US2460139A - Alkamine esters of 2-chloro-4-amino benzoic acid - Google Patents

Alkamine esters of 2-chloro-4-amino benzoic acid Download PDF

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US2460139A
US2460139A US606476A US60647645A US2460139A US 2460139 A US2460139 A US 2460139A US 606476 A US606476 A US 606476A US 60647645 A US60647645 A US 60647645A US 2460139 A US2460139 A US 2460139A
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Henry C Marks
Martin I Rubin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

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  • the present invention relates to chemical compounds useful in the medical arts and :more particularly to local anesthetics.
  • the various local anesthetics derived from p-aminobenzoic acid of which procaine (diethylaminoethyl 4-aminobenzoate hydrochloride), commonly known by its trade name Novocaine, is a well-known example, are specific antagonists for the sulfonamides when present concurrently therewith in the animal body and inhibit the bacterlostatic action of the sulfonamides to such an extent that Novocaine, for example, cannot safely be used for cal anesthesia with a patient Who is under sulfonamide therapy.
  • procaine diethylaminoethyl 4-aminobenzoate hydrochloride
  • a further object of the invention is to provide compounds of good local anesthetic potency, low toxicity and good solubility which at the same time are bacteriostatie in themselves.
  • the invention is based on our discovery of certain novel compounds and their effectiveness for the purposes indicated.
  • These compounds are certain monohaiogenated derivatives of the amino alcohol esters of p-aminobenzoic acid.
  • the esters of this class when unhalogenated show a significant level of local anesthetic potency and are, because of their low toxicity, water solubility and other properties, suitable for use as local anesthetics except in the presence of the sulfonamide compounds, to which they are antagonistic and whose bacteriostatic action they inhibit.
  • the monohalogenated derivatives of the present invention not only show an increased anesthetic potency as contrasted with the known monohalogenated and unhalogenated esters but also are compatible with the sulfonamides and do not inhibit their bacteriostatic action.
  • the particular amino alcohol esters of monohalogenated p-aminobenzoic acid of the present invention exhibit, when tested in the usual manner against E. 0012', a bacteriostatic activity comparable to that of the sulfonamide compounds.
  • Some of the compounds of the preesnt inven tion have been found to possess a local anesthetic potency some tenfold reater than procaine. They are less toxic than procaine, showing a toxicity of the order of /3 that of procaine. They, therefore, may be said to have a flfteenfold therapeutic advantage over procaine, disregarding the advantages resulting from their freedom from antagonism to the sulfonamides.
  • the compounds when utilized concurrently with sulionamide in suppressing the growth of E. coli are free from any significant tendency to interfere with the bacteriostatic action of the suli'onamlde.
  • the compounds in the form of their salts are freely soluble in water. They also can be sterilized in aqueous solution by boiling without appreciable hydrolysis of the ester groups present.
  • the compounds are stable and otherwise suitable physically for the use indicated and free from any tendency to produce undesired physiological eiiects.
  • the compounds of the present invention comprise the amino alcohol esters of 2-chloro, 3- chloro and 3-fiuoro 4-aminobenzoic acids.
  • beta-diethylaminoethyl we have investigated and found suitable for the purposes of the present invention the beta-diethylaminoethyl, the gammadiethylaminopropyl, the beta diethylaminopropyl, the 2-n-amylamino-2-methyl-l-propyl, the beta-diethylamino-ethoxyethyl, the beta-dimethylaminoethyl, the beta-piperidinoethyl, the beta-(gamma-morpholino) ethyl.
  • the beta-di-nbutylaminoethyl the gamma-di-n-butylaminopropyl, the 2-n-butylamino-2-methyl-l-propyl.
  • the 2-n-propylamino-2-methyl-l-propyl the 2-isopropy1amino-2-methyl-1-propy1 alcohol and' esters of said monohalogenated p-aminobenzoic acids.
