lactam compound obtained by the addition of an acid to a solution or suspension of a β-lactam compound obtained by: a) a reaction of acylation of 6-amino-penicillanic acid, 7-amino-cephalosporanic acid, 7-amino-3'-deacetoxydesmethylcephalosporanic acid or its derivatives, with a mixed anhydride of the Dane salt of any one of the compounds comprising D-phenyl -glycine, Dp-hydroxyphenyl-glycine, D-2 (1,4-cyclohexadien-1-yl) glycine O (2-aminothiazol-4-yl) - (2-methoxy -iminoacetic acid) in one or more solvents organic, or b) dissolving or suspending a crude ß-lactam compound in a solution comprising water and / or one or more organic solvents, characterized by the addition, dissolution or suspension of a ß-lactam compound, urea or its derivatives and / or amide or its derivatives. Before starting the crystallization process by the addition of a base, the pH of the solution or suspension of a β-lactam compound is maintained at the desired pH by the addition of an acid. Normally, the pH is maintained between 0.1 and 3.5 and preferably between 0.3 and 2.5, depending on the type of ß-lactam compound to be produced. When the solution of the β-lactam compound is obtained by (a), the acid that is added can aid in the acid hydrolysis of the reaction mixture of the acylation reaction. The temperature at which the acid is added is preferably between -50 ° C and 10 ° C, preferably between -5 ° C and 5 ° C and most preferably between -5 ° C and 0 ° C. The acid can be any acid, preferably an inorganic acid, for example, hydrochloric acid, nitric acid or sulfuric acid.
Preferably, the acid is hydrochloric acid. The temperature during crystallization may vary. Suitably, the crystallization temperature is between -10 ° C and 50 ° C, and preferably between -5 ° C and 35 ° C. It should be clear to those skilled in the art that the preferred conditions should depend on the ß-lactam compound to be prepared.
The β-lactam antibiotic compounds can be isolated in a conventional manner, by adjusting the pH to the isoelectric point of the corresponding β-lactam compounds. The β-lactam compounds are, for example, penicillins and cephalosporins. Examples of penicillins are amoxlcillin, ampicillin and epicillin. Examples of cephalosporins are cefaclor, cefadroxil, cefetamet, cefotaxime, cephalexin, cephaloglycine, cephradine and cefroxadine.
DETAILED DESCRIPTION OF THE INVENTION
The process for the preparation of crystalline β-lactam antibiotic compounds according to the present invention comprises the addition of a base to an acid solution of a β-lactam compound obtained by the addition of an acid to a solution or suspension of a compound of β-lactam obtained by: (a) an acylation reaction of 6-amino-penicillanic acid (6-APA), 7-amino-cephalosporanic acid (7-ACA), 7-amino-3'-deacetoxycephalosporanic acid (7) -ADCA) or 3-chloro-7-aminodesacetoxydesmethylcephalosporanic acid (7-ACCA) or its derivatives, with a mixed anhydride of the Dane salt of any one of the compounds comprising D-phenyl-glycine, Dp-hydroxyphenyl-glycine, D-2 (1, 4-cyclohexadien-1-y!) Glycine or (2-aminothiazol-4-yl) - (2-methoxy-iminoacetic acid) in one or more organic solvents, or (b) dissolve or suspending a crude ß-lactam compound in a solution comprising water and / or one or more organic solvents, characterized by the addition, dissolution or suspension of a β-lactam compound, of urea or its derivatives and / or amide or its derivatives with the formula (A) and (B) respectively.
R4R3N-CO-NR1Ra R.j-CO-NR? R.2 (A) in which R ^, R2, R3 and R4 are each independently selected from the group comprising hydrogen, lower alkyl and allyl, or R1 and R3 form -CH2-CH2-, -CH2-CH2-CH2-, -CH -CO- and - CH = CH-CO-, which give rise together with -N-CO-N- to a five or six membered cyclic ring, and esters of Cj-Cg alkanol and Cj-Cg carboxylic acid. Preferably, R-j, R2, R3 and R4 in the formula (A) are each chosen from hydrogen or methyl, and more preferably R-j, R2, Ro and R4 are each hydrogen. The amount of urea or its derivatives and / or amide or its derivatives present during the crystallization process can vary, and is preferably between 0.001 mol / mol of β-lactam and 7.5 mol / mol of β-lactam, and more preferably between 0.1 mol / mol of ß-lactama and 5.25 mol / mol of ß-iactama. By derivatives of 6-APA, 7-ACA, 7-ADCA and 7-ACCA is meant its salts and esters.
