US3281461A - Process for preparing penicillamine - Google Patents

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US3281461A
US3281461A US322014A US32201463A US3281461A US 3281461 A US3281461 A US 3281461A US 322014 A US322014 A US 322014A US 32201463 A US32201463 A US 32201463A US 3281461 A US3281461 A US 3281461A
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penicillamine
solution
penilloaldehyde
acid
yield
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Restivo Albert Robert
Frank A Dondzila
Jr Hugh Murphy
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues

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  • This invention relates to an improved process for preparing penicillamine and, more particularly, to an improved process for preparing penicillamine by degradation of a penicillin, such as penicillin G.
  • penicillins could be converted to penicillamine by a series of steps involving alkaline hydrolysis of the penicillin to the corresponding penicilloic acid, decarboxylation of the penicilloic acid to penilloic acid, treatment of the penilloic acid with a mercuric salt, such as mercuric chloride, to yield a penicillamine-mercuric salt complex, isolation of the complex, and conversion of the complex to penicillamine by treatment with hydrogen sulfide.
  • a mercuric salt such as mercuric chloride
  • the penicillamine thus formed could be further purified and recovered in higher yield if it was first converted to its isopropylidene derivative, by treatment with acetone, and then reconverted to a salt of penicillamine by reacting the isopropylidene derivative with an acid, such as hydrochloric acid (see British Specification No. 854,339).
  • the main interfering by-product is a penilloaldehyde (e.g., benzyl penilloaldehyde if penicillin G is used as the starting material), which, if not removed prior to the conversion of the mercuric complex, greatly reduces the recoverable yield of penicillamine.
  • penilloaldehyde e.g., benzyl penilloaldehyde if penicillin G is used as the starting material
  • the process of this invention which in its broadest sense entails the step of removing the penilloaldehyde formed in the conversion of a penicillin to penicillamine prior to the conversion of a solution of the penicillamine-mercuric salt complex formed therein to penicillamine.
  • This removal may be achieved by solvent extraction, but preferably is accomplished by converting the penilloaldehyde to an insoluble derivative by treatment with a carbonyl reagent.
  • the penicillamine-mercuric salt complex is dissolved, if not already in solution, in an aqueous or aqueous alcoholic solution, the desired carbonyl reagent is added, and the precipitated derivative is removed as by filtration or centrifugation.
  • the reaction is preferably carried out under acidic conditions.
  • the filtrate, freed from the undesired penilloaldehyde, is then further treated in the manner known to the art to ultimately yield D-penicillamine or a salt thereof.
  • penicillin G is penicillin G.
  • the penicillin preferably in the form of a water-soluble salt, such as an alkali metal salt (e.g., potassium benzylpenicillin) is dissolved in water.
  • a base such as an alkali metal hydroxide (e.g., sodium hydroxide), is then added to hydrolyze the penicillin to the corresponding penicilloic acid.
  • the penicilloic acid is then decarboxylated by treat ment with a concentrated strong acid, such as a concentrated mineral acid (e.g., hydrochloric acid) to yield the corresponding penilloic acid.
  • a concentrated strong acid such as a concentrated mineral acid (e.g., hydrochloric acid)
  • the penilloic acid is then treated with a mercuric salt, such as a mercuric halide (e.g., mercuric chloride) to yield the mercuric salt com plex of penicillamine.
  • a mercuric salt such as a mercuric halide (e.g., mercuric chloride)
  • sufficient acid is added to yield a final pH of about 1.3 to about 1.8.
  • the resulting solution is then filtered or centrifuged to remove insoluble impurities.
  • the resulting solution of the mercuric salt complex of penicillamine is then treated to remove penilloaldehyde.
  • this removal may be done by solvent extraction, as by treating with chloroform, ethyl acetate or methylene chloride, in accordance with the preferred method of this invention, the removal is accomplished by treat ing the solution with a carbonyl reagent to yield an insoluble derivative of the penilloaldehyde.
  • the preferred reagents include hyd-roxylamine, semicarmazide, thiosemicarbazide, substituted semicarbazides, substituted benzohydrazides, and optimally hydrazines, such as phenyl hydrazine and substituted phenyl hydrazines, such as nitro, dinitro, halo (e.g., bromo) and dihalo (e.g., dichloro) phenyl hydrazines.
