WO1999055710A1 - Procede de cristallisation d'une beta-lactamine - Google Patents
Procede de cristallisation d'une beta-lactamine Download PDFInfo
- Publication number
- WO1999055710A1 WO1999055710A1 PCT/NL1999/000246 NL9900246W WO9955710A1 WO 1999055710 A1 WO1999055710 A1 WO 1999055710A1 NL 9900246 W NL9900246 W NL 9900246W WO 9955710 A1 WO9955710 A1 WO 9955710A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lactam
- crystallized
- nitric acid
- acid
- solution
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- 239000003782 beta lactam antibiotic agent Substances 0.000 title claims description 18
- 239000002132 β-lactam antibiotic Substances 0.000 title claims description 18
- 229940124586 β-lactam antibiotics Drugs 0.000 title claims description 18
- 150000003952 β-lactams Chemical class 0.000 claims abstract description 70
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims description 37
- 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 20
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- -1 alkali metal salt Chemical class 0.000 claims description 10
- 239000012670 alkaline solution Substances 0.000 claims description 6
- 229960003022 amoxicillin Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 150000004679 hydroxides Chemical class 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229960000723 ampicillin Drugs 0.000 claims description 3
- 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 3
- 229960005361 cefaclor Drugs 0.000 claims description 3
- 229960004841 cefadroxil Drugs 0.000 claims description 3
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.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 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 claims description 3
- 229960002580 cefprozil Drugs 0.000 claims description 3
- 229940106164 cephalexin Drugs 0.000 claims description 3
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin 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 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 2
- NLARCUDOUOQRPB-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-UHFFFAOYSA-N 0.000 claims description 2
- JBJJTCGQCRGNOL-UHFFFAOYSA-N 2-azaniumyl-2-cyclohexa-1,4-dien-1-ylacetate Chemical compound OC(=O)C(N)C1=CCC=CC1 JBJJTCGQCRGNOL-UHFFFAOYSA-N 0.000 claims description 2
- PGUPJAPHYIEKLT-UHFFFAOYSA-N 2-pyridin-4-ylsulfanylacetic acid Chemical compound OC(=O)CSC1=CC=NC=C1 PGUPJAPHYIEKLT-UHFFFAOYSA-N 0.000 claims description 2
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical compound OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 claims description 2
- GCOOGCQWQFRJEK-UHFFFAOYSA-N 2-thiophen-3-ylpropanedioic acid Chemical compound OC(=O)C(C(O)=O)C=1C=CSC=1 GCOOGCQWQFRJEK-UHFFFAOYSA-N 0.000 claims description 2
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 claims description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 claims description 2
- 229960003012 cefamandole Drugs 0.000 claims description 2
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 claims description 2
- 229960003719 cefdinir Drugs 0.000 claims description 2
- 229960002100 cefepime Drugs 0.000 claims description 2
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 claims description 2
- 229960004261 cefotaxime Drugs 0.000 claims description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].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 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims description 2
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- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 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 2
- 229960002457 epicillin Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-N 0.000 claims description 2
- 229960001977 loracarbef Drugs 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
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- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 230000003068 static effect Effects 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 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 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
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- 229960004920 amoxicillin trihydrate Drugs 0.000 description 14
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- 239000002253 acid Substances 0.000 description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 5
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- 238000000354 decomposition reaction Methods 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Definitions
- the invention relates to a method for crystallizing a ⁇ -lactam and to a ⁇ -lactam obtainable by said method.
- ⁇ -lactam as used herein includes ⁇ - lactam nuclei, for example 6-aminopenicillanic acid (6- APA), 7-aminocephalosporanic acid (7-ACA) , 3-chloro-7- aminodesacetoxydesmethylcephalosporanic acid (7-ACCA) , and 7-amino-3- [ [ (l-methyl-l-H-tetrazol-5- yl) thio] methyl] -3-cephem-4-carboxylic acid (7-ATCA) , 7- aminodesacetylcephalosporanic acid (7-ADAC) , and 7- aminodesacetoxycephalosporanic acid (7-ADCA) , fermentation products, for example penicillin G, penicillin V, cephalosporin C, isopenicillin N, intermediate products for example adipyl-6- aminopenicillanic acid, adipyl-7-aminodesacetoxy- cephalosporanic acid (adipyl-7
- ⁇ -lactams have received a lot of attention, because many compounds of this class show antimicrobial activity.
