EP1075479A1 - Ein verfahren zur kristallisierung von einem beta-lactam-antibiotikum - Google Patents
Ein verfahren zur kristallisierung von einem beta-lactam-antibiotikumInfo
- Publication number
- EP1075479A1 EP1075479A1 EP99917236A EP99917236A EP1075479A1 EP 1075479 A1 EP1075479 A1 EP 1075479A1 EP 99917236 A EP99917236 A EP 99917236A EP 99917236 A EP99917236 A EP 99917236A EP 1075479 A1 EP1075479 A1 EP 1075479A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- lactam
- crystallized
- nitric acid
- acid
- solution
- 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- Withdrawn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
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)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99917236A EP1075479A1 (de) | 1998-04-29 | 1999-04-27 | Ein verfahren zur kristallisierung von einem beta-lactam-antibiotikum |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98201398 | 1998-04-29 | ||
EP98201398 | 1998-04-29 | ||
EP99917236A EP1075479A1 (de) | 1998-04-29 | 1999-04-27 | Ein verfahren zur kristallisierung von einem beta-lactam-antibiotikum |
PCT/NL1999/000246 WO1999055710A1 (en) | 1998-04-29 | 1999-04-27 | A METHOD FOR CRYSTALLIZING A β-LACTAM ANTIBIOTIC |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1075479A1 true EP1075479A1 (de) | 2001-02-14 |
Family
ID=8233663
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99917236A Withdrawn EP1075479A1 (de) | 1998-04-29 | 1999-04-27 | Ein verfahren zur kristallisierung von einem beta-lactam-antibiotikum |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1075479A1 (de) |
KR (1) | KR20010043038A (de) |
CN (1) | CN1298408A (de) |
AU (1) | AU3539599A (de) |
BR (1) | BR9910085A (de) |
ID (1) | ID26418A (de) |
PE (1) | PE20000879A1 (de) |
TR (1) | TR200003131T2 (de) |
WO (1) | WO1999055710A1 (de) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20050087776A (ko) | 2002-08-13 | 2005-08-31 | 산도즈 아게 | 세프디니르 중간체 |
US7534781B2 (en) * | 2003-03-21 | 2009-05-19 | Dsm Ip Assets B.V. | Crystalline amoxicillin trihydrate powder |
ZA200507748B (en) * | 2003-03-24 | 2007-03-28 | Acs Dobfar Spa | Novel crystal of 7-[2-(2-aminothiazole-4-yl)-2-hydroxyimino-acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) and method for preparation thereof |
MX2007006018A (es) | 2004-11-30 | 2007-06-07 | Astellas Pharma Inc | Suspension farmaceutica oral novedosa de cristal de cefdinir. |
CN101448842A (zh) * | 2006-05-19 | 2009-06-03 | 帝斯曼知识产权资产管理有限公司 | 一种用于结晶头孢羟氨苄的方法 |
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 |
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 |
CN106397455B (zh) * | 2016-08-30 | 2018-08-31 | 山东罗欣药业集团恒欣药业有限公司 | 一种抗感染药物头孢布烯晶体化合物及其组合物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE465649A (de) * | 1944-06-19 | |||
JPS6379888A (ja) * | 1986-09-24 | 1988-04-09 | Tanabe Seiyaku Co Ltd | ペニシリン誘導体の安定型水和物 |
RU2024851C1 (ru) * | 1992-07-22 | 1994-12-15 | Шорманов Владимир Камбулатович | СПОСОБ ОПРЕДЕЛЕНИЯ 6-(D-α -АМИНОФЕНИЛАЦЕТАМИДО)-ПЕНИЦИЛЛАНОВОЙ КИСЛОТЫ НАТРИЕВОЙ СОЛИ |
BE1009264A3 (nl) * | 1995-03-31 | 1997-01-07 | Dsm Nv | Werkwijze voor de winning van ampicilline. |
WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
-
1999
- 1999-04-16 PE PE1999000315A patent/PE20000879A1/es not_active Application Discontinuation
- 1999-04-27 AU AU35395/99A patent/AU3539599A/en not_active Abandoned
- 1999-04-27 EP EP99917236A patent/EP1075479A1/de not_active Withdrawn
- 1999-04-27 TR TR2000/03131T patent/TR200003131T2/xx unknown
- 1999-04-27 KR KR1020007011901A patent/KR20010043038A/ko not_active Application Discontinuation
- 1999-04-27 BR BR9910085-1A patent/BR9910085A/pt not_active Application Discontinuation
- 1999-04-27 CN CN99805572A patent/CN1298408A/zh active Pending
- 1999-04-27 WO PCT/NL1999/000246 patent/WO1999055710A1/en not_active Application Discontinuation
- 1999-04-27 ID IDW20002187A patent/ID26418A/id unknown
Non-Patent Citations (1)
Title |
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See references of WO9955710A1 * |
Also Published As
Publication number | Publication date |
---|---|
BR9910085A (pt) | 2000-12-26 |
AU3539599A (en) | 1999-11-16 |
WO1999055710A1 (en) | 1999-11-04 |
TR200003131T2 (tr) | 2001-01-22 |
CN1298408A (zh) | 2001-06-06 |
KR20010043038A (ko) | 2001-05-25 |
PE20000879A1 (es) | 2000-09-23 |
ID26418A (id) | 2000-12-21 |
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