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Publication numberUS2313016 A
Publication typeGrant
Publication dateMar 2, 1943
Filing dateJun 1, 1938
Priority dateJun 5, 1937
Publication numberUS 2313016 A, US 2313016A, US-A-2313016, US2313016 A, US2313016A
InventorsPahlicke Hermann, Horenstein Schmul Hersch
Original AssigneePahlicke Hermann, Horenstein Schmul Hersch
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Process for the production of alkamine esters
US 2313016 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

Patented Mar. 2, 1943 rnocsss no STATES Y PATENT I "i -2,313,016 V THE antic OFFICE rnonuc'rron or ESTERS Schmul Hersch Horenstein, Berlin-Halensee, and

Herman Pahlicke, Berlin-Reinickendorf, Germany; vested in the Alien Property Custodian I N Drawing. Application June 1,1938, Serial No.

211,212. In Germany June 5, 1937 8 Claims.

This invention relates to a process for the production of alkamine esters. V

Three main methods are available for the production of esters viz. the action of acids on alcohols in the presence of a condensing medium, the reaction of acid halides with the alcohols, and the treatment of alkyl halides with the salt of the acid to be esterified. When applying these methods to the production of alkamine esters, various difiiculties are encountered. The first two methods frequently fail when it is desiredto esterify sensitive amino-alcohols or acids of more complicated structure; while the third inethod is not suitable for the esterification ,of the aminoalcohols for the reason that it presupposes the use of the free aminoalkyl halides, which readily tend to decompose or to forminner ring compounds at the high temperatures and protracted periods of treatment required for the reaction. The so-called interchange of ester radicals, i. e. the displacement of simple alcohol residues from the ester bond by aminoalcohols, also only leads the anion changes places with the halogen forming .the ester group. This thus produces the hydrogen halide acid salts of the esters of the aminoalcohols with those acids which were originally combined on a salt-forming basis with the nitrogen of the aminoalcohol. The reaction may be represented diagrammatically 'as follows:

31 140112); ..Ha1. Erlimm X x Hal.

where X indicates'the acid residue. The amine salt of the hydrogen halide acid ester of the aminoalcohol with the acid to be esterified may be produced by known methods, for example by simto the desired end in certain particularly favorable cases. A special possibility for the production of aminoalkyl esters is finally provided by. the reaction of alkyl halide esters with amines.

, However, this reaction does not proceed smoothly ply bringing together the calculatedamounts of the substances in question in th 'presence or absence of a solvent, or by double decomposition between a suitable acid salt and a salt of the.

aminoalkyl halide. In both cases the hydrogen halide acid ester is neutralized immediately and thereby rendered immune from the danger of decomposition or internal ring formation.

In order to bring about the rearrangement, the amine salts produced in this manner or their solutions are heated-for a few hours to temperatures over 50 C. .When double decomposition between two salts is'employed, it is possible to isolate the conversion product, in order to be able to accomplish the subsequent rearrangement with a purifled substance. During the heat treatment, the progress of the rearrangement can be observed in simple fashion by quantitative'examination of .the

the ester bases to decompose, cannot be purified, Q

For the same reason the use of alkyl halide bases is out of the question. Hitherto it was thus substantially only possible to produce esters of choline when alkyl halide esters were treated with trimethylamirie. By this means, however, only the esters of the simple aliphatic acids with choline could be isolated in the form of their pure salts, while most of the other choline esters mentioned in prior publications. have either not been separated at all or only in the form of their platinum double salts. V The present invention relates to a method capable of quite universal application to the production of esters of the aminoalcohols with the most diverse acids, The method is based on the discovery that, if the hydrogen halide acid esters oi alkamines are converted into the amine salts oi the acids to be esterifled, compounds are produced which tend towards a rearrangement in. which formation of ionised halogen. The process represents the mildest universally applicable method of esterification of aminoalcohols. The esterification takes place, with a neutral reaction, within the molecule itself, without needing any auxiliary substances or producing any by-products. On the completion of the reaction, the

resulting salts may be purified in the'usual manner byrecrystallisation .from a suitable solvent or by liberation of the aminoesters and fresh conversion intoasalt.

