CN101321771B - Process for the preparation of a potassium salt of penicillin - Google Patents
Process for the preparation of a potassium salt of penicillin Download PDFInfo
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- CN101321771B CN101321771B CN2006800452303A CN200680045230A CN101321771B CN 101321771 B CN101321771 B CN 101321771B CN 2006800452303 A CN2006800452303 A CN 2006800452303A CN 200680045230 A CN200680045230 A CN 200680045230A CN 101321771 B CN101321771 B CN 101321771B
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- Prior art keywords
- penicillin
- potassium
- water
- group
- butyl acetate
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Links
- 238000000034 method Methods 0.000 title claims abstract description 14
- 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 title claims description 132
- 229930182555 Penicillin Natural products 0.000 title claims description 23
- 229940049954 penicillin Drugs 0.000 title claims description 23
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title abstract description 3
- 229940056360 penicillin g Drugs 0.000 claims description 55
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 44
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 25
- 229910052700 potassium Inorganic materials 0.000 claims description 25
- 239000011591 potassium Substances 0.000 claims description 25
- 238000001704 evaporation Methods 0.000 claims description 17
- 230000008020 evaporation Effects 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 13
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid 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 description 9
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- OAIYNRAQCIOEBD-UHFFFAOYSA-N butyl acetate;hydrate Chemical compound O.CCCCOC(C)=O OAIYNRAQCIOEBD-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- 229930195708 Penicillin V Natural products 0.000 claims 4
- 229940056367 penicillin v Drugs 0.000 claims 4
- 150000002960 penicillins Chemical class 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 abstract description 3
- HCTVWSOKIJULET-LQDWTQKMSA-M phenoxymethylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1 HCTVWSOKIJULET-LQDWTQKMSA-M 0.000 abstract 2
- 241000228143 Penicillium Species 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000003960 organic solvent Substances 0.000 description 33
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 28
- 239000001103 potassium chloride Substances 0.000 description 28
- 235000011164 potassium chloride Nutrition 0.000 description 28
- 238000005516 engineering process Methods 0.000 description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 238000000855 fermentation Methods 0.000 description 8
- 230000004151 fermentation Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 108700023418 Amidases Proteins 0.000 description 5
- 102000005922 amidase Human genes 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical group CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OPEGYZAATHKDEM-HCWXCVPCSA-N (2r,4s)-2-[(r)-carboxy(formamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid Chemical compound CC1(C)S[C@H]([C@H](NC=O)C(O)=O)N[C@H]1C(O)=O OPEGYZAATHKDEM-HCWXCVPCSA-N 0.000 description 2
- LRWFMQCGNBOTQP-UHFFFAOYSA-N 5,5-dimethyl-2-[[(2-phenylacetyl)amino]methyl]-1,3-thiazolidin-3-ium-4-carboxylate Chemical compound N1C(C(O)=O)C(C)(C)SC1CNC(=O)CC1=CC=CC=C1 LRWFMQCGNBOTQP-UHFFFAOYSA-N 0.000 description 2
- WNPVZANXRCPJPW-UHFFFAOYSA-N 5-[isocyano-(4-methylphenyl)sulfonylmethyl]-1,2,3-trimethoxybenzene Chemical compound COC1=C(OC)C(OC)=CC(C([N+]#[C-])S(=O)(=O)C=2C=CC(C)=CC=2)=C1 WNPVZANXRCPJPW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000002028 Biomass Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108010073038 Penicillin Amidase Proteins 0.000 description 2
- 241000228150 Penicillium chrysogenum Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000589634 Xanthomonas Species 0.000 description 2
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 230000020176 deacylation Effects 0.000 description 2
- 238000005947 deacylation reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- YCOFRPYSZKIPBQ-UHFFFAOYSA-N penicillic acid Natural products COC1=CC(=O)OC1(O)C(C)=C YCOFRPYSZKIPBQ-UHFFFAOYSA-N 0.000 description 2
- VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 241000589220 Acetobacter Species 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- 241000588986 Alcaligenes Species 0.000 description 1
- 241000588813 Alcaligenes faecalis Species 0.000 description 1
- 241000726092 Aphanocladium Species 0.000 description 1
- 241000194107 Bacillus megaterium Species 0.000 description 1
- 241000194110 Bacillus sp. (in: Bacteria) Species 0.000 description 1
- 241001619326 Cephalosporium Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- 241000588752 Kluyvera Species 0.000 description 1
- 241000721603 Mycoplana Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000586779 Protaminobacter Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- CUXSAAMWQXNZQW-UHFFFAOYSA-N acetic acid;butan-1-ol Chemical compound CC(O)=O.CCCCO CUXSAAMWQXNZQW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940005347 alcaligenes faecalis Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- -1 hydroxyl penicillin G Chemical compound 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
Classifications
-
- 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
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了从包含青霉素G钾盐(Pen G K)或青霉素V钾盐(PenV K)、有机溶剂和C1至C3的醇的悬浮液制备晶体形式的青霉素G钾盐(Pen G K)或青霉素V钾盐(Pen V K)的工艺。 The present invention discloses the preparation of penicillin G potassium salt (Pen GK) or penicillin V potassium salt (Pen GK ) or Process for Penicillin V Potassium Salt (Pen VK).
