CA1051456A - Process for preparing a glycine - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Optically pure D-(-)- and L-(+)-2-(substituted-phenyl)-glycine derivatives, intermediates in the preparation of penicillin and cephalosporin derivatives, are prepared by chemical resolution of an ester of the corresponding racemic 2-(substituted-phenyl)glycine derivative, employing L-(-)-or D-(+)-dibenzoyltartaric acid or derivatives thereof as resolving agent, and conversion to the free acid of the corresponding D-(-)- and L-(+)-2-(substituted-phenyl) glycine ester so obtained. The invention comprises deesterifying an optically active R 2-(R1O-X1-X2-phenyl)-glycinate or an acid-addition salt thereof.

Description

105i~

This application is a divisional of our copending Canadian Patent Application Serial No. 180,472 filed September 6, 1973.
This invention relates to processes for resolving esters of D,L~ -2-substituted-phenyl)glycine derivatives, to processes for preparing optically active 2-(substituted-phenyl)glycine deri-vatives, and to certain novel intermediates employed in said pro-cesses.
The optically active 2-phenylglycine derivatives and corresponding racemic 2-phenylglycine derivatives from which they are obtained by the processes of this invention are the 2-~R10-Xl-X2-phenyl)glycines represented by the structural formula Xl ~, ~ CH-COOH
/\tJ NH2 where Rl is hydrogen or lower-alkyl; and Xl and X2 each are hydrogen or halo.
D-(-)-2-phenylglycine derivatives and L-(+)-2-phenyl-glycine derivatives of formula I, the optically active enantiomers of the corresponding D,L~ -2-phenylglycine derivatives of Formula I, are useful as intermediates in the preparation of penicillin and cephalosporin derivatives which are of value as antibacterial agents (see, for example, United States Patents 3,140,282 and 3,489,751, and British Specification 1,241,844). However, since the synthetic methods for preparing phenylglycine derivatives of formula I yield these compounds only in racemic form, resolution :into the correspond-ing enantiomers is required.
Certain D,L-(+)-2-phenylglycine derivatives of formula I, have been resolved into the corresponding enantiomers either by biochemical or chemical methods. For example, in a biochem-ical method, the amino group of D,L-(+)-2-(4-methoxyphenyl)-glycine is protected by acylation ~Id the N-acyl derivative is 1(1~145~i then asymmetrically hydrolyzed by the action o an acylase (e.g.
hog kidney acylase), and the D~ N-acyl-2-(4-methoxyphenyl) glycine obtained is converted to the D-(-)-2-(4-hydroxyphenyl) gly~ine. This procedure is not entirely satisfactory, particularly for large scale commercial production, since the use of an expensive enzyme is required. In a chemical method, an ~-acyl or N,O-diacyl derivative of D,L-(+)-2-(4-hydroxy-phenyl)glycine is treated with the resolving agent dehydroa-bietylamine (or CO2 adduct thereof), and the (+) or (-)-dia-stereoisomeric salt respectively which preferentiallycrystallizes is converted to the corresponding optically active

2-(4-hydroxyphenyl)glycine. However, this method is also not entirely satisfactory for large scale commercial production due to low yieids and the use of the expensive dehydroabietylamine.
In accordance with this invention a more facile, less expensive method for commercial separation of the enanti-omers of D,L-(+)-2-(RlO-Xl-X2-phenyl)glycine, where Rl, Xl and X2 have the meaning hereinbefore defined, is provided, which method utilizes novel intermediates having the Formula IV
wherein a diastereoisomeric R 2-tRlo-xl-x2-phenyl)glycinate ~iacylbitartrate of the Formula IV (herein) where R is lower-alkyl or benzyl; Rl is hydrogen or lower-alkyl; Xl and X2 each are hydrogen or halo; and acyl is unsubstituted benzoyl or benzoyl substituted by lower-alkyl or halo. The overall process of this invention for the separation of D,L-(+)-2-(RlO-Xl-X2-phenyl)glyCine into its optically active enantiomers comprises the sequential steps as follows:
An appropriate racemic substituted phenylglycine of ~
the general ~ormula I is esterified by reaction with a suitable alcohol ROH, wherein R represents a lower-alkyl or benzoyl group, tO give the corresponding racemic R 2-(RlO-Xl-X2-phenyl)glycinate (II~.