  • hyd-roxylamine such as phenyl hydrazine and substituted phenyl hydrazines, such as nitro, dinitro, halo (e.g., bromo) and dihalo (e.g., dichloro) phenyl hydrazines.
  • the solution is preferably heated, optimally to a temperature in the range of about C. to about C.
  • the resulting mixture is then allowed to cool to room temperature and the precipitated derivative of the penilloaldehyde is removed by filtration or centrifugation.
  • the mixture is treated with additional acid, optimally about one mole of concentrated mineral acid per mole of penicillin, to assure that no complex is coprecipitated with the penilloaldehyde derivative.
  • the filtrate containing the mercuric salt complex of penicillamine in solution
  • the precipitate is removed by filtration or centrifugation, and the resulting solution is mixed with an ester, such as a lower alkyl ester of a lower alkanoic acid (e.g., isobutyl acetate, ethyl acetate and isopropyl acetate), or an alcohol, such as a lower alkanol (e.g., isopropyl alcohol and n-propyl alcohol), or a mixture thereof, and refluxed and/ or distilled to remove the water. After all the water has been removed, the reaction mixture is cooled and filtered.
  • an ester such as a lower alkyl ester of a lower alkanoic acid (e.g., isobutyl acetate, ethyl acetate and isopropyl acetate)
  • an alcohol such as a lower alkanol (e.g., isopropyl alcohol and
  • the dissolved penicillamine can then be further purified by converting it to the isopropylidene derivative by treatment with acetone and converted to a salt of more purified penicillamine as more fully detailed in Example 1.
  • the process of this invention involving the step of removing the penilloaldehyde from the solution of mercuric salt complex of penicillamine prior to treatment with hydrogen sulfide, is more practical for the commercial production of penicillamine than is any previously known method including the one described in British specification 854,339 for a number of reasons.
  • the yield of recoverable penicillamine is higher.
  • the volumes of solvents used are smaller, the penilloic acid is not isolated, less mercuric salt is used, the mercuric salt complex is not isolated, and there is no need to remove all solvent by concentration to dryness, a step which is impractical on a commercial scale operation. All of these advantages either reduce the cost of the operation and/ or increase the yield or purity of the recoverable penicillamine.
  • Penicillamine Hydrochloride (a) Preparation of mercuric chloride complex of penicillamine.-T0 a solution of 372 g. (1 mole) of potassium benzyl-penicillin in 940 ml. of distilled water at room temperature is added a solution of 40 g. (1 mole) of sodium hydroxide in 180 ml. of distilled water over a period of one-half hour. The solution is then stirred for two hours at room temperature. While maintaining room temperature, 67 ml. of concentrated hydrochloric acid is added at a slow rate. This solution is then added, over a period of time of one-half hour, to a solution of 271 g.
  • step (b) Removal of benzylpenilloaldehyde.To the filtrate obtained in step (a), warmed to 50 is slowly added 108 g. (1 mole) of phenyl hydrazine. The mixture is cooled to room temperature and 84 ml. of concentrated hydrochloric acid are added. The mixture is agitated briefly and the precipitated benzylpenilloaldehyde phenylhydrazone is filtered off.
  • step (c) Preparation of isopropylidene penicillamine hydrochlorfde.-To the filtrate obtained in step (b) is added at 25 a total of 85 g. of hydrogen sulfide. The precipitated HgS is filtered off and the filtrate is concentrated under reduced pressure to a volume of 200-500 ml. Following a polish filtration, the product-rich concentrate is mixed with 1.5 l. of isobutyl acetate. The mixture is refluxed at about 40 under reduced pressure in equipment fitted with a water separation device. When no further water separates, the batch is cooled to and filtered. The reactor is washed with 1 l. of acetone, which is used also to wash the cake. The cake is further washed with 200 ml.
  • step (d) Preparation of penicillamine hydrochl0ride.
  • the 178 g. of isopropylidene penicillamine hydrochloride obtained in step (c) is dissolved in 350 ml. of distilled water.