The process is particularly suitable for the production-or compoundswhich are used as medicaments, or as intermediate products for the production of medicaments. I The rocess will now be illustrated with reierence to the following examples:

J Exmr: 1 I

Bromide of choline lactate shaking. After ashort time no more ionised.

bromine can be detectedv invthe solution. The

. orated again in vacuo.

solution is then filtered off from the silver bromide and the filtrate concentrated in vacuo, when a little more silver bromide separates and is removed. Evaporation to dryness follows, a crystal pulp being then first obtained, which on further heating gives a syrupy residue. The latter is left for six hours at a temperature of about 90 C. during which time the gradually increasing appearance of ionised halogen can be observed by taking samples. ()n completion of the rearrangement, the substance is recrystallised from butyl alcohol and the resulting crystals are washed with ether. The yield amounts to .120 parts (79% of theory). Hygroscopic crystals. 0.7444 grm.=29.05 ccms. n/ AgNOs=31.24% bromide (calculated 31.22% of En).

EXAMPLE 2 Acetyl choline bromide 12.4 parts of trimethylbromethyl ammonium bromide are dissolved in water and mixed as above with 9.2 parts of silver acetate. The filtrate is evaporated in vacuo, freed from silver bromide still separating, and the residue is left in a boiling water bath. The crystals at first present'then disappear and after some time the whole of the contents of the flask then recrystallises spontaneously. The substance is then recrystallised from butyl alcohol, suction-filtered and dried in vacuo. Yield 7.75 parts (68.5% of theory). 'M. P. 142-l43 C. 0.3754 gram of substance=l6.6 ccms. n/10 AgNO3=35.4% of Br. (calculated 35.4% of Br.). The determination of the saponification number at room temperature proves that the substance is not contaminated with choline bromide. 0.2756 grm. consumes 12.22 ccms. n/10 NaOH (calculated 12.19 ccms.).

EXAMPLE 3 Bromide of choline mandelate .0.6004 grm.=18.85 ccms. n/10 AgNOs=25.l% of bromine (calculated 25.16%).

EXAMPLE 4 Bromide of choline phenyl quinoline carborylate A solution produced, from a solution of 24.7

EXAMPLE 5 Bromide of choline deoxycholic acid ester 22 grms. of-deoxycholic acid are dissolved in the calculated amount of ammonia and precipitated with silver nitrate in the presence of methyl alcohol. The resulting ilver salt is washed with methyl .alcohol and ether and dried in vacuo, when however it obstinately retains water and solvent. 13 grms. of trimethylbromethyl ammonium bromide are then dissolved in water, and this solution is mixed with the aforesaid silver salt. The reaction proceeds rapidly in the cold. and the whole contents of the vessel thickens considerably, and it is therefore mixed with the same amount of methyl alcohol whereupon it can easily be filtered off from the silverbromide separated. The filtrate is then evaporated in vacuo and the residue is left for six hours at 60-65 C. After recrystallisation twice from butyl valcohol 21.9 grms. (75% of theory) of the new compound are obtained in the form of a readily water soluble well crystallised salt having a M. P. of 232-234" (with decomposition). 0.6498 grm.=ll.6 ccms. of n/lO AgNO3=14.3% of bromine calculated 14.34%. Saponification number 0.370 grm.=6.7 ccms. n/lO NaOH=l00.8%.

EXAMPLE 6 Bromide of choline cholic acid ester 16.8 grms. of trimethylbromethyl ammonium bromide are treated with grms. of silver cholate (obtained by dissolving cholic acid in the calculated amount of ammonia and precipitation with silver nitrate in aqueous methyl alcoholic soluresidue forms hard fragments, which are finely pulverised and heated for eight hours to 100 C.

parts of trimethylbromethyl ammonium bromide in water, by shaking with 39 parts of. silver phenylquinoline carboxylate is evaporated to dryness in vacuo, the residue is dissolved in hot methyl alcohol and separated from the silver bromide still present, and the filtrate is evap- The residue then first solidifies into a transparent resin, which melts after some time and recrystallises after further heating. After a reaction time of eight hours,

propyl alcohol, whereupon 23.9 grms. (57.4% of the substance is recrystallised twice from isotheory) of the new compound are obtained. Faintly yellowish, readily water-soluble crystals,

0.6902 grm.=16.55 ccms. of bromine (calculated The substance is extracted hot with alcohol, the filtrate is re-evaporated and recrystallised from butyl alcohol. The new compound represents the well crystallised water-soluble salt having a M. P. of 236-238 C. (accompanied by decomposition). 0.5879 grm.=10.1 ccms. n/10 AgNO3=13.75% of bromine. Saponification number 0.7880 grm.=

13.8 ccms. n/lO NaOH=100.2%.