- the ⁇ -lactam antibiotics for example penicillin and cephalosporin antibiotics, are useful because of their antimicrobial activity and play an important role in medicine.
- This class of antibiotics comprises a great variety of compounds, all having their own activity profile.
- ⁇ -lactam antibiotics consist of a nucleus, the so-called ⁇ -lactam nucleus, which is linked through its primary amino group to the so-called side chain via a linear amide bond.
- the synthesis of a ⁇ - lactam antibiotic generally comprises the preparation of a ⁇ -lactam nucleus from fermentation products for example isopenicillin N, penicillin G, penicillin V and cephalosporin C.
- the obtained ⁇ -lactam nucleus is subsequently attached to one of several possible side chains to obtain the antibiotic product.
- the intermediate product and the final product i.e. the ⁇ -lactam nucleus and the ⁇ - lactam antibiotic
- the ⁇ -lactam is isolated from a reaction mixture and purified by crystallization in a procedure which is essentially the same as the procedure that would be performed if the - 3 -
- the conventional crystallization processes start from a hydrochloric acid solution of the ⁇ - lactam, from which the product is crystallized by addition of an alkaline solution, usually an NaOH solution. It has been found that the yield of these conventional crystallization processes is rather low. This is most likely due to a significant loss of product to the mother liquor. Surprisingly, it has now been found, that the yield of a crystallization process of a ⁇ -lactam can be increased by starting from a solution of the ⁇ - lactam in nitric acid. Accordingly, the invention provides a method for crystallizing a ⁇ -lactam, wherein the ⁇ -lactam is crystallized from a nitric acid solution.
- a great advantage of the invention is that the volumetric throughput of a large scale production process of ⁇ -lactam is increased. It has been found that, when the ⁇ -lactam is crystallized from a nitric acid solution, it is feasible to perform the crystallization process using higher concentrations of ⁇ -lactam than hitherto have been thought possible. As a result, less reactor volume is needed in order to obtain an equal amount of ⁇ -lactam.
- a ⁇ -lactam that may be crystallized in a method according to the invention preferably has the general formula (I) :
- R 0 is hydrogen or C 1-3 alkoxy
- Rx is hydrogen or a side chain derived from an organic acid
- Y is CH 2 , oxygen, sulfur, or an oxidized form of sulfur
- R 2 is hydrogen, hydroxy, halogen, C 1-3 alkoxy, optionally substituted, optionally containing one or more heteroatoms, saturated or unsaturated, branched or straight C 1-5 alkyl, optionally substituted, optionally containing one or more heteroatoms, C 5-8 cycloalkyl , - 5
- R 2 is -H, - Cl, -OH, -OCH 3 , -CH 2 0H, -CH 2 CL or -CH 2 OC (O) CH 3 .
- Formula (I) is intended to encompass all ⁇ - lactams as disclosed in "Cephalosporins and
- an oxidized form of sulfur is meant to include groups for example sulfoxide and sulfone.
- groups for example sulfoxide and sulfone.
- alkyl, cycloalkyl, aryl, heteroaryl and benzyl, groups are intended, which have substituents for example alkyl groups of from 1 to 3 carbon atoms .
- ⁇ -lactams to be crystallized in a method according to the invention are ⁇ -lactam antibiotics comprising a ⁇ -lactam nucleus coupled to a side chain.
- ⁇ -lactams are those having formula (I) wherein R x is a side chain.
- Preferred side chains coupled to a ⁇ -lactam nucleus in a ⁇ -lactam antibiotic to be crystallized in a method according to the invention are D-(-)- phenylglycine, D- (-) -4-hydroxyphenylglycine, D-(-)-2,5- dihydrophenylglycine, 2-thienylacetic acid, 2-(2-amino- 4-thiazolyl) -2-methoxyiminoacetic acid, ⁇ - (4-pyridyl- thio) acetic acid, 3-thiophenemalonic acid, 2- cyanoacetic acid, D-mandelic acid, 1-H-tetrazoleacetic acid, 2-furanyl- (Z) -methoxyiminoacetic acid, (2- aminothiazol-4-yl) acetic acid, (2-aminothiazol-4-yl) - (Z) -hydroxyiminoacetic acid, (2-aminothiazol-4-
- ⁇ -lactams to be crystallized in accordance with the invention are amoxicillin, ampicillin, cephalexin, cefaclor, cefadroxil, cephadrine, epicillin, cefamandole, cefotaxime, cefdinir, cefprozil, cefuroxim, cefepime, cefibuten, and loracarbef .