Description
The present invention relates to prepare the technology of the potassium penicillin G (Pen G K) or the DQV-K (Pen V K) of crystalline form.
Penicillium mould is normally produced from zymotechnique with microorganism strains, and said bacterial strain can be produced penicillium mould when having suitable side chain precursor.For example, penicillin G is through when having the side chain precursor toluylic acid, being produced by the selected bacterial strain of Penicillium chrysogenum.After the fermentation, depend on the type of penicillium mould,, from fermentation culture, reclaim penicillium mould according to currently known methods.
Reclaim in the technology at the typical prior art penicillin G; Fermentation culture to obtaining filters, the washing filter residue, afterwards; After to the filtrate acidifying, the penicillin G that exists in the filtrate of collecting is extracted in the organic solvent (for example n-butyl acetate or hexone).Can under gac is assisted, decolour then, and penicillin G acid is stripped in the water, use the sylvite aqueous solution (for example potassium acetate) to neutralize again the extract that obtains thus.With this solution and q.s second solvent (for example propyl carbinol) mix, use the evaporation of n-butanol-water azeotrope to reduce water-content afterwards, through filtering and subsequently washing and drying, reclaim the penicillin G K crystal that forms again.The shortcoming that this prior art reclaims technology is that during its n-butanol-water azeotrope evaporation, because the degraded of Pen G K, Pen G K is loss in a large number, causes the productive rate of Pen G K significantly to reduce (for example,＜92%).
In another kind of prior art processes; Directly obtain crystallization Pen G K from above-mentioned extract, this is then to carry out the azeotrope evaporation through adding potassium acetate or other suitable potassium source, refilters the Pen G K crystal of formation; It is suspended in the propyl carbinol, and filtration and drying realize.The shortcoming that this prior art reclaims technology is that afterwards, mother liquor had both comprised propyl carbinol and also comprised n-butyl acetate to separate final product (Pen G K).Two kinds of solvents all need be recovered; But in view of propyl carbinol is difficult to separate with n-butyl acetate, this solvent recovery step needs expensive equipment.In addition, in this technology, then Pen G K crystal is suspended in through crystallization in n-butyl acetate and obtains Pen G K crystal in the propyl carbinol, need carry out separating step twice Pen G K crystal, and non-once.
For V-cillin, can use identical technology in principle.But, since V-cillin under acidic conditions stability better, V-cillin can also be with sour form but not the potassium salt form crystallization can not cause unacceptable economically loss.
The purpose of this invention is to provide a kind of technology that simply and therefore has more economic attractiveness; Be used for: with sufficiently high (and preferably; Improve) productive rate; Prepare the have good quality potassium salt of penicillin of crystalline form of (preferably, improved quality), said penicillium mould is selected from the group of penicillin G and V-cillin.
" productive rate " is defined as in this article: for the penicillium mould that exists in the extract, and the % productive rate of penicillium mould in the sylvite of the penicillium mould of group crystalline form, that be selected from penicillin G and V-cillin.Enough height are defined as in this article: preferably at least 90%, more preferably at least 92%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, most preferably at least 98%.
