US2596099A - Aminoesters of nu-substituted pyrrolidine 2, 5-dicarboxylic acids - Google Patents

Description

Patented May 13, 1952 UNITED STATES PATENT OFFICE AMINOESTERS OF N-SUBSTITUTED PYR- ROLIDINE 2,5-DICARBOXYLIC ACIDS Arthur Joseph Hill, Jr., and. John Thomas Maynard, Wilmington, Del., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application December 28, 1946, Serial No. 719,108

Claims.

1 This invention relates to a new and novel method of preparing N-substituted pyrrolidine carboxylic acids and esters thereof and to a new and novel group of esters so produced. More particularly, this invention relates to a novel group.

Comment has been made on the frequent occurrence of pyrrolidines in nature. The pyrrolidine nucleus is found in many naturally-occurring products. Particular illustrations include physiologically-active alkaloids such as those of the hygrine, belladonna and tobacco families and the important natural aminoacid, proline. Various pyrrolidine carboxylic acids are frequently found in these and similar compounds, or in degradation products thereof.

It is to be noted, however, that in the compounds derived from nature the heterocyclic nitrogen in the pyrrolidine nucleus is usually either unsubstituted or is substituted only by methyl. Despite the biochemical significance of the pyrrolidines, surprisingly little is known in the prior art about compounds such as the pyrrolidine dicarboxylic acids. Particularly is this true when there is an N-substituent other than methyl, where the carboxylic group or groups is esterified. In large part, this has been due to a-lack of a good synthesis for pure compounds of this type and, therefore, also to the previous lack of such compounds for investigation.

It is, therefore, a principal object of the present invention to develop a synthesis which is comparatively simple, which is reliable, which yields easily-purified products and which can be adapted to the production of a wide range of such compounds. It is also an object of the invention to produce a number of novel N-substituted pyrrolidine carboxylic acids and these esters, particularly the alkamine esters of such acids.

The objects of the present invention have been met by the production of a number of alkamine esters of N-substituted pyrrolidine 2,5-dicarboxylic acids. In general, these compounds have been synthesized by ring-closing a suitable-lower 2 alkyl diester of an alpha,delta dihalogenated adipic acid with a suitable amine, usually a primary amine, preferably in the presence of a suitable catalyst, and then conducting a catalyzed ester interchange whereby the alkamine radical is substituted for the alkyl.

Adipic acid, alpha,delta-dihalogenated adipic acids, and even the alkyl esters of such acids are known. The process of the present invention, therefore, originates with'known compounds of the type H2C-CH2 AIOOC- H tat-000mm Hal Hal in which Al and Al represent the same or diiferent alkyl radicals and Hal represents a halogen.

While Al and Al may differ, and may have any desired number of carbon atoms, for the present procedure they will usually be identical. While they may also be of any reasonable chain length, those longer than butyl are too long and of no particular importance in the present synthesis. On economical considerations both Al and A1 are usually either methyl or ethyl. Of the two, because of the extremely hygroscopic nature of the dimethyl ester of pyrrolidine 2,5- dicarboxylic acid, ethyl is usually preferable.

As noted, Hal may designate any halogen. Practically, however, only chlorine and bromine are ordinarily encountered. For purposes of the synthesis, bromine is preferable and the further discussion will be limited thereto as illustrative.

It should be noted that the alkyl dibromoadipates, in which the alkyl groups are identical, may occur in several forms because of asymmetry. While other forms may be used, in the present work the meso form has been principally used to insure formation of a definite product. While these compounds are known, their preparation for the present purpose may be illustrated by the following procedure.

EXAMPLE 1 M eso ethyl alpha, deZta-dibromoadipate H5C2OOCCH(Br) CH2CH2CH(BI') COOCzHs Adipyl chloride is placed in a quartz flask equipped with reflux condenser and dropping funnel. The flask is continuously subjected throughout the reaction to irradiation by ultra violet light. To the adipyl chloride is added drop-wise bromine in amount sufficient to total about 2.25 moles per mole of adipyl chloride. When reaction appears complete, the mixture is gently heated until excess bromine is removed and evolution of hydrogen bromide ceases. The residue, alpha, delta dibromo adipyl chloride, is slowly added with agitation to absolute ethyl alcohol. As soon as the reaction becomes violent, the reaction vessel is cooled. The reaction mixture is allowed to stand for about twenty-four hours and seeded, being then allowed to stand in the cold until crystallization substantially ceases. The white crystalline ester is removed by filtration, washed with cold ethyl alcohol and vacuum dried. Two successive crystalline products are obtained in further standing in the cold. These products are in the meso form. Alcohol is distilled from the residue, yielding another crop of solid esters and a liquid phase. The liquid phase appears to comprise dl diethyl alpha,delta-dibromoadipate together with a small amount of alpha, alphadibromoadipate. The solid crystalline ester so produced has a melting point of 66-67 C. which checks with that ascribed in published literature.