- the ⁇ -lactam to be crystallized is obtained synthetically.
- a ⁇ -lactam nucleus for example 6-APA, 7-ADCA, 7-ACA, 7-ACCA, 7- ATCA or 7-ADAC, or a derivative thereof is acylated, e.g. according to the so-called Dane process.
- the acylation is carried out with a Dane salt of a precursor for the desired side chain, e.g. a Dane salt of phenyl glycine.
- a Dane salt may be prepared by protecting the amine group of the precursor for the side chain as an enamine, and reacting the product thereof with a reactive acid to a form a mixed anhydride.
- the Dane process has been described in, among others, US-A-4 , 358 , 588 and EP-A-0 439 096.
- the amine group has to be deprotected.
- the deprotection reaction is usually an acidic hydrolysis wherein the protective group is split off.
- the deprotection step can be advantageously be carried out in si tu by using nitric acid to facilitate the acidic hydrolysis.
- the ⁇ - lactam to be crystallized is obtained enzymatically.
- a ⁇ -lactam nucleus is to be crystallized, it can 7 -
- a ⁇ -lactam antibiotic When a ⁇ -lactam antibiotic is to be crystallized, it is preferably obtained by enzymatic acylation. This means, that a suitable ⁇ -lactam nucleus or a salt thereof is reacted with a suitable precursor for a side chain in the presence of a suitable enzyme, for example a penicillin acylase. Enzymes may be isolated from various naturally occurring micro organisms, for example fungi and bacteria.
- Organisms that have been found to produce penicillin acylase are, for example, Acetobacter, Aeromonas, Alcaligenes , Aphanocladium, Bacillus sp., Cephalosporium, Escherichia , Flavobacterium, Kluyvera , Mycoplana, Protaminobacter, Pseudomonas or Xanthomonas species.
- the enzyme as the free enzyme or in any suitable immobilized form.
- functional equivalents of the enzyme wherein for instance properties of the enzyme, for example pH dependence, thermostability or specific activity may be affected by chemical modification or cross-linking.
- functional equivalents for example mutants or other derivatives, obtained by classic means or via recombinant DNA methodology, biologically active parts or hybrids of the enzymes may be used.
- Suitable salts of a ⁇ -lactam nucleus in this regard include any non-toxic salt, for example an alkali metal salt (e.g. lithium, potassium, sodium), an alkali earth metal salt (e.g. calcium, magnesium), an ammonium salt, or an organic base salt (e.g. trimethylamine , triethylamine, pyridine, picoline, dieyelohexylamine, N, N' -dibenzyl diethylene diamine) .
- an alkali metal salt e.g. lithium, potassium, sodium
- an alkali earth metal salt e.g. calcium, magnesium
- an ammonium salt e.g. trimethylamine , triethylamine, pyridine, picoline, dieyelohexylamine, N, N' -dibenzyl diethylene diamine
- the precursor for a side chain of the ⁇ - lactam antibiotic to be prepared in a method according to the invention may be any compound that is recognized by the above defined enzyme, for example penicillin acylase, and that leads to a product of the class of ⁇ - lactam antibiotics. It is possible to use the compound corresponding to the side chain in itself, but also derivatives thereof may be used. Suitable derivatives of these compounds are esters and amides, wherein the side chain molecule is connected to a C ⁇ -C 3 alkyl group through an ester or amide linkage.
- the enzyme is separated from the reaction mixture. This may for instance be done by filtration in case an enzyme is used in immobilized form. After separation of the enzyme, the thus obtained reaction mixture may be used as such in a method according to the invention or it may be further treated. Of course, it is also possible to combine the above described synthetic and enzymatic preparations of the ⁇ -lactam to be crystallized in accordance with the invention.
- the ⁇ -lactam starting material to be crystallized is dissolved using an aqueous nitric acid solution. It has been found that optimum results are obtained when the pH of the resulting nitric acid solution, wherein the ⁇ -lactam is dissolved, is between about 0.3 and about 2.0, preferably between about 0.5 and about 1.5.
- the concentration of the aqueous nitric acid solution to be added to the ⁇ -lactam starting material is preferably between 0.5 mol/liter and 11 mol/liter, more preferably between 5 and 10 mol/liter. It is also possible to use - 9 -
- the concentration of nitrate ions in the mixture wherein the ⁇ -lactam is present is at least 0.3 mol/liter. It is within the expertise of the skilled person to chose the amount of the inorganic acid other than nitric acid such that no (addition) salts of the ⁇ -lactam will be formed.