The formed racemic phenylglycinate II is then reacted il~S~S~
., with nn opticnlly ~c~ivo di~cyltartatic acid (III), whoroin acyl i~ un~u~sti.llt~d b~nzo~l ~r b~nzoyl .qu~3titut~d by lower-~lkyl or h~lo~ to giv~ a mi.~t~ro o~ ~ho corro~.ponding two dia~t~reo-i~om~ric R 2~ 0-Xl-X2-ph~nyl)glycinate diacylbitartrate~ ( IY)o The two ~iastereoi~omeric bitartratos IV are o~
d~fr~ring ~olubilities, and arter eith~r one h~ been ~solat~d, as more fully describ~d hereinbolow, it is hydrolysed with a strong acid (~IZ) to give the corresponding optic~ly ~c~iv~ ~:
2~(Rl~-Xl-X2-phenyl)gl-Jcinate (II) as its acid~addition s&lto The optically active acid~addition salt o~ t.h~:
pherlylg~ycinate II is thereafter reacted with a base, t,C~
the corresponding optically active phenylglycinate.
The forrned optically acti~e phenylglycinate II or its ~oid-addition salt is then rurther reacted with a stron~ acid, tG deesteri~y it, to give the corresponding~optically active aoid-addition sal~ o~ the phenylglycin~ I.
Finally, the acid-addition salt Or the phenylglycine I i8 reacted with a base, to give the desired optically actiYe phenylglycine, Alternatively, the optically active benzyl phenyl-ælycinate (IIj R=benzyl) or its acid-addition salt ~ay be dees;eri~i~d by hydrogenolysis to give the corresponding optically active glycine I or its acid-addition salt, ~n accordance with the present invention there is p.royi~ed a ~rocess fox prepari.ng an optically active 2-(4-hydroxyphen~l)gls~cine of the Formula I or an acid-~.ddi-~ioll x31t . thereof, whi.ch compxi.ses deester.ifying an optically active R ~~
~4-hydroxyphenyl)glycinate of the Formula II where R is lower-alkyl or benzyl, or an acid-addition salt thereof.
The foregoing described overall process is . .i.llust.rated by the following react.;on scheme:

.

~(~5i~5~

Xl Xl ~ \ ~ H-COOH ~ ~ CH-COOR

Rl~ ~ NH2 2 2 II (racemic~
I ~OOH
~HO-acyl lHO-acyl Xl ` ~ 10~H

CH-COOR
~ 1H3 R10 x2 COO
fHO-acyl ; CHO-acyl II HZ salt ~ 1OOH
(optically active) IV

I \ HZ (or hydrogenolysis where base ~ R is benzyl) II (optically active) HZ ~ I HZ salt (optically active) ¦ ~ base Ihydrogenolysis (R=benzyl) I (optically active) >
In the foregoing reaction scheme the variables R, F.l, and Xl and X2 have the meaning hereinbefore described and acyl has the meaning described hereinbelow.
In the compounds of Formulas I, II and IV, R is prefer-ably lower-alkyl, particularly methyl or ethyl; Xl and X~
are pr~ferably hydrogen but when one or both are halo it is preferably chloro, particularly at the 3 and/or 5 position; Rl preferably iS hydrogen but when it is lower-alkyl it is prefer-Sf~
ably methyl; and RlO preferably occurs at the 4 posltlon. In - the compounds of Formula III and IV, acyl is unsubstituted benzoyl or benzoyl substituted with lo~er~alkyl or halo, for example 4-toluoyl, 4-chlorobenzoyl, 2,4-dlchlorobenzoyl and the like. Preferred are the compounds o~ Formulas Ill and IV
wherein acyl is unsubstituted benzoyl~
In another process aspect of thls lnvention there is provided a process for the preparation of a d1astereoisomeric phenyl~lycinate bitartrate of general Formula IV, in which an appropriate racemic phenylglycinate of the general Formula II, wherein Xl, X2, R and Rl have the meaning hereinbefore defined, is reacted with appropriate optically-active diacyltartaric acid of the general Formula III, wherein acyl is as defined hereinbefore, to give the desired diastereoisomeric bitartrate IV, In the processes of thls invention the use of L-l-)-diacyltartaric acids as resolving agents is preferred because of their ready availability from the naturally occuring L-l~i-tartaric acid and hence relati~ely low cost. The compounds of Formula III are known or are readily prepared by known procedures from the corresponding L-(~)- or D-(-)-tartarlc acid by reaction with an appropriate acyl halide lc.L~ ButleL
et. al. J. Am, Chem. Soc, 55~2605 ~1933~]~
The racemic phenylglycines (I~ used in the processes of this invention may be prepared by several methods, e.g., the well known Strecker amino acid synthes~s. Thus, for example, an appropriate R10-Xl-X2-benzaldehyde is reacted with ammonia and hydrogen cyanide followed by hydrolysis of the resultlng 2-(RlO-Xl-X2-phenyl~-2-aminoacetonltrile to give the correspond-ins racemic phenylglycines of E`ormula 1.
The following discussions relates to the variousreaction conditions employed in the processes of this lnvention:

The D~L-(+)-R 2-phenylglycinate of Formula II can ~,si~

be prepared from the appropriate alcohol (ROH) using well known prccedure3, e.g., by re~luxing an acidic solution Or D,L-(+)-2-phenylglycine in the alcohol ROH, or e.g., by treating the D,L-(+)-2-phenylglycine with the alcohol ROH in the presence of an equivalent of cyclohexylcarbodiimide, or instead of from the appropriate phenylglycine itself, ~rom a functional derivativs of the phenylglycine, a.g., the acid halide or nitrile.
Since the prime purpose ~or the preparation of the bitartrates IV is so that they may physically be separated as a stage in the resolution of racemic phenylglycinates Or general formula II, it is clearly desirable that the reaction be perrormed under such conditions which will allow such a separation to be e~rected. In this respect two conditions are of considerable relevance, na~ely the amount Or diacyltar-taric acid III employed, a~d the medium in which the reaction is effected.
So far as the reaction medium is concerned, it i9 highly desirable to perform the reaction in a solvent medium in which all the materials are relatively soluble, and then to convert the medium into one in which one of the two possible dia~tereiosomers is preferentially insoluble. m us, for the - "soluble" medium it is con~enient to employ an alkanol, prerer-ably a lower-alkanol having from 1 to 3 carbon atoms, ror example methanol or ethanol, a ketone, preferably acetone, an alkoxy-alkanol, preferably 2-methoxy-ethanol or 2-ethoxy-ethanol, or an org~ni~ carboxylic acid, pre~erably acetic acid.
For the "insoluble" medium it is convenient t;o employ a mixture o~ the "~oluble" medium and another solvent in which the one diastereoisomer i~ insoluble9 for example water or hsxane, and it 19 con~enient to convert the "soluble" medium into the "insoluble" medium simpl~ by mi~ing the r~action ~olution ~in the l~301uble'~ medillm) with the ~econd solvent, For instancs, i~ the reaction i9 per~ormed in ethanol as the'~oluble~ med~m, 145~
the one diastereoi~omer may be precipitated by adding to thereaction solution an appropriate amount o~ water. The actual ama,unts of the "insoluble" sol~ent employed can a~ect the purity and yield o~ the precipitated diastereoisomer. In general, the smaller the amount o~ the "insoluble" solvent the purer the product but the lower the yield, and vice v~;~a, For example, when ethanol and water are employed a~ "soluble" and "insoluble" medium respectively, a prererred ratio Or water to ethanol is about 1.32:1.
While qeeding with trace amount~ o~ the dia~tereo-isomer being precipitated i9 not necessary to initiate precipi-tation, nevertheless it is preferred ~ince it results in a purer product, The ratio o~ diacyltartaric acid III to glycinate II
i~ critical, i.a., must be greater than 1/2 (0.5) and less than 1. A prererred ratio is ~rom about 0.7 to about o.8.
Ir 1 mole or m~re o~ diacyltartaric acid is used per ~ole Or glycinate, then in general both diastereoisomers will precipitate out. Conver~ely, if 0.5 mole or le~s of diacyl-tartaric acid is used per mole Or glycinate, then little, irany, Or either dia~tereoisomer will precipitate out.
While we do not wi~h to be bound by any theoretical considerations as to what occurs in the reaction mixture, ne~erthele~s the ~ollowing is an explanation of what i~ believed to be happening~
In the reaction mixture each optically-acti~e glyciDate isomer may exi~t combined with the diacy.tartaric acid as the diacylbitartrate or the diacyltartrate, there being an equilibrium ~et up between each diacylbitartrate and diac~ltartrate. The two diacyltartrate~ are considerably ~ore ~oluble than the two d~acylbitartrates, while one diacylbit~rt-rate i3 marginally more soluble than the other~
If, there~ore, 1 mole or more Or diacyltart~ric acid - ~051~S6 is employed per mole o~ glycinate the conditions are right ror both diacylbitartrates to bs formed and ror both o~ these diacylbitartrates to precipitate out.- I~, on the other hand~
0.5 mole or less Or diacyltartaric acid is used per mole of glycinate the conditions are right for both diacyltartrates to be ror~ed and ~or these diasyltartrates (being soluble) to remain in solution and not precipitate out.
Where there is used an amount of diacyltartaric ~cid which is between 1 mole and 0.5 mole per mole glycinate, the con-ditions are partially right for diacylbitartrate fo~m;tion but,because there is too little d$acyltartatic acid to rorm both diacylbitartrates, one diacylbitartrate is formed prererentially, and precipitates out. Naturally, as the rormed diacylbitartrate is removed from solution by precipitation the available diacyl-tartaric acid in the solution i9 also removed, and 90 the amount le~t does not rorm the other diacylbitartrate but rather the other diacyltartrate (which is soluble).
Just which diastereoisomer IV precipitates out depends in general upon the actuaI materials employed. By way Or example~ i~ the reaction is per~ormed to resolve D,L~
ethyl 2-(4-hydroxyphenyl)glycinate, U9 ing L~ dibenzoyltar-taric acid, then the L-(+)-glycinate-L-~-)-dibenzoylbitartrate precipitates out, leav~ng the D-(-)-glycinate in solution.
Conversely~ u9ing D-(+)-dibenzoyltartaric acid the D-(-)-~lycinate-D-(~) dibenzoylbitartrate precipitates out, leaving the L-~+~ glycinate in ~olution.
From the foregoing9 it will be clear that the optical-ly acti~e glycinate isomer that does not precipitate out is le~t in the solutionO Naturally this isomer can be recovered, i~ required, by any convenient method - and one particularly ~on~snient method i9 to add more Or the diacyltartaric acià III
originally used, t~us conYerting the remaining glycinate into lts insoluble bitartrate (the otherdia~tereoisomer IV). It ..a-l~S145~;
i9 generally most convenient to add as muc}l diacyltartaric acid as would make the total diacyltartar~c acid add up to 1 mole (or slightly more) per ~ole o~ total glycinate~ though a little more or les~ is adequate. Seeding with trace amounts Or the appropriate diastereoisomeric salt is not necessary but is prefer-red,, In each case, the precipitated diastereoisomer IV
may be separated mechanically from the reaction medium in any convenient manner - for example, by riltration or decanting.
1~ In the pro~ess in which the acid-addition salt of the optically active phenylglycinate II is prepared by hydrolysis o~ the bitartrate diastereoisomer IV with strong acid, only a slight e~csss o~ strong acid (eOg. lol equivalents) is required although a larger excess may be usedO Such strong acid may be any suitable acid, well known in the art9 capable Or hydrolyz-in~ the glycinate to the gly¢ineO Such acids, designated HZ
throughout the specification, ars illustrated by, but not limited to, mineral acidæ ~uch as hydrochloric acid, hydro bromic acid and sulfuric acid, and organic acids such as sulramic acid, methanesulfonic acid, p-~oluenesul~onic acid, and the like~ The optically acti~e diacyltartaric acid generally precipitates during the .bydrolysi~ in crystalline form and said crystals are readily separated by filtration but other known method~q of separation can be employedO
A ~ormed optically active phenylglycinate acid-addition salt may thereafter be converted into the correspond-ing optically active phenylglycinate of general formula II by reaction with a base ( an acid-acceptor).
Suitable bases are ammonium and alkali-metal hydro-xides (ror exampl0, sodium and potassium hydroxide) and alkali-metal carbonates and bicarbonates (~or example, sodium and pota~3i-~ carbonate, and ~odium and potassium bicarbonate), While less than an equivalent o~ the ba~e may be employed, .