. EXAMPLE 7 Diethylaminoethyl p-nz'trobenzoate 16.7- grms. of p-nitrobenzoic acid are distributed in ccms. of isopropylalcohol and mixed with 13.5 grms. of diethylchlorethylamine. whereupon a clear solution is produced which is boiled for 2 hours under reflux. on cooling, the whole solidifies into a crystal pulp-which is suction filtered and again recrystallised from isopropylalcohol. 23.5 grms. (78% of theory) of the hy drochloride arev obtained with a M. P. of 175-176 C. 0.5024 grm.=16.6 ccms. n/l0 AgNO3=ll.73% chlorine (calculated: 11.79% chlorine).

EXAMPLE 8 Hydrochloride of diethylaminoethyl theobromzne- 1 -acetate 17.2 grms. of diethylchloroethylamine hydrochloride are dissolved in 50 ccms. of water and mixed and shaken with 38 grms. of silver theobromine-l-acetate suspended in ccms. of water. After a short time no more ion'ised chlorine can be detected. The reaction mixture is freed from silver chloride, the filtrate is evaporated in vacuo, and the residue is left for 7 hours in all in the boiling water bath. The contents of the flask are at first syrupy and then gradually solidify into a brittle mass. The substance is twice recrystallised from isopropyl alcohol and forms a well crystallised salt readily soluble in water with a neutral reaction, with a M. P. of 206-208 C. 0.5680 grm.=15.05 n/10 AgNOa= 9.42% of chlorine (calculated 9.5%).

EXAMPLE 9 Hydrochloride of diet'hylaminoethyl beneilate 11.4 grms. of benzilic acid are dissolved in 40 ccms. of isopropyl alcohol and neutralised with 7 grms. of diethylchloroethylamine. The solution is heated to boiling point for two hours under reflux and then cooled, whereupon'the compound crystallises out. After recrystallisation from isopropyl alcohol, 15 grms. (82.7% of theory) of the hydrochloride are produced, with a M. P. of 173-174.5. 0.4014 grm.=11.15 ccms. n/10 AgNOs=9.85% of chlorine (calculated 9.78%). The salt is fairly diil'icultly soluble in water. n mixing the aqueous solution with potash, the free base with a M. P. of 50-51 C. is obtained. In order to produce the substance, the benzllic acid may also be neutralised with the chlorine base in methyl alcohol, the solution may be evaporated and the residue heated at 60 for two hours, whereupon the new salt crystallises directly from the melt.

' EXAMPLE Hydrochloride of diethylaminoethyl diphenyl acetate 21.2 grins. of diphenyl acetic acid are dissolved in acetone together with 13.5 grins. of diethylchloroeth'ylamine, and this solution is evaporated in vacuo. The residue is thereupon heated for six hours to a temperature of 65-70". The reaction product is dissolved in water, mixed with hydrochloric acid until an acid reaction to Congo red is obtained, and freed from any unreacted diphenyl acetic acid by shaking out with ether. The acid solution is rendered alkaline with sodium carbonate, and the base precipitated is taken up in ether. By treatment with alcoholic hydrochloric acid and recrystallisation of the resulting salt from acetic acid, the hydrochloride of diethylaminoethyl diphenylacetate, with a M. P. of 112-113.5 C. is obtained from the ethereal solution. 0.4326 grm.=12.65 ccms. n/10 silver nitrate=10.35% of chlorine (calculated 10.22%).

EXAMPLE 11 Hydrochloride of (p-piperidz'noethyl) beneoate grams of p-piperidinoethyl chloride and 12.2

grams of benzoic acid are dissolved in 70 ccms. of alcohol, and the solution is evaporated at about 45 C. in vacuo. The residue is left for two more hours at about 55, during which it gradually solidifies. The product is comminuted and heated again for six hours at 85 C. The reaction product is then dissolved in butyl alcohol, filtered oif from small undissolved impurities and mixed with a little ether. After a short time the hydrochloride with a M. P. of 174-176 C. crystallises out. 0.3034 grm.=11.25 ccms. n/10 AgNOs: 13.18% of chlorine (calculated 13.18%).