- the ⁇ -lactam is crystallized from a nitric acid solution, in which said ⁇ -lactam is present in a very high concentration.
- concentration of the ⁇ -lactam in the hydrochloric acid solution from which it is crystallized is generally about 0.35 moles/liter. It has now been found that an increased concentration of the ⁇ -lactam in the solution from which it is crystallized leads to a higher yield of the crystallization process. In this text yield is defined as moles of isolated crystal per moles of ⁇ -lactam starting material.
- a high concentration ⁇ -lactam in the nitric acid solution from which it is crystallized in accordance with this preferred embodiment is higher 10 -
- the ⁇ - lacta is crystallized from a nitric acid solution wherein it is present in a concentration of more than about 0.5 moles/liter. Most preferably, said concentration is higher than about 0.6 moles/liter.
- concentration of the ⁇ -lactam in the nitric acid solution from which it is crystallized There is no upper limit for the concentration of the ⁇ -lactam in the nitric acid solution from which it is crystallized. However, it will be evident that a concentration that is so high that crystallization of the ⁇ -lactam in the nitric acid solution starts spontaneously is not suitable.
- the ⁇ -lactam is preferably crystallized by the addition of an alkaline solution.
- an alkaline solution Particularly suited for this purpose are ammonia or hydroxide salt solutions. It is preferred that the hydroxide salt is an ammonium or alkali metal salt.
- the concentration of the alkaline solution will generally lie between about 0.5 and about 8 moles/liter. Preferably, said concentration lies between about 1.5 and about 2.5 moles/liter.
- the temperature, at which the method of the invention is performed, will generally lie between about -5°C and 50°C. Preferably, the temperature will lie between about 0°C and 15°C.
- the ⁇ -lactam will crystallize. Subsequently, the obtained ⁇ -lactam crystals are filtered off and dried in any suitable manner.
- the method of the invention is performed continuously.
- the advantages of this embodiment will be apparent to the skilled person and include short residence times, small losses of desired product due to a decrease in decomposition, and the possibility of using small installations - 11
- the ⁇ -lactam to be crystallized is dissolved into the nitric acid using a static mixer, which leads to a particularly efficient process.
- Amoxicillin trihydrate (132 g) was suspended in water (500 ml) and concentrated 12 M hydrochloric acid (40 ml) was added to give a pH of 0.7. In order to dissolve all material, water (1600 ml) was added. Amoxicillin trihydrate was crystallized by adding a 2M solution of sodium hydroxide in water until a pH value of 5.0 was reached. The crystals thus produced were isolated by means of filtration, washed with water (200 ml) and dried at 35°C during 16 h to give 123 g of Amoxicillin trihydrate. The mother liquor (2.62 1) contained 8.5 g of dissolved Amoxicillin trihydrate .
- Amoxicillin trihydrate 133 g was suspended in water (500 ml) and 8M solution of nitric acid in water (60 ml) was added to give a pH of 0.7.
- Cefaclor monohydrate (11.0 g) was suspended in water (55 ml) and 9.4 M sulfuric acid (7.3 g) was added to give a pH of 1.0. In order to dissolve all material, water (106 ml) is added while the pH is maintained at 1.0 using 9.4 M sulfuric acid (14.3 g) . Cefaclor monohydrate was crystallized by adding a 25% solution of ammonia in water (8.9 ml) until a pH value of 6.2 was reached.
- the crystals thus produced were isolated by means of filtration, washed with water (15 ml) and dried for 16 h at 20°C under vacuum to give 8.2 g of Cefaclor monohydrate.
- the mother liquor (198 g) contained 2.7 g of dissolved Cefaclor monohydrate.
- Cefaclor monohydrate (11.0 g) was suspended in water (55 ml) and 4 M nitric acid (8.1 g) was added to give a pH of 1.0.
- water 31 ml is added while the pH is maintained at 1.0 using 4 M nitric acid (2.5 g) .
- Cefaclor monohydrate was crystallized by adding a 25% solution of ammonia in water (3.8 ml) until a pH value of 6.2 was reached. The crystals thus produced were isolated by means of filtration, washed with water (15 - 13 -
- the temperature was maintained at 20°C and the pH was kept at 3.7 with the aid of 2 M sodium hydroxide solution.
- the volume in the crystallizer was kept at 1800 ml by continuously transferring the contents to a second crystallizer.