" good quality " is defined as in this article: the sylvite of the penicillium mould of that finally obtain, crystalline form, as to be selected from penicillin G and V-cillin group contains considerably less impurity or free from foreign meter, and for example, foreign matter content is less than 5% (w/v), more preferably, is less than 4%; More preferably, be less than 3%, more preferably, be less than 2%; More preferably, be less than 1%, more preferably, be less than 0.5%; More preferably, be less than 0.25%, further more preferably, be less than 0.1%.Impurity can for example be 6-amino-penicillanic acid (6-APA), toluylic acid (PA), the penicillic acid (penicillic acid) to hydroxyl penicillin G, penicillin G, the penicilloic acid (penicilloicacid) of penicillin G and the penilloic acid (penilloic acid) and the corresponding impurity to V-cillin of penicillin G.
In one aspect; The invention provides a kind of technology; Be used for: prepare the sylvite of the penicillium mould of group crystalline form, that be selected from penicillin G and V-cillin from following suspension-s, said suspension-s comprises sylvite, the organic solvent of the penicillium mould of the group that is selected from penicillin G and V-cillin and is selected from C
1, C
2And C
3The alcohol of the group that alcohol constitutes.Preferably, said penicillium mould is penicillin G.Amazing ground; We find; In technology according to the present invention; The productive rate of the sylvite of the penicillium mould of group crystalline form, that be selected from penicillin G and V-cillin is that preamble is defined sufficiently high, and equal or even be higher than technology known in the art, the crystalline quality that obtains simultaneously is good like the preamble definition.Another advantage of technology of the present invention is, only needs a step separating step, and this has not only brought sufficiently high productive rate, has also brought sizable economical advantage.
In technology of the present invention, organic solvent can be any appropriate organic solvent well known by persons skilled in the art.The example of this type of appropriate organic solvent is pentyl acetate, n-butyl acetate, ETHYLE ACETATE, hexone, pimelinketone, isopropylcarbinol or propyl carbinol.Preferably, organic solvent is a n-butyl acetate.
Alcohol according in the technology of the present invention is selected from C
1, C
2And C
3The group that alcohol constitutes, it is methyl alcohol, ethanol, n-propyl alcohol or Virahol preferably.Most preferably, said alcohol is methyl alcohol.
In the technology of the sylvite of the penicillium mould of group crystalline form produced according to the present invention, that be selected from penicillin G and V-cillin, penicillium mould can obtain from any suitable production technique known in the art.Penicillin G can for example be to produce mikrobe according to methods known in the art through fermentation penicillin G when having the side chain precursor toluylic acid, and for example the bacterial strain of Penicillium chrysogenum is produced.Can use any suitable technique, for example centrifugal or filtration from the fermentation culture separating biomass, produces the fermentation fluid that contains penicillium mould thus.Preferably, the application of filtration step is come from the nutrient solution separating biomass.Alternatively, residual solid is washed.
Through adding at least a acid, for example sulfuric acid, spirit of salt or nitric acid or their any combination is acidified to fermentation culture or fluid the pH in 2 to 4 the scope, preferably, and the pH in 2.5 to 3 the scope.Then through being extracted in the organic solvent, with penicillium mould with separate through the acidifying water.Can use any appropriate organic solvent, for example, pentyl acetate, n-butyl acetate, ETHYLE ACETATE, hexone, pimelinketone, isopropylcarbinol or propyl carbinol.Preferably, organic solvent is a n-butyl acetate.The adding of suitable de-emulsifier possibly significantly improve extraction.
" extract " is defined as following organic solvent in this article, and the penicillium mould that is selected from the group of penicillin G and V-cillin has been extracted in the said organic solvent.Alternatively, can be according to methods known in the art, comprise the extract of penicillium mould with activated carbon treatment, to remove impurity.
In one embodiment of the invention; Crossed by activated carbon treatment alternatively, can mix with suitable potassium source subsequently according to the extract of penicillium mould preamble definition, that comprise the group that is selected from penicillin G and V-cillin; Penicillium mould with the group that will be selected from penicillin G and V-cillin is converted into corresponding potassium salt of penicillin, obtains to comprise the mixture of organic solvent and potassium salt of penicillin thus.