  • the preparation of the compounds of the present invention will be illustrated by a description of the preparation of diethylaminoethyl 2- chloro-4 aminobenzoate hydrochloride.
  • the preparation is carried out in two principal steps.
  • 2-chloro-4-aminobenzoyl chloride-hydrochloride is prepared by refluxing a mixture of 25 cc. of purified thlonyl chloride and g. of 2-chloro-4-aminobenzoic acid until all of the solid has gone into solution.
  • To the cooled solution is added 150 cc. of dry ethyl ether.
  • a brisk stream of dry hydrogen chloride is passed into the solution until the precipitation of 2-chloro-4-aminobenzoyi chloride hydrochloride is complete.
  • the acyl halide is removed by filtration and dried in a vacuum desiccator.
  • the diethylaminoethyl 2-chloro-4-aminobenzoate hydrochloride is prepared by refluxing equimolar proportions of the hydrochloride of beta-diethylaminoethanol in a suitable inert solvent such as a mixture of dry toluene and tetrachloroethane and the hydrochloride of 2-chloro-4-aminobenzoyl chloride until the reaction as indicated by the cessation of hydrogen chloride evolution is complete.
  • a suitable inert solvent such as a mixture of dry toluene and tetrachloroethane
  • esters prepared by this general procedure we have found the following compounds, besides the diethyi aminoethyl esters, to be particularly effective for the purposes of this invention:
  • the diethylaminoethyl 2-chloro-4-aminobenzoate hydrochloride prepared as described above showed, on pharmacological tests on the cornea of the rabbit, a local anesthetic potency approximately ten times that of procaine.
  • the toxicity of the compound as indicated by its M. L. D. in mice on intraperitoneal injection in aqueous solution was approximately that of procaine.
  • Diethylaminoethyl-2-ch.loro-4 aminobenzoate hydrochloride prepared as described above was incubated with liver tissue in simulation of the conditions encountered in the in vivo use of this type of compound. At the end of four hours the mixture was filtered and added to a culture of E. 0012'. After incubation for 24 hours at 37 C. it was revealed that this compound in concentration of 1.5 mg. had effectively prevented the growth of the organism. Procaine when subjected to an identical test failed to inhibit the growth of the bacteria.
  • the 3-chloro derivatives and the 3-fiuoro derivatives may be prepared in a similar manner using as a starting material the known corresponding halogen-i-aminobenzoic acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

- Patented Jan. 25, 1949 ALKAMINE ESTERS F 2-CHLORO-4-AMINO BENZOIO ACID Henry C. Marks, Glen Ridge, N. 1., and Martin I. Rubin, New York, N. Y., assignors to Wallace & Tier-nan Products, Inc., a corporation of New Jersey No Drawing. Application July 3-1, 1945, Serial No. 608,478
5 Claims.
The present invention relates to chemical compounds useful in the medical arts and :more particularly to local anesthetics.
The various sulfonamide compounds have in recent years come into extensive use in medicine for their bacteria-static effect in the treatment of a wide variety of infectious diseases and on the basis of extensive clinical use have been found to be valuable therapeutic agents for this purpose. One of the drawbacks to the use of the sulfonamides which has been encountered, however, is their ineffectiveness when employed concurrently with certain of the more widely used local anesthetics. Thus, the various local anesthetics derived from p-aminobenzoic acid, of which procaine (diethylaminoethyl 4-aminobenzoate hydrochloride), commonly known by its trade name Novocaine, is a well-known example, are specific antagonists for the sulfonamides when present concurrently therewith in the animal body and inhibit the bacterlostatic action of the sulfonamides to such an extent that Novocaine, for example, cannot safely be used for cal anesthesia with a patient Who is under sulfonamide therapy.
In those surgical procedures in which local anesthetics are used by methods of continuous perfusion of a body tissue, as in the recently developed caudal anesthesia procedure employed in childbirth, there is a definite risk of infection. It would be desirable to counteract this risk by the addition of a sulfonamlde to the anesthetic, but this is not possible when the anesthetic is one of those derived from p -aminobenzoic acid, of which procaine is a widely employed example.
