GB2119785A - Manufacture of alkali metal salts of penicillin - Google Patents
Manufacture of alkali metal salts of penicillin Download PDFInfo
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- GB2119785A GB2119785A GB08236791A GB8236791A GB2119785A GB 2119785 A GB2119785 A GB 2119785A GB 08236791 A GB08236791 A GB 08236791A GB 8236791 A GB8236791 A GB 8236791A GB 2119785 A GB2119785 A GB 2119785A
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- GB
- United Kingdom
- Prior art keywords
- penicillin
- alkali metal
- mmole
- metal salt
- methylene chloride
- Prior art date
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- -1 alkali metal salts Chemical class 0.000 title claims abstract description 34
- 229930182555 Penicillin Natural products 0.000 title claims abstract description 24
- 229910052783 alkali metal Inorganic materials 0.000 title claims abstract description 23
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical class 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 abstract description 22
- 229940049954 penicillin Drugs 0.000 title claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 150000003951 lactams Chemical class 0.000 claims abstract description 9
- 229910001413 alkali metal ion Inorganic materials 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 99
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 13
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 5
- 238000006297 dehydration reaction Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 3
- 150000002960 penicillins Chemical class 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- 229910001415 sodium ion Inorganic materials 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 15
- QAZCPUUJMFBNJO-UHFFFAOYSA-N pyrrolidin-2-one;sodium Chemical compound [Na].O=C1CCCN1 QAZCPUUJMFBNJO-UHFFFAOYSA-N 0.000 description 13
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 9
- 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 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].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 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 7
- 229960001931 ampicillin sodium Drugs 0.000 description 7
- 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 description 6
- 229960004920 amoxicillin trihydrate Drugs 0.000 description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 5
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 4
- 229960003311 ampicillin trihydrate Drugs 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229960002793 amoxicillin sodium Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- ILVPFTMKCHREDJ-UHFFFAOYSA-N methyl 5-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1F ILVPFTMKCHREDJ-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007524 organic acids Chemical class 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
- 102220093061 rs139517777 Human genes 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- LFBBSWBQNQXKPF-LQDWTQKMSA-M sodium;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1 LFBBSWBQNQXKPF-LQDWTQKMSA-M 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 229940093858 ethyl acetoacetate Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 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 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003567 thiocyanates Chemical class 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Alkali metal salts of penicillin of the formula: <IMAGE> wherein R is a substituent radical, preferably benzyl, phenoxymethyl, alpha-aminobenzyl or alpha-amino-p- hydroxybenzyl, and X is an alkali metal ion, are made by reacting a starting penicillin of the above formula, where. R has the above meaning and X is a hydrogen atom, with an alkali metal salt of a lactam.
Description
SPECIFICATION
Manufacture of alkali metal salts of penicillin
This invention relates to the manufacture of alkali metal salts of penicillin of the general formula:
where R is a substituent radical, preferably benzyl, phenoxy-methyl, alpha-aminobenzyl or alphaamino-p-hydroxybenzyl, and X is an alkali metal ion.
The method of the invention is advantageously used in the preparation of non-toxic salts of native or semi-synthetic penicillins of superior watersolubility, which are indicated for the therapy of infectious diseases of man and animals caused by gram-positive and gram-negative bacteria.
It is known that penicillins may be converted to alkali metal salts by dissolving the corresponding penicillin acid in an organic solvent in the presence of an amine and introducing a corresponding alkali metal salt of a suitable organic acid, the acid most frequently employed being 2-ethyl-caproic acid (GB-A-980,240). It is also known that the above-mentioned salts of organic acids may be replaced by alkali metal alcoholates (GB-A-1,060,034) or by other alkali metal salts, such as ethyl-acetoacetate or thiocyanate salts (GB-A-1,128,235).
It has now been found, in accordance with the present invention, that the preparation of alkali metal salts of penicillin may be carried out in a very successful manner by making use of alkali metal salts of lactams, which are easily obtainable by the reaction of alkali metals with lactams in suitable organic solvents.
According to the present invention, therefore, an alkali metal salt of penicillin of the abovedefined formula (I) is manufactured by reacting a starting penicillin of the formula, where R has the above meaning, but where X is a hydrogen atom, with an alkali metal salt of a lactam.
Preparation of alkali metal salts of penicillin according to the invention is preferably carried out in an inert organic solvent, most suitably methylene chloride, dimethylformamide, chloroform or dimethylacetamide, in the presence of an organic base, preferably diethylamine, dicyclohexylamine or triethylamine.