  • the solution is heated at 9095 for one to one and onehalf hours, removing acetone by distillation through an efficient column.
  • the mixture is refluxed at a temperature of about 40 under reduced pressure in equipment fitted wit-h a water separation device. When no further water separates, the pressure is adjusted so that the mixture distills at a vapor temperature of 8388. A total of 6 50 ml. of distillate is collected.
  • the batch is allowed to cool to 50 and then filtered.
  • the crystals are washed with isobutyl acetate and then dried at for 24 hours.
  • the virtually anhydrous penicillamine hydrochloride obtained weighs about 128 g. (69% from potassium benzyl-pencillin).
  • step (b) is omitted from the procedure of Example 1, the yield of penicillamine hydrochloride is reduced to about 30%.
  • EXAMPLE 3 To a filtrate obtained by the procedure of step (a) of Example 1 is added a solution of 69 g. of hydroxylamine hydrochloride in water. The solution is warmed briefly at After refrigeration, the precipitated benzylpenilloaldehydeoxime is filtered off. The filtrate is then worked up as described in steps (c) and (d) of Example 1 to yield penicillamine hydrochloride in an overall yield of about to EXAMPLE 4 (a) Preparation of mercuric chloride complex of penicillamine.A mixture of 372 g. (1 mole) of potassium benzylpenicillin, 1.5 l. of isopropanol and 168 ml.
  • step (b) Preparation of penicillamine lzydrochloride.
  • the clear solution obtained in step (a) is then treated with 2,4-dinitrophenylhydrazine as described in Example 2 and then further worked up as described in Example 2 to yield penicillamine hydrochloride in an overall yield of about 58-61%.
  • a process as in claim 1 wherein the reagent is dinitrophenylhydrazine.
  • a process for separating a penilloaldehyde from a mixture with a penicillamine-mercuric salt complex which comprises forming an aqueous solution of said penilloaldehyde and penicillamine-mercuric salt complex by acidifying to a pH within the range of about 1.3 to about 1.8 and precipitating the penilloaldehyde from this acidified solution with a reagent selected from the group consisting of hydroxylamine, semicarbazide, thiosemicarbazide, benzohydrazide, phenylhydrazine and substi- References Cited by the Examiner FOREIGN PATENTS 854,339 11/1960 Great Britain.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description

United States Patent EROCESS FQR PREPARING PENICKLLAMKNE Albert Robert Restivo, Belleville, Frank A. Dondz1la, East Brunswick, and Hugh liiiurphy, In, EdlSOH, NJL, assignors, by mesne assignments, to E. IR. Squibb & Sons, inc, New York, N.Y., a corporation of Delaware No Drawing. Filed Nov. 7, 1963, Ser. No. 322,014
8 Claims. (Cl. 260-534) This invention relates to an improved process for preparing penicillamine and, more particularly, to an improved process for preparing penicillamine by degradation of a penicillin, such as penicillin G.
Prior to this invention it was known that penicillins could be converted to penicillamine by a series of steps involving alkaline hydrolysis of the penicillin to the corresponding penicilloic acid, decarboxylation of the penicilloic acid to penilloic acid, treatment of the penilloic acid with a mercuric salt, such as mercuric chloride, to yield a penicillamine-mercuric salt complex, isolation of the complex, and conversion of the complex to penicillamine by treatment with hydrogen sulfide. Moreover, it was known that the penicillamine thus formed could be further purified and recovered in higher yield if it was first converted to its isopropylidene derivative, by treatment with acetone, and then reconverted to a salt of penicillamine by reacting the isopropylidene derivative with an acid, such as hydrochloric acid (see British Specification No. 854,339).
Unfortunately, when such process is carried out, in addition to the desired intermediates and end products, various undesired by-products are also found, which interfere with the desired process and the recovery of the desired products. The main interfering by-product is a penilloaldehyde (e.g., benzyl penilloaldehyde if penicillin G is used as the starting material), which, if not removed prior to the conversion of the mercuric complex, greatly reduces the recoverable yield of penicillamine. In fact, if the reactions are carried out in an aqueous alcoholic menstruum the yield of desired product, if the penilloaldehyde is not removed, is reduced to substantially zero.