Preferably, some of an alkanol of C-j-Cg, specifically
methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, or a ketone, specifically acetone, methyl ethyl ketone, methyl isobutyl ketone or an ester, specifically methyl acetate, ethyl acetate , isopropyl acetate, butyl acetate or an ester of carboxylates of C
C with an alkanol of C ^ -Cg or one of its mixtures is added as co-disodive to the solution or suspension of a β-lactam compound. The Dame salt coupling reaction is carried out in a dry organic solvent insoluble in water, for example dichloromethane. When the solution or suspension of a β-lactam compound is obtained by (a), the co-solvent is preferably added after the Dane salt coupling reaction. The concentration of the co-solvent is between 0.1% and 60%, and preferably between 25% and 60%, depending on the type of the β-lactam compound to be prepared. The pH of the acid solution is maintained between 0.1 and 3.5, and preferably between 0.3 and 2.5, using an acid. The temperature of the solution during the addition of the acid may vary, and is usually between -50 ° C and 10 ° C, preferably between -5 ° C and 5 ° C, and more preferably between -5 ° C and 0 ° C. At higher temperatures, the dissociation of the sensitive β-lactam ring of the antibiotic compound is increased. The acid is an inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or an organic acid, for example, formic acid and appropriate acetic acid or its derivatives. Preferably, hydrochloric acid is used. The β-lactam antibiotic compound is isolated in a conventional manner, adjusting the pH between 2.0 and 7.0, and preferably to the isoelectric point of said β-lactam antibiotic compound by the addition of a base. In addition, seed material is optionally added to the crystallization solution before the addition of the base. The base is an inorganic base, preferably sodium hydroxide, potassium hydroxide, ammonium hydroxide or an organic base, preferably an amine. Accordingly, after filtration and drying, crystalline products substantially free of impurities, such as the acid salt of the β-lactam compounds themselves, are obtained as known processes without application of urea or its derivatives and / or amide or its compounds. Derivatives give higher levels of impurities, especially when the crystallization is carried out at a lower temperature. The process of the present invention is particularly suitable for the preparation of β-lactam antibiotics in the polar-ion amino acid form. Examples of said antibiotics are amoxicillin, ampicillin, epicillin, cefaclor, cefadroxil, cefetamet, cefotaxime, cephalexin, cephaloglycine, defradine and cefroxadine.
According to a further aspect of the present invention, the β-lactam compound is advantageously crystallized by simultaneous addition of the β-lactam solution and a base to a crystallization vessel, as described in the unpublished European Patent Application. No. 97203484. This crystallization process comprises the simultaneous addition of the acid solution of a β-lactam compound comprising urea or its derivatives and / or amide or its derivatives and a titrant, mainly the base, to a crystallization vessel. The crystallization process of antibiotic compounds, according to the present invention, has a major advantage over existing methods because better matching results are possible. The agreement value referred to the difference between valuation with a strong acid and valuation with a strong base has been defined according to the United States Pharmacopoeia, twenty-first revision, dated January 1, 1985. A small match value means a product of constant quality. Ampicillin trihydrate, for example, isolated from the crystallization of a solution comprising ampicillin hydrochloride has a matching value of less than 1 mol%, while crystallization by a prior art method of a number of experiments has given a matching value between 4 and 8 mol%. The β-lactam antibiotic compounds with small agreement value, that is, comprising lower amounts of acid salt of the corresponding β-lactam antibiotics, are suitable for pharmaceutical formulation purposes. In addition, the bad effect of storage and temperature (above ambient temperature) on the stability of the ß-lactam antibiotic compound is increased due to the presence of very small or negligible amounts of the corresponding acid salt of the ß-lactam antibiotic compound . These acid salts of the β-lactam antibiotic are usually of a hygroscopic nature. Therefore, the product obtained by the process according to the invention is new. The invention will now be described with reference to the following Example, which should not be considered as limiting the invention, and is provided simply for illustrative purposes.
EXAMPLE
Stage A
Preparation of methoxycarbonyl-D-1-carbomethoxypropen-2-yl) amino-p-hydroxyphenyl-acetate 85 mL of N, N-dimethylacetamide, 116.4 g of Da- [1- (carbomethoxypropen-2-yl) -amino] -p Potassium hydroxyphenylacetate and 0.3 mL of pyridine were added to 267 mL of dichloromethane and the resulting suspension was cooled to -40 ° C. Subsequently, 46.3 g of pivaloyl chloride were added to this solution. While maintaining a temperature of -30 ° C, the mixture was stirred for 90 minutes and then cooled to -50 ° C.
Step B 63.8 g Triethylamine was added to a suspension of 80.0 g of 6-aminopenicillanic acid in 533 mL of dichloromethane at 20 ° C and the mixture was stirred for 90 minutes. The mixture should comprise sufficient water to obtain a clear solution. At 5 ° C, 78 g of 2-ethylhexanoic acid was added and subsequently the solution was cooled to -50 ° C.
