EP1436299A4 - Verfahren zur kristallisierung von 7-aminocephalosporansäure - Google Patents
Verfahren zur kristallisierung von 7-aminocephalosporansäureInfo
- Publication number
- EP1436299A4 EP1436299A4 EP02781906A EP02781906A EP1436299A4 EP 1436299 A4 EP1436299 A4 EP 1436299A4 EP 02781906 A EP02781906 A EP 02781906A EP 02781906 A EP02781906 A EP 02781906A EP 1436299 A4 EP1436299 A4 EP 1436299A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- aca
- additive
- aminocephalosporanic acid
- crystallization
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002425 crystallisation Methods 0.000 title claims description 24
- 230000008025 crystallization Effects 0.000 title claims description 23
- 239000000654 additive Substances 0.000 claims abstract description 26
- 230000000996 additive effect Effects 0.000 claims abstract description 25
- 239000013078 crystal Substances 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229940093499 ethyl acetate Drugs 0.000 claims description 4
- 235000019439 ethyl acetate Nutrition 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 229940031728 cocamidopropylamine oxide Drugs 0.000 claims description 3
- -1 glycerylmonostearte Chemical compound 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- JNAYPSWVMNJOPQ-UHFFFAOYSA-N 2,3-bis(16-methylheptadecanoyloxy)propyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC(C)C)COC(=O)CCCCCCCCCCCCCCC(C)C JNAYPSWVMNJOPQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 2
- LIFHMKCDDVTICL-UHFFFAOYSA-N 6-(chloromethyl)phenanthridine Chemical compound C1=CC=C2C(CCl)=NC3=CC=CC=C3C2=C1 LIFHMKCDDVTICL-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 claims description 2
- BTBJBAZGXNKLQC-UHFFFAOYSA-N ammonium lauryl sulfate Chemical compound [NH4+].CCCCCCCCCCCCOS([O-])(=O)=O BTBJBAZGXNKLQC-UHFFFAOYSA-N 0.000 claims description 2
- 229940063953 ammonium lauryl sulfate Drugs 0.000 claims description 2
- YSJGOMATDFSEED-UHFFFAOYSA-M behentrimonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCCCCCC[N+](C)(C)C YSJGOMATDFSEED-UHFFFAOYSA-M 0.000 claims description 2
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 150000001983 dialkylethers Chemical class 0.000 claims description 2
- REZZEXDLIUJMMS-UHFFFAOYSA-M dimethyldioctadecylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC REZZEXDLIUJMMS-UHFFFAOYSA-M 0.000 claims description 2
- SMVRDGHCVNAOIN-UHFFFAOYSA-L disodium;1-dodecoxydodecane;sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O.CCCCCCCCCCCCOCCCCCCCCCCCC SMVRDGHCVNAOIN-UHFFFAOYSA-L 0.000 claims description 2
- 239000004664 distearyldimethylammonium chloride (DHTDMAC) Substances 0.000 claims description 2
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 2
- SYELZBGXAIXKHU-UHFFFAOYSA-N dodecyldimethylamine N-oxide Chemical compound CCCCCCCCCCCC[N+](C)(C)[O-] SYELZBGXAIXKHU-UHFFFAOYSA-N 0.000 claims description 2
- 229940068939 glyceryl monolaurate Drugs 0.000 claims description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 2
- 229940073584 methylene chloride Drugs 0.000 claims description 2
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 2
- DCBSHORRWZKAKO-UHFFFAOYSA-N rac-1-monomyristoylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)CO DCBSHORRWZKAKO-UHFFFAOYSA-N 0.000 claims description 2
- 230000009257 reactivity Effects 0.000 claims description 2
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 claims description 2
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 claims description 2
- 229940117972 triolein Drugs 0.000 claims description 2
- ASKIVFGGGGIGKH-UHFFFAOYSA-N 2,3-dihydroxypropyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(O)CO ASKIVFGGGGIGKH-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- IXUSDMGLUJZNFO-BXUZGUMPSA-N (7R)-7-(4-carboxybutanamido)cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCCC(O)=O)[C@@H]12 IXUSDMGLUJZNFO-BXUZGUMPSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000008051 alkyl sulfates Chemical class 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 125000005908 glyceryl ester group Chemical group 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 102000004674 D-amino-acid oxidase Human genes 0.000 description 2
- 108010003989 D-amino-acid oxidase Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 1
- 241001019659 Acremonium <Plectosphaerellaceae> Species 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 229960001124 trientine Drugs 0.000 description 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 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
- 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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
Definitions
- the present invention relates to a method for preparing 7- aminocephalosporanic acid (7-ACA) crystals from 7-aminocephalosporanic acid solution by using additive and acid.