7 7 EXAMPLE 2 -Meso methyl alpha, deZta-dibroanoadipate H3COOCCH(BI)CH2CH2CH(B1)COOCHs This compound is prepared by substituting absolute methyl alcohol for the ethyl alcohol of the preceding experiment. The solid meso methyl ester is readily soluble in benzene, chloroform, acetone or ether, moderately soluble in ethyl alcohol, difilcultly soluble in petroleum ether and insoluble in water. Crystallization from petroleum ether yields long, colorless needles, from alcohol, large colorless, elongated prisms. The solid ester has a melting point of '75-'76 C.

Using the above procedures as illustrative, any alkyl ester in which the alkyl groups are identical may be prepared. As noted above, only the methyl, ethyl and possibly propyl are of any practical significance in the present process, largely because of the economic considerations.

Starting with a dialkyl dibromadipate, the reaction of the present synthesis may be considered as falling into two stages, a ring closure and an alcoholysis, capable 'of representation by the following:

in which'Al is an alkyl radical, R is the residue of a suitable amine and Alk is the residue of a tertiary aminoalcohola In the above formula RNHz has been used to designate a suitable primary amine. In the reaction R may be quite widely varied. It may represent a simple alkyl radical of from 1-12 carbon atoms; a substituted alkyl radical such as methoxymethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, cyclohexylethyl, and the like; an aminoaliphatic radical such as aminoethyl, acetylaminoethyl and the like; a cycloaliphatic radical such as cyclohexyl, ethyl and methylcyclohexyl and the like; an aryl radical such as phenyl, o,mor ,p-tolyl, p-chlorophenyl, 2,4-dimethy1- phenyl, 3,5-dimethyl phenyl, ethyl phenyl, ethoxy phenyl, methoxyphenyl, acetophenyl, acetyllike or an aralkyl radical such as benzyl, phenylethyl, tolylethyl, chlorophenylethyl and the like. If so desired, other than primary amines may be utilized. The product will be an -N--N--dipyrrolidine, in part, together with mixed side reaction products.

The ring closure step may be modified in accordance with certain circumstances. For example, in the case of certain liquid amines, the other constituents may be soluble therein, or sufficiently soluble to permit reaction without any added solvent. This may be illustrated by the followingtypical example.

EXAMPLE 3 Methyl ester of 1-phenylpyrrolidine-2,5-dicarbomylic acid Freshly distilled aniline and meso methyl alpha,delta-dibr0moadipate, in the mole ratio of about 3.511, are combined in a flask and heated under reflux until reaction is substantially completed. The oily solid residue is poured into 6 N hydrochloric acid and extracted three times with ether. The ether extracts are combined, washed with water, dried over anhydrous calcium sulfate, filtered and the ether removed by distillation. The crude ester is purified by distillation at 27 mm. The desired ester is obtained as a light yellow oil in the fraction distilling at 220-230 C. in about 68% yield. Crystallization starts almost immediately but is complete'only after long standing. Recrystallized from ethyl alcohol, the ethyl is obtained as large transparent colorless prisms melting at 88 C.

On the other hand, a suitable solvent may be found highly advantageous. Particularly is this true of the alkyl and substituted alkyl amines. For the purpose, dry benzene is excellent. Other solvents which may be utilized, if so desired, include chloroform and absolute ethyl alcohol. This procedure is illustrated in the following example.

EXAMPLE 4 complete.

action is substantially complete. A small amount tions and the acid extract neutralized with sodium carbonate. The oil which separates is taken up in ether. The aqueous solution is further extracted with ether. The ether extracts are combined, dried, the ether'removed and the yields are lower than is generally desirable. In

accordance with the present invention, it has been found that the cyclization can be catalyzed by the presence of a small amount of potassium iodide. In so doing, the over-all yields may be raised from a third to as much as a half. A good illustrative use of this procedure is given in the following example.