It is an object of this invention, therefore, to provide an improved method for preparing penicillamine from penicillins.
It is another object of this invention to provide in the process for preparing penicillamine from penicillins for the removal of penilloaldehydes prior to the conversion of the penicillaminemercuric salt complex to penicillamine.
These objects are accomplished by the process of this invention which in its broadest sense entails the step of removing the penilloaldehyde formed in the conversion of a penicillin to penicillamine prior to the conversion of a solution of the penicillamine-mercuric salt complex formed therein to penicillamine. This removal may be achieved by solvent extraction, but preferably is accomplished by converting the penilloaldehyde to an insoluble derivative by treatment with a carbonyl reagent. To accomplish this the penicillamine-mercuric salt complex is dissolved, if not already in solution, in an aqueous or aqueous alcoholic solution, the desired carbonyl reagent is added, and the precipitated derivative is removed as by filtration or centrifugation. To assure that only the penilloaldehyde derivative is precipitated, the reaction is preferably carried out under acidic conditions. The filtrate, freed from the undesired penilloaldehyde, is then further treated in the manner known to the art to ultimately yield D-penicillamine or a salt thereof.
Although any penicillin may be used as the starting material and such penicillins as Z- entenyl-penicillin and p-hydroxybenzyl penicillin are operative, because of its availability and comparatively low cost, the preferred penicillin is penicillin G. The penicillin, preferably in the form of a water-soluble salt, such as an alkali metal salt (e.g., potassium benzylpenicillin) is dissolved in water. A base, such as an alkali metal hydroxide (e.g., sodium hydroxide), is then added to hydrolyze the penicillin to the corresponding penicilloic acid.
The penicilloic acid is then decarboxylated by treat ment with a concentrated strong acid, such as a concentrated mineral acid (e.g., hydrochloric acid) to yield the corresponding penilloic acid. The penilloic acid is then treated with a mercuric salt, such as a mercuric halide (e.g., mercuric chloride) to yield the mercuric salt com plex of penicillamine. To assure that the complex re mains in solution, sufficient acid is added to yield a final pH of about 1.3 to about 1.8. The resulting solution is then filtered or centrifuged to remove insoluble impurities.
In accordance with the improvement of this invention, the resulting solution of the mercuric salt complex of penicillamine is then treated to remove penilloaldehyde. Although this removal may be done by solvent extraction, as by treating with chloroform, ethyl acetate or methylene chloride, in accordance with the preferred method of this invention, the removal is accomplished by treat ing the solution with a carbonyl reagent to yield an insoluble derivative of the penilloaldehyde. Although any carbonyl reagent that forms an insoluble derivative with penilloaldehyde may be used, the preferred reagents include hyd-roxylamine, semicarmazide, thiosemicarbazide, substituted semicarbazides, substituted benzohydrazides, and optimally hydrazines, such as phenyl hydrazine and substituted phenyl hydrazines, such as nitro, dinitro, halo (e.g., bromo) and dihalo (e.g., dichloro) phenyl hydrazines. To aid in the rate of reaction between the penilloaldehyde and the carbonyl reagent, the solution is preferably heated, optimally to a temperature in the range of about C. to about C. The resulting mixture is then allowed to cool to room temperature and the precipitated derivative of the penilloaldehyde is removed by filtration or centrifugation. In the preferred method of this invention, the mixture is treated with additional acid, optimally about one mole of concentrated mineral acid per mole of penicillin, to assure that no complex is coprecipitated with the penilloaldehyde derivative.
After removal of the interfering penilloaldehyde byproduct, the filtrate, containing the mercuric salt complex of penicillamine in solution, is treated with hydrogen sul fide to precipitate the mercury as the insoluble sulfide, the precipitate is removed by filtration or centrifugation, and the resulting solution is mixed with an ester, such as a lower alkyl ester of a lower alkanoic acid (e.g., isobutyl acetate, ethyl acetate and isopropyl acetate), or an alcohol, such as a lower alkanol (e.g., isopropyl alcohol and n-propyl alcohol), or a mixture thereof, and refluxed and/ or distilled to remove the water. After all the water has been removed, the reaction mixture is cooled and filtered.
