IL31807A - Process for the n-acylation of 6-aminopenicillanic acid - Google Patents
Process for the n-acylation of 6-aminopenicillanic acidInfo
- Publication number
- IL31807A IL31807A IL31807A IL3180769A IL31807A IL 31807 A IL31807 A IL 31807A IL 31807 A IL31807 A IL 31807A IL 3180769 A IL3180769 A IL 3180769A IL 31807 A IL31807 A IL 31807A
- Authority
- IL
- Israel
- Prior art keywords
- polymer
- solution
- acid
- acylating
- acylation
- Prior art date
Links
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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F212/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
- C08F212/02—Monomers containing only one unsaturated aliphatic radical
- C08F212/04—Monomers containing only one unsaturated aliphatic radical containing one ring
- C08F212/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by heteroatoms or groups containing heteroatoms
- C08F212/22—Oxygen
- C08F212/24—Phenols or alcohols
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/10—Acylation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2800/00—Copolymer characterised by the proportions of the comonomers expressed
- C08F2800/20—Copolymer characterised by the proportions of the comonomers expressed as weight or mass percentages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Cephalosporin Compounds (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Proeees for the N-acylatlon of 6- aminopenlcillanic acid YSDA RESEARCH AND DEVELOPMENT COMPANY LIMITED Gt 30137 The present invention relates to a novel process for the N-acylation of 6-aminopenicillanic acid to give penicillins and non-toxic salts thereof.
The compounds prepared according to the present invention are of value as antibacterial agents, as nutritional supplements in animal feeds, as agents for the treatment of mastitis in cattle, and as therapeutic agents in poultry and animals, including man, in the treatment of infectious diseases caused by bacteria.
The non-toxic salts include non-toxic metallic salts such as sodium, potassium, calcium and aluminium, the ammonium salt and substituted ammonium salts, e.g. salts of such non-toxic amines as trialkylamines, includ ing triethylamine, procaine, dibenzylaine, N-benzyl-β-phenethylamine, 1-ephenamine, Ν,Ν' -dibenzylethylene-diamine, dehydroabietylaine, Ν,Ν' -bls-dehydroabietyl-ethylenediamine, and other amines which have been used to form. salts with benzylpenicillin.
It is an object of the present invention to provide a process for the N-acylation of 6-aminopenicillanic acid wherein the resulting penicillin can be isolated directly in good purity.
Accordingly the present invention provides a process for the N-acylation of 6-aminopenicillanic acid, which process comprises contacting a solution containing 6-aminopenicillanic acid or a salt, ester, amide or other functional deriviative thereof with a solid acylating polymer substantially insoluble in said solution and comprising recurring groups -RCOB-, wherein RCO is an organic acyl radical and B is an activated radical in the polymer, then subsequently separating solid material from the solution and recovering therefrom the N-acyl derivative or nontoxic salt thereof.
Suitable acylating polymers have the formula: wherein RCO and B are as defined above and A is a recurring portion of the backbone of a synthetic polymer or part of a natural polymer which may be modified, and n is an integer. The acylating polymer may be obtained by treating a corresponding non-acylated polymer with an acylating agent to introduce the group RCO. Known acylating methods may be used, especially use of an acid halide RCOX Wherein X is halogen, or coupling with the acid RCOOH in presence of a condensation agent such as a carbodiimide. Typical non-acylated polymers have the following formulae : (5) (6) In these formulae - A^^ represent recurring portions of the polymer backbone and m and n are whole numbers. On acylation of the polymer the group RCO enters in the appropriate position. For example in polymers bearing the group the OH radical becomes RCOO-; with the polymer of Formula (7) the -N:C:N- radical reacts with the acylating acid RCOOH to yield the group -NH.C(OOCR) :N-; and with the polymer of Formula (21) the p_ - COOH group forms with the acylating agent a mixed anhydride RCO.O.0C-. Numerous polymers can be used and these may be cross-linked.
After the N-acylation the resulting penicillin is easily recovered in pure form by separation of the insoluble polymer, and then subjecting the solution to evaporation, extraction or lyophilisation or some other suitable step to give solid material- if desired, the penicillin may be recovered as a nontoxic salt.