It is an object of the invention to providecompounds which possess good local anesthetic potency, low toxicity, and good solubility, but which at the same time are free from any biotic antagonism to the sulfonamides.
A further object of the invention is to provide compounds of good local anesthetic potency, low toxicity and good solubility which at the same time are bacteriostatie in themselves.
The invention is based on our discovery of certain novel compounds and their effectiveness for the purposes indicated. These compounds are certain monohaiogenated derivatives of the amino alcohol esters of p-aminobenzoic acid. The esters of this class when unhalogenated show a significant level of local anesthetic potency and are, because of their low toxicity, water solubility and other properties, suitable for use as local anesthetics except in the presence of the sulfonamide compounds, to which they are antagonistic and whose bacteriostatic action they inhibit. The monohalogenated derivatives of the present invention not only show an increased anesthetic potency as contrasted with the known monohalogenated and unhalogenated esters but also are compatible with the sulfonamides and do not inhibit their bacteriostatic action. Likewise, in contrast to the monohalogenated amino alcohol esters of p-aminobenzoic acid known to the prior art, and indeed in contrast to certain new 'monohalogenated amino alcohol esters of D- aminobenzoic acid which we have prepared and describe below, the particular amino alcohol esters of monohalogenated p-aminobenzoic acid of the present invention exhibit, when tested in the usual manner against E. 0012', a bacteriostatic activity comparable to that of the sulfonamide compounds.
Some of the compounds of the preesnt inven tion have been found to possess a local anesthetic potency some tenfold reater than procaine. They are less toxic than procaine, showing a toxicity of the order of /3 that of procaine. They, therefore, may be said to have a flfteenfold therapeutic advantage over procaine, disregarding the advantages resulting from their freedom from antagonism to the sulfonamides. The compounds when utilized concurrently with sulionamide in suppressing the growth of E. coli are free from any significant tendency to interfere with the bacteriostatic action of the suli'onamlde.
The compounds in the form of their salts are freely soluble in water. They also can be sterilized in aqueous solution by boiling without appreciable hydrolysis of the ester groups present. The compounds are stable and otherwise suitable physically for the use indicated and free from any tendency to produce undesired physiological eiiects.
The compounds of the present invention comprise the amino alcohol esters of 2-chloro, 3- chloro and 3-fiuoro 4-aminobenzoic acids.
Among'these esters, we have investigated and found suitable for the purposes of the present invention the beta-diethylaminoethyl, the gammadiethylaminopropyl, the beta diethylaminopropyl, the 2-n-amylamino-2-methyl-l-propyl, the beta-diethylamino-ethoxyethyl, the beta-dimethylaminoethyl, the beta-piperidinoethyl, the beta-(gamma-morpholino) ethyl. the beta-di-nbutylaminoethyl, the gamma-di-n-butylaminopropyl, the 2-n-butylamino-2-methyl-l-propyl. the 2-n-propylamino-2-methyl-l-propyl, the 2-isopropy1amino-2-methyl-1-propy1 alcohol and' esters of said monohalogenated p-aminobenzoic acids.
The preparation of the compounds of the present invention will be illustrated by a description of the preparation of diethylaminoethyl 2- chloro-4 aminobenzoate hydrochloride. The preparation is carried out in two principal steps.
In the first step, 2-chloro-4-aminobenzoyl chloride-hydrochloride is prepared by refluxing a mixture of 25 cc. of purified thlonyl chloride and g. of 2-chloro-4-aminobenzoic acid until all of the solid has gone into solution. To the cooled solution is added 150 cc. of dry ethyl ether. A brisk stream of dry hydrogen chloride is passed into the solution until the precipitation of 2-chloro-4-aminobenzoyi chloride hydrochloride is complete. The acyl halide is removed by filtration and dried in a vacuum desiccator.