The dissolved penicillamine can then be further purified by converting it to the isopropylidene derivative by treatment with acetone and converted to a salt of more purified penicillamine as more fully detailed in Example 1.
The process of this invention, involving the step of removing the penilloaldehyde from the solution of mercuric salt complex of penicillamine prior to treatment with hydrogen sulfide, is more practical for the commercial production of penicillamine than is any previously known method including the one described in British specification 854,339 for a number of reasons. In the first place, the yield of recoverable penicillamine is higher. In addition, the volumes of solvents used are smaller, the penilloic acid is not isolated, less mercuric salt is used, the mercuric salt complex is not isolated, and there is no need to remove all solvent by concentration to dryness, a step which is impractical on a commercial scale operation. All of these advantages either reduce the cost of the operation and/ or increase the yield or purity of the recoverable penicillamine.
The following examples illustrate the invention (all temperatures being in centigrade):
EXAMPLE 1 Penicillamine Hydrochloride (a) Preparation of mercuric chloride complex of penicillamine.-T0 a solution of 372 g. (1 mole) of potassium benzyl-penicillin in 940 ml. of distilled water at room temperature is added a solution of 40 g. (1 mole) of sodium hydroxide in 180 ml. of distilled water over a period of one-half hour. The solution is then stirred for two hours at room temperature. While maintaining room temperature, 67 ml. of concentrated hydrochloric acid is added at a slow rate. This solution is then added, over a period of time of one-half hour, to a solution of 271 g. (1 mole) of HgCl in 3.52 l. of distilled water in the presence of 50 g. of Hyflo and 5 ml. of octyl alcohol. After one hour of agitation, the resulting mixture is treated with 185 ml. of concentrated hydrochloric acid and filtered.
(b) Removal of benzylpenilloaldehyde.To the filtrate obtained in step (a), warmed to 50 is slowly added 108 g. (1 mole) of phenyl hydrazine. The mixture is cooled to room temperature and 84 ml. of concentrated hydrochloric acid are added. The mixture is agitated briefly and the precipitated benzylpenilloaldehyde phenylhydrazone is filtered off.
(c) Preparation of isopropylidene penicillamine hydrochlorfde.-To the filtrate obtained in step (b) is added at 25 a total of 85 g. of hydrogen sulfide. The precipitated HgS is filtered off and the filtrate is concentrated under reduced pressure to a volume of 200-500 ml. Following a polish filtration, the product-rich concentrate is mixed with 1.5 l. of isobutyl acetate. The mixture is refluxed at about 40 under reduced pressure in equipment fitted with a water separation device. When no further water separates, the batch is cooled to and filtered. The reactor is washed with 1 l. of acetone, which is used also to wash the cake. The cake is further washed with 200 ml. of acetone. The acetone washes are added to the isobutyl acetate filtrate and the mixture is refluxed for 20-30 minutes. After a holding period of one hour at 5, the crystals of isopropylidene penicillamine hydrochloride are filtered and washed with 200 ml. of acetone. On drying for twelve hours at 25 this product, containing one mole of water, weighs about 178 g. (73%).
(d) Preparation of penicillamine hydrochl0ride.The 178 g. of isopropylidene penicillamine hydrochloride obtained in step (c) is dissolved in 350 ml. of distilled water. The solution is heated at 9095 for one to one and onehalf hours, removing acetone by distillation through an efficient column. There is then added 2.6 l. of isobutyl acetate. The mixture is refluxed at a temperature of about 40 under reduced pressure in equipment fitted wit-h a water separation device. When no further water separates, the pressure is adjusted so that the mixture distills at a vapor temperature of 8388. A total of 6 50 ml. of distillate is collected. The batch is allowed to cool to 50 and then filtered. The crystals are washed with isobutyl acetate and then dried at for 24 hours. The virtually anhydrous penicillamine hydrochloride obtained weighs about 128 g. (69% from potassium benzyl-pencillin).
Following the procedure of Example 1 but substituting ethyl acetate, isopropyl acetate, isopropanol or n-propanol for the isobutyl acetate in steps (0) and (d), results in substantially the same yield of penicillamine hydrochloride.