The process is suitable for batch or continuous use, and in the latter case separation of the solution containing the penicillin occurs readily if the acylating polymer is used in the form of a column. The 6-aminopenicillanic acid or salt or functional derivative thereof in solution is passed through a column of the acylating polymer and the course of the reaction may be followed by potentio-metric titration for example by using a glass and a calomel electrode in the usual way.
For the N-acylation reaction aqueous or nonaqueous solvents may be used e.g. dimethylformamide or acetonitrile.
The following Examples 1 - 4 described the preparation of suitable acylating polymers, and Examples 5 - 8 illustrate the invention.
EXAMPLE 1 .4g. of phenylacetic acid (40mmoles) in ml. of acetonitrile was added to a suspension of 4g. of poly-4-hydroxy-3-nitrostyrene cross-linked with 4$ by weight of divinylbenzene (containing .9 mmoles of hydroxyl groups per g) in 50 ml. of acetonitrile. The reaction mixture was stirred for 10 minutes at 0°C whereupon a solution of 8.4 g. (40 mmoles) of N, N' -dicyclohe^ yl-carbodiimide in 20 ml. of acetonitrile was added. The reaction mixture was stirred for 1 hour at 0°C and then for a further 5 hours at room temperature. The phenylacetyl polymer was filtered off, boiled with methanol to remove the by-product Ν,Ν' -dicyclohe¾f phenylacetyl residue per gram.
EXAMPLE 2 4.6g. of a-phenoxypropionyl chloride (25 mmoles) was added to a suspension of 5g. of poly-4-hydroxy-3-nitrostyrene cross-linked with k by weight of divinylbenzene in 50 ml. of acetonitrile. The reaction mixture was stirred for 10 minutes at 0°C whereupon 2.8 ml. of pyridine (30 mmoles) was added, Stirring was continued overnight at 4°C and thereafter the a-phenoxypropionyl polymer formed was filtered off, washed with 0.5N sulphuric acid, water, methanol and ether. Yield after drying in vacuo was 5.7g., and the polyester contained 1 mmole of a-phenoxypropioiyl residue per gram.
EXAMPLE 3 Bv repeating the procedure of either Example 1 or of Example 2, other polyacylated polymers of the fragmentary formula RCOB were prepared, and are listed in the Table 1.
TABLE I Polymer Group RCO Method of Binding Example mMole/g PNP Phenylacetyl 1 3 PNP 3-(2-chlorphenyl )-5- methy1- -isoxazoly1carbon 1 1 2 PNP tt 2 1.6 PNP 2, 6-Dimethoxybenzoyl 1 1.6 PNP Phenylmalonyl 1 1.1 PNP a-Phenoxypropionyl 2 1 NHS Phenylacetyl 1 2.3 NHS 2, β-Dimethoxybenzoyl 1 1.7 poly-4-hydroxy-3-nitrostyrene cross-linked with by weight of divinylbenzene copolymer of N-hydroxysuccinimide and ethylene.
EXAMPLE 4 0.5g- (3.55 mmoles) poly-N-hydroxysuccinimide was dissolved in 30 ml. dimethylformamide with warming to 50 - 60°C for 15 - 30 minutes. Then a solution of lg. (ca. 3.5· mmoles) of D(-)-oc-N- carbobenzoxyaminophenylacetic acid in 5 ml. dimethylformamide was added, followed by 825 mg. (4 mmoles) of N, N' -dicyclohexylcarbodiimide in 5 ml. of dimethyiformamide. The mixture was stirred at room temperature for 12 hours, filtered and the filtrate was poured into 10 volumes of ethanol. The solid product was recovered by spinning in a centifuge, washed twice with ethanol by decantation and dried in vacuo at room temperature. The yield of polymer was 0.85g. and it contained 2.1 mmoles of a-N-carboben- z. ^aibyamino-phenylacetyl residue per gram. Then 0.25g. of this polymer in 3ml. glacial acetic acid was treated with 3ml. of 8$ hydrogen bromide in acetic acid, stirred for 90 minutes at room temperature and the polymer was separated and washed in turn with glacial acetic acid, isopropanol and ether and then dried in vacuo to give 0.2g, polymer containing a-aminophenylacetyl residues. The HBr content of the resin as determined by the Volhard method was 2.3 mmoles per gram.