better yields are obtained by employin~ at least one equiYalent Or the base. ~rolongsd contact with base should be a~oided to prevcnt racemization o~ the optically active phenylglycinate II.
The acid hydrolysis of the optically active glycinate or its acid-addition salt to the optically active phenylglycine I (acid-addition salt) inYolves a standard prccedureO The len~th of time required to heat the strong acid solution Qf the glycinate will vary, depending on the amount of strong acid employed. Preferably the acid employed is the same acid (XZ) as used to hydrolyze the bitartrate diastereoisomer IV as described hereinbe~oreO The temperature at which the hydrolysis is carried out may vary between room temperature and the boil-ing point o~ the solution. If at leaqt two equivalents Or strong acid is employed and the solution is heated at reflux, a reaction time of about one hour is satisfactory to effect complete c)nversion to the optically active phenylglycine acid-addition salt.
The optically active acid-addition salt o~ the phenylglycine I may also be formed directly from the bitartrate diastereoisomers IV, without isolation of any intermediate glycinate acid-addition salts, simply by efrecting strong acid hydrolysis thereo~ under more vigorous conditions thus, with heating, and with at least a 2 molar excess o~ the acid.
In ths proceqs where~n the optically active phenyl-glycine acid-addition salt is converted to the corresponding optically active phenylglycine of ~ormula I, any water soluble base (acid~acceptor) having sufficient basicity to decompose the glycin~ acid-addition salt is suitableO Such acid-acceptor~
are, ~or example, ammonium hydroxide9 alkhli metal hydroxides, e.g., sodium and potassium hydroxide, alkali metal carbonate~
and bicarbonatesJ e~g.9 ~odium potassium carbonate and sodium potassium bicarbonateD and the likeO While less than an ~quivalent of acid-acceptor to the glycine acid-addition salt ~-10-may be employed, optimum yields are obtained by employing at least one equivalent Or acid-acceptorO
The alternative deesteri~ication of the opticàlly active benzyl phenylglycinate (II, R=benzyl) or its acid-addition salt by hydrogenolysis involves standard procedures. The hydro-genolysis i9 carried out preferably at room te~perature and in a suitable qolventD e,g~, ethanol, in the presence Or a suitable catalyst, e.gO, Raney nickel or palladium on charcoal, preferably at about atmospheric pressureO
In the processes Or this invention, pure resolving agent can be readily recovered in good yield. Further~ore, i~
either one Or the two enaniiomers o~ D,L~ 2-(R10-Xl-X2-phenyl) glycine i9 desired, the undesired enantiomer in the ester form, obtained by the processes o~ this invention, can be readily racemized, either by heating above its melting point, or by stirring a basic ~olution thereof in water for several minutes.
Thus by recyclization o~ the DDL-(~)-ester Or the 2-phenylglycine so obtained and the recovered re~olving agent in the processes Or this invention9 it is possible to economically obtain the desired optically active 2-phenylglycine in high yield.
me dia~tereoi omer bitartrates o~ formula IV which are useful as intermediates in the proces~es o~ this invention designated as L-(+)-R 2-(R10-Xl-X2-phenyl)glycinate D~
diacylbitartrat0, D-(-)R 2-(R10-Xl-X2-phenyl)glycinate D-(+)-diacylbitartrateD L-(+)-R 2-(R10-Xl-X2-phenyl)glycinate L-(-)-diacylbitartrate, and D-(-)-R 2-(R10-Xl-X2-phenyl)glycinate L (-)-diacylbitartrate~ where R is lower-alkyl or benzyl, R
i~ hydrog0n or lower-alkyl, Xl and X2 each are hydrogen or halo, and acyl is unsubstituted benzoyl or benzoyl substituted by lower~alkyl or halo are novelD When one or both Or Xl and X2 ars halo, pre~erably they are chloro, particularly at the