By way of contrast, if step (b) is omitted from the procedure of Example 1, the yield of penicillamine hydrochloride is reduced to about 30%.
4 EXAMPLE 2 A filtrate obtained by the procedure of step (a) of Example 1 is added to a hot solution of 198 g. of 2,4-dinitrophenylhy-drazine in 20 l. of 95% ethanol and 300 ml. of concentrated hydrochloric acid. On cooling, the precipitated benzylpenilloaldehyde 2,4-dinitrophenyl-hydrazone is filtered off. After distilling ofl' the ethanol, the filtrate is worked up as described in steps (0) and (d) of Example 1 to yield penicillamine hydrochloride in approximately the same overall yield as was obtained in Example 1.
EXAMPLE 3 To a filtrate obtained by the procedure of step (a) of Example 1 is added a solution of 69 g. of hydroxylamine hydrochloride in water. The solution is warmed briefly at After refrigeration, the precipitated benzylpenilloaldehydeoxime is filtered off. The filtrate is then worked up as described in steps (c) and (d) of Example 1 to yield penicillamine hydrochloride in an overall yield of about to EXAMPLE 4 (a) Preparation of mercuric chloride complex of penicillamine.A mixture of 372 g. (1 mole) of potassium benzylpenicillin, 1.5 l. of isopropanol and 168 ml. of concentrated hydrochloric acid is refluxed for one hour. After cooling to 5, the precipitated salt is removed by filtration. To the filtrate is added a solution of 271 g. (1 mole) of HgCl in 2.7 l. of 50% isopropanol.
(b) Preparation of penicillamine lzydrochloride.The clear solution obtained in step (a) is then treated with 2,4-dinitrophenylhydrazine as described in Example 2 and then further worked up as described in Example 2 to yield penicillamine hydrochloride in an overall yield of about 58-61%.
By way of contrast, if the step of adding 2,4-dinitrophenyl-hydrazine is omitted from the procedure of Example 4, the yield of penicillamine hydrochloride is substantially zero.
EXAMPLE 5 Penicillamine Following the procedure of Example 1 but substituting the following procedure for step ((1) yields penicillamine base:
40 g. of isopropylidene penicillamine hydrochloride obtained in step (c) of Example 1 is dissolved in ml. of distilled water. The solution is heated at 95 for about 45 minutes, removing the formed acetone by distillation. The solution is polish filtered and diluted with 800 ml. of isopropanol. The mixture is distilled at atmospheric pressure to remove about 500 ml. of solvent, leaving a residual solution of about 380 ml., consisting of approximately isopropanol. The solution is cooled to 50, blanketed with nitrogen and treated with 6 ml. of distilled triethylamine. A small amount of gelatinous precipitate forms but it is quickly converted to crystals by agitation. A further 17 ml. of triethylarnine is added over 20 minutes to complete crystallization of the product. The crystals of D-penicillamine are cooled at 5 for one hour, filtered and washed well with isopropanol and dried for 20 hours at 55 to yield about 23.0 g. of D-penicillamine product.
The invention may be variously otherwise embodied within the scope of the appended claims.
What is claimed is:
1. In the process for converting penicillins to penicillamine by hydrolysis of penicillin to penicilloic acid, decarboxylating the penicilloic acid to penilloic acid, treating the penilloic acid with a mercuric salt to yield a solution of penicillamine-mercuric salt complex and a byproduct penilloaldehyde, and converting said complex to penicillamine, the improvement which comprises separating the by-product penilloaldehyde from the penicillaminemercuric salt complex by acidifying said solution to a pH within the range of about 1.3 to about 1.8 and precipitating the by-product penilloaldehyde from this acidified solution with a reagent selected from the group consisting of hydroxylamine, semicarbazide, thiosemicarbazide, benzohydrazide, phenylhydrazine and substituted phenylhydrazine, wherein the substituent is a member of the group consisting of nitro, dinitro, halo and dihalo.