- 7-ACA is used as an intermediate for synthesis of various cephalosporins.
- Cephalosporin antibiotics refer to antibiotics prepared from cephalosporin C (CPC), and CPC is generally isolated from fermentation product of Acremonium chrysogenium.
- Methods of preparing 7-ACA from CPC as raw material are divided into chemical process and enzymatic process. Synthesis of 7-ACA based on the chemical process requires a multi-step reaction at ultralow temperature, and includes problems, remaining of toxic solvent within final product or environmental pollution, accordingly, lately, enzymatic process has been developed and used.
- Representative method of the enzymatic process consists of, first, inverting CPC into glutaryl-7- aminocephalosporanic acid (G1-7-ACA) by reacting with D-amino acid oxidase (DAOD) as shown in reaction formula 1, then reacting G1-7-ACA with G1-7-ACA acylase to obtain 7- AC A as shown in reaction formula 2.
- DAOD D-amino acid oxidase
- Adjusting of pH value of the 7- AC A solution prepared via chemical process or enzymatic process with acid to isoelectric point leads to formation of crystals, and by filtration, 7-ACA crystals can be isolated from medium.
- the shape of 7-ACA crystals influences purity, that is, the larger and harder the crystals are, the higher the purity is, due to ease of filtration and wash, while the smaller and softer the crystals are, the lower the purity is, due to difficulty of filtration and wash.
- precipitation of 7-ACA after the reaction leads to formation of small and soft particles sticking together, causing difficulty of filtration and wash, resulting in lower purity.
- Korean Patent Application No. 1999-7011246 discloses attempts to raise yield by adding organic solvent such as methanol or acetone. Though this method improved granularity to some degree, but the effect was not enough.
- Korean Patent Application No. 1999-7011246 discloses attempts to raise yield by adding organic solvent such as methanol or acetone. Though this method improved granularity to some degree, but the effect was not enough.
- Korean Patent Application No. 1999-7011246 discloses attempts to raise yield by adding organic solvent such as methanol or acetone. Though this method improved granularity to some degree, but the effect was not enough.
- 1999-7011246 discloses a method of using additives such as Cycep 2411R (Cytec), polyacryl such as P3-pherocryl 7262R, organic carboxylic acid ester such as ethylacetate or butylacetate, polyamine such as C 592R(Cytec), polymeric glycol such as PEG 300R (Fluka), amines such as triethylene tetramine or tris-(2-aminoethyl)amine and amino acids such as lysine.
- Korean Patent Application No. 1999-7011246 includes a disclosure on method of isolating 7-ACA by using organic solvent such as methanol or acetone along with the additive or by dropping a portion of solution to the rest thereof.
- the present invention was conceived to resolve the previous problems as described above, and the object of the present invention lies in providing a method for preparing 7-ACA crystals with improved granularity and purity in a high yield through crystallizing 7-aminocephalosporanic acid by using additive and acid.
- the present invention relates to a method for preparing 7- aminocephalosporanic acid (7-ACA) crystals from 7-aminocephalosporanic acid solution by using additive and acid.
- an alkylsulfate of the following formula 1 an amineoxide of formula 2, a quarternary ammonium of formula 3 and a glycerylester of formula 4 can be used alone or in a combination of two or more.