EXAMPLE Ethyl 1-phenylpyrrolidine-2,5-dicarbowylate 327 parts of freshly distilled aniline, 360 parts of meso ethyl alpha,delta-dibromoadipate and 5 parts of dry powdered potassium iodide are combined in a flask equipped for reflux. On gentle warming, spontaneous reaction starts and crystals appear almost immediately. After somewhat violent reaction has subsided, an oily pale orange crystalline mass is obtained. The mass is heated at about 85-90 C. until reaction is substantially The reaction product is suspended in 6 N hydrochloric acid and then extracted three times with ether. Combined ether extracts are washed, dried and filtered. The ether is removed by distillation and the desired ester obtained by distillation of the oil at 2 mm. collecting a frac tion which distills at 168-169 C. The yield is 254 parts or about 90% of theory. The ester is a pale yellow nearly colorless liquid N 1.5230 boiling at 144 C. at 0.5 mm. The advantage of using the potassium iodide is illustrated in repeating the experiment omitting the iodide. The ester produced is the same but the yield is only 61% of theoretical.

It is also to be noted from the reaction that for each mol of amine utilized in the reaction, two mols of hydrobromic acid are released. For that reason, in preparing the reaction mixture for the above examples, an excess of amine has been provided to serve as an acceptor for the HBr. For complete reaction at least three mols of amine are required for each mol of adipate. Usually, an additional slight excess is found to be helpful. So prepared, a good practice is to utilize an amine-adipate ratio of from about 3:1 to 3.521.

These ratios are not objectionable with readily available amines. In some cases, however, the available amount of amine may render the use of such high amine-adipate ratios objectionable. In those cases, an alternative procedure is to provide an extraneous agent to accept or neutralize the HBr. Basic secondary or tertiary amines tend to cleave the bromoester. In accordance with the present invention, it has been found that any suitable salt, such as an alkali metal salt of a weak acid, may be used to neutralize the HBr. Sodium and potassium car-- bonate were found suitable for the purpose. This practice may be illustrated by the following examples.

EXAMPLE 6 1 -cycZohe.ryZ-2,5-dicarbethoxypyrrolidine Thirty parts (.083 mol) of ethyl alpha,deltadibromoadipate, twenty-five parts (.25 mol) of freshly redistilled cyclohexylamine, one part of pulverized potassium iodide and seventy-five parts of dry benzene are admixed, allowed to stand for several hours and refluxed until reaction appears complete. After cooling, the reacted mixture is filtered to remove the insoluble cyclohexylamine hydrobromide. 29.5 parts or 98% of theoretical are obtained. The filtrate is extracted with 70 ml. of 6 N sulphuric acid in three portions and the acid extract is, neutralized the solid sodium carbonate. An oil separates which is taken up in ether and the aqueous phase is extracted with ether. The combined ether extracts are dried, the ether removed by distillation and the residue distilled at about 1 mm. pressure. 21.2 parts of colorless oil boiling at 133 C. and having a ND of 1.4742 are obtained. This is equivalent to a yield of about 85.5% of theory. A sample, redistilled foranalysis, had a No of 1.4738 and was found to have a nitrogen content of 4.62% as compared with the 4.71% of theory.

EXAMPLE. 7

1 -cyclohexyl-2,5-clicarbethoxypyrrolidme (Potassium carbonate method) EXAMPLE 8 I 1-cyclohe.ryl-2,5-dicdrbethoxypyrrolidine Example 7 was repeated extending the reaction time to 52 hours. The product isolated was identical with that in Examples 6 and 7. The yield, however, was 54% of theory.