EXAMPLE 5 60 mg. (Ο.25 mmoles) of the .potassium salt of 6-aminopenicillanic acid was added to 4. ml. of a dime hylformamide suspension containing polymer No.l of Table I in an amount corresponding to 1 mmole of phenylacetyl residue. The reaction mixture was stirred for 1 hour at room temperature and thereafter the polymer was removed by centri-fugation, washed twice with dimethylformamide containing 10$ water and the washings and filtrate were combined. Prom the combined solution the solution was evaporated at low pressure, and the residue was dissolved in ethyl acetatej the resulting solution washed with 0.01 N hydrochloric acid and water, then dried over anhydrous filtered and the solvent was evaporated in vacuo. The yield of benzylpenicillin as determined by iodine titration, sulphur analysis and bioassay corresponded to 92$ of the theory.
The conversion of the benzylpenicillin into its potassium salt is effected by addition of an equivalent amount of an aqueous solution of potassium bicarbonate, followed by lyophilization.
EXAMPLE 6 By repeating the procedure of Example 5 with polyacylated polymers of Table I, other penicillins were prepared, as shown in Table II.
TABLE II Polyacylated polymer of Table I Product Yield used as acylating agent, No. T~ Denz lponlcillto 90 98- 6 51 3 2, 6-Dimethoxyphenyl- penicillln 76 3- ( 2-Chiorophenyl) - 5-methyl-4-isoxazolyl- penicillin 5#-70 a-Phenoxyethyl- penicillin 95 4 a-Carboxybenzyl- penicillin 100 EXAMPLE 7 A column measuring 1 cm. in diameter was packed 10 cm. high with approximately 4 g. of the polyacylated polymer No. 1 of Table I containing approximately 8 mmoles of phenylacetyl residue, in the following manner. The particulate polymer was suspended in dimethylformamide containing of water and the small-size floating particles were removed. The remaining particles were filtered off and mixed with sand in a ratio of polymer to sand of 5 : 1 · The resulting mixture was suspended in dimethylformamide containing $ of water and filled into the column, and the particles were allowed to settle. Then a solution containing 0.5 mmoles of the potassium salt of 6-aminopenicillanic acid in 10 ml. of dimethylformamide was passed twice through the column in about 2.5 hours. From the bottom of the column benzylpenicillin was withdrawn in a yield of 98$.
EXAMPLE 8 The polymer prepared as described in Example 4 was suspended in di ethylformamide and a cold solution of 6-aminopenicillanic acid in aqueous potassium bicarbonate was added, so that the water content of the final mixture was 15 by weight and the molar ratio of activated a-aminophenylacetyl residues to 6-aminopenicillanic acid was 4 : 1. The reaction mixture was stirred for 2 hours at room temperature. Then an aliquot of the reaction mixture was mixed with citrate buffer at pH 2.2 and the solution was examined in an amino acid analyser (Beckman Model 120C) with citrate buffer at pH 4.26 as eluent to determine the amount of D(-)-a-aminobenzylpenicillin present.
Claims (5)
1. A process for the N-acylation of 6-amino- penicillanic acid, which process comprises contacting a solution containing 6-aminopenicillanic acid or a salt, ester, amide or other functional derivative thereof with a solid acylating polymer substantially insoluble in said solution and comprising recurring groups -RCOB-, wherein RCO is an organic acyl radical and 3 is an activated radical in the polymer, then subsequently separating solid material from the solution and recovering therefrom the N-acyl derivative or non-toxic salt thereof.
2. A process as claimed in claim 1 wherein the acylating polymer has the formula : wherein RCO and B are as defined in claim 1 and A is a recurring portion of the backbone df a synthetic polymer or part of a natural polymer which may be modified, and n is an integer.
3. A process as claimed in claim 1 or claim 2, Wherein the penicillin being prepared is a-amino-benzylpenicillin.
4. A process for preparing penicillins substantially as described with reference to any one of Examples 5 to 8 hereinbefore set forth.