Preferably such with the consumption in the suitable potassium source of the extract blended of the penicillium mould that comprises the group that is selected from penicillin G and V-cillin: said consumption makes the potassium that for penicillium mould, adds 0.4 to 3 molar equivalent.Preferably, for penicillium mould, add the potassium of 0.6 to 2 molar equivalent, more preferably, the potassium of 0.7 to 1.6 molar equivalent, more preferably, the potassium of 0.8 to 1.4 molar equivalent, more preferably, the potassium of 0.9 to 1.2 molar equivalent.Most preferably, the potassium that for penicillium mould, adds 1 molar equivalent.Suitable potassium source is to be preferably any sylvite of faintly acid.The example in the potassium source that this type of is suitable is potassium acetate or salt of wormwood.The potassium source can be used with solid form, perhaps can be water-soluble earlier, form the aqueous solution in potassium source.The suitable concn in potassium source is in the aqueous solution, for example, and between 10 to 60%w/v, for example, between 15 to 55%w/v, for example between 20 to 50%.
Subsequently, can from the mixture that comprises the organic solvent and the sylvite of the penicillium mould of the group that is selected from penicillin G and V-cillin, remove a part of anhydrating, perhaps comprise the part of the azeotrope (the for example azeotrope of water and n-butyl acetate) of water and organic solvent.The water that is present in the mixture maybe be from fermentation culture or from organic solvent, or along with the aqueous solution in potassium source is introduced into.Preferably, after the part of water or azeotrope was removed, the water-content that comprises the organic solvent and the mixture of the sylvite of the penicillium mould of the group that is selected from penicillin G and V-cillin was＜10% (v/v), more preferably;＜5% (v/v), more preferably,＜2.5% (v/v); More preferably,＜1% (v/v), more preferably;＜0.5% (v/v), most preferably,＜0.2% (v/v).
According to mentioned above, at first after the part evaporation with the azeotrope of the part of water or water/organic solvent, in mixture, add and be selected from C
1, C
2And C
3The alcohol of the group that alcohol constitutes is with sylvite, organic solvent and the pure suspension-s of the penicillium mould that obtains to comprise the group that is selected from penicillin G and V-cillin.Alcohol can be methyl alcohol, ethanol, n-propyl alcohol or Virahol.Preferably, said alcohol is methyl alcohol.
Preferably, be selected from C
1, C
2And C
3The alcohol of the group that alcohol constitutes is (dry) that does." do " expression alcohol when using in this article and contain the water that is less than 10% (v/v), preferably, be less than the water of 5% (v/v), preferably, be less than 2% (v/v).Most preferably, the alcohol of doing contains the water of 0% (v/v).
After being in contact with one another, can carry out the stirring of certain hour to the suspension-s of sylvite, organic solvent and the alcohol of the penicillium mould that comprises the group that is selected from penicillin G and V-cillin.Preferably, to the suspension-s time of carrying out be the stirring between 5 minutes to 24 hours, preferably, between 10 minutes to 12 hours, more preferably, between 20 minutes to 8 hours, more preferably, between 0.5 hour to 6 hours, more preferably, between 45 minutes to 3 hours.Preferably, to suspension-s stir the sylvite of penicillium mould of the group that is selected from penicillin G and V-cillin crystal formation till.More preferably, to suspension-s stir the sylvite of penicillium mould of the group that is selected from penicillin G and V-cillin crystal formation and do not lump till.Can under any suitable temperature, stir suspension-s, preferably, the temperature between 0 to 40 ℃, more preferably, between 5 to 30 ℃, most preferably, between 10 to 25 ℃.
In the suspension-s according to technology of the present invention, the volume of alcohol can be any suitable ratio with the ratio that comprises the organic solvent and the volume of the mixture of the sylvite of the penicillium mould of the group that is selected from penicillin G and V-cillin.Preferably, this ratio is between 1: 20 to 1: 3, preferably, and between 1: 15 to 1: 4, preferably, between 1: 10 to 1: 6.