EXAMPLE 12 Hydrochloride of diethylaminoethyl salicylate A solution of 15.75 parts of salicylic acid in alcohol is neutralised with 15.5 parts of diethylchloroethylamine and the resulting solution is Hydrochloride of diethylaminopropyl cinnamate 14.8 grms. of cinnamic acid in 100 ccms. of alcohol are neutralised with 14.9 grms. of diethylchloropropylamine, and the alcohol is driven off in vacuo. The residue is heated for 8 hours to 8590 C. whereupon the melt begins to crystallize. On scraping the sides of the vessel, the

whole contents of the vessel then crystallise, and

after recrystallisation from isopropyl alcohol, the salt having a M. P. of 131-133" C. is obtained in the form of a readily water-soluble product.

' 0.4972 grm.=16.45 ccms. n/10 AgNO3=11.'7'7% of chlorine (calculated 11.94% of chlorine).

EXAMPLE 14 Diethylamlnoethyl mandelate 15.2 grms. of mandelic acid and 13.5 grms. of diethylchloro-ethylamine are dissolved in isopropyl alcohol, and the solution is heated for four hours under reflux. 0n evaporation of the solution, the hydrochloride of the new compound is left in the form of a viscous oil, which is readily soluble in alcohols, and is insoluble in ether and benzene. If the hydrochloride is dissolved in water, the base can be precipitated with sodium carbonate and then taken up in ether. The

ether is washed out with cold water and the ester base is produced,.on evaporation of the ether, in the form oi an oil which is insoluble in water. 0.2560 grm.=10.3 ccms. n/ 10 HCl (calculated 10.2 ccms).

EXAMPLE 15 Hydrochloride of the diethylaminoethyl ester of trichlorobutyl adipic ester 30.5 grins. of the acid of trichlorobutyladipic ester (German Patent 583,852) are dissolved in xylene, and neutralised with 13.5 grms. of diethylchlorethylamine. The solution is heated for six hours under reflux, then cooled and separated from a light crystallisation. The clear filtrate is somewhat concentrated in vacuo and the new product is precipitated with dry ether. The substance thereby separates in a flaky viscous form. If it. is allowed to stand under ether, the precipitate changes into a finely crystalline state. The resulting hydrochloride dissolves in water, alcohols and in aromatic hydrocarbons. It is almost insoluble in ether and petroleum ether.

0.5942 g'rm.=13.7 ccms. n/10 AgNOa=8.2% of.

chlorine in ionised form (calculated 8.05). 0.2380 grm., after previous sapomflcation with soda lye, consume 21.3 ccms. n/ 10 AgNO3=31.8% of total chlorine (32.2%).

EXAMPLE 16 Bromide of choline pyroracemcte v 24.7 part of trimethyl bromethyl ammonium bromide are dissolved in methyl alcohol and evaporated under reduced pressure at 40-45, C.

stirred up with 19.5% of silver pyroracemate. The

solution, freed from precipitated silver bromide, is evaporated in vacuo at a low temperature and the residue is heated for four hours at to C. The contents of the flask are then dissolved in alcohol and the substance precipitated with ether. The precipitate is at first oil? but after havin been triturated several times with dry ether and having then been allowed to stand in the vacuum desiccator it becomes solid. The yield amounts to about 80% of theory. 0.3572 grm.=14.05 ccms. 11/10 AgNoa=3L5 bromine (calculated 3l.

EXAMPLE 17 (2.2-dimethyl-3-diethylamino-propyl) dl-tropate 4.1 grms. of dl-tropic acid are mixed with 4.5 grms. of 2.2-dimethyl-3-diethylaminopropyl-lchloride, and slowly heated in the oil bath. The contents of the flask are at first in the form of a melt consisting of two layers, which becomes homogeneous when the temperature is gradually raised to 160-170 C. After a reaction period of one hour the flask is cooled, and the contents are dissolved in water and the resulting ester is precipitated with soda lye and taken up with ether. After evaporation of the ether, the base remains in the form of anoil of thick consistency which, when treated with phosphoric acid in alcoholic solution gives a phosphate having the melting point of 139-141 C. The yield amounts to about 80% of theory.