From the foregoing examples, it will be seen that the potassium carbonate method does not yield as high a quantitative product in'asingle operation as can be expected from the use of an amine-adipate ratio of 3:1. However, the yields are much better on'the basis of the mols of amine consumed. I

By the above outlined procedures, cyclization is readily accomplished to produce the various substituted dialkyl esters of N-substituted pyrrolidine, 2,5-dicarboxylic acids in which the N- substituent has the various values outlined. Typical products. so preparedare shown in the following table. I

TABLE I 1 -s-ubstitute-2,5-dicarbethoxypgrroZidi'nes am o Hi ozHsoooon noooolm Having accomplished the ring-closing operationtof the present process, in accordance with the foregoing procedure, the dicarbalkoxy pyrrolidine is ready for the second step. In general, in the present process, this comprises reacting the pyrrolidine ester with an amino alcohol in the presence of a metal alcoholate as a catalyst, whereby an ester substitution is accomplished. In the present process the alkanol corresponding to the alkyl radical in the adipic ester is one of the reaction products and must be removed. Distillation may be employed after the reaction has been completed. However, there is usually an advantage in removing the alcohol during the reaction as this increases the reaction rate. When continuous distillation is employed, the alkyl of the adipate should be an alcohol having a boiling point suitable for continuous distillation from the reaction mixture at the reaction temperature. The distillation may take place either atatmospheric or reduced pressure.

The process of the present invention is generally applicable to monohydric aminoalcohols having a tertiary amino group. These may be represented by the formula:

in which R is an aliphatic hydrocarbon residue of 1-3 carbon atoms and R1 and R2 are the same straight chain alkyl radicals or formwith the nitrogen atom a heterocyclic ring such as the piperidine or morpholine ring. The most important amino alcohols from a practical standpoint are those in which R is a straight saturated chain which may be represented by the formula:

R Ho 'oH 2)..-N

in which n is a small whole number from 1-3 and where R has 1-3 carbon atoms.

Typical illustrations of the amino alcohols which may be used in the present invention are dimethylaminomethanol, dimethylaminoethanol, diethylaminoethanol, dipropylaminoethanol, di-

ethylaminopropanol, dipropylaminopropanol, methylethylaminopropanol, piperidinoethanol, morpholinoethanol, methylethylaminoethanol and the like.

' The choice ofithe' particular alcohol and acid used depends upon the product to be produced. Variations in the acid or alcohol do not afiect the present reaction except as to the extent to' which the reaction may be carried to completion in a reasonable time and therefore the quantity of the product practically obtainable. The temperature at which the reaction is carried out may be varied in accordance with the particular reagents selected.

In accomplishing our process, the use of a metal alcoholateis very important, apparently being principally. responsible for the superior yields obtained. It also appears to increase the rate of reaction. The metal alcoholate may be added to the reaction mixture as a preformed alcoholate or as a strongly basic metal which will form the alcoholate in situ. The particular metal alcoholate which is used is not so important. Metallic sodium is easily available, relatively cheap, and since it forms the alcoholate in the reaction mixture, produces very satisfactory results. Other alkali metals and alloys, for example, potassium, give similar results but usually do not justify the added cost. Similar results may also be obtained with metal amides such as sodamide. It is an additional advantage of the present invention that the amount of the metal alcoholate present in the reaction as well as its nature is not critical, and it may be used in various proportions throughout a considerable range. 'The optimum amounts, however, will vary somewhat with different alkamine esters to be produced.

In the alcoholysis one feature, as shown in these examples, should be noted. Theoretical requirements for the reaction would be for at least two molecular proportions, of the amino alcohol for each mol of the adipic ester consumed. Experience has shown that a large excess of the amino alcohol is of considerable benefit. The reaction operates best with two to three times or more the theoretical considered amount of amino alcohol. While it is an advantage of the present invention that this excess is not lost but may be recovered and reused, nevertheless, it is inconvenient to use an excess larger than necessary. It ha been found that a good average practice is to employ about five times the theoretically required amount. For this reason, as much more than-the five proportions as may be desired may be used, but there is no particular advantage in so doing.

The alcoholysis will beillustrated by the following examples. Again, these examples are taken as illustrative only and not by way of limitation.