- the temperature was maintained at 20°C and the pH was kept at 5.0 with the aid of 2 M sodium hydroxide solution.
- the volume in the second crystallizer was kept at 1000 ml by continuously - 14 -
- the contents of the dissolution vessel were filtered and added to the first crystallizer, in which the above conditions were maintained. Subsequently, the contents of the first crystallizer were transferred to the second crystallizer, in which the above conditions were maintained, followed by transfer of the contents of the second crystallizer to the buffer vessel.
- the total amount of 8 M nitric acid solution consumed was 625 ml.
- the total amount of 2 M sodium hydroxide solution consumed was 2500 ml.
- the contents of the buffer were cooled to 2°C and kept at this temperature for more than 2 hours.
- the resulting crystal suspension was filtered and washed with 1500 ml water.
- the filter cake was dried in a ventilation stove at 35°C.
- the final yield of amoxicillin trihydrate (assay 99.5%) (assay is defined here as gram amoxicillin trihydrate per gram crystal * 100%) was
- the mother liquor contained approximately 26 g (1.8%) amoxicillin trihydrate.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99917236A EP1075479A1 (fr) | 1998-04-29 | 1999-04-27 | Procede de cristallisation d'une beta-lactamine |
KR1020007011901A KR20010043038A (ko) | 1998-04-29 | 1999-04-27 | β-락탐 항생제의 결정화 방법 |
BR9910085-1A BR9910085A (pt) | 1998-04-29 | 1999-04-27 | Processo para a cristalização de um antibiótico de beta-lactama |
AU35395/99A AU3539599A (en) | 1998-04-29 | 1999-04-27 | A method for crystallizing a beta-lactam antibiotic |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98201398.9 | 1998-04-29 | ||
EP98201398 | 1998-04-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999055710A1 true WO1999055710A1 (fr) | 1999-11-04 |
Family
ID=8233663
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL1999/000246 WO1999055710A1 (fr) | 1998-04-29 | 1999-04-27 | Procede de cristallisation d'une beta-lactamine |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1075479A1 (fr) |
KR (1) | KR20010043038A (fr) |
CN (1) | CN1298408A (fr) |
AU (1) | AU3539599A (fr) |
BR (1) | BR9910085A (fr) |
ID (1) | ID26418A (fr) |
PE (1) | PE20000879A1 (fr) |
TR (1) | TR200003131T2 (fr) |
WO (1) | WO1999055710A1 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2004085443A1 (ja) * | 2003-03-24 | 2006-06-29 | ア・チ・エツセ・ドブフアル・エツセ・ピー・アー | 7−[2−(2−アミノチアゾール−4−イル)−2−ヒドロキシイミノアセトアミド−3−ビニル−3−セフェム−4−カルボン酸(シン異性体)の新規結晶およびその製造方法 |
US7250508B2 (en) | 2002-08-13 | 2007-07-31 | Sandoz Ag | Cefdinir intermediate |
US7307072B2 (en) | 2004-11-30 | 2007-12-11 | Astellas Pharma Inc. | Oral pharmaceutical suspension of Cefdinir crystal |
US7534781B2 (en) * | 2003-03-21 | 2009-05-19 | Dsm Ip Assets B.V. | Crystalline amoxicillin trihydrate powder |
US20100010213A1 (en) * | 2006-05-19 | 2010-01-14 | Carlos Enrique Lenhard | Process for the crystallisation of cefadroxil |
CN103145733A (zh) * | 2013-03-20 | 2013-06-12 | 四川省惠达药业有限公司 | 一种阿莫西林化合物及该化合物和克拉维酸钾的药物组合物 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104059086B (zh) * | 2014-06-19 | 2016-04-13 | 河南牧翔动物药业有限公司 | 一种阿莫西林晶体及其制备方法 |
CN104830523B (zh) * | 2015-05-15 | 2018-01-09 | 湖北民族学院 | 一种高品质植物油的无公害生产装置及生产植物油的方法 |
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EP0261823A1 (fr) * | 1986-09-24 | 1988-03-30 | Tanabe Seiyaku Co., Ltd. | Hydrate de dérivé de pénicilline stable et procédé de préparation |