The reaction is preferably carried out at a temperature in the range from 200 to +250C.
The reaction time ranges typically from 20 to 90 minutes under stirring. According to a preferred embodiment of the method, the starting penicillin is used in anhydrous form or is dehydrated in situ prior to reaction with the lactam salt. Dehydration of the starting penicillin, when required, is preferably effected by means of conventional dehydration agents, most suitably with MgS04, molecular sieves (4 ) or by working up with methanol. Any alkali metal lactam salt can be used in carrying out the method of the present invention, but for practical reasons, sodium proves to be most suitable and so is preferred. The preferred lactam is pyrrolidine-2-one.
The optional dehydration step is most suitably carried out by dissolving the starting penicillin acid in the selected solvent, with the addition of the selected organic base and a solid dehydration agent such as MgSO4, at a temperature of --200 to + 1 90C. and by stirring for 30 to 120 minutes at this temperature range. The dehydrating agent is then separated by filtration and the selected alkali metal salt of pyrrolidine-2-one is introduced into the filtrate, whereupon the above-mentioned reaction takes place. The starting penicillin in hydrate form may also be dehydrated very conveniently by suspending it in methanol, stirring and filtering and then repeating this procedure with methanol and methylene chloride.
The resulting final product may be obtained in the form of crystals, which are aspirated and dried. If spontaneous crystallization of the product does not occur, the organic solvent can be evaporated from the reaction mixture and the residue then suspended in another organic solvent, which selectively dissolves the byproducts and unreacted starting substances, such as pyrrolidine-2-one, leaving the final product undissolved. In this manner, the purity of the product improved and the lactam which separates may be re-used. When dimethylformamide or dimethylacetamide is used as the solvent, it forms a solvate with the final product, which can be dissolved in water and subsequently lyophilized.
The main advantage of the method of the present invention over prior art methods is the high yield obtained. Another advantage of the use of lactams is that they may be prepared absolutely alkali-free, which represents a problem when dealing with alcoholates. Also, the salt itself possesses superior stability. A disadvantage of the known method based on 2-ethyl-caproic acid is that its salt has to be prepared by evaporation of an aqueous solution and the residual water presents difficulties on crystallization of the final product, thus reducing the yield.
The present invention is illustrated by, but in no way limited to, the following Examples.
Phenoxymethylpenicillin-sodium (I;
R=C6H5OCH2, X=Na)
Example 1
Phenoxymethylpenicillin (7 g, 20 mmole) was suspended in methylene chloride (80 ml) and diethylamine (1.46 g, 20 mmole) was added, whereupon the mixture was stirred to give complete dissolution of the penicillin (5 to 10 minutes). Then, sodium pyrrolidine-2-one (2.14 g, 20 mmole) was added in portions, over a period of 1 hour, with stirring, at a temperature of +15"C. The reaction mixture was then stirred for another 30 minutes and the phenoxymethyl penicillin-sodium which separated was aspirated, washed with methylene chloride (20 ml) and then dried under reduced pressure in a vacuum drier.
Yield: 6.52 g (87.5%)
IR: 3365 (m), 1782 (vs), 1610(vs), 1510(s), 1495 (s), 1300 (s),755 (m) cm-1 [a]024=+21 7.80 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Ampicillin-sodium (I; R=C6H5CH(NH2);X=Na) Example 2
Anhydrous ampicillin (7 g, 20 mmole) was suspended in methylene chloride (100 ml) at a temperature of 200C, triethylamine (4.04 g, 40 mmole) was then added and the reaction mixture was stirred for 1 5 minutes. The undissolved part was aspirated and the residual crystals on the filter were washed with methylene chloride (10 ml).Sodium pyrrolidine-2-one (2.4 g, 22.5 mmole) was added to the mother liquor at a temperature of 200C and the reaction mixture was then stirred for 50 minutes, resulting in crystallization of ampicillin-sodium. The crystals which separated were aspirated, washed with methylene chloride (2x15 ml) and dried in a vacuum drier under reduced pressure at +500C for 2 hours.
Yield: 7.06 (95.08%)
IR: corresponding to the standard sample [ai24=+2S7.30 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Contents (microbiol.): 83.6% (calculated on the
dry substance)
Moisture content: 0.64%
Example 3
Anhydrous ampicillin (7 g, 20 mmole) was stirred with triethylamine (4.04 g, 40 mmole) in methylene chloride (100 ml), as in Example 2.