2. A process in accordance with claim 1 wherein the reagent is phenylhydrazine.
3. A process as in claim 1 wherein the reagent is dinitrophenylhydrazine.
4. A process as in claim 1 wherein the reagent is hydroxylamine.
5. A process for separating a penilloaldehyde from a mixture with a penicillamine-mercuric salt complex which comprises forming an aqueous solution of said penilloaldehyde and penicillamine-mercuric salt complex by acidifying to a pH within the range of about 1.3 to about 1.8 and precipitating the penilloaldehyde from this acidified solution with a reagent selected from the group consisting of hydroxylamine, semicarbazide, thiosemicarbazide, benzohydrazide, phenylhydrazine and substi- References Cited by the Examiner FOREIGN PATENTS 854,339 11/1960 Great Britain.
OTHER REFERENCES Clarke: The chemistry of Penicillin, pp. 476485 (1949).
LORRAINE A. WEINBERGER, Primary Examiner.
LEON ZITVER, Examiner.
D. P. CLARKE, A. P. HALLUIN, Assistant Examiners.

Claims (1)

1. IN THE PROCESS FOR CONVERTING PENICILLINS TO PENICILLAMINE BY HYDROLYSIS OF PENICILLIN TO PENICILLOIC ACID, DECARBOXYLATING THE PENICILLOIC ACID TO PENILLOIC ACID, TREATING THE PENILLOIC ACID WITH A MERCURIC SALT TO YIELD A SOLUTION OF PENICILLAMINE-MERCURIC SALT COMPLEX AND A BYPRODUCT PENILLOALDEHYDE, AND CONVERTING SAID COMPLEX TO PENICILLAMINE, THE IMPROVEMENT WHICH COMPRISES SEPARATING THE BY-PRODUCT PENILLOALDEHYDE FROM THE PENICILLAMINEMERCURIC SALT COMPLEX BY ACIDIFYING SAID SOLUTION TO A PH WITHIN THE RANGE OF ABOUT 1.3 TO ABOUT 1.8 AND PRECIPTATING THE BY-PRODUCT PENILLOALDEHYDE FROM THIS ACIDIFIED SOLUTION WITH A REAGENT SELECTED FROM THE GROUP CONSISTING OF HYDROXYLAMINE, SEMICARBAZIDE, THIIOSEMICARBAZIDE, BENZOHYDRATE, PHENYLHYDRAZINE AND SUBSTITUTED PHENYLHYDRAZINE, WHEREIN THE SUBSTITUENT IS A MEMBER OF THE GROUP CONSISTING OF NITRO, DINITRO, HALO AND DIHALO.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3466312A (en) * 1964-06-08 1969-09-09 Robins Co Inc A H Derivatives of dialkyl-cysteines and allied compounds
FR2150319A1 (en) * 1971-08-24 1973-04-06 Degussa
US3894067A (en) * 1971-03-24 1975-07-08 Heyl & Co Production of penicillamine-mercuric-mercaptide and of penicillamine and acid addition salts of penicillamine
US3968154A (en) * 1971-03-24 1976-07-06 Firma Heyl & Co. Chemisch-Pharmazeutische Fabrik Method of producing penicillamine
CN102627592A (en) * 2012-03-16 2012-08-08 石家庄学院 Preparation method of high-purity D-penicillamine

Citations (1)

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Publication number Priority date Publication date Assignee Title
GB854339A (en) * 1957-08-22 1960-11-16 Distillers Co Yeast Ltd Penicillamine production process

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB854339A (en) * 1957-08-22 1960-11-16 Distillers Co Yeast Ltd Penicillamine production process

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3466312A (en) * 1964-06-08 1969-09-09 Robins Co Inc A H Derivatives of dialkyl-cysteines and allied compounds
US3894067A (en) * 1971-03-24 1975-07-08 Heyl & Co Production of penicillamine-mercuric-mercaptide and of penicillamine and acid addition salts of penicillamine
US3968154A (en) * 1971-03-24 1976-07-06 Firma Heyl & Co. Chemisch-Pharmazeutische Fabrik Method of producing penicillamine
FR2150319A1 (en) * 1971-08-24 1973-04-06 Degussa
CN102627592A (en) * 2012-03-16 2012-08-08 石家庄学院 Preparation method of high-purity D-penicillamine

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