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1999
- 1999-04-16 PE PE1999000315A patent/PE20000879A1/es not_active Application Discontinuation
- 1999-04-27 KR KR1020007011901A patent/KR20010043038A/ko not_active Withdrawn
- 1999-04-27 WO PCT/NL1999/000246 patent/WO1999055710A1/fr not_active Application Discontinuation
- 1999-04-27 BR BR9910085-1A patent/BR9910085A/pt not_active Application Discontinuation
- 1999-04-27 EP EP99917236A patent/EP1075479A1/fr not_active Withdrawn
- 1999-04-27 ID IDW20002187A patent/ID26418A/id unknown
- 1999-04-27 AU AU35395/99A patent/AU3539599A/en not_active Abandoned
- 1999-04-27 CN CN99805572A patent/CN1298408A/zh active Pending
- 1999-04-27 TR TR2000/03131T patent/TR200003131T2/xx unknown
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GB599854A (en) * | 1944-06-19 | 1948-03-23 | Shell Dev | Separation of non-neutral electrolytes |
EP0261823A1 (fr) * | 1986-09-24 | 1988-03-30 | Tanabe Seiyaku Co., Ltd. | Hydrate de dérivé de pénicilline stable et procédé de préparation |
RU2024851C1 (ru) * | 1992-07-22 | 1994-12-15 | Шорманов Владимир Камбулатович | СПОСОБ ОПРЕДЕЛЕНИЯ 6-(D-α -АМИНОФЕНИЛАЦЕТАМИДО)-ПЕНИЦИЛЛАНОВОЙ КИСЛОТЫ НАТРИЕВОЙ СОЛИ |
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Cited By (13)
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US7825241B2 (en) | 2002-08-13 | 2010-11-02 | Sandoz Ag | Cefdinir intermediate |
US7250508B2 (en) | 2002-08-13 | 2007-07-31 | Sandoz Ag | Cefdinir intermediate |
US7534781B2 (en) * | 2003-03-21 | 2009-05-19 | Dsm Ip Assets B.V. | Crystalline amoxicillin trihydrate powder |
EP1609793A4 (fr) * | 2003-03-24 | 2008-06-25 | Sandoz Ag | Nouveau cristal de 7- 2-(2-aminothiazole-4-yl)-2-hydroxyimin oacetamido-3-vinyl-3-cephem-4-acide carboxylique (isomere synthetique) et procede de preparation de celui-ci |
JPWO2004085443A1 (ja) * | 2003-03-24 | 2006-06-29 | ア・チ・エツセ・ドブフアル・エツセ・ピー・アー | 7−[2−(2−アミノチアゾール−4−イル)−2−ヒドロキシイミノアセトアミド−3−ビニル−3−セフェム−4−カルボン酸(シン異性体)の新規結晶およびその製造方法 |
US7307072B2 (en) | 2004-11-30 | 2007-12-11 | Astellas Pharma Inc. | Oral pharmaceutical suspension of Cefdinir crystal |
US7351419B2 (en) | 2004-11-30 | 2008-04-01 | Astellas Pharma Inc. | Oral pharmaceutical suspension of Cefdinir crystal |
US20100010213A1 (en) * | 2006-05-19 | 2010-01-14 | Carlos Enrique Lenhard | Process for the crystallisation of cefadroxil |
US8420806B2 (en) * | 2006-05-19 | 2013-04-16 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the crystallisation of cefadroxil monohydrate |
EP2754663A1 (fr) | 2006-05-19 | 2014-07-16 | DSM Sinochem Pharmaceuticals Netherlands B.V. | Procédé pour la préparation de cefadroxil |
CN102351884B (zh) * | 2006-05-19 | 2015-06-17 | 中化帝斯曼制药有限公司荷兰公司 | 一种用于结晶头孢羟氨苄的方法 |
CN103145733A (zh) * | 2013-03-20 | 2013-06-12 | 四川省惠达药业有限公司 | 一种阿莫西林化合物及该化合物和克拉维酸钾的药物组合物 |
CN103145733B (zh) * | 2013-03-20 | 2014-02-26 | 四川省惠达药业有限公司 | 一种阿莫西林化合物及该化合物和克拉维酸钾的药物组合物 |
Also Published As
Publication number | Publication date |
---|---|
PE20000879A1 (es) | 2000-09-23 |
EP1075479A1 (fr) | 2001-02-14 |
KR20010043038A (ko) | 2001-05-25 |
TR200003131T2 (tr) | 2001-01-22 |
CN1298408A (zh) | 2001-06-06 |
AU3539599A (en) | 1999-11-16 |
ID26418A (id) | 2000-12-21 |
BR9910085A (pt) | 2000-12-26 |
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