Sodium pyrrolidine-2-one (2.4 g, 22.5 mmole) was added without previous aspiration of the undissolved crystals. The reaction mixture was then worked up as indicated in Example 2.
Yield: 7.1 6 g (96.4%) IR: corresponding to the standard sample [a]24+265.30 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Contents (microbiol.): 86.15% (calculated on
the dry substance)
Moisture content: 0.64%.
Example 4
Anhydrous ampicillin (7 g, 20 mmole) was suspended in methylene chloride (100 ml), diethylamine (2.2 g,.30 mmole) was added and the reaction mixture was stirred until complete dissolution occurred. Sodium pyrrolidine-2-one (2.14, 20 mmole) was introduced and the reaction mixture was stirred for 20 minutes. The ampicillin-sodium which separated was aspirated, washed with methylene chloride (2 x 15 ml portions) and dried in a vacuum drier under reduced pressure).
Yield: 6.87 g (92.5%)
IR: corresponding to the standard sample [a]24=+266.60 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Contents (microbiol.): 87% (calculated on the
dry substance)
Moisture content: 1.14%
Example 5
Ampicillin trihydrate (8 g, 20 mmole) was suspended in methylene chloride (100 ml) and diethylamine (2.2 g, 30 mmole) and calcined
MgSO4 (8 g) were added at a temperature of 1 50C, whereupon the reaction mixture was stirred for 30 minutes.The MgSO4 precipitate was aspirated and washed with methylene chloride (10 ml); sodium pyrrolidine-2-one (2.14 g, 20 mmole) was added to the mother liquor with stirring at 1 50C. The reaction mixture was stirred for 40 minutes, the crystals of ampicillinsodium which separated were aspirated, washed with methylene chloride (25 ml) and finally dried under reduced pressure in a vacuum drier.
Yield: 6.83 g (84%)
IR: corresponding to the standard sample []D4=+266.5 (c=0.25; 0.02 M
- 66.50 potassium hydrogen phthalate).
Contents (microbiol.): 87% (calculated on the
dry substance).
Moisture content: 0.1%.
Example 6
Ampicillin trihydrate (8 g, 20 mmole) was suspended in methylene chloride (100 ml), triethylamine (3 g, 30 mmole) and calcined
MgSO4 (8 g) were added and the reaction mixture was stirred for 30 minutes at 1 50C. It was worked up in a manner analogous to that indicated in Example 5, whereupon sodium pyrrolidine-2-one (2.14 g, 20 mmole) was added.
Ampicillin-sodium crystallized from the reaction mixture within 30 minutes.
Yield: 6.68 g (90%)
IR: corresponding to the standard sample.
[a] D24=+2 82.40 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Moisture content: 0.87%
Example 7
Ampicillin trihydrate (8 g, 20 mmole) was suspended in methylene chloride (100 ml), dicyclohexylamine (5.44 g, 30 mmole) and calcined MgSO4 (8 g) were added and the reaction mixture was then stirred for 40 minutes.
The MgSO4 precipitate was aspirated and washed with methylene chloride (20 ml) and sodium pyrrolidine-2-one (2.14 g, 20 mmoie) was introduced into the mother liquor in small portions, with stirring, at 1 50C over a period of 30 minutes. The reaction mixture was stirred for 70 minutes and the ampicillin-sodium which separated was aspirated, washed with methylene chloride (25 ml) and dried under reduced pressure in a vacuum drier.
Yield: 6.53 g (87.9%) IR: corresponding to the standard sample [a] D24=+2450 (c=0.25; 0.02 M potassium
hydrogen phthalate).
Example 8
Ampicillin trihydrate (8 g, 20 mmole) was suspended in methylene chloride (100 ml), dicyclohexylamine (5.44 g, 30 mmole) and molecular seives (4 ) were added and the mixture was then stirred at 1 00C until complete dissolution of the ampicillin was achieved. The molecular sieves were aspirated and sodium pyrrolidine-2-one (2.14 g, 20 mmole) was introduced into the mother liquor, with stirring, over a period of 30 minutes. The reaction mixture was then stirred for a further 90 minutes and the ampicillin-sodium which separated was then aspirated, washed with methylene chloride (25 ml) and dried in a vacuum drier under reduced pressure.