During technology of the present invention, be selected from the partly or entirely crystallization of sylvite of penicillium mould of the group of penicillin G and V-cillin.For example; After the extract that comprises penicillium mould adds suitable potassium source and/or during the part of the azeotrope of the part of water or water/organic solvent is evaporated from the mixture that comprises the organic solvent and the sylvite of the penicillium mould of the group that is selected from penicillin G and V-cillin, the sylvite of penicillium mould that is selected from the group of penicillin G and V-cillin can begin crystallization.When the mixture of the sylvite (alternatively, partly or entirely crystalline) that comprises the organic solvent and the penicillium mould of the group that is selected from penicillin G and V-cillin and be selected from C
1, C
2And C
3When the alcohol of the group that alcohol constitutes contacts; And/or during the suspension-s of sylvite, organic solvent and the alcohol of the penicillium mould that comprises the group that is selected from penicillin G and V-cillin stirred, be selected from the sylvite also further crystallization or the recrystallization of penicillium mould of the group of penicillin G and V-cillin.
In another embodiment; In the extract of the penicillium mould of the group that is selected from penicillin G and V-cillin that contains according to preamble said definition and acquisition, add suitable potassium source; And comprise after the azeotrope evaporation of organic solvent and water; For example through filtering the crystal of the sylvite of the penicillium mould of the group that is selected from penicillin G and V-cillin that collection obtains.Under the condition identical (for example), thus obtained crystal is suspended in again comprises the described organic solvent of preamble and be selected from C at aspects such as the ratio of alcohol/organic solvent, time, temperature with aforementioned embodiments
1, C
2And C
3In the mixture of the alcohol of the group that alcohol constitutes.
In any embodiment of the present invention, can be through any suitable method known in the art, the sylvite of the penicillium mould of the group isolation of crystalline form, that be selected from penicillin G and V-cillin from suspension-s for example carries out through centrifugal or filtration.Can obtain the wet cake of the potassium salt of penicillin of crystalline form then.Alternatively, with organic solvent or organic solvent and be selected from C
1, C
2And C
3The mixture of the alcohol of the group that alcohol constitutes washs this wet cake.If used washing step, preferably, organic solvent is identical with the organic solvent that is used for extract, and, be selected from C
1, C
2And C
3The alcohol of the group that alcohol constitutes be used for the pure identical of suspension-s.Can use any suitable technique known in the art, come the wet cake of sylvite of the penicillium mould of the group dried crystals form, that be selected from penicillin G and V-cillin.In this embodiment of the present invention, penicillium mould is penicillin G preferably.
Alternatively, the crystalline wet cake of sylvite that will comprise the penicillium mould of the group that is selected from penicillin G and V-cillin mixes with water, obtains to be selected from the aqueous solution of sylvite of penicillium mould of the group of penicillin G and V-cillin.But extracting then (strip) aqueous solution is with the organic solvent of removing trace and/or be selected from C
1, C
2And C
3The alcohol of the group that alcohol constitutes.Extracting comprises the evaporation of water, organic solvent and/or alcohol.The aqueous solution of sylvite of penicillium mould that is selected from the group of penicillin G and V-cillin can be used for proceeding to through methods known in the art (for example, EP 0,977 883 is described) Enzymatic transformation of 6-amino-penicillanic acid (6-APA).Available suitable penioillin acylase is handled and is comprised the solution of sylvite of penicillium mould that dissolved is selected from the group of penicillin G and V-cillin; Said enzyme for example is suitable penicillin G acylase; So that penicillin G deacylation; And suitable V-cillin acyltransferase, so that V-cillin deacylation.The biology that can produce suitable penioillin acylase that come to light is; For example, the kind of Acetobacter, Aeromonas, Alcaligenes, Aphanocladium, Bacillus sp., Cephalosporium, Escherichia, Flavobacterium, Kluyvera, Mycoplana, Protaminobacter, Providentia, Pseudomonas or Xanthomonas.Confirm that especially the enzyme that obtains from Acetobacterpasteurioanum, Alcaligenes faecalis, Bacillus megaterium, Escherichia coli, Providentia rettgeri and Xanthomonas citrii can successfully be used for according to the method for the invention.In document, penioillin acylase also is called as penicillin amidase.Penioillin acylase can be used as the free enzyme and uses, and also can be suitable for any suitable form that is fixed, and for example, describes among EP 0 222 462 and the WO 97/04086.Through penioillin acylase the Enzymatic transformation that dissolved Pen G K carries out is caused forming 6-amino-penicillanic acid (6-APA) and toluylic acid.