3 and/or 5 position~ Pre~erred compounds are tho~e where R
i9 methyl or ethyl, Rl is hydrogen or ~ethyl, particularly 1~5 1~5 ~
hydrogen, Xl and X? each are hydrogen, and acyl is unsubstituted benæoyl; a~d particularly such prererred compounds where RlO
occur~ at the 4 position.
Certain Or the racemic R phenylglycinates ussd in the proce~ses Or thi~ invention are novel compounds. These have the 9 tructural ~ormula Xl H0 ~ CH-COOR

IIA
and their acid-adcition salts, wherein R is lower-alkyl or benzyl, and Xl and X2 each are hydrogen or halo. ~hen ons or both Xl and X2 are halo, prererably they are chloro, particular-ly at the 3 and/or 5 position. Particularly prererred compounds Or rormula IIA are those whersin R i9 lower-alkyl, particularly methyl or ethyl and Xl and X2 are hydrogen.
Also novel are optically active compounds cr rOrmula II designated as D-(-)-R 2-(RlO-Xl~X2-phenyl)glycinate and L-~ R 2-~RlO-Xl-X2-phenyl)glycinate~ and their acid-addition salt~, where R is lower-alkyl or benzyl, Rl i~ hydrogen or lower-alkyl and Xl and X2 each are hydrogen or halo. When one or both o~ Xl and X2 fire halo, prererably they are chloro, particularly at the 3 and/or 5 poqition. Preferred optically activa co~pounds of rormula II are tho~e where R i~ lower-alkyl, particularly methyl or ethyl~ Xl and X2 ars hydrogen, and Rl i~ hydrogen or msthyl, particularly hydrogen; and particularly ~uch pre~errsd compounds where R10 occurs at the

4 pos~tion. Ths optlcally act~e compounds Or ror~ula II are use~ul a~ intermediates in the proces~es o~ thi~ in~ention.
By way o~ illu3tration only, the total process o~

thl9 in~ention i~ now described in the ~orm o~ a pre~erred ~ _12~

resolution o~ racemic [i.e. D,L-~+)~ 2-(4-hydroxyphenyl) glycine~ via ~he corresponding ethyl glycinate, the dibenzoyl-bit;artrate, and the hydrochloride salts Or the optically acti~e glycinate and glycine.
D,L-(+)-2-(4-hydroxyphenyl)glycine is esteri~ied to gi~e D,L-(+)-ethyl 2-(4-hydroxyphenyl)glycinate which i9 react-ed with either L_(-)-dibenzoyltartaric acid or the D-t+)-analogue, in ethanol, and the ~olution so obtained is diluted with water to precipitate either L_(+)-ethyl 2-(4-hydroxy-phenyl)glycinate L-(-)-dibenzoylbitartrate or its D-(- " D-(+)-analogue (as appro?riate).
After separating off the L-(+)-ethyl 2-(4-hydroxy-phenyl)glycinate L-(-)-dibenzoylbitartrate or its D-(-)~ D-(+)-analogue, to the remaining aqueous solution there is added excess L-(-)-dibenzoyltartaric acid or its D-(~)- analogue (as appropriate) to precipitate D-(-)-ethyl 2-(4-hydroxyphenyl) glycinate L-(-)-dibenzoylbitartrate or it~ L-(+), D~
analogue (as appropriate )9 which is separated orf.
The D-(-)-ethyl 2-(4-hydroxyphenyl)glycinate L-(-)-dibenzoylbitartrate (or its L-(+), D-(+)- analogue, as appropriate) and the L-(+), L-(-)- analogue (or its D-(-), -~ D-(+)-analogue, a~ appropriate) are separately hydrolyzed with / aqueous hydrochloric acid, containing an excess Or one equiva-lent of the acid, to precipitate L-(-)-dibenzoyltartaric acid or its D-(+)-analogue (as appropriate), and after the precipita-ted dibenzoyltartaric acid has been separated Or~, the solution is heated and evaporated to yield D-(-) 2-(4-hydroxyphenyl) glycine hydrochloride or its L~(+)-analogue (as appropriate).
The formed D-(-)-2-(4-hydroxyphenyl)glycine hydro-3 chloride or its L-(+)-analoguc (as appropriate) i~ then dissolved in water, concentrated an~loniu~ hydroxide is added to precipitate D-(-)-2-(4-hydroxyphenyl)glycine or its L-(+)-analogue (as appropriate)~ and the formed D-(-)-2~4-hydroxy-~13-1~5 1'~5 ~