Yield: 6.29 g (84.7%)
IR: corresponding to the standard sample [a]4=+251.80 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Moisture content: 1.18%
Amoxicillin-sodium (I; R=HOC6HsCH(NH2); X=Na)
Example 9
Amoxicillin trihydrate (4 g, 9.5 mmole) was suspended in dimethylformamide (50 ml), diethylamine (1.14 g, 15 mmole) and MgSO4 (5 g) were added, and the reaction mixture was stirred at 1 50C over a period of 30 minutes. The
MgSO4 precipitate was aspirated and washed with dimethylformamide (5 ml). Sodium pyrrolidine-2-one (1.1 g, 10 mmole) was introduced into the mother liquor at 1 50C in several portions, with stirring, over a period of 1 5 to 20 minutes.Subsequently, the reaction mixture was stirred for a further 30 minutes, the undissolved crystalline precipitate was aspirated and the mother liquor was evaporated under reduced pressure to yield a solid residue. The product was suspended in methylene chloride (20 ml), the suspension was stirred for 30 minutes at 200 to 250C and the crystals were aspirated, washed with methylene chloride (10 ml) and dried in a vacuum drier under reduced pressure at 250C. The product so obtained contained amoxicillin-sodium in the form of the dimethylformamide-solvate.
Yield: 3.55 g
IR: 1775 (s), 1670 (s), 1620 (vs), 1515(s) cm1 [a]D4=+180 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Contents (microbiol.): 66% (calculated on the
dry substance)
Moisture content: 1.25%
Dimethylformamide content: 11% Example 10
Amoxicillin trihydrate (4 g, 9.5 mmole) was suspended in dimethylformamide (50 ml), triethylamine (1.25 g, 15 mmole) and MgSO4 (5 g) were added and the reaction mixture was then worked up and subsequently reacted with sodium pyrrolidine-2-one as indicated in Example 9.
Amoxicillin-sodium was obtained in the form of the dimethylformamide-solvate.
Yield: 4.22 g
IR: identical with Example 9 [a]24=+1880 (c=0.25; 0.02 M potassium
hydrogen phthalate)
Contents (microbiol.): 74.3% (calculated on the
dry substance)
Moisture content: 1.13%
Dimethylformamide content: 1 3.7% Example 11
Amoxicillin trihydrate (2.93 g, 7 mmole) was suspended in methanol (15 ml) and the suspension was stirred for 30 minutes at 250C.
The precipitate was filtered and again worked up with methanol (15 ml) and subsequently with methylene chloride (2x15 ml). The solid residue was once more suspended in methylene chloride (9 ml), the suspension was cooled to -200C and first diethylamine (0.655 g, 9 mmole) and then chloroform (18 ml) were introduced dropwise with stirring. The reaction mixture was stirred for 45 minutes at the same temperature and then filtered. Solid sodium pyrrolidine-2-one (0.74 g, 7 mmole) was introduced with stirring into the filtrate and the resulting suspension was further stirred for 30 minutes without cooling. The precipitate was filtered, washed with methylene chloride (2x5 ml) and dried in a vacuum drier under reduced pressure for 2 hours at 250C.
Yield: 2.34 g (85%)
IR: corresponding to the standard sample
Moisture content: 1.27%
Example 12
Amoxicillin trihydrate (2.93 g, 7 mmole) was worked up with methanol and methylene chloride as indicated in Example 11. The solid obtained was suspended in methylene chloride (20 ml), the suspension was cooled to OOC and dicyclohexylamine (1.81 g, 10 mmole) was introduced dropwise with stirring. The reaction mixture was stirred for 10 minutes at OOC and then filtered whereupon solid sodium pyrrolidine2-one (0.749 g, 7 mmole) was added to the filtrate with stirring. The suspension was stirred for 30 minutes at 250C, filtered and the precipitate obtained was washed with methylene chloride (2x5 ml) and then dried in a vacuum drier under reduced pressure for 2 hours at 250C.
Yield: 1.25 g (58.4%)
IR: corresponding to the standard sample
Example 13
Amoxicillin trihydrate (2.93 g, 7 mmole) was worked up with methanol and methylene chloride as indicated in Example 11. The solid residue was suspended in methylene chloride (35 ml), the suspension was cooled to OOC and triethylamine (1.01 g, 10 mmole) was introduced, with stirring.