EXAMPLE 9 V Di-(beta-diethylaminoethyl) ester of 1 -methylpyrrolidine- 2,5-dicarbomz Zic acid I CH3 Fifty-three parts of 1-methyl-2,5-dicarbethoxypyrrolidine and two hundred fifty parts of ,beta-diethylaminoethanol, in which one part of metallic sodium was dissolved, are placed in a reaction vessel'equipped with distillation apparatus. The mixtur isheated at about 170-" 0., until reaction is substantially complete, care .being taken to prevent distillation of amino alcohol. The excess amino alcohol is then removed 2,596,099 9 10 at reduced pressure and the residue is taken up Repeating Example 12 but substituting sixty- 1n ether and sufiicient water to dissolve all the five parts of 1- ;y 1ohe y1-2 -dj car'bethoxypyr material. The ether layer 1s removed and the rolidine for the pyrrolidine f that example water phase extracted twice with ether the ether yielded about 60% of theory of a yellow oil b011- extracts being combined, dried and ether distilled 5 mg at 18804970 C at 1 mm. from a heating bath therefrom. The residue is purified by distillation O o at about one mm. pressure, yielding about 41% of f havmg NDZO of A Sample th of t amino ester having a boiling point lractionated therefrom at 203F204: C. at 1 mm. at; b t one mm of 172 .131 and hayin a from a bath at 235 0. had the slightly lower ND ND of 1.4690. 1 of 1.4803.

EXAMPLE 14 The di-(beta-morpholinoethyl) ester of 1-batyZpyrroZidine-2,5-dicarboa:ylic acid UHF-0E2 CH2-OH2 CHrCHz o NOHZCHZOOO-OE HCOOCHzCHzN C Hz-C z N C HzCz tmomomom EXAMPLE Substituting forty-five parts of beta-morpho- Di-(beta-diethylaminoethyl) ester of linoethanol for the gamma-diethylaminopropanol 1-ethyl-pyrrolidine-2,5-'dicarbozrylic acid of Exampl 12 yielded the dimorpholino-ethyl GET-CH2 ester as a light yellow oil.

(G2HE)2NCH2CE2O O C Cg /(IJHC O O CH2CH.2N(C2H5)2 EXAMPLE. 15

f The 0171- (beta-diethylaminoethyl) ester of 1- V benzyZpyrroZidine-Z,5-dicarboarylic acid Substituting 60 parts of l-ethyl-2,5-dicarbeth CH2 OH2 oxy-pyrrolidine for the 1-methyl2,5-dicarbeth- C H N H C oxypyrrolidine of Example 9, yielded the amino 2 O 2 HZOOQH CHCOOCHNHWCQHQ ester boiling at 168-170 0., having a No of 9 N 1.4675. A further fraction taken therefrom (tracer boiled at 1685 469 3, at about 1 mm. pressure Substituting seventy parts of heating bath The Pmducthad carbethoxypyrrolidine for the 1-methy1-2,5-di- ND of carbethoxypyrrolidine of Example 9 yielded a I ll pale yellow oil distilling at l96198 C. at 0.5 mm. Hydrochloride di-(beta-dzethylammoethyl) ester from a t t 5 0 C A portion redistmed mll fi' therefrom at 195 C. from a 220 C. bath had a Example 10 was repeated- After the reaction N192) of product was taken up in the combined ether ex- 40 EXAMPLE 16 tracts, the hydrochloride salt was precipitated by the addition of anhydrous hydrogen chloride in absolute ether, the precipitated salt was recovered. It proved to be so hygroscopic the melting CH2-CH2 point determinations proved substantially mean- (021192; HBCHZOOOJH HCOOOHZOHQMCQHQZ ingless as a means of identification. This was found to be a common characteristic of the hydro- I chlorides of the esters subsequently prepared. 00115 EXAMPLE One hundred parts of l-phenyl-zj-dicarbox- Di-(gamma-diethylaminopropyl) ester of fi yi g are fi g m s l-batylpyrrolidine-Z 5-dicarborylic acid Vesse h a P five updre for y par 5 0 CH beta-d ethylamrnoethanol 1n whlch 1%; parts of A) metallic sodium is dissolved. The reaction (C2H5)2NCHzOH2CH2OOU-'CH HCOOCH2CH2CH2N(C2H5)2 mixture is heated on a bath of W d metal t 165 C. until reaction is substantially complete, B CH CH CH the liberated ethanol distilling at 7880 C. The i v i 2 2 2 3 pressure is then reduced to about 14 mm. and the Repeating Example 9 Substituting eighty'five excess aminoalcohol removed. The product is parts of 1'butyl'z,5'dicarbethoxypyrrolidine for taken up from the residue by alternately washing the 1methyl-2,5dicarbethoxypyrrondine of with ether and water, the Water extracts being ample 9 and 610 parts of gamma'diethylamino further extracted with ether and the ether expropanol for the betadiethylaminopropanol' tracts being combined, dried and the ether regave a distillate boiling at 173-176 C. at about moved Purification by distillation t 05 mm 05 from a heating bath at The yielded a light yellowish oil, boiling at 189191 Nn was 1.4619. A fraction reclistilled therefrom on having a zrs f 15121 boiling at 186 C. at 1 mm. from a heating bath at The di-(beta-diethylaminoethyl) ester of 1-phenylpyrrolidine-2,5-dicarboxylic acid 210 C. had the same N13 EXAMPLE 17 XQMP The di-(beta-diethylaminoethyl) ester of E LE 13 I-(p-tolyl) -pyrrolidine-2,5-dicarboxylic acid Di-(gamma-diethylaminopropyl) ester of 1-cycloherylpyrrolidine-2,5-dicarboxylic acid GHQ-CH2 CH2-CH2 ozHmNcmomoooog /CHCO oomommozmh l (CzHs) ZNCHzCHzCEhOOCCH EJHCO OOHzCHzCHzN (C2115): 1?