phenyl)glycine or L-(+)-analogue is separated Orr.
Throughout this specification the term lower alkyl means such grou~s containing ~rom one to six carbon atoms which can be arran~ed as straight or branched chains as illustrated by, but not limited to, methyl, ethyl, propyl~ isopropyl, butyl, tert-butyl, pentyl, hexyl and the like; the term lower-alkanol means such alkanols containing from one to three carbon atoms as illustrated by methanol, ethanol, propanol and isopropanol;
and the term halo means chloro9 bromo, fluoro and iodo. It will be understood that when Xl and X each are halo they can be the same or di~erent and that R10, Xl and X2 can occur in any o~ the position combinations relatîve to each other.
The molecular structure and optical purity of the enantiomer~ Or D,L-(~)-2-phenylglycine and of the novel ¢ompounds Or this invention obtained by the processes o~ this invention are determined on the basis of the method o~ their gynthesis, a study o~ their optical rotations, and in some cases, by a study o~ their nuclear magnetic resonance (NMR3 spectra, and confirmed by the correspondence between calcu-lated and found values for the elementary analyses.
The processes of this invention are illustrated by the ~ollowing examples:
EXAMPLE I
A. D,L-(+)-Et~vl 2~ h~dro~vphenvl)~lvcinate A total o~ about 80 g. o~ anhydrous hydrogen chloride `
was passed rapidly ~to a suspension Or 250 g. (1.59 mole) o~
D,L-(+) 2-(4-hydroxyph0nyl)glycine in 2.5 1. of absolute ethanol without coolingO All o~ the amino acid went into solution during the addition. Th~ solution was refluxed ~or 16 hours and concantrated to dryness. The solid residue wa~
dried at 60C. in vaeuo ~or 3 hours. The crude hydrochloride salt weighed 349 g. (100%). This material waq di3solved in 102 1, of cold water and concentrated a~moniu~ hydroxide was 16~5~5~ i added until a pH o~ 8.o was obtain~dO Crystallization was immediat~ and after cooling to 5C. th~ product was ~iltered, pres~ed well on the ~unnel and washed two times with 50 ml. Or ice water- A~ter drying at 60Co n vacuo for 16 hours, tho crude ba~e weighed 27505 g. (94~5%), m.p, 155-158C. The base was dissolved in 106 lo of boiling ab~olute sthanol and char- j coaled (using a steam-~acketed runnel). A~ter cooling at -10C.
for 2 1/2 hours, the product was riltered and washed two times with 30 ml. o~ cold absolute ethanol. After drying in vacuo ~or 16 hours at 60Co~ there was obtained 261.5 g. (89.5~) of D~L-(~) ethyl 2-(4-hydro~yphenyl)glycinate, mOp. 160-161C.
B. Resolution of D L-(~)-Ethvl 2 (~-hvdroxvP~enYl)~l~cinate A mixture of 100 gO (005125 mole) of D,L-(-)-ethyl 2-(4 h~droxyphenyl)glycinate and 141.6 g. (o.3755 mole) o~ L-(-)-d~benzoyltartaric acid monohydrate in 650 ml. of absolute ethanol wa3 stirred at room temperature until qolution was complete (about 1/2 hour). The solution was ~iltered and the ~lask and filter were rinsed with 80 mlO Or absolute ethanol.
To the clear filtrate wa3 added 960 mlO Or water and the solution was seeded with trace amount of L-(~)-ethyl 2-(4-hydroxyphenyl)glycinate L-(~)-dibenzoylbitartrate and stirred until crystallization had well progressed. Arter standing 1 ; hour at room tsmperature, the mixture was cooled overnight at 4c. The precipitated L~ ethyl 2-(4-hydroxyphenyl)glycinate L~ dibenzoylbitartrate waq filteredO The ~ilter cake was proqse~d well and then waqhed two t~meq with 50 ml. o~ cold 25%
ethanol (1:3 ethanol-water)O Tho L-(+)-ethy:l 2-(4-hydroxy-phenyl)glycinate L-(-)-dibenzoyltartrate~ a~ter drying at 60C.
~ we~ghed 122 g~ t86%)~ mopO 171-174Co (dec.), ra~25 -36 (C-1%, MeOH)~ (This salt can be obtained pure by disqolving it i~ 14 volumes o~ re~luxing 25~ ethanol and allowing the mixture to stand at room temperature for 24 hours. The recovery is 85%9 m.p~ 180-181Co (dec.), ~D5 -3Z.2 (C=1~D MeOH).
-15-~