- Ri represents C 1-2 2 alkyl, phenyl, naphthyl or dialkylether
- R 2 , R , R 4 and R 5 represent independently hydrogen, - 22 alkyl, phenyl or naphthyl
- X represents CI, Br or I
- R ⁇ , R 7 and R 8 represent independently hydrogen, C 1 - 22 alkyl, phenyl, naphthyl, OH or R 2 COO (said alkyl, phenyl or naphthyl is unsubstituted or substituted with a group without chemical reactivity toward 7-ACA).
- alkylsulfate of the formula 1 sodiumlaurylsulfate, sodiumlaurylethersulfate, ammoniumlaurylsulfate, triethanolaminelaurylsulfate etc. can be enumerated.
- amineoxide of the formula 2 lauryldimethylamineoxide, cocamidopropylamineoxide and laurylpolyethylenedimethylamineoxide etc. can be enumerated.
- lauryltrimethylamrnoniumchloride, cetyltrimethylammoniumchloride, distearyldimethylammoniumchloride, stearyldimethylbenzylammoniumchloride, lauryldimethylbenzylamrnoniumchloride, stearylditrimethylammoniumchloride and behenyltrimethylammoniumchloride etc. can be used.
- glycerylmonolaurate glycerylmonomyristate, glycerylmonostearte, glycerylmonoisostearte, glycerylmonooleate, glyceryltricaprylate, glyceryltrioleate and glyceryltriisostearate etc.
- glycerylmonolaurate glycerylmonomyristate
- glycerylmonostearte glycerylmonoisostearte
- glycerylmonooleate glyceryltricaprylate, glyceryltrioleate and glyceryltriisostearate etc.
- sodiumlaurylsulfate as an alkylsulfate
- cocamidopropylamineoxide as an amineoxide
- lauryltrimethylammoniumchloride as a quartemary ammomum
- glycerylmonostearte and glyceryltricaprylate as glycerylester.
- hydrochloric acid As the acid, hydrochloric acid, sulfuric acid and acetic acid can be used alone or in a combination of two or more.
- the crystallization method of the present invention can be explained in detail as follows. First, additive is added to 7-ACA solution.
- the 7-ACA solution is a solution converted from CPC by enzymatic process, and concentration of a range of 10 to 40g/L is preferred.
- the amount of additive is preferred to be 0.001 to 5%(w/v) to 7- ACA solution. Addition of acid leads to precipitation of 7-ACA, and for a high yield, it is advantageous to adjust pH value to isoelectric point.
- Temperature at the time of crystallization is 0 to 30°C, preferably 2 to 15°C.
- 7-ACA crystallized according to the present invention is filtered by centrifuging, washed with water and acetone, and vacuum dried at 25 to 45°C.
- organic solvent in addition to the additive improves granularity and purity of 7-ACA crystals, thus preferable.
- organic solvent one or more solvent selected from the group consisting of ethylacetate, carbon tetrachloride, dichloroethane, trichloroethane, methylenechloride, chloroform and methylisobutylketone can be used.
- Organic solvent is added along with the additive, and the amount of organic solvent is 0.5 to 60%(v/v) to 7-ACA solution, preferably 0.5 to 10%(v/v).
- Fig. 1 shows crystal form of 7-aminocephalosporanic acid obtained according to Comparative Example 1 of the present invention.
- Fig. 2 represents crystal form of 7-aminocephalosporanic acid obtained according to Example 1 of the present invention.
- Fig.3 shows crystal form of 7-aminocephalosporanic acid obtained according to Example 23 of the present invention.
- Examples 1 to 22 Crystallization of 7- AC A using additive and acid Additive is added to 7-ACA solution (about HOmM) l,000mL, stirred for
- Example 1 Example 1 , Example 1 and Example 23 were analyzed and the result is shown in Table 9.