In the second step, the diethylaminoethyl 2-chloro-4-aminobenzoate hydrochloride is prepared by refluxing equimolar proportions of the hydrochloride of beta-diethylaminoethanol in a suitable inert solvent such as a mixture of dry toluene and tetrachloroethane and the hydrochloride of 2-chloro-4-aminobenzoyl chloride until the reaction as indicated by the cessation of hydrogen chloride evolution is complete. The
supernatant solvents are decanted from the reaction product which can be conveniently purified by crystallization from absolute ethanol. An alternative purification can be eflected by dissolving the reaction product in water. The ester base is liberated by rendering the clarified aqueous solution alkaline Removal of the base from the alkaline solution is achieved by extraction with a suitable solvent such as benzene or ether. The pure hydrochloride of diethylaminoethyl 2-chloro-4-aminobenzoate is then precipitated from the dried extract by the addition of dry hydrogen chloride. After removal by filtration and recrystallization from ethanol it exhibits the following properties: M. P. 173-174 C. Analysis calculated for CrsHaoOaNaChZ C, 50.8; H, 6.5. Found: C, 50.9; H, 6.6. The compound is freely soluble in water. Its aqueous solution can be sterilized by boiling without appreciable hydrolysis of the ester.
By utilization of the appropriate acid, in place of the hydrogen chloride cited above, one may prepare the corresponding ester sulfate, phosphate, oxalate, tartrate, malate, succinate, borate, etc.
Of the esters prepared by this general procedure we have found the following compounds, besides the diethyi aminoethyl esters, to be particularly effective for the purposes of this invention:
The gamma-diethylaminopropyl ester hydrochloride of M. P. 197-198 C., anaylsis calculated for C14H22O2N2C12t C, 52.4; H, 6.9. Found: C, 52.5; H, 7.0.
The beta-diethylaminopropyl ester dihydrochloride of M. P. 198-199 C., analysis calculated for CnHaaOzNzCla: N, 7.83. Found: N, 7.60.
The 2-n-amylamino-2-methyl-l-propyl ester dihydrochloride of M. P. 202-203 C., analysis calculated for CuI-ImOzNzCla: C, 49.8; H, 7.00. Found: C, 50.30; H, 7.14.
The beta-diethylaminoethoxyethyl ester hydrochloride of M. P. 134-135 C.
The beta-dimethylaminoethyl ester dihydrochloride of M. P. 197-198 C., analysis calcu- 4 lated for CnHnOaNaCla: C, 41.90; H, 5.40. Found: C, 41.90; H. 5.88.
The beta-piperidinoethyl ester dihydrochloride of M. P. 210.5-211 C., analysis calculated for CuHzrOaNzCla: N, 7.99. Found: N, 7.70.
The beta-(gamma-morpholino) ethyl ester hydrochloi'ide of M. P. 227-228 C., analysis calculated for CuHraOsNaClz: N, 8.72; Cl, 22.1. Found: N, 8.75; Cl, 22.5.
The beta-di-n-butyiaminoethyl ester hydrochlorideof M. P. -186 C., analysis calculated for CrzHasOaNzCh: C, 56.20; H, 7.72. Found: C, 56.32; H, 7.91.
The gamma-di-n-butylaminopropyl ester hydrochloride, a hygroscopic solid, analysis calculated for CmHaoOzNaChHzO: C, 54.70; H, 7.85. Found: C, 55.33; H, 7.88.
The 2-n-butylamino-2-methyl-1-propyl ester dihydrochloride of M. P. 189-190 C., analysis calculated for C15H2502N2C13: N, 7.54. Found: W, 7.65.
The Z-isoamyIamino-Z-methyl-l-propyl ester dihydrochloride of M. P. 186-187 C., analysis calculated for CmI-InOzNzClz: N, 7.26. Found: N, 7.35.