The riltrate from above (including the 2 x 50 ml.
washes) wa~ treated i.~ediately with a solution of 51.8 g.
(0.1375 mole) Or L-(-)-dibenzoyltartaric acid monohydrate in 125 ml. Or ab~olute ethanol with good stirring and ~eeded with a trace amount o~ D~ ethyl 2-(4-hydroxyphenyl)glycinate L-(-)-dibenzoylbitartrate. Crystallization was heavy after about 15 minutes. The mixture was allowed to stand 1 hour at room temperature and then it was cooled at 0C~ ~or 2 hours. The resulting precipitate wa~ riltered, the rilter cake was pressed well, then washed three times with 50 ml. Or cold 25% ethanol, and dried at 60Co in vacuo ror 48 hours to give lZ4 g. (87.5%) o~ D-(-) ethyl 2-(4-hydroxyphenyl)glycinate L-( ) dibenzoyl-bitartrate, m.p~ 160~161Cog [~D5 - 12503 (C=1%, MeOH). Thi~
product (40 gm) was disqolved in 480 mlO Or 35% ethanol and allowed to crystallize by standing at room temperature ror 24 hours. The crystals were riltered, pressed well and washed two timeq with 20 mlO Or 25% ethanolO Arter drying at 60Co ~n vacuo for 20 hoursr the optically pure D~ ethyl 2-(4-hydroxyphenyl)glycinate L~ -dibenzoyltartrate weighed 34.5 gm (86.4% recovery), m.pO 161-163C~ (decO )~ ~a~ D5 -131~6 (C=1%, MeO~), C. D-~ 2-(~-h~drox~phenyl)~lycine h~drochloride A mi~ture o~ 25 gO Or (OoO452 mole) o~ D-(-)-ethyl 2-~4-hydroxypheny})glycinata L-(-)-dibenzoylbitartrate,~D5 ~
-131.6 (C=l~ MeOH), in 190 ml. Or 2N hydrochloric acid was stirred at room temperature and ~qeeded with a rew crystals of L~ dibenzoyltartaric scid monohydrate. Crystallization was rap~d and after stirring 1~2 hour at room temperature, the precipitated L-(-) dibenzoyltartaric acid monohydrate was r~ ltered~ pre~ssd wsll and washed tbree times with 15 ml. o~
2N hydrochloric acid~
The combined ~iltrates were re~luxed ~or 1 ho~ and then csncentrated in vacuo at 40Co The white cry~talline ol6 re~idue was dried at 60C. in v~ Q to yield 9.7 gO o~ product~
Thi~ was slurried in 40 ml. o~ glacial acetic acid ~or 20 minutes at roo~ temperature. The product was riltered, wa~hed once w~th 5 ml. Or acetic scid and then with a rew ml. o~ ether.
After drying overnight at 60C- in ~acl~n~ the white crystal~ of D~ 2-(4-hydroxyphenyl~glycine hydrochloride weighed 8.7 g.
(97~), m.p. 207-208C. (dec.), [~ 25 -110 (C=1%J H20). ~ D5 154 ~1% (calculated as ba~e) in lN hydrochloric acid~, The precipitated L~ dibenzoyltartaric acid monohydrate a~ter drying at room temperature ror 2 days weighed 16.5 g. (97.5% o~
theory). It wa~ recrystallized by di~solving it in 2.85 volumes o~ hot chlorororm and allowing this solution to cool to room temperature, After addition o~ 1.35 volume~ o~ benzene, the mixture was cooled at 4c . overnight. The recovery was 89%, m.p. 89-93C., ~ 25 -108 (C=5%, EtOH).
D. D-(-) 2-(~-Hvdrox~phen~l~ lycine To a solution o~ 4.07 g. (0002 mole) o~ D-(-)-2 (4 hydroxyphenyl)glycine hydrochloride (C~ 25 -110 (C=1%,H20) in 12 ml. Or water was added slowly with slight cooling 1.2 ml. o~
concentrated ammonium hydro~ide. To the resulting gelatinous precipitate was added an additional 10 ml. Or water and the mi~ture was warmed to about 45c. The ~olution was cooled and the precipitate was filtered, washed with 5 ml. of ice water, and dried at 80C. in va~uo to yield 2.55 g. (76.5%) o~ D-(-)-2-(4-hydroxyphenyl)glycine as white crystals, m.p. 224C. (dec.) 25 -156.8 tC=1%, lN HC1)~
By ~ollowing the pro~edure described in ~ample lC
but substituting L-(+)-ethyl 2-(4hydroxyphenyl)glycinate L-(-)-dibenzoylbitartrate ~or the D~ ethyl 2-(4-hydroxyphenyl) glycinate L~ dibenzoylbitartrate there is obtained L-(~)-2-(4-hydroxyphenyl)glycine hydrochloride which, when substituted ~or D(-)-2~(4~hydroxyphenyl)glyGine hydrochlorLde in E~ample lD
yields L-t~)-2-(4-hydroxyphenyl)glycLne.