- the content of 7-ACA was determined with HPLC analysis (measurement at 254nm) by dissolving lOmg of 7-ACA prepared in accordance with said Comparative Example 1, Example 1 and Example 23 in pH 7.3 phosphate buffer lOOmL HPLC was carried out in accordance with Liquid Chromatography of General Test Methods, Korea Pharmacopoeia, and the content was calculated based on relative peak area.
- the content of sample means relative value against the analysis result for standard substance by the same method, and was calculated by the following equation 1.
- Example 7-ACA prepared according to said Comparative Example 1, Example 1 and Example 23 were, respectively, filled in lOOmL graduated cylinder to 50mL without compacting, and the weight was measured and bulk density was calculated.
- the content of 7- AC A in case of crystallization using additive and acid according to the present invention was at least 96%>, higher than that in case of crystallization using acid (Comparative Example 1), 92.3%.
- the content of 7-ACA was at least 98%>, showing very good purity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20010061681 | 2001-10-06 | ||
| KR2001061681 | 2001-10-06 | ||
| PCT/KR2002/001851 WO2003031451A1 (en) | 2001-10-06 | 2002-10-04 | Method for crystallization of 7-aminocephalosporanic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1436299A1 EP1436299A1 (de) | 2004-07-14 |
| EP1436299A4 true EP1436299A4 (de) | 2005-01-19 |
Family
ID=19714924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02781906A Withdrawn EP1436299A4 (de) | 2001-10-06 | 2002-10-04 | Verfahren zur kristallisierung von 7-aminocephalosporansäure |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1436299A4 (de) |
| KR (1) | KR100509737B1 (de) |
| CN (1) | CN1697837A (de) |
| WO (1) | WO2003031451A1 (de) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321099A (zh) * | 2011-08-15 | 2012-01-18 | 华北制药河北华民药业有限责任公司 | 一种头孢烷酸的结晶方法 |
| CN103014114B (zh) * | 2012-12-27 | 2014-12-10 | 华北制药河北华民药业有限责任公司 | 一种酶法制备7-氨基头孢烷酸的方法 |
| CN113150010A (zh) * | 2021-04-19 | 2021-07-23 | 瑞阳制药股份有限公司 | 一种7-氨基头孢烷酸纯化工艺 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5142042A (en) * | 1989-01-23 | 1992-08-25 | Purzer Pharmaceutical Co., Ltd. | Process for preparing well crystallized alkali metal salts of 3, 7-substituted 7-aminocephalosporanic acid derivatives |
| JPH088877B2 (ja) * | 1990-06-19 | 1996-01-31 | 塩野義製薬株式会社 | デアセチル―７―アミノセファロスポラン酸の製造法 |
| DE4026630A1 (de) * | 1990-08-23 | 1992-02-27 | Hoechst Ag | Verfahren zur herstellung von kristalliner tacs |
| JPH10291993A (ja) * | 1997-02-19 | 1998-11-04 | Takeda Chem Ind Ltd | セファロスポリン誘導体の結晶及びその製造法 |
| KR100748387B1 (ko) * | 1997-06-04 | 2007-08-10 | 산도즈 게엠베하 | 7-아미노세팔로스포란산(7-ａｃａ)의 개선된 침전 방법 |
| KR100383136B1 (ko) * | 2000-12-20 | 2003-05-12 | 씨제이 주식회사 | 7-아미노세팔로스포라닌산의 결정화 방법 |
-
2002
- 2002-10-04 EP EP02781906A patent/EP1436299A4/de not_active Withdrawn
- 2002-10-04 CN CNA028195434A patent/CN1697837A/zh active Pending
- 2002-10-04 WO PCT/KR2002/001851 patent/WO2003031451A1/en not_active Ceased
- 2002-10-04 KR KR10-2002-0060489A patent/KR100509737B1/ko not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100509737B1 (ko) | 2005-08-23 |
| KR20030029500A (ko) | 2003-04-14 |
| EP1436299A1 (de) | 2004-07-14 |
| WO2003031451A1 (en) | 2003-04-17 |
| CN1697837A (zh) | 2005-11-16 |
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