\N/ 061140 Ha earn, Six hundred forty-seven parts'of freshly distilled beta-diethylaminoethanol in which 1% parts of sodium is dissolved are combined with one hundred twentyr-five parts of l-(p-tolyl)2,5- carbthoxypyrrolidine and the mixture treated as in the preceding example. The light yellowoil distilling at 0.5 to 1 mm. from 175-185 C. on redistillatiomboiled at 175-178 C. at 0.5 mm. had an Nn of 1.5144.

7 dry hydrochloride in dry ether is added. The

hydrochloride of the alkamine ester.,precipitates as a light tan amorphous solid. This solid has better physical properties than most of the hydrochloride salts prepared in accordance with the present invention but is so hygroscopic that purification by recrystallization is impractical as was found true of most of the amino esters. Accordingly, the solid hydrochloride is taken up in water and the free base liberated with aqueous potassium hydroxide, alkali being added to a weakly alkaline pH of approximately 8. The free base is taken up in ether,'washed, dried and recovered as in the preceding examples. Distillation yields a purified product boiling at 187-190 C. at 1 mm. having a N of 1.5023.

Using the procedure illustrated by the above examples, substantially any of the described alkamine esters can be produced. Other illustrative dialkamine esters as prepared include, for example, the di(beta-diethylaminoethyl) esters of l- (R) -2,5-dicarbethoxypyrrolidines shown in the following table,

The dialkamine esters have various physiological activity in and of themselves. Several of these 12 compounds have notable activity as local anaesthetics. Many of them have marked impressive effect on the blood pressure. A number of them are active as antispasmodics, some of the latter being selective to the longitudinal muscle in direct spasm and having a marked parasympathetic accompanying efiect. The particular benefits in use depending upon the particular R-substituent of the particular amino-alcohol chosen as noted above. However, their principal utility is as intermediates in the preparation of other compounds which themselves are not part of the present invention.

We claim:

1. Alkamine esters of an N-substituted pyrrolidine carboxylic acid of the type formula H2CCH2 AlkOOC- H E COOA1k in which R is a. radical selected from the group consisting of the alkyl radicals of 1-6 carbon atoms, cycloaliphatic .radicals of 6-8 carbon atoms, aryl radicals of 6-8 and 10 carbon atoms, and aralkyl radicals of 7-9 carbon atoms; and AIR is the alkamine radical of a tertiary amino monohydric alcohol.

2. An alkamine ester according to claim 1 in which Alk is the radical REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Dickey et a1 July 15, 1941 Hofmann Aug. 14, 1945 Hill et a1 Feb. 12, 1946 OTHER REFERENCES Beilstein, 4th edn., vol. 22, pp. 119, 120.

J. Am. Chem. Society, vol. 51, pp. 1536-1539.

Yale Journal of Biology and Medicine (Jan. 1946) vol. 18, pp. 161 and 171.

Hill: -Alkamine Esters of Certain 'Pyrrolidine Carboxylic Acids, a dissertation presented to the faculty of the Graduate School of Yale University in candidacy for the degree of Doctor of Philosophy (1944).

Number

Claims (1)

1. ALKAMINE ESTERS OF AN N-SUBSTITUTED PYRROLIDINE CARBOXYLIC OF THE TYPE FORMULA