45~i When the procedure d~scribed in Example lB was repeated, but using 0.5 mole of L~ dibsnzoyltartaric acid and 1.0 mole Or D,L-(+)-ethyl 2-(4-hydroxyphenyl)glycinate,lno cryst~lline material precipitated, even with ~eeding.
When the procedure described in Example lB was repeated, but using 48.1 g. (0.128 mole) of L-(-)-dibenzoyltartaric acid and 25.o g. (0.128 mole) of D,L-(-)-sthyl 2-(4-hydroxypheny~)-glycinate, there was obtained a quantitative yield (73.0 g.) of crystalline D,L-(-)-ethyl 2-(4-hydroxyphenyl)glycinate L-(-)-dibenzoyltartrate, m.p. 162-163C., C~ D5 ~77-~ (C=1%, MeOH).

Following the procedure described in Example lB but using D-(+)-dibenzoyltartaric acid there was obtained D-(-)-ethyl 2-(4-hydro~yphenyl)glycinate D-(+)-dibenzoyltartrate (88% yield), m.p. 180-180.5C. (dec.) (25% ethanol), CQ~ 25 ~29.4 (C~1%, MeO~).
By substituting D-(-)-ethyl 2-(4-hydroxyphenyl)-glycinate D-(+)-dibenzoyltartrate for the D-(-)-ethyl 2-(4-hydroxyphenyl)glycinate L-(-)-dibenzoyltartrate in Example lC
there i9 obtained D-(-)-2-(4-hydro~yphenyl)-glycine hydrochloride which is converted to D-(-)-(4-hydroxyphenyl)glycine ~ollowing the procedure described in Example lD.
Following the procedure described in E~ample lB there i3 obtained from the filtrate from which the D-(-)-ethyl 2-(4-hydroxyphanyl)glycinate D-(~)-dibenzoylbitartrate was separated L-(+)-othyl 2-(4-hydroxyphenyl)glycinate D-(+)-dibenzoylbltartrate which, when substituted for D-(-)-ethyl 2-(4-hydroxyphenyl) glyci~ate L-(-)dibenzoylbitartrate in Ex~mple lC yields L-(+)-2-; ¦4-hydroxyphenyl)glyci~e hydrochloride which is converted, as de~Gribed hereinabove, to L-(+)-2-(4-hydroxyphenyl)-glycine.
; Race~zation of D-(-)-Ethyl 2-(4-h~drox~Phen~
,,",, ~
D~ ethyl 2-(4-hydroxyphenyl)glycinate L-(-)-~OS14St;

dibenzoylbitartrRte (18.5 g.) in 60 ml. o~ water was treated with

5.2 ml. Or ammonium hydroxide in 10 ml. of water (precipitation Or ~ree glycinate was immediate) and stirred rive minutes. The resulting precipitate was filtered, wa~hed with a small amount o~
water, and dried at 60C. i~ to give 5.0 g. (80%) of D~
ethyl 2-(4-hydroxyphenyl)glycinate, mOp, 129-130C. C~ 5 -109.2 (C=1%, HCl). This D-(-)-ethyl 2-(4-hydroxyphenyl)-glycinate was heated at about 146Co~ cooled, and cry~tallized ~rom absolute ethanol to give D~L-(~)-ethyl 2-(4-hydroxyphenyl)-glycinate, m.p.
10157-159C.
Alternatively, to a solution o~ D-(-)-ethyl ~-(4-hydroxyphenyl)glycinate L-(-)-dibenzoylbitartrate in water containing ether (to prevent precipitation o~ the ~ree glycinqte when ~ormed) waq added ~odium bicarbonate solution until the solution was basic. A~ter one hour the ether was evaporated in ~ç~aQ, and the D,L-ethyl 2-(4-hydroxyphenyl)glycinate (m.p. '.60-161~) pre¢ipitated immediatelyO

. . . . .

Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing an optically active 2-(4-hydroxyphenyl)glycine of the formula ...I
or an acid-addition salt thereof, which comprises deesterifying an optically active R 2-(4-hydroxyphenyl)glycinate of the Formula II

... II
where R is lower-alkyl or benzyl, or an acid-addition salt thereof.

2. A process according to claim 1, which includes treat-ing an acid-addition salt of the compound obtained with a base in order to obtain the free base of the 2-(4-hydroxyphenyl)-glycine.

3. A process according to claim 2, in which the base is ammonium, sodium or potassium hydroxide, sodium or potassium carbonate, or sodium or potassium bicarbonate.

4. A process according to claim 1, in which the deester-ification is effected by hydrolysis of the optically active glycinate or its acid-addition salt with a strong acid.

5. A process according to claim 4, where the strong acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, methanesulfonic acid or p-toluenesulfonic acid.

6. A process according to claim 1, in which the deester-ification is effected by hydrogenolysis of the optically active glycinate, where R is benzyl, or its acid-addition salt.

7. A process according to claim 6, wherein the hydro-genolysis is effected in the presence of a Raney nickel or palladium on charcoal catalyst.