The diethylaminoethyl ester hydrochloride oi 3-chloro-4-aminobenzoi acid of M. P. 149-150 C.
An alternative procedure for the preparation of the type of compounds described above may be illustrated by the preparation of the diethyl aminoethyl ester hydrochloride of 3-fiuoro-4- aminobenzoic acid:
A mixture of 2 g. of 3-fluoro-4-nitrobenzoic acid, prepared as previously described (C. F. Schmelkes and Rubin, J. A. C. S. 66, 1631, 1944), 5 cc. of purified thionyl chloride and 20 cc. of dry benzene was refluxed until the cessation of hydrogen chloride evolution indicated completion of the reaction. The solvents and excess reagents were removed by distillation in vacuo and a solution of diethylamino ethanol in dry benzene was added. After standing overnight the precipitate which had formed was removed by filtration and purified by recrystallization from absolute ethanol. The pale yellow product had a melting point of -191 C. On analysis it showed the correct values for the diethylaminoethyl ester hydrochloride of 3-fluoro-4-nitrobenzoic acid. Analysis calculated for Ci3Hi804N2FC1Z N, 9.00. Found: N, 8.72.
A solution of 1 g. of this product in 135 cc. of absolute ethanol when subjected to the action of hydrogen gas and 0.5 g. of platinum oxide catalyst rapidly absorbed the calculated quantity of hydrogen. The hydrochloride of diethylaminoethyl-3-fluoro-4-amino-benzoate was isolated from" the filtered solution by evaporation of the solvent.
The diethylaminoethyl 2-chloro-4-aminobenzoate hydrochloride prepared as described above showed, on pharmacological tests on the cornea of the rabbit, a local anesthetic potency approximately ten times that of procaine. The toxicity of the compound as indicated by its M. L. D. in mice on intraperitoneal injection in aqueous solution was approximately that of procaine.
When tested with E. coli in synthetic medium in conjunction with sulfanilamide the diethyiaminoethanol ester of 2-chloro-4-aminobenzoic acid in a concentration of 1 mg. with 50 mg. of sulfaniiamide on incubation for 24 hours at 37 completely inhibited the growth of the organisms. Procaine in 1 mg. when combined with sulfanilamlde in 50 mg. under the same test conditions permitted the free growth of the organism. Since the concentration of the diethylaminoethyl ester of 2-chloro-4-aminobenzoic was too low to have of itself inhibited the growth of the organism, this test serves to indicate that the compound is compatible with sulfanilamide in therapeutic usage and, in contrast to procaine, does not inhibit the bacteriostatic action of the sulfonamide.
Diethylaminoethyl-2-ch.loro-4 aminobenzoate hydrochloride prepared as described above was incubated with liver tissue in simulation of the conditions encountered in the in vivo use of this type of compound. At the end of four hours the mixture was filtered and added to a culture of E. 0012'. After incubation for 24 hours at 37 C. it was revealed that this compound in concentration of 1.5 mg. had effectively prevented the growth of the organism. Procaine when subjected to an identical test failed to inhibit the growth of the bacteria.
The 3-chloro derivatives and the 3-fiuoro derivatives may be prepared in a similar manner using as a starting material the known corresponding halogen-i-aminobenzoic acid.
The properties of the compounds of the present invention of not inhibiting the action of the sulfonamides in conjunction with adequate local anesthetic potency, of being bacteriostatic in themselves, good water solubility and other properties rendering them suitable for clinical use as local anesthetics are quite unexpected in view of the unsuitability of the known corresponding 2 and 3-bromo compounds and the known 2-iodo and 3-iodo compounds.
We have also prepared diethylaminoethyl 2- fiuoro-Q-aminobenzoate hydrochloride of M. P. 134-135 C. which has not heretofore to our knowledge been prepared or described in the literature. This compound was found to be antagonistic to and inhibitory of the action of the sulfonamides and also to be without inherent bacteriostatic action.
ing less than six carbon atoms and their addition salts.