Emma 18 Diethylaminoethyl benzyl phthalate QOO.CHz.CoHi

25.6"grms. of mono-benzyl phthalic acid are EXAMPLE 19 Choline mandelate' 12.3 parts of trimethylbromethyl ammoniumbromide are thoroughly triturated with 8.7 parts of sodium mandelate and this mixture is heated in the oil bath. As soon as the mixture begins to sinter, heating stops and the mixture is left to cool, with stirring. After recrystallisation from butyl alcohol the salt is obtained with a yield of about 75% of theory. Analysis: 0.2164 grin. consume 6.8 ccms. n/lO AgNO3==25.16% bromine (calculated 25.16%).

EXAMPLE 20 Diethylamirwethyl benzilate 10 parts of sodium benzilate are mixed with seven parts of diethylaminoethyl chloride hydrochloride, and heated in the oil bath. The mixture is left for a short time at and the contents of the flask are recrystallised from isopropyl alcohol. The hydrochloride of the benzil acid ester is obtained with a M. P. of I'M-175 C.

What we claim and desire to secure by Letters Patent of the United States is:

1. A process for the production of alkamine esters comprising converting the hydrogen halide ester of an alkamine into the amine salt of the carboxylic acid to be esterifled and subjecting said amine salt to a rearrangement in which the acid radical changes place with the halogen.

2. A process for the production of alkamine esters comprising converting the hydrogen halide ester of an alkamine into the amine salt of the carboxylic acid to be esterifled and subjecting said amine salt to a rearrangement in which the acid radical changes place with the halogen by heating the amine salt to a temperature above 50 C.

3. A process for the production of alkamine esters comprising reacting the hydrogen halide ester of an alkamine with the carboxylic acid to be combined, and subjecting the amine salt thus formed to a rearrangement in which the acid radical changes place with the halogen.

4. A process for the production of alkamine esters comprising reacting the hydrogen halide ester of an alkamine with the carboxylic acid to be combined, isolating the amine salt thus formed, and subjecting said amine salt to a rearrangement in which the acid radical changes place with the halogen.

5. A process for the production of alkamine esters comprising reacting the ammonium halide of a hydrogen halide ester of an alkamine with a salt of the carboiwlic acid to be combined, and subjecting the amine salt thus formed by double decomposition to a rearrangement in which the acid radical changes place with the halogen.

6. A process for the production of alkamine esters comprising reacting an ammonium halide of a hydrogen halide ester of an alkamine with a salt of the carboxylic acid to be combined, isolating the amine salt thus formed by double decomposition, and subjecting said amine salt to a rearrangement in which the acid radical changes place with the halogen.

7. A process for the production of choline esters, comprising converting trimethyl haloethylammonium halide by double decomposition into an amine salt of the carboxylic acid to be esterifled, and subjecting said amine salt to a rearrangement in which the acid radical changes place with the halogen.

8. A process for the production of choline esters comprising converting trimethyl-haloethyl ammonium halide by double decomposition into an amine salt of the carboxylic acid to be esterifled, isolating said amine salt, and subjecting said amine salt to a rearangement in which the acid radical changes place with the halogen.

HERMANN PAHLICKE. SCHMUL HERSCH HORENSTEIN.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US2456363 *Jan 18, 1946Dec 14, 1948Hoffmann La RocheBile acid derivatives and process for the manufacture of same
US2562350 *Oct 12, 1945Jul 31, 1951Searle & CoBasic esters of bile acids
US2562351 *Mar 4, 1949Jul 31, 1951Searle & CoBasic esters of cholanic and ketocholanic acids
US2841610 *Aug 12, 1955Jul 1, 1958Olin MathiesonEsters of aryl-substituted cyclobutanedicarboxylic acids
US4256664 *Mar 1, 1976Mar 17, 1981Colgate-Palmolive CompanySubstantive sunscreen agents
US6087346 *Jun 23, 1994Jul 11, 2000Cambridge Neuroscience, Inc.Sigma receptor ligands and the use thereof
EP0714292A1 *Jun 23, 1994Jun 5, 1996Cambridge Neuroscience, Inc.Sigma receptor ligands and the use thereof
Classifications
U.S. Classification544/271, 560/71, 546/238, 560/179, 560/174, 560/104, 560/196, 552/550, 560/101, 560/58, 560/60, 560/20, 560/253, 560/85
International ClassificationC07D295/088, C07D473/10
Cooperative ClassificationC07D473/10, C07D295/088
European ClassificationC07D473/10, C07D295/088