The reaction mixture was stirred for 20 minutes at OOC, filtered and solid sodium pyrrolidine-2-one (0.74 g, 7 mmole) was introduced. The suspension was stirred for 30 minutes at 250C and filtered. The resulting precipitate was washed with methylene chloride (2x5 ml) and dried in a vacuum drier under reduced pressure at 250C for 2 hours.
Yield: 1.32 g (50.7%) Ip: corresponding to the standard sample.
Example 14
Amoxicillin trihydrate (4 g, 9.5 mmole) was suspended in dimethylacetamide (50 ml), triethylamine (1 g, 10 mmole) and MgSO4 (5 g) were added and the reaction mixture was then stirred at +1 50C for 60 minutes. The MgSO4 precipitate was aspirated and washed with dimethylacetamide (10 ml). Sodium pyrrolidine2-one (1.1 g, 10 mmole) was added to the mother liquor in portions with stirring, over a period of 20 minutes and the reaction mixture was then stirred for a further 1 5 minutes. The undissolved crystals were separated by filtration and the mother liquor was evaporated under reduced pressure at 600C to a volume of 10 to 12 ml. Methylene chloride (20 ml) was introduced dropwise into the residue, with stirring, at 1 50C over a period of 30 minutes and the crystals which separated were then evaporated, washed with methylene chloride and dissolved in water (15 ml). The water and the residual dimethylacetamide were eliminated by lyophilization.
Yield: 3.27 g (88.9%)
IR: corresponding to the standard sample
Contents (microbiol.): 81.3% (calculated on the
dry substance)
Moisture content: 0.89%
Claims (14)
1. A method of manufacture of an alkali metal salt of penicillin of the formula:
wherein R is a substituent radical and X is an alkali metal ion, which comprises reacting a starting penicillin of the formula (I), where R has the above meaning and X is a hydrogen atom, with an alkali metal salt of a lactam.
2. A method according to claim 1 , wherein the starting penicillin is dissolved in an inert organic solvent in the presence of an organic base and the resulting penicillin salt is reacted with the lactam salt.
3. A method according to claim 2, wherein the solvent is methylene chloride, dimethylformamide, chloroform or dimethyl acetamide.
4. A method according to claim 2 or 3, wherein the organic base is diethylamine, dicyclohexylamine or triethylamine.
5. A method according to any preceding claim, wherein the reaction is carried out at a temperature in the range from 200 to +250C.
6. A method according to any preceding claim, wherein the starting penicillin is used in anhydrous form or is dehydrated in situ prior to reaction with the lactam salt.
7. A method according to claim 6, wherein dehydration of the starting penicillin is effected by means of MgSO4 or molecular sieves (4 A) or by working up with methanol.
8. A method according to any preceding claim, wherein the substituent radical R is selected from benzyl, phenoxymethyl, alpha-aminobenzyl and alpha-amino-p-hydroxybenzyl radicals.
9. A method according to any preceding claim, wherein the alkali metal ion is a sodium ion.
10. A method according to any preceding claim, wherein the lactam is pyrrolidine-2-one.
11. A method according to any preceding claim, wherein the resulting crude alkali metal salt of penicillin is isolated by filtration from the reaction solution or by evaporation of the solvent, followed by suspension of the residue in an organic solvent in which the alkali metal salt of penicillin is insoluble and then filtration.
12. A method according to claim 11, wherein an aqueous solution of a solvate of the resulting alkali metal salt of penicillin is lyophilized.
13. A method according to claim 1, substantially as described with reference to the foregoing Examples.
14. An alkali metal salt of penicillin, when made by a method according to any preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU95982A YU42610B (en) | 1982-05-05 | 1982-05-05 | Process for preparing alcalic metal penicillin salts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2119785A true GB2119785A (en) | 1983-11-23 |
| GB2119785B GB2119785B (en) | 1985-09-04 |
Family
ID=25552170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08236791A Expired GB2119785B (en) | 1982-05-05 | 1982-12-24 | Manufacture of alkali metal salts of penicillin |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2119785B (en) |
| YU (1) | YU42610B (en) |
-
1982
- 1982-05-05 YU YU95982A patent/YU42610B/en unknown
- 1982-12-24 GB GB08236791A patent/GB2119785B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2119785B (en) | 1985-09-04 |
| YU42610B (en) | 1988-10-31 |
| YU95982A (en) | 1985-03-20 |
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| Date | Code | Title | Description |
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| PCNP | Patent ceased through non-payment of renewal fee |