2. The acid addition salts of the amino alcohol esters of the group claimed in claim 1.
3. Diethylaminoethyl 2-chloro 4 aminobenzoate.
4. The acid addition salts of diethylaminoethyl 2-chloro-4-aminobenzoate.
5. Diethylaminoethyl 2-ch1oro 4 aminobenzoate hydrochloride.
1 HENRY C. MARKS.
MAR'IIN I. RUBIN.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 1,765,612 Schoeller et a1 June 24, 1930 FOREIGN PATENTS a Number Country Date 321,968 Great Britain Nov. 25, 1929 OTHER REFERENCES Fosdick et al., J. Am. Chem. 800., vol. 65, pages 2305-2306 (1943).
Wyss et al., Proc. Soc. Exp. Tl. Biol. Med, vol. 52 (1943), pages -158.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1007335B (en) * 1953-10-01 1957-05-02 Hoechst Ag Process for the preparation of new chlorinated benzoic acid alcohol esters
US2934538A (en) * 1954-09-03 1960-04-26 Ciba Pharm Prod Inc Bis quaternary ammonium compounds of beta amino ethyl beta'-amino-alpha-methylpropionates
US2980673A (en) * 1954-10-14 1961-04-18 Cutter Lab Bis-quaternary ammonium esters of amino-carboxylic acids and aminoalcohols
US3120551A (en) * 1961-03-20 1964-02-04 Warner Lambert Pharmaceutical 5-(4-biphenylyl)-3-methylvaleric acid and functional derivatives thereof
JPS5216104B1 (en) * 1961-07-25 1977-05-06
CN113185423A (en) * 2021-04-27 2021-07-30 扬州中宝药业股份有限公司 Method for refining chloroprocaine hydrochloride
CN113929600A (en) * 2021-09-13 2022-01-14 赤峰市恒荣化工有限公司 Process for separating 3- (diethylamino) sodium benzenesulfonate and sodium chloride

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB321968A (en) * 1928-07-23 1929-11-25 Schering Kahlbaum Ag Process for the manufacture of halogen substituted aminobenzoic acid alkamine esters
US1765612A (en) * 1928-10-11 1930-06-24 Patterson Frank Howard Measuring apparatus

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB321968A (en) * 1928-07-23 1929-11-25 Schering Kahlbaum Ag Process for the manufacture of halogen substituted aminobenzoic acid alkamine esters
US1765612A (en) * 1928-10-11 1930-06-24 Patterson Frank Howard Measuring apparatus

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1007335B (en) * 1953-10-01 1957-05-02 Hoechst Ag Process for the preparation of new chlorinated benzoic acid alcohol esters
US2850497A (en) * 1953-10-01 1958-09-02 Hoechst Ag New benzoic acid alkamine esters and a process for their manufacture
US2934538A (en) * 1954-09-03 1960-04-26 Ciba Pharm Prod Inc Bis quaternary ammonium compounds of beta amino ethyl beta'-amino-alpha-methylpropionates
US2980673A (en) * 1954-10-14 1961-04-18 Cutter Lab Bis-quaternary ammonium esters of amino-carboxylic acids and aminoalcohols
US3120551A (en) * 1961-03-20 1964-02-04 Warner Lambert Pharmaceutical 5-(4-biphenylyl)-3-methylvaleric acid and functional derivatives thereof
JPS5216104B1 (en) * 1961-07-25 1977-05-06
CN113185423A (en) * 2021-04-27 2021-07-30 扬州中宝药业股份有限公司 Method for refining chloroprocaine hydrochloride
CN113185423B (en) * 2021-04-27 2023-09-01 扬州中宝药业股份有限公司 Refining method of chloroprocaine hydrochloride
CN113929600A (en) * 2021-09-13 2022-01-14 赤峰市恒荣化工有限公司 Process for separating 3- (diethylamino) sodium benzenesulfonate and sodium chloride

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