Embodiment 1 comparing embodiment
The K that in the extract of activated carbon treatment, adds 30% (w/w) to 1000ml
2CO
3The aqueous solution; Make mixture contain the potassium of about 1.0 molar equivalents for penicillin G; The every ml of wherein said extract contains the penicillin G of about 100,000 Oxford units, is in (1 Oxford unit equals the penicillin G of about 0.6 microgram) in the n-butyl acetate.Should mix with the 200ml propyl carbinol by the reextraction thing, use rotary thin film evaporation appearance (50-60 ℃ of temperature bathed) under vacuum, the mixture that obtains to be heated.During evaporating, by a part adding propyl carbinol, the total amount of the feasible propyl carbinol that adds is 200ml.The n-butanol/water of total coevaporation 250ml is cooled to room temperature with resistates.Through the formed Pen G of filtering separation K crystal, with propyl carbinol washing and dry.Productive rate (defined according to preamble) is 91%.
Embodiment 2
Carry out a series of experiments, wherein, in the extract (every ml contains the penicillin G of about 100,000 Oxford units, is in the n-butyl acetate) of activated carbon treatment, add the K of 50% (w/w) to 1000ml
2CO
3The aqueous solution makes mixture contain the potassium of about 1.0 molar equivalents for penicillin G.Rotary thin film evaporation appearance (45-48 ℃ of temperature bathed) heats the mixture that obtains under vacuum, makes a certain amount of mixture evaporate thus---about amount, referring to table 1 to every experiment.Subsequently, in resistates, add methyl alcohol, mixture is carried out stirring in 1 hour at 25 ℃.Filtering suspension liquid is washed wet cake with the 70ml n-butyl acetate, afterwards the dry wet filter cake.
Table 1: the crystallization of Pen G K in the acetate propyl carbinol+in resistates, add methyl alcohol
| # | The volume (ml) of evaporation | Residual moisture content (%) | The methyl alcohol (ml) that adds | Mother liquor volume (ml) | Mother liquor loss (%) | Productive rate (%) |
| 1 | 190(16) | nd | 100 | 770 | 1.7 | 96.5 |
| 2 | 328(16) | nd | 100 | 645 | 1.6 | 96.3 |
| 3 | 292(13) | 0.04 | 100 | 620 | 1.2 | 98.0 |
| 4 | 334(18) | 0.04 | 100 | 650 | 1.7 | 97.5 |
| 5 | 206(19) | 0.18 | 150 | 720 | 2.3 | 94.5 |
The volume of evaporation is the TV of evaporation, and the value in the bracket is represented the volume of water layer in the overhead product.The water-content of resistates after the representative evaporation of water-content one hurdle.All experiments have all produced white Pen G K crystal with high yield (defined according to preamble), and said productive rate is for the penicillium mould content of the extract of handling through carbon (=100%), and mother liquor only has very limited penicillium mould loss.Contain 99.3% Pen G K (that is, good quality) from experiment 1 crystal.
Claims (4)
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| Application Number | Priority Date | Filing Date | Title |
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| EP05111630 | 2005-12-02 | ||
| EP05111630.9 | 2005-12-02 | ||
| EP06110094 | 2006-02-17 | ||
| EP06110094.7 | 2006-02-17 | ||
| PCT/EP2006/069146 WO2007063107A1 (en) | 2005-12-02 | 2006-11-30 | Process for the preparation of a potassium salt of penicillin |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2599401A (en) * | 1947-08-15 | 1952-06-03 | Lilly Co Eli | Process of obtaining crystalline penicillin salts |
| CN1191221A (en) * | 1997-12-31 | 1998-08-26 | 华北制药股份有限公司 | Process for one-shot crystallization of sodium penicillin |
| EP1475444A1 (en) * | 1997-04-22 | 2004-11-10 | DSM IP Assets B.V. | Improved process for the fermentative production of penicillin |
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2006
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2599401A (en) * | 1947-08-15 | 1952-06-03 | Lilly Co Eli | Process of obtaining crystalline penicillin salts |
| EP1475444A1 (en) * | 1997-04-22 | 2004-11-10 | DSM IP Assets B.V. | Improved process for the fermentative production of penicillin |
| CN1191221A (en) * | 1997-12-31 | 1998-08-26 | 华北制药股份有限公司 | Process for one-shot crystallization of sodium penicillin |
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