5. Pencillins and non-toxic salts thereof when prepared by a process as claimed in any of claims 1 to For V e A.F P'lcants
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB03840/68A GB1268631A (en) | 1968-03-21 | 1968-03-21 | Penicillins |
Publications (2)
Publication Number | Publication Date |
---|---|
IL31807A0 IL31807A0 (en) | 1969-05-28 |
IL31807A true IL31807A (en) | 1973-03-30 |
Family
ID=10030313
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL31807A IL31807A (en) | 1968-03-21 | 1969-03-13 | Process for the n-acylation of 6-aminopenicillanic acid |
Country Status (17)
Country | Link |
---|---|
JP (1) | JPS4948436B1 (en) |
AT (1) | AT285816B (en) |
BE (1) | BE730272A (en) |
BR (1) | BR6907214D0 (en) |
CH (1) | CH537414A (en) |
CS (1) | CS154638B2 (en) |
DE (1) | DE1913486A1 (en) |
DK (1) | DK131861C (en) |
ES (1) | ES364962A1 (en) |
FI (1) | FI50424C (en) |
FR (1) | FR2035797B1 (en) |
GB (1) | GB1268631A (en) |
IE (1) | IE32664B1 (en) |
IL (1) | IL31807A (en) |
NL (1) | NL6904041A (en) |
PL (1) | PL79945B1 (en) |
SE (1) | SE359094B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE794118A (en) * | 1972-01-18 | 1973-07-16 | Yeda Research And Dev Cy Ltd | CARBOXYLIC ACID ACYLATION PROCESS |
-
1968
- 1968-03-21 GB GB03840/68A patent/GB1268631A/en not_active Expired
-
1969
- 1969-03-07 IE IE306/69A patent/IE32664B1/en unknown
- 1969-03-13 IL IL31807A patent/IL31807A/en unknown
- 1969-03-14 NL NL6904041A patent/NL6904041A/xx unknown
- 1969-03-17 DE DE19691913486 patent/DE1913486A1/en active Pending
- 1969-03-17 BR BR207214/69A patent/BR6907214D0/en unknown
- 1969-03-18 ES ES364962A patent/ES364962A1/en not_active Expired
- 1969-03-18 SE SE03761/69A patent/SE359094B/xx unknown
- 1969-03-19 CH CH417269A patent/CH537414A/en not_active IP Right Cessation
- 1969-03-19 DK DK150069A patent/DK131861C/en active
- 1969-03-19 AT AT272269A patent/AT285816B/en not_active IP Right Cessation
- 1969-03-20 CS CS200069A patent/CS154638B2/cs unknown
- 1969-03-20 FR FR6908017A patent/FR2035797B1/fr not_active Expired
- 1969-03-20 JP JP44020797A patent/JPS4948436B1/ja active Pending
- 1969-03-20 PL PL1969132469A patent/PL79945B1/pl unknown
- 1969-03-20 FI FI690816A patent/FI50424C/en active
- 1969-03-21 BE BE730272D patent/BE730272A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
BR6907214D0 (en) | 1973-03-13 |
FR2035797B1 (en) | 1974-01-11 |
IE32664L (en) | 1969-09-21 |
DK131861B (en) | 1975-09-15 |
CS154638B2 (en) | 1974-04-30 |
BE730272A (en) | 1969-09-01 |
SE359094B (en) | 1973-08-20 |
DK131861C (en) | 1976-03-22 |
FI50424C (en) | 1976-03-10 |
GB1268631A (en) | 1972-03-29 |
IE32664B1 (en) | 1973-10-17 |
NL6904041A (en) | 1969-09-23 |
FI50424B (en) | 1975-12-01 |
DE1913486A1 (en) | 1969-10-30 |
AT285816B (en) | 1970-11-10 |
ES364962A1 (en) | 1971-02-16 |
FR2035797A1 (en) | 1970-12-24 |
JPS4948436B1 (en) | 1974-12-21 |
PL79945B1 (en) | 1975-08-30 |
CH537414A (en) | 1973-05-31 |
IL31807A0 (en) | 1969-05-28 |
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