Stage C
Preparation of Amoxicillin Trihydrate The reaction mixture obtained in STEP A was added, over approximately 3 minutes, to the solution obtained in STEP B, stirring vigorously. Over a period of 3 hours the temperature gradually rose from -40 ° C / -35 ° C to -10 ° C / -5 ° C. Subsequently, a solution of urea (100 g in 800 mL of demineralized water) was added. While maintaining the mixture between -5 ° C and 0 ° C, concentrated hydrochloric acid was added and hydrolysis was continued for 30 minutes at a pH between 1.4 and 1.5. The organic phase was separated and the product was crystallized from the aqueous layer by addition of about 45 mL of 8 N sodium hydroxide solution to a pH between 4.8 and 5.0 at a temperature between 2 ° C and 5 ° C. The suspension was kept overnight under these conditions, filtered, washed with 100 mL of cold and demineralized water and 300 mL of cold acetone. The cake was dried at 35 ° C until constant weight was reached to obtain 143 g of amoxicillin trihydrate with a purity of 86.1% in the form of anhydrous amoxicillin (HPLC).
Claims (2)
1- A process for preparing a crystalline β-lactam compound by adding a base to an acid solution of a β-lactam compound obtained by adding an acid to a solution or suspension of a β-lactam compound obtained by: (a) an acylation reaction of 6-amino-penicillanic acid, 7-amino-cephalosporanic acid, 7-amino-3'-deacetoxycephalosporanic acid or 3-chloro-7-aminodoacetoxydesmethyl-cephalosporanic acid or salts or esters thereof, with a mixed anhydride of the Dane salt of any of the compounds comprising D-phenyl-glycine, Dp-hydroxyphenyl-glycine, D-2 (1,4-cyclohexadien-1-yl) glycine or (
2-aminothiazol-4-yl) ) - (2-methoxy-imino-acetic acid) in one or more organic solvents, or (b) dissolving or suspending a crude β-lactam compound in a solution comprising water and / or one or more organic solvents, characterized by addition, to the dissolution or suspension of a β-lactam compound, of urea or its derivatives and / or amide or its derivatives with the formulas (A) and (B) respectively, K ^ RjN-CO-NRaRa to -CO-NRjRa (A) (B) wherein R- R2, R and R4 are each independently selected from the group comprising hydrogen, lower alkyl or allyl, and alkanoic esters (Ci-Ce) of carboxylic acid (C? -C6), or R ^ y R form -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CO- and -CH = CH-CO- which give rise, together with -N-CO- N-, to a five or six membered cyclic ring. 2. The process according to claim 1, further characterized in that in the formula (A), R, R, R3 and R4 each is chosen from hydrogen or methyl. 3. The process according to any of claims 1-2, further characterized in that when the solution of a β-lactam compound obtained by (a) is used, the temperature at which the acid is added is maintained between - 50 ° C and 10 ° C. 4. The process according to any one of claims 1-3, further characterized in that the amount of urea or its derivatives and / or amide or its derivatives is between 0.001 mol / mol of ß-lactam and 7. 5 mol / mol of β-lactam, and preferably between 0.1 mol / mol of β-lactam and 5.25 mol / mol of β-lactam. 5. The process according to any one of claims 1-4, further characterized in that the dissolution of the ß-lactam antibiotic compound comprises one or more co-solvents chosen from the alkanol group of Cj-Cg or ketone or ester of a carboxylate of CjC with an alkanol of Cj-Cg 6. The process according to claim 5, further characterized in that when the solution of a β-lactam compound obtained by (a) is used, the co-solvent or Solvents are added after the coupling reaction. 7. The process according to claim 1-6, further characterized in that the pH of the acid solution before the addition of a base has been maintained between 0.1 and 3.5, preferably between 0.3 and 2.5 using an acid. 8. The process according to claim 7, further characterized in that the acid is hydrochloric acid. 9. The process according to any of claims 1-8, further characterized in that during crystallization, the pH is maintained between 2.0 and 7.0, preferably close to the isoelectric point of said ß-lactam compound by the addition of a base. 10. The process according to any of claims 1-9, further characterized in that the base is an inorganic base, preferably sodium hydroxide, potassium hydroxide or ammonium hydroxide. 11. The process according to any of claims 1-10, further characterized in that seed crystals are added before the addition of the base. 12. The process according to any of claims 1-11, further characterized in that the temperature during crystallization is maintained between -10 ° C and 50 ° C, preferably between -5 ° C and 35 ° C. 13. The process according to any of claims 1-12, further characterized in that the β-lactam compounds are penicillins and cephalosporins, preferably amoxicillin, ampicillin, epicillin, cefaclor, cefadroxil, cefatamet, cefotaxime, cephalexin, cephaglycine, cephradine and cefroxadine. 14. The process according to any of the preceding claims, further characterized in that the acid solution of a β-lactam compound and a base are simultaneously added to a crystallization vessel.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP98201399 | 1998-04-29 |
Publications (1)
Publication Number | Publication Date |
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MXPA00010538A true MXPA00010538A (en) | 2001-09-07 |
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